Modern Heterocyclic Chemistry

Edited by Julio Alvarez-Builla, Juan Jose Vaquero, and Jose´ Barluenga Modern Heterocyclic Chemistry

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Edited by Julio Alvarez-Builla, Juan Jose Vaquero, and José Barluenga

Modern Heterocyclic Chemistry Volume 4

The Editors Prof. Dr. Julio Alvarez-Builla Universidad de Alcalá Facultad de Farmacia Dpto. de Química Organíca Campus Universitario s.n. Alcalá de Henares 28871 Madrid Spain Dr. Juan Jose Vaquero Universidad de Alcalá Dpto. de Química Organíca Ctra. Madrid-Barcelona km 33 Alcalá de Henares 28871 Madrid Spain Prof. Dr. José Barluenga Universidad de Oviedo Instituto Universitario de Química Organometálica ‘‘Enrique Moles’’ 33071 Oviedo Spain

All books published by Wiley-VCH are carefully produced. Nevertheless, authors, editors, and publisher do not warrant the information contained in these books, including this book, to be free of errors. Readers are advised to keep in mind that statements, data, illustrations, procedural details or other items may inadvertently be inaccurate. Library of Congress Card No.: applied for British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library. Bibliographic information published by the Deutsche Nationalbibliothek The Deutsche Nationalbibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data are available on the Internet at http://dnb.d-nb.de. # 2011 Wiley-VCH Verlag & Co. KGaA, Boschstr. 12, 69469 Weinheim, Germany All rights reserved (including those of translation into other languages). No part of this book may be reproduced in any form – by photoprinting, microfilm, or any other means – nor transmitted or translated into a machine language without written permission from the publishers. Registered names, trademarks, etc. used in this book, even when not specifically marked as such, are not to be considered unprotected by law. Typesetting Thomson Digital, Noida, India Printing and Binding betz-druck GmbH, Darmstadt Cover Design Schulz Grafik-Design, Fußgönheim Printed in the Federal Republic of Germany Printed on acid-free paper Print ISBN: 978-3-527-33201-4 oBook ISBN: 978-3-527-63406-4

V

Contents List of Contributors

XV

Volume 1 1

1

Heterocyclic Compounds: An Introduction Julio Alvárez-Builla and José Barluenga

2

Three-Membered Heterocycles. Structure and Reactivity S. Shaun Murphree

3

Four-Membered Heterocycles: Structure and Reactivity 163 Gérard Rousseau and Sylvie Robin

4

Five-Membered Heterocycles: Pyrrole and Related Systems Jan Bergman and Tomasz Janosik

269

5

Five-Membered Heterocycles: Indole and Related Systems José Barluenga and Carlos Valdés

377

6

Five-Membered Heterocycles: Furan 533 Henry N.C. Wong, Xue-Long Hou, Kap-Sun Yeung, and Hui Huang

7

Five-Membered Heterocycles: Benzofuran and Related Systems Jie Wu

11

Volume 2 635

8

Five-Membered Heterocycles: 1,2-Azoles. Part 1. Pyrazoles José Elguero, Artur M.S. Silva, and Augusto C. Tomé

9

Five-Membered Heterocycles: 1,2-Azoles. Part 2. Isoxazoles and Isothiazoles 727 Artur M.S. Silva, Augusto C. Tomé, Teresa M.V.D. Pinho e Melo, and José Elguero

593

VI

Contents

10

Five-Membered Heterocycles: 1,3-Azoles 809 Julia Revuelta, Fabrizio Machetti, and Stefano Cicchi

11

Five-Membered Heterocycles with Two Heteroatoms: O and S Derivatives 925 David J. Wilkins

12

Five-Membered Heterocycles with Three Heteroatoms: Triazoles Larry Yet

13

Oxadiazoles 1047 Giovanni Romeo and Ugo Chiacchio

989

Volume 3 14

Thiadiazoles 1253 Ugo Chiacchio and Giovanni Romeo

15

Five-Membered Heterocycles with Four Heteroatoms: Tetrazoles Ulhas Bhatt

16

Six-Membered Heterocycles: Pyridines 1431 Concepción González-Bello and Luis Castedo

17

Six-Membered Heterocycles: Quinoline and Isoquinoline Ramón Alajarín and Carolina Burgos

18

Six-Membered Rings with One Oxygen: Pyrylium Ion, Related Systems and Benzo-Derivatives 1631 Javier Santamaría and Carlos Valdés

19

Six-Membered Heterocycles: 1,2-, 1,3-, and 1,4-Diazines and Related Systems 1683 María-Paz Cabal

20

Six-Membered Heterocycles: Triazines, Tetrazines and Other Polyaza Systems 1777 Cristina Gómez de la Oliva, Pilar Goya Laza, and Carmen Ochoa de Ocariz

1527

Volume 4 21

21.1

1401

Seven-Membered Heterocycles: Azepines, Benzo Derivatives and Related Systems 1865 Juan J. Vaquero, Ana M. Cuadro, and Bernardo Herradón Introduction 1865

Contents

21.2 21.3 21.4 21.5 21.5.1 21.5.1.1 21.5.1.2 21.5.2 21.5.2.1 21.5.2.2 21.5.3 21.5.3.1 21.5.3.2 21.5.4 21.5.5 21.5.5.1 21.5.5.2 21.5.5.3 21.6 21.6.1 21.6.1.1 21.6.1.2 21.6.1.3 21.6.1.4 21.6.1.5 21.6.1.6 21.6.1.7 21.6.1.8 21.6.2 21.6.2.1 21.6.2.2 21.6.2.3 21.7 21.7.1 21.7.1.1 21.7.1.2 21.7.1.3 21.7.1.4 21.7.1.5 21.7.2 21.7.2.1 21.7.2.2 21.8 21.8.1

Relevant Natural and Useful Compounds 1867 Relevant Computational Chemistry, Physicochemical, and Spectroscopic Data 1869 Valence Tautomerism in Seven-Membered Heterocycles 1874 Synthesis 1878 Synthesis of Azepines 1878 From Acyclic Compounds 1878 From Cyclic Compounds 1883 Synthesis of Oxepines 1885 From Acyclic Compounds 1885 From Cyclic Compounds 1890 Synthesis of Thiepines 1896 From Acyclic Compounds 1896 From Cyclic Compounds 1897 Synthesis of Azepanes, Oxepanes, and Thiepanes 1898 Synthesis of Benzo Derivatives 1902 Synthesis of Benzazepines 1902 Synthesis of Benzoxepines 1906 Synthesis of Benzothiepines 1907 Reactivity of Azepines 1911 Reactivity of Azepines and Benzofused Derivatives 1911 Cycloaddition Reactions 1911 Reaction with Metal Carbonyl Complexes 1914 Reactions through Metal Carbonyl Complexes 1916 Pericyclic Reactions 1917 Reactions with Electrophiles 1923 Reactions with Nucleophiles 1927 Reactions with Oxidants 1929 Hydrogenation and Hydrogen Transfer 1932 Reactivity of Partially Reduced Azepine Derivatives 1934 Dihydroazepines 1934 Tetrahydroazepines 1937 Dihydroazepinones 1938 Reactivity of Oxepines 1943 Reactivity of Oxepines and Benzofused Derivatives 1944 Thermal and Photochemical Reactions 1944 Cycloaddition Reactions 1945 Reactions with Electrophiles 1948 Reactions with Nucleophiles 1949 Reactions with Oxidants 1951 Reactivity of Partially Reduced Oxepines 1953 Dihydrooxepines 1953 Tetrahydrooxepines 1955 Reactivity of Thiepines 1958 Reactivity of Thiepines and Benzofused Derivatives 1958

VII

VIII

Contents

21.8.1.1 21.8.1.2 21.8.1.3 21.8.1.4 21.8.1.5 21.8.2 21.8.2.1 21.8.2.2 21.8.2.3

Reactions with Metal Carbonyl Complexes 1958 Cycloaddition Reactions 1959 Thermal and Photochemical Reactions 1962 Reactions with Electrophiles 1965 Reactions with Oxidants 1967 Reactivity of Partially Reduced Thiepine Derivatives Dihydrothiepines 1968 Tetrahydrothiepines 1972 Thiepinones 1975 References 1975

22

Heterocycles Containing a Ring-Junction Nitrogen 1989 Juan J. Vaquero and Julio Alvarez-Builla Introduction 1989 Pyrrolizines 1991 General Structure and Reactivity 1991 Relevant Natural and/or Useful Compounds 1991 Relevant Computational Chemistry and Physicochemical and Spectroscopic Data 1993 Synthesis of Pyrrolizines 1994 By Cyclization Reactions 1995 By [3 þ 2] Approaches 1997 Reactivity of Pyrrolizines 1997 Electrophilic Attack 1997 Cycloaddition Reactions 2000 Reduction Reactions 2000 Ring-Opening Reactions 2001 Derivatives 2001 Indolizines 2003 General Structure and Reactivity 2003 Relevant Natural and/or Useful Compounds 2003 Relevant Physicochemical Data, Computational Chemistry, and NMR Data 2005 Synthesis of Indolizidines 2006 Intramolecular Condensation: Approaches Related to the Chichibabin Synthesis 2006 By a [3 þ 2] Approach: 1,3-Dipolar Cycloaddition 2007 Organometallic Processes 2009 Rearrangement of Acetylenic Derivatives 2009 Reactivity of Indolizidines 2011 Reactions with Electrophilic Reagents 2011 Reactions with Oxidizing Agents 2016 Reactions with Nucleophilic Reagents 2016 Reactions with Bases 2017 Reactions with Reducing Agents 2017

22.1 22.2 22.2.1 22.2.2 22.2.3 22.2.4 22.2.4.1 22.2.4.2 22.2.5 22.2.5.1 22.2.5.2 22.2.5.3 22.2.5.4 22.2.6 22.3 22.3.1 22.3.2 22.3.3 22.3.4 22.3.4.1 22.3.4.2 22.3.4.3 22.3.4.4 22.3.5 22.3.5.1 22.3.5.2 22.3.5.3 22.3.5.4 22.3.5.5

1968

Contents

22.3.5.6 22.3.5.7 22.3.6 22.4 22.4.1 22.4.2 22.4.3 22.4.4 22.4.4.1 22.4.4.2 22.4.4.3 22.4.5 22.4.5.1 22.4.5.2 22.4.5.3 22.4.5.4 22.4.6 22.4.6.1 22.4.6.2 22.4.6.3 22.4.7

23 23.1 23.2 23.2.1 23.2.2 23.2.3 23.2.3.1 23.2.3.2 23.2.4 23.2.4.1 23.2.4.2 23.2.4.3 23.2.4.4 23.2.4.5 23.2.4.6 23.3 23.3.1 23.3.2

Electrocyclic Reactions 2018 Reactions of C-Metallated Indolizines 2019 Derivatives 2020 Quinolizinium Salts 2020 General Structure and Reactivity 2020 Relevant Natural and/or Useful Compounds 2021 Relevant Computational Chemistry, and Physicochemical and Spectroscopic Data 2023 Synthesis of Quinolizinium Salts 2026 By [3 þ 3] Approaches 2026 By [4 þ 2] Approaches 2029 By Cyclization Reactions 2035 Reactivity of Quinolizinium Salts 2038 Reactions with Electrophilic Reagents 2039 Reactions with Nucleophilic Reagents: Ring-Opening Reactions 2040 Reactions with Reducing Reagents 2042 Cycloaddition Reactions 2042 Quinolizinium Derivatives 2043 Alkyl Derivatives 2043 Hydroxy and Amino Derivatives 2045 Halo Derivatives 2048 Benzoquinolizinium Salts and Related Systems 2052 References 2062 Phosphorus Heterocycles 2071 Franç ois Mathey Introduction 2071 Phospholes 2071 History and Nomenclature 2071 Spectral, Structural and Theoretical Studies 2072 Synthesis 2073 Synthesis of Phospholes 2073 Synthesis of Phospholide Ions 2075 Reactivity 2076 Reactions at Phosphorus 2076 Reactions at the Diene 2077 [1,5]-Sigmatropic Shifts 2079 Functionalization Reactions 2082 Ring Openings and Expansions 2082 Phospholes and Phospholides in Coordination Chemistry 2083 Phosphinines 2084 History and Nomenclature 2084 Spectral, Structural and Theoretical Studies 2085

IX

X

Contents

23.3.3 23.3.4 23.3.4.1 23.3.4.2 23.3.4.3 23.3.4.4 23.4 23.4.1 23.4.2 23.4.3 23.5 23.6 23.6.1 23.6.2

Synthesis 2086 Reactivity 2089 Reactions at Phosphorus 2089 Substitution and Functionalization Reactions 2092 Cycloaddition Reactions 2095 Phosphinines in Coordination Chemistry 2096 Other P Heterocycles 2097 Three-Membered Rings: Phosphiranes and Phosphirenes 2097 Four-Membered Rings: Phosphetanes, Dihydrophosphetes and Phosphetes 2100 Five-Membered Rings: Phospholenes 2102 Applications of Phosphorus Heterocycles 2103 Addendum 2105 Phospholes 2105 Phosphinines 2107 References 2109

The Chemistry of 2-Azetidinones (b-Lactams) 2117 Benito Alcaide, Pedro Almendros, and Amparo Luna 24.1 Monocyclic Derivatives 2117 24.1.1 Introduction 2117 24.1.2 Physicochemical Data 2117 24.1.2.1 Computational Chemistry 2117 24.1.2.2 Experimental Structural Methods 2119 24.1.3 Biologically Relevant Monocyclic b-Lactams 2120 24.1.4 2-Azetidinone Nucleus Synthesis 2121 24.1.4.1 Ketene-Imine Cycloaddition (Staudinger Reaction) 2121 24.1.4.2 Metalloester Enolate-Imine Condensation 2124 24.1.4.3 Isocyanate-Alkene Cyclocondensation 2125 24.1.4.4 Chromium Carbene-Imine Cyclization 2126 24.1.4.5 Cyclization of b-Amino Acids and Derivatives 2126 24.1.4.6 Hydroxamate Cyclization 2127 24.1.4.7 Metal-Catalyzed Insertions of Diazo Compounds 2127 24.1.4.8 Multicomponent Reactions 2129 24.1.4.9 Coupling of Terminal Alkynes and Nitrones (Kinugasa Reaction) 2130 24.1.4.10 Photochemical and Radical Methods 2130 24.1.4.11 Synthesis from Carbo- or Heterocycles 2131 24.1.4.12 Miscellaneous 2133 24.1.5 Reactivity of the 2-Azetidinone Ring 2134 24.1.5.1 Nucleophilic Attack at Carbon 2134 24.1.5.2 Electrophilic Attack at Carbon 2136 24.1.5.3 Electrophilic Attack at Nitrogen 2136 24

Contents

24.1.5.4 24.1.5.5 24.1.5.6 24.1.5.7 24.1.5.8 24.1.5.9 24.2 24.2.1 24.2.2 24.2.2.1 24.2.2.2 24.2.3 24.2.3.1 24.2.3.2 24.2.4 24.2.4.1 24.2.4.2 24.2.4.3 24.2.4.4 24.2.4.5 24.2.4.6

25 25.1 25.1.1 25.1.2 25.2 25.2.1 25.2.2 25.2.3 25.2.4 25.3 25.3.1 25.3.2 25.3.2.1 25.3.2.2

Radical Transformations 2137 Reduction Reactions 2138 Cis/Trans Isomerization 2139 Ring-Opening and Rearrangement Reactions 2140 Reactions of Substituents Attached to Carbon Atoms 2142 Reactions of Substituents Attached to Nitrogen Atom Penicillins and Cephalosporins 2144 Introduction 2144 Physicochemical Data 2146 Computational Chemistry 2146 Experimental Structural Methods 2147 Synthesis of Penicillins and Cephalosporins 2148 Classical Syntheses 2148 Industrial Production of b-Lactam Antibiotics 2150 Reactivity of Penicillins and Cephalosporins 2153 Basicity of b-Lactam Nitrogen 2153 Hydrolysis 2153 Alcoholysis, Thiolysis, and Aminolysis 2155 Destruction of b-Lactam Antibiotics by b-Lactamases 2156 Conversion of Penicillins into Cephalosporins 2158 Reactions for the Transformation of Functional Groups in Side Chains 2159 References 2163

2143

The Chemistry of Benzodiazepines 2175 Carlos Valdés and Miguel Bayod Introduction 2175 General Introduction 2175 Structural Classification of Benzodiazepines 2177 Relevant Benzodiazepines 2177 Most Common 1,4-Benzodiazepines 2177 1,4-Benzodiazepines with a Heterocycle Condensed at sides a or d 2179 Other Benzodiazepines with Clinical Application 2181 Naturally Occurring Benzodiazepines 2181 1,4-Benzodiazepines: General Synthetic Methods 2182 1,4-Benzodiazepines Ring Synthesis: Introduction 2182 Ring Synthesis of 1,4-Benzodiazepin-2-ones 2182 Quinazoline N-Oxide Route: Sternbach’s Classical Synthesis 2182 2-Aminobenzophenone Route 2184

XI

XII

Contents

25.3.3 25.3.3.1 25.3.3.2 25.3.4 25.4 25.4.1 25.4.2 25.4.3 25.4.4 25.5 25.5.1 25.5.2 25.5.3 25.5.3.1 25.5.3.2 25.6 25.7 25.7.1 25.7.2 25.8 25.8.1 25.8.2

26

26.1 26.1.1 26.1.2 26.1.2.1 26.1.2.2 26.1.2.3 26.1.2.4 26.2 26.3 26.3.1 26.3.1.1 26.3.1.2

Synthesis of 1,4-Benzodiazepine-2,5-diones 2186 Standard Synthesis: from Anthranilic Acid and a-Amino Acid Derivatives 2186 Ugi 4CC Reaction in the Synthesis of 1,4-Benzodiazepines-2,5-diones 2188 Other 1,4-Benzodiazepines 2192 Modifications of the 1,4-Benzodiazepine Ring 2193 Introduction 2193 Reactions of the C2 Carbonyl Group 2194 Functionalization at C3 2196 Substitutions at C5 2197 1,4-Benzodiazepines with a Fused Heterocycle 2198 Benzodiazepines with a Heterocycle Fused at the a Side (N1-C2 Position) 2198 Benzodiazepines with a Heterocycle Fused at the d Side (N4-C5 Position) 2204 Cycloaddition Reactions in the Synthesis of 1,4-Benzodiazepines with Fused Heterocycles 2206 [3 þ 2] Cycloadditions 2206 [2 þ 2] Cycloadditions 2208 Pyrrolo[2,1-c][1,4]Benzodiazepines (PBDs) 2210 1,5-Benzodiazepines 2213 General Methods of Synthesis of 1,5-Benzodiazepines 2214 1,5-Benzodiazepines with a Fused Heterocycle 2217 2,3-Benzodiazepines 2217 2,3-Benzodiazepine Ring Synthesis 2218 2,3-Benzodiazepines with a Fused Heterocycle 2221 References 2222 Porphyrins: Syntheses and Reactions 2231 Venkataramanarao G. Anand, Alagar Srinivasan, and Tavarekere K. Chandrashekar Introduction 2231 General Introduction 2231 System Isomers 2232 Tetrapyrrolic Systems 2232 Pyrrole Inverted Systems 2233 Core-Modified Porphyrins 2233 Expanded Porphyrins 2235 Synthetic Chemistry of Porphyrins and Expanded Porphyrins 2236 Reactivity of Porphyrins 2254 Electrophilic Reactions 2255 Formylation 2255 Reactions of Formyl Porphyrins 2256

Contents

26.3.1.3 26.3.1.4 26.3.1.5 26.3.1.6 26.3.2 26.3.2.1 26.3.2.2 26.3.2.3 26.3.2.4 26.3.2.5

Halogenation 2257 Nitration 2260 Acylation 2262 Cyanation 2262 Nucleophilic Reactions 2262 Reactions of p-Cation Radicals 2262 Substitution Reactions. Reactions with H2(OEP) 2263 Reactions with 5,15-Disubstituted Porphyrins 2265 Reactions with H2TPP 2266 Reactions with Porphine 2268 References 2268

27

New Materials Derived From Heterocyclic Systems 2275 Javier Santamaría and José L. García-Álvarez Introduction 2275 Color and Fluorescent Agents 2275 Heterocyclic Pigments and Industrial Applications 2275 Fluorescence and Fluorescent Heterocycles 2282 Self-Assembling Materials and Molecular Containers 2286 Introduction 2286 Assembly Mediated by Electrostatic and p-Stacking Interactions 2286 Self-Assembly Through Coordination Chemistry 2288 Self-Assembly Through Hydrogen-Bond Chemistry 2293 Capsules and Encapsulation Behavior 2297 Unnatural Enzyme Models 2300 Organic Conductors 2304 Introduction 2304 Conducting Heterocyclic Polymers 2305 Conducting Heterocyclic Molecules in the Bulk 2308 Single Molecule Conductivity 2313 References 2314

27.1 27.2 27.2.1 27.2.2 27.3 27.3.1 27.3.2 27.3.3 27.3.4 27.3.5 27.4 27.5 27.5.1 27.5.2 27.5.3 27.5.4

28

28.1 28.1.1 28.1.2 28.1.3 28.2 28.2.1 28.2.2 28.2.3 28.2.4

Solid Phase and Combinatorial Chemistry in the Heterocyclic Field 2321 José M. Villalgordo Introduction 2321 Natural Products 2322 Peptides, Peptoids and Peptidomimetics 2324 Small Synthetic Organic Molecules 2324 Solid Supports 2327 Crosslinked Polystyrene-Derived Matrices 2329 Functionalized Polystyrene Resins 2329 Chloromethylated Polystyrenes 2330 Aminomethylated Polystyrene Resins 2333

XIII

XIV

Contents

28.2.5 28.2.6 28.2.7 28.2.8 28.2.9 28.3 28.3.1 28.3.1.1 28.3.1.2 28.3.1.3 28.3.1.4 28.3.1.5 28.3.2 28.3.3 28.3.3.1 28.3.3.2 28.3.3.3 28.4 28.4.1 28.4.2 28.4.3 28.4.4 28.4.5 28.4.6 28.4.7

Other Functionalized Polystyrene Resins 2334 Polyacrylamide Resins 2339 TentaGel Resins 2340 Novel Polymeric Supports 2341 CLEAR Resins 2343 Linkers for Solid-Phase Organic Synthesis 2343 Linker Molecules Releasing One Specific Functional Group. Monofunctional Cleavage 2344 Linkers Releasing Carboxylic Acids 2345 Linkers Releasing Amides 2345 Linkers Releasing Amines 2345 Linkers Releasing Alcohols, Diols and Phenols 2345 Linkers Releasing Hydroxamic Acids 2345 Cyclization-Assisted Cleavage 2348 Multidirectional Cleavage Strategies 2352 Direct Cleavage by Nucleophilic Substitution 2352 Direct Cleavage by Electrophiles 2353 ‘‘Safety-Catch’’ Linkers 2354 Heterocyclic Synthesis on Solid-Phase 2357 Synthesis of b-Lactams 2358 Synthesis of Pyrrolidines 2359 Synthesis of Pyrroles 2362 Synthesis of Furans 2363 Synthesis of Thiophenes 2366 Synthesis of Imidazoles 2369 Synthesis of Thiazoles 2372 References 2375 Index

2381

XV

List of Contributors Ramón Alajarín Universidad de Alcalá Departamento de Química Orgánica Alcalá de Henares 28871 Madrid Spain Benito Alcaide Universidad Complutense de Madrid Facultad de Química Departamento de Química Orgánica I 28040 Madrid Spain Pedro Almendros Instituto de Química Orgánica General (CSIC) Juan de la Cierva, 3 28006 Madrid Spain Julio Alvárez-Builla Universidad de Alcalá Facultad de Farmacia Departamento de Química Orgánica Alcalá de Henares 28871 Madrid Spain

Venkataramanarao G. Anand Regional Research Laboratory (CSIR) Chemical Sciences and Technology Division Photosciences and Photonics Section Trivandrum 695 019 India José Barluenga Universidad de Oviedo Instituto Universitario de Química Organometálica ‘‘Enrique Moles’’ Julián Clavería 8 33006 Oviedo Spain Miguel Bayod Asturpharma S.A. Peña Brava 23 Polígono Industrial Silvota 33192 Llanera, Asturias Spain Jan Bergman Karolinska Institute Department of Biosciences and Nutrition Unit of Organic Chemistry Novum Research Park 141 57 Huddinge Sweden

XVI

List of Contributors

Ulhas Bhatt Albany Molecular Research, Inc. Albany, NY 12212 USA Carolina Burgos Universidad de Alcalá Departamento de Química Orgánica Alcalá de Henares 28871 Madrid Spain María-Paz Cabal Universidad de Oviedo Instituto Universitario de Química Organometálica ‘‘Enrique Moles’’ Julián Clavería 8 33006 Oviedo Spain Luis Castedo Universidad de Santiago de Compostela Facultad de Química Departamento de Química Orgánica 15782 Santiago de Compostela Spain Tavarekere K. Chandrashekar Regional Research Laboratory (CSIR) Chemical Sciences and Technology Division Photosciences and Photonics Section Trivandrum 695 019 India and

Stefano Cicchi Università degli Studi di Firenze Dipartimento di Chimica ‘‘Ugo Schiff’’ via della Lastruccia 13 50019 Sesto Fiorentino-Firenze Italy Ana M. Cuadro Universidad de Alcala Departamento de Química Orgánica Alcalá de Henares 28871 Madrid Spain José Elguero University of Aveiro Instituto de Química Médica (CSIC) Department of Chemistry Juan de la Cierva, 3 28006 Madrid Spain José L. García-lvarez Universidad de Oviedo Instituto Universitario de Química Organometálica ‘‘Enrique Moles’’ Departamento de Química Orgánica e Inorgánica Unidad asociada al CSIC Julian Claveria 8 33006 Oviedo Spain

Indian Institute of Technology Department of Chemistry Kanpur 208 016 India

Cristina Gómez de la Oliva Instituto de Química Médica (CSIC) Juan de la Cierva, 3 28006 Madrid Spain

Ugo Chiacchio Università di Catania Dipartimento di Scienze Chimiche Viale Andrea Doria 6 95125 Catania Italy

Concepción González-Bello Universidad de Santiago de Compostela Facultad de Ciencias Departamento de Química Orgánica 27002 Lugo Spain

List of Contributors

Pilar Goya Laza Instituto de Química Médica (CSIC) Juan de la Cierva, 3 28006 Madrid Spain Bernardo Herradón Instituto de Química Orgánica (CSIC) Juan de la Cierva, 3 28006 Madrid Spain Xue-Long Hou The Chinese Academy of Sciences Shanghai Institute of Organic Chemistry Shanghai-Hong Kong Joint Laboratory in Chemical Synthesis and State Key Laboratory of Organometallic Chemistry 354 Feng Lin Road Shanghai 200032 China Hui Huang The Chinese Academy of Sciences Shanghai Institute of Organic Chemistry Shanghai-Hong Kong Joint Laboratory in Chemical Synthesis 354 Feng Lin Road Shanghai 200032 China Tomasz Janosik Karolinska Institute Department of Biosciences and Nutrition Unit of Organic Chemistry Novum Research Park 141 57 Huddinge Sweden

Amparo Luna Universidad Complutense de Madrid Facultad de Química Departamento de Química Orgánica I 28040 Madrid Spain Fabrizio Machetti Instituto Chimica dei Composti Organometallica del CNR c/o Dipartimento di Chimica Organica ‘‘Ugo Schiff’’ Via Madonna del Piano 10 50019 Sesto Fiorentino (Firenze) Italy François Mathey Nanyang Technical University School of Physical and Mathematical Sciences Division of Chemistry and Biological Chemistry 21 Nanyang Link 637371 Singapore Singapore S. Shaun Murphree Allegheny College Department of Chemistry 520 N, Main Street Meadville, PA 16335 USA Carmen Ochoa de Ocariz Instituto de Química Médica (CSIC) Juan de la Cierva, 3 28006 Madrid Spain Teresa M.V.D. Pinho e Melo Universidade de Coimbra Departamento de Química 3004-535 Coimbra Portugal

XVII

XVIII

List of Contributors

Julia Revuelta Instituto de Quimica Organica General (CSIC) Grupo de Quimica Organica Biologica C/Juan de la Cierva, 3 28006 Madrid Spain Sylvie Robin Université de Paris-Sud ICMMO Laboratoire ed Synthèse Organique et Méthodologie Université de Paris-Sud 91405 Orsay France Giovanni Romeo Università di Messina Dipartimento Farmaco-Chimico Via SS Annunziata 98168 Messina Italy Gérard Rousseau Université de Paris-Sud ICMMO Laboratoire ed Synthèse Organique et Méthodologie Université de Paris-Sud 91405 Orsay France Javier Santamaría Universidad de Oviedo Instituto Universitario de Química Organometálica ‘‘Enrique Moles’’ Departamento de Química Orgánica e Inorgánica Unidad asociada al CSIC Julian Claveria 8 33006 Oviedo Spain

Artur M.S. Silva University of Aveiro Department of Chemistry 3810-193 Aveiro Portugal Alagar Srinivasan Regional Research Laboratory (CSIR) Chemical Sciences and Technology Division Photosciences and Photonics Section Trivandrum 695 019 India Augusto C. Tomé University of Aveiro Department of Chemistry 3810-193 Aveiro Portugal Carlos Valdés Universidad de Oviedo Instituto Universitario de Química Organometálica ‘‘Enrique Moles’’ Julián Clavería 8 33006 Oviedo Spain Juan J. Vaquero Universidad de Alcala Departamento de Química Orgánica Alcalá de Henares 28871 Madrid Spain José M. Villalgordo Villalpharma S.L. Polígono Industrial Oeste C/Paraguay, Parcela 7/5-A, Módulo A-1 30169 Murcia Spain

List of Contributors

David J. Wilkins Key Organics Ltd. Highfield Industrial State Camelford Cornwall PL32 9QZ UK

Jie Wu Fudan University Department of Chemistry 220 Handan Road Shanghai 200433 China

Henry N.C. Wong The Chinese University of Hong Kong Institute of Chinese Medicine, and Central Laboratory of the Institute of Molecular Technology for Drug Discovery and Synthesis Department of Chemistry Center of Novel Functional Molecules Shatin, New Territories Hong Kong SAR, China

Larry Yet 299 Georgetown Ct Albany, NY 12203 USA

and The Chinese Academy of Sciences Shanghai Institute of Organic Chemistry Shanghai-Hong Kong Joint Laboratory in Chemical Synthesis 354 Feng Lin Road Shanghai 200032 China

Kap-Sun Yeung Bristol-Myers Squibb Pharmaceutical Research Institute 5 Research Parkway P.O. Box 5100 Wallingford, CT 06492 USA

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j1

1 Heterocyclic Compounds: An Introduction Julio Alv
arez-Builla and Jos
e Barluenga

1.1 Heterocyclic Compounds: An Introduction

The IUPAC Gold Book describes heterocyclic compounds as: “Cyclic compounds having as ring members atoms of at least two different elements, e.g. quinoline, 1,2-thiazole, bicyclo[3.3.1]tetrasiloxane” [1]. Usually they are indicated as counterparts of carbocyclic compounds, which have only ring atoms from the same element. Another classical reference book, the Encyclopaedia Britannica, describes a heterocyclic compound, also called a heterocycle, as: “Any of a class of organic compounds whose molecules contain one or more rings of atoms with at least one atom (the heteroatom) being an element other than carbon, most frequently oxygen, nitrogen, or sulfur” [2]. Although heterocyclic compounds may be inorganic, most contain within the ring structure at least one atom of carbon, and one or more elements such as sulfur, oxygen, or nitrogen [3]. Since non-carbons are usually considered to have replaced carbon atoms, they are called heteroatoms. The structures may consist of either aromatic or non-aromatic rings. Heterocyclic chemistry is the branch of chemistry dealing with the synthesis, properties, and applications of heterocycles. Heterocyclic derivatives, seen as a group, can be divided into two broad areas: aromatic and non-aromatic. In Figure 1.1, five-membered rings are shown in the first row, and the derivative 1 corresponds to the aromatic derivative, furan, while tetrahydrofuran (2), dihydrofuran-2-one (3), and dihydrofuran-2,5-dione (4) are not aromatic, and their reactivity would be not unlike that expected of an ether, an ester, or

Modern Heterocyclic Chemistry, First Edition. Edited by Julio Alvarez-Builla, Juan Jose Vaquero, and José Barluenga. Ó 2011 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2011 by Wiley-VCH Verlag GmbH & Co. KGaA.

j 1 Heterocyclic Compounds: An Introduction

2

O 1

2

N

N H 6

5

O

O

O

O

O

O 4

3

N H 7

O

N H 8

Figure 1.1 Examples of heterocyclic compounds.

a carboxylic anhydride, respectively. The second row shows six-membered rings, initially in an aromatic form as pyridine (5), while piperidine (6), piperidin-2-one (7), and 1,2,3,4-tetrahydropyridine (8) are not aromatic; their reactivity would not be very different from that expected of an amine, amide, or enamine, respectively. In general, the reactivity of aromatic heterocycles, which is a combination of that expected from an aromatic system combined with the influence of the heteroatoms involved, is usually more complex, while the reactivity of the non-aromatic systems is not too different from the usual non-cyclic derivatives. Thus, most books on heterocyclic chemistry are mainly devoted to the reactivity of aromatic compounds. Tables 1.1–1.4 indicate models of the heterocyclic derivatives described in these volumes. Table 1.1 shows simple heterocyclic systems of three or four members. In this case, the literature examples are mainly non-aromatic, as indicated in the table, and the expected reactivity is always related to the ring strain present in all of them, which produces a release of energy when they are opened to give aliphatic products.

Table 1.1 Main three- and four-membered heterocycles.

Ring size

Heteroatom N

3

4

O

N H Aziridine

O Oxirane

NH N H Diaziridine

O O Dioxirane

NH

Azetidine

O Oxetane

S

Other

S Thiirane

NH O Oxaziridine

S Thietane

Se

P

R

Seletane Phosphetane

1.1 Heterocyclic Compounds: An Introduction Table 1.2 Main five-membered heterocycles.

Ring size

Heteroatom N

5

5

Benzo

N H Pyrrole

N H

Benzo

O Furan

Indole

N N H Pyrazole

O

O Benzofuran

S

S Thiophene

N

Isoxazole

N

S

O Oxazole

N N H

Triazoles

N N N N H

N

N N N N O O N N N N O O

Oxadiazoles

N

Isothiazole

N

N H Imidazole N N N H

O

N S Thiazole S N

N N N

S

S

N

N N N

S

Thiadazoles

Tetrazole

Table 1.2 indicates five-membered heterocyclic systems, such as pyrrole, furan, their benzo derivatives, and thiophene, and a set of heterocycles with more than one heteroatom, as 1,2-azoles, 1,3-azoles, triazoles, oxa- and thiadiazoles, and tetrazole. Table 1.3 shows six-membered rings, namely, pyridine, its benzo derivatives quinoline and isoquinoline, the pyrilium cation, and, as in Table 1.2, other common heterocycles with more than one heteroatom, such as diazines, triazines, and tetrazines. Finally, Table 1.4 shows the simplest seven-membered ring, that is, azepine and its benzo derivative, as well as examples of the nitrogen bridgehead bicyclic systems, pyrrolizine, indolizines, and quinolizinium cation. Other additional chapters have been included with special systems relevant from different points of view: 2-azetidinones or b-lactams, benzodiazepines, and two general chapters on new materials based on heterocyclic systems and solid phase and combinatorial chemistry related to heterocyclic derivatives.

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j 1 Heterocyclic Compounds: An Introduction

4

Table 1.3 Main six-membered heterocycles.

Ring size N

Benzo

O

N

6

Quinoline

N

Pyridine

O

+

Pyrilium

N

Isoquinoline N

N N

N

N

N

Diazines Pyridazine Pyrimidine Pyrazine

N

N N

N N

N N

N N

Triazines N N

NN N

N N

N N

N N

N

Tetrazines

Table 1.4 Other simple heterocycles.

Ring size

Heteroatom

7

N

Benzo

N H

N H

Benzoazepine

Azepine

5-5, 5-6, 6-6

N

N

Pyrroline

Indolizine

N

+

Quinolizinium

1.2 Structure and Reactivity of Aromatic Five-Membered Systems

1.2 Structure and Reactivity of Aromatic Five-Membered Systems

As is indicated in most handbooks of heterocyclic chemistry [3, 4], a pictorial valence bond resonance description is used in most chapters, as a simple way to rationalize the reactivity of the most important aromatic heterocycles. Two examples are described in detail as representative of most of the aromatic rings considered: pyrrole as a model of the p-excessive rings, and pyridine as a model of the p-deficient ones. Pyrrole has a structure that is isoelectronic with the cyclopentadienyl anion, but is electrically neutral, having a nitrogen atom with a pair of electrons, which is part of the aromatic sextet, and its resonance hybrid can be represented as a combination of main forms I–V (Scheme 1.1), one without charge, and the others with charge separation. As expected, not all forms contribute equally to the structure of the pyrrole, with the order of importance being I > III, IV > II, V, that is, the major contribution is produced by the non-charged form, and, of the charged ones, those in which the nitrogen is using its lone pair of electrons. As a combination of all forms, structure 9 indicates how the heteroatom bears a partial positive charge, while the carbon positions show an increase in electronic density, compared with the typical aromatic system, benzene. Thus, a p-excessive system such as pyrrole would be easily attacked by electrophiles and not by nucleophiles.

N

N

H

H

I

+

-

N

+

N H

H

II

IV

III

-

N

+

H V

δ−

δ− δ−

+

N H 9

δ− δ+

Scheme 1.1 Resonance hybrids of pyrrole.

Scheme 1.2 indicates how the attack of an electrophile usually proceeds. The major isomer 13 is formed through intermediates 10–11–12, of which the intermediate 10 contributes most to the stabilization of the intermediate. Alternatively, a minor isomer 16 is produced through the less stable intermediates 14 and 15. Alternatively, Scheme 1.3 shows the attack of a nucleophile on pyrrole. Intermediate 17 is not stabilized, and the lone pair of electrons on the heteroatom does not contribute to the progress of the process. The only process that usually can be detected is deprotonation of the N–H bond to generate the pyrrolate (18), which can be used to make a bond with a suitable electrophile (i.e., an alkyl halide) to produce the N-substituted pyrrole 19.

j5

j 1 Heterocyclic Compounds: An Introduction

6

+ N H

+

H 10

E+

N H 9

+

E

N H

E H N H

+

N H

14

H 11

E

E H +

N H

-H+ E

H 12

N H

E

13

E -H+

15

N H 16 Minor isomer

Scheme 1.2 Electrophilic attack on pyrrole.

_ N H _ Nu N H

H

No stabilization

Nu 17

E+

9

N 18

NuH

N E

19

Scheme 1.3 Attack on pyrrole by nucleophiles.

This behavior can be extended with small differences to other p-excessive heterocycles, with the limit due to the existence or not of a N–H bond at position 1. In the case of rings like thiazole or isoxazole, the lack of the acidic bond makes the process 9–18–19 impossible. Attack by radicals or complex organometallic reagents are more complex and are discussed in every chapter.

1.3 Structure and Reactivity of Aromatic Six-Membered Systems

The structure of pyridine is analogous to that of benzene, with one of the carbons replaced by a nitrogen atom. This produces alterations in the geometry, which is no longer perfectly hexagonal, due to the shorter CN bonds; the existence of an unshared pair of electrons, not related with the aromatic sextet, gives the pyridine basic character, along with a permanent dipole in the ring, due to the electronegative character of the heteroatom compared with carbon. Scheme 1.4 indicates the main canonical forms (I–V) that contribute to the resonance hybrid of the structure of pyridine. Obviously, not all of them contribute equally – the two Kekul
e forms I and II, which are not charged, are the more stable

1.3 Structure and Reactivity of Aromatic Six-Membered Systems

j7

+ N

N

N _

I

II

III

+

+

N _

N _ V

IV

δ+ δ+

N ¨ 20 δ−

δ+

Scheme 1.4 Resonance hybrids of pyridine.

forms, followed by those in which nitrogen is negatively charged. Other forms can be envisaged, but their contributions can be neglected. Thus, the combination of the main forms can be represented as structure 20, in which the nitrogen bears a partial negative charge, and positions 2, 4, and 6 are electron deficient; usually, positions 2 and 6 are the most deficient due to the inductive effect produced by the heteroatom. Positions 3 and 5 can be considered neutral, comparable to benzene carbons. Thus, the more characteristic reactivity of the pyridine ring would be against nucleophiles, which would attack the more electron-deficient positions. As expected from the structure of pyridine, Scheme 1.5 describes the attack of a nucleophile on the system. The main process goes through intermediates 21–22–23 to produce the major isomer 24, substituted at position 2. Alternatively, attack can also occur at position 4, through intermediates 25–26–27, yielding the minor isomer 28.

_ Nu

_

N _ H Nu

_ N

H Nu 20

N

H 23

22

21 N

Nu

H

_ -H

Nu

Nu

N 24 Aromatization

_

N 25

H Nu

N _

26

_

Nu H

Nu

_ -H

N 27

N

28 Minor isomer

Scheme 1.5 Nucleophilic attack on pyridine.

Scheme 1.6 describes an electrophilic attack on pyridine. The initial attack of the electrophile usually takes place on the pyridine nitrogen. When the attacking species can produce a stable bond, the product should be the pyridinium salt 33, but when this product is not stable enough the process goes through intermediates 29–30–31,

j 1 Heterocyclic Compounds: An Introduction

8

that is, by attacking the neutral carbons, to produce the 3-substituted derivative 32. As a general view, the reactivity of pyridine can be taken as a model for other p-deficient systems, and can be easily extended to diazines, triazines, or pyrilium derivatives. Other processes, like radical attack or reaction with complex organometallic reagents are described in every chapter.

E+ N

20 E+ N-substitution

N+ E

+ N

E H 29

+

E H N

30

N

+ 31

E H

-H+

E N

32

33

Scheme 1.6 Electrophilic attack on pyridine.

1.4 Basic Literature on Heterocyclic Compounds

To introduce the recent literature in heterocyclic chemistry, it is necessary to indicate, among the textbooks available [3–6], two of them: one [3] from Eicher and Hauptmann with a highly structured organization, which is simple and efficient and can be used as the basis of a heterocyclic course. The other [4], from Joule and Mills, combines the condensed format with extensive information about the basic heterocycles considered. As reference books, it is necessary to cite the collection Comprehensive Heterocyclic Chemistry from Katritzky and colleagues [7–9]; this is associated with the Handbook of Heterocyclic Chemistry [10], which is regularly updated with the Comprehensive edition. Heterocyclic series are also of great interest, becoming readable collections that allow an update of the literature in the field. Progress in Heterocyclic Chemistry [11] describes mostly the advances in every relevant field of heterocyclic chemistry in a yearly volume. The series of monographs Advances in Heterocyclic Chemistry [12], which consists of 101 volumes to date, covers in depth very different topics in the field. Other recent monographs are of interest in various topics on the field, a good guide called Name Reactions in Heterocyclic Chemistry has been given by Li [13] and the monograph Aromaticity in Heterocyclic Compounds [14] is also a good basic help for heterocyclic chemists, as is the Synthesis of Heterocycles via Multicomponent Reactions [15]. Other recent monographs have centered on synthetic techniques such as palladium chemistry [16], chemistry of heterocyclic carbenes [17–19], or synthesis

References

with microwaves [20]. In addition, a recent monograph on general heterocyclic chemistry emphasizes the importance of heterocyclic compounds in the field of medicinal chemistry and natural products [21].

References 1 IUPAC (2009) IUPAC Compendium of

2

3

4 5

6

7

8

9

10

11

Chemical Terminology - the Gold Book heterocyclic compounds: http:// goldbook.iupac.org/H02798.html (accessed on). Encyclopædia Britannica, Encyclopædia Britannica Online. The official website: heterocyclic compound http://www. britannica.com (accessed on). Eicher, T. and Hauptmann, S. (2003) The Chemistry of Heterocycles: Structure, Reactions, Syntheses, and Applications, 2nd edn, Wiley-VCH Verlag GmbH, Weinheim. Joule, J.A. and Mills, K. (2000) Heterocyclic Chemistry, 4th edn, Blackwell, Oxford. Sainsbury, M. (2002) Heterocyclic Chemistry, Royal Society of Chemistry, Cambridge. Nylund, K., Johansson, P., Puterova, Z., and Krutosikova, A. (2010) Heterocyclic Compounds: Synthesis, Properties and Applications, Nova Science Publishers, Hauppauge, New York. Katritzky, A.R. and Rees, C.W. (eds) (1984) Comprehensive Heterocyclic Chemistry I, Pergamon Press, Oxford. Katritzky, A.R., Rees, C.W. and Scriven, F.V. (eds) (1996) Comprehensive Heterocyclic Chemistry II, Pergamon Press, Oxford. Katritzky, A.R., Ramsden, C.A., Scriven, E.F.V., and Taylor, R.J.K. (2008) Comprehensive Heterocyclic Chemistry III, Elsevier, Amsterdam. Katritzky, A.R., Ramsden, C.A., Joule, J.A., and Zhdankin, V.V. (2010) Handbook of Heterocyclic Chemistry, 3rd edn, Elsevier, Amsterdam. Gribble, G.W. and Joule, J. (eds) (2009) Progress in Heterocyclic Chemistry, Elsevier, Amsterdam.

12 Katritzky, A.R. (ed.) (2010) Advances in

13

14

15

16

17

18

19

20

21

Heterocyclic Chemistry, Elsevier, Amsterdam. Li, J.J. (2004) Name Reactions in Heterocyclic Chemistry, John Wiley & Sons, Inc., Hoboken, New Jersey. Krygowski, T.M. and Cyranski, M.K. (2009) Aromaticity in Heterocyclic Compounds (Topics in Heterocyclic Chemistry), Springer, Heidelberg. Orru, R.V.A., Ruijter, E., and Maes, B.U.W. (2010) Synthesis of Heterocycles via Multicomponent Reactions I (Topics in Heterocyclic Chemistry), Springer, Heidelberg. Li, J.J. and Gribble, G.W. (2006) Palladium in Heterocyclic Chemistry: A Guide for the Synthetic Chemist, 2nd edn, Pergamon, Amsterdam. Nolan, S.P. (2006) N-Heterocyclic Carbenes in Synthesis, Wiley-VCH Verlag GmbH, Weinheim. K€ uhl, O. (2010) Functionalised NHeterocyclic Carbene Complexes, John Wiley & Sons, Ltd., Chichester. McGuinness, D. (2009) Heterocyclic Carbene Complexes: Reaction Chemistry and Catalytic Applications, Lambert Academic Publishing, Koeln. Van der Eycken, E. and Kappe, C.O. (2006) Microwave-Assisted Synthesis of Heterocycles (Topics in Heterocyclic Chemistry), Springer, Heidelberg, http://www. amazon.com/ComprehensiveHeterocyclic-Chemistry-III-15-/dp/ 0080449913/ref¼sr_1_26?s¼books& ie¼UTF8&qid¼1280185250&sr¼1-26. Quin, L.D. and Tyrell, J. (2010) Fundamentals of Heterocyclic Chemistry: Importance in Nature and in the Synthesis of Pharmaceuticals, John Wiley & Sons, Inc., Hoboken, New Jersey.

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2 Three-Membered Heterocycles. Structure and Reactivity S. Shaun Murphree

2.1 Aziridines

The field of aziridine chemistry is brimming with activity and, as a consequence, it has been the subject of multiple recent reviews [1–5]. Of particular note are the efficient and engaging article by Sweeney [6], a brief overview of properties and chemistry [7] and a newer monograph with a more encyclopedic sweep [8]. The present work aims not to be comprehensive, but rather to provide a general landscape and to capture the spirit of best practices available to the synthetic chemist, with an emphasis on preparative utility. 2.1.1 Properties of Aziridines

The smallest and most functionally spartan of the nitrogen heterocycles, aziridine (1), is an isolable liquid at room temperature, but prone to polymerization and other thermal degradation pathways because of its inherent ring strain [9]. It is weakly basic, with a pKa of 7.98 [7], and the basicity trends of variously substituted aziridines have been the subject of a recent theoretical study [10]. From the standpoint of molecular geometry, aziridine describes an almost equilateral triangle, with a C–N–C bond angle of 60.58
(Figure 2.1) [11]. The N-inversion energy is relatively high, at almost 17 kcal mol1; however, conjugating substituents decrease the barrier significantly [12]. The 1 H-NMR signals of the methylene protons are centered at 1.4 ppm, while the carbons resonate at about 27 ppm. Coupling constants range from 3.8 Hz for trans vicinal 1 H-1 H coupling, to 6.3 Hz for cis vicinal 1 H-1 H coupling, and 168.1 Hz for 1 H-13 C coupling [13]. Aziridine moieties are imbedded in structurally diverse natural products from various sources (Figure 2.2), and the reader is directed to Lowden’s excellent recent treatise on this topic [14]. Isolated from Streptomyces griseofuscus [15, 16], azinomycin A (2) and azinomycin B (3, also known as carzinophilin) are among the most intensely studied members of this class [17–19]. As potent antitumor agents, their

Modern Heterocyclic Chemistry, First Edition. Edited by Julio Alvarez-Builla, Juan Jose Vaquero, and José Barluenga. Ó 2011 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2011 by Wiley-VCH Verlag GmbH & Co. KGaA.

j 2 Three-Membered Heterocycles. Structure and Reactivity

12

Figure 2.1 Geometry of aziridine.

biological activity springs from an ability to form interstrand purine base crosslinks in duplex DNA [20–23]. Central to this behavior is the aziridine ring bound up in the 1-aza-bicyclo[3.1.0]hexane system, a structural feature also found in ficellomycin (4), an antibacterial isolated from Streptomyces ficellus [24]. A similar 3,6-diaza-bicyclo [3.1.0]hexane system is at the functional heart of mitomycin C (5), a notable representative of the mitosanes extracted from Streptomyces verticillatus [25] and the target of many synthetic studies [26]. For decades, mitomycin C has found place in the arsenal of clinically relevant antibiotic and anti-tumor drugs, and the mitomycins have inspired studies into many promising non-natural analogs [27]. Also equipped with a 2,3-dialkylaziridine residue is the protease inhibitor miraziridine A (6), which is isolated from the marine sponge Theonella aff. mirabilis [28] and which exhibits a linear peptide structure vaguely similar to madurastatin A1 (7), a compound demonstrated in a culture of a pathogenic Actinomadura madurae IFM 0745 strain, which shows activity against Micrococcus luteus [29]. An even more exposed aziridine ring is seen in the azicemicins A (8) and B (9), antibacterials isolated from Amycolatopsis sp. Mj126-NF4 [30, 31]. These naturally occurring aziridine alkaloids have also inspired a genre of semi-synthetic and synthetic analogs of medicinal interest [32]. 2.1.2 Synthesis of Aziridines

Generally speaking, there are three major synthetic routes to the aziridines (Scheme 2.1): (a) the addition of monovalent nitrogen species to alkenes; (b) the addition of divalent carbon centers to imines; and (c) the N-alkylative ring closure of amines equipped with b-leaving groups . A fourth route (pathway d) is less frequently encountered, but is nevertheless included here because of its potential synthetic utility. Enantioselective protocols in the first two categories have been the subject of a review [33], and aziridine synthesis as a whole has been more generally summarized by Sweeney [34]. 2.1.2.1 Aziridination of Alkenes Analogous to epoxidation, in which olefins react with electrophilic oxygen reagents, the aziridination of alkenes involves the addition of nitrenes (or nitrenoids) to a b-bond. Common nitrene precursors include [N-(p-toluenesulfonyl)imino]phenyliodinane (PhI¼NTs), N-chloro-p-toluenesulfonamide sodium salt (Chloramine-T), and

2.1 Aziridines OH

O

O

O

O MeO

O

O

O

NH

O H N

O MeO

N

NH

O H N

O

O

AcO

N AcO

OH

OH

3, Azinomycin B

2, Azinomycin A

H N

H 2N O

O

O OH

NH 2

O

O OMe

H2 N

N

HN

N

Me

NH

NH

O

H2 N

5, Mitomycin C

4, Ficellomycin

O

O

HO

N H

N H

OH

H N

O N H

O

O

H N

OH

O

NH H2 N

NH

6, Miraziridine A O N OH

O

H N O

Me

O N H

O N OH

NHMe

7, Madurastatin A1

MeO

NR

O OH

HO OH MeO OH

j13

OH

O

8, Aicemicin A, R=H 9, Aicemicin B, R=Me Figure 2.2 Some naturally occurring aziridines.

H

N H

N O

OH

j 2 Three-Membered Heterocycles. Structure and Reactivity

14

N

+

C

:

b

:

N

:

a

:

+

N

N

X

Y

NH d - X=Y

c - "HLG"

LG

Scheme 2.1 General synthetic routes to aziridines.

its N-bromo analogue (Bromamine-T), although use of the more esoteric N-iodo-Npotassio-p-toluenesulfonamide (TsNKI) has also been reported [35]. These precursors can be activated using various transition-metal catalysts (Figure 2.3). Also mirroring epoxidation methodology, a common model reaction is the aziridination of styrene (Scheme 2.2). Some illustrative examples are summarized in Table 2.1. For example, the copper(I) complex of a fluorinated tris(pyrazolyl)borate (or homoscorpionate) ligand forms an adduct with ethylene (12a), which catalyzes the aziridination of styrene with great efficiency using PhI¼NTs as a nitrene precursor [36]. The more readily available Chloramine-T can be used effectively in the presence of methyl homoscorpionate complex 12b, even with equimolar charges of olefin and nitrene precursor [37]. This catalyst motif has been incorporated into a heterogeneous system [38]. Other interesting copper(I) catalysts include those derived from pyridyl-1,5-diazacyclooctanes (e.g., 13) [39] and bispidones (e.g., 14) [40]. A particularly intriguing protocol using copper(I)iodide under aqueous phase-transfer conditions (entry 5) has also been reported [41]. Examples of copper(II) catalysts include the 1,4,7-triazacyclononane complex 15, which requires a rather large excess of olefin [42], copper(II) acetylacetonate immobilized in ionic liquids (entry 7), which can be recycled many times without loss of activity [43], and Cu2 þ exchanged zeolite Y (CuHY) in acetonitrile (entry 8), which allows for respectable conversion using almost equimolar alkene : nitrene ratios [44]. Other transition metals can be used to advantage, as well. For example, the fluorinated iron(III) porphyrin catalyst 16a [45], although certainly dearer to synthesize, exhibits marked advantages over its older manganese-based cousin 16b [46]; and even iron(II) triflate is effective in promoting high-yielding aziridination reactions [47] (Table 2.1, entry 11). In the realm of precious metals, a novel and structurally interesting disilver(I) complex (17) has been shown to function as a competent catalyst in aziridination, a process that may involve high-valent silver intermediates [48]. Some polymersupported ruthenium porphyrin catalysts have been employed for this transformation; however, conversions tend to be low [51, 52]. The use of a metal catalyst can be circumvented in some cases. In one particularly convenient example, a nitrene precursor is generated in situ from p-toluenesulfo-

2.1 Aziridines NTs

conditions

Ph

(seeTable2.1)

Ph

10

11

Scheme 2.2 Aziridination of styrene.

namide using iodobenzene diacetate. The aziridination is facilitated by substoichiometric quantities of iodine [49] (Table 2.1, entry 13). A conceptually related protocol is carried out using t-butylhypoiodite, prepared in situ from t-butylhypochlorite and sodium iodide [50] (Table 2.1, entry 14). R N

H R B N N

R Ar

N N Cu R H2C CH2

N R

R

N Cl N Ar

M

12a, R = CF3 12b, R = Me

N

Ar N

Ar N N

N Cu O2CCF3

Me

PF6

16a, Ar = C 6F5; M = FeIII 16b, Ar = C 6H5; M = MnIII

13

MeO2C

HO

N Me

OH Me N NMe Cu

t-Bu CO2Me t-Bu N

14

i-Pr

N

Ag N

N O O

N

N

i-Pr

Cu N

Ag

t-Bu

N

i-Pr

N

N Me

Cl

t-Bu

N

O

t-Bu O2CCF3 O2CCF3

15

Figure 2.3 Representative catalysts for racemic aziridination.

17

t-Bu

j15

j 2 Three-Membered Heterocycles. Structure and Reactivity

16

Table 2.1 Reaction conditions for styrene aziridination.

Entry

Catalyst (mol.%)a)

Nitrene source

Styrene : nitrene

Solvent

Time (h)

Yield (%)a)

Reference

Copper(I) catalysts 1 12a (5) 2 12b (5) 3 13 (5) 4 14 (3.5) 5 CuI(10)

PhI¼NTs Chloramine-T PhI¼NTs PhI¼NTs Chloramine-T

1 : 1.5 1:1 3.8 : 1 2:1 2:1

CH3CN CH3CN CH3CN CH3CN H2Ob)

16 n.r. 1.5 7 3

99 84 99 80 91

[32] [33] [34] [35] [36]

Copper(II) catalysts 6 15 (5) 7 Cu(acac)2 (8)c) 8 CuHY

PhI¼NTs PhI¼NTs PhI¼NTs

20 : 1 5:1 1 : 1.5

CH3CN CH3CN CH3CN

16 1 3

96 95 86

[37] [38] [39]

Other metal catalysts 9 16a (5) 10 16b (5) 11 Fe(OTf)2 (5) 12 17 (2)

Bromamine-T PhI¼NTs PhI¼NTs PhI¼NTs

5:1 100 : 1 7:1 5:1

CH3CN CH2Cl2 CH3CN CH3CN

12 n.r. 3 6

80 80 82 91

[40] [41] [47] [42]

TsNH2/PhI(OAc)2/ I2/t-BuOK TsNH2/t-BuOCl/ NaI

1:3

DCE

2

88

[49]

2:1

CH3CN

5

95

[50]

No metal catalyst 13 none 14

none

a) Based on nitrene source. b) Bu4NBr used as PTC. c) Immobilized in bmimBF4.

Progress continues to be made in the asymmetric aziridination of olefins using the same general approach (Scheme 2.3), but with chiral catalyst systems (Table 2.2). For example, impressive enantioselectivity has been reported for copper-exchanged zeolite Y (CuHY) modified with the chiral bis(oxazoline) 18a (Figure 2.4) using [N-(p-nitrosulfonyl)imino]phenyliodinane (PhI¼NNs) as the nitrene precursor [53]. Inferior results are obtained when [N-(p-toluenesulfonyl)imino]phenyliodinane (PhI¼NTs) is used [54]. A one-pot homogeneous variant using bis(oxazoline) 18b and commercially available iodobenzene diacetate has also been reported [55]. Evidence suggests that the ultimate stereochemical outcome may be affected by a secondary reaction between the aziridines formed and other components in the reaction mixture [56].

conditions

Ph

(see Table 2.2)

10

Ph

*

NR

11

Scheme 2.3 Asymmetric aziridination of styrene.

2.1 Aziridines Table 2.2 Reaction conditions for asymmetric styrene aziridination.

Entry

Catalyst (mol.%)a)

Nitrene source

Styrene : nitrene

Solvent

Time (h)

Yield (%)a)

ee (%)

Reference

1 2 3

CuHY þ 18 (7%) 19 (5) 20(0.1)

PhI¼NNs PhI¼NTs TsN3

1 : 1.3 1:5 1:1

CH3CN CH2Cl2 CH2Cl2

16 n.r. 24

82 76 78

91 94 85

[45] [49] [51]

based on nitrene source.

a)

Another major avenue for enantioselective aziridination is offered through the use of (salen)manganese(III) complexes, such as the Katsuki catalyst (19) [57]. Evidence from the Jacobsen group suggests that the high enantiofacial selectivity observed for aryl alkenes may derive from well-defined bidentate aromatic interactions between substrate and catalyst [58]. Analogous ruthenium-based catalysts (e.g., 20) allow for the use of tosyl azide as a nitrene precursor and are effective even at extremely low catalyst loadings [59]. Metalloporphyrin catalysts continue to show some promise for asymmetric aziridination, although enantioselectivities remain modest [60]. Some very convenient methodology has developed around bromine-catalyzed aziridination reactions using Chloramine-T as the source of electrophilic nitrogen

Me

O

Mn O

N

R

X N

N

O N

Me

O

Ph Ph

R

18a, R = Ph 18b, R = t-Bu 19, X = OAc

N

X

N

Ru O

O Ar Ar

F

20, X = CO; Ar =

Me F

Figure 2.4 Chiral catalysts for asymmetric alkene aziridination.

j17

j 2 Three-Membered Heterocycles. Structure and Reactivity

18

Chloramine-T

( )n

CH3 CN, rt bromine catalyst (see Table 2.3)

21

( )n

NTs

22

Scheme 2.4 Bromine-catalyzed aziridination.

(Scheme 2.4). For example, when cyclohexene is treated with Chloramine-T trihydrate in the presence of substoichiometric quantities of hydrogen peroxide and hydrobromic acid, the corresponding bicyclic aziridine is produced in good yield (Table 2.3, entry 1). The process involves the in situ generation of hypobromous acid, which in turn gives rise to bromonium intermediates [61]. N-Bromosuccinimide is also a competent catalyst in this regard (entry 2) [62]. Both of these protocols might be seen as modifications to an earlier report by Sharpless [63], which describes the use of phenyltrimethylammonium bromide (PTAB) as both bromine source and phasetransfer catalyst (entry 3). The Sharpless protocol is in some ways complementary to prior art. For example, methylcyclohexadiene oxide (23) can be aziridinated in good yield using ChloramineT trihydrate and catalytic amounts of PTAB (Scheme 2.5), a conversion that failed using PhI¼NTs and Cu(acac)2. Interestingly, only the trans aziridino epoxide (i.e., 24) is observed, presumably due to preferential formation of the cis-epoxy bromonium intermediate 25, which has been calculated to lie about 2.4 kcal mol1 lower in energy than the corresponding trans isomer [64].

1.1 TsNClNa·3H 2 O

O

PTAB (10 mol%) CH3 CN, 12 h, rt 67%

23

O

NTs

O

Br

via

24

25

Scheme 2.5 Aziridination of epoxyalkenes.

Some progress has been made in using sulfonamides as starting materials for aziridination. Thus, the pyridinesulfonamide 26 is converted into a nitrene precursor (i.e., 28) in situ using commercially available iodosobenzene diacetate as an oxidant, providing aziridine 27 in very good yield (Scheme 2.6). Another notable aspect of this Table 2.3 Reaction conditions for bromine-catalyzed aziridination.

Entry

n

Catalyst (loading mol.%)

Chloramine-T type

Olefin : nitrene

Time (h)

Product

Yield (%)

Reference

1 2 3

2 2 1

H2O2/HBr (20) NBS (20) PTAB (30)

trihydrate anhydrous anhydrous

1 : 1.3 1 : 1.0 1 : 1.1

5 3 12

22b 22b 22a

75 82 86

[53] [54] [55]

2.1 Aziridines 10 (1.2 eq.) 1.0 PhI (OAc)2 N

S O2

NH 2

0.03 Cu(tfac)2 CH3 CN, rt 12 h 84%

26

N

S O2

N

Ph

via

N

SO2

[Cu] N

28

27

Scheme 2.6 Chelating sulfonamides.

system is that it obviates the need for external ligands and bases, since the pyridyl nitrogen provides intermolecular chelation. The free aziridine can be accessed by deprotection using magnesium in methanol [65]. A copper-catalyzed aziridination of tosylamides using iodine has also been reported [66]. DuBois and Guthikonda [67] have developed a similar rhodium-based strategy for the aziridination of sulfonamides, which they have applied to various unfunctionalized alkenes. With v-butenyl sulfonamide 29a, an intramolecular process can ensue to provide the bicyclic aziridine in good yield (Scheme 2.7). These and other investigations have shown the process to be stereospecific (Table 2.4, entry 2), whereby alkene geometry is preserved in the product [68]. Moreover, existing chiral centers can impose diastereoselectivity, as shown by the intramolecular aziridination of alkenyl sulfonamide 29c, which proceeds with a 10 : 1 syn : anti ratio [69].

O

O2 S

NH 2

O

conditions (see Table 2.4)

R1 R2

29a, R1 = R 2 = H 29b, R1 = H; R2 = Et 29c, R1 = Me; R2 = octyl

R1

O2 S

N

R2

H

30

Scheme 2.7 Intramolecular aziridinations.

The Padwa group has reported that the analogous intramolecular aziridination of cycloalkenyl carbamates proceeds without the need of a metal catalyst (Scheme 2.8). Thus, cyclohexenyl carbamate 31a underwent clean conversion into the tricyclic heterocycle 32a upon treatment with 2 equivalents of iodosobenzene [70] (Table 2.5,

Table 2.4 Reaction conditions for intramolecular aziridinations.

Entry

Substrate

Catalyst (loading mol.%)

Oxidant

Solvent

Yield (%)

Reference

1 2 3

29a 29b 29c

Rh2(tfacam)4 (1) Cu(CH3CN)4PF6 (10) Rh2(Ooct)4 (2)

PhI(OAc)2 PhI¼O PhI(OAc)2

Benzene CH3CN CH2Cl2

84 80 84

[59] [60] [61]

j19

j 2 Three-Membered Heterocycles. Structure and Reactivity

20

O O

O

O N

conditions

NHR

(see Table 2.5)

31a, R = H 31b, R = Ts

32

Scheme 2.8 Intramolecular aziridination of carbamates.

Table 2.5 Reaction conditions for the intramolecular aziridination of carbamates.

Entry

Substrate

Conditions

Yield (%)

Reference

1 2

31a 31b

PhIO (2.0 eq), CH2Cl2, 40
C K2CO3 (7 eq), Rh2(OAc)4 (5 mol %), acetone, 25
C

75 79

[71] [72]

entry 1). A similar rhodium-catalyzed variant has been reported for N-tosyloxycarbamates [71] (Table 2.5, entry 2). Electron-deficient olefins often require different conditions for efficient aziridination than their unactivated counterparts. Along these lines, while certainly not limited to electron-poor alkenes, N-aminophthalimide (34) acts as a versatile nitrogen donor for aziridinations under various oxidizing conditions. The classical protocol involves the mild but environmentally questionable reagent lead tetraacetate [72], under which conditions the active aziridinating agent is believed to be an N-acetoxy species rather than a nitrene [73]. Meanwhile, other innovative methodologies have evolved. For example, using the conventional oxidant of iodosylbenzene diacetate (Table 2.6, entry 1), chalcone (33) is aziridinated in excellent yield (Scheme 2.9) [74].

Table 2.6 Reaction conditions for phthalimide aziridinations.

Entry

Eq 34

Oxidant (loading where appropriate)

Additive

Solvent

Time (h)

Yield (%)

Reference

1 2

1.4 1.4

K2CO3 K2CO3

CH2Cl2 CH2Cl2

12 12

93 94

[65] [66]

3

1.3

PhI(OAc)2 (1.5 eq) p-MeOPhI/mCPBA (1.4 eq) þ 1.80 V (vs. Ag wire)

Et3NHOAc

CH3CN

4

83

[67]

2.1 Aziridines

O O N

+ Ph

Ph

Pth O N

conditions (see Table 2.6)

NH2

Ph

Ph O

33

34

35

Scheme 2.9 N-Aminophthalimide as nitrogen donor.

These conditions have also been used to advantage for the aziridination of allylic alcohols [75]. The hypervalent iodine reagent can also be generated in situ by combining equimolar amounts of p-iodoanisole and m-chloroperbenzoic acid (entry 2) with no negative impact on yield [76]. An even more atom-economical approach can be realized using electrochemical conditions (entry 3), a stereospecific process that has been described as a click preparation of aziridines [77], and which may proceed via a nitrene intermediate [78–80]. A similarly efficient oxidation has been reported using superoxide ion [81]. Addition of the chiral camphor-derived ligand 36 (Scheme 2.10) can result in an enantioselective process. Thus, the unsaturated oxazolidinone imide 37 is converted into the corresponding aziridine (38) in good yield and impressive enantiomeric excess. By comparison, ( þ )-tartaric acid gave only 42% ee. The choice of solvent is important, as migration to THF results in no loss of yield but an almost total disappearance of enantioselectivity [82]. Chiral bis(oxazoline) (BOX) ligands allow for a tunable aziridination of chalcones (Scheme 2.11) merely by changing the connecting backbone moiety (Figure 2.5). Thus, use of the cyclohexyl catalyst 41 provides the 2R,3S product (Table 2.7, entry 1) with very good enantioselectivity [83], while the anthracene derivative 42 yields the Me

HO 2 C

Me

N

36

O O

Ph

37

Me

CO 2H

Me

1.5 eq 34 1.6 eq 36 1.6 eq Pb(OAc) 4

O N

N

CH2 Cl2, 0°C 5 min 83% yield 95% ee

O O

O

H

N H

N

Ph

Pth

38

Scheme 2.10 Asymmetric N-aminophthalimide-mediated aziridination.

j21

j 2 Three-Membered Heterocycles. Structure and Reactivity

22

Ts

PhI=NTs CuOTf chiral ligand

O Ph

N *

CH2Cl2 (see Table 2.7)

Me

O Ph

*

Me 39

40

Scheme 2.11 Tunable BOX-mediated asymmetric aziridination.

O

O N

Ph

O

N

Ph

N

N

O

i-Pr i-Pr

41, S-cHBOX

42, AnBOX

Figure 2.5 cHBOX and AnBOX ligands.

other antipode with even better yield and enantioselectivity (entry 2). The origin of this interesting crossover has been rationalized on the basis of a more crowded steric environment in the latter case [84]. The scope of the organocatalytic asymmetric aziridination of enones has been expanded to substrates other than chalcones by using a hydroquinine-derived catalyst and N-protected hydroxylamine tosylates as nitrogen donors [85]. Cinnamate esters can be aziridinated using axially dissymmetric binaphthyldiimine copper(I) catalysts, such as those derived from salen-type ligand 43 (Scheme 2.12). Thus, trans-t-butyl cinnamate (44) was aziridinated stereospecifically and enantioselectively to provide the product in excellent yield [86]. A later report from another set of investigators using essentially identical conditions gave the same high enantioselectivity but significantly lower yield [87].

Table 2.7 Reaction conditions for tunable BOX-mediated asymmetric aziridination.

Entry

PhI¼NTs (eq)a)

CuOTf (eq)a)

Ligand (loading mol.%)a)

Time (h)

Yield (%)b)

Configuration

ee (%)

Reference

1 2

0.67 0.67

0.03 0.03

41 (4) 42 (4)

5 5

62 86

2R,3S 2S,3R

94 98

[71] [72]

a) Based on olefin. b) Based on PhI¼NTs.

2.1 Aziridines Cl

N Cl Cl N

43

PhI=NTs 0.05 Cu(MeCN) 4 BF4 43 (5 mol%)

O Ph

Cl

CH2 Cl2 -20°C, 24 h 91% yield 97% ee

Ot-Bu

44

Ts N

O

Ph

Ot-Bu

45

Scheme 2.12 Asymmetric aziridination of cinnamate esters.

Diactivated alkenes can be converted into aziridines by a somewhat different set of conditions. For example, in the presence of calcium oxide, ethyl nosyloxycarbamate (46) functions as a nitrogen source that engages Knoevenagel adducts (e.g., 47) in aziridination (Scheme 2.13), presumably via nitrene intermediates [88]. Modest diastereoselectivities have been achieved by incorporating a menthol-derived chiral auxiliary into the carbamate reagent. Unfunctionalized alkenes give the products of nitrene CH insertions under the same conditions [89]. O O 2N

CN

O S O2

46

O

N H

+

2.0 CaO CO 2Et

OEt

47

CH 2Cl 2 r.t., 2 h 93%

OEt N

H

CN CO 2 Et

48

Scheme 2.13 Aziridination of diactivated alkenes.

2.1.2.2 Aziridination of Imines Another powerful approach to the aziridine moiety is through the aziridination of imines using carbene- or ylide-type species [90–92]. One very popular carbene precursor is the commercially available ethyl diazoacetate (49). This species can be induced to react with imines to form aziridines (Scheme 2.14) under various conditions, including indium trichloride in methylene chloride [93], lanthanide triflates in protic media [94], boron trifluoride in ether [95], a cyclopentadienyl iron(II) dicarbonyl complex [96], a bis(cyclooctadienyl) iridium(II) chloride complex [97] and

j23

j 2 Three-Membered Heterocycles. Structure and Reactivity

24

Ph

O conditions N

N

OEt

N

(see Table 2.8) Ph

H 49

CO2Et 50

Scheme 2.14 Racemic aziridination using ethyl diazoacetate.

Table 2.8 Reaction conditions for racemic aziridinations with ethyl diazoacetate.

Entry

Aldimine components

Catalyst (loading mol.%)

Solvent

Time (h)

Yield (%)

Reference

1 2 3

PhCH¼NPh PhCH¼NPh PhCH¼O þ PhNH2

SnCl4 (1) None LiClO4 (10)

CH2Cl2 bmimPF6 CH3CN

n.r. 5 4.5

>90 93 89

[84] [85] [86]

copper(II) triflate in methylene chloride or tetrahydrofuran [98]. These reactions are often very high-yielding, as demonstrated by the tin(IV) chloride mediated reaction of ethyl diazoacetate with N-phenylbenzaldimine (Table 2.8, entry 1), which proceeds with a Z : E selectivity of 15 : 1 [99]. Interestingly, when the same reaction is run using an ionic liquid as solvent (entry 2), the reaction does not require the addition of a catalyst. In this case, the solvent itself is presumed to fulfill the role of Lewis acid [100]. An operationally attractive procedure has been reported in which the aldimine is formed in situ using lithium perchlorate as a catalyst (entry 3), providing exclusively the cis isomer [101]. Acive methylene compounds serve as useful carbenoid precursors (in the form of phenyliodonium ylides) by treatment with iodobenzene diacetate and a catalytic amount of base under very mild conditions. Thus, tosylaldimines are converted into the corresponding aziridines in a one-pot procedure without the need for a metal catalyst [102]. Some noteworthy asymmetric protocols have been developed using diazoesters, particularly those employing vaulted biaryl ligands [103]. For example, a catalyst derived from (S)-VAPOL (51) and BH3THF complex promotes an enantioselective aziridination reaction between ethyl diazoacetate and N-diphenylmethyl p-bromobenzaldimine (52) with very good yields, almost exclusive cis selectivity and excellent enantiomeric excess (Scheme 2.15). Curiously, impure commercial samples of BH3THF give the best results [104]. Recent crystallographic evidence in an analogous system suggests an unexpected boroxinate species as the active catalyst, the formation of which should be facilitated by adventitious water in the commercial boron reagent [105].

2.1 Aziridines Ph Ph

OHHO

51, (S)-VAPOL

Ph

O N

OEt

N

+

p-BrPh

51 / BH3 (10 mol%) CH2 Cl2 / toluene r.t., 5 h 91% yield 98% ee Z/E > 50:1

Ph

H

49

52

O N

Ph

N

N

O O

54

+

N H

N p-BrPh

CO 2 Et

53

p-BrPh

OH p-BrPh

Ph

BF 3·OEt 2 CF 3

55

CH2 Cl2 -40°C 83% yield 92% de

N

CO2 Xc

F3C

56

Scheme 2.15 Chiral aziridination using diazoesters.

An alternative approach to asymmetric induction is to attach a chiral auxiliary to the diazoester itself, as exemplified by the (R)-pantolactone derived ester 54. Using boron trifluoride as a Lewis acid catalyst, the trifluoromethyl hemiaminal 55 is converted into the corresponding imine and subsequently aziridinated to give products (i.e., 56) in high yield and diastereomeric excess [106]. Other carbon donors for the aziridination of aldimines can be drawn from the ranks of ylide haloanions. For example, the chloroethylthiazole derivative 57 (Scheme 2.16) can be deprotonated with n-butyllithium to give an anion that reacts with N-phenylbenzaldimine (58) to provide the corresponding cis-aziridinyl thiazole 59 in good yield [107]. In an asymmetric variant of this protocol, the anion derived from chloromethyl benzothiazole 60 adds to the chiral aldimine 61 in a highly diastereoselective fashion [108]. In the same vein, Davis has reported the aza-Darzens reaction between the lithium anion of diethyl iodomethylphosphonate (63) and chiral non-racemic arylsulfinyl imines (e.g., 64), which proceeds in good yield and excellent diastereomeric excess [109, 110]. An analogous reaction occurs between t-butylsufinyl imines and the ylide derived from trimethylsulfonium iodide [111] or ylides derived from substituted allyltetrahydrothiophenium salts, which provide access to chiral non-racemic vinyl aziridines [112].

j25

j 2 Three-Membered Heterocycles. Structure and Reactivity

26

Cl S

Me

Ph

+

N

N

Me

57

nBuLi Ph

THF -78°C 84% yield Z/E 100:1

58

Ph

Cl

S

Ph

N

+ N

OMe

60

61

N

N

O I

+

Ph

N

S

Ar

O

O

OTf

66

+

S

NTs

t-Bu

Ph LDA THF -78°C 90% yield > 96% de

OMe N

H

H

Hetaryl

Ph

62

LiHMDS

H

-78°C 78% yield 96% de

Ph

O

S N

H

P(OEt)2 O

65

EtP2 CH2Cl 2 80% yield 98.7% ee

Ph

H

59

64, Ar = mesityl

63

Ph

Me

Ar

(EtO) 2 P

Ph

S

Me

67

Ts H

Ph

N

H t-Bu

68

Scheme 2.16 The ylide/haloanion approach to aziridines.

The chiral sulfur ylide approach has been developed less for aziridine chemistry than for epoxides; nevertheless, some very useful strategies have been pioneered, largely by Dai and Aggarwal [113, 114], and new methodologies continue to appear on the scene. For example, the chiral S-benzyl sulfonium triflate 66 can be deprotonated with the commercially available phosphazene base Et2P to give an ylide that aziridinates N-tosyl pivaldimine (67) in good yield and excellent enantioselectivity [115]. Aggarwal and Vasse have applied a catalytic version of the sulfur ylide methodology to the synthesis of the taxol side chain [116] which uses a novel camphorderived ylide scaffold [117]. The cis : trans ratios in these reactions are very substratedependent. A recent computational study of this reaction manifold provides a useful theoretical framework in good agreement with observed experimental results [118]. The catalytic strategy has also been adapted to novel arsonium ylides [119]. The substrate dependent nature of cis : trans ratios is not limited to sulfur ylide chemistry. A particularly striking example is seen in the reaction of the anion from camphorsultam bromoacetamide 69 with various o-substituted benzaldimines 70 (Scheme 2.17). Both the phenyl and the nitrophenyl derivatives give exclusively cis-

2.1 Aziridines Me

O

O

R +

N

Br

Me

N

SO 2

LiHMDS PPh 2 O

69

THF -78°C

PPh 2 N

H

70

H (see Table 2.8 for yields) Ar

Xc O

71

Scheme 2.17 Camphorsultam as chiral auxiliary in aziridination.

Table 2.9 Yield data for camphorsultam-mediated aziridination.

Entry 1 2 3 4

j27

R

Yield (%)

Cis : trans ratio

H NO2 Me OMe

71 72 87 65

100 : 0 100 : 0 50 : 50 0 : 100

aziridines (Table 2.9, entries 1 & 2), whereas the o-anisole imine provides solely the trans isomer (entry 4), and the o-tolyl analog yields an equimolar mixture of diastereomers (entry 3). The mechanistic underpinnings for this selectivity are not well understood, but are believed to derive from a complex mixture of polar, steric and chelation effects [120, 121]. 2.1.2.3 Ring Closure of Amines The synthesis of aziridines via the ring closure of 2-aminoalcohols has been known for three-quarters of a century [122], and the method has been adapted for such activating agents as triphenylphosphine dibromide [123], diphosphorus tetraiodide [124], the Mitsunobu reagent [125] and molecular sieves [126, 127]. This time-honored approach is, however, still in currency. For example, the chiral nonracemic aminoalcohol 72 (Scheme 2.18) derived from alanine [128] undergoes double tosylation and ring closure in one pot to provide the corresponding Ntosylaziridine (73) in excellent yield [129]. Similarly, the N-(t-butoxycarbonyl)-N-(2nitrobenzenesulfonyl) aminoalcohol 74, derived from the ring-opening of an epoxide, undergoes a sequence of deprotection, O-mesylation and carbonate-mediated ring closure to give aziridine 76, proceeding with inversion of configuration and no loss in optical activity [130]. This concept of ring closure is, of course, open to any good leaving group. For example, an interesting protocol has been reported in which an N-2-bromoalkylimine (e.g., 78), prepared by the addition of the 2-bromoalkylamine hydrobromide to an aldehyde (e.g., 77), suffers nucleophilic attack by methoxide to give an incipient imide anion that engages in immediate 3-exo-tet ring closure [131]. Cyclization of a 2bromoalkylamine is also at the heart of an aziridination of simple amines, such as ammonia, which engages in a tandem series of conjugate addition and ring closure

j 2 Three-Membered Heterocycles. Structure and Reactivity

28

Ts

NH2

N

TsCl

OH

Et3N CH3CN 94%

(S)-72 OH

Boc N

n-Bu

2. Ms2O pyr DMAP

Ns

n-Bu

Et 3N / MgSO 4 CH2 Cl2 0°C, 7 h

77

O Me

N

O

H N

Ns

(R)-76

N

Me

NaOMe

Xc O

81

O

Me

O N

HN

OBn

H N

TiCl4 Me

Ph

Xc

Et 3N CH2Cl 2 96% yield

TsNCl 2 Cu(acac) 2 MeCN

Me O

82

CO 2 Me

79

Me

80

N

N

MeOH ∆, 2 h 71% overall

H N

NH3 DMSO 1.5 h 95% yield 84% de

Ph

OMe

p-Tol

Br

78

Br

Me

N

H 2O/THF ∆ n-Bu 80% overall

p-Tol

N

Me

Ns K2 CO 3

(S)-75

(CH 3 )2CBrCH 2NH2 ·HBr H

p-Tol

OMs

1. TFA

(S)-74

O

(S)-73

81 CO2Me

Na2 SO3 Cl

83

N H

84

Ts

Ts aq NaOH 80% overall

N CO 2 Me

85

Scheme 2.18 Aziridines from ring-closing protocols.

reactions with the chiral a-bromoamide 80 to provide aziridine 81 with good diastereoselectivity [132]. This methodology has also been adapted to a solid-phase protocol using Wang resin derivatives [133]. The same chiral auxiliary can be used to advantage in the synthesis of chiral b-amino acid precursors (e.g., 82), which can be converted into the corresponding

j29

2.1 Aziridines

amino acids by zinc-copper reduction of the NO bond and lithium peroxide hydrolysis of the amide linkage [134]. However, in the presence of a suitable Lewis acid, 82 is converted into aziridine 81 with remarkable efficiency [135]. Aziridinyl esters (e.g., 85) are conveniently prepared from methyl acrylate (83) or its derivatives by the copper-catalyzed addition of N,N-dichlorotosyl sulfonamide and subsequent ring closure [136]. Alternatively, these products can be accessed by treating a,b-dibromoesters with simple primary amines [137]. 2.1.2.4 Ring Contraction of Other Heterocycles Aziridines can be accessed through the extrusion of elements from larger nitrogenous heterocycles, most notably triazolines. Thus, for example, azanorbornene 86 undergoes 1,3-dipolar cycloaddition with phenyl azide to yield a 2 : 3 mixture of regioisomeric tricyclic triazolines in quantitative combined yield (Scheme 2.19). Photolysis of these compounds in a quartz reaction vessel using a mediumpressure mercury lamp led to efficient formation of the fused tricyclic aziridine 88 [138].

PhN 3 N Bn

CH 2Cl2 20°C 5d quant.

N

N

PhN H

H

N N Bn 2

86

+

NPh

N H

:

H

hν

PhN

acetone 4h 90%

N Bn

H

H

N Bn

3

87a

87b

88

Scheme 2.19 Azide addition and ring contraction.

The rather sluggish initial cycloaddition is accelerated significantly by tethering the dipole to the dipolarophile, as seen with the v-alkenylaryl azide 89a (Scheme 2.20), which undergoes complete cycloaddition within 3 h in refluxing toluene [139]. Even with very highly functionalized substrates (Table 2.10), the cycloaddition step proceeds with excellent yield and complete diastereoselectivity, the latter presumably the result of a preferred chair-like reactive conformer in which the TMS group adopts a pseudo-equatorial attitude [140]. Subsequent irradiation with a Hanovia lamp afforded the corresponding aziridines 91 in fair yield.

R 2 R3

R2

OH TMS

N3

89

R2

OH

toluene reflux

R1

R3

TMS R1

H

N N

R3

benzene r.t.

TMS R1

N

N

90

Scheme 2.20 Intramolecular azide addition and ring contraction.

OH

hν

91

H

j 2 Three-Membered Heterocycles. Structure and Reactivity

30

Table 2.10 Yield data for intramolecular azide addition and ring contraction.

Entry

Substrate

R1

R2

R3

Yield 90 (%)

Yield 91 (%)

Reference

1 2

89a 89b

H CH2OBn

H OBn

H CH2OBn

90 99

77 68

[118] [119]

Molteni and Del Buttero [141] have reported the direct aziridination of ethyl acrylate (93, Scheme 2.21) using an alkyl azide supported on poly(ethylene glycol) monomethyl ether (92), which they suggest proceeds through the intermediacy of a triazole. In their studies of triflic acid mediated aziridination of electron-deficient alkenes, however, Johnston and coworkers [142] propose an intriguing concerted mechanism involving a multicentered transition state (i.e., 96).

N3

+

92

O

TfOH EtCN, 0°C

95

N

70°C 16 h 87%

93

BnN3 Me

toluene CO 2 Et

δ + Bn δ + H N2 O N Me 96

CO 2 Et 94

Bn 92%

NH

O

OTf Me

97

Scheme 2.21 Direct aziridination with alkyl azides.

2.1.3 Reactivity of Aziridines

The reactions of aziridines are legion, but most fit into a few broad categories: (i) nucleophilic ring opening, (ii) N-substitution, (iii) aziridinyl anion chemistry and (iv) ring expansion to larger heterocyclic species . Although no longer the most recent, a review of the synthetic applications of chiral aziridines by McCoull and Davis [4] still offers an excellent overview of the diverse field of aziridine chemistry. A more recent (but more specialized) chapter on aziridinecarboxylate esters is equally worthwhile [143]. 2.1.3.1 Nucleophilic Ring Opening Perhaps the most common of aziridine reactions is the ring opening by nucleophiles. This topic has been reviewed recently and fairly comprehensively by Hu [144], and an interesting computational study on CN vs. CC bond cleavage has been published [145]. Some illustrative synthetic examples are given here.

2.1 Aziridines

j31

Ring opening can be used as a means of carbon–carbon bond formation when carbon-based nucleophiles are employed [146]. For example, in the presence of catalytic amounts of cuprous iodide, phenyllithium attacks the less substituted site of the N-tosyl aziridine 98 (Scheme 2.22) to give the corresponding protected amine [147]. The analogous addition of Grignards onto meso-aziridines (e.g., 22b) Ts N

PhLi CuI (15 mol%) THF 75%

Me

Me

99

98 Ph

N O

Cu O

O

O

O Cu

NTs

O

N

Ph

NHTs

Ph

MeMgBr 100 (30 mol%)

NHTs

THF 0°C 52% yield 91% ee

22b

Me

101

100

Ts N

+

Ph

NHTs

CuOTf (10 mol%) Et2O 20 h 93%

n-hexyl

102

Ph

n-BuLi

H

103

n-hexyl

104

O

O O TsN

S +

S

O

105

O

Li

THF 4h 90%

106

O

S S

TsN

107

NHTs

NTs BF 3·OEt2

108

O O

CH2 Cl 2 0°C -> r.t. 2h 92%

Scheme 2.22 Ring opening of aziridines with carbon nucleophiles.

109

j 2 Three-Membered Heterocycles. Structure and Reactivity

32

can exhibit impressive enantioselectivity under the influence of the Schiff base/ amino acid copper(II) complex dimer 100, although relatively high catalyst loadings must be used [148]. Acetylide anions are also competent nucleophiles when a copper(I) catalyst is used, as demonstrated by the high-yielding conversion of the 2-alkylaziridine 102 into the homopropargylamine 104, resulting from attack at the less hindered carbon [149]. Wu and Zhu have used the diastereoselective addition of an aryl Grignard onto a chiral aziridine as a key step in their total synthesis of (–)-renieramycin M and G and (–)-Jorumycin [150]. This exclusive regioselectivity was used to advantage in an approach to 1-deoxymannojirimycin analogs from deoxyglucitol-derived aziridine 105, which engages in a very well-behaved reaction with 1,3-dithiane anion 106 [151]. Similar regiochemical outcomes are observed for cyanide addition using stoichiometric trimethylsilyl cyanide (TMSCN) and tetrabutylammonium fluoride (TBAF) in catalytic amounts [152], as well as an enantioselective protocol used to alkylate active methine compounds with unsymmetrical aziridines under mild basic conditions using a cinchona derived phase-transfer catalyst [153]. The regioselectivity of ring opening can be reversed under more cationic conditions, however, as illustrated by the Lewis acid-promoted intramolecular ring-opening reaction of phenypropylaziridine 108, in which the product outcome is doubly supported by the stability of the Friedel-Crafts-like transition state and geometric considerations [154]. The same regiochemistry is observed in the iron(III)-catalyzed attack of electron-rich arenes onto unsymmetrical C-aryl aziridines [155]. Heteroatomic nucleophiles are equally useful in unlocking the synthetic utility of the aziridine ring. For example, 22b reacts smoothly with aniline to provide the corresponding diamine 110 (Scheme 2.23) under various mild conditions (Table 2.11), including bismuth trichloride in acetonitrile [156], indium tribromide in methylene chloride [157], and lithium perchlorate in acetonitrile [120, 158]. Aqueous conditions have been developed using a cyclodextrin catalyst [159], and silica gel allows for a completely solventless system [160]. NHTs

PhNH2 NTs

conditions (see Table 2.11)

22b

NHPh 110

Scheme 2.23 Ring opening of aziridines with aniline. Table 2.11 Yield data for ring opening of aziridines with aniline.

Entry

Reagent/catalyst

Solvent

Time (h)

Yield (%)

Reference

1 2 3 4 5

BiCl3 InBr3 LiClO4 b-Cyclodextrin Silica gel

CH3CN CH2Cl2 CH3CN H2O/Me2C¼O none

1.5 5.5 5.5 24 1

96 90 90 89 91

[130] [131] [132] [133] [134]

2.1 Aziridines

The asymmetric ring-opening of meso aziridines such as 22b is a useful approach for accessing variously substituted chiral amines, and it has been the subject of some very good reviews [144, 146, 161]. One recently reported protocol involves the use of a titanium binolate catalyst, which can achieve ees of 99% [162]. Still other conditions have been worked out for alkylamines, as exemplified by addition of benzylamine (Scheme 2.24). In what may be one of the biggest catalyst sleepers of the century, the commercially available tris(pentafluorophenyl) borane [163] has escaped the niche of specialized polymerization catalysis and now finds application in various other useful synthetic transformations, including the ring opening of aziridines with simple amines (Table 2.12, entry 1). Interestingly, the active catalytic species involves a water-borane complex [164]. Other novel protocols for this reaction include ceric ammonium nitrate (CAN) in acetonitrile [165] and tributyl phosphite in an organic/aqueous medium [166]. Microwave conditions have been developed using resin-bound alkylamines in a protocol suitable for parallel synthesis [167]. NHTs NTs

PhCH2NH2 conditions (see Table 2.12)

22b

NHBn 111

Scheme 2.24 Ring opening of aziridines with benzylamine.

Azide is also a popular nitrogen-based nucleophile by virtue of its relatively low basicity, high nucleophilicity and ability to undergo subsequent reduction to the primary amine (i.e., a surrogate for ammonia). To achieve virtually neutral conditions, trimethylsilyl azide can be used as the source of azide (Table 2.13, entry 1), along with catalytic amounts of tributylammonium fluoride (TBAF) to liberate the azide in situ [152]. Of course, sodium azide itself can be used as a reactant, with the addition being promoted efficiently by cerium trichloride heptahydrate [168], lithium perchlorate [169] or Oxone [170] (Scheme 2.25). Meso aziridines can be enantioselectively desymmetrized using a dimeric salen yttrium catalyst in near quantitative yield and excellent enantioselectivity [161]. Synthetically useful b-aminoalcohols and aminoethers can be obtained by using oxygen-centered nucleophiles in the ring-opening reaction, and several mild and

Table 2.12 Yield data for ring opening of aziridines with benzylamine.

Entry

Reagent/catalyst

Solvent

Time (h)

Yield (%)

Reference

1 2 3

B(C6F5)3 CAN PBu3

CH3CN CH3CN H2O/CH3CN

12 3 12

99 93 99

[136] [137] [138]

j33

j 2 Three-Membered Heterocycles. Structure and Reactivity

34

Table 2.13 Yield data for ring opening of aziridines with azide.

Entry

Azide source

Additive

Solvent

Time (h)

Yield (%)

Reference

1 2 3 4

TMSN3 NaN3 NaN3 NaN3

TBAF (5 mol.%) CeCl37H2O LiClO4 Oxone

THF CH3CN CH3CN H2O/CH3CN

6 6 6 3

97 90 90 89

[128] [139] [140] [141]

NHTs

conditions

TsN

(see Table 2.13)

N3

112

113

Scheme 2.25 Ring opening of aziridines with azide.

efficient methods have been reported to effect this transformation. For example, the alcoholysis of phenylaziridine 11 (Scheme 2.26) is promoted by ceric ammonium nitrate (Table 2.14, entry 1), which is effective for both alcohols [171] and water [165]; boron trifluoride etherate (entry 2) or tin(II) triflate [172]; montmorillonite KSF clay (entry 3), which serves as a solid-supported mild acid catalyst [174]; phosphomolybdic acid (PMA) on silica gel (entry 4), which gives excellent yields with various aziridines and alcohols [178]; and copper(II) triflate (entry 5) [175]. The watertolerant bismuth(III) triflate is particularly well suited to catalyze hydrolysis reactions (entry 6) [176]. Note that in all cases the oxygen is attached to the benzylic position. With branched alkylaziridines (e.g., cyclohexylaziridine) the regioselectivity is reversed. Ring opening can also occur under basic conditions in the absence Ts N

OR ROH conditions (see Table 2.14)

Ph 11

TsN Ph 114

Scheme 2.26 Ring opening of aziridines with alcohols. Table 2.14 Yield data for ring opening of aziridines with oxygen-centered nucleophiles.

Entry

R

Catalyst

Solvent

Yield (%)

Reference

1 2 3 4 5 6

Me Me Et t-Bu CH2CH2Cl H

CAN BF3OEt2 KSF PMA/SiO2 Cu(OTf)2 Bi(OTf)3

MeOH MeOH CH2Cl2 MeCN HOCH2CH2Cl MeCN/H2O

90 99 86 94 87 88

[142] [143] [144] [145] [175] [176]

2.1 Aziridines

j35

of a Lewis acid catalyst, in which case nucleophilic attack occurs at the less hindered position [177]. It was discovered that the regiochemistry of the hydrolysis of a-aminoaziridine 115 (Scheme 2.27) could be controlled by manipulation of the reaction conditions. Thus, use of a protic acid (such as p-toluenesulfonic acid) led to attack at the terminal carbon, presumably via the highly reactive aziridinium salt, yielding the hydroxydiamine 116. In contrast, if a classic Lewis acid was employed (e.g., boron trifluoride etherate) the opposite regiochemistry predominated, providing the secondary alcohol 117. The stereochemical outcome for the latter product was rationalized on the basis of a double inversion from anchimeric assistance by the dibenzylamino substituent [179].

NHBn OH NBn 2

116

NBn

pTsOH CH3 CN/H 2O (78% yield)

NBn 2

115

1. BF3·OEt2, CH 3CN, ∆ 2. NaHCO 3, H 2O

OH NHBn NBn 2

117

Scheme 2.27 Tunable hydrolysis conditions.

The scope is by no means limited to carbon, nitrogen and oxygen-centered nucleophiles. The nucleophilic palette embraces sulfur-based species, such as thiocyanates and thiols, the addition of which is promoted by a heterogeneous recyclable sulfated zirconia catalyst [180] and poly(ethylene glycol) [181]. The regiochemistry tends to follow the conventional course, with benzylic attack dominating for arylaziridines and terminal attack for alkylaziridines. Thiols can also engage in the enantioselective ring-opening of aziridines under the catalysis of a VAPOL phosphoric acid derivative [182]. The aziridine ring can also be cleaved by phenylselenide [183], reductively cleaved under transfer hydrogenation conditions [184], or opened with halides under fairly straightforward conditions, such as tetrabutylammonium fluoride in DMF [185], aqueous HCl in acetone [186], magnesium bromide in ether [187], and indium triiodide in acetonitrile [188]. 2.1.3.2 N-Elaboration Reactions Aziridines bearing no N-substituent can be elaborated in various ways. For example, cyclohexene imine (118) engages in conjugate addition onto methyl acrylate under solvent-free conditions (Scheme 2.28, route a), although two equivalents of the Michael acceptor is needed [164]. The same aziridine undergoes smooth palladiumcatalyzed allylation with prenyl acetate, whereby the electrophile is captured at the more substituted terminus (route b), although this regiochemistry is substratedependent [189]. N-Arylation is also possible using a palladium/BINAP protocol (route c), in which aryl bromides and arylboronic acids act as suitable reaction partners [190].

j 2 Three-Membered Heterocycles. Structure and Reactivity

36

CO 2Me N

119

a

Cl c

N

NH

121

118

b

N

120 Scheme 2.28 N-Elaboration of cyclohexene imine (Table 2.15). Table 2.15 Conditions for N-elaboration of cyclohexene imine.

Entry Route Electrophile

Catalytic system

Solvent

Yield (%) Reference

1

a

None

Neat

89

[136]

2

c

[Pd(g3-C3H5)Cl]2, BINAP

THF

89

[153]

Pd(dba)3, BINAP, t-BuONa Toluene 95

[154]

CO2 Me

AcO

Cl 3

b

Br

Many other protocols exist in which unprotected aziridines function as nucleophiles, including alkylations using epoxides [191] or alkyl bromides [192] as electrophiles. N-Acylation can be effected with acyl chlorides [193] or a combination of carboxylic acid and dicyclohexylcarbodiimide (DCC) [3, 194] (Scheme 2.29). NHBoc O Me

N

O N

O

O

NH Me

+

HO

Ph NHBoc

Me

Ph

O

DCC CH2 Cl2 / CH3 CN r.t., 12 h (> 95% yield)

Me

N

Me

122

123

Scheme 2.29 N-Acylation using DCC.

O

Ph N

N

Me

Ph

124

2.1 Aziridines

2.1.3.3 Azirdinyl Anion Chemistry Aziridinyl anion chemistry is of growing interest, as evidenced by its inclusion in a symposium-in-print [195]. Hodgson et al. have also authored a noteworthy review dedicated to this topic [196], to which the reader is directed, and computational studies on the physical properties of aziridinyl anions are emerging [197]. Protected aziridines can be deprotonated, and the resulting carbanions add to a range of electrophiles. For example, the t-butylsulfonyl (Bus) protected pentylaziridine 125 (Scheme 2.30) is deprotonated at the less substituted carbon (i.e., more stable anion) upon treatment with an excess of lithium 2,2,6,6-tetramethylpiperidide (LTMP) at low temperature (78
C), and the lithiate adds smoothly to 3-pentanone to give the aziridinyl alcohol 126 in good yield [198]. The aziridinyl anion can also exhibit carbene-like character, so that when alkenes are tethered to the substrate (e.g., 127)

SO2t-Bu N

3 eq. LTMP

Et 2 C=O

THF -78°C

76%

SO 2t-Bu

HO Et

N

Et

125

126 NHSO 2t-Bu

SO2 t-Bu

3 eq. LTMP

N

t-BuOMe 0°C 99%

127

128 O

Ts N CF3

O

H

n-BuLi

Ts N

95%

THF -102°C

OH O CF 3

129

130

OMe

C 10H21

N

O S .. p-Tol

OMe

OMe

Ph

EtMgBr

CF3

THF -78°C

C 10H 21

N

BrMg

131 Scheme 2.30 Reactions of aziridinyl anions.

132

Ph

MeI

C 10H 21

CF 3

CuI r.t. 94%

Me

N

Ph CF 3

133

j37

j 2 Three-Membered Heterocycles. Structure and Reactivity

38

and the anion is formed at somewhat higher temperatures, a remarkably highyielding intramolecular cyclopropanation ensues [199]. When an electron-withdrawing group is attached to the aziridine ring, it directs deprotonation and stabilizes the resulting anion. Thus, aziridine 129 is lithiated adjacent to the trifluoromethyl group, after which treatment with 2-furaldehyde provides the aziridinyl alcohol 130 in excellent yield [200]. Satoh and coworkers have developed a very useful protocol involving sulfinylaziridines (e.g., 131), in which the sulfinyl group (having served as a chiral auxiliary in the prior aziridination reaction) is quantitatively removed in the presence of ethyl Grignard to give the corresponding aziridinylmagnesium bromide (i.e., 132). This anion can then be cross-coupled with alkyl iodides in the presence of cuprous iodide to give alkylated products (i.e., 133) with net retention of configuration [201, 202]. 2.1.3.4 Ring Expansions Aziridines can serve as handy templates for access to other heterocyclic subunits, and quite a few interesting methodologies have been reported. In the case of vinyl aziridines, near quantitative rearrangement to 3-pyrroline derivatives is promoted by copper(II) hexafluoroacetylacetonate in toluene at elevated temperature [203]. Another general approach to ring expansion is through cycloaddition strategies. For example, in the presence of zinc chloride, p-methoxyphenyl protected aziridine 134 (Scheme 2.31) engages in a formal [4 þ 2] cycloaddition with norbornene (135) to provide the tetracyclic piperidine 136. The mechanism proceeds through a Mannich reaction with the initially formed ylide and subsequent intramolecular Friedel–Crafts alkylation [204]. Highly substituted pyrroles can be accessed by reacting aziridines with electron-deficient allenes, a process that involves a formal [3 þ 2] cycloaddition [205]. Pyrroles are also formed by the platinum(II)-catalyzed electrophilic iodocyclization of propargylic aziridines [206]. The ylide itself can be trapped with olefins under thermal conditions [207], as demonstrated by the intramolecular 1,3-dipolar cycloaddition of the terminal aziridine 137 to give the bicyclic pyrrolidine 138 [208]. Harrity and coworkers [209] have developed a [3 þ 3] cycloaddition strategy for access to the piperidine ring system, in which a palladium-trimethylenemethane complex (derived from acetoxy trimethylsilyl methylene compounds such as 139) adds to an aziridine (e.g., 98) to form methylenepiperidines such as 140 in generally good yields. The substituent on nitrogen greatly impacts the efficiency of this reaction, with p-tosyl and p-methoxyphenyl-sulfonyl moieties providing the best results. The next broad class of transformations could be characterized as carbonyl insertion reactions (Scheme 2.32), although it encompasses the insertion of carbon monoxide and carbon dioxide through various modes. Thus, in the presence of sodium iodide, Boc anhydride serves as a carbon dioxide surrogate in the conversion of the ( þ )-pseudoephedrine-derived aziridine 141 into oxazolidinone 143, in which the stereochemistry of the ring substituents is preserved [210, 211]. Hydroxymethylaziridines (e.g., 144) can be bridged with phosgene into labile fused bicyclic oxazolidinone structures (i.e., 145), which undergo in situ nucleophilic attack by chloride to give chloromethyloxazolidinones (e.g., 146) in excellent

2.1 Aziridines

OMe

MeO 1.2 eq ZnCl 2

+ N Ph

H

CO 2 Me 135

134

CO 2 Me

N

H

CH2Cl 2 80%

CO 2Me

CO 2Me

Ph

136 OMe

BnN

O

O

OMe OBn OMe

xylene

BnN

250°C 20 min 85%

H O

137

Ts N

+

O 138

0.10 Pd(OAc)2 0.60 P(Oi-Pr) 3 SiMe 3

AcO

Me 98

OMe

139

OBn

Ts N

0.20 n-BuLi THF 82% 140

Scheme 2.31 Cycloaddition reactions of aziridines.

yield [212]. Also, gaseous carbon dioxide itself can be trapped by aziridines at atmospheric pressure using lithium bromide as a catalyst, as shown by the conversion of arylaziridine 147 into the corresponding oxazolidinone 148. The mechanism proceeds through a series of bromide-induced ring opening, carboxylation of the resulting amide anion, and alkylative ring closure [213]. This transformation has also been shown to proceed under the catalysis of a (salen) chromium(III)/DMAP complex [214]. A novel rhodium-complexed dendrimer (149) is effective in promoting the carbonylative ring expansion of aziridines to b-lactams. The near-quantitative yield exhibited by N-t-butyl-2-phenylaziridine (150) is not unusual, although relatively high pressures [approx. 27 atm (400 psi)] and elevated temperatures (90
C) are required. Nevertheless, the catalyst appears to be easily isolated and recycled without loss of activity [215]. Nitrogen and sulfur can also be introduced via ring expansion strategies. Thus, styrene imine derivative 11 engages in [3 þ 2] cycloaddition with acetonitrile in the presence of boron trifluoride etherate at room temperature to give the corresponding imidazoline (152) in good yield (Scheme 2.33) [216]. The iminothiazolidine nucle-

j39

j 2 Three-Membered Heterocycles. Structure and Reactivity

40

Me

Ot-Bu

(Boc) 2O NaI

Me N

MeN

acetone r.t.

Ph

Me N

Ph Me

O

Me

141

O

72%

1. NaH, THF, 0°C

H

Ph

143

Me

2. Cl2C=O, -78°C

O

Me

Ph

142

O

Ph

OH

MeN

N

O

91%

Me

N

Cl

Me

Cl-

146 O

CO 2 (1 atm) LiBr

Ts N

O

NMP 100°C 24 h 76%

p-Tol

147

148 (CO) 2Cl Rh Ph 2P PPh 2

N Ph2P

N O

N

O

HN

P Ph2

N H

149

t-Bu 149 Ph

150

N NH

O

N

NTs p-Tol

(CO) 2 Cl Rh Ph2P PPh 2

Cl(CO) 2 Rh

O Me

145

144

O

Ph

CO (400 psi) benzene 99%

Scheme 2.32 Carbonyl insertions into aziridines.

PPh 2 Rh (CO) 2Cl

P Ph2

O

t-Bu

O

N

Ph

151

2.2 2H-Azirines

Ts N

+

MeCN

BF3·OEt2

Ph 11

Ts N

Me

CH2 Cl2 r.t. 75%

N 152

1.0 PhN=C=S 0.02 Pd(OAc) 2 N

0.10 PPh 3 THF, r.t., 20h 96%

153

N N

Ph

Ph S

154

Scheme 2.33 Insertion of nitrogen and sulfur into aziridines.

us [217] can be derived from aziridines at room temperature using a palladium(II) acetate/triphenylphosphine catalyst system. Thus, phenylisothiocyanate is inserted into the CN bond of vinylaziridine 153 to give the ring-expanded product 154 in excellent yield [218].

2.2 2H-Azirines

Although the level of activity does not match that of the aziridines, research into the chemistry of azirines is healthy and on the increase. Several reviews have appeared in recent years. The reader is directed particularly to two excellent treatises by Palacios and coworkers [219, 220] as well as an earlier work by Rai and Hassner [1]. 2.2.1 Properties of Azirines

Also referred to as azacyclopropene (and confoundingly as 1-azirine), 2H-azirine is the unsaturated cousin of the aziridine ring, which might well be described metaphorically as a cyclic imine. The alternative 1H-tautomer lies some 35 kcal mol1 higher in energy, in part because it constitutes an antiaromatic ring system [221–223]. It is a weaker base than aziridine, which is analogous to the trend in corresponding open-chain amines and imines [221]. Geometrically, according to calculation at the B3LYP/6-311 þ G(3df,2p) level of theory, the triangular ring is somewhat scalene, with the C–N single bond being the longest side. Consequently, the sp2 carbon vertex is the widest at almost 70
(Figure 2.6) [224]. The 1 H-NMR signals of the methylene protons resonate at 1.26 ppm, while the olefinic proton is shifted significantly downfield to 14.4 ppm. The C3 carbon appears at 164 ppm [225].

j41

j 2 Three-Membered Heterocycles. Structure and Reactivity

42

Figure 2.6 Geometry of 2H-azirine.

Remarkably, the azirine moiety is found in some naturally occurring compounds. For example, azirinomycin (155, Figure 2.7), isolated from Streptomyces aureus [226], exhibits antibiotic properties [227]. Two more biologically active azirines, dysidazirine (156) and antazirine (157), were identified in extracts of the marine sponge Dysidea fragilis [228]. While both enantiomers are found in nature, only the (R)isomers of each are associated with desirable cytotoxic activity, the other antipodes being inactive [229]. N

Me

CO2Me

155, azirinomycin N

N

Me

Br

( )12

CO2 Me

( )9

Br

156, dysidazirine

CO2Me

157, antazirine

Figure 2.7 Some naturally occurring 2H-azirines.

2.2.2 Synthesis of Azirines 2.2.2.1 Neber Route This synthetic methodology has a very interesting history. The Neber rearrangement, first reported in 1926 [230], is the base-mediated conversion of oxime derivatives (originally sulfonates) into a-aminoketones (Scheme 2.34). Ultimately, it represents a useful protocol for the a-amination of ketones, which has recently been used to advantage in the total synthesis of dragmacidin F [231, 232]. While most applications still involve this complete transformation, it became clear early on that the mechanism involved an azirine intermediate that could be isolated under the right conditions [233]. TsO R

N

N

base R'

EtOH

R

Scheme 2.34 Neber rearrangement.

R R'

EtO

H N R'

R

NH2

O

R'

2.2 2H-Azirines

Generally speaking, there are two regiochemical possibilities for a-amination proceeding, in turn, through two regioisomeric azirines. House and Berkowitz [234] demonstrated that the regiochemistry of the Neber rearrangement is driven not by oxime geometry (as with the Beckmann rearrangement), but rather by the relative acidities of the a-protons. In other words, the initial tosylate displacement is effected by the more readily formed carbanion. Thus, in Neber precursors with electronwithdrawing groups, the active methylene almost always ends up as the saturated carbon of the azirine. For example, treatment of phosphonatoketoxime 158 (Scheme 2.35) with triethylamine at room temperature afforded in smooth fashion azirine 159 as the exclusive regioisomer [235]. Equally satisfactory results could be obtained using a solid-supported triethylamine analog (i.e., 160) [236]. TsO

N

O

P(OEt) 2 158

Et N

N

Et 3 N

TsO

N

Et

O

161 O

O

MeHN

N

t-Bu

SMe 163

159

benzene 50°C, 4 d 88%

O

N

acetone/ H 2O r.t., 20 h 81%

Et

PPh2 O 162

N

KMnO 4 SMe

P(OEt) 2

160 (1.1 eq.)

PPh2

160

Et

benzene r.t., 8 h 79%

SO2Me

t-Bu

SMe 164

Scheme 2.35 Azirines from oximes with activating groups.

An unusual set of oxidative conditions has been reported for the thioacetal oxime carbamate 163, which suffers oxidation of only one sulfide linkage in the presence of potassium permanganate and then cyclizes to azirine 164, presumably under the influence of hydroxide liberated during the oxidation [237]. The method is tolerant to other leaving groups on the imino nitrogen. One frequently encountered class of compounds in this regard incorporates the quaternary hydrazonium moiety [238]. For example, the hydrazonium salt 165 (Scheme 2.36) derived from propiophenone is converted into the corresponding azirine 166 in fair yield upon treatment with sodium hydride in DMSO [239], and the similar unsaturated system 167 gives an excellent yield of azirine 168 under identical

j43

j 2 Three-Membered Heterocycles. Structure and Reactivity

44

Me3 N I

Me

Ph 165

Me3 N I

N

NaH

N

N

DMSO r.t., 3 h 63%

Ph 166

N

NaH

Ph Me

Me

DMSO r.t., 7 h 93%

Me

Ph

167

Me

Me

168 O

N 1. H 2NNMe 2 2. MeI / NaH

169

N

NMe 3 I

H H

170

H

HO

N NaOi-Pr

Me

H

DMSO 67%

H

H

HO 171

172

Scheme 2.36 Azirines from quaternary hydrazonium salts.

conditions [240]. In these cases, the regiochemistry is unambiguous, as there is only one set of a-protons. However, the process can be selective even when two regioisomers are possible. Thus, the naphthylacetone derivative 169 provides azirine 170 through sequential hydrazone formation, exhaustive methylation and deprotonation, whereby the product formation proceeds via the benzylic anion [241]. Even more subtle is the reaction course of the pregnenolone hydrazonium salt 171, which gives a reasonably good yield of azirine 172, corresponding to ring closure via the more substituted aza-enolate species. The latter case provides a striking example of the stability of azirines, as the authors report storage in ethanol for two weeks at room temperature without decomposition [242, 243].

2.2 2H-Azirines

There appears to be no universally applicable approach to chiral nonracemic azirines; however, strides are being made. In one example, the chiral amido oxime derivative 173 (Scheme 2.37) is reported to undergo conversion into azirine 174 with exclusive diastereoselectivity [244]. It is also interesting to note here the ability to isolate the azirine from the type of protic media usually encountered in the Neber rearrangement, which appears promising for adapting such protocols to azirine synthesis. The use of chiral bases has met with marginal success. In one case, modest enantioselectivities (up to 70% ee) were achieved using a chiral phase-transfer agent, which is assumed to form a tight ion pair with hydroxide and thus impose an asymmetric environment around the proton-transfer transition state [245]. A chiral base can also be used with good results, as demonstrated by the preparation of azirine 177 mediated by quinidine (175). Best results are obtained using stoichiometric quantities of organic base. However, a 20 mol.% loading could be used in the presence of potassium carbonate with only a slight decrease in selectivity [246]. This strategy has also been applied to the synthesis of azirines derived from phosphine oxides (e.g., 179) [247].

MsO

N

O

H 2N

CO 2 Et N H

Ph

TsO

N

176 OMe

175

TsO

N

175 toluene OEt r.t. 85% yield 80% ee

N N

O

O PPh 2

Me

Ph CO 2Et

174

O

Ph

H N

H2 N

EtOH r.t., 2 h 82%

173

OH

N

NaOMe

178

N Bn

177

175 benzene r.t. 96% yield 82% ee

CO 2 Et

N PPh 2

Me

O 179

Scheme 2.37 Asymmetric induction in azirine formation.

2.2.2.2 From Vinyl Azides Smolinsky reported in 1962 that the vapor-phase thermolysis of a-aziridinylstyrene (180, Scheme 2.38) produced substantial quantities of phenylazirine 181 [248, 249]. Subsequently, the method was adapted to be more amenable to the preparative scale, as exemplified by the synthesis of the trifluoromethylphenylazirine 184, which was carried out on a 10-gram scale [250]. The vinyl azide in this case was synthesized from the corresponding alkene (i.e., 182) through sequential bromination, azide displace-

j45

j 2 Three-Membered Heterocycles. Structure and Reactivity

46

N3

N

∆ vapor phase 80%

Ph

180

3. NaOH / DMSO

181 N3

1. Br 2 / CCl4 2. NaN 3 / DMSO F3 C

Ph

N ∆

toluene (70% yield)

F3C

182

F3 C

183

184

O H

O O

N3

AcO

∆

toluene 20 h 85%

OAc

H

O

N

AcO OAc

186

185 N3

N

Me MeO

187

µw neat 3 min 90%

Me MeO

188

Scheme 2.38 Thermal decomposition of vinyl azides to azirines.

ment and dehydrobromination, a protocol used by Gilchrist and coworkers to access azirinyl esters [251, 252]. More recently, Somfai and coworkers [253] reported a much improved yield of azirine 184 (>95%) by carrying out the thermolysis in methylene chloride at 150
C for 20 min in a sealed tube. Even at atmospheric pressure the process can be quite high yielding and remarkably tolerant to other functionality. Thus, heating the hexopyranose-derived vinyl azide 185 in toluene for 20 h resulted in the smooth formation of azirine 186 [254]. Perhaps the most convenient route is the neat thermolysis of aryl vinyl azides (e.g., 187) in an open container under microwave irradiation, which proceeds in very good to excellent yields within a matter of minutes [255]. The course of the thermolytic reaction is substrate-dependent, and Hassner has generalized that azirines are usually formed when the substituent geminal to the azide is an aryl, alkyl, heteroatomic or ester group, whereas unsubstituted or ketosubstituted substrates tend to form nitriles and other heterocycles upon thermolysis [256]. The same transformation can also be mediated by photolysis. Thus, irradiation of b-phenylethyl vinyl azide 189 (Scheme 2.39) induces loss of nitrogen and concomitant formation of azirine 190 in excellent yield [257]. The obvious advantage of this approach is that the decomposition can be carried out at low temperature, thus

2.2 2H-Azirines N3

N

hν pentane 93%

Ph

Ph

189

190

N3

hν

N

CHCl 3 93%

N3

191

N

192

Scheme 2.39 Photolytic decomposition of vinyl azides to azirines.

affording access to more strained products, including fused bicyclic azirines and bisazirines such as 192. In the latter case, the loss of nitrogen occurs stepwise, and the intermediate vinyl azirine can be isolated [258]. One bottleneck for both the thermolytic and photolytic methodology is access to the requisite vinyl azide substrates [259]. One promising recent contribution to solving this problem is the copper (I)/L-proline mediated coupling of sodium azide with (Z)-1-iodo-1-alkenes [260] which, in turn, can be accessed stereoselectively via the Wittig reaction of aldehydes with iodomethylenetriphenylphosphorane [261]. The mechanism of this reaction has been the matter of some debate. Careful kinetic studies in solution phase point towards a concerted mechanism involving a multi-centered transition state in which the nascent sp2 azirinyl carbon exhibits partial positive character (Figure 2.8). This is supported by Hammett studies in which electron-donating substituents on the aryl ring accelerate the decomposition. Thus, in a solvent of 1-butanol at 80
C, the conversion of the p-methoxy derivative (R¼4OMe) is about 50% faster than that of the phenyl substrate (R¼H) and almost three times faster than the m-nitro analog (R¼3-NO2) [262]. For a-aminoalkenyl azides, then, decomposition to the corresponding aminoazirine is usually spontaneous and rapid even at room temperature. In fact, many protocols simply form the vinyl azide in situ from other precursors. For example, keteneiminium salts (194, Scheme 2.40), available from the treatment of amides

N N δ+ N δR

δ+

Figure 2.8 Proposed transition state for thermolysis of aryl vinyl azides.

j47

j 2 Three-Membered Heterocycles. Structure and Reactivity

48

(e.g., 193) with phosgene, add sodium azide to form transient a-aminovinyl azides (e.g., 195) that subsequently lose nitrogen at room temperature to provide azirine products (e.g., 196) [263]. The use of phosgene can be avoided with diphenyl phosphorazidate (DPPA), an aziridinating agent that reacts with amidate anions to give the corresponding azirines directly, as shown by the conversion of N-methyl-Nphenyl amide 197 into the aminoazirine 199 in 94% yield [264]. This methodology is tolerant of various functionalities [265], but some substrates must first be converted into the thioamide using Lawesson’s reagent [266, 267]. Other suitable precursors include a-chloroenamines (e.g., 200), which undergo sequential azide displacement and rapid thermal conversion into the azirine (e.g., 202) under very mild conditions [268].

O

Cl 2 C=O

Me2 N

Et3 N CH2 Cl2

193

N3

NaN 3

·

LDA

N

r.t.

196

N3

N3 P(O)(OPh) 2

Me

-N2

N

r.t. 94%

Ph

197

N

Me

NaN 3

Et 2N

Et 2O 20°C

200

N3

199 N

-N2 r.t. 92%

Et2 N

N

Ph

198

Cl

Me 2 N

195

THF 0°C

Ph

N

-N2

Me2 N

Et2 O

194 O

Me

Me 2N

201

Et 2 N

202

Scheme 2.40 Synthesis of azirines with electron-donating groups.

There are also high-yielding methods for preparing azirines appended with electron-withdrawing substituents. Thus, allenic phosphonates (204, Scheme 2.41), which can be accessed from propargyl alcohol derivatives (203), are themselves efficient precursors for phosphonylmethyl vinyl azides (205). Irradiation of the latter results in extremely high-yielding photolysis to the azirine (206) [269]. As an additional entry under the rubric of electron-withdrawing substituents, bromoazirinyl ester 210 is formed in almost quantitative yield from the azidoacrylate derivative 209 under thermal conditions in refluxing hexane [270]. Analogous iodo azirinyl esters can be prepared through similar methodology [271]. 2.2.2.3 From Other Heterocycles Synthetically useful yields of azirines can be obtained from the thermolysis of isoxazoles (Scheme 2.42), as demonstrated by the thermal rearrangement of ami-

2.2 2H-Azirines O (EtO) 2 P

·

OH

O

NaN 3

CO 2 Me

CO 2Me

PPh 3

207

O

206

N3

NBS

∆

Br

TMSN 3

heptane (99%)

CO 2Me

208

N

(EtO) 2 P

205

O

O

MeCN (96%)

EtOH

204

203

hν 3500Å

N3

(EtO) 2 P

209

N

Br CO 2 Me

210

Scheme 2.41 Synthesis of azirines with electron-withdrawing groups.

noisoxazole 211 to azirinyl carboxamide 212 at high temperature under argon. Neat thermolysis is the preferred mode, as the use of solvent was found to give lower yields [272]. Alternatively, iron dichloride promotes the analogous rearrangement of alkoxyisoxazole 213 at room temperature. The 5-alkoxy substituent is crucial, as 5alkyl or 5-aryl substituents lead to enaminoketones under the same conditions [273]. Benzisoxazole derivatives (e.g., 215) exhibit a regiochemically distinct mode of thermal rearrangement. Instead of bonding to the internal a-carbon, the nitrogen instead forms the azirine ring with the adjacent carbon of the substituent, so that aromaticity is preserved [274].

N

O

Ph

211

N

O

NBn2

260°C

Ph

Ar, neat 10 min 90%

N Ph

CONBn 2 Ph

212

OMe

N FeCl 2·4H 2O MeCN r.t., 80 min > 95%

O2 N

CO 2 Me O2 N

213

N

214

O

OH NaH

Ph CO 2Me

N

Scheme 2.42 Synthesis of azirines from isoxazoles.

CO 2 Me Ph

DMF r.t., 30 min 90%

215

j49

216

j 2 Three-Membered Heterocycles. Structure and Reactivity

50

In a similar vein, oxazaphosphole 217 (Scheme 2.43) underwent pyrolysis at 400
C under high vacuum to produce azirine 218, which was trapped at low temperature and characterized by IR spectroscopy. Pyrolysis at higher temperatures (700
C) gave nitrile ylides instead [275]. A somewhat more synthetically friendly procedure was reported for oxazaphospholine 220 (available in four steps from a-bromoketoxime 219), which decomposed at 120
C and atmospheric pressure to provide methylazirine 221 as a distillate in good yield [276].

F3 C N

CF3 10 -3 torr

O t-Bu

HO

t-Bu

217

Br 219

CF 3 CF3

218

N

N

Me

N

400°C

P(OMe) 3

Me

O

PPh 3

neat 85% 220

N

120°C Me

221

Scheme 2.43 Synthesis of azirines from dihydrooxazaphosphole derivatives.

Finally, azirines can be synthesized from suitably equipped aziridine precursors. For example, aziridinyl ester 222 (Scheme 2.44) was smoothly oxidized using t-butyl hypochlorite to give the N-chloro derivative 223 in excellent yield. Subsequent DBUmediated elimination to the azirine 224, however, was considerably less efficient [277]. A convenient workaround to this problem was found by using Swern conditions, which effects the same transformation in 86% overall yield [278]. Davis and coworkers have reported an interesting eliminative pathway by treating Nsulfinyl or N-sulfonylaziridines (e.g., 225) with lithium diisopropylamide (LDA) at low temperature [279, 280]. Methyleneaziridines can easily be isomerized to azirines, since the latter lie about 9 kcal mol1 lower in energy [281]. Thus, N-silyl-methyleneaziridine 227 quantitatively isomerizes to azirine 228 via an alumina-mediated Brooks rearrangement at room temperature [282]. 2.2.3 Reactivity of Azirines 2.2.3.1 Addition of Nucleophiles Inasmuch as azirines incorporate an unsaturated nitrogen center within a threemembered ring, it would be reasonable to think of their expected chemical behavior as that of an activated imine. Consequently, nucleophilic addition to the sp2 carbon can be a synthetically useful reaction for azirines. For example, azirinyl phosphonate

2.2 2H-Azirines Ph

H N

t-BuOCl CO 2Me

222

Cl

Et2 O 0°C, 10 min (97%)

N

DBU

N

Ph

CO 2Me

223

Et 2O r.t., 30 min (39%)

Ph

CO 2Me

224

1. DMSO / (COCl) 2 2. Et 3N (86% overall)

Ts N Ph

CO 2 Me Me

225

N

LDA THF -78°C 20 min 87%

Ph

Me

Al2 O3 100%

Me

226

TBDMS N

CO 2 Me

N

TBDMS

Ph

Ph

227

Me

228

Scheme 2.44 Synthesis of azirines from aziridines.

229 (Scheme 2.45) suffers high-yielding nucleophilic allylation in the presence of excess allyl Grignard [283]. Analogous results can be obtained in excellent yield using allylindium reagents generated in situ from the corresponding iodide and indium metal, as shown in the conversion of azirine 231 into allylaziridine 232. The stereochemistry of the latter reaction depends upon the substituent at the saturated carbon: chelating groups (i.e., keto or hydroxy moieties) led to cis-delivery of the nucleophile, whereas alkyl and aryl groups resulted in trans-addition [284]. When the azirine is sufficiently activated, even weak nucleophiles can engage in addition to the ring. Thus, exposure of azirinyl phosphonate 233 to acryloyl chloride results in initial N-acylation followed by subsequent rapid addition of chloride to form chloroaziridine 234 [285]. Aziridines can also be accessed by the stereoselective reduction of azirines with hydride reagents. For example, sodium borohydride reacts smoothly in ethanolic medium with azirine 229 to yield the cis-aziridine 235, resulting from the transaddition of hydride [286]. Alternatively, an asymmetric transfer hydrogenation protocol using the chiral aminoalcohol 236 and a ruthenium catalyst can be used to generate enantiomerically enriched aziridines from achiral azirine precursors. Thus, tolylazirine 237 was converted into (S)-tolylaziridine 238 in good yield and promising enantiomeric excess. The mechanism follows the route elucidated in analogous reactions of ketones, in which hydride addition and proton transfer occur simultaneously [287]. A very clever protocol has been developed by Heimgartner and coworkers, which takes advantage not only of the propensity of the azirine to add nucleophiles but also

j51

j 2 Three-Membered Heterocycles. Structure and Reactivity

52

N Ph

P(OEt)2

229

H N

3.0 H 2C=CHCH 2 MgBr THF -78°C 87%

O

N

230

In THF r.t., 3 h 98%

Me

231

O

H N

H 2 C=CHCH 2 I

Ph

P(OEt) 2

Ph

Ph

Me

232 O

N

H 2C=CHCOCl

Me

P(OEt) 2 O

233

benzene 25°C 96%

N Ph

P(OEt) 2

O N H

236

N

OH

P(OEt)2 O

234

EtOH 0°C 91%

229

N

Me

H N

NaBH 4 O

O

Cl

Ph

P(OEt)2

235

O

H N

[RuCl 2 (p-cymene)] 2

p-Tol

237

i-PrOH i-PrOK 83% yield 72% ee

p-Tol

238

Scheme 2.45 Reaction of azirines with nucleophiles.

of the residual ring strain in the resulting aziridine ring. Thus, aminoazirines such as 240 (Scheme 2.46) engage carboxylates in nucleophilic addition to form transient aziridine intermediates that spontaneously rearrange to give amino acid derivatives (e.g., 241) [288, 289]. This strategy, dubbed the “azirine/oxazolone method,” allows quite a bit of flexibility in introducing structural variation into peptide backbones, as exemplified by the spiroazirines 243 [290] and 245 [266]. Quite a few synthons have been developed within this manifold, including those for 2-methylaspartate [291], a-methylglutamate [267], as well as for dipeptides [292] such as 2-aminoisobutyric acid/4-hydroxyproline [293] and other 2,2-disubstituted glycines [294, 295]. The methodology has been showcased in the synthesis of Trichovirin I derivatives [296] and has been further expanded into the realm of solid-phase synthesis [297, 298].

2.2 2H-Azirines N

O HO

Me

+

OH

N

Me

Ph

239

HO

r.t. 93%

Me N

N H

Me

241

242

BnO

O

N

MeCN r.t. 95%

Ph

245

O

O

PhCO 2H Ph

O

Ph

O

NH

243 N

N

N H

r.t. 87%

Ph

O

Me

MeCN

N

Ph

O

O N +

NH

Me

Me

240

CO 2 H

BnO

O

MeCN

244

Me N

N H

Ph

O

246

Scheme 2.46 Addition of carboxylic acids to aminoazirines.

Nucleophilic substitution can actually be carried out at the saturated carbon of certain uniquely functionalized azirines. For example, the benzotriazolyl azirine 247 (Scheme 2.47) takes part in an intermolecular SN2 reaction with thiophenolate to give the aziridinyl sulfide 248 in fair yield. Carbon-centered nucleophiles, such as Grignard reagents, can also be used [299]. Bromoazirine derivative 250 reacts with o-phenylenediamine (249) in both modes (nucleophilic addition and SN2 displacement) to give the disubstituted quinoxaline 251 in very good yield [300].

N

Ph

N

N

DMF 0°C 1h 60%

247 NH 2 +

NH 2

249

N

PhSH

N

N

Ph

CO 2 Me Br

250

Scheme 2.47 SN2-Type additions to azirines.

Ph

SPh

248

ultrasound DMF 86%

N

Ph

N

CO 2Me

251

j53

j 2 Three-Membered Heterocycles. Structure and Reactivity

54

2.2.3.2 Cycloadditions Perhaps some of the most fascinating chemistry associated with the azirines springs from their propensity to act as 2p donors in cycloaddition reactions. For example, Diels–Alder reactions using azirines as dienophiles [301] can provide synthetically valuable fused azabicyclo[4.1.0]heptane ring systems. In some cases, the reaction proceeds under simple thermal conditions and in very high yield, as illustrated by the quantitative reaction of azirinyl ester 252 (Scheme 2.48) with furan to give the Diels–Alder adduct 253 [302]. The method is amenable to other electron-rich dienes, such as bis(siloxy)diene 254 [303], as well as other dienophiles, such as aziridinyl carboxamides [304]. The reaction rate can be dramatically accelerated and the scope extended to alkyl and aryl aziridines (e.g., 258) by the use of Lewis acids [305]. A particularly high-yielding result was obtained in the magnesium bromide-mediated Diels–Alder reaction between trimethylsiloxycyclohexadiene (260) and chiral nonracemic azirinyl ester 261, which proceeded with almost exclusive endo- and regioselectivity (but apparently low facial selectivity) [306, 307]. Cl

Cl furan

N MeO 2 C

O

Et 2O r.t. 7 days 100%

Cl

252

N

MeO 2C

Cl

253

OTBS

OTBS N

+

r.t.

CO 2 Bn

OTBS

254

toluene 7 days 42%

255

N CO 2 Bn OTBS

256 OMe

OMe +

257

N

ZnCl 2

Ph

toluene 75°C 6h 50%

258

N Ph

259

N MgBr 2 ·OEt2

+ O

TMSO

O Ph

260

261

CH2 Cl2 100°C 30 min 99% yield 97% de

Scheme 2.48 Diels–Alder reactions with azirines.

N TMSO

CO 2X c

262

2.3 Oxiranes

j55

The field is not limited to [4 þ 2] methodology. For example, arylazirine 264 and fulvene 263 engage in a formal [6 þ 3] cycloaddition catalyzed by yttrium triflate and mediated by adventitious water, providing a novel entry into the [2]pyridine system (Scheme 2.49) [308]. The p-nitrophenylazirine 268 was also shown to be an effective 1,3-dipolarophile in the presence of azomethine ylide 267 (generated by the thermolysis of bicyclic oxazolidinone 266), forming a fused tricyclic adduct (269) that was parlayed into an approach to 1-azacephams [309]. N

CO 2Me

+

THF r.t. 12 h 83%

p-ClPh

263

p-ClPh

Y(OTf) 3 N

CO 2Me

264

265 N

H

O

O

N

CO 2PNB

266

H

p-NO 2 Ph

O

MeCN 80°C

O

CHO 2H

N

CO2 PNB

267

268

66%

O

N p-NO 2Ph

N

CO2 PNB

269

Scheme 2.49 Other cycloadditions with azirines.

2.2.3.3 Rearrangements into other Heterocycles Owing to their strain and functionality, azirines are prone to molecular rearrangement. For example, under neutral thermolytic conditions the alkyl aziridinylphosphonate 270 (Scheme 2.50) is converted almost quantitatively into the pyrazine 271. The mechanism is believed to involve the dimerization of unstable nitrile ylides generated from the initial thermal ring-opening of the azirine [310]. Furthermore, Padwa and Stengel have reported some fascinating azirine rearrangements promoted by Grubb’s catalyst. Thus, the azirinyl aldehyde 272 is transformed cleanly into the isoxazole 273 at room temperature. Similarly, vinyl azirine 274 undergoes thermal rearrangement to form exclusively the 2,5-disubstituted pyrrole 276, which is complementary to photolytic rearrangement, a process providing only the 2,3product 275 [311, 312]. Finally, Taber has reported on the high-yielding synthesis of indoles (e.g., 278) from arylazirines 277, which are themselves synthesized from the oximes of aryl ketones [313].

2.3 Oxiranes

It may well be said that the field of oxirane chemistry has escaped the confines of a brief comprehensive overview. Indeed, an encyclopedic summary of just the last

j 2 Three-Membered Heterocycles. Structure and Reactivity

56

O N

Et

N

P(OEt) 2

(EtO) 2 P

N

Et

80°C

Et

P(OEt) 2

toluene 98%

O

O

270 N H

Ph

[Cl2 (Cy 3P)2 Ru=CHPh] CH2 Cl2 r.t. 2h 90%

O

272 Ph

H N

benzene 1.5 h (85%)

MeO 2 C

275

N

O

Ph

273

N

hν

271

Grubbs CO 2Me

Ph

274

Ph

CH 2Cl 2 r.t., 3 h (75%)

H N

CO2Me

276

N o-xylene

Me Br

170°C 88%

277

Me N H

Br

278

Scheme 2.50 Some rearrangements of azirines.

year’s activity would occupy volumes. Several significant reviews have appeared recently [8], many of which pertain to specific areas within epoxide chemistry and will therefore be cited in the appropriate context. The present chapter seeks to assemble a sampling of the diverse applications for organic synthesis. 2.3.1 Properties of Oxiranes

Oxiranes (also known as epoxides and oxacyclopropanes) owe much of their utility, whether as synthetic intermediates or biologically active compounds, to ring strain. For example, oxirane itself (bp 10.5
C) is associated with some 27 kcal mol1 of strain enthalpy. Like most of its congeners, this molecule exhibits the very useful balance of being stable enough for isolation, transportation and so on, while still harboring a remarkable propensity for reaction. Geometrically, oxirane describes an almost equilateral triangle, with a slightly relaxed bond angle at the oxygen center (Figure 2.9). The 1 H-NMR signals of the methylene protons resonate at 2.54 ppm and the carbon atoms appear at 39.7 ppm. The increased s-character of the CH bond leads to an unusually high 13 C-H coupling of 176 Hz [7]. The oxirane ring is found in a host of naturally occurring compounds of biological relevance. Occasionally, the structures can be quite simple, with the oxirane being the

2.3 Oxiranes

Figure 2.9 Geometry of oxirane.

dominant functional group. Such is the case for the newly discovered stilbene oxide derivative 279 (Figure 2.10), which was isolated from the larval G. mellonella infected by the nematode-bacterium complex H. megidis 90/P. luminescens C9. This compound displays broad antimicrobial activity against many troublesome pathogens, including the drug-resistant strain Staphylococcus aureus RN4220 [314]. More commonly, however, the epoxide ring is imbedded within a molecule carrying elaborate functional embellishments. A good example is altromycin B (280), a secondary metabolite of soil Streptomyces which exhibits both antibiotic and anticancer activity [315]. The mode of action has been traced to the inhibition of DNA synthesis caused by the alkylation of guanine through epoxide ring-opening [316]. Another natural product sporting the oxirane and anthraquinone moieties is dynemicin A (281), isolated from Micromonospora chersina, which is cytotoxic at concentrations approaching the parts per trillion range. Here the epoxide ring functions as the trigger for a mouse trap: nucleophilic ring opening of the epoxide results in a conformational relaxation that allows for cyclization of the enediyne array, forming the very reactive arene diradical [317]. Ambuic acid (282), isolated from the rain forest fungi Pestalotiopsis spp. and Monochaetia spp., has shown activity against several plant pathogenic fungi [318]. This polyketide-derived natural product is one representative from a broad range of cyclohexane epoxides found in nature, a class that has been the subject of a quite recent and fairly comprehensive review [319]. The structural and biological diversity even within this classification is impressive. Fumagillin (283), a cyclohexane spiroepoxide produced by Aspergillus fumigatus, is an angiogenic inhibitor that binds to methionine aminopeptidase. Consequently, it is a promising antineoplastic agent and may even inhibit atherosclerosis [320, 321]. Polyketide-derived oxiranyl natural products also extend into macrocyclic species. Amphidinolide B1 (284) is one such cytotoxic 26-membered macrolide, isolated from the marine dinoflagellate Amphidinium sp. Y-5 [322–324]. Similar cytotoxic activity exhibited by the 16-membered macrolide epothilone A (285), a metabolite of the cellulose-degrading myxobacterium Sorangium cellulosum (Myxococcales), has made it an interesting anti-cancer candidate and subsequently the subject of active investigation from both a synthetic organic and chemical biology standpoint [325, 326]. Also of marine origin is the bromotyrosine-derived dimeric spiroisoxazoline ( þ )-calafianin (286), which is found in methylene chloride extracts of the Mexican sponge Aplysina gerardogreeni n. sp (Aplysinidae). Members in this class of compounds have demonstrated activity against Mycobacterium tuberculosis [327, 328].

j57

j 2 Three-Membered Heterocycles. Structure and Reactivity

58

HO OMe

O

OH HO

Me O

HO

279

O

MeO 2C HO

OH

Me

O O

Me H

O

O Me2 N

OH

O

OH

O

Me MeO

OMe H

OH

OH

OH

OH

O

281, dynemicin A

H

O

CO 2H

Me

O

OMe CO 2H

O

O

282,ambuic acid

O

283, fumagillin

OH

OH

O

O

S

O

OH

O

O

Me

O

HO

CO 2 H

HN

O

280, altromycin B

Me

Me

H

OH

N

O

O

OH

O O

O

285,epothilone A

284,amphidinolide B1

Br O

O O O

Br

N

N H

N

H N O

O O O

286,(+)-calafianin

Figure 2.10 Some naturally occurring oxiranes.

2.3.2 Synthesis of Oxiranes

The synthesis of oxiranes has been the subject of several recent reviews, encompassing biosynthetic routes [329] and asymmetric methodologies [330], including

2.3 Oxiranes

those proceeding through homo- and heterogeneous catalysis [331] and epoxidations under the influence of chiral auxiliaries [332]. The preparation of vinyl epoxides has also been reviewed recently [333], as have as other topical works mentioned in the appropriate context below. 2.3.2.1 Using Dioxiranes Epoxides can be prepared by the action of dioxiranes on alkenes under mild conditions and low temperature [334]. For unstable epoxides, such as those derived from enol ethers, dioxirane epoxidation is the method of choice. Several reports have exploited this reaction to obtain the previously unisolable acyloxo, alkoxo and silyloxooxiranes. An example of this approach involves the preparation of epoxide 288 from enol lactone 287 (Scheme 2.51) using one of the simplest dioxirane

DMD O

O

79%

O

O

287

O 288

OTBDMS

O

OH

O DMD

OH

OH

Tf 2 O i-Pr 2NEt

HN CHO

C N

O 290

289 DMD

O

> 90%

O

O

291

292 H

· n-Bu

O 95% yield 9:1 anti/syn

O

293

n-Bu

294

CO 2 Me 295

H

DMD

DMD O

CO 2Me

O 296

Scheme 2.51 Dimethyldioxirane (DMD) epoxidation of sensitive substrates.

j59

j 2 Three-Membered Heterocycles. Structure and Reactivity

60

derivatives, dimethyldioxirane (DMD). Similarly, DMD epoxidation of silyl enol ethers afforded the corresponding epoxides in excellent yields. These substrates readily undergo an acid-catalyzed rearrangement to a-trimethylsiloxy carbonyl derivatives [335, 336]. Danishefsky has described the use of DMD for the direct epoxidation of glycals. The 1,2-anhydrosugars produced were employed in the stereospecific construction of b-linked oligosaccharides [337]. Epoxy isonitriles cannot be prepared by the direct epoxidation of vinyl isonitriles. However, the DMD oxidation of a series of vinyl formamides was found to produce epoxy formamides in good yield. These compounds were readily converted into the epoxy isonitriles using triflic anhydride and H€ unig’s base. A total synthesis of isonitrin B (290) was carried out using this methodology [338]. Adam and coworkers reported the first benzofuran epoxide synthesis (i.e., 292) using DMD in their study on the mutagenesis of benzofuran dioxetanes [339]. The same oxidant has been used to advantage in accessing other labile products, including 1,2-dialkoxyoxiranes [340] and flavone epoxides [341]. Crandall and coworkers have studied the DMD-mediated epoxidation of various allenes 293. The corresponding 1,4-dioxiaspiro[2.2]pentanes 294 were produced in good yields, the mono- and di-substituted allenes giving anti diastereomers with good stereoselectivity. These spirodiepoxides then underwent nucleophilic cleavage under buffered conditions (Bu4NOAc/HOAc) to give highly functionalized a,a0 -dihydroxyketone derivatives [342]. Messeguer and coworkers have employed dimethyldioxirane to prepare the diepoxide 296, a proposed metabolic intermediate of juvenile hormone III [343]. Dioxiranes can also be employed in a catalytic fashion. Practically unrivaled in efficiency and ease of use, DMD itself can be generated in situ from acetone in an appropriate buffer. Thus, the dropwise addition of an aqueous solution of Oxone to a stirred mixture of cis-carveol (297, Scheme 2.52), sodium bicarbonate, and acetone at 0
C led to the selective formation of epoxide 298 in 92% yield [344]. This general methodology has been expanded to include a wide variety of oxygen carriers. For example, in the area of natural products, Marples and coworkers have used dioxiranes generated in situ from a range of ketones to effect 5,6-epoxidation of cholesterol or its acetate in high yield [345]. Bortonlini et al. have used sodium dehydrocholate as an organomediator for the sodium perborate (SPB) mediated preparation of acidsensitive epoxides, in which the intermediacy of a steroidal dioxirane has been suggested [346].

HO

acetone

O

HO

Oxone NaHCO 3 92% 297

298

Scheme 2.52 Catalytic epoxidation using DMD.

2.3 Oxiranes

311

301 or 305

Ph

Ph

Oxone 98% yield 83% ee

Ph

312 C 6H 13

OBn

Oxone 91%

310

Ph

O

299

OBn

Ph

313 O

Oxone

O

Ph

303

C 6H 13

C6 H 13

C 6H 13

O O

via

O

O

R

RO O

O

315

314

316 O

303 or 304 Bu 4NHSO 4 Ph

H Ph

Oxone K2 CO 3

Me

317

320

O

O H Me

Oxone DME / DMM 75% yield 95% ee

NR

O

via O

318

303

Ph

j61

O

O

Ph

O Me

319 O Ph

(+)-321

Scheme 2.53 Epoxidation of alkenes using catalytic dioxiranes.

Denmark has developed a practical phase-transfer protocol for the catalytic epoxidation of alkenes, which uses Oxone as a terminal oxidant. The olefins studied (e.g., 310, Scheme 2.53) were epoxidized in 83–96% yield. Of the many reaction parameters examined in this biphasic system, the most influential were found to be the reaction pH, the lipophilicity of the phase-transfer catalyst and the counterion present. In general, optimal conditions feature 10 mol.% of the catalyst 1-dodecyl-1-methyl-4-oxopiperidinium triflate (299, Figure 2.11) and a pH 7.5–8.0 aqueous methylene chloride biphasic solvent system [347], although these systems are tolerant to neutral and basic pH ranges [348]. The dioxirane derived from the bis(ammonium) ketone 300 also exhibits remarkable reactivity, stability, and water solubility, and has been used to advantage on various substrates [349]. The activation barrier for these reactions is drastically reduced by hydrogen bonding in the transition state, whether by solvent or intramolecularity [350].

j 2 Three-Membered Heterocycles. Structure and Reactivity

62

O N

+ Me

+

-OTf -

O

+

N

N 9

300

299

R O

O O

O2N

O

O2N

O

O

O O

O

O R 301

302

O O

O

O

O

O

N

EtO2C N

Ar

X H

O

O

O

O

O

O

O 304

303

Cl

305

Me Me

O

Me O

X

O

Cl

Ph

X

Ph 307

306

O O SiO2

Si

S

O

O N

F

CF3

O

OMe OH

C6F13

O 308

Figure 2.11 Ketone precursors for dioxirane oxidations.

309

2.3 Oxiranes

The latest twist to this development is the use of chiral ketones in catalytic amounts for the induction of asymmetry during the epoxidation [351]. However, the resultant dioxiranes have two reacting sites, a fact that makes the prediction and execution of asymmetric induction problematic. Yang and coworkers addressed this problem by designing the C2 symmetric, eleven-membered ring ketone 301 as a chiral dioxirane precursor [352]. In this case, both active sites are characterized by the same chiral environment. In fact, a catalytic amount of ketone 301, in the presence of Oxone as a terminal oxidant, was capable of epoxidizing trans-disubstituted and trisubstituted alkenes in excellent yield and modest enantiomeric excess (e.g., 312 ! 313, Scheme 2.53). Electronic and steric embellishments on the ketones (e.g., 302) can lead to mild enhancements [353]. The main conduit of asymmetric induction is assumed to occur via the “steric sensors” on the aromatic ring. Curiously, enantioselectivity increases with the size of the substituent only to a certain point, then begins to decrease again. Shi and coworkers have successfully developed ketalized D-fructose derivatives (e.g., 303) as chiral dioxirane precursors [354]. Excellent ees were obtained, even for the recalcitrant trans-disubstituted alkenes (e.g., 314 ! 315, 81% yield, 90% ee) [355] and trisubstituted alkenes (e.g., 320 ! 321, 75% yield, 95% ee) [356]. However, this system appears to be highly substrate dependent, owing to a complex interaction of steric and electronic factors [357–359]. There are several important features of the key dioxirane intermediate. First, the stereogenic centers are in close proximity to the ultimate reactive site of the dioxirane; second, the carbonyl group is flanked by a fused ring on one side and a quaternary center on the other, preventing epimerization; and, finally, only one face of approach is available, since the other is sterically blocked. As for the actual transitions state, the results are consistent with a spiro configuration (316) that is directed by steric interactions. The protocol has been optimized so that the chiral ketone 303 can be used in catalytic quantities with Oxone as the stoichiometric oxidant. The key to preserving the lifetime of the chiral auxiliary is pH control during the reaction; the optimum range was found to be 10.5 or above, which is conveniently maintained with potassium carbonate [360, 361]. The related oxazolidinone ketone catalyst 304, prepared in six steps from D-glucose [362], has the advantage of exhibiting high ees for both cis- and terminal olefins [363]. Interestingly, for olefins with aromatic substituents, it appears that the transition state shows a preference for positioning the p-system proximal to the oxazolidinone moiety (as in 319), so that aromatic groups can be efficiently differentiated during the epoxidation. In studies involving the epoxidation of cis-methylstyrene (317), the electronic character of the oxazolidino N-aryl group was found to influence the outcome of the reaction, presumably by modulating the interaction between the catalyst and the aromatic substituent of the substrate [364]. Similarly, increasing the steric demand adjacent to the amide carbonyl can improve selectivity [365]. Other catalysts also exhibit a combination of these factors. For example, the tropinone-derived chiral ketone 305 owes its enantioselectivity to the structurally rigid and compact asymmetric ring structure. Incorporation of an electron-withdrawing fluoro substituent at the a-position enhanced the catalytic reactivity. Enan-

j63

j 2 Three-Membered Heterocycles. Structure and Reactivity

64

tiomeric excesses tend to be modest, but occasionally are quite good, as seen in the epoxidation of phenylstilbene (312), which takes place in quantitative yield and with 83% ee [366]. The impact of these electronic effects is intriguing, and can be quite dramatic. A particularly noteworthy example is the non-conjugated electronic interactions that result from a remote substituent in the carvone-derived catalyst 306. In the epoxidation of trans-stilbene, the series of small substituents (F, Cl, OH, OEt and H) give ees of 42–87%, exhibiting a very high correlation with the respective Hammett r values. These results have been rationalized on the basis of stabilization of the favored transition state (307) by field effects [367]. Some interesting immobilized dioxirane precursors have also been reported, such as the novel heterogeneous ketone 308 [368] and the fluoroketone 309, designed for use in fluorous media [369]. 2.3.2.2 Using other Oxidants without Metal Catalysts The epoxidation of alkenes without metal catalysis represents a large and diverse group of preparative methods for oxiranes, and here the various systems can be characterized largely by two key components: the oxygen carrier (or catalyst) and the terminal (stoichiometric) oxidant. In this regard, m-chloroperbenzoic acid (mCPBA) is a tried and true reagent [370], and has been adapted to the large-scale practical synthesis of epoxides [371]. Buffered mCPBA systems are useful for epoxidations in which the alkenes and/or resultant epoxides are acid-sensitive. For example, 2,6-ditert-butylpyridine was shown to give superior results in the case of certain allyl acetals (e.g., 322, Scheme 2.54) [372]. Bicarbonate [373] and phosphate [374] buffers are also frequently encountered in this context. Multifunctional alkenes offer some interesting possibilities. For example, enone 324 undergoes ketone-directed epoxidation when treated with mCPBA to give exclusively the syn epoxyketone 326. As for the mechanism, hydrogen bonding effects were discounted on the basis of solvent insensitivity. Intramolecular attack by some oxidized form of the ketone moiety could be operative, although 18 O labeling studies have ruled out a dioxirane intermediate as the active epoxidizing species. Thus, the observed stereoselectivity was rationalized on the basis of intramolecular epoxidation by an a-hydroxy peroxide (i.e., 325) or possibly by a carbonyl oxide intermediate [375]. Whereas aminoalkenes cannot be converted into epoxides by usual methods (competing N-oxidation), protonation by an arenesulfonic acid and subsequent treatment with mCPBA allows for chemoselective epoxidation. Furthermore, when properly disposed, the pendant ammonium functionality can serve as a potent directing group for the oxidant. Thus, under these conditions cyclohexenylamine 327 affords exclusively the syn epoxide 328 [376]. In the case of dual functionality, the two sites may interact in either a constructive or destructive fashion. This was illustrated by a set of stereoselective epoxidations on a series of allylic carbamates that were appended with a carbomethoxy group, a hydroxymethyl group, or an acetoxymethyl group. In all cases, threo epoxides were favored (syn to the carbamate) upon treatment with mCPBA, which reflects the strong directing power of the carbamate group. However, the magnitude of the syn : anti ratio was dependent upon the type and configuration of the other

2.3 Oxiranes C 4H 9 O

C4 H9

mCPBA

OSit-BuPh 2

O

O

buffer 99%

OSit-BuPh 2

O

O

322

j65

323

18

O

H18O

O O

mCPBA

18

O

Ar O

O16

324

326

325 O

ArSO3H

mCPBA NH2

NH2

327

328

CO 3H CO 2H O

330 1 M NaOH 100% yield 98% de

OH

329

OH

331

pH8.3

O

pH 12.5

O

OH

OH

332

333

OH

334

O HN

O

O

335

O

O H

Scheme 2.54 Epoxidation of alkenes using peracids.

functionality. A relatively low ratio was observed when the two groups compete for face selectivity, whereas “cooperative coordination” leads to higher selectivity. From the magnitude of the perturbation, the following order of directing ability was proposed: carbamate > methyl ester > homoallylic alcohol ¼ acetate [377]. The reaction of allyl alcohol with peroxyformic acid has been examined extensively using molecular modeling calculations [378]. Prompted by the observation that peracid epoxidations can be far more selective in basic aqueous medium than in

j 2 Three-Membered Heterocycles. Structure and Reactivity

66

Figure 2.12 TS for epoxidation of allylic alcohol with performate.

organic solvent [379], Washington and Houk studied transition structures from the epoxidation of allylic alcohol with performate ion at the B3LYP/6-31 þ G(d,p) level of theory in a CPCM continuum model for water [380]. Their findings indicate a preferential hydrogen bonding of performate with the substrate hydroxyl group rather than with water, leading to a directed epoxidation via the transition state depicted in Figure 2.12. This reaction is similar to the corresponding cyclopropanation of allylic alcohols in the presence of aqueous sodium hydroxide. To test this model experimentally, the chiral allylic alcohol 329 was treated with monoperoxyphthalic acid (MPPA, 330) in 1 M NaOH to give the syn epoxy alcohol 332 in quantitative yield with 98% syn/anti selectivity. An interesting regiochemical anomaly has been reported by Fringuelli and coworkers [381]. In the epoxidation of geraniol (332) by MPPA, the reaction could be directed to either double bond by simple modification to the experimental conditions. In the presence of cetyl(trimethyl)ammonium hydroxide (CTAOH) at pH 12.5, 2,3epoxygeraniol (334) is formed exclusively; however, at pH 8.3 in the absence of CTAOH, the formation of 6,7-epoxygeraniol (333) is favored. The magnesium salt of this reagent, magnesium bis(monoperoxyphthalate) hexahydrate (MMPP), is touted as a less expensive and more stable surrogate for mCPBA [382]. With an eye towards industrial applications, Johnstone and coworkers have developed 5-hydroperoxycarbonylphthalimide (335) as a new reagent for epoxidation. An easily prepared, shock-stable, crystalline solid, this peroxy acid was designed to exhibit all the desirable properties of more hazardous or expensive reagents (i.e., ease of work-up, low acidity in reaction medium, etc.). Yields, using various substrates, are excellent [383]. Hydrogen peroxide is another frequently used terminal oxidant for epoxidations, and its use with manganese [384] and palladium [385] catalysts has been the subject of recent reviews. Garcia-Bosch and coworkers have demonstrated that metal-catalyzed disproportionation of hydrogen peroxide in some catalytic systems can be suppressed by using a large excess of acetic acid as an additive, presumably facilitating the formation of peracetic acid [386]. Alternatively, Ti(salan) compounds have been

2.3 Oxiranes

applied effectively to hydrogen peroxide epoxidation systems [387, 388], as well as boron trifluoride in the absence of metal co-catalysts [389]. Another relatively simple metal-free system for the epoxidation of tri- and cisdisubstituted olefins (e.g., 336 ! 337, Scheme 2.55) is formamide-hydrogen peroxide in an aqueous medium. This reagent has the advantage of being pH-independent, which makes it attractive for biochemically mediated transformations. No reaction was observed in the case of trans-disubstituted and terminal olefins. With bifunctional alkenes, the more reactive double bond is selectively epoxidized [390].

Me

HO

Me

Me

H 2 O2, HCONH 2

Me

95%

Me

HO

O

337

336

O

H2 O2 NaHCO 3 H2 O 95%

NaO

O O NaO

338

339 R

R

N

Me

C N

R

H 2O2 H

N

H

N O

O

R

340

(CH 2)CO 2Me

341 2 eq. DCC 10 eq. H2 O2

O

2 eq. KHCO 3

342

(CH 2)CO 2Me

343

Scheme 2.55 Epoxidation of alkenes using hydrogen peroxide.

Water-soluble alkenes can be epoxidized in remarkably high yields using bicarbonate-activated hydrogen peroxide (BAP). Thus, epoxide 339 was obtained in >95% yield from sodium p-vinylbenzoate (338). Diol formation is a competing side reaction with some substrates [391]. The epoxidation of olefins with hydrogen peroxide can also be promoted by the addition of carbodiimides, presumably by the initial formation of a peroxyisourea

j67

j 2 Three-Membered Heterocycles. Structure and Reactivity

68

species (341) [392]. Majetich and Hicks have reported on the epoxidation of isolated olefins (e.g., 342) using a combination of 30% aqueous hydrogen peroxide, a carbodiimide (e.g., DCC) and a mildly acidic or basic catalyst. This method works best in hydroxylic solvents and not at all in polar aprotic media. The type and ratios of reagents are substrate dependent, and steric demand about the alkene generally results in decreased yields [393]. The methodology can be adapted to asymmetric epoxidation by using an aspartate-containing tripeptide [394]. Olefins containing free hydroxyl groups or carboxylic acid moieties can be oxidized rapidly and efficiently at room temperature using an easily prepared acetonitrile complex of hypofluorous acid (HOFCH3CN). The reagent does not induce formation of peroxides with free hydroxy groups, and aromatic rings do not interfere with the reaction. Thus, oleic acid (344, Scheme 2.56) was epoxidized in 10 min and in 90% yield [395].

O

HOF•CH3CN

(CH2)6COOH

C7H15

C7H15

344

345 OH

OH R

OH

I2

•

Et2O

346

(CH2)6COOH

R

I I

R

I CH2I

H

base

R

348a H H

347

H

H

I R

O

I CH2I

349

O-

348b O2 (1 atm)

350

NHPI HFA 83%

HO

O Pr

Pr

351

OOH

F3C

CF3

352

Scheme 2.56 Epoxidation of alkenes using other non-metal oxidizing agents.

Allenic alcohols 346 are converted in the presence of iodine into a mixture of (Z)and (E)-diiodides (347), which, upon subsequent treatment with base, form the transiodovinyl epoxides 349 with a diastereomeric excess of >99%. This high degree of selectivity is rationalized on the basis of steric interactions between the R group and the iodine atom in the transition state leading to epoxide formation (i.e., 348a vs. 348b) [396]. One of the most attractive oxidants for this chemistry is dioxygen, both from an environmental and cost standpoint. In this vein, a metal-free epoxidation protocol

2.3 Oxiranes

was reported that proceeded via the in situ generation of hydrogen peroxide from O2 through a complex series of steps involving N-hydroxyphthalimide (NHPI). Once formed, the H2O2 is activated by addition onto the somewhat esoteric solvent, trifluoroacetone, to give 2-hydroperoxy-hexafluoropropan-2-ol (352) as the oxygen transfer reagent. The reaction appears to be general and yields are very good. Regardless of the starting configuration of the alkene, a strong preference for the formation of trans-epoxides was observed (e.g., 350 ! 351) [397]. 2.3.2.3 Metal-Catalyzed Epoxidation of Alkenes The topic of metal-based catalysis for alkene epoxidation is expansive, and the reader is directed to two excellent reviews of this chemistry by Adolfsson [398] and Adolfsson and Balan [399], as well as an outstanding treatise on mechanism and kinetics by Oyama [400] and an overview of asymmetric methods by Matsumoto and Katsuki [401]. The development of (salen)metal complexes (Figure 2.13) for the epoxidation of alkenes has been nothing less than revolutionary, providing access to epoxides from simple olefins in much the same way Sharpless chemistry paved the way for the epoxidation of functionalized alkenes. An extensive review specifically on the chromium- and magnesium-salen catalyzed epoxidation of alkenes has recently appeared [402]. In the absence of other functionality, typical peroxyacid epoxidation of dienes favors reaction on the more substituted double bond. However, the (salen)manganese complex 353 promotes epoxidation of the less substituted double bond (e.g., 362 ! 363, Scheme 2.57), thus providing a complement to conventional methods. This protocol is also useful for substrates that polymerize under peracid conditions [403]. Allylic alcohols are equally suitable substrates, as demonstrated by the epoxidation of 364 using the vanadyl salen oxo-transfer catalyst 354 in supercritical carbon dioxide with tert-butyl hydroperoxide as a terminal oxidant [404]. The lion’s share of research activity in this area has centered around asymmetric epoxidation using chiral salen catalysts. Thus, the chiral (salen)Mn(III) complex 356, which is readily available on a large scale in high yield from commercially available starting materials [405, 406], is the centerpiece of Jacobsen’s enantioselective synthesis of the taxol side chain 369 [407], in which the epoxy ester 367 is prepared from cis-ethyl cinnamate with very high enantiomeric excess (Scheme 2.58). Typically under these conditions, cis-double bonds are converted stereospecifically into cisepoxides. However, in the case of conjugated dienes, trans-epoxides are the major products. The crossover has been ascribed to a step-wise oxygen transfer mechanism involving an intermediate radical that undergoes bond rotation to give the observed products. This anomalous behavior has been leveraged in a method for the regioselective epoxidation of cis,trans-dienes to give trans,trans-diene monoepoxides (e.g., 370 ! 371) [408]. Cyclic and acyclic trisubstituted alkenes are also epoxidized with high enantioselectivity under the catalysis of 356, as exemplified by the conversion of phenylstilbene 312 into the (S)-epoxide 313 with 92% enantiomeric excess. The sense of enantioselection is opposite that of disubstituted alkenes, and a global mechanistic model has been developed to rationalize the stereochemical outcomes of this class of

j69

j 2 Three-Membered Heterocycles. Structure and Reactivity

70

N

N M

Me

O

O

t-Bu

Me

t-Bu

N

N M

t-Bu

O

O

t-Bu

t-Bu

H N

N M

O

O

R'

R

Ph N

N M

O

O

R'

R

360, R = (i-Pr)3SiO-;R' = t-Bu; M = Mn-Cl

R'

O

O

Ph

Ph N

N

361, M = Cr-OTf

M t-Bu

356, R = R' = t-Bu; M = Mn-Cl 357, R = (i-Pr)3SiO-;R' = t-Bu; M = Mn-Cl 358, R = R' = t-Bu; M = Cr(O)-Cl 359, R = R' = Cl; M = Cr(O)-PF6

R'

Ph

R

355, M = Mn-Cl

t-Bu

H

R

353, M = Mn-Cl 354, R = M = V(O)

O t-Bu

O

t-Bu

t-Bu

Figure 2.13 Salen metal catalysts for alkene epoxidation.

epoxidations [409]. Furthermore, a wide range of terminal oxidants have been employed with this catalyst, including hydrogen peroxide [410], dimethyldioxirane [411], periodates [403] and the organic-soluble oxidant tetrabutylammonium monopersulfate [412]. Terminal olefins typically give relatively low enantiomeric purities, which might be due to poor enantiofacial selectivity during the oxygen addition or facile rotation of a

2.3 Oxiranes

353 362

Ph

OH

O

NaIO 4 imidazole 88%

363

354

O

Me

Ph

t-BuOOH CO 2 (l) 86%

364

j71

Me OH 365

Scheme 2.57 Alkene epoxidations using achiral salen metal catalysts.

O Ph

CO2Et

356 (6 mol%) NaOCl 4-PPNO (56% yield; 97% ee)

366

NH2

O Ph

CO2Et

O Ph

Ph

NH

O

OH Ph

OH

OH OH

367

368

369

356

C5H11

(3 mol%)

EtO2C

O

EtO2C

C5H11

NaOCl

370

(81% yield; 87% ee)

371

Ph Ph

312

Ph

356 Ph

CH2Cl2 4-PPNO

O Ph

Ph

(97% yield; 92% ee)

(S)-313

Scheme 2.58 Alkene epoxidations using chiral salen metal catalysts.

radical intermediate unencumbered by a-substitution. Either of these impediments should be positively impacted by decreasing thermal energy, and this has been borne out by experimental evidence [413]. Katsuki has reported increased ees by adding NaCl to the aqueous hypochlorite system, thus allowing for sub-zero (18
C) reaction temperatures [414]. The asymmetric induction may be further enhanced by modification of the catalyst. Replacement of the tert-butyl group with the triisopropylsiloxy substituent affords a catalyst (i.e., 357) that is not only sterically more defined but also electronically attenuated, and thus is milder and more selective [415]. The diphenyl variant 360 was equally effective in epoxidizing a series of recalcitrant olefins, such as vinylbenzoic acid 372 (Scheme 2.59) in the presence of N-methylmorpholine N-oxide (NMO) as an additive and mCPBA as a terminal oxidant in methylene chloride at 78
C [416]. These conditions were also advantageous for the epoxidation

j 2 Three-Membered Heterocycles. Structure and Reactivity

72

mCPBA NMO, CH2 Cl2 -78°C 97% yield 98% ee

HO 2C

372

HO 2 C

373

Et

Et Br

Me O

O

*

360

Me Me

374

*

Br

360 (5 mol%)

O

Me

*

4-PPNO CH2 Cl2 0°C 97% ee

Me

O

Me

375

Scheme 2.59 More alkene epoxidations using chiral salen metal catalysts.

of tetrasubstituted alkenes, as demonstrated by the conversion of chromene derivative 374 into the corresponding epoxide with 97% ee [417]. Changing the metal center from manganese to chromium can have surprising results. For example, one aggravating phenomenon associated with the (salen)Mn complexes is that the epoxidation of trans-olefins proceeds typically with low ees. However, the analogous chromium complexes (e.g., 359) catalyze such epoxidations with greater selectivity than for the corresponding cis-olefins under the same conditions. Here the mechanism is presumed to involve an electrophilic process, which is supported by the fact that only electron-rich alkenes are effectively epoxidized. In the case of trans-b-methylstyrene (376, Scheme 2.60), enantioselectivities

Me

Ph

376

O

359 Ph3 PO DMF 60% yield 86% ee

Ph

Me

377 O

O

357

361 O

O

O

378

(3R,4R)-379

C2F5

358 (0.1 mol%) O

(3S,4S)-379 O

C 2F5

isoquinoline N-oxide 75%

380 Scheme 2.60 Salen(Cr)-catalyzed alkene epoxidation.

O

381

2.3 Oxiranes

N O

N

Cr

O

O

Figure 2.14 Stepped conformation of a salen(Cr) catalyst.

of up to 86% are achieved [418]. Gilheany and coworkers [419] have observed high (>90%) enantioselectivities for trans-alkenes using stoichiometric chromium complexes, albeit with modest chemical yields, presumably resulting from the formation of a m-oxo Cr(IV) dimer in situ. A systematic study of the effect of aromatic substituents on enantioselectivities [420] is consistent with an oblique approach of the substrate to a nonplanar (stepped) oxidized catalyst (Figure 2.14). An interesting reversal of chiral induction in chromium(III)-salen complexes using a tartaric derived alicyclic diamine moiety (i.e., 361) has been observed by Mosset, Saalfrank and coworkers [421]. Thus, epoxidation of the chromene 378 using catalyst 361 and an oxidant consisting of mCPBA/NMO afforded epoxide 379 in the (3S,4S) configuration, whereas a classical Jacobsen catalyst (357) provided the corresponding (3R,4R) enantiomer. This approach has been applied to the chiral epoxidation of chromene 380 using the readily available chromium salen catalyst 358 in a synthesis of the novel potassium channel activator BRL55834 [422]. The Katsuki group have focused their attention on (salen)Mn(III) catalysts of a slightly different configuration (e.g., 382–386, Figure 2.15), which are characterized as having chiral residues at the aromatic 3,30 -positions. These catalysts have been used to advantage in the epoxidation of conjugated cis-olefins [423], including chromenes [424, 425], benzocycloheptenes [426], dihydronaphthalenes [427] and enynes [428]. The proposed mechanism involves a flanking attack by the substrate, which is steered by both steric interactions (e.g., the cyclohexyl residue) as well as p–p repulsive forces. Generally speaking, the enantiofacial selection of cis-olefins in these catalyst systems appears to be influenced mainly by the chirality on the ethylenediamine bridge, whereas trans-olefin epoxidation seems to be directed more by the C3 and C30 substituents [429]. More subtle arguments have been invoked to rationalize the dichotomous behavior of the so-called “second-generation” Mn-salen catalysts 384 and 385 towards unfunctionalized and nucleophilic olefins. For example, higher yields and ees are obtained with the (R,S)-complex (384) for the epoxidation of indene (387, Scheme 2.61). However, N-toluenesulfonyl-1,2,3,4-tetrahydropyridine (389) gave better results using the (R,R)-diastereomer (385). An analysis of the transition-state enthalpy and entropy terms indicates that the selectivity in the former reaction is enthalpy driven, while the latter result reflects a combination of enthalpy and entropy factors [430]. Other structural modifications to salen catalysts can confer operational advantages. For example, hydrogen peroxide is attractive as a terminal oxidant due to its low cost and ready availability, but epoxidations using this reagent tend to be less enantioselective and more prone to radical-induced side reactions. In some cases, these

j73

j 2 Three-Membered Heterocycles. Structure and Reactivity

74

Ph

Ph N

N

N

PF6-

PF6-

Me H

Ph Et

Et Ph

N

Mn+ O O

Mn+ O O Me

Me H

Ph Me Ph

H Me

382

383

Ph * N

* N

Ph

N

N

Mn

Mn O

Me H

O

O

O

Ph Ph

Ph Ph

386

384 (R,S) 385 (R,R) Figure 2.15 Salen catalysts with chirality at the 3-position.

O

384

387

PhIO 57% yield 96% ee

385 N Ts 389

PhIO 61% yield 94% ee

388

O N Ts 390

Scheme 2.61 Salen(Mn) catalyzed alkene epoxidation.

disadvantages have been circumvented by using bioinspired models [431]. For example, by tethering an imidazole moiety to a chiral salen-type Mn(III) catalyst, an axial ligand is provided that imitates a peroxidase coordination sphere while still taking advantage of the asymmetric active site of the chiral (salen)Mn(III) species.

2.3 Oxiranes NH Ph N t-Bu

N

+

H

Mn

CH3

O

N

N Mn O O

O

N

R

O

Ph O R

Cl

t-Bu

391

Ph O

392

Ph

N

N Mn

N

O

N t-Bu

O

t-Bu

Et

Cl n-Bu

Et

Et Et

393

O

Et

N Mn Cl O

O

t-Bu

Et Et

O

394

Figure 2.16 Modified salens and salen analogs.

The resulting catalyst (391, Figure 2.16) can be used at 10 mol.% loadings with dilute hydrogen peroxide as an oxidant [432]. In a similar vein, the chiral dicarbonyliminato manganese(III) complex 392 is effective using molecular oxygen as the terminal oxidant [433], and the manganese-picolinamide-salicylidene complex 393 exhibits excellent turnover using sodium hypochlorite [434]. The recently disclosed macrocyclic analogue 394 gives very promising results indeed. At a 5 mol.% loading with two equivalents of sodium hypochlorite as a terminal oxidant, chromene 378 is epoxidized in quantitative yield and 93% ee [435]. No small amount of effort has been directed towards the development of immobilized catalysts, both for ease of catalyst recovery and for application to solid-phase combinatorial synthesis. Toward this end, the catalytic moiety has been tethered to a solid support via either the ethylenediamine portion [436] or the salicylaldehyde subunit [437] to give immobilized catalysts of type 395 and 396, respectively (Figure 2.17). These are the first gel-type resins to give results rivaling solution-phase counterparts. The backbone of Jacobsen’s catalyst has also been immobilized on silica gel by radical grafting (e.g., 397) [438] and it has even been prepared in polymeric form (i.e., 398) [439]. Other approaches include the use of perfluoroalkyl-substituted catalysts (e.g., 399) in a fluorous biphasic system [440] and the conventional Jacobsen’s catalyst 356 in a medium of the air- and moisture-stable ionic liquid [bmim][PF6] [441]. A somewhat different approach to catalyst separation has been devised by engineering the chiral salen catalyst to have built-in phase-transfer capability, as exemplified by the Mn(III) complex 400 [442]. Thus, enantioselective epoxidation of

j75

j 2 Three-Membered Heterocycles. Structure and Reactivity

76

H N

O N

O O

N

N

t-Bu

O

O

O

Mn t-Bu

O

t-Bu

t-Bu

395

Ph

t-Bu

t-Bu

396

Ph

N

TMSO

N

Mn O O Cl

O

Cl t-Bu

N

N

Mn

SiO2

S

O

O

Cl

n

t-Bu

n

t-Bu

397

N

N

N

Mn O

O

O

C 8F17

Cl t-Bu

N

Mn O

Cl

t-Bu

C 8F 17

n

398

399 Ph

Ph N

N N

Mn O O

H2 C

H2 C N

Cl t-Bu

t-Bu

400

O N

N

O

Mn O

C 8F 17

O

Ph Ph P

PF6

401 Figure 2.17 Salens designed for biphasic systems.

C8 F17

2.3 Oxiranes

chromene derivatives (e.g., 402) in the presence of 2 mol.% catalyst 400 and pyridine N-oxide (PNO) under phase-transfer conditions (methylene chloride and aqueous sodium hypochlorite) proceeded in excellent yield and very good ees (Scheme 2.62). The catalyst loading could be reduced to about 0.4% with only marginal loss of efficiency. Finally, Smith and Liu [443] immobilized a Katsuki-type salen ligand by an ester linkage to Merrifield’s resin to produce catalyst 401. In a test epoxidation of 1,2dihydronaphthalene (404) using sodium hypochlorite as an oxidant and 4-phenylpyridine N-oxide (4-PPNO) as an activator, the immobilized (salen)Mn complex sustained high enantioselectivity (>90%), even after being recycled six times.

H

400

NaOCl PNO

NC O

402

CH2 Cl2 0°C, 7 h > 99% yield > 98% ee

NC O

403 H

401

NaOCl 4-PPNO

404

CH2 Cl2 0°C, 48 h 70% yield 94% ee

O

O

405

Scheme 2.62 Epoxidation with immobilized metal salen catalysts.

No discussion of metal-catalyzed epoxidation could be complete without addressing Sharpless chemistry. Now an imbedded part of the synthetic organic canon, this topic has been very nicely summarized in a recent review article [444]. Two common catalysts in this regard are VO(acac)2 and Ti(Oi-Pr)4, and although their first applications were reported decades ago, the methodology is still very much in currency. Thus, the vanadium-mediated diastereoselective epoxidation of allylic alcohols, a key step in the synthesis of Cecropia juvenile hormone (i.e., 406 ! 407, Scheme 2.63) described in 1974 [445], was employed in much the same form in 2006 in the epoxidation of the highly functionalized allylic alcohol 408, providing a key intermediate for an approach to the quartromicins [446]. Likewise, the classic tartrate/titanium-mediated asymmetric epoxidation of allylic alcohols (i.e., 410 ! 411), the scope of which was described in detail by Sharpless in 1987 [447], is an almost indispensable tool for the synthetic chemist, as evidenced by its application in the construction of the bicyclic ether core of ( þ )-sorangicin A (i.e., 412 ! 413) reported by Crimmins and Haley [448]. These protocols continue to provide springboards for further development and innovation. For example, Hussain and Walsh [449] have developed a Sharplessinspired tandem alkylation/epoxidation of prochiral enones to provide chiral nonracemic hydroxyepoxides. Yamamoto and coworkers [450] have developed a chiral

j77

j 2 Three-Membered Heterocycles. Structure and Reactivity

78

O

VO(acac)2 TBHP toluene 0°C > 82% yield > 98% de

OH

406 OTBS Me

VO(acac) 2 TBHP toluene 0°C

Me

O

OTBS

OH

TBDPSO

OH

407

Me

PhNCO Et 3N CH 2Cl 2 TBDPSO 88% overall d.r. 20:1

O

NHPh

O

Me

408

409 Ti(Oi-Pr) 4 (+)-DET

OH

O

TBHP CH 2Cl 2 -20°C, 45 min 95% yield 91% ee

410

OH

411

p-MeOPh

p-MeOPh

O

O

Ph Me

OH

Ti(Oi-Pr) 4 (+)-DET TBHP CH2 Cl2 -20°C, 14 h 68%

412

O

O

O

OH

Ph Me

413

Scheme 2.63 Epoxidation under Sharpless conditions.

hydroxamic acid (414) derived from binaphthol, which serves as a coordinative chiral auxiliary when combined with VO(acac)2 or VO(i-PrO)3 in the epoxidation of allylic alcohols. In this protocol, triphenylmethyl hydroperoxide (TrOOH) provides markedly increased enantiomeric excess, compared to the more traditional t-butyl hydroperoxide. Thus, the epoxidation of (E)-2,3-diphenyl-2-propenol with 7.5 mol.% VO(i-PrO)3 and 15 mol.% of 414 in toluene (20
C; 24 h) provided the (2S,3S) epoxide 416 in 83% ee. Malkov and coworkers were able to carry out the same transformation in 92% yield and 94% ee using a cyclohexylamine-derived sulfonamide hydroxamic acid catalyst [451]. An alternative organic peroxide source is also at the heart of another modified catalytic Sharpless epoxidation of allylic alcohols, in which the tertiary furyl peroxide 417 serves as the terminal oxidant in the presence of L-diisopropyl tartrate (L-DIPT). Thus, trans-2-methyl-3-phenylprop-2-en-1-ol (364) was converted into epoxide 365 in 87% yield and with 97% ee using a catalyst loading of 20 mol.% [452] (Scheme 2.64).

2.3 Oxiranes

CO2NHCHPh2 OMe

Ph Ph

414 OH

Ph

VO(Oi-Pr)3 TrOOH

O

j79

Ph *

OH (83% ee)

*

416

415 414

Me

OOH O

Ph

417

417 OH

364

Ti(Oi-Pr)4 L -DIPT

Ph

O

Me *

OH (87% yield; 97% ee)

*

365

Scheme 2.64 Modified Sharpless conditions.

Biological models have inspired the adaptation of metalloporphyrin complexes for synthetic processes. For example, chloroperoxidase (CPO) catalyzes the epoxidation of many simple cis-alkenes with high enantioselectivity, although bulkier substrates tend to lead to low conversion and terminal alkenes alkylate the catalyst [453]. A more generally applicable analog can be found in the iron(III) tetrakis(pentafluorophenyl) porphyrin 418a (Scheme 2.65), for which considerable mechanistic studies have been carried out [454, 455]. Cyclooctene (419) is smoothly epoxidized by 418a using hydrogen peroxide as the terminal oxidant. Many interesting modifications have been made to the porphyrin template, most notably for the purposes of asymmetric induction, which has been the subject of a recent review [456]. Thus, the binaphthyl strapped iron-porphyrin catalyst 424 promotes the enantioselective epoxidation of styrene (10) with iodosylbenzene to give (R)-styrene oxide (421) in excellent yield and enantiomeric excess [457]. Effective non-heme iron catalysts using pentadentate bispidine ligands have also been studied [458]. Some interesting ruthenium porphyrins have also been reported, including a dioxoruthenium(VI) species [459] and the ruthenium(II) catalyst 418b, which functions as a photosensitizer capable of effecting the selective epoxidation of alkenes (e.g., 422) using water as an oxygen source, although the method suffers from the limitation of requiring hexachloroplatinate as an electron acceptor [460]. Metalloporphyrins of all stripes have been appended to solid supports, and the reader is directed to a recent and effective review on the topic for further information [461]. Polyoxometallates (POMs) have been in the research crosshairs lately, as evidenced by a recent review [462]; this interest stems in some portion from their ruggedness and environmental acceptability. As an example, the sandwich-type POM [WZnMnII2(ZnW9O34)2]12 catalyzes the selective epoxidation of chiral allylic alcohols with aqueous hydrogen peroxide under mild conditions. Thus, 4-methylpent-3en-2-ol 425 is converted into the threo epoxide 426 in 88% yield and 84% de (Scheme 2.66). The diastereoselectivity is highly sensitive to the substitution about

j 2 Three-Membered Heterocycles. Structure and Reactivity

80

R2

R1

R2 R1

R1

R1

R2

R2 R1

R1

N N

M

N

N

R1

R1 R2

R2 R1 R1

R1 R1

R2

R2

418a, R1= R2 = F; M = Fe(Cl) 418b, R1= Me; R2 = H; M = Ru(CO) 418a

O

(88%)

H2O2 MeCN/ MeOH

419

420 424 (1 mol%)

Ph

O

PhIO CH2Cl2 -5°C

10

Ph

(R)-421

418b

O

(99.7% selectivity)

K 2PtCl6 H2O MeCN 420 nm

422

(96% yield; 97%)

O

423

H N

H N

O

N OMe OMe

N

Fe

N Cl

MeO MeO

N

O

N H

N H

424 Scheme 2.65 Epoxidations using metalloporphyrins.

O

2.3 Oxiranes OH

[WZnMn II 2(ZnW 9O 34)2 ]12(0.1 mol%) 30% H 2O2 (2 eq) 20°C, 6 h 88% yield 84% de

OH O

425

Ph

Ph Ph

HO

Ph OOH

O

O

427

426

Ph

OH

[ZnW(VO) 2(ZnW 9O 34)2 ]12(0.01 mol%)

427 (1.1 eq)

Ph

428

ClCH2 CH2 Cl 89% yield 84% ee

Ph O

OH

Ph

429

Scheme 2.66 Epoxidations using polyoxometallates (POMs).

the double bond, with trans-pent-3-en-2-ol giving a 1 : 1 mixture of threo and erythro epoxides under the same conditions. The key intermediate is believed to be a tungsten peroxo complex rather than an oxo-Mn species [463]. Self-assembled POM catalysts can also be immobilized within layered double hydroxides (LDH) using ionexchange techniques [464]. A polyoxometallate is also at the heart of an enantioselective epoxidation of allylic alcohols using C-2 symmetric chiral hydroperoxide 427 derived from 1,1,4,4tetraphenyl-2,3-O-isopropylidene-D-threitol (TADDOL). Thus, in the presence of the oxovanadium(IV) sandwich-type POM [ZnW(VO)2(ZnW9O34)2]12 and stoichiometric amounts of hydroperoxide 427, the stilbenemethanol derivative 428 is converted into the (2R) epoxide 429 in 89% yield and 83% ee. The proposed catalytic cycle invokes a vanadium(V) template derived from the POM, substrate and hydroperoxide – a hypothesis supported by the lack of enantioselectivity with unfunctionalized alkenes. The catalytic turnover is remarkably high at about 40 000 TON [465]. Under the rubric of other metal catalysts, methyltrioxorhenium (MTO) represents a fascinating entry. Unlike titanium catalysts (see above), MTO appears not to engage allylic alcohols in tight metal-alcoholate binding, although hydrogen bonding with the substrate can play a role in nonpolar solvents [466]. However, in polar protic media alkenes proximal to a hydroxy group no longer command preferential epoxidation. Thus, treatment of geraniol (410) with MTO affords epoxide 430 as the major product (Scheme 2.67), providing a complementary alternative to conventional methods [467]. For simple allylic alcohols (e.g., 431) formation of the threo epoxide (e.g., 432) predominates – presumably the result of 1,3-allylic strain in the hydrogen bonded catalyst–substrate complex. Unfunctionalized alkenes are also efficiently epoxidized, as illustrated by the practically quantitative conversion of vinylcyclohexane (433) into epoxide 434 [468]. Compatible oxygen donors include hydrogen peroxide and its urea adduct (UHP) [469]; perfluoroalkanol solvents tend to

j81

j 2 Three-Membered Heterocycles. Structure and Reactivity

82

OH

O

MTO

OH

UHP

410

430 OH

OH Me t -Bu

MTO H 2 O2 d.r. > 95:5

431

O

Me t -Bu

432 O MTO (0.1 mol%)

433

pyrazole (5 mol%) H 2O2 (2 eq) F3CCH 2 OH > 99%

434

Scheme 2.67 Epoxidations using methyltrioxorhenium (MTO).

give superior results [470]. A polymer-supported version of MTO has also been disclosed [471]. Other noteworthy biphasic and supported metal catalyst systems [472] include hydrotalcite with hydrogen peroxide [473], cobalt-modified hydrotalcite with molecular oxygen [474], manganese dicarboxylate coordination polymers with hydrogen peroxide [475], a binuclear manganese carboxamide array with dioxygen [476], and aqueous sodium tungstate under phase-transfer conditions [477]. A fascinating “triphase” catalyst for epoxidation of allylic alcohols has been prepared from the combination of phosphotungstic acid and an amphiphilic poly(N-isopropylacrylamide)-derived polymer, which yields a macroporous complex (435, Scheme 2.68). Thus, treatment of allylic alcohol 436 with 0.003 mol.% catalyst 435 and 2 equivalents of hydrogen peroxide in aqueous medium furnished the corresponding epoxide 437 in 96% yield. The catalyst exhibits a very high turnover rate (35 000), is easily recoverable by filtration and is reusable without loss in efficacy [478]. Also in the category of organic–inorganic hybrids, titanium-silsesquioxane catalysts have been prepared by the complexation of titanium to incompletely condensed silsesquioxanes [479]. Lipophilic alkenes such as 404 can be epoxidized in a triphasic system using ionic liquids, with epoxidation components being provided via an aqueous phase and the reaction products (e.g., 405) extracted into a pentane layer [480]. Simple alkenes are also converted into epoxides in high efficiency using a recyclable immobilized molybdenum catalyst (438) prepared by the reaction of aminated polystyrene and molybdenum hexacarbonyl. For example, cyclohexene (439) is quantitatively epoxidized within 5 h using 1 mol.% of catalyst 438 with t-butyl hydroperoxide (TBHP) as an oxygen donor [481]. Finally, a combination of wet copper(II) sulfate and potassium permanganate in t-butanol (Parish conditions) represents a simple and inexpensive reagent for the

2.3 Oxiranes

j83

H3PW12O40

amphiphilic copolymer

435 Ph

OH

436

435

Me 4N + HCO 3[bmim][BF 4 ] 95%

438

N

439

OH

437

405

H N Mo(CO) 5

438

Ph

O

MnSO4 H 2O2

404

O

30% H 2O2 r.t. 96%

TBHP CCl4 100%

O

440

Scheme 2.68 Other immobilized metal epoxidation catalysts.

epoxidation of cyclic alkenes. Thus, stigmasteryl acetate was selectively converted into the 5,6-epoxide in near quantitative yield. The mechanism is believed to involve a series of electron transfers mediated by copper(II) permanganate [482]. 2.3.2.4 Epoxidation of Electron-Deficient Alkenes Different conditions usually apply for the epoxidation of electron-poor olefins [483], most of which capitalize on the susceptibility of the substrate toward nucleophilic attack. More recent innovations in this regard include the use of basic hydrogen peroxide in an ionic liquid/aqueous biphasic system [484] or aqueous hydrogen peroxide in the presence of natural phosphate [485] or hydrotalcite with ultrasound [486]. Non-aqueous systems commonly employ TBHP, and this oxidant can be effectively catalyzed by a non-nucleophilic base, such as the guanidine derivative 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) [487], or even by potassium fluoride adsorbed onto alumina [488]. The methodology is not limited to conventional nucleophilic chemistry: electron-deficient alkenes can also be epoxidized under electrochemical conditions using a silver(III)oxo bis(2,20 bipyridine) catalyst [489] as well as with more electrophilic oxidizing agents, such as iodosylbenzene [490]. As with epoxidation protocols in general, vigorous activity has surrounded the asymmetric synthesis of epoxides from electron-deficient alkenes, and many chiral catalysts and auxiliaries have been developed for this purpose (Figure 2.18). A common test reaction for comparing yields and enantioselectivities is the epoxidation of chalcone (453, Scheme 2.69); Table 2.16 summarizes some illustrative contribu-

j 2 Three-Membered Heterocycles. Structure and Reactivity

84

N

N

N

HO

H

H BzO Br

N

N H

RO

N R'

Br

Cl R"

OMe

441

R'

442

443, R=R'=H; R"=I 444, R=Bn; R'=t-Bu; R"=OMe

Ph Ph

N H

NMe2

445

H

O

N

O N H

H

O

OH

O

N H

454

Me

OOH

H N

OMe

446

H

N

N

448

447

· 2 CF3SO3

MnII

8

8

Me N

N

449

Ph O Yb

Oi-Pr HexO

O

OHex HO OH

Ph

450

OHex OH OH

HexO HO HO

O O=AsPh3 La

Oi-Pr

O

452 451 Figure 2.18 Chiral catalysts and auxiliaries for electron-deficient alkenes.

tions to this methodology. For example, Cinchona-derived phase-transfer catalysts (e.g., 441–444) are effective in aqueous organic systems (entries 1–3) [491–493]. As a further demonstration of chiral pool inspired catalysts, proline-derived aminoalcohols (e.g., 445) promote asymmetric epoxidation of enones through non-covalent catalysis [494, 495]. Oligopeptides also show promise as chiral auxiliaries [496], as

2.3 Oxiranes

O

O

conditions Ph

Ph

(see Table 2.16)

O

O

or Ph

Ph (+)-454

453

O Ph

Ph (-)-454

Scheme 2.69 Asymmetric epoxidation of chalcone.

Table 2.16 Yield data for the asymmetric epoxidation of chalcone.

Entry

Catalyst

Oxidant

Solvent

Yield (%)

ee (%)

Conf.

Ref

1 2 3 4 5 6 7 8

442 443 444 445 447 450 451 452/Et2Zn

NaOCl H2O2/LiOH NaOCl TBHP Urea-H2O2 CHP TBHP TBHP

Toluene Bu2O Toluene Hexane

98 97 91 90 >99 91 95 95

86 84 60 91 94 97 97 74

(þ) (þ) (þ) () () () (þ) ()

[424] [425] [426] [494] [428] [429] [430] [432]

THF THF Et2O

illustrated by the novel poly(ethylene glycol)-supported oligo(L-leucine) catalyst 447 used to carry out the Juli
a–Colonna epoxidation of chalcone through a continuously operated “chemzyme” membrane reactor with urea-hydrogen peroxide as the terminal oxidant [497]. The chiral ytterbium complex formed from Yb(i-PrO)3 and 6,60 -diphenyl-BINOL (450) catalyzed the epoxidation in 91% yield and 97% ee using cumene hydroperoxide as the oxygen source [498]. A similar outcome, but a much more rapid conversion, is achieved using the lanthanoid-BINOL-triphenylarsine complex 451, which provides complete epoxidation in three minutes [499]. This protocol was used as a key step in the synthesis of ( þ )-decursin from commercially available esculetin [500]. Solidsupported catalysts have also been reported, including the complex formed by treating binaphthyl polymers (e.g., 452) with diethyl zinc [501]. The tridentate aminodiether ligand 446 has been used with lithium cumene hydroperoxide to give fair to good enantioselectivities in the epoxidation of certain enones (e.g., 456, Scheme 2.70), presumably through a tetracoordinate lithium complex [502]. The chiral peroxide 448 was effective in the epoxidation of 2methylene-1-tetralone derivatives, such as 458 [503], as was the immobilized synthetic peptide poly-L-leucine (i-PLL) in the presence of urea-peroxide and DBU in a solvent of isopropyl acetate [504]. As is the case with unfunctionalized alkenes, electron-deficient olefins are also subject to asymmetric epoxidation using chiral dioxirane reagents [505]. Interestingly, the chiral cationic manganese bis(pyridyl) catalyst 449 provided for very little asymmetric induction, although it was nevertheless quite efficient in promoting the epoxidation of enones such as cyclohexenone

j85

j 2 Three-Membered Heterocycles. Structure and Reactivity

86

O

O

446 Ph

t-Bu

456

CHP/LiCHP 76% yield 71% ee

O Ph

t-Bu

457

O

O

448 t-Bu

458

O t-Bu

KOH MeCN -40°C 90% yield 90% ee

459 O

O

449

460

CH3CO 3 H MeCN r.t., 5 min 88% yield < 10% ee

O

461

Scheme 2.70 Other epoxidations with chiral catalysts and reagents.

(460). When both electron-rich and electron-poor olefins are affixed to the same substrate, the former are preferentially oxidized [506]. In the realm of on-board chiral auxiliaries, proline-derived cinnamides (e.g., 462, Scheme 2.71) were epoxidized with lithium t-butyl hydroperoxide with excellent diastereoselectivity, although in moderate yield [507]. Use of a 2,2-dimethyloxazolidine chiral auxiliary (e.g., 464) led to superior yields but somewhat attenuated diastereomeric excess [508]. The nucleophilic epoxidation of c-hydroxy-vinyl sulfoxide derivatives (e.g., 466) proceeds both in high yield and exclusive diastereoselectivity. The latter outcome has been rationalized by invoking a geometrically constrained chair-like transition state [509]. 2.3.2.5 Epoxidation of Carbonyl Compounds Just as aziridines can be prepared by the addition of carbenes (or carbene equivalents) across imines, so too can epoxides be synthesized from carbonyl compounds, particularly aldehydes. A recent review has brilliantly captured the synthetic utility of this approach [90]. One prototypical example is the conversion of 4-chlorobenzaldehyde (468) into the corresponding styrene oxide (469) by treatment with diiodomethane and methyllithium at 0
C. The mechanism is believed to proceed through a sequence of lithium–halogen exchange, carbonyl addition and rapid ring closure of the intermediate iodoalkoxide [510]. The Corey–Chaykovsky synthesis [511], by now a standard method, is nevertheless still the subject of current innovation [512]. This reaction, like most other methylenations, relies upon an intermediate sulfur ylide to serve as a methylene transfer reagent. Recent reports have shown that dry mixtures of trimethylsulfonium iodide

2.3 Oxiranes

O

O

N

Ph

TBHP n-BuLi 48% yield > 99% de

O PhHN

N

Ph O

PhHN

463

462

O

O O

O

mCPBA

N

O

CH2 Cl2 r.t. 24 h > 95% yield 86% de

Ph

464

Ph

465

O S

p -Tol

TBDPSO Me

466

O

N

O t-BuOOK

THF 90% yield 100% de

p-Tol

S O

TBDPSO Me

467

Scheme 2.71 Diastereoselective epoxidations with chiral auxiliaries.

and sodium hydride form a shelf-stable source of “instant methylide” upon treatment with carbonyl compounds in a polar aprotic solvent. Thus, combination of 4methylacetophenone (470, Scheme 2.72) with the “instant methylide” reagent in dimethyl sulfoxide (DMSO) resulted in the high-yielding formation of the corresponding epoxide 471 [513]. The Corey–Chaykovsky epoxidation has also been adapted for use in an ionic liquid medium, such as (bmim)PF6 [514]. Some methylides are conveniently available through a novel thermal decarboxylation of carboxymethylsulfonium betaines. Thus, treatment of the sulfonium bromide 472 with silver oxide affords the corresponding betaine 473, which exhibits a half-life of 5 h in chloroform at room temperature, but can be stored for months neat at 98%

Scheme 2.79 Epoxide ring opening with oxygen nucleophiles.

O

OH OTIPS

538

2.3 Oxiranes

carbonate [594] and p-toluenesulfonic acid [595]. In one such intramolecular epoxide ring opening – a key step in the diastereoselective synthesis of a-tocopherol – anhydrous hydrochloric acid in ether/acetonitrile was chosen to promote the disfavored 6endo-tet ring closure mode [596]. Among sulfur-centered nucleophiles, thiocyanate is frequently encountered. For example, the epoxy ester 540 (Scheme 2.80) is smoothly converted into the thiocyanato adduct 541 using stoichiometric ammonium thiocyanate and a quaternized amino functionalized cross-linked polyacrylamide (539) as a solid–liquid phase-transfer catalyst in acetonitrile [597]. Hydroxysulfones can be prepared “on water” by the action of sodium benzenesulfinate on epoxides with no added catalyst [598]. Thiophenol is another useful species that adds under very mild conditions, as shown by the ring-opening of the cyclohexadiene oxide derivative 542 catalyzed by ytterbium triflate in toluene, whereby the thiophenol moiety attacks the allylic site of the epoxide ring [599]. In another example, unfunctionalized epoxides (e.g., 544) can be transformed into allylic alcohols 547 through an initial epoxide ring-opening with thiophenol in hexafluoroisopropanol (HFIP) and in situ oxidation to the sulfoxide (546), followed by pyrolysis in the presence of potassium carbonate [600]. Thiols can also be added using tributylphosphite [166], lithium perchlorate [601, 602], montmorillonite K-10 clay under solvent-free microwave conditions [603], in water [604], and in ionic liquids without additional catalysts [605]. The addition of RongaliteÒ allows for the use of disulfide thiol precursors [606], and the entantioselective cleavage of meso-epoxides with thiophenol can be achieved using a heterobimetallic Ti-Ga-salen catalyst [607].

O

H N

NMe 3

O

O

Cl n

540

O

PhSH

O

Yb(OTf) 3 toluene 89%

O

542

O

541

O O

PhS OH

543 OH

OH

PhSH HFIP

544

SCN

Br

Br

O

OH O

MeCN 1h 91%

O

539

539 NH4SCN

S

SPh

545

546

O

OH Ph

547

Scheme 2.80 Epoxide ring opening with sulfur nucleophiles.

Finally, halides are interesting nucleophiles inasmuch as they preserve the electrophilic character of the center they substitute. As a representative example of these additions, chloride can be introduced using bis-chlorodibutyltin oxide in

j97

j 2 Three-Membered Heterocycles. Structure and Reactivity

98

chloroethanol, as shown in the conversion of phenylmethyl epoxide 521 (Scheme 2.81) into chlorohydrin 548 [608]. Similarly, the terminal epoxide 549 is converted almost quantitatively into the bromohydrin 550 with lithium bromide in the presence of silica gel in methylene chloride [609]. Bromide-mediated ringopening can also be executed using a combination of N-bromosuccinimide, triphenylphosphine and dimethylformamide [610]. Most nucleophilic of all, iodide readily attacks styrene oxide (421) to give the iodohydrin 551, and the use of b-cyclodextrin directs the addition to the less-substituted carbon, presumably due to steric hindrance caused by guest–host complexation [611]. In the realm of asymmetric synthesis cyclic meso-epoxides can be desymmetrized by chloride attack using silicon tetrachloride catalyzed by PINDOX [612].

(Bu2 SnCl) 2O

O

Ph

OH Ph

ClCH 2CH2 OH 93% 521

Cl 548

O O

CH2 Cl2 r.t., 3 h 99%

n-octyl 549

O Ph 421

OH

LiBr SiO2

O

Br

n -octyl 550

β-cyclodextrin HI H 2O 95%

OH I

Ph 551

Scheme 2.81 Epoxide ring opening with halide nucleophiles.

2.3.3.2 Rearrangements Epoxides can be isomerized to allylic alcohols using hindered bases. For example, a-pinene oxide 552 (Scheme 2.82) undergoes eliminative ring opening upon treatment with lithium diethylamide. The transformation proceeds in higher yields in the presence of lithium t-butoxide, which is believed to disrupt aggregation of the anion [613]. Similarly, the optically pure bicyclic epoxide 554 is converted into the methylenecyclohexenol derivative 555 in excellent yield using diethylaluminium 2,2,6,6-tetramethylpiperidide (DATMP) in toluene [614]. Milder bases can be used when activating groups are nearby. Thus, the hydroxyepoxide 556 is smoothly oxidized to the corresponding ketone under Dess-Martin conditions, making the a-protons acidic enough to remove with sodium hydroxide, leading to the enone

2.3 Oxiranes

O

OH

LDEA t-BuOLi 552

553 OH

O DATMP OTBDPS

toluene 0°C 97%

OTBDPS

554

555 H

H

OH

H

O

Dess-Martin

1N NaOH

CH2 Cl2 r.t., 12 h

83%

O

H OH 557

556 R NH

OH

559 (5 mol%)

N

O R

558, R=H 559, R=Me

560

O

LDA / DBU THF 81% yield 96% ee

561

HO 558 (10 mol%)

562

LDA / DBU THF 45% yield 90% ee

563

Scheme 2.82 Base-catalyzed rearrangement of epoxides to allylic alcohols.

product 557 [615]. Finally, the isomerization can occur under essentially neutral conditions using titania-supported gold nanoparticles [616]. The enantioselective isomerization of meso epoxides to allylic alcohols continues to be a promising route for the preparation of these materials in high optical purity. In an extension of their ongoing work in this area with lithium amide bases [617], Andersson and coworkers have designed the optically active (1S,3R,4R)-[N-(trans-2,5dimethyl)pyrrolidinyl]-methyl-2-azabicyclo[2.2.1]heptane (559), which exhibits superior chiral induction in catalytic quantities using lithium diisopropylamide

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j 2 Three-Membered Heterocycles. Structure and Reactivity

100

(LDA) as the stoichiometric base. Thus, the challenging substrate cyclopentene oxide (560) was cleanly isomerized to the chiral cyclopentenol 561 in 81% yield and with 96% ee – a significant improvement over the 49% ee obtained with higher loadings of the earlier generation catalyst 558 [618]. Diamines derived from (R)-phenylglycine have also given promising results [619]. The chiral amide approach has also been applied to the catalytic kinetic resolution of racemic epoxides. For example, exposure of the tricyclic epoxide 562 to 10 mol.% 558 and stoichiometric LDA at 0
C led to the recovery of the chiral spiro[4.5]decenol 563 with 90% ee and in 45% isolated yield, compared to the theoretical 50% maximum [620]. Chiral nonracemic aminoepoxides are isomerized stereoselectively to aminoalcohols using the superbasic mixture of nbutyllithium, diisopropylamide and potassium t-butoxide (LIDAKOR) [621]. In addition to b-elimination, the epoxide moiety also undergoes rearrangement to a carbonyl group, and this reactivity can be quite synthetically useful. The course of the rearrangement is highly dependent upon the nature of the substrate. Generally, the regiochemistry is driven by two factors: (i) the stability of the nascent carbocation generated from ring opening and (ii) the migratory aptitude of the adjacent substituents. For example, the simple monoalkyl-substituted epoxide 564 (Scheme 2.83) undergoes regioselective rearrangement in the presence of iron(III)tetraphenylporphyrin to give the corresponding aldehyde (565) via a 1,2-hydride shift onto an incipient secondary cationic center [622], a process also promoted by sodium periodate under ambient conditions [623]. Terminal epoxides react with tetraallyltin in the presence of bismuth(III) triflate to give homoallylic alcohols 568. The reaction involves an initial 1,2-shift to form aldehyde 567, which is then attacked by the allyl tin species [624]. A similar but operationally more straightforward protocol is available by combining allyl bromide with indium metal, followed by the addition of epoxide [625]. O Ph

Fe(tpp)OTf

H

564 O

Cl

Bi(OTf) 3

565 Cl

O

CH2 Cl2

566

O

Ph

94%

H

Sn(CH 2CH=CH 2 )4

Cl

OH

(one pot) 90%

567

568

Scheme 2.83 Rearrangement of terminal epoxides to aldehydes.

When trans-stilbene oxide (569, Scheme 2.84) is treated with bismuth triflate, aldehyde 570 is formed through a process of benzylic cation formation and subsequent phenyl migration [626]. However, the structurally very similar epoxide 571 provides a ketone upon treatment with Lewis acid, which reflects a more facile hydride shift to the cationic center [627]. Certain alkoxymethyl groups can also easily migrate, as seen in the rearrangements of epoxides 573 [628] and 575 [629]. In the latter example, the siloxy migration was an unwanted (albeit efficient) side reaction of

2.3 Oxiranes O O

Bi(OTf) 3 ·xH 2 O

H

CH 2Cl 2 92%

Ph

Ph

Ph Ph

569

570 O

Ph

O

BiOClO 4 Me

Ph

CH 2Cl 2 70%

571

Me

572 TBSO

O

TBSOTf

TBSO

OBn

O

iPr 2 NEt

OBn

573

574

TBDMSO O

TBDMSO

CO 2Me

O

CO2 Me

BF 3·OEt 2 78% OTBDMS

OTBDMS

575

Me

576 Ph

HO

Et

577

O

Yb(OTf) 3

O

CH 2Cl 2 99%

OH

Me

Et Ph

578

Scheme 2.84 Rearrangement of internal epoxides to aldehydes ketones.

a desired cationic ring closure; changing to a trimethylsilylethoxymethyl (SEM) protecting group resolved this problem. An analogous rearrangement can occur in epoxyalcohols of type 577, which cleanly produced the hydroxyketone 578 in almost quantitative yield after 3 h upon exposure to 20 mol.% ytterbium triflate in methylene chloride [630]. This process can be used to advantage to access cyclic ketones, as well. For example, the cyclopentene oxide derivative 579 (Scheme 2.85) opens up to the more stable benzylic carbocation (i.e., 580), which then provides the cyclopentanone derivative 581 via 1,2-methyl migration in 93% yield [631]. An analogous mechanistic step begins the organoaluminium-promoted cyclization of olefinic epoxides (e.g., 583), whereby the initially formed aldehyde (584) undergoes a highly stereoselective Lewis acid-catalyzed intramolecular ene reaction to give the methylenedecalone 585 in the presence of methylaluminium bis(4-bromo-2,6-di-t-butylphenoxide) (MABR). This strategy is proposed as a route for the stereoselective synthesis of various terpenes [632].

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j 2 Three-Membered Heterocycles. Structure and Reactivity

102

O

OBF 3

O BF 3 ·OEt2

pMeOPh

pMeOPh

pMeOPh

CH 2Cl 2

93%

PNBO

PNBO

PNBO

580

579 tBu Br

581

tBu O

O

Al

Br

Me tBu

tBu

582, MABR

O O

MABR

OH

Al

H

H

H

H H

583

585

584 Scheme 2.85 Rearrangement involving cyclic structures.

The rearrangement sometimes occurs with concomitant ring contraction, as seen in the conversion of cyclohexene oxide derivative 586 (Scheme 2.86) into the cyclopentanealdehyde product 587 [633]. In a similar vein, Kita and coworkers [634] have used a novel acid-promoted rearrangement of cyclic a,b-epoxy acylates (e.g., 588) for the stereoselective synthesis of spirocyclanes (e.g., 589), a technique which is also found in the total synthesis of (–)-pseudolaric acid B by Trost et al. [635], and

O

BF 3

BnO

CHO

BnO 586

587 O

OBz

OBz

BF3 ·OEt2 O

CH2Cl 2 95% 588

Scheme 2.86 Rearrangement with ring contraction.

589

2.3 Oxiranes

which promises broad application to the preparation of optically active compounds of this type. Ring expansions are also possible. For example, treatment of the cyclopentylepoxide 590 (Scheme 2.87) with boron trifluoride etherate induces a cascade reaction involving desilylation of the alcohol and rearrangement to the cyclohexanone derivative 591 [636]. Similarly, cyclohexyl epoxides (e.g., 592) expand to form tropinones (593) [637]. Finally, although the process proceeds through a mechanisH

Me

TMSO

O

O

BF 3·OEt 2

Me

CH 2Cl 2 -78°C 2h 81%

590

Me

591 O

Ph OH

OH Me

O

SnCl 4 (2.0 eq)

Me

OH Ph Me

CH 2Cl 2 94% 592

593 O

O

CO 2 Me

LiI

CO 2Me

DMSO

CO 2Me

CO 2 Me CO 2 Me 594

595 O

I LiI CH2Cl 2

OLi

Ph

597

O

Ph

81% yield 90% de (R)-598

Ph 596 O

LA Et2 AlCl

O

toluene

Ph Ph

90% yield 90% ee

599 Scheme 2.87 Rearrangement with ring expansion.

(S)-598

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j 2 Three-Membered Heterocycles. Structure and Reactivity

104

tically distinct pathway, the iodide-mediated rearrangement of the spiroepoxide 594 produces the ring-expanded cyclohexanone 595 [638]. This was used in a very clever way to access both antipodes of phenylcyclopentanone (598) from spiroepoxide 596. The anionic iodide pathway led to smooth conversion into the (R)-isomer, while Lewis acid catalysis provided equally high optical purity of the (S)-enantiomer [639]. 2.3.3.3 Radical Chemistry Li has authored an excellent overview of the radical reactions of epoxides, to which the reader is directed [640]. While this field encompasses some fascinating chemistry, yields and selectivities tend to be rather widely distributed. Exceptions to this generalization are found in specifically functionalized epoxides. For example, the vinyl epoxide 600 (Scheme 2.88) suffers radical addition of tributyltin radical to give an a-epoxy radical, which immediately opens to the allylic alkoxy radical 601. This species engages in radical ring closure onto the pendant alkene to give, after hydrolysis, the bicyclic alcohol 604 in 89% yield [641, 642]. Samarium iodide promotes similar reactivity in ketoepoxides such as 605. Thus, single electron transfer from SmI2 to the carbonyl moiety gives the typical radical anion, which then isomerizes to the allylic alkoxy radical 607. Trapping of the samarium stabilized enolate 608 with phenylpropionaldehyde gives the dihydroxyketone 609 in excellent yield [643]. Titanocene-mediated radical cyclization of epoxides has been reviewed very recently [644], and this area is rapidly expanding in synthetic utility. Here a titanocene reagent such as Cp2TiCl engages the epoxide ring itself in single electron transfer, typically cleaving the weakest CO bond and forming the more substituted carboncentered radical, which can take part in further reactivity. For example, the epoxynitrile 610 is smoothly converted into the hydroxymethylcyclohexanone derivative 613 through a cascade of radical ring opening and subsequent cyclization onto the nitrile [645] (the intermolecular version of this methodology is promoted by titanocene [646]). Similarly, the propargylic epoxide 614 undergoes ring cleavage to give the secondary radical (615), which proceeds through 6-exo-dig radical cyclization to provide the methylenetetrahydropyran derivative 617 in high yield [647]. 2.3.3.4 Reduction and Deoxygenation Epoxides can undergo reductive ring opening using various reagents [648, 649]. One extremely mild protocol involves the use of bis(cyclopentadienyl)titanium(III) chloride. Significantly, the regioselectivity of the epoxide cleavage is often quite high, being determined by the stability of a radical intermediate, and sometimes opposite to what is expected for a classical SN2 epoxide ring opening. For example, treatment of spiroepoxide 618 (Scheme 2.89) with Cp2TiCl leads to an intermediate carbon radical that can be trapped by a H-atom donor (in this case cyclohexadiene) to give the secondary alcohol 620. By comparison, a “classical” reductive ring opening with lithium triethylborohydride gives only the tertiary alcohol 619 [650]. Iyer [651] and Dragovich [652] have independently reported the regiospecific ring opening of epoxides by way of a palladium-catalyzed transfer hydrogenolysis using ammonium formate as the hydrogen source. Under these conditions, hydride attacks at the less

2.3 Oxiranes HO

O

nBu3 SnH

Ph

AIBN 89%

600 . O

604 Bu 3SnO

Bu3 SnO

SnBu 3

Ph

.

Ph

Ph

. Ph

601

602

603 O

O

SmI 2

O

nPr

Ph

OH Ph

O .

Ph

606

O

O

O

HO

Ph

613

[Ti]O

HO .

.

Me

614

H3 O+

612

[Ti]O Cp 2TiCl

Me

N.

88%

611

THF r.t.

nPr

608

CN

.

H

OSmI 2 Ph

[Ti]O

O[Ti]

Cp2 TiCl (2.2 eq)

O

O Ph

I2 SmO

nPr

607

610

Ph

O.

I2SmO nPr

Ph

CN

nPr

609

605

I 2 SmO

Ph

O

90%

THF -45°C

Ph

HO H

O

615

Ph Me

88% O

616

Ph Me

O

617

Scheme 2.88 Some radical reactions of functionalized epoxides.

hindered carbon atom (e.g., 621 ! 622), except in the case of aryl-substituted epoxides, where ring opening occurs exclusively at the benzylic position (e.g., 421 ! 623). Lithium aluminium hydride has been used for the regio- and diastereoselective reductive ring opening of chiral nonracemic epoxides, such as 624 [653] (a key step featured in the enantiospecific synthesis of ( þ )-hernandulcin [654]), and racemic epoxides can be reduced to an enantiomerically enriched mixture of alcohols by treatment with zirconium tetrachloride–sodium borohydride in the presence of L-proline as a chiral auxiliary [655].

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j 2 Three-Membered Heterocycles. Structure and Reactivity

106

OH OH

O

LiBEt3 H

Cp 2 TiCl 91%

>95%

620

618

619

O Ph

OH

Pd/C HCO 2NH4 80%

Ph

621

622

O

Pd/C

Ph 421

OBn O

623 OH LAH 76% yield 96% de

RO

OH

Ph

HCO 2NH4 100%

624

RO OBn 625

Scheme 2.89 Reductive ring opening of epoxides.

The net reversal of the epoxidation reaction, namely the eliminative deoxygenation of epoxides, has been carried out in various ways. For example, tungsten reagents react with epoxides to form tungsten(IV)-oxo complexes that ultimately lead to the corresponding olefins with predominant retention of configuration [656]. Glycidyl acetates 626 (Scheme 2.90) undergo deoxygenation and concomitant deacetylation upon treatment with lithium telluride, which is conveniently prepared in situ from tellurium metal and lithium triethylborohydride [657]. Another extremely mild epoxide deoxygenation protocol involves the use of bis(cyclopentadienyl)titanium (III) chloride, which promotes homolytic cleavage of the epoxide CO bond. The mildness of this reagent is showcased in the deoxygenation of epoxide 628, which gives the highly sensitive methoxydihydrofuran derivative 629 in 66% yield [650]. Electrophilic halogen reagents are also useful in this regard. Thus, the system of iodine and triphenylphosphine in dimethylformamide effected the quantitative deoxygenation of the allyloxymethyl epoxide 630 [658a]. In addition, a novel deoxygenation protocol has been reported for the conversion of epoxyketones into the corresponding enones using thiourea dioxide as a reducing agent under phase transfer conditions [658b]. Essentially neutral conditions are obtained using molybdenum hexacarbonyl in refluxing benzene. The mechanism proceeds through initial loss of carbon monoxide followed by a complexation of the molybdenum center with

2.3 Oxiranes Te 0 LiEt3 BH

OAc

O Et

nHex

626

O O

TrO

OTr OMe

OH

THF 0°C, 24 h 98%

Et

627

O

Cp 2TiCl

TrO

OTr OMe

66%

628

O

nHex

629

O

Ph3 P I2

O

DMF 100%

630 O

O

O

O

632

631 O

Mo(CO)6

O Mo(CO) 5

benzene

95% O

O

633

634

Scheme 2.90 Reductive deoxygenation of epoxides.

the epoxide oxygen to provide an activated species (i.e., 633) that collapses to form the alkene (i.e., 634) [659]. The low-valent titanium catalyst Cp2TiCl, readily available by the in situ reduction of Cp2TiCl2 with activated zinc, has also been used for this type of deoxygenation [660, 661]. 2.3.3.5 Oxiranyl Anions Epoxides can be deprotonated on the ring, and the anions thus formed undergo interesting and synthetically useful chemistry, much of which has been summarized in recent review articles [196, 662, 663]. When electron-withdrawing groups are present, these stabilized oxiranyl anions engage in smooth SN2 reaction with various electrophiles. Thus, the sulfonyl epoxide 635 (Scheme 2.91) is deprotonated using n-butyllithium in HMPA/THF at low temperature and treated with triflate 636 to give the highly functionalized adduct 637 in 81% yield. This protocol was used for the construction of the ABCDEF-ring systems of yessotoxin and adriatoxin [664]. Similar sulfonyl oxirane strategies have been used in other synthetic applications [665–668]. The oxazolinyl group also provides a useful stabilizing moiety for such alkylations (e.g., 638 ! 639) [669]. In certain cases, even non-stabilized oxiranyl anions can be coaxed into wellbehaved conversions. Hodgson and coworkers [670] have reported on a convenient method of deprotonating terminal oxiranes with lithium 2,2,6,6-tetramethylpiperidide (LTMP), followed by trapping of the anion with silyl-based electrophiles, to

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108

BnO

TESO O

H

+ TfO

pTolSO 2

nBuLi HMPA

O O H

635

O

O

THF -100°C 81%

Si(tBu) 2

OTES

BnO

pTolSO 2

H

636

O

Si(tBu) 2

637 OH

O N

pTol

O

sBuLi TMEDA

Ph2 C=O

pTol

> 95%

Et2 O -100ºC

O

N

638

639 O

Cl

LTMP

Me 3SiCl (3.3 eq)

THF 0°C

63%

O Cl

640

Bu

N

N

SiMe3

641

O

Bu n-decyl

642, DBB

Ph Ph O

643

sBuLi (2.5 eq)

PhCHO

DBB hexane -90°C

75%

O n-decyl

OH Ph

644

Scheme 2.91 Reaction of oxiranyl anions with electrophiles.

provide a,b-epoxysilanes in good yield. For example, chloro-epoxide 640 underwent clean conversion into epoxysilane 641 at 0
C. This approach improves upon an earlier method, which employed sparteine derivatives at very low temperature (90
C) [671]. The initial proton–lithium exchange can be facilitated by diamines, such as dibutylbispidine (DBB, 642). Thus, dodecene oxide 643 was deprotonated with sec-butyllithium and then treated with benzaldehyde to give the epoxyalcohol 644 in 75% yield [672, 673]. Often, though, when no stabilizing group is present, oxiranyl anions tend to exhibit significant carbenoid behavior, as indicated by resonance structure 646 (Scheme 2.92). Indeed, a-alkyloxyepoxide 647 can be regioselectively deprotonated (presumably under chelation control) to form an oxiranyl anion that undergoes a-eliminative ring opening and alkyl insertion to give cyclic allylic alcohols 648 in good to excellent yield. The carbenoid nature of the intermediates was supported by the isolation of the tricyclic alcohol 650, the product of intramolecular trapping by an olefin [674]. Other examples of such cyclopropanation reactions include the allylic epoxide 651, which is deprotonated by phenyllithium to give a highly strained tricyclic intermediate (652) that hydrolyzes to provide spirocyclic ketone 653 [675]. Lithium tetramethylpiperidide (LMTP) is also effective in the deprotonation, as shown in the conversion of alkenyl epoxide 654 into the fused bicyclic epoxide 655 [676]. As is the case with other carbene species, the carbene-like oxiranyl anions can engage in CH insertion reactions. Hodgson and Lee [677] have devised a clever method for accessing enantiopure bicyclic alcohols from meso-epoxides by such a reaction. For example, treatment of cyclononene oxide (656) with isopropyllithium in the presence of an excess of ()-sparteine leads to an enantioselective a-deprotona-

2.4 Thiiranes

R1

MeO

O

O R2

R1

645

Bu

Bu xsRLi

.. R2

R

O

OH

646 647

MeO

648

MeO nBuLi O OH

O

650

649

O

MeO

MeO PhLi

88% O

Me OH

OH

Me

651

653

652 OH O LTMP O

tBuOMe r.t.,15 h 82%

654

655 H

OH

iPrLi O (-)-sparteine 77% yield 83% ee

656

H

657

Scheme 2.92 Carbenoid behavior of oxiranyl anions.

tion, followed by intramolecular C–H insertion, to give bicyclononanol 657 in 77% yield and 83% enantiomeric excess.

2.4 Thiiranes 2.4.1 Properties of Thiiranes

Thiiranes [678] (also known as episulfides and thiacyclopropanes) can be thought of as row 3 epoxide analogs. For example, thiirane itself (bp 55
C) exhibits a ring strain enthalpy of about 20 kcal mol1, which is about 7 kcal mol1 less than oxirane. This

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j 2 Three-Membered Heterocycles. Structure and Reactivity

110

Figure 2.20 Geometry of thiirane.

S

O

H

HO

O

OH

O O

H

OH O

O

H OH

H

O

H

OH

H

O

660, acanthifolicin Figure 2.21 Natural occurrence of thiiranes.

increased stability can be attributed to more flexible geometry about the sulfur center, which is manifested in the extremely acute C–S–C bond angle of less than 48
(Figure 2.20). The 1H-NMR signals of the methylene protons resonate at 2.27 ppm and the carbon atoms appear at 18.1 ppm. The proton NMR shows vicinal coupling of about 6 Hz and geminal coupling of less than 1 Hz [6]. Thiiranes are produced in nature. For example, 3,4-epithiobutanenitrile, also known as 4ETN, is found in many cruciferous vegetables and may function as a weak biological alkylating agent [679], and humulene-4,5-episulfide is one of the components in the essential oil of hops [680]. Acanthifolicin (660, Figure 2.21) is an antibiotic polyether carboxylic acid isolated from the extracts of the marine sponge Pandaros acanthifolium [681], the activity of which is linked to protein phosphatase inhibition [682]. Synthetic episulfides have also been designed as mechanism-based matrix metalloproteinase inhibitors [683]. 2.4.2 Synthesis of Thiiranes 2.4.2.1 From Epoxides Preparatively, the broadest and most useful technique for obtaining episulfides is to launch from an existing epoxide, essentially exchanging an oxygen atom for a sulfur. One common reagent used to effect this transformation is thiourea, which is preferred for its relative stability and ease of handling, and quite a few experimental conditions have been developed for its use. For example, cyclohexene oxide (440, Scheme 2.93) is cleanly converted into the corresponding episulfide using thiourea at elevated temperatures in the absence of solvent (Table 2.18, entry 1) [684]. The reaction also proceeds in methylene chloride under the catalysis of silica gel [685], in

2.4 Thiiranes

(NH2)2C=S O

S

conditions (see Table 2.18)

440

658

Scheme 2.93 Conversion of epoxides into episulfides using thiourea.

Table 2.18 Yield data for the conversion of epoxides into episulfides using thiourea.

Entry

Activator

Solvent

Temp (
C)

Time

Yield (%)

Ref

1 2 3 4

None SiO2 SiO2-AlCl3 b-Cyclodextrin

Neat CH2Cl2 MeCN H2O

120 r.t. 45 r.t.

25 min 30 min 1.3 h 6h

92 92 89 82

[577] [578] [579] [580]

acetonitrile with silica-supported aluminium chloride [686] and in water using b-cyclodextrin as a catalyst [687]. Notably, this sulfurization proceeds with inversion of configuration, and the degree of stereospecificity depends upon the reaction conditions. Thus, when (R)-styrene oxide (421, Scheme 2.94) is treated with thiourea without solvent, very little optical purity is lost during the reaction. However, in methylene chloride at 0
C the enantiomeric excess drops to 70% [685].

O

(NH 2) 2C=S Ph

(R)-421

SiO 2 neat 0°C, 5 min 96% yield 90% ee

S Ph (S)-659

Scheme 2.94 Enantiospecific preparation of episulfides from epoxides.

Ammonium thiocyanate is another convenient sulfur donor for these processes, and a very practical method has been described using cyanuric chloride as a coreagent. Thus, when styrene oxide (421, Scheme 2.95) is treated with stoichiometric ammonium thiocyanate and cyanuric chloride in the absence of solvent, the episulfide 659 is produced in almost quantitative yield within 15 min. The mechanism involves nucleophilic ring opening of the epoxide to give an alkoxide intermediate (660); reaction with cyanuric chloride activates the oxygen towards displacement by sulfur, yielding a cyanatoepisulfenium species (662), which undergoes hydrolysis and subsequent loss of carbon dioxide to provide the observed

j111

j 2 Three-Membered Heterocycles. Structure and Reactivity

112

O

S

NH4 SCN cyanuric chloride neat r.t., 15 min 98%

Ph

421

Ph

659

Cl N

O

N

C

N

O

Ph S

N

S

Cl

OH S

Ph

Ph N C

O

CN

Ph

S:

660

662

661

663

Scheme 2.95 Activation of epoxides using cyanuric chloride.

product [688]. Magnesium hydrogen sulfate has also proven to be an effective activating agent [689]. The addition of thiocyanate is also catalyzed by poly(allylamine) (PAA) under slightly basic aqueous conditions. For example, phenyloxymethyl epoxide 532 (Scheme 2.96) is converted into the corresponding episulfide in excellent yield under these conditions (Table 2.19) [690]. Very good yields have been reported using potassium thiocyanate in a biphasic medium of ionic liquid and water with no additional catalyst [579]. Finally, elemental sulfur can be employed as the donor using diethylphosphite, ammonium acetate and alumina in the absence of solvent under microwave irradiation. The mechanism involves a thiophosphate species [691].

conditions

O

PhO

(see Table 2.19)

S

PhO 664

532

Scheme 2.96 Epoxide–episulfide conversion using other sulfur sources.

Table 2.19 Yield data for epoxide–episulfide conversions.

Entry

S source

Additives

Solvent

Temp (
C)

Time

Yield (%)

Reference

1 2

NH4SCN KSCN

PAA/NaOH None

45 45

70 min 1.3 h

93 89

[583] [579]

3

S/HP(O)(OEt)2

NH4OAc/Al2O3

H2O [bmim] PF6-H2O neat

mw

2 min

68

[584]

2.4 Thiiranes

2.4.2.2 From Alkenes If episulfides were strictly analogous to their cousin epoxides, their preparation would spring predominantly from the direct sulfurization of alkenes. This is, however, not the case. The few direct methods have been nicely summarized in a recent review [692]. Nevertheless, there are some protocols that merit special attention. For example, the sultene 665 (Scheme 2.97), an isolable cycloadduct from fluorinethione-S-oxide and trans-cyclooctene, has been shown to exhibit promising sulfur-transfer capabilities. Thus, treatment of norbornene (666) with sultene 665 in the presence of catalytic quantities of trifluoroacetic acid furnishes exo-episulfide 667 in 83% yield [693]. The dithiophosphate molybdenum complex 668 actually catalyzes the transfer of sulfur from one episulfide to another alkene. This allows the use of a more readily available substrate (e.g., 659) as a sulfur donor, as shown in the episulfidation of transcyclononene 669 [694]. Thiatriazole 671 also functions as a stoichiometric sulfur transfer reagent for a wide range of alkene substrates (e.g., 672 ! 673) [695]. Dinitrogen sulfide has been implicated as the active sulfur-transfer species [696].

O S

665 CF 3CO 2 H (cat) CHCl 3 r.t., 30 min 83%

666

S 667

665

EtO P EtO

S

O Mo

S

S S

OEt

659 (1 eq) 668 (1 mol%)

OEt

benzene 80°C, 30 min > 95%

P

668

S N

669

S

670

S

OPh 671

N N 671 672

MeCN r.t., 3.5 h 80%

673

Scheme 2.97 Thiiranes from alkenes.

2.4.2.3 From Haloketones One very intriguing method that has received surprisingly little attention is the conversion of a-haloketones into episulfides using the commercially available

j113

j 2 Three-Membered Heterocycles. Structure and Reactivity

114

O,O-diethyl hydrogen phosphodithioate as a sulfur donor under microwave conditions. The procedure appears to be fairly general and high yielding. Thus, bromoacetophenone 674 (Scheme 2.98) provides excellent yield of the corresponding episulfide (659) within 3 min. The mechanism is thought to involve a sequence of nucleophilic displacement, phosphorus transfer and cyclization (inset Scheme 2.98). For substrates that yield 1,2-disubstituted episulfides, diastereoselectivity is very high, with trans : cis ratios generally being greater than 10 : 1, as shown in the preparation of diethylepisulfide 677 [697]. O

S Br

Ph

+

P HS

neat µ w (3 min) 94%

OEt

675

674 O

S + HS

Cl

676

P

R1

X

Ph

659

S

NaBH 4-Al2 O3

OEt

neat µ w (3 min) 86%

OEt

Et

Et

677

675

S O

S

NaBH 4-Al2 O3

OEt

S S

(EtO)2 P O

S

R1

R2

R2

P(OEt)2 O S

P(OEt)2 O

S

R1

R2

S R1

R2

Scheme 2.98 Thiiranes from haloketones.

2.4.3 Reactivity of Thiiranes 2.4.3.1 Nucleophilic Ring Opening Like the epoxides, episulfides are prone to ring-opening reactions induced by nucleophiles, whereby the CS bond is cleaved. However, sulfur stabilizes a negative charge better than oxygen and therefore functions as a more active leaving group. The sulfide so-formed is also more nucleophilic than the analogous alkoxide. Furthermore, sulfur supports radical centers more readily than oxygen. Taken together, these behaviors contribute to the fact that the ring opening of episulfides is usually attended by some degree of uncontrolled polymerization and other yield-reducing processes. However, many well-behaved conversions are known, and those outlined below are meant to provide a general impression of synthetic possibilities. Acetate is a frequently employed nucleophile. For example, in their protocol for preparing sulfur-containing disaccharides, Santoyo-Gonz
alez and coworkers [698] heated a mixture of episulfide 678 (Scheme 2.99), sodium acetate and acetic anhydride in acetic acid to obtain diacetate 679 in very good yield. Similarly, the thiiranyl acetal 680 undergoes ring opening in the presence of silver(I) acetate and

2.4 Thiiranes

O

O

OMe

O

NaOAc

S

MeO

Ac 2O AcOH 86%

OH

SAc

O

MeO

OAc OMe

OH

678

679

OEt

S

EtO

OEt

OAc

EtO

AgOAc OTBDMS

OTBDMS

680

681 S

S

O

MeO 2 C O

SH

Ph 3CCl

OAc

KOAc O

HOAc DMF 57%

682

O

O

683 O

MeO 2 C

S

684

KOAc (10 eq) HOAc DMF ∆, 18 h 65%

S OAc 685

Scheme 2.99 Ring opening of thiiranes with acetate.

triphenylmethyl chloride to provide the acetoxythiol 681, a key intermediate in the asymmetric total synthesis of thietanose [699]. These ring openings can also trigger subsequent cyclizations from the sulfur center. Thus, the thiiranyl acetonide ester 682 suffers attack by acetate to give an intermediate sulfide, which engages in intramolecular attack of the ester carbonyl to yield the thiolactone 683 [700]. A similar strategy was used to access the acetoxymethyl thiobutyrolactone derivative 685 [701]. Amines are also competent nucleophiles in these reactions. For example, the benzyloxymethylthiirane (686, Scheme 2.100) is attacked by dibenzylamine at the less substituted position, providing aminothiol 687 in good yield [702]. In like fashion, spiroepisulfide 688 undergoes aminolysis by 4-hydroxypiperidine (689) in solventless thermal conditions to give excellent yield of the b-aminoethanethiol 690 [703]. A twist on this protocol has been reported for the synthesis of taurine derivatives from episulfides. Thus, dibenzylthiirane 691 was treated with ammonia in the presence of silver nitrate to give a silver-chelated adduct that was sequentially treated with hydrogen sulfide (generated in situ from sodium sulfide and hydrochloric acid), sodium hydroxide and performic acid (generated in situ from formic

j115

j 2 Three-Membered Heterocycles. Structure and Reactivity

116

Bn2 NH

S

BnO

686

HN

688

Bn

687

neat +

S

NBn 2

SH

S

Bn

SH BnO

benzene EtOH 60°C,24 h 82%

OH

N

80°C 4h 92%

OH

689

690

NH3

Na 2S

AgNO 3 MeOH

HCl

NaOH

691

H 2O2 HCO2 H 79%

HO 3S Bn

NH2 Bn 692

Scheme 2.100 Ring opening of thiiranes with amines.

acid and hydrogen peroxide), ultimately generating the 1,1-disubstituted taurine 692 in good overall yield [704]. High-yielding processes using other nucleophiles have also been reported. For example, treatment of the terminal episulfide 693 (Scheme 2.101) with lithium aluminium hydride in ether resulted in hydride-mediated reductive ring opening to give 2-hexanethiol (694) in good yield. The internal thiirane 695 underwent nucleophilic ring opening with allyl Grignard, forming the hydroxythiol 696. The regiochemistry of the attack can be rationalized by chelation control in this case [705]. Even halides can engage in this process when appropriate activating agents are employed. Thus, thiiranyl acetal 697 was converted into the disulfide 698 using methanesulfenyl bromide in a medium of tetramethylurea (TMU) and methylene chloride through a process of electrophilic S-activation followed by nucleophilic ring-opening by bromide [706]. A similar process is promoted by acyl chlorides, as shown in the quantitative conversion of terminal episulfide 699 into the chlorothioester 700 upon treatment with acetyl chloride and catalytic tetrabutylammonium bromide (TBAB) [707]. 2.4.3.2 Desulfurization Thiiranes can be converted into alkenes through a process of desulfurization, often in very high yields. For example, methyltrioxorhenium (MTO) catalyzes the stereospecific removal of sulfur by triphenylphosphine, as shown in the quantitative conversion of alkenyl sulfide 701 (Scheme 2.102) to 1,5-hexadiene (702). Performance is enhanced when the catalyst is pretreated with hydrogen sulfide; a ReV species has been implicated as the catalytically relevant species [708]. An extremely efficient copper-mediated desulfurization was used as the key step in the synthesis of C2symmetric dibenzosuberane (DBS) helicene 704, which is of interest as a potential chiroptical switch [709]. Alkyllithium reagents, such as n-butyllithium and phenyllithium, have been known for some time to function as desulfurization agents, as exemplified by the

2.5 Diaziridines

S

SH

LAH Et2 O 73%

693

694

pBrPh

O

OH 69 5

S

EtO

SH

MgBr

S

pBrPh Et 2O 0°C,24 h 62%

6 97

OH 696

S

MeSBr TMU CH 2Cl 2 -78°C 93%

OEt

O

SMe

EtO

Br OEt 6 98 O

O

6 99

S

AcCl TBAB neat 90°C,6 h 100%

S O

Cl

7 00

Scheme 2.101 Ring opening of thiiranes with other nucleophiles.

butyllithium-mediated conversion of cyclohexene oxide 658 into the parent alkene 439. The mechanism involves initial ring-opening by attack on sulfur to give an a-thio anion (i.e., 705) that rapidly undergoes elimination of butyl sulfide to form the observed product [710]. Tributyltin hydride also effects a reductive desulfurization in the presence of a radical initiator, such as triethylborane at low temperature or AIBN at elevated temperatures. Under these conditions, the thiiranyl alcohol 706 is converted into the corresponding allylic alcohol (707) in excellent yield and without the need for protecting group chemistry [711]. Calculations have shown that triethylphosphite should function as a desulfurizing agent through a concerted process, thus promising high stereospecificity [712].

2.5 Diaziridines 2.5.1 Properties of Diaziridines

Diaziridines can be thought of as the smallest cyclic hydrazine derivatives. At 25.5 kcal mol1, the calculated ring strain for diaziridine itself is slightly less than that of oxirane; and just as the open-chain analog, hydrazine, is more stable toward

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j 2 Three-Membered Heterocycles. Structure and Reactivity

118

MeReO 3 Ph3 P

S

H 2S MeCN r.t., 1 h 100%

701 Et

702

Et

Et

Et

Cu xylene ∆ 98%

S

703

704 S

nBuLi

S

nBu 67%

658

705 S

Ph OH 706

nBu 3 SnH Et 3 B (cat) toluene -78°C 90%

439

Ph OH 707

Scheme 2.102 Desulfurization of thiiranes.

interheteroatom cleavage than hydrogen peroxide so too is diaziridine less prone to undergo NN ring opening than dioxiranes are to suffer OO scission. Calculations have also indicated a proton affinity for diaziridine similar to that of ammonia. Geometrically, the diaziridine ring describes an almost equilateral triangle (Figure 2.22), with the N–C–N bond angle opening about 2
wider than the other two; consequently, the NN bond is slightly longer than the CN bond [713]. The 1 HNMR signals of the methylene protons resonate at about 2.2 ppm [714].

Figure 2.22 Geometry of diaziridine.

2.5 Diaziridines

N

H N

H

H

Ea = 23 kcal/mol N

N

∆ E = -4.6 kcal/mol

H Figure 2.23 Cis–trans isomerism in diaziridine.

From a physical organic perspective, diaziridine is a fascinating species. As there is about a 23 kcal mol1 barrier to inversion about the nitrogen center (Figure 2.23), diaziridines exist as isolable cis- and trans-isomers, the latter lying about 5 kcal mol1 lower in energy. For N,N-dialkyl derivatives, this barrier is even higher. For the di-tbutyl variant, it has been calculated at 30 kcal mol1 [715]. As a result, trans-N,Ndisubstituted diaziridines have been recognized as novel C2-symmetric compounds, and efforts have been made to elaborate methods for their resolution [716, 717]. Diaziridines have also been investigated as possible high-energy materials (although not particularly promising in this regard) [713], and there is at least one report of diaziridine derivatives exhibiting psychotropic activity, particularly with respect to monoamine oxidase inhibition and antidepressant behavior [718]. 2.5.2 Synthesis of Diaziridines

The synthesis of monocyclic diaziridines and their fused derivatives is the subject of a recent review [719]. Some of the more common synthetic routes are outlined below. 2.5.2.1 Oxidative Methods using Hypohalites One of the more common routes for accessing diaziridines is the oxidative ring closure of aminals, which are usually formed in situ from the respective amines and carbonyl compounds. Thus, N,N-dibutyldiaziridine (710, Scheme 2.103) is prepared in good yield by combining n-butylamine and formaldehyde in the presence of aqueous sodium hypochlorite [720]. The method can be applied to diamine substrates, such as propylenediamine (711) to construct fused bicyclic derivatives (e.g., 712) in excellent yield. Furthermore, the diamines can be condensed onto substituted aldehydes (e.g., 714) and ketones (e.g., 716) with equal efficiency. The pH of the reaction medium can have an impact on yields and product distributions [721]. The aminals can be formed from other precursors, as demonstrated by the aminoalkylimine 718 (Scheme 2.104), which produces the fused tricyclic diaziridine 719 in the presence of aqueous sodium hypochlorite [722]. The benzimidamide 720 serves as a precursor for diazirines in similar oxidizing environments; however, an intermediate chlorodiaziridine (721) has been identified in the reaction mixture, and it is stable enough to isolate [723]. Similarly, diaziridinimines such as 723 can be prepared in good yield by subjecting tosyl guanidine 722 to sequential treatment by t-butyl hypochlorite and t-butoxide [724].

j119

j 2 Three-Membered Heterocycles. Structure and Reactivity

120

O

NaOCl

+

NH2

H 708

45°C 80%

H 709

NH2

+ H

711

N N

H

NaOCl

N

45°C 95%

N

709 O

NH 2

+

H

713

712

NaOCl

N

45°C 97%

N

714

715

O H2 N

NH 2

+ Me

713

nBu

710 O

H 2N

H2 N

nBu

NaOCl

N

45°C 77%

N

Me 716

717

Scheme 2.103 Synthesis of diaziridines from carbonyls and amines.

NaOCl NH2

N

74%

N

718

719

NH

NaOCl

Cl

Ph

720 NTs NHt-Bu

t-BuHN 722

H N NH

NH2

Ph

N

721 t-BuOCl

t-BuOK 85%

NTs t-BuN N t-Bu 723

Scheme 2.104 Synthesis of diaziridines from imines, imidamides, and guanidines.

2.5.2.2 Via Hydroxylamine Derivatives Another alternative for diaziridine synthesis is presented in the use of O-sulfonated hydroxylamine derivatives, which offers the advantage of a much less oxidizing environment. As an example, the cyclic imino ester 724 (Scheme 2.105) is converted into diaziridine 725 upon treatment with hydroxylamine O-sulfonic acid [725], and

2.5 Diaziridines

Cl

Cl

O

CO 2Me

H2 NOSO 3H OMe

N NH

N

725

724

OBn

OBn NH 3

O

BnO BnO

O

BnO BnO

MeOH

NH BnO N H

N OSO 2 Me

BnO 726

727

O Me

H2 NOSO 3 H NH3 / H2 O

Me

HN NH

716

728

Scheme 2.105 Synthesis of diaziridines from hydroxylamine derivatives.

the same method is effective in preparing the glycosylidene-derived diaziridine 727, which serves as a precursor for the corresponding diazirine and thus a glycosylidene carbene [726]. An operationally more straightforward variant of the methodology can be used for preparing various 2,2-disubstituted derivatives. Thus, a ketone such as acetone (716) is treated with hydroxylamine O-sulfonic acid in the presence of aqueous ammonia to give the desired diaziridine (728) in one pot [727]. 2.5.2.3 Other Methods Although the generality of the methods has not been firmly established, two protocols merit special attention. The first is the direct electrochemical synthesis of diaziridines from amines and aldehydes in a bicarbonate buffered solution, which is directly analogous to methods described in Section 2.5.2.1 but obviating the need for chemical oxidants. Thus, propylenediamine (711, Scheme 2.106) and formaldehyde O H 2N

NH2

H 711

N

1.92 A

+ H

85% efficiency

709 O

hν NMe

t-BuN

N N 729

MeCN

N 712

O

t-BuN NMe 730

Scheme 2.106 Synthesis of diaziridines via electrical and photochemical means.

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j 2 Three-Membered Heterocycles. Structure and Reactivity

122

cleanly provided bicyclic diaziridine 712 under these electrochemical conditions. The current efficiency reached 85% under optimum conditions [728]. The second method is the photolysis of tetrazolone derivatives (e.g., 729) to give diaziridinones (e.g., 730), which could be obtained in high purity [729]. 2.5.3 Reactivity of Diaziridines 2.5.3.1 Diaziridines Like their open-chain analogs, diaziridines are nucleophilic species that engage in well-behaved reaction with various electrophiles. For example, 3,3-dimethyldiaziridine (728, Scheme 2.107) is smoothly N-acylated with 3-phenyoxybenzyl chloroformate (731) in the presence of triethylamine in a medium of methylene chloride to give the carbamate 732 in 63% yield. The remaining nitrogen was further functionalized to produce the diazapyrethroid analog 733, and the diaziridine moiety proved to be remarkably stable to the experimental conditions (particularly zinc in acetic acid) [727]. Diaziridines also engage in conjugate addition onto traditional Michael O + HN NH

Cl

Et 3N

O

O

HN N

CH2Cl 2 63%

728

O

O

O

731

732

Cl O

N N

Cl

O

O

733 Ph NMe NH

O

Ph

benzene

O

r.t., 2 h 98%

+ Ph

734

N

N NH

736

(CO2 H)2 ∆ 95%

737

NMe

n-hexyl

NMe

739

N Me

735

N H

NH 2

738 CO (1 atm) Pd(dba) 2 DMF 120°C, 24 h 66%

Scheme 2.107 Some reactions of diaziridines.

Me N n-hexyl

O N Me

740

O

O

Ph

2.5 Diaziridines

acceptors, such as DMAD [730] and dibenzoylacetylene [731]. The intermediate diaziridinium species formed by the initial addition suffers ring-opening through scission of the CN bond to give a hydrazone derivative (e.g., 736). In fact, under acidic conditions diaziridines spontaneously decompose to form the component hydrazines and carbonyl compounds, as shown by the recovery of N-isopropylhydrazine (738) in 95% yield upon exposure of the precursor diaziridine 737 to oxalic acid [732, 733]. The cyclic NN bond is not totally inert, however. For example, palladium catalyzes the insertion of carbon monoxide into the N–N bond, converting diaziridines (e.g., 739) into the corresponding azalactam derivatives (e.g., 740) [734]. 2.5.3.2 Diaziridinones and Diaziridinimines Diaziridinones also exhibit some interesting chemistry. For example, they too have been reported to engage in carbonyl insertion reactions in the presence of a nickel catalyst to give diazetidine-2,4-diones (e.g., 742, Scheme 2.108) in reasonable yields [735]. Usually, however, their reactivity involves the nucleophilic attack of the carbonyl carbon, as illustrated by the reaction of N,N-di-t-butyldiaziridinone (741)

O

CO (1 atm) Ni(CO) 4

t-BuN N t-Bu

DMF 70°C,1 h 75%

O t-BuN

N t-Bu O

741

742

O NaH

+

CN

N H

t-BuN N t-Bu 741

N

DMF 60°C,10 h 85%

O

743

CN

Nt -Bu N t-Bu 744 O

O

O

BF3 ·OEt2

+ t-BuN N t-Bu 741

HN

OH

R

R 746

745

CN

NTs 110°C t-BuN N t-Bu 747

toluene 5h 58%

O

t-BuN

t-Bu

N

N H

Ts

748

Scheme 2.108 Some reactions of diaziridinones and diaziridinimines.

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j 2 Three-Membered Heterocycles. Structure and Reactivity

124

with the sodium salt of cyanopyrrole 743, which engages in nucleophilic addition to the carbonyl, followed by ring-opening to provide the acylhydrazine 744 in 85% yield [736]. A similar addition event is the first step of many in the Lewis acidcatalyzed conversions of diaziridines into oxadiazinones (e.g., 746) by a-hydroxy ketones (e.g., 745) [737]. Finally, the analogous diaziridinimes (e.g., 747) are thermally unstable, rearranging to N-cyanohydrazine derivatives (e.g., 748) at elevated temperatures [724].

2.6 3H-Diazirines 2.6.1 Properties of Diazirines

With a literature age of less than 50 years old [738, 739], diazirines are relative youngsters among their companion three-membered heterocycles, and an interesting lot they are. Although this ring system might intuitively appear quite unstable, the strain energy has been calculated at a remarkably low 21 kcal mol1 [740]. This, combined with very low basicity, is largely responsible for the observed stability (even in vivo) of the diazirine ring at room temperature. The double bond character between
the two nitrogens results in a short N¼N bond distance (1.23 A), which, in turn, significantly compresses the N–C–N bond angle (Figure 2.24) [741]. Likewise, the diaziridine moiety is planar and symmetrical. Since molecular nitrogen can be rapidly extruded under thermal or photochemical conditions, neat diazirines should be afforded the respect in handling that all potentially explosive compounds deserve. 2.6.2 Synthesis of Diazirines

The lion’s share of protocols for the preparation of diazirines proceed through a diaziridine intermediate. For example, 4-aziadamant-1-amine (750, Scheme 2.109) was synthesized by the chromium(VI) mediated oxidation of the corresponding diaziridine (749) [742]. However, diaziridine precursors can serve as suitable substrates for various one-pot procedures. Thus, the camphor-derived iminium salt 751 was converted into the sterically hindered chiral diaziridine 2-azicamphane 752 by

Figure 2.24 Geometry of 3H-diazirine.

2.6 3H-Diazirines NH 2

NH 2 CrO3 NH

749

N H

(26%)

H2 SO4 acetone 26%

N N

750

Cl NH 2

NH2 OSO3H

I2

NH 3 MeOH

Et3N MeOH 48%

(48%) N N

751

752

O

O

N

O

O O

O

O

O

2. 10% I 2 TEA,MeOH 49% overall

O

O

O O

O

O O

O

O

O O

753 OH

O

O

O O

O

1. H 2 NOSO 3H NH 3, MeOH

O O

N

O

O

O

754

H 2N-CN MeSO 3 H

755

O

NH2 NH 2

756

NaOCl

Cl

O

N

N

757

Scheme 2.109 Synthesis of diazirines.

treatment with hydroxylamine O-sulfonic acid in methanolic ammonia, followed by oxidation with iodine in the presence of triethylamine [743]. Ketones can also be used to advantage in this regard, as illustrated by the construction of the diaziridinyl cluster mannoside 754 from ketone 753 [744]. Alkoxy substituted diazirines can be prepared from alcohols. Thus, norboranol 755 was treated with cyanamide and methanesulfonic acid to afford an intermediate isouronium salt (756) that was oxidized with hypochlorite to give the diazirine 757 [745]. Diazirines have also been prepared by the partial hydrolysis of nitriles, followed by hypochlorite oxidation [746]. Since they have desirable end-application properties, 3-trifluoromethyldiazirines are of particular interest, and these are prepared in similar fashion. For example, the diazirinyl antiotensin II analogue 759 (Scheme 2.110) was produced in very good yield from the silver(I) oxide mediated oxidation of diaziridine 758 [747]. An equally efficient diazirine synthesis was achieved launching from the O-tosyl oxime 760, which was converted into the diaziridine by treatment with liquid ammonia. After the fluoride-mediated desilylation of the alcohol functionality, PDC oxidation afforded

j125

j 2 Three-Membered Heterocycles. Structure and Reactivity

126

CF 3

CF3 Ag2O FmocHN

HN

NH

CO 2t-Bu

FmocHN

Et 2O r.t., 8 h 87%

N CO2 t-Bu

758 F3C

TBSO

N

759 F 3C

OTs

F3 C

NH

NH3

HF (aq)

PDC

MeCN 99%

CH2 Cl2 87%

H

OH

H

OH

761

O

F3 C

N

F3 C

N N

H

762

Br Mg 0

763

THF

80%

O

OMe

763

OMe

764

765

NOH TsCl DMAP

NH2 OH·HCl EtOH pyridine 60°C,12 h 96%

H N

Et 2O -78°C 99%

760

F 3C

(87%)

N

OMe

Et 3N CH2 Cl2

F3C

H N NH

NH3 52%

766

OMe

767

t-BuOCl Et 3N

F 3C

N N

t-BuOH EtOH 77%

OMe

768

Scheme 2.110 Synthesis of trifluoromethyldiazirines.

the desired diazirine 762 in remarkably good overall yield. The target was used as the centerpiece for the construction of a vitamin D analog, a testament to the robustness of the diazirinyl moiety toward various experimental conditions [748]. Ultimately, the trifluoromethyl group is usually introduced by way of an activated trifluoroacetic acid derivative. For example, the aryl Grignard derived from m-bromoanisole (764) smoothly added to N-trifluoroacetylpiperidide (763) to give the trifluoroacetophenone derivative 765, which was converted into the corresponding oxime (764) in excellent yield using conventional methods. Subsequent O-tosylation and treatment with ammonia afforded the diaziridine 767, which was oxidized to the diazirine 768 using t-butyl hypochlorite [749]. 2.6.3 Reactivity of Diazirines

Diazirines with leaving groups at the 3-position can undergo substitution reactions without affecting the azo moiety [750]. As one example, the bromodiazirine 769

2.6 3H-Diazirines

(Scheme 2.111) is converted into the fluoro analog 770 upon treatment with anhydrous tetrabutylammonium fluoride (TBAF) under solvent-free conditions [751]. It would be fair to state, however, that the spotlight shines on diazirines for their propensity to extrude molecular nitrogen to form reactive carbene intermediates [752, 753]. Thus, the 3-acyldiazirine 771 suffers loss of nitrogen under thermal conditions in the presence of alkenes to yield products of carbene–olefin cycloaddition [754]. N

Br

TBAF

N

N

F

N

neat 65%

Ph

Ph

769

770

O

O N

MeO

N

MeO

∆ 89%

Cl

Cl

771

772

NO 2

NO 2 hν (365 nm)

HN N

BocHN

O Me

N

EtOH

CF 3

773

N

D

HO

D 2O >80%

OH

CF 3

775 HO

HO N

hν

gas phase 100%

N

cyclohexane 92%

777 N N Cl

779 Cl

hν THF 100%

780

CF3

HO

hν

Ph

OD

776

778

CF 3

774

H N

hν

N OH

OEt

O Me

H N HO

HN BocHN

O Ph

781

Scheme 2.111 Some reactions of diazirines.

Photolysis of diazirines also generates carbenes, and this procedure is more significant in terms of application [755]. Once the carbene intermediates are formed, the reactivity is much the same as for carbenes generated by any other method. For example, when the aryl diazirine 773 is photolyzed in ethanol, the major product (774) results from the insertion of carbene in the OH bond of the solvent [756]. Similar behavior is observed in aqueous media (i.e., 775 ! 776) [757]. Photolysis of

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128

2-azi-5-hydroxyadamantane (777) in the gas phase results in the quantitative formation of the intramolecular 1,3 CH insertion product 778. When the same substrate is photolyzed in an organic solvent, then the intermolecular process dominates, as illustrated by the cyclohexane adduct 779 [758]. This behavior is fairly general – the carbene derived from arylchlorodiazirine 780 also quantitatively traps THF when generated in that solvent [759]. To summarize, diazirines can be synthesized with a high degree of regioselectivity, launching from various readily available functional groups. The diazirines themselves have a very long half-life at room temperature and under a broad range of conditions. Reaction can be triggered by photolysis in a manner that engages few, if any, other functionalities. It can be assumed that carbene generation is practically quantitative, and these carbenes react quickly with a wide variety of substrates. This particular confluence of behaviors has earned these substrates an important niche, namely within the realm of photoaffinity labels (PAL), an application that has been nicely summarized in a recent review [760]. Interestingly, for the same reasons, diazirines have been investigated as materials surface modifiers. In their study of the underlying chemistry of these processes, Hayes and coworkers photolyzed the fluorenone-modified diazirine 782 in the presence of acetic acid, n-butylamine, and N-butylbutanamide as models of the functional group environment encountered in a medium of nylon 6,6 (and, incidentally, proteins in vivo). In all cases, they observed extremely efficient (>95%) insertion reactions, leading to the products 783, 784, and 785, deriving from OH insertion, amine NH insertion, and amide NH insertion, respectively [761] (Scheme 2.112).

F3 C O

OAc

Ar

hν

O

AcOH 12 h

783 F3 C O

F3 C

N N

Ar

O

O

NH

Ar

hν

O

n-BuNH 2 12 h

784

782

F3 C O

O Ar

hν Ar =

N H

O O

O

n-Bu

N

n-Bu

Scheme 2.112 Insertion reactions of a photoaffinity label (PAL).

785

2.7 Oxaziridines

Figure 2.25 Geometry of oxaziridine.

2.7 Oxaziridines 2.7.1 Properties of Oxaziridines

The oxaziridine moiety incorporates an oxygen, nitrogen and carbon within a cyclic three-atom array (Figure 2.25). The conventional strain energy (CSE) for the parent compound has been calculated at 27.6 kcal mol1, lying between those of cyclopropane and cyclobutane [762]. Each bond in the ring is unique, with lengths ranging

from 1.40 A (CO) to 1.50 A (NO). It follows that the bond angles are also nonidentical, with the N–C–O angle being the widest [763]. These physical characteristics are responsible in part for the fascinating reaction diversity exhibited by this class of compounds. Aside from their synthetic utility, oxaziridines have excited interest due to their potential as antifungal [764], antibiotic [765] and antitumor agents [766, 767]. 2.7.2 Synthesis of Oxaziridines

There are reports of oxaziridine preparation from nitrones [768], and a calculational study has been carried out regarding this isomerization [763]. Oxaziridines are also the products of oxidative amination of ketones [769]. However, these methods have not found wide application in synthetic methodology. Instead, almost all preparative protocols launch from the oxidation of imines. Nevertheless, there is considerable diversity even within this one general category. The N-alkoxysulfonyl oxaziridine 787 (Scheme 2.113) was efficiently prepared from the precursor imine 786 using the fairly traditional oxidant m-chloroperbenzoic acid (mCPBA) [770]. The sulfinylimine 788 was converted into sulfonyloxaziridine 789 in short order and in excellent yield using mCPBA in first acidic and then basic medium [771]. A trichloroacetonitrile–hydrogen peroxide system was found to convert imines such as 790 into oxaziridines in very high yield and exclusive (E)stereochemistry under essentially neutral conditions [772]. Several other near-neutral systems are also available. For example, pyridylimine 792 was oxidized using a buffered monophasic Oxone system [773], and phase-transfer conditions were applied to the mild and quantitative conversion of arylaldimine 794 into the corresponding oxaziridine (795) using tetrabutylammonium Oxone in acetonitrile [774]. The combination of storage-stable urea-hydrogen peroxide adduct (UHP) and maleic anhydride in methanolic solution was also effective in the high-yielding

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130

O

O S

O

O

N

O S

O

mCPBA

CF 3

786

SOTol

787

mCPBA

mCPBA KOH

1 min r.t.

1 min r.t. 97%

Me 788

t-Bu

N

790 i-Pr

N

SOTol

N

O

Me 789

H2 O2 Cl3 CCN

N

NaHCO 3 CH 2Cl 2 1h 93%

Ph

N

O

CH2Cl 2 r.t. 91%

CF 3

N

N

t-Bu O

Ph 791

KHSO 5 NaHCO 3

i-Pr

N

O

N

MeCN H 2O 85% 792 N

793 t-Bu

N Bu4 NHSO 5 MeCN r.t., 1 h 100%

Cl

Cl

794

N

795

Ph

Ph 796

N

CO 2 Me

Ph 798

t-Bu O

UHP maleic anhydride

N

MeOH 0°C 95%

Ph

Ph 797

O2 CoCl2 i-PrCHO 3Å MS CH2 Cl2 0°C 80%

O

N

CO 2 Me

O

Ph

Scheme 2.113 Synthesis of oxaziridines from imines.

799

2.7 Oxaziridines

oxaziridination of N-benzylimine 796 [775]. Even molecular oxygen can be used as the terminal oxidant, using a cobalt catalyst (e.g., 798 ! 799), although the catalyst must be preformed for optimum yields [776]. 2.7.3 Reactivity of Oxaziridines

Oxaziridines have quickly become very important synthetic reagents [777–780]. Furthermore, the related oxaziridium ions, which bear a quaternary nitrogen center, are significant in their own right, both as stoichiometric reagents [781] and putative intermediates in catalytic cycles [782–784]. However, the present chapter is limited to neutral oxaziridines. 2.7.3.1 Nitrogen Transfer Reactions An interesting aspect of oxaziridine chemistry is that either heteroatom can be transferred to other compounds, depending upon the nature of the substrate and the substituents on the oxaziridine [785]. Common oxaziridines used in nitrogen transfer reactions include the spirocyclic derivative of cyclohexanone (800, Figure 2.26), as well as those prepared from electron-deficient carbonyls, such as trichloroacetaldehyde (i.e., 801) and diethyl oxomalonate (i.e., 802). An overview of the oxaziridine-mediated electrophilic amination of organic compounds can be found in a review from the not-too-distant past [786]. Aziridination has been reported using oxaziridines as nitrogen donors, although this reaction is not general. For example, certain styrene derivatives (803, Scheme 2.114) are aziridinated in moderate yield under thermal conditions in the presence of oxaziridine 800 [787], but many other substrates give complex mixtures. The structural influence of this variable behavior has been studied computationally [788]. A more common outcome is the amination of active methylene groups. Thus, treatment of barbituric acid (805) with oxaziridine 800 in a medium of dilute sodium hydroxide led to the production of the 5-aminobarbituric acid (806) in 78% yield [787]. Similarly, deprotonation of phenylacetonitrile 807 with lithium hexamethyldisylazide (LiHMDS), followed by treatment with oxaziridine 802, provided the Boc-protected benzylamine 808 in 46% yield [785]. Oxaziridine 802 also mediates the stereospecific conversion of allylic sulfide 809 into the allylic N-Boc-sulfimide 810, a process that involves a [2,3]-sigmatropic rearrangement [789]. Nitrogen can also be transferred to amines. For example, phenethylamine (811, Scheme 2.115) is aminated by oxaziridine 802 under very mild conditions, providing the Boc-protected hydrazine derivative 812 in good yield. These compounds were

O

NH

800

Cl3 C

EtO2 C

O

NBoc

801

O

NBoc

EtO 2 C

802

Figure 2.26 Some common oxaziridines used for nitrogen transfer.

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j 2 Three-Membered Heterocycles. Structure and Reactivity

132

NH 800 toluene 100°C 58% (R=Cl) 49% (R=NO 2)

R 803

R 804 O

O 800 HN

NH

O

O

HN

NaOH 78%

NH

O

O NH2

805

806 NHBoc CN

Cl

LiHMDS

802

THF

46%

CN Cl

807

808

SHex OH 809

SHex

BocN

802 CH 2Cl 2 76% yield > 95% ee

OH 810

Scheme 2.114 Nitrogen transfer to carbon.

then converted into pyrazoles in a one-pot reaction [790]. Hannachi and coworkers [791] have applied this methodology to synthesize orthogonally diprotected L-hydrazino acids (e.g., 814), which are useful in the biological and structural studies of pseudopeptides containing the NNCC¼O fragment.

802

NH2

Ph

CH2Cl 2 75%

811

N H

H N

NHBoc

812 Me

Me Ph

Ph

Bu 4NOH

801

CO 2H

813 Scheme 2.115 Nitrogen transfer to amines.

KHSO 81%

4

Ph

N

CO 2H

NHBoc 814

2.7 Oxaziridines

Ph

Cl

O NSO2 Ph

815

O N

816

Cl SO2Ph ..

N S O2 O

(+)- 817

N

S O O2

(-)- 817

Figure 2.27 Some common oxaziridines used for oxygen transfers.

2.7.3.2 Oxygen Transfer Reactions Some very exciting and synthetically useful methodology is available from the oxaziridine-mediated oxygen transfer onto organic compounds, and in many regards this technology is complementary to other methods. Oxygen-donating oxaziridines are generally of the 3-alkyl or 3-aryl variety (Figure 2.27), although there are examples of a given oxaziridine exhibiting both O-donating and N-donating behavior under different experimental conditions. In isolated cases, oxaziridines can engage in epoxidation reactions, both in an intramolecular sense [792] and as a bimolecular event, as illustrated by the highyielding conversion of 1,1-diphenylethene (818, Scheme 2.116) into the corresponding epoxide (819) [793]. However, this reaction is not general, and it is usually carried out more conveniently using conventional epoxidation conditions. In contrast, oxaziridines are superb reagents for selective a-hydroxylation reactions. For example, in their synthetic approach towards the microbial immunosuppressive agent FR901483, Weinreb and coworkers [794] employed the readily accessible oxaziridine 815 for the diastereoselective a-hydroxylation of the bicyclic lactam 820. Asymmetric hydroxylations are also possible using chiral oxaziridines, such as the camphor derived reagents 816 and 817. As an illustrative example, the sodium enolate of phenylacetophenone (822) was treated with ( þ )-(10-camphorsulfonyl) oxaziradine (817) to provide the a-hydroxyketone 823 in 80% yield and 94% ee. This reagent was also useful in the diastereoselective preparation of 132-hydroxylated chlorophylls (e.g., 825) [795]. Oxaziridines occupy another synthetic niche in the realm of sulfur chemistry, as they engage in some very specific and selective sulfur oxidation reactions. For example, oxaziridine 815 oxidized the lithium salt of 4-fluorothiophenol (826) selectively to the sulfinate salt, which could be trapped with active electrophiles such as methyl iodide (Scheme 2.117). This particular strategy was used to access 11Clabeled methyl sulfones [796]. Of particular synthetic utility is the oxaziridinemediated asymmetric oxidation of prochiral sulfides to chiral nonracemic sulfoxides, which are receiving increasing attention in their own right. Thus, 4-methylthiotoluene (829) is converted into (S)-methyl tolyl sulfoxide (830) in excellent yield and enantiomeric excess under essentially neutral conditions [797]. 2.7.3.3 Rearrangements Some interesting metal-mediated rearrangements of oxaziridines have been reported, although none appear to be widely general in their scope. For example, the copper(I) catalyst [Cu(CH3CN)4]PF6 induces the conversion of oxaziridine 831

j133

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134

Ph Ph

818

802

Ph

neat 50°C,50 h 82%

Ph

O

819

OTIPS NaHMDS

815

THF

98%

N Boc

OTIPS HO

N

Boc

O

820

O

821 O

O

(+)-817

NaHMDS Ph

Ph

THF -78°C 30 min

822

N

N

OH

823

N

(-)- 817

N Mg

Mg

DBU/THF -25°C 26 h 71% yield 94% de

N

N

Ph

Ph

80% yield 94% ee

phytylO 2C

phytylO 2C

HO MeO 2C

O

MeO 2 C

N

N

824

O

825

Scheme 2.116 Oxygen transfer to carbon.

into the dihydro-2H-pyrrole 832 through a fascinating mechanistic sequence involving initial N–O bond cleavage by single electron transfer, followed by radical cyclization, phenyl migration and loss of acetaldehyde [798]. When the 3-substituent is secondary (or presumably tertiary), the intermediate radical can collapse with SH

MeLi

815

THF

F

SO2 Li

AcOEt H2 O

11CH

76%

F

826

827

Me

95% yield > 95% ee

Me 829

Scheme 2.117 Oxygen transfer to sulfur.

O S

816

F 828

.. S

SO2 11CH3

3I

Me (S)-830

Me

2.8 Dioxiranes

concomitant CC bond cleavage to give amide derivatives. Thus, the 3-isopropyl oxaziridine 833 yields amide 834 under the same conditions [799]. Under the influence of Lewis acids, the oxaziridine ring can be opened by nucleophiles. For example, the 3-methoxyphenyl-oxaziridine 835 suffers nucleophilic attack at the ring carbon by O-benzylhydroxylamine (Scheme 2.118, inset) in the presence of aluminium trichloride, ultimately leading to the liberation of the oxaziridinyl NO fragment, which is subsequently O-protected by the tri(isopropyl)silyl group in situ [800]. Me Ph

N

MeO

MeO O

N

[Cu(CH 3CN) 4]PF 6

Ph

MeO

THF 74% MeO

MeO

831

OMe

832

Me Ph

Me N

[Cu(PPh 3) 4Cl] O

Ph

THF 89%

NH O

833

834

Ph

MeO 2C

N

O

AlCl 3 PhCH 2ONH 2

TIPSOTf

Ph

CH 2Cl 2 ∆ 25 min

imidazole r.t., 3 h 94%

MeO 2 C

N H

OTIPS

MeO

835

836 Ph

MeO 2C

MeO

N

.. H 2N

O AlCl 3

O

Ph

Scheme 2.118 Metal-mediated rearrangements of oxaziridines.

2.8 Dioxiranes 2.8.1 Properties of Dioxiranes

Dioxiranes are cyclic peroxides, and in many respects their chemical behavior can be described as activated peroxy species, or what Greer has dubbed “unusual peroxides” [801]. The strain energy of the parent compound (Figure 2.28) has been

j135

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136

Figure 2.28 Geometry of dioxirane.

calculated at 19.6 kcal mol1. However, this figure drops by almost half to 10.6 kcal mol1 in the case of 3,3-dimethyldioxirane (DMD) [802, 803]. Geometrically, the unsubstituted dioxirane ring describes a mildly distorted triangle [804]. 2.8.2 Synthesis of Dioxiranes

A survey of the preparative synthetic methods for dioxiranes is a little peculiar, because the field is dominated by virtually a single technique. There are certainly isolated alternative conditions that lead to the formation of the dioxirane system, such as the photolytic oxidation of diaryl diazoalkanes (e.g., 837 ! 838, Scheme 2.119) [805]; however, to date they have not been widely adopted by the synthetic laboratory.

t-Bu

t-Bu O O

N2 O2

Me

hν

Me

Me

Me Me

Me 837

O

838 KHSO 5 NaHCO 3

distill

O O

water/acetone 95%

846

O

848

847 OH

DMD acetone r.t.

HO

O

OH

849 OH

O

852

TFD CH2Cl 2 TFP 0°C, 20 min 94%

O +

> 97%

850

851

O

O

853

Scheme 2.120 Dioxirane-mediated hydroxylation.

cohol 852 to the corresponding ketone (853) in excellent yield upon treatment with TFD in methylene chloride and trifluoropropanone (TFP) [120]. Interestingly, this oxidation can be carried out in an intramolecular fashion – a sort of remote functionalization. For example, when the trifluoromethyl ketone 854 (Scheme 2.121) is treated with Oxone in buffered medium, it forms a dioxirane that oxidizes the d-methylene position. The hydroxyketone so formed subsequently cyclizes to the stable hemiacetal 855 [822]. In this intramolecular manifestation, geometric factors override electronic preferences. Thus, the dioxirane generated from ketone 856 also engages the secondary d-position over the adjacent tertiary position, ultimately forming the bicyclic hemiacetal 857 [823]. 2.8.3.3 Oxidation of Sulfur Dioxiranes have been applied to the selective oxidation of sulfides to sulfoxides [824]. For example, the thiochromanone 858 (Scheme 2.122) is converted into the corresponding sulfoxide (859) upon treatment with a slight excess of DMD at near-0
C temperatures. For best selectivity, the reaction was halted at partial conversion (about 75%); longer reaction times and higher loadings of DMD led to excellent yields of

2.8 Dioxiranes

O

Oxone OH

NaHCO 3 MeCN H2 O r.t. 85%

CF 3 854

O 855

H

Oxone Na2EDTA

O CF 3

O

OH CF3

NaHCO 3 MeCN H2 O 74%

856

CF3

H 857

Scheme 2.121 Intramolecular dioxirane-mediated hydroxylation.

O S

S

DMD(1.4 eq) CH2 Cl2 acetone 0-5°C

O 858

(84%) O 859 O

Me S

Me

S DMD

N H

N H

O

8 60

O

861 O

S

S

Ph O

DMD

Ph O

Ar

O

O

8 62

863

Ar

Scheme 2.122 Dioxirane-mediated sulfoxidation.

sulfone derivatives [825]. These oxidations can be quite diastereoselective. Thus, the DMD oxidation of 2,3-dihydro-1,5-benzothiazepinone 860 provided an overwhelming majority of the trans-sulfoxide 861 [826], and the epoxy thiochromanone 862 provided the trans/cis-sulfoxide 863 exclusively [827]. The same diastereomeric bias was observed even with the opposite epoxide stereochemistry, which seems to point

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140

toward a pivotal role of the a-substituent. Enantioselective sulfoxidation using chiral ketone precursors appears promising [828], although results are highly variable and substrate-dependent.

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j163

3 Four-Membered Heterocycles: Structure and Reactivity G
erard Rousseau and Sylvie Robin

3.1 Azetidines 3.1.1 Introduction

This chapter deals with azetidines, which are four-membered rings containing one nitrogen atom. The particular case of azetidin-2-ones (b-lactams) is examined in Chapter 24. Different important reviews have already been reported on their preparation and reactivity [1–3]. Different natural products of terrestrial or marine origins having an azetidine ring have been isolated. We indicate in this chapter only some representative examples. The simple (R) and (S)-azetidine-2-carboxylic acids 1 were found in numerous plants [4, 5]. N-Alkyl derivatives such as nicotianamine (2) [6] (isolated from a culture of Streptomyces) and mugineic acid (3) (isolated from a plant) [7] have also been reported. CO2H

CO2H

HO2C

HO2C

NH

1

N

N H H

CO2H

HO2C

N

N H

OH

NH2

3

2

Some C-alkyl derivatives are known, such as penaresidine-B (4) isolated from various sponges [8] and cis-polyoximic acid (5) isolated from a culture of Streptomyces [9, 10]. HO

NH

HO

HO2C

(CH2)10 4

NH

OH Me 5

Modern Heterocyclic Chemistry, First Edition. Edited by Julio Alvarez-Builla, Juan Jose Vaquero, and José Barluenga. Ó 2011 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2011 by Wiley-VCH Verlag GmbH & Co. KGaA.

CO2H

j 3 Four-Membered Heterocycles: Structure and Reactivity

164

Thenucleusazetidineisalsopresentinmorecomplexproducts,suchaspolyoxinA(6, isolated from culture broth of Streptomyces cacaoi var. asoensis) [11], gelsemoxonine (7) isolatedfromthecreeperGelsemiumelegansandvioprolidesA(n ¼ 1)andB(n ¼ 2)8[12], obtained by fermentation of a strain of the myxo bacterium Cystobacter violaceus [13]. O CO2H HN O H 2N

OH O O OH

NH2

N

O O

OH N

N N O H OMe

O

N H

O OH H O

H

OH OH

7

6 S H OH N Me ( )n N

Me N

Me

O

NH

Me

O O

O

O

HN

O NH

i.Pr N Me

HO

Me

NH

OH O

O

8

Agrochemical applications of azetidine derivatives have been reported [3]. Actions on the central nervous system with various activities (antiepileptic, anticonvulsant, antihypertensive, antidepressant, analgesic, etc.) have been also described [3]. A promising compound appears to be ABT-594 (9), synthesized from ( þ )-epibatidine (10), present in frogs [14]. Compound 9 proved to be more powerful than morphine as a painkiller [15].

O

Cl N

N H 9

Cl

H N

O2N

NO2

N H 10

N NO2 11

The preparation of 1,3,3-trinitroazetidine (11) has been reported [16]. This compound was evaluated as a substitute for TNT, due to its high thermal stability. However, its cost of preparation and its high volatility limit its utilization as explosive or propellant.

3.1 Azetidines

j165

3.1.2 Physicochemical Data

Azetidines appear to be thermally stable. They are unreactive towards numerous reagents and can be prepared without special precautions. They can be analyzed using gas chromatography or liquid chromatography over silica gel, for example. Their reactivities appear closer to these of higher cyclic amines than aziridines. The strain in azetidines explains their difficult formation by cyclization, which is comparable to these of azepines [17]. Electron diffraction and X-ray crystallographic studies have shown the non-planarity of the ring. For azetidine, the angle between the planes formed by the CCC and CNC bonds is 37
, which is similar to that found for cyclobutane. Inversion of the pyramidal nitrogen is very easy for these heterocycles (DG#  10 kcal mol1). Azetidines have been studied by NMR spectroscopy. In the absence of substituents the chemical shift of the hydrogens fixed on the carbon at the 2position are in the range 2.5–3.5 ppm and the hydrogens fixed on the carbon at the 3-position 1 ppm higher. In general the magnitude of the coupling constants for vicinal hydrogens is in the range 6–8 Hz for the cis stereoisomers and 2–4 Hz for the trans stereoisomers. With 3-hydroxyazetidine derivatives, the determination of the stereochemistries could be come very difficult. Structural identification was reported to be possible when the 1 H NMR spectra were recorded out in the presence of known amounts of Eu(Fod)3 [18]. In 13 C NMR, the carbon shifts in 2,4 positions are close to those of carbons in five- and six-membered cyclic amines. Figure 3.1 shows some representative examples of these chemical shifts. The 15 N chemical shift of azetidine (from NH3) was reported to 25.3 ppm. N-Substituted azetidines showed chemical shifts comparable to other nitrogen heterocycles [19].

Ph N

O N

3.58 3.26

1.99

43.0

Ph N

32.4

Me 4.15 4.03

41.5

50.3

Me N

3.36 3.46

1H

56.5

13

shift

1.98-2.11

2.26 O

H N

Me Me

47.7

14.8

Figure 3.1 Representative examples of chemical shifts.

97.4

Me

iPr N

MeO Me 41.2

Me

C shift

j 3 Four-Membered Heterocycles: Structure and Reactivity

166

3.1.3 Synthesis

This chapter reports the main methods that lead to azetidines with acceptable yields. Some less synthetically useful methods can be found in previous reviews. These preparations can be divided into three groups: formation (i) by cyclization, (ii) from other heterocycles and (iii) by [2 þ 2] cycloadditions. 3.1.3.1 Cyclization Reactions 3.1.3.1.1 Formation of a CN Bond Ring Closure of c-Amino Derivatives Apowerfulandsimplepreparationofazetidinesis theintramoleculardisplacementofaleavinggroupfixedonacarbonbyac-aminogroup. Bromo, iodo, tosyloxy, mesyloxy and triflyloxy were mainly used as leaving groups, and alkyl,arylandtosylwereusedasprotectinggroupsonthenitrogenatom(Scheme3.1)[3].

R1 R2

R3 R4 X

base

R6 R5 NHZ

R4 R3

R6

R1 2 R

NZ

R5

Scheme 3.1

This approach was reported as the key step in a synthesis of penaresidine B (4) (Scheme 3.2) [20]. It was subsequently reported that diastereoselective cyclizations of the mesylates lead to similar results (Scheme 3.3) [21]. NH2 OH BnO

C12 H25 OBn

1. TsCl, pyridin e 2. NaH, DMF

BnO

H

Ts N C12H25 H H OBn

49 %

Scheme 3.2

NH2 OH Ar

Ar Me

MsCl, CH2Cl2, Et3N 40 °C, overnight 10-59 %

H Ar

Ms H N Ar Red-Al, benzene N Ar H p H H Ar = Ph, tolyl Ar 3.5 h, reflux Me H Me H 56-76 %

Scheme 3.3

A modification of this method has been investigated. It was shown that utilization of Mitsunobu conditions (X ¼ OH in Scheme 3.1) could be very efficient [22]. This cyclization was applied to the preparation of substituted azetidines, without any epimerization of the chiral centers (Scheme 3.4) [23].

3.1 Azetidines

Ts

NH

iPrO

R2

OH

i 2CN=NCO2 Pr

PPh3, THF, 72 h, rt

R1

Ts N

R2 H

R1 = H, Me, Et, n-Bu, Ph R2 = n-Bu, n-Hex, tBu

R1 H

80-97 %

j167

ee>96%

Scheme 3.4

Cyclization of protected 1-azidopropan-1-ols was also reported to lead to the formation of azetidines. This cyclization occurred when the azido group was reduced using Raney-nickel (Scheme 3.5) [24]. This method appears more efficient than when using PPh3 as reducing agent [25]. N3

Raney Ni

BnO

OMs OBn

BnO

EtOH, rt, 15 h

H N H

BnO

75 %

H

Scheme 3.5

This cyclization was found to be easy with 3-chloroalkylamines obtained by reaction of 1-aminoalkyl chloromethyl ketones with organocerium reagents. The cyclizations occurred during evaporation of the reaction solvents (Scheme 3.6) [26]. These isolable azetidinium salts were subsequently transformed into azetidines by catalytic hydrogenation. Chloromethyl ketones react with ester enolates in similar fashion (Scheme 3.7) [27].

O R1

Cl

1. R2M, CeCl2, -60 °C

R1

2. NH4Cl, H2O

NBn2

R1 = Me, iBu, Bn,

HO R2

Cl 74-84 %

NBn2

R1 H

Bn + Bn N Cl- Pd, HCO2H R2 OH

R1

H N

reflux, overnight H 2 R OH 90 %

R2 = Me, Bu, allyl, Bu

Scheme 3.6

O R1

Cl NBn2

+

H

OLi 1. THF, - 78° C

R2

OEt 2. NH4Cl, H2O

R

Cl CO2Et

HO

1

NBn2

R2

Bn dryness 68-82%

R1 H R2

Bn N+ ClOH CO2Et

R1 = Me, Bn, iBu R2 = H, Bn

Scheme 3.7

Formation of 3-azetidinones from 1-aminoalkyl chloromethyl ketones was also reported to occur by reaction with tributyltin hydride (Scheme 3.8) [28].

j 3 Four-Membered Heterocycles: Structure and Reactivity

168

Bu3SnH, THF Cl AIBN, 65 °C, 12-14h

O Ar1 NC HN

Ar1

Ar1 = Ph, 2-ClC6H4, 3-NO2C6H4,

O

Ar2 = Ph, 4-BrC6H4

NC

72-77%

Ar2

Ar2 N

4-ClC6H4, 4-MeOC6H4, 4-MeC6H4

Scheme 3.8

Another interesting preparation of 3-azetidinones involves carbenoid insertion into a NH bond. 1-Aminoalkyl a-diazomethyl ketones reacts with rhodium acetate to give optically active 2-substituted 3-azetidinones (Scheme 3.9) [29]. These ketones allowed highly diastereoselective additions of nucleophilic reagents or Wittig reactions (Ph3P¼CHCO2Me). Utilization of copper acetylacetonate as catalyst has been subsequently reported [30]. O

R

H N2

Rh2(OAc)4, THF, rt

NHZ

N Z

50-60%

O

NuH R

R = Me, CH2Ph, iPr, (CH2)4CO2CH2Ph

HO Nu N Z

50-95%

R Z = CO2tBu, CO2CH2Ph NuH= L-selectride,MeMgBr, BuMgBr, PhMgBr

Scheme 3.9

Azetidines can be obtained by MgBr2 catalyzed isomerization of aminomethyloxiranes. A mixture of diastereomers was generally obtained (Scheme 3.10). With the trans epoxide substituted by an alkyl group, only one azetidine was detected [31]. MgBr2 (5 mol %) Ph

Ph

NHBn 1,4-dioxane, reflux, 5h O

NBn

+

cis

66 %

trans

73 %

(86 (6.5

NHBn 1,4-dioxane, reflux, 9h

Pr O

58 %

Pr

2. NaOH, H2O, 100 °C, 5 min

Scheme 3.10

OH

65 %

+ Azeridines

:

10

:

4)

:

92

:

1.5)

NBn

HO

1. mCPBA, CHCl3, 0°C to rt NHTs

NBn

HO

HO

MgBr2 (5 mol %)

Me Me

Ph

Me Me

NTs OH OH

3.1 Azetidines

j169

Utilization of sodium hydroxide to carry out ring opening of oxiranes was reported to be possible, if the epoxide function was b of the amino group (4-exo mode cyclization) (Scheme 3.10) [32]. Ring Closure of 1,3-Functionnalized Propane Derivatives with Amines 1,3-Dielectrophiles react with primary amines to afford azetidines (Scheme 3.11). RNH2 X

X

N R

Scheme 3.11

1,3-Dihalopropane derivatives have been used with more or less success, due to the possible formation of side products [3]. However, satisfactory yields were obtained when the halogen atoms were in activated positions (Scheme 3.12) [33]. Br

Br

EtO2C

CO2Et

PhCH2NH2 benzene, reflux, 24 h

EtO2C

N Bn

46 %

CO2Et

Scheme 3.12

Better yields were observed with 1,3-triflates (Scheme 3.13, reactions carried out a 1 kg scale) [34], 1,3-ditosylates [35] or 1,3-dimesylates (Scheme 3.14) [36].

TfO TfO

CO2Et CO2Et

BnNH2, MeCN iPr

2NEt2

EtO2C

70 °C, 2h

CO2Et

1. NaOH, H2O, 50 °C, 45 min

N Bn

HO2C

2. HCl, H2O, rt 61%

Scheme 3.13

HO R

OH R

(ee > 99%)

1. MsCl, NEt3, CH2Cl2, 0 °C 2. NH2Bn, 45 °C, 60 h R 60-85%

N Bn

R

R = Me, Et, Pr, CH2Ph

(ee > 99%)

Scheme 3.14

3-Hydroxyazetidines have also been prepared by the reaction of epichlorohydrin with primary amines. The intermediate formation of c-chloro-b-hydroxyamines or amino methyl oxiranes is a function of the reaction conditions and the nature of the amines. In some cases these two-step reactions were conducted as one-pot reactions (Scheme 3.15).

CO2H N Bn

j 3 Four-Membered Heterocycles: Structure and Reactivity

170

Cl

NHR OH

Cl

+

O

HO

RNH2

NR

RHN O

Scheme 3.15

For example, the reaction of epichlorohydrin with 1-silylalkylamine leads to the formation of 3-hydroxyazetidines in excellent yields. This method was used in a new preparation of 1-methyl-3-hydroxyazetidine (Scheme 3.16) [37]. N-Substituted azetidinols were also obtained by heating aminomethyloxiranes in the presence of triethylamine (Scheme 3.17) [38]. 1. EtOH, reflux, 24 h Cl O

R + Me3Si

NH2

2. NaOH, H2O

HO

SiMe3

N

R

70-83%

R = Et, Pr, iPr, cyclohexyl, SiMe3

Scheme 3.16

Cl O

+ R NH2

iPrOH,

rt, 6-24 h

Et3N, MeCN reflux, 12-24h

RHN O

81-95%

HO

N R

26-85%

R = tBu, iPr, n-Bu, HOCH2CH2-, allyl, PhCH2, Ph2CH Scheme 3.17

Another approach to azetidines implies the addition of nucleophiles such as cyanide, hydride or organolithium reagents (Scheme 3.18) to b-chloroimines [39]. When the nucleophile is KOtBu, 2-methyleneazetidines are obtained if the work-ups are carried out in the absence of water (Scheme 3.18) [40].

Me Me

N

R1 H

Cl 2

R R1

N

R2Li, Et2O, 0 °C to reflux 1-6.5h 60-85 %

N

Me Me

R2

Ar Me

Cl Scheme 3.18

tBuOK, tBuOH,

0.5-3 days

N

reflux

87-95 %

R1

R1

2

R

Ar

R1 = Me, Bu, Ph R2 = iPr, tBu

Ar = Ph, 4-MeC6H4 R1, R2 = H, Me, (CH2)4-

3.1 Azetidines

j171

Electrophilic cyclization of N-cinnamyl tosylamides affords azetidines in good yields. These 4-endo mode cyclizations are diastereoselective (Scheme 3.19) [41]. Br+(collidine)2 PF6Ph CH2Cl2, 2h, rt

Me H Ph

NHTs

83%

NTs

Br

Ph Br

Me 80

NTs

+

Me

:

20

Scheme 3.19

4-Exo mode cyclizations of unsaturated amines have also been reported using iodine [42], NBS [43] and selenium reagents (Scheme 3.20) [44]. R1 R

N H

R1 R2

R1

I2, MeCN, NaHCO3 2 R 1 h, 0°C

2

R3 O

N

78-96%

R2 = H, Cl R3 = Me, CF3, Ph

O SePh

PhSeCl (Br,I), Na2CO3, MeCN 16 h, rt

SePh NBn

R1 2 R

NHBn

R1 = Me, Ph

I R3

+

R1

NBn R2

R1 = H; Me, Et, iPr, tBu, Ph R2 = H, Me, Et

5-15%

85-95% Scheme 3.20

An interesting method for the preparation of enantiopure azetidines is the intramolecular amination of b-aminoallenes catalyzed by Pd(PPh3)4 (Scheme 3.21). When the protecting group on the nitrogen atom was a tosyl, a mixture of alkenyl azetidine and tetrahydropyridine was obtained (R2X ¼ aryl iodide, e.g. PhI). However, with enol triflate as alkylating agent, the exclusive formation of azetidines was Pd(PPh3)4, DMF, K 2CO3 R1 R1 Ts

Me

NH

41-67%

Scheme 3.21

Ts

Pd(PPh3)4, DMF, K 2CO3

R1 S O2

R2 X, 80 °C, 0.5-40 h

•

NH

•

R2X, 40 °C, 0.75-2 h 22-98%

N

Ph +

Ph

R1 = H, CO2Me N Ts

Me

R1 N

S O2

R2

R

1

R1 = iPr, iBu, Bn, MeO2C(CH2)2R2 = Ph, 3-NO2C6H4, Ph

j 3 Four-Membered Heterocycles: Structure and Reactivity

172

observed (35–40%) [45]. This is also the case when the protecting group was a mesitylenesulfonyl (Scheme 3.21) [46]. 3.1.3.1.2 Formation of a C–C Bond Intramolecular reaction of a-aminocarbanions with activated carbon–carbon double bonds is an excellent method by which to prepare functionalized azetidines. Mixtures of diastereomers have been obtained from a-aminonitriles. Better diastereoselectivities were observed from a-aminoesters (Scheme 3.22) [47, 48]. CO2Et

R1

base, THF

N Bn

EtO2C

Z N

R1

Z

R1 = Me, Et, Pr, iPr, tBu, Ph

Bn

LiHMDS, -78 °C to 0 °C, 2 h 58-87% (de: 20-40%)

Z = CN

Z = CO2R (R1 = Me)

50-76% (de > 95%)

BuOK, - 50 °C, 1 h

t

Scheme 3.22

Intramolecular cyclization can also be observed if the carbon b of the amino group bears a leaving group (Scheme 3.23) [49]. This method has been applied to the preparation of cis and trans 3-phenyl-azetidine-2-carboxylic acids [49], azetidine-2carbonitriles, [50] and diethyl azetidine-2-phosphonates (Scheme 3.24) [51]. Ph Ph Ph

N

Cl CO2tBu

NaN(SiMe3)2

Ph

THF, -78 °C 69%

CO2tBu N

Ph

Ph

CO2H N

H

Ph trans:cis = 82:18

Scheme 3.23

Ph

Cl

Me

N Me

LiN(SiMe3)2 OEt P OEt O

THF, -78 °C to 0 °C 50%

Ph Me

O OEt P OEt N

Me

Scheme 3.24

Anotherdiastereoselectivepreparationofsubstitutedazetidineshasbeenreportedby a photochemically induced cyclization of chiral a-aminoketones (Scheme 3.25) [52, 53].

3.1 Azetidines

R1 Ar

hυ, MeCN

Z

O

N Me

70-80%

HO Ar

R1 = H, Me, CH2Ph, Ph, CH2 OSiMe2texyl Z = Tosyl, Boc, Ac Ar = Ph, 3,4-Ac2C6H3

R1 N

j173

Z

Scheme 3.25

Fused azetidine derivatives have been obtained by irradiation of dihydropyridines (Scheme 3.26) [54a]. This methodology has been applied to the formation of an analog of ABT-594 [54b]. However, this compound appeared less efficient than epibatidine as nicotine agonist. hυ (300 nm), acetone N CO2Me

OH

CO2Me H

N

3-4 days

N

H H

OH

20%

O

C l N

Scheme 3.26

Irradiation of 3-allyl or 3-benzyl-2-acyl perhydrobenzoxazine furnishes azetidin-3ol derivatives in moderate chemical yields (50–60%). However, the diastereoselectivity of these cyclizations are good (up to 96%). The menthol part was then removed in low overall yields to give enantiopure azetidin-3-ol derivatives (Scheme 3.27) [55]. Me Me

O O

Me N

hυ, MeCN rt

R1 R2 6-60%

Me Me

N

O HO

Me

Me

R1

+ Me

O

H

R1

R2

minor

major 4 steps 15-25%

Ts R2

N

R1 = H, Me, Ph, 4-MeOC6H 4, 2-furyl

Me N

H

2 OH R

R2 = CH=CH2, CPh=CHEt Ph, 3,4-(MeO)2C6H3

OBn R1

Scheme 3.27

Electroreduction by intramolecular coupling of chiral a–iminoesters in the presence of chlorotrimethylsilane affords cis-2,4-disubstituted azetidin-3-ones in good yields (Scheme 3.28) [56]. 3.1.3.2 Ring Transformations 3.1.3.2.1 Ring Expansions of Aziridines Reactions of N-arenesulfonylaziridines with dimethyloxosulfonium methylide afford azetidines. These ring expansions are stereoselective. The cis-aziridines yield trans-azetidines, and reciprocally, via a

j 3 Four-Membered Heterocycles: Structure and Reactivity

174

Ar N

CO2Me

1. e-, Pt cathode (300 C) 0.3 M Bu4NClO4, THF

Me3SiO

ClSiMe3, NEt3

R

Ar

N Bz

2. BzCl, NEt3 34-60%

OMe

R = Me, iPr, iBu, Bn

R

Ar = 2-MeOC6H4, 3-MeOC6H4, 4-MeOC6H4, 4-FC6H4, 4-NH2C6H4, 1-naphthyl, 2-naphthyl

ee: 90-99%

Scheme 3.28

SN2-type reaction, followed by an intramolecular nucleophilic substitution [57]. This reaction has also been reported using dimethylsulfonium methoxycarbonyl methylide (Scheme 3.29) [58].

Me3

1

R

3

I- ,

NaH

DMSO, 18-20 h, rt

SO2R3 N R2

H

S+(O)CH

H

H

R2

21-80%

H

21-46% Me2S(O)CHCO2Et

R2

DMF, 50 °C, 1-2 h

H

H

then rt overnight

R1 N SO2R3

R1, R2 = Ph,Me

R1

R1, R2 = H, Ph,Me

R3 = Ph, 4-MeC6H4, 4-ClC6H4

CO2Me H N SO2R3

Scheme 3.29

1-Substituted 3-azabicyclo[1.1.0]butanes are easily prepared using the method first developed by Funke [59]. These compounds react with numerous electrophiles to afford azetidines (Scheme 3.30). More recent reports give improved conditions for the preparation of the bicycloaziridines, and their reactions with electrophilic reagents [60–62].

Br Br R

NH2.HBr

base

R N

E-Nu

R

Nu N E

R = H, alkyl, Ph E = H, CO2Et, Ts, Tf, Ms... Nu = F, OH, X, SAc...

Scheme 3.30

3.1.3.2.2 Ring Contractions 5 ! 4 Ring contractions appear rather rare. The reaction of a thiazolidine with Raney-nickel has been reported to lead to yield an azetidine (Scheme 3.31) [63]. Two interesting examples of 6 ! 4 ring contractions have been also reported. They used the transformation of cyclic carbamates. Heating tetrahydro-3-benzyl-5,5-

3.1 Azetidines

Raney-Ni Ph

CO2Me

S

Ph Ph

N

CO2Me Ph

Ph

CH2Cl2, MeOH

j175

Ph CO2Me

Ph

N CO2Me Ph

rt, 48 h 83%

Scheme 3.31

dimethyl-1,3-oxazin-2-one at 250
C in the presence of LiCl affords the corresponding azetidine [64]. 1,2,2,4-Tetrasubstituted azetidines have been prepared using this method. Reaction of a carbamate with a palladium(0) salt led to a comparable decarboxylation. This reaction has not been studied further (Scheme 3.32) [65]. O Bz

N Me

O

N

O

Pd(PPh3)4, EtOH rt, 41 h then 60 °C, 29 h

Me

Me N Bz

Me

39% Me

Me

85%

O Ts

LiCl 250 °C, 30h

Me

Me N Bz

Scheme 3.32

3.1.3.2.3 From b-Lactams Reductions Reductions of b-lactams into azetidines have been reported with common reducing agents such as LiAlH4, LiAlH4-AlCl3, ClAlH2, Cl2AlH, AlH3, BH3 and DIBAL-H [66–69]. With optically active lactams, these reactions occur in general without loss of enantiomeric purity. However, these reagents were not compatible with the presence of ester groups. In this case, diphenylsilane in the presence of a rhodium salt (Scheme 3.33) could be efficient [70].

O

R1 CO2R2 N R3

Ph2SiH2, THF RhH(CO)(PPh3)3 15 h, rt 34-94%

R1 R1 2 H , THF, Pd(OH) CO2R2 CO2R 2 2 N N R2 = Me, tBu H R3 HCl, 15h, 50 °C, 2.7 atm R3 = 4-MeOC6H4CH2 55-95% R1 = Me,CH2Ph,CH2CHMe2, (CH2)2CO2tBu, (CH2)3NHZ, (CH2)3NHBoc

Scheme 3.33

j 3 Four-Membered Heterocycles: Structure and Reactivity

176

Reduction of azetidine-2,4-dione by AlH3 into azetidine has also been reported [71], while the reduction of 2-azetidinethiones is possible using Raneynickel (Scheme 3.34) [72]. Raney-Ni, EtOH reflux, 2 h

Me Me N

S

Me Me N

54%

Ph

Ph

Scheme 3.34

Olefinations Stabilized ylides react with 2-azetidinones to afford 2-methyleneazetidines. This olefination does not take place with unstabilized ylides or when a substituent is present at the 3-position [73]. In such a case, methylenation is possible using dimethyltitanocene (Scheme 3.35) [74, 75].

CO2Bn O

N

Ph3P

R toluene, reflux, 12-48 h

Boc

OAc

Me N

Boc

CO2Bn N

20-98%

TBDMSO

O

Z

Z

R = H, Me

Boc

R

Cp2TiMe 2 toluene, 70°C, 1-3 h 81%

Z = CO2Me, CN, CO2tBu

TBDMSO

OAc

Me N

Boc

Scheme 3.35

3.1.3.3 Cycloadditions [2 þ 2] Cycloadditions of imines or imino compounds with ethylenic derivatives can afford azetidines. However, the yields were generally low [3] until, relatively recently, improved conditions were found. Imines react with allylsilanes catalyzed by Lewis acids to give azetidines in good yields (Scheme 3.36) [76]. Mixtures of diastereomers were obtained. N-Tosylimines have also been reported to react with a-allenic esters and a-allenic ketones in the presence of DABCO (Scheme 3.36) [77]. The reaction of a-imino esters with 1-methoxyallenylsilanes has been achieved by means of copper tetrafluoroborate. In the presence of (R)-Tol.BINAP, optically active azetidines with high enantiomeric excesses were obtained (Scheme 3.37) [78]. 1-Aryl-4-phenyl-1-azadienes undergo [2 þ 2] cycloadditions, after more than 40 days, with allenic esters at room temperature. Attempts to decrease the reaction time by heating gave rise to the exclusive formation of [4 þ 2] adducts (Scheme 3.38) [79].

3.1 Azetidines TiCl 4 or BF3.Et2O, CH2Cl2 Ph

Ar

N

N

Z

SiR3

SiR3 - 78 °C (1 h) then 0 °C (12-24 h) Ph

+

N Z

8-86%

Ts

+

DABCO CO2Et benzene, MS 4 Å, 1 h

•

Ar

42-93%

N Ts

j177

R = Me, iPr Z = Me, iPr, CO2Et, CO2tBu, COPh,

CO2Et Ar = Ph, 4-MeC6H4, 4-EtC6H4, 4-FC6H4, 3-FC6H4, 4-BrC6H4, 4-CF3C6H4, 3-NO2C6H4, 2,3Cl2C6H3, 4-MeC6H4,1-naphthyl, 3-pyridyl

Scheme 3.36

EtO2C

N

Ts

+

•

10 mol%, Cu+(MeCN)4 BF4(R)-Tol.BINAP, THF OMe EtO2C R MS 4Å, -78 °C, 9-24 h 60-92%

OMe

R = SiMe3, SiiPr3, t OSiR3 SiMe2Ph, Si BuMe2, GeEt3

N Ts

ee: 58-97%

Scheme 3.37

benzene, rt 45-65 days

R Ph N Ar

17-28% Ph

N

Ar

+

R

•

CO2Et benzene, reflux 78-97%

H

N Ar

Ph

CO2Et R = H, Me, Et Ar = Ph, 4-MeC6H4, 4-ClC6H4, 4-MeOC6H4, CO2Et CH2R

Scheme 3.38

The cycloaddition of benzyne with N-aryl imines occurs in good yields (Scheme 3.39) [80]. This is also the case for the [2 þ 2] cycloadditions of alkoxy imines with phenyl ketene [81]. 3.1.4 Reactivity and Useful Reactions 3.1.4.1 Reactions at the Nitrogen Atom 3.1.4.1.1 Reaction with Carboxylic Acid Derivatives Reactions of carboxylic acid chlorides with azetidine derivatives lead to N-acyl derivatives in high yields. These reactions were carried out in the presence of bases such as K2CO3 [82], NEt3 or pyridine [3]. Recently, a solid-phase approach has been described for the preparation

j 3 Four-Membered Heterocycles: Structure and Reactivity

178

Ar

N

Ar

Ar

+

HO

bis(2-ethoxy)ethyl ether AmONO, 40-80 °C, 0.5 h

H 2N

O

N

OEt

N

58-67%

+ Ph

reflux, 2 h Cl

Ar

O

EtOAc, NEt3

O

Ar Ar = Ph, , 4-MeC H 4-ClC H , 6 4, 6 4 4-MeOC6H4, 4-EtOC6H4, 3-NO2C6H4

Ar

N Ar

20-48%

Ph

Ar = Ph, 4-MeOC6H4, 2,3-Cl2C6H3

Scheme 3.39

of malondiamides. 2-Methoxyethylamine was fixed on a Bal-resin, and successive reactions with 2,2-dimethylmalonyl dichloride and azetidine lead to the malonamide. Cleavage with trifluoroacetic acid gives rise to the mixed malonamide in high yield (Scheme 3.40) [83].

OMe Bal SP N

1. Me2C(COCl)2 ,6h 2. azetidine, CH2Cl2, DIPEA 3. CF3CO2H, CH2Cl2

H

O Me Me

89%

OMe

N N O

Scheme 3.40

N-Acetylazetidines can also be obtained by reaction with carboxylic anhydrides in the presence of DMAP (Scheme 3.41) [84], by reaction with ester in the presence of Horse Liver esterase [85], or by reaction with acid activated by reagents such as 1-[(3dimethylamino)propyl]-3-ethylcarbodiimide (DMAP) [86] or 1H-1,2,3-benzotriazol1-ol (HBTU) derivatives (Scheme 3.41) [87–89]. H N

OBn

BnO

100%

CO2Et N OBn BnO t

CO2tBu NH

(EtCO)2O, CH2Cl2 DMAP, E t3N, rt

CO2tBu +

HO2C

NHBoc

HBTU, MeCN, N-ethylmorpholine

BuO2C

O N

CO2tBu NHBoc

64%

Scheme 3.41

3.1.4.1.2 Reaction with Aldehydes and Ketones Aldehydes react in the presence of NaBH3CN in acetic acid to furnish N-alkylazetidines (Scheme 3.42) [90]. Formic acid was sometimes preferred as the reducing agent [91].

3.1 Azetidines

CO2tBu

CO2tBu OHC

+

NH

NaBH3CN, THF, MeOH 4 °C, 10 h

CO2tBu

N Boc

CO2tBu

CO2tBu

N

OAc

j179

N Boc

93%

CO2tBu OAc

Scheme 3.42

These N-alkyl azetidines have been also obtained from the corresponding N-acyl compounds by carbonyl reduction after transformation into thioamides (Scheme 3.43) [88].

tBuO

tBuO

2C

O

N

2C

O N Boc

Lawesson's reagent

CO2 tBu

tBuO

benzene, reflux, 3h

NHBoc

tBuO

2C

S

2C

N

N Boc

95% t THF, Raney-Ni (W2) BuO2C rt, 4 h

51%

t

N

BuO2C

S

CO2tBu N Boc

NHBoc

Scheme 3.43

The reaction of (S)-azetidine 2-carboxylic acid with pivaldehyde gives a bicyclic compound. When this reaction is catalyzed by CF3COOH, a racemic product is obtained [92]. With trimethylsilyl-trifluoromethanesulfonate as catalyst, though, racemization was not observed and enantiomerically pure product was obtained (Scheme 3.44) [93].

CO2H NH

1. TMS, NEt3 2. tBuCHO, CH2Cl2 Me3SiSO2CF3 90%

H O N

O t

Bu

96% ee

Scheme 3.44

The reaction of azetidines with ketones affords the corresponding enamines. Kinetic studies have shown that these amines are more reactive than pyrrolidine [94]. 3.1.4.1.3 N-Alkylations N-Aryl azetidines can be obtained by the arylation of Nunsubstituted azetidines with aryl bromide, catalyzed by palladium salts (Scheme 3.45) [36a]. Another interesting method used the SNAr substitution of the fluorine on fluoroaryl. These reactions were carried out under sonication of the reaction mixture (Scheme 3.46) [95].

CO2tBu NHBoc

j 3 Four-Membered Heterocycles: Structure and Reactivity

180

NH

R

Pd2(dba)3, NaOtBu toluene, 70 °C

R + ArBr

N Ar

32-96%

R

R = Me, Et Ar = Ph, 2-MeC6H4, 2-MeOC6H4, 2-BrC6H4, 1-naphthyl, 4-CF3C6H4, 3-(BrCH2)C6H4,

R

Scheme 3.45

DMSO, K2CO3, )))

R NH + F

R

100 °C, 3-5 h

CHO

N

CHO

R = H, Me

24-81% Scheme 3.46

An original preparation of (phosphorothioyl)oxycarbonyl azetidine has been reported by reaction of azetidines with diphenylphosphinothioic chloride [Ph2P(S) Cl] in the presence of K2CO3. This reaction was greatly improved when carried out under carbon dioxide in the presence of crown ether (Scheme 3.47) [96]. Ph2P(S)Cl, MeCN K2CO3, CO2 (10kg/cm 2)

CO2Me

MeCO2

18-crown-6, 48 h, rt

NH

85%

CO2Me

O

N

O

S PPh2

CO2Me

Scheme 3.47

3.1.4.2 Oxidizing Reactions Oxidations of azetidin-3-ols into azetidin-3-ones with common CrO3, Swern or DessMartin reagents have been reported to occur in high yields. No cleavage or degradation of the four-membered ring was noticed [3, 97]. Microbial oxidations of azetidines lead to the formation of azetidin-3-ols (Scheme 3.48) [98, 99]. Oxidations a of the nitrogen-atom (formation of b-lactams) have been performed with a RuO2-NaIO4 mixture (Scheme 3.48) [100] and

N CO2R H

Sphingomonas sp. (HXN-200)

CO2Me

NBoc Scheme 3.48

t N CO2R R = Ph, Bu

HO

89-98% RuO2, NaIO4 EtOAc, H2O, rt 73%

H

O

CO2Me

NBoc

3.1 Azetidines

j181

KMnO4 [101]. Transformations of azetidin-2-carboxylic acids and esters into of b-lactams using oxygen have been also reported [102]. 3.1.4.3 Reactions with Nucleophiles and Bases N-Chloroazetidines can react with DBU to furnish stable azetines (Scheme 3.49) [103]. Azetines were also obtained when the leaving group was in the 3-position. The reaction of 3-mesylazetidines with potassium tbutylate leads to the formation of azetines that can be transformed by flash-thermolysis into 1-aza-1,3-dienes. By smooth heating, these later give rise to bicyclic compounds (Scheme 3.50) [104].

R

1. tBuOCl 2. DBU, Et2O-DMF

Ph

O

NH

R

Ph

O

R = H, Me

N

67-84%

Scheme 3.49

tBuOK,

DMSO or tBuOH, 40-50 °C

MsO N

R

O R = aryl, alkyl

62-93% if R =

350-450 °C R

N

100%

O ( )n

100 °C, 1 h 46-80%

N

O R

N

R = Me, Ph, (CH2)3CH=CH2, (CH2)2CH=CH2, 4-MeC6H4

( )n

O

Scheme 3.50

The reaction of 3,3-dichloroazetidines with NaOMe or NaH also leads to azetines. The presence of an aryl substituent at the 2-position seems to increase their reactivities; subsequent reactions lead, finally, to aziridines (Scheme 3.51) [105].

MeO MeONa

Cl Cl

Ar NaOMe,MeOH, reflux, 20 h Cl N

R

or NaH, DMSO, 80 °C, 3 h

Ar N

R

83-94%

Scheme 3.51

Ar

N R

R = iPr, cyclohexyl Ar = Ph, 4-FC6H4, 4-MeOC6H4

O

H2O 46-75%

OMe

N R

Ar

j 3 Four-Membered Heterocycles: Structure and Reactivity

182

Instead of elimination, substitution occurs when 3-arylsulfonate-azetidines are reacted with benzylamine (Scheme 3.52) [106]. These substitutions, which occur with retention of configurations (due to the participation of the ring nitrogen) were also reported with sodium cyanide [107].

PhO2SO

BnNH2, THF, reflu x

N SO2Ph

BnHN

N SO2Ph

41-50%

Ph

NaCN, DMF 65 °C, 6 h

Ph

81%

Me MsO

N

Me NC

N

Ph Ph

Scheme 3.52

3.1.4.4 Reactions of C-Metallated Azetidines Lithiation of methyl azetidine-2-carboxylate in a of the ester function has been carried out with LiHMDS as base [108]. Metallation of the azetidine ring of a methyl azetidin2-ylidenecarboxylate with KHMDS is also effective. Subsequent addition of electrophiles yields 3-substituted azetidines (Scheme 3.53) [109].

F3C

CO2Me

KHMDS, THF, -78 °C then electrophile

N CO2tBu

68-75%

E F3C

CO2Me

E = Me, PhCH(OH), 3,5-F2C6H3CH2

N CO2tBu

Scheme 3.53

Organozinc compounds, formed by the reaction of 3-iodoazetidine with zinc, couple with aryl chlorides in the presence of palladium salts or with allyl bromide in the presence of CuCN to give 3-substituted azetidines in satisfactory yields (Scheme 3.54) [110]. Zn, THF, rt, 0.75 h then DMA, RCl, Pd2(dba)3 I

N Boc

P(2-furyl)3, 2 h, 80 °C

R

N Boc

R = Ph, 4-CNC6H4, 1-pyridyl, 2-pyridyl, 3-pyridyl, 5-pyrimidyl, allyl

46-63% Scheme 3.54

3.1.4.5 Ring Expansions Ring expansions of azetidines into five-, six- and eight-membered heterocycles have been reported. Pyrrolidin-2-ones have been isolated during the preparation

3.1 Azetidines

of azetidin-2-carbonyl chlorides (Scheme 3.55) [111] or 2-(azetidin-3-yl)acetyl chloride [112]. Cl

CO2H

(COCl)2

N R

MeO2C

46-68%

CO2Me

R = Bn, cyclohexyl

O

N H

Scheme 3.55

Imidazolidines can also be obtained by Beckmann rearrangement of 3-(mesyloxyimino)- or 3-(tosyloxyimino)azetidines (Scheme 3.56) [113].

N

OR1

Al2O3 (neutral or basic) benzene, rt

N CO2R2

O

HN

R1 = SO2Me, SO2Ph R2 = Et, Bn, CH2CCl3

N CO2R2

60-91%

Scheme 3.56

Heating of 2-(phenylselenyl)methyl azetidines [114], 2-(methanesulfonyl)methylazetidines [115] or 2-(chloromethyl)azetidines (Scheme 3.57) [115] affords pyrrolidines in excellent yields. These rearrangements appeared highly diastereoselective. Ring expansions are also possible by treatment of azetidinium salts with bases [116], or by reaction of azetidines with cyclic olefins in the presence of Lewis acids [117]. Ph Me

Cl

N Me

Ph

94%

Me

1. MeOTf, CH2Cl2 Ph 2. KHMDS, -78 °C, THF

Ph N Me

Ph

CHCl3, reflux

R

39-94%

Cl N Me de: 72

Ph

R

N Me

Ph

R = H, Ph, Me, Bn

Scheme 3.57

Photochemical rearrangement of 3-benzoylazetidines leads to pyrroles (Scheme 3.58) [118]. Preparation of pyrroles is also possible by the reaction of 3phenoxy (or 3-isopropylidene) 2-thioacetal-azetidines of cis-stereochemistry with AlEt2Cl (Scheme 3.58) [119]. When the substituents at the 3-position were phenyl or

j183

j 3 Four-Membered Heterocycles: Structure and Reactivity

184

Ph

O

hυ (pyrex filter)

Ph

EtOH, rt, 3 h N tBu

Ph

AlEt2Cl (1 equiv.)

R1 2

SR

CH2Cl2, rt or reflux

SR2

N R3

N tBu

95%

R1

SPh

R1 = PhO, isopropylidene R2 = Ph, (CH2)2

N R3

38-72%

Ph

R3 = Bn, 4-MeOC6H4

AlEt2Cl (1 or 2 equiv.)

R1

R1 CH2Cl2, rt, 12-24h or CH Cl , reflux, 10 min SPh 2 2

N R2

SPh

SPh Et

N R2

31-72%

R1 = Ph, Me R2 = 4-MeOC6H4

Scheme 3.58

methyl groups, the reactions yield pyrrolidines. With cyclic acetals or thioacetals, bicyclic pyrrolidines are obtained [119]. Another interesting preparation of pyrrolidinones is by the cobalt carbonyl catalyzed carbonylation of azetidines. The regioselectivity of the CO insertion depends on the substituent fixed to the nitrogen atom (Scheme 3.59) [120]. Co2(CO)8 CO (3-4 atm.) N Me

Ph

Ph

benzene, 24 h, 85-90 °C N Me

90%

O

Co2(CO)8 CO (3-4 atm.)

N tBu

R

benzene, 24 h, 85-90 °C 83-91%

R

N tBu

O

R = Me, CH2OH, CH2OMe, CH2OCOMe, CO2Me

Scheme 3.59

2-Hydroxymethylazetidines react with m-chloroperbenzoic acid (mCPBA) to furnish the corresponding N-oxides with high diastereoselectivity. Upon heating, these N-oxides rearrange quantitatively into the 1,2-oxazinan-6-ol (Scheme 3.60) [121]. Piperidines, formed by [4 þ 2] cycloadditions, have been isolated by reaction of azetidines with methylene-cycloalkanes (Scheme 3.61) [117]. [4 þ 2] Cycloadditions have also been reported in the reaction of azetidines with nitriles (Scheme 3.61) [122].

3.1 Azetidines

j185

OH N Bn

CH2OH

mCPBA,

CH2OH CH2Cl2, reflux

CH2Cl2

N+ H Bn O -

63%

100%

O N

Bn

Scheme 3.60

Ph Ph

N Ts

+

BF3.Et2O, CH2Cl2, -78 °C ( )n

68-70% BF3.Et2O, CH2Cl2

N Ts

rt, 0.4-3 h

Ar + R C N

Ar

N

R N

42-72%

n = 0, 1, 2

( )n

N Ts

Ts

Ar = Ph, 2,3-MeO2C6H3, 4-MeOC6H4, 3-BrC6H4

Scheme 3.61

Piperidines are also obtained by the reaction of 1,3-butadienyl-azetidines with a palladium(0) salt. The 1,3-butadienyl entity appears necessary for the rearrangement (Scheme 3.62) [123].

R1

R2 N

R1

Pd(PPh3)4 DMSO, 25 °C, 10-12 h

Ts

N Ts

80-91%

R1 = Ph, C11 H23 R2 = H, Me

R2

Scheme 3.62

The reaction of 2-alkenyl-azetidines with cobalt carbonyl leads to azepinones instead of piperidinones, as in the case of 2-unsaturated substituents (Scheme 3.63, cf. Scheme 3.59) [120]. Azocanes can be obtained by thermal rearrangement of 1,2-divinylazetidines (Scheme 3.64) [69].

Me N

Me

R1

Scheme 3.63

Co2(CO)8, CO (3-4 atm.)

Me

Me

80 °C, benzene 52-82%

R1 = H, CH2CH2COMe, CH2CH2CN N R1

O

j 3 Four-Membered Heterocycles: Structure and Reactivity

186

N R1

Me

Me

Me

100-140 °C

O

54-82%

R2

R1 = CO2Me, H, Ph R2 OR

1

R2

N

O R

1

N H

R2 = OMe, Me

Scheme 3.64

3.1.4.6 Cleavage of the Azetidine Ring 3.1.4.6.1 Fragmentation Reactions Flash thermolysis at 900
C of azetidine gives ethylene and N-methylenemethanamine [124]. However, heating under less drastic conditions leads to cleavage of only one of the N–C bonds (Scheme 3.65) [125] to afford unsaturated amines. R2

R1 N

GC column, 120 °C t

R2 R1

Bu

N H

tBu

R1, R2 = alkyl

E:Z ~ 50:50

Scheme 3.65

3.1.4.6.2 Reaction with Nucleophilic Reagents Azetidin-2-carboxylic acid derivatives react with thiophenol (pH 8) to afford a mixture of 3-amino-2-phenyl- and 2amino-3-phenylthiopropanoic acids [126]. Similarly, 3-hydroxyazetidines can be cleaved with phenols. These reactions are highly stereospecific if a substituent was present in the 2-position (Scheme 3.66) [127]. R2

HO N

R1

ArOH, 130 °C 8-80%

ArO

HO H H N H R2

R1 = tBu, Bn, cyclohexyl R1

R2 = H, Me Ar = Ph, 4-BrC6H4

Scheme 3.66

The opening of azetidinium salts with nucleophiles such as NaN3, butylamine or AcONa has also been examined. The regiochemistry of the cleavage appears to be a function of the substituents fixed on the azetidine ring (Scheme 3.67) [128]. 3.1.4.6.3 Reaction with Electrophilic Reagents The reaction of N-alkylazetidines with N2O5 gives 1,3-nitroamine-nitrates (Scheme 3.68) [129]. 3.1.4.7 Enzymatic Resolutions of Azetidines Racemic methyl azetidin-2-carboxylate has been resolved using Candida antartica as lipase in tbutanol saturated with ammonia. Excellent enantiomeric excesses were obtained for the remaining ester and the amide formed (Scheme 3.69) [130].

3.1 Azetidines

Bn

N+ Me

Ph

NaN3, DMF rt, overnight

Ph CO2Et

Bn

CO2Et

N3

100%

Bn

N

Me

N+ Me Me

N3

: Me

BnNH2, CH2Cl2 CO2Et

CO2Et

Me

93 Ph

Me

+

Ph N

Me

7 Ph

N

100%

O NHBn

Me

NHBn

Scheme 3.67

N2O5, CH2Cl2 0.5-1 h, -5-0 °C O NO 2

N R

N

41-95%

R NO2

R = Bu, CN, (CH2)2CO2Et, CO2Et

Scheme 3.68

CO2Me N R

tBuOH,

CONH2

CO2Me

Candida antartica lipase sat. NH3, 35 °C, 3 h

+

N R

N R

R = Bn

conversion: 56%

ee > 99%

ee = 80%

R = allyl

conversion: 50%

ee > 99%

ee = 97%

R = 4-MeOC6H4CH2

conversion: 54%

ee > 99%

ee = 84%

Scheme 3.69

An azetidine with high enantiomeric excess has also been obtained by resolution of a meso-2,4-diol derivative. For a conversion of around 55%, a compound of high enantiomeric purity could be obtained (Scheme 3.70) [131] using porcine pancreas lipase (PPL) immobilized on Celite. Under these conditions, resolution of the racemic trans-2,4-diol gave a mixture of mono- and diacetate of lower enantiomeric excesses.

vinyl acetate PPL-Celite HO

N Bn

OH

95%

AcO

N Bn

OH

ee 96.2% Scheme 3.70

j187

j 3 Four-Membered Heterocycles: Structure and Reactivity

188

O

O

oxetane

O

2-oxetanone

Figure 3.2 Four-membered oxygenated heterocycles.

3.2 Oxetanes 3.2.1 Introduction

Oxetanes are four-membered oxygenated cycles. Their carbonyl-substituted analogues are named oxetanones and, in particular, the 2-oxetanone family is commonly referred as b-lactones (Figure 3.2). The search for effective enantioselective methods of preparation is now the most common challenge. Nonetheless, new syntheses are still a topical question due to the frequent presence of these four-membered cyclic ethers in biologically active substances. These compounds have aroused much interest by their large range of reactivities. The ring strain common in both the oxetane and the oxetanone cycles causes significant susceptibility to thermal cleavage. The basicity of the ring oxygen makes the oxetanes sensitive to electrophile reagents and/or consequently to nucleophilic attacks at carbon. Oxetanes can be subject to polymerization. The 2oxetanones mainly undergo nucleophilic addition at the carbonyl carbon, with or without electrophilic catalysis. 3.2.2 Physicochemical Data

Microwave, electron diffraction and X-ray diffraction methods have permitted a precise determination of bond lengths and angles in several oxetanes [132]. Table 3.1 reports the bond lengths and angles of oxetane and 2-oxetanone. Notably, the CO bond is longer than in other types of compounds: (Csp3O ¼
1.41 A). The oxetane ring may be either coplanar or puckered, depending on the substituents present. A rocking motion allows the substituents to attain a less Table 3.1 Bond lengths and angles of oxetane and 2-oxetanone.

1

O 4

2 3







Bond

Oxetane (A)

2-Oxetanone (A)

C4O1 C3C4 C2O1C4 C2C3C4

1.449 1.549 91.8
84.55


1.45 1.53 89
83


1

O 4

2 3

O

3.2 Oxetanes Table 3.2 Chemical shifts of various compounds in deuteriochloroform.

FOB D E A C

Oxetane 2-Me-oxetane 4-Me-oxetanone

HA

HB

HC

HD

HE

HF (ppm)

4.73 1.35(Me) 1.53(Me)

4.73 4.85 4.57

2.72 2.24 2.98

2.72 2.63 3.50

4.73 4.37 —

4.73 4.49 —

hindered conformation but is opposed by the resulting increase in bond angle deformation. The 2-oxetanone having a carbonyl group in place of a methylene group is strictly planar. 3.2.2.1 NMR Data The proton NMR spectroscopy of oxetanes is largely understood [132]. Table 3.2 gives the chemical shifts of various compounds in deuterochloroform. A substituent can have special effects on the proton chemical shifts due to their proximity in the small ring. This could be also induced by changes in the puckering of the ring. Table 3.3 gives some representative 13C chemical shifts relative to TMS in deuterochloroform [133]. 17 O NMR spectra of oxetanes and 2-oxetanones referenced to water show values of 13 ppm for the oxetane ether O and 347 ppm (C¼O) and 241 ppm (ether O) for the two oxygens in 2-oxetanone [133]. 3.2.2.2 Infrared Spectroscopy A strong absorption band at about 980 cm1 is characteristic of oxetane [132]. The farIR spectrum of oxetane has been obtained at 205 K. The band of ring puckering transition was assigned at 52.92 cm1. 2-Oxetanones present an intense absorption at 1840–1820 cm1 due to carbonyl stretching. 3.2.3 Natural or Bioactive Compounds

The oxetane ring appears in some biologically active compounds. We report in this chapter some representative examples. Taxol 12, isolated from Taxus brevifolia and its derivative the taxotere, is an important drug in cancer chemotherapy [134]. Table 3.3 Representative

1

O 4

2 3

13

C chemical shifts relative to TMS in deuterochloroform.

Oxetane 2-Me-oxetane

C2

C3

C4

Me

72.8 78.3

23.1 29.0

72.8 66.6

— 24.1

j189

j 3 Four-Membered Heterocycles: Structure and Reactivity

190

Montanin D (13) has antifeedant activity. This substance has been extracted from the plant Teucrium tomentosum [135].

()-Tetrahydrolipstatin (14) is a triglyceride mimic, an analogue of lisptatin isolated from Streptomyces toxytricimi. It is a potent and irreversible inhibitor of pancreatic lipase, used as an antiobesity agent under the name Xenical [136]. The antibiotic oxetanocin A (15) is a fermentation product of Bacillus megaterium. It is also known as an anti-HIV compound [137]. Curromycin A (16) is an antibiotic produced by a genetically modified strain of Streptomyces hygroscopicus [138].

Anisatin 17 and neoanisatin 18 are convulsant principles isolated from the fruits of the toxic plant Illicium anisatum L [139]. Salinosporamide A (19) is a bioactive product of a marine microorganism [140].

3.2 Oxetanes

j191

3.2.4 Synthesis of Oxetanes and Oxetan-2-ones 3.2.4.1 [2 þ 2] Paterno–B€ uchi Cyclizations The [2 þ 2] photocycloaddition of carbonyl compounds with alkenes, the Paterno– B€ uchi reaction, is a useful method in organic synthesis. The challenge in this area is the regio and stereocontrol of the reaction. Bach et al. have reported significant facial diastereoselectivities in the reaction with silyl enol ethers carrying a chiral substituent. The carbonyl compound is directed to the less shielded face. With large and polar substituents at the stereogenic center, the facial selectivity leads to diastereomerically pure oxetanes (Scheme 3.71) [141].

H O Ph

R tBu

OTMS

O

hν, PhH

R

R= iPr, Ph, tBu

Bu OTMS t

30°C Ph 57-76%

Scheme 3.71

Photocycloaddition of chiral N-acyl enamines with benzaldehyde produces the cisdiastereomers predominantly, with facial diastereomeric excess from 30 to 62% (Scheme 3.72) [142].

O Ph

R* N

O

hν, MeCN O

30°C 74%

Ph

O N R* Ac

Ph

R*= N R* Ac

Ph

Scheme 3.72

A N-benzylenecarbamate has been irradiated in the presence of various aldehydes. The cis-diastereoselectivity is always predominant [143]. This method has been applied to the synthesis of diastereomerically pure 1,2-amino alcohols. A diastereoselectivity of 62% has been observed in the reaction of benzaldehyde with an atropisomeric enamide (axial chirality) (Scheme 3.73) [144].

O

O N

PhCHO Ph MeCN 30°C hν 63%

Scheme 3.73

O Ph

N O

N O

81

:

19

j 3 Four-Membered Heterocycles: Structure and Reactivity

192

A high facial diastereoselectivity in the photocyclization of a chiral aromatic aldehyde and an enamide has been induced by intermolecular hydrogen bonding. The simple diastereoselectivity led solely to cis-isomers and the facial diastereoselectivity was 95 : 5, when the reaction was carried out at low temperature in toluene (Scheme 3.74) [145]. The same reaction with enantiomerically pure aldehyde produced the oxetane with 95% of enantiomeric excess [146]. Bach et al. have studied the Paterno–B€ uchi reaction with 2,3-dihydropyrrole and a-alkylated enecarbamate as well [147, 148]. O

O

H

N H

O

H O N O O

O

N O H hν -10°C, toluene

O H O N O O

56%

rac.

N H H O N O O

5

95

Scheme 3.74

Griesbeck et al. have worked on the photocycloadditions of oxazole with carbonyl compounds [149]. The 4-unsubstituted 5-methyloxazole gave the cycloadducts with aromatic or aliphatic aldehydes, in high yield and excellent exo-diastereoselectivities (98 : 2) (Scheme 3.75). The cycloadducts are precursor of a-amino b-hydroxycarboxylic acid esters [150]. The [2 þ 2] cycloaddition of methyl pyruvate with 4-alkylated 5-methoxyoxazoles led to the exo-adducts with high diastereoselectivity. When the reaction was run with phenylglyoxylate, oxetanes were formed with moderate diastereoselectivity (79 : 21) [151]. The same authors also studied the Paterno–B€ uchi reaction of enols with carbonyl compounds [152]. Hydrogen bonding effect has been explored in the reaction of allylic alcohols [153–155].

N

H

H

H O

O

O

O

hν, PhH 15ºC 86%

O

N O

d.r.> 98 : 2

O N O

R

O O

Scheme 3.75

O hν, PhH 15ºC 60-74%

O O

R O O

N O

d.r.> 98 : 2

R = Me, Et, Pr iPr, iBu

3.2 Oxetanes

j193

Abe et al. have described the formation of 2-siloxy-2-alkoxyoxetanes, which can easily lead to aldol-type adducts, by photoreaction of cyclic ketene silyl acetals with 2naphthaldehyde (Scheme 3.76) [156]. OTBDMS O

O 2-Napht

H

Me

TBDMSO

O

O

2-Napht H

Me

hν, CH2Cl2 0°C 75%

Scheme 3.76

Reaction of aromatic aldehydes with silyl O,S-ketene acetals produced 3-siloxyoxetanes with high regioselectivity due to a S-directed approach (Scheme 3.77) [157]. The same group has also studied the reactivity of furan derivatives in the Paterno–B€ uchi reaction [158, 159]. Me O Ph

Me H

OTBDMS SMe hν 0°C, MeCN 30%

O Ph

H

Me Me OTBDMS SMe

Scheme 3.77

3.2.4.2 Catalyzed [2 þ 2] Cyclizations [2 þ 2] Cycloaddition can also be performed in a catalytic manner. Oxetanes have been prepared by zirconium(IV) chloride promoted cycloaddition of allylsilane to aldehydes (Scheme 3.78). Previous work was limited to activated carbonyl compounds such as a-ketoesters or a-diketones [160]. O R

H

SitBuPh2

ZrCl4 CH2Cl2, -30°C 28-80%

R

O SitBuPh2

R= Ph(CH2)2, n-C5H11 , cyclohexyl BnOCH2, (iPr)3SiOCH2

Scheme 3.78

Akiyama and Kirino have developed a stereoselective construction of oxetanes by titanium(IV) chloride promoted [2 þ 2] cycloaddition of allylsilane to a-ketoesters. Best results were obtained with bulky substituents on the silicon and toluene as solvent. The diastereoselectivity was up to 96% (Scheme 3.79) [161].

j 3 Four-Membered Heterocycles: Structure and Reactivity

194

O OEt

Ph

SitBuPh2

O

TiCl 4 toluene, 0°C

Ph EtO2C

O SitBuPh2

95%-de>96%

Scheme 3.79

Polyfluorinated oxetanes have been prepared by the reaction between hexafluoroacetone and fluorinated ethylenic compounds. The reaction is catalyzed by aluminium chlorofluoride as Lewis acid. Hydrofluoroethylenes HXC¼CF2 (X ¼ H, F, Cl, Br) led to only one regioisomer (Scheme 3.80) [162].

F

O F3C

CF3

H

F Br

AlClxFy 100°C, 18h 30%

F3C F3C

O

H Br

F

F

Scheme 3.80

3.2.4.3 Ring Contraction of Butanolides Ring contractions of c-lactones into oxetanes have been studied and are used in the synthesis of oxetin or oxetanocin analogues (Scheme 3.81) [163, 164]. OBn

O

O MeO

Me O

O Ph

O

O

OTf

HO2C

MeOH 72%

OBn

OBn

O

NaOH 1N

β-isomer OBn

K2CO3 MeOH/MeCN -78° to -10°C 89%

O Ph

O O

CO2Me

Scheme 3.81

Suzuki and Tomooka have found a new anionic ring contraction reaction. They obtained oxetanes by treating cyclic acetal systems with an excess of alkyl lithium (Scheme 3.82) [165]. The four-membered rings are obtained with high diastereoisomeric excesses. O O

O Ph H

Scheme 3.82

RLi, THF -78°C to rt

R

17% dr>95%

Ph

O HO

H OH

R= tBu, nBu, sBu, Me, C C TBS

3.2 Oxetanes

j195

b-Lactones have been obtained by contraction of butanolides via an intramolecular nucleophilic displacement of an activated group by the carboxylate anion. De Angelis et al. have produced the total inversion of configuration of the (S)-b-hydroxyc-butyrolactone via a b-lactone intermediate. This last product was also presented as a versatile chiral synthon (Scheme 3.83) [166]. MsO

H2O, rt O

HO

CO2H MsO

O Amberlite IR 120(H+)

NaHCO3

HO

H2O, 50°C 50%(2 steps)

1. NaOH 3N O

O

HO

2. HCl 97%

Scheme 3.83

3.2.4.4 Oxirane Ring Opening by Carbanionic Attacks Mordini et al. have synthesized oxetanes by the isomerization of oxiranes using an equimolar mixture of butyllithium/diisopropylamine/potassium tert-butoxide (LIDAKOR) [167]. The reaction occurred when Y is a phenyl or a propargyl group, and the substituted oxetanes were produced in anti-(2,3)-configurations (Scheme 3.84) [168].

O

O

Y

R iPr

2NLi,

tBuOK

HO

Y O R OH 98 (trans major) : 2

-78° to -50°C 50-55%

R

O

R= H, C5H11 , CH2OSi tBu Y= phenyl, C CH , CH CH2

Scheme 3.84

3.2.4.5 Williamson Reactions The intramolecular Williamson reaction has often been used for the preparation of cyclic ethers like oxetanes (Scheme 3.85). This SN2 displacement of a leaving group (halogen, mesylate, tosylate, etc.) by the alkoxides moiety can be performed with considerable variation in the choice of base (DBU, KOH, tBuOK, NaHMDS, etc.) [132, 133]. No recent work has been published about this reaction in particular. HO

X

Base

O

X= Halogene, OMs, OTs

Scheme 3.85

3.2.4.6 Isomerization of Oxiranyl Hydroxyls Since an epoxy oxygen atom can serve as a good leaving group, the isomerization of oxiranyl hydroxyls has been used for oxetane preparation in total syntheses (Scheme 3.86). This reaction can be performed under acidic (BF3Et2O) or basic

O

O

j 3 Four-Membered Heterocycles: Structure and Reactivity

196

OH acid or base HO

O

O

OH

acid or base

O

O

OH

Scheme 3.86

(KOH) conditions [132, 133]. No new studies of this ring opening reaction have been published recently. 3.2.4.7 Oxirane Ring Expansions Oxetanes can be obtained by treating oxiranes with dimethyloxosulfonium methylide (Scheme 3.87) [132, 133]. This well-known reaction has not receive renewed interest in recent years. + Me3S O I-

O

O

tBuOK

Scheme 3.87

3.2.4.8 Electrophilic Cyclizations This reaction, which can be performed with mild experimental conditions, is often used in total synthesis. Few methodological studies have been done. Rousseau et al. have published the preparation of oxetanes via a 4-endo cyclization process on allylic alcohols [169, 170] and via a 4-exo cyclization process on homoallylic alcohols [171], using the electrophilic reagent bis(sym-collidine)bromine(I) hexafluorophosphate (HBB) or hexafluoroantimonate. This reaction was also used to prepare b-lactones starting from a,b-unsaturated acids (Scheme 3.88) [169]. Ph

OH Me Me

HBB

Ph

CH2Cl2, rt 78%

Br

HBB SiMe3 CH2Cl2, rt 80%

Bu Scheme 3.88

Me Me

Br

OH

Bu

O

CO2H

HBB CH2Cl2, rt 60%

O

Bu

O

Bu Br

H

O

H SiMe3

3.2 Oxetanes

j197

3.2.4.9 [2 þ 2] Cycloaddition of Ketene and Carbonyl Compounds The [2 þ 2] cycloaddition of ketenes with carbonyl compounds is an expedient way to substituted b-lactones. Silylketenes are reactant of choice due to their better stability. The most common reagent as Lewis acid is BF3Et2O, but the goal in this area is now the use of chiral Lewis acid catalysts. Asymmetric [2 þ 2] cycloadditions of ketene with aliphatic aldehydes have been catalyzed by chiral aluminium Lewis acids to afford optically active 4-substituted oxetan-2-ones in moderate enantiomeric excesses (Scheme 3.89) [172]. R2 O Al Me O O

O

•

R1

R2 H

toluene, -78°C 45-91% ee: 17-56%

O O

R1= Me, Et, Pr, iPr, Bu, Ph R2= H, Me, SiPh3

R1

Scheme 3.89

Romo and Yang have developed Ti-TADDOL catalysts such as 20, which provide good reactivity and moderate enantioselectivity (9–80% ee) in the asymmetric [2 þ 2] cycloadditions of silylketenes and aldehydes [173].

The same group has also employed chelation controlled [2 þ 2] cycloadditions of trimethylsilyl ketene to chiral a and b-benzyloxyaldehydes to provide a highly diastereoselective route to functionalized b-lactones. The Lewis acid MgBr2.Et2O gave the highest selectivities and yields (Scheme 3.90) [174].

O

BnO

• H

SiMe3

Scheme 3.90

1. MgBr2.Et2O CH2Cl2

O H

2. KF.2H 2O CH3CN, -43°C 94%

BnO

O

O

98: 2

BnO

O

O

j 3 Four-Membered Heterocycles: Structure and Reactivity

198

Yamamoto et al. have disclosed a highly diastereoselective cyclization under the influence of bulky methyl aluminium bis(4-bromo-2,6-di-tert-butylphenoxide) (MABR) as Lewis acid (Scheme 3.91) [175]. No trace of the trans isomer could be detected.

Br O

Al Me

O

Br Me3Si

O

• SiMe3

H

O

H

CH2Cl2, -78°C, 2h 82%

Et

Et

O O

Scheme 3.91

Bis(oxazoline)-Cu(II) complexes have been used by Evans et al. to catalyze the enantioselective cycloaddition between silylketenes and chelating carbonyl substrates. b-Lactones have been produced in excellent yields and selectivities (Scheme 3.92) [176].

O

Me Me N

O

O

• H

Me3C

SiMe3

OMe

Et O

Cu

2+ O

N

2SbF6-

CMe3

O

CH2Cl2, -50° to -40°C then KF, C H3CN 92% ee: 99%

MeO2C Et

O

Scheme 3.92

3.2.4.10 Acyl Halide–Aldehyde Cyclocondensations The acyl halide–aldehyde cyclocondensation can be classified between the [2 þ 2] cycloaddition of ketenes to carbonyl compounds and the catalyzed aldol-lactonization reaction. Actually, the reaction can progress via in situ ketene formation or via an ammonium enolate (Scheme 3.93). This aldol-addition reaction equivalent has induced much interest, especially in its catalyzed asymmetric version. The use of tertiary amines as both base to effect dehydrochlorination and nucleophile to promote the reaction of ketenes and aldehydes has been demonstrated. Romo and Tennyson have taken their inspiration from the Wynberg procedure [177] for the synthesis of optically active dichlorinated b-lactones via an in situ generated ketene. Di-chlorinated aldehydes were reacted with acetyl chloride in the

3.2 Oxetanes

O O

R1

X

3N

Me

O

•

O

•

O

O

catalyst

R2

O

O

R13N

R2

H

H

R13N

O

O

R2 R2

Scheme 3.93

presence of Hunig’s base and 2 mol% of quinidine A (21). Dichlorinated b-lactones were obtained with 93–98% enantiomeric excesses (Scheme 3.94) [178]. O

O

R Cl

Cl Cl

iPr

H

2NEt,

O

toluene, rt R Cl Cl

2 mol% of 21 40-85% ee: 93-98% MeO

O R= Me, iPr, C 6H13, Bn

H HO H N

N

H 21

Scheme 3.94

Romo et al. have also investigated an intramolecular aldol-lactonization reaction. Chiral bicyclic b-lactones have been obtained with high enantiomeric excess from non-activated aldehydes in the presence of 10 mol% of catalyst 21 (Scheme 3.95) [179].

3 equiv. CO2H CHO

Cl N Me I 4 equiv. iPr2Et CH3CN, 25°C 10 mol % of 21 54% ee: 92%

Scheme 3.95

O O

j199

j 3 Four-Membered Heterocycles: Structure and Reactivity

200

In a first stage, Nelson et al. have presented an Al(III)-catalyzed acyl halide–aldehyde cyclocondensation reaction. A catalytic quantity of Al(SbF6)3 in concert with di (isopropyl)ethylamine constituted the most successful reaction promoter [180].They continued with asymmetric cyclocondensations catalyzed by chiral Al(III) triamine derivatives 22 or 23 [181, 182]. This methodology can be applied to a large range of aldehydes and to substituted ketenes. 3,4-Disubstituted b-lactones are accessible with excellent optical purity (Scheme 3.96).

O Br

10-20 mol % of 22 or 23 BTF, -25° C

O R1

R2

H

O

iPr

2NEt

R1

56-96% ee: 54-93% Bn N

Pr

i

F3CO2S

N

Al R

iPr

N

R= Me, Cl

R1=H, Me, Et, iPr, nPr

O

R2= (CH2)2Ph, (CH2)2OBn, C CSiMe3

R2

CF3 i

F3C

SO2CF3

Pr

O2S

i

N N

Al Me

N

Pr SO2CF3

F3C

22

23

Scheme 3.96

In attempting to expand the scope of Wynberg’s original ketene–aldehyde cycloadditions, Nelson et al. have developed a cinchona alkaloid–Lewis acid catalyzed acid chloride–aldehyde cyclocondensation. The TMSQ/LiClO4 catalyst system allows the reaction with a-branched aldehydes or with methyl ketene. The 3,4-disubstituted b-lactones are obtained in excellent enantiomeric excess (Scheme 3.97) [183].

O Cl

R1

10 mol %TMSQ CH2Cl2/Et2O -25°C

O R2

LiClO4, iPr2NEt 71-85% ee: 92-99%

O R1

O R2

R1= H, Me R2= C6H11 , tBu, (CH2)2Ph, C6H4Cl TMSQ= O-trimethylsilylquinidine

Scheme 3.97

3.2.4.11 C–H Insertions Intramolecular CH insertion in the catalytic decomposition of diazomalonic esters has often been used in the preparation of b- and c-lactones. However, this reaction depends on the substitution pattern of insertion centers and the conformational bias

3.2 Oxetanes

of metallocarbenes, leading to a mixture of both b- and c-lactones [184, 185]. Balaji and Chanda have shown that steric effects may play a major role in the C–H insertion of inactivated a-diazo-a-aroyl esters, catalyzed by rhodium(II) carboxylates. The reaction of a-diazo-a-benzoyl esters catalyzed by various rhodium carboxylates yielded b-lactones as the only products (Scheme 3.98) [186].

O

O

O

Ph

Rh2(OAc)4

O

CH2Cl2, reflux 55%

N2

Ph

O

H

H

O

Scheme 3.98

CH insertion reactions catalyzed with immobilized dirhodium(II) salt having mixed chiral ligands have been reported by Doyle et al. They observed that the enantioselectivity was slightly increased with the most selective azetidinone-ligated homogeneous catalyst 25 (Scheme 3.99) [187].

O

10 mol% of 24 or 25 CH2Cl2

O N2

O

O

CO2Me Rh2

Rh2 N O

O 24

Me Me

Ph

71-83% ee: 33-42%

O N

O

O

3

N CO2Me

4

25

Scheme 3.99

3.2.4.12 Carbonylative Ring Expansion Reactions Alper et al. have described the carbonylation of epoxides with a new catalyst, PPNCo(CO)4 [PPN¼bis(triphenylphosphine)iminium], used in conjunction with BF3Et2O. Carbonylations occurred selectively at the unsubstituted CO bond of the epoxide rings. These reactions tolerate various functional groups such as alkenyls, halides, hydroxyls and alkyl ethers. The b-lactones are obtained in good yields without polymeric by-products (Scheme 3.100) [188].

j201

j 3 Four-Membered Heterocycles: Structure and Reactivity

202

CO +

PPNCo(CO)4 BF3.Et2O

R O

R O

DME, 80° 57-86%

O

R= H, Me, CH2OiPr, Ph CH2Cl, CH2OH, nBu nHex, (CH2)4CH=CH2, (CH2)2CH=CH2

Scheme 3.100

Coates et al. have developed three catalyst for the carbonylation of substituted epoxides: [(salph)Al(THF)2][Co(CO)4] (26) [189], [Cp2Ti(THF)2][Co(CO)4] (27) [190] and [(TPP)Cr(THF)2][Co(CO)4] [28, with THF in the axial positions (not shown)] [191]. Catalyst 28 is the most active and selective with a wide range of epoxides. [Co(CO)4]L + N Al O O L N

t

Bu tBu

+ O Ti O

t

Bu

[Co(CO)4]-

tBu

26

27

L= THF

Ph

Ph

N

[Co(CO)4]-

N + Cr N N Ph

Ph 28

3.2.4.13 b-Hydroxy Acid Cyclizations The cyclization of b-hydroxy acids is largely used in the synthesis of molecules possessing a b-lactone moiety. This reaction can be executed following an addition– elimination process or a nucleophilic substitution process [132, 133]. In the addition–elimination way, Adam’s method (pyridine/ArSO2Cl; Ar ¼ Ph, 4-MePh, 4-NO2Ph) [192] is the most commonly used, but different reactants can also activate the carboxylic acid, such as Et3N/BOPCl [bis-(2-oxo-3-oxazolidinyl)phosphonic chloride], DCC/HOBt, EDC/HOBt, etc. The intramolecular nucleophilic substitution can be pursued by the Mitsunobu reaction (PPh3/DEAD or DMAD) [193]. 3.2.5 Reactivity 3.2.5.1 b-Lactones The reactivity of b-lactones has been already [194]. It can be broken down into four areas: . .

nucleophilic attack with ring opening; Lewis acid promoted rearrangement;

3.2 Oxetanes .

j203

decarboxylation; enolate formation and reaction toward electrophiles.

.

3.2.5.1.1 Nucleophilic Attacks It has already been demonstrated that the ring opening of b-lactones can occur through two different pathways. Attack via an addition–elimination process at the carbonyl residue affords access to b-hydroxy adducts. A nucleophilic substitution reaction at the C4 atom can produce b-substituted carboxylic acid derivatives (Scheme 3.101). Nu

O HO

R

O SN2 Nu-

2 3

1

O 4

A.E. Nu-

R

O

OH

Nu

R

Scheme 3.101

Organomagnesium and organolithium reagents attack b-lactones at the carbonyl, leading to oxygen–acyl cleavage. Organocuprates induce the oxygen alkenyl cleavage. Ring opening of b-lactone by hetero-nucleophiles has been much studied. Goodman et al. [195], inspired by Vederas’ results [196], have synthesized lanthiomine derivatives by ring opening of a protected serine b-lactone by the thiolate anion of methyl Boc-(S)-cysteinate derivatives (Scheme 3.102). O HS

CbzHN H O

O

Cs2CO3 O

BocHN O

DMF, rt 92%

HO

BocHN

O CbzHN

O

S

Scheme 3.102

Palomo et al. [197] have obtained dipeptides by coupling an a-dichloro b-lactone with (S)-leucine or (S)-phenylalanine and subsequent dechlorination (Scheme 3.103).

Cl

NHBoc

Cl

O

O

R 1. H2N CO2Me CH2Cl2, rt 2. H2, Pd/C Et3N, EtOH 85-87%

H N

BocHN OH O

CO2Me

R= CH2CH(CH3)2, CH2Ph

R

Scheme 3.103

Ring opening of b-lactones by hydrazone anions, followed by dehydroamination cyclizations of the b-ketohydrazone intermediates in the presence of amberlyst-15 acid resin, yields dihydropyrones (Scheme 3.104) [198].

j 3 Four-Membered Heterocycles: Structure and Reactivity

204

N

N

Li

O

N

THF

O

R2

R1

R3

then Am-15 65°C

N

3

R

R2

R 68-81%

OH R1

O

R2

3

O R1

O

R1= CH2Ph, (CH2)2Ph, (CH2)8CH=CH2 C CSiMe3 , CHOBn R2= H,Et R3= H,Me

Scheme 3.104

Nelson et al. [199] have demonstrated that primary and secondary amines promote a ring opening by addition–elimination to deliver b-hydroxyamides (Scheme 3.105). Sodium azide reacts in an SN2 manner to produce b-azido acids, and sulfonamide anions give rise to b-amino acids. O

PhCH2NH2

O

Et3N, CH2Cl2 88% Ph O

O Ph

N H O

NaN3

O

DMSO, 50°C 95%

OH Ph

N3

HO

Scheme 3.105

Acylation of aromatic compounds with chiral b-trichloromethyl b-propiolactone in the presence of Lewis acid has been investigated by Fujisawa et al. [200]. The Friedel–Crafts products retain completely the stereochemical integrity of the starting b-lactone. This method has been applied to the synthesis of a precursor of enalapril, an angiotensin converting enzyme (ACE) inhibitor (Scheme 3.106). O O

Lewis acid

PhH, 5°C, 9h Ph H CCl3 90%

O

EtO2C

OH CCl3

Ph

N H

N O

CO2H

Enalapril

Lewis acids= AlCl 3, AlBr3, FeCl3, TiCl4, EtAlCl2, Et2AlCl Scheme 3.106

The utility of b-lactones as intermediates for asymmetric synthesis has been limited by the difficulty for their preparation in enantiomerically pure form. Nelson and Spencer [201] have examined enzymatic resolution for the preparation of enantiomerically enriched b-lactones (Scheme 3.107). This method allows the preparation of 4-substituted b-propiolactones with high enantiomeric excesses simultaneously with enantiomerically enriched b-hydroxy esters.

3.2 Oxetanes

O

O

PS lipase

O C6H11

iPr

BnOH 35°C

O

O

2O,

BnO

C6H11 44%; 99%ee

OH C6H11

48%; 92%ee

Scheme 3.107

3.2.5.1.2 Lewis Acid Promoted Rearrangements Ring expansion of b-lactones to afford c-lactones can be performed with various Lewis acids, p.TsOH, ZnCl2, BF3.OEt or Ti(O-iPr)4. The best catalyst appears to be MgBr2 (Scheme 3.108) [202].

O

O

MgBr2 Et2O 64%

Ph

O O

Ph

Scheme 3.108

This dyotropic rearrangement involves simultaneous positional interchange of two adjacent atoms having an anti-coplanar stereochemistry relationship. Inversion of stereochemistry at C4 atom is always observed [203]. Black et al. have prepared spiro [204] and cis-fused c-lactones (Scheme 3.109) [205] via such b-lactones rearrangements. b-Elimination can occur in place of rearrangement when the C4 atom is tertiary [206]. O

O O

Ph H

H

O

O

MgBr2

O

Ph

Et2O, 6h 76%

MgBr2 Me Me Et 2O, 25°C OMe 85%

HMe Me O OMe

O

Scheme 3.109

3.2.5.1.3 Decarboxylations The thermal decomposition of b-lactones into alkenes takes place between 80 and 160
C. The reaction is a stereospecific cis-elimination: cis-disubstituted b-lactones lead to a (Z)-olefins whereas trans-disubstituted b-lactones lead to (E)-olefins. These reactions can be regarded as alternative to Wittig reactions. Dolbier et al. have used this method to synthesize 1,1-difluoroalkenes via a,a-difluoro-b-lactones (Scheme 3.110) [207, 208].

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j 3 Four-Membered Heterocycles: Structure and Reactivity

206

O

O Me

F

Me

F

F

100°C

F

85%

Cl

Cl

Scheme 3.110

Adam et al. [209] have obtained allyl amines and sulfides by conjugate addition of amine and thiol nucleophiles to a-methylene b-lactones and subsequent decarboxylation (Scheme 3.111). Nu O R

Nu

O

O

R

Nu= pyrrolidine PhSH

Nu

O

-

∆

R= Me, iPr

-CO2

R 51%

92% 97%

86%

Scheme 3.111

With the same strategy the conjugate addition of ester and ketone enolates to a-methylene b-lactones followed by decarboxylation leads to c,d–unsaturated esters with complete stereoselectivity (Scheme 3.112) [210].

O O

1. THF, -78°C

180°C

2. aq NH4Cl BuO

LiO

42% Me Me

tBuO

O

O

t

O

O

tBuO

O O

BuO

t

-CO2 87%

O t

BuO

O

cis/trans : 16/84 Scheme 3.112

3.2.5.1.4 Enolate Formation and Reaction Towards Electrophiles The enolate of b-lactones can be generated by treatment with lithium diisopropylamide and trapped with various electrophiles such as alkyl-, allyl- or propargyl halides, aldehydes,

3.2 Oxetanes

dimethyl maleate, etc. Diastereoselective reactions take place when oxetan-2-ones are b-substituted, leading to the trans-disubstituted products (Scheme 3.113) [194]. O

O iPr

2NLi

O

XR2

R2

O

R1

R1,R2= Alkyl

R1

Scheme 3.113

As the alkylation of b-lactones unsubstituted at the a-position leads to low yields, a desilylation–alkylation method has been introduced by Mead et al. [211]. Kocienski et al. have used this modified procedure, in the synthesis of the hypocholesterolemic agent 1233A, to introduce a hydroxymethyl group a to the carbonyl, via the tetrabutylammonium enolate of a b-lactone (Scheme 3.114) [212].

O Me

O SiMe3 OtBu

Me

Me

O

1.TBAF, C O2 -78°C 2. BH3.THF 0°C 42%

O

O

Me

OH OtBu Me

Me

O

Scheme 3.114

3.2.5.1.5 Polymerization of b-Lactones Polymerization of b-lactones has aroused interest as biodegradable polymer products can be applied in biomedical applications [213–215]. Pohl et al. [216] have synthesized chiral polyesters by protic acidcatalyzed polymerization of b-lactones. A stereogenic site repeated in each molecular unit can change the polymer properties, in comparison with the racemic polymers (Scheme 3.115).

O O

TFA MeOH toluene 35°C 97%

O O

n

Scheme 3.115

3.2.5.1.6 Miscellaneous Methyl ketene dimer has been used to prepare b-ketoesters or b-ketoamides by nucleophilic attack on the carbonyl function by lithium amides or amines (Scheme 3.116) [217].

j207

j 3 Four-Membered Heterocycles: Structure and Reactivity

208

Me

O

O

H N

OMe

O

Me

10 mmol % pyridone 72%

Me

O

Me

OMe N Me

Me

Scheme 3.116

3.2.5.2 Oxetanes 3.2.5.2.1 Nucleophilic Attacks Two positions (C2 and C4) in the oxetane are amenable to nucleophilic attack. Bach et al. [218] have studied intramolecular ring opening reactions of 2-phenyl-3-oxetanols. They have obtained tetrahydropyrans, thiotetrahydropyrans or piperidines by anionic attack at the C4 carbon atom of a heteroatom attached at the C3 position via an alkyl or aryl chain (Scheme 3.117).

O Ph

O

MeLi

OPiv

DME reflux

OTMS

O

+

Ph

Ph

HO OH

OTMS

54% O Ph

SAc

13%

S

MeLi

S

Ph

DME reflux

OTMS

Ph

+

HO OH

TMSO OH

37% O Ph

NHTs

MeMgBr

OTMS

OTMS

DME reflux

55% Ts N

Ts N

+

Ph

Ph TMSO OH

HO OH 41%

12%

Scheme 3.117

A second ring-opening reaction proceeds by attack at the C2 position upon activation by acid reagents. Boc-protected 3-oxetanols have been transformed into cyclic carbonates as a mixture of diastereomers (Scheme 3.118) [218].

O Ph

O

iPr

O

OtBu

TFA, CH2Cl2 -20 to 25°C 62%

Scheme 3.118

OH

Ph

iPr

O

O O

OH

Ph

iPr

O

O O

OtBu

Ph

iPr

O

O O

OtBu

Ph

iPr

O

O O

3.2 Oxetanes

Howell and Hashemzadeh [219] have carried out reductive cleavage of 3,3dimethyl-2-methylene-4-phenyl oxetane with lithium and 4,40 -di-tert-butylbiphenyl (DTBB). The resulting dianion reacts with aldehydes and ketones to give aldol adducts (Scheme 3.119).

Li DTBB

Ph O

-78°C

Li

OLi

O

Electrophile

Ph

E

Ph

Product

Electrophile

Rdt

O 100%

Ph

H2O

O Ph

O

48%

HO O

O CH3

H

Ph

43%

Scheme 3.119

The ring opening of oxetanes by samarium diiodide and acyl chloride has been investigated, but the regioselectivity was not always satisfactory. In general, a mixture of iodo products was obtained. In the particular case of 2-phenyloxetane, only the deiodinated product was isolated (Scheme 3.120) [220].

O

Ph

SmI2, AcCl THP, rt 82% Ph O

O

Ph

O O

5

O :

Ph

4

O

SmI2, BzCl THP, rt 89%

I

I

Ph

O

Ph

Scheme 3.120

Kellogg et al. [221] have studied the acid catalyzed ring opening reactions of optically pure 2-aryl-3,3-dimethyloxetanes. The aqueous or alcoholic sulfuric acid catalyzed ring opening reaction occurs at the benzylic position with partial inversion of configuration (Scheme 3.121).

j209

j 3 Four-Membered Heterocycles: Structure and Reactivity

210

H3C CH3

H3C CH3

0,1N H2SO4 1 day, reflux 94%

O Cl (S)

HO

OH

Cl

(R) 64%ee

H3C CH3

1% H2SO4 in MeOH 12h, reflux 87%

O

H3C CH3 HO

(R)

OCH3

(S) 70%ee

Scheme 3.121

Lewis acid catalyzed nucleophilic ring opening with alkyl lithiums or lithium thiolates occurs at the less hindered carbon with preservation of the stereochemical integrity. Benzyl alcohols are obtained in enantiomerically pure form, with good yields (Scheme 3.122) [221]. Grignard reagents or amines with or without acid catalyst were not successful in the ring opening. H3C CH3

H3C CH3

nBuLi, BF3.Et2O THF, -78° C 5-10mn

O Cl (R)

OH (S)

H3C CH3

nC4H9SH, nBuLi BF3.Et2O THF, -78° C 75%

O (R)

H3C CH3 S

nH9C4

OH (R)

Scheme 3.122

Bach et al. [222] have shown that substituted oxetane rings could be opened at the more hindered carbon with LiAlH4. To induce this regioselectivity they attached a hydroxyl group at the arene C2 substituent (Scheme 3.123). O tBu

O

O OTMS

iPr

Scheme 3.123

LiAlH4 THF, 0°C 85%

OH i

Pr OH

OH

3.2 Oxetanes

j211

3.2.5.2.2 Ring Expansions Nozaki and Noyori first reported in 1966 the asymmetric ring expansion of oxetanes to tetrahydrofurans using chiral copper catalyst (Scheme 3.124) [223]. Ph Me

H

N O O

O

H OMe

Ph

O

Cu N

O

MePh

∗

60°C 85%

N2

∗

CO2Me

Ph

cis/trans : 1/2

Scheme 3.124

Katzuki has established that this copper-catalyzed reaction proceeds with good stereoselectivity in the presence of bipyridine ligands [224]. Reaction of 2-aryl substituted oxetanes with tert-butyl diazoacetate in the presence of a chiral Cu complex furnishes 2,3-disubstituted furan derivatives with high enantiomeric excesses (Scheme 3.125).

N Ar

Ar

Ar

O O

N

OtBu N2

TBSO

OTBS

O

CuOTf, CH2Cl2, rt

CO2tBu

O

CO2tBu

(R)-2-Phenyloxetane (89%ee)

Rdt= 35%

89 (92%ee)

11 (16%ee)

(S)-2-Phenyloxetane (85%ee)

Rdt= 30%

25 (11%ee)

75 (93%ee)

Ar = Ph, pClPh, pMePh, PhCH=CH

Scheme 3.125

This enantiospecific ring expansion method has been applied to formal syntheses of the natural products ()-avenaciolide (29) and ()-isoavenaciolide (30). H

nC8H17

H

nC8H17

O O

O H

O

O O

O H

O

(-)-Avenaciolide

(-)-Isoavenaciolide

29

30

j 3 Four-Membered Heterocycles: Structure and Reactivity

212

Fu et al. [225] have explored this reaction with a Cu(I) bisazaferrocene catalyst. Both trans- and cis-disubstituted tetrahydrofurans with good enantiomeric excesses are obtained when (R,R) or (S,S) catalysts 31 are used respectively (Scheme 3.126). 1% CuOTf 1,1% (R,R)-31

O

O

OCMeCy2

Ar

AcOEt, rt 29-81%

N2 O

O

OCMeCy2

Ar

Me

Me

N Fe

Me

CO2CMeCy2 Ar 69-98% ee

1% CuOTf 1,1% (S,S)-31

O

AcOEt, rt 20-74%

N2 Me

O

CO2CMeCy2 Ar 82-95% ee

Me

Me

Me Fe

Ar = Ph,4-(F3C)C6H4, 4-(MeO)C6H4, 1-naphthyl, nC7H5C C C

N Me Me

Me

(R,R)-31

Scheme 3.126

An unusual ring expansion of 2-methyleneoxetane has been observed by Howell et al. [226] in the presence of lithium and 4,40 -di-tert-butylbiphenyl (Scheme 3.127). The resulting lactone was postulated to arise from a coupling between a radical enolate derived from 2-methyleneoxetane and the acetaldehyde enolate, a decomposition product of THF.

tBu

O Ph

tBu

Li THF, -78° C 84%

Ph

O

O

Scheme 3.127

Hara et al. [227] have focused on the stereoselective synthesis of fluorinated cyclic ethers, since their derivatives seemed to be involved in biochemical mechanisms. They have reported the ring expansion of oxetanes using 4-iodotoluene difluoride. Fluorinated furans were obtained in good yield and as a single stereoisomer from 2,4substituted oxetanes (Scheme 3.128).

3.2 Oxetanes

O

H15C7

I

pTol-IF

H15C7

H15C7

O

Et3N-5HF CH2Cl2, rt 88%

Me

O

2

I

pTol-IF

2

F Me

H15C7

O

Et3N-5HF CH2Cl2, rt 86%

Me

j213

F Me

Scheme 3.128

3.2.5.2.3 2-Methylene Oxetanes Ring Openings Howell et al. [228] have worked on 2-methyleneoxetane derivatives. This ring system contains several potential reactive features: the ring strain, an exocyclic double bond, electron-rich enol ether and a latent enolate leaving group. They demonstrated that 2-methyleneoxetanes underwent regioselective ring opening at the C2 position when treated with trimethylaluminium and either phenyl- or butyllithium. The homopropargylic alcohol was then isolated as a single product in good yield. The reaction in the presence of LDA, the additive was not necessary (Scheme 3.129).

O Ph Me

Me3Al PhLi or BuLi THF, -78°Cto rt R1

R

R2 R3

O

Ph Me

OAlMe3 H

1) iPr2NLi THF, 0°C 2) electrophile 48-88%

excess base

R1

Ph Me

R

R2 R3

OH R4

OAlMe3 Li

H+ 60-70%

OH Ph Me

R, R1 = H, Me, (CH2)5 R2, R3 = H, Me, Ph, CH2CH=CH2, (CH2)3OSitBuPh2 R4 = H, Me, Si(Me)3 E = Me3SiCl, CH3I

Scheme 3.129

The same group then achieved nucleophilic ring opening of 2-methyleneoxetanes at C4 [229]. Stabilized carbanionic nucleophiles and heteroatom nucleophiles provided C4 ring opening, leading to b-functionalized ketones (Scheme 3.130). 3.2.5.2.4 Thermolysis and Photolysis Thermolysis of oxetane derivatives can lead to multiple products from unsymmetrically substituted rings. The lack of regioselectivity has been attributed to similar bond dissociation energies for the carbon–carbon and carbon–oxygen bonds (Scheme 3.131) [132, 133]. Photolytic fragmentation of oxetane is the formal reverse of the Paterno–B€ uchi reaction. This reaction has attracted some interest as it appears to be involved in the

H

j 3 Four-Membered Heterocycles: Structure and Reactivity

214

O

O Nu

Ph Me Conditions PhCH2Li, BuLi, PhCH3, TMEDA, 0°C

Ph Me Rdt

Nu

81%

PhCH2

MgCl , THF, reflu x

86%

PhOH, NaH, DMF, 100° C

70%

PhO

NaI, DMF/H2O, 100°C

40%

I

CH2

Scheme 3.130

∆

O

O

O

Scheme 3.131

photoenzymatic repair of the (6–4) photoproducts of DNA dipyrimidine sites by the enzyme photolyase [230]. 3.2.5.2.5 Polymerizations Kakuchi et al. [231] have prepared a fused 15-crown-4 polymer, a novel ladder polymer, by a two-step polymerization of an oxetanyl oxirane. This polymer showed metal cation binding properties (Scheme 3.132). O

O t

O

BuOK

THF or toluene or neat O 72-98%

O

n

BF3.Et2O

O O

CH2Cl2, 0°C 60-90%

n

O O

m

Scheme 3.132

3.3 Thietanes 3.3.1 Introduction

Thietanes have received much less attention than azetidines and oxetanes. Some reviews have, though, been published on their chemistry [232–234]. The ring strain of thietane (80 kJ mol 1) is comparable to that of thiirane (three-membered ring). This

3.3 Thietanes

explains their difficult formation by ring closure and, conversely, their easy cleavage by electrophilic and nucleophilic reagents. 3.3.2 Physicochemical Data

Conformations of 3-substituted thietanes 1-oxide have been studied [235]. Ab initio SCF calculations (G-31G level) of thietanes examined the change of C–C bond lengths and angular deformations [236] compared to sulfur heterocycles of higher ring sizes. Calculations on the reaction of thietane with NH3 explained the greater reactivity of this compound compared to oxetane [237]. Calculations concerning the ring closure of HS(CH2)3S- to thietane were also reported [238]. Details concerning the NMR spectroscopy of thietane derivatives have been reported in previous reviews [232, 233]. The a-protons of thietane appear at d 3.21 ppm (4.09 for thietane 1,1-dioxide). The 13 C NMR chemical shifts have been reported to be at 25 ppm for the a-carbons and 27 ppm for the b-carbon. The a-carbon shifts in thietanes appear in general at higher field than those of the b-carbon [233]. The 33 S NMR spectra of thietane, thietane 1-oxide and thietane 1,1-dioxide have been recorded [239]. In mass spectra, the main fragmentation includes retro [2 þ 2] cycloaddition for thietanes, thiolactones and iminothietanes, and loss of, respectively, SO and SO2 for thietane 1-oxides and thietane 1,1-dioxides [232]. 3.3.3 Natural and Bioactive Compounds

Mono and dialkyl thietanes 32–35 have been detected in anal gland secretions of small mammals (ferrets, polecats, stoats, minks, weasels, kiores, voles, etc.). R

R S

S

Me S

S

32 R = Me, Et, Pr, iPr

Me Me

Me

R 33 R = Me, Et

34

35

L-a-Aspartyl-N-(2,2,4,4-tetramethyl-3-thietanyl)-D-alaninamide (36), a sweetener that is 2000 more efficient than sugar, has been developed by Pfizer under the name Alitame [240] and commercialized in different countries.

O Me Me S Me

Me

O

H N

N H H Me O 36

OH NH2

j215

j 3 Four-Membered Heterocycles: Structure and Reactivity

216

3.3.4 Synthesis of Thietanes 3.3.4.1 Synthesis by Formation of a S–C Bond 3.3.4.1.1 Formation from 3-Halo Thiol Derivatives The reaction of S-benzyl-Nphthaloylcysteinyl chloride with two equivalents of AlCl3 affords the corresponding thiolactone (Scheme 3.133) [241]. Similar result was obtained for the free thiol function. O

O Cl

N O

S

O

AlCl3, benzene 65 °C, 3 h

N

55 %

Bn

O S

O

Scheme 3.133

Intramolecular reaction of thiolate, generated by base cleavage of thioacetate, on a secondary bromide leads to a bridged thietane [242] (Scheme 3.134). This approach to thietanes has been little studied. S

Br

KOH, EtOH, rt

SAc Br

40 %

Br H

Scheme 3.134

3.3.4.1.2 Formation from 3-Hydroxy Thiol Derivatives Cyclization of 4-thio-4methylbutanol into 2,2-dimethylthietane occurs in high yield when diethoxytriphenylphosphorane is used as reagent (Scheme 3.135) [243].

HS R R

OH

Ph3P(OEt)2 toluene

R Ph3P

S

EtO R R

OH - EtOH

Ph3P

S O

R

- Ph3PO 40-90%

S R R

R = H, Me

Scheme 3.135

Sulfur analogues of thromboxane A2 are obtained when the alcohol function is activated as mesylate [244] (Scheme 3.136). Nucleoside derivatives have also been obtained by a similar procedure [245]. Flash vacuum pyrolysis (500–750
C) of (2-mercaptophenyl)methanol derivatives leads to the formation of thietanes, generally in good yields. For example, heating at

3.3 Thietanes NaN(SiMe3)3

OMs

benzene, 60 °C, 1h

CO2Me MeO2C

S

then HMPA, 70 °C, 20 min

O OSiPh3

AcS

O

MsO

OSiPh3

36% NaHCO3, MeOH 30 °C, 1h

OMe H H OMs

O S

81%

CO2Me

S O

OMe H H OMs

Scheme 3.136

750
C of (3,6-dimercapto-1,2-phenylene)dimethanol furnishes 4,9-dithiatricyclo [6.2.0.02,5]deca-1,5,7-triene, which appears to be stable under 90
C (Scheme 3.137) [246]. S

SH CH2OH

F.V.P. (750 °C )

CH2OH

47%

S

SH Scheme 3.137

Such thermal formation of thietanes was shown to be possible when benzotriazoles [247] or acids [248] were present as reaction groups instead of alcohol functions (Scheme 3.138).

N

F.V.P. (750 °C )

N N

58 %

SH

S O

SH

N

S

Scheme 3.138

+

N S O

41%

N

S

O

CO2H F.V.P. (550 °C ) N

j217

S N 30%

O

j 3 Four-Membered Heterocycles: Structure and Reactivity

218

Thietan-2-ones are formed by the reaction of 3-mercaptocarboxylic acids with DCC [249], ibutyl chloroformate [250], methyl chloroformate [251], Ac2O [252], diethyl cyanophosphonate [253] or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDAC) (Scheme 3.139) [254].

SH

EDAC, CH2Cl2 CO2H rt, 1 h

O

S

EDAC = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

86% Scheme 3.139

An original preparation of thietan-2-one has also been reported: the reaction of 3iodopropanoyl chloride with an ammonium tetrathiomolybdate salt (Scheme 3.140) [255]. (PhCH2NEt3)2MoS4, CHCl3 I

O

40 h, 0 °C

Cl O

S

30%

Scheme 3.140

3.3.4.1.3 Formation from Other 3-Functionalized Thiol Derivatives a-Bromomethyl thioesters react with cobalt oximes to give the corresponding organocobalt compounds that, under photolysis, afford thietanes. This method appears synthetically useful only for the structure reported in Scheme 3.141 [256].

NOH 1. CoCl2, Me

O Me Ms

StBu Br

Me

O

NaOMe, MeOH NOH

2. Pyridine, Zn, 0 °C then rt, 5 h

Me Ms

Ms = 2,4,6-trimethylbenzene

Scheme 3.141

StBu [Co]

hν (pyrex) benzene

S

Me Ms

56% H

[Co] =

O

O

HO N

Me

N

Me

Co N py N O HO H

Me Me

3.3 Thietanes

j219

Reaction of ethyl 2-mercaptoacetate with LDA followed by addition of a dichlorodiimine gives a 2,3-diiminothietane derivative (Scheme 3.142) [257]. When the R groups fixed at the nitrogen atoms were phenyl or 4-methoxyphenyl, the 2,3diiminothietanes were not isolated, due to their ring opening in the reaction mixture.

LDA, TMEDA, THF, -40 °C then

O

Cl

SH

EtO

RN

Cl

NR

(R = Tol), THF, -78 °C NR

S

30%

CO2Et NR

Scheme 3.142

1,4-Addition of O,O-diethyl hydrogen dithiophosphate on the carbon–carbon double bond of chalcones affords a compound that then, under microwave irradiation in the presence of nucleophiles, gives thietanes (Scheme 3.143) [258]. This reaction was previously reported to occur by heating in the presence of a NaH–NaBH4 mixture [259].

R1

R2 O

Al2O3 R2 microwaves

R1

S OEt + HS P OEt

S O S P EtO OEt

600 W 3-4 min 8-92%

Nu R2 S H

R1

Nu = NaCN, MeSNa, EtSNa R1, R2 = Ph, 4-ClC6H4

Scheme 3.143

5-Substituted 2-thiooxoimidazolidin-4-ones react with sodium tert-butylate to yield bicyclothietenes (Scheme 3.144) [260].

Ar1N S

N H

tBuONa, tBuOH

O S Ar

2

OEt

P OEt O

reflux, 4 h 70-83%

Ar1N S

N H

S

Ar1 = Ph, 4-MeOC6H4 Ar

2

Ar2 = Ph, 4-ClC6H4

Scheme 3.144

Thietanes are rarely formed by electrophile-induced cyclizations of unsaturated sulfides [261]. A thietane is obtained in mixture with other products by reaction of a c-unsaturated thiol with bromine (Scheme 3.145). Utilization of the corresponding disulfide allowed exclusive formation of the expected thietane [262].

j 3 Four-Membered Heterocycles: Structure and Reactivity

220

Me Br2, CH2Cl2

Me SH NHCO2Me

O

Br

S

+

O

NH

Me

MeO2CHN

Me S

28% Br

S

75%

NHCO2Me

20% Me

Br2, CH2Cl2

S

MeO2CHN

S

S

35% Me

+

NHCO2Me

Me Br

MeO2CHN

Scheme 3.145

The dianion of 1-(prop-2-ynyl)benzene reacts with phenyl thioisocyanate to give a thioimidate that, by reaction with potassium tbutylate, leads to the formation of a thietane (Scheme 3.146) [263]. Ph Ph

1. 2 eq. nBuLi, THF

Ph

N

R

2.

N C S 3. tBuOH

R1

1. tBuOK, DMSO 2. MeI

SH

N R1

Ph or

S

65% (R1 = Me, tBu)

N R1

Me S

77% (R1 = Ph)

Scheme 3.146

An efficient preparation of thietanes in two steps occurs by reaction of 1,3-diols with dibenzoxazol-2-yl disulfide and tributylphosphine, followed by treatment of the resulting 2-(3-hydroxyalkylthio)benzoxazoles with KH (Scheme 3.147) [264]. The thio-Mitsunobu reaction applied to thioamides gives rise to the formation of a-iminothietanes (Scheme 3.147) [265]. N HO R3

R2 R1

S

O

OH

2

Ph3P (or Bu3Ph), THF, rt

N O

S

OH H R 1 R2

R3

KH, THF rt, 4 h 32-72%

38-72% HO

diethyl azodicarboxylate PPh3, THF, rt NHMe

N

Scheme 3.147

S

70%

MeN N

S

R3 H S

R1 = H, Me, Et R2 R2 = H, Me, Bu R1 R3 = H, Me, Ph

3.3 Thietanes

j221

The formation of thietanes is also possible by electroreduction in the presence of Ni(II) salem as catalyst (Scheme 3.148) [266].

Electrolyse DMF, E t4NClO4, 0.1 M Ph

graphite cathode

Et SCO2Me

Ph N S

Ni(II) Salem

O Et

82%

N Ni O Ni(II) Salem

Scheme 3.148

3.3.4.2 Synthesis by Formation of a C–C Bond Under phase transfer catalysis conditions, 1-bromomethylsulfonyl-2-phenylethane affords, in the presence of sodium hydroxide, 2-phenylthietane-1,1-dioxide, via intramolecular cyclization of the benzyl anion. The Ramberg–B€acklund product is not observed (Scheme 3.149) [267].

Br

O O S

NaOH, CH2Cl2

Ph

10 mol % Bu4N+Br-, rt

Ph

S

83%

O O

Scheme 3.149

Thietanols can be formed by fluoride-mediated cyclization of (Z)-a-silyl vinylsulfides (Scheme 3.150) [268].

R1

S

O

SiMe2R2

R3

THF, B u4N+Freflux, 2-4 h 30-86%

R1

S R3 OH

R1 = Et, iPr, Ph R2 = Me, Ph R3 = Me,

Me , OBzl

Me N(Bzl)2

Scheme 3.150

3.3.4.3 Synthesis by Formation of Two S–C Bonds The oldest method for the preparation of thietanes involves the reaction of 1,3dihalides with sodium sulfide. Numerous conditions have been studied [232, 233]. Excellent results have been reported for phase transfer conditions (Scheme 3.151) [269]. A spiro thietane is formed upon reaction of a 1,3-dibromo derivative with Na2S in DMF [270].

j 3 Four-Membered Heterocycles: Structure and Reactivity

222

Na2S, CH2Cl2, H2O R1 R2

X

hexadecylEt3N+Cl-

X

rt, 2-3.5 h

R3

Br

X = Cl, Br

R2

S

R1 = H, OH, Me

R1

R2, R3 = H, ,Me

57-94% O

Br

R3

Na2S.9H2O, DMF

Me Me

O

100 °C, 6 h 97%

O

S

Me Me

O

Scheme 3.151

Derivatives of 1,3-diol benzoates (Scheme 3.152) [271], mesylates [272] and tosylates (Scheme 3.152) [273] were also efficient in these preparations. O

Na2S . 9H2O, DMSO

Me

O

Ph

Ph

O

Ph

Me

90 °C, 6 h

Ph

65%

S

O

O

Ph

S OTs

N O

EtO

S- K+ , acetone reflux, 2 d

Ph S

80%

OTs

Ph

HO2C NH

S

O

NH2

81%

Scheme 3.152

1,3-Diols protected as carbonates can also lead to thietanes by reaction with KSCN at high temperature. This method has been reported for the preparation of (S)-2propylthietane, which is a natural product (Section 3.3.3) (Scheme 3.153) [274]. This procedure was used more recently in the case of a 1,2,3-propane triol derivative [275]. OH Pr

OH ee: 80%

1. (EtO)2CO, NaH, reflux, 3 h 2. KSCN, 200 °C 63%

H

S

Pr ee: 80%

1. (EtO)2CO, KOH, EtOH, 120 °C, 2 h Me

OH OH OH

Scheme 3.153

2. KSCN, 180 °C 38%

S

Me OH

3.3 Thietanes

j223

Reactions of b-halo epoxides with different sulfur reagents give rise to 3-thietanols in good yields. The first sulfur reagent used was H2S in the presence of sodium ethoxide (Scheme 3.154) [276], or Ba(OH)2 [277].

O

Ph

EtONa, H2S, 0 °C, 12 h Cl

Ph

S

62%

OH

Scheme 3.154

Reactions of Li2S [278] and benzyltriethylammonium tetrathiomolybdate [279], ammonium thiocarbamates (Scheme 3.155) [280] and thioacetate [281] with b-halooxiranes are very efficient.

Ph

+ N S- NH2EtPh, MeOH, rt, 5 h 1. Et 2. DMSO, PhNHEt, 50 °C, 0-5 °C, 2 h

O

R1 Y

O

3 R2 R

R1 S

33-84%

R1= H, Ph, Me R2

R2= H, Me

OH

R3= H, Ph

R3

Y = Cl, Br

Scheme 3.155

Thiols react with epichlorohydrin to give the corresponding addition products, which are then transformed into thietanes when reacted with sodium methoxide (Scheme 3.156) [282].

O

N

SH

Cl , EtOH, NaHCO3 rt, 16 h 67%

NaOMe, MeOH N

S

Cl OH

rt, 3 d

N

41% S

Scheme 3.156

The formation of thietanes by reaction of c-hydroxyoxiranes with potassium thiocyanate has been also reported (Scheme 3.157) [283]. Thietanes can also be formed by radical addition of dimethyl disulfide on 1,3dienes, by heating in the presence of iodine (Scheme 3.158) [284]. Electrophilic addition of SCl2 [285], a mixture of POCl3 (or POBr3)/thiobismorpholine [286] or SO2 (Scheme 3.159) [287] with norbornadiene produces thietane

O

j 3 Four-Membered Heterocycles: Structure and Reactivity

224

NH2

NH2 N O

HO

N

N

N

N

KSCN, dioxane

O

18-crown-6, Et3N 40%

O

S

N

N N

OH

Scheme 3.157

MeSSMe, CS2 R1

R2

R1

I2, 53 °C, 24 h

R2

S

MeS

30-40%

R1, R2 = long-chain alkyl

SMe

Scheme 3.158

derivatives. The reaction of SCl2 with d-diketones leads to thietanes in good yields (Scheme 3.159) [288]. SO2, 36 h, rt 100% O

R

O Me

Me Me

O O

O

S

O

SCl2, EtOAc 2 h, 0 °C then rt, 10 h Me

S

Me Me

Me

75-80%

Me

O

O

R = H, Me, iPr, Ph

OR O

Scheme 3.159

3.3.4.4 Synthesis from Other Sulfur Heterocycles 3.3.4.4.1 Formation from Thiirane Derivatives The reaction of 2-(chloromethyl) thiirane with sodium acetate gives the corresponding thietane in 82% yield [289]. Similar ring expansions were reported using ammonium thiocyanate (Scheme 3.160) S

R1 S R2

R3

Cl

NH4SCN Cl

benzene, H2O, rt

Li

THF, -90 to -60 ° C 0.5-2 h

Scheme 3.160

S

R3 SLi 1 2 Cl R R

N C O +

S

OH

51%

30%

-30 °C

S

10-73%

R3

1 R1 R = H, Me, Pr, allyl R2 = Me, Et, Pr, CH2OEt, R2 CHEtBu, allyl R3 = H, Me

3.3 Thietanes

j225

[290], sulfonamides [291] and phenates [291], or from (thiiran-2-yl)methanol under the conditions of the Mitsunobu reaction [292]. Addition of allyl lithium compounds with thiiranes gives rise to thietanes in good yields (Scheme 3.160) [293]. An optically active thiirane has been transformed into a thietane, without epimerization of the chiral centers, in two steps by reaction with silver acetate followed by cyclization of the resultant 3-mercaptoacetal by camphor sulfonic acid (CSA) (Scheme 3.161) [294].

OEt OEt

S

TrCl, AgOAc, toluene reflux, 10 min

SH AcO

OEt OTBDMS

92%

OTBDMS

CSA, benzene reflux, 2.5 h AcO

OEt

S

OEt

34% OTBDMS

Scheme 3.161

Iminothiiranes react with isocyanates to afford 2,4-diiminothietanes (Scheme 3.162) [295]. This rearrangement of thiiranes into thietanes has also been reported during the reaction of diphenyl diazomethane with acyl isothiocyanate [296].

Ph

S

Ph

N

SO2Ar

R1 N C, Et2O, 0 °C 33-52%

R1 N S N

Ph

R1 = Ph, 4-MeC6H4, 4-MeOC6H4, tBu

Ph

Ar = 4-MeC6H4, 4-ClC6H4

SO2

Ar

R Ph2CN2, Et2O, rt Ph N C S

R

Ph

O

N

O Ph Ph

S

CHCl3, reflux 37-73%

Ph Ph S Ph Ph

R = CCl3, CO2Me, Ph, tBu EtO, R

N O

Scheme 3.162

3.3.4.4.2 Formation from Thiolanes and Derivatives 3-Chlorotetrahydro-2methylthiophene reacts with water to give the 2-substituted thietane (Scheme 3.163) [297]. This reaction is reversible, since under acidic conditions (HCl) the tetrahydrothiophene was reformed. S

Me EtOH-H2O, (1-1), rt Cl

Scheme 3.163

75%

S

Me OH

j 3 Four-Membered Heterocycles: Structure and Reactivity

226

4-Diazodihydrothiophen-3(2H)-one derivatives undergo ring contraction to thietan-2-ones upon heating in isooctane [298], irradiation in an alcohol [299] or in the presence of rhodium diacetate (Scheme 3.164) [300].

Rh2(OAc)4, tBuOH

S

Ph O

R1

S

130 °C, 90 min Ph

22-90%

N2

R1 = H, CO2tBu

O

R1

Scheme 3.164

Flash-thermolysis of benzothiophen-2(3H)-one (Scheme 3.165; X ¼ 2H) [299] or benzothiophen-2,3-dione (Scheme 3.165: X ¼ O) [301] gives rise to the corresponding thietanes in excellent yields.

X

X

FVP (600-750 °C) O

S

S

94-100%

O

S

- 40 °C (X = O)

O

X = 2H, O S

Scheme 3.165

Treatment of a 4-thiofuranose derivatives with diethylaminosulfur trifluoride (DAST) leads to the formation of the ring contraction product (Scheme 3.166) [302]. Rearrangement of thiazolotriazoliums, formed by electrophilic addition of bromine on 3-methallylthiotriazoles in basic conditions, affords thietanes (Scheme 3.167) [303]. The same rearrangement was observed with benzimidazole, benzothiazole and imidazole derivatives.

BnO

S

BnO

OAc

diethylaminosulfur trifluoride

H

63%

BnO H

OH

S

H OBn

OAc F

Scheme 3.166

Br

Me Br2, NaClO4

N N Me

N Ph

S

Scheme 3.167

acetone, rt

N Me

N+

N Ph

S

ClO4-

Me KOH, DMF, rt

N N Me

N Ph

S

3.3 Thietanes

Monodesulfurization of 1,2-dithiolanone with triphenylphosphine or tris(diethylamino)phosphine gives the thietanone in medium yields (Scheme 3.168) [304]. An attempt to use this method for the preparation of optically active thietanes was unsuccessful [305].

Me Cl S

(Et2N)3P, benzene

O

S

Cl S

Me O

44%

Scheme 3.168

Reaction of benzyne with a thiophen-2,4-dithione gives a 2-thioacetal thietane in good yield (Scheme 3.169) [306]. Me S Me

nBu4N+F-

Me S

SiMe3

+

OTf

S

Me

CHCl3, rt, 2 h

Me Me S

Me

S

Me

S

78%

Scheme 3.169

3.3.4.4.3 Formation for Thiopyranes and Higher Ring Size Thio Heterocycles Irradiation at low temperature of a 1,3-oxathian-6-one has been reported to lead to an unstable thianone, which leads to the formation of a dimer at room temperature (Scheme 3.170) [301]. O

S

O

hυ

O

S

77 °K

Ph

Scheme 3.170

CO2 is extruded during the flash-thermolysis of 1,3-oxathian-2-ones, affording thietanes that have been isolated in good yields (Scheme 3.171) [307].

S

O O

Scheme 3.171

F.V.P. (550 °C ) 71%

S

j227

j 3 Four-Membered Heterocycles: Structure and Reactivity

228

Ultraviolet irradiation of 1-aza-8-thiacylo[4.2.1]non-2,4-diene-8,8-dioxide yields an unusual tricyclic compound (Scheme 3.172) [308].

hν (350 nm) acetone, MeCN (2:1)

N

S O O

NH

H

H

S O O

28%

Scheme 3.172

3.3.4.5 Synthesis by [2 þ 2] Cycloaddition Photochemical cycloadditions of thiones with unsaturated compounds have received considerable attention. Aromatic, aliphatic and a,b-unsaturated thioketones react as well with electron-poor rather than electron-rich olefins [232–234]. The more recent result concerns the reaction of silyl thioketones, which can be seen as an equivalent of thioaldehydes, with olefins. Irradiation of phenyl triphenylsilyl thioketone in acrylonitrile, methyl acrylate and cis- or trans-1,2-dichloroethene give the silylthietanes with high regio- and stereoselectivity (Scheme 3.173) [309]. Lower yields and selectivities are observed during the reaction with vinyl ether. Subsequent protiodesilylation reactions take place with predominant inversion of configuration at the carbon bearing the silicon group. The intramolecular cyclization of thiones was reported to be very efficient (Scheme 3.173) [310].

Ph Ph3Si

EWG S

in excess

GWE

hν, - 70 °C 58-60% 2-5 h hν, benzene

R1 R2 S

43-69%

H S

Ph

EWG = CN, CO2Me

SiPh3

de: 84% S

R2 R1

R1 = H, allyl R2 = H, Me

Scheme 3.173

Photochemical additions of olefins on the thiocarbonyl function of thioxo-3,4dihydroisoquinolinones (Scheme 3.174) [311], benzooxazole-2-thione [312] and 5thioxopyrrolidinones (Scheme 3.174) [313] have been reported. [2 þ 2] Cycloadditions of thiopivalophenones were also reported by reaction with benzyne (Scheme 3.175) [314].

3.3 Thietanes

R3

R1

Me Me N

, hυ R2 R4 MeCN, rt, 0.3-8 h

X Me

R S R2 3 R R4 Ph

, hυ Ph benzene, rt

N

Ph

X

R1, R2 = Me, Ph R3, R4 =H, Me

Me

X = O, S

R2

S

R1 = Me, Cl, OMe R2 = Me, H

N

65-89%

O R1

N

1

Ph

R2

S

Me Me

88-91%

S

j229

O R1 (one diastereomer)

Scheme 3.174

t

Bu

SiMe3

S +

Ar

I+

Ph

nBu4N+F-, MeCN or CH2Cl2 rt, 1 h

CF3SO2O-

S

12-58%

tBu

Ar = H, OMe, OPh

Ar

Scheme 3.175

Intramolecular cyclizations of unsaturated N-ethanethioylacetamide derivatives have also furnish tricyclic thietanes (Scheme 3.176) [315]. Cycloaddition of 2,4dioxopenta-3-thione with allyltributyltin occurs at room temperature [316].

R

S

X

benzene, 15 °C, 1-6 h

N

Me

H

hν (pyrex)

R Me

33-67%

O

O O Me

PhthNSCl, rt pyridine, CH2Cl2

O Me

O

Me S

X

CHCl3, rt, 48 h 46%

R = H, Me X = O, S

N

SnBu3

O

Me

S

O

Phth = phthaloyl

S

Me Me

SnBu3 O

Scheme 3.176

Thietene-1,1-dioxides, which are precursors of thietanes, can be obtained by reaction of enamines with methanesulfonyl chloride in the presence of triethylamine (Scheme 3.177) [317]. Cycloadditions of acrylates with alkyl(chlorosulfonyl)acetate was reported to lead to 2-carboxylate thietanes [318].

j 3 Four-Membered Heterocycles: Structure and Reactivity

230

Pr

MeSO2Cl

N

NEt3, Et2O

O2 S

1. MeI, acetone 2. THF, CaSO 4, Ag2O

N

36%

Pr

O2 S

1. H2, Pd/C, EtOH 2. NaBH4, (CH2OMe)2 91%

Pr

S Pr

Scheme 3.177

3.3.4.6 Synthesis by Miscellaneous Methods Isomerization of cyclobutane-1,3-dithiones into thietanones occurs in the presence of strong bases [319]. Utilization of tetrabutylammonium fluoride, allows a transformation under milder conditions (Scheme 3.178) [320]. The same product is obtained by reaction of the cyclobutane-1,3-dione with P4S10 at reflux in pyridine [321].

Me Me S

S

nBu4NF, THF 0 °C, 5 min

Me

85%

Me

Me Me

Me

Me S

S

Scheme 3.178

Isoxazolidine-3-thiones react with ZnI2 in chloroform to give 2-iminothietanes (Scheme 3.179) [322].

Me Me Ar

S O

ZnI2, Me3SiI, CH2Cl2 50 °C, 3-6 days

N Ph

29-83%

S

Ar Me

Me

N

Ph

Ar = Ph, 2-ClC6H4, 3-ClC6H4, 4-ClC6H4,

Scheme 3.179

An interesting preparation of thietan-1-oxides involves the reaction of tbutyl sulfide with peroxydodecanoic acid (Scheme 3.180). Mixtures of diastereomers were obtained [323].

C6H13 OH St.Bu

C6H13

C11 H24CO3H pentane, 0 °C, 15 min 98%

Me Me

xylene OH reflux

S O H

5 min

C6H13 OH S H O

Me 22-44%

O S C6H13 de = 2:1

Scheme 3.180

OH

3.3 Thietanes

j231

3.3.5 Reactivity and Useful Reactions 3.3.5.1 Reactions with Electrophilic Reagents Thietanes react with ethyl diazoacetate [324] or diethyl diazomalonate [325] in the presence of rhodium acetate to give ring expansion products. When the carbenes are generated from diaziridines, ring-opening compounds are obtained (Scheme 3.181) [326]. EtOOC

N2

EtOOC R Ar Cl S

R

Rh2(OAc)4, benzene, reflux, 16 h S N N

hυ (350 nm), hexane, 25 °C, 24 h

56-65% Cl

S

Ar H

+

S

or benzene, reflux, 18 h

COOEt COOEt

S Ar H

S S

Cl

R = C6H13, Ph, 4-ClC6H4

R = Ph, 4-ClC6H4, 4-MeC6H4 Cl

18-35%

16-38%

Scheme 3.181

The reaction of 2- or 3-substituted thietanes with cobalt or ruthenium carbonyl [Co2(CO)8 or Ru3(CO)12] produces dihydrothiophenones in good yields [327]. More recently, it has been shown that platinum salts can catalyze this CO insertion (Scheme 3.182) [328]. However, these reactions were not observed with 2,4-disubstituted thietanes. (dppe)MePt-Co(CO)4

S

R

CO, THF, 100 °C, 2-5 h or 30 °C, 24 h 89-99%

R

S

O

R = H, Me

Scheme 3.182

Thietanes undergo ring opening by reaction with chloro reagents [232]. However, mono- or di-chlorinations and brominations of thietane-1,1-dioxides occur easily on C3 by irradiation [329]. 2-Iodination has also been reported by reaction with butyllithium, followed by addition of triethylaluminium and iodine (Scheme 3.183) [330]. 3.3.5.2 Reactions with Oxidizing Agents Oxidations of thietanes to thietanes-1-oxides and thietane-1,1-dioxides have been reported with the reagents generally used in the case of dialkyl sulfides: KMnO4,

j 3 Four-Membered Heterocycles: Structure and Reactivity

232

O

S

62-94%

O

O

S

X2, hυ

X

hυ, (sun lamp) X2, CCl4, reflux

X

CCl4, reflux O

S

X = Cl, Br

82-94%

O

O

1. nBuLi, THF, 0 °C, 30 mi n 2. AlEt3, 0 °C, 30 min O

X

3. I2, 0 °C, 30 min

O

S

S

O

I O

67% Scheme 3.183

mCPBA, NaIO4, H2O2 in CH3COOH or in presence of WO3-H2O, CrO3 [232, 233]. Other reagents have been tested with success, such as cat. OsO4-4-methylmorpholine N-oxide [331], 2-(phenylsulfonyl)-3-phenyl-oxaziridine [332], monoperphthalic acid [333], tpentyl hydroperoxide in the presence of MoCl5 [334], oxone (Scheme 3.184) [309b] or 1-butyl-4-aza-1-azoniabicyclo[2.2.2]octane dichromate [335].

OH oxone, MeOH, H2O rt, 5 h

Me

Ph

S

Ph

Me

90%

O

OH S

O

Scheme 3.184

The diastereoselectivity of the formation of thietane-1-oxides from thietanes has been examined using mCPBA [336]. Better selectivities have been reported using H2O2 in the presence of TiCl3 (Scheme 3.185) [337]. Me Me

1. TiCl3, H2O-MeOH 2. H2O2, H2O, MeOH

S Me Me

Z

Me Me Z

77-80%

S

Me Me

O Me Me

minor (8-20%)

+

Z

S

O Me Me

Z = OH, NHAc

major (80-92%)

:

Scheme 3.185

The potassium enolate of a thietan-2-one reacts with MoO5 to give the corresponding a-hydroxythietanone (Scheme 3.186) [253]. Me O

H S

1. KH, THF, - 20 °C Me 2. MoO5.pyridine.DMPU, - 20 °C, 4 h Me

Scheme 3.186

61%

Me O

OH Me S

Me

3.3 Thietanes

j233

3.3.5.3 Reactions with Nucleophilic Reagents Thietane-1,1-dioxides have been reduced to thietanes by reaction with LiAlH4 (Scheme 3.187) [317]. Reduction of thietane-1-oxides and sulfimides have been reported with a mixture MeSiCl2-Zn [338].

O

S

LiAlH4, Et2O

Pr

S

60%

O

Pr

Scheme 3.187

2-Thietanones react with stabilized phosphoranes to give the corresponding (E)and (Z)-2-alkylidenethietanes (Scheme 3.188) [339]. 3-Thietanones are easily transformed into the corresponding N-hydroxyimines; subsequent reaction with NaBH4 led to 3-aminothietanes (Scheme 3.188) [340].

Z NH O

R1 R2 O

S R3

Me S

Z NH

benzene, reflux

Me

Me EWG

47-90%

NH2OH.HCl KH2PO4, MeOH HO

R4

EWG

Ph3P

R1 R2 N

12 h, 120 °C

S R3

90-95%

R4

S

Me

NaBH4 (MeOCH2CH2)2O 4 h, 110 °C

Z = CO2CH2Ph EWG = CO2Et, CN COMe

R1 H2N

R2 S

R3

R1, R2, R3, R4 = Me, Et, Pr, Bu, Hex, Cycloalkyl, Aryl

R4

Scheme 3.188

Additions of nucleophiles or 3-chlorothieten-1,1-dioxide affords products without cleavage of the thietane ring. By reaction of sodium ethanoate the corresponding 3acetal was obtained, while with sodium dimethyl malonate, the 3-alkylidenethietane was formed (Scheme 3.189) [329b].

MeO2C MeO2C

S

O O

NaOEt, EtOH CH2(CO2Me)2 reflux, 3 h

NaOR, ROH Cl

S

O O

reflux, 2 h 66-72%

RO RO

S

O O

R = allyl, Et, Pr

83% Scheme 3.189

3.3.5.4 Reactions with Bases Thietanes are readily opened by reaction with sodium hydroxide to give linear sulfurs or polymerization products, depending on their structure [341]. With 3-hydroxythietane-1-oxides, ketones were obtained (Scheme 3.190).

j 3 Four-Membered Heterocycles: Structure and Reactivity

234

NaOH, H2O R HO

S (O)n

O

18 °C, 2-20 min

(O)n S Me

R

96-100%

R = H, Ph n = 1, 2

Scheme 3.190

Thiiranes have been formed by pyrolysis of lithium salts of hydrazones formed from thietan-3-ones (Scheme 3.191) [342].

TsHN

BuLi, THF, - 78 °C to rt

R1 R2 N

then concentration and heating

S

(130-150 °C)

R4 R3

R1 S R2

R3

R1, R2, R3, R4 = H, Me, Me2C

R4

50-75%

Scheme 3.191

Thietanes react with lithium diphenylphosphine to give the opened products in modest yields (Scheme 3.192) [275]. HPPH2, BuLi Me R

S

TMEDA, hexane, THF 20-30%

Me

SH

R

R = SCH2Ph, PPH2

PPh2

Scheme 3.192

Reaction of 2-phenylthietane with 4,40 -di-t-butylbiphenyllithium (DTBB-Li) has been reported to produce a dianion, which can react with electrophiles (Scheme 3.193) [343]. This reaction was not observed when starting with 2methylthietane. With CO2 as electrophile, dihydro-3-phenylthiophen-2(3H)-one was formed.

Ph

S

1. Li, 4,4'-ditbutylbiphenyl, THF, - 78 °C 2. Electrophile (-78 °C) then rt 50-86%

E Ph

E = D, tBuCHOH, Et2COH, (CH 2)4COH SLi

Scheme 3.193

Thietane-1-oxides undergo Pummerer rearrangements, when treated with Lewis acids in the presence of amino bases. This method has been used for the preparation of thietane nucleosides (Scheme 3.194) [264, 267, 344]. 3.3.5.5 Reactions with Metal Complexes and Salts Thietane is transformed into crown thio ethers (12S3, 16S4, 18S6, etc.) by the reaction of Re2(CO)9(thietane), Os4(CO)11(thietane) and W(CO)5(thietane). Yields of 40%

3.3 Thietanes

O Me

thymine, Et3N, CH2Cl2

O S

TMSOTf, ZnI2, rt, 30 h

NH

S

N

O

70% OBz OBz

OBz OBz

Scheme 3.194

were reported for the formation of the 12S3 crown ether (Scheme 3.195) [345]. This transformation is possible with 2- and 3-methylthietanes and 3,3-dimethylthietanes. Starting from (R)-2-methylthietane, the corresponding optically active crown ether has been obtained [346].

S

Re2(CO)9 (SCH2CH2CH2 )

S

S S

TMSOTf, ZnI2 40%

12S3

Scheme 3.195

Mannosyl iodide reacts with thietane in the presence of MgO to give mainly the thio b-anomer (Scheme 3.196) [347].

S

+

BnO BnO

OAc OBn O I

MgO, CH2Cl2 reflux, 6h 89%

BnO BnO

OAc OBn O S

I

α−β: 1-30 Scheme 3.196

3.3.5.6 Electrocyclic Reactions Retro [2 þ 2] cycloadditions of thietanes occur at high temperature to generate ethylenic compounds and thioaldehydes. This fragmentation is also possible by irradiation at low temperature. With thietan-3-one, the formation of ketene has been detected [2]. These retrocycloadditions were observed for substituted thietanes. For example, enol ethers are formed during irradiation of 3-alkoxythietanes (Scheme 3.197) [348]. These reactions also lead to the formation of thioketones or thioaldehydes. Irradiations of thietan-2-ones in methanol lead, by Norrish I rearrangements, to five-membered heterocycles (Scheme 3.198) [349]. Dithiolactones give rise to the same kind of rearrangements [350].

j235

j 3 Four-Membered Heterocycles: Structure and Reactivity

236

EtO Me S N NMe S Me Me O

hυ, MeCN

Me S N NMe

EtO

78%

Me Me O

Scheme 3.197

Me Me

S

O

S

hυ, MeOH

Me Me

S O

+

O

OMe

OMe 30%

20%

Scheme 3.198

2-Iminothietanes can be formed by cycloadditions of keteneimines with diphenyl thioketone in methylene chloride. Upon smooth heating, these compounds (R2 ¼ H) are transformed into unsaturated thioamides (Scheme 3.199) [351].

R2 R1

• NR3 +

Ph Ph

S

CH2Cl2, rt

R2

NR3

R1

S Ph Ph

30-50%

R1, R2 = Ph, Me R3 = Me, Ph, 2,6-Me2C6H3, 2,4,6-Me3C6H2

Scheme 3.199

Benzothiete undergoes, by heating or irradiation, an isomerization into methylenecyclohexadienethione. This compound can be trapped by various dienophiles (Scheme 3.200) [299]. In the absence of dienophile, a dimer of methylenecyclohexadienethione is formed. Reaction of this compound with C60 [352], imines and diazenes [353] has also been reported.

FVP (1200 °C) or hν S

S

S

75% R2

toluene, reflux, 3 h R1 Scheme 3.200

S

toluene, reflux, 3 h

R2

S 65-76%

R1

cyclohexenone methyl acrylate N-phenylmaleimide dimethyl acetylenedicarboxylate

3.3 Thietanes

j237

3.3.5.7 Cleavage and Other Reactions Thietane reacts with benzyl bromide in acetonitrile to give the ring cleavage product (Scheme 3.201) [354]. R

CH2Br

MeCN, rt, 16-120 h S

Br

R = H, 2-NO2, 3-NO2, 2-Me, 4-Me, 4-MeO, R 4-Br, 2-CN, 2-Cl, 4-Cl, 3-F, 4-SMe

S

47-85%

Scheme 3.201

Mercaptothiolic acids have been formed by the reaction of thietan-2-ones with H2S [355]. These acids can be transformed into 1,2-dithiolan-3-ones by reaction with FeCl3 [253, 356] or HIO3 (Scheme 3.202) [357].

O 1. H2S, CCl4, -30 to -40 °C HIO3 on alumina HS CHCl3, hexane, rt, 40 min O 2. Et3N, H2S, 0 °C, 7 h COSH (CH2)7 S S (CH2)7 (CH2)7 S t t 87% OSiMe OSiMe2 Bu 2 Bu t OSiMe2 Bu Scheme 3.202

2,3-Diiminothietanes react with the dianion of ethyl mercaptoacetate to give bisthioles, while reaction with dimethyl acetylenedicarboxylate leads to thiopyran derivatives (Scheme 3.203) [358]. O

S RN

S

CO2Et NHR

SH EtO LDA, THF TMEDA, -40 °C 58%

RN

S

MeO2C CO2Et

CO2Me

toluene, 80 °C

NR

64%

MeO2C

S

MeO2C

NHR CO2Et

R =Ph, 4-MeC6H4, 4-MeOC6H4 Scheme 3.203

Intramolecular induced ring opening of 2-iminothietanes, in which the imino group bears a phenol function, occurs by simple heating (Scheme 3.204) [359]. Enzymatic resolution of 3-methylthietan-2-one has been studied in the presence of lipases. Best results were reported using Pseudomonas cepacia lipase (E > 100) (Scheme 3.205) [360].

NR

j 3 Four-Membered Heterocycles: Structure and Reactivity

238

Me Me

R S

Me

O

toluene, reflux OH

N

100%

N

Me Me HS

Me R

R = H, M

Scheme 3.204

S

O

Pseudomonas cepacia lipase cyclohexane, buffer (pH 7.4)

Me

37 °C, 24 h conversion: 52%

O HO

R

SH

Me ee>99%

+

S

O R

Me

ee>95%

Scheme 3.205

3.4 Other Four-Membered Heterocycles 3.4.1 Selenetanes 3.4.1.1 Introduction The chemistry of four-membered heterocyclic compounds containing one selenium atom has been until recently very little studied. These compounds appear to be stable enough to be synthesized and their reactivity examined, even if they have a relatively low thermal stability. CNDO/2 calculations have been performed to determine the conformation of the parent compound [361]. Experiment values were measured by 1 H NMR in the case of 3,3-dimethylselenetane complexed by palladium(II) halides [362] IR and Raman spectra of this compound have been studied and the different vibrations assigned [363]. 1 H and 13 C NMR spectra of some selenetanes have been reported. Chemical shifts of protons and carbons appear comparable to those reported for thietanes. The 13 C-77 Se coupling has been used recently as a criterion of formation of selenetanes, even if the natural abundance of 77 Se is only 7% [364]. The X-ray structure of a selenetane has been reported [365]. In mass spectra, the parent ion corresponds to the retro [2 þ 2] cycloaddition. All ions containing a Se atom are characteristic due to the particular isotopic abundance of selenium [366]. No natural product containing a selenetane ring has yet been reported. Derivative 37 has been tested as an antiviral compound [367].

3.4 Other Four-Membered Heterocycles t

BuCH2

N

j239

Se

N

N Ph

O 37

3.4.1.2 Synthesis of Selenetanes Although much less studied than thietanes, preparations of these compounds have often been made by similar methods. 3.4.1.2.1 Synthesis by Formation of Two Se–C Bonds The first attempt to prepare selenetanes was by the reaction of 1,3-dibromopropane with Na2Se [368]. The selenetane was not characterized due its easy polymerization. This method was reinvestigated and applied to the preparation of various selenetanes (Scheme 3.206) [369]. The parent compound was obtained in low yield (5%). This approach was recently used in the preparation of nucleosides (Scheme 3.206) [364]. Heating cyclic carbonates at high temperature (170–220
C) in the presence of KSeCN gives selenetanes in satisfactory yields (Scheme 3.207) [370].

R1

Br

R2

Br

MsO

O

MsO

K 2Se,EtOH, benzene reflux

R2

40-75% OMe

Se, NaBH4, EtOH 60 °C 83 %

OMe

R1

Se

R1, R2 = -(CH2)5-, 2Me, 2CH2Br

Se

O

OMe

+

Se

O

Se

OMe :

91

OMe OMe

9

Scheme 3.206

RO (CH2)n RO (CH ) 2n

O O

O

KSeCN 170-220 °C 35-50%

RO (CH2)n RO (CH )

2n

Se

R = C1-C8 n = 0-8

Scheme 3.207

Reaction of an excess of NaSeH with 2-hydroxy-1,3-dibromopropane gives the corresponding di-selenoate. This then leads to the formation of 3-hydroxyselenetane by reaction with NaBH4 or a mixture Hg(CN)2–Na2S (Scheme 3.208) [371]. The reaction of 2-hydroxy-1,3-dibromopropane with NaSeH under phase transfer conditions has been reported to give 3-hydroxyselenetane in 56% yield [372].

j 3 Four-Membered Heterocycles: Structure and Reactivity

240

HO

Br

NaSeH, EtOH

Br

rt, 1 h

NaBH4, EtOH

SeNa

HO

SeNa

Se +

HO

HO

Se Se

HO

Se Se

45%

Hg(CN)2, rt HO

Se Hg Se

Na2S, H2S

Se +

HO

EtOH, 12 h, rt

56%

Scheme 3.208

3-Hydroxyseletanes have also been prepared by the reaction of 2-chlorooxiranes with Li2Se, prepared in situ (Scheme 3.209) [372]. Utilization of H2Se in the presence of SnCl4 gives similar results [373]. The oxirane ring opening has been applied to the preparation of a taxol derivative [374] and nucleosides [375]. Opening of oxiranes with the formation of selenetanes is also possible if the leaving group is in the c position (Scheme 3.209) [376]. 3-Hydroxyselenetane was also obtained by electrochemical opening of epichlorohydrin in the presence of selenium. The best results were obtained when the graphite electrode was doped with selenium [377]. O

Cl R

MsO

O

Se O

NaBH4, Se, EtOH

O

Se

HO

55-75%

OMe

R

LiEt3BH, Se, THF, 0 °C

O OMe

60 °C, 2h

R = H, Et, Ph

HO 33%

+

Se

OMe OH 56%

Scheme 3.209

Electrophilic addition of SeBr4 to norbornadiene leads to the formation of a 1,1dibromoselenetane (Scheme 3.210) [378].

SeBr4 Et2O, 0 °C

Br

Br

Br Se Br

Scheme 3.210

3.4.1.2.2 Synthesis by Formation of One Se–C Bond 3,3-Dimethylselenetane-1,1dioxide can be obtained by heating sodium 3-chloro-2,2-dimethylseleninoate (Scheme 3.211) [369].

3.4 Other Four-Membered Heterocycles

Me

Cl

EtOH

Me

Me

SeO2Na

85 °C

Me

Se

j241

O O

Scheme 3.211

2-Selenoalkenylbenzoimidazole derivatives lead to the formation of selenetanes by the sequence indicated in Scheme 3.212 [302].

N

R

Se

1

1. I2, CHCl3 2. R2X 3. NaClO4, CH2Cl2

N

R2 N

R2 N+ ClO4 KOH, CH 2Cl2 N

40-90%

R1

Se

R1 = H, Me O

N

85-95%

R1

I

R2 = Me, CH2Ph

Se

Scheme 3.212

Another interesting preparation of selenetanes uses the reaction of c-seleno alcohols with KH; good yields were generally obtained (Scheme 3.213) [379]. R3 R 2

N Se O

OH

O

+

Ph Se

R3

O

30-84%

R1 Ph

R1 R2

H N

KH, THF, rt, 30 mi n

R1 = H, Et, CH2Ph R2, R3 = H, Me, Et

Scheme 3.213

3.4.1.2.3 Formation by Ring Regression A selenetane has been prepared in low yield by reaction of a diseleno compound with hexamethylphosphotriamine (Scheme 3.214) [380]. The 1,3-oxaselenetane derivative was obtained in 72% yield when the reaction was carried out in the presence of triphenylphosphine.

Ph

Se Se O

Me

Me

Ph Me Me

P(NMe2)3 toluene,reflux, 10 h 18%

Ph Se

O Me Me Me 1

Ph + Me

Ph

Se O

Me :

Ph Me Me

2

Scheme 3.214

An attempt to prepare benzoselenete by photolysis of 3-diazobenzoselenophenone has been reported. A dimer was isolated, the formation of which was postulated to occur by dimerization of the unstable benzoselenete. Calculations show that benzoselenete is 49.5 kcal mol1 less stable than benzothiete (Scheme 3.215) [381].

j 3 Four-Membered Heterocycles: Structure and Reactivity

242

CO2Me

N2

CO2Me

hν, MeOH O

Se

-20 to -60 °C, 1 h

Se

Se 26%

Se MeO2C

Scheme 3.215

3.4.1.2.4 Formation by Cycloaddition Stable benzoselenetes, characterized by X-ray crystallography, have been obtained by cycloaddition of sterically hindered seleno ketones with benzyne (Scheme 3.216) [365].

Me Me

OSO2CF3

Se + Me

SiMe3

Me

nBu4N+F-

Se Me Me

THF, rt 70%

Me Me

Scheme 3.216

R1

(CO)5W Se

Ph

in excess OR2 - 20 °C, several hours 8-45%

H

Ph

(OC)5W Se 2

RO

R1 = H, Me R2= Me, Et, 4-MeC6H4

R1

Scheme 3.217

Benzoselenoaldehyde stabilized as a tungsten complex reacts with enol ethers at low temperature to give stable selenetanes (Scheme 3.217) [382]. 3.4.1.3 Reactivity The reaction of 3,3-dimethylselenetane with electrophiles such as MeI, Br2, I2, SO2Cl2 gives ring cleavage products [383]. Additions of nucleophiles to the reaction mixture allow subsequent reactions. With ozone or hydrogen peroxide, insertions of an oxygen atom in the four-membered cycle are observed (Scheme 3.218). Seleno crown ethers have been formed by the reaction of 3,3-dimethylselenetane with a rhenium carbonyl complex (Scheme 3.219) [384]. Oxidation of 3-hydroxyselenetane with the Dess-Martin reagent gives selenetan-3one in quantitative yield [372]. However, this ketone was reported to be highly instable. In the presence of sodium hydroxymethanesulfonate (Rongalite), 3-phenyl-

3.4 Other Four-Membered Heterocycles

Me Me Me Me Me Me

MeI

Se

Me

69% 1. Br2

Se

Me Me I Se

Me Me

Br

Se

Br

2. ethylene O Se

H2O2

Se

20%

j243

Me

O

Me

Scheme 3.218

Me Me

Re2(CO)9.NCMe Me Me

hexane, reflux, 2 h

Se

Me

Se

Se

115 °C, 8 h Re2(CO)9 (SeCH2CH2CH2)

14%

Me Me

115 °C, 17 h 21% Scheme 3.219

3-hydroxyselenetane leads to the formation 2-phenylallylic alcohol [372]. The reactivity of tungsten-stabilized selenetanes with KSCN and KSeCN has been examined. In the first case a 1,3-selenazinone-2-thione is obtained (Scheme 3.220) [385], while in the second case a 1,2-diselenolane is formed [382b].

Ph KSCN (OC)5W Se

EtO

Ph

Ph KSeCN (OC)5W Se MeO Me Scheme 3.220

W(CO)5

Se

SiO2, H2O, rt OEt

S

N

- 40 °C

H Ph (OC)5W Se Se OMe Me

Se

Me Se Me Me

j 3 Four-Membered Heterocycles: Structure and Reactivity

244

3.4.2 Telluretanes

The chemistry of telluretanes is almost unknown, even though the first attempt to obtain the parent compound was reported in 1945 [386]. Reaction of 1,3-dibromopropane with Na2Te gave, apparently, the unstable tellurane and only a polymer was isolated during work-up of the reaction. A similar report was made on the reaction of a tellurate [387]. The reaction of epichlorohydrin derivatives with Na2Te was also fruitless [372]. However, a telluretane derivative has been reported by reaction of norbornadiene with TeBr4 (Scheme 3.221) [378].

TeBr4 Et2O, 0 °C

Br

Br

Br Br

Br +

Te Br

Te Br Br

Scheme 3.221

3.4.3 Phosphetanes

Four-membered phosphorus compounds have been known since 1957. Phosphorus (III) heterocycles have in general a low stability and are stabilized as P(V) derivatives (oxides, sulfurs, boranes, etc.). Chiral phosphetane derivatives have been studied as ligands in catalytic reactions (hydrosilylation, hydrogenation). Their synthesis and chemistry have been reviewed [388–390]. Chapter 23 of this book is devoted to phosphorous heterocycles. 3.4.4 Arsetanes

Arsetanes, also called arsacyclobutanes, have been known since 1977 [391]. Structural data on arsetene have been explored by PM3 semi-empirical studies [392]. These few compounds studied appear moderately stable at room temperature under inert atmosphere. The first reported preparation of arsetanes involves reaction of (3-chloropropyl) iodo-arsines with sodium (Scheme 3.222) [391]. This method was subsequently modified, and it was reported that the ring closure of (3-chloropropyl)arsines could be carried out using potassium tert-butylate starting from iron(II) complexes of arsines [393]. 1-Phenylarsetane has been also prepared, by the reaction of dilithium phenyl arsenide with 1,3-dichloropropane [393]. An arsetene has been obtained by reaction of a methylenearsorane derivative complexed by iron with dimethyl fumarate. This arsetene has been characterized by

3.4 Other Four-Membered Heterocycles

R As I

Cl

Na, THF 25-42%

Me Ph

MeI

R As

90%

R As+ Me

Me Ph

BuOK, THF 12h, 20 °C

t

Fe+ As Ph Ph Me

Cl

PF6-

I-

85%

R = Me, Ph

Fe+ As Ph Ph Me

Scheme 3.222

spectroscopic analysis and by X-ray diffraction [394]. Similar cycloaddition, leading to an arsetane, has been reported from fumaronitrile (Scheme 3.223) [395]. NC Cp*(CO)2Fe As

Ph NMe2

H CN

CN Et2O, 1 h, rt

Cp*(CO)2Fe As

85%

CN H

Ph NMe2

Scheme 3.223

An original preparation of an arsetene involves metal exchange between titanium and arsenium, starting from a titanium cyclobutane derivative (Scheme 3.224) [396]. Ph Ph

TiCp2 +

Cl2AsPh

hexane, rt instantaneous 50%

Ph Ph

As

Ph

Scheme 3.224

3.4.5 Siletanes 3.4.5.1 Introduction Siletanes, also called silacyclobutanes, have been known since 1954 [397]. As this family of compounds has been reviewed [398], the present chapter focuses on new aspects of their preparation and reactivity. Siletanes have been studied by numerous theoretical methods. The geometry of 1,1-dimethylsiletane has been reported using gas electron diffraction [399]. Ab initio calculations shows that the barrier to inversion of 1-methylsiletane is comparable to that of methylcyclobutane [400]. NMR (1 H, 13 C and 32 Si), IR and UV spectra of substituted siletanes have been

j245

j 3 Four-Membered Heterocycles: Structure and Reactivity

246

reported [398]. In mass spectra, the main fragmentation corresponds to [2 þ 2] retrocycloadditions [398]. 3.4.5.2 Preparation of Siletanes 3.4.5.2.1 Preparation from Chlorosilanes Cyclization of 1-chloro-(3-chloropropyl) silanes by the Wurtz reaction using magnesium is an efficient method to obtain siletanes (Scheme 3.225) [398]. Utilization of other metals (Li, Na, Na-K alloy) and electrochemical conditions extend this method [401]. R1 1

R

R2 Si Cl

R1

Mg, Et2O

Cl

R1

R3

R2

Si R3

Scheme 3.225

Dichlorosilanes react similarly with 1,3-dimetallic species to form polycyclic silacyclobutanes (Scheme 3.226) [402].

Li

Li

R R Si

Cl2SiR2 Et2O, rt

R = sBu, CH2SiMe3

44-71% Scheme 3.226

3.4.5.2.2 Other Intramolecular Cyclizations 1,2-Bissilylalkanes lead, with alkenes, in the presence of palladium(II) catalyst to the formation of 1,2-bis(organosilyl)alkanes by the addition of a Si–Si bond across C–C double bonds. With 1,2-bissilylalkenes, intramolecular additions have been observed that give rise to silacycloalkanes. When the substituent fixed on one of the silicon atoms is a 3-butenyl chain, siletanes of low stability were formed by 4-exo cyclizations (Scheme 3.227) [403].

Me Me Si Si Ph Me Ph Ph

Me Pd(OAc)2, toluene, 35 °C 76%

CN Ph Si Si Me Me Ph Ph (cis-trans: 16-84)

Scheme 3.227

3.4 Other Four-Membered Heterocycles

j247

Substitutions of silicon by sterically overcrowded substituents allow the preparation of stable silylenes. When one of the substituents is a silicon aryl substituted group, simple heating leads to rearrangement of these compounds into siletanes (Scheme 3.228) [404].

Me

Me Me Si

Me Si

CNAr

Si

THF, 60 °C

i

Me

65-78%

i Pr i

or

Pr

Me Me

Si = CH(SiMe3)2

SiMe3

Si

Me

Ar = Me SiH SiMe3

Si

Pr

Si Scheme 3.228

Intramolecular insertion of carbenes into C–H bonds is also possible by irradiation of a-silyl-a-diazoacetates (Scheme 3.229) [405]. If one of the substituents of the silyl group is an allyl group, a bicyclic silacyclobutane is observed [406]. t Bu Bu Si X

Me

t

hν pentane 15-39%

CO2Et N2

iPr

iPr

Si

Me

tBu

Si

hν CO2Me

N2

X = Cl, N3, NCO, NCS

X CO2Et MeO2C

toluene 68%

i Pr Si iPr

Scheme 3.229

3.4.5.2.3 [2 þ 2] Cycloadditions Reaction of trichlorovinylsilane with t-butyl lithium produces, by 1,2 elimination of LiCl, reactive silenes (Si¼C bond). In the presence of enol ethers, elimination does not take place, and the lithio intermediate undergoes an addition on the C¼C double bond, leading by 1,4 cyclization to siletanes (Scheme 3.230) [407]. tBuLi,

Cl3Si

THF

pentane, -78 °C then rt

Cl3Si

tBu

Li

OR

Cl3Si RO

R = Et, Pr, Bu, iBu, tBu Scheme 3.230

tBu

Li

Si

RO 39-75%

Bu

t

Cl Cl

j 3 Four-Membered Heterocycles: Structure and Reactivity

248

3.4.5.2.4 Preparation from Other Heterocyclic Compounds Siliranes (silacyclopropanes) react with diazomethane to give siletanes in good yields [408]. These compounds give rise to similar ring expansions by reaction with isocyanate (Scheme 3.231) [409]. For monosubstituted silacyclopropanes a good regioselectivity in the formation of siletane is observed [409b].

tBu

tBu

Si Me

R N

C

benzene rt, 15 min

Me

Me Si

Me

96-99%

tBu t

R = 4-MeC6H4,tBu

Bu

NR

Scheme 3.231

Sterically hindered 1,2-disiletanes lead to the formation of silenes by heating at 60–100
C. When the reaction is carried out in the presence of styrene, a siletane is formed in excellent yield (Scheme 3.232) [410]. Me3Si SiMe3 Me3Si Si Si SiMe3

SiMe3 Me3Si Si

Ph hexane, 60 °C, 24h

Ph

89% Scheme 3.232

Irradiation of 1,2-disilolane in the presence of isobutene furnishes a stable tricyclic siletane if one of the substituents fixed on the silicon atoms is a phenyl (Scheme 3.233) [411]. Irradiation of a sterically hindered 9-silaanthracene in benzene leads to the formation of a bicyclo[2.2.0] compound of low stability (Scheme 3.233) [412]. On standing at room temperature, the starting anthracene derivative is reformed.

Ph

Si Si Me Ph

hν, isobutene hexane, 17 min, rt

Me

Ph

Me

Si

Si

Me

Me Me

Me Me

6% Si

Si

Scheme 3.233

Si

20%

Si

Si

Si H

Me

Me

Si

Ph

hν (300-350 nm) D6-benzene, 1 h, rt

Si

Si Si

Si = CH(SiMe3)2

3.4 Other Four-Membered Heterocycles

j249

3.4.5.3 Reactivity Pyrolysis or photolysis of siletanes leads to the formation of silenes [413]. Polymerization of silacyclobutanes has also been studied intensively, and compounds with alternating silicon and trimethylene groups have been obtained [414]. Polymers in which the siletane unit was introduced have also been reported [415]. The presence of siletane cycles instead of trialkylsilanes in functionalized compounds increases their reactivity, allowing much easier reactions. For example, reaction of silyl ketene acetals with carbonyl compounds occurs without any catalyst if a siletane is present (Scheme 3.234) [416]. This increase in reactivity has also been reported for crosscoupling reactions of vinyl- and arylsilanes [417]. 1. CHCl3 20 °C

O

tBu

Me

Si O

2

R

H

2. HF, THF

MeO

80-95%

O

OH R2

MeO

R2 = Ph, cinnamyl, npentyl, cyclohexyl

Me

Scheme 3.234

Silacyclobutanes are opened by the action of nucleophilic and electrophilic reagents, sometimes with polymerization [398, 414]. This cleavage can be controlled [418, 419]. For example, in the presence of platinum salts and 1 equivalent of triethylsilane, opening of a benzosiletane occurs cleanly (Scheme 3.235). In the presence of a catalytic amount of triethylsilane, cyclic oligomers or polymers are obtained [418].

Si Me

Pt(II)

SiEt3

Me Si H

HSiEt3 Scheme 3.235

Insertion of a functionalized chain in one of the C–H bonds in the 3-position of 1,1dimethylsiletane is realized by reaction with diazoacetates in the presence of rhodium diacetate (Scheme 3.236) [420].

H N2 Me Me

Si

CO2R

CH2Cl2, Rh2(OAc)4, rt

Me

90-97%

Me

Scheme 3.236

Si

CO2R

R = tBu, Et

j 3 Four-Membered Heterocycles: Structure and Reactivity

250

Reactions of siletanes with carbenoids of type CHX2Li lead to the formation of silacyclopentane derivatives (Scheme 3.237) [421]. Ring expansions are also observed by reaction of 1-(1-iodoalkyl)siletanes with MeLi, tBuOK or AgOAc and by reaction of 1-oxiranylsiletanes with MeLi (Scheme 3.237) [422]. The insertion of sulfur in 1,1dimethysiletane is very efficient in the presence of KF and crown ethers, giving rise to 1,2-thiasilolanes [423].

R R

Si

Me CH2X 2, i Pr2Li, THF -78 °C, 30 min, then rt

Me

40-97%

Si

R

60-80%

I

Si

Me

O

Si R R minor

X

AgOAc, CH3CO2H 25 °C, 1 h

Ph

Ph

Me

Me

Si R R major

R

Si

75%

R = i Pr, C6F13

Ph OAc

MeLi, THF -78 °C, 2 h, then MeOH at -78 °C

X = Cl, Br, I R = Me, Ph X

Si Ph Me

Me Me OH

Scheme 3.237

Insertion of the carbonyl function of aldehydes in the cycle of siletanes is possible in the presence of tBuOK [424]. With 1,1-diphenyl-3-methylenesiletane, tBuOK is not necessary and the reaction occurs by simple heating. It was subsequently reported that this reaction is also possible with aryl ketones (Scheme 3.238) [425].

Si

O

Ph Ph

R1

R2

ClCH2CH2Cl 80 °C 60-80%

R1 R2 O Si Ph Ph

R1 = Ph, nC6H13 PhCH=CH R2 = H, Me

Scheme 3.238

Insertions of SO2, SO3 and phosphorus ylides similarly lead to six-membered heterocycles [398]. With acid chlorides and acetylenic compounds, these insertions occur only in the presence of palladium(II) catalysts (Scheme 3.239) [426, 427]. Insertion of the carbonyl function of CF3COOH into the CSi bond of 2iminosiletanes, instead of the expected hydrolysis, has been reported (Scheme 3.240) [409b]. In the presence of an aqueous solution of CuSO4, ring opening of these

3.4 Other Four-Membered Heterocycles

Si

R4

R1

Si

PdCl2(PhCN)2

O

R1 R2

Cl

R2

R3

O Si 1 R R1

73-94% PdCl2(PPh3)2

R3

R2

toluene, NEt3, 80 °C, 4 h

R1

R4

benzene

R1 = Me, Ph R2 = Ph, 4-MeC6H4, 4-MeOC6H4 4-FC6H4, cyclohexyl, C6H13 2-furanyl R4

R1

reflux, 2 h

Si R2 R3 R3

R1

Si R2 R3 R3 7-60%

6-86%

R1 = CO2Me, Ph R2 = CO2Me, H R3 = Me, Ph R4 = H, Me

Scheme 3.239

tBu

Si

tBu

CF3CO2H, H2O

Si

Me

tBu

NR

Me

CuSO4, H2O overnight, rt 66%

tBu tBu

Si

95-169 °C 0.5-8 days 89-100%

t

tBu tBu

Si

Me

Me

60%

O

Me

Me

Bu O Bu Si t

NR

Me

0 °C, 30 min tBu

OH CF3

O

OH

Me 12%

OH

Me NHR

R = tBu, 4-MeC6H4

Me

Scheme 3.240

substrates is observed. Heating of these 2-iminosiletanes leads to isomerization of the CN double bond, to give the corresponding enamines [409b]. The silicon atom of silacyclobutanes has reactivity comparable to that of other silanes, and is not reported in this chapter. An interesting example concerning the reactivity of such compounds has been reported. Reactions of 1(c-haloalkoxy)-1methylsilacyclobutanes with magnesium leads to the formation of 1-(v-hydroxyalkoxy)-1-methylsilacyclobutanes in good yields, by intramolecular Grignard reagent attack on the silicon atom, followed by alcoholate elimination (Scheme 3.241) [428].

Si

Me

(CH2)n O X

Scheme 3.241

Mg, THF 72-92%

Si

Me (CH2)n

OH

n = 3-6 X = Cl, Br

j251

j 3 Four-Membered Heterocycles: Structure and Reactivity

252

3.4.6 Germetanes 3.4.6.1 Introduction The chemistry of germetanes has been less examined than that of siletanes, since the first report in 1966 [429]. Only limited spectra data are available concerning these compounds. In the IR spectrum, a vibration at 1120 cm1 seems characteristic of this heterocycle [429]. These compounds appear to be stable at room temperature, and the mechanism of thermal decomposition of 1,1-dimethylgermetane has been examined. The formation of cyclopropane, propene and 1,2-digermacyclobutane was observed [430]. The structure of 1,1,3,3-tetramethylgermetane has been studied by gas electron diffraction and ab initio molecular orbital calculations (HF/6–31G and MP2/6–31G ) [431]. An ab initio study has been made on the mechanism of formation of germetane by cycloaddition of alkylidenegermylene and ethylene [432]. 3.4.6.2 Preparations The first method reported for the preparation of germetanes consists in the cyclization of chloro-(3-chloropropyl)germanes with sodium or sodium/potassium alloy (Scheme 3.242) [429].

R1

Ge R1 Cl

Cl R2

Na, xylene, reflux, 5 h or Na-K, toluene, reflux, 5 h

R2

67-75%

Ge

R1 R1

R1 = Et, Bu R2 = H, Me

Scheme 3.242

In more recent studies, the reaction of 1,1-dichlorogermanes with 1,3-dimetallo compounds has been preferred [433]. This method has been applied to the preparation of benzo- [434] and tricyclic germetane derivatives (Scheme 3.243) [435].

Cl Br

1. Mg, THF Ge

2. Me2GeCl2 56%

I

I

Me

Me

Me Me Ge 1. nBuLi, THF

+ dimer

2. Me2GeCl2 79% Scheme 3.243

10%

3.4 Other Four-Membered Heterocycles

Intermolecular hydrogermanylation has been reported to afford 1,1-dimethylgermetane [436]. Heating of dihydrogermylprop-2-en-1-ols was reported to give 2hydroxygermetanes in low yields, by intramolecular cyclization (Scheme 3.244) [437]. H

Me Ge Me

Cl

+

Cl

H Ph Ge H OH

R

cat. H2PtCl6

Me

88%

Me

Ge

OH

heating or irradiation

Ph

10-12%

H

R = H, Me

Ge R

Scheme 3.244

Highly strained germetanes have been obtained by rearrangement of germanylenes [438] and ethylenidene germanes (Scheme 3.245) [439].

Mes Tbt

C6D6, reflux, 13.5 h Ge

•

SiMe3

SiMe3 SiMe3 Ge Mes

Me3Si

81% Me3Si Me3Si

Me Mes =

Me Me

SiMe3

SiMe3

Tbt = Me3Si

SiMe3

SiMe3 SiMe3

Scheme 3.245

3.4.6.3 Reactivity Germatanes react with electrophilic or nucleophilic reagents to give ring cleavage products. Ring cleavages were reported with halogens, LiAlH4, acids, bases [429], hydrosilanes (Scheme 3.246) [440], phenylphosphinidene [441] and alcohols [442].

Ge

Bu

R3SiH cat. H2PtCl6

Bu

60-80%

Scheme 3.246

R3Si

GeBu2H (CH2)3

R3 = Ph2Me, Et3, B Bu2Me, MeCl

j253

j 3 Four-Membered Heterocycles: Structure and Reactivity

254

Heating at 160
C of 1,1-dimethylgermetane leads to formation of a polymer [436], while irradiation of 1,1-diphenylgermane in cyclohexane gives rise to the 1,3digermanocyclobutane derivative (Scheme 3.247) [442].

Ge

Ph

Ph

hν, cyclohexane, 8 h, rt

Ph

Ph

91%

Ge Ge

Ph Ph

Scheme 3.247

When heated (250
C) in the presence of sulfur, an insertion in one Ge–C bond of a sulfur atom occurs (Scheme 3.248). The same insertion is observed on heating at 260
C in the presence of selenium [443]. Comparable insertion was reported with dichlorocarbene, generated from the Seyferth reagent [444]. Reactions with SO2 and SO3 led, as with siletanes, to the formation of six-membered heterocycles [445].

R

Ge

Bu

S8 (Se)

Bu

250 °C 90% (50%)

(Se) S Bu Ge Bu

R = H, Me

R

Scheme 3.248

3.4.7 Bismetanes and Stibetanes

These four-membered ring compounds are still unknown.

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4 Five-Membered Heterocycles: Pyrrole and Related Systems Jan Bergman and Tomasz Janosik

4.1 Introduction

The history of pyrrole 1 dates back to 1834, when Runge observed the presence of a compound that caused red coloration of a wood splinter moistened with mineral acid, in a fraction obtained through distillation of coal tar. He named the substance pyrrole [1] – a name maintained by Anderson, who later isolated a pure sample by distillation of bone oil [2]. Several years later, the correct structure was established by Baeyer and Emmerling [3]. The biological relevance and intriguing reactivity patterns of pyrrole derivatives have triggered intense interest in their chemistry, which has been exhaustively treated in several excellent monographs covering the advances of most essential aspects of the topic [4–6]. A general review with a practical perspective is included in Science of Synthesis [7]. Annual coverage detailing more recent achievements in synthetic pyrrole chemistry is provided in Progress in Heterocyclic Chemistry [8], whereas more comprehensive accounts on structure [9], ring synthesis [10], reactivity [11] and applications [12] are available in the second edition of Comprehensive Heterocyclic Chemistry. Since the scope of this chapter does not permit in-depth coverage of all aspects of pyrrole chemistry, and will be mainly restricted to 1H-pyrroles, which will hereinafter simply be referred to as pyrroles, readers may also want to consult the above mentioned reference works. Additional useful accounts highlighting special topics in pyrrole chemistry are cited in appropriate sections of this chapter. 4.1.1 Nomenclature

The IUPAC numbering convention for pyrrole (1H-pyrrole) is shown in structure 1, including the commonly used designation of the 2(5)-positions as a, and the 3(4)positions as b. The two remaining conceivable tautomeric forms 1a and 1b are known as 2H-pyrroles and 3H-pyrroles, respectively. Trivial names are relatively rare in the

Modern Heterocyclic Chemistry, First Edition. Edited by Julio Alvarez-Builla, Juan Jose Vaquero, and José Barluenga. Ó 2011 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2011 by Wiley-VCH Verlag GmbH & Co. KGaA.

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pyrrole series, but are still used for some derivatives of natural origin. The general IUPAC rules are now generally applied to most pyrrole derivatives. Carbon containing substituents, such as carboxylic acid, nitrile, aldehyde, but also sulfonic acid, as well as derivatives thereof, should be incorporated into names as suffixes, although prefixes, for instance cyano-, may sometimes be encountered. Nomenclature that applies to special classes of pyrrole derivatives, such as partially saturated systems, will be evident from appropriate sections of the text.

5

3

3( )

4

N1 H 1

2( )

N

2

N

1a

1b

4.2 General Reactivity 4.2.1 Relevant Physicochemical Data, Computational Chemistry, and NMR Data

Pyrrole is a colorless liquid [mp
23  C, bp 130  C (760 Torr)] that darkens in contact with air. It has limited water solubility, but is miscible with many common organic solvents. Although some simple pyrroles are oils, many derivatives with higher molecular weights are solids. Pyrrole displays weakly acidic properties (pKa ¼ 17.25 in aqueous medium [13], 17.51 in aqueous hydroxide solution [14] and 23.05 in DMSO [15]). The dipole moment (m) of pyrrole is 1.74  0.02 D, with the negative pole directed towards the ring carbon atoms [16]. The planar C2v symmetric molecular structure of pyrrole has been determined based on microwave spectra [16]; Table 4.1 provides selected bond lengths and angles. Although it has for some time been possible to calculate quite accurate structural parameters for the structure of pyrrole [9], the increasing level of refinement of modern theoretical methods has enabled even better estimations. Some represen

Table 4.1 Selected experimental and calculated bond lengths (A) and angles ( ) of pyrrole (1).

Experimental MM3 B3P86 B3LYP/ 6-311G(2df,p)

N–C2  (A)

C2–C3  (A)

C3–C4  (A)

C2–N–C5 ( )

N–C2–C3 ( )

C2–C3– C4 ( )

Reference

1.370 1.380 1.368 1.370

1.382 1.382 1.374 1.373

1.417 1.417 1.419 1.421

109.8 110.1 109.9 109.8

107.7 107.1 107.6 107.7

107.4 107.8 107.4 107.4

[16] [18] [19] [20]

4.2 General Reactivity

tative values are included in Table 4.1. Computational methods involving complex pyrrole containing molecules are now commonplace, facilitating for instance studies of ligand–receptor interactions. The fundamental physicochemical properties of pyrroles, including the advances in spectroscopic and theoretical methods, have been compiled in several reviews [6, 9, 17]. As a “p-excessive” five-membered aromatic heterocycle with six p-electrons, pyrrole displays many features that are usually associated with such systems, such as high resonance energy, and a tendency to participate in substitution reactions. Both experimental and theoretical aspects of the aromaticity of pyrroles have been studied over the years, sometimes arousing controversy; this topic has been reviewed and discussed in considerable detail. The generally accepted relative aromaticity scale for the common five-membered heterocycles featuring one heteroatom versus benzene is: benzene > thiophene > selenophene > pyrrole > tellurophene > furan [21, 22]. Since detailed spectroscopic data, occasionally including complete assignments, are now included in virtually every research paper devoted to pyrroles, there is an immense wealth of information available on the subject [6, 9]. The chemical shifts of the protons attached to the carbon atoms of 1H-pyrroles reflect the aromatic character of this ring system, typically appearing in the range 5.5–7.8 ppm. Concentration and solvent dependence accounts for the considerable range of measured values for the proton attached to the nitrogen atom, which is often observed as a broad, sometimes even barely discernible peak. Likewise, much information on 13 C NMR spectroscopy on pyrroles has been collected and evaluated in detail. The 13 C resonances of 1H-pyrroles lie in the aromatic region, and the shifts depend on the electronic effects transferred from the substituents. Alkyl- [9] or aryl [23] substituents at the nitrogen atom usually have only limited influence on the ring carbon chemical shifts regardless of their properties, whereas the presence of electron-withdrawing groups can cause relatively large downfield shifts of the resonances; the magnitude of this effect increases with the electron-withdrawing power of the N-substituent [24]. The tetrahedral carbon of 2Hpyrroles usually resonates at 78–98 ppm, in contrast to its counterpart in 3H-pyrroles, which appears in the range 49–70 ppm. The resonances originating from the C¼N carbon in 2H- and 3H-pyrroles appear at 161–185 and 173–191 ppm, respectively [9]. The continuous development of two dimensional NMR experiments, such as gradient enhanced 15N-HMBC, allows practical measurement of 15 N chemical shifts and 1 H
15 N couplings in pyrrole derivatives. The 15 N chemical shifts of pyrroles fall in the approximate d range between
186 and
236 ppm, and may vary considerably due to influence from the solvent; this should be kept in mind when data recorded in different media are compared [25]. 4.2.2 Fundamental Reactivity Patterns

The propensity of pyrrole to react by electrophilic substitution imparts a dominant effect on its general reactivity patterns. Pyrrole itself, as well as simple nondeactivated derivatives thereof, is susceptible to undergo reactions with electrophiles

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predominantly at C2 (a-position). Certain substituted pyrroles will, however, react with electrophiles selectively at C3, provided that an electron-withdrawing group is present at the nitrogen or at C2, or when both a-positions are blocked. Consequently, electrophilic substitution is a very useful tool for elaboration of pyrrole derivatives. An inspection of the Wheland intermediates resulting from attack on a suitable electrophile (E þ ) at C2 (2) or C3 (3) gives an explanation to the preferred C2 substitution pathway observed for simple pyrroles, as the intermediate 2 is stabilized to a higher degree by more extensive delocalization of the positive charge (Scheme 4.1). Computational data on the differences in the total energy of pyrrole and the possible cationic s-complexes formed upon its protonation, performed using for example the ab initio RHF/6-31G(d) and the DFT B3LYP/6-31G(d) methods [26], are in coherence with the experimental observations. H E N H 2

E N H

H

H

E

E

E N H

H

N H 3

H

N H

Scheme 4.1

The electron rich nature of most pyrroles is further manifested by their reluctance to participate in nucleophilic substitution reactions. The intrinsically low reactivity of pyrroles towards nucleophilic regents may, however, be enhanced upon protonation, or introduction of strongly electron-withdrawing substituents. Synthetically useful reactions of pyrroles may also be performed with radical reagents, leading to selective substitution at C2 under special conditions (Section 4.5.7). Pyrrole reacts readily with strong bases giving the pyrrolyl anion 4 (Scheme 4.2). This ambident nucleophile is also of considerable synthetic importance, as it allows introduction of substituents in particular at the nitrogen atom, but also at the carbon atoms. In contrast, pyrroles possessing appropriate N-blocking substituents are usually metallated at C2, providing access to a wide variety of 2-substituted

-H+

Z+

N H

N

1

4

RLi

R1

R2

N Z R2 R1

E

N Z Li

X

Z N

Scheme 4.2

Li

N Z

N Z

E+

RLi

E E

N Z

+

N Z

4.3 Relevant Natural and/or Useful Compounds

j273

derivatives upon quenching with suitable electrophiles. Metallation of pyrroles at C3 is conveniently accomplished by halogen–metal exchange using 3-halopyrroles incorporating a bulky N-protecting group, which effectively blocks access to C2. Owing to its aromatic character, pyrrole itself does not participate in Diels–Alder reactions, instead giving a-substitution products. However, this reactivity path may be precluded by introduction of an electron-withdrawing group on the nitrogen atom, thereby transforming the pyrrole nucleus into a useful diene component in Diels– Alder reactions. Examples of reactions where pyrroles act as dienophiles are quite rare, but have nevertheless found some applications. Taken together, these fundamental reactions, combined with reductions, oxidations, classical functional group interconversions, pyrrole ring syntheses, as well as modern developments, such as transition metal catalyzed couplings, constitute a powerful arsenal of tools for the preparation and elaboration of a wide array of pyrrole derivatives. Additional aspects on the reactivity of the pyrrole nucleus are discussed in appropriate sections of this chapter.

4.3 Relevant Natural and/or Useful Compounds

The pyrrole nucleus is an essential component of several naturally occurring macrocyclic complexes of various metals of utmost importance for living systems by virtue of its ability to participate in coordination of metals. One molecule belonging to this class, chlorophyll-a (5), is a crucial prerequisite for sustaining life on our planet by its ability to participate in the conversion of carbon dioxide into carbohydrates with concomitant liberation of molecular oxygen by photosynthesis. The total synthesis of chlorophyll-a (5) conducted by Woodward constitutes one of the most prominent achievements in organic chemistry [27]. This, and several related pigments, is biosynthesized from the common building block porphobilinogen (6) [28–30]. Likewise, the amino acid L-proline is ubiquitous in biologically important peptides and proteins, as well as other natural products. In addition, numerous naturally occurring compounds incorporating derivatives of proline have been identified [31]. Detailed mechanisms for some of the intricate biosynthetic pathways responsible for pyrrole ring formation and incorporation of pyrrole units in natural products have been formulated [32]. Me

Et

CO2H

O

Me

N

N Mg

CO2Me

N

N

O Me

Me 5

O

H2N Me

Me

Me

N H 6

CO2H

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There are many other pyrrole based molecules of natural and of synthetic origin that exhibit various biological activities. The cytotoxic pyrrole alkaloid roseophilin (7) [33] is an excellent example of such a compound, and has also attracted considerable attention as a challenging target for total synthesis [34]. An increasing group of naturally occurring pyrrole derivatives feature the tetramic acid motif as the main structural element [35, 36], as illustrated by the plasmodial pigment fuligorubin A (8) isolated from the slime mold Fuligo septica [37]. The field of monopyrrolic natural products, including tetramic acid derivatives, has been comprehensively reviewed [38]; an account detailing recent synthetic strategies towards antitumor pyrroles bearing oxygenated aryl groups is also available [39]. Distamycin (9), an antiviral and antimitotic natural product isolated from a Streptomyces sp. [40], has served as a model compound for fruitful studies towards synthetic pyrrole containing polyamides for recognition [41–44] and sequence specific alkylation [45] of DNA. The development of ketorololac (10), a drug with potent anti-inflammatory and analgesic properties [46, 47], demonstrates the importance of synthetic pyrroles in medicinal chemistry. OMe

O

i-Pr

Cl

Me N

O

O

N

NH 7 HN

Me

8

HO2C

CHO

O

H N

N

HO

H N

O N Me

O 9

N

NH2 N H

Me

NH2

Ph O

N

CO2H

10

Pyrrole polymers constitute yet an additional group of derivatives that have captured considerable interest, for instance as new materials for electrocatalysis [48], or conducting polymer nanocomposites [49]. Accounts concerning syntheses (e.g., by electropolymerization [50]), properties and applications of polypyrroles are also available [51, 52].

4.4 Pyrrole Ring Synthesis

Numerous different approaches for the construction of pyrrole derivatives from acyclic materials have arisen from over one century of intense research activity in this particular field. Nevertheless, new developments, as well as further extensions of known methods still continue to attract the attention of synthetic chemists, providing

4.4 Pyrrole Ring Synthesis

additional effective routes to previously known pyrroles, as well as novel, and more exotic, derivatives. This section focuses particularly on general processes of practical importance. Selected syntheses of more specialized derivatives, such as oxypyrroles, aminopyrroles, pyrrolines and pyrrolidines, are incorporated in the sections devoted to these systems. A review detailing many recent advances in pyrrole ring synthesis since 1995 is available [52], whereas a more specialized account provides a survey of routes to pyrroles bearing two aryl or heteroaryl groups on adjacent positions [53]. 4.4.1 Paal–Knorr Synthesis and Related Methods (4 þ 1 Strategy)

The Paal–Knorr pyrrole synthesis [54, 55] deserves particular recognition as one the most valuable of all pyrrole ring forming reactions, as it relies on the condensation of 1,4-dicarbonyl compounds with primary amines or their equivalents, both of which are quite common and readily available materials. In an illustrative example, the 2,5dioxohexanoate derivatives 11 are efficiently converted into the corresponding pyrroles 12 upon treatment with appropriate amines in the presence of acetic acid (Scheme 4.3) [56].

MeO2C

O O

R2

R1NH2, AcOH, MeOH 50-60 °C

MeO2C

65-96%

11

N R1

R2

12

Scheme 4.3

The versatility of the Paal–Knorr reaction is neatly demonstrated by the conversion of cyclododecane-1,4-dione into a pyrrole containing cyclophane [57], or transformation of the c-ketoaldehyde 13 into the bicyclic system 14 in a key step of a synthesis of the bacterial tripyrrole pigment metacycloprodigiosin (Scheme 4.4) [58]. Modern applications emerge continuously, and allow for instance synthesis of 1-aminopyrrole derivatives by using monoprotected hydrazines [59] or N-aminophthalimide [60] as the amine components. A variant employing amine hydrobromides in refluxing pyridine is available [61], and an efficient synthesis of cyclopenta[b]pyrroles from suitable diketones with hexamethyldisilazane (HMDS) as the ammonia equivalent in

Et

O

OHC 13 Scheme 4.4

(NH4)2CO3, H2O, DMF 115 °C 58%

Et

N H 14

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the presence of Al2O3 has also been described [62]. Other useful extensions involve montmorillonite KSF clay [63], titanium isopropoxide [64] or iodine [65] as the catalysts. The Paal–Knorr synthesis has recently been performed under microwave irradiation [66–68], and has also been adapted to the solid phase employing immobilized 1,4-diketones [69]. A solution phase combinatorial approach has also been presented, involving construction of the 1,4-diketones from methyl esters by reaction with an excess of vinylmagnesium bromide in the presence of CuCN, followed by oxidation of the alkene unit in the resulting homoallylic ketones using O2/PdCl2/CuCl in aqueous DMF [70]. The mechanism of the Paal–Knorr condensation has been scrutinized in detail, here exemplified by the conversion of the substituted 2,5-hexanediones 15 into the 2,5-dimethylpyrrole derivatives 16, which appears to involve the intermediacy of the aminals 17, which undergo cyclization to the diols 18, followed by elimination of two equivalents of water (Scheme 4.5). These conclusions were supported by meticulous kinetic studies [71], as well as probing of the influence of the stereochemistry of the starting 1,4-dicarbonyl compounds [71, 72]. The reversibility of this series of events has recently been demonstrated by conversion of various pyrroles into the corresponding 1,4-dicarbonyl compounds by heating at pH 3, which allows exchange of the N-substituent [73]. R1 Me

R2

O O

R1 NH3

Me

Me

HO

Me O HO NH2

15

Me

17 R1

-H2O

R1

R2

Me

OH

R1 -H2O

Me

N H

OH Me

18

R2 N H

R2

Me

R2 N H

Me

16 Scheme 4.5

This versatile method may also be utilized for the synthesis of 2H-pyrroles, as demonstrated by conversion of the 1,4-diketone 19 into the product 20 (Scheme 4.6). The series of events leading to this outcome involves the intermediacy of the

Me Me

Me

O O 19

Scheme 4.6

Me

NH4OAc, AcOH 60 °C, 14 h

Me Me

Me N 21

Me Me

50%

Me Me

N 20

Me

4.4 Pyrrole Ring Synthesis

3H-pyrrole 21, which undergoes rearrangement to the 2H-pyrrole 20 due to the acidic reaction conditions in combination with heating. Nonetheless, this approach can in certain cases enable isolation of the 3H-tautomers [74]. A review detailing the early advances in the chemistry of 2H- and 3H-pyrroles is available [75]. A useful extension of the Paal–Knorr reaction is based on the cyclization of 2,5dimethoxytetrahydrofuran (22) with primary amines, providing facile access to Nsubstituted pyrroles (e.g., 23) (Scheme 4.7) [76, 77]. This process is further facilitated by using phosphorus pentoxide as the catalyst [78], or by heating in acetic acid under microwave conditions [79]. It has also been demonstrated that cyclizations involving 22 and amine components incorporating sensitive substituents proceeds in acceptable yields when carried out in a medium containing acetic acid and pyridine via a path featuring acid–base catalysis [80]. Application of arylsulfonamides as the amine synthons constitutes a useful route to 1-(arylsulfonyl)pyrroles [81]. Likewise, heating of 2,5-dimethoxytetrahydrofuran-3-carbaldehyde with ethyl carbamate [82] or p-toluenesulfonamide [83] under acidic conditions gives the corresponding Nsubstituted pyrrole-3-carboxaldehydes. Treatment of the related four-carbon precursor 2,5-dimethoxy-2,5-dihydrofuran with amines in 10% aqueous HCl gives the corresponding N-substituted 3-pyrroline-2-ones in good yield [84]. Initial hydrolysis of 22 in water to 2,5-dihydroxytetrahydrofuran, followed by reaction with primary amines in an acetate buffer, constitutes an additional modification that permits a broader range of N-substituents because of the less acidic conditions [85].

MeO

O

OMe

PhNH2, AcOH reflux 75%

22

N Ph 23

Scheme 4.7

Relatively mild conditions have also been employed in some related syntheses, wherein exposure of 1,4-dichloro-1,4-dimethoxybutane (24) to amino acids [86], or primary amides [87], led for example to the pyrrole 25, or 1-acylpyrroles, respectively (Scheme 4.8). OMe Cl

Cl

OMe 24

EtCO2CH2NH2·HCl CH2Cl2, Amberlyst A-21 0 °C to rt 92%

N CO2Et 25

Scheme 4.8

The Paal–Knorr condensation has also been incorporated as the key step in multicomponent approaches to pyrroles. A one-pot procedure, involving initial formation of the highly substituted 1,4-dicarbonyl compounds 26 from acylsilanes and a series

j277

j 4 Five-Membered Heterocycles: Pyrrole and Related Systems

278

of a,b-unsaturated ketones in the presence of the thiazolium salt 27 as the catalyst, is completed by ring closure using primary amines to the target pyrroles 28 (Scheme 4.9), featuring for example multiple aryl substituents [88]. A similar approach includes palladium-catalyzed coupling of aryl halides with propargylic alcohols, giving a,b-unsaturated ketones, which thereafter undergo thiazolium salt catalyzed Stetter reactions with aldehydes to provide the requisite 1,4-diketone precursors [89]. R2COSiMe3

27 (20 mol%) DBU, THF, i-PrOH

O R3

R4

R2

O

R3

R5

R1NH2 p-TsOH 4Å ms

O

R4

R5

54-82%

R4 R5

26

R3 N R1

2

R

S

HO Me

N Br Et 27

28

Scheme 4.9

4.4.2 Other Cyclizations of Four-Carbon Precursors (5 þ 0 and 4 þ 1 Strategies)

Apart from the classical and modern variants of the Paal–Knorr reaction outlined above, several related approaches involving cyclization of four-carbon precursors are available. Generation of the c-nitroketones 29 bearing an additional ester functionality geminal to the nitro group by Michael addition of ethyl nitroacetate to suitable enones, and subsequent cyclization thereof with formamidinesulfinic acid and triethylamine, gives the pyrrole-2-carboxylates 30 (Scheme 4.10), via the intermediacy of the oximes or imines 31 (X¼NOH or NH) [90]. NH

R1 EtO2C

O2N O 29

R2

H2N

R1

SO2H

Et3N, i-PrOH

EtO2C

X O 31

R1 R2

45-89%

EtO2C

N H

R2

30

Scheme 4.10

In contrast, reductive cyclization of the precursors 32, available by conjugate addition of 2-nitropropane to a,b-unsaturated ketones, gives the pyrrolidines 33, which may thereafter be converted into the corresponding 2H-pyrroles 34 upon dehydrogenation with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (Scheme 4.11) [91]. Suitable four-carbon precursors may also be prepared from the a-aminoaldehydes or -ketones 35, which are readily available from N-Boc-a-amino acids by conversion

4.4 Pyrrole Ring Synthesis Raney Ni (cat.) H2 (1 atm.) EtOH, rt, 12-16 h

R1 Me Me O2N O

R2

R1 Me

R2

N H

Me

32

j279

R1

DDQ (2.2 equiv.) 1,4-dioxane, rt, 12-24 h

Me

55-81%

Me

33

N 34

Scheme 4.11

into Weinreb amides, followed by reduction with LiAlH4 or treatment with Grignard reagents, respectively. Thus exposure of 35 to lithium enolates of ketones, followed by cyclization of the resulting aldol adducts 36, produced the set of pyrroles 37 (Scheme 4.12), including several fused derivatives, in low to moderate yields [92]. Reductive cyclization of similar aldol intermediates available from a-(N,N-dibenzyl) amino aldehydes or ketones has been utilized in a related, more high-yielding approach to N-benzylpyrroles [93]. Acid-induced cyclodehydration of Boc-protected c-amino-a,b-enals or -enones derived from N-Boc-a-aminoaldehydes via Wittig reactions provides a route to various 1-(tert-butoxycarbonyl)pyrrole derivatives [94].

O BocHN R1

R2

R3CH2COR4 LDA, THF, -78 °C

BocHN

R3

R2 OH O 3

1

HCl, CH2Cl2

R

R

35

R4

R4

36

R2 R1 N Boc 37

Scheme 4.12

An approach based on a microwave assisted domino process involving primary amines and the alkynoates 38, which are derived from two equivalents of methyl propiolate and suitable aldehydes (R1CHO), results in the pyrroles 39 (Scheme 4.13). The series of events leading to this outcome were suggested to involve rearrangement of 1,3-oxazolidine intermediates as the key feature [95]. A set of structurally related substrates has also been converted into pyrroles bearing multiple substituents by initial silver-catalyzed isomerization of the propargyl moiety to an allene, followed by condensation of the resulting intermediates with primary amines, and final goldcatalyzed 5-exo-dig cyclizations [96].

MeO2C

O R2 38

Scheme 4.13

CO2Me

R1NH2, SiO2 900 W, 8 min 38-74%

R2 MeO2C

CO2Me N R1 39

R2

j 4 Five-Membered Heterocycles: Pyrrole and Related Systems

280

It has been known for some time that pyrroles may be obtained from the reactions of azaallylic anions with suitable a-haloketones [97]. A new application of azaallylic anions in pyrrole synthesis has been realized by conversion of the a-haloimines 40 into the intermediates 41, which in turn are cyclized to the 1-pyrrolines 42, eventually giving the pyrroles 43 (Scheme 4.14), including the 3-chloro derivative (R2¼Ph, R3¼Cl) [98].

N

R3

1. LDA, HMPA THF, -78 °C 2. ICH2CH2N3 -78 °C to rt

R1 R2

Cl

R3

N

R2 N3

Cl

77-96%

40 R1 = i-Pr or t-Bu

R1

R3

SnCl2 MeOH

N

76-97%

41

42

Cl R2

R3

NaOMe, MeOH reflux 78-98%

N H 43

R2

Scheme 4.14

Several approaches based on cyclization of propargylamines and homologues thereof have emerged in recent years. Base induced cyclization of the benzotriazol-1yl (Bt) substituted precursors 44, which are readily available from 1-propargylbenzotriazole, gives the corresponding pyrroles 45, presumably via allene intermediates (Scheme 4.15) [99]. Rhodium-catalyzed hydroformylation of 1,3-disubstituted propargylamines affording 2,4-disubstituted pyrroles has also been accomplished [100]. Bt

NaOH, EtOH 90 °C

Ar 44

NHTs

45-60%

N H 45

Ar

Scheme 4.15

Homopropargylamines, which are available, for instance, by addition of propargylic Grignard reagents to Schiff bases, are also useful precursors, as exemplified by the silver(I) mediated conversion of 46 into the pyrroles 47 (Scheme 4.16) [101]. A synthetic route to pyrroles involving cyclization of homopropargylamines generated in situ by ring opening of ethynylepoxides with amines has also been described [102]. TMS R2 46

NHR1

AgOAc, CH2Cl2 78-99%

N R1 47

R2

Scheme 4.16

Annulation of the homopropargylic sulfonamides 48 (R¼Ph, 2-furyl, 2-thienyl), which are prepared by alkylation of the benzophenone imine of methyl glycinate with propargyl bromide, followed by sequential hydrolysis, tosylation and Sonogashira

4.4 Pyrrole Ring Synthesis

j281

coupling at the terminal acetylene unit, has been reported to give the substituted 4iodo-2,3-dihydropyrrole derivatives 49 via a 5-endo-dig process, eventually leading to the b-iodopyrroles 50 (Scheme 4.17) [103, 104], whereas cyclization of related alkenyl derivatives provides access to b-iodopyrrolidine derivatives [105]. R

I2, K2CO3 (3 equiv. each) MeCN, 0-20 °C

NHTs

MeO2C

7 4-7 8 %

I R

48

N Ts

CO2Me

DBU (2.1 equiv.) DMF, rt 85-90%

I R

49

N H 50

Scheme 4.17

Azadienes 51 may also serve as starting materials for construction of pyrroles, as C-alkylation thereof provides the intermediates 52, which undergo annulation to the pyrroles 53 upon heating in toluene or ethanol. A subsequent hydrolysis step completes this synthesis, resulting in the 3-acetylpyrrole derivatives 54 in excellent overall yields (Scheme 4.18) [106, 107]. An approach to, for instance, 1,2,3,5-tetrasubstituted pyrroles, utilizing thermally induced cyclization of iminoalkyne intermediates derived from various substituted 4-pentynones and suitable amines, has also been reported [108, 109].

R2 NHR1 R3

NH 51

X

1. BuLi, THF 2.

NHR1

Br

R2 R3

PhMe or EtOH,

Me

NH 52

HCl, H2O

N R1

R3 R2

53 X = NH 54 X = O

Scheme 4.18

4.4.3 Knorr Synthesis and Related Routes (3 þ 2 Strategy)

The Knorr pyrrole synthesis [110], which relies on the condensation of an a-aminoketone with a carbonyl compound possessing acidic a-hydrogens (each contributing with a two-carbon fragment to the pyrrole ring) is also of considerable synthetic importance. Since a-aminoketones are rather reactive and difficult to handle, the practical procedures often involve generation thereof in situ from a suitable synthetic equivalent, as illustrated by the classical example below (Scheme 4.19), in which addition of one equivalent of sodium nitrite to two equivalents of ethyl acetoacetate (55) generates an oxime, which, upon reduction with zinc dust [110, 111] or

CO2Me

j 4 Five-Membered Heterocycles: Pyrrole and Related Systems

282

O Me

Me

1. NaNO2 (0.5 equiv), AcOH, 5 °C 2. Zn, AcOH, reflux

O OEt

EtO2C

55

CO2Et N H 56

Me

Scheme 4.19

dithionite [112], undergoes condensation with the remaining equivalent of 55 to furnish the pyrrole 56 in excellent yield (Scheme 4.19). It has also been demonstrated that this reaction may follow a different path if a b-diketone is used as one of the reactants, as treatment of diethyl oximinomalonate (57) with 2,4-pentanedione (58) under reductive conditions will afford ethyl 3,5dimethylpyrrole-2-carboxylate (59) [113]. Since this process involves the intermediacy of diethyl aminomalonate (60), the reductive conditions can be avoided by using this very reagent. The mechanism is considered to feature an initial formation of the aminal 61, followed by elimination of water to form the enamine 62, which will cyclize on the ketone carbonyl carbon to provide 63, eventually leading to the final product 59 (Scheme 4.20) [114, 115]. The use of unsymmetrical 1,3-diketones instead of 2,4-pentanedione usually gives mixtures of regioisomeric pyrroles, unless relatively bulky groups (i-Pr, t-Bu, Ph) are present at the terminal carbon [116]. Many substituted pyrrole-2-carboxylate derivatives obtained using these procedures may be readily converted into further derivatives by decarboxylation (Section 4.6.2).

NOH EtO2C

57

CO2Et

H3CCOCH2COCH3 58 Zn, AcOH 60%

Me Me

Zn

N H 59

CO2Et -CO2, -EtOH

Me

Me NH2 EtO2C

58

CO2Et

O CO2Et Me N CO2Et HO H

60

61

-H2O

Me

Me

O CO2Et N H 62

CO2Et

Me

N H

OH CO2Et

CO2Et

63

Scheme 4.20

A modern modification of the Knorr pyrrole synthesis involves elaboration of Weinreb amides, for instance 64, derived from phenylalanine, giving the protected a-aminoketone 65, which can subsequently be deprotected and condensed with 2,4pentanedione to provide the pyrrole 66 (Scheme 4.21) [117]. Reaction of similar Weinreb amides lacking the Boc group with enamines gives N-methoxy-N-methyla-enaminocarboxamides, which take part in related conversions into a-enaminoketones, and ensuing annulations to pyrroles [118].

4.4 Pyrrole Ring Synthesis

O OMe

Ph BocHN

N Me

O

MeMgBr Et2O

Ph BocHN

74%

64

1. HCl (g), CH2Cl2 2. MeCOCH2COMe NaOAc, AcOH, 80 °C Me 58%

j283

COMe

Me Bn

N H 66

65

Me

Scheme 4.21

In a related approach involving an initial C
N bond formation between two C2fragments, addition of the a-aminoketones 67 to dimethyl acetylenedicarboxylate (DMAD) yields the intermediates 68, which finally undergo cyclization to give pyrroles 69 (Scheme 4.22) [119]. A related procedure involving initial reactions of a-amino acid esters with DMAD, and cyclization of the intermediate enamines with sodium methoxide in methanol rendering 3-hydroxypyrroles 69 (R1¼OH), has also been reported [120].

R2

1

R

NH2·HCl

O

DMAD, NaOAc MeOH or PhH reflux

R1

MeO2C R2 O

67

N H

R1 R2

CO2Me

68

CO2Me N H

CO2Me

69

Scheme 4.22

A series of 2-substituted 3-nitropyrroles (70) has been prepared by displacement of a methylthio group of the nitroalkene 71, followed by treatment of the resulting products 72 with aminoacetaldehyde dimethylacetal to furnish the intermediate enamines 73, which underwent a final ring closure in acidic medium (Scheme 4.23) [121]. Intermediates similar to 73 featuring a trifluoroacetyl group instead of the nitro functionality have previously been prepared from b-(trifluoroacetylvinyl) ethers and aminoacetaldehyde dimethylacetal, and were cyclized to the corresponding 3-trifluoroacetylpyrroles in aqueous TFA [122].

NO2

SMe

SMe 71 Scheme 4.23

RMgX, CuI, TMSCl Et2O, THF, -78 °C 65-71%

NO2 R 72

H2NCH2CH(OMe)2 SMe EtOH, reflux

O2N MeO R

N H 73

OMe

HCl Et2O 0-5 °C 51-69%

O2 N R

N H 70

j 4 Five-Membered Heterocycles: Pyrrole and Related Systems

284

4.4.4 Hantzsch Synthesis and Related Approaches (2 þ 2 þ 1 or 3 þ 2 Strategy)

A conceptually related process involving two C2-fragments and an amine component is the Hantzsch pyrrole synthesis (Scheme 4.24) [123]. In a typical procedure, a mixture consisting of an a-halo carbonyl compound (74) and ethyl acetoacetate (75) is treated with ammonia. This initially gives the enamine 76 derived from the b-ketoester, which will subsequently undergo cyclization with 74 to provide pyrrole 77 [124]. Application of b-aminoacrylonitriles as the enamine counterparts has been used to prepare 5-(trifluoromethyl)pyrrole-3-carbonitrile derivatives [125]. A solid phase variant utilizing an immobilized enamino component has also been developed [126].

Br OHC

OEt

O Et

NH3, H2O

O

74

Br OHC

O Et

Me 75

H2N

74

OEt

Et 45%

Me 76

CO2Et N H

Me

77

Scheme 4.24

It has also been demonstrated that titanium mediated annulation of substrate 78, which is available in two steps from the appropriate 1,3-dicarbonyl compound, gives a good yield of 2,3,5-triphenylpyrrole (79) (Scheme 4.25). Similar precursors have also been cyclized in the presence of a preformed titanium–graphite reagent [127]. Ph O

HN

Ph

O Ph

78

Ph

TiCl3, Zn, THF reflux, 3 h 78%

Ph

N H

Ph

79

Scheme 4.25

4.4.5 Syntheses Involving Glycine Esters (3 þ 2 Strategy)

Several useful routes to pyrroles are based on the reactions of glycine esters or related compounds with suitable C3-synthons. For example, condensation of ethyl glycinate hydrochloride (80) with the 1,3-diketone 81 provides access to the pyrrole 82 [128] via the enaminoketone intermediate 83 (Scheme 4.26). Such intermediates may also be isolated in a stepwise approach involving milder conditions [129], whereas cyclization of related condensation products generated from 3-ethoxyacrolein derivatives and N-substituted glycine esters gives 2,4-disubstituted pyrroles [130].

4.4 Pyrrole Ring Synthesis

CO2Et

O

NH2·HCl

O

80

Ph DMF, reflux

EtO2C

Ph 81

O HN 83

j285

Ph

Ph

EtO2C

74%

Ph

N H

Ph

82

Scheme 4.26

Likewise, it has been demonstrated that p-toluenesulfonylglycine esters 84 undergo addition to a,b-unsaturated ketones 85 to render pyrrolidines 86, which will eventually furnish pyrroles 87 by sequential elimination of water and p-toluenesulfinate, via the suggested 3-pyrroline intermediates 88 (Scheme 4.27) [131, 132].

TsHN

84

CO2R4 R1

O R3

DBU THF

R3

R2 R1

CO2R4

N Ts

R2 85

OH

POCl3 pyridine

R2 R1

86

2

R3 N Ts

R DBU PhMe reflux R1 CO2R4 11-70% overall

88

R3 N H

CO2R4

87

Scheme 4.27

Glycine derivatives may also give pyrroles upon treatment with various iminium salts. For example, the reaction of ethyl glycinate hydrochloride (80) with the vinamidinium perchlorates 89 provides 3-arylpyrrole-2-carboxylates (90) in good yields [133]. A related reaction involving the salt 91, which is readily available from 3-acetylthiophene, leads to the thienylpyrrole 92 (Scheme 4.28) [134]. Similar chemistry has also been employed for the preparation of 5-arylpyrrole-2-carboxylates [135] and of various 3,4-disubstituted pyrrole-2-carboxylates [136]. HClO4

Ar

Me2N N H

CO2Et

90

89

Ar

NMe2

NaOEt, EtOH 75-87%

Cl CO2Et NH2·HCl 80

S

91 NaH, DMF 75%

PF6 NMe2 S

Scheme 4.28

4.4.6 Van Leusen Method (3 þ 2 Strategy)

Since its introduction, the van Leusen pyrrole synthesis has enjoyed considerable popularity, as it provides convenient access to 3,4-disubstituted pyrroles from the

N H 92

CO2Et

j 4 Five-Membered Heterocycles: Pyrrole and Related Systems

286

readily available building blocks p-toluenesulfonylmethyl isocyanide (TosMIC) (93) and electron deficient alkenes. Treatment of the anion of TosMIC with the a,b-unsaturated ketones 94 initially gives the intermediate Michael adducts 95. After cyclization to 96, followed by tautomerization to 97, p-toluenesulfinate is eliminated giving the 3H-pyrroles 98, which eventually tautomerize to the final products 99 (Scheme 4.29) [137]. Application of methyl 3-arylacrylates in this approach gives methyl 4-arylpyrrole-3-carboxylates, which may be further converted into the corresponding 3-arylpyrroles by saponification and decarboxylation [138]. A variant involving aryl- or heteroarylalkenes, TosMIC and sodium tert-butoxide in DMSO allows direct access to 3-aryl- or heteroarylpyrroles, respectively, in moderate yields [139]. When acrylonitriles are used as the alkene reactants, pyrrole-3-carbonitriles are produced [137], whereas application of nitroalkenes [140, 141] or tert-butyl (E)-4,4,4-trifluorobutenoate [142] gives the corresponding b-nitropyrrole- or b-(trifluoromethyl)pyrrole derivatives, respectively. Extensions involving substituted TosMIC derivatives offer direct routes to 2,3,4-trisubstituted pyrrole derivatives [143], including 2-stannylpyrroles [144]. The closely related reagent benzotriazol-1-ylmethyl isocyanide (BetMIC) has also been evaluated in similar reactions, and may in some cases give better yields [145]. R2

O Ts

NaH Et2O, DMSO

NC

R1

93

O 94 R2

O

R1 N H 99

Ts

N

7-70%

Ts

C

O

R2

N 96

95 R1

R2

O

R1

R1

O

R1

R2 Ts

N 98

N

R2 H

97

Scheme 4.29

In a further extension of this valuable method, reaction of the 1-isocyano-1-tosyl alkenes 100 with nitromethane in the presence of potassium tert-butoxide enables efficient preparation of the 3-nitropyrroles 101 (Scheme 4.30) [146]. Similar transformations involving suitable substituted ketones instead of nitromethane yield R

NC Ts 100

Scheme 4.30

CH3NO2, t-BuOK, DME 86-94%

R

NO2 N H 101

4.4 Pyrrole Ring Synthesis

j287

various 3,4-disubstituted pyrroles, even such lacking electron-withdrawing substituents [147]. It is also noteworthy that alkenes generated from aldehydes and alkyl isocyanoacetates in the presence of DBU may react with an additional equivalent of the isocyanoacetate component, affording 2-substituted alkyl pyrrole-2,4-dicarboxylates in a convenient one-pot operation [148]. The reactions of TosMIC (93) or the methyl derivative 102 with dienes, for instance 103 [141] or 104 [149], furnish the corresponding substituted 3-vinylpyrroles, 105 and 106, respectively (Scheme 4.31). Treatment of 1,4-disubstituted 2,3-dinitrobutadienes with TosMIC under similar conditions gives 3-alkynylpyrrole derivatives [150]. Ph

O2N

NO2 103

Ph

t-BuOK, THF, -80 °C

Ts

73%

N H 105

PhO2S

SO2Ph 104

R NC

NaH, THF, DMSO, rt 64%

N H 106

93 R = H 102 R = Me

Scheme 4.31

4.4.7 Barton–Zard Synthesis (3 þ 2 Strategy)

The equally versatile Barton–Zard synthesis features an initial conjugate addition of isocyanoacetate esters 107 to nitroolefins 108 in the presence of a base (e.g., DBU), generating the adducts 109, which thereafter undergo cyclization to afford 110. An ensuing isomerization of 110 to 111, followed by elimination of nitrite, provides the 3H-pyrroles 112, which finally tautomerize to the target pyrrole-2-carboxylate derivatives 113 (Scheme 4.32). Sensitive nitroolefins are preferably formed in situ from the corresponding b-nitroacetoxyalkanes [151, 152]. Application of benzyl

RO2C

NC

R1

107

R2

DBU

NO2 108

R1 RO2C

Scheme 4.32

N 109

R1 RO2C

C

RO2C

RO2C

NO2

N 110

R1

R2 N 112

R2

R1

NO2

RO2C

R2 N H 113

R2

R1

R2 N 111

NO2

Me

j 4 Five-Membered Heterocycles: Pyrrole and Related Systems

288

isocyanoacetate in this approach allows efficient preparation of benzyl pyrrole-2carboxylates [153, 154]. Alternatively, the nitroolefin components may be replaced by a,b-unsaturated sulfone derivatives [155–157] or by acetate precursors bearing a vicinal nitro group [158]. A variant of this reaction involving polymer supported reagents has also been developed [159]. Synthesis of the fused pyrrole derivatives 114 and 115 from 9-nitrophenanthrene (116) constitutes an interesting application of the Barton–Zard approach (Scheme 4.33) [160, 161]. Other condensed nitroaromatics, such as 3-nitrobenzothiophene, also give fused pyrrole derivatives under these conditions [162]. In cases where relatively unreactive nitroaromatics are involved, the use of a strong phosphazene base may give improved yields [163]. RCO2CH2NC DBU, THF, rt

CO2R N H 114 R = Et (86%) 115 R = t-Bu (65%)

NO2 116

Scheme 4.33

4.4.8 Trofimov Synthesis (3 þ 2 Strategy)

Various pyrroles have been prepared over the years using the Trofimov synthesis, which relies on cyclization of ketoximes with acetylenes in a strong basic medium [164, 165]. For example, exposure of oxime 117 to acetylene in the presence of KOH in DMSO at elevated pressure and temperature gives the fused pyrrole 118 in excellent yield (Scheme 4.34) [166]. However, the formation of mixtures of Nvinylated products and the corresponding parent pyrroles is a common outcome of this reaction. The N-vinylation may be suppressed by addition of water (about 5%) to the reaction mixture, whereas optimal conditions for synthesis of N-vinylpyrroles require the use of a large excess of KOH [165]. A recent application of this method provided access to 2,6-bis(pyrrol-2-yl)pyridines [167]. Several pyrroles incorporating sulfur containing moieties have been prepared using the Trofimov reaction [168]. H

H

12 atm., 80-90 °C KOH, DMSO

NOH 117 Scheme 4.34

N

quant.

118

4.4 Pyrrole Ring Synthesis

4.4.9 Cycloaddition Reactions and Related Approaches (3 þ 2 Strategy)

1,3-Dipolar cycloadditions between mesoionic compounds and suitable dipolarophiles, for example alkynes, constitute another useful approach to pyrroles [169, 170]. Thus the alkyl- or aryl-substituted m€ unchnones 119, which are readily available from a-amino acids, participate in cycloadditions with acetylene derivatives (e.g., diesters) to provide pyrroles 120, often in excellent yields, through expulsion of carbon dioxide from the intermediate adducts 121 (Scheme 4.35). M€ unchnones may also be generated in situ from N-acyl-a-amino acids and acetic anhydride. Preferably, one of the reactants should be symmetrically substituted, thus avoiding formation of mixtures containing isomeric pyrroles [171, 172]. Nevertheless, regiospecific reactions involving polyfluoro-2-alkynoic acid esters have been reported [173]. The use of N-acylm€ unchnones provides access to N-acylpyrroles as mixtures of isomers [174], whereas 2-arylthio- or alkylthio-substituted 5-amino-1,3-thiazolium salts give 2arylthio- or 2-alkylthiopyrrole derivatives, respectively, upon reaction with dimethyl acetylenedicarboxylate (DMAD) via extrusion of isothiocyanates [175]. Modern, multi-component variants that presumably involve m€ unchnones feature generation of the dipoles from imines, acid chlorides, and carbon monoxide via palladium catalysis [176], or by annulation of products derived from Ugi four-component reactions involving carboxylic acids, primary amines, aldehydes and 1-isocyanocyclohexene [177]. A solid phase version using polymer bound m€ unchnones has also been described. [178] Various aspects concerning the regioselectivity of 1,3-dipolar cycloadditions involving m€ unchnones have been discussed in detail; the outcome appears to be influenced by the electronic nature and location of the substituents on the dipole [179], as well as steric factors [180]. In connection with investigations of regioselective cycloadditions of a certain m€ unchnone with a carbohydrate derived nitroolefin, it was concluded that predictions using frontier molecular orbital theory in combination with semi-empirical studies are not applicable for such processes, and that this particular example proceeded through a concerted, although somewhat asynchronous, transition state, as implied by results from ab initio MO calculations [181].

O R2

R3

O N R1

R2

119

R4

R4 R3

R1 N R2 R2

O

121

R4

R3 O

-CO2

R2

N R1

R2

120

Scheme 4.35

Pyrroles may also be made by cycloaddition of dimethyl 1,2,4,5-tetrazine-3,6dicarboxylate (122) with electron rich alkenes, followed by ring contraction of the resulting 1,2-diazines [182, 183]. In a representative procedure, 122 reacts with

j289

j 4 Five-Membered Heterocycles: Pyrrole and Related Systems

290

1,1-dimethoxyethylene to give intermediate 123, which is subsequently reduced to the pyrrole 124 (Scheme 4.36) [184]. The alkene components may also be replaced with acetylene derivatives [185]. Advances in ring contraction methodology for the construction of pyrroles have been discussed in detail in a specialized review [186]. CO2Me N N

MeO

N N

OMe

1,4 dioxane 25 °C

MeO

CO2Me N N

94%

CO2Me 122

Zn, AcOH 25 °C 68%

MeO MeO2C

CO2Me 123

N H

CO2Me

124

Scheme 4.36

Generation of dipoles from aziridines, and reaction thereof with suitable acetylenes, offers a route to pyrroles [187] that might be otherwise difficult to access. This method has been employed for the synthesis of the 3,4-disilylpyrrole 125 by dipolar cycloaddition of 2-cyano-1-trimethylsilylaziridine (126) with bis(trimethylsilyl)acetylene, followed by N-desilylation of the intermediate product 127 in methanol (Scheme 4.37) [188]. Azomethine ylides generated by desilylation of suitable immonium salts have been demonstrated to add to alkynes, giving pyrroles, or to alkenes to render 2-pyrrolines, which could in turn be further converted into the corresponding pyrroles by treatment with DDQ [189]. Based on a previously reported procedure [190], an approach to pyrroles has been devised that relies on reactions involving alkynes and imines in the presence of Ti(i-OPr)4, i-PrMgCl and carbon monoxide at atmospheric pressure, via azatitanacyclopentene derivatives as intermediates [191].

CN TMSCl, Et3N N H

hexanes

CN N TMS 126

TMS

xylenes 140 °C 85%

TMS TMS

TMS

TMS

TMS

MeOH

N TMS 127

95%

N H 125

Scheme 4.37

An elegant route to pyrroles from isocyanides and electron deficient acetylenes has also become available. In an illustrative example, pyrrole 128 was obtained upon reaction of ethyl isocyanoacetate with alkyne 129 in the presence of dppp [192]. The regioselectivity may be reversed by changing the catalyst to Cu2O, giving instead the product 130 (Scheme 4.38) [193]. A related synthesis of pyrroles involving addition of metallated isocyanides to acetylenes, featuring an intramolecular cycloaddition of an alkene unit with the isocyanide moiety in the initially formed intermediates as the key step, has also appeared [194].

4.4 Pyrrole Ring Synthesis EtO2C EtO2C

Me

dppp (cat.) 1,4-dioxane 100 °C, 2 h

N H

CN Me

60%

CO2Et CO2Et 129

Cu2O (cat.) 1,10-phenanthroline (cat.) 1,4-dioxane, 100 °C, 2 h 64%

Me EtO2C

128

4.4.10 Multi-Component Reactions (2 þ 2 þ 1 Strategy)

Multi-component processes, which are carried out in a one pot operation, have become increasingly popular tools for pyrrole synthesis in recent years. Some of these approaches employ well-known principles for pyrrole ring formation, for example the Paal–Knorr reaction [88], or dipolar cycloaddition of alkynes to m€ unchnones [176, 177] (see above). Samarium-catalyzed three-component coupling of amines, aldehydes and nitroalkanes has been demonstrated to furnish modest to moderate yields of the pyrroles 131 (Scheme 4.39). Two aldehyde units are incorporated in the final products. The aldehydes may also be replaced by a,b-unsaturated aldehydes or ketones in a similar pyrrole ring forming reaction that does, however, not require the use of a catalyst [195]. Likewise, reactions between amines, a,b-unsaturated aldehydes or ketones and nitroethane in the presence of silica [196], or alternatively amines, aldehydes or ketones and nitroalkenes mediated by Al2O3 [197] under microwave irradiation, also produce useful yields of various pyrroles. The latter set of components may also be converted into pyrroles by heating in molten tetrabutylammonium bromide [198].

R2

CO2Et N H 130

Scheme 4.38

R1NH2

j291

CHO

(2.4 equiv.)

R3

NO2

(4 equiv.)

SmCl3 (cat.) THF, 60 °C 8-65%

R2

R2 N R1 131

R3

Scheme 4.39

4.4.11 Miscellaneous Transition Metal Catalyzed Methods (3 þ 2 and 5 þ 0 Strategies)

Transition metal catalyzed/mediated transformations of acyclic precursors to pyrroles have also attracted considerable attention. Although conceptually and mechanistically very interesting, some of these developments still appear to suffer from lack of practical synthetic applicability, involving rather complex starting materials and catalysts. Nevertheless, such procedures are now acknowledged as valuable tools for the preparation of exotic pyrroles having unusual substituents, substitution

j 4 Five-Membered Heterocycles: Pyrrole and Related Systems

292

patterns or oxidation states, which are not easily available via the “classical” procedures. For example, the rhodium-catalyzed reaction of 3-fluoropentane-2,4-dione (132) with ethyl isocyanoacetate furnished the fluoropyrrole 133 (Scheme 4.40), whereas the use of unsymmetrical 1,3-diketones gave, in most cases, mixtures of regioisomeric pyrroles [199]. Me F Me

O

CNCH2CO2Et Rh4(CO)12 (cat.) PhMe, 80 °C

O

Me

CO2Et

Me -CO

NHCHO O

F Me

F Me

CO2Et NH2 O

Me

F 40%

Me

132

CO2Et

N H 133

Scheme 4.40

Metallation of N-allylbenzotriazole 134, followed by treatment with imines provided the intermediates 135, which were thereafter converted into the 1,2diarylpyrroles (136) by palladium-catalyzed annulation (Scheme 4.41) [200]. This approach resembles a previous route featuring lithiation of 1-(3-morpholinoprop-2enyl)benzotriazole, wherein the final cyclization could be effected under acidic conditions [201]. Ar2

1. BuLi, THF, -78 °C

2. Ar2CH=NAr1, -78 °C

Bt

Bt

N H

52-85%

134

Ar1

Pd(OAc)2 (cat.), CuCl2 PPh3, K2CO3, THF, reflux 21-79%

135

N Ar1

Ar2

136

Scheme 4.41

Copper assisted cycloisomerization of the alkynylimines 137 gave useful yields of 1,2-disubstituted pyrroles 138. This reaction tolerates substituents with rather sensitive moieties, such as TBS-ethers [202]. In a similar process, starting from related alkynylimines 139 possessing an additional arylthio- or alkylthio-substituent geminal to R2, 2-alkyl-3-thio-substituted pyrroles 140 were produced in good yields via 1,2migration of the thio group in intermediate thioallenylimines (Scheme 4.42) [203]. CuI (30 mol%), Et3N/DMA (1:7) 110 °C (for X = H) or CuI (cat.), DMA, (for X = SR3)

R2 N R1

X

137 X = H 139 X = SR3 Scheme 4.42

50-93%

X R2 N 1 R 138 X = H 140 X = SR3

4.5 Reactivity

The (Z)-(2-en-4-ynyl)amines 141 undergo Pd(II) [204, 205] or Cu(II)-catalyzed cycloisomerization to the pyrroles 142 (Scheme 4.43). The copper-catalyzed reactions require higher temperatures. Interestingly, the less stable of the substrates 141 (R4¼H, Ph, CH2OTHP) underwent spontaneous cycloisomerization to the target heterocycles [205]. R3 R2

R4

NH

R1

Pd(II) (cat.) DMA, 25-50 °C

R3 R2

R5

141

R4 R5 N R1 142

Scheme 4.43

4.5 Reactivity 4.5.1 Reactions with Electrophilic Reagents 4.5.1.1 General Aspects of Reactivity and Regioselectivity in Electrophilic Substitution As indicated in Section 4.2.2, pyrrole is prone to undergo electrophilic substitution predominantly at the a-position (C2). Introduction of substituents alters both regioselectivity and reactivity by changing the electronic properties of the pyrrole nucleus by inductive effects, and sometimes also by steric interactions with the incoming electrophile. The transmission of electronic substituent effects in pyrroles appears to occur through the carbon atoms rather than via the ring nitrogen [206]. For example, it has been demonstrated that 2-methylpyrrole (R2¼Me; Figure 4.1) undergoes trifluoroacetylation at C5 some 23.8 times faster than pyrrole itself [207], whereas the reactivity of 1-methylpyrrole (R1¼Me; Figure 4.1) towards trifluoroacetic anhydride in 1,2-dichloroethane at 75  C is only 1.9 times higher than that of the

R3 N H

R2

N R1

N TIPS

N H Z3

N SO2Ph

N H

Z2

N H

Figure 4.1 Transmission of electronic substituent effects in pyrroles.

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j 4 Five-Membered Heterocycles: Pyrrole and Related Systems

294

R3 R2

R2

N H

R3

R4(Z4)

Z3 R2(Z2)

N H

N H

R2

N H

Z5

Z4 N H

Figure 4.2 General trends of regioselectivity of electrophilic substitution of disubstituted pyrroles.

parent heterocycle [208]. Pyrroles having an electron releasing group at C3 (R3) display enhanced reactivity both at C2 and C4, but the C2 position is still the most active because of the influence of the ring nitrogen. The introduction of a bulky N-substituent, for instance triisopropylsilyl (TIPS) [209] or trityl [210], gives access to C3 substituted or C3, C4 disubstituted products by blocking the intrinsic a-reactivity by steric interference. Substitution with high selectivity at C3 may also often be obtained with pyrroles having powerful electron-withdrawing substituents at the nitrogen, for example the phenylsulfonyl group [211]. Such electron deficient substrates are also considerably less reactive towards electrophiles than non-deactivated pyrroles. The presence of a strong “meta” directing, electron-withdrawing groups (Z2) at C2 [212] or at C3 (Z3) will direct substitution to C4 or C5, respectively. The general effects of various directing groups in monosubstituted pyrroles are summarized in Figure 4.1 (R¼alkyl, Z¼electron-withdrawing substituent). Additional examples, as well as special cases that deviate from the common pathways are discussed in appropriate sections below. Prediction of the regioselectivity of electrophilic substitution of disubstituted pyrroles is more complicated, as the outcome is dependent on the combined influence of the substituents. There are also cases when the effects of sterically demanding substituents must be taken into account. Detailed studies of the reactivity of such systems have been conducted [213, 214]; Figure 4.2 depicts the general trends. 4.5.1.2 Protonation In acid solution, pyrrole (1) undergoes reversible protonation, predominantly at C2, giving the thermodynamically favored 2H-pyrrolium cation 143, which is stabilized by mesomeric delocalization of the charge (Scheme 4.44). The pKa of
3.80 has been determined for protonation in dilute sulfuric acid solution [215]. It has also been demonstrated that protonation of pyrrole with the mild acids C4H9 þ and NH4 þ in the gas phase occurs at C2, as well as at C3, giving the isomeric 3H-pyrrolium cation 144, and that the affinity for protonation is higher at C2 [216]. The virtually nonexistent N-basicity of pyrrole may be rationalized in terms of the absence of

H N H

H

143 Scheme 4.44

H+

H+

N H 1

H

H N H 144

4.5 Reactivity

j295

mesomeric charge delocalization in the putative 1H-pyrrolyl cation, and the unavailability of the electron pair on the pyrrole ring nitrogen due to its contribution to the aromatic p-electron sextet. This is supported by the fact that the dipole moment of pyrrole is directed into the ring, as opposed to its tetrahydro derivative pyrrolidine, which displays a dipole moment direction towards the nitrogen atom [4]. Based on observations during protonation studies involving various substituted pyrrole derivatives [215, 217], it is clear that the basicity is markedly increased by introduction of alkyl groups by stabilizing the corresponding cations. The presence of tert-butyl groups even allows isolation of stable 2H-pyrrolium salts, for example 145, which was obtained in quantitative yield as a crystalline solid from pyrrole 146 (Scheme 4.45) [218].

t-Bu

N H

t-Bu

BF4

H

HBF4, Et2O

t-Bu

146

N H

t-Bu

145

Scheme 4.45

Although the 3H-pyrrolium cation 144 is the less stabilized, and thus also the less abundant of the two C-protonated species, it is nevertheless very important, as it plays a major role in the acid-catalyzed oligomerization and polymerization of pyrrole because of its higher reactivity. The electrophilic cation 144 undergoes attack by pyrrole (1), thereby forming the unstable dimeric enamine 147 (Scheme 4.46). Protonation thereof generates a new electrophilic intermediate 148, which reacts with an additional equivalent of pyrrole (1), rendering the isolable trimer 149 (ratio trans : cis of 2 : 1) [219], which may subsequently participate in further reactions, eventually giving polymeric products [220], for example fully aromatic polypyrrole [221], unless careful control of the conditions is maintained, and, therefore, the reaction allowing isolation of 149 is performed at 0  C in 20% aqueous HCl [219]. The propensity of non-deactivated pyrroles to undergo polymerization makes such substrates unsuitable for reactions that involve strongly acidic conditions.

H

H H+

1

N H 144

N H

N H 147

1

N H

N H 148

N H

H N 149

Scheme 4.46

4.5.1.3 Halogenation Many electron rich halogenated pyrroles are rather unstable compounds that decompose readily upon exposure to air. Hence, in the early days, the availability

N H

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296

of such pyrrole derivatives was severely limited, although syntheses of several relatively stable iodinated pyrroles, for example 2,3,4,5-tetraiodopyrrole [222], as well as some other bromo- or iodopyrroles featuring additional electron-withdrawing substituents were described [223, 224]. An early study on the bromination of methyl pyrrole-2-carboxylate and pyrrole-2-carboxaldehyde under various conditions clearly demonstrated that formation of mixtures containing several halogenation products is a common course of many of these reactions, thus illustrating yet another complicating factor [225]. The labile 1-chloropyrrole, generated in 65–72% yield by chlorination of pyrrole with NaOCl, was shown to rearrange readily to give mixtures containing several species, such as 2-choro- and 3-chloropyrrole, when subjected to acidic conditions or heated in methanol [226]. Previous findings indicated that both 2-chloro- and 2-bromopyrrole undergo rapid degradation, 2-chloropyrrole being somewhat more stable. Introduction of 1-alkyl substituents increases the stability of these compounds, whereas the presence of C-alkyl groups appears to lead to even faster decomposition. Since hydrogen chloride, which is formed during degradation of 2-chloropyrrole, also catalyzes the decomposition, the process is probably autocatalytic. Stabilization can be effected to some extent by storage in the presence of a suitable base [227]. Consequently, practical halogenations of pyrroles are generally performed under mild conditions that avoid generation of acidic by-products. Bromination of some 1-alkylpyrroles with one or two equivalents of N-bromosuccinimide (NBS) in THF provides the corresponding 2-bromo- or 2,5-dibromopyrrole derivatives, respectively. Chlorination with N-chlorosuccinimide (NCS) in THF gives similar results, albeit with lower selectivity [228]. Interestingly, treatment of 1-methylpyrrole with NBS at
78  C to
10  C in THF employing PBr3 as the catalyst selectively gives 3-bromo-1-methylpyrrole, whereas the use of one equivalent of triethylamine as the additive allows regiospecific synthesis of 2-bromo-1-methylpyrrole [229]. Notably, however, treatment of 1-alkylpyrroles with NCS in chloroform with or without NaHCO3 leads instead to introduction of the N-succinimide moiety at C2 [230]. Application of N-halosuccinimides in DMF provides convenient access to a series of 2,5-disubstituted or 2,4,5-trisubstituted 3-chloro-, 3-bromo- and 3-iodopyrrole derivatives [231]. The selective rearrangement of 1-benzyl-2,5-dibromopyrrole (150) with p-toluenesulfonic acid into the product 151 (Scheme 4.47) is also worth mentioning in this context [232]. In general, 3,4-dihalopyrroles, even such lacking additional electron-withdrawing groups, are stable compounds, which have been studied in detail [233].

Br

Br

p-TsOH, MeCN, PhH

Br

N Bn 150

Scheme 4.47

Br

51%

N Bn 151

4.5 Reactivity

As implied above, the introduction of electron-withdrawing groups increases the stability of halogenated pyrroles. Halogenation of a series of substituted 3-acetylpyrroles with CuBr2 in acetonitrile gave the corresponding 3-acetyl-4-bromopyrrole derivatives in moderate to high yields [234]. Similar bromination of rather densely substituted pyrrole-3-carboxylates 152 furnished the 4-bromo derivatives 153, which could in turn be converted into the 3,4-dibromopyrroles 154 with concomitant decarboxylation (Scheme 4.48) [235]. 1-Methyl-2-(trichloroacetyl)pyrrole undergoes regioselective bromination upon treatment with NBS in chloroform at
10  C, rendering 4-bromo-1-methyl-2-(trichloroacetyl)pyrrole in 79% yield [236]. CO2H R5

N R1

R2

CuBr2 MeCN, 0° C 85-95%

Br

CO2H CuBr2

Br

Br

MeCN, rt

R5

152

N R1

R2

10-95%

R5

153

N R1

R2

154

Scheme 4.48

Stable and synthetically useful simple halogenated pyrroles have become readily available by introduction of the Boc protecting group (Scheme 4.49, cf. Section 4.5.1.6). Efficient preparation of 2-bromo-1-(tert-butoxycarbonyl)pyrrole 155, as well as the related 2,5-dibromo derivative, has been accomplished by bromination of pyrrole with 1,3-dibromo-5,5-dimethylhydantoin 156, followed by installation of the Boc-group on the intermediate 2-bromopyrrole 157 (Scheme 4.49) [237, 238]. On the other hand, 2,5-dibromo-1-(tert-butoxycarbonyl)pyrrole has also been obtained in 61% yield by exposure of 158 to NBS [239]. An alternative route to 155 encompasses conversion of 1-(tert-butoxycarbonyl)pyrrole (158) into the 2-stannyl derivative 159, which thereafter undergoes a stannyl–bromo exchange reaction. 2-Bromo-1-(phenylsulfonyl)pyrrole may also be prepared in a similar manner [240]. The closely related 2-bromo-1-

Br N

O N H

Me Me

1

N Br 156

O

AIBN (cat.) THF, -78 °C

N H

Br

Boc2O Et3N, DMAP (cat.) THF, -78 °C to rt 82-89%

157

NBS, THF, -70 °C 97%

1. LiTMP, THF -70 °C 2. Me3SnCl

N Boc 158 Scheme 4.49

Br N Boc 155

SnMe3 N Boc 159

j297

j 4 Five-Membered Heterocycles: Pyrrole and Related Systems

298

(p-toluenesulfonyl)pyrrole is readily available in two steps from pyrrole via bromination with 1,3-dibromo-5,5-dimethylhydantoin, followed by N-tosylation [241]. The presence of a bulky, removable N-substituent on the pyrrole nucleus enables introduction of halogen atoms at C3 and C4 even in the absence of stabilizing/ blocking groups at C2 and/or C5. Initial studies on the bromination of the sterically hindered 1-(triisopropylsilyl)pyrrole (160) with two equivalents of NBS gave 3,4dibromo-1-(triisopropylsilyl)pyrrole (161), along with the 2,3-dibromo derivative 162 in a 1 : 1 ratio. The use of only one equivalent of NBS afforded predominantly the 3brominated derivative 163, together with minor amounts of the 2-bromo isomer (ratio 97 : 3) [209, 242]. Improved conditions, featuring a portion-wise addition of NBS at
78  C, allow selective preparation of 163 in 78% yield [243]. It was also later emphasized that careful temperature control is essential to suppress the formation of side products [244]. Consequently, useful and high-yielding procedures for the synthesis of 163 are available [244, 245]. Investigation of the synthetic potential of 160 also revealed that attempted chlorination with NCS gives complex mixtures of products and unchanged starting material, whereas iodination with elemental iodine in the presence of mercuric acetate provides 164 in 61% yield [244]. Blocking of the normal a-substitution pathway by a bulky N-substituent has also been employed in the monobromination of 1-tritylpyrrole with pyridinium bromide perbromide, which proceeds cleanly to afford 3-bromo-1-tritylpyrrole (165) in 75% yield [210]. Treatment of the pyrrole 166 with NBS gives the 3-bromo derivative 167 via ipso-bromination. Similarly, ipso-iodination of 166 to provide 168 can be achieved employing iodine in the presence of silver trifluoroacetate [246, 247]. In addition, 3,4-dibromo-1-(ptoluenesulfonyl)pyrrole (169) has been prepared in 43% yield by treatment of 1-(p-toluenesulfonyl)pyrrole with bromine in refluxing acetic acid [248]. X N TIPS

Br

Br N R

160 X = H 161 R = TIPS 163 X = Br 169 R = Ts 164 X = I

Br Br N TIPS 162

Br TMS N CPh3 165

TMS N TIPS 166

X

TMS N TIPS

167 X = Br 168 X = I

Direct fluorination of pyrroles is a process of rather limited applicability, as the strongly oxidizing properties of most common fluorinating agents exert a highly destructive influence on the pyrrole nucleus. Nonetheless, XeF2 has been employed successfully to convert pyrroles possessing an electron-withdrawing group into the corresponding a-fluoro derivatives in low to moderate yields [249, 250]. Other miscellaneous approaches include fluoro-decarboxylation of pyrrole-2-carboxylates with 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) in modest yields [251], or photolysis of a pyrrole-b-diazonium tetrafluoroborate [252]. Halogenation on an a-methyl group of certain polysubstituted pyrroles with sulfuryl chloride in ether [253] or bromine in acetic acid [254] gives the corresponding a-(chloromethyl)- or a-(bromomethyl)pyrrole derivatives, respectively. Such halogenation processes have been suggested to occur via an initial electrophilic attack of the

4.5 Reactivity

pyrrole ring, followed by a rearrangement rendering the final a-(halomethyl)pyrrole products [255, 256]. 4.5.1.4 Nitration Because of the sensitivity of simple pyrroles towards strongly acidic media, nitration must be conducted under relatively mild conditions, or involve deactivated substrates. Nitration of pyrrole itself with nitric acid in acetic anhydride normally gives mixtures of 2-nitropyrrole and 3-nitropyrrole in a ratio of approximately 4 : 1 over a wide temperature range. The reactivities at C2 and C3 are 1.3  105 and 3  104 times higher than for benzene, respectively [257]. A similar reactivity pattern was observed in the case of 1-alkyl- and 1-aryl-pyrroles, with C2/C3 nitration ratios ranging between 3.15 : 1 for 1-methylpyrrole and 0.25 : 1 for 1-(tert-butyl)pyrrole, depending on the electronic and steric properties of the N-substituent. The high reactivity of pyrrole is further manifested in the easy formation of di-, tri-, and even tetranitropyrrole derivatives [258]. Introduction of a deactivating acyl group either on the nitrogen atom or at C2 also proved to be insufficient for selective nitration [259]. Selective and efficient (80% yield) conversion of pyrrole into 2-nitropyrrole has more recently been accomplished using (NH4)2Ce(NO3)54H2O in acetic anhydride [260]. Other practical procedures are based on pyrroles having strategically located, strongly deactivating or bulky N-substituents. For example, 2-(trichloroacetyl)pyrrole (Section 4.5.1.6) may be nitrated with 90% HNO3 at
50  C to provide the corresponding 4-nitro derivative as the major product in 77% yield [212]. In addition, b-acylated pyrroles are cleanly converted into the corresponding 4-acyl-2-nitropyrroles upon treatment with nitric acid in acetic anhydride at
15  C [259]. Likewise, an extensive series of 1,5-dialkyl-4-nitropyrrole-2-carboxylates has been prepared involving nitration of suitable precursors at C4 [261]. Nitration of 1-(phenylsulfonyl)pyrrole (170) with nitric acid in acetic anhydride provides a selective route to 3-nitropyrrole 171 [211, 262]. The parent 3-nitropyrrole (172) can thereafter be obtained after removal of the phenylsulfonyl group with base [262]. In addition, the readily available 1-(triisopropylsilyl)pyrrole (160) can serve as an excellent precursor to 3-nitropyrrole (172), as demonstrated by nitration of 160 with cupric nitrate trihydrate in acetic anhydride to give 173 (77% yield), which may subsequently be efficiently desilylated [244]. X N SO2Ph

NO2 N H

170 X = H 172 171 X = NO2

X N TIPS 160 X = H 173 X = NO2

4.5.1.5 Reactions with Sulfur-Containing Electrophiles Sulfonation of pyrrole with the sulfur trioxide–pyridine complex has long been recognized to give pyridinium pyrrole-2-sulfonate (174) [263, 264]. A more recent reinvestigation of this reaction provided, however, strong evidence that substitution

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300

seems instead to occur at C3, leading to the isomeric pyridinium pyrrole-3-sulfonate (175), the formation of which was verified by detailed NMR studies of the corresponding sodium salt 176, and preparation of several pyrrole-3-sulfonamides [265]. This intriguing preference for selective C3 substitution has yet to be rationalized in detail. When the pyrrole nucleus is already deactivated, sulfonation using acidic reagents is feasible, as illustrated by the transformation of the pyrrole 177 into the sulfonyl chloride 178 in 81% yield using chlorosulfonic acid [266]. Likewise, sulfonation of 1-(arylsulfonyl)pyrroles with chlorosulfonic acid in acetonitrile gives practical access to the corresponding pyrrole-3-sulfonyl chlorides in moderate yields [267]. Similar regioselectivity was observed upon treatment of 1(phenylsulfonyl)pyrrole with dimethylsulfamoyl chloride in the presence of bismuth (III) trifluoromethanesulfonate, providing N,N-dimethyl-1-(phenylsulfonyl)pyrrole3-sulfonamide in 49% yield. As noted in connection with studies of the latter reaction, one has to consider the possibility that the 3-substituted products may arise by a rearrangement of the conceivable 2-substituted products (see below), and further studies are required to gain deeper insight into the mechanistic pathways of such transformations [268]. SO3X N H

SO3X

174 X+ = C5H6N+

X EtO2C

N H

175 X+ = C5H6N+ 176 X+ = Na+

N H

Me

177 X = H 178 X = SO2Cl

The reaction of pyrrole and 1-methylpyrrole with alkyl- or aryl-sulfinyl chlorides at 0  C offers a route to the 2-sulfinylpyrroles 179 (R1¼H or Me) in moderate to good yields, provided that the products are protected from the influence of the liberated hydrogen chloride. Without that precaution, rearrangement of the kinetic products 179 affords the corresponding C3 substituted isomers 180 as the major products. This outcome could be ascribed to an initial protonation of 179 to generate the intermediate 181, which may thereafter undergo a sigmatropic rearrangement, followed by loss of a proton to give 180. Crossover experiments also indicated the possibility of an intermolecular process involving dissociation of the complex 181. Clean conversion of 179 into 180 can be effected by treatment with p-toluenesulfonic acid [269] or TFA [270]. Introduction of the phenylsulfinyl group at C2 may also be accomplished using N-(phenylsulfinyl)succinimide [269]. SOR2 N R1 179

SOR2

N R1

N R1

180

181

H SOR2 X

4.5 Reactivity

Several different approaches are available for the synthesis of (alkylthio)- or (arylthio)pyrroles. Treatment of pyrrole with the N-chlorosuccinimide–dimethyl sulfide adduct 182 (formed in situ) afforded the salt 183, which could then subsequently be converted, by thermal decomposition, into 2-(methylthio)pyrrole 184 in 58% overall yield [271]. Reaction of 1-alkylpyrroles with 1-(methylthio) morpholine in the presence of acid, or, even better, excess pyridine, gives access to 2,3,4,5-tetra(methylthio)pyrroles [272]. Exposure of 2-thiocyanatopyrrole (see below) to phenyl- [273] or alkylmagnesium bromides [274] provides useful routes to 2-(phenylthio)pyrrole or the corresponding 2-(alkylthio)pyrroles, respectively. Notably, the alkylthio unit serves as a protecting group for the a-position of pyrrole in a new approach to dipyrromethanes [274]. A synthesis of densely substituted 3,30 -dipyrrolyl sulfides possessing electron-withdrawing groups by treatment of suitable pyrroles having a vacant b-position with sulfur dichloride has also been reported [275]. O

Cl N SMe2

Cl SMe2

N H

O 182

183

SMe

N H 184

In analogy to the behavior of the sulfoxides 179 (see above), the 2-(alkylthio) pyrroles 185 undergo rearrangement to furnish the isomeric C3 substituted derivatives 186 exclusively in good yields upon heating in a 1 : 1 mixture of TFA and 1,2dichloroethane (Scheme 4.50) [276]. This behavior contrasts with the propensity of unprotected or N-methylated 2-(alkylthio)pyrroles and 3-(alkylthio)pyrroles to undergo acid induced equilibration under mild conditions [277]. The events leading to the conversion of 185 into 186 have been suggested to involve an initial protonation to provide the intermediate 187, subsequent rearrangement via the episulfonium salt 188 to the C3-substituted intermediate 189, and a final deprotonation. This mechanistic rationale was supported by crossover experiments, as no crossover products could be detected [276].

H N Ts

SR

185

H+

N Ts 187

H SR

SR

SR

SR -H+

N Ts

N Ts

N Ts

188

189

186

Scheme 4.50

Thiocyanation of pyrroles with cupric thiocyanate [278, 279], thiocyanogen chloride [276] or, more conveniently, ammonium thiocyanate in the presence of iodine in methanol [280] or CAN [281], provides access to 2-thiocyanatopyrroles.

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4.5.1.6 Acylation Several useful procedures for N-acylation of pyrroles are available, for example by acyl transfer from 1-acetylimidazole, which offers an efficient route to 1-acetylpyrrole [282]. Alternative attractive methods for N-acylation rely on the use of acetic anhydride [283], or acyl chlorides in the presence of and triethylamine and DMAP as the catalyst [284]. Exposure of pyrroles to di(tert-butyl)dicarbonate in the presence of DMAP in acetonitrile solution gives access to many useful 1-(tert-butoxycarbonyl) pyrroles in high yields [285]. Formylation of pyrrole is most conveniently accomplished using the Vilsmeier– Haack reaction. Both pyrrole (1) [286, 287], 1-methylpyrrole (190) [287], as well as several C-methyl derivatives thereof [288], provide excellent yields of the corresponding pyrrole-2-carboxaldehydes 191 and 192 via the intermediates 193 and 194, respectively, upon treatment with the reagent 195 [289], which is readily generated in situ from POCl3 and DMF (Scheme 4.51). The presence of N-alkyl groups larger than methyl leads to mixtures of products formylated at C2 and C3, while sterically demanding N-substituents favor substitution at C3 over C2. Thus, for instance, for 1-tert-butylpyrrole the ratio of products is 14 : 1 in favor of 1-(tert-butyl)pyrrole-3carboxaldehyde. The reactivity differences in the 1-arylpyrrole series are less pronounced (with prevalence for the C2 products), and are influenced by both steric and electronic effects. Formylation of 1-acetyl-, 1-benzoylpyrrole and ethyl pyrrole-2carboxylate leads exclusively to substitution at C2 [290]. Interestingly, Friedel–Crafts acylation of intermediates such as 193 and 194, followed by hydrolysis, provides a one-pot procedure to 4-acylpyrrole-2-carboxaldehydes due to the strong “meta”directing properties of the iminium substituent [291]. Salts related to 193 have also been exploited in reactions with bromine or SO2Cl2, eventually yielding various pyrrole-2-carboxaldehyde derivatives halogenated at C4, or C4 and C5 [292]. Vilsmeier–Haack-type reagents generated from pyrophosphoryl chloride lead to increased preference for substitution at C3 due to more pronounced steric interaction with N-substituents [293]. Likewise, treatment of 1-(triisopropylsilyl)pyrrole with iminium salts gives substitution at C3 [294]. When extended to lactams, the Vilsmeier–Haack reaction allows preparation of imines such as 196 [295], whereas the use of N,N-dimethylamides, for instance DMA, provides an effective route to 2acylpyrroles [296]. In addition, exposure of pyrroles to Vilsmeier–Haack reagents generated from aroylamides gives good yields of 2-aroylpyrroles [297]. An approach to 3,4-dialkylpyrrole-2,5-dicarboxaldehydes relying on treatment of 3,4-dialkylpyrrrole2-carboxylic acids with triethyl orthoformate in TFA has also been described [298].

N H

N H

N 196 Scheme 4.51

O

POCl3

92%

Me N 195 Me

N R 1R=H 190 R =Me

Cl X

NMe2 N X R 193 R = H 194 R = Me

OH

CHO N R 191 R = H 192 R = Me

4.5 Reactivity

Pyrroles are readily acylated at C2, as exemplified by the selective conversion of pyrrole itself into 2-(trichloroacetyl)pyrrole 197 (Scheme 4.52). This material provides easy access to pyrrole-2-carboxylic acid (198) upon alkaline hydrolysis [299]. Likewise, treatment of pyrrole with TFAA in the presence of N,N-dimethylaniline gave the corresponding trifluoroacetyl derivative, which could also be efficiently converted into 198 [300]. Alcoholysis of 2-(trichloroacetyl)pyrroles enables preparation of the corresponding esters, for example, methyl pyrrole-2-carboxylate (199). This reaction is, however, synthetically useful only with primary alcohols [301]. Acetylation with acetic anhydride is not practical, as it has been reported to give 2-acetylpyrrole in 39% yield, and minor amounts (8%) of the C3 acetylated isomer [302]. In contrast, acylation of pyrrole with cyanoacetic acid in acetic anhydride allows smooth introduction of a cyanoacetyl functionality, giving 200. Alkylpyrroles are also cyanoacetylated at C2, unless both C2 and C5 are substituted, leading instead to 3-(cyanoacetyl)pyrrole derivatives in good yields [303]. Both pyrrole itself, as well as 1-methylpyrrole, are also effectively acylated at C2 using N-acylbenzotriazoles in the presence of TiCl4 [304]. NaOH (2 N),

+ CCl3 then H

Cl3CCOCl, CHCl3 78%

N H 1

N H

72%

O

197 NCCH2CO2H Ac2O 92%

N H 200

CO2H

N H 198

NaOMe, MeOH 88%

CN

N H 199

O

CO2Me

Scheme 4.52

Studies on the acid mediated rearrangements of acylpyrroles under anhydrous conditions revealed that 2-acylpyrroles possessing an N-methyl group (201) undergo conversion into the corresponding 3-acylpyrroles (202). In contrast, the parent 2acylpyrroles (203) give equilibrium mixtures containing 203 and 204 under similar conditions (Scheme 4.53). Experiments aimed at explaining this discrepancy failed to

O

O

R2 +

1

R2

H (R = Me)

N Me 202

Scheme 4.53

N R1

O

201 R1 = Me 203 R1 = H

+

1

H (R = H)

N H 204

R2

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give conclusive results, although it seems likely that a 1,2-acyl shift of a C2-protonated intermediate is involved [305]. Pyrroles acylated at C2 are valuable precursors for elaboration to more complex derivatives. As a result of the deactivating and “meta” directing properties of the trichloroacetyl group, 2-(trichloroacetyl)pyrrole 197 undergoes electrophilic substitution at C4 with various reagents, producing the substituted methyl pyrrole-2carboxylates 205 (E¼Cl, Br, I, COMe) in good overall yields after subsequent methanolysis [212]. The scope and limitations of Friedel–Crafts acylation reactions of ethyl pyrrole-2-carboxylate (206) using acyl chlorides have been evaluated in detail, leading to the conclusion that selective C4 acylation or aroylation is best achieved employing AlCl3 as the catalyst, as the use of weaker Lewis acids, such as zinc chloride or boron trifluoride etherate, affords mixtures of C4 and C5 substituted products. This approach allows efficient syntheses of potentially useful pyrroles, for instance 207 [306]. Chlorination of 199 with two equivalents of SO2Cl2 in chloroform gives the corresponding 4,5-dichloro derivative, which may be subsequently iodinated at C3 using iodine in the presence of silver trifluoroacetate to provide methyl 4,5-dichloro3-iodopyrrole-2-carboxylate, a useful partner for regioselective Suzuki reactions (Section 4.5.11) [307]. Pyrrole-2-carbonitrile, which is readily available by treatment of pyrrole with chlorosulfonyl isocyanate followed by warming in DMF [308], displays similar reactivity, affording 4-substituted pyrrole-2-carbonitriles [308, 309]. Likewise, ethyl pyrrole-2-thiolcarboxylate (208) (readily prepared by the action of ethyl chlorothiolformate on pyrrolyl magnesium halides) also takes part in electrophilic substitution reactions, providing good yields of 2,4-disubstituted pyrroles, for example 209. These products can thereafter be converted into the corresponding 3-substituted pyrroles by treatment with Raney nickel [310] or to 3-alkylpyrroles by Wolff–Kishner reduction with concomitant decarboxylation [311]. A detailed study describing the applicability of b-acylpyrroles as useful substrates for Friedel–Crafts reactions leading to 2,4-diacylpyrroles is also available [312]. Cl

E N H 205

CO2Me

N H 206

CO2Et

O

R4 N H

207

CO2Et

SEt N H

O 208 R4 = H 209 R4 = COMe

In an interesting application of Friedel–Crafts chemistry, treatment of 206 with succinic anhydride in the presence of AlCl3 gave the 2,4-disubstituted pyrrole 210. Reduction of the ketone functionality of 210 afforded 211, which was eventually subjected to an acid induced intramolecular acylation, leading to the fused system 212 in 60% overall yield (Scheme 4.54) [313]. The synthetic potential in acylation reactions of pyrrole derivatives possessing removable, strongly electron withdrawing, or bulky N-substituents, is nicely demonstrated by the selective and efficient conversion of 1-(phenylsulfonyl)pyrrole 170 (Section 4.5.1.4) into the corresponding C3 acylated products 213 (Scheme 4.55)

4.5 Reactivity

O O N H

CO2Et

O

O

HO2C

AlCl3

CO2Et

N H

206

Et3SiH, TFA

210

HO2C N H

CO2Et

TFAA, TFA 60 % from 206

211

O

N H

CO2Et

212

Scheme 4.54

O RCOCl or (RCO)2O AlCl3, ClCH2CH2Cl

N SO2Ph 170

O R

N SO2Ph 213

R

NaOH H2O/1,4-dioxane

N H 214

Scheme 4.55

upon treatment with acyl chlorides or carboxylic acid anhydrides in the presence of AlCl3. An ensuing base-induced cleavage of the N-phenylsulfonyl group provides excellent overall yields of pyrroles 214 (R¼alkyl or aryl) [211, 262, 314, 315]. However, there are cases when mixtures of C2 and C3 acylated products have been encountered in connection with related reactions involving relatively electron rich aroyl chlorides [316, 317]. Even though similar selectivity problems were noted during the reaction of 170 with 1-naphthoyl chloride in the presence of AlCl3, selective C3 substitution was achieved by using nitromethane as the co-solvent [318]. Acylation at C3 may also be conveniently performed employing 1-(triisopropylsilyl) pyrrole as the substrate [244]. 1-(Triisopropylsilyl)pyrrole may be selectively acylated at C3 upon reaction with 1-acylbenzotriazoles assisted by TiCl4 in refluxing CH2Cl2 [304]. In contrast, when BF3OEt2 instead of AlCl3 is used as the catalyst during acylation of 170, a dramatic change in regioselectivity is induced, as exclusive formation of the 2-substituted products 215 takes place (Scheme 4.56), providing an alternative route to the parent 2-acylpyrroles after removal of the protecting group under basic conditions. Although attempts to rationalize these differences in regioselectivity in terms of kinetic, steric or electronic factors have been made, no clear conclusions could be drawn [315]. A new contribution to this field allows selective a-acylation of 1(p-toluenesulfonyl)pyrroles with carboxylic acids and TFAA, presumably involving mixed anhydrides as the acylating agents [319]. Friedel–Crafts acylation of 3-alkyl-1(phenylsulfonyl)pyrroles with acetic anhydride also proceeds with pronounced

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N SO2Ph

RCOCl or (RCO)2O BF3·OEt2, ClCH2CH2Cl

R N SO2Ph

O

215

170

Scheme 4.56

selectivity, provided that the alkyl group at C3 is not too bulky, giving 2-substitution with AlCl3, and 5-substitution with BF3OEt2 [320]. 4.5.1.7 Reactions with Aldehydes, Ketones, Nitriles and Iminium Ions The reactions of pyrroles with aldehydes and ketones have been studied extensively, as some of these transformations constitute powerful tools for the construction of the important porphyrin skeleton. Treatment of pyrrole with aldehydes in the presence of acid initially generates the intermediate carbinols 216 (Scheme 4.57), which readily lose water to provide the highly electrophilic 2-alkylidenepyrrolium (azafulvenium) ions 217 (Section 4.5.10).

RCHO, H+

H+

R

N H

N H

1

216

OH

R

-H2O

N H 217

Scheme 4.57

Such condensation reactions eventually lead to the formation of porphyrins (Scheme 4.58) [321, 322], along with other oligomeric or polymeric products [323], for instance so-called “N-confused porphyrins,” which are porphyrin isomers featuring a pyrrole unit linked through its a and b0 positions [324–327]. A widely used older procedure for the preparation of meso-tetraarylporphyrins 218 involves heating of pyrrole with an appropriate benzaldehyde in propionic acid (Scheme 4.58) [328]. This process involves the intermediacy of the porphyrinogens

H

RCHO, H+

N H 1

R H

NH HN NH HN R H 219 R = Ph 220 R = alkyl

Scheme 4.58

R

R H R

O2 , H + ,

(for 219)

O 2 , h , H +; or DDQ (for 220)

NH

N R

R N

HN

R 218 R = Ph 221 R = alkyl

4.5 Reactivity

219, which subsequently spontaneously undergo a rate limiting air oxidation step leading to 218 [329]. More recently it has been demonstrated that pyrrole and benzaldehydes react reversibly at ambient temperature in the presence of an acid catalyst to provide porphyrinogens, which may subsequently be irreversibly converted into the corresponding porphyrins by addition of an oxidant. Consequently, the method of choice relies on initial reaction of pyrrole with an appropriate benzaldehyde in anhydrous CH2Cl2 in the presence of BF3OEt2 or TFA at room temperature, followed by treatment of the resulting mixture with p-chloranil at reflux [330]. Reactions involving aliphatic aldehydes generate relatively stable mesotetraalkylporphyrinogens (220), the conversion of which into the corresponding meso-tetraalkylporphyrins (221) requires an additional forced oxidation step [331, 332]. Likewise, condensation of pyrrole and acetone in the presence of acid gives a good yield of a cyclic tetramer [333, 334]. In contrast, the reactions between pyrrole and ortho esters under acidic conditions give rise to tris(pyrrol-2-yl)alkanes [335, 336]. Moreover, condensation reactions between suitable pyrrole fragments and pyrrole-2carboxaldehyde derivatives constitute a common strategy to numerous dipyrrins and dipyrrinones [337]. Under carefully controlled conditions, the reaction of pyrrole with formaldehyde may give bis(pyrrol-2-yl)methane (dipyrromethane) (222), which is a useful precursor for the synthesis of 5,15-disubstituted porphyrins, for example 223 (Scheme 4.59) [335]. Exposure of aldehydes to excess pyrrole, in the presence of

CH2O, K2CO3, H2O 5 °C, 7 d

N H 1

HO N H 224

84-92%

OH

1, HCl (0.15 equiv.) < 5 °C, 30 min

HN

61%

(CH2O)n, AcOH, MeOH rt, 20 h

NH HN

41%

225 N H

1. 4-(HO)C6H4CHO, BF3·OEt2 CH2Cl2, MeOH, rt, 20 h 2. chloranil, Zn(OAc)2·2H2O 18% reflux, 1 h

222

N H

1. 224, BF3·MeOH CH2Cl2, rt, 30 min 31% 2. chloranil, reflux, 30 min

1

HO

5

N Zn N

N 223

Scheme 4.59

N

15

NH

N

OH N

HN 226

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TFA or BF3OEt2 as catalysts, constitutes an effective protocol (yields up to 86%) for the preparation of meso-substituted dipyrromethanes [338]. Alternatively, such systems are also effectively generated in 5 min from pyrrole and aldehydes (ratio 25 : 1) in the presence of TFA (0.1 equiv.) [339], or in water solution with catalytic amounts of HCl [340]. Treatment of pyrrole with formalin under basic conditions permits isolation of the dialcohol 224, which can subsequently react with two equivalents of pyrrole to provide trimer 225, which is an excellent precursor to the parent macrocycle 226 [341]. In a related process, the 2-acylpyrroles 227 (R¼CF3, CO2Et) have been exposed to paraformaldehyde in the presence of HCl under anhydrous conditions, leading to efficient and selective chloromethylation to render the disubstituted pyrroles 228 (Scheme 4.60) [342]. Cl R (CH2O)n, CH2Cl2, HCl (g) N Me

O

R N Me

88-93%

227

O

228

Scheme 4.60

Application of a nitrile as the electrophilic reagent has been utilized in a concise one-pot synthesis of the monarch butterfly pheromone danaidone (229), wherein N-alkylation of 3-methylpyrrole (230) with acrylonitrile in the presence of DBU gave the intermediate 231, which subsequently underwent intramolecular cyclization, followed by hydrolysis of the intermediate imine (Scheme 4.61) [343].

Me

CN

Me

DBU, rt

N H

N

230

231

Me

1. HCl (g), ZnCl2 2. H2O (pH 9), 80 °C 30% overall

N

O

CN 229

Scheme 4.61

Pyrroles also react readily with iminium ions, generated in situ from formaldehyde and dialkylamines in acetic acid, to provide 2-(dialkylaminomethyl)pyrroles, which are useful synthetic intermediates (Section 4.5.10), or with the Vilsmeier– Haack reagent, affording pyrrole-2-carboxaldehydes (Section 4.5.1.6). Likewise, pyrrole (1) may be converted in high yield into 2-(dimethylaminomethyl)pyrrole 232 via the Mannich reaction (Scheme 4.62) [344]. It has also been found that pyrrole adds upon heating (neat) to 1-pyrroline 233, leading to 2-(pyrrolidin-2-yl)pyrrole (234) [345].

4.5 Reactivity

NMe2

N H

1. H2C NMe2 2. NaOH, H2O

N 233

N H

77%

232

j309

H N

N H 234

1

Scheme 4.62

4.5.1.8 Conjugate Addition to a,b-Unsaturated Carbonyl Compounds Pyrroles are useful nucleophiles in conjugate addition reactions (Scheme 4.63). For instance, pyrrole has been alkenylated efficiently by treatment with (E)-4-(phenylsulfinyl)-3-buten-2-one to furnish the alkenyl derivative 235. This reaction probably proceeds via a sequence featuring a Michael addition, followed by elimination of phenylsulfenic acid [346]. Addition of pyrrole to 1-acyl-2-bromoacetylenes in the presence of silica gives rise to modest yields of di(pyrrol-2-yl)ethenes, for example 236, as the major products [347]. When the silica is replaced by alumina under solvent free conditions, pyrroles ethynylated at C2 are produced in useful yields [348]. Addition of pyrrole to methyl acrylate occurs in the presence of BF3OEt2, providing the diester 237 [349]. Other Lewis acids, such as InCl3, can also catalyze such processes efficiently, as illustrated by the synthesis of 238 [350]. Silica supported zinc chloride has been demonstrated to promote conjugate addition of pyrrole to methyl a-acetamidoacrylate under microwave irradiation to give the amino acid derivative 239 in considerably better yield than under conventional thermal conditions [351]. Michael addition of pyrroles to a series of electron deficient alkenes under microwave irradiation has also been performed without solvent in the presence of silica gel only,

O HN

NH

236

N H 1

31%

CO2Me BF3·OEt2

N H 237

CO2Me

N H 235

98%

O

COMe 85%

27%

InCl3 (10 mol%) CH2Cl2, rt

SiO2/ZnCl2 270 W, 100 °C 70%

CO2Me NHAc

NHAc MeO2C

Scheme 4.63

PhOS

SiO2, rt

S

MeO2C

Br

S

O

Me

COMe

N H 239

Me N H 238

O

j 4 Five-Membered Heterocycles: Pyrrole and Related Systems

310

whereas reactions involving some more sluggish substrates required the use of catalytic amounts of BiCl3 [352]. A further development includes the efficient addition of pyrroles to electron deficient alkenes in water catalyzed by aluminium dodecyl sulfate trihydrate [353]. An interesting modern contribution to this field is the asymmetric Friedel–Craftstype alkylation of pyrroles with a,b-unsaturated carbonyl compounds, which has, for example, been achieved employing organocatalysis by chiral imidazolinones, as illustrated by the conversion of 1-methylpyrrole (190) into the product 240 (Scheme 4.64) [354]. A study of additions of pyrroles to a set of a,b-unsaturated 2-acylimidazoles demonstrated that such reactions can also proceed with high yields and enantioselectivity using a bis(oxazolinyl)pyridine scandium(III) triflate complex as the catalyst [355].

N Me 190

Ph

CHO

241 (20 mol%) THF, H2O, -30 °C 87%

O CHO

N Me Ph 240 (93% ee)

Bn

N

Me

·TFA Me

N Me H 241

Scheme 4.64

4.5.2 Reactions with Oxidants

Powerful oxidants usually have a severely destructive effect on pyrroles, often leading to extensive decomposition or rather complex product mixtures [356]. Consequently, most useful transformations involving pyrroles and oxidizing agents require careful matching of substrates and reagents. A reaction belonging to this category is the oxidation of a-methylpyrroles to the corresponding carboxaldehydes, which can be effected by using Pb(OAc)4/PbO2 as the oxidant system [357]. Certain 2-methylpyrroles have also been successfully oxidized employing Pb(OAc)4 [358]. The oxidation of pyrrole a-methyl groups with ceric ammonium nitrate (CAN) provides a reliable and selective route to the corresponding carboxaldehydes, as exemplified by the conversion 242 into the aldehyde 243 (Scheme 4.65) [359]. An extension of this approach allows, for example, preparation of the 2-(methoxymethyl)pyrrole derivative

CO2Et

Me EtO2C

N H

CHO

243 Scheme 4.65

CAN,THF AcOH, H2O 95%

CO2Et

Me EtO2C

Ce(OTf)4 MeOH, H+

N H 242

Me

60%

CO2Et

Me EtO2C

OMe N H 244

4.5 Reactivity

244 using ceric triflate in methanol [360]. Substituted pyrrolecarboxaldehyde derivatives have also been accessed by oxidation of the corresponding a-methylpyrroles with IBX in DMSO [96]. An alternative route to pyrrole-2-carboxaldehydes involves oxidative cleavage of 2-(polyhydroxyalkyl)pyrroles with CAN [361]. In cases where the pyrrole nucleus is strongly deactivated, oxidation of an aldehyde functionality at C2 to the corresponding carboxylic acid may be achieved using the strong oxidant KMnO4 [362]. A useful oxidative coupling reaction has been elaborated, providing access to quarter-, penta- and sexipyrrole derivatives. For instance, coupling of the 2,20 bipyrrole 245 with K3FeCN6 afforded the system 246 (Scheme 4.66), which could thereafter be converted into its reduced form by treatment with NaBH (OAc)3 [363].

Et Et

Et EtO2C

N H

Et Et

N H

K3FeCN6, NaHCO3 CH2Cl2, H2O, rt 49%

Et

Et Et EtO2C

245

Et Et

Et N

N

HN

NH 246

Et CO2Et

Scheme 4.66

Treatment of the 1-(p-toluenesulfonyl)pyrroles 247 with phenyliodine bis(trifluoroacetate) (PIFA) and BF3OEt2 in the presence of TMSCN gives the pyrrole-2carbonitrile derivatives 248 (Scheme 4.67). This cyanation reaction was suggested to involve initial formation of a pyrrole radical cations, which thereafter react with cyanide ions by a one-electron oxidation, giving the final products after deprotonation [364]. Similar radical cation intermediates are presumably involved in the PIFA/TMSBr (bromotrimethylsilane) mediated oxidative coupling of electron rich pyrroles to bipyrroles [365]. R

R

TMSCN, PIFA BF3·OEt2, CH2Cl2

N Ts 247

72-97%

N Ts 248

CN

Scheme 4.67

The action of benzoyl peroxide on 1-alkyl- or 1-arylpyrroles leads to mixtures of the corresponding 2-hydroxy- and 2,5-dihydroxypyrrole-O-benzoates, whereas pyrrole itself gives only intractable mixtures under the same conditions [366]. Careful oxidation of pyrrole with hydrogen peroxide gives a modest yield of 3-pyrrolin-2one (Section 4.6.3).

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4.5.3 Reactions with Nucleophiles

Owing to their electron rich properties, most pyrroles are relatively unreactive towards nucleophilic reagents, with the exception of some derivatives or intermediates having strongly electron-withdrawing substituents, or carrying a positive charge resulting from, for instance, protonation (Section 4.5.1.2). Treatment of the nitropyrroles 249 with ethylene oxide provides a route to the pyrrolo[2,1-b]oxazoles 250 via intramolecular displacement of the nitro group in the intermediates 251 (Scheme 4.68) [367]. Intramolecular displacement of methanesulfinate- or bromide ions at C2 in electron deficient pyrroles by sodium enolates constitutes an alternative approach to [1,2-a]-fused pyrrole derivatives [271].

O R O

N H

NO2

i-PrOH, H2O 110-130 °C

R O

249

N

R

NO2

O

OH 251

N

O

250

Scheme 4.68

The rather electron deficient molecule 1-methyl-2,5-dinitropyrrole (252) reacts with piperidine in DMSO to produce the substitution product 253 (Scheme 4.69). A similar reaction occurs more readily with methoxide [368], and the rate is further enhanced by the presence of an additional electron-withdrawing substituent (NO2, CN) at the adjacent C3 position [369]. Likewise, exposure of 1-methyl-2,3-dinitropyrrole to sodium methoxide in methanol furnishes 2-methoxy-1-methyl-3-nitropyrrole in 93% yield [370]. The treatment of 1-alkyl-2-nitropyrroles with Grignard reagents gives mixtures of C3- and C5 alkylated products [371], whereas treatment of the anion of chloromethyl phenyl sulfone affords the corresponding 5-substituted 1-alkyl-2-nitropyrrole derivatives via vicarious nucleophilic substitution [372]. It has also been established that the bromine atom in 2-acetyl-5-bromo-1-methyl-4-nitropyrrole may be displaced with various nucleophiles, such as azide, cyanide, alkoxides, thiophenols or amines [373].

piperidine, DMSO, rt

O2N

N

NO2

O2N

N

Me

Me

252

253

Scheme 4.69

N

4.5 Reactivity

An unusual example of nucleophilic attack has been observed upon heating pyrrole with sodium hydrogen sulfite, affording the pyrrolidine derivative 254 (Scheme 4.70). This transformation presumably involves the intermediacy of a C3 protonated pyrrole [374].

NaHSO3, H2O, 100 °C

N H

NaO3S

1

N H

SO3Na

254

Scheme 4.70

4.5.4 Reactions with Bases 4.5.4.1 N-Metallated Pyrroles As a consequence of its weakly acidic properties [13–15], pyrrole will react readily with virtually any strong base to generate a reactive ambident pyrrolyl anion, which can either undergo reaction with electrophiles at the nitrogen atom or at C2/C3. The reaction site is dependent on the properties of the metal–nitrogen bond, and on the solvating power of the solvent used. In general, N-substitution is favored by increasing ionic character of the metal–nitrogen bond, and by stronger solvating power (polarity) of the solvent [375, 376]. Treatment of pyrrole (1) with potassium metal gives the salt 255 [377], which can thereafter be converted into a wide variety of N-substituted derivatives, for instance the useful 1-(arylsulfonyl)pyrroles 256 (Scheme 4.71) [378]. Such procedures have now in most cases been supplanted by modern methods, and the pyrrole anion is now usually generated by treatment of pyrrole with commercially available alkyl lithiums [377, 379]. N-Alkylation of 255 formed by deprotonation of pyrrole by KOH in DMSO offers a high-yielding route to 1-alkylpyrroles [380], although several more convenient and effective procedures rely on phase transfer conditions using 18-crown-6 as the catalyst, in combination with KOH in anhydrous benzene [381], or with potassium tert-butoxide in diethyl ether [382]. Phase transfer alkylation of pyrrole by alkyl halides with aqueous NaOH in CH2Cl2 in the presence of tetrabutylammonium bromide constitutes a useful alternative [383]. Interestingly, 2,5-dialkylpyrrolyl anions generated in the superbase system KOH–DMSO will instead react at C3 with carbon disulfide, providing a route

ArSO2Cl

K, THF

N H 1 Scheme 4.71

N K

N SO2Ar

255

256

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to pyrrole-3-carbodithioates [384]. The pyrrolyl anion is also easily converted into the corresponding 1-silylated pyrroles by treatment with triisopropylsilyl chloride (TIPSCl) [244] or tert-butyldimethylsilyl chloride (TBSCl) [385], as well as with other trialkylsilyl chlorides [386]. The high reactivity of the pyrrolyl anion is neatly demonstrated by the reaction of pyrrolylsodium with hexafluorobenzene, which gives hexa(pyrrol-1-yl)benzene via a SNAr mechanism [387]. Pyrrolylthallium(I), prepared from pyrrole and thallium(I) ethoxide, can also be utilized for N-alkylation of pyrroles [388], but should perhaps be avoided because of its toxicity. Pyrrolylmagnesium halides, which are easily prepared by the action of alkylmagnesium halides on pyrrole, display more complex reactivity patterns towards most alkylating agents, rendering mixtures of C2 and C3 substituted products, as well as diand tri-alkylpyrroles [383, 389]. In contrast, acylation of pyrrolylmagnesium halides is more selective, giving 2-acylpyrroles as the prevailing products [390]. Excellent selectivity for C2 acylation of pyrrolylmagnesium chloride 257 under mild conditions can be achieved by treatment with readily available 2-pyridylthiol esters, which gives high yields of the corresponding 2-acylpyrroles 258 (Scheme 4.72), probably as a result of coordination of the pyridine nitrogen atom to the magnesium [391]. The reaction of 257 with alkyl bromoacetates is an efficient way for selective synthesis of the alkyl (pyrrol-2-yl)acetates 259, which is in this case mediated by coordination between the metal and the carbonyl oxygen of the alkylating agent [392]. A series of (pyrrole-2-yl)acetone derivatives have been prepared by employing a new heteroarylation reaction involving the pyrrolyl anion and suitable enolates in the presence of a Cu(II) oxidant [393]. Transmetallation of pyrrolylsodium with ZnCl2 gives pyrrolylzinc chloride, which undergoes perfluoroalkylation at C2 upon exposure to perfluoroalkyl iodides in the presence of PdCl2(PPh3)2 (10 mol.%) and PPh3 [394].

R N H

O

258

O N

S

R

PhMe, -78 °C 80-95%

N MgCl 257

R1CHBrCO2R2, THF

N H

CO2R2 R1

259

Scheme 4.72

4.5.4.2 C-Metallated Pyrroles Pyrroles possessing suitable N-blocking substituents undergo C-metallation upon treatment with sufficiently strong bases. Initial studies early established that 1-methylpyrrole (190) is slowly metallated at C2 using BuLi in ether to give 2lithio-1-methylpyrrole (260) (Scheme 4.73) [379], but the yield of the lithiopyrrole is improved significantly if N,N,N0 ,N0 -tetramethylethylenediamine (TMEDA) is used as the additive [395]. It was later demonstrated that quantitative and selective generation of 260 is easily achieved using 2.5 equivalents of BuLi in hexane at ambient temperature in the presence of TMEDA [396], while a larger excess (4.5 equivalents) of BuLi and elevated temperatures promotes increasing formation of 2,5- and 2,4dilithio- derivatives [396, 397]. Generation of 260 may also be carried out using BuLi at

4.5 Reactivity

N Me

t-BuLi, THF

190

N Me

Li

1. R3B, THF, rt 2. I2, -78 °C 70-98%

N Me

R

261

260 MgBr2 or ZnCl2

N Me

MX

262 MX = MgBr 263 MX = ZnCl

N

Br

PdCl2(dppb) (cat.) THF, reflux 71% from 262

N N Me 264

Scheme 4.73

ambient temperature in THF–hexane (2 : 1). This lithiopyrrole will subsequently react readily with a wide variety of electrophiles [398], and may for example also be converted into the 2-alkyl-1-methylpyrroles 261 by treatment with trialkylboranes, followed by addition of iodine or NCS [399, 400]. Quenching of 2-lithio-1-methyl-5-noctylpyrrole with N-fluorodibenzenesulfonamide has been used to prepare the labile 2-fluoro-1-methyl-5-n-octylpyrrole [401]. Transmetallation of 260 formed from 1methylpyrrole and t-BuLi with MgBr2 or ZnCl2 gives the corresponding metallated pyrroles 262 and 263, which can subsequently participate in palladium-catalyzed cross-coupling reactions leading to 2-arylpyrroles, or to the 2-pyridylpyrrole 264 [402]. A procedure for selective C2 metallation and functionalization of 1-vinylpyrrole employing the base system BuLi/t-BuOK catalyzed by i-Pr2NH, followed by addition of LiBr and suitable electrophiles, has also been described [403]. Selective C2 mercuration of pyrroles is effected by exposure of 1-acetyl- or 1(phenylsulfonyl)pyrrole to mercuric chloride. The corresponding diorganomercury compounds, which are useful for the synthesis of pyrrole containing transition metal complexes, can thereafter be obtained after treatment with sodium iodide [404]. For N-H pyrroles, mercuration with mercury(II) acetate leads to N-mercuration, while various N-substituted pyrroles are mercurated at C2 or C3. Such C-mercurated pyrroles undergo Heck-type reactions with alkenes [405]. The development of directed metallation techniques has allowed facile access to a multitude of 2-substututed pyrroles that were previously difficult to prepare. The ideal N-protecting and directing group should be easily installed and cleaved, and induce high regioselectivity during metallation. The tert-butoxycarbonyl (Boc) group fulfils all these requirements, and has consequently proven to be extremely useful. For example, 1-(tert-butoxycarbonyl)pyrrole (158) [285] is efficiently lithiated at C2 by LiTMP, and subsequent quenching with aldehydes or acid chlorides gives the corresponding pyrrol-2-yl methanols 265 (Scheme 4.74) and 2-acylpyrroles, respectively. The Boc group may be removed by treatment with sodium methoxide in methanol [406], under thermal conditions [407] or using acid, which may, however, not always be compatible with electron rich substrates. Similar metallation of 158

j315

j 4 Five-Membered Heterocycles: Pyrrole and Related Systems

316

R N Boc

OH

1. LiTMP, THF, -78 °C 2. B(OMe)3, then H+

1. LiTMP, THF, -80 °C 2. RCHO

N Boc

47-75%

265

40%

158

B(OH)2 N Boc 266

Scheme 4.74

followed by quenching with trimethyl borate and subsequent hydrolysis provides a route to the useful boronic acid 266 [239]. An excellent recent review covers the advances in pyrrole protection strategies [408]. An alternative route permits introduction of two a-substituents by halogen–metal exchange on 2,5-dibromo-1-(tert-butoxycarbonyl)pyrrole (267) (Section 4.5.1.3), eventually producing the corresponding 2,5-disubstituted pyrroles, for instance 268 (Scheme 4.75) [237, 239]. Moreover, mono-lithiation of 267 offers access to 2bromopyrroles having an additional substituent at C5 (e.g., 269) [239].

Me3Sn

SnMe3 N Boc

1. BuLi (2 equiv.) THF, -70 °C 2. Me3SnCl (2 equiv.) -75 °C to rt

Br

50%

268

N Boc

1. BuLi, Et2O, -70 °C 2. (MeO)3B Br Br -75 °C to rt 80%

B(OMe)2 N Boc

267

269

Scheme 4.75

Pyrroles that are N-protected with the N-tert-butylcarbamoyl group are also very useful substrates for C2 lithiation; the directing group can subsequently be removed by LiOH in MeOH–THF [409]. Generation of the dilithio species 270, followed by quenching with suitable electrophiles, and final acidic work up which cleaves the carbamate, constitutes a one-pot protocol for preparation of C2 functionalized pyrroles 271 (Scheme 4.76) [410]. 1. BuLi, THF, -70 °C to rt 2. CO2 3. t-BuLi, THF, -70 to -25 °C

N H 1

Li

N LiO

O 270

1. E+, -70 °C to rt 2. H+, H2O 50-95%

N H

E

271

Scheme 4.76

Lithiation of 1-(p-toluenesulfonyl)pyrrole (272) also occurs at C2 with high selectivity, and subsequent quenching with PhSSO2Ph gives the sulfide 273 (Scheme 4.77) [276]. Similar techniques can also be utilized in synthesis of other chalcogen containing systems, as illustrated by the conversion of 272 into the

4.5 Reactivity

N Ts

SPh

1. t-BuLi, THF, -23 °C 2. Te, -23 °C to rt 3. K3Fe(CN)6

1. BuLi, THF, -15 °C 2. PhSSO2Ph, -78 to -40 °C

N Ts

70%

273

N Ts

63%

272

Te Te

Ts N

274

Scheme 4.77

ditelluride 274 [411]. Magnesium can be introduced at C2 in 1-(phenylsulfonyl) pyrrole by the action of 3 equivalents of i-PrMgBr in the presence of 5 mol.% i-PrNH; ensuing treatment with electrophiles gives the corresponding 2-substituted pyrroles in moderate yields [412]. The N-protected pyrroles discussed above are neatly complemented by 1-[2-(trimethylsilyl)ethoxymethyl]pyrrole (1-SEM-pyrrole) (275), which is available by deprotonation of pyrrole with NaH in DMF, followed by treatment with SEMCl [413]. Lithiation is also in this case directed to C2, rendering the lithiopyrrole 276, treatment of which with appropriate electrophiles affords the 2-substituted N-protected pyrroles 277 in moderate to good yields (Scheme 4.78). The electron releasing SEM group may thereafter be conveniently cleaved using tetrabutylammonium fluoride (TBAF) under conditions that tolerate sensitive functionalities [414]. Even structurally rather complex and sterically congested electrophiles may be used in this approach, providing useful yields of unusual 2-substituted pyrroles [415]. Notably, lithiation of 1-(N,Ndimethylamino)pyrrole also occurs at C2, and this electron releasing directing group can subsequently be removed by treatment with Cr2(OAc)42H2O [416].

BuLi, DME, -5-0 °C

N SEM 275

Li

N

E+, DME, -5 °C

O SiMe3

j317

E N SEM 277

276 Scheme 4.78

Metallation of pyrroles at C3 has enabled convenient preparation of derivatives that were prepared previously by cumbersome means [417]. Selective C3 metallation is achieved conveniently by halogen–metal exchange on 3-bromo-1-(triisopropylsilyl) pyrrole (163) by virtue of the steric bulk of the TIPS group (Scheme 4.79) [245]. Subsequent treatment of the so-obtained 3-lithiopyrrole 278 with suitable electrophiles, followed by desilylation with TBAF gives the corresponding 3-substitued pyrroles 279 via the 1-TIPS derivatives 280 [242]. Intermediate 278 may also be generated by lithiation of 3-iodo-1-(triisopropylsilyl)pyrrole (164), and converted into, for example, the boronic acid 281 or the stannyl derivative 282, which are useful substrates in palladium-catalyzed coupling reactions (Section 4.5.11) [418]. Similar

j 4 Five-Membered Heterocycles: Pyrrole and Related Systems

318

Li

X

E+

1. t-BuLi, THF, -78 °C

N TIPS

1. B(OMe)3 2. H2O, MeOH

163 X = Br 164 X = I

N TIPS 278

43%

B(OH)2 N TIPS 281

E

280

Bu3SnCl 90%

TBAF THF

SnBu3

E

N TIPS 282

N TIPS

N H 279

Scheme 4.79

techniques have been employed for the synthesis of 3-fluoro-1-TIPS-pyrrole in 50% yield by quenching of 3-lithio-1-TIPS-pyrrole by N-fluorobenzenesulfonimide [419]. Conversely, lithiations involving pyrroles having a trimethyl or triethylsilyl groups at the nitrogen are more difficult to control in terms of regioselectivity, and are under certain conditions further complicated by migration of the silyl groups [420]. Treatment of dimethoxyethyl protected 4-iodopyrrole-2-carbonitrile with i-PrMgCl and subsequent quenching with electrophiles provides a route to 4-substituted pyrrole-2-carbonitriles in good yields [421]. 4.5.5 Reactions with Radical Reagents

Synthetically useful reactions of pyrroles with radical reagents were not been studied in much detail until it was demonstrated that effective and regioselective synthesis of 2-alkylpyrrole derivatives can be accomplished by radical substitution. The pyrrole-2acetic acid derivatives 283 are readily available by treatment of the pyrroles 1 or 190 (Scheme 4.80) with radicals generated from a-carbonyl-, a,a0 -dicarbonyl- and a-cyano-alkyl iodides [422]. Alternative procedures for the synthesis of pyrrole-2acetic acid derivatives involve generation of radicals from various iodoacetates induced by stannanes [423] or under conditions avoiding stannanes, by irradiation

ICH2CO2Me H2O2, FeSO4·7H2O, DMSO, rt

N R 1R=H 190 R = Me Scheme 4.80

CO2Me N R 283a R = H (59%) 283b R = Me (87%)

4.5 Reactivity

in the presence of Na2S2O3 as the I2 reductant, Bu4NI to aid in solubility, and propylene oxide [423, 424] or epoxydecane as the HI trap [425]. Pyrroles possessing electron-withdrawing groups at C2 undergo related alkylation reactions at C5 with a-acetyl or a-acetonyl radicals generated by exposure of suitable xanthate based precursors to dilauroyl peroxide [426]. Similar intramolecular processes provide routes to fused pyrroles, as illustrated by the manganese(III) acetate generated in situ induced conversion of the 2-aroylpyrrole 284 into the fused system 285 (Scheme 4.81), a useful precursor to the analgesic molecule ketorolac (10) [427]. In addition, [1,2-a]-fused pyrroles are also available via intramolecular radical cyclization of 1-(bromoalkyl)pyrroles induced by Bu3SnH in the presence of AIBN [428, 429], annulation of 1-(iodoalkyl)pyrroles with the H2O2/Fe(II) system (vide supra) [430], or employing electroreduction with a Ni(II) complex as the electron-transfer catalyst [431]. Intramolecular cyclization of acyl radicals onto pyrroles leading to [1,2-a]-fused pyrrole derivatives in modest yields has also been reported [432]. Ph O

N

Mn(OAc)2·4H2O, AgNO3 (cat.) Na2S2O8, NaOAc, Ac2O, AcOH, 80 °C

CH(CO2Et)2

95%

Ph O

284

N

CO2Et CO2Et

285

Scheme 4.81

It has been known for some time that 2-(perfluoroalkyl)pyrroles are formed in low yields upon heating of pyrroles in the presence of perfluoroalkyl iodides under forcing conditions [433]. Application of the H2O2/Fe(II) protocol offers a practical procedure for the preparation of, for example, the perfluoroalkylpyrroles 286 from pyrrole-2-carboxaldehyde (191) and perfluoroalkyl iodides via a homolytic substitution process (Scheme 4.82) [434]. In contrast, perfluoroalkylation of pyrroles at C2 using bis(perfluoroalkanoyl) peroxides follows a different mechanistic path, which appears to proceed via coupling of perfluoroalkyl radicals with pyrrole cation radicals [435].

OHC

I(CF2)nCF3 H2O2, FeSO4·7H2O, DMSO, rt

N H 191

(CF2)nCF3 N H 286a n = 2 (64%) 286b n = 3 (55%)

OHC

Scheme 4.82

Addition of the 3-pyridyl radical generated from N-nitroso-N-(3-pyridyl)-isobutyramide to ethyl pyrrole-1-carboxylate gives 287 in 23% yield [436]. More efficient radical C2 arylations of pyrroles having an electron-withdrawing substituent at the nitrogen atom have been afforded using anilines in the presence of amyl nitrite in

j319

j 4 Five-Membered Heterocycles: Pyrrole and Related Systems

320

warm acetic acid [437]. Intramolecular radical arylations involving pyrroles are useful tools for the construction of more complex systems, such as the tricyclic derivative 288, which was derived from the precursor 289 by exposure thereof to tributyltin hydride in the presence of AIBN in refluxing toluene [438, 439]. Related cyclization reactions may also produce spiropyrrolidinyloxindoles, depending on the properties of the pyrrole protecting group [440]. Boc

N I

N

N CO2Et 287

N Me

O

N Me

O

288

N Boc

289

A radical displacement reaction at C2 of 1-phenylsulfonyl-2-(p-toluenesulfonyl) pyrrole with stannyl radicals generated by the reagent combination Bu3SnH/AIBN in refluxing benzene, resulting in the corresponding 2-stannylpyrrole derivative, has also been described [441]. 4.5.6 Reactions with Reducing Agents

It has long been established that reduction of pyrroles 290 with zinc in hydrochloric acid gives 2,5-dihydropyrroles (3-pyrrolines) 291 (Scheme 4.83) [442, 443], although it was later found that the material obtained from the reduction of pyrrole itself is frequently contaminated with pyrrolidine, which is difficult to separate from the desired product [444]. The synthetic utility is further compromised by the fact that the formation of both cis and trans products occurs upon reduction of 2,5-dimethylpyrrole [445]. Nevertheless, this procedure seems to be useful in certain applications, and a modified version thereof has been applied successfully for the reduction of some 1,2-disubstituted pyrroles to give the corresponding 3-pyrroline derivatives en route to the antibiotic ()-anisomycin [446]. Treatment of pyrrole-2-carboxamide with phosphonium iodide in fuming hydroiodic acid affords 3,4-dehydroprolinamide as the major product, provided that careful control of the reaction conditions is maintained [447]. A similar reduction using the combination H3PO2/HI in acetic acid has been used for the conversion of pyrrole-2-carboxylic acid into 3,4-dehydroproline in 74% yield on a large scale [448]. Reduction of C2 or C3 substituted

R1

N H

R2

290 Scheme 4.83

Zn, HCl (aq.)

R1

N H 291

R2

4.5 Reactivity

1-phenylsulfonylpyrroles with NaCNBH3 in TFA leads to the corresponding 3-pyrrolines in good yields, offering a convenient complement to the procedures discussed above [449]. Catalytic hydrogenation of pyrroles leads to pyrrolidines, and can be performed under various conditions, often proceeding exclusively with cis-stereoselectivity. Useful catalysts for this application are 5% Rh on Al2O3 [450–452], PtO2 or 10% Pd/C in 6 N aqueous HCl [453] or alternatively Pd/C in the presence of catalytic amounts of H2SO4 [454]. Moreover, catalytic hydrogenation of pyrroles at atmospheric pressure offers a convenient procedure for the synthesis of cis-2,5-disubstituted pyrrolidines, as illustrated by the conversion of pyrrole 292 into pyrrolidine 293 (Scheme 4.84) [455].

Me

N Boc

CO2Me

H2, 5% Pt/C, MeOH 88%

Me

292

CO2Me N H Boc

H

293

Scheme 4.84

Birch reduction of pyrroles has not been explored until recently, but has already attracted considerable attention as a tool for preparation of interesting 3-pyrrolines and 2,3-dihydropyrroles (2-pyrrolines). Initial studies demonstrated that pyrroles possessing electron-withdrawing groups, for instance 294, undergo efficient conversion into 3-pyrrolines 295 upon Birch reduction and subsequent alkylation (Scheme 4.85) [456, 457]. Diastereoselectivity at C2 may be induced in alkylation [458] or protonation [459], by using for example pyrrole-2-carboxylates or pyrrole-2-carboxamides, respectively, containing chiral moieties as substrates. A variant featuring a reductive aldol reaction has also been developed [460]. It was later established that such reductions may also be conveniently performed by employing lithium in THF in the presence of bis(methoxyethylamine) and naphthalene [461, 462], or 4,40 -di-tert-butylbiphenyl (296, see below) [463], thus supplanting the classical Birch conditions. Further extensions of this methodology allow reductive acylation [462], and aldol reactions with excellent anti-selectivity [464, 465].

N N Boc

O

294 Scheme 4.85

1. Na (3 equiv.), NH3 THF, -78 °C 2. RX 71-86%

R N N Boc

O

295

j321

j 4 Five-Membered Heterocycles: Pyrrole and Related Systems

322

A recent contribution to this field concerns the enantioselective partial reduction of pyrroles involving chiral protonation using (
)-ephedrine. Thus, diester 297 underwent conversion into a 1 : 1 mixture of the cis- and trans-diastereomers 298a and 298b, the latter of which was found to be formed with an enantiomeric excess of 74%. A simple recrystallization of 298b provided material with >94% ee (Scheme 4.86) [466].

t-Bu

MeO2C

CO2Me N Boc 297

1. Li, 296 (cat.), THF, -78 °C 2. BrCH2CH2Br 3. (-)-ephedrine

MeO2C

CO2Me N H H Boc 298a

84%

MeO2C

CO2Me N H Boc 298b (74% ee) H

t-Bu 296

Scheme 4.86

Pyrroles bearing amide or ester functionalities at the b-position also undergo Birch reduction, and ensuing alkylation provides the corresponding 4,4-disubstituted 2pyrrolines [467]. The 3,4-disubstituted pyrrole 299 (Adoc¼adamantyloxycarbonyl) is converted into cis-pyrrolidines 300 under similar conditions (Scheme 4.87). Sequential alkylation with two different electrophiles gives access to unsymmetrically substituted derivatives [468]. EtO2C

CO2Et

1. Li (6 equiv.), NH3, THF, (MeOCH2CH2)2NH, -78 °C 2. RI

N Adoc 299

70-82%

EtO2C

R

R

CO2Et

N Adoc 300

Scheme 4.87

4.5.7 Cycloaddition Reactions

Cycloaddition reactions involving pyrroles constitute a powerful tool for crafting rather complex heterocyclic structures from simple precursors. It was early recognized that some pyrroles, for example 1-methylpyrrole, give mainly C2 substituted products resulting from Michael-type addition to maleic anhydride [469]. Interestingly, the reaction of 1-methylpyrrole with dimethyl acetylenedicarboxylate (DMAD)

4.5 Reactivity

gives a product for which an indolic structure was proposed [470] – the true identity was later elucidated by Acheson [471]. Further studies of these reactions suggested that Michael additions are favored in the presence of a proton source, whereas under neutral conditions and at elevated temperatures Diels–Alder additions will take place. The adducts, however, being rather unstable, undergo retro Diels–Alder reactions to the starting materials, yield further pyrrole derivatives via extrusion of acetylene derivatives, or react further with DMAD to give more complex indolic products [472]. Based on the results of ab initio calculations on the reaction of 1-methylpyrrole with DMAD, which support the preferential formation of Diels–Alder products instead of Michael adducts, a step-wise mechanism involving a zwitterionic intermediate was suggested, rather than a concerted pericyclic process [473]. Even though elimination of acetylene from intermediate Diels–Alder adducts of the deactivated methyl pyrrole-1-carboxylate with DMAD has also been observed [474, 475], stable addition products could nevertheless be isolated in very low yields from the reactions of 1-benzylpyrrole [476] or methyl pyrrole-1-carboxylate [477] with acetylenedicarboxylic acid. A different decomposition path is in operation during reactions of 1-aminopyrroles with DMAD, which give substituted benzene derivatives as the final products [478]. Conditions for practical Diels–Alder reactions involving deactivated pyrroles soon became available, permitting the synthesis of adduct 301 in a moderate yield upon heating of the pyrrole 302 in neat DMAD (Scheme 4.88) [479], whereas the same reaction performed in CH2Cl2 in the presence of five equivalents of AlCl3 at 40  C is much faster and gives the adduct in 93% yield [480]. The use of high pressure (15 kbar) also leads to high yields of 301, but, even under these conditions, pyrrole itself undergoes mainly C2-substitution [481]. DMAD,

N CO2Me

MeO2C N

42%

302

301

CO2Me CO2Me

Scheme 4.88

Deactivated pyrroles also give good yields of Diels–Alder adducts with alkenes at elevated pressure, as demonstrated by the synthesis of the endo-adduct 303 from 1-acetylpyrrole (304) and N-methylmaleimide (Scheme 4.89). In some cases,

O

Me N O CH2Cl2, 30 °C 1.2 GPa

N Ac 304

Scheme 4.89

77%

Ac N

H H O N O 303

Me

j323

j 4 Five-Membered Heterocycles: Pyrrole and Related Systems

324

mixtures of exo- and endo-adducts are produced, and it has been proposed that the endo-isomers are in some cases formed under kinetic control and isomerize to the exo-products [482]. Mixtures of exo- and endo-adducts have also been encountered during high pressure reactions of methyl 3-methylthio- or 3-phenylthiopyrrole-1carboxylate with N-phenylmaleimide or methyl acrylate [483]. However, it appears that 1-acylpyrroles do not participate in Diels–Alder reactions with alkenes at atmospheric pressure [484]. An intramolecular cycloaddition reaction involving the precursor 305 (Ns¼2nitrophenylsulfonyl), incorporating a deactivated pyrrole as the diene component has been used in an elegant synthesis of the tricyclic system 306 (Scheme 4.90). This study was extended to the efficient construction of several conformationally strained analogues, featuring stereoselective generation of multiple stereogenic centers [485]. CO2Et N Ns

N i-Pr

Ns N

PhMe, 65 °C

N

i-Pr

100%

O

O

CO2Et

305

306

Scheme 4.90

Diels–Alder reactions involving pyrroles and acetylenes are the key feature of several total syntheses of the powerful analgesic natural product epibatidine (307) (Scheme 4.91). The common 4p-component 1-(tert-butoxycarbonyl)pyrrole (158) undergoes efficient conversion into the bicyclic system 308 upon heating with the electron deficient dienophile (p-toluenesulfonyl)acetylene [486]. A similar reaction involving 158 and methyl pyrrole-1-carboxylate has previously been demonstrated to give excellent results [487, 488]. The intermediate 308 proved to be a useful precursor for the synthesis of epibatidine (307) [489, 490]. Other related approaches to 307 employ Diels–Alder reactions of methyl pyrrole-1-carboxylate with (p-toluenesulfonyl)acetylene [491], or a (6-chloro-3-pyridyl)acetylene derivative [492]. Likewise, heating of the pyrrole 158 with the dienophile methyl 3-bromopropiolate gives the adduct 309, which is also a useful vehicle for further manipulations that eventually lead to 307 [493, 494].

R1 N Boc 158

Scheme 4.91

R2

Boc N

Cl R2 R1

308 R1 = Ts, R2 = H (86%) 309 R1 = CO2Me, R2 = Br (60%)

H N

N H 307

4.5 Reactivity

Allenes may also participate in Diels–Alder reactions with electron deficient pyrroles, and high selectivity can be attained, depending on the choice of starting materials and conditions. For example, 1-(tert-butoxycarbonyl)pyrrole (158) gives exclusively the endo-isomer 310 with diethyl allene-1,3-dicarboxylate 311 (Scheme 4.92). Under similar conditions, 1-methyl- or 1-benzylpyrrole give only C2 substitution products [495]. Variants involving endo-selective Diels–Alder addition of 158 to an optically active allene-1,3-dicarboxylate [496], or 1-(benzenesulfonyl)1,2-propadiene to provide 312 [497], have also been disclosed. H

Boc N

•

H

EtO2C 311 CO2Et H CO2Et

CO2Et 310

AlCl3, CH2Cl2, -78 °C 73%

• N Boc 158

SO2Ph

Boc N H

45%

312

SO2Ph

Scheme 4.92

The reactions of 1-methylpyrrole or 1-benzylpyrrole with benzyne give rather unstable adducts that could only be isolated in low yields as the methiodide or the picrate, respectively, as they readily react further with benzyne, finally rendering carbazole derivatives [498, 499], or rearrange to 2-naphthylamines [500]. In contrast, 1-(tert-butoxycarbonyl)pyrrole (158) reacts with benzyne, to afford a stable adduct (313) in moderate yield (Scheme 4.93) [501], as do 1-alkyl-2,3,4,5-tetramethylpyrroles [502, 503]. Tetrafluorobenzyne also adds readily to for, example, 1-methylpyrrole to form a stable adduct [504], whereas the reaction of the benzyne generated from 1-bromo-2,5-difluorobenzene with 1-(trimethylsilyl)pyrrole (314) gives 315 with concomitant desilylation [505]. Related addition products have also been obtained upon addition of tetrachlorobenzyne to 1-alkylpyrroles [506].

X 1.

N R

R N

2. H2O

158 R = Boc 314 R = TMS

X 313 R = Boc, X = H (35-41%) 315 R = H, X = F (49%)

Scheme 4.93

Although the photooxygenation of pyrroles was discussed already in 1912 [507], evidence for the mechanism was not available until almost 70 years later, when it was demonstrated that addition of singlet oxygen to 1-methylpyrrole (190) provides the unstable endoperoxide 316, which undergoes a subsequent rearrangement or reacts

j325

j 4 Five-Membered Heterocycles: Pyrrole and Related Systems

326

with water to furnish, among other products, the oxypyrrole 317 (Scheme 4.94). The intermediacy of 316 was suggested on the basis of low-temperature NMR measurements [508].

1O

2

N Me 190

Me N O O

H2O

O

316

N Me

OH

317

Scheme 4.94

Owing to their aromatic character, the applicability of pyrroles as the 2p reactants in normal electron demand Diels–Alder reactions has been quite limited, requiring harsh conditions and giving only moderate yields of products as mixtures of regioisomers [509]. Recently, however, it was demonstrated that pyrroles possessing the strong electron-withdrawing trifluoromethylsulfonyl (Tf) group plus an acetyl group can indeed act as dienophiles at elevated pressure, as illustrated by the conversion of 318 into 319 (Scheme 4.95) [510, 511]. O Me N Tf 318

Me

ZnCl2 (10 mol%), CH2Cl2 16 kbar, 50 °C

Me

80%

O

Me

Me Me

N H Tf 319

Scheme 4.95

Pyrroles may also play the role of dipolarophiles in cycloaddition reactions. Thus for instance, the reactions of certain 1-alkylpyrroles with nitrileimines have been demonstrated to give pyrrolo-fused pyrazoles [512, 513], whereas intramolecular cyclization of nitrile oxide functionalities onto pyrroles involved unstable pyrrolofused isoxazole adducts that underwent ring opening of the isoxazole ring [514]. It has also been established that a series of osmium pyrrole complexes, for example 320 [Os (II)¼[Os(NH3)5](OTf)2], participate as dipoles in cycloadditions with alkenes, for instance providing the endo-adduct 321 in good yield along with minor amounts of the exo-isomer (Scheme 4.96) [515, 516]. Inverse electron demand Diels–Alder reactions have been used successfully for the synthesis of the pyrrolo[2,3-d]pyrimidines 322 from the 2-amino-4-cyanopyrroles 323 and the 1,3,5-triazine 324 (Scheme 4.97). This process is remarkable, as it proceeds readily even at ambient temperature [517]. Based on a theoretical study of the reaction between 2-aminopyrrole and 1,3,5-triazine, it appears that these transformations involve an initial nucleophilic attack of the aminopyrrole on the triazine to form a zwitterionic intermediate, which is in equilibrium with a neutral species, eventually

4.5 Reactivity

1. i-PrNEt2, TMSOTf, CH3CN 2. N-phenylmaleimide

Os(II) N TMS

TMS N

H H O

Os(II)

N O 321

320

Ph

Scheme 4.96

CN H2N

N

N R 323

EtO2C NC

CO2Et

EtO2C

DMSO

N N

84-96%

CO2Et

N R

N N

CO2Et

322

324

Scheme 4.97

undergoing a rate determining cyclization step [518]. The related reaction between 1methylpyrrole and 4,5-dicyanopyridazine gave only a low yield of 5,6-dicyano-1methylindole [519]. An intramolecular inverse electron demand Diels–Alder reaction involving pyrrole as the dienophile component has been employed for conversion of the pyrroletethered 1,2,4-triazine 325 into the tricyclic system 326 in good yield (Scheme 4.98) [520]. Likewise, 1-acyl- or 1-benzoylpyrroles have been used as 2pcomponents in cycloadditions to masked o-benzoquinones [521].

N N N 325

CO2Et CO2Et

diglyme, reflux

N

CO2Et CO2Et

83%

N

N

326

Scheme 4.98

Since the initial reports that 1-alkyl- and 1-aryl-2(3)-vinylpyrroles may serve as diene components in Diels–Alder reactions leading to indoles with interesting substitution patterns [522, 523], several studies exploiting this strategy have emerged. Heating of 1-triisopropylsilyl-(E)-2-(2-phenylsulfinylvinyl)pyrrole with suitable acetylenecarboxylic acid derivatives furnished TIPS protected 4-acylindoles in good yields [524]. A more practical approach involves the readily available 3-vinylpyrrole 327, which gives the adduct 328 upon reaction with N-phenylmaleimide and

j327

j 4 Five-Membered Heterocycles: Pyrrole and Related Systems

328

subsequent isomerization (Scheme 4.99). Similar reactions yielding isomeric adducts were performed using 1-(phenylsulfonyl)-2-vinylpyrrole [525]. Other related indole syntheses encompass the use of silyl enol ethers of 2-acylpyrroles [526, 527], or a diene generated by S-alkylation of 1-methyl-3-thioacetylpyrrole [528] as the 4pcomponents. It is also noteworthy that some sterically hindered N-substituted 2-vinylpyrroles give mainly Michael-type addition at C5, as the required cisoid conformation is disrupted by steric interaction between the group at the pyrrole nitrogen and the substituted vinyl moiety [529].

O

Ph N

O PhMe,

N SO2Ph

76%

O N PhO2S

327

N O

Ph

328

Scheme 4.99

4.5.8 Reactions with Carbenes and Carbenoids

Although it was established early on that pyrroles readily undergo substitution reactions with carbenes [530] the synthetic utility of this reaction appears to be severely limited, as simple pyrroles, for example 1-methylpyrrole, give mixtures of C2 and C3 substituted products [531–533]. Interestingly, in this context, the reactivity rate of pyrrole versus naphthalene towards thermally generated (ethoxycarbonyl) carbene at 150  C is 23 times higher [534]. A useful ring expansion reaction occurs when 2,5-dimethylpyrrole (329) is exposed to dichlorocarbene under neutral aprotic conditions, rendering the pyridine 330. Under basic protic conditions, very little of 330 is formed, along with even lower amounts the 2H-pyrrole 331 [535]. A similar mixture of products, although in considerably higher total yield, is obtained under basic conditions in the presence of a phase transfer catalyst [536]. The pyridine product may result from a rearrangement of the dichlorocyclopropane intermediate 332, in analogy with observations during studies on similar reactions of 2-tert-butyl-5methylpyrrole [537]. H Cl Me

N H 329

Me

Me

N 330

Me

Me

N 331

CHCl2 Me

Me

Cl Cl

N H

Me

332

Addition of carbenes to pyrroles possessing electron-withdrawing groups at the nitrogen atom is recognized to lead to cyclopropanation, as illustrated by the transformation of pyrrole 302 into the bicyclic system 333, with co-formation of the

4.5 Reactivity

j329

product 334 (Scheme 4.100) [538, 539]. An analogous outcome giving cyclopropanated products can be observed upon CuCl-catalyzed decomposition of diazomethane in the presence of 302 [539, 540]. Similar conditions involving CuOTf 1 /2C6H6 as the catalyst allow cyclopropanation of 1-acylpyrroles with methyl diazoacetate in up to 44% yield [541]. H

N2CH2CO2Et CuBr, 85 °C

N H MeO2C

N CO2Me 302

H CO2Et

H

H

H

H

EtO2C

N H H MeO2C

333 (17%)

CO2Et

334 (5%)

Scheme 4.100

Further studies also indicated that 333 undergoes rearrangement to the dihydropyridine derivative 335 by heating at 285  C. This is also true for the diazomethane adduct 336, which is completely converted into 337 within 30 min under the same conditions (Scheme 4.101) [539]. Based on detailed mechanistic studies, these transformations were suggested to proceed through the intermediate acyclic azatrienes 338/339, which give the dihydropyridines 335/337 after final 6p-electrocyclization [539, 542]. H

H R

N H MeO2C

333 R = CO2Et 336 R = H

N R CO2Me

R

N MeO2C

338 R = CO2Et 339 R = H

H

335 R = CO2Et 337 R = H

Scheme 4.101

Stabilized vinyl carbenes also add readily to deactivated pyrroles, for example 340, providing the expected cyclopropanated intermediates 341, which, however, can not be isolated, as an ensuing Cope rearrangement leads directly to the tropane skeleton 342 (Scheme 4.102) [543, 544]. In analogy with previous findings (see above), pyrrole

340 N TMS(CH2)2O2C

Rh2(O2CC6H11)4

hexane, Ar reflux 62%

MeO2C N2 Scheme 4.102

H N H TMS(CH2)2O2C 341

CO2Me

CO2(CH2)2TMS N CO2Me

342

j 4 Five-Membered Heterocycles: Pyrrole and Related Systems

330

itself gives instead a mixture of C2 and C3 substitution products under similar conditions [543]. 4.5.9 Photochemical Reactions

The photochemistry of pyrroles has been studied relatively scantily, and only few synthetically useful procedures have appeared over the years. Interestingly, during the irradiation of pyrrole-2-carbonitrile (343) in methanol solution the isomeric pyrrole-3-carbonitrile 344 was isolated in 55% yield as the major product (Scheme 4.103) [545]. This intriguing isomerization has been suggested to encompass initial generation of the unstable Dewar pyrrole 345, and a subsequent rearrangement involving the aziridine nitrogen to form intermediate 346 [546]. The N-ethoxycarbonyl derivative of the parent ring system of 345 has, interestingly, been generated and trapped as an adduct with 1,3-diphenylisobenzofuran [547], although the formation and reactions of tetrakis(trifluoromethyl) derivatives thereof had been reported previously [548, 549]. CN

CN N H

h , MeOH

CN

55%

N H 345

343

CN

N H 346

N H 344

Scheme 4.103

The photo-induced reaction of pyrroles with aldehydes or ketones provides a route to C3 substituted pyrroles, as illustrated by the conversion of 190 into 347 (Scheme 4.104). Based on NMR studies of the reaction mixture, the oxetane 348 was proposed as a conceivable intermediate [550]. Similar reactions of 1-benzoylpyrrole with 3- or 4-benzoylpyridine led to the isolation of low yields of related bis-adducts [551]. Me OH Me

H Me

Me2CO, h

N Me

40%

190

N Me 347

N H Me 348

Me

O

Scheme 4.104

Light-induced cyclizations of suitable pyrrole containing precursors offer useful routes to more complex fused pyrroles. Thus the heterocyclic stilbene analog 349 undergoes conversion into the system 350 upon irradiation in the presence of Pd/C

4.5 Reactivity

Me

N

N

h , 4-NO2C6H4CO2H Et3N, Pd/C, CH3CN 85%

Me

Me

N

N

349

Me

350

Scheme 4.105

as the dehydrogenating catalyst (Scheme 4.105) [552]. Photochemical annulation reactions of related precursors may also be performed in the presence of iodine with access to air, or alternatively by employing iodine and excess propylene oxide under an argon atmosphere [553]. 4.5.10 Pyrryl-C-X Compounds: Synthesis and Reactions

Pyrrolyl-C-X compounds constitute an important class of derivatives, as pyrroles possessing aminomethyl- or hydroxymethyl substituents are excellent substrates in reactions with nucleophilic reagents. Conversion of the readily available 2-(dimethylamino)pyrrole 232 into the methoiodide 351, followed by treatment with NaCN provides convenient access to (pyrrol-2-yl)acetonitrile (352, Scheme 4.106) [554], whereas a similar displacement with the anion of diethyl phosphite gives the useful diethyl (pyrrol-2-yl)methylphosphonate in 91% yield [555]. This type of elimination–addition processes with N-substituted pyrroles has been implied to involve the intermediacy of azafulvenium ions [287] (Section 4.5.1.7), or in the case of pyrrole itself the azafulvene 353 [556, 557], both of which are prone to attack by nucleophiles at the exo-cyclic carbon. Likewise, 2,5-bis(dimethylaminomethyl)pyrrole may, for example, be converted into the corresponding 2,5-bis(phenylthiomethylene)pyrrole via an intermediate quaternization with iodomethane in good overall yield [558]. However, products that presumably resulted from nucleophilic attack at C5 of 1-methylazafulvenium ions have also been observed [555, 559].

N H 232

NMe2 MeI 91%

N H 351

NMe3 I

NaCN, H2O 52%

CN N H 352

5

2

N 353

Scheme 4.106

Pyrroles containing acetoxymethyl groups at C2 are particularly useful for the construction of di(pyrrol-2-yl)methanes [560–562]. The reaction of the 2-(acetoxymethyl)pyrrole derivative 354 with 355 leading to the molecule 356 (Scheme 4.107) serves as an excellent illustration of the applicability of such approaches [561]. Related transformations may also be carried out using 2-(hydroxymethyl)pyrroles [341, 563], as well as 3-(hydroxymethyl)pyrroles, which display similar behavior, and may for instance be converted into the corresponding 3-(cyanomethyl)pyrroles upon

j331

j 4 Five-Membered Heterocycles: Pyrrole and Related Systems

332

CO2Me

Me

OAc

t-BuO2C

Cl

Me

N H

N H

354

355

CO2Me

Me p-TsOH (cat.) MeOH

CO2t-Bu

t-BuO2C

N H

82%

Me

HN

Cl

t-BuO2C 356

Scheme 4.107

treatment with NaCN [564]. Introduction of the strong electron-withdrawing (trifluoromethyl)sulfonyl group at the nitrogen of 2-(hydroxymethyl)pyrroles blocks the pathway involving azafulvenium ions, thus enabling Mitsunobu-type reactions at the hydroxymethyl moiety [565]. Di(pyrrol-2-yl)methanes have also been prepared under non-acidic conditions, as demonstrated by the reaction of a magnesium derivative of 357 with the 2-(chloromethyl)pyrrole 358 to afford the product 359 (Scheme 4.108). The compound 358 is readily available from pyrrole-2-carboxaldehyde by N-protection, followed by reduction, yielding a 2-(hydroxymethyl)pyrrole, and treatment thereof with methanesulfonyl chloride in the presence of H€ unig’s base [566]. 2-(Haloalkyl)pyrroles may also be used in displacement reactions with, for example, azide ions [567], pyridine or alkoxide ions [568], giving additional useful synthetic intermediates.

S

1. MeMgI, THF, -10 °C 2. Cl N 358 SO2Me

N H

S

S N H

S

50%

357

359

N SO2Me

Scheme 4.108

Pyrroles bearing an (benzotriazol-1-yl)methyl (Bt) substituent at C2, for example 360, may also serve as versatile substrates for conversion into more exotic derivatives, employing a route featuring initial metallation and alkylation to give 361, followed by nucleophilic displacement of the benzotriazol-1-yl moiety to furnish the final product 362 (Scheme 4.109) [102]. Similar reactions involving a,b-unsaturated aldehydes or Ph Bt N Bn 360 Scheme 4.109

1. BuLi, THF, -78 °C 2. MeI 98%

Ph Bt N Bn 361

Me

NaSPh DMF, 150 °C 79%

Ph SPh N Bn 362

Me

4.5 Reactivity

j333

ketones instead of alkyl halides as the electrophiles, eventually leading to indole derivatives, have also been reported [569]. Reduction of 3-acyl-1-(p-toluenesulfonyl)pyrroles with 0.5 equivalents of NaBH4 in refluxing dioxane containing 1 equivalent of i-PrOH gives the corresponding intermediate 1-(pyrrol-3-yl)methanol derivatives, which undergo dehydration in hot DMSO, rendering 3-vinylpyrroles [570]. C-Vinylpyrroles are useful in various applications, for example cycloaddition reactions (Section 4.5.7), and comprehensive reviews highlighting the preparation [571] and synthetic uses of these compounds have appeared quite recently [572]. 4.5.11 Transition Metal Catalyzed Coupling Reactions

The availability of stable halopyrroles, stannylpyrroles and pyrroleboronic acids has opened new possibilities for functionalization of the pyrrole nucleus by transition metal catalyzed reactions, enabling the synthesis of derivatives otherwise difficult to access [573]. A few reactions involving transition metal catalyzed C
H activation in pyrroles have also emerged. There are only a few examples of N-arylation of pyrrole itself using aryl bromides, performed in the presence of t-BuONa and catalytic amounts of Pd(OAc)2 and diphenylphosphinoferrocene (DPPF) and a suitable base [574], or employing the combination Pd(dba)2/P(t-Bu)3/Cs2CO3 [575]. Pyrrole has also been N-arylated with an aryl iodide using CuI/trans-1,2-cyclohexanediamine in the presence of K3PO4 as the catalytic system [576]. 2-Acetylpyrrole, as well as pyrrole-2-carboxaldehydes possessing an additional electron-withdrawing substituent at C4, undergoes efficient N-arylation with arylboronic acids at ambient temperature using stoichiometric amounts of Cu(OAc)2 [577]. Treatment of pyrroles with vinyl triflates in the presence of the system Pd2(dba)3/Xphos/K3PO4 constitutes a new route to 1-vinylpyrroles [578]. It has also been reported that N-alkynylation of electron deficient pyrroles can be achieved using alkynyl bromides in the presence of catalytic amounts of CuSO45H2O and 1,10-phenanthroline [579]. The readily available N-protected 2-bromopyrrole 155 is an excellent partner for Suzuki couplings, offering a convenient route to the 2-arylpyrroles 363 (Scheme 4.110) [580, 581]. An alternative approach is based on coupling of the pyrrole-2-boronic acid 266 with aryl bromides or iodides [582]. Suzuki reactions have also been performed using 1-(phenylsulfonyl)pyrrole-2-boronic acid [583], 2-bromo1-(p-toluenesulfonyl)pyrrole [241] and 2-iodo-1-(phenylsulfonyl)pyrrole [412]. In

Br N Boc

ArB(OH)2 Pd(PPh3)4 (cat.), Na2CO3 PhMe, MeOH (5:1), 80 °C

155 Scheme 4.110

90-99%

Ar N Boc 363

ArX, Pd(PPh3)4 (cat.) Na2CO3, H2O, DME, reflux 15-98%

B(OH)2 N Boc 266

j 4 Five-Membered Heterocycles: Pyrrole and Related Systems

334

addition, it has been demonstrated that electron deficient di- or tribrominated pyrroles undergo selective Suzuki reactions at the a-position with phenylboronic acid derivatives [584]. Heck reactions at the a-position of iodinated pyrroles involving vinylbenzene derivatives [585, 586], as well as Pd(0)-catalyzed couplings with alkynes [587], have also been reported. Suzuki coupling of the triflate 364 with the boronic acid 266 has been employed as the final step in an elegant synthesis of undecylprodigiosin (365) (Scheme 4.111) [588], as well as during preparation of a series of analogues thereof [589].

OMe TfO

N H

OMe 266, Pd(PPh3)4 (cat.), K2CO3 1,4-dioxane, 90 °C, 6 h

N

73%

N H

N H N

C11H23

C11H23

364

365

Scheme 4.111

A new arylation reaction of pyrrolylsodium (366) (Section 4.5.4.1) has been developed. In a representative set of conditions, exposure of 366 to various aryl chlorides or bromides and ZnCl2 in the presence of Pd(OAc)2 and 2-(di-tert-butylphosphino)biphenyl (367), afforded 2-arylpyrroles 368 in high yields (Scheme 4.112). The products 368 may also be subjected to further arylation under similar conditions at the remaining free a-position, providing access to various 2,5-diarylpyrroles [590]. It has also been known for some time that palladium mediated arylation of 1-acylpyrroles with arenes occurs at the a-position. However, this requires stoichiometric amounts of the palladium source [591]. A recent interesting contribution involving C
H activation features regioselective palladium-catalyzed oxidative alkenylation of N-protected pyrroles at C2 or C3 using alkenes under aerobic conditions. The regioselectivity is highly dependent on the steric and electronic properties of the Nsubstituent of the substrate. For instance, the use of 1-(tert-butoxycarbonyl)pyrrole gives C2 alkenylated products, whereas implementation of 1-TIPS-pyrrole leads to functionalization at C3 [592]. ZnCl2, ArX Pd(OAc)2 (cat.), L (cat.) THF,

N Na 366 Scheme 4.112

(t-Bu)2P N H 368

Ar 367

4.5 Reactivity

j335

Cross-coupling techniques may also be applied to the preparation of various 3-substituted pyrroles. The pyrrole-3-boronic acid 281, which is derived from 1-triisopropylsilyl-3-iodopyrrole, takes part in Suzuki couplings with both electron rich and electron deficient aryl halides (X¼Br or I) to provide useful yields of the 3-arylpyrroles 369 (Scheme 4.113). Stille reactions of 1-triisopropylsilyl-3-(tributylstannyl)pyrrole with suitable aryl halides constitute an alternative route to pyrroles of type 369, whereas palladium-catalyzed coupling of 1-triisopropylsilyl-3-iodopyrrole with terminal acetylenes gives high yields of the corresponding 3-ethynylpyrroles. The TIPS group in all products may be removed efficiently by treatment with Bu4NF [418]. In connection with studies on Suzuki couplings involving ethyl 4bromopyrrole-2-carboxylate, a competing dehalogenation of the halopyrrole was observed. This side reaction was, however, suppressed by using the corresponding N-Boc-protected derivative, leading to good yields of ethyl 4-arylpyrrole-2-carboxylates with a concomitant removal of the Boc-group during the process [593]. Other useful developments in this area encompass palladium-catalyzed coupling of 1-(ptoluenesulfonyl)-4-(tributylstannyl)pyrrole-2-carboxaldehyde with aryl- and heteroaryl halides giving the corresponding 4-arylpyrrole-2-carboxaldehydes [594], and synthesis of 3-vinylpyrroles by Stille reactions between various 3-iodopyrroles and vinyltributyltin [595]. In addition, Suzuki couplings involving the triflate derived from 1-benzylpyrrolidine-3-one are accompanied by concomitant dehydrogenation, giving access to 3-aryl-1-benzyl-pyrroles [596]. Finally, both 2-iodo-1-(phenylsulfonyl) pyrrole and its 3-iodo isomer are efficiently cyanated using CuCN in the presence of catalytic amounts of Pd2(dba)3 and dppf [597]. B(OH)2 N TIPS

Ar

ArX, Pd(PPh3)4 (cat.), Na2CO3 PhH, H2O, MeOH, reflux 59-96%

281

N TIPS 369

Scheme 4.113

In an interesting approach towards unsymmetrically 3,4-disubstituted pyrroles, the 3,4-disilylated pyrrole derivative 125 was N-protected, followed by an ipsoiodination to provide the key intermediate 370, which was in turn subjected to various cross-couplings, providing, for example, the products 371 via the Sonogashira reaction (Scheme 4.114) [246, 247], or the corresponding aryl derivatives R TMS

TMS 1. Boc O, DMAP, CH Cl 2 2 2

TMS

I

2. I2, CF3CO2Ag, THF, -78 °C

N H 125 Scheme 4.114

88%

N Boc 370

R

PdCl2(PPh3)2, CuI Et2NH, rt 83-92%

TMS N Boc 371

j 4 Five-Membered Heterocycles: Pyrrole and Related Systems

336

employing Suzuki conditions. A second ipso-iodination and subsequent palladiumcatalyzed coupling reactions give access to further derivatives [247]. Moreover, phosphine-free Suzuki reactions involving methyl 4,5-dichloro-3-iodopyrrole-2-carboxylate occur selectively at C3, giving access to 3-arylpyrrole-2-carboxylates after final removal of the chlorine atoms by catalytic hydrogenation [307].

4.6 Pyrrole Derivatives 4.6.1 Alkyl Derivatives

N-Alkylation of pyrroles is a well documented process that is conveniently accomplished by treatment of pyrrolyl anions with suitable alkylating agents under various conditions (Section 4.5.4.1). Direct C-alkylation is often not particularly practical, as it has been demonstrated that treatment of pyrrolyl anions with allyl-, crotyl- and benzyl-halides gives mixtures of N- and C- monoalkylated products, along with disubstituted derivatives [375]. The methods of choice for the synthesis of alkylpyrroles rely on pyrrole ring formation from acyclic precursors (Section 4.4), or reduction of readily available 2- or 3-acylpyrroles (Section 4.5.1.6). Reduction of 2-benzoylpyrrole (372) with NaBH4 in boiling 2-propanol gives a high yield of 2-benzylpyrrole (373) (Scheme 4.115) [598]. An alternative procedure employs a tert-butylamine–borane complex in the presence of AlCl3 as the reducing system, enabling for example effective transformation of the N-protected 2-acylpyrrole 374 into the corresponding 2-alkylpyrrole 375. This approach is also useful for the reduction of 1-phenylsulfonylpyrrole-2-carboxaldehyde to the corresponding 2-methylpyrrole derivative [599].

N H

Bn

373

NaBH4, i-PrOH reflux 99%

N R1

R2

t-BuNH2·BH3, AlCl3 CH2Cl2, rt

O

372 R1 = H, R2 = Ph 374 R1 = SO2Ph, R2 = Et

87%

n-Pr N SO2Ph 375

Scheme 4.115

These reductions are neatly complemented by the possibility of crafting a secondary alkyl substituent, as illustrated by the conversion of the 3-acylpyrrole 376 into the 3-alkylpyrrole 377, which proceeds via the unstable tertiary alcohol 378 (Scheme 4.116) [598]. A somewhat related approach involving addition of organometallic reagents to 2-acylpyrroles, followed by reduction with lithium in liquid ammonia, has also been described [600].

4.6 Pyrrole Derivatives

O

Me

C15H31 N SO2Ph

MeMgBr, Et2O

376

OH C15H31

N SO2Ph

1. NaOH, MeOH, H2O reflux 2. NaBH4, i-PrOH reflux 27% from 376

Me C15H31 N H 377

378

Scheme 4.116

4.6.2 Pyrrole Carboxylic Acids and Carboxylates

Many pyrrole carboxylic acids are readily available compounds, which are quite prone to decarboxylation. This particular characteristic is very attractive from a synthetic point of view, extending the scope of those pyrrole ring syntheses that give pyrrole carboxylates (Section 4.4). Pyrrole-2-carboxylates are useful substrates for further functionalization by means of electrophilic substitution, as the substituent is strongly “meta” directing, thereby allowing selective synthesis of 2,4-disubstituted pyrroles (Section 4.5.1.6). It is also worth mentioning that amides derived, for instance, from pyrrole-2,5-dicarboxylic acids have recently attracted interest as anion receptors and membrane transport agents for HCl [601]. Decarboxylation of pyrrole-3-carboxylic acids may, for example, be effected by heating [602], whereas ethyl pyrrole-3-carboxylates can be hydrolyzed and decarboxylated in one pot by heating with aqueous NaOH at 175  C in a sealed vessel [124]. Based on kinetic studies, the mechanism of the decarboxylation of pyrrole-2carboxylic acid 198 in acidic media has been suggested to proceed through the intermediate 379, which eventually releases carbon dioxide (Scheme 4.117) [603]. A striking feature during saponification of pyrrolecarboxylates is the relatively high rate constant for pyrrole-2-carboxylates compared to that of the C3 substituted isomers. This behavior has been ascribed to the possibility of intramolecular hydrogen bonding in the intermediate resulting from the attack of a hydroxide ion on the carbonyl carbon in the C2 isomers [604, 605].

O N H

CO2H

198 Scheme 4.117

H+, H2O, 50 °C

N H

H

379

O

-CO2

N H 1

j337

j 4 Five-Membered Heterocycles: Pyrrole and Related Systems

338

4.6.3 Oxy Derivatives

1-Hydroxypyrrole derivatives are available by several routes, for example employing hydroxylamine in the Paal–Knorr pyrrole synthesis [606], by thermolysis of 1-(tertbutyl)-3-pyrrolin-1-oxide to 1-hydroxy-3-pyrroline [607] or via treatment of suitable monooximes derived from 1,2-dicarbonyl compounds with sodium hydride, followed by vinyltriphenylphosphonium bromide, which gives 2,3-disubstituted 1hydroxypyrroles [608]. Deuterium exchange studies with D2O in CDCl3 performed on 1-hydroxy-2,3-diphenylpyrrole (380) indicated incorporation of deuterium at C4 and C5 along with the expected deuterium exchange at the oxygen, suggesting contributions from the tautomeric forms 381 and 382 (Scheme 4.118) [608]. Ph Ph

Ph

Ph Ph

N O 381

Ph

N OH 380

N O 382

Scheme 4.118

Oxidation of pyrrole employing hydrogen peroxide gives a modest yield of the tautomeric 2-oxypyrroles 383 and 384, the former being the prevalent component as judged from NMR data (ratio 383 : 384 ¼ 9 : 1 in acetone-d6) (Scheme 4.119) [609]. Purified samples of 383 remain rather stable for several weeks upon storage at
10  C, whereas the isomer 384 undergoes much faster isomerization [610]. After initial N-protection of 383, access to a useful synthetic intermediate is gained by trapping of the corresponding 2-hydroxypyrrole tautomer as the silyl ether 385, which reacts with aldehydes, rendering for example the 5-substituted pyrroline-2-one 386 [611, 612]. The oxypyrrole 385 has also been efficiently prepared on multikilogram scale via cyclization of racemic 4-amino-3-hydroxybutyric acid with HMDS H2O2, BaCO3, H2O reflux

N H 1

30%

O

N H 383

1. Boc2O, DMAP, CH3CN 2. TBSOTf, 2,6-lutidine, CH 2Cl2

OHC

O O

N H 384

66% 1. BF3·OEt2, Et2O, -85 °C 2. TMSCl, pyridine, -30 °C

TBSO

N Boc 385

Scheme 4.119

O

63%

H O

N Boc 386

OTMS O

O

4.6 Pyrrole Derivatives

in the presence of pyridine to 4-(trimethylsiloxy)pyrrolidine-2-one, which underwent subsequent Boc-protection, desilylation and elimination to yield 1-(tert-butoxycarbonyl)-3-pyrroline-2-one. This material could then be efficiently converted into 385 using TBSOTf in the presence of triethylamine [613]. It is also noteworthy that electrolytic fluorination of 2-cyano-1-methylpyrrole with Et3N3HF in acetonitrile, followed by treatment with water, gives 5,5-difluoro-1-methyl-3-pyrrolin-2-one, a useful starting material for the construction of some gem-difluorinated heterocycles [614]. The reaction of ethyl N-ethoxycarbonyl glycinate with ethyl fumarate in the presence of sodium in benzene solution, followed by decarboxylation, provides convenient access to the 3-oxypyrrole derivative 387 [615]. This material may for instance be further converted into the substituted 3-methoxypyrrole 388 by ketalization and dehydrogenation over Pd/C with concomitant cleavage of the carbamate functionality (Scheme 4.120) [616]. 3-Alkoxypyrroles have also been prepared by cyclization of alkyl 4-bromo-3-alkoxy-2-butenoates with suitable amines to 4-alkoxy-3pyrrolin-2-ones, and subsequent treatment thereof with diisobutylaluminium hydride [617]. O CO2Et N CO2Et

1. (MeO)2SO2, HCl (cat.) MeOH 2. Pd/C,

MeO N H

387

CO2Et

388

Scheme 4.120

Cyclization of the precursors 389, which are readily available from glycine esters and diethyl ethoxymethylenemalonate, provides a route to the stable 3-hydroxypyrrole derivatives 390 (Scheme 4.121). The C4 substituent may be selectively removed by alkaline hydrolysis, followed by decarboxylation [618]. EtO2C

CO2R2 N R1

CO2Et CO2Et

389

OH

NaOR2, R2OH 24-86%

N R1

CO2R2

390

Scheme 4.121

In an approach based on intramolecular Wittig olefination, alkylation of, for example, N-acetylacetamide (391) with the reagents 392 (X ¼ Br or Cl) afforded the precursor 393, which was in turn cyclized to the 3-oxypyrrole derivative 394 under thermal conditions (Scheme 4.122) [619]. Apart from the examples mentioned above, 3-oxypyrroles are also available by for instance flash vacuum pyrolysis of N,N-disubstituted aminomethylene derivatives of

j339

j 4 Five-Membered Heterocycles: Pyrrole and Related Systems

340

O

O

O

Me

X Me

N H

PPh3

O

391

Me O

NaH, DMF 58%

392

O Me

N

mesitylene 56%

PPh3 393

O N Ac

Me

394

Scheme 4.122

Meldrum’s acid [620]. A representative member of this class, 1-phenyl-1H-pyrrol-3 (2H)-one, exists as mixtures of the tautomeric forms 395 or 396 depending on the medium. In general, polar solvents favor the enol form 396, whereas in the solid state the keto tautomer 395 alone was detected (Scheme 4.123) [621]. The enol form was also detected as the prevalent species in DMSO solution in the case of the parent 3hydroxypyrrole [622]. In addition, preference for the enol tautomers has been observed in connection with studies of derivatives containing an ester functionality at the adjacent C4 position [623]. Regiospecific O-alkylation of 3-hydroxypyrroles can be accomplished in polar aprotic solvents such as dimethylimidazolidinone (DMI), using the hard alkylating agent methyl p-toluenesulfonate to give, for example, pyrrole 397. In contrast, the use of soft alkylating agents, such as iodomethane in relatively nonpolar solvents, leads to increased amounts of C-alkylated products [624]. O

OH

N Ph 395

OMe

NaH, 4-MeC6H4SO3Me DMI

N Ph

80%

N Ph 396

397

Scheme 4.123

Derivatives of tetramic acid (398) constitute a relatively large class of oxygenated pyrroles, which has been studied in considerable detail [35, 625]. The parent compound 398 is a relatively weak acid, (pKa¼6.4 in water), which exists in the keto from in the solid state, whereas in aqueous solution a minor contribution from the enol 399 may be discerned [626]. The enolization behavior of 3-acetyltetramic acids is more complex; studies involving for instance the 3-acetyl-5-isopropyl derivative revealed a considerable contribution from the exo-enol tautomer 400 [627]. Me O

HO

4 2

N H 398

O

O N H 399

O

i-Pr

OH N H 400

O

4.6 Pyrrole Derivatives

The most practical and widely used approach to tetramic acid derivatives has been developed by Lacey, and involves Dieckmann cyclization of N-acyl-a-amino esters. For example, the precursor 401, which is available by treatment of ethyl glycinate with diketene, gives 3-acetyltetramic acid 402 upon treatment with sodium methoxide (Scheme 4.124) [628]. Application of these conditions to substrates derived from optically active amino acids may cause racemization, which can, however, be avoided by conducting the cyclization in the presence of TBAF in THF, or potassium tertbutoxide in tert-butanol during short periods of time. These modified routes also involve generation of the acyclic precursors from b-ketothioesters and amino acids [629]. Suitable precursors to tetramic acids may also be prepared by treatment of hippuric acid [630] or aceturic acid [631] derivatives with anions of active methylene compounds. The Dieckmann cyclization strategy has also been utilized in a solid phase approach starting from amino acid derivatives attached to the resin by an ester linkage [632]. A recent contribution to this field encompasses preparation of 5substituted teramic acid derivatives by cyclocondensation of amidines with DMAD, followed by alkaline hydrolysis of the intermediate 5-amino-4-pyrrolin-3-ones [633].

O

O N H

CO2Et

NaOMe, PhH reflux 3 h

O

Me OH O N H 402

76%

401 Scheme 4.124

The methyl tetramate 403, as well as several similar compounds, is available by treatment of methyl 4-bromo-3-methoxy-2-butenoate 404 with methylamine [634], and may be converted into the corresponding 3-alkoxypyrroles, for instance 405, by treatment with diisobutylaluminium hydride (Scheme 4.125) [617]. Furthermore, the representative tetramate 403 undergoes metallation at C5 upon exposure to butyllithium, and the resulting lithio derivative gives access to various C5 substituted products after subsequent treatment with suitable electrophiles [635]. It has also been established that methyl tetramates of type 403 having an isopropyl moiety [636] or two substituents [637] at C5 may be acylated at C3 via lithiation, followed by introduction of aldehydes, and oxidation of the intermediate alcohols. The active methylene unit of tetramates may also participate in condensation reactions with aldehydes in the presence of sodium hydroxide in aqueous DMSO [588]. MeO

MeO Br

CO2Me

404 Scheme 4.125

DIBAL, THF 0 °C to rt

MeNH2 49%

N Me 403

O

45%

MeO N Me 405

j341

j 4 Five-Membered Heterocycles: Pyrrole and Related Systems

342

4.6.4 Aminopyrroles

Simple aminopyrroles are highly electron rich and thus often labile species, but the stability may be improved considerably by the presence of electron-withdrawing substituents. A series of 1-aminopyrroles, including 406, has been prepared by Namination of the corresponding NH-pyrroles with anhydrous ethereal NH2Cl in the presence of NaH [638]. Recently, a more convenient N-amination protocol for pyrroles has been realized under phase transfer conditions using in situ generated chloramine as the electrophilic aminating agent [639]. Interestingly, 1-(N,N-dimethylamino)pyrrole (407) can be easily prepared by heating 2,5-dimethoxytetrahydrofuran and N,N-dimethylhydrazine in acetic acid, and is cleanly lithiated at C2 [416]. EtO2C

CF3 CO2Et N NH2 406

N NMe2 407

The parent 2-aminopyrrole (408) was generated from the (pyrrole-2-yl)phthalimide 409 [640], which is in turn available by treatment of 1-trimethylsilylpyrrole with chlorophthalimide followed by aqueous workup (Scheme 4.126) [230, 641]. The aminopyrrole 408, as well as 1-alkyl- and 1-aryl derivatives thereof, have to be kept in acid solution. A fast proton exchange at C5 in this series was observed in glacial acetic acid [640], and further NMR studies indicated that the conjugate acids of the 2aminopyrroles exist as protonated imines under these conditions [641]. It has also been demonstrated that 2-aminopyrroles incorporating an electron-withdrawing substituent at the adjacent b-carbon can undergo protonation at either the exocyclic nitrogen atom or C5, depending on the conditions, but react at the exocyclic nitrogen only with acylating agents, thus behaving like typical aromatic amines rather than enamines [642]. O N H

N O 409

1. NaBH4, i-PrOH 2. AcOH, 80 °C 3. NaOH

O N H

NH2

O

408

Scheme 4.126

A useful approach featuring a pyrrole ring synthesis involves treatment of the readily available aminoacetaldehyde dimethyl acetals 410 with malononitrile under acidic conditions to provide facile access to the 2-aminopyrrole-3-carbonitriles 411 in moderate yields (Scheme 4.127). Similar products may also be prepared from ethyl 3cyanopyrrole-2-carboxylates using a route based on the Curtius rearrangement [643]. 2-Aminopyrroles have also been obtained by base induced condensation reactions

4.6 Pyrrole Derivatives

H2N

1. R1CHO, PhH, reflux OMe 2. NaBH4, EtOH

R1

OMe

N H

j343 CN

NCCH2CN p-TsOH·H2O (2 equiv.) OMe CH2Cl2

NH2

N

OMe

R1 411

410 Scheme 4.127

between acetylaminoacetone and substituted acetonitriles [644], or from N-acetyla-aminoketones and malononitrile [645]. Yet another contribution to aminopyrrole chemistry is represented by a procedure for palladium-catalyzed amination of 2-acetyl-5-bromo-1-methylpyrrole (412), which can be performed using various primary and secondary amines, giving for example the 2-aminopyrrole derivative 413 (Scheme 4.128) [646]. An effective amidation of methyl 4-bromo-1-methylpyrrole-2-carboxylate with tert-butyl carbamate in the presence of the combination CuI/K3PO4/N,N0 -dimethylethylenediamine has also been reported [236].

Me O

N Me

Br

HN

N CO2Et

Pd2(dba)3 (2 mol%) BINAP (4 mol%), t-BuONa PhMe, 80 °C

Me

85%

O

412

N Me

N

N CO Et 2

413

Scheme 4.128

3-Aminopyrroles featuring electron-withdrawing moieties have attracted some interest as building blocks for pyrrolo[2,3-d]pyrimidines [647, 648]. Consequently, several synthetic approaches to such derivatives have been described. The a-cyanoaldehydes 414, which are derived from suitable aldehydes by base induced condensation with 3,3-dimethoxypropionitrile, followed by hydrolysis of the acetal and catalytic hydrogenation, serve as excellent substrates for the generation of enamine intermediates 415 by treatment with diethyl aminomalonate (Scheme 4.129). A final cyclization step afforded the 3-aminopyrrole derivatives 416 in moderate to good overall yields [648]. A route based on cyclization of similar enamine intermediates has been used for the synthesis of methyl 3-amino-4-arylpyrrole-2-carboxylates [649].

MeO

1. RCHO, NaOMe OMe 2. 6 N HCl 3. H2, Pd/C

CN

CHO CN R

H2NCH(CO2Et)2 NaOAc

CN R

414 Scheme 4.129

NHCH(CO2Et)2

415

R NH2

NaOMe, MeOH

N H 416

CO2Me

j 4 Five-Membered Heterocycles: Pyrrole and Related Systems

344

A different substitution pattern is displayed in the pyrroles 417, which were prepared by tosylation of the cyanoacetyl compounds 418 rendering the precursors 419 (Scheme 4.130). These intermediates were in turn converted into the target heterocycles by reaction with diethyl aminomalonate hydrochloride in the presence of ethoxide [650]. Treatment of benzyl 4-oxoproline-2-carboxylate derivatives protected at the nitrogen by the 9-(9-phenylfluorenyl) group with primary or secondary amines in the presence of catalytic amounts of p-TsOH provides an efficient route to 4-aminopyrrole-2-carboxylates [651]. CN

Ts2O, Et3N CH2Cl2

O

R

R

418

CN

(EtO2C)2CHNH2·HCl NaOEt, EtOH

OTs

30-61% overall

419

NH2 R

N H 417

CO2Et

Scheme 4.130

3-Amino-1-tritylpyrrole (420) has been prepared from the corresponding pyrrole-3carboxylic acid in several steps using a route involving the Curtius rearrangement, and was demonstrated to exist exclusively as the 3-imino tautomer 421 in CDCl3 solution [210]. A series of 1-arylpyrroles, as well as 1-methylpyrrole, has recently been shown to undergo amination, providing the interesting derivatives 422 in good yields using N-(p-toluenesulfonyl)imino-phenyliodinane (PhI¼NTs) in the presence of a ruthenium(II) porphyrin catalyst [652]. NH2 N CPh3 420

NH N CPh3 421

TsHN

NHTs N R 422

4.6.5 Dihydro- and Tetrahydro-Derivatives

The scope of this chapter only allows inclusion of selected examples of procedures involving dihydro- and tetrahydro derivatives, but it is important to emphasize that many significant compounds belong to these thoroughly studied systems, for instance the amino acid L-proline. Both 2- and 3-pyrrolines (2,3-dihydro- and 2,5dihydropyrroles), as well as pyrrolidines (tetrahydropyrroles), are available by reduction of pyrrole derivatives (Section 4.5.6). The reverse transformation, that is, conversion of pyrrolidines into pyrroles, may be accomplished for instance by dehydrogenation with MnO2 in refluxing THF [653]. In more recent years, several useful ring syntheses of partially, or completely saturated pyrrole derivatives have emerged, for example 2,5-disubstituted pyrrolidines [654]. Several practical approaches rely on the cyclization of suitable diol

j345

4.6 Pyrrole Derivatives

derivatives, for instance 423, which gives the trans-pyrrolidine 424 upon treatment with benzylamine (Scheme 4.131) [655]. Base induced annulation of mesylates derived from suitable chiral c-aminoalcohols constitutes an alternative procedure for the stereoselective preparation of cis- or trans-2,5-disubstituted pyrrolidines [656]. OMs H11C5

BnNH2, rt

C4H9

OMs

H11C5

77%

423

C4H9

N Bn 424

Scheme 4.131

Reductive amination of 1,4-diketones with ammonium acetate [657] or amines in the presence of NaCNBH3 provides routes to pyrrolidines as mixtures of cis- and trans-isomers, the former being favored by increasing size of the amine reactant [658]. A related one-pot approach giving the 1-(2-naphthyl)methyleneor 1-(3,4-dimethoxybenzyl)pyrrolidines 425 involves reductive cyclization of the four-carbon precursors 426, which are in turn available by conjugate addition of the a-(alkylideneamino)nitriles 427 to the a,b-unsaturated ketones 428 (Scheme 4.132) [659].

3

R

CN R2

R4

N

R1

427

1. DBU, THF 2.

O

R3

R5 R4 428

R3

O

R2 R5 N NC R1 426

NaCNBH3

R4

R2

36-84%

N

R5

R1 425

Scheme 4.132

Pyrrolidines containing sensitive substituents have been prepared under mild conditions using a tandem cationic aza-Cope rearrangement–Mannich process. Thus, treatment of the substituted 3-butenamines 429 with appropriate aldehydes in benzene or toluene affords moderate to excellent yields of the substituted 3-acetylpyrrolidines 430 (Scheme 4.133) [660].

R1

RO

N Me H ·HBF4

429 R = H or Me Scheme 4.133

OR Me

R5CHO 24-110 °C 54-97%

R5

N R1

O

OR Me R5

N R1

Me R5

N R1 430

j 4 Five-Membered Heterocycles: Pyrrole and Related Systems

346

A general approach to pyrrolidines involves 1,3-dipolar cycloadditions of alkenes and azomethine ylides, which are for instance available by desilylation of a-silyl iminium salts [661]. This strategy has been exploited in construction of the system 431, which resulted from a reaction of the ylide 432 with N-methylmaleimide (Scheme 4.134) [662]. The various routes to enantiopure pyrrolidine derivatives based on cycloaddition reactions involving azomethine ylides have been recently summarized in a review [663].

X

S S

N Me

TMS

CsF MeCN

O

S S

N Me

Me N

O

82%

Me N

O H S

H

S

432

O

N Me

431

Scheme 4.134

The pyrrolidines 433 incorporating an exocyclic double bond have been synthesized by cycloaddition of the N-tosylimines 434 with a palladium complex derived from the precursor 435 (Scheme 4.135). Similar syntheses of various pyrrolidine derivatives may also be performed starting from aliphatic N-tosylimines (readily generated from the corresponding aldehydes by treatment with chloramine-T and elemental selenium), nitrimines or other electron deficient imines [664].

Ar

N

Ts

AcO

434

TMS

Pd(PPh3)4 THF, 95-98%

Ar

435

N Ts 433

Scheme 4.135

Based on a previous approach for palladium-catalyzed cyclization of 3-alkynylamines yielding 1-pyrrolines [665], the precursors 436, derived from a propargylglycine derivative via Sonogashira coupling, were deprotected under acidic conditions, followed by silver-catalyzed cyclization, providing a route to the 1-pyrrolines 437 (Scheme 4.136) [666]. Palladium-catalyzed ring closure of related precursors may instead give 2-pyrrolines, whereas the application of 4-alkynylamines in similar 1. HCl, EtOAc 2. NH3, 1,4-dioxane, H2O 3. AgOTf (cat.), CH3CN

MeO2C BocHN

54-80%

436 Scheme 4.136

Ar

Ar

N 437

CO2Me

4.6 Pyrrole Derivatives

processes gives pyrrolidines incorporating an exocyclic double bond [667]. Densely substituted 1-pyrrolines may also be accessed by 1,3-dipolar cycloaddition reactions between acrylamide derivatives and nitrile ylides generated from imidoyl chlorides [668]. Preparative routes and transformations involving 1-pyrrolines have been reviewed [669]. A traditional approach to 1-pyrrolines relies on addition of Grignard reagents to c-halonitriles, which gives rise to the 2-substituted systems [670, 671]. It was later demonstrated that application of hydrocarbon/ether solvent mixtures for such reactions constitutes a practical modification [672]. Addition of but-3-enylmagnesium bromide to benzonitriles 438, followed by treatment with NBS, leads to formation of 1-pyrrolines 439 (Scheme 4.137) [673], whereas chlorination using NCS gives the related 5-(chloromethyl)-1-pyrroline derivatives [674]. 1.

MgBr THF, reflux, 5 h 2. NBS, 0 °C to rt

Ar CN

39-71%

438

Ar

Br N 439

Scheme 4.137

Ring closing metathesis (RCM) of the enamides 440 (R1¼Ts, Bz, CO2Et) has been employed for the preparation of the 2-pyrrolines 441 using the catalyst 442 (Scheme 4.138). In some cases, better yields were obtained using a related, Ru–imidazoline RCM catalyst [675]. R3 2

R

N R1

442 (cat.) CH2Cl2 59-84%

R2

440

N R1 441

PCy3 Ph Cl Ru Cl PCy3 442

Scheme 4.138

Likewise, RCM methodology is also applicable for the construction of 3-pyrrolines, as illustrated by the synthesis of 443 from the diene 444 (Scheme 4.139) [676]. In a

Me

N Bn 444

Scheme 4.139

445 (4 mol%) PhH 85%

Me i-Pr N Bn 443

N (F3C)2MeCO Mo (F3C)2MeCO 445

i-Pr C(Me)2Ph

j347

j 4 Five-Membered Heterocycles: Pyrrole and Related Systems

348

related RCM approach to 3-pyrrolines, a suitable set of N-SES protected dienes were constructed from 2-(trimethylsilylethane)sulfonamide, aldehydes and methyl acrylate in an aza-Baylis–Hillman reaction [677]. On the other hand, the cyclization of diallylamines using the second generation Grubbs’ catalyst (10 mol.%) in combination with RuCl3H2O (2 mol.%) gives rise to pyrroles in moderate yields [678]. An alternative route to 3-pyrrolines relies on triphenylphosphine-catalyzed [3 þ 2] cycloaddition reactions of methyl 2,3-butadienoate with N-tosyl aldimines [679]. As a typical secondary amine, pyrrolidine displays pronounced basic character, and reacts readily as an N-nucleophile, affording, for example, amides. A well known application of pyrrolidines is its condensation with carbonyl groups to give enamines, which may subsequently be alkylated or acylated, providing an excellent and versatile route to a-substituted carbonyl compounds after a final hydrolysis step [680]. Reactions at the carbon atoms of simple pyrrolidines have been less studied. Nevertheless, several synthetically useful transformations have been described. It has for example been established that deprotonation and subsequent silylation of N-Bocpyrrolidine (446) gives the intermediate 447 (Scheme 4.140) [681]. This material was subjected to a second lithiation/silylation cycle to provide the pyrrolidine derivative 448. After removal of the Boc-group, followed by N-benzylation, the resulting pyrrolidine 449 was converted into the azamethine ylide 450, which was trapped with ethyl propiolate to furnish adduct 451 [682]. An enantioselective cycloaddition between 450 and a chiral alkene has also been described [683]. Deprotonation of methyl 3-pyrroline-1-carboxylate with LDA at C2, and subsequent quenching with suitable electrophiles, provides an example of the functionalization of 3pyrrolines [684].

N Boc 446

1. sec-BuLi, TMEDA Et2O, -78 °C 2. TMSCl 90%

TMS N Boc 447

1. sec-BuLi, TMEDA Et2O, -45 °C 2. TMSCl 70%

TMS

TMS N Boc 448 1. TFA, CH2Cl2 80% 2. BnCl, K2CO3 CH3CN

Bn N

Ag(I)F, CH2Cl2

CO2Et CO2Et

451

75%

N Bn 450

TMS

N Bn

TMS

449

Scheme 4.140

In an interesting example of enantioselective functionalization at C2, N-Bocpyrrolidine 446 was treated with sec-BuLi in the presence of (
)-sparteine (452) to produce the chiral lithio derivative 453, which upon quenching with suitable electrophiles gave the 2-substituted derivatives 454 (Scheme 4.141) [685, 686]. Two

4.7 Addendum sec-BuLi, 452 Et2O, -78 °C

N Boc

Li

N t-BuO

446

O 453

H

E+ 12-99%

E N Boc

H N

N H 452

454 (ee up to 96%)

H

Scheme 4.141

sequential lithiations of 446, each followed by quenching with dimethyl sulfate, furnished the corresponding trans-2,5-dimethylpyrrolidine derivative [686]. The species 453 may also be used for enantioselective ring opening of epoxides, provided that one equivalent of BF3OEt2 is added directly after the electrophile [687]. Transmetallation of 453 with CuCN2LiCl generates a corresponding cuprate with retention of configuration, and subsequent reactions thereof with, for example, vinyl iodides or triflates give vinylated products with excellent enantioselectivity [688]. Pyrrolidine derivatives may also be functionalized via conversion into N-acyliminium ions, as illustrated by the conversion of the pyrrolidine 455 into the product 456 (cis : trans ratio 7 : 3) employing SnCl4 and TMSCN, via the intermediate 457 (Scheme 4.142) [689].

MeO

OBn SnCl4, CH2Cl2 N CO2Me 455

OBn N CO2Me 457

TMSCN 86%

NC

OBn N CO2Me 456

Scheme 4.142

4.7 Addendum

Even a rather superficial glance at the most recent literature of organic chemistry clearly reflects the tremendous amount of effort currently invested in research activities focusing on pyrrole based molecules. This addendum highlights some selected new developments reported during the production process of this book, as well as some related relevant studies. As usual, an annual summary of the most important recent advances in Progress in Heterocyclic Chemistry provides an excellent source of information [690]. In addition, the new edition of Comprehensive Heterocyclic Chemistry has appeared, covering various aspects of pyrrole chemistry explored during the last decade [691–694]. Several specialized reviews have also emerged, discussing for example some synthetic aspects of pyrroles bearing multiple substituents [695], or asymmetric synthesis of pyrrolidines by [3 þ 2] cycloadditions of azomethine ylides [696]. Because much novel pyrrole chemistry is directed towards synthesis and applications of macrocycles, topics such as carbaporphyrins and related porphyrinoids [697], acyclic oligopyrroles [698], expanded porphyrins [699],

j349

j 4 Five-Membered Heterocycles: Pyrrole and Related Systems

350

and their transition metal complexes [700], and nonlinear optical properties of porphyrins [701], as well as synthetic work towards porphyrins involving the Barton–Zard reaction [702], have received treatment. In addition, the pyrrole alkaloids lamellarins and their relatives have been discussed in detail [703]. Mechanistic aspects of the Paal–Knorr synthesis have been addressed in a density functional theory study [704], supporting the previously suggested pathway [71] that involves a cyclization of a hemiaminal intermediate in the rate-limiting step (Section 4.4.1). Although the extensive arsenal of well-established routes for pyrrole ring synthesis gives access to a wide variety of products, there is a continuous stream of new approaches that attempt to target pyrroles with rare substitution patterns, or serve as complementary methods for construction of known groups of useful derivatives. Numerous routes rely on reactions of substrates containing all the necessary carbon atoms. It has been shown that PtCl4 catalyzes cyclization of homopropargyl azides in the presence of a bulky pyridine as the base, affording for instance 2,5substituted pyrroles, or tetrahydroindole derivatives [705]. The recent surge in goldor silver-catalyzed organic transformations has also exerted some impact on heterocyclic chemistry, as illustrated by the conversion precursor 458 into the pyrrole 459 by exposure to benzyl amine in the presence of silver trifluoromethanesulfonate (Scheme 4.143). Such transformations can also be performed using the catalytic system AuCl/AgOTf/PPh3 [706]. Moreover, palladium-catalyzed reactions between N-protected c-aminoalkenes and functionalized aryl bromides in the presence of a phosphine ligand and a base have furnished a set of multiply substituted pyrrolidines [707]. A series of potentially useful pyrroles has also been prepared by CuI-catalyzed cyclization of 1,4-dihalo-1,3-dienes with tert-butyl carbamate [708]. BocHN

O

BnNH2, AgOTf (5 mol%) ClCH2CH2Cl, 50 °C, 18 h

CO2Me

BocHN N Bn

78%

458

CO2Me

459

Scheme 4.143

Azidodienes are readily available by condensation of azidoacetic acid esters with a,b-unsaturated aldehydes, and contain all the atoms necessary for a construction of a pyrrole ring. This fact was exploited in the conversion of precursor 460 into the pyrrole-2-carboxylate 461 in good yield upon treatment with catalytic amounts of zinc iodide, providing a representative illustration of this route (Scheme 4.144). The Cl CO2Me N3 460 Scheme 4.144

ZnI2 (5 mol%), CH2Cl2 25 °C, 15 h 80%

Cl N H 461

CO2Me

4.7 Addendum

j351

procedure could be applied for the preparation of various pyrrole-2-carboxylates bearing aryl, heteroaryl, and alkyl groups [709]. Likewise, pyrrole derivatives have also been constructed by initial reactions of 1,3-dicarbonyl anions with a-azidoketones, and ensuing annulation of the resulting intermediates employing the Staudinger– aza-Wittig reaction [710]. Precursors for similar reductive cyclizations may also be assembled from 1,3-bis-silyl enol ethers and 1-azido-2,2-dimethoxyethane in the presence of TMSOTf [711]. The elaboration of new [3 þ 2] strategies, as well as the development of new aspects of the classical methods, continues, as illustrated by a new variation of the Barton–Zard pyrrole synthesis (Section 4.4.7), which has been applied for construction of pyrrolic Weinreb amides en route to pyrrole-2-carboxaldehydes and pyrroline-3-ones. For example, the isocyanide 462, which is available in four steps from Boc-glycine, was converted upon reaction with the b-nitroacetate 463 into the Weinreb amide 464 (Scheme 4.145) [712]. The use of ketene S,S- or S,N-acetals in Barton–Zard reactions provides a route to substituted pyrroles bearing methylthio- or amino groups at C3. Such systems could also be prepared employing the related van Leusen method (Section 4.4.6) for the pyrrole ring formation [713]. A practical one-pot route to 4substituted pyrrole-3-carboxylates on a multi-kilogram scale has been presented, featuring a Horner–Wadsworth–Emmons reaction of aliphatic or aromatic aldehydes with trimethyl phosphonoacetate, followed by a van Leusen pyrrole synthesis involving TosMIC [714].

Me N OMe

CN O

462

Et

Me

O2N

OAc

Et

DBU, THF 0 °C to rt

Me N H

95%

463

Me N OMe

O 464

Scheme 4.145

It has been demonstrated that the vinyl azides 465 may serve as an excellent starting point for pyrrole synthesis, as heating of such substrates with acetylacetone in toluene produced pyrroles 466 (Scheme 4.146). Interestingly, a related coppercatalyzed reaction involving instead ethyl acetoacetate proceeded with different regioselectivity, to provide the ethyl pyrrole-3-carboxylates 467, thereby widening the scope of this strategy [715].

EtO2C Ar

COMe N H 466

Scheme 4.146

Me

MeCOCH2COMe PhMe, 100 °C 81-96%

N3 Ar

CO2Et 465

MeCOCH2CO2Et Cu(NTf2)2 (5 mol%) H2O (5 equiv.) CH3CN, 40 °C 54-86%

EtO2C Me

Ar N H 467

CO2Et

j 4 Five-Membered Heterocycles: Pyrrole and Related Systems

352

Palladium-catalyzed pyrrole ring synthesis from the halogenated aminoester 468 with various acetylenes has been examined. For instance, reaction between 468 and diphenylacetylene in the presence of Pd(OAc)2 affords pyrrole 469 with concomitant loss of the acyl group (Scheme 4.147). However, some similar cyclizations gave products where the acyl group was untouched. The use of certain unsymmetrical alkynes (e.g., 1-phenyl-2-trimethylsilylacetylene) can give rise to regioselective formation of pyrroles [716]. MeO2C

H N

Ph Ac

Ph

Pd(OAc)2 (5 mol%) LiCl, K2CO3, DMF, 65 °C

I

77%

Ph Ph

468

CO2Me

N H 469

Scheme 4.147

Pyrrolidines (Section 4.6.5) may be produced efficiently by cycloaddition reactions involving azomethine ylides [696]. An organocatalytic application of this approach has now became available, utilizing the catalyst 470, which could for instance mediate the efficient and enantioselective [3 þ 2] cycloaddition of components 471 and 472, affording the pyrrolidine 473 (Scheme 4.148) [717]. It should also be mentioned that application of a-(alkylideneamino)nitriles in reactions with nitroalkenes provides a useful pyrrole synthesis, which relies on elimination of HCN and HNO2 as the driving force for aromatization. This pathway involves a stepwise annulation mechanism rather than a cycloaddition [718]. In addition, a series of 4-hydroxypyrrole-2,3-dicarboxylates have been prepared by reactions of a-amino acids with acetylenedicarboxylates in the presence of cyclohexyl isocyanide or N,N0 -dicyclohexylcarbodiimide as the coupling reagents [719].

CO2Et Ph

N

CO2Et

CHO

n-Bu

471

472

470 (20 mol%) H2O (4 equiv.) THF, 4 °C 88% (99% ee)

OHC Ph

n-Bu CO2Et N H 473

CO2Et

N H

Ph Ph OH 470

Scheme 4.148

The largely neglected Piloty–Robinson [720–722] pyrrole synthesis has been adapted to microwave conditions [723], providing a route to 3,4-dialkylpyrroles, in particular 3,4-diethylpyrrole, a building block for construction of octaethylporpyrins [724, 725]. Thus, the intermediate azine 474 was generated by exposure of butyraldehyde to hydrazine hydrate in diethyl ether. Subsequent heating of 474 in the presence of benzoyl chloride in pyridine in a microwave apparatus gave the N-substituted product 475 (Scheme 4.149), which could subsequently be hydrolyzed to the desired 3,4-diethylpyrrole [723].

4.7 Addendum

Et

CHO

H2NNH2·H2O Et2O, 0 °C to rt

Et

Et N N 474

PhCOCl pyridine 180 °C, 30 min (microwave)

Et

Et N

55%

Ph

O 475

Scheme 4.149

Several new direct pyrrole syntheses based on multicomponent reactions (Section 4.4.10) have emerged recently, featuring for instance imines, diazoacetonitrile, and alkynes as the reactants in the presence of a rhodium(II) catalyst. The sequence of events leading to pyrroles presumably involves initial decomposition of the diazo compound, formation of an intermediate azomethine ylide upon reaction with the imine, and finally cycloaddition with the alkyne [726]. Similar sets of starting compounds, namely, imines, acid chlorides, and alkynes, may also be converted into pyrroles in the presence of either isocyanides [727] or phosphines [728]. The latter approaches have been suggested to proceed via cycloaddition reactions between mesoionic intermediates with the alkyne components [727, 728]. Intermediate m€ unchnones can also be generated by a palladium-catalyzed reaction between certain a-amidoethers with carbon monoxide, eventually affording pyrroles via cycloadditions with suitable alkynes [729]. Additional efforts resulted in conversion of 1,3-dicarbonyl compounds, arylglyoxals, and ammonium acetate into 2-alkyl-5aryl-4-hydroxypyrroles in water as the reaction medium [730], and preparation of 4,5dimethylpyrrole-2,3-dicarboxylates by cyclizations of butane-2,3-dione with ylides derived from acetylenedicarboxylates and ammonium acetate in the presence of triphenylphosphine [731]. Some useful developments for modification of existing pyrrole rings have also appeared, such as an efficient procedure for CuI-catalyzed arylation of pyrroles with aromatic or heteroaromatic halides in the presence of simple N-hydroxyimides [732]. Moreover, a protocol for assembly of various 2,20 -bipyrrole-5,50 -dicarboxaldehydes by homocoupling of 5-iodopyrrole-2-carboxaldehyde precursors employed palladium on carbon and activated zinc dust as the catalyst [733]. Classical cross-coupling techniques have also found new applications, further demonstrating their extraordinary synthetic potential in pyrrole chemistry. For example, tetramic acid triflates have been demonstrated to participate in Suzuki couplings at C4, giving access to 3,4diarylpyrrolin-2-ones [734], whereas Suzuki reactions have been employed in regioselective conversion of 1-methyltetrabromopyrrole into its 5-aryl-2,3,4-tribromo- or 2,5-diaryl-3,4-dibromo- derivatives [735], or transformations involving 1-phenylsulfonyl-3,4-dibromopyrrole [736]. A reaction sequence featuring an initial iridiumcatalyzed borylation of 1-tert-butoxycarbonyl-2-trimethylsilylpyrrole at C4, followed by Suzuki coupling, as well as an intramolecular palladium-catalyzed C
H bond functionalization at C5, has been implemented in an elegant synthesis of the alkaloid rhazinicine [737]. Efficient conditions for generation of pyrrole-3-boronate esters by

j353

j 4 Five-Membered Heterocycles: Pyrrole and Related Systems

354

palladium-catalyzed reactions of pinacol borane with 3-bromopyrroles, and their subsequent Suzuki reactions in the presence of a monophosphine based catalyst, have also been established [738]. A series of 2,20 -bipyrroles has been obtained by regioselective oxidative coupling of pyrroles in the presence of phenyliodine(III) bis(trifluoroacetate) (PIFA) and bromotrimethylsilane (TMSBr), whereas for instance N-benzylpyrrole gave a 2,30 -coupled product in good yield under different conditions where BF3OEt2 was used instead of TMSBr [739]. Intermolecular radical alkylation of some 3-substituted pyrroles with xanthates mediated by dilauroyl peroxide occurs at C2 in moderate to good yields with high regioselectivity, as shown by preparation of the product 476 from 3-phenylpyrrole 477 (Scheme 4.150) [740]. Ph N H

EtO2C

477

Ph

S2COEt

dilauroyl peroxide ClCH2CH2Cl, reflux 62%

N H

CO2Et

476

Scheme 4.150

Catalytic hydrogenation of 2- or 3-nitropyrroles in the presence of carboxylic acid anhydrides has resulted in a new useful route to the corresponding series of pyrrolylamides or pyrrolylimides [741]. Alternatively, similar chemistry may also be accomplished using tin or indium as the reducing agents [742], while application of 1,4-diketones instead of anhydrides has provided efficient access to 1,20 - and 1,30 bipyrroles [743]. Finally, it should also be mentioned that determination of the second-order rate constants of the reactions of a series of pyrroles with benzhydrylium ions in acetonitrile provided the basis for a nucleophilicity scale, where 1-triisopropylsilylpyrrole was the least nucleophilic member and 3-ethyl-2,4-dimethylpyrrole was the strongest nucleophile, comparable to enamines in its reactivity [744]. A systematic reinvestigation of an acylation, where a solution of 1-(p-toluenesulfonyl)pyrrole and AlCl3 as the Lewis acid in 1,2-dichloroethane as the solvent was quenched with an acyl halide, led to the conclusion that this process may involve the initial formation of pyrrolic organoaluminium species, which thereafter react with the highly reactive electrophile at C3 via a reactant-like transition state [745]. This is in contrast with earlier findings, which gave no evidence of complex formation of the closely related 1(phenylsulfonyl)pyrrole with AlCl3 in CH2Cl2 [315]. On the other hand, reactions featuring weaker Lewis acids such as EtAlCl2 or Et2AlCl, or less than equimolar amounts of AlCl3, gave considerable amounts of products substituted at C2, proceeding via a normal Friedel–Crafts mechanism, where the pyrrole undergoes acylation by a complex generated from the Lewis acid and an acyl chloride [745]. Clearly, these very useful, but mechanistically complex, reactions are not yet completely understood, and further studies are necessary to provide a complete picture accounting for the observed outcomes.

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Reinke, H., and Langer, P. (2008) Tetrahedron Lett., 49, 1698–1700. Fukuda, T., Sudo, E., Shimokawa, K., and Iwao, M. (2008) Tetrahedron, 64, 328–338. Beck, E.M., Hatley, R., and Gaunt, M.J. (2008) Angew. Chem. Int. Ed., 47, 3004–3007. Billingsley, K. and Buchwald, S.L. (2007) J. Am. Chem. Soc., 129, 3358–3366. Dohi, T., Morimoto, K., Ito, M., and Kita, Y. (2007) Synthesis, 13–19. Guadarrama-Morales, O., M
endez, F., and Miranda, L.D. (2007) Tetrahedron Lett., 48, 4515–4518. Fu, L. and Gribble, G.W. (2007) Tetrahedron Lett., 48, 9155–9158. Fu, L. and Gribble, G.W. (2008) Synthesis, 788–794. Fu, L. and Gribble, G.W. (2008) Tetrahedron Lett., 49, 3545–3548. Nigst, T.A., Westermaier, M., Ofial, A.R. and Mayr, H. (2008) Eur. J. Org. Chem., 2369–2374. Huffman, J.W., Smith, V.J., and Padgett, L.W. (2008) Tetrahedron, 64, 2104–2112.

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5 Five-Membered Heterocycles: Indole and Related Systems Jos
e Barluenga and Carlos Vald
es

5.1 Introduction 5.1.1 General Introduction

Indole (1H-indole) (1) is the benzopyrrole with the ring fusion through the 2 and 3 positions of pyrrole. It is one of the most abundant heterocycles found in natural products and biologically active molecules. In fact, it can be regarded as the most important of all the privileged structures in medicinal chemistry [1]. For this reason, research in the different areas of indole chemistry has been, and continuous to be, extraordinarily intense. Many excellent reviews, covering advances in specific topics in the chemistry of indoles, are available and will be referred to throughout this chapter. The present chapter covers the developments in indole chemistry that appeared in the literature until mid-2006 (some subsequent developments are given in the Addendum). For further information the monographs cited in References [2, 3] are recommended.

N H

Indole 1H-Indole

1

The discovery and structure elucidation of indole dates from 1866, when Adolf von Baeyer synthesized indole by zinc-dust pyrolysis of oxindole (2), which had been obtained by reduction of isatin (3), a product of the oxidation of the natural blue pigment Indigo (4) [4]. Consequently, the name Indole derives from that of Indigo.

Modern Heterocyclic Chemistry, First Edition. Edited by Julio Alvarez-Builla, Juan Jose Vaquero, and José Barluenga. Ó 2011 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2011 by Wiley-VCH Verlag GmbH & Co. KGaA.

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O N H

O

O

N H

oxindole

isatin

2

3

O

H N Indigo

N H

O 4

5.1.2 System Isomers and Nomenclature

The tautomers of 1H-indole are 2H-indole and 3H-indole (Figure 5.1). Both systems are highly unstable, although 3H-indole has been characterized spectroscopically, and its derivatives have been isolated [5]. High level quantum chemical DFT calculations predict an energy difference of 5.20 and 24.1 kcal mol
1 between 1Hindole and 3H-indole, and 1H-indole and 2H-indole respectively [6]. The other isomeric benzopyrroles are isoindole and indolizine. Indoline is the name for 2,3-dihydro-1H-indole. Parent compound 5

4

3

3a

Parent compound

Radical 5

4

3

3a

2 6

7

7a

N1 H

6

4

3

3a

7

7a

N

5

4

7

7a

N

6

1

4

3

3a

7a

5

4

7

7a

N

1

3H-Indole

6

7

4

N

2

3H-Indoyl (3H-indol-2-yl shown)

3

3a

1

8

1

4

7

7a

1

Isoindoyl (2-isoindoyl shown) 1

7

2

2

N

6

N 6

3

Indolizine

N

6 5

4

N H Indoline (2,3-dihydro-1H-indole)

Figure 5.1 Indole, tautomers and isomers with conventional numbering.

3

Indolizinyl (2- shown)

3

3a

7a

5

Isoindole

5

2 6

7

7a

8

2H-Indoyl (2H-indol-2-yl shown)

2H-Indole

5

7

3

3a

7 2

N

4

N2 6

3

3a

2 6

5

Indoyl (1-indoyl shown)

Indole

5

2

Radical

5.2 General Properties

5.2 General Properties 5.2.1 Physicochemical Data

Indole is a crystalline solid (mp ¼ 54–54  C, bp ¼ 253–254  C) with a fecal smell. The main commercial source of indole comes from the 220–260  C fraction of coal-tar distillation. It is soluble in organic solvents such as diethyl ether, ethanol and benzene, and also in hot water. The crystal structure of indole [7] and of several simple derivatives is available [8]. In addition, state of the art quantum chemical DFTcalculations provide very accurate results regarding structural [9], electronic [10] and chemical properties of indole and indole derivatives (Figure 5.2) [11]. DFT calculations of the magnetic properties, to estimate the aromaticity of the indole ring, reveal a stabilization due to the p-molecular orbital delocalization of 10 electrons between the two aromatic rings [12]. The 1 H NMR spectra of indole feature all the resonances for the hydrogens in the aromatic region, and corroborate the aromaticity of the ring (Figure 5.3). The upfield shifts observed for H3 and C3 in the 1 H and 13 C NMR spectra indicate the higher electron density around C3. Substitution on the indole ring may cause important variations in the chemical shifts of H2 and H3, which can be rationalized in terms of resonance and inductive effects (Table 5.1). 5.2.2 General Reactivity

Indole is a p-excessive aromatic heterocycle with ten p-electrons. The lone pair of the nitrogen atom (which features sp2 hybridization) completes the ten p-electrons delocalized across the ring. As in pyrrole, the p-excessive nature of the aromatic ring governs its reactivity and chemical properties. Indole is a weak base (pKa ¼
2,4 for the conjugated acid), as protonation of the nitrogen atom would disrupt the aromaticity of the five-membered ring. In contrast, as a p-excessive aromatic heterocycle, electrophilic aromatic substitution is one of the most characteristic reactions. Unlike pyrrole, addition of electrophiles takes place preferentially at C3. A simple explanation for this can be deduced by analysis of the Wheland intermediates resulting from the attack of a nucleophile at C2 and C3 (Scheme 5.1). 1.38

1.40 1.44 1.37

1.41

1.43

1.39

109º

N 1.39 1.38

1.38

Figure 5.2 Indole structural parameters at the B3LYP/6-311 þ G(2p,d) level of theory.

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7.12

7.64 H H

7.18 H H 7.27 Figure 5.3

1

127.7

6.52 H N H 7.81

120.6

102.2

111.1

N H

121.9

H 7.05

119.7

124.3

135.7

H and 13 C NMR chemical shifts in CDCl3 (d, ppm) for indole.

The intermediate of the attack at C3 is stabilized by delocalization of the positive charge. However, no delocalization is possible in the intermediate derived from attack at C2 without disrupting the aromaticity of the six-membered ring. Frontier Molecular Orbital theory considerations provide an alternative theoretical explanation for this reactivity trend. Indole features a relative high-energy HOMO, with the highest value at C3 (Figure 5.4). Moreover, the condensed Fukui function for electrophilic attack fq
[17], takes values of 0.08, 0.05 and 0.15 for N, C2 and C3, respectively, pointing to the higher reactivity of C3 towards soft electrophiles [12]. Table 5.1 Chemical shifts for H-1 and H-2 in substituted indoles (CDCl3).

Substituent

d H2 (ppm)

d H3 (ppm)

None 1-Me 2-Me 3-Me 1-CO2Me [13] 2-CO2Me [14] 3-CO2Me [15] 2-Cl [16] 3-Cl

7.05 6.90 — 6.85 7.55 — 7.93 — 7.44

6.52 6.43 6.20 — 6.57 7.15 — 6.41 —

E E+ N H

N H

E

H H

N H

E

H

-H+

H

N H

H E+ N H

H N H

E

-H+ N H

E

Scheme 5.1 Possible regioisomers in the electrophilic attack on the indole ring.

5.2 General Properties

Figure 5.4 Graphical representation of indole frontier orbitals.

Typical electrophilic aromatic substitution reactions that allow for the introduction of functionalized side-chains at C3 are Friedel–Crafts acylations, Vilsmeier–Haack reaction, Mannich type alkylations and halogenations (Scheme 5.2).

NR2

Ac CH2=O, R2NH

Ac2O, LA N H CHO

N H

DMF, POCl 3

N H Cl NCS N H

N H Scheme 5.2 Some typical electrophilic substitution reactions of indole.

Electrophilic substitution at C2 can be achieved in 3-substituted indoles, although the reaction usually starts with electrophilic attack at C3, followed by rearrangement or reversal of the reaction to produce the substitution at C2 (Scheme 5.3). R E

R

E+

N H 1,2-migration

N H

R

R E

N H Scheme 5.3

H

N H

E

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The indole N
H is weakly acidic and, thus, can be deprotonated by strong bases (pKa 16.7 in water) to provide the indolyl anion. Therefore, substitution at the nitrogen can be achieved through base-promoted processes, such as alkylations, acylations and, more recently, transition metal catalyzed arylations (Scheme 5.4).

N R

R-X Base

RCOX

N H

N

N COR Ar-X Metal cat. N Ar

Scheme 5.4

The most reliable method to carry out the substitution at C2 is the heteroatom assisted metallation at C2 of N-acyl or N-sulfonylindoles, followed by reaction with an electrophile (Scheme 5.5). H

H

BuLi

H

H Li

R-CHO

N S O O Ph

N SO2Ph

OH N R SO2Ph

Scheme 5.5

Metal catalyzed cross-coupling reactions represent nowadays one of the main ways to modify the substituents in both rings of indole. All kinds of Pd catalyzed processes (Stille, Suzuki and Buchwald–Hartwig) can be achieved successfully from properly substituted indole species (Scheme 5.6). X N H(R)

+

M-R'

+

X-R'

M N H(R) Scheme 5.6

Pd cat

R' N H(R)

Pd cat

R' N H(R)

5.3 Relevant Natural and/or Useful Compounds

5.3 Relevant Natural and/or Useful Compounds

The indole nucleus is present in the essential amino acid tryptophan (5), in many metabolites derived from tryptophan and also in natural molecules with high structural complexity. Amongthenaturallyoccurringmoleculesthatfeaturetheindoleringintheirstructure, two worth noting: (i) the family of tryptamines [18], such as serotonin 6, a very important neurotransmitter with numerous functions in the human body, and melatonin 7, a hormone that participates in the regulation of the circadian rhythms (sleep–wake); (ii) the auxins, a group of plant growth substances, such as the natural auxin indole 3-acetic acid (8) and the synthetic auxin indole-3-butyric acid (9) (Figure 5.5) . The indole structure is also present in structurally complex indole alkaloids with biological activity. To name a few: the hallucinogen D-lysergic acid diethyl amide (LSD) (10); the strichnous family of alkaloids (e.g., strychnine, 11); the family of marine indole alkaloids isolated from blue-algae such as Fischer-indole I (12) [19], the bisindole alkaloids vinblastine (13) and vincristine (14), which are extremely potent cytotoxic agents, used in the therapy of leukemia and lymphoma tumor types [20, 21]; and reserpine 15, a pentacyclic alkaloid that is a central nervous system depressant employed in the treatment of hypertension and psychiatric disorders (Figure 5.6) [22]. CO2H NH2 N H 5 L-Tryptophan

HO

NH2

MeO

NHAc N H

N H serotonin (5-hydroxytryptamine) 6

melatonin 7 CO2H

CO2H N H Indole-3-acetic acid 8

N H Indole-3-butyric acid 9

Figure 5.5 Some important simple indole natural products.

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O Et

N Et

N

N

Me Me

Me C N

H O

N H O

N H D-Lysergic acid diethyl amide (LSD) 10

N

H Me Me

N H

Strychnine 11

Cl

12 Fischer-indole I

OH

N H MeO2C

OMe N

N OAc

N H

CO2Me N H OH MeO R 13 R = CH3, vinblastine 14 R = CHO, vincristine

OMe

H O

H

H MeO2C

OMe

OMe O

15 (-)-Reserpine

Figure 5.6 Some important indole alkaloids.

In contrast, several synthetic drugs currently in use contain the indole nucleus, for instance Sumatriptan, a synthetic tryptamine used in the treatment of migraine [23], and the non-steroidal anti-inflammatory drugs Indomethacin and Etodolac (Figure 5.7). 5.4 Indole Synthesis 5.4.1 Introduction

Indole is one of the most important heterocycles, as a result of its abundance in natural products and pharmaceuticals. For this reason, the synthesis of the indole CO2H

H3CO MeHN

S O2

NH2 N H Sumatryptan

N

CH3

O Indomethacin

Figure 5.7 Indole-containing drugs currently in use.

O Cl

Et

N H

Et

Etodolac

CH2CO2H

5.4 Indole Synthesis

ring has attracted great attention in synthetic organic chemistry, and, in turn, an extraordinary large number of different approaches to the synthesis of the indole ring have been devised over the years [24]. Despite the ample repertoire of methods available to build the indole ring, it continues to be an area of active research due to the enormous interest in the indole structure. Moreover, while most classic approaches to the indole ring usually rely on a final cyclization through a condensation reaction, the development of new methodologies for transition catalyzed C
C and C
N bond-forming reactions has led to a new family of methods in which the cyclization step is a metal-catalyzed process. In this area, the Pd-catalyzed reactions have a prominent position. This subject has been reviewed and monographs dealing with this particular subject are available [25, 26]. In addition, the rise of combinatorial approaches to drug discovery has motivated the development of new methodologies, and the adaptation of solution phase chemistries into solid phase synthesis. Specific reviews on this topic are also available [27]. The variety of different approaches to the indole ring is enormous, and an exhaustive coverage would largely exceed the aim of this book. For this reason, this chapter is restricted to the classical methods that still find application in the preparation of indoles and the more recent advances in the area, with particular attention to transition metal catalyzed processes. From a retrosynthetical point of view, the indole ring can be constructed by two main strategies: formation of the pyrrole ring onto a properly substituted benzene precursor and formation of the benzene ring by annelation of a substituted pyrrole. By far, the strategies that start from a substituted benzene have been more extensively used (Scheme 5.7). Y X

Y N H

N H

X

Scheme 5.7

5.4.2 Synthesis of the Indole Ring from a Benzene Ring

In an attempt to organize the many methods, they have been classified according to the formation of the last bond in the cyclization process (Scheme 5.8). Of particular importance in the construction of the indole ring are methods involving a sigmatropic rearrangement: the Fischer indole synthesis and related process, which will be covered in a specific section. 5.4.2.1 Indole Synthesis Involving a Sigmatropic Rearrangement Indole ring syntheses that include a sigmatropic rearrangement are particularly appealing strategies since no o-substitution is required in the starting aniline (Scheme 5.9). The C
C bond is formed during the rearrangement. The most prominent member of this family of methods is the Fischer indole synthesis.

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N

N H

C7a-N disconnection

C3-C3a disconnection 3

3a

2 7

7a

N H

N H

X

sigmatropic rearrangemet

N H

N

C2-N disconnection

C2-C3 disconnection

Scheme 5.8 General strategies for the construction of the five-membered ring of indole.

N

X

N

X

N

Scheme 5.9

5.4.2.1.1 Fischer Synthesis The Fischer indole synthesis [28], which was first discovered in 1883, is still considered as the most popular, and one of the most general and efficient approaches to the indole ring. It consists of the acid-catalyzed cyclization of aryl hydrazones 18 with loss of ammonia. The aryl hydrazones are easily obtained by condensation of a ketone (17) with an aryl hydrazine (16) (Scheme 5.10).

+ NHNH2 16

R2

R2 O

1

R 17

N N H 18

R2

+

H or LA R1

N H

R1

+ NH3

19

Scheme 5.10 Fischer indole synthesis.

The mechanism accepted for the overall reaction was already formulated by Robinson and Robinson back in 1924. It involves a [3,3] sigmatropic rearrangement of the ene-hydrazine tautomer 20 of the arylhydrazone 18, with cleavage of the N
N bond and formation of a C
C bond. Aromatization of 21 to give the intermediate 22, followed by cyclization and NH3 elimination provides the indole 19 (Scheme 5.11). The Claisen-like sigmatropic rearrangement is strongly accelerated by an acid catalyst. Both protic and Lewis acids are effective catalyst for the Fischer indolizidation.

5.4 Indole Synthesis

R2 1

N N H

R

R2

H+

N NH H2

18

H R1

R1 NH2

NH2 22

R1 NH

NH2

20 R2

R2

21 R2

H R2 R1 N NH3 H

R1 + NH3 + H+

N H

23

19

Scheme 5.11 Accepted mechanism for the Fischer indole synthesis.

Sulfuric and hydrochloric aqueous, alcoholic or acetic acid solutions have been used to promote the Fischer cyclization, as well as p-toluenesulfonic acid and phosphorous trichloride. Among the Lewis acids, ZnCl2 is the most frequently used catalyst. Very recently, solid supports such as montmorillonite AK10/ZnCl2 have been used to promote the indolizidation, in combination with microwave heating. This technique allows for the preparation of indoles unavailable through the standard conditions [29]. The nature of the substituents on the aromatic ring exerts a remarkable influence on the rate of the overall reaction: electron-donating substituents accelerate the reaction, while electron-releasing substituents slow the cyclization. For further information, detailed reviews covering all these topics are available [3]. The regioselectivity in the indole synthesis is an issue of major importance when unsymmetrical ketones or m-substituted aromatic rings are involved in the cyclization. For instance, the cyclization of hydrazones of type 24, derived from methyl alkyl ketones, can deliver regioisomeric indoles 25 and 26 (Scheme 5.12).

R3

1

R

R3

R1

R3

+

N N 2 R 24

R1 N R2

N R2 25

26

Scheme 5.12

Usually, under standard conditions, the major (or unique) product obtained is indole 25, the one derived from the more highly substituted ene-hydrazine 27, which is considered the thermodynamically controlled product. Therefore, for indole 25 to be the major isomer, the [3,3] rearrangement must be the rate-determining step of the whole sequence (Scheme 5.13).

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R3

H

rate-determining step

N H N H R2 27 Thermodynamic ene-hydrazine

R3

R1 N R2

N

H

R3

N R2

R3

N R2

N H H

N H H

N R2

N R2 25

R3

H

R3

R1

R1

R3

N H H

N R2 26

28 Kinetic ene-hydrazine Scheme 5.13 The problem of the regioselectivity in the Fischer indole synthesis.

Nevertheless, it has been possible to obtain selectively 3-unsubstituted indoles such as 31 by reacting hydrazine 29 with the unsymmetrical methylketone 30 under kinetic conditions by employing very strong acids such as Eaton’s acid (P2O5/MeSO3) (Scheme 5.14) [30]. 29

RO N

O

NH2 +

P2O5/MeSO3H CO2CH3

CH2Cl2 35 ºC

RO

CO2CH3 N

Cl 29

30

Cl

31 81% 100: 1 isomer ratio

Scheme 5.14 Fischer indole synthesis under kinetically controlled conditions.

Mechanistic studies have suggested that under kinetic conditions the reaction proceeds through the doubly protonated intermediate 32. The activation barrier for the [3,3] rearrangement in this case must be lower (since no aromaticity is lost during the rearrangement) and therefore, the formation of the ene-hydrazine intermediate (and not the rearrangement) becomes rate determining (Scheme 5.15) [31]. In some instances the cyclization can be carried out thermally, in the absence of acid catalyst, although it requires much harsher conditions and a protic solvent as a proton source. In contrast, preformed N-trifluoroacetyl enehydrazines 33 undergo cyclization without the need acid catalyst or very high temperatures to provide 2,3disubstituted indole 34 [32] (Scheme 5.16).

5.4 Indole Synthesis

R3

1

R

rapid equilibrium

N R2

N

R3

1

R

H

H

rate-determining step

H H 32

fast H

H H

N

R3

H [3,3]

N R2

N R2

R

H

H

R3

1

H H

R1

N R2

N H H

R3

N H H

N R2

Scheme 5.15

N

N

COCF3

THF 65 ºC, 4h

N

69 % 34

33 Scheme 5.16

The Fischer indolizidation is a very general process that proceeds with yields ranging from moderate to quantitative, depending on the substrate. Moreover, a large array of functional groups are tolerated by the reaction conditions, including the relatively sensitive, amide, ester or hydroxy. Schemes 5.17–5.20 depict some representative recent examples of the application of the Fischer indole synthesis. NHAc

NHAc HCl/AcOH N H

NH2 +

O

Ph

reflux 95%

N H

Ph

Scheme 5.17 [33].

An interesting variation of the Fischer indolizidation gives rise directly to tryptamines 36, a particularly important type of indole, due to their biological activity. This so-called Grandberg indole synthesis employs 4-halobutenals 35 as carbonyl components. The nitrogen atom, which is usually liberated as ammonia in the Fischer indolizidation, is incorporated to the molecule, likely through the pathway represented in Scheme 5.20 [36].

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i

Pr

O

+ NHNH2·HCl

H2SO4/EtOH

i

NaOAc/AcOH

i

Pr

CO2Et

N H

N

CO2Et

CH2CO2Et

Pr

N H 75% Scheme 5.18 [34].

OH

NHNH2·HCl conc.HCl/AcOH 135 ºC, 5h 65%

+ N

HN

O

N

O

Scheme 5.19 [35].

NHNH2

O

+ Cl

NH2·HCl

EtOH, H2O reflux

H 35

36

N H

cyclization then aromatization N H

N

N H

Cl

N

·Cl

[3,3] then aromatization

N NH2 H

N N H H

Scheme 5.20 Grandberg indole synthesis.

Several examples of the Fischer indole synthesis in the solid phase have been described [37]. A very elegant traceless synthesis has been reported that employs a solid supported hydrazine (37) [38], which participates in the Fischer indolizidation upon treatment with a ketone in the presence of TFA. Interestingly, during the cyclization step, indole 38 is released from the resin in a traceless manner (Scheme 5.21).

5.4 Indole Synthesis

R1 N H

H N

R

O

H H N N

2

R

TFA/CH2Cl2

37

H H N NH

R R2

R2

1

R

NH2

R1

R1

R + 38

N H

R2

Scheme 5.21 A traceless solid-phase Fischer indole synthesis.

A library of structurally diverse indomethacine analogs (45) have been prepared by a “resin-capture-release” strategy, a technique that combines solid-supported and solution chemistry. Aryl hydrazine 39 is “captured” by an aldehyde functionalized resin (40), and the unprotected N
H is acylated, to build an array of solid supported protected acylhydrazines (42). Treatment with trifluoroacetic acid (46) releases the hydrazine 43, which then reacts with a ketone, to provide hydrazone 44, which suffers the indolizidation to deliver the corresponding indole 45 (Scheme 5.22) [39].

R1

O + HN H N 2 40

capture

N

H N

R1

41

39

R2COCl

selective acylation

R3

R1

N 45 O

TFA/CH2Cl2 H2O (traces)

R4

R2

O N

R2

N 42

N

R3

R2

O N

1

R

O

R2

O R4

H2N

R1

N

R4 44

R3

43

Scheme 5.22 Solid-supported synthesis of indomethacine analogs.

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Cyclic enol-ethers and enol-lactones 47 have been used as synthetic equivalents of aldehydes and ketones, giving rise directly to functionalized indoles 48 (Scheme 5.23) [40].

R1 N H

NH2 +

( )n X O

R2

( )n X OH

R1 4% H2SO4aq/DMAc

N H

100 ºC

X = CH2, C=O 47

OH

48 CO2H

OH

F

N H

N H

N H 72%

R2

90%

CH3

75%

Scheme 5.23 Fischer indole synthesis with enol ethers and enol lactones.

5.4.2.1.2 Japp–Klingemann Reaction The condensation of carbonyls (or synthetic equivalents) with aryl hydrazines is not the only route to the aryl hydrazones required for the Fischer indolizidation. The coupling of aryldiazonium salts (49) with the enolates of ketones 50 – the Japp–Klingemann reaction [41] – represents an alternative that has been employed extensively. Hydrazone 52 is formed after a deacylation step of the intermediate diazo compound 51 (Scheme 5.24).

Z R

H COR 50

+

N2-Ar 49

B:

Z R

N N Ar COR

H2O

51

Z R

H N N Ar

+ R-CO2H

52

Scheme 5.24 General scheme of the Japp–Klingemann reaction.

b-Ketoesters are the usual substrates for the Japp–Klingemann reaction. For instance, ketoester 53 reacts with benzenediazonium chloride in an alkaline solution to form hydrazone 54. Indolizidation of hydrazone 54 under standard Fischer conditions affords 2,3-disubstituted indole 55, which can be decarboxylated to give 3-substituted indole 56 (Scheme 5.25) [42]. When cyclic b-ketoesters (e.g., 57) are used, deacylation by ring opening occurs under the basic conditions of the reaction, to provide the carboxylic acid 58. Fischer indolization of 58 gives rise to 2,3-disubstituted indoles 59 [43] (Scheme 5.26).

5.4 Indole Synthesis

O CO2Et NaNO2, HCl 0 ºC

53 CO2Et 6M KOH, EtOH

NH2

0 ºC to rt, 2h

N H

N

54 CH2CO2Et H2SO4, EtOH reflux, 12 h

N H

CO2Et CO2Et CH2CO2H

i) NaOH, EtOH, reflux ii) 1M HCl, EtOH, reflux

CO2Et

N H

55

56

Scheme 5.25

O CO2Et HO2C

NaNO2, HCl 0 ºC NH2

57 KOH, H2O

HO2C N H 58

AcOH/H2SO4 120 ºC

HO2C

N

(CH2)4CO2H CO2Et

(CH2)3CO2H N 59 H

CO2Et

Scheme 5.26

5.4.2.1.3 Hydroamination-Based Fischer Indole Synthesis Recently, an interesting variation to the traditional Fischer approach has been introduced that uses alkyne hydroamination as an alternative way to access the intermediate arylhydrazone. Scheme 5.27 presents a one pot approach to the indole framework based on intermolecular titanium amide-catalyzed hydroamination reactions of alkynes 61 with 1,1-disubstituted hydrazines 60. Subsequent addition of 3–5 equiv ZnCl2 is necessary to convert the generated hydrazone 62 into the corresponding indole 63 [44]. The Grandberg strategy has been combined with the hydroamination to prepare tryptamine analogs 66 (Scheme 5.28) [45]. The Ti-catalyzed hydroamination of terminal chloroalkynes 64 gives rise directly the hydrochloric salt of aminoindoles 65.

j393

j 5 Five-Membered Heterocycles: Indole and Related Systems

394

R1

N R3

NH2

+

60

R1

R2

catalyst

R2

100 ºC

61

Me2N Catalyst:

Me2N

R1

62

N R3

ZnCl2

N

N R3

R2

63 56-95%

NMe2 N Ti N Me2 N

R1, R2 = H, Ar, Alkyl

Scheme 5.27 Hydroamination-based Fischer indole synthesis.

2

R3

R

N R1

Cl ( )n

NH2 +

X

64

2

R3

R

65

+ ( )n NH3 Cl

N R1

Me

NaOH

t-Bu X=

2

R3

R

66

( )n NH2 N R1

Me

49-89%

NMe2 O Ti NMe2 t-Bu 2

Scheme 5.28 Hydroamination-based Grandberg indole synthesis.

This one pot process involves a titanium-catalyzed Markovnikov hydroamination to furnish the corresponding hydrazone, which can follow the same reaction pathway as that proposed in the original Grandberg route. Another interesting modification of the hydroamination makes use of inexpensive TiCl4 as precatalyst for the hydroamination reaction, and it also serves as Lewis acid for the cyclization process. This methodology allows for the preparation of 1,2,3trisubstituted indoles 70 from unsymmetrical alkynes 68 (Scheme 5.29) [46]. The aryl hydrazones required for the Fischer cyclization have also been prepared through a novel rhodium-catalyzed hydroaminomethylation of olefins [47]. Thus, reaction of aliphatic olefins 71 with synthesis gas (CO : H2, 1 : 1) and aryl hydrazines 72 in the presence of rhodium phosphine catalysts leads to the corresponding hydrazones 73, which can be subsequently transformed into indole 74 by treatment with ZnCl2 in a one pot process (Scheme 5.30) [48]. As an alternative method, the Buchwald–Hartwig amination has been applied for the synthesis of the arylhydrazines required for the Fischer synthesis [49]. Thus,

5.4 Indole Synthesis

Ar

N R2

NH2

+

TiCl4, Bu-NH2

Ar

N R2 69

105 ºC

67

Ar R1

t

R1

j395

68

N

N R2

R1

70 55-76% R1 = H, Alkyl R2 = Me, Ph

Scheme 5.29

+

R1 71

H2N

N R2

CO, H2 (10 bar) R3 Ru(CO) acac 2 Ligand 65 ºC, 15 h

R3 N

R1 73

72

ZnCl2

CF3

Ligand:

P

CF3 2

P

CF3 CF3

N R2

2

R1

R3

74

N R2

75-85% Scheme 5.30

Pd-catalyzed cross-coupling of aryl bromides 76 with benzophenone hydrazone (75) furnishes N-arylbenzophenone hydrazone 77, which is hydrolyzed to the arylhydrazine 78 by treatment with acid. If the hydrolysis is carried out in the presence of a carbonyl compound, indole 79 is formed in a one pot process, without isolation of any of the intermediates (Scheme 5.31). 5.4.2.1.4 Gassman Synthesis A [2,3] sigmatropic shift of anilinosulfonium ylide 80 is the key step in the Gassman synthesis [50]. The sulfur substituted indoles 81 so-obtained can be easily reduced with Raney Ni (Scheme 5.32). In the original Gassman procedure the indole is formed directly from the corresponding aniline 82 in a one pot–three step procedure that involves the formation of chloramine 83, which then reacts with a a-thioketone to form the anilinosulfonium salt 84. Low temperature rearrangement of 84 yields the 3-thioindole 85 (Scheme 5.33). The anilinosulfonium salt 86 can be accessed also by a modified procedure that avoids the use of tBuOCl and provides slightly better yields. This strategy has been employed in the synthesis of oxyindoles 87 (Scheme 5.34) [51].

j 5 Five-Membered Heterocycles: Indole and Related Systems

396

N Ph

NH2

R R

+

Pd(OAc)2/BINAP

Br

Ph 75

76

NaOtBu Toluene 100 ºC

Ph

Ph

R2

Tos-OH

HN N

O R1

77

R2

79

N H

Tos-OH H2O

NH-NH2

O

+

Ph

Ph

78

Scheme 5.31

O

N H

SMe

81

O

N H 80

Raney Ni

NEt3

S

S

N H

SMe

SMe

O NH

O NH2

EtOH, 25 ºC

N H

Scheme 5.32

CO2Et

tBuOCl CH2Cl2

CO2Et

O

O EtO2C

S

-70 ºC

- 70 ºC

NH2

NHCl

82

83

NEt3

N H 84 SMe

H3CO2C

- 70 ºC 85

N H

51-70% Scheme 5.33

S

R1

5.4 Indole Synthesis

NH2 O S

CO2Et

Cl S

(COCl)2 CH2Cl2 -78 ºC

i) NEt3

O OEt

CO2Et

- 78 ºC

N H

O

N H

82%

S

86

SMe

ii) 2N HCl

j397

87 Scheme 5.34

5.4.2.1.5 Bartoli Synthesis In the Bartoli synthesis, 7-substituted indoles 89 are obtained from 2-substituted nitrobenzene 88 upon treatment with 3 equivalents of vinylmagnesium chloride (Scheme 5.35) [52]. The availability of the starting materials and its simplicity make this reaction one of the most efficient methods for the preparation of 7-substituted indoles. The necessity of an ortho-substituent on the aromatic ring is the main limitation. Nevertheless, Br is a very suitable substituent that can enforce the sigmatropic rearrangement as requested by the mechanism (see below), and can be easily removed or transformed thereafter. MgCl (3 eq.) THF -40 ºC 50-70%

NO2 R 88

N H

R 89

Scheme 5.35

Scheme 5.36 depicts the mechanism proposed for the Bartoli reaction. The reaction starts with the addition of the first equivalent of vinyl Grignard to an oxygen OMgCl MgCl R

MgCl

NO2

N O

R

88 H

R

N MgCl

91

Scheme 5.36

N R

N

O

R 90

MgCl H

O

[3,3] O

O

MgCl

OMgCl N

R 92

H

OMgCl

MgCl CH2=CH2

R

N H MgCl

89

j 5 Five-Membered Heterocycles: Indole and Related Systems

398

atom of the nitro group of 88, with subsequent elimination of acetaldehyde enolate, to generate nitrosobenzene derivative 90. Then, the second equivalent attacks the oxygen atom of the nitroso functionality. The intermediate 91 generated suffers a Claisen-like [3,3]-sigmatropic rearrangement, with cleavage of the N
O bond, followed by heterocyclization to form the five-membered ring. A third equivalent of the Grignard is required to abstract a proton on 92 before the final elimination takes place. Slightly modified Bartoli protocols [53], including a solid phase version [54], have been implemented more recently. Other examples of [3,3] sigmatropic rearrangement-based indoles synthesis have been described [55, 56]. 5.4.2.2 Cyclization by Formation of the N
C2 Bond The construction of the indole ring with formation of the N
C2 bond includes the most popular approaches other than the Fischer synthesis.

N

N

An important class of methods for indole ring synthesis involves a cyclization of an aminoketone (93) with formation of the C2
N bond (Scheme 5.37). Usually, the precursor that suffers the intramolecular condensation has to be preformed in a preliminary step, and must contain a carbonyl or masked carbonyl (imine, enamine, enolether) functionality. R O NH2

N

R

93 Scheme 5.37

Many different approaches have been investigated to generate the cyclization precursor. Among them, those that rely on the reductive cyclization of o-substituted nitroaryls are noteworthy. 5.4.2.2.1 Reissert Indole Synthesis The Reissert indole synthesis is a very reliable method for the preparation of benzene-substituted indole-2-carboxylates [57]. In the first step, condensation of o-nitrotoluene (94) with ethyl oxalate under basic media affords the potassium salt of o-nitrophenylpyruvate 95 (Scheme 5.38). The key step in the Reissert synthesis is the reductive cyclization of this intermediate, which generates the aminoketone 96 that undergoes cyclization to provide the indole-2carboxylate (97). The reductive cyclization has been effected under different catalytic hydrogenation conditions (Pt/AcOH, Pd-C/EtOH [58]) and also with various low oxidation state metal salts (SnCl2-TiCl3) [59].

5.4 Indole Synthesis

CH3 +

CO2Et

KOEt, EtOH

(CO2Et)2

OK NO2

NO2 95

94 CO2Et

H2, Pt O NH2

AcOH

N H

96

CO2Et

97

Scheme 5.38 Classic Reissert indole synthesis.

Many variations on the classic Reissert synthesis are known, which differ in the way the intermediate o-aminobenzyl ketones or aldehydes, ready for the cyclization, are obtained [60]. Nucleophilic substitution on nitroarenes has been applied extensively in several approaches, a theme that has been reviewed [61]. Silylenol ethers 99 activated with fluoride anion [tris(dimethylamino)sulfonium difluorotrimethylsiliconate (TASF)] behave as strong C-nucleophiles and add to nitroarenes 98 in the ortho position to the nitro group. Subsequent aromatization of the intermediate generated with DDQ leads to o-(2-nitroaryl)alkyl ketones 100. Finally, reductive cyclization under standard conditions provides the indole 101 (Scheme 5.39) [62].

OSiMe3

Cl NO2 +

Cl 98

i) TASF ii) DDQ

NO2

O

Cl

Cl

99

100 Cl H2, Pt(C)-S 54 %

N H

Cl 101

Scheme 5.39

The vicarious nucleophilic substitution (VNS) of hydrogen [63] in nitroarenes 102 with a-chloroalkyl ketones 103 gives rise to nitroaryl ketones 104, which are converted into indoles 105 under classical Reissert conditions (Scheme 5.40). A similar valuable approach to indoles consists of the reductive cyclization of (o-nitroaryl)acetonitriles 108 (Scheme 5.41). The cyanomethyl group is efficiently introduced in nitroarenes 106 by VNS of hydrogen with chloroacetonitrile 107 or aryloxyacetonitrile. Catalytic hydrogenation transforms the cyano group into an

j399

j 5 Five-Membered Heterocycles: Indole and Related Systems

400

NO2

NO2

O +

Cl

Ph

102

Ph

tBuOK, DMF O

44% 104

103

H2, Pd-C

N H

90-100 %

Ph

105 Scheme 5.40

RO

OAr +

tBuOK, DMF

RO

CN

CN

NO2 106

NO2

107

H2, Pd-C

RO N H

83%

108

109

Scheme 5.41

imine and the nitro group to an amine, giving rise to 108, which cyclizes spontaneously to the indole 109 [64]. Carbocyclic-fused indoles have been prepared by several other alternative routes that involve the cyclization of a a-(o-nitrophenyl) ketone (Scheme 5.42). For instance, the intermediate nitroketones 112 can be obtained by arylation of cyclic silylenolether 111 with (o-nitrophenyl)phenyliodonium fluoride 110 [65]. This methodology was employed in the total synthesis of (
)-tabersonine [66]. In a different approach, an Ullman-type cross-coupling of o-halonitroarenes 113 with a-haloenones 114 has been also employed to obtain the o-nitroarylketones 115 [67]. In both cases, reductive cyclization affords the expected indole ring.

I+ PhF +

NO2

R ( )n

R TMSO

110

O NO2

( )n 111

X NO2 113 Scheme 5.42

+

Y O

( )n

R ( )n

112 R ( )n

R

114

TiCl3

Pd(0) Cu powder

O

NO2 115

Pd-C

N H

5.4 Indole Synthesis

j401

In Shibasaki’s total synthesis of strychnine [68] an advanced intermediate is also an a-(o-nitrophenyl)ketone (118), which is prepared by Stille cross-coupling of o-nitrostannylbenzene (116) with a vinyl iodide (117) (Scheme 5.43). R2 SnMe3 NO2

R1

Pd(0), AsPh3 CuI

I + O

R1 117

116 H

R

O

DMF

R2

NO2 118

N (-)-Strychnine

N H 119

H OPG2

OPG1

Scheme 5.43

A remarkable innovation has been uncovered by Buchwald – applying the Pdcatalyzed arylation of ketone enolates [69] to transform o-bromonitrobenzene derivatives 120 into o-nitroketones 122 (Scheme 5.44). Subsequent reductive cyclization provides the corresponding indoles 123 [70]. The reaction is very general and has been utilized successfully in the synthesis of indoles bearing both electron-withdrawing and electron-donating substituents on the benzene ring and a wide variety of ketones 121. Moreover, additional substitution can be introduced if the intermediate R2 X R1 120

NO2

O +

H3C

R2

O TiCl3 NH4OAc

Pd2(dba)3/L K3PO4

121

R1

EtOH, rt

NO2

123 79-45%

NaH, E+ R2

X = Br, Cl R1 = CO2Et, OMe, Me, CF3 R2 = Ar, Alkyl E = MeI, Br-CH2CO2Et

O E

R1

N H

R1

122

R2

NO2 124

E

TiCl3 NH4OAc EtOH, rt R1

N H 125 90-55%

Scheme 5.44

R2

j 5 Five-Membered Heterocycles: Indole and Related Systems

402

nitroketone 122 is deprotonated and alkylated before the reductive cyclization step to furnish substituted nitroketones 124. Therefore, this important development allows for the preparation of very highly substituted indoles 125. 5.4.2.2.2 Leimgruber–Batcho Synthesis The Leimgruber–Batcho synthesis is a very convenient method to prepare indoles with substitution only in the benzene ring [71]. The two-step procedure starts with the three-components reaction of an o-methylnitroaryl (126) with dimethylformamide dimethylacetal in the presence of pyrrolidine, to provide o-nitro-b-pyrrolidinostyrene 127 (Scheme 5.45). Reductive cyclization on 127 furnishes indoles 128, usually in very high yields. R

Me2NCH(OMe)2 NO2

R

N

pyrrolidine 110 ºC

126

Ra(Ni)

R

97-57%

NO2 127

128

N H

R = -CH3, -OCH3, OBn, F, Cl, -CH(OCH3), -CO2R, CN Scheme 5.45

Strong points of this approach are the compatibility with many functional groups, and the ready availability of the starting materials, which make this method a very interesting entry to polysubstituted indoles [72–74]. Enhanced conditions for a Lewis acid catalyzed version of the reaction using microwave acceleration have been described recently [75]. This modification has been applied to the synthesis of a wide variety of substituted nitroenamines, including several examples of heteroaromatics such as 129, which expand the scope of the Leimbruger–Batcho synthesis (Scheme 5.46).

N NO2

Me2NCH(OMe)2 DMF CuI MW(20x7min) 92%

Pd-C N

NMe2 NO2

80%

N HN

129

Scheme 5.46

5.4.2.2.3 Reductive cyclizations o-Nitrostyrenes The reductive cyclization o,b-dinitrostyrenes is another two step synthesis of indoles closely related with the Leimbruger–Batcho approach. The formation of the o,b-dinitrostyrenes 131 is usually achieved by Henry condensation [76, 77] of nitromethane with o-nitrobenzaldehydes 130, or by nitration of benzaldehydes [78]. The reduction step has been carried out with several classes of reducing agents, including different metal/acid combinations [79] and catalytic hydrogenation conditions (Scheme 5.47) [80]. This

5.4 Indole Synthesis

CHO + CH3NO2 H3CO

i) KOH, DMF, EtOH ii) Ac2O, NaOAc, reflux 73%

NO2

j403

NO2 H3CO

NO2 OCH3

OCH3 130

131

Fe/AcOH EtOH reflux 85%

H3CO OCH3

N H

Scheme 5.47

methodology has been applied as starting point in the synthesis of several natural products containing the indole skeleton [81–84]. A versatile methodology, related with the methods described above, is the palladium-catalyzed reductive N-heteroannulation of o-nitrostyrenes 132 [85, 86]. The reaction is carried out under CO pressure and in the presence of a Pd/ligand catalytic system (Scheme 5.48) [87]. R2 R1 132

R3

Pd cat, Ligand pressure CO

R2 R1

N H

NO2

R3

Scheme 5.48

The required precursors, the o-nitrostyrenes, are readily available from o-bromonitrobenzenes, through metal-catalyzed reactions, such as Stille couplings [88] or Heck reactions [89]. Examples of both approaches are represented in Scheme 5.49. CO2Me Br NO2

CO2CH3 SnBu3 PdCl2(PPh3)2 PPh3 66%

NO2

Br NO2

CH3CN, 70 ºC

O

Pd(OAc)2 P(o-Tol)3

Pd(OAc)2, Dppp CO (4 atm)

+

NEt3

NO2 76%

Scheme 5.49

CO2CH3

90% O

O

Pd(OAc)2, PPh3 CO (4 atm)

NO2 20%

DMF, 70 ºC

N H

O

N H 78%

j 5 Five-Membered Heterocycles: Indole and Related Systems

404

5.4.2.2.4 Sugasawa Synthesis Another synthesis of the indole ring from anilines is based on the o-chloroacetylation of aniline, the so-called Sugasawa reaction (Scheme 5.50) [90, 91]. Treatment of an aniline (133) with chloroacetonitrile in the presence of BCl3 and another Lewis acid furnishes o-chloroacetylaniline 134, through the intermediate 135. Chloroacetylaniline 134 can be cyclized to the indole 136 by reduction with NaBH4. The Sugasawa synthesis has been used very efficiently for the preparation of N
H unprotected indoles with substitution in the benzene ring [92, 93].

X

BCl3, TiCl4

+ ClCH2CN 133

NH2

O

X

Cl

134

NaBH4

X

NH2 136

Cl X N H2

N H

N BCl2

135 Scheme 5.50

5.4.2.2.5 Indoles from 5-Aminodihydronaphthalenes: Plieninger Indole Synthesis The oxidative cleavage of 5-aminodihydronapthalenes 137 provides the amino carbonyl 138 required for the N
C2 condensation reaction to form 7-substituted indoles 139 (Scheme 5.51) [94].

O

O

2

R

R2 N R 139

R1

O R2

R1

R1

NHR 138

NHR 137

Scheme 5.51

The key intermediate in this synthesis, the 2-aminodihydronaphthalene 141, is best obtained by [4 þ 2] cycloaddition reaction of a p-benzoquinone mono- or diimine, such as 140 with electron-rich dienes [95]. The great potential of this approach is exemplified by the synthesis of the polysubstituted indole 142, en route to the total synthesis of the antitumor agent ( þ )-yatakemycin (Scheme 5.52) [96].

5.4 Indole Synthesis

a) NHBoc H3CO

96%

b) NEt3

BnO

NHTs

NHBoc H3CO

H3CO

Pb(OAc)4

BnO

OMe

NBoc

NHTs

140

O3, Me2S 71%

OCH3

BnO

57%

NTs

141 CO2Me

BocHN H3CO

CO2Me

BnO

HCl-EtOH 96%

TsN

BocHN H3CO

OH

OBn

N Ts

142

Scheme 5.52

5.4.2.2.6 Cyclizations of Nitrenes Another type of cyclization with formation of the N
C2 bond involves the insertion of nitrenes in a vinylic C
H bond to form indoles (Scheme 5.53). Obviously, the key in this type of methodology is the generation of the unstable nitrene species. R N

H

N H

R

Scheme 5.53

The intermediate nitrenes can be formed by thermolysis of b-substituted-oazidostyrenes 143, which undergo insertion to form the indole [97, 98]. Scheme 5.54 shows, as an example, the synthesis of 2-nitroindole 144, which is not easily available through other procedures [99].

CHO N3

i) CH3NO2, KOH, EtOH, 0 ºC ii) Ac2O, Py, 0 ºC

NO2

81%

N3 143

j405

N H

xilenes, 140 ºC 54%

NO2

144

Scheme 5.54

Nitrenes have also been generated from o-nitrostyrenes or o-nitrostilbenes by deoxygenation of the nitro group with triethyl phosphite [100, 101]. In a more recent modification of this approach, the nitrene is generated by treatment of the nitroarene 145 with phenylmagnesium chloride under very mild conditions (Scheme 5.55) [102].

j 5 Five-Membered Heterocycles: Indole and Related Systems

406

i) ArCHO piperidine

R NO2

R

Ar

80-110 ºC

R = Br, CO2Et, NO2 Ar = Ph, p-MeO-Ph, 3-Py

NO2 145

R

PhMgCl

N H

THF, -40 ºC 76-60%

Ar

Scheme 5.55

Scheme 5.56 shows the mechanism proposed for this novel nitrene generation reaction.

1

Ar -NO2

Ar2-MgCl

1

Ar

OMgCl

N OAr2

1

- Ar2OMgCl

Ar

N

O Ar2-MgCl

Ar

1

OAr2 N Ar1 N MgCl - Ar2OMgCl

Scheme 5.56

5.4.2.2.7 Synthesis from o-Allylanilines or o-Vinylanilines Palladium-catalyzed intramolecular C
N bond formation is one of the most powerful methods for the synthesis of the indole ring. The first contributions in this area were due to Hegedus, who described the cyclization of o-allylanilines 146 using stoichiometric amounts of Pd(II) in a Wacker-type process (Scheme 5.57) [103]. The reaction tolerates functional groups as well as substitution in the allyl moiety.

i) PdCl2(MeCN)2, THF ii) NEt3

R

74-88%

NH2 146

Me

N H

Scheme 5.57

During the reaction the Pd(II) species is reduced to Pd(0). To avoid the use of stoichiometric Pd, benzoquinone is used in the catalytic process as reoxidant. This methodology has been applied in the synthesis of 3-hydroxyindoles 147 (Scheme 5.58) [104]. OTBDMS R2

R1 NH R3 Scheme 5.58

OTBDMS 10-20 % PdCl2(CH3CN)2 benzoquinone, THF, LiCl 84-47%

R1

147

N R3

R2

5.4 Indole Synthesis

5.4.2.2.8 Synthesis from o-Alkynylanilines or o-Alkynylanilides Intramolecular hydroamination of o-alkynylanilines 148, through a 5-endo-dig cyclization, is one of the most popular modern methods for the construction of the indole ring (Scheme 5.59). The required alkynylanilines are usually synthesized by a Pdcatalyzed Sonogashira cross-coupling of an o-iodoaniline with a terminal acetylene [105]. The cyclization reaction has been studied extensively and applied in numerous synthetic efforts. Several metal-based catalytic systems are able to promote the cyclization. Among them, Pd and Cu have been the most studied. Detailed accounts of this methodology have been published [106]. Typically, the cyclization is carried out in the presence of a Pd(II) catalyst, such as PdCl2 (Scheme 5.60) [107]. R'

N R

R'

X

R'

+ NHR

NHR

148

H

Scheme 5.59

R2 cat. PdCl2, MeCN 1

NHR

reflux 52-83%

N R1

R2

R1 = H, -COR; R2 = Alkyl, Ar Scheme 5.60

The mechanism of the reaction is postulated to proceed via an intramolecular aminopalladation of the alkynylaniline 148, which produces the a s-indolylpalladium species 149, followed by protonolysis of the C
Pd bond, which releases the indole 150 and recovers the Pd(II) catalyst (Scheme 5.61). The one pot synthesis of 2-substituted indoles from o-haloaniline derivatives 151 and terminal acetylenes 152 can be achieved by employing a combination of Pd(II) and Cu(I) catalyst (Scheme 5.62). In this process, the Sonogashira coupling to form alkynylaniline 153 and the intramolecular hydroamination occur consecutively and are promoted by the same catalytic system [108, 109]. Indoles are also prepared in one pot fashion from o-chloroalkynylbenzene 154 derivatives and primary amines 155 (Scheme 5.63) [110]. In a first step, a Pd-catalyzed aryl amination takes place to furnish the o-alkynylaniline 156, which then cyclizes to give the indole 157, in a process promoted by the same Pd catalyst. An interesting variation of this methodology is the “aminopalladation/reductive elimination” domino reaction that provides 2,3-disubstituted indoles 160 from o-alkynyl trifluoroacetanilides 158 and organic halides 159 (Scheme 5.64) [111].

j407

j 5 Five-Membered Heterocycles: Indole and Related Systems

408

PdCl H

149

R2

N H

+ H-Cl

150

N H

R2

PdCl2 R

Cl2Pd

R NH2 148

NH2 Scheme 5.61

X R

+ 151

NHSO2Me

152

Pd(PPh3)2Cl2, CuI, Et3N R N SO2Me

100-110 ºC 3-5 h 31-71% R

X = Br, I R= Ar, Alkyl

NHSO2Me 153

Scheme 5.62

R1 2

+ R -NH2 154

Cl

Pd(0), Ligand KOtBu, toluene 100 ºC 99-74%

155 R1

NHR2 156 Scheme 5.63

N 2 157 R

R1

5.4 Indole Synthesis

R1

R2

+ R2-X

Pd(0)

R1 N COCF3 160

NHCOCF3 158

159

Scheme 5.64

A plausible mechanism for this Pd(0)-catalyzed domino reaction involves: (i) oxidative addition of the halide to the Pd(0) species to form Pd complex 161; (ii) coordination of the Pd(II) species 161 to the triple bond of 158 to form the (g2-alkyne) organopalladium complex 162; (iii) intramolecular nucleophilic attack of the nitrogen across the triple bond to form the s-indolylpalladium intermediate 163; and (iv) reductive elimination that regenerates the Pd(0) catalyst and releases the 2,3disubstituted indole 160 (Scheme 5.65). R2 R1 N 160 COCF3

Pd(0)

R2-X oxidative addition

reductive elimination

[R2PdX] 161

2

[Pd-R ]

R1 1

163

R N COCF3

[R2Pd]

R1

NHCOCF3 158

NHCOCF3 162 Scheme 5.65

The reaction has been carried out employing aryl halides [112], alkenyl triflates, alkynyl bromides [113], and allylic carbonates [114] to provide the corresponding 2,3disubstituted indoles. Moreover, if the process is carried out under CO atmosphere, a three-component reaction takes place with incorporation of the carbon monoxide molecule, to yield 3-acyl-substituted indoles (Scheme 5.66) [115].

j409

j 5 Five-Membered Heterocycles: Indole and Related Systems

410

R1

R2 +

NHCOCF3

Pd cat. R2 X

Base

N H

R1

R2 = Aryl, alkenyl, alkynyl; X = I, Br, OTf OTHP +

H3COCO

Ph

NHCOCF3

i) Pd(PPh3)4, THF, 60 ºC, 3h ii) K2CO3, 80 ºC, 1.5 h 77%

N H O

R1 +

R2 X +

NHCOCF3

CO

Pd(PPh3)4 K2CO3 MeCN, 45 ºC 10h

N H

OTHP

R2 R1

R2 = Aryl, alkenyl, X = I, Br, OTf Scheme 5.66

This domino chemistry has been also carried out with a solid support and applied to the preparation of a combinatorial library of indoles 164 with three points of diversity (Scheme 5.67) [116]. A very impressive extension of this approach is the recently described Pt-catalyzed carboamination of o-alkynylanilides 165 [117]. A representative example is presented in Scheme 5.68. During the reaction, the acyl group migrates from the N-atom to C3 to form acylated indole 166. Therefore, this methodology constitutes a very attractive method for the preparation of 2,3-disubstituted indoles. The indolization of o-alkynylanilines has been performed with alternative promoters other than the classic transition metal catalysts. For instance, K and Cs bases promote successfully the cyclization (Scheme 5.69) [118]. This simple procedure appears to be very general regarding the substituents in the alkyne and the aromatic system, and has been adapted to solid-supported synthesis. Moreover, a similar strategy has been applied to the preparation of oxindoles. Iodinating reagents, such as bis(pyridine)iodonium(I) tetrafluoroborate (IPy2BF4) [119], can also promote the cyclization of o-alkynylanilines 167 (Scheme 5.70). Interestingly, the reaction affords 3-iodoindoles 168, offering the opportunity of further transformation by substitution of the iodine substituent by well known cross-coupling protocols. Moreover, the reaction has also been carried out on a solid support.

5.4 Indole Synthesis

Cl

I HO2C

NH2

I O

Cs2CO3, DMF 50 ºC, 24 h

NH2 O R1

R1 R1

(CF3CO)2O, Py

Pd(PPh3)2Cl2, CuI Et2NH, DMF, 2h

O

CH2Cl2, 2h

NH2

R2OTf, Pd(PPh3)4 O

O

R2

N

COCH3

COCH3

R1

PtCl2 anisole, 80 ºC

N

R2

165

166 1

R = OMe, R2 = H: 89% R1 = H, R2 = OMe: 99% Scheme 5.68

Bu F3C

KOtBu NH2 NO2

F3C

NMP, rt 77%

NO2

N H

Scheme 5.69

I

Ph IPy2BF4, HBF4 NHTos 167 Scheme 5.70

CH2Cl2, -60 ºC 87%

R2 HO

Scheme 5.67

R1

NHCOCF3

i) R3X, NaH, DMF, 4h ii) TFA, CH2Cl2, 2h

R1

N H

O

O O

O

R2 K2CO3, DMF, 24 h

j411

N Tos 168

Ph

Bu

N R3 164

R1

j 5 Five-Membered Heterocycles: Indole and Related Systems

412

5.4.2.2.9 Synthesis from o-Alkynyl isocyanides or o-Alkynyl Isocyanates N-Cyanoindoles 171 are prepared by a very elegant Pd-catalyzed three-component coupling reaction of o-alkynylphenylisocyanide 169, allyl carbonate 170 and trimethylsilyl azide (Scheme 5.71) [120]. R1

R2

+

OCO2CH3

+ TMS-N3

NC 169

2.5 % Pd2(dba)3·CHCl3

R2

10 % (2-furyl)3P octane, 100 º

170

171

R1 = TMS, Alkyl R2 = Alkyl, MeO, 4-MeO, CN, CO2Et, Br, NO2, TMS-C C

N CN

R1

77-45%

Scheme 5.71

The catalytic cycle proposed for this remarkable cascade process (Scheme 5.72) starts with the reaction of the Pd(0) species with allyl carbonate 170 and TMSN3 to give the p-allylpalladium azide complex 172. Insertion of the isocyanide in the Pd
N3 bond would give a new p-allylpalladium complex (173). Elimination of N2, with 1,2migration of the p-allylpalladium moiety from C to N, would provide p-allylpalladium carbodiimide complex174. This rearrangement can beenvisionedas a p-allylpalladium

171

N CN

R OCO2Me 170

+ TMSN3

Pd(0)

CO2 + TMSOMe

Pd

176

N CN

175

N C N

Pd

Scheme 5.72

R

172

N C N 174

Pd

NC

R

R

R

R

Pd N3

N N2

N

N

N C

173

Pd

5.4 Indole Synthesis

mimic of the Curtius rearrangement. Complex 174 can be in equilibrium with the p-allylpalladium cyanamide complex 175. Insertion of the alkyne in the Pd
N bond of p-allylpalladium 175 would provide the 2-indolyl-p-allylpalladium complex 176, which upon reductive elimination yields the cyanoindole 171 and the Pd(0) catalyst. A related reaction can be applied to prepare N-methoxycarbonylindoles 178 from oalkynylisocyanates 177 and allyl carbonate 170. In this case a Pd0-CuI bimetallic catalyst is required (Scheme 5.73) [121].

R1 OCO2CH3

+

1% Pd(PPh3)4 4 %CuI

R1 N CO2Me 178

THF, 100 º C

NCO 177

86-62%

170

R1 = Aryl, Cyclopentyl Scheme 5.73

5.4.2.2.10 Synthesis from o-Haloanilines and Acetylenes: The Larock Indole Synthesis The Pd-catalyzed synthesis of indoles from o-iodoanilines 179 and internal alkynes 180 is known as the Larock indole synthesis, and stands as one of the more powerful methods for the preparation of 2,3-disubstituted indoles 181 (Scheme 5.74) [122]. When unsymmetrical alkynes are used, the annulation reaction is regioselective, with the bulkiest substituent being placed at C2 in the indole. In particular, silylated alkynes afford exclusively the C2 silylated indole.

I NHR 179

RS + RL

RS

Pd(OAc)2, PPh3 BuN4Cl, K2CO3, DMF 100 ºC, 51 - 98%

180

N R

RL

181

R = H, Me, Ts RS, RL = Alkyl, Ar, Alkenyl, CH2OH, TMS Scheme 5.74

It is postulated that the mechanism of the annulation involves (Scheme 5.75): (i) oxidative addition of the aryl iodide 179 to the Pd(0) species to form arylpalladium complex 182; (ii) coordination of the alkyne 180 to the arylpalladium complex to form complex 183; (iii) insertion of the alkyne in the Pd
CAr bond, and coordination of the nitrogen with ligand displacement to generate palladacycle intermediate 184; and (iv) reductive elimination to form the indole and regenerate the Pd(0). The regioselectivity of the reaction is determined by the insertion of the alkyne in the Pd
C bond.

j413

j 5 Five-Membered Heterocycles: Indole and Related Systems

414

RS

I RL

N R

PdL2 179

R

L

L

N

L

NHR

HNR

I Pd

Pd RL

L 182

RS

184 base - HI

L

-I

HNR

RL

L Pd RL

RS 180

RS 183

Scheme 5.75

The bulkier substituent is situated next to the Pd, to avoid steric interactions with the aromatic ring. Larock’s heteroannulation has been applied as the key step in the preparation of several indole alkaloids and heterocycles. For instance, 7-methoxytryptophan 185, an early intermediate in the preparation of some indole alkaloids, has been efficiently synthesized with this methodology (Scheme 5.76) [123]. Moreover, recently, the scope EtO

I +

N

NH2 OCH3

TES

EtO N

Pd(OAc)2, K2CO3

N

LiCl, DMF, 100 ºC OEt

75%

N

N OCH3 H

OEt

TES

aq. HCl THF rt, 92% CO2Et NH2 N OCH3 H 185 Scheme 5.76

5.4 Indole Synthesis

of the reaction has been extended to o-bromo- and o-chloroanilines, by using an appropriate supporting ligand for the Pd, which enhances its reactivity towards oxidative addition [124]. A different Pd-catalyzed tandem process, which shares some mechanistic features with Larock’s indolization, has led to indoles from o-(2,2-dibromovinyl)anilines 186 [125]. In this case, the tandem process takes advantage of the different reactivity of the two C
Br bonds towards oxidative addition. Thus, in a first step, Suzuki coupling with substitution of the more reactive trans-bromine atom gives the bromovinyl aniline 187, which undergoes Pd-catalyzed intramolecular C
N bond formation to provide the indole 188 with high yields (Scheme 5.77). OBn

OBn

Br

H3CO Br NH2

H3CO

Pd(OAc)2, Ligand

+ Ph-B(OH)2

K3PO4, Toluene, 100º C 72%

186 Suzuki coupling

188

N H

Ph

Alkenyl amination

OBn Ph

H3CO Br NH2 187 Scheme 5.77

5.4.2.3 Ring Synthesis by Formation of the C3
C3a Bond

N

N

5.4.2.3.1 Electrophilic Cyclizations of the Aromatic Ring: The Bischler Synthesis This section includes those indole syntheses in which the key step is a cyclization by electrophilic attack of the aromatic ring to a nucleophilic center in a 5-exo-trig type of cyclization (Scheme 5.78). O N

N H

Scheme 5.78

Cyclization of a-(N-arylaminoketones), known as the Bischler synthesis, and discovered over 100 years ago [126], is the most characteristic representative of this

j415

j 5 Five-Membered Heterocycles: Indole and Related Systems

416

approach. In the original protocol, arylaminoketone 190 is obtained from N-methylaniline and a-haloketones 189. Acid-catalyzed 5-exo-trig cyclization then leads to indole 191 (Scheme 5.79). + NHCH3

O

O Br

CO2Et

CO2Et

N CH3 190

189 CO2Et

ZnCl2 N CH3 191 Scheme 5.79

Notable among the most relevant modifications of this procedure are the use of an acetal as a masked aldehyde functionality and the acylation or sulfonation [127] of the nitrogen, which allows a much more controlled cyclization. The Nordlander synthesis [128] exemplifies such variations (Scheme 5.80). R

i) BrCH2CH(OEt)2 NH2 ii) (CF3CO)2O NEt3 CF3CO2H (CF3CO)2O 93%

R

EtO

OEt

N COCF3

R N COCF3

Scheme 5.80

In another modification of the Bischler synthesis, the intermediate a-(N-arylaminoketones) 194 are prepared by the N
H insertion reaction of anilines 192 with rhodium carbenoids [129], generated from diazocarbonyl compounds 193 [130]. The final cyclization is carried out using the acidic ion-exchange resin Amberlyst 15, which provides better results than the usual Lewis acid catalysts (Scheme 5.81). A further refinement of the reaction by the same authors allows for the preparation of N
H indoles [131]. Hydroamination of propargylic alcohols with anilines represents another transition metal catalyzed alternative to the classic Bischler synthesis [132]. In a one pot process, the hydroxyimine 196, which comes from the ruthenium-catalyzed hydroamination of the propargylic alcohol 195, undergoes hydrogen migration to the Bischler intermediate 197, followed by cyclization to provide a mixture of regioisomeric 2,3-substituted indoles (Scheme 5.82).

5.4 Indole Synthesis

O N2 X

R CO2R' 193

cat Rh2(OAc)4 Tol reflux

NHCH3

O

R

R

Amberlyst 15

X N CO2R' CH3

192

X

N CH3 31-88%

194

R, R'= alkyl X= Br, Cl, OMe, NO2 Scheme 5.81

R

OH

+

R 0.36 mol% Ru3(CO)12 NH4PF6 or ArNH2·HCl

NH2 195

HO

R

j417

N H

140 ºC, air, without solvent 71-95%

O

N

N H

196

197

+

N H

R

6 :1 - 16: 1

R

Ph-NH2/H+

O

R

N H

Scheme 5.82

5.4.2.3.2 Carbometallation of N-(2-Lithioallyl)anilines The intramolecular carbometallation of lithiated double bonds has been used to prepare several types of functionalized indoles [133]. For instance, N-bromoallyl-o-fluoroanilines 198 are converted into indoles by treatment with 3 equivalents of tBuLi. Cyclization of the benzyne intermediate 199 generated gives rise to C(4)-lithiated 3-methyleneindoline derivative 200. Quenching of the lithiated species 200 with selected electrophiles allows functionalization at this position to provide methyleneindoline 201, which isomerizes on workup or on silica gel chromatography to the corresponding indole derivatives 202 (Scheme 5.83) [134]. Interestingly, 3-methyleneindolines such as 201 are known to participate in Alderene reactions with activated enophiles to furnish 3,4-disubstituted indoles 203 (Scheme 5.84) [135]. Taking advantage of this reaction, addition of an enophile to the reaction mixture provides 3,4-disubstituted indoles in a one-pot sequence. Schemes 5.85 and 5.86 show, as representative examples, the one-pot synthesis of a tryptamine analog 204 and a substituted carbazole 205, respectively.

CO2R'

j 5 Five-Membered Heterocycles: Indole and Related Systems

418

E

E F Br

N

R

+

E

tBuLi (3 eq) THF, -110

rt

SiO2

-78 ºC

rt

198

201

tBuLi

202 50 - 75% E+

Li

R

N R

N R

Li

F Li

N

R

N

Li

N R

199

200

E: Bu3SnCl, PhCHO, Me2CO, ClCO2Et, Me3SiCl, PhCH=NPh Scheme 5.83

E

E X Y

+

201

X

N R

YH

N R 203

X=Y: EtO2C-N N-CO2Et

H H

O NMe2·I

EtO2C

CO2Et

Scheme 5.84

5.4.2.3.3 Palladium-Catalyzed Heck Reactions The intramolecular Heck reactions of o-halo-N-allylanilines 206 and o-halo-N-vinylanilines 207 are very effective methods for the construction of the indole ring (Scheme 5.87). The Pd-catalyzed cyclization of N-allyl-o-haloanilines, such as 208 [136–138], is a very reliable method for the preparation of indoles. The intramolecular Heck reaction

H3CO

Cl N

Br

i) tBuLi, THF, -110 ºC to rt ii) H2O, -78 to 20 ºC iii) CH2=NMe2·I, 67 ºC

NMe2 H3CO N

55% 204

Scheme 5.85

5.4 Indole Synthesis

F

SPh

i) tBuLi, THF ii) PhS-SPh

SPh

NMe2

CH2=NMe2·I

N

N

Br

N 205 58%

Scheme 5.86

X

Pd 5-exo-trig

N

X

Pd 5-endo-trig

N

206

N 207

Scheme 5.87

is usually achieved under Pd ligandless conditions and in the presence of a base (Scheme 5.88) [139, 140]. O2N

OBn

Br

Pd(OAc)2

N H

Et3N, DMF Bu4NBr, 25 ºC 96%

208

O2N

OBn

N R

Scheme 5.88

The formation of the indole can be explained by the accepted mechanism of the Heck reaction. Oxidative addition of the aryl halide to form arylpalladium complex 209, followed by cyclization by olefin insertion, gives rise to the Pd(II) substituted indoline 210. b-Elimination regenerates the Pd(0) species and produces a 3-methylenindoline 211, which isomerizes spontaneously to indole 212 (Scheme 5.89). X

PdX PdX

Pd(0)

N R

- Pd(0) - HX 211 Scheme 5.89

N R

N R 209

210

N R 212

N R

j419

j 5 Five-Membered Heterocycles: Indole and Related Systems

420

Nevertheless, it is possible to isolate the intermediate indoline under certain reaction conditions, which include the use of silver carbonate as base [141]. Many examples have appeared in the literature of the application of this methodology in the synthesis of complex molecules [142], including adaptation to solidphase synthesis [143]. Scheme 5.90 shows a solid-phase synthesis of trisubstituted indoles 213 that allows for the introduction of several points of diversity in the indole scaffold [144].

OH Br

O

O

H2N

H N

O (iPr)2EtNH, DMF

Rink amide resin

I

O (iPr)2EtNH, DMF R2-CH2Br

I

I

N H

R1

Br

NH2 H N

i) Pd(PPh3)2Cl2 Bu4NCl, NEt3, DMF ii) TFA, CH2Cl2

CONH2 R1

N

N R2

H N

213

R2

66-88% Scheme 5.90

The Heck reaction of o-haloenamines has attracted comparatively less attention than the previously discussed reaction with N-allylanilines. The instability of the enamines when compared with the allylamines, as well as the more difficult 5-endotrig cyclization when compared with the 5-exo-trig, may account for this difference. The first examples of this approach were carried out with acylenamines 214, easily prepared through different procedures, which undergo Pd-catalyzed cyclization to provide 2,3-disubstituted indoles 215 (Scheme 5.91) [145]. Direct annulation of o-iodoanilines with ketones is a very convenient variation of this route [146]. The reaction has been extended recently to the more easily available chloroanilines 216 [147]. In a first step, condensation of the amine with the ketone forms the enamine 217, which then undergoes Pd-catalyzed cyclization (Scheme 5.92). The use of a very active catalytic system is crucial. Enamine 217 required for the cyclization has also been prepared by acetylene hydroamination. Thus, the indole ring has been formed from acetylenes 219 and ochloroaniline (218), in a one pot process that requires two different metal catalysts: a Ti catalyst for the hydroamination, and a Pd catalyst for the Heck reaction (Scheme 5.93) [148]. In a related process, indoles have been synthesized from o-haloanilines 220 and alkenyl bromides 221. Notably, in this process the same Pd catalyst promotes two

5.4 Indole Synthesis

R1

j421

COR2

MeOH/DMSO O

X

O

1

R

R

MeOH/DMSO

NH2

COR2 Pd(OAc)2, (o-Tol) 3P NEt3, DMF, 120 ºC

1

N H

O

X = Br, I

COR2

X

2

R

43-88%

214

R1

N H 215

R2 Pd cat. LiCl, THF

Scheme 5.91

1

R

Cl

216

4

+

NH R2

O

R

[Pd(tBu3P)2], K3PO4

R3

HOAc, MgSO4, DMA 90-140 ºC 2-21 h

R1

Cl

R4

N R2 217

R3

R4

R1

N R2

R3

98-50%

Scheme 5.92

Cl NH2 218

Ar + R

TiCl 4

Cl

Ar

Pd(OAc)2 Ligand

tBuNH2

N H

R

KOtBu

Ar N H

R

217

219

Scheme 5.93

different reactions: the alkenyl amination, which forms the intermediate enamine 222, and the subsequent Heck reaction to form the indole (Scheme 5.94) [149]. 5.4.2.4 Ring Synthesis by Formation of the C2
C3 Bond

N

N

R1

j 5 Five-Membered Heterocycles: Indole and Related Systems

422

1

R

4

R

X +

NH R2 X = Br, Cl 220

3

Br

R

Pd2(dba)3, XPHOS NaOtBu, Toluene 100-110 ºC

221

Pd catalyzed amination

1

R

iPr

XPHOS:

iPr

iPr PCy2

X

R4

N R2

R3

R4

R1

N R2 72-55%

R3

Pd catalyzed Heck-reaction

222

Scheme 5.94

5.4.2.4.1 Madelung Synthesis The construction of the indole ring by cyclocondensation of 2-methylanilides (223) is known as the Madelung indole synthesis (Scheme 5.95). In its original formulation the reaction used bases such as NaNH2 and KOtBu, and required extremely harsh reaction conditions with temperatures over 250  C (check out the procedure published in Organic Synthesis Collective) [150]. The replacement of these bases by alkyllithiums or LDA allows the reaction to take place under much milder reaction conditions (Scheme 5.96) [151, 152].

R(Z)

R(Z) O N

N

R'

R'

223 Scheme 5.95

O

X N H

3 eq. n-BuLi R

-20

rt

X

CH2Li OLi N

R

X

N H

R

R = Ph, X = 5-Cl 94% R = tBu, X = H 87% R= Cy, X = 5-OMe 40% Scheme 5.96

5.4 Indole Synthesis

j423

Introduction of electron-withdrawing substituents at the ortho-methyl group makes the benzylic proton of derivatives 224 more acidic and thus facilitates the overall process [153]. This approach is illustrated by the solid-phase synthesis of a library of 2,3-disubstutited-indoles 225 (Scheme 5.97) [154]. O

Z

+

i) Trimethylorthoformate ii) NaBH3CN, CH2Cl2

Z

NH

RCOCl

NH2

H

Z

Z

Z KOtBu

O R

N

DMF

R

N

95: 5 TFA: EtSiH N H

224

R

225

Z = CN, CO2tBu, CONH2 Scheme 5.97

In another variation of the Madelung synthesis, phosphonium salts 227 led to the corresponding indoles through a Wittig-like intramolecular reaction in the presence of base [155] or under thermal conditions [156]. The required phosphonium salts can be easily obtained from o-nitrobenzyl bromide (226) in a sequence that includes substitution with triphenylphosphine, reduction of the nitro group and acylation [157]. This procedure has been applied to the preparation of 2-alkyl, 2-alkenyl and 2-arylindoles 228 (Scheme 5.98). A solid-phase version of this procedure using a polymer-bound triphenylphosphine has also been developed [158].

Br NO2 226

i) PPh3 ii) Zn, AcOH iii) RCOCl

PPh3+BrKOtBu

O N H 227

R

∆

PPh3 O N H

R 228

N H

64 - 93% Scheme 5.98

2,3-Disubstituted indoles 231 have been prepared by a very original strategy from oaminoketones 229 through an intramolecular Horner–Wadsworth–Emmons reaction. The key step in this synthesis is the generation of the intermediate phosphonate 230, required for the olefination reaction, which was prepared by insertion in a N
H bond of an in situ generated Rh carbenoid (Scheme 5.99). The whole sequence can be conducted in a one-pot process [159].

R

j 5 Five-Membered Heterocycles: Indole and Related Systems

424

Ph

N2

O

O

PO(OEt)2

Rh2(OAc)4 Toluene

NH2

Ph

CO2Et

229

NH EtO2C

H

Ph

DBU Toluene

N H

PO(OEt)2

230

CO2Et

231 86%

Scheme 5.99

5.4.2.4.2 F€ urstner Synthesis The intramolecular reductive cyclization of oxo-amides 232 promoted by low-valent titanium (an intramolecular McMurry coupling) [160] is known as the F€ urstner indole synthesis [161] (Scheme 5.100). R3

R3 O

232

N H

R2 O

TiCl 3, Zn TMSCl, MeCN reflux 67-92%

N H

R2

Scheme 5.100

This coupling reaction is a very powerful method for the preparation of 2,3disubstituted indoles – in particular of 2-arylindoles – and has been applied in the total synthesis of several indole alkaloids and biologically active molecules [162]. Scheme 5.101 shows a particular example of this methodology, applied to the preparation of an endothelin receptor antagonist [163]. The oxo-amide 235 required for the cyclization reaction is easily prepared from o-nitrobenzaldehyde (233). Addition of an aryl Grignard followed by oxidation of the resulting alcohol installs the ketone functionality to obtain 234. Then, catalytic hydrogenation of the nitro group followed by acylation provides the amido functionality of 235, which is transformed into indole 236 under the standard low-valent-titanium reduction. 5.4.2.4.3 Radical Cyclizations A wide range of 2,3-disubstituted indoles can be prepared by the tin-promoted radical cyclizations of 2-alkenylphenylisonitriles [164] and 2-alkenylthioanilides 237 devised by Fukuyama [165] (Scheme 5.102). The cyclizations are carried out in the presence of tributyltin hydride and a radical initiator. In a first step, the tin radical adds to the thioamide 237 to form a sp3 radical 238 or an imidoyl radical 239, which cyclizes to yield the indole after a tautomeric equilibrium (Scheme 5.103). The tin-promoted cyclizations are compatible with a wide range of functional groups. Moreover, the required 2-alkenylthioamides are easily available through various procedures. All this factors make this approach a very useful method for the preparation of 2,3-disubstituted indoles. For instance, this reaction has been applied by Fukuyama to build both indole rings present in the alkaloid ( þ )-vinblastine, a

5.4 Indole Synthesis

i) H

O

O

O

O MgBr THF, -78 ºC

O

i) H2, Pd-C, O EtOAc

ii) PDC, CH2Cl2

NO2 233

NO2 ii) MeO2CCOCl CH2Cl2, Py, rt

234

83%

77%

O

O

O O

O

TiCl3, Zn DME, reflux 85%

NH O

N H

CO2Me

CO2Me 236

235 Scheme 5.101

R' X Y

NH S 237

R

R' Bu3SnH Et3B

N H

Toluene, rt 94-70%

R

Scheme 5.102

H R' NH S 237

R

R'

SnBu3

R SSnBu3

N H

N H

R SSnBu3 R

238 - HSSnBu3 R' N 239

Scheme 5.103

R' R

N H

R

j425

j 5 Five-Membered Heterocycles: Indole and Related Systems

426

i) NaBH4, MeOH CHO ii) DHP, CSA, CH 2Cl2

CSCl2, Na2CO3 MsO

THF, H 2O

N

MsO

NCS

OTHP MsO 242

241

240

OTHP

Benzyl Methyl Malonate NaH, THF, 0 ºC

MsO

OTPH CO2Me

Bu3SnH AIBN Toluene, 110 ºC

NH

N H

MsO

CO2Me

S 243

NCS

CO2Bn

CO2Bn

244

N H N H MeO2C MeO

many steps

N (+)-vinblastine OH OAc N H Me CO2Me

Scheme 5.104

potent agent for cancer therapy (Scheme 5.104) [166]. In this example, the 2alkenylthioamide is prepared in several steps from quinoline 240. Ring opening of quinoline 240 promoted by thiophosgene produces 241. Reduction the of the aldehyde functionality, followed by protection of the hydroxyl group with dihydropyran, leads to the isothiocyanide 242, which is transformed into the thioamide 243 by addition of a nucleophile. Finally, radical cyclization under standard conditions gives rise to the highly functionalized indole 244. 5.4.2.4.4 Palladium-Catalyzed Cyclizations The Pd-catalyzed cyclization of 2-(1-alkynyl)-N-alkylideneanilines 245 gives rise to 3-alkenylindoles 246 [167] (Scheme 5.105). According to the authors’ proposal, the reaction most probably proceeds through the regioselective insertion of a Pd hydride in the triple bond of 245, to form vinylpalladium intermediate 247. From this intermediate, both an “oxidative

R1

R1 1% Pd(OAc)2 nBu3P

N 245 Scheme 5.105

Ar

R3

Dioxane, 100 º C

N CO2Me

70-55% 246

5.4 Indole Synthesis

j427

addition/reductive elimination” sequence (path a) and carbopalladation of the imine followed by b-elimination (path b) can explain the formation of the indole (Scheme 5.106).

R1 H Pd

1

R

R1

H H-Pd-OAc

path a

N

PdOAc

N R

H

R

H R

H-Pd-OAc R1

R1

N

245

OAc

N H R

path b

N PdOAc

247

H-Pd-OAc

Scheme 5.106

5.4.2.5 Cyclizations with Formation of the N
C7a Bond NH

N

5.4.2.5.1 Nenitzescu Indole Synthesis The preparation of 5-hydroxyindole 250 derivatives from 1,4-benzoquinone (248) and a b-enaminoester 249 is known as the Nenitzescu reaction and was first reported in 1929 (Scheme 5.107) [168].

O

R' +

O 248

CO2R

HO CO2R

RHN 249

N H

R'

250

Scheme 5.107

Although the mechanism of the reaction remains somewhat obscure, it is presumed that it involves an internal oxidation–reduction process within the following steps: Michael-type addition of the enamine 249 to the quinone 248, oxidation of the hydroquinone 251 into a substituted benzoquinone 252, condensation to form the quinoimmonium cation 253 and reduction to form 5-hydroxyindole 250 (Scheme 5.108).

j 5 Five-Membered Heterocycles: Indole and Related Systems

428

O

R' + RHN

O 248

CO2R

HO

CO2R

250

249

R'

N H

[H] CO2Et R

HO

OH

[O]

CO2Et R

O

NHR

O

NHR

- H2O

252

251

CO2R

O

253

N R

R

Scheme 5.108

The Nenitzescu synthesis has been widely used for the preparation of 5-hydroxyindole derivatives with additional substituents in both rings [169]. An example of its implementation to solid-phase synthesis is given in Scheme 5.109 [170].

O NH2

O

O N H

CH2Cl2, -15 ºC

O

O

R-NH2 TMOF

NHR

N H

R3 O R1

R2

O

CH3NO2, rt

R3

O

HO R1

R2

N R

R3

NH

O

HO 20 % TFA/DCM 86 - 21%

R1

2

R

NH2

N R

Scheme 5.109

The scope of the Nenitzescu reaction has been recently extended to substrates different than the classical b-enaminocarbonyls. Pyrimidine-2,4,6-triamines react with p-benzoquinones to provide hydroxypyrimido[4,5-b]indoles with moderate yields [171]. Benzylimines of simple ketones (254), which are in tautomeric equilibrium with the corresponding enamines 255, are also good substrates for the indolization. This new reaction has been applied to simple cyclic imines, and also to more complex systems such as 256 to prepare new hydroxyindolomorphinans 257 with potent biological activity (Scheme 5.110) [172].

5.4 Indole Synthesis

O N

Bn

N H

254

O

Bn

HO N Bn

CH3NO2 60%

255

NR2 OH

NR2 OH

O

R1O

R1O

NBn

O

O

NR2 OH

O CH3NO2

OH O

R1O

NHBn

257

256 Scheme 5.110

5.4.2.5.2 Synthesis by Nitrene Insertion: The Hemetsberger Synthesis The indole ring can be built by insertion of a nitrene placed on the side-chain (260). In this approach, commonly known as the Hemetsberger indole synthesis, cyclization is achieved by thermolysis of the corresponding azides 259 [173]. Although the reaction may be understood as a nitrene insertion into a C
H bond, an azirine intermediate 261 has been isolated at lower temperatures [174], which provides the indole 262 after a subsequent rearrangement (Scheme 5.111). H

R

j429

O

N3CH2CO2Et

R

CO2Et

258

- N2

N3

NaOEt

R

∆

H

259 CO2Et

N

260 R

N H 261

CO2Et

N H

CO2Et

262

Scheme 5.111

The vinylazides are best obtained by condensation of azidoacetate with aryl aldehydes 258. Thus, this methodology is particularly useful for the preparation of 2-carboxyindoles 262 from aromatic aldehydes [175]. This protocol has been employed successfully in the preparation of polycyclic indole derivatives. For instance, application of the Hemetsberger sequence to the formylbenzoxazine 263 gives oxazinindole 264 in moderate overall yield (Scheme 5.112) [176].

N Bn

j 5 Five-Membered Heterocycles: Indole and Related Systems

430

EtO2C OHC

O N Bn

Cl

i) N3CH2CO2Et NaOEt, - 18 ºC CO2Et ii) xylene reflux 34%

NH O

Cl

263

CO2Et

N Bn 264

Scheme 5.112

5.4.2.5.3 Intramolecular Buchwald–Hartwig Amination The Pd-catalyzed cross-coupling of aryl halides with amines is nowadays one of the most powerful methods for the formation of Caryl
N bonds [177]. The intramolecular version of the reaction leads to indolines, which can be converted into indoles by treatment with Pd/C. Scheme 5.113 shows the cyclization of the in situ generated 1-(o-bromophenyl)-2ethylamine 265 to furnish the corresponding indole 267 after the oxidation step of the intermediate indoline 266 [178]. Further optimization of the reaction showed that modification of the ligand and the base provides better yields under milder conditions [179]. Moreover, a similar copper-catalyzed cyclization has also been reported [180, 181].

Bu Br Br

Bu

Bn-NH2 Pd2(dba)3 P(o-Tol) 3 NaOtBu

Br 265

Bu NHR

N Bn 266

Bu Pd/C, HCO2NH4 MeOH, reflux 267 54%

N H

Scheme 5.113

Intramolecular N-arylation of enamines has also been applied in the synthesis of indoles. Enamine 270 (in tautomeric equilibrium with the imine 269), which is ready for cyclization, is obtained by Ti-catalyzed hydroamination of the o-chloro-substituted alkynylbenzene 268. Then, the Pd-catalyzed C
N bond-forming reaction furnishes N,2-disubstitutedindoles271withgoodyieldsinaone-potprocess (Scheme5.114)[182]. Indoles have been prepared by two consecutive Pd-catalyzed amination reactions on the enoltriflate 272 in a closely related strategy that features two reactive positions towards Pd-catalyzed amination (Scheme 5.115) [183]. First, amination of the more reactive enoltriflate occurs, to produce the enamine 273, which then undergoes intramolecular aryl amination to give indole 274.

5.4 Indole Synthesis

j431

R2 3

+ R NH2

110 ºC, 24 h

Cl

1

R

Cl

1

R

268

R2

R2

5 mol % [Cp2TiMe2]

NR3

269

Cl

1

R

270

5 mol % Pd2(dba)3 10 mol % Ligand KOtBu 1,4-dioxane, 100 ºC, 12h

R1

271

N R3

R2

65-80 % (one pot) Scheme 5.114

Br

OTf

272

+

Bn-NH2

Pd2(dba)3, Ligand CsCO3, Tol, 100 ºC 70%

Br

274

N Bn

NHBn

273 Scheme 5.115

5.4.3 Synthesis of the Indole Ring by Annelation of Pyrroles

Construction of the indole ring by annelation of pyrroles has been much less exploited. Nevertheless, several efficient methods have been disclosed during the last two decades. Most of the existing methods lie in one of the retrosynthetic schemes represented in Scheme 5.116. 5.4.3.1 Synthesis by Electrophilic Cyclization The most popular type of methods for synthesis of the indole ring from pyrroles involves an electrophilic cyclization, with formation of either the C7
C7a or C3a
C4 bond (Scheme 5.117). In both cases, annelation takes place by an intramolecular electrophilic attack of the pyrrole to a carbonyl function. To facilitate aromatization, a leaving group is usually present in the carbon chain. The different methods described in the literature differ in the way to synthesize the intermediate carbonyl pyrrole ready for the cyclization.

NHR3

j 5 Five-Membered Heterocycles: Indole and Related Systems

432

N

N 5

4

3a

3 2

[4+2] cycloadditions

N

6 7

7a

N H

N

N

N Scheme 5.116

X

O

N P

N P

X

O

N P

Scheme 5.117

5.4.3.1.1 Natsume Synthesis In the Natsume approach, the intermediate for cyclization is prepared by addition of a organometallic bearing a masked carbonyl functionality (276) to a pyrrolyl ketone (275). Acid-catalyzed cyclization on the resulting functionalized pyrrole 277, with concomitant aromatization, provides indole 278. This method is a very powerful strategy for the preparation of alkylsubstituted indoles in the benzene portion. Scheme 5.118 shows the preparation of MgX

O O O Cy

N Ts

O

276

O

86%

MgX

O O

Cy N Ts 279 Scheme 5.118

i-PrOH reflux 69%

N Cy OH Ts 277

275

O

H2SO4

Cy OH

Cy 278

Cy H2SO4

276 97%

N Ts

O

N Ts

O 280

i-PrOH reflux 82%

N Ts 281

5.4 Indole Synthesis

j433

both a 7-substituted (278) and a 4-substituted indole (281) by application of the same methodology but starting from 2-acyl (275) and 3-acyl (279) substituted pyrrole, respectively [184]. Modifications of this strategy have been applied to the preparation of several natural indole alkaloids, characterized by complex alkyl-substitution in the benzene ring, such as herbindoles and trikentrins (Scheme 5.119) [185].

EtO2C

COOEt

OH

i) LDA, THF, - 65 ºC ii)

O N SO2Ph - 78 ºC, 48 h

N SO2Ph

OH SO2Ph OsO4, NaIO4 THF-H2O

OH SO2Ph

iii) LiCH2SO2Ph THF, -75 º

N SO2Ph

SO2Ph p-TsOH, PhSH, Tol reflux, 5h

O N SO2Ph

i) MnO2, CH2Cl2 ii) LiCl, HMPA-H 2O 130 ºC

Mg, NH4Cl MeOH N SO2Ph

N H (+)-Herbindole A

Scheme 5.119

5.4.3.1.2 Katritzky Synthesis In the method by Katritzky, the carbonyl substituted pyrrole 283 ready for the cyclization, is generated by a Michael-type addition of the carbanion generated from a benzotriazole (Bt)-substituted pyrrole (282) with a a,b-unsaturated ketone (Scheme 5.120) [186]. The benzotriazolyl functionality acts as both an anion-stabilizing group and leaving group in the overall transformation. Both approaches, cyclization by formation of the C3a
C4 bond (Scheme 5.120) or the C7
C7a bond (Scheme 5.121), have been conducted [187]. 5.4.3.2 Palladium-Catalyzed Cyclizations The six-membered ring of the indole skeleton has also been constructed by Pdcatalyzed intramolecular Heck reactions. In the example shown in Scheme 5.122, a 6-exo-trig cyclization of a bromo-substituted pyrrole (284), bearing a double bond in an appropriate position, provides an advanced intermediate for the synthesis of the antitumor antibiotic duocarmycin SA [188]. The intramolecular Heck reaction has also been employed to build the benzene ring of the indole system with formation of the C5
C6 bond [189].

j 5 Five-Membered Heterocycles: Indole and Related Systems

434

Bt

Bt

Li

i) BuLi, THF -78 ºC

N SO2Ph 282

Bt =

N

N SO2Ph

R1

N N

R2 O

Bt

R2

R2

N SO2Ph

R1

+

O

N SO2Ph

R1

O

R1

10% H2SO4 isopropanol reflux

N PhO2S

283

R2

Scheme 5.120

t-Bu Bt

N

O i) n-BuLi

Ph Ph

ii) Ph

Ph

Ph

t-Bu

Bt

reflux 3h

N

N

Ph

65%

O Scheme 5.121

OBn

BzC

OBn Br

N

O

Pd(OAc)2 N H

CO2Me

(o-Tol) 3P, Et 3N MeCN, 100 ºC 83%

284

BzC

N

O

N H

CO2Me

OH

BzC

N CO2Me

OH Scheme 5.122

t-Bu

TsOH/THF

N Mom

Duocarmycin SA

5.4 Indole Synthesis

5.4.3.3 Electrocyclizations Electrocyclization of 2,3-dialkenyl-4-nitropyrroles 285 gives rise to 3-nitroindoles 286 – compounds that are difficult to prepare selectively through other routes. After the thermal 6p-electrocyclization, aromatization of the intermediate dihydroindoles occurs to provide the indole directly (Scheme 5.123) [190].

NO2 Me Ph

N CH3

285

Ph-NO2, reflux (211 ºC) 85%

Ph

NO2

NO2

N CH3

N CH3

Ph - 2H

NO2

Ph

N CH3

286 Scheme 5.123

5.4.3.4 [4 þ 2] Cycloadditions The cycloaddition of 2- and 3-vinyl pyrroles should allow for the preparation highly functionalized indoles in the benzene ring [191]. In a particularly interesting approach, 4,5-g2-Os(II)pentaammine-3-vinylpyrrole complexes 287 readily undergo Diels–Alder reactions with activated dienophiles such as N-phenylmaleimide to generate the 5,6,7,7a-tetrahydroindole nucleus. The tetrahydroindole complexes 288 can be decomplexed and oxidized with DDQ to generate highly functionalized indoles 289 (Scheme 5.124) [192]. In contrast, the cyclic pyrrolo-2,3-quinodimethanes 290 undergo Diels–Alder cycloaddition with alkynes. After CO2 loss, indoles with high substitution in the benzene ring (291) are obtained (Scheme 5.125) [193]. 5.4.3.5 Indoles from 3-Alkynylpyrrole-2-Carboxaldehydes Benzannulation of readily available 3-alkynylpyrrole-2-carboxaldehydes 292 with alkenes, promoted by iodonium ions, yields indoles 293 with a high level of substitution and functionalization in the benzene ring (Scheme 5.126) [194]. The mechanism proposed for this unusual transformation is represented in Scheme 5.127. Interaction of the iodonium ion with the triple bond of 292 would promote the formation of intermediate 294. Nucleophilic attack of the alkene to the electrophilic carbon of 294; subsequent intramolecular cyclization would then provide 296. The simple loss of a proton to give a conjugated double bond then yields 297. Finally, aromatization by elimination of HI gives the indoles 293. This

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j 5 Five-Membered Heterocycles: Indole and Related Systems

436

R1

R2

Ph N

O

O

2+

[Os ]

R1

R2

[Os2+]

O N

N 287

N O 288

R1

Ph

R2

DDQ

O

120 ºC

N

N 289

O

Ph

60% Scheme 5.124

EtO2C

R1

CO2Et

O N CO2i-Bu

O

+

TMS Ph-Cl reflux

TMS

O O

N CO2i-Bu

290 EtO2C TMS 291 79%

N CO2i-Bu

Scheme 5.125

proposal is supported by detailed mechanistic and spectroscopic studies, which allowed the isolation of analogues of the cationic intermediates 294 and 296 [195]. 5.5 Reactivity of Indole 5.5.1 Reactions with Electrophiles

The chemistry of indole is dominated by the strong electrophilic character of the p-electron excessive heterocycle. Electrophilic aromatic substitution takes place at C3, and is one of the most efficient methods for the introduction of substituents on

5.5 Reactivity of Indole

R1

R1

O i) IPy2BF4 / HBF4 CH2Cl2, 0 ºC

O

N Tos

ii)

R2

R2 N Tos

R3

R3

292

293

O

Ph

O

R1

O

Ph

N

Ph N Tos

N Tos

72%

N Tos

42%

n-C6H13 43%

Scheme 5.126

R1

N Tos 292

R1

O

R2

I+BF4-

O

R3

N Tos

R2

R3 293 HI

I+BF4BF4

R1

I

O O

N Tos

R N Tos

R2 3

294 Scheme 5.127

R

N Tos

297

O R3 295

BF4 R2

Tos

H R2 R3

R3

R1

1

O

I

N Tos

I

I

BF4

R1

N

HBF4

R2

H I O

296

R1 BF4

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j 5 Five-Membered Heterocycles: Indole and Related Systems

438

the indole ring at that position. The regioselectivity of the electrophilic aromatic substitution is easily explained by the different stability of the intermediate indolium cations generated. The positive charge at C2, generated by electrophilic attack at C3, can be delocalized between C2 and the N atom without compromising the aromaticity of the benzene ring. In contrast, electrophilic attack at C2 generates an indolium cation with the positive charge at C3, which cannot be delocalized without breaking the aromaticity of the benzene ring. Electrophilic aromatic substitution on the benzene ring occurs only on indoles strongly deactivated on the five-membered ring. The method of choice to introduce electrophiles at the C2 position of indoles consists in a stepwise procedure, involving N-protection, lithiation at C2, reaction with the electrophile and N deprotection. 5.5.1.1 Protonation Indole and substituted indoles are weak bases, with pKa values ranging from -2.4 for protonated indole to
0.3 for the protonated electron-richer 2-methylindole [196]. As expected, C3 is the main site for protonation of indole, to produce the 3-H-indolium cation. Although the N-protonated indole (1-H-indolium cation) is not detected, even spectroscopically, it is believed that N-protonation occurs rapidly and equilibrates into the more stable C3 protonated species. Under weak acidic media indole undergoes dimerization and oligomerization by attack of a molecule of non-protonated indole to the strong electrophilic C2 position of the 3-H-indolium cation (Scheme 5.128).

H+ N H

H N H

H

H H

N H

H

H H

N H

N H - H+

N H N H

NH

Scheme 5.128

5.5.1.2 Friedel–Crafts Alkylations of Indole Indolyl compounds can be regioselectively alkylated at C3 through different Friedel– Crafts (FC) type of reactions (Scheme 5.129). Alkyl halides, epoxides and aziridines, carbonyl compounds and imines, a,b-unsaturated compounds, alkenes and alkynes, and allylic acetates or carbonates have all been employed as electrophiles. The amount of literature regarding this topic is enormous. These types of reaction usually proceed smoothly in the presence of a Lewis or protic acid as catalyst. Thus, the most recent advances have focused mainly on developing catalytic systems

5.5 Reactivity of Indole

R N H X

R-X R

X

R

R

X R

XH R'

R' N H

N H N H

R

X

X

R

R'

R' N H

Pdcat

N H

XH

R R

R' R'

N H Scheme 5.129

to perform the electrophilic aromatic substitution reaction in a milder, regio- and stereoselective manner [197]. 5.5.1.2.1 Michael Additions The reactions of indoles with a,b-unsaturated compounds, such as a,b-unsaturated ketones, nitriles and nitroolefins, usually require activation of the electrophile by an acid, and proceed with either protic [198] or Lewis acids [199] and clays [200] to provide the corresponding 3-substituted indoles (Scheme 5.130). O + N H

Scheme 5.130

O

N H

AcOH, Ac2O 25 90 ºC

75%

BF3, EtOH - 20 ºC

86%

montmorillonite clay, 40 ºC

75%

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j 5 Five-Membered Heterocycles: Indole and Related Systems

440

These transformations have attracted much attention in recent years, and several different new Lewis acids have been developed, including bismuth(III) salts [201], cerium salts [202], Pd salts [203] and iodine [204]. For instance, the use of lanthanidebased Lewis acids allows for the alkylation of indoles at the 3-position with various Michael acceptors and under mild conditions (Scheme 5.131) [205].

R1

+

R2

N H

EWG

R1

Yb(OTf)3 2.5 % mol CH3CN, rt

R2

EWG

N H O

O 85%

N H Ph

Ph

NO2 85%

NO2

N H

Scheme 5.131

Michael additions have been carried out in water at room temperature using a scandium salt of an anionic surfactant – Sc(DS)3 (scandium dodecyl sulfate) (Scheme 5.132) [206]. O MeO N H

+

O

Sc(SD)3 10 % mol H2O, rt 63%

N H

Scheme 5.132

Indium salts are amongst the most general and effective Lewis acids to promote the Michael addition, which can be performed with relatively hindered enones and 2substituted indoles [207, 208]. The same catalyst promotes the reaction with nitroalkenes, under aqueous conditions, with excellent yields in most instances (Scheme 5.133) [209]. Gold(III) salts are also excellent catalysts for this reaction [210]. Interestingly, when the Michael addition is carried out with 3-substituted indoles, substitution occurs at C2 although with relatively lower yields (Scheme 5.134).

5.5 Reactivity of Indole

Ph

CN +

Ph

CN

N H

CN

CH2Cl2, rt

N H

/8%

Ph +

Ph

CH2Cl2, rt

O

N R1

R3

R4 NO2

2

R

Ph

N H

/3%

R3

O

InBr3 10 % mol

Ph

N H

CN

InCl3 10 % mol

InBr3, THF/H2O rt 99-45%

N R1

R4 NO2 R2

Scheme 5.133

O Ph

N H

O

OCH3

N H 85%

Ph

OCH3

NaAuCl4, 2H2O EtOH

O N H

N H 58%

Scheme 5.134

In the reaction of indoles with b-substituted-a,b-unsaturated compounds one or two new stereogenic centers can be created. Control of the enantioselectivity of such processes has aroused much interest in recent years (Scheme 5.135). Few examples have appeared of the catalytic asymmetric Michael reaction of indoles. To achieve good enantioselectivities the use of bidentate chelating Michael acceptors is required, to keep fixed the chiral environment provided by the ligand (Scheme 5.136). Good to excellent enantioselectivities have been achieved in reactions of alkylidene malonates 298 [211], b,c-unsaturated a-ketoesters 299 [212], acyl

j441

j 5 Five-Membered Heterocycles: Indole and Related Systems

442

R2

R3 R2

R3 * *

EWG

N R1

EWG

N R1

Scheme 5.135

O R

O Y

R

X

LA*

LA* Y

O

R

Y

monodentate Michael acceptor: poor enantioselectivity

298 299 300 301

X = CO2R', Y = OR' X = H, Y = CO2R' X = H, Y = P(O)OMe2 X = H, Y = C(Me)2OH N 302 X = H, Y = N Me

LA* O

Y

R bidentate Michael acceptor: good enantioselectivity

Scheme 5.136

phosphonates 300 [213], a0 -hydroxyenones 301 [214] and a,b-unsaturated-2-acylimidazoles 302 [215, 216], using appropriate chelating C2 symmetric chiral ligands combined with Cu or lanthanide Lewis acids. Scheme 5.137 shows the asymmetric Friedel–Crafts alkylation of indoles with a0 -hydroxyenone 301, yielding 3-substituted indole 303 with very high ee. O OH

R MeO

301

R MeO

cat. CH2Cl2, rt, 2h

N

cat.

303

R

O N

N

Cu tBu TfO OTf

OH

96% yield 97% ee

N

steps O

O

O

X

MeO tBu

N

X = H, R, OMe

Scheme 5.137

In a totally different and extremely elegant approach, the asymmetric Michael addition of indoles to a,b-unsaturated aldehydes has been achieved using a chiral imidazolidinone (304) as an asymmetric organocatalyst [217]. The imidazolidinone

5.5 Reactivity of Indole

plays a double catalytic role: to activate the aldehyde 305 by the formation of the highly reactive iminium species 306, and to create a chiral environment that differentiates both enantiotopic faces of the Michael acceptor (Scheme 5.138). Me

X

X O

+ N R

Y

305 O

Me N

cat:

N H

Ph

H

O

cat: 20 % mol CH2Cl2, iPrOH

N R

Y

Yield: 82-94% ee: 89-97% Me · TFA

O

Me Me

Me N N

304

Me

Me Me

Ph

306 Scheme 5.138

Thiourea-based organocatalyst 307 promotes the asymmetric Friedel–Crafts alkylation of indoles with nitroalkenes with high yields and enantiomeric excesses. The stereochemical course of the reaction is controlled by the asymmetric platform provided by the chiral thiourea organocatalyst, which forms hydrogen bonds simultaneously with both reactants (Scheme 5.139) [218]. Ph MeO

+ Ph

NO2

N H

MeO

cat: 10 % mol CH2Cl2, -20 ºC

N R Yield: 86% ee: 89%

cat:

CF3

F3C

CF3 S N H 307

S N H

OH

H O H

H

N H O

N

N H N

O

Ph Scheme 5.139

CF3

NO2

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j 5 Five-Membered Heterocycles: Indole and Related Systems

444

5.5.1.2.2 Reactions with Unactivated Olefins The intramolecular cyclization of alkenylindoles 308 can be promoted by PtCl2 to give tetrahydrocarbazole derivatives 309 [219]. The cyclization proceeds through nucleophilic attack of the indole on the Pt(II) complexed olefin in intermediate 310, followed by protonolysis of the C
Pt bond in 311 (Scheme 5.140). The same authors have recently reported an extension of this methodology to the use of Pd(II) and Cu(II) catalysts [220].

PtCl2

308

Dioxane 5 % mol HCl

N R

309

R = Me 91% R = H 87%

N R

PtCl

PtCl2

H - HCl

310

N R

311

N R

Scheme 5.140

5.5.1.2.3 Reactions with Carbonyl Compounds Friedel–Crafts alkylation of indoles with aldehydes and ketones takes place under Brønsted [221] or Lewis acid catalysis. The initially formed indole-3-yl-carbinols 312 are usually not isolated and evolve to produce the azafulvenium salts 313. Finally, addition of a second molecule of indole to the azafulvenium salt gives rise to bis(indoylmethanes) 314 (Scheme 5.141).

N H

N H

R1 +

3 HO R R2

O 2

R

R3

R1

N H 312

R3 R2 N H

Scheme 5.141

H+ or LA

N R1 R1 H 314

R3

R1

N H 313

R2 R1

5.5 Reactivity of Indole

Several different types of protic and Lewis acid catalysts have been employed for this transformation. For instance, reaction of indole with aldehydes or ketones such as 315 and 317, in the presence of LiClO4, affords the bis(indoylmethanes) 316 and 318, respectively, in excellent yields (Scheme 5.142) [222]. H3CO N H CHO 5 M LiClO in Et O 4 2

MeO

H

rt, 3h

MeO

N H

93%

315

OCH3

N H

316

N H 5 M LiClO4 in Et2O

O

rt, 8h

N H

89%

317

N H

318

Scheme 5.142

When the reaction is carried out with 2-oxoesters such as glyoxalate 319, the indoylcarbinol 320 does not undergo elimination and can be isolated (Scheme 5.143) [223]. HO

N H

+

O H 319

CO2Et

Pd(CH3CH)2Cl2 CO2Et

CH2ClCH2Cl rt 96%

N H 320

Scheme 5.143

The enantioselective version of this reaction has been successfully carried out both with copper-based chiral Lewis acids 321 [224] and with Cinchona alkaloid organic catalysts 322 (Scheme 5.144) [225]. The organocatalyzed reaction, although not well understood yet, is remarkable, as the appropriate choice of alkaloid (chinchonidine, CD or Chinchonine, CN) provides either enantiomer in quantitative yield and with very high ee. 5.5.1.2.4 Reactions with Imines and Imminium Ions: Mannich Reaction Under typical Mannich conditions indole undergoes alkylation at C3. This reaction leads to the synthesis of gramines 323, which are important intermediates for the

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j 5 Five-Membered Heterocycles: Indole and Related Systems

446

R3

R3

N R1

R2

+

O F3C

cat CO2Et

O

N Cu tBu TfO OTf

N R1

CO2Et CF3 R2

cat.

cat. O

HO

HO

N

tBu

321

322

Yield: 94 - 61% ee: 94 - 83%

98

N CD: C8, R; C9, S CN: C8, S; C9, R

N

Yield: 99 - 96% ee: 95 - 83%

Scheme 5.144

preparation of substituted indoles (Section 5.6.1). When the reactions are conducted in water at low temperatures, the kinetically controlled N-alkylation product 324 is obtained [226]. The resulting N-aminal indoles are relatively stable but convert into the thermodynamically more stable C3-substituted aminomethyl indoles upon heating at neutral pH or acid treatment at room temperature (Scheme 5.145). R1R2NH CH2O H2O

N H

N 324

NR1R2 H2O, ∆ or AcOH, rt NR1R2

R1R2NH CH2O AcOH 323

N H

Scheme 5.145

Gramines can undergo a second Mannich reaction, yielding 1,3-disubstituted indoles 325. This reaction has been applied to the parallel synthesis of an indolebased library (Scheme 5.146) [227]. Indole reacts with imines under acidic conditions to give substituted gramines. For instance the reaction of glyoxylimine 326 with indoles employing Yb(OTf)3 as Lewis acid leads to gramine derivatives 327 (Scheme 5.147) [228, 229].

5.5 Reactivity of Indole O

R1R2NH CH2O

EtO

O

NR1R2

dioxane/HOAc rt, 18 h

N H

R3R4NH CH2O

EtO N H

O

NR1R2

EtO

dioxane/HOAc rt, 48 h

N 325

R1R2NH: pyrrolidine, 77% 4-methylpiperidine, 93% diethylamine, 78% morpholine 57%

Scheme 5.146

BnHN Bn Ph

N H

+

N

Yb(OTf)3, 5 %mol CO2Et

326

CH2Cl2 68%

327

N H

CO2Et Ph

Scheme 5.147

Asymmetric versions of this reaction have been carried out employing Cu-based chiral catalysts [230] and also organic catalysts. Scheme 5.148 presents the Friedel– Crafts alkylation of indoles with N-tosylimines, such as 328, promoted by the quininebased organic catalyst 329 [231].

TsHN

N H

NTs

+

329 (5 mol%) THF, 50 ºC

328

N

H N

H

H N

* N H Yield, 86% ee, 94%

Ph

CF3

S N

j447

CF3 329

Scheme 5.148

5.5.1.2.5 Epoxide and Aziridine Ring Opening Epoxides and aziridines are versatile alkylating agents for indole. The ring opening of these strained heterocycles by indole proceeds with Lewis acid, bases and solid acids, giving rise to triptophols and tryptamine derivatives respectively (Scheme 5.149). Moreover, the ready availability of enantioenriched cis and trans epoxides makes this approach a very valuable entry

NR3R4

j 5 Five-Membered Heterocycles: Indole and Related Systems

448

R1

N H

+

R2 +

N H

R1

XH R1

R2

LA

X R2

XH

N H

Scheme 5.149

into enantiomerically pure indoles. The regiochemistry and stereochemistry of the ring opening are the main issues that have to be addressed during the reaction. The alkylation of indole with enantiomerically pure styrene oxide is catalyzed by most of the common Lewis acids, with InBr3 being the most efficient in terms of regioselectivity, enantioselectivity and yield (Scheme 5.150) [232, 233]. Other catalysts such as Sc(OTf)3 and SnCl4 [234] also promote the ring opening without racemization. Ph

N H

+

InBr3

O

Ph

OH

CH2Cl2

N H

Yield: /0% ee: 99% Scheme 5.150

Enantioenriched chiral triptophols 330 can also be prepared by kinetic resolution of racemic epoxides, or by desymmetrization of meso epoxides, employing Cr(Salen) Cl complex 331 as chiral catalyst (Scheme 5.151) [235]. Ph R N H

+

O Ph

331

R

Ph TBME, rt

Ph 330

N H

Yield: 95-98% ee: 90-98% N

tBu

N Cr O Cl O tBu

Scheme 5.151

331

tBu tBu

OH

5.5 Reactivity of Indole

j449

The ring opening of aziridines with indoles provides tryptamine derivatives. Lewis acids based on Zn [236], Sc, Yb, and indium [237], and SiO2 promote efficiently the FC reaction. Scheme 5.152 shows the alkylation of methyl indole-2-carboxylate with chiral aziridine 332 to produce the enantiomerically pure substituted indole 333. The alkylation occurs cleanly simply by adsorbing both reagents in SiO2 and heating the mixture at 70  C [238]. O O

N H

CO2Me + Ts

N

O

SiO2, 70 ºC

O

48 h 68%

NHTs N H 333

332

CO2Me

Scheme 5.152

5.5.1.2.6 Indole as Nucleophile in Palladium-Catalyzed Allylic Alkylations Indoles are also competent nucleophiles for Pd-catalyzed allylic substitutions (Tsuji–Trost reaction) [239]. The reaction between allyl carbonate 334 and indole leads regioselectively to the C3-allylated indole 335 or the N-allylated indole 336, depending on the reaction conditions applied (Scheme 5.153) [240]. OCO2CH3 Ph N H

334

Me

Me

[PdCl(π-allyl)]2 PPh3 base, solvent CH2Cl2 BSA, Li2CO3 DMF, Cs2CO3

335

Ph +

N H

10 1

N

Ph

336 : :

1 50

Scheme 5.153

The intramolecular variant of this reaction provides a new entry into polycyclic fused indoles. Remarkably, use of the appropriate chiral ligand allows for the asymmetric allylic alkylation (AAA) reaction [241] to take place with very high ee, giving rise to tetrahydro-b-carbolines 338 (Scheme 5.154) [242]. Moreover, when the pedant group is attached at C3, such as in 339, the allylic alkylation takes place at C2, also with very high regio- and enantioselectivity, to produce tetrahydro-c-carbolines 340. 5.5.1.3 Nitration Indoles are highly sensitive to acids, and for this reason the nitration of the indole ring requires carefully designed experimental conditions. Although C3 is the

j 5 Five-Membered Heterocycles: Indole and Related Systems

450

OCO2CH3

N Bn

Li2CIO3, CH2Cl2 rt

N H

337

N Bn

Pd(0)/L* N H 338 Yield: 98% ee: 97%

Bn N

Bn N Pd(0)/L*

*

Li2CIO3, CH2Cl2 rt

N H

N H 340 Yield: 90% ee: 93%

OCO2CH3

339 O

R N H

L*:

R

O

N H

PPh2 Ph2P

Scheme 5.154

preferred position for electrophilic attack on indole, nitration under strong acid conditions proceeds through the 3-H-indolium cation, and nitration occurs mainly at C5, owing to the directing influence of the iminium substituent. Indole itself can be nitrated at C3 with moderate yield with benzoyl nitrate [243], and 2-arylindoles can be successfully nitrated at C3 by treatment with 2-cyano-2-propyl nitrate under phase transfer catalysis conditions [244]. More interestingly, N-protected indoles can be successfully nitrated at C3 by treatment with in situ generated acetyl nitrate at very low temperature (Scheme 5.155) [245]. NO2 N R

X

Ac2O/HNO3 -70 ºC 41-86%

N R

X

R = Me, Bn, CO2R, SO2Ph X = H, Me Scheme 5.155

In contrast, 2-nitroindoles 342 can be synthesized by a lithiation-nitration protocol on N-protected indoles 341 at very low temperature (Scheme 5.156) [246], and by treatment of N-protected-2-bromoindoles 343 with silver nitrite (Scheme 5.157) [247].

5.5 Reactivity of Indole

R

R t-BuLi

341

N Boc

-78 ºC

N Boc

R N2O4

Li

-120 ºC to rt 74-78% 342

N Boc

NO2

R = H, Me Scheme 5.156

Br

343

N CO2Et

AgNO2

NO2 N CO2Et

Acetone: H2O 65 ºC dark, 48 h 63%

Scheme 5.157

5.5.1.4 Acylation Indoles can be acylated at C3 by the Vilsmeier–Haack reaction [248], by Friedel–Crafts acylations [249] and also by reactions of indole Grignard reagents [250] or indole zinc chloride salts with acid chlorides (Scheme 5.158) [251]. CHO DMF, POCl 3 N H N H

COR

RCOCl Lewis Acid

N H

RCOCl N

M

COR N H

Scheme 5.158

The Vilsmeier–Haack reaction is the classical method for the preparation of 3formylindole and other 3-acylindoles, starting from tertiary amides. This reaction provides good yields for the acylation of indoles but is limited to formamide and alkylcarboxamides (Scheme 5.159). Friedel–Crafts acylation is a very convenient process for electron-withdrawingsubstituted indoles and for N-protected indoles. However, the reaction of N
H indoles requires a fine tuning of the catalyst and the reaction conditions to avoid

j451

j 5 Five-Membered Heterocycles: Indole and Related Systems

452

Cl

H

N H

DMF, POCl3

N H

NMe2

N H

NMe2

Cl-

NaOH ∆

Cl H

H

CHO

NMe2

N H Scheme 5.159

N-acylation and polymerization reactions [252]. The use of an excess of dialkylaluminium chlorides as Lewis acids represents a very general method for the Friedel– Crafts acylation of indoles [253]. The excess dialkylaluminum reagent is required to quench the HCl liberated in the acylation process, thereby avoiding side reactions, such as dimerization and polymerization, that might be originated by the presence of the acid (Scheme 5.160). RCOCl

X N H

Y

Et2AlCl

COR

X

N H

0 ºC

X = H; Y = Me; R = Me X = H; Y = Me; R = CH=CH-CH3 X = MeO; Y = H; R = Me X = MeO; Y = H; R = CH=CH-CH3 X = MeO2C-; Y = H; R = Me

Y

89% 80% 89% 71% 91%

Scheme 5.160

The use of N-acylbenzotriazoles 344 represents an alternative to acid chlorides, eliminating the complications associated with the release of HCl [254]. This procedure permits the acylation of both N-H and N-alkylindoles (Scheme 5.161). 5.5.1.5 Halogenation The indole ring can be easily halogenated at C3 by employing bromine and iodine in DMF (the presence of potassium hydroxide is required for the iodination reaction), providing nearly quantitative yields of the corresponding 3-haloindoles [255], while 3-chloroindoles are best prepared with N-chlorosuccinimide (NCS) (Scheme 5.162) [256, 257]. Many other reagents have been described to promote these transformations [258, 259].

5.5 Reactivity of Indole

+ ArCOBt

N X

344

COAr

TiCl4 CH2Cl2

N X

25 ºC, 2h

Yield: 92-64% X = H, Me

Bt = N

N N

Scheme 5.161

Br Br2, DMF N H H3CO

45 min, rt

N H

96% I2, DMF, KOH

I

H3CO

45 min, rt

N H

N H

97%

O

O NCS, MeOH

tBuO N H

0 ºC to rt 10 h

Cl

tBuO N H

42% Scheme 5.162

Halogens are best introduced at C2 by the metallation–halogenation sequence discussed in Section 5.5.2.2. 5.5.2 Reactions with Bases 5.5.2.1 N-Metallation of Indoles Indole is a weak acid (pKa ¼ 16.7 and 20.9 in water [260] and DMSO [261], respectively) and therefore undergoes deprotonation by strong bases to provide a reactive anion. Most of the reactions involving substitution at nitrogen – alkylation, acylation, and sulfonation – are carried out through the indolyl anion. The usual methods for the N-alkylation of indole involve the use of alkali metal hydroxides [262], alkali metal hydrides [263] or NaNH2 in polar aprotic solvents (Scheme 5.163). Alternatives include the use of potassium hydroxide in acetone under phase transfer catalysis conditions [264], caesium carbonate in either DMPU [265] or in the presence of a crown ether [266].

j453

j 5 Five-Membered Heterocycles: Indole and Related Systems

454

N H

PhCH2Br KOH, DMSO 95%

N Bn

Scheme 5.163

Both N-acylation and N-sulfonation of indoles are synthetically relevant transformations, not only for the interest in N-acyl and N-sulfonyl indoles themselves, but also because the protection of the indole N
H in a synthetic sequence almost always involves an acylation orsulfonation step [267].The use of acid chlorides andanhydrides in the presence bases make up the most common reaction conditions. In particular, the Boc group has been introduced using di-tert-butyl dicarbonate, phenyl-tert-butyl carbonate and BocN3 [268]. Scheme 5.164 depicts some representative reactions for the N
H acylation of indole with different acylating agents [269–271]. PhCOCl NaOH, DME 83%

N COPh

O R

O

Cl

NaH, THF, rt 80-100% N H

N CO2R

i) NaOH (NBu)4HSO4 CH2Cl2 ii) PhSO2Cl, CH2Cl2 0º C to rt, 4h 89%

N SO2Ph

i) DMAP, THF ii) Boc2O, rt , 14 h 98%

N Boc

Scheme 5.164

Direct acylation of indoles with aromatic carboxylic acids can be achieved using DCC as coupling agent (Scheme 5.165) [272]. 5.5.2.2 C-Metallation of Indoles N-Substituted indoles undergo direct lithiation at C2, and in certain cases at C3 upon treatment with organolithium reagents [273]. In fact, lithiation followed by reaction with an electrophile is the most common strategy to introduce substituents at C2.

5.5 Reactivity of Indole

F

F

HO2C

DCC, DMAP

+

N H

OCH3

N

CH2Cl2, rt

O

89%

OCH3

Scheme 5.165

Both N-acyl and N-sulfonyl indoles can be selectively lithiated at C2 by treatment with organolithium reagents. The presence of the coordinating group at N1 assists the lithiation at C2 and governs the regioselectivity of the process. Recent applications of this strategy are found in Gribble’s syntheses of 2-nitroindole 345 [274] and 2iodoindole 346 [275] from, respectively, N-Boc-indole and N-phenylsulfonylindole (Scheme 5.166) and in the preparation of the important synthetic intermediates 2-indolylborates 347 (Scheme 5.167) [276].

t-BuLi N Boc

-78 ºC

N Boc

LDA, THF N SO2Ph

N2O4

Li

N Boc

-120 to 0 ºC

NO2

345

-78 ºC, 2h

Li

I2, THF

-78 ºC to rt N 14 h SO2Ph

346

I N SO2Ph

80% Scheme 5.166

R

N Boc

+ B(O-iPr)3

j455

i) LDA, THF, 0-5 ºC ii) 2 N HCl

R

B

OH

N OH Boc

99 - 77% 347

Scheme 5.167

Substitution at C2 on NH indoles can be achieved by employing Katritzkýs elegant indole C2 lithiation protocol [277]. In this sequential process the dilithiated intermediate 348 is formed, which provides the C2 substituted indole 349 after reaction with an electrophile and aqueous workup (Scheme 5.168). A typical example of the application of this methodology is Bergman’s synthesis of 2-bromoindole 350 (Scheme 5.169) [278]. The nature of the N-substituent can direct the position of the lithiation in N-alkyl indoles. While indoles substituted with non-bulky alkyl groups are lithiated at C2, the

j 5 Five-Membered Heterocycles: Indole and Related Systems

456

i) n-BuLi ii) CO2 iii) t-BuLi

N H

O 348

E

Li

N

E

N H

O Li

349

Scheme 5.168

i) n-BuLi ii) CO2 iii) t-BuLi

N H

iv) BrCl2CCl2Br

N H

Br

350

Scheme 5.169

presence of a bulky non-coordinating group drives the lithiation at C3. For instance, N-methyl-2-stannylindole 352 is selectively synthesized from N-methylindole (351) by deprotonation at C2 with BuLi, followed by reaction with tributylstannyl chloride (Scheme 5.170). BuLi

351

N CH3

THF, 0 ºC

N CH3

Li

SnBu3Cl N CH3

SnBu3

352

Scheme 5.170

In contrast, indole 353, bearing the very bulky triisopropylsilyl N-substituent, is lithiated selectively at C3 upon treatment with t-BuLi (Scheme 5.171) [279]. E

Li i) t-BuLi, TMDA

353

N Si(i-Pr)3

hexanes 0 ºC, 3h

E N Si(i-Pr)3

N Si(i-Pr)3

Scheme 5.171

The directing effect of the N-protecting group has been also applied to effect regioselective ortho-metallation at the C7 position [280]. For this purpose, it is necessary to protect the C2 position with a removable group, such as TMS. Then, treatment of N-CONEt2 protected indole 354 with t-BuLi/THF at
78  C followed by quench with TMSCl gives rise to the indole silylated at C2 355. Treatment of 355 with s-BuLi/TMEDA/THF at
78  C produces the regioselective metallation at C7, which

j457

5.5 Reactivity of Indole

provides the corresponding C7 functionalized indole 356 upon reaction with an electrophile (Scheme 5.172). Interestingly, the whole process can be conducted in a one pot fashion. i) t-BuLi, THF - 78 ºC ii) TMSCl

N O 354

NEt2

N O 355

TMS NEt2

i) s-BuLi, TMEDA, THF - 78 ºC ii) E+

N E

O 356

TMS NEt2

E= D, Me, Et, CHO, Br, -B(OR) 2, SnBu3 Scheme 5.172

5.5.3 Transition Metal Catalyzed Reactions

The most reliable synthetic methods to create C
C and C
X bonds from C-sp2 are currently transition metal catalyzed reactions. The well-developed Pd-catalyzed Heck and cross-coupling reactions are doubtless the most prominent methods, and have been applied successfully to the incorporation of new substituents in the indole ring. Moreover, alternative methodologies that make use of different transition metals are also noteworthy, and are discussed in this section. 5.5.3.1 General Considerations on Palladium-Catalyzed Cross-Coupling Reactions Indolyl halides or triflates behave as regular aryl halides in Pd-catalyzed crosscoupling reactions. Thus, 2- and 3-halo or triflate substituted indoles have been employed to synthesize numerous indole derivatives. The process starts with the oxidative addition of indolyl halide 357 to the Pd(0) catalyst to form indolyl-Pd(II) complex 358. The nature of the coupling partner, alkene, alkyne, stannane, boronate, organozinc, amine, determines the subsequent steps of the cross-coupling process. In a prototypical cross-coupling reaction, transmetallation of the organometallic partner followed by reductive elimination produces the cross-coupling product 360 and releases the Pd(0) catalyst (Scheme 5.173). 5.5.3.2 Reactions with Alkenes and Alkynes: Heck Reactions The reaction of indolyl halides or pseudohalides with alkenes under standard Heck conditions gives rise to vinylindoles [281]. For instance, N-protected-4-bromoindole 361 can be transformed into 4-alkenylsubstituted indoles 362 under standard Heck conditions (Scheme 5.174) [282]. The higher reactivity of iodide than bromide towards oxidative addition to Pd, allows for the sequential substitution of 3-iodo-4-bromoindole 363 through two consecutive Heck reactions. In the first step substitution of the more reactive iodine occurs to yield 364. A second Heck reaction with substitution of the bromine leads to 365 (Scheme 5.175). This strategy was employed by Hegedus in the synthesis of ergot alkaloids [283].

j 5 Five-Membered Heterocycles: Indole and Related Systems

458

MX

R-M

transmetallation

358

N R

PdXLn 359

PdRLn

reductive elimination

oxidative addition

X

N R 357

N R

Pd(0)Ln 360

N R

R

Scheme 5.173

R Br

361

N Tos

+

Pd(OAc)2 P(o-Tol) 3 R

Et3N, 100 ºC 60%

N 362 Tos

R = CO2Me (86%), C(Me) 2OH (97%), Ph (74%) Scheme 5.174

In a similar manner to other Pd-catalyzed cross-couplings, the reaction is general regarding the position of the leaving halogen. For instance, 3-substituted 2-iodoindole 366 reacts with methyl acrylate to furnish 2-alkenylindole 367 (Scheme 5.176) [284]. The intramolecular Heck reaction is particularly appealing, as it leads to polycyclic indole derivatives that might be difficult to synthesize through other strategies [285]. For instance, N-allylindoles 368 undergo cyclization to give 3H-pyrroloquinoline 369 under typical Heck reaction conditions (Scheme 5.177) [286], and carbolines 371 are easily prepared from 3-iodoindoles 370 (Scheme 5.178) [287]. 5.5.3.3 Sonogashira Reaction Indolyl halides or triflates react under typical Sonogashira [288] conditions with terminal alkynes to give rise to the corresponding alkynes (Scheme 5.179) [289]. The alkynylation can be employed to prepare 2-alkynylindoles 372, 3-alkynylindoles 373, and also to introduce the alkyne in the benzene ring [290] from the corresponding indolyl halides or triflates.

5.5 Reactivity of Indole

CO2Me Br

Br

I N Tos

CO2Me

+

NHCOMe

5 % Pd(OAc)2 Et3N, MeCN 100 ºC 60%

NHCOMe

N Tos

363

364 OH

OH

CO2Me

8 % Pd(OAc)2 P(o-Tol) 3

NHCOMe

Et3N, MeCN 100 ºC 83%

N Tos 365

Scheme 5.175

OTHP

OTHP CO2CH3

I

N H

5 % Pd(OAc)2 P(o-Tol)3 Et3N, MeCN 100 ºC 83%

366

N H

CO2CH3

367

Scheme 5.176

OMe

Ph N

MeO Br

Ph

OMe

Pd(OAc)2 P(o-Tol) 3 NEt3, MeCN, 100 ºC 96%

MeO

N 369

368 Scheme 5.177

I

NH

N

O O

370 Scheme 5.178

NH

Pd(OAc)2 Bu4NCl, NaHCO3 DMA, 90 ºC 77%

O

N O 371

Ph Ph

j459

j 5 Five-Membered Heterocycles: Indole and Related Systems

460

CO2Et

N H

I

Bu +

CO2Et PdCl2(PPh3)2 CuI, NEt3, r.t 89%

Bu

N H 372 Ph

I N H

Ph CO2Et

+

PdCl2(PPh3)2 CuI, NEt3, 60 C 89%

N H

CO2Et

373 Scheme 5.179

5.5.3.4 Cross-Coupling Reactions with Organometallic Reagents Typical Pd-catalyzed cross-couplings consist of the reaction of an organic halide with an organometallic reagent. The most popular methods involve the use of organotin (Stille reaction), organoboron (Suzuki–Miyaura reaction) [291] and organozinc (Negishi reaction) [292] compounds. Two different strategies are possible to conduct a cross-coupling reaction involving an indole derivative: (i) couple an indolyl halide or triflate with an organometallic reagent and (ii) react an indolylmetal derivative with an organic halide. Regardless of the strategy chosen, in most of the cases, cross-coupling reactions involving indolyl species can be performed efficiently under the typical conditions developed for cross-couplings with benzenoid systems. 5.5.3.4.1 Suzuki–Miyaura Cross-Coupling The Pd-catalyzed reaction of a boronic acid and an aryl or alkenyl halide or sulfonate is one of the most popular C
C bondforming reactions involving aromatic species, and has been extensively applied to the functionalization of indoles on every position of the ring. Indolyl halides and triflates have been employed in the coupling reaction. For instance, the reactions of 2-indolyl triflates with aryl boronic acids afford the corresponding aryl substituted indoles in high yields (Scheme 5.180) [293].

OTf +

N SO2Ph 374

Ar-B(OH)2 375

Pd(PPh3)4 Toluene/EtOH aqNaHCO3 90-60%

376

Ar N SO2Ph

Scheme 5.180

The Suzuki coupling has been also applied to the preparation of vinylindoles. One example is the reaction of vinylboronate 378 with 3-iodoindole 377, which leads to 3-vinylindole 379 (Scheme 5.181) [294].

5.5 Reactivity of Indole

Ts Bn

I

N

Ts Pd(PPh3)4

+

N Ts

O

377

B

N Bn

NaOH, 70 ºC O

N Ts

71%

378

379

Scheme 5.181

Thiophen-3-trifluoroborates 381 have been employed in a coupling reaction with 7bromoindole 380, giving rise to the corresponding thiophene-substituted indole 382 (Scheme 5.182) [295].

S N H

Br

PdCl2(dppf)·CH2Cl2

+ BF3K

380

N H

Et3N, EtOH, reflux 77%

S 382

381

Scheme 5.182

Indoylboronic acids are also appropriate coupling partners in cross-coupling reactions [296]. The sometimes difficult purification of indolylboronic acids recommends its utilization as crude products. An example of this methodology is represented in the synthesis of 386 (Scheme 5.183), a precursor of a tyrosine kinase Boc N

Boc N

N

N i) B(OiPr)3, LDA N Boc

383 O

ii) 2N HCl

H N

Br

Boc N N

O

385

Pd(OAc)2, PPh3 Cy2NH, THF 88% Scheme 5.183

384

N Boc

N Boc 386

NH

B(OH)2

j461

j 5 Five-Membered Heterocycles: Indole and Related Systems

462

inhibitor. The indolylboronic acid 384 required is prepared by metallation of indole 383, followed by reaction with triisopropylborate. The coupling reaction with the corresponding bromide 385 then affords 386 [297]. Remarkably, the sequence can be conducted on a multi-kilogram scale. 7-Arylsubstituted indoles can be synthesized from the corresponding boronates 387, which can be prepared by the synthetic sequence discussed in Scheme 5.167. Subsequent Suzuki reaction leads to the 7-aryl substituted indoles 388 (Scheme 5.184) [298].

tBuLi, TMSCl

sBuLi, TMEDA

TMS

N THF, -78 ºC, 2h CONEt2

N CONEt2

Ar-X TMS N Pd(PPh3)4, DMF CONEt2 K3PO4, 80 °C, 15-20 h. (RO)2B 387

Ar

B(OR)3 THF, -78 ºC, 2h

TMS N CONEt2 388

Scheme 5.184

5.5.3.4.2 Stille Cross-Coupling The Pd-catalyzed coupling of organostannanes with halides or pseudohalides is generally known as the Stille reaction. This coupling reaction has been widely employed in the modification of indoles. Both indolyl triflates (Scheme 5.185) [299, 300] and halides have been employed in the coupling reaction. CO2Et OTf

N Ts

+

Bu3Sn

CO2Et

Pd(PPh3)2 LiCl dioxane, reflux 24 h

88%

N Ts

Scheme 5.185

The Stille coupling has been employed in many syntheses of biologically active indole alkaloids [301]. In the example represented in Scheme 5.186, 2-vinylindole 391 (an intermediate in the synthesis of the natural alkaloid tabersonine) was prepared from 2-iodoindole 389 and vinylstannane 390 [302]. Interestingly, when the Stille cross coupling conditions are applied under a CO atmosphere, the corresponding a,b-unsaturated ketones are isolated (Scheme 5.187) [303].

5.5 Reactivity of Indole

OAc OAc N Boc

I

Bu3Sn

389

CO2Me

390

BnPd(PPh3)2Cl AsPh3, CuI N CO2Me Boc

HMPA, DMF 85 ºC 65%

391

Scheme 5.186

CO2Me +

I

N H

CO2Me Bu3SnR + CO

PdCl2(dppf) DMF, 80 ºC

N H

COR

392 R= R=H

Bu

78% 85%

Scheme 5.187

Indolylstannanes [304] have also been widely utilized for the functionalization of indoles, mostly at C2 [305] and C3 [306]. Scheme 5.188 presents the synthesis of 2arylindoles by coupling of N-protected-2-indolylstannane 393 with aryl halides under typical Stille conditions. A variation of this reaction has also been adapted to a solidphase synthesis [307].

SnBu3

N SEM

+ ArX

Pd(PPh3)2 DMF, 110 ºC 80-98%

Ar N SEM

393 SEM: -CH2OCH2CH2TMS Scheme 5.188

5.5.3.5 C
N Bond-Forming Reactions Application of the Buchwald–Hartwig arylation to N
H indoles allows for the preparation of N-arylindoles from N
H indoles and aryl halides [308–310]. The reaction is very general regarding the structure of both coupling partners, the indole and the aryl halide. Aryl bromides, chlorides, and triflates can be employed successfully upon selection of the proper combination of ligand and base. Scheme 5.189 gives an example of a coupling reaction between indole 394 and m-bromoacetophenone (395). The reaction proceeds in the presence of potentially sensitive functional groups to give arylated indole 396 in quantitative yield. In a similar procedure,

j463

j 5 Five-Membered Heterocycles: Indole and Related Systems

464

O

CO2CH3

Pd2(dba)3, Ligand

+

N H

N

K3PO4, Toluene

Br

394

Ligand:

CO2Et

395

100 ºC

O

95% 396

PtBu2

Pri

Scheme 5.189

treatment with vinyl halides allows for the preparation of the corresponding Nvinylindoles [311]. On the other hand, Buchwald–Hartwig amination can be applied to incorporate an amino group into the indole structure. Thus, coupling of haloindoles with amines provides the corresponding aminoindoles. The coupling reaction can even be conducted with NH-containing indoles such as 397 to give amino substituted indole 398, provided that an excess of base is employed (Scheme 5.190) [312]. H N N H

Cl 397

+ O

Pd2(dba)3, Ligand LiHDMS (2.2 eq) THF, 65 ºC 24 h 66%

N H

N O 398

Scheme 5.190

5.5.3.6 Transition Metal Catalyzed C
H Activation Modification of the indole ring via substitution of a C
H bond by a C
C bond is a very desirable reaction, as it does not require the previous presence of a reactive functionalization such as C–halogen, C–triflate, or C–metal bond in the indole ring. Nevertheless, this challenging transformation has been comparatively much less studied than the cross-coupling reactions, and at the present suffers from some limitations, such as lack of selectivity and generality. Many examples exist of intramolecular Pd(II)-catalyzed oxidative cyclizations of indoles with a proper pedant aryl or alkenyl group [313]. For instance, the oxidative cyclization of bisindolylmaleimides 399 gives rise to indolo[2,3-a]pyrrolo[3,4-c]carbazoles 400 [314], a substructure that is present in a large number of natural products (Scheme 5.191). One approach for the direct substitution of the C
H bond is the reaction with metal salts that usually starts with the electrophilic metallation of the indole (Scheme 5.192).

5.5 Reactivity of Indole

An interesting recent example is the Pd-catalyzed oxidative annulation of alkenyl indoles 401 (Scheme 5.193), which gives rise to tricyclic derivatives 402 [315]. H N

O

H N

O

O

O

Pd(OAc)2 N H

HOAc, 110 ºC 75%

N H 399

N H

N H

400

Scheme 5.191

R

[M]

H

R-X

Metal salt N P

N P

N P

Scheme 5.192

R N 401

10 mol % Pd (OAc)2 Ethyl nicotinate, O2 t-Amyl-OH, AcOH

N

R

402

Scheme 5.193

The mechanism proposed for this annulation includes (i) electrophilic palladation of the indole to form indolyl palladium complex 403; (ii) intramolecular olefin insertion to give palladated complex 404; and (iii) b-hydrogen elimination, which gives rise to the annulated indole 402 and releases a Pd(0) species. To obtain a catalytic reaction, reoxidation of the Pd(0) to Pd(II) is necessary. In this example, a pyridine derivative (ethyl nicotinate) in an oxygen atmosphere is responsible for reoxidation of the Pd catalyst (Scheme 5.194). Some examples of the intermolecular oxidative coupling of indoles with olefins and alkynes have been also described [316, 317]. The intermolecular oxidative Heck reaction of indoles with alkenes allows for the selective alkenylation at C2 or C3, depending on the solvent and reaction conditions chosen [318]. Thus, when the reaction is carried out using a mixture of DMF and DMSO as solvent, and Cu(OAc)2 as oxidant, the expected C3 oxidative alkenylation is produced, giving rise to the C3alkenylindole 405 (Scheme 5.195). However, if the reaction is performed under acidic conditions (dioxane : AcOH), employing tert-butyl benzoyl peroxide as oxidant, the

j465

j 5 Five-Membered Heterocycles: Indole and Related Systems

466

R N

N

R

402

401 palladation

β-Hydrogen elimination R

N

H

olefin insertion

Pd L

PdL

N 404

403 Scheme 5.194

CO2nBu

N H

N H

+

+

Pd(OAc)2, Cu(OAc)2 CO2nBu

DMF/DMSO (9:1) 70 ºC, 18 h 75%

N H 405

CO2nBu

Pd(OAc)2, tBuOOBz CO2nBu

dioxane/AcOH (3:1) 70 ºC, 18 h 51%

406

N R1

Scheme 5.195

regioselectivity of the alkenylation is switched to the 2 position to give alkenylindole 406 as the major product. An explanation of this switch in the regioselectivity can be found in the mechanisms proposed for each process as represented in Scheme 5.196. The reaction starts with the electrophilic palladation at the electron-richer C3 position, to provide cationic indole complex 407. At this point, aromatization by loss of a proton leads to indolyl palladium complex 408 (left-hand cycle), which then follows the path of a typical Heck reaction. The catalytic cycle is completed by oxidation of the Pd(0) species liberated. When the reaction is carried out under acidic media, the deprotonation of complex 407 is disfavored (right-hand cycle). Instead, 1,2-Pd migration takes place to give the new cationic complex 409, which then follows the reaction path of a Heck reaction to produce alkenylation at C2.

5.5 Reactivity of Indole

405

Pd(0)

[O]

[O] N H PdX 2

PdX2

H

j467

406 Pd(0)

H N H XPd

R

R

PdX N H

H

H PdX

PdX - H+ R 408

407

N H

N H

1,2-migration of Pd

N H

409

H PdX H

N H

- H+

Scheme 5.196

In a similar way, indoles add regioselectively to alkynoates 410 in the presence of Pd(OAc)2 and acetic acid [319]. Indole itself gives rise to 3-alkenylindoles 411, while 3methylindole provides 2-alkenylindoles 412, also with good yields (Scheme 5.197). Ph

N H

N H

+

Ph

CO2Et 410

+

Ph

CO2Et

CO2Et

Pd(OAc)2 (5 mol %) AcOH, r.t. 48 h 78%

411

N H

CO2Et

Pd(OAc)2 (5 mol %) AcOH, r.t. 48 h 69%

412

N H

Ph

Scheme 5.197

The mechanism proposed for the reaction involves (i) electrophilic palladation of the indole to form indolyl palladium complex; (ii) complexation of the alkyne followed by regioselective carbopalladation of the triple bond to provide vinyl palladium complex; and (iii) protonolysis of the C
Pd bond by action of the AcOH, affording alkenylated indole 411 and liberating the Pd(II) species (Scheme 5.198) . Direct Pd-catalyzed C
H substitution has also been accomplished by reaction of indolyl anions 413 with organopalladium complexes 414, generated in situ from Pd(0) complexes and aryl halides (Scheme 5.199). Arylation of NH-indoles can be carried out selectively either at C2 [320, 321] or C3 [322], depending on the reaction

R PdX

j 5 Five-Membered Heterocycles: Indole and Related Systems

468

CO2Et Ph

PdOAc + N H

Pd(OAc)2

Ph

Ph

-HOAc N H

CO2Et

N H

Ph

PdOAc

CO2Et H

AcOH

N H

PdOAc

CO2Et

N H 411

+ Pd(OAc)2

Scheme 5.198

I N H

+

Pd(OAc)2, PPh3 MgO Dioxane/DMF, 1:2 150 ºC 84%

N H 415

+ Ph-Pd-I(PPh3)2 N MgOH 413

414

Scheme 5.199

conditions (Scheme 5.200). Thus, reaction with MgO as base gives rise exclusively the C2 arylated product 415, while the use of larger bases such as Mg(HMDS)2 provides the C3 arylated indole 417 with very high regioselectivity. A rationale for this reactivity trend has been found after detailed mechanistic investigations (Scheme 5.201). Electrophilic palladation of the indolylmagnesium salt with the arylpalladium complex 414 gives rise to the cationic indolinylarylpalladium complex 418. Aromatization by deprotonation gives indolylaryl palladium complex 419, and reductive elimination produces the C3 arylated indole 417. In contrast, palladium migration on complex 418 leads to the C2 palladated indole 420, which will evolve through 2-indolylaryl palladium complex to furnish the C2 arylated indole 415. The driving force for the migration step has been related to stabilization of the carbon–palladium bond by the adjacent nitrogen atom on 420. However, bulky ligands on the magnesium destabilize the C2 palladated indole 420 and, therefore, the migration does not occur and so the arylation takes place at C3 (Scheme 5.201).

5.5 Reactivity of Indole

Pd(OAc)2, PPh3 Mg(HMDS)2

I N H

j469

+

Dioxane/DMF, 1:2 125 ºC 77%

N Mg 416

N H 417 26 :1 (C3: C2)

+ Ph-Pd-I(PPh3)2 N TMS TMS

414

Scheme 5.200

In contrast, when the steric interactions are minimized with small bases, such as MgO, the migration step is favored and the arylation occurs at C2. In agreement with this hypothesis, bulkier ligands on the Pd also drive the reaction to the C3 arylation product. Regioselective indole C2 arylation has also been conducted employing Rh(III) complexes as catalysts. The coupling process is achieved in the presence of a catalyst that is assembled in situ from a rhodium species, a phosphine ligand and CsOPiv as base (Scheme 5.202) [323]. The proposed catalytic cycle involves (i) oxidative addition of the aryl halide, to form Rh(III) complex 422, (ii) complexation of the indole to form complex 423, followed by

N MgX

(L)nPd-Ar H

electrophilic palladation

+ II

418

Ar-Pd -XLn

(L)nPd-Ar base

N MgX

419

Ar

reductive elimination

N MgX

417

N H

C3-arylation

414 migration

H

base

H Pd-Ar(L)n

N MgX 420 Scheme 5.201

Pd-Ar(L)n N MgX

reductive elimination

415

N H

Ar

C2-arylation

j 5 Five-Membered Heterocycles: Indole and Related Systems

470

R +

N H

Ph-I

[Rh(coe)2Cl2 ]2 [p-(CF3)C6H4 ]3P

CsOPiv Dioxane, 120 ºC R=H 82% R = NHTos 65%

R

N 421 H

Ph

coe: cis-cyclooctene O

PivO:

O

t-Bu Scheme 5.202

pivalate promoted C
H bond metallation to give indolyl rhodium complex 424 and (iii) reductive elimination to release the C2 arylated indole 421 (Scheme 5.203).

Ph PivO

Ph PivO

Rh

Rh

OPiv H

PivOH

NH

N H

L

L

L

423

OPiv 424

L 422

Ph-I CsOPiv

Ph Rh OPiv L

N H L

RhL2(OPiv) N 421 H

Ph

Scheme 5.203

5.5.4 Radical Reactions

Intermolecular radical aromatic substitution on indole can be effected at C2 with electrophilic carbon-centered radicals. For instance, indole reacts with radicals generated from iodoacetates or bromomalonates 425 to give the alkylated indole 426 (Scheme 5.204) [324, 325]. The reactions proceed with high regioselectivity, although a large excess of indole is required to avoid polysubstitution reactions.

5.5 Reactivity of Indole

N H 5 eq.

+

MeO2C

CO2Me

Br Me

propylene oxide Na2S2O3 Bu4N+BrMTBE, hν 65%

425

CO2Me N H

CO2Me Me

426

Scheme 5.204

A more efficient procedure for the oxidative radical alkylation of indoles employs a-acetyl or a-acetonyl radicals generated from the corresponding xantenes 427. In this way, radical alkylation can be accomplished to prepare 2-indolyl acetate 428 inpreparativelyusefulyieldswithouttheneedofexcessindole(Scheme5.205)[326,327].

O

N H

+

O OEt

EtO

S S 427

DLP dichloroethane reflux 60%

OEt

N H 428

DLP: dilauryol peroxide Scheme 5.205

While the intermolecular reactions of indoles with radicals have found limited application, there are many examples of intramolecular radical additions to the indole ring that have been employed as an entry into more complex heterocyclic structures [328–331]. For instance, spirocyclic dearomatized indole derivatives 430, 432, and 434 are formed via 5-exo-trig cyclizations from aryl, vinyl and alkyl radical precursors 429, 431, and 433, respectively (Scheme 5.206) [332]. In these examples the reaction proceeds by attack of the intermediate radical 435 to the C2 position of the indole ring (Scheme 5.207). The additional stability of the benzylic radical 436 might account for the preference of the C2 attack instead of C3 attack. Nevertheless, it has been observed that the nature of the pedant group may influence the course of the cyclization, and, in some cases, the addition of the radical at C3 is the main or unique reaction pathway [333, 334]. This is the case of the tandem radical sequence that has been applied to the preparation of functionalized indolenine 441 from amidoindole 437 (Scheme 5.208) [335]. Reaction of indole amide 437 with the tributylstannyl radical produces the aryl radical 438 by bromine atom abstraction. The aryl radical undergoes [1,5]-hydrogen atom abstraction, which generates the amido radical 439. Intramolecular addition of the radical to the C3 position of the indole produces indolyl radical 440, which leads to the indolenine 441 after hydrogen atom abstraction of the tributylstannyl hydride. The same authors have further extended the radical sequence to the preparation of tetracyclic structures [336].

j471

j 5 Five-Membered Heterocycles: Indole and Related Systems

472

O N Me

Bu3SnH, AIBN

NMe

Benzene, reflux 89%

Br

429 O N Me

Benzene, reflux

NBn

32%

Br

432 O

N Me

NBn

O

Bu3SnH, AIBN

NBn

431

433

NMe N H 430

N H

O

Bu3SnH, AIBN

NMe

Benzene, reflux 49%

PhSe

N Me O 434

Scheme 5.206

Bu3SnH

H H

5-exo-trig N 435

N 436

N Bu3Sn·

Scheme 5.207

On the other hand, indolyl radicals can be generated from the corresponding haloindoles by treatment with tributyltin hydride in the presence of a radical initiator. The indolyl radical can be trapped in an intermolecular [337] or in an intramolecular sense by reaction with a suitable radical acceptor. Scheme 5.209 shows the generation of 2-indolyl radical 443 from a 2-bromoindole (442) and the subsequent intramolecular cyclization to provide the tricyclic indole 444 [338]. Indolyl radicals such as 446, generated from bromoindole 445, which cannot undergo a direct intramolecular annulation, evolve through a [1,5]-hydrogen atom abstraction reaction to generate transient radical 447. Then, intramolecular radical addition to the indole ring leads to the tetracyclic radical 448, and finally to indoline 449 as a single diastereoisomer (Scheme 5.210) [339]. The reaction proceeds with moderate yield, as a 42% yield of dehalogenated indole 450 is also recovered. A 3-indolyl radical can be also generated by oxidation of the corresponding anion. This strategy has been applied to devise an extremely potent coupling between unprotected indoles and ketone enolates [340]. Thus, simultaneous deprotonation of

5.5 Reactivity of Indole

O

Ph

N Bu3SnH, AIBN

N Me

N

CN

O

tBu-benzene 170 ºC 53%

Br

CN N Me four diastereoisomers

437

441 Bu3SnH

Bu3Sn· O

R

N Me

N

CN

Ph

N

R

CN

N Me 440

O

438 [1,5]-H abstraction

R N Me

N

CN

O

H

439 Scheme 5.208

N 442

Br

Bu3SnH Toluene reflux

N 443

N 444 79%

Scheme 5.209

indole and the ketone 451 gives indole anion 452 and ketone enolate 453. Oxidation with a Cu(II) salt provides 3-indolyl radical 454 and ketone radical 455, which upon radical coupling lead to substituted indole 456 (Scheme 5.211). Importantly, the application of this methodology to ketones bearing stereogenic centers leads to the corresponding coupling products as single diastereoisomers. This strategy has been applied in the crucial step of a highly convergent total synthesis of various indole alkaloids such as Fischer-indoles I and G and welwitindolinone A [341]. Scheme 5.212 shows the coupling of ketone 457 with indole to give enantiomerically pure substituted indole 458.

j473

j 5 Five-Membered Heterocycles: Indole and Related Systems

474

O

O

N Bu3SnH, AIBN Toluene, reflux, 36 h

+

H

N

N

449

445 Bu3Sn·

Bu3SnH O

N H

H

450 42%

54%

O

N

N

Br

N

O

H

N

N

446

O

N H

N

H N

447

448

Scheme 5.210

R2 O X 2 eq.

N H

+

1

R2

R

LiHMDS (3 eq) Cu(II)-2-ethylhexanoate THF, - 78 ºC

R1

X

N H

451

456

LiHMDS

radical coupling

O X

N 452

+

1

2

O

R

Cu(II) oxidation

O X

N

R

454

453

+ 2

R1

R 455

Scheme 5.211

O Me Cl

Me H

N H LiHMDS Cu(II)2-ethylhexanoate

H Me

THF, -78 ºC, 30 min 55%

457 Scheme 5.212

Me

Me

C N

O N H

458

Cl

N H

Cl

H Me Me

(-)-Fischer-indole G

5.5 Reactivity of Indole

5.5.5 Oxidation Reactions

Indoles are highly sensitive to oxidation and, thus, undergo aerial autooxidation to produce 3-hydroperoxo-3H-indoles, which are rarely isolated but decompose to produce complex mixtures of degradation and polymerization derivatives. The transformation of N-tosylindole into indoxyl 459 has been described with oxodiperoxomolybdenum(IV) [342, 343], and by catalytic oxidation with dichlororuthenium(IV)meso-tetrakis(2,6-dichlorophenyl)porphyrin complex [RuIV(2,6-Cl2tpp)Cl2]. The latter process requires the presence of 2,6-dichloropyridine N-oxide as stoichiometric oxidant (Scheme 5.213) [344].

O [RuIV(2,6-Cl2tpp)Cl2] Cl

N Ts

N

O Cl CH2Cl2, 40 ºC

N Ts 459 95%

Scheme 5.213

Indoles can be converted into oxindoles through several different oxidative strategies. A general reaction is the treatment of indoles with conc. HCl in dimethyl sulfoxide, which provides cleanly the corresponding oxindoles 460 [345]. The reaction is likely to proceed through C3 protonation of indole to give indolenium intermediate 461, followed by electrophilic addition of the DMSO to give intermediate 462 followed by elimination of dimethylsulfane (Scheme 5.214). R N H

R

conc. HCl DMSO 20 ºC, 0.5-4h 460

R O

N H

-CO2H (82%) -CH2CH2NH2 (61%) -CH2(NH2)CO2H (54%)

HCl

H R N H 461 Scheme 5.214

H R O S

N H 462

O SMe2 H

j475

j 5 Five-Membered Heterocycles: Indole and Related Systems

476

Oxidation of indoles to oxindoles 460 can also be produced by treatment of the indole with a halogenating agent, followed by hydrolysis. Thus, the intermediate indolenium cation 463 formed gives 2-hydroxy-3-halodihydroindole 464, which suffers dehydrohalogenation to give oxindole 460 (Scheme 5.215) [346]. A closely related procedure allows for the substitution of indoles at C2. This oxidativecoupling procedure involves reaction of the indole with a suitable electrophile [X þ ]. Addition of a nucleophile [Nu
] to the transient indolenium cation 463 formed gives 465, and aromatization by elimination of HX furnishes the functionalized indole 466. X OH R

X

[X+]

N H

463

R

464

N H

N H

R OH

-HX

H

O

N H 460

X Nu

465

R

N H

R

R Nu

-HX

H 466

N H

Nu

Scheme 5.215

Halogenating agents, such as tBuOCl, NCS or NBS are the electrophiles of choice. The oxidative-coupling strategy has been performed with various carbon nucleophiles, such as allyl boranes and stannanes, enol ethers, enamines, acetylide and even indole. Scheme 5.216 presents the synthesis of C2 substituted tryptophan 469 by nucleophilic addition of a silylenol ether (467) to the indolenium cation generated from protected tryptophan 468 [347]. OTBS

CO2Me NBn2

468

N H

i) tBuOCl, NEt3, THF - 78 ºC, 30 min

467

CO2Me

OEt

BF3·Et2O, 12h rt

NBn2 N H 469

CO2Et

77% Scheme 5.216

Heteronucleophiles such as alcohols [348], anilines, phenols and thiophenols [349] are also appropriate reagents for the oxidative coupling, providing the corresponding C2 functionalized indoles. For instance, 2-aminoindole 471 can be prepared from indole 470 by employing this sequence (Scheme 5.217).

5.5 Reactivity of Indole

CO2CH3

470

Cl

NCS 1,4-dimethylpiperazine

CO2CH3

PhNH2 CCl3CO2H r.t., 2h

N H

CH2Cl2, 0 ºC, 2h

N H

CO2CH3

N H

471 58%

Scheme 5.217

Moreover, the versatility and functional group compatibility of this oxidativecoupling procedure has been shown in the coupling of a tryptophan derived peptide 472 with the imidazole ring of the histidine-containing peptide 473, which represents the key step in the synthesis of the right-hand ring of the natural octapeptide celogentin (474) (Scheme 5.218) [350].

PhthN

BnO2C O N

NH CbzHN

+ 472

N H

PhthN

HN

N

N H

HN

O

NHPbf NCS 1,4-dimethylpiperazine

CO2tBu

CH2Cl2, rt 58%

473 BnO2C O N CbzHN

N H

N 474

N

HN

NH O

N H

j477

NHPbf

CO2tBu

Scheme 5.218

A very valuable synthetic transformation is the oxidation of indoles with dimethyldioxirane, which produces the corresponding epoxides 475 [351]. Although the epoxides are unstable in most cases, their generation in the presence of a nucleophile gives rise to 3-hydroxyindoline derivatives 476 (Scheme 5.219). The application of this strategy to protected tryptophan 477 led to pyrrolo[2,3-b] indole 478, an early key intermediate in Danishefsky’s total synthesis of himastatin (Scheme 5.220) [352]. In contrast, aqueous workup of the preformed epoxide leads to 3-hydroxyoxindoles 479 (Scheme 5.221) [353].

NH Ph

j 5 Five-Membered Heterocycles: Indole and Related Systems

478

O O

R'

R'

CH2Cl2 - 78 ºC

N R

475

O

HO R' Nu N R

N R

Nu

476

Scheme 5.219

CO2tBu NHTr

HOAc CH2Cl2 - 78 ºC

N H 477

CO2tBu

HO

O O

NH

MeOH, CH2Cl2

N H H 478 55%

Scheme 5.220

CO2Me N CO2Me

O O acetone r.t. 63%

HO

479

N H

CO2Me O

Scheme 5.221

5.5.6 Reduction of the Heterocyclic Ring

Indoles are reduced to indolines by several methods, including catalytic hydrogenation, dissolving metals and metal hydrides. Some detailed reviews on this subject are available [354]. 5.5.6.1 Catalytic Hydrogenation Catalytic hydrogenation of the heterocyclic ring has been achieved employing various heterogeneous catalysts, but usually requires harsh conditions and sometimes is not very selective. In the presence of strong acids, relatively milder conditions can be used, as the reaction proceeds through the C3 protonated indole [355]. For instance, N-Boc-2,3-disubstituted indoles 480 are hydrogenated to the corresponding cis-2,3disubstituted indolines 481 over a rhodium-alumina catalyst in a EtOH/AcOH mixture (Scheme 5.222) [356]. The catalytic asymmetric hydrogenation of N-acylindoles 482 has been performed employing as catalyst a rhodium complex bearing the chiral diphosphine ligand 484. In this way, optically active substituted indolines 483 can be obtained in high yield and enantiomeric excesses (Scheme 5.223) [357].

5.5 Reactivity of Indole

Me

MeO

N Boc

MeO

CO2Me

H2, 200 psi EtOH, AcOH 84%

480

Me

MeO

Rh-Al2O3

MeO 481

N Boc

CO2Me

Scheme 5.222

482

CO2Me

N Ac

[Rh(nbd)2]SbF6 484 H2, 5 MPa iPr-OH, Cs2CO3

483

84% Ph2P

Chiral ligand

Fe Me

N Ac

CO2Me

Yield: 95% ee: 95%

Me

Fe PPh2

484

Scheme 5.223

5.5.6.2 Metal-Promoted Reductions The reduction of indoles with dissolving metals may give partial reduction of both the benzene and the heterocyclic ring, depending on the particular substrate and reaction conditions applied. In certain examples, high chemo- and stereoselectivity can be achieved. For instance, N-phenylindoles 485 are converted into the corresponding indolines 486 upon treatment with Na/NH3 in THF (Scheme 5.224) [358].

HN N Ph 485

H Na/NH3/THF 83%

HN

N H Ph 486

Scheme 5.224

On the other hand, 2-acylindoles can be reduced to the indolines through several protocols involving metal–acid combinations, such as Mg/MeOH [359] and Sn/ HCl [360]. 5.5.6.3 Metal Hydride Complexes A very general method for the reduction of indoles to indolines 488 consists of treatment with a hydride reagent under acidic conditions (Scheme 5.225). The

j479

j 5 Five-Membered Heterocycles: Indole and Related Systems

480

H

H+ N H

487

H

[H-]

N H

488

N H

Scheme 5.225

reaction proceeds via initial protonation at C3 to generate indolenium ion 487 which is subsequently reduced by the hydride donor [361]. Hence, the best results have been obtained with hydride sources that are stable to acid, such as NaBH3CN in AcOH [362], BH3/THF in TFA [363] and triethylsilane in TFA [364]. Representative examples are given in Scheme 5.226.

NaBH3CN, AcOH N H

N H

79%

BH3-THF/TFA N

0 ºC, 2 min 86%

NH

N

NH

NPh

NPh

N Et3SiH/TFA

MeO MeO

N

N H

80%

MeO MeO

N H

Scheme 5.226

5.5.7 Pericyclic Reactions Involving the Heterocyclic Ring 5.5.7.1 Cycloaddition Reactions The C2–C3 double bond of indole can participate in different types of cycloaddition processes as a 2p or 4p component. As a 2p component it can behave as a dienophile in [4 þ 2] cycloadditions, and as dipolarophile in dipolar [3 þ 2] cycloadditions. On the other hand, 3-vinylindoles 489 and 2-vinylindoles 490 take part as dienes in [4 þ 2] cycloadditions. Moreover, orthoquinodimethane indole derivatives 491 are highly reactive dienes in Diels–Alder reactions, and methylene indolines 492 and oxindoles can react as 2p components in [4 þ 2] and dipolar cycloadditions (Scheme 5.227).

5.5 Reactivity of Indole

a b c N H

N H

489

N H

490

N H

491

492

N H

N H

X

Scheme 5.227

Owing to the high electron density of the C2
C3 double bond, indole derivatives have been mostly employed as electron-rich dienophiles in inverse-electron-demand Diels–Alder reactions [365]. In particular, the use of aromatic heterodienes such as 1,2,4,5-tetrazines, 1,2,4-triazines and pyridazines represents a versatile route into more complex polycyclic structures [366]. Scheme 5.228 shows the synthesis of a 3,9b-dihydro-5H-pyridazino[4,5-b]indole 494 by cycloaddition of 3-methylindole with the 1,2,4,5-tetrazine 493. The final compound 494 is obtained after loss of N2 and hydrogen transposition of the initially formed cycloadduct 495 [367]. MeO2C

CO2Me +

N H

N N

N

dioxane

N N

N H

CO2Me 493

NH CO2Me

494

[4+2]

MeO2C

CO2Me

N H 495 Scheme 5.228

NN NN

CO2Me

-N2 N H

N

N CO2Me

j481

j 5 Five-Membered Heterocycles: Indole and Related Systems

482

The application of [4 þ 2] cycloaddition methodology in an intramolecular version leads to polycyclic skeletons in very short synthetic sequences [368], and has been employed in several approaches to complex indole alkaloids. For instance, transannular cycloaddition of the pyridazinoindolophane 496 gives polycyclic adduct 497, which provides the final dihydrocarbazole 498 after loss of N2 via a retro-Diels–Alder reaction [369]. This particular sequence is the key step in a total synthesis of strychnine (Scheme 5.229) [370].

N N N

N

N

217 ºC N,N-diethylaniline 48 h, 90%

496

N H 497 - N2

N H 498 Scheme 5.229

Another example of an intramolecular inverse-electron-demand Diels–Alder reaction is the cycloaddition of 499, a molecule that features a substituted indole and an aza-o-xylylene, a very reactive heterodiene moiety [371]. Cycloaddition gives rise to 500, which features the heptacyclic ring system present in the natural alkaloid communesin B (Scheme 5.230). N N N N CO2Et

499

N

Scheme 5.230

N

N CO2Et

500

N

N N

160 ºC 70%

R

N

CO2Me N

5.5 Reactivity of Indole

Indoles substituted with electron-withdrawing groups in positions 1 and 3, such as 501, can react with electron-rich dienes like Danishefsky’s diene 502, in normal electron-demand cycloadditions [372]. Very high temperatures are required unless activation by Lewis acids or high pressure are employed (Scheme 5.231) [373, 374]. O

NEt2 O

N Ts 501

H3CO Et2NOCOC

OCH3 i) 12 kbar, 45 ºC

+ OTMS

ii) MeOH, H+ 60%

502

503

O

N Ts

Scheme 5.231

The intramolecular [4 þ 2] cycloaddition of 504, which features an amidofuran moiety tethered onto an indole, can be regarded also as an example of a normal electron-demand cycloaddition [375]. In this process, the cycloadduct 505 undergoes spontaneous rearrangement onto tetracycle 506 [376]. The reactions proceed at very high temperatures and only substrates substituted with an electron-withdrawing group at the indole nitrogen undergo the cycloaddition (Scheme 5.232).

O

504

N Ac

N

O

N

benzene sealed tube

O

240 ºC 506

N

O

O

O

N Ac

N

O

505

N Ac

N O Ac

H

Scheme 5.232

The electron-rich C2
C3 bond of indole can also participate as dipolarophile in 1,3-dipolar cycloaddition reactions. Nitrones [377], azomethine ylides [378], azides [379] and carbonyl ylides are among the dipoles successfully employed, in most cases in an intramolecular fashion. In the example presented below, the carbonyl ylide, generated by cyclization of a rhodium carbenoid generated from diazoimide 507, reacts with the tethered indole giving rise to 508, which presents the

j483

j 5 Five-Membered Heterocycles: Indole and Related Systems

484

Et O N

O N2

O

O

CO2Et

N

Rh(OAc)2 benzene, 50 ºC, 3h 90%

N Me 507

Et O

O

CO2Me

N Me 508

O N O

Et

N O Me CO2Me

Scheme 5.233

pentacyclic skeleton of Aspidosperma alkaloids (Scheme 5.233) [380]. The carbonyl ylide–indole cycloaddition can be also conducted in an intermolecular fashion [381]. The power of intramolecular cycloadditions across the C2
C3 double bond has been shown in a remarkable application of cycloaddition cascades employed by Boger et al. in the total synthesis of (–)-vindoline (Scheme 5.234) [382]. The reaction is initiated by the [4 þ 2] cycloaddition of the tethered enol ether with the 1,3,4oxadiazole on 509, to give a cycloadduct. Loss of N2 by a retro-dipolar cycloaddition then generates the intermediate carbonyl ylide 510. Intramolecular [1,3] dipolar O

O N

N O

Et

N N

N Me CO2Me 509

MeO

OBn

Triisopropylbenzene 230 ºC, 20 h 95%

MeO

[3+2] O

O

N

Scheme 5.234

N Me

N O N

N

retro-[3+2] Et OBn

- N2

MeO

O N Me 510

Et

OBn CO2Me 511

[4+2]

MeO

O

N Me

Et OBn

5.5 Reactivity of Indole

cycloaddition across the indole C2–C3 double bond provides the polycycle 511 with total control of the stereochemistry on the six new stereogenic centers generated along the cascade process. Among the very few intermolecular 1,3-dipolar cycloadditions of indoles known, noteworthy is the reaction of 2- and 3-nitroindoles with the mesoionic m€ unchnones 512 [383]. The reaction gives rise to pyrrolo[3,4-b]indoles 514 in a highly regioselective manner, and is thought to proceed through a 1,3-dipolar cycloaddition to form the unstable cycloadduct 513, which gives the final compounds after loss of CO2 and NO2 (Scheme 5.235). Me

Me NO2 N CO2Et

+

Bn N

O O

THF ∆ 85%

Ph 512

N N CO2Et 514

Bn Ph +

9 O Bn NO

:

regioisomer

1

- CO2 - NO2

N NO2 CO2Et

513 Scheme 5.235

Many examples have been described of [4 þ 2] cycloadditions of 2- and 3vinylindoles as 4p-electron components. Vinylindoles can be seen as electron-rich dienes, and therefore will react preferentially with electron-poor dienophiles in normal electron-demand cycloadditions. Thus, intermolecular reactions involve typical dienophiles such as methyl acetylenedicarboxylate [384], N-phenylmaleimide [385], and benzoquinones [386]. When asymmetric dienophiles are employed, the regiochemistry can be predicted by employing frontier molecular orbital theory principles. For instance, the regiochemistry of the reactions of 3-vinylindole 515 with ethyl acrylate [387], and the cycloaddition of 2-vinylindole 516 with methyl propiolate can be both explained assuming the directing interaction of the HOMO of the vinylindole with the LUMO of the dienophile (Scheme 5.236) [388, 389]. The intramolecular version of the [4 þ 2] cycloaddition leads to complex structures in a convergent manner. In a classical example, the 2-vinylindole 518 generated in situ from indoline 517 undergoes cycloaddition with the enaminic double bond to give 519, a very advanced intermediate in the total synthesis of pseudotabersonine (Scheme 5.237) [390, 391]. Intramolecular Diels–Alder reactions of 3-vinylindoles usually involve a dienophile tethered through the nitrogen atom. For instance, the intramolecular

j485

j 5 Five-Membered Heterocycles: Indole and Related Systems

486

OEt

OEt CO2Et

CO2Et

515

N Boc

N Boc

THF, rt, 12 kbar Toluene, reflux

70%, 70: 30, endo: exo 61%, 27: 73, endo: exo CO2Me CO2Me

SPh

MeAlCl2 Toluene 57%

N Cbz 516

N Cbz

Scheme 5.236

H

N

N

N H

MeCN, Et3N N OH CHO Bn

H

80 ºC, 3h 50%

N Bn

517

CHO

N Bn

518

CHO

519

Scheme 5.237

cycloaddition of the nitrovinylindole with a terminal alkyne 520 provides the tetracyclic structure 521 after loss of HNO2 (Scheme 5.238) [392]. NO2

N O 520

sulfolane ∆ 95%

NO2 N O

- HNO2 N O 521

Scheme 5.238

The oxime-substituted indole 522 behaves as an 1-aza-1,3-butadiene in an intramolecular hetero-Diels–Alder reaction with a tethered alkyne, to give tetracycle 523, which features the skeleton of Canthine alkaloids (Scheme 5.239) [393].

5.5 Reactivity of Indole

j487

OMe N N

toluene 180 ºC, 7 days

N

N

66%

O 522

O 523

Scheme 5.239

Indole-2,3-quinodimethanes are highly reactive dienes in [4 þ 2] cycloadditions and represent a very valuable entry into the carbazole ring structure [394]. They can be generated in situ by fluoride or iodide ion induced 1,4-elimination of silylated indolyl ammonium salts [395], by double elimination on N-protected-2,3-bis(dibromomethyl)indoles [396], by thermal fragmentation of 2-substituted 3-aminomethylindoles [397] and by [1,5]-H shift on 3-cyanomethyl-2-vinylindoles [398]. Moreover, the anionic indole-2,3-dienolate can be formed by deprotonation of 1,2-dimethylindole3-carboxaldehyde [399]. For instance, disubstituted indole-o-quinodimethane 525 is generated by thermal decomposition of gramine 524 in the presence of the dienophile; it then reacts to give the tetracyclic adduct 526 in very high yield (Scheme 5.240).

Ph

O

NMe2

N H

Me N

O O

Ph

Ph

N O

CO2Et

Toluene, reflux 96%

N H

524

N H

CO2Et

CO2Et

526

525

Scheme 5.240

Alternatively, reactive indole-2,3-quinodimethane intermediates 528 can be generated from o-allenylanilines 527, and trapped with dienophiles to obtain directly the corresponding carbazole derivatives 529 in moderate yields (Scheme 5.241) [400]. CO2Me

AcO · NH Boc 527 Scheme 5.241

MeO2C

CO2Me

CO2Me

K2CO3, DMF, rt 0 ºC, 2h 48%

N 528

Boc

N Boc 529

j 5 Five-Membered Heterocycles: Indole and Related Systems

488

5.5.7.2 Electrocyclizations The C2–C3 double bond of indole can participate in electrocyclic reactions. Although the 6p-electron electrocyclization of 2,3-divinylindoles is known, the participation of allene intermediates is more efficient. Thus, a versatile route to carbazoles is based on an allene-mediated electrocyclic reaction of a 6p-electron system involving the indole 2,3-bond [401]. This strategy has been applied in the preparation of numerous alkaloids containing the carbazole moiety. Scheme 5.242 depicts the preparation of oxygenated carbazole 532 from propargyl ether containing indole 530. Treatment with KOtBu produces the acetylene–allene isomerization to give intermediate 531, which suffers electrocyclization leading to the carbazole.

OMe

OMe

Me tBuOK N OMOM SO2 Ph 530

·

tBuOH, THF, 90 ºC 85%

OMOM N SO2 Ph 532

OMe

OMe

·

N OMOM SO2 Ph

· OMOM N SO2 Ph

531 Scheme 5.242

5.5.7.3 Sigmatropic Rearrangements The indole C2–C3 bond can participate in [3,3] sigmatropic rearrangements, and this strategy has been employed in many synthetic efforts to introduce additional substitution at C2 or C3 [402–404]. The Claisen rearrangement of 2-allyloxiindoles leads to oxindoles with creation of a quaternary center. For example, allyloxyindole 534, generated in situ by olefination of 2-allyloxiindoxyl 533, suffers the [3,3]-rearrangement to provide oxindole 535 (Scheme 5.243) [405]. The required 2-allyloxiindoles can be also generated by oxidative coupling of indoles with allyl alcohols (Section 5.5.5) [406]. Another type of [3,3]-rearrangement with functionalization at C3 is found in the conversion of 1-vinylaminoindole 536 into tricyclic compound 538 under thermolysis conditions [407]. The formation of 538 can be explained by [3,3]-rearrangement to form imine 537, which generates the pyrrolo[2,3-b]indole by intramolecular

5.5 Reactivity of Indole

NC

O

(EtO)2P(O)CH2CN O

N 533 Ac

KOtBu, DMF - 78 ºC rt quant.

O

NC

NC

N Ac

535

N H

O

N Ac 534

O

Scheme 5.243

cyclization (Scheme 5.244). On the other hand, the incorporation of a substituent at C2 by a Claisen rearrangement has been also described [408]. MeO2C N N

Ph2O 180-200 ºC 91%

CO2Me

536

N N H

Me

538 MeO2C H N N 537

Scheme 5.244

5.5.8 Photochemical Reactions

Synthetic applications of indole photochemical reactions are very limited, and therefore this technique has been scarcely employed. Ultraviolet light irradiation promotes the [2 þ 2] cycloaddition of N-protected indoles with alkenes and alkynes [409, 410]. For instance, N-acylindoles 539 undergo [2 þ 2] photocycloaddition with monosubstituted alkenes to form the cyclobutane ring regioselectively regardless of the nature of the substituent on the alkene [411]. The reaction is

j489

j 5 Five-Membered Heterocycles: Indole and Related Systems

490

postulated to proceed through the biradical intermediate 540, which is formed by bonding the 2-position of the indole with the less substituted position of the alkene (Scheme 5.245).

CHO

OHC

OAc

Hg Lamp

+

539

OAc

CHO

+

N H COPh

benzene, 10h 78%

N COPh

OHC

N H COPh 0.7

:

1

OAc

OAc

N COPh 540 Scheme 5.245

Several examples have been reported of the intramolecular version of the [2 þ 2] photocycloaddition [412]. Interestingly, the intramolecular reaction with the double bond tethered through the N atom leads to the opposite regiochemistry in the [2 þ 2] cycloadduct [413]. The [4 þ 2] cycloaddition reaction of indoles with electron-rich dienes, which does not proceed thermally, can be promoted photochemically by electron-transfer catalysis. Nevertheless, at present, these procedures are far from being synthetically practical [414]. Another synthetically useful photochemical transformation is the photocyclization of indole-containing stilbenes 541 and related systems to give polycycles 543 featuring the carbazole moiety. The reaction occurs through a 6p-electron conrotatory electrocyclization to give 542, followed by oxidation to furnish directly the aromatic system. Thus, the photocyclization is usually carried out in the presence of an oxidant, such as iodine or Pd/C (Scheme 5.246) [415].

N R 541

Ar X

[O]

hν N R 542

Ar X

N R

Ar X

543

Scheme 5.246

The main application of this methodology is in the preparation of [2,3-a]pyrrolo [3,4-c]carbazoles, a substructure that is present in several naturally occurring

5.6 Chemistry of Indole Derivatives

alkaloids with potent biological activities [416], such as rebeccamycin [417] and staurosporin [418]. In a recent example, naphtho[2,3-a]carbazole 545 is obtained by photooxidation of 2-naphthylindolyl maleimide 544 in nearly quantitative yield (Scheme 5.247) [419, 420]. H N

O

O

H N

O

O

Osram Hg-HP lamp. Acetone, 35 ºC 97%

N H 544

N H

545

Scheme 5.247

5.5.9 Reactions with Carbenes and Carbenoids

The reaction of indole with carbenes or carbenoids does not lead to cyclopropanation but, instead, insertion in the C3–H double bond occurs, to give the corresponding substitution product [421]. In the example shown in Scheme 5.248, the rhodium carbenoid generated from the cyclic diazo compound 546 reacts with indole to give the C3-substituted indole 547 [422]. This chemistry has been applied in the preparation of natural indolocarbazole alkaloids. H N

O O N H

+

NH

N2

Rh(OAc)4 benzene, 80 ºC 65%

O 546

OH N H 547

Scheme 5.248

5.6 Chemistry of Indole Derivatives 5.6.1 Alkylindoles

Deprotonation of the alkyl chain of indoles is usually difficult. Nevertheless, NH-2alkylindoles 548 can be lithiated at the a-position through a one pot sequence that

j491

j 5 Five-Membered Heterocycles: Indole and Related Systems

492

involves formation of the lithium carbonate 549, by NH deprotonation with BuLi and quench with CO2, followed by treatment with t-BuLi to obtain dianion 550. Subsequent reaction with an electrophile yields the 2-(substituted a1kyl)indole 551 after thermally induced loss of CO2 (Scheme 5.249) [423]. R

548

R

N H

E

N H 551 ∆

R n-BuLi THF, -70 ºC

E N CO2H E

R

R

CO2

N Li

Li

t-BuLi THF, -20 ºC

R

N CO2 Li 549

N CO2 Li 550

E = CH3I, n-BuI, (CH2)4CO, t-BuNCO, CO2 Scheme 5.249

Alternatively, NH-2,3-dialkylindoles 552 can be directly deprotonated by treatment with an excess of base that consists of a combination of BuLi and KOt-Bu. Treatment with an electrophile provides the 2-substituted indole 553, indicating that the lithiation is produced exclusively at the C2 side-chain (Scheme 5.250). R2 R1 N H 552

3 BuLi; 2 KOt-Bu -78 ºC to rt

CH3I

Et2O

- 78 ºC

R2 R1 N H 553

CH3

R1 = R2 = H, 86% R1-R2 = (CH2)2, 50% Scheme 5.250

Bromination of the side-chain of N-protected indoles such as 554 can be carried out by treatment with NBS in the presence of a radical initiator. Interestingly, while the reaction under radical conditions provides the indole brominated on the side-chain 555, the same reaction in the absence of the radical initiator gives rise to the C2brominated indole 556 (Scheme 5.251) [424].

5.6 Chemistry of Indole Derivatives

CH3

MeO

554

NBS, AIBN CCl4, ∆ 1h

j493

Br

MeO

555

N PG

PG: SO2Ph, 83% PG: Boc, 92%

N PG

MeO NBS, CCl4

CH3 N PG

∆, 3h

Br

556 PG: SO2Ph, 86% PG: Boc, 95%

Scheme 5.251

Among functionalized alkylindoles, the chemistry of gramines 557 is noteworthy. The elimination of the dimethylamino group can be promoted either by quaternization or by treatment with bases, generating the highly reactive electrophile 558, which undergoes the addition of a nucleophile. The overall reaction is the substitution of the dimethylamino group by the nucleophile (Scheme 5.252). This strategy has been employed for the introduction of different types of carbon [425], nitrogen [426] and sulfur nucleophiles [427].

NMe3·I MeI N H

NMe2

Nu Nu

557

NMe2

N H

N 558

base

N

Scheme 5.252

Scheme 5.253 presents the use of gramine 557 as electrophile in a typical acetylacetate alkylation, leading to substituted indole 559 [428]. This chemistry has been applied in an original method for the preparation of vinylindoles, in a substitution/Wittig olefination tandem sequence. Thus, treatment of gramine with an aromatic aldehyde in the presence of an excess of PBu3, affords directly the vinylindole 561, through the in situ generated ylide 560 (Scheme 5.254) [429].

N H

j 5 Five-Membered Heterocycles: Indole and Related Systems

494

CO2Et

O

NMe2

CO2Et O

PBu3, CH3CN N H

557

85 ºC 85%

559

N H

Scheme 5.253

Ar NMe2

557

Ar-CHO PBu3, CH3CN

N H

80 ºC, 24 h 87-63%

561

N H

Ar-CHO Wittig

PBu3 PBu3

PBu3

N PBu3

560

N H

N Scheme 5.254

5.6.2 Oxiderivatives

Oxindole and indoxyl are the stable tautomeric forms of 2-hydroxy- and 3-hydroxyindole respectively (Figure 5.8). The aromatic 2-hydroxyindole is unstable and undetectable. In contrast, 3-hydroxyindole contributes in the tautomeric equilibrium, and in some 2-substituted-indoxyls is the thermodynamically controlled product. O N H oxindole

O

N H indoxyl

Figure 5.8 Structures of oxi-derivatives of indole.

O N H isatin

O

5.6 Chemistry of Indole Derivatives

O O

MeN

N O

N

H N

O gelsemine

H

j495

N H

O

(-)-Spyrotryptostatin B

Figure 5.9 Some important oxindole alkaloids.

5.6.2.1 Oxindole The substructure of oxindole is present in numerous naturally occurring alkaloids and pharmaceutically active compounds. Substituted oxindoles and, in particular, spirocyclic oxindoles featuring a quaternary center at C3 are attractive targets in organic synthesis due to their usefulness as drug candidates and as intermediates in alkaloid synthesis. Figure 5.9 shows some natural oxindole-containing alkaloids such as the well-known hexacyclic cage-like alkaloid gelsemine [430] and the highly potent cytotoxic agent spyrotryprostatin B [431]. Numerous methodologies for the preparation of oxindoles are available, and detailed coverage would largely exceed the aim of this chapter. Oxindoles can be prepared from indole or indole derivatives, by derivatization of isatin (Figure 5.8), and by cyclization processes. 5.6.2.1.1 Synthesis of Oxindoles from Indoles Indoles can be transformed into oxindoles under the oxidation protocols discussed in Section 5.5.5. Additionally, NBoc-indoles can be cleanly converted into N-Boc-oxindoles 562 by a two-step sequence that involves formation of a 2-indolylborate [432] and oxidation with oxone (Scheme 5.255) [433]. Moreover, as discussed in Section 5.5.7.3, oxindoles can be prepared by Claisen rearrangement of 2-allyloxiindoles.

R

i) LDA, B(OiPr)3 THF N Boc

ii) 2N HCl

R

N Boc

B(OH)2

Oxone NaOH, NaHCO3 THF, acetone, H2O NaHSO3

R

R= 5-Me, 89% 4-Cl, 70% 7-Me, 63% 5-Br, 62% H, 78%

Scheme 5.255

5.6.2.1.2 Synthesis of Oxindoles from Isatins Isatin (Figure 5.8) features two carbonyl groups, a ketone and an amide carbonyl. The higher reactivity of the C3 ketone carbonyl can be exploited to introduce functionalization and prepare 3substituted oxindoles. Thus, reductions [434], aldol reactions [435], additions of

N H 562

O

j 5 Five-Membered Heterocycles: Indole and Related Systems

496

nucleophiles [436] and Wittig olefinations [437] lead to the corresponding substituted oxindoles. Notably, the rhodium-catalyzed asymmetric addition of arylboronic acids to isatin 563 gives rise to enantiomerically enriched 3-substituted-3-hydroxyoxindoles 564 (Scheme 5.256) [438]. O

Cl

563

O N PMB

+ Ar-B(OH)2

Cl

HO

KOH, THF, H 2O 50 ºC, 24 h 564

PMB: p-methoxybenzyl Ar: Ph, p-MeO-Ph, p-F-Ph, 3-Naph,

(R)-MeO-mop:

[RhCl(C2H4)2]2 (R)-MeO-mop

Ar

O N PMB

yield, 92-96% ee, 90-82%

OMe PPh2

Scheme 5.256

5.6.2.1.3 Synthesis of Oxindoles by Cyclization Reactions Cyclization strategies are usually reminiscent of the methods employed for the synthesis of indoles, such as the Fischer synthesis [439], cyclization of o-aminophenylacetic acid derivatives [440], intramolecular Friedel–Crafts alkylations [441], radical cyclizations [442], intramolecular Heck reactions [443], intramolecular Buchwald–Hartwig amidations [444] and intramolecular a-arylation of amide enolates [445]. Extensive coverage of the methods of synthesis of oxindoles is beyond the scope of this chapter, and the reader is referred to the original papers. Nevertheless, some relevant modern alternatives to the general approaches depicted in Figure 5.10 is briefly presented. Cyclization of o-aminophenylacetic acid derivatives is one common approach to the synthesis of oxindoles. Several different strategies can be applied to prepare the intermediate amino acid [446]. The [3,3]-sigmatropic rearrangement of the enolate 568, generated from N,O-diacylated phenyl hydroxylamine 567, is the key step in a three-step synthesis of oxindoles from N-acylhydroxylamines 565 and carboxylic acids 566 [447]. The N-protected amino acid 569 generated in the rearrangement is condensed to give the spirocyclic oxindole 570 (Scheme 5.257). Samarium iodide reductive coupling of isocyanates with a tethered a,b-unsaturated ketone (571) gives rise to oxindoles 572 (Scheme 5.258) [448]. In this original approach, the oxindole is built by formation of the C2
C3 bond, and has been employed in the preparation of advanced intermediates towards the synthesis of welwitindolinone alkaloids. Intramolecular Friedel–Crafts alkylation of a-chloroacetanilides is one of the most classical methods for the synthesis of oxindoles. A variant of this reaction has been recently disclosed by Buchwald, avoiding the harsh reaction conditions required in

5.6 Chemistry of Indole Derivatives

R' OH O NH2 o-aminophenylacetic acid

R' O X

R'

X

N R

O

NHR

Pd or Cu catalyzed amidation

R' N R

FC alkylation O

Heck reaction or radical cyclization

Pd catalyzed α-arylation X

X

N R

O

N R

O

Figure 5.10 General approaches to the synthesis of oxindoles through cyclization reactions.

MeO2C

N

OH

CO2H

MeO2C DCC, DMAP

+ 565

KHMDS/THF

N

O O

85% 567

566

MeO2C

N

O

O

MeO2C

NH

CO2H

-78 ºC rt 82% 569

568 MeO2C

O N

NaOAc, Ac2O 65 ºC 88% Scheme 5.257

570

j497

j 5 Five-Membered Heterocycles: Indole and Related Systems

498

O O SmI , tBuOH, LiCl 2

O Cl CO, Et N 2 3 THF

NH2

NCO 571

N H

THF, -78 ºC 88% (two steps)

O

572

Scheme 5.258

the FC alkylation. Thus, treatment of a-chloroacetanilides 573 with a Pd(0)-based catalytic system leads to the oxindoles 574 in excellent yields, under milder conditions and with high functional group tolerance (Scheme 5.259) [449]. Interestingly, the overall process results in a Pd-catalyzed aromatic C
H activation. Nevertheless, at present there is no unambiguous mechanistic proposal. MeO MeO 573

N Bn

Cl

Pd(OAc)2, JohnPhos

MeO

O

NEt3, Tol, 80 ºC

MeO

94%

574

N Bn

O

Scheme 5.259

5.6.2.1.4 Oxindole Reactivity The chemistry of oxindole resembles a typical fivemembered ring lactam. Deprotonation at the b-carbon occurs readily, as the resulting anion is stabilized by the aromatic character of the oxindole enolate. Thus, the oxindole anion can react with electrophiles in alkylation, acylation and condensation reactions. On the other hand, oxindoles can be transformed into the corresponding indolyltriflates 575 (Scheme 5.260) [450], which can be further employed in metal-catalyzed cross-coupling reactions (Section 5.5.3.6).

O

N SO2Ph

Tf2O, DIPEA CH2Cl2, 0 ºC 70% 575

OSO2CF3 N SO2Ph

Scheme 5.260

5.6.2.2 N-Hydroxyindoles The structure of N-hydroxyindole is also present in a considerable number of biologically molecules. Moreover, several N-hydroxylated analogues of biologically inactive indoles have shown biological activity [451]. The most common approach to the preparation of N-hydroxyindoles is the reductive cyclization of o-nitrobenzylketones 576 or aldehydes in the presence of a metal reducing agent [452]. A fairly general and chemoselective protocol is the

5.6 Chemistry of Indole Derivatives

j499

reaction with the Pb/TEAF system (TEAF: triethylammonium formate), which provides N-hydroxyindoles 577 in very high yields (Scheme 5.261) [453].

Pb, TEAF O NO2

EtO2C

MeOH, 55 ºC 97%

576

EtO2C 577

N OH

O NH OH

EtO2C

Scheme 5.261

In a closely related reaction, structurally diverse substituted N-hydroxyindoles 580 can be prepared in a tandem process from nitroaromatic a,b-unsaturated ketoesters 578 [454]. The initially formed nitrone 579 is trapped by a hetero- or carbonucleophile to provide substituted N-hydroxyindoles 580 (Scheme 5.262). NuNu CO2Et

X

O NO2

SnCl2

X

578

N O

CO2Et

579

X

N OH

CO2Et

580

Scheme 5.262

For instance, the reaction in the presence of silylenol ethers gives rise to the corresponding C-alkylated derivatives 581 (Scheme 5.263).

CO2Et O NO2

DME, 4Å MS, 40 ºC OTMS 61%

Scheme 5.263

O

SnCl2·2H2O N OH 581

CO2Et

j 5 Five-Membered Heterocycles: Indole and Related Systems

500

5.6.3 Aminoindoles

Although most amino-substituted heterocycles exist mainly in the amino tautomer, 2-aminoindole exists predominantly as the 3H-tautomer, which is stabilized by the amidine resonance form (Scheme 5.264). NH2

N H

N

NH2

N

NH2

Scheme 5.264

Regarding the synthesis, the most reliable modern method to introduce an amino group in the heterocyclic indole ring is Pd- or Cu-catalyzed amination (Section 5.5.3.5). N-Amination of indole can be accomplished with different “NH2 þ ” type of reagents such as monochloramine (NH2Cl) [455] or hydroxylamine o-sulfonic acid [456] under basic media (Scheme 5.265). HOSO2ONH2 t-BuOK, NMP rt, 180 min 90%

N H

N NH2

Scheme 5.265

On the other hand, N-aminoindoles 583 can be prepared by the Pd-catalyzed intramolecular cyclization of o-chloroarylacetaldehyde hydrazones 582 (Scheme 5.266) [457]. Cl

Cl Pd(dba)2, Pt-Bu3 Cl

N

NMe2

NaOtBu o-xilene, 120 ºC

582

583

N NMe2

Scheme 5.266

5.6.4 Indole Carboxylic Acids

Decarboxylation of indole-3-carboxylic acid, and also indoyl-2-acetic acid, takes place under reflux of water (Scheme 5.267). The reaction proceeds through the protonated 3H-indolium cation 584 [458].

5.7 Addendum

CO2H

O

H

O

+

H

H

H

N H 584

N H

N H

Scheme 5.267

Decarboxylation of indole-2-carboxylic acid requires much harsher conditions, such as heating in the presence of either mineral acids or copper powder [459]. The latter is a valuable synthetic transformation that has been employed to prepare 2unsubstituted indoles 586 from the more readily available 2-indole carboxylates 585. Scheme 5.268 gives an example of the application of this sequence [460, 461]. OBn CHO

OBn NaOEt, EtOH -15 ºC 75%

Br

N3

ii) LiOH THF, H2O 91%

Br

OBn

Br

i) Toluene CO2Me reflux

N3CH2CO2Et

OBn

N H

CO2H

585

Cu powder quinoline 237 ºC 71%

Br 586

N H

Scheme 5.268

5.7 Addendum

During the production of this book, and since the initial elaboration of this chapter, remarkable advances have occurred in the field of indole chemistry, which indicate the high interest in this particular type of heterocyclic structure. This addendum is not intended to be a comprehensive revision of the most recent literature, and collects only some important advances that have not been mentioned above. First of all, several reviews covering synthesis and different aspects of indole reactivity have appeared recently [462]. 5.7.1 Ring Synthesis 5.7.1.1 Fischer Indole Synthesis The direct synthesis of N-Cbz indoles from the corresponding N-Aryl-N-Cbz hydrazide has been disclosed [463].

j501

j 5 Five-Membered Heterocycles: Indole and Related Systems

502

An improved methodology for the sequence hydrohydrazination of alkynes/ Fischer indolization has been described employing inexpensive and environmentally friendly Zn salts as catalysts [464]. 5.7.1.1.1 Cyclizations by Formation of the N
C2 Bond The synthesis of indoles by cyclization of nitrenes, generated from aryl azides, has been carried out employing rhodium catalysts [465]. The aryl amination/hydroamination sequence on o-chloroalkynyl benzenes has been implemented for the preparation of indoles with sterically demanding Nsubstituents [466]. Similar routes have been employed for the synthesis of 2aminoindoles [467] and 4-alkoxyindoles [468]. A multicomponent domino process for the preparation of 2-aminomethyl indoles, involving the cyclization of an oalkynylaniline, has been reported [469]. A new approach for the synthesis of indoles is the cycloisomerization of 2propargylanilines (591). This reaction has been effected employing Pt-based and Brønsted acid catalysts, and leads to functionalized indole skeletons 592 (Scheme 5.269). The mechanism proposed for the acid-catalyzed reaction involves a 5-exo-dig cyclization followed by an aza-Cope rearrangement [470]. MeO

OMe Conds. N R

N 591

R

592

PtCl2 (5 %mol), 80 ºC SiO2 (5 eq), rt MeO

H+

OMe

N

R

R

92% 90% H OMe

N

N R

OMe N R

Scheme 5.269 Synthesis of
ındoles by cycloisomerization of propargylanilines.

A 5-exo-dig cyclization is also the first step for the cycloisomerization of o-alkynylN,N-dialkylanilines 593 that leads to annulated indoles 594 (Scheme 5.270) [471]. Me F3 C

W(CO)6 N 593

F3C

68%

N 594

Scheme 5.270 Cycloisomerization of o-alkynyl-N,N-dialkylanilines.

5.7 Addendum

The reaction involves activation of the alkyne by the action of the metal catalyst, followed by 5-exo-dig cyclization to produce a metal-containing ammonium ylide (595). Then, a [1,2]-Stevens rearrangement, followed by a [1,2]-alkyl migration, renders the fused indole structure (Scheme 5.271). [M] R

[M] N

N

[M] R

R

N 595

[M]

Stevens rearrangement

R

R

1,2-alkyl migration -[M]

N

N

Scheme 5.271 Mechanism proposed for the cycloisomerization of o-alkynyl-N,N-dialkylanilines.

Indoles have been synthesized from o-iodobenzoic acids and alkynes in a sequential process that involves a Curtius rearrangement followed by a Pd-catalyzed Larocktype indolization [472]. Quite similarly, o-alkynylamides have been employed to synthesize indoles through a Hoffmann-rearrangement/alkyne hydroamination sequence [473]. The Pd-catalyzed synthesis of indoles from o-amino-gem-dihalostyrenes has been studied in detail, and represents a very powerful methodology for the synthesis of substituted indoles [474]. A new approach to tryptamines from readily available N-Boc anilines 596 and NBoc-3-pyrrolidinone 597 has been developed (Scheme 5.272). The process, which NBoc

NBoc R

2 t BuLi 596

R

NHBoc

Li NBoc Li

O

597

R

LaCl3 ·2LiCl

OH NHBoc

tBuOK THF, 70 ºC NBoc NH2 TFA CH 2Cl2 R

R

598

N H

NBoc NH2

Scheme 5.272 Stepwise synthesis of triptamines.

tBuOK TBSCl LDA

R

O N H

O

j503

j 5 Five-Membered Heterocycles: Indole and Related Systems

504

consists of various steps, as represented in the scheme, allows for the synthesis of a large variety of tryptamines 598 substituted in the benzene ring [475]. 5.7.1.1.2 Cyclizations by Formation of the C2
C3 Bond The synthesis of cyclicketone fused indoles has been achieved by a Pt-catalyzed cycloisomerization of N-(2alkynylphenyl)lactams [476]. A structural variety of 2-substituted indoles 601 can be prepared from o-amino-2chloroacetophenones 599 and Grignard reagents [477]. The reaction involves a [1,2]migration of the R group from the intermediate magnesium alcoholate 600 (Scheme 5.273). O

Cl

R O

R-MgX THF -10 to 22 ºC 91-55%

NH2 599

Cl

MgX N H

NH 2 600

R

601

R: Alkyl, aryl, alkynyl Scheme 5.273

N-fused indoles have been synthesized through a catalytic carbenoid C–H insertion approach. In this novel reaction, a niobium carbenoid (603) is generated from a CF3 group of the o-trifluoromethylaniline derivative 602 (Scheme 5.274). Then, an intramolecular C–H insertion leads to a mixture of indole 605 and indoline 604. Subsequent oxidation leads to the N-fused indoles 605 with good yields. X ( )n

N

602

CF3

NbCl5 (30 %) NaAlH 4, 4 eq

dioxane, ref lux n: 1-5 X: CH 2, O, S, NMe

X

N

( )n

O2 RuZr-P (8%)

N

X ( )n

605

604

56-85%

( )n N C F 603

· Nb

N F

H

Scheme 5.274

5.7.1.1.3 Cyclizations by Formation of the C3
C4 Bond A very versatile new methodology for indole ring synthesis is the Pd-catalyzed oxidative cyclization of

5.7 Addendum

Pd(OAc) 2 (10% mol) Cu(OAc)2 (3 eq) K2CO 3, DMF

R1

R N H

COR

606

COR 2 R

2

607

R1

N H

Scheme 5.275

N-arylenaminones 606 (Scheme 5.275) [478]. This methodology, which leads to 3-acyl substituted indoles 607, is clearly advantageous when compared with strategies based on intramolecular Heck reactions, which require o-haloanilines as starting materials. The mechanism proposed for this reaction (Scheme 5.276) starts with the electrophilic palladation of the enaminone 606, to give acylpalladium intermediate 608, followed by formation of palladacycle 609 by a s-bond metathesis or a baseassisted deprotonation. Reductive elimination furnishes the indole 607 and releases a Pd(0) species that is reoxidized to the active Pd(II) by the stoichiometric Cu(II) salt. More recently, a similar reaction, but employing CuI as a catalyst [479], and a metalfree version of this transformation, mediated by phenyl-iodide diacetate, have been reported [480]. R1

R

XPd

COR

N H 608

R1

R

N H

COR 2

606

PdX2 Base

Base· HX

Base

X Pd R 609

H

COR R1

N H

R

Pd

COR

N R1 H -bond metathesis

H or

R

X Pd

COR

N R1 H deprotonation

COR 2 R 607

N H

R 1 + Pd(0)

Scheme 5.276

Moreover, this type of cyclization has been adapted to a domino process in which indoles are prepared directly from electrophilic alkynes and anilines in a Pd(II)catalyzed process [481].

j505

j 5 Five-Membered Heterocycles: Indole and Related Systems

506

The same type of products obtained from the cyclization of enaminones has been obtained by a metal-free cascade reaction between N-arylamides and ethyl diazoacetate [482]. Some other Heck based cyclizations have been reported recently: a Pd-catalyzed Suzuki–Heck sequence [483], a Pd-catalyzed aryl amination-Heck sequence [484], and a Cu-catalyzed cyclization of 2-iodoenaminones [485]. Acetanilides have been employed in a rhodium-catalyzed oxidative indole synthesis (Scheme 5.277). In this impressive reaction, 2,3-disubstituted indoles 612 are built from acetanilides 610 and internal alkynes 611 [486]. As in the oxidative cyclization of enaminones described above, the reaction does not need an ortho substituent to enable the cyclization. Cp*RhCl2 (2.5% mol) AgSbF6 (10% mol) Cu(OAc) 2H 2 O (2.1 eq)

MeO + NHAc

Ph 611

610

MeO

t-AmOH (0.2 M) 120 ºC, 1h 82%

612

N Ac

Ph

Scheme 5.277

5.7.1.1.4 Cyclizations with Formation of the N
C7a Bond A Pd-catalyzed N
C7a bond-forming reaction is the last step in the Pd-catalyzed cascade synthesis of indoles from 1,2-dihalobenzene 613 derivatives and imines 614 (Scheme 5.278). This synthesis consists of two independent reactions catalyzed by the same Pd catalyst: the imine a-arylation and the intramolecular C
N bond-forming reaction. It is worth noting the high modularity of this synthesis of indoles, which are prepared from three fragments: the aromatic system and the carbonyl compound and the amine employed in the preparation of the imine [487].

X

R4

+ Y 613

N

R3

R1 R

Pd2(dba)3 XPhos NaOtBu dioxane, ∆

2

R3 614

R4

615

C-C

C-N R

R4 Y

3

R3

R2 1

NR

X = I, Br, Cl; Y = Br, Cl Scheme 5.278

N R1

R

4

Y

R2 NHR1

R2

5.7 Addendum

j507

This methodology has been extended to employ o-chlorononafluorosulfonates (ochlorononaflates) 616 (Scheme 5.279). The reaction is totally regioselective, with the C
C bond being formed between imine a-carbon and the C-atom that supports the nonaflate. This is an important improvement, because o-chlorononaflates are readily prepared from phenols, and moreover is particularly adequate for the preparation of 6-substituted and 4,6-disubstituted indoles, which are not easily prepared by other conventional methods [488].

R' +

Cl

R

R'

R3

ONf

R

2

N

R1 614

616

R3

Pd 2(dba) 3, XPhos LiOtBu dioxane, ∆

R

615

N R1

R2

Nf: O2 SCF 2CF2CF2 CF3

R'

R' OH

OH R

Cl

R

Scheme 5.279

5.7.1.1.5 Synthesis of Indoles by a [4 þ 2] Cycloaddition A very elegant construction of the functionalized indole skeleton has been carried out by the sequence presented in Scheme 5.280 [489]. The key step is the MW-promoted intramolecular [4 þ 2] cycloaddition of the aminofuran intermediate 617, which forms both rings at the same time. The method is particularly useful for the synthesis of 4-substituted indoles (618).

R

O

N Boc

Li +

R

R O

O

N OH Boc 617

[4+2] MW 30 min, 180 ºC

O

OH

R

OH

HO

N Boc

N Boc - 2 H 2O - Boc R

618

Scheme 5.280

N H

j 5 Five-Membered Heterocycles: Indole and Related Systems

508

5.7.2 Reactivity 5.7.2.1 Reactions with Electrophiles 5.7.2.1.1 Michael Additions and Reactions with Nitroolefins The recent explosion of the field of asymmetric organocatalysis has had an important impact in the chemistry of indoles, in particular in the reactions of indoles with electrophiles such as a,b-unsaturated compounds, nitroolefins, carbonyl compounds, and imines. A review on this field is available [490]. The Friedel–Crafts alkylation of indoles with a,b-unsaturated carbonyl compounds has been carried out employing chiral primary amines as organocatalyst [491]. A chiral binol N-triflylphosphoramide derivative has been employed as a Brønsted acid catalyst in the Friedel–Crafts alkylation of indoles with b,c-unsaturated-a-ketoesters [492]. An intramolecular version has also been reported [493]. Regarding Lewis acid based asymmetric catalysis, highly enantioselective Friedel– Crafts alkylations with a,b-unsaturated phosphonates have been uncovered employing bis(oxazolinyl)pyridine-scandium(III) triflate complexes [494]. Several organocatalytic approaches for the asymmetric addition of indoles to nitroolefins have been reported, employing thiourea based organocatalysts [495], and promoted by a chiral phosphoric acid derivative [496]. Also noteworthy is a recent catalytic asymmetric version employing a Cu(I) chiral catalyst [497]. 5.7.2.1.2 Asymmetric Organocatalyzed Pictet–Spengler Reactions Several asymmetric variants of the Pictet–Spengler (Scheme 5.281) reaction of have been reported [498].

HN X N H

+ R-CHO

organocatalyst

NH

N X N H

R

N H

R

Scheme 5.281

For instance, carboline 621 was obtained in the chiral Brønsted acid catalyzed reaction between a properly functionalized tryptamine (619) and aliphatic aldehyde (620) (Scheme 5.282) [499]. 5.7.2.1.3 Indole as Nucleophile in Pd-Catalyzed Allylic Alkylations The Pd-catalyzed allylic alkylation reaction has been applied in the allylation of 3-substituted indoles, leading to indolenines featuring a C3-quaternary center [500]. The electrophilic arylation of 3-substituted indoles employing diaryl l3-iodanes as electrophilic aryl transfer reagents leads to indolenines 622, which also feature a C3-

5.7 Addendum

j509

SiPh 3 O O P O OH

HN I

N H 619

O

I N

SiPh 3

+

N H

toluene,rt

O 621

O 620

CHO

O

yield: 86%, ee: 89%

Scheme 5.282

quaternary center (Scheme 5.283) [501]. The relative unstable indolenines 622 are isolated upon reduction to the corresponding indolines 623.

Ar N H

+

Ar2 I· BF4

BTMG CH2 Cl2

BTMG: tert-butyl tetramethylguanidine

Ar NaBH3 CN N H

N

622

623

Scheme 5.283

5.7.2.2 Transition Metal Catalyzed Reactions 5.7.2.2.1 Direct Alkenylation, Alkynylation, and Arylation reactions The indole ring has served as a platform to develop new C
C bond-forming cross-coupling from C
H bonds. Indeed, much effort has been made in very recent years in the study of the direct arylation of indoles, which has led to very exciting achievements in transition metal catalysis. A review in this field is available [502]. Palladium(II)-catalyzed C2-alkenylation has been reported that employs N-(2pyridyl)sulfonyl indoles [503]. Very recently, an intermolecular Au(I)-catalyzed alkynylation of indoles has been disclosed [504]. Palladium-catalyzed selective arylation of indoles at C2 under mild conditions has been accomplished employing a PdII/IV catalytic cycle [505]. A different strategy for the C–H arylation, employing boronic acids, has also been reported [506]. Site-selective arylation at either C2 or C3 has been described that employs a Cu(II) catalyst and diaryl-iodine(III) reagents as electrophiles (Scheme 5.284) [507]. Aryla-

j 5 Five-Membered Heterocycles: Indole and Related Systems

510

Ar

R = H, Me 35 ºC iPr Ar

+

N R

I

iPr · OTf

Cu(OTf)2 10% mol

624

iPr R = Ac 60 ºC

N R

Cu(I)OTf

base· OTf

H base OTf 627

627

H

O

N R

OTf CuIII Ph

N R

H

N

N

[Ph-I-Ph]OTf

[PhCu IIIOTf ]OTf 626

N R

Cu III Ph

Ar

PhI

CuIII Ph

OTf

625

N Ac

Ph

Tf O

H

N R

O

H

OTf Cu III Ph

N 628

N

H

OTf CuIII Ph O

Ph O

Scheme 5.284

tion at C3 to give 624 occurs on N-H and N-Me indoles, while N-acetylated indoles undergo arylation at C2 leading to 625. The catalytic cycle proposed for this reaction involves a CuI/CuIII system (Scheme 5.284), and involves oxidative addition to give a highly electrophilic Cu(III) species (626) that undergoes attack at the 3 position of the

5.7 Addendum

j511

indole to form intermediate 627. Rearomatization and reductive elimination releases the arylated product and regenerates the Cu(I) catalyst. For the N-acetylated indole, the intermediate 627 suffers a C3–C2 migration directed by complexation with the oxygen atom of the carbonyl, giving rise to the C2metallated system 628. Reductive elimination and rearomatization provide the C2arylates indole. A truly remarkable achievement, carried out by the group of the late Keith Fagnou, is the arylation of indoles with unactivated arenes (Scheme 5.285) [508]. The reactions take place in the presence of a Pd(II) catalyst and a stoichiometric oxidant. C3 or C2 selectivity can be controlled by modification of several parameters: the stoichiometric metal oxidant, the substitution at the N atom of the indole, and the additives present in the reaction. Typically, N-acetyl indoles 629 give C3 arylation, while N-pivaloyl indoles 630 suffer arylation at C2. Ph

+

R 629

R

Pd(TFA)2 10-20% mol CuOAc 2, 3 eq CsOPiv

N Ac

110-140 ºC

major

+ N O 630

110 ºC

N Ac

Ph

N Ac

+

R

30 eq

Pd(TFA) 2 5% mol AgOAc, 3 eq PivOH

R

Ph

R

N Ac

Ph

Ph R

N

60 eq

Ph

+

R

O major

Scheme 5.285

5.7.2.2.2 C
N Bond-Forming Reactions The introduction of secondary and tertiary substituents at the N position of the indole is a challenging transformation. Important advances in this sense have been achieved recently. A one-step tert-prenylation of indoles has been devised employing a Pd(II) catalyst (Scheme 5.286) [509]. This is an important transformation as the prenyl group is present in a large number of indole natural products and intermediates. Various contributions have appeared regarding the asymmetric N-allylation of indoles [510]. For instance, a method has been described employing a chiral metallacyclic iridium phosphoramidite complex (631, Scheme 5.287) [511]. This important reaction provides the corresponding N-allylated indoles 632 with total regioselectivity (no C3-allylation occurs) for a wide range of 2,3-disubstituted, 3-

N O

j 5 Five-Membered Heterocycles: Indole and Related Systems

512

Pd(OAc)2 40 %mol AgOTf, Cu(OAc) 2

R

R

CH 3CN, 40 ºC, 24h

N H

N

R: CO2 Me, 87% R: CHO, 75%

Scheme 5.286

+ Ph

CO2 Et

N H

cat (2 %mol)

CsCO3 ,10% mol THF, 50 ºC OCO 2t Bu

CO2 Et

N Ph

+

O P O N

Ir Ar

Ph

632 97

cat

CO 2Et

N

:

3

89% yield 99% ee

Ar

Ar: 2-MeOC 6 H4 631 Scheme 5.287

substituted, and also 2-substituted indoles. In the last case, the presence of an electron-withdrawing group at C2 is necessary to reduce the reactivity of the C3 position and direct the reaction to the N-position. The branched regioisomer 632 is always obtained as major or exclusively with very high enantiomeric excesses. 5.7.2.2.3 Pericyclic Reactions A Claisen rearrangement involving the C2
C3 bond of the indole is the key step in the synthesis of kojic acid derivatives 634 (Scheme 5.288) [512]. The intermediate pyranone substituted indole 633 is prepared employing the Larock indole synthesis. RO

O O

I

O

+

NHBoc

Larock OR Indole synthesis

O N Boc

O O 633

Scheme 5.288

O

HO

O

Toluene MW, 190 ºC 85%

Claisen

N Boc 634

OR

References

O N H

+

N Ph

i) cat. CH2Cl2 -55 ºC ii) TFAA

O

O

N

N

91% 98% ee

F3 C

O 635

CF3

O O

CF3

S

S cat.

N

N H

N N H

Ph

O

CF3

636

N H H N

N H

CF3

O Ph

N O

637 Scheme 5.289

A highly enantioselective organocatalytic [4 þ 2] cycloaddition of 3-vinylindoles with maleimides has been reported recently (Scheme 5.289) [513]. The reaction gives rise to indolenines 634 with very high yields and enantioselectivities. The chiral thiourea 635 is the catalyst for the reaction. The nearly complete enantioselectivity obtained has been justified by the simultaneous interaction of the organocatalyst with diene and dienophile, as presented in the transition state model 636.

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J. Am. Chem. Soc., 126, 10558. (b) Seayad, J., Seayad, A.M., and List, B. (2006) J. Am. Chem. Soc., 128, 1086. (c) Wanner, M.J., van der Haas, R.N.S., de Cuba, K.R., van Maarseveen, J.H., and Hiemstra, H. (2007) Angew. Chem. Int. Ed., 46, 7485. (d) Bou-Hamdan, F.R. and Leighton, J.L. (2009) Angew. Chem. Int. Ed., 48, 2403. (e) Muratore, M.E., Holloway, C.A., Pilling, A.W., Storer, R.-I., Graham Trevitt, G., and Dixon, D.J. (2009) J. Am. Chem. Soc., 131, 10796. Wanner, M.J., Boots, R.N.A., Eradus, B., de Gelder, R., van Maarseveen, J.H., and Hiemstra, H. (2009) Org. Lett., 11, 2579. (a) Trost, B.M. and Quancard, J.J. (2006) Am. Chem. Soc., 128, 6314. (b) Kagawa, N., Malerich, J.P., and Rawal, V.H. (2008) Org. Lett., 10, 2381. Eastman, K. and Baran, P.S. (2009) Tetrahedron, 65, 3149. Joucla, L. and Djakovitch, L. (2009) Adv. Synth. Cat., 351, 673. Garc
ıa-Rubia, A., G
omez Array
as, R., and Carretero, J.C. (2009) Angew. Chem. Int. Ed., 48, 6511. Brand, J.P., Charpentier, J., and Waser, J. (2009) Angew. Chem. Int. Ed., 48, 9346.

and Sanford, M.S. (2006) J. Am. Chem. Soc., 128, 4972. (b) Lebrasseur, N. and Larrosa, I. (2008) J. Am. Chem. Soc., 130, 2926. Yang, S., Sun, C., Fang, Z., Li, B., Li, Y., and Shi, Z. (2008) Angew. Chem., Int. Ed., 47, 1473. Philipps, R.J., Grimster, N.P., and Gaunt, M.J. (2008) J. Am. Chem. Soc., 130, 8174. (a) Stuart, D.R. and Fagnou, K. (2007) Science, 316, 1172. (b) Stuart, D.R., Villemure, E., and Fagnou, K. (2007) J. Am. Chem. Soc., 129, 12072. Luzung, M.R., Lewis, C.A., and Baran, P.S. (2009) Angew. Chem. Int. Ed., 48, 7025. (a) Bandini, M., Eichholzer, A., Tragni, M., and Umani-Ronchi, A. (2008) Angew. Chem. Int. Ed., 47, 3238. (b) Cui, H.-L., Feng, X., Peng, J., Lei, J., Jiang, K., and Chen, Y.-C. (2009) Angew. Chem. Int. Ed., 48, 5737. Stanley, L.M. and Hartwig, J.F. (2009) Angew. Chem. Int. Ed., 48, 7841. Xion, X. and Pirrung, M.C. (2008) Org. Lett., 10, 1151. Claudio Gioia, C., Hauville, A., Bernardi, L., Fini, F., and Ricci, A. (2008) Angew. Chem. Int. Ed., 47, 9236.

499

500

501 502 503

504

506

507

508

509

510

511 512 513

j531

j533

6 Five-Membered Heterocycles: Furan Henry N.C. Wong, Xue-Long Hou, Kap-Sun Yeung, and Hui Huang

6.1 Introduction

Furan (1) is prepared by a gas-phase decarbonylation procedure starting from furfural, which, in turn, is produced in large amounts via an acid treatment of vegetable residues after industrial production of porridge oats and cornflakes [1]. In addition, acid-promoted dehydration of saccharides such as D-fructose also leads to the formation of hydroxymethylfurfural (2) [2, 3]. In this connection, furan (1) and hydroxymethylfurfural (2) are generally regarded as compounds that are readily accessible from renewable resources. O 1

HO

O 2

CHO

The structure of 1 is closely related to those of pyrrole and thiophene. There are two electron lone pairs on the oxygen atom, one being conjugated with the two double bonds to form a sextet, and the other located in the molecular plane in an sp2 hybrid orbital. Furan molecular frameworks are found in many naturally occurring molecules, and play a very significant role in the field of heterocyclic chemistry. Furans have been applied to various commercially important products such as pharmaceuticals, flavors and fragrant products, and functional polymers. They are also versatile precursors and synthetic intermediates in the preparation of cyclic and acyclic molecules. For example, furans are latent 1,4-dicarbonyl units and are also widely employed as 1,3dienes in Diels–Alder reactions. Efficient synthesis of polysubstituted furans therefore continues to be of great interest to synthetic chemists due to their widespread applications and frequent occurrence in Nature [4].

Modern Heterocyclic Chemistry, First Edition. Edited by Julio Alvarez-Builla, Juan Jose Vaquero, and José Barluenga. Ó 2011 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2011 by Wiley-VCH Verlag GmbH & Co. KGaA.

j 6 Five-Membered Heterocycles: Furan

534

β′

β

43 51 2

α′

α

O

Figure 6.1 Numbering of the furan ring system.

6.1.1 Nomenclature

The positions next to the oxygen atom are indicated as a and a0 , while those away from the oxygen are called b and b0 . Figure 6.1 shows the numbering of the furan ring system [5]. Reduced furans are called 2,3-dihydrofuran (3), 2,5-dihydrofuran (4) and 2,3,4,5-tetrahydrofuran (5). O

O

O

3

4

5

6.1.2 General Reactivity

Sections 6.3 and 6.4 give a much more thorough discussion on the reactions of furan 1 and its derivatives. Here we concentrate on the overall reactivity of 1 [1, 6]. In general, furans are rather stable towards weak aqueous acids. However, in concentrated sulfuric acid or Lewis acids the furan framework will be decomposed. Of the three types of five-membered heterocycles that contain NH, S or O, furans are the least aromatic [7] and would therefore react like dienes. Electrophilic substitution reactions with 1 are regiospecific and lead to mostly a-substituted furans 6 via a general addition–elimination pathway (Scheme 6.1) [1, 6, 8]. b-Substitution reactions only occur when both the a and a0 positions are occupied by substituents. Scheme 6.2 depicts an example of b-acylation, in which 7 is converted into 8 [9]. E

+

+

E

O 1

–H

O

O 6

+ H

E

Scheme 6.1

Me Me

N O 7

Scheme 6.2

O

MeCOCl AlCl 3

Me

CS2 reflux, 6 hr 65%

Me

O

Me N

O 8

O

6.1 Introduction

In a nitration reaction, furan 1 reacts with acetyl nitrate to give, initially, an addition product, which undergoes subsequent elimination to offer 2-nitrofuran (9) (Scheme 6.3). AcONO 2 –5° to –30°C

O 1

+C5H5N AcO

O

NO2 –C5H5NHOAc

O 9

NO2

Scheme 6.3

In sulfonation reactions, furan (1) is again sulfonated at C2, with a pyridine–sulfur trioxide complex, followed by acidification with hydrochloric acid to afford 10 (Scheme 6.4). 1. C5 H5N•SO3 2. HCl

O 1

O 10

SO3H

Scheme 6.4

Halogenation reactions are trickier with furans. Thus, polyhalogenated products are obtained from 1 through reactions with chlorine and bromine at room temperature. Pure 2-chlorofuran and 2-bromomfuran can only be obtained when 1 reacts with chlorine in dichloromethane at
40  C, and bromine in dioxane at 0  C, respectively. 3-Methylfuran (11), in contrast, reacts with N-bromosuccinimide (NBS) to furnish 2-bromo-3-methylfuran (12) (Scheme 6.5) [10]. Me

Et2O reflux 75%

O 11

Me

NBS AIBN O 12

Br

Scheme 6.5

Acylation under Vilsmeier–Haack conditions with a catalyst such as boron trifluoride etherate or phosphoric acid converts 1 into 2-acylfurans. As shown in Scheme 6.6, treatment of 3,4-bis(trimethylsilyl)furan (13) with acetyl chloride and titanium(IV) chloride affords the a-acetylfuran 14 [11]. Me3 Si

SiMe3 O 13

Scheme 6.6

MeCOCl TiCl4 CH 2Cl2 –78°C, 1 hr 73%

Me3Si

SiMe3 O 14

COMe

j535

j 6 Five-Membered Heterocycles: Furan

536

Scheme 6.7 gives an appropriate example of a Lewis acid catalyzed alkylation of a furan moiety (15) [12]. This reaction is stereospecific, leading only to the trans-fused diastereomer 16. O

O BF3•Et2O 84%

H

15

16

Scheme 6.7

Condensation of 1 with acetone in the presence of an acid, intriguingly, gives 16membered macrocycle 17 (Scheme 6.8) [13].

Me2 C=O MeSO3H EtOH reflux

O 1

Me

Me O O

Me

Me Me O

O Me

Me Me

17 Scheme 6.8

Metallation such as mercuration with mercury (II) chloride and sodium acetate leads to a-mercurated furans. As demonstrated in Scheme 6.9, 3-methylfuran (11) undergoes mercuration to give the corresponding furanmercuric chloride 18 [14]. Lithiation with alkyllithium in refluxing diethyl ether proceeded smoothly at C2, providing a 2-lithiofuran (19). In the presence of tetramethyl ethylenediamine (TMEDA) in hexane, 2,5-bis(lithio)furan (20) is formed instead (Scheme 6.10) [15].

Me

Me HgCl2 H2 O-MeOH r.t. 95%

O 11

O

HgCl

18

Scheme 6.9

n-BuLi (excess)

n-BuLi O 19

Li

Scheme 6.10

Et2O

O 1

TMEDA C6H14

Li

O 20

6.1 Introduction

Lithium chemistry opens up an avenue for the realization of some useful a-substituted furans. An example is shown in Scheme 6.11 [16]. As can be seen, an excess of butyllithium presumably generates a 2,5-bis(lithio)furan, which is then silylated at the less hindered side to give furan 22 with a 2,4-disubstituted pattern. Me3SiO

O O

1. n-BuLi (2.0 equiv) THF –78°C

Me3SiO O

2. Me3SiCl (0.5 equiv) Me3Si THF 80%

O 21

O

O 22

Scheme 6.11

Furan (1) undergoes catalytic hydrogenation to afford the very commercially important solvent tetrahydrofuran. As mentioned above, furans behave like a 1,3diene, so the reaction of 2,5-disubstituted furan 23 with methanolic bromine produces 2,5-dimethoxy-2,5-dihydrofuran 24 (Scheme 6.12) [17]. CO2 Me

H33C16

O 23

Br2 H33C16 MeO

MeOH r.t., 2 hr 96%

CO2Me O 24

OMe

Scheme 6.12

The diene character of furan can be further demonstrated by its Diels–Alder cycloaddition reaction with maleic anhydride, forming the endo-adduct 25 at a lower temperature as the kinetic product, and an exo-product 26 as the thermodynamic product after much longer reaction times or at a higher temperature (Scheme 6.13). Notably, this cycloaddition reaction was one of the reactions that led Otto Diels and Kurt Alder to report their now famous Diels–Alder reaction [18]. A recent example utilizing an intramolecular Diels–Alder reaction between the furan unit 27 and maleic anhydride, leading to the Diels–Alder adduct 29 via 28, is shown in Scheme 6.14 [19].

O O

+

1

O O

O 40°C MeCN

H H

O O 25

O

Prolonged reaction

O

O

O 26

H

H O

Scheme 6.13

Under the conditions of the Paterno–B€ uchi reaction, hydroxymethylfuran (30) reacts readily with benzophenone to form the [2 þ 2] adducts oxetanes 31 (65%) and

j537

j 6 Five-Membered Heterocycles: Furan

538

O

Me

O

Me F

O N H

O

Me F

27

N

F

C6H6 20°C 5–10 d 92%

N O

O

O 29

28

O CO2H

HO2C Scheme 6.14

32 (20%) (Scheme 6.15) [20]. Reductive methylation of furan 33 with sodium in liquid ammonia and subsequent addition of methyl iodide, on the other hand, afforded 2,5dihydrofuran 34 (Scheme 6.16) [21]. Ph

hv HO

O 30

Ph 2C=O 96 hr

O O 31

HO

Ph

Ph

+ HO

Ph

O O 32

Scheme 6.15

1. Na liq. NH3 THF –78°C

OMe Me O

N O

OMe

2. MeI 93%

33

Me O

OMe N

Me O

OMe

34

Scheme 6.16

6.1.3 Relevant Physicochemical Data [8]

Furan (1) shows only limited solubility in water (1 part in 35 at 20  C) [8]. The hydrogen bonding effect of its oxygen atom with the water protons is the reason why it is more soluble in water than thiophene (1 part in 700 at 20  C). Microwave spectroscopy of 1 and its deuterated analogs in the gas phase has been reinvestigated, and highly accurate structure parameters have been obtained [22]. The dimensions are shown in Figure 6.2. In contrast, the solid-state structural dimensions of furan-2-carboxylic acid [23] and furan-3,4-dicarboxylic acid [24] have been determined by an X-ray diffraction study; the values obtained are in good agreement with those found in the gas phase study [22].

6.1 Introduction

H 1.4301 Å

1.0768 Å 127.83 °

1.3610 Å

106.07 ° 110.65 °

1.3622 Å

106.56 °

O

1.0748 Å 115.98 °

H

Figure 6.2 Geometry of furan.

The UV/Visible spectroscopic absorption maximum of furan (1) in ethanol is lmax 208 nm (log e 3.9). This value is the smallest amongst pyrrole (210 nm) and thiophene (235 nm), and is therefore a good indication that 1 behaves more like a diene than a conjugated system [25]. Chemical shifts of protons are related to the electron-density of the carbons they are attached to, with lower field shifts corresponding to electron-deficient carbon centers. Thus, the a-proton signals of furan (1) at d 7.29 are at a lower field than those of the b-protons (d 6.24), which is primarily due to the inductive electron-withdrawing effect of the oxygen atom [26]. Coupling constants between protons on 1 are J2,3 ¼ 1.75 Hz, J2,4 ¼ 0.85 Hz, J2,5 ¼ 1.40 Hz and J3,4 ¼ 3.30 Hz [27]. 13 C NMR chemical shifts also show the electron-withdrawing effect of the oxygen atom, giving signals at d 142.7 ppm of the a-carbons and d 109.6 ppm for the b-carbons [28]. In its mass spectrum, the fragmentation pathway of furan 1 is like that of other fivemembered heterocycles (Scheme 6.17). For 1, the strongest peak (70%) is the molecular ion [29]. The He(1a) photoelectron spectrum of furan (1) [30] reveals the energy of the third molecular orbital (p3) as 8.89 eV, which is also the energy of the highest occupied

+• O

– C2 H2 –e O

+ • :+ O

H

•

+• O

–

O

• +

HC O Scheme 6.17

•

– HC=O

+

j539

j 6 Five-Membered Heterocycles: Furan

540

–0.090 O +0.209

–0.015

Figure 6.3 p-Electron excess at positions 2 and 3 of furan.

molecular orbital as well as close to the first ionization potential (IP1) of 1 (8.99 eV) [31]. Other molecular orbital energies p1 and p2 are measured at 14.4 and 10.2 eV, respectively. Since a high p-donation character of a compound always leads to substantial p-electron excess, the best measure of p-donation is the value of the first ionization potential (IP1). In this connection, furan and thiophene (p3 ¼ 8.92 eV) [32] show almost equal p-donor properties, while that of pyrrole is significantly larger (p3 ¼ 8.2 eV) [32]. HMO calculations lead to the same conclusion, namely that the total p-electron excess of 1 is smaller than that of pyrrole [8]. As can be seen in Figure 6.3, the b-carbon atoms carry significantly larger negative charges than the a-carbons. Such a distribution of p-electron excess is also in good agreement with the larger shielding of Hb- and Cb-nuclei in the proton and 13 C NMR spectra, respectively [8]. The Pariser–Parr–Pople (PPP) approximation method reproduces well the electronic spectral features of furan (1) [33], while the simple H€ uckel method has also been employed to compute the resonance energy of 1 in a quantitative manner, providing a value of 18 kcal mol
1, which is less stable than thiophene (resonance energy 29 kcal mol
1) [34]. Satisfactory molecular geometry and heat of formation for 1 have been obtained from MINDO/3 semi-empirical MO calculations [35]. In addition, MINDO/3 calculated vibration frequencies for 1 [36] agree well with values obtained experimentally [37]. In addition, satisfactory dipole moment [38] and ionization energies [39] for 1 have been obtained from an ab initio calculation. The electronic spectrum [40] and electronic structure [41] of 1 have also been computed by other ab initio methods. 6.1.4 Relevant Natural and Useful Compounds

As mentioned in Section 6.1, the furan molecular skeleton is found widely in many naturally occurring molecules. Shown below are several furan-containing natural products (35–40) identified in 2004 and 2005. Thus, shinsonefuran (35), a sesterterpene exhibiting cytotoxicity against HeLa cells with an IC50 of 16 mg mg
1, was obtained from the deep-sea sponge Stoeba extensa [42]. A limonoid containing also a 3-substituted furan, namely xyloccensin L (36), was isolated from the stem bark of Xylocarpus granatum [43]. The new furanocembranolide 37 was isolated from the octocorals Leptogorgia alba and Leptogorgia ridida collected on the Pacific coast of Panama [44]. The linderazulene 38, a novel azulenoid showing moderate activity against the PANC-1 pancreatic cell line with an IC50 of 18.7 mg ml
1, was obtained from a deep-sea gorgonian Paramuricea sp. [45]. In

6.1 Introduction

a chemical and genetic study of Ligularia tongolensis in the Hengduan Mountains of China, a strongly Ehrlich-positive furanoeremophilane compound (39) was identified [46]. During automated screening for small-molecule agonists to peroxisome proliferator-activated receptor-c (PPAR-c), a new biologically active linear triterpene 40 was isolated and characterized from the bark of Cupaniopsis trigonocarpa [47]. O O

HO

MeO 2C

H

H OH

O O

Me OH 35

O O

O

O 36

Me Me

CHO Me O

H

O

O

O O

O 37 O

Me

O MeO2C

Me 38

O Me

CO2H O 39

Me O Me

Me

Me Me

O

CO2H

Me

Me CO2H

Me 40

Furan-containing molecules are also useful as catalysts, pharmaceuticals and electronic devices. For example, in the synthesis of a highly potent and selective serotonin reuptake inhibitor (BMS-594726), MacMillan’s furan-containing imidazolidinone catalyst 41 [48] has been employed in the key enantioselective indole alkylation step, leading to a desired product with an enantiomeric excess of 84% [49]. Ranitidine (42) (ZantacÓ), a histamine H2-receptor antagonist that inhibits gastric acid secretion, possesses a furan framework as the pivotal structural unit [50]. Anther furan-containing oligoarylcyclophanene (43) – showing a strong broad luminescence at 499 nm, due presumably to an intramolecular interaction between the chromophores and the presence of a double bond – has potential use in opto-electronic devices [51].

j541

j 6 Five-Membered Heterocycles: Furan

542

O

Me N N H

NO2 O

Me2N Me

41

S O

N H

N H

Me

42

Bu O

O Bu 43

6.2 Synthesis of Furans 6.2.1 Introduction

The synthesis of furans has continued to attract the attention of synthetic chemists during the past several decades [4]. In this connection, many efficient procedures have been documented. Some of these methods have become standard procedures and have been extremely useful in the synthesis of furans with different substituted patterns. One of these classical methods is the acid-catalyzed dehydration reaction of 1,4-diketones to form furans, known as the Paal–Knorr synthesis [52]. Not only 1,4ketones but also masked diketones, such as chloroallyl ketones and oxiranes with appropriate substituents, as well as 1,4-dicarboxylic acid derivatives, including esters and nitriles, are suitable substrates. Many variants have also been recorded. Furthermore, cyclization of c-hydroxy ketones or aldehydes in the presence of an acid catalyst can also provide the corresponding substituted furans. Various acids, such as sulfuric acid, p-toluenesulfonic acid, oxalic acid, Amberlyst 15 and zinc bromide, have been used as catalyst. Some examples (44 ! 45 and 46 ! 47) are shown in Scheme 6.18 [53]. Reaction of oxazole derivative 48 and a dienophile via a Diels–Alder cycloaddition–retro-Diels–Alder reaction strategy provides a useful protocol to produce furan 49 with different substitution patterns, provided these starting materials are carefully chosen (Scheme 6.19). The procedure has been employed in the total synthesis of (
)-teubrevin G (50) [54]. Furans themselves may also serve as dienes in the reaction with electron-deficient alkynes, leading to 7-oxabicyclic compounds, which undergo a retro-Diels–Alder reaction to provide the corresponding furans. The advantages of this strategy lie in the functional group compatibility as well as the starting material

6.2 Synthesis of Furans

O

(CH2 )7COOMe

n-Hexyl

HCl (trace)

O 44

n -Hexyl

CHCl3 reflux 80% CO2Et CHO

EtO

EtO2C

H2SO4 68%

OEt

(CH2 )7COOMe

O 45

CO2 Et O 47

46 Scheme 6.18

Me

N

tBuMe SiO 2

O

O

Me O

H

OSiMe2t Bu 250°C 52% single isomer

O 48

CHO O

O O

Me O

O

O O

Me

O O (–)-Teubrevin G 50

49

Scheme 6.19

accessibility. If the availability of starting materials is not a problem, this procedure may be regarded as the simplest and the most efficient. Organometallic compounds have found significant application in furan synthesis in recent years. A lithiation–electrophile trapping strategy has been widely applied to the synthesis of 2,3-disubstituted and 2,3,5-trisubstituted furans. These furyllithium species have been obtained by various means, such as the direct metallation of furans at the a-position using n-BuLi or LDA (Scheme 6.10) [15] or using lithium magnesates [55] and metal–halogen exchange methodology. All these furyllithium compounds can be converted into the corresponding substituted furans upon quenching with various electrophiles such as halides or carbonyls. As shown in Scheme 6.20, 3-bromofuran 51 can be lithiated and alkylated at the a-carbon to afford 52, which undergoes further reactions to give rosefuran (53) [56]. Furyllithium species can also be converted into other organometallic species, such as titanium and manganese derivatives through a transmetallation procedure. In addition to titanium and manganese derivatives, organocopper, zinc and tin have all been utilized in the preparation of polysubstituted furans [57]. Br O

Br

1. LDA Me

2.

51

Me

Br 78%

Scheme 6.20

O 52

Me

1. n-BuLi Me Me

2. MeI 63%

O 53

Me Me

j543

j 6 Five-Membered Heterocycles: Furan

544

Despite the fact that a lot of strategies and procedures for the synthesis of furans have been recorded, the quest for efficient and reliable synthetic methodologies, especially with acceptable regioselectivity, is still an active research field. Some progress in this area is reviewed in the following section. 6.2.2 Monosubstituted Furans

Transition metal catalyzed coupling reactions of arenes and halides and amines have been very popular in the synthesis of arene derivatives. These protocols can also be used in the synthesis of furans with substituents at different positions. C
N cross-coupling reaction of a bromo-substituted furan with various amides, carbamates and lactams catalyzed by CuI furnishes 2- and 3-substituted amidofurans in 45–95% yield [58]. Arylboronic acid has been employed as an aryl source in the synthesis of 2-arylfuran under Mn(II) acetate-promoted radical reaction conditions. Although the yields are not high, they are better than those of the phase-transfer Gomberg–Bachmann synthesis using arenediazonium ions [59]. Arylation of 3-furoate with 3-bromonitrobenzene using Pd(PPh3)4 as catalyst in toluene affords 2,3-disubstituted furan while 5-aryl products are generated predominantly when Pd/C is used as the catalyst and NMP as solvent [60]. 2-Substituted furan 56 has been prepared using the phosphorylated allenic glycol 54 through a cyclization pathway under basic conditions, followed by dehydration of intermediate 55 in the presence of a catalytic amount of p-TsOH (Scheme 6.21) [61].

(EtO)2 OP

HO OH Et 3N

HO

Ph

H 54

72%

PO(OEt)2

O 55

p -TsOH

O

89%

Ph

56

PO(OEt)2 Ph

Scheme 6.21

2-Substituted furans can be prepared under mild conditions. Thus, reaction of 2,5dimethoxy-2,5-dihydrofuran (57) and an appropriate vinyl ether in the presence of a catalytic amount of MgBr2Et2O affords a functionalized 2-alkylfuran 58 in good yields (Scheme 6.22). The reaction might proceed through a concerted mechanism, in which the MgBr2-activated dihydrofuran reacts with the vinyl ether via a cyclic intermediate [62].

MeO

O 57

Scheme 6.22

OMe

+

OMe

MgBr2 O

Et2O 75%

O 58

O

6.2 Synthesis of Furans

Furyldifluoromethyl aryl ketones 59 are formed when furan (1) is allowed to react with difluoroenol silyl ethers in the presence of Cu(OTf)2 as depicted by an example in Scheme 6.23 [63]. If 2-furfurylcarboxylate is used, the corresponding substituted furan is also obtained [63].

O

+

F

OSiMe 3

Cu(OTf)2

F

Ph

MeCN-H2O (50:1) 88%

1

O O 59 F F

Ph

Scheme 6.23

The Yb(fod)3-catalyzed carbonyl-ene reaction of 3-methylene-2,3-dihydrofuran (60) and aldehydes is a mild, efficient way to provide 2-substituted furans, which can be transformed into furano[2,3-c]pyrans 61 in good yield via the oxa-Pictet– Spengler procedure (Scheme 6.24) [64]. Similarly, 60, produced from the Wolff– Kishner reduction of 2-furylhydrazone, reacts with aldehydes in the presence of Yb (fod)3 or Ti(OPr-i)4, to afford the same 2-substituted furans. Notably, an optically active product is realized when Ti(OPr-i)4/(S)-BINOL is the catalyst [65]. Me Me

Yb(fod)3 72%

O 60

Me

CHO

OH Me

O

Me

Me

Me

Me

CHO

p-TsOH 76%

O

O Me Me

61

Scheme 6.24

The 2-position of furan is usually derivatized by a simple electrophilic aromatic substitution or metallation. However, the introduction of a substituent to the 3position of furans requires special strategies. Several such procedures have been developed, one of which is the synthesis of furan-3-carboxylic acid (63) via aromatization of 3-trichloroacetyl-4,5-dihydrofuran (62) followed by a nucleophilic displacement with hydroxide, alcohols and amines (Scheme 6.25) [66]. O

CCl 3

O 62

NBS CCl4 reflux, 2 hr 60%

O

O

CCl 3

1 M NaOH C6H6 reflux, 16 hr 70%

O

OH

O 63

Scheme 6.25

Reductive annulation of 1,1,1-trichloroethyl propargyl ether 64 in the presence of a catalytic amount of Cr(II) regenerated by Mn/Me3SiCl provides another entry to

j545

j 6 Five-Membered Heterocycles: Furan

546

a 3-substituted furan (65) in high yields (Scheme 6.26). The reaction conditions proved compatible with most other common functional groups. Some natural products, such as perillene and dendrolasin, have been prepared by utilizing this procedure [67]. OAc AcO O Cl3C 64

CrCl2 (cat.) Mn, Me 3SiCl 82%

O 65

Scheme 6.26

The reaction of furan with N-tosylimine produced in situ from TsN¼S¼O and aldehydes in the presence of ZnCl2 gives no Diels–Alder reaction products. Instead, furyl sulfonamides have been separated in high yields (Scheme 6.27) [68]. This procedure provides an efficient synthesis of 2-substituted furans such as 67 from 66, and is general with respect to aldehydes. Moreover, it is possible to synthesize 2,3disubstituted furans by an intramolecular aromatic substitution of N-tosylimines at the 3-position of furans. O Me

Me

TsN=S=O H

Me 66

Furan ZnCl2 81%

Me

O 67

NHTs

Scheme 6.27

Ring closing metathesis (RCM), one of the most powerful tools for ring-formation, has demonstrated its high efficiency and functional group tolerance. Recently, the RCM reaction has also been employed in the synthesis of substituted furans (e.g., 68 ! 69). A range of different substitution patterns and functional groups are compatible with this sequence, such as the formation of both 70 and 72, employing also the Grubbs catalyst 71(Scheme 6.28) [69]. 6.2.3 Disubstituted Furans

Direct metallation of 2-substituted furan with t-BuLi in the presence of TMEDA followed by treatment of the lithiated furan species with electrophiles provides a simple and efficient way to the corresponding 2,3-disubstituted furans [70]. 2-Furancarboxamide reacts with vinylsilanes catalyzed by Ru3(CO)12 or RuHCl (CO)(PPh3)3 to deliver 3-trialkylsilyl-2-furancarboxamide also in high yield [71]. A general protocol has been developed towards a mild, regioselective arylation of

6.2 Synthesis of Furans

1.10% Grubbs catalyst 71 CH2Cl2, refllux p-MeOC6H 4

Ph

O 68

1. 10% Grubbs catalyst 71 CH2Cl2, reflux OMe

O

O

Ph

MesN O 70

Cl Cl

NMes Ru

PCy3Ph Grubbs catalyst 71

1.10% Grubbs catalyst 71 CH2Cl2, reflux

MeO2 C

2. TFA 70%

Me

OMe

O 69

2. TFA 70%

MeO2C Me

p -MeOC6H4

2. TFA 79%

OMe

O 72

Scheme 6.28

2-furaldehyde using functionalized aryl halides in the presence of a catalytic amount of PdCl2-PCy3. Slow addition of aryl halides to the reaction mixture avoids the homocoupling efficiently [72]. A one-pot Suzuki coupling of aryl halides with in situ generated 5-(diethoxymethyl)-2-furylboronic acid catalyzed by palladium(0) also gave 5-aryl-2-furaldehydes in high yields [73]. A simple procedure to prepare 5-aryl- and 5pyridyl-2-furaldehydes from the inexpensive and commercially available 2-furaldehyde diethyl acetal through direct lithiation–transmetallation–electrophile trapping has been reported. The reaction proceeded in a four-step, one-pot manner and the yields of the coupling step were usually 58–91% [74]. Allene derivatives are useful starting materials in the synthesis of furans containing different substitution patterns. In 1990, Marshall found that Rh(I) and Ag(I) can catalyze the isomerization of allene 73 to the corresponding substituted furan 74 in high yield (Scheme 6.29) [75]. Later, this strategy was successfully applied to the synthesis of furanocembranes and other related natural products [76]. H

n-C 7H15 RhCl(PPh3)3

Me 73

H

O

MeCN 90°C 80%

n-C 7H15

O 74

Me

Scheme 6.29

Several reports have discussed the isomerization between allenes and propargyl groups. One example is the intermolecular reaction of allenyl ketone 75 and an a,b-unsaturated ketone catalyzed by AuCl3, which gives rise to 2,5-disubstituted furan 76 in good yield (Scheme 6.30) [77]. Both ethyl propargyl ketone and ethyl allenyl ketone lead to the same 2,5-disubstituted furan.

j547

j 6 Five-Membered Heterocycles: Furan

548

O

OMe

MeO

AuCl3 (1 mol%) 64%

75

O

Me

Me

H

Me

O

Me

76

O

Scheme 6.30

A general, efficient procedure for the preparation of 2,5-disubstituted furans containing acid- and base-labile groups via CuI-catalyzed cycloisomerization of alkynyl ketones such as the conversion of 77 into 78 has appeared (Scheme 6.31), for which a plausible mechanism has been proposed [78]. The allenyl ketone produced from the triethylamine-Cu(I)-catalyzed isomerization of the starting material should be the intermediate. Coordination of copper to the terminal double bond of allene followed by an intramolecular nucleophilic attack of the oxygen lone pair and subsequent isomerization eventually leads to furans as final products. Indeed, 2-phenylfuran was afforded in 33% yield when allenyl phenyl ketone was treated with CuI in DMA. Me

O

CuI (5 mol%)

Me

C 3H7

77

Me

Et3 N-DMA (1:7) C3H7 100°C 88%

Me

O 78

Scheme 6.31

2,4-Disubstituted furan 81 has been obtained in high yield through a novel oxidative cyclization–dimerization reaction between the two different allenes 79 and 80 (Scheme 6.32) [79]. Ph

Pr

H

+

COOH2 79

PdCl 2(MeCN)2 (5 mol%)

H

80

O

Me

Ph

O

O Pr

MeCN 90%

Me

O

81

Scheme 6.32

As shown in Scheme 6.33, 2,5-disubstituted furan 84, with a cyclopropane subunit at the 5-position, has been synthesized in acceptable yield by a metal-catalyzed Ph O

+

82 Scheme 6.33

Ot Bu 83

Cr(CO)5(THJF) (5 mol%) THF 63%

Ph

O 84

OtBu

Ph

O 85

M

6.2 Synthesis of Furans

j549

cyclization reaction of 1-benzoyl-cis-1-buten-3-yne (82) and the enol ether 83 via (2furyl)carbene complex 85. Many types of metal complexes, such as Mo, W, Ru, Rh, Pd, and Pt, complexes are suitable catalysts [80]. Reaction of 2-alkynal acetal with a divalent titanium reagent and aldehydes provides, after an acid work up, 2,3-disubstituted furans in good to excellent yields [81]. Michael addition–aldol condensation reactions of a,b-unsaturated enones with an organocopper reagent and (tetrahydropyranyloxy)acetaldehyde have been followed by treatment of the products with p-TsOH to afford 2,3-disubstituted furans in moderate to good yields [82]. a,b-Unsaturated carbonyl compounds with an appropriate leaving group undergo 1,5-electrocyclization reactions to yield 2,5disubstituted furans upon heating in the presence of an acid, presumably through an intermediate formed from 1-oxapentadienyl cations, whose conformational and energy properties were also studied by DFT calculations (B3LYP/6-31 þ G ) [83]. A 2,3-disubstituted furan, such as 88, with different functionalities has been synthesized through an acid-catalyzed elimination reaction of 2-alkylidenetetrahydrofuran 87, which can be prepared from the cyclization of 86 in high regioselectivity (Scheme 6.34) [84]. 2-Substituted furans and bicyclic furans can be synthesized by this methodology. MeO

O

O

Cl

OEt

DBU (2 equiv) THF 20°C 80%

86

O MeO O 87

TFA CH2Cl 2 OEt 20°C 100%

O 88 O

OEt

Scheme 6.34

Aldol reaction of aziridine and a,b-epoxyaldehydes (e.g., 89) followed by an intramolecular enol cyclization in the presence of Bu2BOTf/DIPEA furnishes 5-substituted-2-furyl amines and carbinols 90 in good yields. The reaction proceeds in a one-pot manner (Scheme 6.35) [85].

X Me

CHO +

89 Me

O Me

Me

Me O Me 90

Me X

Bu2BOTf DIPEA CH2Cl 2 0-25°C

X Me

OH O Me Me

X = NHBoc, 72% yield X = O, 75% yiel

Scheme 6.35

Mercury triflate-catalyzed cyclization of 1-alkyn-5-one 91 produces 2-methyl-5phenylfuran (92) (Scheme 6.36). The reaction may involve a protodemercuration of a vinylmercury intermediate generated in situ. When the substituent is at the

j 6 Five-Membered Heterocycles: Furan

550

O

Ph

Hg(OTf)2 (1 mol%) Ph

C6H6 4 hr 94%

91

O

Me

92

Scheme 6.36

a-position of the carbonyl group, 2-methyl-4,5-disubstituted furans are formed. A plausible reaction mechanism has also been provided [86]. Trifluoromethylsulfonamidofuran 94 has been prepared in high yield through the reaction of a cyclic carbinol amide 93 with triflic anhydride (Scheme 6.37). Many lactams have been tested and the reaction proceeds under mild conditions. Ketoamides are also suitable substrates in these reactions [87]. O

Tf2O C 5H5N

N

83%

OH 93

Me

N

O

SO2 CF3

94

Scheme 6.37

A two-step electrochemical annulation directed to polycyclic systems containing annulated furans has been developed. This pathway involves an initial conjugate addition of a furylethyl cuprate to cyclopentenone (95) and trapping of the enolate as the corresponding silyl enol ether 96. The second step involves anodic coupling of the furan and the silyl enol ether to form the cis-fused six-membered ring 97 with high stereoselectivity (Scheme 6.38) [88]. The reaction can be extended to the formation of seven-membered ring fused furan 98 [89]. However, the substituent on the 3-position of cyclopentanone is important for the formation of a seven-membered ring fused

MgBr

1. carbon anode iPrOH, LiClO 4 2,6-lutidine, MeCN

O CuI, THF TMEDA Me3 SiCl

O 95

Me3SiO

Me O Me3SiO Scheme 6.38

O

2. 1N HCl 64% (two steps)

96 1. carbon anode iPrOH, LiClO 4 2,6-lutidine, MeCN 2. 1N HCl 61%

O

H 97

O HO 98

O

6.2 Synthesis of Furans

furans. If the substituent is H, no desired cyclization product is provided. The results show that the gem-dialkyl effect plays a crucial role in this electron transfer reaction. 6.2.4 Trisubstituted Furans

Many procedures mentioned above can also be utilized effectively to the synthesis of 2,3,4- and 2,3,5-trisubstituted furans. In addition, several novel procedures have also been reported. 3-Trifluoromethylfuran 100 has been obtained from (Z)-2-alkynyl-3-trifluoromethyl allylic alcohol 99 through a palladium-catalyzed cyclization-isomerization procedure (Scheme 6.39) [90].

F3C

I HO

+

C6H13

iPr

CF3

C6H13

Pd(PPh3)4 CuI

PdCl2(MeCN)2

F3C

Et3N 66%

99 HO

i

Pr

64%

iPr

O 100

C6H13

Scheme 6.39

A mild, simple reaction of dimethyl acetylenedicarboxylate with an ammonium ylide supplies trisubstituted furan 101 in good yield (Scheme 6.40) [91].

MeO2C

CO2Me

+

O

N N

+

Me

K 2CO3 (200 mol%) CH 3CN 58%

Br–

MeO2C Me

CO2 Me O 101

Scheme 6.40

The reaction of 1,4-diarylbut-3-yne-1-one 102 with NBS, NIS or ICl affords, via a 5-endo-dig electrophilic cyclization, 3-halofuran 103 in high regioselectivity and high yield (Scheme 6.41) [92]. Me

Br

O NBS Br

102

acetone 89%

O Br

103

Me

Scheme 6.41

M€ uller has reported the synthesis of 3-halofurans [93]. Thus, cross-coupling of acid chlorides with THP-protected propargyl alcohols gives rise to the corresponding

j551

j 6 Five-Membered Heterocycles: Furan

552

alkynones, which undergo an acid-assisted electrophilic addition of hydrogen halide with concomitant deprotection and cyclization to afford 3-chlorofuran 104. If RB (OH)2 is added to the reaction system before workup, this reaction can provide Suzuki-coupling products in moderate yields (Scheme 6.42).

O Ph

Cl

OTHP

+

1. Pd(PPh3)4 (2 mol%) CuI (4 mol%) Et3N (100 mol%) 2. NaCl (200 mol%) PTSA (110 mol%) MeOH, 60°C 70%

Et

Cl Ph

O

Et

104

Scheme 6.42

Organic molecules can also be used as catalysts in furan ring formation reactions. Krische has reported an example of organophosphine serving as catalyst in the construction of substituted furans, in which various c-acyloxybutynoates such as 105 were converted into 2,3-disubstituted, 2,4-disubstituted, and 2,3,5-trisubstituted furans (e.g., 106) (Scheme 6.43) [94].

O2N

CO2Et PPh3 (120 mol%)

NO2 EtO

O

O

105

EtOAc Sealed tube, 110°C 86%

Me

NO2

O 106 NO2

Me

Scheme 6.43

Reaction of 2-penten-4-yn-1-one 107 with benzaldehyde initiated by tributylphosphine delivers 2-vinyl substituted furan 108 in a good yield. The reaction might proceed through a 1,6-addition of phosphine to the enynes, and is followed by ring closure and Wittig reaction between the ylide resulting from cyclization and an aldehyde (Scheme 6.44) [95].

Bu Me Ph O 107 Scheme 6.44

Ph

PhCHO PBu3

Bu

CH2Cl2 64%

Ph

O 108

Me

6.2 Synthesis of Furans

3-Aminofuran-2-carboxylate 109 has been prepared in good yield through the reaction of a cyanoketone with glycolate under Mitsunobu conditions followed by treatment with NaH (Scheme 6.45). 4-Pyridylcarbinol and 4-nitrobenzyl alcohol can also react with cyanoketone to furnish 3-aminofurans [96].

t

CN

Bu

O

PPh3 OEt DEAD tBu

O

+ HO

O

80%

O

OEt

CN

NH2

NaH 88% tBu

CO2Et

O 109

Scheme 6.45

2,3,5-Trisubstituted furan 112 has been synthesized from a two-step one-pot reaction from epoxyalkyne 110. A facile SmI2-mediated reduction generates 2,3,4trien-1-ol 111, and the reduction is followed by a Pd(II)-catalyzed cycloisomerization (Scheme 6.46) [97]. An attractive variant of this reaction has been extended to the preparation of tetrasubstituted furans. Thus, when electrophilic Pd(II) complexes are generated in situ by an oxidative addition of aryl halides or triflates to Pd(0), the oxypalladation process is followed by a reductive elimination and, as a result, tetrasubstituted furans are formed [98]. OAc Ph

Me

2. BzOH, Pd(OAc)2 (PPh3)2

O

BnO

110

Me BnO

–HX, + L

BnO

PdL2X

oxypalladation

BnO

69%

O

PdX2L

Me

1. SmI2, THF, –5°C

Ph

O H Me

Ph 111

O 112

Ph

Scheme 6.46

Nucleophilic substitution of sulfinylfuran 113 with acetylacetone and allyl tin reagent via a Pummerer-type reaction has been used in the formation of 2,3,5trisubstituted furan 114, as well as with other 2,3-disubstituted furans, in high regioselectivity (Scheme 6.47) [99]. SnBu 3 Me

O 113

Scheme 6.47

S O

Ph

(CF3CO) 2O 0°C, 30 min 63%

Me

O 114

S

Ph

j553

j 6 Five-Membered Heterocycles: Furan

554

Regioselective gold-catalyzed cyclization of 2-(1-alkynyl)-2-alken-1-one 115 in the presence of a nucleophile affords 2,3,5-trisubstituted furan 116 in an efficient, atomeconomical manner. Various alcohols, 1,3-diketones as well as some indoles and amines can serve as nucleophiles. This reaction provides another good example of using gold as catalyst in furan synthesis (Scheme 6.48) [100]. O

OMe

1 mol% AuCl 3 1.5 eq MeOH CH 2Cl2 1 hr 80%

115

O 116

Scheme 6.48

Yamamoto has demonstrated that, in the presence of CuBr as a catalyst, trisubstituted furan 118 is formed from 117 and isopropanol (Scheme 6.49) [101], while Liu has shown that tetrasubstituted 3-iodofurans are afforded on employing similar starting materials and I2/K3PO4 as reagents (see below) [102].

O

Ph

Ph

+

O Me

OH Me

117

CuBr (10 mol%)

Me

DMF 80°C 62%

O 118

Me

Scheme 6.49

Conjugated ene-yne-carbonyl 119 has been employed as a precursor of 2-furylcarbene 121. In this way, 121 was allowed to react with an allyl sulfide to form an S-ylide followed by [2,3]sigmatropic rearrangement to give the corresponding trisubstituted furan 120 in an excellent yield (Scheme 6.50) [103]. O H

+ Bz

119

SPh

[Rh(OAc)2]2 (2.5 mol%) CH2Cl2 reflux 98%

O SPh Bz 120

O Bz 121

[Rh]

Scheme 6.50

Palladium-catalyzed cyclization of a-propargyl a-keto ester 122 provided 2-alkenyl4,5-disubstituted furan 123a. High E/Z-selectivity is realized when the Me3Si- group is introduced to the a0 -position of the triple bond. The geometry of the double bond

6.2 Synthesis of Furans

j555

in 123a is almost completely inverted by reaction with a catalytic amount of diphenyl diselenide, providing 123b. (Scheme 6.51) [104]. CO2Me Pd(OAc)2/ dppf K2CO3 73%

O PMBO

BzO

O

Me

SiMe3

Me

CO2Me

THF reflux OPMB 96% Me3Si

SiMe3

122

CO2Me

PhSeSePh O Me

123a

OPMB

123b

Scheme 6.51

Ma has reported an elegant regioselective synthesis of 2,3,4-trisubstituted furan 126 using a Cu-catalyzed ring-opening cycloisomerization reaction of cyclopropenyl ketone 124 (Scheme 6.52). Notably, the regioselectivity of this reaction can be tuned using different catalysts. 2,3,5-Trisubstituted furan 125 is produced from the same starting materials with excellent regiocontrol using a Pd catalyst [105]. EtO2C

O

CO2Et Ph

Me conditions Ph

Ph 124

Me

O 125

+

CO2Et CuI (5 mol%), CH CN, reflux: 3 125 : 126 = 1 : 99, 89% PdCl2 (CH3CN)2 (5 mol%), Me O CHCl3, reflux: 125 : 126 = 99 : 1, 73% 126

Scheme 6.52

Alkylidenecyclopropyl ketones, analogs of allene ketones, have been used as a starting material in the synthesis of polysubstituted furans. Ma has given another example in which highly regiocontrolled transformation of an alkylidenecyclopropyl ketone (127), easily prepared by the regioselective cyclopropanation of an allene or the reaction of alkylidenecyclopropanyllithium with N,N-dimethyl carboxylic acid amide, into 2,3,4-trisubstituted furan 128 is realized in the presence of NaI. Interestingly, the same starting material 127 gives rise to 2,3,4,5-tetrasubstituted furan 129 if Pd (PPh3)4 or PdCl2(MeCN)2 is the catalyst (Scheme 6.53) [106].

CO2 Et Pd(PPh3) 4 (5 mol%)

Me C7H15

O 129

Me

MeCN 80°C, 12 hr 84%

O

Me

C 7H15

OEt 127

O

NaI (100 mol%) acetone reflux, 24 hr 75%

C 7H15 CO2Et O 128

Me

Scheme 6.53

Allene derivatives are important precursors in the regioselective synthesis of substituted furans. One example is the reaction of thioallenyl ketone via a 1,2migration of the thio group from an sp2 carbon atom in allenyl sulfide 130 catalyzed

j 6 Five-Membered Heterocycles: Furan

556

by CuI to afford trisubstituted furan 131 in high yield (Scheme 6.54) [107]. Propargyl sulfides led to similar results. If thiopropargyl aldehydes are used as starting materials, 2,3-disubstituted furans are obtained. This route therefore provides a simple entry for the preparation of disubstituted and trisubstituted furans. Similarly, reaction of propargylic dithioacetals with an organocopper reagent followed by treatment with an aldehyde and then with acid also furnishes 2,3,5trisubstituted furans, in moderate to good yields [108]. Bu

H

O PhS MOMO(CH2)3 130

CuI (5 mol%) 36 hr 82%

PhS Bu

(CH2)3OMOM

O 131

Scheme 6.54

Isomerization of a-allenylcyclopentenone 132, obtained from propargyl ether and morpholino unsaturated amide, in the presence of Hg-catalyst gives furylcyclopentenone 133, therefore providing another example of the conversion of allenyl ketones into furans (Scheme 6.55) [109]. Me

Ph

HO

Ph

Hg(O2CCF3 )2 TFA

Me

CH2Cl 2 71%

O

O

O

133

132 Scheme 6.55

Gevorgyan has reported a regio and divergent synthesis of halofuran 135 via 1,2halogen migration of haloallenyl aldehyde 134 catalyzed by AuCl3 (Scheme 6.56) [110]. The procedure furnished 3-halofurans, some of which are otherwise difficult to access.

Br

H

C7H15

CHO 134

AuCl3 (2 mol%) PhMe 73%

Br C7H15

Me O 135

Scheme 6.56

Reaction of aryl or alkyl-1-enyl halides with allenyl ketone 136 in the presence of Pd-catalyst followed by cyclization affords substituted furans with aryl or alk-1-enyl as substituent at the 3-position. This reaction is a new route to 3-substituted furan 137 (Scheme 6.57) [111].

6.2 Synthesis of Furans

C12H25 H

PhI Pd(PPh 3)4 (5 mol %) Ag2 CO3 (10 mol%)

H 136 O

Et 3N-PhMe 100°C 75%

Me

Ph C12H25

O 137

Me

Scheme 6.57

6.2.5 Tetrasubstituted Furans

Many procedures discussed above are also suitable for the synthesis of tetrasubstituted furans if there are substituents at appropriate positions in the starting materials. However, some special methodologies have also been developed solely for the synthesis of tetrasubstituted furans. Liu has shown that cyclization of 2-(1-alkynyl)-2-alken-1-one 117 in the presence of a nucleophile affords fully substituted furan 138 in high regioselectivity and a good yield if I2 and K3PO4 are also used. This reaction provides a mild, efficient route to 3iodofurans. The reaction might be initiated by the formation of iodonium through coordination of the triple bond to an iodine cation, followed by cyclization and, finally, a nucleophilic attack (Scheme 6.58) [102].

O

Ph

Ph

+ MeOH 117

I2 (110 mol%) K 3PO 4 (110 mol%) CH2 Cl2 30 min 94%

O

138

I OMe

Scheme 6.58

Ruthenium- and platinum-catalyzed sequential reaction of propargylic alcohols (e.g., 139) and cyclohexanone affords tri- and tetrasubstituted furans such as 140 (Scheme 6.59) [112]. In this reaction, two different kinds of catalysts sequentially promote each catalytic cycle in the same medium and give the products in high regioselectivity and good yields.

O Ph OH 139

+

Scheme 6.59

Cp*RuCl(µ2-SMe)2RuCp*Cl (10 mol%) PtCl2 (20 mol%) NH4BF4 (20 mol%) reflux, 36 h (Cp* = η5-C5Me5) 75%

Ph Me

O 140

j557

j 6 Five-Membered Heterocycles: Furan

558

Another example of the regioselective synthesis of substituted furan 142 from the reaction of allenyl ketone 141 with organic halides initiated by Pd-catalyzed nucleophilic attack of the aryl group to allene followed by cyclization reaction has been reported (Scheme 6.60) [113]. This methodology shows a high substituent-loading capacity and functional group tolerance, as well as generality and versatility. If one of the substituents of the allenyl ketones is H, 2,3,4- and 2,3,5-trisubstituted furans can also be generated.

n-H11 C5

Bu

• 141

PhI (2 equiv) Pd(PPh3) 4 (5 mol %) K2CO3 (2 equiv)

O

Me

Ph

TBAB (0.2 equiv) DMA 100°C 72%

n-C5H11

Bu O 142

Me

Scheme 6.60

Gold-catalyzed reactions of propargyl vinyl ether 143 furnish tetrasubstituted furan 145 in high yield. The reaction proceeds through cyclization of the 2-allenyl-1,3-dicarbonyl intermediate 144 produced from a propargyl-Claisen rearrangement (Scheme 6.61) [114]. Me O

O OEt

143

Me

(PPh3)AuCl/AgBF4 (2 mol%) CH2Cl 2 95%

Me

O

O

OEt Me 144

Me Me

O

O 145

OEt Me

Scheme 6.61

Palladium-mediated sequential cross-coupling Sonogashira reaction–Wacker-type heteroannulation and deprotection reactions of pyridones, alkynes and organic halides furnish substituted furo[2,3-b]pyridones (e.g., 146) in a one-pot operation (Scheme 6.62) [115]. The coupling products of pyridones and alkynes can be separated and a single palladium catalyst intervenes in three different transformations. A palladium-catalyzed three-component cyclization–coupling reaction of acetoacetate, propargyl bromide or carbonate and aryl halides gives tetrasubstituted furan 147 in high regioselectivity and a good yield (Scheme 6.63) [116]. Several examples concerning the synthesis of tetrasubstituted furans utilizing acetylenecarboxylate, aldehydes and nitrile or isonitrile have been reported. One such example is a one-pot reaction, affording tetrahydrofuro[2,3-c]pyridine 148 in high yield (Scheme 6.64) [117]. Scheme 6.65 shows a further example, in which the reaction is carried out in an ionic liquid under mild conditions, leading to tetrasubstituted furan 149 in high

6.2 Synthesis of Furans

I N Me

CO2Me

MeO2C

OBn

PdCl2(PPh3)2 (4 mol%)

+

CuI (4 mol%) Et3N-MeCN 60°C, 24 hr 63%

O

O

OBn

N Me

O

Ph

PhI N Me

CO2Me

O 146

Scheme 6.62

PhI Pd(PPh3)4 K2CO3

OCO2Me

O CO2Me +

Me

DMF 100°C 50%

Me Ph

CO2Me Ph Me

O 147

CO2Me

+ O

99 : 1

Me

Scheme 6.63

Bn

CO2 Et

+

N H

Ph

O N

NC

PhMe reflux 82%

O

CO2Et

C6H 13CHO NH4Cl Bn

N

O

N

O

C6H13 148

Scheme 6.64

NC

+

CHO MeO2C

CO2Me

[bmim]BF4 0.5 hr 85%

MeO2C

CO2Me O

149

N H

Scheme 6.65

yield [118]. A similar reaction employing 2-furyl-2-oxoacetamides instead of aldehydes in the preparation of substituted furylfurans was also recorded [119]. A detailed description of the synthesis of furylcyclopropane 150 from the reaction of an alkene and previously reported 2-furylcarbenoid by a metal-catalyzed cyclization of enyne ketone has been disclosed (Scheme 6.66) [120]. This protocol has been expanded by the same authors to the synthesis of furylcyclopropane-containing

j559

j 6 Five-Membered Heterocycles: Furan

560

Ph

Ph

O

+

Ph

Cr(CO)5•THF (5 mol%)

O

THF 14 hr 85%

Ph

150

Scheme 6.66

polymers as well as furfurylidene-containing polymers when phenyl enyne ketones with a vinyl and formyl group at the ortho position of the benzene ring are employed [120]. Cycloisomerization of acyloxy-, phosphatyloxy- and sulfonyloxy-substituted alkynylketones gives tri- and tetrasubstituted furans (e.g., 151) with good regioselectivities; the allene intermediates are produced in situ via migration of the substituents, catalyzed by CuCl or AgBF4 (Scheme 6.67) [121]. AcO

AcO

AgBF4 (5 mol%) CH2Cl2 86%

O

O

151

Scheme 6.67

N-Heterocyclic carbenes (NHC) have found use as reagents in the synthesis of polysubstituted aminofurans. Multicomponent reaction of an imidazolinium salt with an aldehyde and an acetylenecarboxylate in the presence of NaH leads to tetrasubstituted furan 152 in a good yield (Scheme 6.68). A plausible reaction mechanism has been proposed [122]. A similar procedure for the synthesis of tetrasubstituted 3-aminofurans, using a thiazolium salt, aldehydes and acetylenedicarboxylate, has also been reported [123]. CHO

Ph

+ CF3

+ CO2Me

tBu N+ Cl – N tBu

MeO 2C

NaH PhMe 90°C 58%

Ph O

F3C

152

N tBu

NHt Bu

Scheme 6.68

6.3 Reactivity

This section primarily deals with the reactivity of furans that results in an overall transformation of the ring. Reactions of furans, particularly reactions of C-metallated

6.3 Reactivity

furans, that lead to substituted furan derivatives have been discussed in Section 6.2.1. Most examples in this section are extracted from recent literature so as to document the progress made in each reaction category [4]. 6.3.1 Reactions with Electrophilic Reagents

Furans are reactive p-nucleophiles. Nucleophilic additions of furans to electrophiles, from either the 2-position or 3-position, often involve regeneration of the furan ring from the oxonium ion intermediate by loss of a proton, as shown, for example, in Scheme 6.7, Section 6.1.2. An interesting example of direct hydrolytic cleavage that occurs subsequent to furan addition to an N-acyliminium ion is shown in Scheme 6.69. The initially formed oxonium ion likely undergoes a 1,5-proton shift to generate an intermediate that is then hydrolyzed to the dicarbonyl compound 153 [124]. Me

OH N

n

HCO2H C6H12

Me

O

r.t., 30 min n =1, 75% n = 2, 64%

O

Me O O

O n

N

n

O

N O

153

Scheme 6.69

2-Silyloxyfurans 154 are chemically equivalent to “cyclic” vinyl silyl ketene acetals, and have been employed for vinylogous additions to electrophiles under Lewis acid catalyzed conditions to provide c-butenolides 155, which are common structures present in natural products. These include vinylogous Mannich [125, 126], aldol [126] and Michael reactions. Consistent with vinylogous reactions of acyclic silyloxy dienolates, additions generally occur at the 5-position of 2-silyloxyfurans 154 (Scheme 6.70). Further synthetic manipulations of these adducts can lead to carbocycles, piperidines, sugars and azasugars. A subsequent intramolecular Michael/ hetero Michael addition to the a,b-unsaturated system of butenolide can also be exploited to form polycyclic ring structures [127]. Although the factors and the transition state structures (Diels–Alder like versus open chain) that govern the stereoselectivity have not been well-defined, anti (erythro) adducts are in general isolated as the major isomers for additions to iminium ions, except cyclic acylimiXH R1SiO

O

154 Scheme 6.70

+ X=

X H NR 3;

Lewis acid

R2

2

R

X=O

O O

155a syn-isomer

XH R2

+

O O

155b anti-isomer

j561

j 6 Five-Membered Heterocycles: Furan

562

nium ions, from which the syn-isomers are obtained preferentially. For reactions with aldehydes, syn (threo) products generally predominate. The synthetic utility of vinylogous additions using 2-siyoxyfurans (e.g. 156) is exemplified by the total synthesis of the plant alkaloid croomine (157), in which two vinylogous Mannich reactions of 2-silyloxyfuran to a pyrrolinium ion constitute the key steps for assembling the carbon framework (Scheme 6.71) [128]. Me Me iPr

3SiO

+ MeO

O

Br

156

N Boc

CO2 Me

5% TIPSOTf O

O

CH2 Cl2 0°C 32%

H

Boc

Br 4 steps

Me Me

Me

Me iPr3SiO O POCl3

O O

CO2Me

N

H

N

H H

O

O

O O

DMF 31%

CO2H

N

H

157 Scheme 6.71

Vinylogous Michael additions of 2-silyloxyfurans to 3-alkenyl-2-oxazolidinones are anti-selective, and are highly enantioselective in the presence of a BINAP-Lewis acid catalyst [129]. As illustrated in Scheme 6.72, a complementary, syn-selective, organocatalytic, enantioselective vinylogous Michael addition of 2-silyloxyfuran 158 with an a,b-unsaturated aldehyde to produce c-butenolide 159 has been achieved by using the chiral amine catalyst 160 [130]. Me Me3 SiO

O

Me

+

Me 158 O

O

160 (20 mol%) H2 O-CH2Cl 2 –40°C syn : anti = 24 : 1 92% ee 73%

O Me

Me Me 159

O O Ph

N N H

160

Me Me Me Me

Scheme 6.72

As shown in the example in Scheme 6.73, 2-trimethylsilyloxyfuran (161) also reacts with Morita–Baylis–Hillman acetate 162 to provide the interesting c-butenolide 163. These triphenylphosphine-catalyzed substitutions proceed regio- and diastereoselectively. However, the reaction mechanism (vinylogous Michael versus Diels–Alder) has not been elucidated [131].

6.3 Reactivity

O O Me3 SiO

O

OAc

PPh3 (20 mol%)

+ MeO

161

Ph

162

THF 25°C >95:5 d.r. 84%

O

O H

H

MeO

163

Ph

Scheme 6.73

Similar to 2-silyloxyfuran, the relatively unexplored 3-silyloxyfuran also participates in an aldol addition manner with aldehydes under Lewis acidic conditions. High syndiastereoselectivity is obtained with bulky a-branched aldehydes [132]. In addition, 2-methoxy, 2-aryloxy and 2-phenylthiofurans also serve as nucleophiles [133]. The nucleophilicity of furans can be modulated by complexation to transition metals. When furan is dihapto-coordinated to a rhenium p-base, the nucleophilicity of the uncoordinated C3-position is enhanced. In this manner, furan acts as an enol ether [134]. 6.3.2 Reactions with Nucleophilic Reagents

Electron-deficient furans, for example 2-nitrofuran (9), can undergo nucleophilic substitutions. Various Grignard reagents react with 9 in a Michael addition fashion, providing predominantly trans-2,3-disubstituted 2,3-dihydrofurans such as 164 (Scheme 6.74) [135].

OMe O 9

NO2

+

ClMg OMe

THF 78 to 0°C trans : cis = 12 : 1 65%

O 164

NO2

Scheme 6.74

The chiral Fischer-type furan carbene complex 165 (Scheme 6.75) participates in 1,4-addition with organolithium reagents in a regioselective and diastereoselective manner. Consecutive oxidative decomplexation and reductive cleavage of the chiral auxiliary provides 2,3-dihydrofuran 166, which contains a quaternary C3 center [136]. 6.3.3 Reactions with Oxidizing Reagents

Furans are valuable precursors to 1,4-dicarbonyl compounds, which are not directly accessible from the reactions between electrophiles and nucleophiles, such as those employed for the synthesis of 1,3- and 1,5-dicarbonyl compounds. Furans are

j563

j 6 Five-Membered Heterocycles: Furan

564

Me

Me

1. PhLi Et2O –80°C

Me O (OC)5Cr

Me O

(OC)4Cr Me 2. MeOTf –80°C to r.t. 84 : 16 d.r. Ph 78%

O 165

HO

3 steps Me

78% ee Me 90%

Ph

O

Me O 166

Scheme 6.75

hydrolytically cleaved to saturated 1,4-dicarbonyl compounds under reflux in strongly acidic conditions (Section 6.3.5). The 1,4-dicarbonyl moiety can also be revealed by oxidation of furans using various oxidizing reagents [4, 137]. 2,5-Dialkoxy-2,5-dihydrofurans formed from the oxidation of furans in a methanolic solution of bromine (e.g., Scheme 6.12, Section 6.1.2) can be hydrolyzed to cisa,b-unsaturated-1,4-dicarbonyls. Oxidation of 2-substituted or 2,5-disubstituted furans to cis-a,b-unsaturated-1,4-dicarbonyls 167 can be performed using m-CPBA, PCC or NBS [4, 137], magnesium monoperoxyphthalate (MMPP) [138], dimethyldioxirane [139], methyltrioxorhenium/urea hydrogen peroxide [140] and buffered sodium chlorite [141] (Scheme 6.76). The corresponding trans isomers 168 are obtained by in situ isomerization, especially in the presence of an amine base, or directly by Mo(CO)6-catalyzed oxidation using cumyl hydroperoxide [142]. Furans also serve as surrogates to carboxylic acids, which are obtained by oxidative disassembly of the aromatic ring using ruthenium tetroxide [143].

R1

R2

O

oxidation

R2 = H RuO4

R

R2 = H oxidation

O R1

1

OH

R1

O O

O O

R

2

R2

O 168

167

OH

O

isomerization R1

R1 HO

O

O

2

R =H oxidation O

R1

OH O

Scheme 6.76

The 1,4-dicarbonyl compounds are useful precursors towards the syntheses of cyclopentenones and cyclopentanones [137]. Interception of the transient oxonium ion during oxidation of furans (e.g., by NBS) by pendant nucleophiles leads to interesting spiro ring systems [144]. Scheme 6.77 depicts an application of furan oxidation in the total synthesis of the indolizidine alkaloid monomorine (169) [145]. Regioselective oxidation of unsymmetrical 3-substituted furan 170 to butenolide 172 has been accomplished by using alcoholic bromine or NBS and controlling the acid-catalyzed hydrolysis of the 2,5-dialkoxy intermediate 171 in acetone–water mixture [146] (Scheme 6.78).

6.3 Reactivity

Me

MMPP

O Bu

NHCbz

Me

EtOH H2O r.t., 3 hr 61%

O

H

H2 10% Pd/C

N

Bu MeOH r.t. 45%

O

NHCbz

Bu Me 169

Scheme 6.77

NBS BnO NaHCO3

OBn O 170

catalytic HCl

EtOH CHCl3 r.t.

EtO

OBn

OEt H 2O Acetone r.t. 78%

O 171

O

O 172

Scheme 6.78

Alternatively, regioselectivity can be controlled by the incorporation of a silyl group in the furan ring (Scheme 6.79), producing 173 in a regiospecific manner [147]. tBuMe SiO 2

O O

Me3 Si

Me

Me

t 32% MeCO3H BuMe2SiO NaOAc

CH2Cl 2 0°C to r.t., 10 hr 70%

O

O

O O

O

Me

Me

173

Scheme 6.79

Photooxidations of furans by singlet oxygen, sensitized by, for example, methylene blue, Rose Bengal or tetraphenylporphyrin, generate endoperoxides [148] (e.g., 174, Scheme 6.80) via a Diels–Alder cycloaddition. Intermediate 174 is prone to Baeyer–Villiger type rearrangement to provide carboxylate 175 (R including silyl).

O2, hv photosensitizer

R

O

O R

O

O

O

MeOH

H

O

174

R O 177

Scheme 6.80

O

O Me H HOO

H

R

OMe

organic base

reduction

O

O O

OR 175 R

O

H

OH 176 R

O O

dehydration O

178 R

O

179 OMe

j565

j 6 Five-Membered Heterocycles: Furan

566

Deprotonation at the bridgehead carbon of 174 by an organic base provides hydroxybutenolide 176. This provides a useful method for the regioselective oxidation of unsymmetrical 3-substituted furans by using a hindered base (e.g., i-Pr2NEt) [149]. Reaction of 174 with an alcohol (MeOH is often used as a solvent) at higher temperature forms hydroperoxide 177 regio and stereoselectively due to a hydrogen bonding assisted front side attack of the alcohol on the most stabilized carbocation. Reduction of hydroperoxide 177 and subsequent eliminative ring opening provides 1,4-dicarbonyl compound 178, while dehydration of 177 gives butenolide 179. Photooxidations of furans have the benefit of being performed selectively in the presence of alkenes. Scheme 6.81 shows a novel example of taking advantage of the singlet-oxygen photooxidation of furan in the presence of two trisubstituted alkenes in the side chain (R group) during the total synthesis of litseaverticillols 180 [150]. The unusual regio and diastereochemistry obtained from the methylene blue (MB) sensitized oxidation in MeOH is, presumably, the result of a backside attack of MeOH on the intermediate endoperoxide.

O

O2 hv MB

R Me

MeO

MeOH 0°C

H

O

OOH R

Me2S

Me

CHCl3 25°C

OH

O Me

iPr NEt 2

R O

CHCl3 25°C

R = geranyl or neryl

H

Me

R O 180

Scheme 6.81

Oxidation of furfuryl alcohols under similar conditions leads to ring expansion to form dihydropyranones. These Achmatowicz oxidations are often accomplished by using buffered NBS, VO(acac)2/t-BuOH and singlet oxygen. Dimethyldioxirane [139] and methyltrioxorhenium/urea hydrogen peroxide [140] are also effective oxidants. The corresponding aza-Achmatowicz oxidation of furfurylamines [151], frequently by NBS or m-CPBA, provides a novel method for the synthesis of azasugars and piperidine-containing compounds [152]. An interesting example of simultaneously applying both reaction variants in the synthesis of aza-C-linked disaccharide, such as 182 from 181, is shown in Scheme 6.82 [153].

O Tol

O S O

NH OH 181

Scheme 6.82

1. NBS NaOAc THF H2O 2. (MeO)3CH BF3•Et2O CH2Cl2 33%

O

O NTs O

OMe

182

OMe

6.3 Reactivity

j567

A novel route for the construction of the daphnane BC-ring in the quest for resiniferatoxin (Scheme 6.83) employed furan 183 in an Achmatowicz rearrangement via, presumably, oxidopyrylium ion 184, which participates in an intramolecular [5 þ 2] cycloaddition to provide dihydropyranone 185 [154, 155].

OAc

Me

1. m-CPBA THF 0°C 2. Ac 2O DMAP C5 H5N 96%

OBn

OH O

3. DBU MeCN 80°C 84%

183 OSi

tBuMe

OAc Me O

OAc

O

OBn

O

O 184

2

Me

185

OSi tBuMe2

H

OBn

OSi t BuMe2

Scheme 6.83

The furan nucleus can be oxidized electrochemically, and the radical cations generated at the anode can be trapped by the reaction medium, for example, methanol, to give 2,5-dioxygenated-2,5-dihydrofurans. Intramolecular electrochemical annulation of furans provides an interesting avenue for the synthesis of polycyclic ring systems. Anodic oxidation of furans that contain pendant vinylsulfide, methyl or silyl enol ethers generates radical cation intermediates that cyclize to form six- and seven-membered rings [156]. Scheme 6.84 shows a recent example of the construction of the complex tetracyclic core 186 of guanacastepenes, obtained as a single diastereoisomer, by such an electron transfer reaction [157]. A gem-dialkyl effect has been identified as essential for the efficient formation of a seven-membered ring in this type of reaction [89, 158]. Me Me2tBuSiO Me2tBuSiO

Me Me Me O

Me

Me RVC anode (0.2 mA) 2,6-lutidine t 0.06 M LiClO4 Me2 BuSiO

20% MeOH CH2 Cl2 2.44 F/mol r.t., 17 hr t OSi BuPh 2 70%

Me H

Me

O H O 186 OMe

OSi tBuPh2

Scheme 6.84

6.3.4 Reactions with Reducing Reagents

Furans are reduced by catalytic hydrogenation (Pd/C, Raney Ni and Rh), dissolving metals (Birch reduction) and alkylsilanes to dihydrofurans and tetrahydrofur-

j 6 Five-Membered Heterocycles: Furan

568

ans [159]. 2,5-cis-Reduction products 187a and 187b are obtained from 2,5-disubstituted furans, an example that is essential in the total synthesis of tetranactin (Scheme 6.85) [160]. OH OH MeO2C

O Me

Me

H2 (3 atm) 5 % Rh Al2O3 MeOH r.t., 1.5 hr

MeO2C

H Me

O

H

Me + 187a OH

MeO2C

H Me

OH Me 187b

Scheme 6.85

In the stereoselective reduction of electron-deficient chiral furoic amides (Scheme 6.16, Section 6.1.2), under Birch-type reductive alkylation to form dihydrofuran derivatives, methyl and trimethylsilyl substituents at the 3-position of the furan moiety are essential for achieving high diastereoselectivity in the alkylation step, presumably by controlling the enolate geometry [161]. 6.3.5 Reactions with Acids or Bases

Rearrangement of furfuryl alcohols in aqueous acidic medium at pH 4.0–6.0 is a useful reaction for the preparation of hydroxycyclopentenones on a preparative scale (Scheme 6.86). 5-Unsubstituted and 5-methylfurfuryl alcohols having a range of R groups are generally good substrates for this type of reaction. 5-Nitrofurfuryl alcohol, however, does not undergo the rearrangement [137]. As illustrated in Scheme 6.86, this kind of rearrangement provides trans-4-hydroxy-5-substituted 2-cyclopentenones, which can isomerize to 2-substituted 2-cyclopentenones 188 under mild basic conditions, for example, using alumina and phosphate buffer pH 7.9 [137], as well as amine bases [162]. When R is phenyl or 2-thienyl, a reaction in refluxing water without the use of any acid leads directly to isomer 188 [163]. O R O

OH

acid pH 4-6 H2 O heat

R OH

O

mild basic conditions

R HO

188

Scheme 6.86

A 2-acylfuran derivative reacts with aqueous ammonia to give 3-hydroxypyridine 189 (Scheme 6.87). An initial attack of ammonia at the C5-position of the furan followed by a subsequent ring opening/ring closing sequence has been proposed as the reaction mechanism [164].

6.3 Reactivity

N Me

O

OH

aq. NH3 Me

Sealed tube 150°C 31%

O

N 189

N

Scheme 6.87

6.3.6 Reactions of C-Metallated Furans

C-Metallated furans are primarily used for the synthesis of substituted furans (Section 6.2.1). 2-Furylcuprate 190, as shown in Scheme 6.88, was recently discovered to undergo a 1,2-metalate rearrangement to form 191 [165]. A similar dyotropic rearrangement of 2-furylzirconocene complexes has also been reported [166].

O

1. t-BuLi THF –78°C

Bu

2. Bu2CuLi Et2O-Me2 S –78 to 0°C

Bu Cu Bu Li2

O

Bu

O Bu Cu Li2 Bu

190

O

Bu H O 2 68% Bu overall

Bu

191

Scheme 6.88

6.3.7 Reactions with Radical Reagents

Furans react with radical reagents at the a-positions. For example, an acetyl radical, generated from a xanthate, reacts with 2-acetylfuran to provide the a-substituted product [167]. As illustrated in Scheme 6.89, addition of the alkenyl radical generated from the cyclohexenyl bromide 192 to the pendant furan moiety gives the spirodihydrofuran radical intermediate 193. Radical fragmentation in 193 then provides a cyclohexyl radical, leading to unsaturated ketone 194 [168]. Similar methodology has been examined in the synthesis of polycyclic ring system [169].

TBSO

O Br 192

Scheme 6.89

Me Bu3SnH AIBN PhMe reflux, 14 hr 34%

OTBS O

OTBS Me

O Me

193

194

j569

j 6 Five-Membered Heterocycles: Furan

570

6.3.8 Electrocyclic Reactions

There is a large volume of literature on both inter- and intramolecular Diels–Alder reactions of furans with dienophiles, for example, alkenes, alkynes, allenes and benzynes, under thermal, Lewis acid promoted or high-pressure conditions. These [4 þ 2] cycloadditions, which form six-membered rings, have been applied to the total synthesis of natural products, and are well documented and reviewed [4, 170]. Diels–Alder reaction of furans often requires elevated reaction temperature, as furans are generally poor dienes, unless the dienophiles are reactive or Lewis acids are used. However, structural elements can be incorporated into the starting materials such that these cycloadditions proceed at or below ambient temperature. For example, the cycloaddition of 195 which has an unactivated double bond, occurs at room temperature to furnish 196 (Scheme 6.90). This reaction is a consequence of 195 being populated in a reactive conformation imparted by the amide carbonyl of the tether [171]. Me

SMe N

SMe

O

Me r.t., 12 hr

O

O

195

O

N 196

Scheme 6.90

Examples of transannular Diels–Alder reactions of furanophanes are very rare. In such an approach, macrocyclic conformational control can offer high diastereoselectivity, as demonstrated in the synthesis of the chatancin core 198 from 197 (Scheme 6.91) [172]. Me i

Pr

Me

Me

O

HO CO2Me 197

H2O DMSO (1:2) 115°C, 72 hr 67%

O iPr

OH

CO2Me

198

Scheme 6.91

The [4 þ 3] cycloadditions of furans have been used to form seven-membered rings, which are widely present in natural products. Reactions with oxyallyl cations are the most explored [4 þ 3] cycloadditions of furans [173], although reactions with oxyallyl equivalents, for example, silyloxyacroleins [174] and cyclopropanone hemiacetals [175], and aminoallyl cations [176], have also been reported. These cycloadditions of furans with oxyallyl cations and their equivalents are generally considered as concerted processes. However, theoretical calculations support an alternative

6.3 Reactivity

stepwise mechanism for certain examples [174, 177]. An example of employing such a reaction as the key step in the total synthesis of colchicine is shown in Scheme 6.92 [178]. Thus, coupling of the highly substituted furan 199 with the oxyallyl cation generated from silyl enol ether 200 produces the desired endo-adduct 201 as a single isomer. MeO

MeO

NHBoc

MeO

+

O

OMe 199

OTMS Me3SiOTf

MeO

OMe 200

NHBoc

MeO

EtNO2 60°C 45%

O

MeO 201

O OMe

Scheme 6.92

An enantioselective organocatalytic [4 þ 3] cycloaddition of furan using the chiral amine catalyst 160 has been realized [179]. As shown in Scheme 6.93, the endo selective [4 þ 3] cycloaddition between 3-methylfuran (11) and the nitrogen stabilized oxyallyl cation 202 derived from an allenamide can also be rendered highly enantioselective by using a 1,2-cyclohexanediamine derived C2 symmetric salen(Cu) complex as the catalyst, leading to the formation of 203 [180]. Me O O

O

O O Me

N

Me

•

O

O

+

N

H

–O

202

11

Cu(OTf) 2 (25 mol%) salen (32 mol%) AgSbF 6

O

O N

H

acetone-CH2Cl 2 4Å molecular sieves -78°C, 8-10 hr 91% yield, 99% ee

O O

Me

203

Scheme 6.93

The [6 þ 4] cycloaddition between furan and tropone, a previously unsuccessful transformation, has recently been realized in an intramolecular conversion of 204 into 205 during the assembly of the ABC-ring of ingenol (Scheme 6.94) [181]. O Me O O

Me MeOCH 2O

204 Scheme 6.94

Si tBuPh2 OSi tBuPh2

C6H 6 reflux 70%

O

MeOCH 2O

H Si tBuPh 2 OSi tBuPh2

205

j571

j 6 Five-Membered Heterocycles: Furan

572

Gold-catalyzed intramolecular cycloisomerization of furans with a pendant terminal alkyne provide phenol product 207 (Scheme 6.95) [182]. Although the reaction may be a result of a [4 þ 2] or [2 þ 2] process, a viable mechanism has not been identified. The formation of arene oxide intermediate 206, however, has been characterized experimentally [183].

Me

AuCl3 (2 mol%)

O

NTs

NTs

NTs Me

MeCN 40°C 97%

O

Me OH 207

206

Scheme 6.95

2-Vinylfurans participate in extra annular [4 þ 2] cycloadditions in which the vinyl group and the furan 2,3-p bond function as the 4p component to form tetrahydrobenzofurans [184]. 2-Butadienylfuran 208 has recently been shown to behave as an 8p-component in cycloaddition with dimethyl acetylenedicarboxylate, providing an oxygen-bridged ten-membered ring (209, Scheme 6.96) [185].

CO2Me

+ O

CO2Me

1,4-dioxane 80°C, 10 hr 84%

208

O MeO 2C

209

CO2Me

Scheme 6.96

Furans also behave as dienophiles and dipolarophiles. The 2,3-p bonds of furans react with o-quinodimethide [186] and o-benzoquinones. Scheme 6.97 shows an example of a regio- and diastereoselective cyclization involving (R)-furfuryl alcohol 211 and a masked o-benzoquinone 210, producing the ortho, endo adduct 212 [187]. The a-hydroxyl group controlled the facial selectivity of the Diels–Alder type reaction. Recent studies, however, suggest a stepwise, double Michael addition as the mechanism for this type of reaction [188].

HO OMe OMe

MeO2C

O OMe 210 Scheme 6.97

+

O

Me Me

211

O

OH MeOH 40°C, 1 hr 60% 99% de

Me

Me CO2Me

MeO MeO O

Me

212

6.3 Reactivity

Furans are less reactive dipolarophiles. However, 1,3-dipolar cycloaddition between nitrile oxides and furans to give furoisoxazolines has been developed as a novel entry to amino sugars and amino acids [189]. Recently, intramolecular cycloaddition of a furan with a carbonyl ylide dipole was also shown to proceed under microwave promoted conditions, providing the cycloadduct in modest yield [190]. The furan 2,3 p-bond also undergoes cyclopropanation with metal carbenoids. Asymmetric cyclopropanation of furan-2-carboxylate with ethyl diazoacetate to provide the exo-diastereoisomer has been achieved under copper(I)-bisoxazoline catalyzed conditions [191]. A retro-Claisen type rearrangement often accompanies cyclopropanation with diazocarbonyl compounds, leading to a 2,4-diene-1,6-dicarbonyl structural motif. Intramolecular versions are attractive methods for synthesizing [6,7]-, [6,6]-, [6,5]- and even [6,4]-fused ring systems [192]. Scheme 6.98 gives an example of a rhodium-catalyzed reaction as applied in the synthesis of guanacastepene core structure 213 [193]. Me

O CO2Et

Me Rh2 (OAc)4

N2

Ph2tBuSiO O

O Ph2tBuSiO

CH2Cl 2 r.t. 50%

O

CO2Et

H

213

Scheme 6.98

6.3.9 Photochemical Reactions

In addition to furan behaving as a 4p-component in photochemical reactions with aromatic compounds, the furan 2,3-p bond also reacts photochemically. The most synthetically interesting photochemical reaction involving furans is the Paterno–B€ uchi [2 þ 2] cycloaddition with carbonyl compounds. The oxetane products obtained are useful intermediates for the synthesis of natural products. Regio- and stereoselectivities of the reaction are determined by the conformational stability of the triplet diradical intermediate [194]. As illustrated in a study with 2-silyloxyfurans (Scheme 6.99) [195], reaction with ketones provided higher substituted products

Me

+

O

Ph

O OSi tBuMe2

R hv (>290 nm) MeCN 0°C

Me

R

Ph O

O

R

Ph

+

OSi tBuMe2

Me

O O

214 215 R = Me, 214 : 215 = 93 : 7 R = H, 214 : 215 = 60 : 40 Scheme 6.99

OSi tBuMe2

j573

j 6 Five-Membered Heterocycles: Furan

574

(e.g. 214) regioselectively, while those with aldehydes are regio-random. As usual, exo-oxetanes were produced predominantly in both examples. The [2 þ 2] photocycloaddition of furans with alkenes is also synthetically useful. A remarkable example is the pivotal intramolecular cyclization to form 216 (Scheme 6.100), as employed in the total synthesis of ginkgolide B [196]. O

O

CO2 Et

Et 3SiO

O

hv (>350 nm)

C6 H14 100%

tBu

Et 3SiO

CO2Et O tBu

216

Scheme 6.100

6.4 Oxyfurans and Aminofurans 6.4.1 Oxyfurans

Hydroxyfurans exhibit fairly low stability that is quite different from their benzenoid counterparts. This phenomenon can be explained by a careful structure investigation on 2-furanol (217), which can be treated as the enol form of 2- or 3-butenolide. Estimations of resonance energy reveal that 2-furanol is of much higher energy than the corresponding furanone structure. Therefore, 2(3H)-furanone (218) and 2(5H)furanone (219) dominate at equilibrium in the absence of additional stabilizing effect for enolization (Scheme 6.101) [197, 198]. O

OH

217

O 218

O

or

O

O

219

Scheme 6.101

Both the 2(5H)-, and 2(3H)-furanone structures widely occur in biologically active natural products. They are, in general, also called “butenolides,” as derivatives of 4hydroxybutenoic acids, and not as furan derivatives. Thus, 3-butenolide corresponds to 2(3H)-furanone (218) and 2-butenolide corresponds to 2(5H)-furanone (219) [199]. 2(5H)-Furanones are important synthetic intermediates in the construction of substituted c-butyrolactones. In addition, they also serve as useful building blocks in the syntheses of various organic compounds [200]. Several excellent reviews dealing with the synthesis of these unsaturated lactones have been published [199, 201–203]. Instead of providing a thorough literature survey, only recent advances are discussed here.

6.4 Oxyfurans and Aminofurans

Palladium-catalyzed cyclocarbonylation of propargyl alcohol is an excellent method for the construction of 2(5H)-furanones. Thus, a combination of Pd(dba)2 and dppb has been used to catalyze the transformation of 220 into 5,5-disubstituted 2(5H)furanone 221. The reaction mechanism involves the insertion of a Pd(0) species into the C
O bond of the substrate, followed by rearrangement to the allenylpalladium intermediate. Insertion of CO and subsequent reductive elimination then lead to the 2,3-dienoic acid, which then affords 221 (Scheme 6.102) [204].

OH

Pd 2(dba)3 CH3Cl3 , dppb CO (600psi), H2 (200psi)

O

CH 2Cl2 95°C, 36 hr 92%

221

220 (L)Pd

OH

OH

O

HO Pd(L) C H

+ PdL

CO

220 O C

OH

O

Pd(L)

C

H

OH Pd(0), H2, H+

O

O

H 221

Scheme 6.102

A highly functionalized 2(5H)-furanone (222) has been prepared from a triphenylphosphine-catalyzed reaction of activated carbonyl compound with dimethyl acetylenedicarboxylate (Scheme 6.103) [205]. O CO2 Me O2 N

CO2Me

+ CO2Me

MeO 2C

PPh3 (20 mol%) PhMe 70°C 94%

O2 N

MeO2C

O

O OMe

222

Scheme 6.103

Besides acyclic substrates, 2(5H)-furanones can also be synthesized from cyclobutenone precursors. Thus, when hydroxycyclobutenone 223 was subjected to reaction with a hypervalent iodine reagent, an oxidative ring enlargement took place to give 5-acetoxy-2(5H)-furanone 224 (Scheme 6.104) [206]. The presence of an a,b-unsaturated carbonyl moiety renders the 2(5H)-furanones highly reactive towards different reagents (Section 6.3).

j575

j 6 Five-Membered Heterocycles: Furan

576

OH

EtO

O

AcO

PhI(OAc)2

OEt 223

ClCH2CH2Cl r.t. 84%

O

EtO

O

OEt 224

Scheme 6.104

Attempts to synthesize simple 2(3H)-furanones usually result in a mixture containing also 2(5H)-furanones [207]. Generally, 2(3H)-furanone (218) is thermodynamically less stable than 2(5H)-furanone (219). Computational (SCF-MO) results reveal that the energy of 2(3H)-furanone (218) is of 53 kJ mol
1 higher than that of 2 (5H)-furanone (219) [198]. Experimentally, isomerization can be achieved by amine bases or at elevated temperature (Scheme 6.105) [208].

O

Et3N or O refluxing PhMe

218

O

O

219

Scheme 6.105

The reactively low stability of 2(3H)-furanones makes them susceptible to nucleophilic attack to give ring-opening products, which may be employed to construct other important heterocyclic systems [209]. As illustrated in Scheme 6.106, a hydrazide 226 is formed on treatment of furanone 225 with hydrazine hydrate. Further reaction with a mixture of NaNO2 and HCl promotes ring closure to afford 227 with a pyridazinone structure [210].

O

O 225

O

NH2NH2

O

76% 226

NHNH2

NaNO2

O O

1N HCl

N

NH O O

227

Scheme 6.106

Similar to their 2-hydroxyl isomers, 3-hydroxyfurans tend to exist in the keto form as 3(2H)-furanones [198]. As depicted in Scheme 6.107, free 3(2H)-furanone 228 can be synthesized from 3-bromofuran (51) [211]. Although the 3(2H)-furanone motif is less common than 2(5H)-furanones and 2 (3H)-furanones in bioactive naturally occurring molecules, a series of 4,5-diaryl substituted 3(2H)-furanones (229–233) have been studied as cyclooxygenase-2 inhibitors and show excellent anti-inflammatory activities [212].

6.5 Addendum

Br1. n -BuLi, hexane –78oC O

OSiMe3

2. Me3 SiOOSiMe2

O

O

O

51

228

Scheme 6.107

MeO2S

H 2NO2S Ar O

MeO 2S

MeO2S Ar

O

229

O

MeO 2S Ar

Ar O

O

230

O

O

231

Ar O

232

O

O

233

6.4.2 Aminofurans

3-Aminofuran is stable only in an inert atmosphere or in vacuo. It polymerizes rapidly upon contact with air. 2-Aminofuran is also a reactive species. However, as illustrated in Scheme 6.108, 234 is one of the exceptions, whose stability may be attributed to the presence of a conjugated electron-withdrawing group on the furan ring. When 234 is treated with a dienophile, the rearranged cycloadduct 235 is obtained in high yield [213].

O2N

O

CO2Me

H2 Pd/CaCO3

H2N

O

63% 234

CN

MeO2C

OH

CO2 Me C6H6 reflux 99%

CN NH2 235

Scheme 6.108

6.5 Addendum 6.5.1 Additional Syntheses of Furans

In the past few years, several procedures for the synthesis of substituted furans in high regioselectivity and efficiency have appeared. Amongst them, reports on the using of Au-catalysts have increased substantially. In all cases the starting materials

j577

j 6 Five-Membered Heterocycles: Furan

578

contain an alkynyl or allenyl group. Because of the exceptionally alkynophilic, but not as oxophilic, property of Au-catalysts, the Au-catalyzed reactions are oxygen-, water-, and alcohols-tolerated and thus do not need air- and moisture-free conditions. Also noteworthy is that in Au-catalyzed reactions non-classical carbocation or carbenoid intermediates are very often involved so that the selectivity of these reactions can be controlled. A few examples are shown below. Cyclization of allenones in the presence of Au(III)-porphyrin gave rise to the corresponding substituted furan in good to high yields. The catalyst can be recycled several times and its catalytic activity remained intact [Scheme 6.109, reaction (1)] [214a]. Another example of Au catalysis has been

Scheme 6.109

6.5 Addendum

reported using alkynyl cyclopropyl ketones as a starting material. Trisubstituted furans were afforded in high yields under mild conditions via a domino reaction process [Scheme 6.109, reaction (2)] [214b]. A carbonyl-ene-yne compound is also a suitable starting material in Au-catalyzed furan formation. In the presence of Aucatalyst, 2-alkynyl-1-cycloalkenecarbaldehydes were converted into trisubstituted furans via an Au-carbene intermediate [Scheme 6.109, reaction (3)] [214c]. Alkynyl cyclopropyl ketones have also been employed as starting material, as 1,4-dipoles in an Au-catalyzed [4 þ 2] annulation reaction, providing fully substituted furans in high yields [Scheme 6.109, reaction (4)] [214d]. In addition to Au-catalysis, transition metals were still used widely as efficient catalysts in the synthesis of furans with full control of regioselectivity. Employing ruthenium complexes as catalysts, trisubstituted furans have been provided through an unprecedented 1,4-shift of the sulfanyl group of allenyl sulfides in high yields. Furan products have also been afforded in a one-pot reaction from a-diazocarbonyls and propargyl sulfide using both Rh- and Ru-complexes or only Ru-complexes as catalysts [Scheme 6.110, reaction (1)] [215a]. The second reaction in Scheme 6.110 provides another example of furan synthesis using metal catalysts. In the presence of In(OTf)3, terminal disubstituted allenyl ketones were smoothly converted into

Scheme 6.110

j579

j 6 Five-Membered Heterocycles: Furan

580

tri- and tetra-substituted furans in high yields. The 1,2-shift of the terminal alkyl group was a key step in this reaction [215b]. In addition to In salt, some other Lewis acids, such as Sn(OTf)2, AgOTf, and [Au(PPh3)]OTf, could also be used in similar reactions. Control of regioselectivity in the synthesis of multi-substituted furans has been realized by using Cu-catalyst in the reaction of bis-propargylic ester via Cucarbene intermediate [Scheme 6.110, reaction (3)]. The reaction is suitable for the preparation of tetra-substituted furans, and silane is not necessary when CuBr or CuCl is the catalyst [215c]. 1-(1-Alkynyl)-cyclopropyl ketones have proved useful as a building block in the synthesis of multi-substituted furans by using an Au-catalyst [215b,c]. They are also useful in transition-metal catalyzed furan-formation reactions. In the presence of Rh-catalyst, carbonylation takes place and thus the procedure was developed for the synthesis of tetra-substituted furans in high regioselectivity via a Rh-catalyzed carbonylation/cyclization [Scheme 6.110, reaction (4)] [215d]. A domino-reaction is a powerful strategy that has been adopted by many groups to synthesize furans. Some examples are shown below (Scheme 6.111). Thermally induced cascade cyclizations under metal-free conditions using epoxyhexene as acid scavenger provided polycyclic furans in high yields [Scheme 6.111, reaction (1)] [216a]. Another Pd-catalyzed cascade reaction using conjugated enynals as starting materials has been reported. Here, good to high yields of 2,3,4-trisubstituted furans were realized [Scheme 6.111, reaction (2)] [216b]. Tetrasubstituted furans have been obtained in the three-component Michael addition–cyclization–cross coupling reaction by using a Pd-complex as catalyst. [Scheme 6.111, reaction (3)] [216c].

Scheme 6.111

6.5 Addendum

6.5.2 Additional Reactions of Furans

Noteworthy and interesting transformations of furan nucleus that are related to the types of furan reactions as described in Section 6.3 have been reported between 2006 and 2009. The reaction of a furan tethered at the 2-position to an iminium ion gave a spiro2,5-dihydrofuran derivative as the sole diastereoisomer. This spirocyclization has been used in forming the ABC tricyclic core of manzamine A [217]. Several new catalytic asymmetric addition reactions of silyloxyfurans to electrophiles using various chiral catalysts have been developed and reviewed in detail [218]. The addition of 2-trimethylsilyloxyfuran to Morita–Baylis–Hillman acetates to form c-butenolides has been rendered enantioselective by using a chiral phosphine catalyst [219]. As exemplified in Scheme 6.112, regioselective addition of 2-methoxyfuran or 2-trimethylsilyloxyfuran to chromium(0) alkynylcarbene complexes furnished interesting dienyne and dienediyne carboxylates by proceeding through a formal vinylogous Michael intermediate [220]. 2-Methoxyfuran reacted with chiral tungsten (0) alkenylcarbene complexes in a similar fashion [221].

Scheme 6.112

Scheme 6.113 shows a reaction of 2-furaldehyde with a secondary amine nucleophile in a lanthanide-catalyzed condensation/ring-opening/electrocyclization process to provide trans-4,5-diaminocyclopenten-2-ones, presumably via a ring-opened, deprotonated Stenhouse salt [222].

Scheme 6.113

The opposite regioselectivity was obtained in the photooxidation of 3-bromofuran to bromo-c-hydroxybutenolides by using DBU and phosphaxene [223]. The regioselectivity provided by the commonly used H€ unig’s base was reversed by using n-Bu4NF in the photooxidation of unprotected furan Baylis–Hillman adducts to a-substituted c-butenolides [224].

j581

j 6 Five-Membered Heterocycles: Furan

582

2-Furanyl carbamates undergo iodine-promoted oxidative rearrangement to form 5-methoxypyrrol-2(5H)-ones, which have been used as intermediates for the synthesis of 2,4-disubstituted pyrroles [225]. Enantiomeric enriched dihydropyranones can be obtained from Achmatowicz oxidation of furfuryl alcohols under Sharpless kinetic resolution conditions. This approach was adopted in a recent total synthesis of the acetogenin pyranicin [226]. As illustrated in Scheme 6.114, a “homologous” Achmatowicz oxidation of 2,5-disubstituted, 2-(b-hydroxyalkyl)furans by singlet oxygen produced 3-keto-tetrahydrofurans, presumably via a Michael addition to an intermediate 1,4-enedione [227].

Scheme 6.114

As depicted in Scheme 6.115, electrochemical oxidation of furans tethered to silyl enol ethers at the 2-position leads to a spiroannulation product as a result of the higher nucleophilicity of the furan 2-position [228].

Scheme 6.115

An enantioselective hydrogenation has been developed in which 2-substituted furans using chiral iridium/pyridine-phosphinite complexes as catalysts provide tetrahydrofurans with ee up to 93% [229]. Another interesting example is the Rh/ butiphane-catalyzed enantioselective cis-hydrogenation of a furylnucleoside to form the reduced product with 72% ee [230]. The presence of a halogen or methoxy substituent at the 2-position of furan enhances the rate of intramolecular Diels
Alder reactions and the yield of cycloadduct. This phenomenon is attributed to the decreased activation energy and a greater stabilization of the cycloadduct imparted by the substitution as determined by CBSQB3 calculations. The same substitution at the 3-position can also provide a similar effect although to a lesser extent than that of the 2-position [231]. In the example shown in Scheme 6.116, the Diels
Alder reaction occurred mainly at the 3-chloro-

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Scheme 6.116

furan ring, which suggests a dominant effect of a 3-halo substituent on intermolecular cycloaddition [232]. The [4 þ 3] cycloaddition of furans with epoxy enol silane derived oxyallyl cations (Scheme 6.117) has been rendered a viable process by optimization of the reaction conditions and use of a bulky triethylsilyl group [233]. Dioxines were used as oxyallyl cation equivalents in a Au/Ag-catalyzed [4 þ 3] cycloaddition with furan [234].

Scheme 6.117

A novel Nazarov cyclization of silyloxyfuran as catalyzed by a strong Lewis acidic iridium complex (Scheme 6.118) was the pivotal step in a total synthesis of the sesquiterpene merrilactone A [235].

Scheme 6.118

Besides reacting with rhodium carbenoids, furans also react regioselectively with ruthenium and platinum carbenoids derived from tertiary propargyl carboxylates [236] and sec-O-propargyl thiocarbamates [237], leading to interesting triene systems.

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as, M. (2005) Angewandte Chemie, International Edition, 44, 6583–6585. Li, S.-W. and Batey, R.A. (2007) Chemical Communications, 3759–3761. Aquino, M., Bruno, I., Riccio, R. and Gomez-Paloma, L. (2006) Organic Letters, 8, 4831–4834. Patril, S.N. and Liu, F. (2007) The Journal of Organic Chemistry, 72, 6305–6308. Kiren, S., Hong, X., Leverett, C.A. and Padwa, A. (2009) Organic Letters, 11, 1233–1235. Griggs, N.D. and Phillips, A.J. (2008) Organic Letters, 10, 4955–4957. Tofi, M., Koltsida, K. and Vassilikogiannakis, G. (2009) Organic Letters, 11, 313–316. Sperry, J.B., Ghiviriga, I. and Wright, D.L. (2006) Chemical Communications, 194–196.

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229 Kaiser, S., Smidt, S.P. and Pfaltz, A.

230

231

232

233

(2006) Angewandte Chemie, International Edition, 45, 5194–5197. Feiertag, P., Albert, M., Nettekoven, U. and Spindler, F. (2006) Organic Letters, 8, 4133–4135. Pieniazek, S.N. and Houk, K.N. (2006) Angewandte Chemie, International Edition, 45, 1442–1445; Padwa, A., Crawford, K.R., Straub, C.S., Pieniazek, S.N. and Houk, K.N. (2006) The Journal of Organic Chemistry, 71, 5432–5439. Ram, R.N. and Kumar, N. (2008) Tetrahedron Letters, 49, 799–802;232.Ram, R.N. and Kumar, N. (2008) Tetrahedron, 64, 10267–10271. Chung, W.K., Lam, S.K., Lo, B., Liu, L.L., Wong, W.-T. and Chiu, P. (2009) Journal of

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the American Chemistry Society, 130, 4556–4557. Harmata, M. and Huang C. (2009) Tetrahedron Letters, 50, 5701–5703. He, W., Huang, J., Sun, X. and Frontier, A.J. (2007) Journal of the American Chemistry Society, 129, 498–499; He, W., Huang, J., Sun, X. and Frontier, A.J. (2008) Journal of the American Chemistry Society, 130, 300–308. Miki, K., Fujita, M., Uemura, S. and Ohe, K. (2006) Organic Letters, 8, 1741–1743; Miki, K., Senda, Y., Kowada, T. and Ohe, K. (2009) Synlett, 1937–1940. Ikeda, Y., Murai, M., Abo, T., Miki, K. and Ohe, K. (2007) Tetrahedron Letters, 48, 6651–6654.

j593

7 Five-Membered Heterocycles: Benzofuran and Related Systems Jie Wu

7.1 Introduction

Benzofuran is a very important heterocycle and broadly found in natural [1] and biologically important [2] molecules and is frequently used as a building block in materials science [3a] and in organic synthesis [3b]. Several recent mini-reviews cover the investigation of benzo[b]furans in natural products, bioactivity and synthesis [4]. Two general approaches are commonly used for the preparation of substituted benzofurans: (i) functionalization of existing benzofuran-containing precursors by introduction of new substituents [5] and (ii) the formation of a new benzofuran ring by cyclization of acyclic substrates [6–10]. The methods based on the first approach are not general. Derivatization of benzofuran via an electrophilic substitution is not easy due to poor regioselectivity and the low stability of benzofurans under strongly acidic conditions, whereas protocols involving metallation of benzofuran derivatives followed by trapping of the benzofuryl anion with electrophiles are limited to basestable benzofuran substrates and, in the case of alkylation, to primary electrophiles only. Among cyclization approaches, the classical oxidative cyclocondensation of phenol or related precursor remains the most powerful method for the construction of some naturally occurring benzofurans. Significant attention has been paid to the development of metal-catalyzed approaches aimed at cascade cyclization with substituted phenols or iodophenols under rather mild or neutral conditions [10]. In this chapter, in consideration of the limited space, we first discuss recent progress in the synthetic methods for metal-catalyzed benzofuran synthesis based on the reaction classification, and then discuss their important uses in terms of drug discovery and material science. For other synthetic methods regarding the synthesis of benzofurans, please see the references provided.

Modern Heterocyclic Chemistry, First Edition. Edited by Julio Alvarez-Builla, Juan Jose Vaquero, and José Barluenga. Ó 2011 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2011 by Wiley-VCH Verlag GmbH & Co. KGaA.

j 7 Five-Membered Heterocycles: Benzofuran and Related Systems

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5

4

6 7

3

O

2

1

-0.38 -0.01

0.47

-0.38

O

-0.23

0.54

Figure 7.1 Structure numbering and frontier electron populations of benzo[b]furan.

7.2 General Structure and Reactivity 7.2.1 Relevant Physicochemical Data, Computational Chemistry and NMR Data

Benzo[b]furan is an aromatic compound and is usually recognized as a heterocyclic analog of naphthalene. Each of the ring atoms in the benzo[b]furan rings is in the same plane and has a p-orbital perpendicular to the ring plane. Additionally, (4n+2)pelectrons are associated with each ring. The oxygen in benzo[b]furan acquires considerable positive charge since it provides two p-electrons for the aromatic sextet. Accordingly, the same amount of negative charge is displayed in the all ring carbon atoms. Figure 7.1 illustrates the frontier electron populations of the parent benzo[b]furan according to frontier orbital theory [11], and Table 7.1 shows the UV absorption bands and NMR signals of benzo[b]furan. In benzo[b]furan, the p-electron excess of C2 is lower than that of C3. Consequently,. 13 C NMR chemical shifts show that C2 (141.5 ppm) is deshielded in comparison with C3 (106.9 ppm). It is noticeable that C7 is in the upfield position compared with the other benzenoid carbons at positions 4, 5, and 6. The benzenoid protons H4 and H7 appear downfield from H5 and H6. Also noteworthy is that the long-range coupling between H3 and H7 is of considerable diagnostic value in establishing the orientation of a substituent on the benzo[b] furan ring [12b].

Table 7.1 UV and NMR data of benzo[b]furan [12].

UV (ethanol) l (nm) (e, mol
1 dm3 cm
1) 244 (4.03) 274 (3.39) 281 (3.42)

1

H NMR (acetone-d6) [d (ppm)]

H2: 7.79 H3: 6.77 H4: 7.64 H5: 7.23

H6: 7.30 H7: 7.52

13

C NMR [d (ppm)]

C2: 141.5 C3: 106.9 C4: 121.6 C5: 123.2

C6: 124.6 C7: 111.8 C3a: 127.9 C7a: 155.5

7.3 Isolation of Naturally Occurring Benzofurans

j595

7.3 Isolation of Naturally Occurring Benzofurans

Numerous biologically active benzofurans have been isolated from natural sources [1]. Table 7.2 shows some examples of naturally occurring compounds containing the benzo[b]furan skeleton. For instance, a new benzofuran dimer, 5,6,50 ,60 -tetrahydroxy[3,30 ]bibenzofuranyl2,20 -dicarboxylic acid dimethyl ester (kynapcin-24, entry 5) has been isolated from Polyozellus multiflex and shown to noncompetitively inhibit prolyl endopeptidase (PEP), with an IC50 of 1.14 mM. Kynapcin-24 is less inhibitory to other serine proteases such as chymotrypsin, trypsin and elastase [1c]. Recently, naturally occurring furocarbazole alkaloids were also identified [13]. These molecules have a broad range of useful pharmacological activities [14]. Their useful bioactivities and their interesting structural features attracted the attention of synthetic chemists and has led, over the last decade, to the development of many different synthetic strategies [13a, 15]. Table 7.2 Naturally occurring compounds containing benzo[b]furan skeleton.

Entry Compound name

Source

Biological activity

1

Ulexins C, A and D

2

Paradisin C

Ulex europaeus ssp. europaeus Grapefruit juice

3

5

Skimmianine and dictamnine Millettocalyxin C and pongol methyl ether Kynapcin-24

No inhibition of the growth [1a] of Cladosporium cucumerinum [1b] Inhibition of cytochrome P450 (CYP) 3A4 (IC50 ¼ 1.0 mM) N/A [1g]

6

Stemofurans A–K

7

Tournefolal and tournefolic acid B

4

Reference

Teclea trichocarpa Enge. (Rutaceae) Stem bark of N/A Millettia erythrocalyx Fruiting bodies of Non-competitively inhibited Polyozellus multiflex prolyl endopeptidase (PEP) (IC50 ¼ 1.14 mM) Roots of Stemona Antifungal activity against collinsae Cladosporium herbarum Stems of Anti-LDL-peroxidative activity Tournefortia sarmentosa

[1d] [1c]

[1f ] [1e]

CO2H O

O

MeO2C

OH OH O Ulexin A

O

OH

O OH

OH

Tournefolic acid B

OH

O

OH

HO HO

O

CO2Me

Kynapcin-24

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O

N H

furocarbazole

7.4 Synthesis of Benzofuran

As described above, major synthetic strategies for benzofurans include (Scheme 7.1): (i) dehydrative cyclization of a-(phenoxy)alkyl ketones [6a–6e]; (ii) dehydration of o-hydroxybenzyl ketones under acidic conditions [7a, 7b]; (iii) decarboxylation of o-acylphenoxyacetic acids or esters on treatment with a base [8a–8d]; (iv) cyclofragmentation of oxiranes, prepared in three or four steps from the corresponding o-hydroxybenzophenones [9]; and (v) palladium(II)-catalyzed cyclization of arylacetylenes [10a–10e]. R1 R2 R3

O

R6

O

R5

R4

R1 O

i

Acid

2

R1 R2

R2 R3

R6

R5

ii

1

R5

3

Base

four steps R1

iv

R2

O OH

R3

R4 (R5 = Me)

O R4

R5

R4

Acid

R3

iii

R6 O

R3 R1

R6 COOR

R2

O R6 OH

R4

(R1 = R4 = H, R6 = Ph)

4

5

Scheme 7.1

7.4.1 Transition Metal Catalyzed Benzofuran Synthesis 7.4.1.1 Synthesis of 2,3-Disubstituted Benzo[b]furans The metal-catalyzed intramolecular cyclization of aryl-substituted alkynes possessing a nucleophile in proximity to the triple bond has proven effective for the synthesis of five-membered heterocycles (Scheme 7.2) [16]; the first report describing synthetic

7.4 Synthesis of Benzofuran

X-LG

X

cat. Cu or Pd

R

R'

R LG = leaving group

X = O, S, N R, R' = alkyl, aryl, silyl alkenyl, ester, ketone

Scheme 7.2

efforts relevant to 2,3-diarylbenzo[b]furan with this approach was given by Arcadi in 1996 [17a]. The reaction of o-ethynylphenols with a wide variety of unsaturated halides or triflates RX (R¼vinyl, aryl; X¼Br, I, OTf) in the presence of a palladium catalyst gives 2-vinyl- and 2-arylbenzo[b]furans 10 in good to high yield, through an intramolecular cyclization step (Scheme 7.3). Small amounts of 2,3-disubstituted benzo[b]furans 9 are usually isolated as side products. In some cases, however, benzofurans 9 are generated in significant yield or even as the main products. The formation of 10 can be prevented by employing alternative procedures that use o-[(trimethylsilyl)ethynyl] phenyl acetates as starting building blocks. One procedure is based on the palladiumcatalyzed reaction of o-[(trimethylsilyl)ethynyl]phenyl acetates with RX in the presence of Pd(PPh3)4, Et3N and n-Bu4NF, followed by the hydrolysis of the resultant coupling derivative under basic conditions. The other procedure affords 10 through an in situ coupling/cyclization of o-[(trimethylsilyl)ethynyl]phenyl acetates with RX in the presence of Pd(PPh3)4 and KOBut. The utilization of o-alkynylphenols as the starting alkynes in the palladium-catalyzed reaction with RX leads to the formation of 2,3-disubstituted benzo[b]furans through an annulation process promoted by X Ln Ar Pd R

R'

R 10

R'

7

O

O Ar

ArPdIIXLn

base

R

R' Ar-X R 6

Scheme 7.3

Base

Pd(0) + R

R' O 8

Ar

O H

Pd Ln

R' O

9

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s-vinyl- and s-arylpalladium complexes generated in situ. The best results in this case are obtained by using KOAc and Pd(PPh3)4. In the presence of KOAc and Pd(PPh3)4, and under an atmosphere of carbon monoxide, the reaction of o-alkynylphenols with RX provides 2-vinyl- and 2-aryl-3-acylbenzo[b]furans. Later, Arcadi reported that the 5-endo-dig-iodocyclization of 2-alkynylphenols with I2 in the presence of NaHCO3 at room temperature produces 2-substituted 3iodobenzo[b]furans, which are useful synthetic intermediates for the preparation of 2,3-disubstituted benzo[b]furans via Pd-catalyzed cross-coupling reactions [17b]. More recently, Flynn and colleagues [18] have disclosed an efficient approach to synthesize 2-substituted-3-arylbenzo[b]furan by a palladium-catalyzed multicomponent sequential coupling strategy, starting from iodophenol and terminal phenyl acetylene. In this reaction, MeMgBr was used as an essential base to form the corresponding magnesium salts of phenolate. Although the method was applied successfully to one substituted iodobenzene, utilization of MeMgBr to form the magnesium salts could hamper application of this method to other substrates having functional groups such as ketone, ester or amide, thus limiting the universality required in diversity oriented synthesis (Scheme 7.4).

I

MeO

OH 11

R

MeMgCl 2 equiv, Pd(PPh3)2Cl2 (3 mol %)

+

R

12

THF, 65 οC 1.5 h under N2

MeO

13

ArI Ar I Pd

MeO

O MgCl

R

DMSO, 80 οC 16-18h

Cyclization reductive elimination Ar

MeO

Scheme 7.4

O

16 45-88%

ArI DMSO, 80 οC 16-18h CO O Ar I Pd

MeO

14

OMgCl

R

O MgCl

15

Cyclization reductive elimination O

R

Ar R

MeO

O 17 64%

7.4 Synthesis of Benzofuran

To realize a strategy of diversity oriented synthesis and branching reaction pathways Yang [19] has described the palladium/bpy-catalyzed annulation of o-alkynylphenol with various aryl halides to generate diversified 2,3-diarylbenzo[b]furans (19). In the reaction process, the presence of bpy ligand is essential for the successful transformation. This method provides an efficient synthetic pathway for the combinatorial synthesis of conformationally restricted 2,3-diarylbenzo[b]furan (Scheme 7.5). R2 Pd2(dba)3 (5 mol%) bpy (10 mol%)

R1

ArI, K2CO3 MeCN, 50οC

OH

Ar R2

R1

O 19 52-87% yield

18 Scheme 7.5

Yang [20a] has also developed a highly effective co-catalysis system (PdI2-thiourea and CBr4) for carbonylative cyclization of both electron-rich and electron-deficient ohydroxylarylacetylenes to the corresponding methyl benzo[b]furan-3-carboxylates. This was the first time using carbon tetrabromide (CBr4) as a superior oxidative agent for the turnover of palladium(0) to palladium(II) (Scheme 7.6). R'

CO2Me PdI2-thiourea

R 18

O X MeO C Pd R

O

R

CBr4, Cs2CO3, CO MeOH, 40οC

OH

R'

20 79-84% yield

R'

R O OMe

base

XPdII(CO)OMe

O

R' R O H 18 Base

R + XY, MeOH, CO O Pd(0) + R

Scheme 7.6

R'

O

O 20

OMe R'

Pd Ln O

R'

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j 7 Five-Membered Heterocycles: Benzofuran and Related Systems

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The overall process may involve attack of a carboalkoxypalladium(II) intermediate on the alkyne 18 to generate a complex, followed by nucleophilic addition of the phenolic oxide to the XPdII(CO)OR-activated alkyne to give intermediate, which went through reductive elimination to produce ester 20 and palladium(0). The palladium(0) is then oxidized to palladium(II), which re-enter the catalytic cycle. The method has been successfully applied in the solid-phase synthesis of benzo[b] furan-3-carboxylates [20e]. Further studies shows the carbonylative annulation of o-alkynylphenols mediated by PdCl2(PPh3)2 and dppp in the presence of CsOAc at 55  C in acetonitrile under a balloon pressure of CO generates functionalized benzo[b]furo[3,4-d]furan-1-ones 25 in good yields [20b]. This novel synthetic approach provides a highly efficient method for diversification of the benzofuran scaffold for combinatorial synthesis. The authors speculated that the overall process may involve attack of alcohol 21 on the PdIIXYLn to generate complex 22, followed by insertion of CO to give intermediate 23. Intramolecular nucleophilic addition of the phenolic oxide to the resulting acylpalladium complex 23 leads to formation of intermediate 24, which might undergo reductive elimination to produce the five-membered lactone 25 and palladium(0). The palladium(0) is then oxidized to palladium(II), thereby completing the cycle (Scheme 7.7).

R

O Pd XYLn + XY

R2 O 25

R1

-HY

Pd(0)

O

R1

X Ln Pd O R2 R1

R

O Ln Pd O R

21

OH

II

O R

OH R2 R1

Ln X Pd

R2

OH

O O R2 R1

24 R O H

22

CO

23 Base

Scheme 7.7

Recently, Yang [20h] further described a novel, mild method for the rapid synthesis of benzo[b]furan-3-carboxylic acids 26 directly from the substituted o-alkynyl- phenols

7.4 Synthesis of Benzofuran

j601

18 in good yields by utilizing a PdII-mediated carboxylative annulation since, from a drug discovery perspective, synthesis of benzofuran-based carboxylic acids could be more interesting because of their increased solubility in aqueous media and the potential enhancement of ionic interactions with basic residues in their association with biological receptors (Scheme 7.8). R2

O

Pd(MeCN)2Cl2, AgOTs, 2-PyPPh 2

1

R

CO, CsOAc, MeCN, 50οC, 1-2hrs

OH

R1

18

OH

O

R2

26 66-81%

Scheme 7.8

Cacchi has also described palladium catalysis in the construction of the benzo[b] furan ring from alkynes and organic halides or triflates [16m,16n]. 3-Spiro-fused benzofuran-2(3H)-ones can be conveniently synthesized starting from vinyl triflates and o-iodophenols through palladium-catalyzed chemoselective carbonylation and subsequent regioselective intramolecular Heck reaction. For example, 2-iodo-4-methylphenol reacted with trifluoromethanesulfonic acid 4-(1,1dimethylethyl)-1-cyclohexen-1-yl ester leading to 4-(1,1-dimethylethyl)-1-cyclohexene-1-carboxylic acid 2-iodo-4-methylphenyl ester. Subsequent ring closure of this intermediate furnishes spirobenzofuranone C (85% yield) [17c].

O

O

Spirobenzofuranone C

Arcadi [17d] has reported the synthesis of 2,3-disubstituted furo[3,2-b]pyridines, 2,3-disubstituted furo[2,3-b]pyridines and 2,3-disubstituted furo[2,3-c]pyridines under mild conditions via the palladium-catalyzed cross-coupling of 1-alkynes with o-iodoacetoxy- or o-iodobenzyloxypyridines, followed by electrophilic cyclization by I2 or by PdCl2 under a balloon of carbon monoxide (Scheme 7.9). R1 N

O

R2

R3

COOMe 28 31-70%

Scheme 7.9

PdCl2, CO, NaOAc K2CO3, CuCl2.H2O MeOH, RT

R1

OE

I2, NaHCO3

N R2 27

MeOH, RT R3

R1 N R2

O

I 29 57-76%

R3

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Dibenzofuran-type molecules can be formed from the reaction of o-iodophenols with silylaryl triflate in the presence of a palladium catalyst. Nucleophilic addition of o-iodophenols to benzyne (generated by treatment of silylaryl triflate with CsF) and subsequent Pd-catalyzed intramolecular arylation are involved in the reaction [21] (Scheme 7.10).

OH MeO2C

I

SiMe3

+

OTf 31

30

1. CsF (3.0 eq.) MeCN, RT

MeO2C

2. [Pd] (5 mol%) PCy3 (10 mol%), 80οC

O 32 87% yield

Scheme 7.10

Recently, Stoltz [22] has developed a method for the synthesis of electron-rich, highly substituted benzofuran and dihydrobenzofuran derivatives (50–80% yields) via an intramolecular Fujiwara-Moritani/oxidative Heck reaction (Scheme 7.11); 15 examples are demonstrated in the article. No extra functionalization step was required for palladium(II)-catalyzed oxidative carbocyclizations, which provided highly substituted benzofurans and dihydrobenzofurans by net dehydrogenation. The direct C
H bond functionalization of the aromatic ring and cyclization with unactivated olefins is involved in the oxidation process. Furthermore, the products contain quaternary carbon stereocenters that can be obtained in diastereomerically pure form.

MeO

O

Pd(OAc)2 (10 mol%) MeO Ethyl nicotinate (20 mol%)

OMe

Me OBn

33 MeO

O

OMe 35 Scheme 7.11

Benzoquinone (1.0 equiv.) NaOAc (20 mol%) 60%

O

OMe

Me OBn

34 Pd(OAc)2 (10 mol%) ethyl nicotinate MeO benzoquinone (1.0 equiv.) tAmOH:AcOH (4:1) 80-120οC, 12-24h 71%

O

OMe 36

7.4 Synthesis of Benzofuran

Ionic liquid ([BMIm]BF4) has been utilized as an effective solvent for the PdCl2-catalyzed benzofuran formation via an intramolecular Heck reaction [23]. This strategy has been applied to construct the seven-membered ring based (
)-frondosin B [24]. The palladium-catalyzed annulation of 1,3-dienes with o-iodoacetoxyflavonoids for the generation of biologically interesting dihydrofuroflavonoids was realized (Scheme 7.12). This reaction is quite general and regioselective, and a wide variety of terminal, cyclic and internal 1,3-dienes are applicable [25].

O O

AcO

O

Ph

I

+

R1

R4

R2

37

R5

R3

Pd(dba)2 (5 mol%) dppe (5 mol%) Ag2CO3 (2.0 equiv.) Dioxane-H2O (4:1)

R3 R2

38

O

O

Ph

R4 R5 39 R1 62-95% yield

Scheme 7.12

One of the key intermediates (43) towards the total synthesis of frondosin B has been synthesized by a sequential reaction from phenol 40, enyne 41, and bromide 42 in a one-pot operation (Scheme 7.13) [26]. Palladium-catalyzed intramolecular C
O bond formation between aryl halides and enolates has been employed to form 2,3disubstituted benzo[b]furans [27].

MeO

Br + OH 40

O

1. MeMgBr, THF, 0 οC 2. PdCl2(PPh3)2 (5 mol%) O

3. DMSO, 80οC 41

MeO O

Br 42

43 61% yield

Scheme 7.13

Synthesis of 3-fluoroalkylated benzo[b]furans was achieved via a palladium-catalyzed reaction of fluorine-containing internal alkynes with various 2-iodophenols in the presence of P(tBu)3 as an essential ligand [28] (Scheme 7.14).

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j 7 Five-Membered Heterocycles: Benzofuran and Related Systems

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I F3C

Cl +

CF3

Pd2(dba)3 (20 mol%) PtBu3 (80 mol%)

ο OH K2CO3, DMF, 100 C 80% 45

44

Cl

O 46

Scheme 7.14

As shown in Scheme 7.15, the optically active dihydrobenzo[b]furan-ring 48 has been constructed efficiently via a C
H insertion reaction, leading to the total synthesis of (
)-ephedradine A [29]. Ar O

H N2

N O O

Br

O O

Rh2(S-DOSP)4 (0.3 mol%)

Me

Ar H

N O

O

DCM, 63% Br

47

O Me

48

Scheme 7.15

Herndon has reported benzannulation of heterocyclic ring systems through coupling of Fischer carbene complexes and heterocycle-bridged enynes [30]. The benzofuran rings are easily annulated onto furan, thiophene and imidazole ring systems in a reaction process involving the coupling of Fischer carbene complexes with either 2-alkenyl-3-alkynyl- or 3-alkenyl-2-alkynyl-heteroaromatic systems (Scheme 7.16). R1

1.

Z

MeO

Y

2. H+

R2 49

Cr(CO)5 Me

42-89%

R1

CH3 O

Z Y 50

R2

Scheme 7.16

Arylboronic acids reacted with nitriles catalyzed by a cationic palladium complex leading to aryl ketones in moderate to good yields [31]. Based on this result, a one-step synthesis of benzofurans from phenoxyacetonitriles under the catalysis of [(bpy) Pd þ (OH)]2(–OTf)2 or [(bpy)Pd2 þ (H2O)2](–OTf)2 has been developed that shows that the cationic palladium catalyst is highly active for these addition reactions (Scheme 7.17). 2-Chloroaryl alkynes, which are generated from 1,2-dihaloarenes using known methodology, undergo the reaction conditions shown in Scheme 7.18 successfully providing benzofurans 54 in good yields [32]. While the cyclization of 2-hydroxyalk-

7.4 Synthesis of Benzofuran

OMe CN

ArB(OH)2 + MeO

O

R

j605

OMe Ar

Pd cat. CH3NO2 reflux

MeO

51

R

O 15-91% 52

Scheme 7.17

R' R

KOH (3.0 equiv) Pd2dba3 (0.5-2.0 mol%) L1 or L2 (2.0-8.0 mol%) H2O / 1,4-dioxane 100 οC, 8h

Cl 53

R

O

R'

54

O

PtBu2 Pr Pri

S

i

L1

L2

O

87% (L1)

85% (L2)

Scheme 7.18

ynyl arenes is known, this is the first time this strategy has been employed starting with a 2-haloaryl alkyne. The formation of 2-alkynyl benzofurans is described via a new tandem coupling approach [33]. This reaction utilizes easily accessible gem-dibromovinyl substrates and terminal alkynes and proceeds via Pd/C- and CuI-catalyzed tandem Ullman/ Sonogashira couplings (Scheme 7.19).

Br

MeO2C OH 55

Br

C6H13 Pd-C, CuI P(p-MeOC6H4)3 MeO2C Pr2NH / toluene

i

O

i

i

N O

83% (L1)

i

Pr

F3C n-C8H17

Pri

C6H13

56 93% yield

Scheme 7.19

An efficient synthesis of benzofurans from o-anisole-substituted ynamides has been reported by Hsung and co-workers via an unexpected Rh(I)-catalyzed demethylation-cyclization sequence (Scheme 7.20) [34]. The silver salt is critical for the successful transformation in the reaction process.

Pr

PtBu2 Pr

j 7 Five-Membered Heterocycles: Benzofuran and Related Systems

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O Ph

O

N

cat. RhCl(PPh3)3 cat. AgBF 4

O O

ΜeΟ

N

O

Ph 58 50-70% yield

57 Scheme 7.20

Trost has reported that benzofurans can be formed chemoselectively from the Rh-catalyzed cyclo-isomerization reaction of easily prepared 2-alkynylphenol substrates (e.g., 2,4-dichloro-6-ethynylphenol) [35]. The reaction may proceed by nucleophilic capture of a vinylidene intermediate (Scheme 7.21).

Cl

5% [{Rh(cod)Cl}2], 60% (4-FC6H4)3P

Cl

DMF, 85 οC 77% yield

OH Cl

O Cl

59

60

Scheme 7.21

Benzofuran products can be delivered in good yields through palladium-catalyzed intramolecular C
O bond formation of enolates derived from a-(ortho-haloaryl)substituted ketones (Scheme 7.22) [36]. A catalyst generated from Pd2(dba)3 and the ligand DPEphos effects the key bond formation to produce various substituted products from both cyclic and acyclic precursors. In the meantime, a cascade sequence that produces the required a-aryl ketones in situ has been developed. However, the substrate scope is more restricted.

R3

X

Pd2dba3, DPEphos base

O 1

R2 61

R

toluene, 100 οC

R3

O R2 50-95% 62

R1

Scheme 7.22

Li has presented a novel and selective palladium-catalyzed annulation of 2-alkynylphenols method for the synthesis of 2-substituted 3-halobenzo[b]furans [37]. In the presence of PdX2, 2-substituted benzo[b]furans were afforded in good yields, whereas in the presence of 5–10 mol% of PdX2, 3.0 equiv of CuX2 and 0.2 equiv of

7.4 Synthesis of Benzofuran

HEt3NI, 2-disubstituted 3-halobenzo[b]furans were selectively produced as the major products (Scheme 7.23). A possible mechanism was also proposed. R

X PdX2 / CuX2

OH

HEt3NX, DCE, r.t.

O

H R +

64 major 37-92% X = Cl, Br

63

R

O

65 minor 0-58%

Scheme 7.23

3-Zinciobenzofurans 66, generated in excellent yield through a metallative 5-endodig cyclization reaction of 2-alkynylphenoles in the presence of BuLi and ZnCl2, can be further transmetallated to the corresponding cuprates 67, which then react with electrophiles to produce various 2,3-disubstituted benzofurans 68 [38] (Scheme 7.24). R 1) BuLi 2) ZnCl2 OH 18

toluene reflux

Cu(CN)ZnCl

ZnCl O 66

R

CuCN/2LiCl

R

O

67

E+ E O 68-98% 68

R

Scheme 7.24

7.4.2 Oxidative Cyclization

Recently, Bellur [39] has reported an efficient synthesis of functionalized benzofurans based on a [3 þ 2] cyclization/oxidation strategy. The functionalized benzofurans were prepared by DDQ oxidation of 2-alkylidenetetrahydrofurans, which are readily available by one-pot cyclizations of 1,3-dicarbonyl dianions or 1,3-bis-silyl enol ethers (Scheme 7.25). The first total and biomimetic synthesis of violet-quinone has been accomplished by utilizing an oxidative dimerization of a substituted 4-methoxy-1-naphthol with a ZrO2/O2 system, the so-formed dimer eventually led to the target molecule (Scheme 7.26) [40]. The same research group later published the SnCl4-mediated oxidative biaryl coupling reaction to build up the dinaphthanofuran framework [41]. Silver(I) acetate is an efficient agent with which to obtain the dimer of resveratrol in

j607

j 7 Five-Membered Heterocycles: Benzofuran and Related Systems

608

Me3Si

O

OSiMe3

OMe

R1 R4 R3 69

O

Cl

O

O MeO

(iii) DDQ 1,4-dioxane R1 reflux, 24 h

(i) Me3SiOTf (0.5 equiv) R4 R2 CH2Cl2, -78-20 oC R 3 (ii) 2.0 equiv, DBU 70 THF, 20 oC 38-90% yield

R2

Me3Si

MeO

R3

OSiMe3

O

R1

R3

69

R4

R2 R3 71 53-75% yield

R3

O

R1

DDQ 1,4-dioxane

O

O

R1

TiCl4 (2 equiv) 4A MS, CH2Cl2

R2

O

O

O

R2

R1 R2 73 31-65% yield

72 28-37% yield

Scheme 7.25

OH

O

Me

ZrO2, O2 OMe OMe

OMe

O

Me

OH

Me

CHCl3, RT 96%

O

OMe OMe 2 75

74

OH O

Me

76

Scheme 7.26

high yield [42]. Oxidation of phenol with PIFA has also been applied to construct the framework of (
)-galanthamine [43]. A new family of benzo[b]furans has been synthesized by an anodic oxidation of an aqueous solution of 3-substituted catechols followed by coupling with dimedone (78) (Scheme 7.27) [44]. Me

O

Me OH

+ O

OH 77

- 4e- 4H+

78

OH

O

OH

87% O

79

Scheme 7.27

Compound 80 can be cyclized in the presence of either mercury acetate in acetic acid or bromine in chloroform to give 3-chloromercurio- or 3-bromobenzofuran,

7.4 Synthesis of Benzofuran

j609

respectively. The 3-chloromercurio intermediates could be reduced to proton or derivatized to ester or bromide, leading to the synthesis of ailanthoidol (30% yield), XH-14 (15% yield) and obovaten (11% yield), respectively [45] (Scheme 7.28).

OMe OBn HgCl 1. Hg(OAc)2/AcOH

R

2. satd NaCl (aq.), RT

OMe

OBn

O 81

80 COOMe OMe R

R

OMe

PdCl2, MgO, LiCl CO, MeOH

reduction OMe R

OBn

O

OBn

O 83

82 Scheme 7.28

5-[2-(4-Hydroxyphenyl)vinyl]benzene-1,3-diol 84 (resveratrol) was treated with an equimolar amount of silver(I) acetate in dry MeOH to afford its (E)-dehydrodimer, 5{5-[2-(3,5-dihydroxyphenyl)vinyl]-2-(4-hydroxyphenyl)-2,3-dihydrobenzofuran-3-yl} benzene-1,3-diol 85, as a racemic mixture in high yield [46] (Scheme 7.29). This method is applicable to the oxidative dimerization of 4-hydroxystilbenes such as trans-styrylphenol and 5-{6-hydroxy-2-(4-hydroxyphenyl)-4-[2-(4-hydroxyphenyl)vinyl]2,3-dihydrobenzofuran-3-yl}benzene-1,3-diol (viniferin), giving rise to the corresponding 2-(4-hydroxyphenyl)-2,3-dihydrobenzofurans.

HO

O

HO OH

AgOAc in MeOH at 50οC for 1h

84 Scheme 7.29

OH

OH HO OH 85 97% yield

OH

j 7 Five-Membered Heterocycles: Benzofuran and Related Systems

610

7.4.3 Radical Cyclization

A radical initiated benzo[b]furan formation has been applied to the synthesis of spiro [chroman-3,30 -(20 H)-benzofurans] in the presence of n-Bu3SnCl and Na(CN)BH3 [47] (Scheme 7.30).

R2 Cl

OH Br

O

O

R3 R1

+

86

R3 87

K2CO3, acetone reflux, 5–8h

R1 Br

O

R2

R3

O O 88 80-95%

R2 R1

Bu3SnCl, Na(CN)BH3 AIBN, benzene N2, reflux, 7h

O O O 89 60-75%

Scheme 7.30

A similar approach has also been demonstrated by the same group to obtain spiro [pyrimidine-6,30 -20 ,30 -tetrahydrobenzofuran]-2,4-diones [48]. On the other hand, n-Bu3GeH is reported to be an effective alternative compared with n-Bu3SnH in the synthesis of 3-substituted-2,3-dihydrobenzo[b]furans [49]. Moreover, a photoinduced fast tin-free reductive radical dehalogenation has found use for the synthesis of 2,3-dihydrobenzo[b]furans [50]. 2,3-Disubstituted benzofuran derivatives have been synthesized from o-acylphenols in two steps. The b-aryloxyacrylates prepared from the o-acylphenols react with n-Bu3SnH/AIBN and then with 5% HCl-EtOH leading to 2,3-disubstituted benzofurans [51]. A radical [3 þ 2] annulation reaction with an N-centered radical has been developed. The reaction of alkenes with N-allyl-N-chlorotosylamide yields the corresponding pyrrolidine derivatives 90 in good yields, in the presence of Et3B as a radical initiator, via an atom-transfer process [52] (Scheme 7.31). Grimshaw [53] has reported that the cyclization of 20 -bromodeoxybenzoin with Cu powder in refluxing AcNMe2 gives 2-phenylbenzofurans in 65–70% yield (Scheme 7.32).

7.4 Synthesis of Benzofuran

j611

Cl +

O

Ts

Et3B, PhH

N Cl

NTs O 90 82% yield

Scheme 7.31

CH2COPh Br

CH2COPh

Cu(0)

Cu(I)

91

Ph Cu(I) O 92 65-70% yield

Cu(0)

O

Ph

Scheme 7.32

7.4.4 Acid- and Base-Mediated Cyclization

Katritzky [54] has disclosed the preparation of 2,3-disubstituted benzofurans by reactions of o-hydroxyphenyl ketones or o-(1-hydroxy-2,2-dimethylpropyl)phenol with 1-benzotriazol-1-ylalkyl chlorides in two or three steps (Scheme 7.33). These

O R1

H

Bt

R1

BtH, SOCl2 Bt

+

R1

Cl

O

O R4

OH O R4 R2

Bt O

R2

LDA/THF R2

R3

R1

OH R4

R3 TiCl 3/Li DME

93 R3 O

R1 R4

R2

Scheme 7.33

R3

94

j 7 Five-Membered Heterocycles: Benzofuran and Related Systems

612

approaches provide a facile route to a variety of benzofurans in good overall yields and complements a previous benzotriazole-mediated preparation of benzofurans. 2-Arylbenzo[b]furan can be cyclized in a modest yield from a non -symmetrical diarylethyne, which was generated via palladium -catalyzed Sonogashira reaction of an aryl bromide and an aryl acetylene (Scheme 7.34) [55]. Other types of 2-alkyl/aryl substituted benzo[b]furans have also been obtained by the palladium-catalyzed coupling reaction of o-iodophenols (even o-iodophenols with a base-labile nitro group) with various alkynes in the presence of prolinol as base in water. This environmental friendly procedure does not need the phase transfer or water-soluble phosphine ligands and is free from the use of any organic co-solvent [56]. A similar process has also been reported with an amphiphilic polystyrene–polyethylether (PS-PEG) resin-supported palladium-phosphine complex as a catalyst in water to give the corresponding aryl-substituted alkynes in high yield under copper-free conditions [57]. In the total synthesis of pterulinic acid, the core structure of 2-substituted benzofuran was generated by the palladium-catalyzed heteroannulation of an o-iodophenol derivative with methyl 3-butynoate [58]. AcO Br

OAc 95

+

OAc

O

AcO

OAc OMe

Pd(OAc)2, CuI DIPA, 50 οC, 95%

O 96

O

97

KOH HO

MeO O O

MeOH 62% O

O 98

Scheme 7.34

Base-mediated conditions have also been applied to afford 2-arylbenzo[b]furan, employing the coupling product generated from the ultra-fine nickel-catalyzed Sonogashira reaction of iodophenols with phenylacetylenes [59]. Four 2,6-linked and 2,5-linked benzo[b]furan trimers as organic electroluminescent materials have been prepared by the base-mediated cyclization of 2-alkynylphenols [60]. In the synthesis of furoclausine A, acid-catalyzed conditions were used to produce the furo[3,2-a]carbazole framework from a ketal as depicted (Scheme 7.35) [61]. An acid-catalyzed intramolecular cyclization to form the scaffold of furoquinoline

OEt

Me O MeO

Amberlyst 15, PhCl ο

120 C, 20h, 82%

N H 99

Scheme 7.35

OEt

Me O MeO

N H 100

7.4 Synthesis of Benzofuran

alkaloids has also been achieved from 3-oxiranylquinolines [62]. Furanoeremophilane sesquiterpenes have been synthesized by acid-mediated furan ring formation from their corresponding phenolic-ketone ethers [63]. 3-Aryl-2,2-dialkyl-2,3-dihydrobenzo[b]furans have been delivered from phenols and 2-aryl-2,2-dialkylacetaldehydes in the presence of a catalytic amount of CF3SO3H [64]. A ZnCl2-mediated benzo[b]furan formation has been utilized to produce 2-carboxylate benzo[b]furans from 3-dimethylaminopropenoates [65]. Synthesis of different types of substituted benzoheterocycles under metal-free protocols have been developed. The combination of o-alkynylbenzaldehyde derivatives, iodonium ions and alkenes was demonstrated to effectively produce the corresponding benzofurans [66]. The rapid access to benzofurans with interesting di- and tri-substitution patterns and featuring the 2,3-unsubstituted ring motif has been established (Scheme 7.36). Ph

Ph

1. IPy2BF4 / HBF4 (1.1 equiv) CH2Cl2, 0 οC to r.t.

O O 101

2. Ph

O

Ph

(1.2 equiv), r.t.

O 102 36% yield

Scheme 7.36

A simple procedure for the construction of the trans-5,6-ring system existing in phenylmorphans was developed by the displacement of nitro-activated aromatic fluorine with a hydroxyl group [67] (Scheme 7.37). O2N

O2N F OH

H2N

NaH, THF

Pd-C

reflux, 97%

HCOONH4

O

NMe 103

O

90% 104

NMe 105

NMe

Scheme 7.37

Synthesis of coumestrol (108) has been achieved by sequential condensation between phenyl acetate and benzoyl chloride, followed by demethylation and cyclization (Scheme 7.38) [68]. Hellwinkel has reported 2-arylbenzofurans formation using MF/Al2O3 basesystems [69]. Saito has described a novel method for the generation of 4-acetoxy2-amino-3-arylbenzofurans from 1-aryl-2-nitroethylenes and cyclohexane-1,3diones [70]. This one-pot operation shows high efficiency (Scheme 7.39).

j613

j 7 Five-Membered Heterocycles: Benzofuran and Related Systems

614

CO2Me

2. MeO

MeO

Me O CO2Me

OMe 1. LDA, THF, -78 οC MeO

O BBr3, DCM

O MeO

Cl

106

HO

72h, 100%

OMe

O

O

O coumestrol

OMe 107

OH

108

Scheme 7.38

X X

O +

R O

Y Et3N (10 mol%), RT, 12h

Y O2N

OAc

Ac2O, Et3N, DMAP, RT, 5h 109 X

Et3N (10 mol%), RT, 12h

Y

O 110

N

NH2 O 111 23-70% yield

Ac2O, Et3N, DMAP, RT, 5h

O R

R

OH

Scheme 7.39

Wagner [71] has described the synthesis of 2-(6-hydroxy-2-methoxy-3,4-methylenedioxyphenyl)benzofuran (113, Scheme 7.40) via an acid mediated cyclization.

OH O

O O

HCl

CN 112 Scheme 7.40

O

MeO NH

+ ZnCl3

O

O

1. ZnCl2, HCl 2. H2O

HO O O MeO 113 10% yield

O

7.4 Synthesis of Benzofuran

j615

Johnson [72] has reported benzofuran formation via a organolithium-induced cyclization. Treatment of 2,2,2-trifluoroethyl phenyl ethers with 4 equivalents of an aryl or alkyl lithium reagent (R3Li) causes in almost all cases complete dehalogenation of the trifluoroethyl side chain with the concomitant introduction of an alkyl or aryl group (R3) at the acetylenic 2-position (Scheme 7.41). This is followed apparently by ortholithiation to give the lithio intermediates; the latter then spontaneously cyclize to the 2-lithioheterocyles. Subsequent electrophilic quenching leads to the corresponding benzofurans depending whether the electrophile is a proton or another electronegative species. OCH2CF3 R1 R2

R3

R3

R1

R2

114 a R1 = H b R1 = Li

R2

O

4R3Li

O

115

116

H+ or E

R2

Li

R3 O

117 30-40% yield

Scheme 7.41

Banerji [73] [Scheme 7.42 (1)] and Clerici [74] [Scheme 7.42 (2)] have reported titanium-mediated benzofuran synthesis, respectively.

R2

O Zn TiCl4

O R1

R1

O

CHO OH 120

O

(1)

119 > 90% yield

118 R

R2

2 Ti(III), H + HOAc

R

R (2)

O 121

HO

up to 95% yield Scheme 7.42

Jha has also reported a facile synthesis of 2-arylbenzo[b]furans through an unusual acid-catalyzed 1,2-elimination [75]. 2-Phenoxyalkanals react with methanol at room temperature under homo- or heterogeneous acid-catalysis conditions leading to the formation of diacetal as well as some quantities of appropriate 2-alkylbenzofurans. 2-Alkylbenzofurans can be obtained in high yields via cyclization of the 1,1dimethoxy-2-phenoxyalkanes under mild conditions over Amberlyst 15 [76]. An effective route to chiral optically active 2-substituted benzofurans directly from carboxylic acids has been reported (Scheme 7.43) [77]. This procedure, which allows

R

j 7 Five-Membered Heterocycles: Benzofuran and Related Systems

616

Ph

OCOPh

Cl

O

N

+

OH

Cl

Et3N, DCM

N N

Cl

ο

MW, 40 C, 10 min

N PhOCO

N N

OCOPh

123

122 PPh3Br OH O 124 93% yield

Et3N, DCM / PhCH3 MW, 110 οC, 60 min

Ph

Scheme 7.43

the preparation of R-alkyl-2-benzofuranmethanamines from N-protected R-amino acids without sensible racemization phenomena, proceeds in good yields under mild conditions with the help of microwave irradiation. Treatment of benzyl 2-halophenyl ethers with 3 equivalents of t-BuLi results in Li–halogen exchange and lithiation at benzylic methylene simultaneously. These dianions can be trapped with electrophiles. Their reactions with carboxylic esters afford the corresponding 2-aryl-3-hydroxy-2,3-dihydrobenzo[b]furans, which subsequently undergo acid-catalyzed or mediated dehydration to give moderate to good overall yield of various 2-aryl-3-substituted benzo[b]furans (127) (Scheme 7.44) [78].

HO

X G O

Ar

125 X = Br, I G = Me, Cl, ... Ar = Ph, 1-Np...

G

O 126

R

R Ar

G

O 35-73% 127

Ar

Scheme 7.44

Zn(OTf)2 (10 mol%) catalyzes the cyclization of propargyl alcohols with PhOH in hot toluene (100  C) without additive to give benzofuran products in good yields. Its mechanism has been elucidated. This catalytic cyclization is also applicable to the synthesis of oxazoles through the cyclization of propargyl alcohols and amides without a 1,2-nitrogen shift (Scheme 7.45) [79]. Asao has described an efficient synthesis of functionalized aromatic compounds from enynals and carbonyl compounds [80]. The reaction most probably proceeds through the reverse electron demand-type Diels–Alder reaction between the pyrylium intermediate and enol 2p-system, derived from carbonyl compounds. The scope of the reaction was extended to the synthesis of benzofused heteroaromatic compounds. For instance, benzofuran synthesis using furan derivatives 130 has been

7.4 Synthesis of Benzofuran

OH OH Zn(OTf) 2

+

Ph

MeO

Ph (10 mol%)

OMe

128

129

O

91% yield Scheme 7.45

examined. As expected, the reaction of 130 with propionaldehyde proceeded in the presence of AuBr3 or Cu(OTf)2 catalyst to give the corresponding product 131 in 58 or 67% yields, respectively. The AuBr3-catalyzed reaction of 130 with b-methoxystyrene gave 132 in 50% yield (Scheme 7.46). Ph

O +

CHO

O

CHO

130

cat. Lewis acid O AuBr3: 58% yield Cu(OTf)2: 67% yield

Ph

O OMe +

CHO

O

131

Me

Ph

cat. AuBr3 50%

Ph

Ph

O

Ph 132

130 Scheme 7.46

SanMartin has reported copper-catalyzed straightforward synthesis of benzo[b] furan derivatives in neat water [81]. This on-water methodology delivers a range of benzo[b]furans (134) in good to excellent yields starting from readily available substrates 133 (Scheme 7.47).

O

R2 CuI, TMEDA

1

R

133 O

Br

[Cu]

R1 Br Scheme 7.47

H2O, 120 οC

TMEDA

R1

O

74-99% yield Me2 N H O R1

Cu

N Me2

R2 134

TMEDA

TMEDAH+ R1 [Cu]

O

j617

j 7 Five-Membered Heterocycles: Benzofuran and Related Systems

618

A microwave-mediated solvent-free Rap–Stoermer reaction has been reported for the synthesis of benzofurans from various salicylaldehydes and phenacyl halides (Scheme 7.48) [82]. Some of the advantages and highlights of this microwave protocol include, solvent-free clean reaction conditions and high yields of benzofurans obtained in short reaction times. In addition, the 2-aroyl benzofurans formed using this method are also important as the corresponding carbinols (reduction products) are known to have hypolipidemic activity. R1

R2 135

R1

O

CHO

+

OH

X

R

O

K3PO4

O R2

MW

136

64-98% 137

R

Scheme 7.48

DiMauro has reported a rapid, efficient synthesis of various substituted fused benzofurans using a microwave-assisted one-pot cyclization-Suzuki coupling approach [83]. The benzofuran scaffold was formed under base conditions. Further elaboration via Suzuki cross-coupling reactions afforded the desired products 140 in moderate yields (Scheme 7.49). B(Pin)

B(Pin) X R1 base CHO OH 138

µW

O 139

R1

[Pd] cat. cross-coupling

N

µW

N

R1 O 140

a: R1 = CO2Et, X = Br, 33% yield b: R1 = CONHPh, X = Cl, 40% yield c: R1 = COPh, X = Br, 74% yield d: R1 = COtBu, X = Br, 72% yield

Scheme 7.49

7.4.5 Olefin-Metathesis Approach

Sequential isomerization and ring-closing metathesis for the synthesis of benzofused heterocycles has been reported [84]. 2-Allylphenol is converted into allyl-2(allyloxy)benzene (141) under suitable conditions. [RuClH(CO)(PPh3)3] is then added to a solution of 141 in benzene-d6 or toluene-d8 and the reaction mixture heated at 60–80  C for 18 h (Scheme 7.50). Analysis by 1 H NMR spectroscopy confirmed that the isomerization of both allyl substituents had occurred to afford

7.4 Synthesis of Benzofuran

[RuClH(CO)(PPh3)3] (1 mol%)

O

N Mes Mes N Cl Ru Cl PCy3 Ph 5 mol%

O

benzene-d6 141

O

DCM, reflux 143 > 80% yield

142

Scheme 7.50

the acid-labile compound, which was not isolated. The introduction of catalyst (Grubbs Generation I) then readily affords the benzo[b]furan in excellent conversion, as determined by further 1 H NMR spectroscopy. This result constitutes a novel approach to the ubiquitous benzo[b]furan skeleton. Grubbs et al. have described a method for the synthesis of cyclic enol ethers (including benzofuran) via molybdenum alkylidene-catalyzed ring-closing metathesis (Scheme 7.51) [85]. To demonstrate an application of this process, the authors chose the naturally occurring benzofuran 2,4,20 ,40 -dihydroxyphenyl-5,6-(methylenedioxy)benzofuran (Sophora compound I), the antifungal phytoalexin isolated from aerial part of Sophora tomentosa L [86], as a synthetic target. RO

OR RO

O

O O

12 mol% Cat.

O

PhH, 2h

O

Me 144

Me

Pri Cat.

N RO Mo RO

O

145

i

Pr Ph Me Me

R = CMe(CF3)2

j619

OR

R = Bn: 85% yield

H2, 10% Pd-C EtOAc, RT, 1h HO O

O

O

OH

146 96% yield

Scheme 7.51

Several 2,3-dihydrobenzo[b]furans can be made by the Ru-catalyzed olefin metathesis approach in the presence of trimethylsilyl vinyl ether (Scheme 7.52) [87]. The isovanillin derived benzo[b]furan has also been synthesized by the C-propenylationO-vinylation and olefin metathesis approach [88]. A strategy employing a second generation Grubbs catalyst to facilitate the production of various cyclic enol phosphates, including benzofuran-2-yl enol phosphate scaffolds, has been described. This work represents the first case of an olefin

j 7 Five-Membered Heterocycles: Benzofuran and Related Systems

620

N Mes Mes N Cl 5 mol% Ru Cl PCy3 Ph

MeO O

OSiMe3

147

Toluene, reflux, 73%

MeO O 148

Scheme 7.52

metathesis reaction in which one of the groups participating in the metathesis event is an enol phosphate moiety [89]. 7.4.6 Miscellaneous

3-Cyano or ethoxycarbonyl-2-methyl-benzo[b]furans have been prepared in a onestep synthesis by the microwave induced Claisen rearrangement under solvent-free conditions (Scheme 7.53) [90]. The Fries rearrangement has been employed in the synthesis of benzo[b]naphtha[2,3-d]furan-6,11-dione [91]. A [2,3]-Stille–Wittig rearrangement has also been utilized to make 2,3-disubstituted benzo[b]furans from 2stannane substituted benzo[b]furans [92].

Me

Microwave 6-8 min

O

149

X

X = CN or COOEt

O

Me

X

O

Me

Me

X

150 > 70% yield

Scheme 7.53

An efficient generation of 2-arylbenzofurans proceeds via a route involving acylation and subsequent [3,3]-sigmatropic rearrangement of oxime ethers [93]. Its synthetic utility is demonstrated by a short synthesis of stemofuran A (153) and eupomatenoid (154) in which no procedure for protection of the phenolic hydroxyl groups is needed (Scheme 7.54). The synthetic strategy involving an intramolecular hydroxyl epoxide opening has been applied to build up the cyclopenta[b]benzofuran ring for the total synthesis of naturally occurring rocaglaol [94] (Scheme 7.55). Horaguchi has reported the synthesis of benzofurans using photocyclization reactions of aromatic carbonyl compounds [95]. Benzofurans functionalized with hydroxy and acetyl functionalities are not only the core structures found in numerous biological important natural products but are also the vital precursors for several

7.4 Synthesis of Benzofuran

OH

Me

Me

CF3CO2SO2CF3 O 151

N

DMAP DCM, 86%

152

OH

Me

Me O 153

OH

O

OH

O

OH

154

Scheme 7.54

HO HO

OH OBn

O

Pd-C (10 mol%) EtOAc, 5h, 57%

MeO

HO O HO

155

O

156

O

OMe

rocaglaol

O

OMe

Scheme 7.55

naturally occurring furanoflavonoids. Numerous synthetic methodologies are available in the literature for the synthesis of functionalized benzofurans, but few references appear on the access of benzofurans with adjacent hydroxy and acetyl functionalities. Dixit [96] has reported a highly convenient synthesis of naturemimicking benzofurans and their dimers from easily accessible precursors. The crystal structure of 5,50 -diacetyl-20 ,30 -dihydro-2,30 -bibenzofuran-6,60 -diol is reported. 7.4.7 Progress in Solid-Phase Synthesis

Novel titanium benzylidenes (Schrock carbenes) bearing an arylboronate group are generated from thioacetals with low-valent titanium species, Cp2Ti[P(OEt)3]2, and alkylidenate Merrifield resin-bound esters to give enol ethers. Treatment with 1% TFA gives 2-substituted (benzo[b]furan-5-yl)boronates, and solid-phase Suzuki crosscoupling gives 2,5-disubstituted benzofurans (Scheme 7.56) [97]. Yang et al. have reported a combinatorial synthesis of a 2,3-disubstituted benzo[b] furan library via palladium(II)-mediated cascade carbonylative annulation of o-alkynylphenols on silyl linker-based macrobeads (Scheme 7.57) [98].

j621

j 7 Five-Membered Heterocycles: Benzofuran and Related Systems

622

TiCp2 (pin)B 3 eq.

O O R1 157

OMOM OMOM

(pin)B

THF, reflux

R1 O 158 1. ArI, [Pd], base 2. 1% TFA, DCM O

Ar O

R1

R1

10% HCl-MeOH Ar OMOM 159 25-57% yield

160 54-100 yield Scheme 7.56

R1 + I R R

OH 161

O

R1 Pd(II), dppp CsOAc, R2OH

Pd(0)

162

OH

CO (balloon) 45οC, 20h

R

O

OR2 R1

50-90% 163

Scheme 7.57

The same authors have developed a novel catalytic system of AgOTs-CuCl2TMEDA for the homocoupling of aliphatic acetylenes on solid support. It is the first observation that an Ag(I)-activated triple bond can facilitate Cu(II)-mediated oxidative acetylenic homocoupling. This procedure provides an efficient way to synthesize a diversified symmetric 1,3-alkadiynediol bis(benzo[b]furan-carboxylate) library on solid support [99]. Furthermore, a split-pool synthesis of dimeric benzo[b]furans has been developed employing the Sonogashira reaction, palladium-mediated carbonylative annulation and olefin cross-metathesis as the key steps on high-capacity, lightly cross-linked, silyl-linker-based polystyrene macrobeads. This protocol provides direct access to a range of dimeric molecules that are ideal for high-throughput screening of protein–protein interactions in a cell-based assay system [100]. Subsequently, the authors described a conformationally restricted 2,3-diarylbenzo [b]furan library built up on a solid-phase by the palladium/bipyridyl-catalyzed annulation of o-alkynyl phenols with aryl halides (Scheme 7.58) [101].

7.5 Uses of Benzofuran

A 2-substituted furo[3,2-b]quinolines library has been made on solid support by K2CO3-mediated sequential deprotection and cyclization [102] (Scheme 7.59).

R1 Pd (dba) (5 mol%) 2 3 bpy (10 mol%), MeCN 50οC, R2I, K2CO3

OH

R

R2 O

R

164

R1

165

Scheme 7.58

O

N

R1

AcO

K2CO3 R2 18-Crown-6 DMF-H2O (19:1)

166

R1

N O

R2

167

Scheme 7.59

7.5 Uses of Benzofuran 7.5.1 Uses of Benzofuran in Drug Discovery

Jones has synthesized benzbromarone analogs (168) screened for inhibitory potency against 2C19, or used as substrates or metabolite standards [103]. The findings illustrate the increased utility of benzbromarone analogues since they have now been adapted to act as 2C19 inhibitors. According to this study with benzbromarone and previous works on phenobarbital analogues and proton pump inhibitors, it is demonstrated that for 2C19, ligands with two hydrophobic regions separated by a polar group are the most complementary. Interestingly, high-affinity binding of benzbromarone ligands to 2C19 appears to be achieved without constraining substrate mobility within the enzyme.

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j 7 Five-Membered Heterocycles: Benzofuran and Related Systems

624

O

R1

R4

O

R3

168

R2

A series of benzofuran-2-yl-(phenyl)-3-pyridylmethanol derivatives have been prepared in good yields using an efficient one-step procedure. Additionally, to determine the effect of the benzene ring in benzofuran with respect to inhibitory activity, furan-2-yl-(phenyl)-3-pyridylmethanol derivatives have been synthesized in the meantime. The pyridylmethanol derivatives were all evaluated in vitro for inhibitory activity against aromatase (P 450AROM, CYP19), using human placental microsomes. The benzofuran-2-yl-(phenyl)-3-pyridylmethanol derivatives displayed good to moderate activity (IC50 ¼ 1.3–25.1 mM), which was either better than or comparable with aminoglutethimide (IC50 ¼ 18.5 mM) but lower than arimidex (IC50 ¼ 0.6 mM), with the 4-methoxyphenyl substituted derivative displaying optimum activity. Moreover, it shows the activity to reside with the (S)-enantiomer based on molecular modeling of the benzofuran-2-yl-(4-fluorophenyl)-3-pyridylmethanol derivatives. The essential role of the benzene ring of the benzofuran component for enzyme binding is demonstrated since the furan-2-yl-(phenyl)-3-pyridylmethanol derivatives were devoid of activity [104]. Histamine H3 receptor antagonists are being developed to treat various neurological and cognitive disorders that may be ameliorated by enhancement of central neurotransmitter release. A nonimidazole, benzofuran ligand ABT-239 [4-(2-{2[(2R)-2-methylpyrrolidinyl] ethyl}-benzofuran-5-yl)benzonitrile] (169) has been utilized in the in vitro pharmacological and in vivo pharmacokinetic profiles and compared with several previously described imidazole and nonimidazole H3 receptor antagonists. The assay results demonstrate that ABT-239 is a selective, nonimidazole H3 receptor antagonist/inverse agonist with similar high potency in both human and rat and favorable drug-like properties [105]. The potency and selectivity of this compound and of analogs from this class support the potential of H3 receptor antagonists for the treatment of cognitive dysfunction [106]. CN

N

O 169 (ABT-239)

A series of 2-(4-hydroxyphenyl)benzofuran-5-ols with relatively lipophilic groups in the 7-position of the benzofuran has been synthesized for measurement of the affinity and selectivity for ERb. Some analogs are active as potent and selective ERb ligands. The structural modifications at the benzofuran 4-position as well as at the 30 -position of the 2-Ph group (e.g., 170) further increase selectivity. Such

7.5 Uses of Benzofuran

modifications have lead to compounds with 100-fold selectivity for ERb [107]. F

HO O NC

OH

170

5-Chloro-3-methyl-2-acetylbenzofuran reacts with bromine in acetic acid leading to 5-chloro-3-methyl-2-bromoacetylbenzofuran, which then undergoes condensation with various substituted aromatic amines to afford 2-N-arylaminoacetyl-5-chloro-3methylbenzofurans. These compounds have been screened for their antibacterial, antifungal, analgesic, antiinflammatory and diuretic activities and some hits were discovered [108]. A series of 1-(1-benzofuran-2-yl-ethylidene)-4-substituted thiosemicarbazides along with some derived ring systems, substituted-2,3-dihydro-thiazoles and thiazolidin-4-ones, have been synthesized and evaluated for their in vitro anti-HIV, anticancer, antibacterial and antifungal activities. Among the tested compounds, two produced a significant reduction the viral cytopathic effect (93.19% and 59.55%) at concentrations of >2.0  10
4 M and 2.5  10
5 M, respectively. One compound displayed moderate anti-HIV activity. Several compounds showed mild antifungal activity. However, no significant anticancer activity was discovered for the tested compounds [109]. 7.5.2 Uses of Benzofuran in Material Science

New functionalized mono- and bis-benzo[b]furan derivatives which possess a CN, CHO, CH¼CHPh, CH¼CPh2, or CH¼CHCOOH group at C4 have been synthesized and developed as blue-light emitting materials [110]. Two benzo[b]furan nuclei in bis-benzo[b]furan derivatives have been connected by a divinylbenzene bridge. Bisbenzo[b]furan 171 was fabricated as a device with good volatility and thermal stability. It emitted blue light with brightness 53 430 cd m
2 (at 15.5 V) and a high maximum external quantum efficiency 3.75% (at 11 V) (Scheme 7.60). The direct anodic oxidation of 2,3-benzofuran on stainless steel sheet in boron trifluoride di-Et etherate (BFEE) contained 10% poly(ethylene glycol) (PEG) with a molar mass of 400 (by vol.) affords a visible-light transparent high-quality substratesupported poly(2,3-benzofuran) (PBF) film [111]. The oxidation potential of 2,3benzofuran in this medium was measured to be only 1.0 V vs SCE, which is lower than that determined in acetonitrile þ 0.1 M Bu4NBF4 (1.2 V vs SCE). Good electrochemical behavior and good thermal stability with a condense of 10
2 S cm
1, are displayed for these PBF films, and the doping level of as-prepared PBF films was determined to be only 8.9%. The structure of the polymer has been studied by UV/Vis, IR spectroscopy and SEM.

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j 7 Five-Membered Heterocycles: Benzofuran and Related Systems

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OMe O

OLED

Cathode Electron Transporting Layer Light Emitting Layer Hole Transporting Layer Anode Glass

O OMe

171

Scheme 7.60

Yang has reported the synthesis and spectral properties of novel 4-benzofuranyl1,8-naphthalimide derivatives [112]. A series of 4-benzofuranyl-N-alkyl-1,8-naphthalimides has been prepared from 4-ethynyl-N-alkyl-1,8-naphthalimides and substituted o-iodophenols catalyzed by a Pd(PPh3)2Cl2/CuI system under mild conditions. The absorption and fluorescence spectra of these benzofuran-1,8-naphthalimides have been recorded and the quantum yields are measured using quinine sulfate as the standard. The UV/Vis absorption spectra were in the range of 380–400 nm and the emission spectra were in the range of 500–520 nm. A novel fluorescence active 12H-benzo[e]indolo[3,2-b]benzofuran and its derivatives (172) has been prepared from 6-R1-2-naphthols in good yields. The synthesized compounds with planar geometry and extended conjugation exhibit excellent fluorescence properties [113]. R2 N

R1

O 172

Four linear benzofuran trimers have been prepared and tested as materials for organic electroluminescence (OEL). The solubility, aggregation, and film-forming properties were modulated by tert-butyl and n-hexyl substituents on the benzofurans. Additionally, two tert-butyl groups prevented aggregation in the solid state, thus maintaining emission in the blue region of the visible spectrum. The OEL characteristics of the tert-butyl-substituted benzofuran trimer have been explored, and blue emission observed. The two-stage synthetic procedure employed for the preparation of these benzofuran trimers may be applied to a wide variety of benzofuran oligomer and polymer targets [114].

7.5 Uses of Benzofuran

THPO

1) Ph Pd(PPh3)4 / PPh3 CuI, Et3N, piperidine

Br

OTHP 2) p-TsOH, CH2Cl2 / MeOH

Br 173

j627

Ph 1) BuLi / THF 2) ZnCl2 / PhCH3

HO OH Ph

81% (2 steps) 174

R

ZnCl Ph

O

ArI or ArBr

Ph

O

O

Pd2(dba)3, PtBu3 toluene / NMP, 100 οC

ClZn

O

175 R

R = H, 65% R = Me, 70% R = Ph2N-C6H4, 69% R = (p-tol)2N-C6H4, 60%

176

Scheme 7.61

Recently, Nakamura has described a facile route to 2,3,6,7-tetraarylbenzo[1,2-b:4,5b]difurans (BDFs) (Scheme 7.61), which could be functioned as the hole-transporting material (HTM) in layered organic light-emitting diodes (OLEDs) [115]. The high performance of the compounds is primarily due to the BDF core itself, which is in sharp contrast to the fact that the biphenyl scaffold in R-NPD alone does not function as a HTM. They also found that there is a synergetic effect of the BDF core and the substituents. The physical properties can be improved by suitable functionalization. It can be expected that the BDF molecule will serve as a useful new molecular scaffold on which multiple functional groups can be attached to obtain new properties.

O Pd(PPh3)2Cl2 CuI, Et3N

O N H

N

N

HO Cl +

177

N

N

DMF, 75 οC, 16h

OHC 178 O

179

HO

O N H

N

N O

180

Scheme 7.62

N H

(FBAN) OHC

N H

N

N O R

181 182 183

(BAN) R = H 53% (HBAN) R = CH2OH 78% (ABAN) R = CH2NHC12H25 64%

CHO

j 7 Five-Membered Heterocycles: Benzofuran and Related Systems

628

Benzofuran-naphthyridine links show high-yield fluorescence with solvatochromic properties. For instance, after formation of fluorescent organic nanoparticles (FONs1.) of ABAN (183, Scheme 7.62), the photophysical properties (such as the spectral features and intensity) are remarkably different from those at the molecular level (solution) and in bulk material [116].

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11

12

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30 31 32

33 34

35

36 37

38

39 40 41

42

43

44

45 46

47 48

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86 (a) McKittrick, B.A., Scannell, R.T., and

87

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92 93 94 95 96 97 98

99 100 101

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K.M., Miller, T.R., Kang, C.H., Denny, L.I., Witte, D.G., Yao, B.B., Pan, L., Wetter, J., Marsh, K., Bennani, Y.L., Cowart, M.D., Sullivan, J.P., and Hancock, A.A. (2005) Journal of Pharmacology and Experimental Therapeutics, 313, 165. Cowart, M., Faghih, R., Curtis, M.P., Gfesser, G.A., Bennani, Y.L., Black, L.A., Pan, L., Marsh, K.C., Sullivan, J.P., Esbenshade, T.A., Fox, G.B., and Hancock, A.A. (2005) Journal of Medicinal Chemistry, 48, 38. Collini, M.D., Kaufman, D.H., Manas, E.S., Harris, H.A., Henderson, R.A., Xu, Z.B., Unwalla, R.J., and Miller, C.P. (2004) Bioorganic & Medicinal Chemistry Letters, 14, 4925. Basawaraj, R., Parameshwarappa, G., and Sangapure, S.S. (2006) Indian Journal of Heterocyclic Chemistry, 16, 75. Rida, S.M., El-Hawash, S.A.M., Fahmy, H.T.Y., Hazza, A.A., and El-Meligy, M.M.M. (2006) Archives of Pharmacal Research, 29, 16.

110 Hwu, J.R., Chuang, K.-S., Chuang, S.H.,

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114

115

116

and Tsay, S.-C. (2005) Organic Letters, 7, 1545. Xu, J., Nie, G., Zhang, S., Han, X., Pu, S., Shen, L., and Xiao, Q. (2005) European Polymer Journal, 41, 1654. Yang, J.-X., Wang, X.-L., Tu, So., and Xu, L.-H. (2005) Dyes and Pigments, 67, 27. Karnik, A.V. and Upadhyay, S.P. (2004) Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 43B, 1345. Anderson, S., Taylor, P.N., and Verschoor, G.L.B. (2004) Chemistry - A European Journal, 10, 518. Tsuji, H., Mitsui, C., Ilies, L., Sato, Y., and Nakamura, E. (2007) Journal of the American Chemical Society, 129, 11902. Sun, Y.-Y., Liao, J.-H., Fang, J.-M., Chou, P.-T., Shen, C.-H., Hsu, C.W., and Chen, L.-C. (2006) Organic Letters, 8, 3713.

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8 Five-Membered Heterocycles: 1,2-Azoles. Part 1. Pyrazoles Jos
e Elguero, Artur M.S. Silva, and Augusto C. Tom
e

8.1 Introduction

Pyrazoles belong to the family of azoles, which for some authors include pyrroles and indoles while for others it contains only by imidazoles, benzimidazoles, pyrazoles, indazoles, 1,2,3-triazoles, benzotriazoles, 1,2,4-triazoles, tetrazoles and pentazoles. The dubious position of pyrroles is due to their very different reactivity and less aromatic stability. We have carried out a search in the Chemical Abstracts “on line” (1987–2004) using the following truncated words: pyrazol
, indazol
, imidazol
, benzimidazol
, triazol
(thus treating together 1,2,3 and 1,2,4-triazoles), benzotriazol
, tetrazol
and pentazol
. In this way, fused compounds are included although they will not be discussed in detail in this chapter. Table 8.1 gives the number of references and the percentages in each case. The evolution of the number of publications between 1999 and 2004 show an increase of all of them, with the most cited, imidazoles and pyrazoles, growing the fastest. From Figure 8.1 is can be concluded that benzazoles are much less studied than the corresponding azoles and that an increase in the number of nitrogen atoms diminishes the importance of the azoles, with pentazoles being only a curiosity. In the Chemical Abstracts 2004, the word pyrazol
appears 1931 times. Regarding these 1931, it is possible to classify them (at the price of some simplifications) into six different fields (Table 8.2). As expected, the medicinal chemistry aspects of pyrazoles dominates largely the 2004 production, but note their great importance as ligands in coordination chemistry. As materials, the main applications are as dyes, inks and luminescent devices.

Modern Heterocyclic Chemistry, First Edition. Edited by Julio Alvarez-Builla, Juan Jose Vaquero, and José Barluenga. Ó 2011 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2011 by Wiley-VCH Verlag GmbH & Co. KGaA.

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Table 8.1 Relative importance of azoles in the literature.

Azol


Total

%

Pyrazol
Indazol
Imidazol
Benzimidazol
Triazol
Benzotriazol
Tetrazol
Pentazol


20701 1451 31118 10158 15688 6429 8008 42

22.12 1.55 33.25 10.85 16.76 6.87 8.56 0.05

Another way to classify pyrazoles is to made a class of 1,2-azoles formed by pyrazoles, isoxazoles and isothiazoles. This is not entirely satisfactory, because there is an important difference between pyrazoles on the one hand and isoxazoles and isothiazoles (Chapter 9) on the other: the presence of an NH (NR) in pyrazoles (1–3) 3500

3000

Number of publications

2500

2000 Pyrazol* Indazol*

1500

Imidazol* Benzimidazol* Triazol*

1000

Benzotriazol* Tetrazol* Pentazol*

500

0

-500 1998

1999

2000

2001

2002

Year

2003

2004

2005

Figure 8.1 Evolution of the number of publications devoted to azoles between 1999 and 2004.

8.1 Introduction Table 8.2 Use of pyrazoles according to the number of citations.

Pyrazol


References

%

% Without biol. appl.

Biological applications Coordination chemistry Synthesis Properties Application as materials Reactivity

785 423 375 125 118 105

40.65 21.91 19.42 6.47 6.11 5.44

— 36.91 32.72 10.91 10.30 9.16

that confers to this heterocycle a specific behavior to the point that we have treated it separately from the two other heterocycles.

4

N N H 1H-pyrazole (1) 1

5

4

5

3 2

3a

6

1 N2 N H 1H-indazole (2) 7

4

5

3

3a

6

3 2

7a

7

7a

N

N H

1

2H-indazole (3)

8.1.1 Nomenclature

We have represented above the three main heterocycles of this chapter. Notably, the migration of the proton of a pyrazole from N1 to N2 changes the numbering of the ring, that is 3-methyl-1H-pyrazole (4a) becomes 5-methyl-1H-pyrazole (4b), whereas in indazoles the same migration transforms 3-methyl-1H-5a into 3-methyl-2Hindazole (5b). Me N H 4a

N

Me

Me Me

N H 4b

N

N H 5a

N

N

N H

5b

A series of books or chapters in books have been devoted to this heterocycle, including its benzo derivative, indazole, with exclusion of the very large topic of pyrazoles fused with other heterocycles. In 1966, Kost and Grandberg published the first systematic approach to pyrazole chemistry [1]. It is still a valuable source of information because it summarizes in a short and clear way the knowledge

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638

accumulated in Russia after the seminal contribution of Karl Friedrich von Auwers (1863–1939) to the chemistry of these compounds. A year later, a book appeared that contains tables describing many pyrazoles, indazoles and their reduced derivatives, one of the authors, Fusco, was at that time very active in the chemistry of pyrazoles [2]. A book on all azoles is very useful since it represents a more structural and comparative study with much spectroscopic data [3]. In 1984 (updated in 1996) Comprehensive Heterocyclic Chemistry provided an extensive treatment of the structure and reactivity of pyrazoles and indazoles but with a concise report on synthetic aspects [4, 5]. The synthesis is well developed in HoubenWeyl, Methoden der Organischen Chemie and its continuation, Science of Synthesis, which contains synthetic recipes [6–9].

8.2 General Reactivity

Depending on the oxidation degree, pyrazoles can be classified into different families (Scheme 8.1). Indazoles saturated in the benzene ring (4,5,6,7-tetrahydroindazoles) are better considered as 3(5),4-tetramethylenepyrazoles. The 3H-indazoles, a third isomer of indazoles, are unstable if one (or both) of the substituents at position 3 is an H atom, that is, there are no 3H-indazole tautomers. 8.2.1 Relevant Physicochemical Data, Computational Chemistry and NMR Data

Figure 8.2 shows the structures of the three parent compounds, giving an image of their compact character. Table 8.3 summarizes the properties of pyrazole (1) and 1Hindazole (2) (the other tautomer, 3, is unstable – see under tautomerism). In general, pyrazoles unsubstituted at position 1, NH-pyrazoles, and NH-indazoles are solids, the exception being some pyrazoles substituted at position 4, like 4methylpyrazole [28]. The N-substitution, especially the N-alkylation, is accompanied by a large decrease in the melting point. Figure 8.3 presents, in a simplified manner, the geometry of 1 in the gas phase (both from MW spectroscopy and from high-level theoretical calculations). Pyrazole is planar and to a first approximation has a regular pentagonal geometry. Closer examination reveals alternating single (C3-C4)/(C5-N1) and double (C4-C5)/(N2-C3) bonds. Particularly relevant to determining the position of the NH, when it is not observed in X-ray crystallography due to disorder, is the fact that the angle on N1 is always larger than that on N2 (the same happens at C3 and C5). Structural assignment of pyrazoles and indazoles is usually carried out by NMR (Schemes 8.2–8.4), at one time by using tables of reference compounds and/or coupling constants [29] but now more often by 2D spectroscopy, such as NOESY, which detects the proximity of substituents [30]. The identification of pyrazole isomers is easy by NMR when there is only one substituent at positions 3(5). The 1 H NMR chemical shifts are dependent on the

8.2 General Reactivity

R3

O Three double bonds

N N R1 Pyrazoline-4,5-diones O

R4

N N R1 1H-Pyrazoles R4 O R4' R5 N R5' N

1

-Pyrazolin-3-ones O

O

5

R R5'

N R1

N R2

R4 R3 4' R R3' One 5 R double N N R5' bond

N R2 N R1 Pyrazolidine-3,4,5-triones R4

R3 R3' N

R5

No double bond

R R4' R5 R5'

R4 R4'

N N 4H-Pyrazoles (Isopyrazoles)

R4 R4'

R3

O 5

R R5'

N N 1 R 2 -Pyrazolin-4-ones R4 R4' O

R3

R5

N 3H-Pyrazoles (Pyrazolenines)

R3

N N R1 2 -Pyrazolin-5-ones O

R4

R3

N R2 N R1 3 -Pyrazolin-5-ones O

O N R1

R4 R3 R4' R5 N R5' N R1 1 -Pyrazolines 2-Pyrazolines 4

O

O

R3

R5

Two double bonds

O

j639

N R2

Pyrazolidinediones

R4 R5 R5' 3

R3 N R1

N R2

-Pyrazolines

R4 O R4' R5 N R2 N R5' R1 Pyrazolidin-3-ones

O R5 R5'

N R1

R3 R3' N R2

Pyrazolidin-4-ones

3

R R3' N R2

N R1 Pyrazolidines

Scheme 8.1 Different structures of pyrazole derivatives depending on their oxidation degree

Figure 8.2 Space filling models of (a) pyrazole (1), (b) 1H-indazole (2) and (c) 2H-indazole (3).

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Table 8.3 Properties of the parent compounds.

Property

Pyrazole (1)

Indazole (2)

Mp ( C) Bp ( C) Log P Dipole moment (m, D) pKa (proton addition) pKa (proton loss) Enthalpies of formation (kJ mol1) UV (lmax nm, log e) IR (cm1) X-ray (CSD) [12] 1 H NMR 13 C NMR 15 N NMR MS PES MW Best theoretical calculations Aromaticity (benzene ¼ 0.991)

69–70 186–188 (758 mmHg) 0.13–0.26 1.92 (benzene) 2.52 14.21 179.4 [10] 211 (3.49) [4] 3524 (nNH gas) [4] PYRZOL Source: [13] Source: [15] Source: [17] Source: [18] Source: [20] Source: [22] Source: [24] 0.900: [26]

145–149 269–270 (743 mmHg) 1.82 1.60 (benzene) 1.31 13.80 243.0 [10] 250 (3.65), 284, 296 (3.52) [4] Source: [11] INDAZL Source: [13, 14] Source: [16] Source: [17] Source: [19] Source: [21] Source: [23] Source: [25] 0.808: [26]a)

a)

Naphthalene: 0.811, 2H-indazole: 0.792 (using as criteria the HOMA) [27].

solvent, but the 3J34 VS. 3J45 coupling constants are not, so the fact that J45 > J34 is always a useful test. The ration J45/J34 depends on the substituent on the nitrogen, with EWG (like tosyl) the difference is large and the criteria easy to apply. With EDG (like amino) the difference tends to blur and J34  J45 [31]. For isomeric pyrazoles bearing different substituents at positions 3 and 5, the 13 C chemical shifts of carbons C3 and C5 is a better method of assignment if both isomers are available. If only one is obtained, one must rely on a comparison with the large amount of data available [15]. In contrast, indazoles are easily identified by 13 C NMR spectroscopy [16]. 15 N NMR spectroscopic data can be routinely obtained from unlabelled samples (natural abundance). But their utility as a diagnostic tool is limited. Note that the 15 N chemical shifts are very sensitive to hydrogen bonds and, obviously, to protonation. H

H

1.08

1.08

1.42

1.37 104.5 111.9 106.4 104.1 113.1

1.08

H

1.36 128.5

N

1.33

N

1.35 118.4

1.00

H Figure 8.3 Geometry of pyrazole.

8.2 General Reactivity

6.31 H

H 8.08

H 7.61

N N H 13.04

N N H 12.64

7.61 H

H Solution DMSO-d6 (only this tautomer) J37 = 1.1 Hz

Solution CCl4 (fast tautomerism)

6.22 H 7.35 H

N N CH3 3.95

N N CH3 3.88

Solution CDCl3 J34 = 2.0, J45 = 2.3 J35 = 0.7 Hz

6.90 H 8.18 H

Solution CDCl3

H 8.18

6.87 H

N H 12.5 N H 12.5

8.57 H

105.8

1

N CH3 3.80

Solution CDCl3 J(Me-H3) = 0.5 Hz

H 9.28 N CH3 4.49 N CH3 4.34

N CH 4.20 3 N CH3 4.20

Solution DMSO-d6

H NMR spectra [d (ppm) and J (Hz)] of some representative compounds

134.6

N 134.6 N H Solution CH2Cl2 (fast tautomerism)

103.9

138.1

107.0

138.7

109.1

135.2

N N N H 135.2 N N 128.8 N H H H Solution HMPT (–17ºC) (slow tautomerism) Solid state (CPMAS) Solution H2O 127.6

122.8 120.4 133.4 120.1 N 125.8 N 110.0 H 139.9 Solution DMSO-d6 (only this tautomer) Scheme 8.3

N

H 8.57

Solution DMSO-d6

Solution H2SO4 Scheme 8.2

H 7.67

H 7.94

H 7.49

121.8 119.6 123.1 121.2 120.2 N CH3 39.7 N 125.9 125.4 N N 116.8 108.6 CH3 35.3 139.7 148.7 123.8 120.8 132.4

Solution CDCl3

Solution CDCl3

13

C NMR spectra [d, (ppm)] of some representative compounds

NMR information on the non-aromatic derivatives of pyrazoles is very abundant, particularly on D2-pyrazolines and on pyrazolones [4, 7]. Scheme 8.5 contains some multinuclear NMR data on D2-pyrazolines.

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j 8 Five-Membered Heterocycles: 1,2-Azoles. Part 1. Pyrazoles

642

–183.5 N –132.9 N –79.8 N –90.5 N H –132.9 N –183.5 N –167.8 N –171.3 N H H H H Solution DMSO-d6 Solution CHCl3 Solid state Solution H2O/HCl (CPMAS) (fast tautomerism) (slow tautomerism) N –65.6 N –194.4 H Solution DMSO-d6 (only this tautomer) Scheme 8.4

–161.0 N CH3

N –56.6 N –202.8

N –91.2

CH3 Solution DMSO-d6

Solution DMSO-d6

15

N NMR spectra [d, (ppm)] of some representative compounds

33.2 142.9 2.65 H H 6.88 H H N –30.4 3.31 H N –18.5 45.4 H 5.33 Neat

31.6 149.0 Ph 3.12 H H H N 3.76 H N 48.1 Ph

2.89 H Ph 3.35 H 4.02 H N Ph N H

CDCl3

CDCl3

45.1 148.4 H Me H 91.1 2 N J = 30.1 HO F3C N H 124.4 1 J = 282.3 CDCl3

Scheme 8.5 NMR data on some D2-pyrazolines

8.2.2 Tautomerism

The study of the tautomerism of NH-pyrazoles and indazoles (annular tautomerism) and that of functional compounds (e.g., pyrazolones) has been of considerable importance for the development of structural chemistry [32–34]. Some protonated cations also shown tautomerism. This huge amount of data is difficult to summarize, but the principal conclusions are as follows: 1)

2)

Tautomerism occupies a multidimensional space (Scheme 8.6): the three states of the matter, the thermodynamic and kinetic aspects, and the proton (prototropy versus elementotropy). All these aspects have been observed in pyrazoles although those situations marked with a gray circle are very rare. Theoretical studies of the tautomerism of pyrazole and its derivatives mainly concern the gas phase. Concerning thermodynamic aspects, the main conclusion about annular tautomerism of pyrazoles (6a * ) 6b) is that the equilibrium tautomeric constant KT is never far from 1 [35–37]. The preference of 6a versus 6b has been analyzed using the Taft–Topson model [35, 36]. BH2, COF, CO2H, and CHO substituents stabilize the 6a tautomer, while the 6b tautomer is stabilized by OH, F, NH2, Cl, CONH2, CN, NO2, and CH3 groups (this paper contains a wealth of information about the IR of NH-pyrazoles) [37]. A more detailed analysis of the annular tautomerism of 3(5)-aminopyrazoles (R¼NH2) shows that both tautomers are present in solution and even in the solid state [38].

8.2 General Reactivity

Gas phase K

Solid state

Solution K

UV, MS, ICR, PES

j643

K

90%

X-ray, neutron diffraction

Proton k

NMR, relaxation

NMR, relaxation k

K

K

K

X-ray

NMR

X

NMR

k

k

k

Theoretical chemistry Scheme 8.6 The tautomerism twelve regions

For indazole, the 1H-tautomer (2) is more stable than the 2H-tautomer (3) by about 20 kJ mol1, and this tendency cannot be reversed by phase effects; consequently, in solution and in the solid state the only tautomer present is 2 [39]. To displace the equilibrium towards one of the tautomers it is necessary to use a combination of substituents, aza and annelation effects [39]. For instance, substituents like NO2 and CO2Me at position 3 favor the 2H-tautomer, the replacement of a CH by an N atom at position 7 favors the 1H-tautomer (by lone-pair/lone-pair repulsion in 7b), and a fused benzo group at positions [ f ] and [g] favors, respectively, the 1H- (8a) and 2H-tautomers (9b). R N H

N

R

N H

N

N H

6b

N H 7a

N

N

N 7b

NH

NH

8b

R N

N

8a

R N

R

R

6a

3)

k

R

R N H 9a

N

N

NH

9b

In terms of kinetic aspects, the transfer of group R between both nitrogen atoms is an intermolecular process in the case of prototropy [40]. This requires other

j 8 Five-Membered Heterocycles: 1,2-Azoles. Part 1. Pyrazoles

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4)

molecules (another pyrazole, water, a solvent, etc.) or a surface, for instance that of the measuring instrument [41]. Other groups on the nitrogen migrate either intermolecularly (COR, CH3, etc.) or intramolecularly (SiR3, GaR2, GeR3, SnR3, HgR) with barriers that can be very low in some cases [34, 41]. The tautomerism of functional derivatives, such as pyrazolones, is well understood and is no longer a research subject [32, 34]. However, there remains always some interesting cases, for instance that of 4-nitroso-5-aminopyrazoles 10 [42]. The compound exists as a mixture of rotamers 10a/10c of the amino-nitroso tautomer, rather than a mixture of amino-nitroso/imino/ oxime tautomers 10a/10b. O N H

N N Bn 10a

N H

O N H N H

O N N N Bn 10b

H

N H

N N Bn 10c

8.3 Relevant Natural and/or Useful Compounds

The common belief is that heterocycles are natural if they can be found in DNA (nucleosides and nucleotides) or in proteins. That is why indole (tryptophan), pyrrole (proline, porphyrins), imidazole (histidine, biotine) and benzimidazole (vitamin B12) are considered “naturals” while pyrazole is not. One of the rare natural products that contains a pyrazole ring is Withasomnine [5,6-dihydro-3-phenyl-4H-pyrrolo[1,2b]pyrazole (11) an alkaloid isolated from the roots of an Indian medicinal plant, Withania somnifera]: its simplicity means that several synthesis are known, with the most recent described in 2002 [43, 44]. Ph N

N 11

Other pyrazoles found in nature are pyrazofurin or pyrazomycin (an antibiotic isolated from the fermentation broth of Streptomyces candidus), formycin (a naturally occurring isomer of adenosine) and L-b-pyrazolylalanine (found in the seeds of many species of Cucurbitaceae). From this it must not be concluded that the pyrazole skeleton is not a good scaffold for making drugs. A recent review examines the topic “Pyrazoles as Drugs: Facts and Fantasies” [45]. This review describes the past and the present of pyrazole derivatives in medicinal chemistry. From an important past, exemplified in the analgesic and anti-inflammatory pyrazolones and pyrazolinediones, not devoid of severe complications, to a glorious present with some of the most important drugs of recent times (sildenafil, celecoxib) being pyrazole derivatives.

8.3 Relevant Natural and/or Useful Compounds

Analgesics were, by far, the main area of biological activity of pyrazoles, often associated with antipyretic activity. They belong to three main classes: pyrazolin-5-ones [antipyrine –phenazone – (12), pyramidon (13), dipyrone (14)], pyrazolin-3,5-diones [phenylbutazone (15)] and pyrazoles [actually, an acetic acid, lonazolac (16)] [46]. Indazole proved to be an interesting nucleus in this field. Structural modifications of the anti-inflammatory agent bendazac (17), an indazole derivative, have been realized and, in some cases, the synthesized compounds showed analgesic effects along with anti-inflammatory properties [47].

O

Me

Me2N

N Me N Ph 12

O

Me NaO3S-CH2 N

Me N Me N Ph 13

Me N Me N Ph

O

14

Cl O

Bu O

O CH2CO2H

HO2C-CH2

N Ph N Ph

N N Ph

15

16

N N Bn 17

Lesopitron (18) (E-4424), a pyrimidylpiperazine substituted by 1-butyl-4-chloropyrazole, was introduced as a new non-benzodiazepine anxiolytic acting on 5-HT1A receptors. It differed from other 5-HT1A receptors ligands mainly because of its greater anxiolytic potency, its lack of sedative effects, its sustained activity even on long-term treatments and its lack of withdrawal problems [48]. Lesopitron, currently in advanced clinical trials (phase III), and has been shown to be efficient and safe in patients with generalized anxiety disorder. Of particular interest is zaleplon, N-[3-(3cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-ethylacetamide (19), a BZ1-receptor selective ligand [49]. Zaleplon (Sonata, Wyeth-Pharma, MI 10165) is a non-benzodiazepine sedative hypnotic that has been recently introduced for clinical use. It is indicated for short-term treatment of insomnia and presents the advantages of showing weak anxiolytic activity and reduced risk of tolerance.

N Cl N

N (CH2)4 N 18

N

CN N N

N N

O 19

N Et

Me

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The implication of glutamate receptors in memory processes has initiated great interest in anti-Alzheimer therapy. In an attempt to obtain heterocyclic analogs of glutamic acid, a synthetic strategy has been developed to prepare pyrazoles that show biological activity at central glutamate receptors [50]. The discovery by Sanofi [51] in 1994 of the pyrazole SR141716A (20) has been of great interest in the field of cannabinoids because this study reported the first cannabinoid antagonist possessing nanomolar affinity. This selective and orally active CB1 receptor subtype antagonist has become an experimental tool for insights into CB1 subtype recognition and activation and for clinical applications such as treatment of psychosis, eating disorders or memory deficits [52]. Recent studies of analogs retaining the central pyrazole structure of 20, tested for CB1 binding affinity and in a battery of in vivo tests, suggest that the structural properties of 1- and 5-substituents are primarily responsible for the antagonist activity of SR141716A. O

Me

NH N N

Cl

N Cl

20

Cl

The availability in 1997 of the highly specific antagonist SR144528 (21) [53] for the CB2 receptor has allowed the investigation of both the architecture of ligand binding sites, an approach that is difficult due to the structural disparity of cannabinoid agonists, and the respective contribution of cannabinoid receptor subtypes in functional cannabinoid effects in vivo. Its potential therapeutic applications include immune disorders such as rheumatoid arthritis, multiple sclerosis, psoriasis, infections and asthma. Me

O NH N

Cl Me

21

N

Me Me Me

Various derivatives of SR141716A have been synthesized [54] and Makriyannis et al. [55] have reported a study of structure–activity relationships of pyrazole derivatives as cannabinoid receptor antagonists and have proposed structural requirements for CB1 antagonistic activity.

8.3 Relevant Natural and/or Useful Compounds

6-Aryl-tetrahydropyridazin-3-ones are prototypes of cardiotonic agents, having both inotropic and vasodilator activities. Imazodan and bemoradan are two representatives of this family, which are supposed to exert their actions by selective inhibition of phosphodiesterase type 3 enzymes (PDE3). Many different structural variations have been devised in this series and, related to pyrazoles, the most interesting compound from a series of heterocyclic benzimidazolyl-pyridazinones is meribendan (22). It inhibited myocardial PDE3, showed an interesting calcium sensitizing effect and was selected for development as a positive inotrope [56]. The synthesis and inhibitory effects on cyclooxygenase, lipoxygenase and thromboxane synthetase of 3-amino-4,5-dihydro-1H-pyrazoles and related compounds have been reported. Among these, the trifluoromethylphenyl derivative 23 is the most interesting [57].

Me N HN N

N H

O N

N

H

N

N

N 23

22

CF3

Progress in understanding inflammatory processes has led to the search of inhibitors of both the cyclooxygenase (COX) and lipoxygenase (LOX) pathways of the arachidonic acid cascade. In this way tepoxalin (24) has been prepared and found to be a potent anti-inflammatory agent [58]. Cl

O

N

Me N OH

N

OMe

24

The discovery of a second, inducible form of cyclooxygenase (COX-2) that exists along with the constitutive form (COX-1) led to the hypothesis that selective inhibitors of COX-2 would be anti-inflammatory without causing the side effects associated with inhibition of COX-1 in the gastrointestinal tract and kidney. This is the moment most promising approach at present and has ultimately led Searle to SC-58125 (25) and then to celecoxib SC-58635 (26) (MI 1968), which is useful for the treatment of rheumatoid arthritis and osteoarthritis [59]. Other pharmaceutical companies have explored this avenue; for instance Fujisawa has developed 27 [60].

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CF3 N

F

25

SO2Me CN

CF3 N

Me

26

N

N

N

MeO2S

F

27

SO2NH2

N

Other groups, like ASTA, have approached the problem by inhibiting the enzyme 5-LOX. By analogy with zileuton, one of the first launched 5-LOX inhibitors for the treatment of asthma, they prepared a series of 1,5-disubstituted indazol-3-ones, the most potent being 28 [61]. Mosti et al. have also reported indazoles related to angelicin, like compound 29a, which shows good anti-inflammatory and antipyretic properties, while 29b shows significant local anesthetic activity [62]. For the treatment of diabetes, a series of hypoglycemic agents derived from pyrazoles have been prepared and tested. The most interesting antidiabetic in this field is WAY-123783 (30) – obtained after extensive SAR studies; it acts by blocking SGTL (sodium-glucose co-transporter) in the kidney [63]. MeO

O N

N

O 28

MeO2C

NH

O

29a, R = Me 29b, R = Ph

OH

MeS

O

N R

N

F 3C 30

N H

N

For the treatment of obesity, Henke from Glaxo Wellcome has optimized a series of 3-(1H-indazol-3-ylmethyl)-1,5-benzodiazepines – potent and orally active CCK-A agonists derived from 31 [64]. Me

OMe N

Me O

31

N N Ph

O

O

H N N H

8.3 Relevant Natural and/or Useful Compounds

Steroidal pyrazoles have long been known. Kirschke [6] has reported several of these compounds, like cortivazol (32) (X-ray structure) [65] and stanozolol (33), both important and commonly used drugs. Cortivazol (32) is an anti-inflammatory glucocorticoid while stanozolol (33) is an anabolic steroid used as androgen. Nivazol (34) also belongs to the glucocorticoid class [66].

HO Me

COCH2OAc Me

Me

OH Me

Me

N

32

HC C HO Me

OH Me

N

Me

N H 33

N

N

N

34 F

Liver alcohol dehydrogenase (EC 1.1.1.1) catalyzes the first step in alcohol metabolism and is a rational target for inhibiting alcohol metabolism. Prevention of poisoning by methanol and damaging effects of ethanol metabolism are potential applications of inhibitors of alcohol dehydrogenase. From the pioneering work of Theorell [67] it is known that pyrazole and some of its 4-substituted derivatives (4methyl, 4-iodo and 4-bromo) are potent inhibitors of ethanol metabolism in vivo. Pyrazoles have been proposed as therapeutic agents for treatment of alcohol intoxication. Unfortunately, pyrazole is itself toxic and may not be useful for longterm treatment of humans. Although some interesting efforts have been made, including X-ray studies and molecular modeling [68], 4-methylpyrazole (fomepizol) continues to be the most efficient and less toxic of all the liver alcohol dehydrogenase inhibitors and inactivators. Note also that pyrazole itself, an alcohol dehydrogenase inhibitor, has dual effects on N-methyl-D-aspartate (NMDA) receptors of hippocampal pyramidal cells, agonist and noncompetitive antagonist [69]. One of the most prominent of the anticancer agents with a pyrazole skeleton is pyrazoloacridine (PZA, 35), 2-(N,N-dimethylaminopropyl)-9-methoxy-5-nitro-(6H)pyrazolo[3,4,5-kl]acridine (NSC 366140). PZA is the first of a new class of rationally synthesized acridine derivatives to undergo clinical testing as an anticancer agent. Recent studies suggest that PZA might be a dual inhibitor of DNA topoisomerases I and II and exerts its effects by diminishing the formation of topoisomerase-DNA adducts. Consistent with this unique mechanism of action, PZA exhibits broadspectrum antitumor activity in pre-clinical models in vivo. In addition, this agent displays several remarkable properties, including solid tumor selectivity, activity against hypoxic cells, and cytotoxicity in noncycling cells. PZA has been studied in phase I trials in adults and children, and is currently undergoing broad phase II trials in several tumor types. No significant anti-tumor activity has been seen in

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gastrointestinal malignancies and prostate cancer. Owing to its unique properties, combination studies with other antineoplastic agents are in progress [70]. N N

(CH2)3NMe2

MeO N H

NO2

35

We end this section by summarizing the most promising fields of application of pyrazoles and indazoles with four compounds. First, edaravone –norphenazone–, 3methyl-1-phenyl-2-pyrazolin-5-one (36), is a very simple compound, known from old, that it is a free radical scavenger and a very potent antioxidant agent against lipid peroxidation. In vivo studies have revealed that edaravone shows brain-protective activity in a transient ischemia model [71]. The second one is tolfenpyrad, 4-chloro-3ethyl-1-methyl-N-[4-(p-tolyloxy)benzyl]pyrazole-5-carboxamide (37) one of the most promising insecticides recently discovered in Japan [72]. Me O

N

O

N

Me

H N O

36

37

Cl

Et N N Me

The normal biological functions regulated by nitric oxide are attributed to three nitric oxide synthase (NOS) isoforms (neuronal, endothelial or inducible macrophage). A dysfunction of these enzymes is implicated in various diseases such as Alzheimer’s disease, septic shock, inflammatory arthritis, schizophrenia, impotence and susceptibility to infection. 1H-Pyrazole-1-carboxamidines are competitive inhibitors of all three isoforms: the most selective compound, 1H-pyrazole-N-(3-aminomethylanilino)-1-carboxamidine, is 100-fold selective for neuronal NOS over endothelial NOS [73]. In the field of neuroprotective activity, studies carried out by Wolff and Gribin [74] on inhibition of nitric oxide synthase by indazole agents confirmed the proposal that 5-nitro-, 6-nitro- and 7-nitroindazoles exert inhibitory actions by interaction of nitric oxide synthase such that oxygen does not bind. 7-Nitroindazole (38), a selective inhibitor of neuronal nitric oxide synthase, has been studied for neuroprotective activity and has been used to investigate the role of nitric oxide [75–77].

N H

O2N 38

N

8.4 Synthesis of Pyrazoles and Indazoles

On 27 March 1998 the US Food and Drug Administration approved sildenafil citrate (Viagra) (39) for treating male erectile dysfunction (MED). The drug works by inhibiting cyclic guanosine monophosphate (cGMP) phosphodiesterase Type 5 (PDE5). Further structural manipulations have included a-thiagra, the thiophene bioisostere [78], and Monagra, a chiral 5-(2-methyl-2,3-dihydro-7-benzofuryl)-pyrazolopyrimidone analog [79]. At Bristol-Myers Squibb a PDE5 screening of a series of pyrazolopyridines identified a lead compound with modest potency. Based on this template, and using parallel synthesis, from a large and diverse library emerged a new pyrazolopyridine showing comparable in vitro functional PDE5 inhibition when compared to sildenafil and improved PDE isozyme selectivity. Thus, due to its pharmacokinetic profile, it is expected to have fewer PDE-related side effects than sildenafil [80]. Me

N N

SO2

Me N

Me

O

H

N O

N N Me

39

8.4 Synthesis of Pyrazoles and Indazoles

Since the synthesis of pyrazoles and indazoles have very few items in common it is better to treat them separately. Ring transformations, when a heterocycle is transformed into a pyrazole (or indazole), are discussed in the synthesis section. On the other hand, cases where a pyrazole (or indazole) is transformed into another heterocycle are reported under reactivity (Section 8.5). For the same reasons, oxido-reduction reactions, for example, transformation of pyrazolines into pyrazoles or vice versa, will also be covered under reactivity. 8.4.1 Synthesis of Pyrazoles

There are many methods for the synthesis of the pyrazole ring; it can be formed both by cyclization and by cycloaddition reactions. The reaction of hydrazines with 1,3dicarbonyl compounds (or their equivalents) is probably the most general and versatile method; however, a disadvantage, in some cases, is the formation of mixtures of isomeric pyrazoles from unsymmetrical dicarbonyl compounds. The 1,3-dipolar cycloaddition reaction of diazo compounds, nitrilimines and azomethine imines with alkynes is also a general route to pyrazoles.

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Scheme 8.7 shows the different possibilities for the creation of the pyrazole ring according to the bonds formed.

Formation of one bond

N

N

N

N

N

N

Formation of two bonds a) from 4 + 1 atom fragments N

b) from 3 + 2 atom fragments

N

N

N

N

N

N

N

N

N

N

N

Scheme 8.7

The synthesis and chemistry of pyrazoles has been the subject of recent reviews [6, 8, 81–84]. 8.4.1.1 Formation of One N–N Bond Dioximes of 1,3-dicarbonyl compounds give oxidative cyclization to 4H-pyrazole-1,2dioxides 42 (Scheme 8.8). Various oxidants have been used, namely lead(IV) acetate [85, 86] and N-bromoacetamide [87–89]. Dehydration of dioximes 41 with thionyl chloride leads to the monooxides 43 [88, 89]. Base-induced cyclization of 1,3diketone dioximes affords 1-hydroxypyrazoles, but in low yield (10–30%) [90].

R2 R1

R2 R1 + N N+ O O42

Oxidant

1

R

HO

R2

R2

N

N 41

1

R

OH

SOCl2/SO2

R2 R1

R2 R1 N N+ O43

Scheme 8.8

Imines 44 react with thionyl chloride, at room temperature, to furnish 1,2,6thiadiazine 1-oxides 45. Thermal extrusion of sulfur monoxide leads to pyrazoles 46 (Scheme 8.9). Alternatively, reaction of imines 44 with thionyl chloride in pyridine at 90  C leads directly to pyrazoles 46 [91, 92]. Iminohydrazones 47 give NH-pyrazoles 48 when treated with an aqueous solution of sulfuric acid (Scheme 8.10). In contrast, they are converted into the N-alkenyl derivatives 49 when treated with an equimolar amount of anhydrous trifluoroacetic acid in dry THF [93].

8.4 Synthesis of Pyrazoles and Indazoles

R4

R3

NH

2

R

NH R1 44

SOCl2, Py, 0 ºC - rt, 2 h

3

R

72-87%

1

R4

2

R

N R1 45

2

N S

toluene, 90 º C, 8 h - SO 73-94%

O

R3 R2

j653

R4 N R1

N

46

3

4

R = Ph, o-Tolyl, p-Tolyl; R = Ph, 4-ClC6H4; R = H, Me, Cl, Br; R = Ph, p-Tolyl, cyclohexyl Scheme 8.9

Me

Cl Ar

N

N H

Cl

2 M H2SO4, THF, rt, 4 h

Ar

66-75%

Me

NH NH N Ph

48

47

Cl

TFA, THF, 50 ºC, 15 h 78-85%

CH2R1

Ar

Me N

Ph

49

N CHR1

Ar = Ph, 4-ClC6H4, 4-MeC6H4; R1 = H, Me Scheme 8.10

8.4.1.2 Formation of One N–C Bond Oxidative cyclization of arylhydrazones 50 leads to 1,3,5-trisubstituted pyrazoles 51 in high yields (Scheme 8.11). Lead tetraacetate [94], manganese dioxide [95] and thianthrene cation radical perchlorate [96] have been used as the oxidants in these transformations. R Ph

HN Ar 50

N

R Oxidant Ph

73-100%

N Ar 51

N

R = Me, Ph

Scheme 8.11

Diazoalkenes 52 give 1,5-electrocyclizations to 3H-pyrazoles 53, which isomerize spontaneously to 1H-pyrazoles 54 (Scheme 8.12). These reactive intermediates can be generated by alkaline decomposition of ethyl alkenylnitrosocarbamates [97], tosylhydrazones of a,b-unsaturated carbonyl compounds [98] or N-methoxypyridaR2 R3

R1 N

N

52 Scheme 8.12

R2 R3

R1 N 53

N

R2 R3

R1 N H 54

N

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zinium salts [99] or from the reaction of carbonyl compounds with ethyl lithiodiazoacetate [100]. 8.4.1.3 Formation of One C–C Bond Dieckmann cyclization of hydrazones 55 leads to 4-hydroxypyrazole-5-carboxylic acid derivatives 56 in moderate to good yields (Scheme 8.13) [101, 102]. Trifluoroacetic anhydride-pyridine induced cyclization of hydrazones 57 affords 1-alkyl-4-trifluoromethylpyrazoles 58 [103]. R3O

R2

O

NaOEt, EtOH, reflux, 2 h

N

39-85%

N R1 55

EtO2C

EtO2C

N R1

R1 = H, Me, Ph R2 = Me, tBu, Ph R3 = Me, Et R2

F3C

R2

HO

TFAA, Py, CHCl3, rt, 4-48 h

O N Me N R1 57

N

56

R2

F3C N R1

15-69% R1 = Me, tBu R2 = H, Et, iPr, Bn, 4-MeC6H4

N

58

Scheme 8.13

When heated with trace amounts of concentrated hydrochloric acid at 140  C for 100 h, azines of methyl ketones 59 are converted into 3,5-dialkyl-5-methyl-2-pyrazolines 60 in 65–79% yields (Scheme 8.14) [104]. Heating these azines with nickel or cobalt(II) halides at 200  C also affords pyrazolines 60 in good yields [105]. Under these conditions, other azines give pyrrole derivatives [105]. When acetone azine is heated at 100  C in the presence of trace amounts of TiCl3, 90% conversion into pyrazoline 60 (R1¼Me) is effected after 20 h [106]. R1 Me

N

N

Me

HCl (trace), 140 ºC, 100 h 65-79%

R1

59 R1 Ph

R2 61

Scheme 8.14

Ph R1

R Me

N H 60

R2

170-200 ºC, 20-30 min

R2

N N

R1 1

Ph

R1 N

R1

N

N

2 62 R

R1 = Me, 65% R1 = Et, 79% R1 = Me(CH2)4, 78%

R1 = R2 = H, 90-95% R1 = H, R2 = Me, 90% R1 = Ph, R2 = H, 85% Ph

8.4 Synthesis of Pyrazoles and Indazoles

Cinnamaldehyde azine and derivatives 61 are converted into pyrazoles 62 in high yields when heated at about 200  C (with or without solvent) (Scheme 8.14) [107]. Other a,b-unsaturated azines behave similarly [108, 109]. The thermal decomposition of polyhalogenated propenal azines can be used for the synthesis of mono- and dihalogenated N-unsubstituted pyrazoles [110]. Treatment of benzyl phenyl ketazine with two equivalents of LDA generates a dianion that, when heated at 65  C for 1 h in THF-HMPA, provides 3,4,5triphenylpyrazole [111]. 8.4.1.4 Formation of Two Bonds 8.4.1.4.1 From 4 þ 1 Atom Fragments Formation of One C–N and One N–N Bond [N-C-C-C þ N] Iminoposphoranes 63 react with 2-azido-cyclopent-1-enecarbaldehyde 64 to afford azidoimines 65. When heated in refluxing toluene, these compounds extrude nitrogen and cyclize to pyrazoles 66 (Scheme 8.15) [112]. R1 N3 + PPh3 PhMe, rt, 4 h - N2 1

R N PPh3 63

+

PhMe, reflux, 4 h

OHC

R1 = Bn, Ph, CH2CO2Et

N3 64

- Ph3PO N R1

N3 65

- N2 36-66%

N R1 66

N

Scheme 8.15

Nitrosation of a,b-unsaturated oximes unsubstituted in the a-position with sodium nitrite and acetic acid leads to pyrazole 1,2-dioxides 68 and 69 while the a-substituted ones afford 1-hydroxypyrazole 2-oxides 70 (Scheme 8.16) [113–115]. Nitrosation of oximes 67 with butyl nitrite in the presence of pyridine and copper sulfate affords copper complexes 71, which can be conveniently converted into the 1hydroxypyrazole 2-oxides 70 [116]. Formation of One C–N and One C–C bond [N-N-C-C þ C] Hydrazones of methyl ketones react with the Vilsmeier–Haack reagent to afford 1H-pyrazole-4-carbaldehydes 74 (method A, Scheme 8.17) [117]. The reaction time can be reduced from 4–5 h to 35–50 s if microwave irradiation is used instead of conventional heating [118]. An interesting variation of method A consists in the substitution of phosphorus oxychloride by cyanuric chloride (2,4,6-trichloro[1,3,5]triazine, TCT) (method B) [119]. This variation requires milder reaction conditions. Condensation of the Vilsmeier–Haack reagent with arylhydrazones of b-ketoesters and c-ketoesters yields, respectively, pyrazole-4-carboxylic acid esters [120] 75 and 4pyrazoleacetic acid esters [121] 76 (Scheme 8.18).

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R1 4

R R3

+ N N+ O OHNO2 68

HNO2

R1

O

R2 = H

+ N N+ O O 69

R3

R2 = R4 = H

2

R

R3

R2

R1

HNO2

R4 N OH 67

R =H

i) CuSO4, EtOH ii) Bu-ONO, Py, rt R1 R2 R3

+ N ON OH 70

R3

4

R1

i) NaOH (dil), EtOH

+ O O N N Cu N N O O + 71

ii) H3O+

R3 R2 R1

Scheme 8.16

R1

Me HN Ar 72

A) POCl3/DMF, 70 - 90 ºC, 4-5 h

N

or B) TCT/DMF, rt, Br > I) that are seldom isolated. 1-Bromopyrazole resembles NBS and can act as a source of the electrophilic brominium ion [4]. 8.5.1.1.8 N-Amination and N-Nitration The powerful aminating agents hydroxylamino-O-sulfonic acid and O-mesitylenesulfonylhydroxylamine have been used to aminate pyrazole and indazole (60% of 1-amino and 40% of 2-aminoindazole) [4]. Amination of C-aminopyrazole 370 affords both diamino isomers 371 and 372 (Scheme 8.114) [323]. R1 H2N

N H

N

370

R1 H2N

N N NH2 371

NH2 +

R1

N N NH2 372

Scheme 8.114

8.5.1.2 Electrophilic Attack at Carbon Pyrazole is less reactive towards electrophiles than pyrrole. As a neutral molecule it reacts as readily as benzene and, as an anion, as readily as phenol. Pyrazole cations (pyrazolium ions), formed in strong acid media, show a pronounced deactivation (nitration, sulfonation, Friedel–Crafts reactions). Electrophilic attack on pyrazoles takes place at C4. 8.5.1.2.1 Nitration Pyrazole is very stable in acid media and even under rather vigorous conditions neither ring opening nor ring oxidation was observed. Nitration occurs at the 4-position; in the case of 4-R substituted pyrazoles, mono- and dinitration at positions 3 and 5 are observed [4]. 8.5.1.2.2 Sulfonation Direct sulfonation of the pyrazole ring is rather difficult due to cation formation and takes place at position 4 only on prolonged heating with 20% oleum [4, 5]. 8.5.1.2.3 H/D Exchange Qualitatively it was observed that in D2SO4 exchange of 1methylpyrazole occurs initially at C4 and then simultaneously at C3 and C5, while in 1,2-dimethylpyrazolium it occurs only at C4 [4, 5]. 8.5.1.2.4 Halogenation Halogenation is one of the most studied electrophilic substitutions in the pyrazole series [4]. Many reagents can chlorinate pyrazoles:

8.5 Reactivity

chlorine-water, chlorine in carbon tetrachloride, hypochlorous acid and chlorine in acetic acid (one of the best experimental procedures). Bromine in chloroform and bromine in acetic acid are the reagents used most often to brominate pyrazoles. To effect polybromination of pyrazoles the use of iron as catalyst is necessary. Pyrazole does not react with iodine although pyrazolsilver is converted into 4iodopyrazole. Ultrasound irradiation using N-halosuccinimides [324], N-iodosuccinimide [325] and a mild and efficient method for the regioselective iodination of pyrazoles have been reported [326]. 8.5.1.2.5 Acylation: Vilsmeier–Haack and Friedel–Crafts reactions 1-Substituted pyrazoles are formylated and acetylated at C4. C-Alkylation of pyrazoles is rather uncommon and only groups like benzyl or adamantyl can be introduced directly on the 4-position. 8.5.1.2.6 Diazo Coupling and Nitrosation Generally, pyrazoles do not react with diazonium salts. However, when an activating group (hydroxy, alkoxy, amino) is present at position 3 or 5, the reaction proceeds easily at position 4. The reaction is very common in pyrazolone chemistry; pyrazolone diazo coupling is an important industrial reaction since the resulting azo derivatives are important dyestuffs, like tartrazine. The behavior of pyrazoles towards nitrosation is similar to that towards diazo coupling. 8.5.2 Reactions with Oxidizing Agents

Pyrazoles are resistant to oxidation but with agents like potassium permanganate the indazole ring is completely destroyed. Side chains can be oxidized; for instance, methyl groups into carboxylic acids. 8.5.2.1 Oxidation The most important of all oxidation reactions in the chemistry of pyrazoles is the aromatization of pyrazolines into pyrazoles. Various oxidizing agents transform pyrazolines into pyrazoles: sulfur, bromine, chloranil, potassium permanganate, lead dioxide and mercury(II) acetate are all effective. The problem is not totally solved, as shown by the numerous papers devoted to this topic. Oxidations using chlorine in CCl4 [327], chloranil [164, 328], trichloroisocyanuric acid [329], Pd/C in acetic acid [330], DDQ [331] and Bi(NO3)3 with MW irradiation [332] have been reported. 8.5.3 Reactions with Nucleophilic Reagents

Little is known about nucleophilic attack on an unsubstituted carbon atom of pyrazoles. Some nucleophiles do not attack the heterocyclic ring carbon atoms but

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instead the substituent linked to nitrogen with subsequent N-deprotection, for instance dequaternization (pyrazolium salts) [4] or debenzylation (pyrazoles and indazoles) [333]. 8.5.3.1 Reduction by Complex Hydrides When an electron (mass spectrometry, electrochemistry) attacks a pyrazolium salt, two different radicals are formed, one leading to a pyrazoline (reduction of a CC double bond) and the other to an open-ring diamine (NN bond cleavage) [334]. With lithium aluminium hydride, D3-pyrazolines and pyrazolidines are obtained from quaternary pyrazolium salts [4]. 8.5.4 Reactions with Bases

This section corresponds to topics like metallation at ring carbon atoms (mainly lithiation) [335], hydrogen/deuterium exchange in neutral pyrazoles and pyrazolium cations, ring cleavage via C-deprotonation (opening to b-amino acrylonitriles or ortho-cyano anilines in the case of indazoles) – all of them of secondary importance. 8.5.5 Reactions of N-Metallated Pyrazoles

The main use of N-metallated pyrazoles and indazoles (sodium or silver salts) is for the preparation of N-substituted derivatives. 8.5.6 Reactions of C-Metallated Pyrazoles

This is a field of growing importance related to Suzuki, Miyaura, Sonogashira [325] and other cross-coupling reactions. Examples of C-arylation [52, 54, 154, 336], Calkylation [154, 159] and C-alkynylation [325, 337, 338] have been reported. 8.5.7 Reactions with Radicals

Expansion of pyrazoles into pyridazines by the action of dichlorocarbenes has been reported [4]. Similarly, indazole and chloroform at 555  C yields 2-chloroquinazoline. Little interest has been shown in the radical reactions (methyl and phenyl radicals) of pyrazoles because they afford mixtures of C-substituted derivatives. A complete study of the chemistry of ground and excited state of ortho-pyrazolylphenyl nitrenes 373 (Scheme 8.115) has been carried out by Carra, Bally and Albini: different kinds of heterocycles have been isolated, amongst them 374–376 [339].

8.5 Reactivity

R R

N

R

N

h

N

N

254 nm

_ N _

R

N

_

N3

R

R

j703 R

R

N

R

+

N

N N

N

+

N

N

HN

NEt2 372, R = H, Me

373

376

374

375

only when R = Me

Scheme 8.115

8.5.8 Reactions with Reducing Agents

The reduction of pyrazole and 1-phenylpyrazole with H2, in the presence of palladium on active charcoal, gives the pyrazolines or, under more drastic conditions, the pyrazolidines [4]. 8.5.9 Ring Transformations 8.5.9.1 Ring Opening without Fragmentation Scheme 8.116 shows two of the most illustrative examples of this kind of reaction: the opening of 1-substituted indazoles 377 into 2-alkylaminobenzonitriles and the rearrangement of 1-(ortho-nitrophenyl)pyrazoles 379 into benzotriazole 1-oxides (cis and trans 381) through intermediate azo compound 380 [4]. R2

R2 N

377

N R1

R1

R2

3

h

CN N 1 R 378

R2

3

R

N

N

R1

R h NO2

X 379, X = H, NO2

O

N

N N

X

O N N N

X O

381

380

Scheme 8.116

8.5.9.2 Ring Isomerization The most studied reaction is the transformation of pyrazoles into imidazoles and of 2substituted indazoles into benzimidazoles. 8.5.9.3 Ring Enlargement In dilute sulfuric acid (pH 2–4) rearrangement of indazoles 382 (Scheme 8.117) into benzimidazoles is suppressed and dihydroazepinones 383 and 384 are formed [4].

R1 R2

R3 O

j 8 Five-Membered Heterocycles: 1,2-Azoles. Part 1. Pyrazoles

704

R2

R2

2

R

O h

1

N

N R

NH

382

383

O +

O

NH

O

384

Scheme 8.117

8.5.10 Electrocyclic Reactions

Concerning Diels–Alder and 1,3-dipolar cycloadditions, pyrazole never reacts as an alkene towards a diene or a 1,3-dipole nor as an azadiene towards a dienophile. There are very few examples of reactions related to this topic: some are reported in Schemes 8.105–8.107 and 8.118 [4, 5]. H

H H

N

MeO2C C C CO2Me

N Ph 385

387

386

MeOC C N N

N

N N Ph

MeO2C MeO2C

Ph

N Me

Ph

Ph H N N

388

N N Me

N N

H+ COMe

COMe

N NH Me 389

Scheme 8.118

Stephanidou-Stephanatou et al. have described the sequence of reactions reported in Scheme 8.119. From the N-benzoyl derivative 390, through bromination and dehydrobromination, pyrazole ortho-quinodimethane 392 was generated and trapped with several dienophiles to afford the Diels–Alder adducts 393 [340].

N O

N

H

Br

Me

Me

NBS

Ph

390 Scheme 8.119

N

Br O

N Ph

391

H Me

Me NaI, DMF N

80 ºC O

N Ph

392

R N O

N Ph

393

8.6 Derivatives

8.6 Derivatives 8.6.1 C-Substituted Pyrazoles and Indazoles

In pyrazoles the simplest way to characterize the carbon atoms is to consider that C3 is similar to the pyridine a-position, C4 to the pyrrole b-position and C5 to both the c-pyridine and the a-pyrrole positions. 8.6.2 Oxy- and Aminopyrazoles and Indazoles

Probably the most studied pyrazole derivatives are the oxy (pyrazolones and indazolones) and the amino derivatives in the order 5-substituted > 3-substituted  4substituted. For a long time, the only comprehensive source on pyrazolones was the book from Wiley and Wiley of 1964 [341]. Fortunately, Varvounis et al. have updated it recently (they use 3-ones for the 3- and 5-ones, a logical but uncommon decision) [342]. Pyrazolin-4-ones exist as 4-hydroxypyrazoles and are much less common [4–6, 8], although deserving attention for their biological potentialities. Indazolones exist as such and not as 3-hydroxyindazoles [343]. The chemistry of pyrazolidinones has been reviewed [344]. 3-, 4- and 5-Aminopyrazoles are interesting in themselves and also as precursors of many pyrazoles with fused five- [345], and six-membered rings [323, 346–349], as well as larger heterocyclic rings [350]. 8.6.3 Other Substituents

The synthesis and reactivity of many different C-substituted pyrazoles have been described in the literature. Some of the most important (because of much studied or because very rare) are: CHO [351], CCR [352], NO2 [353–355], 11 B [356], 19 F [357–360], 31 P [361, 362], 32 S [363], 28 Si (for instance TMS) [364] and 127 I [326, 337, 365, 367]. 8.6.4 N-Substituted Pyrazoles and Indazoles 8.6.4.1 Quaternary Pyrazolium and Indazolium Salts Pyrazolium 394 and indazolium salts 395 main importance was as precursors of D3pyrazolines and indazolines [4, 5]. But in recent years the extraordinary development of ionic liquids has promoted the study of pyrazolium salts as an alternative to imidazolium salts [366, 367]. Pyrazolium salts have been used to generate carbenes [368], and several papers dealing with their mass spectrometry have been published [369].

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706

R4 R5

R3

R3 N R1

N R 2

N R1

394

N R 2

395

8.6.4.2 Azolides N-Acyl azoles (azolides) are much studied compounds both for their use as synthons and for their structural properties [370]. Pyrazolides 396 and related compounds (like the addition products to aldehydes 397 and 398) are in an equilibrium similar to prototropy and only the most stable isomers are usually isolated [371]. R1 N O

N

N

R1

R2

N O

N

N N CH2OH

R2

397

396

H HO N

N OH H

N 398

8.6.4.3 Coordination Chemistry of Pyrazoles As we recalled in the introduction, the use of pyrazoles as ligands is one of the most prominent in their chemistry. Not considering biological properties, which include most patents, this aspect represent 36% of all 2004 references, according to the Chemical Abstracts (Table 8.2). Since this topic has been covered in several reviews, only a classification of the pyrazoles as ligands is described here (see Refs [4, 5, 372–375]). .

Simple pyrazoles: pyrazolate anions. Both examples of pyrazoles acting as exobidentate ligands (399) and, much less common, as endobidentate – chelating – agent (400). N Au N N Au N Au N N 399

. .

N N Cp U Cp Cp

400

Simple pyrazoles: neutral pyrazoles. These compounds act as 2-monohaptopyrazoles. Bis-, tris- and poly-pyrazolyl derivatives: Ligands such as 401 (polypyrazolylmethanes) [376], 402 [poly(pyrazolylmethyl)benzenes] [377], 403 (polypyrazolylbenzenes, propellenes) [315], and 404 (polypyrazolylazines) [378] often form chelate complexes with different metals.

8.6 Derivatives

N N

N

N N

H

N

N

N N

N N

401 .

N N

N

N

N

N N

N N

402

N

N

403

N N

N

N N

N

N N

N

N N

404

Tris(pyrazolyl)borates (scorpionates) [310, 379]: The synthesis by Trofimenko of the pyrazolylborates (bis, tris and tetrakis, the tris 405 being the most interesting) is one of the major discoveries of pyrazole coordination chemistry. The anionic nature of 405, which can be isolated with the Cp anion, confers to 405 and related compounds very rich coordination chemistry.

N

N N N B H N N

405 .

Ferrocenylpyrazoles: The possibility that the pyrazole has a C-substituent with interesting properties has enriched the usefulness of pyrazoles in organometallic chemistry. Amongst these substituents, ferrocene is one of the most promising. Two representative structures are 406 [380] and 407 [381]. Other ferrocene-based pyrazolylborates (similar to 407) have been described by Wagner et al. [382] Multidentate ferrocenyl-pyrazoles have been described by Thiel et al. [383]. F3C

CF3

P(Ph)2 N N Fe

Me

(S)-(R)-406

N

N

N N B N N

Fe

N N B NN N N

407

8.6.5 Chiral Derivatives

The increasing interest in chiral compounds comes from the pharmaceutical industry and from the catalytic properties of coordination complexes (e.g., asymmetric hydrogenation). The chiral pyrazoles can be classified into three groups: (i) the

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chirality is in the substituent; (ii) the chirality is in a fused ring, tetrahydroindazoles from natural chiral ketones; (iii) the chirality pertains to a ring that is partially – pyrazolines – or totally – pyrazolidines – saturated. 8.6.5.1 Pyrazoles bearing N- or C-Chiral Substituents Pyrazoles derived from steroids, carbohydrates and vitamins share the chiral properties of the starting materials. Thus compound 408, an analogue of vitamin D, has been prepared [384]. Others, like 409, a CNS agent, have been obtained by resolution [385]. Pyrazoles substituted at position 3 by (2R)-bornane-10,2-sultam 410 have been described and their annular tautomerism determined by X-ray and NMR spectroscopy [386]. Compounds related to Tr€ oger’s bases, such 411, retain the inherent chirality of this family of compounds [387]. The synthesis of enantiomerically pure 5-substituted pyrazoles from 2,3-dihydro-4H-pyran-4-ones and from 2formyl glycals has been reported (Schemes 8.59 and 8.60) [209, 210]. Me

N H

Me OH N Ph

N

O

H

N S

N Me

Me

N H

NMe2 HO

OH

408

409

N

O

O

Ph N N

N N

N N Ph

411

410

8.6.5.2 Tetrahydroindazoles from the Chiral Pool Here, the most important compound by far is camphopyrazole – (4S,7R)-7,8,8trimethyl-4,5,6,7-tetrahydro-4,7-methano-2H-indazole – 412; this compound and related ones have been the subject of many studies: synthetic [146, 388–390], structural [391], reactivity [392, 393] and coordination chemistry [394, 395]. Other ketones found in natural sources have also been used to prepare compounds such as 413 [396–399]. Me

Me

Me

Me

412

N

R N H

NH Me

Me

N

413

8.6.5.3 Pyrazolines and Pyrazolidines These compounds have several stereogenic centers: carbons C4 and C5 in D2pyrazolines 414 and carbons C3, C4 and C5 in pyrazolidines 415. Even taking into

8.6 Derivatives

j709

account the nitrogen inversion, stereogenic nitrogen atoms should be considered. Chiral pyrazolines have been prepared by resolution [400], and by inclusion in a chiral host [401]. The formation of a ruthenium complex from a racemic pyrazoline lead to diastereomeric structures 416 that have been separated [402].

R4

R3

*

R4

R5 * N N

R3

*

R5 * N

R1

R1

414

415

* N

N *

R2

X

N

* Ru(bpy)

N

2

416

Using cycloaddition methodologies a series of pyrazolines and pyrazolidines enantiomerically pure have been prepared by Barluenga (417, and then reduced to pyrazolidines) [403], 418 [404], Molteni (419) [405], Ortu~ no (420) [406] and Kobayashi (421) (Scheme 8.50) [200]. A highly enantioselective [3 þ 2] acylhydrazone-enol ether cycloaddition has been reported for the preparation of mono-benzoyl (similar to 421) and dibenzoylpyrazolidines [407]. This is a very interesting field that it is expected to become very important in the near future. R4 R

CO2R N

5

R2

RO2C R

N Boc

417

N

5

N Ph

CO2Me R O

N R1

N

R 2P

419

418

X

CO2Me N H

N

420

MeS MeS Ph

N C

R2

N

R2

N

R2

O

422 R

3

Ph

N R1

N

423

R3 N R*

R1 1 R O

N

N O

Me

O

421

A series of compounds by Sibi are worth mentioning in this context: 422 (used for enantioselective intermolecular free radical conjugate additions) [408], 423 (a new ligand system) [409] and 424 (a pyrazolidinone template used with chiral Lewis acids) [410]. R1

NH

R2

424

Finally, the resolution of compounds 425 and 426, whose chirality resides exclusively in the nitrogen atoms, has been reported by Kostyanovsky [411]. For previous studies on chiral nitrogen atoms in pyrazole reduced derivatives due to hindered inversion see Reference [412].

Ph

j 8 Five-Membered Heterocycles: 1,2-Azoles. Part 1. Pyrazoles

710

Me N t Bu

N tBu

Me

N i Pr

425

N iPr

426

8.6.6 Macrocyclic Pyrazoles

This is an important field that has been treated in detail in other monographs [4, 5]. Particularly relevant are the results of Navarro et al. [413–415] (structures 427 and 428) and of Kohnke et al. (429) [416]. O O

HN N

O

O

O

O

O

O O

N NH

O

O HN N

O

RN

N N NR

O

O

O

O

427

N NH

O

N N

N N

N N

O 428

429

8.6.7 Labeled Derivatives

For biological purposes or by spectroscopic necessities (microwave, IR, NMR, etc.) many labeled pyrazoles have been prepared, mainly deuterium and 15 N derivatives for spectroscopy [4, 5, 417], and radioligands for biological studies: tritium [418, 419], 11 C [420], 18 F [421], and 125 I [422].

References 1 Kost, A.N. and Grandberg, I.I. (1996)

Progress in Pyrazole Chemistry – Advanced Heterocyclic Chemistry, 6, 347. 2 Behr, L.C., Fusco, R., and Jarboe, C.H. (1967) in Pyrazoles, Pyrazolines, Pyrazolidines, Indazoles and Condensed Rings (ed. R.H. Wiley), Interscience, New York. 3 Schofield, K., Grimmett, M.R., and Keene, B.R.T. (1976) The Azoles,

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38

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41 42

43

44

45

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46 Merck Index, 11th Edition, (2001). 47 Mosti, L., Menozzi, G., Fossa, P., and

48 49 50

51

52 53

54

55

56

57

58

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and Wagner, M. (2005) Journal of Organometallic Chemistry, 690, 1971. Rossler, K., Kluge, T., Schubert, A., Sun, Y., Herdtweck, E., and Thiel, W.R. (2004) Zeitschrift f€ ur Naturforschung B, 59, 1253. Fall, Y., Barreiro, C., Fern
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ıguez, J.A., Berrocal, J., Gut
errez, B., Farr
e, A.J., and Frigola, J. (1993) Bioorganic & Medicinal Chemistry Letters, 3, 269. Moreno-Ma~ nas, M., Sebasti
an, R.M., Vallribera, A., Piniella, J.F., AlvarezLarena, A., Jimeno, M.L., and Elguero, J. (2001) New Journal of Chemistry, 25, 329. Cudero, J., Pardo, C., Ramos, E., Guti
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j723

j 8 Five-Membered Heterocycles: 1,2-Azoles. Part 1. Pyrazoles

724

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397

398

399

400

401

402

403

404

405

406

Tolman, W.B. (1998) Organometallics, 17, 1984. (a) Kashima, C., Fukuchi, I., and Hosomi, A. (1994) The Journal of Organic Chemistry, 59, 7821; (b) Kashima, C., Fukuchi, I., Takahashi, K., and Hosomi, A. (1996) Tetrahedron, 52, 10335; (c) Kashima, C., Takahashi, K., Fukusaka, K., and Hosomi, A. (1998) Journal of Heterocyclic Chemistry, 35, 503; (d) Kashima, C., Fukusaka, K., Takahashi, K., and Yokoyama, Y. (1999) The Journal of Organic Chemistry, 64, 1108. LeCloux, D.D., Keyes, M.C., Osawa, M., Reynolds, V., and Tolman, W.B. (1994) Inorganic Chemistry, 33, 6361. Chibiryaev, A.M., Popov, S.A., and Tkachev, A.V. (1996) Mendeleev Communications, 18. Faure, R., Frideling, A., Galy, J.-P., Alkorta, I., and Elguero, J. (2002) Heterocycles, 57, 307. Elguero, J., Claramunt, R.M., Shindo, Y., Mukai, M., Roussel, C., Chemlal, A., and Djafri, A. (1987) Chem Scripta, 27, 283. Toda, F., Tanaka, K., Infantes, L., Foces-Foces, C., Claramunt, R.M., and Elguero, J. (1995) Chemical Communications, 1453. Wang, P., Onozawa-Komatsuzaki, N., Katoh, R., Himeda, Y., Sugihara, H., Arakawa, H., and Kasuga, K. (2001) Chemistry Letters, 940. Barluenga, J., Fern
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alez, R., Aguilar, E., Revelli, G.A., Viado, A.L., Fa~ nan
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407

408 409

410

411

412

413

414

415

416

417

418

419

and Ortu~ no, R.M. (2002) Tetrahedron Asymm, 13, 2593. Shirakawa, S., Lombardi, P.J., and Leighton, J.L. (2005) Journal of the American Chemical Society, 127, 9974. Sibi, M.P., Shay, J.J., and Ji, J. (1997) Tetrahedron Letters, 38, 5955. Sibi, M.P., Zhang, R., and Manyem, S. (2003) Journal of the American Chemical Society, 125, 9306. Sibi, M.P., Ma, Z., and Jasperse, C.P. (2004) Journal of the American Chemical Society, 126, 718. Usachev, S.V., Nikiforov, G.A., Strelenko, Y.A., Chervin, I.I., Lyssenko, K.A., and Kostyanovsky, R.G. (2003) Mendeleev Communications, 136. Elguero, J., Marzin, C., and Tizan
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an, V.J., Ochoa, C., Escart
ı, F., Garc
ıa-Espa~ na, E., Latorre, J., Luis, S.V., and Miravet, J.F. (2001) Journal of the American Chemical Society, 123, 10560. Miranda, C., Escart
ı, F., Lamarque, L., Yunta, M.J.R., Navarro, P., Garc
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References Medicinal Chemistry Letters, 13, 4035. 420 Kumar, J.S.D., Prabhakaran, J., Arango, V., Parsey, R.V., Underwood, M.D., Simpson, N.R., Kassir, S.A., Majo, V.J., Van Heertum, R.L., and Mann, J.J. (2004) Bioorganic & Medicinal Chemistry Letters, 14, 2393.

421 Vijaykumar, D., Al-Qahtani, M.H.,

Welch, M.l.J., and Katzenellenbogen, J.A. (2003) Nuclear Medicine and Biology, 30, 397. 422 El-Wetery1, S., El-Azoney1, Kh.M., El-Ghany1, E.A., El-Mohty1, A.A., and Deeb, A. (2001) Journal of Radioanalytical and Nuclear Chemistry, 250, 335.

j725

j727

9 Five-Membered Heterocycles: 1,2-Azoles. Part 2. Isoxazoles and Isothiazoles Artur M.S. Silva, Augusto C. Tom
e, Teresa M.V.D. Pinho e Melo, and Jos
e Elguero

9.1 Introduction

Isoxazole 1 (1,2-oxazole) and isothiazole 2 (1,2-thiazole) are five-membered heterocyclic compounds having a pyridine-like N-atom bonded to an O- or an S-atom, respectively. These N
O and N
S s-bonds are the weakest bonds in each molecule, being their energy much lower than that of N
C, O
C or S
C bonds, and are cleaved in all ring-opening reactions. Isothiazoles react more slowly with nucleophiles than isoxazoles and in both cases the reactions usually originate ringopening [1]. 5

O 1

1

N2

3

4

3

4

5

S

N2

1

2

The first reference to the isoxazole structure 1 was made by Claisen in 1888, for the reaction product of benzoylacetone with hydroxylamine [2]. He proposed the corrected structure (3-methyl-5-phenylisoxazole 3) for a compound isolated several years before and suggested the name monoazole; however, Hantsch modified it to isoxazole, a name derived from the already know isomeric ring oxazole [3]. Claisen reported the fundamental outline of isoxazole chemistry in 1891 [4] and synthesized the parent compound of the series, isoxazole 1, in 1903, by oximation of propargylaldehyde acetal [5]. After the fundamental work of Claisen and coworkers and some other contemporary authors [6], the next important contribution to the chemistry of isoxazoles was made by Quilico in 1946, when he began to study the formation of isoxazoles from N-oxides and acetylenic compounds [7]. The saturated derivatives had long been know (1892) but it was only in the 1960s that these compounds were studied extensively [8]. The extensive studies on isoxazoles since the 1980s are due to their versatility in the synthesis of various compounds, namely heterocycles and natural products, as well as their applications in several fields, such as agriculture, medicine and industry [1, 6, 8, 9]. In terms of the literature on isoxazole derivatives,

Modern Heterocyclic Chemistry, First Edition. Edited by Julio Alvarez-Builla, Juan Jose Vaquero, and José Barluenga. Ó 2011 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2011 by Wiley-VCH Verlag GmbH & Co. KGaA.

j 9 Five-Membered Heterocycles: 1,2-Azoles. Part 2. Isoxazoles and Isothiazoles

728

one can find an enormous number of references on their chemistry, physicochemical and biological properties, as well as some book chapters (in Comprehensive Heterocyclic Chemistry, 1984 [10] updated in 1996 [8], and Science of Synthesis [11–13]) and monographs (Isoxazoles and Related Compounds, published in 1962 by Quilico [14] and Isoxazoles – Part 1 and Part 2, published in 1991 [6] and 1999 [9] by Gr€ unanger and VitaFinzi) which collate all this information. Part 1 of the last monograph is restricted to mononuclear isoxazoles and their hydrogenated derivatives (dihydroisoxazoles and tetrahydroisoxazoles), except for the isoxazolones, while Part 2 is devoted to the chemistry of condensed isoxazoles, namely benzisoxazoles and related compounds. Me O

N

3

Isothiazole (2) was first described in 1956 [15] while the benzisothiazoles have long been known. The most widely known derivative, saccharin (4), the first noncarbohydrate sweetening agent discovered in 1879, is 300–500 times as sweet as sucrose [16]. Saccharin (4) is manufactured commercially by the cyclization of orthosubstituted benzenesulfonamides with strong bases [17]. It still be used in many countries as a non-nutritive sweetener, although it was found that massive doses administered to rats caused bladder cancer, a fact which led to its ban in developing countries [18]. The controversy over its danger when used in small amounts is still unresolved [19]. Although all types of pharmacological activity have been claimed for isothiazoles, some are notable, such as that of thiomuscinol (5) on the central nervous system, as a potent agonist of c-aminobutyrate (GABA) receptors [20], and the significant antifungal activity of isothiazolones (6) (marketed under the name Kathon) [21]. Several reviews on isothiazoles and on benzisothiazoles have been published [21–26]; the chapters in Comprehensive Heterocyclic Chemistry (1984 [16] and updated in 1996 [27]) and Science of Synthesis [28, 29] describe both types of compounds. 4

5 6 7

3a

O 3

NH S 2 O O 4

OH H2N

7a

5

S

N

R2 R3

O S

N R1

6 6a R1 = Me, R2 = R3 = H 6b R1 = Me, R2 = H, R3 = Cl 6c R1 = Me, R2 = R3 = Cl 6d R1 = n-octyl, R2 = R3 =H

9.1.1 Nomenclature

The structure and numbering system of the two mononuclear heterocycles (1 and 2) treated in this chapter and some of their best known derivatives is shown above.

9.2 General Reactivity

j729

However, before discussing their physicochemical properties, synthesis and transformations, it is important to present the structure and nomenclature of all known saturated and benzo-derivatives. For isoxazoles, one can find 4,5-dihydroisoxazoles (7) (also known as D2-isoxazoline or 2-isoxazoline), 2,3-dihydroisoxazoles (8) (also known as D4-isoxazoline or 4-isoxazoline), isoxazolidines (9), 1,2-benzisoxazoles (10), 2,1-benzisoxazoles (11) and 2,3-dihydro-1,2-benzisoxazoles (12). Structure 10 has also been described as indoxazene, 4,5-benzisoxazole, a,b-benzisoxazole and benzo[d] isoxazole (IUPAC nomenclature) and benzisoxazole. It is indexed in Chemical Abstracts as 1,2-benzisoxazole and numbered as shown below. The first member of the family, 3-phenyl-1,2-benzisoxazole (13), was synthesized at the end of the nineteen century (1892) [30] and the 1,2-benzisoxazole itself 10 was obtained in 1908 [31]. Structure 11 has also been described as anthranil, anthroxan, 3,4-benzisoxazole, b,c-benzisoxazole, benzo[c]isoxazole (IUPAC nomenclature) and benzisoxazole. It is indexed in Chemical Abstracts as anthranil and numbered as shown below. 4 5

3

Z

N2

1

5

Z 1

7Z=O 14 Z = S

4

3

4

NH

5

2

8Z=O 15 Z = S

N 13

3

Z 1

NH 2

4

5 6 7

9Z=O 16 Z = S

7a

Z

N2

1

10 Z = O 17 Z = S

4

5

3a 3

3a 3

6 7

7a

N

Z2

1

11 Z = O 18 Z = S

4

5

3a 3

6 7

7a

Z

NH 2

1

12 Z = O 19 Z = S

O

For isothiazoles one can find the same type of dihydroisothiazoles (14 and 15), tetrahydroisothiazoles (16), and benzisothiazoles (17 and 18) and their reduced form (19). The saturated isothiazole 1,1-dioxides 20 are known as sultams and 1,2benzisothiazole 1,1-dioxides 21 are called saccharins. O

R O

S

NR O

20

O

S 21

NH O

9.2 General Reactivity 9.2.1 Relevant Physicochemical Data, Computational Chemistry and NMR Data

The calculated p-electron density distributions of isoxazole (1) and isothiazole (2) are consistent with electrophilic substitution occurring at the 4-position (highest electron

j 9 Five-Membered Heterocycles: 1,2-Azoles. Part 2. Isoxazoles and Isothiazoles

730

density) rather than at other ring positions [32–34]. The positional selectivity in the electrophilic attack on heterocyclic molecules can be explained according to the magnitude of the HOMO electron density of each atomic center [35], which predicts the reactivity order of electrophilic substitution of isoxazole (1) as C4 > C5 > C3, in agreement with the experimental data. Comparison of partial rate factors of isothiazole (2) with those of benzene and related compounds shows that its 4-position is 104 times more reactive towards electrophiles than expected on the basis of the calculated p-electron density at carbon atoms and the electronegativity of the heteroatoms [36]. This indicates that when attempting to correlate the theoretical calculations with chemical reactivity one must be careful and consider whether ground or excited states are involved, or whether it is the electron density of intermediates, rather than the original molecule, that determines the product of a chemical transformation. The p-electron density distribution also suggests that nucleophiles must attack the 3-position of both isoxazole (1) and isothiazole (2) since it presents the lowest electron density. The positional reactivity of isothiazole 2 can also be evaluated by 1 H NMR. The relative rate of deuterium exchange of H5 and H3, under basic conditions, has been demonstrated to be 400 : 1, with no exchange of H4, whereas those of the hydrogens of the methyl groups of 5-, 4- and 3-methyl-isothiazoles were 100 : 1 : 10
4, respectively [37]. The high reactivity of the 5-position can be due not only to the electron distribution in the ground state but also to the stabilization of the formed anion by the s-3d (sulfur) bonding. A similar study with isoxazoles provided the same conclusions [36, 38]. The very low p-order of the N
O bond of isoxazole (1) (Table 9.1) relative to those of the other ring bonds and the largest localized dipole due to the N
O bond suggests that this bond can be a site of attack of hydrolytic reagents, which is in agreement with the experimental reactivity. Jug classified isoxazole (1) in the range of moderate aromatic compounds (1.548–1.332), based on the index of aromaticity, which corresponds to the value of the lowest bond order (Table 9.1, calculated by MO-SINDO1) [39]. These calcula-

Table 9.1 Calculated p-bond orders of isoxazole (1) and isothiazole (2).

X(O,S)-N

N-C

C3-C4

C4-C5

C-X(O,S)

Calculation method

Compound, Reference

0.285 0.412 0.404 0.296 1.361 0.502 0.474 0.227

0.795 0.772 0.735 0.858 1.957 0.705 0.707 0.870

0.546 0.580 0.617 0.452 1.501 0.634 — 0.410

0.817 0.776 0.738 0.833 1.955 0.707 — 0.850

0.342 0.458 0.526 0.448 1.498 0.594 — 0.302

HMO MO-LCAO PPP-SCF-CI CNDO/2 MO-SINDO1 HMO PPP CNDO/2

1, [42] 1, [43] 1, [44] 1, [45] 1, [39] 2, [21] 2, [46] 2, [34]

9.2 General Reactivity

tions indicate that isoxazole (1) (1.361) is less aromatic than oxazole (1.392) and imidazole (1.423) but more than pyrazole (1.297). These results have been confirmed by using other quantitative measurements of aromaticity, such as empirical resonance energy values for heteroaromatic systems as well as conjugation energies [40]. The aromaticity of isothiazole (2) is greater than that of isoxazole (1), just as the aromaticity of thiophene is greater than that of furan. The tendency of 1 JCC coupling constants in 13 C NMR to converge towards that of benzene (56 Hz) is another possible criterion of degree of aromaticity, increasing with the convergence [41]. Although an interesting model, these coupling constants also depend on the geometry of the molecule. The fact that isothiazole (2) is planar and their 1JCC (1JC3
C4 52.5 Hz and 1JC4
C5 62.2 Hz) are less divergent than those of the less aromatic isoxazole (1) (1JC3
C4 48.7 Hz and 1JC4
C5) 67.7 Hz) seems to support this method. The proton resonances of isoxazole (1) and isothiazole (2) are strictly related to electron density distribution on the ring (referred above). The 1 H NMR spectrum of isoxazole (1), neat or dissolved in various solvents, has been reported in many papers (Table 9.2) [34, 47–49]. The signals of H4 (d, 6.28–6.41 ppm) appear at lower frequency values than those of H3 (d, 8.15–8.40 ppm) and H5 (d, 8.39–8.61 ppm), but all of them are in the aromatic region. For isothiazole (2) the same kind of chemical shifts appears, H5 is at a higher frequency than H3, but in some cases it can be reversed. The resonance is deshielded (0.5 ppm) when spectra are acquired in DMSO-d6 solution, owing to the interaction of this hydrogen with proton acceptors.

Table 9.2

1

H NMR chemical shifts (d, ppm) of some isoxazole and isothiazole derivatives.

Compound

H3

H4

H5

3

3

3

1 [47] 1 [48] 1 [49] 1 [34] 22 [49] 23 [49] 24 [49] 25 [49] 26 [49] 27 [49] 28 [52] 29 [49] 2 [53] 30 [53] 31 [53] 32 [53]

8.34 8.40 8.19 8.15 (2.28) 7.90 (2.24) — 8.43 8.15 — — 8.54 (2.46) 8.24 8.24

6.41 6.40 6.32 6.28 6.02 5.85 5.85 6.58 — 6.39 — 6.74 7.26 7.00 (2.32) 6.92

8.51 8.61 8.44 8.39 8.13 (2.42) (2.41) 8.39 8.58 — 9.08 — 8.72 8.54 8.21 (2.56)

1.5 1.7 1.6 1.78 — 1.6 — — — 2.0 — — 1.66 — — 1.63

1.5 1.7 1.6 1.69 1.6 — — 1.6 — — — — 4.66 4.55 — —

— 0.5 — 0.27 — — — — — — — — 0.15 — 0.33 —

JH3
H4 (Hz)

JH4
H5 (Hz)

JH3
H5 (Hz)

Solvent CDCl3 Neat CCl4 CS2 CCl4 CCl4 CCl4 CCl4 CCl4 CCl4 CHCl3 CCl4 CCl4 CCl4 CCl4 CCl4

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j 9 Five-Membered Heterocycles: 1,2-Azoles. Part 2. Isoxazoles and Isothiazoles

732

Me Z

N

Me

Z

N

23 Z = O 32 Z = S

22 Z = O 30 Z = S

O

N

O

25 Me Me

O 24

N

N

O

N

28

26

Me S 31

N

O 27

N

O

N

29

The interaction between H3 and the ring nitrogen atom, due to the quadrupole relaxation of 14 N, is responsible for the broadening of H3 signals of isoxazole and isothiazole derivatives. This broadening is sometimes the diagnostic for the differentiation of H3 and H5 resonances and it is generally reduced in solvents with high viscosity, lower temperatures or nitrogen protonation [2 Jð14 N3-H3Þ from 10 to 3 Hz] [47, 50]. As one can see from Table 9.2, the presence of methyl substituents (electrondonating groups) causes a shielding in the resonances of the isoxazole 22–24 and isothiazole 30–32 protons. The 1 H NMR spectra of methylisoxazoles can be used as a tool to calculate the ratio of 3- and 5-methylisoxazoles in some reaction mixtures and to determine the isomeric purity of products, since the chemical shift of the corresponding methyl groups are very different. The 1 H NMR chemical shifts of the isoxazole ring of 3-, 4- and 5-phenylisoxazoles 25–27 seem to indicate a different conformation for these compounds, presenting different angles between the planes of the two ring, the most important being that of 5-phenylisoxazole (27). This conclusion is based on the deshielding effect of the phenyl ring on the protons lying in the same plane, which decreases with increasing torsional angle. The resonance of H4 can also be used to distinguish between isomeric 3,5disubstituted isoxazoles [51]. In the case of unsymmetrical 3(5)-substituted-5(3)phenyl-isoxazole derivatives bearing one substituent more electron-donating than the phenyl ring, the H4 resonance is shielded (Dd 0.03–0.80 ppm) for the isomers where the electron-donating substituent group is at the 5-position. Opposite results were obtained for those compounds containing stronger electron-withdrawing groups. In these cases the H4 resonance is deshielded (Dd 0.11–0.31 ppm) for compounds bearing an electron-withdrawing substituent at the 5-position of the isoxazole ring compared to those of the 3-isomer. The 1 H NMR spectra of 1,2-benzisoxazole and 1,2-benzisothiazole derivatives have the characteristics of both condensed benzene and isoxazole/isothiazole rings. A typical resonance of these compounds is that of H3, which appears around d 8.7–8.8 ppm and presents long-range coupling with H-7 (5J 0.9–1.2 Hz) due to the well-known zigzag route [22, 54]. The vicinal coupling constants of the phenyl ring protons are consistent with some degree of ortho-quinonoid structure and

9.2 General Reactivity Table 9.3

13

C NMR chemical shifts (d, ppm) of some isoxazole and isothiazole derivatives.

Comp.

C3

C4

C5

Comp.

C3

C4

C5

1 [56] 22 [57] 23 [57]

150.0 159.2 150.9

140.5 105.7 101.4

158.9 159.2 169.2

2 [58] 30 [58] 32 [58]

157.0 166.7 157.6

123.4 123.9 123.3

147.8 148.1 163.0

Table 9.4 Physical properties of isoxazole, isothiazole and their fused benzo-derivatives.

Compound

1

10

11

2

17

18

Mp ( C) Bp ( C/mmHg) pKa Dipole moment (m, D)


80 95/769
2.03 2.90

— 84/11 — —

— 994.5/11 — —

— 113/760
0.51 —

37 — — 2.44

242/760
0.05 —

correlate with the bond orders of 2,1-benzisoxazoles and 2,1-benzisothiazoles (3JH43 H5  9 Hz and JH5-H6  7.5 Hz) [55]. Table 9.3 presents the 13 C resonances of isoxazole (1), isothiazole (2) and some of their methyl derivatives as examples of the 13 C NMR spectra of such compounds. The presence of a methyl group as ring substituent implies a deshielding into the signal of the carbon to which the methyl is bonded. A comprehensive collection of 1 H and 13 C NMR chemical shifts of several isoxazole derivatives is reported in the first monograph of isoxazoles [6]. Unsubstituted isoxazole (1) (Table 9.4) and its alkylisoxazole derivatives are usually liquids; the introduction on the ring of more than one substituent with a long chain leads to solid compounds. Phenylisoxazoles are usually solids [6]. Isothiazole (2) and their alkylisothiazole and benzisothiazole derivatives are usually liquids or solids with low melting points (Table 9.4). The presence of polar substituents increases the melting points. Isothiazole (2) has a low solubility in water (3.5%) and is miscible with most organic solvents. Benzisothiazoles are insoluble in water, but are soluble in strong acids (salt formation) and in organic solvents [6]. Table 9.4 shows the physical properties of unsubstituted compounds, isoxazole (1) and isothiazole (2), and their fused benzo-derivatives, 1,2- and 2,1-benzisoxazole (10) and (11) and 1,2- and 2,1-benzisothiazole (17) and (18), discussed in this chapter. 9.2.2 Tautomerism

Annular tautomerism does not occur in isoxazoles, benzisoxazoles, isothiazoles and benzisothiazoles, but they present some substituent tautomers. Isoxazolin-3(5)-ones

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j 9 Five-Membered Heterocycles: 1,2-Azoles. Part 2. Isoxazoles and Isothiazoles

734

or isothiazolin-3(5)-ones can exist in equilibrium with the corresponding hydroxyderivatives. Isoxazolin-3-ones or isothiazolin-3-ones have been more studied than the corresponding 5-substituted derivatives. The spectroscopic data indicate that they exist as 3-hydroxy tautomers in solid state or in non-polar solvents, such as cyclohexane or ether, but more polar solvents resulted in a great contribution of the keto tautomers [6, 21, 59, 60]. In the solid state these compounds form hydrogenbonded dimers 33. One of the best known 3-hydroxyisoxazoles, due its important neuropharmacological activity, is the natural compound muscinol (34), isolated from an Amanita species [61, 62]. O H Z

N

N

Z

OH H2N

H O

O 34

33

N

The infrared (IR) spectra have been useful in establishing the position of the tautomeric equilibrium in 1,2-benzisoxazolin-3-one. The enol form of 35 is preferred in the solid state, as shown by the strong band at 3000–2500 cm
1 and the lack of carbonyl band and the C¼N band at 1620 cm
1. Both tautomeric forms are present in chloroform solution, since the carbonyl (1670 cm
1) and hydroxyl band (as above) are present [63]. However, X-ray and other spectroscopic data show that 1,2-benzisothiazolin-3-one and its derivatives, 2,1-benzisothiazolin-3-one and saccharin, all exist in the keto form [64]. Studies on tautomerism have shown that in general isoxazolin-4-ones exist preferentially as 4-hydroxy-isoxazoles [65]. The structure of the bioactive natural compound triumferol (36) has also been established as a 4-hydroxy-derivative by 1 H NMR (dH3 8.25 ppm, dH5 8.33 ppm, dOH 8.18 ppm, acetone-d6) and O-acyl and O-methyl derivatives [66]. OH O

O

N 35

O

NH

HO O

N

36

9.3 Relevant Natural and/or Useful Compounds

Although isoxazole and isothiazole moieties are rarely found in nature, they present important biological applications. Muscinol (34), a potent CNS depressant and agonist of the neurotransmitter 4-aminobutyric acid [67], has been isolated from Amanita muscaria [61, 62]. The naturally occurring amino acid ibotenic acid (37), a widely used neurotoxin and pharmacological tool for studies of glutamic acid receptors [68], has also been isolated from Amanita muscaria and from Amanita pantherina [62]. Brassilexin (38a) and sinalexin (38b) are

9.3 Relevant Natural and/or Useful Compounds

j735

phytoalexins, with fungicidal activity, isolated from the leaves of Brassica juncea (Cruciferae) [69, 70]. Aulosirazole (39) is the major cytotoxin in the blue-green alga (cyanobacterium) Aulosira fertilissima Ghose. It shows selective cytotoxicity against solid tumors [71]. OH O

OH HO2C NH2

N

O

OMe

N S

N R 38a, R = H 38b, R = OMe

37

S O

N

39

Isoxazoles are a large group of heterocyclic compounds that display interesting medicinal, agricultural and some other industrial utilities. Some of the most important are the pharmacologically active isoxazoles, including antibacterial sulfonamides 40–42, semi-synthetic penicillins 43–46, semi-synthetic cephalosporin 47, anabolic steroid 48 and the monoamine oxidase inhibitor 49 (used in psychotherapy) [72]. O

NH2 HO2C 1

R

Me Me

RN SO2

N

Me

2

S

HC Me

O N

R1

O 43 R = R = H, Oxacillin 44 R1 = H, R2 = Cl, Chloxacillin 45 R1 = R2 = Cl, Dichloxacillin 46 R1 = R2 = Cl, Floxacillin

Me O 40 R = R1 = H, Sulfamethoxazole 41 R = H, R1 = Me, Sulfisoxazole 42 R = Ac, R1 = Me, Acetylsulfisoxazole

AcOH2C

2 OR

N H

S 1

N

HO2C

N

O

O N H Me

47 Cefoxazole

Cl O

N

Me

HN NH

N O 49 Isocarboxazid

Me

H H

N

O

C OH

48 Danazol

The isosteric relationship of 1,2-benzisoxazole with that of the indole nucleus has led to its use as a carrier of pharmacophoric moieties in the search for potential drugs. From the many compounds studied, only a few have emerged as candidates for clinical use. 1,2-Benzisoxazole-3-sulfonamide 50 (zonisamide) is a potent antiepileptic drug [73], 6-fluoro-1,2-benzisoxazole 51 (risperidone) is a potent antipsychotic agent with thymosthenic properties [74], its analogue 52 (HRP 913) is a potent dopamine antagonist with antipsychotic properties [75], and 1,2-benzisoxazole-3acetamidoxime 53 (PF-257) is a psychotropic agent with seemingly new properties [76]. Phosphonate 54 (Bay 52957) is a potent insecticide [77]

H

j 9 Five-Membered Heterocycles: 1,2-Azoles. Part 2. Isoxazoles and Isothiazoles

736

O R2

N

R1 O

F

N

1

O

N

N

NH

N

Me

N

N

52

O

2

50 R = CH2SO2NH2, R = H 53 R1 = CH2C(NH2)NOH, R2 = H 54 R1 = OP(S)(OC2H5)2, R2 = Cl

F O

N

51

As referred to in the introduction, the most widely known isoxazole derivative is the benzisothiazole saccharin (4), the first non-carbohydrate sweetening agent discovered [16, 27]. Although many isothiazole compounds exhibited biological activities (all types of pharmacological activity have been claimed!), the most important are (i) saccharin derivative 55, which presents potent sedative, hypnotic and anticonvulsant activity [78]; (ii) the adrenergic b-blockers 56 [79]; (iii) the cyclizine analogue 57, which presents appetite suppressant activity [80]; (iv) the amide 58, which has potent antiinflammatory activity [81]; (v) thiomuscinol (5), which is active on the CNS as a potent agonist of GABA receptors (Section 9.1) [20]; (vi) the acid 59, the most interesting compound in the agrochemical sphere, having high herbicidal activity [17, 78]; and (vi) the allyloxy-1,2-benzisothiazole 1,1-dioxide 60, known as Probenazole or Oryzaemate, which is useful in rice crop protection [82]. O NCH(C2H5)CONH2 S O O

S

N 56

N

55

N H 58

CH2CO2H

Me

O S

N

Cl

Me

OCH2CH(OH)CH2NHBut

R

S 59

N

N H3C

S

N

57

OCH2CH=CH2 N S O O

60

Numerous biological, pharmacological and biocidal activities are fully described in reviews and monographs published about the compounds treated in this chapter [6, 8–10, 16, 26, 27, 83]. 9.4 Synthesis of Isoxazoles and Isothiazoles 9.4.1 Isoxazoles

Synthetic methodologies for the construction of the isoxazole ring can be classified based on the number of atoms of the component synthons, which are subdivided

9.4 Synthesis of Isoxazoles and Isothiazoles

j737

according to the type and arrangement of the atoms in each component. The [3 þ 2] approach includes the two major routes to isoxazoles: CCC þ NO reactions (reaction of hydroxylamine with a three-carbon atom component) and CNO þ CC reactions (1,3-dipolar cycloaddition of nitrile oxides). Isoxazoles can also be obtained via [4 þ 1], [5 þ 0] and [3 þ 1 þ 1] routes. Ring transformation reactions also lead to isoxazoles. 9.4.1.1 [3 þ 2] Routes 9.4.1.1.1 [CCC þ NO] Reactions: Reactions of Hydroxylamine with a Three-Carbon Atom Component In 1888 Claisen described the first general synthesis of isoxazoles [2]. The process involved the reaction of b-diketones with hydroxylamine followed by cyclization–dehydration of the intermediate oxime (Scheme 9.1). This became an important route to 4-unsubstituted or 4-substituted isoxazoles bearing the same substituent at 3- and 5-positions. 4-Monosubstituted isoxazoles 62 and unsubstituted isoxazole 61 have also been prepared from the reaction of tetraalkoxypropanes (or b-dialdehydes) with hydroxylamine (Scheme 9.1) [6, 10, 84, 85]. This route was applied to the synthesis of 3,5-disubstituted isoxazole-4-carbaldehydes using also diketones as the three-carbon building-block in the reaction with hydroxylamine [86]. O O

R

R R'

+ NH2OH

R' - H2O

R

R

HO O

R

R' - H2O

N

R

R

O

N

R

CH(OEt)2

R

O

R

R' N OH

NH2OH.HCl

CH(OEt)2

O

72% 61 R = H 62 R = Me, Et or Ph 43-67%

N

Scheme 9.1

The drawback of this approach is that unsymmetrical 1,3-diketones or their derivatives can lead to mixtures of the two isomeric isoxazoles. This is the case in the solid-phase synthesis of isoxazoles outlined in Scheme 9.2 [87]. However, the HO2C R1

H2N

SO2

O

O2 S

DIC, DIEA, cat. DMAP 1:1 THF/DCM, r.t. 3 h

NH2OH 50-60 ºC

O2 S

O N H

O R1

+ isomer Scheme 9.2

O N H

O 1

R

R2CO2Me 80-90 ºC, 1 h

1. Me3SiCHN2 1:1 THF/hexanes N O 2. NHR2 R2 R2

O2 S

NaH, DMA

R1 O

N

O

O

N H

R2

R

NR2 O

O

1

R2N

R2

O R1

O

N

j 9 Five-Membered Heterocycles: 1,2-Azoles. Part 2. Isoxazoles and Isothiazoles

738

selection of a CCC synthon with dissimilar terminal carbon atoms in terms of electronic and/or steric effects, the protection of one terminal carbon or the control of the pH of the medium can lead to selectivity. Nevertheless, many variants of this reaction have been developed and in fact isoxazoles have been prepared from the reaction of hydroxylamine with several three-carbon atom components, namely b-keto aldehydes, b-keto esters, a-acetylenic ketones or aldehydes, a,b-unsaturated ketones, b-imino nitriles and b-keto nitriles [6, 10, 84, 85]. 3-Hydroxy-isoxazole is a synthetic unit present in several biologically active compounds. They have been prepared mainly by cyclization of b-keto esters with hydroxylamine. However, this method usually leads to the formation of isoxazol-5ones as a by-product. By using Meldrum’s acids the problem of the lack of regioselectivity in the addition of hydroxylamine can be overcome (Scheme 9.3) [88].

O O

O

RCOCl pyridine/DCM

O

0 ºC, 1.5 h then rt 1.5 h O 74-100%

O

OH R

O

OBoc HN Boc Toluene, 65 ºC, 4 h 53-91%

Boc N OBoc

R O

O

OH

MeOH/HCl conc. 50 ºC 1 h or 4 M HCl aq./MeOH rt 16 h

O

R

O

N

76-99%

Scheme 9.3

The regioselective synthesis of 5-substituted 3-alkoxyisoxazoles can be achieved using b-oxo thionoesters (Table 9.5, entry 1) [89]. 3-Aryl-5-alkoxyisoxazoles have been obtained in moderate yields from cyclocondensation of acylketene O,S-acetals with hydroxylamine in the presence of sodium alkoxide/alcohol (Table 9.5, entry 2). 5Alkoxy-3,4-annulated isoxazoles can also be obtained using the same synthetic approach (Table 9.5, entry 3) [90]. The a-keto methylene group in 3,5-diarylcyclohexen-2-ones has been used to obtain fused isoxazoles via Claisen-like condensation with ethyl formate followed by cyclocondensation with hydroxylamine hydrochloride (Table 9.5, entry 4). The same type of approach can be applied to prepare other types of fused isoxazoles [91], including those derived from triterpenoids, namely methyl oleanonate and lanost-8en-3-one [92]. The reaction of vinyl ketones bearing a potential leaving group at the b-position (such as halogen, alkoxy or dialkylamino) with hydroxylamine has been extensively explored (Scheme 9.4) [6, 10, 84, 85, 93, 94]. The amine exchange reaction of an enamine ketone has also been used for the regioselective synthesis of 4,5-diarylisoxazoles [95–98]. The one-pot reaction of enamino ketones 63 with hydroxylamine hydrochloride leads to the corresponding

9.4 Synthesis of Isoxazoles and Isothiazoles

j739

Table 9.5 Reaction of hydroxylamine with three-carbon atom components.

1 [10]

R

OEt OH

S

OR1 2 [90]

O

3 [90]

H

NaOR1/R1OH

Ar

reflux, 8-10 h 45-53%

4 [91]

Ar

Ar

OMe

CH2Ph

5 [104]

R2 6 [108]

O

CCl3

NH2

OR

MeO

N

Ph

Ar

R

N

R1 = Me, Et or n-Pr

n

R1O

O

X = CH2, n = 1, R1 = Et X = S, n = 2, R1 = Me

N

Ar

NH2OH.HCl/AcOH OH 70-80 ºC, 6-8 h 75-78%

Ar

NH2OH.HCl/NEt3

MeO2C

EtOH, reflux, 5 h 73%

Me

N

O

CH2Ph O

N

R2 R3O

R1 O

N R3 = H, Me, Et or Pri Ph

40%

O Ar

Ar

O

NH2OH.HCl, NaOH MeOH, reflux, 4 h

Na2CO3

O

X

Ar

NH2OH.HCl O

N

65-95%

H

pH 3-5 81-94%

OH

O

Ph

8 [110]

O

NH2OH.HCl/H2SO4 conc. R3OH, reflux, 8-12 h

R1

F3C(F2C)4 7 [109]

R1O

O

1. HCO2Et NaOMe 2. HCl aq.

N

Ar

reflux, 8-10 h 45-53%

O

Me

O

NaOR1/R1OH

OR O

O

N

OEt

OEt CH3OH/H2O reflux, 3 h

R

NH2OH.HCl

X

n 1

O

O

NH2OH.HCl

R2S

R2S

OEt

NH2OH.HCl rt, 2 h HO NEt3/CH3CN R 68-82%

F3C(F2C)4

Ph

Ar = C6H4-OMe-p

O

N

NH2OH.HCl pyridine/EtOH reflux, 3 h

Ar N

O

Ph

j 9 Five-Membered Heterocycles: 1,2-Azoles. Part 2. Isoxazoles and Isothiazoles

740

EtO2C R

O

N

NH2OH.HCl NaHCO3/EtOH/H2O

R1

R = CO2Et R2 = OEt

NH2OH.HCl

R2

R

1

R1 = H R2 = NR'2

O

R

O

N

Scheme 9.4

isoxazoles 64 (Scheme 9.5) [95]. This strategy has been applied to the synthesis of the cholinergic channel activator ABT-418 [99].

O Ar

NH2OH.HCl Na2CO3 MeOH/H2O

2

Ar

1

NMe2 63

O

Ar2

Ar1

pH 4-5 (AcOH) reflux, 2 h - HNMe2

Ar2

H+

Ar2

NH Ar1 O HO

HOHN

88-99% Ar1

O

N

64

Scheme 9.5

The reaction of 2-acyl-3-(dimethylamino)propenoates with hydroxylamine in refluxing methanol leads to 5-substituted isoxazole-4-carboxylates in high yields (68–90%) [100] and open-chain and cyclohexane syn-2-(dimethylamino)ethylene-1,3diones are converted into 5-substituted 4-acylisoxazoles [101]. A cellulose-based resin has also been used to prepare 5-substituted isoxazole-4-carboxylates via in situ generation of a polymer-bound enaminone [101–103]. The same strategy can be used to prepare tri-substituted isoxazoles. In fact, a b-enamino ketoester reacts with hydroxylamine hydrochloride in the presence of triethylamine to give a tri-substituted isoxazole (e.g., Table 9.5, entry 5) [104–107]. The reaction of vinyl ketones bearing a potential leaving group (bromo or benzotriazole) at the a position with hydroxylamine has also been reported (Scheme 9.6) [111, 112]. Depending on the leaving group or the experimental conditions 3(5)-substituted-5(3)-phenylisoxazoles are regioselectively obtained. R Ph

O

Br Ph NH2OH.HCl NH2OH.HCl NaOEt in abs. EtOH K2CO3 in 95% EtOH R O 1h R = Me, Et, Prn or Pr1

N

30-49% Bt

Ph O

Bt

RCHO EtOH, rt 40 h 55-66%

Scheme 9.6

R

Bt

Ph O

NH2OH

R

Ph O

N

Ph R

O

N

25-33% Ph

55-81% - BtH

R

O

N

9.4 Synthesis of Isoxazoles and Isothiazoles

Reaction conditions were found to allow the exclusive formation of isoxazole-5carboxylic acid derivatives by conjugate addition, in acidic medium, of hydroxylamine to a b-alkoxyvinyl trichloromethyl ketone (Table 9.5, entry 6) [108]. The trichloromethyl group is the carboxyl group precursor: using water as solvent it leads to the formation of carboxylic acids whereas the use of an alcohol leads to ester derivatives. In contrast, the b-perfluoroalkyl-b-alkoxyvinyl phenyl ketone undergoes a selective attack on the carbonyl group upon reacting with hydroxylamine in basic medium, affording an isoxazole bearing a perfluoroalkyl substituent (Table 9.5, entry 7) [109]. Isoxazoles can be obtained via oxidative cyclization of a,b-unsaturated oximes with iodine/potassium iodide [113], with N-bromosuccinimide [114] or with palladium complexes in the presence of sodium phenoxide [115]. 3,5-Diarylisoxazoles can also be obtained using lead(IV) acetate as oxidant, although in moderate yields (24–28%) [116]. The method of preparation of 3,5-disubstituted isoxazoles by oxidative closure of a,b-unsaturated oximes can be carried out using tetrakis(pyridine)cobalt(II) dichromate (TPCD) as oxidant, under mild reaction conditions and very short reaction time (Scheme 9.7) [117]. A route to ABT-418 involving the same type of strategy for the isoxazole ring has been described [118].

Ar2

Ar1 HO

N

Ar1 TPCD/60% AcOH aq. 60 ºC, 1 min

Ar2

O

N

51-94%

Scheme 9.7

The synthesis of isoxazoles attached to sugar moieties via oxidative cyclization of a,b-unsaturated oximes has been reported [119]. The isoxazoles were obtained by reacting the oximes with potassium iodide and sodium hydrogen carbonate at 100  C (64–68% yield). The reaction of a,b-alkynic ketones with hydroxylamine hydrochloride gives 3- or 5-substituted isoxazole isomers, depending on the conditions used (Table 9.5, entry 8) [110]. This route to isoxazoles has been applied to the synthesis of non-proteinogenic isoxazole substituted a-amino acids [120]. 9.4.1.1.2 [CNO þ CC] Reactions: 1,3-Dipolar Cycloaddition of Nitrile Oxides The study of Quilico et al. on the formation of isoxazoles from nitrile oxides and unsaturated compounds is a milestone in the chemistry of isoxazoles [7]. Since then, the 1,3-dipolar cycloaddition of nitrile oxides has became an important approach to isoxazoles [6, 10, 85, 86, 121, 122]. Nitrile oxides can undergo dimerization to give furoxans (1,2,5-oxadiazole-2-oxides), the rate of this process being strongly dependent on the nature of the nitrile oxide substituent. Thus, steric and electronic effects determine the stability of the nitrile oxides, as illustrated by the time required for complete dimerization of some derivatives (Table 9.6) [123]. To avoid dimerization, nitrile oxides are usually generated in situ.

j741

j 9 Five-Membered Heterocycles: 1,2-Azoles. Part 2. Isoxazoles and Isothiazoles

742

Table 9.6 Stability of some nitrile oxides towards dimerization to furoxans [123].

R 2 R

N O

N

R O

N O

furoxans

R

Complete dimerization (at 18  C)

R

Complete dimerization (at 18  C)

Methyl t-Butyl Phenyl

70%

Scheme 10.152

Simple thiazolidine has been obtained by reacting at rt cysteamine hydrochloride with formaldehyde. Under these reaction conditions cysteamine can be replaced by aziridine and hydrogen sulfide [434]. Diastereomeric mixtures have obtained by reacting N-protected amino glyoxals 267 with L-cysteine methyl ester (268) (Scheme 10.153) [435].

CbzHN

O

R 267

H O

+

HS

KHCO3 MeO2C EtOH/H2O

H2N CO2Me 268

NHCbz

NH S > 90%

R O

Scheme 10.153

Several derivatives of carbonyl compounds can be used, such as acetals [436], hemiacetals [437], Schiff bases and orthoesters. The reaction of N-tosylaminoalcohols with orthoformates affords 2-methoxy-oxazolidines 269 that react with allyltrimethylsilane or trimethylsililenolether at 0  C in a zinc chloride or trimethylsilyl triflatecatalyzed reaction to afford new oxazolidine derivatives [438]. The kinetic derivative

10.5 Derivatives R5 Ts NH

R4

R4

MeSO3H

OH

HC(OMe)3

R5

> 95%

TMS

O N Ts

OMe

269

TMSOTf 0 °C 30-72 %

R4

R5

O

R4

TMSOTf

R5

rt > 95%

N Ts

j889

270

O N Ts 271

Scheme 10.154

270 isomerizes to the all-cis oxazolidine 271 when treated at room temperature with TMSOTf (Scheme 10.154). Similar reactivity is found with titanium enolates [439]. Similar substrates, in the enantiopure form, have been obtained in the solid phase by reaction of enantiopure aminoalcohols with solid-supported aldehydes and subsequent reaction with a sulfonyl chloride [440]. A new procedure for the formation of oxazolidines derived from ketones has been reported. It is based on the use of isopropoxytrimethylsilane and a catalytic amount of trimethylsilyl trifluoromethanesulfonate and has found application in the synthesis of a polymer-supported oxazolidine aldehyde [441]. A vicinal aminoalcohol moiety is a perfect starting point for the construction of an oxazolidine ring; however, if the oxazolidine ring is built up in a different manner, hydrolysis of the ring is an efficient way to obtain aminoalcohols in stereoselective fashion. Intramolecular conjugate addition of the N-hydroxymethyl moiety onto an a,b-unsaturated ester affords the corresponding oxazolidine 272 with high stereoselectivity. Finally, the oxazolidine ring was cleaved (Scheme 10.155) [442].

Boc

N

OH

N

K2CO3

CO2Me

MeO2C

ClNH3

Boc 1) HCl 2) ion exchange resin

O 272

OH

85%

CO2Me 41%

(-)-statine

Scheme 10.155

Recently, a novel MCR has been developed using four components for the synthesis of highly substituted 1,3-oxazolidines. The reaction may be catalyzed by transition metals; however, the use of microwaves can efficiently substitute the metal catalysis (Scheme 10.156) [443]. R5

CO2Me O CO2Me

5

R

Scheme 10.156

NEt3 cat. CH2Cl2, 0 °C

MeO2C

O

CO2Me

MeO2C R3NH2 R5 SiO 2

MW

N O

R3 CO2Me

j 10 Five-Membered Heterocycles: 1,3-Azoles

890

10.5.4 Alkyl-1,3-Azoles

The synthesis of alkyl-1,3-azoles is described throughout Section 10.3, for this reason this short section will deal only with the most characteristic reactivity of the alkyl residues linked to the heteroaromatic nuclei. Alkyl groups attached to heterocyclic systems undergo many of the same reactions as those on benzenoid rings. For example, free radical bromination with NBS is often performed on these substrates. Bromination with NBS of 2-alkylthiazoles affords a-dibromothiazoles in good yields. The hydrolysis of these compounds leads to 2-acylthiazoles [444]. The side chains can, under certain circumstances, be oxidized. For example, methyl thiazoles with SeO2 give thiazolecarbaldehydes but oxazole derivatives cannot be easily oxidized since the oxazole itself is reactive towards strong oxidants. However, it is stable to the Sharpless oxidation conditions with certain precautions [445]. In addition to these reaction, alkyl groups in the 2-positions of imidazole, oxazole and thiazole rings show reactivity that results from the easy loss of a proton from the carbon atoms of the alkyl group adjacent to the ring [compare Scheme 10.1 (2)]. Very strong bases, such as sodamide, LDA or butyllithium convert 2-methyl-oxazole and -thiazole and 1,2-dimethylimidazole essentially completely into the corresponding anions, although this transformation is not always straightforward since it is very sensitive to reaction conditions and the nature of the substituents [446]. Butyllithium reacts with 1,2-dimethylimidazole at
80  C to lithiate the 2-methyl group, but at higher temperatures some 5-metalation also occurs [447], while treatment with LDA at
78  C gives 84 % of 2-methyllithiation and 18% of 5lithiation [448]. Much better control was obtained with 1-dimethylaminomethyl-2methyl-imidazole, which was converted by butyllithium into the stabilized anion 273, which reacted with benzyl chloride to form 274 (Scheme 10.157) [449]. N N NMe2

N BuLi

N

Li 273 N Me2

N BnCl

Bn

N 274 NMe2

Scheme 10.157

BuLi reacts at
78  C with 2-methylthiazole to give a mixture of 2-lithiomethyl and 5-lithio derivatives in a ratio of 1 : 4 [450], while when the 2-position is blocked 4-or 5- methyl groups can be lithiated [451]. These anions all react readily even with mild electrophilic reagents; thus the original alkyl groups can be modified through alkylation, acylation, carboxylation and reaction with aldehydes [452]. Extremely useful are the reactions of alkyl-1,3-azoles in which traces of the reactive anion is involved. In aqueous or alcoholic solutions, many 2-alkyl-1,3-azoles react with bases to give traces of anions. With suitable electrophilic reagents these anions undergo reasonably

10.5 Derivatives

j891

rapid and essentially non-reversible reaction. 2-Methyl and 2-ethylbenzothiazoles condense with aromatic aldehydes at room temperatures in 50% aqueous sodium hydroxide under phase-transfer catalysis conditions to afford secondary carbinols [453], while 2-methyl thiazole heated at 150 C with ZnCl2 and benzaldehyde gives the styryl derivatives. To confirm the peculiar reactivity of the 2-alkyl group, neither 4- nor 5-methyl thiazole undergo such condensation. 1-Benzyl-2-methylimidazole 275 reacts with benzoyl chloride in the presence of a tertiary amine to give the phenacyl derivative 276, but with 1-benzyl-5-methylimidazole the product is the 2-benzoyl derivative due to the substitution at C2 (Section 10.4.1.2) [454]. The reaction has also been extended to 2-methylimidazole [Scheme 10.158 (1)] [455]. N

PhCOCl

N 275 Bn

N Bn

NEt3 CN

N 277

N

N H

Ph

N OCOPh

N

Me2CO NMe3

278

N Bn

Ph 276

O

CN

(1)

(2)

N H

Scheme 10.158

The presence of other activating group makes the condensation reaction even easier. In the presence of trimethylamine, 2-cyanomethylbenzimidazole (277) condenses with acetone to give the unsaturated derivative 278 [Scheme 10.158 (2)] [456]. 10.5.5 Quaternary 1,3-Azolium Salts

In the past literature methods for the synthesis of azolium and azolinium salts have generally focused on N-alkylation reactions (Section 10.4.1.1). However, these reactions are limited to reactive halides and are inappropriate for introduction of chiral substituents. Since this class of compounds has very important applications, new general synthesis of them are of substantial interest. In this context, imidazolium salts are precursors of carbene ligands used for the synthesis of metathesis catalysts [457] and have been used also as ionic liquids (Scheme 10.159) [458]. R1 N

Base

N XR2 Scheme 10.159

R1 N N R2

BF4N Mes Mes N Cl Ru Cl PCy3 Ph

Me N

N nBu

PF6Me N

N nBu PPh2

j 10 Five-Membered Heterocycles: 1,3-Azoles

892

Ar 2

H Ar

Me

O

+ NH2

H

H + O

O H

N H

HCl H

-3H2O

N Ar

H

O

H

O

2 NH2R 279

R N

NaBH4

N R

R NH

NHR

Br

Br

(1)

H

Me

HC(OEt)3

R NH

(2)

N Cl280 R

NH R

Br Pd(0), RNH 2

Me

'

Pd(0), R NH2

NHR' NHR

1. (MeO)3CR2 2. HX

R1 N

(3) R2

N ClR2

Scheme 10.160

Chiral imidazolium salts have been synthesized in one step (Scheme 10.160). Starting from racemic amines the meso-forms were produced. In contrast, only the C2-symmetric imidazolium salts are formed when enantiomerically pure amines are employed [Scheme 10.160 (1)] [459]. In a similar reaction, starting from glyoxal, 1,3-diarylimidazolium chlorides are obtained in a three-step sequence via the diimine 279, which is then reduced. Finally, cyclization of the diamines afforded the imidazolinium salt 280 [Scheme 10.160 (2)] [460]. Benzimidazolium salts have been prepared through a subsequent Buchwald– Hartwig amination and ring closure. This method is suitable for the preparation of 2-substituted salts and benzimidazolium salts that bear chiral substituents on one or both the nitrogen atoms [Scheme 10.160 (3)] [409]. Solid-supported azolium and benzoalium salts have been prepared. Azole derivatives react with bromoacetic acid to give azolium acetic acids that have been anchored to a Wang resin [Scheme 10.161 (1)]. Compounds 281–283 have been employed in the Westphal reaction, obtaining cycloiminium salts [Scheme 10.161 (2)]. The synthesis of 1-amino-3-alkylimidazolium 284 [461] and N-imidazolium-Nmethyl-amides 286 [462] has been reported. In the first case, the salts are obtained by direct amination of the corresponding alkoxycarbonylazoles using mesitylenesulfonylhydroxylamine (MSH) as the aminating agents (Scheme 10.162). In the second case, the amino derivatives 284 are acylated with acyl chlorides, and the resulting betaines 285 are alkylated with methyl iodide to give the salts 286. Azolium N-aminides 287, generated from the corresponding salts in the presence of N-ethyldiisopropylamine, and cycloimmonium N-ylides are 1,3-dipoles, usually involved in 1,3-dipolar cycloaddition reactions (Figure 10.12) [463]. 2-Alkyl- and 2-amino-substituted structures 288 have the potential to function as 1,4-dinucleophiles through deprotonation and can react

10.5 Derivatives

Het

CO2H

1. BrCH2CO2H 2. HBr

N

Het

N

N

Br-

Het

Me

Me N Br

O

OH

Br-

Me

-

O

N 281

Me N

Me -

Br

CO2

O

N

Br-

Het

N 282

O

(1)

Me S Me -

Br

CO2

N

Me

CO2 283

O O

Me

Me O

O

Me

(2)

Me

N Het

Me

Br-

Scheme 10.161

R4

Me N

R5

N

284

CO2Et

Me N

R4

MSH

CO2Et N MSTSNH2 MSTS-= Mesytilenesulfonate 284

(1)

R3

RCOCl K2CO3

R4 5

R

285

Me N N N

CO2Et O

R

MeI

R4

Me N

R5 I- N N 286 Me

CO2Et

(2)

O R

Scheme 10.162

with 1,2-dicarbonyl compounds to afford a great variety of derivatives [464]. 2-Alkoxycarbonylazolium N-ylides-N-aminides 289 are species that have the potential to act as efficient 1,4-dipole equivalents when they react with heterocumulenes such as iso(thio)cyanates and carbodiimides [465]. X 287

N Z

Z = NH, CHR 1,3-Dipole Figure 10.12

X

Y

X

δ−

N − δ 288 Z

Y = NH2, CH2R Z = NH, CHR 1,4-Dinucleophile

289

Y

δ+

N − δ Z

Z = CO2R, CN, COR X = NH Y = OR 1,4-Nucleophile-electrophile

j893

j 10 Five-Membered Heterocycles: 1,3-Azoles

894

O R1

Esters

Me N

1.LDA 2.R1M

O OR

IMe

N N

1.BuLi 2.R1M

O R1 R Ketones

O R

Scheme 10.163

N-Imidazolium-N-methylamides and bis-amides behave as highly selective acylating reagents towards organometallics, leading to ketones [462] and diketones. The metallation of alkoxycarbonyl-N-imidazolium-N-methyl amides with LDA followed by the addition of a Grignard reagent affords 4-oxo and homologous esters (Scheme 10.163). 10.5.6 Oxy- and Amino-1,3-Azoles

Cyanogen chloride (or bromide) as well as cyanamide are the reagents of choice for the synthesis of 2-aminoderivatives. These reagents have found application in the synthesis of the simple heterocycles as well as their benzofused derivatives by reaction with a-hydroxy [466] or a-amino ketones (an extension of the Marckwald synthesis in which cyanamide replaces cyanate, thiocyanate and isothiocyanate as a counterpart of a-aminoaldehydes or ketones) (Scheme 10.164) [467, 468].

R4

O +

R5

XH

R4

N C Y

-H2O -YH

X = O, NH Y = Cl, Br, NH2 H HN

NH X R5

R4

O R4(5)

5

R

H

R5 X HO

N X

NH2

R4

NH NH -H2O

R5

NH X

NH

Scheme 10.164

An application of this routes allows the synthesis of 2-aminoimidazole-containing natural products, demonstrating the usefulness and power of this methodology [469]. Another application of cyanogen chloride (or isocyanide dichlorides) for the synthesis of 2-aminoimidazoles is the reaction with DAMN, in which the nucleophilic addition of DAMN proceeds through a mechanism analogous to that reported above [470].

10.5 Derivatives

The reaction of o-aminophenols with cyanogen bromide or cyanamide affords 2-aminobenzoxazoles 290 or benzoxazoleimines 291; yields are high and the general method can be adopted to give 2-substituted amino derivatives (Scheme 10.165). NH2 BrCN

N

OH

O

H N

R

OH

290

NH2

R N

BrCN

O

291

NH

Scheme 10.165

Alternatively, the reactivity of 2-bromo derivatives towards amines in the presence of CuBr can be used as well as the direct nucleophilic amination of benzimidazole by sodium amide. The reaction of a b-aminoalcohol with BrCN affords the correspondent 2-aminooxazoline, whose reactivity is nicely exploited in the synthesis of the bis-oxazoline 292 (Scheme 10.166) [471].

OH R

O

BrCN, MeOH

NH2

N 89%

R

H N

O

292

O R

N

O

H N Ph N O

O R

N

Ph

HN

N

53-58% R

R

R

NH2

N

N

R

O N

N R

O

PhCHO, 0.5 eq. NH2 TsOH

O OEt

Et3OBF4

O

R

N H

O

EtO

OEt

NaOEt R

OH NH2

Scheme 10.166

The cycloaddition of azides across a double bond provides another method of imidazole preparation. In this reaction an iminium species, 293, generated in situ under Vilsmeier conditions, attacks an azide functionality [472]. The method is intrinsically limited to 2-dimethylamino substituted imidazoles 294 (Scheme 10.167). A variation of the Hantzsch procedure uses thiourea with a-halocarbonyl compounds to produce 2-aminothiazoles, while a-halocarboxylic acids afford the correspondent 2-amino-4-hydroxythiazoles [Scheme 10.168 (1)].

j895

j 10 Five-Membered Heterocycles: 1,3-Azoles

896

N Ar

H N

DMF/POCl3

O

Ar

-H2O -N2

N3 N

Ar

41-62%

294 Cl

O - H2O

Cl 293 N

N

N

N

N N N N O

Ar

N

N N N N O

N

N Ar

N

H

N

N N N Cl

N

N

Ar N

N -N2

Cl

N

N

Scheme 10.167

This reaction has found application for the development of a solid-supported synthesis of 2-aminothiazole using the amino group as a convenient, traceless point of attachment to acid-sensitive resins [Scheme 10.168 (2)] [473].

HO

X

HO

S

O H2N

NH2

-H2O

(1)

N NH2

S

O NH R

Fmoc-NCS, DCM 20% piperidine/DMF

S N R

R4 NH2

R5

Br

S

R5

N R

N

R4 TFA

R4

R5

(2) N S

N H

R

R = H, Alk R 4 = Ar R 5 = H, Ph 70-95%

Scheme 10.168

2,4-Diaminothiazole (295) can be prepared by the reaction of thiourea with chloroacetonitrile (Scheme 10.169). H2N

S NH2

+

N C

H2N Cl

-HCl -H2S

295 S

N NH2

Scheme 10.169

Mono-, di-, and tri-substituted arylthioureas 296 are very easily cyclized to 2-aminobenzothiazoles by the action of bromine in a solvent such as CHCl3, CCl4

10.5 Derivatives

H N

H N

R 296

R

Ar

i) Br2 ii) SO2, NaOH

N S

S

HN

CO2Me N CO2Me 1) Pb(OAc)4 NH 2) ∆, MeOH NH

CO2Me NH

N H

297

O

(1)

NHAr

N

j897

(2)

Scheme 10.170

(Hugershoff ’s method) followed by a treatment with SO2 and with a base [Scheme 10.170 (1)]. Under oxidative or acidic conditions, or merely by heating the reagents, appropriately functionalized guanidines 297 cyclize to 2-aminobenzimidazoles [Scheme 10.170 (2)] [474]. A variation of the Hantzsch synthesis has been introduced for the preparation of 2-aminoimidazoles using a-haloketones and N-acetylguanidines to afford the corresponding 4(5)-substituted N-(1H-imidazol-2-yl)acetamides 298. These compounds are then hydrolyzed to their corresponding 2-aminoimidazoles 299 (Scheme 10.171) [475]. O X

R4(5)

+

R5(4)

H2N H2N

DMF, rt

NAc

R4(5) R5(4)

298

H2SO4

N

NHAc

N H

R4(5) R5(4) 299

N N H

NH2

R = Alk, Ar, H 31-78% Scheme 10.171

Iminophosphoranes have found several applications in the synthesis of 2-aminoimidazole derivatives and particularly for the synthesis of natural product [476]. Aza-Wittig-type reactions of properly substituted iminophosphorane 300 with CO2, isocyanates or isothiocyanates afford heterocumulenes that undergo NH2

Y=C=Y

NH2

NH N 301

N C Y

N=PPh3 300 O

O 1

OR R N=C=O N=PPh3 Scheme 10.172

(1)

YH

O OR

R2NH2

N C NR1 302

OR NHR2

N 303 NHR1

N -ROH

O

N R1

(2) NHR2

j 10 Five-Membered Heterocycles: 1,3-Azoles

898

nucleophilic attack of the amino group to give the five-membered heterocycles 301 [Scheme 10.172 (1)]. A variation to this method is the use of azido esters in combination with isocyanates. The intermediate carbodiimide 302 reacts with a primary amine to afford the guanidine derivative 303 that finally cyclizes on the ester group [Scheme 10.172 (2)] [476]. Concerning the reactivity of 2-aminoazoles, some general points can be made. In aminoazoles with the amino group a to C¼N, the imino resonance structure justifies the increased reactivity of the pyridine-like nitrogen atom towards electrophilic reagents, but decreases that of the amino group. Consequently, protons, alkylating agents and metal ions usually react with amino azoles at the annular nitrogen. This is exemplified by the behavior of 2-aminothiazole. If the thiazole reacts in its neutral form, the ring nitrogen atom is the more reactive center, except when bulky substituents are present at the C4 position. If the thiazole reacts in the form of its conjugate base, the ambident anion leads to a mixture of products resulting from Nring and N-exocyclic reactivity [Scheme 10.173 (1)].

N

E+

E+ NH2

S

N

N S

NH

S Ph

Ph

N S

NH2

ArCHO

N N CHAr

S

Ar

(2)

S Ph

(1)

NH

N CHAr N

Scheme 10.173

Under mild conditions, 2-aminothiazoles react at their exocyclic nitrogen atom with aromatic aldehyde, yielding Schiff bases. Under more forcing conditions, however, the 5 position can also react [Scheme 10.173 (2)]. Acylation of 2-, 4- and 5-aminothiazoles takes place on the exocyclic nitrogen atom. Acetic anhydrides acetylate aminothiazoles and benzothiazoles on the exocyclic nitrogen atom. The reaction of 2-aminothiazoles with alkyl or aryl isocyanates or isothiocyanates gives the corresponding thiazolylureas or thioureas. Alkylation of D4-thiazolin-2-ones may yield O
R or N
R derivatives according to experimental conditions. With diazomethane in ethanol, O-methylation takes place whereas N-methylation occurs when a basic solution of the thiazolinone reacts with methyl iodide. Alkylation of 2-amino imidazole occurs at the exocyclic N atom. Azolidin-2-ones are popular tools in asymmetric synthesis and as synthetic intermediates, and new methods for their synthesis are described in the literature. Azolidin-2-ones are commonly prepared from aminoalcohols, vicinal diamines and aminothiols by incorporation of a carbonyl unit. Additions to the list of reagents that effect the transformation are bis(trichloromethylcarbonate) [477, 478] and

10.5 Derivatives

j899

trichloromethyl chloroformate [479], which offer the advantages of easier handling and reduced risk of exposure compared to phosgene [480]. Another reagent of choice is carbonyldiimidazole, which by reaction with cysteine affords derivative 304 [Scheme 10.174 (1)] [481]. O N

O HS

N

N

OEt

EtO2C

N

NH2

304

NH2

O t-BuO

X H

(1) O

S

O

O O

NH

DMAP

Ot-Bu

Ot-Bu

N 305 X

(2)

O

X = NR, OH Scheme 10.174

Vicinal aminoalcohols and diamines react with Boc2O/DMAP to afford the corresponding azolidinones 305 substituted on the N atom with Boc groups, while aminothiols are less efficient in this transformation [Scheme 10.174 (2)] [482]. A recent method for the effective synthesis of imidazolidinones and oxazolidinones is MW irradiation. The proposed mechanism is shown in Scheme 10.175 [483].

O H2N

NH2

N H

NH2

NH

ZnO, MW

N

- 2 NH3

- NH3

-H+

O C NH N H

O 99%

NH2

N H

H N

NH2 O

- NH3

N H

N

C

O

N

N

H

+H+

O

Scheme 10.175

The ability of the benzotriazole nucleus to act as a good leaving group has found another application in the synthesis of polysubstituted imidazolidinones. Treating amine 306 with s-BuLi and subsequently with an aldimine or an aldehyde, affords imidazolidinones or oxazolidinones bearing a benzotriazolyl group on C4.

HN

N O

H

j 10 Five-Membered Heterocycles: 1,3-Azoles

900

With imidazolidinones 307 it is possible to substitute the benzotriazolyl group with various C-nucleophiles to obtain differently substituted imidazolinones (Scheme 10.176) [484]. s-BuLi R5CH=Y

Bt N Ph

Bt R5

Boc 306

Ph

N

O Y Y = NAn Y=O

An = 4-MeO-C6H4 OSiMe3

O

Ph Ph

N

Ph R5

Bt BF3.Et2O

O

N An

R5

N

N 307 An

R2

Ph R2MgX ZnCl2 O

R5

N N An

Ph O

Scheme 10.176

Aziridines in the presence of Lewis acids rearrange to afford substituted oxazolidinones. This approach has found interesting application for the production of enantiopure 4- and 5-carboxymethyl oxazolidinones, which are important precursors for the synthesis of amino acid analogs or as starting material for the synthesis of natural products. In the first case, aziridine 308 was treated with methyl chloroformate to afford the corresponding oxazolidinone 309 with retention of configuration on the reacting stereocenter due to a double inversion of configuration as described in Scheme 10.177 [485]. O Ph

Cl OMe CH3CN, reflux

N

CO2Et H 308

O Cl

OMe

Ph O N Cl-

OMe CO2Et H

MeO2C H 309

Ph O N

Ph

N O

O

-MeCl Me O

H CO2Me Cl

Scheme 10.177

In contrast, treating aziridine 310 with Lewis acids induces a rearrangement in which it is the carbonyl group of the carbamoyl moiety, activated by the exit of

10.5 Derivatives

j901

isobutene, that induces the enlargement of the three-membered ring (Scheme 10.178) [486]. O

O R

OMe Cu(OTf) 2

N O

R

O

O 310

O

R

OMe N [Cu]

OMe

O

O

NH O

H

R = Me 99% R = iPr 85% R = Ph 98%

Scheme 10.178

The reaction of vinyl epoxides with aryl isocyanates is facilitated by Pd catalysis [487]. The intermediate p-allyl complex equilibrates to afford stereoselectively the cis derivative from either isomer of the epoxide [Scheme 10.179 (1)].

X R

(dba)3Pd2.CHCl3

X = NR, O, S ArNCO

R

N R

X

(η3 C3H5PdCl)2 Ligand R2 NCO N + R1

Ar

(1)

O

N R

N R2

R1 O Ligand

O

NH HN

O

PPh2 Ph2P

Scheme 10.179

The same reactivity has been extended to aziridines [488] and to thiiranes [489]; for every substrates the enantioselective version of the transformation has also been described [Scheme 10.179 (2)]. Oxazolidinones can be obtained also through a palladium-catalyzed oxidative carbonylation of b-aminoalcohols [490]. In an analogous procedure vicinal diamines are converted into imidazolidinones through an oxidative carbonylation catalyzed by W(CO)6 [491]. Particularly important, especially for the breakthrough that it allowed in the synthesis of tetrodotoxin [492], is the Rh-catalyzed C
H insertion reaction for the oxidative conversion of carbamates into oxazolidinones [493] and the more recent expansion to the synthesis of imidazolidines (Scheme 10.180) [494]. Some specific reported syntheses for the obtainment of benzo-1,3-azol-2-ones have found recent application. The most direct approach to these derivatives is the reaction of a 2-substituted aniline with the general reagent 311 (Scheme 10.181). The reagent of general formula 311 stands for a series of different reagents in which the Z groups represents good leaving groups. For this reason, good reagents

(2)

j 10 Five-Membered Heterocycles: 1,3-Azoles

902

[Rh2(OAc)4] PhI(OAc))2

NH2 O

O H2N

O N

Ph

Rh2(esp)2 PhI(OAc))2

NH O Ph

O 86%

NH O N 87% SO2CH2Cl3

SO2CH2Cl3

Scheme 10.180

NH2

+

X

O Z

NH

Z 311

Y

O

+ 2 HZ

Scheme 10.181

are phosgene [495], urea [496],carbonyldiimidazole [497], dimethyl carbonate [498], N,N-diethylcarbamyl chloride and carbon dioxide [499]. 10.5.7 Azole N-Oxides and Azoline N-Oxides

Oxazole and imidazole N-oxides cannot be synthesized by oxygenation of oxazoles or imidazoles, respectively. The only method described for the synthesis of oxazole N-oxides is the condensation of monooximes of 1,2-dicarbonyl compounds with aldehydes in acidic medium [Scheme 10.182 (1)]. The aldehyde may be aromatic or aliphatic (including formaldehyde) and the oxime may be derived from an aromatic

R4

NOH

R5

O

R4

NOH

R5

R4

O N

R5

O

OCHR2 NH2R1

R4

O N

-H2O

R5

NR1

OCHR2 -H2O

O

R2

(1)

R2

(2)

R = alkyl, aryl, OH H R R

NOH

R2

NOH

X

-H2O X = O, NOH

Scheme 10.182

R R

O N N OH

R2

(3)

10.5 Derivatives

diketone or it may be an a-keto aldoxime, leading to a 2,5-disubstituted oxazole Noxide. For imidazole N-oxides the most common approach is the condensation of an a-oximinoketone with an aldehyde and a primary amine. The use of an hydroxylamine in this condensation [Scheme 10.182 (2)] or the reaction of the aldehyde oxime or aldehyde with a 1,2-dioxime [Scheme 10.183 (3)] afford 1-hydroxyimidazole-3oxides. O N O 93-98%

1. R2C(OEt)3 2. Et3N

R2

OH

route A

Ph

OEt

R2

HCl

O N

NMe3

O

route B

1. HC(OEt)3 Ph 2. Et3N

NHOH NHBn

EtO

NHOH

2HCl

R2

59% R2 = Ph

O N N Bn

Scheme 10.183

A similar method has been used for the synthesis of 4,5-dihydrooxazole-3-oxides (cyclic C-alkoxynitrones). In this case the condensation of an b-hydroxyamino alcohol hydrochloride with an ortho ester (Scheme 10.183, route A) [500] or an amide acetal (Scheme 10.183, route B) [501] affords the desired compound. 4,5-Dihydro-1Himidazole-3-oxides (cyclic C-aminonitrones) have been prepared using route A with N-(2-aminoethyl)hydroxylamine dihydrochloride as starting material. Treatment of 2-(hydroxyamino)alkan-1-one oximes with phenyl or methylglyoxal affords 4,5-dihydro-1H-imidazole 3-oxides. The reaction is occurs through the formation of intermediates 312–314 (Scheme 10.184). O R4

NOH

R5

NHOH

R4

R

R5 N NOH O

COR3 312

R4

CHO

OH O N

R5

R4 R5 313

O N N OH

N H

+ H2O COR3

-H2O

R4 R5 314

O N N

COR

COR3

Scheme 10.184

On the other hand, oxidation of 4,5-dihydrooxazoles with 3-chloroperoxybenzoic acid (MCPBA) produces oxaziridines that undergo isomerization to the corresponding nitrones upon treatment with trifluoromethanesulfonic acid (TfOH) [Scheme 10.185 (1)] [502].

j903

j 10 Five-Membered Heterocycles: 1,3-Azoles

904

N

N O

MCPBA

O

O

O N

O N

TfOH

n-BuLi -78 °C

Li

N 315 R

(1)

O

Cl

O N

316 90%

N R

TsCl

O N N R

O Ph2P Ph2P(O)Cl

317 60%

(2)

O N N R

Scheme 10.185

Lithiation of 315 followed by treatment with 4-toluensulfonyl chloride or diphenylphosphoryl chloride [503] affords the C-chloronitrone or the C-phosphorylnitrone, 316 and 317, respectively [Scheme 10.185 (2)]. Oxidation of 315 in methanol with lead(IV) acetate or manganese(IV) or lead(IV) oxides affords predominantly the corresponding C-methoxynitrones 318 [504], which react with potassium hydrosulfide to afford the thiohydroxamic acids 319 [505]. Compound 319 has also been obtained by treatment of the nitrone 320 with sodium sulfide (Scheme 10.186) [506]. O N N R

oxidizing agent / MeOH 315 MeO

O N N R

MeO

O N N R

KSH

HS

O N N R

318

S

Na2S 319

NC

O N

320

N R

OH N N R

Scheme 10.186

Finally, the reactivity of azole-N-oxides is somewhat similar to that of the azolonium ions, particularly when the cationic species is involved. In the case of imidazoline-N-oxides (cyclic C-amino nitrones) and oxazoline-N-oxides (cyclic C-hydroxy nitrones) the reactivity is well known. These compounds are versatile synthetic intermediates that readily undergo 1,3-dipolar cycloaddition [507] and addition of nucleophiles [508] and are also useful as radical spin traps [509].

References

References 1 Laurent, A. (1845) Journal Fur Praktische 2 3 4

5 6 7

8 9

10

11

12

Chemie, 35, 455. Rochleder, F. (1842) Justus Liebigs Annalen der Chemie, 41, 89. Debus, H. (1858) Justus Liebigs Annalen der Chemie, 107, 199. Cornforth, J.W. and Cornforth, R.H. (1947) Journal of the Chemical Society, 96. Zinin, N. (1840) Annalen, 34, 186. Hantzsch, A.R. (1888) Chemische Berichte, 21, 924. Bredereck, H. and Bangert, R. (1962) Angewandte Chemie International Edition, 1, 662. Wallach, O. (1874) Chemische Berichte, 7, 903. Imidazoles: Grimmett, M.R. (1984) Comprehensive Heterocyclic Chemistry I, Vol. 5, Pergamon, Oxford, Ch 4.06, p. 345; Oxazoles: Boyd, G.V. (1984) Comprehensive Heterocyclic Chemistry I, Vol. 6, Pergamon, Oxford, Ch. 4.18, p. 177; Thiazoles: Metzger, J. (1984) Comprehensive Heterocyclic Chemistry I, Vol. 6, Pergamon, Oxford, Ch. 4.19, p. 235. Imidazoles: Grimmett, M.R. (1996), in Comprehensive Heterocyclic II Chemistry, Vol. 3, Pergamon, Oxford, Ch. 2, p. 77; Oxazoles: Hartner, F.V., Jr (1996) in Comprehensive Heterocyclic Chemistry II, Vol. 3, Pergamon, Oxford, Ch. 4, p. 261; Thiazoles: Dondoni, A. and Merino, P. (1996) Comprehensive Heterocyclic Chemistry II, Vol. 3, Pergamon, Oxford, Ch. 6, p. 373. Imidazoles: Grimmett, M.R. (2002) Science of Synthesis, Vol. 12, Georg Thieme Verlag, Stuttgart, Ch.3, p. 325; Oxazoles: Boyd, G.V. (2002) Science of Synthesis, Vol. 11, Georg Thieme Verlag, Stuttgart, Ch. 12, p. 383; Thiazoles: Kikelj, D. and Urleb, U. (2002) Science of Synthesis, Vol. 11, Georg Thieme Verlag, Stuttgart, Ch, 17, p. 627. Nicolau, K.C., Rao, P.S., Hao, J., Reddy, M.V., Rassias, G., Huang, X., Chen, D.Y.K., and Snyder, S.A. (2003) Angewandte Chemie International Edition, 42, 1753; Burgets, A.W.G., Li, Q., Wei, Q.,

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457 Stragies, R., Voightmann, U., and

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461 462

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466

Blechert, S. (2000) Tetrahedron Letters, 41, 5465; Smulik, J.A. and Diver, S.T. (2000) Organic Letters, 2, 2271; Morgan, J.P. and Grubbs, R.H. (2000) Organic Letters, 2, 3153; Lee, C.W. and Grubbs, R.H. (2000) Organic Letters, 2, 2145; Briot, A., Bujard, M., Gouverneur, V., Nolan, S.P., and Mioskowski, C. (2000) Organic Letters, 2, 1517; F€ urstner, A., Thiel, O.R., Ackermann, L., Schanz, H.-J., and Nolan, S.P. (2000) The Journal of Organic Chemistry, 65, 2204. Mathews, C.J., Smith, P.J., and Welton, T. (2000) Journal of the Chemical Society. Chemical Communications, 1246; McCluskey, A., Garner, J., Young, D.J., and Caballero, S. (2000) Tetrahedron Letters, 41, 8147; Lau, R.M., van Rantwijk, F., Seddon, K.R., and Sheldon, R.A. (2000) Organic Letters, 2, 4189; Sirieix, J., Obberger, M., Betzemeier, B., and Knochel, P. (2000) Synlett, 1613; Howarth, J., James, P., and Dai, J. (2000) Tetrahedron Letters, 41, 10319. Herrmann, W.A., Goossen, L.J., Artus, G.R.J., and K€ocher, C. (1997) Organometallics, 16, 2472. Arduengo, A.J., Krafczyk, R., and Schmutzler, R. (1999) Tetrahedron, 55, 14523. Tamura, Y., Minamikawa, J., and Ykeda, M. (1977) Synthesis, 1. de las Heras, M.A., Molina, A., Vaquero, J.J., Garc
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j 10 Five-Membered Heterocycles: 1,3-Azoles

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467 468

469

470 471

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474

475 476 477 478 479

480 481

482 483 484

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486

Prime, D.M., Ross, W.J., Todd, A., and Verge, J.P. (1976) Synthesis, 591. Lawson, A. (1956) Journal of the Chemical Society, 307. Baran, P.S., Zografos, A.L., and O’Malley, D.P. (2004) Journal of the American Chemical Society, 126, 3726. Garg, N.K., Sarpong, R., and Stoltz, B.M. (2002) Journal of the American Chemical Society, 124, 13179. Merchan, F.L., Garin, J., and Tejero, T. (1982) Synthesis, 984. Werner, H., Vicha, R., Gissibl, A., and Reiser, O. (2003) The Journal of Organic Chemistry, 68, 10166 and reference cited therein. Majo, V.J., and Perumal, P.T. (1998) The Journal of Organic Chemistry, 63, 7136. Kearney, P.C., Fernandez, M., and Flygare, J.A. (1998) The Journal of Organic Chemistry, 63, 196. Rajappa, S., Sreenivasan, R., and Khawadekar, A. (1986) Journal of Chemical Research, 5, 158. Little, T.L. and Webber, S.E. (1994) The Journal of Organic Chemistry, 59, 7299. Fresneda, P.M. and Molina, P. (2004) Synlett, 1 and references cited therein. Sicker, D. (1989) Synthesis, 875. Schmitz, W.D. and Romo, D. (1996) Tetrahedron Letters, 37, 4857. Pridgen, L.N., Prol, J., Alexander, B., and Gillyard, L. (1989) The Journal of Organic Chemistry, 54, 3231. Gaupp, S. and Effenberg, F. (1999) Tetrahedron : Asymmetry, 10, 1777. D’Ischia, M., Prota, G., and Rottevele, R.C. (1987) Synthetic Communications, 17, 1577. Hassner, A. and Basel, Y. (2000) The Journal of Organic Chemistry, 65, 6368. Kim, Y.J. and Varma, R.S. (2004) Tetrahedron Letters, 45, 7205. Katritzky, A.R., Luo, Z., Fang, Y., and Steel, P.J. (2001) The Journal of Organic Chemistry, 66, 2858. Sim, T.B., Kang, S.H., Lee, K.S., and Lee, W.K. (2003) The Journal of Organic Chemistry, 68, 104. Tomasini, C. and Secchione, A. (1999) Organic Letters, 1, 2153; Lucarini, S. and Tomasini, C. (2001) The Journal of Organic Chemistry, 66, 727.

487 Trost, B.M. and Hurnaus, R. (1989)

488

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494

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497

498 499

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501

Tetrahedron Letters, 30, 3893; Larksarp, C. and Alper, H. (1997) Journal of the American Chemical Society, 119, 3709. Trost, B.M. and Fandrick, D.R. (2003) Journal of the American Chemical Society, 125, 11836; Dong, C. and Alper, H. (2004) Tetrahedron : Asymmetry, 15, 1537. Larksarp, C., Sellier, O., and Alper, H. (2001) The Journal of Organic Chemistry, 66, 3502. Gabriele, B., Mancuso, R., Salerno, G., and Costa, M. (2003) The Journal of Organic Chemistry, 68, 601. Qian, F., McCusker, J.E., Zhang, Y., Main, A.D., Chlebowski, M., Kokka, M., and McElwee-White, L. (2002) The Journal of Organic Chemistry, 67, 4086. Hinman, A. and Du Bois, J. (2003) Journal of the American Chemical Society, 125, 11510. Espino, C.G. and Du Bois, J. (2001) Angewandte Chemie International Edition, 40, 598. Espino, C.G., Fiori, K.W., Kim, M., and Du Bois, J. (2004) Journal of the American Chemical Society, 126, 15378. Weinstock, J., Gaitanopoulos, D.E., Stringer, O.D., Franz, R.G., Hieble, J.P., Kinter, L.B., Mann, W.A., Flaim, K.E., and Gessners, G. (1987) Journal of Medicinal Chemistry, 30, 1166. Khajavi, M.S., Hajihadi, M., and Naderi, R. (1996) Journal of Chemical Research (S), 92. Mewshaw, R.E., Zhao, R., Shi, X., Marquis, K., Brennan, J.A., Mazandarani, H., Coupet, J., and Andree, T.H. (2002) Bioorganic and Medicinal Chemistry Letters, 12, 271. Fu, Y., Baba, T., and Ono, Y. (2001) Journal of Catalysis, 197, 91. Preston, P.N. (1981) Benzimidazoles and Congeneric Tricyclic Compounds (ed. P.N. Preston), Interscience-Wiley, New York. Ashburn, S.P. and Coates, R.M. (1984) The Journal of Organic Chemistry, 49, 3127. Ashburn, S.P. and Coates, R.M. (1985) The Journal of Organic Chemistry, 50, 3076.

References 502 Hendrickson, J.B. and Pearson, D.A. 503 504

505

506

(1983) Tetrahedron Letters, 24, 4657. Voinov, M.A. and Grigor’ev, I.A. (2002) Tetrahedron Letters, 43, 2445. Shchukin, G.I., Starichennko, V.F., Grigor’ev, I.A., Dikanov, S.A., Gulin, V.I., and Volodarskii, L.B. (1987) Izvestiya Akademii Nauk SSSR Seriya Khimicheskaya, 125 [Bulletin Academy of Sciences USSR, Division of Chemical Sciences (English Translation), (1987) 36, 125.] Grigor’ev, I.A., Bakunova, S.M., and Kirilyuk, I.A. (2000) Russian Chemical Bulletin, 49, 2031. Shchukin, G.I., Grigor’ev, I.A., and Volodarskii, L.B. (1990) Chemistry of Heterocyclic Compounds (English Translation), 26, 409.

507 Tufariello, J.J. (1984) 1,3-Dipolar

Cycloaddition Chemistry, Vol. 5 (ed. A. Padwa), John Wiley & Sons, Inc., New York, p. 83; Breuer, E., Aurich, H.G., and Nielsen, A. (1989) Nitrones, Nitronates and Nitroxides, John Wiley & Sons, Ltd., Chichester, UK; Dirat, O., Kouklovsky, C., Mauduit, M., and Langlois, Y. (2000) Pure and Applied Chemistry, 72, 1721. 508 Frederickson, M. (1997) Tetrahedron, 53, 403; Gothelf, K.V. and Jorgensen, K.A. (1998) Chemical Reviews, 98, 863; Merino, P., Franco, S., Merchan, F.L., and Tejero, T. (2000) Synlett, 442. 509 Janzen, E.G. and Haire, D.L. (1990) Advances in Free Radical. Chemistry, 1, 253; Free Radical Research Janzen, E.G. (1971) Accounts of Chemical Research, 4, 31.

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j925

11 Five-Membered Heterocycles with Two Heteroatoms: O and S Derivatives David J. Wilkins

11.1 Introduction

A general review of chemistry for all the derivatives described in this chapter covering the period up to 1995 can be found in Comprehensive Heterocyclic Chemistry first edition (Volume 6) and second edition (Volume 3).

11.2 1,2-Dioxoles and 1,2-Dioxolanes 11.2.1 Introduction

Most work on 1, 2-dioxole systems has been on derivatives of the fully saturated 1, 2dioxolane (1) and as cyclic peroxides these have been the subject of three major reviews [1–3]. 1,2-Dioxoles are unstable and they have only been detected spectroscopically at temperatures below
60  C [4]. O

O

1

11.2.2 Relevant Physicochemical Data 11.2.2.1 NMR Spectroscopy 1 H and 13 C NMR data for trans- and cis-3, 5-dimethyl-1,2-dioxolane 2, 3 have been published [5]; proton resonances appear (in ppm) at dH ¼ 4.25 cis and 4.3 trans for H3, at dH ¼ 2.77 cis and 2.19 trans for H4, and at dH ¼ 4.25 cis and 4.30 trans for H5.

Modern Heterocyclic Chemistry, First Edition. Edited by Julio Alvarez-Builla, Juan Jose Vaquero, and José Barluenga. Ó 2011 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2011 by Wiley-VCH Verlag GmbH & Co. KGaA.

j 11 Five-Membered Heterocycles with Two Heteroatoms: O and S Derivatives

926

The cis and trans isomers are readily identified by 13 C NMR, which shows cis d 19.25 Me, 49.34 C4 and 77.30 C3,5; trans d 18.40 Me, 48.61 C4 and 77.04 C3,5. O

O

O

2

O

3

11.2.2.2 Electron Diffraction Studies Electron diffraction has been used to obtain the following dimensions for the  heterocyclic ring of perfluorinated 1,2-dioxolane (4) [6]: O
O, 1.443 A; C
O,   1.377 A and C
C, 1.531 A; C
C
C, 98.1 ; C
C
O, 107.3 and C
O
O, 102.9 . O

F F

O F

F F F 4

11.2.3 Synthesis 11.2.3.1 Synthesis by Ring Construction Oxidative addition of elemental fluorine to appropriate 1, 3-dicarbonyl compounds provides a convenient synthesis of perfluorinated 1,2-dioxolanes. Compound 4 can be synthesized by treatment of difluoromalonyl difluoride with fluorine [6] and 5 is similarly prepared from either hexafluoroacetylacetone or the copper(II) or nickel(II) chelate of trifluoroacetylacetone [7]. F F3C

O

O

F F F CF 3 5

Several studies have appeared on the formation of 1, 2-dioxolanes either by endo cyclization of allylic hydroperoxides [8] or by exo cyclization of homoallylic hydroperoxides upon treatment with various electrophilic reagents [9]. For example, cyclization of the homoallylic peroxide 6 with ButOCl affords the 1, 2-dioxolane 7 (Scheme 11.1) [10]. Photooxygenation of arylcyclopropanes 8 (R ¼ Ph) provides direct access to the corresponding 1,2-dioxolanes 9 (R ¼ Ph), although the reaction is non-stereospecific [11]. The addition can also be radical mediated, as in the conversion of 8 (R ¼ H) to 9 (R ¼ H) by treatment with O2 in the presence of PhSeSePh and AIBN (Scheme 11.2) [12].

11.2 1,2-Dioxoles and 1,2-Dioxolanes

R1

HO O

R2

R3

R1 Cl R2

Bu tOCl

O O

6

R3

7

Scheme 11.1

Ph

Ph

R

R 8, R = H or Ph

O O

9, R = H or Ph

Scheme 11.2

a,b-Unsaturated imines 10 react directly with singlet oxygen to give 3-amino-1,2dioxolanes 11 (Scheme 11.3) [13].

NHBut

NBut

O O

10

11

Scheme 11.3

11.2.3.2 Ring Transformations of Heterocycles Leading to 1,2-Dioxoles and 1,2Dioxolanes 3-Hydroperoxypyrazolines 12 react readily with oxygen with the loss of N2 to give 3-hydroxy-1,2-dioxolanes 13 (Scheme 11.4) [14].

R2 R1

N N

R3 OOH

12

O2

R2 R1

O O

R3 OH

13

Scheme 11.4

Lewis acid treatment of 1,2,4-trioxolanes gives metallated carbonyl oxides that may be trapped by cycloaddition to allylsilanes to give 1,2-dixolanes 14 [15]. R2 R1

SiMe3 O O 14

j927

j 11 Five-Membered Heterocycles with Two Heteroatoms: O and S Derivatives

928

11.2.4 Reactivity of 1,2-Dioxoles and 1,2-Dioxolanes

Solution thermolysis of the bicyclic dioxolane 15 gives epoxy aldehyde 16 in non-polar solvents and the diketone 17 in polar solvents [16]. Flash vacuum pyrolysis of 15 at 450  C and 10
3 Torr gave only 16 [17]. Monocyclic dioxolanes such as 18 [17] and 19 [18] give under similar conditions a mixture of epoxide and carbonyl compounds (Scheme 11.5).

H

H

and / or

O

O O

O O 15

16

O

17 R2

O

O

O

O

R1

Ph 18

19

Scheme 11.5

11.3 1,3-Dioxoles and 1,3-Dioxolanes 11.3.1 Introduction

There has been relatively little work published on the fully conjugated system, 1,3dioxolium salts 20 and their benzo analogues 21, but there are reviews on these compounds [19, 20]. More recently a comprehensive review chapter on 1,3-dioxolium salts has appeared [21]. A much larger volume of work has been published on 1,3dioxoles 22, although most work published in this area is on the fully saturated compounds, 1,3-dioxolanes 23. A major review of these compounds has been published [22]. O + O

O + O 20

21

O

22

O

O

23

O

11.3 1,3-Dioxoles and 1,3-Dioxolanes Table 11.1 X-ray structural data for 24. 

Bond length (A) O1
C2 1.281 Internal angle ( ) O1 108.1

C2
O3 1.282

O3
C4 1.472

C4
C5 1.505

C5
O1 1.480

C2 103.4

O3 103.1

C4 108.6

C5 116.8

11.3.2 Relevant Physicochemical Data 11.3.2.1 X-Ray Diffraction Studies X-Ray diffraction studies on the 1,2-dioxolan-2-yl cation 24 has given molecular dimensions (Table 11.1). The data show the structure to be essentially planar at C2 [23].

O + O 24

11.3.2.2 NMR Spectroscopy Table 11.2 presents the 1 H NMR spectra of 1,3-dioxolane derivatives. 13 C NMR data for 1,3-dioxolium salts 24–26 and 1,3-dioxolane 27 are shown in Table 11.3. The high frequency for C2 signals in 1,3-dioxolium salts is notable when compared to the dioxolane 27.

Table 11.2

1

H NMR data for ring protons of 1,3-dioxolane derivatives. dH (ppm)

Compound 2H 4,4-Dimethyl-1,3-dioxolane 2-Imino-1,3-dioxolane cis-2,2,4,5-Tetramethyl-1,3-dioxolane trans-2,2,4,5-Tetramethyl-1,3-dioxolane

4H

5H

Reference

4.40 4.15 3.38

3.51 4.40 4.15 3.38

[24] [25] [26] [26]

4.9

j929

j 11 Five-Membered Heterocycles with Two Heteroatoms: O and S Derivatives

930

13

Table 11.3

C NMR data for ring carbons of 1,3-dioxole derivatives. dC (ppm)

Compound

24 25 26 27

C2

C4

C5

Reference

174.7 175.4 181.9 101.5

146.6 147.9 90.6 153.2

146.6 147.9 90.6 69.1

[27] [27] [27] [28]

F3C O

O + O R

+

CF3

O

O

O

R

24, R = Ph 25, R = Me

26

27

O NMR studies have been carried out on 1,3-dioxolanes 28 and a few simple derivatives. The chemical shift for the parent compound has been given variously as dO (with respect to H217O): þ 34 [29], þ 35.8 [30] and þ 34.8 [31]. 17

O O 28

11.3.3 Synthesis 11.3.3.1 Synthesis by Ring Construction 1,3-Dioxolium salts have been prepared from a-diazoanhydrides 29 by palladiumcatalyzed decomposition to give a carbene intermediate that undergoes electrocyclization to give 30 (Scheme 11.6) [32]. Ar2

O

Ar1

N2

O

O

29 Scheme 11.6

O

+

Ar1 30

O

Ar2

11.3 1,3-Dioxoles and 1,3-Dioxolanes

Other methods that involve the decomposition of diazo compounds include the reaction of the diazoketone 31 with PhCO2Tf to afford the diazolium salt 32 [27] and the copper-catalyzed decomposition of the 2-diazo-1,3-dicarbonyl compound 33, which in the presence of aldehydes or ketones gives 4-acyl-1,3-dioxoles 34 (Scheme 11.7) [33]. R1

O

R2

N2

R1 R2

31

O + O

Ph OTf

-

32

R3 O R1

R2

N2

O

R2

O

O

R3

O

R1 O

33

34

Scheme 11.7

Rhodium-catalyzed reaction of the diazo esters 35 with carbonyl compounds, R1COR2, provides a new route to silyl dioxolanones 36 in a process involving an intermediate carbonyl ylide (Scheme 11.8) [34]. O

O R3Si

O N2

35

Ph

R1

Ph R2

SiR3 O

O R1

O R2 36

Scheme 11.8

The treatment of chloroesters 37 and 38 with SbCl5 results in cyclization with rearrangement of the carbon skeleton to give, respectively, the salts 39 [35] and 40 [36] (Scheme 11.9). Vinyl esters such as 41 react with benzoyl or t-butyl hexachloroantiminoate to give the 1,3-dioxolium salt 42 (Scheme 11.10) [37, 38]. A simple preparation of 2-methyl-1,3-dioxolane (44) involves heating the vinyl ether 43 with KOH to give 44 in 66% yield [39]. A similar preparation involving enol ethers starts with 45, which reacts with either EtMgBr or Bu2iAlH followed by benzaldehyde to give hydroxyalkyldioxolanes 46 (Scheme 11.11) [40].

j931

j 11 Five-Membered Heterocycles with Two Heteroatoms: O and S Derivatives

932

R1

R2

Cl

R3

R3 O R2 + O R1

O

O

R4

37

39

Pri

O + O

O Cl

R4

O

R

38

R

40

Scheme 11.9

O O

Ph

R

41

O + O

Ph

42

Scheme 11.10

O

KOH O

O

OH 43

R1

44 1. EtMgBr or Bu2 AlH

R2 O

OH 45

2. PhCHO

O

R1 R2

O

Ph

OH 46

Scheme 11.11

Treatment of glycidic esters like 47 with cationic zirconium species and AgClO4 affords the dioxolane 48 [41]. Epoxides like 49 react with CO2 to give dioxolanones 50 (Scheme 11.12) The reaction may be catalyzed either by mixed alkali metal or manganese halides [42] or alkali metal/lead/indium halides [43]. The use of ionic liquids to catalyze this reaction has also been described [44].

11.3 1,3-Dioxoles and 1,3-Dioxolanes

CO2Et O O

O

EtO2C

ZrClCp 2

Bun

O

Bun

O HO

47

48

CO2

O R1

R1

R2

R2

49

O

O

O 50

Scheme 11.12

Treatment of the acetylenic alcohol 51 with aq LiOH affords the dioxolane 52; the yield of this reaction is increased by the addition of acetone (Scheme 11.13) [45].

CN

O

LiOH

CN

O

HO 51

52

Scheme 11.13

Reaction of the stabilized iodonium ylide 53 with ketones affords 1,3-dioxoles 54 (Scheme 11.14) [46].

O MeO2C

-

+

I Ph

R1

R1 O

53

CO2Me

O

R2

O R2 54

Scheme 11.14

The palladium-catalyzed reaction of propargyl acetates with CO in methanol results in cyclization to give dioxolanes 55 (Scheme 11.15) [47].

j933

j 11 Five-Membered Heterocycles with Two Heteroatoms: O and S Derivatives

934

O

R3

R3

R1 R2

O

O

O

O

R1 R2 CO2Me 55

Scheme 11.15

Treatment of a-hydroxyketones, R1CH OH COR2, with triphosgene, Cl3CO2CO, gives the 1,3-dioxol-2-ones 56 in moderate yield [48]. O O

O

R1

R2 56

2-Imino-1,3-dioxoles 57 can be prepared either by electrochemical reduction of benzils 58 in the presence of Ar2N¼CCl2 [49] or by the treatment of bis tin derivatives such as 59 with Ar2NCS (Scheme 11.16); 59 also reacts with CS2 to give 1,3-dioxole-2thiones [50].

Ar1

O

Ar1

O

O

Ar1

O

Ar1

58

N

Ar2

57

Ar1

OSnBu3

Ar1

OSnBu3 59

Scheme 11.16

2,2-Disubstituted-1,3-dioxolanes 61 may be formed by nucleophilic attack with stabilized carbanions on 2-haloalkyl esters 60 (Scheme 11.17) [51].

O O

R1

Br

O R3

O

R2

R2 60

R1

61

Scheme 11.17

The transfer hydrogenation of the tosylacetophenone 62 using a chiral ruthenium catalyst and formic acid as the hydrogen source unexpectedly gives the chiral dioxolanone 63 in 94% ee (Scheme 11.18) [52].

11.3 1,3-Dioxoles and 1,3-Dioxolanes

O OTs

Ph

Ru*

O

O

Ph

O

HCO2H 62

63

Scheme 11.18

1,2-Diols like 64 react with oxalyl chloride and triethylamine to give the 1,3dioxolanone 65 rather than the expected six-membered ring products (Scheme 11.19) [53]. R1

OH

R2

OH 64

O

R1 R2

O

O

65

Scheme 11.19

The treatment of styrene oxide with ruthenium trichloride in acetone gives the dioxolane 66 [54]. Titanium-based catalysts for the reaction of epoxides with acetone to give 2,2-dimethyl-1,3-dioxolanes are TiO CF3CO2 and TiCl CF3SO3 [55]. O O Ph 66

The most widely used method for the preparation of 1,3-dioxolanes involves the reaction of carbonyl compounds with 1,2-diols. A wide range of catalysts has been used in this reaction, trimethylsilyl triflate in the presence of a trimethylsilyl ether [56], K10 montmorillonite under solvent-free conditions [57, 58], scandium triflate [59] and N-benzoylhydrazinium salts [60]. 11.3.3.2 Ring Transformations of Heterocycles Leading to 1,3-Dioxoles and 1,3-Dioxolanes The treatment of 1,3-dioxane 67 with mCPBA provides an interesting route into 1,3-dioxolane aldehydes 68, presumably via an epoxide rearrangement (Scheme 11.20) [61]. 11.3.4 Reactivity of 1,3-Dioxoles and 1,3-Dioxolanes

The phenyliminodioxolane 69 (R¼Ph) undergoes isomerization to the oxazolidinone 70 upon heating at 200  C with LiCl [62]. The parent compound 69 (R¼H) undergoes

j935

j 11 Five-Membered Heterocycles with Two Heteroatoms: O and S Derivatives

936

R1

R2

R1

R2

O

O

O

O CHO

67

68

Scheme 11.20

spontaneous isomerization and trimerization to give the 1,3,5-triazine 71 (Scheme 11.21) [63]. OH OH O N

O

O

O Ph

RN

70

N

O

O

N N O HO

69

71 Scheme 11.21

11.3.4.1 Reactions with Nucleophiles There has been several studies on stable cations such as 72 and their reactions with nucleophiles; 72 reacts with NaOMe at C2, but with NaHCO3 or LiCl at C4 to give ring open 2-hydroxyethyl or 2-chloroethyl methyl carbonates, respectively [64]. The reaction of salts like 73 with acetylenic Grignard reagents takes place at C2 [65].

O

+O

BF4

O

+O

OMe 72

R

ClO4

73

Efficient hydrolysis of 2,2-disubstituted-1,3-dioxolanes to carbonyl compounds has been an area of much interest. Methods for the hydrolysis of 2,2-dimethyl-1,3dioxolanes include cerium ammonium nitrate and oxalic acid [66] and a polymersupported dicyanoketene acetal [67]. Cleavage may also be achieved using Ph3P/ CBr4 [68] or CpTiCl3 [69], other reagents used include DDQ in aq. CH3CN [70] and TeCl4 [71].

11.3 1,3-Dioxoles and 1,3-Dioxolanes

11.3.4.2 Uses in Asymmetric Synthesis There has been a large volume of work published on the use of 1,3-dioxolanes in asymmetric synthesis. TADDOL complexes 74 have been used widely in asymmetric synthesis and have been the subject of a major review [72]. Further developments in this area involve the synthesis of polymer-supported TADDOLs [73] and TADDOL crown ethers [74]. Benzylcyclohexanone has been deracemized by the formation of an inclusion complex with TADDOL compound 74, R,R¼cyclohexyl. The X-ray structure of this complex has also been published [75]. The TADDOL complex 74, R,R¼cyclopentyl, has been used to direct enantioselective Diels–Alder reactions in aqueous solution [76].

R

Ar Ar O OH

R

O

OH Ar Ar 74

There has also been considerable work on C
C bond formation by attack on suitable dioxolane systems by carbanions, and of particular interest has been the use of chiral dioxolanes in asymmetric synthesis. Conjugate addition of organozinc compounds to chiral dioxolanes such as 75 and 76 affords adducts with a high degree of enantioselectivity [77, 78]. O O O

O

MeO2C

O

Bu 75

76

11.3.4.3 Reactions with Carbenes and Radicals Treatment of 1,3-dioxolane (23) with ferrous sulfate and a peroxide in the presence of pyridine gives predominantly 77 together with small amounts of products resulting from reaction at the 4-position of the dioxolane and the 2-position of the pyridine [79]. O O

O

23

N O 77

The reaction of 1,3-dioxolanes with carbenes generally proceeds by insertion into the C2
H bond and this has been examined for phase-transfer generated Cl2C: and Br2C: [80, 81] and for various arylchlorocarbenes (ArClC:) [82, 83]. Ethoxycarbonylcarbene behaves differently and reacts with 78 by insertion into the C2
O bond to give 79 [84].

j937

j 11 Five-Membered Heterocycles with Two Heteroatoms: O and S Derivatives

938

O

O O

O O

EtO2C

78

O

79

11.3.5 Compounds of Interest

1,3-Dioxolane derivatives such as 80 have been used as a fungicide [85] and related derivatives have anti-fungal activity [86–88]. The structurally related compounds 81 and 82 have been prepared as intermediates for ketoconazole synthesis by lipasecatalyzed kinetic resolution [89]. Cl

Cl Cl

Cl

O N

O

N O Br

O Ph

F 80

O R

81, R = CH2OH 82, R = CO2H

Tertiary ammonium salts containing a 1,3-dioxolane ring (83) have been described as muscarinic acetylcholine antagonists [90]. Ar

I

O +

O

N

83

11.4 1,2-Dithioles and 1,2-Dithiolanes 11.4.1 Introduction

The 1,2-dithiolane system 84 is known but the partially unsaturated 1,2-dithiole system 85 is very common, along with its derivatives 85 (X¼O, S, NR). There are only

11.4 1,2-Dithioles and 1,2-Dithiolanes

a few references to systems where X¼H,H or alkyl. Cationic species such as 86 and 87 are also known. 1,2-Dithiolanes have a greater reactivity than acyclic disulfides, which is attributed to some repulsion between the lone pairs on the adjacent sulfur atoms [91]. 1,2-Dithiolium cations are aromatic 6p systems and are very stable except to nucleophilic reagents. A comprehensive review of 1,2-dithiolium salts has been published [92]. X +

S S

S S

R

84

+

S S R

R

85

86

+

S S R

R 87

11.4.2 Relevant Physicochemical Data

X-Ray methods for 1,3-dithiolanes have shown the S
S bond distances to be in the range of acyclic disulfides [91]. Figure 11.1 shows the bond lengths and angles of 1,2dithiol-3-thione [93]. The 1 H NMR spectrum of 1,2-dithiolane 84 has signals at d2.09 ppm for H4 and d3.36 ppm for H3 and H5 [91]. Protons in 1,2-dithiole-3-ones absorb at higher field than the corresponding 1,2-dithiole-3-thiones. In the unsubstituted 1,2-dithiolium ion 88, the H3 and H5 protons absorb at d10.7 ppm and the H4 proton at d8.88 ppm [91].

+

S S 88

The 13 C NMR chemical shifts for 1,2-dithiolanes are 41 ppm for C3 and C5 and 56 ppm for C4; the chemical shifts for 1,2-dithiole-3-one are 216 ppm for C3, 140.2 ppm for C4 and 155.1 ppm for C5 [94].

1.34A

1.38A

o 119.04 o 111.1

1.69A 93.0o 96.8o

S

S

120.0o

2.05A

S

1.67A 1.77A

Figure 11.1 Geometry of 1,2-dithiol-3-thione.

j939

j 11 Five-Membered Heterocycles with Two Heteroatoms: O and S Derivatives

940

11.4.3 Synthesis 11.4.3.1 Synthesis by Ring Construction The synthesis of 1,2-dithioles and 1,2-dithiolanes has been the subject of a review [95]. The most practical method for the synthesis of 1,2-dithiols involves direct S
S bond formation, usually via oxidation or displacement of a leaving group on one of the sulfur atoms. For example, treatment of dithiols with bromine on hydrated silica has affords 1,2-dithiolanes 84 and 89 [96]. OH OH S S

S S

84

89

A mild method for the preparation of 1,2-dithiolanes involves the treatment of 1,3dithiocyanates with Bun4N þ F
[97]. Treatment of b-ketoamides such as 90 with Lawesson’s reagent gives the 1,2dithiole-3-thione 91 [98]. In a similar preparation, treatment of malonates 92 with Lawesson’s reagent and sulfur in xylene in the presence of a catalytic amount of 2-mercaptobenzothiazole and ZnO affords the 1,2-dithiol-3-thione 93 [99]. O

O

N H

S

Ph S S

90

91 R1 O

O

RS OR

RO

S S S

R1 92

93

Dicyclic 1,2-dithiolane 94 has been prepared by treating either the ylide Ph3¼Ar2 or the thione Ar2C¼S with sulfur in boiling xylene in the presence of maleic anhydride [100]. The cycloaddition of thiocarbonyl sulfides with reactive alkynes gives access to 1,2-dithioles 95 [101].

S Ar

O

S

O Ar

O 94

Ph Ph

S

R

S R

95

11.4 1,2-Dithioles and 1,2-Dithiolanes

1,2-Dithiolanes are formed by the reaction of 1,3-halopropanes or haloalkenes with disulfide ions. Hydrogen disulfide provides the source of disulfide ion and it readily condenses with phenylpropynyl chloride to form 5-phenyl-1,2-dithiol-3-one (96) [102]. Similarly 1,3-diketones condense with hydrogen disulfide to give 1,2dithiolium salts 97 (Scheme 11.22) [102]. O

Ph

H2S2

Ph

O S S

Cl

96 R2

R1 O

H2S2

R1

R2 +

S S

O

97 Scheme 11.22

a-Thioderivatives of enamines or enol ethers react with carbon disulfide to form 5-amino or 5-alkoxy-1,2-dithiole-3-thiones [103]. An interesting reaction of the oxime 98 with S2Cl2 gives the bicyclic 1,2-dithiole isomers 99 and 100 (Scheme 11.23) [104]. CN

Cl N OH

S2Cl2

Cl S

Cl 98

CN

99

S

+

Cl

Cl S

Cl

S

100

Scheme 11.23

A common method for the synthesis of 1,2-dithioles is the sulfurization of various 3-carbon units by elemental sulfur. The conversion of 101 into 102 and 103 into 104 is usually carried out under thermal conditions (180–250  C) (Scheme 11.24) [105]. 11.4.3.2 Ring Transformations of Heterocycles Leading to 1,2-Dithioles and 1,2-Dithiolanes The synthesis of 1,2-dithioles by the transformation of other heterocyclic rings is a common method of preparation. Thiophene derivative 105, when reacted with Na2S in air affords the 1,2-dithiole 106 (Scheme 11.25) [106]. Ring contraction of 1,3-dithianes or 1,3-dithienes is also a well reported method for the preparation of 1,3-dithioles and 1,3-dithiolanes. The reaction is usually carried out under oxidizing conditions in the presence of acid or from 1, 3-dithiane-S-oxides with acids. Bromine has been used to transform the 1, 3-dithiane 107 into the 1,2dithiolane 108 (Scheme 11.26) [107].

j941

j 11 Five-Membered Heterocycles with Two Heteroatoms: O and S Derivatives

942

S8, Δ

Ph S

Ph

S S

101

102

S8, Δ

S S S

103

104

Scheme 11.24

OMe

EtO2C

S

EtO2C

O

105

CO2H S S 106

Scheme 11.25

R

R R

S N

R

S CONH2 107

S S

108

Scheme 11.26

Isoxazoles possess a three-carbon unit suitable for conversion into the 1,2-dithiole skeleton. Thus, 5-phenylisoxazole (109) is thionated to afford 5-phenyl-1,2-dithiole-3thione (110) [108] and isoxazoline-3-thiones 111 affords 1,2-dithiole-3-imines 112 on treatment with H2S (Scheme 11.27) [109]. Thiazolidinones 113 react with Lawesson’s reagent to give 3-imino-1,2-dithioles 114 [110]. 11.4.4 Reactivity of 1,2-Dithioles and 1,2-Dithiolanes 11.4.4.1 1,2-Dithiolium Salts 11.4.4.1.1 Reactions with Nucleophiles 1,2-Dithiolium salts react readily only with nucleophiles and often at the least hindered 3 or 5 position to form 1,2-dithioles.

11.4 1,2-Dithioles and 1,2-Dithiolanes

Ph

Ph O N

S S

109

110

Ph

Ph

S O N

112

S

Ph

Ph

N H

O

NH S S

R

111

R

S

N S S

O

113

R S

114

Scheme 11.27

These 1,2-dithioles may reform 1,2-dithiolium salts if there is a suitable leaving group at the 3-position Scheme 11.28. Nuc

X

X Nuc S S

+

S S

- X-

Nuc +

S S

Scheme 11.28

Oxygen and sulfur nucleophiles react in a similar fashion to give 3-alkoxy or 3-alkylthio substituted 1,2-dithioles, again if there is a suitable leaving group at the 3-position the products obtained are 1,2-dithiolium salts [111]. 1,2-Dithiolium salts react with nitrogen nucleophiles at the 3-position but the final product depends on the substitution pattern on the dithiolium ring. Dithiolium salts 115, without a leaving group at C3, react with ammonia to form isothiazoles 116 [111] and with primary and secondary amines to form aminothiones 117 (Scheme 11.29) [111].

R1

R2 +

NH3

R1

R2

S S

S N

115

116

HNR3R4 Scheme 11.29

R1

R2 S

N R3 R4

117

j943

j 11 Five-Membered Heterocycles with Two Heteroatoms: O and S Derivatives

944

The reaction of 1,2-dithiolium salts with carbon nucleophiles usually leads to ring opening and recyclization to give thiopyrans or thiophenes – these reactions are similar to those involving nitrogen nucleophiles by attack at C3 or it may involve an initial attack of the carbanion on a ring sulfur [112, 113]. 11.4.4.1.2 Reduction Electrochemical reduction of 1,2-dithiolium salts 118 gives bis-1,2-dithiole dimers 120 via radical intermediates 119 whose stability depends on the substitution pattern (Scheme 11.30) [114]. R2

R2 R1

R1

R3 +

S S

118

R3

R2

C R3 S S 119

R1

S

S

S

R3

S

R1 R2

120

Scheme 11.30

11.4.4.2 1,2-Dithioles To a certain extent 1,2-dithioles behave like acyclic disulfides in their reactions. 1,2Dithioles with exocyclic double bonds are potentially aromatic and readily undergo reactions that result in the formation of 1,2-dithiolium salts. 11.4.4.2.1 Reactions with Electrophiles 1,2-Dithioles react with electrophiles at the ring sulfur atoms; thus chlorine, sulfuryl chloride and sulfenyl chlorides react at the ring sulfur to afford acyclic products [115]. 11.4.4.2.2 Reactions with Nucleophiles 1,2-Dithiole-3-thiones react with nucleophiles at S2, C3, C4 or C5, the exact position depending on the substitution pattern on the ring and on the hard/soft character of the nucleophile [116–118]. 1,2-Dithioles are attacked at C3 by hydroxide ion. Ethoxide ion attacks Oltipraz (121) at C5; subsequent ring opening and recyclization forms pyrrolodiazine 122 [116]. SMe

N N N

N S S 121

S

OEt 122

1,2-Dithiole-3-ones and 3-thiones behave like acyclic ketones and thiones, forming imines such as 125, oximes and hydrazones with nitrogen nucleophiles [119]. 1,2Dithioles 123 can also undergo ring opening and recyclization to afford isothiazoles 124 (Scheme 11.31). This pathway is dependant on the substituents at R1 and R2 and is particularly common with fused dithioles [120]. 1,2-Dithioles react with carbon nucleophiles at a range of sites. Grignard reagents react as thiophiles, attacking at S2 of 1,2-dithiol-3-ones. Phosphonium ylides and

11.4 1,2-Dithioles and 1,2-Dithiolanes

R2 R1

RNH2

S

R2

R2

R1

and / or

S

S S

S N

123

124

R1

NR S S

R

125

Scheme 11.31

other carbanions attack at C3 of 1,2-dithiole-3-ones and 3-thiones to form 3-alkylidene-1,2-dithioles [121]. Reaction of the 1,2-dithiole-3-thione 126 with trimethyl phosphate affords some of the desired coupling product but also the phosphonate derivative 127 (Scheme 11.32) [122]. S S S

Cl

S S

(MeO)3P Cl

CN

CN

126

R P(O)(OMe) 2

127, R = H or Me

Scheme 11.32

11.4.4.2.3 Reactions with Carbenes and Nitrenes 1,2-Dithioles react with carbene and nitrenes at the S
S bond, leading to insertion and sometimes with loss of one sulfur atom to form thiophenes (128) or isothiazoles (129), respectively, Scheme 11.33 [123, 124]. R2 :CR2

S

R2 R1

X

R1

R

X S S

S

S 128 X

R1 S

X

R R2

:NR

R2 R1

N R

S

R R R2

R1

X S N 129

R

Scheme 11.33

11.4.4.3 1,2-Dithiolanes 11.4.4.3.1 Reaction with Electrophiles Reactions of 1,2-dithiolanes all occur at the ring sulfur atoms. The sulfur is nucleophilic and is readily alkylated to form 1,2dithiolium salts 130 (Scheme 11.34) [125].

j945

j 11 Five-Membered Heterocycles with Two Heteroatoms: O and S Derivatives

946

Me3O+ BF4-

+

S S

S S 84

Me

130

Scheme 11.34

11.4.4.3.2 Reaction with Nucleophiles Alkyl lithium reagents, Grignard reagents and cyanide ion attack 1,2-dithiolanes at a sulfur atom to form ring open products [126, 127]. 1,2-Dithiolanes 131 react with lithium acetylides to give the ring expanded product 132 [128]. If the 1,2-dithiolane 131 is reacted with dimethylsulfoxonium methylide the 1,3-dithiane 133 is formed (Scheme 11.35) [129].

R

R

Bu

R R

S S 131

R R

Bu

S

Li

S

S

132

S 133

Scheme 11.35

11.4.4.3.3 Reactions with Carbenes Carbenes react with 1,2-dithiolanes to afford insertion products at the S
S bond. The 1,2-dithiolane 134 reacts with diphenylcarbene to afford a mixture of the 1,3-dithiane insertion product 135 and the desulfurization product 136 (Scheme 11.36) [130]. O

O

:CPh2

S S 134

S

S

Ph

Ph

135

+

S

136

Scheme 11.36

11.4.4.3.4 Compounds of Interest 1,2-Dithiolane-4-carboxylic acid (asparagusic, 137) is thought to act in biological systems as a substrate of a dehydrogenating enzyme and to stimulate pyruvate oxidation. Lipoic acid 138 is involved in the oxidative decarboxylation of 3-ketoacids, oxidative phosphorylation and in photosynthesis [91]. The sulfonamide derivative of lipoic acid (139) is a glutathione reductase enhancer [131]. Oltipraz (121) has schistosomicidal activity [116].

11.5 1,3-Dithioles and 1,3-Dithiolanes

O

R

CO2H S S

S S

137

138, R = OH 139, R = NHSO 2Me

11.5 1,3-Dithioles and 1,3-Dithiolanes 11.5.1 Introduction

This section deals with 1,3-dithioles derivatives such as 1,3-dithiolylium ions 140, mesoionic 1,3-dithiol-4-ones 141, 1,3-dithioles 142, 1,3-dithiolanes 143 and the tetrathiafulvalene (TTF) system 144. The latter system has been the subject of a large number of publications because of its organic conducting properties. O

+

S

S

140

R1 +

S

S S

S

S

S

S

S

S S

R2 141

142

143

144

A comprehensive review chapter on 1,3-dithiolium salts has appeared [132]. The synthesis and reactions of 1,3-dithioles and dithiolanes have also been reviewed [95]. There have also been several reviews on the properties of TTFs [133–135]. 11.5.2 Relevant Physicochemical Data 11.5.2.1 X-Ray Diffraction Studies Several X-ray crystal structure determinations on 1,3-dithioles and 1,3-dithiolanes have been published; bond lengths and angles are presented in Tables 12.4 and 12.5, respectively. Interestingly, the TTF system 144 is not planar but is slightly distorted into a chair conformation [136]. 11.5.2.2 NMR Spectroscopy 1 H NMR data of variously substituted 1,3-dithiolylium ions have been published [113, 138]. Table 11.6 contains 1H NMR data for several derivatives.

j947

j 11 Five-Membered Heterocycles with Two Heteroatoms: O and S Derivatives

948



Table 11.4 Bond lengths (A) for 1,3-dithiolane derivatives.

Bond

S S

S

S O

S

S

Ph S1
C2 S3
C2 S3
C4 C4
C5 S1
C5 Reference

1.756 1.758 1.729 1.314 1.732 [136]

Ph

1.72 1.76 1.80 1.54 1.83 [137]

Table 11.5 Bond angles ( ) for 1,3-dithiolane derivatives.

Bond

S S

S

S O

S

S

Ph S1
C2
S3 C2
S3
C4 S3
C4
C5 C4
C5
S1 C5
S1
C2 Reference

Table 11.6

114.5 94.3 118.6 118.0 94.5 [136]

1

Ph

115.5 96.7 115.4 108.3 94.6 [137]

HNMR data for 1,3-dithiole derivatives.

Compound

H2 (d, ppm)

H4 & 5 (d, ppm)

Reference

S + S C H

11.65

9.67

[139]

7.2

[138]

6.74

[138]

S S S S S O

11.5 1,3-Dithioles and 1,3-Dithiolanes Table 11.7

13

C NMR data for 1,3-dithiole derivatives.

Compound

C2 (d, ppm)

C4 (d, ppm)

Reference

S + S C BF4 H

179.5

146.2

[140]

S + S C BF4 H

221.2

46.4

[140]

182.4

146.0

[140]

140.7

133.7

[141]

S + S C BF4 H

S S S

13

C NMR data for 1,3-dithiole derivatives are presented in Table 11.7. Calculated electron densities have been correlated with observed 13 C chemical shifts for the benzo-1,3-dithiolylium ion [140]. 11.5.2.3 Theoretical Methods Simple LCAO-MO calculations for 1,3-dithiole-2-thione, benzo-1,3-dithiolylium ion,1,3-dithiole-2-one and 1,3-dithiolylium ions indicate that the lowest electron density is found at the 2-position of the 1,3-dithiolylium cation and showed that the C4
C5 bond order corresponded approximately to that of an isolated double bond [138]. 11.5.3 Synthesis 11.5.3.1 1,3-Dithiolium Salts, 1,3-Dithiolones and 1,3-Dithioles Several methods are known for the preparation of 1,3-dithiolylium salts from acyclic precursors by the formation of one bond. Acid-catalyzed cyclization of thioesters 145, dithioesters 146 or thio analogues 147 using either mixtures of perchloric acid and glacial acetic acid or sulfuric acid in the presence of H2S [138] or H2S/BF3 [113] results in the formation of 148 (Scheme 11.37). Dithiocarbamates like 149 afford the perchlorate salt 150 upon reaction with perchloric acid (Scheme 11.38). Reduction of 150 with sodium borohydride gives the 1,3-dithiole 151, which can then be treated again with perchloric acid to afford the 1,2dithiolylium salt 152 [142].

j949

j 11 Five-Membered Heterocycles with Two Heteroatoms: O and S Derivatives

950

R1

S

R2

X

R3

S

R1

Y

R2

145, X = O, Y = O 146, X = O, Y = S 147, X = S, Y = O

+ C R3 S

148

Scheme 11.37

S

HClO4

N

S

S

S

O 149

NaBH4

+

N

S

N S

ClO4-

150

HClO4

S

151

+ C H S ClO4-

152 Scheme 11.38

1,3-Dithiol-2-ones 154 are also obtained by acid-catalyzed cyclization of thioxodithiocarbamates 153 (Scheme 11.39) [143]. R2 R1

OR3

S S

H+

S

R2

S

R1

153

O S

154

Scheme 11.39

In a similar approach S-vinyl-N,N-dialkyldithiocarbamates 155 afford, upon reaction with bromine, the 1,3-dithiolylium bromides 156 (Scheme 11.40) [144, 145].

NR2

S R1

S 155

Scheme 11.40

S

Br2 R1

+ C NR2 S Br

156

11.5 1,3-Dithioles and 1,3-Dithiolanes

Thiobenzoylthioglycolic acid 157 reacts with acetic anhydride in the presence of boron trifluoride results to form dithiolylium salt 158 (Scheme 11.41) [146].

Ph

S OH

Ac2O

S

Ph

S

O

O S

+ C Ph S

O

BF3.Et2O

157

158

Scheme 11.41

Various methods have been described for the synthesis of 1,3-dithiole-2-thiones, which are widely used as precursors for the preparation of 1,3-dithiole derivatives. Dithiocarbamates 159 are easily cyclized with conc. sulfuric acid or 70% perchloric acid to yield the 1,3-dithiolylium salts 160, which upon treatment with H2S afford the 1,3-dithiole-2-thiones 161 (Scheme 11.42) [147]. R1

S

R2

O

NR2

S

R1

H+

S

R2

159

+ C NR2 S

160

H2S

R1 R2

S

S S

161

Scheme 11.42

An alternative approach uses propargyl-t-butyltrithiocarbamates 162, which afford mono substituted 1,3-dithiole-2-thiones 163 on treatment with trifluoroacetic acid/ glacial acetic acid (Scheme 11.43) [148]. R

S

S

TFA

S

AcOH

S

S S

R 162

163

Scheme 11.43

A two-step conversion of alkynes into dithiolones 164 and dithiolethiones 165 has been reported. The initial step involves palladium-catalyzed addition of Pri3Si-S-SSiPri3 followed by treatment with fluoride ion and either PhSOCl or CSCl2 [149]. R1

S

X S

R2 164, X = O 165, X = S

j951

j 11 Five-Membered Heterocycles with Two Heteroatoms: O and S Derivatives

952

A convenient synthesis of 1,3-dithiole-2-thiones 166 involves the treatment of a terminal alkyne with butyllithium, sulfur and then CS2 (Scheme 11.44) [150]. In similar fashion, the reaction of phenylacetylene with sulfur and KOH in DMSO leads to direct formation of the dithiole 167, albeit in low yield [151].

R

1. nBuLi, S8

H

2. CS2

S

R

Ph

S

Ph

S S

S

(166)

(167)

Scheme 11.44

The bis-dithiole salt 168 reacts with long-chain alkyl iodides to give dithioles 169 (Scheme 11.45) [152]. +

K

R-I

S

+

K S

R

S

S

168

NO2

S

NO2

169

Scheme 11.45

Unsubstituted 1,3-dithiole-2-thione (172) can be prepared from 1,2-dichloroethyl ethyl ether (170) and potassium trithiocarbonate (Scheme 11.46). The intermediate 4-ethoxy-1,3-dithiolane-2-thione 171 is treated with p-toluene sulfonic acid to give 172 [153]. +

K

S

+

K S

Cl

EtO S

+

EtO

EtO

S

S

S

S

S

171

172

Cl

170

pTSA

S

Scheme 11.46

1,3-Dithiolylium salts 175 have also been prepared by the reaction of a-haloketones 173 with an excess of dithio-carboxylic acids 174 in the presence of strong mineral acids at 60–80  C (Scheme 11.47) [154]. O X

R2 R3 173

Scheme 11.47

+

R1

S SH

174

HX

R3 R2

S

+ C R1 S

175

11.5 1,3-Dithioles and 1,3-Dithiolanes

a-Haloketones 176 also react with N,N-dialkyldithiocarbamidates 177 in the presence of strong acid to afford 2-alkylamino-1,3-dithiolylium salts 178 (Scheme 11.48) [155, 156].

O X

R4

+

R3

R1 R2

S

N

176

S

R3

H+

R4

S

177

R1 + C N R2 S

178

Scheme 11.48

Benzo-annellated 1,3-dithiole-2-thiones (180) can be prepared by the reaction of benzene-1,2-dithiol (179) with thiocarbonyldiimidazole in glacial acetic acid (Scheme 11.49) [157]. S N

N

N

SH SH

N S S

AcOH

179

S

180

Scheme 11.49

11.5.3.2 Ring Transformations of Heterocycles Leading to 1,3-Dithiole Derivatives Thermolysis of 1,2,3-thiadiazoles 181 in carbon disulfide provides a useful route to 1,3-dithiole-2-thiones 182 (Scheme 11.50) [158]. R1 R2

N

N S

181

CS2 sealed tube 220oC

R1 R2

S

S S

182

Scheme 11.50

1,2-Dithiole-3-thione derivatives can also be used as starting compounds for 1,3dithiole synthesis. 1,2-Dithiole-3-thiones 183 react with alkynes or even benzyne to afford 1,3-dithioles 184 (Scheme 11.51) [159]. Alkynes bearing electron-withdrawing groups also react with O,S-ethylene dithiocarbonate 185 (X¼O) or ethylene trithiocarbonate 185 (X¼S) to afford 1,3-dithiole-2ones 186 (X¼O) or 1,3-dithiole-2-thiones 186 (X¼S) (Scheme 11.52) [160, 161].

j953

j 11 Five-Membered Heterocycles with Two Heteroatoms: O and S Derivatives

954

S

S R1

S S

R2

+

R3

S

R3

R4

S

R4

183

R2 R1

184

Scheme 11.51

X R1

+

R2

S

S 185

R1

S

R2

S

X

186

Scheme 11.52

11.5.3.3 Ring Synthesis of 1,3-Dithiolanes The most widely used method for the synthesis of 1,3-dithiolanes involves the condensation reaction of an aldehyde or ketone with suitably substituted 1,2-dithiols in the presence of a catalyst. Catalysts for the conversion of aldehydes and ketones into 1,3-dithiolanes with ethanediol include HCl [162], BF3Et2O [162], iodine [163], MoCl5 [164], indium triflate [165] and Cu(CF3SO3)2 [166]. Iodine and indium triflate and indium chloride are also good catalysts for effecting the transthioacetalization of 1,3-dioxolanes [167]. ZrCl4 has also been used in this transformation [168]. The use of BF3Et2O as a catalyst allows the synthesis of some very sensitive systems; the cyclopropanone 187 reacts with 1,2-dithiols 188 in 24–58% yield to give the spiro derivatives 189 (Scheme 11.53) [169].

R2 O

+ Ph

R1 187

R2 SH

HS

BF3Et2O 25oC, 2h.

188

S Ph

S R1 189

Scheme 11.53

Carbonyl compounds possessing an a-methylene group (190) react with 1,2bis(chlorosulfenyl)alkanes 191 to give 2- formyl-1,3-dithiolanes 192 (Scheme 11.54) [170].

11.5 1,3-Dithioles and 1,3-Dithiolanes

j955

R2 H

R1

Cl

+

O

S

S

S

Cl

R2

190

OHC

191

S R1

192

Scheme 11.54

Compound 191 also reacts with ethyl acetoacetate to give 2-acetyl-2-ethoxycarbonyl-1,3-dioxolanes 193, which are readily hydrolyzed and decarboxylated to give 2-acetyl-1,3-dioxolanes 194 (Scheme 11.55) [170].

Cl

S

S

Cl

+

O

S

CO2Et

R2

O

191

S

S CO2Et

O

193

194

Scheme 11.55

1,2-Bis(triphenylphosphonium)ethane dibromides 195 react with 1,2-ethanedithiol in the presence of a base to give an almost quantitative yield of 2-triphenylphosphoniomethyl-1,3-dithiolane (196), which can then undergo Wittig reactions (Scheme 11.56) [171].

+

PPh3

+

+

Ph3P

+

PPh3 2 Br

HS

S

SH

195

S

Br-

196

Scheme 11.56

2-Amino substituted 1,3-dithiolanes 198 can be obtained from amide acetals such as 197 and 1,2-ethanedithiol (Scheme 11.57) [172].

R

OMe OMe NMe2 197

Scheme 11.57

+

HS

SH

R

NMe2

S

S

198

S

j 11 Five-Membered Heterocycles with Two Heteroatoms: O and S Derivatives

956

Ethane-1,3-dithiol also reacts with dichloromethyl methyl ether in the presence of sodium to give 2-methoxy-1,3-dithiolane 199 (Scheme 11.58) [173]. It also reacts with phosgene to give 1,3-dithiolan-2-one 200 [174]. Cl O S

O

Cl S

Cl2CO

SH

HS

199

O S

S

200

Scheme 11.58

The reaction of ethylene dibromide with sodium trithiocarbonate affords 1,3dithiolan-2-thione (201) (Scheme 11.59) [175].

Br

Br

S

+

Na2CS3

S

S 201

Scheme 11.59

11.5.3.4 Ring Transformations of Heterocycles Leading to 1,3-Dithiolane Derivatives 2-Substituted 1,3-dioxolanes react with ethanediol in an ionic liquid – transthioacetalization occurs to afford the corresponding 2-substituted 1,3-dithiolanes [176]. The asymmetric synthesis of various nucleoside analogues in which the ribose base is replaced by a 1,3-dithiolane ring has been described [177]. The transformation of complex and sensitive carbonyl compounds under neutral conditions into 1,3-dithiolanes 203 can be achieved using 2-phenyl or 2-halogeno 1,3,2-dithiaborolanes 202 (Scheme 11.60) [178].

R1 B S S

O

+

R2

202, R1 = Ph or Cl

R3

R2

R3

S

S

203

Scheme 11.60

An alternative method for the synthesis of 1,3-dithiolanes 205 from acid-sensitive carbonyl compounds involves the reaction of 2-ethoxy-1,3-dithiolane (204) in the presence of mercury(II) chloride or other Lewis acids (Scheme 11.61) [179].

11.5 1,3-Dithioles and 1,3-Dithiolanes

O S

O

+

S

R1

HgCl2 R2

R2

R1

S

S

204

205

Scheme 11.61

11.5.3.5 Synthesis of Tetrathiafulvalenes Tetrathiafulvalenes (TTFs) are electron donors that easily form charge-transfer complexes with electron acceptors such as radical salts. The discovery of the exceptional electron conductivity of TTFs has encouraged a great deal of research into their synthesis. The vast majority of syntheses of TTFs involve the preparation of the p-bond in between the two 1,3-dithiole rings as the final step. This bond can be formed via an elimination reaction involving either two-proton electrochemical oxidation or the s- and p- bonds can be formed simultaneously by a coupling reaction between two carbenes. The electrochemical oxidation of the 1,3-dithioles 206 and 208 in the presence of pyridine has been described. The respective TTFs 207 and 209 were obtained in low yield, 30 and 40%, respectively (Scheme 11.62) [180].

S

S S

Ph

Ph

206

S

S

S

Ph

207

S

S S

208

S

S

S 209

Scheme 11.62

The synthesis of TTF via elimination of a proton from 1,3-dithiolylium salts in the final synthetic step involves the reaction of a carbene or phosphonium ylide on a 1,3dithiolylium salt bearing a hydrogen at C2. These precursors can be prepared either by an alkylation of 2-alkylthio-1,3-dithioles 210 [181] or by oxidation of 1,3-dithiole-2thiones 211 either with peracid or hydrogen peroxide (Scheme 11.63) [182]. Treatment of these precursors with a tertiary amine base affords TTF (144). The presence of alkyl groups in the 4 or 5 position does not interfere with this reaction; however, electron-withdrawing groups in these positions can lead to no reaction.

j957

j 11 Five-Membered Heterocycles with Two Heteroatoms: O and S Derivatives

958

S

SMe S

S

HBF4

210

S

Et3N

+ C H S

S

S

S

S 144

S

MeCO3H

S 211 Scheme 11.63

The reaction of carbon disulfide with either a strained or electron-rich acetylene derivatives in the presence of an acid or under high pressure is another common method for the preparation of TTFs. This method can be used to afford TTFs with electron-withdrawing substituents in the ring. Acetylenes 212 and 213 react with CS2 to give the TTFs 214 [183] and 215 (Scheme 11.64) [184]. CF3

+

CF3CO2H

CS2

F3C

100oC, 100h.

F3C

CF3

S

S

CF3

S

S

CF3

214

212 CO2Me

+

CS2

CO2Me

MeO2C

S

S

CO2Me

MeO2C

S

S

CO2Me

215

213 Scheme 11.64

1,3-Dithiolylium salts 217 react with 2-triphenylphosphino-1,3-dithioles 216 to afford an intermediate that eliminates a proton and triphenylphosphine on treatment with base to give the TTF 218 (Scheme 11.65) [185]. S S

1. S S 216 Scheme 11.65

217 PPh3 2. Et3N

+

C H S

S

S

S 218

11.5 1,3-Dithioles and 1,3-Dithiolanes

Similarly, TTF (144) is obtained from a mixture of trialkylphosphanes and alkynes in the presence of carbon disulfide (Scheme 11.66) [186].

R3P

+

+ R3P

CS2

CO2Me

S S

-30oC

S

S

S

S 144

Scheme 11.66

TTF may be obtained by dethioxygenation of 2-thioxo-1,3-dithioles by transition metal complexes. The reaction of 2-thioxo-1,3-dithioles 219 with Fe3(CO)12 or Co2(CO)8 furnishes TTFs 220 with aryl, alkyl or electron-withdrawing groups in the 4- and 5-positions of the dithiole ring (Scheme 11.67) [187, 188].

R1

S

S

Fe3(CO)12 or

R1

S

Co2(CO)8

R2

S

S

R2

219

R1

S S

R2

220

Scheme 11.67

2-Thioxo-1,3-dithioles bearing electron-withdrawing groups such as in 221 also react with trivalent phosphorus compounds to form the corresponding TTFs (222) as a mixture of regioisomers (Scheme 11.68) [189].

MeO2C

S

S S

221

P(OEt)3

MeO2C

S

S S

S

CO2Me

+

trans isomer

222

Scheme 11.68

Tetrachloroethylene has also been used as a central building block for TTF synthesis. This method is suitable for the synthesis of symmetrical and unsymmetrical TTFs. The reaction of tetrachloroethylene with 1,2-benzenethiols 223 and 224 leads to a mixture of benzotetrathiafulvalenes 225 (Scheme 11.69) [190]. TTF (144) has been synthesized in two steps (85% overall yield), starting from 4,5bis(benzoylthio)-1,3-dithiole-2-thione (226) (Scheme 11.70). The intermediate tetrathianaphthalene 227 is treated with base to afford TTF. This method is suitable for the large-scale synthesis of TTF as no chromatography is required [191].

j959

j 11 Five-Membered Heterocycles with Two Heteroatoms: O and S Derivatives

960

SH

SH

+

Cl

Cl

Cl

Cl

223

224

R

S

S

SH

SH

S

S

R

225; R = H or Me

Scheme 11.69

Ph

O S

S O

S S

S

S

S

S

S

S

S

S

S 144

Ph 226

227

Scheme 11.70

11.5.4 Reactivity of 1,3-Dithiolylium Ions, Mesoionic 1,3-Dithiol-4-ones and 1,3-Dithioles 11.5.4.1 Thermal and Photochemical Reactions 1,3-Dithiole-2-one 228 undergoes a photochemically induced decarbonylation to afford the dithione derivative 229, which may react further to give the dithiete 230 (Scheme 11.71) [192].

Ar

S

O

hv

S

Ar

S

Ar

S

Ar

228

Ar

S S

Ar

229

230

Scheme 11.71

Photolysis of the 1,3-dithiolylium-4-oate 231 gives a mixture of the 1,2-dithiol-3one 232 along with diazine 233 and thiophene 234 (Scheme 11.72) [193].

O

S

Ph +

Ph

S

231 Scheme 11.72

hv

S

O Ph

232

S

+

Ph

S

Ph

Ph

S

Ph

233

Ph

+

Ph

Ph S

234

Ph

11.5 1,3-Dithioles and 1,3-Dithiolanes

11.5.4.2 Reactions with Electrophiles The attack of electrophiles at the ring carbons of 1,3-dithiolylium ions is seldom observed. 1,3-Dithiole-2-thiones can be alkylated on the ring sulfur atom to give a 1,3dithiolylium system – strong alkylating agents such as triethyloxonium tetrafluoroborate must be used [194]. 11.5.4.3 Reactions with Nucleophiles 1,3-Dithiolylium salts react with nucleophiles at the 2-position while 1,3-dithiolylium-4-oates undergo nucleophilic attack at the 4-position. 1,3-Dithiolylium cations are hydrolyzed to the corresponding 2-hydroxy-1,3-dithioles, which upon treatment with acid reform the 1,3-dithiolylium cation [195]. The reaction of 1,3-dithiolylium salts 235 with alcohols leads to stable 2-alkoxy-1,3-dithioles 236 (Scheme 11.73) [196]. These alkoxy derivatives are useful precursors of 2-aryl-1,3-dithioles [197]. Sulfur nucleophiles react in a similar fashion to alcohols with 1,3-dithiolylium salts to afford 2-alkylthio or 2-arylsulfanyl-1,3-dithioles [196].

R1

S

ROH

X

S

R1

+

S

R2

R2

235

X OR S

236

Scheme 11.73

Secondary amines react with 1,3-dithiolylium salts that are unsubstituted at the 2-position (237) to afford 2-amino-1,3-dithioles 238 (Scheme 11.74) [196]. 2-Methylsulfanyl-1,3-dithiolylium salts 239 give the corresponding 2-amino-1,3-dithiolylium salts 240 with secondary amines [198]. Primary amines react with 239 to afford 2-imino-1,3-dithioles 241 [199].

S

R1

H

HNR3R4 R1

+

S

R2

R2

237

R1 R2

R3 N

S

R3NH2

R1

S

SMe +

R2

Scheme 11.74

S

R3 N R4

238

S 241

S

S

239

HNR3R4

R1

S

N +

R2

S

240

R3 R4

j961

j 11 Five-Membered Heterocycles with Two Heteroatoms: O and S Derivatives

962

2-Methylsulfanyl-1,3-dithiolylium salts 239 also react with Grignard reagents to form 2-alkyl-2-methylsulfanyl-1,3-dithiolylium salts 242, which may react with excess Grignard reagent to give 2,2-dialkyl-1,3-dithioles 243 (Scheme 11.75) [200].

S

R1

SMe

R3MgX

+

S

R2

S

R2

239

SMe

S

R1

242

R3

R3MgX

R1 R2

R3

S S

R3

243

Scheme 11.75

11.5.4.4 Reductions 1,3-Dithiolylium salts are easily reduced by NaBH4, LiAlH4 or NaSH to give the corresponding 1,3-dithiole [196]. If 1,3-dithiolylium salts 244 are reduced with zinc [201] or V(CO)6 [202] the dimer 245 is formed (Scheme 11.76). 2-Methylsulfanyl-1,3-dithiolylium iodide (246) forms TTF (144) when reduced with zinc in the presence of bromine [203].

S

H

Zn or

S

S

V(CO)6

S

S

+

S

244

245

S

SMe +

S

I

246

Zn / Br 2

S

S

S

S 144

Scheme 11.76

1,3-Dithiolylium-4-olates 248 can be regarded as masked 1,3-dipole thiocarbonyl ylides; they react with dipolarophiles to give cycloadducts. Thiophenes 249 are obtained when 248 are reacted with alkynes (Scheme 11.77) [204]. Stable adducts such as 250 are formed when 248 is reacted with electron-deficient alkenes [205]. 11.5.4.5 Coupling Reactions The palladium-catalyzed coupling of the tributyl tin 1,3-dithiole derivative 251 with 2-iodoquinoline to give the coupled product 252 has been described (Scheme 11.78) [206].

11.5 1,3-Dithioles and 1,3-Dithiolanes

S O O

S

R2

+

+

S

R1

S R3

R4

R1

R3

R3

R2 R4

R1

247

248

R4 R2

S

249 S 248

O

CN

+

S

R1

R2 CN

250 Scheme 11.77

O

O S

S

N O

Bu3Sn

O

Me

I

S N

Me

251

S O

Me

O

Me

252

Scheme 11.78

11.5.5 Reactivity of 1,3-Dithiolanes

1,3-Dithiolanes are resistant to both acid and alkaline hydrolysis, they are also resistant to nucleophilic attack by nucleophiles such as hydride ions. 11.5.5.1 Cleavage Reactions A review of methods for cleaving 1,3-dithiolanes to aldehydes or ketones has been published [207]. The ring can be cleaved by a mixture of HgCl2/CdCO3 quite effectively [208]; alternatively, sodium in ethanol in liquid ammonia [209], NBS in acetone [210], or thallium(III) nitrate in methanol can be used. The latter method has been used for the selective cleavage of a mixture of thioketals 253 to afford the unsaturated ketone 254 (Scheme 11.79) [211]. SOCl2-treated silica and DMSO is a good combination with which to cleave 2-substituted-1,3-dithiolanes; however, under similar conditions 2,2-disubstituted1,3-dithiolanes undergo ring expansion to give dihydro-1,4-dithiins [212].

j963

j 11 Five-Membered Heterocycles with Two Heteroatoms: O and S Derivatives

964

O S

S

Tl(NO3)3 MeOH 5 min. 67%

S

S

S

S 253

254

Scheme 11.79

Recent methods for the cleavage of 1,3-dithiolanes include the use of 2,4,6trichlorotriazine and DMSO [213], oxone on wet alumina [214] and ferric nitrate on K-10 montmorillonite clay [215]. Treatment of 2-substituted-1,3-dithiolanes with NBS followed by 1,2-ethanediol affords 1,3-dioxolanes [216]. 11.5.5.2 Electrophilic Attack at Carbon 1,3-Dithiolanes can be deprotonated at C2 with equimolar amounts of butyllithium. The resultant carbanions can then be trapped by various electrophiles [217]. 2-Alkynyl-1,3-dithiolanes 255 affords allenes 256when treated with an organocuprate compound followed by an electrophile and then a Grignard reagent with nickel catalysis (Scheme 11.80) [218]. Similarly, the reaction of 2-alkenyl-1,3-dithiolanes 257 with Bu2CuLi or BuLi and an electrophile followed by treatment with a Grignard reagent under nickel catalysis affords alkenes 258 [219]. R2

S S

R1

+

1. Cu, E

2. R3MgX, Ni

255

R2 R1

S S 257

R1

R3

E

R2 256

+

E

1. BuLi, E

2. R3MgX, Ni

R3 R2

R1 258

Scheme 11.80

11.5.5.3 Oxidations 1,3-Dithiolanes can be oxidized to afford 1,3-dithiolane-1-oxides by photooxidation [220], while oxidation under more vigorous conditions leads to mono and bis

11.5 1,3-Dithioles and 1,3-Dithiolanes

sulfones [221]. Enantioselective oxidations of 1,3-dithiolane (143) by microbial oxidation gives the corresponding S-oxide 259 in high enantiomeric excess (Scheme 11.81) [222]. A review of the preparation and use of the C2 symmetric bis-sulfoxide 260 has been published [223]. microbial

S

oxidation

S 143

O S

S

S O

S O 259

260

Scheme 11.81

On a similar theme the 2-phenyl monosulfoxide derivative 262 has been prepared in a diastereoselective manner by the reaction of 2-phenyl-1,3-dithiolane (261) with ButOOH and Cp2TiCl2 (Scheme 11.82) [224].

tBuOOH

S

Cp2TiCl 2

S

Ph

S S

Ph

261

O

262

Scheme 11.82

11.5.5.4 Radical Reactions Intramolecular addition of the 1,3-dithiolan-2-yl radical generated from 263 by photolysis affords the spirocyclic derivative 264 (Scheme 11.83) [225].

S S

CO2Et

263

S

S CO2Et 264

Scheme 11.83

11.5.5.5 Ring Transformation Reactions Treatment of dithiolane 265 with WCl6 in DMSO gives the ring-expanded dithiin 266 (Scheme 11.84) [226].

j965

j 11 Five-Membered Heterocycles with Two Heteroatoms: O and S Derivatives

966

WCl 6

S Ar Me

S

DMSO

Ar

S

Cl

S

265

266

Scheme 11.84

Ethylenediamine reacts with 1,3-dithiolane derivatives 267 to give imidazolines 268 (Scheme 11.85) [227]. O

O

R1

H2N

R2 S

O

NH2

O

R1

R2

HN

S

267

NH 268

Scheme 11.85

11.5.6 Compounds of Interest

TTF derivatives have been the focus of scientific interest since the mid-1970s. Indeed, their organic metal properties and superconductivity has prompted the publication of several reviews discussed earlier in this section [133–135].

11.6 1,2-Oxathioles and 1,2-Oxathiolanes 11.6.1 Introduction

The parent oxathiolone 269 is known but most work published has been on the S-oxidized derivatives like 270 and 271. The corresponding saturated derivatives 272 and 273 have also been described. A comprehensive review of 1,2-oxathiolium salts has been published [228]. O

S

269

O

270

S

O

O

271

S

O O

O

272

S

O

O

273

S

O O

11.6 1,2-Oxathioles and 1,2-Oxathiolanes

t

o

1.469 109.3 1.374

Bu

O S

t

Bu

114.1

o

1.682

1.748 93.1o

274

Figure 11.2 Geometry of a 1,2-oxathiolone derivative.

Table 11.8

1

H NMR data for 1,2-oxathiolanes derivatives.

Compound

3-H (d, ppm)

4-H (d, ppm)

5-H (d, ppm)

Reference

1,2-Oxathiolan-2-oxide (272) 1,2-Oxathiolan-2,2-dioxide (273)

1.35 3.1

1.35 2.5

3.45 4.82

[230] [231]

11.6.2 Relevant Physicochemical Data 11.6.2.1 X-Ray Diffraction The X-ray structure of 274 has been published to give the dimensions [229] shown in Figure 11.2. 11.6.2.2 NMR Spectroscopy Table 11.8 gives 1 H NMR data for S-oxidized 1,2-oxathiolane systems 272 and 273. 11.6.3 Synthesis 11.6.3.1 Ring Synthesis of 1,2-Oxathioles Chlorination of 1,3-thioalcohols using either Cl2 or SO2Cl2 affords 1,2-oxathiolan-2oxide 272 by way of an intermediate 3-hydroxysulfinyl chloride (275) (Scheme 11.86) [232].

HO

S 275

HO

SH

Cl O

S O

272 Scheme 11.86

j967

j 11 Five-Membered Heterocycles with Two Heteroatoms: O and S Derivatives

968

Oxathiolane 277 is prepared by treatment of N-alkylcystinol 276 with NCS or NBS (Scheme 11.87) [233].

HO

SH

O

NCS or NBS

NHR

S O

NHR

276

277

Scheme 11.87

Substituted 1,3-thioalcohols 278 can also be oxidized with NaIO4 to give the corresponding 1,2-oxathiolane-2-oxides 279 (Scheme 11.88) [234]. R2 R1 R1 HO

SH

NaIO4

O

R2

S O

R1 278

R1

279

Scheme 11.88

A ring-closing metathesis reaction of the allylvinyl sulfonate 280 using a secondgeneration Grubb’s catalyst gives the oxathiole 270 (Scheme 11.89) [235].

O

O

S

O

S

O

O

280

270

Scheme 11.89

Full details of the asymmetric synthesis of chiral c-sultones 281 have been described [236]. H2N R1

O O S O R2 281

11.6 1,2-Oxathioles and 1,2-Oxathiolanes

The direct reaction of cyclopropanes 282 with SO2 in TFA to give 1,2-oxathiolane-2oxides 283 and 284 has been studied extensively to determine the regioselectivity of this reaction (Scheme 11.90) [237]. SO2 Ar

R

O S

R

O

TFA

+

Ar

282

O S

O Ar

R

283

284

Scheme 11.90

Similarly, treatment of the methylene cyclopropane 285 with SO3 affords 286 directly (Scheme 11.91) [238]. Ph

Ph

O O S O

Ph

SO3

Ph

285

286

Scheme 11.91

The adamantyl alcohols 287 can also be treated with SO3 to afford 1,2-oxathiolane2,2-dioxides 288 (Scheme 11.92) [239].

OH

O O S O

SO3

R

R 287

288

Scheme 11.92

The epoxide 289 can be cyclized with triethylamine to give the 1,2-oxathiolane-2,2dioxides 290 (Scheme 11.93) [240].

SO2Cl

R

Et3N R

289 Scheme 11.93

290

O S O O

j969

j 11 Five-Membered Heterocycles with Two Heteroatoms: O and S Derivatives

970

11.6.3.2 Ring Transformations of Heterocycles Leading to 1,2-Oxathiole Derivatives Oxidative ring expansion of thietan-2-ones 291 by treatment with chlorine or SO2Cl2 and acetic anhydride gives the 1,2-oxathiolan-5-one 292 (Scheme 11.94) [241]. R1 R2

O

O

R1

S

R2 291

O S O 292

Scheme 11.94

Cyclic sulfides 293 undergo ring contraction upon treatment with BF3Et2O to give the 1,2-oxathiolane-2,2-dioxides 294 (Scheme 11.95) [242].

R

O

O S O O

BF3Et2O

O O S O

R

293

294

Scheme 11.95

11.6.4 Reactivity of 1,2-Oxathioles and 1,2-Oxathiolanes

Most reactions in this area have involved either 1,2-oxathiolane 2-oxides or 2,2dioxides. The type of reactions involve either thermal extrusion of SO or SO2 or nucleophilic attack at the cyclic sulfinate or sulfonate functions. 11.6.4.1 Thermal or Photochemical Reactions 1,2-Oxathiolane 2-oxides 295 readily undergo thermal extrusion of SO to afford a,b-unsaturated carbonyl compounds. The reaction is most likely to proceed via an initial tautomerization from the 5H to the 3H form 296, which then undergoes an electrocyclic process to give cinnamaldehyde (Scheme 11.96) [243].

Ph

O S

O

295

Ph

O S

O

-SO

Ph

O H

296

Scheme 11.96

1,2-Oxathiolan-5-one 2,2-dioxide derivative 297 undergoes thermally induced elimination of SO2 at 180  C to give methacrylic acid (Scheme 11.97) [244].

11.7 1,3-Oxathioles and 1,3-Oxathiolanes

O O S O

-SO2

O OH

O 297 Scheme 11.97

11.6.4.2 Nucleophilic Attack Nucleophilic attack on the cysteine-derived chiral 4-amino-1,2-oxathiolane 2-oxide 298 by alkyllithiums takes place on the sulfur atom with inversion of configuration to give 299 (Scheme 11.98) [245]. O S

R2Li

O

R1NH

OH

O S R2

R1NH 298

299

Scheme 11.98

Reaction of the 1,2-oxathiolane 2-oxide 300 with bromine results in the loss of SO2 to give the 1,3-dibromo derivative 301 (Scheme 11.99) [246]. Compound 300 also reacts with PCl3 to give the ring open product 302 [247]. Ar2

Ar1 Br

Br2

Ar2

Br

301

Ar1 S O O 300

PCl3

Ar2

Ar1 O

P

Cl2

302

Scheme 11.99

11.7 1,3-Oxathioles and 1,3-Oxathiolanes 11.7.1 Introduction

Little work has been published on 1,3-oxathiolium salts 303 and their mesoionic system 304 [20]. A review on 1,3-oxathiolium salts has appeared [248]. A larger amount of material has been published on 1,3-oxathioles 305. Most studies have been

j971

j 11 Five-Membered Heterocycles with Two Heteroatoms: O and S Derivatives

972

1.763 90.3o

S

1.743

1.318

NC

NAc

1.361

O

111.3o

1.394 112.0o

307 Figure 11.3 Geometry of a 1,3-oxathiolone derivative.

carried out on the fully saturated systems, 1,3-oxathiolanes (306), and reviews covering this system have appeared [249, 250]. +

O

O

S

+

S

S

O

S

O

O 303

304

305

306

11.7.2 Relevant Physicochemical Data 11.7.2.1 X-Ray Diffraction The X-ray structure of 307 has been published to give the dimensions [251] shown in Figure 11.3. 11.7.2.2 NMR Spectroscopy Table 11.9 gives 1 H NMR data for 1,3-oxathiolane systems 308 and 309. S

S

O O

O

308

309

C NMR data for the mesoionic 1,3-oxathiolium 4-oxide compound 310 has been published (Figure 11.4) [254]. 13

Table 11.9

1

H NMR data for 1,3-oxathiolane derivatives.

Compound

2-H

4-H

5-H

Reference

5-Methyl-1,3-oxathiolane (308) 1,3-Oxathiolan-2-one (309)

4.72/4.89

2.5/3.0 3.59

3.96 4.53

[252] [253]

11.7 1,3-Oxathioles and 1,3-Oxathiolanes +

S

O

154.6

O

SMe

215.5

110.3

F3C

O 310 13

Figure 11.4

C NMR data for a mesoionic 1,3-oxathiolium-4-oxide compound.

11.7.3 Synthesis 11.7.3.1 Ring Synthesis of 1,3-Oxathioles and 1,3-Oxathiolanes An important method for the preparation of 1,3-oxathiolium salts has been published. Phenacyldithiocarbamates 311 can be desulfurized with a silver, mercury or copper salt to afford 2-amino-1,3-oxathiolium salt 312 (Scheme 11.100) [255].

NR2

NR2 S

O

S O

+

S

Ar

Ar 311

312

Scheme 11.100

Thermolysis of the bis-dithiocarbonates 313 results in loss of COS to afford the 1,3oxathiolane 314 in up to 90% yield (Scheme 11.101) [256].

R

S

O O

SMe SMe

O

heat -COS

R

S

SMe SMe

S 313

314

Scheme 11.101

The 1,3-oxathiolane 2,2-dioxide 316 has been prepared by treatment of the diazosulfone 315 with BF3 (Scheme 11.102) [257]. Similarly, rhodium-catalyzed decomposition of a-diazoketones 318 in the presence of CS2 affords the 1,3-

j973

j 11 Five-Membered Heterocycles with Two Heteroatoms: O and S Derivatives

974

Ph BF3

O S

O O

O S O O

N2

315

O

S

R1

S

316

CS2

R2

317

O

R1

N2

R2

R3NCS

R1 R2

O

NR3

S 319

318

Scheme 11.102

oxathiolane-2-thione 317 [258]. If the decomposition is carried out in the presence of an isothiocyanate then 2-imino derivatives 319 are formed [259]. The reaction of hydroxyethylthiocyanates 320 with a tertiary alcohol in sulfuric acid gives the 2-iminooxathiolane 321 (Scheme 11.103) [260]. OH

O

R1OH

R2 NCS R3

NR1

S R2 R3

320

321

Scheme 11.103

Routes to fully conjugated systems include the reaction of the phenacyl benzoate 322 with H2S and iodine to give the oxathiolium salt 323 in 88% yield (Scheme 11.104) [261]. Ph O

O O Ph 322

Scheme 11.104

H2S, I2

O Ph

S

Ph +

323

I3

-

11.7 1,3-Oxathioles and 1,3-Oxathiolanes

The addition of diazomethane to an a-oxothioester 324 affords 4-alkylthio substituted 1,3-oxathioles 325 (Scheme 11.105) [262].

R1 R2

O

S

CH2N2

R1

S

R2 S

324

O S

325

Scheme 11.105

The standard method of preparation of 1,3-oxathiolanes is to condense a carbonyl compound with 2-thioethanol. Several catalysts have been used for this reaction – the most common is BF3Et2O [263]. More recently, other catalysts used for this reaction include triisopropyl triflate [264], indium triflate [265], NBS [266], tetrabutylammonium tribromide [267] and scandium triflate [268]. A catalyst that is selective for aldehydes in the presence of acyclic ketones is LiBF4 [269]. A catalyst that is suitable for a,b-unsaturated ketones is an aminopropyl functionalized silica [270]. Dimethyl acetals can also be used in place of the carbonyl component for this reaction [271]. The iodonium salt 326 reacts with either carbon disulfide or a thioketone to form 2-thione 1,3-oxathiolane derivative 327 (Scheme 11.106) [46]. S

_ I+ Ph MeO2C O

326

R1

R2

CO2Me

O R1

S R2 327

Scheme 11.106

The phosphonate derivative 329 is prepared by the condensation of the a-haloaldehyde 328 with KSCN (Scheme 11.107) [272]. Acetylenic alcohols 330 also react with KSCN by a more complex course to give the 1,3-oxathiolane derivative 331 [273]. The standard method for the preparation of 2-imino-1,3-oxathioles 333 is to condense a phenacyl bromide with either a dithiocarbamate 332 (X¼SR) [274] or a thiourea 332 (X¼NMe2) (Scheme 11.108) [275]. Silyl enol ethers 334 and a-halosulfonyl bromides when treated with DBN afford 1,3-oxathiole 3,3-dioxide 335 (Scheme 11.109) [276].

j975

j 11 Five-Membered Heterocycles with Two Heteroatoms: O and S Derivatives

976

O P

(PriO)2

KSCN

CHO

O P

O HN

X

(PriO)2

S

328

329

R1

R2 R1 R2 HO

KSCN

O

CN

S NCS

CN

NC R1 R2 330

331

Scheme 11.107

Ar1SO2

H N

X

Ar2COCH2Br Ar1SO2

S

O

N

Ar2

S

332

333

Scheme 11.108

Cl R1

OTMS

R2 334

R3

SO2Br

DBN

R1 R2

O

R3

S O O 335

Scheme 11.109

Treatment of the silyl derivative 336 with CsF generates a thiocarbonyl ylide that can then be trapped by addition of aldehydes to give 5-substituted 1,3-oxathiolanes 337 (Scheme 11.110) [277]. 11.7.3.2 Ring Transformations of Heterocycles Leading to 1,3-Oxathiole Derivatives The 1,2,4-dithiazol-3-one 338 undergoes cycloaddition to ynamines 339 to give 2imino-1,3-oxathioles 340 (Scheme 11.111) [278]. Similarly, the 1,2,4-thiadiazol-3-one 341 reacts with enolates 342 to also give 2-imino-1,3-oxathioles 343 [279].

11.7 1,3-Oxathioles and 1,3-Oxathiolanes

1. CsF Me3Si

Cl

S

O

R

S

2. RCHO

336

337

Scheme 11.110

S

Ar S

Ar

S

N

+

S

N R

NEt2

R

O

NEt2

O

338

339

340

Ph

Ph S

Cl

N

N

+

O

N H

S

N

R1CH2COR2

O

O

341

342

R1 R2

343

Scheme 11.111

The 1,4-oxathiane 344 undergoes rearrangement to the 2-acyl-1,3-oxathiolane 3oxide derivatives 345 and 346 on treatment with singlet oxygen (Scheme 11.112) [280].

R1

O

R2

S 344

R1

R2 O

O O

S

345

+

R2

R1 O

O O

S

346

Scheme 11.112

11.7.4 Reactivity of 1,3-Oxathioles 11.7.4.1 Reactions with Electrophiles Electrophilic substitution on the heterocyclic ring of 1,3-oxathioles is essentially unknown.

j977

j 11 Five-Membered Heterocycles with Two Heteroatoms: O and S Derivatives

978

11.7.4.2 Reactions with Nucleophiles 1,3-Oxathiolium salts 347 react with NaN3 by attack at C2, followed by loss of nitrogen and rearrangement to give the 1,4,2-oxathiazine 348 (Scheme 11.113) [281]. +

S

Ph

NaN3

S

Ph

N

O

Ph

347

Ph

O

348

Scheme 11.113

11.7.4.3 Cycloaddition Reactions Mesoionic 1,3-oxathiolium-4-olates 349 undergo ready cycloadditions with alkene and alkyne dipolarophiles. Addition of 349 to CS2 or PhNCS proceeds by formation of a bicyclic adduct that then loses COS to give a new mesoionic system (350) (Scheme 11.114) [282]. O O O

O

R2 +

R1

S

+

X

S

S

R1

X R2

S

S R1

+

X O

R2

X = S, NPh 349

350

Scheme 11.114

11.7.5 Reactivity of 1,3-Oxathiolanes 11.7.5.1 Thermal Reactions Pyrolytic extrusion of CO2 from both 1,3-oxathiolan-2-ones and 5-ones affords thiiranes. 2-Imino-1,3-oxathiolanes 351 rearrange to the isomeric thiazolidinones 352 at 80  C where R¼alkyl; where R¼Ph an alternative pathway leads to the formation of RNCO and a thiirane (Scheme 11.115) [283]. 11.7.5.2 Reactions with Electrophiles Oxidation of 1,3-oxathiolanes to the corresponding 3-oxides is readily achieved in high yield using peroxyacetic acid [284]; mCPBA can also be used [285]. Asymmetric 3-oxidation using ButOOH/TiOPri4 and diethyl tartrate has been examined. The diastereoselectivity observed was moderate but the enantioselectivity observed was very poor [286].

11.7 1,3-Oxathioles and 1,3-Oxathiolanes

S

RN

S

O

O

R

N

R = Ph or alkyl 351

352

Scheme 11.115

11.7.5.3 Reactions with Nucleophiles New catalysts for the efficient hydrolysis of 1,3-oxathiolanes to the corresponding aldehydes or ketones include H2O2/CH3CN [287], NaNO2/AcCl [288] and Amberlyst15/glyoxylic acid under solvent-free conditions [289]. A method that is selective for 1,3-oxathiolanes in the presence of 1,3-dioxolanes is NBS in aqueous acetone [290]. The 1,3-oxathiolan-2-one (353) reacts with secondary amines in toluene to afford, by loss of CO2, thioethylamines 354 [291], when the same reaction is performed in dioxan the thiopropyl carbamate is formed (Scheme 11.116) [292].

R 2N

O

SH

R2NH dioxan

O

355

O

S O 353

R2NH

R 2N

SH

toluene 354

Scheme 11.116

1,3-Oxathiolane-5-ones such as 356 can be deprotonated and alkylated with reactive electrophiles at C4 when R¼Me but not when R¼H [293]. O

O

S R 356

11.7.5.4 Radical, Electrochemical Reactions 2-Substituted 1,3-oxathiolanes 357 can undergo reductive cleavage when treated with trimethylsilyl hydride. Reduction occurs at the C2
S bond to give 358 (Scheme 11.117) [294]. 2-Substituted 1,3-oxathiolan-5-ones react in a similar way. They also undergo selective anodic fluorination to give the 4-fluoro derivatives [295]. 11.7.5.5 Ring Expansion 2-Substituted 1,3-oxathiolanes 357 react with carbenes to give ring-expanded 1,4oxathianes 359 via insertion into the C2
S bond (Scheme 11.118) [296].

j979

j 11 Five-Membered Heterocycles with Two Heteroatoms: O and S Derivatives

980

S

TMS3SiH

R

R

O

S

O 357

Si(TMS)3

358

Scheme 11.117

S

+

O

CO2Et

Et3Si

R

O

N2

R

S

357

SiEt3 SiEt3

359

Scheme 11.118

The titanium tetrachloride mediated reaction of a,b-unsaturated oxathiolanes 360 with styrene or a-methylstyrene gives the ring-expanded dihydrothiapyrans 361 (Scheme 11.119) [297].

O

R4

R3 R1 R2

S

+

Ph

360

TiCl4

R1

R2

R4 R3

S

Ph

361

Scheme 11.119

11.7.6 Other Compounds of Interest

1,3-Oxathiolanes bearing a 2-propenyl, 2-furyl- or 2-phenyl group have been used as flavorings [298]. Anti-viral activity has been claimed for the nucleoside analogue 362 [299]. NH2 F

N N

HO

O S 362

O

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Society, Chemical Communications, 1145. Sakai, S., Niimi, H., Kobayashi, Y., and Ishii, Y. (1977) Bulletin of the Chemical Society of Japan, 50, 3271. Lee, W.S., Hahn, H.E., and Nam, K.D. (1986) The Journal of Organic Chemistry, 51, 2789. Ogawa, K., Yamada, S., Terada, T., Yamazaki, T., and Honna, T. (1985) Chemical & Pharmaceutical Bulletin, 33, 2256. Bortolini, O., Di Furia, F., Licini, G., Modena, G., and Rossi, M. (1986) Tetrahedron Letters, 27, 6257. Chavan, S.P., Dantale, S.W., Pasupathy, K., Tejwani, R.B., Kamat, S.K., and Ravindranathan, T. (2002) Greem Chemistry, 4, 337. Khan, A.T., Mondal, E., and Sahu, P.R. (2003) Synlett, 377. Chavan, S.P., Soni, P., and Kamat, S.K. (2001) Synlett, 1251. Karimi, B., Seradj, H., and Tabaei, M.H. (2000) Synlett, 1798. Reynolds, D.D., Massad, M.K., Fields, D.L., and Johnson, D.L. (1961) The Journal of Organic Chemistry, 26, 5109. Reynolds, D.D., Fields, D.L., and Johnson, D.L. (1961) The Journal of Organic Chemistry, 26, 5111. McIntosh, J.M., Mishra, P., and Siddiqui, M.A. (1984) The Journal of Organic Chemistry, 49, 1036. Arya, P., Lesage, M., and Wagner, D.D.M. (1991) Tetrahedron Letters, 32, 2853. Fuchigami, T. (1997) Phosphorus Sulfur and Silicon and the Related Elements, 120–121, 343. Ionnou, M., Porter, M.J., and Saez, F. (2002) Journal of the Chemical Society, Chemical Communications, 346. Kerverdo, S., Lizzani-Cuvelier, L., and Du~ nach, E. (2003) Tetrahedron Letters, 44, 853. Yang, Y., Zheng, F., Sun, B., Ding, F., Liu, Y., and Ren, Y. (2001) Chemical Journal on Internet, 3, 57. Mansour, T.S. and Jin, H. (1995) PCT Int. Appl. WO 29 176.

j989

12 Five-Membered Heterocycles with Three Heteroatoms: Triazoles Larry Yet

12.1 1,2,3-Triazoles 12.1.1 Introduction

The chemistry of 1,2,3-triazoles is reviewed extensively elsewhere [1]. This chapter will focus on the general synthesis and reactivity of the monocyclic 1,2,3-triazole system with recent methods, which include solid-phase and microwave-assisted reactions. 12.1.2 General Reactivity 12.1.2.1 Relevant Physicochemical Data and NMR Data N-Unsubstituted 1,2,3-triazole can be shown as either 1H- or as 2H-triazoles since these two tautomeric forms are in equilibrium in the solution phase (Figure 12.1). In this chapter, for simplication, this type of compound will be represented as 1Htriazoles, independent of the predominant tautomer. In the gas phase, the 2Htautomer of the 1,2,3-triazole represents more than 99.9% of the equilibrium mixture [2]. 1H-1,2,3-Triazole is both a weak base (pKa ¼ 1.17) and a weak acid (pKa ¼ 9.40). The basicity of N-unsubstituted and N-methyl-1,2,3-triazoles in the gas phase, in solution, and in the solid state has been determined [3]. The 1 H and 13 C NMR spectra of the parent 1,2,3-triazole for the protons and carbons at the 4- and 5-positions are identical because the compound exists as both 1H- and 2H-triazoles in solution at room temperature (Table 12.1). Other 1 H and 13 C NMR data of the methyl group attached to the 1,2,3-triazole in the 1- and 2-positions are listed for comparison.

Modern Heterocyclic Chemistry, First Edition. Edited by Julio Alvarez-Builla, Juan Jose Vaquero, and José Barluenga. Ó 2011 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2011 by Wiley-VCH Verlag GmbH & Co. KGaA.

j 12 Five-Membered Heterocycles with Three Heteroatoms: Triazoles

990

4 5

N3 N N H

4 2

5

N3 NH N 2

1

1

2H-1,2,3-triazole

1H-1,2,3-triazole stable, water-soluble, colorless crystals mp 120-121 °C pKa = 9.40

pKa = 1.17 of the protonated species Figure 12.1 Tautomeric structures of 1,2,3-triazoles.

12.1.3 Relevant Natural and/or Useful Compounds

1,2,3-Triazoles are not present in natural products and are remarkably stable to metabolic transformations such as oxidation, reduction, and both basic and acidic hydrolysis. 1,2,3-Triazoles have found broad use in industrial applications such as dyes and brighteners for fibers, corrosion inhibitors for many metals and alloys, light stabilizers for organic materials and polymers, and agrochemicals such as herbicides, fungicides, and antibacterial agents [1d]. They have been considered as an interesting component from the viewpoint of biological activity and are seen in many drugs such as potent HIV-inhibitors [6], antimicrobial agents [7], and selective b3-adrenergic receptor agonists [8]. Figure 12.2 shows the structures of b-lactam antibiotics tazobactam [9] and cefatrizine [10]. 12.1.4 Synthesis of 1,2,3-Triazoles

The most important general approach to the synthesis of 1,2,3-triazoles involves the use of azide reagents. Azides that have been employed in these syntheses can be alkyl,

Table 12.1

1

H and 13 C NMR data (ppm) of 1,2,3-triazoles.

4 5 1 H NMR (DMSO-d6)

Substituents — 1-Me 2-Me

H4 7.91 7.72 7.77

H5 7.91 8.08 7.77

Reference

[4] [4] [4]

N 1 N N H 13 C NMR (DMSO-d6)

C4 130.3 134.3 133.2

C5 130.3 125.5 133.2

Reference

[5] [5] [5]

12.1 1,2,3-Triazoles

H O O S O

N

H CO2H

HO N

N

N

O NH2

tazobactam

H N H O

j991

S N

S CO2H

NH N N

cefatrizine

Figure 12.2 Structure of b-lactam antibiotics containing 1,2,3-triazole rings.

aryl, heteroaryl, acyl, alkoxycarbonyl and sulfonyl azides, trimethylsilyl azide, hydrazoic acid, and sodium azide. Azides can react with substituted alkynes and alkenes and with activated methylene compounds to yield various 1,2,3-triazoles. 12.1.4.1 1,3-Dipolar Cycloadditions of Alkynes with Azide Reagents 1,3-Dipolar cycloaddition of azides to alkynes is the most popular method for the syntheses of various 1,2,3-triazoles since it provides the desired product directly. A review on 1,2,3-triazole formation via 1,3-dipolar cycloaddition of acetylenes with azides under mild conditions has been published [11]. When unsymmetrical alkynes are used, two possible regioisomers are usually obtained. Isomers with the electronwithdrawing groups at the C4 position and the electron-donating groups at C5 are usually the major products. N-Unsubstituted-1,2,3-triazoles are prepared by direct addition of hydrazoic acid [12] or with azide ions [13] to alkynes, such as the reaction of a,b-acetylenic aldehydes 1 with sodium azide in dimethyl sulfoxide (DMSO) followed by hydrolysis to give 5-substituted-4-carbaldehyde-1,2,3-triazole derivatives 2 (Scheme 12.1) [14]. The major disadvantage of this method is that often thermal conditions are required for these reactions and that sodium azide can be explosive.

O

R 1

H

R 1. NaN3, DMSO 2. Hydrolysis (>98%)

N

CHO N H 2

N

R = Ph, (CH2)nOTBS, (CH2)nOTHP n = 1, 3

Scheme 12.1

The most prominent method employed for the synthesis of 1,2,3-triazoles is the addition of alkyl, aryl, and heteroaryl azides to alkynes. Azides can add to acetylene [15] and symmetrically substituted alkynes [16] to give only 4,5-unsubstitutedand 4,5-disubstituted-1,2,3-triazoles, respectively. Addition of azides to monosubstituted alkynes afford mixtures of 1,4- and 1,5-disubstituted 1H-1,2,3-triazoles 3 and 4, respectively (Table 12.2). The ratio of the two products depends on the structure of the monosubstituted alkyne; alkynes with the electron-withdrawing groups preferentially give products substituted at C4 like 3, while alkynes with electron-donating groups provide major products substituted at C5 like 4.

j 12 Five-Membered Heterocycles with Three Heteroatoms: Triazoles

992

Table 12.2 Addition of azides to monosubstituted alkynes.

R2 R1 N3 +

R2

N N

+

N R1 3

R

2

N N

N R1 4

Yield (%) R1

R2

3

4

Reference

Ph Ph Bn CF2CFHCF3 CH2PO(OEt)2 4-Tol Benzotriazolylmethyl

Ph CO2Me CONHBn Bu CH2OH Bz Ph

43 88 65 37 30 60 40

52 12 22 58 69 11 60

[17] [18] [19] [20] [21] [22] [23]

Recent advances in this area are the acceleration and regioselectivity of these azide additions to alkynes, which can sometimes be slow. “Click chemistry” is a recently coined term to denote a growing family of powerful chemical reactions that are based on “spring-loaded” energy-intensive substrates that can, under the right conditions, unload their energy to form stable products in high selectivity [24]. A microreview on copper(I)-catalyzed alkyne–azide “click” cycloadditions from a mechanistic and synthetic perspective has been written [25]. A mini-review has been published on the 1,3-dipolar cycloadditions of azides and alkynes as a universal ligation tool in polymer and materials science [26]. A highlight has been published on the click reaction in the luminescent probing of metal ions and its implications on biolabeling techniques [27]. A perspective on the Cu(I)-catalyzed 1,3-dipolar cycloaddition of azides and alkynes in carbohydrate chemistry, highlighting developments in the preparation of simple glycoside and oligosaccharide mimetics, glyco-macrocycles, glycopeptides, glyco-clusters, and carbohydrate arrays has been reported [28]. A review titled “Click chemistry – What’s in a name? Triazole synthesis and beyond” has been published [29]. A highlight on the copper-free azide–alkyne cycloadditions with new insights and perspectives has been written [30]. Substituent effects in the 1,3dipolar cycloadditions of azides with alkenes and alkynes have been investigated with the high accuracy CBS-QB3 method [31]. For example, a high-yielding copper-catalyzed reaction, which involves the reaction of azides to terminal alkynes in the presence of copper(II) sulfate with ascorbic acid or sodium ascorbate, gave 1,4-disubstituted-1,2,3-triazoles 5 regardless of the group on the alkynes or azides (Scheme 12.2) [32]. The mechanism of the ligand-free Cu(I)catalyzed azide–alkyne cycloaddition reaction has been proposed in a literature report [33]. Triazole-linked glycopeptides have been obtained by Cu(I)-catalyzed cycloadditions of either azide-functionalized glycosides and acetylenic amino acids

12.1 1,2,3-Triazoles

CuSO4•5H2 O 1

R2

sodium ascorbate

2

R N3 + R

H2 O/t-BuOH (2 : 1)

R 1 = CH 2Cbz, adamantyl, Ar, Bn R 2 = CH 2NEt2 , CO2 H, Ph, cholesterolyl, H N NH 2

N N

N R1 5

25 ºC (84-94%)

NH Scheme 12.2

or acetylenic glycosides and azide-containing amino acids in the presence of sodium ascorbate [34]. A highly efficient one-pot synthesis of 1,2,3-triazole-linked glycoconjugates involving a Cu(I)-catalyzed 1,3-dipolar cycloaddition as a key step has been reported [35]. Microwave irradiation has also become a recent method for the synthesis of 1,2,3triazoles under solvent-free conditions. For example, 1,3-dipolar cycloaddition of organic azides 6 with acetylenic amides 7 under solvent-free microwave irradiation produced N1-substituted-4C-carbamoyl-1,2,3-triazoles 8 (Scheme 12.3) [19]. Microwave irradiation allowed a substantial decrease in reaction times and offered greater simplicity in the purification step. O ( )n

N3

6 n = 1, 3

O

+

R

microwave, 55 ºC

R 7 R = piperidyl, NHBn

N N N

(62-84%) Ph

( )n 8

Scheme 12.3

Addition of azides to unsymmetrical disubstituted alkynes often yields mixtures of isomeric 1,2,3-triazoles. The relative ratios of the two products depend strongly on the nature of the substituents on the alkyne. A more recent example showed the 1,3dipolar cycloadditions of azido ester 10 with electron-deficient alkynes 9 to give 1,4,5trisubstituted 1,2,3-triazoles 11 under mild conditions in water (Scheme 12.4) [36]. 1,3-Dipolar cycloaddition of tributyl(3,3,3-trifluoro-1-propynyl)stannane (12) with O R

EWG 9

OEt 10

N3

EWG

H2O, 50 ºC R = H, Me, CO2Et EWG = CO2Me(or Et), CH2OSO2Ph (81-94%)

Scheme 12.4

j993

N

R N

N

OEt 11

O

j 12 Five-Membered Heterocycles with Three Heteroatoms: Triazoles

994

phenyl azide gave the corresponding 1,2,3-triazole 13, which was a useful building block for further functionalization (Scheme 12.5) [37]. An interesting approach to prepare regiospecifically 4,5-disubstituted-1,2,3-triazoles is the addition of bromomagnesium acetylides 15 to aryl azides 14 to yield 1,5-disubstituted-1,2,3-triazoles 16, which could be trapped with various electrophiles to form 1,4,5-trisubstituted 1,2,3triazoles 17 (Scheme 12.6) [38]. In addition, copper(I) iodide promoted reaction of alkyl azides and terminal alkynes in the presence of iodine monochloride led to a regiospecific synthesis of 5-iodo-1,4-disubstituted-1,2,3-triazole 18, which could be further elaborated to a range of 1,4,5-trisubstituted-1,2,3-triazole derivatives (Scheme 12.7) [39]. A series of 4,5-disubstituted-1,2,3-triazoles has been regiospecifically prepared directly from propargyl halides and sodium azide via the Banert cascade [40]. PhN3 F3C

SnBu3 12

F3C

CH(OMe)3 85 ºC

Ph N N N

Bu3Sn

(66%)

13

Scheme 12.5

Ar

N3

+ R

14

MgBr

TH F, 5 0 º C

Ar N N N R

15 R = Ph, n-C3 H7, n-C 5H 11, (EtO) 2CH

16

R

Elec tr o phile s

MgBr

(45-95%)

E

N

Ar N N

17

Scheme 12.6

I R1 N 3 +

R2

CuI (1 equiv), Et3N ICl, THF, 25 ºC

R2

(34-81%)

R1 N N N 18

R1

= CF3CH 2, CHF2CF2CH, Bn, n-C 8H17 R 2 = Ph, n-C 4 H9, CO2allyl, CONHallyl Scheme 12.7

Recently, metal-mediated methodologies have been published where 1,2,3-triazoles can be prepared regiospecifically, with non-activated terminal alkynes and trimethylsilyl azide as the safe synthetic equivalent of the highly explosive hydrazoic acid or sodium azide. Various triazoles (19) were synthesized from non-activated terminal alkynes, allyl methyl carbonate, and trimethylsilyl azide (TMSN3) in a [3 þ 2] cycloaddition with the use of a Pd(0)-Cu(I) bimetallic catalyst (Scheme 12.8) [41]. The

12.1 1,2,3-Triazoles

j995

Pd2(dba)3•CHCl3 (2.5 mol%) R

H

OCO2Me + TMSN3

+

CuCl(PPh3)2 (10 mol%) P(OPh)3 (20 mol%) EtOAc, 100 ºC (50-83%)

1. HRuCl(CO)(PPh3)2, toluene, R

reflux

N

N

N

R

2. O3; Me2S

N

or t-BuMgCl, NiCl2(dppe), toluene, 25 ºC

19

N H

N

20

(78-92%) R = t-Bu, Ph, Ar, n-C6H13, BnOCH2, 1-naphthyl Scheme 12.8

allyl group of 19 is efficiently deprotected by ruthenium-catalyzed isomerization followed by ozonolysis or by nickel-catalyzed Grignard addition reaction to give 4substituted triazoles 20 [42]. 2-Allyl-1,2,3-triazoles 21 have been prepared regiospecifically by the palladium-catalyzed three-component coupling reaction of alkynes, allyl methyl carbonate, and trimethylsilyl azide (Scheme 12.9) [43]. Similarly, the fourcomponent coupling reactions of silylacetylenes, allyl carbonates, and trimethylsilyl azide catalyzed by a Pd(0)-Cu(I) bimetallic catalyst led to trisubstituted 1,2,3-triazoles [44]. The [3 þ 2] cycloaddition of non-activated terminal alkynes and trimethylsilyl azide proceeded smoothly in the presence of copper catalyst and N,N-dimethylformamide and methanol to give the corresponding N-unsubstituted-1,2,3-triazoles in good to high yields [45]. [3 þ 2]-Cycloadditions of alkyl azides with various unsymmetrical internal alkynes in the presence of Cp
RuCl(PPh3)2 as catalyst in refluxing benzene led to 1,4,5-trisubstituted-1,2,3-triazoles, whereas alkyl phenyl and dialkyl acetylenes underwent cycloadditions to afford mixtures of regioisomeric 1,2,3triazoles and acyl-substituted internal alkynes reacted with complete regioselectivity [46]. In the presence of catalytic Cp
RuCl(PPh3)2 or Cp
RuCl(COD), primary and secondary azides reacted with a broad range of terminal alkynes containing a range of functionalities to produce selectively 1,5-disubstituted-1,2,3-triazoles [47]. 1,3-Dipolar R1 2

R1

R

+

OCO2Me

+

TMSN3

R1 = H, Et, Et, i-Bu, Cy 2

R = CN, CHO, CO2Me, SO2Ph, COMe Scheme 12.9

Pd2(dba)3•CHCl3 dppp, EtOAc, 100 ºC (29-66%)

N 21

R2 N

N

j 12 Five-Membered Heterocycles with Three Heteroatoms: Triazoles

996

cycloaddition of trifluoromethylated propargylic alcohols with azides in the presence of catalytic [Cp
RuCl2]n afforded exclusively 4-trifluoromethyl-1,4,5-trisubstituted1,2,3-triazoles in high yields [48]. Copper-catalyzed [3 þ 2] cycloaddition of azides to mono- and disubstituted alkynes with N-heterocyclic carbene ligands has been found to be a versatile and highly efficient reaction in which an internal alkyne was successfully shown to work for the first time [49]. Azides can be prepared in situ from their respective halides and then reacted with their alkyne partners. 1,4-Disubstituted-1,2,3-triazoles 22 have been obtained in excellent yields by a convenient one-pot procedure from various aryl and alkyl iodides and terminal alkynes without isolation of potentially unstable organic azide intermediates (Scheme 12.10) [50]. The microwave-assisted synthesis of this version has been published by the same group [51]. A similar one-pot procedure uses benzyl and alkyl halides for generation of the azides with a series of terminal and disubstituted alkynes [52]. A one-pot sequential and cascade sequence involving the formation of allylic azides, from aryl/heteroaryl/vinyl halides, allene, and sodium azide, by palladium-catalyzed anion capture, and cyclization-anion capture, followed by 1,3dipolar cycloaddition provided various 1,2,3-triazoles in good yields [53]. A copper(I)catalyzed three-component reaction with amines, propargyl halides and azides in water affords 1-substituted-1H-1,2,3-triazol-4-ylmethyl)dialkylamines [54]. Terminal alkynes reacted with benzyl- or alkyl halides and sodium azide in the presence of a copper(I) catalyst immobilized on 3-aminopropyl- or 3-[(2-aminoethyl)amino]propylfunctionalized silica gel in ethanol to generate exclusively the corresponding regiospecific 1,4-disubstituted-1,2,3-triazoles in good to excellent yields [55]. An efficient and improved procedure for the preparation of aromatic azides from the corresponding aromatic amines 23 is accomplished under mild conditions with tert-butyl nitrite and trimethylsilyl azide and their application in the Cu(I)-catalyzed azide–alkyne 1,3dipolar cycloaddition gives 1,4-disubstituted-1,2,3-triazoles 24 without the need for isolation of the azide intermediates (Scheme 12.11) [56].

Ar-I

+

R

Conditions

R = alkyl, TMS, aryl, CH2 OAr, CH2 NEt 2

R

Ar N N N 22

Condition A: NaN 3, L-Proline, CuSO 4·5H 2O, sodium ascorbate, Na2 CO 3, DMSO/H 2O (9 : 1), 60 ºC (66-98%) Condition B: NaN 3, tr ans-1,2-(methylamino)cyclohexane, CuI, sodium ascorbate, DMSO/H 2 O (5 : 1), 25 ºC (38-99%) Scheme 12.10

Many recent reports have shown that polymer-supported azides and alkynes can be employed in the synthesis of 1,2,3-triazole derivatives. Functionalized 1,2,3-triazoles 26 and 27 were prepared by [3 þ 2] cycloaddition of resin-bound a-azido esters 25 with terminal alkynes (Scheme 12.12) [57]. Polystyrene resin-bound azide 28 reacted

12.1 1,2,3-Triazoles

t-BuONO, TMSN 3 , CH 3 CN;

R

Na ascorbate, aq. CuSO4 ,

ArNH 2 23

j997

N N

N Ar 24

alkyne (79–87%)

Scheme 12.11

R2 O O

N3 R1

25

2

R , DMA

1.

N N N

HO

2. TFA, CH 2Cl2 (4-27%)

O

R1

+

N N N

R2 HO

26

O

R1

27

Scheme 12.12

with disubstituted alkynes followed by acidic cleavage to give 1,2,3-triazoles 29 (Scheme 12.13) [58]. Regiospecific copper(I)-catalyzed 1,3-dipolar cycloadditions of resin-bound alkynes 30 to azides afforded solid-supported 1,2,3-triazoles 31, which were ligated further to give 1,4-substituted-1,2,3-triazole-peptide compounds (Scheme 12.14) [59]. Immobilized REM resin azides have provided a regioselective method for the preparation of 1,5-trisubstituted-1H-1,2,3-triazoles via a 1,3-dipolar cycloaddition of trimethylsilyl-propynoic acid [60]. A library of peptidotriazoles have been prepared by solid-phase peptide synthesis combined with a regiospecific copper (I)-catalyzed 1,3-dipolar cycloaddition between resin-bound alkynes and protected amino azides [61]. R2 N3

DMF, 80-120 ºC

2. TFA, CH 2 Cl2

O 28

1.

R 2,

R1

R 1 = H, Ph, CO 2Me, CHO, CH2 OH, TMS R 2 = H, Ph, CO 2Me, CH2 OH (17-58%)

Scheme 12.13

O

CuI, R-N3, DIPEA (>95% conversion, 75-99% purity)

30 Scheme 12.14

O N R N N 31

HO

N N N 29

R1

j 12 Five-Membered Heterocycles with Three Heteroatoms: Triazoles

998

There are published reports on the use of polymer-supported azide reagents in the 1,3-dipolar cycloadditions of alkynes. Different alkyl bromides reacted with Merrifield resin supported ammonium azide (32) to give various alkyl azides, which were reacted with methyl propiolate to give 1,2,3-triazoles 33 in excellent yields (Scheme 12.15) [62]. The monomethyl ether of poly(ethylene glycol) (PEG)- or MeOPEG-bound azide 34 has been utilized in the 1,3-dipolar cycloadditions with various alkynes to afford regioisomeric mixtures of 35 and 36 (Scheme 12.16) [63]. The 1,2,3-triazoles could be cleaved with formic acid in dioxane in one example (R ¼ CO2Me). 1,3-Dipolar cycloaddition of poly(ethylene glycol)-supported azide with various dipolarophiles followed by acidic cleavage afforded 4- and 5-substituted-1,2,3triazoles [64].

N 3 32

R Br

DMA, 25 ºC, 72 h

MeO2C CO2 Me

R N3

DMA, 80 ºC, 24 h

(35-98%)

(73-100%)

N N N R 33

R = Bn, PhO(CH2 )2, (EtO) 2P(O)(CH 2) 2, 3-indolylethyl Scheme 12.15

R PhMe, reflux

N3

(93-98%; 57:43

34

to 87:13 ratio)

N

N N 35

R = Ph, CO 2Me, (CH 2) nOH, CH 2X

+ R

N

N N

R

36

Scheme 12.16

12.1.4.2 Reactions of a,b-Unsaturated Systems with Azide Reagents a,b-Unsaturated systems are good substrates for azide additions to prepare 1,2,3triazole derivatives. Frequently, the azides undergo addition to unactivated or activated alkenes with electron-withdrawing or electron-rich substituents, such as enamines, enamides, enol ethers, and ketene acetals, to give 4,5-dihydro-1H-1,2,3triazoles, which are unstable and by elimination of a stable fragment functional group aromatizes to 1,2,3-triazoles. Generally, the addition of azides to alkenes is regioselective and only one isomer is obtained. Several reports have been published on sodium azide additions to alkenes with strongly electron-withdrawing substituents to give N-unsubstituted-1,2,3-triazoles [65]. For example, tetrabutylammonium fluoride-catalyzed [3 þ 2] cycloaddition reactions of 2-aryl-1-cyano(or carbethoxy)-1-nitroethenes 37 with trimethysilyl azide under solvent-free conditions provided 4-aryl-5-cyano(or carbethoxy)-1H-1,2,3triazoles 38 in good to excellent yields under mild conditions (Scheme 12.17) [66a].

12.1 1,2,3-Triazoles

Ar

Ar

TMSN 3 , TBAF•3H 2O

NO2 CN (CO2 Et) 37

solvent-free conditions (70-90%)

(EtO2 C) NC

N N N H 38

Scheme 12.17

Similarly, nitroalkenes or vicinal acetoxy nitro derivatives underwent a clean reaction with sodium azide in hot dimethyl sulfoxide to give the corresponding 1,2,3-triazoles in good yield [66b]. There are reports of additions of azide reagents to enol ethers [67], vinyl acetates [68], a-acylphosphorus ylides [69], allenes [70], and alkenes with very strong electron-withdrawing groups like nitro and sulfonyl [71] to produce the corresponding 1,2,3-triazoles. There are several interesting reports on the additions of various azide additions to enamine-type alkenes to give 1,2,3-triazoles where the amine portion either becomes part of the product or is eliminated as a fragment via the unstable 4,5-dihydro-1H1,2,3-triazole intermediate. For example, aroyl-substituted ketene aminals 39 react with aryl azides to provide polysubstituted 1,2,3-triazoles 40 (Scheme 12.18) [72]. A series of 5-fluoroalkylated 1H-1,2,3-triazoles 42 have been prepared in good yield by the regiospecific 1,3-dipolar cycloaddition reaction of (Z)-ethyl-3-fluoroalkyl-3-pyrrolidinoacrylates 42 with aryl azides (Scheme 12.19) [73]. Benzyl azides also participated in these reactions but sodium carbonate was required to provide good yields of the triazoles. Condensation of enaminones 43 with mesyl azide (MsN3) gave 1,4,5trisubstituted-1,2,3-triazoles 44 (Scheme 12.20) [74]. A solid-phase version of this reaction has also been reported [75].

X

N H

X

O

H N

Ar

H 39

N3

dioxane, 80 ºC X = Cl, NO 2

H N

Ar N

N

(37-80%)

40

Scheme 12.18

EtO2C ArN 3, 80 ºC

N CO2 Et

Rf 41

(66-97%)

Rf

N N N Ar 42

R f = ClCF2 , BrCF 2, CF3 , Cl(CF2) 2CF2 Scheme 12.19

N N

j999

j 12 Five-Membered Heterocycles with Three Heteroatoms: Triazoles

1000

R 2HN

MsN 3

O

NaH

R1

R1

CH3 CN

43

R2 N R 1 = OEt, Me N R 2 = Bn, n-Bu, n-decyl, Ph N

O

(50-81%)

44

Scheme 12.20

4-Acyl-1H-1,2,3-triazoles 46 have been formed from diethylaluminium azide and a,b-unsaturated ketones 45 by [3 þ 2] cycloaddition of azide, followed by 1,5-hydride transfer to the b carbon of the triazoline side chain and fragmentation of the tertiary amino group (Scheme 12.21) [76]. R1 Et2AlN 3

R1

PhMe

R2

Bn2 N

25 ºC

O 45

O R2

(10-41%)

R1 = i-Pr, Bn R2 = Me, Bn, i-Pr

N N

N H 46

Scheme 12.21

12.1.4.3 Reactions of Azides and Hydrazines with Active Methylene Compounds Base-catalyzed condensation of azides with active methylene compounds, known as the Dimroth reaction, is a versatile method for the preparation of 1,2,3-triazoles regioselectively. The 5-position of the 1,2,3-triazole can be an alkyl, aryl, hydroxyl, alkoxycarbonyl, or an amino group depending on the functional group of the active methylene compound used. Various azides can react with 1,3-diketones, 3-oxoesters, and 3-oxoamides to give 4-carboxy-1,2,3-triazoles 47 in good yields (Table 12.3) [77–79].

Table 12.3 Reactions of azides with active methylene compounds to give 4-carboxy-1,2,3-triazoles.

R1 N3 +

O R2

O

NaOEt, EtOH

R3 R2

R3

O N N N R1 47

R1

R2

R3

Yield (%)

Reference

4-O2NC6H4 3,5-Cl2C6H3CH2 2-O2N-4-ClC6H3

Me Me Me

Me OEt NHPh

83 89 80

[77] [78] [79]

12.1 1,2,3-Triazoles Table 12.4 Reactions of organic azides with malonic esters and amides to give 1H-1,2,3-triazol-5-

ols.

R1 N3

O +

R2

R2

O R2

R1 Bn 4-pyridyl Ph

NaOMe MeOH

O N N N R1 48

HO

R2

Yield (%)

Reference

OEt OEt NHPh

88 75 72

[80] [81] [82]

Furthermore, the base-catalyzed reaction of organic azides with malonic esters and malonamides gave the best synthesis of 1H-1,2,3-triazol-5-ols 48 with an alkyloxy(or aryloxy)carbonyl or carbamoyl functions at C4 (Table 12.4) [80–82]. Similarly, reactions of azides under base-catalyzed conditions with acetonitrile derivatives yielded 1substituted-1H-1,2,3-triazol-5-amines 49 (Table 12.5) [83–85]. There are also reports where activated acyl compounds can react with hydrazines instead of azides to give substituted 1,2,3-triazoles. For example, a-aminoacetophenones 50 react with hydrazines in acetic acid to give an efficient preparation of 2,4disubstituted-1,2,3-triazoles 51 (Scheme 12.22) [86]. Various phenacyl halides 52 react with excess tosyl hydrazide in refluxing methanol to provide 4-aryl-1-(ptoluenesulfonylamido)-1,2-3-triazoles 53 (Scheme 12.23) [87]. A general and efficient

Table 12.5 Reactions of organic azides with acetonitrile derivatives to give 1H-1,2,3-triazol-5-

amines.

R2 R1 N3 +

R1 PhSCH2 Bn Bn Bn 2-O2NC6H4

R2

CN

R2 2-FC6H4 Ph CN CONH2 CONH2

Base/Solvent

H 2N

Base/solvent K2CO3/DMSO K2CO3/DMSO K2CO3/DMSO K2CO3/DMSO NaOEt/EtOH

N N N R1 49 Yield (%)

Reference

29 84 48 84 55

[83] [84] [84] [84] [85]

j1001

j 12 Five-Membered Heterocycles with Three Heteroatoms: Triazoles

1002

O NH 2 R

1

R2 N N N

HOAc, CuCl (5 mol%) ref lux, 2 h

+ R 2NHNH 2

(41-75%) R1 = Cl, Br, OMe, F R2 = Me, Ph

50

R1

51

Scheme 12.22

TsNHNH 2 (3 equiv) Ar

O X

Ar 52

N N N NHTs 53

MeOH, 65 ºC X = Cl, Br (33-48%)

Scheme 12.23

method for the preparation of 2,4-diaryl-1,2,3-triazoles 55 from a-hydroxyacetophenones 54 and arylhydrazines has been reported (Scheme 12.24) [88].

O OH

Ar1 R 54

Ar2 NHNH2 , CuCl2

Ar1

HOAc, reflux (52-86%)

R

R = H, Ph

N N Ar 2 N 55

Scheme 12.24

12.1.4.4 Oxidation/Cyclization of Hydrazones Oxidation of bis(hydrazones) 56 with manganese dioxide or mercury(II) oxide affords 4-aryl-1H-1,2,3-triazol-1-amines 57 as the only regioisomer (Scheme 12.25) [89]. However, other vicinal bis(hydrazones) have generated regioisomeric 1H-1,2,3triazoles [90, 91]. Unsymmetrical vicinal bis(arylsulfonylhydrazones) have been cyclized either with acid or base to give 1-(arylsulfonylamino)-1H-1,2,3-triazoles as a mixture of regioisomers [92]. NH2 N

Ar H 56

N NH2

Scheme 12.25

MnO2

Ar

N N

or HgO (35-45%)

H

N NH2 57

12.1 1,2,3-Triazoles

O

MeOH

N OBn

CuSO 4•5H 2O

NH 2 N

NH 2NH 2

pyridine 100 ºC

N OBn 59

0 ºC

58

(63%)

N N

N OBn 60

Scheme 12.26

Imine hydrazones can be cyclized in the presence of oxidants to give 1,2,3-triazole derivatives. Glyoxal O-benzyloxime hydrazone 59, which is generated in situ from the reaction of glyoxal O-benzyloxime 58 with excess hydrazine, afforded 1-(benzyloxy)1H-1,2,3-triazole (60) by oxidative cyclization (Scheme 12.26) [93]. Similarly, iodobenzene diacetate-mediated oxidation of hydrazones 61 furnished fused 1,2,3-triazoloheterocycles 62 (Scheme 12.27) [94]. a-Hydroxyimino hydrazones 63 undergo intramolecular cyclization with elimination of water to generate 2H-1,2,3triazole derivatives 64 in the presence of acetic anhydride or phosphorus pentachloride (Scheme 12.28) [95]. PhI(OAc)2 R

N N 61

NH2

CH 2Cl2

N N N

(68-93%)

R

R = H, Me, Ph

62

Scheme 12.27

R1 R2

NHR 3 N N OH 63

Ac2O or PCl5 heat

R1 R2

N N R3 N 64

Scheme 12.28

12.1.4.5 Other Methods for Preparations of 1,2,3-Triazoles Several other recent methods for preparation of 1,2,3-triazoles do not fall into the above categories. Treatment of oxazolone 65 with iso-pentyl nitrite in the presence of acetic acid gives 1,2,3-triazole 66, a precursor to b-(N-1,2,3-triazolyl)-substituteda,b-unsaturated-a-amino acid derivatives (Scheme 12.29) [96]. 2-Aryl-2H,4H-imidazo[4,5-d][1,2,3]triazoles 68 have been prepared from the reaction of triethyl N-1ethyl-2-methyl-4-nitro-1H-imidazol-5-yl phosphoramidate (67) with aryl isocyanates (Scheme 12.30) [97]. N-(Uracil-6-yl)-S,S-diphenylsulfilimine (69) reacted with aryldiazonium salts to give arylsulfilimines 70, which were thermolyzed to the 1,2,3-

j1003

j 12 Five-Membered Heterocycles with Three Heteroatoms: Triazoles

1004

O

O

Ph

O

O

N iso-pentyl nitrite

NH NH 2

NC

Ph N

N N N

HOAc, 25 ºC NC

(65%)

CN

NC

66

65 Scheme 12.29

Me

Et N

ArNCO

N P(OEt)3

MeCN

N NO2 67

Me

(57-79%)

Et N

N

N

N

N Ar

68

Scheme 12.30

O Me O

N

ArN 2 Cl N Me

R

O H O, DMF N SPh 2 2 THF, 5 ºC

Me O

69

N

N N Me

PhMe, reflux

N

- SPh 2

N SPh2

70

O Me

(86-98%) R = H, Me, OMe, Cl, NO 2

O

N

N N Me

N

N

R

71

Scheme 12.31

triazolopyrimidine diones 71 in good yields (Scheme 12.31) [98]. Polystyrene-sulfonyl hydrazide resins 72 reacted with various amines to give regiospecifically 1,4-disubstituted-1,2,3-triazoles 73 via traceless cleavage reactions (Scheme 12.32) [99]. Palladium-catalyzed synthesis of 1H-triazoles 75 from alkenyl bromides 74 and sodium azide in the presence of xantphos ligand has been reported (Scheme 12.33) [100]. A new one-pot procedure has been developed to synthesize 1-aryl- and 1-vinyl-1,2,3triazoles directly from boronic acids and alkynes, which avoids the need to isolate unstable azide intermediates [101]. O2 S

NHN

R1 CHCl2

72

Scheme 12.32

R2 NH2 MeOH 25 ºC (28-57%)

R1

N N

N R2 73

12.1 1,2,3-Triazoles

NaN 3, Pd2(dba)3 Br

R 74

R

xantphos, dioxane or DMSO, 90-110 ºC R = Ph, Ar, 2-furyl, CH 2OBn (45-94%)

N N N H 75

Scheme 12.33

12.1.5 Reactions of 1,2,3-Triazoles 12.1.5.1 Reactions of Carbon of 1,2,3-Triazoles In general, the 1,2,3-triazole ring system is relatively resistant to both oxidation and reduction conditions but many synthetically useful reactions can still be achieved with this system. For example, lithiation of N-protected 1,2,3-triazoles is one of the most general methods for introduction of carbon or hetero substituents onto the C5 position of the ring. 1-Substituted-1,2,3-triazoles 76 react easily with n-butyllithium, lithium diisopropylamide (LDA), or with lithium tetramethylpiperidine (LTMP) to generate lithio species 77, which are quenched with various electrophiles to give 1,5disubstituted-1,2,3-triazoles 78 (Table 12.6) [93, 102, 103]. Low temperatures must be maintained, otherwise cycloreversion to the alkyne species can result. Alkyl, alcohol, Table 12.6 Lithiation of 1H-1,2,3-triazoles and quenching with electrophiles.

N N N R1 76 R1 SEM SEM SEM SEM OBn OBn OBn OBn OBn OBn OBn Me Me Me Me

n-BuLi or LDA or LTMP THF, -78 ºC

R2 CH(OH)Ph Me Cl SPh Me CHO Cl Br SnBu3 CO2Me TMS Me CH(OH)Ph PhC(O) PhCOCH2

Li

N N

N R1 77

Electrophile PhCHO MeI Cl3CCCl3 PhSSPh MeI DMF Cl3CCCl3 Br2 Bu3SnCl ClCO2Me TMSCl MeI PhCHO PhCONMe2 PhCOCH2Br

electrophile THF

2

R

N N N R1 78

Yield (%)

Reference

45 30 50 80 93 87 88 86 91 76 93 56 61 78 66

[102] [102] [102] [102] [93] [93] [93] [93] [93] [93] [93] [103] [103] [103] [103]

j1005

j 12 Five-Membered Heterocycles with Three Heteroatoms: Triazoles

1006

halogen, sulfur, silicon, tin, aldehyde, and ester products can be formed from these reactions. The 2-(trimethylsilyl)ethoxymethyl (SEM) and benzyloxyl (OBn) N-protecting groups both stabilize the intermediate triazol-5-yllithium species by intramolecular coordination. The SEM group can be deprotected easily with dilute hydrochloric acid or with tetrabutylammonium fluoride to give the 5-substituted1H-1,2,3-triazoles, while the Bn group can be deprotected with catalytic hydrogenation to give the corresponding 5-substituted-1H-1,2,3-triazol-1-ols. From Table 12.6, higher yields are generally obtained for the same type of reaction (Cl, Me) when the nitrogen was protected with the benzyloxy group [93]. Lithiation of 1-methyl-1H1,2,3-triazole with n-butyllithium or with LTMP followed by addition of electrophiles gives moderate yields of 5-alkyl- or 5-acyl-1-methyl-1,2,3-triazoles [103]. Bromine– lithium exchange can be carried out on 4,5-dibromo-1-(methoxymethyl)-1H-1,2,3triazole with n-butyllithium and subsequent quenching with various electrophiles gives high yields of the corresponding 5-substituted-1,2,3-triazoles [104]. 1-(Benzyloxy)-1H-1,2,3-triazoles 79 have been lithiated followed by transmetalation to the zinc species 80, which undergoes Negishi cross-coupling with aryl iodides to generate 5-aryl-1,2,3-triazoles 81 (Scheme 12.34) [105].

N N N OBn 79

n-BuLi THF, -78 ºC

Li

N

N N

OBn

ZnI2

IZn

N N N OBn 80

ArI, DMF Pd(PPh 3)4 80 ºC (30-87%)

Ar

N N N OBn 81

Scheme 12.34

Substitution of halogens by nucleophiles is possible in N-substituted-1,2,3-triazoles. Displacement of the chloro group in N-substituted-1,2,3-triazoles 82 by nucleophiles, such as cyanide, phenolates, arene, and furylthiolates, gave moderate to good yields of derivatives 83 (Table 12.7) [106–109]. Heating 1-aryl-5-chloro-1H1,2,3-triazoles with hydrazine gave 5-substituted-1H-1,2,3-triazol-1,5-diamines, via the 5-hydrazinotriazole intermediates which spontaneously rearrange under the reaction conditions [110]. 5-Bromo-1-methyl-1H-1,2,3-triazole reacts with aniline to give the corresponding 5-anilino derivative [111]. 12.1.5.2 Reactions of Nitrogen of 1,2,3-Triazoles 1H-1,2,3-Triazoles can be N-alkylated with alkyl halides in the presence of bases such as sodium alkoxide, sodium hydride, or sodium hydroxide to give mixtures of 1- and 2-alkylated-1H-1,2,3-triazoles [112]. Selectivity for alkylation at the 1-position has been achieved in the presence of silver or thallium salts of 1,2,3-triazoles on reaction with alkyl halides [113]. Reaction of 2-(trimethylsilyl)-2H-1,2,3-triazoles with primary alkyl halides afforded products of selective alkylation at N1 [103]. 1H-1,2,3-Triazoles can be N-acylated with acyl halides and anhydrides to give exclusively 1-acyl-1H-1,2,3triazoles; however, the acyl group can migrate to the 2-position on heating or on treatment with base [114].

12.1 1,2,3-Triazoles Table 12.7

R2 Cl

Nucleophilic displacement of 5-chloro-N-substituted-1,2,3-triazoles with nucleophiles.

R2 N N N R1 82

nucleophile

Nuc

DMF, 80 °C

R1

N N

N R1 83

R2

Nucleophile

Nuc

Yield (%)

Reference

PMB PMB Ph Bn

CO2Et CO2Et Ph CO2Et

[106] [106] [107] [108]

CO2Me

CN 4-OMeC6H4S CN OPh S S

66 74 75 82

Bn

NaCN 4-OMeC6H4SNa NaCN NaOPh S SNa

48

[109]

PMB

CO2Me

34

[109]

S

SNa

S

S

N-Arylation of 1,2,3-triazoles is possible with activated aryl halides. Activated aryl halides such as 1-fluoro-2-nitrobenzene and 1-fluoro-4-nitrobenzene with 1H-1,2, 3-triazoles afforded mixtures of the corresponding 1- and 2-nitrophenyl-1,2,3-triazoles [115, 116]. However, reactions with even more activated halides such as 1-fluoro-2,4-dinitrobenzene and 2-chloro(or fluoro)-1,3,5-trinitrobenzene provided only 1-substituted-1H-1,2,3-triazoles 84 (Scheme 12.35) [116]. The copper-catalyzed arylation of 1,2,3-triazole with iodobenzene proved to be problematic as competitive N-1/N-2 arylation products were observed [117]. Efficient post-triazole regioselective N-2 arylation to give 86 has been developed from C4, C5 disubstituted-1,2,3-NHtriazoles 85 (Scheme 12.36) [118].

N H

N N

N N N

O2 N +

(NO2 ,F) Cl O2 N

NO2

DMF or DMSO

O2 N

NO2

(58-96%) NO2 84

Scheme 12.35

1H-1,2,3-Triazoles can also N-substituted with heteroatoms. For example, 4,5diphenyl-1H-1,2,3-triazole has been aminated with hydroxylamine-O-sulfonic acid to yield mixtures of N-aminotriazoles substituted in the 1- and 2-positions [119]. 1H1,2,3-Triazoles can be oxidized by peracids such as 3-chloroperoxybenzoic acid and hydrogen peroxide to give 1H-1,2,3-triazol-1-ols [92, 120], which are also obtained by catalytic hydrogenation of 5-substituted-1-(benzyloxy)-1H-1,2,3-triazoles [92, 121].

j1007

j 12 Five-Membered Heterocycles with Three Heteroatoms: Triazoles

1008

ArF or ArCl, base or ArB(OH)2 , Cu(OAc) 2 (20 mol%)

R1 R2

N 85

N NH

O 2, 1 atm, 50 °C, 12 h or

R1 R2

ArI, CuCl (10 mol%), L-proline (20 mol%),

N N Ar N 86

110°C, 24 h (or microwave, 160 °C, 30 min) (50-95%)

Scheme 12.36

12.1.5.3 Electrophilic Reactions of 1,2,3-Triazoles Halogenations are the most common type of electrophilic reactions of 1,2,3-triazoles. For example, 1H-1,2,3-triazole reacts with bromine to afford 4,5-dibromo-1H1,2,3-triazoles (87) in almost quantitative yield (Scheme 12.37) [122]. 4-Bromoand 5-bromo-1H-1,2,3-triazoles are obtained indirectly by bromination of a triazole with a protecting group at N1 [123]. In general, most halogens are introduced into the carbons of the ring system by a lithiation/electrophilic sequence (Section 12.1.5.1). Direct nitration of 1H-1,2,3-triazole is not possible. Nitration of 1-phenyl and 4-phenyl-1H-1,2,3-triazole was also unsuccessful as nitration occured only on the phenyl ring [124]. However, nitration of 2-methyl-2H-1,2,3-triazole (88) with a mixture of fuming nitric acid and concentrated sulfuric acid afforded 2-methyl-4nitro-2H-1,2,3-triazole (89), which can be nitrated further to 90 under more vigorous conditions (Scheme 12.38) [125].

N N N H

Br Br 2, H2 O (97%)

Br

N H

N N

87

Scheme 12.37

N HNO3 , H 2SO4 N Me 25 ºC, 3 h N 88 Scheme 12.38

(98%)

O2 N

N N Me N 89

HNO3 , H 2SO 4 100 ºC, 10 h (97%)

O2 N O2 N

N N Me N 90

12.2 Benzotriazole

12.2 Benzotriazole 12.2.1 Introduction 12.2.2 General Reactivity 12.2.2.1 Relevant Physicochemical Data and NMR Data The parent benzotriazole is a weak base with a pKa of 8.2, which is a stronger NH acid than indazole, benzimidazole, or 1,2,3-triazole (Figure 12.3). The 1-substituted 1Hbenzotriazole is remarkably stable to strong acid and bases and to oxidative and reductive conditions. The two tautomeric forms of benzotriazole (Figure 12.4) are in equilibrium, but 1H-benzotriazole is the predominant species (99.9%) in both the gas and solution phases [2]. The 1 H and 13 C NMR spectra of the parent benzotriazole for the protons and carbons at the 4-/7- and 5-/6-positions are identical because benzotriazole undergoes rapid proton exchange between the tautomeric forms at room temperature (Table 12.8). Other 1 H and 13 C NMR data of the methyl group attached to the benzotriazole in the 1- and 2- positions are listed for comparison. 12.2.3 Synthesis of Benzotriazoles 12.2.3.1 Synthesis by Ring-Closure Reactions Diazotization of benzene-1,2-diamine derivatives is the most common synthetic route to 1-substituted benzotriazoles. Diazotization is mostly commonly performed with nitrous acid, generated in situ from sodium nitrite and a mineral acid source such as nitric, sulfuric, or acetic acids. A range of various 1-substituted benzotriazoles 92 can be prepared from the corresponding benzene-1,2-diamine derivatives 91 (Table 12.9). N

N

N H

acid pKa 8.2 for proton loss very weak Bronsted base (pKa for proton addition) Lewis base of appreciable strength non-volatile, crystalline, odorless, nontoxic almost insoluble in water, soluble in sodium carbonate solution

Chemical Stability of Benzotriazole Ring System N

N N R

Stable: thermally to 400 °C to hot strong sulfuric acid to fused potassium hydroxide to oxidation to reduction

Figure 12.3 Physical and chemical properties of the parent and 1-substituted 1H-benzotriazole.

j1009

j 12 Five-Membered Heterocycles with Three Heteroatoms: Triazoles

1010

N

N

N H

N

2 1 N

2 NH

1

2H-benzotriazole

1H-benzotriazole

Figure 12.4 Tautomerisim in benzotriazoles.

Table 12.8

1

H and 13 C NMR data (ppm) of benzotriazoles.

4 5 6 7 1

Substituents

13

H NMR (DMSO-d6)

H4 8.00 8.02 7.85

— 1-Me 2-Me

H5 7.44 7.47 7.34

H6 7.44 7.47 7.34

H7 8.00 7.36 7.85

N

1 N N H

Reference [126] [127] [127]

C4 130.3 119.3 117.5

C NMR (DMSO-d6) C5 130.3 123.4 125.9

C6 130.3 126.8 125.9

C7 130.3 108.8 117.5

Reference

[128] [129] [129]

1-Substituted benzotriazoles can be prepared from various azides with a benzyne intermediate generated in situ from 2-aminobenzoic acid (Table 12.10). 1-Chloro-2nitrobenzenes 93 react with hydrazine to yield benzotriazol-1-ols 95 via the 2nitrophenylhydrazines 94 (Table 12.11). The polymer-supported synthesis versions of benzotriazol-1-ols has also been published [141, 142]. These benzotriazol-1-ols can be readily deoxygenated to their NH derivatives by reductive cleavage with either phosphorus trichloride or samarium(II) iodide [142]. Various substituted benzotriaTable 12.9 Diazotization of benzene-1,2-diamine derivatives to give 1-substituted benzotriazoles.

NH 2 R2

NHR1

NaNO2 , HCl or H2 SO4 or HOAc, 0 ºC

91 R1

R2

H Me Ac CO2Et SO2Ph Benzotriazol-2-yl

H 5,6-(NO2)2 5-6-Me2 7-Cl-4-OEt-5-CO2Me 5-Me H

R2

N

N N 1 92 R Yield (%)

Reference

81 83 63 68 100 63

[130] [131] [132] [133] [134] [135]

12.2 Benzotriazole Table 12.10 Synthesis of 1-substituted benzotriazoles from azides and a benzyne intermediate.

CO 2H

N

RN3

BuONO

N N R

NH2

R

Yield (%)

Reference

52 62 63 52 60 75

[136] [137] [137] [137] [137] [138]

Ph 4-O2NC6H4 Bz SO2Ph 4-OMeC6H4CO 1-Naphthalenyl

Table 12.11 Benzotriazol-1-ols from 1-chloro-2-nitrobenzenes and hydrazines.

Cl R NO 2

93

NH 2NH2 EtOH

NHNH2 R

reflux

N

R

NO 2 94

R

- H 2O

95

N N OH

Yield (%)

Reference

90 67 90 6 39 96

[139] [139] [140] [140] [140] [135]

H 4,5,6-Cl3 6-CF3 6-OMe 6-CONH2 6-SO2NHBn

zoles 97 have been prepared by the [3 þ 2] cycloaddition of azides to benzynes generated from aryl triflates 96 and cesium fluoride (Scheme 12.39) [143]. 2-Substituted benzotriazoles can be prepared by several methods. For example, 2aminoazobenzenes 98 can be converted into their 2-aryl-2H-benzotriazoles 99 TMS Z OTf 96 Scheme 12.39

RN 3, CsF CH 3CN, 25 °C (20–100%) R = Ph, Ar, Bn, alkyl

N

Z 97

N N R

j1011

j 12 Five-Membered Heterocycles with Three Heteroatoms: Triazoles

1012

by oxidation with copper(II) sulfate in refluxing pyridine [144], copper(II) acetate in air [145], or by refluxing the azo compound in thionyl chloride (Scheme 12.40) [145a]. 2-Aryl-2H-benzotriazoles 101 can be prepared directly by reaction of 1-halo(or nitro)-2-nitrobenzenes 100 with an excess of an arylhydrazine (Scheme 12.41) [146]. CuSO 4, pyridine, reflux N R

N

NH2 98

Ar

or

N

Cu(OAc)2 , air, DMF, reflux

R

or SOCl2, PhH, reflux

N

N Ar

99

Scheme 12.40

X R 100

ArNHNH2 , heat

NO2

R

N N

N Ar

101

X = Cl, Br, NO2 Scheme 12.41

12.2.4 Reactions of Benzotriazoles

The growing applications of benzotriazole methodology as a versatile synthetic tool have been reviewed extensively [147]. Practically all the chemistry occurs on the N1position of the benzotriazole. The benzotriazole group conveys multiple activating influences such as a leaving group, proton activator, ambident anion directing group, cation stabilizer, radical precursor, and anion precursor. The benzotriazole group can also easily be eliminated by radical-type reactions, by hydrolysis, by palladiumcatalyzed SN20 substitution, and by reductive metal reductive reactions. This section will not describe the chemistry needed to give the benzotriazole derivatives; however, the intermediates of these substitution reactions will be used to explain the myriad of useful synthetic reactions. 12.2.4.1 Acylation of 1-Benzotriazoles and Benzotriazole Methodology The classical preparation of N-acylbenzotriazoles uses the corresponding acid chlorides (Table 12.12) [148]. More recently, two methods have been developed for the preparation of N-acylbenzotriazoles directly from carboxylic acid without the necessity of isolating the acid chlorides. Carboxylic acids are converted into the mixed carboxylic sulfonic anhydride, which is then attack by the benzotriazole anion with methanesulfonylbenzotriazole as the reagent [149]. Treatment of carboxylic acids

12.2 Benzotriazole Table 12.12 Synthesis of N-acylbenzotriazoles.

Acyl Reagent

+

Benzotriazole Reagent

N

Base

N R

Acyl reagent

Benzotriazole reagent

RCOCl RCO2H RCO2H/SOCl2 CO/iodonium salts

BtH BtSO2Me BtH (4 equiv) BtH

N O

Reference [148] [149] [150] [151]

with thionyl chloride in the presence of excess benzotriazole provided N-acylbenzotriazoles in high yields [150]. N-Acylbenzotriazoles can be synthesized by palladiumcatalyzed carbonylation of benzotriazole and hypervalent iodonium salts [151]. N-Acylbenzotriazoles are useful intermediates in several synthetically valuable reactions (Table 12.13) [152]. N-Acylbenzotriazoles can react with ammonia and primary and secondary amines to give high yields of their respective amides [149]. OAlkyl, N-alkyl, and O,N-dialkylhydroxamic acids have been synthesized from Nacylbenzotriazoles [153]. C-Acylation of N-acylbenzotriazoles with furan, thiophene, pyrrole, and indole under Friedel–Crafts conditions gave products in high yields [154]. b-Diketones have been prepared from monoketones and N-acylbenzotriazoles in the Table 12.13 Benzotriazole-mediated methodology of N-acylbenzotriazoles.

N N O

N R

Reactants

Products

Amines (ammonia, primary, secondary) R1NHOR 2 HCl

Amides (primary, secondary, tertiary) O-Alkyl, N-alkyl, O,N-dialkylhydroxamic acids C2-acylated heterocycles b-Diketones a-Substituted b-ketonitriles b-Ketosulfones b-Ketoesters/b-diketones Ketones Acyl azides Aroylindoles

Five-membered heterocycles Cyclic and acyclic ketones Nitriles (primary, secondary) Sulfones Acetoacetic esters Grignards/heteroaryllithiums Sodium azide Indoles

Reference [149] [153] [154] [155] [156] [157] [158] [159] [160] [161]

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j 12 Five-Membered Heterocycles with Three Heteroatoms: Triazoles

1014

presence of base [155]. a-Substituted b-ketonitriles have been synthesized from N-acylbenzotriazoles with primary and secondary alkyl nitriles [156]. C-Acylation of sulfones with N-benzotriazoles affords b-keto sulfones [157]. b-Ketoesters and b-diketones have been prepared by an acylative-deacylative sequence [158]. Stable and easily accessible N-acylbenzotriazoles, derived from various aliphatic, unsaturated, (hetero)aromatic, and N-protected-R-amino carboxylic acids, have been reacted with Grignard and heteroaryllithium reagents to afford the corresponding ketones [159]. A general synthesis of acyl azides from the corresponding N-acyl benzotriazoles have been described [160]. Stable and easily accessible N-aroylbenzotriazoles react with indoles in the presence of a base to afford the corresponding Naroylindoles [161]. 12.2.4.2 Benzotriazole-Mediated Imidoylation N-(Imidoyl)benzotriazoles have found synthetic applications in the syntheses of various substituted guanidines. For example, benzotriazole-1-carboxamidinium tosylate (102) was found to be an efficient reagent for the synthesis of mono- and disubstituted guanidines 103 in moderate to good yields and offers advantages over previous procedures (Table 12.14) [162]. Introduction of Boc groups on both nitrogens of the amidine moiety and nitro or chloro group on the benzotriazole enhances the ability of the benzotriazole moiety as a leaving group [163]. Bis(benzotriazolyl) carboximidamide (104) has been developed as a new guanylating agent for the synthesis of tri- and tetrasubstituted guandines 105 [163, 164]. Benzotriazolyl carboximidoyl chlorides (106) are stable, colorless, and conveniently handled reagents for the synthesis of unsymmetrical guanidines 107 [165]. Polysubstituted acylguanidines and guanylureas 109 [166] have been prepared from N-acyl-N,Ndisubstituted benzotriazolyl carboximidates 108. Table 12.14 Synthesis of substituted guanidines with various benzotriazole imidates.

Benzotriazole imidate

NH2 Bt

NH 2

OTs

Reagents

102

NH Bt

Bt

R1R2NH, R3R4NH

104

NR 1 Bt

Cl

R1R2NH

R2R3NH, R4R5NH

106

Products

NH

Bt

103

NR1 R2

H2 N

[162]

NH R 2 R1 N

NR3 R 4 105 NR1

R 2R 3N

O R1

Reference

NR 4R 5

107

[163, 164]

[165]

O

N NR2 R3

108

R 1 = aryl, alkyl, NHAr

R4R5NH

R1 4 5

R R N

N 2 3

NR R

109

[166]

12.2 Benzotriazole

R

R Bt

NR1R2 110

Bt

O N H

R1

R1 R

111

Bt

OR 2 112

Bt

SR2 113

Figure 12.5 Structures of amino- (110), amido- (111), alkoxy- (112), and alkylthio- (113) methylbenzotriazoles [167].

12.2.4.3 Benzotriazole-Mediated Amino-, Amido-, Alkoxy-, and Alkylthio-Alkylations A very detailed recent review describes extensively the synthesis and the broad utility of aminomethylbenzotriazoles 110, amidomethylbenzotriazoles 111, alkoxymethylbenzotriazoles 112, and alkylthiomethylbenzotriazoles 113 (Figure 12.5) and so this chemistry will not be presented here [167]. 12.2.5 Benzotriazole-Containing Reagents

Substituents located in the N1 position of 1,2,3-benzotriazoles have become useful reagents in various reactions (Table 12.15). 1-Hydroxybenzotriazole (114) is a useful co-reagent in peptide coupling reactions in the activation of carboxylic acids [168]. Aminium-based 115 [169] and phosphonium-based 116 [170] benzotriazoles are currently utilized as peptide coupling reagents. 1-Aminobenzotriazole (117) is a useful reagent in the generation of benzyne intermediate, which can be trapped with various dienes [171]. 1-Cyanobenzotriazole (118) has been found to participate in electrophilic cyanations of sp2 and sp carbanions [172]. 1H-Benzotriazole-1-yl methanesulfonate (119) has been explored as a regioselective N-mesylating reagent [173]. Reagent 119 mesylated molecules containing both primary and secondary amines on the primary amino position and mesylation occurred on the amino group in molecules containing both amino and hydroxy groups. 1H-Benzotriazole-1-yl alkyl carbonates (120) are convenient and inexpensive coupling agents in the preparation of active esters for the synthesis of amides [174]. A general and efficient route to thionoesters via thionoacyl nitrobenzotriazoles 121 has been reported [175]. The Vilsmeier-type reagent 122 with b-enaminonitriles provides a regioselective route to the preparation of nicotinonitriles [176] and was employed in the direct and efficient synthesis of dimethylformamidrazones from hydrazines [177]. 1-(Chloromethyl)benzotriazole reacted with sodium dialkyl phosphites to give dialkyl-(1-benzotriazolmethyl)phosphonates 123, which are potential Horner–Emmons reagents [178] for the stereoselective preparation of (E)-1-(1alkenyl)benzotriazoles [179]. 2-Benzotriazolyl-1,3-dioxolane (124) has been utilized as a novel formyl cation equivalent [180]. The novel three-carbon synthon 1-(1H-1,2,3benzotriazol-1-yl)-3-chloroacetone (125) has been used for the synthesis of benzothiazoles, pyrido[1,2-a]indoles, styryl-substituted indolizines, and imidazo[1,2-a]pyridines [181]. Various functionalized N-allylamines and N-allylsulfonamides have been synthesized by Pd(II)-catalyzed intermolecular amination of the corresponding N-allylbenzotriazoles 126 [182]. S-(1H-1,2,3-Benzotriazol-1-ylmethyl)-O-ethylcarbo-

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j 12 Five-Membered Heterocycles with Three Heteroatoms: Triazoles

1016

Table 12.15 Synthetic utility of 1-substituted benzotriazole reagents.

N N N R R

Number

Synthetic utility

Reference

OH

114

Co-reagent in peptide coupling

[168]

115

Peptide coupling agent

[169]

116

Peptide coupling agent

[170]

117 118 119 120 121

Benzyne intermediate Electrophilic cyanations N-Mesylating reagent Synthesis of active esters Synthesis of thioesters

[171] [172] [173] [174] [175]

122

Vilsmeier-type reagent

[176, 177]

123

Horner–Emmons reagent

[178, 179]

124

Formyl cation equivalent

[180]

125 126 127 128 129 130 131 132 133

Three-carbon synthon N-Allylating reagent Benzotriazolylmethyl radical One-carbon synthon Sulfonylating reagents Thioacylating reagents Mosher-Bt reagent Formaldehyde generation Carbamoyl chloride reagent

[181] [182] [183] [184] [185] [186] [187] [188] [189]

CHNR2 X OP(NHR 2)3 X NH2 CN OMs OCO2R C(S)R


CH=NMe2Cl CH2P(O)(OR)2 O

O CH2C(O)CH2Cl CHRCH ¼ CH2 CH2SC(S)OEt CH2TMS SO2R C(S)X X ¼ R, OR, SR, HetNH PhC(OCH3)(CF3)C(O)) CH2OH CONH2

nodithioate (127) has been used to generate the benzotriazolylmethyl radical, which was trapped by various olefins [183]. 1-(Trimethylsilylmethyl)benzotriazole (128) has been utilized as a one-carbon synthon in the conversion of alkyl and aryl carboxylic acids into their corresponding homologated acids or esters [184]. NAlkane-, N-arene-, and N-heteroenesulfonylbenzenetriazoles 129 have been exploited as efficient sulfonylating agents [185]. Several benzotriazole sulfur reagents 130 have been prepared and used for thioacylations, thiocarbamoylations, alkyl/ alkoxythioacylations, and aryl/alkylthioacylations [186]. Benzotriazole of 3,3,3-trifluoro-2-methoxy-2-phenylpropionic acid (131) reacted with water-soluble amino acids and peptides in an acetonitrile/water (2 : 1) mixture to give the corresponding Mosher derivative in quantitative yield [187]. Anionic in situ generation of formaldehyde from benzotriazolylmethanol 132 has proved to be a very useful and versatile tool in synthesis [188]. Carbamoyl-1H-benzotriazole 133, an effective carbamoyl

12.3 1,2,4-Triazoles

chloride substitute, and a range of its analogs have been synthesized in good yields in two very simple steps from 1,2-diaminobenzene [189]. 12.3 1,2,4-Triazoles 12.3.1 Introduction

The chemistry of 1,2,4-triazoles is extensively reviewed elsewhere [190]. A comprehensive review on the chemistry of mercapto- and thione- substituted 1,2,4-triazoles and their utility in heterocyclic synthesis has been published [191]. This section will focus on methods for the synthesis of the monocyclic 1,2,4-triazole system, including solid-phase and microwave-assisted reactions. 12.3.2 General Reactivity 12.3.2.1 Relevant Physicochemical Data and NMR Data The parent 1,2,4-triazole consists of a five-membered aromatic ring containing three nitrogen atoms, two of which are adjacent; it is a stable, water-soluble solid. Two tautomeric forms, 1H-tautomer and 4H-tautomer, can be envisaged (Figure 12.6). Theoretical and analytical methods show that the 1H-tautomer is the preferred structure. Every carbon atom in 1,2,4-triazole is linked to two nitrogen atoms and, thus, this ring system is electron deficient. The ring is deactivated towards electrophilic attack so nitration and other reactions at carbon typical of aromatic chemistry do not apply to the parent compound. However, electrophilic attack at nitrogen is found in abundance in the literature and this will be discussed later. The parent compound has a pKa of 10.26 and so alkali metal salts form readily at the N1 position. The pKa of the protonated species is 2.19 and the weakly basic nature allows electrophilic attack at the N4 position in 1-substituted-1,2,4-triazoles. The 1 H NMR spectrum of the parent 1,2,4-triazole in HMPT is temperature dependent; the H3 and H5 protons show one broad singlet at slightly above or below room temperature due to the rapid proton exchange between the tautomeric forms 4 5

4

3

N N H

N

3

HN 2

5

N

N2

1

1

1H-tautomer stable, water-soluble, colorless crystals mp 120-121 °C pKa = 10.26 pKa = 2.19 of the protonated species Figure 12.6 Tautomerism of 1,2,4-triazoles.

4H-tautomer

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j 12 Five-Membered Heterocycles with Three Heteroatoms: Triazoles

1018

Table 12.16

1

H and 13 C NMR data (ppm) of 1,2,4-triazole.

3

N 5

1

Temperature ( C) 37 10 34

N H

N

13

H NMR (HMPT)

H3 8.03 8.17 7.92

C NMR (CD3OD-d4)

H5 8.03 8.17 8.85

C3 147.4

C5 147.4

(Table 12.16) [192]. However, at 34  C, the H3 protons and H5 protons are observed separately. The 13 C NMR spectrum shows a single peak for the parent triazole. 12.3.3 Relevant Natural and/or Useful Compounds

1,2,4-Triazoles have several applications in analytical chemistry, in industrial, and in molecular recognition processes [190d,190f ]. The 1,2,4-triazole ring is also a component of a wide range of biologically active pharmaceutical products. For example, rizatriptan benzoate, marketed as MaxaltÔ, was launched in 1998 by Merck & Co. as an antimigraine medication (Figure 12.7) [193]. Voriconazole is sold as VfendÔ by Pfizer for treatment of fungal infections [194]. Aprepitant is sold as EmendÔ for the treatment of chemotherapy-induced nausea and vomiting [195]. 12.3.4 Synthesis of 1,2,4-Triazoles 12.3.4.1 Reactions of Acylhydrazines with Various Nitrogen-Containing Reagents One of the most common methods of preparing 1,2,4-triazoles is the reaction of acylhydrazines with various nitrogen-containing reagents. For example, reactions of O N N

NMe 2

N N H

(Maxalt TM )

rizatriptan benzoate Merck & Co.

N N

N F

CH 3 F OH N

HN

NH N

Me

O N

CF 3

O

N CF3

F voriconazole (Vfend TM) Pfizer

F aprepitant (Emend TM ) Merck & Co.

Figure 12.7 Some biologically active pharmaceutical products that contain a 1,2,4-triazole ring.

12.3 1,2,4-Triazoles

j1019

acylhydrazines with isothiocyanates or isocyanates to give 1,2,4-triazoles can be seen in the following examples. Acylhydrazines 134 and isothiocyanates 135 afforded 1,2,4-triazole-3-thiones 136, which were intercepted by alkyl halides to give substituted 3-thio-1,2,4-triazoles 137 (Scheme 12.42) [196]. Solid-supported acylhydrazines 138 react with isocyanates or isothiocyanates followed by base-induced cyclization/ cleavage to provide 1,2,4-trisubstituted urazoles and thiourazoles 139 (Scheme 12.43) [197]. A traceless liquid-phase synthesis of 3-alkylamino-4,5-disubstituted-1,2,4-triazoles on poly(ethylene glycol)-supported thioureas and acylhydrazines has been reported [198]. O R1

N H

NH 2

R2

+

N=C=S

R1

N

135

S

R1

CH 2Cl2

R2

134

N N

R 3 X, Et3N

N NH

THF

(45-95%)

137

136

Scheme 12.42

R1

O O

N R1

N

1.

H

R 2 NCX,

ClCH 2CH2 Cl (X = O,S) (18-44%)

138

O

R1

2. Et3N, PhMe or KOt-Bu, THF

R

N 1N

N R2

X 139 X = O,S

Scheme 12.43

Acylhydrazines can also be used in conjunction with substituted imidates to give 1,2,4-triazole derivatives. The three-component condensation of acylhydrazines in the presence of S-methyl isothioamide hydroiodide 140, silica gel, and ammonium acetate under microwave irradiation afforded 1,2,4-triazoles 141 in good yields (Scheme 12.44) [199]. Acylhydrazines 142 react with imidates 143 to yield 1,2,4triazoles 144 (Scheme 12.45) [200].

O R1

NHNH 2

+

NH2 I R2

SMe 140

silica gel, NH 4OAc

Et3N, microwave (900 W) (66-91%) R1

= Me, Ar R 2 = Me, Ph

N R2

N N R

1

N H

R2

141

Scheme 12.44

Other non-traditional reactions of acylhydrazines with nitrogen reagents for the synthesis of 1,2,4-triazoles are also available. An efficient one-pot, three-component synthesis of substituted 1,2,4-triazoles 146 has been prepared from primary acylhy-

SR3

j 12 Five-Membered Heterocycles with Three Heteroatoms: Triazoles

1020

R2 N

NH•HCl R

1

EtO

NHNH 2

O

142

( )n

143

HN N

R3 R1

i-PrOH, Et3 N, 65 ºC

O

O

N

NR2 R3

( )n

144

Scheme 12.45

drazines, dimethylamino acetals 145, and amines (Scheme 12.46) [201]. 1,3-Benzoxazine 147 reacts with acylhydrazines in refluxing methanol to give 1,2,4-triazoles 148 (Scheme 12.47) [202]. Diethoxyphosphinyl acetic acylhydrazine 150 was found to be a unique reagent that provided a convenient and efficient process to prepare fused [5,5]-, [5,6]-, and [5,7]-3-[(E)-2-(arylvinyl)]-1,2,4-triazoles 151 from aldehydes and alkoxyimines 149 (Scheme 12.48) [203]. A convenient and efficient one-step, base-catalyzed microwave-assisted synthesis of 3,5-disubstituted-1,2,4-triazoles by condensation of a nitrile and acyl hydrazide has been reported [204].

O R1

CH3CN, 50 ºC

OMe R 2 NH2

+

NHNH 2

+

(9-87%)

Me2N 3 OMe R

R 1 = alkyl, aryl R 2 = alkyl, Bn, aryl R 3 = Me, H

145

Scheme 12.46

RCONHNH2

O

MeOH, 65 ºC

O N 147

Ph

(60-63%) R = 4-CH3 C6 H 4, 2-ClC6 H4

CO 2H Ph N R 148

N N

Scheme 12.47

( )n ( )n N

OMe

149 Scheme 12.48

1. (EtO)2 P(O)CH 2CONHNH 2 (150), PhMe

N

2. NaOEt, EtOH, ArCHO 3. PhMe, 110 ºC (33-81%)

Ar

N N 151

R2 N R1

R3 N

N

146

12.3 1,2,4-Triazoles

j1021

12.3.4.2 Reactions of Hydrazones Substituted hydrazones are a rich source of precursors for the syntheses of 1,2,4triazoles. For example, hydrazonyl chlorides can be used as partners in reactions with compounds containing a C–N multiple bond that lead to 1,2,4-triazoles. Arylsubstituted hydrazonyl chlorides 152 reacted with cycloalkanone oximes 153 to give 1,2,4-triazolospiro compounds 154 (Scheme 12.49) [205]. Intermolecular cyclization of hydrazonyl chlorides 155 with nitriles catalyzed by ytterbium(III) triflate afforded a series of 1,3,5-trisubstituted-1,2,4-triazoles 156 in good yields (Scheme 12.50) [206]. Dipolar cycloadditions between hydrazonyl chlorides 157 and nitriles in aqueous sodium bicarbonate in the presence of a surfactant provided mild conditions for the synthesis of 1-aryl-5-substituted-1,2,4-triazoles 159 via intermediate 158 (Scheme 12.51) [207]. A series of 1,2,4-triazoles have been prepared by oxidative intramolecular cyclization of heterocyclic hydrazones with copper dichloride [208]. Other C–N multiple partners include aryl cyanides [209], amidines [210], and cyanamides [211]. X

X

N NH

R

+

(44-58%)

( )n

Cl 152

N N

Et3N, THF

HON

R

N H

153

( )n 15 4

Scheme 12.49

RCN, Yb(OTf) 3

Cl Ph

N

NHPh (Ar)

155

PhCl

N R

(70-85%) R = Me, Ph, Ar

Ph

N N Ph (Ar) 156

Scheme 12.50

MeO2 C HN

N

Cl CO 2Me

5% aq. NaHCO 3 THAC, 25 ºC

R

1

157

Scheme 12.51

N

N 2

R1

R CN N N

CO2 Me

158 R 1 = H, Me R 2 = CO2Et, CO2 Bn, CCl3

N

(24-95%) R1 159

R2

j 12 Five-Membered Heterocycles with Three Heteroatoms: Triazoles

1022

Aminohydrazones or amidrazones are versatile reagents that can react with various electrophilic carbon compounds to give 1,2,4-triazoles. As an example, N-tosylamidrazones 160 can react either with acid chlorides or with ethyl chloroformate to give tosylated 1,2,4-triazoles 161 or 1,2,4-triazole-3-ones 162, respectively (Scheme 12.52) [212]. Other amidrazone reactions can occur with carboxylic acids [213], cyanogen bromide [214], aldehydes [215], and orthoesters [215, 216]. Amidrazones 163 have been oxidized to 1,3,5-trisubstituted 1,2,4-triazoles 164 in good yields by silver carbonate, Dess–Martin periodinane, sodium and calcium hypochlorites, and tetrapropylammonium perruthenate (TPAP)/N-methylmorpholine N-oxide (NMO) combination (Scheme 12.53) [217–219].

N N R1

Ts

CHCl3, 0 ºC

O

N H 162

NNHTs

ClCO2 Et, pyridine R1

(90%)

R 2COCl, pyridine CHCl3, 0 ºC

NH 2 160

N N R1

Ts R2

N

(70-90%)

161

1

1

R = Ph, Bn, i-Pr, 4-MeC 6H 4

R = Ph, Bn, i-Pr, 4-MeC6 H4 R 2 = Me, Bn, i-Pr

Scheme 12.52

R2

NH R1

N 163

NHR

3

R2

[O]

N R1

N

[O]

NHR 3

(45-86%)

[O] = Ag 2CO3 , Dess-Martin periodinane,

N R2

N R3

R1 N

164

NaOCl, Ca(OCl) 2, TPAP/NMO Scheme 12.53

Other hydrazone intermediates have been utilized in the synthesis of 1,2,4triazoles. Addition of primary amines to a-nitrohydrazones 165 followed by addition of sodium nitrite affords 1,3,5-trisubstituted-1,2,4-triazole 166 (Scheme 12.54) [220]. 1,3,-Dipolar cyclocondensation of C-acetyl-N-arylnitrilimines 167 with benzoylhydrazones 168 furnished 1,2,4-triazoles 169 (Scheme 12.55) [221]. Iodobenzene

N Me

NHAr NO 2

165 Scheme 12.54

N

1. RCH 2NH2, ref lux 2. NaNO 2, PhMe, TEBA

R

(52-65%) R = n-C 3H 8, CH=CH 2, CH2 OMe

N Ar 166

Me N

12.3 1,2,4-Triazoles

CH3COC N N Ar

+

167

N R1

O

COPh N H

PhOCHN

THF, 25 ºC

2

R

(44-75%)

R2

1

R = H, Me R2 = Me, Et R1 = R 2 = cycloalkyl

168

Me

N

R1 N Ar 169

N

Scheme 12.55

diacetate or lead tetraacetate cyclization of hydrazones 170 [222] or 172 [223] afforded fused 1,2,4-triazoles 171 and 173, respectively (Scheme 12.56). OMe

OMe PhI(OAc)2 N

N

solid state

NHN=CHAr

N

(74-82%)

170

Ar

H N N

N

PhI(OAc)2 , CH2 Cl2

N

(17-69%) 172

N N

171

Pb(OAc) 4 or NHCOPh

N

N

173

N NHCOPh

Scheme 12.56

12.3.4.3 Reactions of Oxadiazoles or Thiadiazoles 1,2,4-Triazoles can be synthesized from oxadiazoles. Photolysis of 1,2,4-oxadiazoles in the presence of nucleophiles led to 1,2,4-triazole products [224] and 1,3,4oxadiazoles can undergo ring-cleavage with nitrogen nucleophiles followed by recyclization of the intermediates to give 1,2,4-triazoles. For example, the unusual hydrazinolysis of 5-perfluoroalkyl-1,2,4-oxadiazoles 174 provided an expedient route to 5-perfluoroalkyl-1,2,4-triazoles 175 (Scheme 12.57) [225]. Similarly, 3,5bis(trifluoromethyl)-1,3,4-oxadiazole is particularly activated towards nucleophilic

N Rf

O

R N

174 Scheme 12.57

NH2 NH2 MeOH 25 ºC (44-88%)

R

N Rf

N H

N

175

Rf = CF3 , n-C3 H 7, n-C 7H 15 R = Ph, n-C 11 H23

j1023

j 12 Five-Membered Heterocycles with Three Heteroatoms: Triazoles

1024

attack by primary amines to yield 4-substituted-1,2,4-triazoles [226]. Microwaveassisted rate acceleration of reactions between 2-aminothiadiazoles 177 with oxadiazoles 176 on alumina support affords thiadiazolyl-substituted-1,2,4-triazoles 178 (Scheme 12.58) [227]. Photochemistry of some fluorinated oxadiazoles gives rise to mixtures of fluorinated 1,3,4-oxadiazoles and 1,2,4-triazoles [228]. 2-Amino-1,3,4oxadiazoles 179 reacted with alcohols followed by subsequent ring-cleavage and ringcyclization to give 3-alkoxy-1,2,4-triazoles 180 (Scheme 12.59) [229], while amines and hydrazines react with 2-amino-1,3,4-oxadiazoles to afford 3-amino- and 3,5diamino-1,2,4-triazoles, respectively [230]. Condensation of highly reactive chloromethyloxadiazoles with ethylenediamines provides a concise synthesis of [1,2,4] triazolo[4,3-a]piperazines [231]. Reaction of some fluorinated 1,2,4-oxadiazoles in the presence of methylamine or propylamine under photochemical irradiation in methanol or acetonitrile led to the corresponding fluorinated 1-methyl- or 1-propyl1,2,4-triazoles [232]. N N N N R1

+

SH

O

R1

N N R2

176

Alumina

NH 2

S

S

Microwave

R2

(77-93%)

177

R1 = R2 = alkyl

SH

N N N 178

Scheme 12.58

NH2

O R1

N

R2 OH

N

R1 HN

O

NH2

N

-H2 O

OR

2

(38-100%)

179

N R1

N H

OR2 N

180

Scheme 12.59

12.3.4.4 Synthesis of 1,2,4-Triazoles from Thioureas, Thiocyanates, and Thioamides Unsaturated and saturated thio compounds have been employed in the syntheses of 1,2,4-triazoles. D2-1,2,4-Triazolin-5-ones 182 have been prepared from 1-aryl/alkyl-6phenyl-2-thiobioureas 181 in the presence of benzyl chloride and aqueous ethanol (Scheme 12.60) [233]. A novel one-pot synthesis of 1,2,4-triazole-3,5-diamine derivatives 184 and 185 from isothiocyanates 183 and monosubstituted hydrazines has O PhHN

N H

H N

181 Scheme 12.60

NHR S

R

BnCl aq. EtOH

O

N BnS

N

NH

182

12.3 1,2,4-Triazoles

j1025

been reported; derivatives 185 were obtained with higher regioselectivity when aromatic and sterically bulky hydrazines were used (Scheme 12.61) [234]. S-Ethyl thioamides 186 react with acyl hydrazides 187 in refluxing n-butanol to give 3,4,5trisubstituted 4H-1,2,4-triazoles 188 (Scheme 12.62) [235]. An efficient synthesis of substituted 1,2,4-triazoles involved condensation of benzoyl hydrazides with thioamides under microwave irradiation [236]. 3-N,N-Dialkylamino-1,2,4-triazoles 191 have been synthesized from S-methylisothioureas 189 and acyl hydrazides 190 in moderate to good yields (Scheme 12.63) [237].

1. NaNHCN, DMF, 25 ºC

R 1NCS

N

2. R 2 NHNH 2, EDC, Et 3N, 60 ºC

183

NHR 1

H 2N

N R2 184

(42-90%, 3:1 to 20:1 ratio) R 1 = Ph, CH3 CH 2 CH 2 R 2 = t -Bu, Ph, nC6H11, Ar

N

+

NHR1

N H 2N

N

N R2

185

Scheme 12.61

O N

N

+

R

R NHNH2

X

SEt

reflux (52-73%)

18 7

186

n-BuOH

R = Me, i-Bu, Ar X = CH, N

N

X

N N

N

1 88

Scheme 12.62

R1

SMe N R2

N

R3

189

THF/HOAc

O +

H 2N

N H 190

R4

(10:1) reflux (33-72%)

R3

N

R4

N

R2 N R1 N

191

R1 = R2 = piperidinyl derivatives R3 = Ar, CH 2Ar, pyridyl

R4 = Me, CH 2NHBoc,

CH2 Ar, CH 2OMe

Scheme 12.63

Combinatorial solid-phase reactions have been used in the synthesis of libraries of 1,2,4-triazole compounds. Reaction of resin bound S-methyl-N-acylisothioureas 192 with hydrazines followed by acidic cleavage yielded 3-amino-1,2,4-triazoles 193 under mild conditions (Scheme 12.64) [238]. 3,4,5-Trisubstituted 1,2,4-triazoles 195 have been synthesized on solid-phase from various thioamides 194 and hydrazides, leading to peptidomimetic scaffolds (Scheme 12.65) [239]. A robust “catch,

j 12 Five-Membered Heterocycles with Three Heteroatoms: Triazoles

1026

O O

SMe O N

1. R2 NHNH 2 , DMF, 40 ºC

R1

N H

2. TFA/CH 2Cl2 (1:1)

R1

N N R2 193

R2 N

R3

(62-75%)

192

NH2

N

1

R = alkyl, CH2 Ar R2 = H, Ph

Scheme 12.64

1. NH 2 NHCOR3 , O O

R1 N H

H N S

Hg(OAc)2 , DMF

R1

2. TFA, CH 2Cl2,

R2

N

H2 O, i-Pr 3 SiH

N

H 2N (31-80%) 195 R 1 = Bn, i-Bu, indol-3-yl-methyl R 2 = Bn, CH2 CHPh2 , indol-3-yl-methyl R 3 = H, Ph, Bn

194

Scheme 12.65

cyclize, and release” preparation of 3-thioalkyl-1,2,4-triazoles mediated by the polymer-bound base P-BEMP has been described [240]. 12.3.4.5 Reactions of Semicarbazides A couple of reports present the use of semicarbazides in the synthesis of 1,2,4triazolones. Condensation of semicarbazide hydrochloride 196 with orthoester 197 resultedina simple synthesisof chlorotriazolinone 198 (Scheme 12.66), and themethod was applied to the convergent synthesis of an NK1 antagonist [241]. Amines have been converted into 1-formyl semicarbazides 199, which were cyclized smoothly to 2,4dihydro-3H-1,2,4-triazolin-3-ones 200 with hexamethyldisilazane (HMDS), bromotrimethylsilane, and a catalytic amount of ammonium sulfate (Scheme 12.67) [242]. H2 N O

Cl NH •HCl NH2

+

MeO

196

OMe

197

3d (98%)

Cl

HN

MeOH, 20 ºC

MeO

O

N H

N

198

Scheme 12.66

phosgene R NH2

CHO HN NH

NH 2NHCHO NaHCO 3 CH 2Cl2 (57-91%)

Scheme 12.67

R NH

O 199

R HMDS, TMSBr (NH 4) 2SO4 (cat) (65-90%)

O

N N

NH

200

12.3 1,2,4-Triazoles

N N

N

R 4NHNH2 N

R 2 R1N

O

201

CHCl3

R3

R3

N R1R 2N

(25-95%)

N 202

N R4

Scheme 12.68

12.3.4.6 Synthesis of 1,2,4-Triazoles via Benzotriazole Methodology Solution- and solid-phase benzotriazole-mediated methodologies are employed in the synthesis of 1,2,4-triazoles. Acyl 1H-benzotriazol-1-carboximidamides 201 and hydrazines have been employed in a general synthesis of N,N-disubstituted 3-amino1,2,4-triazoles 202 (Scheme 12.68) [243]. Polymer-supported N-acyl-1H-benzotriazole-1-carboximidamides 203 reacted with hydrazines followed by acidic cyclizative release to give 3-alkylamino-1,2,4-triazoles 204 (Scheme 12.69) [244]. Reaction of acyl hydrazides 206 with imidoylbenzotriazoles 205 in the presence of catalytic amounts of acetic acid under microwave irradiation afforded 3,4,5-trisubstituted triazoles 207 (Scheme 12.70) [245].

N N 2

R

R1 Bt

1. R 3NHNH 2, DBU, THF 2. TFA, CH 2Cl2 (45-65%)

O 203

N R2

N R3 204

NHR1 N

Scheme 12.69

N N R1

HOAc, microwave N

+ NR2

205

R 1 = Me, Bn, p-Tol

O R3

NHNH 2 206

R 2 = p-Tol, 4-OMeC6 H4 R 3 = Me, Ph, p-tol (77-100%)

R2 N R1

R3 N

N

207

Scheme 12.70

12.3.4.7 Other Synthesis of 1,2,4-Triazoles Three-component condensation of ethyl trifluoroacetate (208), hydrazine, and amidines in the presence of sodium hydroxide gave 3-trifluoromethyl-5-substituted1,2,4-triazoles 209 (Scheme 12.71) [246, 247]. The amidine supplies a C–N bond to the new ring system while the other two nitrogen atoms are derived from hydrazine. Reaction of aromatic nitriles with hydrazine dihydrochloride in the presence of hydrazine hydrate in ethylene glycol under microwave irradiation gave 3,5-disubstituted-4-amino-1,2,4-triazoles 210 (Scheme 12.72) [248]. 1,3-Dipolar cycloadditions

j1027

j 12 Five-Membered Heterocycles with Three Heteroatoms: Triazoles

1028

between poly(ethylene glycol) supported m€ unchnones and diethyl azodicarboxylate led to synthesis of 3,5-disubstituted-1,2,4-triazoles [249]. 1. NH 2NH2 •H2 O, THF, reflux 2.

O F3 C

NH R

OEt

CF3

N N H 209

R

THF, reflux

208

N

NH 2·HCl, NaOH,

(70-95%) Scheme 12.71

H2N

ethylene glycol, NH2NH2 •2HCl NH2NH 2•H 2O, microwave

ArCN

(58-96%)

Ar

Ar

N N

N

210

Scheme 12.72

12.3.5 Reactions of 1,2,4-Triazoles 12.3.5.1 Reactions on the Nitrogen of 1,2,4-Triazoles 12.3.5.1.1 N-Alkylation of 1,2,4-Triazoles 1,2,4-Triazoles that are unsubstituted on nitrogen can be readily alkylated. 1-Substituted-1,2,4-triazoles are the predominant products of these base-catalyzed alkylation reactions; 4-substituted-1,2,4-triazoles are rarely isolated after purification. DBU is found to be a mild and convenient base for the alkylation of 1,2,4-triazole with alkyl halides in the high-yielding syntheses of 1substituted-1,2,4-triazoles 211 (Scheme 12.73) [250]. Sodium hydroxide [251], sodium methoxide [252], and sodium hydride [253] are other bases that have been successfully employed in these reactions. The synthesis of 1,2,4-triazole-functionalized solid-support 212 and its use in the solid-phase synthesis of various N1 and N2 trisubstituted-1,2,4-triazoles 213 has been reported (Scheme 12.74) [254]. 1,2,4-Triazoles can be alkylated at N4 by using a removable protecting group at N1 and then forming a quaternary salt with the 1-substituted triazole. 1-Acetyl and 1-cyanoethyl groups have been used as removable protecting groups [255]. N N H

N

RX, DBU, THF R = Me, CPh 3, Bn (73-100%)

Scheme 12.73

N N N R 211

12.3 1,2,4-Triazoles

R1

R1 N N H O

N

N

1.

R 2X,

N H

NaOH

2. 20%TFA

N

R2

HO

(>95%, 70-90% purity,

212

j1029

2 13

18:82 to 94:6 ratio) Scheme 12.74

The sequence involving quaternization/dealkylation with 1,10 -methylenebis(triazolium) salts 214 linked at the N1 position is shown in Scheme 12.75 [256]. Other similar sequences have also been reported [257]. Alternatively, 3-phenylthio-1,2,4triazoles 215 were alkylated to their triazolium salts 216, which under aqueous basic conditions provided 2,4-disubstituted-1,2,4-triazol-3-ones 217 (Scheme 12.76) [258].

N N H

CH 2Br 2

N

(77%)

N

N

N

N

N N

RX (2 eq) (70-99%)

R N

N

R N

EtOH

N

N N

reflux

R

2X 214

N N H X

Scheme 12.75

R 2X

N PhS

N R1

EtOAc or

N

215

R2 N

CHCl3 or neat 80 ºC 1

R = Me, Et, Bn R 2 = Me, Bn, allyl, Bu

PhS

N R1 216

X N

R2 N

K2 CO 3 water (5-92%)

O

N N R1 217

Scheme 12.76

12.3.5.1.2 N-Acylation of 1,2,4-Triazoles N-Unsubstituted-1,2,4-triazoles can be readily acylated at N1 by common acylating reagents such as acetyl chloride or acetic anhydride under standard conditions to give 1-acyl-1,2,4-triazoles [259]. 1H-1,2, 4-Triazol-3-amines are acetylated first on N1 and then on the 3-amino group [260]. 12.3.5.1.3 N-Arylation of 1,2,4-Triazoles 1,2,4-Triazole can be N-arylated at the 1-position by activated aryl halides such as 1-fluoro-2-nitrobenzene or 1-chloro-2nitro-4-(trifluoromethyl)benzene [261]. N1-Phenylation can be achieved with triphenylbismuth diacetate and copper(II) acetate [262].

N

j 12 Five-Membered Heterocycles with Three Heteroatoms: Triazoles

1030

Recent protocols of copper-catalyzed N-arylations of aryl iodides with 1,2,4triazoles represent a new landmark in the field of Ullmann-type arylation couplings of nitrogen-containing heterocycles. The aryl iodides 218 reacted efficiently and regioselectively at the N1 position with 1,2,4-triazole in the presence of copper(I) iodide and trans-diamine ligand 219, with potassium phosphate as a base, to give 220 (Scheme 12.77) [117]. Another similar procedure employs copper(I) oxide, Chxn-PyAl as the ligand, and cesium carbonate as the base [263]. However, these procedures are limited to aryl iodides; aryl bromides and aryl chlorides are not efficiently crosscoupled under these conditions. CuI (5 mol%)

N R

I

+

N H

N

ligand 219 (10 mol%) K3 PO 4 (2 equiv)

R

DMF, 110 ºC, 24 h

21 8

N

N N

MeHN 219

22 0

(83-89%)

NHMe

R = H, OMe, Ac Scheme 12.77

12.3.5.2 Reactions on the Carbons of 1,2,4-Triazoles 1,2,4-Triazoles are electron-deficient aromatic systems and so conventional electrophilic substitution reactions are not a practical method for the introduction of carbon substituents at C3 or C5. The most common methods for introduction of groups to C3 or C5 are by triazolyllithium intermediates or more recently by radical or carbene species. 12.3.5.2.1 C-Substitution by Triazolyllithium Hydrogen–metal exchange by n-butyllithium can occur at C5 if N1 is substituted to give organolithium species, which then react quickly with alkylating agents or with other electrophiles (Scheme 12.78) [264]. If the N1 is a removable protecting group, then monosubstituted 1,2,4-triazoles can be prepared by this method [264b,264c]. 1-(Methoxymethyl)-1H-1,2,4-triazole is converted directly into 5-acyl derivatives by reaction with acyl chlorides and triethylamine and the methoxymethyl protecting group could be removed in a subsequent step [265].

N N R1

N

n-BuLi, THF

N Li

N 1 R

N

R2X or R2COCl

N 2

R (R2CO)

N R1

N

Scheme 12.78

Methods are available for preparation of 3-substituted-1,2,4-triazoles. A C5 removable group such as a phenylthio is employed in a protection/deprotection sequence to give 1-substituted 3-acyl-1,2,4-triazoles 221 (Scheme 12.79) [266]. 1H-1,2,4- and

12.3 1,2,4-Triazoles

n-BuLi, PhSSPh

N

THF

N N Me

(97%)

N PhS

R

1. LiTMP, RCONMe 2 (35-67%)

N N Me

2. RaNi (31-52%)

N

O

N N Me 221

Scheme 12.79

1-methyl-1H-1,2,4-triazoles have been transformed directly into their 3(5)-arylcarbamyoyl derivatives by heating with aryl isocyanates [267]. These C-acylations are suggested to proceed by formation of N-acylated triazoles, followed by thermal rearrangements. 12.3.5.2.2 Radical Reactions of 1,2,4-Triazoles Reaction of 1-N-alkyl triazoles 222 with an alkyl radical generated from the corresponding secondary carboxylic acid in the presence of silver nitrate affords the triazole ring 223 alkylated selectively in the 5-position (Scheme 12.80) [268]. N N R1

N

R 2CO2H, AgNO 3 (NH 4) 2S2 O8 , TFA, H 2O (35-60%)

N

222

R2

N R1

N

223

Scheme 12.80

12.3.5.2.3 Carbene Reactions of 1,2,4-Triazoles There are two published reports on the syntheses of stable 1,2,4-triazolyl carbenes. Thermal decomposition in vacuo of 5-methoxytriazoline 224 provided in quantitative yield 1,2,4-triazol-5-ylidene 225, a stable carbene in the absence of oxygen and moisture (Scheme 12.81) [269]. Nucleophilic carbene 225 could react with various alcohols, thiols, amines, oxygen, sulfur, selenium, isocyanantes, and metal carbonyls to form a myriad of addition products. Reactions of 1,2,4-triazolyl perchlorate salts 226 with base afforded stable nucleophilic 1,2,4-triazol-5-ylidenes 227, which could react with acetonitrile and elemental sulfur and selenium to yield addition products (Scheme 12.82) [270]. Ph N N Ph

N Ph

Ph N N

90 ºC OMe

224 Scheme 12.81

0.01 mbar neat

Ph

N Ph 225

j1031

j 12 Five-Membered Heterocycles with Three Heteroatoms: Triazoles

1032

Ad N N

ClO4

N R2

R1

KOt-Bu, PhH

Ad N N

or H

2 26

NaH (60%), CH 3 CN R1

R1 = Ph, 4-BrC 6H 4 R2 = Ph, 4-BrC 6H 4 Ad = 1-adamantyl

N R2 2 27

Scheme 12.82

12.3.5.2.4 Halogenations of 1,2,4-Triazoles Most halogenation reactions of 1,2, 4-triazoles are N-chlorotriazoles, kinetic products that rearranges to 3-halo-1,2,4triazoles slowly upon storage or heating in water [271]. 5-Chloro derivatives of 1-substituted-1,2,4-triazoles have been obtained by C5-lithio derivatives [272]. C-Halo-1,2,4-triazoles can be prepared more directly without isolation of the Nhalo-1,2,4-triazoles. For example, bromination of 1H-1,2,4-triazole in excess aqueous sodium hydroxide afforded 3,5-dibromo-1H-1,2,4-triazole (228), which selectively exchanges a bromine with a fluorine to give 229 (Scheme 12.83) [273]. 1. Br 2, 50% aq NaOH,

N N H

CH2Cl2, H 2O, -15 °C

N

2. cHCl (90%)

Br

N Br

CsF, DMSO

N

N H

(70%)

Br

N F

N H

N

229

228

Scheme 12.83

12.3.5.2.5 Other Reactions of 1,2,4-Triazoles Urazoles 230 can be converted into the corresponding 1,2,4-triazol-3,5-diones 231 by various oxidizing reagents (Table 12.17). Trichloroisocyanuric acid [274], a silica gel/sodium nitrite combination [275], an ionic complex, obtained from N2O4 and 18-crown-6 [276], Oxone/ Table 12.17 Dehydrogenation of urazoles to 1,2,4-triazol-3,5-diones with various oxidants.

R O

O N N H

R

Conditions NH

230

O

O N N

N

231

Conditions

Reference

Trichloroisocyanuric acid Silica gel/NaNO2 N2O4/18-crown-6 Oxone/NaNO2/wet silica gel Silica sulfuric acid/NaNO2

[274] [275] [276] [277] [278]

12.3 1,2,4-Triazoles

j1033

sodium nitrite in the presence of wet silica [277], and silica sulfuric acid/sodium nitrite [278] have all been reported as oxidants in this reaction. 1,2,4-Triazoline-3,5-dione 233 underwent an ene reaction with olefins 232 to yield trialkylated allylic urazoles 234, which were further elaborated into allylic amines 235 (Scheme 12.84) [279]. 1-Methyl-1,2,4-triazole 236 participated in a palladium-catalyzed C–H arylation reaction with 3,5-dimethoxychlorobenzene (237) to give coupled product 238 (Scheme 12.85) [280].

HN NH R3

R4 R5

R2 R1

O

N

R3 R2 N NH

R4

O

5

R

Me 233

R1

CH 2Cl2, 20 ºC

O

234

232

N Me

1. NaH 2. BrCH 2COPh O

R3

R4 R5

3. aq. KOH

R2 NH 2

R1 235

(40-68%)

Scheme 12.84

Cl

N N N Me

N

MeO

N N Me

Pd(OAc) 2 (5 mol%), BuAd2 P (10 mol%)

+ MeO

236

OMe

K3PO 4 (2 equiv), NMP, 125 °C

237

(76%)

MeO

238

Scheme 12.85

12.3.6 1,2,4-Triazole-Containing Reagents

Monocyclic 1,2,4-triazole-containing structures have found synthetic utility. For example, 4-phenyl-1,2,4-triazole-3,5-dione (239) was found to be a novel and reusable reagent for the aromatization of 1,4-dihydropyridines under mild conditions [281] and to be an efficient and chemoselective reagent for the oxidation of thiols to their corresponding symmetrical disulfides [282]. N-4-(p-Chloro)phenyl-1,2,4-triazole-3,5dione 240 has been used as an effective oxidizing agent for the oxidation of 1,3,5trisubstituted pyrazolines to their corresponding pyrazoles under mild conditions at room temperature [283]. 1-Benzylsulfanyl-1,2,4-triazole (241) is a useful electrophilic sulfur source in the organocatalyzed a-sulfenylation of aldehydes [284]. Catalyst 242 catalyzed the oxidation of allylic alcohols to allylic esters with manganese(IV) oxide in excellent yields [285] and the oxidation of unactivated aldehydes to esters with manganese(IV) oxide in excellent yields [286]. The asymmetric synthesis of hydrobenzofuranones via desymmetrization of cyclohexadienones using the intramolecular Stetter reaction has been accomplished with 1,2,4-triazolium salt catalyst 243 [287].

j 12 Five-Membered Heterocycles with Three Heteroatoms: Triazoles

1034

N N O

N

O

N R

N

239 R = Ph

N S

241

240 R = 4-ClC 6H 4

Me N Ph

N N Me 242

I

Me N N PF6 P N N N NO2 Me N 243

1,2,4-Triazolium salt catalysts 244 and 246 have been employed in the highly enantioselective azadiene Diels–Alder reactions [288]. Chiral catalyst 245 promoted the intramolecular Stetter cyclization of an aldehyde onto a vinylphosphine oxide or vinylphosphonate Michael acceptor [289]. Chiral triazolium salt 246 has been employed successfully in the hetero Diels–Alder reactions of a-chloroaldehyde bisulfite adducts with various oxodienes under biphasic reaction conditions with high levels of enantioselectivity [290] and in the highly enantioselective cis-cyclopentene-forming annulation reactions [291]. O N

N X N R

244 R = 4-OMeC 6H 4 , X = BF4 245 R = C6 F5 , X = BF4 246 R = Mes, X = Cl

Bicyclic 1,2,4-triazolium salts have varied synthetic utility in a host of reactions. 1,2,4-Triazolium salts 247 have been identified as a new family of stable annulated Nheterocyclic carebenes that found applications in catalytic benzoin condensations and transesterifications at ambient temperature [292]. N-Pentafluorophenyl triazolium tetrafluoroborate salts 248 were found to be useful catalysts in the macrocyclization of a,v-dialdehydes to a-hydroxyketones [293] and in the synthesis of 1,2amino alcohols via azidation of epoxy aldehydes (where modest asymmetric induction was achieved) [294]. N-Pentafluorophenyl triazolium tetrafluoroborate salt 249 was found to be useful catalyst in the asymmetric intermolecular Stetter reaction of glyoxamides with alkylidenemalonates [295]. Chiral catalyst 250 has been utilized in the N-heterocyclic carbene-catalyzed redox amidations of a-functionalized aldehydes with amines [296]. The N-heterocyclic catalyst 251 promoted O to C carboxyl transfer on a range of indolyl and benzofuranyl carbonates [297] and also promoted the formal [2 þ 2] cycloaddition of ketenes with N-tosyl imines to give the corresponding b-lactams [298]. Chiral triazolium catalyst 252 has been found to be efficient in the formal [2 þ 2] cycloaddition reactions of alkyl(aryl)ketenes with 2-oxoaldehydes to afford b-lactones with a-quaternary-b-tertiary stereocenters in high yields with good diastereoselectivities and excellent enantioselectivities [299]. The asymmetric Michael addition of aromatic heterocyclic aldehydes to arylidenemalonates catalyzed

References

N N

X N

R R2

R1 247 X = BF4 , PF6

Me

BF4 N

N N

C6 F5

Me

Cl N N

N

248 R = H

N Me

250

249 R = Bn

N

j1035

BF4 N R2

R1 251 R1 = H, R2 = Ph 252 R1 = CPh 2OTBS, R2 = Ph

253 R1 = CH 2 OTBDPS, R2 = Bn

by N-heterocyclic carbene 253 has been disclosed [300]. Catalyst 253 was also effective in an intermolecular Stetter reaction to give 1,4-diketones [301].

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20 Lermontov, S.A., Shkavrov, S.V., and

21

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j1047

13 Oxadiazoles Giovanni Romeo and Ugo Chiacchio

13.1 Introduction

There are four isomeric types of oxadiazoles (1–4). N

N

N N

N

N

O

O

1

2

N

N O

O

3

4

Examples of all these ring derivatives are reported; the 1,2,3-oxadiazole system is well represented by the mesoionic sydnones (5, X ¼ O) and sydnonimines (5, X ¼ NR). In fact, potential 1,2,3-oxadiazoles 6 are not known: when formed in some reactions, they isomerize, instantaneously, into the open a-diazoketone tautomeric forms 7 (Figure 13.1). Arguments concerning the existence of 6 and 7 have been summarized [1], but the firmly established 1,2,3-oxadiazole ring system is of the sydnone type. Ring systems of type 2 are commonly termed azoximes and the 1,2,5-oxadiazoles 3 are often referred to by the trivial name furazan, while 1,2,5-oxadiazole-2-oxide, a well-known derivative, has the trivial name furoxan. Notably, 1,2,4-oxadiazoles have received great attention in the pharmaceutical industry. In contrast, 1,3,4-oxadiazoles have recently found extensive application in the field of new materials for the development of electric as well as optical devices. The chemistry of 1,2,3- [2], 1,2,4- [3], 1,2,5- [4], and 1,3,4-oxadiazoles [5] has been widely reported in a series of books and reviews. We refer here to the cited references for general aspects of reactivity of these heterocycles. Particular attention is paid to the literature published after 1995.

Modern Heterocyclic Chemistry, First Edition. Edited by Julio Alvarez-Builla, Juan Jose Vaquero, and José Barluenga. Ó 2011 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2011 by Wiley-VCH Verlag GmbH & Co. KGaA.

j 13 Oxadiazoles

1048

R2 N X

N O

R

R

R1

N

N R

R

N

N

O

O

6

7

5

Figure 13.1 Mesoionic sydnones (5, X ¼ O) and sydnone imines (5, X ¼ NR) are well represented, while potential 1,2,3-oxadiazoles 6 are not known since when formed in some reactions they isomerize instantaneously into the open a-diazoketone tautomeric forms 7.

13.2 1,2,3-Oxadiazoles

These are the least common of the oxadiazole group of heterocycles and the literature relating to them is rather sparse. With a very limited and still not perfectly defined number of exceptions, simple 1,2,3-oxadiazoles 6 are not isolable because they isomerize immediately to the their more stable open-chain tautomers, the a-diazoketones 7. The sterically protected 1,2,3-oxadiazole 8 is the only known oxadiazole, bearing alkyl substituents, which exists in the cyclic form in the crystalline state but as diazoketone in chloroform solution [6]. 1,2,3-Oxadiazoles have been proposed [7] as not-isolated intermediates in the oxidation of alkenes with nitrous oxide: a recent DFT analysis predicts that the reaction consists of two steps, with the formation of 1,2,3-oxadiazole in the first and its decomposition in the second, leading to carbonyl compounds [8] (Scheme 13.1).

N S

N O 8

N N

RCH=CHR + N2O

O

RCH2COR + N2

R R Scheme 13.1

Fusion with an aromatic ring does not stabilize the system. 1,2,3-Benzoxadiazole (9) is more stable as an o-quinone diazide (10$11): the ionization potentials, measured by MS for 10 and 11 and estimated for 9, indicate that the stabilizing influence of the zwitterionic structures is more important than the gain in aromaticity [9, 10].

13.2 1,2,3-Oxadiazoles

N

N N

N N

O

O

N O 9

10

11

Some substituted 1,2,3-benzoxadiazoles have been shown to exist in equilibrium with their open chain tautomers. The relative concentration of the species at the equilibrium is strongly dependent upon solvent and substitution effects: the diazoketone structure is stabilized by hydrogen bonding and polar interactions. The most stable of these compounds is 5,7-di-t-butyl-1,2,3-benzoxadiazole (12) which is 6.3 kJ mol
1 more stable than its diazocyclohexadienone valence isomer 13 in the vapor phase. t-But

t-But

N

N2

N O

O t-But

t-But

12

13

Several examples in the literature report on compounds that have been incorrectly formulated as 1,2,3-oxadiazoles [11]: the previously formulated diazoesters 14 were successively established as non-cyclic 15. N EtO

N

CHCO2 Et N

O

N

14

15

13.2.1 Sydnones and Sydnonimines

The 1,2,3-oxadiazole ring system is present in the stable mesoionic sydnones (5a, X ¼ O and sydnone imines (5b, X ¼ NR). The trivial term “sydnone” comes from the University of Sidney, where the first example of these compounds, the 3-phenylsydnone 16, was synthesized (by Earl and Mackney) by cyclodehydration of N-nitroso-N-phenylglycine with acetic anhydride [12] (Scheme 13.2). Baker and Ollis coined the term mesoionic [13] to describe the structure of such compounds, for which a totally covalent structure cannot be written, and which cannot be represented satisfactorily by any one polar structure. The term was then extended to several compounds that can be depicted only as resonance hybrids of dipolar structures. Structure 17, in which the positive charge is delocalized, can be represented as the summary of three canonical forms 18–20 [14]. The formal positive charge is associated with the ring atoms, and the formal negative charge is associated

j1049

j 13 Oxadiazoles

1050

R2 X

O

R1 N N

5a: X = O 5b: X = NR 1 R 1 = Me, Ph, Bn R 2 = Me, Et, Ph, Bn

O Ph HO 2 C

Ph N N O

Ph HNO2

N H

- H2 O

N HO 2 C

N O

Ac2 O - H2 O 73%

O

Ph N N O 16

Scheme 13.2

with ring atoms or an exocyclic nitrogen or chalcogen atom. X-Ray evidence shows that the valence tautomer 21 should also be considered in discussions of the structure of the sydnones [15]. R2 O

R2

R1 N N O 17

R2 C O

O

N

R1 N O

21

R1 N N O 18

R2 O

R2 O

R1 N N O 19

R1 N N O 20

13.2.2 1,2-3-Oxadiazolines

The partially reduced 4,5-dihydro-1,2,3-oxadiazole system, theoretically assemblable by dipolar cycloaddition of diazoalkanes to carbonyl compounds, has never been detected directly in such reactions, although dihydro-1,2,3-oxadiazoline structures

13.2 1,2,3-Oxadiazoles

j1051

have been proposed in the literature [16]. Ab initio and DFTcalculations indicate that, in the reaction of diazomethane with formaldehyde, the kinetically most favorable cycloadduct is less stable than the reactants and has a lower barrier for nitrogen elimination [17]. Derivative 22 has been postulated as intermediate in the metabolism of some (2-hydroxyethyl)- or (2-haloethyl)nitrosoureas, a class of highly active antitumor agents (Scheme 13.3) [18]. O

H N

ON N

O Cl

H N

N N O

Cl

N N O

Cl

+

N2O

22 Scheme 13.3

One derivative, the salt 23, has been isolated as a crystalline solid [19]. Me N N ClO4 O OH 23

An unambiguous characterization of the so-called “Traube’s oxazomalonic acid,” obtained from the condensation of dimethyl malonate with nitric oxide, has demonstrated that the compound is really an unusual five-membered heterocycle and corresponds to 3-hydroxy-2-carboxysydnone dianion 24 (Scheme 13.4): the synthesis, structure and spectroscopic analysis of the potassium salt and methyl ester have also been reported [20]. MeO NO CH(CO 2Me) 2 MeOH/MeO 2.5 Atm

O

O

N O N

O

O

O

MeOH/MeO O 17%

N O N

O

24

31% Traube's "oxazomalonic" acid Scheme 13.4

The oxidation state represented by an N-oxide lends stability to the 1,2,3-oxadiazole system [21]. Thus, the reaction of diene 25 with nitrosyl chloride afforded 4,4dimethyl-5-(2-methylpropenyl)-D2-1,2,3-oxadiazoline 3-oxide 26, whose structure was confirmed by chemical and spectroscopic data (Scheme 13.5). A wide variety of 1,2,3-oxadiazole 3-oxides, valuable candidates for drug frameworks, have been synthesized by the reaction of nitric oxide with functionalized

j 13 Oxadiazoles

1052

Me Me

NOCl

(CH3)2C=CHCH=C(CH3)2

Me Me O N N O 26 30%

25 Scheme 13.5

alkynyllithium derivatives [22]. A theoretical study [23] indicates that the overall reaction is stepwise and is considered to include two processes. In the first, the nitrogen atom in nitric oxide at first attacks the C1 atom in alkynyllithium to afford the intermediate 27. In the second, another nitric oxide reacts with 27 to produce 28. Then, attack of the oxygen atom at C2 to form a five-membered-ring geometry (29) is followed by addition of water, leading to the final 5-alkyl-1,2,3-oxadiazole 3-oxides 30 (Scheme 13.6). O R

Li

NO - 78 °C

R

N

NO

O Li

R 28

27

N Li N O

R = n-C8H17, Ph, -(CH2)3OBn, -CH2OCH2CCPh CH2N(p-Ts)CH2CHCH2

R

O

N N

H2O

R

O

O

30

N N Li O

29

72-88% Scheme 13.6

The structure of some of the obtained compounds was confirmed by X ray crystallography and spectroscopic data. The isomeric 2-oxide system is present in 32, isolated as a crystalline solid from the reaction of the nitroazo-compounds 31 with bases [24]. As a general process, the intramolecular alkylation of 2-halo- or 2-cyano-substituted nitramines proceeds through an O-alkylation and leads to 4,5-dihydro-1,2,3-oxadiazole 2-oxides 32 (Scheme 13.7) [25]. Recently, a new synthetic approach to functionally substituted 4,5-dihydro-1,2,3oxadiazolo 2-oxides 34 has been described, starting from sulfamic acid derivatives 33 (Scheme 13.8) [26].

13.2 1,2,3-Oxadiazoles

Br

N X

O N O

CO 2 Me Br

42-48%

NO 2

j1053

N 32

31 X = Cl, Br, CN Scheme 13.7

OH HN R SO 3H 33

HNO3 H2SO4 - 30°C

ONO 2 HN NO2

R

R 1) NH3

gas,

Et 2O

O N N O

2) NaOH, MeOH 45- 50 °C

34 26-63%

a: R = H b: R = CH2 OMe c: R = CH 2Cl Scheme 13.8

Stable derivatives of the 1,2,3-oxadiazolidine ring system 35 are unknown. O N N H H 35

13.2.3 Theoretical Aspects

Ab initio theoretical studies and semiempirical MNDO calculations [27], performed on 1,2,3-oxadiazoles, indicate that the heterocycle is too unstable to be isolated and predict a major stability for its tautomer the diazoacetaldehyde. MNDO calculations on substituted 1,2,3-benzoxadiazoles and the isomeric diazocyclohexadienones reach the same conclusion [10]. Ab initio methods have also been used to calculate the geometry and the energy of 4,5-dihydro-1,2,3-oxadiazole (22): the molecule is predicted to be unstable, its most favorable mode of decomposition being a retro 1,3-dipolar addition to diazomethane and formaldehyde [28]. Several theoretical studies have addressed the structure and aromaticity of sydnones [20–34]. Sydnones could be regarded as aromatic because their structures could be represented as cyclic arrays of p-orbitals containing six p-electrons, with four from the C¼N
N system and two from the lone pair on oxygen. However, sydnones are not a delocalized “aromatic” ring system, as confirmed by their chemical reactivity: the reactions of sydnones include both substitutions and additions

j 13 Oxadiazoles

1054

Semiempirical and ab initio calculations provide the same overall description of the bond lengths. The bond from C5 to the exocyclic oxygen atom is essentially a double bond, while the bonds O1
N2, O1
C5, and C4
C5 are approximately single bonds. N2
N3 and N3
C4 are partial double bonds (36). On this basis, these compounds could be regarded as 1,3-dipolar azomethyne imines bearing a conjugative carbonyl group at C5 [29]. O

O 4

R

5 O1 N N 3

R

2

36

O N N

37

X-Ray structural measurements confirm that the exocyclic C
O bond is close in length to that of a normal carbonyl group [35–38]. Therefore, according to the values of the net atomic charges on the ring, determined by semiempirical methods, the resonance structure 37 appears to be the best single representation. The large dipole moments of sydnones (>6 D) are consistent with their strongly polar character and the charge separation shown in structure 37 [29, 36]. Frontier orbital energies and coefficients for sydnones and for some substituted sydnones, performed by the MINDO/3 method, show that the HOMO is a pure p-orbital with a large coefficient on N2 and C4 (Figure 13.2) [29, 33]. On this basis, 1,3dipolar cycloadditions of sydnones to electron-deficient alkenes should be controlled by the HOMO of the sydnone and the LUMO of the dipolarophile. 13.2.4 Structural Aspects

Structural parameters, IR spectra, ionization potentials, relative energies, isomerization barriers, and solvation energies have been calculated for sydnones and for the aromatic benzo-1,2,3-oxadiazole (prevalent tautomer in the gas phase) and zwitterionic 6-diazocyclohexa-2,4-dienone (prevalent tautomer in a polar solvent) molecules. The calculations indicate that unsubstituted 1,2,3-oxadiazole is unstable in all solvents [39].

-0.67 C

N

N + 0.59

HOMO (- 8.48 eV)

-0.44 C

N

C

N

N

HOMO

N -0.56

LUMO (+ 0.37 eV)

C

C

LUMO Z

Figure 13.2 Frontier orbital energies and coefficients for sydnones and for some substituted sydnones show that the HOMO is a pure p-orbital with a large coefficient on N2 and C4.

13.2 1,2,3-Oxadiazoles

13.2.4.1 X-Ray Diffraction Crystal structure data of several sydnones have been reported [34, 40]. The ring is nearly planar and the values for bond lengths are in the range illustrated in structure  38. The exocyclic carbonyl bond length is 1.21 A; the N2
N3 and N3
C4 bonds are somewhat shorter than a single bond, while the only C
C bond present is longer than a double bond. 1.32-1.34 1.39-1.40 1.21-1.22

O

N 1.31-1.32 N O 1.38-1.39

1.39-1.42 38

13.2.4.2 UV and IR Spectra UV and IR spectroscopy have afforded useful information in studies of the equilibrium between 1,2,3-benzoxadiazole and o-quinone diazide structures. The IR spectra of 1,2,3-benzoxadiazoles show absorptions at 1626, 1611, 1464, and 1457 cm
1, whereas the isomeric quinone diazides show strong absorptions at 2090 and 1718 cm
1 [41]. The UV spectrum of 1,2,3-benzoxadiazole in an argon matrix shows maxima at 201, 243, and 289 nm [10]. Carbonyl stretching frequencies of sydnones are in the range 1720–1790 cm
1. Alkylsydnones show a single maximum at 290 nm in the UV spectrum. 13.2.4.3 NMR Spectra The 1 H and 13 C spectra of several sydnones and sydnonimines have been reported [42]. In accord with the dipolar structure 5, the H4 proton resonates upfield in the range 6.2–6.8 ppm. Analogously, for the strong deshielding effect of positively charged N3 atom, the 3-alkyl protons are shifted downfield (4.10–4.40 ppm) with respect to 4-alkyl protons (2.20–2.50 ppm). For 3-methylsydnone, the 14 N and 17 O spectra have also been determined and a complete set of chemical shift values for all the atoms have been reported [45]. The 13 C chemical shifts are reported on structures 39 and 40. 40.4 Me

97.7 N O

O

N

170.7

39

109.8 33.9 NC NC

Ph

N N O 174.2

40

j1055

j 13 Oxadiazoles

1056

According to a synthetic approach that allowed for the independent labeling of the nitrogen atoms (Section 13.2.5.1), the NMR chemical shift for each 15N has been determined unambiguously. 13.2.4.4 Mass Spectra Electron impact mass spectra of the sydnone ring are characterized by the loss of NO (M–30) and CO (M–28) fragments, which can occur consecutively or simultaneously. The fragment M-58 represents generally the base peak and the molecular ion is often distinguishable [44]. Reported CI spectra indicate the same pattern of fragmentation. In the fused sydnone 41, the initial loss of NO is followed by CO, HCN, acetylene, and finally Ph, as the principal fragment ion [45].

O

O

N N

41

13.2.4.5 Other Properties The highly polarized yet neutral electrical character and the high dipolar moments of sydnones have been exploited for the design of technologically interesting thermotropic liquid crystals (LCs) with properties between those of covalent and ionic LC. The molecular design, synthesis, and characterization of the first examples of both classical and non-conventional chiral mesoionic (mesomeric þ ionic) liquid crystals derived from sydnones have been reported (Scheme 13.9) [46, 47].

F

Br

N

F

R

N O

F

B(OH)2

O

F N

R

57-61%

N

O O

HO O O H2N

N

N O

( )n O

O

87-92%

R

O HO

O N

N

N O

( )n O

R

Scheme 13.9

The occurrence of chiral smectic phases in these novel compounds was evidenced by optical microscopy, calorimetry, and X-ray studies.

13.2 1,2,3-Oxadiazoles

A side-chain polysiloxane containing 3-(4-aminophenyl)sydnone moieties at terminal and aliphatic spacer has been prepared and its structure was confirmed by IR and NMR measurements. By introducing sydnone into polysiloxane, the polymer displays a high electrorheological effect due to the increased interaction between sydnone moieties [48]. 13.2.5 Synthesis of 1,2,3-Oxadiazoles

The synthetic approach towards substituted 1,2.3-benzoxadiazoles is based on the synthesis of the tautomeric open-chain 6-diazo-1,2-cyclohexadienones [49, 50]. Thus, the diazotization of 2-aminophenols by treatment with sodium nitrite or isoamyl nitrite, followed by careful neutralization with potassium carbonate, afforded the diazoketones (Scheme 13.10), which is in equilibrium with the cyclic tautomer benzoxadiazole (42) (Section 13.2). An alternative route exploited the reaction of a substituted o-benzoquinone with tosyl hydrazine [43]. Naphthoxadiazole (43), stable in the solid state at
19  C, has been prepared according to this synthetic route.

NH2 R OH

1. NaNO 2 , HCl 2. K2CO 3 N2

19-56%

N

R

N

R O

O O

42

1. TsNHNH 2

R O

2. Al 2O3 28-65%

N R = Me, OMe, NO 2, CF 3

N O 43

Scheme 13.10

13.2.5.1 Sydnones and Sydnonimines Despite extensive studies of the sydnone ring, practically only one general synthetic entry is available [51]. The method involves (a) nitrosation of amino acids to give 44; (b) formation of a mixed anhydride 45 and (c) cyclization to the sydnone ring 46 (Scheme 13.11). The nitrosation step has been carried out under neutral conditions, using isoamyl nitrite. Among the dehydrating agents, trifluoroacetic anhydride gives the most rapid

j1057

j 13 Oxadiazoles

1058

O

H N R1

OH

2

R OH

R2

23-63%

R1

R N N O

O 72-88%

44

R1 = Me,Et, Ph, Bn R2 = Me,Ph, Bn

OAc

2

R1

1N

R

O N O

23-76%

O

R2 N N O 46

45

Scheme 13.11

results; thionyl chloride, phosphorus oxychloride, phosphoric anhydride, and carbodiimides have also been used successfully. The cyclization step can be aided by ultrasonic irradiation [52, 53]: in this way, functionalized 3-aryl sydnones have been prepared in good yields. A similar general method towards sydnonimines involves the nitrosation of the corresponding a-aminonitriles 47 and cyclization of the intermediate 48 (Scheme 13.12) [54]. Substituents can be introduced at the exocyclic nitrogen atom by normal methods in acidic or buffered solutions: sydnone imines are more stable in acid and less stable in base than sydnones.

Me

H N

O CHMe2 CN

HONO HCl 62%

47

Me

N N

CHMe2 CN 48

dry HCl

Me HN

Me N N O

68% 49

Scheme 13.12

A three-component reaction of the Mannich type has been exploited to prepare 3-Nhydroxy- (50) and3-N-amino- (51)substituted sydnone imines (Scheme13.13) [55–57]. 13.2.5.2 4,5-Dihydro-1,2,3-Oxadiazolines Methods for the synthesis of the few reported compounds of this type have been described in Section 13.2.2. Scheme 13.14 describes the synthesis of 4,5dihyro-3-methyl-1,2,3-oxadiazolium tosylate (52) [58]. Accordingly, 5-alkoxy-substituted derivatives can be prepared by cyclization of 2,2-dialkoxy-N-methyl-Nnitrosoethylamines [59]. 13.2.6 Reactivity of 1,2,3-Oxadiazoles

With the exception of some benzo-fused derivatives and 4,5-dihydro-1,2,3-oxazolidinium salts, the chemistry of the 1,2,3-oxadiazole system is nearly confined to the mesoionic sydnones or sydnonimines.

13.2 1,2,3-Oxadiazoles

RCHO + NH 3 OH + CN

HO

H N

16-92%

R

HONO HO HCl

CN

N O R N CN

63-86%

2

R CHO +

R

R1 N

NH 2

+ CN 17-56%

R

R1 N

CN

R

dry HCl

HN

50

57-82%

R

R1 N O

R = Me, Ph, Bn R 1 = H, Me, Et, Ph R 2 = Me, Et, Ph, Bn

R2 N N

CN

16-72%

R2 H2 N

R N R1 N N O

51 Scheme 13.13

O Me

N N

heat OTs

O

CH2 Cl2

Me N N O

OH N N

23-67%

R2 N H

j1059

TsO

52 83% Scheme 13.14

13.2.6.1 Benzo-1,2,3-Oxadiazoles UV irradiation cleaves the benzoxadiazole ring to 2-diazocyclohexadienones: subsequent loss of nitrogen and Wolff rearrangement leads to ketene 53 (Scheme 13.15) [10]. The formation of 2-naphthol 54 and methyl indene-2-carboxylate 55 by irradiation of naphthoxadiazole 43 is amenable to the loss of nitrogen from the diazocarbonyl tautomer [60]. 13.2.6.2 4,5-Dihydro-1,2,3-Oxadiazoles The known chemistry is limited to 4,5-dihydro-3-methyl-1,2,3-oxadiazolinium salts. The cation reacts with nucleophiles at the methyl group (methylation of the nucleophile) or at C5, with opening of the ring. 13.2.6.3 Sydnones 13.2.6.3.1 General Aspects Sydnones are crystalline compounds that are sensitive to hydrolysis, especially in basic media where they are rapidly cleaved. The ring is also

j 13 Oxadiazoles

1060

.. O 76%

N 43

O

54

OH

N2 N

O

C O

MeOH 62%

53

CO2Me 55

Scheme 13.15

cleaved by catalytic reduction and, oxidatively, by reaction with nitric acid, potassium permanganate, and other oxidants. The chemical reactivity of the sydnone system is displayed in ring cleavage reactions and in processes in which the ring system is retained such as substitution or addition reactions (at the 4-position). Substituents can be introduced into the 4-position by conventional electrophilic substitution or after metallation at C4. Standard transformation of functional groups at C4 of sydnone have also been investigated extensively and targeted to the synthesis of various 4-substituted sydnones. Sydnones can act as 1,3-dipoles in dipolar cycloaddition reactions. 13.2.6.3.2 Ring Cleavage Hydrolysis (Acid and Basic Ring Cleavage) The alkaline hydrolysis of sydnonimines (Scheme 13.16) proceeds through an experimentally ascertained third-order kinetics, and leads to ring cleavage that affords the nitrosonitrile 56 [61]. 1

R

R N N

HN

O

OH 13-46%

R

R1

N CN

N O

56 R = Me, Ph 1

R = Me, Et, Bn Scheme 13.16

Acidhydrolysisofsydnones,whichoccursatelevatedtemperatures,hasbeenexploited as a synthetic path to alkyl- and arylhydrazines (Scheme 13.17) [62–64]. Oxidative Ring Cleavage Ring cleavage of sydnones with oxygen in the dark affords a mixture of products; thus, oxidation of 3-phenylsydnone gives benzaldehyde, benzyl

13.2 1,2,3-Oxadiazoles

R N N O

R1 O

j1061

H RNHNN 2 H2 O 41-59%

R = Ph, Pyridyl R1 = Me, Ph, Bn Scheme 13.17

alcohol, and benzyl formate, while 3-benzyl-4-phenylsydnone affords benzyl phenylglyoxylate, benzyl benzoate, diphenylmethane, benzyl alcohol benzaldehyde, and benzoic acid (Scheme 13.18) [65]. Ph O

Ph

N

O

O

N

O2

Ph

O

O O + Ph

O

+ PhCH 2Ph + PHCH 2OH + PhCHO + PhCO 2H Ph

Ph 8.3%

29%

1.6%

3.4%

3.4%

Scheme 13.18

The proposed mechanism, which implies radical intermediates, arises from an initial electron-transfer reaction of the sydnone with oxygen. Recombination of the radical ion with . O2
would lead to the hydroxyperoxy zwitterion 57, which could then cyclize at the 3- or 2-position to give 58 and 59, respectively. Further collapse of 58 and 59 afforded the obtained mixtures of compounds (Scheme 13.19). Oxidation with ozone of 4-methylsydnones leads to pyruvate esters (Scheme 13.20) [66]. Thermal and Photochemical Ring Cleavage Thermochemical and photoinduced decomposition of sydnones give different products as a function of the nature of substituents present in the ring. 3,4-Diarylsydnones lose carbon dioxide by UV irradiation or by flash photolysis and give transient nitrile imines, which can be intercepted by external or internal dipolarophiles [67, 68]. For example, the photochemically induced reaction of 3,4diphenylsydnone affords, in the presence of DMAD, the dimethyl 2,5-diphenylpyrazole-3,4,dicarboxylate (61) (Scheme 13.21), which originates from the loss of CO2 and the addition of the dipolarophile to the dipolar intermediate 60 (Scheme 13.21) [69]. In the thermochemically induced process, the addition of DMAD occurred first to give 62, followed by elimination of carbon dioxide to form the dimethyl 1,5diphenylpyrazole-3,4-dicarboxylate 63. Alkenes and other trapping agents have been used to capture the dipolar nitrilimine [70–72]. When 1,3-butadiene was used as a dipolarophile, 1,3-diphenyl-5-vinylpyrazole (64) was obtained, so confirming that 60 is the trapped fragment (Scheme 13.22) [73].

54%

j 13 Oxadiazoles

1062

Ph

Ph

Ph

Ph

N N O

N N O2 O O

O

+

Ph O

O O O

O N N O

Ph

57

Ph

N N OCOPh

Ph

NO N

N Ph

CH2Ph Ph O

O O N O

O

Ph O O N N O O 58

Ph

N O

Ph

N

O

COCOPh

59

PhCHO + PhCH2OCOCOPh

PhCH2Ph + PhCH2OCOPh

Scheme 13.19

Ph Me O

N N O

Ph

O3

N N OCOMe

- N2

Ph

O O COMe 16%

Scheme 13.20

O O Ph

Ph C N NPh hν Ph C N NPh

O

Ph N N O

∆ DMAD

Ph MeO2C

Ph N N CO2Me

60 62 DMAD - CO2 Ph MeO2C

N N Ph MeO2C 61 47%

Scheme 13.21

MeO2C MeO2C

N N Ph Ph 63 98%

13.2 1,2,3-Oxadiazoles

j1063

Ph Ph O

Ph

Ph C N NPh

hν

N N O

N N Ph

58%

Ph C N NPh

64

60 Scheme 13.22

3-Aryl-4-[2-(2-vinylphenyl)ethenyl]sydnones undergo fast isomerization to the trans isomer and competitive photolysis of the sydnone moiety, giving the corresponding nitrile imine, which cannot react intramolecularly. In the presence of acrolein, a [3 þ 2] cycloaddition takes place to give the trans-styrylpyrazoline derivative 65, which during isolation aromatizes to the pyrazoles 66 and 67 (Scheme 13.23) [74].

Ar Ar

Ar

N N N N O

N N

hν

CHO

- CO2 CHO

O

65

Ar = Ph, Tolyl Ar N N

Ar CHO

66 10%

N N

67 30%

Scheme 13.23

Nitrile imines have not been detected from 3-arylsydnones unsubstituted at C4; ESR techniques have, however, revealed the presence of the radical species 68, which originates from the photolysis of 3-phenylsydnone [75]. Nitrile imines have also been claimed as intermediates in the formation of triazole derivatives by photochemical decomposition of a sydnone in dioxane. By labeling the nitrogen atoms in 69, the mechanism for the formation of the triazole 71, based on 70 as key intermediate, has been supported (Scheme 13.24) [76]. The photosensitized oxidation of sydnones with singlet oxygen has also been reported to give a mixture of products. In the presence of Rose Bengal as a sensitizer, singlet oxygen adds to a sydnone as a dipolarophile. The identification of benzoic acid and dibenzoylphenylhydrazine among the reaction products has been rationalized on the basis of two simultaneous reaction pathways (Scheme 13.25) [77].

j 13 Oxadiazoles

1064

Ph

N

N O

N

Ph

68 Ph Ph O

N 15 N O 69

Ph

hν

Ph

Ph C N NPh 15

NPh N15 15 N N Ph

70

45%

Ph – PhN

–

PhNH2

Ph +

15 N

N15 N Ph 71

Scheme 13.24

Ph Ph N N O 69

O

Ph

Ph hν O2 , Sens.

O O

N O N O

Ph

- CO2

O O

N Ph N

Ph N N OCOPh

H N

Ph O

44%

N

Ph

COPh

PhCO 2 H 10%

Scheme 13.25

Several sydnones develop a color when irradiated by UV light; for instance, a blue color has been observed by irradiation of the 3-(3-pyridyl)sydnone. The phenomenon has been explained through the formation of diketene 72, which has been identified as the blue species [78].

13.2 1,2,3-Oxadiazoles

C N

O

NO

N 72

13.2.6.3.3 Nucleophilic Substitution at C4 Replacement reactions at C4 in sydnones have been reviewed. Butyllithium has been exploited to displace the bromine atom from a 3-phenylsydnone [46b]: the resulting organometallic compound has been carbonylated, added to ketones and converted into a silyl derivative [79]. Grignard compounds have also been prepared from 3-bromosydnones, and subsequently reacted with ketones to give the corresponding alcohols (Table 13.1) [80]. Metallation reactions have been exploited as a synthetic tool for effecting electrophilic substitution at C4 (Section 13.2.6.3.4) [81]. 13.2.6.3.4 Electrophilic Substitution at C4 Electrophiles can be directly introduced at C4 in the sydnone ring. Table 13.2 summarizes a series of such reactions reported in literature [82, 83]. With 4-unsubstituted 3-alkyl- or 3-phenylsydnones, substitution occurs only at the electron-rich C4, while when aryl substituents are present at C3 the position of the electrophilic attack depends upon the nature of the aryl group, Exclusive aryl ring nitration occurs with electron donors on the aryl group [84]. Thus, 3-(2-aminophenyl) sydnone is brominated in the benzene ring para to the amino group [85] while the nitration of 3,4-diphenylsydnone affords the 4-nitrophenyl derivative. As further

Table 13.1 Nucleophilic replacement reactions at C4 in sydnones.

X O

N O

Ph

Y

Reagent A

N

O

N O

Ph

Z

N

Reagent B O

N

O

Ph

N

60-84% X

Reagent A

Y

Reagent B

Z

Br, H

BuLi

Li

Br

Mg, ether, MeI

MgBr

SMe

H2O2

SO2Me

CO2 COCl2 MeCOCHMe2 I2 Ac2O RCHO NaBH4

COOH (CO)1/2 MeC(OH)CHMe2 I COMe CH(OH)R H

j1065

j 13 Oxadiazoles

1066

Table 13.2 Electrophilic replacement reactions at C4 in sydnones.

Ph N O

O

Ph

Y

N

80-90%

N O

O

N

Reagent

Y

(a) Br2, ether, NaHCO3 (b) HONO2 þ HOSO3H, O  C (c) SO3 (dioxane) (d) ClSO3H þ H3PO4 (e) Ac2O þ BF3 (ether) (f) HCONMe2 þ POCl3 (g) Hg(OAc)2 (h) DMSO þ AcCl

Br NO2 SO3H SO2Cl COMe CHO HgOAc SMe

examples, the sydnone ring is brominated in preference to a pyrazolyl system at C3, while nitration of 3-methyl-4-phenyl sydnone affords the 4-nitrophenyl substituted derivative. Intramolecular electrophilic substitutions at C4 provide a route to fused sydnones such as 73 [86] and 74 [87].

ArHN O

N

HN

O N N O

N N O

O

73

74

Electrophiles have also been introduced at the 4-position through organometallic derivatives. 4-Lithio intermediates [46b] (Section 13.2.6.3.3) have been used to introduce several S, Se, and Te electrophiles [88, 89], and also formyl or acetyl substituents (Scheme 13.26) [90]. This strategy has been exploited for the synthesis of 3-amino-4-benzoylsydnone (75), the first example of a sydnone containing an amino group at C3 [91].

N O

H N

ON

O

Ph a. 2 BuLi b. PhCOCl 76%

Ph O

O

H N

N N

O

Ph NBS 85%

Ph O

O

Ph

Ph N N N

HCl

O

87% O

O

NH2 N N 75

Scheme 13.26

13.2 1,2,3-Oxadiazoles

j1067

Vinyl and aryl substituents at C4 have been introduced by means of other organometallic species. Thus, the reaction of 4-lithio-3-phenylsydnone with copper(I) bromide affords the stable copper derivative 76, which gives palladium (0)-catalyzed coupling to iodobenzenes and vinyl bromides [92]. The reaction of the lithium intermediate with copper(II) bromide leads to the dimer 77 (Scheme 13.27). Ph

N O

O

Cu

a. BuLi

N

b. CuBr

O

N O

Ph

Ph

BrCH=CHPh

N

Ph

N

Pd(Ph3)4

O

O

N

86%

76 CuBr2

O Ph O N N

ClHg

N N O

O

N O

Ph O

Br(PPh3)2M

Ph

N

O

M=Pd, Pt Scheme 13.27

Various 4-arylethynyl sydnones have been prepared in good yields by the reaction of 4-bromo-3-phenylsydnone with aryl acetylenes under palladium catalysis [93]. Chloromercuro derivatives 78 have also been used in Heck coupling reactions with vinyl halides, and sydnones with platinum or palladium substituents 79 have been prepared from 4-bromo-3-phenylsydnone and M(PPh)3 [94]. 13.2.6.3.5 Reactions of Substituents Standard transformations occur in various functional groups present on the sydnone ring. Thus, 3-phenylsydnone-4-carboxylic acids can be easily converted into the corresponding esters, amides, and hydrazides; tertiary alcohols can be dehydrated to alkenes and ketones can be condensed with benzaldehyde. Aldehyde 80 can be converted into the corresponding (E)- and (Z)alkenes by a Wittig reaction (Scheme 13.28) [95].

OHC N O

O

Me

N

80

Ar +

ArCH2 PPh 3

DMSO

Br

NaH

N O

O

Me

N

56-90% Scheme 13.28

O

N

79

78

77

N

Ph

j 13 Oxadiazoles

1068

Sydnonyl-substituted a,b-unsaturated ketones have been synthesized by Claisen–Schmidt condensation of 4-acetyl-3-arylsydnones with aryl aldehydes. An easy, eco-friendly synthetic version has also been reported that involves grinding 4acetyl-3-aylsydnones with aryl aldehydes in a mortar [96]. Further reaction of sydnonyl-substituted a,b-unsaturated ketones with hydrazine hydrate afforded sydnonyl-substituted pyrazolines 81, which possess useful applications in medicine (Scheme 13.29) [97].

H R1

R

O N N O

NH2-NH 2. H 2O

H

N N O

22-76%

O

H N

N

R1

R

O

81

R = Me, Et, Ph, Bn R 1 = Me, OMe, NO 2 Scheme 13.29

Moreover, the reaction of 3-aryl-2-bromo-1-sydnonylpropenones with 3-arylaminomethyl-4-amino-5-mercapto-1,2,4-triazoles gives 3-arylaminomethyl-6-(3-arylsydnon-4-yl)-8-aryl-1,2,4-triazolo[3,4-b][1,3,4]thiadiazepines 82 with antibacterial activity (Scheme 13.30) [98].

R

R1 O

N

N O

R

Ar O

Br 23-67%

+ N N HS

N NH2

Ar

N

S

N N N N O

N NH

O 82

H N R1

R = Me, OMe, CF3 R1 = Me, OMe, NO2

Scheme 13.30

4-Aryl-3-formylsydnones can be easily converted into their oximes, from which other functionalized sydnones such as the nitrile 83 [99] and the nitrile oxide 84 [100] can be obtained.

13.2 1,2,3-Oxadiazoles

O N

N Ar

Ar

N O

O

N

N

O

O

83

N

84

The reaction of 3-aryl-4-carbohydroximic acid chlorides with hydrazine hydrate gives hydrazino(3-arylsydnon-4-yl)methanone oximes, which by reaction with aldehydes are good precursors of 4-triazolyl-sydnones (85, Scheme 13.31) [101].

Cl Ar

N N O

N

H2NHN

OH .

NH2-NH2 H2O

Ar

O

Ar = Ph, Tolyl, MeOC6H4, EtOC6H4 R = C5H11, C6H13, C6H11, Ph, Tolyl, 4-ClC6H4, 2-furyl, 2-thienyl

N

N N O

36-88%

OH

O

RCHO N NH

Ar

N N O

N

R

O 85

Scheme 13.31

4-Formylsydnones undergo reduction, Claisen condensation with acetophenone, and condensation with nitroalkanes and active methylene compounds. Thus, the Knoevenagel reaction of 3-aryl-4-formylsydnones affords multifunctional derivatives [102]. 3-Aryl-4-formylsydnone-40 -phenyl-thiosemicarbazones and 30 aryl-4-formylthiosemicarbazones 86 react with ethyl chloroacetates, ethyl 2-chloroacetoacetate, and 2-bromoacetophenone to produce heterocyclic substituted sydnone derivatives 87a–c that possess 4-oxo-thiazolidine and thiazoline groups (Scheme 13.32) [103]. The antioxidant activity of the synthesized compounds was evaluated. Among these compounds, 4-methyl-2-[(3-arylsydnon-4-yl-methylene)hydrazono]-2,3-dihydro-thiazole-5-carboxylic acid ethyl ester and 4-phenyl-2-[(3-arylsydnon-4-yl-methylene) hydrazono]-2,3-dihydro-thiazoles exhibit potent DPPH (1,1-diphenyl-2-picrylhydrazyl) radical scavenging activity, comparable to that of vitamin E. A suitable substituent at C4 can be used as a temporary blocking group to allow reaction to take place at another side of the sydnone. For example, 4-acetyl-

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j 13 Oxadiazoles

1070

O Cl

O

Ar

H N

N N O

O

S N H

86

O

N

O

S N R

O

87a

O

O

H

Ar

OC2H5 Cl 80°, 20-24h 40-47%

NHR

N

N N O

80°, 27-35h 52-68% O

H

Ar

C2H5

N

N N O

N

O

S N R

OC2H5 Me

87b

Br

H

Ar

N N O

0°, 8-19h 48-57%

N

N

O

S N R

87c Ar = Ph, Tolyl, MeOC6H4, EtOC6H4

R = Ph, H Scheme 13.32

or 4-formyl-3-phenylsydnones can be nitrated in the aromatic ring (in the meta position) and subsequently the acyl group can be removed under basic conditions. Similarly, a thioether group at C4 can be removed by oxidation to sydnone sulfone and subsequent reduction with sodium borohydride. 13.2.6.3.6 1,3-Dipolar Cycloaddition Reactions Sydnones can be regarded as cyclic azomethine imines and as such they undergo thermal cycloaddition reactions with a range of dipolarophiles. As previously discussed (Section 13.2.6.3.2), on photolysis 3,4-diaryl-sydnones lose carbon dioxide and afford transient nitrile imines, which can be trapped by alkynes to give pyrazole derivatives. Thermal reactions with acetylenic dipolarophiles also lead to pyrazoles by spontaneous loss of carbon dioxide from the cycloadducts. According to this reaction route, a series of 5-halopyrazoles (89) with potential pharmacological activity has been synthesized in good yields by 1,3-dipolar cycloaddition of 4-halogenated sydnones 88 with dimethyl acetylenedicarboxylate (DMAD) (Scheme 13.33) [104]. Me

X N

Me

Me X

O

N

O

88

X = Cl, Br, I Scheme 13.33

DMAD 80-82%

Me

O

N N 89

OMe OMe O

13.2 1,2,3-Oxadiazoles

O

R N N O 90

Z

MeO 2C

CO 2Me

Z

79-90% +

Z

CO 2 Me N R

91 Z = CHO, CH2OH

R = Ph, PhCH 2

+

N

N R

40:60

92

N

93

72:28

Scheme 13.34

With unsymmetrical alkynes 91, the cycloaddition reactions of sydnones 90 rarely show a good regioselectivity (Scheme 13.34) [105]. With monosubstituted alkenes bearing conjugative electron-withdrawing groups, the regioselectivity of the reaction is that predicted by frontier orbital analysis (Figure 13.2), that is, with the carbon bearing the electron-withdrawing group next to nitrogen. The obtained products are usually dihydropyrazoles or pyrazoles formed by oxidation of the intermediate dihydropyrazoles. The unstable species formed by loss of carbon dioxide are also azomethine ylides: thus, in the reaction of 3-phenylsydnone with N-phenylmaleimide, a second dipolar cycloaddition reaction can take place (Scheme 13.35) [106].

O

O -CO2

Ph O

N N O

+

N Ph

N Ph

Ph- N N

O

O

O N Ph O

O Ph N

O N Ph N Ph N O

O 76%

(exo, exo and exo, endo) Scheme 13.35

The tandem 1,3-dipolar cycloaddition between sydnones and 1,5-cyclooctadiene afforded 9,10-diazatetracyclo[6.3.0.0.4,110.5,9]undecanes (Weintraub reaction) [107].

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13.2.7 Important Compounds and Applications

1,2,3-Oxadiazole derivatives show a wide range of biological activities. In particular, two most important and studied compounds are the sydnonimines molsidomine (94) and sydnocarb (95). O N N O

N O

OEt

N O

94

Ar

N N N O

N

NHPh 95

Molsidomine (94), endowed with very low toxicity, has a long-term effect in vasodilation, thus exerting a positive effect in cases of ischemic heart diseases. In combination with the b-blocker propanolol, molsidamine has shown a high efficacy for the treatment of portal hypotension [108]. Molsidomine is also used in treating angina pectoris [109]. The pharmacological activity is correlated to the formation of a metabolite, the N-morpholino-N-nitrosoaminoacetonitrile, which acts as a nitric oxide donor (Scheme 13.36) [110]. O

OH OH

N N

OHOH O OH

HO OH

O HO OH

O O

N

N O

β-galactosidase

NO

Scheme 13.36

Accordingly, to achieve site-specific delivery of nitric oxide (NO), a new class of glycosidase activated NO donors has been developed, in which glucose, galactose, and N-acetylneuraminic acid were covalently coupled to 3-morphorlinosydnonimine, via a carbamate linkage at the anomeric position [111]. The b-glycosides were successfully prepared for these conjugates, while the a-glycosidic compounds were very unstable. The new stable sugar–NO conjugates could release NO in the presence of glycosidases (Scheme 13.37). Such NO prodrugs may be used as enzymeactivated NO donors in biomedical research. With analogous aim, conjugates of cephalosporin with 3-morpholinosydnonimine have been designed and evaluated [112]. The obtained compounds demonstrated promising b-lactamase dependent NO releasing ability.

13.2 1,2,3-Oxadiazoles

R2

R1 OAc

a) O OAc

AcO

R1 OAc

R2

NO 2

R1 OH b)

O OH

AcO

90-92%

j1073

OAc

O

O

R2 HO

28-90%

OH

OAc

R 1 = H, OAc, R 2 = H, OAc

c)

O

H 2N

35-100%

O

N N O N Cl

O

O N N

R1 OH O

O

R2 HO

OH

O

N

N O

a) BnNH 2, THF, rt, 30h; b) p-NO 2 C6 H4 OCOCl, Et 3N, CH2 Cl2, rt, 4.5h; c) pyridine, rt, 12h.

Scheme 13.37

Sydnocarb acts on the central nervous system and has been used as a psychostimulant and an antidepressive. Nitrososydnonimines 96 and 97 showed potent antithrombotic activity [113, 114]. Me

N O N

N N O

O N N Me(H 2C)4 H 2C

96

NO N

NO N

O N N CH 2(CH 2) 4Me

97

A series of derivatives – 98 and 99 – prepared by manipulation of the carboxylic group of 3-(3-carboxyphenyl)- and 3-(3-carboxyphenyl)sydnones, or by Claisen–Schmidt condensation of 3-(4-acetylphenyl)sydnone with aldehydes or malononitrile, showed high antibacterial activity against both Gram-positive and Gram-negative organisms [115]. O

H N R

R1

O O 98

R = H, EtO, Ac, CO 2H, CO2 Et

N N O

O

O N

N H 99

N N O

O

R 1 = Ph, 2-Furyl, 4-Cl-C 6 H4 , 4-NO 2-C6 H4 , 2-Cl-4-NO2-C6 H 3

j 13 Oxadiazoles

1074

NH 2

HN

CO2 H

ON N

CO2 H

O X

NO 2 X

X=

N O

O2 N

X

X CH 3CH2

NO2

NO2

N

N

CH3 CH2 O

N R O2 N

N

N

N O

100 45-76%

N Scheme 13.38

A series of 40 -substituted-30 -nitrophenylsydnones 100 have been synthesized (Scheme 13.38) and evaluated [116, 117] for anticancer activity and it was found that the 40 -chloro, 40 -fluoro and 40 -pyrrolidino compounds significantly enhanced the survival of Sarcoma 180 (S180), Ehrlich carcinoma (Ehrlich), and Fibrous histiocytoma (B10MCII) tumor bearing mice. Many other sydnones have been tested for antioxidant, antimicrobial, antifungal, analgesic, anti-inflammatory, and antipyretic activities [118]. 4-Styrylcarbonyl-3-phenylsydnone derivatives 101 and 102 showed activity similar to that of aspirin, at the same dosage [119]. Ph

N N O

COCH=CH O 101

NO2

Ph

N N O

COCH=CH O 102

13.3 1,2,4-Oxadiazoles

The chemistry of 1,2,4-oxadiazoles 103 has been extensively reported [120]. Research on this class of heterocycles has registered great interest in medicinal chemistry. Many derivatives possess diverse biological activities [121–123]. Some 1,2,4-oxadiazoles can reduce pain and inflammation in rats and mice [124, 125]; for example, N-[3-aryl-1,2,4-oxadiazol-5-yl-methyl]phthalimides have been found to be analgesic, and one of them, namely, N-[3-phenyl-1,2,4-oxadiazol-5-yl-methyl]phthalimide, possesses highly enhanced analgesic activity compared to aspirin [124].

13.3 1,2,4-Oxadiazoles

N O

N

103

Furthermore, the 1,2,4-oxadiazole ring has been exploited as a peptidomimetic, as a stable ester and amide isostere; specific 1,2,4-oxadiazoles have been used as inhibitors in several biological systems [126, 127]. In particular, numerous papers deal with applications of the soluble guanylyl cyclase inhibitor 1H-[1,2,4]-oxadiazole[4,3-a] quinoxalin-1-one (ODQ) (104) and with applications of the neuroexcitatory quisqualic acid (105), the only naturally occurring 1,2,4-oxadiazole known hitherto [128].

O

O N N O N

104

O

HN O

N

NH3 CO2

105

Partially or fully saturated 1,2,4-oxadiazoles (106–109) have also been reported. In particular, 4,5-dihydro-1,2,4-oxadiazoles 106 have been evaluated very little for biological activities compared to 1,2,4-oxadiazoles, but some of them have shown interesting pharmacological results. For example, some are fungicides [129, 130], and other 3,4,5-triaryl-4,5-dihydro-1,2,4-oxadiazoles demonstrated bronchodilator, anticholinergic, hypertensive, analgesic, anti-inflammatory, diuretic, antiulcer, vasodilatatory, and sedative properties [131]. Some 4-adamantyl-5-aryl-3-phenyl-1,2,4oxadiazolines have been evaluated in vitro for antiviral activity against human immunodeficiency virus (HIV), where the 5-phenyl substituent produced a reduction of more than 50% of viral cytopathic effects [132]. The present chapter updates the previous work and reviews the literature published since, with reference to new advances, preparations, reactions, and uses.

N O

N

106

N O

N

107

N O

N

108

N O

N

109

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j 13 Oxadiazoles

1076

13.3.1 Structure

The 1,2,4-oxadiazole ring is planar and described as having little aromatic character [133] – lower than furan on the Bird index [134]. Dipole moments and Kerr constants of certain oxadiazoles seem to indicate some ability of the ring oxygen atom to donate p electrons into the ring. This heterocyclic system has an appreciable heterodiene character, as suggested by X-ray analysis, which indicates, for both C
N distances, conjugated double bond character. The low aromaticity manifests itself by allowing rearrangement to more thermodynamically stable ring systems, thus making 1,2,4-oxadiazoles good substrates for ring-to-ring transformations [135]. The ring of 4,5-dihydro-1,2,4-oxadiazoles, according to CNDO/2 calculations, is nonplanar, adopting an envelope conformation with one atom sitting above the plane described by the four others, and, in contrast to the 1,2,4-oxadiazole ring, it is quite polar [136]. The parent compound 103 is an extremely volatile liquid, very soluble in water and organic solvents, but it is unstable at room temperature. 3,5-Dialkyl and 3,5-diaryl 1,2,4-oxadiazoles are thermally stable and do not hydrolyze by treatment with aqueous sodium hydroxide or hydrochloric acid. In contrast, 103 and monosubstituted oxadiazoles 110 and 111 are thermally and hydrolytically markedly less stable (Scheme 13.39) [137].

Me N MeOCN + MeCN O

N

NH2 Me

+

HCO2H

NOH

110

H N

Me

NH2

N CN

O

Me

O

N

Me

+

MeCO2H

NOH

111 Scheme 13.39

Tautomerism of 3- and 5-hydroxy, 3- and 5-amino, and 3- and 5-sulfur analogues has been recently reviewed [138]. In 5-hydroxy-3-phenyl-1,2,4-oxadiazole (112a), the keto forms 112b and 112c predominate according to NMR data [139]. The tautomer 113b is more important in the 5-phenyl isomer in solution, but in acetone and oxygenated solvents 113a allows for an effective hydrogen bonded dimer 114 (Figure 13.3).

13.3 1,2,4-Oxadiazoles

Ph

Ph

N HO

O

OH N

O H N

Ph

O

N

O

O N

N

Ph

O Ph

N Ph

O

NH

113c

113b

N

H O

N H

112c

N

O

O

O

H

113a

O

O

112b

N

Ph

N

O

112a

N

N

N

O

Ph

Ph

HN

N H O

H N O O

Ph

N

114b

114a Figure 13.3 Tautomerism exhibited by hydroxy derivatives.

In aminooxadiazole derivatives the tautomeric imino form 115b is less significant, since 115a is more basic; in the corresponding sulfur analog there is only evidence for the thione form 116 with the hydrogen at N2. N H2N

O

Ph

Ph

HN

N

HN

115a

O

N

115b N S

O

Ph NH

116

Interestingly, the 5-aryl-4,5-dihydro-1,2,4-oxadiazole 117a undergoes formal tautomerism with the 4-aryl-1,3-diaza-1,3-butadiene 117b, which in turn can undergo ring closure with loss of water to form the quinoxaline 118 (Scheme 13.40) [140]. 13.3.2 Theoretical Aspects

Theoretical studies on the structure and properties of 1,2,4-oxadiazoles have been reported. Semiempirical (PM3 and AM1) and ab initio molecular orbital

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j 13 Oxadiazoles

1078

Ph Ph HN Me

O

117a

Ph N

N Me 117b

Ac2O

N

N OH

N Ph

118

Scheme 13.40

calculations have been performed for diaryl-1,2,4-oxadiazoles and 4,5-dihydro1,2,4-oxadiazoles to determine bond orders, total energies, ionization potentials, and dipole moments [141]. In particular, ab initio molecular calculations give values close to those obtained by crystallographic techniques and NMR spectroscopy. Proton affinities and pKa values of amino-substituted oxadiazoles have been calculated [142]. INDO studies on 3-phenyl-1,2,4-oxadiazole and its 5-methyl analog suggest that nucleophilic attack should occur on C3 and C5 [143]. In connection with pharmacological structure–activity relationships, semiempirical and ab initio molecular orbital calculations have been reported for a series of analgesic compounds, leading to new suggestions for their mechanism of activity [120, 144]. A new model of interaction between the drug and the enzyme has been proposed that involves an electron transfer from the amino acid residue of the enzyme to the drug. A theoretical study of photoinduced ring-isomerization of 3-amino-5-methyl- and 3-amino-5-phenyl-1,2,4-oxadiazoles has been reported. The results agree well with experimental data and explain the ring-photoisomerization into the corresponding 2amino-1,3,4-oxadiazoles through a ring contraction–ring expansion route [145] (see Scheme 13.19 in 1,3,4-oxadiazoles). On the same basis a theoretical study of degenerate Boulton–Katritzky rearrangements concerning the anion of the 3-formylamino-1,2,4-oxadiazole has been carried out by using semiempirical MNDO and ab initio Hartree–Fock procedures [146]. A combined kinetic and theoretical study of the monocyclic rearrangements of the (Z)-hydrazone of 3-benzoyl-5-phenyl-1,2,4-oxadiazole into the corresponding triazole (Scheme 13.41) has been investigated at the DFT level [147]. The synthetic approach towards 1,2,4-oxadiazoles, based on the BH3- or BF3mediated cycloaddition of benzonitrile oxide to nitriles, has been investigated theoretically according to quantum chemical methods (MP2 and B3LYP) together with a topological analysis of the charge density (Section 13.3.4.2) [148]. Activation by the Lewis acid occurs via two different mechanisms: if the Lewis acid is coordinated to the nitrile oxide, the reactant is activated, so that the reaction is expected to be catalytic. If the Lewis acid is coordinated to the nitrile and strong enough, the process requires a stoichiometric amount of Lewis acid and forms a stable Lewis acid–product complex.

13.3 1,2,4-Oxadiazoles

R2

O

R1

NHR 3

R2

HN

N N R1

O

N

N

N

N

R3 120

119 R 1 = Ph, H

R 2 = Ph

R 3 = Ph, 2,4-NO 2-C6 H 3

Scheme 13.41

13.3.3 Structural Aspects 13.3.3.1 X-Ray Diffraction X-Ray data of many 1,2.4-oxadiazoles confirms that the ring is planar [149–154]. Values of C
N bond lengths are consistent with a heterodiene character and account for the low aromaticity of the system. Table 13.3 shows the reported bond lengths and bond angles for methyl 2-[3-(4-methylphenyl)-1,2,4-oxadiazol-5-yl]benzoate (121), a compound used as spacer in the synthesis of a potential non-peptide angiotensin receptor antagonist [155].

Table 13.3 Molecular dimensions for methyl 2-[3-(4-methylphenyl)-1,2,4-oxadiazol-5-yl]benzoate

(121).

Me 11

N 6

7

O

12

N

CO2Me 121



Bonds

Distances (A)

Bond angles

( )

O1
N2 N2
C3 C3
N4 N4
C5 C5
O1

1.415 1.310 1.325 1.298 1,347

O1
N2
C3 N2
C3
N4 C3
N4
C5 N4
C5
O1 C5
O1
N2

103.51 114.10 102.83 113.30 106.25

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The 3,5-diphenyl-oxadiazole fragment is almost coplanar. The angles between the planes of the rings C5
N4/C6
C7 and C5
N4/C11
C12 are 11.13 and 2.28 , respectively. The phenyl rings are tilted to the same side with respect to the oxadiazole ring and the angle between them is 8.86 . An interesting aspect of the crystal structure is the presence of two weak C
H
O bonds between two neighboring molecules in the same layer. Each molecule behaves as both donor and acceptor, leading to a dimer formation [155]. Crystal structures for a series of 2,3-dihydro-1,2,4-oxadiazoles have been reported [156–158]. The 4,5-dihydro-1,2,4-oxadiazole ring in compounds 122 [156] and 123 [151] are in an envelope conformation, with the oxygen atom above the plane occupied by other atoms. Me O

H MeO2 C

Me

N

H

O

H

N

122

N O

N

123

Yu and coworkers have reported the preparation and spectroscopic and X-ray diffraction studies of two diastereoisomeric D2-1,2,4-oxadiazolines (124, showing the assigned configuration of the diastereoisomer) having a spiral junction at C3 of fructopyranose. These compounds show extensive applications as drugs [159, 160]. Me

H

Me H O

O N

O O

Me Me

N Ac 124

According to the biological activities of 1,2,4-oxadiazole derivatives, the combination of an oxadiazole moiety with a sugar framework has been performed. Unsaturated glycosides having an 1,2,4-oxadiazole part as an aglycone, 125 and 126, have been reported [153]: crystallographic data, providing precise information regarding the configuration at C8 and also about the molecular conformation, have shown that compound 125 has a torsion angle H(15)–C(15)–C(10)–H(10) of
43.2 , which clearly shows that the anomeric proton is disposed equatorially. The ring oxygen atom is a little above the C(10)-C(15)-C(14)-C(13) plane; the C(12) atom is slightly below this plane. The p-tolyl ring and the 1,2,4-oxadiazole rings are coplanar [torsion angle N(2)–C(3)–C(16)–C(17)Z10.618 ]. The bond distances C(13)–C(12)  and C(12)–O(11) are 1.54 and 1.43 A, respectively.

13.3 1,2,4-Oxadiazoles 25 24

O H

13

AcO

12 14

OAc

OAc 11

O H

10

O

15

23

9

AcO

H 8 7

6

5

N 4

O

Me H

Me

O1 N 2

N

O N

3

16

17

21 20

18

19

22

Me

Me

126

125

Based on the recent observation that Pt(II) mono- and bis-1,2,4-oxadiazoline complexes exhibit in vitro cytotoxicity against a series of platinum-sensitive and resistant human cancer cell lines, with a potency comparable to that of cisplatin and superior to carboplatin [161], a series of PtX2(nitrile)(oxadiazoline) (127) and PtX2 bis-1,2,4-oxadiazoline (128) complexes have been prepared. R2 X

Me

Pt N N X

R1 N O

127

Me

R2 X

Pt N N X O R2 N 1 Me R

R1 N O

Me

128

13.3.3.2 NMR Spectroscopy Protons on the 1,2,4-oxadiazole ring are shifted downfield with respect to protons in benzene, according to the electron deficiency of the heterocyclic ring. In the parent compound 103, the signal for the C3 proton is at 8.99 ppm, while the C5 proton resonates at 9.49 ppm. The presence of an alkyl or aryl substituent shifts the resonance upfield; for 3-phenyl-1,2,4-oxadiazole, the H5 in CCl4 is at 8.70 ppm [120]. Resonances for H5 of 4-unsubstituted 5-alkyl-4,5-dihydro-1,2,4-oxadiazoles appear at 5.4–5.7 ppm [125, 162]. Chemical shifts for H5 of 5-alkyl-2,5-dihydro-1,2,4-oxadiazoles have been found at 6.1–6.3 ppm [163]. For 3-substituted 2,3-dihydro-1,2,4-oxadiazoles, the H3 shift is in the range 5.7–6.2 and 7.2–7.6 ppm, according to the presence of N-alkyl or N-aryl substituents, respectively [164]. Many fully assigned 13C data for C3/C5 disubstituted 1,2,4-oxadiazoles have been reported [165–168]. C3 resonances are in the range 148–169, while chemical shifts for

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j 13 Oxadiazoles

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13

Table 13.4

C NMR shifts (ppm) for C3/C5-disubstituted 1,2,4-oxadiazoles 129–132.

1,2,4-Oxadiazole

129

130

131

132

C3 C5 Solvent

148.6 164.1 CD3CN

168.8 174.7 CDCl3

176.9 182.7 CDCl3

169.3 173.4 DMSO

Me

NC

CN

N

N O N

O

N

N

129

O

Me

N

N

O

130

furanose

N

131

O

N

N

132

C5 are downfield, in the range 165–185 ppm. Table 13.4 summarizes the data for oxadiazoles 129–132. 13.3.3.3 UV and IR Spectroscopy UV spectra of aryl-substituted 1,2,4-oxadiazoles have been reported [162, 169]; nonaryl 1,2,4-oxadiazoles have no UV absorption. UV and fluorescence spectra of Cu(II) complexes of 5-(2-hydroxyphenyl)-3-phenyl-1,2,4-oxadiazole (133) have been reported [170]: Cu (II) binds to monodentate oxadiazole via N4 and the OH group in a 2 : 1 complex. A detailed IR analysis exists for the parent compound and a series of fully conjugated 1,2,4-oxadiazoles [162]. Diagnostic absorptions are at 1590–1560 (C¼N), 1119–1218 (C
O) and 895–910 (N
O) cm
1 [171, 172]. For 4,5-dihydro-1,2,4oxadiazole 134, the C ¼ N absorption is shifted to around 1600 cm
1 [162, 173]. 2,3-Dihydro-1,2,4-oxadiazoles exhibit a nC ¼ N between 1670 and 1676 cm
1 [156, 183], while in 2,5-dihydro the same absorption is at 1622–1640 cm
1 [162, 173]. Ph OH

N O

133

N

Ar HN N H O R1 134

13.3.3.4 Mass Spectrometry The diagnostic fragmentation pattern of 1,2,4-oxadiazoles is a 1,3-dipolar cycloreversion process, which proceeds via initial cleavage of the 1,5 (C
O) and 3,4 (C
N)

13.3 1,2,4-Oxadiazoles

j1083

bonds: the positive charge is retained in the predominant nitrile oxide fragment (Scheme 13.42) [175, 176].

-CN R1

R1

R1

-R2CN

N

N

N

O R1

O

R2

R1

N

N

-CO C

N

O R1=Ar

Scheme 13.42

The nitrile oxide fragment itself fragments further, either by expulsion of oxygen to give a nitrile, which may then lose a CN fragment, or via rearrangement and expulsion of CO. A recent review reports a detailed mass spectrometric analysis of a series of 1,2,4oxadiazoles and 4,5-dihydro-1,2,4-oxadiazoles [177]. The fragmentation mode of the latter compounds differs from that of 1,2,4-oxadiazoles. For example, the electron impact dissociation of compounds 135 is reported in Scheme 13.43.

a) Ph N b)

R O N

PhCO

PhCHO

Ph a)

Me

Ph N

b)

O

+ MeCN

H2 C C N

R 135

Ph

Scheme 13.43

13.3.4 Synthesis

Many synthetic routes for the 1,2,4-oxadiazole system have been reported [120]. 1,2,4Oxadiazoles can be achieved from open-chain precursors through conventional heterocyclization reactions: the best represented approach exploits the cyclodehydration of O-acyl-amidoximes, a method first used by Tiemann and Kruger [178], or N-acylamidoximes, a method developed by Beckmann and Sandel (amidoxime route) [179]. Another different general synthetic route is based on the 1,3-dipolar cycloaddition of nitrile oxides to nitriles, developed by Leandri (cycloaddition route) [180].

j 13 Oxadiazoles

1084

13.3.4.1 Amidoxime Route 13.3.4.1.1 Cyclization of O-Acylamidoximes According to the most represented route, 1,2,4-oxadiazoles 138 can be prepared by cyclization of O-acylamidoximes 137, which are obtained from the appropriate amidoxime 136 (easily prepared by reaction of the corresponding nitrile with hydroxylamine) and an acylating reagent [120] (generally acyl halides [181, 182], esters [183], or anhydrides [184]) (Scheme 13.44).

O NOH

RCN NH2 OH

R

NH2 136

R1

Cl

H2 N O R1

R 1 = R 2 = Alkyl, aryl

O

R N

137

R

∆ 17-91%

N R1

O

N

138

Scheme 13.44

The cyclization of O-acylamidoximes is performed by heating them at their melting point [185], or at reflux in a high-boiling solvent (DMF [186], toluene [187], pyridine [188], ethanol [189], acetonitrile [190], glacial acetic acid at reflux) [191, 192], eventually in the presence of a dehydrating agent (phosphorous pentoxide, phosphorus oxychloride, or acetic anhydride). The experimental conditions required to realize the ring closure of the corresponding O-acylamidoximes vary as a function of their structures. In some cases, depending on the substrates, the cyclodehydration reaction occurs under the same conditions as the acylation reaction and the open-chain intermediate is not isolated. An efficient one-pot method based on the reaction of nitriles with hydroxylamine hydrochloride in the presence of magnesia-supported sodium carbonate, followed by reaction with acyl halides under solvent-free conditions and microwave irradiation, has been reported [193a]. The use of microreactors (microfluidic chips) as an alternative to “in flask” chemistry has been exploited for a rapid synthesis of bissubstituted 1,2,4-oxadiazoles from aryl nitriles and acyl chlorides or succinic anhydride in a single continuous microreactor sequence. In this way, a multiday, multistep sequence has been amended to a highly efficient procedure lasting less than 30 min (Scheme 13.45) [193b]. Cyclization can be performed under mild conditions if the weak nucleophilic amide group is converted into the more nucleophilic amide ion. Thus, 1,2,4oxadiazoles 140 have been obtained by treatment of 139 with DBU at 70  C [205]. A significant advance is the use of TBAF at room temperature as a cyclization media, a process that occurs in high yields in the presence of 0.1–1 eq of TBAF, with the fluoride ion acting as both a homogeneous and strongly basic reagent (Scheme 13.46) [194, 195]. A wide variety of carboxylic acid derivatives can be used for the formation of Oacylated amidoximes, such as esters [196], acid chlorides [152, 154, 171, 175, 187, 197],

j1085

13.3 1,2,4-Oxadiazoles

O ArCN

R1

NOH

NH 2OH

or

R

Het-CN

Cl

H2 N O

NH 2

R1

O

136

R

∆

N

R1

45-63%

R

N O

N

138

137

R = Ar, Het

N R

N

N

N

N N N

N

F

OMe

O

R1

O

O

CN

Scheme 13.45

H2 N O R2

R1

F

N

F

H2 N O

O R2

139

R1

R1

H N

N O

R2

O

N O

F H

R1

H

N

N R2

R1

F

N O

50-98%

R2

N O

HO

140

R 1 = Ph,2-,3- or 4-Tol,2-,3- or 4 MeOC 6H 4,2-,3-, or 4-NO 2 C6 H4, Me, 4-BocHNC 6H 4, 2-Cl, 5-1,4-BocHNC 6H 2 R 2 = Me, Ph, OMe, But, CH2 Cl, CH2OCH 2 CH 3, CF3 , Pr i, 2-, 3-, or 4-NO 2C 6 H4 , CH2 Ph

Scheme 13.46

j 13 Oxadiazoles

1086

acid anhydrides [197b, 152, 171, 198], including symmetrical acid anhydrides derived from amino acids [184c], and amino-acid activated as succinimides [183]. Succinic [199] and glutaric anhydrides [200] are excellent substrates for reaction with amidoximes, giving 1,2,4-oxadiazol-5-yl carboxylic acids 141 and 142, respectively: the obtained compounds are excellent substrates for coupling to amino acid derivatives (Scheme 13.47). Ph

O

NH 2 N

O

+

O

O R

NH2 N

H N

141

R2 R2

O

O

1,4-dioxane, heat

HO2C

N

R1

142 H N

N

N

R3

O N

40-90%

OH

Ph

O N

70%

OH

R3

1

N

HO 2C

heat

THPO

R1 =

R2 = H, Me

N

MeO N

O

O

N

O

O

R3 N

N Me

S

Ph N N

C CR

S

R = H, Ph, Me, 3-FC6 H 4, 3-pyridyl Scheme 13.47

Examples of the amidoxime route, by which two 1,2,4-oxadiazole moieties can be linearly joined by alkyl chains through the annular 5,50 -positions, have been reported. Thus, the 5,50 -bis-1,2,4-oxadiazolyl system 144 has been obtained by reaction of malonates 143 with two equivalents of an amidoxime in the presence of potassium carbonate (Scheme 13.48) [196f ]. The use of carboxylic acids, activated in situ and reacted with an amidoxime, has also been exploited, using various coupling reagents, including dicyclohexylcarbodiimide (DCC) [184a–f ], 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide(EDC) [184a,d, 201c], (EDC)/HOBt [201b,c, 202], bis(2-oxo-3-oxazolidinyl)phosphinic

13.3 1,2,4-Oxadiazoles

R2 OR

RO

R1

O

O

N

+

OH NH2

j1087

R2

K2CO3 toluene,reflux

R1

40-83%

N

N N

O

O N

R1

144

143

R1 = Me, Et, Bn, 4-FC6H4, 4-MeOC6H4, cyclopropylmethyl, CH2CH2OMe R2 = H, Bn R = Me, Et Scheme 13.48

chloride (BOP-Cl) [184a], 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyl-uronium tetrafluoroborate (TBTU) [186, 201c], 1,10 -carbonyldiimidazole (CDI) [184a, 203], and/or high-speed microwave irradiation (Scheme 13.49) [186,197a, 201].

O R

N

+ OH

1

OH

activating agent R

27-91%

NH2

R

R1

N O

N

145 R1 = 4-MeC6H4, Me, 4-FC6H4, 3-pyridyl R = Ph, 4-MeC6H4, 4-MeOC6H4, 4-NO2C6H4, 4-EtOC6H4, 3-MeOC6H4 Scheme 13.49

Chiral 1,2,4-oxadiazoles 147 have been synthesized from amino acids by reaction of the readily available N-protected (a-aminoacyl)benzotriazoles 146 with amidoximes in ethanol (Scheme 13.50) [189]. EtOH R

O

N

+ Pg HN

Bt

R1

OH

25°C to rt

R

R1

N O

NH2

70-94%

Pg HN

146

147

R 1 = 4-Tol, 4-pyridyl, Bn R = Me, Me2 CH, PhCH 2, MeSCH 2 CH2, NH2 COCH 2CH 2, C8 H6 NCH 2 Pg = Boc, Fmoc Scheme 13.50

In some cases, nitriles can be used as acylating reagent for amidoximes, and the subsequent heterocyclization involves loss of ammonia in the final step, with formation of 1,2,4-oxadiazoles 148 (Scheme 13.51) [204].

N

j 13 Oxadiazoles

1088

NOH

O

H2N NH

RCN

NH2

R

NO2

O

O

- NH3

O

N R

N

O

N

148 R = Alky, Aryl Scheme 13.51

For this purpose the reaction is carried out in the presence of an ammonia acceptor reagent (a carboxylic acid or an excess of the nitrile). For example, from the reaction of benzamidoximes with perfluoroalkyl nitriles, a series of fluorinated 5-alkyl-1,2,4oxadiazoles can be obtained [205]. Disubstituted 1,2,4-oxadiazoles have been synthesized in good yields and good purity in a one-pot procedure by reaction of aromatic nitriles, hydroxylamine hydrochloride, and sodium carbonate in ethylene glycol under heating at 195  C [168]. Microwave irradiation of nitriles in the presence of hydroxylamine and different aromatic aldehydes, under solvent-free conditions, affords fully conjugated 1,2,4oxadiazoles 149 in high yields (Scheme 13.52) [206]. R1 N

MW, AcOH(cat.) R 1CN

+

Ar

NH2OH ArCHO, 4 min. 92-97%

O

N

149

R1 = Ph, 4-MeC 6 H4, 3-ClC 6 H4 Ar = Ph, 4-MeC 6H4, 4-ClC 6 H4 , 4-MeOC 6H4 Scheme 13.52

Other methods to obtain 1,2,4-oxadiazoles 150 include the palladium-mediated coupling of an aryl iodide with an amidoxime in the presence of carbon monoxide (Scheme 13.53) [207]. I N +

R

1

OH NH2

X

R1 CO

Scheme 13.53

O

PdCl2 (PPh3 )2, Et 3N 25-71%

R 1 = Me, CO 2 Et

N

X

150

X = 2-OMe, 4-OMe, 4-Br, 4-NO2 , 4-CO 2 Me

N

13.3 1,2,4-Oxadiazoles

Similarly, 1,2,4-oxadiazoles 152 have been prepared by palladium-catalyzed reactions of diaryliodonium salts (151) with amidoximes in the presence of carbon monoxide (Scheme 13.54) [208]. X I

BF4

N

+

R

OH NH2

CO

O

PdCl2(PPh3)2, K2CO3

X

X

42-78% 151

R

N

N

152

X = H, 4-Me, 4-Cl, 4-OMe, 3-NO2 R = Ph, 4-MeOC6H4, 4-ClC6H4, PhCH2

Scheme 13.54

13.3.4.1.2 Cyclization of N-Acylamidoximes N-Acylamidoximes 158 cannot be prepared by acylation of amidoximes because O-acylation is faster. Suitable starting materials for N-acylamidoximes can be found in N-acylimidic chlorides 153 (X ¼ Cl), cyanides 154 (X ¼ CN), acylamidines 155 (X ¼ NHR, NR2), N-acyl(alkylthio)imides 156 (X ¼ SR), or N-acyl(alkoxy)imides 157 (X ¼ OR), which, by reaction with hydroxylamine, lead to 1,2,4-oxadiazoles 159 (Scheme 13.55) [209]. R2 N R1

X O

H

NH2 OH 50- 97%

R2

N R1

N

OH

O

158 153-157: X = Cl, CN, NHR, NR2 , SR, OR R 1 = R 2 = Me, Et, Ph

∆

38-95%

R2 N R1

O

N

159 Scheme 13.55

Imidates such as 160 react with cyanamide to give N-cyanoamidines 161, while the hydrochloride 162, is transformed into 163 [210]. Both 161 and 163 give 3-amino1,2,4-oxadiazoles 164 on treatment with hydroxylamine (Scheme 13.56).

j1089

j 13 Oxadiazoles

1090

NH2 OMe

NH 2OH

NH 2

NH 2CN Ph

Ph NH

72%

160

N CN

N N OH NH 2

Ph

31%

161 - NH 3

R = Ph

OMe NH 2

NH 2CN 66%

NH 2

NH 2OH

OMe N CN

69%

N R

O

N

Cl 162

164

163

Scheme 13.56

A different approach involves the nitrosation of dimethylaminopropenoates 165, with formation of the corresponding oximes 166, which undergo cyclization to give the 5-substituted 1,2,4-oxadiazoles 3-carboxylates 167 (Scheme 13.57) [211].

CO2 R CO 2R NHCOR1

Me 2N

HNO 2

N HO

CO 2R NHCOR

1

38-78%

166

165

N

-H 2O 1

R

N O

167

R = Me, Et; R 1 = Ph, 2-ClC 6 H4 , 4-ClC 6 H4 , 4-Tol, 4-MeOC 6H 4 , Me, styryl, 2,6-dichlorostyryl, 2-methystyryl, 2-methoxystyryl Scheme 13.57

The reaction of cyanohydrines 168 with hydroxylamine leads to the non-isolable amidoximes 169, which, through intramolecular acylation to 170, cyclize to epimeric 1,2,4-oxadiazoles 171 (Scheme 13.58) [212]. A series of substituted 1,2,4-oxadiazoles 176 have been synthesized through a new and versatile solid-phase synthesis protocol using resin-bound nitriles (172). This resin was treated with hydroxylamine and converted into resin-bound amidoximes 173, which were transformed into the polymer supported O-acylamidoximes 174 upon treatment with acyl chloride. These compounds were subsequently converted into immobilized 1,2,4-oxadiazoles 175, and then to 176 by treatment with 95% aqueous TFA in 15–52% overall yield (Scheme 13.59) [213].

13.3 1,2,4-Oxadiazoles

MeO O

OMe

MeO O

OMe NH 2OH

j1091

OCOR

OCOR CN

NOH

H 2N

168

169

R = Ph, Me

R

OMe

OH

OH N

MeO O

OMe

MeO O

38-42% NOCOR

H 2N

N O 171

170

Scheme 13.58

Ph Ph

N

O

H 2N

N

Ph N

N O

MeO

NH2OH

O

RCOCl

MeO

MeO Py

∆

174 172

173 H2N

CN

N

OH

O O

TBAF

Ph H

Ph N

O

95 % aqeous TFA

N

O

N O

N

MeO (15-52% overall yield)

N O

N R

176

R

175

R = Me, t-butyl, Ph, 1-Naphthyl, 2-Naphthyl, 2-furyl, 2-thienyl, 4-pyridyl, 3-pyridyl, 2-MeO-C6 H 4, 3-MeO-C6 H4, 4-MeO-C6 H 4, 2-F-C 6H4, 3-F-C 6H 4, 4-F-C6 H4, Cyclopropyl, Cyclobutyl, Cyclopentyl, Cyclohexyl, Phenylacetyl, hydrocinnamyl

Scheme 13.59

R

j 13 Oxadiazoles

1092

13.3.4.2 Cycloaddition Route Another general and well-established route to 1,2,4-oxadiazoles 159 relies on the 1,3-dipolar cycloaddition between a nitrile 176 and a nitrile oxide 177 (Scheme 13.60) [120]. Aromatic and electron-deficient nitriles showed good reactivities, while aliphatic nitriles do not undergo cycloaddition to the oxadiazole derivative. However, under Lewis acid catalysis even aliphatic nitriles form cycloadducts [148].

N C R2

+

R1 C N O

R2

29-37%

O

177

176

R2 = Methyl-tetrazolyl ring

R1

N

N

159 R1 = 3-NO2-C6H4, 4-NO2-C6H4

Scheme 13.60

Non-activated nitriles undergo cycloaddition with especially reactive nitrile oxides such as bromo- and chlorocyanogen oxide (Scheme 13.61) [214].

N C R

X C N O 35-79%

N Br

O

R N

178 X = Cl, Br R = i-propyl, ClCH2, BrCH2, PhCH2 Scheme 13.61

Several methods are reported in the literature for the in situ generation of nitrile oxides. Huisgen’s base-induced dehydrohalogenation of hydroximoyl chlorides [215] and Mukaiyama’s dehydration of primary nitro compounds, using phenyl isocyanate with a catalytic amount of triethylamine [216], are the most frequently used routes to generate nitrile oxides. Thus, the loss of HCl from imidoyl chloride 179 leads to the nitrile oxide 180, which undergoes cycloaddition to the dicyanoketene acetal 181, producing the 1,2,4-oxadiazole 182 (Scheme 13.62) [217]. The ultrasound cycloaddition of nitrile oxide, formed by Mukaiyama’s dehydration of nitroethane, with trichloroacetonitrile 183 affords the 1,2,4-oxadiazole 184 whose remarkable reactivity towards nucleophilic substitution by amines has been widely exploited (Scheme 13.63) [218]. Treatment of nitriles with acetone or acetophenone in the presence of iron(III) nitrate affords 3-acetyl- or 3-benzoyl-oxadiazoles 186; the reaction proceeds through enolization and nitration to give an a-nitroketone, which undergoes an acid-catalyzed dehydration to the intermediate nitrile oxide 185 (Scheme 13.64) [219].

13.3 1,2,4-Oxadiazoles

NOH Et 3 N

Cl

R

N

O

R Et 2 O

180

179

CHCl 3, BF 3 -OMe 2

O NC

79-91% O

CN

181

R

R = H, 4-OMe, 4-Cl, 3-NO2 N

O

N O

O CN

182 Scheme 13.62

Me

EtNO 2

N

N C CCl3 PhNCO, Et 3N

183

Cl3C

O

)))) 24h

N

184

53% Scheme 13.63

Me

R

80 °C

O

O

Fe(NO 3) 3

O

H 2C R NO2

O

N

C

R

185 R1 C N

R= Me, Ph R1 = Me, Et, Pr, i-Pr

O R

N N O

186 Scheme 13.64

25-95%

R1

j1093

j 13 Oxadiazoles

1094

A similar reaction leading to 1,2,4-oxadiazoles from ketones, nitriles, and nitric acid has been described using yttrium triflate as catalyst (Scheme 13.65) [220]. O

Me R

N O

HNO3 , 80°C

R 1 CN

+

Y(OTf) 3

R1

N

R

46-810% R = Me, 4-FC6 H 4, 4-ClC 6 H4 , 3-NO 2C 6H 4, 2,4-Cl 2-5FC 6H 2 , 3-NO 2-4MeC 6 H3 R 1 = Me, Ph, 2-FC 6H 4 Scheme 13.65

The reaction mechanism involves the 1,3 dipolar cycloaddition of nitriles with nitrile oxide 187, which is obtained by enolization of the ketones promoted by yttrium triflate, followed by nitration and subsequent dehydration (Scheme 13.66).

O

Me

Y(OTf) 3 OH

Y(OTf) 3

R

NO 2 O

HNO 3

R

R

- H 2O

N O R

R1 CN

O O N

R1

R

N 187

Scheme 13.66

A less common method for the formation of nitrile oxides is the oxidation of aromatic aldoximes with ceric ammonium nitrate (Scheme 13.67) [221]; the subsequent cycloaddition to nitriles leads to 1,2,4-oxadiazoles 188. H HO

Ar N

(NH4 )2 Ce(NO 3 )6 RCN, ∆

Ar

N N O

R

188 R = Me, Et Ar = Ph, 4-MeC 6H 4, 4-MeOC 6H 4, 4-Cl, 4-NO 2 C6 H4 Scheme 13.67

13.3 1,2,4-Oxadiazoles

j1095

The cycloaddition methodology has been employed for the synthesis of complex systems. The reaction between nitrile oxides 189 and trans-[PdCl2(RCN)2], or RCN (R ¼ Me, Et, CH2CN, NMe2, Ph) in the presence of PdCl2, proceeded smoothly under mild conditions and allowed isolation of the trans-[-PdCl2]-1,2,4-oxadiazole complexes (190–197) in 40–85% yields. (Scheme 13.68) [222].

R1 N R1 [PdCl2(RCN)2

O

R1

189

PdCl2

CH3CN

CH3CN 1

R = Me, Et, CH2CN, NMe2, Ph

R R

1

R = OMe, Me

O N

Cl

N R1

R1

R1

Pd Cl

R1

N R

O

N

190: R= Me,

R1 = Me

191: R= Et,

R1 = Me

192: R= CH2CN, R1 = Me 193: R=NMe2, R1 = Me 194: R= Ph,

R1 = Me

195: R= Me,

R1 = OMe

196: R= Et,

R1 = OMe

197: R= NMe2,

R1 = OMe

R1 190-197 40-85% Scheme 13.68

3-Aryl-5-C-glucosyl-1,2,4-oxadiazoles 199 and 200, assayed as glycogen phosphorylase inhibitors, have been prepared in high yield by 1,3-dipolar cycloaddition of aryl nitrile oxides to benzoylated glucosyl cyanide 198 and subsequent cleavage of the protecting group (Scheme 13.69) [223]. 1,2,4-Oxadiazoles have been prepared by cycloaddition of nitrile oxides to different dipolarophiles. Thus, the cycloaddition of nitrile oxides to amidoximes 201 proceeds with loss of diethylamine to give the 1,2,4-oxadiazole-4-oxide 202, which can be deoxygenated with trimethyl phosphite to give 1,2,4-oxadiazole 203 (Scheme 13.70) [224]. The reaction of nitrile oxide 204 with imine 205 affords the 1,2,4-oxadiazole 207 via the non-isolable intermediate 206 (Scheme 13.71) [225]. 13.3.4.3 Miscellaneous Synthesis of 1,2,4-Oxadiazoles Fully conjugated 1,2,4-oxadiazoles have been prepared by oxidation of 4,5-dihydro1,2,4-oxadiazoles 208 (Section 13.3.4.4.1), containing hydrogen atoms in the 4- and 5-positions: the oxidation can be performed by MnO2 [125], nitric acid [125], NaOCl [162], or N-chlorosuccinimide (NCS) [169] (Scheme 13.72).

j 13 Oxadiazoles

1096

R

BzO O

BzO BzO

ArCNO

CN

OBz

BzO

N

90-99%

N O

O

BzO BzO

OBz

198

NaOMe MeOH, CHCl 3

R

R

+

HO

N O

HO HO 4-7%

HO

N O

200

199

Scheme 13.69

HO

R1

R +

N

HO

NEt2

Et3 N

OH N NEt2

R

N O

N

R1

201

R = Ph, 4-Me, 4-MeO, 4-Cl, 4-NO 2, Me - Et2 NH

R1 = Ph, 4-Me, 4-MeO, 4-Cl, 4-NO2

R

P(OEt)3

N N O 203

Scheme 13.70

R1

∆ 20-52%

R

O N N O 202

N O

OH

R = H, 4-MeO, 4-NO 2

Cl

N O

HO HO

R1

75-92%

13.3 1,2,4-Oxadiazoles

Me C N O

Me

H N

+ N

204

HN

N O

Ph

Ph N

206

205

Me +

N N O 207

Ph

N H

49%

Scheme 13.71

H N

Ar

N O 208

Ox R

Ar

74-96%

N N O

R

Ox=MnO2, HNO3, NaOCl, NCS

R=Pr, i-Pr Ar=Ph,4-MeO-C6H4, 4-Cl-C6H4, 4-NO2 -C6H4 Scheme 13.72

Oxidation of N-benzylamidoxime 209 with KMnO4 affords 1,2,4-oxadiazole 211, through the intermediate 4,5-dihydro-1,2,4-oxadiazole 210 (Scheme 13.73) [226]. Bicyclic 4,5-dihydro-1,2,4-oxadiazole 212 leads to 213 through a retro-[2 þ 2] cycloaddition via loss of styrene in toluene at reflux (Scheme 13.74) [227]. Some recent synthetic procedures concern ANRORC-like reactions that consist of the Addition of a Nucleophile to a p-deficient heterocycle, followed by Ring-Opening and Ring-Closure steps. By this approach, a heterocycle can be transformed into a different one containing the heteroatoms originally belonging to the nucleophilic reagent. Thus, the reaction of 5-fluoroalkyl-1,2,4-oxadiazoles 214 with hydroxylamine furnishes high yields of 3-fluoroalkyl-1,2,4-oxadiazole 217 in a virtual C5–C3 annular shift (Scheme 13.75) [228]. The reaction is promoted by nucleophilic attack of the hydroxylamine to the electron-deficient C5 to produce 215. Heterocyclization of the dioxime intermediate 216 and removal of hydroxylamine leads to the more stable oxadiazole 217, in an irreversible ring-degenerate process.

j1097

j 13 Oxadiazoles

1098

O 2N

O 2N KMnO 4

H N N OH

Ph

H N

69%

Ph

N O 210

209

O 2N N Ph

N O 211 Scheme 13.73

Ph PhMe N N3

N O

N

∆ SEt

N3

-PHCH=CH2 213

212

SEt

N O 33%

Scheme 13.74

R

Rf

NH2OH

N Rf

N O

N

70-94%

214

R

H N N O

217

R NHOH Rf

215 Scheme 13.75

R

N O

H N

Rf NOH

N OH Rf

H N N O 216

NHOH R

13.3 1,2,4-Oxadiazoles

Accordingly, photoinduced rearrangements of O
N bond containing azoles can be useful for the synthesis of 3-amino-5-alkyl-1,2,4-oxadiazoles [229]. This procedure exploits the photofragmentation pattern of the furazan heterocycle into a nitrile and a nitrile oxide. Thus, irradiation of 3-alkanoylamino 217 at l ¼ 313 nm in methanol and in the presence of ammonia or primary aliphatic amines gives the corresponding 3-amino- or 3-N-alkylamino-5-alkyl-1,2,4-oxadiazoles 219 as a result of the heterocyclization of the intermediate 218 (Scheme 13.76) [230, 231].

H N

Ph N

O

N

O

R

R

hν 313 nm, MeOH

O N

NH

– PhCN

217

R 1 NH2

H N

N R

O

R

1

– H2 O

N

H R1 N HO N

219

R O

218 R = C 3F7, C 7 H15 R 1 = H, Me, Pr, nC 8 F17

Scheme 13.76

Unfortunately, yields of isolated products (about 30–40%) were not very good because of the photoreactivity of oxadiazoles under irradiation conditions; this, however, appears to be the only method that allows these derivatives to be obtained. 13.3.4.4 Synthesis of Dihydro-1,2,4-Oxadiazoles 13.3.4.4.1 4,5-Dihydro-1,2,4-Oxadiazoles The main methodology towards the synthesis of 4,5-dihydro-1,2,4-oxadiazoles 220 relies on the reaction of carbonyl compounds with amidoximes 136 under acidic conditions (Scheme 13.77) [120, 162, 232]. The use of chloroformate or diethyl carbonate leads to 4,5-dihydro-1,2,4-oxadiazolones 222 via an intermediate acetamidoxime, which cyclizes under base treatment (Scheme 13.78) [233]. The reaction with phosgene or thiophosgene constitutes an alternative route towards the 4,5-dihydro-1,2,4-oxadiazol-5-ones or-5-thiones 223 (Scheme 13.79) [234]. A widely exploited route to 4,5-dihydro-1,2,4-oxadiazoles is the 1,3-dipolar cycloaddition of nitrile oxides to azomethines [120, 235]. Thus, the reaction of imines 224 with hydroxyimoyl chlorides 225 in the presence of triethylamine gives 4,5-dihydro-1,2,4-oxadiazoles 226 (Scheme 13.80) [236].

j1099

j 13 Oxadiazoles

1100

N

OH +

NH2

R

R1

O

N

O R2

R1

29-94%

R

OH R

NH2

136 H H R

R1 N

R

O

N

220

R = Ph, Bn, 2-furyl, 2-thienyl, 2-Tol, 3-Tol, 4-Tol, 4-pyridyl, 2-MeO-C6H4CH2, R1 = H, Me, Me2CH, Et, 4-MeO-C6H5, R2 = H, Me; R1, R2 = -(CH2)5Scheme 13.77

N R

OH

40-80%

O +

NH2

X

OEt

N R

R = Me, 4-Tol

136

O

O

H

Base

OEt NH2

O

221

Scheme 13.78

OH NH R

O

X +

Cl

N R

O O

O R = H, Ph, 4-Tol, X = O, S Scheme 13.79

N O

80-92% Cl

O

N

222

X = Cl, OEt

N

R N

223

X

j1101

13.3 1,2,4-Oxadiazoles

N

H

N +

Ar

Ar 1

Ar

OH

30-80%

X

Et3N

Ar1

H N

Ar

O

Ar

226

225

224

N

Ar = Ph, 4-MeC 6 H4 , 4-ClC 6 H4 , 4-BrC 6 H4 , 3NO2 -C 6H 4 , 4-C6 H4 , 4-C 6H 4, 4-C6 H4 , Ar 1 = Ph, 4-MeC 6H 4 Scheme 13.80

Scheme 13.81 reports a parallel synthesis of 4,5-dihydro-1,2,4-oxadiazoles, through a cycloaddition reaction of imines with poly(ethylene glycol) (PEG) supported nitrile oxide. 4-Formylbenzoic acid (227) was attached to the dihydroxylated PEG by esterification in the presence of DCC. The PEG-bound derivative 228 was converted into oxime 229 by treatment with hydroxylamine hydrochloride, in the presence of trioctylamine, which with N-chlorosuccinimide afforded the PEG-bound chlorooxime 230. This derivative was then treated with several imines to give the corresponding cycloadducts 231, which were released from the PEG by treatment with sodium methoxide in methanol, to afford 1,2,4-oxadiazolines 232 in 71–91% overall yield [237].

O

O HO 2C OH

DCC, DMAP

+

O

NH2 OH

CHO

dihydroxy-PEG

O

base

CHO

229

CHNHOH

228

227

NCS

Me

O

O

O

O O

O Base

MeONa

N O R1

3 N R

R2 232

MeOH

R N R1 3

N O R2

R1

R2 N

R3

231

R 1 = H, Me R 2 = Ph, 4-MeO-C 6H 4, 4-F-C 6 H4 , 4-Me-C 6H4, 3-NO 2-C6 H4 , 4-C7 H5 O2 , R 3 = Ph, 4-F-C 6H4 , 4-Me-C 6 H4 , PhCH2 , butyl

Scheme 13.81

Cl HOHN 230

j 13 Oxadiazoles

1102

The use of cyclic imines in the cycloaddition reaction is a useful route to various fused 4,5-dihydro-1,2,4-oxadiazoles. In this way, oxadiazolo-1,4-diazepines, 233 [238], oxadiazole-1,5-benzodiazepines 234 [239], and oxadiazolotriazole-1,5benzodiazepines 235 have been prepared [240] (Scheme 13.82).

R

N

Me

N

+ N Me

Me

Me

Me N

Me

N

R O

O Me

N

27-30%

Me

Me 233

R = Ph, Me

N

R1

Ph

R1

N HO +

N

Me

Cl

Et3 N

N

91%

R

Ph

N N

R

R = 3-Cl,4-Me-C 6H 3,

O

234

R1 = SMe

EtO2 C N

N

EtO2 C

R HO + Cl

N

Et3 N

N R1

N N

N

47-58% R1

R = NO 2 , Cl,

Ph O

N

Ph

R

N 235

R1 = 4- NO 2 -C 6H 4, 4- Me-C 6H 4,4- Cl-C 6 H4 Scheme 13.82

13.3.4.4.2 2,5-Dihydro-1,2,4-Oxadiazoles Aminonitrones 236, prepared by reaction of hydroxylamines with ethyl cyanoformate, cyclize by treatment with triphosgene to 2,5-dihydro-1,2,4-oxadiazin-5-ones 237 (Scheme 13.83). A related reaction involves the acylations of 2-aminopyridine N-oxides 238 and 239 with ethyl chloropyruvate or phosgene, respectively (Scheme 13.84) [241].

j1103

13.3 1,2,4-Oxadiazoles

CH 2 Cl2 EtO2 C C N

H 2N

RNHOH

+

65-79% O

CO 2Et N

R 236

O Cl3 CO

Et3 N OCCl3

54-89% CO2 Et

N O

O 237

N R

R = Me, i-propyl, Ph, 4-BrC 6H 4 , 4-MeC 6H 4, 3-MeC 6H 4 Scheme 13.83

R

+ N

R

O

CO 2Et

Cl

CO 2Et

56% CO2 Et

NH 2

O 238

239

NH 2

O

O

N O

+ Cl

Cl

N

EtO2 C

60%

O N

NH 2

CO 2Et

R = 4-pyridyl

O

N

N O

N O

Scheme 13.84

The reaction of substituted oxazoles 241 with arylnitroso derivatives 240 affords 2-aryl-2,5-dihydro-1,2,4-oxadiazoles 242 regioselectively, through a formal [3 þ 2] cycloaddition, proceeding via a ring opening of oxazoles promoted by a nucleophilic attack of the nitroso compound at the 2-position of the penta-atomic ring (Scheme 13.85) [242]. A facile one-pot synthesis of 2,3,5-substituted 1,2,4-oxadiazolines from nitriles in aqueous solution has been reported [243]. Thus, alkyl/aryl amidoximes, prepared from the corresponding nitriles and N-alkylhydroxylamines, readily undergo consecutive double Michael additions to electron-deficient alkynes and provide highly

j 13 Oxadiazoles

1104

R3

R3

NO

N R2

+ R1

R

O

N

R 3O2 C

29-100%

R1

N

241

240

R3

O N N

R1

O

R3 R

242

2 N R

R1

R2

O O

R1 = Me, MeO, EtO,

R = H, Cl, Me

R

O

N

Me

R2 = Me, nonyl, 4-MeC 6H 4, 4-MeOC 6 H 4

R3 = H, Me, CO2 Et, Ph, 4-NO2 C6 H 4 Scheme 13.85

substituted 1,2,4-oxadiazolines 243 in good yields in homogeneous aqueous solution (Scheme 13.86).

1

R CN

R2 N H HO HCl

+

EtOH/H2O

R1

Na2CO3, 80 °C

EtO2C

N R1

O

N R2 141

CO2Et EtO2C

CO2Et

EtO2C

OH N R2

HN

36-100%

O CO2Et N R2

HN R1

R1 = Me, i-pr- Ph, PhCH2, 2-furyl, 2-pyridyl, 3-pyridyl, 4-pyridyl R2 = Me, Cy, PhCH2 Scheme 13.86

13.3.4.4.3 2,3-Dihydro-1,2,4-Oxadiazoles A general route to 2,3-dihydro-1,2,4-oxadiazoles is based on the 1,3-dipolar cycloaddition of nitrones to nitriles. Thus, 3-tbutyl-2,3-dihydro-1,2,4-oxadiazoles 246 have been prepared through cycloaddition between butylnitrone 244 and different activated nitriles 245 (Scheme 13.87) [244].

13.3 1,2,4-Oxadiazoles

j1105

R

R N

+

O

∆

N C R1

N

80-100%

245

R

1

O

N

246

244 R = Ph, 4-NO2-C6H4 R1 = ClC(CN)2, Br2(CN), C(CN)3, CCl3 Scheme 13.87

The cycloadditions have been performed in the absence of solvent, under microwave irradiation within 2–10 min [245]. Recently, a series of 5-trichloro- and 5-(2-methylpropanenitrile)-D4-1,2,4-oxadiazolines 247 have been synthesized by 1,3-dipolar cycloaddition of nitrones to trichloroacetonitrile and 2,2-dimethylmalononitrile, respectively. These oxadiazolines rearrange into formamidine derivatives 248 by prolonged heating, via ring opening and a 1,2-aryl shift from carbon to the adjacent amino nitrogen (Scheme 13.88) [246].

R C N +

R1 O

H N

Me

R1

CHCl3 60 °C, 1-5 h 95-100%

N R

H N Me O

247

60 °C, 12 h- 70 d 15-82%

R1 N

H N

Me O

R

248

R = CCl 3 , Me 2CCN R1 = 2-MeOC 6 H4 , 2,3-(MeO) 2C 6H 3, 2,4-(MeO) 2 C6 H3 , 2,5-(MeO) 2C 6 H3 , 2,6-(MeO) 2 C 6H 3, 3,4-(MeO) 2 C6 H3 , 2,3,4-(MeO) 3C 6 H2 , 3,4,5-(MeO) 3C 6H 2, 2,4,5-(MeO) 3 C6 H 2, 2,4,6-(MeO) 3 C6 H2

Scheme 13.88

Based on a recent observation that Pt(II) mono- and bis-oxadiazoline complexes exhibit in vitro cytotoxicity against a series of platinum-sensitive and resistant human cancer cell lines with a potency comparable to that of cisplatin and superior to carboplatin [247] a series of 2,3-dihydro-1,2,4-oxadiazoles have been synthesized by 1,3-dipolar cycloaddition of coordinated dinitriles 249a,d to nitrones 250a–c (Scheme 13.89). Moreover, Pt(II)oxadiazoline complexes 251a and 251d, having only one of the coordinated nitriles, have been used for various new mixed ligand complexes. Thus, 252–254 have been obtained by reaction of the corresponding oxadiazolines with pyridine, 4-N-dimethylpyridine, and 1-benzyl-2-methylimidazole, respectively (Scheme 13.90) [248]. A novel type of heterocycle, 2,3a-disubstituted 5,6-dihydro-3aH-[1,3]oxazolo[3,2-b] [1,2,4]oxadiazoles 258a–g, has been generated by an intermolecular Pt(II)-mediated 1,3-dipolar cycloaddition between the oxazoline N-oxide 256 and coordinated nitriles

j 13 Oxadiazoles

1106

Ph C X

O

Pt

+ X

N

Me N O

R1

N

N

R2

C

Me

R2

68-76%

X

R1

N

Pt

Ph

Ph

N C

250a-c

249a,d

Ph

251a-d

R2

R1

X

X

O

N

46-71% a

Cl

H

Ph

b

Br

H

Ph

c

I

H

Ph

d

Cl

CO 2E

CH2 CO 2Et

R2 R1 R2 X Ph

N

Pt N

O N Me

250a-c R1

Me N O Ph

X

R2

R1

Me

261a-d

Scheme 13.89

Ph H Cl

N

Pt

Me

Me N

Ph N

Cl

Me N O

N

Ph Pyridine

H

CHCl 3 , 60 °C

Ph

Cl

24 h, 77%

Cl

N

Pt N

251a

252

EtO 2 C

N Ph Me

CHCl 3 , 60 °C 24 h, 62%

Me N O

EtO 2 CH2 C N Cl Pt Ph Cl N N Ph

Me

254

Me N O Ph

Cl

C Ph

EtO 2 CH2 C N Cl Pt Ph N Cl C Ph 251d

Scheme 13.90

N

24 h, 27%

N

Me N O

Pt

CHCl 3 , 60 °C

253

EtO 2 C

H Cl

Ph

N Me N Me

Me N O

13.3 1,2,4-Oxadiazoles

j1107

in the complexes trans/cis-[PtCl2(R-CN)2] 255. The reaction is unknown for free RCN and oxazoline N-oxides, but under PtII-mediated conditions the reaction proceeds smoothly and gives pure complexes 257a–g in 42–79% yields (Scheme 13.91) [249].

R1

R1

C N

Cl

O

Pt N 1

R

+

42-79%

N O

Cl

C

R

256

255

Cl O R Pt N N Me Me O R1

R = Me, Et

15-86%

O N

Me N

Me

R O Cl 257

ethane-1,2-diamine

1

R = Me, Et, Ph. Bn

O R N N Me Me O R1 258 Scheme 13.91

13.3.4.5 Synthesis of 1,2,4-Oxadiazolidines A general synthetic approach to 1,2,4-oxadiazolidines 259 exploits the 1,3-dipolar cycloaddition of nitrones to a C¼N double bond, a method first used by Beckmann (Scheme 13.92) [250].

EtO 2 C H

R1 N

+ CCl3

O

52-84% N

R

R1 R

CO 2Et N CCl3 N O 259

R = CH2 Ph, Me, Ph R1 = Ph, 4-O 2NC6 H4, 4-MeOC 6H 4 Scheme 13.92

j 13 Oxadiazoles

1108

The use of isocyanates and isothiocyanates as dipolarophiles affords an easy entry to 1,2,4-oxadiazolidinones and thiones 260 (Scheme 13.93) [251]. R1 Ph N C X

+ O

MeCN, ∆ N

Ph

27-57%

R

X

R= Me, PhCH2, 4-O2NC6H4, 2,3-(MeO)2C6H3CH2

R1 N O

N R

260 X = O, S

R1 = Ph, 2-O2NC6H4, 3-O2NC6H4, 2,3-(MeO)2C6H4, 3,4-(MeO)2C6H4 Scheme 13.93

On this basis, 1,2,4-oxadiazolidinones as stable chiral building blocks have been prepared by 1,3-dipolar cycloaddition of isocyanates with mannosyl- or erythrosyl derived nitrones 261. The reaction proceeds with a good diastereoselectivity, giving enantiopure 1,2,4-oxadiazolidin-5-ones 262 after removal of the auxiliary (Scheme 13.94) [252]. R1

R1 R N C O

Me O

+

69-87% N

Me

O Aux 261

O

Me Me

O

Aux= O H

O

Me

R

;

O

N

N Aux O 262

Me O

O

O H

R= Ph, PhCH2 , PhCO, 4-O 2NC6 H4, 4-CF 3C 6 H4, 4-FC 6H 4, 4-MeOC 6H 4, 2,6-Cl2 C 6H 3, R1 =Me, Cy, t-Bu, Ph, 3-Py, 2-furyl, 1- Naph, 4-O 2NC 6H 4, 4-CF3 C6 H 4, 4-BrC 6 H4, 4-MeOC 6H 4 Scheme 13.94

The reaction of oxaziridines 263 with isothiocyanates affords 1,2,4-oxadiazolidin-5thiones 264; interestingly, the reaction of 263 with chlorosulfonyl isocyanate 265 leads to 1,2,4-oxadiazolidin-3-ones 266, as established by X-ray crystallography (Scheme 13.95) [253]. 13.3.4.6 Synthesis of 1,2,4-Oxadiazole-N-Oxides The 1,3-dipolar cycloaddition of amidoximes 267 with nitrile oxides affords an easy entry to 1,2,4-oxadiazole-N-oxides 268, through elimination of an amine (Scheme 13.96). A version of this approach exploited the use of Wang-supported nitrile oxide [224, 254].

13.3 1,2,4-Oxadiazoles

Ph

R1 R

R2

R2 N C S toluene, ∆ , 3-10 h

N O

N R O

S

30-85%

263

N

264

R = t-Bu; R 1 = H R 2 = Bn, Cy, allyl

CH 2Cl 2, ∆

ClO 2 S N C S

30 min

265

O O ClO2 S

N

H

Et 3 N/H 2O

N R

R1 R

N

N R O

77-92%

O 1

266

R= i-Pr, t-Bu R1 = H, 4-Cl, 4-Me

Scheme 13.95

R1 +

N O

NR3

R2 N

25-53%

OH

267

j1109

O N

R1

N O

R2

268

R1 = Ph, 4-MeOC6H4, 4-ClC6H4, 4-O2NC6H4, 4-MeC6H4 R2= Me, Ph, 4-O2NC6H4, 4-MeOC6H4, 4-ClC6H4 R3 = H, Et Scheme 13.96

13.3.5 Reactivity of 1,2,4-Oxadiazoles 13.3.5.1 Reactions with Electrophiles 1,2,4-Oxadiazoles are rather inert against electrophilic attack. Halogenation, nitration, Friedel–Crafts alkylation, and acylation do not occur in this ring system. However, electrophilic mercuration of 5-unsubstituted oxadiazoles 269 is possible (Scheme 13.97) [120]. 3,5-Diaryl-substituted 1,2,4-oxadiazoles serve as monodentate ligands for some transition metal complexes. The reaction of 1,2,4-oxadiazole 270 with Cu(II)acetate, to give 271, occurs selectively on N4 (Scheme 13.98) [170].

j 13 Oxadiazoles

1110

R

R

45-50%

N

30d,HgCl 2

N O 269

N N O

HgCl

AcONa/H 2 O

R=Me,Ph Scheme 13.97

O N Ph

N Ph

HO

N

O Cu

67%

N O

Ph

Cu(OAc) 2 /EtOH

N

O

N O

270

271 Scheme 13.98

The closely correlated oxadiazole 272 is, by treatment with dimethyl sulfate and perchloric acid, methylated at N2 to give the 1,2,4-oxadiazolium salt 273 (Scheme 13.99).

Me

N

H O

Me 2SO4

N O

HClO4 /AcOH

Me

N

Me

N O ClO4 273

70%

272

HO

Scheme 13.99

An interesting example of an intramolecular electrophilic attack at the N2, reported in Scheme 13.100, yields oxadiazolopyrimidinium salts 274 [255]. R R

H N

HClO4 /MeCN

N N O

R

N

R1

N N O

30-60% R

O

274 R = H, Me, CF3 R 1 = Me, Ph Scheme 13.100

R1

13.3 1,2,4-Oxadiazoles

Acetylation of 1,2,4-oxadiazoline 275 with acetic anhydride in pyridine furnishes the N2-acetylated compound 276, while the treatment with potassium hydride in 1,2dimethoxyethane (DME) gives mixtures of the N2 and the N4-acetylated heterocycles 276 and 277, respectively (Scheme 13.101) [120b]. Ar

HN Et

O

O

Et

275

N Ac O 276

Ar = Ph, Tolyl Ac

Ar

N

Ar

N

70 °C, 47-90%

Ac2O DME

KH

Et

N

Ac2O, Py

+

N Ac

Et

Ar

N O

276

N

277

Scheme 13.101

4,5-Dihydro-1,2,4-oxadiazol-5-one 278 can be N-alkylated with alkyl halides or with epoxides in the presence of bases to give 279 and 280, respectively (Scheme 13.102) [256]. O

Me HO

N O

Ph

N O 280

H

Me 77-90%

O

Ph

N O

N

278

RX 58-90%

R O

Ph

N O

N

279 R = Me, Et, Pr

Scheme 13.102

Similarly, 4,5-dihydro-1,2,4-oxadiazol-5-one 278 reacts with alkyl halides 281 and 283 to give the N4 substituted derivatives 282 and 284, respectively. Compound 278 also reacts with acrolein, via Michael addition, to give 285 (Scheme 13.103) [257]. Unsubstituted 1,2,4-oxadiazolidine 3,5-dione (286) undergoes alkylation preferentially at N2. Thus, the reaction with benzyl bromide leads to 2-benzyl derivative 289, which can be further methylated at N-4 to give 290 [258]. Similarly, the reaction with (S)-aziridine 287 produced the protected (S)-quisqualic acid 288 (Scheme 13.104) [259]. 13.3.5.2 Reactions with Nucleophiles Nucleophilic attack on 1,2,4-oxadiazole systems occurs mainly at C5 with nucleophilic displacements of good leaving groups. Table 13.5 summarizes some of these reactions [120, 121, 198, 218, 260].

j1111

j 13 Oxadiazoles

1112

R Br EtO

OEt

Cl O

Me N

O O

Me O

O 281

O

O

N

O 278

Cs 2CO 3 58%

282

Me

R

283

HN

N

N O

87-90% O

N O 284

R = H, Br, NO 2

100% O Me N O

O

N

285 Scheme 13.103

BOC N H

O

N

O

O

287

N H

O

CO2t-Bu

N O

N

NHBOC

288

DMF

PhCH2Br Na2CO3

O

DMF, 98 °C 18h, 49%

286

H

H

CO2t-Bu

91%

MeI

N O

N

289

Ph

DMF

Na2CO3 87%

Me O

N O

N

Ph

290

Scheme 13.104

The 3-position is remarkably stable to nucleophilic attack. While the 5-trichloromethyl group of 291 leads, by treatment with KOH, to the 5-oxo compound 292, the 3-trichloromethyl isomer 293 gives carboxylic acid 294, which rearranges with loss of CO2 to acetyl cyanamide 295 (Scheme 13.105) [261].

13.3 1,2,4-Oxadiazoles Table 13.5 Nucleophilic displacements on 1,2,4-oxadiazoles.

R1

N X

O

Reagent

R1

N

N

Y

23-60%

O

N

R1

X

Reagent

Y

Me Me Me C6H4-p-NO2 C6H4-p-Me C6H4-p-NO2

Cl Cl OEt S-C6H2-[2-Cl-4,6-(NO2)2] Cl CCl3

OH MeNH2 Me2NH (CH2)5NH PhCH2ONa NH3

OH MeNH Me2N (CH2)5N PhCH2O NH2

Me N Cl3C

N

∆

291

100%

O

CCl3 N Me

O

H

KOH, EtOH

N

293

O

O

N

292

CO2H

KOH, MeOH HCl, EtOH

Me N

N Me

O

N

294

H - CO2

N Me

N

O 295

Scheme 13.105

Nucleophilic addition of hydrazine or hydroxylamine to the 5-position of 5fluoroalkyl-1,2,4-oxadiazoles leads to triazole or oxadiazole derivatives 296 and 297 (Scheme 13.106) [135, 228, 262]. The reaction of fully conjugated 3,5-diaryl-1,2,4-oxadiazoles 298 with butyllithium allows facile access to 5-butyl-3,5-diaryl-4,5-dihydro-1,2,4-oxadiazoles 299 (Scheme 13.107) [263]. A similar reaction occurs with 3-methyl derivative 300 to produce 301 [120a], while the 5-methyl of 302 is deprotonated by butyllithium to afford the anion 303, which produces, after CO2 treatment, the corresponding acid 304 (Scheme 13.108) [264]. 4,5-Dihydro-1,2,4-oxadiazol-5-one 305 hydrolyzes by treatment with NaOH to give amidoximes 306 (Scheme 13.109) [153]. 13.3.5.3 Reductions and Oxidations of 1,2,4-Oxadiazoles Catalytic hydrogenation of 1,2,4-oxadiazoles 307 have been reported, and begins with N-O fission, leading to the corresponding iminoamides intermediates 308 that under

j1113

j 13 Oxadiazoles

1114

R1 N R

N

N O H R

HCl, EtOH

R1

H

N HX

N

O

R1

H

NH2XH

N

HX N

R

N OH

R = CF3, C3F7, C7F15 R1 = PhCO, 4-MeOC6H4, C11H23 H R

N R1

X

R N

HO

N

N 1X H R

70-94%

N

296 : X = NH, NMe 297 : X = O Scheme 13.106

R1 N Ar

N

O

R1

H THF, BuLi - 78 °C

N Ar Bu

O

23-60%

298

N

299

Ar = Ph. 2-ClC6H4, 2-OHC6H4, R1 = Ph, 2-ClC6H4 Scheme 13.107

Ph

THF, BuLi

O

N Ph Bu

N

300

- 60 °C

Me

Ph N H2 C

N

302 Scheme 13.108

N

301

THF, BuLi

O

O

83%

Ph N

Me

H

Me N

- 60 °C, 30 min

O

N

Ph HO 2C HCl/H 2O

303

N

CO 2

67%

O

N

304

13.3 1,2,4-Oxadiazoles

R

Me

NaOH

N O

O

R

j1115

Me HN

N

61-83% HO

N

305 306 R = H, Br, NO 2 Scheme 13.109

the reaction conditions adopted are converted into amidines 309 (Scheme 13.110) [265].

N R=

N

CO 2t-Bu

N

O

O 80% 1) H 2, Pd/C, EtOH, AcOH 2) H 2O

R N Me

O

N

R

H 2, Ni/Raney

77%

HN

MeOH/AcOH

Me

307

O

NH

308

R

NH2 NH 309

OMe N

O

N Me

NH R=

Me

Scheme 13.110

LiAlH4 reduction furnishes N-substituted amidoximes [121, 266]. An application of this reaction concerns the reduction of the Wang resin-bound 1,2,4-oxadiazole 310 to furnish directly the amidooxime 311 via a reductive cleavage from the resin followed by a reductive ring opening of the 1,2,4-oxadiazole ring (Scheme 13.111) [267].

j 13 Oxadiazoles

1116

Me

N O

LiAlH 4

O

N

Me

HN

N 95%

HO

H N

N

O 310

311

Scheme 13.111

Amidines are also obtained by catalytic hydrogenation of 4,5-dihydro-1,2,4-oxadiazoles. Thus, 1,2,4-oxadiazolo[4,5-a]indolines 312 are catalytic hydrogenated over Raney nickel to furnish the corresponding amidines 313 that under tautomerization reaction lead to the opened structures 314 (Scheme 13.112) [268]. Me O

Me Me

N

H2 , Ni-Ry

Me

N Ar

O

Me OH NH N Ar

Me

60-92%

Me Me

313

312

Me NH 2 N

Ar

314

Ar= Ph, 4-Cl-C 6H 4,2-Cl-C 6 H4 , 2,6-Cl 2-C6 H3 , 2,4,6-Mel3 -C6 H2 Scheme 13.112

Similar reactions have been reported for 4,5-dihydro-1,2,4-oxadiazole 5-ones 315 (Scheme 13.113) [269]. R1 N O

R

O

N

R1 N

H2 , Pd/C 91-99%

Ph

O

R NH

R

R1 NH NH

315

R = Me, 4-Me-C 6H4 R1 = H, Me Scheme 13.113

Oxidation of 4,5-dihydro-1,2,4-oxadiazoles 316 leads to fully conjugated 1,2,4oxadiazoles 317; the oxidation has been performed with different oxidants such as N-chlorosuccinimide, manganese dioxide, and concentrated HNO3 (Scheme 13.114) [125, 162, 169].

13.3 1,2,4-Oxadiazoles

H

R N

H R

1O

N

R

Ox

N R1

74-95%

O

N

317

316 R = Me, 4-Me-C 6H4 R 1 = H, Me Scheme 13.114

13.3.5.4 Thermal and Photochemical Ring Cleavage Owing their low aromaticity, 1,2,4-oxadiazoles undergo, by thermal or base-treatment, an easy ring rearrangement known as the Cusmano–Ruccia or Boulton–Katritzky rearrangement. This rearrangement involves a nucleophilic attack on N2 by the oxygen, sulfur, selenium, nitrogen atoms, or carbon anion of a side chain (W) linked at the 3-position of the heterocycle. The generalized rearrangement is reversible only when atom W is oxygen. Table 13.6 summarizes the more common rearrangements [270]. The ring degenerate version of the process has also been reported and investigated as a function of substituent effects and experimental conditions [271]. Thus, for the interconversion 318–319, mixtures enriched in compound 318 are obtained, while in neutral conditions compound 319 predominates. The effect of substituent X is significant in basic media (Scheme 13.115). The rearrangement has been used for a synthesis of a series of 3-amino-5-aryl-, 3amino-5-alkyl-, and 3-amino-5-polyfluorophenyl-1,2,4-oxadiazoles 321 starting from 3-amino-5-methyl-1,2,4-oxadiazoles 320 (Scheme 13.116). Detailed studies of experimental and theoretical aspects of the rearrangement of phenylhydrazones of 3-benzoyl-1,2,4-oxadiazoles 322 and 323 into the corresponding triazoles 324 and 325 have been performed (Scheme 13.117) [272]. Table 13.6 Rearrangement reactions of 1,2,4-oxadiazole rings.

X

N Ar

O

N

Y W

X

N Ar

OH

N

Y W

Sequence atoms XYW

Rearranged products

Sequence atoms XYW

Rearranged products

NCC CNO NCS NCSe

Imidazole 1,2,5-Oxadiazole 1,2,4-Thiadiazole 1,2,4-Selenadiazole

CNN NCN CCO CNC

1,2,3-Triazole 1,2,4-Triazole Isoxazole Imidazole

j1117

j 13 Oxadiazoles

1118

H N

N Me

O

N

O

O

7-93%

N X

H N COMe N

X 319

318

X=H, p-Me, p-OMe, p-Cl, p-CF 3, p-CN, p-NO 2, m-NO2 , m-Me, m-Cl, m-CF3, p-CN, m-OMe Scheme 13.115

NH2

N Me

N

O

RCOCl Py

N Me

O

H N

R

O

R

N

9-91%

320

N

O

NH2 N

N

H,EtOH R 50-90%

O

H N COMe N

321 R = n -Pr, t-Bu, n -C11H23, Ph, 4-CF3 -C6 H 4, 2-NO2 -C6 H 4, 2-CF3 -C6 H 4, 3-CF3 -C6 H 4, 2-Furyl, 2-Thienyl, 2,3,4,5-Tetrafluorophenyl, 2,3,4-Trifluorophenyl Scheme 13.116

1,2,4-Oxadiazoles undergo photochemically induced azole to azole interconversions, similar to the previously mentioned thermal rearrangements (Scheme 13.118) [273]. Thus, photolysis of the 3-acetamino-1,2,4-oxadiazole 326 involves cleavage of the N
O bond and the formation of the new oxadiazole 327 (Scheme 13.119). Similarly, the irradiation of 3-(o-aminophenyl)-1,2,4-oxadiazole 328 affords the indazole 331 from the photolytic species 329 and the benzimidazole 332 as

13.3 1,2,4-Oxadiazoles

N Me

Ph C N

O

N H

N

X

H N

O KOH, EtOH

Ph

N

90-99%

Ph N

N

X 322 324 X= H, p-Me, p-OMe, p-Cl, p-CF3, p-CN, p-NO2, m-NO2, m-Me, m-Cl, m-CF3, p-CN, m-Me, m-Et, p-Et, p-Fl, m-Fl, m-Br, p-Brl

O2N Ph C N N N N H O

X

O EtOH

NO2

X

82%

H N N

Ph N

N NO2

X = Ph, NH2

323

NO2 325 Scheme 13.117

X

N Ph

O

N

Y W

X

N

hν Ph H

O

N

Y W

H

X=O,NR;Y=W=COR X Y

O Ph

N H

W N

Scheme 13.118

a byproduct originating from the carbodiimide 330, the rearrangement product of 329 (Scheme 13.120) [274]. UV irradiation of 1,2,4-oxadiazoles 333 in the presence of nucleophilic nitrogen sources (primary amines, ammonia, hydrazine) affords triazoles 335, via cleavage of the N
O bond and addition of the nucleophile to the intermediate 334 (Scheme 13.121) [275].

j1119

j 13 Oxadiazoles

1120

H N

N Ph

O

N 326

C O

Me

H N

N

hν, 18h Ph

MeOH

O

N

Me O

90%

Me O Ph

N N

N H

O

327 Scheme 13.119

h ν, 254 nm N 1

R

O

N

NH R 2

328

+ N

MeOH

R1

O

NH R 2

N

N C N 1

R

O

329

HN R2 330

R 1 = Ph, Me, H R 2 = Me, H R1 O

N

H R2 +

N

N R2

331

20-40%

O N H

N N R1 332 50-60%

Scheme 13.120

The use of methanol as nucleophile leads to a 1 : 1 mixture of 1,3,4-oxadiazole 337 and triazole 336 (Scheme 13.122). When an amino group is present at C5, the reaction with a sulfur nucleophile leads to 1,2,4-thiadiazoles 338 (Scheme 13.123) [276]. Irradiation of 1,2,4-oxadiazoles-4-oxides 339 in methanol causes the initial formation of an isolable nitrile together with the nitrosocarbonyl derivative 340, which

13.3 1,2,4-Oxadiazoles

Ph N O

R1

N

Ph

R 2 NH2 h ν, 254nm MeOH

N O

R1

37-60%

333

Ph N R

Ph N

N

1

335

N

N R2

R1

O

N NHR 2

334

Scheme 13.121

OMe

NHR N R1

O

N

Et 3 N h ν, 254nm MeOH 27-40%

N 1

R

336

N

N R

+

N N R1

O

NHR

337

R=Me,Pr R 1 =C7 F15, C3 F7 Scheme 13.122

can be trapped by cyclohexadiene to give the hetero-Diels–Alder adducts 341 in good yields (Scheme 13.124) [277]. The intermediate nitrosocarbonyls 340 can also be trapped in ene reactions to give adducts 342 and 343 [254, 278]. The 1,2,4-oxadiazol-5-ones 344 undergo, when heated in vacuum, a retro-1,3dipolar cycloaddition to give nitrones 345 (Scheme 13.125) [251]. 13.3.5.5 Reactivity of Substituents Reactions involving substituents attached to ring carbons reveal the particular stability of the heterocyclic system. A series of examples are related to the formation and reactivity of a-anions. Thus, 5-methyl-3-phenyl-1,2,4-oxadiazole (302) is deprotonated by bases to the corresponding anion, which adds to carbonyl group of ketones or CO2 [264]. Conversely, the methyl group of 3-methyl-5-phe-

j1121

j 13 Oxadiazoles

1122

Ph N O

H2N

Ph

h ν, 254 nm

N

N

MeOH

H2 N

45-67%

N

O

S R = Ph, Me, H

X

NHR

X = MeO, NH2 Ph

Ph N S

RHN

HN

N

O

H2 N

N S

X NR

338 Scheme 13.123

N R

1

O

R N

hν, 313 nm

R CN +

MeOH

O

339

N

1

73-87%

R

O

O

O 340

R2 R3

HO

H

343

R5 O R3 R2

R4

90-99%

N ROC

N R O 341

61-95%

Ph

R2, R3, R4, R5 = H, Ph, Me

N H

R5 R4 342

R = Ph, 2,4,6-MePh, p-Cl-Ph, p-MeOPh R1 = Ph, 2,4,6-MePh, p-Cl-Ph Scheme 13.124

nyl-1,2,4-oxadiazole (300) by treatment with butyllithium does not form the anion: the reagent adds to the 4,5-bond (Scheme 13.108) [120a]. 1,2,4-Oxadiazole 302 also undergoes the aldol condensation with benzaldehyde (Scheme 13.126) [120a].

13.3 1,2,4-Oxadiazoles

Ph

R

N O

N

O

H

∆

R

N O

vacuum R1

R1

26-57%

H

345

344

R = Ph,2,3-(MeO)2 Ph, 2-NO2 Ph,3,4-(MeO)2 Ph R 1 =H, Ph, 2,3 - (MeO)2 Ph Scheme 13.125

Ph

N Me

O

PhCHO Ph

N

O

ZnCl2

N

65%

190 °C, 15 h

302

Ph

N

Scheme 13.126

Phosphonate 347, obtained by Arbuzov reaction of 3-chloromethyl-1,2,4-oxadiazole 346, has been used in Wadsworth–Emmons reactions: the methodology provides useful access to 3-alkenyl-1,2,4-oxadiazoles 348 (Scheme 13.127) [264].

O

Cl

N

Ph

O

N

P(OEt) 3

Ph

78%

N

O

347

346

OTMS

Me

TMSO R=

O

Me

NaH

22%

RCOMe

OTMS R

O

N

Ph

O

Me N

348 Scheme 13.127

P OEt OEt

N

j1123

j 13 Oxadiazoles

1124

The formation of a-anions has been exploited for the synthesis of a library of 5-alkenyl-substituted 1,2,4-oxadiazoles 353. Compounds 353 have been prepared starting from a polystyrene-supported oxadiazolyl-substituted selenium resin 350, prepared by reaction of polystyrene-supported selenyl acetic acid 349, with amidoxime and DDC through Porco’s two-step, one-pot condensation. Alkylation of 350 by base treatmentand additionof allyl bromidesproducedthe a-alkylatedseleniumresins351, whichwereusedasdipolarophiles ina1,3-dipolar cycloadditionto furnishpolystyrenesupported oxadiazolyl- and isoxazolinyl-substituted selenium resins 352. Oxadiazolyl and isoxazolinyl substituted olefins 353 were then obtained stereoselectively through selenoxide syn-elimination from resins 352 by H2O2 treatment (Scheme 13.128) [279].

DCC, 95°C, 20h Se CH 2CO 2 H 349

N Se

R HON

R

O

N

350

NH2

LDA, -60-40°C, 1h

R

N Se

O R1

R1

Br

351 R2

R = Ph, p-Me-C 6 H4 , p-F-C 6 H4 , p-Cl-C 6 H4 , R1 =Ph,H

rt,24 h

N O

2

R =CO2Et, p-MeO-C 6 H4 , p-Br-C 6 H4 , p-Cl-C 6 H4 , p-NO 2 -C6H 4

N R2 N

O O 353

R1

N

N

R

N

R H 2O 2,THF 0°C/rt, 80 min 48-72%

Se R1

O O

N N

R2 352

Scheme 13.128

The stability of the oxadiazole ring is pointed out in many reactions that substituents at C3 or C5 undergo. Among the more recent reactions, Scheme 13.129 shows the synthesis of aryl ethers 354 [280], the nucleophilic attack of methanol to a pentafluorophenyl or tetrafluorophenyl 1,2,4-oxadiazole (355) [275b], a Sonogashira coupling to afford 356 [195a], and the synthesis of amino compounds 357 by tetrapropylammonium perruthenate (TPAP) oxidation of the hydroxyl group followed by reductive amination of the resulting aldehyde [200]. The reaction of 5- and 3-chloromethyl-1,2,4-oxadiazoles 358 and 359, respectively, with pyrazolyl-purine affords the corresponding derivatives 360 and 361 (Scheme 13.130) [187]. Analogously, the polymer supported-1,2,4-oxadiazole 362 reacts with primary amines to give 5-aminomethyl oxadiazoles 363 (Scheme 13.131) [281].

13.3 1,2,4-Oxadiazoles

1) BBr3, CH2Cl2 R

N O

X

O

F

X = piperazine, morpholine

NH2

N O

F

N

X

F

MeOH, TEA

F

F

hν, λecc = 254 nm

N

X

F

X = H, F

NHBOC

NHBOC Cl

Cl

Cu(I), Et3N

I N

Pd(Ph3P)2Cl2

Ph

N

Ph

N O

NH2

N O

MeO

10-11%

355

Me

N

354

60-85%

R = H, 4-CF3, 4-OPh, 4-F, 4-Cl, 3-Cl

F

O

K2CO3, 90°C, DMF

MeO

R

N

2) chloroalkylamine

N

j1125

Me

O

N

72%

R

356 OH MeO2C

Ar

NH 1) NMO, TPAP

N O

N

2) 2- (NH2)-4-Me-Py, 2(NH2)-4-MeO-Py 3) NaBH(OAc)3 40-53%

MeO2C

Ar

N

N O

N

357

Scheme 13.129

A series of highly p-conjugated nonsymmetrical liquid crystals, based on the core 3,5-(disubstituted)-1,2,4-oxadiazole with a shape similar to a hockey stick, have been synthesized by Sonogashira coupling reaction. Thus, compounds 366 were prepared in 74–82% yield, by reaction of an aryl iodide containing the 1,2,4-oxadiazole ring (364) with the terminal arylacetylenes 365, using 10 mol.% of dichlorobis(triphenylphosphine)palladium, 5 mol.% of the co-catalyst copper(I) iodide, in a triethylamine–tetrahydrofuran mixture (7 : 3). The obtained compounds showed liquid crystal phases, in particular smectic and nematic typical of calamitic structures, and moreover exhibit strong blue fluorescence in solution (Scheme 13.132) [282].

R = Me, OMe

j 13 Oxadiazoles

1126

Pr R

N

Cl

O

O

O

358

O

SEM N

Pr N 1)

N

N

O N

NH N

N

NH

N Pr

N N

N

O

N

360

Pr K2CO3, MeOH, rt

R

R

N

Cl

N O

N

2) 3MHCl, EtOH

R

O

65-88%

359

N

N N

361

R = H,4-Cl,4-CF 3 ,4-CN,4-OMe,4-Me, 3-Cl,3-CF 3 ,3-OMe,3-Me, 2-Cl,2-CF 3 ,2-OMe,

Scheme 13.130

N

X

N

RNH 2

N O Cl

X

DMF 60-73%

362

O N

NHR

363

Me, PhCH2

Scheme 13.131 I C 10H 21O

365 CuI, PPh 3

N N

O

N

PdCl 2(PPh 3) 2

N O

Et3 N-THF

C 10H 21O 364

366

rt 18 h

OC nH 2n+1 L L = H, NO 2 n = 10, 12

Scheme 13.132

N

74-82%

N N H

Pr N

O N

O

Pr

13.3 1,2,4-Oxadiazoles

13.3.6 1,2,4-Oxadiazoles in Medicine

1,2,4-Oxadiazole ring occurs widely in biologically active synthetic compounds, and is often used in drug discovery as a hydrolysis-resisting bioisosteric replacement for amide or ester functionalities [283] because of its electronic properties. Its derivatives can be found in a vast number of compounds exerting biological activity, such as ligands of benzodiazepine receptors [284, 285], anti-inflammatory agents [131, 199, 234], antiviral agents [283], inhibitors of protein tyrosine phosphatases [286], agonists of muscarinic receptors [287], inhibitors of Src SH2 [183], antagonists of histamine H3-receptors [288], integrin receptor antagonists [200], angiotensin II receptor antagonists [289], and HIV-1 reverse transcriptase inhibitors [290]. 1,2,4-Oxadiazole moieties have been used in the design of dipeptidomimetics as peptide building blocks [184a,b]. Compounds 367 contain, at C5 of the 1,2,4-oxadiazole nucleus, a residue of an amino group linked to peptide moieties, and a carboxyl or ester functionality attached at C3 directly or through a methylene chain [291]

N O ROC

n =0, 1,2 R = OH, OEt, NHMe

n

N

R1 N H

R2

367 R 1 = PhCH2 , Me, i-Prop

R 2 = Ac, Boc, H-Tyr-D-Ala, H-Arg-Pro--Lys-Pro-Gln-Gln-Phe

Numerous 1,2,4-oxadiazoles have been suggested as potential agonists for cortical muscarinic [292], benzodiazepine [293], and 5-HT1D (5-hydroxytryptamine) receptors [294], and as antagonists for 5-HT [295] or histamine H3 receptors [296]. They show activity as antirhinoviral agents [297], growth hormone secretagogues [298], anti-inflammatory agents [234], and antitumor agents [183, 188, 299]. They also inhibit the SH2 domain of tyrosine kinase [300], monoamine oxidase [301], human neutrophil elastase [302], and human DNA topoisomerases. Finally, tropane derivatives of 1,2,4-oxadiazoles display high affinity for the cocaine binding site of the dopamine transporter [303]. More recently, it has been reported that the ring opening of N-oxides of adenosines 368, followed by exocyclic ring closure, in the presence of carboxylic anhydrides and thiophenol, followed by ammonia treatment, generates 1,2,4-oxadiazolyl imidazoles 369 (Scheme 13.133) [304]. The so-obtained separation of the fused imidazole and pyrimidine rings of purine nucleosides increases the conformation flexibility: these shape-modified analogues have been used to investigate triple helix formation and as probes for the study of enzyme interactions [305a].

j1127

j 13 Oxadiazoles

1128

O

AcO AcO

N

NH 2

N OAc

N

N

1) PhSH, (RCO) 2 O ( 48-83%)

HO

2) MeOH/NH 3

O

O

HO

(29-63%)

368

N N OH

N

R

NH2 N O 369

R = Me, Et, pr, i-pr, t-bu, C 5 H11, C7 H15, C9 H19 , Ph Scheme 13.133

Furthermore, a series of keto-1,2,4-oxadiazoles (370) have been prepared that have been shown to be potent inhibitors of human mast cell tryptase and useful in the treatment of asthma and allergic diseases. H N

O

O

R

N N

H2N

O

O 370

HCl

Cl

Cl

R = CF3 , C 3 H5 , OEt, N(CH2 )4 O, t-bu, i-pr, n-pentyl, 2,4-F2 C 6H 3, 3,4-F2 C 6H 3, 4-FC6 H4, 4-ClC6 H4

The 1,2,4.oxadiazol-5-one moiety can act as a bioisostere of the carboxylic acid function in retinoid structures. Recently, the solid-phase or solution-phase syntheses of a new series of non-carboxylic acid retinoic acid receptor ligands (RARs) bioisosteres of Am580 or tazarotene-like retinoids has been reported [305b]. In particular, the retinoidal activity of compound 371 (RAR-b,c selective) is significant. These non-carboxylic acid type RAR ligands may exhibit different pharmacological behaviors from classical carboxylic acid compounds, as well as unique biological activity, and they may provide further scope for clinical applications. N

O N H

371

O

13.4 1,2,5-Oxadiazoles

13.4 1,2,5-Oxadiazoles

1,2,5-Oxadiazole (372) is often referred to by the trivial name furazan; for 1,2,5oxadiazole-2-oxide (373), a common derivative, the trivial name furoxan is still in wide usage. The first report on a 1,2,5-oxadiazole ring system appeared in the 1850s: the parent compound 1 was prepared in 1964 by treatment of glyoxime with succinic anhydride [306]. For 2,1,3-benzoxadiazoles (374) and the corresponding N-oxide 375, the terms benzofurazan and benzofuroxan are commonly used. The partially reduced dihydro- (D2, D3) and tetrahydro-derivatives 376–378 are very rare.

N

O

N

N

N

372

O

N O

N

373

N

O

NH

376

O

374

HN

O

NH

377

HN

O

O N O N 375

NH

378

1,2,5-Oxadiazoles, their N-oxides, as well as their benzo-fused systems are biologically active compounds. Some of their derivatives are important because of their anthelmintic, fungicidal, bactericidal, and herbicidal action. They have also been found to possess antitumoral activity. Several reviews have been published on 1,2,5-oxadiazoles [307–311]: the most comprehensive account of the chemistry of furoxans and benzofuroxans is that by Gasco and Boulton [312], and the more recent one by Paton [313]. 13.4.1 Structure

1,2,5-Oxadiazole is a heteroaromatic compound; strictly, it should be regarded as a p-excessive heterocycle with six electrons distributed over five atoms. However, the p-electron density on the heteroatoms is so great that the values for the C-atoms are smaller than one, where p-deficiency prevails, thereby influencing the reactivity [314]. Despite low p-electron density on the C-atoms, 1,2,5-oxadiazoles do not react at all or onlyslowlywithnucleophiles:treatmentwithstrongbases, suchasNaOHinmethanol, causes ring opening to form sodium salts of a-oximinonitriles 380 (Scheme 13.134). The 1,2,5-oxadiazole ring is a stable system and annular-group tautomerism is not favored [308]. Thus, the two theoretically possible tautomeric forms 381a and 381b for 3-hydroxyfurazans 381 can be discarded on the basis of IR and NMR data, which show the exclusive presence of the hydroxy compound in chloroform solution (Scheme 13.135).

j1129

j 13 Oxadiazoles

1130

OH H N

R O

R

NC

N

N O 380

379 Scheme 13.134

OH

R N

O

N

R N

381

R

O O

O

H N O N

NH

381b

381a

Scheme 13.135

However, the formation of 2-alkyl-1,2,5-oxadiazol-3(2H)-ones 382 by alkylation of trimethylsilyl derivatives of 3-hydroxyfurazans using triethyl orthoformate has been reported [315]. The compounds were characterized by NMR and MS measurements. O

R N

O

N R

382

The N-oxide structure for furoxans and their benzo-derivatives was ascertained by Wieland [316] and Werner [317]. Ring-chain tautomerism is a distinctive feature of furoxan chemistry, as evidenced in the interconversion of 2-oxide 383 and 5-oxide isomers 384 (Figure 13.4: see Section 13.4.2).

R

R1

R1

R

O N O N 383a

O N O N 384a

O N O N

N

R

383b

R

O N O 384b

Figure 13.4 Example of ring-chain tautomerism shown by the interconversion of 2-oxide 383 and 5-oxide isomers 384.

13.4 1,2,5-Oxadiazoles

A furazan fused to a five-membered heterocycle was first described in 1908 [318]: annelation in 5/5-byciclic systems suggests the presence of strain energy in the molecules, which is manifested in the difficulty to form these compounds. Destabilization of the distorted aromatic oxadiazoles results not only from bond stretching, angular distortion, and torsional effects, but also from the decreased resonance stabilization [319]. 5,7-Dimethyl-3-phenyl-furazano- and –furoxano[5,4-a]pyridinium perchlorates (385 and 386), a new type of condensed system, have been obtained by cyclocondensation of aminophenylfuroxan and aminophenylfurazan with acetylacetone in the presence of HClO4. The structure of these compounds is supported by crystallographic analysis and CNDO/2 calculations [320]. Ph

N

N

O

Me ClO4

N Me 385

Ph

N

O N O N

Me

Me

ClO4

386

Very few partially or totally reduced 1,2,5-oxadiazole ring systems has been reported. For instance, a Japanese patent [321] describes the synthesis of 5-(4-oxo2,5-diphenyl-1,2,5-oxadiazolidine-3-yl)-2,4(1H,3H)-pyrimidinedione (387), the first representative of 1,2,5-oxadiazolidines. HN

O NH

O

O Ph N O N Ph 387

As a result of the low aromatic character of the benzofuroxan system, recent studies have revealed that nitrobenzofuroxan acts as very versatile Diels–Alder reagent, with the carbocyclic ring being capable of acting as a dienophile [322], a heterodiene [322], or a carbodiene [323], depending upon the experimental conditions. Thus, treatment of 4-nitro-6-trifluoromethylfurazan (388) and -furoxan (389) with 1,3-cycloexadiene afforded a mixture of fused derivatives 390 and 391, respectively (Scheme 13.136) [324]. 13.4.2 Theoretical Aspects

Theoretical studies on the structure and properties of 1,2,5-oxadiazoles have been reported. Molecular orbital calculations [325, 326] and ab initio quantum mechanical methodologies have been used to determine bond orders, total energies, ionization potentials, and dipole moments [327]: a good match with experimental data has been obtained.

j1131

j 13 Oxadiazoles

1132

NO2

NO2 N

O

+

83%

N (O)n

F3C

N O F3C

N (O)n

388 n = 0 390 389 n = 1 391 Scheme 13.136

Dipole moments for a set of substituted 1,2,5-oxadiazoles and 1,2,5-oxadiazole 2-oxides have been measured in benzene solution [328]. The dipole moment of furazans is oriented with the negative end towards the oxygen atom, while in furoxans the data revealed a strong electron shift from the exocyclic oxygen back into the heterocyclic system, corresponding to a mesomeric moment of approximately 3 D. The molecule of furoxan is well characterized as electron-overcrowded, particularly near the nitrogen atom N2. Dipole moments of 3-amino-4R-furazans 392 have been determined experimentally and also calculated by HF ab initio (STO-3G, 3-21G, 4-31G, 6-31G, 6-31G/431G, 6-31G levels) and semiempirical (MNDO, AM1, PM3) quantum chemical methods; good agreement with the experimental values has been found. R N

NH2 O

N

392 R = H, NH2, OMe, N3, COOH, COOMe, NO2

For these compounds, the amino–imino tautomeric equilibrium is strongly shifted towards the amino-form [329]. A great deal of interest has been taken in the 2-oxide and 5-oxide tautomers and the pathway of their interconversion (393$395) has been studied in some detail [330–335]. Structures and relative stabilities of furoxan and its open-chain tautomers have been calculated by semiempirical and ab initio procedures. The obtained results support a mechanism that involves the cis-1,2-dinitroethene 394 as intermediate/transition state, with an energy about 120 kJ mol
1 above that of furoxan. R

R1

O N O N

393

R

NO

R1

NO

394

R1

R

O N O N

395

Analogously, in the benzofuroxan series, MP2 calculations afford a correct prediction of the structure [336]: the most likely intermediate in the interconversion

13.4 1,2,5-Oxadiazoles

396$398 is anti-1,2-dinitrosobenzene (397) with an energy of 50 kJ mol
1 above that of benzofuroxan [337]. O N

O N O N

N

O N O

N O 397

396

398

The involvement of 1,2-nitrosoarenes as intermediates in the equilibration process has been established by matrix isolation experiments [338–340]: photolysis (360 nm) of benzofuran in an argon matrix at 14 K generated 1,2-nitrosobenzene, which was characterized by UV and IR spectroscopy, and subsequent thermolysis or photolysis (320 nm) afforded benzofuroxan. The gain of resonance energy of the benzene ring does not compensate for the energy needed to open the furoxan ring, and therefore dinitrosobenzene is less stable than benzofuroxan. More recently, the first experimental evidence for the formation of 2,3-dinitroso2-butene as a reactive intermediate, during the photolytically induced decomposition of dimethylfuroxan, has been reported by matrix isolation experiments [341a]. DFT calculations gave the geometry of the dinitrosoalkene intermediate [341b]. However, this species is photolabile and decomposes upon prolonged photolysis time to give acetonitrile N-oxide as the final, photostable product. The two photoproducts were characterized using a combination of experimental and quantum chemical results. Factors influencing the equilibrium constants and rates have been reviewed [312, 342–344]. The equilibrium between annelated furoxans and the isomeric dinitroso derivatives, for example, 399 and 400, has been investigated theoretically by semiempirical (AM1, PM3) and ab initio methods (MP2/6-31G//6-31G and RHF/6-31G ) [345]. For both 1,2- and 2,3-dinitrosonaphthalene, several conformers exist as minimum on the potential energy surface (PES). Calculations of the energy difference between [1,2,5]thiadiazolo[3,4-e]benzoxadiazole-1-oxide and -3-oxide are in agreement with experimental data. O N

O N O N

399

N O 400

Ab initio and density functional theoretical studies on non-classical furoxans 401 (Y ¼ O, NH, S for each of the following combinations of X,Z: CH,CH; N, CH; CH,N; and N,N) and their open-chain anti-1,2-dinitroso isomers 402 have been reported [346, 347]. Calculations indicate that, in all cases considered, the non-classical furoxans are less stable than the corresponding open-chain isomers.

j1133

j 13 Oxadiazoles

1134

Y

O N O N

X Z

401

Y

X

NO

Z

NO

402

Density functional theory (DFT) has been used to calculate the heats of formation and IR active vibrational frequencies of 12 furazan compounds [348]. The assignments of the vibrational motions to IR frequencies based on a force field analysis are given to clarify the complex coupling in these molecules. Dissociation enthalpies of terminal (N
O) bonds, DH (N
O), in furoxans have been calculated from enthalpy of formation, enthalpy of sublimation, and enthalpy of vaporization data [349]. 13.4.3 Structural Aspects 13.4.3.1 X-Ray Diffraction X-Ray crystal structures have been reported for various furazans and furoxans [350– 357]. Bond lengths and bond angles have been determined also by double resonance modulation microwave spectroscopy [358]. For furazans, crystallographic data show that the heterocyclic ring is essentially planar and possess C2v symmetry. p-Bond orders are 0.72–0.82 for N2
C3 and C4
N5 and 0.45–0.52 for C3
C4. These data suggest a significant p-delocalization; in contrast, O1
N2 and N5
O1 are essentially single bonds (0.32–0.36). Benzofurazans show similar parameters and a significant double bond fixation in the fused ring. The molecular geometry for the parent furazan (403) has been determined by microwave spectroscopy. 0.5051

N

0.8116

N O 0.3563 403

As for furazans, the oxadiazole ring of furoxans in nearly planar, but the exocyclic  oxygen at N2 causes substantial distortion, lying 0.05 A out of the plane of the heterocycle. Structures are characterized by the long O1
N2 and the short N2
Oexo bonds. Moreover, C3
C4 is shortened, with about 30% double bond-character, while N2
C3 is longer than C4
N5. Benzofuroxans show a similar pattern of bond lengths and angles. In the homocyclic ring, significant bond localization is supported by the consideration that the C4
C5 and C6
C7 bonds are notably shorter than C5
C6, in accord with their chemical reactivity (Section 13.4.5.2). Crystal structure simulations for three azoxyfurazans, 4,20 -dichloroazoxyfurazan (404), 4,40 -di(morpholin-1-yl)azoxyfurazan (405), and 4,40 -dimethylazoxyfurazan (406), have been carried out to test the reliability of standard force fields for

13.4 1,2,5-Oxadiazoles

j1135

furazan derivatives [359]. The predicted crystal structures were compared with experimental ones, obtained by X-ray diffraction analysis. O N N

MeN N N O N

Cl

Cl O

N

N

O N N

O N N O N

O

N O

N N O N

Me

N

405

404

Me O

N

406

X-Ray data for 1,2,5-oxadiazoles fused with a pyrazine ring have been reported recently [360]. Azofurazan annulated macrocycles 407 [361], 408 [362], and 409 [363] have been synthesized and then characterized by X-ray analysis. Lactam 407 show two furazan rings linked to a piperazine system, while compound 408 contains four furazan rings bonded by three azo bonds. The ion binding ability of compounds 409 was tested. N O N

N

N

O N

O

N

N O N

O

N N

N

O

N N X N O N

407

O N N

N N N N N

N N

R1

N N N O

O

N

O

O

N N O

R R1

408 X = O, S, O(CH2)2O

R

O

N N O

409

13.4.3.2 NMR Spectroscopy Monosubstituted furazans [364], phenylfurazans [365], azoxyfurazans [366], and hydroxy-, alkoxy- and phenoxyfurazans [367] have been studied by NMR spectroscopy. Additive schemes have been developed and spectrum–structure correlations have been elucidated. Table 13.7 reports the NMR chemical shifts (1 H, 13 C, 15 N, and 17 O) of furazan, furoxan, and their benzo derivatives [308].

Table 13.7 NMR chemical shifts (ppm) for furazan, furoxan, and their benzo-fused derivatives.

Compound

H3

H4

C3

C4

N2

N5

O1

Furazan Benzofurazan Furoxan Benzofuroxan

7.92

7.92 8.50

142.0 148.6 146.8 152.2


33.5
35.6
15.4
25.3


33.5
35.6 3.9
13.2

450

7.44

142.0 148.6 105.2 113.7

507.5

O-exo

364.0

N

O N

j 13 Oxadiazoles

1136

In the furoxan series the lower chemical shifts of 3H with respect to 4H is due to the contribution of the resonance structure 411. R

R

O NO N 410

R

R

O N O N 411

R

R

R

R

O N O N

O NO N

412

413

The strong shielding effect exerted by the exocyclic oxygen atom on the proton attached to the substituents at C3 allows one to identify the individual isomer 383a and 384a. Thus, for dimethylfuroxan the resonance at 2.16 ppm is assigned to the 3-methyl group, while that at 2.38 ppm is attributable to the 4methyl group [368]. In benzofuroxans, the shielding effect exerted by N-oxide shifts all the signals to higher frequency with respect to the resonances of benzofurazans, with the larger shifts for H7 and for H4 [369]. The ring-chain tautomerism of these compounds has been investigated by 1 H spectroscopy. The unsymmetrical ABCD pattern for the homocyclic protons, observed at
40  C, changes into a symmetrical A2B2 pattern at 100  C, as a consequence of the rapid equilibration of two isomers. In this way, exchange rates over a range of temperatures have been determined and thermodynamic activation parameters calculated [344, 370]. The most noteworthy feature of the 13 C NMR of furoxans is the large difference in chemical shifts of C3 and C4 resonances. As indicated in Table 13.7, C3 resonates at higher field in the range 100–123 ppm, while C4 appears in the range 140–160 ppm [368]. The chemical shifts and multiplicities of the two bridgehead carbons in the 13 C NMR spectra of various fused furoxans have been shown to provide a general method for assigning structure in these tautomeric systems [371]. 3-Methylfurazans with nitrogen-containing substituents at C4 have been studied by 1 H, 13 C and 14 N NMR spectroscopy [372]. A correlation between the chemical shifts in 13 C NMR spectra of these furazans and monosubstituted benzenes with the same substituents was found. The influence of substituents on the NMR data of the iodofurazans was also investigated [356]. The 15 N NMR spectra of furazan and benzofurazan show a single absorption at
33 and
36 ppm, respectively [373, 374]. The nitrogen atoms of furoxans show distinct signals in the range
26 to
15 for N2 and
14 to þ 4 ppm for N5: these resonances coalesce on heating. The parent furoxan 373 has 17 O signals at 508 and 364 ppm, while furazan 372 shows a single resonance at 450 ppm [368]. The corresponding figures for dimethylfuroxan are 460 and 350 ppm, and 475 ppm for dimethylfurazan. 13.4.3.3 UV and IR Spectroscopy Characteristic peaks in the IR spectra of furazans are in the ranges 1525–1560 (C¼N
O), 1430–1385 (N
O), and 1040–1030 and 890–880 cm
1 (heterocyclic ring). Furoxans show diagnostic peaks at 1625–1600 (CN
O), 1490–1400 (C¼NO2),

13.4 1,2,5-Oxadiazoles

1360–1280 (N
O), and at 1190–1150, 1030–1000, and 890–875 cm
1 (heterocyclic ring) [308]. MINDO/3 and DFT methods have been used to calculate the IR active vibrational frequencies of a series of furazans and furoxans [348]. The 1605 cm
1 band of furoxans was assigned to vibrations of the C:N(O) group [326]. Monocyclic furazans and dimethylfurazan have UV absorption bands at 228–241 nm, while typical monocyclic furoxans have a peak at 255–295 nm [375]. The extended conjugation in the chromophores of benzofurazans and benzofuroxans results in a shifts of lmax to longer wavelengths (350–410 nm); the energy band can extend into the visible region when conjugating groups are present. 7-Halo-4-nitro and 7-halodinitrobenzofurazans are used as analytical reagents because of the strong visible fluorescence in the region 525–545 nm when reacted with ethers, thioethers, and amines. Thus, tyrosil, cysteinyl, and amino residues of proteins can be labeled by this method, providing access to a fluorescence probe incorporating various biological interesting molecules [376]. 13.4.3.4 Mass Spectrometry Two general patterns of fragmentation under ionizing radiation characterize monocyclic furazans (Scheme 13.137) [377–379]. Initial ring opening by cleavage of the weak O1
N2 bond is followed by the C3
C4 bond breaking to yield nitrile and nitrile oxide (path a) or by the extrusion of NO (path b) [380]. Peaks attributable to RC þ are usually observed. R C N OH

R

R N

O

a

N

R C N O

+

R

N

b

R2C2N

+

NO

Scheme 13.137

Unlike many aromatic N-oxides, the (M–16) þ peak for furoxans is weak. The electron impact mass spectra of furazans are characterized by diagnostic peaks at (M–30) þ and (M–60) þ , due to the loss of NO and two NO molecules, respectively [381, 382]. The fragmentation pattern (Scheme 13.138) is consistent with the O1
N2 bond cleavage, with formation of the 1,2-dinitrosoethene tautomers, followed by sequential expulsion of NO. In parallel with this route, cleavage of the C3
C4 bond yields two nitrile oxides.

j1137

j 13 Oxadiazoles

1138

Ar

O N O N

Ar

Ar

Ar eV a

O N O N

b

Ar C N O

c

Ar

Ar

O N

N O

- 2NO d

Ar

Ar

Scheme 13.138

The acetylenic structure of the (M–60) þ fragment has been ascertained by massanalyzed ion kinetic energy (MIKE) spectroscopy performed under high energy collision activation conditions [312]. The direct generation of NO by a chemical decomposition suggests that the furoxan derivatives can be utilized as a potential NO-related biological probe [381]. 13.4.4 Synthesis

Many synthetic routes for the 1,2,5-oxadiazole system have been reported [308, 313, 384]. Different approaches are generally required for furazans, furoxans, and their benzo-fused analogues; thus separate subsections are devoted to the synthesis of furazans, benzofurazans, furoxans and benzofuroxans. Moreover, according to the stability of the heterocyclic ring, numerous different 1,2,5-oxadiazole derivatives can be generally prepared by exploiting appropriate interconversion reactions of the substituents present on the five-membered ring. 13.4.4.1 Furazans Three main routes have been designed for the synthesis of furazans: (i) dehydrative cyclization of 1,2-dioximes, (ii) deoxygenation of furoxans, and (iii) Boulton–Katritzky rearrangement of other five-membered heterocycles. 13.4.4.1.1 Dehydration of 1,2-Dioximes Furazan 372 was first prepared in 1964, by melting glyoxime with succinic anhydride, in 57% yield [306]. Cyclization of substituted glyoximes 413 is the most exploited methodology for the preparation of mono and disubstituted furazans 414 (Scheme 13.139). The starting material is prepared by reaction of 1,2-diketones 411 with hydroxylamine or by a-nitrosation of an alkylketone 412, followed by oximation of the resulting 1,2-dione monooxime. A “one-pot” method for the synthesis of 3-alkyl-, 3-aryl-, and 3-hetaryl-4-aminofurazans

13.4 1,2,5-Oxadiazoles

R N

R1 O

N O

H 2/Pd

RCOCH 2R 1 412

RONO NH2 OH

R1

NOH

R

NOH

NH2 OH

RCOCOR 1 411

413 -H 2O R N

R1 O

N

R = Me, Et, Ph R 1 = Et, Pr, t-Bu, Adamantyl

414 31-57% Scheme 13.139

from b-alkyl- or b-aryl and b-hetaryl-b-oxoesters has been reported recently. The multistep process involves hydrolysis of the ester, nitrosation at the activated methylene group, and treatment of the resulting intermediate with an alkaline solution of hydroxylamine in the presence of urea [385]. Dioximes can be also obtained by reduction of furoxans with H2, Pd/C (Section 13.4.4.1.2); thus, when furoxan is easily available, as for example by dimerization of nitrile oxides, the sequence furoxan–glyoxime–furazan constitutes a valuable synthetic route for symmetrically substituted furoxans. Various dehydrating agents have been utilized, such as acetic, succinic and phthalic anhydrides, sulfuric acid, dicyclohexylcarbodiimide, phosphorus oxychloride, thionyl chloride, and alcoholic sodium hydroxide. According to this procedure, diaminofurazan 418 has been prepared in good yield by reaction of glyoxime 416 and hydroxylamine hydrochloride in aqueous NaOH, to give diaminoglyoxime 417, followed by KOH mediated dehydration; the reaction has also been performed under microwave irradiation in 2/3 min (Scheme 13.140) [386]. For monosubstituted furazans such as 419, basic dehydrating agents must be avoided because most of these compounds are isomerized to oximes of a-ketonitriles (421), according to a sequence that originates from the initial deprotonation at C4 (Scheme 13.141) [387]. Thus, in these cases, dehydration of the corresponding dioximes is conveniently carried out with anhydrides or sulfuric acid. In contrast, disubstituted furazans are stable to both heat and chemical conditions and a wide range of dehydrating agents may be used. An unusual synthesis of

j1139

j 13 Oxadiazoles

1140

NH2 OH

HCOCOH

HON

NaOH

415

NOH 416

NH2 OH

NH2

H 2N N

O

76%

KOH

N

H 2N

NH 2

HON

NOH

418

417

Scheme 13.140

Ph

H

N

O

Ph

OH

N

N

419

O

H 2O

N

Ph

NOH N

421

420

Scheme 13.141

F3 C

Ar

SiO2

HON

NOH

40-86%

422

Ar

F3 C N

O

N

423

Ar =Ph, Tolyl Scheme 13.142

3-(trifluoromethyl)-4-aryl-furazans 423 has been reported (Scheme 13.142) [388]: dehydration of 1,1,1-trifluoromethyl-2,3-dione dioximes 422, which failed with traditional methods, was performed on heating with silica gel. A modification of the dehydration route involves the conversion of dioximes into diesters, followed by cyclization via distillation or reaction with alkali [389]. The 1,2-dioxime dehydration route is compatible with various substituents, such as alkyl, aryl, acyl, carboxyl, and amino groups. For example, 3-amino-4-phenylfurazans (425) are obtained by treatment of aroyl cyanides 424 with hydroxylamine and sodium acetate in ethanol or on heating N-hydroxy-2-(hydroxyimino)-2-arylacetimidamide (426) with sodium acetate in ethanol (Scheme 13.143) [390]. 13.4.4.1.2 Deoxygenation of Furoxans Furazans have been prepared by deoxygenation of furoxans: this method is suitable for furazans bearing different substituents, including alkyl, aryl, acyl, cyano, and amino groups (Scheme 13.144) [313].

13.4 1,2,5-Oxadiazoles

H2 N NH 2 OH

ArCOCN

N

NaOAc 424

Ar

26-72%

O

H2N

NOH

Ar

NOH

N 38-81%

425

426

Ar = Ph, p-OMeC 6 H4, p-NO2 C6 H4 Scheme 13.143

Ph

Ph

O N O N

Ph [H] 80%

Ph

N

O

N

428

427 Scheme 13.144

However, the reduction process must be carried out so as to avoid over-reduction and, when the furazan is thermally labile, the formation of by-products by ring opening [319]. The most employed reducing agents include trialkyl and triarylphosphites and phosphines, phosphorous pentachloride, stannous chloride in acetic acid, and Zn/acetic acid [308]. The strategy is particularly efficient for the preparation of symmetrical substituted furazans because the corresponding furoxans can be easily prepared via dimerization of the appropriate nitrile oxides (Section 13.4.4.3.3) (Scheme 13.145) [391].

NH2 N O

N

N

429

70 % O

N O N

NH2

H 2N

N O N

O N O N

430

Scheme 13.145

Vinyl azides 431 [392] and vicinal vinyl nitro compounds 433 [393] can be precursors for furoxans and furazans (Scheme 13.146). 13.4.4.1.3 Boulton–Katritzky Rearrangement Oximes of several classes of 3-acyl-1oxa-2-azoles, such as isoxazoles, 1,2,4-oxadiazoles, and furazans, undergo a thermal or base-catalyzed rearrangement, known as the Boulton–Katritzky rearrangement, which leads to furazans (Scheme 13.147) [342, 394]. The reaction can proceed by a concerted electrocyclic mechanism or, in the presence of a base catalyst, in two steps by an intramolecular nucleophilic attack at the nitrogen atom of an anionic intermediate.

j1141

j 13 Oxadiazoles

1142

R

R'

NO 2 BF 4

N3

12-80%

R

'R

N

N O

O

R

NaN3

R'

O 2N

62-75%

NO 2

433

432

431 R = H, Me, n-Bu R' = H, Me, Ph Scheme 13.146

R N HO

N

O

R

Z Y

N

O

Z Y OH N

A) Z=Y=CH; B) Z=N, Y=CH; Z=CH, Y=N Scheme 13.147

The process is geometry dependent, with the (Z)-isomer rapidly transformed, while the (E)-isomer is generally stable. Thus, the reaction of 3-benzoyl-5-phenyl1,2,4-oxadiazole (434) with hydroxylamine gives rise to a mixture of (E)-oxime 436 and the amido furazan 437 resulting from the rearrangement of (Z)-oxime 435 [395]. The addition of an acid improves the process because of the (Z/E)-oxime isomerization. Under this condition the amidofurazan 437 is hydrolyzed to its amino derivative 438 (Scheme 13.148).

H

Ph O

NH 2OH

N N

HO

Ph

O

Ph

65%

N HO

+

N N

Ph N

Ph

O

N N

435

434

Ph O 436

70% Ph N

NHCOPh O

N

437 Scheme 13.148

86%

Ph N

NH 2 O

N

438

13.4 1,2,5-Oxadiazoles

The transformation is not limited to oximes, but also amidoximes and hydrazidoximes can give the corresponding furazans [396]. The (Z)-oximes of 3-acylisoxazoles 439, which are more stable than the corresponding 1,2,4-oxadiazole derivatives, do not react in the absence of a catalyst; the rearrangement occurs easily by treatment with bases, leading to the formation of b-ketoalkylfurazans 440 (Scheme 13.149). R1 N HO

N

R2

OH

R3

O

36-92%

R1 N

439

CHR 2COR 3 O

N

440

1

R =H,Me,Et,Ph R 2 =H,Me,Ph,Bn R 3 =Me,Et,i-Pr Scheme 13.149

Various oximes of 3-acyl-substituted furazans 441 undergo the Boulton–Katritzky rearrangement in which the oxadiazole ring is converted into a new furazan system bearing a hydroxyiminoalkyl group (442). Several examples of N-mono and N,Ndialkylfurazanamidoximes (443$444) have been reported (Scheme 13.150) [397]. H

R

R N

HON

N OH

N O 441

N

R H 2N N

O

N

443

H

HON

N OH

N O 442

NH2 N

56-67%

O

R N

444

R = PhNH,PhCH2 NH, (CH2) 5N, (CH 2) 4ON, Me2 N, Me2CHN, (Me 2 CH)2 N Scheme 13.150

13.4.4.2 Benzofurazans The main synthetic routes towards benzofurazans are (i) dehydration of o-quinone dioximes, (ii) cyclization of o-substituted nitrosoarenes, and (iii) deoxygenation of benzofuroxans (Scheme 13.151) [307, 309].

j1143

j 13 Oxadiazoles

1144

R

NOH

R

NOH 445

N N

O

446

R

NO

R

X 447

O N O N 448

Scheme 13.151

Various dehydration conditions have been used for the conversion of o-quinone dioximes into benzofurazans, such as the use of acetic anhydride, thionyl chloride, sulfuric acid, phenyl isocyanate, and alcoholic sodium hydroxide. Alternatively, cyclization may be performed by thermolysis of the corresponding dioxime diacetates or dibenzoates [307, 309]. The utility of this synthetic approach is linked to the availability of dioxime precursors, which can be prepared by direct oximation of o-quinones or by reduction of the corresponding benzofuroxans, although, in many cases, direct deoxygenation to benzofurazans can occur. A different widely exploited methodology starts from o-nitrosoarenes: thus, o-azido nitroso derivatives, generated from the o-chloro analogues, can be converted into benzofurazans by thermolysis [398], while 1-amino-2-nitrosoarene affords benzofurazan by oxidation with ferricyanide or hypochlorite, probably through an o-quinone dioxime intermediate. In addition, o-nitrosophenol heated in the presence of hydroxylamine leads to furazans, presumably by oximation of the tautomeric o-quinone monooxime followed by dehydration. Other approaches involve the thermolysis of o-nitroanilines or the reaction of o-dinitroarenes with sodium azide [399] and the reduction of o-dinitroarenes with sodium borohydride [400] (Scheme 13.152) Moreover, benzofurazans can be synthesized by a Boulton–Katritzky rearrangement. Thus, 7-nitrosobenzofuroxan or 3-methyl-7-nitroso-2,1-benzisoxazole afford the corresponding 4-nitrofurazan [398] and 4-acetylbenzofurazan [401]. Analogously, benzofurazan is formed by photolysis of 2,1,3-benzoselenadiazole N-oxide. This reaction involves cleavage of the heterocyclic ring, and the extrusion of selenium followed by ring closure [402]. 13.4.4.3 Furoxans The most exploited routes towards furoxans are (i) oxidative cyclization of 1,2dioximes, (ii) dehydration of a-nitroketoximes, and (iii) dimerization of nitrile oxides for symmetrically substituted furoxans. For unsymmetrical furoxans, the possibility

13.4 1,2,5-Oxadiazoles

Cl

NO

NO

NH 2

N3

Ox

∆

48%

93%

N

O ∆

N

H

2

O H

N

10%

NO

NaBH 4

43%

NO 2 N3

NO 2 OH NO 2 Scheme 13.152

of formation of mixtures of 2- and 5-isomers must be taken in account in choosing a suitable synthetic strategy. No data have been reported on the direct oxidation of furazans to furoxans. 13.4.4.3.1 Oxidation of 1,2-Dioximes The oxidation of 1,2 dioximes offers a valuable route towards furoxans. The oxidation can be carried out with t-butyl hypochlorite [403], lead tetraacetate, dinitrogen tetroxide [404], as well as electrochemically [405]; as an example, Scheme 13.153 shows the oxidation reaction of compound 449 to give 450. Ph

NOH

Cl

NOH

Ph Ox

449

60-70%

N

Cl N

O

450

Scheme 13.153

Ring closure can be achieved stereospecifically, thus allowing the formation of individual isomers for asymmetrically substituted furoxans 452 and 453 (Scheme 13.154) [406]. This approach is suitable for the synthesis of 1,2,5-oxadiazoles fused to other carbocyclic and heterocyclic systems [406, 407]. 13.4.4.3.2 Dehydration of a-Nitro Ketoximes Mono- and polycyclic furoxans have been easily prepared by a synthetic strategy that starts from readily available alkenes [312, 408]. The process involves the initial reaction of alkenes 454 with

j1145

j 13 Oxadiazoles

1146

R

N

R1

N OH

OH

R1

R

Ox

N

15-70%

N O

O

452

451 R R1

N

OH

N OH 451

R1

Ox

N

15-70%

R O

N O

453

R = NH2, CN, SPh, t-Bu R1 = Me, Ph, Me-C6H4, SO2-C6H4-Cl Scheme 13.154

nitrogen trioxide to afford the 1-nitro-2-nitroso adduct 455 – isolable as its nitroso dimer 456 – followed by thermal isomerization to the a-nitro ketoxime tautomer 457 and dehydration with cyclization to the target furoxans 458 (Scheme 13.155).

R

N2O3 R 454

R

NO

R

O O N N

NO2

R

NO2

R

R NO2

R

455

456

R = Alkyl, Phenyl, Alkoxyphenyl

R

NOH

R

NO2 457

R

R - H2O

N

O

N O

458 27-83%

Scheme 13.155

Mixtures of isomers are obtained from non-symmetrical alkenes. The reaction route is compatible with a wide range of functional groups; thus, nitrosation of crotonoaldehyde leads to 4-formyl-3-methylfuroxan [409] and similarly the reaction of b-nitrostyrene with N2O3 yields the corresponding aryl nitrofuroxan isomers [410]. Recently, it has been reported that AgNO2/TSMCl reacts with olefins to afford nitrosonitrates that are then converted into furoxans in high yields (Scheme 13.156): the reaction of AgNO2 with TSMCl furnishes first hexamethylsiloxane and N2O3

13.4 1,2,5-Oxadiazoles

N AgNO2

(CH2)n

(CH2)n

TMSCI

O

50-67% 459

N

n= 3, 4, 5, 6

460

Scheme 13.156

which in situ add to alkenes 459 [411]. The approach has been applied to the synthesis of furoxans fused to penta-, six-, seven-, and eight-membered saturated rings 460. A general method for the synthesis of furoxans 463 starts from a-nitroketones 461 [412], by conversion into the corresponding a-nitro-ketoximes 462, followed by treatment with acidic alumina (Scheme 13.157) [413]. R R1

O NO2

NH2OH Amberlyst A 21

NHOH

R

R1

461

CH3CN

NO2 462

R = Et, Ph(CH2)2, i R1 = Me, Et, n-Pr

Acidic Al2O3

Pr

R

N

R1 N O O 463

83-91%

Scheme 13.157

A number of symmetrically substituted dibenzoylfuroxans have been synthesized by treating substituted acetophenones with nitric acid distilled from sulfuric acid [414]. 13.4.4.3.3 Dimerization of Nitrile Oxides Besides their characteristic and synthetically important 1,3-dipolar cycloaddition reactions, nitrile oxides undergo spontaneous [3 þ 2] dimerization, usually regarded as an unwanted side reaction, which can be exploited for the preparation of furoxans (Scheme 13.158). R R

N O

R

O N O N

Scheme 13.158

Two paths have been proposed for the dimerization of nitrile oxide to furoxans, but the detailed mechanism is unknown. The most widely accepted mechanism is a concerted 1,3-dipolar cycloaddition process, where one nitrile oxide acts as a dipole, while the C
N multiple bond in the other nitrile oxide acts as a dipolarophile (Scheme 13.159) [415, 416]. A (closed-shell) stepwise mechanism, often called the carbene mechanism, has also been proposed [417–419]. In the carbene mechanism, the first step corresponds to bond formation between the carbenoid carbons of

j1147

j 13 Oxadiazoles

1148

Concerted

R

R

N O N O

2 R

N O

Stepwise (closed-shell)

R

N O

R

N O

O

N

R

R

N

R

R

O N O N

O

R

N O

R

N

O

Stepwise diradical Scheme 13.159

two nitrile oxides to form a dinitroso alkene intermediate, which then cyclizes to the furoxan. DFT calculations performed at the B3LYP/6-31G level on the dimerization reactions of acetonitrile oxide and para-chlorobenzonitrile oxide to form furoxans indicate that these processes are stepwise, involving dinitrosoalkene intermediates that have considerable diradical character (stepwise diradical mechanism in Scheme 13.159). The rate-determining steps for these two reactions correspond to C
C bond formation [420]. The retardation of dimerization in aromatic nitrile oxides arises from the interruption of conjugation between the nitrile oxide and aryl groups in the C
C bond formation step. The reluctance of aromatic nitrile oxides to dimerize with respect to aliphatic nitrile oxides is attributed to conjugative stabilization of the former. The dimerization processes in solution are slower than in the gas phase, and polar solvents retard the reaction rates. The method is not appropriate for bicyclic furoxans; a few examples of intramolecular dimerization have been reported. The bimolecular dimerization competes with the unimolecular rearrangement to the isomeric isocyanate, with the latter dominant at higher temperature. Therefore, the preparation of furoxans from nitrile oxides is carried out in concentrated solution at room temperature. Nitrile oxides are conveniently accessible from many compounds such as oximes, hydroximoyl halides, nitromethyl compounds, alkyl esters of a-nitroalkanoic acids, and others.

13.4 1,2,5-Oxadiazoles

The most useful methods have been widely reported in reviews and specialized books [421, 422]. 13.4.4.4 Benzofuroxans The benzofuroxan system can be constructed by suitable modification of the synthetic methods used to synthesize benzofurazans. Thus, the main routes involve the thermolysis of o-nitroaryl azides, the oxidation of o-quinone dioximes, the oxidation of o-nitroanilines (Scheme 13.160), and the Boulton–Katritzky rearrangement.

NO2

R

R

N3 464

N

NOH

Ox

O

R

N 448 O

NOH 445

Ox

R

NO2 NH2

Scheme 13.160

The most exploited methodology for the synthesis of benzofuroxans and heterosubstituted analogues is the thermolysis or photolysis of o-nitroarylazides, which can be easily generated from the o-nitrohaloarene and sodium azide [423]. The reaction mechanism involves the intramolecular displacement of the nitrogen by the oxygen of the adjacent nitro group. The method can be used to prepare various hetero-substituted analogues, such as thieno-, imidazo-, oxadiazolo-, thiadiazolo-, pyrido-, quinilino-, pyridazino-, and pyrimidino-derivatives. Thus, photolysis of 4-azido-5-nitrothiophene-2-carboxylic acid ester 465 gives a mixture of thieno[2,3-c]furoxan isomers 466 and 467 (Scheme 13.161) [424].

N3 MeO2C

NO2

S 465

O hν 97%

MeO2C

N

S 466

O N O

+

MeO2C

N S

N

O

467

Scheme 13.161

In analogy with the formation of furoxans by oxidation of 1,2-dioximes, benzofurazans can be prepared by oxidation of o-quinone dioximes. The method is, however, limited by the availability of the starting materials.

j1149

j 13 Oxadiazoles

1150

Oxidative ring closure of o-nitroanilines constitutes a preferable and commonly used alternative route towards benzofuroxans [425, 426]. Alkaline hypochlorite is the most used reagent: the mechanism involves an initial N-chlorination, followed by deprotonation and loss of chloride ion (Scheme 13.162).

NO2

NO2

CIO 469

O N O N

- CI

NCI

NHCI

NH2 468

NO2

-H

470

448

68%

Scheme 13.162

13.4.5 Reactivity of the Heterocyclic Ring

The parent 1,2,5-oxadiazole, with pKa about
5, is less basic than isoxazole (pKa ¼
2.97). 1,2,5-Oxadiazoles are aromatic in nature and are to be considered as p-excessive heterocycles with relatively p-deficient C-atoms. Despite the electron deficiency of carbon atoms, nucleophilic substitution reactions are not common; however, when good leaving groups are present, then reactions can take place. Generally, electrophilic substitutions at the C-atoms cannot be achieved. 13.4.5.1 Furazans and Benzofurazans 13.4.5.1.1 Reactions with Electrophiles and Oxidizing Agents The heterocyclic ring of 1,2,5-oxadiazoles is particularly resistant to attack by electrophilic reagents; thus, halogenation, nitration, and oxidation take place at substituent groups. Electrophilic substitutions in benzofurazan and phenylfurazan occur on the aromatic ring, predominantly at the 4-position and in ortho–para positions, respectively. For example, bromination of phenylfurazan with bromine in the presence of Ag2SO4/H2SO4 gave the p-bromophenyl derivative in 82% yield [427]. Similar results have been obtained on nitration with fuming nitric acid, which gives 4-nitro- or 2,4-dinitro products [428, 429]. There is a single example of an electrophilic reaction at the ring carbon of furazans: insertion of methoxymethylcarbene in the C
H bond of a furazan occurred on thermolysis of furazans 471 with methyl diazoacetate in the presence of copper stearate to give the corresponding methoxycarbonylmethylfurazans 472 in 9–12% yield (Scheme 13.163) [430, 431]. For benzofurazans and benzofuroxans the most facile electrophilic substitution is nitration, which occurs preferentially at the 4-position; a second nitro group can sometimes be inserted at C6. Other electrophiles react less readily, with nitrosation and diazo-coupling occurring only in the presence of activating groups. 5-Methylbenzofurazan reacts with bromine to give substitution at the 4-position; however,

13.4 1,2,5-Oxadiazoles

OMe

R

R N

Cu2+ N2CHCO2Me

N

N

O 471

O

N

O

472 9-12%

R = H, thien-2-yl-3-aminofurazan-4-yl Scheme 13.163

bromine in the presence of sun light undergoes electrophilic addition to the 4,5,6,7tetra-adduct rather than substitution. Direct oxidation of furazans to furoxans has not been achieved, as can be expected from the high ionization energy. For instance, oxidation of 3,4-dimethyl-1,2,5oxadiazole (473) [432] and 3-methyl-4-phenylfurazan (474) [433] with potassium permanganate occurs at the alkyl substituents, giving rise to 1,2,5-oxadiazole-3,4dicarboxylic acid (475) and 4-phenylfurazan-3-carboxylic acid (476), respectively. Under mild conditions, oxidation of fused furazan 477 afforded the dicarboxylic acid 478 (Scheme 13.164) [434]. R

Me

N

N

O

473: R= Me

R

KMnO4 H

32-75%

474: R= Ph

N

CO2H O

N

475: R= CO2H 476: R= Ph CO2H

N N

O

477

KMnO4 H

86%

HO2C N

O

N

478

Scheme 13.164

The heterocyclic ring is also resistant to acid attack; pKa values for protonation of methylphenylfurazan and benzofurazan are
4.9 and
8.4, respectively. Quaternization with dimethyl sulfate in sulfolane proceeds under forcing conditions, more slowly than that of isoxazoles with iodomethane, to give the corresponding N-methylfurazinium salt [435]. N-Ethyl salts of furazan and 3-phenylfurazan have been obtained by reaction with triethyloxonium tetrafluoroborate. The reaction of the silyloxy-furazan derivative 479 with triethyl orthoformate led to a mixture of 2-ethyl-1,2,5-oxadiazole-3(2H)-one (480) and O-ethyl compound 481 (Scheme 13.165). Compound 480 is a rare example of a tricoordinate N-substituted 1,2,5-oxadiazole [436].

j1151

j 13 Oxadiazoles

1152

Ph

OSMT

N

Ph

HC(OEt)3

N

O 479

Ph

O O

N Et

+

OEt

N

O

N

480

481

45%

37%

Scheme 13.165

13.4.5.1.2 Reactions with Nucleophiles and Reducing Agents Furazans and benzofurazans are generally resistant to attack by nucleophiles. As reported in Scheme 13.134, treatment of the parent compound and monosubstituted furazans with strong bases, as NaOH in methanol, causes the ring opening to form sodium salts of a-oximinonitriles. Disubstituted furazans are comparatively inert. Furazan ring cleavage occurs also when 482 is treated with Ac2O at elevated temperatures to produce acylated derivatives 483 [387]. Ring opening with subsequent recyclization has been observed by nucleophilic attack of hydroxylamine on monosubstituted furazans 482, leading to aminofurazans 485 (Scheme 13.166) [437]. NC

R

N AcO

Ac2O 56-92%

483

H N

R O

N

482

R = H, Me, Et, Ph, Bn

OH

NC

R N HO 484

NH2OH - H2O

H2N N

R O

N

485 23-82%

Scheme 13.166

However, when a good leaving group is present, then substitution can occur. Thus, displacement of the nitro group by a hydroxy group has been observed on heating 3-nitro-4-phenylfurazan 486 with sodium hydroxide (Scheme 13.167) [436]; displacement of nitrite or phenylsulfonyl group by alkoxy nucleophiles and by ammonia [438] has also been reported. Similarly, the homocyclic ring of benzofurazans is susceptible to analogous nucleophilic substitutions. Thus, halides are displaced by various nucleophiles such as alkoxides, fenoxides, cyanide, amines, and thiolates. 4-Halogenobenzofurazans give 4- or 5-substitued products generated from normal ipso or cine reactions; the cine products are amenable to an addition–elimination mechanism (AE), while ipso substitution can result from both AE and SNAr (Scheme 13.168) [439]. However, substitution reaction on the homocyclic ring can take place even in the absence of a leaving group: benzofurazan has been converted into its 4-formyl derivative by treatment with LDA in DMF. The furazan ring is susceptible to reduction. Thus, benzofurazans give 1,2diaminoarenes by treatment with tin and hydrochloric acid, while catalytic reduction

13.4 1,2,5-Oxadiazoles

Ar

OR

N Ar

OH

N

O

Ar

NaOH

N

N

16-65%

N O 488

Na OH /E tO H 96%

N

O 486

22-85%

487

RO

NO2

NH3 37-60% Ar

Ar = Ph, Tolyl R = Me, Et, n-Bu, i-Pr

Ar

NH2

N

O

N

N

SO2Ph O

N

490

489 Scheme 13.167

Nu

Nu

X

SN Ar

N N

O

N

-X

N

O

X

X N N

O

Nu-

N AE N

N O

N

- HX

O

Nu

Nu X Nu AE

N N

Nu O

j1153

- HX

N N

O

Scheme 13.168

takes place at the homocyclic ring to afford tetramethylenefurazans. 1,2-Diamines are also formed by reduction of furazans with sodium borohydride, whereas LiAlH4 causes fragmentation of the C3
C4 bond, yielding primary amines as final products. Treatment with phosphites results in both fragmentation and deoxygenation to nitriles. Zinc and acetic acid can lead to a selective reduction of the oxadiazolo moiety in the presence of other heterocyclic systems: furazano[3,4-d]pyrimidines 491 and furazano[3,4-e]pyrazines 492 have been converted into the corresponding o-amino compounds (Scheme 13.169) [440]. 4,6-Dinitrobenzofurazan, which is strongly electrophilic, undergoes facile s-complexation with weak nucleophiles to form stable Meisenheimer complexes (Section 13.4.5.3).

j 13 Oxadiazoles

1154

O N N Y

N

Zn, AcOH 70-75%

X

NH2

H2N

N Y

X

491: X= N, Y=CH 492: X= CH, Y=N Scheme 13.169

13.4.5.1.3 Thermal and Photochemical Ring Cleavage Thermolysis and photolysis of 1,2,5-oxadiazoles proceeds by cleavage of the O1
N2 and C3
C4 bonds to give nitrile and nitrile oxides, together with products derived therefrom. The thermal process requires temperatures above 200  C, except for ring-strained derivatives, where less drastic conditions are needed. Thus, diphenylfurazan decomposes at 250  C to give benzonitrile, phenyl isocyanate, and 3,5-diphenyl-1,2.4oxadiazole, with the latter two products arising from the rearrangement and 1,3dipolar cycloaddition with benzonitrile of the initially formed benzonitrile oxide. In contrast, the ring-strained acenaphthofurazan 493 fragments at 120–150  C to produce the transient 494, which in the presence of phenylacetylene gives 495 in 53% yield (Scheme 13.170) [441]. N O

N

N O

493

Ph N CN 494

O

H

Ph

CN

53%

495

Scheme 13.170

The kinetics of the gas-phase thermolysis of several furazans to phenyl isocyanate and 3,5-diphenyl-1,2.4-oxadiazole have also been examined [442], and a biradical mechanism has been proposed. Benzofurazans, which are thermally more stable, may be cleaved photochemically. For example, benzofurazan 446 in benzene affords cyanoisocyanate 498 and azepine 499 (Scheme 13.171). Compound 499 probably originates from the reaction of the solvent with the acylnitrene intermediate 497 [443]. 13.4.5.2 Furoxans and Benzofuroxans 13.4.5.2.1 Reactions with Electrophiles and Oxidizing Agents As reported for furazans, the furoxan nucleus shows low reactivity towards electrophiles; reactions occur at the substituents or at the homocyclic ring of benzofuroxans [444]. Reaction with acids is also slow: benzofuroxans have pKa values of about
8, similar to those of

13.4 1,2,5-Oxadiazoles

N

N N

N O N

hν

O

O

O N

CN .

499 58%

CN 496

446

N C O

497

CN 498 52% Scheme 13.171

benzofurazans. Treatment of the parent furoxan 372 with concentrated H2SO4 proceeds with ring-cleavage to (hydroxyimino)acetonitrile oxide 500, followed by dimerization to bis(hydroxyiminomethyl)furoxan 501 in nearly quantitative yield (Scheme 13.172) [375]. N N

O

H2SO4

372

NOH HON

HON 500

N O

N O

N O

501 73%

Scheme 13.172

Quaternization is difficult for all furoxans: benzofuroxan does not react with triethyloxonium tetrafluoroborate. The heterocyclic ring of furazans is also resistant to attack by oxidizing agents, with reactions occurring preferentially at the substituents groups. However, benzofuroxan is oxidized by persulfuric or trifluoroperacetic acid to 1,2-dinitrobenzene, while the 4,6-dinitro compound affords the 1,2,3,4-tetranitrobenzene [445]. 13.4.5.2.2 Reaction with Nucleophiles and Reducing Agents The reactivity of furoxans with nucleophiles and reducing agents is good. In fact, Grignard reagents react with disubstituted furoxans, primarily at C3, leading to nitrile and nitronate fragments, which, in the presence of an excess of Grignard reagent, yield the corresponding ketones. Monosubstituted furoxans give glyoximes. Nucleophilic substitution of substituents at C3 and C4 is an easy and valuable pathway towards the synthesis of a wide series of derivatives. The nitro group in particular is readily displaced by numerous nucleophiles such as amines, alkoxides, thiols, azide, halides, and sulfonyl groups [375, 446]. In the benzofuroxans series, nucleophilic reactions take place preferentially at the homocyclic ring; the reactivity is

j1155

j 13 Oxadiazoles

1156

enhanced by the presence of nitro groups [447]. Numerous biologically interesting applications of this kind of reaction have recently appeared in the literature (Section 13.4.6). In the absence of a good leaving group, nucleophilic attack occurs at N5 of the oxadiazole ring: in this case, the reaction with secondary amines proceeds via ring opening to furnish o-nitroarylhydrazines. However, a substitution reaction on the homocyclic ring can take place even in the absence of a leaving group: with 4-nitrobenzofuroxan, carbanions of the form RSO2ClCH
cause the displacement of the hydrogen at C5 and at C7 [448]. All monosubstituted furoxans are quite sensitive to bases, which causes ringopening reactions, with the formation of nitrile oxides 503 from 4-substituted furoxans 502 and aci-nitro compounds 505 from 3-substituted furoxans 504 (Scheme 13.173) [313].

R N

N O O

B

R HON

502

R N

N O O 504

B

NC

N O 503

R NOOH 505

Scheme 13.173

Base attack is favored at the position adjacent to the more highly electronwithdrawing substituent. Ring opening with subsequent recyclization has been observed by nucleophilic attack of hydroxylamine in aqueous KOH on 3-thien-2-yl and 4-thien-2-yl furoxans (506, 507), leading to aminofurazans 508 (Scheme 13.174) [449]. Furoxans and benzofuroxans can be reduced by various reagents to yield furazans a-dioximes, 1,2-diamines, and nitriles, according to the experimental conditions. Catalytic hydrogenation usually leads to dioximes, but, under forcing conditions, ring cleavage at C3
C4 and N1
O2 can occur. For example, tetramethylenefuroxane 509 affords cyclohexane-1,2-dione dioxime (510) by treatment with H2 and Pd/C at room temperature, while the use of Raney nickel at 100  C leads to 1,6-diaminohexane (511) (Scheme 13.175). NaBH4 behaves in a similar way, while LiAlH4 reduction is accompanied by ring cleavage to give primary amine fragments. Benzofuroxans are reduced to o-nitroaniline derivatives by ferrous salts [450] and to o-phenylenediamines by ammonium sulfate–sodium borohydride [451].

13.4 1,2,5-Oxadiazoles

S N

O

N O

506 S

N

O

NH2OH - H2O

N O

H2N N

R N O 508

37-65%

507

R = Me, Et, t-Bu

Scheme 13.174

NH2

Ra-Ni

NH2

100 °C

511

72%

O N O N

H2

NOH

Pd/C

NOH

63%

509

510

Scheme 13.175

Reduction with tervalent phosphorus compounds, such as trialkyl and triaryl phosphites and phosphines, causes deoxygenation of furoxans and benzofuroxans to give furazans and benzofurazans, respectively, leaving the heterocycle intact. 13.4.5.2.3 Thermal and Photochemical Ring Cleavage Monocyclic furoxans undergo by thermolysis ring cleavage at the O1
N2 and C3
C4 bonds to give two nitrile oxides fragments, in a formal retro 1,3-dipolar cycloaddition reaction. In the presence of a dipolarophile, the nitrile oxide can be trapped as its 1,3-dipolar cycloadduct; otherwise, the nitrile oxide rearranges to the isomeric isocyanate (Scheme 13.176).

N O

N C O

O N O N N O Scheme 13.176

N O

j1157

j 13 Oxadiazoles

1158

Under flash vacuum pyrolysis conditions, the nitrile oxides can be isolated [452a]. Bicyclic furoxans afford bisnitrile oxides and diisocyanates. The process is sensitive to the ring strain: for decamethylenefuroxan 513 a temperature above 200  C is required, while the trimethylene analog 512 reacts at 80–100  C (Scheme 13.177) [452b,c]. In general, benzofuroxans are much less susceptible to decomposition.

N (CH2)n

N

O O

NCO

CNO

∆ 40-60%

(CH2)n

CNO

+

(CH2)n

NCO

512 n= 3 513 n= 10 Scheme 13.177

13.4.5.3 Meisenheimer Complex Formation 4,6-Dinitro compounds 513 and 514 are strongly electrophilic and form stable Meisenheimer complexes when treated even with weak nucleophiles under mild conditions. In particular, 514 is regarded as a super-electrophile – more powerful than 1,3,5-trinitrobenzene. Thus, 514 reacts with methanol, enols, phenols, anilines, thiophenes, pyrroles and indoles, and nitroalkanes to form, in the absence of base, stable C-bonded s-adducts 516. Moreover, the electrophilic character of 515 is also confirmed by its reaction with 1,8-bis(dimethylamino)naphthalene, the so-called “proton sponge,” yielding carbon-linked compound 517 (Scheme 13.178) [453]. NMe2 NMe2

NMe2

Me2N

On N O N

O2N On N O N

O2N

O

N

O

517

56%

NO2 514 n= 0

Nu HNu

O2N

70-90% O

N

On N O N

O 516

515 n= 1

Scheme 13.178

13.4.5.4 Heterocyclic Ring Rearrangements of Furoxans and Benzofuroxans Furoxans have been extensively used as starting material for synthetic conversions into various other heterocyclic systems, some of which show interesting biological activity. The Boulton–Katritzky rearrangement is the most exploited reaction route, affording an easy entry towards isoxazoles, pyrazoles, and furazans. Other conversion reactions give access to isoxazolines, quinaxoline, and benzimidazole N-oxides.

13.4 1,2,5-Oxadiazoles

13.4.5.5 Rearrangements of Furoxans The Boulton–Katritzky rearrangement [342, 393] of non-condensed furoxan derivatives has been reported for oximes of 4-furoxanylcarbonyl compounds [454]; in particular, the base-catalyzed rearrangement of the (Z)-isomer of 4-benzoyl-3methylfuroxan oxime (518) leads to 3-(1-nitroethyl)-4-phenyl-1,2,5-oxadiazole 519 (Scheme 13.179). E

D

D E N

N

O N O Ph N OH N

Ph

Me O

N

NO2

N O N

Base

O

56%

Cat

190

Me O

N

NO2 CHMe

Ph

H

N

O

O

N

192

191

Scheme 13.179

Other variants of rearrangement of monocyclic furoxans have been performed for derivatives involving different side chains: C-N-N (phenylhydrazones), N-C-N (amidines), and N-C-S (thioureides) [455]. Thus, treatment of (Z)-isomers of phenylhydrazones 520 with ButOK and heating yielded 1,2,3-triazoles 523, formed with a Nef-type [456] reaction via 5-(1-nitroethyl)-1,2,3-triazole 522 intermediate (Scheme 13.180). R

Ph

N NH N

R

Me N

O

ButOK, DMF 10°C, 10 h

O

520

Ph

N N N K

R

Me N

O

O

N 521

Me

O N

O

N N O K Ph

t

Bu OK, DMF 120°C, 2 h

NO2 R N

Me N

N

Ph 522 Scheme 13.180

40%

a R = Ph b R = Me

O R N

Me N

N

Ph 523 82-95%

5% HCl

j1159

j 13 Oxadiazoles

1160

Analogously, the rearrangement of 3-aryl(alkyl)-1-(3-R-furoxan-4-yl)amidines 526 – synthesized by reaction of aminofuroxans 524 with triethyl orthoformate or triethyl orthoacetate, followed by the action of various amines on the resulting iminoethers 525 – afforded the 1,5-disubstituted 3-[1-nitroethyl(benzyl)]1,2,4-triazoles 527 (Scheme 13.181) [455]. NO2 NH2

R O

N

O

N

R1C(OEt) 3

56-92%

N

R O

N

524

O

N

R1 OEt

N

R

R2NH 2

N

O

525

O

R1 NHR2

N

R

1. MeOK or Bu tOK 2. AcOH

43-78%

526

N N

N R2

R1

527

R = H, Me R1 = Me, Et, Ph R2 = Me, Et, i-Pr

Scheme 13.181

5-Ethoxycarbonylamino-3-(1-nitroalkyl)-1,2,4-thiadiazole derivatives 530 have been obtained by refluxing a mixture of aminofuroxans and ethoxycarbonyl isothiocyanate in various solvents: the reaction proceeds through a not-isolated 4-(3-ethoxycarbonylthioureido)-3-substituted-furoxan intermediate (529) (Scheme 13.182) [456].

R

H 2N N

O

N

EtO2CNCS O

19-82%

528 a R = Ph b R = Me d R = COMe

H N

EtO 2 CHN S

EtO 2 CHN

R N

529

O

N

O

43-78%

N S

N

530

CHR NO2

a R = Ph b R = Me e R=H

Scheme 13.182

A different kind of rearrangement has been described that proceeds through a dinitrosoethylene intermediate. In particular (Z)-isomers of 4-benzoyl or 4-acetyl-3methylfuroxan phenylhydrazones 520, thermally or in the presence of various bases, give oximes of 5-acetyl-4-phenyl(methyl)-2-phenyl-2H-1,2,3-triazole 1-oxide 532 (Scheme 13.183) [457]. It has been suggested that the reaction starts with rupture of the O1–N2 bond in the furoxan ring, which results in formation of dinitrosoethylene intermediates 531, followed by the reaction of one nitroso group with the phenylhydrazone moiety and transformation of the second nitroso group into the oxime group. Another example of this rearrangement is represented by the thermally induced transformation of 3,30 -disubstituted-4,40 -azofuroxans 533 in an oxidizing medium into triazole 1-oxide derivatives 536 (Scheme 13.184) [458].

13.4 1,2,5-Oxadiazoles

Me

N Ph

NOH

R

R NH N

O

N

O

N

o-xilene

reflux

Ph

520

R

Me

N

N N N O H O 531

Me N N O Ph 532

a R = Ph b R = Me

48-67%

Scheme 13.183

O

N R

O

N

N N

N

O 533

R ∆

R N

O N

CH3CO2OH

N O N N

O

a b c d e

N

R

N O O 534

R O

N

N O N N

535

N

O

R N

O

[O]

R = CO2Me R = CONH2 R = Ph N R = COR = Me

R O 26-52%

N

NO2 N N

N

O

R N O

536 Scheme 13.184

Furoxans 537 bearing a methyl group at C3 give hydroximino derivatives of isoxazolines 538 on treatment with alkoxides or alcoholic alkali hydroxides (the so-called isoxazoline transposition or Angeli rearrangement) (Scheme 13.185) [459].

R N

Me O

N O

537

R 1. NaOEt 2. H 67-87%

N

NOH O 538

R = Ph, PhCH2, Cl-C6H4, MeO-C6H4 Scheme 13.185

j1161

j 13 Oxadiazoles

1162

13.4.5.6 Rearrangements of Benzofuroxans The Boulton–Katritzky rearrangement of benzofuroxans bearing at the 4-position a ring-conjugated side chain has been studied in detail from both a synthetic and mechanistic point of view [342, 370, 393, 460–465]. As a rule, rearrangements are initiated thermally, photochemically or in the presence of bases; the first example of acid catalysis has been published [466]. Several types of unsaturations can constitute the X ¼ Ygroup, such as C¼O, N¼N, C¼N, and N¼N, so allowing the construction of a series of new heterocyclic systems. Thus, 4-acetylbenzofuraxan 539 rearranges spontaneously to 3-methyl-7-nitrobenzo[c]isoxazole 540, while nitroindazoles 542 are formed from 4-formylbenzofurazan 541 and primary amines (Scheme 13.186).

O N O N

O N O 76%

N O

O 539

540

O N O N

O N O

RNH2 72-80%

N

O 541

542

N R

R= Me, Et, Cy Scheme 13.186

Analogously, nitrosation of 5-(dimethylamino)benzofuroxan (543) affords 4-(dimethylamino)-7-nitrobenzofurazan (545) through the rearrangement of the intermediate 4-nitroso compound 544. Similar behavior has been observed for 4arylazobenzofuroxans 546 yielding 4-nitrobenzo-1,2,3-triazoles 547 (Scheme 13.187). Quinoxaline-1,4-dioxides 551, 553, and 555 are readily obtained from the reaction of benzofurazans with enamines or carbonyl compounds in the presence of ammonia or amines (Beirut reaction) (Scheme 13.188) [467]. In the absence of the a-hydrogen required for the elimination, the 2,3-dihydroquinoxaline intermediate 550 can be isolated. Enolates derived from b-diketones react in an analogous way, affording 2-acylquinoxalines [468]. This process formally involves the insertion of a two-carbon fragment between the N
O groups of the furoxan (Scheme 13.188). Various quinoxalines are endowed with interesting biological activity: this feature has considerably extended the scope of this reaction. In the same context, the reaction also gives ready access to polycyclic compounds: for example, phenazine derivatives result from benzofuroxans and phenolates, p-benzoquinone, or hydroquinone [312, 469].

13.4 1,2,5-Oxadiazoles

O N O N

N

O N O

O N O N

NO N N

543

N

65%

N

O

N O 545

544

O N O

O N O N

22-76%

N2

Ar

j1163

N 547

546

N N Ar

Ar = Ph, Tolyl

Scheme 13.187

O O N

O R N

0% -9 7 2

O N O N

R 548

- HNMe2

N O

549

N O 551 O N

Cl

O

Ac2CH2 554

Me Me

R

550 39%

64%

O N

N

N 552 O N N O

N O

CH2 Ph

Ph

553

Ac Me

555

R = H, 5(6)Cl, 4,7-Cl2, 5,6-Cl2, 4(7)-Me, 5(6)Me, 5,6-Me2, 5(6)-CF3, 4(7)-MeO, 5(6)-MeO, 5(6)-Ac Scheme 13.188

j 13 Oxadiazoles

1164

Benzimidazole oxides, in 25–90% yields, are also accessible from benzofuroxans. The reaction with primary nitroalkanes leads to 2-substituted-1-hydroxybenzimidazole-3-oxides 556 via displacement of the NO2 group; similarly, the nitrile group of a-cyanoacetamides is removed with formation of 2-amide derivatives 557 (R0 ¼ CONR2). Secondary nitroalkyl compounds afford 2,2-disubstituted-2H-benzimidazole-1,3-dioxides 558.

R

O N N OH

O N R' R' N O

R'

556 : R' = Alkyl

558

557 : R' = CONR2

Benzimidazoles are also obtained from the reaction of benzofuroxans with phosphorus ylides [470], nitrones [471], and diazo compounds [472]. A mechanism has been suggested that involves the nucleophilic attack at N3 of the benzofuroxan 396 (or at one of the nitroso groups of the o-dinitroso tautomer), followed by cleavage of the O2–N3 bond to give the di-N-oxide 561, with subsequent cyclization to five- or six-membered ring products, according to the nature of the nucleophile (Scheme 13.189).

396

O N O N

O N O N Nu

Nu

O N

N

O N Nu

559

O N Nu

560

products

561

Scheme 13.189

13.4.5.7 Cycloaddition Reactions of Benzofuroxans The double bonds at the 4,5- and 6,7-positions in benzofuroxans are sufficiently localized and activated to undergo [3 þ 2] and [4 þ 2] cycloaddition reactions. Thus, isoprene (563) gives in 80% yield the 1:1 Diels–Alder adduct 562 with 4-nitro-6trifluoromethansulfonylbenzofuroxan (564) (Scheme 13.190) [473].

O N O N

O O F3C S

NO 2 564 Scheme 13.190

Me

Me

H 563

F3C

S O O NO 2 562

O N O N

13.4 1,2,5-Oxadiazoles

Similarly, alkyl diazoacetates 566 afford pyrazolo derivatives 567 by reaction with 6-nitrobenzofuroxan (565) (Scheme 13.191) [474].

O N O N

O2 N

565

N 2CHCO 2 R

566 70-100°C

N HN

CO 2R O N O N 567

45-55%

R=Et, Me Scheme 13.191

Mesitonitrile oxide gives mixtures of 1 : 1 and 2 : 1 adducts [475], and diazomethane reacts at C5
C6 of 4-nitrobenzofuroxan to give the 5-6-cyclopropa-fused derivative 568, probably by loss of nitrogen from the initial pyrazoline cycloadduct [476]. O N O N NO2 568

13.4.5.8 Alkyl and Aryl Furazans and Furoxans Reactions of aryl furazans and furoxans have been studied in detail. The heterocyclic ring exerts an ortho–para-directing influence with the predominant formation of para products. For example, nitration or chlorosulfonation of phenylfurazan and phenylfuroxan take place at the phenyl group, at the 40 -position, leaving the heterocycle intact. In benzofurazans and benzofuroxans, electrophilic attack occurs, as previously reported (Section 13.4.5.1.1), at the 4-position; a second group can be sometimes inserted at the 6-position. Alkyl groups on the furazan or furoxan ring can undergo functional transformations that depend on the electron-withdrawing properties of the rings. Treatment of alkylfurozans 569 with NBS in the presence of BPO or AIBN gives a-bromoalkyl derivatives 570 (Scheme 13.192) [477]. Similar results were obtained with 3-methylfuroxans 571 [478]. These a-haloyl derivatives are excellent starting materials for side-chain substituted furazans and furoxans through classical nucleophilic substitution reactions. The halogen atom is readily displaced by a wide range of oxygen, sulfur, nitrogen, phosphorus, and carbon nucleophiles to give the corresponding products in good yields [477–483].

j1165

j 13 Oxadiazoles

1166

R

R

Me N

NBS

N

O

R N

AIBN 55-65%

569

R = H, Me, Et

N

R NBS

N O

O

O

570

R Me N

Br

Me

Br

N

AIBN 63%

571

R = Me, Ph, CH=NOH, CONH2; OEt, OPh

N O O 572

Scheme 13.192

a-Metalation offers an alternative approach to functionalization of the methyl compounds. 3,4-Dimethylfurazan readily undergoes lithiation by treatment with nbutyllithium: the lithiated intermediate 573 reacts with electrophiles at –55 C to give various a-functionalized alkylfurazans (Scheme 13.193) [484–486]. The electrophile R

Me

Me

N

O

N

N

R = Et, Ph X 80-94% Me

Me

N

O

BuLi

N

99%

N N

MeO N

O

N N

OMe O

N 48%

Me

O

N

N NH N

O

OMe

N N O N

Scheme 13.193

N

95%

2. H+

Me

Li

N

N

N

R

MeCN or MeCO 2Et 95%

O 573

Me X Si Me Me

OH O

N R = 2-furyl

1. CO2

98%

Me

OH

R

O R

Me N

O

N

O

R = Me, Ac

Cl 2 95%

Me

N O N MeO

R

O

O

N

84% Me Si Me Me

Me N

Cl O

N

13.4 1,2,5-Oxadiazoles

can be an alkyl halide, a chlorosilane, a carbonyl compound, a nitrile, or an ester, an azo compound, and chlorine. A similar procedure using two equivalents of BuLi and two equivalents of the electrophile offers access to a,a0 -difunctionalized derivatives. 13.4.6 Furazans, Furoxans, and Benzo-Related Compounds in Medicine

Furazans, benzofurazans, and in particular furoxans and benzofuroxans are very important bioactive compounds. They have shown anti-microbial, anti-parasitic, antiviral; mutagenic, anticancer and immunosuppressive, anti-aggregating, and vasorelaxant activity. Moreover, compounds containing the furoxan or benzofuroxan moiety inserted in a classical active principle have produced hybrid compounds that have been used, very recently, as new anti-ulcer drugs, calcium channel modulators, and vasodilatators. Several furoxan and furazan derivatives have been evaluated as antibacterial (Gram-negative and Gram-positive), antiprotozoal (Trichomonas vaginalis and Entamoeba histolytica), and antifungal compounds. 4,7-Dicyanobenzofurazan (574) presents a bacteriostatic effect in Escherichia coli, due to inactivation of 2,3-dihydroisovalerate [487]. 3-Nitro-4-phenylfuroxan (575) and its tautomer 576 displayed anti-infective properties, but with mutagenic activity; 3bromo-4-phenylfuroxan (577) shows strong antimicrobial activity [488]. CN N N

Ph O

N

NO 2 O

O2 N

N O

N

Ph O

Ph

N O

N

Br O

N O

CN 574

576

575

577

Furoxans and benzofuroxan 578–580 have been reported to inhibit in vitro the growth of Trypanosoma cruzi, the etiologic agent of Trypanosomiasis americana, the so-called Chagas’ disease, and their activity is in the order 580 > 579 > 578. Me

R

O N O N 578

Ph

R

O N O N 579

N R 580

O N O

R = CH=NNHCONH-butyl

Anti HIV-1 reverse transcriptase activity has been described for compounds 581 and 582. In particular, compound 582 has shown the best anti-viral activity with a selectivity index (ratio of cytotoxic concentration to effective concentration) ranked in the order of 582 > 581.

j1167

j 13 Oxadiazoles

1168

Ar

O

O O N O N

Me N Pr

581 Ar = Ph 582 Ar = 2,6-di-Cl-Ph

4-Nitro (583), 4-thio (585) or 4-phenoxy- (587) benzofurazans and 4-nitro- (584), 7thio (586) or 7-phenoxy (588) benzofuroxans present optimal drug activity as inhibitors of RNA synthesis in sheep lymphocytes [489]. NO 2

N N N

N

O

583

N

N

584

N 587 N

O

O N OPh O

N O

SH

O

OPh

SH 585

NO 2 O N O

N O

588

586

Since the first report indicating that some nitrobenzofurazans displayed antileukemic properties, numerous 7-nitro-2,1,3-benzoxadiazole derivatives have been evaluated as anticancer agents. In particular, 7-nitro-2,1,3-benzoxadiazoles such as 589 [R1 ¼ alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, etc.; X ¼ O, S] have been prepared recently and used as agents able to inhibit glutathione S-transferase (GST). These compounds are useful in the production of pharmaceutical drugs to be used in anticancer therapy, and may be employed either alone or in combination with other chemotherapeutic agents. Thus, 4-[(7-nitro-2,1,3benzoxadiazol-4-yl)sulfanyl]butanol 590, prepared by reacting 4-chloro-7-nitro2,1,3-benzoxadiazole with 4-mercapto-1-butanol in EtOH and potassium phosphate buffer, has shown a relevant activity against different cancer cell lines, such as K562 human myeloid leukemia, HepG2 human hepatic carcinoma, CEM1.3 human T-lymphoblastic leukemia, and GLC-4 human small cell lung carcinoma [490].

Cl

OH

S N N

NO2 589

N

O

N NO2 590

O

13.4 1,2,5-Oxadiazoles

Combretafurazan (592), obtained from combretastatin A-4 (591), an antitumoral and antitubulin agent that is active only in its cis configuration, has shown to be a potent in vitro cytotoxic compound compared to combretastatin in neuroblastoma cells, while maintaining a similar structure–activity relationship and pharmacodynamic profiles [492]. H3 CO

OCH3

H3 CO

OCH3

H 3CO

OCH3

OCH3

H 3CO

OH

OH N

Combrestatin A-4 (591)

O

N

Combretafurazan (592)

Recently, another class of furazans, and in particular the furazano[3,4-b]pyrazines 593 have been prepared and used as antitumoral agents. Their activity is not limited to sarcomas, melanomas, neuroblastomas, carcinomas (including but not limited to lung, renal cell, ovarian, liver, bladder, and pancreatic carcinomas), and mesotheliomas. Moreover, specific assays, conduced for compound 594, have demonstrated that it exhibited an IC50 of 0.00834 nM against sarcoma tumors [492]. Cl

X

N

N O N

N

N 593

R2 N

N O N

R3

N N

NH NH

R1 Cl 594

R1 = H, Alkyl

X = O, S, NH

R2 = H, Aryl, Heteroaryl, alkyl R3 = H, Ary, Heteroaryl, alkyl

Some furazanobenzimidazoles 595 (R ¼ aryl, haloaryl, etc.; R1, R2 ¼ H, alkyl, cycloalkyl, etc.; R3, R4, R5, R6 ¼ H, alkyl, haloalkyl, cycloalkyl, etc.; X ¼ O, C:Y; Y ¼ O, NOH, etc.) and their salts have been synthesized as apoptosis inducers for the treatment of neoplastic and autoimmune diseases. In particular, compound 596 exhibits a strong apoptotic activity in the Hoechst 33342 nuclear staining assay [493]. R4 R5

R3

R6

N

R

X

N

R2 R 1N 595

N

O N O

N H 2N 596

N

N

N O

j1169

j 13 Oxadiazoles

1170

It has also been found that azabenzimidazoles 597 – in which R1 is H or C1–6 alkyl; R2 is halo or optionally substituted Ph, heteroaryl, or carboxamide; R3 is halo, (un) substituted C1–6 alkoxy, (un)substituted phenoxy, heteroaryloxy, or heterocyclyloxy – are inhibitors of Rho-kinases. Rho-kinase is implicated in the phosphorylation of myosin light chain downstream of Rho, which is thought to induce smooth muscle contraction and stress fiber formation in non-muscle cells [494]. R3 R2

N N NH 2

N

R1

N

O

N

597

Moreover, compound 598 is useful for the treatment of diseases such as hypertension, heart failure, and ischemic angina [495]. AcHN

N

O

N Ph

N

NH 2 N

598

O

N

Many other furoxans and furazans have been synthesized to improve their cytotoxic activity; their biological assays have established that the furazan analogues are, usually, less active than the corresponding furoxans. These results indicate the relevance of N-oxide in terms of the bio-response. One of the most interesting pharmacological properties of furoxans and benzofuroxans is the nitric oxide (NO) releasing capacity. NO displays diverse potent physiological actions. As regards the cardiovascular system, it plays a crucial role in vascular homeostasis through several mechanisms, including vasodilation, inhibition of platelet aggregation, and modulation of platelet and leukocyte adherence. In the central nervous system, it plays roles in learning and memory formation. In the peripheral nervous system, it regulates several gastrointestinal, genitourinay, and respiratory functions as neurotransmitter at the endings of nonadrenergic, noncholinergic nerves. NO is also potentially toxic and can induce genomic alterations. Figure 13.5 gives some examples of these drugs.

13.5 1,3,4-Oxadiazoles

1,3,4-Oxadiazole (599) is a partially aromatic and thermally stable molecule [496]. Exocyclic-conjugated mesoionic 1,3,4-oxadiazoles (600), 1,3,4-oxadiazolium cations

13.5 1,3,4-Oxadiazoles

j1171

Vasodilating agents: ON O N N

Me

SO2Ph

N N O O

O

Ph

N O

N

O

CN

NC

N O

N

Ph O

N O

Human platelet-SGS activators: Ph

SO2Ph

N

O

EtO

N O

N

SO2Ph O

N O

Hybrid Antiulcer agents:

N

O

(CH2)3

H N

PhO2S

H N

O

NCN

H2N

O N O N

H2N

N

S

N S

Ph

O N O N

N O N O CO2Et

EtO2C

Me

H N NCN

PhO2S O

CO2Me

MeO2C

Me

N H

Me

(CH2)2

H N

Me

N H

Figure 13.5 Examples of drugs that contain a furoxan moiety.

(601), and 1,3,4-oxadiazolines (602) are also stable molecules. The partially and fully reduced systems designated as 4,5-dihydro-(D2) (603), 2,5-dihydro-(D3) (604), and 2,3,4,5-tetrahydro-1,3,4-oxadiazole (605) are also known. N N O 599

R

R

N N

N N

N N

O

O

X

O

601

600 X = O, S, NR

N N O 603

H

R X

602 X = O, S, NR

N N

HN NH

O

O

604

605

O N O N

j 13 Oxadiazoles

1172

1,3,4-Oxadiazoles are of great practical importance. In particular, these compounds are used in medicine, as leprostatics, tuberculostatics, antibacteric, antiproteolytic, and anticonvulsants. They also possess analgesic, antipyretic, antiphlogistic, bactericides, insecticides, fungicidal, and several other biological activities [496]. More recently, compounds containing the 1,3,4-oxadiazole motif have been used as HIV integrase and angiogenesis inhibitors [497]. 1,3,4-Oxadiazoles have also been used in agriculture, in the production of polymers, laser dyes, photographic materials, or scintillators. Furthermore, they show a combination of interesting properties, which makes them suitable for the development of new electrical and electro-optical devices. A good number of reviews on the chemistry of the 1,3,4-oxadiazoles are present in the literature [496]: the most recent report covers the literature up to the early part of 2007. 13.5.1 Structure 13.5.1.1 Theoretical Aspects 1,3,4 Oxadiazole is not fully aromatic; it has an aromaticity index of 50 (43 and 66 for furan and thiophene, respectively), while the bond orders for O
C, C
N, and N
N bonds are 1.3124, 1.9062, and 1.3348, respectively. Theoretical studies on the structure and properties of 1,3,4-oxadiazoles are numerous [496]. In particular, MNDO and STO-3G ab initio methods have been used to calculate the proton affinities; CNDO/2 methods have been used to calculate the total energies, ionization potentials, and net atomic populations; INDO/S has been used to calculate the electron distribution of ground and excited states. Diels–Alder reactions of several 1,3,4-oxadiazoles used as dienes with alkenes have been investigated through molecular orbital calculations at the B3LYP/6-31G(d)AM1 theory level [498]. MNDO-PM3 calculations have been used to calculate the geometry and electronic structure of mesoionic 1,3,4-oxadiazolium-2-aminides 606 (R ¼ 4-MeO-3-O2NC6H3, R1 ¼ Me, Ph; R ¼ 4-Cl-3-O2NC6H3, R1 ¼ Me; R ¼ Me, R1 ¼ Ph) and 1,3,4-oxadiazolium-2-olates 607 (Ar ¼ 4-Cl-3-O2NC6H3, 4-MeO-3-O2NC6H3) [499]. N N N Ph

R1 N N R

O

Ar

Me O

O 607

606

2-Hydroxy, 2-amino and 2-thiol derivatives 608 are in tautomeric equilibrium with D2-1,3,4-oxadiazolin-5-ones, 5-imino, and 5-thiones 609, respectively. Usually, one of the forms distinctly predominates. N N O

X

N N

H

H

O

608

609 X = O, NH, NR, S

X

13.5 1,3,4-Oxadiazoles

Most of 1,3,4-oxadiazoles are solids, apart from the parent compound (bp 150  C) and its lower alkyl derivatives, which are liquids. Some of them are soluble in water, with a solubility that decreases with increasing molecular weight. 13.5.1.2 Structural Aspects 13.5.1.3 X-Ray Diffraction Many papers related to the X-ray structures of 1,3,4-oxadiazoles have been reported [500]. The oxadiazole ring has a nearly flat structure: all the atoms of the ring lie in the same plane with very slight deviation from it. Table 13.8 shows the reported bond lengths and bond angles for 2,5-di(4-pyridyl)1,3,4-oxadiazole 610 and for 2-(4-cyanophenyl)-5-(4-dimethylaminophenyl)-1,3,4oxadiazole 611. In the crystal, compound 610 has an almost planar structure. All three rings of the molecule are planar but they show a slight torsion relative to each other. The deviation of the planes of the two pyridyl rings relative to the plane of the oxadiazole ring is þ 3.3 for one ring and
3.4 for the other. Owing to the absence of significant steric hindrance the torsion angle between the neighboring rings is small and, therefore, the conjugation is not lost. Compound 611 is almost planar. The planarity of the three single rings is nearly perfect but again the rings show a slight torsion relative to each other. The rotation of the inter-ring bond between the oxadiazole ring and the benzonitrile is þ 6.5 and between the oxadiazole ring and the dimethylaniline is þ 4.2. In this molecule the two substituents are tilted in the same direction relative to the oxadiazole ring whereas in 610 the rings are tilted in opposite directions [501]. Table 13.8 Molecular dimensions for 2,5-di(4-pyridyl)-1,3,4-oxadiazole (610) and for 2-(4-

cyanophenyl)-5-(4-dimethylaminophenyl)-1,3,4-oxadiazole (611).

N N

N N N

O

O

Me2 N

N

610

611 Compound 610

Bond lengths (nm)

O1
C2 C2
N3 N3
N4 N4
C5 C5
O1

CN

0.1365 0.1292 0.1409 0.1292 0.1365

Compound 611

Bond angles ( )

O1
C2
N3 C2
N3
N4 N3
N4
C5 N4
C5
O1 C2
O1
C5

112.50 106.20 106.20 112.50 102.50

Bond lengths (nm)

O1
C2 C2
N3 N3
N4 N4
C5 C5
O1

0.1368 0.1292 0.1407 0.1294 0.1374

Bond angles ( )

O1
C2
N3 C2
N3
N4 N3
N4
C5 N4
C5
O1 C2
O1
C5

111.36 106.97 106.13 112.36 102.82

j1173

j 13 Oxadiazoles

1174

Table 13.9 Proton NMR data (ppm) for ring hydrogens of 1,3,4-oxadiazoles.

N N H

O

R

R

Solvent

d

H Me Et PhCH2 Ph MeS

CDCl3 CDCl3 CDCl3 CDCl3 CDCl3 d6-DMSO

8.73 8.53 8.48 8.26 8.50 9.42

13.5.1.4 NMR Spectroscopy The 1 H NMR spectrum of the parent compound 599 shows the relative signals at 8.73 d in CDCl3 [496, 502]. The presence of alkyl groups or phenyl group moves the proton of the ring upfield, while the shift is downfield for 2-alkylthio derivatives (Table 13.9). The 13 C chemical shift for C2, or C5 carbon in the parent compound is centered at 152.1 ppm. The presence of a phenyl ring at C2 moves this carbon to 164 d [502]. The chemical shifts of the ring carbon atoms in several 1,3,4-oxadiazoles have also been reported. For example, in 2-methoxy-1,3,4-oxadiazole the C2 signal is shifted downfield in comparison with signal of C5. The same trend has been observed for the oxadiazolinone and oxadiazolinethione derivatives where the C2 carbons resonate downfield with respect to C5 carbon [496]. Recently the structure of some 2,5-disubstitued-1,3,4-oxadiazoles has been elucidated by spectral (IR, 1 H NMR, 13 C NMR) analysis. The 13 C NMR analysis revealed that the presence of alkyl groups attached to C2 and C5 of the ring induced a downfield shift of both carbons by at least about 20–22 ppm in comparison with the relative signal present in 599 [503]. The 15 N and 17 O data of different 1,3,4-oxadiazoles have also been used to elucidate their structures. In particular, the 17 O resonances registered for the 1,3,4-oxadiazolium-2-olate have demonstrated that the value centered at 181 ppm, relative to exocyclic oxygen, is that expected for an enolate form instead of that for a carbonylic function [496]. 13.5.1.5 UV and IR Spectroscopy The electronic spectrum of the 1,3,4-oxadiazole system is equivalent to that of benzene and the maxima are only slightly hypsochromically shifted. Substituted 2,5-diaryl- derivatives show strong fluorescence in solution on stimulation by UV or b-irradiation, and some of them are electroluminescent with irradiation of blue light [504]. The electronic effects of conjugated rings on 1,3,4-oxadiazoles are maintained and the absorption and emission spectra of these compounds have been extensively studied and reported [499, 505]. The IR absorption spectra for 1,3,4-oxadiazoles show bands at 1640–1560 (nCN), 1030–1020 (nCO), and 970 cm
1 [496, 503, 506]. These bands occur at longer

13.5 1,3,4-Oxadiazoles

wavelengths in the spectra of 2,5-dialkyl-1,3,4-oxadiazoles and at shorter values in 5thione derivatives [496]. A band in the range 1785–1740 cm
1 is reported for C¼O absorption in the case of oxazolidin-5-ones [496]. 13.5.1.6 Mass Spectrometry The electron impact mass spectra of most 1,3,4-oxadiazoles exhibit a very intense signal for the molecular ion [496, 503, 506]. Moreover, the predominant fragment is represented by R-C ¼ O þ . . In the case of 2-substituted 1,3,4-oxadiazoles, diagnostic fragments derive from loss of CO and HCO. Loss of HNCO is fundamental in the spectrum of 2-amino-5-phenyl-1,3,4-oxadiazole. Oxazolidin-5-ones easily lose CO2 to give the corresponding ions of general formula R-C¼N¼NH þ . A study regarding the electron-spray ionization mass spectra of 2,5-diaryl and 2arylamino-5-aryl-1,3,4-oxadiazoles together with their complexes with copper cations has been reported [507]. In this latter case, loss of NH3 and HNCO was observed. In some protonated 2,5-diaryl derivatives an unusual elimination of HNCO was also detected [508]. 13.5.2 Synthesis of 1,3,4-Oxadiazoles

The common synthetic routes to these compounds involve: 1)

2) 3)

cyclization of diacylhydrazines with various anhydrous reagents such as BF3OEt2 [503], thionyl chloride [509], phosphorous pentoxide [510], phosphorous oxychloride [511], triflic anhydride [512], triphenylphosphine [513], polyphosphoric acid [514], and sulfuric acid [515]; cyclization of acylhydrazones [516], semicarbazones, and thiosemicarbazides; ring transformations [517].

13.5.2.1 Cyclization of Diacylhydrazines The first synthesis of this ring, reported by Robert Stolle, exploits a condensation reaction of N,N0 -diacid hydrazides 612 under vigorous conditions to produce in variable yields 2,5-diaryl(alkyl)-1,3,4-oxadiazoles 613 (Scheme 13.194) [518]. HN NH R

R'

O O 612

N N

-H2 O R

O

R'

613

Scheme 13.194

Useful as agricultural fungicide, Boesch has reported the synthesis of 2-cyanooxadiazole 617 by cyclocondensation of ethyl 2-(2-benzoylhydrazinyl)-2-oxoacetate 614 with P2O5 followed by NH3 treatment and dehydration with POCl3 (Scheme 13.195) [519].

j1175

j 13 Oxadiazoles

1176

O N H

H N

614

N N

P2O 5

O

Ph

95%

CO 2 Et

CO 2 Et

O 615

NH3 97%

Ph

Ph

94%

CN

O

N N

POCl 3

N N

CO 2 Et

O 616

617 Scheme 13.195

Using hot polyphosphoric acid (PPA) 5-substituted [1,3,4]oxadiazol-2-yl compounds 619 have been obtained in good yield (75–95%) (Scheme 13.196). R4 R3

N

N N R1

R2 618

PPA

O R5 HN NH

O

120°C,60min 75-95%

R 1 = H, Br, Cl

R4

N

N N

R3 R

R 2 = Me

2

N N O

R1

R5

619

R 3 = Et,Pr, allyl, CH3 CH=CH R 4 = OMe

R 5 = H, Me, Et,Pr,CF3, Ph

Scheme 13.196

The 2-(oxadiazolyl)imidazo[1,2-a]pyrimidines (619) thus obtained are a class of compounds that bind to benzodiazepine receptors with moderate to weak affinity, and yet display antianxiety properties of similar potency to chlordiazepoxide in animal models, while demonstrating reduced or negligible myorelaxant effects [514]. A polymer-supported Burgess reagent under microwave conditions has been efficaciously used for the cyclodehydration of 1,2-diacylhydrazines 620 to provide 1,3,4-oxadiazoles 621 in excellent yields (Scheme 13.197) [520]. A convenient, one-pot procedure has been reported by Mashraqui and coworkers for the synthesis of various 2,5-disubstituted-1,3,4-oxadiazoles 625 by condensing mono-aryl hydrazides 622 with acid chlorides 623 in HMPA solvent under microwave heating (involving as intermediates diaroylhydrazines 624) (Scheme 13.198) [521]. The yields are good to excellent; the process is rapid and does not need any added acid catalyst or dehydrating reagent.

13.5 1,3,4-Oxadiazoles

R1

HN NH

O O O S Et3 N N O R2

PEG

N N R1

MW (2-4 min 100 W) 70-96%

O O 620 R1

R2

O

R2

621

Yield

HPLC Purity (%)

Ph

Ph

96

91

2-Methoxyphenyl

Me

89

>99

2-Chlorophenyl

Me

70

97

2-Nitrophenyl

Me

95

>99

2-Tyhiophenyl

Ph

95

97

3-Pyridyl

Ph

95

>99

4-Pyridyl

NHPh

95

>99

4-Chloro-3-

Ph

90

92

Nitroamminophenyl Scheme 13.197

Ar

HN NH2 O

622

+ ArCOX

HMPA

HN NH Ar

MW

O O

Ar

624

623

N N

Ar

O

Ar

625 Scheme 13.198

13.5.2.2 Cyclization of Acylhydrazones, Semicarbazones, and Thiosemicarbazides Mono and disubstituted 1,3,4-oxadiazoles 629 have been prepared by oxidation of acylhydrazones 628 prepared in situ by the condensation of aryl carboxylic acid hydrazides 626 with orthoesters 627 (Scheme 13.199). In two examples, the 1-acyl-2ethoxymethylenehydrazine 628 intermediate was isolated [522]. This reaction has been used to prepare the parent 1,3,4-oxadiazole (599) [523]. The above reaction has been revised recently by Varma et al., who have used a green protocol to synthesize 1,3,4-oxadiazoles 629 [502]. In particular, various

j1177

j 13 Oxadiazoles

1178

O R

NHNH 2

12/16 h

627

626

O

150-190°

R 1C(OC 2 H5 )3

+

R

NN H

N N

H R

OC 2H 5

O

R1

629

628

R Phenyl

R1 H

Yield (%) 70

o-Methoxyphenyl p-Chlorophenyl p-Nitrophenyl α-Naphthyl 4-Pyridyl 3-Pyridyl 2-Quinolyl Phenyl 4-Pyridyl Phenyl o-Methoxyphenyl p-Chlorophenyl p-nit rophe n y l α-Naphthyl 4-Pyridyl

H H H H H H H Me Me Et Et Et Et Et Et

79 78 79 63 82 68 70 70 70 80 79 86 92 80 84

Scheme 13.199

hydrazides 626 have been reacted with triethyl orthoalkanates or triethyl orthobenzoate (627), in the presence of Nafion NR50, under microwave irradiations and in the absence of any solvents to afford the desired 1,3,4-oxadiazoles 629 in good yields (68–90%) (Scheme 13.200).

O R

NHNH 2 626

+

1

R C(OC 2 H 5) 3 627

Nafion NR50 Mw (40-140 W) (80°C, 10 min.) 68-90%

N N R

O

R1

629

R = Ph, p-F-C 6H 4, p-OMe-C 6 H4 , 2-furyl, 2-thienyl, 4-pyridyl, PhCH 2 R 1 = H, Et, Ph Scheme 13.200

Owing to the selective absorption of catalyst, the reaction rate is strongly accelerated (10 min). Moreover, Nafion NR50 is easy to handle because it involves a simple addition of Nafion beads in a reaction vessel, which can be physically removed by forceps after completion of the reaction.

j1179

13.5 1,3,4-Oxadiazoles

Electrolytic oxidation of ketone N-acylhydrazones 630 and aldehyde N-acylhydrazones 631 in methanolic sodium acetate affords, through their intramolecular cyclization, the corresponding 2-methoxy-D3-1,3,4-oxadiazolines 632 and oxadiazoles 633, respectively (Scheme 13.201) [524].

R R2

R1

1

N

H N

R

I = 0.5A

R3

OMe R3

O 632

T = 15°C 22-89%

O 630, 631 630

2

N N

N N

R 1 = R 2 =Me, n-Pr, i-Pr, -(CH 2) 5-

R1

R 3 = Ph, Me, n-Pr, i-Pr, OMe

R3

O 633

R 1 = Me, n-Pr, i-Pr, -(CH 2 )5 631

R2 = H R 3 =Ph, Me, n-Pr, i-Pr, OMe

Scheme 13.201

The formation of heterocycles 632 and 633 has been rationalized according to a three-step process. The first step involves the formation of a cationic intermediate generated from 630 or 631 by the loss of two electrons and one proton. In the second step, a 1,3,4-oxazolidinyl carbocation (634) is formed by an intramolecular cyclization promoted by the oxygen of the carbonyl group; and the third step consists of attack by methanol followed by expulsion of a hydrogen in the case of compound 630 or hydrogen extrusion in the case of 631 (Scheme 13.202). ROH R1 2

(R = no H) R1 R2

N

H N

R3 O

630, 631

-2e, -H

1

N N

R2

O

R

R

–H

N N

2

R3

O

R1 R

2

N N O

OMe R3

632

634 R3 R1 (R2 = H)

N N

R2 O

R3

N N

–H R

634

Scheme 13.202

Another method of oxidation of N-acylhydrazones 635 and 636 involves a hypervalent iodine reagent. Thus, Dai et al. have reported the synthesis of 2-alkoxy-D3-1,3,4-

1

O

633

R3

j 13 Oxadiazoles

1180

oxadiazolines 639 and 2,5-disubstitued-1,3,4-oxadiazoles 641 in good to excellent yield by means of phenyl-iodine(III) diacetate (Scheme 13.203). The yields in 1,3,4oxadiazoles was improved by the use of 2 mmol of NaOAc [525].

R1

1

R R2

N

H N

PhI(OAc) 2

R3

R

O

MeOH, or EtOH

O(Me)Et R3

639

T = 0-25 °C 41-100%

O

N N

R 1 = R2 = Me, n-Pr, -(CH 2 )5 -, -(CH 2 )6 -

635

2

N N

R1

3

R = Ph, PhCH 2

O

R3

641

R 1 = Me, n-Pr, i-Pr, n-Bu, Ph R2 = H

636

R 3 = Ph, PhCH 2 Scheme 13.203

Scheme 13.204 explains the formation of these compounds.

R R2

Ph

1

N

H N

PhI(OAc) 2

R3

OAc I

R1

R1

R3

R2

O

R1 = H

–PhI – AcOH

– AcOH

Ph N N

–PhI, – AcOH R

3

641 Scheme 13.204

– AcO

H R2

R3

638

637

NaOAc

O

I OAc N N

O

635, 636

R1

Ph

N N

R2

O

OAc H

R-OH

– AcOH

R1

I OAc N N O 640

2

R

3

R

N N O

639

O(Me)Et R3

13.5 1,3,4-Oxadiazoles

j1181

More recently, starting from 1-aroyl-2-arylidene hydrazines 644, a microwave assisted synthesis of 2,5-disubstituted 1,3,4-oxadiazoles 645 has been reported using as oxidizing agent potassium permanganate supported by montmorillonite K10. The reaction was more efficient when acetone/H2O (20 : 5) was used as solvent, and occurs in only 10 min, with a yield in the range 59–100%. Interestingly, the starting hydrazines 644 have been prepared in good yields under microwave irradiation, mixing in ethanol 6 mmol of acid hydrazide 642, 6 mmol of aldehyde 643, and three drops of phosphoric acid (Scheme 13.205) [526]. R 2CHO 643

O R1

N H 642

NH2

SiO2 – Mw, H 79-96%

H R

2

N

H N

R1 O

644

KMnO4 SiO2 - Mw

N N 1

R

59-100%

1

R = Me, Ph, 4-Cl-C 6 H 4 R2 = Ph, 4-NO 2 -C6H 4, 3-NO 2 -C6H 4, 4-Cl-C 6H 4 , 3-Cl-C 6 H4 , Me, 4-I-C6 H4 , 4-Br-C 6H 4, 4-Cl-C 6H 4 , 4-Me-C 6 H4 , 4-MeO-C 6H 4, 4-CN-C 6H 4 , 4-Cl-C 6 H4 , 4-MeOOC-C 6H 4, 4-(NMe)2 -C6H 4 , Scheme 13.205

Semicarbazones have also been used for the synthesis of 2-amino-1,3,4-oxadiazoles, through their cyclization performed with a mixture of sodium acetate, bromine, and glacial acetic acid. In fact, this procedure was used recently to prepare some Schiff bases of 2-amino-5-aryl-1,3,4-oxadiazoles (649a–t) that posses antibacterial activities. In particular, semicarbazones 646 have been reacted with a mixture of sodium acetate, bromine, and glacial acetic acid, and transformed into the corresponding 2-amino-5-aryl-1,3,4-oxadiazoles 647 that in turn have been condensed with aldehydes 648 to give the expected 1,3,4-oxadiazole derivatives 649a–t (Scheme 13.206). The antibacterial properties of the compounds were investigated against Proteus mirabilis, Pseudomonas aeruginosa, Bacillus subtilis, and Staphylococcus aureus. The most active compounds were 649c,649f,649m, and 649q with a MIC in the range 62–68 mg ml
1. Antifungal activity against Aspergillus niger and Candida albicans were also found for compounds 649g,h,i,m. The corresponding MICs are in the range 52–60 mg ml
1. The biocidal activities of these compounds were attributed to the toxophoric C¼N linkage [527]. The mixture of sodium acetate, bromine, and glacial acetic acid has also been used to prepare several antibacterial 1,2-bis(1,3,4-oxadiazol-2-yl)ethanes 651 from the corresponding diacylhydrazones 650 (Scheme 13.207) [528]. In particular, compounds 651c–e show a good antibacterial activity against Pseudomonas aeruginosa, Bacillus subtilis, Staphylococcus aureus, and Escherichia coli, with a MIC of 6 mg ml
1. Another cyclization method towards the synthesis of 1,3,4-oxadiazoles involves the cyclodesulfurization of thiosemicarbazides 652 using either dicyclohexylcarbodii-

O 645

R2

j 13 Oxadiazoles

1182

H N N R

N N

Br2 /AcOH

NH2

AcONa 72-80%

O

NH2

O

R

647

646

CHO 74-85%

R1

648

N N R

R1

N CH

O

649 a: R =–OMe b: R =–OMe c: R =–OMe d: R =–OMe e: R =–OMe

R1 = –OMe R1 = – NO2 R1 = –Cl R1 = –Me R1 = –OH

f: R =– NO2 R1 = –OMe g: R =– NO2 R1 = – NO2 h: R =– NO2 R1 = –Cl i: R =– NO2 R1 = –Me j: R =–NO2 R1 = –OH

k: R =–Cl R1 = –OMe l: R =–Cl R1 = –NO2 m: R =–Cl R1 = –Cl n: R =–Cl R1 = –Me o: R =–Cl R1 = –OH

p: R =–Me R1 = –OMe q: R =–Me R1 = –NO2 r: R =Me R1 = –Cl s: R =–Me R1 = –Me t: R =–Me R1 = –OH

Scheme 13.206

N R

O

H C

O

H N N O 650a-e

N H

N

Br2/AcOH C H

O

R

O

R

O

AcONa 74-78%

O

N

N

N

O R

651a-e

R = a: NO2; b: p-nitrophenyl; c: p-chlorophenyl; d: p-bromophenyl; e: 2,4-dichlorophenyl Scheme 13.207

mide (DCC), or a mixture of I2/NaOH. By this procedure 2-amino-substituted-1,3,4oxadiazoles 653, having anti-inflammatory activity, have been synthesized (Scheme 13.208) [529]. The anti-inflammatory activity was investigated by determining the inhibitory effect of the oxadiazole derivatives 653a–p on histamineinduced edema in rat abdomen. Compounds 653a,653c,653e,653j, and 653n proved to be more potent anti-inflammatory agents at 200 mg kg
1 p.o. than Ipobrufen, the standard reference drug. 2-Amino-5-aryl-1,3,4-oxadiazoles 656 have also been prepared, in good yield, by cyclodesulfurization of thiosemicarbazides 654 using 1,3-dibromo-5,5-dimethylhydantoin (655) as primary oxidant in the presence of potassium iodide (Scheme 13.209) [530].

13.5 1,3,4-Oxadiazoles

R1 NH

O NH NH

R

I2 /NaOH or DCC 60-77%

S 652a-p

N N R

O

NHR1

653a-p R1

Et

R

N

Cyclohexyl

Ph

Me-C6 H4

652a

652b

652c

652d

653a

653b

653c

653d

652e

652f

652g

652h

653e

653f

653g

653h

652i

652j

652k

652l

653i

653j

653k

653l

652m

652n

652o

652p

653m

653n

653o

653p

N

N Me Me Et Scheme 13.208

O Br N O Ar

NH NH2 NH S 654

N

Br O 655

KI, NaOH i-PrOH/CH3CN 53-97%

N N Ar

O

j1183

NH2

656

Ar: Ph, 4.Cl-Ph, 4-OMe-Ph, 2-Furyl, PhCH2CH2, PhCH=CH Scheme 13.209

13.5.2.3 Ring Transformations Thermal decomposition of N-acyl-tetrazoles 657 is a common way to obtain 1,3,4oxadiazoles 659 [496]. This reaction has been easily explained by the loss of nitrogen, formation of the corresponding nitrilimines 658, and an intramolecular 1,5-cycloaddition (Scheme 13.210).

j 13 Oxadiazoles

1184

O N N N N

R

N N

N N

∆ – N2

R

R

R

O

R

659

658

657

R

O

Scheme 13.210

The mechanism of the process was demonstrated by labeling with 15 N the atoms N1 and N4 in 5-phenyltetrazole. Half of the 15 N was found in the 2,5-diphenyl-1-3-4oxadiazole, obtained by the breakdown of the N-benzoyl-5-phenyltetrazole. Therefore, either the atoms N1 and N2 or N3 and N4 were eliminated as N2 [531]. Scheme 13.211 shows that the thermolysis of N-aroyl-5-phenyltetrazoles 660 affords oxadiazoles 661 [532].

Ph N N N N O

N N

∆

Ph

91-98%

Ar

O

Ar

661

660 Ar = Ph, 2-Cl-C6 H4 ; 2-Br-C 6 H4 ; 4-NO 2-C6 H4 ; 4-Me-C 6 H 4 Scheme 13.211

(5-Nonyl-1,3,4-oxadiazol-2-yl)benzothiazine dioxide 664, a compound that shows anti-inflammatory properties by virtue of its inhibition of arachinodate 5-lipoxygenase [533], has been prepared starting from tetrazol-5-yl derivative 662, which undergoes a Huisgen rearrangement on refluxing with decanoic anhydride 663 in toluene, followed by saponification (Scheme 13.212).

Me(H 2C)8 N N N N H N Me S O O OH

662 Scheme 13.212

O O

(CH2 )8 Me O

OH

663 PhMe, reflux NaOH/MeOH 75%

O

S

N O

664

N N C (CH2 )8 Me O Me

13.5 1,3,4-Oxadiazoles

j1185

By exploiting the thermal decomposition of alkoxycarbonyl tetrazoles, the 4-[5(dipyrido[3,2-a:20 ,30 -c]phenain-11-yl)-1,3,4-oxadiazol-2-yl]-N,N-diphenylaniline 668 has been prepared. Thus, the dipyrido[3,2-a,20 ,30 -c]phenazine 8-carboxyl chloride 665 in dry pyridine was refluxed for 72 h with triphenylamine tetrazole 666 to afford 668 via the corresponding alkoxycarbonyl tetrazole intermediate 667, in 60% yield (Scheme 13.213) [534]. N NH N N

N N

Cl N

N

N

N

O

666

N

Py, reflux 60%

665

N

N

N

N

N N N O

667

N

N

N

N

N N O

N

668 Scheme 13.213

The above compound, which contains a hole-transporting triphenylamine and an electron-transporting 1,3,4-oxadiazole unit, is an efficient light-emitting material. In particular, the absorption spectrum of 668 is extended into the visible region and shows a typical CT band around 416 nm and a broad p–p transition band around 347 nm. This is the result of the extended conjugation of the phenanthroline moiety. The emission maximum of 668 is at 635 nm (red) with lex at 416 nm, and a quantum yield of 40%. Moreover, preliminary studies performed on this compound showed that it can be used as anorganic light emitting diode (OLED). Microwave methodology has also been used to prepare various 3-(1,3,4-oxadiazol2-yl)pyridines 671 in good to excellent yields, by reaction of 3-(5-tetrazolyl)pyridines 669 with different acid anhydrides (670) (Scheme 13.214) [535]. 1,3,4-Oxadiazoles can also be obtained by photo-isomerization of 1,2,4-oxadiazoles. Irradiation of 5-alkyl-3-amino-1,2,4-oxadiazoles 672 at 254 nm in methanol and in presence of Et3N, even if in moderate yields, leads to 2-amino-5-alkyl-1,3,4-

j 13 Oxadiazoles

1186

(R3 CO)2 O

N NH N N R1

N N

670a–f Me

R

O

R1

MeCN; MW, 120°C

R2

N

2

R3

Me N 671a–f

669a–f

R1 R2 R3 a: Ph H Me b: Ph H CF3a c: –o–C6H4–(CH2)2– t-Bu d: –o–C6H4–OCH2– MeO(CH2)2 e: –(CH2)3– i-Pr f: –(CH2)5– 4–Cl– C6H4 a The reaction was performed at room temperature for 2 h.

Yield (%) 95 100 96 80 99 68

Scheme 13.214

oxadiazoles 675. A small amount of the ring-degenerate isomers 3-alkyl-5-amino1,2,4-oxadiazoles 678 (Scheme 13.215) was also obtained [536].

NH2

N R

O

N

N N

hν MeOH, Et3 N λex 254 nm

672

R

O

NH 2

R

N

+ H2N

O

N

22%

6%

675

678

R = C11 H23; C8 H17 Scheme 13.215

The formation of 675 has been explained according to the ring contraction–ring expansion (RCRE) route, while 678 originates via a competing internal cyclization (IC)–isomerization mechanism, with an anionic species (673) as a common precursor (Scheme 13.216). By a similar approach, 2-amino-5-alkylfluorinated-1,3,4-oxadiazoles 680 have been prepared utilizing the photochemical interconversion of 3-N-alkylamino-5-perfluoalkyl-1,2,4-oxadiazoles 679 in the presence of triethylamine. A moderate yield of 5-amino-3-alkyl-1,2,4-oxadiazoles 681 was also obtained, as a rearrangement product (Scheme 13.217) [537]. In this context, the same authors have reported that 1,2,5-oxadiazoles containing an acetylamino moiety are able to photochemically interconvert into 1,3,4-oxadiazoles. Thus, irradiation of 2,2,2-trifluoro-N-(4-phenyl-1,2,5-oxadiazol-3-yl)acetamide

13.5 1,3,4-Oxadiazoles

NH 2

N R

O

R

MeOH, Et3 N

N

*

NH

N

hν

O

NH RC

N

N

R

674

IC R

N H 2N

O

NH 2

N

N

R

678

N

N

O

R

O

677

N

O

673

672

j1187

RE

NH N N

N

R

NH2

O 675

676

Scheme 13.216

NH2

N R

N

O

N N

hν R

MeOH, Et3N λex 313 nm

O

679

NH2

R

N

+ H2N

O

N

60%

25%

680

681

R = C7F15; C3F7 Scheme 13.217

682, in methanol in the presence of methylamine, produces, via 3-N-methylamino-5trifluoromethyl-1,2,4-oxadiazole (683), a mixture of 2-N-methylamino-5-trifluoromethyl-1,3,4-oxadiazole (684) and 1-methyl-3-N-methylamino-5-trifluoro-methyl1,2,4-triazole (685) in 32% and 15% yield respectively (Scheme 13.218) [538]. O

F3 C Ph N

NH O

N

682

hν MeOH, MeNH 2 λex 313nm

N F3C

O

HN Me N

N N F3C

O

NHMe

32%

683

N

+ F3C 15%

684

Scheme 13.218

The study of organic transformations within constrained media is a research topic that has received considerable attention in recent years. In this regard the

HNMe

N N Me

685

j 13 Oxadiazoles

1188

first intrazeolite-photoinduced rearrangement of 1,2,4-oxadiazoles leading to 1,3,4oxadiazoles has been reported. Irradiation of a perfluorohexane slurry of 3,5diphenyl-1,2,4-oxadiazole (686) in zeolite (NaY) at 254 nm for 24 h furnished 2,5diphenyl-1,3,4-oxadiazole (689) in 60% yield together with N-benzoyl-N0 -phenylurea (691) (4%) and unreacted starting compound (35%). The formation of 689 and 691 is unknown in solution (Scheme 13.219) [539]. O Ph

N Ph

O

N N

hν NaY λ ex 254 nm 24 h

N

Ph

Ph

O

+

N H

N H

Ph

4%

60% 689

686

Ph

O

691

hν MeOH

O Ph

N

OMe

N Ph H 26% 692

Scheme 13.219

In fact, a photochemical study performed on 686 in MeOH afforded product 692. This dramatic difference of photo-behavior is explainable through a common intermediate (687), which in the zeolite cage leads to compounds 689 and 691, via intermediates 688 and 690, respectively, while 687 in methanol undergoes a nucleophilic addition of the solvent, giving rise to 692 (Scheme 13.220). Ph

N Ph

O

hν

N

MeOH

Ph

N Ph

O

687

Ph

N

hν NaY

Ph

N

O

N

N Ph

O

688

687

686

Ph

N

MeOH

O Ph

N N H

OMe Ph

O Ph

N H

691

692 Scheme 13.220

O

O N H

Ph

H 2O

Ph

N N N C N Ph

690

Ph

O

689

Ph

13.5 1,3,4-Oxadiazoles

j1189

It was found recently that a thermal rearrangement promoted by base is also effective in the formation of 1,3,4-oxadiazoles 698 starting from 3-acylamino-1,2,4oxadiazoles 693 (Scheme 13.221) [540].

O

H

N

N R

O

R

N

R t-BuOK/DMF

O

150°C 60-77%

N N N H

R

O 698

693 R = Me, Pr, Ph, 2-Thienyl Scheme 13.221

The reaction consists of a one-atom side-chain rearrangement that is base activated, occurs at higher temperature, and irreversibly leads to the corresponding 2-acylamino-1,3,4-oxadiazoles. The reaction mechanism has been studied in depth by computational methods, using the hybrid DFT B3LYP method and the 6-31 þ þ G(d,p) basis set. Following these computational studies, the proposed mechanism is that reported in Scheme 13.222, where the route involving migration–nucleophilic attack–cyclization (MNAC) is the activated route, while the ring contraction–ring expansion route (RCRE) is ruled out.

M

H N R

O

N

R

N

Me

695

∆

N

N

t-BuOK/DMF R

O

N

R

Me

O

Me N

O

697 H

C E

R

694

N N C

R

693

O

N

O

O N

C NA

O

N

Me

Me O

N N

Me R

O

696

O

N N N H

O

698 Scheme 13.222

R

j 13 Oxadiazoles

1190

13.5.2.4 Synthesis of Mesoionic 1,3,4-Oxadiazoles (600), and 1,3,4-Oxadiazolium Cations (601) The simplest way to prepare mesoionic 1,3,4-oxadiazoles 600 is by the thermal cyclization of 1-carbonyl-substituted-1-substituted hydrazine hydrochloride and phosgene [541]. Thus, the 4,5-dihydro-3-methyl-5-oxo-2-phenyl-1,3,4-oxadiazolium inner salt 701 has been synthesized from 1-benzoyl-1-methylhydrazine hydrochloride (699) and phosgene (700) (Scheme 13.223) [541]. O O

Ph

Cl NH2

N Me 699 HCl

Cl 700

Me

70°C 46%

N

Ph

N O

O

701

Scheme 13.223

In the same way, 5-(dimethylamino)-4-methylisosydnone 705 has been prepared, via the aminoisocyanate 704 intermediate, by heating at 70  C the 2,4,4-trimethylsemicarbazide 702 with trichloromethyl chloroformate (703) (Scheme 13.224) [542].

O Cl

Cl

O

Me

NH2 N N Me Me 702

Cl O Cl 703

O

Me

70°C 44%

N Me

Me N C O

N Me

Me

704

N

N Me

N O

O

705

Scheme 13.224

1,3,4-Oxadiazolo[3,2-a]pyridylium-2-aminides 708 are available in 75–91% yield by reaction, in refluxing toluene, of 1,3,4-oxadiazolo[3,2-a]pyridylium-2-olate 706 with N-aryliminotriphenyl-phosphoranes 707 (Scheme 13.225) [543]. Ph

Ph N N Ph

O 706

∆, PhMe O

ArN PPh 3 707

N Ph

N

O 708

N Ar

75-91% Ar = Ph, 4-BrC 6 H4, 4-ClC 6 H 4, 4-MeC 6 H4, 4-MeOC 6H 4, α-C10H 7 Scheme 13.225

13.5 1,3,4-Oxadiazoles

1,3,4-Oxadiazolium cations 601 are easily obtained by treatment of 1,3,4-oxadiazoles with several alkylating agents to give in about 100% yield the corresponding salts. A recent example is the synthesis of 2,5-diaryl-3-trimethylsilylmethyl-1,3,4oxadiazolium trifluoromethanesulfonates (711) [544]. These compounds have been prepared in 99–100% yield by mixing a solution of 2,5-diaryl-1,3,4-oxadiazoles 709 with trimethylsilylmethyl trifluoromethanesulfonate 710 in dry CH2Cl2 at 50  C under reflux condenser for 24 h (Scheme 13.226). O Me O S CF3 Me Si O Me 710

N N

Ar

O

N N

Ar

99-100%

Ar

SiMe3

O

CF3 SO3 Ar

711

709 Ar = Ph; 4-Brl-C 6 H4 , 4-Me-C 6 H4 , Scheme 13.226

Another method involves the cyclization reaction of N-substituted diacylhydrazides with a mixture of HClO4–Ac2O. Thus, cyclization of RCONR1NHAc 712 with HClO4–Ac2O gave 47–98% yields of 1,3,4-oxadiazolium salts 713 (Scheme 13.227) [545].

R

R

HN N

R1

Me O O

HClO4 /Ac2 O 47-98%

712

ClO 4

N N R

O

R1

713

R= F, Me, Cl, NO 2, OMe

R1 = F, Me, NO 2, OMe, Cl, SMe, H, NH2 , SO2 Me

Scheme 13.227

13.5.2.5 Synthesis of Oxadiazolinones, Oxadiazolinethiones, and Oxadiazolimines (602) 1,3,4-Oxadiazolin5-ones are, usually, synthesized by reaction of substituted acid hydrazide with phosgene or by thermal cyclization of acylcarbazates.

j1191

j 13 Oxadiazoles

1192

5-tert-Butyl-3-(2,4-dichloro-5-isopropoxyphenyl)-1,3,4-oxadiazolin-2-one – a very active herbicide, that goes under the commercial name of Oxadiazon (716, R ¼ CMe3), commonly used in rice production for controlling weeds and increasing seed yield in soya beans, containing the oxadiazolinones ring – has been prepared by reaction of 1-trimethylacetyl-2-(2,4-dichloro-5-isopropoxyphenyl)hydrazide 714 with phosgene (715) in toluene at 100–110  C (Scheme 13.228) [546].

O R

N H

Cl

H N

+

Cl

O

Cl

Cl Me

Cl Me

Cl

O

∆ /PhMe 100-110°C 75%

O

N N R

Me

O

O

715

Me

716

714 R = CMe3, OMe, OEt, O-n-Pr, OBu, O-sec-Bu, O-iso-Bu Scheme 13.228

Similarly, 5-substituted-3-(2,4-dichloro-5-isopropoxyphenyl)-1,3,4-oxadiazolin-2ones have been prepared (R ¼ MeO, EtO, n-PrO, BuO, sec-BuO, iso-BuO). Condensation of ethyl 2-(2-chlorophenyl)hydrazine-carboxylate 717 with phosgene has furnished 5-ethoxy-3-(2-chlorophenyl)-1,3,4-oxadiazolin-2-one 718, which is active orally against gastrointestinal nematodes of domestic animals and man (Scheme 13.229) [547]. Cl O O

N H

H N

717

Cl

Cl +

Cl

O

∆ /PhMe 100-110°C 75%

715

N N EtO

O

O

718

Scheme 13.229

Cyclization of acylcarbazates has been utilized fruitfully for the synthesis of 2-(2,3dihydro-2-oxo-1,3,4-oxadiazol-5yl)benzoxazoles, a class of compounds that are potent inhibitors of anaphylactically induced histamine release from rat peritoneal mast cells and are orally active as inhibitors of IgE-mediated passive cutaneous anaphylaxis in the rat [548]. The 2-(2,3-dihydro-2-oxo-1,3,4-oxadiazol-5-yl)benzoxazole 722a (R ¼ H), chosen as an example, was synthesized by heating ethyl 3-(2-benzoxazolyl)hydrazine-carboxylate (721) in Dowtherm at 230–240  C for 1 h. Intermediate 721 was prepared by treating 3-chloro-1,4-benzoxazin-2-one 719 with ethyl carbazate 720

13.5 1,3,4-Oxadiazoles

j1193

in dioxane and triethylamine at room temperature for 4 h. In a similar manner, compounds 722b–g have been prepared (Scheme 13.230). H N

O

R N

Cl

O +

O

N H

H N

dioxane H

Et3N, 4h, rt

O N

63%

720

719

R

HN NH O 721 ∆

77%

R = H, 5-Cl, 5-CO 2 Me(7-OMe), 6-Me, 5-CO 2 Et, 4-Me, 5-Me

R

230-240°C

O

N NH

N

O 722

Scheme 13.230

5-Imino-2-substituted D2-1,3,4-oxadiazolines 725, as hydrochloride salts, which are able to produce a profound flaccid paralysis in rats, have been prepared by hydrochloric reaction of 2-amino-5-aryl-1,3,4-oxadiazoles 724, in DMF/H2O or in ethanol–ether as solvents. These latter compounds have been synthesized by reaction of 1-acyl-3-thiosemicarbazide 723 with Pb3O4 (Scheme 13.231) [549]. O R

N H

Pb3O 4

H N

NH2

OEt

O

N N R

S

NH2

O 724

723

HCl 80-82% N NH R

O

NH

HCl

725 R = Ph, Me-C6 H4 , Me-C6 H 4, 2-CF 3-C6 H 4, 3-CF 3 -C6H 4, Scheme 13.231

Diphenylnitrilimine 728, prepared from 2,5-diphenyltetrazole (726) or by triethylamine treatment of diphenylchlorohydrazone 727, adds to C¼O and C¼N double bond of aryl isocyanate to give 2,4-diphenyl-1,3,4-oxadiazol-5-phenylimino 729, and 1,3-diphenyl-4-aryl-1,2,4-triazolin-5-ones (730) in a 2 : 1 ratio respectively (Scheme 13.232) [550].

O

j 13 Oxadiazoles

1194

Ph Cl Ph

Ph N N N N

∆ 150- 180 °C Ph

726 Et3N

N N Ph H

N N Ph 728 ArNCO 17-80%

C6H6 refluxed

727

Ar = Ph, p-OMe-C6H4, p-Cl-C6H4, p-NO2-C6H4 Ph N N Ph

O

NAr

Ph N N

+ Ph

N Ar

O

730

729 Scheme 13.232

5-Hydroxy-2-methyl-6-phenyl-7H-[1,3,4]oxadiazolo[3,2-a]pyrimidin-7-one (733) has been obtained in 79% yield via a solvent-free microwave cyclocondensation reaction using di(2,4,6-trichlorophenyl) 2-phenylmalonate (732) and 2-methyl-5amino-1,3,4-oxadiazole (731) in a 1 : 2 ratio under heating at 250  C for 15 min (Scheme 13.233) [551].

Cl N N

Me

O

+

NH2

Cl

731

HO

Cl O

Cl

O

732

O

Cl

N N

MW, 15 min

O

Cl

250°C 79%

Me

O

N

O

733

Scheme 13.233

The synthetic procedure based on the ring closure of substituted acid hydrazide 734 with carbon disulfide leads to 5-aryl-2,3-dihydro-1,3,4-oxadiazole-2-thiones 735 in excellent yield (Scheme 13.234). The obtained compounds have been conveniently transformed into 3,5-disubstituted-2,3-dihydro-1,3,4-oxadiazole-2-thiones 738 in 72–92% yield, by reaction with dapsone (736) and aromatic aldehydes 737 in methanolic solution. Compound 738a has been shown to be very active against Mycobacterium tuberculosis H37Rv and isoniazid (INH) resistant M. tuberculosis with MIC of 0.1 and 1.10 mM respectively [552].

13.5 1,3,4-Oxadiazoles

R1

Ph N N

CS 2 /KOH

O N H

NH2

70-90%

O

R1

j1195

S

NH2

735

734

R 2CHO

737

O S O

NH2 72-92%

736

R 1 = Ph, 4-NO 2 -C6H 4, PhNHPh, β-C10H 7-O-CH 2, α -C10H7 -O-CH2 , PhOCH 2, PhCH2 R 2 = Ph, 2-furyl O S O

S O R1

N

N

HN R2

R2

NH

S N

O N

R1

738 Scheme 13.234

O O S O

S O N

N

HN O

S N

NH

O N O

O

738a

Acyclic C-nucleoside 5-(1,2-dihydroxyethyl)-3H-[1,3,4]oxadiazole-2-thione 742, containing an 1,3,4-oxadiazolinethione ring, as mimic of ribose unit, has been synthesized starting from ()-2,2-dimethyl-[1,3]dioxolan-4-carboxylic acid methyl ester 739 via reaction with hydrazine to give the corresponding hydrazide 740, followed by CS2 treatment and subsequent deacetonation with Amberlyst 15 (Scheme 13.235) [553]. The synthesis of this optical active compound has been performed by the same common route using as chiral source the D-mannitol. Furthermore, the use of D-xylose 743, via (tetrahydro-[1,3]dioxino[5,4-d][1,3]dioxin-4-yl)-methanol 744, leads

j 13 Oxadiazoles

1196

O

O MeO

O

Me Me

O

NH2NH 2

H 2NHN

EtOH/ ∆ 89%

O

Me

O

Me

740

739

82%

CS2 KOH, EtOH

S HN

S

O OH

N

Amberlyst 15 82%

OH

HN

O N

O

Me

O

Me

741

742 Scheme 13.235

to 5-(1,2,3,4-tetrahydroxybutyl)-3H-[1,3,4]oxadiazole-2-thione 745 in enantiomerically pure form, in 8.5% total yield (Scheme 13.236). HO

O

H C OH HO C H H C OH CH2OH 743

OH H H

H O H O

C O H C H H C O CH2

744

S HN

O N HO

OH OH

HO 745

Scheme 13.236

13.5.2.6 Synthesis of (D2) (603), (D3) (604), and 2,3,4,5-Tetrahydro-1,3,4Oxadiazoles (605) The D2-1,3,4-oxadiazoline 751, which inhibits cell proliferation and binds to tubulin, has been synthesized, as reported in Scheme 13.237, according to a process that involves as the key reaction the cyclization of acylhydrazone 749 with acetic anhydride [554]. The synthesis starts from the 4-azido-3-methylbenzoic acid (746), which was reacted with tert-butylcarbazate in the presence of 1-[3-(dimethylamino) propyl]-3-ethylcarbodiimide hydrochloride (EDCI) and a small amount of 4-(N,N,dimethylamino)pyridine as base, to give, after trifluoroacetic acid (TFA) treatment, 98% of 4-azido-3-methylbenzoylhydrazide (747). This compound was condensed with 3,4,5-trimethoxybenzaldehyde (748) to give in 67% yield the corresponding acylhydrazone 749, which was then cyclized to 2-(4-azido-3-methlphenyl)-4-acetyl-5(3,4,5-trimethoxyphenyl)-D2-1-3-4-oxadiazoline (750). Compound 750 was converted into the target compound 751 by reduction of the azido group with a suspension of SnCl2, thiophenol, and triethyl amine, in 80% yield (total overall yield 32%).

13.5 1,3,4-Oxadiazoles

j1197

O O

Me

N3

748 NHNH 2

DMF, TFA, 98%

OH

O

N3

NH 2NHBoc, EDCI

O

Me

O

Me

N3

O

67%

O

N O

747

746

NH

749

O O

Ac 2O

64%

Me

Me O

N N

N N

O

SnCl 2, TEA

O

Me

751

O

750

Scheme 13.237

The method has been exploited to prepare various 2-[4-(N,N-dimethylaminophenyl]-4-substituted-(3,4,5-trimethoxyphenyl)-D2-1-3-4-oxadiazolines 753, which present interesting antitumoral activity (Scheme 13.238)[555].

Me H2N

R O NH

N

N N (a-d) 55-100%

O

O O

O

O

H2N Me

O

O O

752

R = H, C2H5OCO, ClCH2, CH3O

753a-d

(a) Ac2O/HCO2H; (b) ethyl oxalyl chloride; (c) chloroacetic anhydride; (d) dimethylpyrocarbonate Scheme 13.238

O O

N3

80%

O

Me

O

O

Thiophenol

O

H2 N

125 °C

j 13 Oxadiazoles

1198

C,N-Diphenyl nitrilimine 728 reacts, by 1,3-dipolar cycloaddition, with aldehydes 754 to produce in 50–75% yield 5-aryl-substituted-2,4-diphenyl-1,3,4-oxadiazolines (755) (Scheme 13.239) [555, 556].

Ph

N N Ph 728

ArCHO 754 50-75%

Ph

Ph N N H O Ar 755

Ar = Ph, p-OMe-C6 H 4, p-Cl-C 6 H4 , p-NO2 -C6 H 4 Scheme 13.239

N-Substituted 2,3-dihydrooxadiazoles have been prepared recently by intramolecular cyclization of protected amino-aldehydes (1,5-dipolar cycloaddition) [557]. Thus, the N,N-dibenzylated aldehyde 756 after heating at reflux for 72 h, in toluene, with N1acetyl-N2-methylhydrazine 758, for 16 h, gave rise to the 2,3- dihydro-1,3,4-oxadiazole 760a (7%), through a cyclization involving the hydrazine N-acetyl group of the notisolable intermediate 759 (Scheme 13.240). 2-Benzyloxypropanal 757 gave the analogous product 760b (11%). R = NBn 2 7% MeNHNHCOMe 758

O H R

756,757

Me R

PhMe, Reflux Dean-Stark trap

N O

R = OBn 11%

N N

N Me

O

Me

R

760a,b 759

Scheme 13.240

Ylidine-N-phenylhydrazine-carbothioamides 762 react, in glacial acetic acid at reflux temperature, with 2,3-diphenylcyclopropenone (761) by way of an initial [2 þ 3] cycloaddition to give 763, which undergoes a cyclization process with extrusion of H2S to afford the pyrrolo[2,1-b]-1,3,4-oxadiazoles 764a–e in 60–77% yield (Scheme 13.241) [558]. D3-1,3,4-Oxadiazolines (604) can be easily prepared by oxidation of acylhydrazones (see Schemes 13.201 and 13.203) [524, 525]. Thus, the oxidation of methoxycarbonyl hydrazone of acetone (766) with lead tetraacetate (LTA) furnishes the 2-acetoxy-2methoxy-5,5-dimethy-D3-1,3,4-oxadiazoline (767) in 60–72% yield (Scheme 13.242). This reaction route was further developed, transforming 767 into various D3-1,3,4oxadiazolines 768 and 769 by reaction with alcohols or phenols. Notably, these compounds have been used as a carbene source, because they fragment quite cleanly in solution at about 100  C to give as by-products acetone and N2 [559].

13.5 1,3,4-Oxadiazoles

R H O + Ph

Ph

H N

H N

Ph

H

AcOH R

N

Ph

4-8 h

S 762

761

N

N H

Ph

N S

j1199

Ph O H

763

R = 2-Thienyl, Ph; 4-Cl-C 6H 4, 4-OMe-C 6 H4 , 4-OH-C 6H 4

N

PhHN

R

N

O

–H 2 S

HS PhHN

60-77%

Ph

H N

R

N

O

Ph Ph

Ph 764

765 Scheme 13.241

H N N

LTA (AcOH) CO2 Me

60-72%

766

Me Me

N N

OMe OAc O 767

ROH 67-94%

Me Me

N N

OMe OR

O 768

61-68% ArOH

Me Me

N N O

OMe OAr

769

R

Me

Et

Pr

i-Pr

Bu

t-Bu

CH2CF3

Ar

Ph

4-CNC6H4

4-OMeC6H4

––

––

––

––

But3ynyl ––

Pent4ynyl ––

Scheme 13.242

2,3,4,5-Tetrahydro1,3,4-oxadiazoles are obtained by reaction of 1,2-disubstituted hydrazines with aldehydes. Zwanesburg et al. have reported the synthesis of a series of 2,3,4,5-tetraalkyl-1-3-4-oxadiazolidines (772) by reaction of 1,2-dimethylhydrazine (771) with aliphatic aldehydes 770. Thus, the appropriate aldehyde (2 equivalents) in 50 ml of dry ether and a few grams of MgSO4 treated drop-wise during 15 min, below 5  C, with one equivalent of aldehyde gave after 1 h the corresponding 1,3,4 oxadiazolines in 60–75% yield (Scheme 13.243) [560].

j 13 Oxadiazoles

1200

H N

O R

H

+

Me

770

0-5°C N H

Me

771

Et 2O, MgSO 4 60-75%

Me R

N N

Me R

O 772

R = Me, Et, Pr, Bu Scheme 13.243

In a similar way Zinner and Kliwing have prepared other 1,3,4-oxadiazolines (775) using different hydrazines (774) (Scheme 13.244) [561]. O R

H

R1

+

H N

N H

1

R

R1 R1 N N

18-80% R

774

773

R

O 775

R = H, Me, Et, Pr, i-Pr, t-Bu, Ph R 1 = Me, i-Pr, Cyclohexyl, -CH 2CHMeCH 2 Scheme 13.244

3,4-Diaryl substituted 1,3,4-oxadiazolidines 777 have been synthesized in moderate to good yields (16–54%) by TiO2-photocatalyzed reaction of azobenzenes 776 in methanol through a uranium glass filter (lex > 320 nm). The reaction probably involves a photoreduction of azobenzenes to 1,2-diarylhydrazine, an oxidation of methanol to formaldehyde, and the subsequent cyclization to 1,3,4-oxadiazolidines (Scheme 13.245) [562].

R1

R

R

N N 776

R1

hν

N N

TiO 2 -MeOH uranium filter

O

16-54%

777

R = H, Ph R 1 = 4-Cl-C 6 H4 , 4-Me-C 6 H4 , 3-Cl-C 6H 4 Scheme 13.245

Tricyclic fused-1,3,4-oxadiazole systems that display in vitro fungitoxicity comparable to that of fungicide Dithane M45 at 1000 ppm concentration against Aspergillus niger and Fusarium oxysporum have been obtained starting from 2-aryl-3-thioureido-4-

13.5 1,3,4-Oxadiazoles

thiazolidinones 778. These compounds were treated with a mixture of KI/I2 under basic conditions to afford bicyclic compounds containing the D2-1,3,4-oxadiazoline core (779) that were then converted into the target compounds by reaction with formaldehyde and various a-amino acids 780 (Scheme 13.246) [563]. S Ar

N HN 778

O S NH2

Ar = Ph, 4-Cl-C6H 4

KI/I 2 NaOH 76%

O

S

NH2

N N

Ar

779 R

EtOH, reflux

R = H, Me

HCHO

H 2N

780

70-74%

O S

CO 2 H

N

N N Ar

N

CO 2H

R 781

Scheme 13.246

Another versatile method for the synthesis of 1,3,4-oxadiazolidines (605) is the 1,3-dipolar cycloaddition of azomethinimines to carbonyl compounds. In particular, thermal decomposition of 8,8a,16,16a-tetrahydro-8,16-diphenyl[1,2,4,5]tetrazino[6,1-a:3,4-a0 ]diisoquinoline (782) at 50–80  C gave the 3,4-dihydroisoquinolineazomethinimine 783 that in presence of various carbonyl compounds (784) gave rise to substituted 1,3,4-oxadiazolidines 785 (79–100% yield) (Scheme 13.247) [564]. The obtained compounds, at high temperature, are thermolabile and decompose to azomethinimines and carbonyl compounds. This is recognizable by a color change to reddish-brown. Moreover, the azomethinimines thus obtained can be trapped with a wide range of dipolarophiles [565]. Hydrazide 786 (R ¼ Me) and semicarbazides 787 (R ¼ NHAr) have been used for the synthesis of azomethine imines 789 that, in situ, react with methyl glyoxylate hemiacetal 788 to give the corresponding 1,3,4-oxadiazolidines 790 in good yields (60–70%) (Scheme 13.248) [566]. Similarly, the cyclic hydrazine 791 reacts with ethyl glyoxylate (792) in the presence of MgBr2Et2O in THF at 65  C to give in 71% yield the bicyclic 1,3,4-oxadiazolidine 794 with a diastereomeric ratio of 46/38/16, via the azomethinimine intermediate 793 (Scheme 13.249) [567].

j1201

j 13 Oxadiazoles

1202

R

N

N N

R

∆ N

N

50-80°C

783 R1

782

R N

N

O

Scheme 13.248

R2

Yield

H

H

H

88

H

Me

H

79

H

CCl3

H

84

NO 2

CCl3

H

99

H

Ph

H

93

H

p-MeO-C 6 H4

H

92

R1

H

p-Cl-C 6H 4

H

92

2

H

2-pyridyl

H

98

H

2-furyl

R

785

Scheme 13.247

O

R 2 784

R

R1

R

N

H

85

H

CO 2Et

H

NO 2

CO 2Et

H

93 100

13.5 1,3,4-Oxadiazoles

j1203

Scheme 13.249

13.5.3 Reactivity

The reactivity of the 1,3,4-oxadiazole system is expressed in a series of different chemical transformations that can be amenable to (i) ring cleavage reactions, (ii) reactions due to the reactivity of heterocycle ring, and (iii) reactions of substituents. 13.5.3.1 Ring Cleavage Reactions Ring-opening reactions of 1,3,4-oxadiazoles can be achieved by the action of nucleophilic reagents; in some cases the ring opening occurs by thermolysis or photolysis. 2,5-Dialkyl-1,3,4-oxadiazoles are cleaved by water in basic or acid conditions to produce diacylhydrazines that suffer further hydrolysis under vigorous conditions to give carboxylic acids and hydrazine (Scheme 13.250). N N R

O

R1

H2 O, H ∆ 70%

795

O R

N H

H N

R1

H2 O, H

RCO2 H + R1 CO 2 H + NH2 NH2

O

796

Scheme 13.250

This ring cleavage is dependent on the solubility. In fact, no hydrolysis was observed for 2,5-diphenyl-1,3,4-oxadiazole, which has a solubility in water of 0.03% [568]. The presence of an electron-withdrawing group at C2 and C5 of the ring increases the reactivity towards nucleophiles. Thus, 2,5-bis(perfluoroalkyl)-1,3,4-oxadiazoles 797a–c are very sensitive to nucleophilic attack. They react with ammonia to give the corresponding 1-(perfluoroalkylimidoyl)-2-(perfluoroacyl)hydrazines 798a–c (R ¼ H). The reaction occurs by attack of nucleophiles on the electron-deficient oxadiazole ring carbon to afford the 798a–c. The reaction with the more nucleophilic methylamine provides 1,2-bis(N-alkyl)perfluoroalkylimidoyl)hydrazines 799a–c via the hydrazine intermediates 798a–c (R ¼ Me) (Scheme 13.251) [569]. Interestingly, thermal dehydration or deamination of these hydrazine derivatives 798 and 799 produces the corresponding 4-substituted-3,5-bis(perfluoroalkyl)-4H-1,2,4-triazoles 800a–c or 801a–c in 88–94% yield (Scheme 13.251).

j 13 Oxadiazoles

1204

R

1

O

RNH 2

N N R

O

1

1

R

75- 93%

N H

H N

R1 N

798a-c 797a-c R 1 = CF3 , C 2F5 , C 3F 5 NMe R1

N H

N N

∆

MeNH 2 R = Me

90-95%

R = H, Me

R

88-94%

R

1

R1

N R

800a-c, 801a-c H N

R N

1

Me

799a-c Scheme 13.251

In a similar fashion 3,5-bis(trifluoromethyl)-1,3,4-oxadiazole 802 reacts with hydrazine in methanol at
42  C to afford the N2-(a-hydrazonotrifluoromethyl)N1-(trifluoroacetyl)hydrazine 803, which under heating is converted into the 4-amino-3,5-bis(trifluoromethyl)-4H-1,2,4-triazole (804) (85%). Dihydrotetrazine 805 in 36% yield is, instead, obtained if the reaction is performed in ethanol at 0  C (Scheme 13.252) [570]. CF 3 N N

NH NH CF 3

NH 2NH2 0°C, EtOH 36%

805

NH 2NH2

N N F3 C

O 802

CF 3

-42°C 76%

H2 N

N

F3 C

N H

H N

CF 3 O

803

∆

AcOH 85%

N N F3 C

CF 3 N NH 2 804

Scheme 13.252

2-Aryloxadiazolinethiones 806 also react with hydrazines, giving rise to triazoline thione derivatives 807 (Scheme 13.253) [571].

13.5 1,3,4-Oxadiazoles

H N N

S

O

Ar

H N N

RNHNH 2 65-85%

Ar

806 Ar = Ph, 4-MeO-C6 H 4 , 4-NO2 -C6 H4 , 4-Pyridyl

N NHR 807

S

R = H, Ph, Me

Scheme 13.253

The ring-opening reaction promoted by hydrazine has been used by El-masry et al. to prepare, starting from 5-[2-(2-methylbenzimidazol-1-yl)ethyl-[1,3,4]-oxadiazole-2 (3H)thione (808), 1-[(1-amino-2-mercapto-1,3,4-triazol-5-yl)ethyl]-2-methylbenzimidazole 809, a biologically active compound, which possesses a moderate activity against Bacillus cereus (Scheme 13.254) [572]. N

N

Me

N

NH2NH2

Me

N

EtOH, reflux O S 808

N NH

85%

H2N N

N N

HS 809

Scheme 13.254

The reaction of 802 with primary alkyl amines 810 in methanol at
42  C leads to complexes 811 whose structure has been elucidated by X-ray crystal analysis. These complexes can be conveniently transformed into 4-substituted-3,5-bis(trifluoromethyl)-4H-1,2,4-triazoles 812 by heating in methanol. The reaction of 802 with aromatic amines 813, performed at reflux, provides directly the triazole derivatives 814 in moderate to good yields (Scheme 13.255) [573]. 1,3,4-Oxadiazol-2-ones 815 react with water to form 1,5-diacylcarbohydrazides 819. The pathway of this reaction appears to be the hydrolytic ring opening to form the hydrazide 818, via either an acylhydrazinoformic acid 816 or the acyl hydrazonoformic acid 817, followed by loss of carbon dioxide to produce 818, which, in turn, attacks the remaining oxadiazolone 815 to form the observed product 819 (Scheme 13.256) [574]. Oxadiazolones 815 also react with hydrazine and amines to give semicarbazides 820 and carbohydrazides 821, respectively (Scheme 13.257) [575]. This reaction is quite general and similar to the above reported reactions. The reaction with NaOMe promotes the formation of 822 (Scheme 13.258) [575]. 3-Substituted 5-trifluoromethyl-1,3,4-oxadiazolones 823a–d are attacked by N and S-nucleophiles to give, as initial products, compounds deriving from the ringopening reaction. In some cases, ring-enlargement products are formed. The

j1205

j 13 Oxadiazoles

1206

RNH2 810

N N F3C

802

N

F3 C

-42°C 78-90%

CF 3

O

R

H N

N H

CF 3

MeOH

O

811 R = CH 3, C 2 H5 , CH(CH 3)C2 H5

∆

ArNH 2 813

MeOH 29-76%

MeOH

∆

26-83%

N N F3C

N Ar

CF 3

N N F3C

814

CF 3

N R

812

Ar = Ph, 4-Cl-C6 H 4, 4-Me-C 6 H4 , 3-F-C 6 H4 , 4-CF 3-C6 H4 , 4-MeO-C6 H 4 Scheme 13.255

H 2O

N NH R

O

O

815

∆

RCONHNHCO 2 H 816 or R

HO 2 CO

- CO 2

RCONHNH 2 818

NNH 2

N NH

22-98%

817

R

O

O

815 O R R = 2-Furyl, 5-Nitro-2-furyl, Phenyl, 2-Chlorophenyl, 4-Pyridyl

N H

H N

H N O 819

O N H

R

Scheme 13.256

reaction of 3-iodomethyl-5-trifluoromethyl-1,3,4-oxadiazol-2-(3H)-one (823d) with thiols (827) produces 830 through a Grob-type fragmentation (Scheme 13.259) [576]. 2-Methyl-6-phenylimidazo[2,1-b]oxadiazole 831, a cyclic oxadiazolimine, is cleaved with concentrated HCl or an 8% solution of KOH to give 832 and then 833 in quantitative yield. The reaction of 831 with 48% HBr gives 834 in 40% yield. In addition, 833 has been transformed into 834 by reaction with HBr (Scheme 13.260) [577].

13.5 1,3,4-Oxadiazoles

BH

N NH R

∆

O

O

16-98%

815

26-56%

821

RCONHNH 2 818

R = Phenyl, 3-Pyridyl, 4-Pyridyl, 2-Furyl BH = NH3 , Isopropylamine, Piperidine, Aniline, Benzylamine, Tetrahydroisoquinoline, Phenylhydrazine, p-Nitrophenylhydrazine, p-Chloroaniline, p-Toluidine

NH2 NH2

∆

∆

RCONHNHCOB

78-80% RCONHNHCONHNH 2 820 Scheme 13.257

X R1 R2 NH

N N R

O 815

DMSO

j1207

O

67-93%

RCONHNCONR 1 R2 X

MeONa 83-45%

RCONHNCOOMe

R = CF 3 ; OEt; OPh; O- t-Butyl R 1 = R2 = Me; Et; -CH2 (CH2 )3 CH2 X = H; 2,4-Cl 2; 3-Cl; 3,4-Cl 2; 3Cl,4-F; 2-NO 2 ,4-CF 3

X

822 X = H, 2-NO 2,4-CF 3 R =t -Butyl, OEt Scheme 13.258

2,5-Diphenyl-1,3,4-oxadiazole 835 is cleaved under photolytic conditions in the presence of alcohols to yield benzonitrile imine 837 and benzoic acid esters 838 in moderate yields [578]. These compounds are produced by an initial nucleophilic attack of alcohols on the C¼N bond of the oxadiazole ring, followed by cycloelimination. Moreover, as expected, the benzonitrile imine 837 undergoes a 1,3dipolar cycloaddition with the unreacted 1,3,4-oxadiazole 835 to furnish the bicycloadduct 839. This compound is then transformed into benzamide (841) and 3,5diphenyl-1,2,4-triazole (842), via 4-benzamido-3,5-diphenyl-1,2,4-triazole (840) produced by ring opening of 839 and concurrent hydrogen shift (Scheme 13.261).

j 13 Oxadiazoles

1208

X

N N F 3C

O

O

HNu X = Cl, CH2 Br, HC

F3 C

O

O

X

N N F 3C

N

N

CONu

O

O

826

SR O

828

Grob-type fragmentation

–CO2 , –X

F3 C

SR

RSH

CH2

N N

73-91%

N NH CH2SR F 3C

829

SR

830

R = Me, Et, I-Pr, Bn

Scheme 13.259

HN N

H2 O /HCl

N N

Ph

Me

or 8% KOH

Ac O

831

N H 832

40% 48% HBr

100% H2 O /HCl

N

O

H N

Ph

N H

834 Scheme 13.260

O

Ph

NH2 N

48% HBr

40%

Ph

X = Cl

F3 C

N H

833

O

51-65%

827

F3 C

HN NH

H 2O

O

Nu

O

825

X = CH2Br

48-100%

RSH, Et3 N X = I

Nu

824

60-89%

823

X

HN N

NuH H N

Me

H N

Me

MeSH

13.5 1,3,4-Oxadiazoles hν, 300 nm

N N Ph

O

N NH Ph

ROH 16-66%

Ph

O

OR

Ph

N NH

Ph

835

R = Me, Et, i-Pr, t-Bu

Ph N N Ph

Ph

N H

+

PhCONH2

Ph

841

842

N

N N N

Ph N NHCOPh

N H

840

N

Ph

O Ph

839

Scheme 13.261

In the case of 2-phenyl-1,3,4-oxadiazole (843), the regioselective addition of methoxy group at C2 of 1,3,4-oxadiazole ring affords, as the only detectable compound, 1-(a-methoxybenzylidene)-2-formylhydrazine 845 in 7% yield, produced by an initial nucleophilic attack of methanol followed by a ring opening reaction (Scheme 13.262). hν, 300 nm

N N O

N NH

MeOH

Ph

O

7%

843

MeO

OMe

N NHCHO

Ph

Ph

844

845

Scheme 13.262

Thione 846 forms a stable salt with p-toluidine (847), which gives rise to ring-open product 848 on heating (Scheme 13.263) [579]. H 2N H N N O

S

16 h 846

40%

Me

S

847 ethanol reflux

O O2 N

Me

O2 N

O

HN N H O

+ PhCO 2 R

838

837

836

835

j1209

N H

848

Scheme 13.263

Alkylhydrazine and arylhydrazines 850 react with 1,3,4-oxadiazolium bromides 849 to produce 2-methyl or 2-phenyl-4-acylamino-3-imino-6-aryl-2,3,4,5tetrahydro-1,2,4-triazines 852. These compounds are probably obtained via inter-

j 13 Oxadiazoles

1210

mediate 851, which rearranges to 852 through a ring opening reaction followed by a ring closure (Scheme 13.264) [580].

O

R

Br

R2

N N 1

-N2H3R3 HBr

NH2

O

R2 NH2 O NR3NH2

N N

850 R1

R2

–H2O

R1 = Me, Et, Ph, Ph-CH2

R2 = Ph, 4-Cl-C6H4, 4-Me-C6H4, 4-MeO-C6H4

N N

63-70%

851

849

R1

O

O

2 NH2NHR3

NH

N NH R3 852

R3 = Me, Ph

Scheme 13.264

1,3,4-Oxadiazolium salts 853 react with ethyl cyanoacetate (854) in the presence of triethylamine to yield 1,5-substituted 3-aminopyrazole-4-carboxylic esters 857. An open chain intermediate 855 was isolated and the reaction involves an initial attack at C2 of the oxadiazole ring (Scheme 13.265) [581].

O

CO 2 Et 2

N N Ph

R

854

Ph H

Et 3 N

R1

O 853

CN

N C

38-78%

X

N N

R2 R1 CO 2 Et

855

O

R2

R

R1

H 2N

N N

1

N N

R2 R1

HN

CO 2Et

CO 2Et

857

856

R 1 = Ph, Me, Et, i-Pr

R 2 = Ph, Et, 4-NO2 -C6H 4 , 2,4-(NO 2 )2 -C6H 3

Scheme 13.265

Isosydnone 858 undergoes a ring-opening reaction by treatment with sodium hydroxide followed by addition of an ethanol–hydrogen chloride mixture to give 1benzoyl-1-methylhydrazine hydrochloride (859) (Scheme 13.266) [541].

13.5 1,3,4-Oxadiazoles

Me

N

Ph

N O

O

1) NaOH

O

2) AcOH

Ph

3) HCl/ethanol 32%

858

j1211

NH2 N Me HCl 859

Scheme 13.266

13.5.3.2 Oxidative and Reductive Processes 1,3,4-Oxadiazoles are very stable to strong oxidizing and reducing agents. However, some oxidations or reductions involving atoms linked to the heterocycle ring have been performed. Thus, recently, sulfonyl derivatives 863, with antifungal activity, containing trimethoxyphenyl substituted 1,3,4-oxadiazoles have been synthesized, in 67–94% yield, by hydrogen peroxide oxidation, catalyzed by ammonium molybdate in ionic liquid ([bmim]PF6), of substituted 1,3,4-oxadiazole sulfide 860 [582]. In particular, 1,3,4-oxadiazole sulfides 862 have been prepared, in 31–93% yield, by thioetherification, catalyzed by indium tribromide, of 5-(3,4,5-trimethoxyphenyl)1,3,4-oxadiazole-2-thiol (860) with organic halides (Scheme 13.267). RBr MeO

O

MeO MeO

861

N N

860

SH

InBr3 – 3%NaOH

N N

MeO MeO

31-93%

R = Me, Et, Pr, Allyl, Bn, 2-F-C 6 H4 -CH2 , 3-F-C 6 H4 -CH 2, 4-F-C 6H 4-CH 2 , 2-Cl-C 6 H4 -CH 2, 4-Cl-C 6H 4 -CH2 , 2-MeOC6 H 4-CH 2, 3-MeO-C 6H 4 -CH2 , 4-MeO-C 6 H4 -CH 2, 3NO 2-C6 H4 -CH 2, 4-NO2 -C6H 4-CH 2 ,

S

O MeO

67-94%

MeO

862

30% H 2O 2, (NH 4 )6 Mo7 O24 (1 mol%) ionic liquid [bmin]PF 6

N N O

MeO MeO

R

863

O S R O

Scheme 13.267

The oxidation of sulfides 864 with m-CPBA furnishes, in contrast, the corresponding sulfoxides 865 (Scheme 13.268) [583]. It has also been reported that the oxidation of 866 with hydrogen peroxide and no catalyst affords oxadiazolone derivatives 867 (Scheme 13.269) [584]. Oxidation of 2,5-di m- or p-tolyl-1,3,4-oxadiazoles 868 with potassium permanganate/pyridine leads to the corresponding dicarboxylic acids 869 (78–94%) [585]; if the oxidation is performed with chromium trioxide/acetic anhydride, diacetoxymethyl derivatives 870 are obtained. These latter compounds can be conveniently transformed by acid hydrolysis into dialdehydes 871 (Scheme 13.270) [586].

j 13 Oxadiazoles

1212

S

O

MeO

mCPBA

R

4°C 2h, and then 5h rt 40-51%

864

MeO

N N

MeO

N N

MeO

S R O

O

MeO MeO

865

R = Me, Et, Pr, Allyl, Bn, 2-F-C 6H 4-CH 2, 3-F-C 6H 4-CH 2 , 4-F-C 6 H4 -CH 2, 2-Cl-C 6H 4-CH 2 , 4-Cl-C 6 H4 -CH 2, 2-MeOC 6H 4 -CH2 , 3-MeO-C 6 H4 -CH 2, 4-MeO-C 6H 4-CH 2 , 3NO 2 -C6H 4-CH 2 , 4-NO 2-C6 H4 -CH 2, Scheme 13.268

N N S R

O

R1

N NH

30% H 2O 2, AcOH 100%

O

R1

O

867

866 R = CH2 =CHCH 2, HC C CH 2, HOH2 C C C CH 2, R1 = H, Me, Br Scheme 13.269

N N O

R

R

78-94%

O

R R1

R1

868

R1

N N

KMnO4 /Py

R = CO 2 H; R = H R = H; R 1 = CO2H

R = H; R 1 = Me CrO3

20-57%

Ac2 O/AcOH

N N R R1

870

R R1

R = CH(OAc) 2 ; R 1 = H

R = H; R 1 = CH(OAc) 2 Scheme 13.270

N N

H,H 2O/EtOH

O

R 1

R = Me; R 1 = H

5°C, 4h

R 1

869

2 h, reflux 60-80%

O

R R

1

871

R = CHO; R 1 = H R = H; R 1 = CHO

R R1

13.5 1,3,4-Oxadiazoles

Reduction of the nitro group linked to phenyl moiety of 1,2,4-oxadiazoles with phenylhydrazine or hydrogen/palladium has been reported to give aminoaryl 1,3,4oxadiazoles in good yield [587]. Thus, 2-phenyl-5-(p-nitrophenyl)-1,3,4-oxadiazole (872), carefully heated to 110–15  C for 75–90 min, gives 2-phenyl-5-(p-aminophenyl)-1,3,4-oxadiazole 873 in 84% yield (Scheme 13.271) [588]. Similar results have been obtained with nitrophenyl derivatives such as 874, which upon hydrogenation with Pd/C yields 875 [589]. N N

N N

PhNHNH 2

O

O2 N

110-115°C 84%

872

N N

O 2N

O

5% Pd-C MeOH,1 h

O

H2 N

873

N N H 2N

O

60% 874

875

Scheme 13.271

Hydrogenation, performed on 5-tert-butyl-3-(4-chloro-2-nitrophenyl)-1,3,4-oxadiazolin-2-one (876) in AcOEt, conversely, leads to a partial reduction of nitro group with the formation of the 4-chloro-2-(hydroxyamino)phenyl derivative 877 in 44% yield (Scheme 13.272) [590].

Cl

Cl

O2 N N N Me O Me O Me 876

HOHN H 2 /Pd/C 5 h, rt

44%

N N Me O Me O Me 877

Scheme 13.272

It has been reported that the hydrogenation of D3-1,3,4-oxadiazoline 878, performed in ethanol over Pd/C, gives acetic acid and N-cyclohexyl-N-benzoylhydrazine (880) via the corresponding 2,3,4,5-tetrahydro-1,3,4-oxadiazole derivative 879 (Scheme 13.273) [591].

j1213

j 13 Oxadiazoles

1214

N N OAc O

Ph

878

5% Pd-C EtOH

HN NHOAc O

Ph

879

5% Pd-C EtOH 87%

H NH N AcOH

+

Ph O

880

Scheme 13.273

13.5.3.3 Reactions due to the Reactivity of the Heterocyclic Ring 1,3,4-Oxadiazoles are weak bases. The pKa values of 2,5-diaryl-1,3,4-oxadiazoles measured by the method of Yates and MacClelland in aqueous solution of sulfuric acid are in the range of
1.15 to
2.49. 2-Amino derivatives (pKa ¼ 2.3
2.7) are more basic and form stable salts. As already reported, some hydrochloride salts have been obtained by hydrochloric reaction of 2-amino-5-aryl-1,3,4-oxadiazoles, in DMF/H2O or in ethanol–ether as solvents, giving rise to compounds having muscle relaxant properties (Scheme 13.230) [549]. In the same context, 5-imino-2-phenyl-D2-1,3,4oxadiazoline-maleate, -citrate, -sulfate, and -nitrate, together with 5-imino-2-(p-aminophenyl)-D2-1,3,4-oxadiazoline dihydrochloride, 5-imino-2-(1-ethylpropyl)-D2-1,3,4oxadiazoline hydrochloride, 5-imino-2-(1-ethylbenzyl)-D2-1,3,4-oxadiazoline hydrochloride, and 1-ethyl-3-(5-phenyl-1,3,4-oxadiazol-2-yl)urea have also been prepared. Electrophilic substitution on the C-atoms of the ring is difficult, because protonation of the nuclear nitrogen in acidic media reduces strongly the possibility of electrophilic attack. Thus, no nitrations, sulfonations, or halogenations of unsubstituted oxadiazoles are known. Mono-substituted derivatives are not able to reactwith electrophiles because they are sensitive to acid conditions. In fact, for example, 2-phenyl 1,3,4-oxadiazole is easily hydrolyzed by acids at room temperature to give benzohydrazide and formic acid [588]. In addition, the mono- and 2,5-dialkylderivatives undergo a ring-opening reaction on treatment with acids [592]. There are several examples of reactions of alkyl halides with 1,3,4-oxadiazole derivatives. The alkylation reactions occur preferentially at the N3 ring atom, except for amino and thio derivatives, where the alkylation, essentially, occurs at the sulfur or the exo-nitrogen atom. Thus, it has been reported that the reaction of 5-(4-chloro-3-ethyl-1-methyl-1Hpyrazole-5-yl)-1,3,4-oxadiazole-2-one (881) with methyl iodide in the presence of NaOH gives rise to the corresponding N-methyl derivative 882, while alkylation of the 2-thioxo derivatives 883 with NaOH, tetrabutylammonium bromide (TBAB), and alkyl iodide leads to the corresponding thioalkylated derivatives 884 in good yield. In the same context, it has been noted that the 2-alkylthio derivatives so obtained are active against rice sheath blight, which is a major disease of rice in China (Scheme 13.274) [593]. Analogously, a series of bis-oxadiazolyl sulfides 887 (R ¼ Ph, substituted Ph) have been synthesized via alkylation reaction of 5-[[2-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl]-1,3,4-oxadiazole-2(3)thione(2-trifluoromethylbenzimidazol-1ylmethyl)-5-mercapto-1,3,4-oxadiazoles 885 with 2-aryl-5-chloromethyl-1,3,4-oxadiazoles 886. Interestingly, the relative oxidation of these sulfides performed at 0  C

13.5 1,3,4-Oxadiazoles

Cl

N N

Et

NaOH, MeI O

O

N N Me

Cl

H

N N

Et

5 h, rt

N N Me

73%

N N

N N Me

O

O

X

Et

Me

882

881

X

j1215

H

NaOH,TBAB, RI

N N Me

24 h, rt 87-71%

S

O

N N

Et

S

O

R

884

883

X = H, Cl R = Me, n-Pr, n-C5H11 , n -C7H15 , n -C8H17 , CH(CH 3 )CO2 Et Scheme 13.274

with HNO3 produces (Scheme 13.275) [594].

the

sulfoxide

derivatives

888

in

good

N N N

CF3 H N N O

885

+ S

Cl

AcONa

N N O

886

N

CF3 N N

N

S

O

H 2O/EtOH R

yield

O

60°C, 6 h

66-91%

N

887 R

HNO 3

62-77%

0°C, 3 h

R = H, Me, MeO, F, Cl, NO 2

N N

CF3 N N O

S O

N O

N

888 R

Scheme 13.275

Methylation of 5-methyl or 5-aryl-2-thioxo-2,3-dihydro-1,3,4-oxadiazoles 889 with trimethyloxonium tetrafluoroborate in CH2Cl2 at room temperature furnishes, as

j 13 Oxadiazoles

1216

expected, the corresponding methyl(methylthio)oxadiazolium tetrafluoroborates 890 in 86–96% yield (Scheme 13.276) [595].

N N R

Me

Me 3O BF 4 CH2Cl 2, rt 88-96%

S

O 889

BF 4 N N R

Me

O

S

Me

890

R = Me, Ph, 4-Me-C 6 H4 , 4-MeO-C6 H 4 Scheme 13.276

The Mannich reaction of 1,3,4-oxadiazole-2-thione derivatives 891 with different secondary amines and paraformaldehyde in absolute ethanol occurs at the N3 ring atom and leads to 5-[2-(2-methylbenzimidazol-1-yl)ethyl-3-N-methylamino-1,3,4-oxadiazole-2-thiones (892) in 60–65% yield (Scheme 13.277). In particular, the diethylamino derivative 892 has shown to exhibit moderate antimicrobial activity against one strain of Gram-positive bacteria (Bacillus cereus) [596]. N N

Me

CH2O

N NH O 891

R2NH

Me N

N

N N O

R S

60-65%

S

892

R = N(C2H5)2, N(C4H8O), N(C4H8)NMe Scheme 13.277

The 1,3,4-oxadiazole ring 893 has been, recently, used as 4p component in a Diels–Alder reaction. This ring is considered an electron poor diaza-diene and reacts with extremely electron rich (aminoacetylenes) or strained dienophiles in an inverse electron demand reaction. Unfortunately, the mono cycloadduct 895 thus obtained has never been isolated, but it extrudes N2 and generates a carbonyl ylid 896, which further reacts with olefin in a 1,3-dipolar cycloaddition to give the final product 897 (Scheme 13.278). The first example of such a cycloaddition cascade was reported by Vasiliev et al. Heating at 200–220  C of the 2,5-bis(trifluoromethyl)-1,3,4-oxadiazole 802 with ethylene (898) or cyclopentadiene (899) affords the oxabicycloheptane 900 in 41%, or oxatetracyclotridecane 901 in 33% yield respectively (Scheme 13.279 [597]. Other examples of this cycloaddition have been reported, giving rise to the formation of strained structures (Scheme 13.280) [598]. In some cases, the intramolecular version of this reaction is more productive and leads to bicyclic or monocyclic derivatives (Scheme 13.281) [599].

13.5 1,3,4-Oxadiazoles

894

N N

O

O

N N 895

893

–N2

894

O

O 896

897 Scheme 13.278

CF3 898

N N F3C

CF 3

O

200-220°C -N2

802

O

41%

CF3 900

200-220°C -N2

899 CF3

O

33%

CF3 901 Scheme 13.279

The synthetic efficiency of the process can be improved through the development of domino reactions that allow the formation of complex compounds, starting from simple substrates, in a single transformation consisting of several steps. A domino reaction can be defined as a process involving two or more bond-forming transformations that take place under the same reaction conditions, without adding

j1217

j 13 Oxadiazoles

1218

N N F3C

CF3

O 802

N N EtO 2 S

140°C,16 h 17%

F3C

44%

902

905

SO2Et

904 CF3

O

O CF3

903

O F3 C 906

Scheme 13.280

∆,165-175°C

N N N O COCF 3

CO 2 Me

18 h 71%

N F3COC

CO 2 Me

908

907

C

COPh

∆,165-175°C

N N N O COMe

O

Ph

25 min 65%

N COMe 909

Scheme 13.281

additional reagents and catalysts and in which the subsequent reactions result as a consequence of the functionalities obtained in the previous step. Thus, the intramolecular Diels–Alder (DA)/1,3-dipolar cycloaddition (1,3-DC) cascade of 1,3,4-oxadiazoles has became a powerful tool for the rapid generation of molecular complexity. Specifically, this methodology has been featured in the construction of the pentacyclic ring systems and ultimately in the total syntheses of vindoline and several structurally related natural products [600]. Vindoline (913) constitutes the most complex half of vinblastine (914), a member of the bisindole alkaloid family that is used as an antineoplastic drug. The method is based on a combination of a DA and 1,3-DC. The synthesis proceeds by a diastereoselective tandem [4 þ 2]/[3 þ 2]-cycloaddition of a substituted 1,3,4-oxadiazole. The reaction leading to vindoline is initiated by an intramolecular [4 þ 2]-cycloaddition of 1,3,4oxadiazole 910 with the tethered enol ether. Loss of N2 from the initially formed

13.5 1,3,4-Oxadiazoles

cycloadduct 911 provides the carbonyl ylid dipole 912, which undergoes a subsequent 1,3-dipolar cycloaddition across the proximal indole moiety (Scheme 13.282) [601].

O

O

OBn

N

N

MeO

O

N Me

N N

MeO

Et

N Me

CO2 Me

N O N

OBn CO 2 Me

911

910

- N2

O

O

N

N

MeO

N Me

MeO

O N OBn H Me CO 2 Me

O

MeO2 C

Et OB n

912

913

N

OH

HN

O N

MeO Vinblastine

O N OBn H Me CO 2 Me

914

Scheme 13.282

Some other examples of this methodology (916, 918) are reported in Scheme 13.283 [599]. The double bond of the 1,3,4-oxadiazole ring has also been used as 2p component in a [2 þ 2] photochemical cycloaddition. Thus, it has been reported that 2,5diphenyl-1,3,4-oxadiazole (835) with indene (919), with or without benzophenone as a sensitizer, affords the bis adduct diazetidine derivative 920, while if the reaction is

j1219

j 13 Oxadiazoles

1220

O

O N

N MeO

N N

O

N Me

61%

CO 2Me

O N H Me CO 2Me

MeO

915

916

O

O N

N MeO

N N

O

N Me

CO 2Me

Et 74%

O N H Me CO 2Me

MeO

917

918

Scheme 13.283

performed in the presence of iodine the photoreaction leads to the mono-adduct 921 (Scheme 13.284) [602].

N N Ph

O

Ph

Ph-H 919

835

Ph2 CO (or none) 26%

hν, 300 nm

N N

hν, 300 nm

+

Ph

Ph 920

I2

Ph-H

N N Ph

O

Ph

921 Scheme 13.284

A 1 : 1 adduct with 923 (26%) was obtained when a solution of 835 was irradiated with an excess of furan (922) in the presence or absence of benzophenone used as sensitizer. The reaction did not occur in the presence of a triplet quencher such as piperylene, indicating that the photoaddition takes place from an

13.5 1,3,4-Oxadiazoles

j1221

excited triplet state [603]. The presence of iodine promotes a different reaction pathway, leading to the formation of 3-benzoylfuran (927) (17%). This product has been rationalized by an initial valence tautomerization of furan into cyclobutadiene oxide 924, which undergoes a [2 þ 2] cycloaddition with a double bond of 1,3,4oxadiazole ring, leading to monoadduct 925. This compound, via ring opening and photoisomerization reaction, produces the N0 -[3-furyl(phenyl)methylene]phenylhydrazide (926) that is easily hydrolyzed with trace amounts of water to give 927 (Scheme 13.285). Ph 2CO (or none) hν, 300 nm

O

Ph

O

N N

922

Ph

O

Ph

Ph

923

835 Ph-H

O

N N 26%

hν, 300 nm I2 N N Ph

O 835

O

Ph

N N

O

O

Ph

924

Ph Ph

Ph

NNHCOPh

O

O O

926

925

927 17%

Scheme 13.285

13.5.3.4 Reactions with Nucleophiles Direct nucleophilic substitutions of ring C-substituents in 1,3,4-oxadiazoles are seldom. These reactions occur only for compounds containing a good leaving group, via addition–elimination reaction. Thus, for example, 3-(5-phenyl-[1,3,4]oxadiazol-2yl]pentane-2,4-dione (930, R ¼ Me) and 3-(5-phenyl-[1,3,4]oxadiazol-2-yl]-dibenzoylmethane (930, R ¼ Ph) have been synthesized, in 63% and 85% yield, respectively, by nucleophilic substitution of 2-methylsulfonyl-5-phenyl-1,3,4-oxadiazole (928) with b-diketone anions, formed by the corresponding carbonyl compounds 929 with NaH (Scheme 13.286) [604]. O N N O

O S Me O

928

R

O 929

NaH/THF rt, 12 h 65-83%

R = Me, Ph Scheme 13.286

R

N N

O

O 930

R O

R

j 13 Oxadiazoles

1222

A similar displacement reaction has been performed with 2-methylsulfonyl-5pyrazolyl-1,3,4-oxadiazole 931 that by reaction with arylamines 932 produces bioactive 2-substituted-amino-5-pyrazolyl-1,3,4-oxadiazoles 933, which exhibit moderate fungicidal activity (Scheme 13.287) [605]. ArNH2 N N

O S Me O N N O Me 335

N N

336 Dioxane N N

8h, reflux 64-95%

Ar

O Me

337

Ar = Ph, 4-Cl-C6H4, 3-Cl-C6H4, 4-Br-C6H4, 4-Me-C6H4, 4-MeO-C6H4, Scheme 13.287

Nucleophilic substitution of 2-methylsulfonyl-1,3,4-oxadiazoles 934 has been reported to occur with other nucleophiles, such as sodium azide, amines, and acylhydrazines (Scheme 13.288). The compounds containing the acylhydrazine group have shown to posses strong antibacterial activity against Bacillus subtilis and Escherichia coli (2.0  10
4 mol l
1) [606]. N N

MeO

O S Me O

O

MeO MeO

934

NaOH Dioxane

N N

MeO

R

O

MeO

Nu–H 25-50%

MeO

935

Nu–H H N

H N

NaN3 O

N N N N H

Ph

O

O N H

NH2 N

N H

NH2

Scheme 13.288

Recently an efficient conversion of 5-substituted-1,3,4-oxadiazolin-2-ones 936 into 2-amino-1,3,4-oxadiazoles 937, via a nucleophilic aromatic substitution, appeared in the literature (Scheme 13.289) [607]. The reaction is activated from benzotriazol-1-yloxytris(dimethylamino)-phosphonium PF6
(938), and occurs according to Scheme 13.290, using as co-reagent 2 equivalents of base. The key step of the reaction is the attack of the oxygen atom of the carbonyl group on the phosphonium salt, promoted by base. The intermediate 939 thus obtained undergoes a facile reaction with the nucleophile 940 at C2 of the oxadiazole ring, followed by extrusion of HMPA (941).

13.5 1,3,4-Oxadiazoles

R

O

N N

2 eq. DIPEA

N NH O

R

R1 NH2 or R1 R 2NH DMF, rt, 1-18 h

936

O

R2 N R1

937

63-99% 1

R1 R2 NH

R NH2

R

NH2

NH O

NH2

H N

MeO H N

H 2N N

NH2 N H 2N

O

O

OMe H 2N OH

O OMe

NHBoc NH2 Scheme 13.289

A nucleophilic substitution has also been reported for quaternary intermediate salts obtained by reaction of alkyl iodide with phenylalkoxyoxadiazoles. The reaction produces the corresponding 3-alkyl-5-phenyl-1,3,4-oxadiazol-2-ones via a nucleophilic attack promoted by iodine ion on the R1 group of quaternary salts (Scheme 13.291) [608]. 13.5.3.5 Reactions of Substituents Electrophilic reaction can occur on diphenyl derivatives. Thus, 2,5-bis(4-nitrophenyl)-, bis(3-nitrophenyl)- and bis(2-nitrophenyl)-1,3,4-oxadiazoles have been obtained in 27%, 20%, and 40% yield, respectively, by mixing 2,5-diphenyl-1,3,4oxadiazole (835) with HNO3 at 30  C and then at 80  C for 4 h (Scheme 13.292). The addition of HNO3 to the oxadiazole in concentrated H2SO4 at 50  C and subsequent heating for 6 h at 100  C gave bis(3-nitrophenyl)-1,3,4-oxadiazole (38%) and 2-phenyl5-(m-nitrophenyl)-1,3,4-oxadiazole (31%) [609].

j1223

j 13 Oxadiazoles

1224

B N N R 936

–BtO

H

R

O BtO P (NMe 2) 3

O

N N Me 2N NMe 2 O P O NMe 2 939 R1 NH2 940

938

N N

+

HMPA 941

R

O 937

1 N R H

Scheme 13.290

N N O

O

R1

N N

R2 I

O

160-250°C 90 min

942

R2 O

R1

N N 90-100%

R2 O

O

944

943 2

R = Me, n-pr

R 1 = Et, n-pr

Scheme 13.291

N N O2N

O

N N

O2N

N N

HNO3

O

O

30-80 °C

946 20%

835

NO2

N N O

947 40% Scheme 13.292

NO2

945 27%

NO2

NO2

13.5 1,3,4-Oxadiazoles

j1225

2-(4-Nitrophenyl)-5-phenyl-1,3,4-oxadiazole undergoes selective electrophilic bromination of the phenyl ring in the presence of potassium bromate to produce o-, m-, and p-derivatives in 16%, 14%, and 26% yield, respectively (Scheme 13.293) [610]. N N O2 N

Br

O 949 16% N N

N N

Br 2 /KBrO3

O2 N

O

O2 N

Br

O 950

948

14% N N O

O2 N 951

Br

26%

Scheme 13.293

A sulfonamide group directly linked to 1,3,4-oxadiazole ring has been utilized to synthesize N-(anilinocarbonyl)-5-(2,4-dichlorophenyl)-1,3,4-oxadiazole-2-sulfonamide 953 (R ¼ Cl) and N-(anilinocarbonyl)-5-phenyl-1,3,4-oxadiazole-2-sulfonamide 953 (R ¼ H) with aim of preparing potential pesticides. These compounds have been obtained by reaction of phenyl isocyanate with 5-(2,4-dichlorophenyl)1,3,4-oxadiazole-2-sulfonamide (952, R ¼ Cl) or with 5-phenyl-1,3,4-oxadiazole-2sulfonamide (952, R ¼ H) respectively (Scheme 13.294). The compounds so obtained have been tested for fungicidal activity against the fungal species Cephalosporium saccharii and Helminthosporium oryzae, and have been shown to possess a good level of activity [611].

H 2N O

N N S

O

R

O 952

PhNCO R

dioxane, rt, 6h 55-48%

Ph

H N

H O N N N S O O O 953

R R

R = Cl, H Scheme 13.294

Some acetamides carrying a substituted-1,3,4-oxadiazole moiety with local anesthetic activity have synthesized by reaction of 5-aryl-2-chloroacetamido-1,3,4-oxadiazoles 956 with different secondary amines (Scheme 13.295). Compound 956 was easily prepared in 63% yield from the reaction of 5-(4-fluorophenyl)-1,3,4-oxadiazol-

j 13 Oxadiazoles

1226

N N H2 N

O

F

954

+

O

N N

O

PhH

Cl Cl

reflux 3 h 63%

F

Cl

N H

O 956

955 EtOH, Et3 N

R 2NH

reflux 6 h

957

R = NH(CH 2CH2 OH)2 , C 6H 11 NHMe, C4 H 8ONH

52-54% O

N N F

O

N H

NR2

958 Scheme 13.295

2-amine (954) with chloroacetyl chloride (955). The local anesthetic activity was investigated using the rabbit corneal reflex method and guinea pig’s wheal derm method, using lidocaine as standard drug [612]. Monosubstituted oxadiazoles are deprotonated at the ring carbon atom to give the corresponding anion, which has been subsequently alkylated with various alkylating agents. Thus, for example, 2-substituted-1,3,4-oxadiazoles 959 after treatment with butyllithium in the presence of MgBr2 diethyl etherate in THF, followed by the addition of N-[(1S)-1-(methylethyl)-2-oxoethyl](tert-butoxy)carboxamide (N-Boc-L-valinal) (961), affords the corresponding N-Boc alcohols 962 in 53–79% yield. Similar treatment of (5-phenyl-1,3,4-oxadiazol-2-yl)lithium (963) with Boc-leucinal (964) produces [1-[(R/S)-hydroxy-(5-phenyl-[1,3,4]oxadiazol-2-yl](S)-methyl]-3-methylbutyl]carbamic acid tert-butyl ester (965) in 70% yield (Scheme 13.296) [613, 614]. In addition, the methyl group attached at carbons of 1,3,4-oxadiazoles shows a marked acidity when it is treated with strong bases. Thus, when 2,5-dimethyl- or 2methyl-5-phenyl-1,3,4-oxadiazoles 966 and 971 were treated with isopropylmagnesium bromide (967) or NaH, followed by addition of alkyl carboxylates, 5-substituted 1,3,4-oxadiazol-2-ylmethyl ketones 969, 970, and 972 were obtained. The yield in ketones has been shown to depend on the nature of substituents present in the carboxylate moiety (Scheme 13.297) [615]. Interestingly, when the lithium anion of 971 was allowed to warm from
78  C to room temperature, the N-benzoylated hydrazone 973 was isolated from the reaction mixture in 34% yield (Scheme 13.298) [616]. The formation of this latter compound is easily rationalized as the nucleophilic attack of the lithium anion to the not de-protonated 971 still present in solution. 1,3-4 Oxadiazoles containing a good leaving group at the methylene moiety are able to give nucleophilic substitutions. Thus, 2-aryl-5-chloromethyl-1,3,4-oxadiazoles 974,

13.5 1,3,4-Oxadiazoles N N R

n-BuLi H

O

MgBr 2

OEt 2

R

N N

–45/–20°C 3.5h 53-79%

O

-70°C

959

Boc-L-Valinal 961

N N

960

R

NHBoc

O

962

N N

OH

N N

Li

O

O

O

963

O

N H

O

NHBoc OH

965

H 964

R Me

Me Me

Me Me

Me

j1227

N Me

Me

Me

Me

Me

Me

O OMe

Me

O Me

Scheme 13.296

via condensation of piperazine (975), give 1,4-bis[(5-aryl-1,3,4-oxadiazol-2-yl)methyl] piperazines 976 that in vitro displayed relatively potential antibacterial activities (Scheme 13.299) [617]. 5-(p-Cyanomethylphenyl)-2-n-nonyl-1,3,4-oxadiazole 979, useful precursor for organic light-emitting diodes (OLEDS), has been synthesized in 82% yield, by reaction of the bromide derivative 978 with tetraethylammonium cyanide. The 5(p-bromomethylphenyl)-2-n-nonyl-1,3,4-oxadiazole (978) was easily prepared by the reaction of 5-(p-methylphenyl)-2-n-nonyl-1,3,4-oxadiazole (977) with N-bromosuccinimide(NBS) (Scheme 13.300) [618]. Substituents linked to 1,3,4-oxadiazoline moiety have also been involved in the synthesis of compounds having interesting properties. Thus, the herbicide 5-tertbutyl-3-(2,4-dichloro-5-isoprooxyphenyl)-1,3,4-oxadiazol-2-one (981) has been obtained starting from 877 via 5-tert-butyl-3-(2-amino-4-chloro-5-hydroxyphenyl)1,3,4-oxadiazolin-2-one (980) (Scheme 13.301) [590].

j 13 Oxadiazoles

1228

MgBr

967

N N Me

Me

O

Me

966 DMF NaH

N N

AcOEt

N N

Me

O

O

968

O Me

969

60°C RCO2 Et 2h O

N N Me

O

R

R = CO 2Et, CH(Me) 2, CH 2CO 2 Et,

970 N N

NaH

O

AcOEt

Me

N N

O

O

972

971 Scheme 13.297

N N

N N

BuLi

971

N

O

-78°C to rt 34%

O

Me

NHCOPh

972

Scheme 13.298

H N

O NaHCO3

R

N N

Cl

O 974

N 975 H MeCN, 24 h, rt 41-81%

R

N N

N N

R

N N

O 976

R =, H, Cl, F, OMe, Me, NO 2 Scheme 13.299

Some 3-acyl-1,3,4-oxadiazoline derivatives 983, having antitumoral activity, have been prepared by nucleophilic displacement of the chlorine atom in 982 (Scheme 13.302).

13.5 1,3,4-Oxadiazoles

N N Me

N N

NBS, CCl4

C 9H19

O

j1229

Br

AIBN, 10 h, reflux 51%

C 9H 19

O 978

977 CH 2Cl 2

Et4CN rt, 5h

82%

N N NC

C 9H 19

O 979

Scheme 13.300

H2 SO4 20 min

HOHN N N Me Me O Me

Cl

Cl

Cl

70% O

H2 N

1) NaNO2 /H OH

N N Me Me O Me

O

2) CuCl2 3) NaI, K2CO 3, Me2CHBr 56%

Cl

O

N N Me Me O Me

981

980

877

O

Scheme 13.301

R

Cl O

N N

Me O

O

O

N Me

O

26-100% Me

Me

N Me

Me O

O

O Me

O

983

982 Nu = KOAc, NaN3, Me2 NH

O

N N

Nu

R = OAc, N3,NMe 2

Scheme 13.302

13.5.3.6 Metal Complexes 1,3,4-Oxadiazole derivatives are widely used as electron-transporting groups due to their high electron deficiency and good thermal stability [619]. According to these properties, compounds containing the 1,3,4-oxadiazole core have prepared and used

Me

j 13 Oxadiazoles

1230

Me

N N

O

O Me

O

Me

N N

t-BuOK/H2 O 1/3 TbCl 3 (aq)

O

98%

Tb

O

Me

930a

OH2

O

OH 2 3

984

Scheme 13.303

in the production of organic light-emitting diodes (OLEDs). An OLED converts electrical energy into light and it is formed by an emissive chromophore, an electrontransporting group, and a hole-transporting unit. Recently, heavy metal ions have been incorporated in OLEDs as a cyclometalated ligand to increase the phosphorescence at room temperature, because these ions are able to increase the efficiency of the intersystem crossing from the singlet to triplet excited state. Based on the above consideration, here are two reported examples of 1,3,4-oxadiazole metalated complexes together with their syntheses. The first synthesis of 1,3,4-oxadiazole-functionalized terbium (III) b-diketonate for organic electroluminescence has been reported by Zheng et al. The synthesis was performed by treating compound 930 with a suspension of t-BuOK and an aqueous solution of TbCl3 (Scheme 13.303). The crystal structure of 984 was

N N

O

Ir

O O

Me

Me F

2

390

N N

O 1) OHCH2CH2OCH3:H2O=3:1,reflux, 24h

N N Ar

O

389

Ar1

+ IrCl3 3H2O

Ir

O

2) OHCH2CH2OCH3,Na2CO3,acetyl acetone reflux, 24h

F

70-85%

F F

O

391

N N Ir

O O

OMe

392 Scheme 13.304

O

2

Me

Me

2

Me

Me

References

established by X-ray diffraction. The Tb(III) ion is surrounded by eight oxygen atoms, six of which are from the bidentate b-diketonate ligands and the other two from the coordinated water molecules. The coordination polyhedron is best described as square antiprismatic. This compound was used as an emitting material, and a bright and highly efficient green-emitting LED was fabricated [604]. An interesting series of iridium(III) complexes linked to 1,3,4-oxadiazole systems has been synthesized and utilized to prepare three organic light emitting diodes devices, which showed stable green-yellow luminescence. The synthetic procedure involved two steps. In the first step, IrCl33H2O was allowed to react with an excess of 2,5-diaryl-1,3,4-oxadiazoles 985 in a 2-ethoxyethanol–water mixture. In the second step, the resulting iridium compounds were treated with sodium carbonate and acetyl acetone in 2-ethoxyethanol as solvent to afford the cyclometalated derivatives 986–988 in 70–85% yield (Scheme 13.304) [620].

References 1 Thomas, E.W. (1996) Comprehensive

2

3 4

5

6

7 8

Heterocyclic Chemistry, vol. 4 (ed. K.T. Potts), Pergamon Press, Oxford, p. 289. (a) Meier, H. and Hanold, N. (1994) Heteroarenes III, Part 3, vol. E8c (ed. E. Schaumann), Goerg Thieme Verlag, Stuttgart, p. 397; (b) Newton, C.G. and Ramsden, C.A. (1982) Tetrahedron, 58, 2965; (c) Rychlewska, U., Hodgson, D.J., Yeh, A., and Tien, H.-J. (1991) Journal of the Chinese Chemical Society, 38, 467. Clapp, L.B. (1976) Advances in Heterocyclic Chemistry, 20, 65. (a) Gasco, A. and Boulton, A.J. (1981) Advances in Heterocyclic Chemistry, 29, 251; (b) Paton, R.M. (1984) Comprehensive Heterocyclic Chemistry, vol. 6 (ed. K.T. Potts), Pergamon Press, Oxford, p. 393. (a) Hetzheim, A. and Mockel, K. (1966) Advances in Heterocyclic Chemistry, 7, 183; (b) Hill, J. (1984) Comprehensive Heterocyclic Chemistry, vol. 6 (ed. K.T. Potts), Pergamon Press, Oxford, p. 427. Clapp, L.B. (1984) Comprehensive Heterocyclic Chemistry, vol. 6 (ed. K.T. Potts), Pergamon Press, Oxford, p. 365. Buckley, G.D. and Levy, W.J. (1951) Journal of the Chemical Society, 3016. (a) Avdeev, V.I., Ruzankin, S.F., and Zhidomirov, G.M. (2005) Kinetics and Catalysis, 46, 177; (b) Avdeev, V.I., Ruzankin, S.F., and Zhidomirov, G.M. (2005) Kinetics and Catalysis, 46, 191.

9 Thorstad, O. and Undheim, K. (1974)

Chemica Scripta, 6, 222. 10 Schweig, A., Baumgartl, H., and Schultz,

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R. (1991) Journal of Molecular Structure, 247, 135. Kuchen, A., Bigler, P., and Schlunegger, U.P. (1984) Chimia, 38, 387. Earl, J.C. and Mackney, A.W. (1935) Journal of the Chemical Society, 899. (a) Ollis, W.D. and Ramsden, C.A. (1976) Advances in Heterocyclic Chemistry, 19, 1; (b) Newton, C.G. and Ramsden, C.A. (1982) Tetrahedron, 38, 2965. Stewart, F.H.C. (1964) Chemical Reviews, 64, 129. Thiessen, W.E. and Hope, H. (1967) Journal of the American Chemical Society, 89, 5977. Bridson-Jones, F.S., Buckley, G.D., Cross, L.H., and Driver, A.P. (1951) Journal of the Chemical Society, 2999. Branchadell, V., Muray, E., Oliva, A., Ortuno, R.M., and Rodriguez-Garcia, C. (1998) The Journal of Physical Chemistry, 102, 10106. (a) Brundrett, R.B. (1980) Journal of Medicinal Chemistry, 23, 1245; (b) Sapse, A.M., Allen, E.B., and Lowen, J.W. (1988) Journal of the American Chemical Society, 110, 5671; (c) Kroeger Koepke, M.B., Schmiedekamp, A.M., and Michejda, C. (1994) The Journal of Organic Chemistry, 59, 3301.

j1231

j 13 Oxadiazoles

1232

19 Loeppky, R.N., Fleischmann, E.D.,

20

21 22

23 24

25

26

27

28

29

30

31

32

33

34 35

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and Pilipovich, D. (1961) The Journal of Organic Chemistry, 26, 4407. Chen, H., Li, Z., and Han, Y. (2000) Journal of Agricultural and Food Chemistry, 48, 5312. Liu, C.-J., Shi, T.-H., and Li, Y.-P. (2007) Youji Huaxue, 27, 985; (2007) Chemical Abstracts, 149, 200836. Molina, P., Tarraga, A., and Espinosa, A. (1988) Synthesis, 690. (a) El-masry, A.H., Fahmy, H.H., and Ali Abdelwahed, S.H. (2000) Molecules, 5, 1429; (b) Mekuskiene, G., Burbuliene, M.M., Jakubkiene, V., Udrenaite, E., Gaidelis, P., and Vainilavieius, P. (2003) Chemistry of Heterocyclic Compounds, 39, 1364. Vasiliev, N.V., Lyashenko, Y.E., Kolomietz, A.F., and Solkolskii, G.A. (1987) Khimiya Geterotsiklicheskikh Soedinenii, 562. Thalhammer, F., Wallfahrer, U., and Sauer, J. (1988) Tetrahedron Letters, 29, 3231;ibidem 1995, 36, 5275. Wilkie, G.D., Elliot, G.I., Blagg, B.S.J., Wolkenberg, S.E., Soenen, D.R., Miller, M.M., Pollack, S., and Boger, D.L. (2002) Journal of the American Chemical Society, 124, 11294. (a) Elliott, G.I., Gregory, I., Velcicky, J., Ishikawa, H., Li, Y., and Boger, D.L. (2006) Angewandte Chemie, 45, 620; (b) Ishikawa, H., Elliott, G.I., Velcicky, J., Choi, Y., and Boger, D.L. (2006) Journal of the American Chemical Society, 128, 10596. Choi, Y., Ishikawa, H., Velcicky, J., Elliott, G.I., Miller, M.M., and Boger, D.L. (2005) Organic Letters, 7, 4539. Tsuge, O., Tashiro, M., and Oe, K. (1968) Tetrahedron Letters, 9, 3971. Tsuge, O., Oe, K., and Tashiro, M. (1973) Tetrahedron, 29, 41. Wang, J., Wang, R., Yang, J., Zheng, Z., Carducci, M.D., Cayou, T., Peyghambarian, N., and Jabbour, G.E. (2001) Journal of the American Chemical Society, 123, 6179.

605 Yuan, D.-K., Li, Z.-M., Zhao, W.-G., and

606

607 608 609

610

611 612 613

614

615

616 617

618 619 620

Chen, H.-S. (2003) Yingyong Huaxue, 20, 624. CAN 140:4994 AN 2003: 617213. Feng, X.-M., Chen, R., and Lin, T. (1994) Youji Huaxue, 14, 293; (1994) Chemical Abstracts, 121, 205276. Levins, C.G. and Wan, Z.-K. (2008) Organic Letters, 10, 1755. Golfier, M. and Milcent, R. (1974) Tetrahedron Letters, 44, 3871. Grekov, A.P., Azen, R.S., and Kharkov (1961) Zhurnal Obshchei Khimii, 31, 1919. Blackhall, A., Brydon, D.L., Javaid, K., Sagar, A.J.G., and Smith, D.M. (1984) Journal of Chemical Research (S), 382. Srivastava, M.K. (2000) Bollettino Chimico Farmaceutico, 139, 161. Rajak, H., Kharya, M., and Mishra, P. (2008) Archiv der Pharmazie, 341, 247. Ohmoto, K., Yamamoto, T., Okuma, M., Horiuchi, T., Imanishi, H., Odagaki, Y., Kawabata, K., Sekioka, T., Hirota, Y., Matsuoka, S., Nakai, H., Toda, M., Cheronis, J.C., Spuce, L.W., Gyorkos, A., and Wieczorek, M. (2001) Journal of Medicinal Chemistry, 44, 1268. Rydezewski, R.M., Burrill, L., Mendonca, R., Palmer, J.T., Rice, M., Tahilramani, R., Bass, K.E., Leung, L., Gjerstad, E., Janc, J.W., and Pan, L. (2006) Journal of Medicinal Chemistry, 49, 2953. Kuebel, B. (1982) PCT German Patent CODEN: GWXXBX, DE 3105222, A1 19820909. Application: DE 81-3105222, 19810213. Knaus, G. and Meyers, A.I. (1974) The Journal of Organic Chemistry, 39, 1189. Hu, G., Xu, Q., Zhang, Z., Chen, B., Xu, Q., Huang, W., and Zhang, H. (2004) Huaxue Zazhi, 14, 76. Ryu, H., Subramanian, L.R., and Hanack, M. (2006) Tetrahedron, 62, 6236. Huges, G. and Bryce, M.R. (2005) Journal of Materials Chemistry, 15, 94. Xu, Z., Li, Y., Ma, X., Gao, X., and Tian, H. (2008) Tetrahedron, 64, 1860.

j1253

14 Thiadiazoles Ugo Chiacchio and Giovanni Romeo

14.1 Introduction

There are four isomeric types of thiadiazoles (1–4).

S

N N

N S

N

2

1

N N N

S 3

N

S 4

Many biologically active derivatives of this ring system have been synthesized and incorporated into commercial drugs and pesticides. For instance, the 1,2,5-thiadiazole timolol (5), is used as maleate salt to treat glaucoma; the sulfonamide derivative, acetazolamide 6, is a diuretic. N N

O OCH2 CHOHCH 2 NHCMe 3

N N

S

H2 NO 2S

S

NHCOMe

N 5

6

Timolol

Acetazolamide

14.2 1,2,3-Thiadiazoles

1,2,3-Thiadiazoles are heterocycles of great practical and theoretical interest. Most of the literature has been devoted to thermal and photochemical reactions of the 1,2,3thiadiazole ring, whose cleavage and rearrangement allow easy access to a series of functionalized compounds. Derivatives of this heterocyclic system are important in industry, medicinal chemistry, and agriculture. However, although interest in

Modern Heterocyclic Chemistry, First Edition. Edited by Julio Alvarez-Builla, Juan Jose Vaquero, and José Barluenga.
2011 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2011 by Wiley-VCH Verlag GmbH & Co. KGaA.

j 14 Thiadiazoles

1254

isomeric thiadiazoles is continuously increasing, there is a gap of knowledge in the area of 1,2,3-thiadiazoles, which still account for the fewest literature citations. A good number of reviews on the chemistry of 1,2,3-thiadiazoles are present in literature [1]: one of the most recent reports cover the literature up to the early part of 2004 [2]. 14.2.1 Structure

While the 1,2,3-oxadiazole system occurs nearly exclusively as open-chain tautomers, 1,2,3-thiadiazoles are stable compounds: the neutral aromatic structure 7 is preferred with respect to a-diazothiaketone species 8. R R

S

R

N N

R

7

S

N N

8

However, it has been suggested that a-diazothiaketones 8 are involved as intermediates in some reactions [3]. The existence of these intermediates has been supported by the isolation of the complex of 2-diazothione 10 with iron nonacarbonyl, obtained by reaction of 1,2,3-benzothiazole (9) with Fe2(CO)9 (Scheme 14.1) [4].

N 9

S

N

Fe2(CO)9

80%

N CO N S (OC)3Fe Fe(CO)3 Fe S N N

10 Scheme 14.1

The parent compound is a yellow liquid with a boiling point of 157
C at atmospheric pressure, and is soluble in alcohol, diethyl ether, and water. Other 1,2,3-thiadiazoles are soluble in methylene chloride and chloroform. Benzo-fused analogues of 1,2,3-thiadiazoles 7 have also been reported [5]. Fully aromatic mesoionic compounds have been synthesized [6], but information is limited. More recently, mesoionic 1,2,3-thiadiazoles as 11 have been obtained by methylation at N3 of 1,2,3-thiadiazoles containing an oxime or phenylhydrazone function at the 5-position [7]. Very few examples of non-aromatic 1,2,3-thiadiazoles such as 12 and 13 have appeared in the literature [8].

14.2 1,2,3-Thiadiazoles

Ph

N N

S

Me N N

11

Ph S

N N

12

Ph

H N N

S O

SO2Ph

13

14.2.2 Theoretical Aspects

Theoretical studies on the structure and properties of 1,2,3-thiadiazoles are not numerous, probably due to the difficulty associated with calculating sulfur-containing organic compounds [9]. Bond angles and lengths have been determined by ab initio methods for the parent compound (Table 14.1) [10, 11]. The distribution of the electronic charge density shows that the largest negative values are adjacent to the nitrogen atoms [10, 11]. The relative stabilities of 1,2,3-thiadiazolines and 1,3,4-thiadiazolines, which are formed as a mixture of regioisomers in the cycloaddition reaction of aliphatic diazo compounds to thioketones (Pechmann synthesis), have also been determined by semiempirical and ab initio [12] 1,2,3-Thiadiazoline is 0.9 kcal mol1 more stable than 1,3,4-thiadiazoline. The reverse trend has been found for alkyl-substituted derivatives. According to frontier molecular orbital theory, the reaction between diazomethane and thioformaldehyde can be classified as HOMO-CH2N2/LUMO-CH2S controlled: the formation of two regioisomeric adducts is predicted (Figure 14.1) [12]. The aromaticity of 1,2,3-thiadiazole 1,1-dioxide has been studied by ab initio calculations [13] and compared with that of isomeric thiadiazoles: the heteroaromaticity of 1,2,3-thiadiazole 1,1-dioxide is higher than that of 1,3.4-thiadiazole 1,1dioxide, but lower than that of 1,2,5-isomer.

Table 14.1 Calculated geometry of 1,2,3-thiadiazole.


Bond

Length (A)

Bond

Angle (
)

S–C S–N N–N C–C C–H

1.6872 1.7357 1.2786 1.3809 1.0937

C–S–N S–N–N N–N–C C–C–S S–C–H N–C–H

92.11 110.27 115.45 106.67 124.01 119.93

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j 14 Thiadiazoles

1256

CH2 N2

+

N N

CH2 S

+ S

S

C

S

N N

S

C

N

C

N C

N

N

Figure 14.1 Frontier molecular orbital theory prediction of the reaction between diazomethane and thioformaldehyde.

14.2.3 Structural Aspects 14.2.3.1 X-Ray Diffraction Many papers related to X-ray structures of 1,2,3-thiadiazoles have been reported [14]. The thiadiazole ring is essentially flat: all atoms of the ring lie in the same plane, with a very slight deviation of less than 0.02
from the plane. Table 14.2 shows the reported bond lengths and bond angles for 1,2,3-benzothiadiazole (9) and for 4-phenyl-1,2,3-thiadiazole (14). For compound 14, the N2–N3 and C4–C5 bond lengths show a nearly double bond character, while the bond lengths of S–N2 and S–C5 indicate partial double bond character for both sulfur bonds; an aromatic behavior has been ascribed to this ring. The distance between C4–C6, 0.14 nm as expected for a sp2–sp2 carbon–carbon bond, Table 14.2 Molecular dimensions for 1,2,3-benzothiadiazole (9) and 4-phenyl-1,2,3-thiadiazole

(14).

Ph

N

N N

S

S 14

N

9 Compound 14

Compound 9

Bond lengths (nm)

Bond angles (
)

Bond lengths (nm)

Bond angles (
)

S–N N–N N–C C–C C–S C–Ph

C–S–N S–N–N N–N–C N–C–C C–C–S

S–N N–N N–C C–C C–S

C–S–N S–N–N N–N–C N–C–C C–C–S

0.1666 0.1286 0.1378 0.1363 0.1670 0.1469

93.2 111.2 114.4 112.2 109.0

0.1706 0.1279 0.1384 0.1397 0.1708

92.6 112.7 113.4 114.2 107.1

14.2 1,2,3-Thiadiazoles

indicates that there is a little conjugation between the two rings [15]. Similar values of bond angles and bond lengths have been reported for benzo-1,2,3-thiadiazole 9 [5]. X-Ray data have also been reported for the mesoionic 5-(methoxycarbonyl)amino3-methyl-1,2,3-thiadiazole (15) and for 4-phenyl-1,2,3-thiadiazole 3-oxide (16) [6].

MeO2CN

S

N N

Me

Ph

N N

O

S 16

15

14.2.3.2 NMR Spectroscopy 1 H NMR spectroscopy confirms the aromatic character of the 1,2,3-thiadiazole ring. Proton chemical shifts are found in the region 7.44–9.37 ppm. N-Alkylation of the ring shifts these signals 1.0–1.5 ppm downfield (Table 14.3). 13 C NMR spectroscopy is a useful tool for the elucidation of heterocyclic structures where few or no ring protons are present. For symmetrically substituted 1,2,3thiadiazoles, the carbon adjacent to the nitrogen atom resonates at lower field than the carbon atom adjacent to the sulfur atom. The body of 13 C reported data allows us to predict accurately the chemical shift of ring carbons, assuming the tabulated incremental effects of substituents at C4 and C5 (Table 14.4) [16]. Very few references are present in the literature for the 14 N and 15 N NMR of 1,2,3thiadiazoles. One paper, regarding solvent effects on the 14 N NMR spectra of isomeric thiadiazoles, suggests that an increase in solvent polarity favors the delocalization of the lone electronic pair from the sulfur atom into the ring, thus leading to an increase of electronic charge at the nitrogen atom [17]. The 15 N NMR spectra of a series of 1,2,3-thiadiazoles reveal the strong influence of substituents on the N2 resonance, which can be rationalized by the conjugation Table 14.3 Proton NMR data for ring hydrogens of 1,2,3-thiadiazoles (see text for details).

N N S .

R

1

R2

Me

N N

R1 S

R2

Me

R1

R2

Methyl Phenyl H H H H H Phenyl Phenyl

H H Methyl Phenyl Acetyl Formyl Diethylamino H H

N N

R1 S

R2

N2

N3

Methyl Methyl

d (ppm) 8.20 8.60 8.35 8.70 9.04 9.20 7.44 9.93 10.17

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1258

13

Table 14.4

R1

N N

C NMR spectral data (ppm) for ring carbons of 1,2,3-thiadiazoles.

S

R2

R1

R2

C4

C5

H Phenyl H Phenyl

H H Phenyl Phenyl

147.3 163.9 144.2 157.5

135.8 130.9 152.2 150.8

effect. Conversely, little influence on the chemical shifts is exerted by substituents at position 4. The 15 N chemical shifts of some mesoionic compounds have also been determined and explained by the dual effect of 5-substitution and salt formation [18]. 14.2.3.3 UV and IR Spectroscopy Data on IR [19] and UV [20] spectroscopy have been reported for some 1,2,3thiadiazoles. Characteristic infrared absorptions are at 1560–1475 and 1350–1280 cm1 (ring skeletal). Simple 1,2,3-thiadiazoles show three absorption bands in the UV spectra: 211–217, 249–253, and 290–294 nm. 14.2.3.4 Mass Spectrometry The electron-impact mass spectra of the most 1,2,3-thiadiazoles exhibit a very intense signal for the molecular ion [21]. Moreover, the predominant fragmentation is represented by the loss of N2 (M–28) þ , which gives rise the most intense peak in the spectrum (Scheme 14.2). Other types of molecular ion fragmentations are negligible and are of some interest only for complex structures [22].

N N

R R

S

R C S S Scheme 14.2

R

R

R S

14.2 1,2,3-Thiadiazoles

The structure of the [M–N2] þ fragment has been investigated and found to depend on the substitution pattern. For the unsubstituted 1,2,3-thiadiazole, the fragment shows the thioketene and the distonic . CH¼CH–S þ structure, while for 5-amino1,2,3-thiadiazoles the ion exists in the thiirene form [23]. 14.2.4 Synthesis

The synthetic approaches towards the 1,2,3-thiadiazole system can be classified according to five methodologies: 1) cyclization of hydrazones with thionyl chloride: the Hurd–Mori reaction [24]; 2) heterocyclization of a-diazocarbonyl compounds: the Wolff synthesis [25]; 3) 1,3-dipolar cycloaddition of diazo compounds 3 to isothiocyanates: the Pechmann and Nold synthesis [26]; 4) ring transformation of other sulfur-containing heterocycles; 5) elaboration of preformed 1,2,3-thiadiazoles. 14.2.4.1 Hurd–Mori Synthesis Hydrazone derivatives, possessing a methylene moiety and an electron-withdrawing group (CO2Et, SO2R) at N2, give rise to 1,2,3-thiadiazoles upon treatment with thionyl chloride [27]. Retrosynthetically, the Hurd–Mori reaction is a [4 þ 1] approach where four atoms come from hydrazone and one (the sulfur atom) from the thionating agent. Thus, the reaction of 2[(ethoxycarbonyl)hydrazono]propanoic acid (17) with SOCl2 affords 1,2,3-thiadiazole-4-carboxylic acid (18) in 53% yield, accompanied by traces of 5-methyl-2H-1,3,4-oxadiazine-2,6(3H)-dione (19) (Scheme 14.3) [24].

N H3C

H N

CO2Et

CO2H 17

SOCl2

N

S

N N

+ CO2H

H N

O O

H3C O

18

19

53%

trace

Scheme 14.3

The obtainment of 1,2,3-thiadiazoles has been interpreted according to the initial formation of intermediate 21, which originates from the nucleophilic attack of 20 to the sulfur atom [28]. A fast ene–hydrazine tautomerism promotes the cyclization to the sulfoxide 23, which, probably through a Pummerer-type rearrangement [2], evolves towards the 1,2,3-thiadiazole system 25, with extrusion of NH3 and CO2 (Scheme 14.4). The presence of intermediate thiadiazoline-1-one 23, isolated and characterized in some cases [29], was also ascertained by the crystallographic investigation of the

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j 14 Thiadiazoles

1260

N H3C

H N

CONH2

Ar

SOCl2 - 2HCl

20

Ar

Ar

N

H3C N CONH2 Cl S O 21

H N

H2C N CONH2 Cl S O 22

Ar = Ph, p-MeC6H4, p-OMeC6H4, p-ClC6H4 p-NO2C6H4, p-BrC6H4, p-CNC6H4, Bn N S N

- CO2 Ar

- NH3

O S

CONH2

N N H

O H2N

Ar 24

25 16-80%

O S

N HN

Ar

23

Scheme 14.4

compound 27 isolated by Kobori et al. [30] in the reaction of 26 with SOCl2 (Scheme 14.5).

CO2Et N N H C N

O Me

O SOCl2 - 2HCl 38%

26

EtO

O S

N N

NOMe 27

Scheme 14.5

Substituted hydrazones 29, obtained from 1,2-diaza-1,3-butadienes 28 and methylenic or methinic activated substrates, afford, in the presence of thionyl chloride as solvent-reagent, functionalized 1,2,3-thiadiazoles 30 in good yields (Scheme 14.6) [31]. Similarly, the reaction of 1,2-diaza-1,3-butadienes 28 and trialkyl phosphites, under solvent-free conditions, leads to alkyl 3,3-dialkoxy-2H-1,2,3,l5-diazaphosphole-4-carboxylates 31 that are easily converted into the corresponding (E)-hydrazinophosphonates 32 by treatment with water. Subsequent reaction with thionyl chloride affords 4 substituted 1,2,3-thiadiazoles 33 (Scheme 14.7) [32]. The Hurd–Mori reaction is by far the most widely exploited synthetic methodology for 1,2,3-thiadiazoles. The reaction is especially suitable for alkyl- and (het)arylsubstituted 1,2,3-thiadiazoles; in the same way, fused 1,2,3-thiadiazoles have been prepared from cyclic ketones. Several substituted thiadiazoles, possessing halide [33],

14.2 1,2,3-Thiadiazoles

R5 R1O2C

R2

N

N

O

R3

CO2R4

90-95%

R3 R5 R4O

2C

H N

N CO2R1

28

R"' O

29 SOCl2

R1 = Me, Et R2 = Ot-Bu R3 = H, Me, Ph, CO2Et, i-Pr R4 = Me, Et, Bn R5 = CO2Me, CO2Et, CO2Bn, p-NO2Ph

R5

R4O2C

CO2R1

R3 S

N N

30 75-87% Scheme 14.6

O R 2O

N

R3

N O

28

OR1 P R1O OR1

R2O2C

87-98%

R1O

R1O

P

31

N N COR3

R1 = Me R2 = Me, Et, Bn

88-95%

R3 = NH2 O O R1O P R1O

OR2

S 33

N N

SOCl2 71-77%

H2O

O 2

R O

N O P OR1 OR1

H N

R3 O

32

Scheme 14.7

ester [34], carboxy [24], aldehyde [35], sulfide [36], and amino groups [37], have also been obtained. 4,5-Diaryl and 4-aryl-substituted 1,2,3-thiadiazoles 36, with potential antithrombotic activity, have been prepared starting from aldehydes and ketones 34 (Scheme 14.8) [38].

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j 14 Thiadiazoles

1262

O R

R1

2

NH2NHX R1

NNHX R2

R1

SOCl2

R2

35

34

S

N N

36 31-92%

R1 = Ph, 4-MeO-C6H4, 4-Me-C6H4, 4-NO2-C6H4, 4-NO2-C6H4, 4-MeS-C6H4, 4-Cl-C6H4,3,4-Cl2-C6H3, 3,4,5-(MeO)3-C6H2, R2 = H, Ph, 4-MeO-C6H4, 4-NO2-C6H4, 2-(C4H3S), 3,4-(-OCH2O-)C6H3

Scheme 14.8

The 1,2,3-thiadiazole ring annelated to the benzazepine ring 38 was obtained by the Hurd–Mori reaction of hydrazonobenzazepine 37 (Scheme 14.9) [39]. H2NOCHNN MeO

MeO

SOCl2

MeO

N Ts

MeO

37

N

N

S

N Ts 38 75%

Scheme 14.9

An interesting solid-phase synthesis of 1,2,3-thiadiazoles 41 has also been reported. A Merrifield type resin functionalized with sulfonhydrazide groups (39) was used to capture ketones from the reaction mixtures (Scheme 14.10) [40].

SOCl2

R1CH2COR2

+

2

SO2NHNH2

SO2NN

R

CH2R1

R1 S

R2

SO2NHNH2

40

39

N N

39

41 79-100%

R1 = Me, Et, n-Bu, iso-Bu, Bn R2 = p-OMeC6H4, p-ClC6H4, pPhC6H4, o-BrC6H4, m-BrC6H4p-BrC6H4 Scheme 14.10

14.2.4.2 Wolff Synthesis Wolff’s synthesis of 1,2,3-thiadiazoles is one of the earliest methods [25]; it implies the heterocyclization of a-diazothiocarbonyl compounds, which can be prepared via different routes. According to this methodology, 5-alkyl and 5-aryl-1,2,3-thiadiazoles have been prepared by reaction of 2-diazo-1,3-dicarbonyl compounds with ammonium sulfide [41]. The method has been exploited to prepare various 5-amino- and

14.2 1,2,3-Thiadiazoles

5-mercapto-1,2,3-thiadiazoles bearing different functional groups at the 4-position (Scheme 14.11) [41, 42]. Diazothiocarbonyl compounds 43, 46 and 50 may be generated: (i) by introducing the diazo group into compounds containing a C¼S bond, (ii) by constructing a C¼S group into the a-position of a diazo compound, or (iii) by simultaneous introduction of both these functions.

H2 N

CN

S

NH2

HCl

N2

CN

S

NH2

NaNO2

NC H2N

78%

S

N N

45%

R

R

O

44

43

42 R

(NH4)2S O

85%

N2

R

O

S

N N

68%

N2

S

R

47

46

45

COR

R = Me, Ph Me3Si

Cl

Li N2 48

+

NEt2

NEt2 S

SiMe3

S

72%

N2

49

50

N N

CSNEt2 S 51 35%

NEt2

+

N N

H S

NEt2

52 44%

Scheme 14.11

Thiadiazole 44 has been prepared by diazotation of 2-amino-2-cyano-thioacetamide (42) [41, 43]. The method requires the presence of two electron-withdrawing groups at the a-carbon atom, which stabilize the intermediate diazothiocarbonyl compounds 43. The same stabilization can be achieved by including the carbon atom attached to the diazo function onto an aromatic ring. In this way, benzo-1,2,3-thiadiazole 9 has been synthesized in 77% yield by reaction of ortho-aminothiophenol (53) with sodium nitrite in acetic acid (Scheme 14.12) [44].

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j 14 Thiadiazoles

1264

NH2

NaNO2

S

SH

AcOH 77%

N

53

N

9

Scheme 14.12

An alternative way to generate a-diazothiocarbonyl compounds exploits the reaction of species bearing an active methylene group such as compound 54, with azides (Scheme 14.13) [45].

EtS

CO2Ph S

+

TsN 3

72%

N N

CO2Ph S

SEt

55

54 Scheme 14.13

2-Diazo-1,3-dicarbonyl derivatives 45 react with thionating reagents to give diazocarbonyl intermediates that spontaneously cyclize to 4-carbonyl-5-alkyl- or 5-aryl1,2,3-thiadiazoles 47 (Scheme 14.11) [41]. As an example, 5-ethyl-4-ethoxycarbonyl-1,2,3-thiadiazole has been prepared from an a-diazoketone via its thioketone intermediates using Lawesson’s reagent (Scheme 14.14) [46]. Et

OMe

O

O N2 56

Lawesson's reagent 95%

N N

CO2Et S

Et

57

Scheme 14.14

Lithium trimethylsilyldiazomethane (48) reacts with thiocarbamoyl chloride 49 to give a mixture of 5-amino-1,2,3-thiadiazoles 51 and 52. The proposed mechanism involves the formation of a diazothioacetamide that undergoes a rapid cyclization (Scheme 14.16) [47]. Wolff’s methodology has been exploited in the first solid-phase synthesis of benzo1,2,3-thiadiazoles and related structures, starting from resin bound chloro, bromo, or iodo triazenes and using a functionalization on cleavage [48]. In particular, the synthesis was realized employing two different, synergetic methods: an anionic approach, via a halide metal exchange, and a cross-coupling approach, via an innovative palladium catalyzed C–S bond forming reaction. Anilines 58 were diazotated with tert-butyl nitrite and subsequently coupled with piperazine resin 59. The resulting triazene aryl halides 60 have been converted into the corresponding thiol 61 bonded to the resin by two alternative methods: (A) reaction with n-BuLi and

14.2 1,2,3-Thiadiazoles

TMEDA, followed by treatment with elemental sulfur; (B) reaction with triisopropylsilylthiol in the presence of palladium acetate. Cleavage from the resin with dilute trifluoroacetic acid (TFA) resulted spontaneously in the desired cyclization reaction, yielding benzo[1,2,3]thiadiazoles 62 in good yields (Scheme 14.15). N

1) BF3 .OEt2, t-BuONO

NH2

N

X N R

N

59 52-100%

Method A or Method B

R = Me, OMe, NO2,CF3 N R

R

60

NH

58

X N

S

TFA

N

10-63%

N N

SH N 61

62

N R

Scheme 14.15

14.2.4.3 Pechmann and Nold Synthesis One of earliest synthesis of 1,2,3-thiadiazoles is the Pechmann and Nold synthesis [26], which involves the 1,3-dipolar cycloaddition between diazoalkanes 63 and isocyanates 64 (Scheme 14.16) [1]. R R

1

H N N

N C S 64 35-70%

63

N N

R1 S

NHR

65 R = Me, Et, Ph, Bn R1 = Pn, pMe-C6H4, pMeO-C6H4

Scheme 14.16

This method includes the reactions of diazo compounds with various thiocarbonyl derivatives, such as thioketones, thioesters, thioamides, and carbon disulfide [49]. The reaction of diazoalkanes 67 with thioketones 66 gives a mixture of 1,2,3- 68 and 1,3,4-thiadiazolines 69[50]: the regioisomeric distribution depends on the solvent polarity and steric effects (Scheme 14.17) [12]. The reaction has been studied in detail by ab initio RHF and CASSCF calculations (3-21G , 6-31G , CAS/3-21G ) and semiempirical calculations (AM1 and MNDOPM3). In particular, ab initio calculations, in accord to experimental data, show that

j1265

j 14 Thiadiazoles

1266

R3

H R2

R3

N2 67

R1 S

N N

SH

66

H R1 R2

S

+

R3

N N

H

R2

69

68

15-87%

60-85%

R1 = Et, n-Pr, i-Pr, t-Bu R2 = Et, n-Pr, i-Pr, t-Bu R3 = H, Me, Ph

S

R1

SH = (Et)2O, MeOH

Scheme 14.17

1,2,3-thiadiazoline products are formed in higher ratio in more polar solvents and that this is explainable by the higher dipole moment (about 5 D as compared to circa 2 D) of the transition structure [12]. If the cycloaddition reaction is performed with chlorodithioformates 70 or thiophosgene (73) as dipolarophiles, the initial thiazolidines undergo elimination of HCl and form a mixture of 1,2,3- (71 and 74) and 1,3,4-thiadiazoles (72 and 75) (Scheme 14.18) [41, 50, 51]. RS

Cl

H

H N2

S

76-92%

70

N N

SR

S

N N

+

S

SR

72

71

R = Et, Pr

Cl

Cl

H

S

CO2Et N2 67-84%

73

N N

CO2Et + S 74

Cl

N N Cl

S

CO2Et

75

Scheme 14.18

A variation of this method, which probably does not proceed through a concerted [3 þ 2] cycloaddition, involves the reaction of lithium (trimethylsilyl)diazomethane (77) with thioesters or dithioesters 76 and with carbon disulfide to afford various 5substituted-1,2,3-thiadiazoles 78 and 80 (Scheme 14.19) [52]. 14.2.4.4 Transformations of Other Heterocycles The 1,2,3-thiadiazole ring can also be obtained by chemical transformation of other sulfur-containing heterocycles. Thus, treatment of 1,3,4-thiadiazin-2-ones 81 with tert-butyl hypochlorite gives rise to 1,2,3-thiadiazole 84, probably via the intermedis 82 and 83, as reported in Scheme 14.20 [41].

14.2 1,2,3-Thiadiazoles

Li

SiMe3 N2

R1

X

N N

77

S

R1

S

78 4-95%

76 X = OMe, SMe R1 = Me, Et, Ph, Bn Li

SiMe3 N2 77

CS2

N N

R = Me, Et, Ph, Bn

SiMe3 S

RX

N N

SLi

SiMe3 SR

S

80 30-70%

79

Scheme 14.19

HN O

N

Ar

S

R

81

t-BuOCl

HN O

N

Ar

H2N HO2C

H N

Ar

S R O O 86

S R O O 85

- CO2 - H2O Ar = Ph, Tolyl R = Me, Et

Ar N N S 84 26-55%

- H2O R

HN HN

S O

Ar R

87

Scheme 14.20

A different mechanism has been proposed for this reaction, based on the oxidation of 81 to thiadiazine dioxide 85, which undergoes hydrolysis of the imine double bond. Subsequent loss of CO2 and H2O leads to the final product 84 (Scheme 14.21) [2]. As support, a suspension of thieno thiadiazine dioxide 88 in acid media affords thienothiadiazole 91 (Scheme 14.22) [53]. Another interesting conversion is represented by the rearrangement reaction of 1,2,3-triazoles containing a thiocarbonyl group. Thus, 1,2,3-triazolo[4,5-b]pyridin-4 (7H)-thione (92) rearranges by thermolysis into 1,2,3-thiadiazolo[4,5-c]pyridine 93 (Scheme 14.23) [41, 54].

j1267

j 14 Thiadiazoles

1268

HN O

N

Ar

S

R

t-BuOCl

HN O

81

N

Ar

H2N HO2C

S R O O 85

O

H N S

Ar

O

R

86 - CO2 - H 2O

Ar = Ph, Tolyl Ar

R = Me, Et

N N S

- H2O R

84 26-55%

S

S

O

N H

CO2Me

SO2 COCO2Me

N

NHNH2

S

88

89 - CO2H CO2Me

N N

S

- H2O

56%

S

HN HN

S O

S 91

90

Scheme 14.22

S N H2N

N H

N H 92

Scheme 14.23

NH2 N

67%

N

N

S

H2N 93

S O

87

Scheme 14.21

O

HN HN

N

Ar R

14.2 1,2,3-Thiadiazoles

14.2.4.5 Elaboration of Preformed 1,2,3-Thiadiazoles Various 1,2,3-thiadiazole derivatives have also been easily prepared by chemical modification of substituents present at C4 or C5 in a preformed 1,2,3-thiadiazole system. Thus, 1,2,3-thiadiazole carboxylic acids have been obtained by oxidation of 4- or 5-methyl-1,2,3-thiadiazole [55], or by hydrolysis of the corresponding esters [56]. The acids can be easily converted by standard procedures into the corresponding esters, chlorides, amides, hydrazides, azides, thioamides, and nitriles [36, 57]. The carbaldehyde function has been introduced by oxidation of a hydroxymethyl group [58] or by acid-catalyzed hydrolysis of the corresponding hydrazones and oximes [7, 35, 59]. 4- and 5-Amino- [1, 3, 41, 42], 5-halo- [3, 42], 5-mercapto- [36], and 5- and 4-alkenyl 1,2,3-thiadiazoles [60–62] have been prepared following the same synthetic approach. In particular, different 5-substituted derivatives have been synthesized by Katritzky et al. [63] following a procedure that exploits the chemistry of the benzotriazole system. Thus, the 1-(1,2,3-thiadiazol-5-yl)-1H-1,2,3-benzotriazole 94 has been transformed into 5-[(4-methylphenyl)thio]-1,2,3-thiadiazoles 96 (X ¼ S) and 5-phenoxy-4-phenyl-1,2,3-thiadiazoles 97 (X ¼ O). The reaction mechanism includes the known ring-chain tautomerism of substituted 1,2,3-thiadiazoles, involving cleavage of 1,2-bond to afford 2-diazoethanethione tautomers 95. This intermediate then undergoes a direct nucleophilic substitution of the benzotriazole moiety and sequential ring closure to give 5-substituted 1,2,3-thiadiazoles 96 and 97 in yields ranging from 11% to 76% (Scheme 14.24).

R1 N N S

R1 N

N

N

N N S

R1 N

N

N

2

R XH NaH

N N S

XR2

96,97 94 X = S,O

95

11-76%

1

R = H, Ph, Thiophen-2-yl, Furan-2-yl

R2 = Ph, p-CH3-C6H4, 2-Naphthyl, Bn, p-Cl-C6H4, p-CH3O-C6H4

Scheme 14.24

14.2.5 Reactivity

The reactivity of the 1,2,3-thiadiazole system is expressed in a series of different chemical transformations: (i) ring cleavage reactions, (ii) base-catalyzed decompositions, (iii) rearrangement processes, (iv) oxidative and reductive processes, (v) reactions due to the reactivity of the heterocycle ring, and (vi) reactions of nucleophiles.

j1269

j 14 Thiadiazoles

1270

14.2.5.1 Ring Cleavage Reactions The easy ring cleavage of the 1,2,3-thiadiazole system, which produces highly reactive fragments, affords a useful synthetic access to different functionalized compounds. The most important reaction pathways are:

loss of the nitrogen molecule with production of a-thioxocarbene which, in turn, can rearrange to thioketenes; simultaneous loss of a molecule of nitrogen and the sulfur atom.

1) 2)

As an example of the first case, compounds 98 upon thermolysis extrude nitrogen, leading to transients a-thioxocarbenes 99 and 101 and thiirenes 100, which can follow different reaction routes [64–66]: (i) rearrangement to thioketenes 102, (ii) dimerization to 1,4-dithiins 103, or (iii) cycloaddition of the intermediate a-thioxocarbenes with the rearranged thioketene 102 to give 4-dithiafulvenes 104 (Scheme 14.25).

N N

R1

R1 S

R2

S

98

R1

C S

R2

R2 R

40%

R2

100

1

102

R1

S

R2 99

R1

S

R2

S S 103 10%

101

R2

R1/R2 1

2

R /R

S R2

S R1

R1

104 10%

R1 = H, Me, Ph R2 = H, Me, Ph Scheme 14.25

Formation of thioketenes 102 from 99 and 101 involves a 1,2-shift of the substituent at the carbon atom of the thiocarbonyl group. The structure of thioketenes has been confirmed by NMR [67] and IR spectra [68]. The intermediate four-electron systems 99–101 have been trapped by reaction with acetylenes 105 [69–72], affording a mixture of isomeric thiophenes 106 and 107 in a ratio of 1 : 1 (Scheme 14.26).

14.2 1,2,3-Thiadiazoles

N N

R1

R3 R3 105

R2

S

R3

R2

+

1

R

∆ 12-37%

98

R

S

3

R3

R1 R2

S

R3

107

106

R1 = H, Me R2 = H, Me R3 = CF3 Scheme 14.26

The formation of the same product distribution (111–113) from regioisomeric thiadiazoles supports the suggested equilibrium between the two isomeric 1,3diradicals 99 and 101 via thiirene 100 (Scheme 14.27) [73]. Me

N N

S

N N

Ph

R1

R2

S 99

109

S

R2

R2

100

101 ∆

Ph 110

Me

+

+ Ph

Ph

Ph

Ph

Ph

Me S

R1

S

Ph Ph 110

Me Ph

Me

S

108

R1

∆

Ph

Me

S

Me

Me

S

111

112

113

45%

15%

37%

Ph

Scheme 14.27

Capture of the thiirene intermediate by an intramolecular reaction has been reported by Katritzky et al. [74] in the thermal rearrangement of 5-benzotriazolyl1,2,3-triazoles 114 to zwitterionic 3-phenyl-[1,2,3]thiadiazolo[3,4-a]benzimidazol-9ium-4-ide 117 (Scheme 14.28).

j1271

j 14 Thiadiazoles

1272

R N N

S

N

R 60-65%

N N N

S N

117

114

R

R

S

N

N N N 115

S

C N N2 116

R = Ph, 2-thienyl Scheme 14.28

Thermolysis of 1,2,3-benzothiazole 9 gives, as main products, thianthrene (119) [64, 65] and dibenzo[1,2]dithiin (120). The formation of these compounds can be explained on the basis of the dimerization of biradical 118, formed after the nitrogen extrusion (Scheme 14.29).

S N

S

S

N

S

9

118

119 7%

+

S

S

120 12%

Scheme 14.29

When heated in the presence of sulfur, 1,2,3-benzothiadiazole 121 loses nitrogen and produces benzopentathiepine 122 (Scheme 14.30) [75]. In this way several heterocycles fused to the pentathiepine nucleus have been obtained by starting from the corresponding thiadiazoles [76]. R

S N 121

N

S8 ∆

R

S S S S S 122 20-57%

R= H, Cl, CF3, OMe, N(CH3)2, Br, CF3, CN, NH2 Scheme 14.30

14.2 1,2,3-Thiadiazoles

2-Aryl-1,2,3-thiadiazole-4H-5-imines 123, when heated in boiling pyridine, undergo extrusion of sulfur to form hydrazones 124, which by reaction with the starting thiazolidin-5-imines give 1,2,4-thiadiazoles 125 (Scheme 14.31) [77]. R R

R N N S Ar

NH

Ar

123

N CN NH

N S

NNHAr N R

ArHNN

123

124

125 47-75%

Ar =Ph, Tolyl R = Me, Ph, Bn Scheme 14.31

In analogy to thermolysis, photolysis of 1,2,3-thiadiazoles proceeds with extrusion of nitrogen and leads to many products, all of which correspond with the above reported intermediates (Scheme 14.25) [78, 79]. Thus, thioketenes 102, 1,4dithins 103 and 1,4-dithiafulvenes 104 have been obtained. Photolysis of 1,2,3thiadiazole 1 in an argon matrix at 8 K produced thiirene 126, as seen by the appearance of its IR spectrum [80]. Upon further irradiation, this intermediate affords the corresponding thioketene 127. Evidence for the thiirene intermediate has been obtained during the photolysis of 5-phenyl-1,2,3-thiadiazole by 13 C NMR spectroscopy [81]. Further support of thiirene intermediates has been given by the photolysis of either 128 or 129, which in the presence of hexafluoro-2-butyne (130) lead to the thiophene 131 (Scheme 14.32) [72].

N

N

hν

S

hν

8K

S

40%

127

126

1

F3C Me S

N N

128,129

hν

Me

S C CH2

CF3

CF3

130 Me

S

CF3

131 12%

Scheme 14.32

The photochemical decomposition of 1,2,3-thiadiazole 1 in the presence of amines 132 leads to thioamides 133 in yields of 60–75% (Scheme 14.33) [82, 83].

j1273

j 14 Thiadiazoles

1274

N

N

R2NH hν

S

S

132

S C CH2

R2N

127

1

133 55-72%

R = H, Me, Et, Bn Scheme 14.33

In the presence of alcohols (134), photolysis or thermolysis leads to thioesters 135 (Scheme 14.34) [64, 65, 84]. N

N

hν

S

ROH 134

S C CH2

S RO

127

1

135 12-72%

R = Me, Et, i-Pr, t-Bu, Bn Scheme 14.34

The photochemical decomposition of benzothiadiazoles, followed by acylation of the obtained products, affords thioesters of acetic acid (138 and 139) (Scheme 14.35) [85]. R

S N

R

R

N

SCOMe +

S

SCOMe R

137

136

138 19-42%

R = Me, OMe, NO2, Cl, -Br

139 16-56%

Scheme 14.35

Photolysis of substituted 1,2,3-thiadiazoles has also been used to generate highly reactive intermediates such as heterocumulenes [86]. Heterocumulenes 142 and 143 have been obtained by photolysis of quinone 140 and indandione 141, respectively (Scheme 14.36) [87, 88]. O N

N

S

S

N

N

hν 45%

S C C C C O

O 140

142

O N

N

N2

S

hν 50%

S C C C C S

O 141 Scheme 14.36

143

14.2 1,2,3-Thiadiazoles

An example of the simultaneous loss of a molecule of nitrogen and the sulfur atom arises upon treatment of 4,5-disubstituted 1,2,3-thiadiazoles with strong bases, which results in ring cleavage. Thus, treatment of 4,5-diphenyl-1,2,3-thiadiazole (144) with n-butyllithium at 60
C gives 1,2-diphenylacetylene (145) with evolution of nitrogen and extrusion of the sulfur atom (Scheme 14.37) [1]. N N

Ph

n-BuLi

Ph

65%

Ph

S

Ph + N2 + BuSLi 145

144 Scheme 14.37

Upon irradiation, fused compounds like 146, through the simultaneous loss of nitrogen and sulfur, give acetylene derivatives 147 (Scheme 14.38) [89, 90]. (CH2)n

N S

(CH2)n N

43%

146

147

Scheme 14.38

Monocyclic 1,2,3-thiadiazoles 148, acting as heme ligands, are oxidized by cytochrome P450 and oxygen to give acetylenic derivatives 150. The formation of these compounds has been rationalized by the production of an unstable S-oxide (149), which loses nitrogen and SO (Scheme 14.39) [91]. R1 R2

S N

O S N N

R1 N 2

R

150

149

148

R2 + SO + N2

R1

19-65% R1 = Me, Et, i-Pr, Ph, Bn R2 = Me, i-Pr, Ph Scheme 14.39

Pyrolysis of 1,2,3-thiadiazole 151 produces the arylethynyl sulfone 152 in satisfactory yields via N2 and S displacement (Scheme 14.40) [92]. Ar

N N

S

SO2 H 151

Scheme 14.40

O Ar H Ar

S O

H

H

Ar 152

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j 14 Thiadiazoles

1276

A study of the thermal decomposition of unsubstituted 1,2,3-thiadiazole has suggested the formation of alkynethiol, thioketene, and acetylene. Ab initio calculations indicate that thioketene 127 is 74 kJ mol1 more stable than ethynethiol 153 and 552 kJ mol1 more stable than thiirene 126 (Scheme 14.41) [93, 94]. N N

153

126

+

+ S C CH2

SH

S

S 1

154

127

Scheme 14.41

14.2.5.2 Base-Catalyzed Decompositions The ring cleavage of 4-monosubstituted 1,2,3-thiadiazoles in the presence of strong bases affords reactive alkynethiolates 157 [95, 96]. The alkynethiolate can be alkylated to give sulfide derivatives 160, or acylated, reacted with nucleophiles to give 162, dimerized to 1,4-dithiafulvenes 166, cyclized with CS2 to give 1,3-dithiole-2thiones 165, which are useful intermediates towards tetrathiafulvalenes 167 (Scheme 14.42) [97–99].

R1 = Me, Et, Bn 60- 75% Ph S

N N

Base

Ph

Nu ( RNH2, RSH, N3 ) 60- 70% 161

R1X 159

Ph

S

Nu

162

160

N N

S

SR1 PhH2C

Ph

Ph

H

S

C S

H

157

158

156

155 ClSiMe3

THF - 78 °C

86% N N

Ph S

157 82%

CS2 57% Ph

SiMe3

S S

H

S

Ph

S

Ph

H

S

H

166

165

164

83% Ph

S

H

S

S S 167

Scheme 14.42

Ph

14.2 1,2,3-Thiadiazoles

j1277

Thomas and Zimmerman have trapped the anion 157 in situ, by reaction with chlorotrimethylsilane, giving rise to the formation of compound 164 [100]. In contrast to 4-monosubstituted thiadiazoles, 5-derivatives produce stable anions that can react with many electrophiles to give various 4,5-disubstitued 1,2,3-thiadiazoles. For example, the metallation of 5-phenyl-1,2,3-thiadiazole (168) with methyllithium gives 4-lithio-5-phenyl-1,2,3-thiadiazole (169), which is stable and can react with aldehydes or ketones at 70
C in tetrahydrofuran to produce 4-oxymethyl-1,2,3-thiadiazoles 170 in good yields (Scheme 14.43) [100].

N N

N N

MeLi Ph

S 168

Li S

Ph

R1 R1RCO 80-95%

N N

OH R Ph

S

170

169

R = H, Me, R1 = Me, Et, cycloexyl,cyclopentyl, Bn, n-Pr, n-eptyl Scheme 14.43

4-(o-Hydroxyaryl)-1,2,3-thiadiazoles 171 have proven to be susceptible to relatively weak bases such K2CO3 and give, in the presence of alkylated agents, the unexpected benzofuran-2-sulfides 174 instead of the O-alkylated 1,2,3-thiadiazoles (Scheme 14.44) [101, 102].

S N N

R R

1

OH

S Base 2

R X

R

R

R1

R1

171

OH

172

O

S

R R

173

R = H, OH R1 = H, OH R2 = Me, Bn, C16H33 X = Cl, Br, I

Scheme 14.44

H NMR data proved that the benzofuran-2-thiolate 173 is really the intermediate of the reaction. This methodology has been exploited to produce nitrogen heterocycles: thus basecatalyzed ring cleavage of derivatives of 1,2,3-thiadiazole-4-carbonylhydrazide 175, followed by alkylation, affords the pyrazoles 178 (Scheme 14.45) [103]. 1

O

1

174 46-97%

SR2

j 14 Thiadiazoles

1278

O N N

O NHNHCOPh

HN HN

1.1 eq t-BuOK RX

S

Ph O

175

S

H

C

O

NHNPh

O HN

S

177

176

N H

SR

178

20-35% 2 eq. t-BuOK

R = Me, C 16H 33, Bn, X = Cl, Br, I

O HN N

O HN N

S RX

O

O O

RS SR RX

N N

O

R

Ph

181

180

179

40-51%

Scheme 14.45

The presence of two or more equivalents of base promotes a different reaction course that leads to the formation of the 1,3,4-oxadiazine structure 181. 5-Chloro-1,2,3-thiadiazoles 182, which are stable in the presence of weak or moderately strong bases, react with organometallic reagents to give alkyne sulfides 183 as a consequence of the ring cleavage. Metallation of 182 with lithium affords the unstable 1,2,3-thiadiazol-5-yllithium 184, which loses nitrogen to give the alkynethiolate 185, which in turn can be easily transformed into 186 (Scheme 14.46) [104]. N N

R1

R2 M

R1

Cl

S

SR 2 183

182

55-61%

Li

N N

R1 S

184

R1

R1

SMe 186 20-88%

185

R1 = Ph, t-Bu R2 = Me, Et, n-Bu, Ph, t-Bu, PhC Scheme 14.46

MeI

S

C

14.2 1,2,3-Thiadiazoles

j1279

The formation of alkynethiolates, by decomposition of the 1,2,3-thiadiazole ring in the presence of bases, has been used for the synthesis of a series of dendrimers. Thus, 1,3,5-tris(1,2,3-thiadiazolyl-4-yl)benzene 187, prepared from 1,3,5-triacetylbenzene by the Hurd–Mori reaction, upon treatment with potassium t-butoxide gives the trithiolate anion 188, which can be coupled with dendron 189 to afford the second generation dendrimer 190 (Scheme 14.47) [105]. S

N S N

O O

t-BuOK

+

O

59% S

N N

N

S

N

Br

O S

S

187

O

188

O

189

60%

O

O

O O O

S

O

O O

O O

O

O O

O

O

O O S

O

O

O O

O

O

O

O

O S O

190

O

O

O

O

O O O

O O

O

O

O

O

O

Scheme 14.47

14.2.5.3 Rearrangement Processes The chemistry of the 1,2,3-thiadiazole system has found extensive application in organic synthesis as a useful approach to a series of functionalized five-, six-, and seven-membered heterocyclic systems. The reaction routes starting from 1,2,3thiadiazoles are promoted by (i) the cleavage of the weak N–S bond, (ii) the

O

j 14 Thiadiazoles

1280

equilibrium between 1,2,3-thiadiazole and a-diazothiocarbonyl structures, and (iii) the cyclization of these functionalities onto electrophilic and nucleophilic substituents [3]. 14.2.5.3.1 Dimroth-Type Rearrangement The Dimroth rearrangement [106] has been observed in a series of heterocyclic derivatives possessing several N-atoms. In the 1,2,3-thiadiazole system, this rearrangement occurs through cleavage of the N–S bond to give the corresponding diazothiocarbonyl compound 193. 5-Amino-1,2,3thiadiazoles 191 easily undergo this type of rearrangement, upon treatment with base, to form 5-mercapto-1,2,3-triazoles 194 (Scheme 14.48). In this rearrangement, the nitrogen atom of the chain at position-5 takes part in the process.

N N

R1 N H

S

Base

N N S

R2

R1 N H

N N

R2

192

191

R1 N R2 193

R 1 = H, COMe, COOMe R 2 = H, Ph

SH

N N

R1 N

SH

R2 194 12-37%

Scheme 14.48

The suggested mechanism is supported by the kinetics of the process and by the influence of the solvent polarity. The acidity of the mercapto group shifts the reaction forward with the formation of thiolate salts in basic conditions. The transformation of hydrazones 195 into 1,2,3-triazoles 196 by treatment with PCl5 could proceed by the same reaction route, although the mechanism has not been perfectly elucidated (Scheme 14.49) [107, 108].

N N

CO2 Et S

NH N

PCl 5/Toluene

N N

86%

N N

S Ph

Ph 196 195 Scheme 14.49

A double Dimroth rearrangement has been reported for the conversion of ethylene bis(thiadiazol-5-amine) (197) into the intermediate bis thiol, which undergoes an intramolecular nucleophilic substitution reaction with loss of H2S to give tricyclic triazole 199 (Scheme 14.50) [108].

14.2 1,2,3-Thiadiazoles

EtO 2C

CO 2Et N

HN

NH

N S

N S

N N

N EtO 2 C

197

j1281

CO 2 Et

N N N

SH

- H 2S

N N N

N

CO2 Et

CO 2Et S

SH 198

N N N 199 54%

Scheme 14.50

By the same reaction route, 5-halo-1,2,3-thiadiazole 200 reacts with 1,8-diaminonaphthalene (201) to afford the tetracyclic derivative 203 (Scheme 14.51) [27, 109].

NH2 NH2

COR N N S

Br

COR

N N NH2 N

SH

ROC HN

N N N

+

200

202

201

203 76%

Scheme 14.51

14.2.5.3.2 Cornforth-Type Rearrangement 1,2,3-Thiadiazoles, bearing a C¼N and or C¼S function at the 4-position, when treated with base, rearrange to give 1,2,3triazoles (X ¼ NR) or isomeric 1,2,3-thiadiazoles (X ¼ S). The process, in contrast to the Dimroth rearrangement, involves two atoms of the 4-substituent and is similar to the interconversion reactions of isomeric 4-acyl-substituted oxazoles via the dicarbonyl nitrile ylides discovered by Cornforth in 1949 [110]. The rearrangement has been rationalized on the basis of a 1,3-dipolar intermediate diazo compound 205 bearing two nucleophilic groups (two thiocarbonyl functions or a thiocarbonyl and an iminocarbonyl function) (Scheme 14.52).

N N

R1 R2

S

S

X

X

204 1

R =Me, Ph, Bn R 2 = H, Me, Et, Ph, Bn X = O, S, NH Scheme 14.52

R1

N2 S

R2 205

N N

R2 X

R1

206 40-60%

j 14 Thiadiazoles

1282

The example reported in Scheme 14.53 shows the different course of the Cornforth rearrangement with respect to the Dimroth reaction. Treatment of 5-amino-1,2,3thiadiazole-4-carbothioamide (207) with bases involves two atoms of the side chain to give 5-mercapto-1,2,3-triazoles 209 rather than the isomeric product 210 resulting from the Dimroth rearrangement [111]. Dimroth

S N N

S

NHMe N H

N N

SH

210

NHMe

N N

Base

NH2

S

Cornforth

S NMe S

Acid

NH2

N N

NH2 N

SH

Me

209 77%

208

207

S

Scheme 14.53

14.2.5.4 Oxidative and Reductive Processes 1,2,3-Thiadiazoles are very stable to strong oxidizing and reducing agents. However, oxidation with peracetic acid gives 1,2,3-thiadiazole 3-oxides 211 and, with an excess of oxidizing agent, 1,2,3-thiadiazole 1,1,3-trioxides 212. Photolysis of 212 produces several products such as dioxazoles 213, nitriles 214, and acetylenes 215 (Scheme 14.54) [112].

N N

R1 S

R2

O

RCO3H

N N

88%

210

R1

RCO3H

R2

S

78%

211

O

N N

O

R1 S

O

R2

212

R = Me, Ph R1 = H, Me, Ph, Bn R2 = H, Me, Ph

hν R1

O

N

O

O

+

R1CN +

213

214

23%

15%

R1

R2 215 37%

Scheme 14.54

Oxidation of 1,2,3-benzothiadiazole 9 with hydrogen peroxide leads to 1-oxo-1,2,3benzothiadiazole (216), which thermally decomposes into benzoxathiete 217 or its valence tautomer 218. Photochemical oxidation of 9 affords the benzoxathiete S-oxide 219 and biphenylene (220) (Scheme 14.55) [113].

14.2 1,2,3-Thiadiazoles

S

N

N

O S N N

H2 O2 ∆ 60%

– N2

216

9 S N

N

9

217

H2 O2

O

hν 65%

S

219

O

O or S

S

218

+ O

220

Scheme 14.55

Reduction of benzothiadiazole 221 with hydrogen on palladium gives methyl 3amino-2-mercaptobenzoate (222) (Scheme 14.56) [114]. CO 2 Me S N

N

221

[H]

CO 2 Me SH

76% 222

NH 2

Scheme 14.56

14.2.5.5 Reactions due to the Reactivity of Heterocyclic Ring Electrophilic substitution on the C-atoms is difficult, while nucleophiles prefer to attack the 5-position. 1,2,3-Thiadiazoles are weak bases and form a deliquescent hydrochloride salt that is decomposed by water. There are several examples of reactions of alkyl halides at the nitrogen atoms of 1,2,3-thiadiazoles to give salts or mesoionic compounds [5]. Alkylation reactions occur preferentially at N3 ring atom; Table 14.5 shows the effect exerted by substituents at the 4 and 5-position of the ring with the relative formation of compounds 223 and 224. The presence of a bulky group at the 4-position directs alkylation towards the preferential formation of the 2-alkyl derivative [18]. The alkylation of 1,2,3-thiadiazoles with trimethylsilylmethyl-trifluoromethanesulfonate occurs at N3 to produce the corresponding thiadiazolium salts 226, which, when treated with CsF, give rise to 1,2,3-thiadiazol-3-ium-3-methanides 227 [115]. These non-stabilized azomethine ylides react in situ, via 1,3-dipolar cycloaddition, with electron-deficient alkynes or alkenes to give pyrazolo-thiadiazole systems 228. The fused bicyclo compounds can in turn undergo a ring-opening reaction to form pyrazole or pyrazoline derivatives 229, depending on the nature of the dipolarophiles (Scheme 14.57). 1,2,3-Thiadiazoles are not easily halogenated. It has been reported that 5-phenylureido-1,2-3-thiadiazole 230 reacts with chlorine or bromine to give the compound 231, produced by halogenation on both the thiazole and phenyl rings (Scheme 14.58) [116].

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Table 14.5 Product distribution in the methylation of 1,2,3-thiadiazoles with Meerwein’s reagent.

BF 4 Me

N N

R4

(Me 3O)

N N

R4

223

BF 4

R5

S

Me

N N

R4

4

R

223 (%)

224 (%)

H Cl H H H

96 100 19 13 92

4 81 87 8

CF 3 SO3

R2 S

224

5

H H Ph t-Bu CO2Me

N N

R5

S

BF 4 R

R5

S

CF 3SO3 CH2 SiMe 3

R1

Me3 Si

quantitative yields

N N

225

CsF

R2 R3

R1

S

H2 C

N N

R4

R4

R1 R2

Scheme 14.57

X2 S

NHCONHPh

230 Scheme 14.58

X2 = Br 2, Cl2 86%

N N

X S

N N S

228

229

70-88%

N N

R2

R3

N

S R4

R1

R3

R4 N

S

227

226

R 1 = Ph R 2 = Ph, p-OMeC 6 H4 R3 = H R 4 =CO 2Me

R2

NHCONH(C 6 H4 )p-X 231

R1

14.2 1,2,3-Thiadiazoles

Mesoionic 3-phenyl-1,2,3-thiadiazoles 232 can be nitrated, formylated, and aminomethylated, as a result of the influence of the olate moiety (Scheme 14.59) [37].

Ar

N N

Ar

O S

HNO3 NO2

N N

Ar

O DMF/POCl3 S

N N

232

234

O S

233

CHO 22-45%

36-65% CH2O/NH(Me)2

Ar = Ph, Tolyl Ar

N N

O CH2N(Me)2

S

235

19-57%

Scheme 14.59

With 1,2,3-benzothiadiazoles, electrophilic substitution occurs on the benzene ring. For instance, the reaction with nitric acid leads to 4- and 7-nitro-1,2,3benzothiadiazoles [1]. 14.2.5.6 Reactions with Nucleophiles 1,2,3-Thiadiazoles containing a good leaving group at the C5 atom are able to give nucleophilic substitutions. Thus 5-nitrosoamino-1,2,3-thiadiazoles 236 in presence of acid, via the intermediate diazonium salt, react with nucleophiles to give, through a nucleophile displacement, the corresponding derivatives (Scheme 14.60) [2].

N N

CO 2Et S

NHNO 236

HX

N N

CO 2 Et N2

S 237

X = OH, OEt, Cl, Br

N N

CO 2 Et S

X

238 60-65%

Scheme 14.60

Moreover, 5-chloro and 5-bromo-1,2,3-thiadiazoles in turn can react with different nucleophilic reagents to give a large variety of 5-substituted 1,2,3-thiadiazole derivatives [117]. For example, the reaction of the 5-chloro derivative 239 with sodium azide affords in good yield the 5-azide derivative 240 [118] (Scheme 14.61).

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N N

CO 2Et Cl

S

N N

N3 76%

239

CO 2Et N3

S

240

Scheme 14.61

14.2.6 1,2,3-Thiadiazoles in Medicine and Agriculture

1,2,3-Thiadiazoles exhibit various types of biological activities and some of these compounds are useful pharmacophores. This nucleus is found in some cephalosporin derivatives such as 241 (cefuzonam), which show antibiotic properties, in compounds that are antipsychotic agents, in derivatives such as 242 and 243, which exhibit activity against herpes viruses, herpes simplex viruses, varicella-zoster, human cytomegalovirus, and HIV-1 [119]. O

S

S

N H N OMe O

N

H 2N

N N S

N

S

241 Cefuzonam

Br N N

CONH NHCSNHCH 2

N

S

242

S

N

N

R

R N

N R 243

N

In general, it is interesting to note that the introduction of the 1,2,3-thiadiazole nucleus in molecules of known biological activity leads to an increase of their pharmacological profiles. 1,2,3-Thiadiazoles are also used in agriculture as pesticides. In particular, the 5phenylureido-1,2,3-thiadiazole 244 (thidiazuron) is a very active cotton defoliant, while the S-methyl ester of 1,2,3-benzothiadazole-7-thiocarboxylic acid 245 (Bion), introduced by Novartis, has been shown to induce disease resistance in wheat,

14.3 1,2,4-Thiadiazoles

tobacco, melons, maize, and Arabidopsis. Moreover, compounds showing antibacterial, antiviral, and antifungal activities have also been reported. COSMe N N

S N H

S

CONHPh

N

N

245 Bion

244 Thidiazuron

14.3 1,2,4-Thiadiazoles

The parent compound 246 was prepared in 1955 and the first natural product containing the 1,2,4-thiadiazole system (dendroine, 247, a cytotoxic compound isolated from marine tunicate Dendrodoa grassularia) was reported in 1984 [120]. O

NH

N

N S

N Me2N

S

N 247

246

The partially reduced ring systems 248–250 are designated as 4,5-dihydro- (D2), 2,5-dihydro- (D3), and 2,3-dihydro-1,2-4- (D4) thiadiazole; the fully reduced ring is termed thiadiazolidine. HN S

N

248

N S

NH

249

N S

NH

250

Many synthetic 1,2,4-thiadiazole derivatives are biologically active compounds and find use as insecticides, fungicides, herbicides, and antibacterials. As an example, 5-ethoxy-3-trichloromethyl-1,2,4-thiadiazole (ethridiazole) is used to combat or prevent fungal infestation of plants, fruit, cotton, and soil [121]. Azodyes derived from diazotized 5-amino-1,2,4-thiadiazoles are used as dyestuffs for polyester and polyacrylonitrile fibers. During the last decade, very interesting therapeutic applications have been explored: the 1,2,4-thiadiazole nucleus is a fundamental constituent of several synthetic products with biological activities concerning the central nervous system (CNS), G-protein coupled receptors, cardiovascular system, or antibiotic activity. Extensive reviews have been published on 1,2,4-thiadiazoles [120, 122, 123].

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14.3.1 Structure

1,2,4-Thiadiazole is a heteroaromatic compound. It is a p-excessive heterocycle, but the presence of two nitrogen atoms exerts a considerable effect on its properties, leading to a relative p-deficiency on the carbon atoms. Electrophilic substitution reactions on carbon atoms are extremely rare, while nucleophilic substitution reactions are common and take place very readily in this ring system, because both nitrogen atoms can assist in stabilizing the intermediates. An example is provided by the high reactivity of 5-chloro-3-phenyl-1,2,4-thiadiazole (251) towards nucleophiles: the compound reacts faster than many activated six-membered heteroaromatics (Scheme 14.62). Ph Y N

N

Cl

S 251

Ph –Cl N

N

Y

Cl

S

Ph

N

N S 252

Y

Scheme 14.62

The inductive effect of the sulfur undoubtedly contributes to the stabilization. This effect is selective, since the 3-chlorine in 3,5-dichloro-1,2,4-thiadiazole is much more difficult to displace than the 5-chlorine. For 3-hydroxy-1,2,4-thiadiazoles three tautomeric forms are possible (253a–c). HO

O

N

N

R

S

HN

253a

O

N

N

N

R S 253b

H R

S 253c

UV data suggest that the lactam form 253b is the major tautomer in ethanol [120]; however, 3-hydroxy-5-phenyl-1,2,4-thiadiazole has been shown by X-ray studies to exist as the OH tautomer 253a [124]. 3-Amino and 5-amino-1,2,4-thiadiazoles exist predominantly in the amino forms (Figure 14.2), as supported by spectroscopic methods and ab initio MO calculations [125].

H2N N

N S 254

HN

N

HN

S

255

NH

N N

S 256

NH2

N

S

NH

257

Figure 14.2 3-Amino and 5-amino-1,2,4-thiadiazoles exist predominantly in the amino forms.

14.3 1,2,4-Thiadiazoles

The IR spectrum of 5-mercapto-1,2,4-thiadiazole does not show the SH absorption of structure 258, thus suggesting the thione tautomers 259 and 260. On the same basis, IR experiments indicated that perthiocyanic acid exists as dithione 261 and not in tautomeric form 262 [120]. R N

R

R

N

N

SH

S

NH S

S

S H

HS

NH

N

S

S

S

260

259

258

N

HN

N

S

261

N S

SH

262

1,2,4-Thiadiazoles fused with heteroaromatic systems have also been reported: the 5,7-dimethoxy-2-(2,4-dichlorophenoxyacetylimino)-2H-1,2,4-thiadiazolo[2,3-a] pyrimidine (263) [126] shows interesting herbicidal properties. Bicyclic imidazo[1,2d][1,2,4]thiadiazoles 264 and tricyclic benzo[4,5] imidazo[1,2-d][1,2,4]thiadiazoles 265 have been described as compounds able to react with enzyme cysteine residues to form a disulfide adduct, thus inhibiting the enzyme [127–129]. O N S N

N

O

N O

Cl O

S

N

N

N

N

Cl

N Y

Y 265

264

263

S

N

The structure of the 1,2,4-thiadiazole[2,3-a]pyridinium salts 267 (Scheme 14.63), obtained from the oxidation of N-alkyl-N-benzylthiourea or N-benzyl-N0 -(2-pyridyl) thiourea 266 with sulfuryl chloride in toluene, has been confirmed by 1 H and 13 C NMR spectroscopy [130].

N

Ox

S N H 266

R= Me, Et, Bn Scheme 14.63

NHR

51-78%

N

S N 267

Cl NHR

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The N-methyl-1,2,4-thiadiazolium salt 268 has been proposed as an interesting pharmacophore in the design of inhibitors targeting the cysteine residues of proteins [131]. Ph

N Ph

N

S

Me

268

As mentioned above, the partially reduced 1,2,4-thiadiazoles (1,2,4-thiadiazolines) can exist in three tautomeric forms 248–250, depending on the position of the double bond. The tautomer 248, with the double bond between the a-nitrogen and the b-carbon, is the one with the lowest energy, lying 3.3 and 4.6 kcal mol1 off the other forms, and thus is the more stable geometric structure [132]. Stable N-substituted D4269 [133] and D3-thiadiazolines 270 [134] have been suggested as scaffolds for structure–activity investigation as N-S cysteine thiol trapping agents in enzyme systems [135]. O

N Ph

N

S

Cl

Ph

N

Me

N

269

S

N

Me

270

The 5-amino-1,2,4-thiadiazolin-3-one 271, analog of cytosine, can exist in two stable tautomeric forms: lactam (oxo) 271a and lactim (enol) 271b. 13 C and 1 H NMR spectra and ab initio molecular orbital calculations support the idea that 271 exists in the lactam rather than in the lactim form [136, 137]. HO

O

N

N

HN

N

NH2

S 271a

S

NH2

271b

The fully saturated 1,2,4-thiadiazole system (1,2,4-thiadiazolidine) is present in a series of compounds endowed with important biological activities. Compounds 272 and 273 are characterized by interesting antibacterial, antifungal, anti-inflammatory, and analgesic activities [138, 140]. R N

MeN N R

S

NMe 272

MeO C N H N S O

N H 273

R N

14.3 1,2,4-Thiadiazoles

Thiazolidinones 275 have been obtained by reaction of oxathiadiazolium salt 274 with aromatic and cycloalkyl amines (Scheme 14.64). The (Z) configuration for 275 was assigned by AM1 calculations and 1 H NMR data [139].

NH2

1) Cl 2

EtNCS

2) R 1NCO

1

R = Me, Et, Ph, Bn

Et Cl

O N S

Me N

N

N

O

S N

R1 275a

N

48-72%

N R1

Me N

NH2

274 N Me

N Me

N

S N

O R1

275b 58-82%

Scheme 14.64

Synthetic approaches towards 1,2,4-thiadiazolidine systems are reported in Section 14.3.4.1. The synthesis and chemistry of two classes of meso-ionic 1,2,4-thiadiazoles (276, X ¼ O, X ¼ SO2C6H4Me-p) have also been reported [133]. S

Ph

N

N

X

Me

276

14.3.2 Theoretical Aspects

Theoretical studies on the structure and properties of 1,2,4-thiadiazoles are not numerous, because of the difficulties linked to the presence of the sulfur atom. AM1 calculations have been performed on the parent compound to predict the degree of aromaticity and to calculate some energetic and magnetic parameters [141]. With the view to establishing structure–activity relationships, the charge densities of 3,5disubstituted 1,2,4-thiadiazoles have been calculated and possible conformations estimated [142]. The reactivity of the 5-position in nucleophilic substitution reactions for non-protonated 1,2,4-thiadiazoles has been supported by a molecular orbital method with the LCAO approximation [120]. Electrostatic potentials at N2 and N4 have been calculated for 3,5-dimethyl-1,2,4thiadiazole and other 5-substitued-3-methyl-1,2,4-thiadiazoles and correlated with the relative binding to cortical muscarinic receptors [143].

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Table 14.6 Equilibrium geometry parameters performed at the B3LYP with a 6-31G basis set for the 1,2,4-thiadiazoline nucleus.


Bond

Length (A)

Bond

Angle (
)

S–N(1) S–C(1) N(1)¼C(2) C(1)–N(2) C(2)–N(2) C(1)–H(3) N(2)–H(2)

1.746 1.862 1.280 1.463 1.386 1.093 1.011

N(1)–S–C(1) S–N(1)–C(2) S–C(1)–N(2) N(1)–C(2)–N(2) C(1)–N(2)–C(2) S–C(1)–H(3) C(1)–N(2)–H(2)

93.9 108.3 101.6 121.1 112.7 110.1 117.6

Geometrical bond lengths and bond angles for the 1,2,4-thiadiazoline nucleus have been estimated by density functional theory (DFT) methods (Table 14.6) [132]. Dipole moments, ionization potentials, and electron affinities as a measure of aromaticity have also been calculated to determine the reactivity of different sites within the molecules studied. The results were compared with existing experimental evidence on thiazolidines and related compounds. Ab initio calculations performed on thiadiazoline 271 confirm that the lactam form 271a is more stable than lactim form 271b by 9.82 kcal mol1 at the HF/3-21G level. On the same basis, bond lengths and angles have been estimated (Figure 14.3) [144].

1.229 1.403

N

1.336

H2 N

O

1.770

1.202 113.5

1.400

S

N H

O

N

124.6

H2 N115.6

1.692

123.,7

S

109.1

N H

115.4

86.6

271a

122.6 1.373

1.336

N 1.299

H2 N

OH

N

1.337

1.289

1.752 S 1.678

OH

108.9 N 123.7

H2 N

119.7

112.2

S

N

108.9

90.4

271b Figure 14.3 According to ab initio calculations performed on thiadiazoline 271, lactam form 271a is more stable than lactim form 271b.

14.3 1,2,4-Thiadiazoles 107.7

1.313

1.366

N

1.317

120.1

N

1.707

N

112.3

S 1.649

S

N

107.1

92.8

Figure 14.4 Bond lengths and angles determined by double resonance modulation microwave spectroscopy.

14.3.3 Structural Aspects 14.3.3.1 X-Ray Diffraction X-Ray diffraction measurements of several 1,2,4-thiadiazoles and 1,2,4-thiadiazolidines have been reported; [122, 126, 145–149] bond lengths and angles have been determined by double resonance modulation microwave spectroscopy (Figure 14.4) [122]. The X-ray analysis of 5-cyano-3-phenyl-1,2,4-thiadiazole (277) shows the molecule to be almost planar with only ca 2
torsional twist about the bond linking the thiadiazole and the phenyl system. The experimental data are consistent with the presence of a formal N¼C double bond for the N2–C3 and N4–C5 linkages, though there is some evidence for delocalization that extends from S1 via C3 to C5 [150]. The pattern of bonding is similar to that observed for 1,2,4-thiadiazole-3,5-dicarbonitrile (278) [151], indicating that the nature of the substituent on C3 has little effect on the bonding within the ring. Ph

N

NC

S

CN

N

N

NC

S

N

278

277

The X-ray structure of 5-carboxamide-3-phenyl-1,2,4-thiadiazole 4-oxide (279), the first 1,2,4-thiadiazole N-oxide reported [150], shows that this molecule too has a nearly planar conformation, the torsional twists about the C(3)–C(Ph) and C (5)–C(O) bonds being only ca 8
and 5
, respectively. The conformation is stabilized by intramolecular NH. . .O and CH(Ph). . .O hydrogen bonds, with the former producing the syn relationship between the N-oxide oxygen and the amido nitrogen. The bonding in the thiadiazole ring differs noticeably from that observed in 277, where a pattern of delocalization is present extending from C3 via S1 to N4. O H2N

Ph

N S

N

O

279

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More recently, the X-ray crystal structure of the bicyclic imidazo[1,2-d][1,2,4] thiadiazole 264 was obtained: some of the salient features include the C1–S1 and
N1–S1 bond lengths of 1.730 and 1.693 A, respectively, which are slightly longer

than the C–S (1.707 A) and N–S (1.649 A) bond lengths of monocyclic [1,2,4] thiadiazole [152]. The crystal structure of the adduct of cathepsin B and Apo501 (280), a member of a series of 1,2,4-thiadiazole analogues designed as inhibitors of cysteine proteases, clearly indicates that the cysteine thiol reacts with the N–S bond of the thiadiazole moiety, thus resulting in the inactivation of the enzymes [127]. MeO N

N H N

O

CO2H

S

280

14.3.3.2 NMR Spectroscopy 1 H NMR spectral data on several 1,2,4-thiadiazole derivatives have been reported [126, 153, 154, 158]. In general, the resonances of protons in the 1,2,4thiadiazoles are shifted downfield with respect to benzene protons, with the proton at C3 more deshielded than the proton at C5. In 3-phenyl-1,2,4-thiadiazole, H3 resonates at 9.9 d, while H5 appears at 8.55 d [125]. The solvent effect on the 1 H NMR spectral data of a series of 1,2,4-thiadiazole derivatives has been determined by measuring the chemical shift differences observed in various solvents. For methyl and methylene groups linked to a sp2hybridized nitrogen, Dn shows a linear correlation with Hammett s constants, while the same groups attached to a sp3-hybridized nitrogen correlate with Taft s0 constants [122, 155]. 1 H and 13 C NMR data have been reported for 1,2,4-thiadiazolidines 281 [156]. S N

R

N

N R

Ar O

281 13

C NMR spectroscopy has been widely used to elucidate the structures of various 1,2,4-thiadiazoles and thiadiazolines [159–163]. More recently, 13 C chemical shifts of 3,4-disubstituted-1,2,4-thiadiazole-5-ones were determined [164]. Exceptionally good Hammett correlations of 13 C chemical shifts with s were obtained. The negative r values observed indicate p-polarization of C¼N, and C¼O bonds. Unequivocal assignment of all chemical shifts (1 H and 13 C NMR) has been performed using two-dimensional experiments such as HMQC for one-bond correlations and HMBC for long distance proton/carbon correlations [171].

14.3 1,2,4-Thiadiazoles

Solvent and concentration effects in 14 N NMR spectroscopy have been investigated [165, 166]. High precision 14 N NMR measurements are reported for all possible thiadiazole isomers in various solvents. Both solvent polarity and hydrogen bonding effects produce an increase in the nitrogen shielding. Analysis of the experimental data and molecular orbital studies indicates that an increase in the polarity of the solvent favors the delocalization of the lone pair electrons from the sulfur atom into the conjugated ring, thus leading to an increase in electronic charge at the nitrogen atoms. In the case of 1,2,4-thiadiazoles, nitrogen shielding ranges from 11 to 20 ppm, with the range for N3 approximately twice that for N2. The mechanism of the reaction and the formation of 1,2,4-thiazolidine N-oxide 284 by reaction of O-substituted benzamidoxime 282 with 4,5-dichloro-1,2,3-dithiazolium chloride (283) (Scheme 14.65) has been investigated by analysis of 13 C and 14 N NMR spectra of 15 N-labeled and unlabeled precursors (Scheme 14.66) [150].

Ph

Cl

NH2

+

NOH

Ph

Cl

S N S Cl 283

282

N

64%

N

O

CN

S

284

Scheme 14.65

Ph

NOH

15

NH3

Ph 15

Cl

NOH

Ph

MeNCO

NOCONHMe

15

NH2

NH2

283 OCOPh

Cl Ph 15 N

N S

Ph

O

CN

15 N

N S

O COPh

CN

Ph 15

H

Cl

N N

S

S

N

Cl

Scheme 14.66

The signal at d 110.9, corresponding to the unoxidized nitrogen atom, in the 15 N NMR spectrum of the N-oxide – and the signal at d 70.7, characteristic of heterocyclic N-oxides, in the 14 N NMR spectrum – clearly suggests that all the 15 N labels are on the unoxidized nitrogen atom.

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14.3.3.3 UV and IR Spectroscopy Data on IR and UV spectroscopy have been reported for some 1,2,4thiadiazoles [120]. Characteristic infrared absorptions are seen at 1560–1590 and 1490–1550 cm1 (ring skeletal vibrations), 1215–1270, 1080–1185, and 1020–1050 cm1 (CH in plane deformations), and 735, 795–860 cm1 (CH out-of-plane deformations) [167]. 1,2,4-Thiadiazoles show an absorption band in the UV spectra at 229 nm: the presence of amino groups in the ring induces a bathochromic shift (247 nm for 5-amino- and 256 nm for 3,5-diamino-1,2,4-thiadiazole). 14.3.3.4 Mass Spectrometry The electron-impact mass spectra of 1,2,3-thiadiazoles exhibit an intense signal for the molecular ion [139]. Moreover, the predominant fragmentation pattern follows two general pathways (a and b) as reported in Scheme 14.67. 3-Aryl-1,2,4-thiadiazole5-thiones 285 and 286 fragment much less than 3,4-disubstituted compounds 287, 288 [168]. R2

R1

N a 2 N S a1 R b S b 1

1

R CHNH

2

a1

N S

R1

N S S

a

285 :R1 = Ph; R2= H 1

or

or

R2N=CS

286 :R = p.MeC6H4; R = H

287 :R1= p.ClC6H4; R2= o.MeC6H4

288 :R1= p.NO2C6H4; R2= n.propyl

Scheme 14.67

3-Aryl-5-alkyl- or arylthio-1,2,4-thiadiazoles 289 have been shown to exhibit rather stable M þ . ions and relatively simple fragmentation patterns (Scheme 14.68), which are usually dominated by the R1CNS þ . ion, which is even the base peak. R

1

N a N S a1 2 b SR b 1

R2S 1

R CHNH

or

S

a

a1

289 R1SCN b Scheme 14.68

N

or

R2SCN b1

14.3 1,2,4-Thiadiazoles

j1297

The mass spectra of 1,2,4-thiadiazole 4-oxides 279 and 284 show as first fragmentation the loss of the oxygen atom, followed by the fragmentation observed for the corresponding deoxygenated compounds, which is the usual fragmentation of the 1,2,4-thiadiazole ring [150]. 14.3.4 Synthesis 14.3.4.1 1,2,4-Thiadiazolidines The most general synthetic entry to thiadiazolidinediones 292 starts from N-alkyl- or N-aryl-S-chloroisothiocarbamoyl chlorides 290, obtained by treatment of alkyl or aryl isothiocyanate with chlorine. Thus, the reaction of 290 with aliphatic or aromatic isocyanates gives the sparingly soluble 3-oxothiadiazolium salts 291, which, in the presence of moist air, hydrolyzes to 1,2,4-thiadiazolidine-3,5-diones 292 with evolution of hydrogen chloride (Scheme 14.69) [169, 170].

Cl2

1

R N=C=S

1

R

N

SCl

55-98%

Cl

R1 N

R2N=C=O Cl

290

R1 = Et, Bu, Ph, cycloexyl R2 = Et, Bu, iso-Pr, C8H17, p-MeC6H4, p-MeOC6H4

O S

N R2

Cl 291

R1 N O

O S

N R2

292

Scheme 14.69

Introduction of an imino moiety at the 5-position of the thiadiazolidine framework, leading to compound 295, has been achieved by the basic hydrolysis of urea derivative 294 (Scheme 14.70). This last compound was easily obtained following a described procedure of 5-aminophenyl-1,2,3,4-thiatriazole 293 rearrangement with isocyanates and isothiocyanates [171]. Treatment of 293 with ethoxycarbonyl isothiocyanate leads to thiadiazolidine 296.

N N N S

NHPh 293

75% EtCO2NC=S S EtO2C

Ph N N S 296

Scheme 14.70

EtNCO

O

Ph N N S

Et

NCONHEt 294

50% NaOH/MeOH

O NCO2Et Et

Ph N N S 295

NH

j 14 Thiadiazoles

1298

Alternatively, 5-imino-3-oxo-1,2,4-thiadiazolidines 298 have been obtained in good yields by addition of arylureas to benzoyl isothiocyanate and oxidation of intermediate 2-thiobiourets 297 with hydrogen peroxide (Scheme 14.71) [172].

O ArHN

ArCONCS NH2

80-92%

S

O Ar

CONHAr

N H

N H

76-87%

297

H N

O

H+, H2O2

N S

Ar

NCOAr

298

Ar = Ph, Tolyl Scheme 14.71

Similarly, amidinothioureas 300, obtained by reaction of aryl isothiocyanates with guanidines 299, have been converted into 3,5-diarylimino-1,2,4-thiadiazoles 303 by reaction with bromine in ethanol or by reaction with benzyl chloride followed by bromine treatment (Scheme 14.72) [173].

NAr ArHN

NH2

NAr S

ArNCS 21-63%

ArHN

299

N H

NHAr

BnCl 55-84%

NAr S ArHN

300

Br2

Ar = Ph, Tolyl ArN Ar

H N N S 303

NAr

N H 301

Br2

Bn

Ar NAr

43-75%

ArN

N

Br

N H 302

S

Bn NAr

Scheme 14.72

An alternative synthesis of amidinothioureas 305 involves the reaction of a-chloroformamidines 304 with substituted thioureas: oxidation of 305 with hydrogen peroxide leads to thiadiazolidine 306 (Scheme 14.73) [174]. The 1,2,4-thiadiazolidone system has also been prepared starting from other heterocycles by a cycloaddition–elimination sequence. The reaction of 5benzylimino-1,2,4-dithiadiazolidin-3-one 307 with isocyanates leads to the corresponding 1,2,4-thiadiazolidinone 308 with elimination of carbonyl sulfide (Scheme 14.74) [175]. An alternative way to obtain 5-imino-1,2,4-thiadiazole-3-ones 310 is based on the reaction of 5-imino-1,2,3,4-thiatriazolines 309, as masked 1,3-dipoles, with isocyanates via a cycloaddition–elimination process (Scheme 14.75) [176].

14.3 1,2,4-Thiadiazoles

S RHN

+

NH2

ArHN

R

NH

Cl

H N

S NH

22-65%

NHAr NH

304 R = H, Me, Et, Bn, Ph Ar = Ph, Tolyl HN

Ar N

HN S

H2O2 NH

R

16-73%

H N

Ar N NH

NH2 S

305

306 Scheme 14.73

Ph

Ph O

N S S

N

R1 NCO

36-97%

Ph

O

N

R1

N S

N

Ph

308

307 1

R = Ph, p-ClC6 H4, PhSO2, PhCH2 Scheme 14.74

Me N N NR1 N S

309

Me N N NR1 N S

Me N

R2NCO

O

-N2 7-95%

N S R 310 2

NR1

R1 = Me, Ph,CHMe2, CMe3 R2 = Et, n-Bu, t-Bu, Ph, PhCH2, PhSO2, p-ClC6H4, p-NO2C6H4, p-MeOC6H4 Scheme 14.75

Finally, 3-(phenylimino)-1,2,4-thiadiazolidin-5-ones 312 and 313 can be synthesized by reaction of substituted guanidines 311 with chlorocarbonylsulfenyl chloride (Scheme 14.76) [177]. Bicyclic imidazo[1,2-d][1,2,4]thiadiazol-3(2H)-one (316) was prepared by condensation of 2-amino- or 2-mercaptoimidazole (314) [152] with alkyl isocyanates, to give compound 315, followed by oxidative ring closure with bromine in triethylamine at ice cold temperature (Scheme 14.77). Tricyclic benzimidazo derivatives have been obtained by a similar pathway.

j1299

j 14 Thiadiazoles

1300

R1

Ph N N H

N H

ClSCOCl

Ph

Ph

Ph N

N

O

N S R

+

1

12-82%

Ph

R1 N N S

O

313

312

311 R1 = Me, Et, Bu, Ph, Bn

Ph

N

Scheme 14.76

N SH

N H

N O

314

Br2

N

SH

Et3N

N

Bu

92%

N

n-BuNCO ∆ 93%

N H 315

O

S N

Bu

316

Scheme 14.77

14.3.4.2 Dn1,2,4-Thiadiazolines 14.3.4.2.1 D2-1,2,4-Thiadiazolines D2-1,2,4-Thiadiazolines 320, the so-called Hector’s bases, have been synthesized in good yields by oxidation of N-arylthioureas 317, with hydrogen peroxide or other oxidizing reagents, via the intermediate dithioformamidines 318 and N-arylamidinothioureas 319 (Scheme 14.78) [178]. NH 2 S

N H

NH

H 2O2

Ar

S

ArHN

N S

Ar

318

317

Ar N

N H

Ar N

ArHN NH

320

80-90%

2

NH

S

NH 2

319

Ar = Ph, Tolyl Scheme 14.78

Usually, the preparation of 3,4-disubstituted-1,2,4-thiadiazole-5-ones 322 includes the reaction of amidoximes 321 with chlorocarbonylsulfenyl chloride in the presence of base as a catalyst (Scheme 14.79) [179] or the reaction with thiophosgene to afford 3,4-disubstituted 1,2,4-oxadiazoline-5-thiones 323, which, in the presence of a catalytic amount of copper powder, is converted into 322 (Scheme 14.80) [180].

14.3 1,2,4-Thiadiazoles

R2

R1 HO

N H

N

2

R

ClSCOCl Et3N

O

R1

N SCl

R2

-HCl

O

N OH

321

ClSCOCl

R = Me, Et, n-Pr, n-Bu, Ph R2 = Me, Et, n-Pr, n-Bu, Ph

R

R2 N

R2

N S 322 25-71%

O

O

N

N S O

1

1

R1

R1

N

R2

N S O SCOCl

O

N

R1

N Cl S O SCOCl

Scheme 14.79

R1

HO

N

321

N H

ClSCCl Et3N

R2

R2 N

R1

N O

R1 = Me, Et, n-Pr, n-Bu, Ph R2 = Me, Et, n-Pr, n-Bu, Ph 1

R

R2 N N S 322 50-80%

O

S

323 Cu0

-Cu0

R2 N

S O

R1

Cu1

N

Scheme 14.80

However, these methods require highly toxic reagents and often lead to a mixture of products. New methods have been developed from amidoximes 321 by a Lewis acid-mediated rearrangement (Scheme 14.81) [181]. The reaction of 2-hydroxylamino-4,5-dihydroimidazolium-O-sulfonate (323) with carbon disulfide took two different courses, dependent on the base–solvent combination. Thus, when the reaction of 323 was performed in DMF in the presence of an equimolar amount of triethylamine, 6,7-dihydro-5H-imidazo[2,1-c][1,2,4]thiadiazole-3-thione 324 was produced in 50% yield as a result of a tandem nucleophilic addition–electrophilic amination. In the presence of an excess of triethylamine, 324 underwent subsequent reaction with a second molecule of carbon disulfide to give di (5,6-dihydro-7H-imidazo[2,1-c][1,2,4]thiadiazole-3-thione-7-yl)methanethione 325. The resulting mixture contained 324 and 325 in a ratio of about 7 : 1 (Scheme 14.82) [182].

j1301

j 14 Thiadiazoles

1302

S

R1 HO

N

N

+

NH2

-Imidazole

N

N

N

H2N

321

R1

R1 = Ph, Bn, p-OMeC6H4, p-NO2C6H4 p-MeC6H4, m-MeC6H4, o-MeC6H4

H N

R1

-Imidazole

O

N S

HN

322 10-67%

S

LA

AL

N

N

HN S R1

N

N

N O

LA HN

O

LA N HN O

N

LA

S

R1

Scheme 14.81

N

H N

OSO3

CS2

H

N

Et3N

323

S

S

N S

S N

N

S

H N

S

N

11%

N S

S

Scheme 14.82

N S 326

N S

N

NH S 324a

S

324

PhCONCS Ac2O 74%

N

N

S

325

COMe N

OSO3

– SO4-2 74%

Et3N 2.3mole CS2 50% N

N

PhCH2Br

52%

82% COPh N

Ph N N S

N S 327

N S

N S 328

14.3 1,2,4-Thiadiazoles

The imidazothiadiazole 324 can exist in two likely (i.e., low-energy) tautomeric forms, the N7–H tautomer 324 and the N1–H tautomer 324a, which can interconvert via a 1,3-prototropic shift. Calculations [135] indicated that 324 has a relative energy 12.9 kcal mol1 below that of 324a. NMR spectroscopy showed that the low-energy tautomer 324 is also present in DMSO-d6 solution. The methylene groups of the imidazoline moiety are non-equivalent, and a NOE was observed between an upfieldshifted C6–H proton and the N–H proton. Compound 324 reacted in the normal manner with acetic anhydride and benzyl bromide (Scheme 14.82) to afford 326 and 327, respectively. The structure of 7-benzyl-6,7-dihydro-5H-imidazo[2,1-c][1,2,4]thiadiazole-3-thione (327) was confirmed by an X-ray crystallographic study. The reaction of 324 with benzoyl isothiocyanate carried out in THF in the presence of Et3N at room temperature led to the formation of the N7-benzoyl derivative 328 [182]. Bicyclic and tricyclic [1,2,4]thiadiazolines 329 and 331, respectively, have been synthesized starting from the corresponding [1,2,4]thiadiazol-3(2H)ones 316 and 330, by an exchange reaction with cyanogen bromide at room temperature, with extrusion of alkyl isocyanate (Scheme 14.83) [152].

N N O

N X–CN

S N

Bu

– BuNCO 66-96%

316

N

N S

N 330

Bu

N X

S N

X 329

X= Br, Tos, CH 2Br,NH2 CO2Me, COPh O

N

– BuNCO

N

76%

N

S N X

331

Scheme 14.83

14.3.4.2.2 D3-1,2,4-Thiadiazolines N-(2,3-Diphenyl-1,2,4-thiadiazol-5-(2H)-ylidene methanamine 335, SCH-202676, is a D3-thiadiazoline, identified in 2001 as an inhibitor of both agonist and antagonist binding to G protein-coupled receptors [183]. The synthetic approach moves from benzamide 332, which was converted into benzimidoyl chloride 333 by reaction with thionyl chloride. Substitution of chlorine with NCS, followed by addition of methylamine, afforded thiourea 334 in good yield. Finally, oxidation with bromine led to the target 2,3-diphenyl-5-methylimino-2H[1,2,4]thiadiazole hydrobromide 335 (Scheme 14.84) [184]. More recently, a new series of 335 were synthesized with different N-imino substituents [185]. Receptor–ligand binding experiments and stability studies

j1303

j 14 Thiadiazoles

1304

SOCl2

O HN

NaSCN

Cl

79%

MeNH2 88%

N

HN

NH S

N

Br2 N

79%

333

HBr

NMe

NHMe

332

S

335

334

Scheme 14.84

showed that these compounds are highly reactive sulfhydryl modifying agents rather than allosteric inhibitors. Bicyclic D3-1,2,4-thiadiazolines are formed in moderate yields by treatment of cyclic amidines 336 as 2-aminopyridine, 3-aminopyridazine, 2-aminobenzothiazole, 2-aminopyrimidine, and 2-aminothiazole with chlorocarbonylsulfenyl chloride (Scheme 14.85) [186].

H N

N

O

N

S

13-45%

Cl

338

337 NH2 N

O

N S

ClSCOCl H N

336 N

O

N

N

S N H

15-38%

N S

O

340

339

NH2 N 336

+

N

Cl

PhN

SCl 341

27-53%

N 342

S

O

Scheme 14.85

The products obtained depend on the mode of addition. When 336 is added to chlorosulfenyl chloride, derivatives 338 are isolated via the intermediate 337. Addition of chlorocarbonylsulfenyl chloride to 336 leads to 5-oxo derivatives 340, via the bis(intermediate) 339.

14.3 1,2,4-Thiadiazoles

j1305

Treatment of amidine 336 with 1-chloro-1-phenylimonomethanesulfenyl chloride (341) affords 3H-1,2,4-thiadiazoles 342. 14.3.4.2.3 D4-1,2,4-Thiadiazolines The most general synthetic approach to D4 -1,2,4-thiadiazolines is based on the ring closure of thiobiourets in the presence of different oxidizing agents. In this way, 5-amino-1,2,4-thiadiazole-3-ones 344 have been synthesized from 343 via N–S bond formation by treatment with hydrogen peroxide in alkaline solution (Scheme 14.86) [136, 158, 187].

R1

O

S

N H

N H

N H

R2

Ox 69-85%

O R1

343 R1 = Me, Ph, C(O)Ar R2 = H, Me

R2 NH

N N

S

344

Scheme 14.86

Other oxidizing agents such as molecular bromine [136] or N-bromosuccinimide [188] have been used for cyclization. Analogously, the oxidation with bromine of amidinothioureas 345, derived from 2-aminobenzimidazole, afforded the tricyclic benzimidazole[1,2-b]-1,2,4-thiadiazoline 346 (Scheme 14.87) [189]. O N N H

NH2

N

ArCONCS

N H

36-70%

S N H

Br2

O N H

Ar

N

19-65%

345

346

Ar = Tolyl, 4-MeOC6H4 Scheme 14.87

The reaction of arylthioamides 347 with phenyl isocyanate leads to arenethiocarboxamide 348, which can be converted into 5-aryl-3-oxo-2-phenyl-1,2,4-thiadiazoline (349) by direct oxidation with bromine (Scheme 14.88) [190]. S H2N

NHAr S

PhNCO 26-75%

347 Ar = MeOC6H4, EtOC6H4 Scheme 14.88

Ar

O N H 348

N H

Ph

Br2 15-70%

O Ph

N N S 349

Ar

NH

S

N

Ar

N

j 14 Thiadiazoles

1306

14.3.4.3 1,2,4-Thiadiazoles In general, 1,2,4-thiadiazoles are prepared by the appropriate intra- or intermolecular ring closure reactions, starting from different compounds containing nitrogen and/ or sulfur atoms. The main synthetic route towards 3,5-diaryl- or dialkyl-1,2,4-thiadiazoles is based on the oxidation of thioamides derivatives [170, 191]: various oxidizing agents as halogens, hydrogen peroxide, or thionyl chloride promote the oxidative cyclization in moderate yields. More recently, the condensation reactions of thioamides (as well as thionicotinamide and isothionicotinamide) have been performed in the presence of an oxidative DMSO–HCl mixture to give symmetrically substituted 1,2,4-thiadiazoles 350 (Scheme 14.89) [192].

S R1

R1

Ox

S

N H2N

NH2

S

S R

1

R1

SH N

R1

NH R1

90%

S N 350

1

R = Ph, 3-pyridyl

N

R1

Scheme 14.89

Under oxidative cyclization conditions, N-substituted thioureas have also been converted into 1,2,4-thiadiazole derivatives [192]. Thus, 3,5-diamino-1,2,4-thiadiazoles 352 (Dost’s bases) [193] have been obtained in 48% yield, as a result of isomerization, by heating a suspension of 5-imino-4-phenyl-3-phenylamino-4H1,2,4-thiadiazoline 320 (Ar ¼ Ph, Hector’s base) in ammonia alcohol solution at 135
C (Scheme 14.90) [194].

317

H 2O2

ArHN

51-72% Ar = Ph, Tolyl

Ar N N S 320

NH

NH3

H2N ArHN

NH2 N S 351

NAr

ArHN 48-56%

N N S

NHAr

352

Scheme 14.90

The appropriate Hector’s base has been obtained by oxidation of 1-phenyl-1phenylamidinothiourea bromohydrate 319 (Scheme 14.78) with molecular bromine (73% yield) [178] or by oxidation of phenylthiourea 317 with hydrogen peroxide (70%) [195], tert-butyl hypochlorite (46%) [196], dioxane dibromide (85%) [197], or diaryl telluroxide (97%) [198]. Compound 352 has also been synthesized by reaction of 3,5-dichloro-1,2,4-thiadiazole with boiling aniline for 100 h [199]. In comparison with all these oxidative processes needing preliminary, often laborintensive synthesis of precursors, a recent method affords 352 starting from arylthioureas 317 at room temperature by a single-step reaction [200]. The process

14.3 1,2,4-Thiadiazoles

uses [bis(acyloxy)iodo]arenes as a more specific oxidant reagent than the traditional ones (Scheme 14.91).

S 2

NH2

PhI(OCOCF3)

NHAr

S

NH ArHN

N H

317

N H

ArHN

Ar

70-75%

N

352

353

Ar = Ph, Tolyl

NHAr

N S

Scheme 14.91

Reaction of nitrile sulfides 354 with acyl cyanides 356 provides a useful access to 5acyl-1,2,4-thiadiazoles 357 [201]. The synthetic route is based on the 1,3-dipolar cycloaddition of short-life nitrile sulfides 355, generated in situ by thermal decarboxylation of 1,3,4-oxathiazol-2-ones 354 [202], to strongly activated dipolarophiles such as the acyl cyanide (Scheme 14.92). O O

S O

R N

R1

N S

R1

O

2

CN 356

17-91%

N

357

355

354

S

R2

N R1

1

R = Me, Ph, 4-MeC 6H 4, 2-furoyl, CH3 (CH2 )5 R 2 = Ph, Tolyl Scheme 14.92

Analogously, the reaction of 354 with tosyl cyanide (358) leads to the key intermediate 359, which, by displacement of the tosyl group with ammonia, provides the 5-amino-1,2,4-thiadiazoles 360 (Scheme 14.93) [203].

Me R1

O N

S

O

354

1) ∆ / Decaline 2) p.Tolyl-SO 2CN 358 85%

R1 = 2,6-di-tert-butylphenol Scheme 14.93

R1

N

N

S S O O

359

NH3 78%

R1

N N

S

360

NH2

j1307

j 14 Thiadiazoles

1308

5-Amino-1,2,4-thiadiazoles 362 have also been generated by thermolysis of 2thiocarbamoyl-5-phenyltetrazoles 361 (Scheme 14.94) [204]. Ph

N N

S

N

N 361

∆

S

Ph N3

NR2

Ph

- N2

N

NR2

N

N

NR2

S 362

R = Me, Et, Ph, Bn

37-65%

Scheme 14.94

A more recent synthetic strategy towards 3,5-dialkyl 1,2,4-thiadiazoles 365 involves the amination-cyclization of N0 -(thioaroyl)-N,N-dimethylamidines 364 with an aminating agent such as hydroxylamine-O-sulfonic acid (HSA) or O-(mesitylenesulfonyl) hydroxylamine (MSH) (Scheme 14.95).

S R

1

NH2

+

MeO R2

S

OMe NMe2

R1

NMe2 N

XSO3NH2

R2 HSA: X=OH MSH: X=mesityl

364

363 R1 = R2 = Me, Et, Ph

H2N R1

S

R1

NMe2 N

S N

R2

N

R2

SO3X

365 19-66%

Scheme 14.95

Amidines 364 are prepared by reaction of thioamides with N,N-dimethylformamide dimethyl acetal or N,N-dimethylacetamide dimethyl acetal (363) [205]. 1,2,4-Thiadiazole derivatives have also been synthesized by skeletal rearrangements of different five-membered rings. In this way, methyl 2-(5-alkoxycarbonylamino-1,2,4-thiadiazol-3-yl)acetates 368 have been prepared by reaction of 3-amino-isoxazole 366 with isothiocyanates, following skeletal (Dimroth) rearrangement of the intermediate thiourea derivative 367 (Scheme 14.96) [206]. NH 2 MeO

O

HN

KSCN/ClCO 2 R

N

366 R = Me, Et

MeO

O

N

367

NHCO 2R S

MeO 2C

N N

S

NHCO 2R

368 17-69%

Scheme 14.96

5-Amino-3-(a-nitroalkyl)-1,2,4-thiadiazoles 371 have been obtained by thermal rearrangements of 3-substituted 4-(3-ethoxycarbonylthioureido)-1,2,5-oxadiazole 2-oxides 370 (Scheme 14.97). The reaction was performed by refluxing a mixture of aminofuroxans 369 with ethoxycarbonyl isothiocyanate [207].

j1309

14.3 1,2,4-Thiadiazoles R

H2N N

EtO2CNCS

N O O

H N

EtO2CHN

N

S

369

R

R

O2N

N O O

NHCO2Et

S

371

370

R = Me, Ph, COMe

N N

40-59%

Scheme 14.97

An interesting access to 3-phenyl-5-substituted-1,2,4-thiadiazoles 374 has been exploited by the photoinduced molecular rearrangement of five-membered heterocycles containing a N–O bond. In fact, photolytic species, which originates from the ring cleavage of 1,2,4-oxadiazoles, react with sulfur reagents by forming a new N–S bond. Thus, irradiation of 5-amino-3-phenyl-1,2,4-oxadiazole (372) in the presence of thiourea leads to 1,2,4-thiadiazole 374, through the intermediate 373 (Scheme 14.98) [208]. Ph

Ph

hν

N

N

N

NH2

O

Ph

N O

N

NH2

372

S N O

H2N

NHR

Ph

NH2

N N

373

NHR

S

374

R = H, Me, Ph

45-67%

Scheme 14.98

N-Unsubstituted-N0 -chlorobenzamidines (375, R1 ¼ H), by treatment with potassium S-methyl cyanimidodithiocarbonate 376, afford 2-arylimidoyl-3-imino-5methylthio-1,2,4-thiadiazoles 378 [209]. In contrast, substituted amidines (375, R ¼ aryl and methyl) give 5-cyanimino-4,5-dihydro-3-aryl-1,2,4-thiadiazoles 380 containing in the ring both the nitrogen atoms of amidines (Scheme 14.99) [210]. NCl Ar

NCN

+

NHR

1

KS

R1=H

Ar HN

SMe 376

375

HN S

SMe NCN

377

HN 18-60%

R =Aryl, Me

379 Scheme 14.99

- HSMe 15-58%

R1 N

Ar N

S 380

N N

NH

1

NHR1 SMe Ar NCN N S

Ar

NCN

Ar = Ph, Tolyl

S 378

SMe

j 14 Thiadiazoles

1310

At the same time, aminothiadiazole 382 has been obtained by cyclization of amidine 381 with potassium thiocyanate and bromine (Scheme 14.100) [211, 212]. N S

KSCN, NaOMe, Br2

NH

19%

NH2

N

NH2

382

381 Scheme 14.100

14.3.5 Reactivity

1,2,4-Thiadiazoles are aromatic in nature and are to be considered as p-excessive heterocycles with relatively p-deficient C-atoms. Electrophilic substitutions at the Catoms could not be achieved. The p-electron density at the 5-position, calculated by the HMO method, is markedly lower than that at the 3-position, thus influencing many of the properties of substituted derivatives. As an example, 5-halo derivatives are susceptible to replacement of halogen by nucleophiles, whereas 3-halo derivatives are relatively inert. Thus, 5-chloro-1,2,4-thiadiazole (383) undergoes nucleophilic substitution with silver fluoride to give the 5-fluoro derivative 384 (Scheme 14.101).

N

F Cl

S

N

383

F Cl

N S

N

N

–Cl F

S

N

384

Scheme 14.101

In the case of 3-chloro-1,2,4-thiadiazole, delocalization of the negative charge in the intermediate with involvement of both nitrogen atoms is not possible; for this reason, it does not react or reacts only slowly with nucleophiles. The parent compound 246 is quite sensitive to acid and bases, as well to oxidizing and reducing agents. It reacts rapidly with cold alkali hydroxides, undergoing ring opening with formation of ammonia, hydrogen sulfide, and sulfur. Treatment of 246 with a weak base (K2CO3) in D2O gives the 5-deuteroderivative 385 (Scheme 14.102) [122]. With hydrochloric acid, hydrolytic ring-opening occurs via the 1,2,4-thiadiazolium ion. Substituents in the 3- and 5-positions of 1,2,4-thiadiazoles exert a marked stabilizing influence: for example, the 3,5-diphenyl derivative resists the action of hot mineral acids and prolonged boiling is required for attack by alkalis [178].

14.3 1,2,4-Thiadiazoles

D2O

N S

N

N D

K2CO3

N

S 385

246 Scheme 14.102

Catalytic and dissolving metal reductions usually cleave the nucleus at the N–S bond by a reaction that can be considered as the reverse of its synthesis by oxidative cyclization of amidinothio-derivatives (Section 14.3.4). For example, reduction of the diamino derivative 386 affords amidinothiourea (387), from which 386 may be prepared by oxidation (Scheme 14.103). NH2

N H2N

S

N

[H]

H N

H2N

[O]

NH

NH2 S

387

386 Scheme 14.103

Reduction of 3,5-diphenyl-1,2,4-thiadiazole (388) results in the loss of sulfur and formation of benzamidine 389 (Scheme 14.104) Ph

N Ph

S

[H]

H N

Ph

N

Ph

NH 389

388 Scheme 14.104

14.3.5.1 Aromatic Ring Reactivity 1,2,4-Thiadiazoles are weak bases. Methylation with iodomethane occurs at N4; when trimethyloxonium tetrafluoroborate is used as methylating agent, the reaction takes place at both nitrogen atoms, leading to the diquaternary salt 390 (Scheme 14.105) [213].

Me

N S

N

2 [Me3O]BF4

246 Scheme 14.105

60%

N S

N

390

Me

j1311

j 14 Thiadiazoles

1312

Methylation of 5-amino-1,2,4-thiadiazoles 360 (R ¼ H, Ph) affords the N4 derivatives 391; further methylation gives 4-methyl-5-methylimino-3H-1,2,4-thiadiazolines 392 (Scheme 14.106) [214]. On warming in ethanol, compound 391 (R ¼ H) undergoes a Dimroth rearrangement to give 393.

H2N

Me

R

N S

N

MeI HN

R

N S

360

Me

MeI

N

MeN

391

S 392

N

67-70%

EtOH ∆

R = H,Ph

R

N

Me EtO R N N H HN S

OEt NHMe

R N

S

N

–EtOH

NH

MeHN

R

N S 393 30-93%

Scheme 14.106

The N4 derivatives 394, obtained by reaction of phenacyl bromide with 5-amino1,2,4-thiadiazoles 360, spontaneously cyclizes to the fused imidazolothiadiazoles 395 (Scheme 14.107) [178]. R

N H 2N

S

N

PhCOCH2Br

PhOC H2 N

360

R

R

N S

N

Br

–H2O

N

–HBr

394

N S

N

Ph

395

R = Me, Et, Ph, Bn

62-85%

Scheme 14.107

Reaction of 3-amino-1,2,4-thiadiazole (396) with trimethyloxonium tetrafluoroborate occurs at N2 to yield the thiadiazolium salt, which, on basification, undergoes a Dimroth rearrangement to give the 5-methylamino derivative 397 (Scheme 14.108) [215].

N S

NH2 [Me3 O]BF 4 N

396

N

NH2 N Me S

BF4

NaOH

N MeHN

S

N

397 81%

Scheme 14.108

14.3 1,2,4-Thiadiazoles

Analogously, the sulfonamide 398 by reaction with methyl fluorosulfonate gives the N2 derivative 399, together with the mesoionic compound 400 (Scheme 14.109) [133]. NHSO2 R

N Ph

S

N

MeOSO2 F

NSO 2R

N Ph

N Me

S

398

+

Ph

S

399

N Me

400 17%

15%

R = Ph, p-MeC6 H 4

NSO2 R

N

Scheme 14.109

Similar behavior has been observed for 3-hydroxy-5-phenyl-1,2,4-thiadiazole (401). The reaction with dimethyl sulfate and sodium hydroxide leads to N2 methylated derivative 402; when methylation was carried out with toluene-4-sulfonate, 402 was obtained together with the meso-ionic compound 403 (Scheme 14.110) [133]. OH

N Ph

S

N

O

N

p-MeC6H4SO3Me Ph

19%

S

N Me

+

Ph

402

401

O

N S

N Me

403

Me2SO4,NaOH 16% Scheme 14.110

The reaction of 3 substituted 1,2,4-thiadiazole-5-thiols (404) with formaldehyde and with arylsulfonyl chlorides leads to N4 derivatives 405 and 406 (Scheme 14.111) [216]. HOH2C S

R

N S

N

405

19-43%

R

N

HCHO HS

S

N

404

ArSO2Cl 23-65%

ArO2S S

R

N S

N

406

R = Me, Et, Ph Ar = Ph, Tolyl Scheme 14.111

In general, hard nucleophiles attack at the C5 carbon atom of 1,2,4-thiadiazoles, while soft nucleophiles react at the sulfur atom.

j1313

j 14 Thiadiazoles

1314

For examples, nucleophilic attack at C5 has been suggested as the initial step in many ring-opening reactions leading to linear products that, according to the substituents, can recyclize to other heterocyclic systems [120]. Thus, 3,5-diamino1,2,4-thiadiazole (386) upon treatment with hot alkali undergoes a nucleophilic attack at C5 to give the proposed intermediate 407, which affords, by extrusion of sulfur, the amidinourea (408) (Scheme 14.112). The stability of 5-alkylamino and 5-arylamino homologues is considerably higher; thus, the reaction does not occur even after several hours refluxing in 3N sodium hydroxide solution. NH2

N H2N

S

OH, ∆

N

H2N

NH2

HN

H O

386

S

N

–S

H N

H2N

good yields

NH

NH2 O

408

407

Scheme 14.112

2-Methyl-3,5-diphenyl-1,2,4-thiadiazolium chlorosulfate (409) is cleaved by alkoxides to give the benzimidate 410 (Scheme 14.113) [167]. Ph

N Ph

S

RO

N Me

Ph

O R

409

Ph

N S

N

Me

–S 70%

Ph

N Ph

OR

N Me

410 R = Me, Et

Scheme 14.113

Primary and secondary amines also function as hard nucleophiles and attack at the C5 position of 409 to yield the open-chain salts 411; when hydrazines and hydroxylamines are used, the initially formed salts cyclize to give a 1,2,4-triazole or oxadiazole 412 (Y ¼ N or O) (Scheme 14.114) [131]. A carbon nucleophile, the dicyanomethanide ion, also attacks at the C5 position of 409; the open-chain product 413 cyclizes to the dihydropyrimidine 414. On further treatment with dicyanomethanide ion or aqueous base, a Dimroth rearrangement occurs to pyrimidine 415 (Scheme 14.115) [131]. Soft nucleophiles attack at the sulfur atom. For example, 3-hydroxy-5-phenyl-1,2,4thiadiazole (402) reacts with acetic anhydride in the presence of DBU at 130
C to give thiazole 417 (Scheme 14.116) [215]. When the reaction is carried out at room temperature, acetylation occurs at the N2 position to give compound 418 in low yields (Scheme 14.117) [215]. However, the most important nucleophilic attack at the sulfur atom is related to the ability of 1,2,4-thiadiazoles to act as a class of small heterocyclic thiol trapping agents. In fact, heterocyclic compounds possessing a N–S bond are cleaved by thiolates to form compounds such as 419 via a disulfide intermediate (Scheme 14.118) [131].

14.3 1,2,4-Thiadiazoles

Ph

N Ph

S

SO3X

R1R2NH

Ph

N Me

Ph

N

N R R2 1

–S

N

S

Ph

N

1 2

Me

R RN

N Me H

Ph

SO3X

411

409

j1315

R1 = H, (CH2)5 R2 = Ph, CH2Ph, (CH2)5 N Ph

Ph

Ph

Ph

N Me NYH H

SO3X

411

N

Y HN CH3

Ph

N

-MeNH2 Ph

H

Y

N

412 59-76%

Y= NH, NPh, O Scheme 14.114

N Ph

S

Ph

CH(CN)2

N Me

60%

N

Ph Me N H

N

Ph

Ph

CN

(CN)2HC

60%

NH

Me

N

415

N N

Ph

Me N

N

CN NH

413

409

N

Ph

CN

SO3X

Ph

Ph

414

Ph

Ph

(CN)2HC

CN NHMe

Me

N N

Ph CN

NH

Scheme 14.115

OH

N Ph

S

N

401

Ac2O, DBU 130 °C

HO

N NH

S O

O O

416 Scheme 14.116

– CO2

Ph

O

N

AcHN S H2 C

Ph

AcHN

N S

417 6%

Ph

j 14 Thiadiazoles

1316

OH

N Ph

S

O

N

Ac2O, DBU

N

Ph

S

N Ac

418 3%

401 Scheme 14.117

Ph

N Ph

S

PhS

N Me

Ph

N Ph

S

N Me

-PhS

N Ph

N Me

+ PhSSPh

PhS

409

S

Ph

H2O

H Ph

N S

Ph N Me 419 63%

Scheme 14.118

It has been widely reported that three different families of 1,2,4-thiadiazoles are able to react with enzyme cysteine residues to form a disulfide adduct, thus inhibiting the enzyme (Scheme 14.119) [127–129].

Y

N G

S

N 420a

N

S N

S

N N

Y 420b

N

N

Y 420c

Enzyme-SH

Y

N G

S S

NH Enzyme

Scheme 14.119

The design of inhibitors based on the monocyclic 1,2,4-thiadiazole scaffold 420 involves the use of substituent G as a recognition arm for the enzyme binding, and the substituent Y for tuning the reactivity of the ring opening. The presence of a fused ring in bicyclic 420b and tricyclic 420c derivatives is preferred for the inhibition of certain enzymes such as H þ /K þ ATPase.

14.3 1,2,4-Thiadiazoles

j1317

14.3.5.2 Reactions of 1,2,4-Thiadiazolidines 2,4-Dimethyl-1,2,4-thiadiazolidine-3,5-dithione (421) isomerizes in acid solution to 4-methyl-5-(methylimino)-1,2,4-dithiazolidine-3-thione (422): the reverse reaction occurs in alkaline media [163]. Compounds 421 and 422 are interconvertible also in the presence of electrophilic nitriles and give 1,2,4-thiadiazoline-5-thiones 424 as final products. The interconversion has been rationalized on the basis of a cycloaddition–elimination mechanism that involves hypervalent sulfur intermediates (Scheme 14.120). Me N

S Me

R

422

Me

N

S

S S

N

C

Me

R

S

S

N

S

N S N

C

R

N

R

R Na N

CS

S N

MeN S

S N N Me

R

R

S S

N

423

CN

S

N N

S N

R RC

N

R Me R

N

Me

S

N

MeN Me

Me

421

Me

422

S

S

S S

C

N

N S

–R

C

N

MeN

N aN C S

Me N

Me acid

S

Me R

S

N N

S

N R

N N S

N

C

–R

R = Ph

421 Scheme 14.120

Substituted 2,4-diimino-1,2,4-thiadiazolidines 425 isomerize under acidic conditions to 2-guanidinobenzothiazoles 427. The suggested mechanism involves the protonation of 425 at N2, followed by the N–S bond cleavage to 426 and subsequent electrophilic attack of the sulfur at the aromatic ring (Scheme 14.121) [167]. 14.3.5.3 Reaction of D2-1,2,4-Thiadiazolines Hector’s base, 3-arylamino-4-aryl-5-imino-1,2,4-thiadiazole (320), undergoes a basecatalyzed Dimroth rearrangement to give Dost’s base 352 (Scheme 14.90); the reduction of 320 under mild conditions (H2S/25
C) gives amidinothiourea 428, which hydrolyzes to diphenylguanidine (429). Compound 429 can be obtained directly from 320 by reduction under drastic conditions (Scheme 14.122) [178]. Hector’s base forms a 1 : 1 adduct (430) with CS2 [217], while reaction with electron-deficient alkynes gives 2-arylaminothiazoles 431 (Scheme 14.123) [120].

424

S

j 14 Thiadiazoles

1318

Ph N

PhN Ph

N S

NPh

N S Ph H

425

Ph

N

N PhHN

Ph N

PhN

H

H

Ph N

PhN

S

PhN

NPh

NPh

N S

427

426

Scheme 14.121

PhHN

N

NHPh

N S

EtOH

Ph

Ph N

PhHN

Zn, HCl NH

N S

NH3

PhHN

- HCNS

NH 429 55%

320

352 64%

NH

H2S

H

Ph PhHN

N NH

NH2 S

428 67% Scheme 14.122

S

NPh

N S S

N Ph 430

Scheme 14.123

NH2

CS2 68%

PhHN

Ph N N S 320

X NH

X 70%

X = CO 2 Me

X

N

X

S 431

NHPh

14.3 1,2,4-Thiadiazoles

It has been suggested [120] that these reactions proceed via a stepwise mechanism (Scheme 14.124).

Ph N

PhHN

X

NH

N S

X

Ph N

PhHN

X

N

N S

H

X

320 X = CO2Me

X

X

N

NHPh

S

X

- PhNHCS

N 70%

431

Ph

H

S

N

X

Scheme 14.124

An analogous nucleophilic substitution pattern has been proposed for the reaction of 3,4-disubstituted 5-imino-D2-1,2,4-thiadiazolines with arylcyanamides and imidates. These reactions give rearranged products that result from bond switching at hypervalent sulfur intermediates [218]. Thus, treatment of 432 with ethyl acetimidate leads to derivative 433, which on methylation with Meerwein’s reagent (Me3O þ BF4) affords the salt 434. The structure of compounds 433 and 434 has been confirmed by X-ray analysis (Scheme 14.125) [219]. EtO

Me N

NH

N S

Me

NH

Me

N N S

N HN

N

N

N

S N H

432

Me N

TFA

N

N S MeHN 434 75% Scheme 14.125

BF 4

Me N N S

N MeN

Me 3OBF4

N N S

Me N HN

433 60%

j1319

j 14 Thiadiazoles

1320

Bond switching rearrangement using the propensity of sulfur to assume a hypervalent state has been observed in the reactions of bicyclic thiadiazolines 435 with nitriles: an exchange of nitrile units has been observed to give 436 (Scheme 14.126) [220]. RCN +

N

R1

N

S

R

N

N

N R

1

N

S

R1 CN +

N R

N

N N

S

436

435 R = Me R1 =H, Me, Ph, 4-NO2 C6 H4, 4-pyridyl, CH2OMe, 2-OHC6H4, CD3, CH=CHCN

62-82%

Scheme 14.126

The products 438 of the addition of nucleophiles (i.e., alcohols, amines) to the cyano group of 5-(cyanoimino)thiadiazolines 437 undergo a Boulton–Katritzky rearrangement, followed by the elimination of a nitrile from the intermediate 439 to give thiadiazoles 440 (Scheme 14.127) [221]. R2

R1

N

NCN

N S

HNu

R1

R2 N

N

N S

Nu

HN 438

437 R 1 = Me, Et, Ph, Bn R 2 = Me, Et, Ph, Bn

Nu

N N S

440 19-65%

R2 NH

Nu

N N S

R2 N

R1

HN 439

Scheme 14.127

14.3.5.4 Reaction of D3-1,2,4-Thiadiazolines D3-1,2,4-thiadiazolines react with electrophilic reagents to give rearrangement products. As an example, treatment of thiadiazoline 441 with trichloroacetonitrile affords a mixture of tautomers 443 and 444, through the intermediacy and rearrangement of imine 442 (Scheme 14.128) [222].

14.3 1,2,4-Thiadiazoles

R1

N

CCl3CN

NH

N S Me

R1

Me

N N S

441

N

CCl3

HN 442

1

R =Me, Bn

Cl3C

Cl3C

N

N

1

R N S MeHN

N S

444 64-73%

H N

N

R1

MeN 443

Scheme 14.128

Thiadiazolines 441 have been acylated in the presence of triethylamine [223]. The use of diphenylketene as acylating agents leads to 445 which, by heating in polar solvents, rearranges to D2-thiazolin-4-one 446, whose structure has been confirmed by X-ray analysis. A similar rearrangement is observed when 441 is reacted with DMAD to give 447 (Scheme 14.129). R1

N

NH +

N S Me

Ph Ph

R1 C O

N

N

N S Me

Ph Ph

O

445

441 DMAD MeO2C MeO2C

N S

N

MeHN

R1

O

N

Ph Ph

S

447 56-76%

N

R1

MeHN 446

R1 = Ph

48-62%

R1 = Me, Ph, p-MeC6H4, p-MeOC6H4, CH(CH3)2 Scheme 14.129

14.3.5.5 Reaction of D4-1,2,4-Thiadiazolines Bond-switching rearrangement via hypervalent sulfur occurs when 5-anilino-2benzyl-3-oxo-D4-1,2,4-thiadiazoline (448) reacts with ketenes (or isothiocyanates or

j1321

j 14 Thiadiazoles

1322

carbon disulfide) and nitriles to give the products 449 and 450, respectively (Scheme 14.130) [224]. Ph N O

R

N S

N

RCN Et3N

Y

O

N

Bn N S

NHBn

NHPh

X C Y

O PhHN

448

450 64-90%

Ph N

X S

N 449 61%

R = Ts, CCl 3 X = NEt, S, Ph2C, (EtO2C)2C Y = S, O, NCOPh, NCO2Et, NC6H4NO2(p) Scheme 14.130

2-Benzyl-5-chloro-1,2,4-thiadiazole-3-one (451) and 2-aminobenzyl cyanide (452) in ethanol containing triethylamine react to afford the intermediate 453, which, through yet another example of bond switching, gives the indolinothiadiazolone 454 (Scheme 14.131) [225].

O

NH2

N

Bn N S

Cl

+

452

N

HN

EtOH CN

451

Et3 N O

N

S N

N O

N

S N NH

Bn

Bn

453

454 60%

Scheme 14.131

D4-1,2,4-Thiadiazolines are readily cleaved at the N–S bond under very mild conditions to give thiobiouret by a reaction that is inverse to that reported in Scheme 14.86. 3-Imino-1,2,4-thiadiazoline provides example of reductive ring cleavage in which the products immediately recyclize to new heterocyclic system. Thus, the D4-1,2,4thiadiazoline 455 is cleaved with H2S to give triazines 456 and 457 (Scheme 14.132) [167]. 14.3.5.6 Reactions of Substituents Owing to the lower electron density at the 5-position of the 1,2,4-thiadiazole ring with respect to the 3-position, methyl or methylene groups attached at C5 show a marked acidity, which promotes different reactions patterns, following hydrogen abstraction by bases. In fact, the resulting carbanions, stabilized by conjugation, react, for

14.3 1,2,4-Thiadiazoles

NH2 HN HN Ph

H 2S

N

N

SMe

S

HN

N

SMe

Ph

-H 2S

N

SH

Ph

NH

N SMe

N 456

455

52%

-MeSH NH2 N Ph

N SH

N 457 45%

Scheme 14.132

example, with aromatic aldehydes to give 5-styrylthiadiazoles 458, with CO2 to yield the carboxylic acids 459, and with carboxylic acid esters to afford the keto derivatives 460 (Scheme 14.133) [120]. 1

R

1

1

R

N Ar

S

N

N

-H ArCHO

R

Me

-H

N

S

2

R CO 2R

2

3

R OC

N S

N

460

458 36-72%

35-70% -H CO 2

R 1 = Me, Ph, Bn R 2 = Me, Ph, Bn R 3 = Me, Et

1

HO 2C

R

N S

N

459 26-65% Scheme 14.133

Analogously, treatment of the methyl ester 461 with triethylamine and tosyl azide leads to diazoester 462 through the formation of an intermediate carbanion (Scheme 14.134) [226]. 3-Methyl-1,2,4-thiadiazole is less acidic and will not undergo the above reported reactions.

j1323

j 14 Thiadiazoles

1324

Me

N

MeO2C

S

N

Et3N

MeO2C

TsN 3

N2

27%

461

Me

N S

N

462

Scheme 14.134

According to standard procedures, 3-alkyl-1,2,4-thiadiazole-5-carboxylates 463 are transformed into hydroxymethyl derivatives 464, primary amines 465, and tertiary amines 466 (Scheme 14.135) [226].

EtO O

R

N S

N

R NaBH 4

N

N

MeSO 2Cl OH

S

N

N

S

NMe 2

466

464

463

Me 2NH

R

55-76% Phthalamide DEAD, Ph3P N 2H 4

R = Me, Ph, Tolyl

R

N

N

S

NH2

465 23-69% Scheme 14.135

3-Amino-1,2,4-thiadiazoles are alkylated at N4 by treatment with MeI, while methylation of 3-amino derivatives with trimethyloxonium tetrafluoroborate produces the N4 quaternary salt (Section 14.5.5.1): the obtained compounds can undergo a Dimroth rearrangements (Schemes 14.106 and 14.108). In contrast, harder electrophiles, such as benzydryl and thrityl chlorides, alkylate 3-amino and 5-amino derivatives at the amino functionality [227]. 3-Amino and 5-amino-1,2,4-thiadiazoles are acylated under the usual conditions at the amino group. Moreover, they easily react with isocyanates, carbamates, and chloroformates (Scheme 14.136); the 5-amino derivatives 467 and 468 are used as herbicides and bactericides [120]. A bond-switching reaction, already described in the Section 14.3.5.2 (Scheme 14.120) for 1,2,4-thiadiazolidines, can occur at the p-hypervalent sulfur atom of 5-amino derivatives. In fact, when compounds 360 were reacted with aliphatic or aromatic nitriles, a mixture of 1,2,4-thiadiazoles 470 and 471 via the intermediate 469 were obtained (Scheme 14.137) [167].

14.3 1,2,4-Thiadiazoles

R1 N

N NH

S

R1

Ethyl Chloformiate

N

N

S

OEt

O

RNCO

R1 N

NH2

N NH

S

NHR

O

468

360

467

42-76%

25-60%

1

R =R = Me, Ph, Bn Scheme 14.136

R

N H 2N

S

R1CN

N

R

N S H

115

R

N

N

R1

N H

224

N

N N

S H2N

R1

225 29-70%

R = R1 = Me, Ph, Bn

R1 N

N S

N

H2N

R

226 32-75% Scheme 14.137

5-Nitrosoamino-1,2,4-thiadiazoles are moderately reactive and can be converted into different functional groups by reaction with the appropriate reagents [120]. For example, the 5-hydrazino-1,2,4-thiadiazoles 473 can be easily prepared by simple reduction with LiAlH4 of the corresponding nitrosoamine 472. Compounds 473 are stable in acidic or basic conditions and can be transformed into the corresponding hydrazones by reaction with suitable carbonyl compounds. In contrast, the 3-hydrazino derivatives 474, obtained by ring closure procedures, are very sensitive to both acids and bases, giving 1,2,4-triazoles 475 by sulfur extrusion (Scheme 14.138). 5-Amino-1,2,4-thiadiazoles 360 can be diazotized, by treatment with sodium nitrite, to give the diazonium salts 476. These compounds, because of the strong electron attraction of the 1,2,4-thiadiazole ring, are particularly reactive and can even couple with the hydrocarbon mesitylene, leading to the monoazo dye 477 [227], or can be transformed into the 5-azido derivatives 478 by treatment with sodium azide (Scheme 14.139).

j1325

j 14 Thiadiazoles

1326

R1

N ONHN

S

N

56-80%

R1

N

LiAlH4 H2NHN

S

N

473

472 R = Me, Ph, Tolyl NHNH2

N Me

S

H

N

or OH Me

–S good yields

474

NH2

N N H

N

475

R =, Me, Ph, Tolyl Scheme 14.138

R1

N H 2N

S

N

NaNO2 H

R1

N N2

476

360 R1 = Me, Ph

N

N

S

R1

N

–H

N

S

N

477 48-76%

NaN3 R1

N N3

S

N

478 45-90% Scheme 14.139

Both 3- and 5-hydroxy-1,2,4-thiadiazoles are generally acidic compounds, comparable to phenol and nitrophenol, respectively. The mercapto-1,2,4-thiadiazoles are even more acidic [178]. 3-Hydroxy-1,2,4-thiadiazoles 253 react with electrophiles either at the hydroxylic function or at N2. Normally, hard electrophiles (acyl chlorides) attack the oxygen of the hydroxyl group, giving rise to 3-acyl derivatives 479, while soft reagents (acid anhydrides) attack the N2 position, giving rise to 1,2,4-thiadiazolin-3-ones 480 (Scheme 14.140) [167]. As already reported in Section 14.3.1, 5-mercapto-1,2,4-thiadiazoles 258 do not show any SH absorption, thus suggesting that the position of the equilibrium is

14.3 1,2,4-Thiadiazoles

HO

O O

N

N

Me

Ac2O R

S

N

N

68-85%

ROCO

RCOX R

S

N

N

56-78%

R

S

253

480

j1327

479

R =Me, Et, Bu, Ph, Bn X = Cl, Br Scheme 14.140

shifted towards the thione tautomers 259 and 260. The presence of 259 at the equilibrium is confirmed by the reaction with either formaldehyde or with sulfenyl chlorides, which give rise to N4 derivatives 481 and 482, respectively. In contrast, treatment with diazomethane, methyl iodide, methyl sulfate, and bromoacetic and 3bromopropionic acids gives only the S- derivatives 483 and 484 (Scheme 14.141), so indicating that the 5-mercapto form 258 contributes to tautomeric equilibrium [227]. R N

R

CH2N2 or

N SMe

S 483

N

MeI or Me2SO4

R

N S

SH

258

N

ArSO2Cl

Br(CH2)nCO2H R N

R

N S(CH2)nCO2H

S

N

N

R

N

N

S S 259

38-78%

R = Me, Ph, Tolyl

HCHO

NH

CH2OH

S S 481

29-65%

SO2Ar S

S

Ar = Ph, Tolyl

482

484 24-76%

32-56%

Scheme 14.141

The sulfide derivatives 483 can be oxidized to the corresponding sulfoxides 485 and sulfones 486 using m-chloroperbenzoic acid (MCPBA) and hydrogen peroxide respectively (Scheme 14.142) [216]. R N

N S

S

Me

O

O

486 24-68% R = Me, Ph Scheme 14.142

H 2O2 AcOH

R N

N S 483

MCPBA SMe

R

N

N

S

485 35-72%

Me S O

j 14 Thiadiazoles

1328

The 5-sulfonyl group can be easily removed by nucleophilic displacement: for example, the reaction of 486a with various amines gives 487 (Scheme 14.143) [228]. But

HO But

RH

N N

S

S

O

But

HO

Me

But

N N

O

R

S

486a

487 72%

R = NH2,HNC(NH)NH2 HCl, HNC(NH)Me HCl, HNC(NH)SMe HCl Scheme 14.143

14.3.6 Thiadiazoles in Medicine

1,2,4-Thiadiazoles constitute a distinctive class of small heterocycles exhibiting various types of biological activities and some of these compounds are useful pharmacophores. Furthermore, they have found use as dyestuffs, lubricant additives, and vulcanization agents [120]. The 1,2,4-thiadiazole nucleus is found in some compounds that show analgesic and anticonvulsant properties, such as 488–490 [227]. More recently, it has been reported that 3-arylamino-4-aryl-5-(N-arylthiocarbamoyl)-4,5-dihydro-1,2,4-thiadiazoles block strychnine seizures [228]. H2N R

ArN R N S

Ar

ArHN

N NAr

N

N

S

Ar

ArHN

S

N

NHMe

N

N

489

488

N H

S

Ar

N N

S

S NHAr

491

490

Anti-inflammatory activity has been described for compounds 492–494 [229]. In particular, several 1,2,4-thiadiazoles containing a di-tert-butyl-phenol substituent have been identified as active and selective cyclooxygenase (COX-2) inhibitors [230]. HO Ar

BnN

N

Ar N S 492

NBn

N

t-Bu

Ar

H 2N

t-Bu

N S

N NBn

493

N

S 494

R

14.3 1,2,4-Thiadiazoles

Cephalosporins incorporating the 1,2,4-thiadiazole system have been prepared and shown to possess good antibiotic activity. Thus, compounds of type 495 have been the subject of patent specifications [167]. With the aim of developing a broadspectrum cephalosporin, new b-lactams bearing various condensed-heterocycles have been reported [231]. In particular, improvement of anti-pseudomonal and anti-MRSA (methicillin-resistant Staphylococcus aureus) activities was obtained by introducing a 5-amino-1,2,4-thiadiazol-3-yl moiety and a hydroxyimino group as C7 substituent (as in compound 496) [231, 232]. XHN

S N

O

S

CO2H

S

N S N

N

R

N

H2N

NOMe

O O

495

H

N

S N

N

N

. HCl N

CO2 496

The novel cephalosporin 497 showed an extremely potent activity against Grampositive and Gram-negative bacteria [233, 234]. Novel C30 condensed-heterocyclic pyridinium cephems have also been prepared to enhance the antibacterial spectrum and water solubility [235, 236].

S H2N

NOMe

N

F

H

N

N

O O

S N

N

CO2

N

N

N H

O

. H SO 2

N N S

4

497

O

498

Thiadiazolidinediones such as 498 are the first examples of potent and selective inhibitors of bacterial dihydroorotate dehydrogenase (DHO), a critical enzyme of the pyrimidine biosynthesis [237]. During the last decade, several 1,2,4-thiadiazoles have been reported with relevant biological activities concerning the central nervous system, G-protein coupled receptors, and cardiovascular system. Among the thiadiazoles that act on the cardiovascular system, KC 12 291 (499) has shown cardioprotective actions due to the inhibition of voltage-gated Na þ channels [238]. Me O

N S

N

N

OMe OMe

499

N N

S 500

NSO2R

j1329

j 14 Thiadiazoles

1330

The 2-sulfonylimino-2H-1,2,4-thiadiazolo[2,3-a]pyridine derivatives 500 have been described as possessing platelet aggregation inhibitory and cardiotonic actions, although the mechanism of action at the molecular level has not been disclosed [239]. Remarkable antiplatelet and anticoagulant activities have also been observed in 1,2,4-thiadiazol-5(2H)-iminium chlorides 501 [240]. In addition, 5-oxo-1,2,4-thiadiazoles 502 have shown efficient oral bioavailability as angiotensin II receptor antagonists [241]. O Cl

HN

NH N

S N

S N HO2C

R 501

R

OEt

N N

502

Some 1,2,4-thiadiazoles have been described as potential drugs for the treatment of Alzheimer’s disease. Thus, 3-(thiadiazolyl)pyridine-1-oxides 503 are endowed with antioxidant and muscarinic receptor binding properties [242], while a series of 1,2,4thiadiazolidinones containing the N-benzylpiperidine fragment (504) have revealed acetylcholinesterase inhibitory activity [243]. Furthermore, it has been stated that in a series of 1,2,4-thiadiazoles bearing a mono-or bicyclic amine at C5 (505), the ring can be regarded as an ester mimic in the binding of muscarinic ligands capable of displaying high receptor affinity [143]. More recently, the thiadiazolidin-3,5-diones 506 were described as the first non-ATP competitive inhibitors of glycogen synthase kinase 3b [171], an interesting target for the development of new promising drugs for the treatment of Alzheimer’s disease, stroke, cancer, and diabetes type II. N N

S N

Et

O

N N R

N

Et

O

503

N

R

O

R N

O R

505

N Me

504

S N

N

S N

N

S

O

506

Compound 507 has been found to be a general allosteric modulator of both agonist and antagonist binding to a wide series of G-protein coupled receptors such as the human m-, d-, and k-opioid, a- and b-adrenergic, muscarinic M1 and M2, and dopaminergic D1 and D2 receptors [183, 244].

14.4 1,3,4-Thiadiazoles

Some 2,3,5-substituted-1,2,4-thiadiazoles of general formula 508 were able to inhibit at a final concentration of 1 mM the [3H]CCPA (2-chloro-N6-cyclopentyladenosine) agonist binding to human A1 adenosine receptors. At the same concentration, the same compounds were able to increase [3 H]DPCPX(1,3-dipropyl-8-cyclopentylxanthine) antagonist binding [184, 185].

N N

N

HBr

N

N Me

S 507

S

N

HBr

Me 508

R

Thiadiazoles with different N-imino substituents have been synthesized; the results of receptor–ligand binding showed that these compounds are best described as protein modifiers (sulfhydryl modifying agents) rather than allosteric modulators. 4-(Diethoxyphosphoryl)methyl-N-(3-phenyl[1,2,4]thiadiazol-5-yl)benzamide (509) acts as a potent mesangial cell proliferation inhibitor [245], 6-(1,2,4-thiadiazol-5-yl)-3aminopyridazine derivatives 510 are novel angiogenesis inhibitors [246], and 2,3diaryl-5-anilino-1,2,4-thiadiazolium bromide 511 has been identified as a melacortin4 receptor agonist [247].

N

PO3Et2

H N

S N

N

O

Me

509

N N

S

N

N

Cl

N

510

MeO Br

N N H

S

N

Me

511

14.4 1,3,4-Thiadiazoles

1,3,4-Thiadiazole ring systems include aromatic derivatives such as the parent compound 512, the mesoionic systems 513, the 1,3,4-thiadiazolium cation 514 and the non-aromatic forms such as the tautomeric compounds 515, the 1,3,4-thiadiazolines 516 and 517, and the tetrahydro-1,3,4-thiadiazolidines 518. All the structures are well known.

j1331

j 14 Thiadiazoles

1332

R

R

N N

N N

S

S

512

513

X

N NH

N N S

S

514

515 X = S, O, NR

X = S, O, NR

N N

R

S 516

N N

X

R

N N

R

S

S

517

518

The chemistry of 1,3,4-thiadiazoles has attracted continued interest over the years because of the great practical importance of these compounds. Several thiadiazoles have been broadly applied in agriculture, industry, polymer chemistry, and, especially, in the pharmaceutical field, because some compounds have shown to be active as fungicides, bactericides, herbicides, and plant-growth regulators. In particular, 1,3,4-thiadiazoles are used in medicine, as antimicrobial [248], antituberculosis [249], anti-inflammatory [250], anticonvulsant [251], antihypertensive [252], local anesthetic [253], anticancer [254], and hypoglycaemic compounds [255]. This ring system has been the subject of several reviews [256–258]; this chapter will be essentially devoted to the recent published reports (2000–2008). 14.4.1 Structure 14.4.1.1 Theoretical Aspects The structure and electronic parameters have been obtained by means of theoretical calculations using the computational methodologies of quantum chemistry [259]. Reported DFT and ab initio calculations of the molecular geometry of the parent compound 512 (Table 14.7) are in agreement with experimental data


DFT/6-31G computational method versus experimental bond lengths (A), angles (
), and dipole moment (Debye) of 1,3,4-thiadiazole (512). Table 14.7

Coordinates


C–S (A)
C¼N (A)
N–N (A)
C–H (A) C–S–C (
) S–C¼N (
) C¼N–N (
) S–C–H (
) N¼C–H (
) m (Debye)

DFT/6-31G

Microwave spectroscopy

Electron diffraction

X-ray

1.747 1.300 1.373 1.082 85.6 114.7 112.5 122.1 123.3 3.43

1.720 1.303 1.371 1.077 86.4 114.6 112.2 122.5 122.9 3.28

1.722 1.304 1.381 1.081 86.4 114.8 112.0 124.1 121.1

1.74 1.31 1.38 0.98 87 114 113 123 123 —

—

14.4 1,3,4-Thiadiazoles Table 14.8 Net charges and condensed Fukui functions for 1,3,4-thiadiazole (512) obtained through BLYP-DFT calculations.

Atom

Net charges

fþ

f

f0

S C N H

0.818 0.3275 0.0308 0.2673

0.2445 0.2153 0.0930 0.0694

0.2633 0.1233 0.1740 0.0711

0.2539 0.1693 0.1335 0.0703

(electron diffraction, microwave spectroscopy, dipole moment, and X-ray spectroscopy) [260]. DFTmethods have also been used to calculate the net atomic charges and the Fukui functions f þ , f , and f 0 for 1,3,4-thiadiazole 512 (Table 14.8) [261]. The obtained data show that 512 is reactive towards nucleophiles, with the sulfur atom as the favorite position. In particular, the sulfur atom, which has the largest f þ value (0.2445) is the preferred site of soft nucleophiles, while the carbon atom is the preferred site of hard nucleophiles. More recently, the molecular geometry of 2-tert-butyldithio-5-methyl-1,3,4-thiadiazole (519) has been investigated by Hartree–Fock (HF) and density functional methods (B3LYP and BLYP), with the 6-31G(d) basis set, and compared with experimental data (Table 14.9) [262]. The best agreement with the experimental Table 14.9 DFT/6-31G(d) and Hartree–Fock computational methods versus experimental bond


lengths (A) and angles (
) of 2-tert-butyldithio-5-methyl-1,3,4-thiadiazole (519) in the ground state. Me Me Me

S

3

S2

S

C1

1

Me N N C2

N1

N2

519 Coordinate


S1–C1 (A)
S1–C2 (A)
S2–C1 (A)
N1–C1 (A)
N1–N2 (A)
N2–C2 (A) C1–S1–C2 (
) N1–C1–S1 (
) C1–N1–N2 (
) C2–N2–N1 (
) S2–C1–S1 (
) S2–C1–N1 (
) C3–C2–S1 (
) C1–N1–N2–C2 (
)

Experimental

HF

B3LYP

BLYP

1.732 1.736 1.760 1.299 1.383 1.294 86.7 107.1 119.0 109.9 127.2 125.7 122.7 0.1

1.738 1.736 1.771 1.271 1.361 1.275 86.2 104.9 116.1 111.4 123.6 123.5 120.0 0.1

1.760 1.761 1.779 1.304 1.372 1.302 86.4 107.0 117.4 110.0 124.9 123.3 123.7 0.6

1.741 1.741 1.779 1.309 1.378 1.313 87.1 106.3 117.7 111.1 123.0 123.8 120.1 1.3

j1333

j 14 Thiadiazoles

1334

values has been reached using the optimized bond lengths by HF and bond angles by DFT (B3LYP) methods. Fukui functions, the HOMO and a Mulliken population analysis of 1,3,4-thiadiazoles 520–528 have been calculated by using the B3LYP functionals and a STO-3G basis set [259].

Me

S

Me

N N

S N N

520

S

Me

N N

521

OH S N N

O Me

525

S

Me

N N

522

OH S N N 526

S

Me

N N 524

523 SH

Me

H 2N

S N N 527

Me

Cl Me

S N N

Me

528

According to these calculations the most susceptible sites for electrophilic attacks are the N3 and N4 atoms of the thiadiazole ring. These sites present the highest values in fk with a range of 0.0839–0.2144. Derivatives 524, 527, and 528 show other sites susceptible to electrophilic attack, corresponding to the atoms of nitrogen, sulfur, and chlorine present as substituents in the alkyl chain. Nevertheless, in compound 527 the sulfur atom of the thiole group was demonstrated to be much more reactive than atoms N3 and N4 with a fk equal to 0.2931. In all the cases studied the site prone to nucleophilic attack was shown to be the sulfur atom of the ring that possesses the highest values of fkþ falling in a range 0.1983–0.2520. 14.4.2 Structural Aspects 14.4.2.1 X-Ray Diffraction A gas-phase electron diffraction investigation of the molecular structure of 1,3,4thiadiazole 512 has been reported by Markov et al. [263]. The compound is planar and
has a C2V symmetry with the following bond lengths (A) and bond angles (
): C–H ¼ 1.081  0.028, N–C ¼ 1.304  0.010, N–N ¼ 1.381  0.016, S–C ¼ 1.722  0.006; C–S–C ¼ 86.4  0.4, S–C–N ¼ 114.8  0.5, C–N–N ¼ 112.0  0.4, S–C–H ¼ 124.1  3.0, and H–C–N ¼ 121.1  3.0. The technique has been largely used to determine the structure of 1,3,4-thiadiazoles. The X-ray structure of 2-amino-5-(m-nitrophenyl)-1,3,4-thiadiazole (529) shows that this compound is also planar [264]. The single crystals are monoclinic, a ¼ 11.832



A, b ¼ 9.862 A, c ¼ 8.353 A, b ¼ 110.40(3)
, V ¼ 913.6(3) A3, dcalcd ¼ 1.212 g cm3,

14.4 1,3,4-Thiadiazoles


Table 14.10 Bond lengths (A) and angles (
) in the structure of 2-amino-5-(m-nitrophenyl)-1,3,4thiadiazole (529).

NO2 C(3)

H N N(3) N C(2) H N(1) N

C(1)

S

N(2)

529


Bond

d (A)

Bond

Angle (
)

S–C1 S–C2 N1–C1 N1–N2 N2–C2 N3–C2 C1–C3 —

1.742 1.730 1.285 1.380 1.311 1.353 1.471 —

C1–S1–C2 N1–C1–S C1–N1–N2 C2–N2–N1 N1–C1–C3 C3–C1–S N2–C2–N3 N2–C2–S

86.8 113.7 113.6 112.0 124.5 121.8 124.7 113.9

m(MoKa) ¼ 0.253 mm1, Z ¼ 4, and space group P21/c. Table 14.10 gives the relative bond lengths and angles. The lone pairs of nitrogen and sulfur atoms are conjugated with the double bonds

of the five-membered ring. This is indicated by the N2–C2 (1.311 A), N1–C1 (1.285 A),
and N1–N2 (1.380 A) bond lengths. The lengths of two endocyclic N–C bonds are intermediate between the standard lengths of the sesqui-bond and double bond. The planes of the thiadiazole and benzene rings form a dihedral angle of 27.7
. The angle between the benzene ring and the nitro group is 8.3
. The X-ray analysis of 2-trifluoro-N-1,3,4-thiadiazole-2-yl)ethanethioamide (530) shows that this molecule is a dimer and exhibits intermolecular hydrogen bonds and intramolecular nonbonding 1,5-type S. . ..S interactions. The distance between the thiocarbonyl sulfur and the thiadiazole ring sulfur is
2.905 A [265]. CF3 S 2.905A

N S

N N

H

N N H

530

S N

2.905A S

CF3

j1335

j 14 Thiadiazoles

1336

The crystal structure of 6-(2-chlorophenyl)-3-ethyl-[1,2,4]triazole[3,4-b]1,3,4-thiadiazole (531) has been reported recently [266]. The compound crystallizes in

monoclinic space group P21/c with a cell parameters a ¼ 11.879 A, b ¼ 15.112 A,
c ¼ 13.95 A, Z ¼ 8, and the final R factor is R1 ¼ 0.0524. The five-membered and
phenyl rings are planar with a maximum deviation of 0.021 A for C1. The structure exhibits both intra- and intermolecular hydrogen bonds of the type C–H. . .N. N N

C1

N N

S

Cl

531

14.4.2.2 NMR Spectroscopy The 1 H NMR signals of 1,3,4-thiadiazoles are usually shifted downfield with respect to protons in benzene, according to the electron deficiency of the heterocyclic ring. In the parent compound 512, the protons are equivalent and resonate at 9.12 ppm as singlet. The presence of alkyl or aryl substituents shifts the resonance upfield, similarly to amino and alkoxy groups. In particular, the 2-amino-1,3,4-thiadiazole (532) shows the H5 proton as singlet at 7.06 d and the NH2 protons at 8.54 ppm; for 2amino 5-trifluoromethyl-1,3,4-thiadiazole (533), the NH2 resonance appears as singlet at 7.71 d [267]. N N H C2 S 532

C1

NH2

N N F3C C2 S 533

C1

NH2

N N Ph C2 S

C1

Ph

534

The 13 C chemical shift for C1, or C2 carbon, in the parent compound is at 153.1 ppm. The presence of phenyl substituents in 534 moves these carbons to 167.7 d [268]. In the case of compounds 532 and 533, the C2 signals are shifted upfield compared with C1 carbons, which, respectively, resonate in the range 144.8–146.8 d and 171.2–173.8 d [267]. Many fully assigned 1 H and 13 C data for disubstituted 1,3,4-thiadiazoles have been reported [269]. Table 14.11 summarizes the 1 H and 13 C NMR spectra of 2,5disubstituted-3-trimethylsilymethyl-1,3,4-thiadiazolium trifluoromethanesulfonates 535–537, which are useful starting materials for the preparation of 1,3,4-thiadiazolium-3-methanide species used as 1,3-dipoles [270]. 14.4.2.3 UV, ESR, and IR Spectroscopy The electronic spectra of 1,3,4-thiadiazoles containing substituents with lone pairs are bathochromically shifted. Substituted alkylthio- derivatives show a greater bathochromic shift than the amino derivatives. p-Nitrophenyl groups cause large bathochromic shifts, while m-nitrophenyl groups cause hypsochromic shifts.

14.4 1,3,4-Thiadiazoles Table 14.11 1 H and 13 C NMR data (ppm) of 2,5-disubstituted-3-trimethylsilymethyl-1,3,4thiadiazolium trifluoromethanesulfonates (535–537).

N N R

SiMe 3SO 3CF3 R

S

535–537 R = H, Me, Ph Salts

Me3Si

Me-2/Me-5

NCH2

Aromatic protons

H2/H5

d 1 H ppm (CDCl3) 535 0.21 536 0.10 537 0.19

— 2.90/2.71 —

4.48 3.98 4.34

— — 7.55–10.96 (10H)

10.63/9.78 — —

d 13 C ppm (CDCl3) Salts Me3Si 535 3.0 536 2.6 537 2.2

Me-2/Me-5 — 15.8/14.8 —

NCH2 51.0 46.9 48.9

Aromatic carbons — — 122.1–134.1 (8C)

C2/C5 158.7/158.6 171.6/166.0 170.4/168.6

Unconjugated 1,3,4-thiadiazoles have no selective absorption above 220 nm. The electronic spectra of some 2-arylazo-5-phenyl-1,3,4-thiadiazole derivatives, made in pure and mixed organic solvents with different polarities, display two bands in the UV region: the first one at 204–238 nm was ascribed to the p–p transition in the benzenoid system, while the second one, at 237–313 nm, was attributed to a p–p transition of the 1,3,4-thiadiazole moiety [271]. Electron spin resonance (ESR) spectroscopy has also been used to study the surface complexes of CuX (X ¼ CI, Br, ClO4) on silica gel chemically modified with 2amino-1,3,4-thiadiazole (532) [272]. ESR indicated a tetragonal distorted structure with low degrees of metal loading on the silica gel. Recently, the electronic spectra of some organotin(IV) derivatives of 5-amino-3H-1,3,4-thiadiazole 2-thione 538, together with the uncoordinated thiazole-2-thione 539, have been reported (Figure 14.5) [273]. These spectra show two absorption bands, at 256  2 and 318  4 nm, which may be assigned to p–p and n–p transitions, respectively, of the chromophore (C¼N) present in thiadiazole ring. These bands undergo a hyperchromic shift upon complexation, indicating the participation of C¼N group in coordination. The infrared spectra of these compounds have also been reported. In particular, the uncoordinated ligand 539 exhibits two bands, at 2622 and 1240 cm1, assigned to n(SH) and n(C¼S), indicating the coexistence of both thione and thiol forms in the solid state. N N S 532

NH2

j1337

j 14 Thiadiazoles

1338

NH2

S S

N

N

R Sn

S

R

H2N

N

N

N

Sn

R S

S S

NH2

S

N H

R R

N N S NH2

538: R =n-Pr, N-Bu N NH H 2N

N N S

S

H2N

S

SH

539b

539a

Figure 14.5 Organotin(IV) derivatives of 5-amino-3H-1,3,4-thiadiazole 2-thione (538 and 539) and the uncoordinated thiazole-2-thione (540).

In the IR spectra of the organotin(IV) compounds 538, n(SH) is not observed, indicating the deprotonation of the thiol form. The n(C¼S) band shifts downward by 53  13 cm1, thus indicating the coordination of thione sulfur to tin. The other significant signals for compound 539 are at 3347 (NH2), 3244 (NH2), 3180 (N3–H), 1604 (N–H þ C¼N), 1547 and 1476 (C¼N/ring mode), 1058(N–N), and 672 (C–S–C). Some other IR absorption spectra for 1,3,4-thiadiazoles show bands at 1230–1165, 1190–1120, 1075–1045, 1040, 975–905, 905–875, 850, and 775–750 cm1 [257]. 14.4.2.4 Mass Spectrometry The main fragmentation of 1,3,4-thiadiazoles is the loss of a nitrile group. Thus, 2,5diphenyl-1,3,4-thiadiazole (534) shows intense ions due to the loss of PhCN, S, and HCN (Scheme 14.144). Ph

N N Ph

S

Ph

–PhCN

S

N

534

–HCN S Scheme 14.144

PhSCN

–S

PhCN

14.4 1,3,4-Thiadiazoles

b

c

a

N N

Me

S

S CCl3-nFn d S

n = 0,1,2

540

b c a N N e S SCCl3-nFn Me S 541

Figure 14.6 Fragmentation pattern of trihalomethylsulfenyl derivatives of 5-methyl-1,3,4thiadiazole-2-thiols.

In the presence of a methylthio substituent, such as 5-(methylsulfanyl)-1,3,4thiadiazol-2-amine, the major process is the loss of . SH and the fragmentation at the heterocyclic sulfur atom. In the case of 3,5-diphenyl-2,3-dihydro-1,3,4-thiadiazole, the predominant fragment is represented by PhS. , while 1,3,4-thiadiazolidinethione 515 decomposes by fragmentation of the ring [257]. More recently, fragmentation studies of several trihalomethylsulfenyl derivatives of 5-methyl-1,3,4-thiadiazole-2-thiols 540 and 541 have been reported [274]. The diagnostic fragments are characterized by the loss of the halogenated substituents, and in all cases cleavage via fragmentation “a” (Figure 14.6) generated the base peak of m/z 59 Da [CH3C¼S] þ . . Other fragmentations of the substituent occur, producing Cl3C þ , Cl2FC þ , and ClF2C þ . Fragments and losses common to all derivatives were also [M–CClnF3n] þ , [M–SCClnF3n] þ , [M–(S–SCClnF3n)] þ , [CS] þ , and [CH3CN] þ . . 14.4.2.5 Thermodynamic Aspects The parent compound 512 does not show tautomerism in its fully conjugated form. Nevertheless, in the presence of some substituents tautomerism is possible. N NH S

N N X

XH S 515b

515a X = O, S

1,3,4-Thiadiazolin-2-ones (X ¼ O) and -2-thiones (X ¼ S) exist, in the oxo and thione forms 515a. This result is confirmed by 13 C NMR spectra of 5-methylamino-1,3,4-3H-thiadiazoline-2-thione 542a, where the C2 signal appears at 180.6 ppm, while the oxidized species, the bis(5-methylamino-1,3,4-thiadiazol-2-yl)disulfide 543, obtained from 542 with aqueous hydrogen peroxide, shows the same carbon (C2) resonating at 148.6 ppm (Scheme 14.145) [275]. Tautomeric energy differences also calculated for 515, using the HF/6-31G , B3LYP/6-311G , and B3LYP/6-311 þ þ G levels of approximation, confirm that these compounds are oxo or thione compounds rather than hydroxyl and mercapto tautomers [276].

j1339

j 14 Thiadiazoles

1340

N N

N NH

MeHN

MeHN

SH S 542b

H2 O2 / MeOH

92%

S C2 S

542a

N N

N N

MeHN

S C2 S S

S

NHMe

543 Scheme 14.145

2-Amino-1,3,4-thiadiazoles 532 exist in the amino form, in solution and in the solid state, while the presence of the sulfonamido group shifts the equilibrium towards the imido tautomer [256, 257]. 1,3,4-Thiadiazolidine-2-thiones 544 are in equilibrium with the open-chain hydrazone tautomers 545; under basic conditions, the hydrazone salt is the predominant form (Scheme 14.146) [277].

R

HN NR2

R1

S

R 1

X

R

545a

544 R = Ph, 2-pyridyl

N N C SH R2 S

R1 = H

OH

H

R R1

S N N R2

S

545b

R 2 = Me

Scheme 14.146

1,3,4-Thiadiazoles are solids; some of them are soluble in water, with a solubility decreasing with increasing molecular weight. 14.4.3 Synthesis 14.4.3.1 Synthesis of 1,3,4-Thiadiazoles The parent compound, described in 1956 by Goerdeler et al., was obtained by hydrogenation of 2-bromo-1,3,4-thiadiazole with Adams catalyst in 90% yield [278]. Compound 512 was also obtained by cyclization, in the presence of hydrogen sulfide, of N0 -[(dimethylamino)methylidene]-N,N-dimethylhydrazonoformamide (548), prepared in a two-step sequence by reaction of DMF with thionyl chloride,

14.4 1,3,4-Thiadiazoles

followed by treatment with N,N0 -diformylhydrazine (547) and sodium ethoxide (Scheme 14.147) [279].

H

Me N Me

SOCl 2

Me Cl N Me

H

Cl

O

546 HN NH 1) H

(2) EtONa

O O

H

547 N N

N N

H2 S

Me 2 N

S 65%

548

NMe 2

512 Scheme 14.147

A general procedure for the preparation of 1,3,4-thiadiazoles is the cyclization of 1acylthiosemicarbazides by cold concentrated sulfuric acid. Using this method, several 5-(5-nitro-2-furyl)-1,3,4-thiadiazoles (550) have been obtained from 549 (Scheme 14.148) [280]. O2N

H N

O O 549

H2SO4

S N H

N H

R

0 °C

O2N O

52-76%

S N

N

NR H

550

Scheme 14.148

A convenient procedure has been reported by Nami and coworkers for the synthesis of N-(5-phenyl-1,3,4-thiadiazol-2yl)benzamide (554), by condensing thiosemicarbazide 551 with benzoyl chloride (552) under microwave irradiation, involving as intermediate the 2-benzoylhydrazinecarbothioamide (553) (Scheme 14.149) [281]. Compound 553 can also be cyclized into compound 554 with H3PO4 under conventional heating at 120
C for 10 min [282]. This cyclization is quite general and other dehydrating agents have been used such as polyphosphoric acid [283] and phosphorus oxychloride [284]. Different 2-amino-1,3,4-thiadiazoles, screened for the antituberculosis activity against Mycobacterium tuberculosis H37Rv, have been synthesized from the reaction

j1341

j 14 Thiadiazoles

1342

H 2N

HN NH 2 + S

2 PhCOCl

HN NH

30s

H 2N

MW

Ph S O 553

552

551

85% 3m Ph O

N N

N H

Ph

S 554

Scheme 14.149

of various 1-acylthiosemicarbazides (556) with sulfuric acid. Compounds 556 were prepared by reaction of 4-substituted benzoic acid hydrazides 555 with different aryl isothiocyanates (Scheme 14.150). Among the tested compounds, 2-phenylamino-5-(4-fluorophenyl)-1,3,4-thiadiazole showed the highest inhibitory activity (69%) [285]. O

O Ar

N H

NH 2

RC 6H 4N=C=S

Ar

67-95%

NH

N H

556

555

NH S

R

H 2SO 4 50-92% R N N Ar

S

N H

557 Ar = Ph, p-FC 6 H4 , p-ClC6 H 4, p-BrC6 H 4, p-NO2 C 6H 4, C5 H4 N R = H, F, Cl, Br, Me, NO 2 Scheme 14.150

5-Hydrazinyl- and 5-amino-1,3,4-thiadiazole-2-thiols (559 and 560) have been prepared in 50% and 12% yields, respectively, starting from 2-(hydrazinylcarbonothioyl)hydrazinecarbothioamide (558), by reaction with hydrochloric acid; a better yield of both compounds was obtained starting from 2,20 -carbonothioyldihydrazinecarbothioamide (561) (Scheme 14.151) [286]. Oxidation of ethyl or butyl (2-carbamothioylhydrazinylidene)ethanoate 561 with ferric chloride leads to ethyl 5-amino-1,3,4-thiadiazole-2-carboxylates showing that the electron-donating group increases the stability of 1,3,4-thiadiazole carboxylic acids (Scheme 14.152) [287].

14.4 1,3,4-Thiadiazoles

HCl conc.

HN NH S S NHNH 2

H2N

N N H2NHN

∆

H 2N

H2N

S

50%

NH2

N N

N N

HCl conc.

S

H2NHN

∆

SH

560

12%

NH NH

S

S

N N

559

558

HN NH

SH

S

+

S

SH

+

H2N

S 560

559

561

75%

20% Scheme 14.151

RO2C

S

N N

FeCl3

N NH NH2

H2 N

40%

CO2R

S

562 R = Et, Bu Scheme 14.152

Oxidative cyclization has also been performed with substituted thiosemicarbazones [288]. Thus, the reaction of substituted thiosemicarbazides 563 with aldehydes yields the corresponding thiosemicarbazones 564, which by oxidative cyclization, achieved with iron(III) chloride or K3Fe(CN)6, lead to substituted 1,3,4-thiadiazoles 565 in good yields (Scheme 14.153) [289].

CHO HN NH2 R N R1

S

S 71-96%

O

R

O

HN N N R1

S

S 564

563 R = H, Me, t-Bu, Ph

FeCl 3

71-94%

EtOH

R 1 = H, Me R

Scheme 14.153

N N N R1

j1343

S

S 565

O

SH

j 14 Thiadiazoles

1344

2-Alkoxy-2-amino-1,3,4-thiadiazoles 567 have been prepared, in good yields, by oxidation of the corresponding O-alkyl 2-carbamothioylhydrazinecarbothioate 566 with hydrogen peroxide (Scheme 14.154) [290]. HN RO

H2 N

52-86%

NH2

SS

N N

H 2O2 /3%

NH

OR

S 567

566 R = Me, Et, n-Pr, i-Pr, n-Bu Scheme 14.154

The oxidation method has also been applied to 1,2-hydrazinedicarbothioamide 568 (dithiobiurea), using iodine, ferric chloride and hydrogen peroxide, to produce 2,5diamino-1,3,4-thiadiazole (569) (Scheme 14.155) [291]. HN H 2N

H 2O2 /26%

NH NH2

SS

N N H2 N

90-96°C 96%

568

S

NH2

569

Scheme 14.155

Ammonium ferric sulfate dodecahydrate has been used to prepare, in 90% yield, 2amino-5-(5-nitro-2-thienyl)-1,3,4-thiadiazole (571), starting from 5-nitrothiophene-2carboxaldehydethiosemicarbazone (570) (Scheme 14.156) [292]. H N O 2N

H N

S

NH 2 S

N N

Fe(SO 4) 2NH 4,12H 2 O

H2 N

H2 O, 100°C, 4.5h 90%

570

S

S

NO 2

571

Scheme 14.156

A similar oxidation has been accomplished using a mixture of sodium acetate, bromine, and glacial acetic acid, which is useful in preparing 2-amino-5-phenyl-1,3, 4-thiadiazole (573) starting from 2-benzylidenehydrazinecarbothioamide (572) (Scheme 14.157) [293]. H N N

NH2 S

572 Scheme 14.157

Br 2 /AcOH AcONa rt, 2h, 62%

N N S 573

NH2

14.4 1,3,4-Thiadiazoles

An efficient one-pot procedure for the preparation in excellent yields of 1,3,4thiadiazoles 575 in ionic liquid, as dual solvent and catalyst, has been reported recently [294]. The reaction involves a one-pot, three-component condensation of hydrazine hydrate with substituted phenyl isothiocyanates, followed by the addition of substituted benzaldehydes 574 in the presence of the ionic liquid 1-butyl-3methylimidazolium tetrafluoroborate ([bmim]BF4) and in the absence of any other catalyst, under mild conditions (Scheme 14.158). The reaction workup is simple, and the ionic liquid is easily recovered from the reaction and reused. R

N N

NH 2NH2 .H2 O ArNCS ([bmim]BF4), 4 min.

R

N H

S

Ar

80-90%

O

575

574 R = H, Br, Cl, F, NO2 Ar = Ph, 4-NO2 C6 H4 , 4-MeC6 H4,3-MeC6 H4 Scheme 14.158

1,3,4-Thiadiazoles can be also obtained from the reaction of diacylhydrazines with a sulfur source. Thus, N 0 -formyl 1-benzothiophene-2-carbohydrazide derivative 577, prepared by condensation of 3-chlorobenzo[b]thiophene-2-carboxylic acid hydrazide 576 with formic acid, reacts with phosphorous pentasulfide in xylene at reflux to give the corresponding 2-(3-chloro-1-benzothien-2-yl)-1,3,4-thiadiazole (578) in 63% yield (Scheme 14.159) [295]. Cl

Cl

S

CONHNH 2

HN NH

HCO2 H ∆, 73%

S

O H 577

576

Xylene

P2S5

∆,1h

63%

Cl N N S

S 578

Scheme 14.159

O

j1345

j 14 Thiadiazoles

1346

Moreover, some 2,5-diaryl-1,3,4-thiadiazoles have been prepared in 74–91% yields using Lawesson’s reagent and microwave irradiation in the absence of solvent for 3–8 min [296]. Thus, for example, 2-phenyl-5-m-tolyl-1,3,4-thiadiazole (580) was prepared in 91% yield from of a mixture of 579 and Lawesson’s reagent (LR) (Scheme 14.160) [297]. HN NH Me

O O 579

Me LR MW 91%

N N S 580

Scheme 14.160

A series of 2-alkylthio-5-alkylamino-1,3,4-thiadiazoles have been synthesized through a new and versatile solid-phase synthesis protocol using the commercially available 2-(3,5-dimethoxy-4-formylphenoxy)ethoxymethyl polystyrene (581). This resin was treated with a range of primary amines under standard reductive amination conditions to yield the respective resin bound derivatives 582, which were transformed into resin bound benzyl-thiocarbamic acid O-pyridin-2-yl esters 583 upon treatment with di-(2-pyridyl)-thionocarbonate (DPT). These compounds were subsequently converted into thiosemicarbazides 584 by reaction with hydrazine, and then treated with 10 equivalent of DPT in dichloromethane (DCM) to give immobilized thiones 585. Alkylation of thione 585 with primary alkyl- or benzyl bromides in a mixture of 1,4-dioxane–methanol and aqueous sodium hydroxide, followed by TFA/DCM treatment, yielded 1,3,4-thiadiazoles 586 in 45–82% yield (Scheme 14.161) [298]. Some benzaldehyde N0 -(5-benzoylmethyl-1,3,4-thiadiazol-2-yl)hydrazone hydrobromides 590, subsequently converted into the free bases 591 by treatment with aqueous ammonia, have been synthesized by the reaction of 1-benzylidenethiocarbohydrazones 587 with 3-bromo-1-phenylprop-2-yn-1-one (588). This reaction involves, presumably, a nucleophilic replacement of the bromine atom with the formation of benzoylethynyl sulfide intermediate 589 and intramolecular cyclization of the NH2 group at the electron-deficient b-carbon of the triple bond (Scheme 14.162) [299]. Varma et al. have used a green protocol to synthesize in a single step several 1,3,4thiadiazoles 594 [300]. In particular, various hydrazides 592 have been reacted with triethyl orthoalkanates or triethyl orthobenzoate (593), in the presence of phosphorous pentasulfide in alumina under microwave irradiations and in the absence of any solvents, to afford the target 1,3,4-thiadiazoles 594 in good yields (65–70%) (Scheme 14.163). N-alkylhydrazinecarbothiamides 595 can react with triethyl orthoformate (596) in the presence of a small amount of concentrated hydrochloric acid to yield unsubstituted alkylamino-1,3,4-thiadiazoles 597 (Scheme 14.164) [301]. Triethyl orthoformate (596) has been used to prepare in good yield 5-amino-3(methylthio)-1-(1,3,4-thiadiazol-2-yl)-1H-pyrazole-4-carbonitrile (600). Thus, starting

14.4 1,3,4-Thiadiazoles

j1347

N O

O R NH

RNH 2

O

R N

50°C, 16h

NaBH3 CN

H

N

S (DPT)

O

N

S

582

583

581 NH2NH2 50°C, 14h R N

R N

DPT

N NH S

50°C, 16h

R = PhCH2 , PhCH2 CH2 , C 3H 5CH 2

45-82%

2) R 1Br

NH2

S 584

585 S 1) Dioxane/MeOH/NaOH

H N

R1 = PhCH 2, MeNH, 4-MeOC 6H 4CH 2

3) TFA/DCM

4-pyridyl-CH 2, C3 H 5CH2 R

N N N H

S

S

R1

586 Scheme 14.161

O S N R

N H

N H

NH2

+

Br 588

587

R

N

H N

S N N

Ph O

Ph

AcOH

O

r.t. 3h

N

Aq. NH3

89-92%

R = Ph, 4-ClC6 H4 , 4-NO2 C 6H 4 , 4-Me 2 NC6 H4

R

N

H N

N

NH2

589

S

Ph

N N

HBr

S

N H

R

63-70%

591

Scheme 14.162

HBr

590

O

Ph

j 14 Thiadiazoles

1348

O R

NHNH2

N N

P2S5/Al2O3

R1C(OC2H5)3

+

R

Mw (120°C, 10 min.) 65-70 %

593

592

R1

S 594

R = Ph, p-F-C6H4, p-OMe-C6H4, 2-furyl, 2-thienyl, 4-pyridyl, PhCH2 R1 = H, Et, Ph Scheme 14.163

S R

N H

+

NHNH 2

N N

HCl

HC(OC 2 H5 )3 596

595

NHR

S

71-92%

597

R = Me, Et, nPr, PhCH 2 , t-C 8H 17, 1-Adamantyl Scheme 14.164

from 5-amino-4-cyano-3-(methylthio)-1H-pyrazole-1-carbothiohydrazide (599), 600 was synthesized in 76% yield. Compound 599 was also used to generate 601 and 602 in 55% yield (Scheme 14.165) [302].

S

O

O

O

N N

+ MeS

596

H N

S

76%

NH2

N N

NH2

MeS

599 CN

CN 600

O PhNCS

Cl 55%

55%

Cl 598 Cl

PhHN S

MeS

CN 601

Scheme 14.165

S

N N

N N

N N

N N NH2

N N

MeS

CN 602

NH2

NH2

14.4 1,3,4-Thiadiazoles

2,5-Disubstituted-1,3,4-thiadiazoles 607, in high yields and good purity, have been prepared in a one-pot three-component condensation of aromatic aldehydes 603, hydrazine, and sulfur in ethanol under microwave irradiation (300 W, 1 h) [303]. The reaction involves as intermediates the corresponding azines 604, which can be isolated in good yield if the reaction is stopped after 15 min. The same reaction performed with aromatic aldehydes under conventional heating led to 2,5-diaryl1,3,4-thiadiazoles 607 (Scheme 14.166) [304]. O

S/NH2NH2/EtOH H

2

Mw (150°C, 60 min.)

N N Ar

75-97%%

R

Ar 604

603

H2S

Ar

S 607

HN N

HN NH

N N Ar

Ar

S 606

Ar

Ar

SH

Ar

605

Ar = Ph, p-OH-C6H4, m-OH-C6H4, o-OH-C6H4, p-OMe-C6H4, o-OMe-C6H4, m-OMe-C6H4, 3-thienyl, 2-thienyl, 3-pyridyl, 2-pyridyl, p-Me-C6H4, p-Me2N-C6H4, Scheme 14.166

2,5-Diaryl-1,3,4-thiadiazoles 610 can be also prepared in relatively good yield starting from the corresponding 1,3,4-oxadiazoles 608 by reaction with thiourea. The reaction involves an initial nucleophilic attack of the sulfur of thiourea on the carbon atom of 1,3,4-oxadiazole ring, followed by formation of an oxathiadiazepine intermediate 609, and subsequent ring contraction and extrusion of urea (Scheme 14.167) [305]. Recently, a solid-phase synthetic route using the Merrifield resin (611) has been utilized to prepare various substituted-1,3,4-thiadiazoles 613, by a dehydrative cyclization of acyldithiocarbazate resins 612 with TMSCl in DCE at 60
C [306]. Acyldithiocarbazate resins 612 have been prepared by reaction of the Merrifield resin 611 with carbon disulfide, various hydrazides, and NaH (Scheme 14.168). 14.4.3.2 Synthesis of Exocyclic-Conjugated Mesoionic 1,3,4-Thiadiazoles (513) and of 1,3,4-Thiadiazolium Cations (514) The simplest way to prepare 2-oxo or 2-thio mesoionic 1,3,4-thiadiazoles 513 is the thermal cyclization of 1-thioacyl hydrazine with phosgene or thiophosgene. Thus,

j1349

j 14 Thiadiazoles

1350

N N R

1

R

O

THF,120-50°

S

+ H2 N

NH2

N

24-30h

R

R1

N

S O

609

608

NH2

NH2

55-69%

O H 2N

N N

+

NH 2

R1 S 610

R

R 1 = Ph, 4-NO 2C 6 H4

R = Ph, 4-MeOC 6H 4, 3,4,5-(MeO) 3 C6 H 2 Scheme 14.167

Cl 611

S

RCONHNH 2

S

CS 2,NaH

N H

H N

R O

612

TMSCl in DCE at 60°C

50-70% N N S

S 613

R

R = Ph, 4-t-ButylC 6H 4, 4-F 3C-C 6H 4, 3FC 6 H4 Scheme 14.168

mesoionic 1,3,4-thiadiazolium-2-olate 615 and 1,3,4-thiadiazolium-2-thiolate 616 have been synthesized from thiocarboxylic acid hydrazide hydrochloride 614 with phosgene or thiophosgene (Scheme 14.169) [307]. Potassium 2-phenylhydrazinecarbodithioate (617), warmed at 50
C in benzene for 1 h with benzoyl chloride, has afforded a 56% yield of 4,5-diphenyl-1,3,4thiadiazolium-2-thiolate 620, most probably involving as intermediates the species 618 and 619 (Scheme 14.170) [308]. Mesoionic 2-methylene-1,3,4-thiadiazole 623 has been synthesized from thiocarboxylic acid hydrazide (614) and 3,3-dichloroacrylonitrile 622, while the reaction of 614 with carbon disulfide leads to 4,5-disubstituted-1,3,4-thiadiazolium 2-thiolate 624 [309]. Starting from 625, it is possible to obtain in good yield the corresponding mesoionic compounds 624 (Scheme 14.171).

14.4 1,3,4-Thiadiazoles

O

S NH2

N

Ph

Cl

Me

Cl 70°C

Me 614

N

Ph

N S

46%

O

615

S 56%

Me

Cl

Cl

N

N

Ph

S

S 616

Scheme 14.169

O S KS

Ph N H

NH

Ph

N N S

Ph

S

620

Ph S

S 618

56%

- H2O

O

Ph NH HN

50 °C, 1 h

617

Ph

Cl

Ph H

OH

N N

S

Ph

S 619

Scheme 14.170

A similar reaction performed with thiohydrazides 626 and isonitrile dichloride (627) or isothiocyanate leads to 2-amino-1,3,4-thiadiazolium salts 628 and 629, respectively [310]; treatment of 628 with a chloroform solution of anhydrous ammonia yielded the mesoionic compounds 630 (Scheme 14.172) [311]. 2-Substituted 5,7-diphenyl-1,3,4-thiadiazolo[3,2-a]pyridilyum derivatives 633 and 634 have been prepared by reaction of 1-amino-4,6-diphenylpyridine-2-thione (631) with phenyl isothiocyanate, in 65% and 78% yield, respectively. This transformation presumably involves the corresponding thioureas 632 as highly reactive intermediates, which easily undergo cyclodehydrosulfuration. Iminophosphorane 635,

j1351

j 14 Thiadiazoles

1352

NC S

C

Cl

Cl 622

Me

70°C

Ph

NH2

Ph

N Me 614

CN

N

N

CN C CN

S

46%

623

S C 621

R1 = Me

S R

1

N N

S

S

Ph

CS2 1

R = Me, Ph

R1 N

Ph Ph

625

94-98%

624

NH2

Scheme 14.171

N S Ph

Cl

N R 626

67%

N C

NH2

Ph

Cl 627 70°C

R

N N

Ph

S

65-93%

Cl NHPh

628

Ph

NH3

R= Me, Ph, PhCH2

67%

S Me Ph

N N

Cl

S

R

N N

Ph

S

NHPh

629

NPh

630

Scheme 14.172

obtained by reaction of 631 with Br2 and triphenylphosphine, alternatively produces, by reaction with carbon disulfide, 5,7-diphenyl-1,3,4-thiadiazolo[3,2-a]pyridinium-2thiolate (636) in 80% yield (Scheme 14.173) [312]. Some 1,3,4-thiadiazolium perchlorates 638 have been prepared by reaction of N0 acyl-N0 arylbenzenecarbothiohydrazide 637 with acetic anhydride–perchloric

14.4 1,3,4-Thiadiazoles

Ph

Ph

Ph

65-78%

R=N=C=S Ph

Ph

N S NH2 631

N HN

Ph

S NHR

N N

S NR

S 632

633, 634

Br2 , PPh 3

R = Ph, CO 2 Et Ph

Ph CS2 Ph

N S N PPh 3

80%

Ph

N N 636

635

S S

Scheme 14.173

acid [313]. Moreover, these compounds have also been synthesized starting from benzenecarbothiohydrazide 639, by reaction with a nitrile–perchloric acid mixture (Scheme 14.174) [314]. Ar H

R O S

N N

Ar N N

Ac2O HClO4

Ph

77-94%

Ph

76-85%

Ar = Ph, Tolyl

HN N H

RCN S

R

638

637

Ar

S

HClO4

Ph

Ar N N NH3 R S ClO

4

Ph 639 R = Me, Et, Ph Scheme 14.174

3-(2,4-Dibromophenyl)-2-methylthio-5-phenyl-1,3,4-thiadiazolium methosulfate (641) can be prepared by reaction of 3-(2,4-dibromophenyl)-5-phenyl-1,3,4-thiadiazole-2-thione (640) with dimethyl sulfate in dry benzene at reflux for 12 h. The

j1353

j 14 Thiadiazoles

1354

corresponding perchlorate 642 is synthesized by treatment of the methosulfate salt with a solution of sodium perchlorate in acetic acid (Scheme 14.175) [315].

Ar N N Ph

S

Ar N N

Me2 SO4 S

∆,Ph-H,12h

96%

640

Ph

S 641

MeSO4 SMe

NaClO4 10min. AcOH r.t. 86%

Ar =2,4-Br 2C 6H 3

Ar ClO 4 N N SMe S Ph 642

Scheme 14.175

1,3,4-Thiadiazolium cations 514 are easily obtained by treatment of 1,3,4-thiadiazoles with several alkylating agents to give, in about 100% yield, the corresponding salts. A recent example is the synthesis of 3-trimethylsilylmethyl-1,3,4-thiadiazolium trifluoromethanesulfonates 645. These compounds have been prepared in 75–99% yields by mixing a solution of 1,3,4-thiadiazoles 643 with trimethylsilylmethyl trifluoromethanesulfonate (644) in dry CH2Cl2 at 50
C under reflux for 24 h (Scheme 14.176) [270].

O Me O S CF 3 Me Si O Me 644

N N R

S

R

75-99%

N N R

S 645

643 R =H, Me, Ph Scheme 14.176

SiMe 3 CF3 SO3 R

14.4 1,3,4-Thiadiazoles

14.4.3.3 Synthesis of Thiadiazolinones, Thiadiazolinethiones, and Thiadiazolimines (515) 1,3,4-Thiadiazolin-2-ones can be prepared in good yields by acidic thermal cyclization of substituted thioylhydrazinecarboxamides 647. Thus, the reaction of substituted dithioate 646 with semicarbazide gave 647, which on cyclization furnished the substituted 3-acetyl-1,3,4-thiadiazol-2-ones 648 (Scheme 14.177) [316]. NH 2CONHNH 2 R

SMe

H N

R

60-70%

S

S 646 R = CONH 2 , CONHPh, CONHC 6 H 4OMe, CONHC6 H4 N=NPh, CONH- α-Naftyl, CONH- β-Naftyl

O N H

NH2

647 AcOH 50-80%

Ac N N R

S

O

648 Scheme 14.177

5-tert-Butyl-3-[2,4-dichloro-5-(2-propynyloxy)phenyl]-1,3,4-thiadiazol-2(3H)-one (651), an arylthiadiazolone herbicide structurally related to oxadiargyl and oxadiazon, has been prepared in high yield in a two-step synthesis starting from N-2,4-dichloro5-(2-propynyloxy)phenyl]-N0 -pivaloylhydrazine (649). Thus, 649 was transformed into the corresponding N-thiopivaloylhydrazine 650 by reaction with tetraphosphorus decasulfide and then converted into 651 by reaction with trichloromethyl chloroformate in dioxane at room temperature for 3 h (Scheme 14.178) [317]. 1,3,4-Thiadiazol-2-(3H)-ones 655 and -2(3H)-thiones 656 can be prepared in good yield by 1,10 -carbonyldiimidazole or 1,10 -thiocarbonyldiimidazole induced cyclization of 3-mercaptopropanoic acid derivatives 654. The reaction starts from 2-oxo-Narylpropanehydrazonoyl chloride 652, which in the presence of triethylamine is converted into the corresponding nitrile imines 653, which in situ undergo a nucleophilic attack of 3-mercaptopropionic acid leading to 3-[[2-oxo-1-(arylhydrazono)propan-1yl]mercapto]propanoic acids 654 (65–71% yield). These propanoic acids were then treated with 1,10 -carbonyldiimidazole (CDI) or 1,10 -thiocarbonyldiimidazole (TCDI) to afford the corresponding 1,3,4-thiadiazole derivatives 655 and 656 (Scheme 14.179) [318]. The cyclization reaction is explained as reported in Scheme 14.180, in which CO2, ethylene, and imidazole are simultaneously formed.

j1355

j 14 Thiadiazoles

1356

Cl

H N

Cl

O N H

H N

P4 S10

C(Me) 3

dioxane ∆,3h

Cl O

S N H

C(Me) 3

Cl O

80%

650 CCl3 OCOCl dioxane

649

(Me)3 C

rt,3h 78%

S

O

N N

O

Cl

Cl 651

Scheme 14.178

Cl

H N Ar N

Ac 652

Et 3N

Ar HN N

HO 2 C Ac

N N Ar

65-71%

HS

S

CO 2H

653

Ar= Ph, MeC 6H 4, ClC6H 4

Ac 654

CDI 59-68%

or TCDI

Ar

N N

Z

S

Ac

655 : Z = O 656 : Z = S Scheme 14.179

5-[4-(Benzyloxy)phenyl]-3-(2-cyanoethyl)-1,3,4-thiadiazol-2(3H)-one (662) and 5[(4-benzyloxy)phenyl]-3-(2-cyanoethyl)-1,3,4-thiadiazole-2(3H)-thione (663), used as monoamine oxidase inhibitors of type B (8 and 16 mM), have been synthesized starting from ({[4-(Benzyloxy)phenyl](thiocarbonyl)}thio)acetic acid (660). In

14.4 1,3,4-Thiadiazoles

H N

R O

H2SO4

S N H

SK

S

R

N N

0 °C 17-73%

664

j1357

S H

665

R = Ph, 4-MeOC6H4, 4-ClC6H4, n-C7H15, 2-furyl, 3-pyridyl Scheme 14.180

particular, compound 660 was treated with NaOH and (2-cyanoethy1)hydrazine in EtOH at 0
C to give 1-{[4-(Benzyloxy)phenyl](thiocarbonyl)}-2-(2-cyanoethyl)hydrazine (661), which by subsequent reaction with phosgene or thiophosgene gave the resulting 1,3,4-thiadiazole derivatives 662 and 663 in 62% and in 51% yield, respectively (Scheme 14.181) [319].

S S Ph

O

CO 2H N N

660

NaOH EtOH

CN

S O

H 2N NH Cl S S

Ph

O 661

H N

O

O 662 62%

CHCl3 , ∆

CN

N H

Ph Cl

CN

S

38%

Cl

Cl

CHCl3 , ∆

N N S

Ph

O 663

CN S 51%

Scheme 14.181

5-Substituted-1,3,4-thiadiazole-2-thiones 665 are obtained in moderate–good yields from potassium 2-acyl- or 2-aroylhydrazinecarbodithioate 664 and cold concentrated sulfuric acid (Scheme 14.182) [320].

j 14 Thiadiazoles

1358

H N

R O

H2SO4

S N H

SK

S

R

N N

0 °C 17-73%

664

S H

665

R = Ph, 4-MeOC6H4, 4-ClC6H4, n-C7H15, 2-furyl, 3-pyridyl Scheme 14.182

Another method for preparing 5-substituted-1,3,4-thiadiazole-2-thiones is the reaction of carbon disulfide with amidrazones. Thus, starting from aromatic and heterocyclic amidrazones 667, obtained from the reaction of corresponding nitriles 666 with hydrazine, a series of 5-substituted-1,3,4-thiadiazole-2-thiones (668) were obtained in excellent yields (Scheme 14.183) [321]. R C N 666

NH2NH2 68-91% 4-days, rt

R

NH HN NH2 667 CS2

73-95%

EtOH, 2h S

R

N N 668

S H

R = Ph, α-naphthyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, 1-isoquinolyl Scheme 14.183

Various 5-imino-D2-1,3,4-thiadiazolines have been synthesized from activated thiocyanates and benzenediazonium chloride. The reaction has been performed in NaOAc buffered solution of EtOH to yield 5-imino-4-aryl-2-phenyl-D2-1,3,4-thiadiazolines (671) in 75% yield (Scheme 14.184) [322]. Ph

O

NCSH2C 669

ArN2 Cl 670 EtOH, NaOAc 75%

Ar

N N

HN

S

Ph

671

Ar = Ph, ClC6H4, NO2C6H4 Scheme 14.184

4-Methyl-5-imino-2-thienoyl-D2-1,3,4-thiadiazolines (675) have also been prepared by condensation of thienylglyoxal (673) with suitable thiosemicarbazides (672) followed by oxidation of the resulting 674 with FeCl3 (Scheme 14.185) [288].

14.4 1,3,4-Thiadiazoles

Me R N H

CHO N NH2

S

S

673

O

91-95%

Me R

O

N N

N H

S

S 674

672

FeCl3

67-75%

R = H, Me

Me

EtOH

N N

RN

S

S

O

675 Scheme 14.185

Hydrazonoyl halides offer a versatile tool in the synthesis of azoles. Thus, 5-imino4-phenyl-2-trifluoromethyl-D2-1,3,4-thiadiazoline (677) has been prepared in 83% yield by the reaction of N-phenyltrifluoroacetohydrazonoyl bromide (676) with potassium isothiocyanate [323]. If the reaction is performed with methyl isothiocyanate, the analogous N-methylthiadiazoline 678 was obtained, but in low yield (Scheme 14.186). Br F3C

Et3N

N NHPh

KNCS MeOH, ∆, 3h 83%

676

Ph

N N

HN

S

CF3

677

MeNCS 14%

Ph

N N

MeN

S

CF3

678 Scheme 14.186

A similar reaction has been reported for the synthesis of some 5-acyl-2,3-dihydro-2imino-3-(3-phenyl)pyrazol-5-yl)-1,3,4-thiadiazoles 681. Thus, phenylpyrazolylhydrazonoyl chlorides 679 undergo cyclocondensation with potassium thiocyanate to give 681 in 80–85% yield. At the same time, treatment of 681 with sodium nitrite in acetic acid, followed by heating, provided the thiadiazolones 683 in good yield (Scheme 14.187) [324].

j1359

j 14 Thiadiazoles

1360

R Cl R

KNCS NH N EtOH, rt, 2h

N NH O

N

80-85% Ph

Ph

Ph

H

N

Ph 679

N

S

O

O

S

N N

O

S

R

NH N

HN

680

NaNO2

681

N NH N N

N NH

Ph

O

∆

R

89-91%

AcOH

N NH N N

O

S

R

ONN

683

682

R = Me, OMe Scheme 14.187

Bi(4,5-dihydro-1,3,4-thiadiazol-5-imines) have been prepared in good yield by the reaction of N,N0 diaroyldihydrazonoyl dihalides with potassium thiocyanate. The formation of 687 is assumed to proceed via a nucleophilic attack of the thiocyanate anion to afford intermediates 685, followed by an intramolecular cyclization. Compounds 687 were also obtained from the reaction of dihalides 684 with thiourea, through the formation of the non-isolable intermediates 686, which cyclized readily via loss of ammonia (Scheme 14.188) [325].

NH ArHN N H2N

85-90%

S

NH2 N NHAr

S

HN

NHAr N Cl

KSCN

NH2CSNH2 Cl N ArHN

65-85%

684

686

N N

HN

S

S

NH

N N Ar 687

Ar = Ph, 4MeC6H4, 4ClC6H4, 2,4Cl2C6H3, 4NO2C6H4

Scheme 14.188

NCS

SCN N NHAr

685

–NH3 Ar

ArHN N

14.4 1,3,4-Thiadiazoles

1,3,4-Thiadiazole derivatives 691 and 693 have been synthesized via reactions of hydrazonoyl bromide 688 with alkyl carbodithioates 689, potassium thiocyanate, or thiourea, according to Schemes 14.189 and 14.190 [326].

H N Ar N +

Br R

688

R3 R2

Et 3N

NNHCSSR1

R

S

690 –R 1 SH

69-90% R = 4-(Me) 2CHC 6 H4

R3

1

N N SR Ar

689

R2

NH N

Ar, 4-NO 2C 6H 4

R = Me, Et, Bn

R2

S

R

1

N N

N N

R 2 = H, Me, C 4H 8, C5 H10, C6 H12 , C 9H 10

Ar

R3 691

3

R = Ph, 4-MeC6 H 4, 4-MeOC 6 H4 , C 4H 8, C5 H10, C6 H 12, C 9H10 , 2-C 4H 3S, 2-C5 H 4 N Scheme 14.189

H 2N

NH2 S R

C NH H N Ar N

H 2N

EtOH, ∆

694

R

S

H

Br

N

N Ar

R

C N H N N Ar

S

KSCN R

EtOH, rt, 3h

692

688

S N N

695

NH2

73%

NH2

73%

S

R

N N

Ar

NH Ar

693 R = 4-(Me) 2 CHC6 H 4

Ar, 4-NO2 C6 H 4

Scheme 14.190

14.4.3.4 Synthesis of 2,3-Dihydro-(D2) (516), 3,4-Dihydro-(D3) (517), and 2,3,4,5Tetrahydro-1,3,4-Thiadiazoles (518) Under ultrasonic irradiation conditions a series of 2,3-dihydro-1,3,4-thiadiazole derivatives 698 and 700 and 5,50 -bi(3H-3-phenyl-2-(1-methyl-5-oxo-3-phenyl1H,4H-pyrazol-4-ylidene)-1,3,4-thiadiazole 702 have been synthesized from reaction of 1-methyl-5-oxo-3-phenyl-2-pyrazolin-4-thiocarboxanilide (696) with different hydrazonyl halides [697, 699], or N,N0 -diphenyl-oxalodihydrazonoyl dichloride

j1361

j 14 Thiadiazoles

1362

Me N N Ph Ph N

Et3N, EtOH

O

)))), 7 min Ph X

S N

Me N N

N

Ph

698

O

Ph

Ph N H 697

PhHN

SH

Me N N

Et3N, EtOH )))), 3-15 min ROC

X N

696

Ph Ar N

Ph N H 699

O S

N

COR

700

93%

90-95%

R = Ph, Me, OEt, PhNH, 2-thienyl Ar = Ph, 4ClC6H4, 3ClC6H4, 3MeC6H4

Me N N

NHPh N Cl O

Ph PhHN 696

SH

+

Cl N PhHN 701

O Et3N, EtOH

Ph

S

)))), 15 min 90%

Me N N

Ph N

N

Ph N

N Me

N

N Ph

S O

702

Scheme 14.191

(701). This technique reduces the time of reaction from several hours to minutes and increases the yields of the obtained products (Scheme 14.191) [327]. A general method for the synthesis of 1,3,4-thiadiazolines is the reaction of carbonyl compounds with substituted thiohydrazides. Thus, chiral 1,2,4-triazolo [3,4-b]-1,3,4-thiadiazoles 705 have been synthesized by the Mannich reaction of 3pyridyl-4-amino-5-mercapto-1,2,4-triazole (703) (synthetic equivalent of a thiohydrazide), with aromatic aldehydes or furaldehyde in the presence of a catalytic amount of tartaric acid. Some of the obtained products have shown significant antibacterial activities against Staphylococcus aureus, and Escherichia coli at 500 and 100 ppm concentrations (Scheme 14.192) [328]. Another recent application of this methodology is the synthesis of 50 -phenyl-30 Hspiro[indoline-3,20 -[1,3,4]thiadiazol]-2-ones 708, compounds that are able to inhibit the aggrecanase-2 with a selectivity in the sub-micromolar range. In particular, the reaction involves a condensation between arylthiohydrazides 706 and isatins 707 (Scheme 14.193) [329]. 4,5-Dihydro-1,3,4-thiadiazole-2-carboxamides 712 have been synthesized by acylation of hydrazones of thiooxamic acid hydrazides 711, which were obtained from thiooxamic acid hydrazides 709 with different aldehydes 710. Oxidation of

14.4 1,3,4-Thiadiazoles

N N

N

N NH2

N N

RCHO

SH

N N

L-(+)-tartaric acid

j1363

SH R

N

45-70°C, 5h

704

703 R = Ph, 4ClC6 H4 , 4NO2 C 6H 4, 4MeOC6 H 4, 4-HO-3MeOC6 H 3, 4ClC6 H4 , 2HOC6 H 4 , 2-furyl

53-95%

N N

S

N

N H

N

R

705 Scheme 14.192

R2 S N H

1

NH2

O

R2 +

R

706

R3

N R4

R3

O

EtOH

R1

40°C 65-72%

707

R1 = H, OMe, Me

R2 = H, Br, Me, Et, OCF3, Cl, NO2

R3 = H, n-Pr, Me, Cl,

R4 = H, Me, i-Pr, Bn, 2-MeC6H4, 4-ClC6H4

S N N

N R4

HO 708

Scheme 14.193

712 with hydrogen peroxide in acetic acid leads to 2-carbamoyl-4,5-dihydro-1,3, 4-thiadiazole 1-oxides 713 in good yields (Scheme 14.194) [330]. 2-Amino-5-aryl-5-hydrothiazolo[4,3-b]-1,3,4-thiadiazoles 715a,b have been prepared in 78–80% yield by treating 2-aryl-3-thioureido-4-thiazolidines 714a,b with cold concentrated sulfuric acid. These compounds were then transformed into unnatural a-amino acids 716a–d, containing the 1,3,4-thiadiazole core, by condensation with HCHO and a-amino acids (74–80%) (Scheme 14.195). Fungitoxicity has also been evaluated in vitro against Aspergillus niger and Fusarium oxysporium and it was found that compounds 716c,d (Ar ¼ ClC6H4, R ¼ H, Me) displayed activities comparable with that of the commercial fungicide Dithane M45 [331].

j 14 Thiadiazoles

1364

RCHO

O Ar

N H

O

710

H N

NH2

S

EtOH, 20 min. 50 °C

709

60-80%

Ar

N H

H N

N

O O

S

O N

R1

R 713

R1

Cl

DMF, r.t.

Ar HN

AcOH

O

H2O2

R

O

711 47-52%

Ar HN

N

S

N S

∆, 15 min

712

50-60%

O N

R1

R

Ar = Ph, 3,4-Cl2C6H3, 2,3-Me2C6H3, 3-MeC6H4 R = 2-Thienyl, Ph; 4-NO2C6H4, 5-methy-2-Thienyl R1 = Me, Et, Ph, 2-Thienyl Scheme 14.194

S Ar

N HN 714a,b

O S

H2SO4 78-80%

NH2

S

S N N

Ar

NH2 715a,b NH2CHRCO2H

HCHO

74-80%

S

S N N

Ar Ar = Ph, ClC6H4

N

R = H, Me, 716a-d

R

CO2H

Scheme 14.195

5-Benzilydene-1,3,4-thiadiazole-2,2(5H)-dicarbonitrile (718), in 28% yield, has been synthesized through the cyclization of N0 (phenylmethylidene)thicarbonohydrazide (717) promoted by tetracyanoethylene (TCNE) (Scheme 14.196) [332].

14.4 1,3,4-Thiadiazoles

Ph

N

H N

H N

TCNE NH2

N N CN

Ph

S

EtOAc, rt, 2h

S

28%

717

CN

718

Scheme 14.196

3-Phenyl- and 3-(p-tolyl)-10bH-1,3,4-thiadiazolo[2,3-a]isoquinoline-2(3H)-thiones (720) have been prepared in 86% and 82% yield, respectively, by 1,3-dipolar cycloaddition of N-phenyl or N-p-tolylimides, obtained by sodium carbonate treatment of 2-anilino or 2-(p-toluidino)isoquinolinium chlorides 719, with carbon disulfide (Scheme 14.197) [333].

N Cl 719

N H

Na2CO3

Ar

N

N

Ar

CS2

82-86%

48 h Ar = Ph, 4-MeC6H4 N S

N Ar S

720 Scheme 14.197

2,3,4,5-Tetrahydro-1,3,4-thiadiazoles 722 have been prepared by treating cyclohexanones 721 with hydrazine and H2S in ethanol at reflux for 12 h (Scheme 14.198) [334]. O

85-87%

R

HN NH

N2H4, H2S

721

R

S

R

722 R = H, OBz

Scheme 14.198

Phenyl isothiocyanate in the presence of sodium hydride reacts with different phenyl hydrazones 723 to afford 1,3,4-thiadiazolidines 724 in good yields (Scheme 14.199).

j1365

j 14 Thiadiazoles

1366

R1 2

R

N NH Ph + NaH 723

R1 = Me, Ph

1) PhNCS 2) H2O

H R1

Ph N N S

R2

NPh

724

55-97% R1 = R2 = (CH2)5

R2 = Me, Et, Ph, H Scheme 14.199

It is presumed that the anion of the hydrazones 725, formed initially, attacks the isothiocyanate and gives an intermediate ion 726 that cyclizes to 727, producing after water treatment the 1,3,4-thiadiazolidine 724 (Scheme 14.200). R1 R2

R1

N NH Ph + NaH

N N

R2

723

S C NPh

Ph

R1

N N

2

R

S

725

R1

N N

R2

S

NPh

726

Ph

Ph

H

Ph

H2O NPh

R1

N N 2

R

724

S

NPh

727

Scheme 14.200

Alternatively, the reaction of 723 with carbon disulfide yields 3-phenyl-1,3,4thiadiazolidine-2-thiones 728 (Scheme 14.201) [335]. Ph 1

R

R2

N NH Ph + NaH 723

R1 = Me, Ph R2 = Me, Et, Ph Scheme 14.201

1) SCS 2) H 2O 50-80%

R1 = R2 = (CH2)5

H R1

N N

R2

S 728

S

14.4 1,3,4-Thiadiazoles

14.4.4 Reactivity

The reactivity of the 1,2,3-thiadiazole system is expressed in a series of different chemical transformations: (i) ring cleavage reactions and rearrangements, (ii) reductive and oxidative processes, (iii) reactions due to the reactivity of heterocycle ring, and (iv) reactions of substituents. 14.4.4.1 Ring Cleavage Reactions and Rearrangements The 1,3,4-thiadiazole system is cleaved by bases. In particular, Goerdeler and Galinke have shown that 2-amino-1,3,4-thiadiazole (532) on heating with benzylamine gives mixtures of triazoline thione 730 and 2-benzylamino-1,3,4-thiadiazole (732) in a 1 : 1 ratio (80%) [336]. Formation of 730 most probably occurs via the ring-opened amidrazone intermediate 729 (Scheme 14.202).

N N H 2N

N NHCSNH 2

PhCH 2-NH 2

H

S 532

H

NHCH 2Ph

40%

729

N N

H 2N S HN CH2 Ph

-NH3

N N

40%

S

-NH3

N NH S N CH2 Ph 730

NHCH 2 Ph

732

731 Scheme 14.202

Under the same conditions, 2-methylamino-, 2-amino-, and 2-amino-5-phenyl1,3,4-thiadiazoles 733 react with methylamine to produce the corresponding triazoline-thiones 734 (Scheme 14.203).

N N R N H

S

MeNH2 R1

733 R = H, Me R1 = H, Me, Ph Scheme 14.203

50-70%

N NH N R 734

S

j1367

j 14 Thiadiazoles

1368

2-Amino-5-chloro-1,3,4-thiadiazole (735) and 5-amino-1,3,4-thiadiazole-2(3H)thione (736) react with a large excess of hydrazine hydrate on heating to give a mixture of 3,4-diamino-1H-1,2,4-triazole-5(4H)-thione (739) and 4-amino-3-hydrazinyl-1H-1,2,4-triazole-5(4H)-thione (740). This rearrangement probably arises from the ring-opened intermediates 737 and 738 (Scheme 14.204) [337]. N N H2N

Cl

S

HN NH

NH2NH2 H2O

735

S O NHNH 2

H2N

N NH H2N

S

HN +

H N

S

S

NHNH2

737

S

NHNH2

738

736 N NH H2N

S N NH2

45%

739

N NH H2NHN 45%

S N NH2

740

Scheme 14.204

Mesoionic thiadiazoles undergo ring fission at C2 to give open chain compounds. Thus, 5-phenyl-4-methyl-1,3,4-thiadiazolium-2-olate (741) produces by reaction with aniline compound 742 (Scheme 14.205) [256]. Me Ph

N N S

H

PhNH2 O

741

50%

HN Ph

N N

Me

O Ph

S

742

Scheme 14.205

Similarly, compound 743 on treatment with alkali hydrolyzes to N-benzoyl-Nphenyldithio-carbamate 745. This compound was gently warmed on a steam bath and transformed into 746 by extrusion of CS2; subsequent reaction with p-nitrobenzaldehyde furnishes hydrazone derivate 747 in 50% yield (Scheme 14.206) [338]. Hydrazine or alkylhydrazines cleave and recyclize the 1,3,4-thiadiazolium salts 748 to 1,2- dihydro-1,2,4,5-tetrazines 749 or 1,4-dihydro-1,2,4,5-tetrazines 750, respectively, in high yields (Scheme 14.207) [339]. The action of phenylhydrazine on 748 results in an alternative cyclization to yield 4amino-1,2,4-triazolium salts 752, most probably via the ring opened intermediate 751 (Scheme 14.208).

14.4 1,3,4-Thiadiazoles

Ph Ph

Ph

OH

N N

Ph

S

S

H

N N

HO

743

S

S

N N

HS

Ph

S Ph

744

O

745 H

Ph O

N

Ph NO2

N CH

747

Ph

4-NO2-C6H4CHO

N

O

50%

Ph NH2

746

Scheme 14.206

R3 N N R2

S

R1

R4 NHNH2

H

70-85%

R1

X

N

R3 N N

748

2

R N

or

N R1

R3 N N R4

R2 N

750

749

R2 = Ph, 4-MeOC6H4, 1-naphthyl, 2-furanyl, 2-thienyl R3 =Me, Ph, 4-BrC6H4, 4-O2NC6H4; R1 = Me, Ph, 4-MeOC6H4 R4 = H, Me, Et

X = ClO4, 4-MeC6H4SO3

Scheme 14.207

R3 N N R2

S

PhNHNH 2 R1

60-70%

X 748

R3 2

R

Ph

R1 N SH NH

751

R2 = Ph, 4-MeOC6H4, 1-naphthyl, 2-furanyl, 2-thienyl R3 =Me, Ph, 4-BrC6H4, 4-O2NC6H4; R1 = Me, Ph, 4-MeOC6H4 X = ClO4, 4-MeC6H4SO3 Scheme 14.208

R3 N N

N N

1

R

R2 N NHPh 752

j1369

j 14 Thiadiazoles

1370

Under mild, neutral conditions, 5-amino-2-imino-3-phenacyl-1,3,4-tiadiazolines 753, in accord with to the Dimroth rearrangement, isomerize to 5-amino-3-mercapto1-phenacyl-1,2,4-triazoles 754 in good yields (Scheme 14.209) [340].

N N H2N

S

CH2COAr NH

N

Et OH

H2N

reflux 60-66%

753

SH

N N CH2COAr 754

Ar = Ph, 4-MeOC6H4, 4-BrC6H4, 4-O2NC6H4; Scheme 14.209

A Dimroth rearrangement is also found when a solution of 5-ethyl-3-phenyl-1,3,4thiadiazol-2(3H)-imine (755) in aqueous NaOH is heated at 80
C for 5 h, to afford the triazole derivative 757 in 45% yield (Scheme 14.210) [341].

N N Et

S

Ph NH

755

OH 45%

N N Ph

Et S

Et

N

NH

N H N Ph

756

757

S

Scheme 14.210

Ring cleavage has also been reported for 1,3,4-thiadiazolo[3,2-a]pyrimidines. The substituent R2 influences the site of ring scission. Thus, isomers 758 and 760 react with 5% sodium hydroxide to give quantitative yields of methyl-thiouracil 759 by N–N bond cleavage. When R2 is an alkyl group (Me, Et, i-Pr), however, the S–C is broken, giving rise to 761 (Scheme 14.211) [342]. 1,3,4-Thiadiazoles, according to the substitution pattern, undergo thermal or photochemical fragmentation processes similar to that observed in a mass spectrometer. Thus, it was found that pyrolysis of 5-sulfanyl-1,3,4-thiadiazole-2 (3H)-thione (762) gave HNCS, CS2, and HCN, while the 5-methyl-1,3,4-thiadiazole-2(3H)-thione (763) yielded HCNS, MeNCS, HCN, and CS2 [343]. Analogous pyrolysis of 2-(tert-butyldisulfanyl)-5-methyl-2,3-dihydro-1,3,4-thiadiazole (764) produces, besides the expected fragmentation products, 2-methylpropene by an initial b-hydrogen elimination Scheme 14.212) [344]. 2-Alkylidene-1,3,4-thiadiazolines 765 irradiated in benzene solution at a wavelength greater than 360 nm produces a mixture of 766–768 in 19%, 29%, and 11% yield, respectively. The formation of these compounds can be explained by several different reactions, all of which are amenable to an initial cleavage of the 1,3,4thiadiazole ring (Scheme 14.213) [345].

14.4 1,3,4-Thiadiazoles

O

O N N S

R1

100%

R2

OH

R1

HN HS

N N

100% N

Me

OH

O

N

759

758

R2

S 760

R1 =Me R2 = H

R1 = Me R2 = H

R1

O

O N N

H2N

OH

R2

S

R1

j1371

N

HS

N N

OH

N

O

Me

760

761

758

R1 = Me R2 =Me, Et, i-Pr

1

R = Me R2 =Me, Et, i-Pr

S

N

R2

60-70%

Scheme 14.211

N NH HS

pyrolysis

S

S

HCN + HNCS + CS2

762 N NH Me

pyrolysis S

S

HNCS + MeNCS + HCN + CS2

763 N N Me

S

S

Me

Me

CH2

H

N N

pyrolysis

Me

S

S

S

SH

+

Me

Me

764

HNCS + MeNCS + HCN + CS2 + S2 Scheme 14.212

TMS

t

Bu

S N N 765

Scheme 14.213

t

Bu

hν > 360 nm

t

S Bu TMS

N N 766 19%

+ t

Bu

+ TMS

N N But

t

Bu

TMS

C S

767

768

29%

11%

j 14 Thiadiazoles

1372

Thermolysis of 1,3,4-thiadiazolines 769 yields the corresponding thiiranes 770. In contrast, matrix photolysis in an organic glass at 77 K or in solid Ar at 10 K allows the detection of the thiocarbonyl ylides 772, which were characterized by intense UV maxima at l ¼ 350 nm. The thiocarbonyl ylides are formed in a stepwise manner, and not directly from the thiadiazolines, by elimination of N2. In the first step, compounds 769 are cleaved into the thioketones 771 and diazomethane. This latter compound generates methylene as carbene that, reacting with thioketones 771, produces the corresponding thiocarbonyl ylides 772 (Scheme 14.214) [346].

S

R R

770

53-78%

R R

R R

O C=

C

C ;

;

C

∆

N N S

R

hν > 360 nm

R

769

771 R

R

S

+

S

R

CH 2N2 –N2

S CH2

R 772 Scheme 14.214

4,5-Diphenyl-1,3,4-thiadiazolium 2-thiolate (773a) is cleaved on irradiation at 253.7 nm, in acetonitrile as solvent, to give N-phenylthiobenzamide in 27% yield and sulfur 35%. Similarly, irradiation of 1,3,4-thiadiazolium 2-thiolates 773b gives Nphenylthiacetoamide and N-methylthiobenzamide in 20% and 21%, respectively, together with elemental sulfur (35–40%). This fragmentation has been rationalized through an initial valence tautomerization to N-isothiocyanatothioamide 774, which undergoes homolytic fission of N–N bond to yield the radical precursor of the thioamide and isothiocyanate radicals. The latter radical loses elemental sulfur, while the former abstracts a hydrogen from the solvent and produces the corresponding thioamide (Scheme 14.215) [347]. 14.4.4.2 Reductive and Oxidative Processes 1,3,4-Thiadiazoles are stable to reducing and oxidizing agents. However, some reductions have been reported. In particular, reduction with hydrogen/palladium of 2-bromo- and 2-bromo-5-methyl-1,3,4-thiadiazoles 775 produced, in about 90% yield, the corresponding debrominated 1,3,4-thiadiazoles 512 and 520, respectively (Scheme 14.216) [278].

14.4 1,3,4-Thiadiazoles R1 R

S

R

N N

R1

S

hν

S

N N

MeCN

773 a,b

S 774

R = Ph, Me R 1 = Me, Ph

R

NH

R1

S

R

MeCN 20-27%

R1

N S

N C S

35-40%

S

Scheme 14.215

N N R

S

N N

H2 /Pd Br

90%

775 R = H, Me

R

S 512, 520

Scheme 14.216

2-Amino-5-phenyl-1,3,4-thiadiazole 573 has been reduced with sodium amalgam to benzaldehyde and thiosemicarbazone 776 (Scheme 14.217) [256].

H2N

S

HN N

Na(Hg)

N N Ph

79%

H 2N

Ph

S

+

PhCHO

776

573 Scheme 14.217

2-Acetylamino-5-benzylmercapto-1,3,4-thiadiazole (777) is reduced to 2-ethylamino-5-benzylmercapto-1,3,4-thiadiazole 778 in 41% yield by reaction with lithium aluminum hydride (Scheme 14.218) [348].

PhH2C

N N S

S 777

LiAlH4 NHCOMe

41%

PhH2C

N N S

S

NH

Et

778

Scheme 14.218

Lithium aluminum hydride also reduces the mesoionic compound 779 to hydrazine derivative 780 with loss of sulfur (Scheme 14.219) [256].

j1373

j 14 Thiadiazoles

1374

Me

LiAlH4

N N

Ar

O

S

HN N Me

63%

Me Ar

780

779 Ar = Ph, Tolyl Scheme 14.219

Oxidation of 1,3,4-thiazolidine-2,5-dione 781 with tert-butyl hypochlorite gives at 78
C thiadiazolinedione (782), which in situ undergoes Diels–Alder reactions with several dienes to provide the corresponding cycloadducts 783 in good to excellent yield (Scheme 14.220) [349]. O

Cl

HN NH O

N N O

S

O

-78°C

S

781

O

57-76%

782 Me

O N N 783:

O

Diene

O

N N

S O

Me

75%

S O

76% N N S 62% O

R N R N

S

783 Me

O

N N Me

S O

O O

Me

N N

Me

50%

75% O Ph

O Ph

N N 57%

S O

O S O

Scheme 14.220

Sulfoxide 785 and sulfone 786 derivatives have been obtained by oxidation of 2(ethylsulfanyl)-1,3,4-thiadiazole- 784 with m-chloroperbenzoic acid (MCPBA) (Scheme 14.221) [350]. 14.4.4.3 Reactions due to the Reactivity of the Heterocyclic Ring Electrophilic substitution on the C-atoms of the ring is very difficult owing to two main problems: (i) the presence of two nitrogen atoms in the ring, which leaves these carbons with a very low electron density, and (ii) the protonation of nuclear nitrogen in acidic media, which reduces strongly the possibility of this type of reactions. Thus, reactions such as nitration, sulfonation, acetylation, halogenation, and so on normally do not take place.

14.4 1,3,4-Thiadiazoles

Et

N N S O

S

Me N

NO2

S

MCPBA 70%

N

785

Me N

N N

Et

1 eq.

S 784

MCPBA

NO2

N

3 eq.

80% Me N

N N

Et

S O O

S

NO2

N

786 Scheme 14.221

However, it has been reported that the presence of amino groups linked to position2 allow the bromination reaction; thus, and 2-amino-substituted-5-bromo-1,3,4thiadiazoles 788 have been prepared in good yield, starting from 2-amino-1,3,4thiadiazoles 787 (Scheme 14.222) [351]. N N R1RN

S

N N

Br2 /AcOH

R1RN

70-90%

787

S

Br

788

R = H, Me R1 = H, Me, NO, COMe, COPh Scheme 14.222

The alkylation reaction occurs easily on the annular nitrogen atoms; thus, quaternary salts are formed. In the case of mono- or dialkyl-1-3,4-thiadiazoles 789, the alkylation is regioselective and the product distribution 790 versus 791 depends on the bulky group present at C2. When this carbon is substituted with a tertbutyl group, quaternization occurs almost exclusively at N4 (Scheme 14.223) [352]. Me N N R1

S 789

R2

CH3I 50°C

R1

N N R2 S 790 2-55%

R1 = H, Me, Et, i-Pr, t-Bu Scheme 14.223

N N

+

R2 = Me, Et, i-Pr

R1

Me

R2 S 791 45-97%

j1375

j 14 Thiadiazoles

1376

Trimethylsilylmethyl trifluoromethanesulfonate 792 is an efficient alkylating agent for 2,5-disubstituted-1,3,4-thiadiazoles. In fact, 2,5-diphenyl- and 2,5-dimethyl-1,3,4-thiadiazoles 793 react in dry dichloromethane (DCM) with 792 to give in high yield the corresponding salts 794 (Scheme 14.224) [270].

TMSCH2OTf

+

792

dry DCM

N N R

R

S

Me3Si

75-95%

793

R

N N S

R

794 R = H, Me, Ph

Scheme 14.224

Other alkylating agents have been used, such as triethyloxonium tetrafluoroborate, benzyl chloride, p-bromophenacyl bromide, octyl iodide, and so on (Scheme 14.225) [353]. N N

R

R1 X

N N

72-95%

S

S

512

514 X = BF4, Cl, Br, I

R = Et, PhCH2 , 4-Br-C6 H4 -COCH2 Scheme 14.225

In most cases, 2-amino-1,3,4-thiadiazoles are also alkylated at the N3 atom of the ring [354]. Thus, 2-amino-5-methyl-1,3,4-thiadiazole (733) reacts with chloroacetone to afford the N-alkylated thiadiazolimine 795 in 75% yield (Scheme 14.226). Me

O

Cl

N N

Me

S

NH2

733

Me 75%

O

N N

Me HN S HCl 795

Scheme 14.226

Amino derivatives are acylated at the amino group. Thus, it has been reported that 2-amino-5-(5-nitro-2-furyl)-1,3,4-thiadiazole 796 by reaction with acetic anhydride is transformed into 2-acetylamino derivative 797 in 95% yield (Scheme 14.227) [355].

14.4 1,3,4-Thiadiazoles

N N

O2 N

NH2

S

O

NH

S

Pyridine

O2 N

80-90°C

796

O

N N

Ac2O

Me

797

95%

Scheme 14.227

A similar reaction is observed with chloroacetyl chloride. Thus, starting from 798, a series of 2-chloro-N-(5-aryloxymethylene/aryl-1,3,4-thiadiazol-2-yl)acetamides 799 have been synthesized in 81–91% yield (Scheme 14.228) [356]. O Cl

N N R

S

NH2

O

N N

Cl R

K2CO3 /DMF

NH

S

r.t.

798

Cl

799

74-91%

R = PhOCH2, 2-ClC6H4OCH2, 2-Me-C6H4OCH2, 4-Me-C6H4OCH2, 4-Cl-C6H4OCH2, 4-MeO-C6H4OCH2, 2-MeO-C6H4OCH2, 3-Me-C6H4OCH2, 3-NO2-C6H4OCH2, 4-NO2-C6H4OCH2, 2,4-Cl2-C6H3OCH2, Ph, 2-ClC6H4, 3-MeC6H4, 3-NO2C6H4 Scheme 14.228

Owing to the strong electron-withdrawing effect of the thiadiazole ring, carboxylic acids with the carboxyl group attached to the ring are rather unstable. Thus, Holmberg, on acidification of the sodium salt of 5-phenyl-1,3,4-thiadiazole-2-carboxylic acid (800), obtained a mixture of the acid 801 (40%) and 2-phenyl-1,3,4thiadiazole (802) (60%) (Scheme 14.229) [357].

N N Ph

S 800

ONa O

H

N N S

CO2H

+

N N Ph

S 802

801 60%

40%

Scheme 14.229

The Mannich reaction of 1,3,4-thiadiazole derivatives with different amino groups occurs at the N3 ring atom. Thus, it has been reported that 1,3,4-thiadiazolidine-2,5dithione 803 with dialkylamines and formaldehyde give N,S-aminomethylated thiadiazoles 804. With urea, thiourea, semicarbazide, or thiosemicarbazide N,Naminomethylated thiadiazoles 805 have been obtained (Scheme 14.230) [258]. Cycloaddition reactions have been reported for the 1,3,4-thiadiazole moiety. In particular, 2,5-bis(trifluoromethyl)-1,3,4-thiadiazole (806) has been used as 4p

j1377

j 14 Thiadiazoles

1378

R2NH/CH2O

HN NH S

S

S

S

69-70%

NR2

S N N 804

803

S NR2

R2NH = Diethylamine, Morpholine, Piperidine 89-98%

CuCl R2NH/CH2O

S

S

S

N N

R2N

NR2

R2NH = urea, thiourea, semicarbazide, thiosemicarbazide

805 Scheme 14.230

component in a Diels–Alder reaction, giving rise with norbornadiene to bicycloadduct 809. The formation of this compound was rationalized via the initial cycloadduct 807, which loses molecular nitrogen to generate a thiocarbonyl ylide (808) that reacts with a second molecule of norbornadiene (Scheme 14.231) [358].

S N N F3C

S

CF3

F3C

CF3 N N

807

806

-N2

S CF3 F3C 809

CF3 S

29% F3C 808

Scheme 14.231

A Diels–Alder reaction has also been reported for mesoionic 1,3,4-thiadiazoles. Thus, treatment of 4,5-diphenyl-1-thia-2-thio-3,4-diazolium thiols 810 with a twofold molar excess of dimethyl azodicarboxylate (811) in benzene under reflux for 12 h yields the corresponding adducts 812, which undergo subsequent sulfur extrusion to intermediates 813, which with a concomitant oxidation reaction produce the final products 814 in 62–65% yield (Scheme 14.232) [359].

14.4 1,3,4-Thiadiazoles

Ph

N N

Ar

CO2Me N N MeO2C 811

S

S

S S N Ar

Ph

810

812

Ar = Ph, ClC6H4

–S

S

S N N

CO2Me N N CO2Me

N

MeO2C

811

N N

MeO2C

Ph

N N

Ar

N N

Ph

Ar 813

814 Scheme 14.232

2,5-Dihydro-1,3,4-thiadiazoles are able to produce under thermal conditions thiocarbonyl ylides that can be trapped with suitable dipolarophiles. Thus, as already reported [346], compound 815 gave 816 and then 2,5-dihydrothiophenes 818 by reaction with different acetylenic derivatives 817 (Scheme 14.233). R

N N

∆

R

S

R

S

R

815 R R

R1

41-65%

O C=

816

817

C R1

R1 = CN, PhCO, CO2 Me

R1

R1

R R

S 818

Scheme 14.233

2,3-Dihydro-[(thioacyl)methylene]thiadiazoles 819 undergo cycloaddition reaction with acetylenedicarboxylate to furnish spiro cycloadducts 820 in 50–60% yield. The reaction was carried out in chlorobenzene solution under reflux. Surprisingly, the reaction rates were strongly enhanced upon UV irradiation (l > 300 nm), which allowed the reaction to occur at room temperature in dichloromethane solution (Scheme 14.234) [360].

j1379

j 14 Thiadiazoles

1380

S S

R1

CO 2Me

MeO 2 C

R2

CO 2 Me

MeO 2 C

N N

S

R1

S

N N

50-60% R 819

R2 R

820 R1

Ph

COMe

CO 2 Et

R2

Ph

Me

Me

R

H

3,5-dimethyl

H

Scheme 14.234

The thiocarbonyl moiety of 1,3,4-thiadiazole-2(3H)-thiones 821 reacts as 2p component in a 1,3-dipolar cycloaddition reaction with N-methyl-C-phenylnitrilimine (822) to give, via the intermediate cycloadduct 823, the rearranged products 824 and 825 in 16–28% yields (Scheme 14.235) [361].

Ph HN N S

S 821

S R

+

Ph

N N

CH3

N S CH3

822

S

N N H3C

825

S R

823

R = Me, Et, t-Bu, Me-C6H4-CH2, Cl2-C6H3-CH2

CH3 N N N N S Ph

H S N N

Ph

16-28%

CH3 N N

+ Ph

S

S S S S

N

N

S

Ph

N N H3C

824

Scheme 14.235

1,3,4-Thiadiazolium-3-methanide 1,3-dipoles 827, generated in situ from 3-trimethylsilylmethyl-1,3,4-thiadiazolium trifluoromethanesulfonates 826 with CsF at 60
C, afforded by reaction with substituted alkenes the substituted pyrrolo[2,1-b] [1,3,4]-thiadiazole systems with endo selectivity. In particular, the reaction performed with N-substituted maleimide is the first example of bowl-shaped tricyclic

14.4 1,3,4-Thiadiazoles

nitrogen–sulfur (828 and 829) analogues of the tripentagon bowl, a 3,4,10-triaza-6thiatricyclo[6,3,0,03,7]undecane ring system (endo selectivity range 6.6–1.1) (Scheme 14.236) [270].

Me3Si R

S 826

H2C

CsF

N N

N N

R

R

R

S 827

R = H, Me, Ph R1 = Me, CH2Ph, t-Bu, adamantyl, Ph, p-MeC6H4, p-BrC6H4

O N R1

37-70%

O

H R

S

RH 829

H

O

N N

N R1

+

N N R

S

O

RH

828

Exo

O N R1

O Endo

Scheme 14.236

1,3,4-Thiadiazoles containing a good leaving group at the carbon atoms of the ring can undergo nucleophilic substitutions. Thus, it has been reported that 2-bromo1,3,4-thiadiazole (830), by reaction with methylamine or thiourea, affords the Nmethylamino and 2-mercapto-1,3,4-thiadiazoles 831 and 832 in 80% and 75% yield respectively (Scheme 14.237) [278]. N N

(NH2)2 CS/OH Br

S 830

S 832

NH2 Me 80%

N N S

75%

N NH

NHMe

831 Scheme 14.237

S

j1381

j 14 Thiadiazoles

1382

Some other nucleophilic reactions, involving 2-chloro-5-aroyl-1,3,4-thiadiazoles 833 (Scheme 14.238) lead to the corresponding thiadiazoles 834–837 [362]. N N

Ar O

S Ph

S 835

PhSNa

N N

Ar

62%

O

PhNH2

79%

S 833

(NH2)2CS/OH

Cl

NaN3

75%

S

O

836

O

S

S

834

79%

N N

Ar

N NH

Ar

N N

Ar

NH Ph

O

S

N3

837

Ar = 4-ClC6H4, 4-MeC6H4, 4-NO2C6H4 Scheme 14.238

A chlorine atom can be easily displaced in reactions involving simple esters as anion. Thus, tert-butyl 2-(5-phenyl-1,3,4-thiadiazol-2-yl)acetate 839 in 79% yield has been recently prepared by reaction of 2-chloro-5-phenyl-1,3,4-thiodiazole (838) with tert-butyl acetate in the presence of sodium hexamethyldisilazide (Scheme 14.239) [363].

Ph

S

N N

t-ButylOCOMe

N N Cl

838

PhMe, NaHMDS

Ph

CO2 t-Butyl

S

79% 839

Scheme 14.239

Thioalkyl or sulfonyl substituents, which are good leaving groups, can be substituted by a range of nucleophiles. Scheme 14.240 shows several examples of such reactions, leading to different 1,3,4-thiadiazoles 841, 843–845, and 847 [364]. A solid-phase synthetic route, from Merrifield resin, has been exploited to prepare various 2-amino-5-substituted-1,3,4-thiadiazoles (849) by nucleophilic displacement of the sulfonyl group (Scheme 14.241) [306]. 14.4.4.4 Reactions of Substituents 2-Amino-1,3,4-thiadiazoles are easily diazotated using strongly acid solutions. The intermediate diazonium salts have been used to prepare various substituted 1,3,4thiadiazoles (Scheme 14.242) [278]. 2-Halo-1,3,4-thiadiazoles can be also prepared according to Sandmeyer reactions. Thus, 2-chloro-5-phenyl-1,3,4-thiadiazole (853) has been synthesized in 85% yield by reaction of 2-amino-5-phenyl-1,3,4-thiadiazole (573) with amyl nitrite in the presence of CuCl generated in situ (Scheme 14.243) [363].

14.4 1,3,4-Thiadiazoles

H N O

N

N

S N

S

N N

O

CH3

N

N

O

S N

∆, 55%

R2

N N R

Me N N ClO4

R1NH2

N R1 S 843

O

N

N N 841

840

Me

R

85-90%

R3

SMe

S

NH2 N N N

74-99%

R

79-96%

Me N

S

842

1

R2 = Me

R1NHNH2

N N

R3 = Ph

R

Me

S

N

NHR1

845 N N S

HO t-Bu

O

846

S

t-Bu

NaOR

CH3

S

HO

56-84%

O

N N O

R

t-Bu 847

R = Me, Et, Pr, I-Pr

Scheme 14.240

N N S O O

S 848

1,4-dioxane R

1 2

R R NH 100°C

N N R

S 849

R2 R3

844

R = C6H11, Ph

t-Bu

j1383

R2 N R1

40-70% R1R2 NH = Piperidine, Isobutylamine, Morpholine, Cyclohexylamine, Dibenzylamine Scheme 14.241

2-Chloro-N-(5-aryloxymethylene/aryl-1,3,4-thiadiazolo-2-yl)acetamides 799 treated with ammonium thiocyanate under microwave irradiation provide, in only 5 min, 2-(5-aryloxyme-thylene/aryl-1,3,4-thiadiazolo-2-ylimino)thiazolidin-4ones 854 in optimal yields (Scheme 14.244) [356].

j 14 Thiadiazoles

1384

N N R

N N

NaNO2 /HCl NH2

S

H

R=H 70%

850

Cl

S 851

HBr

NaNO2

75-80% N N R

R = H, Me

Br

S 852

Scheme 14.242

Ph

N N

amylnitrite, CuCl2

N N

MeCN, 55 °C

NH2

S

Ph

85%

573

S

Cl

853

Scheme 14.243

O O

N N R

S

NH 799

Cl

NH4SCN DMF, MW 78-98%

HN

N N R

S

N

S

854

R = PhOCH2, 2-ClC6H4OCH2, 2-Me-C6H4OCH2, 4-Me-C6H4OCH2, 4-Cl-C6H4OCH2, 4-MeO-C6H4OCH2, 2-MeO-C6H4OCH2, 3-Me-C6H4OCH2, 3-NO2-C6H4OCH2, 4-NO2-C6H4OCH2, 2,4-Cl2-C6H3OCH2, Ph, 2-ClC6H4, 3-MeC6H4, 3-NO2C6H4 Scheme 14.244

A series of 5-thiosubstituted-1,3,4-thiadiazo-2-yl-2-carbamates 858 and 862 as potential antimicrobial agents has been synthesized starting from 2-amino-5-mercapto-1,3,4-thiadiazole (856), according to standard procedures. In particular, the corresponding 5-alkyl or alkenylthio derivatives 858 have been prepared via 857 by reacting 856 with alkyl or allylic halides, followed by treatment with ethyl or allyl chloroformate in 72–80% yield. The butynylamino derivatives 862 have been prepared by reaction of 856 with propargyl bromide (859), via the propynylthio analog 860 (75%), followed by reaction with chloroformates to give 861 and subsequent reaction with formaldehyde and secondary amines (Scheme 14.245). Most of the thiadiazoles so obtained exhibited some activity against Pseudomonas aeruginosa and Candida albicans. The thiadiazole containing the perhydroazepino moiety was more active against C. albicans than phenol (used as standard) [365].

14.4 1,3,4-Thiadiazoles

R

S

NH2

S

N N

R1X

N N

1

HS

OH

72-80%

H2N

856

857

N N

OH NH2

S

859

j1385

S

S 860

Br

75%

ROCOCl

65-75%

ROCOCl

R1 = Allyl, Et, Pr R1

N N S

S

N N

NHCOOR

HN

RO

858

O CuCl HN

(CH2)n = Morpholine, Piperidine, Pyrrolidine

S 861

CH2O/HN

HN

S

O

S

N

862

Scheme 14.245

5-(Benzylthio)-N-ethyl-1,3,4-thiadiazol-2-amine (864) can prepared in similar way in 100% yield by reaction of 2-ethylamino-5-mercapto-1,3,4-thiadiazole (863) with KOH and benzyl chloride (Scheme 14.246) [348]. N N

HS

S

NH

863

Et

KOH PhCH2 Cl

PhH2 C

N N S

100%

S

(CH2)n

60-80%

N N RO

S

NH

Et

864

Scheme 14.246

It was found that the methyl group attached at carbons of 1,3,4-thiadiazoles shows fair acidity when treated with a strong base. Thus, when 2-methyl-5-phenyl- or 2,5dimethyl-1,3,4-thiadiazoles 865 and 867 were reacted with butyllithium, or NaH, or lithium diisopropylamide, followed by addition of CO2, aldehydes, ketones, or acetic acid, 5-substituted derivatives were obtained (866 and 868–870) (Scheme 14.247) [366]. 14.4.5 1,3,4-Thiadiazoles in Medicine and Agriculture

One of the best known drugs based on a 1,3,4-thiadiazole is acetazolamide (871, acetazolam), a carbonic anhydrase inhibitor launched in 1954. Compound 871 has

(CH2)n

j 14 Thiadiazoles

1386

N N R

S 865

BuLi Me

N N R

CO2

CO2H

S

31-72%

866

R = Me, Ph N N Me

LDA (1 equiv)

OH

S

- 78 °C

Ph

868

LDA (5 equiv)

N N Me

PhCHO

PhCHO

867

43-79%

Ph

- 78 °C

Me

S

OH

N N

S

HO Ph

869

41-77%

NaH (2 equiv) AcOH

Me

N N

COMe

S 870 50%

Scheme 14.247

many indications, including the treatment of glaucoma, epilepsy, and congestive cardiac failure [367]. 1,3,4-Thiadiazoles exhibit various types of biological activities and some of these compounds are useful pharmacophores. This nucleus is found in some antiviral derivatives such as 872 (anti HIV-1 and HIV-2) [368] and 873 (anti HIV-1) [369], and also in the treatment of neurodegenerative diseases and cancer (such as 874 [370] and 875 [371]). H2N O

N N S

O

S

NH Me

O

871

N

N

Me

S

H N

NH2

N N

O

Cl

Cl

872

S N

N

S

Me

873

Anticancer activity has also been found for 2-amino-1,3,4-thiadiazole (ATDA, NSC-4728) and related compounds (EATDA, NSC-143 019) [372]. Recently several N-substituted-2-amino-5-(2,4-dihydroxyphenyl)-1,3,4-thiadiazoles have shown

14.4 1,3,4-Thiadiazoles

a marked antiproliferative activity in vitro. In particular, the highest antiproliferative activity was found for 2-(2,4-dichlorophenylamino)-5-(2,4-dihydroxyphenyl)-1,3,4thiadiazole (876), with an ID50 two times lower (human cell lines SW707 and T47D) than cisplatin studied comparatively as the control compound [373].

N

O S

S N N

Me N

O H2 N

N

S

Me N N

O

S

N

Cl

874

875

Cl HO

N N

NH

S HO

Cl

876

It is also used as bactericidal; compounds 877 and 878 are active against Helicobacter pylori [374]. Cl N N O2 N

O

S

SEt

S O2 N

N N

Me N

S

S

N 878

877

Some compounds posses muscle relaxant properties. Thus, recently, Bhandari et al. have shown that derivatives 879 and 880 have significant anticonvulsant activity against maximal electronic shock model compared to standard drugs phenytoin, diazepam, and phenobarbital [375]. Me N Me

N N

O N

S

Me N Me

N N

O N

S

N

N

F

NO2 879

880

Moreover many 1,3,4-thiadiazole derivatives have also been patented in the agricultural field as pesticides, herbicides, insecticides, fungicides, and so on. Two examples are reported here: in particular compound 881, which shows fungicidal

j1387

j 14 Thiadiazoles

1388

activity against Venturia inaequalis [376], and compound 882, which is an anti-tobacco mosaic virus agent [377]. Me Cl O F3 C

N

O S N N

NH

S

N

N N

Ph

Me Cl

N N

881

S

882

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2

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6

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j1401

15 Five-Membered Heterocycles with Four Heteroatoms: Tetrazoles Ulhas Bhatt

15.1 Introduction

Tetrazoles are five-membered ring aromatic compounds composed of one carbon atom and four nitrogen atoms such that the four nitrogen atoms are linked contiguously to each other. Tetrazoles have 6p electrons and exist as either the 1H- or the 2H-tautomer (Figure 15.1). In solution, the 1H tautomer is the predominant form, but in the gas phase the 2H-tautomer is more stable. Disubstituted tetrazoles can be prepared by substituting the ring hydrogen, producing both 1,5- and 2,5-disubstituted tetrazoles. Various substitutions can adorn the tetrazole ring, from heteroatoms like N, O and S, to alkyl, aryl and heteroaryl groups. In addition, the tetrazole ring can be part of a fused ring system. X-Ray structures have confirmed the planarity of the ring system with N
N bond lengths being of nearly equal length. The cyclic C
N¼N and N
N¼N groups’ vibrational frequencies are observed at 1000–1100 cm
1 in their infrared (IR) spectra. Weak to medium intensity bands occur in the 1200–1300 cm
1 region due to N
N vibrations and a strong N
N stretching band can be seen at 1270–1300 cm
1. The C¼N band occurs at 1450–1500 cm
1. The 5-CH stretching frequency of tetrazole is at 3146 cm
1 and in several N-alkyl compounds this is shifted to below 3138 cm
1. 15 N and 13 C NMR spectroscopy are useful tools in the determination of the substitution pattern. The C5 signal in 2-substitued tetrazoles is usually up to 10 ppm deshielded when compared to the 1-substitued tetrazoles. Although tetrazoles are an important compound class in their own right, they are used extensively as surrogates for carboxylic acids in medicinal chemistry. They have similar pKa values (tetrazole has a pKa of 4.76) and generally exhibit greater metabolic stability than carboxylic acids. Tetrazoles are also weak bases, exhibiting a pKa in the range of
3. The hydrogen at position 1 (N1) can participate in intermolecular hydrogen bonding with the other pyridine-type nitrogen atoms. Tetrazoles carrying an N1 substituent are unable to create these strong hydrogen bonds and thus exhibit significantly lower melting and boiling points than N1 unsubstituted tetrazoles. The tetrazole ring exhibits a strong electron-withdrawing inductive effect (
I effect) that is more

Modern Heterocyclic Chemistry, First Edition. Edited by Julio Alvarez-Builla, Juan Jose Vaquero, and José Barluenga. Ó 2011 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2011 by Wiley-VCH Verlag GmbH & Co. KGaA.

j 15 Five-Membered Heterocycles with Four Heteroatoms: Tetrazoles

1402

4

3

N N

5

R

N N

N2

N H

1

1H-tautomer

NH

N

R

2H-tautomer

Figure 15.1 Tautomers of tetrazoles.

effective than its weaker mesomeric effect ( þ M effect). The tetrazole ring thus has a deactivating effect, especially when substituted with a strong activating group. Tetrazoles are useful in various applications like pharmaceuticals, agriculture, photography, polymers and explosives (Figure 15.2). In medicinal chemistry, biphenyl tetrazoles have shown potential as stimulators of growth hormone release, metalloprotease inhibitors and chloride channel blockers. Tetrazole chemistry has been extensively reviewed and so this chapter will cover the latest advances in the field [1]. Special attention has been paid to syntheses performed using newer technologies like solid-phase and microwaves.

15.2 Synthetic Methods

Many methods for the synthesis of tetrazoles utilize an azide as the source of three of the four nitrogen atoms. A range of compounds, like acid chlorides, amides, amidines, carbodiimides, carbonimidic dichlorides, cyanates, imines, isocyanates, isothiocyanates, isocyanides, ketones, nitriles, nitrilium salts, orthoesters, oximes, oxazolones, and thiocyanates, react with inorganic azides (e.g., sodium azide) to produce tetrazoles. This is by far the most popular and extensively studied route for Cl N n-C4H9

OH

OH N N N NH

N

H3C O2N

HN N

Losartan (antihypertensive)

N N N N

I

Fungicide

I I

H2N

N N

HN N

Fuel additive

N N

N

N PTZ (CNS agent)

Figure 15.2 Useful tetrazole compounds.

R1 N

O N NH N N

N

Image stabilizer

R2

CH3

N

Tomelukast (anti-asthmatic) R1 Ar N N N+ N R22X-

N+ N N Ar electronic display component

15.2 Synthetic Methods

the synthesis of tetrazoles. The most commonly used azide sources are sodium azide (as a suspension in DMF or acetone or under phase-transfer conditions), ammonium azide (generated in situ) and trimethylsilyl azide. Tetrazoles can also be prepared from azidoaziridines, triazoles, and triazines. 15.2.1 Amides as Substrates

Amides react with sodium azide in presence of reagents like PCl5, POCl3 or SOCl2 to generate the corresponding 5-substituted tetrazoles. This reaction proceeds through the chlorination of the amide to generate the imidoyl chloride, which reacts with the azide to produce the tetrazole. When PCl5 is the chlorinating reagent, the reaction is called the von Braun–Rudolph reaction, but product yields are usually moderate. This methodology has been utilized to prepare tetrazole derivatives 1 (Scheme 15.1) [2]. O R1

N H

R2

Cl

PCl5 R1

pyridine

NaN3 N

R2

acetone, H2O

R2

R1

R1

N N N N R2 1 Yield

30–50% N

R

N

R = 4-Me, 4-Cl, 2-Cl, 4-NO2 30% N

NH

50% N

S N OMe 40%

Cl(CH3)4

Scheme 15.1 Synthesis of tetrazoles from amides [2].

In a Mitsunobu-type variation of this reaction, an amide is treated with excess triphenylphosphine, trimethylsilyl azide and diethylazodicarboxylate (DEAD) to generate the corresponding tetrazoles [3]. This methodology was utilized in the

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j 15 Five-Membered Heterocycles with Four Heteroatoms: Tetrazoles

1404

synthesis of a series of tetrazole-ring containing growth hormone secretagogues. It was also used successfully to prepare compound 2 (Scheme 15.2) where the cyanoethyl group does not react under these conditions with TMSN3 to produce the second tetrazole ring and can be removed later under basic conditions. When poor yields of tetrazole products are observed using this route, it may be worthwhile treating the amides with Lawesson’s reagent and then subjecting the resulting thioamides to Mitsunobu conditions to produce the tetrazole products. This strategy has been cleverly utilized to convert linear Nv-tritylated v-amino thiobenzylamides and Na,Nv-ditritylated polyamino mono- or bisthioamides into the corresponding tetrazole derivatives 3 [4]. O H2N

O R

1. 2 eq TMSN3 PPh3, DEAD

CN R

NH

2. OH-

OH CN S

Trt

Trt

N H H N

NH X NH

10-60%

Me3SiN3 PPh3, DIAD

Trt

[50–75%]

Trt

N H H N

S

3 X = (CH2)4, (CH2)8, (CH2CH2O)2CH2CH2, C6H4CH2C6H4

N N N N R H 2

N N N N X N N N N

Scheme 15.2 Synthesis of tetrazoles from amides and thioamides under Mitsunobu conditions [3, 4].

In a related reaction sequence, substituted anilines are reacted with ethyl oxalate and triethylamine to produce the corresponding ketoamides (Scheme 15.3) [5]. These were treated with triphenylphosphine in refluxing carbon tetrachloride followed by reaction with sodium azide to produce the tetrazole compounds 4. Recently, the conversion of amide into tetrazole has been reported by using tributyltin chloride and sodium azide [6].

O NH2 ethyl oxalate, NEt3 R

OEt

HN O

OEt O

2. NaN3, CH3CN

80–95%

R = F, Cl, CN, NO2

1. PPh3, CCl4, reflux

N N N N

R

R

23–82% 4

Scheme 15.3 Synthesis of tetrazoles from ketoamides [7].

The tetrazole ring has also been proposed as a replacement of the cis-amide bond in peptides (Figure 15.3) [7]. Peptides that contain the tetrazole group in place of a

15.2 Synthetic Methods

O HN Peptide

H N

N

O

R' R

HN Peptide

Peptide

cis-amide

j1405

N

N N

O

R' R

Peptide

tetrazole analog

Figure 15.3 Tetrazole ring as a replacement for cis-amide bond [6, 7].

cis-amide bond are able to adopt most of the conformations available to the original peptide. Tetrazolyl analogs of bradykinin and scyliorhinin I were among the first few peptides studied. More recently, quinoxaline-based antifolates, with tetrazole modified glutamate side chain peptidomimetics, have been synthesized (Scheme 15.4) [8]. The reaction of a glutamate derivative with quinoline, phosphorus pentoxide and hydrazoic acid provided the corresponding tetrazole derivative 5. The Cbz group was removed under hydrogenating conditions and the resulting amine was coupled with a pteroic acid derivative to produce the desired analogs 6. These analogs exhibited potent thiamidyl synthase and L1210 cell growth inhibitory activities. Along similar lines, an analog of thyrotropin releasing hormone (TRH) containing the tetrazole

CbzHN CO2CH3 H N H O

1. PCl5, quinoline 2. HN3 3. H2, Pd/C

COOCH3

H2N

CO2CH3

CO2CH3 N

H

N N N 5

F CO2H R

F

N

O N

H HN DEPC, NEt3

H3C

CO2CH3

NH CO2CH3

O

N N N

N N

6

CH3

quinazoline based antifolate CbzHN

PCl5, HN3 quinoline

NH

N N Bz

O

O

O

CbzHN N

CH3 28% OBz

N Bz

O

N N N N CH3 OBz

7

H N NH N N H

O

N N N N CH3 NH2

TRH analog

Scheme 15.4 Tetrazole ring as a replacement for the cis-amide bond in peptides [9, 10].

j 15 Five-Membered Heterocycles with Four Heteroatoms: Tetrazoles

1406

ring as a mimic for the cis amide bond has been prepared (Scheme 15.4) [9]. Cbz-HisAla-OBz dipeptide derivative was treated with PCl5, quinoline and hydrazoic acid to produce the tetrazole product 7 that was later transformed into the desired tripeptide TRH analog. The lack of binding for this particular analog suggests that the amide bond geometry was not a critical factor in the binding of TRH with its receptor. In a recent development, an interesting methodology was reported for the synthesis of tetrazole ring compounds starting from an amide [10]. The amide substrate was first converted into an oxazoline and then treated with hydrazine hydrochloride in methanol to yield an amidrazone. Subsequent reaction with sodium nitrite formed the desired tetrazole via a nitrosation process. This procedure avoided the use of azides altogether and was amenable to scale-up. 15.2.2 Acid Chlorides as Substrates

Acid chlorides react with sodium azide and phosphine imide to generate tetrazoles (Scheme 15.5) [11]. This reaction proceeds through the formation of imidoyl chloride that, in some cases, can be isolated prior to its reaction with the azide source. These reactions occur by the displacement of the chlorine by the azide anion. Other leaving groups can also be displaced by the azide anion and examples of such substrates include imidates, thioimidates, and amidines. Aromatic and aliphatic acid chlorides react with Lewis acids and two equivalents of metal azide to produce 1-substituted tetrazolols. Trimethylsilylazide has been used in place of the metal azide and the Lewis acid with excellent results. This reaction proceeds via the formation of the isocyanate followed by reaction of the second equivalent of the azide anion to complete the formation of the tetrazole ring.

R1

Cl

Cl

O

NaN3

N

R1 NaN3, AlCl3 or TMSN3

O R1

R2

PPh3=NR2

O

Cl

H N

R2 N N

N

R1

N

HO

N

R1

N

N

N R1

N

Scheme 15.5 Synthesis of tetrazoles from acid chlorides [11].

15.2.3 Nitriles as Substrates

Nitriles react with azides to generate tetrazoles and this method is widely used as a large number of nitriles are either commercially available or easily prepared. Earlier procedures used hydrazoic acid generated in situ from sodium azide and acid, but were often slow and gave poor yields. Use of polar solvents like DMF and DME and

15.2 Synthetic Methods

the addition of ammonium chloride or alkylammonium salts tends to shorten reaction times considerably and give better yields. Various 5-substituted tetrazoles 8 have been prepared by reacting nitriles with sodium azide in an aromatic solvent like toluene in the presence of an amine salt like triethylammonium chloride (Scheme 15.6) [12]. Several different conditions have been studied, including the effect of the number of equivalents of sodium azide used, the type of salt and the solvent. Following this protocol, the synthesis and pharmacological characterization of 1- and 2-alkyltetrazolyl analogs of 2-Me-Tet-AMPA ((RS)-2-amino-3-[3-hydroxy-5(2-methyl-2H-5-tetrazolyl)-4-isoxazolyl]propionic acid), a highly potent and selective agonist at AMPA receptors, has been described recently [13]. These tetrazole derivatives (9) have been synthesized by reacting nitriles with sodium azide and triethylamine hydrochloride in DME. Similarly, tetrabutylammonium fluoride has been used as the catalyst to prepare tetrazoles 10 from nitriles and trimethylsilyl azide under solvent-free conditions [14]. 1. Et3N·HCl toluene, reflux

H N

R

RCN + NaN3 2. HCl R: alkyl, aryl, heteroaryl 70–95%

N N 8

i

OiPr

O Pr R O

R: H, CH2CH(NBoc2)(CO2tBu)

CN

N

DME 45–50%

R

R

NaN3, Et3N·HCl N

NC

N

TMSN3 (1.5 eq.), TBAF (0.5 eq.)

N N

O

N NH 9

R

HN N N N

solvent-free 80–95%

10

R: H, 4-NO2, 3-OMe, 4-COMe, 2-tolyl Other nitrile substrates include pyridine, furan, indole, benzyl, alkyl Scheme 15.6 Synthesis of tetrazoles from nitriles and sodium azide [12–14].

Bis(tributyltin) oxide has also been used as a catalyst in the reaction between nitriles and trimethylsilyl azide to produce tetrazoles 11 and 12 (Scheme 15.7) [15]. Excellent yields of both alkyl and aryl tetrazoles are usually obtained by this method, which avoids the use of hydrazoic acid and also minimizes exposure to toxic tin compounds. Sharpless’s group has disclosed that the reaction of sodium azide with nitriles proceeds nicely in presence of zinc salts to give 1H-tetrazoles [16]. This has been called click-chemistry and these reactions are performed in water with or without an organic co-solvent. For example, the synthesis of compound 13 proceeded readily

j1407

j 15 Five-Membered Heterocycles with Four Heteroatoms: Tetrazoles

1408

R

TMSN3, (nBu3Sn)2O (10 mol%)

CN

R

HN N N N

toluene, reflux R: Br, CO2Me, Ph alkyl nitriles also used

11

60–98%

TMSN3, (nBu3Sn)2O (10 mol%) toluene 80% CN

N NH N N 12

Scheme 15.7 Further syntheses of tetrazoles from nitriles and sodium azide. [15].

in water with zinc salts as catalysts (Scheme 15.8). The scope of the reaction is quite broad; various aromatic nitriles, activated and unactivated alkyl nitriles, substituted vinyl nitriles, thiocyanates and cyanamides are all viable substrates under these conditions. However, this method works best for electron-deficient nitriles. The authors have extended this methodology by using a mixture of water and 2-propanol at reflux to transform N-Cbz amino nitriles into the corresponding tetrazole compounds 14 using sodium azide and half-an-equivalent of zinc bromide (Scheme 15.8) [17]. This methodology has found wide acceptance [18]. For instance, 1.1 eq. NaN3 1.0 eq. ZnBr2

HN N N R N

N

R

water, reflux 52–96%

R: Ar, Alk, Vinyl, SR, NR2

Cbz

H N

13

2.0 eq. NaN3 0.5 eq. ZnBr2

N

water, isopropanol reflux

R

Cbz

R 14

90–98% N R2

R1

N R2

NaN3, cat. ZnBr2 H2O, mW, 185 °C, 20 mins

NC

HN N N N

H N

75–91%

R1

N N N NH 15 32 compounds; kinase inhibitors

Scheme 15.8 Synthesis of tetrazoles from nitriles and azides using zinc bromide [16–19].

15.2 Synthetic Methods

Merck researchers have utilized this methodology under microwave conditions to prepare a small library of tetrazoylpyridines 15. These compounds were evaluated for their role as dual inhibitors of the serine/threonine kinases Akt1 and Akt2. Using the same protocol, tatrazole analogs of glycyl-L-prolyl-L-glutamic acid have been prepared. Fmoc amino acids were also converted into the corresponding tetrazole compounds where the carboxylic acid group was replaced by the tetrazole ring. Recently, nanocrystalline ZnO was also shown to be an effective heterogeneous catalyst for the [2 þ 3] cycloaddition of azides to nitriles to afford 5-substituted-1Htetrazoles in good yields [19]. Palladium-catalyzed three-component coupling reaction of cyano compounds, allyl methyl carbonate and trimethylsilyl azide, under a catalytic amount of Pd2(dba)3CHCl3 (2.5 mol%) and tri(2-furyl)phosphine (10 mol%), gives 2-allyltetrazoles 16 in good to excellent yields (Scheme 15.9) [20]. A p-allylpalladium azide complex has been proposed as a key intermediate in this reaction. This methodology has been extended to N-cyanoindoles to produce the corresponding indole-fused tetrazoles 17. Along similar lines, palladium-catalyzed reaction between allene, trimethylsilyl azide and 2-iodo-5-bromobenzene-1-carbonitrile generates tetrazoyltetrahydroisoquinoline 18 [21]. TMSN3 cat. Pd(0)

RCN

R

Pd-N3

OCO2Me

N N N N 16

40–80% R R

TMSN3 cat. Pd(0) N CN

Br

60–90%

CN + I

H H

N

OCO2Me

+

H

Pd2(dba)3 CH3Cl (2.5 mol%) P(2-furyl)3 (10 mol%) KOAc (2 eq), TMSN3

H

DMF, 48 h, 70 °C

C

N

N N Allyl 17

Br

N N N N

62% 18 Scheme 15.9 Synthesis of tetrazoles under palladium catalysis [20, 21].

Fused bicyclic tetrazole-piperazines 19 have been obtained in very good yields by reacting N-cyanomethyl b-amino chlorides (derived from the corresponding b-amino alcohols) with sodium azide in DMSO at 150  C (Scheme 15.10) [22]. Fused 5-heterotetrazole ring systems 20 have been obtained in high yields by the intramolecular cycloaddition reaction of organic azides and heteroatom substituted

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j 15 Five-Membered Heterocycles with Four Heteroatoms: Tetrazoles

1410

R3

OH

R2

N R1

SOCl2 N

R1 = Me, Bn R2 = Me R3 = Ph

R3

Cl

R2

N R1

N

NaN3

R3

DMSO, 150 °C, 1 hr

R3

70–84%

N N N N N R1 19

CN Z

heat N3

N N N Z N

25-95% n

n

Z = O, S, N n = 0,1

20

Scheme 15.10 Synthesis of tetrazoles in a fused ring system [22, 23].

nitriles [23]. Cyanates, thiocyanates and cyanamides are all competent dienophiles for this reaction. Tetrazoles have also been synthesized using fluorous chemistry (Scheme 15.11) [24]. A fluorous tin azide reagent (21) is prepared and reacted with nitriles to produce the corresponding tetrazole compounds 22. Subsequent cleavage by concentrated hydrochloric acid gives pure tetrazole products 23 and the fluorous tin chloride, which could be reconverted into tin azide. In most cases, a 2–5-fold excess of the fluorous tin reagent is used and good yields of the tetrazole products are obtained. R RCN

(C6F13CH2CH2)3SnN3 (21)

R = aryl, alkyl

N N N N (C6F13CH2CH2)3Sn 22

R HCl 60–99% 7 examples

N N HN N 23

Scheme 15.11 Synthesis of tetrazoles under fluorous conditions [24].

15.2.4 Isocyanides as Substrates

Isocyanides can also be used to prepare tetrazoles. Hydrazoic acid reacts with isocyanides to produce 1-substituted tetrazoles [25]. This reaction proceeds via the attack of the azide anion on the protonated isocyanide followed by cyclization to give the tetrazole ring. To avoid the use of toxic hydrazoic acid, 1-substituted tetrazoles 24 were synthesized via the [3 þ 2] cycloaddition between isocyanides and trimethylsilyl azide in the presence of an acid catalyst and methanol (Scheme 15.12) [26]. Various 1-substituted tetrazoles have been obtained in good to high yields under these conditions. The reaction probably proceeds through the in situ formation of hydrazoic acid, followed by a successive [3 þ 2] cycloaddition with the isocyanide activated by an acid.

15.2 Synthetic Methods

TMSN3, cat. HCl

RNC

MeOH, ether 60 °C, 24 hr

R N

N N N 24

R

Yield (%)

p-MeOC6H4 o-MeOC6H4 2,6-(CH3)C6H3 C6H5 p-CO2MeC6H4 p-NO2C6H4 CH3(CH3)2 C6H11 t-Bu Me3SiCH2

92 85 87 67 58 77 57 78 92 81

Scheme 15.12 Synthesis of tetrazoles form isonitriles [26].

The isocyanide can also be electrophilically activated by iodinium ion or the acylium ion. Thus, if iodine azide is used instead of hydrazoic acid, 1-substituted 5iodotetrazole can be obtained. Similarly, the reaction of an isocyanide, an acid chloride and sodium azide generates 1-substituted 5-acyltetrazole where the acylium ion activates the isocyanide to the nucleophilic attack by the azide anion. The reaction of isonitriles with azide in the presence of Mannich-type reagent (e.g., formaldehyde and piperidine) provides 1,5-disubstituted tetrazoles. This is a variation of the wellknown Ugi reaction and is discussed in more detail later. 15.2.5 Oximes as Substrates

Oximes react with an azide source and reagents like thionyl chloride, chlorosulfonic acid, phenylsulfonyl chloride or phosphorus pentachloride to give 1,5-disubstituted tetrazoles. This transformation occurs via the attack of the azide anion on the nitrilium ion intermediate followed by cyclization to produce the tetrazole ring. Oximes of methyl olenonate and methyl betulonate have been treated with sodium azide in the presence of chlorosulfonic acid to give tetrazoles 25 and 26 respectively (Scheme 15.13) [27]. 15.2.6 Orthoesters as Substrates

Orthoesters (especially orthoformates) react with sodium azide and amines or anilines to produce tetrazoles. This method can be carried out conveniently with aliphatic, aromatic or heteroaromatic anilines and gives good yields of the corresponding tetrazoles. A synthesis of 1-(2-iodophenyl)-1H-tetrazole 27 has been described recently by treating 2-iodoaniline, triethylorthoformate and sodium azide in refluxing acetic acid (Scheme 15.14) [28]. This tetrazole derivative, when used as a ligand in palladium-catalyzed Heck reactions, gives the cross-coupled products in

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j 15 Five-Membered Heterocycles with Four Heteroatoms: Tetrazoles

1412

COOCH3 HO

NaN3, ClSO3H

O N N N N

N

O

25

O NaN3, ClSO3H HO

O

N N N N

N

26

Scheme 15.13 Synthesis of tetrazoles from oximes [27].

excellent yields. Condensation of p-methoxybenzylamine with 2-chloro-1,1,1triethoxyethane in the presence of sodium azide in acetic acid produces the corresponding tetrazole 28 [29]. Similarly, 2-aminopyridine has been heated with sodium azide and triethylorthoformate in acetic acid to produce 2-tetrazolylpyridine [29]. N

NH2

N N N

HC(OEt)3, NaN3

I

AcOH, reflux

I 27

NH2

N N N N

ClCH2CH(OEt)3, NaN3

MeO

Cl

AcOH, reflux MeO 28

Scheme 15.14 Synthesis of tetrazoles from orthoesters [28, 29].

15.2.7 Ketones as Substrates

Ketones react with an azide source to generate tetrazoles in the Schmidt reaction. Mixtures of 1,5-disubstituted products are generally obtained in this reaction.

15.2 Synthetic Methods

j1413

Originally, hydrazoic acid was used for this transformation, but now several other reagents are available. A few steroidal ketones have been converted into their corresponding tetrazole derivatives when an excess of hydrazoic acid was used [30]. Undesired side products, like the corresponding amides and lactams, were also formed under these conditions. Boron trifluoride etherate has been used in combination with hydrazoic acid in this type of reaction, but still both tetrazole and lactam products were observed when steroidal ketones were used [31]. In another example, using Pummerer’s ketone, 35% of the tetrazole product and 22% of the uncyclized azide product was obtained by the use of hydrazoic acid and boron trifluoride etherate [32]. Other Lewis acids like aluminium trichloride, tin(II) chloride, tin(IV) chloride, titanium tetrachloride, tetrachlorosilane, zinc(II) chloride and trimethylsilyl azide have all been used with success. Typically, an excess of the azide is used in the presence of a Lewis acid and the ketone in this reaction. Mixtures of 1,5-disubstituted 1H-tetrazoles 29 and 30 are obtained when aliphatic or aromatic ketones are reacted with excess sodium azide in the presence of titanium chloride in refluxing acetonitrile (Scheme 15.15) [33]. The use of a large excess of sodium azide relative to the amounts of ketone and titanium(IV) chloride (i.e., 8 : 1 : 2) provides the most satisfactory results. Performing the reactions in other solvents like benzene, THF, ether or methylene chloride led to lower yield of the tetrazole products in this study. NaN3, TiCl4

R2

acetonitrile, reflux

R1

R1 O R2

50–90%

N N

R1

N N

R2

N

N +

N 29

N

30

R1 = Ph, 4-ClPh, 4-OMePh, 4-NO2Ph -(CH2)4-, -(CH2)5-, Me, PhCH=CH2 R = Ph, 4-MeOPh Scheme 15.15 Synthesis of tetrazoles from ketones [33].

A series of tetrazoles 31 have been prepared by using b-keto esters with trimethylsilyl azide and zinc bromide (Scheme 15.16). These were subsequently transformed into amino acids 32 [34]. O

TMSN3 (2.5 eq) ZnBr2 (1 eq)

O

Me

OEt Me

R

R = Et, Bn, iBu, Ph

60 °C, 18 h 50–90%

N N N N

O

O OEt

Me Me

R 31

H2N

OEt

Me

R 32

Scheme 15.16 Synthesis of tetrazoles from b-keto esters [34].

The reactions of a few cyclic a,b-unsaturated ketones with trimethylsilyl azide in the presence of trimethylsilyl triflate produce the corresponding ring-expanded tetrazole derivatives 33 (Scheme 15.17) [35].

j 15 Five-Membered Heterocycles with Four Heteroatoms: Tetrazoles

1414

O TMSN3, TMSOTf

N N N N 33

Me

O

Me

Yield (%)

N N N N

78% Me Me

Me Me Me

O

Me

N N N N

74% Me

O

Me

Me Me O

O

N N N N

61%

Me Me Me O Me

O

Me O Me

67%

N N N N

Scheme 15.17 Synthesis of fused tetrazoles from cyclic ketones [35].

Triazidochlorosilane (ClSiN3) is also an excellent reagent for the conversion of ketones and a,b-unsaturated ketones into the corresponding tetrazole derivatives 34 in nearly quantitative yields (Scheme 15.18) [36]. 15.2.8 Tetrazoles from Other Substrates

Tetrazoles have also been prepared from amidines, carbodiimides, carbonimidic dichlorides, isocyanates, isothiocyanates, isocyanides, nitrilium salts, oxazolones and thiocyanates; however, these substrates have been utilized on very few occasions in the recent literature and hence are not described here. Moreover, this chemistry is well-documented elsewhere. The syntheses of tetrazole compounds using methods that have rapidly evolved recently and are now being increasingly used in both academia and industry is described next. These include the solid-phase synthesis, microwave synthesis and multicomponent synthesis of tetrazoles.

15.2 Synthetic Methods

Triazidochlorosilane (SiCl4 : NaN3 = 1:3)

Ar O

N N R

R

j1415

N N 34 Ar

Yield (%)

Ketone Acetophenone 4-chloroacetophenone 3-nitroacetophenone benzophenone 1-indanone benzalacetone benzalacetophenone 4-methoxybenzalacetophenone 4-chlorobenzalacetophenone

87 87 60 97 93 95 94 90 95

Scheme 15.18 Synthesis of tetrazoles from ketones [36].

15.2.9 Solid-Phase Syntheses

The synthesis of tetrazole derivatives has been reported using solid-phase conditions to produce libraries of compounds – especially in the realm of pharmaceutical research. Rink amide resin has been attached to a suitably substituted benzonitrile that was then reacted with trimethylsilyl azide and a catalytic amount of bis(tributyltin) oxide for 50 h at 90  C in o-xylene to produce the corresponding tetrazole compounds 35 (Scheme 15.19 [37]. This procedure was adapted from the report by Wittenberger that promoted the use of bis(tributyltin) oxide to facilitate the reaction of trimethylsilyl azide with nitriles to produce tetrazoles. The final products were obtained in moderate yields (20–45%) and in reasonably good purity (65–93%). CN

CN I

NH2 + HO

I DIC, HOBt DMF, rt

O

O

O

CN

CN R1

H N

H N

R2OH, PPh3 DEAD

H N

DMF, rt O

OH R1 = Ph, 4-MeC6H4 4-ClC6H4, 2-ClC6H4 3-OMeC6H4

O

OR2

O

1. Me3SiN3, n-Bu2SnO R1 o-xylene 90 °C 2. TFA, CH2Cl2

R2 = isobutyl, 2-isopropoxy-ethy 2-phenylethyl, isopropyl

R1B(OH)2, Pd(PPh3)4 DIEA, DMF 100 °C N N N NH R1 H N O

OR2

35 purity: 65-95% yield: 20-45%

Scheme 15.19 Synthesis of tetrazoles under solid-phase conditions using a Rink amide resin [37].

j 15 Five-Membered Heterocycles with Four Heteroatoms: Tetrazoles

1416

The use of trimethylsilyl azide in contrast to azidotrimethyltin or sodium azide makes this process less toxic. In this study, diversity was introduced at two places on the phenyl ring by (i) Suzuki coupling at the iodo atom and (ii) Mitsunobu reaction at the phenolic site. A dihydropyran carboxylic acid type linker has been attached to tetrazoylarylbromide that then underwent Suzuki coupling with two different aryl boronic acids to produce biphenyl-tetrazole products [38]. Parallel solid-phase synthesis of 5-aminotetrazoles 36 was recently achieved by the reaction of resin-bound thioureas with excess mercuric chloride and sodium azide (Scheme 15.20) [39]. The final products were obtained in good yields (60–70%) and good purity (75–85%).

R1NH2 (6 eq) NaBH(OAc)3 (6 eq) CHO DMF, AcOH 99/1

NaN3 (6 eq) HgCl2 (6 eq) DMF

N N N N N R2 R1

N H

R

1

S

R2-NCS (6 eq) N R1

CH2Cl2

CF3CO2H CH2Cl2

N H

R2

N N N R N N H R2 36 1

Scheme 15.20 Synthesis of tetrazoles under solid-phase conditions [39].

Tetrazoles have also been incorporated into privileged structures. A series of nitrile-containing benzopyran scaffolds were prepared on selenium-tethered resin and reacted with azidotrimethylstanane to provide the corresponding stannylated tetrazoles (Scheme 15.21) [40]. The trimethylstannyl group was removed using aqueous trifluoroacetic acid (TFA) and the tetrazoles were further alkylated with various alkyl halides. Finally, the resin-bound tetrazoles were cleaved under oxidative conditions to afford the substituted tetrazole products 37. MeOPEG-supported azide has also been utilized as the azide source for the reaction with activated nitriles to produce the corresponding tetrazoles 38 in excellent yields (Scheme 15.22). Subsequent acid hydrolysis provided clean tetrazole products [41]. 15.2.10 Microwave Syntheses

The use of microwaves has become an increasingly important component in organic synthesis as more and more types of reactions are successfully performed in their unique environment. The synthesis of tetrazoles often requires high temperatures

15.2 Synthetic Methods

R1

Se Me O

NC

R1

Me3SnN3 (5 eq)

Me

toluene, 100 °C

Me

X

R1 = H, OMe

N N

O

R2

N N

O

Me

CH3CN, 80 °C

N N X = SnMe3 X=H

TFA

R1

R2X (10 eq) NEt3 (15 eq)

Se

Se

H2O2 (6 eq)

Me

THF

R1 Me

Me

N

R2

N

N N

O

Me

N N

37

(>90% purity)

R2 = CH2CO2Et, CH2C6H4OMe, CH2CH2CH(CH3)2 CH2C6H3(CF3)2, CH2C14H9, CH2C(O)C6H3(OMe)2

Scheme 15.21 A further example of the synthesis of tetrazoles under solid-phase conditions [40].

OMs

NaN3 DMF

R C N N3

N

N N N

R 38 R = PhCO: 92% COOEt: 95% COOBn: 96% pTolSO2: 95% Scheme 15.22 Synthesis of tetrazoles using PEG [poly(ethylene glycol)] [41].

and long reactions times under standard conditions. Microwave chemistry promises to improve yields using lower temperatures and very short reaction times. Under microwave conditions, aryl bromides were converted into the corresponding nitriles by using zinc cycanide and Pd(PPh3)4 in DMF for 2 min at 60 W. These nitriles were then reacted with sodium azide and ammonium chloride in DMF using 20 W power for 15 min to produce the corresponding tetrazoles 39 in good yields (80–95%) (Scheme 15.23) [42]. The same reactions performed using conventional heating took 4–10 h and gave slightly lower yields of the products. The synthesis of hindered tetrazoyl pyridines has recently been described under microwave conditions [43]. Under conventional heating conditions, only one nitrile substrate could be converted into the corresponding tetrazole. Using microwave irradiation at 2450 MHz and 140  C for 8 h, substituted pyridinyl nitriles were reacted with trimethylsilyl azide and

j1417

j 15 Five-Membered Heterocycles with Four Heteroatoms: Tetrazoles

1418

R

Br

Zn(CN)2, Pd(PPh3)4

R

DMF, 10-20 min, mW 20 W

DMF, 2 min mW 60 W

HN N N N 39

50-95%, 8 examples

R = aryl, heteroaryl R2

R

NaN3, NH4Cl

CN

R1

R2

Me3SiN3, Bu2SnO N

dioxane, mW, 140 C, 8 h

N

N N N NH

N 40

[40-80%], 10 examples R1, R2 = cyclic aryl, heteroaryl

R1

Me3SiN3:Bu2SnO:nitrile = 4:0.3:1

Scheme 15.23 Synthesis of tetrazoles under microwave conditions [42, 43].

bis(tributyltin) oxide in dioxane to generate tetrazole products 40 in decent yields (50–80%). A substantial amount of the unreacted starting nitrile was recovered whenever lower yields of final product were isolated. As microwave instruments become more common in organic laboratories, more examples of its utility in the synthesis of tetrazoles will emerge. 15.2.11 Multicomponent Reactions

It has been known since the 1960s that tetrazoles could be obtained by reacting hydrazoic acid, isonitriles, aldehydes and amines by a variation of the now wellknown Ugi reaction (Scheme 15.24) [44].

R1 O R2

+

R3 NH R4

HN3, R5NC

R4 R3 N R1

N N

N N R2 R5

Scheme 15.24 Synthesis of tetrazoles from a modified Ugi reaction.

The Ugi reaction has been increasingly employed to prepare libraries of compounds. It has especially been employed to prepare tetrazole compounds fused to a second ring system. In this regard, a four-component, two-step, one-pot reaction between an aldehyde, a primary amine, methyl-b-(N,N-dimethylamino)-a-isocyanoacrylate and hydrazoic acid has been used to prepare bicyclic pyrazole compounds 41 in moderate yields (Scheme 15.25) [45]. More recently, a five-centre-four-component Ugi reaction that employed an aldehyde, a primary amine, trimethylsilyl azide and 2-isocyanoethyl tosylate to create tetrazoylpiperazine ring products 42 has been described [46].

15.2 Synthetic Methods

CN R1R2CO + R3NH2 +

CO2R4

R3

HN3

(H3C)2N

R1

MeOH

R1, R2 = alkyl, H, cyclic ketone R3 = alkyl, benzyl R4 = Me

CO2R4

N N

N N N

R2

30–80%

41

R2

MeOH R1NH2 + R2CHO + TMSN3 + TsOCH2CH2CN 40–70%

R1 = CH2Ph, 4-MeOOCC6H4 2-MeOOCC6H4, CH2CH(OMe)2 R2 = CH(CH3)2, 4-MeOC6H4, Ph 4-MeOOCC6H4

N

N N N

R1 N 42

Scheme 15.25 Synthesis of fused tetrazoles using multiple components [45, 46].

A more recent report demonstrates the synthesis of a series of tetrazoles by a Ugi reaction using the universal Rink-isonitrile resin (Scheme 15.26). The resin-bound nitrile group reacts with aldehydes, secondary amines and trimethylsilylazide to produce the corresponding tetrazoles 43 [47].

R1CHO R2R3NH TMSN3

R2 N R 3

R1

NC THF/MeOH

N

N N N

R1 PhCH2CH2 PhCH2Ch2 Ph Bn 4-OCH3-Ph

15% TFA CH2Cl2

R2R3NH piperidine morpholine piperidine morpholine morpholine

R2 N R 3

R1

N N N 43 Yield 67% 76% 89% 25% 75%

HN

Scheme 15.26 Solid-phase multi-component synthesis of tetrazoles [47].

In a very interesting variation, a series of fused azepine-tetrazoles 44 have been prepared that utilize the Ugi reaction sequence (Scheme 15.27) [48]. This generated diversity at five positions on the scaffold. Similarly, the reaction of an aldehyde, primary amine, methyl isocyanoacetate and trimethylsilyl azide in methanol at reflux affords bicyclic tetrazole-ketopiperazines 45 in good yield [49]. This efficient one-step protocol creates products with four potential diversity points and has been used to generate arrays of biologically relevant small molecules for general and targeted screening. These examples demonstrate the power of multicomponent reactions to rapidly generate a diverse set of compounds sharing a common core.

j1419

j 15 Five-Membered Heterocycles with Four Heteroatoms: Tetrazoles

1420

R3 MeO

NC O

Boc

O

H N

R4R4NH, TMSN3 R2

O R3

R1

H N

R1

N N

N

R4 N R5

N 44

R1 O

+

MeO2C

R2

NC R4

TMSN3, R3NH2

R1 R2

N N N N

R3

R4 O 45

Scheme 15.27 Multi-component syntheses of fused tetrazoles [48, 49].

15.3 Reactions of Tetrazoles

The tetrazole ring contains a carbon atom, a pyrrole-type nitrogen atom and three pyridine-type nitrogen atoms. These atoms exhibit their own unique chemical nature and reactivity. The pyrrole-type nitrogen exerts an electron-donating effect (activating the ring) whereas the pyridine-type nitrogens exert an electron-withdrawing effect (deactivating the ring). As mentioned earlier, tetrazoles are nitrogen analogs of carboxylic acids. Tetrazolic acids (R-CN4H) are easily generated in basic medium as they exhibit a lower pKa than carboxylic acids. The nature of the R-substituent controls the reactivity – electron-withdrawing groups being more acidic. These tetrazolic acids can react at either the N1 or N2 position and mixtures are often obtained in these types of reactions. 15.3.1 Reactions at C5

1-Benzyltetrazoles or 1-(para methoxybenzyl)tetrazoles have been regioselectively lithiated at the 5-position using nBuLi in TMEDA/THFat
98  C (Scheme 15.28) [50]. These conditions were necessary to obtain regioselectivity consistently. Subsequent addition of electrophiles (aldehydes, ketones, a,b-unsaturated ketones, Weinreb amides, iodine and diethylchlorophosphate) furnishes the corresponding adducts 46. The benzyl or para methoxybenzyl groups can be cleaved under acidic or hydrogenation conditions to produce 5-substituted tetrazoles in good yields. N1-protected tetrazoles can be brominated using a strong base like nBuLi and bromine to produce the C5-bromo products. These activated products can then be

15.3 Reactions of Tetrazoles

N N

N N

1. nBuLi

N

N R

N N R

X

2. E+

46 R = Bn, PMB, H

R = Bn, PMB E

X

CH3I

CH3

C6H5CH2Br

C6H5CH2

O

OH

R

R

H

OH

O R

H

R

O R

O Cl

R O RO P RO

O RO P RO Cl

I

I2

Scheme 15.28 Electrophilic addition to tetrazoles [50].

utilized to prepare various heterocyclic compounds. 1-Benzyl-5-bromotetrazole (47) has been conveniently prepared by lithiation of 1-benzyltetrazole with nBuLi in THF at
78  C followed by treatment with bromine (Scheme 15.29) [51]. It was then coupled with various aryl boronic acids to produce the corresponding 5-aryl derivatives 48 under standard Suzuki reaction conditions.

N N N N Bn

1. nBuLi 2. Br2 THF -78 °C

Br

N N N N Bn 47

ArB(OH)2, Na2CO3 cat. Pd(PPh3)4 toluene, H2O, EtOH reflux 80–90%

Ar

N N N N Bn 48

Scheme 15.29 Suzuki coupling on tetrazoles [51].

15.3.2 Reactions at N1 and N2

The 2-position of the tetrazole ring is activated and thus reacts under several different conditions.

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j 15 Five-Membered Heterocycles with Four Heteroatoms: Tetrazoles

1422

Oxidation of the commercially available sodium salt of ethyl-tetrazole-5-carboxylate using oxone in aqueous acetone at pH 7.5 forms, exclusively, N-2-hydroxytetrazole-5-carboxylate (49) (Scheme 15.30) [52]. Subsequent standard basic hydrolysis gives the corresponding acid that can be further decarboxylated to generate 2hydroxytetrazole (50).

N N CO2Et N N Na

HO

Oxone pH 7.5

N N CO2Et N N 49

1. NaOH, EtOH reflux 2. c.HCl, reflux 3. c.HCl, reflux, 90h

HO

N N N N 50

Scheme 15.30 Oxidation of tetrazoles [52].

5-Phenyltetrazole can be selectively benzylated by using O-benzyl-S-propargyl xanthate in refluxing toluene to give exclusively 2-benzyl-5-phenyltetrazole (51) (Scheme 15.31) [53]. In contrast, the use of benzyl bromide generates both 1- and 2-benzyltetrazoles. O-benzyl-S-propargyl xanthate is prepared by the reaction of the xanthate salt derived from benzyl alcohol with propargyl bromide.

S HN N N N

BnO

S

Ph toluene, reflux 97%

Bn

N N N N 51

Ph

Scheme 15.31 Benzylation of tetrazoles [53].

5-Substituted tetrazoles react with Michael acceptors having electron-withdrawing groups to produce 1,5-disubstituted and 2,5-disubstituted products 52 and 53 (Scheme 15.32) [54]. These reactions are also applicable to 1-substituted-tetrazolin-5-ones and 5-substituted-1-hydroxy tetrazoles. An asymmetric version of this reaction has recently been disclosed where 5-methyltetrazole and 5-phenyltetrazole undergo highly enantioselective catalytic conjugate addition to a,b-unsaturated ketones and imides in the presence of chiral[(salen)Al(III)] complexes [55]. Mixtures of 1,5- and 2,5-disubstituted products 54 and 55 were obtained when 5-methyltetrazole was used but 2,5-disubstituted products 55 were exclusively obtained when 5phenyl tetrazole was used. Tetrazole itself fails to react under these conditions. Tetrazoles with the C5 substituted as an aryl ether can be conveniently acylated at N2 using the corresponding acyl chlorides and triethylamine to produce products 56 (Scheme 15.33) [56]. C-Arylated tetrazoles react with tetrafluoroborate aryliodinium salts using either copper or palladium catalysts to produce the corresponding C,2N-diaryl

15.3 Reactions of Tetrazoles

N N N N H

Ar

+

R2 X + R1

X = Me, Ph

Z

N N N N

N N N N

Ar +

Ar

50–70%

Ar = Ph, 4-ClPh

N N N N H

NEt3

Z

Z

Z = CN, CO2Me

52

N N N N

III

O [S,S (salen)Al ] complex toluene, 24 h, 0 °C 80–90%, 90–95% ee

R1 = Pr, iPr, CH2CH2OBn R2 = Me, NHCOPh

53

R1

X R1 + O

N N N N

R2 O 54 55 X = Me (both 1,5- and 2,5-disubstituted products) X = Ph (only 2,5-disubstituted products)

O OR1

R1 Ph Ph 2,4,6-Me3Ph 2,4,6-Me3Ph 4-NO2Ph 4-NHAcPh 4-BrPh 4-ClPh 4-MePh

ClCOR2, NEt3 R2

R2 Me Et Me Et Me Me Me Me Me

X

R2

Scheme 15.32 Michael addition reactions of tetrazoles [54, 55].

N N N N H

j1423

N N N N 56 Yield 55% 57% 70% 65% 72% 92% 94% 80% 52%

OR1

Scheme 15.33 Acylation reactions of tetrazoles [56].

products 57 and 58 (Scheme 15.34) [57]. Phenyl boronic acids and aryl bismuth salts can also be used with copper catalysts to produce C,2N-diaryl tetrazoles 59 and 60, respectively, from C-arylated tetrazoles [58]. Tetrazole can displace fluorine from 4-nitrofluorobenzenes to produce N(4-nitrobenzene) derivatives 61 (Scheme 15.35) [59]. Tetrazoles react with epoxides readily to produce both N1 and N2 substituted adducts depending on the conditions used. When a base like potassium t-butoxide is used to deprotonate the tetrazole, both N2 and N1 adducts 62 and 63, respectively, are obtained (Scheme 15.36) [60]. In contrast, when tetrazole is reacted directly, albeit on a strained epoxide, only N2 adduct 64 is obtained [61].

N

+

+

Cl

(HO)2B

+

Br

Pd(pentadione) (cat.)

DMF

Cu(OAc)2 (cat.), pyridine

Cl

Br

K2CO3, CuI (cat.)

Cu(OAc)2 (cat.), THF

Ph3Bi(OAc)2, Me2NC(=NH)NMe2

CH3

-

BF4I+

BF4 I+

Scheme 15.34 Arylation of tetrazoles [57, 58].

N N N N H

N N N N H

N N N N H

N N N N H

H3C

Cl

Br

60

N N N N

N N N N 59

58

N N N N

57

N N N N

N

1424

j 15 Five-Membered Heterocycles with Four Heteroatoms: Tetrazoles

15.3 Reactions of Tetrazoles

R

R Na2CO3

O2N

N N N N H

O2N

+ F

DMF 61

R = H, Me

N N N N

Scheme 15.35 Nucleophilic addition on activated fluorobenzenes [59].

H N N N N

Ph N BnS

Ph BnS

tBuOK N

O

N BnS

N OH

DMF, 60 °C

Ph

Ph

H N N N N

Ph

THF, 0 °C

O

N OH

+ Ph

N N N N 62

O

Ph

N

N

N N N (1:1)

63

HO N N N N O 64

Ph

Scheme 15.36 Reactions of tetrazoles with epoxides [60, 61].

15.3.3 Miscellaneous Reactions

C-Phenyltetrazoles can be lithiated at the ortho position of the phenyl ring – hence the tetrazole ring is seen as an ortho-directing substituent (Scheme 15.37) [62]. These OH N N N N H

1. sBuLi, TMEDA 2. RCHO

R HN N N N

R = CH2=CH : 85% : 95% = CH3

N N N N H

1. sBuLi, TMEDA 2. RI

65

R HN N N N

Scheme 15.37 Tetrazole ring as an ortho-directing group [62, 63].

66

j1425

j 15 Five-Membered Heterocycles with Four Heteroatoms: Tetrazoles

1426

lithiated species can be quenched with various electrophiles to produce the corresponding adducts 65 and 66 [63]. Tetrazole compounds are also used as catalysts in various reactions. They have been extensively used in nucleotide chemistry to couple individual phosphoramidite nucleotides to form long chain RNA molecules. 1H-Tetrazole itself has been prominent in this chemistry. More recently, 5-(benzylmercapto)-1H-tetrazole (67) has been shown to be an excellent activator for RNA synthesis (Scheme 15.38) [64]. Compared to routinely used 1H-tetrazole, application of a 0.25 M solution of 67 in acetonitrile allows higher coupling yields (>99%), lower coupling times (3 min) and R

DMTrO O NC O

OTBDMS S

O P N(iPr)2

H N N N N

O NC O

67

+ R

HO O

N

N HN N 68

O +

R1

NPMP

O NO2

+

O

68

NHPMP

R1

COOEt

R2

COOEt R2

68

O

R NO2

R

O

O ent - 68

O O

Scheme 15.38 Tetrazole derivative used in nucleotide coupling [64].

N H

R

O

>99%

OTBDMS

OTBDMS

O P

CH3CN, 3 min

O

R

DMTrO

OH

PhIO or Davis's oxaziridine 20–50% 40–50% ee Scheme 15.39 Reactions using tetrazole compounds as catalysts [65–67].

OTBDMS

References

reduced excess of phosphoramidites in solution over the solid-phase nucleotides (eight-fold). It has been synthesized by reacting benzylthiocyanate with sodium azide and ammonium chloride in a dioxane/water mixture. The chiral tetrazole compound 68, derived from proline, has been utilized in asymmetric Mannich, nitro-aldol and nitro-Michael reactions (Scheme 15.39) [65]. It has also been successfully used in asymmetric oxidation recently [66]. Its enantiomer has been utilized in aldol, nitroso-addition and a-fluorination reactions [67].

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Soliman, H., and Amer, F.A. (1995) Tetrahedron Letters, 36, 7337–7340. Kivrakidou, O. Brase, S. Hulshorst, F., and Griebenow, N. (2004) Organic Letters, 6, 1143–1146. Yoo, S.-E., Seo, J.-S., Yi, K.-Y., and Gong, Y.-D. (1997) Tetrahedron Letters, 38, 1203–1206. Yu, Y., Ostresh, J.M., and Houghten, R.A. (2004) Tetrahedron Letters, 45, 7787–7789. Nicolaou, K.C. Pfefferkorn, J.A. Roecker, A.J. Cao, G.-Q. Barluenga, S., and Mitchell, H.J. (2000) Journal of the American Chemical Society, 122, 9939–9953. Molteni, G. and Del Buttero, P. (2005) Tetrahedron, 61, 4983–4987. Alterman, M. and Hallberg, A. (2000) The Journal of Organic Chemistry, 65, 7984–7989. Bliznets, I.V., Vasil’ev, A.A., Shorshnev, S.V., Stepanov, A.E., and Lukyanov, S.M. (2004) Tetrahedron Letters, 45, 2571–2573. Ugi, I. and Steinbruckner, C. (1961) Chemische Berichte, 94, 734–742. Ugi, I. and Meyr, R. (1961) Chemische Berichte, 94, 2229–2233. Bienayme, H. and Bouzid, K. (1998) Tetrahedron Letters, 39, 2735–2738. Umkehrer, M., Kolb, J., Burdack, C., Ross, G., and Hiller, W. (2004) Tetrahedron Letters, 45, 6421–6424. Chen, J.J., Golebiowski, A., Klopfenstein, S.R., and West, L. (2002) Tetrahedron Letters, 43, 4083–4085. Nixey, T., Kelly, M., Semin, D., and Hulme, C. (2002) Tetrahedron Letters, 43, 3681–3684. Nixey, T., Kelly, M., and Hulme, C. (2000) Tetrahedron Letters, 41, 8729–8733. Satoh, Y. and Marcopulos, N. (1995) Tetrahedron Letters, 36, 1759–1762. Yi, K.Y. and Yoo, S. (1995) Tetrahedron Letters, 36, 1679–1682. Giles, R.G., Lewis, N.J., Oxley, P.W., and Quick, J.K. (1999) Tetrahedron Letters, 40, 6093–6094. Faure-Tromeur, M. and Zard, S.Z. (1998) Tetrahedron Letters, 39, 7301–7304.

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64 65

66

67

Organic Chemistry, 59, 6391–6394.Another related example: Shi, Y., Robl, J.A., Kennedy, L.T., and Malley, M.A. (2007) Tetrahedron Letters, 48, 555–558. Welz, R. and Muller, S. (2002) Tetrahedron Letters, 43, 795–797. Cobb, A.J.A., Shaw, D.M., Longbottom, D.A., Gold, J.B., and Ley, S.V. (2005) Organic and Biomolecular Chemistry, 3, 84–96. Engquist, M., Casas, J., Sundan, H., Ibrahem, I., and Cordova, A. (2005) Tetrahedron Letters, 46, 2053–2057. Torri, H., Nakadai, M., Ishihara, K., Saito, S., and Yamamoto, H. (2004)

Angewandte Chemie, International Edition, 43, 1983–1986. Momiyama, N., Torri, H., Saito, S., and Yamamoto, H. (2004) Proceedings of the National Academy of Sciences of the United States of America, 101, 5374–5378. Steiner, D.D., Mase, N., and Barbas, C.F., III (2005) Angewandte Chemie, International Edition, 44, 3706–3710. Some new ligands containing the tetrazole ring have been reported recently: Dabbagh, H.A., Chermahini, A.N., and Banibairami, S. (2006) Tetrahedron Letters, 3929–3932.

j1431

16 Six-Membered Heterocycles: Pyridines Concepci
on Gonz
alez-Bello and Luis Castedo

16.1 Introduction

Pyridine is the simplest six-membered heterocyclic aromatic compound that is structurally related to benzene with one CH group in the six-membered ring replaced by a nitrogen atom. It is a liquid, with a fish-like, putrid and sour odor, that is obtained from crude coal tar or is synthesized from acetaldehyde and ammonia. Pyridine, widely used as a solvent and reagent in organic chemistry, is a harmful substance by inhalation, ingestion or absorption through skin and it can produce cancer and reduce male fertility. Pyridine derivatives are named as pyridines, indicating the positions of the substituents as a, b or c or by numbers 2-, 3-, 4-. The radical is named as pyridyl. Some examples are shown in Figure 16.1. Some alkylpyridines are known by trivial names. For instance, methylpyridines are known as picolines, dimethylpyridines as lutidines, and trimethylpyridines as collidines (Figure 16.2). 16.1.1 Relevant Pyridine Derivatives 16.1.1.1 Natural Pyridines are rarely found in nature, being exemplified by some vitamins, cofactors and alkaloids (Figure 16.3). For example, niacin is a water-soluble vitamin that assists in the functioning of the digestive system, skin and nerves, and is also related with food metabolism. In addition, pyridoxine (vitamin B6) is an important contributor of protein metabolism. In contrast, the redox-active part of nicotinamide adenine dinucleotide (NAD þ ) or nicotinamide adenine dinucleotide phosphate (NADP þ ), important cofactors for enzymatic redox processes, is a nicotinamide heterocyclic ring. Few alkaloids contain monocyclic pyridine derivatives, with the notable exceptions being the tobacco alkaloids. Of particular importance is nicotine, which is present in

Modern Heterocyclic Chemistry, First Edition. Edited by Julio Alvarez-Builla, Juan Jose Vaquero, and José Barluenga. Ó 2011 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2011 by Wiley-VCH Verlag GmbH & Co. KGaA.

j 16 Six-Membered Heterocycles: Pyridines

1432

4γ 5

3β

6

2α

N

3

N

1

3-pyridyl

pyridine Cl

MeO

NO2 N

N

3-Nitropyridine

N

Br

2-bromo-4-chloropyridine

CO2Me

Methyl 5-methoxy-2-pyridinecarboxylate

Figure 16.1 Examples of pyridine nomenclature.

dried tobacco leaves and is the active ingredient in cigarettes and other tobacco products. Nicotine produces stimulant and depressant phases of action on all autonomic ganglia and is found in many insecticides. In addition, nicotyrine and anabasine are also important pyridine derivatives of tobacco alkaloids. 16.1.1.2 Unnatural Over the last 50 years interest in pyridine derivatives has risen sharply with the discovery of many bioactive compounds containing a pyridine ring. The development of different pyridine drugs has been especially interesting for the pharmaceutical industry, as the existence of over 7000 drugs with a pyridine ring demonstrates (Figure 16.4) [1, 2]. For instance, isoniazide is an antibiotic used to treat tuberculosis; sulphapyridine is used to help control dermatitis herpetiformis; ABT-594 is a powerful analgesic many times more potent than morphine, without the serious side effects; niaprazine is an antihistamine, bronchodilator and sedative; piroxicam is a non-steroidal anti-inflammatory drug used to relieve the pain, tenderness inflammation and stiffness caused by arthritis; niflumic acid is used as an antirheumatic

N

N

α-picoline

N

β-picoline

N

N

2,6-lutidine

2,5-lutidine

γ-picoline

N

N 2,4,6-collidine

2,3,5-collidine

Figure 16.2 Nomenclature of some methylpyridines.

16.1 Introduction

OH HO

CO2H

OH N

N Niacin

Pyridoxine CONH2 OH

RO N

N

N

O O P P O -O -O O O

O

HO

N

H2N

O

N+ OH

NAD+ (R = H) NADP+ (R = OPO3-2)

H

H N Me

N

N Me

N

N H N

Nicotyrine

Nicotine

Anabasine

Figure 16.3 Relevant natural pyridine compounds.

H N

O

NH2

O O S N H

N

N Isoniazide

N NH2

Sulphapyridine

ABT-594

F H N

N

O

N

S

O N

H N

N

O

OH Niaprazine

O

O N H

CF3

Niflumic acid Figure 16.4 Relevant pyridine drugs.

N

Piroxicam

N HO2C

O

N H

N Doxylamine

NMe2

Cl

j1433

j 16 Six-Membered Heterocycles: Pyridines

1434

Cl Cl

NH2

N

Cl

NC

CO2H

Cl

Picloram (herbicide)

CN N

Cl

Pyridinitrile (fungicide)

Cl

N

CCl3

Nitrapyrin (bactericide)

Figure 16.5 Examples of agrochemical pyridine derivatives and their applications.

and analgesic; doxylamine is an antihistamine used for short-term treatment of insomnia and also to treat symptom soft allergy, colds and upper respiratory infections. Pyridine derivatives are also very important compounds for the agrochemical industry due to their applications as herbicides, fungicides or bactericides (Figure 16.5) [3–5]. 16.1.2 Spectroscopic Data 16.1.2.1 NMR Data The presence of the nitrogen atom in the aromatic ring produces a strong deshielding influence of the ring a-hydrogen and a-carbon atoms, and a similar but smaller effect on the ring c-hydrogen and c-carbon atoms. Typical 1 H NMR and 13 C NMR chemical shifts are indicated in Figure 16.6. The coupling constants of the pyridine aromatic protons are usually similar to benzenes, except in the case of the H2 proton whose coupling constant is reduced from 7–8 to 4–6 Hz. Substituent effects follow the same general trend as in substituted benzenes. The 15 N NMR signal for pyridine-type nitrogen appears at comparatively low field (57 ppm in CCl4). Substituent effects are often considerable, particularly when electron-donating groups are present in the aromatic ring and, consequently, downfield shifts are observed. For instance, the chemical shift of N1 in 4-methoxypyridine, 4-aminopyridine and 4-nitropyridine is 90, 105 and 35 ppm (in acetone), respectively (Figure 16.7). The nitrogen chemical shift of pyridine increases up to 100 ppm when the lone electron pair is protonated. For instance, the nitrogen signal of pyridinium hydrochloride appears at 181 ppm (in water). N-Oxidation of the nitrogen also shifts the signal downfield, but only between 10 and 30 ppm. Hydrogen bonding to the nitrogen lone pair leads to a downfield shift that depends on the strength of the bonding. Shifts of approximately of 20 ppm are usually found. 16.1.2.2 UV Data Pyridine shows two absorption maxima, at 195 and 250 nm (in CCl4). The UV spectra varies with pH because of quaternary salt formation. For example, 4-tert-butylpyridine

16.1 Introduction 4 5 6

J2,3= 4-6 J2,4= 0-2.5 J2,5= 0-2.5

3

N

2

J2,6= 0-0.6 J3,4= 7-9 J3,5= 0.5-2

7.75 7.38

N

8

6

8.59

4 PPM

2

0

130.2 122.0

N

150

100

148.1

50

PPM

0

Figure 16.6 Proton coupling constants (Hz) and 1 H and 13 C NMR spectra of pyridine.

has an absorption maximum at 262 or 255 nm in 0.1 M HCl or 0.1 M NaOH, respectively. 16.1.2.3 IR Data The pyridine IR spectrum is quite similar to the corresponding vibrations of benzene. Pyridine has C–H stretching frequencies in the range 3020–3070 cm
1 as well as C¼C and C¼N stretching frequencies at 1590–1660 cm
1 and near 1500 cm
1.

N 57 ppm

OMe

NH2

NO2

N

N

N

90 ppm

105 ppm

35 ppm

N+ H Cl 181 ppm

Figure 16.7 Examples of effect of substituents on the nitrogen chemical shift.

j1435

j 16 Six-Membered Heterocycles: Pyridines

1436

+ N

+

N

N-

N-

-N

N 2.23 D

Figure 16.8 Pyridine resonance forms. The ring nitrogen atom has a negative charge.

16.1.3 General Reactivity

Pyridine can be considered a benzene derivative in which an sp2-hybridized nitrogen atom replaces a CH unit. The pyridine ring is aromatic and several resonance structures may be drawn (Figure 16.8). The aromatic ring electronic structure is strongly modified by the presence of the electronegative nitrogen atom, which has a lone pair of electrons in one of the sp2 hybrid orbitals orthogonal to the p-system. Consequently, this excess electron density is localized on the ring nitrogen atom and it is not delocalized around the ring. On the other hand, the ring nitrogen atom pulls charge from the ring because the nitrogen atom is more electronegative than carbon and, therefore, pyridine is more polar than benzene, as its dipole moment (2.23 D) shows. Pyridine reactivity is based on the charge distribution within the ring, the electronic effects of ring substituents and to a lesser extent on steric effects. Pyridines are electron-deficient heterocycles that have many analogies in reactivity with nitrobenzene due to their electron distribution. In both molecules, the positive charge is located at positions 2 and 4 of the ring, and the negative charge is placed in the ring nitrogen atom for pyridines or in the C1 carbon atom for nitrobenzene (Figure 16.9). The ring nitrogen atom of pyridines is a reasonable nucleophile to react with electrophiles such as alkyl and acyl halides, leading to stable quaternary salts (Scheme 16.1). In addition, pyridines are weak bases compared with the corresponding piperidines; they react with Brønsted acids such as HCl, HNO3, H2SO4 and so on, to form pyridinium ions, and with Lewis acids such as AlCl3, SnCl4, and so on to afford stable pyridinium complexes. δ+

δ+ δ+

N δ-

δ+

δ+

δ+ δN+ O O

Figure 16.9 Pyridine and nitrobenzene charge distributions.

16.2 Synthesis of Pyridines

Reactivity with electrophiles

j1437

Reactivity with nucleophiles Nu Nu

N

N E

N

N

and/or Nu

E

E = H+, RX, RCOX, (RCO)2O, etc.

Nu: H2N-, HO-, organometallic compounds, etc.

Scheme 16.1

The electron-deficient nature of the pyridine ring allows nucleophiles to react with pyridines by a nucleophilic aromatic substitution mainly at the a- and c-positions. A wide range of nucleophiles can be employed, such as amide anions, hydroxyl groups, organometallic compounds, and so on, allowing the selective functionalization of the a- and c-positions of the pyridine ring with a large variety of functional groups. Pyridine electrophilicity is enhanced in the presence of electron-withdrawing groups in the ring.

16.2 Synthesis of Pyridines 16.2.1 Synthesis by Cycloaddition Reactions 16.2.1.1 [2 þ 2 þ 2] Cycloadditions One of the most convenient synthetic approaches to pyridines is the [2 þ 2 þ 2] cycloaddition of alkynes to nitriles catalyzed by transition-metals (Scheme 16.2) [6–10]. It is an atom-economical and extraordinarily effective method to prepare substituted pyridines. Although in principle thermal [2 þ 2 þ 2] cycloadditions are symmetry allowed, entropic barriers associated with the approximation of the three components and enthalpic activation energy contributions disfavor the pericyclic process [11–13]. In fact, reports of purely thermal [2 þ 2 þ 2] cycloadditions are rare in literature. However, these energetic barriers can be circumvented by the use of metals that coordinate to the reaction partners in a step-wise process.

+

Metal catalyst R

N

∆ R = alkyl, vinyl, aryl

Scheme 16.2

N

N

R

j 16 Six-Membered Heterocycles: Pyridines

1438

Until recently, most reported examples of co-cyclization reactions of alkynes to nitriles focused on cobalt-based catalysts. For example, Wakatsuki and Yamazaki [14, 15] reported in 1973 the first synthesis of pyridines using stoichiometric and, later on, catalytic cobaltacyclopentadienes. The mechanistic and synthetic studies reported by B€ onnemann were crucial for the development of this reaction [16–20]. The proposed mechanism is shown in Scheme 16.3. Thus, two alkyne moieties coordinate to the metal, and then oxidative coupling proceeds to give the Co(III)-metallacycle 1. Because nitriles are generally better s-donors than alkynes and, therefore, are better ligands for Co(III), the nitrile addition (path a) is more favored than the addition of a third alkyne (path b). Coordination of a nitrile to the metallacycle 1 takes place initially through the nitrogen to afford Co complex 2, which finally evolves by insertion of the nitrile to the metallacycle followed by reductive elimination to yield the pyridine derivative with concomitant regeneration of the CpCo catalyst. Whereas the nitriles undergo practically exclusive conversion into pyridine derivatives, the alkyne component always undergoes some degree of conversion into benzene derivatives. The ratio of pyridines to benzene products can be directed in favor of pyridines by using an excess of the nitrile. If catalysis is conducted in the

CpCo

2x

Co Cp 1 Cp

Co

"CpCo"

path b

R-CN path a

N

R

Cp 2

Scheme 16.3

Co N C R

Cp= cyclopentadienyl

16.2 Synthesis of Pyridines

presence of a permanent excess of nitrile and a stoichiometric amount of alkyne, pyridines can be obtained in yields up to 90%. The photochemical variant of the reaction provides a valuable extension of the existing methods, avoiding the harsh reaction conditions of the thermally initiated method. By irradiation of the reaction mixture with UV-Vis light (350–500 nm), or, alternatively, with sunlight as the energy source for catalyst activation [21, 22], the reaction could be carried out at ambient temperature and pressure and even permits the use of water as solvent. Besides improved operational safety with respect to the thermally initiated variant, the photochemical cycloaddition bears the opportunity to improve chemoselectivity by avoiding the homocyclotrimerization of the alkyne moieties [23, 24]. For instance, a series of 2-pyridines 3 have been synthesized at 25  C in 3–4 hours by the photocatalyzed [2 þ 2 þ 2] cycloaddition of various nitriles with acetylene (Table 16.1) [25]. The co-cyclization of monosubstituted alkynes 4 to nitriles 5 usually gives a mixture of 2,4,6- (6) and 2,3,6-trisubstituted pyridines (7), with the former products being predominant (Table 16.2). The regioselectivity of the reaction is related to the electron density on the metal. Co complexes containing electron-withdrawing Table 16.1 Examples of [2 þ 2 þ 2] cycloaddition of acetylene with nitrilesa).

+ N

R

O O OEt OEt

N O 7

a)

COD ¼ cyclooctadiene.

CpCo(COD) R

hυ, 25 ºC, 3-4 h

N

R

3 Solvent

Yield (%)

Hexane

90

Toluene

80

Hexane

81

Water þ 2% (v/v) toluene

85

Toluene

79

Toluene

80

j1439

j 16 Six-Membered Heterocycles: Pyridines

1440

ligands, for instance (C5H4COMe)Co(COD) [18, 26] (COD¼cyclooctadiene) or (C5H4CO2Me)Co(COT) [27], (COT¼cyclooctatetraene), give high yields but low regioselectivities (1.5 : 1), whereas Co complexes containing electron-rich ligands, for instance (C5Me5)Co(COD), afford higher regioselectivities (3.5 : 1) but low yields. Table 16.2 shows the effect of the type of Co catalyst on the reaction regioselectivity. The low regioselectivity of the [2 þ 2 þ 2] cycloaddition reactions can be circumvented by tethering two of the three reaction components. Two approaches have been employed, either reaction of dialkynes and nitriles (Scheme 16.4a) or alkynenitriles and alkynes (Scheme 16.4b). (a) Co-oligomerization of dialkynes with nitriles affords chemo- and regioselective formation of oligoheterocyclic systems in a single step. For instance, the cooligomerization of diyne 8 with various substituted nitriles 9 gives pyridines 10 in good yields and high selectivities (Scheme 16.5) [29]. Pronounced regioselectivity has been observed in the reaction of 1,7-decadiyne (11) with valeronitrile (12), affording tetrahydroisoquinoline 13 as the major regioisomer (Scheme 16.5) [29]. Table 16.2 Reaction temperature and regioselectivity for 65% propyne conversion.

R1 2

N

+ R1

R2

4

5

Co complex

Co(I)

R1

+ R1

N 6

R2

R1

N

R2

7

T ( C)

Ratio 6 : 7 (R1 ¼ Me; R2 ¼ Et) [18, 26, 28]

PhOC

Co(COD)

119

1.22 : 1

MeOC

Co(COD)

123

1.46 : 1

144

1.67 : 1

140

1.73 : 1

147

1.71 : 1

180

2.50 : 1

220

3.51 : 1

Si

Co(COD)

Co(COD) Co(COD)

Co(COD)

Co(COD)

16.2 Synthesis of Pyridines

R +

(a)

R

Metal N

N

R

Metal

+

(b)

j1441

R

N

N Scheme 16.4

R +

n 8

R

CpCo(CO)2

N

xylene, ∆

9

43-81%

N

n 10

n= 1, 2, 3 R = alkyl, aryl, CH2OMe, CH2CO2Et

nBu +

11

N

nBu

CpCo(CO)2 N

xylene, ∆

12

nBu +

N 14, 4%

13, 73%

Scheme 16.5

(b) a,v-Alkynenitriles 15 are catalytically co-cyclized with alkynes 16 in the presence of CpCo(CO)2 to furnish chemo- and regioselective [b]annulated pyridines 17 (Scheme 16.6) [30]. Chiral pyridine derivatives can be obtained by metal-catalyzed cycloaddition of optically pure nitriles and alkynes. Under thermal conditions, the enantiomeric excess of the product decreases in many cases by 2–10%, which is attributed to the high reaction temperatures (>100  C) necessary to initiate the catalysis [31–39]. However, using the photochemical version of the reaction, this problem is

CpCo(CO)2

+ N 15 Scheme 16.6

TMS 16

xylene, ∆, hυ 70%

N 17

TMS

j 16 Six-Membered Heterocycles: Pyridines

1442

circumvented, affording optically pure pyridine derivatives without detectable loss of enantiomeric purity (Scheme 16.7) [40].

BnO

CpCo(CO)2

N

N

+

2

O

toluene, hυ 89%

N

CpCo(CO)2 +

NHAc

2

N BnO

O

N

>99% ee

N

toluene, hυ 83%

NHAc >99.5% ee

Scheme 16.7

Recently, it has been shown that by using modified chiral Co(I) complexes of the type CpCo(COD) homochiral 1-aryl tetrahydroisoquinolines 20 are obtained in 82–93% ee by co-oligomerization of diyne 18 and various nitriles 19 (Scheme 16.8) [41].

R R OMe

18

+

N 19

*Co(I), hυ

N OMe

THF, −20 ºC - 3 ºC 74-88% 20, 82-93% ee

R = Ph, Me, tBu Scheme 16.8

Although many examples of Co-catalyzed [2 þ 2 þ 2] cycloaddition of nitriles to alkynes have been reported, the regioselective assembly of two different unsymmetrical alkynes and a nitrile, leading to a single pyridine derivative, still remains unsolved. In a few cases, a single pyridine has been obtained with the assistance of a functional group such as an ester group [42]. However, in most cases a mixture of regioisomers is obtained. This can be attributed to the two possible orientations of the nitrile during the formation of the cobaltacyclopentadiene. Therefore, the regioselectivity of the reaction is completely dependent on the substitution of the alkynes. This selectivity problem has been greatly improved with the use of other

16.2 Synthesis of Pyridines Table 16.3 Examples of [2 þ 2 þ 2] cycloaddition of nitriles to alkynes mediated by diverse transition-metal complexes.

Alkynes

C6H13

Nitrile

Ph

Metal complex

Product

Ph

SO2Tol

TMS

Hex

N

N

TsN

Hex

Cp2ZrBu2 NiCl2(PPh3)2

N

[43]

Et

59

[44]

N

95

[45]

Ph

TsN

CN



a)

Cp Ru(COD)Cl

CN

CN

N

Cp ¼pentamethylcyclopentadienyl.

a)

70

CONEt2

TMS

Et

Ph

Reference

C6H13

Ti(OiPr)4/iPrMgCl

CONEt2

Yield (%)

transition-metal complexes such as Fe, Rh, Ni, Ti, Ta, Ru, Zr/Ni and Zr/Cu [6]. Table 16.3 shows some examples. 16.2.1.2 [4 þ 2] Cycloadditions Pyridine derivatives can be efficiently synthesized by the [4 þ 2] cycloaddition (hetero-Diels–Alder) of an azadiene and a dienophile (Figure 16.10a and b) or a diene and an azadienophile (Figure 16.10c). Careful selection of the appropriate azadiene/diene and the complementary dienophile/azadienophile and well-defined reaction conditions can result in a good approach to substituted pyridines. In selecting an appropriate diene and dienophile it is important to understand that the Diels–Alder reactions can be classified as three types: (i) normal Diels–Alder

(a) N O

(b)

N

N

(c)

O

N

O

N

Figure 16.10 Hetero-Diels–Alder approaches to pyridine.

N

N N

N

N

N

j1443

j 16 Six-Membered Heterocycles: Pyridines

1444

NEUTRAL

NORMAL HOMOdiene-controlled EDG

INVERSE LUMOdiene-controlled EWG

EWG

EDG

LUMO

LUMO LUMO

LUMO HOMO

HOMO

HOMO

HOMO

Figure 16.11 Classification of the Diels–Alder reactions.

(HOMOdiene-controlled), customarily employing an electron-rich diene (increased HOMOdiene) and electron-deficient dienophile (decreased LUMOdienophile); (ii) inverse electron demand Diels–Alder (LUMOdiene-controlled), which is favored by employing an electron-deficient diene (decreased LUMOdiene) and electronrich dienophile (increased HOMOdienophile); and (iii) neutral Diels–Alder (Figure 16.11) [46–48]. 16.2.1.2.1 Diels–Alder Reaction of Azadienes and Dienophiles Azadienes as electron-deficient dienes are ideally suited for participation in inverse electron demand Diels–Alder reactions [49–51]. Electron-withdrawing groups in the azadiene accentuate its electron-deficiency and permit the use of electron-rich, strained and even simple alkenes as dienophiles. Strong electron-donating groups in the azadiene reverse its electron-deficient nature and permit the use of conventional dienophiles for normal Diels–Alder reactions. The most commonly used azadienes are azabutadienes, oxazoles, 1,3-diazines, 1,2,4-triazines, and so on (Figure 16.12). Aza-1,3-butadienes Several examples of hetero-Diels–Alder pyridine synthesis using aza-1,3-butadienes have been reported. For example, Boger and coworkers [52, 53] recently published the total synthesis of Piericidin A1 and B1, in which the pyridine core was synthesized by an inverse electron demand Diels–Alder reaction between N-sulfonyl-1-aza-1,3-butadiene 22 and tetramethoxyethene (23) followed by Lewis acid-promoted aromatization to give pyridine 24 in good yield (Scheme 16.9).

16.2 Synthesis of Pyridines

R

R R

R R

N

N X

N

O

oxazinones

oxazoles

R

R

R

R N

O R

R

azabutadienes

R

R

O

j1445

R

N

N N

N

R

R

1,3-diazines

1,2,4-triazines

Figure 16.12 Examples of azadienes employed in the Diels–Alder reaction.

+ EtO2C

MeSOCl, Et3N

N R

MeO

OMe

MeO

OMe

toluene, 50 ºC 64% from 21

EtO2C

23

21, R=OH 22, R=SO2Me OMe EtO2C

N

OMe OMe OMe N OMe SO2Me

BF3.OEt2 88%

OMe

24 Scheme 16.9

In addition, cationic aza-1,3-butadiene 25 reacts with dialkyl acetylenedicarboxylate 26 by a tandem [4 þ 2] cycloaddition/deamination reaction in the presence of triethylamine to give the product pyridines in satisfactory yields (Scheme 16.10) [54].

NMe2

MeS

H N H I 25

Scheme 16.10

CO2R + CO2R 26

NMe2 CO2R

CH2Cl2, Et3N, rt 62-66%

R= Me, Et

MeS

N H

CO2R

CO2R MeS

N

CO2R

j 16 Six-Membered Heterocycles: Pyridines

1446

Heating 1,3-diynyl bis(a,b-unsaturated hydrazone) 27 results in double intramolecular Diels–Alder reaction to give, after aromatization by loss of dimethylamine, 2,20 -bipyridine 28 (Scheme 16.11) [55].

N

N

N

N

Xylene, ∆ 76%

N

N

27

28

Scheme 16.11

1,3-Oxazin-6-ones 1,3-Oxazin-6-ones react with a large variety of alkynes to afford highly substituted pyridines. Table 16.4 shows some examples of this heteroDiels–Alder reaction. The initial [4 þ 2] cycloadduct 31 undergoes a retro-Diels– Alder reaction with loss of carbon dioxide providing regioselectively pyridine derivatives 32 in good to high yields. Alternatively, these cycloaddition reactions can also be performed with electron-rich alkenes such as 1-ethoxy-1-(dimethylamino) ethylene (Scheme 16.12). Table 16.4 Hetero-Diels–Alder reaction of 1,3-oxazin-6-ones 29 and alkynes 30.

O

R3

2

4

R

O

R

N

R

∆

+

O

2

29

R

Ph Piperidine Pyrrolidine NMe2 CO2Et CO2Et H nPr nPr

R5

CO2

R1

R4 R5

32

31

Oxazinone substituents R1

R

N 1

30

R3

2

R4

N

R5

R1

O

R3

Alkyne substituents

R2

R3

R4

R5

Yield of 32 (%)

Reference

CF3 CF3 CF3 CF3 Ph Ph Ph Me Me

H H H H H H H H H

H H CO2Me CO2Me TMS TMS TMS NBn2 NEt2

CO2Et CO2Et CO2Me CO2Me H TMS TMS Me Me

96 54 82 85 81 88 71 69 83

[56] [56] [56] [56] [57] [57] [57] [58] [58]

16.2 Synthesis of Pyridines

O N

EtO

+

O

NMe2

∆

NMe2

N CO2, EtOH

R

R

80-94%

R = iPr, iBu, tBu, CF3 Scheme 16.12

Oxazoles Oxazoles have been used extensively as azadiene in the hetero-Diels– Alder synthesis of pyridine derivatives [50, 51]. The initial cycloadduct 35 is usually very stable, and even isolable in many cases, and can provide, depending of the reaction conditions, pyridines 36 (dehydratation/aromatization) or 3-hydroxypyridines 37 (elimination/aromatization) (Table 16.5). 1,3-Diazines 1,3-Diazines can undergo [4 þ 2] cycloaddition reactions across positions C2/C5 or N1/C4. The regioselectivity of the reaction depends on the dienophile employed as well as the substituents present in the diazine nucleus. For example, diazine 38 reacts with N,N-diethyl-1-propynylamine (39) by an inverse electron demand Diels–Alder reaction across position C2/C5 (Table 16.6) [64]. Diazines 38a and 38b react via the cycloadduct 40, affording exclusively regioisomers 41 in excellent yield. However, the opposite regioselectivity is obtained with diazine 38c, which gives pyridine 42 in 81% yield. A [4 þ 2] cycloaddition reaction across N1/C4 occurs in the reaction of diazine 43 with enamine 44 to give 2-morpholino-5-nitropyridine 47 in 57% yield (Scheme 16.13) [65]. Its formation can be explained via intermediates 45 and 46.

O

4

N

N

O

O

NO2

O N

N

+

EtOH, RT

N

57%

1

43

N

N

NO2

4

N

1

45

44

O N H O

NO2 N O Scheme 16.13

N 47

CN

N N

NO2 N 46

j1447

j 16 Six-Membered Heterocycles: Pyridines

1448

Table 16.5 Examples of hetero-Diels–Alder synthesis of pyridines using oxazoles as azadienes.

X

R2 X

R2

+

O

N

R3

R2

∆

N

R3

R1 33

34

O

X

R3

R3

N

- H2O

R

36

R3 R1

R3

1

-XH

OH

R2

35

R3

N

R3

1

R

Dienophile 33

Diene 34

CN

O

N

OEt N

i

O

OEt

Product

Yield (%) Reference

OH

O

O

N

Conditions

37

Pr

(1) MW, 120  C HO (2) H þ

CO2Et CO2Et

F3C

CO2H

O



(1) 115 C (2) HCl, EtOH



120 C

80

[59]

51

[60]

56

[61]

N 69

[62]

76

[63]

OH N CO2Et CO2Et

HO

N

HO

CF3

N N NR

N H

O DBNa), D

R=Boc

R=Boc N

N O

DBN , D a)

CO2Me a)

NR

N H

DBN ¼ 1,5-diazabicyclo[4.3.0]non-5-ene.

CO2Me

16.2 Synthesis of Pyridines Hetero-Diels–Alder reaction of N,N-diethyl-1-propynylamine (39) with diverse diazines.

Table 16.6

2

R

R3

R

N

2

R1

2

R

38

R

NEt2 N

2

N

39 N

R1 41 R3

CN

5

R3 2

R

N

2

R1

38a 38b 38c

NEt2

5

R3

2

40

∆

+

N

CN

R1

NEt2

5

R3

N

N 2

j1449

R1

NEt2

NEt2 42

R1

R2

R3

41

42 (% yield)

H H CO2Me

H CO2Me CO2Me

CO2Me CO2Me H

90 80 0

0 0 81

1,2,4-Triazines Aside from oxazoles, substituted 1,2,4-triazines constitute the most thoroughly investigated heteroaromatic azadienes in hetero-Diels–Alder reactions. Two potential modes of [4 þ 2] cycloaddition reaction can occur, across positions C3/ C6 or C5/N2 of the 1,2,4-triazine nucleus (Scheme 16.14). Regioselective inverse Reactivity N

X=

R= EWG 6 N

N N

3

N

TMSO

EtS

Me

X R dienophile

Regioselectivity TMSO

N

X=

R=

Scheme 16.14

H

O

H

Me

O

N

j 16 Six-Membered Heterocycles: Pyridines

1450

electron demand Diels–Alder reactions across positions C3/C6 can be achieved with 1,2,4-triazines substituted with electron-withdrawing groups and dienophiles substituted with electron-donating groups. Typical dienophiles are enamines, enol ethers and reactive or strained alkenes. Although the regioselectivity of the C3/C6 cycloaddition is controlled by several factors, such as the electronic and steric properties of the triazine and the dienophile [66] and the reaction conditions, it is the strong preference for the nucleophilic carbon of the dienophile to attack the C3 position of the 1,2,4-triazine nucleus that determines the regioselection outcome. Scheme 16.15 shows the established mechanism for the reaction of 1,2,4-triazines 48 and EDG-dienophiles 49, in which the first step is the inverse electron-demand Diels–Alder reaction, followed by in situ loss of nitrogen and subsequent elimination/ aromatization to give pyridine derivative 50. For instance, 1,2,4-triazines 51 and 54 react with bicyclic alkene 52 and trimethoxyethene 55 to afford pyridines 53 [67] and 56 [68], respectively, in high yields (Scheme 16.16). N

R3 6

R2 N

3

X

N N

+

R5

Diels-Alder

R

49

48

N

R3

6

N 3 R1

R4

1

R2

X

R5 4

R

Retro Diels-Alder N2 R3

R2 N

1

R

R5 R4

Elimination/aromatization

R3

R2 N

R1

X R5 R4

50 Scheme 16.15

Enamines have been widely used as dienophiles in the [4 þ 2] cycloaddition synthesis of highly substituted pyridines [69–71]. For instance, diverse fused bicyclic pyridines 59 have been prepared from 1,2,4-triazines 57 and enamine 58 (Scheme 16.17). Using enamine 61 the reaction takes place with an entirely different regiochemistry, depending on the triazine substitution (Table 16.7). This approach had two main limitations: the requirement of preformed enamine and the unusual stability of the cycloadduct intermediate. Boger and coworkers [72]  circumvented these difficulties by the addition of 4 A molecular sieves, which allowed enamine formation to catalyze the elimination step (Scheme 16.18). Recently, Taylor and coworkers [73] reported an improved version of this method using a microwave

16.2 Synthesis of Pyridines

CO2Et R

N N

N

CO2Et

R

EtOH, ∆

+

N

72-84% 52

CO2Et

j1451

CO2Et

51

53 R= aryl, alkyl

CO2Et

EtO2C

MeO

N N

N

OMe

+ OMe

CO2Et

dioxane, Et3N 100 ºC, 30 min

N

85%

55

CO2Et OMe

EtO2C

54

OMe CO2Et 56

Scheme 16.16

XR2

R1

N

N N

N

Dioxane, ∆

+

XR2

R1 N

57

59

58

X = S, SO, SO2 R1= Me, Ph, CH(Me)2 R2= Me, Bn

X = S, 91-98% X = SO, 68-92% X = SO2, 46-88%

Scheme 16.17 Table 16.7 [4 þ 2] cycloaddition of 1,2,4-triazines 60 and enamine 61.

R3

2

R

N N

N

∆

+ R2N

1

R3

2

R

1

R

R 61

60

NR2

+

62a

Triazine 60

NR2

R N

XEt

R3

2

Enamine 61

N R1 62b

Product (% yield)

R1

R2

R3

X

R

62a

62b

Me Ph H Me CO2Me

H H Ph H H

H H H Ph H

O O O O S

Me Me Me Me Et

— 81 8 — 82

60 — 58 83 —

j 16 Six-Membered Heterocycles: Pyridines

1452

H N

O N N

N

N

CHCl3, 4A MS, 45 ºC, 96h 93% O

3

R

R2

n N N

N

H N

n

N

MW, 120-160 ºC

R1

R3

R2

15-90 min

R1

64-91%

63

1

R = Py, CO2Et R2, R3= H, Me, Aryl

n=1,2,3,4,8

Scheme 16.18

(MW)-promoted procedure. Under these conditions tri-, tetra- and pentasubstituted pyridines 63 can be synthesized in good yields with relatively short reaction times. Although, addition across C3/C6 of the 1,2,4-triazine nucleus is nearly always favored, ynamines 64 react exceptionally across C5/N2 with subsequent loss of nitrile by a retro-Diels–Alder reaction to form pyrimidines 65 (Scheme 16.19) [74–78].

R3

R2

5

Et2N N N2

N

+

R1

N NEt2 64

R1

R2 N 2

5

N

R2 R3

N R3CN

1

R

N

NEt2

65

R1= OMe, R2= R3= H; 87% R1= SMe, R2= R3= H; 86% R1= NMe2, R2= R3= H; 91% R1= CO2Me, R2= R3= H; 100% R1= CO2Me, R2= H; R3= Ph; 100% Scheme 16.19

In addition, 1,2,4-triazines undergo intramolecular inverse electron demand Diels–Alder cycloadditions to produce bicyclic pyridines. For instance, 1,2,4-triazine-5,6-dicarboxylate 66 in refluxing diglyme afforded 67 in 8 h (Scheme 16.20) [79–81]. Addition of Eu(fod)3 [europium tris(6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedionate)] enabled completion of the reaction in only

16.2 Synthesis of Pyridines

CO2Et N N

CO2Et

diglyme, ∆

N

N

CO2Et CO2Et

Eu(fod)3 (cat) 2 h No cat 8 h

66

N Ph

N

N

N

N

87% 67

Bromobenzene, ∆ n

55%-98%

Ph

SO2R

68

N

n SO2R

69 n = 1, 2 R = Aryl, NMe2, OCH2tBu, Morphyl, Pyrrolidyl

Scheme 16.20

2 h. Also, several quinoline derivatives 69 have been synthesized from acetylenic 1,2,4-triazines 68 [82]. 16.2.1.2.2 Diels–Alder Reaction of Dienes and Azadienophiles Pyridines can be also synthesized by Diels–Alder cycloaddition of azadienophiles, such as nitriles or imines, and dienes [83, 84]. Usually, imine dienophiles need to be activated by Lewis acids such as Yb(OTf)3, Sc(OTf)3, In(OTf)3, ZnCl2, SnCl4, TiCl4, Et2AlCl, and so on. For instance, 5-alkyl-2(p-tolylsulfonyl)pyridines 72 are obtained in good yields at room temperature by [4 þ 2] cycloaddition of 2-alkyl-1-ethoxy-1,3-butadienes 70 to p-toluenesulfonyl cyanide (71), followed by aromatization of the dihydropyridine intermediate via 1,4-elimination of ethanol (Scheme 16.21) [85]. OEt

OEt R

+

N Ts

70

71

RT

R

R

N Ts H

EtOH

N Ts 72, 64-89%

R = alkyl Scheme 16.21

Oximino derivatives 74 undergo Diels–Alder cycloadditions with dienes 73 to afford adducts 75, which can be converted into pyridines 76 in refluxing ethanol or by base-promoted elimination (Scheme 16.22) [86–89]. Alternatively, oximinosulfonates derived from Meldrum’s acid 78 undergo Diels–Alder cycloaddition reaction with dienes 77 in the presence of dimethylaluminium chloride [90]. The [4 þ 2]

j1453

j 16 Six-Membered Heterocycles: Pyridines

1454

N

+

R1

NC 73

OR

∆

N R1

X 74

OR CN X

75

EtOH, ∆

N CN

R1

HX HOR

76

R1= H, Me, Ph X = CN, CO2Me R= Ts, Ms, COAr

R1

2

N

R

+

R3

OTs O

O O

O

1) Me2AlCl, CH2Cl2, -78 ºC

R

2) NaOMe, NCS, MeOH-THF, RT

R3

40-77%

R4 77

2

78

R1 N CO2Me

R4 79

R1- R4 = H, alkyl NCS

2

R1

R

R3

N R4 80

OTs O O O

O

NaOMe O

CO2

2

R1

R

N

OTs OMe

3

R

R4 81

2

O

R1

R TsO-

R3

N R4

CO2Me

82

Scheme 16.22

cycloadducts 80 can be transformed by the simultaneous action of a nucleophilic alkoxide and suitable oxidizing agent into the corresponding pyridines 79 under treatment with NaOMe and N-chlorosuccinimide (NCS). The mechanism of this multistage reaction probably involves initial cleavage of the dioxandione ring by methoxide with concomitant elimination of acetone and carbon dioxide. b-Elimination of tosylate from the resulting ester enolate 81 then generates a dihydropyridine 82, which by subsequent chlorination with NCS and elimination of HCl provides pyridines 79. In addition, heating acyl oximes 83 under high dilution conditions leads to the corresponding cycloadducts 84, which by a double elimination reaction under treatment with caesium carbonate give pyridines 85 (Scheme 16.23) [91]. These cycloaddition reactions can also be promoted by high pressure in similar yields. 16.2.1.3 Formal Cycloaddition Reactions with Organometallic Derivatives Aumann and coworkers [92] have shown that pyridinium salts 90 and pyridines 91 can be synthesized by a formal [3 þ 3] cycloaddition reaction of alkylnylcarbene

16.2 Synthesis of Pyridines

O n

1

R

R2

O N

CN

Toluene, ∆ or 12 kbar

X

R3

R

N

R2

3

R

35-85%

83

O

n

1

O

Cs2CO3

X CN

DMF, RT

R2

38-79%

84

X = CN, CO2Et R1, R2, R3 = H, Me, Ph n = 0, 1

n

R1

j1455 CO2H

N R3

X

85

Scheme 16.23

complexes 87 [93] and enaminoketones or enaminoimines 86 (Scheme 16.24). The reaction involves the Michael addition of the enamino derivatives 86 to the alkynylcarbene complex 87 to give 1,3,5-trienes 88 (characterized by NMR spectroscopy), which in turn spontaneously cyclize to form 1,2-dihydropyridin-2-ylidene complexes 89. Protonation of 89 takes place at the metal–carbon bond, affording the pyridinium salt 90 and the recovery of the metal complex. Treatment of the pyridinium salt 90 (R¼H) with base affords the corresponding pyridine derivative 91. Under these conditions pyridine 91 (X¼O) has been obtained in 75% yield. R

N

OEt

H

+

X 86

THF, RT

X

X

H

R

EtOH

N

(OC)5W

Ph

(OC)5W

(OC)5W 87

R N H EtO

Ph H

88

Ph

HBF4 CO

W(CO)6 X = O, NMe R = H, Me

X Base

N H

Ph H

(R = H)

BF4-

X

R + N H

91

Scheme 16.24

Pyridines and pyridinium salts can also be obtained from (amino)vinyl carbene complexes and alkynes by a formal [4 þ 2] cycloaddition. The reaction of [(Z)b-(monoalkylamino)vinyl] carbene complexes 92, readily prepared by addition of primary amines to alkynylcarbene complex 93, with alkynes 94 involves the highly regioselective formation of 4(1H)-pyridinylidene complexes 95 (Scheme 16.25) [94].

89

Ph H

90

j 16 Six-Membered Heterocycles: Pyridines

1456

MLn OEt R2

MLn

R3

THF, 50-70 ºC

+

NH R1

94

EtOH 19-71%

92

R2

N R1 95

R3

R3

HBF4 83-90%

R2

+ N R1 96

BF4-

MLn = Cr(CO)5, W(CO)5 R1 = Me, iPr, Ph, Bz R2 = nBu, Ph R3 = nBu, Ph, CH2OMe

R1NH2 MLn OEt R2

93 Cr(CO)5 OEt Ph

nBu +

66%

NH2 97

nBu

THF, 60 ºC

98

Ph

N 99

Scheme 16.25

Protonation of 95 with HBF4 leads to pyridinium salts 96. On the other hand, heating [(Z)-b-aminovinyl]chromium complex 97 and 1-hexyne (98) gives pyridine 99 in 66% yield. In addition, organolithium derivatives 101 of 1,3-dienes, generated in situ by lithiation of their corresponding 1-iodo-1,3-dienes 100, react with arylnitriles to give N-lithioketimines 102 as the first intermediates, which undergo an intramolecular cyclization to produce 103, which after elimination of LiH or LiTMS (R4¼TMS), generate pyridine derivatives 104 in good yields (Scheme 16.26) [95–97]. 16.2.2 Synthesis by Cyclocondensation Reactions

Pyridine ring have also been synthesized successfully by cyclocondensation reactions, of which the most important is the Hantzsch synthesis. 16.2.2.1 Hantzsch Cyclocondensation The original Hantzsch synthesis consists of a four-component reaction between two molecules of ethyl acetoacetate (105), an aldehyde 106 and ammonia to afford 1,4dihydropyridines (107), which by further oxidation afford the corresponding symmetrical pyridine derivatives 108 (Scheme 16.27). The reaction is usually carried out by warming the reagents in ethanol, and has been widely used for the preparation of diverse 1,4-dihydropyridines 107, where R could be an alkyl or an aryl group [98].

16.2 Synthesis of Pyridines

R2

R1 I

R2

tBuLi

3

R

R1

R1 1) HMPA, RT

Li

2) Ar-CN, RT

3

R

R4 100

R4

Ar

R2

NLi

R3 R4

75-87%

102

101

R1-R4 = alkyl or TMS

R1 R2

Ar

R

N

R3

4

R

104

R1

2

R3

HLi (or LiTMS)

Ar NLi 4

R H

103

Scheme 16.26

R EtO2C

106 O

+ O

CO2Et

O NH3

105

R

105

EtO2C

EtOH, ∆

CO2Et N H 107

(a) Hantzsch

[O]

(b) Oxidation R= Alkyl, aryl R EtO2C

CO2Et N 108

Scheme 16.27

The formation of the 1,4-dihydropyridine derivatives 111 can occur by two pathways (Scheme 16.28) [99]. The first consists of the Knoevenagel condensation of one b-ketoester molecule 109 and the aldehyde 110 to afford a,b-unsaturated ketone 112, which undergoes a Michael addition reaction with the other b-ketoester molecule to give the 1,5-dicarbonyl derivative 114. Finally, enamine formation followed by cyclocondensation affords the 1,4-dihydropyridine nucleus 111. Alternatively, 1,4dihydropyridine derivatives 111 can be formed by reaction first of ammonia and one

j1457

j 16 Six-Membered Heterocycles: Pyridines

1458

R2

110 O

EtO2C

CO2Et

+

O R1 109

O

NH3

Knoevenagel condensation

EtO2C O

H2N

N H

R1 111

EtO2C O O 114

cyclocondensation

R1 113

109 R2

R1

R1

R1 109

CO2Et

CO2Et +

112 Michael addition

EtO2C

enamine formation R2

R1

R2

Michael addition R2

CO2Et R1

CO2Et R1

EtO2C enamine formation

R1

O

NH2 115

Scheme 16.28 Proposed mechanism for the Hantzsch synthesis of 1,4-dihydropyridines.

b-ketoester 109 molecule to afford b-enaminoester 113, which undergoes Michael addition with a,b-unsaturated ketone 112 to give also, as the first pathway, enaminone 115. 1,4-Dihydropyridines can be oxidized using diverse oxidants, such as HNO3 [100], KMnO4 [101], quinones [102], cerium(IV) ammonium nitrate (CAN) [103], NaNO2 [104], Cu(NO3)2 [105], Mn(OAc)3 [106], Zr(NO3)4 [107], Pb(OAc)4 [108], and so on Recently, more efficient and environmentally benign methods have been developed, such as electrochemical oxidations [109], and catalytic aerobic oxidations by using RuCl3 [110], Pd-C [111], activated carbon [112], Fe(ClO4)3 [113] or N-hydroxyphthalimide [114]. Remarkable improvement of the reaction conditions has been reported, including the promotion by microwave [115], TMSCl, ionic liquid [116], Bu4NHSO4 [117] and supported reagents [118]. 16.2.2.2 Variants of the Hantzsch Cyclocondensation Although the Hantzsch 1,4-dihydropyridines synthesis was discovered in 1882, it was not fully developed until 1980 with the discovery that 1,4-dihydropyridines prepared from aromatic aldehydes are calcium channel blocking agents and, therefore,

16.2 Synthesis of Pyridines

valuable drugs for heart disease with useful effects on angina and hypertension. Since its discovery, more effective and versatile variants of the original reaction have been developed, including (Scheme 16.29):

Y + R

COXR

R O

NH2

O

R

R

Y

COXR

+ R

+

NH2

O

R

N

X= O, S Y= CO2R, CN, COR

O

O

O

O

+

NH3

+

NH3

Scheme 16.29

1) Replacement of ammonia and a molecule of b-ketoester by b-enaminoesters, b-enaminonitriles or b-enaminoketones. 2) Utilization of a,b-unsaturated ketones instead of an aldehyde and the b-ketoesters. 3) The use of 1,5-dicarbonyl derivatives. 16.2.2.3 From Enamines Enamines have been widely used in the cyclocondensation synthesis of highly substituted pyridines. For example, Jacobson and coworkers [119] have reported the synthesis of pyridines 119 by condensation of b-ketoester 116, aldehyde 117 and b-enaminoester 118 and subsequent oxidation of the resulting 1,4-dihydropyridines with tetrachloroquinone (Scheme 16.30). Alternatively, cyclocondensation of enamines and a,b-unsaturated carbonyl derivatives has also been achieved. For example, Wolfe and coworkers [120] have recently described the use of bicycloenamine 120 and a,b-unsaturated ketones 121 in the synthesis of pyrazolopyridines 122 (Scheme 16.31). Treatment of a,b-unsaturated ketones 121 with enamine 120, generated from 1-cyanoacetylpyrazolidine hydrochloride, followed by oxidation of the corresponding dihydropyridines afforded pyridines 122 in good yields.

j1459

j 16 Six-Membered Heterocycles: Pyridines

1460

R3 2

R SOC

117 O

+

R1

O

H2N

116

R3

R2SOC

CO2R5

1) EtOH, 80 ºC, 24h

R4

2) Tetrachloroquinone, THF, ∆

R1

N

CO2R5 R4

119

118

R1 = Alkyl, Fluoroalkyl, hydroxyalkyl, thioacetylalkyl R2 = Alkyl, Fluoroalkyl, hydroxyalkyl R3 = Alkyl, Fluoroalkyl, hydroxyalkyl, aminoalkyl, thioacetylalkyl R4 = Aryl R5 = Alkyl, Fluoroalkyl Scheme 16.30

X

CO2H X

O N

N

+ NH2

1) NaOEt, EtOH, ∆ 41-64%

CO2Et

2) CAN, CH3CN 66-76%

O

120

121

Y

O N

N

CO2H

CO2Et N 122

Y

X = S, O, CH=CH Y = F, CF3 Scheme 16.31

In addition, Gordeev and coworkers [121] have exploited the enamine/ a,b-unsaturated carbonyl approach to the efficient solid-phase synthesis of diverse pyridines 127 (Scheme 16.32). Treatment of O-immobilized ketoester 123 with diverse aldehydes afforded Knoevenagel derivatives 124, which by condensation with diverse b-enaminoketones 125 gave 1,4-dihydropyridines 126. Finally, oxidation and cleavage from resin yielded pyridines 127. On the other hand, Katritzky and coworkers [122] have developed a mild and highly regioselective route to diverse nicotinonitriles 131 from b-enaminonitriles 128 with a Vilsmeier-type reagent 129 (Scheme 16.33). The reaction proceeds via intermediate 130 (identified by NMR spectroscopy), which upon treatment with base induced a spontaneous electrocyclization–elimination process to furnish the pyridine core. The b-enaminonitriles 128 were synthesized by a tandem addition–elimination process from b-aminocrotonitrile 132 and ketone 133. Alternatively, malononitriles have been employed as enamine synthons in the enamine/a,b-unsaturated carbonyl cycloaddition approach. For example, a,b-unsaturated ketones 135 were condensed with malononitrile (134) in the presence of NaOEt or NaOMe to yield the corresponding cyanopyridines 136 (Scheme 16.34) [123].

16.2 Synthesis of Pyridines

O

O OH

j1461

O

O

O

R

O

DMAP, DCM

O

124 O R2

125 R3

H2N R1

O

O

HO2C

1) CAN, Me2NCOMe

R2

R2 N H

127

DMF, ∆

O

O

2) TFA, DCM

R3

N

R1

R3

126

Scheme 16.32

R1

N

R2

NC

+ NH2

N

R1 CH2Cl2, RT

N NMe2

Cl

128

129

N

N

R2

NC

NMe2 NH2 130

Cl

N H NaOH, RT

TiCl4, Et3N, DCM, RT

NC

+ NH2 132

Me2NH R1

R1 2

R

O 133

R1

O

Piperidine (cat), iPrOH-C6H6, ∆

123

Wang or Sasrin resin

O

1

NC

R2

N 131, 50-74%

Scheme 16.33

16.2.2.3.1 From 1,5-Dicarbonyl Derivatives A good approach to pyridine ring synthesis is the cycloaddition of 1,5-dicarbonyl derivatives and ammonia. For example, pyridine 138 has been synthesized from 1,5-diketone 137 by treatment at room temperature with ethanolic ammonia (Scheme 16.35) [124].

j 16 Six-Membered Heterocycles: Pyridines

1462

R2

R2 NC

3

R ONa, R OH

+

CN 134

55-85%

135

NC

NC

RT

R1

O

R2

NC

3

O

R1

R3O

N

R1

136

R1, R2 = Aryl; R3= Me, Et Scheme 16.34

Ts

CO2Me

Ts

NH3 (2M in EtOH) Ph

O O

RT, 14h

Ph

CO2Me

CO2Me N H

137

Ph

N 138, 83%

Scheme 16.35

The 1,5-dicarbonyl/ammonia approach has been successfully applied to a solidphase synthesis of 2,4,6-trisubstituted pyridines 142 from hydroxyacetophenones 139 (Scheme 16.36) [125]. The strategy includes a Claisen–Schmidt reaction to form a,b-unsaturated ketones 140, a Michael reaction with trimethylsilyl enol ethers to form a 1,5-pentanediones 141, and cyclization with ammonium acetate to yield, after acid cleavage from resin, pyridine derivatives 142. 16.2.2.4 Bohlmann–Rahtz Heteroannulation The synthesis of trisubstituted pyridines from b-aminocrotonates and ethynyl ketones was first reported by Bohlmann and Rahtz in 1957 [126]. Originally, the reaction consisted of a two-step process, involving the initial conjugate addition of enamine 143 to alkynone 144 at 50  C in ethanol to generate an aminopentadienone intermediate 146, which is isolated and subsequently cyclodehydrated by heating the residue at 120–160  C under reduced pressure to afford trisubstituted pyridines 145 (Scheme 16.37). Since its discovery, remarkable improvements have been reported, most notably a single synthetic step using either acetic acid, Amberlyst 15 ion exchange resin or Lewis acid catalysts, such as ZnBr2 or Yb(OTf)3 [127–129]. The Bohlmann–Rahtz heteroannulation reaction has also been successfully applied to the combinatorial synthesis of tri- and tetrasubstituted pyridines in solution [130]. Lewis acid-catalyzed methods provided the best overall yields, product ratios and library purity. 16.2.3 Synthesis by Aza-Electrocyclization Reactions

Pyridine rings can also be synthesized by aza-6p-electrocyclic reactions, which result in the formation of just one new s bond across the ends of a single conjugated

16.2 Synthesis of Pyridines

O

R1

R1

Cl Cs2CO3, NaI, DMF, 50 ºC

HO 139

O

O

2 RCHO, NaOMe, MeOH, CH(OMe)3

R2 R1

OTMS

O

R3

R3

O O

R2 R1

O

CsF, DMSO, ∆ O

141

140

NH4OAc, AcOH, DMF, ∆ R2

R2 R1

N

R3

R1

50% TFA-DCM

HO

O

R3

N 142

Scheme 16.36

R3

R2 + R1

NH2

143

O

R4 144

R3 2

AcOH or Amberlyst 15, Tol, 50 ºC

R

or ZnBr2 or Yb(OTf)3, Tol or DCM, ∆

R1

145

R2

EtOH, 50 ºC

R3 120-160 ºC

1

4

R

R NH2 O 146

R1= alkyl, aryl; R2= CN, CO2R; R3= Me, CO2Et; R4= H, alkyl, aryl, TMS Scheme 16.37

N

R4

j1463

j 16 Six-Membered Heterocycles: Pyridines

1464

p-system (Scheme 16.38). A good example of this approach has also been reported by Brandsma and coworkers [131, 132] in the synthesis of pyridine derivatives 154 (Scheme 16.39). Reaction of lithiated allene 149, obtained from allenes 147 or methylacetylenes 148, with alkylthioisocyanate 150 and subsequent alkylation affords adduct 151, which isomerizes via [1,5]-hydrogen shift, quantitatively, under mild reaction conditions to generate 1,3-butadienyliminoformates 152. Electrocyclization of 152 gives 2,3-dihydropyridines 153 in good to excellent yields which under acidic conditions or by heating at high temperatures eliminate methanol to produce 3-substituted 2-methylthiopyridines 154. (a)

(a) N

N

N (b)

(b) or (c)

(a) N

N

X

N

X

(a) aza-electrocyclization; (b) oxidation; (c) elimination Scheme 16.38

•

R

1) S C N

H 147 nBuLi

or

R

THF-hexane

•

R

OMe

150 2) MeI

Li

R

•

MeS

N

149

H OMe

151

148 [1,5] H shift

R= OMe, OCH(Me)OEt, SMe, Me

R MeS

H+ or ∆ N 154

MeOH

R MeS

∆ N 153

OMe

R MeS

N

OMe

152

Scheme 16.39

In addition, b-arylvinyliminophosphoranes 156 react with a,b-unsaturated aldehydes 155 to give regiospecifically 3-arylpyridines 157 (Scheme 16.40) [133].

16.2 Synthesis of Pyridines

j1465

R1 R1

155

O

+ Ph3P

toluene

R2 N

sealed tube, 160 ºC

R1

R2 N

CO2Et

R2

CO2Et

N

CO2Et

157, 30-53%

156

R1= alkyl, aryl; R2= aryl

Scheme 16.40

Also, intramolecular approaches have been successful. A good example is the synthesis of pyridine 159 reported by Tanaka and Katsumura [134]. It consists of the treatment of the (E)-carbonyltrienal 158 with excess of lithium bis(trimethylsilyl) amide (LHMDS), which produces, via intermediate 160, an aza-electrocyclization reaction to afford the corresponding unstable 1,2-dihydropyridine derivative 161, which upon oxidation with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) leads to pyridine derivative 159 (Scheme 16.41).

CO2Et

TBSO

CHO

158

N

1) LHMDS, THF

TBSO

2) DDQ

CO2Et 159

LHMDS

Si TBSO 160

DDQ

Si

N CO2Et

N

TBSO 161

CO2Et

Scheme 16.41

16.2.4 Synthesis via Ring Transformation of Other Heterocycles 16.2.4.1 From Five-Membered Rings Furan derivatives 162 substituted with an acyl- or carboxylic acid functionality in the 2-position are transformed, in low to moderate yields, into 2-substituted 3-hydroxy pyridines 163 by treatment with ammonia at 150  C in a sealed tube (Scheme 16.42) [135].

j 16 Six-Membered Heterocycles: Pyridines

1466

R2

R1

O

O

NH3 (aq.), 150 ºC

R2

sealed tube

H2N

R1

O

OH

12-37%

162

R1= aryl; R2= H, Me

OH

OH R2

R2

R1

N

R1 NH2

O

163 Scheme 16.42

16.2.4.2 From Six-Membered Rings Pyrones and pyrylium salts are six-membered heterocycles that have been successfully used as templates in pyridine synthesis. For example, 2-aminopyridines 165 have been synthesized regioselectively through nucleophilic-induced ring transformation reaction of 2H-pyran-2-ones 164 with urea (Scheme 16.43) [136]. O

SMe CN Ar

O

H2N

O

SMe NH2 , py, ∆ Ar

82-91%

164

O Ar

NH2

165

O MeS

N

O

C N NH2

MeS

O Ar

MeS

NH NH

CO2

NH NH

Ar

Scheme 16.43

In addition, pyrylium salts 166 upon reaction with ammonia undergo ringopening/ring-closing reaction sequences to afford excellent yields of the corresponding pyridine derivatives 167 (Scheme 16.44) [137–140]. If primary amines are used pyridinium salts are obtained.

16.3 Reactivity

R2

R2 NH3 (aq.), RT

R1

R3

O

R1

R3

N

X 166

167

R2

R2

R1

R1

NH2 R3

O

R3 O H2N

X= I, ClO4, BF4 R1, R2, R3 = alkyl, aryl, OR, SR, NR2 Scheme 16.44

16.3 Reactivity 16.3.1 Reactions with Electrophilic Reagents

Pyridines react easily at the nitrogen atom with a wide range of electrophiles such as, protic acids, Lewis acids, reactive alkyl and acyl halides and transition metal ions to form tertiary salts 168, complexes 169, quaternary salts 170 and 171 and coordination compounds 172, respectively (Scheme 16.45).

HX N H X 168

Lewis acid (LA)

N L 169

N

N RCOX

RX

M 172

N A

N R 170

Scheme 16.45

Metal ion

X

O

R 171

X

j1467

j 16 Six-Membered Heterocycles: Pyridines

1468

16.3.1.1 Reactions with Acids Pyridines form stable salts with Brønsted acids such as HCl, HNO3, H2SO4, and so on. Pyridine itself, with a pKa of 5.2 in water, is a much weaker base than saturated aliphatic amines, which have pKa values mostly between 9 and 11. In general, electron-donating groups in the pyridine ring, especially in the 4-position, increase their basicity. For instance, 2-methyl- and 4-methylpyridine are more basic than pyridine (pKa 6.0). The opposite effect is produced when electron-withdrawing groups are present in the pyridine ring, especially in the 2-position. For instance 2-nitro- and 2-chloropyridine have a lower pKas of -2.6 and 0.7, respectively. In the case of substituents such as methoxy or aryl groups, which are resonance donors as well as inductive acceptors, variable effects on pyridine basicity are observed. The position of the substituent in the ring determines which of these effects are predominant. For instance, whereas 2-methoxypyridine (pKa 3.3) is less basic than pyridine, 4-methoxypyridine (pKa 6.6) is more basic. Although steric effects are usually unimportant, very hindered pyridines such as 2,6-di-tert-butylpyridine (pKa 3.6), are usually less basic than pyridine. Some pyridinium salts are commercially available reagents that are widely used. This is the case for pyridinium perbromide 173, which is employed as brominating agent, pyridinium dichromate (174, PDC) and pyridinium chlorochromate (175, PCC), used as mild and selective oxidizing agents, and pyridinium teflate (176), which is utilized as a source of teflic acid, a very weakly coordinating agent (Figure 16.13). Lewis acids such as AlCl3, SnCl4, BF3, SbCl5, SO3, and so on react with pyridines to afford stable pyridinium complexes, some of which are also used as reagents. For instance, sulfur trioxide pyridinium complex (PySO3) is employed as a mild sulfonating agent. 16.3.1.2 Reactions with Metal Ions Pyridines can act as monodentate ligands in transition metal complexes. This is the case with simple complexes such as Ni(Py)4 þ 2, Ag(Py)2 þ , and so on. When a-substituents, such as carbonyl groups, imines, metilenamines, heteroaryl groups, and so on, susceptible to coordination are present in the pyridine ring, chelate complexes are formed (Figure 16.14) [141–144]. Based on pyridyl units, many polydentate ligands have been developed in the field of the metallosupramolecular chemistry. A good example is the interaction of two molecules of oligopyridine with various metal ions (Fe þ 2, Co þ 2, Cu þ 2, etc.) to form

N H 173

Br3

N H 174

Cr2O7 2

2

N H 175

ClCrO3

N H 176

Figure 16.13 Examples of commercially available pyridinium salts used as reagents.

TeOF5

16.3 Reactivity

j1469

Pyrr Pyrr

N N

N Ar

N

N Cr

Cl

Cl

Ar

Fe2+

N

N

N

N

Ru2+

N

N

Cl

N N

N

Pyrr

Ar= aryl

Pyrr

N

Pyrr= pyrrol

Pyrr

Figure 16.14 Examples of pyridine chelates.

a double-helical complex in which the metal is bonded to a tridentate region from each ligand [145–147]. Pyridines can also act as p-ligands to afford g6-complexes with transition metals such as chromium. Such complexes are usually prepared by thermolysis with hexacarbonyl chromium (Scheme 16.46) [148]. However, pyridine derivatives that lack bulky alkyl groups at the 2- and 6-positions do not afford the corresponding p-complexes. Tricarbonyl(trispyridine)chromium complexes [Py3Cr (CO)3] (177) [149] are obtained instead, in which pyridines are coordinated through their nitrogen lone pairs.

Cr(CO)3

Cr(CO)6 R

N

TMS

dioxane, ∆

R

N

TMS

41-48% R= Me, Et, CH2CH2CH=CH2

Cr(CO)3

Cr(CO)6 N

N

N OC

N Cr N

CO CO

177 Scheme 16.46

16.3.1.3 Reactions with Halides and Related Compounds Alkyl halides, tosylates, triflates, and so on react readily with pyridines by an SN2 reaction to give alkylpyridinium salts (Scheme 16.47) [150]. Bulky substituents around the nitrogen ring atom, or tertiary halides or related compounds cause an

Pyrr

j 16 Six-Membered Heterocycles: Pyridines

1470

I

OMe

OMe

OMe

MeO Et2O, RT

CO2Me

N

MeI N

92%

Et2O, ∆

CO2Me

92%

I

N

CO2Me I

MeO Scheme 16.47

increase in the competing elimination reaction giving rise to the corresponding alkene and tertiary salts. In fact, 2,4,6-collidine is often used as base in elimination reactions. 16.3.1.4 Reactions with Acyl Halides and Related Compounds Acyl and sulfonyl halides and anhydrides react rapidly with pyridines by an addition–elimination reaction to form quaternary salts, which are rarely isolated, since they decompose rapidly on reaction with water, forming salts of the original pyridines. Some acyl pyridinium salts such as 180 can be obtained in good to excellent yields by treatment of pyridines 178 with acid chloride 179 (Scheme 16.48) [151].

179 R1

R2

OO

O

Cl

DCM, iPr3SiOTf

N

81-95%

178

TfO OO

O

N

R1 R2

180

R1= H, CO2Me R2= aryl, SR3, OMe Scheme 16.48

N-Acyl and N-sulfonylpyridinium salts are very useful acylating and sulfonating agents. Electron-donor substituted pyridines such as 4-N,N-dimethylaminopyridine (DMAP) are commonly used as catalysts in acylation reactions (Scheme 16.49) [152]. The dimethylamino function of DMAP increases both the nucleophilicity and the basicity of the ring nitrogen atom, making intermediate 181 relatively more stable than the corresponding pyridine analogue. These facts lead to a greater concentration of the acylating species 181 and, thus, speed up the reaction. This methodology dramatically enhance yields as well as reaction rates, leading to successful acylations even with the use of tertiary and sterically hindered alcohols.

16.3 Reactivity

NMe2

O R´O

O

R

R

O O

R

N

NMe2 R´OH

N O R 181

RCO2

Scheme 16.49

16.3.1.5 Electrophilic Substitution Reactions Pyridines undergo electrophilic substitution reactions (SEAr) exclusively at the 3-position but much more slowly than benzene, and usually under very drastic reaction conditions. For example, nitration of pyridine with nitric–sulfuric acids mixtures requires 300  C to afford 3-nitropyridine (183) in only 15% yield (Scheme 16.50). In contrast, sulfonation of pyridine affords 3-sulfonic acid 182 in 71% but only at 230  C and using HgSO4 as a catalyst [153]. The lack of pyridine reactivity in electrophilic substitution derives from protonation of the ring nitrogen. In fact, 2,6-dichloropyridine (184), which has two electron-withdrawing groups is significantly less basic than pyridine, and undergoes nitration as the free base to give 2,6-dichloro-3-nitropyridine (185) in 64% yield [154].

1) N2O5, MeNO2 2) SO2/HSO3-, H2O SO3H N

182

HgSO4, 230 ºC

300 ºC, 15%

N

71%

184 Scheme 16.50

Cl

N

1) HNO3, TFAA 83% NO2

HNO3 N

NO2

HNO3, H2SO4

H2SO4-SO3

2) Na2S2O5

Cl

77%

H2SO4, 100 ºC 64%

Cl

N 185

Cl

183

j1471

j 16 Six-Membered Heterocycles: Pyridines

1472

Bakke and coworkers [155, 156] have overcome the low reactivity of pyridines against common nitrating systems by using dinitrogen pentoxide in an organic solvent, followed by treatment with an aqueous solution of SO2/HSO3
(Scheme 16.51). Under these conditions, an N-nitropyridinium ion intermediate is formed that, when reacted with SO2/HSO3
in water, gives 3-nitropyridine (77% yield). It has been suggested that the reaction mechanism implies a [1, 5] sigmatropic shift of the nitro group. Recently, Katrizky and coworkers [157] have developed an improved method that consists of the in situ generation of dinitrogen pentoxide from nitric acid and trifluoroacetic anhydride (TFAA) (Scheme 16.50). NO2

1) N2O5, MeNO2 2) SO2/HSO3-, H2O

N

O

O N

O

O N

NO3

183

O

HSO3N NO2

N

SO3 N H NO2

[1,5] sigmatropic shift

N

NO2 H SO3 H

Scheme 16.51

16.3.2 Reactions with Oxidizing Agents

The pyridine ring is remarkably stable towards oxidation. Because of its resistance to oxidation, pyridine can be used as a solvent in oxidation reactions, such as in the Collins oxidation with CrO3. Only under vigorous conditions, such as neutral aqueous KMnO4 in a sealed tube at 100  C, can pyridine be oxidized to carbon monoxide, and at about the same rate as benzene. In alkaline media pyridines are oxidized more rapidly than benzenes. As with other tertiary amines, pyridines react smoothly with diverse oxidizing agents, such as peracids, H2O2/AcOH, dimethyldioxirane (DMD), bis(trimethylsilyl)peroxide, oxaziridines, and so on, to give N-oxides (Scheme 16.52) [158–160]. Alkylpyridines can be oxidized at benzylic positions by various oxidizing agents such as KMnO4, O2, SeO2, HNO3, and so on to afford pyridine carboxylic acids (Scheme 16.53). For instance, KMnO4 has been employed in the synthesis of niacin (187) from b-picoline (186) [161]. Selective oxidation of the methyl group of disubstituted pyridine 188 has been achieved using SeO2 as the oxidizing agent of choice to give carboxylic acid 189 [162].

16.3 Reactivity

MeO

MCPBA CHCl3, ∆

Br

N

MeO N O

84% O2 N H2N

N

NO2

H2O2, AcOH

O2N

NH2

80%

H2N

N

NO2 N O

O O

X

Br

NH2

X

acetone, RT 98%

N O

X= 4-CN, 4-CF3, 4-Ph, 4-Me, 4-OMe, H, 3-Br Scheme 16.52

CO2H

KMnO4, H2O N 186

70-90 ºC

N

77%

187 CO2H

SeO2, py N

72%

188

N 189

Scheme 16.53

16.3.3 Reactions with Nucleophilic Reagents

The electron-deficient nature of the pyridine ring allows nucleophilic reagents to attack pyridines, preferably at their 2- or 4-ring carbon atoms and less readily in the 3-position. However, only strong nucleophiles such as amide ions, hydroxides or organolithium compounds react. The reaction proceeds by an addition–elimination mechanism, that is, by SNAr, which involves in the first stage the formation of adduct 190 with concomitant de-aromatization of the pyridine ring and, once formed, loss of hydride occurs to afford pyridine derivative 191 (Scheme 16.54, Z¼H). Electronwithdrawing substituents on the pyridine ring, such as nitro or cyano groups, favor the reaction.

j1473

j 16 Six-Membered Heterocycles: Pyridines

1474

Nu

+ Z

N

Z N

Nu

N

Z

190

Nu

191

Z= H, leaving group Scheme 16.54

SNAr reactions with pyridines substituted with halogens or other leaving groups such as alkoxy groups, and so on are most common and proceed much faster than the corresponding unsubstituted rings (Scheme 16.54, Z ¼ leaving group). Usually, the reaction takes place with a wide range of nucleophiles at 2- or 4-positions, but not at 3-positions. Scheme 16.55 shows examples of reactions of this type [163–165]. Li , Et2O

X N

-40 ºC to 0 ºC

F

N

78-82%

X

X= H, Cl, F Cl

SMe Br

Br

NaSMe 85%

N

N NH2

NH2 O O Br

O S O

S amine, dioxane, RT N

Br

70-90%

Br

N

Y

Y= NHMe, piperazinyl, pyrrolidinyl Scheme 16.55

16.3.3.1 Reactions with Amide Ions Pyridine reacts with sodium amide in toluene at 100  C to give, mainly, 2-aminopyridine (192) (75%) and a small amount of 4-aminopyridine (Scheme 16.56). At 180  C, 2,6-diaminopyridine is produced in good yield along with a small amount of 2,4,6triaminopyridine. This transformation, known as the Chichibabin reaction, is usually carried out at relatively high temperatures in an inert atmosphere or without solvent. It has been suggested that the reaction proceeds via initial formation of an adsorption complex 193 with a weak nitrogen–sodium coordination that increases the electrophilicity of the a-carbon ring atom. Subsequently, amide nucleophilic

16.3 Reactivity

1) NaNH2, 100 ºC N

2) H2O

H

N

NaNH2

N

H

NH2 192

75%

H2O

NH Na

N

193

196

Na NH2

NaH H N NH2 Na 194

NaH

N

NH2

195

Scheme 16.56

attack occurs with formation of intermediate 194, which undergoes a sodium hydride elimination followed by deprotonation to give amide salt 196. The 2-aminopyridine 192 is finally obtained after a work-up with water. More vigorous conditions are required for the amination of alkylpyridines because proton abstraction from the side-chain by the amide ion occurs preferentially, and therefore ring attack must involve a dianionic intermediate. Nonetheless, 4-alkyl pyridines 197 have been successfully aminated at 150  C to afford reasonable yields of 2-aminopyridines 198 (Scheme 16.57) [166, 167]. R

R NaNH2, N,N-dimethylaniline, 150 ºC

N 197

56-61% R= alkyl

N

NH2

198

Scheme 16.57

16.3.3.2 Reactions with Hydroxide Ions Pyridines react with hydroxide ions under extreme conditions (KOH-air, 300  C) to give 2-pyridones, the stable tautomers of 2-hydroxypyridines, which are formed by oxidation of the initial adduct. As expected, the reaction is favored by electronwithdrawing substituents on the pyridine ring. The reaction proceeds much faster and under milder conditions with pyridines substituted with halogens or other good leaving groups. For example, even fluoro pyridines can be transformed into pyridones with lithium hydroxide at room temperature (Scheme 16.58) [168].

j1475

j 16 Six-Membered Heterocycles: Pyridines

1476

EtO2C

HO2C LiOH, THF/H2O, RT

N

60%

F

N H

O

Scheme 16.58

16.3.3.3 Reactions with Carbon Nucleophiles Pyridines undergo nucleophilic aromatic substitutions (SNAr) with carbon nucleophiles such as alkyllithium or aryllithium derivatives, affording 2-alkyl- and 2-arylpyridines, respectively (Scheme 16.59). Grignard reagents give the same reaction products but in lower yields. The reaction requires rather vigorous conditions (e.g., xylene, 100  C) and proceeds via the dihydropyridine N-lithio salts 199, which are less basic than those formed by reaction of pyridines with sodium or potassium amide and eliminate hydride anions with relative difficulty. The N-lithio salts 199 can be detected by NMR spectroscopy and in some cases have been isolated as solids [169–171]. These salts are stable at room temperature for several hours but, on heating, eliminate lithium hydride to give the 2-substituted pyridines 200.

1) RLi, 100 ºC N

2) H2O R= alkyl, aryl

N Li

H R 199

LiH

N

R

200

Scheme 16.59

The SNAr reaction of 3-substituted pyridines 201 with an organolithium compound may lead to the 2,3-isomer 202, or a mixture of the latter and the 2,5-isomer 203 (Table 16.8). The rate and orientation of such nucleophilic substitution depends on steric and coordination effects. An increase in steric hindrance produces less of the 2,3-isomer 202 (Table 16.8, entry 2 vs. 4), while coordination of the lithium atom with a free electron pair on the substituent favors nucleophilic attack at the 2-position (Table 16.8, entries 6 and 7). 16.3.4 Reactions with Bases

The regiospecific exchange of one aryl hydrogen atom by a metal such as lithium, by treatment with a strong base, usually requires the presence of substituents with lone pairs on heteroatoms (directing metallation groups, DMG), which enable the formation of coordination complexes with the metal, resulting in metallation at sites adjacent to the substituent. This transformation, known as the directed orthometallation reaction, in comparison with the same reaction in p-excessive heterocycles, has an extra complication in p-deficient heterocycles such as pyridines,

16.3 Reactivity Table 16.8 Reaction of 3-susbstituted pyridines 201 with phenyllithium.

X

X

PhLi

N

N

201

202

Entry

X

1 2 3 4

H Me Et tBu

5

N

6 7

NH2 OMe

X +

Ph

Ph

N 203

Yield (%)

202

203

Reference

69 42 39 25

100 95 84 4

5 16 96

[172] [172] [172] [172]

34

50

50

[173]

25 21

100 100

0 0

[174] [174]

because the soft alkyllithium reagents (nBuLi, PhLi) commonly used can undergo a facile nucleophilic addition to the azomethine (C¼N) bond (see Section 16.3.3.3) [175]. However, it is possible to achieve clean metallation reactions with alkyllithium reagents for many DMGs (NHCOR, OR, OCONR2, CONHR, Cl, F) (Scheme 16.60). For pyridines with DMG groups such as CONR2, SOR, I, Br, and so on, which are more reactive towards nucleophilic reactions or halogen–metal exchange, the harder and the less basic lithium diisopropylamine (LDA) or lithium 2,2,6,6-tetramethylpiperidine (LTMP) is normally used. DMG

DMG H

N

Li

RLi or lithium amide N

R= nBu, Ph, sBu Lithium amide= LDA or LTMP DMG= NHCOR, OR, OCONR2, CONHR, CONR2, halogen, SOR Scheme 16.60

The regioselectivity of the reaction is the result of mainly four effects: (i) the strength of the coordination between the DMG-heteroatom and the lithium; (ii) the inductive effect of the DMG; (iii) the electronic repulsion between the carbanion and

j1477

j 16 Six-Membered Heterocycles: Pyridines

1478

stabilizer effects of DMG Li

Li

DMG

DMG

coordination

induction

Kinetic control

Thermodynamic control

DMG

DMG N

Li

N

electronic repulsion

H

Li

R

2-position is favored

3- and 4-positions are favored

Figure 16.15 Factors affecting the regioselectivity of the reaction.

the lone pair of the nitrogen; and (iv) the complexation of the lithium base with the nitrogen (Figure 16.15). The reaction is usually under thermodynamic control when metal amides such as LDA or LTMP are used, leading to 3- and 4-carbanions. Conversely, alkyllithium reagents proceed under kinetic control. In this case, solvent effects become more important because of the absence of a strong DMG on the ring and because complexation with the nitrogen can occur, in the absence of a chelating solvent such as THF. Therefore, deprotonation takes place at the C2 proton. 3-Fluoropyridine (205) is a good example of a metallation substrate in which regioselectivity can be induced by choosing the appropriate base (Scheme 16.61) [176]. LDA abstracts the proton from the 4-position in 205 (thermodynamic) giving lithium derivative 204, while nBuLi in the presence of 1,4-diazabicyclo[2.2.2]octane (DABCO) affords lithium derivative 206 resulting from proton abstraction at the 2-position in 205 (kinetic).

Li F N 204 Scheme 16.61

F

LDA, THF -75 ºC, 2h

N 205

F

nBuLi, DABCO Et2O, -60 ºC, 1h

N 206

Li

16.3 Reactivity

16.3.5 Reactions of C-Metallated Pyridines

Among all possible ways of introducing a pyridine moiety into a more complex structure, the use of C-metallated pyridines is probably one of the most direct. This fact makes C-metallated pyridines one of the most important and widely used pyridyl intermediates, particularly in carbon–carbon bond forming reactions [177]. Basically, they are used in the following type of reactions (Scheme 16.62): . .

(a) nucleophilic attack of lithium or Grignard derivatives to electrophiles; (b) metal-catalyzed cross-coupling reactions of: –(i) halopyridines or related compounds with organometallic derivatives; –(ii) metal-containing pyridines with halides or related compounds.

M (a)

E

E+

N

N

M= Li, MgBr, MgCl

Z (b.1)

N

M N

R

RM

N

Z= Br, I, OTf

(b.2)

PdII

Pd(0) (cat)

N

M= SnR3, B(OH)2, etc. R= aryl, alkenyl, alkynyl R

Pd(0) (cat) RZ

N

M= SnR3, B(OH)2, etc. R= aryl, alkenyl, alkynyl Z= Br, I, OTf Scheme 16.62

16.3.5.1 Reactions of Pyridyl Lithium/Grignard Derivatives with Electrophiles Pyridines can be readily functionalized upon treatment of either their corresponding organolithium or Grignard derivatives with a large variety of electrophiles. However, the difficulties of preparing pyridine Grignard derivatives have limited their use in synthetic organic chemistry, resulting in their progressive displacement by the more accessible lithium derivatives [177].

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j 16 Six-Membered Heterocycles: Pyridines

1480

Pyridyl-lithium derivatives are usually prepared either by ortho-metallation using strong bases (Section 16.3.4) or by halogen–metal exchange between halopyridines, mainly bromopyridines, and an organolithium reagent such as nBuLi or tBuLi or lithium metal. The lithiated species generated by all these methods can react with a wide range of electrophiles such as N,N-dimethylformamide (DMF), carbon dioxide, iodine, acid chlorides, ketones, trimethylsilyl chloride, and so on, leading to pyridine functionalization with a large variety of functional groups in a single step (Scheme 16.63). SiMe3 N CHO

ClSiMe3

N

HO R R´

O R

DMF

R´

N

Li N CO2

ClCOR

CO2H I2

N

COR N

I N Scheme 16.63

The great synthetic utility of this type of reaction has been demonstrated by Zhai and coworkers [178] in the synthesis of pyridine derivative 209 in three steps starting from simple 3-bromopyridine (207) (Scheme 16.64). Ortho-lithiation of 207 with LDA at
90  C followed by treatment with acrolein at the same temperature gave alcohol 208 in 75% yield. After protection of alcohol 208 as the methoxymethyl ether (MOM), reaction with nBuLi produced a bromine–lithium exchange, which was followed by treatment with DMF to afford an excellent yield of aldehyde 209. The direct preparation of Grignard derivatives using standard procedures, consisting of the reaction between an haloheterocycle and magnesium, is sometimes rather difficult, mainly due to the basicity of the nitrogen ring atom. In these cases, the usual procedure is the treatment of an halopyridine with commercially available aryl or alkyl Grignard reagents such as PhMgBr, iPrMgCl, EtMgBr, and so on. For instance, Madsen and coworkers [179] have employed the Grignard reagent of

16.3 Reactivity

OH

Li Br

Br

LDA THF, -90 ºC

N

j1481

Br

CHO THF, -90 ºC

N

207

N 208, 75%

NaH, MOMCl, THF, RT 92%

OMOM

OMOM

CHO

Li

DMF

N

OMOM

THF, -78 ºC

Br

nBuLi THF, -78 ºC

N

N

209, 92% Scheme 16.64

3-bromopyridine (211), obtained by treatment of 210 with commercially available phenylmagnesium bromide, in the 1,4-addition–elimination reaction with a,b-unsaturated carbonyl derivative 212 to furnish pyridine 213 in 86% yield (Scheme 16.65). O N CO2tBu

Me2N Br N 210

MgBr

PhMgBr THF, RT 98%

N 211

212

CO2tBu

THF, -78 ºC 86%

O N CO2tBu N 213

Scheme 16.65

16.3.5.2 Metal-Catalyzed Cross-Coupling Reactions In the last several years, the use of transition metals, particularly palladium, as catalysts for coupling reactions involving metallated species has increased sharply the use of heterocyclic organometallics in all kinds of organic transformations. Metalcatalyzed cross-coupling reactions have remarkably enlarged the toolbox of organic chemistry since their first examples appeared in the late 1960s. A broad variety of substrates, good tolerance of different functional groups, mild reaction conditions,

CO2tBu

j 16 Six-Membered Heterocycles: Pyridines

1482

Table 16.9 Types of metal-catalyzed cross-coupling reactions.

X N

Z

X= halogen

N

Coupling

Reagents

Z

Stille Suzuki Sonogashira Heck Kumada Negishi Hiyama Buchwald

RSn(nBu)3 RB(OH)2/base R
C:CH/Cu(I) R
CH¼CH2/base RMgX RZnX RSiR0 3/F
R2NH/base

R (alkenyl, alkynyl, aryl) R (alkenyl, alkynyl, aryl) R
C:C R
CH¼CH R (alkyl, alkenyl, alkynyl, aryl) R (alkyl, alkenyl, alkynyl, aryl) R (alkenyl, alkynyl, aryl) R2N

high yields and efficient catalysis make these modern transformations the most widely used reactions for the formation of C
C, C
O, C
N and even C
S bonds. Nucleophilic attack occurs preferentially at the a and c positions of pyridines. This performance has been attributed to the electronegativity of the ring nitrogen atom, which induces a partial positive charge at these positions of pyridines. A similar trend occurs in the context of metal catalyzed cross-coupling reactions. In fact, a and c-halopyridines are more susceptible to the oxidative addition to Pd(0), relative to simple carbocyclic aryl halides [180]. Even a- and c-chloropyridines are viable electrophilic substrates for Pd-catalyzed reactions under standard conditions [175]. Although nickel, copper and, occasionally, platinum have been used as catalysts for cross-coupling reactions, palladium is the most widely employed catalyst. Table 16.9 summarizes the most important cross-coupling reactions, indicating the reagents usually employed and the type of group (Z) introduced in the pyridine ring in each case. Palladium-catalyzed cross-coupling reactions of organohalides or related compounds with organometallic reagents follow a general mechanistic cycle that involves oxidative addition, transmetallation, isomerization and reductive elimination sequences (Scheme 16.66) [181]. A Pd(0)L2 complex (L¼ligand, typically a phosphine such as PPh3) is assumed to be the active catalytic species in the cycle. Sometimes, these Pd(0) species are generated in situ by reduction from Pd(II) complexes, such as Pd(OAc)2, in the presence of a suitable ligand such as PPh3. The first step of the cycle consists in the oxidative addition of R1–X (X¼halogen, OTf, etc.) to form complex 214, which then undergoes a transmetallation reaction with the organometallic reagent R2–M to give complex 215. Both intermediates 214 and 215 have been isolated and/or characterized by different spectroscopic methods. The intermediate 215 undergoes an isomerization reaction followed by a reductive elimination giving rise to a Pd(0) species along with

16.3 Reactivity

R1

R2

R1

[ Pd(0)L2 ]

Oxidative addition

Reductive elimination

R2

L

II

1

X

II

R Pd L

R1 Pd X

L

L

Isomerization

214

Transmetallation R2 L

L= ligand M= metal

1

M

II

R Pd R2 L

215

MX

Scheme 16.66

the homocoupling product R1–R2. When Pd(0) is regenerated the catalytic cycle starts again. The oxidative addition is often the rate-limiting step and the relative reactivity of R1–X decreases in the order: I > OTf > Br  Cl. 16.3.5.2.1 Stille Coupling This type of cross-coupling reaction consists of the Pdcatalyzed reaction between an organostannane and a halide. Typically, the stannane is sp2 or sp hybridized (aryl, alkenyl, alkynyl) but alkyl-, allyl- and benzylstannanes have also been used. The halides are usually, aryl, vinyl or acyl, bromides, or iodides (and also triflates). In addition, aryl chlorides have also been employed, but they are typically much less reactive. For a Stille coupling involving a pyridine moiety, the pyridine fragment may be either the nucleophilic or the electrophilic coupling partner (Scheme 16.67). Therefore, two approaches can be employed: the reaction of (i) a pyridyl-stannane (nucleophile) and an halide; or (ii) a halopyridine (electrophile) and an organostannane. In the first case, the pyridyl-stannane is usually prepared either by orthometallation or by lithium–halogen exchange followed, in both cases, by treatment with a halide stannane such as ClSn(nBu)3. Procedure (i) is exemplified by derivatives 216 [182] and 218 [183, 184], respectively (Scheme 16.68). A notable example of procedure (ii) appears in the recent literature with the synthesis of the biheteroaryl derivative 221 by Stille cross-coupling using electrophilic pyridine derivative 219 and the stannane 220 [185].

j1483

j 16 Six-Membered Heterocycles: Pyridines

1484

SnR3 R´X

+

(i) Py-nucleophile

R´

Pd(0) (cat) N

N

X +

(ii) Py-electrophile

R´SnR3

R´

Pd(0) (cat) N

N Scheme 16.67

Cl N

1) LDA, THF, -78 ºC

Sn(nBu)3 Cl

2) ClSn(nBu)3, -78 ºC

N

83%

Br N

X

218 X= Sn(nBu)3

OMe Br

219

N

63%

, Pd(PPh3)4, toluene, ∆

N N

N

1) nBuLi, THF, -78 ºC 2) ClSn(nBu)3, -78 ºC 96%

Me3Sn

OMe

N

PdCl2(PPh3)2 CuI, DMF, ∆

216

Br

Cl

I

75%

217 X= Br

MeO2C

N

HO

HO

OSiEt3

N S

OMe 4

PdCl2(PPh3)2, dioxane, ∆ 76%

OMe

220 MeO2C

N

N

221

S

OSiEt3 4

Scheme 16.68

16.3.5.2.2 Suzuki Coupling In this reaction, a halide is coupled with an aryl or vinyl boronic acid or boronic ester. The major advantages of the Suzuki reaction are: (i) the stability and rather low toxicity of the boron reagents; (ii) easy access to a broad variety of boronic acids, many of which are commercially available; (iii) tolerance for different functional groups; (iv) straightforward experimental procedures.

16.3 Reactivity

Similar to the Stille coupling, two approaches are possible, depending on whether the boron derivative is contained in the pyridine ring or in the reagent (Scheme 16.69). The pyridine boron derivatives are usually prepared by treatment of an organolithium or magnesium pyridine with a trialkylborate (Scheme 16.70). Recently, metal-catalyzed methods have been developed using bis(pinacolato) diboron or pinacolborane as the boron source. B(OR)2

R´

R´X Pd(0) (cat), base

N

Pd(0) (cat), base

N

R= H or alkyl

Py-Nucleophile

X

R´B(OR)2 N

Py-Electrophile

Scheme 16.69

M

B(OH)2

1) B(OR)3 2) H+

N

N

M= MgX or Li; R= alkyl

O X N

O

B B

O O

or

Pd(0) (cat), base

H B

O

O B O

O N

X= Halogen, OTf Scheme 16.70

Scheme 16.71 shows examples of Suzuki coupling. The 2-fluoropyridyl group of epibatidine analogue 224 has been introduced by Pd(0)-mediated cross coupling between fluoropyridyl boronic acid 222 and vinyl triflate 223 [186]. In inverse fashion, iodopyridine 225 has been transformed into 2-phenylpyridine 227 using phenylboronic cid 226 [187]. 16.3.5.2.3 Sonogashira Coupling The Sonogashira reaction is the most direct approach for the synthesis of alkenyl- and arylacetylenes. It consists of the palladium-copper catalyzed coupling of terminal acetylides to arylhalides (Br, I) or triflates to yield alkynylarenes (Scheme 16.72). Chloropyridines can be also used, but these compounds require much higher temperatures. Control of the reaction regioselectivity arises from the difference in electrophilicity at the a, b and c positions of the pyridine ring. For instance, mono-acetylenation of 2,5-dibromopyridine (228) with triisopropylsilylacetylene has been achieved under

j1485

j 16 Six-Membered Heterocycles: Pyridines

1486

O

O O B(OH)2 N

O

N Pd(PPh3)4, Na2CO3 (aq)

+

F

PhMe/EtOH, ∆

TfO

N

83%

223

222

F

224

R

R F N

N

+

I

(HO)2B

Pd(PPh3)4, K2CO3 (aq)

BocHN

PhMe, ∆

225

N

82-91%

226

F

BocHN 227

R= H, Me Scheme 16.71

R X

H +

N

R

Pd(0) (cat) Cu(I) salts (cat), base

N

X= Br, I, OTf Scheme 16.72

mild conditions (0  C to room temperature, 2 h) at the more electrophilic a position of the pyridine ring to regioselectively afford pyridine 229 (Scheme 16.73) [188]. Further elaboration required much harder reaction conditions (reflux for 24 h) to achieve the second coupling at the less reactive b position of the pyridine ring, which gave pyridine 230 in 78% overall yield. The use of silylated acetylene avoids the coupling at both positions of the tripe bond and, also, enables a second coupling reaction if the silyl protecting group is removed, leading to unsymmetrical ethynes. For instance, bromopyridine 231 is first coupled with trimethylsilylacetylene to give a good yield of pyridine 232 (Scheme 16.73) [189]. Under similar reaction conditions, but in the presence of tetrabutylammonium fluoride (TBAF) for the in situ removal of the silyl protecting group, pyridine 232 undergoes a second Sonogashira coupling with 3-iodophenol to afford bisarylethyne 233 in 67% yield. 16.3.5.2.4 Heck Reaction This type of cross-coupling reaction was discovered at the end of the 1960s and consists of the coupling of an alkene with an aryl(or alkenyl) halide (Br, I) or triflate to afford vinylarenes (or dienes) (Scheme 16.74). Terminal

16.3 Reactivity

Br N

Br

228

231

PdCl2(PPh3)2, CuI, Et3N, 0 ºC to RT, 2h

Si(iPr)3

Br

N

PdCl2(PPh3)2, CuI, Et3N, RT, 16h 71%

SiMe3

Br N

N Si(iPr)3

229

PdCl2(PPh3)2, CuI, Et3N, ∆, 24h

HO

SiMe3

232

TBAF, PdCl2(PPh3)2, CuI, Et3N, DMF 70 ºC, 16h

OH

I

67% HO

N

N

230, 78%

Si(iPr)3

OH

233

Scheme 16.73

X + N

R

R

Pd(0) (cat) base

N

X= Br, I, OTf Scheme 16.74

alkenes are usually good substrates for the Heck reaction and react at the nonsubstituted carbon. 1,2-Disubstituted alkenes usually give product mixtures, with a preference for the less sterically hindered carbon. The mechanism of the Heck cross-coupling reaction (Scheme 16.75) differs slightly from the general scheme presented earlier (Scheme 16.66). Although the first steps in both processes are identical, in the Heck reaction there is an absence of the transmetalation step. Alternatively, the C
C bond is formed by an insertion

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j 16 Six-Membered Heterocycles: Pyridines

1488

X 2

R1

[ Pd(0)L2 ]

X

II

L Pd L

R

R1

base

H

Oxidative addition

syn β−hydride elimination X L Pd L H R1

L

II

R1 Pd X

R2

L

H

Rotation

alkene insertion

R1 H

R2

X L Pd L R2 H

Scheme 16.75

process, which is followed by a b-hydride elimination to form the substituted alkene product. Examples of Heck reactions are shown in Scheme 16.76. Bromopyridine 234 can be coupled with inexpensive acrylates to give a,b-unsaturated esters 235 in good to excellent yields [190]. The tert-butyl acrylate of pyridine 237 is introduced in 236 CO2R Br CO2R EtO2C

N

CO2Et

Pd(OAc)2, PPh3, DMF, ∆

EtO2C

72-92%

234

N

CO2Et

235 R= iBu, iPr, tBu

CHO nBu

N 236

Scheme 16.76

Br

CHO

CO2tBu [PdCl(allyl)]2, (o-Tol)3P, NaOAc, PhMe, ∆ 83%

nBu

N 237

CO2tBu

16.3 Reactivity

(in 83% yield) by Heck coupling with tert-butyl acrylate, using allyl palladium chloride dimer and tri-o-tolylphosphine [191]. 16.3.6 Reactions with Reducing Agents

Pyridines can be reduced by catalytic hydrogenation, by metal hydrides or by metals in protic media to piperidines, 1,2- or 1,4-dihydropiperidines, depending on the reducing agents employed and the reaction conditions. Pyridines are much more easily reduced than benzenes. While the catalytic hydrogenation of benzene requires high pressure and high temperatures, pyridine can be reduced at normal pressure and room temperature to afford piperidine in excellent yield [192]. This fact can be exploited for the selective reduction of pyridines in the presence of phenyl groups. For instance, benzylpyridines 238 have been converted into benzylpiperidines 239 by catalytic hydrogenation (Scheme 16.77) [193]. However, the reaction proceeds smoothly only when piperidines are obtained as ammonium salts, because free bases tend to poison the catalyst. Therefore, hydrogenation of pyridine 240 using PtO2 as catalyst and in acetic acid gave at room temperature piperidine 241 in 80% yield [194]. X

X H2, Pd/C, 10 bar AcOH, 60-65 ºC

N

53-95%

238

N H 239

X= F, CF3, OMe, Me PO(OEt)2

PO(OEt)2 H2, PtO2

N

CO2iBu

240

AcOH, 20 ºC 80%

N H

CO2iBu

241

Scheme 16.77

Pyridines can also be reduced with various metal hydrides, but the results depend on the type of hydride. Whereas diisobutylaluminium hydride (DIBALH) or Et2AlH reduce pyridine slowly, LiEt3BH (super hydride) efficiently leads to piperidine [195]. In contrast, the reaction of LiAlH4 and pyridine results in the addition of one hydride equivalent to pyridine, yielding the complex 242, which contains two 1,2- and two 1,4dihydropyridine units (Figure 16.16) [196–198]. Complex 242, also known as Lansbury’s reagent, has been used as a selective reducing agent of ketones, especially in the presence of carboxylic acids and esters.

j1489

j 16 Six-Membered Heterocycles: Pyridines

1490

H H

H H N N H

N

Al H

H

Li(Py)4

N H

242 Figure 16.16 Lansbury’s reagent.

Although NaBH4 does not reduce pyridine itself, electron-withdrawing substituted pyridines areeffectively reducedto di-or tetrahydropyridines in thepresenceof NaBH4. For instance, pyridines 243 undergo reduction with NaBH4 to give mixtures of the corresponding 1,4- (244) and1,2-dihydropyridines (245) (Scheme 16.78) [199].Also,the pyridine ring of compound 246 has been fully reduced by treatment with NaBH3CN, leading to a cis-trans diastereomeric mixture of piperidines 247 and 248 [200]. RO2C

CO2R

NaBH4, AcOH

RO2C

CO2R

57-76%

N

N H

R= Me, Et

243

CO2Et

CO2Et

AcOH, RT

N O

O

N H

246 Ph

Ph

N H

244

NaBH3CN

CO2R

RO2C +

245

CO2Et

+ O

N H

247, 23% Ph

Ph

248, 46% Ph

Ph

Scheme 16.78

Metals in protic media, typically sodium in ethanol, reduce pyridines to piperidines. This type of reduction is considered to be similar to the Birch reduction of arenes. For instance, reduction of 2,6-diphenylpyridine (249) afforded a cis-trans mixture of diastereomers 250 and 251 (Scheme 16.79) [201]. Under aprotic conditions, reduction fails and bipyridines are produced instead (Section 16.3.7). 16.3.7 Reactions with Carbenes, Nitrenes and Radical Reagents 16.3.7.1 Reactions at the Ring Nitrogen Atom: Carbenes and Nitrenes Electrophilic carbenes can react with compounds containing free electron pairs, such as carbonyls, nitriles, ethers, alcohols, and so on to form ylides. In addition, carbenes

16.3 Reactivity

Na, EtOH, ∆ Ph

+

Ph

N

Ph

249

N H

Ph

Ph

250, 39%

N H

Ph

251, 54%

Scheme 16.79

react with pyridines at the ring nitrogen atom to form pyridinium ylides, which have been extensively used as trapped carbenes in studies of carbene reactions by laser flash photolysis. In some cases, pyridinium ylides have been isolated and characterized. For instance, pyridinium cyclopentadienides 254 have been obtained in yields between 17 and 81% by irradiation of diazo derivatives 252 in the presence of pyridines 253 (Scheme 16.80) [202]. R2

2

R N2 R1

Ph

Ph

hυ

253 R2

R2

N

17-81%

Ph

R2 R1

Ph

Ph

252

R2

N

254

Ph

R1= H, Ph R2 = H, Me

1

R

hυ

Ph

R2

R2 Ph

N 253

R2

Ph

Scheme 16.80

Nitrenes give similar results with pyridines to afford pyridinium iminoylides. For instance, treatment of the nitrene precursor PhI ¼ NTs with various pyridines 255 in the presence of a catalytic amount of Cu(II) affords the corresponding p-tolylsulfonyliminopyridinium ylides 256 in good yields (Scheme 16.81) [203]. Z

PhI=NTs, Cu(OTf)2 (cat) CH3CN, 20 ºC

N

55-85%

255

Z= H, Me, CN Scheme 16.81

Z N NTs

256

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j 16 Six-Membered Heterocycles: Pyridines

1492

16.3.7.2 Reactions at the Ring Carbon Atom: Carbon and Halogen Radicals 16.3.7.2.1 Carbon Radicals Free radical substitutions in aromatic systems have long been known, but are used rarely in organic synthesis. Of greater preparative value are the reactions of nucleophilic radicals, such as HOCH2 and R2NCO, which can be easily generated under mild conditions. Minisci and coworkers [204] were the first to report that carbon radicals can be used to regioselectively synthesize 2- and 4-alkyl and acylpyridines. These substitutions are carried out on the protonated pyridine, which provides both increased reactivity and selectivity for the 2-position, a transformation that is known as the Minisci reaction (Scheme 16.82) [204]. The radical species are generated either by oxidative silver-catalyzed decarboxylation (alkyl radicals) or by Fenton-type reaction with organic hydroperoxides and Fe(II) or Ti(III) reagents (acyl radicals) [205–207]. R

[O]

N H

N H

alkyl radicals

R H

RCO2H

N

AgNO3, (NH4)2S2O8

R

R

CO2

R= alkyl Radical generation

acyl radicals

RCHO

tBuOOH, FeSO4, H2SO4

RCO

R= alkyl, aryl, NR2 Reactivity:

pyridinium cation > neutral pyridine

Selectivity:

2- > 4- >> 3-position

Scheme 16.82

Scheme 16.83 shows examples of reactions of this type. Diverse alkyl radicals generated by oxidative silver-catalyzed decarboxylation of various carboxylic acids have been reacted with 4-cyanopyridine (257) to give pyridines 258 with control of regioselectivity [208]. On the other hand, 3-acylpyridines 259 have been regioselectively carbamoylated via the Miscini reaction with RHNCO radicals generated by treatment of various formamides with t-butyl hydroperoxide and Fe(II) to yield pyridines 260 [209]. Alkylmercury halides are also convenient sources of alkyl radicals that react with pyridines, attacking mainly at the a-position to give the corresponding 2-alkyl

16.3 Reactivity

CN

CN RCO2H, AgNO3 (NH4)2S2O8, H2SO4 (aq), ∆

N

24-38%

257

N

R

258

R = Me, Et, Pr, iPr, nBu

COR

FeSO4, H2SO4 (aq)

N

COR

HCONH2, tBuOOH H2NOC

31-91%

259

N 260

R = Pr, aryl, tBu, CH2CH2CN, iBu Scheme 16.83

derivatives 261 (Scheme 16.84) [210]. Reaction yields decrease from tertiary, secondary to primary alkyl groups, in accordance with decreasing radical stability.

RHgX, hυ 40 ºC, 20 h

N

R= nHex (50%) R= iPr (89%) R= tBu (98%)

N

R

261

Scheme 16.84

In contrast with alkyl and acyl radicals, aryl radicals generated from (PhCO)2O, PhI (OCOPh)2, and so on give mixtures of 2-, 3- and 4-arylpyridines with low reaction yields. Certain metals, such as Na, Zn or Ni, under aprotic conditions react with pyridines to form radical anions 262 resulting from an electron-transfer from the metal to the pyridine ring (Scheme 16.85). These radical anions dimerize to give bipyridines in a reaction considered equivalent to the pinacol reduction. At room temperature, pyridine reacts with sodium in tetrahydrofuran (THF) to afford 4,40 -bipyridine (264), mainly by coupling through the c-positions of two pyridine radicals. At higher temperatures, 2,30 -, 3,30 - and 3,40 -bipyridines are also formed. If the reaction is carried out with Zn in the presence of acetic anhydride, the dihydropyridinium intermediate 263 is trapped and 4,40 -bidihydropyridine 265 is obtained [211]. However, pyridines under dimerization conditions using Ni afford 2,20 - (266) instead of 4,40 -bipyridine (264). This has been attributed to the favored chelation of the radical anion to the metal surface.

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j 16 Six-Membered Heterocycles: Pyridines

1494

Na

N Na, THF N

N

N

H

20 ºC

2 NaH

N

N

Na

262

Zn, Ac2O

H

Ac N

N

H

N 264

263

N Ac

H 265

Raney Ni N

N

O2

H N

N

Ni

N

N

H

N

Ni

266

Scheme 16.85

16.3.7.2.2 Halogen Radicals Pyridines can be halogenated via radical substitution at high temperatures where chlorine (270  C) or bromine (500  C) are appreciably dissociated into their corresponding radicals, affording mixtures of 2-halo 267 and 2,6-dihalopyridines 268 (Scheme 16.86). 2-Fluoropyridines can also be synthesized by reaction with fluorine diluted in an inert gas using polyhalogenated solvents. However, these methods are rarely used in preparative synthesis due to the extreme reaction conditions required, which may be incompatible with other functional groups present in the pyridine nucleus.

reagent, ∆

+ N

N reagent: Cl2, 270 ºC Br2, 500 ºC CuBr-Br2, 350 ºC Scheme 16.86

267

X

X

N 268

X

16.4 Pyridine Derivatives

16.3.8 Photochemical Reactions

Pyridines under photochemical irradiation undergo an intramolecular electrocyclic 4p-ring closure to afford highly strained 2-azabicyclo[2.2.0]hexadienes 269, so-called Dewar pyridines, which contain at least two new stereogenic centers. Complex structures 269 are observable spectroscopically but, usually, are unstable and revert thermally to pyridines or in the presence of water are hydrolyzed to conjugated aminoaldehydes 271 (Scheme 16.87). However, these intermediates can also be trapped by reduction with sodium borohydride to afford amines 270. hυ (254 nm) N

H

H

NaBH4/H2O

H

H NH

N

∆ t1/2 = 2 min

hυ, H2O

269

270 CHO NH2 271

Scheme 16.87

Of particular utility is the photoirradiation of 2-alkylpyridines 272 with electronwithdrawing groups on the alkyl substituent, which under base-catalyzed conditions give stable azabicycles 274 resulting from a proton shift over the initial cycloadduct 273 (Scheme 16.88) [212].

hυ (254 nm) X

N 272

H

NaOH (aq)

Y

N 273

H

X

H

Y

X

H NH

Y

274, 13-47%

X= H, Me Y= CN, CO2Me, CO2Et Scheme 16.88

16.4 Pyridine Derivatives 16.4.1 Oxyderivatives

The 2- and 4-hydroxypyridines exist almost entirely in the carbonyl tautomeric forms, known as 2- and 4-pyridones, respectively (Scheme 16.89). Their hydroxyl forms are

j1495

j 16 Six-Membered Heterocycles: Pyridines

1496

OH

O OH

N

OH

N H

2-hydroxypyridine

O

N

2-pyridone

N H

4-hydroxypyridine

4-pyridone

N 3-hydroxypyridine

O

O N H

O N H

N H

Scheme 16.89

detected only in non-polar solvents or in the gas phase. However, 3-hydroxypyridines behave as regular pyridines, which can also be in equilibrium with their zwitterionic forms in a ratio that depends on the type of solvent. 16.4.1.1 Reactions with Electrophilic Reagents 16.4.1.1.1 Reactions with Acids According to their structure, pyrones react mainly as unsaturated lactams whereas 3-hydroxypyridines behave as pyridines. As a consequence, 2- and 4-pyridones are protonated on their carbonyl groups (pKa 0.8 and 3.3, respectively) whereas 3-hydroxypyridines react through their ring nitrogen atom (pKa 5.2) (Figure 16.17). 16.4.1.1.2 Reactions with Acid Chlorides and Related Compounds Acid chlorides react with pyridones and 3-hydroxypyridines through their oxygen atom, affording the corresponding pyridinyl esters. For example, treatment of 4-pyridone and 2-pyridone 277 with benzoyl chlorides 275 and 278 gives, respectively, pyridines 276 [213] and 279 [214] in good yields (Scheme 16.90). Also, the reaction of 2-pyridone 280 with tosyl chloride affords an excellent yield of tosylate 281 [215].

H O

N H

O

H pKa 0.8

N H

pKa 3.3 OH N pKa 5.2

H

Figure 16.17 The pKas of pyrones and 3-hydroxypyridine.

16.4 Pyridine Derivatives

R1 ClOC

O

R3

O

275

R2 R3

Py, RT

N H

R1

O

R2

N

69-90%

276

R1, R2, R3 = H, Me, Br, Cl, NMe2, OMe, NO2

R1 278

ClOC OMe N H

OMe

R2

Br

O

N

K2CO3, (nBu)4NBr, acetone

O

O

80-89%

277

Br

R1, R2 = H, Me

Cl

N H

279 R1 R2

Cl

NO2

TsCl, Et3N

O

DCM, RT

NO2 N

98%

280

OTs

281

Scheme 16.90

16.4.1.1.3 Electrophilic Substitution Reactions Pyridones and 3-hydroxypyridines are more reactive to electrophilic substitutions than pyridines and the regioselective preference is to undergo substitution in the ortho and para positions relative to the oxygen functionality (Figure 16.18). These pyridine derivatives can be readily halogenated, nitrated or sulfonated. For example, the nitration of pyridones 282 and 284 affords regioselectively nitropyridones 283 and 285, respectively (Scheme 16.91) [216, 217]. 16.4.1.1.4 Reactions of Oxypyridine Anions with Electrophiles Pyridones are weak acids with pKas of around 11. They form mesomeric anions that readily react with electrophilic reagents at the nitrogen or oxygen atoms depending on the reaction

E+ N H

O

O

N H

E+

OH N

E+

Figure 16.18 Regioselectivity in electrophilic substitutions of pyridones and 3-hydroxypyridine.

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j 16 Six-Membered Heterocycles: Pyridines

1498

O

O NO2

HNO3 H2SO4(c), 100 ºC

N H

N H

38%

282

283 NO2

HNO3 N H

O

H2SO4(c), 5 ºC

284

O

N H

90%

285

Scheme 16.91

conditions (Scheme 16.92). For example, 2-pyridone 286 [218] is quantitatively O-methylated with methyl iodide using silver carbonate as base, whereas 2-pyridone 287 [219] preferentially affords N-methylation using the same alkylating agent but in the presence of sodium hydride (Scheme 16.93).

N

E+

base N H

N E

O

and/or

O

N

N

O

Scheme 16.92

MeI N H

Ag2CO3, DCM

O

N

100%

OMe

286 Ar

Ar MeI

NC

N H

O

287 Scheme 16.93

NaH, DMF

Ar= aryl

76%

NC

N

O

O

O

E

16.4 Pyridine Derivatives

j1499

16.4.1.2 Replacement of Oxygen Function The pyridone oxygen can be replaced by other atoms such as chloro or sulfur to afford the corresponding chloropyridines and thiopyridones, respectively. In particular, the conversion of the carbonyl group of pyridones into a good leaving group such as chloride, typically using phosphorus oxychloride, is an important reaction in pyridone chemistry, because chloropyridines are susceptible to cross-coupling reactions with organometallic reagents to form new carbon–carbon bonds or addition–elimination reactions with diverse nucleophiles (amines, cyanide, etc.) (Scheme 16.94). Usually, pyridones are converted into thiopyridones using Lawesson’s reagent [2,4bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide] [220].

N

RM

N H

reagent

S

MeO

S

P

S S

P

S

Cross-coupling reactions

POCl3

Lawesson´s N H

O

R

N

Cl Nu

Addition-elimination reactions OMe

Lawesson´s reagent Scheme 16.94

16.4.1.3 Photochemical Reactions of Pyridones Intramolecular electrocyclic 4p-ring closure represents the key photochemical reaction of 2-pyridones. This reaction has been extensively utilized in the synthesis of the carbapenem antibiotics core. Herein, photocyclization of the chiral pyridine 288 leads quantitatively to a mixture of diastereomers 289 and 290 (7 : 5 ratio, respectively) (Scheme 16.95) [221]. Furthermore, N-alkylated pyridones 291 undergo this type of reaction, affording diastereomeric bicycles 292 and 293 [222]. 16.4.2 Amino Derivatives 16.4.2.1 Reactions with Electrophilic Reagents Aminopyridines have three possible nucleophilic centers: the ring nitrogen atom, the amino nitrogen and the ring carbon atom (Scheme 16.96). As expected from their resonance forms, aminopyridines react with certain electrophiles such as proton, alkylating and acylating agents preferentially through their ring nitrogen atom.

N

Nu

j 16 Six-Membered Heterocycles: Pyridines

1500

O iPr N H

O

O

O

(7:5)

H

R

R O

H

O R= H, CO2Me, OMe,

H

+

Et

O N

H

O

292 Et

290

O N

64-98%

O

291

NH H

289

hυ

O

+

H

R

N

H

RO

O NH

quant R= (-)-menthol

288

H

RO

hυ

293

O

Et O

O

Scheme 16.95

NH2

NH2

N

N

N

NH2

NH2 N

N

NH2

N

NH2

Scheme 16.96

However, other electrophilic reagents react with aminopyridines through their ring carbon atom by an alternative electrophilic substitution pathway. In these cases, the 5- and 3-positions of 2- and 4-aminopyridines, respectively, are favored. 16.4.2.1.1 Reactions with Acids The three aminopyridines are all more basic than pyridine itself and form crystalline salts by protonation at the ring nitrogen atom. The a- and c-isomers are monobasic, because the positive charge is delocalized over both nitrogen atoms, which prevents further protonation (Scheme 16.97). This effect is stronger in the c-isomer than in the a-isomer, but it is not possible in the b-isomer. As a consequence b-aminopyridines can be further protonated using strong acids.

16.4 Pyridine Derivatives

j1501

Monobasic aminopyridines H N

H

NH2

N H

NH2

NH2

N H

NH2

NH2

NH2

H

H

N

N H

N H

Dibasic aminopyridines NH2

NH2

H

NH3

H

N H

N

N H

Scheme 16.97

16.4.2.1.2 Reactions with Alkylating Agents Aminopyridines react with alkylating agents through the more nucleophilic ring nitrogen atom to afford quaternary ammonium salts. For example, 4-aminopyridine has been alkylated with bromide 295 and chloride 296 to give quaternary pyridinium salts 294 [223] and 297 [224], respectively (Scheme 16.98).

NH2

Br

SO3Na 295 DMF

N SO3 294

62%

NH2

Cl

O

O

296 NH2

3 F

N

86%

F

N Cl 297

O

Scheme 16.98

16.4.2.1.3 Reactions with Acylating Agents Acid chlorides and related compounds react with aminopyridines through their amino substituent to afford the corresponding amides (Scheme 16.99). The ring nitrogen atom of the aminopyridine reacts first to give N-acylpyridinium salts 299, which then undergo a second acylation reaction

O

j 16 Six-Membered Heterocycles: Pyridines

1502

O NH2

HN

O Cl , Et3N

1) 2) H2O

N

N

O

298

H2O

Cl

O NH2

NH2

Cl

O

HN Cl

N

Et3N

N

Cl

N

O

O

Cl

O

299

300

Scheme 16.99

through the amino substituent to yield intermediate 300. Finally, aqueous work up affords amide 298. Some examples are shown in Scheme 16.100 [225, 226]. Ac2O, PhMe N

NH2

NH2 MeO2C

N

77%

N

NHAc

NHAc

Ac2O, AcOH 80%

MeO2C

N

Scheme 16.100

16.4.2.1.4 Electrophilic Substitution Reactions Aminopyridines undergo electrophilic substitution under milder conditions than pyridine itself. Usually, the substitution reaction takes place selectively at 5- and 3-positions of 2- and 4-aminopyridines, respectively. For example, 2-aminopyridine has been selectively sulfonated to give pyridine 301 in good yield (Scheme 16.101) [227]. Bromination of 2-aminopyridine afforded mainly 5-brominated pyridine 302, and also some dibrominated pyridine 303 [228]. In contrast, bromination of 4-aminopyridine gave an almost 1 : 1 mixture of mono- and dibrominated pyridines 304 and 305, respectively. The nitration of aminopyridines proceeds via a nitroamino derivative (306) resulting from the nitration of the amino substituent, which on further reaction

16.4 Pyridine Derivatives

Br2, NaHCO3 H2SO4-SO3 140 ºC

N

NH2

j1503

Br

Br

CH3CN, DCM

N

NH2

Br

+

N

302, 68%

80%

NH2

303, 23%

HO3S N

NH2

NH2

NH2 Br2, NaHCO3

301

+

CH3CN, DCM

N

NH2

Br

Br

N

N 304, 45%

305, 48%

Scheme 16.101

with concentrated H2SO4 gives the corresponding nitropyridine (Scheme 16.102). Nitration of 4-aminopyridine 307 using potasium nitrate in concentrated H2SO4 gave first the nitrated amino derivative 308 in 73% yield, which was followed by treatment with concentrated H2SO4 to, finally, afford 3-nitropyridine 309 in good yield [229]. H N NO 2

NH2 N

O2N

NH2 N

N 306

F

HN

NH2 KNO3, H2SO4(c) N

F

307

4 ºC to RT, 1.5 h 73%

NO2

F

H2SO4(c) N 308

F

RT, 24 h 87%

F

Br

NH2

N 309

Scheme 16.102

16.4.2.2 Diazotization of the Amino Group Similar to anilines, treatment of aminopyridines with nitrites affords the corresponding diazonium salts, which easily decompose and react with diverse nucleophilic reagents such as HBr, HCl, HF, and so on (Scheme 16.103). The diazonium salts of 2- and 4-aminopyridines decompose particularly fast and immediately react with the aqueous solvent to give the corresponding 2-and 4-pyridones, respectively. For example, diazotization of 2-aminopyridine 310 in the presence of 10% H2SO4 gave 2-pyridone 311 in 72% yield (Scheme 16.104) [220]. However, under controlled conditions, these diazonium salts are susceptible to reaction with diverse nucleophilic reagents. By carrying out the diazotization of aminopyridines 312 and 314 in 50% HI and HF-pyridine solution, respectively, good

NO2 F

j 16 Six-Membered Heterocycles: Pyridines

1504

H2O

Pyridones

N2

NH2 N

N

HX

X= halogen

X N

Scheme 16.103

CF3

CF3 HNO2, H2SO4(10%)

N

NH2

0 ºC to 70 ºC

NO2

KNO2, CuI

NH2

DMSO, HI, 60 ºC

310

N 312

72%

63%

N H 311

O

NO2 N

I

313 F

NH2 NaNO2, HF-Py N 314

0 ºC to RT 81%

N 315

Scheme 16.104

and excellent yields of iodo- 313 [230] and fluoropyridines 315 [231] can be obtained. The diazonium salts of 3-aminopyridines are reasonably stable, affording similar substitution reactions and coupling reactions. 16.4.3 Alkyl Derivatives

Similar to alkylbenzenes, alkylpyridines undergo special reactions at the side-chain such as halogenations and oxidations (Scheme 16.105) [232, 233]. Of particular interest is the deprotonation reaction with strong bases, such as LDA, nBuLi, NaNH2, and so on, which occurs 105 more rapidly with alkylpyridines than with the corresponding alkylbenzenes (Scheme 16.106). The 2- and 4-isomers are considerably more acidic than the 3-isomer due to the nitrogen stabilization, with the 4-isomer being the most acid. The resulting alkylpyridines anions can react with mild electrophilic reagents to afford a large variety of derivatives. For example,

16.4 Pyridine Derivatives

Cl

Cl Cl

hυ, ∆

N

N

72% CrO3, H2SO4(c)

N

Cl

Cl2, CCl4

HO2C

0 ºC to 75 ºC

N

CCl3 CO2H N

90%

N

Scheme 16.105

1) Base N

E

2) E N

N

Acidity : N

N

N

N

N

Scheme 16.106

functionalization of the methyl group of pyridines 316 and 318 by proton abstraction of the corresponding methyl groups with nBuLi followed, respectively, by reaction with formaldehyde and primary bromide leads to pyridines 317 [218] and 319 [234], respectively (Scheme 16.107). 3-Alkylpyridine also undergoes this type of reaction but the yields are usually lower. Side-chain hydrogens of alkylpyridines are sufficiently acidic to undergo condensation reactions with aldehydes or acetals. For example, c-picoline has been condensed with various benzaldehydes to give reasonable yields of heterostilbenes 320 (Scheme 16.108) [235]. Furthermore, treatment of dimethylpyridine 321 with dimethylformamide dimethyl acetal (322) in the presence of catalytic CuI and microwave acceleration at 180  C affords an excellent yield of dienamine 323 [236].

j1505

j 16 Six-Membered Heterocycles: Pyridines

1506

1) nBuLi, THF, 0 ºC MeO

2) (CH2O)n, RT

N

MeO

316

OH

N

60%

317 Z

AcHN

1) nBuLi, THF, -78 ºC

MeO

2) ZCH2Br, -50 ºC

N 318

AcHN MeO

N 319

Z= Me (73%), Ph (75%)

Scheme 16.107

Y

Y

OHC N

N

Ac2O, ∆

320

Y= H (47%), NO2 (58%) O 2N

(MeO)2CHNMe2, CuI (322)

O2N N 321

DMF, MW, 180 ºC

Me2N

N

95%

NMe2

323

Scheme 16.108

16.4.4 Pyridine Aldehydes, Ketones, Carboxylic Acids and Derivatives

In general, these types of compounds behave similarly to the corresponding benzene derivatives. In the case of pyridine carboxylic acids, the presence of the ring nitrogen atom favors the existence of their zwitterionic forms in aqueous solution(Figure 16.19).

CO2

N H isonicotinic acid

CO2 N H nicotinic acid

N H

CO2

picolinic acid

decreasing acidity Figure 16.19 Zwitterionic forms of pyridine carboxylic acids in aqueous solution.

16.4 Pyridine Derivatives

All three isomers are more acidic than benzoic acid with the 4-isomer (isonicotinic acid) being the most acidic. On heating, pyridine carboxylic acids readily undergo decarboxylation to afford the corresponding protonated derivatives. This reaction occurs more easily with pyridine carboxylic acids than with benzoic acids, decreasing in the reactivity order a > c  b isomer according to the inductive stabilization of the generated carbanions (Scheme 16.109). If the reaction is carried out in the presence of an electrophile such as an aldehyde or a ketone, the resulting carbanion can be trapped to form the corresponding alcohol in a process know as the Hammick reaction [237, 238]. Pyridylacetic acids also undergo a facile b-decarboxylation reaction to afford the corresponding picolines [239, 240]. R O

N H

CO2

O

R

R

∆

N H

N PhCHO R

Hammick reaction

N

O

N H

OH

∆

O

Ph

CO2

N H

N

Scheme 16.109

16.4.5 Quaternary Pyridium Salts 16.4.5.1 Nucleophilic Additions The reactivity of quaternary pyridinium salts is explained by the increased electrophilicity of a and c ring carbon atoms, which allows them to react easily with a large variety of nucleophiles (Scheme 16.110).

H Nu Nu N R Scheme 16.110

N R

H Nu

and/or N R

j1507

j 16 Six-Membered Heterocycles: Pyridines

1508

Usually, organometallic reagents react at both a and c positions; however, selective c-addition can be achieved using cuprates and also when bulky alkyl groups are present on the ring nitrogen atom. For example, treatment of pyridinium salt 324 with nBuLi gave an almost 1 : 2 mixture of 1,2- 325 and 1,4-tetrahydropiperidines 326 (Scheme 16.111) [241]. Selective addition at the 4-position of pyridinium salt 327 was obtained with phenylmagnesium chloride in the presence of catalytic copper(I) iodide to yield 1,4-tetrahydropiperidine 328 in excellent yield [242].

Ph

Ph

Ph nBu

nBuLi, Et2O Ph

N Me 324

Ph

Ph N nBu Me

Ph

ClO4

+ Ph

325, 25%

N R

Ph

326, 48%

Ph CO2Me

CO2Me

PhMgCl, CuI(cat) THF, RT

N

N

91%

I 327 R1

R1

1) ClCO2Et THF

N

Cl

329 R1= H, Me

R2

328

N CO2Et 330

R1

2) ArCH2MgBr CuI(cat), -78 ºC

N 331, 21-62%

R2= H, 2-Me, 4-Me, 4-OMe, 4-tBu

Scheme 16.111

The stronger reactivity of pyridinium salts compared with pyridines with nucleophiles has been exploited to achieve more effective nucleophilic additions to pyridines by in situ generation of pyridinium salts that are hydrolyzed during the workup. For example, formylation at the ring nitrogen atom of pyridines 329 with ethyl chloroformate generates pyridinium salts 330, which react with Grignard reagents selectively at the 4-position to afford pyridines 331 in good yields [243]. By a related mechanism, pyridinium salts can be oxidized at the a position using potassium ferrocyanide in basic media to afford the corresponding N-alkyl-2-pyridones (Scheme 16.112). The reaction involves initial a-nucleophilic attack of hydroxide to afford hydroxy derivative 332 which is then oxidized by potassium ferrocyanide [244].

16.4 Pyridine Derivatives

K3Fe(CN)6 NaOH(aq)

N R

N I Me

N

N R

H OH

N R

332

K3Fe(CN)6 NaOH(aq), 5 ºC

N

52%

N Me

O

O

Scheme 16.112

16.4.5.2 Reductions The reduction reactions of pyridinium salts are of particular interest because of their relation to important biological processes, such as the enzymatic NAD þ /NADH or NADP þ /NADPH oxidation/reduction reactions. The pyridinium salts are more easily reduced than pyridines to give N-alkyl piperidines, 1,2-dihydropiperidines or 1,2,3,4-dehydropiperidines depending on the reducing agents and the reaction conditions. N-Alkyl piperidines are usually obtained by catalytic hydrogenation whereas metal hydrides and active metals give partially unsaturated piperidines. For example, catalytic hydrogenation of pyridinium iodide 333 affords selective and complete reduction of the pyridinium ring, giving N-methylpiperidine hydroiodide 334 in 63% yield (Scheme 16.113) [245]. Conversely, treatment of pyridinium iodide 335 with sodium borohydride gives, mainly, 3,4dehydropiperidine 336 together with a small amount of 4,5-dehydropiperidine 337 [246].

OnHex

O

H2, PtO2

N H N

I

N

N H

60psi, EtOH 333

3 OTBS I

335

N H

63%

NaBH4 MeOH-H2O 74%

OnHex

O

3 OTBS

I

3 OTBS

+

N

N

336

337 336/337 (90:10)

Scheme 16.113

334

j1509

j 16 Six-Membered Heterocycles: Pyridines

1510

16.4.5.3 Reactions at the Alkyl Side Chain As with pyridines, a and c-alkyl substituted pyridinium salts can be functionalized at the side chain via the intermediacy of enamine 338, which is generated by treatment with base. Further reaction of 338 with an electrophile such as an aldehyde or ketone would lead to derivatives 339 (Scheme 16.114). base H

N R

E

N R

E

N R

338

339

Scheme 16.114

For example, reaction of porphyrin 340 with either 1,4-dimethyl- or 1,2-dimethylpyridinium iodides in the presence of K2CO3 gives condensation products 341 and 342, respectively (Scheme 16.115) [247]. In addition, triple Knoevenagel condensation of collidine salt 343 with aldehyde 344 affords conjugated pyridinium salt 345 (Scheme 16.116) [248].

Ph N

N H H N

Ph

I N

Ph

Ph N H

CHO N

N

K2CO3, THF/MeOH, 30 ºC 65%

Ph

Cl

Ph

N

N

H N Ph

Ph

341

340

Ph N

I N

K2CO3, THF/MeOH, 30 ºC 60%

Ph

N H

Ph

H N

N

N

Cl Ph

342

Scheme 16.115

16.4.5.4 a-Cyclizations Intramolecular free radical substitution of pyridinium salts 346 gives good yields of bicyclic compounds 347 (Scheme 16.117) [249]. Also, compounds 349 have been synthesized by intramolecular cyclization of pyridinium radicals generated from 2bromo-N-alkylpyridinium salts 348 [250].

16.4 Pyridine Derivatives

N N

CHO 344

piperidine, nBuOH, ∆

N

N

68%

F3CSO3

N

N F3CSO3

343

345

Scheme 16.116

nBu3SnH N

I

346

AIBN, PhMe

I

I

60-65%

n

N n 347

n= 1,2 1) nBu3SnH AIBN, PhMe 2) H2, PtO2, MeOH

N F3CSO3

F3CSO3

n 348

N n 349, 53-74%

n= 1,2

Scheme 16.117

16.4.6 Pyridine N-oxides

Pyridine N-oxides are stable dipolar species with the oxygen electrons delocalized throughout the pyridine ring (Scheme 16.118). These N-oxides are particularly useful in pyridine synthesis because the usual pyridine reactivity is enhanced by the presence of a positively charged ring nitrogen atom, even more than in quaternary pyridinium salts due to the electron release of the oxygen. This fact is shown in their dipole moment, which is almost twice the value of corresponding pyridines.

-N O 4.25 D Scheme 16.118

N O

N O

j1511

j 16 Six-Membered Heterocycles: Pyridines

1512

16.4.6.1 Reactions with Electrophilic Reagents Pyridine N-oxides react with electrophilic reagents through their oxygen atom. Of particular interest is the reaction with alkylating agents such as Me2SO4 because it affords N-alkyloxypyridinium salts 350, which are susceptible to further nucleophilic attack at the 2- and 4-positions of the pyridine ring (Scheme 16.119). Subsequent elimination of alcohol ROH gives 2- and 4-substituted pyridines, with the latter usually being the major regioisomer. This transformation has been used for the synthesis of cyanopyridines, the so-called Reissert–Henze reaction, which affords, usually, low reaction yields and mixtures of both 2- and 4-cyanopyridines. However, using an improved method developed by Fife [251], which consists of the use of acid chlorides instead of alkylating agents, permits cyanation exclusively at the 2-position of the pyridine in excellent yields. For example, cyano-derivative 352 has been synthesized from bipyridine N-oxide 351 in 90% yield (Scheme 16.120) [252]. Similarly, diverse aryl and alkyl groups have been introduced successfully at the 6-position of protected pyridoxal N-oxide 353 to give derivatives 354 [253]. H Nu Nu N O RX or N O

Nu

RCOCl X

N O

N and/or

and/or

Z N O

350

Z= alkyl, acyl X= halogen

Z

ROH or RCO2H

H Nu Z

Scheme 16.119

Me2NCOCl, TMSCN, DCM N O

N

90%

351 EtO tBuCO2

353

352 EtO

O ClCO2iBu, RMgBr, THF

N O

-78 ºC to RT 60-85% R= vinyl, phenyl, benzyl

Scheme 16.120

CN

N N

O

tBuCO2 N 354

R

N

Nu

16.4 Pyridine Derivatives

j1513

In consistent fashion, chloropyridines can be obtained directly from pyridine N-oxides by treatment with PCl5, POCl3 or SOCl2 (Scheme 16.121). The chlorinating agent (i.e., PCl5) reacts with the N-oxide through its oxygen atom and the evolved chloride adds to the 2- or 4-position of the pyridine ring. Finally, elimination of POCl3 gives the corresponding chloropyridine. For example, chloropyridines 356 and 358 have been synthesized from N-oxides 355 and 357, respectively [254].

H Cl PCl5 N O

N Cl4PO Cl

N Cl4PO

H Cl

+

N Cl4PO

POCl3

N +

HCl

Cl

N POCl3, ∆ iPrO 355

N O

63%

iPrO

N

Cl

356

POCl3, ∆

357

N O

64%

N

Cl

358

Scheme 16.121

Electrophilic substitutions to the neutral pyridine N-oxides occur selectively at the 4-position; however, if the reaction is carried out through the protonated N-oxides typical pyridinium reactivity is found and 3-substitution is observed (Scheme 16.122). Whereas nitration proceeds by electrophilic addition to the neutral pyridine N-oxide to give 4-nitroderivatives, sulfonation goes through the protonated form and 3-substitution is normally achieved. For example, nitration of pyridine N-oxide 359 affords 4-nitroderivative 360 in good yield [255]. Sulfonation of pyridine N-oxide yields 3-sulfonated derivative 361 [153]. 16.4.6.2 Reactions at the Alkyl Side Chain Consistent with the alkylpyridines, a and c alkyl pyridine N-oxides undergo important alkyl side chain reactions such as halogenation, condensation or oxidations. In addition, acyl rearrangement reactions may occur to introduce oxygen functionalities into the side chain, via the so-called Boekelheide reaction. The procedure consists of treatment of pyridine N-oxides with acetic anhydride, which initially produces oxygen

Cl

j 16 Six-Membered Heterocycles: Pyridines

1514

F

HNO3 H2SO4, 80 ºC

N O

72%

359

N OH

N O

F

NO2

N O 360 SO3H

SO3-H2SO4 HgSO4, 220-230 ºC

N O

71%

N O 361

Scheme 16.122

acylation, followed by proton lost from the alkyl side chain to give an uncharged intermediate 362, which finally undergoes a [3, 3] sigmatropic rearrangement to afford acetate 363 (Scheme 16.123). OAc

Ac2O ∆

N O

N O

[3,3]

H

N O

O

362

N O

OAc 363

Scheme 16.123

Under these conditions, pyridine N-oxide 364 is efficiently transformed into alcohol 365 by a two-step procedure involving an initial Boekelheide reaction followed by basic hydrolysis of the resultant acetyl derivative (Scheme 16.124) [256]. OBn

OBn OBn N O 364

OBn

1) Ac2O, ∆ 2) NaOH (2M), ∆ 81%

N

OH

365

Scheme 16.124

16.4.6.3 Deoxygenation Reactions Several pyridine N-oxide deoxygenation procedures have been developed, including phosphorous trihalides, catalytic hydrogenation over Raney-Ni or Pd-carbon, SmI2, NaBH4/AlCl3 or Fe/AcOH. Many of these methods are limited by side reactions such

16.5 Appendix

as substituent reductions. Recently, a milder and highly efficient deoxygenating method has been developed, based on the transfer of oxygen from the N-oxide to PPh3 catalyzed by Re(V) [257] or Mo(VI) [258] complexes. Scheme 16.125 shows some examples of the deoxygenation reaction [254, 257].

NO2

NO2 PBr3 N O

Cl

EtOAc, 70 ºC 82%

OMe

N

Cl

OMe PPh3

N O

THF, RT 93%

N

Scheme 16.125

16.5 Appendix 16.5.1 Synthesis of Pyridines by Cycloaddition Reactions

A new review on [2 þ 2 þ 2] cycloaddition reactions catalyzed by transition metal complexes has appeared [259] that includes recent progress in the synthesis of aromatic and heterocyclic compounds such as pyridines, pyridones, and so on. In this context, two novel variants of the cobalt-catalyzed intramolecular [2 þ 2 þ 2] cycloadditions have recently been published, allowing the formation of highly functionalized pyridines. Both approaches deal with the co-cyclotrimerization of nitrilediynes. Snyder and coworkers [260] have reported the microwave-promoted cobalt-catalyzed [2 þ 2 þ 2] cyclization of dialkynylnitriles A1 to afford tetrahydronaphthyridines A2 (n ¼ 1) and related pyridine derivatives in moderate to excellent yields (Scheme 16.A.1). Alternatively, Cheng and coworkers [261] use the CoI2(dppe)/ Zn system to achieve the efficient synthesis of tetra- and pentacyclic pyridine derivatives A4 even with highly substituted nitrilediynes A3 having steric conjunction at the a and b positions to the nitrile group and a bulky substituent at the terminal carbon of alkyne (Scheme A.1). Also important has been the extensive study reported by Yamamoto and coworkers on the scope of the substrate as well as the reaction mechanism of rutheniumcatalyzed [2 þ 2 þ 2] cycloaddition of 1,6-diynes and nitriles to afford bicyclic pyridines [262].

j1515

j 16 Six-Membered Heterocycles: Pyridines

1516

R3 O N

R2

CpCo(CO)2

N

R3

O

R1

R2

N

W, 180 ºC, 15 min

n

71% (n= 0) 83-99% (n= 1) 25% (n= 2)

A1

R1

N A2

R1 = H, Me, Et, nBu, Ar, CH 2OPh, CH2 OH, TMS, Ph R2 = H, Me, iBu, iPr, CH 2CH2 OPh R3 = Me, CH2 OC 6H 4OPh n= 0, 1, 2

2

R X

Z R1 A3

R2 N

CoI2 (dppe)/Zn 80 ºC, CH 3 CN, 16h 46%-94%

R1 = Ph, Ar, H, TMS, Me R2 = H, Me; R2 +R2 = (CH 2) 2, (CH2 )5 X= O, NTs, CH 2, (CH 2 )2 Z= H, O

Z R2 X

N

R2

R1 A4

Scheme 16.A.1

16.5.2 Reactivity of Pyridines

The use of pyridines as monodentate ligands in transition metal complexes has recently been exploited in the development of novel, efficient Pd-NHC complex A5 (Figure 16.A.1) [263], which is very useful as catalyst in the carbon–carbon R

R N R

N

R Cl Pd Cl N Cl A5 R= iPr

Figure 16.A.1 A useful new catalyst in carbon–carbon cross-coupling reactions.

References

R2 R1

TMS + N O A6

R2

4 CsF

2

MeCN, RT, 24 h

TfO

R1 OH

N

A8

A7 R 1 = H, Me, CN R 2 = F, OMe, alkyl

R1

R1 N O

R2

R1 H

R2

N O

R2 N

O

Scheme 16.A.2.

cross-coupling reactions [263–265], particularly in the formation of sp3-sp3 carbon–carbon bonds [263, 264]. 16.5.3 Pyridine Derivatives

An interesting application of the reaction of pyridines N-oxides with electrophilic reagents has been reported recently. Various substituted hydroxyphenylpyridines A8 have regioselectively been prepared in one step by reaction between pyridine Noxides A6 and arynes generated from silylaryl triflates A7 in the presence of caesium fluoride in acetonitrile at room temperature (Scheme 16.A.2) [266]. This transitionmetal-free, mild, coupling reaction proceeds in good yield through what appears to be a series of rearrangements.

References 1 Roth, H.J. and Kleemann, A. (eds) (1988)

4 Ware, G.W. (1983) Pesticides: Theory and

Pharmaceutical Chemistry, Drug synthesis, Vol 1, Prentice Hall Europe, London, p. 407. 2 Kleemann, A., Engel, J., Kutscher, B., and Reichert, D. (2001) Pharmaceutical Substances: Syntheses, Patents Applications, 4th edn, Georg Thieme Verlag, Stuttgart. 3 Matolcsy, G. (1988) Pesticide Chemistry, Elsevier Scientific, Amsterdam, Oxford, p. 427.

Applications, Freeman, San Francisco, Oxford, p. 102. Meister Publishing (2000) Farm Chemicals Handbook, Vol. 86, Meister Publishing Co, Willoughby, Ohio. Varela, J.A. and Sa
a, C. (2003) Chemical Reviews, 103, 3787. Schore, N.E. (1988) Chemical Reviews, 88, 1081. Lautens, M., Klute, W., and Tam, W. (1996) Chemical Reviews, 96, 49.

5

6 7 8

j1517

j 16 Six-Membered Heterocycles: Pyridines

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9 Vollhardt, K.P.C. (1984) Angewandte

10 11 12

13

14

15 16

17

18

19

20

21

22 23

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Grierson, D.S. (2005) Tetrahedron Letters, 46, 2919. Benjahad, A., Croisy, M., Monneret, C., Bisagni, E., Mabire, D., Coupa, S., Poncelet, A., Csoka, I., Guillemont, J., Meyer, C., Andries, K., Pauwels, R., de B
ethume, M.-P., Himmel, D.M., Das, K., Arnold, E., Nguyen, C.H., and Grierson, D.S. (2005) Journal of Medicinal Chemistry, 48, 1948. Brignell, P.J., Katritzky, A.R., and Tarhan, H.O. (1968) Journal of the Chemical Society, Section B: Physical Organic, 12, 1477. Padwa, A. and Brodney, M.A. (2002) ARKIVOC, vi, 35. Wang, L., Lin, N.-H., Li, Q., Henry, R.F., Zhang, H., Cohen, J., Gu, W.-Z., Marsch, K.C., Bauch, J.L., Rosenberg, S.H., and Sham, H.L. (2004) Bioorganic & Medicinal Chemistry Letters, 14, 4603. Dunn, A.D. (1999) Journal of Fluorine Chemistry, 93, 153. Sato, M., Katagiri, N., Muto, M., Haneda, T. and Kaneko, C. (1986) Tetrahedron Letters, 27, 6091. Hongo, H., Iwasa, K., Kabuto, C., Matsuzaki, H., and Nakanao, H. (1997) Journal of the Chemical Society, Perkin Transactions 1, 1747. Kupyatis, G.-K., Shaduikis, G., Nivinskene, O., and Eicher-Lorka, O. (2001) Chemistry of Heterocyclic Compounds, 37, 781. Sato, M. and Arimoto, M. (1982) Chemical & Pharmaceutical Bulletin, 30, 719. Schmuck, C. and Machon, U. (2005) Chemistry – A European Journal, 11, 1109. Chand, P., Kotian, P.L., Morris, P.E., Bantia, S., Walsh, D.A., and Babu, Y.S. (2005) Bioorganic and Medicinal Chemistry, 13, 2665. Dale, D.J., Draper, J., Dunn, P.J., Hughes, M.L., Hussain, F., Levett, P.C., Ward, G.B., and Wood, A.S. (2002) Organic Process Research & Development, 6, 767. Paudler, W.W. and Jovanovic, M.V. (1983) The Journal of Organic Chemistry, 48, 1064. Sakthivel, K. and Cook, P.D. (2005) Tetrahedron Letters, 46, 2883. Sapountzis, I., Dube, H., Lewis, R., Gommermann, N., and Knochel, P.

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j 16 Six-Membered Heterocycles: Pyridines

1524

231

232

233 234 235

236

237

238 239

240

241

242 243 244

245

246

247

(2005) The Journal of Organic Chemistry, 70, 2445. Fukuhara, T., Yoneda, N., and Suzuki, A. (1988) Journal of Fluorine Chemistry, 38, 435. Tiwari, A., Waud, W.R., and Struck, R.F. (2002) Bioorganic and Medicinal Chemistry, 10, 3593. Garelli, N. and Vierling, P. (1992) The Journal of Organic Chemistry, 57, 3046. Marakos, P., Pouli, N., Wise, D.S., and Townsend, L.B. (1997) Synlett, 561. Lorance, E.D., Kramer, W.H., and Gould, I.R. (2002) Journal of the American Chemical Society, 124, 15225. Siu, J., Baxendale, I.R., and Ley, S.V. (2004) Organic and Biomolecular Chemistry, 2, 160. Cantwell, N.H. and Brown, E.V. (1953) Journal of the American Chemical Society, 75, 1489. Brown, E.V. and Shambhu, M.B. (1971) The Journal of Organic Chemistry, 36, 2002. Stermitz, F.R. and Huang, W.H. (1971) Journal of the American Chemical Society, 93, 3427. Headley, G.W. and O’Leary, M.H. (1990) Journal of the American Chemical Society, 112, 1894. Schwarz, M. and Kuthan, J. (1989) Collection of Czechoslovak Chemical Communication, 54, 1880. Hilgeroth, A. and Baumeister, U. (2001) Chemistry – A European Journal, 7, 4599. Shiao, M.J. and Chia, W.L. (1991) Synthetic Communications, 21, 401. Norrby, T., B€orje, A., and Åkermark, B. (1998) Acta Chemica Scandinavica (Copenhagen, Denmark: 1989), 52, 77. De Marco, A., De Candia, M., Carotti, A., Cellamare, S., De Candia, E., and Altomare, C. (2004) European Journal of Pharmaceutical Sciences, 22, 153. Maia, A.A., Mons, S., Gil, R.P.F., and Marazano, C. (2004) European Journal of Organic, 1057. Silva, E.M.P., Giuntini, F., Faustino, M.A.F., Tom
e, J.P.C., Neves, M.G.P.M.S., Tom
e, A.C., Silva, A.M.S., SantanaMarques, M.G., Ferrer-Correia, A.J., Cavaleiro, J.A.S., Caeiro, M.F., Duarte,

248

249 250 251 252

253 254

255

256

257 258

259 260 261

262

263

R.R., Tavares, S.A.P., Pegado, I.N., d’Almeida, B., De Matos, A.P.A., and Valdeira, M.L. (2005) Bioorganic & Medicinal Chemistry Letters, 15, 3333. Abbotto, A., Beverina, L., Bazio, R., Facchetti, A., Ferrante, C., Pagani, G.A., Pedron, D., and Signorini, R. (2003) Chemical Communications, 2144. Murphy, J.A. and Sherburn, M.S. (1991) Tetrahedron Letters, 47, 4077. Dobbs, A.P., Jones, K., and Veal, K.T. (1997) Tetrahedron Letters, 38, 5383. Fife, W.K. (1983) The Journal of Organic Chemistry, 48, 1375. Norrby, T., Borje, A., Zhang, L., and Akermark, B. (1998) Acta Chemica Scandinavica (Copenhagen, Denmark: 1989), 52, 77. Kim, Y.-C. and Jacoson, K.A. (2000) Synthesis, 119. Connon, S.J. and Hegarty, A.F. (2004) European Journal of Organic Chemistry, 3477. Ife, R.J., Dyke, C.A., Keeling, D.J., Meenan, E., Meeson, M.L., Parsons, M.E., Price, C.A., Theobald, C.J., and Underwood, A.H. (1989) Journal of Medicinal Chemistry, 32, 1970. Piyamongkol, S., Zhou, T., Liu, Z.D., Khordr, H.H., and Hider, R.C. (2005) Tetrahedron Letters, 46, 1333. Wang, Y. and Espenson, J.H. (2000) Organic Letters, 2, 3525. Sanz, R., Escribano, J., Fern
andez, Y., Aguado, R., Pedrosa, M.R., and Arnaiz, F.J. (2005) Synlett, 1389. Chopade, P.R. and Louie, J. (2006) Advanced Synthesis and Catalysis, 38, 2307. Zhou, Y., Porco, J.A., Jr, and Snyder, J.K. (2007) Organic Letters, 9, 393. Chang, H.-T., Jeganmohan, M., and Cheng, C.-H., Organic Letters, (2007) 9, 505. Yamamoto, Y., Kinpara, K., Ogawa, R., Nishiyama, H., and Itoh, K. (2006) Chemistry – A European Journal, 12, 5618. O’Brien, C.J., Kantchev, E.A.B., Hadei, N., Valente, C., Chass, G.A., Lough, A.C., Hopkinson, A.C., and Organ, M.G. (2006) Chemistry – A European Journal, 12, 4743.

References 264 Organ, M.G., Avola, S., Dubovyk, I.,

Hadei, N., Kantchev, E.A.B., O’Brien, C.J., and Valente, C. (2006) Chemistry – A European Journal, 12, 4749. 265 Organ, M.G., Abdel-Hadi, M., Avola, S., Hadei, N., Nasielski, J., O’Brien, C.J., and

Valente, C. (2007) Chemistry – A European Journal, 13, 150. 266 Raminelli, C., Liu, Z., and Larock, R.C. (2006) The Journal of Organic Chemistry, 71, 4689.

j1525

j1527

17 Six-Membered Heterocycles: Quinoline and Isoquinoline Ram
on Alajarín and Carolina Burgos

17.1 Quinoline 17.1.1 Introduction

Quinoline (1) is a benzo-fused pyridine heterocyclic compound and is also known as 1-azanaphthalene, 1-benzazine, or benzo[b]pyridine. Formally, quinoline is derived from naphthalene by replacement of one of its a-CH units by nitrogen. Quinoline (1) is a colorless, high-boiling liquid with a sweetish odor. Important derivatives include quinaldine (2), lepidine (3), 2- and 4-quinolones (4, 5), and the quinolinium cation (6). The numbering system of this heterocycle, as treated in this chapter, is shown on structure 1 [1]. CH3

4

5

3

6 7 8

N

2

1

Quinoline 1

N

CH3

Quinaldine 2 (2-methylquinoline)

N Lepidine 3 (4-methylquinoline)

O

N H

O

N H

2 and 4-quinolones (4 and 5) (1H-quinolin2-one and 1H quinolin-4-one, respectively)

N R

+

Quinolinium cation 6

Modern Heterocyclic Chemistry, First Edition. Edited by Julio Alvarez-Builla, Juan Jose Vaquero, and José Barluenga. Ó 2011 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2011 by Wiley-VCH Verlag GmbH & Co. KGaA.

j 17 Six-Membered Heterocycles: Quinoline and Isoquinoline

1528

17.1.2 General Reactivity 17.1.2.1 Relevant Physicochemical Data, Computational Chemistry, and NMR Data The presence of nitrogen in this structure produces an irregular distribution of the electron density in both heterocyclic and carbocyclic rings, a situation that alters the physicochemical properties and reactivity. The electronegative nitrogen causes inductive polarization, mainly in the s-bond framework but also affecting the p-electron system, and also stabilizes those polarized canonical structures in which nitrogen is negatively charged. Consequently, there are fractional positive changes, mainly located on the C2 and C4 pyridine positions, but the local p-deficiency also increases in the benzene ring [2, 3]. The localization energies and total electron densities (s þ p) calculated by extended H€ uckel theory (EHT) [2] correlate quite conclusively with the experimentally observed data. The values of atomic charges in the quinoline structure are shown here [4].

+0.011 -0.003 +0.016

+0.068 -0.009

-0.002 +0.043 -0.013

N

+0.104

-0.216

Quinoline 1

Additionally, it has been demonstrated that the positional selectivity in electrophilic attack on this heterocyclic molecule can be explained according to the magnitude of the HOMO electron density of each atomic center. The calculated values predict that electrophilic substitution of quinoline will occur at C5 and C8 – in agreement with the experimental data [5]. Other relevant UV and NMR data are compiled in Tables 17.1–17.3

Table 17.1 1 H NMR chemical shifts (ppm) and selected coupling constants (Hz) for quinoline (1) [6].

d (ppm) H2 H3 H4 H5 H6 H7 H8 1

3

8.80 7.22 7.96 7.66 7.41 7.59 8.10

4

JH–H

H2–H3 H3–H4 H5–H6 H6–H7 H7–H8

H NMR Spectra recorded at 100 MHz in CCl4.

4.18 8.24 8.20 6.92 8.53

H2–H4 H5–H7 H6–H8

JH–H 1.78 1.44 1.23

17.1 Quinoline Table 17.2

13

C NMR chemical shifts (ppm) for quinoline (1) [7].

d (ppm) C2 C3 C4 C5 C6 13

d (ppm) 150.2 120.9 135.7 127.6 126.4

C7 C8 C4a C8a

129.2 129.4 128.2 148.3

C NMR spectra recorded at 20 MHz in CDCl3.

17.1.2.2 General Reactivity and Tautomerism Taking into consideration the physicochemical and structural data outlined above, quinoline, in a similar way to pyridine, undergoes a range of simple electrophilic additions involving donation of the nitrogen lone pair to an electrophile to give “quinolinium salts” 6. This donation does not destroy the aromatic sextet and the quinolinium salt 6 remains aromatic. Concerning electrophilic substitution on the C-positions, quinoline (1) has a benzene ring annelated to the pyridine ring and comparisons with naphthalene chemistry must be considered. For example, SEAr reactions occur on the carbocyclic ring, preferentially on those of the more activated benzene moiety, and the positional selectivity is C8 > C5 >
other positions. In general, the SEAr process occurs preferentially via the conjugate acid, that is, the quinolinium ion, which prevents attack on the heterocyclic ring. The electron-deficiency of the C-heterocycle in quinoline (1), in particular on the C2 and C4 positions, makes nucleophilic addition reactions very important in quinoline chemistry. The nucleophilic substitution of quinoline usually proceeds through addition of a nucleophile and then elimination of a negatively charged entity such as H– or, more favorably, Hal–. The SNAr process proceeds more rapidly in quinoline than pyridine because the fused benzene ring stabilizes the addition product through conjugation. Quinolinium salts 6 are highly resistant to electrophilic substitution but are very susceptible to nucleophilic additions. Annular tautomerism does not occur in quinoline (1) but this system does have some substituent tautomers. 1H-Quinolin-2-one (4) and 1H-quinolin-4-one (5), 2and 4-quinolones, respectively, could exist in equilibrium with the corresponding Table 17.3 UV data for quinoline (1) in H2O [8].

UV (H2O) l (nm)

log e

226 275 299 312

4.36 3.51 3.46 3.52

j1529

j 17 Six-Membered Heterocycles: Quinoline and Isoquinoline

1530

hydroxy derivatives. However, the tautomeric equilibrium lies completely over to the carbonyl tautomeric form [9]. All aminoquinoline derivatives exist predominantly as amino tautomers and their polarized resonance contributions are shown here for the 2-substituted derivatives.

+

O

N H

+

N H

NH

N H

O

N

OH

N

OH

N H

NH

N

NH2

N

NH2

+

+

17.1.3 Relevant Natural and/or Useful Compounds

Quinoline (1) is mainly used as a building block for other chemical compounds. For example, 8-hydroxyquinoline is a chelating agent and a precursor for pesticides, whereas 2- and 4-alkylquinolines are precursors of cyanine dyes. Quinoline was first extracted from coal tar in 1834 by Friedlieb Ferdinand Runge. Several years later, this compound was also observed as a pyrolytic degradation product of cinchonamine, a Cinchona alkaloid closely related to quinine (7). The name “quinoline” comes from the term “quinine,” an antimalarial agent isolated from cinchona tree bark by Pelletier in 1820 [10]. H

H3CO

HO H

H N H3CO N

(-) Quinine 7

H HO H

H N

N (+) Quinidine 8

OH

OCH3 N N OCH3

O

γ-Fagarine 9

O

O Toddaquinoline 10

In contrast to isoquinoline, there are comparatively few naturally occurring quinolines. In addition to Cinchona alkaloids [11] – pairs of diastereomeric compounds such as quinine–quinidine (7 and 8), dihydroquinine–dihydroquinidine, as well as cinchonidine–cinchonine – some remarkable members of these families are the biologically relevant quinoline alkaloids from rutaceous plants, such as c-fagarine (9), which was isolated from stems of Glycosmis arborea. This compound showed inhibitory activity toward the induction of Epstein–Barr virus early antigen (EBV-EA) in Raji cells by the tumor promoter 12-O-tetradecanoylphorbol 13-acetate, and is thus potentially useful as a chemoprotective agent in chemical carcinogenesis [12]. Additionally, 9 showed useful cytotoxicity towards the murine leukemia P-288 cell line [13]. c-Fagarine (9) and related furoquinolines also inhibited human phospho-

17.1 Quinoline

j1531

diesterase 5 (hPDE5A), a hydrolytic enzyme that regulates the intracellular levels of cGMP and influences vascular smooth muscle tone [14]. In 1993 Chen and coworkers [15] reported the isolation of toddaquinoline (10), a benzo[h]quinoline alkaloid that is a constituent of many Asian folk medicines. The alkaloid was extracted from the root bark of Formosan Toddalia asiatica – another rutaceous plant [16]. Pyrroloquinoline-based alkaloids have attracted significant interest due to their intriguing structures and biological activity. The best known example is camptothecin (11), a novel alkaloid isolated from the stem wood of the Chinese tree Camptotheca acuminate, and its analogues. These compounds are collectively known as captothecins and they have potent antitumor activity. Since the isolation of camptothecin (11) in 1966 and the elucidation of its structure by Wall and coworkers [17] this compound has been the subject of numerous syntheses [18]. Recently, camptothecin has also shown potent anti-retroviral activity at dose levels that are well tolerated by cells. This compound may therefore represent a new direction in AIDS chemotherapy. Derivatives of camptothecin have a unique mechanism of action: they kill cells by binding to and stabilizing a complex of DNA and the enzyme topoisomerase I [19].

N

H N

O

N O H3C

H2N

H N

N

O CH3

NH

OH O

HN

O

Camptothecin 11

N H

CH3 CH3 H N

H N NH

Martinelline 12

In 1995 Witherup et al. [20] reported the isolation of martinelline (12) from an extract of Martinella iquitosensis roots. This new alkaloid was found to possess antibacterial activity as well as affinity for adrenergic, muscarinic, and bradykinin receptors. The structure of martinelline has attracted considerable attention and several research groups have reported approaches for the preparation of this compound [21]. N

N N CH3

N CH3

Cryptotackieine 13

Cryptosanguinolentine 14

In 1996 two groups [22] independently reported the isolation of cryptotackieine (13) and cryptosanguinolentine (14), two new alkaloids extracted from Cryptolepis sanguinolenta, a shrub indigenous to tropical West Africa. Cryptotackieine 13 displays a strong antiplasmodial activity against Plasmodium falciparum chloroquine-resistant strains, and both compounds display various interesting biological properties [23].

CH3 CH3

j 17 Six-Membered Heterocycles: Quinoline and Isoquinoline

1532

H3C

CH3

O

CH3 OH CH3

H3C CH3 OH O

CH3

H3C O

O

OH O N CH3

O N CH3

H3C

Huajiaosimuline

Simulenoline 15

O

O N CH3

Zanthodioline

16

17

Pyranoquinoline alkaloids are another important group of quinoline derivatives. Simulenoline (15), huajiaosimuline (16), and zanthodioline (17) are representative examples of these natural products isolated from root bark of Zanthoxylum simulans, a shrub found in Taiwan and mainland China. These novel monoterpenoid pyranoquinolines are potent inhibitors of platelet aggregation. While simulenoline (15) and zanthodioline (17) are not cytotoxic, huajiaosimuline (16) is toxic toward several human culture cell lines, especially the estrogen receptor-positive breast cancer cells [24]. An important group of quinoline derivatives are those obtained from fungal and microbial sources. The prototypical example is thiostrepton (18), a thiopeptide antibiotic that contains a 7,8-dihydroquinoline core [25]. O S

N H

N O

N S N O

HN

O HN

NH HO

O

S

O N S

H

H N

NH2

O

O

H N

N N H

O

H N

H N O

H N

O

N H

H

OH

N

O OH

N S

O HO OH Thiostrepton 18

As far as synthetic quinoline derivatives are concerned, there are a large group of heterocyclic compounds that display interesting medicinal, agricultural, or some other industrial utility. Quinoline derivatives provided the first photographic film sensitizer: the cyanine dye ethyl red (19) [26]. However, some of the most important examples are the pharmacologically active compounds, including several antimalarial drugs based on the quinine parent, for example, chloroquine (20) [27]

17.1 Quinoline

j1533

and mefloquine (21) [28], and some antibacterial fluoroquinolones such as ciprofloxacin (22) [29]. CH3

CH3

N H H

H3C N

N

Cl

CH3

O

HO

N

HN

N +N

H3C

CF3 Mefloquine

Chloroquine 20

Ethyl red 19

CF3 HN 21

N

O

O

Cl HN

NHPh

N H

CO2H

N N

Cl

O O

O

N

CH3 O

OH CH3

Irinotecan 23

N

Ciprofloxacin

In recent years some quinoline derivatives have attracted considerable interest for various pharmacological targets. For example, irinotecan (23) is an anticancer drug marketed by Pfizer [30], whereas L-689,560 (24) is a strong NMDA receptor antagonist identified by the Merck group. Overactivation of the NMDA subtype of excitatory amino acid receptors is implicated in several neurodegenerative disorders, including epilepsy, stroke, and Alzheimer’s disease [31]. In conclusion, a great number of biological, pharmacological, and biocidal activities have been fully described in the reviews and monographs published on the compounds treated in this chapter. N

CO2H

F

L-689,560 24

17.1.4 Ring Synthesis of Quinolines 17.1.4.1 Classical Syntheses 17.1.4.1.1 Anilines Plus 1,3-Dielectrophiles Combes Synthesis Condensation of a 1,3-dielectrophile, in the simplest case a 1, 3-dicarbonyl derivative, with an aniline furnishes a b-aminoenone, which can evolve to an aromatic derivative by treatment with concentrated acid [32]. The cyclization step can be viewed as an electrophilic substitution by the aniline derivative on the O-protonated aminoenone 25 (Scheme 17.1). Quinolinophanes 26 (Scheme 17.2) have been prepared using this method, starting from the appropriate aniline and the 1,3-dicarbonyl derivative [33].

22

j 17 Six-Membered Heterocycles: Quinoline and Isoquinoline

1534

R

1

O

+ O O

NH2

R R

HO R

R

2

N H

R R

1

R

N H

+

1

2

N H

1

N

2

OH

1

R

2

25

R

2

Scheme 17.1

EtOH

+ O NH2

O

R

O

R

PPA

R

CH3 93-95%

N

120ºC

CH3

N

75-80%

CH3

26

Scheme 17.2

3-Cyanoquinolines are prepared by condensation of anilines with 3,3-dimethoxy-2formylpropanenitrile [34]. In an unconventional approach to the classical Combes reaction, Tom and Ruel [35] have reported an efficient synthesis of functionalized 3-formylquinolines 27 from substituted anilines and vinamidium salts 28. The cyclization was followed by hydrolysis of the masked aldehydes 29 to provide the desired products (Scheme 17.3). H3C

2BF4R

1

+ NH2

H3C H3C

N

CH3

N

+

H3C EtOH

+

CH3

N CH3

reflux

R

+ CH3

H+/H2O

1

N 29

O

N

R

H

1

N 27

28 Scheme 17.3

Conrad–Limpach–Knorr Synthesis Primary arylamines and b-ketoesters condense in the presence of strong acids to form 2-quinolones (Knorr synthesis) via the corresponding b-ketoanilides (e.g., 30, Scheme 17.4), whereas a thermal reaction involving b-anilinoacrylic esters (e.g., 31, Scheme 17.4) yields 4-quinolones (Conrad–Limpach synthesis). The formation of the 2-quinolone is due to an SEAr process, analogous to a Combes synthesis, whereas formation of the 4-quinolone, especially in cases where

17.1 Quinoline

R

O H2SO4

R N H 30

R + O NH2

N H

O

OEt

diphenyl ether

O

O

O O

j1535

OEt N H

260ºC

N H

R

R

31 Scheme 17.4

the benzene ring carries an electron-withdrawing group, is probably due to an electrocyclic cyclization [36]. 4,2-Trifluoromethyl-substituted 2- or 4-quinolinones have been prepared by condensation of anilines with ethyl trifluoroacetate under different reaction conditions [37]. Recently, Zewge et al. [38] discovered that Eaton’s reagent (7.7/92.3 wt.% P2O5/ MeSO3H) could be used to promote the cyclization of aniline derivatives to give substituted 4-quinolones. The use of microwave technology in this kind of synthesis continues to gain in popularity. A microwave synthesis of 4-hydroxy-2-quinolinones 32 (Scheme 17.5) under solvent-free conditions has been developed. The quinolinones are easily obtained in a one-pot procedure as a result of the formal amidation of a malonic ester derivative with an aniline and subsequent cyclization of the intermediate malondianilide [39].

1

R

+ EtO2C NH2

R 2

R

Microwave

15 min, 500 W

OH

O

1

EtO2C

N H O

R N H

2

R

2 1

1

R

R

Scheme 17.5

Skraup and Doebner–Miller Syntheses [40] Construction of the quinoline system by the Skraup [41] and Doebner–Miller [42] methods is based on the reaction of an aromatic amine, containing at least one free ortho position, with a reagent that is the source of a three-carbon fragment. In the classical Skraup method, the aromatic amine, in the simplest case aniline, is heated with glycerol, sulfuric acid (which catalyzes the dehydration of glycerol to acrolein), and an oxidizing agent, such as nitrobenzene, which transforms the initially formed 1,2-dihydroquinoline into the

N H 32

O

j 17 Six-Membered Heterocycles: Quinoline and Isoquinoline

1536

fully aromatic heterocycle. The Doebner–Miller synthesis was originally limited to the reaction with crotonaldehyde to give quinaldines, but this name is increasingly used as a generic term for this type of reaction. The sequence of this reaction was established by different methods; the first step being the Michael addition of the amine to the enal system, to supply the b-aminocarbonyl derivative. These systems cyclize, via the protonated carbonyl derivative, to give 33. Subsequent dehydration and dehydrogenation affords quinoline 34 (Scheme 17.6).

OH

HO

H2SO4

O

R

O

NH2

H

OH

H + O

H

R

R

N H

OH NO2Ph

R

R

N H R N 34

N H

N 33 H

H

Scheme 17.6

A modification of the Skraup synthesis, using InCl3 on silica gel and microwave irradiation under solvent-free conditions, has been reported by Ranu et al. [43] starting from anilines and alkyl vinyl ketones (Scheme 17.7).

R

O R

1

NH2

+

R

4

R

3

R

2

InCl3 /SiO2 microwave 5-30 min

R

4

R

1

N

3

R

2

45-78%

Scheme 17.7

Furthermore, 2,2,4-trisubstituted 1,2-dihydroquinolines have been prepared by a Skraup synthesis in the presence of a lanthanide catalyst and microwave irradiation [44]. The vapor phase synthesis of quinoline from aniline and glycerol in a single step has been investigated over ZnO-Cr2O3, CuO-ZnO/Al2O3, MoO3-V2O5/Al2O3, and NiO-MoO3/Al2O3 catalysts in the presence of air at 623–723 K at atmospheric pressure. Among the catalysts investigated, the CuO-ZnO/Al2O3 combination effectively performed this reaction with high activity and selectivity [45]. A related process is the reaction of anilines with the iminium triflate 35 to yield trifluoromethylquinolines 36 (Scheme 17.8) [46]. Matsugi et al. [47] have reported an improved version of the Doebner–Miller cyclization. The reaction was carried out in a two-phase solvent system. The method

17.1 Quinoline

H3 C +

R

NH2

N

+

CH3

∆

R

TfOTfO

N

CF3

CF3

36

35 Scheme 17.8

proved to be advantageous in terms of the yield and ease of the work-up process (Scheme 17.9).

R

2

R

1

R

3

H3C NH R

4

CHO R

2

Toluene/ 6M HCl reflux, 2h

R

1

R

3

N

Scheme 17.9

The double condensation of nitroarenes with substituted cinnamyl phenyl sulfones in the presence of DBU/silane or DBU/Lewis acid is a procedure that exploits the opposite polarity used in the Skraup reaction (Scheme 17.10) [48]. SO2Ph

SO2Ph DBU, BTMSA

+ NO2

Ph

MeCN

N

Ph

Scheme 17.10

17.1.4.1.2 o-Acylanilines Plus Carbonyl Compounds Friedlander Synthesis and Related Processes o-Acylanilines condense with enolizable carbonyl compounds through a base- or acid-catalyzed process to give quinolines. The outcome of the condensation was found to be dependent on the type of catalyst used, with acid catalysis leading predominantly to formation of the thermodynamic product 37 and base catalysis giving mostly the kinetic derivative 38 (Scheme 17.11) [49]. One of the more common ways to synthesize quinolines is through the Friedlander synthesis and, as a result, several variations and improvements have been published for this reaction. For example, in the Friedlander synthesis of quinolines the use of bases such as 1,3,3-trimethyl-6-azabicyclo[3.2.1]octane (TABO) can lead to an increase in the overall yield and the regioselectivity of process. The reaction has been carried out using o-aminobenzaldehydes and unactivated methyl ketones to furnish the corresponding substituted quinolines in excellent yields and ratios (6 : 1) (Scheme 17.12) [50].

j1537

j 17 Six-Membered Heterocycles: Quinoline and Isoquinoline

1538

R CH3

H2SO4, AcOH HO

Reflux

CH3

CH3

CH3

N 37

R

CH3 O +

NH2

O

CH3

R CH3

KOH, EtOH 0ºC

O

CH3

N

CH2

38 Scheme 17.11

1.1 equiv TABO 1 0.05 equiv H2SO4 R

O

1

R

CH3

H 2

R

+

NH2

O

3

3

R

3

1

R

R

65-70ºC

2

R

N

+ 2

R

R

90-93%

R1=

Cl, Br R2= H, Br R3= n-Pr, CH2CO2Et

N

CH3

ratio (6:1)

Scheme 17.12

In the same way, the use of 2-aminobenzophenones and lactones has enabled a mild and scalable synthesis of 4-aryl-quinolin-2-ones (Scheme 17.13) [51]. Additionally, other Friedlander variations and improvements have been published for the synthesis of quinoline analogues that were regiospecifically functionalized on both the pyridine and benzo-fused rings [52, 53]. A new methodology has been described that employs ionic liquids as “green” solvents and involves o-acyl anilines and various ketones to produce the desired quinolines in high yields and under very mild conditions [54].

R

R

2

R R

O

1

NH2 Scheme 17.13

R

3

+

2

LiHMDS, THF

O O

0ºC-rt

R

3

1

O N H 65-96%

17.1 Quinoline

Wang et al. have reported a solvent-free method for the Friedlander quinoline synthesis; this involved the reaction of o-acyl anilines with various b-ketoesters, using p-TsOH and microwave conditions (Scheme 17.14) [55]. R

O R NH2

CO2Et

1

+

O

R

1

CO2Et

p-TsOH, Mw 15-60 s N

2

R

2

Scheme 17.14

In addition to this work, the same authors reported a water-mediated Friedlander quinoline synthesis, in this case using hydrochloric acid and conventional heating [56]. A direct preparation of selectively protected derivatives of 3-hydroxyquinoline-2carboxylates 39 was discovered in a modified version of this process, which employed the readily accessible O-methyloxime 40 (Scheme 17.15) [57].

R

1

R

2

O

OBn H

+

NH2

R

1

b) NaH CO3, CH3I R

2

a) KOH, EtOH N OCH3

CO2Et

OBn N

CO2CH3

39

40 Scheme 17.15

Yus et al. [58] have reported a Friedlander synthesis of polysubstituted quinolines 41 under solvent-free conditions, using in this case RuCl2(dmso)4 (Scheme 17.16). 2

O 1

R

2

R

+ NH2 HO

4

R

t-BuOK, Ph2CO

3

R

R

RuCl2(dmso)4

100 ºC, 48 h

4

R

1

R

N

3

R

41, 65-99%

Scheme 17.16

Various other environmentally friendly strategies or methods that utilize mild conditions for the preparation of quinoline derivatives by Friedlander synthesis have also been reported [59–63]. A modification of the Friedlander synthesis of quinolines has been published for the conversion of o-nitrobenzaldehydes into quinolines in the presence of ketones or aldehydes. This process occurs through a concomitant nitro reduction in the presence of SnCl2/ZnCl2 [64] or, alternatively, in the presence of iron and a catalytic amount of HCl [65].

j1539

j 17 Six-Membered Heterocycles: Quinoline and Isoquinoline

1540

A modified version of this strategy has been reported in which the formyl group is introduced in situ by directed ortho-metallation onto a N-tert-butoxycarbonylanilide 42 (Scheme 17.17) in the presence of s-BuLi and DMF. The addition of an enolizable carbonyl compound furnished the corresponding substituted quinoline derivative 43 [66]. CHO

a) s-BuLi

NH t CO2Bu

b) DMF NH t CO Bu 2 42

a) PhCH2CHO

Ph

b) KHSMDA N 43

c) NH4Cl

Scheme 17.17

The use of organometallic reagents has also been successful in a modified version of this approach. Thus, 2-aminobenzyl alcohol was oxidatively cyclized with various ketones in the presence of several Ru catalysts to afford 2-substituted quinolines in good yields [67]. Other variations of the process related to the Friedlander synthesis have also been reported. For example, cyclization of Schiff base 45, derived from 2-(trifluoromethyl) aniline and a methyl naphthone, mediated by lithium 2-(dimethylamino)-ethylamide 44 (Scheme 17.18), furnished a series of substituted 2-(2-naphthyl)quinolines designed to target triplex DNA [68].

CF3

CF3

CH3

+ O NH2

H3C

N CH3 44 THF

NHLi

HN

N 45

OR CH3 N CH3

CH3

OR

N OR

Scheme 17.18

The reaction of a-aroylketene dithioacetals with esters of o-aminobenzoic acid under different conditions afforded quinoline and quinolone derivatives [69], whereas silylketene dithioacetal 46 (Scheme 17.19) reacted with 2-aminobenzaldehyde in the presence of a Lewis acid to produce quinoline 47 [70]. A one-pot quinoline synthesis has also been described from 2-aminobenzyl alcohol and carbonyl derivatives, using ruthenium-grafted hydrotalcite as the heterogeneous catalyst. In this approach molecular oxygen was used for the oxidation of the ruthenium species [71]. In a project devoted to the a-alkylation of ketones by alcohols

17.1 Quinoline

j1541

Si(CH3)3 BF .OEt 3 2

CHO +

EtS

NH2

46

SEt

N EtS + SEt H2

SEt

N H

SEt N 47, 40%

SEt

Scheme 17.19

in the presence of [Ru(dmso)4]Cl2, Yus et al. found that the reaction between 2-aminobenzyl alcohol and aryl alkyl ketones gave 2,3-disubstituted quinoline derivatives in good yields [72]. 17.1.4.2 Other Processes 17.1.4.2.1 From Ynones, Enones, and Related Substrates: Formation of Bond 1–2 Ynones and related substrates are frequently used as starting materials for quinoline compounds. For example, a,b-ynone derivatives 48 (Scheme 17.20) can be converted into 2,4-disubstituted quinolines through tandem nucleophilic addition– annulation reactions [73]. O R

Nu NuNO H2

NH2

48

Nu

H R

N

R

Scheme 17.20

In a related study, the synthesis of functionalized 4-alkylquinolines was developed using electrogenerated carbanions derived from nitroalkanes. In this approach, the desired 4-alkylquinolines were prepared through a sequential alkylation/heterocyclization of a,b-ynone derivatives 49 (Scheme 17.21). This method avoids the use of metal and base catalysts and is performed under solvent-free conditions [74]. NO2

H3C

O

electrolysis H3C

-

NO2

F

H3C

F + F

Scheme 17.21

NO2

OCH3

NH2

49

F

H NO H2

NO2

H3C F N

O CH3

F

H3CO

j 17 Six-Membered Heterocycles: Quinoline and Isoquinoline

1542

When the o-nitrochalcones 50 (Scheme 17.22) were treated with low-valent titanium (prepared from TiCl4 and Sm powder in THF), the intramolecular reductive coupling products were obtained in moderate yields [75]. Similar results were obtained starting from substituted o-nitroacrylonitriles [76]. O 1

R

4

3

2

R

R

R NO2

Sm/TiCl4/THF RT

1

3

R

2

R

50

R N

4

R

54-72%

Scheme 17.22

Comparable results have been obtained by Barros and Silva [77] in the preparation of 2-(2-hydroxyaryl)quinolines from 20 -hydroxy-2-nitrochalcones induced by stannous chloride in an acidic medium or ammonium formate/Pd–C in methanol. The development of environmentally friendly methods that exploit these approaches has attracted considerable attention. For example, Ahmed and van Lier have prepared 2,3-dihydroquinolin-4-ones 51 (Scheme 17.23) under solvent-free and thermal conditions starting from 2-aminochalcones supported on silica gel and TaBr5 as a catalyst [78]. A similar process has been reported by Kumar and Perumal [79] on using microwaves irradiation. O

O Ar 1

R

NH2

TaBr5-SiO2 140-150 ºC, 3-5 min

1

R

N H 51

Ar

Scheme 17.23

Baker’s yeast reduction of o-nitrocinnamaldehydes affords quinolines directly [80]. Similarly, other o-nitrocinnamic derivatives undergo reduction of the aromatic nitro group followed by cyclization with Zn in near-critical water at 250  C [81]. The reaction of the Baylis–Hillman adducts of o-nitrobenzaldehydes 52 and trifluoroacetic acid at 60–70  C gave unexpected cyclization products 53, 3-ethoxycarbonyl-4-hydroxyquinoline N-oxide derivatives, in good to moderate yields [82]. However, compounds 52 furnished 3-carboalkoxyquinolines 54 by acylation with AcCl and cyclization by carbon monoxide, catalyzed by [Cp Fe(CO)2]2 [83], or 2-quinolones 55 by treatment with iron in acetic acid (Scheme 17.24) [84]. In a related study, reported by Batra et al. [85], the synthesis of highly functionalized quinolines, derived from Baylis–Hillman adducts, was accomplished using SnCl2 to mediate tandem reactions. As part of ongoing efforts to develop methods for the generation of quinoline libraries, titanium alkylidene reagents 56 have been treated with resin-bound esters

17.1 Quinoline

OH CF3CO2H R

CO2R

1

60-70ºC

+

N O

OH R

CO2R

1

52

2

53

2

NO2

OH

OAc

AcCl/py R

2 CO2R [Cp*Fe(CO)2]2 1 R CO 6atm NO2 150ºC Fe/AcOH 39-89%

1

71-99%

R

CO2R

2

N 54

OAc

1

O N H R1=H, R2= Me, 71% 55 Scheme 17.24

followed by acid-mediated cleavage to give arylammonium salts (Scheme 17.25). Oxidation with MnO2 gave quinolines of high purity and in moderate yields [86]. TiCp2 O O

O

a) R

R

1

1

R MnO 2

56 N(TMS)Boc

2

+

b) 10%TFA

R

NH3

2

TFA-

R

N

2

R

1

Scheme 17.25

The synthesis of quinoline derivatives using metal-catalyzed, and particularly palladium-catalyzed, chemistry has become of interest for this type of approach. For example, acetylenic acetals (e.g., 57, Scheme 17.26) or ketals have been reacted with various aryl or vinyl halides in a palladium-catalyzed process to afford alkenes 58 OEt OEt

OEt NH 57 Ac Scheme 17.26

DMF

R

OEt

R-X, Pd(OAc)2 HN

R

Ac

58

N 59

j1543

j 17 Six-Membered Heterocycles: Quinoline and Isoquinoline

1544

in good yield. Cyclization to quinolines 59 was performed in the presence of TsOH/EtOH [87]. A related process has been reported in which a palladium-catalyzed hydrogenation/heterocyclization gave the quinoline derivative 60 (Scheme 17.27) [88]. O R

Pd(OAc)2-L2

NH2

N

HCO2H/R13N

R

60

Scheme 17.27

In a similar way, o-iodoanilides reacted with terminal acetylenic carbinols in a palladium-catalyzed process to yield o-substituted anilides, the starting materials for the synthesis of quinoline or 4-quinolone derivatives [89]. In another metal-catalyzed quinoline synthesis NiBr2(dppe) was used to catalyze the reaction of o-iodoanilines with aroylalkynes in acetonitrile to give 2,4-disubstituted quinolines in good yields [90]. 17.1.4.2.2 From Alkynes, Propargyl Amines, and Related Systems: Formation of Bond 4–4a Internal and terminal alkynes have been coupled and cyclized to N-aryl trifluoroacetimidoyl chlorides 61 (Scheme 17.28) in the presence of catalytic Rh(I) complexes to afford 2-trifluoromethylated quinolines 62. Various alkynes were applied to this cyclization coupling and high levels of regioselectivity were achieved [91]. 1

R

1

R N CF3

+ Cl 61

2

R

3

R

base, toluene, 110ºC

3

1

R

N

[RhCl(cod)] 2 phosphine ligand CF3

Rh(III)Cl 2

R

3

R

2

R

R

N 62

CF3

Scheme 17.28

N-(1,1-Disubstituted propargyl)anilines can be cyclized to 2,2-disubstituted 1,2dihydroquinolines by heating under reflux in toluene containing CuCl (Scheme 17.29) [92]. A new and general method has been developed for the preparation of 2-quinolinones by intramolecular hydroarylation of alkynes. Various aryl alkynanilides undergo rapid intramolecular reaction at room temperature in the presence of a

17.1 Quinoline

R N H

2

R

R

CuCl

1

R

1

PhCH3, refl.

N H

R 2

R

Scheme 17.29

catalytic amount of Pd(OAc)2 in a mixed solvent containing trifluoroacetic acid. This process affords 2-quinolinones in moderate to excellent yields with turnover numbers (TONs) of more than 1000 with respect to Pd (Scheme 17.30) [93]. R

R

Pd(OAc)2

1

R

N H

O

1

R

N H

TFA/CH2Cl2

O

50-91% Scheme 17.30

Campos et al. have reported the synthesis of 3-haloquinolines 63 by irradiation of amino haloalkenimines 64 (Scheme 17.31) [94]. R X Ph

R NH

hν, THF

NH Ar

X

1

R N

Ph

63

64 Scheme 17.31

Variations of the Friedel–Crafts reaction are also of interest for the synthesis of quinolines. For example, Saito et al. [95] have described a novel method to synthesize a quinoline backbone by incorporating allenyl cations into a catalytic intramolecular Friedel–Crafts reaction. The initial products were isomerized and aromatized upon treatment with acid and base, respectively, to give quinoline derivatives (Scheme 17.32).

Ph Ph

N Ts Scheme 17.32

Ph

C LA

X

Ph

Ph

Ph OTMS

a) acid

X N Ts

b) base

X N

j1545

j 17 Six-Membered Heterocycles: Quinoline and Isoquinoline

1546

Quinolines substituted in the 3-position by an iodo- or phenylseleno-group are readily prepared by an electrophilic cyclization from propargylic anilines with appropriate electrophiles under mild reaction conditions. This method can be followed by palladium-catalyzed substitution reactions to provide further elaboration of the 3-position of the quinoline core (Scheme 17.33) [96]. F

N Ms

-78ºC 80%

I

I NaOH, EtOH

ICl, CH2Cl2

Ph

F

F

F

N

50ºC

N Ms

92%

B(OH)2

PdCl2(PPh3)2

Ph

K2CO3, DMF-H2O N

100ºC 73% Scheme 17.33

In a similar way, Hajra et al. have prepared a series of tetrahydroquinoline derivatives from allyl anilines using a Lewis acid-catalyzed halocyclization [97]. 17.1.4.2.3 From Oximes, Azadienes, and Related Derivatives: Formation of Bond 1–8a Oxime derivatives are also suitable intermediates for the synthesis of quinolines. Several papers concerning intramolecular cyclization involving some classes of oximes and oxime derivatives have been published [98–103]. Scheme 17.34 shows an example of this methodology. NOR O O

CH3

Bu4NReO4, CF3SO2H

O

chloranil

O

N

CH3

Scheme 17.34

Campos et al. [104] have reported that the irradiation of azadiene 65 in the presence of HBF4 furnishes 4-aminoquinoline derivatives in excellent yields (Scheme 17.35). Quinoline derivatives have been prepared by Quideau et al. [105] from nitrogentethered 2-methoxyphenols. Oxidative acetoxylation in the presence of phenyl iodide (III) diacetate, followed by an intramolecular Michael addition, gave the desired quinoline derivatives (Scheme 17.36).

17.1 Quinoline

HN

Ar

HN CH3

CH3

HBF4, Et2O, MeOH hν, 25 ºC, 5 min 95%

Ph

HN

Ar

65

N

Ph

Scheme 17.35

O

O a) CO2/ Et3N, TIPS-Otf

OCH3

O

TBAF

O OAc OCH3

b) H2, Pd/C c) Phenyl iodide (III) diacetate

OBn

NH2

O

NH2

O

O OCH3 N

80%

OH

Scheme 17.36

17.1.4.2.4 Other Processes Involving Metal-Catalyzed Methods Palladium-catalyzed coupling of o-allyl or o-isopropenyl-N-tosylanilides with vinyl halides or triflates produces dihydroquinolines (Scheme 17.37) [106–110]. CH3

CH3

CH2 NH Ts

+

Br

R

Pd(AcO)2, Na2CO3 Bu4NCl/ DMF

N Ts

R

Scheme 17.37

A palladium-mediated multicomponent domino reaction involving ethynylarylamines 66, aryl iodides, primary amines, and carbon monoxide has been reported to give various substituted quinolines (Scheme 17.38) [111]. Intramolecular addition of anilines to methylenecyclopropanes proceeds smoothly in the presence of catalytic amounts of Pd(PPh3)4 to afford the corresponding hydroamination products, which ultimately gave quinoline derivatives 67 (Scheme 17.39) [112]. The Buchwald–Hartwig palladium-catalyzed aryl-amino coupling reaction has also been applied successfully to the synthesis of functionalized N-phenyl 2-quinolinones [113]. Additionally, aryl–N-bond formation can be used to prepare quinoline

j1547

j 17 Six-Membered Heterocycles: Quinoline and Isoquinoline

1548

1

HN I R + R1 NH 2

+ NH2

+

CO

R

Pd(OAc)2/P(o-tol)3 THF

66

N

R

Scheme 17.38 2

2

1

R

R

1

R

Pd(PPh3)4

R

N H 67

P(O)n-Bu3 120ºC 70-86%

NH2

Scheme 17.39

derivatives by intramolecular coupling of amines or amides with an aryl bromide [114]. A successful ruthenium-catalyzed oxidative coupling and subsequent cyclization has beenreported between 2-aminobenzylalcohol and secondaryalcohols inthe presenceof KOH and 1-dodecene to give 2-substituted quinolines (Scheme 17.40) [115]. [Ru], KOH CH3 OH + HO Ph dioxane, 80ºC NH2 1-dodecene

N

Ph

Scheme 17.40

Functionalized zinc reagents – derived from readily available o-iodoaniline derivatives and obtained by a straightforward iodine–magnesium exchange followed by transmetalation with zinc bromide – can be used to prepare a wide range of nitrogen heterocycles. For example, treatment of the benzylimine-protected iodoaniline 68 in the presence of a Grignard reagent and subsequent Negishi cross-coupling leads to the quinoline derivative 69 (Scheme 17.41) [116]. a) i-PrMgBr

I

EtO2C

b) ZnBr2

N 68

EtO2C

c) Pd(dba)2 Ph

OTf CO2Et

Scheme 17.41

N O H 69 74%

17.1 Quinoline

j1549

Various diallylanilines have been shown to undergo cobalt-carbonyl-catalyzed rearrangement to quinolines, with the diallylaniline acting as a source of the allyl group in these transformations (Scheme 17.42) [117]. CH2

CH3

Co2(CO)8

N

CO

N CH3

CH2 Scheme 17.42

InBr3 promotes the dimerization of 2-ethynylaniline derivatives 70 to give polysubstituted quinolines in good yields (Scheme 17.43) [118].

R R

1

InBr3/MeOH

2

70

NH2

R

1

R

2

CH3 R

N

56-89%

H2N

1

R

2

Scheme 17.43

o-Halo-N-trifluoroacetylanilines 71 (Scheme 17.44) undergo sequential Wittig and Pd reaction under a CO atmosphere to supply 4-quinolone derivatives [119, 120]. O X

R

N H 71

R

O CF3

X

CO2Et Pd(OAc) /Ph P 2 3

N H

CF3

R

CO

CO2Et N H

CF3

Scheme 17.44

3-Aryl 2-quinolinones have been prepared by a convergent one-pot cascade sequence involving palladium-catalyzed cross-coupling reactions of 2-bromobenzaldehydes with phenylacetamides in the presence of caesium carbonate and xantphos (Scheme 17.45). Final products 72 were obtained by cyclization of the resulting amide intermediate [121]. O

CHO Br

Scheme 17.45

H2N

Ph

Ph

Pd2(dba)3/Xantphos Cs2CO3

N H 72

O

j 17 Six-Membered Heterocycles: Quinoline and Isoquinoline

1550

A novel and efficient route to 4-trifluoromethyl-substituted quinoline derivatives through the Zn(II)-mediated alkynylation/cyclization of o-trifluoroacetylanilines 73 has been described by Jiang et al. (Scheme 17.46) [122]. CF3

CF3

H

ZnX2

O

1

R

73

NH2

1

R

N

Et3N

2

R

CF3

Scheme 17.46

Palladium(0)-catalyzed termolecular queuing processes involving oxidative addition to o-iodoanilides followed by low-pressure carbonylation, allene insertion, and capture of the resulting p-allyl palladium(II) species by the internal N-nucleophile affords 3-methylene quinolones in good yields (Scheme 17.47) [123].

O I NHTs

Pd(PPh)3

Pd[II]

CO, K2CO3 PhMe, 45 ºC

CH2 C CH2

NHTs

O

O

CH2 Pd[II]

N Ts

NHTs

Scheme 17.47

Gold-catalyzed intramolecular hydroarylation of allenic anilines offers an efficient route to dihydroquinoline derivatives under mild reaction conditions. The reaction has been carried out in the presence of [2-(di-tert-butylphosphino)-1,10 -biphenyl]gold (I) chloride (74) and silver(I) triflate (Scheme 17.48) [124].

R

C

P(tBu)2AuCl

Au(I)AgOTf

R dioxane or AcOH N rt-reflux CO2CH3

N CO2CH3

74

Scheme 17.48

In the same way, Che and coworkers have devised an efficient method to prepare substituted 1,2-dihydroquinolines and quinolines by Au(I)-catalyzed tandem hydroamination–hydroarylation under microwave irradiation [125]. The first enantioselective synthesis has been reported of the martinelline core, a new alkaloid (12) that shows antibacterial activity as well as an affinity for adrenergic, muscarinic, and bradykinin receptors, [21c]. The synthesis proceeded in seven steps and gave 23% overall yield through a modification of the palladium-catalyzed carbonylative cyclization procedure reported by Negishi.

17.1 Quinoline

j1551

17.1.4.2.5 Cycloaddition Processes Diels–Alder and Aza-Diels–Alder (Povarov) Reactions The preparation of quinoline derivatives by cycloaddition processes is an important method for the synthesis of this class of compounds. Several cyclization/elimination reactions that formally correspond to Diels–Alder or hetero-Diels–Alder cycloaddition could proceed by a SEAr mechanism and are usually catalyzed by Lewis acids. For example, the [4 þ 2] cycloaddition reaction of N-arylaldimines 75 is effectively catalyzed by ytterbium(III) triflate to give quinoline derivatives (Scheme 17.49) [126]. OEt Yb(OTf)3

CH2

R N

Ph

MeCN, RT

R N

Ph

75 Scheme 17.49

Pyrrolo[3,4-b]quinolines can be formed through the coupling of anilines with N-propargylic-substituted heterocyclic aldehydes in the presence of mild Lewis acid catalysts. The coupling proceeds through sequential imine formation and a formal intramolecular aza-Diels–Alder (Povarov) reaction. This approach has been applied in a total synthesis of luotonin A and a formal synthesis of camptothecin (Scheme 17.50) [19a].

+ NH2 R2

O

H

X

N 1

R 76

Dy(OTf)3 O

O

N

N X

1

2

R

N N

R

Scheme 17.50

Menendez and colleagues [127] have reported another aza-Diels–Alder reaction between aromatic imines and methacrolein dimethyl hydrazone in the presence of InCl3. The treatment of azadiene 77, obtained in situ from the carbonate 78, in the presence of dienophiles produced tetrahydroquinolines 79 (Scheme 17.51) [128]. Reaction of the same azadiene with C60 gave a quinoline-fused fullerene [129]. Hetero-Diels–Alder reaction of 1,2,3-benzotriazine in the presence of dienophiles produces quinoline derivatives after extrusion of N2. 1,2,3-Benzotriazine intermediate 80 can be obtained by oxidative rearrangement of 1-aminobenzotriazole (Scheme 17.52) [130]. Liu and coworkers [131] have developed an efficient synthetic method for the preparation of 4-functionalized-quinoline derivatives 81. Ethynyl ketene-S,S-acetals 82 can react in a one-pot procedure with various arylamines and aldehydes under

O 1

R

X 2

R

j 17 Six-Membered Heterocycles: Quinoline and Isoquinoline

1552

OMe

CO2Et

O

N

N CO2Et

NH CO2Et

DCB, 180 ºC

EtO

O

77

78

OMe

79

Scheme 17.51

Ph N

Ph

N N

N NH2

N

N N

N

-N2

80

- HN

Scheme 17.52

mild conditions through consecutive arylimine formation, regiospecific aza-Diels–Alder (Povarov) reaction, and reductive amination (Scheme 17.53). S S R

S

1

NH2

+

R

S

R +

R2-CHO

82

CF3SO3H

R

1

N 81

CH2Cl2, RT

CH3

Scheme 17.53

Takasu and coworkers [132], using cascade and one-pot reactions, have carried out an inverse electron demand hetero-Diels–Alder reaction and oxidative aromatization to synthesize substituted quinolines starting from aryl aldimines and allylsilanes (Scheme 17.54). The construction of hetero-polycyclic aromatic compounds has been addressed by intermolecular cycloaddition reaction of a dihalogenated heteroarene with zircona"Si" R

"Si"

"Si" CH2 Tf2NH

1

N Scheme 17.54

Ar

R

Tf2NH

1

N H

Ar

imine or DDQ

R

1

N

Ar

17.1 Quinoline

j1553

cyclopentadiene. For instance, 2-bromo-3-iodopyridine was reacted in the presence of a zirconacyclopentadiene, CuCl, and 1,3-dimethyl-3,4,5,6-tetrahydro-2-pyrimidinone (DMPU) to give the corresponding quinoline in 85% yield (Scheme 17.55) [133]. Et

Et

I

Et

+ Cp2Zr N

Br

Et

CuCl

Et DMPU 50ºC, 3 h

Et

Et

N Et 85%

Scheme 17.55

Other Pericyclic Processes Enolizable vinyl quinone mono- and diimide substrates 83 (Scheme 17.56) yield protected 6-aminodihydroquinolines by thermal 6p-electrocyclization. Aromatization provides the corresponding quinolines in quantitative yields [134]. OCH3

O NR R

1

R NR

K2CO3

electrocyclic closure

NR

enolization

O

OCH3

O

83

H2SO4 OCH3

N O

1

NHR

NHR

RHN

DMF

RN R

1

OCH3

H2N OCH3

N

RT

O

R= SES, trimethylsilylethanesulfonyl Scheme 17.56

A series of substituted 3H-quinolin-4-ones have been synthesized from N-{[2(alkyl- or arylthio)carbonyl]phenyl}ketenimines 84 by means of a [1,5]-sigmatropic migration followed by 6p-electrocyclic ring closure (Scheme 17.57) [135].

1

O

R

2

N 84 Scheme 17.57

SR

[1,5]-SR2

C

R

3

C Ph

1

R

C N

O 3

R

1

Ph

O

6π-ERC R

3

R

Ph N

j 17 Six-Membered Heterocycles: Quinoline and Isoquinoline

1554

Indenoquinoline has been obtained by a formal [4 þ 1] cycloaddition process from o-phenylprop-1-ynyl benzoisonitrile in the presence of t-BuOK/t-BuOH. The starting material was prepared in two steps from o-iodoformanilide. However, only poor yields were obtained when the method was applied to other related systems (Scheme 17.58) [136].

H N I

+

N

O

C N

t-BuOK/ t-BuOH

H

rt 51%

Scheme 17.58

N-Methylformanilides 85 reacted with various electron-rich alkenes in POCl3 solution to supply N-methylquinolinium salts in good yields. The mechanism of the cyclization was elucidated and was shown to involve an electrocyclic p6s process (Scheme 17.59) [137].

R

1

H

POCl3

R

R

1

O N CH3 85

+ Cl N CH3

EDG

3

R

2

R

1

R

3

R

2

N+ CH3

Scheme 17.59

17.1.4.2.6 Radical Reactions As far as radical chemistry is concerned, a series of annulated quinolines are readily available from thioamides, thiocarbamates, or thioureas in the presence of tris(trimethylsilyl)silane (TTMSS) and hn irradiation (Scheme 17.60) [138].

S N H

TTMSS X

Ph-H, hv

N

X

44-88% Scheme 17.60

The intramolecular 6-endo-dig cyclization of an aryl bromide onto a silylated acetylene using Bu3SnH/AIBN provides dihydroquinoline derivatives (Scheme 17.61) [108].

17.1 Quinoline

SiMe3

Br

Bu3SnH/AIBN

N H

N

N H

Ac

N

Ac

Scheme 17.61

Similarly, the cyclization of an aryl radical onto a pyrrole allows the synthesis of either the spiropyrrolidinyloxindole or the pyrrolo[3,2-c]quinoline skeleton, depending on the nature of the protecting group at the N-pyrrole atom [139]. Toddaquinoline (10) has been obtained by Harrowven and coworkers by a radical cyclization onto a pyridine ring [16a] and by a cobalt-mediated radical addition to a pyridine derivative [16b]. Free radical cyclization reactions of alkylsulfonyl- and alkylthio-substituted aromatic amide derivatives have been described. These radicals undergo either six- or five-membered ring cyclization onto the aromatic ring and provide synthetically useful methods for the preparation of quinolinones among other heterocyclic derivatives [140]. A formal synthesis of martinelline (12) has been accomplished by Naito and coworkers using two types of radical reactions as the key steps [141]. Schmittel et al. have reported that the thermolysis of enyne carbodiimides 86 (Scheme 17.62) produces the biradical intermediates 87, which can evolve to quinoline derivatives 88 [142, 143].

.

R Ph N

86

R

. Ph

N

Ph

C

R N 88

Ph

87

Ph Ph

Scheme 17.62

17.1.4.2.7 Ring Transformations of Heterocycles Leading to Quinolines An efficient and practical method for the preparation of 4-hydroxyquinolinone esters and amides has been developed by Beutner and coworkers. Compounds 89 were synthesized in good yields and on a kilogram scale from substituted isatoic anhydrides (Scheme 17.63) [144]. a) R2-Br DIPEA DMAc

O R

O

1

N H

Scheme 17.63

O

b) CH2(CO2Me)2 NatBuO DMAc

OH R

O OCH3

1

N 2 R 89

O

j1555

j 17 Six-Membered Heterocycles: Quinoline and Isoquinoline

1556

Previously, in a related study, Igglessi-Markopoulou et al. [145] described an efficient route to 3-aryl-4-hydroxyquinolin-2-ones through cyclization of the b-ketoesters produced by reaction of arylacetic ester enolates with 2-alkoxy-3,1benzoxazin-4-ones. A new one-step methodology has been introduced for the synthesis of quinoline 2,4-diones. The reaction is based on a modification of the Mukaiyama aldol condensation and makes use of the high reactivity of benzoxazin-4-ones 90 in the presence of ketene silyl acetals 91 (Scheme 17.64) [146]. OTMS

H3C

O

O

CH3 CH3

H3C 91 OCH3

O R

N 90

O

N H

TiCl4

Scheme 17.64

Substituted 2,4-quinolines can be obtained by a novel synthesis that involves cyclization and thermal extrusion of sulfur. The method starts from ortho-thioaniline (92) and acetylenic ketones 93 and proceeds through the benzo[b][1,4]thiazepine 94 (Scheme 17.65) [147]. The same methodology was applied for the preparation of enantiomerically pure 2,4-disubstituted quinoline derivatives [148]. EtO

OEt

EtO

a) THF

SH NH2

O

92

CF3

N

b) PPTS

94

93

CHO

OEt

S

a) PhCH3, refl. b) HCO2H

CF3

N

CF3

Scheme 17.65

17.1.4.2.8 Other Notable Methods A convenient method for the preparation of highly functionalized quinolines in the presence of Vilsmeier’s reagent has been reported (Scheme 17.66) [149].

1

2

R

2

O

3

R

1

Ar

R

4

R

N H

Scheme 17.66

SMe

Ar

R

DMF/POCl3 R 80ºC

O

3

R

4

R

N

SMe

17.1 Quinoline

j1557

A microwave preparation of 2-quinolinone derivatives obtained by cyclization of the corresponding o-vinyl-substituted isocyanate has been described. The method provides access to cryptotackieine (13) and cryptosanguinolentine (14) [23]. A new method for the synthesis of phenanthridine and related compounds has been developed using the condensation of o-phenylaniline and its homologues with cyclic ketones under hydrothermal conditions (Scheme 17.67). The method has been extended to the reaction of 2-isopropenylanilineHCl to obtain quinoline derivatives.

+

NH2

+ 250ºC 24 h

O

N

C5H11

N 84% ratio (86:14)

Scheme 17.67

The product yields and side product distributions were found to be strongly dependent on the reaction temperature [150]. A novel metal free approach for the synthesis of substituted quinolines has been reported from imines and enolizable carbonyl compounds under aerobic conditions (Scheme 17.68). A catalytic amount of HCl in DMSO activated the carbonyl compounds, which reacted with benzylidenanilines to supply quinolines 95 [151]. This simple and practical method is applicable on a large scale. Other related metalfree conditions in the presence of iodine have also been communicated [152]. 5

3

R

O

H 2

N

R

1

R

+

5

R

4

R

R

3

4

R

HCl (5 mol %) R DMSO

2

R

N 95

1

R

Scheme 17.68

Cyclohexanones have been converted into 8-chloroquinolines and other quinoline or dihydroquinoline derivatives through a series of reactions involving imination, a-alkylation with N,N-disilyl-protected v-bromoamines, transimination, a-chlorination of the resulting bicyclic imines, dehydrochlorination, and/or dehydrogenation [153]. A versatile alternative approach to the synthesis of 2-quinolones has been developed by Arcadi and coworkers that involves galvanoplastic electrolysis and subsequent intramolecular cyclization of alkynes and malonyl moieties [154]. Ogura and coworkers found that the reaction of 2-(arylamino)-1-(methylthio)-1tosylethenes 96 (Scheme 17.69) with hydrogen iodide in refluxing toluene gave 3tosyl-2-(tosylmethyl)quinoline derivatives 98 in good yields. In this reaction,

C5H11

j 17 Six-Membered Heterocycles: Quinoline and Isoquinoline

1558

MeS 1

Ts

R

Ts

Ts

HI

1

1

R

R

Ts

N

N H 97

N H 96

40-87% 98

Scheme 17.69

hydrogen iodide not only reductively removes the methylthio group but also serves as a protic catalyst for the subsequent dimeric cyclization of 97 to give the quinoline derivatives 98 [155]. Movassaghi et al. [156] have described a flexible procedure for the synthesis of polysubstituted quinolines by direct condensation of aryl amides and p-nucleophiles (Scheme 17.70).

O H3CO

O N H

O

O

O N + c-Hex

O Tf2O, 2-ClPy

O

N

H3CO

CH2Cl2, -78 to 0ºC

N

c-Hex

Scheme 17.70

Finally, several examples of intramolecular Schmidt reactions of azides and carbocations have been reported for the synthesis of quinoline and other heterocyclic derivatives. In this way, gephyrotoxin, a naturally occurring substance isolated from the secretions of the poison-dart frog Dendrobates histrionicus, was prepared [157]. 17.1.5 General Reactivity: Useful Reactions 17.1.5.1 Addition to Nitrogen As in pyridine, the nitrogen in quinoline undergoes protonation, alkylation, acylation, N-amination [158], and with peroxyacids or in the presence of other oxidative systems, such as O2/2-methylpropanal [159], oxidation to the N-oxide. These reactions involve donation of the nitrogen lone pair to electrophiles. The pKa for N-quinoline is 4.94, which shows a similar basicity to pyridine. 17.1.5.2 Reactions with Electrophilic Reagents at Carbon 17.1.5.2.1 Nitration In contrast to pyridine, and according to the above comments, SEAr reactions occur on the carbocyclic ring, preferentially on the more activated positions of the benzene ring, with a positional selectivity in the order C8 > C5 >
other positions. In general, the SEAr process occurs preferentially through the conjugate acid, that is, quinolinium ion, which prevents attack on the heterocyclic

17.1 Quinoline

j1559

ring. Nitration takes place in the presence of a nitrating agent under mild conditions: mononitrations occur exclusively at the C5 and C8 positions to furnish compounds 99 and 100, respectively (Scheme 17.71). NO2 HNO3, H2SO4 N

+ N

25ºC

N NO2 100

99 Scheme 17.71

17.1.5.2.2 Sulfonation Sulfonation of quinoline produces different products depending on the reaction temperature. At 90  C the 8-sulfonic acid is formed predominantly; raising the temperature increases the proportion of 5-sulfonic acid [1]. Reactions at higher temperatures produce other isomers under thermodynamic control. 17.1.5.2.3 Halogenation As expected, quinoline in the presence of Br2 in H2SO4 yields 5- and 8-monosubstituted products by attack of the halogen on the corresponding salt. However, the introduction of a halogen atom onto the heterocyclic ring occurs through a non-electrophilic process, by reaction of quinoline hydrochloride with excess Br2 and catalytic Br– in PhNO2, to supply the 3-bromo derivative (Scheme 17.72) [160].

Br Br2, PhNO2 +

N H

N H

Br

Br H

Br

+

N H

Br H Br H

Br N Scheme 17.72

17.1.5.2.4 Substitution in Quinolines Bearing Activating Nitrogen and Oxygen Substituents Electrophilic substitution at carbon on the heterocyclic ring can be effected more readily on oxy- and aminoquinolines than in quinoline itself, and this reaction generally occurs ortho and para to the activating functionality. For example, acylation of 4-dimethylaminoquinoline with 1-trifluoroacetyl-4-dimethylaminopyridinium trifluoroacetate (101) proceeded cleanly to give 3-trifluoroacetyl-4-dimethylaminoquinoline, which can undergo N–N exchange with various amines to furnish 3-trifluoroacetyl-4-aminoquinolines in excellent yields (Scheme 17.73) [161].

Br N H

Br H

j 17 Six-Membered Heterocycles: Quinoline and Isoquinoline

1560

H3C

H3C

N

CH3

N

CH3

N

CF3CO2+

N 101 COCF3

H3C

N

CH3

R

COCF3 R1R2NH

N

Xylene, reflux

1

N

R

2

COCF3 N

Scheme 17.73

17.1.5.3 Reactions with Oxidizing Reagents Oxidation of the quinoline system can affect the pyridine ring, the carbocyclic ring, or both. As a result, oxidation can supply the quinoid derivative or the dihydrodiol. In addition, alkyl derivatives can be converted into the corresponding carboxylic acids. Degradation of the benzene ring to generate pyridine dicarboxylic acids, in an alkaline potassium permanganate medium, can be considered the most common oxidative reaction [162]. A series of quinoline-bearing substituents on the pyridine ring have been oxidized electrolytically in sulfuric acids to the corresponding quinolinic acids [163]. Oxidation of 2- and 3-haloquinolines in the presence of either ozone/H2O2 or catalytic ruthenium tetroxide gave the corresponding 5- and 6-halopyridine, 2,3-dicarboxylic acids [164]. The conditions have been developed to oxidize 5,8-dimethoxy-2-methylquinoline to 2-methylquinoline-5,8-dione (102) using NBS, H2O, and H2SO4 without bromination (Scheme 17.74) [165].

O

OCH3 NBS/H2O/H2SO4 N OCH3

CH3 THF, RT

N O

CH3

98% 102

Scheme 17.74

The pyridine ring can be oxidized enzymatically to give various oxygenated derivatives. As part of an earlier study on the bacterial metabolism of bicyclic azaarenes using Pseudomonas putida, cis-dihydroxylation of quinoline was observed to occur at the carbocyclic ring to yield cis-dihydrodiols along with 3-hydroxyquinoline and anthranilic acid [166]. In contrast, hypervalent iodine reagents have also been used in the oxidative transformation of tetrahydro-derivatives into full aromatic quinoline derivatives [167]. In addition, tetrahydroquinolines undergo anodic oxidation with the incorporation of cyanide in the 2-position to supply 2-cyanoquinolines [168].

17.1 Quinoline

17.1.5.4 Nucleophilic Substitution Reactions As expected, nucleophilic substitution of quinoline occurs in the heterocyclic ring at the C2 and C4 positions. In general, SNAr reactions proceed more rapidly in quinoline than in pyridine because the fused benzene ring stabilizes the reaction intermediate. 17.1.5.4.1 Nucleophilic Substitution with Hydride Transfer Arylation and Alkylation Reactions These processes occur almost exclusively at the C2 position. In these cases the nucleophilic reagent is an aryl- or alkyllithium or a Grignard reagent. The reaction seems to proceed in two steps: Addition at the C2 position, to give a dihydroquinoline N-lithio 103 or N-magnesium salt, which can be hydrolyzed to furnish a 2-substituted-1,2-dihydroquinoline 104. This derivative can be handled and spectroscopically characterized but can also be oxidized in the presence of an oxidant to afford the full aromatic heterocycle (Scheme 17.75).

n-BuLi N

N + Li 103

Et 2O, RT

H n-Bu

H2O N H

H n-Bu

104

PhNO2 N

n-Bu

Scheme 17.75

Chichibabin Amination In a similar way to pyridine, the Chichibabin amination on quinoline proceeds with alkali metal amides in liquid ammonia. Quinoline first reacts with the amide to give the 2-amino-1,2-dihydroquinolinide ion (kinetic product), which subsequently rearranges to the more stable 4-amino-1,4-dihydroquinolinide ion (thermodynamic product) at higher temperatures. Thus, oxidative trapping of the quinoline adducts at different temperatures provides 2- or 4aminoquinoline [169]. Hydroxylation In contrast to pyridine, quinoline can be hydroxylated directly with potassium hydroxide at high temperature. The formation of 2-quinolone can be regarded as a SNAr process that proceeds with the evolution of hydrogen [170]. 17.1.5.4.2 Nucleophilic Substitution with Displacement of Good Leaving Groups The SNAr reactions of quinoline take place in the presence of leaving groups such as halogen when located at the C2 or C4 positions. The reaction works well with a wide range of charged or neutral nucleophiles. A novel synthesis of 4-quinolyl isothiocyanates from 4-chloroquinoline in the presence of silver thiocyanate in refluxing anhydrous toluene has been reported [171]. The method did not seem to proceed through a classical SNAr process but rather through a radical pathway.

j1561

j 17 Six-Membered Heterocycles: Quinoline and Isoquinoline

1562

17.1.5.5 Reactions with Bases C-Deprotonation of quinoline usually requires bases such as n-BuLi and this is not a preparative method. Simple lithioquinolines are generally prepared by metal– halogen exchange. However, the presence of ortho-directing substituents, such as chloro, fluoro, methoxy, methylthio, and various carboxamides, makes the process straightforward and such derivatives have been widely used [172]. 17.1.5.6 Reactions of C-Metallated Heterocycles Although Li–halogen exchange reactions are important methods for the preparation of lithioquinolines, the competitive nucleophilic addition at activated positions could constitute an additional problem. Consequently, in recent years several groups have devoted some of their effort to the development of selective methods for the preparation of lithioquinolines. For example, Queguiner and coworkers have reported methods for the selective exchange of lithium for bromide followed by electrophile quenching in the preparation of substituted quinolines at benzene ring positions [173]. Comins et al. [174] have reported a regioselective lithium–halogen exchange in 2,4-dibromoquinolines to furnish 2-bromo-4substituted derivatives. Additionally, Marull and Schlosser [175] have studied the functionalization of polyhalogenated quinolines through organolithium intermediates and used trimethylsilyl entities and iodo-substituents as the sole auxiliary substituents. In these cases, the organolithium intermediates could be generated and the protective groups removed without impairing the bromo-substituent present in the starting materials. A study of the direct lithiation of unprotected quinoline-carboxylic acids with lithium 2,2,6,6-tetramethylpiperidide (LTMP) has also been reported [176]. As far as magnesium derivatives are concerned, Knochel and coworkers [177] used halogen–metal exchange reactions to prepare a wide range of polyfunctionalized quinolines by regioselective magnesiation reactions using appropriate Mg reagents (Scheme 17.76). Br Br N

Br

Regioselective Br/Mg exchange

MgX N

Br

E+

E N

Scheme 17.76

The application of Pd, Zn, Cu, or Ni-mediated coupling reactions was shown to be particularly effective in most examples with quinoline derivatives. Several reports concern cross-coupling reactions and substitution reactions of halo-substituted quinolines. For example, Sonogashira conditions have been applied to 2-chloroquinoline and para-substituted phenylethynes to supply fluorescent compounds as blue–green emitters (Scheme 17.77) [178]. Alkynylation of 2-quinoline triflate with TMS-acetylene by Pd-catalyzed crosscoupling methods, and their application for a dynemicin A model, has been reported (Scheme 17.78) [179].

17.1 Quinoline

N

Cl +

R

PdCl2(PPh3)2, CuI

N

R

Et3N, THF, reflux

Scheme 17.77

+ N

H

TMS

"Pd" N

OTf

TMS

Scheme 17.78

Treatment of 5-iodoquinoline with bromoenoate 105 in the presence of Pd(OAc)2, tri-2-furylphosphine, norbornene, and Cs2CO3 provided benzoxepine derivatives. This methodology is based on a palladium-catalyzed aromatic substitution followed by an intramolecular Heck sequence (Scheme 17.79) [180]. EtO2C I

N

+

Br

O 105

CO2Et

O

Pd(OAc)2, TFP norbornene Cs2CO3 MeCN, 85 ºC

N 72%

Scheme 17.79

Strategies for controlling the regiochemistry of the addition reaction between organozinc reagents and 2,4-dichloroquinoline have been developed [181]. Similarly, the palladium-catalyzed carbonylation of quinolyl bromides and triflates has been described [182]. In the same way, the regiochemistry of the palladium-catalyzed carbonylation of 4,7-dichloroquinoline was evaluated [183]. Kappe et al. [184] have developed two general microwave methods for the synthesis of symmetrical heterobiaryls from 4-chloroquinolin-2-one in the presence of either Pd(0) or Ni(0). Buchwald et al. [185] have communicated a general and efficient copper-catalyzed method for the amidation of 3-bromoquinoline using copper iodide, a diamine ligand, and K2CO3. Margolis and coworkers [186] have reported a convenient alternative to the SNAr process for the formation of the C–N bond in 4-aminoquinolines, an approach that involves a Pd-catalyzed methodology starting from 4-haloquinolines. 17.1.5.7 Reaction with Reducing Agents Quinolines are reduced to 1,2,3,4-tetrahydroquinolines with zinc borohydride and dimethylaniline under sonication conditions [187] or with indium metal in

j1563

j 17 Six-Membered Heterocycles: Quinoline and Isoquinoline

1564

ethanol [188], NiCl22H2O–lithium arene [189], NiCl2–NaBH4 [190], lithium N,Ndialkylaminoborohydrides [191], in the presence of an Ir catalyst [192–197], and Hantzsch DHP and an organophosphate derivative [198]. Hydrogenations of quinolines to tetrahydroquinolines or decahydroquinolines have also been described [199, 200]. A method to prepare amino-substituted 5,6,7,8-tetrahydroquinolines by catalytic hydrogenation – in the presence of PtO2 – of the corresponding acetamido-substituted quinolines followed by acetamide hydrolysis has been described [201]. Some of these derivatives were synthesized in an enantioselective manner. 17.1.5.8 Reaction with Radical Reagents Concerning intermolecular processes, quinoline derivatives have been substituted by nucleosides in radical substitution reactions [202]. Russell and coworkers have reported the homolytic radical aromatic tert-butylation of quinolinium salts and quinoline N-oxides [203]. Harrowven et al. [204] have studied the intramolecular radical additions of aryl radicals to C2, C3, and C4 quinoline positions. In each case the formation of heteroaromatic products, rather than dihydroquinolines, was observed (Scheme 17.80).

O

O

O

O I

Bu3SnH/AIBN PhMe

N H2N-NHTs, NaOAC THF-H2O

N O

O

O

O I N

Bu3SnH/AIBN PhMe

N

Scheme 17.80

17.1.5.9 Other Reactions A metal-free method involving the use of a new thiourea catalyst (106) has been reported for the preparation of 1,2-dihydroquinolines 107. The catalyst 106 activates organoboronic acids to facilitate the enantioselective Petasis transformation of quinolines to give substituted 1,2-dihydroquinolines 107 with a high degree of stereocontrol (Scheme 17.81) [205]. Collis and coworkers [206] have reported the transient existence of the hetaryne 7,8-quinolyne and its reaction with furan through a Diels–Alder process (Scheme 17.82).

17.1 Quinoline

R

1

R

2

R

3

R

4

B(OH)2 R

1

R

PhOCOCl H2O, NaCO3H CH2Cl2

N

N H

2

107

R

3

R

4

CF3 S F3C 106

N N H H HO

N

CH3

Scheme 17.81

RLi, THF Br

N OTs

-78ºC

O N

O

N

Scheme 17.82

17.1.6 Some Quinoline Derivatives 17.1.6.1 Reactions of Quinolones N-Unsubstituted quinolones are acidic derivatives and can be deprotonated using the appropriate base. These ambident anions can react with different electrophiles and the selectivity is strongly dependent on the solvent, cation, and alkylating agent. The N- versus O-alkylation of quinolinone derivatives has been investigated extensively [207]. In addition, the reaction of 4-hydroxy-2-quinolones with alkyl halides in the presence of Ag2CO3 afforded 2,4-dialkoxyquinolines in moderate to excellent yields [208]. Electrophilic substitution at carbon in 2- and 4-quinolones can be effected more readily than in quinoline itself, and this reaction generally occurs ortho and para to the activating functionality. However, experimental conditions play an important role and the process is highly dependent upon pH [209]. Several research groups have studied alternative methods of carrying out this type of process. The orthodirecting effect of the amide function in the regioselective lithiation of 2-quinolinone was studied by Avendano and coworkers. Subsequent electrophilic substitution can furnish 3-substituted derivatives in good yields (Scheme 17.83) [210]. A series of 3-(N-substituted)-aminoquinolin-2-ones have been synthesized by palladium-catalyzed C–N coupling reactions starting from 3-bromoquinolin-2-ones.

j1565

j 17 Six-Membered Heterocycles: Quinoline and Isoquinoline

1566

R

a) BuLi N H

O

b) RX

N H

O

Scheme 17.83

Various nucleophiles, including amines, amides, sulfonamides, carbamates, and ureas, have been used successfully [211]. Some examples of cycloaddition reactions have been reported for the quinolone system. For example, phenanthridone derivatives were prepared by Diels–Alder reactions from 2-quinolones and butadiene compounds [212]. On the other hand, the first total syntheses of the novel pyranoquinoline alkaloids simulenoline (15), huajiaosimuline (16), and ()-7-demethoxyzanthodioline have been described. The key feature of these concise total syntheses is the formal [3 þ 3] cycloaddition reaction using a,b-unsaturated iminiums and 4-hydroxy-2-quinolones [24a]. Intermolecular [2 þ 2] photocycloaddition of 4-alkoxy-2-quinolones such as 108 (Scheme 17.84), in the presence of chiral lactams such as 109a or 109b, proceeds with excellent enantioselectivity (81–98% ee) and gave high yields (61–89%) [213].

O

H N O N

H3C H3C

109a

109b O

hν, PhMe -60 ºC

H3C H3C

109b

H

CH2

O

N H 108

CH3

H N O N O CH3

O

H N H

O

87%, >90% ee

Scheme 17.84

The 3-aza-Grob fragmentation of THF-protected 3,4-dihydro-2-quinolinone analogues in the presence of hydride reagents gave products 110 and demonstrates that various hydride reagents can reduce this class of aromatic lactam (Scheme 17.85) [214].

17.1 Quinoline

j1567

H H H N

H

O

-

N

O

+

OM

OM

O

OH

O

NH

NH OH

H 110

M= metal Scheme 17.85

17.1.6.2 Reactions of Alkylquinolines Protons on alkyl groups at the 2- and 4-positions of quinoline are sufficiently acidic for deprotonation by strong bases and are more acidic than alkyl groups at other positions. The main feature of the reactivity of alkylquinolines is deprotonation of such alkyl moieties and reaction with electrophiles [215]. In this context, several 2-ketomethylquinolines have been synthesized by heating 2-methylquinolines with acyl chlorides in a conventional microwave oven and in the presence of silica gel (Scheme 17.86) [216].

R

1

+

CH3

N

R

2

R

Silica gel

O Cl

Mw, 4 min

N H

1

R

O

2

Scheme 17.86

On the other hand, the aerobic oxidation of methylquinolines to carboxylic acids has been achieved by using N-hydroxyphthalimide (NHPI)/Co(OAc)2/Mn(OAc)2 as a catalyst in the presence of small amounts of nitrogen dioxide as an initiator (Scheme 17.87) [217]. NHPI Co(OAc)2, Mn(OAc)2 H3C

+ N

O2

HO2C AcOH

N

Scheme 17.87

17.1.6.3 Reactions of Quinolinium Salts 17.1.6.3.1 Nucleophilic Additions and Related Processes Nucleophilic additions to quinoline occur readily after quaternization of the nitrogen and are often the key step in preparatively useful reactions. For example, N-protected quinolin-4-ones

j 17 Six-Membered Heterocycles: Quinoline and Isoquinoline

1568

undergo 1,4-addition of organolithium or Grignard reagents by conversion into the 4-silyloxyquinolinium triflate (Scheme 17.88) [218]. i

Pro O

O

Si

a) TIPSOTf b) PhLi

N Cbz

i

Pro i Pro

O

TfO+

Ph N Cbz

N Cbz

c) H+

Scheme 17.88

Other related studies into this type of process include the use of arylzinc reagents in the presence of chlorotrimethylsilane and rhodium-catalysis, as reported by Hayashi et al. [219]. In this case the reaction is conducted in an enantioselective fashion. Addition of allylsilane to the 2-position of quinolinium salts acylated by chloroformate derivatives can be accomplished in the presence of AgOTf (Scheme 17.89) [220, 221].

Br N

a) ClCO2R b) H2C

Si

Br +

N CO2R

Br N CO2R

CH2

AgOTf

Scheme 17.89

A similar Ir-catalyzed addition of ethynyl(trimethyl)silane to the 2-position of quinoline was also reported [222]. Other examples of functionalization of the quinoline at the 2-position to yield 2-substituted 1,2-dihydroquinolines, by activation with ethyl chloroformate or diethyl pyrocarbonate, have also been reported [223–225]. A regioselective route to cyanomethyl-1,2-dihydro-N-methylquinolines has been published and this process starts from methylquinolinium iodide and tris(trimethylsilyl)acetonitrile in the presence of fluoride [226]. A novel one-step synthesis of pyridoquinolines from quinolinium salt derivatives 111 (Scheme 17.90) under Friedel–Crafts conditions has been described [227]. 17.1.6.3.2 Cycloadditions of Quinolinium Salts and Related Processes Concerning the ring expansion of N-acyl derivatives, Yadav et al. [228] have reported a new process to give easy access to benzoazepine derivatives 112 (Scheme 17.91). Treatment of a quinoline N-acyl derivative with a-diazoketones in the presence of catalytic CuOTf in 1,2-dichloroethane (DCE) under reflux gave the target compounds in excellent yields.

17.1 Quinoline

Cl2CHCOCl N

AlCl3

Cl

Cl

N

+

N

O

O Cl 111

OH Cl

Scheme 17.90

+

N+ O

N2

CuOTf

R O

DCE, reflux

OEt

N EtO 112

R

O O

Scheme 17.91

Quinolinium salts, obtained from the corresponding 1-substituted-4-quinolones, have been used in cycloaddition reactions with silyloxy-1,3-butadienes to give acridine compounds [229]. 17.1.6.3.3 Reissert Reaction Takamura et al. [230] have reported an enantioselective version for quinoline derivatives of the Reissert-type reaction with trimethylsilyl cyanide and acyl chlorides in the presence of binaphthols and diethylaluminium chloride. Chiral dihydroquinoline carbonitriles 113 (Scheme 17.92) were obtained with up to 91% ee. 1

R

2

R

1

R

TMSCN/RCOCl N

2

3

R

R

O Al Cl O

N

CN

R O 113

3

R Scheme 17.92

The same authors have published the development and application of this method to the synthesis of the potent NMDA receptor antagonist ()-L-689,560 (24) [31]. A new safety-catch linker for solid phase organic synthesis that is based on a quinoline moiety has been developed. Cleavage from the resin proceeds in two steps: oxidative aromatization leading to an activated quinolinium derivative and nucleophilic displacement of the quinoline resin (Scheme 17.93) [231].

j1569

j 17 Six-Membered Heterocycles: Quinoline and Isoquinoline

1570

Ph

Ph

Ph

XN H

N

N O

DHQ-resin

R

1

O

+

R

1

Nu

Stable form

Scheme 17.93

17.1.6.4 Reactions of Quinoline N-Oxides Quinoline reacts with peracids to give the N-oxide. In a similar way to pyridine, the presence of the N-oxide serves to facilitate both electrophilic and nucleophilic additions to the C2 and C4 positions. In some cases, electrophilic substitution is dependent on the experimental conditions. For instance, nitration of quinoline N-oxide in mixed acids takes place at the C5 position, via the O-protonated species, but with a lower acid strength the reaction occurs at C4 [232]. Numerous methods are available for the reduction of the N–O bond in N-oxides. In this context, baker’s yeast is also a useful reagent for the reduction of N-oxides to the respective quinoline [233]. Rearrangements are important processes in the case of quinoline N-oxides. For example, 2,3-dichloroquinoline has been prepared in three steps from 3-bromoquinoline through N-oxide formation and subsequent rearrangement [234]. More recently, a simple and novel approach for the direct conversion of quinoline N-oxides into 2-amidoquinolines has been described [235]. The treatment of primary amides with oxalyl chloride yielded an acyl isocyanate, which reacted in the presence of quinoline N-oxide, via intermediate 114, to give 2-amidoquinolines 115 in good yield (Scheme 17.94). This methodology is complementary to the Abramovich reaction, which is limited to the introduction of secondary amides via imidoyl chlorides [236].

b) O

a) Oxalyl chloride NH2

O

N

C

O

O N O

Scheme 17.94

+

N O

O

N O 114

N H

N 115

17.2 Isoquinoline

17.2 Isoquinoline 17.2.1 Introduction

Isoquinoline (116) (b-quinoline, 2-azanaphthalene, benzo[c]pyridine), a structural isomer of quinoline, is a low-melting solid with a penetrating smell. It was first isolated from coal tar in 1885 by Hoogewerff and van Drop by fractional crystallization of the acid sulfate [237]. This compound was also isolated from the same source in 1914 by Weissgerber through selective extraction [238]. The structure, properties, reactivity, synthesis, and applications of isoquinoline have been reviewed extensively [1, 3, 5, 239–242]. 5 6 7 8

4

4a

3

N

8a

2

1

116

17.2.2 General Reactivity

The presence of the nitrogen sp2 lone pair makes 116 basic and it will react with protons, or other electrophilic species, at nitrogen by electrophilic addition to give isoquinolinium salts 117, which in many instances are isolable [243, 244]. Protonation, alkylation, acylation, and oxidation with peroxy acids take place on the nitrogen. The basicity and N-nucleophilicity are enhanced by electron-releasing substituents and diminished by electron-withdrawing groups. Moreover, steric interference of substituents at either or both C1 and C3 positions will slow the rate of N-alkylation [245]. Isoquinoline is a p-deficient heterocycle as a consequence of conjugation of the p-electron pair on the nitrogen. Hence, aromatic electrophilic substitution will take place at a slower rate than in naphthalene [246]. Another major difference is that SEAr reactions occur through 117, a more p-deficient heterocycle, which reacts on the benzene ring rather than the electron-poorer pyridine ring, through a high-energy doubly charged Wheland-type intermediate 118, to give the 5-substituted derivative 119 as the major product [247]. E E+

E+ N

N

+ 116

117

E

H -H +

+ N

E

+ 118

N

E

+ 119

E

j1571

j 17 Six-Membered Heterocycles: Quinoline and Isoquinoline

1572

Aromatic nucleophilic substitution is a very important process for p-deficient heterocycles such as 116 [248–250]. This process involves a two-step sequence: addition of a nucleophile species to give a Meisenheimer complex (120) is followed by elimination of a good leaving group (usually halide or nitrite). The reaction takes place when the leaving group is located at C1, since the negative charge resides largely on the nitrogen, and at a much slower rate when it is located at C3, due to the higherenergy intermediate 1200 . Thus, the SNAr reaction of 1- and 3-chloroisoquinolines with ethoxide is about 104 times faster in the former [251]. Quaternization greatly increases the rate of nucleophilic substitution [252]. -X-

Nu -

N

N-

N X

X

Nu

Nu

120 X

X Nu -

Nu N-

N

Nu

-XN

120'

Another important feature in the reactivity of 116, with no counterpart in the chemistry of aromatic carbocycles, is nucleophilic substitution with hydride transfer by means of strong nucleophilic reagents such as organolithiums, Grignard reagents, or sodium amide to give stable intermediate addition products 121, which can be characterized as such. These intermediates can be oxidized to afford the substitution products. In this case, only attack at C1 has been observed [253–255]. H2O

Nu -

[O]

N-

N Nu - : RLi, RMgX, NH2-

H

N

NH

Nu

H

Nu

Nu

121

17.2.2.1 Relevant Physicochemical Data, Computational Chemistry, and NMR Data Isoquinoline is a hygroscopic solid that crystallizes as platelets that have low solubility in water but dissolve in common organic solvents. This compound is as basic (pKa 5.4) as pyridine and quinoline (pKa 5.2 and 4.95, respectively) and 116 is also soluble in dilute acids (Table 17.4). Table 17.4 Physical properties of 116.

Mp ( C)

Bp ( C/Torr)

Density (g cm3)

pKa

m (D)

24.25

242.5/760

1.096

5.4

2.52

17.2 Isoquinoline Table 17.5

1

H C

13

1

H and

13

C NMR chemical shifts (ppm) of 116 (in CDCl3).

d1

d3

d4

d4a

d5

d6

d7

d8

d8a

9.15 152.5

8.45 143.1

7.50 120.4

— 135.7

7.71 126.5

7.57 130.6

7.50 127.2

7.87 127.5

— 128.8

Isoquinoline shows structural and spectroscopic similarities to pyridine and naphthalene. Both the proton and carbon chemical shifts (Table 17.5) are related to the electron density, at a given position, as a result of the mesomeric and inductive electron-withdrawing effects of the nitrogen. As a result, the H1/H3 and C1/C3 signals are shifted to lower field than the other signals in the heterocycle or than the corresponding signals in naphthalene (dH1: 7.8, dH2: 7.5, dC1: 128, dC2: 126 ppm). The UV spectrum of 116 (Table 17.6) resembles that of naphthalene [lmax (nm)/ log e: 311/2.39, 275/3.75, and 219/5.10]. The spectrum contains three long wavelength bands that correspond to the p ! p transitions. However, as the heteroatom has a lone pair, n ! p transitions are possible but they are overlapped by the much more intense former bands. Molecular mechanics have been used by Allinger and coworkers, through their MM3 force field program, but they were unable to estimate the vibrational spectra for 116 with accuracy. However, they did reach a good match for the heat of formation (calculated 49.94 kcal mol1; experimental 48.2 kcal mol1) and the dipole moment (calc. 2.30 D; expt. 2.53–2.75 D), with the resonance energy also estimated (25.68 kcal mol1) [256]. The observed and calculated vibrational spectra were in good agreement when density functional theory (DFT) calculations were performed with the B3LYP functional and 631G basis set [257]. Bond orders were calculated at the Hartree–Fock and the secondorder Møller–Plesset (MP2) levels for 116 and other heteroatomic rings [258]. The p-electron charge distribution was calculated by the LCAO method and gave good agreement with experimental data [259]. Aromaticity shows a significant collinearity with magnetic susceptibility, as calculated at the (DFT) B3LYP level with the 6-31G basis set [260]. Polarizability was calculated using accurate ab initio studies at the HF/6311þþG(3d,2d) and BLPY/6-311þþ G(3d,2p) levels of theory [261]. As regards other physicochemical parameters estimated by computational chemistry methods, the proton affinity of 116 calculated at the 3-21G and 3-21þG ab initio levels and at the MNDO and AM1 semiempirical levels gave, after inclusion of diffuse functions, good agreement with experimental data [262]. The extended H€ uckel theory (EHT) was applied to localization energies and total electron densities (s þ p), which correlate quite conclusively with the experimentally observed site of predominant nucleophilic attack by an amine ion in the Chichibabin reaction (Table 17.7) [2]. Table 17.6 Ultraviolet data (p ! p transitions) for 116 (in hexane).

lmax (nm)

Log e

lmax (nm)

Log e

lmax (nm)

Log e

317

3.49

266

3.61

217

4.57

j1573

j 17 Six-Membered Heterocycles: Quinoline and Isoquinoline

1574

Table 17.7 Electron densities (Q) in 116 obtained using extended H€ uckel theory (EHT).

Position

1

2

3

4

4a

5

6

7

8

8a

p s sþp

0.78 2.87 3.65

1.45 4.49 5.94

0.91 2.86 3.77

1.03 3.12 4.15

0.90 2.98 3.88

1.02 3.12 4.14

0.96 3.11 4.07

1.01 3.11 4.12

0.97 3.11 4.08

0.97 2.99 3.96

Calculation of the proton and carbon chemical shifts relative to tetramethylsilane, with accuracies of about 2.62 ppm (13 C) and 0.32 ppm (1 H) can be performed using a linear regression formula that converts magnetic shielding constants calculated at common ab initio and DFT levels [263]. 17.2.2.2 Tautomerism In a similar way to oxypyridines, oxyisoquinolines also show tautomerism. The benzo-fusion to the pyridine ring involved in tautomerism has the effect of shifting the equilibrium towards the tautomer that retains full aromaticity of the benzene ring. Thus, isoquinolin-1-ol (122) completely tautomerizes to 2H-isoquinolin-1-one (123) whereas isoquinolin-3-ol (124) remains in the equilibrium with 2H-isoquinolin-3-one (125) in a proportion significantly greater than in the corresponding unfused heterocycle. OH N

NH

OH 122

O 123

O

N 124

NH 125

Tautomerism also arises in the case of 1-phenacylisoquinolines 126 (X ¼ O) and their corresponding ketenimines 126 (X ¼ NH). The enol and the enamine are reported to exist as a single tautomer due to intramolecular hydrogen bonding [264]. MeO MeO

N

H X

C6H5 126 (X = O, NH)

17.2.3 Relevant Natural and/or Useful Compounds

Isoquinoline plays an important role as a secondary metabolite in a large number of alkaloids that have different biogenetic origins. Many isoquinoline alkaloids occur as 1,2,3,4-tetrahydroderivatives, which can be considered as being derived from

17.2 Isoquinoline

j1575

b-phenylethylamines [265]. The synthesis, reactions, and biological activities of isoquinoline natural products have been reviewed extensively [266]. The asymmetric synthesis of these alkaloids has been the focus of significant efforts by both academic and industrial research groups seeking stereochemically modified traditional methods and new advances using the C1-Ca connectivity approach [267], and the use of a-amino acids as excellent chiral building blocks [268]. Diverse biological activities have been reported for isoquinoline natural products and these include anti-inflammatory [269], cardiovascular [270], and antimalarial [271] among others. Isoquinoline marine compounds are also of interest [272]. Some examples of isoquinoline alkaloids are given below and include papaverine (127), an opium poppy alkaloid, berberine (128), an isoquinolinium alkaloid found in several Korean and Chinese medicinal plants, mimosamycin (129), one of the simplest isoquinoline quinones of marine origin, and maritidine (130) a chiral tetrahydroisoquinoline alkaloid. O

MeO

O Me

N

MeO

OH

O

OMe OMe

OMe

N

MeO

N +

MeO

MeO

Me

MeO

129

In recent years, several reports have been published on new isoquinoline-based materials with interesting properties. Recently, some studies have highlighted iridium(III) complexes bearing isoquinoline-derived ligands as chemiluminescent materials [273, 274], and some of these can be applied as red or white OLEDs (e.g., 131) [275, 276]. On the other hand, a new type of donor–spacer–acceptor based on bis(isoquinoline-N-oxide) (e.g., 132) has proved to be an efficient dual channel fluorosensor that acts as a pincer for lithium, magnesium, and calcium cations [277]. O N

O

O

Me Me

O

O

Me O Ir O

N 2

131

N

O

128

127

O

O +

-

-

O + N

132

17.2.4 Synthesis of Isoquinolines

Synthetic methods for the isoquinoline skeleton are constantly being updated. Starting from conveniently substituted benzenes, these methods can be classified into two major categories: those that create the fully aromatic heterocyclic ring, which

130

j 17 Six-Membered Heterocycles: Quinoline and Isoquinoline

1576

are covered in this chapter, and those that build the fully or partially reduced pyridine ring [278, 279], which will not be considered here, but are important for the preparation of many isoquinoline natural products [267], such as the classical Bischler–Napieralski and Pictet–Spengler syntheses. 17.2.4.1 Classical Methods 17.2.4.1.1 Pomeranz–Fristsch Synthesis This two-step method involves the initial condensation of an aryl aldehyde with a 2-aminoaldehyde acetal [280] or, conversely, a benzylamine with glyoxal diethyl acetal – if C1-substituted isoquinolines are desired [281] – to give an aldimine. The second step involves the cyclization of the aldimine by treatment with a strong acid. For example, 116 has been prepared by condensation of aminoacetal 133 with benzaldehyde to give imine 134, which was cyclized with sulfuric acid. For C1-substituted isoquinolines, benzylamine 135 was condensed with glyoxal diethyl acetal to give imine 136, which then cyclizes to 137 (Scheme 17.95). EtO OEt NH2

EtO PhCHO

N

100 ºC 134

133

OEt

H2SO4

(45%) EtO

NH2

MeO

Me 135

116

OEt 75% H2SO4

(EtO)2CHCHO 140 ºC (75%)

N

100 ºC

N

MeO

Me 136

10 ºC (50%)

N

MeO

Me 137

Scheme 17.95

This synthesis works well when the aryl component bears electron-donating groups, preferably para to the position of ring closure. However, the overall yield is limited by imine hydrolysis during the cyclization. Two solutions have been developed to overcome this drawback: (i) the use of trifluoroacetic acid/boron trifluoride [282] and (ii) carrying out the cyclization at the amine level instead of the imine. For example, imine 138 was reduced to amine 139, which can be cyclized directly with chlorosulfonic acid to give 140 [283] or tosylated to give 141 before treatment with HCl (Scheme 17.96) [284]. Tosylamides can be prepared by benzylating the sodium salt of 2-tosylaminoethanal acetal [285], or by Mitsunobu reaction of a benzylic alcohol with N-sulfonyl-aminoacetals [286, 287]. 17.2.4.1.2 Pictet–Gams Modification of the Bischler–Napieralski Synthesis Although the Bischler–Napieralski synthesis provides access to 3,4-dihydroisoquinolines or

17.2 Isoquinoline

j1577

MeO ClSO3H, r.t. MeO

MeO

N

MeO

OMe

NaBH4

N

MeO

MeO

or H2, Pt

MeO

140 (81%)

NH

N

138

(48%)

OMe

N

MeO

139

MeO

TsCl, pyr

MeO

6N HCl dioxane, reflux MeO N 141

Scheme 17.96

3,4-dihydroisoquinolin-1-ones, the Pictet–Gams modification allows the preparation of fully aromatic isoquinolines starting with unsaturated or potentially unsaturated arylethanamines. Thus, amides from 2-aryl-2-hydroxyethanamines 142 led to isoquinolines 143 when treated with phosphoryl chloride or phosphorus pentoxide (Scheme 17.97) [288–291]. OH X

X = H; 6,7-diOEt; 5,8-diOMe. R = Me; o-ClC6H4; 1-naphthyl

N R

(62-80%)

O

142

X

reflux

R

HN

Me

POCl3 or P2O5

Me

143

Scheme 17.97

In addition, cinnamic esters substituted with an acetamido group at the C2-position can be converted into isoquinolines. In this way 144 was cyclized to isoquinoline carboxylate 145. The cinnamic ester derivative was prepared by photocycloaddition of 5-methoxy-2-methyloxazole (146) with benzaldehyde to give the oxetane 147, which under acidic conditions gave first 148 and then 144 (Scheme 17.98) [292].

Me

H

hν

N O 146

OMe PhCHO (87%)

Ph

H+/H2O (80%)

AcNH

Me

O

Ph O OMe

H+/H2O (70%)

HO AcNH

POCl3

CO2Me

(78%)

Ph CO2Me 148

147

H

144 Scheme 17.98

N

CO2Me N 145

Me

OMe NTs

j 17 Six-Membered Heterocycles: Quinoline and Isoquinoline

1578

Milder conditions with trifluoromethanesulfonic anhydride in the presence of 2-chloropyridine have been described for the synthesis of isoquinoline and b-carboline derivatives through electrophilic amide activation [293]. Isoquinolines 149 were prepared from sensitive (Z)-N-vinylamides 150 in good to excellent yields (Scheme 17.99). Moreover, condensation reaction conditions proved to be far more efficient than phosphoryl chloride, oxalyl chloride/FeCl3, or Tf2O/DMAP.

R

1

R

Tf2O/2-ClPyr

R

O 150

NH R

2

CH2Cl2 - 78 to 140 ºC

TfO - R +

R R

H

1

N + H N R TfO 2

R - TfOH

Cl

- TfOH,2-ClPyr (40-99%)

1

R N

R 149

R

2

R = H, OMe R1 = H, Ph R2 = cHx, Ph, 4-MeOPh

Scheme 17.99

17.2.4.2 Modern Methods 17.2.4.2.1 Electrophilic Cyclization-Based Methods Methods based on electrophilic cyclization reactions have been developed using different starting materials. Iminoalkynes 151 prepared by reaction of tert-butylamine with o-(1-alkynyl)benzaldehydes 152 have been cyclized in the presence of electrophiles such as I2, ICl, PhSeCl, PhSCl, and p-O2NC6H4SCl to give the corresponding halogen-, selenium-, and sulfur-containing isoquinolines 153 at the C4-position in moderate to excellent yields (Scheme 17.100). Furthermore, silver-catalyzed ring-closure of 151 provides an entry to C4-unsubstituted isoquinolines 153 [294, 295].

r.t.

N 151

152

R

E+

t-BuNH2 CHO

E

R

R

t-Bu

N 153

E = I, ICl (30-68%); SePh (18-96%); SC6H4-p-NO2 (25-46%); SPh (40-45%); H (45-100%) R = Aryl; 1-Cyclohexenyl; isopropenyl; cyclohexyl

Scheme 17.100

A copper(I)-catalyzed domino four-component coupling–cyclization method using 2-ethynylbenzaldehydes 154, paraformaldehyde, a secondary amine, and tert-butylamine has been reported to give 3-(aminomethyl)isoquinolines 155 in high yields (Scheme 17.101) [296]. This method is efficient when either electron-donating or electron-withdrawing substituents are present in the benzene ring.

17.2 Isoquinoline

1

R

O

+

(HCHO)n

NR2

cat CuI DMF

1

R

R2NH

O

t-BuNH2

j1579

1

R

N

(60-87%)

155

154 Scheme 17.101

Related to the former method, 2-alkynylbenzaldoximes 156 give C3-substituted4-iodoisoquinoline-N-oxides 157 in good to excellent yields when treated with iodine [297]. Silver(I)- and gold(I)-catalyzed procedures have also been reported to afford C4-unsubstituted-N-oxides 158 (Scheme 17.102) [298]. I R N + O 157

R I2/EtOH N

r.t. (65-92%)

OH

156

AgOTf or Au(IMes)OTf

R N + O

CH2Cl2 r.t. (21-97%)

158

R = H; Alkyl; Aryl; Heteroaryl; Cyclohexyl; Benzyl; 1-Cyclohexenyl; O-Alkyl Scheme 17.102

Iodine-mediated electrophilic cyclization of 2-alkynyl-1-azidomethyl benzenes leads to highly substituted isoquinolines [299]. Azides 159 react with iodine, Py2BF4–HBF4 (Barluenga reagent) or NIS as iodium donors to give iodoisoquinolines 160, via a cyclic iodonium ion 161 followed by nucleophilic cyclization of the azide and subsequent elimination of nitrogen (Scheme 17.103). Electron-neutral or electron-donating substituents at the alkyne terminus are favored. This methodology was applied to the synthesis of norchelerythrine.

I +

R N3 159

I2, K3PO4 or NaHCO3

R

CH2Cl2, r.t., 24 h

R

(58-95%)

3

N3

2

R

3

R

- H+, - N2

R N

2

R

1

161 R = Aryl, heteroaryl, alkyl, H, alkenyl, CH2TMS R1 = Phenyl, alkyl, cycloalkyl, H R2 = H, OMe R3 = H, NO2, OMe R2-R3 = OCH2O

Scheme 17.103

I

R

R 160

1

NR2

j 17 Six-Membered Heterocycles: Quinoline and Isoquinoline

1580

17.2.4.2.2 Nucleophilic Cyclization-Based Methods Ring-fluorinated isoquinolines 162 have been prepared by means of nucleophilic intramolecular cyclization of o-isocyano-b,b-difluorostyrenes 163 with organometallic reagents via intramolecular sp2 nucleophiles, which cyclize by substitution of the vinylic fluoride (Scheme 17.104) [300].

R

R

R R'M

CF2 N

F

CF2 N

(62-88%)

N

R'

163

162

R'M = alkylMgCl, alkylLi, PhLi, HAl(alkyl)2

R'

Scheme 17.104

In a similar way, 1,4-disubstituted isoquinolines 164 were obtained by reaction of a-substituted 2-lithio-b-methoxystyrenes 165 with nitriles (Scheme 17.105) [301]. This process has also been carried out starting from o-cyano-b-methoxystyrenes 166 [302]. When lithium dialkylamides were used as nucleophiles, 1-dialkylaminosubstituted isoquinolines 167 were obtained.

R

1

R

2

OMe Br

n-BuLi

R

R

1

2

OMe

Et2O, 0 ºC

Li

1

CN

166

LiNR2 THF - 78 ºC to rt (29-67%)

R

2

OMe

R

1

R

2

R

3

N

NR

(36-73%)

Ph OMe

R3CN

R

1

0 ºC or rt

165

R

R

3

164

Ph

1

N

167

NR2

Scheme 17.105

17.2.4.2.3 Condensation Reaction-Based Methods The heteroaromatic ring in isoquinoline can also be obtained by ring closure through a condensation reaction on appropriate ortho-substituted benzenes. Reaction of nitriles 168 with ammonia, or primary or secondary amines, in the presence of catalytic amounts of TFA leads to 3-aminosoquinolines 169 [303]. Primary amines, as opposed to ammonia or secondary amines, give the aldimine and this slowly dissociates to add to the cyano group (Scheme 17.106). In a similar fashion, 2-acylphenylacetonitriles react with primary amines by acid-catalyzed condensation to give 1-substituted-3aminoisoquinolines [304].

17.2 Isoquinoline

CN O

X

R N

HNR1R2 cat TFA EtOH Reflux (20-89%)

168

1

R

R N

2

NH

X

j1581 1

R

2

N

X

O

X = H; Cl

169

Scheme 17.106

Aromatic 1,2-dialdehydes 170 react with protected phosphonoglycine 171 derivatives using DBU as base to give methyl isoquinoline-3-carboxylates 172 in good to high yields (Scheme 17.107) [305]. This method allows the preparation of isoquinolines bearing electron-withdrawing groups. X

O O

X

P(O)(OMe)2

+

CO2Me

RCONH

171

170 X = H; OMe, Cl

R = Me; OBn

X

DBU CH2Cl2 0 ºC to r.t. (78-92%)

CO2Me

X

- RCO2H

NHCOR

X

O

2-Benzopyrilium salts 173, prepared by Friedel–Crafts acylation of benzyl ketones, are converted into isoquinolines 174 by treatment with aqueous ammonia through a Schiff base intermediate (Scheme 17.108) [306].

O + BF4173

Ph

Ph aq. NH3

Ph

O NH

(86%) Ph

N

172

Scheme 17.107

Ph

CO2Me

X

N 174

Ph

Scheme 17.108

More recently, isoquinolines 175 have been prepared by a one-pot procedure from o-alkynyl-benzamides, -benzoates, -benzaldehydes, or -benzophenones 176. The twostep procedure, which proceeds via the 2-benzopyrilium salt 177, proved to be equally efficient (Scheme 17.109) [307]. Unexpectedly, isoquinoline-3-carboxylate 178 was obtained when the N-acetylphenylalanine methyl ester derivative 179 was treated with HMTA/TFA. This process occurred through the formyl intermediate 180, which then cyclizes and dehydrogenates to give 178 (Scheme 17.110) [308]. 17.2.4.2.4 Metal-Catalyzed Ring Closing Methods Larock’s group has reported a series of isoquinoline syntheses based on palladium-catalyzed annulation processes. The reaction of tert-butylimines of o-iodobenzaldehydes 181 with internal acetylenes

j 17 Six-Membered Heterocycles: Quinoline and Isoquinoline

1582

R O+

HX

R

CH2Cl2

176

R

X = TfO; BF4

NH3(g) CH2Cl2

(21-74%)

O R

177

X-

1

1

R a) TfOH b) NH3(g) CH2Cl2

R = Ph, p-MeC6H4; p-(n-C10H21)OC6H4 R1 = NMe2; OEt; H; Ph

N 175

R

1

Scheme 17.109

CO2Me

Me

Me

reflux (40%)

MeO

Me

HN

MeO

HMTA/TFA

O

OH

OH

HN CHO

CO2Me

-AcOH

Me

-H2

N

MeO OH

O

180

179

CO2Me

Me

178

Scheme 17.110

182 in the presence of catalytic Pd(OAc)2 gave various 3,4-disubstituted isoquinolines 183 in moderate to excellent yields (Scheme 17.111) [309, 310]. When a relatively unhindered diyne and enyne, or an electron-rich imine, are employed mixtures of stereoisomers are obtained with high selectivity. The use of trimethylsilyl-containing acetylenes produced 3-substituted isoquinolines. These compounds were also available using terminal acetylenes as substrates and the methodology has been applied to the total synthesis of decumbenine B [311]. A nickel(II) catalyst proved to be efficient to give 3,4-disubstituted isoquinolines by this method in a highly regioselective manner [312]. In addition, 3-substituted 4-fluoroalkylated isoquinolines were prepared using a Pd(0) catalyst [313]. R1 I X

N

181

t-Bu

+

R1

R2

182

cat Pd(OAc)2/PPh3 Na2CO3 DMF, 100 ºC (11-100%)

R2 X

N

X = H, OR, CHO, NMe2 R1, R2 = H, alkyl, alkenyl, Ph, CH(R)OH, CO2Et

183

Scheme 17.111

The former methodology was subsequently expanded to the synthesis of 3-substituted-4-aroylisoquinolines 184 by palladium-catalyzed carbonylative cyclization of 2-(1-alkynyl)benzaldimines 185 and aryl halides (Scheme 17.112) [314, 315]. The reaction is useful for both electron-rich and electron-poor aryl halides. Benzaldimines 185 are also versatile starting materials for the synthesis of isoquinolines

17.2 Isoquinoline

j1583

R1 Method A cat PdBr2, Cu(OAc)2 NaOAc, DMSO, 70 ºC

R N

Method B cat PdBr2/CuCl2, O2 NaHCO3, DMSO, 70 ºC

186

R1

+

N

t-Bu

+

ArX

185

R

cat Pd(PPh3)4 N

(n-Bu)3N, CO (1 atm) DMF, 100 ºC

184

(28-84%)

+

(27-89%)

O

Ar

R

R1X Pd(PPh3)4, K2CO3 DMF, 100 ºC (13-80%) R1 R N

187 Scheme 17.112

186, by palladium-catalyzed cyclization followed by a Heck reaction with olefins [316, 317], or isoquinolines 187 by cross-coupling with aryl, vinyl, alkynyl, allyl, or benzyl halides [318, 319]. Rhodium(I)-catalyzed tandem ortho-alkenylation–cyclization of aromatic N-benzylketenimines 188 with alkynes has been applied to the synthesis of mixtures of isoquinolines 189 and 190 [320]. The 1-phenethyl substituted compound 190 is postulated to be formed by the intermolecular migration of the benzyl group in the vinylated ketenimine intermediate 191. The one-pot tandem process from aromatic ketones 192 was also performed more efficiently (Scheme 17.113). The reaction R

R CH3 188 Ph

NBn

+

cat Rh(PPh3)3Cl

Ph

R

cat Rh(PPh3)3Cl

CH3

toluene, 150 ºC Ph

CH3

Ph

NBn

191

(55-73%)

toluene, 170 ºC (82-89%)

192

O

+ Ph

H2N

+ Ph

Ph

Ph N 189 Scheme 17.113

CH3

Ph

R

Ph

R

+

N 190

CH2CH2Ph

R = H, CF3, OMe

Ph

j 17 Six-Membered Heterocycles: Quinoline and Isoquinoline

1584

works well when either electron-donating or electron-withdrawing groups are present in the benzene ring. A Suzuki cross-coupling/reductive debenzyloxycarbonylation sequence has been reported for the synthesis of [c]annulated isoquinolines [321]. The reaction of boronic acid 193 with cyclic iodoenones 194 catalyzed by palladium(0) gave intermediates 195 that then cyclized to isoquinolines 196 under reductive conditions (Scheme 17.114). This method has been applied to the synthesis of pancratistatin-like isoquinolines. X R

I

B(OH)2 NHCbz

R

O

O ( )n

+

X X

193

cat Pd(PPh3)4 benzene/EtOH

194

( )n X

R

cat Pd(OH)2/C R H2, 1 atm

X NHCbz

R

(82-92%)

R

X

( )n N

196 R = H, OCH2O

195

X = H, Me n = 1, 2

Scheme 17.114

17.2.4.2.5 Electrocyclic Ring Closing Methods Hetero-Diels–Alder processes have been widely used to build nitrogen-containing six-membered rings from azadienes. 1,3-Disubstituted isoquinolines 197 can be prepared by electrocyclic ring-closure when aldehydes react with N-vinylic phosphazenes 198 through a [4 þ 2] cycloaddition [322]. Phosphazenes 198 are obtained by an aza-Wittig [2 þ 2] process between phosphoranes and nitriles (Scheme 17.115). The reaction can be performed with isolation of the aza-diene 199 or in a one-pot procedure. R N

140 ºC 1 199 R

R Ph3P

N

198

+

R1

O

(70-83%)

140 ºC R

140 ºC

N 197 R

1

Scheme 17.115

This methodology has been used in the synthesis of a derivative of the marine alkaloid renierol [323]. Thus, phosphacene 200 was reacted with trimethylsilylketene to give the ketenimine 201, which was then converted into the isoquinoline 202 (Scheme 17.116).

17.2 Isoquinoline OMe

OMe CO2Et

Me N

MeO OMe

toluene rt

PPh3

OMe CO2Et

Me

TMS-CH=C=O

1) toluene, 160 ºC

N

MeO

2) silica gel

OMe

200

j1585 CO2Et

Me N

MeO OMe

(85%)

202

201 SiMe3

Scheme 17.116

Interestingly, a strong-base-induced [4 þ 2] cycloaddition of homophthalic anhydrides, such as 203, with enolizable enones 204 has been reported to build a key isoquinoline intermediate (205) of the antitumor antibiotic fredericamycin A (Scheme 17.117) [324]. Notably, as opposed to the main strategy in the syntheses of isoquinolines, that is, the building of the pyridine ring, in this case it is the benzene ring that is created. The reaction is accelerated in the presence of base to give diene 206, which cyclizes to the proposed cycloadduct 207 followed by elimination of phenylsulfinic acid and carbon dioxide.

OMe O N

O

Me

O S Ph +

+

-

O

O O

O

204

203 OMe O N Me

206

O O Ph S + O

OMe OH O

-

( )n

NaH

O

N

1,4-dioxane Me reflux

205 -PhS(O)H -CO2

- Ph OMe O O +S

O N Me

O

O

O

O

-

H

207

Scheme 17.117

Aryne [4 þ 2] cycloaddition reactions have been expanded to the synthesis of isoquinolines. Thus, when aryne 208, prepared from a silyl aryl triflate (209), is reacted with an enamide (210), a [4 þ 2] addition reaction takes place followed by a dehydrative aromatization to give diversely substituted isoquinolines 211 (Scheme 17.118) [325]. Similarly, the reaction of 2-amidoacrylate esters 212 with silyl aryl triflates 209 using CsF as a fluorine source yields mixtures of isoquinoline-3carboxylates 213 and benzocyclobutanes 214 (Scheme 17.118) [326]. 17.2.4.2.6 Ring Expansion- and Ring Contraction-Based Methods o-Quinodimethanes are highly reactive diene systems in Diels–Alder reactions. In view of this, a traceless solid-phase synthesis based on a benzocyclobutanyl ether resin 215, a precursor of solid-supported o-quinodimethane, has been reported for the heteroDiels–Alder reaction with trichloroacetonitrile to give isoquinoline 216 in low

( )n

n = 2 (58%) n = 3 (40%)

j 17 Six-Membered Heterocycles: Quinoline and Isoquinoline

1586 R

SiMe3

R OTf TABT

209

+

R

R

R2

R HO

N

(51-87%)

R1

R1

211

208

R1

N H

R2 R = H, Me, OMe, OCH2O, F R1 = Alkyl, Bn, CF3, CO2Me, CH2OMe R2 = Alkyl, CO2Me R3 = H, Alkyl

210

R

R2

R

N

THF, r.t.

R3

O

R3

R3

R

R

O

SiMe3

R

+

R

1

OTf

R

CsF N H

O

R

+R

N

MeCN r.t.

R1

NH CO2Me

R1

209 (R = H, Me, OMe, 212 (R1 = H, Alkyl, ArCH2, OCH2O, F)

CO2Me

R

CO2Me

214 (11-27%)

213 (41-69%)

ArCH2O, Ph)

Scheme 17.118

yield [327]. Resin 215 was prepared from a hydroxymethyl resin via the trichloroacetimidate 217 (Scheme 17.119).

NH

1) NaHDMS, THF OH

2) Cl3CCN (90%)

O

217

CCl3

Cl3CCN

HO

CCl3

TfOH CH2Cl2-hexane

O

215

toluene 105 ºC (13%)

N

216

Scheme 17.119

Related to the above method, 3-substituted isoquinolines 218 have been obtained through zirconocene/copper-mediated coupling of benzocyclobutadiene with nitriles (Scheme 17.120) [328]. 1-Bromobenzocyclobutene (219) was used as a synthon and was readily converted into Cp2Zr(g2-benzocyclobutadiene)(PMe3) (220), which couples with nitriles to give five-membered-zirconacycles 221. Subsequent treatment with CuCl gave isoquinolines 218 in high yields. PMe3

Br 1) Mg

219

2) Cp2ZrMeCl 3) PMe3

ZrCp2

220

R R-CN

N ZrCp2

221

R

2 CuCl THF (85-89%)

N

218 R = t-Bu, Ph

Scheme 17.120

An unprecedented rearrangement of a 1H-benzazepine (222) to 1,3-disubstituted isoquinolines 223 has been reported to occur in good yields by treatment with silica

17.2 Isoquinoline

j1587

gel under normal or UV light, but the mechanism of this process has not been disclosed (Scheme 17.121) [329]. CO2R

1

R N H

CO2R

2

silica gel hv, rt (72-82%)

CO2R

R

R, R1, R2 = Alkyl

N CO2R 223

222

1

2

Scheme 17.121

17.2.4.2.7 Photochemical Methods Irradiation of substituted a-dehydrophenylalanine 224 in acetonitrile with Pyrex-filtered light has been found to give a mixture of isoquinoline 225, azetine 226, and (E)- and (Z)-227 in low yields (Scheme 17.122) [330]. Compound 225 was proposed to occur through a 1,5-acetyl migration from (Z)-227, and 226 by a 1,3-acetyl shift from (E)-227. CONHBu NHAc

NHAc

CONHBu

hν MeCN

+

N

Cl

Me

Cl

CONHBu

CONHBu

Me

224

+ Cl

225 (32%)

Cl 227 (49%)

226 (19%)

Scheme 17.122

Photocyclization of 2-azadienes 228 in a neutral medium using Pyrex-filtered light has been reported to give 1,3-disubstituted isoquinolines 229 (Scheme 17.123) [331]. When 228 bears a phenyl group at the 4-position this group was involved in the cyclization. MeO

N

Ar hν

R1 = H - H2

R1 MeO

N R

H Ar

228

Scheme 17.123

N

(38-69%) MeO

R1 = Ph

Ar

N R

Ar

hν - MeOH

R 229 (R = OMe, Ph, Me)

j 17 Six-Membered Heterocycles: Quinoline and Isoquinoline

1588

17.2.5 Reactivity of Isoquinolines 17.2.5.1 Reactions with Electrophilic Reagents 17.2.5.1.1 Addition to Nitrogen Like pyridine, isoquinoline reacts as a base (pKa ¼ 5.4) by protonation or as a nucleophile by quaternization through the electron lone pair on the ring nitrogen to form an aromatic isoquinolinium cation (Scheme 17.124). For instance, O-(2,4-dinitrophenyl)hydroxylamine (230) has proven to be a more efficient aminating reagent than hydroxylamine-O-sulfonic acids like HOSA or MSH to give 231 [332]. Nitrogen atom oxidation, as for pyridine, can be performed with peracids to afford isoquinoline-N-oxides. Other mild procedures to prepare 232 have been reported and these involve the use of oxygen in the presence of ruthenium trichloride [333], or hydrogen peroxide in the presence of molecular sieves as a catalyst [334]. N-Alkylisoquinolinium salts like 233 are obtained using alkyl halides, sulfonates [335], or methyl salicylate [336]. Stable salts of N-acylisoquinolinium cations such as 234 can be prepared in the presence of SbCl5 [337]. On the other hand, a large number of transition metal complexes bearing isoquinoline units as ligand have been prepared. Isoquinoline usually links to the metal center through the nitrogen lone pair, except when this is hindered, in which case p-bonded complexes are obtained [338]. E+ N

N + E

233 FSO3Me benzene r.t.

N

+ O

FSO3 + N Me

quant.

ONH2 NO2

RuCl3, O2 -

232

(CH2Cl)2 (60%)

NO2

N

(99%)

PhCOCl SbCl5

N

Scheme 17.124

N

MeCN, 40 ºC, 24 h

116

234

230

+

SbCl6 O

Ph

231

+

- ODNP NH2

17.2 Isoquinoline

17.2.5.1.2 Substitution at Carbon Protonation N-Protonated isoquinoline gives facile protonation of the carbocyclic ring, as observed in the kinetic study of its reaction with deuteriosulfuric acid at high temperatures [339]. The protonation occurs at positions C5 (235) > C8 > C7, but at lower acid strength the isoquinolinium cation 236 exchanges a to the nitrogen at C1 to give the zwitterion 237 (Scheme 17.125). H

H

+

+ H+

- H+

N + H 236

235

N H - + 237

N + H

Higher acid strength

Lower acid strength

Scheme 17.125

Energies of the LUMO (ELUMO), the square of the coefficients on carbon atoms at the LUMO, NBO charges on CH groups, and total and relative energies of dications have been calculated by the DFT method. The results predict 238 to be the most favorable dication and C6 and C8 to be the electrophilic reaction centers for this dication. Thus, when isoquinoline was activated under superacidic conditions (CF3SO3H-SbF5, HBr-AlBr3-CH2Br2, or HBr-AlBr3) and then reacted with cyclohexane or benzene, ionic hydrogenation and electrophilic substitution were observed to give 239 and 240, respectively (Scheme 17.126) [340]. C6H12

+

N

N

N + H

H+

239

superacidic C6H6

116 N + H

+ 238

Ph N Ph 240

Scheme 17.126

Nitration Nitration of 116 with fuming nitric acid and concentrated sulfuric acid gives 5-nitroisoquinoline (241) with high regioselectivity (Scheme 17.127) [341]. Nitration using dinitrogen pentoxide in liquid SO2 yields 241 regioselectively in low yield [342]. Sulfonation Isoquinoline (116) has been sulfonated using 50% oleum under icecold conditions to afford isoquinoline-5-sulfonic acid (242) (Scheme 17.128) [343].

j1589

j 17 Six-Membered Heterocycles: Quinoline and Isoquinoline

1590

NO2 HNO3, H2SO4 N

N

0 ºC, 80%

116

+ 9:1

241

N NO2

Scheme 17.127

SO3H H2SO4, H2O N 116

0 ºC, 48 h, r.t. (72%)

N 242

Scheme 17.128

Halogenation Isoquinoline (116) has been brominated using bromine in the presence of aluminum chloride [344], or N-bromosuccinimide in sulfuric acid, to give 243 (Scheme 17.129) [345, 346]. Halogenation at the pyridine ring to yield 244 occurs at C4 through a different mechanism, which involves the following steps: (i) protonation at nitrogen to give the isoquinolinium cation, (ii) nucleophilic addition of bromide at C1 to yield an enamine; (iii) electrophilic addition of bromine at C4 to produce a b-brominated enamine, and (iv) aromatization through HBr elimination [160]. Br

Br NBS, H2SO4 (72%) N 243

1) HCl N

or Br2, AlCl3 (78%) 116

N

2) Br2, PhNO2, 80 ºC (40%)

244

Scheme 17.129

Friedel–Crafts chlorination gives polychloroisoquinolines [347, 348]. Chlorination of 6-aminoisoquinoline with NCS affords 6-amino-5-chloroisoquinoline [349]. Acylation Friedel–Crafts acylation or alkylation reactions on isoquinoline are not possible due to the nucleophilic nitrogen, which rapidly forms the corresponding Nacyl or N-alkylisoquinolinium salts. However, a few examples of intramolecular Friedel–Crafts acylation have been reported, such as the preparation of cyclopenta[ f ] isoquinoline derivatives 245 (Scheme 17.130) [350] and the synthesis of dinapsoline [351]. 17.2.5.2 Reactions with Oxidizing Reagents Although isoquinoline is rather stable to oxidative conditions – except for peracids, which cause N-oxidation to give isoquinoline N-oxide – both benzene and pyridine

17.2 Isoquinoline

O

j1591

O

OH

HSO3F

OEt N

Me

(75%)

OEt N

Me 245

Scheme 17.130

rings can be degraded by ozonolysis followed by oxidative cleavage [352], treatment with alkaline potassium permanganate [353], or fuming nitric acid [354] to give a mixture of phthalic acid (246) and cinchomeronic acid (247) (Scheme 17.131). During the oxidation of 116 in neutral media the benzene ring is not affected and phthalimide is formed [237, 355]. CO2H

Oxidant N

CO2H

116

+

HO2C N

HO2C

247 ([O] = O3; 44%) ([O] = HNO3; 69%)

246

Scheme 17.131

17.2.5.3 Reactions with Nucleophilic Reagents 17.2.5.3.1 Nucleophilic Substitution with Hydride Transfer place faster at C1.

These reactions take

Alkylation and Arylation Isoquinoline selectively undergoes addition of organolithium reagents at C1 to give 1,2-dihydroderivatives [356]. The addition product can be aromatized using an oxidant. Thus, 116 was treated with 248 to give, after quenching with H2O, 1,2-dihydroisoquinoline 249 which was rearomatized to 250 by oxidation in refluxing nitrobenzene (Scheme 17.132) [253]. Direct C–C coupling of ferrocenyllithium (251) with 116 by nucleophilic substitution of hydrogen, using DDQ as an oxidant in the aromatization step, has been performed [357]. Interestingly, coupling was reported to take place at C3 to give 1-(isoquinolin-3-yl)ferrocene (252) (Scheme 17.133). Li N

OMe

+

116

NLi Et2O

H2O

NH OMe

OMe

N OMe

reflux

248 249

Scheme 17.132

PhNO2

250

j 17 Six-Membered Heterocycles: Quinoline and Isoquinoline

1592

N Li Fe

1) Et2O, r.t., 15 min

+

251

N

Fe

2) DDQ, 15 min (60%)

116

252

Scheme 17.133

Indirect benzylation at C4 has been carried out by addition of 116 to lithiated N,Ndiethyl-o-toluamide 253 to give the adduct 254, which was then treated with benzyl chlorides to afford, in the basic reaction conditions, anion 255. This ion further eliminates anion 253 to give the 4-benzylisoquinolines 256 (Scheme 17.134) [358]. CH2Ar O

N

116

NEt2

+

CH2Li

N

THF

Li

- 78 ºC

253

CH2Ar

N H

ArCH2Cl -78 ºC to r.t. Et2NOC

Et2NOC

255

254

N

(60-78%)

256

Scheme 17.134

1-Methylisoquinoline, isolated as its hydrochloride 257, can be easily prepared from 116 with a catalytic amount of sodium hydride in dimethyl sulfoxide and ultrasound activation (Scheme 17.135) [359]. 1) DMSO, cat. NaH 2 h, r.t. N 116

NH

2) HCl, Et2O (74%)

257

+

Cl -

Me

Scheme 17.135

Amination and Nitration Isoquinoline reacts with potassium amide in NH3 to give, after hydrolysis, 1-aminoisoquinoline (258) (Scheme 17.136) [254]. A lower yield was obtained for 258 (20%) when 116 was treated with sodium amide in liquid ammonia under modified Oppenauer oxidation conditions using 9-fluorenone as the hydrogen acceptor [360]. In cases where the isoquinoline ring bears a nitro group, the reaction, in the presence of potassium permanganate, takes a different course. For example, 5-nitroisoquinoline (241) was aminated to give the 6-amino derivative 259 (Scheme 17.137) [361]. In contrast, when 1-nitroisoquinoline (260) was aminated

17.2 Isoquinoline

j1593

KNH2, NH3 N

N

- 33 ºC, (60-75%)

116

258

NH2

Scheme 17.136

NO2

NO2 H2N

KMnO4, NH3 N

N

- 33 ºC, (86%)

241

259 KMnO4, MeNH2 N

260

N

NO2

NHMe 258a

Scheme 17.137

with a liquid methylamine solution of potassium permanganate, displacement of the nitro group occurred to give 258a (Scheme 17.137) [362]. 1-Nitroisoquinoline (260) can be easily prepared from 116 using potassium nitrite, dimethyl sulfoxide, and acetic anhydride [363]. In this case, attack of the nucleophile takes place on an intermediate isoquinolinium cation (Scheme 17.138).

+ NO2-

KNO2, DMSO, Ac2O N

N + S OAc

r.t. (88%)

116

N -Me2S, - AcOH 260

NO2

Scheme 17.138

Hydroxylation Hydroxylation of 116 to give 123 can be performed directly at high temperature by potassium hydroxide [170], or cupric sulfate [364], or at room temperature by biotransformations (Scheme 17.139) [365, 366].

Conditions N

116 Scheme 17.139

NH

123 O

NaOH-KOH (98%) CuSO4, H2O (25%) Streptomyces viridosporus T7A (ATCC 39115) (14%) Pseudomonas putida UV4 (78%)

j 17 Six-Membered Heterocycles: Quinoline and Isoquinoline

1594

17.2.5.3.2 Nucleophilic Substitution with Displacement of Halide Halogens on the pyridine ring are only prone to nucleophilic displacement when the halogen atom is located at C1 or C3, with the halogen at C1 being far more reactive. Halogens on the benzene ring are inert and behave in the same way as halobenzenes. Thus, 1,3dichloroisoquinoline (261) reacts with sodium methoxide to give the monosubstitution product 262 (Scheme 17.140) [367]. Several nucleophiles can displace the halogen atom. For example, reactions on 1-chloro or 1-bromo-substituted isoquinolines with water [368], sodium hydroxide [368], alkoxides [369–371], thioalkoxides [372], trimethylsilanolate [373], ammonia [374], amides [375], amines [376], potassium cyanide [377], and phosphorus ylides [378] have been reported.

Cl N 261

Cl

MeONa, MeOH N

100 ºC (60%)

Cl

262

OMe

Scheme 17.140

Phenylacetonitrile, unlike other active methylene compounds, reacts with 4-bromoisoquinoline (244) by halogen displacement, in the presence of sodium hydride, to afford 263, whereas 3-haloisoquinolines 264 react at C1 to give naphthalene derivative 265 (Scheme 17.141) [379].

Ph

Br

CN

PhCH2CN, NaH N

N

THF, reflux, 10 h (62%)

244

263

CN X N 264

NH2

PhCH2CN, NaH THF, reflux, 14-16 h

(X = Br, 71%; X = Cl, 66%)

Ph 265

Scheme 17.141

Although 3-haloisoquinolines react slowly, their reactions with sodium amide are unusual and do not follow SNA but, rather, an ANRORC (addition of nucleophile, ring opening and ring closure) mechanism [380]. By means of this mechanism, the endocyclic nitrogen in the reaction product 266 comes from the nucleophile and the exocyclic nitrogen comes from the starting isoquinoline 267 (Scheme 17.142).

17.2 Isoquinoline

Br N

Br

N -

NH3 (liq), - 33 ºC

H

(90%)

267

- Br -

N-

NH2

H

NH2

NH2

NH

N H

Br

NaNH2

j1595

N

NH

NH2

266

Scheme 17.142

17.2.5.4 Reactions with Bases 17.2.5.4.1 Direct Metallation Isoquinoline cannot be directly lithiated with organolithium reagents since they are strong nucleophiles. Interestingly, 1-(halophenyl) isoquinolines 268 are lithiated by n-butyllithium, in the position ortho to the halogen, under kinetic control, to give 269 without nucleophilic addition on the isoquinoline ring (Scheme 17.143) [381].

1) n-BuLi THF, -75 ºC

N

N

2) Electrophile R

(66-86%)

268

E = D, I R = F, Cl

E R 269

Scheme 17.143

Direct metallation with a less active metal has also been carried out by reaction of the complex [Ru3(CO)10(NCMe)2] (270) with 116 in tetrahydrofurane. In this way the isomeric ortho-metalated complexes [HRu3(CO)10(C9H6N)] 271 and 271 have been prepared (Scheme 17.144) [382]. [Ru3(CO)10(NCMe2)] 270 N 116

THF, r.t.

N Ru(CO) 3 (OC)3Ru H

Ru(CO)4

271 (25%)

+

Ru(CO)3 N

H Ru(CO) 4 Ru(CO)3

272 (40%)

Scheme 17.144

Isoquinoline magnesium derivatives 273 have been prepared with high regioselectivity using mixed Mg/Li amides of the type R2NMgClLiCl as bases

j 17 Six-Membered Heterocycles: Quinoline and Isoquinoline

1596

(Scheme 17.145) [383]. Subsequent reactions with electrophiles such as iodine, benzoyl chloride, or iodobenzenes give 1-substituted isoquinolines 274. (i-Pr)2N-MgCl.LiCl N

116

R-I N

THF, r.t., 12 h (> 90%)

MgCl.LiCl

273

N

THF, r.t., 2 h (82-92%)

R = I, PhCO, 4-EtO2CC6H4

R

274

Scheme 17.145

17.2.5.5 Reactions of C-Metallated Isoquinolines 17.2.5.5.1 Lithium Derivatives Metal–halogen exchange at low temperature is the method of choice to prepare lithioisoquinolines while avoiding competing nucleophilic addition. Thus, 1-isoquinolyllithium (275), prepared from 1-bromoisoquinoline (276), was reacted with benzophenone to give alcohol 277. Furthermore, 4-isoquinolyllithium (278), obtained from 244, reacted with dry ice to give 4isoquinaldic acid (279) (Scheme 17.146) [384]. These types of metallation at C1 [385] and C4 [386, 387] have recently been used as intermediate steps in the preparation of bovine amine oxidase and B-Raf kinase inhibitors [388, 389].

n-BuLi N Br

1) Ph2CO N

Et2O, - 50 ºC 275

276

Li

Ph OH 277

Ph

Li

Br n-BuLi N 244

1) CO2, -100 ºC N

Et2O, - 50 ºC 278

N

2) satd. aq. NH4Cl

CO2H N

2) 10% aq. NaOH (46%)

279

Scheme 17.146

On the other hand, the tellurium–lithium exchange reaction on 1-isoquinolyl telluride 280 has proven useful in the preparation of 1-isoquinolyllithium (275) (Scheme 17.147) [390]. Only one example of an isoquinoline derivative lithiated at C3 (281) has been reported [391]. C1 must be substituted, otherwise nucleophilic addition takes place as in 3-bromoisoquinoline (282) (Scheme 17.148). 17.2.5.5.2 Zinc Derivatives 1-Isoquinolylzinc salt 283 has been efficiently prepared by direct insertion of zinc into 284, a process that is mediated by the addition of

17.2 Isoquinoline BuTeLi N

1) Me3CCHO, - 78 ºC

BuLi N

THF

N - 78 ºC

Br

280

Te-Bu

j1597

275

N

2) H3O +, r.t.

Li

(36%)

Me3C

OH

Scheme 17.147 Br

Br

MeSNa

N

N

Br

Li

n-BuLi

Br N

N

N

SMe

SMe

THF, < - 70 ºC

SMe

281

E

Electrophile

E = H, Alkyl, CHO, COMe, CO2Me (19-85%)

Br

n-BuLi

NH

THF, < - 70 ºC Bu

282

Scheme 17.148

lithium chloride [392]. Subsequent reaction with benzoyl chloride in the presence of Cu(II) yields 285 (Scheme 17.149).

1) LiCl, Zn, 10-20 min. 150-170 ºC N I 284

2) cat. I2, cat. Me3SiCl cat. BrCH2CH2Br, THF 3) NH4Cl, H2O (96%)

N Zn I Cl 283

Li +

1) [Cl2CuCN]2-2Li+ 5 min, 0 ºC 2) PhCOCl - 20 ºC; 1h, r.t. (90%)

Scheme 17.149

4-Isoquinolylzinc bromide 286, prepared in situ from dihaloisoquinoline 287, provides the substrate for a palladium-catalyzed Negishi coupling step with 7-isoquinolyl triflate 288 to give the key intermediate 289 in the synthesis of B-kinase inhibitors (Scheme 17.150) [389]. 17.2.5.5.3 Boron Derivatives 1-Isoquinolyl and 4-isoquinolyl boronic acid derivatives have been prepared from the corresponding halides. Thus, 4-isoquinolylboronic acid derivative 291 was obtained from 4-bromoisoquinoline derivative 290 and reacted under Suzuki conditions to give the kinase inhibitor 292 (Scheme 17.151) [389, 393]. 4-Isoquinolylboronic acid (293) is also a nucleophilic substrate in palladiumcatalyzed Suzuki–Miyaura reactions [394–396]. Reaction of 293 with iodo derivative 294 gives the KDR kinase inhibitor 295 (Scheme 17.152).

N Ph O 285

j 17 Six-Membered Heterocycles: Quinoline and Isoquinoline

1598

N

Br

ZnBr

1) n-BuLi, THF, hexane 10 min, -70 ºC

N

N 2) ZnBr , THF, - 70 ºC 2 287

N

CF3SO3

NH4Cl

288

Pd(PPh3)4, THF, 0ºC to r.t.

Cl 286

Cl

N

H2O (52%) 289

Cl

Scheme 17.150

N

Br N

N

2) B(Oi-Pr)3, 4.5 h, -74 ºC 3) HCl, H2O, r.t.

HN

290

B(OH)2

1) n-BuLi, THF. hexane 1 h, -74 ºC

HN

(73%)

t-Bu

291

N

TfO

N

K2CO3, PdCl2(PPh3)2 DMF, 2 h, 100 ºC t-Bu

HN

(65%)

t-Bu

292

Scheme 17.151

N I S

B(OH)2

Na2CO3, Pd(PPh3)4

N N 293

+

NH2 294

H2O, (CH2OMe)2, 90 ºC (70%) NH2

S N NH2 295 NH2

Scheme 17.152

17.2.5.5.4 Tin Derivatives Trialkylstannylisoquinoline derivatives at the C1, C3, and C4 positions have been prepared and reacted with electrophiles in both noncatalyzed and palladium-catalyzed processes. The reaction of chloro- or bromoisoquinolines 296 with trimethylstannylsodium – generated in situ from chlorotrimethylstannane and sodium – provides stannylisoquinolines 297. Acylation, alkoxycarbonylation, and iodination reactions were subsequently performed on 297 [397–399]. For example, 1-trimethylstannylisoquinoline (298) reacts with iodine to give 299 (Scheme 17.153). The palladium-catalyzed Stille reaction has been carried out on both 3-stannylisoquinoline N-oxide 300 [400] and 4-stannylisoquinoline [401]. N-Oxide 300 was

17.2 Isoquinoline

N

X

Me3SnNa N

296

j1599

SnMe3

297 I2 N

N

(96%)

298 SnMe3

299

I

Scheme 17.153

prepared from 3-tri-n-butylstannylisoquinoline (301) and m-chloroperbenzoic acid (MCPBA). The Stille reaction of 300 with 5-bromopyrimidine (302) yields 303 (Scheme 17.154). Br Sn(n-Bu)3 N 301

Sn(n-Bu)3

MCPBA CHCl3 (80%)

N + O 300

302

N

N

N

N

Pd(PPh3)4 toluene (58%)

N + O 303

Scheme 17.154

17.2.5.5.5 Palladium-, Nickel-, and Manganese-Catalyzed Reactions Numerous metal-catalyzed reactions on haloisoquinolines have been reported. Both Suzuki– Miyaura and Stille reactions provide high yields of coupling products on diversely substituted boronic acids [402–404] and stannanes [375, 404, 405]. Nickel-catalyzed processes using both Grignard reagents [404, 406, 407] or lithium borides [404] have been performed and also lead to interesting homocoupling products [408, 409]. Based on the differential reactivity of the carbon–chlorine bonds in 261, several carbon–carbon bond forming cross-coupling reactions have been exploited (Scheme 17.155) [404]. Under palladium catalysis, arylboronic acids regioselectively couple at C1 to give 1-aryl-3-chloroisoquinoline derivatives 304. Further coupling with aryl boronic acids, 2-trimethylstannylpyridine (palladium catalyzed) or arylmagnesium bromides (nickel-catalyzed) gives 1,3-diarylisoquinolines 305. Furthermore, 304 furnishes 3,30 -bis-isoquinolines 306 under nickel-catalyzed zinc-based Colon reaction conditions. Recently, a manganese-catalyzed cross-coupling reaction of heterocyclic chlorides with aryl- and alkylmagnesium halides has been developed [410]. Thus, 1-chloroisoquinoline (307) yields 1-n-butylisoquinoline (308) under these conditions (Scheme 17.156). Heck and Sonogashira couplings have also been performed on haloisoquinolines. 4-Bromoisoquinoline (244) couples to 1,5-hexadiene under solid-phase conditions to

j 17 Six-Membered Heterocycles: Quinoline and Isoquinoline

1600 Cl N

261

Cl

Cl Coupling conditions

ArB(OH)2, CsF

Ar

N

Pd(PPh3)4, DME, 6 h

304

2

N

Ar

305

NaI, Zn, NiCl2, PPh3 THF, reflux, 3 h

Ar

Coupling conditions: Ar2MgBr, NiCl2(dppf), THF, 0 ºC to r.t., 1 h or Ar2B(OH)2, Cs2CO3, Pd(PPh3)4, DMF, 100 ºC, 18 h or 2-(Me3Sn)C5H4N, Pd(PPh3)4, DMF, 100 ºC, 18 h

Ar N N Ar

306

Scheme 17.155

1) n-BuMgCl, MnCl2 THF, 0 ºC, 2 h N 307

N

2) NH4Cl

Cl

308

n-Bu

Scheme 17.156

give 309 as result of a three-component process (Scheme 17.157) [411]. 1-Chloroisoquinoline (307) couples to 1-hexyne to yield 310 (Scheme 17.157) [412]. NH

H N

N

Br O

1) DIPEA, Pd(OAc)2, DMF

+

N

N 307

Cl

H

N 309

(86%)

244

+

H2NOC

2) 25% TFA/CH2Cl2

n-Bu

CuI, DIPEA, PPh3

N

PdCl2(PPh3)2 (81%)

310 n-Bu

Scheme 17.157

Negishi couplings have been performed in the synthesis of ferrocenyl-QUINAP (311), a planar P,N-ligand for palladium-catalyzed allylic substitution reactions. Directed ortho-lithiation of chiral ferrocenyl sulfoxide 312 with LDA and subsequent

17.2 Isoquinoline

addition of zinc(II) bromide yields organozinc 313, which is treated with 1-iodoisoquinoline (299) under Negishi conditions to give chiral complex 314. This compound was then converted into 311 in three steps (Scheme 17.158) [413].

Fe

O S 1) LDA, THF p-Tol -78 ºC, 30 min

Fe

NO S p-Tol

O S p-Tol

Fe

2) ZnBr2 - 78 ºC to r.t. 60 min

312

Zn

N 299 I Pd(dba)2, 60 ºC, 20 h (78%)

313

N 3 steps

PPh2 Fe

(69%) 314

311

Scheme 17.158

17.2.5.6 Reactions with Reducing Reagents Selective reduction of the pyridine ring in 116 to the tetrahydroisoquinoline 315 can be achieved with sodium cyanoborohydride in acid solution [414], sodium borohydride in the presence of nickel(II) chloride [415], or zinc borohydride (Scheme 17.159) [187]. The dihydride ruthenium complex RuH2(PPh3)2 yields 315 with low conversion [416], while hydrosilylation of 116 catalyzed by [Rh(cod)(PPh3)2] PF6 afford 315 in high yield [417]. 1) NaBH4, cat. NiCl2 MeOH (86%) N 116

1') Zn(BH4)2, cat. PhNMe2 DME (75%)

NH 315

Scheme 17.159

Catalytic hydrogenation reduces the pyridine ring in 116 to give 315 when performed on cupric chromite [418], Raney nickel [419], platinum oxide [420], platinum [421], rhodium [422], or palladium [423]. The benzene ring can be hydrogenated in trifluoroacetic acid solution to provide 316 (Scheme 17.160) [424]. This product can also be obtained by ionic hydrogenation with cyclohexane through superacidic activation, as mentioned in Section 7.2.5.1.2 ) (Protonation) [340].

j1601

j 17 Six-Membered Heterocycles: Quinoline and Isoquinoline

1602

NH 315 Ru/Al2O3

H2 (200 atm) CuCr2O4 200 ºC, EtOH (100%)

N 316

+

H

H

315

+

N

318

H

116 H2, Pd TFA

NH

NH

H2 (50-100 atm) 135-170 ºC

NH

Ru/C

H NH

317

315 N 316 Scheme 17.160

Full hydrogenation using ruthenium leads to cis- and trans-decahydroisoquinolines 317 and 318. When the catalyst is supported on carbon the hydrogenation proceeds via 315. If ruthenium is supported on alumina there is competition between the two tetrahydro intermediates 315 and 316 [425]. The metal hydride complex Mo(PMe3)H4 can also be used to perform the catalytic hydrogenation of 116 to 315 [426]. Dihydroisoquinolines can be produced using either sodium in liquid ammonia (3,4-dihydro, 319) [427] or lithium aluminum hydride (1,2-dihydro, 320) [427–429]. The dihydroisoquinolines can be oxidized back to 116 with chloranil or disproportionate in acid solution to give a mixture of 1,2,3,4-tetrahydroisoquinoline (315) and 116. Tetrahydroisoquinoline 315 can be obtained directly from 116 by reduction with sodium in a non-protic solvent or from 319 using sodium in liquid ammonia (Scheme 17.161). 17.2.5.7 Reactions with Radical Reagents The replacement of hydrogen at C1 through homolytic processes is also possible in 116, with the Minisci reaction being by far the most important approach [430]. Since 116 is a p-deficient heterocycle, nucleophilic free radicals such as hydroxymethyl, alkyl, and acyl give better results. Moreover, acidic conditions are essential to promote N-protonation because this makes C1 more reactive towards the nucleophilic radical [431]. Formylation [432] and carbamoylation [433] reactions have been performed on 116 to give 321 and 322, respectively, in a selective manner (Scheme 17.162). tert-Butyl peroxide, hydrogen peroxide, or N-hydroxyphthalimide were used as free radical promoters. Acetylation gives mixtures of acetylated and methylated products [434].

17.2 Isoquinoline

1) Na, NH3 liq - 70 ºC

LiAlH4 NH

N

Et2O

NH

2) NH4Cl

116

320

N H

1) Na, (CH2OMe)2 1) [Ru(cod)(PPh3)2]PF6 r.t. SiH4, toluene, r.t. 2) MeOH (87%) 1) Na, NH3 liq, - 50 ºC NH 315

N

2) NH4Cl

319

Scheme 17.161

HCONH2 CAN, NHPI

(CH2O)3 t-BuOOH, FeSO4 N 321

N

N TFA, 6 h, 70 ºC

TFA, MeCN

CHO

(78%)

116

322

CONH2

Scheme 17.162

Alkylation of 116 has been carried out with alkyl iodides [435, 436] or alkyl xanthates to give 323 selectively or a mixture of 324 and 325 (Scheme 17.163) [437].

SMe

O N 325

+

X

i-PrI, DMSO N

(PhCO2)2, TFA PhCl, reflux N

324

(CH2OH)2 (NH4)2S2O8, AgNO3 TFA, H2O, 3 h, reflux (58%)

326

CH2OH

N

H2O2, 50 ºC 88%

116

N

Scheme 17.163

j1603

323

i-Pr

j 17 Six-Membered Heterocycles: Quinoline and Isoquinoline

1604

Hydroxymethylation carried out by persulfate oxidation of ethylene glycol can be performed regioselectively to give 326 [438]. 17.2.5.8 Electrocyclic and Photochemical Reactions The greater tendency of isoquinolinium salts towards nucleophilic addition at C1 in comparison to isoquinoline is demonstrated by the number of cycloaddition reactions reported to date. Isoquinoline itself does not undergo cycloaddition processes and this reaction always occurs through an isoquinolinium intermediate. Nevertheless, a theoretical G3(MP2) study regarding the concerted cycloaddition reaction between ethylene and 116 has been published and concluded that 1,4-cycloaddition is the most favorable in terms of both transition state energy barrier and NBO atom charges [439]. Isoquinoline reacts with dimethyl acetylenedicarboxylate to give quinolizinetetracarboxylate 327 [440]. When isocyanate is present in the reaction mixture, pyrimidoisoquinoline 328 is obtained [441]. A four-component reaction with dibenzoylacetylene, diketene, and amines to give pyrroloisoquinolines 329 [442], or water to give 1,2-dihydroisoquinolines [443], has been reported. Isoquinoline also gives the cycloadduct 330 with benzonitrile oxide (Scheme 17.164) [444].

N

Ph

N

Ph

RNHCO Ac OH

Ph O

Ph

O

330 + N O

(60%)

diketene dibenzoylacetylene

DMAD, MeOH - 10 ºC to r.t. N

RNH2, CH2Cl2, r.t. (R = s-Bu, 78%)

116

329

(59%)

DMAD, PhNCO, CH2Cl2 - 5 ºC to r.t.; (99%)

N Ph

N O

N MeO2C

CO2Me

CO2Me CO2Me

327

CO2Me CO2Me

328 Scheme 17.164

Stable isoquinolinium salts and ylides give cycloadditions with several dienophiles. Thus, both N-alkyl- [445] and N-arylisoquinolinium [446] salts react with electron-rich

17.2 Isoquinoline

j1605

dienophiles such as vinyl sulfides or ethers through the Bradsher cycloaddition reaction. N-Methylisoquinolinium iodide (331) and ethyl vinyl ether give adduct 332 (Scheme 17.165). Isoquinolinium methylides bearing one or two electronOEt OEt N

+ IMe

331

N

MeCN, r.t. (83%)

332

Et3N + Cl N CH2CO2H PhMe

333

+ IMe

N 334

N

DMAD

+ -

CO2

(77%)

MeO2C 335

O

+ IN NH2

337

1)

K2CO3 DMF, r.t. 336

+ N NH -

CO2Me

O H

338

N

2) TFA, CH2Cl2, r.t.

HO2C

(15%)

Scheme 17.165

withdrawing substituents at the ylide undergo cycloadditions with aryl- and alkylsubstituted electron-rich olefins [447] or dimethyl acetylenedicarboxylate [448, 449]. This reaction has been exploited in the synthesis of pyrrolo-isoquinolines related to the lamellarins [450]. The reaction of the salt 333 with DMAD in the presence of triethylamine occurs via methylide 334 to yield pyrroloisoquinoline 335. Quaternary isoquinolinium ylides such as isoquinoline azomethine imine 336, generated in situ from 2-aminoisoquinolinium iodide (337), react with polymer-bound alkyne 338 to give pyrazoloisoquinolines 339 after cleavage from the resin [451]. There is very little literature concerning photochemical reactions for isoquinolines when compared with electrocyclic methods. Photochemical free-radical alkylation [452, 453] and phenylation [454] reactions have been reported on 116. Ethanol or propanoic acid can act as the source of ethyl radicals under light irradiation to give 340. Phenylthallium bis-trifluoroacetate (341) allows selective substitution at C1 under acidic conditions to afford 342 (Scheme 17.166). 1) EtCO2H, C6H6, hv (20%)

PhTl(OCOCF3)2 341 N 342

Ph

Scheme 17.166

hv, CF3CO2H (81%)

N 116

1') EtOH, HCl, hv (22%)

N 340

Et

N

339

j 17 Six-Membered Heterocycles: Quinoline and Isoquinoline

1606

Photolysis of isoquinoline N-oxides leads to different products depending upon the reaction conditions and the substitution pattern on the heterocycle. Irradiation of 343 (R, R1 ¼ H) furnished isoquinolone (123) via the S1 state through a radical–ion-pair mechanism, as concluded from magnetic-field effect experiments [455]. However, irradiation of the 1-cyano derivative 343 (R ¼ CN; R1 ¼ H) affords 1,3-oxazepine 344 (R1 ¼ H), via the S1 state, through oxaziridine intermediates (Scheme 17.167) [455, 456]. 1-Cyanoisoquinoline N-oxides substituted at C3 can give two consecutive photochemical reactions, resulting first in oxazepine 344 (R1 ¼ Me) and then in benzofuroazete 345 (Scheme 17.167) [457].

R1

NC

N O

R N O

R1

R1

N O

CN

Me R1 = Me

N O

CN

CN

345

344

R = CN R1 + N O

343 R

hv S + N - 1 O

EtOH R=H

R

HOEt

+ N . O EtOH .

+ N OH EtO

H

+ N OH EtO

-

NH

123

O

Scheme 17.167

17.2.5.9 Isoquinoline Derivatives 17.2.5.9.1 Oxyisoquinolines The main feature of hydroxy-substituted isoquinolines is the tautomerism shown by some members of this family. With the exception of 1-hydroxy- and 3-hydroxy-substituted isoquinolines, the others are true phenols; they are in equilibrium with their zwitterions such as, for instance, 346 and 347, and they behave as naphthols [458–461]. In contrast, isoquinolin-1-ol (122) completely tautomerizes to 123 (1-isoquinolone, 2H-isoquinolin-1-one) since the hydroxyl tautomer 122 lacks a stable polarized resonance contribution, in contrast to 123 [462]. Isoquinolin-3-ol (124) remains in an intermediate situation since 125 (3-isoquinolone, 2H-isoquinolin-3-one) is of comparable stability. The less polar tautomer 124 (colorless) predominates in low polarity solvents such as diethyl ether, whereas the more polar 125 (yellow) dominates in water or ethanol [463, 464]. The similar stability of these two systems is due to two opposite factors. In 124 the stability relies on the complete benzene ring, whereas in 125 the amide unit is the major contributor to stability.

17.2 Isoquinoline

N OH

N

O

346

-

NH + 347

N + OH

OH

NH O

122 OH

123 O

N

NH

124

125

Classical reactions of isoquinolin-1-ones are N- and O-alkylation. Deprotonation of 123 with base and reaction of the resulting bidentate anion with alkyl halides or tosylates are reported to result in alkylation exclusively at nitrogen to give products like 348 (Scheme 17.168) [465], although traces of the corresponding O-alkylated products are also obtained [466]. Harder electrophiles, such as triflic anhydride and silylating agents, react at the exocyclic oxygen, although the nucleophile may be the neutral molecule in these cases [467, 468]. These O-substituted products have also been prepared by displacement of halides from 1-halo-substituted isoquinolines by alkoxides, but harsh conditions are necessary for this to occur. Regioselective Oalkylation to give 349 can be achieved using the Mitsunobu reaction with benzylic electrophiles under mild conditions (Scheme 17.168) [469]. A classical reaction of isoquinolones is their conversion into haloisoquinolines with phosphorus halides. For example, 123 reacts with phosphoryl chloride to give 307 (Scheme 17.168) [470]. KOH, EtOH

POCl3 N 307

Cl

NH

(100%)

PhCH2Cl (99%)

O 123 PhCH2OH PPh3, DEAD THF, r.t.

(39%)

N 349 Scheme 17.168

O

j1607

Ph

N 348

O

Ph

O

NH + -

j 17 Six-Membered Heterocycles: Quinoline and Isoquinoline

1608

17.2.5.9.2 Aminoisoquinolines The whole family of aminoisoquinolines, in contrast to hydroxyisoquinolines, exists only as amino tautomers and all are protonated on the ring nitrogen. Dissociation constants for aminoisoquinolines 350 have been determined by potentiometric titration [471] or spectrophotometry [472]. The most basic aminoisoquinoline bearing the amino group on the benzene ring is the 6-isomer 351; the high basicity is due to its most stable resonance contribution, that is, a para-quinoid structure. When the amino group is located on the pyridine ring, the most basic isomer is 1-aminoisoquinoline (258) since this is the only system that retains the aromaticity of the benzene ring in its most stable resonance contribution. The basicity of aminoisoquinoline derivatives has been studied and it was found that the steric effects of bulky substituents neighboring the protonated ring nitrogen atom influence electron transfer in such arrangements [473]. 5.59

5.05

7.17 N

+ H2N

H2N

6.28

NH +

NH2

NH 351

6.20 6.06

7.62

pKa values for unsubstituted aminoisoquinolines 350

NH + NH2

NH 258

+ NH2

17.2.5.9.3 Alkylisoquinolines Heterobenzylic hydrogen atoms of the side chain in the 1-position of isoquinoline are acidic. These protons may be abstracted with strong bases such as n-butyllithium, lithium diisopropylamide, or sodium amide to give metalated intermediates that can condense with various electrophiles. Heterobenzylic hydrogens at the 3-position are much less acidic and thus regioselective deprotonation in 1,3-dialkylisoquinolines is possible [264, 474]. Condensation products can also be prepared in acidic media, where the nucleophilic species is an enamine and the acidity of the heterobenzylic hydrogens is enhanced by the prior formation of an isoquinolinium cation [475]. Treatment of 1,3-dialkylisoquinoline 352 (R ¼ Me, R1 ¼ H) with n-butyllithium regioselectively gives the 1-isoquinolylmethyllithium derivative 353 (R ¼ Me, R1 ¼ H). Heterobenzyllithiums derivatives 353 react with benzophenone or benzenenitrile to afford 354 and 355, respectively (Scheme 17.169). When 352 (R ¼ R1 ¼ H) is heated with benzaldehyde in the presence of a Lewis acid such as zinc chloride, the reaction proceeds via the enamine 356 to afford 1-styrylisoquinoline (357) (Scheme 17.169). It is possible to oxidize alkyl side-chains while leaving the ring intact [476]. The oxidation of 358 with manganese dioxide affords mainly a mixture of 359 and 360. Selective oxidation of 1-methyl groups, as in 361, can be achieved with selenium dioxide, in the presence of other methyl groups in both the benzene and pyridine rings, to give 362 (Scheme 17.170).

17.2 Isoquinoline

j1609 Me

PhCOPh THF, 1 h 1

1

R

R

N

1

R

N

1

THF, hexane 30 min

Me

(R = Me, R1 = H) (75%)

R

R

n-BuLi

R

= OMe) (R = H, (85%) R1

ZnCl2 100 ºC 1

R NH

1

R

CH2

Ph

354

N

100 ºC, 20 h (R,

R1

= H) 357 Ph

MnO2

HO

O

O

359 (46%)

358 Me

NH

benzene

Me

Me

Me

+

NH Me

O

360 (34%)

Me

SeO2 N Me

Me 361

dioxane (43%)

NH2 355

Scheme 17.169

Me

N

MeO

PhCHO

356

N

Ph

MeO

353

R

HO

PhCN THF, 30 min

CH2Li

352

N

N Me

CHO 362

Scheme 17.170

17.2.5.9.4 Isoquinoline Carboxylic Acids These derivatives behave as typical aromatic acids. The main difference arises in isoquinoline- and N-alkylisoquinolinium1-carboxylic acids, which can decarboxylate via an ylide intermediate that can be trapped by electrophiles such as aldehydes, diazo compounds, or diazonium ions [477, 478]. Isoquinoline-1-carboxylic acid (363) affords 285a when heated under reflux with benzaldehyde. Betaine 364 yields the corresponding ylide 365 when heated (Scheme 17.171). 17.2.5.9.5 Quaternary Isoquinolinium Salts Although some reactions in this chapter are performed by means of a quaternary isoquinolinium salt, here the high

C 6H 5

j 17 Six-Membered Heterocycles: Quinoline and Isoquinoline

1610

PhCHO NH + CO2

N CO2H

N

NH - +

reflux (57%)

HO 237

363

Ph

285a

Heat N + Me CO2

N Me - +

364

365

Scheme 17.171

versatility of these compounds will be discussed in more detail. One of the most characteristic features of these compounds is their ease of nucleophilic addition at the 1-position, as compared with isoquinolines, to give relatively stable neutral 1,2dihydroisoquinolines, which in some cases may disproportionate or be oxidized. Nucleophiles such as organometallics add to different isoquinolinium salts. Organolithiums, for instance, react with isoquinoline-N-borane (366, R ¼ H3B) as precursors of substituted tetrahydroisoquinolines 367 [479]. Grignard reagents give 1,2-dialkyl-1,2-dihydroisoquinolines (368) when reacted with N-alkylisoquinolinium salts (366, R ¼ Me) [480]. N-Acylisoquinolinium salts (366; R ¼ CO2Me) add benzylstannanes to yield dihydroisoquinoline 369 (Scheme 17.172) [481]. Both stannanes

N

CO2Me

Me

367

1) MeLi 2) DIBAH 3) ClCO2Me 4) H3O+

(67%) (R = H3B - ) THF, (100%) N

Me

370 Me

N

(R = Me) (X = BMe4)

366 (56%)

(R = CO2Me)

+ (X-) R

Scheme 17.172

N

(R = Me) 368

PhCH2SnMe3 CH2Cl2

N

369

MeMgBr

CO2Me CH2Ph

Me

Me

17.2 Isoquinoline

j1611

and Grignard reagents add to chiral isoquinolinium salts in a diastereoselective manner [482, 483]. In addition, Zincke’s salt of isoquinoline [366; R ¼ 2,4(NO2)2C6H3] may be transformed into chiral isoquinolinium salts [484] by reaction with chiral amines and the products are then reacted with Grignard reagents to afford 1,2-dihydroisoquinolines diastereoselectively [485]. N-Alkylisoquinolinium tetraalkylborates (366; R ¼ Me, X ¼ BMe4) transfer alkyl groups efficiently under thermal or photochemical activation to give 370 (Scheme 17.172) [486]. On the other hand, the enantioselective addition of chiral allylsilanes activated by silver salts to an Nacylisoquinolinium cation has been reported to give 1-allyl-1,2-dihydroisoquinolines [487]. These compounds may also be prepared using allyl bromides in the presence of indium [488]. Softer nucleophiles also add to isoquinolinium cations (Scheme 17.173). Silyl enol ethers 371 react with isoquinolinium salts (366, R ¼ CO2Me) to give dihydroisoquinolines 372 [489]. A diastereoselective version of this approach has been applied to the synthesis of (–)-homolaudanosine [490]. N-Methylisoquinolinium salts (366, R ¼ Me) undergo oxoalkylation with ketone enolates under ultrasound (US) activation to give 373 [491]. When the N-alkyl chain bears an aldehyde, as in 366 [R ¼ ( CH2)4CHO], an organocatalytic cyclic oxoalkylation reaction has been performed to give 374 in a high diastereomeric ratio [492]. Active methylene compounds react with

N Me

CO2Me

CO2H

372 OSiMe3

(R = CO2Me )

Me

(56%)

371

OSiMe3

CH2Cl2, 0 ºC to r.t. HCBr3, MeCN, H2O, KOH r.t. 45 min N

CH2Ph

N

(R = Bn); (89%)

acetone, NaOH, US N

(R = Me); (70%)

R

366

376 CBr3

Ph

(R = CH=N-t-Bu)

HN

(79%)

N

N O HN

375 O

O

O

H2O, 70 ºC, 12 h

Scheme 17.173

+ X-

O NH

NH O

Ph

N H

Et3N, CH2Cl2 - 20 ºC

373

(R = (CH2)4CHO) (94% conv.)

N

t-Bu H O

374

O

Me Me

j 17 Six-Membered Heterocycles: Quinoline and Isoquinoline

1612

intermediate N-formylisoquinolinium imines (366, R ¼ CH ¼ N-tert-butyl), produced by reaction of isocyanides with isoquinoline, to yield dihydro derivatives 375 through a three-component one-pot reaction [493]. N-Benzylisoquinolinium salt 366 (R ¼ Bn) reacts with tribromomethylsodium (generated in situ from bromoform) to give the addition product 376 (Scheme 17.173) [494]. The cyanide anion also adds to N-acylisoquinolinium salts to give so-called Reissert compounds such as 377 (Scheme 17.174). These compounds can be prepared using conventional phase-transfer catalysis [495], or accelerated with ultrasound [496], as well as crown ether catalysis [497]. Thus, 116 reacts with benzoyl chloride to give the intermediate N-benzoylisoquinolinium salt 378, which in the presence of potassium cyanide affords the dihydroisoquinoline 377 under phase-transfer catalysis conditions. Reissert compounds are useful materials in preparing 1-alkyl- and 1-cyanoisoquinolines. Deprotonation of 377 with NaH followed by alkylation and further removal of the acyl and cyanide groups gives rise to 379 [498]. Furthermore, the N-sulfonyl analogues, such as 380, are prone to eliminate an arylsulfinate to yield 381 [499]. The solid-phase Reissert reaction has also been performed using benzoyl chloride resin through solid-supported intermediate 382 [500]. A highly enantioselective version of the Reissert reaction has been reported using a chiral substituted BINOL catalyst [501]. PhCOCl

TsCl, KCN, r.t. NTs

380

N

CN

116

378

+

KCN

Cl O

(69%)

1)

(58%)

2) TMSCN 3) LDA, THF, -78 ºC 4) PhCH2Cl, THF, r.t.

CN

382

377

CN

Ph

1) NaH, DMF 2) PhCH2Cl

O N

O

N

CH2Cl2, H2O, r.t.

Ph

COCl

DBU, 0 ºC

N

381

N

CN

NaOH, H2O

KOH, THF Ph

reflux (50%)

N

379

Ph

N

reflux, (70%) Ph

O

CN Ph

Scheme 17.174

Reduction of quaternary isoquinolinium salts gives stable N-substituted 1,2dihydro- or tetrahydroisoquinolines. Hydrides such as sodium hydride or lithium tetrahydroaluminate react under mild conditions. Isoquinoline-N-borane 383 (R ¼ H3B; R1 ¼ H) adds NaH to give a dihydroisoquinoline that is further transformed into tetrahydroisoquinoline 384 [479]. Lithium tetrahydroaluminate reacts with Nalkylisoquinolinium salts 383 (R ¼ Me; R1 ¼ H) to give the corresponding dihydroderivatives such as 385 [480, 502]. On the other hand, hydrogenation of isoquinolinium salts can also be performed. The iridium-catalyzed asymmetric hydrogenation of 383 (R ¼ CO2Me; R1 ¼ Me) affords 386 (Scheme 17.175). This procedure has been applied to the synthesis of naturally occurring alkaloids [194].

17.2 Isoquinoline

N

j1613

CO2Me

384 (68%) (R = H3B - ) (R1 = H)

1) NaH/ DIBAH 2) ClCO2Me 4) H3O+

[(IrCl8(cod))2]/ (S)-segphos H2, LiCO3, LiBF4, THF N

386

Me

Me

N

(R = CO2Me); (R1 = Me) (80%)

383

R

+ (X-) R

1

LiAlH4, Et2O, r.t. N

(R = Me; R1 = H) (70%)

Me

385

Scheme 17.175

As mentioned earlier in this chapter, isoquinoline gives electrocyclic reactions through isoquinolinium intermediates. Thus, 116 reacts with dimethyl acetylenedicarboxylate (DMAD) through a Huisgen process [503] to give the 1,4-dipolar intermediate 387, which can be trapped by benzoquinones or activated alkenes to give highly functionalized polycyclic adducts [504, 505]. For example, adduct 388 has been obtained using p-benzoquinone (Scheme 17.176).

O

DMAD N

N +

(CH2OMe)2, r.t.

116

387

CO2Me -

O 6 h, (75%)

H

N

O

CO2Me 388 O

Scheme 17.176

17.2.5.9.6 Isoquinoline N-Oxides The chemistry of isoquinoline N-oxide (232) differs from that of pyridine through the ability to undergo electrophilic substitution at the C5-position of the benzene ring. For example, 389 is prepared by nitration of 232 with mixed acid (Scheme 17.177) [506]. Compound 232 has been shown to be less reactive than the corresponding pyridine- and quinoline N-oxide towards electrophilic substitution through base-induced deprotonation [507]. Treatment of 232 with lithium 2,2,6,6-tetramethylpiperidide (LTMP) and subsequent reaction with benzaldehyde affords a mixture of mono- and disubstituted N-oxides 390 and 391. Although there are several deoxygenation methods by which to convert 232 into 116, recently the molybdenum pentachloride/sodium iodide system has proven to be a mild and efficient process [508].

CO2Me CO2Me

j 17 Six-Membered Heterocycles: Quinoline and Isoquinoline

1614

NO2 N

+ O

389 HNO3 H2SO4 60 ºC MoCl5, NaI N

116

N

MeCN, r.t. (86%)

OH

(85%)

+ O

1) LTMP, Et2O TMEDA, -78 ºC

N

2) PhCHO

HO

232

+ O

+

Ph

390 (28%)

N HO

+ O

Ph

Ph

391 (17%)

Scheme 17.177

Some reactions performed on N-oxides, such as deoxygenation with phosphorus pentahalides, take place with both Ca-substitution and elimination of an oxygen atom as part of a good leaving group. A base is usually necessary to promote the elimination. As an example, the reaction of 232 with ethyl chloroformate and ethanol leads to 392 [509]. Similarly, treatment of 232 with diethyl cyanophosphonate or trimethylsilyl cyanide gives 1-cyanoisoquinoline (381) (Scheme 17.178) [510, 511]. ClCO2Et, Et3N N 392

+ N O

EtOH, (73%)

OEt

(EtO)2P(O)CN, Et3N N

(80%)

381 CN

232

Scheme 17.178

Isoquinoline N-oxide compounds can also be interesting catalysts and reagents. QUINOX (393), a chiral isoquinoline N-oxide, performs asymmetric allylation of aldehydes to give allylic alcohols 394 in good enantiomeric excess (Scheme 17.179) [512]. N

O Ph

H

+

SiCl3

+

O OMe

CH2Cl2, - 40 ºC, 12 h (68%; 87% ee)

Scheme 17.179

OH

393 Ph

394

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and Yohannes, D. (1984) The Journal of Organic Chemistry, 49, 4056. Lorsbach, B.A., Bagdanoff, J.T., Miller, R.B., and Kurth, M.J. (1998) The Journal of Organic Chemistry, 63, 2244. Funabashi, K., Ratni, H., Kanai, M., and Shibasaki, M. (2001) Journal of the American Chemical Society, 123, 10784. Gensler, W.J. and Shamasundar, K.T. (1975) The Journal of Organic Chemistry, 40, 123. Huisgen, R., Morikawa, M., Herbig, K., and Brunn, E. (1967) Chemische Berichte, 100, 1094. Nair, V., Sreekanth, A.R., Biju, A.T., and Rath, N.P. (2003) Tetrahedron Letters, 44, 729. Nair, V., Devi, B.R., and Varma, L.R. (2005) Tetrahedron Letters, 46, 5333. Ochiai, E. and Ikehara, M. (1953) Journal of the Pharmaceutical Society of Japan, 73, 666. Tagawa, Y., Hama, K., Goto, Y., and Hamana, M. (1995) Heterocycles, 40, 809. Yoo, B.W. and Park, M.C. (2008) Synthetic Communications, 38, 1646. Hayashida, M., Honda, H., and Hamana, M. (1990) Heterocycles, 31, 1325. Harusawa, S., Hamada, Y., and Shiorii, T. (1981) Heterocycles, 15, 981. Miyashita, A., Matsuda, H., Iijima, C., and Higashino, T. (1992) Heterocycles, 33, 211. Malkov, A.V., Ramirez-Lopez, P., Biedermannova, L., Rulisek, L., Dufkova, L., Kotora, M., Zhu, F., and Kocovsky, P. (2008) Journal of the American Chemical Society, 130, 5341.

485

486 487

488

489

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494 495 496

497

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18 Six-Membered Rings with One Oxygen: Pyrylium Ion, Related Systems and Benzo-Derivatives Javier Santamaría and Carlos Vald
es

18.1 Introduction

Six-membered oxacycles are a family of compounds that are widely present in natural products as well as in pharmaceuticals and other useful compounds and materials. The parent member of the family is the pyrylium cation 1, which is the oxa-analog of benzene. Other important unsaturated derivatives are 2H-pyran (2) and 4H-pyran (3), which can be seen as the result of the addition of a hydride to the pyrylium cation. Carbonyl-containing pyran-2-one (4) and pyran-4-one (5) are prominent derivatives of pyrans. Moreover, the benzo derivatives of all these structures also constitute important types of heterocycles. Some of the more common structures, including their usual names are presented in Figure 18.1. Owing to the structural variety of pyrylium and pyran derivatives, this chapter will concentrate mostly on the parent pyrylium salt, as well as on the important oxa derivatives pyranones and benzopyranones.

18.2 Pyrylium Cation and Benzo-Derivatives 18.2.1 Pyrylium Salts: General Considerations

The pyrylium cation (1) is the ring system in which a CH of benzene is replaced by an oxygen atom. It is a cationic and highly perturbed aromatic ring, as a result of the high electronegativity of the oxygen atom. The aromaticity of pyrylium salts is supported by the physical properties of these cations, such as magnetic properties, vibrational spectra, and electronic absorption spectra, and also by their structural parameters [1]. Nevertheless, some of the more common aromaticity indexes indicate that pyrylium salts are less aromatic than most of other aromatic six-membered rings [2]. Figure 18.2 presents the structural parameters of the equilibrium geometry of the pyrylium cation obtained from calculations at different levels of theory [3]. Modern Heterocyclic Chemistry, First Edition. Edited by Julio Alvarez-Builla, Juan Jose Vaquero, and José Barluenga. Ó 2011 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2011 by Wiley-VCH Verlag GmbH & Co. KGaA.

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1632

O O

O

O

1 pyrylium

2 2H-pyran

3 4H-pyran

O

O

O 4 5 2-pyrone 4-pyrone (2H-pyran-2-one) (4H-pyran-4-one)

O

O

O

8 7 2H-chromene 4H-chromene

6 chromylium (1-benzopyrylium) (benzo[b]pyrylium)

O

O

O

O

9 Coumarin (2H-1-benzopyran-2-one)

O 11 isochromylium (2-benzopyrylium) (benzo[c]pyrylium)

10 chromone (4H-1-benzpyran-4-one)

O

O

O 12 13 isochromene isocoumarin (1H-2-benzopyran) (1H-2-benzopyran-1-one)

Figure 18.1 Most common six-membered ring oxacycles.

Pyrylium salts are stable but highly reactive species. The nature of the counterion of pyrylium salts depends on the method of preparation, and the most common salts are derived from multi-atomic anions, typically perchlorates, tetrafluoroborates, and hexafluorophosphates. Owing to their easy accessibility and high reactivity,

Figure 18.2 Calculated structural parameters of the pyrylium cation.

18.2 Pyrylium Cation and Benzo-Derivatives Table 18.1 Selected anthocyanidines.

Cyanidine Delphinidin Pelargonidin Malvidin Peonidin Petunidin

R1

R2

R3

R4

R5

R6

R7

Color

OH OH H OCH3 OCH3 OH

OH OH OH OH OH OH

H OH H OCH3 H OCH3

OH OH OH OH OH OH

OH OH OH OH OH OH

H H H H H H

OH OH OH OH OH OH

Magenta Purple, blue Orange, salmon Purple Magenta Purple

pyryliums have found widespread applications as synthetic intermediates, mainly for the synthesis of other heterocycles or carbocycles through attack by nucleophile– ring opening–ring closure (ANRORC) sequences. An early review on the synthesis and applications of pyryliums salts is recommended [4]. Moreover, pyrylium compounds are constituents of materials with various interesting applications such as photographic materials, photosensitizers in electrophotography, laser dyes, optical recording material, fluorescent probes, anticorrosion agents, and polymerization initiators. A particularly important type of pyrylium salts is the flavylium salts (2-phenyl-1benzopyrylium salts), which constitute the aglycon part of anthocyanines, a family of natural pigments present in flowers, fruits, and leaves. The sugar-free part of anthocyanines, which are called anthocyanidines, are polyhydroxylated flavylium salts, which are used as food additives [5]. Table 18.1 presents some common anthocyanidines. 18.2.2 Synthesis of the Pyrylium Ring

The main strategies for the synthesis of pyrylium salts are based on intramolecular condensations of 1,5-dicarbonyl compounds, according with the scheme presented in Figure 18.3. The cyclocondensation of a penten-1,5-dione 14 gives directly the pyrylium salt. On the other hand, if the reaction involves the condensation of a pentane-1,5-dione (15), after the formation of 4H-pyran 16 a hydride abstraction step is required. The different variations of these methodologies differ in the way in which the 1,5-dicarbonyl compounds are accessed.

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1634

OH

O

OH O

O O 14

H

O 17

OH O

O 16

O O 15

Figure 18.3 Retrosynthetic analysis of the pyrylium cation.

A classical example is the preparation of 2,4,6-trimethylpyrylium perchlorate (17) by acylation of pentenone 18 by an anhydride or an acid chloride under strong acidic conditions (Scheme 18.1) [6].

Ac2O O

HClO4 18

O

O 17

·ClO4

O O

HO

O O

Scheme 18.1 Synthesis of pyrylium salts by acylation of pentenone 18.

Closely related with this reaction is a very versatile methodology, namely, the classical Balaban synthesis, which involves the diacylation of an alkene. Usually, the alkene is generated in situ from the corresponding halide or alcohol [7]. Scheme 18.2 provides a recent application of this methodology leading to the pentasubstituted pyrylium salt 19. 2,6-Diaryl substituted pyrylium salts 21 can be efficiently synthesized by another variation of this method, which consists of the reaction of methyl ketones 20 with triethyl orthoformate in the presence of perchloric acid (Scheme 18.3) [8]. A synthesis of pyrylium salts 24 through the pentenone intermediate includes the reaction of enolizable ketones 22 with 1,3-dicarbonyl compounds 23 under strong acidic conditions (Scheme 18.4) [9]. A recent variation of this procedure involves the synthesis of trisubstituted pyrylium salts 29 by reaction of acetophenones 25 with benzoic acids or benzoyl esters 26. The reaction proceeds through the addition of the enol of the acetophenone

18.2 Pyrylium Cation and Benzo-Derivatives

Scheme 18.2 Classic Balaban synthesis of pyrylium salts.

H(OC2H5)2 + Ph

O

OC2H5 Ph

O

·ClO 4 Ph

89 %

20

OC2H5

O

1. 15 min,rt 2. HClO4, 30 min,0ºC 60 min,rt O 21

Ph

C2H5O

Ph H+

Ph

O O

Ph

Scheme 18.3 Synthesis of 2,6-diphenylpyrylium salt from acetophenone and an orthoformate.

Scheme 18.4 Synthesis of pyrylium salts from 1,3-dicarbonyl compounds and enolizable ketones.

to the ester, to give dicarbonyl compound 27, followed by aldol condensation of another molecule of acetophenone with the dicarbonyl to give pentenedione 28, and final cyclization to provide the pyrylium salt 29 (Scheme 18.5) [10]. A similar synthetic route, although in a multistep procedure, has been employed to prepare the chiral C2-symmetric bis-camphorpyrylium salt 34, taking camphor 30 as starting material (Scheme 18.6) [11]. In this case, the key pentenedione 33 is prepared by Michael addition of the enolate of camphor to chloropentenone 32, which was obtained by condensation of camphor with methyl benzoate. Regarding the reactions that consist of the cyclization of saturated diones, one of the most popular strategies is the reaction between a chalcone (35) and a methyl

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1636

Scheme 18.5 Synthesis of pyrylium salts from acetophenones and benzoyl esters.

Scheme 18.6 Synthesis of chiral pyrylium salts 34 from camphor.

ketone (36) (Scheme 18.7) [12]. The reaction must be carried out with two equivalents of chalcone 35. It has been proposed that the second equivalent serves as hydride abstractor to generate the pyrylium salt from the 4H-pyran 38 (Scheme 18.8). This modular approach allows for the synthesis of pyrylium salts 39 with three different aryl substituents [13]. An extension of this strategy consists of a one-pot reaction in which the chalcone is generated from acetophenones and an aromatic aldehyde. In this case the reaction is restricted to symmetrical pyrylium salts such as 41 (Scheme 18.9). Nevertheless, taking into account that the reaction is compatible with several functionalities and the starting materials are very easily available, this reaction is one of the most often employed methods for the preparation of pyrylium salts [14]. Pyrylium salts can also be prepared by the oxidation of cyclopentadienes with silver salts [15] or by the action molecular oxygen in the presence of perchloric acid [16]. In the

18.2 Pyrylium Cation and Benzo-Derivatives

Scheme 18.7 Synthesis of pyrylium salts from chalcones.

Scheme 18.8 Mechanism of the synthesis of pyrylium salts from chalcones.

Scheme 18.9 One-pot synthesis of pyrylium salts from aromatic aldehydes and methyl ketones.

latter case, presented in Scheme 18.10, the oxygen insertion on the cyclopentadiene 42 can be explained by a mechanism that implies auto-oxidation to give 43, followed by an acid-promoted rearrangement that leads directly to the pyrylium salt 44. 18.2.3 Synthesis of the 1-Benzopyrylium Ring

The synthesis of 1-benzopyrylium salts 45 is closely related to the procedures for the synthesis of pyryliums. As presented in Figure 18.4, most of the methodologies rely

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1638

R

R

R R 42

R

R

O2,HClO4

H

Tol, CH3CN 3-8h, rt R = Ph, Me

R

R

R O

R

44

O2 R

R

R

R

H

O OH

R 43

R

R

R

R R

-H2O

O OH2 R

R R

R O

R

Scheme 18.10 Pyrylium salts by oxidation of cyclopentadienes.

R'

R' R R'

R'

R

OH

R O 45

R''

+

O

or O

R''

R''

O

O OH R'' 46

O H OH

+

R O

Figure 18.4 General strategies for the preparation of 1-benzopyrylium salts 45.

on the intramolecular cyclizations of properly substituted phenols 46. These cyclization precursors can be prepared by the reactions of phenols with 1,3-bidentate electrophiles, such as 1,3-dicarbonyl compounds or a,b-unsaturated carbonyl compounds. Alternatively, the intermediate phenol 46 can be generated by reaction of salicyl aldehydes or o-hydroxyketones with enolizable ketones. One of the most classical synthesis of flavyliums 50 (2-aryl-1-benzopyryliums) is the Robinson condensation of salicylaldehydes 47 or 48 with acetophenones 49 [17]. Scheme 18.11 presents a recent application of this methodology oriented to the preparation of ligands to brain GABA-A receptors [18]. Flavylium ions such as 53 (Scheme 18.12) are also efficiently prepared by the condensation of activated phenols with 1,3-dicarbonyl compounds. The presence of additional activating groups in the aromatic ring is essential to facilitate the initial electrophilic aromatic substitution reaction. Scheme 18.12 presents a recent example of the reaction of m-methoxyphenol (51) with benzoylacetone (52) catalyzed by gaseous HCl [19].

18.2 Pyrylium Cation and Benzo-Derivatives

R2

R3

H

1

R

O

47

OH

O

R4 +

AcOH,rt

O H OH

R HPF6 (50%water)

R6

R5'

48

R1

R4 ·PF 6

O 50

49

6

R5

R

O

R4' +

R3

2

5

R

BF3·Et 2O

R4' ·BF 4

O

rt R6'

6'

R5'

R

R1, R2, R3, R4, R5, R6 = H, OH, OMe

Scheme 18.11 Classical synthesis of flavyliums from salicyl aldehydes and methyl ketones.

+ MeO

O

O

51

HCl(g) Ph EtOAc, 2h, rt 82 %

OH

j1639

52

·Cl MeO

O

Ph

53

Scheme 18.12 Synthesis of 1-benzopyryliums from 1,3-dicarbonyl compounds and phenols.

18.2.4 Synthesis of the 2-Benzopyrylium Ring

Figure 18.5 presents the main retrosynthetic routes to the 2-benzopyrylium cation 54. The classical strategy involves the cyclization of dicarbonyl compounds 55 [20]. The most general approach to the dicarbonyl intermediate is the Friedel –Crafts acylation of the benzylic carbonyl compound. Another alternative, which has gained in popularity in recent years, is the electrophilic cyclization of o-alkynylbenzaldehydes 56, which are readily available through Pd-catalyzed cross-couplings.

Figure 18.5 General strategies for the preparation of 2-benzopyrylium salts 54.

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1640

Many examples have been disclosed over the years of the first route. For instance, acylation of ketone 57 with acetic anhydride in acidic media gives directly the corresponding pyrylium salt 58 (Scheme 18.13). Nevertheless, this particular reaction is generally restricted to carbonyls that bear activating substituents in the aromatic ring, to facilitate the Friedel–Crafts acylation [21]. MeO

Ac2O, CH2Cl2 O OMe 57

MeO O

HClO4 or HBF4 76 or 82 %

·X

OMe X : ClO4,BF4 58

MeO O

O

OMe Scheme 18.13 Synthesis of 2-benzopyryliums.

As noted, the cycloisomerization of o-alkynylbenzaldehydes has emerged recently as an alternative for the preparation of 2-benzopyryliums. The reaction can be promoted by different electrophilic reagents [22], but gold salts have been found to be the best catalysts to promote this type of transformation [23]. For instance, o-alkynyl aldehyde 59 is quantitatively converted into benzopyrylium salt 60 in just 1 min (Scheme 18.14) [24].

Scheme 18.14 Cycloisomerization of o-alkynylbenzaldehydes.

18.2.5 Reactivity of Pyrylium Salts

Pyrylium cations are extremely p-deficient heterocycles, and therefore they are highly reactive towards nucleophilic systems. Moreover, pyrylium salts are totally unreactive towards electrophiles. The chemical behavior of pyrylium cations towards nucleophiles can be rationalized by considering the resonance forms depicted in Figure 18.6. Addition and substitution reactions can take place at the electron-deficient positions 2, 4, and 6. The particular type of reaction and the regioselectivity depend on the nature of the nucleophile and the substituents of the pyrylium ring.

18.2 Pyrylium Cation and Benzo-Derivatives

O

O

O

O R4

R2 Nu 1

R

O

1

R

R3

O

H

Figure 18.6 General reactivity of pyrylium cations.

18.2.5.1 Reactions with Nucleophiles The reactivity of the pyrylium ion is similar to that of a protonated carbonyl compound. Therefore, nucleophiles attack preferentially position 2. In 4-unsubstituted pyryliums, the addition of the nucleophile can take place regioselectively at position 4 (Figure 18.6). The reaction with hydroxides (Figure 18.7) serves as a model of a nucleophilic addition on the pyran ring. Attack at position 2 gives hemiketal 61, which can evolve through ring opening to the pent-2-en-1,5-dione 62. The equilibrium can be shifted back to the pyrylium under acidic conditions. When the pyrylium salt features an enolizable alkyl group at position 2, a phenol (63) can be formed through an intramolecular aldol condensation. These two reactivity patterns can be extended to C, N, S, and P nucleophiles and offer numerous opportunities in the synthesis of heterocyclic and carbocyclic systems through ANRORC cascades, as will be shown below. 18.2.5.1.1 Synthesis of Other Heterocyclic Systems Following a similar mechanism, different heterocyclic systems 64 can be prepared from pyrylium salts, employing N, P, S, and other heteroatom-based nucleophiles. Indeed this is a very powerful transformation for the synthesis of certain classes of heterocycles (Figure 18.8).

Figure 18.7 Reactivity of pyrylium cation with nucleophiles.

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1642

Figure 18.8 General strategy for the synthesis of other heterocycles from pyryliums.

Pyryliums can be transformed into pyridines by treatment with NH4OAc. This method is an alternative for the preparation of pyridines with some particular substitution patterns. In the example presented in Scheme 18.15 a pyridine carrying a benzo-15-crown-5 (67), which is a fluorescent sensor for Mg(II), is prepared through a straightforward two step sequence that involves: (i) formation of the pyrylium perchlorate 66 by the classical reaction of an aromatic aldehyde (65) with acetophenone and (ii) treatment with ammonium acetate to give the desired pyridine 67 (Scheme 18.15) [25].

Scheme 18.15 Synthesis of pyridine 67 from the corresponding pyrylium salt.

The same reaction can be applied to 2-benzopyryliums, to provide isoquinolines. In the example of Scheme 18.16, the presence of an electron-withdrawing group in the pyrylium nucleus of 68 enables the transformation into isoquinoline 69 under milder conditions [26]. The reactions of pyrylium cations with primary amines give rise to pyridinium cations [27]. This transformation is continuously employed to build molecular structures with interesting properties that are inaccessible through other methodologies. One example application of this methodology is the synthesis of 71, a molecule that features a tridentate ligand domain and the pyridinium substructure,

18.2 Pyrylium Cation and Benzo-Derivatives

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Scheme 18.16 Synthesis of isoquinoline 69 from 2-benzopyrylium salt 68.

and is the monomer of a photosensitized supramolecular assembly, by condensation of triphenylpyrylium salt with 4-aminopyridine (70) (Scheme 18.17) [28]. Other recent examples include the synthesis fluorescent probes for hydrogen abstraction [29], molecular wires based on oligomeric pyridinium chains [30], calixarenebased tricyclic assemblies [31], and the preparation of pyridinium based lipophilic oligomers for gene delivery [32]. Moreover, the reaction can be also applied to 2-benzopyrylium salts to obtain isoquinolinium salts [33].

Scheme 18.17 Synthesis of a pyridinium salt from a pyrylium salt.

Pyrylium salts are the simplest source of phosphinines, the phospha analogs of benzene. The O þ –P exchange can be carried out employing P(CH2CH2OH)3 or P[Si (CH3)]3. This reaction has been utilized recently in the preparation of phosphinines with some particular substitutions, to be used as ligands in transition metal catalyzed reactions [34]. As an example, the wide bite-angle diphosphinine 73 has been prepared by this methodology (Scheme 18.18) [35]. The bis-pyrylium derivative 72 is prepared by employing the typical condensation of chalcones with acetophenones. Ph

Ph

O O Ph

O Ph

Ph 2 BF4

HBF4·Et2O O

P

Ph

P

Ph

P(SiMe3)3 CH3CN

Ph

O 72

Ph

Scheme 18.18 Synthesis of phosphinine 73 from pyrylium salt 72.

73

Ph

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Analogously, thiopyrylium salts are synthesized by reaction of the corresponding pyrylium salts with Na2S in acidic media. To illustrate this transformation, Scheme 18.19 shows the synthesis of the thiopyrylium Hg2 þ and Cu2 þ sensor 75 from the corresponding pyrylium salt 74 [36]. O

O

S

O S

O

S

N

S N

Na2S/acetone

·ClO 4

HClO4 Ph

O 74

Ph

Ph

S 75

Ph

Scheme 18.19 Synthesis of thiopyrylium 75 from pyrylium salt 74.

18.2.5.1.2 Synthesis of Carbocycles The reactions of pyryliums with certain nucleophiles can lead to a ring opening/ring closure sequence that gives rise to the formation of benzene derivatives. For this type of process to occur it is necessary that the acyclic intermediate 76 (Figure 18.9), which is formed upon addition of the nucleophile, has active hydrogens to permit the C–C bond forming cyclization. There are several variations of this reaction depending on the nature of both the pyrylium salt and the nucleophiles. For instance, the reaction of secondary amines with trialkylpyrylium salts gives rise to N,N-dialkylanilines 78 through the formation of an intermediate enamine (77) (Scheme 18.20) [37]. Nevertheless, most of the reactions of synthesis of carbocycles from pyrylium salts rely on the second equation presented in Figure 18.9 and employ of C-nucleophiles.

Figure 18.9 General strategy for the synthesis of carbocycles from pyryliums.

18.2 Pyrylium Cation and Benzo-Derivatives

H N ·BF 4 O

Et3N, CH3CN - 40 ºC 95 %

R2

R2 R1

O

N 78

N

R1

O 77

N

Scheme 18.20 Synthesis of anilines from pyryliums.

Classical examples are the reactions of pyrylium salts with nitroalkanes in the presence of mild bases, which lead to the corresponding nitroaromatic derivatives [38]. Scheme 18.21 shows a recent application of this reaction. Treatment of pyrylium salt 79 with nitromethane gives trisubstituted nitrobenzene 80, which has been employed in the preparation of 2,4,6-trisubstituted aniline 81 [39].

Scheme 18.21 Synthesis of carbocycles from pyryliums and nitromethane.

Another interesting synthetic application is the annulation of sodium cyclopentanedienide with pyrylium salts [40]. In this case, the intermediate cyclopentadienyl anion 82 undergoes intramolecular cyclization to produce azulene derivatives 83 (Scheme 18.22). Pyrylium salts can also react under specific conditions with species that feature weak C–H acids such as anhydrides, esters, or ketones [41]. From a synthetic point of view, an important transformation in this context is the reaction of pyrylium salts with phenylacetates to give o,o-disubstituted biaryl systems [42]. Modern applications of this reaction take advantage of the availability of the starting pyrylium salts, and the possibility to include halogens in the aromatic rings, to build complex polyaromatic molecules combining pyrylium chemistry and Pd-catalyzed cross-coupling

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1646

Scheme 18.22 Synthesis of azulenes 82 from pyryliums and cyclopentadiene.

reactions [43]. In the example of Scheme 18.23 the pyrylium salt 84 is the starting material to the preparation of dibenzo[ fg,op]naphthacenes 87 [44]. The key step of the synthesis is the formation of the aromatic dibromide 86 by reaction of pyrylium salt 84 with the corresponding sodium arylacetate 85.

Scheme 18.23 Pyrylium salt 84 as staring material for the synthesis of naphthacene 87.

18.2.5.1.3 Reactions with Organometallic Reagents Addition of organometallic reagents can take place at positions 2 or 4 depending on the substitution of the pyrylium salt. Organolithium and Grignard reagents add to the 2 position, giving rise to an intermediate 2H-pyran 88, which undergoes an electrocyclic ring opening to give dienones or dienals 89 with retention of the configuration of the double bonds (Scheme 18.24). This reaction has found widespread applicability for the stereocontrolled synthesis of polyenes in natural products synthesis [45, 46]. On the other hand, organocuprates add to 4-position of pyrylium salts, leading to 4-substituted-4H-pyrans 90, which can be subsequently converted into the corresponding 4-substituted pyrylium salts 91 by oxidation with trityl hexafluorophosphate (Scheme 18.25) [47]. An alternative to the preparation of 4-substituted pyrylium salts is the benzotriazole-mediated reaction developed by Katritzky. In a first step, the 4-unsubstituted

18.2 Pyrylium Cation and Benzo-Derivatives

Scheme 18.24 Stereocontrolled synthesis of dienals from pyrylium salts.

Bu Bu2CuLi

·ClO4

Bu Ph3C·PF 6

O

O

·PF 6

45 %

O 91

90

Scheme 18.25 Synthesis of 4-substituted-4H-pyrans by addition of organocuprates to pyrylium salts.

pyrylium salt 92 undergoes addition of benzotriazole to the 4-position to give 4Hpyran 93. Then, deprotonation by treatment with n-BuLi produces an 8p-electron heterocyclic anion that can be trapped with an electrophile to give intermediate 94, which is not isolated and releases the benzotriazole unit upon treatment with a mineral acid to produce the 4-substituted pyrylium salt 95 (Scheme 18.26). The Bt 1. n-BuLi 2. PhCH2Br

BtNa O

O BF4

OMe

92

OMe

93 Ph

Ph

Bt

HClO4 - BtH 90 %

O OMe

94 Bt:

N N

O ClO4 95

OMe

N

Scheme 18.26 Benzotriazole mediated substitution in the pyrylium ring.

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1648

overall transformation can be envisioned as an indirect electrophilic aromatic substitution in the pyrylium ring. The reaction can be applied to pyrylium and 1-benzopyrylium salts [48]. Pyrylium salts can also react as electrophiles in Friedel–Crafts-like electrophilic aromatic substitutions on electron-rich aromatic rings. For instance, 2,6-diphenylpyrylium perchlorate (96) reacts with anilines 97 to furnish the corresponding 4substituted pyrylium salts 98 (Scheme 18.27) [49].

Scheme 18.27 Pyrylium salts as electrophiles in Friedel–Crafts reactions.

18.2.5.2 Cycloaddition Reactions Pyrylium and benzopyrylium salts can participate in several types of cycloaddition reactions. 18.2.5.2.1 [2 þ 1] Cycloadditions Benzopyrylium salt 99, generated in situ from chromone (10), undergoes cyclopropanation with ethyl diazoacetate to give the cyclopropanation adduct 100, which leads ultimately, after acid-promoted ring opening, to the corresponding benzoxepine 101 (Scheme 18.28) [50].

Scheme 18.28 Synthesis of benzoxepine 101 by a cyclopropanation/ring expansion sequence on a pyrylium salt.

18.2.5.2.2 Dienophiles in [4 þ 2] Cycloadditions 4-Silyloxypyrylium triflate 102, which is readily prepared from 4-pyrone (5), reacts in a domino sequence with

18.2 Pyrylium Cation and Benzo-Derivatives

2-silyloxydienes 103 to give polyfunctionalized pyran derivatives 105. The reactions are triggered by a stepwise [4 þ 2] cycloaddition between the electron-rich diene and the C2–C3 bond of the pyrylium salt. Upon formation of intermediate 104, the attack of a second molecule of silyloxydiene produces polycyclic structure 105 with total diastereoselectivity (Scheme 18.29) [51].

Scheme 18.29 Example of a pyrylium salt as dienophile in a [4 þ 2] cycloaddition.

18.2.5.2.3 Dienes in [4 þ 2] Cycloadditions Pyrylium and benzopyrylium salts can also react as the 4p-component in [4 þ 2] cycloadditions. Scheme 18.30 presents the synthesis of pyridinium salt 108 by reaction between triphenylpyrylium perchlorate and dihydroisoquinoline 106. The mechanism proposed involves a [4 þ 2] cycloaddition between the pyrylium salt and the iminic C¼N bond, which gives intermediate adduct 107 and provides pyridinium salt 108 after subsequent ring opening and expontaneous oxidation. A similar reaction has been observed with 2-benzopyrylium derivatives [52]. Of particular interest are processes in which the pyrylium salts are generated in situ during the annulation of alkynyl aldehydes. For instance, the benzannulation reaction of 3-alkynylpyrrole-2-carboxaldehydes 109 with alkenes, promoted by iodonium ions, yields indoles 110 with a high level of substitution and functionalization in the benzene ring (Scheme 18.31) [53]. Scheme 18.32 shows the mechanism proposed for this unusual transformation. Interaction of the iodonium ion with the triple bond of 109 would promote the formation of 4-iodopyrylium salt 111. Nucleophilic attack of the alkene to the

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Scheme 18.30 A pyrylium cation as diene in a [4 þ 2] cycloaddition.

R1

O

R1

i) IPy2BF4 / HBF4 CH2Cl2, 0ºC

O

N Tos

ii)

R2

N Tos

R3

109

O

R2 R3 110

Ph

O

O

Ph

R1 N

Ph N Tos

72%

N Tos

42%

N Tos

n-C6H13 43%

Scheme 18.31 Synthesis of indoles 110 from in situ generated pyrylium cations.

electrophilic carbon of 111, followed by intramolecular cyclization, would provide 112. The simple loss of a proton to give a conjugated double bond yields 113. Finally, aromatization by elimination of HI gives the indoles 110. This proposal is supported by detailed mechanistic and spectroscopic studies that allowed the isolation of analogues of the cationic intermediates 111 and 112 [54]. Related reactions have been reported in which the formation of the intermediate pyrylium salt is mediated by transition metal catalysts such as Cu and Au [55].

18.2 Pyrylium Cation and Benzo-Derivatives

R1

N Tos 109

R1

O

R2

I +BF 4-

O

R3

N Tos

R2

R3 110 HI

I+BF 4BF4

R1

I

O

N Tos

I

R

R O

N Tos 111

R2 R3

N Tos

113

R3

1

1

O BF4

3

R

Tos

H R2 R3

N Tos

I

I

BF4

R1 O

N

R2

HBF4

R2

H I O

R1 BF4

112

Scheme 18.32 Mechanism proposed for the formation of indoles 110.

Moreover, Pt-bound pyrylium ions generated in situ through the benzannulation of alkynylaldehydes react as dipoles in intramolecular [3 þ 2] cycloadditions [56]. 18.2.5.2.4 [5 þ 2] Cycloadditions A particularly interesting derivative is the 3-oxidopyrylium betaine 114 that can participate in [5 þ 2] dipolar cycloadditions with the proper dipolarophiles. This reaction has found wide applicability in organic synthesis and a recent review is available [57]. An intermolecular example is the cycloaddition with indene to give polycycle 115 (Scheme 18.33) [58]. Moreover, higher order [6 þ 3] reactions with pentafulvenes have also been reported [59]. This methodology is particularly useful in the intramolecular version, and has been extensively employed in the total synthesis of natural products. The interested reader is encouraged to revise the abundant literature cited in Reference [60]. In the example presented in Scheme 18.34, the intramolecular [5 þ 2] cycloaddition on the betaine generated from 116 is the key step towards the synthesis of daphnetoxins. This reaction highlights the synthetic power of this cycloaddition reaction in the preparation of structurally complex molecules with a high level of stereocontrol. The structures TS-92 and TS-93 correspond to the proposed transition states for the formation of each diastereoisomer.

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Scheme 18.33 [5 þ 2] dipolar cycloaddition with 3-oxidopyrylium betaine (114).

AcO O AcO OAc

DBU, CH3CN OAc OBn 80ºC, 2h

Me 116

OBn

79% 117:118 = 5:1

O O

OBn O

H

TS-92

+

OBn

O O

118

H

OBn

OAc

H OAc

O

OBn OBn

OBn OAc

OBn

OAc 117

OAc O

AcO

OBn

O

TS-93

Scheme 18.34 Intramolecular dipolar cycloaddition with a 3-oxidopyrylium betaine.

Related reactions employing in situ generated 2-benzopyrylium-4-olates have also been described, including catalytic asymmetric versions [61]. 18.2.5.3 Side Chain Reactions Alkyl substituted pyrylium salts feature relatively acidic hydrogens and, in turn, can react with electrophiles in a similar way to enolizable carbonyl compounds. Therefore, homologous to aldol condensations, Mannich additions and Michael additions can be carried out employing pyrylium salts. In contrast to the reactions with nucleophiles, substituents at C4 react in preference to substituents at C2 (Figure 18.10).

Figure 18.10 General reactivity of the side chain of pyrylium salts.

18.2 Pyrylium Cation and Benzo-Derivatives

Thus, alkylpyrylium salt 120 reacts with aromatic aldehydes 119 to give the new polyconjugated pyrylium salts 121. This reaction finds application in the synthesis of pyrylium dyes (Scheme 18.35) [62].

Scheme 18.35 Aldol-like condensation of a pyrylium salt.

Similar reactions can be carried out with benzopyrylium salts, such as in the reaction of 5-hydroxy-4-methylflavilium salts 122. In this case, subsequent intramolecular cyclization of the initial adduct 123 gives rise to the pyranoflavylium derivative 124 (Scheme 18.36). A charge-transfer complex has been proposed as initiator of this reaction [63].

Scheme 18.36 Synthesis of a pyranoflavylium through the condensation of a flavylium with an aldehyde.

An interesting application of a Michel-type addition is the reaction of 4-methylpyrylium salt 125 with 3-dimethylaminoacrolein to furnish 4H-pyranylidene 126, which has nonlinear optical properties (Scheme 18.37) [64].

Scheme 18.37 Michael-type addition with a pyrylium salt.

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18.2.5.4 Reactions with Reducing Agents The addition of metal hydride complexes such as NaBH4 to pyrylium salts takes place preferentially at C2, giving rise to 2H-pyrans 127, which undergo ring opening under the reaction conditions to produce dienones 128 (Scheme 18.38). Under more intensive reaction conditions (NaBH4/AcOH) further reduction takes place and D3-dihydropyran derivatives 129 can be isolated. Nevertheless, the regiochemistry of the hydride addition is strongly dependent on the substitution of the pyrylium ring [65].

1 O 16 +

NaBH4 O ClO4

EtOH

O 127

O O 15

:

H

8 O 128

NaBH4 O ClO4

AcOH 78%

O 129

Scheme 18.38 Reduction of pyrylium salts with NaBH4 under different reaction conditions.

Catalytic hydrogenation of alkyl substituted pyryliums leads to the saturated pyran derivatives 130 (Scheme 18.39) [66]. Depending on the reaction conditions and the particular substrates, different types of ring-open compounds can be isolated from pyrylium salts. A review on this subject is available [67].

Scheme 18.39 Catalytic hydrogenation of pyrylium salts.

On the other hand, catalytic hydrogenation in the presence of a primary amine leads to piperidine derivatives such as 131 (Scheme 18.40), in a reaction that could be considered a reductive amination of the pyrylium salt [68].

18.3 2H-Pyrans and 4H-Pyrans

Scheme 18.40 Reductive amination of pyrylium salts leading to piperidines.

18.3 2H-Pyrans and 4H-Pyrans

The most relevant compounds featuring the 2H-pyran and 4H-pyran structures are the corresponding carbonyl systems, 2H-pyran-2-one and 4H-pyran-4-one, respectively. Each family of compounds is discussed in a separate section. A brief commentary is dedicated here to the ring synthesis of 2H-pyrans and 4H-pyrans. 18.3.1 2H-Pyran Ring Synthesis

The most characteristic property of 2H-pyran derivatives is their ability to undergo reversible electrocyclic ring opening to the oxatriene (Figure 18.11). The equilibrium distribution between 2H-pyrans and 1-oxatrienes is greatly influenced by the substituents on the ring [69]. Therefore, the main strategies for the preparation of 2Hpyran derivatives are directed to the synthesis of the acyclic precursors. The most classical approach is the Knoevenagel condensation of 1,3-diketones with a,b-unsaturated aldehydes [70]. The reaction between 5-methyl-1,3-cyclohexanedione (132) and aldehyde 133 gives rise to pyran 136 (Scheme 18.41) [71]. The reaction proceeds more efficiently in the presence of a secondary amine, through the formation of an iminium salt 134, which reacts readily with the 1,3-dicarbonyl compound to provide the oxatriene 135. Electrocyclic ring closure then leads to the pyran 136. Several approaches have been devised for the preparation of the oxatriene precursor, such as the oxidation of dienols [72] or Wittig olefination [73]. In a recent approach, monocyclic functionalized 2H-pyrans 140 can be synthesized from propargyl vinyl ethers 137 (Scheme 18.42). The cascade process involves a metalcatalyzed Claisen rearrangement to give allene 138, base-promoted isomerization to oxatriene 139, and finally the 6p-electrocyclization [74].

O

O

Figure 18.11 Equilibrium 2H-pyran$oxatriene.

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O

O

H

O

132

Piperidine, Ac2O

O

+

R

133

Toluene, 90ºC 70%

136

Ac2O

N H

O

R

O

electrocyclic ring-closure O

Knoevenagel condensation

N + H OH 134

O

R

R

135

Scheme 18.41 Synthesis of 2H-pyrans by Knoevenagel condensation.

Me O Et 137

Me

CO2Et i) AgSbF6 (5 mol %) ii) DBU (5 mol %) Et

Ph

Ph 140

[Ag+]

electrocyclization

Me O Et

CO2Et Ph

138

CO2Et

O

Me DBU isomerization

O Et

CO2Et Ph

139

Scheme 18.42 Synthesis of 2H-pyrans by metal-catalyzed isomerization of propargyl vinyl ethers.

Bicyclic 2H-pyrans 143 have been prepared by a ruthenium-catalyzed cycloisomerization of diyneols 141, which gives rise to oxatrienes 142 that undergo subsequent electrocyclization (Scheme 18.43) [75]. Another unconventional synthesis is the Pd-catalyzed cycloisomerization of enynols 144 through a 6-endo-dig cyclization that leads to 2H-pyran 145 (Scheme 18.44). The presence of the electron-withdrawing CF3 substituent is essential. Otherwise, the formation of a furan, through a more favorable 5-exo-dig cyclization, occurs [76].

18.3 2H-Pyrans and 4H-Pyrans

OH

E E

TMS 141

5 mol% [CpRu(CH3CN)3]PF6 acetone, water 60ºC 94%

Ru-catalyzed cycloisomerization

E E

O 142

E E

O 143

TMS

electrocyclization

TMS

Scheme 18.43 Synthesis of 2H-pyrans by metal-catalyzed cycloisomerization of diyneols.

Scheme 18.44 Synthesis of 2H-pyrans by Pd-catalyzed 6-endo-dig cyclization of enynols.

18.3.2 4H-Pyran Ring Synthesis

The main approach for the preparation of the 4H-pyran ring is the intramolecular condensation of 1,5-dicarbonyl compounds (Figure 18.12). The cyclization proceeds in the presence of either protic or Lewis acids. A review that covers the different variations of this reaction is available [77]. In many cases, the dicarbonyl compound is prepared in situ by Michael addition of an active methylene or an enolate to an a,b-unsaturated carbonyl compound [78].

Figure 18.12 General strategies for the synthesis of 4H-pyrans.

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If the methylene group is activated by the presence of a nitrile, such as malononitrile, intramolecular cyclization of the intermediate adduct 146 takes place at the CN group, giving rise to 2-amino-4H-pyrans 147 (Scheme 18.45) [79].

Scheme 18.45 Synthesis of 2-amino-4H-pyrans.

Gold-catalyzed cyclization of alk-4-yn-1-ones affords different oxygen heterocycles depending on their structure. Alkynones with one substituent at C3 undergo a 5-exodig cycloisomerization to substituted furans. However, a 6-endo-dig cyclization to 4Hpyrans 149 is observed with alkynones 148 bearing two substituents at C3 (Scheme 18.46) [80].

Scheme 18.46 Synthesis of 4H-pyrans by gold-catalyzed 6-endo-dig cyclization of enynones.

The hetero-Diels–Alder cycloaddition of alkynes with a,b-unsaturated compounds is also a methodology that has been widely employed in the synthesis of 4H-pyrans. Owing to the low reactivity of alkynes, highly electron-rich alkynes, typically ynamines, are generally required. Scheme 18.47 presents the reaction between ethylidenemalonate 150 and ynamine 151 to produce polysubstituted pyran 152 [81].

Scheme 18.47 Synthesis of 4H-pyrans by inverse-electron-demand [4 þ 2] cycloaddition.

Some of the limitations of this disconnection for the synthesis of 4H-pyrans have been overcome recently by the development of a Ni-catalyzed process [82]. Under these conditions, neutral alkynes 153 can be employed in formal [4 þ 2] cycloadditions with a,b-unsaturated compounds 154 to give pentasubstituted 4H-pyrans 156 (Scheme 18.48). It has been proposed that the reaction proceeds through initial the

18.3 2H-Pyrans and 4H-Pyrans

Scheme 18.48 Synthesis of 4H-pyrans by a Ni-catalyzed formal [4 þ 2] cycloaddition.

formation of an oxa-nickelacycle 155, which enables the cycloaddition with the alkyne. An organocatalyzed [4 þ 2] annulation between 3-formylchromones 157 and electron-poor alkynes 158 gives rise to 4H-pyrans (Scheme 18.49). The reaction takes place under catalysis by phosphines or tertiary amines [83]. The mechanism involves addition of the nucleophile to the alkyne to give an intermediate zwitterion 159 that adds to the formylchromone through a conjugate addition to afford the intermediate adduct 160. Ring closure with release of the nucleophile gives the final pyran 161. O O

R

Nu

+

O

CO2R

157 R

Nu

O

R Tol, rt

O

R O

158

161

R CO2R

R C

Nu CO2R

O OR 159 O O

R Nu: PPh3

O

O RO2C

R

+

Nu

O

R

RO2C

ONu+ R

160 Scheme 18.49 Synthesis of 4H-pyrans by an organocatalyzed formal [4 þ 2] cycloaddition.

The reaction also proceeds with acyclic oxadienes 162; however, the 4H-pyran cycloadduct 163 undergoes a Claisen rearrangement to give 2H-pyran 164 (Scheme 18.50).

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Scheme 18.50 Synthesis of 2H-pyrans by an organocatalyzed formal [4 þ 2] cycloaddition.

The intramolecular version of the [4 þ 2] cycloaddition can be performed with neutral alkynes in the presence of transition metal catalysts. For example, the bicyclic 4H-pyran 166 is obtained from readily available precursor 165 in a copper-catalyzed intramolecular cycloaddition (Scheme 18.51) [84]. It has been postulated that the reaction proceeds through the formation of a Cu-acetylide, and therefore is limited to terminal alkynes. Analogous adducts 168, derived from internal alkynes 167, can be obtained by a Ru-catalyzed reaction that operates through a totally different mechanism [85]. Ts N

R

N

CuI(10%) NEt3 CH2Cl2

O

R = H, Me, Ph 165

R

83-67%

O 166

Ts N

Ph

O

Ts

Ts N

RuCp(MeCN)3PF6 acetone, 4h. 89%

Ph

167

O 168

Scheme 18.51 Synthesis of bicyclic 4H-pyrans by metal-catalyzed intramolecular [4 þ 2] cycloadditions.

18.4 Pyrones, Coumarins, and Chromones

This section is dedicated to the family of oxygenated six-membered rings with the structure of unsaturated lactones. The properties, synthesis, and reactivity of 2Hpyran-2-ones (a-pyrones) (4), 4H-pyran-4-ones (c-pyrones) (5), and the corresponding benzofused analogues such as coumarins (2H-1-benzopyran-2-ones) (9) and chromones (4H-1-benzopyran-4-ones) (10) are compiled (Figure 18.13).

18.4 Pyrones, Coumarins, and Chromones

O

O 4

O

O

O 5

O 9

O

O 10

Figure 18.13 Structure of a-pyrone (4), c-pyrone (5), coumarin (9) and chromone (10).

Figure 18.14 Resonance structures for 2H-pyran-2-one.

18.4.1 a-Pyrones (2H-Pyran-2-ones)

The structure of 2H-pyran-2-ones can be presented as a resonance hybrid between two structures: an enol-lactone and a zwitterionic aromatic structure (Figure 18.14). However, a-pyrones present an absorption frequency in their infrared spectra at around 1730 cm
1 [86], which is characteristic of a ketone function. This value indicates low participation of the zwitterionic structure and, as the result, low aromaticity [87]. On the other hand, NMR spectra indicate the location of positive charges at positions 4 and 6 – as a downfield shift in proton [88] and carbon [89] spectra – relative to positions 3 and 5. As an indication of the interest of these compounds it is worth noting that the a-pyranone structure can be found in several natural compounds [90], some of which exhibit biological properties. As an example, compounds of the family of gibepyrones (6-substitued-3-methyl-2-pyrones) (169, 170) (Figure 18.15) have demonstrated inhibitory activity against some types of bacteria [91]. In addition, while several other examples have been reported related to the properties of a-pyrones, their benzofused derivatives (coumarins) have found greater applicability. These compounds are analyzed in Section 18.4.2.

Figure 18.15 Compounds of the family of gibepyrones.

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Figure 18.16 Retrosynthetic analysis for the formation of 2H-pyran-2-one (4) from 5-ketoacid derivative 171.

18.4.1.1 Synthesis of a-Pyrones The most common methodology for the formation of 2H-pyran-2-ones involves ring closure from isolated, or in situ synthesized, 1,5-ketoacid derivatives. This procedure has been followed by many authors and can be achieved by three different approaches:

(a) from ester enolates, (b) from ketone enolates, (c) through acylation of ester dienolates (Figure 18.16). The use of malonates or b-ketoesters is a classic procedure for the first approach. In this sense, Scheme 18.52 shows an example following this methodology by using dialkyl malonate 172 and an a,b-unsaturated ketone 173 [92]. The procedure involves the formation of the 5-ketoester 174, which is transformed, through an ester exchange under acidic treatment, into pyranone 175.

Scheme 18.52 Synthesis of a-pyrone 175 from malonate 172.

This methodology, starting from malonates, is still described in numerous publications. As an example, Scheme 18.53 shows an a-pyrone formation from a cyclic malonate ester (176) and a propionaldehyde (177) [93]. After the initial attack, MeO

O O

O

O

O R 176

K2CO3,TMMEA

+

THF MeO OMe 177

65 - 90%

OMe

R O

O 178

R = Me,Et,Ph Scheme 18.53 Synthesis of a-pyrone 178 from cyclic malonate 176.

18.4 Pyrones, Coumarins, and Chromones

the reaction evolves towards the formation of the pyranone 178 through a diol deprotection and ester decarboxylation. Among the numerous electrophiles that follow this methodology, allenyl ketones have also been reported. Thus, Scheme 18.54 describes the synthesis of polysubstituted 2H-pyran-2-one 180 from the reaction of substituted allenyl ketone 179 and malonic ester or other activated methylene groups [94]. The reaction takes place in the presence of a catalytic amount of base and involves a double bond isomerization to form the corresponding 5-ketoester, which suffers an in situ cyclization to the pyranone 180. Me RO

O

O

+

1

Bu

R2

H

H

Bu Base (10% mol) 39 - 88%

Me O

179

Me O 180

1

R = Me, Et R2 = CO2Me, CN Scheme 18.54 From allenyl ketone 179 to a-pyranone 180.

On the other hand, several approaches to 2H-pyran-2-ones from 5-ketoesters have been reported following route (b) (Figure 18.16). This methodology can be considered as the complementary to that of route (a). As an example, Scheme 18.55 shows a procedure that involves a Michael-type addition of the enolate of ketone 181 to the propionic ester 182 [95].

Scheme 18.55 Synthesis of 2H-pyran-2-ones 183 through via route (b) in Figure 18.16.

Finally, route (c) (Figure 18.16) implies the acylation of an ester enolate to form the corresponding 5-ketoacid derivative that can be isolated, or in situ cyclized, to the corresponding a-pyrones. Thus, Stille coupling of vinyltin 184 affords the 5-ketoester intermediate 185. This intermediate suffers in situ transformation into the corresponding 2H-pyran -2-one 186 (Scheme 18.56) [96].

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1664

O Bu3Sn

Pd(PPh3)4

OSnBu3 184 O

dioxane, 50ºC 48 - 85%

R

O O 186

O

R 185

OSnBu3

R = Ph, 4-MeO-C6H4, 2-Br-C6H4, (Z)-CH=CHMe, CMe=CH2,CH=CMe2, (Z)-CH=CHPr (Z)-CH=CHPh, i-Pr, i-Bu, (CH2)3-Cl, Bn Scheme 18.56 Synthesis of 2H-pyran-2-ones 186 though via route (c) in Figure 18.16.

In a similar approach, carbonylation of the alkenyl ketone 187, under palladium catalysis, followed by O-enolate cyclization affords pyranone 188 (Scheme 18.57) [97].

Scheme 18.57 Synthesis of a-pyrones 188 via carbonylation–cyclization.

In addition to synthesis through the formation of 5-ketoacid derivatives, many alternative methodologies for synthesis of 2H-pyran-2-ones have also been reported. Among of them, several examples of lactonization of (Z)-2-en-4-ynoate derivatives can be found. Scheme 18.58 describes two examples: an iodolactonization and an

Scheme 18.58 Lactonizations for the synthesis of 2-pyranones.

18.4 Pyrones, Coumarins, and Chromones

intermolecular Stille coupling, followed by the corresponding lactonization. Thus, iodine or N-iodosuccinimide (NIS) addition to the (Z)-2-en-4-ynoic acid 189, in a basic media, induces its cyclization to the a-pyrone 190 [98]. On the other hand, the (Z)-2-en-4-ynoic derivative is in situ generated from an alkynyltin 192 and a 3-iodoacrylate 191 to undergo further cyclization [99]. 18.4.1.2 Reactivity of a-Pyrones As already mentioned, a-pyrones can be described as hybrids between two resonance structures: an aromatic pyrylium salt and a lactone (Figure 18.14). Although, some reactions can be associated to the aromaticity, most of the reactive patterns are related to a 1,3-diene or a lactone structure. Participation of a-pyrones as 1,3-dienes in Diels–Alder reactions was described as early as 1931 [100]. In this sense, pyran-2-one (4) reacts with maleic anhydride (193) to give the corresponding adduct 194 (Scheme 18.59).

Scheme 18.59 Diels–Alder cycloaddition of a-pyranone (4).

This reactivity pattern has also found application in the modern organic synthesis as several structures have been accessed starting from a-pyrones and dienophiles. Scheme 18.60 describes the Diels–Alder reaction of a-pyrone 195 and vinyl ether 196 in the route to biologically active compounds [101]. Examples of enantioselective Diels–Alder reactions with 2H-pyran-2-one have also been reported [102]. O

O

O

O Br

O

195 + OTBS

Toluene 100ºC 71%

Br O O

O OTBS

(+/-)-Crinine

196 Scheme 18.60 Diels–Alder reaction of pyranone 195 in the synthesis of ()-crinine.

Interestingly, a-pyrones also participate in Diels–Alder reactions as dienophiles. Thus, reaction of the pyran 2-one 198 and cyclopentadiene 197 produces the bicyclic

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1666

lactone 199 (Scheme 18.61) [103]. This dienophilic capability of pyranone 198 is facilitated by the presence of an electron-withdrawing group.

Scheme 18.61 a-Pyrone 198 reacting as a dienophile.

Taking account of their dienone structure, 2H-pyran-2-ones are also reactive towards nucleophiles [104]. This reaction can occur at three different electrophilic sites: C4, C6, and the carbonylic carbon C2. Scheme 18.62 shows two examples of nucleophilic attacks to C4 and C2 positions, respectively. In the first example, nucleophilic substitution of the halogen atom has been achieved at the C4 carbon of the pyran-2-one 200 [105]. In the second example, addition of two equivalents of a Grignard reagent to pyranone 201 furnishes 2,2-disubstituted pyrans 202 [106].

Scheme 18.62 Nucleophilic attacks on a-pyrones at C4 and C2.

Transformation of 2-pyranones into other heterocycles through nucleophilic additions at C2 is also possible. Scheme 18.63 shows the transformation of 3-amino-2-pyranone 203 into pyridazines 204–206 [107], initiated by a nucleophilic attack of hydrazine on the carbonylic carbon followed by a ring closure. This reaction yields tetrahydropyridazine 204 along with different amounts of dihydropyridazine 205 and pyridazine 206. Further transformations allow the formation of 206 as the sole product. C6-attack is also very common, and the reaction usually evolves to the formation of aromatic structures. These reactions begin by a nucleophilic attack, followed by an

18.4 Pyrones, Coumarins, and Chromones

R2

O

O

R2

N

R1

O

∆ 71- 84%

NH2

R1 203

R2

N2H4·H2O

CONHNH2 NH

R1 H N

R2 NH + NHNH2 CONHNH2

N

R1

204

R2

N

+ CONHNH2

205

N

R1

CONHNH2

206

1

R = H, Me R2 = Ph, 2-Py, t-Bu Scheme 18.63 Transformation of 2-pyranone 203 into pyridazine derivatives.

intramolecular cyclization and decarboxylation. Scheme 18.64 reports one such example in which the bicyclic aromatic derivative 209 is formed. This reaction is initiated by the nucleophilic attack of the enolate of ketone 208 on the C6 position of a-pyrone 207 followed by ring opening, decarboxylation, and recyclization [108].

SMe CO2Me R

O

+

O

207

( )

CO2Me

n

KOH DMF, rt 72 - 76%

R ( ) n 209

208

SMe

SMe OH

CO2Me

O R

SMe

O

R ( )

n

CO2Me

OMe

O

H

SMe OH

R ( )

n

( )

n

R = 1-naphthyl, 2-naphthyl n = 1,2 Scheme 18.64 Transformation of a-pyrone 207 into arene 209.

In a less general approach, a-pyrones also react with electrophiles through the C3 position. In this sense, 2H-pyran-2-ones bearing a hydroxy or alkoxy group at C4 have been described as useful intermediates for accessing natural compounds with the skeleton of 4-hydroxy-3-substituted-2-pyranones [109]. Scheme 18.65 shows the

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Scheme 18.65 a-Formylation of pyranone 210.

reaction of the 4-methoxy-2-pyranone (210) with an electrophile, in the presence of titanium tetrachloride, to give the 3-formylpyranone 211 [110]. Finally, other reactions such as photochemical reactions [111], hydrogenations [112], and palladium-catalyzed couplings [113] can also take place at the a-pyranone structure. 18.4.2 Coumarins (2H-Chromen-2-ones or 2H-1-Benzopyran-2-ones)

Coumarins (2H-benzopyran-2-ones) are nearly planar compounds and are also considered as enol-lactone systems in a similar way to the corresponding a-pyrones. As noted above, coumarins (1,2-benzopyrones) have been widely reported in the scientific literature in respect of their important applications. Pharmacological properties are good examples of this, such as warfarin (212, Figure 18.17), a coumarin derivative that has found application as anticoagulant for preventing thrombosis [114]. Owing to its anticoagulant activity it has also found application as pesticide to eradicate rats and mice plagues [115]. Figure 18.18 shows the structure of ensaculin (213), another interesting coumarin. It is a 3,4-dimethylcoumarin, with a tethered piperazine moiety, that has demonstrated potential activity against dementia [116].

Figure 18.17 Structure of warfarin.

Figure 18.18 Structure of ensaculin.

18.4 Pyrones, Coumarins, and Chromones

Figure 18.19 Fluorescent coumarin 214 is used in laser devices.

In addition to their use in pharmacology, coumarins can also be found in other fields such as material science. For instance, coumarin 214 has found applicability as part of laser devices, due to its fluorescent properties (Figure 18.19) [117]. Perhaps one of the easiest ways to access to the coumarin structure consists in an intramolecular lactonization, as several examples of the synthesis of coumarins following this methodology have been reported. In the reaction shown in Scheme 18.66, coumarin 216 has been synthesized through an acidic and basic deprotection/transesterification sequence from the acetoxy compound 215 [118]. OH

R1

CO2R3

HCl, MeOH

3

CO2R OAc

2

R

OH

R1

EtONa, EtOH 54 - 83%

R2

215

O

R3 O

216

1

R = H, Me, Cl R2 = H, Me, OMe R3 = Me, Et Scheme 18.66 Synthesis of coumarin 216 through an intramolecular lactonization.

Salicylaldehydes are often used as staring materials for the intramolecular lactonization. These compounds can be transformed, following simple procedures such as Wittig [119] or Knoevenagel reactions [120], into intermediates that in situ cyclize to the corresponding coumarins. Scheme 18.67 describes the Wittig reaction of phosphorane 217 with salicylaldehyde derivative 218 to form an a,b-unsaturated ester that lactonizes in situ to give furanocoumarin 219 [121]. OHC EtO2CHC PPh3 217

+

HO

O 218

xylene ∆

R

O

O 219

O R

Scheme 18.67 Synthesis of the furanocoumarin 219.

One of the most extended procedures for coumarin synthesis consists of a Pechmann condensation, an acid-catalyzed condensation of phenol with a b-ketoester. The reaction mechanism is initiated by an electrophilic aromatic substitution

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and involves a final step of lactonization. Among the different reaction conditions reported, Scheme 18.68 describes a coumarin synthesis, in the absence of solvent, through a Pechmann condensation catalyzed by titanium tetrachloride [122].

Scheme 18.68 Pechmann condensation for the synthesis of coumarin 220.

Propionic acids [123] or propionic esters [124] are also used as 1,3-dicarbonyl synthetic equivalents for this reaction. Other intramolecular reactions such as condensations [125], ring closing metathesis [126], or transition metal catalyzed arylation of aryl alkynoates [127] have also been reported. Finally, it is worth noting an interesting procedure that involves a transition metal catalyzed carbonylation. Thus, Scheme 18.69 describes a coumarin synthesis from ortho-alkynylphenols [128]. Rhodium-catalyzed carbonylation followed by lactonization furnishes coumarin 221, along with certain amount of a benzofuranone.

Scheme 18.69 Synthesis of coumarin 221, involving a carbonylation step.

Related to their reactivity, coumarins follow similar reaction patterns to those described for a-pyrones. In this sense, reactions with nucleophiles [129], electrophiles [130], and also Diels–Alder cycloadditions [131], with the participation of the lactone ring, are common examples. Only a few procedures involving the benzene fused ring, such as selective nitration of the aromatic ring [132], differ from the reactivity of a-pyrones. 18.4.3 c-Pyrones (4H-Pyran-4-ones)

4H-Pyran-4-ones, similarly to 2H-pyran-2-ones, can be presented as resonance hybrids between a cross-conjugated cycloenone and a zwitterionic aromatic structure (Figure 18.20).

18.4 Pyrones, Coumarins, and Chromones

Figure 18.20 Mesomeric structures for 4H-pyran-4-one.

O

O 5

O

O

O 222

Figure 18.21 Retrosynthetic approach to c-pyrones.

Taking account of the absorptions in the infrared spectra, c-pyrones are also mainly considered as lactones instead of aromatic compounds. To support this theory an absorption at the IR spectra around 1660 cm
1 is observed [133], similarly to the C¼O stretching seen in cyclohexadienones. However, this value is slightly lower than the absorption observed for a-pyrones. These values, in addition to their higher basicity compared to enones, indicate a greater contribution from the aromatic structure [134]. 18.4.3.1 Synthesis of c-Pyrones The most commonly accepted methodology for the synthesis of 4H-pyran-4-ones (5) lies in the cyclocondensation of 1,3,5-tricarbonylcompounds (222), usually performed under acidic conditions (Figure 18.21) [135]. As an example of this approach, Scheme 18.70 shows a high yield, multi-gram scale (10 g) synthesis of c-pyrone (5) from diketalic bis-aldehyde 223 [136].

Scheme 18.70 Large-scale synthesis of c-pyranone (5).

The main differences in the reported methodologies for the synthesis of c-pyrones usually occur in the procedures involved for accessing the 1,3,5-tricarbonyl compound or analogues. Thus, use of the enolate of diketone 224, in the reaction with carboxylic esters, yields triketones 225 that cyclize under acidic conditions to give 2,6disubstituted c-pyrones 226 (Scheme 18.71) [137]. As another example of this approach, c-pyrones can also be obtained from a-pyrones. Thus, a-pyrones, after acidic treatment, are cleaved and transformed into a 1,3,5-triketone that in situ undergoes recyclization to the corresponding c-pyrone [138].

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Scheme 18.71 4-Pyranone 226 from diketone 224.

The synthesis of 4H-pyran-4-ones has also been reported involving a totally different approach. As an example, Scheme 18.72 describes a hetero-Diels–Alder reaction between the ethoxyethyne (228) and ketoketene 227 to form the corresponding substituted c-pyrone 229 [139]. In a similar way, the use of enol-esters gives rise to 6-unsubstituded pyranones, after elimination of ethanol. MeO2C

C

O

O Hexane, rt

+ R

O

OEt

227

80%

MeO2C R

228

O

OEt

229

Scheme 18.72 Hetero-Diels–Alder cycloaddition to form c-pyrone 229.

18.4.3.2 Reactivity of c-Pyrones c-Pyrones can be easily transformed into a-pyrones upon irradiation. This evolution is proposed to involve an initial step of electrocyclization to form the intermediate 230, which can evolve to the formation of the epoxycyclopentenone 231. Finally, oxygen migration followed by ring expansion leads to the 2H-pyran-2-one (4) (Scheme 18.73) [140]. O

O

O

O

5

230

O

O

O

O 231

4

Scheme 18.73 Photochemical transformation of c-pyrone (5) into a-pyrone (4).

The reactivity of 4H-pyran-4-ones shows great similarity to that of 2H-pyran-2ones. Thus, cycloadditions with the participation of one or both pyranone double bonds are good indications of the low aromaticity of c-pyrones. Scheme 18.74 shows the participation of c-pyrone 233 as a dienophile in a Diels–Alder reaction with Danishefsky’s diene (232) to form the bicyclic pyranone 234 [141]. On the other hand, c-pyrones can be transformed into medium-sized rings through cycloadditions that involve the participation of both unsaturations. In this sense, several intermolecular [5 þ 2] cycloadditions have been reported [142].

18.4 Pyrones, Coumarins, and Chromones

OMe

t

BuO2C

+ TMSO

O 232

t

BuO2C O MeO

O Toluene ∆ Ph 54% TMSO

233

O H 234

Ph

Scheme 18.74 c-Pyrone 233 as a dienophile.

Among of them, the optically active 8-oxabicyclic[3.2.1]octane 236 has been produced from optically active b-silyloxy-c-pyrone 235 (Scheme 18.75) [143]. TBSO O

O

X O

: S p-Tol O

Toluene ∆

X

TBSO

95 - 98% 82 - 94% dr

235

O

H H : S p-Tol O 236

X = C(CN)2, C(CO2Et)2, S Scheme 18.75 Intramolecular [5 þ 2] cycloaddition of c-pyrone 235.

4H-Pyran-4-ones, similarly to 2H-pyran-2-ones, react with nucleophiles, involving an opening–reclosing of the six-membered ring. Nucleophilic attack on c-pyrones can occur in two different ways: 1,2-addition at the carbonyl group and 1,4-conjugated additions. Scheme 18.76 shows two representative examples that describe this regioselectivity. Thus, 1,2-addition followed by double bond formation is observed in the reaction of the reactive methylene group of the cyanoacetamide (238) and c-pyrone 237 [144]. On the other hand, c-pyrone 239 has been transformed into the

Scheme 18.76 Nucleophilic attacks on 4-pyranones.

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O

O

OMe

O O

HO O

O

O

O

OH O

O

OH O

OMe 241

242

Figure 18.22 Structures of khellin (241) and cromoglicic acid (242).

pyridone 240 by a nucleophilic 1,4-addition upon ammonium hydroxide treatment [145]. 18.4.4 Chromones (4H-Chromen-4-ones or 4H-1-Benzopyran-4-ones)

As described above for coumarins, several examples of natural occurring compounds with the structure of chromones (4H-1-benzopyran-4-ones) have been described. As an example, khellin (241) is a natural biologically active chromone that has been widely used in traditional Egyptian medicine for the treatment of renal colic and it is known that it can also act as a vasodilatator (Figure 18.22) [146]. However, due to the important secondary effects of khellin, resulting headaches or intestinal disorders, other synthetic analogues such as cromoglicic acid (242) have been developed. The sodium salt of 242 has found application in the treatment of allergic rhinitis or asthma [147]. Flavones (2-phenylchromones) are also natural occurring compounds, widely found, usually as glycoside derivatives, as pigments in plants. Compounds of this type are luteolin (243), which is present in celery, green pepper, and camomile tea, which shows antioxidant properties [148], and apigenin (244), a component of parsley and celery with important potential biological [149] and industrial properties as a dye for wool (Figure 18.23). In addition, 3-hydroxyflavones, also known as flavonols, form

Figure 18.23 Structures of luteolin (243), apigenin (244), and myricetin (245).

18.4 Pyrones, Coumarins, and Chromones

another interesting family of biologically active chromones. As an example, myricetin (245), found in grapes and other plants, has demonstrated antitumor activity [150]. The most extensive methodology for the synthesis of 4H-1-benzopyran-4-ones (chromones) involves the formation of the pyranone ring starting from orthohydroxyarylketones or related compounds. As a general example, Scheme 18.77 shows the synthesis of isoflavone 247 through the treatment of ortho-hydroxyphenone 246 with a mixed anhydride (of acetic and formic acids) and further dehydration [151]. R1

OR1 O

O Ar

HO

OH 246

Ar

Ac2O HCO2H 70 - 90%

R2O

O 247

R1 = H,OH R2 = H,HCO Ar = 4-NO2-C6H4 Scheme 18.77 Formation of chromone 247 from o-hydroxyarylketone 246.

The intramolecular cyclization followed by dehydration of o-hydroxyacetophenones can be achieved using different experimental conditions. Scheme 18.78 shows a procedure promoted by iron trichloride [152]. The phenols 248 also cyclize under copper treatment and microwave irradiation [153] to form chromones 249.

Scheme 18.78 Iron-promoted formation of chromone 249.

The synthesis of chromones starting from o-hydroxyketones or related compounds has also been reported through an intramolecular cyclization of aryl ethynylketones [154] or 2-acetoxy- [155], benzyloxy- [156], or hydroxychalcones [157], followed by oxidation. In addition to the procedures reported here, it is worth mentioning an interesting example involving a carbonylation step. This reaction is described in Scheme 18.79: chromone 252 is synthesized through a palladium-catalyzed carbonylation of o-iodophenol 250, in the presence of a terminal alkyne (251) [158].

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1676

R1

I OH 250

PdCl2 /PPh3

+ R2 251

NEt3 /H2O CO 35-95%

R1

O

O

R2

252

R1 = H, Me, t-Bu, Ph, Cl, CO2 Et R2 = n-Bu, t-Bu, n-C6H13,TMS Scheme 18.79 Synthesis of chromone 252 through a palladium-catalyzed carbonylation.

Finally, chromones can also be synthesized starting from other heterocycles. Scheme 18.80 shows the transformation of benzofuran 253 into chromone 254 upon treatment with osmium tetroxide followed by hydrolysis [159]. The reaction involves a double bond oxidation followed by opening of the furan ring and a final recyclization to form a six-membered ring.

Scheme 18.80 Transformation of benzofuran 253 into chromone 254.

Finally, no section is specifically dedicated to compiling reported examples of the reactivity of chromones because, in addition to the typical aromatic substitution at the arene ring and similar behavior to coumarins, their reactivity follows a similar pattern to the non-benzofused compounds, the c-pyrones.

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102 Soh, J.Y.-T. and Tan, C.-H. (2009)

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j1683

19 Six-Membered Heterocycles: 1,2-, 1,3-, and 1,4-Diazines and Related Systems María-Paz Cabal

19.1 Introduction

Diazines are aromatic six-membered heterocycles that contain two sp2-hybridized nitrogen atoms in the ring. The three diazine isomers are pyridazine (1,2-diazine) [1–3] (1), pyrimidine (1,3-diazine) [4] (2), and pyrazine (1,4-diazine) [5] (3). They are stable, colorless compounds that are soluble in water. Being rather expensive, and not readily available, these parent compounds are rarely used as starting materials for the synthesis of their derivatives. 4

4

5

3

5

N3

5

6 1 N2 N Pyridazine

6 1 2 N Pyrimidine

6

1

2

4 N

3

1 2 N Pyrazine 3

Four types of bicyclic variants in which a benzene ring is fused onto the diazine include cinnoline (benzo[c]pyridazine) (4), phthalazine (benzo[d]pyridazine) (5), quinazoline (benzo[d]pyrimidine) (6), and quinoxaline (benzo[e]pyrazine) (7). In addition, pteridine (8) and the diazanaphthalene system phenazine (dibenzopyrazine) (9) are also important derivatives.

N Cinnoline 4

N

N N Phthalazine 5

N N Quinazoline 6

N N Quinoxaline 7

N

N N

N

Pteridine 8

N N Phenazine 9

Modern Heterocyclic Chemistry, First Edition. Edited by Julio Alvarez-Builla, Juan Jose Vaquero, and José Barluenga. Ó 2011 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2011 by Wiley-VCH Verlag GmbH & Co. KGaA.

j 19 Six-Membered Heterocycles: 1,2-, 1,3-, and 1,4-Diazines and Related Systems

1684

19.2 General Reactivity 19.2.1 Physical and Spectroscopic Properties [6]

As 6p-electron heteroaromatic compounds diazines are electron-deficient due to the inductive effects of the nitrogen atoms that induce a partially positive charge on the carbon atoms. The calculated p-electron density [7] distributions for each ring, compared to pyridine (Figure 19.1), are consistent with the observed reactivities towards electrophiles, which are notably lower than those towards nucleophiles. Pyridazine and pyrimidine have a planar, slightly distorted hexagonal geometry, while pyrazine is planar with D2h symmetry. Each of these heterocycles can be regarded as aromatic in character, and, consequently, the bond lengths and internal
bond angles (Figure 19.2) are also very similar to those in benzene (1.39 A), based on X-ray diffraction, gas-phase electron diffraction and microwave spectroscopy studies [8]. However, the resonance energies of pyrimidine (110 kJ mol1) and pyrazine (100 kJ mol1) are significantly lower than those of benzene (150 kJ mol1) or pyridine (117 kJ mol1), which means that these compounds are less aromatic. Another way to measure the degree of aromaticity is by the structural index of aromaticity that is calculated based on the bond lengths; in such set of values the aromaticity is expressed as a percentage of that of benzene (Table 19.1). The NN bond in pyridazine has significant single bond character, supporting theoretical calculations suggesting that canonical form 1a, having double bonds

0.942

0.734

0.965 1.051

0.795

N 1.029

N

N N 1.240

N 1.449

Pyridazine

Pyrimidine

0.584

N 1.368

0.816

0.787 N 1.426 Pyridine

Pyrazine

Figure 19.1 Calculated p-electron density distributions for each ring, compared to pyridine.

1.37

1.39

117.1 123.7

1.39

N

1.36

116.8

115.5

N

1.34

1.39 118.4

121.8 1.39

119.3 1.34

N

N 1.33

Pyridazine

122.3 127.6 116.3 1.34

N

1.34

Pyrimidine


1.39 123.8 116.9

N

N

Pyrazine

Pyridine

1.34

Figure 19.2 Bond lengths (A) and internal bond angles (
) of pyridazine, pyrimidine, pyrazine, and pyridine.

19.2 General Reactivity Table 19.1 Aromaticity index (%).

Benzene Pyridine Pyridazine Pyrimidine Pyrazine

Table 19.2

100 82 65 67 75

1

H NMR chemical shifts (ppm) of diazines compared with pyridine.

Compound

H2

H3

H4

H5

H6

C2

C3

C4

C5

C6

Solvent

Pyridazine Pyrimidine Pyrazine Pyridine

— 9.26 8.60 8.52

9.17 — 8.60 7.16

7.52 8.78 — 7.55

7.52 7.36 8.60 7.16

9.17 8.78 8.60 8.52

— 158.4 145.9 149.5

153.0 — 145.9 125.6

130.0 156.9 — 138.7

130.3 121.9 145.9 125.6

153.0 156.9 145.9 149.5

CDCl3 CDCl3 CDCl3 CDCl3

between the nitrogens, contributes less to the resonance hybrid than the NN single bond structure 1b.

N

N

N

1a

N

1b

The 1 H and 13 C NMR spectra of the diazines show close similarities with pyridine (Table 19.2). The additional nitrogen atom in the ring is responsible for a greater downfield shift of the ring protons and C-atoms at the 3- and 6-positions in pyridazine, the 2-, 4-, and 6-positions in pyrimidine, and in all the carbons in pyrazine. The symmetrical 1,4-diazines structure, of course, is reflected in the 1 H and 13 C NMR spectra, showing one signal for the four ring protons and C-atoms. The vicinal coupling constants of ortho protons on the rings vary considerably, depending on the type of heterocycle, and are typically smaller for those protons located closer to the heteroatoms (Figure 19.3). The magnitude of the coupling constants in effect reflects the degree of double bond character in the particular CC bond. 15N NMR spectroscopy has also been used to estimate the hybridization of the nitrogen atoms [9].

8.0-9.6

5.1

H H

H N

N

5.0

6.8-9.1

H

H

H N

N

N

H

H

4.0-5.7

1.8-2.1 N

H

Figure 19.3 Vicinal coupling constants (Hz) of ortho protons.

N

H

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j 19 Six-Membered Heterocycles: 1,2-, 1,3-, and 1,4-Diazines and Related Systems

1686

Table 19.3 UV absorption bands of the diazines versus pyridine.

Compound

p ! p

Log e

n ! p

Log e

Solvent

Pyridazine

241 251 238 243 261 267 195 251

3.02 3.15 3.48 3.50 3.81 3.72 2.65 3.30

340

2.56

Hexane

272

2.62

H2O

301

2.88

H2O

270

3.87

Hexane

Pyrimidine Pyrazine Pyridine

Table 19.3 lists the principal bands in the UV spectra of the three monocyclic systems. The six-membered aza-aromatic compounds possess the 6p-electron system of benzene, and have non-bonding electron pairs on the nitrogen atoms. These electron pairs are responsible for n ! p electronic transitions at longer wavelengths. These absorptions are weak in comparison to the p ! p transition of the ring electrons and are frequently difficult to locate in spectra except when the two nitrogen atoms are adjacent. Thus, the n ! p bands are more obvious features of the UV spectra of compounds such as pyridazine (1) and cinnoline (4). The introduction of a nitrogen atom into a benzene ring tends to make a derivative more crystalline and less volatile; this effect is even greater for the diazines, especially pyridazine and pyrazine. Pyridazine, in contrast, is a colorless liquid, soluble in water and alcohols but insoluble in hydrocarbons. The high boiling point of pyridazine, 80–90
C – higher than the other two diazines (Table 19.4) – is attributed to the polarizability of the N–N unit, which results in extensive dipolar association in the liquid state. Alkyl groups attached to ring carbon atoms usually increase the boiling points by 20–60
C, while hydrogen bonding groups such as carboxylic acids, amides, amino, and hydroxy substituents afford solids. Methoxy, methylthio, and dimethylamino derivatives are often liquids, while chloro compounds have boiling points similar to those of the corresponding ethyl derivatives, and approximately 25
C lower than their bromo analogues.

Table 19.4 Physical properties of pyridazine, pyrimidine, and pyrazine versus pyridine.

Property

Pyridazine

Pyrimidine

Pyrazine

Pyridine

Mp (
C) Bp (
C/760 mmHg) pKa Dipole moment (m, D) DH
(kJ mol1)

8 208 2.3 4.22 4397.8

22.5 124 1.3 2.33 4480.2

57 116 0.4 0 4480.6

42 115 5.2 2.22

19.2 General Reactivity

The basicities of the diazines are sharply reduced from that of pyridine and, consequently, they are more difficult to protonate on the nitrogen centers. This is reflected by the significantly lower pKa values the protonated species have compared to pyridinium cation (pKa 5.2): 2.3 for protonated pyridazine, 1.3 for protonated pyrimidine, and 0.4 for protonated pyrazine. The dipolar moment of pyridazine is higher than that of pyrimidine, while pyrazine is symmetrical and has no dipole moment. The calculated enthalpies of formation for the diazines show that pyridazine is 83 kJ mol1 more stable than pyrimidine and pyrazine. 19.2.2 Tautomerism

Table 19.5 summarizes the tautomeric features of hydroxy-, mercapto-, and aminosubstituted azines for dilute solutions in water at 20
C. For systems having X ¼ O or S, the non-aromatic tautomer form(s) in general is favored over the aromatic species,

Table 19.5 Tautomeric equilibria of some monofunctional azines.

Entry

Compounds

1

XH N A

2

N

N

N

N H

N XH

XH

N B

X

X

N

N N H

A>B

B>A

B>A

A>B

B/C > A

B/C > A

A > B/C

B/C > A

B/C > A

A > B/C

N B

A

B>A

B>A

A>B

XH

N H

X B

N N H

N

N

X C

X NH

N

A

B>A

N

NH

A

N

B>A

B

N

5

X¼N

NH

X

A 3

X¼S

B

XH

N

4

X

X¼O

C

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j 19 Six-Membered Heterocycles: 1,2-, 1,3-, and 1,4-Diazines and Related Systems

1688

although in the vapor phase the thiol predominates over the thione. For 4-hydroxypyrimidine (entry 4), which can exist as three different tautomers, the general tendency favors amide B over the vinylogous amide C. For X ¼ N, the aromatic structure is consistently favored over the other tautomers B and C.

19.3 Relevant Natural/Biological Compounds 19.3.1 Pyridazines (1,2-Diazines)

Unlike other heterocycles found in many important natural products, pyridazines were discovered only after 1970, and relatively few pyridazines have thus far been isolated from natural sources. The first representative examples include some fungal metabolites from Streptomyces species. These are now a big group of over 15 related compounds. Monomycin X [10] (10, from Streptomyces jamaicensis) is just one example of cyclohexadepsipeptide antibiotics. Antrimycins [11] (11, from Streptomyces xanthocidiens) are tuberculostatic peptides that also contain nonribosomal amino acids. The quaternary salt pyridazinomycin [12] (12, from Streptomyces violaceoniger) is an antifungal antibiotic whose amino acid side chain can be viewed as L-ornithine with its terminal nitrogen atom as part of the pyridazine ring. R2

O

H N N (S) H (R) H O O N N(S )

(R ) O NH

O (S)

N

(R)

N Me

O

O

H (S) N N (S) H O OH OH H2N

O

H2N

O N N

H( ) N S (S ) 1 R

O N H

H (S) N CO2H O

OH

R1 = Me, Et, n-Pr, i-Bu R2 = Me, Et

O

11 Antrimycins

10 Monomycin X H2NOC

Cl N

N

NH2 CO2H

12 Pyridazinomycin

As synthetic compounds, pyridazines constitute an important pharmacophoric moiety present in many drugs acting on various pharmacological targets. Minaprine (13) [13] is a synthetically-derived aminopyridazine possessing dopaminergic, serotoninergic, cholinergic, and GABA-ergic activities, while SR 95103 (14) [14], an

19.3 Relevant Natural/Biological Compounds

analog of c-aminobutyric acid (GABA), serves as a powerful inhibitor of monoamine oxidase and acetylcholine esterase [15, 16]. Me

Me

Ph

N

H N

N

NH O

N

N

Ph 13 Minaprine

N

COOH

14 SR 95103

Several pyridazines are selective plant growth regulators and are used as herbicides. Pyridate, 15, and 3-hydroxy-6(1H)-pyrazinone, 16, are two examples currently used in commercial lawn weed killers. n-C8H17SO2 Ph

OH

Cl N

N

O

15 Pyridate

N H

N

16 3-Hydroxy-6(1H)-pyrazinone

19.3.2 Pyrimidines (1,3-Diazines)

The most important naturally occurring diazines are the pyrimidine bases uracil, thymine, and cytosine, which comprise the fundamental nucleoside building blocks in deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) [17]. These compounds exist as tautomers in which the hydroxypyrimidines adopt the lactam form [uridine (17) and thymidine (18)] whereas aminopyrimidines prefer the enamine structure (cytidine, 19).

Uracil

NH N

NH2

O

O Thymine

NH N

O

O

N N

O

O

HO

HO

HO

Cytosine

O

O

OH OH

OH OH

OH OH

17 Uridine

18 Thymidine

19 Cytidine

In addition, several pyrimidine nucleoside analogues have been developed as antiviral agents [18]. Idoxuridine, 20, is used in the treatment of herpes infections of

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j 19 Six-Membered Heterocycles: 1,2-, 1,3-, and 1,4-Diazines and Related Systems

1690

the eye; AZT (21) is the most widely used anti-AIDS drug; stavudine, 22, is effective in the treatment of HIV infections and AIDS, and lamivudine, 23, is used to treat both hepatitis B and AIDS. O

O Me

I

NH

NH N

N

O

O

HO

HO

NH2

O Me N

O

N

O

O

HO

HO

O

N

NH

O

O S

N3

OH 20 Idoxuridine

23 Lamivudine

22 Stavudine

21 AZT

Barbituric acid, 24, and orotic acid, 25, a key compound in the biosynthesis of naturally occurring pyrimidine derivatives, are also important pyrimidine derivatives. 5,5-Diethylbarbituric acid was the first therapeutic barbiturate (E. Fischer 1903, veronal or barbital, 26), and other derivatives are still used as sedatives, antiepileptic drugs, and anesthetics. Sedative barbiturates have toxicity and dependency problems and have now been replaced by other drugs. O

O

R1 NH

NH HOOC

N O H 24 Barbituric acid O

N H

O

25 Orotic acid

O NR3

R2 O

N H

O

26 Veronal (Barbital) R1 = R2 = Et R3 = H

Vitamin B1 (thiamine), 27, occurs in yeast, rice husk, and various cereals, and represents another well-known naturally-occurring pyrimidine essential in our daily lives. A deficiency of vitamin B1 causes beriberi and damage to the nervous system (polyneuritis). NH2 N Me

OH

N N

Cl

S

27 Vitamin B1

Several pyrimidine-containing antibiotics, especially those isolated from Streptomyces, possess potent antitumor properties, such as the structurally complex bleomycins. Trimethoprim, 28, an antibacterial agent widely used in combination with sulfamethoxazole, and the antimalarial pyrimethamine, 29, are examples of synthetic 2-amino-substituted pyrimidines in the pharmaceutical area.

19.4 Synthesis of Pyridazines (1,2-Diazines)

Cl

NH2 H3CO

NH2

N

H3CO

N

N NH2

Et

N

NH2

OCH3 28 Trimethoprim

29 Pyrimethamine

Bensulfuronmethyl, 30, a sulfonylurea derived from 4,6-dimethoxy-2-aminopyrimidine, acts as a powerful plant growth regulator and is an active herbicide. 7-Hydroxy-5-methyl-1,2,4-triazolo[1,5-a]pyrimidine, 31, serves as an emulsion stabilizer in various photographic materials.

S O2

H N

OH

H N O

N

OCH3

N N

N Me

N

N

OCH3 30 Bensulfuronmethyl

31

19.3.3 Pyrazines (1,4-Diazines)

Alkylpyrazines occur frequently as constituents in foodstuffs and are responsible for their flavor and strong aroma. Although being present in very small amounts, they are highly odiferous and can be detected at extremely low concentrations (105 ppm). 3-Isobutyl-2-methoxypyrazine, 32, is a simple natural derivative isolated from green peas and wine, and 2-methyl-6-vinylpyrazine, 33, is an aromatic component of coffee. Several polyalkylpyrazines such as 2-ethyl-3,5-dimethylpyrazine, 34, also act as alarm pheromones in ants. Several pyrazin-2(1H)-ones and 1-hydroxypyrazin-2(1H)-ones (35) have antibiotic properties. N N 32

N O

N

Me

Me

N

Et

N

R2

R1

34

O N 35 OH

pheromone

antibiotic

Me

33

Food aroma components

N

19.4 Synthesis of Pyridazines (1,2-Diazines)

The first pyridazines were first synthesized as early as 1886 by Fischer [19], but their chemistry has only been explored since the 1950s. This is likely because pyridazines do not occur as natural products despite having a nitrogen–nitrogen linkage that

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j 19 Six-Membered Heterocycles: 1,2-, 1,3-, and 1,4-Diazines and Related Systems

1692

could conceivably be obtainable from biochemical transformation of dinitrogen. However, since many pyridazines possess potential therapeutic or plant growth inhibitory effects, a wide variety of new syntheses have been developed more recently. 19.4.1 Synthesis by Ring-Closure Reactions 19.4.1.1 Three-Component Couplings Although the assembly of pyridazines from three discrete coupling units is relatively uncommon, three-component reactions do represent a useful method for the preparation of 1,2-diazines (Scheme 19.1). Z

N

Z

three-component coupling

O +

N

O

O H2N

NH2

Scheme 19.1

As an example (Scheme 19.2), a 1,2-diketone, a cyanoacetate, and hydrazine combine under basic alcoholic conditions to afford 5,6-disubstituted pyridazine-3 (2H)-ones 36 bearing a nitrile group at position 4 [20], a versatile precursor to fused pyridazines [21, 22]. Similarly, the reaction of 1-aryl-2-nitroprop-1-enes with an acetoacetate ester and hydrazine offers 3,6-dimethylpyridazines 37 bearing an aryl group at position 5 and a carbohydrazide at position 4 [23, 24]. R2

CN O +

R1

OR3

NC O

O

H2NNH2.H2O

R2

O

NaOEt, reflux R1 = R2 = Ph R3 = Et

R1

N

NH

36 (44%) CONHNH2

H2NNH2.H2O

Me Ar

CO2Et

+ NO2

O

Ar

Me

NaOEt, reflux Me

N

N

37 (68-78%) Scheme 19.2

19.4.1.2 Two-Component Couplings Two different strategies can be considered for the assembly of pyridazines by a twocomponent coupling (Scheme 19.3).

19.4 Synthesis of Pyridazines (1,2-Diazines)

O

O

+ H2N

O

N N

+

N

O

H2N

NH2

Scheme 19.3

A more common route to 1,2-diazines involves a coupling of formal [4 þ 2] cyclocondensation precursors to create the six-membered ring in one step. Examples are illustrated below. 19.4.1.2.1 [C-C-C-C] þ [N-N] The condensation of hydrazine or substituted hydrazines with appropriate four-carbon synthons represents one of the most widely used approaches to pyridazines and pyridazinones (Scheme 19.4) [25a]. Carbons 1 and 4 of these building blocks must bear functional groups that are susceptible to nucleophilic attack by a hydrazine nitrogen atom (usually followed by elimination of a small molecule like water, an alcohol, etc.). Depending on the degree of saturation of the C2C3 bond, fully aromatic or partially saturated pyridazines are obtained, in which case various methods for oxidation/aromatization are available (Br2/AcOH; CuCl2/ CH3CN, etc.). two component reaction N

O +

N

O

H2N

NH2

Scheme 19.4

A long-established method to prepare 3,6-disubstituted pyridazines is the condensation of saturated 1,4-dicarbonyl compounds with hydrazine, semicarbazide, or similar hydrazine derivatives (Scheme 19.5). The fully aromatic pyridazines can often be obtained by spontaneous oxidation of the dihydro intermediates [25b]. When saturated 1,4-diketones are used, the reaction is carried out in the presence of mineral acids to prevent the competing formation of N-aminopyrroles. R1 O O

R1

H2NNH2.H2O

R1

AcOH

R1

N

N

R1

[O] R1

N

N

R1 = tBu 91%

Scheme 19.5

One interesting alternative is the use of Meldrum’s acid derivatives 38, which are easily available and readily cyclize with hydrazine at room temperature, with subsequent decarboxylation, to provide the 4,5-dihydropyridazin-3(2H)-ones 39 (Scheme 19.6) [26]. 4-Oxoalkanoic acids where R3 ¼ alkyl/aryl/heteroaryl residues, with or without further substituents R1 and R2, have been employed for condensation reactions with

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j 19 Six-Membered Heterocycles: 1,2-, 1,3-, and 1,4-Diazines and Related Systems

1694

O R1 R2

O

R1 O

O

H2NNH2.H2O

O

O

R2

N

NH

39

38 Scheme 19.6

hydrazine (Scheme 19.7) [27]. Whereas in most cases the free carboxylic acids (R4 ¼ H) are employed, esters are also frequently used [28]. For the latter case, a protocol suitable for high-throughput organic synthesis has been developed that is based on construction of the oxo ester precursor by silver(I)-catalyzed addition of zirconocenes to epoxy esters [29]. R1 CO2R4

O R3

R1 R2

H2NNH 2.H2O

R2

heat 66-100%

R3

R1 O NH

N

R2

[O] 52-95%

O

R3

N

NH

Scheme 19.7

When 4-oxoalkanoic acids with a 2-hydroxy group are employed for cyclization with hydrazine spontaneous dehydration of the initial intermediate occurs to give pyridazine-3(2H)-ones 40 (Scheme 19.8). In some cases, the 4-hydroxydiazinone intermediate can be isolated [30].

O R

CO 2R

3

R2

R1 OH

R1

R1

4

OH

R3

N

NH

O

R2

O

R2

H2NNH2 .H2O

-H2O

R3

N

NH

40 Scheme 19.8

A useful one-pot protocol based on this route has been developed by Coates (Scheme 19.9) [31] that employs substituted acetophenones with glyoxylic acid monohydrate in the presence of ammonium hydroxide, in which the initial aldol adduct is converted into the pyridazin-3(2H)-one 41 with hydrazine. The reported yields are, however, highly variable. O Ar

OHCCO2H.H2O H2O, NH4OH

O Ar

CO2 NH4 OH

-H2O (33-86%)

Scheme 19.9

O

H2NNH2.H2O Ar

N 41

NH

19.4 Synthesis of Pyridazines (1,2-Diazines)

j1695

Lam and Lee have devised a solid-phase procedure for the synthesis of various 3,6disubstituted pyridazines (Scheme 19.10) [32]. Sodium benzenesulfinate resin was treated sequentially with a-bromoketones in two steps to give immobilized diketo sulfones, from which a library of substituted pyridazines could be prepared by condensation with hydrazine. Release of the adducts from the resin occurs by spontaneous elimination driven by ring aromatization.

O 1.

Br

R1

R1 OO S

KI, NBuI, DMF, r.t. SO2Na

O

2. Br

R1 O O

R2

K2CO3, DMF, r.t.

R2

NH2-NH2

N N

ethanol/1,4-dioxane

R2 (10-40%)

Scheme 19.10

Unsaturated 1,4-dicarbonyls likewise undergo cyclization with hydrazine to afford directly the pyridazine product 42 (Scheme 19.11) [33]. While (Z)-alkenyl diketones react readily with ethanolic hydrazine hydrate at room temperature, cyclization of the corresponding (E)-isomer also occurs but requires higher reaction temperatures [34]. R1 O O

R1

H2NNH2.H2O

R1

ethanol

R1

N

N

R1 = Me, Ar

42 Scheme 19.11

The unsaturated 1,4-dicarbonyl compound can be generated electrolytically from polymer-bound furans [35]. The initial oxidation product 43 can be hydrolyzed in aqueous acid and, through condensation with hydrazine and concomitant hydrazinolysis of the ester linkage, pyridazines 44 are obtained in 50–65% overall yield (Scheme 19.12). The use of maleic acid derivatives with substituted hydrazines is a general method for the preparation of 6-hydroxypyridazin-3(2H)-ones 45, bearing various substituents at the 2, 4, or 5 positions (Scheme 19.13). These serve as versatile intermediates to other pyridazines since the oxo/hydroxyl groups at C3 and C6 can be easily converted into chloro substituents for nucleophilic replacement [36]. 3-Formylpropenoic acids and their hydroxylactone tautomers react with hydrazine to afford pyridazin-3(2H)-ones 46 in a single step (Scheme 19.14). Thus, the

j 19 Six-Membered Heterocycles: 1,2-, 1,3-, and 1,4-Diazines and Related Systems

1696

Me O

MeO O

Bu4N Br Me MeOH-1,4-dioxane C-electrodes j = 15 mA/cm2

O

O

OMe

H2SO4 aq.

Me

1,4-dioxane

O

O

O

O

O

O

43

H2N-NH2 HCl Me

Me HO

N

O

N

N

N

O

44 Scheme 19.12

R2

R2

R1

R1

H2NNH2.heat O

O

O

R1 = H, Me R1 = H, Me,Cl

HO

R2 O

N

NH

R1

OH

O

N H

(81-94%)

N

45 Scheme 19.13

R2 OHC

R1

R1

R2

H2NNH 2.H2O

R1

HO2C

HO

O

R1 = R 2 =Cl 95% R1 = R 2 =Br 98%

O

R2

O N

NH

46 Scheme 19.14

condensation of 2,3-dichloro-4-oxobut-2-enoic acid (mucochloric acid, R1 and R2 ¼ Cl) or its bromo congener with hydrazine gives the corresponding 4,5-dihalopyridazin-3(2H)-ones [37]. The same precursors have been used for the preparation of 6-aryl-4,5-dihalopyridazin-3(2H)-ones 47, via an intermediate lactone resulting from the Friedel–Crafts reaction of an arene with the 3-formyl acid (Scheme 19.15) [38].

O Cl O Cl

Ar

Cl H2NNH2.H2O

Cl Ar

O N 47

Scheme 19.15

NH

19.4 Synthesis of Pyridazines (1,2-Diazines)

j1697

a-Amino-c-cyanopropenoate esters can be used to obtain the corresponding 3,5diaminopyridazines (Scheme 19.16) [39].

NC

CO2Me

NHCOR O

H2NNH2.H2O EtOH, rt, 2 h

HNHCOR

N

H2N

NH

R = Me 62% R = Ph 81% Scheme 19.16

An interesting variation of this reaction has been described by Ohta and coworkers in the synthesis of the pyridazine-fused isopropylidene norbornadiene 51 (Scheme 19.17). The cyclization was carried out by hydrolysis of diethyl acetal 50 with formic acid followed by condensation with hydrazine hydrate [40]. Compound 50 was prepared by the Diels–Alder cycloaddition of propargylic aldehyde 48 with dimethylfulvene 49.

CHO tol., reflux

+

1. formic acid CHO

CH(OEt)2

2. NH2NH2.H2O N

CH(OEt)2

48

49

N

50 (40%)

Scheme 19.17

As an alternative to hydrazine-based cyclizations, Elassar has reported a Japp– Klingemann type reaction of aryldiazonium salts to produce pyridazines 52 (Scheme 19.18) [41].

CN

Ar N N Cl

X X = CO2Et, CN

X

N NAr NH 52

Scheme 19.18

19.4.1.2.2 [N-N-C-C] þ [C-C] Reaction of Methylene-Activated Hydrazides with 1,2-Dicarbonyl Compounds The two-component reaction of 1,2-dicarbonyl compounds with hydrazides possessing an active methylene group, such as cyanoacetohydrazide [20], heteroaryl-substituted

51

j 19 Six-Membered Heterocycles: 1,2-, 1,3-, and 1,4-Diazines and Related Systems

1698

acetohydrazides [42], or similar derivatives of 2-nitroacetic acid [43, 44], gives pyridazin-3(2H)-ones in fairly good yields (Schemes 19.19 and 19.20). Glyoxal, a-keto aldehydes, and a-diketones can all be employed as 1,2-dicarbonyl units for these cyclizations, thereby affording a wide range of substituted pyridazines. O + N

N

H2 N

O

N

Scheme 19.19

R3 O H2N

R3

NH

R2 R1

base R1

O

R2

O

O N

NH

NO2 R3 H2N

NO2 R2

N

R1

base

R3 N

NH

Scheme 19.20

Reaction of 1,2-Dicarbonyl Monohydrazones with Methylene-Activated Compounds An alternative method for the construction of pyridazin-3(2H)-ones 53 is the use of monohydrazones of 1,2-dicarbonyl compounds in combination with esters or nitriles possessing reactive a-methylene groups (Scheme 19.21) [45–47]. As for the above method, an assortment of substitution patterns can be introduced through selection of suitably substituted starting materials.

R2

+ R1

N NH2

R3

R3

O

O OEt

base

R

2

R1

O N

NH

53 Scheme 19.21

Reactions of 1,2-Diaza-1,3-Dienes with Alkyl 2-Acetylacetoacetate Derivatives In addition to their use as dienes in hetero-Diels–Alder reactions, 1,2-diaza-1,3-dienes 54 with an electron-withdrawing group at N1 can be coupled with acetyl acetoacetates 55

19.4 Synthesis of Pyridazines (1,2-Diazines)

under mildly basic conditions to give pyridazine products 57 (Scheme 19.22). Mechanistically, this sequence involves a 1,4-addition of the carbanion generated from the acetyl acetoacetate, followed by attack of the NH nitrogen atom on the oxo function and subsequent elimination of acetic acid and loss of the carbamoyl residue [48, 49]. These N-unsubstituted-1,4-dihydropyridazines 56 can be aromatized to pyridazines using, for example, a solid-phase supported brominating agent [50].

O

O O R1

N

N

CONH2 +

54

O R2

K2CO3

H R1

R2

N

R1

OH N

N NH CONH2 CH2N+Me3Br3-

N

O

THF

55

R1

R2

R2

CH2Cl2

57

N

CONH2

R2 R1 N

NH

-AcOH -CONH2

56

Scheme 19.22

19.4.1.3 One-Component Couplings 19.4.1.3.1 [N-N-C-C-C-C] The conceptually simplest route to pyridazines is the cyclization reaction of a hydrazone onto a suitably positioned carbonyl functionality (Scheme 19.23).

O N

N N

NH2

Scheme 19.23

There are two different strategies for the synthesis of pyridazines using a onecomponent reaction for the ring closure. Cyclization of Hydrazones of 4-Oxoalkenoic Acid Derivatives The intramolecular ringclosure reactions of the hydrazones of 4-oxoalkenoic acid derivatives, such as esters or nitriles, occur under various reaction conditions to afford pyridazinones or iminopyridazines (Scheme 19.24) [51]. In most cases, arylhydrazones [52] have been used as the cyclization substrates, being conveniently available by electrophilic substitution of methylene-activated precursors with arenediazonium salts [53].

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j 19 Six-Membered Heterocycles: 1,2-, 1,3-, and 1,4-Diazines and Related Systems

1700

CO2Et Ph

CO2Et

NC

EtO 2C

CO2Et

ArN2 Cl

Ph

NaOAc, EtOH, rt (64-68%)

NC

N

Ph

CO2Et O

NC

N

NaOAc, EtOH reflux (58-62%)

NHAr

NAr

Scheme 19.24

Reductive Cyclization of Diazo(vinyl)methanes Bearing a Carbonyl Group 4-(Trifluoromethyl)pyridazine-3-carboxylate esters 60 bearing an alkyl or alkoxy group at C6 can be prepared in two steps from the trifluoroacetyl-substituted diazo esters 58 (Scheme 19.25). First, the ketone is olefinated with stabilized Wittig reagents to afford the (E)-configured alkoxycarbonylvinyl diazomethane 59, which undergoes ring closure under very mild conditions by treatment with triphenylphosphine. Mechanistically, a “diaza-Wittig” reaction of an intermediate phosphazine has been suggested [54]. CF3 CF3

CF3 CO2Et

O N2

PPh3 + R1

O

58

Et2O, rt (56-88%)

CO2Et R1

O

Ph3P

R1

CO2Et O

N2

N

N PPh3

59 -Ph3PO

CF3 CO2Et R1

N

N

(57-83%)

60

Scheme 19.25

19.4.2 Cycloaddition Reactions

One of the most versatile methods for synthesizing functionalized pyridazines lies in the use of cycloaddition reactions between suitable dienes and dienophiles. 19.4.2.1 [4 þ 2]-Cycloaddition Reactions of 1,2,4,5-Tetrazines A reaction that has been used extensively for the synthesis of a wide variety of substituted pyridazines is the inverse-electron-demand (LUMO diene-controlled) Diels–Alder reactions of 1,2,4,5-tetrazines with alkene- or alkyne-type dienophiles, followed by elimination of dinitrogen to give the 1,2-pyrizadine (Scheme 19.26) [55]. This process works best when the tetrazine has electron-withdrawing substituents

19.4 Synthesis of Pyridazines (1,2-Diazines)

R3 R1 N N

R4

N N

R1

N 1 N R R3 N R2

R2

R3 -N2

R4

N N

R4 R2

Scheme 19.26

and the dienophile is electron-rich, thereby decreasing the energy gap between the respective frontier molecular orbitals (LUMOdiene–HOMOdienophile) [56]. Commonly used dienophiles are mono- and disubstituted alkynes such as ynamines, but also a wide range of substituents, including nitro, trimethylsilyl and trimethyltin, can be incorporated onto the acetylene. Alternatively, electron-rich alkenes such as enamines, enol ethers, and ketene acetals can be employed to provide routes to substituted pyridazines not easily available by other methods [57]. Wan and Snyder have applied this strategy to the inverse-electron demand cycloadditions of 2-substituted imidazoles 61 with 1,2,4,5-tetrazine-3,6-dicarboxylate, 62, to afford imidazo[4,5-d]pyridazines 63 in high yields (Scheme 19.27) [58]. CO2Me Me2N

N

N N

+

N N H

CO2Me THF

N N

Me2N

N N H

CO2Me

61

N N

N

62

CO2Me

(86%) 63

Scheme 19.27

This methodology has been extended to solid-phase synthesis for the rapid assembly of pyridazine compound libraries (Scheme 19.28). A resin-bound aminotetrazine with a functional group at the C6 position (64) has been used in combination with a wide range of electron-rich dienophiles to give pyridazines 65 after cleavage from the solid support [59].

HO O O

N N N

Scheme 19.28

R1 N N

X 64

Boc

NH 1. dioxane, reflux

R1

N N

+ R2

2. 20% TFA/Cl2CH2 3. K2CO3 MeOH/THF (2:1)

2

R

X 65

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j 19 Six-Membered Heterocycles: 1,2-, 1,3-, and 1,4-Diazines and Related Systems

1702

19.4.2.2 [4 þ 2]-Cycloaddition Reactions of Azodicarboxylic Esters Tetrahydropyridazines 66 can alternatively be produced by a Diels–Alder reaction of substituted 1,3-butadienes with azodicarboxylic esters (Scheme 19.29). The usual stereochemical and substituent effects of these reactions follow according to Woodward–Hoffmann considerations. R2

COOR N N COOR

+ R1

R2 R1

N N COOR COOR

66 Scheme 19.29

19.4.2.3 Cycloaddition Reactions with N-Phenyltriazolinedione Thiophene S,S-dioxides with bulky 3,4-disubstitution (R ¼ adamant-1-yl) react with N-phenyltriazolinedione by a Diels–Alder reaction to give 1:2 adducts, followed by hydrolysis to afford 4,5-disubstituted pyridazines (Scheme 19.30) [60].

R

R

R

R

N N +

S O2

O

N Ph

1. tol. reflux O

2. KOH, air MeOH, rt

-N2

R N N

R

N N

N

N

(56%)

Scheme 19.30

19.4.2.4 Hetero-Diels–Alder with Electron-Rich Alkenes A convenient method for the preparation of various pyridazines is the inverseelectron-demand hetero-Diels–Alder reaction of 1,2-diaza-1,3-dienes bearing at least one acceptor group with electron-rich alkenes such as enol ethers or enamines [61]. These [4 þ 2]-cycloaddition reactions show a high degree of regio- and stereochemical control [62, 63]. The primary reaction products are tetrahydropyridazines but they can be oxidatively transformed into the fully aromatic compounds (Scheme 19.31) [64].

R3 R2

R2 R1 N

N EWG Scheme 19.31

R4

Y

R3 R4 Y

R1 N N EWG

R3 R4

R2 R1 N

N

19.4 Synthesis of Pyridazines (1,2-Diazines)

j1703

19.4.3 Synthesis by Ring Enlargement 19.4.3.1 From Furan Derivatives Several examples of this reaction have been shown already (Section 19.4.1.2.1). Aromatic furans have been reported to undergo synthetically useful ring transformation into pyridazines in two steps [65]. First, the furan is converted into 2,5-dialkoxy2,5-dihydrofuran by oxidative addition of two moles of an alcohol, followed by an acid-promoted ring expansion in the presence of hydrazine (Scheme 19.32) [66]. R2

R2 [O] R1

R3

O

R4OH

H2N-NH 2

R2

H 3O

R1

R1 R3 R4O O OR4

R3 N

N

(40-85%) Scheme 19.32

19.4.3.2 From c-Bicyclic Lactams Bicyclic lactams have been used as precursors for the synthesis of chiral 4,5-dihydro2H-pyridazin-3-ones 67 through thermal ring expansion reaction with hydrazines (Scheme 19.33) [67].

R1

R3 R4

Ph

Ph O

R3 R4

N O

R2

PhNHNH 2, HCl dioxane:H 2O, 1:1 85 ºC

N

O

N Ph

(65-89%)

67 Scheme 19.33

19.4.3.3 From Bromocyclopropenes Under mild conditions a-diazoesters undergo 1,3-dipolar cycloadditions with di, tri-, and tetrahalocyclopropenes, leading to unstable cyclopropane-fused pyrazolines, which readily rearrange to pyridazines with loss of hydrogen halide (Scheme 19.34) [68]. H N2CHCO2Et Br

Br

Et2O, rt

H Br

Br N EtO2C

N H H

Scheme 19.34

Br EtO2C H

Br

Br N H

N

(52%)

EtO2C

N

N

j 19 Six-Membered Heterocycles: 1,2-, 1,3-, and 1,4-Diazines and Related Systems

1704

19.4.4 Synthesis by Ring Atom Exchange 19.4.4.1 Rearrangement of 1,2,4-Triazines This elegant method is based on ring transformation of an appropriate 6-aryl-3chloro-1,2,4-triazine, 68, to give 3-amino-6-arylpyridazines 69 with an electronwithdrawing substituent (R1 ¼ cyano, aryl, phenylsulfonyl or ester) at C4 (Scheme 19.35) [69]. R1 N Ph

N

Cl N

R1 +

NH2

t-BuOK

CN

Ph

DMF

N

N

69 (50-73%)

68 Scheme 19.35

In the mechanism, a nucleophile [phenylacetonitrile, ethyl cyanoacetate, malonitrile, or (phenylsulfonyl)acetonitrile anions] attacks the C5 position of the 1,2,4triazine, inducing a ring-opening, ring-closing process that leads to the diazine (Scheme 19.36).

CN

CN R1 Ph

N N

CN N

R1

Cl N

Ph

R1

base N

N

R1

N

Ph

N

N

R1

CN N

Ph

N

NH2

1. H3O+

N

2. - CO2

Ph

N

N

Scheme 19.36

19.4.5 Synthesis by Ring Contraction 19.4.5.1 From 1,2-Diazepines Pyridazines can be synthesized by contraction of 1,2-diazepines by two different mechanisms. Acid hydrolysis of 5-carboalkoxydihydroazepines with hydrochloric acid in ethanol affords pyridazinones in high yields (Scheme 19.37) [70]. EtO2C CN

EtO2C

EtO2C

CN

HCl / EtOH Ph N N

Ph

Scheme 19.37

Ph

N N H

O H Ph

Ph

PhCOCH2

CN

N Ph NH2

O

Ph

CN O N

NH

87%

19.4 Synthesis of Pyridazines (1,2-Diazines)

j1705

Using a second strategy, the C5 carbon can be extruded by halogenation of the dihydroazepine through a diazanorcaradiene 70 intermediate (Scheme 19.38). The products in these reactions were found to be strongly dependent upon the nature of C5 substituents as well as the reaction conditions [71].

R1

R1

Br

Br2 Ph N N

Ph

MeOH

R1

- HBr

HH

CH2R1 Ph

Ph N

Ph N N

Ph

Ph

N

Ph

N

N

70

R1 = CO2Et, CN

Scheme 19.38

On the other hand, 1,2-diazepines, consisting of a seven-membered, ring can undergo ring contraction through loss of one of the ring atoms as a stable entity upon thermolysis. As an example, 3,7-diphenyl-5,6-dihydro-4H-1,2-diazepines bearing strong electron-withdrawing substituents at C5 (CN, CO2Et) have been reported to be unstable and undergo thermal ring contraction at the temperature of boiling xylene, to afford the 3,6-diphenylpyridazine (Scheme 19.39) [72]. No mechanism has been suggested for this reaction. R1 CN Ph

Xylene Ph N N

Ph

reflux

Ph

N

N

(40%) Scheme 19.39

19.4.5.2 From Hetero-1,2-Diazepines Similarly to the above transformation, 1,2-diazepines containing an additional heteroatom at the C5 position (71) undergo ring contraction to afford pyridazines 72 (Scheme 19.40). The heteroatom unit can be nitrogen [73], sulfur [74], or selenium [75]. The reaction conditions involve either halogenation or heating in an inert solvent.

S R2

O O

Scheme 19.40

H2NNH2.H2O R1

TsOH, EtOH reflux

R1

S R2

N N 71

HOCH 2CH2OH R1

reflux

R2

N

N

72 (70-94%)

j 19 Six-Membered Heterocycles: 1,2-, 1,3-, and 1,4-Diazines and Related Systems

1706

The mechanism suggested for this process presumes a thermal tautomerization to an enamine, followed by ring opening and electrocyclic ring closure with loss of hydrogen sulfide (Scheme 19.41).

H S R2

N N

S R2

R1

N N H

H

S R2 R1

SH

R2 N N

R1 N N

R1

R1 - SH2

R2

N

N

Scheme 19.41

19.5 Synthesis of Pyrimidines (1,3-Diazines) 19.5.1 Synthesis by Ring-Closure Reactions 19.5.1.1 Three-Component Couplings There are two main strategies for the synthesis of pyrimidines by a three-component coupling (Scheme 19.42).

O C

O N 2

N

C N

NH2

O HN

Scheme 19.42

19.5.1.1.1 [C-C] þ [C] þ [N-C-N] The Biginelli reaction, a three-component condensation reaction between an aldehyde, a urea or thiourea, and an easily enolizable carbonyl compound, was originally described by the Italian chemist Pietro Biginelli in 1893 [76]. This multi-component reaction provides a straightforward approach to functionalized 3,4-dihydropyrimidine-2-(1H)-ones 73 (Schemes 19.43 and 19.44) [77].

O C

N N Scheme 19.43

NH2

O HN

19.5 Synthesis of Pyrimidines (1,3-Diazines)

R1 O

X

O +

+

R1

H

H 2N

NH

EWG

R2

NH2

EWG

cat.

R2

O

N H

X = O, S

73 Scheme 19.44

In recent decades, many efforts have focused on the preparation of optically active 3,4-dihydropyrimidine-2-(1H)-ones. In this context, the enantioselective version of the Biginelli reaction was achieved using chiral phosphoric acids as catalysts (Scheme 19.45) [78]. Ar O O P O OH

O R

1

X

O

+ H

H 2N

NH2

Ar

O

∗

NH

10 mol%

R2

+

R1 R 2 O 2C

N H

CH2Cl2, 25ºC 6 d.

X = O, S

X

(88-97% ee)

Scheme 19.45

Eynde and coworkers [79] have reported a three-component [80] coupling of a b-keto ester, aryl aldehyde, and guanidine to obtain 1,4-dihydropyrimidines 74 in good yields (Scheme 19.46).

+ Ph

Ar H

NH

EtO2C ArCHO +

O

H 2N

NH2

NaHCO 3, DMF

EtO2C Ph

75-85%

N N H

NH2

74 Scheme 19.46

Typically, this tandem Michael addition–elimination–cyclodehydration requires refluxing in a high-boiling solvent under acid catalysis. In this same manner, microwave irradiation proves to be an effective alternative in giving excellent yields of pyrimidine-thiones [81] without the need for a solvent or long heating periods (Scheme 19.47). Ar EtO 2C

NH2

+ Me

O

Scheme 19.47

H2N

S

Ar

+ H

µw O

EtO2C Me

NH N H

S

j1707

j 19 Six-Membered Heterocycles: 1,2-, 1,3-, and 1,4-Diazines and Related Systems

1708

Molteni and coworkers [82] likewise have reported that microwave irradiation promotes the conversion of enaminoketones, formed in situ from formamide acetals and active b-diketones in water, into pyrimidines by reaction with amidines (Scheme 19.48). The method offers short reaction times and facile purification by precipitation of the product in aqueous media. O

O MeO +

n

O

MeO

H2 O

OH n

O

NH

µw

Me N Me

R

N

NH 2 n

O

N

R

(54-68%)

Scheme 19.48

M€ uller has reported the three-component coupling of acid chlorides with terminal alkynes under Sonogashira conditions, with trapping of the intermediate alkynyl ketone with an amidine, as a one-pot procedure for synthesizing 2,4-di- and 2,4,6trisubstituted pyrimidines 75 (Scheme 19.49) [83]. R1

Cl

[2% Pd(PPh3)2Cl2, 4% CuI] +

O

R2

R3

Et3N, THF, r.t., 1 h

Cl

R2 N

Na2CO3 10H2O, heat

NH2

H2N

R1 N R3

75 (26-82%)

Scheme 19.49

The same author [84] has used the methodology for the one-pot, three-component synthesis of 2,4-disubstituted pyrimidines 76 (Scheme 19.50), using TMS-acetylenes in the Sonogashira coupling. 1. O R1

Cl

TMS Pd/Cu, Et3N NH

2. R2

NH2

(30-81%)

R1 N

N

R1 = heteroaryl R2 = various

R2 76

Scheme 19.50

19.5.1.1.2 [C-C] þ [C-N] þ [C-N] The reaction of aliphatic and alicyclic ketones with triflic anhydride (Tf2O) under mild conditions in the presence of a nucleophile such as an aliphatic or aromatic nitrile leads to the formation of pyrimidines 77 and condensed pyrimidines 78 [85] where the substituents at C2 and C4 of the ring are identical (Schemes 19.51 and 19.52). As an extension, Fern
andez and coworkers have

19.5 Synthesis of Pyrimidines (1,3-Diazines)

j1709

O N 2

N

C N

Scheme 19.51

O

Me

O

N N

Me Me

Me

78

Tf2O/Cl2CH2, rt 24 h, 85%

2 CH3CN

O

Tf2O/Cl2CH2, rt 24 h, 90%

N

Me

N 77

Me

Tf2O/Cl2CH2, rt 24 h, 75%

O

OEt Me Me

N N

Me

79 Scheme 19.52

reported the preparation of biologically interesting 4-alkoxypyrimidines 79 by the condensation and cyclization of readily available aliphatic esters [86]. The reaction is postulated to take place via a (triflyloxy)carbenium intermediate 80 [87], which in the presence of another molecule of the nitrile is trapped to give sequential resonance-stabilized nitrilium intermediates before cyclizing to the pyrimidine (Scheme 19.53).

OTf R1

R3-CN

R1

R2

R2

OTf N

R3

R3-CN

R1

R2

3 OTf R

N

R3 N

80 R2

R3

N N

R1 R3

- H+

R2 R1

R3

N

- TfOH

N R3

Scheme 19.53

Lejon and coworkers have optimized the production of 4-substituted pyrimidines using Pd(0) or Pd(II) catalysts in the Leuckart reaction between formamide and a-methyl or a-methylene ketones (Scheme 19.54) [88].

j 19 Six-Membered Heterocycles: 1,2-, 1,3-, and 1,4-Diazines and Related Systems

1710

O H2NCHO

N

Pd(OAc) 2/Ph 3P 160ºC, 8 h.

Ph

N (80%)

Scheme 19.54

19.5.1.2 Two-Component Couplings There are several two-component strategies for the synthesis of pyrimidines (Scheme 19.55). NH2 + NH2

NH

+

N

C

+ RNH 2

N

N

O

N

O

NH2

+ HN

NH

+ NH2 Scheme 19.55

19.5.1.2.1 [C-C-C] þ [N-C-N] The most general pyrimidine ring synthesis involves the combination of a 1,3-dicarbonyl component with an amidine as source of the requisite [N-C-N] unit (Scheme 19.56). The [N-C-N] component can also be formamide or an orthoester in the presence of ammonia, a guanidine, a urea, or thiourea, affording pyrimidines with different substitution at C2. O

N N

O

NH2

+ HN

(R, O, N, S)

Scheme 19.56

The following modifications are noteworthy: the amidine can be replace by guanidine [89], or urea [90], affording to 2-amino- or 2-hydroxypyrimidines, respectively. Replacement of one of the carbonyls by a cyano group leads to 4-aminopyrimidines (Scheme 19.57). When thiourea used instead of an amidine [91], 2-thiopyridazines are obtained. In this case, 1,1,3,3-tetramethoxypropane can be also used as a synthon for the dicarbonyl unit (Scheme 19.58) [92].

19.5 Synthesis of Pyrimidines (1,3-Diazines)

NH H2 N

O

NH2

NH H2N

EtONa EtOH, reflux

OEt

NH2

(87%)

O O

N

N

OH

H2N

NH2

N

EtONa EtOH, reflux

H2N

OH

N (85%)

Scheme 19.57

OEt O

CH(OMe) 2 CH(OMe) 2

N S N H (66%)

O

S H2N

HCl,EtOH

OH

NH2

reflux

N

MeONa MeOH, reflux

N

SH

(80%)

Scheme 19.58

In addition, an orthoester in the presence of ammonia can be used as an in situ amidine source, although the yield is low (Scheme 19.59) [93]. Ph

Ph EtO

O + O

OEt

EtO

OEt

NH 3 /EtOH

Me

100 ºC, 11h

N O

N Me H (25%)

Scheme 19.59

If one or both of the carbonyl groups in the 1,3-dicarbonyl is replaced with a carboxylic ester, 4-pyrimidinones and 6-hydroxy-4-pyrimidinones are formed (Scheme 19.60) [94]. The widespread use of pyrimidine-containing compounds as anticancer drugs has led to the development of numerous pyrimidine preparations using this basic approach. One of these is illustrated here, involving the opening of butyrolactone esters with guanidine to give pyrimidinone 81 (Scheme 19.61) [95]. Use of an a,b-unsaturated carbonyl compound as the addend gives a dihydropyrimidine framework, which can be oxidized to the saturated heterocycle

j1711

j 19 Six-Membered Heterocycles: 1,2-, 1,3-, and 1,4-Diazines and Related Systems

1712

OH CO 2Et

NH 2Cl

+

CO 2Et

H 2N

EtONa

N

EtOH , rt

H

O

N H (80%)

Scheme 19.60

+

O

O

CH3

HO

COCH3

NH H2N

Et3N.EtOH

N

(69%)

NH2

O

N H

NH2

81 Scheme 19.61

(Scheme 19.62). This methodology has been developed into a solution-phase parallel synthesis of 4,6-diarylpyrimidine-2-ylamines with polymer release being executed via a rearrangement reaction [96].

Ar 1

Ar2

1. EtOH 50% aq. KOH reflux, 1-3 h

NH +

O

H 2N

NH2

Ar 1

Ar 2 N

2. 30% aq. H2O2

N NH 2

(40-60%) Scheme 19.62

The same protocol has been used by Almansa and coworkers, in the search for COX-2-selective inhibitors, who synthesized various pyrazolo[1,5-a]pyrimidines 82 (Scheme 19.63) by condensing 3-aminopyrazoles and various enones in the presence of zinc chloride [97].

F

R1

H2N

R1 R3 +

R2 O

ZnCl2 N

70%

N H

F N

R2 N R3

N H

SO2Me

SO2Me

82 Scheme 19.63

19.5 Synthesis of Pyrimidines (1,3-Diazines)

j1713

Enaminones (vinylogous amides) also react with guanidines to produce 2-aminopyrimidines by a conjugated addition followed by ring closure and aromatization (Scheme 19.64) [98].

H

O NMe 2 +

Ar CN

H 2N

NMe 2 O

NH2

Ar

CN

Ar

NH

NH HN

NC - H 2O

NH 2

N N

- NHMe 2

NH 2

(80%)

Scheme 19.64

Molina and coworkers have used this reaction in their synthesis of the biologically active marine natural products meridianins C, D, and E (Scheme 19.65) [99]. H2N N R

O

1

R1

R2 N Ts

R3 R4

DMF-DMA

R2

DMF, 110ºC

R3

O

NMe 2

NH H2N

R4

N Ts

R

NH2

MeO(CH 2)2OH

R3 R4

This methodology has been used to prepare several new chiral ligands that contain pyrimidine rings (83), through the bis-condensation of a chiral amidine with a,b-unsaturated carbonyl compounds, in high yield (Scheme 19.66) [100].

NMe2

N O +

HCl HN

N N

O

N Ts

(72-82%) Meridianin C, D, E

Scheme 19.65

Me2N

N

R2

K2CO3

(41-83%)

R1, R 2, R3, R4 = H, OBn, Br

1

N

N

N

EtONa/EtOH 88%

H2N 83 Scheme 19.66

Other dicarbonyl synthons can be used as well, such as 1,1,3,3-tetramethoxypropane [92] (for malonodialdehyde), nitriles, and tosyl isocyanates [101], to prepare pyrimidine derivatives in good yields. Fomum and coworkers have reported a novel

j 19 Six-Membered Heterocycles: 1,2-, 1,3-, and 1,4-Diazines and Related Systems

1714

synthesis of biologically active pyrimido[1,2-a]benzimidazole 84 by the cycloaddition of different aminobenzimidazoles with allenic nitriles (Scheme 19.67) [102]. H N

R2

NH 2 + N

R1

R4 R

R2

N

R1

N

N

3 C C CHCN

R3

84

NH2

R4

Scheme 19.67

Certain alkynes can be also be implemented as dicarbonyl synthons for these cyclizations. In this context, conjugated addition of amidines to cyanoalkynes followed by subsequent ring closure of the resulting amidate nitrogen onto the pendant nitrile affords 4-iminopyrimidines with nearly complete regioselectivity [103]. Moreover, product regioselectivity can be reversed by the use of sodium hexamethyldisilazide (NaHMDS) as a base (Scheme 19.68).

R2

Ar

H N

NH R1

Ar

NH

Ar

NH

CN

5% MeCN/THF RT (5-65%)

R2

N

No base

N

N

N

R1

R

98

2 99

1

NaHMDS (2eq)

+

R2

1

Scheme 19.68

One-pot syntheses of pyrimidines continue to be developed as efficient routes to pyrimidines. For example, pyrimidines can be prepared in a single step from propargylic alcohols by in situ oxidation to the aldehyde with o-iodoxybenzoic acid (IBX) or manganese dioxide, which reacts with amidines to yield the pyrimidines (Scheme 19.69) [104]. The heteroannulation can be executed under either thermal or microwave-assisted conditions, although the latter affords higher yields. NH R HO

Ph

N

NH 2

oxidant, MeCN heat (30-69%) µwave (61-84%)

R

N

Ph

R = Me, Ph

Scheme 19.69

Highly reactive diacetylenic ketones react smoothly with amidines to yield a range of alkynyl-substituted pyrimidines 85 in high yields (Scheme 19.70) [105]. Notably,

19.5 Synthesis of Pyrimidines (1,3-Diazines)

NH.HCl O

R2

R1

CO2Et

j1715

R2

NH2

N

N CO2Et

MeCN, K2CO3 R1

(75-92%)

85 Scheme 19.70

the pyrimidine compounds were obtained as single regioisomers, which is attributed to the acetylenic carbon bearing the ester group being the most electron deficient, making this the preferential site for nucleophilic attack of the amidine. Microwave irradiation is now an established tool in organic synthesis, and its use in pyrimidine syntheses is particularly valuable. In this context, a microwave-assisted synthesis of 2,4-disubstituted and 2,4,6-trisubstituted pyrimidines in high yield has been reported from amidines and a range of readily available alkynones described (Scheme 19.71) [106]. R1 O

R1

R2

+

NH.HCl R3

NH 2

MeCN, Na2CO3

N

120ºC (90 W) µwave, 40 min

R3

N

R2

(82-100%)

Scheme 19.71

Solid-phase syntheses of pyrimidines continue to appear at a rapid pace. A versatile solid-phase approach for the synthesis of a series of pyrimidinone derivatives has been described (Scheme 19.72) [107]. In the key step, a polymer-bound thiouronium salt is condensed with different b-ketoesters by adding an excess of Ca(OH)2 in aqueous ethanol solution.

O R2

EtO

O

O NH.Br

O

S NH2

Ca(OH) 2 H2O/EtOH

R1

R2

HN S

N

R1

Oxone H2O or MeOH

R2

HN RO

N

R1

R = OH or OMe (60-90%)

Scheme 19.72

j 19 Six-Membered Heterocycles: 1,2-, 1,3-, and 1,4-Diazines and Related Systems

1716

The use of iminophosphoranes has been emerging as a valuable tool for the construction of nitrogen-containing heterocycles [108]. The aza-Wittig reaction of iminophosphorane 86 with acyclic a,b-unsaturated aldehydes has been reported by Rossi and coworkers as a means to produce 1,6(1,4)-dihydropyrimidines 88 through electrocyclic ring closure of 1,3-diaza-1,3,5-triene intermediate 87 (Scheme 19.73) [109].

Ph

R1

NH + N

PPh3

OHC

R2

NH

Ph

H N

Ph

xylene N

heat

R

N

Ph HN

R2

R2

87

86

R1

N

R1

1

R2

88

Scheme 19.73

Molina has used this methodology in the last step of his synthesis of the tricyclic ring system 90, which is present in the marine natural products variolins (Scheme 19.74) [99]. In this case the aza-Wittig reaction takes place between the iminophosphorane 89 with several aromatic isocyanates in dry THF at room temperature to give directly the desired pyrimido annelation products in high yields. OMe

OMe R1NCO N H

N

THF, r.t.

CO2Et N PPh3

(90%)

89

N

N

R1HN

CO2Et N

90

Scheme 19.74

19.5.1.2.2 [C-C-N] þ [C-C-N] 2,4,6-Trisubstituted pyrimidines 92 can be obtained from an interesting reaction of a-chloro oxime ethers 91 with Grignard reagents (Schemes 19.75 and 19.76). This methodology presents the advantage that alkyl and aryl groups can be easily introduced at the 2-position of the pyrimidine core [110].

N

+ N Scheme 19.75

NH2

NH

19.5 Synthesis of Pyrimidines (1,3-Diazines)

R2 OMe

LDA, R2MgBr

N

THF, -78ºC to r.t.

Cl

R1

N

N

R1

R1

(22-84%) 91

92

Scheme 19.76

The authors propose a plausible mechanism (Scheme 19.77) involving deprotonation of a-chloro oxime ether 91 to generate a carbenoid species, which then undergoes Neber-type cyclization [111] to provide a reactive chloroazirine 93. Nucleophilic addition of a second molecule of the oxime to the azirine intermediate, and subsequent intramolecular cyclization, is believed to yield 2-chloro-1-azabicyclo [1.1.0]butane 94. Halide displacement by the Grignard alkyl group triggers ring opening to an imino oxime, which undergoes electrocyclization and methanol elimination to the pyrimidine 92.

N N

OMe

N

base Cl

1

R

91

R1

Cl

N

MeO N

Li

Cl

N

R1

93

Li

Cl 2

OMe

R

N R1

Cl

R1

OMe

R1

OMe

R2MgBr

N

N R1

R1 94

R2

MeO

Cl

Cl

R1

N

N R1

- MeOH

N

1

R1

R

92

Scheme 19.77

19.5.1.2.3 [C-C-C-N] þ [C-N] Fused pyrimidones can be synthesized from the cyclization of vinylogous carbamates with isocyanates, isothiocyanates, or thiomethyleneglycinates in acetic acid (Schemes 19.78 and 19.79) [112].

N + N Scheme 19.78

NH 2

N

j1717

j 19 Six-Membered Heterocycles: 1,2-, 1,3-, and 1,4-Diazines and Related Systems

1718

O X

Bn

CO2Et

C N

N

X= O, S Bn

N X H (69-82%)

CO 2Me

N

N

NH 2 MeS

CO2Et

N

CO2Et

O Bn

SMe

CO2Et

N

N N

SMe

(69-82%) Scheme 19.79

In related fashion, Kumar and coworkers [113] have reported the conversion of 2-amino-3-cyanopyridines into aminopyrimidinethiones 95 in good yield by cyclization with thiourea (Scheme 19.80). R1 CN 2

R

N

R1

S

NH2

H 2N

NH2

NH2

N 2

R

(67-75%)

N H

N

S

95 Scheme 19.80

19.5.1.2.4 [C-C-C-N-C] þ [-N-] Uracil derivatives can be prepared by addition of primary amines to 3-ethoxyacryloylisocyanate [114], methoxyacryloylisothiocyanate [115], or acryloylcarbamates [116] by addition and intramolecular displacement of the vinylic alkoxy group (Schemes 19.81 and 19.82). This method is suitable for complex amines and has found applications in recent years in the synthesis of nucleoside analogues as potential anti-viral agents [117]. N N + NH2

N Scheme 19.81

O HO

NH2 HO

Scheme 19.82

EtO HO

NCO + EtO

O NH

O

49% HO

HN

O

NH 2N H2SO4 heat 57%

HO

N HO

O

19.5 Synthesis of Pyrimidines (1,3-Diazines)

19.5.1.2.5 [N-C-C-C-N] þ [-C] The Remfry–Hull synthesis based on cyclocondensations of 1,3-diaminopropene or 1,3-diaminopropanes with carboxylic esters has been adapted to the use of malonamides to afford 6-hydroxypyrimidin-4(3H)-ones 96 (Schemes 19.83 and 19.84).

N

NH2 + NH2

N

CH

Scheme 19.83

O R1

O O

NH2

O

+ R2

NH2

R1

NaOR

NH

OR N

HO

R2

96 Scheme 19.84

19.5.1.3 One-Component Couplings 19.5.1.3.1 [N-C-N-C-C-C] From Cyanoacetylureas Condensation of an N-substituted urea with cyanoacetic acid yields cyanoacetylureas, which when heated in the presence of HMDS/TMSCl (hexamethyldisilazane/trimethylchlorosilane) affords 6-aminouracil derivatives. The reported mechanism (Schemes 19.85 and 19.86) involves activation of the cyano functionality with TMSCl, which triggers the cyclization [118]

N

N HN

N Scheme 19.85

O R2 O

C

N NH R1

O

N HMDS/TMSCl

R2 O

N

C N TMS R1

N

O

TMS NaHCO 3

R2 O

N N R1

(16-92%)

Scheme 19.86

NH 2

j1719

j 19 Six-Membered Heterocycles: 1,2-, 1,3-, and 1,4-Diazines and Related Systems

1720

19.5.2 Cycloaddition Reactions 19.5.2.1 [4 þ 2]-Cycloaddition Reactions of 1,3,5-Triazines Boger [119] has described a simple pyrimidine annulation process based on the regiospecific, inverse electron demand cycloaddition of 1,3,5-triazine with an alkyne. This reaction presumably proceeds via formation and retro-cyclization of a bridged cycloadduct with loss of hydrogen cyanide (Scheme 19.87).

N

N

R2

N

R1

R1

N

+

N

N

R1 -HCN

R2

N N

R2

Scheme 19.87

This process can also utilize various acetylene synthons such as pyrrolidine enamines (Scheme 19.88), wherein the initial [4 þ 2]-cycloadduct loses pyrrolidine, which enables rearomatization through expulsion of HCN [120].

N N

N

N

dioxane, 95

+

N

5h

N

N

N

N H

N N N

N -HCN

N

(72%) Scheme 19.88

Highly electron-deficient triazines such as 2,4,6-tris(ethoxycarbonyl)-1,3,5triazine react with ynamines or amidines (via the a-aminoenamine) to afford excellent yields of amino-substituted 1,3-pyrimidines 97 and 98 respectively (Scheme 19.89) [121].

19.5 Synthesis of Pyrimidines (1,3-Diazines)

CO2Et Me

dioxane, 101ºC 21 h, 97%

CO2Et N EtO2C

NBn2

N Bn2N

CO2Et CH3

97

N N

N

CO2Et

NH.HCl

CO2Et

N

NH2

N

H2N

DMF, 100ºC 72 h, 80%

CO2Et CH3 98

Scheme 19.89

19.5.2.2 Other [4 þ 2] Cycloaddition Reactions Pyrimidine nucleosides 99 have been prepared by [4 þ 2]-cycloadditions of glycosyl isothiocyanates with diazadienium iodide as a cationic heterodyne (Scheme 19.90) [122]. The advantages of this methodology are the ready availability of starting materials, good yields in the cycloaddition, high diastereo- and regioselectivity, and experimental simplicity of the procedure. These types of N-nucleosides have important applications as antiviral and antitumor drugs.

S S C N

H2N

S Cl2CH2, Et3N

+

Sugar

I N

r.t., 3 h

N N Sugar

S

(72-84%)

99 Scheme 19.90

19.5.3 Synthesis by Ring Enlargement 19.5.3.1 From Isoxazolidin-5-ones Besides well-established strategies for the preparation of pyrimidines, some new pathways have been developed. Weinreb and Keen [123] have reported a novel route to pyrimidones from an isoxazolidin-5-one by treatment with phenyl chloroformate to

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j 19 Six-Membered Heterocycles: 1,2-, 1,3-, and 1,4-Diazines and Related Systems

1722

give the N-acylation product. Ammonolysis and aromatization give the pyrimidone product. Isoxazolidin-5-one can be obtained as a 1:1 mixture of diastereoisomers, from the reaction of a,b-unsaturated ester and N,O-bis-(trimethylsilyl)hydroxylamine (a convenient source of hydroxylamine) (Scheme 19.91).

H OMOM

NOTMS

OMOM TMS CO 2Me

O

EtOH, heat

HN O

68%

OMOM

HO

N

O

ClCH 2CH2Cl reflux, 21 h

NH O

2. NH 4OH i-PrOH 65% OMOM

TsCl, DMAP

O

1. PhOCOCl THF, NEt 3

N

NH OH

81%

Scheme 19.91

19.5.4 Synthesis by Ring Atom Exchange

Similarly to the rearrangement of 1,2,4-triazines in the presence of a nucleophile to afford 3-aminopyridazines (Section 19.4.4.1) [69], 1,3-oxazin-6-ones are converted by amines into 4-pyrimidinones 100 (Scheme 19.92). The reaction occurs via a nucelophilic cleavage of the ester followed by cyclocondensation to close the ring.

O R3 R2

O R4NH2

O N

R1

R3 R2

NR4 N

R1

100 Scheme 19.92

The same methodology can be applied to prepare pyrimidines from 2-bromopyridines (Scheme 19.93). NaNH 2 / NH 3 R

1

N

Br

Scheme 19.93

N R1

N

Me

19.6 Synthesis of Pyrazines (1,4-Diazines)

19.6 Synthesis of Pyrazines (1,4-Diazines) 19.6.1 Synthesis by Ring-Closure Reactions 19.6.1.1 Two-Component Couplings Four strategies have been devised for the synthesis of pyrazines by two-component couplings (Scheme 19.94). NH COR

ROC N H

O

H 2N +

N

O

N

NH2

H 2N

O + O

H 2N

H C N C

2 Scheme 19.94

19.6.1.1.1 [C-C] þ [N-C-C-N] The most common way to construct the pyrazine ring is the cyclocondensation of 1,2-dicarbonyl compounds with 1,2-diaminoethanes (with double imine formation) to afford 2,3-dihydropyrazines, which are conveniently oxidized to pyrazines by CuO or MnO2 in KOH/ethanol (Schemes 19.95 and 19.96). Symmetrical starting compounds yield the best results using this straightforward approach [124]. N

O +

N

O

H2N H2N

Scheme 19.95

R1

O

R1

O

H 2N

R2

H 2N

R2

R1

N

R2

[O]

R1

N

R2

R1

N

R2

-2 H

R1

N

R2

+

Scheme 19.96

-2 H 2O

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j 19 Six-Membered Heterocycles: 1,2-, 1,3-, and 1,4-Diazines and Related Systems

1724

McKervey and coworkers [125] have used N-protected a-amino glyoxals from diazoketones 101, as 1,2-dicarbonyl components, to condense with simple 1,2diamines to form dihydropyrazines (Scheme 19.97). These adducts can be dehydrogenated to pyrazines 102 by treatment with manganese dioxide in the presence of potassium hydroxide.

NHCbz

CbzNH

OH

R1

R1 O

CbzNH

R2 CbzNH

N2

O

R1

H O

1. H2N H

R1

NH2

2. MnO2, KOH

O

N R2 N (28-60%)

101

102

Scheme 19.97

Similarly, the pyrazine moiety of pyrazine-fused-isopropylidene norbornadiene 103 has been prepared by condensation of a 1,2-diketone and ethylenediamine, followed by dehydrogenation in the presence of nickel peroxide (Scheme 19.98) [40].

H2N

NH2

NiO2

O

N

N

p-TsOH O

N

N

103 (41%) Scheme 19.98

Using this methodology, Kamitori has reported a new procedure to synthesize fluorinated pyrazines 106 (Scheme 19.99). Dialkylhydrazones 104 were treated with trifluoroacetic anhydride (TFAA) followed by hydrolysis with H2SO4 to afford a-diketohydrates 105, which react readily with diamines such as diamino succinonitrile to afford pyrazines 106 in good yields [126].

R1 N N Me

R2

1. TFAA 2, 6-lutidine 2. H2SO4

104

O R2

OH OH CF3 105

NC

NH2

NC

NH2

NC

N

CF3

NC

N

R2

106

Scheme 19.99

Direct synthesis of aromatic pyrazines requires a 1,2-diaminoalkene but simple examples of such compounds are rare; however, diaminomalononitrile can condense

19.6 Synthesis of Pyrazines (1,4-Diazines)

with 1,2-diketones [127] or b-keto sulfoxides [128] to yield 2,3-dicyanopyrazines (Scheme 19.100). R1

O

R1

O

R1

N

CN

R1

N

CN

NC

N

R1

NC

N

R2

-2 H2O H 2N

CN

H 2N

CN

Me

O

R1

S O

R2

ethanol, reflux

(35-77%) Scheme 19.100

a-Amino malonamides 107 are also unsaturated diamine synthons from which pyrazinones 108 can be formed (Scheme 19.101) [129].

Me

O

NaOH, NaHSO 3 80ºC

H2N

O

H2N

CONH 2

+ H

O

Me

(45%)

107

H N

O

N

CONH 2

108

Scheme 19.101

To avoid the need to isolate the highly reactive 1,2-dicarbonyl intermediates, Taylor has developed a novel methodology for the conversion of a-hydroxyketones into pyrazines in fair to good yields, via a tandem oxidation procedure with in situ trapping using 1,2-diamines (Scheme 19.102) [130].

OH

H2N

R2

H2N

R2

+ R1

O

MnO 2, CH 2Cl 2 reflux 0.4 M KOH/MeOH

R1

N

R2

N

R2

(33-66%) Scheme 19.102

Functionalized pyrazines have been prepared in excellent yields (69–99%) from common 1,2-diketones and 1,2-diamines under microwave irradiation, which

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j 19 Six-Membered Heterocycles: 1,2-, 1,3-, and 1,4-Diazines and Related Systems

1726

suppresses the formation of the polymeric by-products characteristic of conventional thermal heating (Scheme 19.103) [131]. R2

+ R1

MeOH: HOAc (9:1)

NH 2

O S

O

R2

N

R1

S

60ºC, 5 min µw

NH 2

N

Scheme 19.103

19.6.1.1.2 [C-C-N] þ [C-C-N] Cyclodimerization of a-Amino Carbonyl Compounds An important preparation of pyrazines involves the self-condensation of a-amino ketones to give 2,5-dihydropyrazines that subsequently oxidize to the corresponding pyrazines (Schemes 19.104 and 19.105). The required a-amino aldehydes or ketones are usually prepared in situ because of their instability, and can be obtained from a-hydroxycarbonyl compounds and ammonium acetate or by catalytic reduction of a-oximino- or a-azidocarbonyl compounds. N

O +

N

H2N

NH2

O

Scheme 19.104

R1

O

R2

H 2N

R1

NH 2

R2

N

R1

[O]

R1

N

R2

-2 H

R2

N

R1

R1

N

R2

+ R2

O

-2 H 2O

Scheme 19.105

Cyclodimerization of a-Amino Acids Correspondingly, cyclodimerization of a-amino acids or their esters gives 2,5-dioxopiperazines 109 (Scheme 19.106), which by treatment with trialkyloxonium salts followed by oxidation with DDQ (2,3-dichloro5,6-dicyano-1,4-benzoquinone) provides 3,6-dialkoxypyridazines 110 [132].

O

OR 2

H 2N

R1

R2 O

O

O

H N

R1

N H

O

1. (R 3O)BF 4

RO

N

R1

N

OR

+ R1

NH 2

-2 HOR 2

R1

109

Scheme 19.106

2. DDQ

R1

110

19.6 Synthesis of Pyrazines (1,4-Diazines)

j1727

Meier has described a new and efficient synthesis of trisubstituted 1H-pyrazin-2ones 111 and tetrasubstituted pyrazines by coupling Boc-protected amino acids with a-amino ketones or with a-amino alcohols and subsequent oxidation (Scheme 19.107). These syntheses afford the advantage of the use of readily available starting materials yielding various products in high yield [133]. R1

NH2

O

HBTU, DIPEA Cl2CH2, r.t.

OH

+ R2

OH

then [O] (70-97%)

R3

HN Boc

O

R3

H N

R2 R1

N H

O

Boc

1. HCl, MeOH 2. Py, 80ºC

R1 R2

H N

O

N

R3

(76-99%)

111 Scheme 19.107

Cyclodimerization of a-Phosphazinyl Ketones An alternative synthesis of pyrazines utilizes an aza-Wittig cyclization of a-phosphazinyl ketones, which are accessible from a-azido ketones and triphenylphosphine (Scheme 19.108). R1

N3

Ph 3P

2 R2

-N2

O

R1

N

R2

O

2

PPh3 -2 Ph3PO

R2

N

R1

R1

N

R2

Scheme 19.108

Metal-Assisted Reactions A series of a-diazo-b-ketoesters have been reacted with Boc-protected a-amino amides in the presence of rhodium octanoate catalyst, and the resulting N-H insertion products were treated with acid to provide pyrazine-6ones 112 after air oxidation of the intermediate 1,4-dihydropyrazines. These products were further derivatized to tetrasubstituted pyrazines 113 by N-alkylation or by conversion into the arylpyrazines using sequential bromination and Suzuki coupling reactions (Scheme 19.109) [134]. The authors have shown that this methodology is amenable to the synthesis of compound libraries using solid-phase procedures.

R1

O O

O R1

EtO N2

+

Rh 2Oct 4

H2N

NHBoc O

ClCH 2CH 2Cl

EtO

N HN

N

EtO N

O (65-83%)

112 Scheme 19.109

R1

O Suzuki

R2 (72-90%)

113

j 19 Six-Membered Heterocycles: 1,2-, 1,3-, and 1,4-Diazines and Related Systems

1728

19.6.1.1.3 [C-N-C] þ [C-N-C] Cyclodimerization of Nitrile Ylides In an interesting approach, Chandrasekhar has used a thermal Beckmann rearrangement to construct fully substituted pyrazines from dimerization of oximes (Schemes 19.110 and 19.111). The starting oxime hydrochloride 114 was thermally dehydrated and deprotonated to the nitrile ylide 115, which dimerizes to form, after air oxidation, the corresponding tetrasubstituted pyrazines 116 [135]. N

H C N C

2 N Scheme 19.110

N Bn

Ph

OH .HCl Bn

110 ºC

N C Bn

20 h

114

Bn C N Ph

Ph

N

Bn

Bn

N

Ph

[O]

Ph

N

Bn

Bn

Ph N (67%) 116

115

Scheme 19.111

Similar methodology was used for the synthesis of tetrasubstituted pyrazines containing two phosphonate groups by the thermal treatment of 2H-azirine-2phosphonate (Scheme 19.112) [136].

N

O P(OEt) 2

80ūC R1 C N

O P(OEt) 2

R1 (EtO) 2OP

N

PO(OEt) 2

N

R1

R1 (53-97%)

Scheme 19.112

19.6.1.1.4 [C-C-N-C-C] þ [N] Pyrazines are obtained by oxidative ring closure of bis (acylmethyl)amines with ammonia (Scheme 19.113).

O R

H N

O

NH 3

R

N

R N

Scheme 19.113

R

19.6 Synthesis of Pyrazines (1,4-Diazines)

19.6.1.2 One-Component Couplings 19.6.1.2.1 [N-C-C-N-C-C] Electrocyclic Ring Closure Alkylpyrazines are obtained regioselectively from a-hydroxyimino ketones that condense with allylamines followed by olefin isomerization, O-acylation, and electrocyclization with loss of CO2 and CH3OH (Schemes 19.114 and 19.115) [137]. N

N

N

N

Scheme 19.114

R1

OH N

R2

O

NH2

R1

OH N

R2

N

KOtBu

R1

OH N

R2

N

CH3

O R1

N

R2

N

heat

R1

O N

- CO 2 - CH 3OH

R2

N

CH3

O

OCH 3 CH3

Cl

OCH3

Scheme 19.115

19.6.2 Cycloaddition Reactions 19.6.2.1 [4 þ 2]-Cycloaddition Reactions of a-Diimines The cycloaddition reaction of a-diimines and ketenes yields tetrahydropyrazinones 117 (Scheme 19.116). Ph

NPh + NPh

C C O

Ph

[4+2]

Ph N N Ph 117

Ph Ph O

Scheme 19.116

Another pyrazine preparation is the [4 þ 2]-cycloaddition of electron-rich dienophiles with 1,4-diaza-3-oxa-2-ones 118 to produce lumazines 119 (Scheme 19.117) [138], which are of the same class of compounds as many natural pteridines of biological importance.

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j 19 Six-Membered Heterocycles: 1,2-, 1,3-, and 1,4-Diazines and Related Systems

1730

O Me O

N

N N Me

N

OO

Me

O

N

R

+ O

N

O

O N N

R

N

R

Me

118 -CO2

O Me O

N N Me

N

(13-74%)

119 Scheme 19.117

19.7 Reactivity of Diazines

The reaction chemistry of diazines has very little in common with that of benzene and its derivatives. The notable reactivity differences already existing between benzene and its nitrogen variant, pyridine, are further accentuated by having a second nitrogen atom in the ring. Some of the general features of diazine chemistry can be summarized as follows. 1)

2)

Owing to the presence of the two nitrogen atoms in the ring, the energies of the p-molecular orbitals are lowered, particularly those with large coefficients on nitrogen. As a result, this makes electrophilic attack on the ring carbon atoms rather difficult while facilitating nucleophilic addition onto the ring. All the ring carbon atoms in the diazines, with the exception of C5 of pyrimidine, are ortho or para to at least one ring nitrogen atom. Intermediates formed by nucleophilic attack onto the ring, or by deprotonation at these positions, are well stabilized. This provides selective activation of specific positions in each of the three diazine ring systems as shown below (a  indicates a propensity for nucleophilic attack, while  reflects an even greater degree of reactivity). N N

3)

N

N

N N

The availability of nitrogen lone pair(s) is also reduced, making each of the diazines less basic that pyridine. Cations derived from these heterocycles by electrophilic attack on nitrogen are less stabilized due to the electron-withdraw-

19.7 Reactivity of Diazines

ing influence of the second nitrogen, thereby making the heterocycles more difficult to N-alkylate or N-oxidize. 19.7.1 Thermal and Photochemical Reactions 19.7.1.1 Pyridazines (1,2-Diazines) Pyridazine can be regarded as a cyclic bis-hydrazone and the mutual proximity of the nitrogen atoms is reflected in different physical properties and reactions compared to those of pyrimidine and pyrazine. The reactivity of 1,2-diazines under thermal and photochemical conditions are particularly noteworthy (Scheme 19.118). Pyridazine (1,2-diazine) is converted into pyrimidine (1,3-diazine) upon heating to 300
C, most likely via a diazabenzvalene intermediate. Conversely, photolysis yields mainly pyrazine (1,4-diazine), where, presumably, a transient intermediate similar to Dewar benzene is involved in the process [139]. Thus, in this way, pyridazine can undergo isomerization to either of its other two diazine forms. heat

N

N N

N

N

N

N

hν

N N

N

Scheme 19.118

19.7.1.2 Pyrimidines (1,3-Diazines) Pyrimidines experience a similar fate under photochemical conditions, reverting to a Dewar pyrimidine species [140]. In the case of 4-amino-2,6-dimethylpirimidine, photoisomerization yields an acyclic aminoimine by ring-opening of the Dewar pyrimidine intermediate (Scheme 19.119).

NH2 N N

NH2 hν

N C

N N

NH2

H2N

CN C C

C NH

N

Scheme 19.119

19.7.2 Reactions with Electrophilic Reagents

Owing to the electronegativity of the two nitrogen atoms, all of the diazines are electron-deficient heterocycles that fail to react with most electrophiles. Electrophilic

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j 19 Six-Membered Heterocycles: 1,2-, 1,3-, and 1,4-Diazines and Related Systems

1732

substitution at one of the carbon centers of the ring must first break the aromaticity of the p-system, giving an intermediate that is further deactivated by the two electronegative nitrogen atoms. This is exemplified in Scheme 19.120 by the case of pyrimidine (top pathway). The electrophilic susceptibility of pyrimidine is comparable to that of 1,3-dinitrobenzene or 3-nitropyridine. Consequently, the kinetically preferred pathway for electrophilic addition is at nitrogen (bottom pathway). Activation of the diazine ring by attachment of one or more electron-donating substituents promotes electrophilic substitution on the ring, as will be illustrated in examples below. H E

N

E+ N

C-attack

+

N

E+

N

N-attack

N + N E

Scheme 19.120

19.7.2.1 Electrophilic Addition at Nitrogen Diazines behave as tertiary amines in their reactions with a wide range of electrophiles (Scheme 19.121): protic acids (to give salts), Lewis acids (to form coordination compounds), transition metal ions (to form complex ions), alkyl halides (to give quaternary salts), halogens (to form halo adducts), and oxidizing agents (to yield amine oxides) [141]. The facility of these reactions depends on two major factors: the nucleophilicity of the nitrogen atom and the degree of steric hindrance. Although the pKa of a protonated nitrogen is a convenient measure of thermodynamic basicity of the free amine, it is not a reliable indicator of E+ N

N

N

N

N

N

N

E+

N + N E

Scheme 19.121

+ E

+ E N

E+

N

N

19.7 Reactivity of Diazines

kinetic nucleophilicity where steric effects of nearby substituents on the ring (particularly at the a-carbon) are likely. 19.7.2.1.1 Protonation Pyridazines (pKa 2.3 for protonated form) are much weaker bases than pyridine (pKa 5.2 for pyridinium cation) due to inductive withdrawal by the second ring nitrogen. The a-effect of the two nitrogen electron pairs is not sufficiently strong to overcome the electron-withdrawing effect of the NN bond. N,N0 -Diprotonation has only been observed in very strong acidic media (pKa(2) 7.1 for the dicationic species). Predictably, electron-donating substituents on the ring enhance the nitrogen’s basicity, with protonation of 3-substituted pyridazines occurring on N2. In 4-substituted pyridazines, where steric and inductive effects are less important factors, protonation occurs at N1 for electron donor groups, and at N2 for electron acceptor substituents. In 3,6-disubstituted pyridazines, protonation occurs a to the less bulky and more powerful electron-donating substituent. 19.7.2.1.2 Metal Ions As a monodentate ligand in transition metal complexes, pyridazine forms tetrahedral and octahedral structures [e.g., Co(II) salts], and as a bidentate ligand it gives polymeric complexes. Pyrazine can replace three of the carbonyl groups in group VI metal hexacarbonyls to form compounds of the type Cr (CO)3Py3. The other diazines are known to also form metal complexes. 19.7.2.1.3 Alkylation Diazines react with activated alkyl halides by SN2 displacement to give the anticipated mono-quaternary salts. Unsymmetrically-substituted diazines can give rise to two isomeric quaternary salts. Pyridazines are the most reactive of the diazines towards alkylation due to the a-effect. Substituents influence the orientation mainly by steric and inductive effects, rather than mesomeric effects. For example, methylation of 3-methoxy-6-methylpyridazine takes place adjacent to the methyl substituent, at N1, although mesomeric release would have been expected to favor attack at N2 (Scheme 19.122) [142]. OMe

OMe MeI Me

N

N

Me

N Me

N I

Scheme 19.122

Pyrimidines react with alkyl halides to give mono-quaternary salts. Dialkylation can be achieved with trialkyloxonium tetrafluoroborate (Scheme 19.123) [143].

N N Et

Et3O+BF4 – Cl(CH2)2Cl

Et 2BF4

-

Scheme 19.123

86%

N N

MeI MeOH, rt 85%

N N Me I

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j 19 Six-Membered Heterocycles: 1,2-, 1,3-, and 1,4-Diazines and Related Systems

1734

2,4-Disubstituted pyrimidines undergo selective alkylation at the less sterically hindered N1. Kumar and coworkers have reported the coupling of 2,4-bis(silyloxy) pyrimidine with benzyl bromides in the presence of iodine to yield one regioisomeric bis-adduct (120) (Scheme 19.124) [144]. This was a key intermediate in their synthesis of heterocalixarenes 121, which were use in subsequent biological cation binding studies. R2

OTMS

I2 N N

R2

H N

O

O

H N

O

O

+ N

60-90%

OTMS Br

1

R

N 1

Br

R

120

R2

O

O N N

R1 O O R4

N N

R3 121 Scheme 19.124

19.7.2.1.4 Oxidation Pyridazines react with peracids to give N-monoxides [145]. For substituted diazines, the regiochemistry of N-oxidation is governed by the same factors as alkylation, thus 3-aminopyridazine gives mainly 2-oxides, but 3-methylpyridazine provides the 1-oxide as the main (3:1) product (Scheme 19.125) [146]. The acidity of the medium can also influence the regiochemistry of oxidation; for example, 3-cyanopyridazine reacts at N1 with peracetic acid, but under strongly acidic conditions oxidation occurs at N2, presumably due to the heterocycle existing as its N1-protonic salt [147].

Me N

N

Me

m-CPBA CHCl3, r.t.

Scheme 19.125

N O

N

Me

+ N (3:1)

N

O

19.7 Reactivity of Diazines

Pyrimidine and its simple alkyl derivatives can be converted into N-oxides 122, although the yields are usually low due to the relative instability of the products under the acidic conditions (Scheme 19.126) [148]. N

m -CPBA CHCl3, rt

N

N + N O

-

122 Scheme 19.126

Pyrazine and its benzo derivatives are easily converted into both the mono-N-oxide (major) and di-N-oxides (minor) (Scheme 19.127) [145], although di-N-oxides have also been reported for pyridazines and pyrimidines.

Me

N N

H2O2 Me

AcOH, 60ºC

Me

N N O

Me + Me

O N N O

Me

86% (5:1) Scheme 19.127

19.7.2.2 Electrophilic Substitution at Carbon The SEAr reaction at the ring C-atoms of diazines is difficult to carry out due to deactivation by the second nitrogen. Nitration or sulfonation of a diazine or alkyldiazine has been reported to take place only in the presence of multiple strong electron-donating substituents [149]. In addition, it should be noted that N-oxidation facilitates the substitution in some cases [150]. 19.7.2.2.1 Nitration Pyridazines (1,2-Diazines) 4-Amino-3,6-dimethoxypyridazine undergoes nitration to afford the 5-nitro compound. However, the less highly activated 3-methoxy-5methylpyridazine requires more vigorous conditions, yielding a complex mixture of 4-nitro, 6-nitro, and 4,6-dinitro derivatives [151]. Pyridazine 1-oxide and many of its substituted derivatives undergo nitration with nitric and sulfuric acid to form the corresponding 4-nitropyridazine-1-oxide 123 (Scheme 19.128) [152]. If the 4-position is occupied nitration can occur at the 6-position. Pyrimidines (1,3-Diazines) Notably, C5 in pyrimidine is the only position, in all three diazines, that is not in a a- or c-relationship to a ring nitrogen, and in effect is equivalent to a b-position in pyridine, which is susceptible to electrophilic substitution. Nevertheless, electrophilic substitution at carbon is not observed in the parent compound. Electron-donating substituents (OH, NH2) increase the SEAr reactivity in

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j 19 Six-Membered Heterocycles: 1,2-, 1,3-, and 1,4-Diazines and Related Systems

1736

NO2 R1 R2

N O

R1 HNO3

N

R2

H2SO4

R1, R2 = H, alkyl, alkoxy, chloro

N O

N

123

Scheme 19.128

the pyrimidine system and thus enable nitration, nitrosation, aminomethylation, and azo-coupling to take place at the 5-position [153]. Two or more electron-releasing substituents make nitration of pyrimidines relatively easy; 2,4-dihydroxy-6-methylpyrimidine, for instance, yields the 5-nitro compound 124 (Scheme 19.129). OH

OH HNO3/HOAc

N Me

N

20ºC

OH

O2 N Me

O O2N

N N

OH

Me

NH N H

O

124 Scheme 19.129

19.7.2.2.2 Halogenation Pyridazines (1,2-Diazines) Pyridazines undergo electrophilic substitution only with difficulty, and thus direct halogenation is not expected to be a method of wide application. Nevertheless, dehydrochlorinations of pyridazines are known. 3,6Dichloropyridazine can be converted by means of PCl5 into 3,4,5,6-tetrachloropyridazine [152]. Simultaneous introduction of chlorine (or bromine) followed by dehydrohalogenation and substitution of the potential hydroxyl with chlorine has been performed with several 3(2H)-pyridazinones using a mixture of POCl3 and PCl5. The halogen atom always enters at the C4 position. Thus, 1-methyl-2-phenyl3,6-pyridazinedione (125) adds bromine or chlorine to give the 4,5-dihalo adduct 126, which is stable in neutral media, but dehydrohalogenation occurs in the presence of base to give solely the 4-halogenated product 127 (Scheme 19.130) [154].

Cl

Cl O O

N N Ph Me 125

Scheme 19.130

Cl2 AcOH

Cl O 126

O

O N N Ph Me

O

N N Ph Me 127

19.7 Reactivity of Diazines

Perchlorinated pyridazines 129 (Scheme 19.131) can be prepared in good yields via chlorination of pyridazone 128 using phosphorus oxychloride [155]. Cl

Cl Cl O

Cl N H

N

POCl3

Cl

no solvent 81%

Cl

Cl N

N 129

128 Scheme 19.131

Pyrimidines (1,3-Diazines) As with nitration, pyrimidine undergoes halogenation under vigorous conditions to give the 5-substituted product; bromination occurs at 230
C. When the diazine has one or more activating groups the reaction proceeds much more easily (Br2 or Cl2 in H2O, AcOH, or CHCl3, 20–100
C). Sometimes 5,5dihalo products are formed, however (Scheme 19.132). O

O NH

HO

N H

Br2/H2O

O

Br

Br NH

N H

HO

O

+

O NH

Br O

N H

O

Scheme 19.132

As strong donor substituents, amino groups activate the heteroarene towards ortho- and para-substitution. However, other substituents may alter the substitution pattern. Pyrazines (1,4-Diazines) Chlorination of 2-methylpyrazine occurs under such mild conditions that it is almost certain that an addition/elimination sequence is involved, rather than a classical electrophilic aromatic substitution (Scheme 19.133) [156]. N N

Cl2 Me

CCl4, 40ºC

N

Cl

N

Me

(67%) Scheme 19.133

Also in this case, the halogenation reaction depends on the presence of other substituents on the diazine ring (Scheme 19.134). For instance, 2-aminopyrazine readily undergoes ring halogenation to give 3,5-dibromo-2-aminopyrazine 130, but 3aminopyrazine-2-carboxylic acid 131 is too electronically-deactivated on the heterocycle and, instead, the amino group is halogenated [153].

j1737

j 19 Six-Membered Heterocycles: 1,2-, 1,3-, and 1,4-Diazines and Related Systems

1738

N

Br

Br2, AcOH

N

NH2

N

Br

N

NH2

130

N

CO2H

N

NH2

Cl2, AcOH

N

CO2H

N

NHCl

131

Scheme 19.134

19.7.3 Reactions with Nucleophilic Reagents

Diazines are considerably more reactive toward nucleophilic addition than are pyridines due to the presence of an extra nitrogen atom. There are still only a few synthetic approaches to inducing substitution on this electron-deficient ring and, therefore, more diverse methods for functionalization of these heterocycles continues to be of interest. 19.7.3.1 With Replacement of Hydrogen 19.7.3.1.1 Alkylation and Arylation The diazines readily add alkyl and aryllithiums and Grignard reagents to give dihydro-adducts that can be rearomatized by oxidation with reagents such as potassium permanganate or 2,3-dichloro-5,6-dicyano-1,4benzoquinone (DDQ). Pyridazines (1,2-Diazines) Reactions with carbon nucleophiles occur at the C4 center (Grignard reagents) [157] or at C3 (organolithium compounds) (Scheme 19.135). R 1. RMgX N

N

2. H2O

R

1. RLi N

N

2. H2O

N

N

Scheme 19.135

Alternatively, O-acylation of 3-substituted pyridazine 1-oxides gives a cationic species that reacts with nucleophiles such as cyanide by analogy to a Reissert reaction, functionalizing the C6 position (Scheme 19.136). R

PhCOCl

+ N N O

R + N N OCOPh

R

-CN -HO2CPh

NC

N

N

Scheme 19.136

Ohsawa has reported a three-step procedure to regioselectively introduce an alkyl sulfone substituent (and thus potentially other groups) to position C4 of 3-substituted pyridazines (Scheme 19.137) [158]. First, pyridazine is reacted with tetracyanoethy-

19.7 Reactivity of Diazines

j1739

lene oxide to form a dicyanomethylide zwitterion 132 (with subsequent loss of hexafluoroacetone), in which the existing C3 substituent blocks formation of the ylide at N2 in favor of N1. This species then undergoes base-promoted alkylation by an a-halosulfone, which the authors propose as occurring by a vicarious nucleophilic substitution (VNS) process, and cleavage of the dicyanomethylene group to afford exclusively the 4-alkylated pyridazine 133. O OEt N

N

NC NC

CN CN

0ºC, 2-5 h (94%)

N

CH2 SO2 p-Tol OEt

ClCH 2SO 2-p-Tol KOt -Bu/ THF

OEt N

0ºC (75%)

C(CN) 2

N

N

C(CN) 2

132 (NH4 )2 S2O 8 (100%) MeOH, reflux CH2 SO2 p-Tol OEt N

N

133 Scheme 19.137

Pyrimidines (1,3-Diazines) Nucleophilic attack on pyrimidine may occur at the 2-, 4-, or 6-position; although only a few such examples are known for pyrimidine itself, the addition of organometallic compounds gives the 4-alkylated pyrimidine 134 upon air oxidation of the dihydro adduct (Scheme 19.138).

N

M = Li, Mg

N

R

H R

H R RM

N

M

H2O

N

NH -2H

N

N

N 134

Scheme 19.138

Interestingly, 2-chloropyrimidine does not undergo nucleophilic substitution at the halogenated carbon, but instead gives the halogen-retained product with the new substituent at C4 (Scheme 19.139) [159].

+ N

Cl

Scheme 19.139

S

N

N

N

N

Et2O, -30ºC Li

N S

N Li

DDQ Cl

aq. THF, r.t.

N

N S (83%)

Cl

j 19 Six-Membered Heterocycles: 1,2-, 1,3-, and 1,4-Diazines and Related Systems

1740

Another example of the regioselective addition of a nucleophile to an unsubstituted position on the pyrimidine ring, with C4 typically being the site of addition, has been reported by Fort and coworkers (Scheme 19.140); addition of 2-chloro-6-lithiopyridine to pyrimidine forms the coupled adduct 135 after rearomatization, albeit in low yield [160]. Cl N Li

N

N

Cl N

N N

(25%) 135 Scheme 19.140

Electron-donating substituents enhance the nucleophilicity of pyrimidines and thus increase the effectiveness of electrophilic attack on the ring. As an example, the reaction of ethyl cyanoacetate with an aryl aldehyde produces a three-component coupling adduct 136, by the conjugated addition of stabilized cyanoacetate carbanion to the initial Knoevenagel condensation adduct (Scheme 19.141) [161].

R1

O

CHO

O NH H2N

R1

N

NCCH2CO2Et

+

NH HN

65-70%

OMe

O NC

R1

N

OMe

NH

O

N H

N

OMe

136

Scheme 19.141

The process shown in Scheme 19.142 is thought to proceed by an analogous mechanism [162]. The authors noted that this tandem Nef reaction/Michael addition produced the final product 137 in a single step with sonication.

Ar

NH2 CHO

N H2N

N

CH3NO2

NH2

O2N

+ NH2

R

ultrasound

H2N

N

NH2

Ar 1. NaOH

N NH2

2. H2SO4

N N H

N 137

Scheme 19.142

NH2

19.7 Reactivity of Diazines

19.7.3.1.2 Amination The Chichibabin reaction of diazines is less general than that for pyridines due to the diminished aromaticity of the diazine p-system. However, the initial addition is quite easy, while the subsequent loss of hydride (rearomatization) is difficult, but high yields of 4-aminopyridazine 138 (Scheme 19.143), 4-aminopyrimidine, and 2-aminopyrazine can be obtained by in situ oxidation of the dihydroadduct with potassium permanganate [163]. NH2

NH2 KMnO4

KNH2/NH3 N

N

N H

N

N

N

138 (91%) Scheme 19.143

Pyrimidines (1,3-Diazines) Pyrimidine is converted into pyrazole when heated with aqueous hydrazine by a process that involves nucleophilic addition as a first step, which triggers ring opening and subsequent reclosure to the five-membered aromatic ring (Scheme 19.144).

NHNH2 N

aq. N2H4 130ºC

N

NHNH2 NH

NH N H+

N

NH HN

N NH

H

NH N (75%)

Scheme 19.144

Amination can be achieved by direct lithiation of pyrimidine derivatives with LDA, or sec-BuLi, and in situ quenching with nitroso electrophiles (Scheme 19.145) [164]. O

O NH

N O Sugar

NH

1. LDA t

2. BuN=O

t

Bu

N OH

N O Sugar

(45-59%) Scheme 19.145

19.7.3.2 With Replacement of Good Leaving Groups All the halodiazines, except 5-halopyrimidines, react readily with nucleophiles (amines, thiolates, malonate anions) with substitution of the halide. The relative reactivity is summarized here.

j1741

j 19 Six-Membered Heterocycles: 1,2-, 1,3-, and 1,4-Diazines and Related Systems

1742

X

X N

N

>

N

N

> X

N

X N

>

N

N

N

> N

X

19.7.3.2.1 Pyridazines (1,2-Diazines) Nucleophilic aromatic substitution (SNAr) reactions with an assortment of anionic nucleophiles proceed smoothly with pyridazines having a halogen leaving group at C3 (Scheme 19.146).

CN Cl N

N

Ph

PhCH2CN, NaNH2 PhH, reflux

N

N

(65%) Scheme 19.146

Methoxy groups can also serve as leaving groups that can be exchanged by carbanions via an addition/elimination process (Scheme 19.147) [165].

OMe

CH(CN)2 CH2(CN)2/ NaH

N

N

dioxane, reflux

N

N

(62%) Scheme 19.147

Unsymmetrical 3,6-disubstituted pyridazines 139 can be prepared in a mild, efficient manner from commercially available 3,6-halopyridazines through stepwise nucleophilic mono-substitution followed by palladium-catalyzed coupling with an arylboronic acid (Scheme 19.148) [166].

I I

N

NaOMe/ MeOH

N

Scheme 19.148

reflux, 12 h (92%)

I

OMe PhB(OH)2, Pd(PPh3)4 Na2CO3, PHME N heat N Ph (76%)

OMe N

N

139

19.7 Reactivity of Diazines

Grignard reagents can be prepared efficiently from halopyridazines followed by quenching with electrophiles such as acetaldehyde, ethyl cyanoformate, DMF, or phenyl sulfide to give 140 in acceptable yields (Scheme 19.149) [167]. I

MgX OMe

E OMe

RMgX MeO

N

N

MeO

N

N

OMe

+

E

35-70%

MeO

N

N

140 Scheme 19.149

19.7.3.2.2 Pyrimidines (1,3-Diazines) Remarkable differences in reactivity with nucleophiles exist for halopyrimidines and triflate derivatives, which depend on the location of the leaving group on the ring. Leaving groups at the C4 and C6 positions are much more prone to SNAr processes than the C2 center due to the stabilizing effect of the nitrogen centers. The facility of SNAr displacement for halopyrimidines follows a predictable order, as shown here. X N N

>

N X

N

>>

X

N N

Nucleophilic aromatic substitution reactions have also been commonly applied to the transformation of pyrimidines into introduce a wide variety of new hetero and carbon ring substituents, as illustrated in Scheme 19.150 [168]. OMe O

OMe

N Cl

N

BnHN OMe

CO2Me

Et3N, CHCl3

O BnN

N N

OMe

(82%) CO2Me Scheme 19.150

An intramolecular version of this reaction has been reported by Volovenko, where pyridine or other nitrogen-containing heterocycles can nucleophilically cycloadd to chloropyrimidines to produce various condensed pyrimidines (Scheme 19.151) [169]. The following reaction exemplifies the difference in reactivity of polychloropyrimidines with aliphatic nucleophiles (Grignard reagents, organolithiums, organo-

j1743

j 19 Six-Membered Heterocycles: 1,2-, 1,3-, and 1,4-Diazines and Related Systems

1744

N

O

Cl

NC

N

Et3N, dioxane, reflux CN

N

N

O

96%

N

SO2CH3

N SO2CH3

Scheme 19.151

sodiums, and thiolates) (Scheme 19.152), which predominantly yield 4-substituted pyrimidines 141 [170], versus heteroaromatic nucleophiles, which afford the 2-substituted pyrimidines 142 [171].

R3 2

THF, -78ºC (87-93%)

R1

N N

Cl

Cl

141

R2 Cl

R

R3MgCl

R1=Cl R2=alkyl

N N

Cl R5 R1=NHR4 R2=Cl

R1

N

Cl

toluene, reflux (37-90%)

Cl

N N

Cl

+ N R5

142 Scheme 19.152

Generally, all nucleophilic substitution reactions on halodiazines go by a conventional addition–elimination pathway. However, some transformations are not as straightforward, such as the reaction of 2-chloro-4-phenylpyrimidine with potassium amide in liquid ammonia, which gives 2-amino-4-phenylpyrimidine 143 (Scheme 19.153). Although this process appears to be an addition–elimination, radiolabeling experiments have revealed that a nucleophilic ring opening–ring closure mechanism is involved [172].

Ph

Ph

N* KNH2, NH3 N *

Cl -33ºC

Scheme 19.153

* N

Cl

HN

Cl HN *

Ph

N*

N*

N* H2N

Ph

Ph

N H

N* * NH

N 143

* NH2

19.7 Reactivity of Diazines

j1745

When the corresponding chloride fails to provide the desired substitution compound, triazoles are also often used as leaving groups in CN bond formation. This procedure has been utilized by Leumann in the synthesis of deoxynucleosides 144 (Scheme 19.154) [173]. Other leaving groups, such as sulfonate, have also been reported for the introduction of N-substituents onto pyrimidines [174].

N N

O 1

R

N H

N

N

POCl3, TEA

N O Sugar

N

N

NHR2

1

2

R

R NH2

N N O Sugar

R1

N N O Sugar 144

Scheme 19.154

2-Chloropyrimidine can be displaced by alcohols through the use of sodium methylsulfinate as a catalyst (Scheme 19.155). Significant rate enhancements as well as improved yields have been reported with this method [175]. OMe MeSO2Na, base

N MeO

N

OMe

OMe

Cl

ROH

N

N N

MeO

SO2Me

66-83%

MeO

N

OR

Scheme 19.155

Iodopyrimidines could be converted into their Grignard derivatives by the action of i-PrMgCl, which then react with various electrophiles [167]. Qu
eguiner and coworkers have reported the synthesis of pyrimidines 145 bearing alcohols, aldehydes, and esters through this methodology (Scheme 19.156). Y

1. i-PrMgCl 2. E+

N N

X

X = I, Y = OCH3 X = SCH3, Y = I

27-69%

E (Y) N N

E (X)

145

Scheme 19.156

Fluorinated pyrimidones 147 are also of general interest as building blocks in agrochemicals and because of their antitumor activity. The selective substitution of the 4-fluoro substituent of 2,4,6-trifluoropyrimidine 146 by a hydroxyl group was

j 19 Six-Membered Heterocycles: 1,2-, 1,3-, and 1,4-Diazines and Related Systems

1746

realized by the reaction with [Ni(cod)2] in the presence of triethylphosphine followed by caesium hydroxide oxidation of the aryl nickel intermediate (Scheme 19.157) [176]. F F

Et3P Ni PEt3 [Ni(cod)2], PEt3

N F

N

F

N

(72%)

F

N

O 1. CsOH

NH

2. HCl

F

F

146

N

F

147

Scheme 19.157

19.7.3.2.3 Pyrazines (1,4-Diazines) Pyrazine is more reactive than pyridine towards nucleophilic attack. The Chichibabin amination of pyrazine itself is unsatisfactory, but substitution of the halogen in 2-halopyrazine occurs readily using ammonia, amines, amides, cyanide, alkoxide, and thiolate anion. In the example shown in Scheme 19.158, primary amines react with pyridazine to first yield the corresponding 3-amino derivatives, which subsequently added to the carbonyl group to give the ringclosed aminal [177]. The products prepared are all of interest as potential pesticides. O H NC

N

NC

N

Cl

R1NH2

NC

N

83-95%

NC

N

O NHR1

NC

N

NC

N

N OH R1

Scheme 19.158

Halo- and methoxy-substituted pyrazines (Scheme 19.159) can likewise be displaced by various carbon and hetero-nucleophiles [148]. OK N

N N

Cl

DMF, 0ºC 34%

N

O

N N

CH2(CN)2, NaH OMe

THF, reflux 46%

N N

CH(CN)2

Scheme 19.159

Sato and Narita have provided an improved synthesis of halopyrazines 149 in which hydroxypyrazines 148 were activated with TMSCl to give silyl ethers [178]. Subsequent treatment with the appropriate phosphorus-based halogen source provided halopyrazines in 46–94% overall yield (Scheme 19.160). This two-step

19.7 Reactivity of Diazines

R3

N

OH

R2

N

R1

R3

N

OTMS

R2

N

R1

HMDS TMSCl

PBr3 or PCl5 46-94%

R3

N

X

R2

N

R1

j1747

X = Cl, Br, I 149

148 Scheme 19.160

process was accomplished without isolation of the siloxyl intermediate and provides a milder, more convenient approach than the traditional heating of hydroxypyrazines with PXn directly. Pyrazines undergo Grignard formation from halopyrazines and subsequently react with certain electrophiles to produce pyrazine derivatives 150 (Scheme 19.161) [167]. N

X

N

I

1. RMgCl 2. E+

N

X

N

E

150 (11-59%) Scheme 19.161

19.7.4 Cycloaddition Reactions

All the diazines with electron-withdrawing substituents undergo inverse-electron demand Diels–Alder additions with electron-rich dienophiles [179]. 19.7.4.1 Pyridazines (1,2-Diazines) The inverse electron demand Diels–Alder of pyridazines continues to be a commonly explored topic. The adjacent nitrogen atoms of pyridazines not only help create an electron-deficient heteroatomic diene but the N¼N bond also functions as a good leaving group in a subsequent retro-Diels–Alder reaction. Intramolecular reactions of this type occur very rapidly, without even the presence of activating substituents. The immediate products of the initial [4 þ 2]-cycloaddition usually lose dinitrogen (N2) through rearomatization to generate benzene products (Scheme 19.162) [180].

CO2 Me N

N N

-N2

230ºC Cl

N

N

Scheme 19.162

inverse e--demand [4+2]-cycloaddition

CO2 Me N

Cl

MeO2C N

Cl (91%)

j 19 Six-Membered Heterocycles: 1,2-, 1,3-, and 1,4-Diazines and Related Systems

1748

Intermolecular variants of this cycloadditive route to functionalized fused benzene derivatives are also readily executed, as shown for 4,5-dicyanopyridazine 151 with N-methylpyrrole (Scheme 19.163). The reaction occurs thermally at 150
C to give a Diels–Alder adduct (152), which goes on to provide the indole heterocycle 153 upon expulsion of H2 and N2 [181]. Numerous examples of both the intramolecular and intermolecular processes similar to these have been described in the literature and applied to natural products total synthesis. N

CN NC

xylene +

N

N

N Me

150ºC

NC

NC N

loss of N2

NC

and H2

N Me

151

NC

152

N Me (20-62%) 153

Scheme 19.163

19.7.4.2 Pyrimidines (1,3-Diazines) The corresponding [4 þ 2]-cycloadditions of pyrimidines with electron-rich alkynes takes place to give regioselective substituted pyridine products, through loss of hydrogen cyanide (Scheme 19.164) [182]. EtO2C

N N

Me

N

NEt2

-HCN Me

N

heat

EtO2C

NEt2

EtO2C

N

Et2N Me (90%)

Scheme 19.164

Intramolecular inverse-electron demand Diels–Alder reactions of pyrimidines with a dienophilic side chain have received considerable attention during the last few years. The broad scope and relatively mild conditions of these reactions make them fruitful. (Scheme 19.165) [183].

R2

R1

1

R

R2

N

O

N

R1 = H, Ph, Cl R2 = H, Me Scheme 19.165

O

200 ºC 4h

2

R

N (66- 87%)

19.7 Reactivity of Diazines

j1749

Following the earlier studies by van der Plas, Dehacen and coworkers have illustrated how the electron-deficient pyrimidine ring 154 can be exploited in the intramolecular inverse electron demand Diels–Alder reactions to obtain 2-chloropyridines 155 under thermal conditions (Scheme 19.166) [184]. O Cl

O O

N N

Y

PhNO2, 180 ºC 48 h

Cl N

- ClCN

Cl

O Y

Y = CH2 45% 154

155

Y = CMe2 95%

Scheme 19.166

In a novel application, pyrimidine enediynes 156 have been prepared and subjected to Bergman cyclization to give tricyclic pyrimidines 157 (Scheme 19.167), which were shown to cleave dsDNA [185]. X

Cl

OMe

OMe

N

N

N

N

OMe 156

X

OMe

hv or heat OMe

N

82-93%

N

OMe

157

X = H, OH X=O Scheme 19.167

19.7.4.3 Pyrazines (1,4-Diazines) Likewise, pyrazines can be employed as electron-deficient dienes to prepare substituted pyridines, as shown in the following example [186]. A mixture of 8H-5,6dihydropyrano[3,4-b]pyridine 159 and 1H-3,4-dihydropyrano[3,4-c]pyridine 160 are obtained (Scheme 19.168). In the formation of the intermediate cycloadduct 158 considerable steric hindrance develops between the trimethylsilyl group and the C ¼ N bridge, and the fact that product 159 is favored over 160 implies that loss of hydrogen cyanide from cycloadduct 158 indicated by route a is faster than of that indicated by route b. 19.7.5 Reactions with Reducing Agents

Owing to the lower degree of aromaticity, diazines are more easily reduced than are pyridines. All the diazines can be reduced to tetrahydro derivatives with in situ

j 19 Six-Membered Heterocycles: 1,2-, 1,3-, and 1,4-Diazines and Related Systems

1750

TMS via a TMS b N N

a

N

TMS

undecane N

O

195ºC

O

N

159 (40%) TMS

-HCN O

via b N

[4+2]adduct 158

O 160 (23%)

Scheme 19.168

carbamation on nitrogen, which aids in stabilization and thus allows isolation [187]. Yields, however, are generally not very high (Scheme 19.169).

N

NaBH3 CN

NCO2Bn

ClCO2Bn MeOH, r.t. (37%)

N

N CO2Bn

Scheme 19.169

Caution must be exercised in carrying out these conversions for pyridazines, however, since over-reduction to the hexahydro derivative may lead to subsequent cleavage of the NN bond. As an example, reduction of pyridazine with sodium metal in hot ethanol affords tetramethylenediamine (via NN bond cleavage) as well as partially hydrogenated ring products (Scheme 19.170). Under these conditions pyrimidines and pyrazines are normally reduced to hexahydro derivatives [6]. Nao N

N

N H

hot EtOH

NH

NH2

H2N

Scheme 19.170

Reductive ring contraction of pyridazines is an efficient methodology to produce densely functionalized pyrrole derivative, capitalizing on the versatility of the azadiene Diels–Alder cycloaddition route to 1,2-diazines (Scheme 19.171) [188]. Ar N N MeO2C

Ar CO2Me

N N

Scheme 19.171

Ar

Ar

Ar [4+2]

MeO2C

CO2Me N N

Ar

Zn MeO2C

N H

CO2Me

19.7 Reactivity of Diazines

j1751

In this sense, activated pyridazines 161 have been converted into the corresponding functionalized pyrroles 163 by nitrogen extrusion by electrochemical reduction process, proceeding through 1,2-dihydro intermediate 162 (Scheme 19.172) [189]. R1

R1

R2

CO2Me

MeO2C

N

N

2e + 2H C.P.R.

R2

R2

+

MeO2C

161

CO2Me N H

NH

162

R1

+

2e + 2H

60-70%

MeO2C

N H 163

Scheme 19.172

19.7.6 Reactions with Oxidizing Agents

Diazines are generally resistant to oxidative attack at the ring carbons, although alkaline oxidizing agents (H2N-NH2, heat) can afford degradation via intermediates produced by initial nucleophilic addition (Section 19.7.3.1.2). Alkyl substituents and fused aromatic rings [190] can be oxidized to carboxylic acid residues without affecting the heterocyclic ring (Scheme 19.173). KMnO4 90º C

N

75%

N

HO 2 C

N

HO2 C

N

Scheme 19.173

Some bacteria such as Pseudomonas putida (ATCC 33 015) can be used as biocatalysts for the selective oxidation of a methyl group in the 2,5-dimethylpyrazine to the corresponding mono-carboxylic acid 164 (Scheme 19.174) [191].

N Me

Me

N

P. putida pH 7, xylene, r.t. (90%)

N Me

CO2H

N 164

Scheme 19.174

Similarly, other bacteria such as Agrobacterium can selectively C-hydroxylate unsubstituted C2 and/or C4 positions of pyrimidines without altering side chains on the ring (Scheme 19.175) [192].

CO2Me

j 19 Six-Membered Heterocycles: 1,2-, 1,3-, and 1,4-Diazines and Related Systems

1752

O Agrobacterium sp, DSM 6136

N Me

aq DMF, r.t.

N

NH Me

N H (78%)

O

Scheme 19.175

The first oxidative cleavage of the pyrimidine ring has been reported by Soai and coworkers [193]; thus RuO4 (prepared in situ from RuCl3 and NaIO4),provides a new route for the transformation of acetates of chiral pyrimidylalkanols into chiral a-acetoxy-N-acetylamides 165 and a-acetoxyamides 166, which are synthetic equivalents of chiral a-hydroxy carboxylic acids, without racemization (Scheme 19.176).

R1

OAc

AcO

RuCl3, NaIO4

N N

Me

H2O, CCl4, MeCN

OAc

R1 NH

+

O O 165 59-80% 89-95% ee

R1 NH2 O 166 11-17% 91-95% ee

Scheme 19.176

19.7.7 Reactions of Metallated Pyridazines

Qu
eguiner and coworkers have reviewed the directed deprotonation (ortho- metalation) of azines and diazines [194]. In general, diazines are more difficult to orthometalate than are pyridines, due to having sufficiently lower LUMO energies, which makes them prone to nucleophilic additions and electron-transfer processes. For this reason, non-nucleophilic lithium 2,2,6,6-tetramethylpiperidide (LiTMP) is a more efficient ortho-metalating agent than are alkyllithiums, but the resulting heteroaryllithium species are very unstable and can easily dimerize. These by-products can often be avoided by using very short lithiation times or by in situ trapping with a compatible electrophile (Scheme 19.177) [195].

N

N

4 LiTMP THF, -75ºC 6 min.

Scheme 19.177

CH(OH)Ph

PhCHO N N (31%)

19.7 Reactivity of Diazines

j1753

19.7.7.1 Pyridazines (1,2-Diazines) Queguiner and coworkers [196] have reported the ortho-lithiation of pyridazine with subsequent trapping with chiral sulfinate esters, affording chiral sulfoxides 167 with high enantiomeric excesses (% ee) (Scheme 19.178). These sulfoxide adducts can then be subjected to a second ortho-lithiation-electrophile trapping sequence with aldehydes to provide fully-substituted pyridazines 168 with high diastereoselectivities (% de).

O* OH STol

O* STol OMe 1. LTMP MeO

N

N

OMe

2. (S) or (R)-menthyl MeO p-toluenesulfinate (76-77%)

N

N

1. LTMP or LDA

R *

2. RCHO

MeO

(76-80%)

167 (97%ee)

OMe N

N

168 (93 - 99%de)

Scheme 19.178

A surprising result is obtained for pyridazine thiocarboxamides (Scheme 19.179), which undergo metalation–electrophilic attack regioselectively meta to the thiocarboxamide group [197].

t-BuNH

S N N

t-BuNH 1. LiTMP, THF -75ºC 2. E+

E

S N N

(14-63%) Scheme 19.179

19.7.7.2 Pyrimidines (1,3-Diazines) For pyrimidines, ortho-lithiation occurs selectively at C4, not at C2, despite the enhanced electronegativity of C2 due to its two electron-withdrawing nitrogens (Scheme 19.180).

TMS N N

Me3SiCl

LiTMP

THF

-75ºC

N N (54%)

Scheme 19.180

j 19 Six-Membered Heterocycles: 1,2-, 1,3-, and 1,4-Diazines and Related Systems

1754

Metalation of diazines bearing directing groups (chloro, fluoro, methoxy, methylthio, and carboxamides) has been widely reported [198]. Interestingly, pyrimidines can be lithiated either by deprotonation or by halogen exchange (Scheme 19.181). Deprotonation is favored at higher temperature (10
C) using lithium diisopropylamide (LDA), while lithium–halogen exchange occurs at low temperature (100
C) with n-BuLi. The presence of ring substituents at the C2 and/ or C4 centers help to stabilize the resulting lithiated pyrimidines [199].

Br

LDA Br

N N

Et2O, -10ºC

Li

N

Et2O, THF -100ºC

Br

N

E

N

Li

n-BuLi

E+

N

N

E

E+

N

N

N

Scheme 19.181

5-(Pyrimidinyl)magnesium chloride and 5-(pyrimidinyl)cerium dichloride reagents 169, prepared from bromopyrimidines via metal–halogen exchange, react with aldehydes and ketones to give high yields of alcohols 170 (Scheme 19.182) [200].

OtBu Br

BuCeCl2

N OtBu

N

O

OtBu Cl2Ce

1

1. R

N N

OtBu

OH O 1

R

2

R

NH

R2

2. HCl

N H

169

O

170 (79-96%)

Scheme 19.182

Similarly, lithiation of 5-bromopyrimidine and reaction with enantiomericallypure chiral sulfinate esters gives chiral sulfoxides 171 with high enantioselectivities (Scheme 19.183) [196].

O Br

N N

BuLi

Li

N N

(S) or (R)-menthyl p-toluenesulfinate (22 - 47%, 99%ee)

TolS *

N N 171

Scheme 19.183

19.7 Reactivity of Diazines

19.7.7.3 Pyrazines (1,4-Diazines) Directed metalation of pyrazines has been reported as well, and can be used to prepare ortho-halogenated derivatives (Scheme 19.184). N THF, -75ºC

N

N

I2

LiTMP

(44%)

I

N

Scheme 19.184

Ortho-metalation of 2,6-dichloropyrazine 172 with lithium 2,2,6,6-tetramethylpiperidide (LTMP) followed by quenching with a lactone produces the C-heteroaryl glycoside 173 (Scheme 19.185) [194].

Cl

N Cl

N

1. LTMP Cl

2.

BnO

172

BnO O

OBn

OBn OBn

N

O

O

Cl

N

OH OBn

173 (72%)

Scheme 19.185

It is reported that pyrazine thiocarboxamides undergo lithiation at the para position (Scheme 19.186), although the ortho product could be selectively generated under certain conditions [201]. N

R1 N

N

1. LTMP R2

2. E+

S

E

N N

R1 N

R2

S 35-100%

Scheme 19.186

19.7.8 Palladium-Catalyzed Reactions

Organopalladium chemistry is a rapidly growing field with wide application to heterocyclic synthesis [202]. This section shows representative types of palladiummediated transformations of diazine derivatives. 19.7.8.1 Coupling Reactions 19.7.8.1.1 Pyridazines (1,2-Diazines) New developments in the field of palladiumcatalyzed cross-coupling reactions have included halodiazines and diazene triflates.

j1755

j 19 Six-Membered Heterocycles: 1,2-, 1,3-, and 1,4-Diazines and Related Systems

1756

Rival and coworkers reported what is described as being the first Suzuki crosscoupling for the synthesis of 3-amino-6-arylpyridazines [203]. Electron-donating substituents on the arylboronic acid provided optimal yields (Scheme 19.187). NH2 R1

NH2 N

Cl

B(OH)2

+

N

Pd(PPh3)4

R1 N

N

Na2CO3 (30-60%)

Scheme 19.187

Aldous and coworkers have reported similar studies on palladium-catalyzed Stille and Suzuki coupling reactions of pyridazinyl triflates 174 with electron-rich arylstannanes and aryl boronates, respectively (Scheme 19.188). In general, Suzuki couplings were found to be more efficient than the corresponding Stille couplings [204].

OTf N

Me

+

N

Pd(PPh3)4 X

S

S

X = Sn(n-Bu)3 (77%) X = B(OH)2 (84%)

N

Me

N

174 Scheme 19.188

In the absence of palladium catalysts, the direct amination of 3-chloropyridazines with primary amines requires drastic conditions with difficult work up procedures, giving poor yields of the desired product and low reproducibility. For this reason the formation of a carbon–nitrogen bond via palladium cross-coupling reactions represents a powerful synthetic tool. Hibert [205] has developed an operationally simple and efficient palladium-assisted procedure for the amination of 3-iodo-6-arylpyridazines 175 (Scheme 19.189).

H2N

I Ph

N

N

H N

PdCl2(dppf), dppf

+ N Bn

t-BuONa, 80ºC, 6 h (75%)

Ph

N

N

N

Bn

175

Scheme 19.189

Palladium-catalyzed alkynylations have also been studied with pyridazines. As an illustration, several 6-phenyl-3(2H)-pyridazinones (Scheme 19.190) bearing different alkynyl groups at position 5 have been prepared by Sonogashira cross-coupling [206].

19.7 Reactivity of Diazines

R1 R1 Pd(PPh3)2Cl2 CuI/Et3N/DMF 60ºC

Br Ph O

N N MOM

Ph O

N N MOM O

Ph CH(OH)Ph Pd(PPh3)2Cl2 CuI/Et3N/DMF 55ºC/ 12h

Ph O

N N MOM

Scheme 19.190

When 1-phenyl-2-propyn-1-ol was used, the (E)-chalcone adduct was isolated in excellent yield. An efficient one-pot bis-functionalization of the 4,5-positions of the 3-pyridazinone ring has been performed using Suzuki, Sonogashira, and Stille cross-coupling reactions assisted by a retro-ene fragmentation (Scheme 19.191) [207]. This route allows quick access to several pharmacologically useful novel 3(2H)-pyridazinonebased antiplatelet agents [208].

O

R

X

X N

N H X = Br, Cl

CH2O reflux

O HO

O

R

X

X

N

N

Pd-catalyzed reactions

O H O

N

N

Retro-ene HN N - CH2O

R

R (80-90%)

Scheme 19.191

This same methodology has been applied to a “traceless” solid-phase synthesis of 3 (2H)-pyridazinones 176, employing a dihydropyran-functionalized resin and cleavage conditions that promoted a retro-ene fragmentation (Scheme 19.192) [209]. In the case of 1,2-diazines, the lithiopyridazines prepared by ortho-lithiation have been converted by reaction with zinc chloride into the more stable zinc compounds for use in palladium-catalyzed cross-coupling reactions [210]. The use of sonication, for the first time in a Negishi reaction, lowered the reactions times significantly and improved the yields (Scheme 19.193). 19.7.8.1.2 Pyrimidines (1,3-Diazines) Palladium-catalyzed cross-coupling reactions have also been reported for pyrimidines. The increased stability of organozinc reagents compared to lithium or magnesium organometallics allows the Negishi reactions to be carried out at high temperature. In this way, ortho-lithiation of

j1757

j 19 Six-Membered Heterocycles: 1,2-, 1,3-, and 1,4-Diazines and Related Systems

1758

X X

O

O

R

Y

N

O

N

R

Y O

N

PPTS, C2H4Cl2

Ar Ph

N Suzuki

60ºC

O

Coupling

O

N

O THP

O

HO

O

R = H, Ph Y = H, Br, Cl X = Br, Cl

N

20% TFA/ DCM Ar

Ar Ph O

N H

Ph

60ºC

N

N

O

N OH

176 (91-93%)

Scheme 19.192

OMe MeO

N

N

ZnCl2 OMe

1. n-BuLi - 70ºC, THF, 10 min 2. ZnCl2 -70ºC to 20ºC

MeO

N

N

Ph OMe

Ph-I Pd(PPh3)4 / THF

MeO

N

N

(90%)

65ºC, 3 h sonication

Scheme 19.193

4-chloro-2-methylthiopyrimidine 177 using LTMP and subsequent treatment with ZnCl2 led to organozinc reagent 178, which was then cross-coupled with iodobenzene to furnish the 5-arylpyrimidine 179 (Scheme 19.194) [210]. Cl

MeS

Cl 1. LTMP, THF, -75ºC, 1.5 h

N N

2. ZnCl2,-75 to 20ºC

177

MeS

ZnCl

N N 178

Cl

I

Ph

N Pd(Ph3P)4 , THF 65ºC, 20 h, 52%

MeS

N 179

Scheme 19.194

Although alkyl halide substrates are prone to b-hydride elimination in these reactions, alkylzinc or alkylboron reagents can take part in Negishi or Suzuki coupling without detectable b-hydride elimination to produce alkylpyrimidines (Scheme 19.195) [211]. The cross-coupling reaction of methylthiopyrimidines 180 with organozinc compounds in the presence of palladium was found to produce substituted pyrimidines 181 in good to excellent yields (Scheme 19.196) [212].

19.7 Reactivity of Diazines

n-BuZnBr

N

N

Pd(Ph3P)4, THF, 50ºC

OTf

N

j1759

N

Bu

(71%) Scheme 19.195

R1

R1 2

2

R

ArCH2ZnBr

N N

R

N

Pd(PPh)4

SMe

Ar

N 181 (71-90%)

180 Scheme 19.196

The traditional Stille-type cross coupling of stannanes with bromopyrimidines has been reported to provide chlorobiaryls 182 in good yields (Scheme 19.197) [160].

Br

N

+ Bu3Sn

N

Cl

N

Pd(PPh3)4

Cl

N

80% 182

N N

Scheme 19.197

A modular synthesis of functionalized pyrimidinones via a selective sulfide versus halide cross-coupling protocol has been reported (Scheme 19.198) [213]. The exchanges are complementary and depend solely on the experimental conditions. O Pd(PPh3)4 O Br

N N

CH2CO2But + SR1

ArB(OH)2 or ArSn(n-Bu)3

Br

CuTC or CuMeSal THF 25-60ºC

N N

CH2CO2But Ar

(59-89%) O

Pd(PPh3)4 THF or dioxane + base 80-95ºC Scheme 19.198

Ar

N N

CH2CO2But SR1

(65-80%)

j 19 Six-Membered Heterocycles: 1,2-, 1,3-, and 1,4-Diazines and Related Systems

1760

In the same way, 2-amino-6-iodo-4-tosyloxypyrimidine (183, which is easily prepared from commercially available material, is a key intermediate for the preparation of differentially substituted 2-aminopyrimidines by means of sequenced Suzuki and/or Sonogashira reactions (Scheme 19.199) [214]. R2 OTs 1. ii

N N R1

NH2

Ar 2

N

2. ii

I

N 183

R2 = TMS

NH2

1. i 2. i

N Ar1

N

NH2

Ar1 = Ph, PMP

1. i 2. ii Ar N N R1

NH2

R1 = Ph

(i) : ArB(OH) 2,Pd(PPh 3 )4, Na 2 CO 3 , DMF-H 2 O, MW (ii) :R

, CuI, PdCl 2 (PPh 3 )2 , NEt 3 , MW

Scheme 19.199

Microwave activation is becoming a very popular and useful technique in organic chemistry. The combination of solvent-free reaction conditions and microwave irradiation leads to significantly reduced reaction times, enhanced conversions, and, sometimes, higher selectivity, with the advantage of an eco-friendly approach (green chemistry). In this context, Botta has described a microwave-assisted Sonogashira coupling of pyrimidinones with alkynes to give the corresponding 5-alkynyl derivatives 184, or furano-fused pyrimidines 185 when using propargyl alcohol (Scheme 19.200) [215]. 19.7.8.1.3 Pyrazines (1,4-Diazines) Chloropyrazines and their N-oxides both undergo a wide range of palladium-catalyzed carbon–carbon bond-forming reactions. The oxidative addition of chloroarene to Pd(0) occurs using sterically hindered, electronrich phosphine ligands, as reported by Reetz [216], Fu [217], and Buchwald [218]. In 1981, Otha et al. [219] introduced a cyano group by refluxing chloropyrazine 186 with KCN in DMF in the presence of a catalytic amount of Pd(Ph3P)4 to give cyanopyrazine 187 (Scheme 19.201). Palladium-catalyzed coupling reactions between chloropyrazines and organometallic reagents without b-sp3-hydrogens are straightforward and generally proceed in

19.7 Reactivity of Diazines

R3

R2

R3 R2 I O

NH N

NH

PdCl2(PPh3)2 Et3N, CuI, DMF MW, 5 min

O

N

X

184

(50-80%)

X

R2 OH N PdCl2(PPh3)2 Et3N, CuI, DMF MW, 5 min (80-85%)

HOH2C

O

N

X

185

Scheme 19.200

N N

Cl

1.5 eq. KCN 5 mol% Pd(Ph3P)4

N

DMF, reflux, 2.5 h

N

(77%)

186

CN

187

Scheme 19.201

good yields. Stille coupling of chloropyrazines and their N-oxides has been carried out with tetraphenyltin [220] and aryl-, heteroaryl-, allyl-, and alkylstannanes [221]. Acylation of pyridazines by Stille reactions of bromopyrazines with 1-ethoxyvinylstannanes (Scheme 19.202) has been accomplished by Sato et al., using a copper cocatalyst [222]. They found that the copper additive increased the yields from 31% to 93%. The Cu-induced acceleration was most prominent for electron-deficient pyrazines, which are more reactive in Pd-catalyzed reactions. O R3

N

Br +

R2

N

R1

EtO

4

R

Bu3Sn 4

R = H, Me

1. Pd-cat, CuX 2. aq. HCl (77-96%)

R3

N

R2

N

R5 R1

5

R = Me, Et

Scheme 19.202

Suzuki couplings have likewise been conducted using halopyrazines and boronic acids. In this way (Scheme 19.203), bromopyrazine 188 and 2-thiopheneboronic acid have been coupled to deliver the desired thienylpyrazine 189 [223]. In addition, some pyrazine derivatives can be coupled with aryl halides through a Negishi reaction (ortho-lithiation and transmetalation with ZnCl2) [210]. In this case, sonication has a great influence on the yield and reaction time (Scheme 19.204).

j1761

j 19 Six-Membered Heterocycles: 1,2-, 1,3-, and 1,4-Diazines and Related Systems

1762

Br

N

NH2

N

COPh

B(OH)2

S

PdCl2 (dppb) 1 M Na2CO3 EtOH-PhMe

188

N

NH2

N

COPh

S 189 (96%)

Scheme 19.203

N

R1

N

1. LTMP, THF, -75ºC, 1.5 h

N

R1

2. ZnCl2,-75 to 20ºC

N

ZnCl

R1 = Cl, OMe

I

N

Pd(Ph3P)4, THF 65ºC, 20 h, 52% sonication

R1

N (88-99%)

Scheme 19.204

Palladium-catalyzed alkylation reactions of chloropyrazines with alkyl organometallic reagents bearing b-sp3-hydrogens have sometimes proven to be difficult [224]. In addition to coupling, dehalogenation may also take place. In comparison, when trialkylaluminium or dialkylzinc reagents are used low yields of the alkylated product are obtained, while trialkylboranes give the best results (Scheme 19.205).

N

N

EtnM, Pd(0)

N +

N

N

ZnEt2, Pd(Ph3P)4, K2CO3, DMF

23% 25%

BEt3, Pd(Ph3P)4, K2CO3, DMF

74%

49% 49% 5%

N

Cl

AlEt3, Pd(Ph3P)4, 1,4-dioxane

Scheme 19.205

Akita and Otha disclosed one of the earliest Sonogashira reactions of chloropyrazines and their N-oxides [225]. Under standard cross-coupling reaction conditions [Pd(Ph3P)2Cl2, CuI, Et2NH], many alkynylpyrazines have been synthesized [226], among them being some natural products (Scheme 19.206) [227].

OH

N I

N

OMe

Pd(Ph3P)2Cl2 CuI, Et3N, 2 h

N HO

Scheme 19.206

N

N

5 steps OMe

(90%)

H2N 66%

H N

N

NH Arglecin

O

19.7 Reactivity of Diazines

j1763

Heck reactions of 2-chloro-3,6-dimethylpyrazine 190 with styrene in the presence of Pd(Ph3P)4 and KOAc provides a convenient route to vinylpyrazine derivatives 191 (Scheme 19.207) [228]. This methodology was also extended to 2-chloropyrazines N-oxides, although the yields were considerably lower (28–38%) [229].

N

N

H

Pd(Ph3P)4, KOAc DMA, 100ºC, 15 h (95%)

Cl

N 190

N H

Ph

191

Scheme 19.207

Ohta’sgroup hasadvancedthis methodology toHeckreactions ofhalopyrazineswith both p-electron-rich and p-electron-deficient heteroarenes (Scheme 19.208) [230].

N

R1

N

Cl

Pd(Ph3P)4, KOAc DMA, 100ºC, 6-12 h

R1 = Me, Et, i-Bu

X = O, S, NH, NMe

R1

N

X R1

R1

N

X

( 25-75%)

Scheme 19.208

A stereospecific Heck-cross-coupling reaction of an iodo-substituted diaminopyrazine has been reported by Townsend in which a glycal serves as the acceptor, giving exclusively the b-configuration of the C-glycosidic bond [231]. It was not necessary to protect the two amino groups of the pyrazine due to the relatively weak basicity of the amino nitrogens on the electron-deficient pyrazine ring (Scheme 19.209). I TBDMSO

O

TBDMSO

H2N

N N

Cl NH2

Pd(OAc)2/AsPh3, Et3N CH3CN, 50ºC

1. TBAF/THF 2. NaB(OAc)3H CH3CN, 0ºC

HO

H2N O

N N

OH

Scheme 19.209

19.7.8.2 Carbonylation Reactions Alkoxycarbonylation reactions of halo-substituted diazines can be carried out with carbon monoxide and palladium acetate in an alcohol solvent, providing an effective route to pyrimidine esters (Scheme 19.210) [232].

NH2 Cl

j 19 Six-Membered Heterocycles: 1,2-, 1,3-, and 1,4-Diazines and Related Systems

1764

OMe

OMe CO, ROH

N MeO

N

Cl

N

Pd(OAc)2, dppf AcONa

MeO

CO2R

N

(54-90%) Scheme 19.210

Similarly, pyrazine-carboxylic esters 192 and pyrazine carboxamides can be synthesized in excellent yield from chloropyrazines by Pd-catalyzed carbonylation in the presence of either an alcohol or dialkylamine (Scheme 19.211) [233]. CO (40 Kg.cm-2)/MeOH Et3N/Pd(dba)2/Ph3P

N N

150ºC, 16 h

Cl

N N

(>85%)

CO2Me

192

Scheme 19.211

19.8 Important Derivatives 19.8.1 Diazines N-Oxides

Pyridazine N-oxides and pyrazine N-oxides can be prepared by selective N-oxidation of the parent heterocycles, but pyrimidine N-oxides are more difficult to obtain in this way and are best prepared by ring synthesis [234, 235]. Pyridazine N-oxides and pyrazine N-oxides give electrophilic aryl substitution and nucleophilic displacement (Scheme 19.212). Interestingly, the nitro group can be removed readily either at the b- or c-position to the N-oxide function.

HNO3/H2SO4 140ºC N O

N

22%

OMe

NO2 MeONa/MeOH N O

N

64%

N O

N

Scheme 19.212

All three diazene N-oxide systems are prone to nucleophilic substitution by halide, cyanide, enamines, or acetate with loss of the oxide function [236]. Depending on the types of substituents present on the ring, the site of introduction of the nucleophile is not always a to the N-oxide as would be predicted by analogy with pyridine chemistry (Scheme 19.213).

19.8 Important Derivatives N

Me

N O

POCl3 Me

80%

Me

N

Cl

N O

Me

H2N

N

TMSCN DMF, 100ºC

NC

N

N O

80%

H2N

N O

j1765

Scheme 19.213

The N-oxide group can also serve as an activating substituent to allow regioselective metalation (ortho-lithiation) and further reaction with electrophiles, as shown in Scheme 19.214. The N-oxide can be removed with phosphorus tribromide [237]. N

s-Bu

N O

s-Bu

LiTMP

DMF

THF/TMED -78ºC

73%

N

s-Bu H

N O

O

PBr3 s-Bu EtOAc, heat 70%

s-Bu H

N O

Scheme 19.214

19.8.2 Aminodiazines

Aminodiazines exist in the fully aromatized amino form but significant anionic charge character is built up on the ring nitrogen by resonance (a shown below), making protonation occur on the anionically-enriched ring nitrogen. The order of preference for protonation of a ring nitrogen is c > a > b to the amino group. N

N N

-

N

NH2

NH2

The presence of an amino group facilitates electrophilic substitution, as illustrated for halogenation (Scheme 19.215). Predictably, two amino groups further activate the ring to enable attack by weaker electrophiles.

N N

Br2, H2O NH2

80ºC

Br

N N

N

NH2

41% Scheme 19.215

Often, it is difficult to regioselectively alkylate 2-aminopyrimidines without producing a mixture of endo- and exocyclic N-alkylation products. Alvarez-Builla and coworkers [238] have reported methodology for selectively preparing 2-alkylaminopyrimidines 194 with high regioselectivity, after reductive removal of the pyridine moiety from the N-alkylated product (Scheme 19.216). The reaction is

s-Bu

j 19 Six-Membered Heterocycles: 1,2-, 1,3-, and 1,4-Diazines and Related Systems

1766

N N

H N

R-Br acetone

R

N N

H N

Br

RHN

Zn / AcOH 65-76%

N N

N

N

194

193 Scheme 19.216

thought to proceed through formation of an intramolecular hydrogen bond between the pyridine and pyrazine rings, which prevents alkylation of the ring nitrogens. Similar methodology can be applied to 2-aminopyrazines. Various biologically important natural products contain the 2-aminopyrimidine moiety in their structure, and various reactions involving these substituted heterocycles have been reported (condensation with aldehydes and ketones [239], Michael additions [240]). For example, Grubb has employed the cyclocondensation of an a-bromoaldehyde with diaminopyrimidone in a total synthesis of quinine (Q Base), found in tRNA (Scheme 19.217) [241].

Br

O

Ns N

O HN H2N

+

H

NH2

N

2. deprotection

HN H2N

O O

H N

O

1. NaOAc

N

N H

O O

Scheme 19.217

19.8.3 Alkyldiazines [242]

Alkyldiazines undergo condensations that involve deprotonation of the pendent alkyl group. The intermediate anions are stabilized by mesomerism involving one or both nitrogens. Thus, pyrimidines system shows side-chain reactivity; CH3 groups at the C2, C4, or C6 undergo aldol or Claisen condensations with marked preference at C4 (Scheme 19.218).

OH CH3

CCl3

N Cl3CCH=O N

py, 95ºC 60%

Scheme 19.218

N N

19.8 Important Derivatives

The regioselectivity of the side chain reactions on disubstituted pyrimidine can be controlled by adjusting the reaction conditions (Scheme 19.219). Thus, in the bromination of 4,5-dimethylpyrimidine (195) under ionic conditions (Br2, HOAc) substitution at the C4 methyl group 196 is favored, but under radical conditions (NBS, CCl4) the halogenation occurs at the C5 methyl group (197) [243]. Br2, AcOH Me Me

80ºC 75%

N

N N

BrH2C

196

N NBS, (PhCO2)2

195

Me

hν, CCl4, reflux 77%

BrH2C

N

Me

N 197

Scheme 19.219

Like the other diazines, alkylpyrazine can undergo base catalyzed CC bondforming reactions of the CH groups adjacent to the heteroatom. Thus, 2-methylpyrazine (198), after deprotonation with NaNH2 in liquid NH3, can be alkylated, acylated, and nitrosated (Scheme 19.220). N N 198

NaNH2, NH3 (l) CH3

N R

N

R-X

Scheme 19.220

19.8.4 Hydroxydiazines

All the mono-oxygenated diazines, except 5-hydroxypyrimidine, exist predominantly as carbonyl tautomers and are thus categorized as diazinones. The dioxydiazines do not obey a straightforward rule, for where both oxygens are a or c to a nitrogen both are expected to exist in carbonyl form but one remains in the hydroxyl form, as seen in the case of maleic hydrazide. The preference for the mono-oxo tautomer is likely due to the favorable interaction between two adjacent, oppositely charged nitrogen atoms as opposed to dual cationic nitrogens in the di-oxo form (Scheme 19.221). δ+ OH δ− O

δ+ N δ− N H

Scheme 19.221

Oδ− δ−O

δ+ NH N δ+ H

j1767

j 19 Six-Membered Heterocycles: 1,2-, 1,3-, and 1,4-Diazines and Related Systems

1768

On the other hand, uracil, 199, thymine, 200, and cytosine, 201, all exist in the dione form and most of their reactions can be interpreted on this basis [244]. Similarly, barbituric acid, 24, prefers the tricarbonyl tautomer. O

O NH N H

NH2

Me

NH N H

O

N

O

199

NH O

N H

Thymine

Uracil

O

O

Cytosine

O

Barbituric Acid 24

201

200

N H

Diazinones are highly susceptible to nucleophilic attack, generally via Michael-type addition rather than by direct attack at a carbonyl center (Scheme 19.222). There are, of course, exceptions to this general trend. Grignard reagents add to the ring to give dihydro-compounds and good leaving groups can be displaced [245]. OSO2Ar

OSO2Ar

MeMgCl THF

N

(53%)

N O Sugar

NH Me

N O Sugar

Scheme 19.222

For certain synthetic transformations it is often convenient to use halo- or alkoxysubstituted diazines to enhance solution solubility, or product yield, compared to the underivatized compound. Oxydiazines with the oxygen a to nitrogen can be converted into halo- and thio-compounds using the same reagents used for 2- and 4pyridones, including N-bromosuccinimide with triphenylphosphine or phosphorus oxyhalide (Scheme 19.223) [246]. X

OH PPh3 / N-halosuccinimide

N Me

N

Me

dioxane / reflux

N Me

N

Me

X = Br (84%) X = Cl (74%) Scheme 19.223

This same transformation can be effected via generation of the O-silylated pyrazinones with phosphorus(III) halide or phosphorus(V) chloride under mild conditions and without the need for isolation of the silyl intermediate (Scheme 19.224) [247]. The iodo adducts were obtained in low yield. Diazinones 202 can be converted into aminodiazines 204 by various processes, including the use of 1,2,4-triazole intermediate 203 (Scheme 19.225) [248].

19.8 Important Derivatives

Ph

N

Me

N

OH

TMSCl

Ph

N

HMDS

Me

N

OTMS

Ph

N

Me

N

PX3 or PX5

j1769

X

X = Cl (46-94%) X = Br (62-81%) X = I (15-20%) Scheme 19.224

N O N

NH

+ N H

N S Sugar

N

N

POCl3 / Et3NH MeCN, 0ºC to r.t.

N N

(93-99%)

NH2

NH3 / MeOH r.t.

S N Sugar

N

(93-97%)

S N Sugar

203

202

204

Scheme 19.225

Owing to the importance of light-induced mutagenesis, photochemical transformations of the double bond in oxypyrimidines have been investigated in depth. From this comes useful [2 þ 2] cycloaddition methodology, as illustrated in the reaction of uracil with vinylene carbonate to prepare a 5-alkylated derivative (Scheme 19.226) [249].

O

O O

HN O

+

light O Me2CO aq.

O

N H

O O

HN O

O

Et3N, DMF

O

N H

H

HN

40%

O

N H

O

Scheme 19.226

Uracils also undergo radical additions (Scheme 19.227), which are of possible relevance to mutagenesis mechanisms [250]. O R1 = H O Me O

N Me

N Me

Me

R1 = CH3

Me

O

N Me O

CH2

N N Me

OCOPh

N

O

hexano

O

Scheme 19.227

O OCOPh

N

O

R1 (PhCOO)2

N

Me

Me O

CH2OCOPh

N N Me

j 19 Six-Membered Heterocycles: 1,2-, 1,3-, and 1,4-Diazines and Related Systems

1770

19.8.5 Halodiazines

Most of the chemistry concerning halodiazines derivatives has been discussed above in the context of various nucleophilic sing substitutions (Sections 19.7.3.2 and 19.7.8).

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Matsuoka, M. (2000) Journal of Heterocyclic Chemistry, 37, 1299. Sato, N. and Narita, N. (1999) Journal of Heterocyclic Chemistry, 36, 783. Boger, D.L. and Weinreb, S.N. (1987) Hetero Diels–Alder Methodology in Organic Synthesis, Academic Press, New York, p. 313. Boger, D.L. and Coleman, R.S. (1984) The Journal of Organic Chemistry, 49, 2240. Giomi, D. and Cecchi, M. (2002) Tetrahedron, 58, 8067. Martin, J.C. (1980) Journal of Heterocyclic Chemistry, 17, 1111. Stolle, W.A.W., Frissen, A.E., Marcelis, A.T.M., and Van der Plas, H.C. (1992) The Journal of Organic Chemistry, 57, 3000. Tarasov, E.V., Henckens, A., Ceulemans, E., and Dehaen, W. (2000) Synlett, 625. Choy, N., Blanco, B., Wen, J., Krishan, A., and Russell, K.C. (2000) Organic Letters, 2, 3761. Biedrzycki, M., De Bie, D.A., and Van der Plas, H.C. (1989) Tetrahedron, 45, 6211. Russell, J.R., Garner, C.D., and Joule, J.A. (1992) Journal of the Chemical SocietyPerkin Transactions 1, 409. Boger, D.L., Boyee, C.W., Labroli, M.A., Sehon, C.A., and Jin, Q. (1999) Journal of the American Chemical Society, 121, 54. Manh, G.T., Hazard, R., Pradere, J.P., Tallec, A., Raoult, E., and Dubreuil, D. (2000) Tetrahedron Letters, 41, 647. Jones, R.G. and McLaughlin, K.C. (1963) Organic Syntheses, Coll Vol. IV, 824. Keiner, A. (1992) Angewandte Chemie – International Edition, 31, 774. Gotor, V., Quir
os, M., Liz, R., Fridga, J., and Fern
andez, R. (1997) Tetrahedron, 53, 6421. Tanji, S., Kodaka, Y., Shibata, T., and Soai, K. (2000) Heterocycles, 52, 151. Turck, A., Pl
e, N., Mongin, F., and Qu
eguiner, G. (2001) Tetrahedron, 57, 4489. Turck, A., Pl
e, N., Couture, K., and Qu
eguiner, G. (1995) The Journal of Organic Chemistry, 60, 3781.

196 Pollet, P., Turck, N., Pl
e, N., and

197

198

199

200

201

202

203

204 205 206 207

208

209 210

211 212 213

214

Qu
eguiner, G. (1999) The Journal of Organic Chemistry, 64, 4512. Fruit, C., Turck, A., Pl
e, N., Mojovic, L., and Qu
eguiner, G. (2002) Tetrahedron, 58, 2743. Qu
eguiner, G., Marsais, F., Snieckus, V., and Epszajn, J. (1991) Advances in Heterocyclic Chemistry, 52, 187. Turck, A., Pl
e, N., Mongin, F., and Qu
eguiner, G. (1990) Journal of Heterocyclic Chemistry, 27, 1377. Shimura, A., Momotake, A., Togo, H., and Yokoyama, M. (1999) Synthesis, 495. Fruit, C., Turck, A., Pl
e, N., and Queguiner, G. (1999) Heterocycles, 31, 2407. Li, J.J. and Gribble, G.W. (2000) Palladium in Heterocyclic Chemistry, Pergamon Press, New York, p. 355. Guery, S., Parrot, Y., Rival, C., and Wemuth, G. (2001) Tetrahedron Letters, 42, 2115. Aldous, D., Bower, S., Moorcroft, N., and Todd, M. (2001) Synlett, 150. Parrot, I., Ritter, G., Wermuth, C.G., and Hibert, M. (2002) Synlett, 1123. Coelho, A., Sotelo, E., and Ravi~ na, E. (2003) Tetrahedron, 59, 2477. Sotelo, E., Coelho, A., and Ravi~ na, E. (2003) Tetrahedron Letters, 44, 4459. Sotelo, E., Fraiz, N., Y
anez, M., Terrados, V., Laguna, R., Cano, E., and Ravi~ na, E. (2002) Bioorganic and Medicinal Chemistry, 10, 2873. Sotelo, E. and Ravi~ na, E. (2003) Synlett, 1113. Turck, A., Pl
e, N., Lepretre-Graquere, A., and Qu
eguiner, G. (1998) Heterocycles, 49, 205. Sandosham, J. and Undheim, K. (1994) Heterocycles, 39, 501. Angioletti, M.E., Casalnuovo, A.I., and Shelby, T.P. (2000) Synlett, 905. Kusturin, C., Liebeskind, L.S., Rahman, H., Sample, K., Schweitzer, B., Srogl, J., and Neumann, W.I. (2003) Organic Letters, 5, 4349. Benderitter, P., de Ara
ujo, J.X. Jr., Schmitt, M., and Bourguignon, J.-J. (2007) Tetrahedron, 63, 12465.

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j 19 Six-Membered Heterocycles: 1,2-, 1,3-, and 1,4-Diazines and Related Systems

1776

215 Petricci, E., Radi, M., Corelli, F., and

216

217

218

219 220 221 222 223 224 225 226

227

228 229

230

231

232

Botta, M. (2003) Tetrahedron Letters, 44, 9181. Reetz, M.T., Lohmer, G., and Schwickardi, R. (1998) Angewandte Chemie – International Edition, 37, 481. Littke, A.F. and Fu, G.C. (1998) Angewandte Chemie – International Edition, 37, 3387. Buchwald, S.L. and Wolfe, J.P. (1999) Angewandte Chemie – International Edition, 38, 2413. Akita, Y., Shimazaki, M., and Otha, A. (1981) Synthesis, 974. Otha, A., Otha, M., and Watanabe, T. (1986) Heterocycles, 24, 785. Nakamura, H., Takeuchi, D., and Murai, A. (1995) Synlett, 1227. Sato, N. and Narita, N. (2001) Synthesis, 1551. Jones, K., Keenan, M., and Hibbert, F. (1996) Synlett, 509. Otha, A., Itoh, R., Kaneko, Y., Koike, H., and Yuasa, K. (1989) Heterocycles, 29, 939. Akita, Y. and Ohta, A. (1982) Heterocycles, 19, 329. Nakamura, H., Wu, C., Takeuchi, D., and Murai, A. (1998) Tetrahedron Letters, 39, 301. Turck, A., Pl
e, N., Dognon, A.D., Harmony, C., and Qu
eguiner, G. (1994) Journal of Heterocyclic Chemistry, 31, 1449. Akita, Y., Inoue, A., and Ohta, A. (1986) Heterocycles, 24, 2093. Akita, Y, Noguchi, T., Sugimoto, M., and Ohta, A. (1986) Journal of Heterocyclic Chemistry, 23, 1481. Aoyagi, Y., Inoue, A., Koizumi, I., Hashimoto, R., Tokunaga, K., Gohma, K., Komatsu, J., Sekine, K., Miyafuji, A., Cono, J., Honma, R., Akita, Y., and Ohta, A. (1992) Heterocycles, 33 257. Walter, J.A. II, Chen, J.J., Hinkley, J.M., Wise, D.S., and Townsend, L.B. (1997) Nucleosides & Nucleotides, 16, 1999. Bessard, Y. and Crettaz, R. (1999) Tetrahedron, 55, 405.

233 Takeuchi, R., Suzuki, K., and Sato, N.

(1990) Synthesis, 923. 234 Yamanaka, H., Sakamoto, T., and

235

236 237

238

239

240

241 242

243

244

245 246 247 248

249 250

Niitsuma, S. (1990) Heterocycles, 31, 923. Kocevar, M., Mlakar, B., Perdih, M., Petric, A., Polanc, S., and Vercek, B. (1992) Tetrahedron Letters, 33, 2195. Sato, N. (1989) Journal of Heterocyclic Chemistry, 26, 817. Aoyagi, Y., Maeda, A., Inoue, M., Shiraishi, M., Sakakibara, Y., Fukui, Y., and Otha, A. (1991) Heterocycles, 32, 735. Martinez-Barrasa, V., Delgado, F., Burgos, C., Garc
ıa-Nav
ıo, J.L., Izquierdo, M.L., and Alvarez- Builla, J. (2000) Tetrahedron, 56, 2481. Laneri, S., Saachi, A., and Abignente, E. (2000) Journal of Heterocyclic Chemistry, 37, 1265. Insuasty, B., P
erez, A., Gonz
alez, D., Quiroga, J., and Meier, H. (2000) Journal of Heterocyclic Chemistry, 37, 193. Barnett, C.J. and Grubb, I.M. (2000) Tetrahedron, 56, 9221. Abu-Shanab, F.A., Wakefield, B.J., and Elnagdi, M.H. (1997) Advances in Heterocyclic Chemistry, 68, 181. Strekowski, L., Wydra, R.L., Janda, L., and Harden, D.B. (1991) The Journal of Organic Chemistry, 56, 5610. Wanhoff, H., Dzenis, J., and Hirota, K. (1992) Advances in Heterocyclic Chemistry, 55, 129. Bischofberger, N. (1989) Tetrahedron Letters, 30, 1621. Sugimoto, O., Mori, M., and Tanji, K.-I. (1999) Tetrahedron Letters, 40, 7477. Sato, N. and Narita, N. (1999) Journal of Heterocyclic Chemistry, 36, 783. Reese, C.B. and Varaprasad, C.V.N.S. (1994) Journal of the Chemical SocietyPerkin Transactions 1, 189. Bergstrom, D.E. and Agosta, W.C. (1974) Tetrahedron Letters, 15, 1087. Itahara, T. and Ide, N. (1992) Bulletin of the Chemical Society of Japan, 65, 2045.

j1777

20 Six-Membered Heterocycles: Triazines, Tetrazines and Other Polyaza Systems Cristina G
omez de la Oliva, Pilar Goya Laza, and Carmen Ochoa de Ocariz

20.1 Introduction

Triazines and tetrazines have been the subject of previous surveys. Reference textbooks include Comprehensive Heterocyclic Chemistry I [1–4], Comprehensive Heterocyclic Chemistry II [5–9] and The Chemistry of Heterocyclic Compounds [10]. In addition, Progress in Heterocyclic Chemistry [11] which appears annually and always includes a chapter with these ring systems. In other heterocyclic series, such as Advances in Heterocyclic Chemistry, several chapters have dealt with 1,2,3-triazines [12], dihydrotriazines [13, 14], reaction of triazines with nucleophiles [15–17] and 1,2,4triazine-N-oxides [18]. Some of the references cited therein have been considered in the present chapter and the reader is referred to them for additional details. Among the three triazine isomers the 1,2,3-triazines (1) are the least studied in comparison with their 1,3,5- (3) and 1,2,4- (2) isomers, because of the well known fragility of chains and rings with contiguous nitrogen atoms [19]. 4

4 5 6

N 1

1

N N

3

5

2

6

4

N N

3

N

2

5

N 6

N N

1

1

2

3

3 2

Several reviews on the chemistry of 1,2,3-triazine, also called n-triazine, have been published [12, 20–26]. Study of the reactivity and stability of the unsubstituted ring systems has been possible only since 1981 when the first synthesis of the parent compound 1 was reported [27]. 1,2,4-Triazines, also called a-triazine or as-triazine, are well-known compounds and a wide variety of synthetic methods for the preparation of substituted derivatives are available. Compounds containing the 1,2,4-triazine moiety are found in natural materials and some of them show biological activity. Several reviews dealing with 1,2,4-triazines have appeared, particularly on account of their biochemical properties [16, 18, 24, 26, 28–32]. The parent compound 2 was prepared for the first time by Paulder and Barton in 1966 [33]. Modern Heterocyclic Chemistry, First Edition. Edited by Julio Alvarez-Builla, Juan Jose Vaquero, and José Barluenga. Ó 2011 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2011 by Wiley-VCH Verlag GmbH & Co. KGaA.

j 20 Six-Membered Heterocycles: Triazines, Tetrazines and Other Polyaza Systems

1778

4

4

5N 6

N N

3

5

N2

6

N N

N N

3

4

5

2

N 6

10

9

N

3 2

1

1

1

N N

11

Figure 20.1 Numbering of the three possible isomers of tetrazine.

1,3,5-Triazines have been known for almost 200 years. Originally, they were called the symmetric triazines, usually abbreviated to sym-triazine. Like many heterocyclic compounds, 1,3,5-triazines are often referred to by trivial names such as cyanuric acid (4), cyanurates (5), cyanuryl chloride (6), isocyanurates (7) and melamines (8). OH N HO

OR

N N

N OH

4

RO

N N 5

O

Cl N OR

Cl

R N

N 6

Cl

O

N

N N R 7

NH2

R N O

H2N

N N

NH2

8

Therehavebeenmanystudiesdealingwiththechemistryof1,3,5-triazine[26,34–41]. Triazine 3 was first isolated in 1895 by Nef [42]. An incorrect molecular weight determination led Nef to assign a wrong structure. This incorrect assignment was accepted by other workers, but in 1954 a correct cryoscopic molecular weight determination established the structure of 3 [43]. Tetrazines have been less studied than triazines since there are fewer known examples [44]. The three possible isomers of tetrazine are known and numbered as indicated in Figure 20.1. There are more examples of 1,2,4,5-tetrazines (9), also named s-tetrazines and sym-tetrazines, than of the other two isomers. 1,2,3,4Tetrazine (10) is also known as n-tetrazine. 1,2,3,5-Tetrazines (11), also named as-tetrazines, are the least studied class. The parent compound of the 1,2,4,5-tetrazine series (9) was first synthesized by Hantzsch and Lehman in 1900 [45].

20.2 1,2,3-Triazines 20.2.1 Relevant Computational Chemistry, Physicochemical and Spectroscopic Data

Few monocyclic 1,2,3-triazines are known, so knowledge of the structure of these compounds is poor. 4,5,6-Tris(4-methoxyphenyl)-1,2,3-triazine was the first monocyclic triazine to be studied by X-ray crystallographic analysis [46]. This work showed the planarity of the triazine ring, as expected for a molecule with some degree of electron delocalization. The X-ray analysis of the parent compound 1 has been performed and the results fully agree with the planar and aromatic nature of the ring system [47–49]. X-Ray crystallographic analyses with alkyl and aryl substituents of

20.2 1,2,3-Triazines

j1779

1,2,3-triazines 12 [50], 13 [50], 14 [51] and triazinium salts 15 [50], 16 [50], 17 [50] and 18 [52] have been described. R4 R5 R6

N

N N

X

12 R4 = Ph, R5 = H, R6 = Me; 13 R4 = Ph, R5 = R6 = (CH2)4 4 6 5 14 R = R = Ph, R = NEt2 15 R4 = Ph, R 5= H, R6 = Me, X = O-; 16 R4 = R6 = Me, R5 = H, X = O17 R4 = R5 = R6 = Me, X = NH-; 18 R4 = R6 = Ph, R5 = H, X = CH3

In 2004, Fabian and Lewars described a computational study of the stability, homodesmotic stabilization energy, electron distribution and magnetic ring current of triazines [53]. The proton affinity of 1 has been calculated [54]. The results suggest that 1,2,3-triazine has almost the same basicity as pyrazine and 1,2,4-triazine, but it is more basic than 1,3,5-triazine [54]. The electronic absorption spectrum of 1,2,3triazine has been obtained [55, 56]. In addition, the excited state geometries and vibrational spectra of 1 have been calculated using different levels of ab initio theory, with the results being in agreement with experimental studies [55, 57]. Harmonic [58] and anharmonic [58, 59] frequencies have also been calculated. Solvent effects on the lowest excitation of 1,2,3-triazine have been studied using a method developed for estimating solvent shifts of triazines that have strong specific interactions with the solvent [60]. The heat of formation has been calculated for 1,2,3-triazine [61]. Most known 1,2,3-triazines are stable at room temperature. The parent compound 1 can be obtained as colorless plates from ether and it undergoes slow thermal decomposition at room temperature, but is stable for several months when stored under vacuum at
20  C. Table 20.1 gives the melting points, 1 H and 13 C NMR data of various 1,2,3-triazines. The relatively high melting point of 1 suggests the tight stacking of the unsubstituted triazine ring, which was shown in X-ray data [48]. The low-field chemical shifts of the ring protons are consistent with deshielding by a ring current of p-electrons; thus the triazine ring is aromatic. The 13 C NMR data show the aromatic nature of the triazine ring. Figure 20.2 shows the 15 N-signals of 1,2,3-triazines 1 [48], 19 and 20 [72] and those obtained recently for 21 and 27–29 [67]. 15 N NMR spectra of 1,2,3-triazines derivatives havebeenrecordedinCDCl3 solution,usingnitromethaneasinternalstandard.Insaltsall nitrogen signals are shifted to higher field compared to the corresponding 1,2,3-triazines. Mass spectrometry of 1,2,3-triazine affords a characteristic fragmentation. The general fragmentation pattern of monocyclic 1,2,3-triazines shows peaks for [M þ N2], and for an acetylene and a nitrile, which is in accordance with the results of thermolysis and photolysis. The mass spectrum of the parent triazine 1 shows peaks at 81 (M þ , 47%), 53 (M þ –N2, 69%), 27 (HCN, 13%), 26 (C2H2, 100%) [62]. The presence of alkyl and/or aryl substituents diminishes the molecular ion peak [67]. 20.2.2 Relevant Natural and Useful Compounds

To date, no compound containing the 1,2,3-triazine system has been isolated from natural sources. Derivatives of 1,2,3-triazine are an important class of heterocyclic

j 20 Six-Membered Heterocycles: Triazines, Tetrazines and Other Polyaza Systems

1780

Table 20.1 Melting point and 1 H and

R6

N

C NMR data of 1,2,3-triazines.

1 R4 = H, R5 = H, R6 = H; 19 R4 = Me, R 5 = R6 = H; 21 R4 = R6 = H, R5 = Ph; 23 R4 = R6 = Me, R5 = CH2COPh; 25 R4 = R6 = Me, R5 = CONH2;

R4 R5

13

N N

14 R4 = R6 = Ph, R5 = NEt2 20 R4 = R6 = Me, R5 = H 22 R4 = R6 = H, R5 = Me 24 R4 = Ph, R5 = OH, R6 = Me 26 R4 = R6 = Me, R5 = CH2SO2Ph

mp ( C)

1

1

70

14

216

19

30

20 21

87 145

22

67

9.06 (2H, d, J ¼ 6.0 Hz), 7.45 (1H, t, J ¼ 6.0 Hz) [62] 7.20–8.00 (10H, m), 2.68 (4H, q, J ¼ 7.0 Hz), 0.90 (6H, t, J ¼ 7.0 Hz) [63] 8.92 (1H, d, J ¼ 6.0 Hz), 7.33 (1H, t, J ¼ 6.0 Hz), 2.70 (3H, s) [64] 7.11 (1H, s), 2.68 (6H, s) [66] 9.95 (2H, s), 7.69–7.63 (2H, m), 7.57–7.51 (3H, m) [67] 8.93 (2H, s), 2.40 (3H, s) [64]

23

130

8.08–8.06 (2H, m), 7.72–7.68 (3H, m), 7.55–7.59 (2H, m), 2.44 (2H, s), 2.59 (6H, s) [68]

24

182

8.12–8.25 (2H, m), 7.31–7.41 (3H, m), 2.41 (3H, s), 2.17 (1H, bs) [69]

25

210

6.60 (2H, bs), 2.72 (6H, s) [70]

26

136

7.36–7.92 (5H, m), 4.44 (2H, s), 2.52 (6H, s) [71]

H NMR (CDCl3) d (ppm)

δ = 13.7 N N δ = 80.8

N δ = 12.5 19

δ = 71.48

N N δ = 10.62

N δ = 71.48 21 Figure 20.2

Ph

δ = -17.49 N δ = -81.46 N BF4 N δ = -17.49

27 15

N NMR data of some 1,2,3-triazines.

C NMR (CDCl3) d (ppm)

149.7, 117.9 [62] 153.0, 137.0, 129.4, 128.7, 128.4, 46.1, 12.8 [63] 159.7, 148.8, 117.8, 21.4 [65] 158.8, 117.6, 21.1 [65] 147.4, 131.4, 131.1, 130.1, 127.3 [67] 146.9, 137.4, 123.5, 17.4 [65] 193.1, 158.8, 135.7, 134.3, 129.1, 128.2, 124.9, 37.2, 19.6 [68] 164.1, 156.4, 147.7, 132.3, 129.5, 127.9, 127.7, 15.5 [69] 166.1, 154.8, 126.5, 17.5 [70] 159.6, 138.2, 134.9, 129.9, 128.2, 118.8, 54.9 [71]

δ = 3.8 N N δ = 78.6

δ = 3.6 N N δ = 79.9

N δ = 13.7 1 Ph

13

N δ = 3.8 20

Ph

Ph

δ = 83.14

N N δ = 8.32

δ = -21.46 N δ = -69.93 N BF

N δ = 83.14

N δ = -21.46

28

29

4

20.2 1,2,3-Triazines

j1781

compounds that are useful in organic synthesis, their importance being due to the fact that they can react as diene in inverse-demand Diels–Alder cycloadditions with electron-rich dienophiles. The use of 1-t-butyl-3-ethyl-2-methylhexahydro-1,2,3-triazine as a corrosion inhibitor for steel is mentioned in the literature [73]. For several other compounds containing the 1,2,3-triazine system, claims for biochemical or technical applications have been made, but these seem to have been mostly for the purposes of obtaining patents on the compounds involved, and it appears that no significant uses are yet known. Reports on the medicinal chemistry of 1,2,3-triazine have appeared [74–82]. 20.2.3 Synthesis 20.2.3.1 From Tricycles The rearrangement of cyclopropenyl azides 30 (Scheme 20.1) is a method used for the synthesis of monocyclic 1,2,3-triazines [83–90]. This method is limited to the synthesis of trisubstituted triazines, because only trisubstituted cyclopropenyl azides have been rearranged. R R

R

N3

N

R

30 R

N

R

R R

N

R

R N N

R

N

R

N

N N

Scheme 20.1

Diphenylchloroazine 31 and diazomethane yield 4,5-diphenyl-1,2,3-triazine 32 (Scheme 20.2) [91]. Ph

Ph Cl

CH2N2

Ph

N

Ph

Cl

31

Ph

N N

N

N 32

Ph

N N

Scheme 20.2

Matsumoto et al. have reported the preparation of 5-amino-4,6-dialkyl-1,2,3triazines 35 from the corresponding dialkylcyclopropenones 33 [63, 92, 93] (Scheme 20.3).

O R4

33

EtSO3F R6

Scheme 20.3

R' HN

OEt R4

34a

SO3F R6

R R R4

N

R'

34b

BF4 R6

NaN3

R'

R N

R4

6

N 35

R

N N

j 20 Six-Membered Heterocycles: Triazines, Tetrazines and Other Polyaza Systems

1782

20.2.3.2 From Pentacycles The more general synthetic method to obtain various mono-, di- and tri-substituted alkyl- and aryl-triazines, besides the parent triazine 1, is by oxidation of N-aminopyrazoles 36 with lead(IV) acetate (LTA; Pb(C2H3O2)4), nickel peroxide or sodium perchlorate [27, 48, 64, 66, 94, 95] (Scheme 20.4). The amino nitrogen is incorporated into the triazine ring as the central nitrogen N2, probably via insertion of the nitrene moiety to the N
N bond of the pyrazole ring [72]. R5

R4

R5

N N NH2 36

R6

R6

R4

N

N N

Scheme 20.4

Butler et al. have reported that 2,5-dihydro-1,2,3-triazine derivatives are obtained by the 1,3-dipolar cycloaddition of 1,2,3-triazole N-oxide and dimethylacetylene dicarboxylate (DMAD) [96, 97]. The same group have reported another synthesis in which pyrrolo[2,3-d]-1,2,3-triazoles thermally rearrange to 2,5-dihydro derivatives [98]. 20.2.3.3 Cycloaddition of [3 þ 3] Fragments Another 1,2,3-triazine system (39) has been obtained by the reaction of triazenes 37 with chloroformylketones 38 (Scheme 20.5) [99].

R

N

N

NH R

37

R5

R5

O C

O

Cl

O

38

O

N R 39

N N

R

Scheme 20.5

20.2.3.4 Cycloaddition of [5 þ 1] Fragments The cycloaddition of [5 þ 1] fragments has also been used indirectly for the synthesis of one monocyclic 1,2,3-triazine. Compound 40 (Scheme 20.6) is cyclized with NH H2N H2N

NH2 N

HNO2

N Cp 40 Cp = Cyclopentyl

Scheme 20.6

N N N

N

H2N

N Cp

CpHN

41

NH2

N 42

N N

20.2 1,2,3-Triazines

j1783

nitrous acid to give 4-aminoimidazo[4,5-d][1,2,3]triazine 41, which affords 4,5diamino-6-cyclopentylamino-1,2,3-triazine 42 [100]. 20.2.3.5 Cycloaddition of [6 þ 0] Fragments Cyclization of triazenes 43 affords 1,3-disubstitued-3,4,5,6-tetrahydro-1,2,3-triazinium salts 44 [101] (Scheme 20.7).

R

N

N

N R

3 Br

N R

43

N N

R

44

Scheme 20.7

20.2.4 Reactivity 20.2.4.1 Thermal and Photochemical Reactions Flash vacuum thermolysis (FVT) of 1,2,3-triazines affords nitriles 45 and 46, alkyne 47 and nitrogen (Scheme 20.8). With unsymmetrically substituted triazines, fragmentation proceeds selectively. The results indicate that a bulky substituent at C4(6) makes the adjacent C
N bond break more easily than the opposite C
N bond. The photolysis of triazines (Scheme 20.9) gives the fragments nitriles 45 and 46, alkyne 47 and nitrogen, as under FVT conditions [83, 85, 102–104]. In contrast to the FVT, unsymmetrical triazines also give the other possible alkyne 48.

R5 R6

R4

N

N N

630 ºC 10-5 mmHg

R4

N 45

R6

46

N

R4

N

R4

47

R5

N2

R5

R6

Scheme 20.8

5

R4

R

R6

N

N N

h

R4

N 45

R6 46

47

R5 48

Scheme 20.9

FVT has been applied to the synthesis of fluorinated alkynes, such as perfluoro-3methyl-1-butyne (50) and difluoroethyne (51) [105, 106] (Scheme 20.10). Seybold et al. have obtained the first isolable unfused azete 54 by FVT of tris(dimethylamino) triazine (53) [87] (Scheme 20.11).

N2

j 20 Six-Membered Heterocycles: Triazines, Tetrazines and Other Polyaza Systems

1784

F (F3C)2FC

700 ºC

F

10-2 mmHg

50

R = CF(CF3)2

R F

N N

N 49

700 ºC 10-2 mmHg R=F

F

F 51

N

F 52

Scheme 20.10

Me2N Me2N

NMe2

N

N N

527 ºC 10-4 mmHg

53

Me2N Me2N

NMe2 N 54

Scheme 20.11

20.2.4.2 Reactions with Electrophilic Reagents Electrophilic reaction on ring carbon C5 of 1,2,3-triazines cannot proceed because of the intensive p-electron deficiency of the ring system. Protonation of alkyl and/or aryl substituted 1,2,3-triazines is difficult due to the low basicity of the ring nitrogen, and only when 4-phenyl (28) and 5-phenyl-1,2,3triazines (21) are treated with tetrafluoroboric acid is the isolation of protonated 1,2,3-triazinium salts 55 possible [67]. The N2 substituted isomer is the most stable (Scheme 20.12).

R5

R4 N N

N 21 R4 = H, R5 = Ph 28 R4 = Ph, R5 = H

HBF4

5

R

R4 N NH BF4 N 55

Scheme 20.12

However, 4,6-diamino-1,2,3-triazines have relatively high nucleophilicity at N2 and undergo various kinds of reactions with electrophiles [107] (Scheme 20.13). Other electrophilic reactions proceed on the ring nitrogen of substituted 1,2,3triazines (Scheme 20.14). The reaction with methyl iodide takes place easily to give 2-methyl derivatives 62 [63, 68, 92, 108]. Ethylation of substituted 1,2,3-triazines occurs when these compounds are treated with triethyloxonium, and so derivatives 63 have been obtained [67, 109]. Both N-amination and N-dicyanomethylidation of triazines also occurs and the corresponding 2-substituted isomers 64 [70] and 65 [109] are obtained in good yields. The N-phenylated 1,2,3-triazinium 66 has been obtained from copper-catalyzed reaction between 1,2,3-triazines and diphenyliodonium hexafluorophosphate [67]. Treatment of triaryl-1,2,3-triazines with aqueous hydrochloric

20.2 1,2,3-Triazines

NR2

X R2N

Cl

N N

NR2

R2N

HBF4

NR2

X

R2N

N N

R2N N 56 X = NR2 ClCO2Me 57 X = Cl

IMe

NR2

X

ClO4

NR2 N 2ClHO4 NR2 58 NR2 X N I N R2N N 61

N 59

N NH

R4

R

R5

N N

R6

6

R

N 62 I

NH2

IMe

CN

H

Ph 68a

R4 = R6 = H, R5 = Ph R4 = Ph, R5 = R6 = H CN

Ph

6

HOSA

NH2 H 68b

R5 6

R

O

R H3O R4

O 67 R = R = R6 = Ar 4

5

R5

R4

N N Cl N CO2Me 60

R2N

N 63

N N

R4

5

R

6

Et X

N 64

R

N N

NH

Et3O X SO3NH2

R4

N

N N

R5 NC NC

PhI2 PF6

CN O CN

6

R

R4

N 65

N N

CN CN

R4 R5 R6

BF4

NR2

X

Scheme 20.13

5

j1785

N N

N Ph 66 PF6

Scheme 20.14

acid at higher temperatures leads to hydrolysis of the ring and formation of 1,3dicarbonyl compounds 67 [83]. The reaction of monosubstituted 1,2,3-triazines with hydroxylamine-O-sulfonic acid gives 3-amino-2(3)-phenylacrylonitriles 68a,b [109]. 20.2.4.3 Reactions with Nucleophilic Reagents 1,2,3-Triazines are highly p-electron deficient and are readily attacked by nucleophiles. The reaction site is almost exclusively at the C4 position, even in the presence of a substituent at C4 [69, 110, 111]. Gompper et al. [107] have reported that 4,5,6-trichlorotriazine undergoes substitution reactions with amines and alcohols. The first reaction site was the C4 position, and successive displacement(s) occur, depending on the nature of the nucleophile (Scheme 20.15).

j 20 Six-Membered Heterocycles: Triazines, Tetrazines and Other Polyaza Systems

1786

NiPr2 Cl Cl

N 70

N N

i

NR Cl

OR Pr2NH

Cl N 69

Cl Me2NH or piperidine

N N

MeONa, rt or PhOH, Et3N

Cl N N

MeONa, heat or EtSNa, rt

RO

R R

N 57 R = Me2 R = [CH2]5

RN

Cl

N N N R = Me 71 R = Ph R N N

N R = OMe 72 R = SEt

Scheme 20.15

Therefore, the 1,2,3-triazine ring system has been shown to have insufficient stability for direct introduction of substituents. For example, the parent triazine slowly decomposes in methanol at room temperature, which suggests that nucleophilic attack of methanol occurs in the solution. Also, softer nucleophiles undergo a redox reaction with triazine (1) to give 2,5-dihydro derivatives 73 without ring substitution [112] (Scheme 20.16). R

N 1

N N

RMgX

R

or RLi

N

R

N NH

H

O

73

Scheme 20.16

On the other hand, 4-methyl-1,2,3-triazine (19) reacts with sodium amide in ammonia to give 5-amino-4-methyl-2,5-dihydro-1,2,3-triazine (74) [48] (Scheme 20.17).

N 19

N N

NaNH2 NH3 R = Me

H2N N

N NH

74

Scheme 20.17

The introduction of nucleophiles at the C5 position of 1,2,3-triazine has been carried out for ring activation of N2, that is, addition of nucleophiles was successful when 1,2,3-triazinium salts were used as substrate. The dicyanomethylene group is a good activator, whose removal was simultaneously effected under the reaction conditions. Makosza [113] has developed a method named vicarious nucleophilic substitution of hydrogen to transform 1,2,3-triazinium 2-dicyanomethylylides 65

20.2 1,2,3-Triazines

j1787

into 5-benzenesulfonylmethyltriazines 75 [71, 114] by a radical reaction (Scheme 20.18). Radical nucleophilic carbamoylation, which was developed by Minisci [115], has been applied to triazinium dicyanomethylides to form 5-carbamoyl-1,2,3-triazines 76 [70, 116]. R4

R4 Ph

R6

N

S O O R6

1. PhSO2CH2Cl/NaH 2. HCl

R4 N N

CN

65

O

CN

N

R6

N 76

CN CN

R4

H2N

(NH4)2S2O8 HCONH2

N N

Ph (NH4)2S2O8 i

S O O R6

PrOH

N N

Scheme 20.18

However, this procedure was limited to these two reactions because of the instability of the dicyanomethylene group toward other nucleophiles. Ohsawa et al. [68, 117] have found an alternative method for ring activation – ketene silyl acetals or silyl enol ether react with 1,2,3-triazine in the presence of 1-chloroethyl chloroformate to give 2,5-dihydro adducts 77, which upon aromatization with ceric ammonium nitrate (CAN) give the corresponding 5-substituted triazines 78. 2,5Dihydro-1,2,3-triazine 79 has been obtained by hydrolysis in acetonitrile/water under reflux (Scheme 20.19). O

O

R4

R6

N

N N

1. Cl 2.

R R'

Cl O OSiMe3 R''

O

1. CAN 2. CH3CN H2O

R'' 4 R R'

R R6

N 77

N N

R R6 O

O O

R'' 4 R R'

Cl

CH3CN H2O

N N

N 78 R'' 4 R R'

R R6

N 79

N N

H

Scheme 20.19

Hydrolysis of 5-amino-1,2,3-triazinium salt 62 with aqueous sodium hydroxide affords 1,2,3-triazin-5-ones 80 [63, 92, 93] (Scheme 20.20). 2-Methyltriazinium quaternary salts are highly reactive to nucleophiles; the reactive site is the 5-position, giving 2,5-dihydro derivatives 81 and 82 [118]. When 2-ethyl-1,2,3-triazinium salts are allowed to react with C-nucleophiles the expected attack occurs in the case of the 4-alkyl triazinium salt to obtain 83

N 75

N N

j 20 Six-Membered Heterocycles: Triazines, Tetrazines and Other Polyaza Systems

1788

R4 R R4 O 6

R

N 80

NaOH aq MeOH

N N

R5

= NRR'

R4

R5

N N N I 62

R6

6

R

RMgX R5 = H EtO2C

N 81

N N R4

(EtO2C)2HC R6

CO2Et

N 82

N N

Scheme 20.20

(Scheme 20.21); however, 5-alkyl-1,2,3-triazinium salts did not react [67]. Reactions with these C-nucleophiles suffer from poor yields due to the weak nucleophilicity. Reaction of 63 with compounds with acidic protons allows one to obtain 84 in good yields. R' R''

Y X

R'''

R

R X

R4

N 83

N N

Et

R'''

Y R' R''

R4 N N X N Et 63

R' R

R' Na

R4

R N 84

N N

Et

Scheme 20.21

In addition, other nucleophiles can react with 1,2,3-triazines while keeping the aromaticity of the ring. Consequently, reaction between 4,6-dimethyl-1,2,3-triazine with halogenating reagents yields 5-halotriazine [119]. The use of interhalogen reagents affords 5-halotriazines derived completely or mainly from the more electronegative halogen. Monocyclic 1,2,3-triazine 2-oxides are quite stable and unreactive toward reagents such as Grignard reagents, alkyl- and aryllithiums and other organometallic compounds. This fact suggests that the N-oxide moiety back-donates electrons to the triazine ring, thus making the a- and c-positions less reactive toward nucleophiles. 20.2.4.4 Cycloaddition Reactions 1,2,3-Triazines are useful compounds that participate in cycloaddition reactions [120]. These compounds behave as p-deficient dienes and undergo inverse-demand Diels–Alder cycloadditions with electron-rich dienophiles [121]. Several reactions of 1,2,3-triazines with ynamine or enamine have been reported to afford pyridines 85 [48, 122] or 86 [94, 123] respectively (Scheme 20.22). This approach has been successfully employed for the total synthesis of pyridine alkaloids [124, 125], such as fabianine (87) [48, 126] and fusaric acid (88) [127, 128]. The mechanisms proposed for these reactions are described in Scheme 20.23.

20.2 1,2,3-Triazines

j1789

CH3 R R = H, Me

1. C4H9 C4H9 HO2C

N

N 85

N

H3C

N

R = Me

N

88

NEt2

R

2. SeO2, pyridine

CO2H

NEt2

R' N N R=H

N

R'

N Me

ZnBr2, 90ºC R = Me

N 86

87

Scheme 20.22

H

R

N

R'

N N

NEt2

N N N

N N

R'' N

R'

R

N N N

R' R'

NEt2

H

R

N

H

R

H

N2

R

N

NEt2

R'' R''

N R'

NH N2

R

N

R'

Scheme 20.23

4,6-Dimethyl-1,2,3-triazine (20) also reacts as diene with enamines under microwave irradiation [129, 130] (Scheme 20.24). The presence of alkyl substituents in the triazine ring diminishes the electron deficiency of the ring and increases the steric hindrance experienced in the cycloaddition. For these reasons, cycloaddition reactions are scarce and reaction conditions are very energetic, therefore microwave irradiation in solvent-free conditions is used. To date, Diels–Alder reactions of 4,5,6trimethyl-1,2,3-triazine have not been reported.

N 20

N N

Scheme 20.24

microwave 150º C N NH

N2

N

j 20 Six-Membered Heterocycles: Triazines, Tetrazines and Other Polyaza Systems

1790

In 2004 [109] the first report was made of a 1,3-dipolar cycloaddition reaction between 1,2,3-triazonium N-ylides 65 and electron-deficient dipolarophiles, affording a new class of bicyclic heterocycles (89) (Scheme 20.25).

R5

R4

N

N N

O

O

O

O

CN

100º C

CN

65

R4

5

R

N CN N CN N

MeO2C

89

CO2Me

Scheme 20.25

20.2.4.5 Reactions with Reducing Reagents Sodium borohydride reduction of 4,6-disubstituted triazines in methanol afforded 2,5-dihydrotriazines 90 in good yields [66]. 4,5,6-Triaryltriazines have been reduced with LiAlH4 to give also the corresponding 2,5-dihydro compounds 91 in moderate yields [48] (Scheme 20.26). R4

R6

N 90

N NH

NaBH4 R5 = H

R5 R6

R4

N

N N

R5

LiAlH4

R6

R5 = H

R4

N 91

N NH

Scheme 20.26

Reduction of the 2-oxide 92 with NaBH4 gives tetrahydro derivatives 93 (Scheme 20.27) in good yields [131]. Reduction of the triazine 1-oxide 94 affords 2,5-dihydrotriazines 90.

R6

N 92

R4

R4

R4 N N

NaBH4 O

MeOH

R6

NH N N O 93

R6

N O 94

R4 N N

NaBH4 MeOH

R6

N

N NH

90

Scheme 20.27

20.2.4.6 Reactions with Oxidizing Reagents 2-Oxides 92 and/or 1-oxides 94 have been obtained by treatment of monocyclic 1,2,3triazines with MCPBA or AcOH/H2O2 (Scheme 20.28). Triazines with bulky aryl groups on C4 and C6 give predominantly 2-oxides 92, while with alkyl groups on C4 and/or C6 it is possible to obtain 1-oxides 94 [48]. There are no reported 1(3)-oxides without substituent on the adjacent carbon.

20.2 1,2,3-Triazines

R5 R6

R4

N

N N

R5

MCPBA or AcOH/H2O2

R6

R4

N

N N

R5 + O

6

R

92

R4

N O 94

N N

Scheme 20.28

5-Halo-1,2,3-triazines 95 react with superoxide to give 1,2,3-triazin-5(2H)-ones 96 [69, 111] (Scheme 20.29). The 5-oxo forms are predominant rather than the 5-hydroxy tautomers. R4

R4 X R6

N

N N

95

superoxide CH3CN X = Br, Cl

O R6

N 96

N NH

Scheme 20.29

The reactions of triazinium salts 62 [111, 118] and 2,5-dihydrotriazines 97 [132] with superoxide give 5,50 -bi(2-methyl-2,5-dihydrotriazinyls) 98, which are formed by one-electron reduction with superoxide followed by dimerization (Scheme 20.30). R4

R6

N

R4

R4 N N

KO2 CH3CN

R6

62 I

N 98

KO2

N N

CH3CN

R6

N 97

2

N N

Scheme 20.30

2,5-Dihidrotriazines 90 slowly oxidize in air to give the corresponding triazines (Scheme 20.31), whereas oxidation with MCPBA affords 2-oxides exclusively 92; NR4 R4

R4 O R6

N 80

N N

Scheme 20.31

R = Me MCPBA

R6

N

O2 N N

R6

R=H R

90 R = H 97 R = Me

N

N N

R4

MCPBA R6

N 92

N N

O

j1791

j 20 Six-Membered Heterocycles: Triazines, Tetrazines and Other Polyaza Systems

1792

methyl derivatives 97 are oxidized with MCPBA to afford 5-oxo-2,5dihydrotriazines 80 [133]. 20.2.4.7 Relevant Examples Direct Diels–Alder reactions of 1,2,3-triazine with fullerene C60 should be unfavorable because 1,2,3-triazines behave as p-deficient dienes with inverse-electron demand and the 6-6 junction double bond of C60 acts as an electron-deficient dienophile. However, the reaction took place to give an azacyclohexadiene fused derivative such as 99 by extrusion of N2 [134, 135] (Scheme 20.32)

N

N 20

N N

C60

1. o-dichlorobenzene 180 ºC 2. H2O Si2O 99

Scheme 20.32

20.3 1,2,4-Triazines 20.3.1 Relevant Computational Chemistry, Physicochemical and Spectroscopic Data

Much detailed data on the structure of 1,2,4-triazine have been published. Two Kekul
e structures can be drawn for this molecule (2a and 2b,Scheme 20.33). Theoretical calculations suggest that structure 2a gives a higher contribution to the ground state of the molecule. This is supported by X-ray crystallographic structure determinations. It is explained by the fact that structures with a formal N¼N double bond are energetically unfavorable; they are destabilized and so tend not to be formed [136]. H

N

H

N 2a

H N

Scheme 20.33

H

N

H

N 2b

H N

20.3 1,2,4-Triazines

Several theoretical methods have been used to study 1,2,4-triazines. Thus, the H€ uckel method was used to calculate the p-electron energies [137, 138], the electronic excitation energies and intensities were calculated by the RPAC molar properties program [139], the electronic state of 1,2,4-triazines were obtained [140] and the ionization energies were calculated by the outler valence Green function technique (OVGF) [141]. The CNDO/2 method has been used to calculate the sites of protonation and alkylation [142]. The acidities and basicities of 2 have been calculated by the MOSP method [143]. The proton affinities have been calculated by the 321 þ G, 3-21G, MNDO, and AM1 methods [54], the tautomeric equilibrium by the AM1 and MNDO-PM3 methods [144] and the lithium-triazine binding energies by the 6-31G method [145]. A computational study of the stability, homodesmotic stabilization energy, electron distribution and magnetic ring current of 1,2,4-triazines has been conducted [53]. The geometry and vibration spectra of 1,2,4-triazine have been obtained [57]. Harmonic [58] and anharmonic [58, 59] frequencies have also been calculated. The heat of formation of 1,2,4-triazine have been reported [61, 146]. Investigations employing the semi-empirical AM1, MNDO and MINDO/3 in the program package AMPAC to calculate both electronic charge distribution and structure optimization on compounds containing a 1,2,4-triazine ring demonstrate that these methods are not useful in studying heteroaromatic compounds containing nitrogen–nitrogen ring bonds [147]. The relative stability of the nine possible dihydro-1,2,4-triazines and three dihydrotriazinium cations has been studied at HF, MP2, generalized gradient approximation DFTand CBS-4 levels of theory. The quantum chemical calculations support that the most stable isomer is the 2,5-dihydro-1,2,4-triazine [148]. Most 1,2,4-triazines are crystalline compounds, the melting points depending on the structure and the substituents present. Alkyl-substituted 1,2,4-triazines are yellow and melt at low temperatures, or a few cases are liquid at room temperature and they are reasonably stable. Aryl-substituted 1,2,4-triazines have melting points around 100  C, while all heterosubstituted 1,2,4-triazines have melting points in the 200  C region – these compounds are thermally very stable. Several X-ray crystallographic studies have been reported for 1,2,4-triazines derivatives [149–161]. The X-ray studies on two Lamotrigine analogs, 3,5-diamino-6-(2-fluorophenyl)-1,2,4-triazine methanol solvate and 3,5-diamino-6-(2methylphenyl)-1,2,4-triazine monohydrate, show that these compounds contain two conformers of the triazine molecule, each conformer with significant, distinct dihedral angles between their respective phenyl and triazine rings [162, 163]. The reader is referred to the Cambridge Structural Database for further structure determinations. NMR spectra of 1,2,4-triazines are well documented. The parent compound 2 shows three signals in the 1 H NMR spectrum: d ¼ 9.88 (1H, d, H3), 8.84 (1H, d, H5), 9.48 (1H, dd, H-6) ppm [33]; coupling between H3 and H5 is never observed in simple 1,2,4-triazines. The 13 C and 15 N NMR data of 1,2,4-triazine and some derivatives are gathered in Table 20.2. 15 N NMR data for 101 and 102 have only been measured with the addition of Cr(acac)3.

j1793

j 20 Six-Membered Heterocycles: Triazines, Tetrazines and Other Polyaza Systems

1794

Table 20.2

13

C and 15 N NMR [164] data of 1,2,4-triazines.

R5

N

R6

N

R3 N

2, 100

R5

N

R6

N X 101

R3 N

Substituent

13

R3 ¼ R5 ¼ R6 ¼ H (2) R3 ¼ SCH3, R5 ¼ OCH3, R6 ¼ H (100a) R3 ¼ OCH3, R5 ¼ SCH3, R6 ¼ H (100b) R3 ¼ SCH3, R5 ¼ SCH3, R6 ¼ H (100c) R3 ¼ SCH3, R5 ¼ SCH3, R6 ¼ CH3 (100d) R3 ¼ SCH3, R5 ¼ OCH3, R6 ¼ CH3 (100e) R3 ¼ OCH3, R5 ¼ CH3, R6 ¼ H, X ¼ O (101a) R3 ¼ SCH3, R5 ¼ CH3, R6 ¼ H, X ¼ O (101b) R5 ¼ OCH3, R6 ¼ CH3, X ¼ CH3 (102)

158.3, 150.7, 149.2 [165] 170.9, 161.1, 138.6, 54.1, 13.1 [164] 167.8, 163.8, 143.4, 55.1, 11.3 [164] 171.1, 165.1, 144.3, 13.0, 11.3 [164] 168.7, 164.4, 151.5, 18.0, 13.1, 11.7 [164] 168.8, 160.3, 146.5, 54.8, 16.1, 13.1 [164] 168.1, 166.3, 135.7, 49.8, 54.1 [164] 174.6, 163.5, 136.5, 49.7, 12.6 [164] 163.8, 153.6, 134.8, 39.3, 54.5, 15.5 [164]

C NMR (DMSO-d6) (d, ppm)

R5

N

R6

N N X 102

15

O

N NMR (DMSO-d6)a) (d, ppm)

d (N1) 39.24 33.3

d (N2)
4.89
56.1

d (N3)
80.34
140.0

27.1


79.0


129.4

23.0


50.0


108.5

14.6


52.3


108.2

23.0


58.3


141.3


140.5


123.3


153.7


122.6b)


123.1


125.1


28.61


142.4


142.4

a) Nitromethane as reference. b) Assignment of nitrogen ascertained by HMBC exponent.

Palmer has determined the 1,2,4-triazine 14 N quadrupole coupling constants from a joint study by microwave spectroscopy and ab initio calculations [166]. The mass spectra of 1,2,4-triazines have been extensively studied since they can be used for structure determination. The fragmentation pattern depends on the structure of the 1,2,4-triazine system (2) and on the substituents [2, 6]. Detailed studies on 1,2,4-triazines substituted with oxygen or sulfur in the 3- and 5-position have shown that five distinct fragmentation patterns can be observed upon electron impact, but none involve initial loss of nitrogen [167]. Information on the IR spectra of 1,2,4-triazines can be found [168–171]. UV spectra have been used to determine tautomeric structures in 1,2,4-triazin-3-ones [172–174], 1,2,4-triazin-5-ones [175, 176], 1,2,4-triazin-6-ones [177], 1,2,4-triazinethiones [178] and amino-1,2,4 triazines [179]. Unsubstituted 1,2,4-triazine [180] 2 has two absorption bands in methanol, at 374 (e ¼ 400) and 247.8 nm (e ¼ 3020). The UV spectra of the different 1,2,4-triazines have been reviewed [168]. For many 1,2,4-triazines of varied structure the pKa values have been determined and, depending on their structure, they range from 1.5 to 10.3 [181–186].

20.3 1,2,4-Triazines

j1795

20.3.2 Tautomerism

As mentioned already, UV spectra have been used to determine the predominant tautomeric forms of 1,2,4-triazinones, 1,2,4-triazinethiones, and amino-1,2,4-triazines. In most cases, 1,2,4-triazines with oxygen or sulfur substituents exist predominantly in the oxo form (103 [172, 173], 104 [168, 175], 105 [187], 106 [178]) or thioxo form (106 [178], 107, and 108), while 1,2,4-triazines with a nitrogen substituent occur predominantly as the amino tautomer (109 [179], 110). R5

N

R6

N

O NH

O

H N

R6

N

103 R5

N

R6

N 107

R N

O

H N

R6

N

104 S

S

NH

R6

H N

O NH

S

H N

R6

N

105 R5

S

NH N 108

R6

O NH

106

N

NH2

N N 109

O

H N

R6

N N 110

NH2

On the other hand, 1 H NMR spectroscopy shows that 5-alkyl-1,2,4-triazine-3-ones 111 [173] and 5-alkyl-1,2,4-triazine-3-thiones 112 [188] (Scheme 20.34) with a proton at C1 of the alkyl group can occur in two tautomeric forms, the alkylidene group (111a or 112a) and the structure with an alkyl form (111b or 112b). The ratio of the two tautomers depends on the solvent. R R' R6

R

H N N

O N

111a

R2

R N

R' R6

N

O N

R2

111b

R' R6

H N

R S

N 2 R N 112a

N

R' R6

S

N 2 N R 112b

Scheme 20.34

Azido-1,2,4-triazines may exist also as tetrazolo-fused tautomers. 3-Azido-1,2,4triazines 113 spontaneously cyclize to give the tetrazolo[1,5-b][1,2,4]triazines 114 (Scheme 20.35), if cyclization to N2 is possible; no cyclization to N4 has been observed [189, 190]. 5-Azido-2H-1,2,4-triazin-3-ones 115 also cyclize to give 116 [191, 192]. In contrast, when the 6-azido tautomer 117 is stirred for a few minutes in a polar solvent it is quantitatively transformed into the tetrazole tautomer 118 [193]. 20.3.3 Relevant Natural and Useful Compounds

1,2,4-Triazines are biologically very active compounds. Many have been tested for use in agrochemistry or medicine. Amino-1,2,4-triazin-5-ones are, biochemically, highly

j 20 Six-Membered Heterocycles: Triazines, Tetrazines and Other Polyaza Systems

1796

R5

N3

N

6

R

N

N

R5

N

R6

N N N 114

113 O

N

N3

N

N

R6

NH

N

117

NH

N N N

O

NH N 116

R6

115 NH2 N

O

NH2

N

N N N N

O

N

N3

N

NH 118

Scheme 20.35

active substances and are used as herbicides [168]. Some potent herbicides are 4-amino-6-tert-butyl-4,5,-dihydro-3-methylthio-1,2,4-triazin-5-one (119) (Metribuzin, Sencor, Lexone), 6-tert-butyl-4,5,-dihydro-4-isobutylideneamino-3-methylthio-1,2,4triazin-5-one (120) (Isomethiozin), 4-amino-4,5,-dihydro-3-methyl-6-phenyl-1,2,4triazin-5-one (121) (Metamitron, Goltix) and 6-tert-butyl-4,5,-dihydro-3-dimethylamino-4-methyl-1,2,4-triazin-5-one (122) (Amibuzin).

O But

NH2 N S N N 119

O But

N N

S

O

N N 120

Ph

NH2 N

N

O

N N 121

N

N N 122

But

Two reviews on the role of uncondensed 1,2,4-triazine derivatives as biocide plant protection and therapeutic agents appeared in 2001 [194, 195]. Several 1,2,4-triazines show pharmacological properties (123–125). Compound 123 has been tested for its antibacterial and tuberculostatic activity [168]. 3,5-Diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine (124) (Lamotrigine), a sodium channel blocker, is the active component of Lamictal and is in clinical use as an anticonvulsant therapy. Cefriaxome (125) [196, 197], a semi-synthetic parenteral cephalosporin, is a leading injectable antibiotic in hospital use. CO2 Na H2N NH2

N O2N

O

N

N

N

123

N

Cl Cl

O

NH2

N

124

N O Na O

S

N N

S

R

N

125

Several 1,2,4-triazines have been tested as analgesic and anti-inflammatory agents [198–202]. Significant activity towards leukemia, ovarian cancer and antiHIV were observed in vitro for some 3,5,6-trisubstituted-1,2,4-triazines [203–208]. 1,2,4-Triazine-N-oxide derivatives have been studied as potential hypoxic cytoxins [209–211]. Recently, the pyrrolotriazine nucleus has been identified as a potent and selective inhibitor of the tyrosine kinase [212–214].

20.3 1,2,4-Triazines

j1797

Dihydro-1,2,4-triazine derivatives have been described as antimalarials due to their ability to inhibit multiple mutants of Plasmodium falciparum dihydrofolate reductase [215]. Many 1,2,4-triazines form complexes with metal ions and can be used for their determination [168, 216–219]. Other metallic complexes of 1,2,4-triazine have been also reported [220–224]. 20.3.4 Synthesis

The 1,2,4-triazine ring can be synthesized by cycloaddition reactions of several different fragments – [3 þ 3], [4 þ 2], [5 þ 1] – or by cyclization of a chain containing the necessary six carbon and nitrogen atoms. However, in many cases, reaction occurs in more than one step starting from smaller fragments. Other examples, starting from different heterocycles, have also been described. A review dealing with the synthesis of 1,2,4-triazine mono-N-oxide appeared in 2002 [18]. 20.3.4.1 From Other Heterocycles There are some examples of preparation of 1,2,4-triazines by transformation of different heterocycles. For example, treatment of diaziridinone with a-metallated isocyanides yields 5-substituted 1,2-dihydro-6-hydroxy-1,2,4-triazines [225]; the reaction of 3-benzoyl-1,2,4-oxadiazoles with hydrazine furnishes the (Z)-oxime of 1,4dihydro-6-phenyl-1,2,4-triazin-5-ones [226]; cyclization of 2,6-difluorphenylpyruvic acid with 2-aryl-5,5-dimethyltriazolidinine under acidic conditions affords the 6-(2,6difluorbenzyl)-2-aryl-1,2,4-triazine-3,5-dione [227]; the reaction of arenediazonium salts with 5-methyl- and 5-ethylpyrimidine-4,6-diones yields 2,4-dihydro-6-alkyl-2aryl-1,2,4-triazin-5-ones [228]. N-Aminoimidazolidinone 126 undergoes acid-catalyzed rearrangement to yield 1,2,4-triazinone 127 (Scheme 20.36). This product is also formed by reacting the aziridinone with hydrazine followed by cyanogen bromide [229]. On the other hand, 1,4-dinitroimidazole 128 reacts with hydrazine to give the product of imidazole ring expansion 129 [230]. But But N

O N NH 2 NH 126

R H

O

t Bu NH N

N H 127

N

H

5

R

O2N

NO2 N NH2NH2 R2 N

N N

128

R2

R5 N

HN NH

N

R5 129

Scheme 20.36

The transformation of 1-benzohydrazonoyl-1,2,3-triazoles 130 into 1,2,4-triazines 131 by heating with a slight excess of sodium hydride in dry benzene has been

R2 N N

j 20 Six-Membered Heterocycles: Triazines, Tetrazines and Other Polyaza Systems

1798

described recently [231]. This process can be considered to proceed via the formation and decomposition of aryl(1,2,3-triazol-1-yl)diazomethanes I by a Bamford–Stevens reaction, followed by the ring enlargement of the resulting carbenes II as shown in Scheme 20.37 [231]. Ar R5 R6

Ar

NNHSO2Ph N

NaH

N

-PhSO2Na

N 130

R5 R6

Ar

N2 N N I

5

R

N

R6

N N II

R5 N

R6

N

Ar

N N 131

Scheme 20.37

The transformation of 1,2,3-triazolium salts 132 to yield substituted 2,3-dihydro1,2,4-triazines 134 has been achieved on treating 132 with different bases via 1,2,5triazahexa-1,3,5-trienes 133 [232–234] (Scheme 20.38). R5

R6 N

Base

X

N

N ClO4 Ar 132 X = H, TMS

R5

N

R6

N

N

Ar

R5

N

R6

N

133

N

Ar

134

Scheme 20.38

Some examples of the preparation of 1,2,4-triazines by transformation of 1,2,4,5tetrazines are considered in Section 20.5.4.2. Treatment of 1,3,5-triazine-2,4,6tricarboxylic acid triethyl ester 135 with arylhydrazines provides 5-amino-6-oxo1,6-dihydro-1,2,4-triazine-3-carboxylic acid ethyl esters 136, after intramolecular rearrangement, in moderate to good yields [235–237] (Scheme 20.39). CO2Et N EtO2C

N 135

H2N ArNHNH2

N CO2Et

EtOH, rt

O

N

CO2Et

N N Ar 136

Scheme 20.39

In 1996 Morioka reported the reaction of 137 with diethyl ether-boron trifluoride (1/1) to give 1,2,5,6-tetrahydro-1,2,3-triazine derivatives [238, 239]. Nevertheless, in 1998 X-ray crystallography analysis demonstrated the uncorrected assignment of this structure. The product obtained was established as 2,3,4,5-tetrahydro-1,2,4-triazine 138 [240] (Scheme 20.40).

20.3 1,2,4-Triazines

R N

R N

Ar

Ar1 137

NNHZ

BF3OEt2 Z = NH2CO, Ts

Ar

N

Ar1 N

Z

138

Scheme 20.40

20.3.4.2 Cycloaddition of [3 þ 3] Fragments Few examples have been reported of this method. Among them, the reaction of a-amino ketones with thiosemicarbazides affords 3-amino-4,5-dihydro-1,2,4-triazines and dihydrotriazine-3-thiones [241]; and the cyclocondensation of nitrilimines with a-amino esters gives 1,4-dihydro-1,2,4-triazin-6-ones [242]. 20.3.4.3 Cycloaddition of [4 þ 2] Fragments As for other six-membered rings, cycloadditions of [4 þ 2] fragments are the most frequently used methods to obtain 1,2,4-triazines. Several examples of combinations of [4 þ 2] atom fragments are known [243]. Of all possible [4 þ 2] fragment combinations, [N(1)N(2)C(3)N(4) þ C(5)C(6)] (A), [C(3)N(4)C(5)C(6) þ N(1)N(2)] (B), [N(4)C(5)C(6)N(1) þ N(2)C(3) (C), [C(5)C(6)N(1)N(2) þ C(3)N(4)] (D), C(6)N (1)N(2)C(3) þ N(4)C(5)] (E) and [N(2)C(3)N(4)C(5) þ C(6)N(1)] (F), many examples have been reported save for combination (F) which is unknown to date. The following examples of the more frequent combination (A) are now considered. The reaction of symmetrical 1,2-dicarbonyl compounds 139a with derivatives 140 is the method most suitable to synthesize trisubstituted 1,2,4-triazines [180, 244, 245] (Scheme 20.41). Thus, this procedure has been used to obtain the parent 1,2,4triazine and for the synthesis of compounds containing more than one 1,2,4-triazine nucleus [246]. When dione 139a is an asymmetrical compound the reaction often leads to a mixture of regioisomeric triazines. Also, reactions of semicarbazide 141a or thiosemicarbazide 141b with 139a afford the corresponding 1,2,4-triazin-3-ones 103 or 3-thiones 107 [247] (Scheme 20.41). Furthermore, the reaction of compounds 141 with monosubstituted glyoxal oxime 139b (R5 ¼ H) is a suitable method to obtain 6-substituted-1,2,4-triazin-3-ones 103 (R5 ¼ H) and 3-thiones 107 (R5 ¼ H) [248]. However, reaction of monosubstituted glyoxal 139a (R6 ¼ H) with semicarbazide (141a) affords mainly 5-substituted-1,2,4-triazin-3-ones 103 (R6 ¼ H) [248].

R5 R6

R3

N N

N

H2N

N

140 a = R, Ar b R3 = NHR c R3 = NHNH2 d R3 = SMe R3

Scheme 20.41

R3

H2N

R5 R6

Y

O 139 aY=O b Y = NOH

H2N

X NH

R5

N

141 aX=O bX=S

R6

N

H2N

X NH

103 X = O 107 X = S

j1799

j 20 Six-Membered Heterocycles: Triazines, Tetrazines and Other Polyaza Systems

1800

Substitution of 1,2-dicarbonyl compounds by acylcyanides 142 affords 5-amino1,2,4-triazines 143 and 144 [249] (Scheme 20.42). The condensation/cyclization of aminoguanidine (141c) with the acylnitrile 142 leads to Lamotrigne (124) (Scheme 20.42).

R6

R3

N

H2N

N 143

N

R3

H2N H2N

N

140

H2N

O R6 CN 142

H2N

NH

NH H2N H2N

H2N

X

N

H2N

NH

R6

141

X

N 144

NH

141c N

NH2

N N 124 R6 = 2,3-dichlorophenyl R6

Scheme 20.42

3-Amino-4,5-dihydro-1,2,4-triazine 146 can be synthesized by the reaction of a-haloketones 145c and 140b (Scheme 20.43), whilst reaction of a-hydroxy 145a, a-methoxy 145b, a-halo 145c or a-amino ketones 145d with semicarbazide (141a) affords 4,5-dihydro-1,2,4-triazin-3(2H)-ones 147 [250] (Scheme 20.43).

R

H

R

H N

NH2

H2N NH2

N N 146

H2N

N

140b

R

O

H2N

O R

Y 145 a Y = OH b Y = OMe c Y = Halo d Y = NH2

H2N

NH

141a

R

H

R

H N N 147

O NH

Scheme 20.43

Reaction of 149 with a-ketocarboxylic acids 148 is a suitable way to obtain 4-amino1,2,4-triazin-5-ones 150 [251] (Scheme 20.44). On the other hand, carbonohydrazide (151a) or thiocarbonohydrazide (151b) yields the 4-amino-3,5-diones 152a and 4amino-3-thioxo-1,2,4-triazin-5-ones 152b respectively. Cyclization of 148 with N-aryl thiosemicarbazide 141c affords the 3-thioxo-1,2,4-triazin-5-one 153 [227] (Scheme 20.44). Another literature method for obtaining 1,2,4-triazin-5-one involves the cyclization of a-ketoamide 154 with 140d to give 3-methylthio-1,2,4-triazin-5-one 155 [252]; similarly, 156 can react with 2-methylsemicarbazide (157) to afford 6-hydroxy-2methyl-3-thioxo-1,2,4-triazin-5-one (158) [196] (Scheme 20.45).

20.3 1,2,4-Triazines

NH2 N R3

O R6

N 150

R3

H2NHN

O

N

H2N

N

R6

CO2H 148 S 141c

149 ArHN H2N

NH Ar N

O R6

H2N

NH2 N X

X

H2NHN

O

NH

R6

151 aX=O bX=S

j1801

NH N 152 aX=O bX=S

S

NH N 153

Scheme 20.44

H2N

O NH2

Ar O 154

H2N

SMe N

O Ar

140d

H N N 155

H2N

O

SMe

Cl

MeO

N

O 156

H2N

S

O

H N

HO

N

N

157

A recent example of the reaction between an a-ketocarboxylic acid and derivatives 140a has been developed to obtain a ring-open isofervenulin analog 160 through triazine 159 [253] (Scheme 20.46).

O

O

EtO2C

CO2Et

H2N

N

140a

O EtO2C

H N N N 159

Cl

Cl O

NH2

N

158

Scheme 20.45

H2N

S

HN H N O

N N

N

160

Scheme 20.46

The combination [C(3)N(4)C(5)C(6) þ N(1)N(2)] – listed as (B) above – is also a much used method to prepare 1,2,4-triazines. In this method, hydrazine, its derivatives or different diazo compounds are used as starting materials. Thus, a-acylamino 161a and a-thioacylamino ketones 161b react with hydrazine to yield 4,5-dihydro-1,2,4-triazines 162, which can be oxidized to 1,2,4-triazines [254] (Scheme 20.47). Since, compounds 161 can be obtained by acylation of a-aminoketones or thioketones, this procedure can also be considered as a [3 þ 1 þ 2] combination method. Similarly, hydrazine or substituted hydrazines react with N-alkyl(N-acyl) a-aminoester [255], malonamide [256], a-imidoyl esters [177], a-isocyano esters [257], and

j 20 Six-Membered Heterocycles: Triazines, Tetrazines and Other Polyaza Systems

1802

R5

NH2

R6

O

R3

X

H N

R5

Y aX=O bX=S

R6

X

NH2NH2

R3 O 161 aX=O bX=S

R5 H

H N

R6

N 162

R3 N

oxid

R5

N

R6

N

R3 N

Scheme 20.47

N-(cyanomethyl)-imidates [258, 259] to give 1,2,4-triazin-ones, diones, thioxo and amino derivatives. Another method to introduce the [N(1)N(2)] fragment is the reaction of diazonium salts or other diazo compounds with activated methylene groups to obtain 1,2,4-triazin-3,5-dione [260]. The reaction of imidate ester 163 with substituted hydrazines is a known reaction for the preparation of 1-substituted 4,5-dihydro-1,2,4-triazin-6(1H)-one 164 [177, 261, 262]. This synthesis has also been studied in the solid phase [263] (Scheme 20.48). Another procedure for the solid-phase synthesis of functionalized 4,5-dihydro-1,2,4-triazin-6(1H)-ones 166 has been developed from thioamide 165 and hydrazine [264, 265] (Scheme 20.48).

O

N R3

H N

R1NHNH2

O OEt

O

163

N R1 164

R3 N

R5 O

HN R3

S

NH2NH2

O

R5 O

165

H N

R3

N N H 166

Scheme 20.48

Cycloaddition of 2-azabutadienes 167 with azo compounds 168 affords 1,2,3,6tetrahydro-1,2,4-triazines 169 [259, 266–268] (Scheme 20.49). N

N R 167

N N R 168

N R

N

R

169

Scheme 20.49

Frequently, five-membered heterocyclic systems have provided the [C(3)N(4)C(5)C (6] fragment used in this method, as mentioned in Section 20.3.4.1. The combination [N(4)C(5)C(6)N(1) þ N(2)C(3) – listed as (C) above – has been used in the synthesis of 1,2,4-benzotriazines but for monocyclic 1,2,4-triazines there are no examples.

20.3 1,2,4-Triazines

An interesting case of the combination [C(5)C(6)N(1)N(2) þ C(3)N(4)] – listed as (D) above – has appeared in the literature in which the first solid-phase synthesis of 3-amino-1,2,4-triazin-5-ones are described. The polymer-bound isothiourea 170, which supports the C(3)N(4) fragment, reacts with a stoichiometric amount of 2,3diaza-3-pentenoic anhydride 171, the C(5)C(6)N(1)N(2) fragment, to give 3-amino1,2,4-triazin-5(4H)-ones 172 [269] (Scheme 20.50). O

S

NH2 Cl N

R 170

Ar

O N

N H 171

O O

Ar

H N

N S

N NH2

R

O Ar

H N

H N

R

N

N 172

Scheme 20.50

Another reported combination (D) involves the reaction of aryl bromomethyl ketone phenylsulfonylhydrazones with benzylideneaniline to give 6-aryl-3,4-diphenyl-2-phenylsulfonyl-2,3,4,5-tetrahydro1,2,4-triazine [270]. 1,2,4,5-Tetrazines are the main starting material to use combination (E), C(6)N(1)N (2)C(3) þ N(4)C(5), since they are reactive dienes in Diels–Alder reactions with inverse electron demand and can react with both C
C and C
N multiple bonds (Section 20.5.4.2). 20.3.4.4 Cycloaddition of [5 þ 1] Fragments Many of the methods discussed in this section can be considered as a combination of more than two fragments, since the fragment with five atoms usually is obtained previously from shorter chains. Only C(3) and N(4) atom-fragments are found in the literature for the synthesis of 1,2,4-triazine derivatives using cycloadditions of [5 þ 1] fragments. Compounds that provide the C(3) include aldehydes [271–274], isothiocyanates [275], nitriles [276], imidates [276, 277], thioimidates [276], ketones, orthoesters [278–281], carbon disulfide, phosgene, and thiophosgene [282]. Some examples are shown in Scheme 20.51. The reaction of hydrazono-2-oximinoethane 178 with pyridine-2,6-dicarboxaldehyde led to 179 [283], however, in the presence of Pb3O4 yields 4-oxide-1,2,4-triazines 180 [284] (Scheme 20.52) Compounds reported to date that provide N(4) are ammonia or its derivatives [285–289] (Scheme 20.53). 20.3.4.5 Cycloaddition of [6 þ 0] Fragments Most reactions dealing with the cyclization of a six-membered chain can also be considered as a synthesis of 1,2,4-triazines from more than one fragment since, usually, the chain is obtained from two or more fragments. Several of these cyclizations occur by photochemical or thermal processes, the latter carried out in many cases in basic or acid conditions.

j1803

j 20 Six-Membered Heterocycles: Triazines, Tetrazines and Other Polyaza Systems

1804

R5

NH2 HCO2H H N N Ph EtOH H

O

EtO

R5 O

NH Ar2CONCS H N N Ar2

Ar1

H N

N R1

N

Ar1

N O

O

H N

R4 N

R3CN R3CO2H

R4 NH2

S N

R C(OEt)3 X OEt

3

3

R

R5

NOH

R6

NNH2

R

3

R C(OEt)3

Ar2

6

R

N

N 176a

O

Cl

6

R

X=O, S

R3 H

R3

R4 N

X Cl

R3

N N 176b

R6

R4 O NH H N 2 R6 N R 2 1 R

R3

O N

O N

R5

174

N N 1 R 175

3

R3

O

N Ph N H 173 EtO

R5

R6

N R1

X N

R2

177

Scheme 20.51

R6

N

N

N N

N

R6

R6

N

N

N

N OH 178

N

179 R6 = Ar

R6

CHO

NH2

N

Pb3O4

N

N O

CHO

N N

N

R6

N O

180

Scheme 20.52

O R6

R5 R3 N

O

NH3

NH

R5

H N

R6

N N 181

R3

Scheme 20.53

Photolysis of 1,6-diazido-2,5-diphenyl-3,5-diaza-2,4-hexadiene afforded 3,6-diphenyl-1,2,4-triazine [290], photochemical cyclization of thiosemicarbazones 182 yields 3-thioxo-1,2,4-triazin-5-ones 183 [291] and photolytic cyclization of 184 gives 5-amino-1,2,4-triazine 185 [252] (Scheme 20.54). R4 HN Me O

S

h

N 2 MeOH N R 182

Scheme 20.54

O

R4 N

H2N S

N 2 R N 183

SMe N

Ar

N 184

N

h PrOH

H2N

N N N 185

SMe

20.3 1,2,4-Triazines

j1805

Basic cyclization of hydrazonomalonic diamides 186 yields 3,5-dioxo-1,2,4-triazine-6-carboxylic acids 187 while their thermal cyclization gives carboxamides 188 [292] (Scheme 20.55). H N

O

O

O

base

N 2 R N H 187

HO2C

EtO

O N H

O

O

N H N NHR2 186

O OEt

EtO2C

H N O

H N N H

20.3.4.6 Synthesis from More than Two Fragments Many of the above-mentioned examples could be considered under this section. The synthesis of 1,2,4-triazines, via the condensation of 1,2-diketones 139a with acyl hydrazides 189 and ammonium acetate under traditional thermal [293] and dry media microwave-assisted reaction conditions [294], has been reported (Scheme 20.56). The extension to hetaryl acyl hydrazides 190 and diaryl 1,2-diketones using the microwave assisted-method on a Smith synthesizer has allowed the synthesis of a 48-membered library of 1,2,4-triazines 191 in very high yields [295].

6

R

R5

R3

O 139a O

NHNH2 189

Ar

Ar

NH4OAc, HOAc 6-24 h

O

O

O Ar

X

NHNH2 190

or

NH4OAc, SiO2, Et3N MW 5-15 minutes NH4OAc (10 eq) HOAc 180 ºC, MW 5 minutes

Ar Ar

R5

N

R6

N

N

R3 N

X

N

188

Scheme 20.55

O

O

Ar

N

N 191

Scheme 20.56

20.3.5 Reactivity

The most reactive position of the 1,2,4-triazine ring is position 5. This position is easily attacked by nucleophilic agents and many times this attack is followed by an electrophilic attack at positions 4 or 2. Most 1,2,4-triazines are less stable toward bases than toward acids. The reactivity of 1,2,4-triazine mono N-oxides was reviewed in 2002 by Chupakhin et al. [18]. 20.3.5.1 Thermal and Photochemical Reactions Since most 1,2,4-triazines are thermally very stable, only a few examples of thermal reactions have been described [296–300].

R2

j 20 Six-Membered Heterocycles: Triazines, Tetrazines and Other Polyaza Systems

1806

Photochemical hydration of the C(6)
N(1) bond of 1,2,4-triazines has been described for 1,2,4-triazine-3,5-dione and 5-amino-1,2,4-triazin-3-ones to yield 6-hydroxy-1,2,4-triazine-3,5-dione and 5-amino-6-hydroxy-1,2,4-triazin-3-ones, respectively [301]. Chemical and photochemical induced reduction of some dihydro-1,2,4-triazines and aromatic 1,2,4-triazines have been described [302–305]. The [2 þ 2] cycloaddition reactions of 1,2,4-triazine-3,5-diones 192 with alkenes 193 involve a photochemical addition of the alkene to the C(6)–N(1) double bond of 1,2,4-triazines to give azeto[2,1-f ][1,2,4]triazinediones 194 [306–308] (Scheme 20.57).

R4 N

O R6

N 192

R

O N

R2

R'

X

O

h

R6

R''

R R'

193

R4 N N

O N

R2

X R'' 194

Scheme 20.57

20.3.5.2 Reactions with Electrophilic Reagents The salts of simple 1,2,4-triazines are obtained by addition of dry acids to a solution of the triazine in organic solvents. Addition of concentrated hydrochloric acid to a solution of 5,6-diphenyl-1,2,4-triazine in sulfuric acid leads to the precipitation of the crystalline hydrochloride [309]. Alkylation and acylation of 1,2,4-triazine systems have been extensively studied. Alkylation of 1,2,4-triazines with methyl iodide gives mainly 1-methyl-1,2,4-triazinium iodides 195a and in few cases the colorless 2-methyl isomers 195b. The formation of 195a or 195b depends on the substituents on the triazine ring [175, 176, 310–312]. Alkylation and acylation of 1,2,4-triazin-3-ones 103 yield 2-alkyl(acyl)-1,2,4triazin-3-ones 196 [173, 313, 314] (Scheme 20.58). R5

N

R6

N

R3 N

IMe

R5 R6

N N N I Me 195a

R3

R5 R6

N

R3

N Me I 195b N

R5

N

R6

N 103

N

O

R5

N

H RX

R6

N

O N

R

196

Scheme 20.58

When 1,2,4-triazin-5-ones are methylated with diazomethane, 2-methyl-, 4-methyland 5-methoxy- derivatives are obtained in different ratios depending on the solvent used [311, 312]. Alkylation of 1,2,4-triazine-3,5-diones with methyl iodide affords the N(2)-methyl derivative while dimethyl sulfate or diazomethane yield first the N(4)-methyl derivative. In all cases, the 2,4-dimethyl derivative is obtained on further alkylation [315]. Acylation of 1,2,4-triazine-3,5-diones yields mainly 2-acyl derivatives.

20.3 1,2,4-Triazines

The results of alkylation of 3-amino-1,2,4-triazines depend on the alkylating agent and the nature of the 5- and 6-substituents. Reaction of 3-amino-5,6-diphenyl-1,2,4-triazines with ethyl iodide [316] or halo-acetic acid [317] yields 2-alkyl-3imino-5,6-diphenyltriazine. However, alkylation with dimethyl sulfate affords 3-amino-1-methyl-1,2,4-triazinium salts and other authors have reported the isolation of a mixture of 1-methyl and 4-methyl-3-amino-1,2,4-triazinium salts on treating 3-amino-1,2,4-triazine with methyl iodide [318]. Direct halogenation of the parent 1,2,4-triazine (2) has not been reported, and any electron-donating substituents present will not necessarily counteract the inherent resistance of the ring to electrophilic substitution [319, 320]. An oxo substituent at the 5-position is sufficiently activating to permit the 6-bromination of some 1,2,4-triazin5-ones and -3,5-diones [183]. Although the presence of an N-oxide function proved insufficient to allow chlorination and bromination, both the 3-amino- and 3-methoxy1,2,4-triazine 1- or 2-oxides gives 6-halogeno derivatives [321–323]. 20.3.5.3 Reactions with Nucleophilic Reagents Nucleophilic attack on the carbon atoms of the 1,2,4-triazine ring is well known [324]. 1,2,4-Triazines and some of its 3-methoxy, 3-methylthio or 3-aminoderivatives 197 react with potassium cyanide to give two products, the 1,2,4-triazine-5-carboxamide 198 and the bis-1,2,4-triazin-5-yl derivatives 199 [325, 326] (Scheme 20.59).

R3

N R6

O KCN

N

H2N

N 197

R3

N R6

N 198

N

N N R3

R6 R6 N

N 199

N N R3

Scheme 20.59

Guillaumet has studied the control of relative positions 3, 5 and 6 of the 1,2,4triazine ring with Grignard reagents. Indeed, the most active position is C5 and the least active is C3 [327]. As expected, the addition of aryllithium to 3-thiomethyl-1,2,4triazine 200 led to 5-substituted compounds and a further oxidation step gave 5-aryl1,2,4-triazine 201 [327] (Scheme 20.60). However, when palladium-catalyzed the reaction of 200 with different organoboron compounds in the presence of copper(I) 3-methylsalicilate affords the corresponding 3-substituted 1,2,4-triazines 202 in good yields [328]. Addition of arylmagnesium bromide to 201 occurs at the 6-position [327].

Ar

SMe

N N 201

N

Scheme 20.60

1. ArLi 2. DDQ

N N N 200

SMe

R-B(OH)2, CuMeSal Pd(PPh3)4

N N N 202

R

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j 20 Six-Membered Heterocycles: Triazines, Tetrazines and Other Polyaza Systems

1808

Most leaving groups in the 3-, 5-, or 6-positions of 1,2,4-triazines can be substituted by carbon nucleophiles prepared from aldehydes, malonates, acetonitrile, malonodinitrile, and other CH acidic compounds [329–333]. Carbanions bearing leaving groups at the carbanionic centers react with 1,2,4triazines by replacement of hydrogen atoms in the 5-, 6-, and 3-positions with the carbanionic moiety and loss of the leaving group. Carbanions of nitroalkanes, chloromethyl, phenylsulfones, chloromethane, sulfonomorpholides and acetonitriles and 4-pentenyl iodide have been used in this vicarious nucleophilic substitution [334–339]. There are many examples of exchange of a heterosubstituent in the 3-, 5-, or 6position by another heterosubstituent. This class of exchange has been widely used for the preparation of 3-, 5-, or 6-alkynyloxy-, alkynylthio- and alkynylamino-1,2,4triazines [340–344]. 1,2,4-triazin-5-ones react with electron-rich heterocycles in acetic anhydride to yield 6-aryl-1,2,4-triazin-5-ones [345]. An easy access to 3- or 5-heteroarylamino-1,2,4-triazines by selective nucleophilic substitution of 1,2,4-triazines has been reported recently. In reactions of 3-amino1,2,4-triazine (203) with different halo-heterocycles using palladium acetate as catalyst and xantphos as ligand, an SNAr process takes place and 3-heteroarylamino-1,2,4-triazines 204 are obtained [346, 347]. In contrast, the use of bases such as 2,20 ,6,60 -tetramethylpiperidine/tBuOK/nBuLi (KTMP) in the reaction of 3-methylthio-1,2,3-triazines (200) and aminoheterocycles leads regioselectively to 5-substituted 1,2,4-triazines 205 via SNH substitution [347] (Scheme 20.61). NH2

N

Het X X = Cl, Br

N

N 203 N

SMe

N N 200

Het

NH2

THF

Het

N

K2CO3/dioxane

KTMP

H N

N

Pd(OAc)2/xantphos

Het

H N

N 204 N N 205

SMe N

Scheme 20.61

1,2,4-Triazine is converted in high yield into 5-amino-1,2,4-triazine on treatment with liquid ammonia and potassium permanganate [348]. Similar reactions have been reported for 3- and 6-substituted 1,2,4-triazine. The substitution of chlorine by amino groups using potassium amide in liquid ammonia has been studied by Rykowski and Van der Plas [349–351]. In the reactions of 5-unsubstituted-1,2,4-triazines 206, with a good leaving group at C3, and a-chlorocarbanions 207, ring contraction into a pyrazole 208 is preferred to vicarious nucleophilic substitution at C5 and displacement of the C3 substituent [352] (Scheme 20.62). In contrast, the reaction of 206a with a carbon nucleophiles bearing a cyano substituent yields the corresponding 3-aminopyridazines 210 via an

20.3 1,2,4-Triazines

N Ph

Ph

X

N N 206 a X = Cl bX=F Cl N N

O R Cl S O 207

N

R

N X

Ph

Cl O S O Ph

N N

SO2R

H2O

N

N

CO2 HCl

Ph

X

R

N

R

N

NH N 208

Ph

CN X

N

R

CN 209

206a

X

N

CN R

N

Cl O S O Ph

R

N

j1809

N

NH2

H3O CO2

N N 210

Ph

Scheme 20.62

ANRORC mechanism involving addition of the nucleophiles at position 5, ring opening with cleavage of the N4
C5 bond and intramolecular ring closure of the resulting open-chain intermediate [353]. Nucleophilic attack at the 5-position of 1,2,4-triazin-4-oxides is often accompanied by ring-opening reactions [32, 354–356]. However, ammonia addition at the 5position of 6-aryl-3-pyrrolidin-1,2,4-triazine-4-oxides 211 is followed by a [1,5]sigmatropic hydrogen shift to give intermediate II followed by ring-opening with cleavage of the C3
N4 bond. In this case, this ring opening is a reversible process that allows the cyclic dihydro intermediates to be aromatized with elimination of the dialkyamino group, to give 5-amino-1,2,4-triazine-4-oxide 212 [357] (Scheme 20.63). O N Ph

N 211

N N

R HNR2

OH R H N N N Ph

N I

N

R

R N

Ph

OH H N N N II

N

R

R N

Ph

OH N N N III

N

Scheme 20.63

Nevertheless, reaction of 6-aryl-3-dimethylamino-1,2,4-triazine-4-oxide with the cyanide anion causes a similar [1,5]sigmatropic hydrogen shift-ring-opening, followed by recyclization into 3-amino-4-nitrosopyrazoles (according to the ANRORC mechanism) [358]. Reaction of hydroxylamine at the 3-position of 6-aryl-5-amino-1,2,4-triazine-4oxide leads to 6-aryl-5-hydroxylamino-1,2,4-triazines [359]. Cyanation of 3,6-disubstituted-1,2,4-triazine-4-oxide has been achieved with acetone cyanhidrine in the presence of triethylamine to afford 3,6-disubstituted-5-cyano-1,2,4-triazine [284]. 1,2,4-Triazine 4-oxides can be hydrolyzed by bases, affording 2-acylhydrazono oximes. [354] In this case, initial attack occurs at the 3-position. 20.3.5.4 Cycloaddition Reactions Diels–Alder reaction with inverse-electron demand is the most extensively studied reaction of 1,2,4-triazines. Triazines behave as reactive electron-deficient dienes and

R

R N

Ph

O N N 212

N

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so are able to react with dienophiles such as electron-rich alkenes and acetylenes among others. Some reviews on inter- and intramolecular Diels–Alder reactions have appeared [30, 120, 360, 361]. 1,2,4-Triazines participate as electron-poor dienes in inverse type Diels–Alder reactions with electron-rich dienophiles such as dienes [120, 244], enamines [362– 372] or methoxyethylene [373] to yield pyridine derivatives 213 (Scheme 20.64). Cycloaddition of 1,2,4-triazines with ynamines to yield pyrimidines 214 [374–376] has also been studied. It has been demonstrated that this type of reaction is a [4 þ 2] cycloaddition to N2 and C5 and not a [2 þ 2] cycloaddition to the N(4)-C(5) bond [377]. If the 5-position is substituted, dienophile attack occurs at the 3-position [375, 377, 378]. A tethered imine-enamine methodology has been developed for the direct conversion of 1,2,4-triazines into highly substituted pyridines [379].

R6 R5

N2 N 213

R3

X

R5

N

R6

N

R3

R6

NR2

N

R5

RCN

N R3

N 214

XH N2 Scheme 20.64

Several examples of a new and simple “LEGO” system to obtain 2,6-oligopyridines 216 [244, 246, 283, 284, 380–385] from 1,2,4-triazines have been described (Scheme 20.65). R6

N

R5

N

N

N N

N R5

N N R6 215

N

R6

R6

N

R5

R5

R6 N

N

N

R5

N R5

R6 216

Scheme 20.65

Ethynyltributyltin cycloadds to 3,5-disubstituted-1,2,4-triazine to furnish mainly 2,4-disubstituted-4-tributylstannylpyridine [386, 387]. A Diels–Alder reaction has been employed to obtain 4,5-dihydroazocines from 3-(ethoxycarbonyl)-5-phenyl1,2,4-triazines, cyclobutanone and secondary amines [388]. In addition, the intermolecular Diels–Alder reaction has been studied and used to obtain condensed pyrimidines, pyridines [339, 370, 389, 390] and b-carbolines [391], tetrahydro-1,5-naphthyridines and related heterocycles [392].

20.3 1,2,4-Triazines

j1811

Reaction of the unsubstituted 1,2,4-triazine 1-oxides 217 with benzyne gives the 1,3-benzoxazepidines 218 via 1,3-dipolar cycloadducts [393] (Scheme 20.66). R5

N

R5

R3

N N O 217

N N2

R3

O 218

Scheme 20.66

20.3.5.5 Reactions with Reducing Reagents Treatment of 1,2,4-triazines and their 3-oxo derivatives with reducing agents such as Raney nickel, sodium borohydride, titanium(III) chloride, hydrogen and palladium catalyst, or electrochemical reduction affords dihydro and further tetrahydro-1,2,4tetrazine derivatives [290, 310, 394, 395]. In the case of oxo derivatives reduction occurs in the triazine ring, affording dihydrotriazinones that can further yield tetrahydotriazinones or imidazoles [395, 396]. 1-Methyl-3,5,6-triphenyl-1,2,4-triazinium iodide reacts with zinc in acetic acid to yield 2,4,5-triphenylimidazole and methylamine, probably through 1,2-dihydrotriazine [310]. Deoxygenative versus vicarious nucleophilic substitution of hydrogen in reactions of 1,2,4-triazine-4-oxide with a-halocarbanions has been described [397]. 20.3.5.6 Reactions with Oxidizing Reagents Oxidation of 1,2,4-triazines can follow different ways, yielding several derivatives. Thus, oxidation at nitrogens of the heterocyclic ring affords mainly 1- or 2-N-oxide derivatives, whereas oxidation at the triazine ring occurs first at the 5-position and then at 6-position, affording 5-oxo or 5,6-dioxo derivatives. Dihydro-1,2,4-triazines can be oxidized to the corresponding aromatic derivatives; p-benzoquinone is one of the best reagents for this purpose. 20.3.5.7 Relevant Examples A metallation and intramolecular inverse Diels–Alder strategy may open up a short pathway for the synthesis of various fluorenones; in this way, 1,2,4-triazine 219 (Scheme 20.67) reacts with LiTMP, followed by addition of several 2-bromobenzalSiMe3 R5 R6

N

5

R

1. LiTMP

N 2. R N 219 R

R6 CHO Br

Scheme 20.67

OH

Br

N N

N

220

R R

R6

O

R5

N

R6

N 221

R5 N

R R

R R

N O 222

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dehydes to give 220. Several transformations led to 221, which upon intramolecular Diels–Alder reactions in triisopropylbenzene and desilylation under TBAF-conditions resulted in 1-azafluorenones 222 [398]. A Diels–Alder reaction takes place when 3-(2-pyridyl)-5,6-diphenyl-1,2,4-triazine (223) reacts in a thermal liquid-phase with fullerene C60 to afford aza open-cage fullerene derivative 224, which has an eight-membered-ring orifice in the fullerene cage [399] (Scheme 20.68).

N

Ph

Py Ph Ph

Py

N N

N

C60

Ph

o-dichlorobenzene 180 ºC

223 224 Scheme 20.68

20.4 1,3,5-Triazines 20.4.1 Relevant Computational Chemistry, Physicochemical and Spectroscopic Data

1,3,5-Triazines have been studied extensively both theoretically and experimentally. The 1,3,5-triazine ring is known as an important conjugated heterocycle whose electronic properties are expected to show subtle differences from those of benzene due to the alternate replacement of CH groups by nitrogen atoms. The IR and Raman spectra of 1,3,5-triazine have been determined [400–407]. Likewise, different approaches for the calculation of a force field for this molecule  have been accomplished [407–412]. The analysis gave: C
N bond length ¼ 1.338 A,  C
H ¼ 1.106 A, CNC bond angle ¼ 113.9 , NCN ¼ 126.1 , HCN ¼ 116.9 . The geometries of 3 and its protonated form have been fully optimized at STO-3G, 3-21G levels [413]. Ab initio calculations of the electronic spectra of 1,3,5-triazine have been determined via the complete active space method (CASSCF). This method describes the major features in the electronic structure of the excited state of 3 [414]. More recently, the molecular structure of 1,3,5-triazine (12 C3 14 N3 H3 ) and its isotopomers (12 C3 15 N3 H3 , 13 C3 14 N3 H3 , 13 C3 15 N3 H3 and 12 C3 14 N3 D3 ) in gas, solution and crystal phases and by ab initio calculations (6-31G , 6-311G ) has been studied. By combining gas- and solution-phase data in a single analysis a very precise structure has been obtained, with final parameters values (ra ) of r(C
N) 133.68(1) pm,

20.4 1,3,5-Triazines

r(C
H) 108.9(2) pm, and 600  C) and photochemical conditions. X-Ray crystallographic studies have been used to obtain the molecular dimensions  of 1,3,5-triazines. The C
N bond length has been reported as 1.319 A with CNC and NCN bond angles of 113.2 and 126.8 , respectively. The presence of substituents has little effect on the bond lengths or bond angles [434].  Cyanuric acid (4) has C
N, C
O and N
H bond lengths of 1.37, 1.22 and 0.9 A respectively. The CNC and NCN bond angles have been reported to be, respectively, 124.6 and 115.4 . An X-ray analysis confirms the predominance of the triketo form.  The molecule is hydrogen bonded and the bond lengths are 2.77–2.80 A [435]. 2,4,6Trihydrazino-1,3,5-triazine molecules are hydrogen bonded; the shortest hydrogen  bond is particularly close, 2.83 A [436]. An X-ray crystal structure determination of 2,4-diphenyl-6-(2-hydroxyphenyl-4methoxyphenyl)-1,3,5-triazine has been carried, out together with absorption and emission spectra and 1 H and 13 C NMR studies, as this compound can be employed to inhibit the photodegradation of polymers. These studies have established the intramolecular hydrogen bond in this type of 1,3,5-triazines for the solid state [437]. The reader is referred to the Cambridge Structural Database for further structure determinations of 1,3,5-triazines. The 1 H NMR spectra of 1,3,5-triazines are quite simple, as expected [438–444]. The chemical shifts of the ring protons are 1 to 2 ppm downfield from benzene protons, due to the effect of the ring nitrogens. The presence of electron-releasing substituents

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leads to slight upfield shifts. The parent compound 3 shows one signal in the 1 H NMR spectrum at 9.25 ppm [438]. 1 H NMR of dihydrotriazines has been used to examine the position of the NH protons [445]. Structural determination and a study of the dynamic behavior of 2-chloro-4,6-bis(pyrazolylamino)-1,3,5-triazines have been carried out by means of 1 H and 13 C NMR dynamic studies [446]. The 13 C chemical shifts of ring carbon atoms of some 1,3,5-triazine derivatives are gathered in Table 20.3. The 13 C NMR spectrum of 3 shows a peak at 166.1 ppm. The introduction of a methyl group at position 2 results in a deshielding of 10 ppm. The 13 C NMR spectrum of cyanuric acid (4) shows only one signal whilst the spectrum of 230 shows two broad signals at 165.32 ppm and 157.19 ppm with a sharp peak at 160.09. This indicates a keto-enol tautomeric exchange process [442]. The room temperature proton decoupled spectrum of 227 displays three distinct signals for the triazine ring, indicating non-equivalence of C(2) and C(4) due to the hindered rotation of the C (6)–NHEt bond at room temperature [447]. The 15 N NMR spectrum of the parent compound 3 shows a unique signal at 98.5 ppm (relative to nitromethane) [454, 455], which reflects the high p-electron density at the nitrogens. This chemical shift ranges from 95.3 to 106.1 ppm, depending on the solvent used [456]. Table 20.4 shows 15 N chemical shifts of some 1,3,5-triazine derivatives. 13

Table 20.3

N R6

C NMR data of 1,3,5-triazines (CDCl3).

R4

O

4

4

6

N

HN

N 2

R2

A

Me2N

6

N

O R5 N

4 6

2

NMe2

X

B

Compound A A A A A A A A B C C D D

N

R2 ¼ R4 ¼ R6 ¼ H (3 [446]) R2 ¼ R4 ¼ R6 ¼ OH (4 [442]) R2 ¼ R4 ¼ R6 ¼ Cl (6 [442]) R2 ¼ Me, R4 ¼ R6 ¼ H (225 [446]) R2 ¼ Ph, R4 ¼ R6 ¼ H (226 [446]) R2 ¼ R4 ¼ Cl, R6 ¼ NHEt (227 [447]) R2 ¼ R4 ¼ CF3, R6 ¼ CCl3 (228 [448]) R2 ¼ R4 ¼ CF3, R6 ¼ NH2 (229 [449]) (230 [440]) R1 ¼ Me, R3 ¼ R5 ¼ H, X ¼ O (231 [450]) R1 ¼ Ph, R3 ¼ R5 ¼ H, X ¼ S (232 [451]) R1 ¼ tBu, R3 ¼ R5 ¼ Me, (233 [452]) R1 ¼ R3 ¼ R5 ¼ iPr, (234 [453])

N R1 C

N

R3 R5

2

6

X

N N R1

4

R3 N 2

D

C2 (d, ppm)

C4 (d, ppm)

C6 (d, ppm)

166.1 149.8 172.5 176.7 171.2 169.2 161.6 166.6 160.1 149.0 177.8 70.2 74.7

166.1 149.8 172.5 165.8 166.3 170.8 161.6 166.6 157.2 148.3 143.0 77.8 74.7

166.1 149.8 172.5 165.8 166.3 165.4 164.0 168.9 165.3 149.0 177.8 70.2 74.7

20.4 1,3,5-Triazines Table 20.4

15

N NMR data for 1,3,5-triazinesa).

Ab) A A A A A A

Compound

N(1) N(2) N(3) (d, ppm)

R2 ¼ R4 ¼ R6 ¼ H (3 [455]) R2 ¼ R4 ¼ R6 ¼ Cl (6 [457]) R2 ¼ R4 ¼ R6 ¼ F (235 [457]) R2 ¼ R4 ¼ R6 ¼ 1-pirazolyl (236 [458]) R2 ¼ R4 ¼ R6 ¼ 1-imidazolyl (237 [458]) R2 ¼ R4 ¼ R6 ¼ 1-triazolyl (238 [458]) R2 ¼ R4 ¼ R6 ¼ 1-benzaimidazolyl (239 [458])

98.5c) 110.6c) 168.8c) 173.9d) 158.2d) 160.3d) 157.0d)

a) Referenced to NO2CH3. b) See Table 20.3 for structure. c) CDCl3 as solvent. d) CF3CO2H as solvent.

15

N NMR spectroscopy has been used to study internal rotation and structural information in the solid state of 2,4,6-tris(amino)-1,3,5-triazines [459], thione-thiol tautomerization in the solid state and acetone solution of 6-[(4-vinylbenzyl)propylamino]-1,3,5-triazine-2,4-dithione (VBATDT) [460] and 15 N–1 H couplings in natural abundance in the nematic phase [461]. Some 35 Cl NMR [462] and 19 F NMR [463] studies in halogen derivatives of 1,3,5-triazine have been carried out. Mass spectra of 1,3,5-triazine (3) show the molecular ion (m/z 81) as base peak. The major fragments (m/z 54 and 27) are formed by the stepwise loss of two molecules of hydrogen cyanide. Aryl-1,3,5-triazines show molecular ions with base peaks of the aryl cyanide ions [464, 465]. The spectra of cyanuric chloride (6) and other chloro1,3,5-triazines are characterized by either loss of a chlorine atom or ring cleavage with elimination of cyanogen chloride [466]. The UV spectrum of 1,3,5-triazines has been reported in a review [37]. The UV absorption of the parent 3 shows two bands, at 272 and 222 nm, assigned as n-p and p–p transitions, respectively. The UV spectra of 1,3,5-triazine derivatives that contain p-electron donors have also been studied [467]. The presence of substituents that can conjugate with the triazine ring results in the expected bathochromic shift and the band may be very intense [468]. 20.4.2 Tautomerism

The tautomerism of 1,3,5-triazines has been reviewed [469]. 1 H NMR, IR, UV, and X-ray studies have shown that cyanuric acid exists in the trioxo form. Although the cyanurates 5 and isocyanurates 7 are the two major derivatives, compounds with both types of functional groups present in the same molecule are possible (Scheme 20.69). In general, triazine derivatives bearing oxygen or sulfur atoms at 2-, 4-, and/or 6-positions exist in the oxo/thioxo instead of the OH/SH form. In contrast melamine (8) exists mainly in the triamino form.

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OR

OR N

N

N N

RO

N N O R 240

RO

OR

OR R

5

N

O R

N N O R 241

O

N

O

N N R 7

R O

Scheme 20.69

The hydroxy tautomer of 2,4,-diamino-6-hydroxy-1,3,5-triazine predominates in the gas phase. Ab initio calculations found the hydroxyl tautomer to be 4.82 kcal mol
1 lower in energy than the carbonyl one [470]. Prototropic tautomerism of dihydro-1,3,5-triazines has been studied by means of 1 H NMR, UV, and IR techniques [445]. The existence of the two possible tautomers, 1,2-dihydro (242a) and 1,4-dihydro (242b) (Scheme 20.70), in an equilibrium mixture of both tautomers, with a ratio of 2 : 1 in favor of the 1,2-dihydro form, has been confirmed by 1 H NMR spectroscopy. R4

R4 N R6

N

N 6

R2

N H 242a

N

N R2 H 242b

R

Scheme 20.70

20.4.3 Relevant Natural and Useful Compounds

One of the most important applications of 1,3,5-triazines is in the agricultural field as fungicides, insecticides and herbicides. Some representative examples include Anilazine (243) as fungicide, Menazon (244) [471]and N-oxydihydrotriazines (245) [472] as insecticides and Simazine (246), Atrazine (247), Hexacinone (248), Chlorsulfuron (249a), Metsulfuron (249b) [473], Dipropetryn, Prometon, Prometryn, Propazine, Simetryn, Thifensulfuron-methy, Trietazine and Cyanazine as herbicides. Cl S HN N Cl

N

N N 243

H2N

Cl

N N 244

S OCH3 P OCH3

R3 R

NH2

N N H

Cl N

N N 246

N H

N H

O

247

N H

R2

N

N N H

N

R

O H

N N

N N

N H

R1

245

N N

Cl

O

O

N

N

R

N N

248

O S N H O

OMe

249a R = Cl 249b R = CO2Me

20.4 1,3,5-Triazines

j1817

1,3,5-Triazines are also important as pharmaceuticals [474–477] and are claimed as antibacterial (5-Azacytidine, Sulfasymazine), antimalarial (Cycloguanil), antiprotozoal (Melarsoprol), antispasmodic (Hydramitrazine), antitrypanosomal (Antiprotozoal), antiulcerative agents (Irsogladine), antineoplastic (Triethylenemelamine; Altretamine) and to possess diuretic properties (Amanozine, Chlorazanil). 5-Azacytidine (250a) exhibits cancerostatic, bacteriostatic and mutagenic properties. It is incorporated into both RNA and DNA, and it disrupts protein synthesis, probably through its incorporation into RNA [478]. It has proved particularly effective against myelogeneous leukemia [479, 480] but the full clinical use of the drug has been limited by its facile hydrolysis. The dihydro derivative 250b is more stable and shows potential as an antitumor drug [481]. NH2 N

NH2

N

Cl HN

N

O

O

HO

NH N

HO OH OH 250a

OH OH 250b

Almitrine (251), which is useful in respiratory problems, served as the lead compound to develop triazine derivatives as potent modulators of multidrug resistance in cancer therapy [482]. On the other hand, Melarsoprol (252) (Mel B, Arsobal, Aventis), another derivative of melamine, is one of the drugs licensed for the treatment of sleeping sickness [483]. An extensive range of 1-aryl substituted 2,4-diamino-1,6dihydro-6,6-dimethyl-1,3,5-triazines have shown potent antimalarial activity, such as Cycloguanil (253) [484]. Triazinetriones are an important class of molecules with pharmaceutical [485–487] and agricultural utility [488–490]. An example of such biologically interesting derivatives is toltrazuril (254). Compound 255 (TPT) is a new and mild esterification agent for the preparation of penicillin and cephalosporin ester [491]. This esterification procedure has been successfully applied to the industrial production of diphenylmethyl 6b-(4-toluamido)penicillate, an important intermediate for the production of Shionogi b-lactam antibiotics Lactamoxef, Flomoxef and Ceftibuten. The use of 255 is safer and more economical on a large scale with a better product yield than other known esterification procedures. 1,3,5-Triazine-2,4-dithione derivative 256 (VBATDT) is an important dental material [460].

S As

NH N N H

N N

F

N

S

Cl

HN

N

N

N N

H2N

251 H2N

N 252

F

OH

NH2

N N

253

NH2

j 20 Six-Membered Heterocycles: Triazines, Tetrazines and Other Polyaza Systems

1818

O N O

NH N

O

N N N

O

254

SCF3

N 3 Cl

N

N N

255 (TPT)

N S

NH

N S H 256 VBATDT

1,3,5-triazine derivatives are important reagents for the synthesis of peptides [492–495]. High-loading resins functionalized with 1,3,5-triazine dendrimers can be used as scavenger resins for combinatorial chemistry [496, 497]. 1,3,5-Triazines have been used to form new classes of star-shaped discotic liquid crystals (LC) for potential nonlinear optical applications [498–502]. Substituted 1,3,5-triazines have been used as chiral solvating agents for chiral discrimination [503–506]. For the separation of ( þ ) and (
) isomers of amino acids by HPLC, bis[carbamoyl](alkyl)methylamino]-6-chloro-1,3,5-triazine derivative can be used as stationary phase [507]. Transition metal complexes of 2,4,6-trimercapto1,3,5-triazine (TMT) can be used as precursors of nanoparticulate metal sulfides [508]. Melamines are an important class of organic compounds since they have shown a wide range of biological activities such as anti-angiogenesis [509], anti-tumor activity for breast [510, 511] and ovarian [475] cancer treatment, effective treatments for menopausal symptoms and postmenopausal osteoporosis [512, 513] and anti-metastatic activities [514]. Melamine and its polymers have application in many industrial fields. The major uses of the resins are in the formation of highpressure laminates for home furniture, as moldings for crockery and in finishing textiles, to improve crease resistance, and as coatings for wet strength paper. Polymer gels containing melamine derivatives are stable catalytic systems [515]. Melamine derivatives bearing a guanidinium ion can recognize nucleotides through hydrogen bondings [516]. Melamine derivatives bearing thiourea and thiouronium ions have been prepared as flavin receptors [517]. Trichloromelamine is a useful reagent for the selective oxidation of alcohols to the corresponding carbonyl compounds [518]. Cyanuric chloride (6) is the precursor of many fiber-reactive dyes [519, 520]. The fiber-reactive dyes are prepared by nucleophilic displacement of one or two chlorines with a dye or dyes, then the product is bound on to the textile by displacement of the third chlorine with the hydroxyl group in cellulose fiber or with amino functions in polyamide, silk and wool. Cibacron blue 3GA (257) and Procion scarlet MXG (258) are typical examples of reactive dyes.

20.4 1,3,5-Triazines

SO3 NH N Cl

O3S

N N

N H 257

SO3

Cl

NH2 N

O

N H

Cl O

OH

O3S

OMe

N N

N H

SO3 258

Cyanuric chloride has been loaded on different types of NH2-functionalized resins [521, 522]. This reagent has been used for the solution-phase synthesis of different amides [521, 522] and dipeptides [522, 523]. Cyanuric chloride is used as a coupling reagent in the formation of macrocyclic lactones [524] and b-lactams [525, 526]. In addition, it has been employed as condensing agent in several reactions to utilize mild conditions such as Beckmann transformation of ketoxime into amides and aldoximes into nitriles [527]; the transformation of carboxylic acids to alcohols [528], to Weinreb amides [529] or to diazoketones [530]; the oxidation of alcohols to carbonyl compounds [531, 532]; the selective conversion of primary alcohols into the corresponding esters [533]; and the preparation of sulfonyl chlorides from sulfonic acids [534] or to prepare pyrazoles from ketones [535]. 2,4-Dichloro-6-methoxy-1,3,5-triazines have been used to prepare affinity chromatography adsorbents; these compounds are valuable for the purification of enzymes [536]. 2-Chloro-4,6-dimethoxy-1,3,5-triazine has been used as reagent for the synthesis of aldehydes [537], esters [538], amides [539, 540] or oxazolines [541] from carboxylic acids; as coupling agents for cephalosporin derivatives [542]; and to separate an enantiomeric mixture of amides or dipeptides [543]. 4-(4,5-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride has been employed as condensing agent for the preparation of amides or esters by coupling between carboxylic acids and amines [544–546] or alcohols [547]. Triallyl cyanurate is used as a minor comonomer with a range of monomers and performed polymers, imparting heat resistance, solvent resistance, adhesion and strength to the polymers. It is particularly valuable for the preparation of high temperature electrical insulation components. It is also used in curing fluoro polymers such as Vinton. Triallyl isocyanurates may be used similarly. 1,3,5Trichloroisocyanurate is used as a disinfectant of swimming pools. Substituted perhydro-1,3,5-triazines have shown utility as corrosion inhibitors [548], biocides [549], crosslinking agents for the manufacture of polyurethanes [550, 551], stabilizers for natural rubber latex foam and scavengers for the removal of sulfide gases from petroleum fuels. 20.4.4 Synthesis

This section is divided according to the nature of the compounds to be synthesized and not to the class of reactions used.

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j 20 Six-Membered Heterocycles: Triazines, Tetrazines and Other Polyaza Systems

1820

20.4.4.1 Synthesis of 1,3,5-Triazines and Mono-, Di- and Tri- 2-, 4-, 6-Substituted Derivatives The best method to obtain the parent compound 1,3,5-triazine (3) is the reaction of ammonium acetate and triethyl orthoformate described by Maier and Bredereck in 1979 [552] (Scheme 20.71). Various imino derivatives 259 have been used in the synthesis of 1,3,5-triazine (3) via a cyclotrimerization reaction.

HC(OEt3)

N

AcONH4

NH

N

3

N 3

X 259

X = OEt, Cl, NH2, SH, OCH2Ph

Scheme 20.71

Melamine (8) is synthesized from cyanimide on heating above its melting point or by fusing dicyanamide [553] (Scheme 20.72). Substituted cyanamides 260 react to afford either the expected 1,3,5-triazine derivative 261 [554, 555] or their imino isomers 262 [554]. On the other hand, nucleophilic displacement of chlorine atoms of cyanuric chloride is the most useful method to obtain symmetrical 2,4,6-trisubstituded-1,3,5-triazines. Thus treatment of 6 with different amines [556–558] or arylamine 263 [558–561] affords 2,4,6-trisubstituded-1,3,5-triazines 261. NH2 N

3 NH2CN

H2N

NH R HN

N

N N R 262

R NH

N N 8

RNHCN 260

3/2 H2N

NH2

NH NHCN

NHR N RHN

Cl NH2R(263)

N N 261

NHR

Cl

N

N N 6

Cl

Scheme 20.72

Trimerization of cyanogen chloride in the gas phase on activated charcoal is probably the most useful industrial route to obtain cyanuric chloride (6) [562]. Trimerization of isocyanates, isothiocyanates and carbodiimides lead to isocyanurates (7), isothiocyanurates and ¼NR derivatives of compound 262, respectively [563]. Cyanuric acid (4), cyanurates (5) and thiocyanuric acid can be synthesized by treatment of cyanuric chloride (6) with acetic acid, alcohols in basic medium or sodium sulfide, respectively. The reaction of cyanuric chloride with hydroxyaryl(alkyl) compounds affords 2,4,6-triaryl(alkyl)oxy-1,3,5-triazines (5) [557, 564, 565]. Cyclotrimerization of aryl [555, 566, 567] or alkyl [555, 557] nitriles 264, thiocyanates [555] 265, ethyl cyanoformate [237] 266, trifluoroacetonitrile 267 [568], or imidates 268 [569] yields symmetrical 2,4,6-trisubstituted-1,3,5-triazines (Scheme 20.73).

20.4 1,3,5-Triazines

R 3 RCN 264 R = Aryl, Alkyl 265 R = SMe 266 R = CO2Et 267 R = CF3

N R

N N

3 R

R 268

NH OR1

Scheme 20.73

The use of solvent-free reactions is an alternative in organic synthesis to eliminate substances hazardous to human health and environment [570]. In the literature, methods of synthesis of tris(aryl)-1,3,5-triazines by cyclotrimerization of aromatic nitriles in solvent-free conditions have been described [566, 571]. Unsymmetrical 2,4,6-substituted 1,3,5-triazines are formed in different ways. The condensation of imidates or acylamidines with amidines proved an excellent route to obtain 6-substituted 2,4-dialkyl-1,3,5-triazines. 2,4,6-Substituted 1,3,5-triazines are synthesized conveniently by the reaction of acylamidines 269 with amidines 270 [572] (Scheme 20.74). R4

O R6

N

NMe2

269

R2 270

NH NH2

R4 dioxane

N R6

N N

R2

Scheme 20.74

In general, the best routes available to obtain trisubstituted 1,3,5-triazines are substitution reactions of chlorine atoms of cyanuric chloride with different nucleophiles [207, 497, 522, 556, 565, 573–583]; it is possible to substitute one, two or three selectively (Section 20.4.5.3). 2-Amino-1,3,5-triazines can be obtained by treatment of 1,3,5-triazine (3) with 1-amidinopyrazole. However, they are best prepared by reaction of triformamidomethane with formyl guanidine [38]. 2-Amino-4,6-bis(disubstituted-amino)-1,3,5triazines can be obtained in one pot from disubstituted cyanamindes and formamides [584]. 6-Substituted 2,4-diamino-1,3,5-triazines 271 have been prepared by reaction of dicyandiamide with nitriles 264 under microwave irradiation [585–587]. This method can be considered as a green procedure due to the reduction in the use of solvents during synthesis and purification (Scheme 20.75). Various aldehydes 272 reacted with iodine in ammonia/water to give the nitrile intermediates 264, which have been trapped by addition of dicyandiamide to produce 271 [588]. Aldehyde 272 also reacts with guanidine to give diaminotriazine 271 [589]; this method was employed to protect aldehydes. Diamino-1,3,5-triazines 273 have been synthesized from amidines 270, which are readily prepared from the corresponding phenylacetonitriles, and isoureas 274 [577] or from carboxylic acid ester 275 with biguanidine 276 [444, 590, 591] (Scheme 20.75).

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j 20 Six-Membered Heterocycles: Triazines, Tetrazines and Other Polyaza Systems

1822

R6CN 264 H2N

NH 6

R

272

6

H NH3/H2O

R CN

NH2

270

NC

N H

N R6

R' N

NH2 R

N

N

R6

274

N H

NH2

CN

264

PhO

NH R6

H2N

I2

O

NH CN

R6

N

N 271

NH2

272

O

N N 273

N R'

R

R6

OEt 275

NH

O

NH2

H2N

H

NH R

N R'

NH

N NH2 H 276

Scheme 20.75

There are several ways of obtaining unsymmetrical trisubstituted 1,3,5-triazines from other heterocycles, with pyrimidines being the most used starting material. Photosensitized oxygenation of 5-aryl 2,4-diaminopyrimidines 277 in protic solvents affords 4-amino-1,3,5-triazin-2-yl ketones 278 [592] (Scheme 20.76). NH2

NH HN 6

NH2

R

N

O2

N Ar 277

R6

O

NH2

N O

Ar

N NH2

R6

N

O NH2

NH2 N

Ar O

6

R

N N

COAr

278

Scheme 20.76

The reaction of chloroacetamidine and phosgene followed by treatment of POCl3 and then H2/Pd has been used to obtain 2,4-dimethyl-1,3,5-triazine [593]. Muchowski has reported a specific way to prepare 2-dimethylamino-4-trichloromethyl-1,3,5-triazine from trichloroacetonitrile and 4-dimethylamino-4-trichloromethyl-1,3-diaza-1,3-butadiene [594]. Phenyl-1,3,5-triazine [595] and triphenyl-1,3,5-triazine [596] have been obtained by irradiation or electroreduction of 5-phenyl-1,2,4-thiadiazole and 3,4-diphenyl-1,2,5thiadiazole respectively. With respect to monosubstituted 1,3,5-triazines, 2-alkyl(aryl) derivatives 279 are prepared by the reaction between 1,3,5-triazine (3) and imidates 268 [597, 598] (Scheme 20.77). Triazine has elicited considerable interest as an ideal combinatorial library scaffold due to its ease of manipulation andthe lowprice of thestarting material, resulting inthe publication of several triazine libraries [575, 578, 599–605]. All of the reported library synthesis procedures utilize the reactivity differences of the three reaction sites.

20.4 1,3,5-Triazines

N

N

R1

N 3

OR N 2 R

NH

N

N

OR2 268

N

R2OH

N N 279

HCN

j1823

R2

NH

Scheme 20.77

20.4.4.2 Synthesis of 1,3,5-Triazinones and 1,3,5-Triazinthiones Known synthesis of 4(6)-amino-1,3,5-triazin-2-ones include: cyclocondensation of N-carbamoylguanidine hydrochloride with orthoesters 281 [606] (Scheme 20.78); reactions of biguanidines 282 with diethyl azodicarboxylate [607]; reactions of cyanoguanidines with carboxylic acid [608, 609], cyclizations of N-acyl-N-cyanoguanidines [610], cyclization of isobiurets with ethyl orthoformate [610, 611], reactions of guanylureas with dimethylformamides dimethylacetal [610] and sequential displacements of two chlorine atoms followed by hydrolysis of the third chlorine in cyanuric chloride [556]. More recently, Katritzky and coworkers have described a new method to prepare 4(6)-amino-1,3,5-triazin-2-ones 286 and 289 and 2-thiones 287, consisting in the reaction of 1-acyl derivatives of 1H-benzotriazole-1-carboxamides 283 with ureas 284 or thioureas 285 in the presence of potassium tert-butoxide [612] (Scheme 20.78). NH2 O H2N

NH2 N

NHCl

6

N

2

R C(OR )3 281

R6

NH

N N H 280

O

R6

O

NH

N NH3 H 282

EtO

N

N

OEt O

R R R4 R N t-BuOK, t-BuOK, R N AMDS Ph THF, rt NH THF, rt N N N N N N N O O N X N R R Ph N X R1 N N O N O Ph R4 O H NH N 1 4 NH N 2 2 R R R R H H 283 288 289 1 284a 286 X = O R = H, Alk 287 X = S 284 X = O 285 X = S R4

Scheme 20.78

Triazapentadienium iodides react with arylisocyanates or isothiocyanates to give 1,3,5-triazinones and triazinethiones [613]. Cyclization of N-acyl-N’-carbamoyl-Smethylisothioureas affords 1,3,5-triazin-2-ones [572]. Cycloaddition reactions of 2,4-diphenyl-1,3-diazabuta-1,3-dienes 290 with aryl isocyanates 291, alkyl isocyanates 292 and isothiocyanates 293, in a sealed tube

j 20 Six-Membered Heterocycles: Triazines, Tetrazines and Other Polyaza Systems

1824

under nitrogen atmosphere without solvent, afford various 1,3,5-triazin-2-one and 2-thione derivatives 294 [614] (Scheme 20.79). Ph N Ph

R1 N 290

Ph R3 R3 N N2 N N C Ph X N X R1 291 X = O, R3 = Aryl 294 292 X = O, R3 = Alkyl 293 X = S

Scheme 20.79

Hexahydro 1,3,5-triazin-2-thione 295a can be prepared by aminomethylation of thioureas 285 with formaldehyde and aromatic/heterocyclic amines 263 [615] (Scheme 20.80). This reaction can be performed under microwave irradiation [616]. 1,3,5-Triazin-2-ones 295b can be obtained by a multi-component condensation of substituted ureas 284, aqueous formaldehyde and substituted amines 263 under microwave irradiation [616, 617] (Scheme 20.80). R5

X H2N

N H

R1

CH2O

R5NH2

NH

N X R1 295a X = S 295b X = O

263

285 X = S 284 X = O

N

Scheme 20.80

In general, hexahydro 1,3,5-triazine-2,4-dione derivatives 298 are obtained by cyclocondensation of biurets 296 with aldehyde acetals 297 in the presence of boron trifluoride etherate [618] (Scheme 20.81). The reaction of carbomethoxy O-methylisoureas with isocyanates is another general way to obtain 1,3,5-triazinediones [619].

R1

H N

R3 N O O 296

H N

R5

R6CH(OR)2 297

BF3OEt2

R5 R6

O N

N N R1 298

R3 O

Scheme 20.81

Metal complex 299 reacts with two equivalents of alkyl isocyanates 292 to yield complex 300. Reaction of 300 with triflic acid (HOTf) cleanly gives demetallated 1,3,5triazine-2,4-diones 301 [620] (Scheme 20.82)

20.4 1,3,5-Triazines O Re N

Ph

RN C O

292 299 [Re] = [Re(CO)3(bpy)] Ph

Re N Ph

O

NR

Re N

Ph

Ph

NR RNCO R N Ph

O Re

j1825

O

O

R HOTf N Ph Ph N

R

N

O

N N H 301

300

Scheme 20.82

A novel route to synthesize 1,3,5-triazin-2,4-diones consists in the desulfurization of thiocarboamides, such as 1,3-disubstituted 2-thioureas, trisubstituted thioureas and N-substituted thioamides, by silver cyanate [621]. A new synthetic method to afford 6-aryl-1,3,5-triazine-2,4-diones lies in the reaction of N-t-butylbenzamidines with diphenyl imidodicarboxylate [622]. Several papers have described the solid-phase synthesis of 6-amino-1,3,5-triazine2,4-diones. Scheme 20.83 shows two approaches to employ the resin–bound guanidine, 302 and 304. 6-Amino-1,3,5-triazine-2,4-dione 303 was synthesized utilizing chlorocarbonyl isocyanates [623] while 305 was synthesized via intramolecular cyclization of guanidine 304 with potassium ethoxide [624]. HN HN R1

R N R' O

O

O

ClCONCO THF, rt, 2h

R'

N N R

O

NH N R1

O O

R

N H

KOEt

N O

O 303

302

N H

HN

O

R3

O 304

N R

N H

N N H 305

R3 O

Scheme 20.83

1,3,5-Triazine-2,4-diones 307 have been obtained unexpectedly by intramolecular aza-Wittig reaction of 306 with aryl isocyanate 291 followed by attempted heterocyclization by use of primary amines 263 [625] (Scheme 20.84). Another unexpected reaction was found in the reduction of the methylpyridinium salt 308, which afforded the piperidine spiro 6-thioxo-1,3,5-triazin-2-one derivative 309 [626].

N

O

CO2Me 1. R3NCO 291 2. RNH2 263 N PPh3 3. HCl 306

N

N N H

N R

O

307

Et N

R3 O

N Me

S N Pr 308

O O

BH4Na

Pr

N

N

N H N Me 309

Scheme 20.84

1,3,5-Triazine-2,4,6-triones can be prepared by cyclotrimerization of isocyanates with several catalysts, such as Lewis bases [627], anions [628] and metallic

Et S

R Ph Ph

j 20 Six-Membered Heterocycles: Triazines, Tetrazines and Other Polyaza Systems

1826

compounds [629, 630]. However, the best catalysts are CsF or tetrabutylammonium fluoride (TBAF). Trimerization of aryl isocyanates 291 with CsF or TBAF as catalyst at room temperature yields triazinetrione 310 [628] (Scheme 20.85). Phenyl isocyanate trimerized in the reaction with (C5Me5)2Nb(¼O)H [631]. Zirconacyclopentanes react with p-chlorophenyl isocyanate to give the trimerization product [632]. O Ar

CsF/n-TBAF

3 ArNCO 291

rt, 20 min

O

N

Ar

N

O

N Ar 310

Scheme 20.85

The electrochemical approach of Carelli et al. is also a useful procedure to obtain 1,3,5-triazinetriones [633]. This method consists of the cyclotrimerization of aryl isocyanates in the presence of the anionic species generated in situ by electrochemical reduction of catalytic amounts of a-bromoesters in dipolar aprotic solvents. 1,3,5-Trihydroxycyanuric acid 314 (THICA) and its alkoxy derivatives can be prepared by several methods [634–637]. Butula and Takac [638] have reported an alternative synthesis of THIC in three steps using 1-benzotriazolecarboxylic acid 311 as a key compound (Scheme 20.86). Recently, a new synthetic route to THICA using benzyloxycarbamic acid phenyl ester 312, synthesized from O-benzylhydroxyamine and phenyl chloroformate, has been developed [639]. N N

N

Cl 311

Ph

O

RONH2 O

H N

N N ROHN

N O

O BnO O

OPh

312 O

DMAP 120 ºC

Ph

O N C O

N

O N

OBn

O N OBn 313

H2/Pd

HO O

N

N

OH

O N OH 314

Scheme 20.86

Symmetrical 1,3-disubstituted triazinetriones can be prepared by condensation of two molecules of isocyanates with a metal isocyanate in a dipolar aprotic solvent [640]. There are few literature reports on the synthesis of asymmetric triazinetriones with two or three different substituents. Kappe and coworkers have synthesized 1-(benzimidazol-2-yl-methyl)-3-phenyl-s-triazine-2,4,6-trione from the corresponding urea and N-ethoxycarbonyl isocyanate [641]. Biouret 296a cyclized with NaOEt in EtOH with diethyl carbonate to give 1-aryl-1,3,5-triazine-2,4,6-trione 315 [642]

20.4 1,3,5-Triazines

j1827

(Scheme 20.87). Recently, a one-pot synthesis of asymmetric 1,3,5-triazine-2,4,6triones 316 was developed by loss of an equimolar amount of isocyanate 291/292 and primary amine 263 in dichloromethane, followed by addition of N-chlorocarbonyl isocyanate [643]. H N

Ar

O

O

H N

NH2 NaOEt O

O O 296a

O OEt

EtO

HN

NH N Ar

R1NCO 291 R1 = aryl 292 R1 = alkyl

O

R2NH2 263

1. CH2Cl2

HN

2. ClCONCO O

315

N N R1 316

Scheme 20.87

An efficient parallel solid-phase synthesis of 1,3,5-trisubstituded 1,3,5-triazine2,4,6-triones 319 from chlorocarbonyl isocyanate with resin-bound urea 317 has been reported [644]. Triazinetrione 318 was cleaved from the resin using HF (Scheme 20.88).

R

H N O

O N H

N H

R3 ClCONCO

O N

O

65 ºC, 7h, Toluene

317

R

H N

O

N N H 318

R3 O

R HF O ºC

H2N

O N

O

O

N N H 319

Scheme 20.88

20.4.4.3 Synthesis of Hydro-1,3,5-Triazines Acid-catalyzed reaction between the corresponding biguanidine and carbonyl compounds is an effective route to obtain 4,6-diamino-1,2-dihydro-1,3,5-triazine [645]. This method has been used to synthesize a solution-phase combinatorial library of 1-aryl-4,6-diamino-1,2-dihydro-1,3,5-triazines 322 from a set of carbonyl compounds 321 and arylbiguanidines 320 (Scheme 20.89) [646, 647]. NH2

NH HN HN

NH2

NH Ar 320

O R

N

H R'

321

H2N

N

R N R' Ar 322

Scheme 20.89

Microwave assisted parallel synthesis of a library of 20 aryl dihydrotriazines 323 was successfully achieved from dicyandiamide, acetone and primary amines [648]

R3 O

R3 O

j 20 Six-Membered Heterocycles: Triazines, Tetrazines and Other Polyaza Systems

1828

(Scheme 20.90). This reaction can be considered as a cycloaddition of [4 þ 1 þ 1] fragments. This method decreased the reaction time from an average of 22 h to 35 min in comparison to conventional parallel synthesis. NH2 NCHN

NH2

MeCOMe

MW

RNH2

N

HN

H2N

N

N Cl H 323

R Me Me

Scheme 20.90

Wakefield and coworkers have described the formation of triphenyl dihydrotriazines by the reaction of 2,4,6-triphenyl-1,3,5-triazine with lithium reagents [649]. Lappert and coworkers have reported the facile synthesis of monosubstituted dihydrotriazines 325 from parent triazine (3) and alkyllithium reagent and subsequent protonolysis of the presumed lithio(alkyl)triazines 324 [650, 651] (Scheme 20.91). R4 N

N

LiR4

N

R4 N

N

H2O

N Li 324

N 3

N N H 325

Scheme 20.91

Reaction of aziridines 326 with cesium fluoride and HMPA, followed by treatment of intermediate 327 with water, yields triazines 328 [652] (Scheme 20.92).

RO2C

CsF, HMPA

N

rt TMS

326

N CO2R 327

H2O

RO2C

N

N

CO2R

N CO2R 328

Scheme 20.92

The reaction of aniline derivatives with 1,3,6,8-tetrazatricyclo[4.4.1.13,8]dodecane affords 1,3,5-triaryl-hexahydro-1,3,5-triazines 329 [653] (Scheme 20.93). Nitroimino-1,3,5-triazine derivatives 331 are formed via Mannich condensation of nitroguanidine 330, formaldehyde and the appropriate primary amine 263 [654, 655] (Scheme 20.94). A general way to obtain 1,3,5-triazinetriimines is the co-trimerization of amines with cyanogen bromide [656, 657].

20.4 1,3,5-Triazines

ArNH2

N

N

N

N

Ar

N

AcOH 15 min

Ar

N N Ar 329

Scheme 20.93

R1

N N H

NO2

CH2O

NH2

R5

H2O

R5NH2

rt, 80 ºC

263

N

NH N R1 331

330

N NO2

Scheme 20.94

20.4.4.4 Synthesis of N-Amino and N-Oxide 1,3,5-Triazines N-Amino-1,3,5-triazine derivatives 332 have been synthesized from ethoxycarbonylhydrazones 333 and two equivalents of aryl or methyl isocyanates followed by hydrolysis of intermediate triazine 334 [658] or by transformation of sodium salts of 1,3,4-oxadiazol-2-ones 335 with two equivalents of aryl or ethyl isocyanates and hydrolysis of intermediate 336 [659] (Scheme 20.95). O

R1

N R2 NH EtO2C

2 RNCO Et3N

R

N N N

O

333

334 O N N R1

O

Ph NH O

335

R

N

O R1 R2

O R 2 RNCO NaH

O

N

N

N HN

R O O

H H2O

H H2O

O R O

N

N

R

O N NH2 332

336 R1

Scheme 20.95

With respect to the preparation of N-oxide derivatives of 1,3,5-triazines, Shaw has described the oxidation of triazines with peracetic acid and the preparation of 2,6diamino-4-methyl-1,3,5-triazine N-oxides from potassium dicyanoacetamide and hydroxylamine [660]. Formation of triazine N-oxides by reaction of amidooxime with ethyl orthoacetate gives poor yields [661].

j1829

j 20 Six-Membered Heterocycles: Triazines, Tetrazines and Other Polyaza Systems

1830

20.4.5 Reactivity

The reactivity of 1,3,5-triazine (3) has been thoroughly reviewed [26, 39, 41, 474, 662] and the chemistry of melamine, cyanuric acid and cyanuric halides has also been reviewed [34, 35, 120, 663]. In general, many of the reactions of 1,3,5-triazines reflect the chemistry of the ring substituents. 20.4.5.1 Thermal and Photochemical Reactions The parent compound 3 decomposes to form three molecules of hydrogen cyanide on heating above 600  C. The thermal decomposition of hexahydro-1,3,5-trinitro-1,3,5triazine has been studied [664]. Thermal isomerization of cyanurates and thiocyanurates to isocyanurates and thioisocyanurates, respectively, is also known [665, 666]. A novel reversible thermal electrocyclic reaction of chiral 1,2-dihydro-1,3,5-triazines has been described [667]. Photodissociation of 1,3,5-triazine to yield hydrogen cyanide is also known [419, 421, 422]. Photolysis of 2-azido-4,6-dichloro-1,3,5-triazine, in a low temperature argon matrix, yields a cyclic carbodiimide containing four nitrogen atoms in a sevenmembered ring [668]. Consecutive photolysis of triazido-1,3,5-triazine, in a low temperature nitrogen matrix, has been studied [669, 670]. 2,2,4,6-Tetraphenyldihydro-1,3,5-triazine undergoes photochemical reactions to yield a mixture of six products, among which 2,4,5-triphenylimidazole and 2,4,6-triphenyl-1,3,5-triazine could be identified [671, 672]. The S-chlorination reaction of isothiocyanuric affords 1,3,5-triazine-2,4,6acid under UV-irradiation at
45  C trisulfenyltrichloride [673]. 20.4.5.2 Reactions with Electrophilic Reagents Chlorination and bromination of 1,3,5-triazine occur only under vigorous conditions, bromination being rather more successful. The reactions are probably not electrophilic [35, 39, 43, 320, 674]. Treatment of 1,3,5-triazine with chlorine or bromine at room temperature gives rise to perhalides [43]. Melamine has been halogenated to form products containing one to six halogens, depending on the reaction conditions [35]. Sulfonation or nitration preferentially leads to the ring hydrolysis [39]. Alkyl side chains of 1,3,5-triazine are quite readily a-halogenated by what are believed to be ionic mechanisms [675]. Some examples on the preparation of nitro derivatives of 1,3,5-triazine are found in the literature. Thus, when 1,3,5-triazine is allowed to react with dinitrogen pentoxide, at 0  C, and quenched with methanol the cis and trans isomers of 2,4,6-trimethoxy1,3,5-trinitrohexahydro-1,3,5-triazine 337 and 338 can be isolated in equimolar ratio [676] (Scheme 20.96). Alkylation of thiocyanuric has been described [565]. Phase-transfer has been employed to catalyze polycondensation of 6-dialkylamino-1,3,5-triazine-2,4-dithiols with 1,10-dibromodecane [677]. Carboxylic acids have been condensed with 1,3,5-triazine by activation of the triazine ring. Thus, chlorotriazine 339 is activated with amine, to give the salt 340 that

20.4 1,3,5-Triazines

N

N

O2N

2. MeOH

N 3

OMe

OMe

1. N2O5 CH3NO2 0 ºC

NO2

O2N

OMe N NO2 337

MeO

N

MeO

N

j1831

N

N

NO2

OMe N NO2 338

Scheme 20.96

reacts with a carboxylic acid to generate the ester 341 [522, 539, 543, 544] (Scheme 20.97).

N R6

R4

R4

R4 R

N N 339

Cl

N R''

R'

N R

N N 340

R'' R' N R Cl

N

RCOOH R

N N 341

O O

R

Scheme 20.97

N-Alkylation of 1,3-disubstituted 1,3,5-triazine-2,4,6-triones is well documented [643, 644]. Silylation of the amino groups of melamine and 2,4-diamino-6substituted-1,3,5-triazines is achieved by reaction with chlorotrimethylsilane and triethylamine in refluxing acetonitrile to give the monosilylated amino derivatives [678]. 20.4.5.3 Reactions with Nucleophilic Reagents 1,3,5-Triazines are extremely sensitive to nucleophilic substitution, particularly hydrolysis in the presence of even trace atmospheric water [35]. Nucleophilic attack at the aromatic 1,3,5-triazines results in ring cleavage in most cases. The reaction of 1,3,5-triazine 3 with a primary amine is an example of this fact [39] (Scheme 20.98). N

N RNH2 N N 3

263

N

N N H

NHR

NH2 N

RNH2 263 NHR

N

NH2 N

NHR NHR

NR NHR

NH2 N

Scheme 20.98

In the Gattermann aldehyde synthesis, 1,3,5-triazine can be used as a substitute for hydrogen cyanide [679]. On treatment of triazine (3) with aryl Grignard reagents the corresponding aryl aldehyde is obtained. Several nucleophilic substitutions of halogen derivatives of 1,3,5-triazines can be found in the literature. The more common method is displacement of chlorine atoms of cyanuric chloride with different nucleophiles. It is possible to obtain mono-, di- or tri-substituted-1,3,5-triazine by controlling the nature of the nucleophiles or the reaction temperature. Thus, 2-amino-1,3,5-triazine 342, 2,4-diamino-1,3,5-triazine

NH

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343, or 2,4,6-triamino-1,3,5-triazine 344 can be obtained by sequential addition of amines [497, 558, 577, 578, 580–582, 680, 681] (Scheme 20.99). 2,4-Diamino-1alkoxy-1,3,5-triazine [565, 578, 579], 2-amino-4-alkoxy-1,3,5-triazine [576, 577], 2-amino-4,6-dialkoxy-1,3,5-triazine [207, 544, 682], 2,4-dialkoxy-1,3,5-triazine [573, 574], and 2,4,6-triaryloxy-1,3,5-triazines [564] have also been described. Cl N Cl

Cl RNH2

N Cl

N 6

O ºC

N Cl

NHR' R'NH2

N N 342

NHR

25 ºC

N Cl

NHR' R''NH2

N N 343

NHR

80 ºC

N

N N 344

R'HN

NHR

Scheme 20.99

Reaction of cyanuric chloride with 1-benzylpyrazole under solvent-free conditions and microwave irradiation yielded, within 10 min, tris-2,4,6-(pyrazol-1-yl)-1,3,5-triazine by a quaternization–dequaternization procedure [683]. This compound has been employed as a 5-connecting building-block for infinite nets [684]. Organometallic alkylations of cyanuric acid (6) [577] or 2-chloro-4,6-dimethoxy1,3,5-triazine (345) [685] have been described to afford alkyl-1,3,5-triazines 346 (Scheme 20.100). Alkynyl-1,3,5-triazines 347 have been synthesized by reaction of cyanuric chloride 6 with Grignard reagents [583] or by Pd-catalyzed cross-coupling between alkynes and 345 [686, 687]. Cl N

RMgX

N N 6

Cl

Cl

R

Cl

N

RSnBu3

N

Y Y N Y = Cl, OMe

Pd(PPH3)2Cl2

N MeO

N N 345

OMe

346 R Cl

Cl N Cl

R

N N 6

Cl

MgX

N

N

N Y Y Y = Cl, OMe 347

R Pd/C, PPh3, CuI MeO

N

N N OMe 345

Scheme 20.100

A new synthetic route, via the Suzuki cross-coupling of resin-bound 2,4-diamine-6chlorotriazines, using various arylboronic acids and palladium catalysts has been developed to prepare a 2,4-diamine-6-aryl-1,3,5-triazine library [604]. Reaction of 2,4,6-trifluoro-1,3,5-triazine and hexafluoropropene yields perfluoro(isopropyl)-1,3,5-triazines, which react with a range of oxygen nucleophiles [688].

20.4 1,3,5-Triazines

There are other similar reactions to obtain 2,4,6-tris(perfluoroalkyl)- and perfluoroalkylether-1,3,5-triazines from 2,4,6-trihalotriazines [689]. Other substituents than halogen at 2-, 4- and 6-positions may be displaced by nucleophilic reagents. Thus, reactions of 2,4,6-tris[di(t-butoxycarbonyl)nitromethyl]1,3,5-triazine with nucleophiles have been reported [690]. Substitution of an OMe group by a hydrazino group in a methoxyribosyltriazinone has been accomplished [691]. N-Methyleneamine equivalents can be generated in situ from hexahydro-1,3,5triazines 348 (Scheme 20.101) in the presence of a Lewis acid (LA) and reacted with various nucleophiles for the synthesis of aziridine 349 [692, 693], azetidin-2-ones 350 [694, 695], anilines 351 [696, 697], tetrahydroquinolines 352 [697], 5-aminomethyl-dihydrofuran-2-ones [698], and anilinomethylazides [699]. Synthetic applications of N-methyleneamine equivalents were reviewed in 2002 [700]. R1 N

O

R

R N

LA CO2R1 N2CHCO2R1

349

350

R

LA

R1

N

N

CO2R2 R R=

N R 348

LA HCCCH2SiMe3

Me

LA, NaOH, I2, N2 351

Cl

N H

Me

R= Cl

Cl

Cl

Me

N H 352

Scheme 20.101

20.4.5.4 Cycloaddition Reactions 1,3,5-Triazines may also undergo inverse electron demand cycloaddition reactions, although in to minor extent compared with 1,2,4-triazines, to yield heterocyclic compounds such as substituted [120] or condensed [701–707] pyrimidines. Theoretical studies [708, 709] of an inverse-electron demand Diels–Alder reaction between amino-substituted heterocycles and 1,3,5-triazines have been described. Scheme 20.102 show the mechanism proposed for this reaction.

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j 20 Six-Membered Heterocycles: Triazines, Tetrazines and Other Polyaza Systems

1834

R N R

N

X N R1

R H2N

N

R N R R Y N N Y N X X R N N R N RCN R1 R1 353

N R RH N Y N R H N N X 2 NH3 R1

Y

Scheme 20.102

An isocyanurate-containing fullerene has been obtained by [3 þ 2]-cycloaddition of 5-[50 -azidopentyl)]-1,3-diallyl-1,3,5-triazine-2,4,6-trione to C60 [710]. 20.4.5.5 Reactions with Reducing Reagents A few examples of reduction reactions of 1,3,5-triazines can be found in the literature. 2,4,6-Tricyano-1,3,5-triazine 354 (TCT) undergoes an irreversible one-electron reduction with Na or K to form 355 [711] (Scheme 20.103). Chemical reduction of TCT with strong reducing agents, such as bis(mesitylene)chromium(0), affords the dimerized compound 356 (TCBT) [712, 713] (Scheme 20.103) N

N

N

N

N

N

N

Na or K

Cr(mes)2

N

N N

N

355

N N

N

354 TCT

N N

N

N

N 356 TCBT

N

N N

Scheme 20.103

20.4.5.6 Reactions with Oxidizing Reagents There are few oxidation reactions on the ring of 1,3,5-triazines. Study of the kinetics and energies of one-electron oxidation of 1,3,5-triazines has been published [714]. Oxidation of a substituent cyano group to the corresponding amide has been described recently. One-pot preparation of triazinyl amide 358 via a sequential SNAr substitution and oxidation has been achieved using diethylaminoacetonitrile as amide synthon. An important advantage of this process is that the oxidation of the intermediate 357 occurs under mild conditions using NiO2–H2O in THF at room temperature [715] (Scheme 20.104).

OMe N MeO

NC

N N

OMe

OMe

Cl

NaHMSD NEt2 THF

345

N MeO

N N 357

Scheme 20.104

NiO2/H2O NEt2 TMSO-OTMS CN

N MeO

N NEt2

N 358

O

20.5 Tetrazines

Reactions of substituted 1,3,5- triazines with peroxides [716] and peracids [717] afford the corresponding oxygenated substituents. Dihydro-1,3,5-triazines are aromatized to triazines on oxidation with potassium permanganate [718]. 20.4.5.7 Reactions of Metallated 1,3,5-Triazines Metallated triazines react with electrophiles to give different substituted derivatives. Chloro-1,3,5-triazines are lithiated using lithium powder and naphthalene in the presence of various electrophiles such as aldehydes and ketones to give, after hydrolysis, the expected substituted triazines. The reaction presumably takes place through the organolithium intermediate [719]. 1,3,5-Triazine reacts with lithium alkyl to give 1,4-adducts, which on hydrolysis yielded the first simple 4-substituted 1,4-dihydrotriazines [650]. The reaction of 1,3,5triazines and lithium amidinate, alkyl- or 1-azaallyllithium affords substituted 1,3,5triazines [651].

20.5 Tetrazines

Tetrazine chemistry has been extensively reviewed in Comprehensive Heterocyclic Chemistry I [4] and Comprehensive Heterocyclic Chemistry II [9]. A whole chapter is devoted to 1,2,4,5-tetrazine in Comprehensive Heterocyclic Chemistry II [8]. The chemistry of 1,2,3,4-tetrazines has recently been updated in Chemical Reviews [44]. Therefore, only the most important relevant data that have appeared since these publications is considered here. 20.5.1 Relevant Computational Chemistry, Physicochemical and Spectroscopic Data

Theoretical calculations of the 1,2,3,4-tetrazine [53] and 1,2,3,5-tetrazines [53, 720] system have been published. The 1,2,4,5-tetrazine system is the only stable isomer of the three possible tetrazines. Most theoretical studies have dealt with the 1,2,4,5-tetrazine isomer. Fabian and Lewars have described a computational study of the stability, homodesmotic stabilization energy, electron distribution and magnetic ring current of tetrazines [53]. Harmonic [58] and anharmonic [58, 59] frequencies have also been calculated. The electronic spectrum [721–725] and density functional calculations [57, 726–728] have been published. Heats of formation of tetrazines have been calculated [61]. The coordination chemistry of 1,2,4,5-tetrazines and its 3,5-disubstituted derivatives has been described [729]. The X-ray crystallographic analysis of 1,2,4,5-tetrazines derivatives recently reported include: trans-3,6-dibenzyl-1,2,4,5-tetrazine 3,6-diphenyl-1,2,4,5tetrazine [730]; diphenyl 3,6-bis(4-chlorophenyl)-1,2-dihydro-1,2,4,5-tetrazine-1,2dicarboxylate [731]; 3,6-diphenyl-1,4-bis(p-tolylsulfonyl)-1,4-dihydro-1,2,4,5-tetra-

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j 20 Six-Membered Heterocycles: Triazines, Tetrazines and Other Polyaza Systems

1836

zine [732]; dipropyl 3,6-diphenyl-1,2-dihydro-1,2,4,5-tetrazine-1,2-dicarboxylate [733]; 1-acetyl-3,6-diphenyl-1,4-dihydro-1,2,4,5-tetrazine [734]; ethyl 3,6-diphenyl-1,4-dihydro-1,2,4,5-tetrazine-1-carboxylate [735]; 1-acyl-3,6-disubstituted phenyl-1,4-dihydro1,2,4,5-tetrazines [736]; 3,6-bis(2-chlorophenyl)-1,4-dihydro-1,2,4,5-tetrazine [737]; 3,6-bis(2-pyridinio-1,2,4,5-tetrazine) diperchlorate [738]; 3,6-bis(2-pyridinyl)-1,2,4,5tetrazine [739]; hexahydro-1,2,4,5-tetrazines [740]; and 1,5-dimethyl-1,2,4,5-tetrazinane-3,6-dione [741]. 20.5.2 Tautomerism

Unexpected azido-tetrazolo tautomerizations and irreversible tetrazolo transformation have been studied in a report dealing with 3,6-diazido-1,2,4,5-tetrazine (DiAT), for which an improved synthetic pathway is also provided [742]. DiAT undergoes azido-tetrazolo equilibria in CD3OD, (CD3)2CO and CD3CN and transforms into tetrazolo isomer 359 in DMSO (Scheme 20.105). The transformation from 359 into 360 only occurs when the temperature is at least 80  C.

N3

N N N N

CD3OD (CD3)2CO CD3CN

N3

DMSO

N N 359

N3

DiAT

N N

N3

N

N N

N N N N 359

N

N N

80 ºC DMSO

N N N N N N N N N N 360

Scheme 20.105

20.5.3 Relevant Natural and Useful Compounds

Recent reports have dealt with the antitumor activity of the 1,2,4,5-tetrazine skeleton [736, 743–751]. On the other hand, 1,2,4,5-tetrazines have demonstrated powerful synthetic utility through their ability to participate in inverse electron demand Diels–Alder reactions, providing access to a wide range of other heterocycles and natural products [30, 752] (Section 20.5.4.2). The 1,2,4,5-tetrazine ring system displays unique material properties as well. This electroactive, colored ring system typically exhibits high electron affinity, low lying p orbitals and n-p transitions in the visible light region – attractive properties for optical and electroactive materials applications [753]. Furthermore, tetrazines also posses high positive heats of formation and crystal densities, properties important in energetic material applications [754, 755].

20.5 Tetrazines

j1837

3,6-Diethyl-1,2,4,5-tetrazine has been employed as unique solvatochromic probe in the Solvent Acidity Scale [756]. 3,6-Diazido-1,2,4,5-tetrazine has been synthesized for the preparation of carbon nanospheres and nitrogen-rich carbon nitrides [757]. 20.5.4 Synthesis of 1,2,4,5-Tetrazines

Only recent synthetic methods of tetrazines are commented on here. Kaszynski has developed an alternative route to obtain 3,6-diphenyl-1,2,4,5thiatriazine 362 in a one-pot reaction from a nucleophilic double substitution on dichloride 361 [758] (Scheme 20.106). Ph Cl

N

N

361

Cl Ph

1. NaN3/TEBA 2. PrSH/Et3N

N

N Ph

Ph N

N N 362

Pr

S

Scheme 20.106

3,6-Bis(phenanthrolin-2-yl)-1,2,4,5-tetrazine has been synthesized from the reaction of 2-cyanophenanthroline with hydrazine followed by oxidation with nitric acid in acid acetic [759]. Hydrazine reacts with 4-hydroxybenzimidic acid methyl ester followed by oxidation with sodium nitrite to give 3,6-bis(4-hydroxyphenyl)-1,2,4,5tetrazine [760]. Aryl nitriles react with hydrazine to form 1,2-dihydro-3,6-diaryltetrazines [761], which are oxidized to 3,6-diaryl-1,2,4,5-tetrazines [753]. Imidate 363 reacts with hydrazine hydrate to afford 1,4-dihydrotetrazine 364. Deliberate oxidation of 364 has been accomplished by treatment with ferric chloride to provide tetrazine 365 [762] (Scheme 20.107).

OH OEt

Ar

NH2 Cl 363

NH2NH2

N Ar OH

N H

OH

OH

H N

Ar N

364

FeCl3

N Ar

N N

OH

Ar N

365

Scheme 20.107

New 1,2,4,5-tetrazines derivatives has been synthesized from substituted nitrilimines and different hydrazines [763–765] or hydrazones [765, 766]. A new neutral oxoverdazyl radical conjugated with the corannulene system has been designed and synthesized for the first time as a stable solid in air [767]. The radical 367 was synthesized by the condensation of aldehyde 366 with

j 20 Six-Membered Heterocycles: Triazines, Tetrazines and Other Polyaza Systems

1838

2,4,-dimethylcarbonohydrazide at room temperature followed by treatment with PbO2 (Scheme 20.108).

NH2 NH2 N N RCHO 366 O R = corannulene

HN R

N N H

O N

PbO2

N R

N

O

N N 367

Scheme 20.108

The synthesis of 1,5-diisopropyl substituted 6-oxo-verdazyls has been accomplished starting from 2,4-diisopropylcarbonohydrazide bis-hydrochloride. The introduction of isopropyl groups results in free radicals more stable and soluble than their methyl counterparts [768]. 6-(4-Substituted-phenyl)-2,4-diphenylverdazylium salts have been prepared by the reaction of 3-(4-substituted-phenyl)-1,5-diphenylformazans with formaldehyde and different organic and inorganic acids in a two-phase chloroform/water medium by brief and gentle heating [769]. 20.5.5 Reactivity of 1,2,4,5-Tetrazines

Some examples of the reactivity of 1,2,4,5-tetrazines published since 1995 are described here. 20.5.5.1 Reactions with Nucleophilic Reagents The electron-deficient aromatic ring of tetrazine and its reactivity towards nucleophiles have been utilized in the preparation of non-symmetrically substituted tetrazines by substitution of leaving groups, such as chloro [770, 771], methylthio [770, 772–775] or dimethylpyridazolyl [755, 757, 776, 777] with nitrogen, oxygen or sulfur nucleophiles. The use of carbon nucleophiles, such as organolithium or Grignard reagents, with 3,6-disubstituted 1,2,4,5-tetrazines 368 led to the addition of an organic group onto a ring nitrogen atom to afford 1,4-dihydrotetrazines 369 [778] (Scheme 20.109).

R2

N N N N 368

R1

R3-M

R2

N NH N N

R3

R1

369

Scheme 20.109

The first cross-coupling reactions in tetrazines have been described: a series of substituted chlorotetrazines 370 were reacted with different terminal alkynes under Sonogashira or Negishi coupling conditions to furnish alkynyl-tetrazines 371 [779] (Scheme 20.110).

20.5 Tetrazines N N

R1

N N

R2

Cl

370

5 % (PPh3)PdCl2 5 % CuI

N N

R1

2 eq. TEA DMA

R2

N N 371

Scheme 20.110

20.5.5.2 Cycloaddition Reactions A simple, yet non-obvious method for the construction of pyrazol-4-ols 374 by a consecutive series of condensation–fragmentation–cyclization extrusion reactions of thietanone 372 with 1,2,4,5-tetrazine 373 has been described [780] (Scheme 20.111).

O

Ph

N N

Ar

S

N N

372

Ar

KOR/ROH THF

H RO

O

Ar N

N Ar

Ph 374

373

Scheme 20.111

Inverse electron demand Diels–Alder reaction of 1,2,4,5-tetrazines are well known in the literature. Cycloadditions with electron-rich alkynes [759, 762, 774, 776, 781–788] or alkenes [602, 762, 772, 773, 781, 784, 789–792] afford the expected donor-substituted pyridazines (Scheme 20.112). Fusedpyridazines have also been obtained[269,770, 775, 784, 793–802].

R3 N R2

R1

N N

R4

N R3

X R4

N R2 N R3 N N R1 R4

R4 N2

R1

N R2 N R3 N N R4 R1 X XH N2

R3

N

R4 R1

R2 N

R3

N

R2 N

Scheme 20.112

1,2,4-Tetrazine 377 can be obtained the from reaction of thioimidate 375 with 1,2,4,5-tetrazine 376 [762] (Scheme 20.113). Zhou et al. have described an alternative Diels–Alder route to the well-known C,C cycloaddition (Carboni–Lindsey reaction). Quantum mechanical calculations showed that N,N cycloaddition of alkenes and alkynes to s-tetrazines is possible.

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j 20 Six-Membered Heterocycles: Triazines, Tetrazines and Other Polyaza Systems

1840

NH Ar

X 375

N R

R

N N

N

376

Ar R

N

R

N N 377

Scheme 20.113

The formation of 1,2,4-triazole derivatives (formal product of N,N cycloaddition) along with the pyrazole (formal product of C,C cycloaddition) corroborates this theoretical prediction [803]. Thermal Diels–Alder reactions between C60 and electron-deficient 3,6-diaryl1,2,4,5-tetrazines yielded monoadducts possessing a diaryldihydropyridazine function nested atop the fullerene [804]. However, when 3,6-diaryl-1,2,4,5-tetrazines and C60 react upon irradiation with visible light, the four membered ring-containing C62 derivatives were obtained [805]. 20.5.5.3 Reactions with Oxidizing Reagents 1,4-Dihydrotetrazines have been aromatized to tetrazines by exposure to nitrous gases [784]. 1,2,4,5-Tetrazines have been oxidized by DBU to obtain a novel azepine derivative [806]. In contrast, 1,2,4,5-tetrazines have been oxidized by methyl(trifluoromethyl)dioxirane to form the N(1)-oxide isomer [807].

References 1 Neunhoeffer, H. (1985) 1,2,3-Triazines

and their benzo derivatives, in Sixmembered Rings with Oxygen, Sulfur or Two or More Nitrogen Atoms, Comprehensive Heterocyclic Chemistry I, Vol. 3 (eds A.R. Katritzky and C.W. Rees), Pergamon Press, Oxford, pp. 369–384. 2 Neunhoeffer, H. (1985) 1,2,4-Triazine and their benzo derivatives, in Sixmembered Rings with Oxygen, Sulfur or Two or More Nitrogen Atoms, Comprehensive Heterocyclic Chemistry I, Vol. 3 (eds A.R. Katritzky and C.W. Rees), Pergamon Press, Oxford, pp. 385–456. 3 Quirke, J.M.E. (1985) 1,3,5-Triazines, in Six-membered Rings with Oxygen, Sulfur or Two or More Nitrogen Atoms, Comprehensive Heterocyclic Chemistry I, Vol. 3 (eds A.R. Katritzky and C.W. Rees), Pergamon Press, Oxford, pp. 457–530. 4 Neunhoeffer, H. (1985) Tetrazines and Pentazines, in Six-membered Rings with Oxygen, Sulfur or Two or More Nitrogen Atoms, Comprehensive Heterocyclic

Chemistry I, Vol. 3 (eds A.R. Katritzky and C.W. Rees), Pergamon Press, Oxford, pp. 531–572. 5 Ohsawa, A. and Itoh, T. (1995) 1,2,3Triazines and their benzo derivatives, in Six-membered Rings with Two or More Heteroatoms and Fused Carbocyclic Derivatives, Comprehensive Heterocyclic Chemistry II, Vol. 6 (eds A.R. Katritzky and C.W. Rees), Pergamon Press, Oxford, pp. 483–506. 6 Neunhoeffer, H. (1995) 1,2,4-Triazine and their benzo derivatives, in Sixmembered Rings with Two or More Heteroatoms and Fused Carbocyclic Derivatives, Comprehensive Heterocyclic Chemistry II, Vol. 6 (eds A.R. Katritzky and C.W. Rees), Pergamon Press, Oxford, pp. 507–573. 7 Bartholomew, D. (1995) 1,3,5-Triazines, in Six-membered Rings with Two or More Heteroatoms and Fused Carbocyclic Derivatives, Comprehensive Heterocyclic Chemistry II, Vol. 6 (eds A.R. Katritzky

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8

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746 Wang, Y.F., Lambert, P., Zhao, L.X., and

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j1865

21 Seven-Membered Heterocycles: Azepines, Benzo Derivatives and Related Systems Juan J. Vaquero, Ana M. Cuadro, and Bernardo Herrad
on

21.1 Introduction

The replacement of a carbon atom by a heteroatom in a seven-membered carbocycle leads to the corresponding seven-membered heterocyclic ring system. Different types of heterocycles can be formed depending on the nature of the carbocycle. In a cycloheptatriene the replacement can involve any of the six sp2 hybridized carbons or the sp3 carbon atom, whereas in cycloheptane all carbon atoms are equivalent and replacement affords exclusively the fully saturated heterocyclic systems. Partially saturated seven-membered heterocycles can be viewed as derivatives or related systems of these two main seven-membered heterocyclic units arising from carbon replacement in cycloheptatriene and in cycloheptane. Replacement of the sp3 hybridized carbon atom in cycloheptatriene by a nitrogen leads to an azacycloheptatriene known as 1H-azepine (1) and the corresponding 2H-, 3H-, and 4H-azepines (2–4) are the tautomeric forms generated by the replacement of the sp2 carbons. 1H-Azepine is an unstable red oil that is prone to rearrange to the also unstable 3H-azepine in the presence of acids and bases. However, this tautomer seems to be more stable than both 4H- and 2H-azepine. The structures related to 1H-azepine that bear an oxygen or sulfur atom are known as oxepine (5) and thiepine (6) (thiepin is favored by Chemical Abstracts Service). Oxepine is much more stable than thiepine and has been synthesized, isolated, and characterized at room temperature while thiepine has not been detected to date. Stable monocyclic thiepines were prepared and characterized in the 1980s. Azepines, oxepines, and thiepines that are constrained to planar or almost planar conformations should be antiaromatic molecules with negative resonance energy and, as a consequence, these compounds are unknown. The fully saturated seven-membered heterocycle containing one nitrogen is azepane (7) (hexahydroazepine or perhydroazepine); the oxygen and sulfur analogues are known as oxepane (8) and thiepane (9). All of these compounds are stable and show typical behavior of secondary amine, ether and thioether, respectively. Two

Modern Heterocyclic Chemistry, First Edition. Edited by Julio Alvarez-Builla, Juan Jose Vaquero, and José Barluenga. Ó 2011 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2011 by Wiley-VCH Verlag GmbH & Co. KGaA.

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other interesting systems are the sulfur-oxidized forms of 6 and 9, which are known as thiepine 1,1-dioxide (10) and thiepane 1,1-dioxide (11), respectively.

N H

N

N

N

O

S

1H-Azepine

2H-Azepine

3H-Azepine

4H-Azepine

Oxepine

Thiepine

1

2

3

N H

O

Azepane

Oxepane

7

4

5

S Thiepane

8

S

O

6

S

O

O

O

Thiepine 1,1-dioxide Thiepane 1,1-dioxide

9

10

11

Annelation of all these seven-membered heterocycles to aromatic and heteroaromatic rings leads to a great variety of heterocyclic systems. The most widely studied are those generated by fusion of one or two benzene rings to the fully unsaturated nuclei. There are three possible ways for this annulation of a benzene ring to heterocycles 1–11 and four isomeric possibilities result from the fusion with two benzene rings (12–32). In general, the resulting benzo derivatives and dibenzo derivatives are more stable than the parent monocyclic systems. 6

5

6

4

7

3

8

X

9

9

12: X = NH: 1H-1-Benzazepine 13: X = O: 1-Benzoxepine 14: X = S: 1-Benzothiepine 9

6

4

1

9

15: X = NH: 2H-2-Benzazepine 16: X = O: 2-Benzoxepine 17: X = S: 2-Benzothiepine

11

7

6

4

5

21: X = NH: 5H-Dibenz[b,d]azepine 22: X = O: Dibenz[b,d]oxepine 23: X = S: Dibenz[b,d ]thiepine

10

2 7

6

5

4

4

5

10 11

1

8

X

3

X

24: X = NH: 5H-Dibenz[b,e]azepine 25: X = O: Dibenz[ b,e]oxepine 26: X = S: Dibenz[ b,e]thiepine 9

11

1 2

7

3

X

11

8

2

9

1

3

27: X = NH: 5H-Dibenz[b,f ]azepine 28: X = O: Dibenz[b,f ]oxepine 29: X = S: Dibenz[b,f ]thiepine

1

8

2

7 6

2

18: X = NH: 3H-3-Benzazepine 19: X = O: 3-Benzoxepine 20: X = S: 3-Benzothiepine

10

9

1

4

X3

8

X2

10

8

6

5

7 3

8

2

1

5

7

X

3 5

4

30: X = NH: 5H-Dibenz[c,e]azepine 31: X = O: Dibenz[c,e]oxepine 32: X = S: Dibenz[c,e]thiepine

21.2 Relevant Natural and Useful Compounds

The chemistry and properties of most common seven-membered heterocycles have been reviewed in previous surveys, mainly in Comprehensive Heterocyclic Chemistry I [1, 2], Comprehensive Heterocyclic Chemistry II [3–5] and Comprehensive Heterocyclic Chemistry III [6–8]. Other reviews on azepines have been published [9–11] and benzazepines have been covered in a reference series [12]. The synthesis of oxepines and oxepanes has been reviewed elsewhere [13–16], as have the synthesis and applications of some dibenzoxepines [17]. Earlier studies on the chemistry of thiepines and thiepanes have been reviewed [18, 19] and, more recently, these heterocycles have been described in Houben-Weyl’s Science of Synthesis [20]. A review of dibenzo[b,f ]thiepine has also been published [21]. In addition to these general surveys, annual accounts on seven-membered heterocyclic ring systems are given in Progress in Heterocyclic Chemistry [22].

21.2 Relevant Natural and Useful Compounds

The seven-membered lactam 33 (e-caprolactam or hexahydroazepin-2-one) is probably the most relevant azepine derivative to date. This compound has been isolated from natural sources and has biological properties such as growth-inhibiting activity [23] and allelopathy [24]. However, its most relevant use is as an intermediate in the synthesis of nylon 6 through a polymerization process [25, 26]. The structural fragment of e-lactam is incorporated into various naturally occurring products such as the bacterial translocase 1 inhibitor 34 isolated from Streptomyces griseus SANK 50 196 [27] and the azepinone bengamides Z (35) and Q (36) isolated from a Jaspis species [28]. Muscaflavin (37) has been isolated from the poisonous mushroom Amanita muscaria and is one of the few examples of simple monocyclic azepine derivatives found in nature [29]. The most useful compounds based on the azepine system are fused-ring derivatives that exhibit a wide range of pharmacological activities. Examples of benzazepine derivatives with pharmacological interest are the 1H-2-benzazepine derivative 38, which is an inhibitor of acetylcholinesterase [30], and the potential anti-HIV agent 39 [31]. Examples of dibenzazepines include imipramine (40) and clomipramine (41), two 10,11-dihydrodibenz[b,f ]azepine alkaloids that have been used for the treatment of depressive disorders [32], perlapine (42), a dibenzo[b,e]azepine with antipsychotic and sedative activities [33], and azapetine (43), an antiadrenergic dibenzo[c,e]azepine [34]. The instability of most monocyclic oxepines precludes any significant commercial application, although they do play a remarkable role as intermediates in the biosynthesis and metabolism of natural products and xenobiotics [35]. It has been assumed that oxepines such as 44 and 45 are involved in the biosynthesis of tyrosine [36] and gliotoxin [37] and that the formation as intermediates of oxepines 46 and 47 occurs in the conversion of cinnamic acid into ortho- and para-coumaric acid, respectively [38]. Methyl-substituted oxepines 48 have also been postulated as intermediates in the metabolism of arenes by liver enzymatic systems [39]. Some

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OH

N H

HN

O

O

OHC

HO

N OH O

N Me

O N H

OH OR

t

NMe

CO2H

O

H N O

O

38

37

39

NO2

R N NMe2

40: R = H 41: R = Cl

O

Bu N

BuO

N

O

35: R = H 36: R = CO(CH2)12Me

O O

N H

O

H2NOC

34

Me2N

O

OMe OH

H N

HO O

Me

33

HO2C

OH

H N

O

N Me

N

42

S O

N

Pr

N

N CH-CH=CH2

43

annelated oxepines are found in nature and these include bauhiniastatin (49) [40], janoxepin (50) [41], and perillosin (51) [42], and some relevant pharmacological activities have been described for some dibenzoxepine derivatives inter alia anxiolytic activity for 52 [43] and anti-inflammatory action for artocarpol (53), a natural product isolated from the root bark of Artocarpus rigida [44]. Oxepanes and partially reduced oxepines are of considerable interest, with oxepan2-one (54) (e-caprolactone) being an important monomer used in the synthesis of poly-e-caprolactone, a polymer with a wide range of relevant applications [45]. A remarkable number of natural marine products contain oxepane or a reduced oxepine in their structure [46]. Representative examples are isolaurepinnacin (55) [47] and lobatrienetriol (56) [48], both of which are structurally based on a monocyclic tetrahydrooxepine, armatol A (57) [49], with two oxepane and one tetrahydrooxepine rings, and ciguatoxin 3C (58), which is one of the most powerful polyether neurotoxins [50]. Significant applications of simple monocyclic thiepines and thiepanes and their monobenzo derivatives have not been reported to date. On the other hand, interesting biological activities have been described for some dibenzo derivatives – especially those belonging the dibenzo[b,f ]thiepine and dibenzo[b,e]thiepine series. Dibenzo[b,f] thiepine derivatives of the general structure 59 display a wide range of pharmacological activities, including antischizophrenic, anti-inflammatory, antidepressant, antihistaminic, anti-bradykinin, neuroleptic, and as 5-HT2A/2C inhibitors [51, 52].

j1869

21.3 Relevant Computational Chemistry, Physicochemical, and Spectroscopic Data HO2C

NH2

O

44

CO2H

NH2

CO2H O

O

O

O

45

46

47

48

Me OH MeO O

O

OH

N

Me

O

O

NH

X O

OMe

50

X = F, Cl, Br, OMe

51

52

Me

Me

Me

OH O

Me

O

Me O

HO

O

O

Me Me

49

NMe2

HO Me Me

Me O

N

Me

Me

CO2H

Me

Et

O

O Br

54

55

OH

HO H O

O

O

O

OH

O

O H OH

H

Me

56

53 HO

O

Me

Cl

H H O

H

H

O

H

HO O H H

H

H O O H H

OH

H O H

58

57

The activity of dibenzo[b,e]thiepines is represented by 60, which has antidepressant activity [53], tiopinac (61), an anti-inflammatory agent [54], and 62, a calcium antagonist [55]. Apart from these applications, liquid crystals based on the dibenzo[c,e]thiepine scaffold have been reported and the enantiomerically pure compound 63 shows axial chirality [56].

21.3 Relevant Computational Chemistry, Physicochemical, and Spectroscopic Data

1H-Azepine (1) was first obtained in 1963 [57] by hydrolysis and decarboxylation of ethyl 1H-azepine-N-carboxylate, but it was not characterized until 1980 [58]. This azepine isomer is stable for only a few hours in solution even at
78  C [it polymerizes and tautomerizes to the 3H-tautomer (3)]. 3H-Azepine (3) is less

O

O OH

j 21 Seven-Membered Heterocycles: Azepines, Benzo Derivatives and Related Systems

1870

NMe2 R

O

S

S

59

60

HNCO(CH2)3

N

N

F

CO2H

S

H25C12O

61

O

Me

Me

O

O S

S

62

O

O-C12H25

63

prone to polymerization than 1 and it can be distilled under vacuum. N-Substituted 1H-azepines are oils or stable solids with well-defined melting points. Azepane (7) was first obtained in 1963 and is a typical secondary amine with a pKa of 11.29 [59]. Oxepine (5) is a heterocyclic compound that at room temperature is in equilibrium with its valence bond isomer, the benzene oxide, but it has been synthesized, isolated, and characterized. Thiepine (6) is a highly unstable structure and this compound remains unknown. Oxidation of the sulfur atom to form the thiepine 1,1-dioxide (10) stabilizes the thiepine ring system. Table 21.1 gives the bond lengths for some of these seven-membered heterocycles. 

Table 21.1 Bond lengths (A) for some representative seven-membered heterocycles.

Heterocycle

N H

5

S

S

C1
C2

C2
C3

C3
C4

Method

Reference

1.420

1.347

1.466

1.350

SCF-MO

[60]

1.434

1.284

1.444

1332

Ab initio

[61]

1.791

1.347

1.466

1.450

HMO

[62]

1.723

1.344

1.429

1.333

X-ray

[63]

1.781

1.321

1.448

1.308

X-ray

[64]

1

O

O

Het
C1

6

O

10

S

14

Het ¼ Heteroatom.

21.3 Relevant Computational Chemistry, Physicochemical, and Spectroscopic Data

The conformation of these fully unsaturated seven-membered heterocycles has made them the focus of enormous interest since a planar structure would involve an overlap of the nitrogen lone pair with the cyclic triene system, leading in turn to the formation of an antiaromatic 8p electronic system [60, 65]. Theoretical calculations carried out on 1H-azepine (1) have demonstrated that this tautomer is not a planar molecule; instead the results suggest that this heterocycle has a boat conformation with a significant contribution (22%) of the chair conformation. Consequently, this out-of-plane conformation allows the destabilizing overlap of the nitrogen lone pair to be avoided and the p-delocalization of the cyclic triene is at a similar level to that found in a linear polyene (Scheme 21.1). Comparative molecular-orbital-based molecular mechanics (MOMM) calculations carried out on 1H- and 3H-azepine (3) show that the p-electronic system is highly localized in both systems and the geometry of 1H-azepine is better represented for a defined boat conformation. Similarly, a boat conformation is the preferred geometry for 3Hazepine, which is predicted to be 4.7 kcal mol
1 more stable than the planar conformation and 17 kcal mol
1 more stable than 1H-azepine [66]. Recent studies [67] using DFT methods (B3LYP6-31G and B3LYP/6-311 þ þ G ) and MP2/6311 þ þ G calculations show that destroying the antiaromaticity of 1 results in a reward of 10.8 kcal mol
1. X X

X = NH, O, S Scheme 21.1

Extensive 1 H NMR studies have been carried out to establish the energy barriers for the ring inversion between the two stable boat conformations of the azepine ring. The barrier for boat-to-boat inversion depends on the number and nature of the substituents and the azepine tautomer. For simple substituted azepines it has been established that the barrier is below 5 kcal mol
1. Semiempirical and ab initio studies have shown that both oxepine (5) and thiepine (6) also adopt a boat-type conformation similar to that found in 1H-azepines, with four carbons (C2, C3, C6, and C7) arranged in the same plane and the heteroatom and the remaining two carbons (C4 and C5) out of the main plane (Scheme 21.1). Barriers for the ring inversion of thiepine have been obtained at different levels of theory [68] and range from 5.8 to 11.4 kcal mol
1. From nucleus-independent chemical shift (NICS) values the planar structure is antiaromatic and the boat-like conformation appeared to be nonaromatic. Experimental evidence for the boat-like conformation in azepines [69], oxepines [70], and thiepines [71] has been obtained by X-ray crystallography. These studies confirmed the boat-like conformation for the seven-membered rings of derivatives 64–66, with bond lengths for C2
C3, C4
C5, and C6
C7 very close to those of the C(sp2)
C(sp2) single bond and the C
heteroatom lengths very similar to the distance of a single bond.

j1871

j 21 Seven-Membered Heterocycles: Azepines, Benzo Derivatives and Related Systems

1872

R

1

R

4

R R

S

O

N 2

R

4

R R

3

2

Bu

3

Bu

65

64

t

t

66

Conformational analyses of azepane (7) [72], oxepane (8) [73] and thiepane (9) [74] using different force fields have been described. Such compounds show a complex pseudorotational equilibrium between the chair, twist-chair, boat, and twist-boat forms, with the twist-chair conformations generally the most abundant conformers (Scheme 21.2). When a double bond is introduced into the ring, the number of conformations present in the pseudorotational equilibrium is reduced and the twistboat or chair forms are usually stabilized. X

Boat

X

Twist-boat

X

X

Twist-chair

Chair

X = NH, O, S Scheme 21.2

The potential structural diversity of benzo and dibenzo fused seven-membered heterocycles and the lack of systematic conformational studies make it difficult to establish general conclusions for the preferred conformations of these systems. It is clear that the annelation of a benzene ring results in an increase in the barriers to ring inversion and that chair conformations appear to be preferred in benzo derivatives of the fully saturated systems 7–9 [75]. However, analysis of the benzoannelated system involving the fully unsaturated heterocycles 1–6 is much more complex because of the potential whole range of aromatic, antiaromatic, and nonaromatic situations and valence tautomerism (detailed below) that can be found. NMR data for azepines, oxepines, and thiepines have also been very valuable in establishing their preferred conformations and provide detailed information about the ring inversion energies of these ring systems. The nonplanar character of the seven-membered nuclei results in the chemical shifts of the protons and carbons lying in the polyene region of the spectra. Tables 21.2 and 21.3 give 1 H NMR and 13 C NMR data for some representative compounds. 1 H and 13 C NMR data for monocyclic thiepines also provide relevant structural information. In the 1 H NMR spectra the ring proton signals clearly appear in the alkene region, with coupling constants consistent with a nonplanar seven-membered triene structure. This finding confirms the nonaromatic character of the nucleus. Chemical shifts in the 13 C NMR spectra are also consistent with the triene structure.

21.3 Relevant Computational Chemistry, Physicochemical, and Spectroscopic Data 1

Table 21.2

H NMR data (ppm) for some representative seven-membered heterocycles.

Heterocycle

N H

2

N

3

5

N Me

O

H2

H3

H4

H5

H6

H7

H8

H9

Reference

—

5.22

4.69

5.57

5.57

4.69

5.22

—

—

[58]

—

3.61

5.69

6.35

6.74

6.60

7.84

—

—

[76]

—

6.2–6.7

2.42

5.35

6.2–6.7

6.2–6.7

7.55

—

—

[58]

—

5.7

5.7

6.3

6.3

5.7

5.7

—

—

[77]

—

5.62

4.47

2.32

2.32

4.47

5.62

—

—

[78]

—

—

6.9

6.4

6.5

5.8

5.9

—

—

[79]

—

—

6.76

7.43

6.40

—

—

[80]

—

6.21

5.45

6.01

6.63

6.89–7.22

[81]

—

5.86

6.40

6.40

7.06

7.16–7.28

[81b,82]

6.72

5.89

—

5.89

6.72

7.10–7.18

[82]

1

N

O

H1

CO2Me

CO2Et

Bu

t

t

S

Bu

O

13

S

14 S

20

MS, IR, and UV spectroscopic methods seem to be considered less significant for the structural elucidation of seven-membered heterocycles except for some isolated cases and systematic studies have not been reported. The UV data for some stable monocyclic derivatives have been used to confirm the nonplanar structure of the trienic ring. The UV spectra of 1H-azepine derivatives show three bands at 210–215, 240–247 and 285–330 nm, with the latter being the strongest absorption band [84]. The simplest stable compound 2,7-di-tert-butylthiepine shows three bands at 226, 252 and 362 nm with log e values of 4.02, 3.35 and 2.51, respectively [85]. Notably, the mass spectrum of 2,7-di-tert-butylthiepine does not show ions generated by the loss of sulfur, an observation that is unexpected.

j1873

j 21 Seven-Membered Heterocycles: Azepines, Benzo Derivatives and Related Systems

1874

13

Table 21.3

C NMR data (ppm) for some representative seven-membered heterocycles..

Heterocycle

N H

C3

C4

C5

C6

C7

C8

C9

Reference

138.0

113.0

132.3

132.2

113.0

138.0

—

—

[58, 83]

50.9

126.7

129.3

136.7

130.8

158.5

—

—

[76, 83]

136.4

34.3

113.3

127.3

117.5

141.0

—

—

[58, 83]

141.8

117.6

130.8

130.8

117.6

141.8

—

—

[77b]

126.0

127.0

134.0

140.0

151.0

158.2

—

—

[80]

146.74

115.09

126.68

132.55

121.01

24.61, 128.97

130.10

[81b]

124.5

130.5, 133.9

136.9

127.9, 128.7, 130.1, 132.0

1

N

2

N

3

O

C2

5 CO2Et

Bu

t

t

S

Bu

O

13

S

14

[81b,84]

Tautomerism in azepines via an allowed 1,5-hydrogen shift has been studied for different azepine isomers and it was found that the ratio of azepine tautomers is related to their relative thermal stabilities [69d, 86]. For instance, when heated in toluene both 2H- and 3H-azepines 2 and 3 are converted into mixtures containing the 2H-, 3H-, and 4H-azepine tautomers in similar ratio (about 10: 50: 1). A similar result has been found in the demethoxycarbonylation of the 3H-azepine derivative 67, which upon heating in toluene in the presence of DBU affords a mixture of 67 and the 2H- and 4H-tautomers 68 and 69, respectively. However, under the same conditions the methyl 2,5-di-tert-butyl-3H-azepine-1-carboxylate 70 gave only the 3H-tautomer 71 (Scheme 21.3).

21.4 Valence Tautomerism in Seven-Membered Heterocycles

An interesting structural feature of fully unsaturated seven-membered heterocyclic systems is the possibility of valence tautomerism [87]. Early studies based on X-ray analysis discarded the azepine–benzeneimine equilibrium (Scheme 21.4) for simple 1H-azepines in the solid state, and 1 H NMR data obtained at different temperatures were also consistent with the azepine structure [58]. However, other NMR studies [88]

21.4 Valence Tautomerism in Seven-Membered Heterocycles

Bu

N

N

N

2

3

4

t

Bu +

Xylene DBU

t

Bu

N CO2Me 67

Bu

+

t

t

Bu

Bu

t

t

Bu

N

N

68

69

Xylene DBU

Bu

t

N

t N Bu CO2Me

t

Bu

t

71

70 Scheme 21.3

X X

X = NH, O, S Scheme 21.4

demonstrated the existence of the azepine–benzeneimine equilibrium in densely substituted 1H-azepines such as 72, where the bicyclic isomer 73 is present at a level of 3–10% in the equilibrium mixture (Scheme 21.5). Further theoretical studies (MINDO/3) showed that the benzeneimine is a nonplanar bicycle in which the aziridine ring is 72.6 out of the plane of the six-membered ring. Moreover, the stability of the tautomers was calculated from their heats of formation, which showed that 1H-azepine 73 is much more stable than the benzeneimine form (43.10 versus
8.50 kcal mol
1) [61]. Valence tautomerism studies on 4H-azepines proved that 4H-azepine can also be in equilibrium with its bicyclic tautomer, the 3-azanorcaradiene. Early studies showed that 4H-azepine was the most stable isomer [89]. However, in some substituted derivatives such as 74 the equilibrium is displaced towards the bicyclic isomer 75 and it is necessary to heat the sample to 178  C to detect the 4H-azepine form in the 1 H NMR spectrum [90]. With regard to 3H-azepines, it was found that acid treatment of some 7-amino-3trityl-3H-azepines (76) led to the stable azanorcaradiene salts 77, which reverted to 76 when treated with potassium carbonate (Scheme 21.5) [91]. Moreover, the selective formation and isolation of 2-methoxy-2H-azepine 79 from 3,6-di-tert-butyl-3H-azepine (78) – probably via an azatropylium cation – has been reported. The isolated compound 79 did not revert into its valence isomer at room temperature [92].

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j 21 Seven-Membered Heterocycles: Azepines, Benzo Derivatives and Related Systems

1876

R R

4

R

3

3

R N R

R

4

R

4

R

4

3

N-R R

1

1

3

73

72

R1 = p-Ts, Ac, CO2Me; R3 = H; R4 = CO2Me R R

4

3

N

R

R

4

R

R

3

2

N

4

R

4

R

2

75

74

R2 = CO2Me; R3 = Ph; R4 = Me CPh3 R2N

N

HBF4 K2CO3/acetone

R2N

N+ H BF4 77

76

Bu

t

Bu N 78

t

1. Br2/CH2Cl2 2. MeOH

Bu

CPh3

t

Bu MeO

t

N+ H BF4 79

Scheme 21.5

The parent oxepine (5) is in spontaneous equilibrium with the valence isomer benzene oxide at room temperature (a thermal disrotatory electrocyclic reaction according to Woodward–Hoffmann rules). Different NMR and UV studies have been carried out to investigate this equilibrium. At room temperature the 1 H NMR spectrum of 5 contains three multiplets at d 5.20, 5.65, and 6.10 ppm, which correspond to H4, H3, and H2, respectively, involved in a fast exchange process. At lower temperatures (
134  C) both the oxepine and the benzene oxide are distinguishable in the 1 H and 13 C NMR spectra [77b]. UV spectroscopy has also proven to be very valuable in detecting both isomers since the oxepine tautomer shows an absorption band at 305 nm whilebenzene oxideabsorbsat271 nm (e ¼ 900and1430,respectively). Studies on monosubstituted oxepines 80 also support the existence of two enantiomers in equilibrium with the oxepine (Scheme 21.6) [93]. The oxepine–benzene oxide ratio depends on temperature, solvent, and substitution of the oxepine ring. The oxepine form seems to be favored in less polar solvents [94] while at low

21.4 Valence Tautomerism in Seven-Membered Heterocycles

OCOPh

OCOPh O

OCOPh

O

O 80 Scheme 21.6

temperatures the benzene oxide is the preferred form. As a general remark, substituents at the C3 position favor the benzene oxide tautomer and substitution at C2 and C4 the oxepine form. Recent theoretical studies (ab initio) have also being carried out on the tautomerization oxepine benzene-oxide of substituted oxepines [95]. Theoretical studies at a high level of theory dealing with the stability of thiepine and its valence tautomer have shown a significant preference for the valence tautomer benzene sulfide, which was estimated to be 7.02 kcal mol
1 more stable than the parent thiepine [96]. A remarkable difference with azepines or oxepines is that valence isomers in simple thiepines are prone to extrude the sulfur atom in an irreversible process (Scheme 21.7). It is assumed this loss of sulfur precluded the isolation of the parent thiepine (6). Monocyclic thiepines can be stabilized by steric effects. For example, the presence of bulky substituents at C2 and C7 produces derivatives that are very stable at high temperatures (130  C) with long half-lives (>250 h) [85]. Recent theoretical studies show how steric effects can favor thiepines over their benzene sulfide tautomers [97]. R

R

R -S

S

S

Scheme 21.7

Azepines, oxepines, and thiepines fused with benzene rings are stabilized by electronic effects and may also be in equilibrium with their corresponding valence isomers. Resonance energies have been calculated for the three possible isomeric benzoxepines 13, 16, and 19 as 19.55, 1.15, and 18.77 kcal mol
1, respectively [98]. These data support experimental evidence that benzo derivatives 13 and 19 are relatively stable compounds while the formation of 16 from the 1,2-naphthalene oxide would involve a significant loss of resonance energy since one of the benzene nuclei in this valence tautomer retains aromatic character [99]. Aromatic ring annelation of thiepine (6) can lead to quite stable derivatives [100]. Resonance energy calculations for benzothiepines 14 ( þ 6.14 kcal mol
1), 17 (
5.90 kcal mol
1), and 20 ( þ 7.13 kcal mol
1) have been used to predict that 14 and 20 should have nonaromatic character whereas 17 should be a highly unstable molecule [101]. As was the case with the oxepine–arene oxide equilibrium, electronic

j1877

j 21 Seven-Membered Heterocycles: Azepines, Benzo Derivatives and Related Systems

1878

effects could also strongly affect the thiepine–episulfide equilibrium of naphthalene. Benzothiepine 14 only exists in the thiepine form and has been characterized by X-ray analysis [64]. The higher stability of the valence tautomer of 17 explains why this thiepine has not been isolated (Scheme 21.8).

X

X

X

X

X

X X = O, S

Scheme 21.8

21.5 Synthesis 21.5.1 Synthesis of Azepines 21.5.1.1 From Acyclic Compounds The formation of the seven-membered ring of an azepine from an appropriate acyclic compound through a cyclization reaction has been extensively used for the synthesis of azepine fused-ring derivatives but had rarely been used for monocyclic azepine derivatives until the advent of the metathesis reaction [102]. The power and utility of the ring-closing metathesis (RCM) reaction (Scheme 21.9) for the preparation of different tetrahydroazepines using Grubbs I and Grubbs II catalysts is exemplified in Table 21.4. RCM (CH2)m (CH2)n N R n = 1-3 m = 1-3 Scheme 21.9

Catalyst

(CH2)m (CH2)n N R

Table 21.4 Synthesis of tetrahydroazepines by ring-closing metathesis (RCM) reactions.

Diene

Conditions

Azepine

CH2Cl2, 40–50  C

N R

R

Yield (%) Reference

R = Ts, SO2CH2Br

N R

3

N 1 R

CH2Cl2, heat R

2

R

R

2

R N 1 R Cbz

ClCH2CH2Cl, reflux

2

R CO2Me

2

R1 = H, Me R2 = Ph, Me

CO2Me N 1 R

R

O

CH2Cl2 or ClCH2CH2Cl, r.t./40  C/90  C

N DMB

R1 = Bn

F

F

N O

O X

N 1 R

O

[106]

88–92

[107]

58

[108]

97

[106b]

75

[109]

87

[110]

N

BzHN

CH2Cl2, 10  C

N DMB

O

F

F

O

O Ph

82–90

R3 = NHBoc

BzHN O

[105]

3

2

N 1 R

O

75–89

R1 = Bn, Boc R2 = H, CH2OTBS

R

R

[104]

2

CH2Cl2

N 1 R 3

90–99

2

R1 = Boc, CBz, (2-Py)SO2 R2 = H, Me

N 1 R Cbz R

[103]

O

O N 1 R

100

N Boc

Ph

CH2Cl2, reflux

N O

O

O

X

O

N Boc

HO

HO

CH2Cl2, reflux

N SO2

N SO2

N

Ph

N

O

Ph

O

C6H6, reflux O

Grubbs I

N Me P(Cy)3 Cl Ru Cl Ph P(Cy)3

O

N

N Me

N

Cl Ru Cl P(Cy)3

Grubbs II Ph

j 21 Seven-Membered Heterocycles: Azepines, Benzo Derivatives and Related Systems

1880

Other alternatives to the ring-closing metathesis reaction to access tetrahydroazepine derivatives through cyclization include the different approaches shown in Scheme 21.10. The intramolecular insertion of nitrenes by thermolysis of the corresponding azides (the Staudinger reaction) [111] is an efficient route to cyclic imines [112] that has been applied to the synthesis of the tetrahydroazepine derivative 81, an intermediate in the synthesis of ( þ )-croomine [113]. The reaction of a bromoallene in the presence of Pd(Ph3)4 afforded the tetrahydroazepine derivative 82 in good yield [114]. Azepinones can also be obtained from substituted allenes, which on deprotection followed by reflux in acetonitrile gave the azepinone derivative 83 in excellent yield [115]. Simple substituted azepine derivatives 84 have been obtained by ruthenium-catalyzed intramolecular hydroamination of an aminoalk-

O

R O

PPh3

N3

O

R O

THF

(+)-Croomine

N

81 Br

C

Me

Pd(Ph3)4

Me

Me

OMe

MeOH, NaH

Me

NHTs

N Ts

76%

82 C

BnO2C

HNBoc Me Me

O

NH2

(CH2)5

Ph

2. MeCN reflux

Me

83

NH Ar 85

Scheme 21.10

N

Boc

84 Me

HCl (aq.) CHCl3 86%

Ph

N

140 ºC

Ar Ar

Me

Ru3(CO)12

Me Me

O

N Me H

95%

60% Ar

CO2Bn

O

1. TFA

Me O

N Ar 86

21.5 Synthesis

j1881

yne [116]. A more classical cyclization leading to azepine derivatives is exemplified by the formation of azepinone 86 by acid treatment of 85 [117]. N-Substituted dihydroazepines 87 and 88 can be obtained by lithium-promoted electrocyclization of imine-dienes followed by N-alkylation or N-acylation. Yields are poor to moderate depending on the R1 substituent [118]. A carbanion-promoted 1,7-electrocyclization of 89 led to the antiaromatic azepine anion 90, which loses methylthiolate to generate the thienyl-substituted 3H-azepine 91 (Scheme 21.11) [119]. R

1. LDA, THF, -78ºC 2. R2-X, 40ºC R

1

N

1

N 2 R

6-45%

R1 = Ph, 2-Furyl R2 = Et, Bu, ArCO, ROCO

87 1. LDA, THF, -78ºC 2. R1-X, 40ºC Ph

N

Ar

Ar

27-54%

N 1 R

88

Me

Me

S

MeS

DMSO

Ar = p-Tolyl R1 = CHO, PhCO, CO2Me, CO2Et

-SMe

t-BuOK Me

N

Ph

S

Me

89

N

Me

MeS

45%

Me

N

S

91

90

Scheme 21.11

A novel synthesis of azepinone derivatives 92 has been reported and a key step in this process is an intramolecular cycloaddition of a nitrone followed by rearrangement through N
O homolysis and subsequent electrocyclic recyclization. On heating 92a (R1 ¼ R2 ¼ Ph) in toluene an isomerization was observed to the azepinone isomer 93a, although the latter is present in the equilibrium at a level of only 3% (Scheme 21.12) [120]. + Me N R

1

MeNHOH.HCl NaOAc/CH2Cl2

O R

2

28-94%

R

1

R N Me

2

Toluene, reflux

O

92 92a : R1 = R2 = Ph (94%) 92b : R1 = Me; R2 = H (28%) Scheme 21.12

Ph Ph N Me 93a

O

Me

j 21 Seven-Membered Heterocycles: Azepines, Benzo Derivatives and Related Systems

1882

The parent 2H-azepine (2) and the enantiomerically pure derivatives 94 were obtained for the first time by cyclization of an N-protected e-amino aldehyde or ketone [76]. The ring formation involves deprotection with TFA followed by treatment with a base (Scheme 21.13). Although the yield of 2 was only 1%, this isomer was stable enough at 25  C to allow its characterization. 2H-Azepines 94 were obtained in yields in the range 45–72% but are prone to isomerize to the more stable 3H-isomers [121]. R

AcO R

1

2

O H NH Boc

1. TFA/CH2Cl2 2. DMAP or Et3N 45-72%

R

N

2

H

R

1

2: R1 = R2 = H (1%) 94: R1 = Me, Bn, RCO2CH2 R2 = Me, n-Bu Scheme 21.13

The formation of the azepine nucleus by processes involving the formation of two bonds is exemplified by a few cases such as the [4 þ 3] annulations of Fischer chromium carbene complexes with azadienes [122]. Thus, the reaction of 95 and 96 affords the dihydroazepine 97 through the formation of an aziridine followed by an aza-Cope rearrangement and 1,3-proton shift (Scheme 21.14). The dihydroazepine derivatives 98 have been obtained by reaction of ylides generated in situ from styryldiazoacetates and imines [123] (Scheme 21.14). H t N-Bu R

1

NH

(CO)3Cr

MeO

THF or hexane

95 +

R R

96

Ph

1

t

NBu

+

Rh2(OAc)4 CH2Cl2 73%

Ar

R

Scheme 21.14

R N Ar 98

N

R

1

R1 = Ph, Me R2 = PH, SiMe3, t-Bu Ph

Ph

MeO

H t NBu

2

97

H

N2

N

R 57-93%

2

CO2Me

Ph

2

HN

20 ºC

OMe

R

CO2Me Ar = p-NO2C6H4

21.5 Synthesis

j1883

21.5.1.2 From Cyclic Compounds 21.5.1.2.1 From Carbocycles The first approach to fully unsaturated azepines was reported by Wolff in 1912 and involves the thermal decomposition of a phenylazide in aniline, although it was Huisgen in 1955 who assigned the structure of 7-anilino-2Hazepine to the reaction product, which had remained unknown. On the basis of 1 H NMR data, this initial structure assignment subsequently had to be modified in favor of the 3H tautomer 101. This procedure is considered to be the most useful method for the synthesis of 3H-aminoazepines [124] and some related compounds since nucleophiles other than amines have been successfully used [125]. The mechanism of the formation of the 3H-azepines is shown in Scheme 21.15 and involves the intermediacy of a benzazirine (99) via the initial generation of a nitrene. The attack of the nucleophile on the azirine ring promotes an electrocyclic ring opening to give the 1H-azepine 100, which rearranges to the more stable 3H-tautomer. Nitroso and nitroarenes have also been used as alternatives to azides as the source of nitrenes. In this case the nitrene is generated by treatment with phosphines or phosphites. The aryl nitrene generated by photochemical decomposition of the corresponding azide is trapped with tetracyanoethylene and this leads to the formation of spiroazepine 102 (Scheme 21.15) [126]. Based on this approach to the azepine system, Hafner [57] and Lwowski [127] reported independently the most synthetically useful procedure for the synthesis of 1H-azepines. They discovered that some nitrenes were able to react with arenes to afford azanorcaradienes (the valence isomers of azepines), which rearrange to give stable azepines (Scheme 21.16). The nitrene is usually generated by thermal or photolytic decomposition and, in general, the reaction is more appropriate for N3

¨N

Heat or hv

Nu

Nu

N

N H

99

N H

N

Nu

101

100

Me

N3

NC Me

Me

NC

Nu

CN CN

NC NC Me

CN N+

hv MeCN

Me

CN Me

Me Me

Me

CN

N NC

CN

102 Scheme 21.15

CN

j 21 Seven-Membered Heterocycles: Azepines, Benzo Derivatives and Related Systems

1884

N-substituted azepines 103 bearing electron-withdrawing substituents. The reaction of the nitrene with substituted benzenes usually has poor regioselectivity and mixtures of 1H-azepines are formed, a fact that limits the scope of this method (Scheme 21.16) [128].

R-N3

hv or heat

Ar-H

¨

R-N

N-R

60-70%

N R 103 R = CO2R, CN, SO2R

Scheme 21.16

4,5-Dihydroazepines have been synthesized using cyclopropane derivatives in a multicomponent reaction that also involves primary amines and dimethyl acetylenedicarboxylate (DMAD). Initial formation of the corresponding cyclopropylimines followed by a rhodium-mediated [5 þ 2] cycloaddition afforded substituted 4,5-dihydroazepines 104 in good yields (Scheme 21.17) [129]. R

4

R

3

H2N-R

O R

2

MeO2C

R

1

+

[Rh(CO)2Cl]2 Toluene, 60ºC

CO2Me

up to 99%

R

MeO2C MeO2C

4

N 1 R

R

3

2

104 R1

= n-Bu, Bn, n-C6H11 R2 = Ph, cyclopropyl R3 = H, i-Pr R4 = H, Me

Scheme 21.17

21.5.1.2.2 From Heterocycles 2H-Azirines react with cyclopentadienones in a [4 þ 2] cycloaddition reaction to give polysubstituted 3H-azepines 106 by loss of carbon monoxide from the endo adduct 105 [130]. Aziridines have also been transformed into dihydroazepine or azepine derivatives 107 [78, 131] and 108 [132] by a Cope-type rearrangement on warming or at room temperature. Studies on these rearrangements show that the trans isomers are less prone to cyclization than cis isomers and higher temperatures are needed to produce the rearrangement (Scheme 21.18). Five-membered heterocyclic rings can also be converted into azepine systems by cycloaddition and rearrangement reactions. One example of the first process is the 1,3dipolar cycloaddition of heterobetainic compounds with cyclobutenes to yield the 4,5dihydro-1H-azepines 109 through the loss of carbon dioxide from the initially formed cycloadduct (Scheme 21.19) [133]. Rearrangements leading to azepines from five-membered rings are illustrated by the examples shown in Scheme 21.19. In the first case

21.5 Synthesis

R

2

R

Ph

1

+

N

R

O

Ph

3

R

Toluene

R

3

Heat

R

3

-CO

N

Ph

O

Ph

R

3

R

2

105 R

R

R

R

55-90% R

1

R

40-50%

N t Bu

R

Ph 1

N

R

3

106

R = H, Me

90ºC N t Bu

Ph

R1 = H, Me, Ph R2 = Ph, CH2Ph R3 = Me, Et, Ph

107

Sealed tube C6H6

3

2

Heat

N t Bu

j1885

N t Bu

108

Scheme 21.18

cycloadducts110,obtainedfromDMADandpyrroles,arephotochemicallyconvertedinto thermally unstable azaquadricyclanes, which rearrange to the substituted 1H-azepine derivatives 111 [134]. The other two examples concern the synthesis of the 1-phenyl-1Hazepine 113 by thermal decomposition of the triazole derivative 112 [135] and the preparation of azepinones 115 by ring expansion of the dioxopyrrole derivatives 114 [136]. The ring expansion of six-membered heterocycles is one of the main strategies for the formation of 4H-azepines. 4-Chloromethyl-1,4-dihydropyridines can be transformed into the 4H-azepine derivatives 116 in the presence of various nucleophiles, including alkoxides, amines, cyanide, thiolates, and enolates [137]. On the other hand, the 4H-azepine derivatives 117 are obtained by sequential Diels–Alder reaction of 1,2,4-triazines and cyclopropenes [138] followed by N2 extrusion and ring enlargement (Scheme 21.20). In both cases the isolated 4H-azepines are prone to isomerization to the more stable 3H-isomers. A substituted 2-pyridone has also been transformed into the 3H-azepinone 118 by treatment with LDA (Scheme 21.20) [139]. 21.5.2 Synthesis of Oxepines 21.5.2.1 From Acyclic Compounds As with azepines, ring-closing metathesis (RCM) has become the main strategy for the synthesis of dihydro- and tetrahydrooxepines through a C¼C bond forming reaction as this approach is simple and allows the easy identification of the target acyclic precursor of the desired oxepine. Although most of the RCM strategies have been applied to benzo and other fused azepine derivatives, one of the first examples of the application of the RCM to simple oxepines was reported by Nicolaou during the

j 21 Seven-Membered Heterocycles: Azepines, Benzo Derivatives and Related Systems

1886

R R

1

3

R

+ N

2

R

O

O

N

Ac2O

+

R

O

2

CN 76-93%

R

3

N 1 R

R

2

CH2Cl2 or C6H6

4

R1 = H, Me R2, R3 = Me, Ph, CH2Ph R4 = CN, CO2Me

MeO2C

R

hν

110

CO2Me

CO2Me

N R

10-95%

CO2Me

111 R = Ar, Ac, CO2Me, CONH2 p-Tosyl, Mesyl

N Ph N N

C6D6 36%

N Ph

150 ºC

112 MeO2C

O O

Ph

R

109

N

CO2Me

4

CN

R CO2Me

R

3

NC N

R

O

95 ºC

NC

1

Ph

N H

114

1. SnCl4/CH2Cl2 2. HCl/THF-H2O 60%

CO2Et Ph Ph

N Ph

113

OH N

O

115

Scheme 21.19

total synthesis of the complex polyethers ciguatoxin and brevetoxin. Different 4,5,6,7tetrahydroazepine derivatives 119 were obtained in a tandem reaction involving the metathesis of an alkene and a vinyl ether promoted by a titanium catalyst [140]. An alternative approach to tetrahydroazepine 120 involved RCM reactions of two alkenes (Scheme 21.21) [141]. The reaction was carried out in the presence of Grubbs’ secondgeneration catalyst (G-II) and H2 (5%) to facilitate the double bond migration through the formation of a ruthenium hydride species. The 2,5,6,7-tetrahydroazepine 122 has been reported by van Boom and was synthesized by RCM of 121 in 68% yield using Grubbs’ first-generation catalyst (G-I) [142]. This catalyst was also employed successfully in the synthesis of the more complex 2,3,6,7-tetrahydroazepine derivative 124, which was obtained in 95% yield from 123 [143] (Scheme 21.22). In an example of a double RCM reaction, the bistetrahydrooxepine 126 has been obtained from the tetraene derivative 125 [144]. An ene-allene carbocyclization reaction mediated by rhodium(I) has been reported to give 2,3,4,5-tetrahydrooxepines 127 in moderate yields (Scheme 21.23) [145]. Complete decomposition of the same substrates was observed depending upon their substitution pattern.

j1887

21.5 Synthesis H CH2Cl R

EtO

R

Me

NaOMe/MeOH

Me

N H

N H

Me

R

R

EtOH

R

Me

Heat 83%

Me

R

N

Me

116 R = CO2Me

R

R

2

3

R N N

N R

N

7

R

+

1

R

R

4

5

R

6

2

N N

R

R

3

R

R

7

R

5

R

1

R

R 17-87%

6

4

5

R R6

4

3

R

R N

2

R

Ph

Ph

LDA Ph

N Ph

THF -78ºC

O

Ph

N Ph

Me

O

O

16%

Me

= CO2Me R2 = Me, Ar R3 = Me, Ph R4, R7 = H, Me, Ph R5 = H, Me R6 = H, Ph

Ph

N H

Ph Me

118

Scheme 21.20

O O

R R

O

RCM, G-II O

32-78%

R

119 R = Me, Ph Ph

O

G-II CH2Cl2 45-70 ºC

Ph

O

Ph

O

54%

O

Ph

G-II CH2Cl2 45-70 ºC

Ph

O

1

117 R1

Ph

7

50%

120

Scheme 21.21

Formation of the oxepine ring through C
O bond formation has been achieved by exploiting the nucleophilicity of the oxygen towards an appropriate electrophilic carbon. Several different strategies leading to tetrahydrooxepine derivatives based on this bond formation have been described. The cyclization of 1,6-diols is one of the classical approaches to oxepane and oxepane derivatives. It was also found that hexane-1,6-diol cyclizes to give 4,5,6,7-tetrahydrooxepine (128) in the presence of

j 21 Seven-Membered Heterocycles: Azepines, Benzo Derivatives and Related Systems

1888

BnO

O

BnO

G-I

BnO

Toluene

BnO

BnO

68%

OBn

O

121

122

Pr Et BnO

H

O

H

i

i

Pr O

N O

G-I CH2Cl2, 40ºC

O

95%

Et BnO

123

H

O

N O

O

124

G-I

O

O

O

H

C6H6, rt

O

O

50% 125

126

Scheme 21.22

Me

O C

R Toluene, 90 ºC

R

Me

[Rh(CO)2Cl]2 40-55%

O 127 R = C6H13, t-Bu

Scheme 21.23

Cu-Cr catalyst at high temperature (250  C) [146]. Substituted derivatives 129 are obtained from acyclic hydroxy-acetals (Scheme 21.24) [147]. 2,7-Dimethyl-4,5-dihydrooxepine (131) has been synthesized by the cyclization of diester 130 upon treatment with hydrochloric acid [148]. The intramolecular version of the Nicholas reaction [149] has been employed to obtain oxepine derivatives by attack of the oxygen of an alcohol to propargylic carbocations, which are stabilized by alkynyl-dicobalt complexes. The decomplexation is carried out under reducing conditions or with cerium ammonium nitrate (CAN). Two different arrangements of the carbocation and the oxygen, leading to the 2,5,6,7-tetrahydrooxepine and 2,3,6,7-tetrahydrooxepine derivatives 132 and 133, respectively, are shown in Scheme 21.25. The first approach has been used in the synthesis of ciguatoxin [150] and the second one in the preparation of 2,7-disubstituted oxepines similar to isolaurepinnacin [151]. The transition metal-mediated cycloisomerization of alkynols, which is extensively used for five- and six-membered rings, has also been expanded to the synthesis of

21.5 Synthesis

j1889

Cu-Cr Heat

O O H

O

O O

128

R

R

MeO

R

O

OMe

OAc

O

OMe

129

Mg Br

Me

O

H

H

HO

38%

OH

HCl

Et2O

68%

O O

Me

Ac Ac

O

Me

131

130 Scheme 21.24

1. Co2(CO)6

R HO

Co2(CO)6

R

2. Lewis acid

Co2(CO)6

+

CH2Cl2

O OH

OH

79-90%

R

O

R

132 R = alky, alkenyl

1. Co2(CO)6 2. Lewis acid HO

3. CAN

HO R

HO

+

Co2(CO)6 R

O

Co2(CO)6

68-79%

R

O

133

R

R = H, Me, n-C5H11, CH2OBn

Scheme 21.25

some 4,5,6,7-tetrahydrooxepines such as 134 and 135 from furanose-derived alkynols (Scheme 21.26) [152]. The cycloisomerization to the corresponding seven-membered cyclic enol ethers under tungsten carbonyl catalysis proceeds with good yields and virtually complete regioselectivity for all diastereomers, favoring the product resulting from endo-mode cyclization. The unexpected regioselectivity may be dependent on the presence of the dioxolane structure tethering the terminal alkyne and diol functional groups. Palladium-mediated C
O bond formation via a cationic p-allylic palladium complex has proven its utility in the cyclization reaction of bromoallenes through intramolecular attack of an oxygen nucleophile. Appropriate allenes can

j 21 Seven-Membered Heterocycles: Azepines, Benzo Derivatives and Related Systems

1890

OH

R

Base H

HO

H

O

M(CO)5

R

OH C M(CO)5

1. W(CO)5, Et3N THF, hν

OH

O

R

2. Ac2O, DMAP

O

R O

M(CO)5

O

O

AcO O

61%

134 Me

HO

1. W(CO)5, DBACO THF, hν

OH

O O

H

2. Ac2O, DMAP

O

O

AcO

69%

O

135

Scheme 21.26

lead to seven-membered rings that, in the presence of a second nucleophile, afford substituted 3,4,5,6-tetrahydrooxepines [153] 136 and 137 (Scheme 21.27). A mechanistically related reaction is the cyclization of allenyl sulfoxides and sulfones, which under basic conditions afford the corresponding 1-methyl-2-sulfinyl- and 1-methyl-2sulfonyl-tetrahydro-oxepines 138a and 138b in goods yields [154]. 21.5.2.2 From Cyclic Compounds 21.5.2.2.1 From Carbocycles Three-, four-, and seven-membered carbocycles have been employed as starting materials for the construction of the oxepine ring system, although the most synthetically useful procedures involve cyclopropanes and cyclohexenes as starting carbocycles. The most efficient method for the synthesis of dihydro- and tetrahydrooxepines involves the ring expansion of alkenylcyclopropylcarbinols. These cyclopropane derivatives are transformed into the corresponding aldehydes under controlled oxidation conditions (Swern or Dess–Martin periodinane). Subsequent hetero-Cope rearrangement affords substituted 2,5-dihydrooxepines 139 (Scheme 21.28) [155]. MP2/6-31G studies on vinylcyclopropane carbaldehyde as a model show that the aldehyde and the oxepine are almost isoenergetic and the activation energy is about 25 kcal mol
1 [156]. The ring expansion of a four-membered ring is illustrated by the formation in low yield of oxepine (5) from bicyclo[2.2.0]hexa-2,5-diene (Scheme 21.29). The method involves epoxidation of the bicyclobutene ring followed by rearrangement of the resulting tricycle [157]. The method has also been applied to the formation in low yield of perfluorinated dihydrooxepines 140 from perfluorobicyclo[2.2.0] hexanes [158].

21.5 Synthesis OH

R

Pd(0)

R

R

OH

R

Nu

C

C

O

PdBr

Br

j1891

PdBr

O

Nu

O NaH/Pd(Ph3)3

OH O

C

O

Br

C

Me

BnOH/THF 72%

Br

OBn

O

136 Me

NaH/Pd(Ph3)3

OH

Me

O

MeOH/THF 72%

Me

OMe

O

137 OH

KOtBu

C

R

HOtBu

O

R

Me

138a: R = SOPh (81%) 138b: R = SO2Ph (82%)

Scheme 21.27

R

3

R

R

2

4

R

1

OH

(COCl)2 DMSO/Et3N

R

3

or Dess-Martin R

4

R

2

R O

R

1

2

R 90-97%

R

1

O

R

3

4

139 R1 = H, alkyl, CH2OH, CO2R R2 = OTBS R3, R4 = H, Me

Scheme 21.28

The formation of the oxepine ring from six-membered carbocycles is one of the most useful routes to monocyclic oxepines. The method is based on the epoxidation and bromination of 1,4-cyclohexadienes. The dibromoepoxides, when subjected to dehydrohalogenation conditions, afford the corresponding oxepine–benzene oxides and these tautomerize to oxepines (Scheme 21.30). The electronic nature of the substituents in the cyclohexadiene ring determines which of the two possible substituted azepines is formed and this depends on which of the two double bonds are initially involved in the epoxidation or bromination reactions [159]. 2-Vinylox-

j 21 Seven-Membered Heterocycles: Azepines, Benzo Derivatives and Related Systems

1892

115 ºC

O

O 5

F

F F

F hν

O

F F

F

F

F

F

n-C5F12

F

F F

F O

F

F

140

Scheme 21.29

R

R

Br2

R

Br

R O

Br2

41-80%

Base

O

O

O

O

RCO3H

R

R

Br

R O

Base

R=H

R O

75% Br

O

Br

R

R = Me, vinyl

Scheme 21.30

epine, one of the less stable oxepines, has been synthesized using this approach [160], which has also been used for the synthesis of disubstituted oxepines such as 2,7diphenyloxepine [70a]. Arene oxides can also be formed by the acid-catalyzed dehydration of some substituted cyclohexene-1,4-diols. The subsequent ring expansion produces relatively stable polysubstituted oxepines 141 (Scheme 21.31) [161].

R

1

R

OH

R

1

1

TFA R

4

R

3

OH

R

+

2

R

17-70% R

4

R

3

OH

R

2

R

4

O

R R

3

1

R

2

R

2

O

R

2

3

141 R1 = Ph, Ar; R2 = tBu R3 = Ar

Scheme 21.31

j1893

21.5 Synthesis

21.5.2.2.2 From Heterocycles Oxiranes have been used as extensively starting heterocyclic compounds in the preparation of oxepanes. Some oxirane derivatives have also been employed in the synthesis of oxepine derivatives. The two examples shown in Scheme 21.32 lead to 2,6- and 2,3-disubstituted-4,5-dihydrooxepines 142 and 143, respectively [162]. O

CO2Me

Heat

OHC

Quantitative

O

O

CO2Me

142 O

CO2Me

Heat

CHO

Quantitative

O

O

CO2Me

143

Scheme 21.32

The parent oxepine (5) can be prepared by a short and efficient route starting from 7-oxanorbornadiene as the five-membered heterocycle. Isomerization of this bicyclic compound into the monocyclic oxepine is promoted photochemically and this is followed by thermal rearrangement [163]. Several di-, tri-, and tetrasubstituted oxepines 144 have been prepared using the same approach, which is based on a Diels–Alder reaction of substituted furans with alkynes to give the corresponding 7-oxonorbornadienes (Scheme 21.33) [164]. O

O

Heat

hν Me2CO

O

5

R

2

O R

R

3

R

3

O

O R

+

1

R

2

R

1

R

3

3

hν

R R

2

R

1

R

3

3

C6H6 or Toluene

R

3

R

3

R

Heat 36-95%

O

R

2

1

144 R1, R2 = H, Me, Br R3 = CO2Me

Scheme 21.33

A 2,3-dihydrofuran is the starting material in a [2 þ 2] cycloaddition reaction with alkynyl or alkenyl compounds to give bicyclic adducts, which in turn give 2,3dihydrooxepines 145 by thermolysis or acid Lewis catalysis (Scheme 21.34) [165].

j 21 Seven-Membered Heterocycles: Azepines, Benzo Derivatives and Related Systems

1894

In a similar approach the substituted oxepine 146 can be obtained from a bicyclic furan derivative under thermolysis conditions [166]. H

CO2Me O

R

CO2Me

+ O

CO2Me

65-85% CO2Me

R

CO2Me

Heat or Lewis acid

CO2Me O

R

145

R = H, Me, alkenyl H

CO2Me

CO2Me

CD3CN

Me O

Me

70%

CO2Me

CO2Me Me

O

Me

146 Scheme 21.34

An alternative procedure for the synthesis of 4,5-dihydrooxepine (148) involved the use of the fused sulfolane 147. This tricyclic system under flash vacuum pyrolysis produces the cis-2,3-divinyloxirane, which by a Cope rearrangement affords 148 in 55% yield (Scheme 21.35) [167].

O

O 2S 147

FPV

O

55%

O 148

Scheme 21.35

Six-membered O-heterocycles have also been used as starting materials in different approaches to oxepines. One of the most efficient routes starts with pyrilium salts, which are converted into the 4-diazomethyl-4H-pyrans. A ring enlargement promoted by allylpalladium chloride as a catalyst affords the corresponding substituted oxepines 149 in almost quantitative yield (Scheme 21.36) [168]. Another route to dihydrooxepinones involves the reaction of 2,3-dihydropyran derivatives with carbenes. The intermediate bicycles undergo a similar ring expansion process to that shown in Scheme 21.37, giving the corresponding tetrahydrooxepinones 150 [169] and 151 [170]. Alkynylpyranosides have also been used as starting heterocyclic compounds for the synthesis of oxepines. Examples of this strategy are shown in Scheme 21.38 for the synthesis of tetrahydrooxepines 152 and dihydrooxepine 153. The synthetic route starts with the formation of the cobalt complexes and this is followed by a

21.5 Synthesis

R

Me

2

Li R

1

1

O + F4B

R

Me

N2

R

R

1

2

R

(µ−C3H5PdCl)2

92-98%

1

O

2

Me

N2

j1895

R

1

O

R

1

R

149 R1 = Me, tBu R2 = CO2Me, P(O)(OMe)2, Ph(O)OMe, P(O)Ph2

Scheme 21.36

1.HCCl2Me/BuLi 2. MeOH, heat O

O

Me

Me Cl OTMS

O

60%

O

150

OTMS Br

:CBr2 O

HP(O)(OEt)2

Br

Br OTMS

O

Et3N

O

O

75%

O

151

Scheme 21.37

AcO

AcO O 1

OR

R

Co2(CO)6

OR

2

OAc

O

2

R

I2

1

OR

2

O

BnO

1

OR O

Co2(CO)6 R

AcO

H

152

R1 = TBDPS R2 = TMS 2

R

20-35% OH

AcO

OAc

O OTBDMS

1

OR

AcO

1

BnO

Scheme 21.38

OAc

TfOH

O

153

OAc

2

R

j 21 Seven-Membered Heterocycles: Azepines, Benzo Derivatives and Related Systems

1896

ring-opening reaction catalyzed by TfOH. Recyclization of the resulting ring-opening products followed by decomplexation affords the corresponding oxepine derivatives [171]. 21.5.3 Synthesis of Thiepines 21.5.3.1 From Acyclic Compounds Although cyclization reactions have been used extensively for the synthesis of thiepane derivatives, the use of acyclic compounds as starting materials in thiepine synthesis is very limited. One of the few examples was reported in 2001 for the synthesis of the 2-tosyl-4,5,6,7-tetrahydrothiepine (155), which was obtained by cyclization of the hexane derivatives 154 in the presence of sodium iodide in DMF (Scheme 21.39) [172]. It was suggested that cyclization of the chloride and methanesulfonate takes place via the iodo derivative.

NaI X

DMF

Ts

MeS

55-62%

154

S

Ts

155

X = I, Cl, OSO2Me R R

3

R

2

4

R

1

R

THF

Cl

Cl

R

Li2S/Al2O3

Me Me

Bu

Bu

t

158

2

R

1

157 R1, R2, R3, R4 = H, Cl, tBu

t

S2Cl2

R

S

66-82%

156

Me Me

3

4

Me Me Me Me

Cl

Bu

t

SSCl Bu

t

Me Me Me Me

Bu

t

S S Bu

99% t

Bu

Me Me

t

S

Me

Bu

Me

t

159

Scheme 21.39

Based on a reported method for the synthesis of the parent thiepane by a double nucleophilic substitution, the reaction of the dienic dichlorides 156 with Li2S gave the corresponding 2,7-dihydrothiepines 157 in moderate or good yields (Scheme 21.39) [173]. An excellent yield has been reported for the reaction of decadiyne 158 with S2Cl2 to afford the 4,5-dihydrothiepine 159 [174] through the mechanism shown in Scheme 21.39.

21.5 Synthesis

21.5.3.2 From Cyclic Compounds 21.5.3.2.1 From Heterocycles A similar thermal rearrangement to that used for the synthesis of 4,5-dihydrooxepine from divinyloxirane has been reported for the preparation of the corresponding 4,5-dihydrothiepine 160 from cis-1,2-divinylthiirane (Scheme 21.40) [175]. Heat H

100%

H

S

S 160

Scheme 21.40

Stable monocyclic thiepines have been obtained from thiophene derivatives, which react with DMAD in a cycloaddition reaction to afford the corresponding bicyclic adduct. Subsequent thermal isomerization gave the first monocyclic thiepine 161, which has been fully characterized (Scheme 21.41) [176].

Me

N

DMAD -30ºC

S

N

Me S

CO2Me

CO2Me

N

CO2Me

Me

CO2Me

S 161

Scheme 21.41

The ring expansion of thiopyrans has been used as the main strategy to synthesize monocyclic thiepines, although moderate or low yields have usually been obtained. For example, one of the most widely studied thiepines, 2,7-di-tert-butylthiepine 163, was obtained in 30% yield from the thiopyran derivative 162 by treatment with acetic acid in the presence of sodium acetate and acetic anhydride at 90  C. The formation of the seven-membered ring is assumed to take place via the carbenium ion intermediate under the solvolysis conditions (Scheme 21.42) [71]. OMs

+ AcOH/NaOAc

Bu

t

S 162

Scheme 21.42

Bu

t

Heat Bu

t

S

Bu

t

30%

Bu

t

S 163

Bu

t

j1897

j 21 Seven-Membered Heterocycles: Azepines, Benzo Derivatives and Related Systems

1898

Six-membered thiopyrylium salts have also been used as starting heterocycles in the synthesis of other stable monocyclic thiepines. For example, salts 164 react with ethyl lithiodiazoacetate to give the corresponding thiopyrans, which in the presence of palladium or under acidic conditions are able to generate the corresponding substituted thiepines 165 via a carbene intermediate (Scheme 21.43) [177].

CO2Et

Me Li Bu

t

S + F4B

Bu

t

EtO2C Me

N2

CHCl3

Bu

t

EtO2C

N2

S

Bu

Me

100%

t

Bu

t

CO2Et

:

Me

Pd

S

Bu

t

Bu

t

S

Bu

t

165

164 Scheme 21.43

21.5.4 Synthesis of Azepanes, Oxepanes, and Thiepanes

Most of the synthetic methodologies based on cyclization reactions used for the preparation of monocyclic azepine, oxepine, and thiepine derivatives can also be applied to the synthesis of fully unsaturated seven-membered systems 7–9, especially given that hydrogenation of dihydro-, tetrahydro-, or even fully unsaturated seven-membered heterocyclic rings is an easy process that can be carried out under very mild conditions. A RCM reaction followed by hydrogenation of the resulting dihydro derivative is one of the most successful approaches to azepane systems. Several examples of this strategy are represented in Scheme 21.44 [109, 178]. Several densely functionalized chiral azepanes have been prepared by multistep sequences starting from carbohydrates. In a typical example, an appropriate carbohydrate is transformed into a suitable amine or azide, such as 170 [179] or 172 [180], and this is cyclized to the corresponding azepane derivatives 171 and 173 under the conditions shown in Scheme 21.45. Two classical synthetic approaches are useful in the synthesis of azepin-2-ones and these include the industrial synthesis of hexahydro-1H-azepin-2-one (33) (e-caprolactam). One is the Beckmann rearrangement of oximes generated from cyclohexanones [181] and the other is the Schmidt reaction applied to cyclohexanones [182]. The main problem associated with these reactions as synthetic strategies for some azepinone derivatives is that unsymmetrically substituted cyclohexanones can give two isomeric products (Scheme 21.46). In a similar strategy to that used for the synthesis of azepane, dihydro- and tetrahydrooxepines have been transformed into oxepane (8) by catalytic hydrogenation under standard conditions, such as those used on the conversion of 2,3tetrahydrooxepine into oxepane (Scheme 21.47) [183].

21.5 Synthesis

EtO2C

90-97%

R

R

1

R

2

H2, Pd/C 50 psi, AcOH

RCM

1

G-II 75-88%

N Boc

Xc

1

R

74-100%

N Boc

O

O

O

G-I 97%

Ph

O

2

N H

R1 = Me, Et, Ph R2 = H, Me, OEt

1. LiOOH 2. H2, Pd/C

N

RCM N Boc

O

Ph

OH

87%

N Boc

168 Xc O OH

N SO2 Py

R

167

N N Boc

N Boc

166

2

O

Et2OC

90%

N Boc

G-I or G-II N Boc

R

H2, Pd/C

Et2OC

RCM

j1899

RCM

OH

G-I 75%

N SO2

O Xc = O

N

O

Ph

Py

HO 1. LiOOH 2. H2, Pd/C 89%

O OH

N SO2 Py

169

Scheme 21.44

Another of the most widely used approaches to oxepane (8) and oxepane derivatives such as 174 is the intramolecular cyclization of 1,6-hexanediols using various dehydrating agents (Scheme 21.48) [184]. Other similar cyclization reactions of 1,6-disubstituted hexanes involving different leaving groups in the presence of various catalysts have also been employed in the synthesis of oxepane derivatives (Scheme 21.49) [185]. One of the most interesting versions of this cyclization is the regioselective intramolecular ring-opening reaction of epoxyalcohols catalyzed by acidic or basic conditions, a strategy that has been successfully used in the total synthesis of polyethers [16, 186]. Careful control of the ring-opening process is necessary to avoid the formation of the tetrahydropyran derivative. The Baeyer–Villiger oxidation [187], a typical transformation of cyclic ketones into lactones, has been used in the synthesis of seven-membered lactones (e-caprolactones) from cyclohexanone derivatives in the presence of typical peracids

O

j 21 Seven-Membered Heterocycles: Azepines, Benzo Derivatives and Related Systems

1900

HO

OH

H2N

O

HO

HO

NaHCO3/THF 40 ºC

OH

HO

83% HO

OH

N H

HO

OH

170

OH OH OH

171

N3

Me

Me

O

O Me Ph3P/MeCN 50 ºC then H2O O

Me

O OBn

29%

OBn NH2 N H

OH

173

N3 172 Scheme 21.45

NH2OH

PPA N

O R

O

+

H+ N3

Scheme 21.46

R

R and/or N H

O

N H

O

OH

N3

H+

O

O

PPA N

O

R

OH

R

NH2OH

N H 33

HO

OH

N

+ N N

N H 33

R

R and/or N H

O

N H

O

O

21.5 Synthesis

H2/Pt 89%

O

O 8

Scheme 21.47 -H2O OH

HO

28-72%

O 8

PtCl2/AgSbF6 Ph

O O H H

Ph

ClCH2CH2Cl 75%

Ph

O

Ph

174

Scheme 21.48

(Scheme 21.50). Some recent developments include oxidation by urea/hydrogen peroxide and trifluoroacetic anhydride [188], and aqueous hydrogen peroxide with diaryl diselenides [189] or tin zeolite [190]. Additionally, some biocatalytically driven methods include monooxygenase [191] and genetically modified yeasts [192] as well as the combination of hydrogen peroxide and myristic acid catalyzed by lipases [193]. The use of oxygen as an oxidant catalyzed by mixtures of Fe(II) and Ni(II) or with MnO2 or RuO2 in the presence of benzaldehyde has also been reported [194]. The use of chiral metallic complexes gave lactones in high ee yields [195]. Some representative examples of these oxidations are shown in Scheme 21.50 for lactones 179–181. Thiepane (9) was first obtained by a radical cyclization reaction of 5-hexenethiol under photolysis conditions (Scheme 21.51) [196]. It has also been prepared by a double nucleophilic substitution from 1,6-dibromohexane either using sodium sulfide (59%) [197] or, better still, by in situ generated lithium sulfide (from hexamethyldisilathiane and methyllithium in a polar aprotic solvent) (Scheme 21.51) [198]. Chiral thiepane derivatives such as 182 and 183 have been synthesized by a thioheterocyclization method involving bis-epoxides and a sulfide salt [199]. This approach is based on an initial regioselective ring opening of one of the epoxides followed by attack of the resulting thiolate to the other epoxide to form the sevenmembered thiepane ring (Scheme 21.52). Thiepan-2-one (184) has been prepared by a similar strategy to that employed for 9 by cyclization of 6-bromohexanoic acid chloride using lithium sulfide generated in situ (Scheme 21.53) [200]. The synthesis of thiepan-3-one (185) was described initially by a Dieckmann-type cyclization [201] and later by reaction of the thiacyclohexan-3-one with diazomethane [202], a procedure also employed for the preparation of the thiepan-4-one (186) [203] (Scheme 21.53).

j1901

j 21 Seven-Membered Heterocycles: Azepines, Benzo Derivatives and Related Systems

1902

R

R X

O H

Base or Lewis acid O

O R = H (28-70%)

(CH2)n

O

Base or Lewis acid

OH

OH O H

n=1,2

MeO O

O

OH

OMe

La(OTf)3

OH R

O

80-90%

O 1 R2 R H

and/or

O

R

1

2

R1, R2 = H, Me

175

O OH

OBn

Zn(OTf)2 83-98%

O

176

O

(Bu3SnO)2/Zn(OTf)2 85%

BnO OH

OMPM

OBn

H OH

BnO

H

O

H

OBn OH

177

Scheme 21.49

21.5.5 Synthesis of Benzo Derivatives 21.5.5.1 Synthesis of Benzazepines The three isomeric parent benzazepines are not known, although stable derivatives of 12, 15, and 18 have been prepared using many of the synthetic strategies employed in the preparation of monocyclic azepines. 1H-1-Benzazepine derivatives 187 have been obtained by cyclization reactions [204, 205]. An unusual ring expansion of quinolinium salts also afforded N-substituted derivatives 188 in good yields [206], and the ring-closing metathesis reaction is an important method for the preparation of stable dihydro derivatives [207] (Scheme 21.54).

21.5 Synthesis

R-CO3H O

HO

O

O

O R

F3C Se F3C

2

H2O2/CF3CH2OH

O

56%

Ph

O

54

O

O Ph OH 178 O

R

O

Ph

1. Urea-H2O2 (CF3CO)2O CH2Cl2 2. NaHCO3/H2O

Ph

O O

O

96%

O 179

Ph

Ph OH

O

Engineered baker’s yeast

O

R

Yield: 15-82% ee: 49->98%

180 R = Me, Et, n-Pr, i-Pr, allyl, n-Bu

O

O2/RuO2/PhCHO ClCH2CH2Cl

O R

1

O

54-95% 181

R

2

R1 = H, Me R2 = H, Me, (CH2)6Me, i-Pr, t-Bu, CH2CH2COMe Scheme 21.50

j1903

j 21 Seven-Membered Heterocycles: Azepines, Benzo Derivatives and Related Systems

1904

hv S.

S H

Na2S 59%

Br

S

Li2S/THF

Br

9

61% Scheme 21.51

PO

OP

PO

OP

HO

S2

OP

HO

O

O

O

PO

OH S

S

P=Protecting group

O

Na2S, EtOH reflux

O O

O

90%

O

O

HO

OH S 182

BnO

OBn

O

O

Na2S, EtOH reflux 75%

BnO

OBn

HO

OH S 183

Scheme 21.52

2H-2-Benzazepine (15) is unknown and only a few 1H-, 3H-, and 5H-derivatives have been prepared. The examples shown in Scheme 21.55 include a ring expansion of dihydroisoquinolines 190 [208], the ring-closing metathesis reaction of diene 193 [209], the acid-catalyzed cyclization of phenylsulfanylacrylamides 195 [210], and the transformation of nitrones 197 into the 1H-2-benzazepin-3-ones 198 by a complex mechanism [211]. 3H-3-Benzazepines are known as 1H-tautomers or N-substituted derivatives but the parent compound 18 remains unknown. As is the case for 2H-2-benzazepines,

21.5 Synthesis

Li2S Br

THF 13%

COCl

S

O

184 CO2Et

CO2Et

NaOEt/EtOH

CO2Et

H2SO4

O

75%

S

S

O

Reflux 85%

S 185 CH2N2

O

O CH2N2

O

BaO 42%

S

S

S

186

Scheme 21.53

OH O OBu NO2

t

1. Pyridine/CH2Cl2 2. K2CO3/DMF 3. SnCl2/MeOH

+ Et2OC

62%

N H

NO2 N2

Cl

CO2Me

N+ CO2Et

CO2Me

187

R O

CuOTf, DCE reflux 82-98%

N EtO2C

R O

188 R = OEt, Ar, alkyl RCM/G-I N COPh

Toluene 86%

N COPh 189

Scheme 21.54

j1905

j 21 Seven-Membered Heterocycles: Azepines, Benzo Derivatives and Related Systems

1906

R

2

OMs

Me

OEt

R

t-BuOK DMSO

2

2

R

1

Me OEt

and/or

OEt

N

N

N R 190

R

Me

R

1

1

192 (15-90%)

191 (69-71%)

R1 = H, Ph R2 = H, Me i

Me

i

OPr MeO

G-I, Toluene

Ts N

OPr MeO

Quantitative

N

194

193 R

2

R

3

R

1

1. PhS NH2 R

CO2Ar

2. MeI

4

R

2

R

3

R

Ts

SPh

1

O N R

4

p-TsOH 15-77%

Me

R R

3

+R

1

NaOMe/MeOH

N O R

2

197

24-93%

R

3

R

3

R

3

R

1

O N R

4

Me

196

195 3

R

2

R

R1, R2, R3, R4 = H, OMe

2

O N

R

1

198 R1 = Me, Ph, t-Bu R2 = H, Me, Br, Ar, SiMe3 R3 = H, OMe

Scheme 21.55

the number of known derivatives is limited and only a few procedures are synthetically useful for the preparation of such compounds. These methods include the synthesis of derivatives 200 from 199 [212], the insertion of nitrenes generated in situ from thermolysis of azidocinnamates such as 201 and 202 [213], and the ring expansion of isoquinolinium salts 204 [214] (Scheme 21.56). 21.5.5.2 Synthesis of Benzoxepines The parent 1-benzoxepine (13) was first obtained from a tetrabromoepoxide precursor (207), which under basic conditions is transformed into the corresponding arene oxide 208. The valence tautomerization of 208 yields a mixture of 13 and the bicyclic oxepine 209 [215]. The reaction of pyridazine N-oxide with benzyne produced 13 (and some derivatives from pyridazines) in moderate yield, via a 1,3-cycloadduct [81b]. An intramolecular Wittig reaction on 210 also afforded 13 in 25% yield

21.5 Synthesis

H N

Ph OH

O

MeO

1. H3PO4/PPA, 100 ºC 2. DDQ, C6H6, heat

j1907 Ph

MeO

NH

91%

MeO

MeO

O

200

199 CO2Et

R

N3 Ph

CO2Et

Heat

201

N

Toluene CO2Et

R

R 203

N3

R = Me (21%) R = Ph (37%) 202

N

HCBr3 MeCN/H2O/KOH

+

Br 204

Bn

AgNO3/MeOH N

89%

CBr3

Bn

N Bn

44%

205

OR

O

206 R = H, Me

Scheme 21.56

(Scheme 21.57) [216]. The RCM reaction of enynes 212 has also been used in the synthesis of dihydro-1-benzoxepines 213 with yields ranging from 61% to 99% depending on the reaction conditions [217]. 2-Benzoxepine (16) has not been prepared to date and only a few derivatives are available. For example, the dihydro derivatives 214 have been obtained by the cyclization of allene ethers in the presence of palladium catalysts [218]. 2-Benzoxepin-5-ones 215 have been prepared in a multistep synthesis from phthalides (Scheme 21.58) [219]. 3-Benzoxepine (19) has been prepared in 55% yield from phthalaldehyde and an appropriate bis-phosphonium salt by a double Wittig reaction (Scheme 21.59) [220]. 21.5.5.3 Synthesis of Benzothiepines The parent 1-benzothiepine (14) and various substituted 1-benzothiepines 218 have been obtained from 2H-1-benzothiopyrans 216. This precursor reacts with n-BuLi/ CH2Cl2 and the intermediate anions formed by quenching with electrophiles afford

j 21 Seven-Membered Heterocycles: Azepines, Benzo Derivatives and Related Systems

1908

Br

Br KOH/EtOH O

+

O

Br

Br

O 13

208

207

209 Br + PPh3 CHO OH

Ph3P.HBr

CHO

O

O

O

210

61-99% R

O N+

O

213 R = H, Me, OMe, NO2

212 Scheme 21.57

R

C Br O

R

PdCl2(PPh3)2 K2CO3/EtOH-DMF

O 214 R = H (75%) R= Me (61%)

O

O

O R

R

Me O R R 215 R = H, Me, Et, Pr, i-Pr, vinyl, Ph

Scheme 21.58

O

211

RCM

R

25%

13

N

O

O

60%

21.5 Synthesis

CHO CHO

Br

+

+ Ph3P

O

Br NaOMe/MeOH + 55% PPh3

j1909

O 19

Scheme 21.59

the tetracyclic compounds 217, which under mild conditions in the presence of a Rh (I) catalyst isomerize to the corresponding 1-benzothiepines (Scheme 21.60) [221]. An alternative route to 14 has been described from the 1-benzothiepinone 219 in a four-step sequence that involves isomerization of the double bond in the presence of Et3N, reduction of the ketone with CeCl3/NaBH4, formation of the tosylate, and elimination with potassium tert-amylate [81b] (Scheme 21.60). R

n-BuLi/CH2Cl2

57-100%

217

216

S

Rh(I) S

S

O

R

R

1. Et3N/CH2Cl2 2. CeCl3-NaBH4 89%

HO

S

S

14: R = H 218: R = 2-Cl, 3-Me, 4-Me, 4-Cl, 4-CHO, 5-Me 1. KH/TsCl 2. KOAmt 80%

14

219 Scheme 21.60

The ring expansion method shown in Scheme 21.43 for the preparation of monocyclic thiepines has also been employed in the synthesis of ethoxycarbonylsubstituted 1-benzothiepines 220 from benzo-1-thiopyrilium tetrafluoroborate [222]. The reaction of dibromostyrene with alkynes in the presence of a palladium catalyst leads to the formation of the corresponding enynes in good yields. These enynes can be transformed into 2-alkyl-1-benzothiepines 221 in moderate or low yields by metalation with tert-butyllithium followed by reaction with sulfur and ethanol (Scheme 21.61) [223]. Although 2-benzothiepane and some derivatives have been described, the parent 2-benzothiepine (17) and stable simple derivatives remain unknown. However, 3-benzothiepine (20) has been prepared from phthalaldehyde [224] under the conditions shown in Scheme 21.62. Among the few simple 3-benzothiepine derivatives known, the dicarboxylic acid was the first 3-benzothiepine derivative obtained from phthalaldehyde by a double Knoevenagel condensation (Scheme 21.63) [225]. The 2-tert-butyl-4,5-dihydrobenzothiepine (223) is reported to be obtained by cathodic reduction [226].

j 21 Seven-Membered Heterocycles: Azepines, Benzo Derivatives and Related Systems

1910

N2LiCCO2Et S +

F4B

or

THF-Et2O

Br

CO2Et

S

S

CO2Et

19-31%

S

N2

220

1. t-BuLi/THF, -80ºC 2. S, -80ºC 3. EtOH, 55 ºC

R Br

Allylpalladium choride dimer CHCl3

CO2Et

N2

PdCl2(Ph3P)2/CuI

Br

Benzene

R

SH

R

5-25%

S

R

221

80-90%

R = Me, Bun, But, n-Hex, c-Hex, n-Oct

Scheme 21.61

CHO

+ BrCH2PPh3 Br

CHO

t-BuOK

Li

t-BuLi/Et2O

Br

Li

Br

90%

(PhSO2)2S

S

15% 20 Scheme 21.62

CHO CHO

+

EtO2C

S

CO2Et

222 Bu

Cl Scheme 21.63

S

51%

S S

CO2H

1. NaOH 2. H3O+

t

e

S

8% 223

Bu

t

CO2H

21.6 Reactivity of Azepines

21.6 Reactivity of Azepines 21.6.1 Reactivity of Azepines and Benzofused Derivatives

As stated above, the azepine systems occur in four tautomeric forms, and the derivatives of the 1H- and 3H-tautomers are the most widely studied. The parent heterocycle 1H-azepine (1) is a red oil that rearranges in the presence of acid or base to the more stable 3H-azepine (Scheme 21.64). The 1H-azepine tautomer is unstable [83, 227] and, as a consequence, only N-substituted derivatives of 1H-azepine exist in the 1H-tautomeric form. The 4H-azepine can be isolated and stored but in basic solution also isomerizes to the 3H-azepine. Isomerization

OH N CO2Et

-CO2

N H 1

H H N 3

Scheme 21.64

The stability of the 1H-azepine is enhanced by the presence of electron-withdrawing substituents, particularly at the 1-position, because they decrease the electron density in the 8p antiaromatic ring system. Consequently, reduced and partially reduced azepines are particularly common, together with the benzo derivatives. The increase in ring size constrains these compounds and they are nonplanar so as to decrease the ring strain. The lack of planarity, however, affects aromaticity, and so the reactivity of unsaturated azepines is similar to that of cyclic polyenes. In general, the reactions of these compounds involve neutral molecules. Although stable as anions, the cations or radicals derived from azepines are less common, but some processes have been described as occurring through these species, particularly for partially saturated systems. Thus, anions derived from 1H-, 3H-, and 4H-azepines are difficult to obtain because they would lead to the formation of antiaromatic 8p species; however, annulation increases the stability and in 2004 the generation of the first azepinium ion reported [228]. Recently, attention has been drawn to the role of azepinium ions as intermediates in different reactions. 21.6.1.1 Cycloaddition Reactions The polyenic structure of an azepine and its bicyclic tautomer both determine its reactivity in cycloaddition reactions [9]. Thus, azepines can participate in cycloaddition reactions as 2p, 4p, or 6p components (Scheme 21.65). Cycloaddition reactions of N-substituted azepines with various dienophiles have been studied. For example, 1-alkoxycarbonyl-1H-azepines undergo [4 þ 2] p Diels–Alder reactions with most dienophiles at the C2
C5 positions, as exemplified in Scheme 21.66 with tetracyanoethylene (TCNE) [229]. On the other hand, asymmet-

j1911

j 21 Seven-Membered Heterocycles: Azepines, Benzo Derivatives and Related Systems

1912

N R N

N R

R

z [6+2]

N

[2+2] N R

[4+2]

N R [6+6]

[2+4]

[6+4] N

N R

z

[2+4]

[2+2]

[2+2]

[4+2]

R

N R

N

R

R

N N

R

R Scheme 21.65

CN NC

R

NC

CN CN

N CO2Et

NC R

CN N CO2Et

C6H6, rt

R = H (60%) R = CH3 (65%)

R=H R = CH3 CN NC

NC

CN CN

N Me CO2Et

Scheme 21.66

NC

CN CN N Me CO2Et low yield

CN NC

Me N CO2Et

CN

NC

CN CN

NC

Toluene Me

NC CN CN N CO2Et

+

NC

66%

CN CN

Me N CO2Et

N

R

21.6 Reactivity of Azepines

j1913

rically substituted 1H-azepines can undergo addition at C4
C7 or a mixture of isomers can result from C2
C5 and C4
C7 addition [230]. However, the presence of sterically bulky substituents at C3 and C6 makes the azepine function as a triene-[6 þ 2] p-system; this is the case even with unsubstituted azepines when the reaction is performed in the presence of tricarbonylchromium(0) to produce the homotropane as a single diastereomer in 77% yield (Scheme 21.67) [231]. CO2Et N

EtO2C N CO2Et

NpCr(CO)3 (9 mol%)

CO2Et 77%

Np = naphthalene

Scheme 21.67

The ability of alkyl-1H-azepine-1-carboxylate to participate simultaneously as a diene and dienophile in cycloaddition reactions can be exemplified by the reaction of methylpyrone-3-carboxylate (Scheme 21.68) and the 5-isomer [232]. The 3-substiO

N

O

O CO2Me

O

CO2Me N

Toluene, 80º C, 68 h

CO2Et

2+4

MeO2C

O O

224b (11%) O 2+4

N

MeO2C

+ CO2Et

225a (25%)

N CO2Et

226 Scheme 21.68

MeO2C

N

MeO2C

225b (20%)

-CO2

EtO2C

6+4

O

O

O Toluene, 80º C, 57 h

N EtO2C Azepine 6+4 dimer

224a (5%) N CO2Et

CO2Et

j 21 Seven-Membered Heterocycles: Azepines, Benzo Derivatives and Related Systems

1914

tuted pyrone adducts 224a and [6 þ 4]-type dimer 224b were obtained in low yield. Under similar reaction conditions, 5-substituted pyrone gave adducts 225a and 225b. The former, on prolonged heating, lost carbon dioxide to form benzo[d]azepine 226. The reaction of 1-ethoxycarbonyl-1H-azepine with 3,4,5,6-tetrachloro-1,2-benzoquinone [233] acting as a heterodiene gave a [6p þ 4p] and two regioisomeric [2p þ 4p] adducts. This behavior is representative of the dual character of azepine in cycloaddition reactions. Furthermore, interestingly, the [6p þ 4p] adduct rearranges to the [2p þ 4p] isomer on heating in toluene (Scheme 21.69). Toluene Cl

(63%)

O

Cl Cl

O

Cl

Cl

N CO2Et

Toluene, rt

Cl Cl

Cl

6+4 CO2Et N O O

2+4

Cl O

Cl

N CO2Et

+ Cl

O

+ Cl

O Cl

Cl

46%

EtO2C

Cl

16%

N

O Cl

8%

Scheme 21.69

The reported examples of 1,3-dipolar cycloaddition to azepines are limited to diazomethane and N,a-diphenylnitrone. Thus, the reaction of 1-ethoxycarbonyl-1Hazepine with N,a-diphenylnitrone afforded exo- and endo-cycloadducts in similar distributions through a concerted process (Scheme 21.70) [234]. Ph

N CO2Et

+ Ph N O

Ph Ph N

O

H N CO2Et H

Scheme 21.70

21.6.1.2 Reaction with Metal Carbonyl Complexes In contrast to cycloheptatriene, the metal complex chemistry of azepine has received rather limited attention. In 1965 Fisher and R€ uhle [235] reported the formation of iron carbonyl complexes of several azepines, including the parent system 1Hazepine. The isolated azepine is very unstable and was generated in the complexed state from the N-ethoxycarbonyl derivative. The tricarbonyl chromium, molybdenum, and tungsten complexes of azepine 1-carboxylate have also been prepared by treating the azepine 1-carboxylate with the metal tricarbonyl tris-acetonitrile complex in THF solution. The tricarbonylruthenium complex has also been reported (Scheme 21.71) and this undergoes interesting cycloaddition reactions with electron-deficient alkenes and ketones.

21.6 Reactivity of Azepines

N

CO Fe CO CO R1 = H, CO2Et

R

1

N R

j1915

1

M

CO

CO

CO

M = Cr, Mo,

Scheme 21.71

The synthesis, structure, and dynamic behavior of some cyclopentadienyl- and pentamethylcyclopentadienyl-cobalt complexes of N-methoxy- and N-ethoxycarbonylazepines or N-methylazepine have been carried out by Wadepohl [236]. Cyclopentadienylcobalt complexes of N-ethoxy- and N-methoxy compounds were obtained by treatment of the 1-ethoxycarbonyl-1H-azepine with Jonas reagent [(CpCo(C2H4)2]. Subsequent reaction with excess NaOMe in methanol gave approximately 50% conversion to the N-methoxy derivative, although these compounds could not be separated by column chromatography (Scheme 21.72). (Jonas reagent)

CO2Et

CO2Me

N

R

N

Co Co

Light Petroleum, 50 ºC, 3h

Co

NaOMe ex

R=H

50% conversion R

R

227a ( 84%) Me

CO2Et N CO2Et

N

N

R Co Toluene, reflux, 2h

Co

R = Me

Co

LiAlH4 Et2O

Me

227b ( 92%)

Me

227c (82%)

Scheme 21.72

The complexes undergo a degenerate valence tautomerization, which is more facile in pentamethylcyclopentadienylcobalt[2-5-g-(N-methyl)azepine] (227c) than in cyclopentadienylcobalt[2-5-g-N-ethoxycarbonyl)azepine] (227a) and pentamethylcyclopentadienylcobalt[2-5-g-(N-ethoxycarbonyl)azepine] (227b). At low temperatures,

j 21 Seven-Membered Heterocycles: Azepines, Benzo Derivatives and Related Systems

1916

compound 227a has restricted rotation around the amide bond, which leads to the presence of two diastereomers. Tricarbonyl(N-cyanoazepine)metal(0) complexes of chromium (228a), molybdenum (228b), and tungsten (228c) are formed when tricarbonyl-tris(acetonitrile)chromium(0), -molybdenum(0) and -tungsten(0), respectively, are treated photochemically with N-cyanoazepine at room temperature in toluene (Scheme 21.73) [237]. The resulting complexes take part in [6 þ 2] cycloadditions with alkynes (see next section).

CN

N M(CO)3(CH3CN)3

N CN

hν , toluene, r.t.

CO

M CO

M= Cr, Mo, W CO

228a, M = Cr (84%) 228b, M = Mo (74%) 228c, M = W (60%) Scheme 21.73

21.6.1.3 Reactions through Metal Carbonyl Complexes The ease with which 1H-azepines form transition metal carbonyl complexes has led to interesting reactions. For example, tricarbonyl(2-5-g-1H-azepine)iron, which is unstable, reacts with the tropylium cation and several electrophiles to give derivatives that, after decomplexation with trimethylamine oxide, afforded 3-(2,4,6-cycloheptatrienyl)-3H-azepine. This compound is stable but undergoes a facile 1,5-hydrogen migration in benzene to give 6-(2,4,6-cycloheptatrienyl)-3H-azepine in 97% yield after purification [238] (Scheme 21.74). Fe(CO)3

Fe(CO)3 NaOMe

N CO2Et

MeOH

N H

+

_ BF4

46%

Fe(CO)3

N

Me3NO

80 ºC

acetone

C6 H 6

73%

N

97%

N

Scheme 21.74

Chromium(0)-mediated higher-order cycloaddition reactions have emerged as an important method for the rapid assembly of structurally elaborate polycyclic systems. Rigby’s group have been particularly active in this area, using both thermally and photochemically activated cycloadditions of chromium(0) complexes of azepines with alkenes and alkynes. A successful route to the tropane alkaloid ( þ )-ferruginine by reaction between tricarbonyl N-(methoxycarbony1)azepinechromium(0) and (
)-8-phenylmenthyl acrylate provided the desired diastereomerically homogeneous homotropane endo adduct as the major product with high diastereomeric excess

j1917

21.6 Reactivity of Azepines

(Scheme 21.75) [239]. Furthermore, [6p þ 2p] cycloaddition reactions mediated by solid-supported Cr(0) [240] have also been described for azepines with yields comparable to those obtained in photochemical and thermal versions.

O O

Cr(CO)3

Ph hν N CO2Me

(58%)

H

N

H

CO2Me

CO2R*

R* = (-)-8-phenylmenthyl

Scheme 21.75

Other examples of [6p þ 2p] cycloadditions with alkynes through the Cr(0) complex have been reported. The decomplexation can be performed either thermally or oxidatively, depending on the nature of the substituent (Scheme 21.76).

CN Toluene, reflux

N

Ph

CN N Cr(CO)3 R-C N CN

hν

C-R

Ph

R

71% R

Cr CO CO

R = Ph, SiMe3

(NH4)2Ce(NO3)6

CN N

SiMe3 SiMe3

66% Scheme 21.76

21.6.1.4 Pericyclic Reactions The nonplanar polyene nature of azepines allows them to take part in a wide variety of intra- and intermolecular pericyclic processes. Irradiation of 2-methyl-1H-azepine selectively gives a 4,7-ring closure product due to the steric interaction between the methyl group and the N-substituent. In contrast, the 3-methyl and 4-methyl derivatives give two four-membered products in a 1 : 1 ratio (Scheme 21.77) [221].

j 21 Seven-Membered Heterocycles: Azepines, Benzo Derivatives and Related Systems

1918

hν N Me CO2Me

Me N CO2Me

4,7-closure Me

Me

hν N CO2Me

N CO2Me

Me

+

N CO2Me

Scheme 21.77

The orbital symmetry-allowed disrotatory processes of 2-substituted 3H-azepines could yield both 3-substituted- and 5-substituted 6-azabicyclo[3.2.0]hept-2,6-dienes. However, the reaction is selective and gives only the 3-substituted derivative through a 4,7-closure rather than a 2,6-closure (Scheme 21.78) [241]. hν N X

2,6-closure

hν N

X

4,7-closure

X= NMe2, NH2, OEt

N

X

X = NMe2 (70%) X = NH2 (50%) X = OEt (60%)

Scheme 21.78

Different photochemical behavior for 3,6-di-tert-butyl-3H azepines and 2,5-di-tertbutyl-3H-azepines has been observed [242]. For example, photoisomers were not detected upon photoirradiation of the 3,6-isomer in hexane through a Pyrex filter. In contrast, irradiation through a quartz filter in hexane gave the 4,7-di-tert-butyl-2azabicyclo[3.2.0]hepta-2,6-diene along with the azepine 68 (Scheme 21.79). Irradiation of 2,5-di-tert-butyl-3H-azepine (71) through a Pyrex filter gave the 2,5-di-tertbutyl-6-aza-bicyclo[3.2.0]hepta-2,6-diene through a 2,6-closure, as confirmed by formation of the methanol addition product (Scheme 21.79). These results indicate that the regioselectivity for photoelectrocyclization is not exclusively caused by the steric hindrance of the product. It is known that the four tautomeric monocyclic azepines are interchangeable to the more stable derivative by 1,5-sigmatropic hydrogen shift, and the accepted order of stability of the azepines is 3H > 4H > 2H > 1H. The 1H-azepine isomerizes under thermal catalytic (acid/base) and non-catalytic conditions and 2H-azepines isomerize easily to the thermodynamically more stable 3H derivatives by 1,5-sigmatropic hydrogen shift [121, 238, 243]. This rearrangement occurs on standing in organic solvents at room temperature or on warming. Thus, (S)-2-methyl-6,7,8,9-tetrahydro2H-l-benzazepine undergoes a thermally allowed suprafacial [1,5]-sigmatropic H-shift (Scheme 21.80) in tert-butyl methyl ether at 30  C to give the optically active 3H-azepine derivative 229a in low yield, which exhibits a high optical rotation and supports a stereoselective mechanism for the rearrangement. At elevated

21.6 Reactivity of Azepines

hν

Bu

t

Bu

Pyrex

Bu

t

Bu

quartz

Bu

t

N

Bu

Bu

t

N

Bu +

t

Bu

68 (12%)

t

hν

Pyrex hexene

N

Unstable

t

N

H 26%

Bu

t

t

hν t

Bu

8%

hν

N

t

t

H

Bu

t

Bu

N

N 78

H

- :CH2

Bu

t

N H

Pyrex MeOH

Bu

H

OMe

Bu

t

t

80%

71

Scheme 21.79

temperatures a second, reversible hydrogen migration occurs and this establishes an equilibrium with the achiral 3H-azepine 229b. H

30ºC H3C

N

t-BuOMe

H3C

N 229a (18%)

55ºC t-BuOMe

H3C

N 229b

Scheme 21.80

Recently, Satake and co-workers [244] have described an unusual competitive reaction between a [1,5]-sigmatropic alkylthio shift and a [1,5]-sigmatropic hydrogen shift in a 2H-azepine ring, to afford 7-propylthio- and 3-propylthio-3H-azepines 230a and 230b, respectively, in a 1 : 1 ratio (Scheme 21.81). Kinetic measurements revealed that the observed [1,5]-propylthio shift proceeds through a concerted mechanism. On the other hand, when 2-methoxy-2H-azepine 231 was heated in chloroform a hydrogen shift was observed exclusively to give a mixture of 5-tert-butyl- (231a) and 4-tert-butyl-2,7-dimethoxy-3H-azepine (231b) in a 1 : 8 ratio (Scheme 21.82). The thermal [1,5]-sigmatropic hydrogen shift was studied by 1 H NMR spectroscopy and the spectrum of the isomerization of 4-tert-butyl-2,7-dimethoxy-2H-azepine (231) in CDCl3 showed that 231a and 231b were formed in a 1 : 8 ratio with a simultaneous decrease in 231, suggesting that the [1,5]-hydrogen shift from 231a and 231b is very

j1919

j 21 Seven-Membered Heterocycles: Azepines, Benzo Derivatives and Related Systems

1920

Bu

t

Bu

t

Bu H

Heat H

SPr

N

H

OMe

N SPr

t

SPr

+ H

OMe

N

OMe

230b (43%)

230a (51%) Scheme 21.81

Bu

Bu

t

t

Bu H

Heat H N MeO

CDCl3

OMe

MeO

231

N

t

H

OMe

N

MeO

231a

OMe

231b

Scheme 21.82

fast. These results indicate that the rapid equilibrium between 231a and 231b is reached as soon as the isomerization of 231 occurs. The [1,5]-methoxy shift was not observed in the thermal isomerization of 231. The same group has described the formation of 4H-azepines (232c) for the first time from the 2-methoxyazepiniun ion and its sigmatropic isomerization. This process apparently occurs as a two-step reaction from 232c to initially give 232d, which is then converted into the most thermally stable 232e (Scheme 21.83) [245]. The absence of a substituent at position 5 in the azepinium ring offers a good example of the reactivity and electrophilic character and allows the formation of rare 4Hazepines.

TiCl4 N

iPrO

N

OMe

C6H6

+

OMe

232

+ N

Ph

232a (49%)

Ph

Ph

OMe

Scheme 21.83

+ OMe

K3

K2 N

OMe

N

232b (3%)

N

232d

232c

N

Ph

K1 N

OMe

Ph

Ph

OMe

OMe

232c (43%)

Ph

N

232e

OMe

21.6 Reactivity of Azepines

j1921

The dimerization of 1H-azepines [246] involves a temperature-dependent cycloaddition process, which in turn depends on substitution. N-Methylazepine undergoes dimerization at 0  C to give a [6 þ 6] dimer. On the other hand, the N-cyano- and N-ethoxycarbonyl derivatives dimerize at higher temperature through a [6 þ 4] process. The initially formed [6 þ 4] adducts rearrange to the [6 þ 6] adducts on heating at high temperature (Scheme 21.84).

R

N

R [6+4]

N

[6+6] 0º C

N R

N

R R = CO2Me (130 ºC) R = CN (25 ºC)

N

R = Me R = CO2Me R= CN

R

R= Me

> 200ºC

R = CO2Me R = CN Scheme 21.84

In contrast to N-substituted 1H-azepines and their 3- and 4-methyl derivatives, which readily undergo dimerization at elevated temperatures, in cases where the positions directly involved in the dimerization process (2-, 4-, and 7- positions) are substituted the dimerization process is hindered and a valence tautomerization reaction takes place [247]. Thus, 2-methyl-, 4,5-dimethyl-, and 3,6-dimethyl derivatives (233) at 200  C were converted into the aromatic carbamates (Scheme 21.85). This behavior is not shared by the 2,7-dimethyl derivative, which is stable even at 250  C, probably due to steric hindrance.

R R

1

R

2

1

MeO2C R

2

200ºC

3 N R CO2Me

233 R1

Scheme 21.85

R

2

MeCO2N R

3

R

2

R

1

1

R

H R

2

3

R R

2

R

1

(64-68%)

a: = H, CH3 b: R1 = CH3, R2 = R3 = H c: R1 = R3 = H, R2= CH3 R 2=

R

N

H

R3 =

1

j 21 Seven-Membered Heterocycles: Azepines, Benzo Derivatives and Related Systems

1922

Recently McNab and co-workers [248] have identified a new thermal ring contraction of dibenzo[b,f ]azepines by controlled flash vacuum pyrolysis (FVP) of N-allylor N-benzyldibenzo[b,f ]azepine at temperatures (750–950  C). When the N-benzyl derivative was subjected to FVP at 750  C, four products were identified from the reaction mixture (Scheme 21.86). Me FVP N R

Ph

Ph

+

(when R= CH2Ph)

R= CH2Ph R = CH2CH=CH2

+

N H

750ºC

+

N

N

27 20%

20%

2%

35%

Scheme 21.86

The formation of bibenzyl (20%) provided confirmation that radical generation had been successful. Cleavage of N-benzyl or N-allyl groups led to recovery of 5Hdibenzo[b,f ]azepine (20%) and, in addition, two ring-contraction products were obtained. One of them, 9-methylacridine (2%), is likely to be formed by ring contraction of 5H-dibenzo[b,f ]azepines (by the 1,5-shift, electrocyclization, ring cleavage, hydrogen shift sequence mechanism indicated in Scheme 21.87) and the major product is pyrrolo[3,2,1-jk]carbazole (35%). However, under more vigorous conditions (950  C) this process gave 9-methylacridine as the sole product in 60% yield. H H

N H

Me

N

N

N

27 Scheme 21.87

The temperature of the pyrolysis proved to have a dramatic effect on the product distribution, because the N-allyl derivative at 950  C gave 63% yield of pyrrolocarbazole (Scheme 21.88). Me 900º C

900º C R = CH2CH=CH2

N 63%

Scheme 21.88

N R

R = CH2Ph

N 60%

21.6 Reactivity of Azepines

j1923

Although several N-substituted derivatives of 5H-dibenzo[b,f ]azepines are known to give [2 þ 2] cycloadducts photochemically to form a cyclobutane (Scheme 21.89), the parent compound and its N-alkyl derivatives are photochemically inactive [249]. R N [2+2] N R1 R1 = Ac, COMe, COPh, CO2Et; CONH2

N R

Scheme 21.89

A structural analysis by 1 H NMR spectroscopy of the photoproducts of N-acyl derivatives of 5H-dibenzo[b,f ]azepines proved the presence of two stereoisomers (Scheme 21.90), probably due to restricted rotation of the amide bond [250]. R

[2+2] N R R = COMe R = COEt

R N

O

O

R

N

N

N

N

N R

R

Z

O

Scheme 21.90

21.6.1.5 Reactions with Electrophiles The conjugated azepines – and their partially unsaturated derivatives – are unstable in acidic media and undergo either rearrangement or ring contraction to an aromatic system. 1H-Azepines with N-alkyl substituents are unstable in acidic solutions and afford resinous products. However, N-acyl- or N-ethoxycarbonyl derivatives lead rapidly to N-phenylcarbamate under acidic conditions (Scheme 21.91). For example, the 3,6-dimethyl-1H-azepine (233c) on standing in 10% sulfuric acid at room temperature for 2 h yields 82% of the corresponding carbamate [247]. Similar treatment of the 2,7-dimethyl derivative for 4 h led only to recovery of unreacted starting material, probably due to steric hindrance. However, when the same mixture was heated under reflux for 1 h, the 2,7-dimethylazepine 234 was completely transformed into a viscous brown oil. The major identifiable component of this oil was the 2,6-dimethyl-N-methoxycarbonylaniline (16%) in addition to 3,4- and 2,6dimethylphenols, with the remainder being polymeric material (Scheme 21.91).

R E

O

j 21 Seven-Membered Heterocycles: Azepines, Benzo Derivatives and Related Systems

1924

+

H

R

NHCO2Me

N CO2Me

CH3

R = H, CH3 H3 C

NHCO2Me CH3

OH +

6%

16%

+

H Me

N Me CO2Me

NHCO2Me CH3

H 2O

234

CH3

H3 C

OH +

CH3

CH3

1%

CH3

1%

Scheme 21.91

The acid-catalyzed rearrangement of dibenzo[b,f ]azepines to 9-methylacridines was first described by Schindler and Blattner [251] (Scheme 21.92).

H

Me

HBr 48 % N O

30 min. CH3

+N

H

+N

H

N 73%

Scheme 21.92

In general, the alkylation of azepines is effected by alkyl halides or tosylates in the presence of base. Quaternization of 2-dialkylamino-3H-azepine with methyl iodide takes place at the exocyclic nitrogen and its hydrolysis provides a useful path to 3Hazepinones [252]. The N-alkylation of some 5H-dibenzo[b,f ]azepines (and 10,11-dihydro derivatives) has been studied extensively under classical conditions and under phase-transfer catalysis (PTC) [253], although the method is less successful with 10,11-dihydro derivatives [254]. The alkylation can be effected with an alkyl chloride, bromide, or tosylate, using a wide range of bases and refluxing in toluene. N-Methyl-, N-ethyl-, and N-propyl derivatives, for example, can be prepared in good yield under mild conditions from the iminostilbene and the corresponding alkyl iodide using thallium ethoxide as base (Scheme 21.93) [255].

21.6 Reactivity of Azepines

j1925

MeI/ EtOH/ Tl N H

N R

DMF-Et2O

R = Me, Et, Pr Scheme 21.93

C-Alkylation, described by Streef and van der Plas [256], is achieved through reaction of the anion of 2-diethylamino-5-phenyl-3H-azepine with different electrophiles to give azepines substituted at C3 (Scheme 21.94). Ph

N

Ph

Ph

H H

LDA

NEt2

_

H

N

NEt2

R-X

H R N

NEt2

R = CH3, SCH3, CH2Ph (60-65%) Scheme 21.94

Satake and co-workers reported the specific formation of 2-methoxy-2H-azepine derivatives 235a–e by sequential reaction of 3H-azepines with bromine, methanol, and aqueous potassium carbonate (Scheme 21.95). Studies on the mechanism of the reactions of 3H-azepines with bromine and NBS [243, 257] suggest the 1,4-addition of an electrophile and subsequent 1,2-dehydrobromination. R R

R

2

2

R N

R

3

1

1. Br2 (1.0 equiv.) 2. MeOH 3. aq. K2CO3

R

2

1

MeO

R N 235a-e

R

3

1

a: R1 = R2 = H; R3 = OMe (46%) b: R1 = H; R2 = tBu; R3 =OMe (52%) c: R1 = H; R2 = Me; R3 = OMe (30%) d: R1 = tBu; R2 = R3 = H (43%) e: R1 = H, R2 = R3 = tBu (52%)

Scheme 21.95

On the other hand, the sequential reaction of 235b with half an equivalent of bromine and aqueous potassium carbonate (Scheme 21.96) gives the 7-bromo-3Hazepine derivative 236 (12% yield) and the ether 237 (82% yield). An alternative attempt to understand the mechanism of the previously described conversion of 3H-azepines into 2H-azepines has been carried out by replacing bromine with NBS (Scheme 21.97). In the presence of methanol, quantitative conversion of 3H-azepines 235a,b into 2-methoxy-2H-azepines was observed, although the reaction with 235c produced both 2-methoxy-2H-azepine (66% yield) and the 2-succinimido-2H-azepine (33% yield). In the absence of methanol the 3Hazepines 235a–c and efficiently gave 2-succinimido-2H-azepines in good yields

j 21 Seven-Membered Heterocycles: Azepines, Benzo Derivatives and Related Systems

1926

t

Bu

t

t

Bu

Bu

1. Br2 (0.5 equiv.) N

OMe

t

Bu

+

2. aq. CO3K2

N

Br

235b

N

OMe

236 (12%)

O

N

OMe

237 (82%)

Scheme 21.96 R

2

Br

R

R

N

N

OMe

OMe

R3N, N2

N

-98ºC

OMe

R3N, -98ºC

235a: R2 = H, 235b: R2 = tBu 235c: R2 = Me

a: R2 = H (81%) b: R2 = t-Bu (100%) c: R2 = Me (73%)

c: R2 = Me (22%)

R

2

NBS/MeOH, N2

O a: R2 = H (19%)

2

NBS

O

+ N

2

2

R

N

OMe

a: R2 = H (99%) b: R2 = t-Bu (100%) c: R2 = Me (66%)

NBS (0.5 equiv) aq. K2CO3 , rt R

MeO

2

O N

N

O

N

O

OMe

238 (84%) Scheme 21.97

together with the brominated products (19–22%). Replacing bromine by NBS led to improved yields due to the chemoselectivity of the reagent as well as the lower concentration of HBr [258]. Reaction of 235b and NBS in a 2 : 1 molar ratio at room temperature produced the ether 238 in 84% yield. Acylation of 2-amino-3H-azepines under Schotten–Baumann conditions did not afford the azepine derivative but the 2-(benzamido)diphenylamine through the intermediacy of an azanorcaradiene [259] (Scheme 21.98). However, benzenesulfonylation proceeds normally at the exocyclic nitrogen. R2 -CO-X N

1

NHR

N COR

NHR 2

NHR

1

H

1

N 2 COR

NHR

1

COR

2

Scheme 21.98

Treatment of the densely substituted 3H-azepines 239 with benzoyl chloride in the presence of DABCO gave the 2-methylene-3H-azepine derivatives 240

21.6 Reactivity of Azepines

j1927

(Scheme 21.99) [260]. When the 2-methyl group was replaced by a phenyl group, there was no reaction even under forcing conditions. Attempts to isomerize the exomethylene azepine 240 to the conjugate 1H-isomer 241 failed, both by treatment with weak or strong bases. In the latter case the starting 3H-azepine was obtained. RCH2

Ph

Ph

Ph H

H

N

RCH2 Ph -CO-Cl

CH2R

Ph

DABCO

Ph H N CHR COPh

H

239 R = H, Me, Ph

RCH2

Ph

Ph

Ph

//

Ph N CH2R COPh

H

240

241

R = H, Me

R = H, Me

Scheme 21.99

The reaction of 2-amino-3H-azepine with either trityl tetrafluoroborate or dimethyl (methyl)sulfonium tetrafluoroborate [91] has been reported to give the product substituted at C6 (Scheme 21.100). In the former case, the corresponding azanorcaradiene was isolated. _ + Ph3C BF4

Ph3C _

BF4 N

K2CO3 +N H

NH2

Ph3C N

NH2

NH2 _ Me2S+ -SMeBF4

MeS N

NH2

Scheme 21.100

21.6.1.6 Reactions with Nucleophiles Satake and co-workers have reported the formation of the azepinium ion from the reaction of a 2-methoxy-2H-azepine derivative and titanium tetrachloride (TiCl4) (Scheme 21.101) [243,257b]. In contrast to analogous tropylium systems, which have poor reactivity [261], the azepinium ions are quite reactive [249, 262] – as shown in Schemes 21.102 and 21.103. The results indicate that the azepinium ion is a strong electrophile. In the reaction with aromatic compounds these systems undergo nucleophilic substitution primarily at position C7 and, less frequently, at position C3. An interesting

j 21 Seven-Membered Heterocycles: Azepines, Benzo Derivatives and Related Systems

1928

t

Bu +

Bu

TiCl4 N

MeO R=

tBu,

H

t

Bu

t

N

R

N

R

OMe Bu

Bu

H2O

t

+

R = OMe

HO

MeO- TiCl4

OMe

H

t

+

CDCl3, rt

+

H

N

OMe 45%

t

O

O

OMe 24%

Bu iPrNH2 iPrHN H

N

OMe

85%

Scheme 21.101 t

Bu

N

OMe

R CDCl3 reflux t

Bu

R

t

Bu N

R= H, OMe, OH

t

Lewis acid N

OMe CDCl3, rt

N

t

t

Bu +

X= O, S, NH

N

X

OMe

N

X

t

Bu

OMe R = H (5%) R = OMe (3%) R = OH (3%)

Bu

X

1,5-H shift

R

+

R R = H (49%) R = 4-OMe (47%) R = 2-OMe (28%) R = 4-OH (33%) R = 2-OH (30%)

Bu

MeO

OMe

X = S (52%) X = O (14%) X = NH

OMe X = S (5%) X = O (2%) X = NH (12%)

X = NH

t

N X

Bu

OMe

X = S (14%) X = O (11%) X = NH (11%)

Scheme 21.102

HN N

tBu OMe

N H 37%

OMe

21.6 Reactivity of Azepines

j1929

result was obtained in the reaction with pyrrole, which gave a ring-contracted product. OH

O

H2O

PDC

Citric acid

MeO2C

N H

CO2Bu

t

DMF

MeO2C

89%

t N CO2Bu H 32%

OMe MeOH MeO2C

N

CO2Bu

t

MeO2C

t N CO2Bu H 99% CN

1.TMS-CN/Pd(OAc)2 2. H2O +

MeO2C

N H

CO2Bu

t

43% Scheme 21.103

4H-Azepine-2,7-dicarboxylic esters undergo 1,4-addition of nucleophiles [263] catalyzed by either acid or Pd(II) (Scheme 21.103). Although it is known that the alkoxy group of the 2-alkoxy-3H-azepine derivative is displaced by alkylamines or carbanions from active methylene compounds, Satake and co-workers have explored the reactivity of 3H-azepines having an imidate conjugation with various alkoxy groups at the 2-position (Scheme 21.104). Thus, the nucleophilic reaction of 5-tert-butyl-2-methoxy-3H-azepine 235b with an appropriate alkoxide [264] took place effectively at the 2-position of the ring. When a bulky alkyllithium was used as a nucleophile, a similar displacement occurred to give the 2-alkyl-3H-azepine derivative as a single product. In contrast, the reaction of 235b with methyllithium gave not only 2-methyl-3Hazepine 242, but also 2,2-dimethyl derivative 243 (37%) and methylenedi-3H-azepine 244, which tautomerized into the thermodynamically more stable vinamidine or 5-tert-butyl-2-(5-tert-butyl-2,3-dihydro-1H-azepin-2-ylidenemethyl)-3H-azepine 245 (25%). 21.6.1.7 Reactions with Oxidants To investigate similarities and differences in the chemical behavior of 3H-azepines and the isoelectronic 1,3,5-cycloheptatriene, Kimura and co-workers [265] have studied the oxidative ring cleavage of dialkyl-3H-azepines on treatment with selenium dioxide. Thus, the oxidation of 2,5-di-tert-butyl derivative 71 afforded, inter alia, 4-oxo-octa-2,5-dienal by a new ring cleavage along with the 2-azatropone 246

j 21 Seven-Membered Heterocycles: Azepines, Benzo Derivatives and Related Systems

1930

Bu

t

NaOR/ROH reflux

N

R = Et, Pr, i-Pr Bu

R = Et (94%) R = Pr (95%) R = i-Pr (92%)

OR Bu

t

t

t-BuLi Et2O, rt N

N

OMe

Bu

Bu

t

t

44%

235b Bu MeLi

N H

MeLi

Et2O, rt

Me Me

t

N

Bu

243 (37%)

Me

Bu

242 (12%)

t

t

N

OMe

N _ CH2

Bu

NH

t

N

Bu

t

Bu

N

N

t

Bu

t

244

245 (25%) Scheme 21.104 t

t

Bu

t

Bu

Bu

O

SeO2 N

71 t

t Bu dioxane/H2O (9:1) 65ºC, 7h

t

Bu

Bu N

78

+

NH

t

Bu

O

NH

t

Bu

t

Bu

+

H

N O

O

(13%)

36%

(12%)

t

Bu

+ O

N

t

Bu

246 (6%)

t

SeO2 dioxane/H2O (9:1) 65ºC, 17 h

Bu

N

OH (55%)

t

t

Bu

Bu

t

Bu

+

N (5%)

Scheme 21.105

(Scheme 21.105). Under the same conditions the isomeric 3,6-di-tert-butyl-3Hazepine 78 gave pyridylpropanol as the major product. The putative reaction course for the formation of 246 from 71 is indicated in Scheme 21.106. Compound 71 gave the dihydroxy derivative I, which rearranged to

j1931

21.6 Reactivity of Azepines SeO2 Bu

H2O

t

Bu

SeO(OH)2 N

Bu

71

t

HO

t

Bu

OH

N

Bu

I

t

H2N

t

OH

O

-NH3

Bu

II

Bu

t

t

Bu

OH

O

Bu

III

t

O

Bu

O

t

t

246

1

R a

2

SeO2 H2O

1

R R

2

2

R N

SeO(OH)2

1

R 2

HO

N

1

R

R

R

1

2

N

Bu

1

OHC

R

a

t

b

R1 = tBu, R2 = H R1 = H, R2 = tBu

b

1

1

R

2

2

R OH R1 =

N

R

H,

R2 = tBu

1

2

R

Bu

2

R

N R1 =

R H,

1

OH

R2

=

tBu

the 2-amino-2H-oxepine II. Subsequent elimination of ammonia was followed by Claisen rearrangement to 246, On the other hand, the formation of pyridinecarbaldehyde or pyridylpropanol can be explained in terms of electrophilic attack of selenous acid on the C¼N double bond in 3H-azepine 71 or 78 and subsequent nucleophilic attack by the carbonyl group of selenous acid on the methylene proton in the 3-position (Scheme 21.106). After this attack, the intermediates are formed with an N
Se bond, and this leads to intermediates through a [2,3]-sigmatropic shift. Finally, the intermediates are converted into the 2-azanorcardienes, which ultimately give the final products. A different type of behavior has been described for N-methoxycarbonyl-2,7dimethyl-1H-azepine in dioxane, which by oxidation with SeO2 gave N-methoxycarbonyl-1H-azepine-2,7-dicarboxaldehyde (Scheme 21.107) in moderate yield [266].

SeO2 dioxane/H2O (9:1) reflux

OHC

N CHO CO2Me (56%)

t

R

Scheme 21.106

Scheme 21.107

Bu

1 N R Se O OH

R

Me

N

R1 = tBu, R2 =H

R1 = tBu, R2 =H R

1

N Me CO2Me

t

2

R

2

R

R

71, R1 = tBu, R2 = H 78, R1 = H, R2 = tBu

R

2

R HO

Bu

N

OH (55%)

t

j 21 Seven-Membered Heterocycles: Azepines, Benzo Derivatives and Related Systems

1932

In this case, as expected, oxidation of the alkyl groups is faster than oxidation of the aromatic ring. The reaction of benzazepines with m-CPBA [267] proceeds through N-oxidation and double bond epoxidation (Scheme 21.108). On the other hand, the oxidative behavior of N-substituted dibenzo[b,f ]azepines 248 is complex because several products were obtained depending on the nature of the N-substituents. N-Alkyl derivatives, with the exception of N-methyl, afford mixtures of diphenylamines and acridones (Scheme 21.108). The N-methyl derivative 248d gave the N-oxide along with ring-opening and ring-contracted products (Scheme 21.108). The N-acyl deri-

Ph

Ph N

Ph

PH Me Ph

O N+

m-CPBA

PH R Ph

rt

247

_

Ph

Ph m-CPBA

(59%)

(55%)

O

HO H

R

+

N R

O

a: R= C3H7 b: R= CH2CH2CH2OH c: R= CH2Ph

N Me

248d

a: R= C3H7 ( 25 %) b: R= CH2CH2CH2OH (12%) c: R= CH2Ph (18%)

N R O

m-CPBA

a: R= C3H7 ( 32%) b: R= CH2CH2CH2OH (48%) c: R= CH2Ph (23%)

N

m-CPBA

248

_

PH R Ph Ph O

reflux

O

N R

O N+

+ N _ O Me 66%

+

O

HO H N Me 10%

+

N Me 1%

Scheme 21.108

vatives undergo epoxidation of the C10–11 bond and the N-aryl derivatives are hydroxylated at the phenyl ring [268]. Electrochemical oxidation [269] by ring contraction of N-alkoxycarbonyl-1H-azepine leads to N-alkoxycarbonylaniline by initial oxidation of the carbamate to give the radical cation, followed by electrocyclic rearrangement and C
N cleavage (Scheme 21.109). 21.6.1.8 Hydrogenation and Hydrogen Transfer Complete reduction of the azepine ring in the monocycles and in their benzo derivatives is readily achieved with hydrogen and the appropriate metal or metal oxide

21.6 Reactivity of Azepines

.

Pt, - e , 2.0 V CH3CN TBAP

N CO2R R = Me, Et

N

N

O

+

N H

OR

. + OR

O

Scheme 21.109

catalyst. Extensive use of Raney nickel, palladium charcoal [270] and platinum oxide [271] has been reported. With 2-aminobromoazepine 249 [12a, 72], partial reduction is accompanied by hydrodebromination. Initially, the hydrogenation in aqueous dimethylformamide in the presence of potassium bicarbonate or in dioxane containing triethylamine in the presence of a 10% palladium-charcoal catalyst was unsuccessful, but in ethanol, in the absence of a base, reduction occurred rapidly through a hydrogen-transfer reaction. However, only the saturated amidine hydrobromide could be isolated (Scheme 21.110). Partial reduction of 2-dimethylamino-3H-azepine can be effected in the presence of 5% Pd/C to give 4,5-dihydro- and 4,5,6,7-tetrahydro-3H-azepine derivatives [273].

Pd/C (10%) N

NH2

EtOH

_ Br + NH3

N

249 Pd/C (5%) N

+ N

NH2

N

NH2

NH2 30%

70% Scheme 21.110

The similarity of keto derivatives of azepines and tropones has prompted some studies on the reactivity of the former systems. As shown here, there are three types of azepinones –aza analogues of tropone – corresponding to the three isomeric parent compounds, 2H-azepin-2-one, 3H-azepin-3-one, and 4H-azepin-4-one. O O O

N

2H-azepin-2-one

N 3H-azepin-3-one

CO2R

R = Me (79%) R = Et (62%)

TBAP: tetra-n-butylammonium per-ruthenate

Br

j1933

N 4H-azepin-4-one

j 21 Seven-Membered Heterocycles: Azepines, Benzo Derivatives and Related Systems

1934

The chemistry of these systems has been reviewed. Examples of all three types have been synthesized, although the parent compounds themselves are unknown. By far the most common are derivatives of 2H-azepin-2-one. Among them, 2H-azepin-2one and 4H-azepin-2-one have been obtained from azepinediones with trimethyl- or triethyloxonium tetrafluoroborate in acceptable yields [274]. These compounds undergo facile hydrogenation – to the perhydro-derivatives – and acid hydrolysis (Scheme 21.111).

O

CH3

N

H3 C O

O

H 2O

O

N H

O

(Me)3O+BF4-

H3 C

OEt

O

H2O

MeO

H3 C

R = H, CH3

OEt

MeO 3H2, Pd/C

R N H

N

62% CH3

H3 C

CH3

2H2, Pd/C

5%

R

H3C

N

H3C

CH3

H3C

CH3

(C2H5)3O+BF4-

CH3

H3C H3C

O

R = H (51%) R = CH3 (63%)

N H

O

65%

Scheme 21.111

Although these compounds do not exhibit special chemical reactivity, the 3-hydroxy-2H-azepin-2-one derivative 250, described for first time in 1990 by Sano and co-workers [275], is extremely reactive in protic solvents, undergoing a ring contraction to give the pyridine-2-carboxylate 251 (Scheme 21.112). This result demonstrates that the azatropolone nucleus has a strongly electrophilic character. CO2Et

CO2Et

OH Ph

N

O

CO2Et

O Ph

250

N H

O

CO2Et

O Ph NH2 O

OMe

Ph

N

CO2Me

251

Scheme 21.112

21.6.2 Reactivity of Partially Reduced Azepine Derivatives 21.6.2.1 Dihydroazepines Although there are references on this group of compounds, we have restricted the discussion of reactivity to those cases in which the starting materials are stable or have

21.6 Reactivity of Azepines

j1935

similarities with the azepine reactivity considered previously (some examples are given here).

N R

N R

2,3-Dihydro-1H-azepine

N R

2,5-Dihydro-1H-azepine

N

N

2,7-Dihydro-1H-azepine

N

N R

4,5-Dihydro-1H-azepine

N

3,6-Dihydro-2H-azepine 5,6-Dihydro-2H-azepine4,5-Dihydro-3H-azepine 3,4-Dihydro-2H-azepine

Among these compounds, the 2,3-dihydro-1H-azepines are relatively stable due to the conjugated dienamine structure. Protonation takes place at the C4 position [276]. Thus, Paquette has described the preparation of 6,7-dihydroazepinium 252a by reaction of 252 with perchloric acid (Scheme 21.113).

Me

Me HClO4

Me N Me Me 252

Me + N Me Me 252a

Scheme 21.113

The [4 þ 2] cycloaddition reaction occurs readily even with DMAD [277], which ordinarily reacts with enamines in a [2 þ 2] manner following a ring expansion process [278]. However, the 6,7-dihydro-1H-azepine reacts with DMAD to give the tetrahydroindole derivative 253 [279]. The first step is the formation of a [2 þ 2]p adduct, which undergoes ring expansion and subsequent recyclization (Scheme 21.114). Alternatively, the reaction in polar solvents [280] proceeds due to the enamine character of the dihydroazepine, generating a heterobetainic intermediate that, depending on the solvent, affords different products. Dihydroazepines and tetrahydroazepines can undergo several rearrangements that generally involve a ring contraction. As an example, oxidation of 6,7-dihydro-1Hazepine 254 [281] with DDQ (2,3-dicyano-5,6-dichoro-para-benzoquinone) (Scheme 21.115) gives the arylurethane 255. 4,5-Dihydro-1H-azepines are sensitive to many reagents. The N-alkyl derivatives of 4,5-dihydro-1H-azepines appear to be rather reactive [78,132b,282] because they contain a double enamine moiety, but the N-acyl derivatives are more easily handled. Electron-withdrawing groups at C2, C3, C6, and C7 have an effect on the stability. Catalytic hydrogenation of these materials affords azepanes [283].

j 21 Seven-Membered Heterocycles: Azepines, Benzo Derivatives and Related Systems

1936

CO2Me

MeO2C

MeO2C CO2Me

MeO2C

DMAD

N N=PPh3 Tos

CO2Me

MeO2C MeO2C

CO2Me

CO2Me N N=PPh3 Tos

N N=PPh3 Tos

CO2Me CO2Me

MeO2C

N Tos N CO Me 2 Ph3P

Tos N CO Me 2 CO2Me

MeO2C

N PPh3 CO2Me

253

CO2Me CO2Me

CO2Me DMAD MeO2C

N CH2Ph

MeO2C

+

N MeO C 2 CH2Ph

-

MeO2C

CO2Me

CH3CN

CO2Me

MeO2C

CO2Me

MeO2C

CO2Me N N=PPh3 CH2Ph

N CO2Me CH2Ph

MeOH

CO2Me CO2Me

MeO2C

+N

CH2Ph

CO2Me

Scheme 21.114

NC

R CO2Me

Ph

NC DDQ

N NH2 CO2Me

254 R = H, CO2Me

Ph

NC

R CO2Me N NH2 CO2Me

Ph

R CO2Me N NH2 CO2Me

R

CO2Me NH2

NC Ph

NHCO2Me

255 R = H, CO2Me (48%,)

Scheme 21.115

In the case of 2,3-dihydro-1H-azepines, protonation occurs at the d-position and for 4,5-dihydro-1H-azepines protonation occurs at the electron-rich b-position. For example, the rearrangement of 5-cyano-4,5-dihydro-1H-azepine 256 to the furo[2,3-b] pyridine 257 with sodium nitrate in acetic acid in aqueous ethanol proceeds by initial protonation of C3 or C6 (Scheme 21.116) [284]. The synthesis of derivatives of 4,5-dihydro-1H-azepines fused with thiophene and pyrazole rings has also been reported [284] from b-chlorovinyl aldehydes with 2-mercaptoacetate or phenylhydrazine, respectively (Scheme 21.117).

21.6 Reactivity of Azepines CN

N H

Me

CN

CN CO2Me

MeO2C

AcOH

CO2Me

MeO2C

Me

Me

+

N H

j1937

H2O

Me

Me

O H2 N

CO2Me

MeO2C

CO2Me

MeO2C

Me

Me

256

O

N

257

Scheme 21.116

N

N Ph

N N Ph

N R

PhNHNH2 AcOH

COH

HOC N R

Cl

HSCH2CO2H

Cl

N R

S

R = CH2Ph (83%) R = Ph (68%)

R = CH2Ph, Ph

R = CH2Ph (82%) R = Ph (83%)

S

Et3NH2/Py

Scheme 21.117

21.6.2.2 Tetrahydroazepines The 2,3,4,5-tetrahydro-1H-azepines are enamines and are fairly reactive compounds, particularly those that are unsubstituted on the N atom. Alkylation or acylation on the N atom produces more stable compounds, which react mostly as enamine derivatives (Scheme 21.118) [285].

O R

N SCH3 CH3

N=C=O

N CH3

N H SCH3

R

O R

N=C=O

N N

N

H3C

R= H, CH3, Cl, Br R (54-71%) Scheme 21.118

2,3,4,5-Tetrahydro-1H-azepines also undergo ring contraction reactions by treatment with bromine followed by water/triethylamine. The enamino ester 258 was converted into the formyl ester 259 in quantitative yield. A similar reaction on the enamino aldehyde 260 gave the aldehyde derivative 261a as the major product. In this case, the formation of about 5% of the minor isomer 261b was observed (Scheme 21.119) [286]. Palladium-catalyzed cross-coupling reactions have been carried out by reaction of triflate 262 with alkoxydienylboronates 263 (Scheme 21.120) to afford azepine derivative 264 in 45% yield after chromatography. Subsequent acid-catalyzed

O

Me

j 21 Seven-Membered Heterocycles: Azepines, Benzo Derivatives and Related Systems

1938

CO2Me Br2 N R

Br R +N

H2O/Et3N

R

Ph

Ph

258

Br

CO2Me N

CO2Me R +N

OH

Ph

Ph

CO2Me

R

OH

Ph

259

R = C5H11 CHO

R

N

Br2

MeOH/Et3N

R

N

CH(OMe)2 CHO

Ph

Ph

261a

260

CHO CO2Me

N

+

R

95:5

N

CHO CH(OMe)2

Ph

261b

Scheme 21.119

N OTf Cbz

262

+

O

B

O

(Ph3P)4Pd (3%)

OEt Toluene, EtOH, K2CO3 45%

263

Amberlyst N Cbz OEt

264

N Cbz O

+

N Cbz

41%

13%

265

266

O

Scheme 21.120

hydrolysis over Amberlyst gave the fused azepines 265 in 41% yield together with a smaller amount of azepine unsaturated ketone 266 (13%) [287]. Although the functionalization of lactams to substituted heterocycles via the corresponding enol triflates has been reported, they are rather unstable and the triflate reagent is expensive. In contrast, lactam-derived phosphate [288] intermediates present remarkable stability. Thus, N-Boc or N-CO2Ph protected lactams, via their potassium enolates, gave the diphenyl phosphate derivatives 267 and the reactions with appropriate partners under Stille or Sonogashira coupling conditions and carbonylation (Scheme 21.121) have been tested. 21.6.2.3 Dihydroazepinones This section describes only several relevant examples of all the possible derivatives. 21.6.2.3.1 Dihydroazepin-2-ones The most extensive research on 1,5-dihydroazepin-2-ones has been carried out by Sano and co-workers [275]. The chemistry is essentially based on their relationship with azatropolones and azatropones by dehydrogenation. For example, dehydrogenation of 268 with DDQ yielded the corresponding azatropolones, but the reaction is affected by the nature of the substituents. The oxidation of 6-OEt and 6-H derivatives gave the corresponding azatropolones in moderate yields (65% and 50%, respectively) but with the other derivatives the yields were lower (2–17%) (Scheme 21.122).

21.6 Reactivity of Azepines

j1939

N CO2Me CO2Ph 72% CO (1 atm) Pd(OAC)2, PPh3 MeOH, Et3N, DMF (Me3Sn)2 SnMe3 Pd(PPh3)4, LiCl, THF

N Boc

N R

O

O P

Bu3SnCH=CH2 (OPh)2

N

Pd(PPh3)4, LiCl, THF

Boc 85%

267 R = Boc, CO2Ph

77%

Me3SiC CH Pd(PPh3)4, CuI, Et2NH-THF

N Boc

TMS

84% Scheme 21.121

CO2Et

O

Ph

X

Y

N X H O

OH O

Y

269(60%) X = Cl, CN ; Y= Cl, CN

O Cl

CN

Cl

CN (DDQ)

O

Toluene, R = vinyl

CO2Et R Ph

OH N H

O

DDQ

CO2Et R

Benzene, 100 ºC sealed tube (5-45 min.) Ph

OH N

O

268 R = H, Ph, OEt, OAc, SPh, Et , vinyl

R = H, Ph, OEt, OAc, SPh, Et

Scheme 21.122

The vinyl derivative of 268, when heated with DDQ in toluene, underwent a Diels–Alder reaction to give the adduct 269 in 60% yield rather than the dehydrogenation product (Scheme 21.122). Methylation of 1,5-dihydro-2H-azepin-2-ones 268 with diazomethane takes place at the enolic 3-OH and gives the corresponding compound 270, and the reaction with triethyloxonium tetrafluoroborate occurs at the lactam oxygen to afford the azepine 271. Treatment of the methyl ether 270 with DDQ in benzene at 100–120  C gave the dehydrogenated product or azatropolone 272 in moderate yield. Dehydrogenation of 271 (R ¼ H) and (R ¼ OEt) occurred in a few

j 21 Seven-Membered Heterocycles: Azepines, Benzo Derivatives and Related Systems

1940

minutes while for the rest of compounds longer reaction times were required (Scheme 21.123). These results indicate that the rate of dehydrogenation is affected by the electronic character and the bulk of the substituent in C6 position.

R

DDQ

O N

Ph

CO2Et

CO2Et

CO2Et

R Ph

OEt

273

OH N

Et3OBF4

R Ph

OEt

271

CO2Et

OH N H

CH2N2

O

R

OMe N H

Ph

268

Ph, 8 min. 77% OEt, 310 nm

D

D

O

D O 5b-d6

5a-d6 R

R O

3

hν >310 nm

+ O

OH 74%

15%

11%

hν D

D O

acetone-d6

D

D O

5c-d6

2

1

R

+

254nm - 80ºC

O 5b

5a

100%

D

ether

R

1

R

2

R

3

O

Scheme 21.134

The photolysis of (5a/5b) has been reexamined [300] using isotopically labeled compounds (D at the 3- and 6-positions). Thus, irradiation at 254 nm (acetone-d6 and room temperature) gave (NMR-analysis) phenol (40%) along with 12% of the isomeric oxepine 5c through an oxygen-walk or circumambulatory [301] rearrangement of arene oxides. The photoreactions of benzoxepines are analogously dependent on the wavelength and the yields are higher on using wavelengths up to 310 nm (Scheme 21.134) [302]. 21.7.1.2 Cycloaddition Reactions Oxepines undergo cycloaddition reactions with unsaturated molecules due to their cyclic polyenic character. This structure possesses different reaction centers and can behave as an ene, diene, and triene according to the kind of dienophile and considering the oxepine–benzene oxide (5a/5b) system. The cycloaddition reaction proceeds more readily on the benzene oxide form (5a/5b) in which the diene is closer to planarity. Thus, with dienophiles such as

j 21 Seven-Membered Heterocycles: Azepines, Benzo Derivatives and Related Systems

1946

DMAD or maleic anhydride [88] the [4 þ 2] cycloadducts were obtained as indicated in Scheme 21.135. O O

O

DMAD

O

O

O

O

MeO2C

O

O

CO2Me

O

5a/5b

Scheme 21.135

The reaction of 4,5-disubstituted oxepines [303] with azo compounds gives similar adducts to those indicated above (Scheme 21.136), whereas 2,7-disubstituted oxepines afforded an adduct from the oxepine valence isomer that is not stable but undergoes Claisen rearrangement to a cyclopropyl ketone (Scheme 21.136) [304].

R

1

R

2

MeO2C N Me N

O R1 = R2 = CH3

N N

CO2Me

O 79%

Me

CO2Me CO2Me

O

MeO2C R

2

O

R

1

R1 = R2 = CH3

MeO2C

N Me N O

H H Me

Claisen

Me H N N Me 60%

Scheme 21.136

Similar behavior has been described by Boyd and Berchtold [305]. In this case, the reaction of 1-(trimethylsilyl)benzene oxide–oxepines 289 with 4-methyl-1,2,4-triazoline-3,5-dione is also affected by substituents and affords the expected Diels–Alder adducts 290a and 290c from the benzene oxide valence isomer, and the adduct 290b (100%) from reaction of the oxepine valence isomer (Scheme 21.137). More recently, Golding and co-workers [306] have described the reaction of benzene oxide–oxepine (5a/b,292a/b) with 4-phenyl-1,2,4-triazoline-3,5-dione (291a) in acetone at
80  C. This gave a single adduct 294b,295b, whose structure

21.7 Reactivity of Oxepines

O

O Me

N

O

j1947

R

O

2

R

SiMe3

290b

SiMe3

SiMe3

N Me N O

R

N

O

2

R

1

O

1

R 289

N N

OSiMe3 O

2

290a,c

a: R1 = R2 =H b: R1 = Me, R2 = H c: R1 = H, R2 = Me Scheme 21.137

was validated by NMR and X-ray diffraction, showing that the dienophile approaches the diene anti to the epoxide moiety of the diene. These data are consistent with the previous adducts of benzene oxide obtained with other dienophiles [307, 308] and with other studies carried out recently by Harper and co-workers [35c]. The reaction of 293a/b with 291a gave two adducts, one of which is the expected [1 þ 1] adduct 296b (derived from 293b) and shows again the preference for anti addition (dienophile versus epoxide) and the second adduct arises from two molecules of dienophile 291a and one molecule of 293a/b (Scheme 21.138). Formation of 297 requires molecular rearrangement and its structure has been elucidated by NMR and X-ray diffraction analysis.

Me O

O Ph N O

N N

N

Me O N

O

297

N

Ph

O

Ar N

2

N N -80º C

O

R

1

R

O R

1

O 2

a/b

R

2

5a/b: R1 = R2 =H 292a/b: R1 = H, R2 = Me 293a/b: R1 = R2 = Me

291a= Ar= Ph 291b= Ar = C6F5 Ar N O O O N N -80º C

1

R 2 R N

N

O

N Ar O 294a/b: R1 = R2 =H 295a/b: R1 = H, R2 = Me 296a/b: R1 = R2 = Me

Scheme 21.138

Oxepines also undergo cycloaddition reactions at the C4
C5 bond, where they participate as a dienophile in [2 þ 4] cycloaddition with cyclopentadienone [270] and with 1,2,4,5-tetrazine or 1,2,4-triazine derivatives [309] bearing electron-withdrawing groups (Scheme 21.139). The benzo derivatives also undergo cycloaddition reactions. For example, reaction with tetracyanoethylene (TCE) [82, 310] affords the corresponding adduct 298 (Scheme 21.140).

j 21 Seven-Membered Heterocycles: Azepines, Benzo Derivatives and Related Systems

1948

CO2Me N HN

O

R

R O

O 80ºC

R

R= H

R= H

E1= CO2Me, E2= CN

Me

Me

O

R

X= N X= C-CO2Me

O

Ph

Ph N N

E2

CO2Me

HN

X N

-N2 1,3-H shift

CO2Me MeO2C

E1

E1= E2= CO2Me

Me

O

Ph Ph O

Me 65%

CN

Scheme 21.139

Ph

NC NC

TCE O

CN CN

Ph

O 298

Scheme 21.140

21.7.1.3 Reactions with Electrophiles The protonation of oxepine–benzene oxides takes place at the ring oxygen atom and generally results in C
O ring cleavage with the formation of several carbocations before conversion into phenol (Scheme 21.141). The acid-catalyzed isomerization has been studied extensively [311]. Deuterium and tritium labeling experiments have established a sequence that involves a 1,2-shift of the hydrogen isotope (X ¼ 2 H, 3 H) and an enolization step. This process has been described as the NIH-shift1) (Scheme 21.141). H

H

H

O

O

+

OH

X

X

X

X= 2 H, 3 H H OH X

+

H OH X

H X + OH

Scheme 21.141

1) The NIH-shift, named after the National Institute of Health, Bethesda, USA, where it was discovered in the context of biosynthetic studies.

21.7 Reactivity of Oxepines

j1949

The acid-catalyzed isomerization is dependent on the nature and position of the substituents relative to the ring oxygen atom. The sequence observed in the NIH-shift was also found for Cl, Br, Me, and CO2R substituents. Potential reaction pathways are indicated in Scheme 21.142 at C2 in the acidcatalyzed process and these include: (a) loss of R, (b) loss of X, (c) 1,6-migration and retention of X, and (d) 1,3-migration and retention of X.

R

2

R

1

H

+

R

2

R

O

O

X

X R

X

2

R

1

3

2

R

d

2

4

1,3-

OH

1

c

1

R + OH X b

1,62

R

R

1

1

R

a

2

OH

-R

X

R= 1H or 2H

-X 2

R

R

1

X= CO2H, CHO, CH2OH

OH OH X Scheme 21.142

The parent compound 5 has been halogenated by successive addition of bromine [312] and the resulting compound reacted with cyclopentadienylmagnesium to give 299, which upon treatment with triethylamine gave fulvalene derivatives (Scheme 21.143).

Br2 O 5

Et3N

MgBr

Br

O

Br

O

299

Scheme 21.143

21.7.1.4 Reactions with Nucleophiles The arene oxide valence tautomer of oxepines could react with nucleophiles as a simple epoxide. However, the oxepine–benzene oxide is quite unreactive towards

j 21 Seven-Membered Heterocycles: Azepines, Benzo Derivatives and Related Systems

1950

nitrogen nucleophiles such as NH3, NH2–, and RNH2 although it reacts with the azide anion to give cyclohexadiene derivatives (Scheme 21.144) [313].

O

O

N3

N3

H2O

OH

5a/b Scheme 21.144

The reactivity of benzene oxide–oxepine has also been studied with carbon, oxygen, and sulfur nucleophiles, affording in most instances 1,2-dihydroaromatic products. The reaction with methyllithium gave only cis-6-methylcyclohexa-2,4-dien-1-ol in 67% yield by 1,6-addition (Scheme 21.145). On the other hand, reaction with dimethylmagnesium gave a mixture of alcohols consisting of 37% cis isomer by 1,6-addition and 63% trans isomer by 1,2-addition. The mechanistic rationale was established by reactions with benzene-oxide oxepin-3,6-d2.

6

CH3

+

OH trans

(CH3)2Mg

OH

Et2O

5

1

CH3Li

O

O 4

3

cis

H2O

O

O

epoxide hydrolase

S

MeOH, MeO

-

OH

OH

or EtOH

OR R= Me, Et

Na2S

HO

CH3

Et2O

2

cis

OH OH

CH3

OH

NaSR

SR OH R= Et, Ac

Scheme 21.145

Alcohols add only with difficulty, and the addition of water occurs in the presence of epoxide hydrolase enzyme [314]. Sulfur nucleophiles readily attack the oxepine ring as soft nucleophiles to produce the corresponding trans derivative as a result of direct 1,2-opening (Scheme 21.145). The reaction of the 3-benzoxepine (19), which appears to exist exclusively in the oxepine form, with methyllithium was much slower and resulted in ring-opening to give the propenylphenylpropanol 300 (Scheme 21.146). The reaction of intracellular glutathione with benzene oxide–oxepine gave an initial metabolite of benzene, presumed to give 1-[S-glutathionyl]-cyclohexa-3,5-dien-

21.7 Reactivity of Oxepines

j1951

CH3Li O

OH ether

19

300

Scheme 21.146

2-ol, which underwent dehydration to S-phenylglutathione, the precursor of S-phenylmercapturic acid. In an effort to validate the proposed route to S-phenylglutathione, reactions of benzene oxide–oxepine with glutathione and other sulfur nucleophiles have been studied by Golding and co-workers [35b]. The data obtained confirm that benzene oxide–oxepine can be captured by glutation to give (1R,2R) and/ or (1S,2S) products as indicated in Scheme 21.147. Further dehydration leads to the S-phenylglutathione. The process at pH 7 is relatively inefficient but is accelerated at higher pH.

R

O

O

Glutathione HO

pH= 7-10

OH

R S O

HO H N

N H

O

O

S

O NH2

+ HO

OH

HO H N

S S N H

O

O

O NH2

O

Scheme 21.147

Herrad
on and co-workers have reported the opening of dibenzo[c,e]oxepin-5,7dione (301) with amino acid and peptide derivatives to give peptide-biphenyl hybrids that are calpain inhibitors (Scheme 21.148) [315]. The method has also been applied in the solid phase [316].

O O O 301

R1-NH2 2,4,6-collidine DMF, rt

NHR

O O

HO 87-99%

1

R2-NH2 HOBt/ EBC Et3N, DMAP; DMF, rt

R

NHR

O

2

O

N H 79-94%

Scheme 21.148

21.7.1.5 Reactions with Oxidants The reactions of oxepine with NBS/H2O or m-CPBA gave only stereoisomers of muconaldehyde (Scheme 21.149) [317]. The epoxides are assumed to be intermediates.

1

j 21 Seven-Membered Heterocycles: Azepines, Benzo Derivatives and Related Systems

1952

Br NBS/H2O

O

O

DMSO rt

CHO

O O

m-CPBA

O

CHO

O

OH

O

C6H6

CHO E, E

CHO E,Z

Reflux

O

m-CPBA C6H6, 0ºC or air/C6H6, -3ºC 36 days

CHO CHO

O

Z,Z

Scheme 21.149

However, in 2004 Nauduri and Greenberg [318] described the first unambiguous observation of an oxepine-2,3-oxide, as determined by 1 H-NMR spectroscopy (Scheme 21.150). 3-Benzoxepine (19) reacted with deuterated dimethyloxirane (DMDO) at 50  C in acetone-d6 to give the corresponding 2,3-oxide, which at 5–10  C rearranged rapidly to its isomer 1H-2-benzopyran-1-carboxaldehyde. In contrast, 2,3oxides of monocyclic oxepines rearrange to stable ring-opened dialdehydes or diketones as occurs, for example, with 2,7-dimethyloxepine.

O O

DMDO

CHO O

CHO Z,Z

19 O

Me

O

O

Me

Me O

Me

Me

Scheme 21.150

O Me E,E

O CHO

21.7 Reactivity of Oxepines

21.7.2 Reactivity of Partially Reduced Oxepines 21.7.2.1 Dihydrooxepines Rovis and Nasveschuk [319] have described an interesting ring contraction reaction from 2,5-dihydrooxepins to cyclopentenes, which involved a diastereoselective 1,3rearrangement promoted by ethylaluminium dichloride as a Lewis acid. The scope of the 1,3-ring contraction was evaluated with various substituents in different positions. The reaction provides access to cis- and trans-cyclopentene carboxaldehydes with good selectivities and can lead to tetrasubstituted cyclopentenes in high enantiomeric excess and with high diastereoselectivity (Scheme 21.151).

R

O

R

1

EtAlCl2 R

O

CH2Cl2

2

1

r.t, 10 min.

H

R

2

52-89% R1= Ph, p-Tol, p-C6H4CF3 R2= Me, Ph(CH2)2-, TBDPSO(CH2)2Scheme 21.151

2-Trifluoromethyl-substituted 4,5-dihydrooxepines 302 have been obtained by palladium(0)-mediated cross-coupling reactions from boryl, silyl, and stannyl dihydrooxepines (Scheme 21.152) [320].

Ph

Ph

CF3

R-X O

M

Pd2(dba)3(2.5 mol%) P(t-bu)3 (10 mol %)

CF3

O

M= SnMe3, B O

O

R

302

, TMS

a: iodobenzene, CsF, dioxane, 100ºC b: vinyl bromide, KOH, THF, r.t c: bromopphenylacetylene, KOH, THF, r.t

R= Ph (80%) R= vinyl (75%) R= Ph (78%)

Scheme 21.152

2-Trifluoromethyl-2,5-dihydrooxepine 303 has been hydrogenated to the fully saturated 304 and oxidized to oxepine 305 (Scheme 21.153).

j1953

j 21 Seven-Membered Heterocycles: Azepines, Benzo Derivatives and Related Systems

1954

R DDQ

H2 (1 atm) t

O

F3C

SiMe2Bu

Pd/C, MeOH, r.t

304 (93%)

O

CF3

E

Toluene, 100º C F3C

SiMe2Bu

305 (93%)

303

cis/trans =90: 10

t

O

E= t-BuMe2Si

Scheme 21.153

The photochemical behavior of 3,30 -dimethyl-3H-oxepin-2-ones has been reported [321]. The method efficiently proceeds through cyclization to give exclusively compound 306. However, reexamination of this photoreaction also found small amounts of the product arising from a 1,2-acyl shift (2.5–5%). A study of the photochemical process showed that the product distribution is greatly affected by the reaction temperature and that the yield of the 1,2-acyl shift product may be increased up to 28% at 70  C (Scheme 21.154).

Me

O

Me

Me hν

O

Me O hν

O

O

O Me

O

Me

Sensitizer rt

R

O +

306

Me

O O

Sensitizer or direct

O Me

O

heat

Me

O

O O

R O

R= Me (42%) R= Ph (unstable)

R= Me, Ph O

R O

307

Me

O

Me

hν

Me H

O R O

R= Me (24%) R= Ph (63%)

O hν CH3CN 10-15ºC

O O

Scheme 21.154

Other photochemistry studies have been carried out on 3-acetyl and 3-benzoyl 3-methyloxepine-2-ones (307), which efficiently undergo a 1,5-acetyl or 1,5-benzoyl shift (Scheme 21.154) followed by double bond isomerization [322]. Cyclization of 1,5-products by a second photoreaction to give the bicyclic systems is a common reaction, but this process can be suppressed completely when the photolysis is carried out at
60  C (6 h, R ¼ Me) and the reaction mixture is allowed to stand at room temperature overnight, yielding only the 1,5-acethyl product in 80%.

21.7 Reactivity of Oxepines

j1955

Oxepine-2,7-diones [323] also undergo photochemical ring closure to the corresponding bicyclic anhydrides (Scheme 21.154). Pterulone a, a chlorinated benzoxepine derivative that has potent antifungal activity, has been synthesized from 4,5-dihydro-2H-benzoxepin-3-one in a sequence of three reactions (Scheme 21.155). The first step is an oxidation to generate the double bond and this was carried out by radical bromination with NBS. This was followed by elimination of HBr to give the 3(2H)-oxepinone in 67% yield. The keto group was transformed into a chlorovinyl group by a Wittig reaction to afford only the (Z)-isomer in 76% yield. Finally, a Friedel–Crafts acetylation with silver triflate and acetyl chloride in DCM yielded a 1: 3 mixture of peterulone a and its(Z)-isomer in 60% overall yield [324].

O O

CCl4, reflux

+ Ph3PCH2Cl , Cl -

O

NBS/ Bz2O2 O 67%

Cl

O

tBuOH, THF, -78ºC

76% AcCl, AgTf, CH2Cl2 O

Cl

O

+ O

O Peterulone a

1:3 60% overall

Peterulone b

Scheme 21.155

21.7.2.2 Tetrahydrooxepines Several syntheses of acyclic and carbocyclic natural products are based on the use of (Z)-4-hexenolide (4,7-dihydro-3H-oxepin-2-one) and substituted derivatives. This lactone reacts with allyltrimethylsilane [325] in the presence of trimethyloxonium tetrafluoroborate in a ring-opening process to give methyl 4,8-nonadienoate with exclusive (Z)-configuration in 87% yield (Scheme 21.156). SiMe3 + Me3O BF4 O

O

O

OMe

CH2Cl2, rt, 94 h 87%

Scheme 21.156

To understand the role of the heteroatom on the rate of hydroboration, Brown and co-workers [326] undertook a study of representative heterocyclic olefins in comparison with the corresponding carbocyclic analogues. The results showed that

Cl

j 21 Seven-Membered Heterocycles: Azepines, Benzo Derivatives and Related Systems

1956

Table 21.5 Relative reactivity of olefins towards 9-BBN in THF at 25  C (1-hexene ¼ 100).

Hetero and related olefins

Relative rates

1-Hexene Cycloheptene 1-Methyl-1-cyclopentene 2,5-Dihydrofuran 2,3,4,5-Tetrahydrooxepin

100 6.9 1.59 1.54 2.31  10
1

2,3,4,5-tetrahydrooxepine reacts 30 times slower than cycloheptene (Table 21.5), and the hydroboration with 9-borabicyclo[3.3.1]nonane (9-BBN) is exclusively directed to the 3-position, which is probably controlled by a strong mesomeric contribution of the oxygen (Table 21.5, Scheme 21.157).

9-BBN X

25 ºC

B X X= O, 0.034 X= CH2, 100

Scheme 21.157

Another type of reactivity that has been studied [327] is the metallation of 2,3,4,5tetrahydrooxepine with n-BuLi or t-BuLi to afford 7-lithio-2,3,4,5-tetrahydrooxepine by vinylic deprotonation (Scheme 21.158).

O n-BuLi O 128

O

Li

37%

O

OH Me Me

Scheme 21.158

Under standard silylation [328] conditions (LDA, t-BuMe2SiCl, THF,
70  C) lactone 308 gave 309 in 97% yield and this rearranged to give cyclopropane carboxylic acids (e.g., the cis-chrysanthemic ester) by Claisen–Ireland rearrangement (Scheme 21.159). Although seven-membered a,b-unsaturated lactones can be used as dienophiles, they are less reactive than their acyclic counterparts and the Diels–Alder reaction is not a general approach to complex polycyclic systems. In an effort to overcome these synthetic problems, Taguchi and co-workers [329] have developed an efficient Lewis

21.7 Reactivity of Oxepines

H CO2 R

OTBDS

O

LDA, t-Bu(Me)2 SiCl

O

O

H

THF, -70ºC

308

j1957

cis-chrysanthemic ester

309 (97%)

Scheme 21.159

acid by mixing Tf2CH2 and Me3Al for the Diels–Alder reaction with cyclopentadiene (CP), which in the case of c- or e-methylated seven-membered lactone derivatives preferentially reacted with CP by the syn face (Scheme 21.160).

O O

"Tf2CH2 + Me3Al"

H

DCM 60 ºC, 4 h

H

+ 30 equiv

H

"Tf2CH2 + Me3Al" H endo-cis

O

endo/exo a, b

+

80% H

H

17:1 (1: 1.8)

exo

endo-trans O

H

O

+

+

Toluene 60 ºC, 8h

34 equiv

H

H

endo-cis O H

+

O

+

O O

O

70% 19:1 (1:3.8)

H

H endo-trans

exo

a: Determined by 1H NMR b: Ratio endo-cis/endo-trans isomers in parentheses

Scheme 21.160

The 1,3-cycloaddition reaction of nitrones to olefins is an effective tool for the preparation of isoxazolidones. In particular, the adduct from the cycloaddition of cyclic nitrones to a,b-unsaturated lactones [330] such as 6,7-dihydro-5H-oxepin-2one was converted into the corresponding piperidyl (and pyrrolidyl) oxepinone by reduction of the nitrogen–oxygen bond (Scheme 21.161) [331].

X + n N + O n= 1, 2

X H O N O

O

n=1; X= H, OAc, SPh, SAc n=2; X=H, Br, OTs, OAc, SPh, SAc Scheme 21.161

O

H O

Zn/HCl 50-100%

X HO

O

HN H O

j 21 Seven-Membered Heterocycles: Azepines, Benzo Derivatives and Related Systems

1958

21.8 Reactivity of Thiepines

The development of the chemistry of thiepines is linked to their theoretical and biological interest. The theoretical interest concerns the question of whether thiepines with 8p electrons are nonaromatic or antiaromatic. Research in this field has focused on simple derivatives that could provide information to increase our understanding of the nature of thiepines while the biological interest is linked to the pharmacological activity of this system. Since simple thiepines are generally very reactive, the chemical reactivity has been studied on polycyclic systems. On the other hand, the reactivity of this system can be considered separately from the bicyclic isomer thiirane, which on desulfurization and ring contraction yields arenes (Scheme 21.7). Thiepine thus appears to exist exclusively in this valence isomer. The stability of thiepines is enhanced by the presence of bulky substituents [332] at the C2 and/or C7 positions and electrondonating or -withdrawing groups. Additional stability is achieved in the transformation to S,S-dioxides (sulfones) and thiepinium salts. 21.8.1 Reactivity of Thiepines and Benzofused Derivatives

As simple thiepines are thermally unstable, the reactivity of these heterocycles has been studied with either monocyclic structures stabilized by tert-butyl groups at the 2,7-positions or annulated thiepines, 1,1-dioxide derivatives, or as transition metal derivatives. 21.8.1.1 Reactions with Metal Carbonyl Complexes The capacity of transition metals to stabilize labile species by complexation allows the isolation of unstable conjugated molecules such as, for example, norcaradiene [333] among others. In the field of thiepines, the transition metal complexation strategy has been used to synthesize and isolate thermally unstable compounds. Thiepine-1,1dioxide has been isolated as a stable crystalline compound, but the 1-oxides are considered to be extremely unstable [18]. In relation to the benzo-derivatives, 1-benzothiepine and its 1,1-dioxide are well characterized but the 1-benzothiephine 1-oxides are referred to polysubstituted derivatives. Consequently, efforts have been directed to the unstable 1-benzothiepine-1-oxide and thiepine and its 1-oxide. The first synthesis and characterization of thiepine-iron tricarbonyl (310) was carried out by Nishino and co-workers [177a] from thiepine 1,1-dioxide with Fe2(CO)9, a process that gave (thiepine 1,1-dioxide)iron tricarbonyl in 99% yield. Subsequent treatment of this complex with p-toluenediazonium tetrafluoroborate promoted by ultrasound irradiation led to the corresponding tolyloxysulfoxonium tetrafluoroborate as a mixture of stereoisomers, which were reduced by reaction with samarium diiodide/THF complex without affecting the 6,7-double bond to produce 310 in 38% yield (Scheme 21.162). Other complexes of thiepine 1,1-dioxide with Cr-, Mo-, and W-carbonyls have also been described [334].

21.8 Reactivity of Thiepines

THF, 50 ºC, 12 h

S

O

S

O

O

10

Fe(CO) 3

_ + p-CH 3C6H5-N2 BF4

Fe(CO) 3

1.5 equiv. Fe 2(CO) 9

99%

))))))

O

CH3

5 min.

O

+ S

O

21% 15 equiv. SmI 2 THF, 0 ºC

Cr(CO) 3

(MeCN) 3Cr(CO) 3

j1959

Fe(CO) 3 THF, N 2, rt, 12 h

S

O

O

86%

S

310 (38%) Scheme 21.162

Application of the transition metal strategy to 1-benzothiepine (14) gave the complex 311 in 41% yield, which on oxidation with m-CPBA was converted into monoxide 312 in 98% yield [335]. This compound, under analogous reaction conditions, gave the 1,1-dioxide complex (Scheme 21.163). Fe(CO)3

Large excess F e2(CO)9

S

Hexene 200
C) is converted into the 1-bromoquinolizinium bromide (262) (Scheme 22.66) [160b, 186]. The high temperature needed for this process is consistent with a radical reaction but an electrophilic mechanism can not be ruled out despite the fact that the C1 position is not the preferred site for the entry of the electrophile. Br Br2 N + Br

200 ºC N +

Acetone Br3

69%

Br

N + 262

Scheme 22.66

Electrophilic aromatic substitution on the quinolizinium cation requires strongly electron-donating substituents such as hydroxy or amino groups for the success of this reaction [169, 181]. 1-Hydroxyquinolizinium salts (219) undergo electrophilic substitution preferentially at the C2 position [187]. Nitration is carried out with nitric acid but this gives a yield of only 31% of the 2-nitrated betaine. In contrast, a much better yield (80%) is obtained with bromonation using bromine and hydrobromic acid (Scheme 22.67). Under the same conditions of bromination as for 219, the 2-hydroxyquinolizinium (218) gives the 1-bromo derivative 266 in 67% yield. Quinolizin-4-one (229) [the most stable tautomeric form of the 4-hydroxyquinolizinium (228)] yields the 1,3-dinitro derivative 267 when the nitration is carried out with nitric acid in acetic acid. Mononitration can be achieved using cupric nitrate in acetic anhydride to yield a mixture of the 1- and 3-nitro isomers (Scheme 22.68) [187b]. 1-Amino- and 2-aminoquinolizinium salts behave in a similar way to the hydroxy derivatives in promoting electrophilic substitution at the C2 and C1 positions, respectively. In the only reported example of activation by amino groups, substituted 1-amino quinolizinium salts give 2-bromo- or 4-bromo-substituted derivatives 270 and 271 while 8-amino-2,3-dimethylquinolizinium bromide undergoes bromination at the C1 position (Scheme 22.69) [188].

j2039

j 22 Heterocycles Containing a Ring-Junction Nitrogen

2040

O HNO3 N +

X = NO3

OH

OH + N N

1. H2, C/Pd, EtOH 2. HBr/NaNO2

NO2

N +

42% Br

31%

Br

265

263

N +

OH

X

Br

Br2/HBr

219

N +

X = Br Br

80%

264 Scheme 22.67

Br OH

OH Br2/HBr

Br

N +

N + Br

67%

218

266 NO2

HNO3 43%

N

NO2

O 267

N O 229

Cu(NO3)2.3H2O Ac2O

NO2 +

N O 268

NO2

N O 269

Scheme 22.68

22.4.5.2 Reactions with Nucleophilic Reagents: Ring-Opening Reactions The lability of the quinolizinium cation towards nucleophiles is a key feature of its reactivity, although substitution can modify this reactivity, depending on the nature and position of the substituents. Theoretical calculations predict that the reaction of nucleophiles should take place at C4 although the resulting product (pseudobase) 273 is an intermediate that evolves to the most stable ring-opened compound 274 (Scheme 22.70).

22.4 Quinolizinium Salts

NH2 R=H NH2 N + Br

52% R

Br

N Me + Br 270

Br2/acetone

NH2

Me R = Me

N + Br Br

90%

Me Me

271

NH2

Me N + Br

Me

Br Br2/acetone 90%

NH2

Me N +

Me Br

272 Scheme 22.69

Nu N +

N X

Nu 273

N Nu 274

Scheme 22.70

Early in the study of the chemistry of natural alkaloids having a quaternary bridgehead nitrogen it was observed that treatment of tetracyclic coralyne 193 with an alkaline solution gave the corresponding isoquinoline derivative (see Scheme 22.47), which is presumably formed by nucleophilic attack of the hydroxide anion followed by ring opening to form the enol and tautomerization to the most stable ketone [164]. This is the first and only example of the isolation of the carbonyl compound by reaction of the hydroxide ion with a quinolizinium system. Treatment of the parent quinolizinium iodide (16) with 10 M NaOH leads to decomposition and both rings lose their aromaticity. When 16 reacts with Nnucleophiles such as aniline a complex mixture of fragmentation products is also formed [189] but good yields of trans,trans-1-piperidinyl-4-(2-pyridyl)butadiene (275) have been obtained from the reaction of 16 with secondary amines such as piperidine [190]. 1-Methyl-4-(2-pyridyl)-1,3-butadiene (276) is also isolated when Grignard reagents are reacted with 16 although in this case the main product is the cis,trans isomer (Scheme 22.71) [191].

j2041

j 22 Heterocycles Containing a Ring-Junction Nitrogen

2042

NH

N N

EtOH 68%

X

N +

275

MeMgBr THF N

15%

276

Ph

Scheme 22.71

Although the reaction with stabilized carbanions is exemplified with benzoquinolizinium salts, examples with quinolizinium itself have not been reported. Similarly, the reaction with the cyanide anion has not yet been described. 22.4.5.3 Reactions with Reducing Reagents Quinolizinium iodide is fully hydrogenated in the presence of Adams catalyst to give quinozilidine hydroidide (277). This reaction with five moles of hydrogen was initially used to prove the structure of the quinolizinium cation [171]. Partial reduction can be accomplished with sodium borohydride in ethanol to give a mixture of the tetrahydro and hexahydro products. However, the attempted reduction with a stronger hydride donor such as lithium aluminum hydride in THF affords 1-(2-pyridyl)-1,3-butadiene (279) with cis stereochemistry, presumably via the 4Hquinolizine (278) (Scheme 22.72) [192]. NaBH4

I

N+ H

EtOH

H2 PtO2

277

N +

X

16

+

N +

N

H4LiAl THF

N H H

65%

N 279

278 Scheme 22.72

22.4.5.4 Cycloaddition Reactions A common reaction of some benzo[b]quinolizinium cations is as dienes in the Diels–Alder cycloaddition. However, neither quinolizinium nor 2,3-dimethylquinolizinium react with typical electron-poor or electron-rich dienophiles such as maleic anhydride or 1,1-diethoxyethylene. The only quinolizinium derivative known to

22.4 Quinolizinium Salts

undergo the Diels–Alder reaction is the anhydride of the quinolizinium 2,3-dicarboxylic acid (280), which reacts with styrene to yield the adduct 281 across the C1 and C4 positions (Scheme 22.73) [193].

Ph O

O N +

O X

Ph +

O

280

MeNO2 N + X

O O

281

Scheme 22.73

22.4.6 Quinolizinium Derivatives 22.4.6.1 Alkyl Derivatives The four most common substituents on the quinolizinium nucleus (methyl, hydroxy, amino, and bromo) usually enhance the reactivity of the substituted quinolizinium cation. Hydrogens of the methyl groups attached to the quinolizinium cation are acidic, particularly those at the C2 and C4 positions. The acidity of the methyl protons can be theoretically estimated on the basis of the resonance stabilization energy. Perturbation theory suggests that this energy is highest for methyl groups in positions C2 and C4. In addition, the values for p energy carbanion formation predict that methyl groups in the a- and c-positions to the nitrogen are the most reactive in benzoquinolizinium salts. Experimental results are in good agreement with these theoretical expectations [160f,194]. For example, in the presence of a base the methyl groups at C2 are easily deprotonated and the resulting anion behaves as a reactive stabilized carbanion towards different electrophiles such as aldehydes or nitroso compounds to afford styryl and anyl derivatives 282 and 283 in moderate yields (Scheme 22.74) [165b]. The 2,4,6-trimethylquinolizinium salt reacts selectively at the 2-methyl-substituent [165a]. The activation of these methyl groups makes 2-methyl- and 4-methylquinolizinium salts good substrates for the Ortoleva–King reaction, forming dications 284 in the presence of iodine and pyridine. Reaction of these salts with nitrosoarenes produces the expected nitrones 285 (Scheme 22.75) [195]. The electronic effect on these two positions also facilitates the oxidation of alkyl substituents and this can be used to achieve selective oxidation in the presence of other substituents in the C1 and C3 positions. In an example of this behavior the reaction of 1-acetylamino-2,3-dimethylquinolizinium (286) with selenium dioxide affords a mixture of the aldehyde 287 and the acid 288 as result of the oxidation of the 2-methyl substituent while the 3-methyl remained unaltered (Scheme 22.76) [196].

j2043

j 22 Heterocycles Containing a Ring-Junction Nitrogen

2044

N(CH3)2

N +

282

X

Py/EtOH

CH3 N +

(CH3)2N

CHO

CH2

Base

CH2

+N

N

X

224

(CH3)2N

N=O

N(CH3)2 N N +

X

283

Scheme 22.74

R N +

+ CH2 N

I2/Py N +

X

+ CH=N

O=N Piperidine/MeOH

N +

90%

X

X 285

284

R = 2-methyl, 4-methyl

O

Scheme 22.75

NHAc Me N +

X

286

Scheme 22.76

Me

SeO2 BuOH/Py

NHAc CHO N +

X

Me

+

NHAc CO2H N +

X

33%

35%

287

288

Me

22.4 Quinolizinium Salts

j2045

22.4.6.2 Hydroxy and Amino Derivatives Hydroxy and amino substituents clearly enhance the reactivity of the quinolizinium cation towards electrophiles. In fact, most of the electrophilic substitution reactions on the quinolizinium nucleus are facilitated by the presence of this type of strongly electron-donating substituent. Although substituted 1-, 2-, and 3-aminoquinolizinium derivatives are known, only the parent 1-aminoquinolizinium cation (290) has been obtained, from ketone 216 (Scheme 22.77) [197]. Examples of 4-aminoquinolizinium derivatives have not been described. NOAc

O NH2OH Br

N +

NaOAc EtOH 43%

N +

43% Br

+ NH3

NHAc

HCl/ HOAc/Ac2O

HBr N +

N + 2Br

heat Br

289

216

290

Scheme 22.77

The four isomeric hydroxyquinolizinium derivatives are known and their acidities have been determined by UV spectroscopy and calculated using both a resonance effect and a solvation effect. The calculated pKa (Table 22.8) largely depend on solvation effects rather than on resonance effects [198] and they are in good agreement with those experimentally determined for hydroxyl groups at the C1 and C3 positions. Calculated values predict that hydroxyl groups in the C1 and C4 positions (d and a to the nitrogen, respectively) should be more acidic than those in the C2 and C3 positions (c and b to the nitrogen, respectively) but experimental values show that the most acidic hydroxyls are located at C2 and C4, which is in better agreement with reactivity results. Notably, all of these hydroxyl derivatives are much more acidic than the corresponding naphthols, and the hydroxyl at C4 is so acidic that this derivative loses HBr very easily to form the uncharged covalent structure 4-quinolizone (229). 2-Quinolizone 291 is also obtained from a 2-hydroxyquinolizinium salt in moderate yield by treatment with potassium carbonate (Scheme 22.78). 1-Hydroxy- and 3-hydroxyquinolizinium salts 219 and 251 can also be easily deprotonated to generate the corresponding dipolar structures. In these isomers both the negative and the positive charges can be delocalized within the common p-electron system but, in contrast with the 2- and 4-hydroxyquinolizinium derivatives Table 22.8 pKa values for monohydroxyquinolizinium bromides.

Position

C1

C2

C3

C4

Calculated Observed

4.94 5.03  0.69

5.76 4.14  0.66

5.34 5.06  0.47

3.43 90%. Chemical and enzymatic hydrolysis process technology for 6-aminopenicillanic acid (6-APA) 85 or 7-aminocephalosporanic acid (7-ACA) 86 is also highly efficient (80–90%), with new enzyme technology leading to major cost reductions over the past decade. H 2N

S N

O

Me

Me CO 2H H

85

H2 N

S N

O

CH 2OAc CO 2H

86

24.2.3.2.1 Commercial Production of Penicillins The fermentation production of penicillin-G or -V is a fed-batch process carried out aseptically in stainless steel tank reactors of 30 000–100 000 gallon capacity. The fermentation usually involves two to three initial seed growth phases followed by a fermentation production phase having a time cycle ranging from 120 to 200 h. High dissolved oxygen levels are critical, especially during peak growth periods that often occur at the 40–50 h time-period of the cycle. The fermentation mode is fed-batch and crude sugar and precursor are fed throughout the cycle. Current penicillin fermentations are highly computerized and automated. Temperature, pH, dissolved oxygen, carbon dioxide, sugar,

24.2 Penicillins and Cephalosporins

precursor, ammonia, and so on are closely monitored and controlled for optimal antibiotic production [199]. Various carbon sources have been adopted for the fermentation, including glucose, sucrose and other crude sugars. About 65% of the carbon is metabolized for cellular maintenance, 20–25% for growth and 10–12% for penicillin production [200]. Sugar and precursor are fed continuously and the sugar is also used to help regulate the pH of the fermentation to between 6.4–6.8 during the active penicillin production phase. Corn steep liquor and cottonseed or soybean meal, ammonia and ammonium sulfate represent major nitrogen sources. The essential precursor substances are phenylacetic acid (for penicillin G) or phenoxyacetic acid (for penicillin V) that are either fed or batched. Mini-harvest protocols are often used in penicillin fermentations. This “batch-fill and withdraw” system involves the removal of 20–40% of the fermentor contents with replacement with fresh sterile medium. This procedure can be repeated several times during the fermentation without yield reduction and, in reality, can enhance the total penicillin yield per fermentor. Penicillin is excreted into the medium and is recovered at the end of the fermentation. Whole broth extraction is usually performed at acidic pH by most manufacturers and has resulted in a 2–5% improvement in overall extraction efficiency by the elimination of the rotary vacuum filtration step. Solvent extraction of chilled acidified broth is carried out with amyl, butyl or isobutyl acetate. Multiple back-extractions into buffer and solvent at varying pH using countercurrent contactors has led to considerable penicillin concentration in the early recovery stages of the purification process. Pigments and other broth impurities are removed by the use of activated charcoal. The penicillin is crystallized upon the addition of potassium acetate and is isolated as a crystalline potassium salt. Additional carbon treatments and solvent washes result in a highly purified final product. Approximately 75% of the total bulk penicillin volume produced in 1995, 33 000 tons, was used for the production of semi-synthetic penicillins and cephalosporins. The penicillin nucleus (6-APA) has enabled researchers to develop many excellent semi-synthetic penicillins. 6-APA can also be chemically ring-expanded to 7-ADCA to generate several important orally-active cephalosporins (cephalexin, cephradine, cefadroxyl, etc.). 6-APA has now grown to be the world’s largest selling b-lactam bulk intermediate. 24.2.3.2.2 Commercial Production of Cephalosporin C High-yielding strains of A. chrysogenum are used in large-scale, fed-batch fermentations. Major fermentation producers of cephalosporin C obtain harvest titers in the range of 20–25 g L1. Production-scale fermentations are fed-batch with carbon supplied as simple or complex carbohydrate feeds during the growth phase of the fermentation. As the fermentation progresses, sugar feeds are reduced and are usually replaced by higher energy oils such as soybean oil or peanut oil. Energy conservation from oil as a substrate is considerably less efficient and leads to slower growth, with the vegetative mycelium becoming largely transformed into multicellular arthrospores. The arthrospore stage leads to greater oxygen availability to the organism and results in rapid cephalosporin production. DL-Methionine addition, which also results in the onset of arthrospore formation, is often added to the medium during the early growth

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phase of the fermentation. The formation of arthrospores is also correlated with improved dissolved oxygen concentration in the broth and is critical for maximal expression of the important biosynthetic cyclase and expandase enzymes. Organic nitrogen is often supplied as a combination of soybean and cottonseed meals supplemented with ammonium sulfate and ammonia that is also used to help control the pH throughout the fermentation. Corn steep liquor is also supplied as a cheap nitrogen source and is rich in amino acids, vitamins, organic acids and trace elements. The pH of the fermentation is maintained between 6.2 and 7.0 and the temperature range is controlled between 24 and 28  C. A major problem associated with cephalosporin C fermentation is the inherent chemical instability of the cephalosporin C molecule. This is probably one of the major reasons why long-cycle cephalosporin C fermentations often result in reduced cephalosporin production compared to typical long-cycle penicillin fermentations. Cephalosporin C is readily degraded to 2-(D-4-amino-4-carboxybutyl)thiazole-4-carboxylic acid, which can account for as much as a 40% loss of the cephalosporin C produced [201]. The biosynthetic precursor molecules of cephalosporin C, deacetylcephalosporin C and DAOC have much more chemical stability. Strains of the yeast Rhodosporidium toruloides possess a potent acetyl esterase and, when the organism is added to active cephalosporin C fermentations, result in increased levels of deacetylcephalosporin C with an increase in total cephalosporin nucleus levels of 40%. Over the past decade, the cloning of many of the genes involved in the biosynthetic pathway of cephalosporins has resulted in more productive strains. The purification and recovery of harvest cephalosporin C broth begins with the rapid chilling of the active broth to 3–5  C followed by removal of the mycelial solids either by filtration or by centrifugation. The active broth contains not only the desired cephalosporin C component but also small quantities of the biosynthetic precursors penicillin N, DAOC, deacetylcephalosporin C and the degraded cephalosporin C product, 2-(D-4-amino-4-carboxybutyl)-thiazole-4-carboxylic acid. Two major strategies can be used for the recovery and purification of cephalosporin C. One strategy involves the use of activated carbon or the use of a non-ionic resin. Because of the high selectivity of the resin, cephalosporin C is preferentially adsorbed over penicillin N or the contaminating biosynthetic precursor molecules. Most of the penicillin N is removed in the pH 2.0 acidification step. An additional anion- and cation-exchange step usually results in high quality cephalosporin C. A large fraction of the cephalosporin C is converted into 7-ACA and derivatized to semi-synthetic cephalosporins. A second purification strategy involves the substitution of the amine moiety on the a-aminoadipyl side-chain at C7. Two substituted derivatives, N-2,4-dichlorobenzoyl cephalosporin C and tetrabromocarboxybenzoyl cephalosporin C, can be crystallized from acidic aqueous solution. Alternatively, salts can be formed between the N-substituted derivatives, and an organic base such as dicyclohexylamine or dimethylbenzylamine results in cephalosporin salts that are solvent extractable. Bristol-Myers Squibb uses a solvent-extractable process resulting in the isochlorobutylformate (ICBF) ester of cephalosporin C, termed cephalosporin D. Several extraction steps are usually necessary to achieve the final desired purity.

24.2 Penicillins and Cephalosporins

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N-Substituted cephalosporin C salts containing small amounts of contaminants can be effectively converted into 7-ACA. Efficient enzymatic processes are now utilized for the conversion of cephalosporins into 7-ACA, which has resulted in a dramatic cost reduction for this important bulk intermediate. Two key genetically engineered enzymes are involved. The initial step is reaction of the a-aminoadipyl group with D-amino acid oxidase to produce glutaryl-7-ACA. This reaction proceeds through a keto-7-ACA intermediate that undergoes an oxidative decarboxylation in the presence of hydrogen peroxide. A glutaryl acylase is used to remove the glutaryl side-chain to produce 7-ACA. Two-thirds of the commercial cephalosporins are derived from 7-ACA that is produced from cephalosporin C by either chemical or enzymatic deacylation. In the chemical process, after protection of the amino and carboxyl groups, reaction with potassium pentachloride in the presence of base forms an iminochloride derivative. The iminoether is formed on the addition of alcohol. The iminoether is hydrolyzed to form 7-ACA. 24.2.4 Reactivity of Penicillins and Cephalosporins 24.2.4.1 Basicity of b-Lactam Nitrogen If amide resonance in penicillins is inhibited because of the pyramidal nature of the b-lactam nitrogen, penicillins should show enhanced basicity compared with normal amides. By contrast, penicillins appear to show reduced basicity and cannot be detectably protonated even in 12 M hydrochloric acid [202]. Another indication of increased nitrogen basicity would be a large binding constant of penicillin to metal ions. The equilibrium constant for metal-ion coordination between the carboxyl group and the b-lactam nitrogen in penicillins is about 100–200 M1 for various metal ions [203], which is the same order of magnitude expected for coordination between a normal amide and a carboxyl group. Therefore, it became evident that there is not a substantial enhancement for the electron pair donating ability either to a proton or to a metal in penicillins. 24.2.4.2 Hydrolysis The bicyclic system in penicillin consists of a four-membered ring and a fivemembered ring. As a result, penicillin suffers large angle and torsional strains. Ring opening relieves these strains by cleavage of the more highly strained four-membered lactam ring (Scheme 24.46).

H N

R O H 2O

O

S N

Scheme 24.46

Me Me CO 2H

–H+

O

H N

R O

S

–O HO

N

H+

Me Me CO 2 H

R

HN HO 2C HN

S

Me Me CO 2 H

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The carbonyl group in the b-lactam ring is highly susceptible to nucleophiles and as such does not behave like normal tertiary amides, which are usually quite resistant to nucleophilic attack. This difference in reactivity is due mainly to the fact that stabilization of the carbonyl is possible in the tertiary amide but impossible in the b-lactam nucleus. The b-lactam nitrogen is unable to feed its lone pair of electrons into the carbonyl group since this would require the bicyclic rings to adopt an impossibly strained flat system. As a result, the lone pair is localized on the nitrogen atom and the carbonyl group is far more electrophilic than one would expect for a tertiary amide. The acyl side chain can actively participate (neighboring group participation) in a mechanism to open up the 2-azetidinone moiety (Scheme 24.47). Thus, penicillins have a built-in self-destruct mechanism. However, if a good electron-withdrawing group is attached to the carbonyl group, then the inductive pulling effect should draw electrons away from the carbonyl oxygen and reduce its tendency to act as a nucleophile. H N

R O

O

S N

Me Me CO 2 H

–H+

R

N O

S – O

Me

N

Me CO 2H

H+

N H O

N

S

O

O

HN

Me Me CO 2H

steps

HS

R

R

Me Me CO 2H

O

penicillenic acids

HO 2C +

N R

S N

Me Me CO 2H

penillic acids

Scheme 24.47

Enzyme-catalyzed hydrolysis of the b-lactam ring uncovers the thiazolidine-ring nitrogen as a nucleophile that drives a rapid intramolecular displacement on the side chain. Attachment of 7-hydroxy-4-methylcoumarin as the releasable group of this side chain generates a penicillin structure that can function as a fluorescence-based reporter substance/diagnostic for the presence of low levels of b-lactamase enzyme in solution [204]. The major structural differences between penicillins and cephalosporins are that the five-membered thiazolidine ring of penicillins is replaced by a six-membered dihydrothiazine ring in cephalosporins and that the degree of pyramidalization of the b-lactam nitrogen is generally smaller in cephalosporins. In addition, many cephalosporins bear a potential leaving group at the C30 position (pyridine, acetate, or thiol), which is expelled during the hydrolysis of the 2-azetidinone nucleus to give an exo-methylene cyclic imine (Scheme 24.48). Experimental observations have led to the conclusion that b-lactam CN bond fission is not concerted with the departure of the leaving group, and that the tetrahedral intermediate breaks down by proton

24.2 Penicillins and Cephalosporins

H N

R O H 2O

O R

O

S N

HN HO2 C

CH2 CO 2 H

H N

R O

CH 2X CO 2 H

S N

–H +

S

– O HO

N

H+

O +X

–

– X–

R

HN HO 2C HN

CH2X CO 2H

S CH2X CO 2H

Scheme 24.48

transfer to generate an intermediate enamine, which subsequently, in a separate step, expels the leaving group [205]. The similarity in the second-order rate constants for the hydroxide-promoted hydrolysis of penicillins and cephalosporins points to an absence of influence of the leaving group at C30 in cephalosporins. The hydrolysis of an acetoxy ester side chain at C3 in cephalosporins is competitive with the hydrolysis of the b-lactam ring. It may be due to the comparable reactivity of the 2-azetidinone nucleus of cephalosporins and a simple ester such as ethyl acetate. No significant spontaneous hydrolysis is observed in the pH–rate profile for the hydrolysis of penicillins, but the b-lactam moiety does undergo an acid-catalyzed degradation. By contrast, the hydrolysis of cephalosporins shows a spontaneous pHindependent hydrolysis and is less reactive by a factor of about 104 towards acid than are penicillins [206]. Penicillins undergo an acid- and a base-catalyzed hydrolysis, but there is no significant uncatalyzed reaction, the pH minimum being around 7 for spontaneous or water-induced degradation. However, cephalosporins often exhibit a significant pH-independent reaction in the pH range 3–7. The evaluation of different glutaryl acylase mutants to improve the hydolysis of cephalosporin C in the absence of hydrogen peroxide has been reported [207]. 24.2.4.3 Alcoholysis, Thiolysis, and Aminolysis The reactions of b-lactam antibiotics and their derivatives with nucleophiles have been studied extensively. For example, nucleophilic substitution at the b-lactam carbonyl center of penicillins occurs, in water, with amines [208], alcohols [209], and thiols [210] in competition with that by hydroxide ion. These are acyl transfer processes involving covalent bond formation between the carbonyl carbon and the nucleophile and CN bond fission of the b-lactam. In general, covalent bond formation to the incoming nucleophile occurs before b-lactam CN bond fission, resulting in the reversible formation of a tetrahedral intermediate. The rate-limiting step in these reactions is thus commonly ring opening and breakdown of the tetrahedral intermediate. Formation of the tetrahedral intermediate also changes the basicity of the leaving group amine, as amide resonance in the b-lactam is lost and

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proton transfer to nitrogen changes from an unfavorable to a thermodynamically favorable process. Thus, many of these reactions require general acid catalysis and protonation of the amine nitrogen leaving group to facilitate CN bond fission and avoid amine anion expulsion. Although the release of strain energy, which accompanies ring opening, could possibly decrease the need for protonation, CN fission in penicillins appears to require some form of catalysis. For example, the alcoholysis and thiolysis of penicillins occur with rate-limiting breakdown of the tetrahedral intermediate facilitated by proton transfer from solvent water to the departing amine. Exceptionally, the thiolysis of some cephalosporins appears to involve the breakdown of the tetrahedral intermediate by the expulsion of an enamine anion [211]. Unlike the strongly base catalyzed aminolysis of b-lactam antiobiotics, such as penicillins and cephaloridines, the rate law for the aminolysis of N-aroyl b-lactams is dominated by a term with a first-order dependence on amine concentration in its free base form, which is indicative of an uncatalyzed aminolysis reaction that proceeded by a concerted mechanism [212]. The relative sequence of bond making and breaking between heavy atoms in the aminolysis of b-lactam antibiotics is a result of subtle effects that often involve proton transfer. A step-wise process for aminolysis occurs through the formation of a tetrahedral intermediate, resulting from the attack on the carbonyl center by an amine, which gives rise to a large change in the pKa of the amine NH as a result of covalent bond formation. Proton transfer from the amine nucleophile to a base catalyst thus occurs after full covalent bond formation, as it changes from a thermodynamically unfavorable to a favorable process. Hence aminolysis usually requires general base catalysis to remove a proton from the attacking amine and this is the dominant term in the rate law – in fact it is experimentally difficult to determine the rate constant for any uncatalyzed reaction. With penicillins and cephalosporins this proton transfer occurs after initial CN bond formation in a rate-limiting step that is diffusion controlled. The aminolysis of b-lactam antibiotics also requires b-lactam CN bond fission and expulsion of an amine. The rate of aminolysis of benzylpenicillin and cephaloridine by hydroxylamine, unlike other amines, shows only a first order dependence on amine concentration [213]. The rate enhancement compared with that predicted from a Brønsted plot for other primary amines with benzylpenicillin is greater than 106. This is much more than an a-effect and is compatible with rate-limiting formation of the tetrahedral intermediate due to a rapid intramolecular general acid catalyzed breakdown of the intermediate. For cephaloridine, the rate enhancement is greater than 104, which demonstrates that b-lactam CN bond fission and expulsion of the leaving group at C30 are not concerted. 24.2.4.4 Destruction of b-Lactam Antibiotics by b-Lactamases b-Lactamases hydrolyze the four-membered b-lactam ring in both penicillin and cephalosporin classes of antibiotics (Scheme 24.49). They thereby destroy the antibacterial activity by deactivating the chemical warhead in the molecule [182], the strained b-lactam that is the chemically reactive acylating group for modifying the active-site serine side chains in the penicillin-binding proteins (PBPs) (the transpeptidases and carboxypeptidases in peptidoglycan [PG] crosslinking).

24.2 Penicillins and Cephalosporins

O

H N

R O

S

O

N

O

Me Me CO 2 H

R

O

N

HN

S

HO 2C HN

S

β-lactamase

CH2X CO 2 H

H2 O

R

Me Me CO 2 H

H2 O O

H N

R

β-lactamase

S

HN HO 2 C HN

CH2X CO 2H

Scheme 24.49

b-Lactamase activity was detected a few years before clinical use of penicillins in humans, indicating its presence in soil bacteria that combat the natural product penicillins, and to date more than 190 b-lactamases have been described [214], and categorized into class A, B, C and D lactamases [215]. The A, C and D classes are active-site serine enzymes, with architectural and mechanistic similarities to the PBPs [216], suggesting evolution from PBPs. In the A, C and D classes of b-lactamases the same type of penicilloyl-O-Ser enzyme covalent intermediate is formed as in the catalytic cycle of PBPs that attack and open the 2-azetidinone ring and become self-acylated. There is no such covalent penicilloyl enzyme intermediate in the catalytic cycle of the zinc-dependent class B b-lactamases, which has consequences for the failure of class B b-lactamases to be inhibited by certain drugs, because direct attack by water is carried out (Scheme 24.50).

H N

R O

O

S N

Me CO 2 H

H

Enz-Ser-O

H N

R O

O

H 2O H O H Zn Zn

S N

Me

Me Me CO 2 H

O serine β-lactamase R

O zinc β-lactamase R

HN O

S

HN O Ser Enz

HN O

Me CO 2 H H 2O

S

HN OH

Me

Me Me CO 2 H

Scheme 24.50

A simple, novel gold nanoparticle based colorimetric method has been developed for efficient screening of class A b-lactamase activity and inhibitors in vitro and in

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bacterial strains [217]. A novel protein labeling system that combines a genetically modified, noncatalytic b-lactamase variant and specific mechanism-based fluorescent probes has also been developed [218]. BcII is a B1 metallo-b-lactamase that is found in both mononuclear and dinuclear forms. Despite very elegant studies, there is still controversy over the nature of the active BcII species. A non-steady-state study of the hydrolysis of penicillin G catalyzed by Co(II)-substituted BcII has been carried out, and the modifications occurring at the active site of the enzyme have been followed. Working at different metal/enzyme ratios it has been demonstrated that both mono-Co(II) and di-Co(II) BcII are active metallo-b-lactamases. In addition, evidence has been presented that during penicillin G hydrolysis catalyzed by mono-Co(II) BcII the metal is localized in the DCH site (the Zn2 site in B1 enzymes) [219]. To probe the role of the Zn(II) sites in metallo-b-lactamase L1, mononuclear metal ion containing and heterobimetallic analogues of the enzyme have been generated and characterized using kinetic and spectroscopic studies. Mononuclear Zn(II)-containing L1, which binds Zn(II) in the consensus Zn1 site, was shown to be slightly active; however, this enzyme did not stabilize a nitrocefin-derived reaction intermediate that had been previously detected. Mononuclear Co(II)- and Fe(III)-containing L1 were essentially inactive, and NMR and EPR studies suggest that these metal ions bind to the consensus Zn2 site in L1. Heterobimetallic analogues (ZnCo and ZnFe) analogues of L1 have been generated, and stoppedflow kinetic studies revealed that these enzymes rapidly hydrolyze nitrocefin and that there are large amounts of the reaction intermediate formed during the reaction. These studies demonstrate that the metal ion in the Zn1 site is essential for catalysis in L1 and that the metal ion in the Zn2 site is crucial for stabilization of the nitrocefin-derived reaction intermediate [220]. 24.2.4.5 Conversion of Penicillins into Cephalosporins The chemical relationship of the penicillin (thiazolidine) and the cephalosporin (dihydrothiazine) skeletons was established in the early 1960s, when it was demonstrated that penicillin sulfoxides could be rearranged to form 3-methylated cephalosporins [221]. Treatment of phenoxymethylpenicillin sulfoxide methyl ester 87, which can be obtained from phenoxymethyl penicillin via periodate oxidation followed by esterification with diazomethane, with a trace of p-toluenesulfonic acid in xylene at reflux temperature gave the cephalosporin derivative 88. A plausible pathway for this acid-catalyzed ring-expansion involves a sulfoxide elimination to intermediate 89, subsequent addition of the sulfenic acid to the double bond with the sulfur becoming attached to the primary carbon and the loss of a proton to yield 88 (Scheme 24.51). Eventually, a more efficient process was developed using silyl protection during the ring expansion rearrangement. Silyl protection chemistry has led to efficient chemical production of 7-ADCA and has led to highly efficient production of the oral cephalosporins, cephalexin and cephradine. Cephadroxyl is synthesized after silylation of 7-aminocephalosporanic acid (7-ACA) followed by acylation with a mixed anhydride prepared from a salt of p-hydroxyphenylglycine and ethylchloroformate.

24.2 Penicillins and Cephalosporins – O S + Me

H N

R O

N

O

Me CO 2Me

PTSA (cat.)

O

xylene, reflux

OH H S CH 2

H N

R

+

N

O

Me CO 2Me

O

H N O

89

S N

O

88

N

O

87

R

OH S

H N

R

–H2O

H N

R O

CH3 CO2Me

O

S N H

H+ OH

–H+

H N

R O

CH 3 CO 2 Me

O

CH3 CO 2Me

S N H

H2 O +

CH3 CO 2Me

R = PhOCH 2

Scheme 24.51

Amoxicillin is synthesized using a similar process. An important Lilly product, cefaclor, involves a ring enlargement of a penicillin V ester to an expanded cephalosporin-S oxide with an exocyclic double bond. The product is a useful intermediate in that it can be converted into 3-substituted cephalosporins and into cefaclor, a highly prescribed oral cephalosporin with chlorine on the C3 position. 24.2.4.6 Reactions for the Transformation of Functional Groups in Side Chains This chapter cannot give a complete overview of all the possible transformations for penicillins and cephalosporins at a specific position, because of the enormous variety of reactions involved. We focus instead on some of the most relevant reactions [181, 222]. The most important transformation for the amino function in penicillins and cephalosporins is the protection, which is introduced in general as amide by acylating the 6-APA or 7-ACA [223]. In a recent contribution, 6-aminopenicillanates 90 have been N-acylated in a three-component reaction with an aldehyde and Ph3PCCO to give the corresponding 6-[(E)-20 -alkenoyl]amides 91 via a domino addition–Wittig alkenation sequence (Scheme 24.52) [224]. In addition to the amide group, several different protective groups are used for the transformation of the amino moiety of penicillins and cephalosporins. The amine can be converted into a carbamate group, to give the corresponding Boc [225], Cbz [226] or Teoc [227] derivatives. The Dane protecting group is very suitable for penicillins and cephalosporins, because the

H2 N O

S N

90 Scheme 24.52

Me Me CO 2 R1

Ph3 P=C=C=O, R2 CHO, THF, 60 oC 50–77%

H N

R2 O

O

S N

91

j2159

Me Me CO 2R 1

j 24 The Chemistry of 2-Azetidinones (b-Lactams)

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proton remaining on the nitrogen is stabilized by hydrogen bonding with the ester carbonyl group, which allows reactions that are normally possible only in doubly protected derivatives [228]. Double protection of the amino group is desirable in many operations, particularly with strongly basic reagents, and imines are often used [229]. The amino moiety of penicillins and cephalosporins can be transformed into different heteroatomic groups, as shown in Scheme 24.53. 6-Hydroxypenicillanic acid (92) has been synthesized by treatment of a solution of 6-APA in aqueous perchloric acid with sodium nitrite [230], while 6,6-dibromopenicillanic acid 93 has been prepared on reacting 6-APA with bromine [231]. A regiospecific methodology for the preparation of penicillate derivatives 6a-(1R-hydroxyoctyl)penicillanic acid and 6b-(1R-hydroxyoctyl)penicillanic acid – which will be valuable tools in the investigation of mechanistic and structural details of class D b-lactamases – has been described from 6,6-dibromopenicillanic acid 93 [232]. Esterification of 7-ACA followed by sequential treatment with excess triethylamine and trifluoromethanesulfonic anhydride gives an imine, which can then be hydrolyzed to generate the 7-oxo-cephalosporanate 94 [233]. A carbenechromium(0)-containing tether may be incorporated into penicillin G or cephalotin by using a (bromopropylamino) carbenechromium(0) complex to give metalla-penicillin and-cephalosporin derivatives, stable compounds which can be transformed into antibiotic derivatives bearing tripeptide side-chains [234].

HO O

S N

Me Me CO 2H

HClO4 (aq), H2N NaNO 2, H2 O, 0 oC 32%

O

S N

Me

Br2 , NaNO 2, 2.5 N H 2SO4

Br

o

Me CH2 Cl2 , 5 C CO 2 H 80%

O

Br

S N

92 H2N O

Me Me CO 2H

93 S

OAc

N

CO 2H

i) Ph2CN2 , MeOH, CH2 Cl2 , RT ii) Et3N, Tf 2 O, CH2Cl2,–78 oC

O

iii) HCl (aq), RT 40%

O

S N

OAc CO 2CHPh2

94 Scheme 24.53

6-Aminopenicillanic acid and two of its derivatives, 6-APA benzyl ester and penicillin G, have been evaluated as catalysts for use in direct cross-aldol reactions in different solvents and mixtures [235]. A thermal decarbonylation of penam b-lactams has been reported [236]. With the exception of monobactams, a carboxylic acid function a to the b-lactam nitrogen is essential for good antibacterial activity, and it is nearly always necessary to protect this carboxylic acid function during the preparation of derivatives. The first esterification of the carboxylic acid of penicillins was achieved on preparing penicillin G benzhydryl ester [237]. For penicillins and

24.2 Penicillins and Cephalosporins

j2161

cephalosporins, the most often used protective groups are functionalities that can be removed under acidic conditions, such as benzhydryl [238], tert-butyl [239] and p-methoxybenzyl [240]. A procedure that has been employed for some time to improve the absorption of penicillins and cephalosporins after oral administration is the use of special esters that readily undergo enzymatic hydrolysis in vivo, with liberation of the active drug. These esters, which are mostly bis-acyl derivatives of formaldehyde or acetaldehyde, can also provide protection for carboxylic acid functions during derivatization and synthetic transformations [222]. Transformations of 3-acetoxymethyl cephalosporins are of central importance. The cleavage of the acetyl residue can be carried out both enzymatically [241] and chemically [242] under mild conditions. Oxidation of alcohols obtained in this way allows preparation of the corresponding 3-formylcephalosporins, which can suffer further transformations such as the Wittig olefination [243] or Barbier-type allylation [244]. 3-Halomethyl cephalosporins can be synthesized via substitution reactions in 3-acetoxy(hydroxy)methyl cephalosporins [245]. These 3-halo derivatives usually act as building blocks for more complex derivatives. For example, the cephalosporin derivative 96, which has been confirmed as a novel fluorogenic substrate for imaging b-lactamase gene expression, has been prepared from the 3-chloromethyl cephalosporin 95 (Scheme 24.54) [246]. A practical route to the preparation of nitrocefin from a 3-chloromethyl cephalosporin related to 95 has been reported using a similar synthetic sequence [247]. Employing a multivalent approach to drug discovery, vancomycin and cephalosporin synthons have been chemically linked to yield heterodimer antibiotics, which simultaneously target the principal cellular targets of both glycopeptides and b-lactams [248]. H H H S N

Bn O

O

i) NaI, acetone, RT

N

Cl

O

OCHPh 2

Bn

ii) PPh3, EtOAc, RT

O

H H H S N O

O

PPh 3I

N O

Bn O

O

O

N O

O

O

TFA, anisole, CH2 Cl 2, 0 oC

17% OH

96

O

iii) 1M NaOH, CH2Cl 2, RT iv) MCPBA, CH2Cl 2, RT

OCHPh2

95 – H H H O S+ N

O

OHC

– H H H O S+ N

Bn O

O

O

O

N O

OCHPh 2

Scheme 24.54

The sulfur in penicillins and cephalosporins can be oxidized, leading to sulfoxides or sulfones [224, 231, 246, 249]. This oxidation is usually accomplished for one of three reasons: (i) sulfoxide formation to obtain reactive intermediates for further transformations; (ii) sulfoxide formation with subsequent reduction in cephems to shift the double bond from position 2 to position 3; (iii) preparation of sulfones as b-lactamase or elastase inhibitors.

O

j 24 The Chemistry of 2-Azetidinones (b-Lactams)

2162

Abbreviations

AIBN 7-ACA 6-APA Bn Boc BOM BTPP CAN Cbz Cp CSI DABCO DBN DBU DCC DEAD DIBAL-H DMAP DMF DMSO de dr ee Fmoc HIU HMDS HPLC IR LHMDS LDA MCPBA MCR MOM MM MMPP MS NCA NMP NMR PBP PDC Phth PMB

a,a0 -azoisobutyronitrile 7-aminocephalosporanic acid 6-aminopenicillanic acid (6-APA) benzyl tert-butyloxycarbonyl benzyloxymethyl phosphazene base P1-t-Bu-tris(tetramethylene) ceric ammonium nitrate benzyloxycarbonyl cyclopentadienyl chlorosulfonyl isocyanate 1,4-diazabicyclo[2.2.2]octane 1,5-diazabicyclo[4.3.0]non-5-ene 1,8-diazabicyclo[5.4.0]undec-7-ene N,N0 -dicyclohexylcarbodiimide diethyl azodicarboxylate (diisobutyl)aluminium hydride 4-dimethylaminopyridine dimethylformamide dimethyl sulfoxide diastereomeric excess diastereomeric ratio enantiomeric excess 9-fluorenylmethoxycarbonyl high intensity ultrasound hexamethyldisilazane high-performance liquid chromatography infrared lithium hexamethyldisilazane lithium diisopropylamide meta-chloroperoxybenzoic acid multicomponent reaction methoxymethyl molecular mechanical magnesium monoperoxyphthalate mass spectrometry N-carboxy anhydride N-methylpyrrolidone nuclear magnetic resonance penicillin binding protein pyridinium dichromate phthalimidoyl p-methoxybenzyl

References

PMP PPTS PTSA QM RCM RT TBDPS TBS TES TFA THF TIPS TEMPO Ts

p-methoxyphenyl pyridinium p-toluenesulfonate p-toluenesulfonic acid quantum mechanical ring closing metathesis room temperature tert-butyldiphenylsilyl tert-butyldimethylsilyl triethylsilyl trifluoroacetic acid tetrahydrofuran triisopropylsilyl 2,2,6,6-tetramethylpiperidine 1-oxyl tosyl

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Journal of the American Chemical Society, 82, 3790. Schobert, R. and Stangl, A. (2005) Tetrahedron Letters, 46, 1127. Sheehan, J.C., Buku, A., Chacko, E., et al. (1977) The Journal of Organic Chemistry, 42, 4045. Tsuji, T., Kataoka, T., Yoshioka, M., et al. (1979) Tetrahedron Letters, 2793. Kurita, A., Atarashi, S., Hattori, K., and Takano, T. (1966) The Journal of Antibiotics Series A, 19, 243. Corbett, D.F., Frydrych, C.H., Southgate, R., and Basker, M.J. (1990) Journal of Antibiotics, 43, 1042. Dane, E. and Dockner, T. (1965) Chemische Berichte, 98, 789; Manhas, M.S., Gala, K., Bari, S.A., and Bose, A.K. (1983) Synthesis, 649. Cama, L.D. and Christensen, B.G. (1973) Tetrahedron Letters, 3505. Heuser, L.J., Anderson, C.F., Applegate, H.E., et al. (1974) The Journal of Organic Chemistry, 39, 3929. Grant, J.W. and Smyth, T.P. (2004) The Journal of Organic Chemistry, 69, 7965. Buynak, J.D., Borate, H.B., Lamb, G.W., et al. (1993) The Journal of Organic Chemistry, 58, 1325. Volkmann, R.A., Carroll, R.D., Drolet, R.B., et al. (1982) The Journal of Organic Chemistry, 47, 3344; Buynak, J.D., Ghadachanda, V.R., Vogeti, L., et al. (2005) The Journal of Organic Chemistry, 70, 4510. Testero, S.A., O’Daniel, P.I., Shi, Q., Lee, M., Hesek, D., Ishiwata, A., Noll, B.C., and Mobashery, S. (2009) Organic Letters, 11, 2515. Buynak, J.D., Khasnis, D., Bachmann, B., et al. (1994) Journal of the American Chemical Society, 116, 10955. Sierra, M.A., Rodr
ıguez-Fern
andez, M., Casarrubios, L., G
omez-Gallego, M., and Manche~ no, M.J. (2009) European Journal of Organic Chemistry, 2998. Emer, E., Galletti, P., and Giacomini, D. (2009) European Journal of Organic Chemistry, 3155. Wiitala, K.W., Tian, Z., Cramer, C.J., and Hoye, T.R. (2008) Journal of Organic Chemistry, 73, 3024. Meyer, K., Hobby, G.L., and Chaffee, E. (1943) Science, 97, 205.

238 Kametani, T., Sekine, H., and Honda, T.

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244

245

246

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(1982) Chemical & Pharmaceutical Bulletin, 30, 4545; Yokoo, C., Goi, M., Onodera, A., et al. (1988) Journal of Antibiotics, 41, 181; Torii, S., Tanaka, H., Taniguchi, M., et al. (1991) The Journal of Organic Chemistry, 56, 3633. Takasugi, H., Kochi, H., Masugi, T., et al. (1983) Journal of Antibiotics, 36, 846. Guest, A.W., Branch, C.L., Finch, S.C., et al. (1987) Journal of the Chemical Society, Perkin Transactions 1, 45. Iwamatsu, K., Atsumi, K., Sakagami, K., et al. (1990) Journal of Antibiotics, 43, 1450. Heyninge, E.V. (1965) Journal of Medicinal Chemistry, 8, 22; Peter, H. and Bickel, H. (1974) Helvetica Chimica Acta, 57, 2044. Mobashery, S. and Johnston, M. (1986) Tetrahedron Letters, 27, 3333; Murakami, M., Aoki, T., and Nagata, W. (1990) Heterocycles, 30, 567; Koyama, Y., Huang, S.-P., Ikeda, D., and Kondo, S. (1990) Synlett, 389. Naito, T., Hoshi, H., Aburaki, S., et al. (1987) Journal of Antibiotics, 40, 991; Kamachi, H., Oka, M., Narita, Y., et al. (1990) Journal of Antibiotics, 43, 533. Keltjens, R., Vadivel, S.K., de Gelder, R., et al. (2003) European Journal of Organic Chemistry, 1749. Yamanaka, H., Chiba, T., Kawabata, K., et al. (1985) Journal of Antibiotics, 38, 1738; Bonjouklian, R. and Philips, M.L. (1981) Tetrahedron Letters, 3915. Gao, W., Xing, B., Tsien, R.Y., and Rao, J. (2003) Journal of the American Chemical Society, 125, 11146. Lee, M., Hesek, D., and Mobashery, S. (2005) The Journal of Organic Chemistry, 70, 367. Long, D.D., Aggen, J.B., Christensen, B.G., Judice, J.K., Hegde, S.S., Kaniga, K., Krause, K.M., Linsell, M.S., Moran, E.J., and Pace, J.L. (2008) Journal of Antibiotics, 61, 595. Micetich, R.G., Singh, R., and Maiti, S.N. (1984) Heterocycles, 22, 531. Micetich, R.G., Singh, R., and Shaw, C. (1986) The Journal of Organic Chemistry, 51, 1811. Tanaka, M., Konoike, T., and Yoshioka, M. (1989) Synthesis, 197.

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25 The Chemistry of Benzodiazepines Carlos Vald
es and Miguel Bayod

25.1 Introduction 25.1.1 General Introduction

The discovery of the psychotropic activity of 1,4-benzodiazepine derivatives (Figure 25.1) [1] opened a whole new area of activity in the treatment of mental diseases associated with depressive processes and affective alterations. More recently, compounds featuring the basic structure of 1,4-benzodiazepine, and exhibiting non-psychotropic biological activity, such as anti-cancer [2], anti-HIV [3], and anti-Alzheimer [4] activities have been discovered. Prominent examples are the benzodiazepinic alkaloids circumdatin A, B, and C, 1–3, which are employed in the treatment of gastrointestinal disorders [5], and the naturally occurring pyrrolo[2,1-c] [1,4]benzodiazepines (4), which are potent antitumor antibiotics isolated from various species of Streptomyces (Figure 25.2) [6]. Currently, the structure of 1,4-benzodiazepine represents one of most important privileged structures in medicinal chemistry, a term coined by Evans to define “a single molecular framework able to provide ligands for diverse receptors” [7]. In fact, the development of benzodiazepines chemistry has been directed to the search for new and more active compounds. The introduction of chlordiazepoxide (5) (Figure 25.3) in clinical medicine, in 1961, can be regarded as the starting point of the benzodiazepine era. Since then, thousands of these compounds have been synthesized through conventional and combinatorial techniques. Currently, over 50 benzodiazepines find clinical application in different regions of the world. Most of the benzodiazepines that have reached the market were selected due to their high anxiolytic potency due to their depressing function of the central nervous system. Most of them feature some sedative hypnotic properties to various extents, and therefore also find clinical application as sleep promoters. Moreover, their low tendency to induce lethal depression of the CNS has

Modern Heterocyclic Chemistry, First Edition. Edited by Julio Alvarez-Builla, Juan Jose Vaquero, and José Barluenga. Ó 2011 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2011 by Wiley-VCH Verlag GmbH & Co. KGaA.

j 25 The Chemistry of Benzodiazepines

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R1 N

9 8

R2 2

1

7

R5

5

6

N

R4

3

R3

4

Figure 25.1 General Structure of 1,4-benzodiazepines.

OMe

O O

O

N H

N N

R

NH

HO

O

R1

N

N

Me

N

H N

R2 O

R3

O

1 R = OMe, Circumdatin A 2 R = H, Circumdatin B

3 Circumdatin C

4 Pyrrolo[2,1-c] [1,4]benzodiazepines

Figure 25.2 Some compounds that feature the basic structure of 1,4-benzodiazepine and exhibit non-psychotropic biological activity.

ensured that benzodiazepines have replaced almost completely the barbiturics as sedative hypnotics. Over the last decade it has been shown that the effects of most of the 1,4benzodiazepines with clinical application result from benzodiazepine’s modulation of c-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the central nervous system, by influencing the GABAA receptor complex [8]. Benzodiazepines bind to the GABAA receptor, reducing the quantity of GABA required to open the chloride channel, hyperpolarize the neuron, and inhibit neurotransmission [9]. Benzodiazepines are lipo-soluble substances that are easy to crystallize and have basic character. The common characteristic of benzodiazepines is a bicyclic structure composed of a benzene ring fused to a diazepine (a seven-membered ring with two nitrogen atoms). In addition, most of the biologically active benzodiazepines feature substitution at C5 with an aromatic ring. Each particular benzodiazepine is derived

NHCH3

N Cl

N O

5 Chlordiazepoxide Figure 25.3 Structure of chlordiazepoxide (5).

25.2 Relevant Benzodiazepines

Ha N 5 4

d

H N

b

1 2

3

N

c

1H-1,4-benzodiazepine

N 1H-1,5-benzodiazepine

N NH

N N

3H-2,3-benzodiazepine

3H-2,4-benzodiazepine

Figure 25.4 Basic structures of benzodiazepines.

by the incorporation of different substituents at the different positions of the basic structure [10]. 25.1.2 Structural Classification of Benzodiazepines

Depending on the position of the two nitrogen atoms in the seven-membered heterocyclic ring, the benzodiazepines can be classified in four main different groups (Figure 25.4): . . . .

1,4-benzodiazepines 1,5-benzodiazepines 2,3-benzodiazepines 2,4-benzodiazepines.

By far, 1,4-benzodiazepines are the most interesting derivatives, due to their clinical applications. In addition, some examples of therapeutic applications of 1,5and 2,3-benzodiazepines exist. Thus, this chapter will focus mainly on the chemistry of 1,4-benzodiazepines, and in particular on the biologically more active members of this family. Nevertheless, 1,5- and 2,3- derivatives are covered in Sections 25.7 and 25.8, respectively.

25.2 Relevant Benzodiazepines 25.2.1 Most Common 1,4-Benzodiazepines

Table 25.1 gives the particular structures of some of the most important 1,4benzodiazepines with clinical applications. Variations on the substituents denoted by R1, R2, R3, R4, and R5 are responsible for the different biological activity of 1,4-benzodiazepines.

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Table 25.1 Chemical structure of the most common 1,4-benzodiazepines. 1

8

R5

9

R N

R2 2

1

7

5 6

N

3

R3

4

R4

Compound

Name

R1

R2

R3

R4

R5

6 7 8 9 5 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31

Bromazepam Camazepam Clonazepam Clorazepate Chlordiazepoxideb),c) Demoxepamc) Diazepam Fletazepam Flunitrazepam Flurazepam Fosazepam Halazepam Lorazepam Lormetazepam Medazepam Metaclazepam Nimetazepam Nitrazepam Nordazepam Oxazepam Pinazepam Prazepam Quazepam Temazepam Tetrazepam Tifluadom Uldazepamb)

H Me H H — H Me CH2CF3 Me (CH2)2NEt2 CH2POMe2 CH2CF3 H Me Me Me Me H H H CH2CCH CH2 CH2CF3 Me Me Me —

O O O O NHMe, H O O H, H O O O O O O H, H CH2OMe, H O O O O O O S O O

H OCONMe2 H CO2K H H H H H H H H OH OH H H H H H OH H H H OH H H H

a)

Br Cl NO2 Cl Cl Cl Cl Cl NO2 Cl Cl Cl Cl Cl Cl Br NO2 NO2 Cl Cl Cl Cl Cl Cl Cl H Cl

e) f)

H Cl H H H H F F F H H Cl Cl H Cl H H H H H H F H d)

F Cl

a)

2-Pyrido as substituent at C5. Double bond between N1 and C2. c) Oxygen at N4. d) 1-Cyclohexenyl as substituent at C5. e) Thieno-2-carbonylaminomethyl. f) Allyloxiamino. b)

Regarding the benzene ring, only substitution at C7 (R5) presents pharmacological interest. Moreover, usually anionic derivatives are more interesting than cationic forms. Substitution at positions 6, 8, and 9 diminishes substantially the activity or even makes the benzodiazepines biologically inert.

25.2 Relevant Benzodiazepines

Alterations in the substituent attached at C5 render some compounds pharmacologically interesting. For instance, bromazepam (6) with anxiolytic activity, features a 2-pyridyl substituent, and the muscle relaxant tetrazepam (29) a cyclohexenyl group. Modifications in the diazepinic ring give rise to most of the benzodiazepines with pharmacological activity. For example, methylation of the amide nitrogen of position 1 (R1 ¼ Me; R2 ¼ ¼O) is found in diazepam (11), while the addition of longer alkyl chains is detrimental to the anxiolytic activity. Other variations of R1 determine the formation of compounds with a high sedative effect: flurazepam (14, R1 ¼ (CH2)2 NEt2), anticonvulsant; halazepam (16, R1 ¼ CH2CF3), with activity similar to chlordiazepoxide (5); and pinazepam (25, R1 ¼ CH2C:CH) and prazepam (26, R1 ¼ CH2cyclopropyl) with diazepam-like activity. The introduction of modifications at position 2 leads to chlordiazepoxide (5), metaclazepam (20), and uldazepam (31). The 2-acylaminomethyl derivatives do not have affinity for the same receptor, and therefore lack anxiolytic activity. However, these type of derivatives act selectively on the opiaceous receptors. This is the case for tifluadom (30), which has shown K-selective agonist activity, with a potential of action over this subgroup of receptors 25-fold superior than that of morphine [11]. The introduction of functionality at position 3 leads to a new family of benzodiazepines, with camazepam (7), clorazepate (9), lorazepam (17), and oxazepam (24) as the most distinguished members. Camazepam (7) has shown excellent anxiolytic activity, with low sedative and relaxant effects. Reduction of the lactam of camazepam leads to fletazepam (12) and medazepam (19), compounds with lower pharmacological activity. The structural variants in which the benzene ring is replaced by a heterocycle hold great interest, since they exhibit similar pharmacological properties to the classic benzodiazepienes, and extend the therapeutic scope of these drugs. In this context, thienodiazepines, such as brotizolam (32), clotiazepam (33), and bentazepam (34) (Figure 25.5) have been extensively studied. 25.2.2 1,4-Benzodiazepines with a Heterocycle Condensed at sides a or d

Another interesting variation of pharmacological interest is present in systems that feature an additional five- or six-membered nitrogenated heterocycle condensed at N N

O

O

N S

S

N

S

N

Br N

N

Cl

Cl

32 Brotizolam

33 Clotiazepam

N

34 Bentazepam

Figure 25.5 Thienodiazepines brotizolam (32), clotiazepam (33), and bentazepam (34), which have been studied extensively in terms of their pharmacological properties.

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R X N

R

N N

N

N

N

Cl

N

N

N

X

F

X

A

B

N Cl

C

35 R=H, X=H; Estazolam 36 R=Me, X=Cl, Triazolam 37 R=Me, X=H, Alprazolam

R=Me, CH 2 NMe 2,CH 2Cl X= O, H2

O 2N

N

N

N N

Cl

N

Cl

N

O

38 Midazolam

39 Loprazolam

Figure 25.6 Benzodiazepines with a heterocycle condensed at the a face.

the a face of the benzodiazepine. Triazino-, triazolo-, and imidazobenzodiazepines (A,B, and C respectively in Figure 25.6) have been studied thoroughly. Triazinobenzodiazepines (A) have shown an effect similar to diazepam (11) (with the exception of the anticonvulsant effect), but the derivatives featuring a nitrogenated five-membered ring have attracted more interest in the pharmaceutical industry. Figure 25.6 shows some of the most relevant members of this type of benzodiazepines. Triazolam (36) is the most active triazolo-benzodiazepine. Both triazolam and estazolam (35) have exhibited excellent action as hypnotic agents. Of particular interest is alprazolam (37), which features rapid and strong anxiolytic activity, and antidepressive effects [12]. Regarding the imidazobenzodiazepines C, worth noting is midazolam (38), a benzodiazepine with relatively short action, which holds anxiolytic, hypnotic anticonvulsive, amnesic, and muscle relaxant effects [13]. Among the cyclofunctionalized 1,4-benzodiazepines, another interesting subgroup is formed by structures that feature a fused heterocycle at the d face (N4C5) of the diazepine ring (Figure 25.7). In particular, oxazolobenzodiazepines and oxazinobenzodiazepines have been studied extensively. Representative members of these families of heterocycles are oxazolam (40), cloxazolam (41), and mexazolam

O

H N N

X O

O

N

R

Cl

Ph

N O

O

Y 40 Oxazolam X = Cl, Y = H, R = Me 41 Cloxazolam X, R = H, Y = Cl 42 Mexazolam X = Y = Cl, R = Me

43 Ketazolam

Figure 25.7 Benzodiazepines with a heterocycle condensed at the d face.

25.2 Relevant Benzodiazepines

(42) for the oxazolobenzodiazepines, and ketazolam 43 for the oxazinobenzodiazepines. The latter is an analog of diazepam (11) that features good anxiolytic activity with low secondary effects. 25.2.3 Other Benzodiazepines with Clinical Application

Although 1,4-benzodiazepines represent the vast majority of benzodiazepines with pharmaceutical applications, some other examples exist of benzodiazepine drugs that feature the nitrogen atoms in different positions. This is the case of tofisopam (44), a 2,3-benzodiazepine with anxiolytic properties, and clobazam (45), a 1,5benzodiazepine employed in the treatment of several psychotic disorders (Figure 25.8). 25.2.4 Naturally Occurring Benzodiazepines

Many years after the discovery of synthetic 1,4-benzodiazepines as biologically active substances, several natural alkaloids featuring the basic 1,4-benzodiazepine substructure have been discovered. The benzodiazepine-quinazoline scaffold is found in several alkaloids with interesting biological activity. The simplest member is sclerotigenin, isolated from the sclerotia of Penicillium sclerotigenum [14]. More complex structures are found in benzomalvins A–C, isolated from the fungus Penicillium sp. [15], asperlicins [16] (Figure 25.9), and circumdatins A–G (Figure 25.2), isolated from the fungus Aspergillus ochraceous [5, 17]. Another important class of natural products that contains the 1,4-benzodiazepine structure are pyrrolo[2,1-c][1,4]benzodiazepines (PBDs). These compounds are a family of naturally occurring of antitumor antibiotics that have attracted great attention in recent years. Section 25.6 provides more detailed coverage of these systems.

O N N

O

O

N Cl

N

O

O

O

44 Tofisopam

45 Clobazam

Figure 25.8 Tofisopam (44), a 2,3-benzodiazepine with anxiolytic properties, and clobazam (45), a 1,5-benzodiazepine used in the treatment of several psychotic disorders.

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O N

O

N H

O

N

N

NMe

NMe

NMe

O

O Benzomalvin A

O N

O

Benzomalvin B

N

O

Benzomalvin C

N

N

H

NH HO

NH O

N O

N

HN N

O

O

Sclerotigenin

Asperlicin

Figure 25.9 Compounds containing the benzodiazepine-quinazoline scaffold.

25.3 1,4-Benzodiazepines: General Synthetic Methods 25.3.1 1,4-Benzodiazepines Ring Synthesis: Introduction

Since 1960, when the first benzodiazepine with clinical applications (chlordiazepoxide, 5) was introduced onto the pharmaceutical market, several methods have been developed for the preparation of a large variety of members of this family of products. With the advent of parallel and combinatorial techniques, the solid-supported synthesis of 1,4-benzodiazepines has been thoroughly developed. The synthetic strategies applied are common to both solution- and solid-supported synthesis. For this reason, the different methodologies will be presented regardless of whether they are employed in solution or solid support. This section is divided in two parts, dedicated to the most important members of this family, namely, 1,4-benzodiazepin-2-ones and 1,4-benzodiazepin-2,5-diones (Figure 25.10). 25.3.2 Ring Synthesis of 1,4-Benzodiazepin-2-ones 25.3.2.1 Quinazoline N-Oxide Route: Sternbach’s Classical Synthesis The synthesis of chlordiazepoxide (5) was reported by Leo Sternbach back in 1961 [18] by treatment of quinazoline N-oxide 48 with amines, followed by ring expansion of

25.3 1,4-Benzodiazepines: General Synthetic Methods

R1 N

2

1

5

R3

R1 N

O

N

3

O 2

1

R2

5

4

N 4

O

1,4-benzodiazepin-2-one

j2183

3

R2

R3

1,4-benzodiazepin-2,5-dione

Figure 25.10 The two most important members of the 1,4-benzodiazepine family.

the piperazine ring formed (Scheme 25.1). Hydrolysis of the amidine function of chlordiazepoxide gives rise to the corresponding lactam demoxepam (10) and further reduction of the N-oxide provides nordazepam (23) (Scheme 25.1). The discovery of the first benzodiazepine by Sternbach is a fascinating example of a serendipitous discovery that turned out to have an enormous impact in our society. Readers are encouraged to read Sternbach’s own version [1]. Chlordiazepoxide (5) had been prepared inadvertently and its structure had been wrongly assigned in 1955 during a synthetic project aimed at substituted quinazoline N-oxides (Scheme 25.1). Treatment of quinazoline N-oxide (48) with methylamine led to chlordiazepoxide (5) through an unexpected nucleophilic addition/ring-opening/ring-closure sequence, instead of the desired SN2 reaction. The crystals of chlordiazepoxide, which had remained in a flask in the bench for two years, were discovered during a laboratory H N

NH2 O ClCH 2CHO NH2OH

Cl

N

Cl

O

N MnO 2

H NHCH 3 N Cl N O

Cl

Cl N

Cl

47

46

CH3NH 2

Cl

O

48 NHCH 3

N

Cl N

Cl

OH

N

Cl

5

H N

Hydrolysis

O reduction N

Cl

10

Demoxepam

O

O

H N

N

Cl

23

Nordazepam

Scheme 25.1 Sternbach’s synthesis of chlordiazepoxide (5).

NHCH 3

N

Chlordiazepoxide

O

j 25 The Chemistry of Benzodiazepines

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clean-up operation and then submitted for pharmacological testing. The unparalleled properties found for that compound triggered the development of this important type of drugs in pharmaceutical industry. Demoxepam (10) can be directly obtained from 2-chloromethylquinazoline Noxide 48 by treatment with base [19]. In addition, reaction with anhydrides or acid chlorides leads to 3-acyloxy derivatives through the Polonovsky rearrangement [20], which upon hydrolysis gives 3-hydroxybenzodiazepines. This route has been employed for the synthesis of highly active benzodiazepines such as lorazepam (17) [21], lormetazep