Progress in Heterocyclic Chemistry, Volume 19 (Progress in Heterocyclic Chemistry)

PROGRESS IN HETEROCYCLIC CHEMISTRY Volume 19 Related Titles of Interest Books CARRUTHERS: Cycloaddition Reactions in...

Author: Gordon W Gribble | J. Joule

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PROGRESS IN

HETEROCYCLIC CHEMISTRY Volume 19

Related Titles of Interest Books CARRUTHERS: Cycloaddition Reactions in Organic Synthesis CLARIDGE: High-Resolution NMR Techniques in Organic Chemistry FINET: Ligand Coupling Reactions with Heteroatomic Compounds GAWLEY & AUBÉ: Principles of Asymmetric Synthesis HASSNER & STUMER: Organic Syntheses Based on Name Reactions KATRITZKY: Advances in Heterocyclic Chemistry KATRITZKY & POZHARSKII: Handbook of Heterocyclic Chemistry, 2nd Edition LEVY & TANG: The Chemistry of C-Glycosides MATHEY: Phosphorus-Carbon Heterocyclic Chemistry: The Rise of a New Domain McKILLOP: Advanced Problems in Organic Reaction Mechanisms OBRECHT: Solid Supported Combinatorial and Parallel Synthesis of Small-Molecular-Weight Compound Libraries PELLETIER: Alkaloids; Chemical and Biological Perspectives SESSLER & WEGHORN: Expanded Contracted and Isomeric Porphyrins WONG & WHITESIDES: Enzymes in Synthetic Organic Chemistry Major Reference Works BARTON, NAKANISHI, METH-COHN: Comprehensive Natural Products Chemistry BARTON & OLLIS: Comprehensive Organic Chemistry KATRITZKY & REES: Comprehensive Heterocyclic Chemistry I CD-Rom KATRITZKY, REES & SCRIVEN: Comprehensive Heterocyclic Chemistry II KATRITZKY, METH-COHN & REES: Comprehensive Organic Functional Group Transformations SAINSBURY: Rodd’s Chemistry of Carbon Compounds TROST & FLEMING: Comprehensive Organic Synthesis Journals BIOORGANIC & MEDICINAL CHEMISTRY BIOORGANIC & MEDICINAL CHEMISTRY LETTERS CARBOHYDRATE RESEARCH HETEROCYCLES (distributed by Elsevier) PHYTOCHEMISTRY TETRAHEDRON TETRAHEDRON: ASYMMETRY TETRAHEDRON LETTERS Full details of all Elsevier Science publications, and a free specimen copy of any Elsevier Science journal, are available on request at www.elsevier.com or from your nearest Elsevier Science office.

PROGRESS IN

HETEROCYCLIC CHEMISTRY Volume 19 A critical review of the 2006 literature preceded by two chapters on current heterocyclic topics Editors

GORDON W. GRIBBLE Department of Chemistry, Dartmouth College, Hanover, New Hampshire, USA and

JOHN A. JOULE The School of Chemistry, The University of Manchester, Manchester, UK

Amsterdam – Boston – London – New York – Oxford – Paris San Diego – San Francisco – Singapore – Sydney – Tokyo

Elsevier Linacre House, Jordan Hill, Oxford OX2 8DP, UK Radarweg 29, PO Box 211, 1000 AE Amsterdam, The Netherlands

First edition 2008 Copyright © 2008 Elsevier Ltd. All rights reserved No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means electronic, mechanical, photocopying, recording or otherwise without the prior written permission of the publisher Permissions may be sought directly from Elsevier’s Science & Technology Rights Department in Oxford, UK: phone (+44) (0) 1865 843830; fax (+44) (0) 1865 853333; email: [email protected]. Alternatively you can submit your request online by visiting the Elsevier web site at http://elsevier.com/locate/permissions, and selecting Obtaining permission to use Elsevier material Notice No responsibility is assumed by the publisher for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions or ideas contained in the material herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress ISBN: ISBN: ISSN:

978-0-08-045407-8 (Hardcover) 978-0-08-045408-5 (ISHC members edition) 0959-6380

For information on all Elsevier publications visit our website at books.elsevier.com Printed and bound in the United Kingdom 08 09 10 11 12 10 9 8 7 6 5 4 3 2 1

v

Contents Foreword

x

Editorial Advisory Board Members

xi

Chapter 1:

1

Recent progress in the chemistry of 2,1-benzothiazines

Xuechuan Hong and Michael Harmata, Department of Chemistry, University of Missouri-Columbia, Columbia, Missouri, USA 1.1 1.2 1.2.1 1.2.2 1.2.3 1.2.4 1.2.5 1.2.6 1.2.6.1 1.2.6.2 1.2.7 1.3 1.3.1 1.3.2 1.3.3 1.3.4 1.3.5 1.3.6 1.3.7 1.3.8 1.4 1.5

Introduction The synthesis of 2,1-benzothiazines and related compounds Synthesis of 3,4-dihydro-2,1-benzothiazine 2,2-dioxide derivatives Synthesis of dibenzo[c,e][1,2]thiazine 5,5-dioxide derivatives Synthesis of 1H-2,1-benzothiazine 2,2-dioxide (sulfostyril) derivatives Synthesis of azathiabenzenes and azathiaphenanthrenes Synthesis of 1,2-thiazine S-oxide by cycloaddition of N-sulfinylaniline Synthesis of Harmata-type benzothiazines Lewis acid-mediated synthesis of 2,1-benzothiazenes Synthesis of enantiomerically pure 2,1-benzothiazines Heterocyclic ring-fused thiazines and ring-fused 2,1-benzothiazine derivatives Chemistry of 2,1-benzothiazines Reactions of 2,1-benzothiazine 2,2-dioxide Reactions of azathiabenzenes and azathiaphenanthrenes Functionalization of Harmata-type benzothiazines via a sulfoximine-stablized vinyl carbanion Indole Synthesis Aniline Synthesis Chiral ligands in asymmetric allylic alkylation New chiral benzothiazine ligand for catalysis and molecular recognition Application of 2,1-benzothiazines in natural products syntheses Acknowledgements References

Chapter 2:

1 1 1 5 7 9 10 12 12 14 20 25 25 26 31 31 32 34 36 36 40 40

Porphyrins in Diels-Alder and 1,3-dipolar cycloaddition reactions

44

Ana M. G. Silva and José A. S. Cavaleiro, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal. 2.1 2.2 2.2.1 2.2.2 2.2.3 2.3 2.4 2.5

Overview of the cycloaddition reactions of porphyrins Porphyrins in cycloaddition reactions Porphyrins as dienophiles in Diels-Alder reactions Porphyrins as 1,3-dipoles in 1,3-dipolar cycloadditions Porphyrins as dipolarophiles in 1,3-dipolar cycloadditions Conclusions Acknowledgements References

Chapter 3:

44 45 45 49 58 67 67 67

Three-membered ring systems

70

Stephen C. Bergmeier and Damon D. Reed, Department of Chemistry & Biochemistry, Ohio University, Athens, Ohio, USA 3.1 3.2 3.2.1 3.2.2 3.3 3.3.1 3.3.2 3.4

Introduction Epoxides Preparation of epoxides Reactions of epoxides Aziridines Preparation of aziridines Reactions of aziridines References

Chapter 4:

70 70 70 74 80 80 85 90

Four-membered ring systems

92

Benito Alcaide, Departamento de Química Orgánica I, Facultad de Química, Universidad Complutense de Madrid, Madrid, Spain and Pedro Almendros, Instituto de Química Orgánica General, CSIC, Madrid, Spain. 4.1 4.2 4.3

Introduction Azetidines, azetines, 3-azetidinones, and diazetines Monocyclic 2-azetidinones (β-lactams)

92 92 95

vi 4.4 4.5 4.6 4.7 4.8

Contents Fused and spirocyclic β-lactams Oxetanes, dioxetanes, oxetenes and 2-oxetanones (β-lactones) Thietanes, β-sultams, and related systems Silicon and phosphorus heterocycles. miscellaneous References

Chapter 5:

Five-membered ring systems

Part 1.

Thiophenes and Se/Te analogs

98 100 103 104 106

112

Tomasz Janosik and Jan Bergman, Department of Biosciences and Nutrition, Karolinska Institute, Novum Research Park, Huddinge, Sweden. 5.1.1 5.1.2 5.1.3 5.1.4 5.1.5 5.1.6 5.1.7 5.1.8

Part 2.

Introduction Thiophene ring synthesis Reactions of thiophenes Non-polymeric thiophene organic materials Thiophene oligomers and polymers Thiophene derivatives in medicinal chemistry Selenophenes and tellurophenes References

112 112 116 121 123 125 127 128

Pyrroles and benzo analogs

135

Erin T. Pelkey, Hobart and William Smith Colleges, Geneva, NY, USA and Jonathon S. Russel, St. Norbert College, De Pere, WI 54115, USA, 5.2.1 5.2.2 5.2.2.1 5.2.2.2 5.2.2.3 5.2.3 5.2.3.1 5.2.3.2 5.2.3.3 5.2.4 5.2.4.1 5.2.4.2 5.2.4.3 5.2.5 5.2.5.1 5.2.5.2 5.2.6 5.2.6.1 5.2.6.2 5.2.6.3 5.2.6.4 5.2.7 5.2.7.1 5.2.7.2 5.2.8 5.2.8.1 5.2.8.2 5.2.8.3 5.2.8.4 5.2.9 5.2.9.1 5.2.9.2 5.2.10

Part 3.

Introduction Synthesis of pyrroles Intramolecular approaches Intermolecular approaches Transformations of other heterocycles Reactions of pyrroles Substitution at nitrogen Substitution at carbon Functionalization of the side-chain Pyrrole natural products and materials Natural products and biologically active small molecules Macrocycles and oligopyrroles Non-oligomeric materials Synthesis of indoles Intramolecular approaches Intermolecular approaches Reactions of indoles Substitution at C–3/C–2 Substitution at nitrogen Functionalization of the benzene ring Functionalization of the side-chain Carbazoles and azaindoles Carbazole ring synthesis and annulation Azaindole ring synthesis Indole natural products Natural products isolation and characterization Indole alkaloid total synthesis β-Carboline and tetrahydro-β-carboline total synthesis Oxindole total synthesis Biochemical and medicinal chemistry Indole alkaloid biosynthesis Medicinal applications of indole alkaloids References

135 135 135 138 142 143 143 143 148 148 148 149 149 150 151 154 155 155 158 158 159 159 159 160 160 160 161 163 163 164 164 165 165

Furans and benzofurans

Xue-Long Hou, Shanghai-Hong Kong Joint Laboratory in Chemical Synthesis and State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China, Zhen Yang, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of the Ministry of Education, Department of Chemical Biology, College of Chemistry, Peking University, Beijing, China, Kap-Sun Yeung, Bristol-Myers Squibb Pharmaceutical Institute, Wallingford, CT, USA, and Henry N. C. Wong, Department of Chemistry, Institute of Chinese Medicine and Central Laboratory of the Institute of Molecular

176

vii

Contents

Technology for Drug Discovery and Synthesis, The Chinese University of Hong Kong, Hong Kong, China and Shanghai-Hong Kong Joint Laboratory in Chemical Synthesis, Shanghai Institute of Organic Chemistry, The Chinese Academy of Sciences, Shanghai, China. 5.3.1 5.3.2 5.3.2.1 5.3.2.2 5.3.3 5.3.3.1 5.3.3.2 5.3.3.3 5.3.3.4 5.3.4

Part 4.

Introduction Reactions Furans Di- and tetrahydrofurans Synthesis Furans Di- and tetrahydrofurans Benzo[b]furans and related compounds Benzo[c]furans and related compounds References

176 177 177 181 184 184 188 193 198 200

With more than One N Atom

208

Larry Yet, Albany Molecular Research, Inc., Albany, New York, USA. 5.4.1 5.4.2 5.4.3 5.4.4 5.4.5 5.4.6 5.4.7

Part 5.

Introduction Pyrazoles and ring-fused derivatives Imidazoles and ring-fused derivatives 1,2,3-Triazoles and ring-fused derivatives 1,2,4-Triazoles and ring-fused derivatives Tetrazoles and ring-fused derivatives References

208 208 219 226 231 233 235

With N and S (Se) atoms

242

Yong-Jin Wu, Bristol Myers Squibb Company, Wallingford, Connecticut, USA and Bingwei V. Yang, Bristol Myers Squibb Company, Princeton, New Jersey, USA 5.5.1 5.5.2 5.5.2.1 5.5.2.2 5.5.2.3 5.5.2.4 5.5.2.5 5.5.2.6 5.5.2.7 5.5.2.8 5.5.3 5.5.3.1 5.5.3.2 5.5.3.3 5.5.3.4 5.5.4 5.5.5 5.5.6 5.5.7

Part 6.

Introduction Thiazoles Synthesis of thiazoles Synthesis of fused thiazoles Synthesis of thiazolines Reactions of thiazoles and fused derivatives Thiazole intermediates in synthesis Thiazolium-catalyzed and -mediated reactions Thiazole-containing natural products Thiazole-containing drug candidates Isothiazoles Synthesis of isothiazoles Reactions of isothiazoles Isothiazoles as auxiliaries in organic syntheses Pharmaceutically interesting isothiazoles Thiadiazoles 1,3-Selenazoles, 1,3-selenazolidines and 1,2,3-selenadiazoles Acknowledgement References

242 242 242 245 247 249 254 258 261 262 263 263 266 268 270 271 272 273 274

With O and S (Se, Te) atoms

277

R. Alan Aitken and Lynn A. Power, University of St Andrews, UK. 5.6.1 5.6.2 5.6.3 5.6.4 5.6.5 5.6.6 5.6.7 5.6.8

Part 7.

1,3-Dioxoles and dioxolanes 1,3-Dithioles and dithiolanes 1,3-Oxathioles and oxathiolanes 1,2-Dioxolanes 1,2-Dithioles and dithiolanes 1,2-Oxathioles and oxathiolanes Three heteroatoms References

277 280 282 283 283 283 283 284

With O and N atoms

288

Stefano Cicchi, Franca M. Cordero and Donatella Giomi, Università degli Studi di Firenze, Italy. 5.7.1 5.7.2 5.7.3 5.7.4 5.7.5 5.7.6 5.7.7 5.7.8

Isoxazoles Isoxazolines Isoxazolidines Oxazoles Oxazolines Oxazolidines Oxadiazoles References

288 291 294 298 302 306 309 310

viii

Contents

Chapter 6:

Six-membered ring systems

Part 1.

Pyridine and benzo derivatives

314

Heidi L. Fraser, Darrin W. Hopper, Kristina M.K. Kutterer and Aimee L. Crombie, Chemical and Screening Sciences, Wyeth Research, Pearl River, New York, USA 6.1.1 6.1.2 6.1.2.1 6.1.2.2 6.1.2.3 6.1.3 6.1.3.1 6.1.3.2 6.1.4 6.1.4.1 6.1.4.2 6.1.5 6.1.5.1 6.1.6

Introduction Pyridines Preparation of pyridines Reactions of pyridines Pyridine N-oxides and pyridinium Salts Quinolines Preparation of quinolines Reactions of quinolines Isoquinolines Preparation of isoquinolines Reactions of isoquinolines Piperidines Preparations of piperidines References

314 314 314 318 322 325 325 328 330 330 332 333 334 343

353

Part 2 (2005) Diazines and benzo derivatives (2005) Michael P. Groziak, California State University East Bay, Hayward, CA, USA 6.2.1 6.2.2 6.2.3 6.2.3.1 6.2.3.2. 6.2.3.3 6.2.4 6.2.4.1 6.2.4.2 6.2.4.3 6.2.5 6.2.5.1 6.2.5.2 6.2.5.3 6.2.6

Introduction Reviews and general studies Pyridazines and benzo derivatives Syntheses Reactions Applications Pyrimidines and benzo derivatives Syntheses Reactions Applications Pyrazines and benzo derivatives Syntheses Reactions Applications References

353 353 354 355 356 356 357 360 365 367 370 371 372 373 374

383

Part 2 (2006) Diazines and benzo derivatives (2006) Keith Mills, Ware, Hertfordshire UK. 6.2.1 6.2.2 6.2.3 6.2.3.1 6.2.3.2 6.2.4 6.2.4.1 6.2.4.2 6.2.4.3 6.2.5 6.2.5.1 6.2.5.2 6.2.5.3 6.2.6

Part 3.

Introduction General studies Pyridazines and benzo derivatives Synthesis Reactions Pyrimidines and benzo derivatives Synthesis Reactions Applications Pyrazines and benzo derivatives Synthesis Reactions Applications and structural studies References

383 383 385 385 388 389 390 400 405 406 406 407 409 410

Triazines, tetrazines and fused ring polyaza systems

Pilar Goya and Cristina Gómez de la Oliva, Instituto de Química Médica (CSIC), Madrid, Spain. 6.3.1 6.3.1.1 6.3.1.2 6.3.1.3 6.3.2 6.3.3 6.3.3.1 6.3.3.2 6.3.4 6.3.5 6.3.6

Triazines 1,2,3-Triazines 1,2,4-Triazines 1,3,5-Triazines Tetrazines Fused [6]+[5] polyaza systems Triazino and tetrazino [6+5] fused systems Purines and related structures Fused [6]+[6] polyaza systems Miscellaneous References

414 414 415 416 420 422 422 423 427 428 429

414

ix

Contents

Part 4.

With O and/or S atoms

436

Chapter 7:

Seven-membered rings

437

John B. Bremner, Institute for Biomolecular Science and Department of Chemistry, University of Wollongong, Wollongong, NSW, Australia and Siritron Samosorn Department of Chemistry, Faculty of Science, Srinakharinwirot University, Bangkok, Thailand. 7.1 7.2 7.2.1 7.2.2 7.2.3 7.2.4 7.3 7.3.1 7.3.2 7.3.3 7.4 7.4.1 7.5 7.6 7.7

Introduction Seven-membered systems containing one heteroatom Azepines and derivatives Fused azepines and derivatives Oxepines and fused derivatives Thiepines and fused derivatives Seven-membered systems containing two heteroatoms Diazepines and fused derivatives Dioxepines, dithiepines and fused derivatives Miscellaneous derivatives with two heteroatoms Seven-membered systems containing three of more heteroatoms Systems with N, S and/or O Seven-membered systems of pharmacological significance Future directions References

Chapter 8:

437 437 437 442 445 448 449 449 452 453 457 457 459 461 461

Eight-membered and larger rings

465

George R. Newkome, The University of Akron, Akron, Ohio, USA. 8.1 8.2 8.3 8.4 8.5 8.6 8.7 8.8 8.9 8.10 8.11 8.12 8.13 8.14 8.15 8.16 8.17 8.18

Index

Introduction Carbon-oxygen rings Carbon-nitrogen rings Carbon-sulfur rings Carbon-oxygen/carbon-nitrogen rings Carbon-nitrogen-oxygen rings Carbon-nitrogen-sulfur rings Carbon-phosphorus-oxygen rings Carbon-phosphorus-sulfur rings Carbon-sulfur-oxygen rings Carbon-nitrogen-sulfur-oxygen rings Carbon-silicon/selenium/tellurium rings Carbon-metal rings Carbon-nitrogen-metal rings Carbon-oxygen-nitrogen-metal rings Carbon-silicon/germanium-nitrogen-metal rings Carbon-phosphorus-oxygen-metal rings Referencees

465 466 468 470 471 471 474 475 475 476 476 477 477 478 478 479 479 479

484

x Foreword

This is the nineteenth annual volume of Progress in Heterocyclic Chemistry, and covers the literature published during 2006 on most of the important heterocyclic ring systems.

References are

incorporated into the text using the journal codes adopted by Comprehensive Heterocyclic Chemistry, and are listed in full at the end of each chapter. This volume opens with two specialized reviews. The first, by Xuechuan Hong and Michael Harmata, covers ’Recent progress in the chemistry of 2,1benzothiazines’. The second, by Ana Silva and José Cavaleiro, discusses ‘Porphyrins in Diels-Alder and 1,3-dipolar cycloaddition reactions’. The remaining chapters examine the 2006 literature on the common heterocycles in order of increasing ring size and the heteroatoms present. In the previous volume, Vol. 18, it was not possible to include a chapter on ‘Six-membered ring systems: diazines and benzo derivatives’ so this volume has two chapters on this topic: chapter 5.4 (2005) covers the literature of 2005 and chapter 5.4 (2006) covers the publications of 2006. Due to unforeseen and

unfortunate circum stances, ‘Six-m embered ring system s: with O and/or S atom s’ does not appear in this volume; Volume 20 will include a double chapter on this topic, covering the literature of 2006 and 2007. The Index is not fully comprehensive – it includes only systematic heterocyclic ring system names. Thus, wherever a pyrrole is discussed, that would be indexed under 'pyrroles'; wherever 'pyrido[3,4-b]indoles' are mentioned an indexed entry under that name will be found; similarly 'aceanthryleno[1,2-e][1,2,4]triazines', 'azirines', '2H-pyran-2-ones', '1,2,4-triazoles', etc., etc. are listed. But, subjects like '4-ethyl-5-methylpyrrole', '5-acylazirines', '6-alkyl-2H-pyran-2-ones', '3alkylamino-1,2,4-triazoles', are not listed as such in the Index. 'Diels-Alder reaction' or 'Heck coupling' etc., are also not indexed. However, again this year, the Contents pages list all the subheadings of the chapters which we hope will considerably improve accessibility for readers. We are delighted to welcome some new contributors to this volume and we continue to be indebted to the veteran cadre of authors for their expert and conscientious coverage. We are also grateful to Joan Anuels of Elsevier Science for supervising the publication of the volume. We hope that our readers find this series to be a useful guide to modern heterocyclic chemistry. As always, we encourage both suggestions for improvements and ideas for review topics.

Gordon W. Gribble John A. Joule

xi

Editorial Advisory Board Members Progress in Heterocyclic Chemistry 2006 - 2007 PROFESSOR M. BRIMBLE (CHAIRMAN) University of Auckland, New Zealand

PROFESSOR D. ST CLAIR BLACK University of New South Wales Australia

PROFESSOR H. HIEMSTRA University of Amsterdam The Netherlands

PROFESSOR M.A. CIUFOLINI University of British Columbia Canada

PROFESSOR D.W.C. MACMILLAN California Institute of Technology USA

PROFESSOR T. FUKUYAMA University of Tokyo Japan

PROFESSOR M. SHIBASAKI University of Tokyo Japan

PROFESSOR A. FÜRSTNER Max Planck Institut Germany

PROFESSOR L. TIETZE University of Göttingen, Germany

PROFESSOR R. GRIGG University of Leeds UK

PROFESSOR P. WIPF University of Pittsburgh USA

Information about membership and activities of the International Society of Heterocyclic Chemistry (ISCH) can be found on the World Wide Web at http://webdb.uni-graz.at/~kappeco/ISHC/index.html

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1

Chapter 1 Recent progress in the chemistry of 2,1-benzothiazines

Xuechuan Hong and Michael Harmata∗ Department of Chemistry, University of Missouri-Columbia, Columbia, Missouri 65211, USA [email protected]

1.1 INTRODUCTION The study of the chemistry of 2,1-benzothiazines 1 started in the 1960s . Subsequently, their preparation and intensive biological and physiological studies have been reported . In recent years, 2,1-benzothiazines 1, have been of enormous interest to synthetic chemists. The current review is intended to present the progress of synthetic procedures and applications of 2,1-benzothiazines 1 and related compounds. 5

4

6 7 8

N 1

3 S2

(1)

Figure 1. General structure of 2,1-benzothiazines 1 1.2 THE SYNTHESIS OF 2,1-BENZOTHIAZINES AND RELATED COMPOUNDS 1.2.1 Synthesis of 3,4-Dihydro-2,1-benzothiazine 2,2-dioxide Derivatives 3,4-Dihydro-2,1-benzothiazine 2,2-dioxide derivatives 2, a type of benzosultam, possess very strong biological activities and have been used as drugs for treating heart diseases and as lipoxygenase inhibitors (Figure 2). These remarkable biological activities have made the synthesis of the 3,4-dihydro-2,1benzothiazine 2,2-dioxide skeleton of interest. Several different methods of synthesis of 3,4dihydro-2,1-benzothiazine 2,2-dioxide derivatives are already established.

*∗ This review is dedicated to Professor Albert Padwa (Emory University) on the occasion of his 70th birthday

2

X. Hong and M. Harmata

R2 R3

R1= H, PhCH2 N R1

R2= H, alkoxyl, hydroxyl

SO2

R3= H, piperazinyl

(2)

Figure 2. 3,4-Dihydro-2,1-benzothiazine 2,2-dioxide derivatives. In 1965, the first 2,1-benzothiazine 2,2-dioxide was synthesized by Leov’s group through cyclization of 2-(ortho-aminophenyl)ethanesulfonic acid or its sodium salt with phosphorus pentachloride and acetyl chloride. They also demonstrated that 4-phenyl-3,4-dihydro-2,1-benzothiazine-2,2 dioxide (6) can be smoothly obtained by treatment of styrenesulfonanilide 5 with polyphosphoric acid (PPA) . Sianesi and co-workers developed an alternative approach to prepare 4 in 73% yield by pyrolysis of the corresponding aminosulfonamide hydrochloride 7 (Scheme 1). NH 2

H N

PCl5, AcCl SO 3X

4

3: X= Na, H H N

5

SO2

H N

PPA

6

Ph

NH 2.HCl SO 2NH2

SO 2

~40%

Ph H N

o

200 C

SO 2

SO 2

73% 4

7

Scheme 1 In 1969, Hromatka et al. found that the cyclization of 5-chloro-2-(Nmethyl-iodomethanesulfonamido)-benzophenone 8 with ammonia or alcoholic ammonia gave 6-chloro-4-hydroxy-1-methyl-4-phenyl-3,4-dihydro-2,1-benzothiazine 2,2-dioxide 9 and 6chloro-4-hydroxy-3-iodo-1-methyl-4-phenyl-3,4-dihydro-2,1-benzothiazine 2,2-dioxide 10 in 30% and 33% yields, respectively (Scheme 2).

3


CH 3 N SO2 CH 2 I O

Cl

CH3 N SO2

NH 3, CHCl3 30%

Cl

OH Ph

Ph 8

9 CH3 N SO 2CH2 I O

Cl

CH 3 N SO 2

NH 3, EtOH 33%

Cl

OH Ph

Ph 8

I

10

Scheme 2 Abramovitch and co-workers also synthesized 3,4-dihydro-2,1benzothiazine 2,2-dioxide 4 by flash vacuum pyrolysis of ȕ-arylethanesulfonyl azides 11. The 3,4-dihydro-2,1-benzothiazine 2,2-dioxide 4 was obtained in 13% yield at 300 oC along with some side products, such as dihydropyrindine, indoline, indole, and styrene. Although the reaction yield was low, this new approach appeared very promising for the synthesis of 2,1-benzothiazenes (Scheme 3). After an extension of this work reported by the same group, the thermolysis of compound 11 (R1 = H; R2, R3 = OMe) at 400 oC in Freon 113 as solvent gave compound 12 in 46-62% yield. R2

R2 SO2N3

R3

H N

SO2

R3 R1

R1 4: R1= H, R2, R3= H

11

12: R1= H, R2, R3= OMe

Scheme 3 5-Hydroxy-3,4-dihydro-2,1-benzothiazine 2,2-dioxide 15 can be synthesized in a convenient manner . Blondet and co-workers used a cyclization of an ortho(chloromethyl or carboxaldehyde) N-protected sulfonanilide 13 or 16 with sodium hydride in DMF to give the benzothiazine dioxide 14 or 17 in 35% and 47% yields, respectively (Scheme 4). Finally, removal of the methoxy group and hydrogenation led to the formation of 5-hydroxy-3,4-dihydro-2,1-benzothiazine 2,2-dioxide 15 in good yield over two steps.

4


OCH 3

OCH 3 Cl

NaH, DMF

1. BBr3 , CH2 Cl2 , 77%

o N SO2 CH 3 60 C, 35%

13

N

Ph

14

SO2

2. H2 , Pd(OH)2 , 85%

NaH, DMF 25 o C, 47%

N H

15

Ph

OCH 3

OCH3 CHO

SO2

OH 1. BBr3 , CH 2Cl2, 65%

N

N SO 2CH3 16

OH

17

Ph

SO2

2. H 2, Pd(OH) 2, 82%

N H

15

Ph

SO2

Scheme 4 An improved synthesis of 3,4-dihydro-2,1-benzothiazine 2,2-dioxide was reported by Togo and co-workers using photochemical conditions . Treatment of N-alkyl 2-(aryl)ethanesulfonamides 18 with (diacetoxyiodo)arenes under irradiation with a tungsten lamp at 20-30 oC afforded 2,1-benzothiazines 19 and 20. Chemical yields and selectivities were dependent upon the choice of solvents and the reactant’s substituents 18 (Table 1). When THF and EtOH were used as solvents, the reactions failed to give the cyclized products, since their Į-hydrogen was abstracted by the intermediate sulfonamidyl radical. Compound 20 was obtained as a major product when 1,2-dichloroethane was employed as a solvent. In contrast, in the case of EtOAc as solvent, compound 19 was obtained as the major product. Table 1. Formation of 3,4-dihydro-2,1-benzothiazine 2,2-dioxides with N-alkyl 2(aryl)ethanesulfonamides

R'

X'

I2 (1.0 eq), 20-30 oC

I

R'

SO2NHR PhI(OAc)2 (1.6 eq.) X'

W-hυ, 2 h 18

N R

SO2 +

R'

X'

19

N R

SO2

20

Entry

Solvent

R

Rƍ

Xƍ

Yield % of 19

Yield % of 20

1

THF

CH3

H

H

0

0

2

EtOH

CH3

H

H

0

0

3

AcOEt

CH3

H

H

81

10

4

ClCH2CH2Cl

CH3

H

H

6

89

5

ClCH2CH2Cl

Et

H

H

0

89

6

ClCH2CH2Cl

CH3

CH3

H

0

97

7

ClCH2CH2Cl

CH3

H

CH3

0

94

8

ClCH2CH2Cl

CH3

H

Cl

34

49

5


Table 2. Cyclization of N-methoxyl 2-(aryl)ethanesulfonamides

SO2NHOCH3

ArI(OH)OTs (1.1 eq.) 0 oC- rt. 20 min.

R

SO2 N OCH3

R

21

Entry 1 2 3

R H H H

22

Solvent CHCl3 AcOEt ClCH2CH2Cl

İ 4.7 6.0 10.4

o

Temp./ C

Time/min

Yield % of 22

o

20

18

o

20

29

o

20

73

o

0 C to rt 0 C to rt. 0 C to rt

4

H

CH3CN

37.5

0 C to rt

20

86

5

H

CH3CN

37.5

60-65

5

65

6

H

CH3CN

37.5

0

20

65

7

H

CH3CN

37.5

10-15

20

84

37.5

o

20

85

o

20

52

o

20

44

8 9 10

CH3 Cl F

CH3CN CH3CN CH3CN

37.5 37.5

0 C to rt 0 C to rt 0 C to rt

Togo’s group also reported the preparation of the 2,1-benzothiazines via an ionic pathway with hypervalent iodine compounds . Using this method, it was found to be far easier to synthesize five- or seven-membered benzosultams and avoid the difficult deprotection of the N-alkyl group in the six-membered benzosultams to give the free NH group. The reaction of N-methoxy 2-(aryl)ethanesulfonamides 21 with various hypervalent iodine reagents produced the cyclization products in various yields, which were dependent on the dielectric constant (ε) of solvents. The best yield of 2,1-benzothiazines 22 was 85% by treatment of N-methoxy 2-(aryl)ethanesulfonamides 21 with [hydroxy(tosyloxy)iodo] benzene in CH3CN solvent from 0 oC to room temperature for 20 minutes (Table 2). An electron-withdrawing group on the para position of the aromatic ring in 21 (e.g., Cl, F) reduced the yields of the cyclization reaction. In 2003, Togo and co-workers described a radical cyclization and ionic cyclization onto the aromatic rings of 2-(aryl)ethanesulfonamides 21 to produce 3,4-dihydro-2,1benzothiazine 2,2-dioxides with polymer-supported hypervalent iodine reagents in good yields . 1.2.2 Synthesis of Dibenzo[c,e][1,2]thiazine 5,5-dioxide Derivatives Dibenzo[c,e][1,2]thiazine 5,5-dioxide derivatives 23 are pharmacologically interesting . Various methods for the construction of these biarylthiazines have been reported (Figure 3) .

6


N R1

R1 = H, alkyl

SO2

23

Figure 3. Dibenzo[c,e][1,2]thiazine 5,5-dioxide derivatives

PhO2S

Pd(OAc)2, Na2CO3 N

PhO2S

N,N-dimethylacetamide reflux, 56%

24

N H

SO2

25

Scheme 5 Ames and Opalko have developed a palladium-catalysed cyclization of compound 24 to afford compound 25 in 56% yield (Scheme 5) . Glover and co-workers published a study involving the synthesis and photolysis of N-halogenobiphenyl-2-sulfonamides (26a or 26b) . The photolysis of compound 26a or compound 26b in benzene formed an intermediate N-methylbiphenyl-2-sulfonamidyl radical, which resulted in compound 27a or 27b in 21% or 50% yield, respectively. In this procedure, the reaction only afforded the six-membered ring product 27(Scheme 6). R CH3 N hυ SO2 benzene

CH3 N SO2

SO2 N CH3

26a: R = I

27a: 21%

26b: R = Br

27b: 50%

Scheme 6 A reductive, intramolecular, free radical arylation using tributyltin hydride/AIBN was introduced by the Motherwell group . The reaction of 28 under radical conditions produced the direct addition product 29 and ipso-substitution product 30 in various yields, which depended on the ortho and para substituents. Electron-withdrawing groups favored the formation of compound 29, while the ortho carbomethoxy group, and even the CH3 group led to greatly improved yields of the ipso substitution product 30 (Scheme 7).

7


H3C

N

O2 S

R1

I

R2

(n-Bu)3SnH, AIBN, benzene, reflux

H3C

N

O2 S

R1

R1 NHMe R2

28

R2

29 29a: 39% 29b: 10% 29c: 44% 29d: 19% 29e: 0%

28a: R1= H, R2= CH3 28b: R1= H, R2= OCH3 28c: R1= H, R2= F 28d: R1= COOMe, R2= H 28e: R1= Me, R2= H

30 30a: 34% 30b: 33% 30c: 29% 30d: 65% 30e: 57%

Scheme 7

1.2.3 Synthesis of 1H-2,1-Benzothiazine 2,2-dioxide (sulfostyril) Derivatives The synthesis of 1H-2,1-benzothiazine 2,2-dioxide was pioneered by Loer and coworkers and also by the Rossi group . The general class of compounds is represented in Figure 4. R3 R2 N R1

SO2

R1= H, CH3 R2= H, ester, acid, ketone, arene R3= H, CH3, Phenyl

(31)

Figure 4. 1H-2,1-Benzothiazine 2,2-dioxide derivatives Compound 34 can be synthesized by a Bamford-Stevens procedure from compound 33. Loer explored the cyclization of 32 with polyphosphoric acid (PPA), followed by decomposition of the tosylhydrazone to form the desired 1H-2,1-benzothiazine 2,2-dioxide 34 in good overall yield (Scheme 8) . H N

SO2

PPA

H N

SO2

1)TosNHNH2

H N

2) Base

O OH

O

32

33

Scheme 8

34

SO2

8


An improved synthesis of 1H-2,1-benzothiazine 4(3H)-one 2,2-dioxide 33 that results in a relatively high overall yield was developed by Lombardino’s group . This general method offered an easier entry into the 2,1-benzothiazine 2,2dioxide heterocyclic system . Treatment of methyl N-benzyl-Nmethylsulfonylanthranilate 35 with sodium hydride led to 1-benzyl-4-oxo-1H-2,1benzothiazine-4(3H)-one 2,2-dioxide 36 in 68% yield. Reduction of 36 gave 4-oxo-1H-2,1Bn N SO2 CH3

Bn N

NaH

SO2

Pd/H2

SO 2

68%

68%

CO2 Me

H N

35

O

36

33

O

Scheme 9 benzothiazine-4(3H)-one 2,2-dioxide 33 in 68% yield (Scheme 9). Lombardino also reported the reaction of 37 with isocyanates in dimethyl sulfoxide to yield the 1H-2,1-benzothiazine3-carboxanilide 2,2-dioxide 38 in high yield (Scheme 10) . CH 3 N SO 2

CH3 + RNCO

N

Et3 N

SO2

DMSO

O

NHR OH

37

O

38 R= alkenyl, arene

Scheme 10 Rossi and co-workers independently reported the synthesis of 33 using the same method. Reduction of 33 with sodium borohydride, followed by dehydration afforded 34 in 80% yield. Compounds 40a and 40b were prepared from 39a and 39b with phosphorus oxychloride in 92% and 65% yields, respectively (Scheme 11) .

R

H N

SO2

POCl3

R

H N

SO2

O Ph

Ph

39a: R = CH3

40a: R = CH3, 92%

39b: R = OCH3

40b: R = OCH3, 65%

Scheme 11 Rossi and co-workers also showed that ortho-acyl methanesulfanilides 41 carrying an electron-withdrawing group at the α position of the sulfonyl group can readily

9


convert under basic conditions to 3,4-disubstituted 1H-2,1-benzothiazine 2,2-dioxides 42 in good to excellent yields (Scheme 12). Similar work was also reported by Sianesi and coworkers . R4 N R3

SO2 CH 2R 1

R4 N

NaOEt

COR2

SO 2

R3

R 2 = CH 3, Ph

R 1 R 3 = H, Cl R2

42

41

R 1 = ArCO, CO2 Et

R 4 = H, CH 3

Scheme 12 1.2.4 Synthesis of Azathiabenzenes and Azathiaphenanthrenes Cyclic sulfilimines are considered useful reagents in organic synthesis . The chemistry of cyclic sulfilimines has been studied extensively since the 1970s. Hori and co-workers accomplished the first synthesis of azathianaphthalene and azathiaphenanthrene in 1979 . Their approach began with the formation of an olefin from ortho-nitrobenzaldehyde 43, via a Wittig reaction with an ylide and a subsequent reduction with zinc to afford cis and trans ortho-aminostyryl methyl sulfide 45. The cisolefin was then treated with NCS, AgClO4 and KOH to yield 2-methyl-1-aza-2thianaphthalene 47 in 41% yield. 9-Methyl-10-aza-9-thiaphenanthrene 48a and 9-ethyl-10aza-9-thiaphenanthrene 48b were obtained in a similar fashion in almost quantitative yields, whereas 6-benzyl-6H-dibenzo[c,e][1,2]thiazines 50 were isolated in moderate yields via a 1,2-rearrangement (Scheme 13) . CHO

CH CHSCH 3

Ph3 P CHSCH 3 89%

NO 2

44

1. NCS 2.AgClO4

N H 46

41%

S

S

KOH CH 3

57%

N

Cl

2. KOH CH 2R

48a: R = H, 100% 48b: R = Me, 90%

NH2 45

S

CH3

47

1. NCS

1. NCS N

80%

NO2

43

CH CHSCH 3

Zn-CaCl2

SCH 2R NH 2

2. n-BuLi

49

S N CH 2Ar 50a: R = Ph, 50% 50b: R = pTol, 57%

Scheme 13

10


Moody and co-workers independently reported the synthesis of azathiabenzenes by thermolysis . Azides 51a and 51b were decomposed in boiling toluene to give the corresponding cyclic sulfimides 52a and 52b in 52% and 13% yields, respectively (Scheme 14). N3

N

SR

S R

CO2Et

CO2Et

51a: R = Ph

52a: R = Ph, 52%

51b: R = Me

52b: R = Me, 13%

Scheme 14 1.2.5 Synthesis of 1,2-Thiazine S-oxide by Cycloaddition of N-Sulfinylaniline The reaction of aryl sulfinylamines as heterodienes has been well documented in the literature . The first cycloaddition of N-sulfinylanilines, ArN=S=O 53, to an alkene was reported by Collins in 1964 and afforded the 1,2-thiazine S-oxide 54 in 82% yield (Scheme 15) . S

N

O

H O S NH toluene, reflux, 82%

H

53

54

Scheme 15 Several years later, Macaluso and Hamer extended the research to bicycloalkenes . They also pointed out that this type of reaction occurred only when bridged bicyclic alkenes were used. However, Beecken reported some cycloaddition reactions of heterocyclic sulfinylamino compounds to ethoxyacetylene. Hanson and Stone demonstrated that cycloadditions of compound 53 and substituted derivatives with certain hetero-bridged bicyclic alkenes, particularly with 1,4-epoxy-1,4dihydronaphthalene 55 are pericyclic reactions (Scheme 16) .

N

S

O O

H

55 O

H 53

56

Scheme 16

S O

NH

11


In order to explore the regioselectivity of aryl sulfinylamines as heterodienes, a variety of unsymmetrical (N-sulfinylamino)azines, such as (N-sulfinylamino)pyridines (57, 60, 63), were studied by Hanson . In refluxing toluene, 1,4-epoxy-1,4dihydronaphthalene 55 prefers to react at the C-2 position of 3-(N-sulfinylamino)pyridine 60. On the other hand, 2-(N-sulfinylamino)pyridine 63 reacted at the ring nitrogen with 1,4epoxy-1,4-dihydronaphthalene 55 to give only a single trans-exo-adduct 64 in 64% yield (Scheme 17). Hogeveen and co-workers also reported the synthesis of tricyclic sulfinamides by the reaction of cyclobutadiene aluminum halide ı complexes (65 or 66) with 53 at low temperature. Treatment of 65 or 66 with 53 at –60 oC resulted in the formation of 67 or 68 in 52% and 55% yields, respectively (Scheme 18).

N

O

S

N H

O 55%

N

H

57

S O

58 S

N

N

H

O

O

NH

H

S O

NH

59

5:1

O H

O

N H

O N H 60

61

S O

O

NH

H

S

S O

62 5.5%

75%

N

N

O H

O N

N

O 64%

H

63

S O

N

64

Scheme 17 H3C

H Al2Br6

H3C

CH3 65

H3C

H Al2Br6

H

CH3 66

Figure 5. Cyclobutadiene aluminum halide ı complexes.

NH

12


N

S

O

CH3 H CH3

65 52%

S NH O

H3C 53 N

67 S

O

CH3 H H

66 55%

S NH O

H3C 53

68

Scheme 18

1.2.6 Synthesis of Harmata-type Benzothiazines Recently, the Harmata group developed several novel ways to synthesize 2,1benzothiazines represented by the general structures 69 and 70 (Figure 6) . R1

R1

R2

R2 R3 N 69

S O Ar

R3 N

S O Ar

70

Figure 6. Harmata-type benzothiazines.

1.2.6.1 Lewis Acid-mediated Synthesis of 2,1-Benzothiazenes In 1987, the Harmata group reported a general and novel procedure for the synthesis of benzothiazenes during an attempt to synthesize alkynyl sulfoximines . They demonstrated the Lewis acid-mediated electrophilic addition reaction of the N-aryl substituted sulfonimidoyl chlorides to alkynes. Intermediate vinyl carbocations may formed in the reaction, and converted into benzothiazenes by a Friedel-Crafts electrophilic substitution reaction. As an example, the reaction of N-phenylsulfonimidoyl chloride 71 with 1-trimethylsilyl-1-propyne and aluminum chloride in dichloromethane at –78 oC generated 72 in 75% yield (Scheme 19). This and other reactions took place with high Markownikov regioselectivity (Table 3). Whether the formation of the σ complexes 74 could be a concerted “cycloaddition” between the iminosulfonium “heterodiene” 73 and the alkyne dienophile or more likely a stepwise process, does not appear to have been established (Scheme 20) .

13


Cl N S O + R1C CR2 Ph pTol

R2 R1

AlCl3, CH2Cl2, -78 oC 75%

S O pTol

N

71

72: R1 = TMS, R2 = Me

Scheme 19 R2 Cl N S O Ph pTol

R1 O S N pTol

R1C CR2 AlCl3

71

73

R2

H

R1 N

S O pTol

74

R2 R1 N

S O pTol

75

Scheme 20 Table 3. N-Phenylsulfonimidoyl chlorides with alkynes in the presence of Lewis acids R2

Cl N S O + R1C CR2 Ph pTol

R1 N

S O pTol

Entry

R1

R2

Yield%

1

H

Ph

90

2

H

n-Bu

60

3

TMS

Me

75

An extension of this work was also reported by this group, in which the reaction was applied with success to alkenes, as shown in Scheme 21. The reaction not only proceeded with high Markownikov regioselectivity, but sometimes was very diastereoselective as well (Table 4).

14


H Et Cl H N S O + Ph Et pTol

Et

78 oC, 74%,

H

Et H H Et

AlCl3 , CH2 Cl2 , N

121:1

76a

S O pTol

Et H

+ N 76b

S O pTol

Scheme 21 Table 4. Reaction of N-phenylsulfonimidoyl chlorides with alkenes Cl N S O + Ph pTol

R2

R3

R1

R4

Entry

R1

R2

1

H

H

2

H

3

R3 R2

N

R3

R4

R1 R4

R2 R3

S O pTol

N

76a

76b

R4 R1

S O pTol

Yield %

Ratio (76a : 76b)

-(CH2)4-

91

25:1

H

-(CH2)3-

81

5:1

H

H

-(CH2)5-

70

2.4:1

4

H

H

-(CH2)6-

76

2.1:1

5

H

Et

H

Et

85

122:1

6

H

H

Et

Et

85

2.3:1

7

H

Me

H

Me

62

45:1

8

H

H

Me

Me

78

2.3:1

9

H

Bu

H

H

77

1.6:1

10

H

Et

H

H

90

1.5:1

11

H

n-Pr

H

H

66

1.6:1

12

H

i-Pr

H

H

78

2.4:1

13

H

Ph

H

H

62

1.4:1

14

H

t-Bu

H

H

65

4.1:1

15

H

TMS

H

H

35

10:1

1.2.6.2 Synthesis of Enantiomerically Pure 2,1-Benzothiazines The Harmata group has also developed a route to enantiomerically pure 2,1benzothiazines. The process involves the N-arylation of sulfoximines using the BuchwaldHartwig reaction conditions, a reaction first reported by Bolm

15


. The Bolm group has already made use of this reaction in the preparation of a variety of chiral ligands and unique cyclic sulfoximines . Critical to the development of this reaction in the preparation of enantiomerically pure 2.1benzothiazines is the ready availability of enantiomerically pure sulfoximines 77a or 77b . NH S Ar O Me

NH S Ar Me O (R)-77a, Ar = pTol (R)-77b, Ar = Ph

(S)-77a, Ar = pTol (S)-77b, Ar = Ph

Figure 7. Enantiomerically pure sulfoximines. The Harmata group’s initial report concerned a one-pot, one-operation procedure for the synthesis of enantiomerically pure 2,1-benzothiazines via the Buchwald-Hartwig reaction reported by Bolm for sulfoximine Narylation. For example, treatment of ortho-bromobenzaldehyde 78 with enantiomerically pure N-H sulfoximine 77a in the presence of a palladium catalyst and base afforded the benzothiazine 79 in 78% yield (Scheme 22). Both C-N bond formation and condensation occurred during the reaction, a phenomenon that appears general for aldehydes like 78. pTol

CHO +

N S O H

Br

Me

5-10% Pd(OAc)2, 7.5%-15% BINAP, 1.8 eq. Cs2CO3, toluene,

(R)-77a

78

N

110 oC, 40 h, 78%

S O pTol

(R)-79

Scheme 22 Examples of coupling reactions of ortho-bromobenzoate ester 80 or orthobromobenzonitrile 87 with sulfoximine (R)-77a were also reported (Scheme 23a/b). In these cases only coupling occurred. However, the products could be converted into the 2,1benzothiazines 82 and 85 by treatment with a strong base. pTol CO2Me + N S O H Br Me

5% Pd(OAc)2, 7.5% BINAP, 1.4 eq. Cs2CO3, toluene, 115 oC, 40 h 84%

(R)-77a

80 CO2Me Me S O N pTol

OH 1.8 eq. KH, THF 0 oC to rt, 73%

(R)-81

N (R)-82

Scheme 23a

S O pTol

16


pTol

CN +

Cs2CO3, toluene, 115 oC, 40 h

N S O H

Br

5% Pd(OAc)2, 7.5% BINAP, 1.4 eq. 94%

Me (R)-77a

83

NH2

CN N

Me S O

2.0 eq. n-BuLi, THF 0 oC to rt, 68%

N

pTol

(R)-84

S O pTol

(R)-85

Scheme 23b Enantiomerically pure bis-benzothiazines 87 and 89, are potentially useful templates for asymmetric catalysis. The Harmata group reported their syntheses from the corresponding dibromodialdehydes 86 and 88 under the reaction conditions used for the production of (R)79 (Scheme 24) . OHC

pTol

CHO +

Br

N S O H

Br

+ Br 88

O S

N

N S O H

Me

N

Tolp

S O pTol

(R, R)-87

pTol

CHO

OHC

48%

(R)-77a

86 Br

Me

Pd

Pd 41%

(R)-77a

pTol N O S N

S O pTol

(R, R)-89

Scheme 24 In 2003, the Harmata group reported a stereoselective, intramolecular Michael addition of sulfoximine carbanions to α,β-unsaturated esters as exemplified in Scheme 25 . Preparation of sulfoximine 90 was conducted via the methodology introduced by Bolm as used in the initial studies of catalyzed benzothiazine synthesis . The sulfoximine 91 was transformed via treatment with LDA into 92. Importantly, 92 was formed as a single stereoisomer. This appears to be a general phenomenon for these types of reactions. Two procedures were reported for this cyclization. The first involved adding a THF solution of 2.0 equivalents of base in THF to the sulfoximine at -78 °C, but addition of the sulfoximine to base worked as well, and was occasionally absolutely necessary.

17


CO2Me

5% Pd(OAc)2, 7.5% BINAP 1.4 eq. Cs2CO3, 1.2 eq. (R)-77b toluene, reflux, 44 h

Br

91%

90 CO2Me

CO2Me

2.0 eq. LDA,THF -78 oC to -20 oC, 1 h

Me S O N Ph

92% N

91

S O Ph

92

Scheme 25 Two substrates could not be cyclized under normal addition conditions. An N-thienyl sulfoximine afforded benzothiazine 98 in good yield, but the corresponding the furanyl sulfoximine appeared to polymerize when base was added in the normal way. This problem was circumvented simply by adding the furan to a solution in base. The best reaction conditions involved adding a THF solution of the N-furanyl sulfoximine to 2.0 equivalents of LiHMDS in THF at –50 °C at a very slow rate. Stirring the solution for an additional 3 hours gave the benzothiazine 99 as a single stereoisomer in 85% yield. Similarly, the N-pyridyl sulfoximine also gave either decomposition or side products when treated with base. This problem was solved by addition of the sulfoximine to base coupled with degassing, and the desired benzothiazine 100 was obtained in 77% yield. The rationalization for the outcome of these cyclization reactions was based on minimizing steric interactions in the transition state leading to benzothiazine formation. For example, at least two possible transition states 101 and 102 could give rise to product 92 (or a diastereomer). Transition state 102 has gauche steric interactions that appear to be absent in the staggered transition state 101. This favors the latter and leads to the observed products 92 (Figure 8).

N S O H Ph

H H MeO2C H

101

N S O Ph H H H CO2Me

H

102

Figure 8. Possible transition state structures of the intramolecular Michael reaction of sulfoximine 91.

18


Table 5. Reaction of sulfoximines with an amide base CO2Me

CO2Me LDA or LiHMDS (2.0 eq.)

Me S O N Ph

Entry

THF, -78 oC N

Yield (%)

Product

Entry

Product

CO2Me 1

BnO

91

5

93 S

S O N Ph 97

93

CO2Me

CO2Me 83

6

S

94

98 CO2Me

CO2Me

Me

3

S O N Ph

87

7

O

95

99 CO2Me

CO2Me O O

88 S O N Ph

96

85 S Ph N O

OMe

4

91 S Ph N O

S Ph N O

Me

Yield (%)

CO2Me

S Ph N O

2

S O Ph

8

77 N

S Ph N O 100

The Harmata group demonstrated that benzothiazine formation via the intramolecular Michael addition is stereospecific, at least in one case. When sulfoximine Z-103 was treated with 2.0 equivalents LDA the 2,1-benzothiazine 104 was obtained in 89% yield (Scheme 26) as the only product. Rationalizing this outcome was not straightforward. Transition state 106 suffers from gauche interactions and should be disfavored. However, the interaction of the ester group with a neighboring hydrogen (highlighted) in 105 was argued to be more severe. As it stands, these rationalizations are at best hypotheses that need to be investigated further.

19


CO2Me

MeO2C 2.0 eq. LDA,THF

Me S O N Ph

-78 oC to -20 oC

N

1 h, 89%

103

S O Ph

104

Scheme 26

N S O H Ph

HH MeO2C

H H

H H

HH

105

N S O Ph CO2Me

106

Figure 9. Putative transition states structures for the Michael reaction of sulfoximine 103. The Harmata group also found that certain ortho-bromocinnamates underwent a Michael addition during the course of the Buchwald-Hartwig reaction. This one-pot process produced the same products as the two step process and with the same, complete stereoselectivity. For example, this was first observed with bromocinnamate 107, where the reaction with (R)-77b afforded a 53% yield of sulfoximine 108 as well as a 36% yield of benzothiazine 95 under standard coupling conditions (Scheme 27). The cyclization was attributed to a buttressing effect of the ortho-methoxy in bromocinnamate 107. This presumably favored a conformation that placed the methyl group of its sulfoximine functionality near the β-carbon of the α,ѽβ-unsaturated ester, thus favoring cyclization. CO2Me Me

1.4 eq. Cs2CO3, 1.2 eq. (R)-77b Br

CO2Me

CO2Me

5% Pd(OAc)2, 7.5% BINAP

Me

toluene, reflux, 44 h OMe

OMe 107

Me S O N Ph

108: 53%

Me N

OMe

S O Ph

95: 36%

Scheme 27 Two other substrates, 109 and 111, exhibited this behavior. Most interesting was that the reaction of both 109 and 111 with (S)-77b under standard reaction conditions gave only benzothiazines 110 and 112, respectively, with no sign of the corresponding sulfoximine (Scheme 28). While using the argument of a buttressing effect may be useful, the Harmata group also reported that the reaction of bromocinnamate 113 with (S)-77b gave not only the sulfoximine 114, but the benzothiazine 96 as well (Scheme 28). There is no buttressing effect possible in this case and it is likely that other factors (e.g., electronic effects) can also favor direct benzothiazine formation.

20


CO2Me

CO2Me

5% Pd(OAc)2, 7.5% BINAP 1.4 eq. Cs2CO3, 1.2 eq. (S)-77b toluene, reflux, 44 h, 61%

Br

N

109

S Ph O

110 CO2Me

CO2Me

5% Pd(OAc)2, 7.5% BINAP 1.4 eq. Cs2CO3, 1.2 eq. (S)-77b Br N CH3

toluene, reflux, 44 h, 82% N H3C

111

O

Br

S Ph O

112

CO2Me O

N

CO2Me

5% Pd(OAc)2, 7.5% BINAP 1.4 eq. Cs2CO3, 1.2 eq. (R)-77b

O

toluene, reflux, 44 h

O

113

Me S O N Ph

114: 60% CO2Me

O O

N

S O Ph

96: 25%

Scheme 28

1.2.7 Heterocyclic Ring-fused Thiazines and Ring-fused 2,1-Benzothiazine Derivatives The first synthesis of pyrazolo[5,1-c]-1,2,4-thiadiazines 116 and pyrazolo[3,4-c]-1,2thiazines 118 was reported by Aiello and co-workers . Compound 115 was heated five degrees above its melting point to afford the novel ring system 116. However, compound 117 gave compound 118 when treated with triethylamine. Similar ring systems were prepared by Coppo and Fawzi from the reaction of substituted ethyl 5-[methyl(methylsulfonyl)amino]-1H-pyrazole-4-carboxylates 119 with sodium hydride. This gave the 7-substitued 1,7-dihydro-1-methylpyrazolo[3,4c][1,2]thiazin-4(3H)-one 2,2-dioxides 120 in fair to good yield (Scheme 30). They also extended this synthesis by treating methyl 2-[methyl(methylsulfonyl)amino]-6(trifluoromethyl)-3-pyridinecarboxylate 121 with sodium hydride in dimethylformamide to yield 1-methyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazin-4(3H)-one 2,2-dioxide 122 in 79% yield (Scheme 31) .


R2

R2

R1

R1 N

N N H

N

NHSO2CH2COPh Ph

21

116a: R1 = Ph, R2= CH3

116b: R, R2 = (CH2)4 NH 116c: R1 = (CH2)3, R2 = (CH2)3 SO2

115 R1

Ph

R1 Et3N

N

118a: R1 = CH3

N

NHSO2CH2COPh

N Ph

N Ph

N H

SO2 118b: R1 = Ph

117

Scheme 29 CO2Et

O NaH/DMF

N N R1

NSO2CH3 CH3

N N R1

SO2 N CH3

120: R1 = Ar, CH3, 27-72%

119

Scheme 30 O

CO2CH3 NaH/DMF F3C

N

NSO2CH3 CH3

79%

121

F3C

N

SO2 N CH3

122

Scheme 31 The first synthesis of substituted 2,2-dioxo-1H-thieno[3,4-c][1,2]thiazines 124a and 124b was achieved by Fanghanel and co-workers . Reaction of the thiazinecarboxaldehydes 123a and 123b with Et3N in DMF at room temperature gave compounds 124a and 124b in 59% and 49% yields, respectively (Scheme 32). The methyl group of 125a,b is easily deprotonated by a base, such as NaOEt. The corresponding intermediate attacks the nitrile group to yield the benzo[c]thiazines 126a and 126b in 53% and 72% yields, respectively. This method is a very convenient way to prepare substituted 2,2-dioxo-benzo[c]1,2-thiazines (Scheme 33) .

22


CHO H3C X

S CH3

N S Ph O O

H3C

sulfur, triethylamine dimethylformamide

X

N S Ph O O

124a: X= SCH3, 59%

123a, b

124b: X= Cl, 49%

Scheme 32 R1

R1 H H3C MeS

NH2

R2 CH3

NaOEt, EtOH

H3C

N S Ph O O

N S Ph O O

X

126a: R1 = CO2Et, R2 = CN, 53%

125a, b

126b: R1 = CN, R2 = CN, 72%

Scheme 33 Moody and co-workers independently prepared the fused 1λ4,ѽ2-thiazines by mild thermolysis . The thieno[3,2-c][1λ4,ѽ2]thiazines were successfully synthesized from the azides 127a-g in boiling toluene with varying yields (Scheme 34), which were generally good. Thermolysis of 127g gave a very poor yield of the corresponding sulfimide 128g, since product 128g lacks a stabilizing substituent, and thereby is unstable in refluxing toluene. Ethyl 2-phenyfuro[3,2-c][1λ4,ѽ2]thiazine-3-carboxylate 130 has been prepared by a similar procedure from 129 (Scheme 35). N3

N

S

S

RS

Z

127a-g

S

R Z

128a: R = Ph, Z = CO2Et, 90% 128b: R = Me, Z = CO2Et, 85% 128c: R = Et, Z = CO2Et, 30% 128d: R = Ph, Z = COMe, 90% 128e: R = Ph, Z = CHO, 75% 128f: R = Ph, Z = CN, 90% 128g: R = Me, Z = H, 4%

Scheme 34

23


N3 N O

O

70%

PhS

S

Ph CO2Et

CO2Et

129

130

Scheme 35 Chiacchio and co-workers reported a stereoselective synthesis of 133 via an intramolecular 1,3-dipolar cycloaddition. Intermediate 132 was generated in situ by the reaction of trans-N-(2-formylphenyl)-N-methyl-2-phenylethene-1-sulfonamide 131 with Nmethylhydroxylamine and afforded a tricyclic benzothiazine 133 in 51% yield (Scheme 36). Me

O

N H

Ph

N SO2 CH3

N3

Me N O H

MeNHOH

Ph

Ph

51%

131

N

O

H SO2

N SO2 CH3

N Me

132

N

O S O

Ph Ar

O

PPh3, THF, 25 oC

133

N PPh3

S O

Ph Ar

N O reflux, toluene,

Ph

5h N

S Ar

134a: Ar = pTol

135a: Ar = pTol, 91%

136a: Ar = pTol, 50%

134b: Ar = Ph

135b: Ar = Ph, 95%

136b: Ar = Ph, 48%

Scheme 36 Isoxazolo[4,3-c]-2,1-benzothiazine, a new heterocyclic system, was synthesized by an intramolecular aza-Wittig type ring closure process . This was the first example of the construction of a cyclic sulfimide using aza-Wittig chemistry. Treatment of 3-(oazidophenyl)-4-sulfoxyaryl-isoxazoles 134 with triphenylphosphine under Staudinger reaction conditions gave the corresponding aryliminophosphoranyl 4-sulfoxyaryl-isoxazoles 135a and 135b in the yields of 91% and 95%, respectively. A subsequent aza-Wittig type cyclization of 135a and 135b in refluxing toluene produced isoxazolo[4,3-c]-2,1benzothiazines 136a and 136b in the yields of 50% and 48%, respectively (Scheme 36). In order to study heterocyclic steroid analogues, such as the 7,11-dithiaazasteroid analogues, Fravolini developed the synthesis of new heterocyclic ring systems: tri- and tetracyclic 2,1-benzothiazines . Intermediate 137 was prepared from 1-methyl4-oxo-1H-2,1-benzothiazine-4(3H)-one 2,2-dioxide 37 and thioglycolic acid and could be converted into 6-methyl-4-oxo-3,4-dihydro-2H,6H-thiopyrano[3,2-c][2,1]benzothiazine 5,5dioxide 138 by cyclization with polyphosphoric acid. The reaction of 138 with dimethyl

24


oxalate afforded the glyoxylate 139 in 60% yield. Condensation of the glyoxylate 139 in acetic acid with hydrazine hydrate and hydroxylamine hydrochloride respectively, furnished 5-methyl-1-carbomethoxyl-5H,11H-isoxazole[4,5-c]thiopyrano[3,2-c][2,1]benzothiazine 4,4dioxide 140a and 5-methyl-1-carbomethoxyl-5,11-dihydro-3H-pyrazolo[4,3c]thiopyrano[3,2-c][2,1]benzothiazine 4,4-dioxide 140b in the yields of 62% and 39%, respectively. Decarbonylation of 139 gave the β-keto ester 141 in 69% yield. Reduction of 141 afforded 5-methyl-1-hydroxy-5,11-dihydro-3H-pyrazolo[4,3-c]thiopyrano[3,2c][2,1]benzothiazine 4, 4-dioxide 142 in 40% yield (Scheme 37). O O

OH O

R

144a: R = 2-chloro-4-(methylsulfonyl), 68%

R

144b: R = 2-(2,4-Dichloro-phenyl)-vinyl, 17%

SO2 N CH3

SO2 N CH3

144c: R = 2-(2,6-Dichloro-phenyl)-vinyl, 40%

143

Ph

O O

S CO2H

O

64% N CH3 37

N CH3 137

SO2

N CH3

SO2 N CH3

146a: R = H, 31%

145a,b: 44-64%

57% S

S

O 60% SO2

O SO2 N CH3 139

N CH3 138

140a: X= O, 62%

69% CO2CH3

S N N H

N X

SO2 N CH3

OH S

146b: R = Me, 27% CO2Me

COCO2CH3

S

SO2 N CH3 142

O

R SO2

SO2

R

O

Ph

40%

140b: X= NH, 39%

O SO2

N CH3 141

Scheme 37 Recently, Coppo and Fawzi reported the synthesis of tricyclic 2,1benzothiazines starting from compound 37 (Scheme 37). They discovered that the O-benzoyl compound 143 can rearrange to the C-benzoyl compounds 144a-c in the presence of acetone and triethylamine in fair to good yields. However, a rearrangement of 145a-b under similar reaction conditions resulted in the formation of novel tricyclic 2,1-benzothiazines 146a and 146b in the yields of 31% and 27%, respectively.

25


1.3 CHEMISTRY OF 2,1-BENZOTHIAZINES 1.3.1 Reactions of 2,1-Benzothiazine 2,2-dioxide As mentioned previously, 1H-2,1-benzothiazine 2,2-dioxide (34, R = H) can be converted into 3,4-dihydro-2,1-benzothiazine 2,2-dioxide 4 by hydrogenation . Alkylation and arylation of 4 occurred on the sulfonamide nitrogen to give compound 152 in high yield . A similar reaction was further reported by the Loev group in which 2,1-benzothiazine 150 was formed from acrylonitrile and 34 via a Michael addition reaction, followed by a reduction . Electrophilic aromatic substitution reactions have been studied by Loev and Kormendy and by Sianesi and co-workers. Bromination and nitration of 152 only afforded a 6mono-brominated product 153, whereas bromination and nitration of 4 gave a mixture of mono- and disubstituted products 151, where the yields are dependent upon the reaction conditions . Another interesting reaction has been reported by Rossi and Pagani . Indole 148 and N-methylaniline 149 were isolated from treatment of 2,1-benzothiazine 147 with copper powder at around 300 oC (Scheme 38) . R1 153: R =CH 3 R1 = Br, NO 2

CH2 CH 3

N R

SO2

NBS or

NHMe

HNO3

CH 3

149 CH 3

N

SO 2 N CH 3

Cu

N R 152

147

SO2

CH3 R 1 = CH 3

148 O

Me2 SO4

Base, RX

R1 H2

N H 33

SO2

N H

SO2 R1 = H

N H

SO2

4

34: R 1 = H or CH3 NBS or HNO3

1. CH 2=CHCN

R1 = H

2. H2 R1 N

SO2

(CH3 )3 NH 2 150

Scheme 38

R2

N H

SO2

151 :R 1, R2 = Br, NO 2

26


1.3.2 Reactions of Azathiabenzenes and Azathiaphenanthrenes A further study of azathiabenzenes and azathiaphenanthrenes was reported by the Hori group and the Moody group . An interesting reaction of azathiabenzenes with electrophiles was observed as their compounds possess an ylidic structure . This structure was confirmed by spectral and some chemical evidence . For example, treatment of 52a with dimethyl acetylenedicarboxylate (DMAD) 154 in an aprotic solvent, such as dry benzene, at room temperature gave the adduct 157 in 47% yield. The proposed mechanism involves a fourcentered intermediate 156, which can arise from the first intermediate 155, which was formed by a nucleophilic addition of the ylide anion to DMAD (Scheme 39). When the solvent was changed to a protic solvent (e.g., methanol or ethanol), no thiazocine was observed, but adduct 160 (2:1) was isolated in 65% yield. The structure was determined by X-ray crystallography. It is possible that intermediate 155 was protonated by the protic solvent to give a relatively stable species 158. The next step requires intermediate 158 to be attacked by another molecule of 52a to result in the formation of intermediate 159, which afforded the final product 160 after deprotonation (Scheme 39) . CO2Et

CO2Et S

N

N

Ph

52a

S

MeO2C

CO2Et PhH

Ph CO2Me

MeO2C

155

MeO2C CCO2Me

CO2Et N

S

Ph

MeO2C

H

158

CO2Et

CO2Et N

S

CO2Me 156

EtOH

154

S Ph

N

S Ph

Ph

CO2Me

N

52a

CO2Me

CO2Me

157: 47%

CO2Et

CO2Et CO2Me

S

Ph

N

N

H

N

MeO2C MeO2C

PhS

S Ph

N CO2Me

CO2Et

CO2Et

159

160: 65% 2:1

Scheme 39

SPh

27


Azathiaphenanthrenes can be oxidized by KMnO4 or m-chloroperbenzoic acid to the corresponding sulfoximines 163 in good yields. Azathiaphenanthrene 48a underwent a thermal ring expansion to afford 7H-dibenzo[d,f][1,3]thiazepine 163 in 26% yield by a Stevens-type rearrangment while compound 48c underwent dealkylation to furnish compound 165 by cycloelimination via 164 (Scheme 40).

N

S

xylene

S

N H

CH2 R

48a: R = H 48c: R = alkyl

S

CH 2

N H 162 : R = H, 26%

161

KMnO4 xylene

N

S

CH2 H HC R' 164

S N CH2 R O 163

N H

S

165 . R= alkyl, ~40%

Scheme 40

S N CH2 R 48c RI ( R = Me, Et, et al.)

TMSCl

LDA N 48a

S

CH3

S

N

S CH2

Li 166

TMS 167

RCO 2Et

S

N

N H

R OH

168

Scheme 41

28


The methyl hydrogen of 9-methyl-10-aza-9-thiaphenanthrene 48a is acidic. It can be readily deprotonated by LDA in THF . The corresponding anion can be quenched by alkyl iodides to give various 9-alkyl-10-aza-9-thiaphenanthrenes 48c in fair yields (Scheme 41). However, none of the expected products were found when the anion was quenched by TMSCl or esters. Ring expansion product 167 was obtained via sulfonium ylide intermediate 170 derived from the expected product 169 by a 1,2-shift (Scheme 42) . The novel spiro compound 168, the structure of which was confirmed by X-ray analysis, was generated by Sommelet-Hauser rearrangement (Scheme 43) .

TMSCl

LDA N

S

CH3

N

S

CH2

166 Li

48a

N H

N

S

CH2TMS

169

S

S

S NH CHTMS

CHTMS

170

N H

171

TMS

167

Scheme 42

1. LDA N

S

2. RCO2Et CH3

N

48a

S

CH2COR

172

S

N H

S

CHCOR

173

S R

NH O 174

N

R OH

168

Scheme 43 Recently, Shimizu reported a novel polar cycloaddition of a 1,2-thiazinylium salt . Compound 175 was generated in situ from the reaction of compound 165 with trifluoroacetic anhydride and lithium tetrafluoroborate. It can undergo a cyclization reaction

29


with 1,3-butadienes in 1,2-dichloroethane to afford the corresponding cycloadducts 176 in good yields (Scheme 44). R1

R2

(CF3CO)2O N H

S

LiBF4

N

S

N

S

BF4 R2

BF4 R1

165

175

176

Scheme 44 Fused 1λ4-2-thiazines prepared by Moody and co-workers were expected to be photo-labile and indeed the sulfur-nitrogen bond was cleaved to give pyrrole products in good yields under irradiation in acetonitrile at 300 or 350 nm (Scheme 45 and Table 6) . N

S R

X

Z

H N

hu

MeCN

Z X SR

177a-f

178a-f

Scheme 45 Table 6. Photochemical rearrangement of fused 1λ4, 2-thiazines Entry

X

R

Z

Yield (%)

1

S

Me

CO2Et

50

2

S

Ph

CO2Et

83

3

S

Ph

COMe

77

4

S

Ph

CHO

75

5

O

Ph

CO2Et

32

6

CH=CH

Ph

CO2Et

75

The initial intermediates in the photolysis of the fused 1λ4, 2-thiazines, 177a-f were the nitrenes 179. Then electrocyclic ring closure of the resulting nitrenes 179 led to the nonaromatic fused 2H-pyrrole 180, followed by [1,5] sigmatropic shifts of –SR and hydrogen to give the pyrrole products 178a-f. It is very interesting that the observed products arose from the exclusive migration of the sulfur substituent in 180 in the presence of ester, ketone and aldehyde groups (Scheme 46) .

30


N

S R

X 177a-f

N

hu

Z

SR

X

Z

179

Z X H

N SR

[1,5] shift

N

of -SR

Z

X

SR

180

181 2X[1,5]H shift

[1,5]Z shift

H N

N SR

Z

X

X 178a-f SR

Z

182 H

Scheme 46 On the other hand, thermal rearrangement of sulfimides gave completely different products, resulting from [1,4] shift . Usually, fused 1λ4, 2-thiazines are thermal stable up to 120 oC, but they were gradually consumed when they were heated in boiling xylene. They were found to rearrange to the 4aH-isomers 183a-g in good to excellent yield, with the exception of the benzo compound, which was thermally stable (Scheme 47 and Table 7). N X

N

S R X

Z

R

177a-g

S

Z 183a-g

Scheme 47 Table 7. Thermal rearrangement of fused 1λ4, 2-thiazines Entry

X

R

Z

Yield (%)

1

S

Me

CO2Et

40

2

S

Ph

CO2Et

94

3

S

Ph

COMe

80

4

S

Ph

CHO

54

5

O

Ph

CO2Et

98

6

CH=CH

Ph

CO2Et

-

7

S

Ph

CN

88

31


1.3.3 Functionalization of Harmata-type Benzothiazines via a Sulfoximine-Stablized Vinyl Carbanion Lithiation of to form 184 was reported by the Harmata group to be the first example of a sulfoximine-stabilized vinyl carbanion. The resulting organolithium species 184 reacted with various electrophiles to supply structurally diverse benzothiazines . However, the diastereoselectivity of the reactions with aldehydes was low (Scheme 48). CH3 TMS CH3

N

S O pTol

CH3I 79%

N

S O pTol

3

EtCHO Et 83%, 1.9:1

Li

S O pTol

Br

pTol

TMSCl 89% C2Br2Cl4 CH 98%

CH3 OH

N

CH3

S O

N

CH3

N Ph2CO, 65%

184

CH3 OH Ph Ph S O N pTol

CH3

ClCO2C3H5 73%

S O pTol

CO2C3H5 N

t-BuCHO 76%, 2.4-2.8:1

S O pTol

CH3 OH

PhCHO 84%, 1.2:1

t-Bu N

CH3 OH

S O pTol

Ph N

S O pTol

Scheme 48 1.3.4 Indole Synthesis Harmata and Herron , discovered that the adducts from Lewis-acid mediated synthesis of 2,1-benzothiazines could have use in the synthesis of the other heterocyclic H

185

H S O N pTol

1. n-BuLi 2. MoOPH 3. KOH

N H 186 : 55%

Scheme 49

32


systems. For example, benzothiazine 185 was reacted with n-BuLi followed by oxidation of the corresponding carbanion with MoOPH. A hydrolytic work-up gave tetrahydrocarbazole 186 in 55% yield (Scheme 49). 1.3.5 Aniline Synthesis Harmata and co-workers introduced a procedure for the reductive desulfurization of selected 2,1-benzothiazines with sodium amalgam, leading to the formation of the 2alkylanilines in high yields . This method is regioselective and general. As an example, alkylation of 187 followed by treatment with Na/Hg resulted in the formation of the aniline 188 in 68% overall yield (Scheme 50). 1. n-BuLi TMS I N

S O pTol

TMS

2. Na/Hg NH2

68%

187

188

Scheme 50 Harmata and co-workers also discovered that 2,1-benzothiazines could be conveniently converted into 2-alkenylanilines by treatment with KDMSO in DMSO . For example, the reaction of benzothiazine 185 with KDMSO for 20 minutes at 70 oC resulted in the formation of the 2-alkenyl sulfinamide 189 in 90% yield (Scheme 51). H H N

2.0 eq. KDMSO 90%

S O pTol

NHSOpTol

185

189

Scheme 51 The 2-alkenyl sulfinamides appeared to be slightly unstable. They could, however, be quickly converted into anilines by base-catalyzed hydrolysis in good yields (Scheme 52) . This general route to 2-alkenyl anilines is regioselective, but not stereoselective. R2

R2 R3

1. KOH (2.0 eq.) +

2. H R1 NHSOpTol 190

R3 R1 NH2

191: R1, R2, R3 = H, alkyl, cycloalkyl 67-92%

Scheme 52

33


The Harmata group also used the reductive desulfurization of 2,1benzothiazines to produce 2-alkenylanilines 192 in good yields (Scheme 53). This method is quite general, regioselective and stereoselective in some cases. R1

R1 R2

N

Na/Hg

R1 H

S O pTol

R2

+

R2 NH2

H NH2

(Z)-192 (major)

(E)-192 (minor)

R1, R2 = H, alkyl, TMS, phenyl 57%-92%

Scheme 53 A general route to allylanilines, reported by Harmata and co-workers could be of value in organic synthesis. Deprotonation of 2,1-benzothiazines 193 with n-BuLi followed by alkylation with iodomethyltrimethylsilane, and subsequent desilylation with fluoride followed by hydrolysis led to allyl aniline 194 in good yields (Scheme 54). R1 R2

1. n-BuLi

R2

R1

2. TMSCH2I N

3. TBAF

S O pTol

4. KOH

NH2 194: R1, R2 = H, alkyl

193

Scheme 54 In 1998, Harmata and co-workers published a new synthesis of 2-alkenyl anilines. The silylated 2,1-benzothiazines 187 could be deprotonated by n-BuLi and alkylated by different electrophiles. The corresponding products could be desilylated by fluoride with concomitant cleavage of the carbon-sulfur bond to give 2-alkenylsulfinanilides that can then be hydrolyzed by base to the anilines 195 in good yields (Scheme 55). TMS

1. n-BuLi R

2. RX N 187

S O pTol

3. TBAF 4. KOH

Scheme 55

NH 2 195

34


1.3.6 Chiral Ligands in Asymmetric Allylic Alkylation The development of sulfoximines as ligands for transition metal-catalyzed asymmetric organic reactions is only currently being realized . Recently, Harmata and Ghosh reported the preparation of both enantiomers of ligand 197 using the procedure mentioned earlier starting with the dialdehyde 196, as shown in Scheme 56. O S Ph N

CHO Ph

Br + Br

Pd(dba)2, rac-BINAP, Cs2CO3,

N S O H

toluene, 110 oC, 2 days, 68%

N S Ph O

Me

CHO (R)-77b

196

(R, R)-197

Scheme 56 OAc + CH2(CO2Me)2 Ph

Ph 198

2.5 mole% Pd, (R, R)-197, (10 mol%) solvent, BSA (3 eq.), KOAc (cat.)

MeO2C Ph

199

CO2Me

Ph (S)-200

Scheme 57 Table 8. Reacemic 1,3-diphenylallyl acetate with dimethyl malonate under various conditions Entry

Ligand

Pd source

Sovent

Time (h)

Yield (%)

Ee (%)

1

(R,R)-197

[Pd(allyl)Cl]2

THF

5

80

80

2

(S,S)- 197

[Pd(allyl)Cl]2

THF

3.5

90

80

3

(R,R)- 197

[Pd(allyl)Cl]2

benzene

3

90

82

4

(S,S)- 197

[Pd(allyl)Cl]2

benzene

3

85

82

5

(R,R)- 197

[Pd(allyl)Cl]2

toluene

3.5

85

78

6

(S,S)- 197

[Pd(allyl)Cl]2

toluene

3.5

70

78

7

(R,R)- 197

[Pd(allyl)Cl]2

CH2Cl2

4

30

0

8

(R,R)- 197

[Pd(allyl)Cl]2

CH3CN

5

45

0

9

(R,R)- 197

Pd2(dba)3

THF

3.5

75

86

10

(S,S)- 197

Pd2(dba)3

THF

3.5

69

86

11

(S,S)- 197

Pd(OAc)2

THF

7.5

67

73

12

(R,R)- 197

Pd(OAc)2

THF

7.5

68

73

13

(S,S)- 197

Ph(PPh3)4

THF

5

90

16

14

(R,R)- 197

Ph(PPh3)4

THF

5

79

6


35

They demonstrated that the C2-symmetric bis-benzothiazine (R,R)-197 was an effective ligand in the asymmetric allylic alkylation reaction. The best result in this case was the reaction of 198 and 199 in the presence of BSA, Pd2(dba)3 and (R,R)-197, which gave the product (S)-200 in 75% yield and 86% ee. More experimental data revealed that solvent effects are very important in this reaction (Scheme 57). Relatively nonpolar solvents resulted in good yields and enantiomeric excesses while reaction in CH3CN and CH2Cl2 gave only racemic products in moderate yields (Table 8).

O S N Cu N S O Ph Ph

201

Figure 10. X-ray structure of 201, a chiral, copper(I) complex of styrene Although the basis for the stereochemical outcome of asymmetric allylic alkylation reaction by bis-benzothiazine is not very clear , bis-sulfoximines, the closely related bis-benzothiazines, and other ligands stereogenic at sulfur are important and potentially practical ligands for the future . In order to expand the scope of the chemistry associated with 197, the Harmata group has examined asymmetric cyclopropanation reactions using ligand (R,R)-197 . As a part of this research, the crystal structure of a chiral, copper(I) complex of styrene 201 was obtained, which suggested that edge-face interactions as well as stacking may be important in the recognition of enantiofaces of alkenes by chiral copper(I) complexes of 197 .

36


1.3.7 New Chiral Benzothiazine Ligand for Catalysis and Molecular Recognition A new chiral benzothiazine ligand 205 was synthesized by Harmata and co-workers . It could be converted into a chiral molecular receptor 207 in a simple way. This chiral species 207 could be used as a new class of chiral molecular tweezers. The synthesis of 205 commenced with the protection of the commercially available compound 202, which was then coupled with (R)-sulfoximine 77b using the one-pot, one-operation procedure affording enantiomerically pure benzothiazine 204. This was followed by deprotection to produce benzothiazine 205 in good yield.

CHO

CHO 5% Pd(OAc) 2, 7.5% BINAP

5.0 eq. TEA, 0.5 eq. Br OH

THF, rt, 2 h

202

OMOM

93%

N OMOM

S O Ph

1.6 eq. Cs2 CO3 , 1.2 eq. (R)-77b

Br

NaI, 2.0 eq. MOMCl,

toluene, reflux, 48 h 89%

203

i-PrOH, THF, H2 O, rt, 3 h N

100% OH

204

S O Ph

205 N

Cl Cl

N H

Cl

2.3 eq. NaH, 2.1 eq. 205, DMF, 20 h, rt 89%

206

O N S Ph O

O N Ph 207

S O

Scheme 58 1.3.8 Application of 2,1-Benzothiazines in Natural Products Syntheses The Harmata group has shown that the benzothiazines prepared by the conjugate addition of sulfoximine carbanions to α,β-unsaturated esters can be used as enantiomerically pure starting materials for the synthesis of natural products. The benzothiazine synthesis establishes a stereogenic center with complete fidelity at a postion alph to a benzene ring. There are a number of natural products that possess such stereogenic centers. The Harmata group has successfully applied the methodology to the synthesis of such compounds including (+)-curcumene 208 , (+)-curcuphenol 209 , erogorgiaene 210 , pseudopteroxazole 211 and several related natural products.

37


Me

Me

Me

Me

Me Me H

Me Me

Me

R

Me Me H

Me N

208. R = H, S-(+)-curcumene

O

Me

209. R = OH, S-(+)-curcuphenol

210. erogorgiaene

Me

211. pseudopteroxazole

Figure 11. Natural product targets. Pseudopteroxazole 211 is a member of the amphilectane class of diterpenes and was isolated from a marine soft coral Pseudopterogorgia elisabethae . Pseudopteroxazole 211 possesses considerable inhibitory activity against M. tuberculosis H37Rv at a concentration of 12.5 ȝg/mL (97% growth inhibition). Given continuing global problems with respect to the treatment of tuberculosis, both the structure of 211 and its biological activity provide an impetus for syntheis. The total synthesis commenced with the coupling of ester 212 with (R)-sulfoximine (R)-77b to afford enantiomerically pure sulfoximine, which was then treated with LDA followed by a proton quench to produce benzothiazine 213 as a 10:1 mixture of diastereomers in good yield. Subjecting 213 to a twostep reduction/oxidation and spontaneous epimerization sequence afforded aldehydes 214a and 214b in a 1.6:1 ratio (Scheme 59). The mixture was treated with a Wittig reagent to provide 215a and 215b in 52% and 33% yields, respectively, as single stereoisomers. Me

CO2Et

Me

EtO 2C Me

a, b Br

N

OMe

OHC

Me H

OMe

212

H

Me

c, d

S O Ph

N OMe

213 Me

OHC Me

OMe

Me

Me

H

Me

+

S O N Ph

N OMe

214b

Me

Me e

S O Ph

214a

Me

Me H

Me

S O Ph

215a (52%)

H

Me N OMe

S O Ph

215b (33%)

(a) Pd(OAc)2, BINAP, (R)-sulfoximine, 81%; (b) LDA, 88%; (c) LAH; (d) Swern, 81%, 1.68:1, 2 steps; (e) Wittig

Scheme 59

38


Interestingly, treatment of diene 215a with methanesulfonic acid afforded 216 as a single diastereomer in 88% yield, the structure of which was confirmed by X-ray analysis (Scheme 60). The transformation of 216 into 217 started with an alkylation, followed by reductive desulfurization and triazene formation to afford compound 217 in 92% yield. Upon treatment with diiodomethane, triazene 217 was smoothly converted to aryl iodide 218 in 75% yield. Pd-catalyzed intramolecular Heck coupling of 218 led to the desired product 219b in 62% yield. Me

Me

Me

Me Me H

Me 215a

a

H

Me N OMe

b, c, d

Me

S O Ph

OMe

216 Me

Me

Me

f

N N NEt2 217

Me Me H

e

Me

Me

Me Me H

Me Me

+

H

Me

I OMe 218

OMe CH2 219a (14%)

OMe Me 219b (62%)

(a) MsOH, 88%; (b) LiHMDS, allyl bromide; (c) Na/Hg, 92%, 2 steps; (d) HONO, Et2NH, 100%; (e) CH2I2, 20 h, 75%; (f) 2% Pd(OAc)2, 4% (o-Tol)3P, TEA, 120 oC, 38 h

Scheme 60

Stereoselective reduction of 219b was conducted using one of Pfaltz’s chiral catalyst to deliver compound 220 in 90% yield (Scheme 61). Demethylation of 220 with NaSEt afforded the phenol in 87% yield. Subsequent nitration of the phenol with concentrated HNO3 produced the corresponding nitrophenol in 84% yield. With the nitrophenol in hand, the last stage of the synthesis involved assembling the benzoxazole ring. Reduction of the nitrophenol with Zn dust, followed by treatment with methyl orthoformate and catalytic TsOH, completed the synthesis of pseudopteroxazole 211 in 65% yield for the last two steps (Scheme 61). After the successful synthesis of pseudopteroxazole 211, the synthesis of the structurally-related compound erogorgiaene 210, which also shows antituberculosis activity, was reported . This synthesis was a formal synthesis of erogorgiaene using essentially the same methodology (Scheme 62) as that used for the synthesis of 211. Aniline 221 was converted into the iodide using triazene chemistry. A Sonogashira coupling reaction of the corresponding iodide followed by Swern oxidation and Wittig reaction afforded the

39


intermediate 222 in excellent yield. Hoveyda and co-workers. Me

219b

a

This compound was convered to erogorgiaene by

Me

Me Me H

Me

b, c, d, e

Me Me H

Me N

OMe Me

O 211

220

Me O (o-Tol)2P

Me

Me

CF3

O Ir

B

N

4 CF3

tBu

Pfaltz chiral catalyst

(a) 3% catalyst, 200 psi H2, rt, 1 h, CH2Cl2, 90%, 158:1; (b) 7.0 eq. NaH, 6.0 eq. EtSH, DMF, overnight, reflux, 87%; (c) HNO3, Hexanes, 1.5 min, 84%; (d) Zn, NH4Cl, 90% MeOH, rt, 1 h; (e) CH(OMe)3, TsOH (cat), 65%, two steps

Scheme 61

CO2 Me

Me

N

S

Me a, b

Ph

c, d, e, f, g Me

O

NH2 OH

94

221 Me

Me 12 steps

Me

H

Me 222

Me

TMS Me

Me

210; erogorgiaene ( tr an/ syn )

(a) LAH: (b) Na/Hg, (c) 4.5 eq. HCl, 3.4 eq NaNO2, 5.0 eq K2CO3, 5.0 eq. Et2NH, 90%; (d) CH3I, 130 o C, 0.5 h, 80%; (e) 0.12 eq PPh3, 0.06 eq PdCl2, 0.06 eq. CuI, Et3N, 2.0 eq. (trimethylsilyl)acetylene, 90%; (f) Swern oxidation, 96%; (g) Ph3PCH3, n-BuLi, THF, 98%.

Scheme 62

40


In addition to these studies, the Harmata group also successfully achieved the total synthesis (+)-curcumene 208 and curcuphenol 209 utilizing the 2,1-benzothiazine chemistry . The synthesis of (+)-curcuphenol was accomplished by reduction of benzothiazine 94, followed by protection, desulfurization, reductive deamination and deprotection to give diol 223 in good yield. The latter was then converted into (+)curcuphenol 209 (Scheme 63). The total synthesis of (+)-curcumene involved a similar approach to that of (+)-cucurphenol. CO2Me

Me a, b ,c, d, e

Me

N

S

Ph

OH Me

O 94

OH 223

a, f, g Me OBn Me

h, i, j, k

209 ; (+)-curcuphenol 208; (+)- curcumene

NH2 224

(a) LAH; (b) DHP, TsOH; (c) Na/Hg, 74%, three steps; (d) isoamyl nitrite, DMF, 50%; (e) H+ (f) NaH, BnBr; (g) Na/Hg; (h) HONO, NaBH3CN, 61%; (i) Pd/C, H2; (j) (Ph2PCH2-)2, Br2; (k) 2-methylpropene lithium

Scheme 63

1.4 ACKNOWLEDGEMENTS We are grateful to Prof. Paul A. Wender, Prof. Andreas Pfaltz, Prof. Abimael D. Rodriguez and Dr. Jeff Zablocki (CV Therapeutics) for their constant encouragement and informative conversations in the course of our work on benzothiazines. All those past and present members of our research group at the chemistry department at the University of Missouri-Columbia as well as all individuals whose names are included in the references are gratefully acknowledged. Our work in this area has been supported by the NIH (1R01AI59000-01A1) and the donors of the Petroleum Research Fund, sponsored by the American Chemical Society (38288-AC1 and others), to whom we are extremely grateful. 1.5 REFERENCES 64JOC1688 65JOC3163 66AC(R)728 66AC(R)741 66JOC3531 66MI1 66MI2

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42 90TL7021 91CC877 91JCS(P1)1733 91JMC2477

91JOC5059 91T8855 91TL4359 92MI1 92MI1 93JMC2242

94JCS(P1)1709 94MI1 94S142 94TL2911 95TL4769 97JHC1693 97T13855 97TA909 97TL137 98JHC1449 98JHC499 98JHC983 98JOC6845 98MI1 98T9995 98TL5731 99AG(E)2419 99BMCL673

99JOM(576)125 99JPR403 99OL527 99TL95 00JOC169 00JOC8086 00JOC8391 00JOC926 00S1 00SL475 01JA3830 01JNP100 01OL3321 01SL1878 01T5915 02MI1


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02MI2

02MI3 02SL832 03ARK11 03JA5754 03JOC9574 03JSMC349 03MI1 03OBC1342 03OL427 03TL7261 04JA96 04MI1 04OL2201 04SL101 04TL5233 05OL3581 05TL3847 06JOC3650

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I. Yoshida, N. Yoneda, Y. Ohashi, S. Suzuki, M. Miyamoto, F. Miyazaki, H. Seshimo, J. Kamata, Y. Takase, M. Shirato, D. Shimokubo, Y. Sakuma, H. Yokohama, WO 2002088107, 2002; Chem. Abstr., 137, 353066. J.F. Hartwig, Handbook of Organopalladium Chemistry for Organic Synthesis 2002, 1, 1051. C. Bolm, M. Martin, L. Gibson, Synlett 2002, 832. K. Sakuratani, H. Togo, ARKIVOC. 2003, vi, 11. M. Harmata, X. Hong, J. Am. Chem. Soc. 2003, 125, 5754. J.T. Manka, F. Guo, J. Huang, H. Yin, J.M. Farrar, M. Sienkowska, V. Benin, P.Kaszynski, J. Org. Chem. 2003, 68, 9574. M. Harmata, S.K. Ghosh, C.L. Barnes, J. Supramol. Chem. 2003, 2, 349. M. Harmata, Chemtracts 2003, 16, 660. Y. Misu, H. Togo, Org. Biomol. Chem. 2003, 1, 1342. C. Bolm, M. Martin, O. Simic, M. Verrucci, Org. Lett. 2003, 5, 427. M. Harmata, X. Hong, C.L. Barnes, Tetrahedron Lett. 2003, 44, 7261. R.R. Cesati, J. De Armas, A.H. Hoveyda, J. Am. Chem. Soc. 2004, 126, 96. C. Yoakim, J. O'Meara, B. Simoneau, W.W. Ogilvie, R. Deziel, WO 2004026875, 2004; Chem. Abstr., 140, 303707. M. Harmata, X. Hong, C.L. Barnes, Org. Lett. 2004, 6, 2201. K. Hemming, C. Loukou, S. Elkatip, R.K. Smalley, Synlett 2004, 101. M. Harmata, X. Hong, S.K. Ghosh, Tetrahedron Lett. 2004, 45, 5233. M. Harmata, X. Hong, Org. Lett. 2005, 7, 3581. M. Harmata, X. Hong, Tetrahedron Lett. 2005, 46, 3847. M. Harmata, N.L. Calkins, R.G. Baughman, C.L. Barnes, J. Org. Chem. 2006, 71, 3650.

44

Chapter 2 Porphyrins in Diels-Alder and 1,3-dipolar cycloaddition reactions Ana M. G. Silva and José A. S. Cavaleiro* Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal E-mail: [email protected]

2.1

OVERVIEW OF THE CYCLOADDITION REACTIONS OF PORPHYRINS

Interest in porphyrin chemistry started centuries ago with Man trying to understand why blood is red and plants are green . However it was only in 1929 that the macrocylic structure of a porphyrin was unambiguously demonstrated by Hans Fischer at his Munich school with the first synthesis of protoporphyrin IX. The iron complexes of such natural compounds play key roles in several vital functions (e.g., respiration and drug detoxification) and its magnesium complex is a precursor of chlorophyll a. As a result of this pioneering synthetic work Fischer was awarded the Nobel Prize in 1930 . Mainly after the second world war, chemists have looked for better synthetic methodologies leading to porphyrins and for the understanding of their biosynthesis, mode of action and catabolism. With the advent of synthetic porphyrins, potential applications in medicine, in catalysis and in other areas have become possible. Several research groups have been dedicating their efforts to the synthesis of simple porphyrins containing groups on meso- and/or betapositions of the macrocycle. Other topics of research have centred on the transformation of the periphery of the macrocycle via functionalization reactions including electrophilic substitutions, nucleophilic addition of alkyllithium reagents, peripheral reduction, oxidation and pericyclic reactions . Benzoporphyrins, chlorins (dihydroporphyrins) and bacteriochlorins (tetrahydroporphyrins) are important derivatives which can demonstrate significant medicinal applications. The search for new synthetic methodologies leading to such compounds is a target for many groups. Diels–Alder (DA) and 1,3-dipolar cycloaddition (1,3-DC) reactions are simple and very versatile transformations to introduce a wide range of substituents at the meso- and betapyrrolic positions of porphyrins, thus leading to promising derivatives obtained in many cases in one-pot transformations. The use of beta-vinylporphyrins as dienes in DA reactions has been known for decades and has been recently reviewed . This review will focus only on the use of porphyrins as dienophiles in DA reactions as well as on the use of porphyrins and porphyrinic derivatives in 1,3-DC reactions.

45


2.2 2.2.1

PORPHYRINS IN CYCLOADDITION REACTIONS Porphyrins as dienophiles in Diels-Alder reactions

The possibility of using porphyrins as dienophiles in DA reactions emerged in 1997 when Cavaleiro and coworkers found that meso-tetraarylporphyrins 1a-d can behave as dienophiles in the presence of o-benzoquinodimethane, a highly reactive diene generated in situ by the thermal extrusion of SO2 from a sulfone by refluxing in 1,2,4trichlorobenzene, TCB, giving chlorins 2a-d in moderate yields (Scheme 1). O2S Ar X NH

NH

N Ar

Ar N

Ar

TCB reflux

+

Ar HN

N

HN

Ar

X

N

Ar

Ar

1

2 a Ar= Ph, X=H b Ar= m-MeOC6H4, X=H c Ar= p-MeOC6H4, X=H d Ar= C6F5, X=H e Ar= Ph, X=NO2

Scheme 1. DA reactions of porphyrins 1 with o-benzoquinodimethane. As well as the synthesis of chlorins 2a-c, the DA reactions of porphyrins 1a-c with obenzoquinodimethane gave two naphthoporphyrins 3 and 4 (Figure 1) resulting from the diand tetradehydrogenation reactions of the corresponding chlorins. On the other hand, the reaction with porphyrin 1d having pentafluorophenyl groups in the meso positions, afforded the chlorin 2d and a diastereomeric mixture of two bacteriochlorin bis-adducts 5d and 6d (Figure 2), showing that the presence of electron-withdrawing groups at the meso-position of the porphyrin greatly improve the DA reactions with o-benzoquinodimethane.

Ar

NH

Ar

NH

N Ar

Ar N

HN

Ar

N Ar

Ar HN

N

3

Ar a Ar= Ph b Ar= m-MeOC6H4 c Ar= p-MeOC6H4

Figure 1. Naphthoporphyrins 3 and 4.

4

A.M.G. Silva and J.A.S. Cavaleiro

46

C6F5 NH

NH

N C6F5

F5C6

NH

N C6F5

F5C6

HN

N

Ph

C6F5

C6F5 5d

Ph HN

N

HN

N

N

Ph

C6F5

Ph

6d

7

Figure 2. Bacteriochlorins 5d and 6d and bis-naphthoporphyrin 7.

A beta-substituted porphyrin, such as beta-nitro-meso-tetraphenylporphyrin 1e, also reacts with o-benzoquinodimethane to give the corresponding nitrochlorin 2e, together with the naphthoporphyrin 4a and the bis-naphthoporphyrin (bisadduct) 7; the formation of these 4a and 7 derivatives imply HNO2 elimination and dehydrogenation reactions . Subsequently, other publications have appeared involving the DA reactions of porphyrins with other dienes. For instance, the reaction of mesotetrakis(pentafluorophenyl)porphyrin 1d with the diene generated from pyrrole-fused 3sulfolene gave rise to the isoindole-fused chlorin derivative 8 accompanied by a mixture of stereoisomeric bacteriochlorins 9 (Scheme 2) . NH

NH

O2S NH

NH

NH

N HN

Ar

TCB, reflux

NH

N Ar

N

Ar

CO2Et

Ar

Ar

Ar N

Ar

CO2Et

Ar

N Ar

Ar

+

N

HN

Ar

CO2Et

EtO2C

HN

Ar HN

1d Ar= C6F5

8 (32-39%)

9 (mixture of stereoisomers)

Scheme 2 DA Reaction of porphyrin 1d with a pyrrole-fused 3-sulfolene.

Furthermore, it was shown that porphyrin 1d can also react with a pyrazine o-quinodimethane derivative ( Scheme 3) . However, in this case the reaction did not afford the expected DA adduct, the product being the porphyrin derivative 10 resulting from the tetradehydrogenation of the corresponding adduct. The porphyrin derivative 11 was also obtained although in minor amount; this product must result from a cyclization reaction between the beta-fused quinoxaline ring and the adjacent meso-aryl group. Also, bisadducts 12 and 13 were isolated; these are the result of site specific bisaddition to opposite pyrrolic rings followed by oxidative processes.

47


CN

CN

N Ar

Ar

NH

Br Br

N

N

CN

N

CN

NH

N

NH

N Ar +

Ar NaI, TCB, reflux

HN

N

CN

Ar

N

F

Ar

Ar

N

CN

N

F

Ar

HN

HN

N

F

Ar

Ar

F

Ar

10 (34%)

1d Ar= C6F5

N

11 (3%)

CN N

Ar

CN N

CN Ar

N

CN N F

NH

NH

N Ar +

Ar N N NC

N N NC

N NC

F

Ar

HN

Ar 12 (6%)

N HN F

F

Ar N 13 (1%)

NC

Scheme 3 DA reaction of porphyrin 1d with pyrazine o-quinodimethane derivative. C6F5

Ph

C6F5 N

NH N

C Ph

Ni

Ph

N

N

NH

N

N

HN

C6F5

C6F5

N C6F5

14

Ph

benzene, reflux

C6F5 16

1. benzene, reflux 2. DDQ

C6F5

Ph

C6F5 N

N N Ph

C Ph

Ni N

N

NH

N

N

HN

C6F5

C6F5

N Ph

15 (23%)

C6F5

C6F5 17 (55%)

Scheme 4. DA Reactions of N-confused porphyrin 14 and hexaphyrin 16 with obenzoquinodimethane.


48

The DA reactions with o-benzoquinodimethane have also been extended to nickel(II) Nconfused porphyrin 14 to yield nickel(II) N-confused isoquinoporphyrin 15 ( Scheme 4) . The reaction occurred selectively in the peripheral carbonnitrogen bond, showing that this bond is more reactive than the other carbon-carbon double bonds. This can be understood by the resonance contributions to the overall structures. Figure 3 shows two such resonance structures. In the canonical form II the C=N is both “cross conjugated” and in an iminium form which is known to be electron-deficient and an active dienophile . Ph

Ph NH

N

Ph

Ni

Ph

NH N

C

Ph

Ni

Ph

N

N

C N

N

Ph I

Ph II

Figure 3. Two canonical forms of N-confused porphyrin 14. Similarly, the DA reaction of o-benzoquinodimethane with the hexaphyrin 16, followed by treatment with DDQ, gave rise to the naphthohexaphyrin 17 . This result revealed that the first addition of the diene took place selectively at the inner inverted betapyrrolic double bond, suggesting that this double bond is the most reactive position of the macrocycle. In minor amount the reaction also gave rise to a bisnaphthohexaphyrin. Curiously, this compound resulted from the selective addition of a second obenzoquinodimethane species to an outer beta-pyrrolic double bond of the naphthohexaphyrin 17, and is in agreement with the theoretical calculations that predicted that the second cycloaddition could not occur at the other side of the inner double bond of 17. C6F5

C6F5 N H N

N H N C6F5

C6F5 1d C6F5

C6F5

C6F5

C6F5

N H N

N H N

N

H N C6F5

N H N

C6F5 18d

8 h, 200 °C , 22% MW, 3x10 min, 200 °C , 83%

C6F5

C6F5 19d

heat, no reaction MW, 3x15 min, 180 °C , 23%

Scheme 5. DA Reaction of porphyrin 1d with pentacene and naphthacene.


49

It has also been shown that polycyclic hydrocarbon derivatives can react successfully with porphyrins. In fact, meso-mono-, meso-di- and meso-tetraarylporphyrins react with pentacene providing chlorin-type derivatives in moderate to good yields, depending on the number, steric hindrance and electron withdrawing character of the meso-aryl groups (Scheme 5) . In the particular scenario of the DA reaction of mesotetrakis(pentafluorophenyl)porphyrin 1d with pentacene (after 8 h at 200 ºC), chlorin 18d was obtained in 22% yield. This yield was improved to 83% and the reaction time reduced to 30 minutes by performing the reaction under microwave irradiation (after 3x10 min at 200 ºC) . Moreover, using microwave irradiation, the same porphyrin 1d reacted with naphthacene (after 3x15 min at 180 ºC) providing a synthesis of the corresponding chlorin 19d (as a mixture of isomers), which could not be obtained by a procedure using conventional heating. DA reactions with polycyclic hydrocarbon derivatives have also been applied to other macrocycles. Lukyanets and coworkers have explored this methodology by adding the unsubstituted tetraazaporphine 20 to a series of anthracene derivatives (Scheme 6). For instance, the reaction with naphthacene (after 6 h at reflux) afforded the chlorin 21 and a tetraazabacteriochlorin (bisadduct) in small amounts .

N

N H

N

N N

N

N

H N

N C6H5Cl, reflux

N

N H

N

N N

H N

20

N 21 (39%)

Scheme 6. DA Reaction of the tetraazaporphine 20 with naphthacene.

The same strategy provides a useful tool to derivatize corrole 22 and sapphyrin 25 (Scheme 7). In the case of corrole 22, the reaction with pentacene (after 6 h at 200 ºC) afforded mainly the dehydrogenated adduct 23; this is formed from the selective addition of pentacene to the beta-pyrrolic double bond near to the direct pyrrole–pyrrole link and subsequent dehydrogenation . In minor amount, the reaction also gave rise to the dehydrogenated adduct 24 resulting from an unexpected thermal [4+4] cycloaddition reaction. In the reaction with sapphyrin 25, adduct 26 was produced with high selectivity (MW, 1 h, 200 ºC), showing once again that the beta-pyrrolic double bond close to the pyrrole-pyrrole link contains the most reactive position of this type of macrocycle .

2.2.2 Porphyrins as 1,3-dipoles in 1,3-dipolar cycloadditions In 1995, Boyd and co-workers covalently linked a porphyrin to fullerene C60 through a 1,3-dipolar cycloaddition reaction involving the porphyrinic azomethine ylide 28 (Scheme 8). The ylide was generated in situ from beta-formyl-meso-tetraphenylporphyrin 27 and N-methylglycine, and provided the porphyrin–C60 diad 29 in good yield.


50

C6F5 R HN

N

N C6F5

C6F5

N H N

NH HN

H N

22

25 R=(CH2)3OAc MW TCB, 200 °C

TCB 200 °C C6F5

C6F5 N

R

N H

N

HN C6F5

C6F5

+

R

HN C6F5

C6F5

N

NH HN

NH HN

23 (23%)

R

N H N H N

H N

26 (51%)

24 (13%)

Scheme 7. DA reactions of corrole 22 and sapphyrin 25 with pentacene.

Ph

N

CHO

N M

Ph N

Ph

+

HN CH2 CO2H

N

Me toluene reflux

Ph 27 (M= 2H) Ph

N

HC N CH2 Me N

M

Ph N

N

N

N N

C60 Ph

M

Ph

Ph Me

N Ph N

Ph Ph

28

29 (40%)

Scheme 8. 1,3-DC reaction of the porphyrinic azomethine ylide 28 with C60.

51


Subsequently, other research groups have used this strategy for the construction of other porphyrinic diads. As an example, the porphyrinic azomethine ylide 28 (M = Ni) has been successfully trapped in 1,3-DC reactions with a range of dipolarophiles including Nphenylmaleimide, dimethyl fumarate, dimethyl acetylenedicarboxylate, trans-β-nitrostyrene, 1,4-benzoquinone and 1,4-naphthoquinone. In general, the reactions afforded the expected adducts, e.g. 30, in very good yields (Scheme 9) . Exceptions were found in the reactions with 1,4-benzoquinone and 1,4-naphthoquinone which only gave rise to the formation of the dehydrogenated adducts, e.g. 31. More recently, porphyrinic azomethine ylide 28 (M = Ni) has been trapped with isatin to give a spiro porphyrin derivative 32 (Scheme 9) . O

O

N Ph

O N H

28

O

O

O

O Me N Ph

N

N Ph

Ph

Ph N

N

Ph

Ph

30 (96% mixture of diastereomers)

N H

N Ni

Ph

N

N

Ph

N

N Ni

Ph

N

N

O

O

N Ni

O

Me N Ph

Me N Ph

N Ph O

Ph

O

31 (94%)

32 (13%)

Scheme 9. 1,3-DC reactions of porphyrinic azomethine ylide 28 with different dipolarophiles It has also been demonstrated that in the absence of dipolarophiles, porphyrinic azomethine ylide 28 can participate in 1,5-electrocyclization reactions, to yield pyrroloporphyrins, e.g. 33 (Scheme 10) . Ph

N 28

N N

Ph

Ni

Ph

Me

N

N

Ph

33 (55%)

Scheme 10. 1,5-Electrocyclization reaction of 28.


52

Numerous studies have been reported concerning the use of 1,3-DC reactions as powerful tools for the construction of other systems employing porphyrins or chlorins as electron donors and fullerene as electron acceptor, mimicking the photosynthetic reaction centres. One of these studies involves the preparation porphyrin-(C60)2 triads 34a and 34b from the 1,3-DC reaction of a porphyrin having two formyl groups in the para position of the 5,10- or 5,15phenyl groups, with N-methylglycine and C60 (Figure 4) . Ar N

N H H N

Ar N

Me

Me

N

N

Ar Me NH N

N

N

HN

N

Me Ar

34a

34b

Figure 4. Examples of porphyrin–(C60)2 triads 34.

N

1. pyridine, 100 ° C 2. 5% H2SO4, MeOH

N Mg N

N

O Phytyl

N HN

N

O

H3CO2C

O

NH

35

MeO

O 36 (90%)

O

OsO4, NaIO4

CHO

Me N NH N

MeO

O

N HN

O 38 (49%)

NH

N-methylglycine, C60 toluene, reflux

MeO

N

O

Scheme 11. Synthesis of phytochlorin-C60 diad 38.

N HN

O 37 (63%)

53


Hynninen and coworkers used a similar approach to prepare phytochlorin-C60 diad 38 (Scheme 11). The protocol employed the pyrolysis of the natural chlorophyll a molecule 35, followed by transesterification and demetallation to furnish derivative 36. Subsequent oxidation of 36 with OsO4 and NaIO4 has allowed the synthesis of the formyl derivative 37, which was further used as precursor of the azomethinic ylide intermediate in the 1,3-DC reaction with C60 leading to the formation of diad 38. Photochemical studies revealed that this diad underwent a fast intramolecular photoinduced electron transfer in polar solvents such a benzonitrile . Based on studies showing that the close proximity between the porphyrin and the C60 is essential for the observation of an electron transfer process, Fukuzumi and co-workers have prepared the porphyrin-C60 diad 41, in which the C60-pyrrolidinyl moiety is directly connected to the meso position of the porphyrin macrocycle (Scheme 12) . The strategy adopted for the synthesis of the starting porphyrin involved the 2+2 condensation of a meso-unsubstituted dipyrrylmethane with 3,5-di-tert-butylphenylsubstituted dipyrrylmethane and 3,5-di-tert-butylbenzaldehyde, to give 39, in 11.5% yield. Subsequent Ni(II) metallation, followed by Vilsmeier-Haack formylation and demetallation, gave rise to 40 which was used as the 1,3-dipole precursor; this dipole in the presence of Nmethylglycine and C60, yielded the expected diad 41.

Ar CHO +

NH HN

NH HN

NH

N

Ar

+

N

Ar=

HN 39

Ar

1. Ni(OAc)2, CHCl3, reflux 2. POCl3, DMF, CH2ClCH2Cl 3. CH3COONa (aq) 4. TFA, H2SO4, CHCl3

Ar Me

NH

N

Ar

N

Ar N

HN

NH

N-methylglycine, C60

N CHO

Ar Ar 41

toluene, reflux

N

HN

Ar

40

Scheme 12. Synthesis of porphyrin-C60 diad 41.

Similar protocols have been followed for the synthesis of other porphyrin-C60 diads where the linkage between C60 and porphyrin moieties occurs through the ortho, meta or para positions of the phenyl ring of the porphyrin macrocycle .


54

Another interesting strategy for the construction of a porphyrin-C60 diad linked by a disilane chain was devised by Ito and coworkers (Scheme 13) . This method involves the use of the meso-iodo triphenylporphyrin 42, prepared by iodination of porphyrin 39 using a mixture of bis(trifluoroacetoxy)iodobenzene-iodine . An iodo porphyrin 42 was reacted with 1,2-diethynyl-1,1,2,2-tetramethyldisilane using Sonogashira coupling conditions to give rise to derivative 43; this compound then reacted with Ar

Ar

NH

I2, (CF3COO)2IPh, CHCl3

N

NH

Ar N

I N

HN

HN

Ar

39

Ar

N

Ar

42

Zn(OAc)2.2H2O, MeOH, CH2Cl2

Ar=

Me Me Si Si Me Me [PdCl2(PPh3)2], CuI, THF, NEt3

Ar

N

N

Me Me Si Si Me Me

Zn

Ar

N

N

Ar

43 I

Ar

N

Pd(PPh3)4, CuI, THF, NEt3 N

Me Me Si Si Me Me

Zn

Ar

N

N

CHO

Ar

CHO

44 N-methylglycine, C60 toluene, reflux

Ar

Me N

N

Me Me Si Si Me Me

Zn

Ar

N

N

Ar

N

45

Scheme 13. Synthesis of porphyrin-C60 diad 45.

55


p-iodobenzaldehyde using similar coupling conditions allowing the formation of porphyrin 44. This porphyrin was then allowed to react with N-methylglycine and C60, giving rise to the final diad 45. Fukuzumi and co-workers have developed another strategy aimed at a synthesis of imidazoporphyrin-C60 diad 49 (Scheme 14). Using the Crossley approach as for the synthesis of 17,18-dioxochlorin 47, the Cu(II) complex of betanitro-meso-tetraphenylporphyrin 1e was demetallated and reduced to the beta-amino derivative 46, and this was photo-oxidised and hydrolysed to give 47. Condensation of 47 with the terephthalaldehyde in the presence of excess of NH4OAc in a refluxing 1:1 mixture of AcOH-CHCl3 for 2 h, gave the expected derivative 48, which, with N-methylglycine and in the presence of C60 produced the corresponding imidazoporphyrin-C60 diad 49. Interestingly, the Zn(II) complex of that imidazoporphyrin-C60 diad has shown the longest lifetime in solution of the charge-separated state ever reported for donor-acceptor-linked diads.

Ar

Ar N N

Cu

Ar

Ar N H

NO2 N

N

N

Ar

Ar 1e

N H

1. hυ, O2

H N

Ar

Ar

Ar 47

OHC NH4OAc AcOH/ CHCl3 Ar

Ar N H

Me N

N

N

N H

H N

N

N H

N CHO

N

N

N H

H N Ar

Ar 49

CHO

Ar

Ar N-methylglycine, C60 toluene, reflux

Ar

Ar

O

Ar

46

Ar=

O N

N

2. H+/ H2O or sílica gel

H N

N

Ar

Ar NH2

48

Scheme 14. Synthesis of porphyrin–C60 diad 49. In terms of synthetic methodologies for the preparation of porphyrinic azomethine ylides, the porphyrin moiety, in the examples above, was the carbonyl component. However, there are also examples where the porphyrin is used as the α-amino acid component. Lemmtyinen and coworkers have devised a protocol, in which the phytochlorin 37 containing a formyl group was transformed into glycine derivative 50 via reductive amination (Scheme 15). In the final step, derivative 50 was reacted with benzaldehyde and C60, and gave rise to the phytochlorin–C60 diad 51.


56

CO2H HN

CHO

NH

N

O

MeO

37

O

NH

HN

N

Me O

1. GlyOt-Bu.HCl, NaBH3CN 2. TFA

N

N HN

O 50

O

benzaldehyde, C60 toluene, reflux

N

NH N

MeO

N HN

O O

51

Scheme 15. Synthesis of phytochlorin-C60 diad 51.

Ph

Ph N N

Ni

N

N Ph

1. HCl.NH2CH2CO2Me La(OTf)3, K2CO3, toluene, reflux CHO 2. NaBH , MeOH 4 CH2Cl2, 0 °C 3. NaOH (aq)

Ph

Ph N N

Ni N

Ph

Ph

N H

N

Ph 52

Ph

HCHO, dimethyl fumarate toluene, reflux

Ph N N

Ni

CO2Me N

N

CO2Me

N Ph

Ph 53

Scheme 16. Synthesis of diad 53.

CO2H

57


A convenient route to N-(porphyrin-2-ylmethyl)glycine 52 was described by Cavaleiro and coworkers (Scheme 16); it involves the coupling of the Ni(II) complex of beta-formyl-meso-tetraphenylporphyrin with an excess of glycine methyl ester hydrochloride followed by reduction of the product imine with sodium borohydride and alkaline hydrolysis. Once synthesized, the Ni(II) complex of N-(porphyrin-2-ylmethyl)glycine, 52 was used as an azomethine ylide precursor; the latter was generated in the presence of paraformaldehyde and dimethyl fumarate, allowing the formation of diad 53 in 74% yield. Besides the use of porphyrins as azomethinic ylide derivatives, the porphyrin macrocycle can also be used to generate porphyrinic nitrile oxides 55 (Scheme 17) . Thus, the treatment of oxime 54 with N-bromosuccinimide in the presence of triethylamine, led to the formation of nitrile oxide 55, which was trapped in 1,3DC reactions with dimethyl maleate and 2,5-norbornadiene to afford 56 and 57, respectively. In the reaction with 2,5-norbornadiene, if an excess of 55 was used, then the corresponding bis-adduct was obtained in good yield.

N

N Ni

CH

NOH

NBS, NEt3

54

N Ni

N

N

N

N

C

N O

N

55 (92%) CO2Me CO2Me

N

N

N O

N

N

N

56 (91%)

CO2Me CO2Me

N

N O

Ni

Ni N

N

57 (97%)

Scheme 17. 1,3-DC Reactions of porphyrinic nitrile oxide 55 with dipolarophiles.

Another example with porphyrinic dipolar species uses pyridinium salt derivatives as precursors of porphyrinic pyridinium ylides (Scheme 18) . The procedure involves the reaction of porphyrin 58 with methyl bromoacetate, in refluxing chloroform, to give pyridinium salt 59. The latter, in the presence of K2CO3, reacts with 1,4-benzoquinone to yield only the mono-addition compound 60. Notably, when the reaction was performed in the presence of DBU, bis-addition occurred and the porphyrinic dimer 61 was the only isolated addition product.


58

Ph

NH

N N

Ph HN

N

Ph

58

BrCH2CO2Me CHCl3, reflux

Ph

O NH

N NCH2CO2Me

Ph HN

N

Ph

+

Br

O

59 K2CO3 toluene, reflux

DBU toluene, reflux Ph Ph

Ph

O Ph

N NH

N

Ph N

HN

N

HN CO2Me

N

NH

O

N

NH

Ph

Ph

N

HN

Ph

O Ph 60 (16%)

N

N MeO2C

O

CO2Me

61 (23%)

Scheme 18. 1,3-DC reactions of porphyrinic pyridinium ylide with 1,4-benzoquinone.

2.2.3

Porphyrins as dipolarophiles in 1,3-dipolar cycloaddditions

Our first entry to the use of porphyrins as dipolarophiles in 1,3-DC reactions involved the reaction of porphyrins with azomethinic ylides, generated in situ from α-amino acids and aldehydes, to yield chlorins and isobacteriochlorins (bisadducts) . In the particular scenario of the reaction of meso-tetrakis(pentafluorophenyl)porphyrin 1d with the azomethine ylide, generated in situ from N-methylglycine and paraformaldehyde, in refluxing toluene during 15 hours, the pyrrolidinochlorin derivative 62 was obtained as the main product (Scheme 19), together with a small amount of isobacteriochlorin 63 (bis-adduct, Figure 5).

59


H C O

+

HN CH2 CO2H

H

Me

C6F5 NH

N

H C N CH2 H Me

C6F5 +

C6F5 N

HN

C6F5

C6F5 NH

N

C6F5 HN

N

C6F5

1d

Me N

C6F5 + bisadduct (11%)

62 (61%)

Scheme 19. 1,3-DC Reactions of porphyrin 1d with azomethine ylide.

When a larger excess of the azomethine ylide precursors was used and the reflux was prolonged for 40 hours, the reaction afforded isobacteriochlorin 63 as the major adduct together with a small amount of bacteriochlorin 64 (Figure 5). This result demonstrates that the attack of the second azomethine ylide species to the chlorin macrocycle occurs preferentially at the adjacent β-pyrrolic double bond, yielding the isobacteriochlorin with high site selectivity. Me

C6F5

N N

Me

C6F5

N NH

N C6F5

C6F5

C6F5 63

N C6F5

C6F5 N

NH HN N Me

Me N

HN

C6F5 64

Figure 5. Bis-adducts obtained in 1,3-DC reaction.

This strategy has been successfully applied to other porphyrins, however the best yields were obtained with porphyrins having electron-withdrawing groups at the meso positions of the macrocycle . Knowing the great potential of such 1,3-DC with porphyrins, Gryko and co-worker predicted that if two electron-withdrawing groups were placed in vicinal (β,β’) positions of the same pyrrolic unit of a porphyrin, then stable, locked chlorins could be synthesized in a regioselective way. As a result, they undertook the synthesis of a range of porphyrins to be used as starting materials in 1,3-DC reactions with azomethine ylides. The starting porphyrins were synthesised via 3+1 condensations of a tripyrrane (compound containing three pyrrolic units such as 65) with an α,α'-diformyl pyrrole. Thus, for the synthesis of the tripyrrane 65, they have performed the condensation of the aryl aldehyde with pyrrole (Scheme 20). On the other hand, the synthesis of the diformyl pyrrole 66 involved the dimerization of esters of acetoacetic acid using I2 or cerium ammonium nitrate (CAN) to give the corresponding 1,4-diketones; these, when treated with NH3, gave rise to an α,α'-dimethylpyrrole derivatives, which were then transformed into the required


60

diformylpyrroles 66 by selective oxidation of the methyl groups using CAN in MeCN/ H2O at room temperature (Scheme 21). Ar

Ar N H

TFA

ArCHO + N H

NH

HN 65

Scheme 20. Synthesis of the tripyrrane 65.

O

1. NaOMe 2. I2 or CAN

CO2R

RO2C

CO2R

O O

R= Me, Et, t-Bu

NH3aq or NH3, MeOH RO2C

CO2R

OHC

N H

CAN MeCN, H2O

RO2C

CHO

CO2R N H

66

Scheme 21. Synthesis of diformylpyrrole 66.

CO2R RO2C OHC

Ar

CO2R N H

CHO

Ar N H

+

NH

CO2R NH Ar

HN

N

66

N HN

65 Ar Me

RO2C NH

N

67

HCHO N-methylglycine toluene, reflux

CO2R

N

Ar N

HN

Ar

68

Scheme 22. Synthesis of locked chlorins 68. Finally, the condensation of the tripyrrane 65 with the diformyl pyrrole 66, in a TFA/CHCl3 solution, gave porphyrins 67. Such porphyrins were then used in 1,3-DC

61


reactions with azomethinic ylides affording the locked chlorins 68 (Scheme 22). The results obtained showed that if electron-withdrawing groups are introduced at β-pyrrolic positions, the presence of electron-withdrawing groups at meso positions is no longer necessary for the success of a 1,3-DC reaction. The usefulness of such 1,3-DC reactions was also demonstrated when C- and Nglycoconjugated pyrrolidine-fused chlorins 69 and 70 were synthesised via azomethinic ylide cycloadditions with meso-tetrakis(pentafluorophenyl)porphyrin 1d (Schemes 23 and 24) . While the reaction of 1d with the azomethinic ylide, generated in situ from the galactosyl configured aldehyde and N-methylglycine, afforded a diastereomeric mixture of two chlorins 69, the reaction of 1d with the N-substituted symmetrical azomethinic ylide, generated in situ from the galactose-substituted glycine derivative with paraformaldehyde, gave chlorin 70 as the only isolable product. C 6 F5

O OHC

O O

O - + H2C N C H Me

N-methylglycine

O O

O O O

O

1d

HN

N C6F5

C6F5 NH

N

C6F5

* N Me O

O

O O O 69 (51% mixture of diastereomers)

Scheme 23. Synthesis of the C-glycoconjugated pyrrolidine-fused chlorin 69.

C6F5

O

O O

NH O CH2 CO2H

O

HCHO

H2C

+

O

N -

CH2

O O O

O

1d

N

HN

C6F5

C6F5 NH

N O C6F5

N O

70 (19%)

O O O

Scheme 24. Synthesis of the N-glycoconjugated pyrrolidine-fused chlorin 70.

Another example illustrating the versatility of 1,3-DC reactions is concerned with the reaction of [36]octaphyrin 71 with azomethine ylide generated in the usual way from Nmethylglycine and paraformaldehyde, to give mono- and bis-pyrrolidine-fused adducts 72 and 73 (Scheme 25)


62

Ar

Ar

N Ar

NH

HN Ar

Ar

N

N

NH

N Ar

HN

71 Ar= C6F5

Ar

Ar

HCHO, N-methylglycine toluene, reflux Ar

Ar

Ar

N

NH

N

HN Ar

Ar

N

HN

Ar

72 (3%)

Ar

Ar

Ar

+

Ar

N N NH

N

Ar

N

NH N HN

N

HN

Ar

Ar

Ar

N N NH Ar

Ar

73 (7%)

Scheme 25. 1,3-DC Reaction of [36]octaphyrin 71 with azomethine ylide.

Ar H O N C Me H

NH

Ar

Ar N

Ar 74 (72%)

Ar

HN

Ar

Ar NH

HN O N Me

O

O

N Ar

N

O

1d, Ar= C6F5

N

Ar

O

HN

Ar

Ar

NH

N

O + O N C H Bn

N O * N

Ar

Bn O

O O

O

75 (66%)

Scheme 26. 1,3-DC reactions of porphyrin 1d with nitrones.

O

63


Reaction of porphyrins with nitrones has also been studied and the results obtained showed that this is a versatile approach leading to the synthesis of isoxazolidine fusedchlorins (Scheme 26). For instance, chlorin 74 was successfully prepared from the reaction of the N-methylnitrone, generated in situ from N-methyl hydroxylamine and paraformaldehyde, with porphyrin 1d . It is important to note that bis-addition also took place, yielding exclusively bacteriochlorin type derivatives 76 and 77 (Figure 6). This result contrasts with those obtained in 1,3-DC reactions with azomethinic ylides where isobacteriochlorins were obtained preferentially. In an attempt to explain the different behaviour of azomethinic ylides and Nmethylnitrones in 1,3-DC reactions with porphyrins and chlorins, a theoretical study has been carried out. The results obtained showed that while in the cycloadditions of porphyrins and chlorins with azomethinic ylides the processes are irreversible and consequently are kinetically controlled, the cycloadditions of such macrocycles involving N-methylnitrone are clearly reversible, showing that the products from such reactions should be thermodynamically controlled . O N Me

C6F5 NH

NH

N C6F5

C6F5 N

Me

C6F5

N O

N C6F5

C6F5

HN

N

C6F5

O N Me

O N

76

HN

C6F5

Me

77

Figure 6. Bacteriochlorins 76 and 77. Ph

NH

NO2 N Ph

Ph N

HN

Ph

1e

N N CH2 H

Ph O2N N N NH

NH

N

N

Ph N

HN

Ph

78

+

Ph

Ph N

HN

Ph

N

NH

N

Ph + Ph

Ph

Ph O2N

N N

Ph

79

HN

Ph

DBU toluene, reflux

Scheme 27. 1,3-DC Reactions of porphyrin 1e with diazomethane.

80


64

Glycoconjugated isoxazolidine-fused chlorins and bacteriochlorins were also elegantly synthesised using a 1,3-DC approach (Scheme 26). For instance, the galactosylnitrone reacted with porphyrin 1d in a small volume of toluene, at 60 ºC, to yield chlorin 75, accompanied by a small amount of two related bacteriochlorins . Extension of the 1,3-DC approach to the synthesis of novel pyrazoline-fused chlorin 78 by the reaction of β-nitro-meso-tetraphenylporphyrin 1e with diazomethane has also been explored by Cavaleiro and co-workers (Scheme 27) . The resulting chlorin 78 could be further converted into the pyrazole-fused porphyrin 79 by treatment with DBU or into the methanochlorin 80 by refluxing in toluene. The same approach was subsequently used by Dolphin and co-workers and also by Robinson and co-workers to prepare pyrazoline cycloadducts from porphyrins and chlorins. Scheme 28 shows new chlorin derivatives (81 and 82) which have been obtained in this way. N N

NH

O

hν, heat

N

O

N HN

N

O

MeO

NH

HN

N

36

O

NH

N N CH2

HN

N

MeO

N

MeO

81

O 82

O

Scheme 28. 1,3-DC Reaction of phytochlorin 36 with diazomethane.

Carbonylic ylides represent other class of 1,3-dipolar reactive species to be used in 1,3DC reactions with porphyrins. For example, reaction of meso-tetraphenylporphyrin 1a with carbonyl ylide derived from tetracyanoethylene oxide gave chlorin 83 (Scheme 29) . Moreover, a large range of 1,3-DC reactions with carbonyl ylides has been patented . The resulting adducts containing one or more cyano groups can be further derivatized aiming to obtain photosensitizing agents of interest in photodynamic therapy.

O NC NC

Ph

CN CN

Ph

Δ

NH

N Ph +

N

HN

Ph

1a

NC NC

CN CN

NH

O

Ph

NC CN O

CN CN

N

Ph

Ph N

HN

Ph

83 (20%)

Scheme 29. 1,3-DC Reactions of porphyrin 1a with a carbonyl ylide.

65


Nitrile oxides have been also widely applied in 1,3-DC reactions with porphyrins . The reactions using unstable nitrile oxides, such as benzonitrile oxide, have failed or have given products in low yields; however reactions using stable nitrile oxides usually gave good results. In this way, the addition of 2,6dichlorobenzonitrile, to meso-tetra(p-chlorophenyl)porphyrin 84 afforded chlorin 85, together with a minor amount of related bacteriochlorins (Scheme 30). Ar

NH

N

Ar

Ar N

Ar

O N C +

NH

Cl

Cl

N

Ar N

HN

Ar

O N

Cl Ar

HN

Ar

84, Ar= p-ClC6H4

Cl

85 (53%)

Scheme 30. 1,3-DC Reactions of porphyrin 84 with nitrile oxide.

Finally, it is important to mention that there are other related publications in which porphyrin macrocycles are not directly used as dipolarophiles but are transformed into new derivatives that can react with carbonyl ylides via ACE (alkene cyclobutene epoxide) reactions. This idea arose in 1997, when Russell and co-workers found that fused esteractivated cyclobutene epoxides 86 can be ring-opened to give carbonyl ylides 87, and that these can be trapped stereospecifically by ring-strained alicyclic dipolarophiles, such as 2,5norbornadiene, to form hetero-bridged norbornanes 88 in good yields, through ACE transformations (Scheme 31) .

110 °C , 3 h

O

O 86

O E

E

E E

E 87

E 88

E= CO2Me

Scheme 31. A typical ACE (alkene cyclobutene epoxide) reaction.

Gunter and co-workers have applied this methodology to the condensation of norbornene derivative 90 (block A, Scheme 32) with epoxide 94 (block B, Scheme 33) . Thus, using the Crossley porphyrin-α-dione 47, condensation with 1,2,4,5benzenetetramine tetrahydrochloride and then the product with a strained dione, gave 90 as block A.


66 -Cl+H

Ar

Ar N H

O

-Cl+H

N

N H N

NH3+Cl-

3N

N H

NH3+Cl-

3N

Ar

Ar

H N

O Ar 47

Ar

Ar

Ar

O

N

NH2

N

NH2

N

N

89

O Ar

Ar N H

N

N

N

N

N

N H N

Ar

Ar

90, block A

Scheme 32. Synthesis of block A.

Typically, the synthesis of block B involves the Diels-Alder reaction of 1,4naphthoquinone with cyclopentadiene, followed by reduction and OH methylation to give 92 (Scheme 33). The next step involves a Ru-catalysed [2+2] cycloaddition of 92 with dimethyl acetylenedicarboxylate (DMAD), followed by epoxidation (MeLi, ButOOH) to give 94 as block B. O

O + O

O

MeO

MeO

1. NaH, THF 2. MeI 91

MeO

DMAD RuH2CO(Ph3)3

MeO2C CO2Me MeO ButOOH, MeLi

MeO

92

CO2Me

-78°C O

MeO

93

CO2Me

94, block B

Scheme 33. Synthesis of block B.

Finally, the condensation of blocks A and B under thermal conditions gave 96, where the porphyrin ring is rigidly linked to the dimethoxynaphthalene chromophore, through an ACE reaction (Scheme 34). The ACE reaction has proved to be an extremely versatile method for linking other chromophores to porphyrin macrocycles through a rigid spacer .

67


MeO

CO2Me

heat

94, B-BLOCK

90, block A

O MeO 95 MeO

O

MeO2C

CO2Me

Ar

MeO

N

MeO2C

Ar N H

N

N

N N Ar

H N

N Ar

96, ACE-coupled product

Scheme 34. ACE Reaction.

2.3 CONCLUSIONS This survey has highlighted the importance of cycloaddition reactions as powerful tools for the functionalisation of meso and beta-positions of a porphyrin macrocycle. As shown above, porphyrins can be used as dienophiles and as dipolarophiles in DA and 1,3-DC reactions with a wide range of reactive dienes and 1,3-dipoles to achieve monoadducts of the chlorin type, as the main products, or related compounds. Furthermore, under certain conditions, bis-adducts of the iso- or bacteriochlorin types can be obtained depending on the 4ʌ species used. Porphyrins can also be used as precursors of 1,3-dipolar species, and this has been widely explored, mainly when targets are concerned with the synthesis of porphyrinic diads. Several novel porphyrin derivatives can then be obtained by following the mentioned cycloaddition methodologies; many of the new products fulfil the requirements to be considered as potential new drugs mainly for the detection and treatment (PDT) of cancer situations and in the photo-inactivation of microorganisms.

2.4

ACKNOWLEDGEMENTS

Thanks are due to all colleagues and students who are co-authors in our cited publications. Thanks are also due to our University, to “Fundação para a Ciência e a Tecnologia” (FCT, Portugal) and POCI 2010 (FEDER) for funding the Organic Chemistry Research Unit. A.M.G.S. thanks FCT for her SFRH/BPD/8374/2002 grant.

2.5

REFERENCES

78MI1 94MI1 95TL7971 95JCSCC2379 97CC1199

D. Dolphin In The Porphyrins I; Dolphin, D., Ed.; Academic Press: New York, 1978; Vol. I, General Preface. R.A. Sheldon In Metalloporphyrins in Catalytic Oxidations; Sheldon, R.A., Ed.; Marcel Dekker: New York, 1994; p 6. T. Drovetskaya, C.A. Reed, P. Boyd, Tetrahedron Lett., 1995, 36, 7971. M.J. Crossley, L.J. Govenlock, J.K. Prashar, J. Chem. Soc., Chem. Commun., 1995, 2379. A.C. Tomé, P.S.S. Lacerda, M.G.P.M.S. Neves, J.A.S. Cavaleiro, Chem. Commun. 1997, 1199.

68 97CC1023 98CC2355 98CL605 98S593 99CC1767 99JACS9378 99JCS(PT1)2403 99JOC4218 00COC139 00JPP525 00JPP532 00MI1 00OL131 00PP598 00TL3065 01JCS(PT1)2752 01JPP835 01M406 02CC1816 02CC2622 02JOC726 02S1155 02T3445 02TL603 02TL7281 03A107 03JPC(A)8834 03OL2719 03T499 04JBCS923

04RCB(E)2192 04S1291 04MI1 05AC(E)932 05JOC2306 05OL1749 05S857 05S1030


R.N. Warrener, A.C. Schultz, D.N. Butler, S. Wang, I.B. Mahadevan, R.A. Russell, Chem. Commun. 1997, 1023. M.G.H. Vicente, M.T. Cancilla, C.B. Lebrilla, K.M. Smith, Chem. Commun. 1998, 2355. S. Higashida, H. Imahori, T. Kaneda, Y. Sakata, Chem. Lett. 1998, 7, 605. R.N. Warrener, M.R. Johnston, M.J. Gunter, Synlett 1998, 593. A.M.G. Silva, A.C. Tomé, M.G.P.M.S. Neves, A.M.S. Silva, J.A.S. Cavaleiro, Chem. Commun. 1999, 1767. N.V. Tkachenko, L. Rantala, A.Y. Tauber, J. Helaja, P.H. Hynninen, H. Lemmetyinen, J. Am. Chem. Soc. 1999, 121, 9378. J. Helaja, A.Y. Tauber, Y. Abel, N.V. Tkachenko, H. Lemmetyinen, I. Kilpeläinen, P.H. Hynninen, J. Chem. Soc., Perkin Trans. 1 1999, 2403. R.N. Warrener, A.C. Schultz, M.R. Johnston, M.J. Gunter, J. Org. Chem. 1999, 64, 4218. M.G.H. Vicente, K.M. Smith, Curr. Org. Chem. 2000, 4, 139. E.A. Makarova, G.V. Korolyova, O.L. Tok, E.A. Lukyanets, J. Porphyrins Phthalocyanines 2000, 4, 525. A.C. Tomé, P.S.S. Lacerda, A.M.G. Silva, M.G.P.M.S. Neves, J.A.S. Cavaleiro, J. Porphyrins Phthalocyanines 2000, 4, 532. M.G.H. Vicente and L. Jaquinod in The Porphyrin Handbook; Kadish, K. M., Smith, K.M., Guilard, R., Ed.; Academic Press: San Diego, 2000; Vol. 1, p 149-238. F. Odobel, F. Suzenet, E. Blart, J.-P. Quintard, Org. Lett. 2000, 2, 131. J.L. Bahr, D. Kuciauskas, P.A. Liddell, A.L. Moore, T.A. Moore, D. Gust, Photochem. Photobiol. 2000, 72, 598. A.M.G. Silva, A.C. Tomé, M.G.P.M.S. Neves, J.A.S. Cavaleiro, Tetrahedron Lett. 2000, 41, 3065. A.M.G. Silva, M.A.F. Faustino, A.C. Tomé, M.G.P.M.S. Neves, A.M.S. Silva, J.A.S. Cavaleiro, J. Chem. Soc., Perkin Trans. 1 2001, 2752. A. Efimov, N.V. Tkatchenko, P. Vainiotalo, H. Lemmetyinen, J. Porphyrins Phthalocyanines 2001, 5, 835. M.R. Johnston, Molecules 2001, 6, 406. Z. Xiao, B.O. Patrick, D. Dolphin, Chem. Commun. 2002, 1816. A. Desjardins, J. Flemming, E.D. Sternberg, D. Dolphin, Chem. Commun. 2002, 2622. A.M.G. Silva, A.C. Tomé, M.G.P.M.S. Neves, A.M.S. Silva, J.A.S. Cavaleiro, J. Org. Chem. 2002, 67, 726. A.M.G. Silva, A.C. Tomé, M.G.P.M.S. Neves, J.A.S. Cavaleiro, Synlett 2002, 1155. M.R. Johnston, M.J. Gunter, R.N. Warrener, Tetrahedron 2002, 58, 3445. A.M.G. Silva, A.C. Tomé, M.G.P.M.S. Neves, A.M.S. Silva, J.A.S. Cavaleiro, D. Perrone, A. Dondoni, Tetrahedron Lett. 2002, 43, 603. J. Flemming, D. Dolphin, Tetrahedron Lett. 2002, 43, 7281. J.A.S. Cavaleiro, M.G.P.M.S. Neves, A.C. Tomé, Arkivoc 2003, xiv, 107. N.V. Tkachenko, H. Lemmetyinen, J. Sonoda, K. Ohkubo, T. Sato, H. Imahori, S. Fukuzumi, J. Phys. Chem. A 2003, 107, 8834. Y. Kashiwagi, K. Ohkubo, J.A. McDonald, I.M. Blake, M.J. Crossley, Y. Araki, O. Ito, H. Imahori, S. Fukuzumi, Org. Lett. 2003, 5, 2719. A.N. Kozyrev, J.L. Alderfer, B.C. Robinson, Tetrahedron 2003, 59, 499. A.P.J. Maestrin, A.O. Ribeiro, A.C. Tedesco, C.R. Neri, F.S. Vinhado, O.A. Serra, P.R. Martins, Y. Iamamoto, A.M.G. Silva, M.G.P.M.S. Neves, A.C. Tomé, J.A.S. Cavaleiro, J. Braz. Chem. Soc. 2004, 15, 923. Y.V. Morozova, Z.A. Starikova, B.I. Maksimov, D.V. Yashunskii, G.V. Ponomarev, Russ. Chem. Bull., Int. Ed. 2004, 53, 2192. J.F.B. Barata, A.M.G. Silva, M.A.F. Faustino, M.G.P.M.S. Neves, A.C. Tomé, A.M.S. Silva, J.A.S. Cavaleiro, Synlett 2004, 1291. J.K. MacAlpine, E.D. Sternberg, D. Dolphin, USA Pat. 6,825,343 (2004) [http://www.freepatentsonline.com/6825343.html] H. Hata, H. Shinokubo, A. Osuka, Angew. Chem. Int. Ed. 2005, 44, 932. A.M.G. Silva, A.C. Tomé, M.G.P.M.S. Neves, A.M.S. Silva, J.A.S. Cavaleiro, J. Org. Chem. 2005, 70, 2306. D.T. Gryko, M. GaáĊzowski, Org. Lett. 2005, 7, 1749. A.M.G. Silva, A.C. Tomé, M.G.P.M.S. Neves, J.A.S. Cavaleiro, D. Perrone, A. Dondoni, Synlett 2005, 857. X. Liu, Y. Feng, X. Chen, F. Li, X. Li, Synlett 2005, 1030.


05S3632 05TL1555 05TL2189 05TL4723 05TL5487 06BCSJ1338 06H885 06JOC5942 06JOC8352 06OL1169 06SC2135 06SC2655 06TL3131 06TL8437 07MI1

69

L. Xingang, F. Yaqing, H. Xiaofen, L. Xianggao, Synthesis 2005, 3632. X. Li, J. Zhuang, Y. Li, H. Liu, S. Wang, D. Zhu, Tetrahedron Lett. 2005, 46, 1555. S. Zhao, M.G.P.M.S. Neves, A.C. Tomé, A.M.S. Silva, J.A.S. Cavaleiro, M.R.M. Domingues, A.J. Ferrer Correia, Tetrahedron Lett. 2005, 46, 2189. A.M.G. Silva, A.C. Tomé, M.G.P.M.S. Neves, J.A.S. Cavaleiro, C.O. Kappe, Tetrahedron Lett. 2005, 46, 4723. S. Zhao, M.G.P.M.S. Neves, A.C. Tomé, A.M.S. Silva, J.A.S. Cavaleiro, Tetrahedron Lett. 2005, 46, 5487. H. Tsuji, M. Sasaki, Y. Shibano, M. Toganoh, T. Kataoka, Y. Araki, K. Tamao, O. Ito Bull. Chem. Soc. Jpn. 2006, 79, 1338. S. Ostrowski, P. WyrĊbek, A. Mikus, Heterocycles 2006, 68, 885. M. GaáĊzowski, D.T. Gryko, J. Org. Chem. 2006, 71, 5942. A.M.G. Silva, P.S.S. Lacerda, A.C. Tomé, M.G.P.M.S. Neves, A.M.S. Silva, J.A.S. Cavaleiro, E.A. Makarova, E.A. Lukyanets, J. Org. Chem. 2006, 71, 8352. H. Hata, Y. Kamimura, H. Shinokubo, A. Osuka, Org. Lett. 2006, 8, 1169. M.E. Milanesio, E.N. Durantini, Synth. Commun. 2006, 36, 2135. X.G. Liu, Y.Q. Feng, C.J. Tan, H.L. Chen, Synth. Commun. 2006, 36, 2655. J.P.C. Tomé, D.-G. Cho, J.L. Sessler, M.G.P.M.S. Neves, A.C. Tomé, A.M.S. Silva, J.A.S. Cavaleiro, Tetrahedron Lett. 2006, 47, 3131. S. Ostrowski, P. WyrĊbek, Tetrahedron Lett. 2006, 47, 8437. G.J. Osés, A.M.G. Silva, A.R.N. Santos, A.C. Tomé, M.G.P.M.S. Neves, J. A.S. Cavaleiro, J.I. Garcia, unpublished results.

70

Chapter 3


Stephen C. Bergmeier and Damon D. Reed Department of Chemistry & Biochemistry, Ohio University, Athens, OH, USA [email protected] and [email protected]

3.1

INTRODUCTION

This review covers the chemical literature on epoxides and aziridines for the year 2006. As in previous years, this review is not comprehensive but rather covers a selection of synthetically useful and interesting reactions. Three-membered ring systems, epoxides and aziridines in particular, are excellent synthetic intermediates. This is largely due to their ability to be converted into other functional groups such as diols, diamines, and amino alcohols to name but a few. While the synthesis of aziridines and epoxides can be quite challenging, the rewards for a selective and high yielding synthesis can be substantial. The chapter has been divided into two sections, one covering epoxides and the other covering aziridines. Each of these sections has been further divided into two additional sections, one on the synthesis of the heterocycle and one on the reactions of the heterocycle. There is some overlap between methods for the synthesis of epoxides and aziridines and any overlap has been noted in the text. 3.2 3.2.1

EPOXIDES Preparation of Epoxides

Epoxides are possibly the most studied of the three-membered heterocycles. While a host methods for the synthesis of epoxides have been developed, work continues, especially in the development of more chemo-, regio-, and stereoselective methods. The development of new metal-based epoxidation catalysts continues to garner significant levels of activity. The use of the Mn-based catalyst, 1, with a water-soluble ligand provides excellent yields of the corresponding epoxides . A Mn-salen complex was modified by the addition of phosphonium groups at either end to render it water-soluble. The use of 5 mol% of this catalyst with NaIO4 as the oxidant provided a quantitative yield of cyclohexene oxide from cyclohexene.

71


NaIO4, 1 (5 mol%) 100%

Cl Ph3P

O

N

Cl

N

PPh3

Mn O

O 1

A number of additional metal-catalyzed epoxidations have been reported in the past year. Platinum is a rarely used catalyst in oxidation reactions. The use of chiral Pt-catalyst 2 in the epoxidation of terminal alkenes provides the epoxide products in moderate yield and enantiomeric excess . The chiral hydroxamide 3 is used with a Mo catalyst to provide the epoxide product in excellent yields and moderate enantioselectivity . A bis-titanium catalyst, 4, has also been used to epoxidize the usual set of alkenes with H2O2 as the oxidant . Substrate

Product

Conditions

H

2 (2 mol%), H2O2

R

Yield, %ee R = C4H9, 48%, 83% ee R = CH2Ph, 75%, 66% ee

O

R O

79%, 98% ee

30% H2O2, 4 (5 mol%) H

O

47%, 82% ee

Ph

Ph

O [MoO2(acac)2] (2 mol%) 3, cumene hydroperoxide

82%, 87% ee H

Ph

Ph OH Pt P C6F5 Ph Ph

O

95%, 85% ee

Ph

Ph O

C(4-t-Bu-C6H4)3

P

N

CF3SO3 2

N 3

O

OH OH C(4-t-Bu-C6H4)3

H

H N

N Ti

O

O

Ph O

Ph 2

4

The use of supported catalysts to carry out epoxidation reactions has seen considerable activity in the past year. A primary rationale for the use of supported catalysts is the ease in the reuse of the catalyst. The solid supports used range from silica gel to polystyrene. Quinine and other Cinchona alkaloids were linked to a soluble PEG polymer to generate dimeric polymers such as 5 . Reaction of chalcone with 5 using t-BuOOH as the oxidant provides the product epoxide in good yield and with good enantioselectivity. The PEG-linked ligand was reused three times with only minimal degradation in the enantiomeric excess of the product.

72

S.C. Bergmeier and D.D. Reed

O

O

t-BuOOH, 5, KOH, 90%, 86% ee Ph

Ph

Ph

O

Cl

OMe N

H N

N

H N

OH

HO O

N

OMe

Cl PEG2000

Ph

O

5

N

Another method for generating an epoxidation catalyst on a solid support is to simply absorb or non-covalently attach the catalyst to the solid support . Epoxidation of olefin 6 with mCPBA and catalyst 8 provides 7 in quantitative yields and with 89% ee. The immobilization of 8 on silica gel improves the enantioselectivity of the reaction providing 7 with 95% ee. Recycling experiments with silica-8 show a decrease in both yield and the enantiomeric excess for each cycle (45% ee after 4 cycles). This is attributed to a leaching of the catalyst from the silica gel. Two other solid supports, a Mg-Al-Cl-LDH resin (LDH) and a quaternary ammonium resin (Q-resin) were also examined. It was expected that ionic attraction between 8 and the LDH or Q-resin would allow the catalyst to remain immobilized through multiple cycles better than with silica gel. Both of these resins showed improved catalytic properties upon reuse of the catalyst (92-95% ee after 4 cycles). O NC 6

8, mCPBA, 100%, 89% ee silica•8, mCPBA, 100%, 95% ee LDH•8, mCPBA, 100%, 93% ee Q-resin•8, mCPBA, 100%, 97% ee

N

O NC 7

O

N Mn

O3S

O t-Bu

O acac

SO3

t-Bu

8

Vinyl epoxides are highly useful synthetic intermediates. The epoxidation of dienes using Mn-salen type catalysts typically occurs at the cis-olefin. Epoxidations of dienes with sugarderived dioxiranes have previously been reported to react at the trans-olefin of a diene. A new oxazolidinone-sugar dioxirane, 9, has been shown to epoxidize the cis-olefin of a diene . A variety of substitution on the diene is tolerated in the epoxidation, including aryl, alkyl and even an additional olefin. All of these substitutions provided moderate yields of the mono-epoxide with good enantioselectivity.

73


O

O R

oxone, 9 (10-30 mol%), K2CO3

R

O

R = Ph, 66%, R = 85% ee R = nC5H11, 80%, 89%ee R = CO2Et, 64%, 94% ee R = CH=CHCO2Et (trans), 74%, 94% ee

O O

O

N

CH3

O O 9

An exploration of structural modifications on the activity of prolinol catalysts has been published . More electron-rich aromatic rings on the prolinol scaffold improve the activity in the epoxidation of α,β-enones. The reaction of 10 with an enone and t-BuOOH provides the epoxy-ketones with moderate levels of enantioselectivity. Iminoiodinanes are not normally used as epoxidation reagents. An organocatalytic route to epoxides using an iminoiodinane as the oxidant has been reported . The reaction of 11 and NsNIPh with α,β-unsaturated aldehydes provides the target epoxides in excellent yield and with excellent enantioselectivity. A number of other oxidants had been examined with iodosobenzene being the optimal oxidant. However the substrate scope of this oxidant was not ideal. NsNIPh was found to slowly generate iodosobenzene under the reaction conditions and provide wide substrate scope. O

O

Conditions R2

R1

O

R1

R2

Conditions

Substitution

% Yield, % ee

t-BuOOH, hexane, 10

R1 = Ph, R2 = Ph R1 = CH3, R2 = Ph R1 = Ph, R2 = CH2CH2Ph

93%, 89% ee 55%, 83% ee 80%, 71% ee

NsNIPh, 11•HClO4 (20 mol%) R1 = H, R2 = CH3 R1 = H, R2 = Ph R1 = H, R2 = n-C3H7 CH3

OH

O OCH3

N H H3C

88%, 93% ee 92%, 92% ee 72%, 88% ee

CH3 CH3 OCH3

H3C

N

Bn N H

t-Bu 11

10

Sulfur ylides are a classic reagent for the conversion of carbonyl compounds to epoxides. Chiral camphor-derived sulfur ylides have been used in the enantioselective synthesis of epoxy-amides . Reaction of sulfonium salt 12 with an aldehyde and base provides the epoxide 13 in generally excellent yields. While the yield of the reaction was quite good across a variety of R groups, the enantioselectivity was variable. For example benzaldehyde provides 13 (R = Ph) in 97% ee while isobutyraldehyde provides 13 (R = i-Pr) with only 10% ee. These epoxy amides could be converted to a number of epoxide-opened

74


products using fairly standard chemistry. In a particularly interesting transformation, amide 14 was converted to ketone 15 in excellent yield by treatment with an organolithium reagent. Me O S OMe

O

RCHO KOH R = Ph, 93%, 97% ee R = i-Pr, 79%, 10% ee

NEt2

12

R

CONEt2 13 O

O

RLi, -78 °C

O

CONEt2 Cl

R = Ph, 88% R = Me, 81%

14

R

Cl

15

A very interesting organocatalyzed one-pot Michael addition/aldol condensation/Darzens condensation has been reported for the asymmetric synthesis of epoxy-ketones . An initial asymmetric Michael condensation between 16 and 17 is catalyzed by proline derivative 18. Intermediate 19 then undergoes an aldol condensation followed by a stereoselective Darzens condensation to provide epoxy-ketone 20 in moderate yield and with surprisingly good enantiomeric excess.

O O

+

O

O 18, AcONa

Cl

O

Cl

Oallyl

Oallyl

16

O

17

19 O K2CO3, DMF 57% yield 86% ee

O

CF3

TMSO Oallyl

O

N H

CF3

20 F3C

CF3 18

3.2.2

Reactions of Epoxides

The primary type of epoxide reaction remains the nucleophilic ring-opening reaction. Research on the development of novel catalysts or catalytic systems for epoxide opening continues to be a highly active area of study. Epoxides have been found to cleanly react with acetic anhydride to provide the diacetate under solvent-free conditions . Treatment of epoxides with ammonium-12molybdophosphate and a slight excess of acetic anhydride (1.2 equivalents) provides the corresponding diacetate in excellent yields. A number of epoxides were examined and all worked quite well. It was also found that N-tosyl aziridines participate in this reaction providing the corresponding acetoxysulfonamides.

75


O

NTs

Ac2O, (NH4)3[PMo12O40]6 93%

OAc

Ac2O, (NH4)3[PMo12O40]6 93%

OAc

OAc

NHTs

The conversion of epoxides to other three-membered heterocycles is often a multi-step process involving an initial ring opening followed by a ring closure. Two recent reports detail a one step conversion of an epoxide to a thiirane. Treatment of an epoxide with KSCN in PEG-400 provides the corresponding thiirane in excellent yields . A related solvent-free approach uses NH4SCN and catalytic cyanuric chloride to provide the thiirane in equally good yields . O

PEG-400, KSCN, 93% or NH4SCN, cyanuric chloride (2 mol%), neat 90%

S

Typical epoxide ring-opening conditions with amine nucleophiles usually involves some type of acid catalyst. Consequently the development of milder catalysts for use with either sensitive epoxides or sensitive amines is of interest. Ring-opening reaction of epoxides with α-amino acid esters can be catalyzed by Ca(OTf)2 . Reaction of 21 with an alanine ester provides the ring opened product 22 in moderate yields. Of note, the t-butyl ester is retained. This is a significant improvement over previously reported procedures in terms of yields. The products, 22, were prepared as hydroxyethylamine dipeptide isosteres. The use of Al(OTf)3 for the catalysis of epoxide opening by amines has also been reported . O PhO 21

O

+ H N 2 O

R

Ca(OTf)2 PhO CH3CN R = Et, 68% R = t-Bu, 54% R = Bn, 61%

OH

H N

O O

R

22

A polymeric version of Jacobsen’s Cr-salen catalyst has also been reported . This polymeric catalyst worked well with a variety of amines, showed excellent enantio- and diastereoselectivity with an enantiomeric excess of 90-98%. Most importantly the catalyst was reusable with no loss in stereoselectivity of the products. The synthesis of α,α-disubstituted amino acids is a difficult task and continues to attract attention. An efficient route that utilizes the ring-opening of an epoxide with azide has been reported . Treatment of the sulfoxide substituted epoxide 23 with NaN3 provides intermediate azido aldehyde 24. This aldehyde was not isolated but oxidized to the acid and then the azide reduced to provide the α,α-disubstituted amino acid 25. The regioselectivity of this reaction was impressive with only one product reported.

76


O S(O)tol

O O

N3 CHO

NaN3, MeOH/H2O O O

23

1) NaClO2, NaH2PO4 H2O2, 86% 2) H2, Pd/C, 98%

24 NH2 COOH

O O

25

The addition of Grignard reagents or other organometallic reagents to epoxides is a highly useful reaction for monosubstituted epoxides. However, when the epoxide is 2,3disubstituted, the selectivity of the addition is poor and overall yields are generally poor as well. A recent report on the addition of propenyl Grignard to epoxides identifies a set of conditions that improves regioselectivity . In addition, this method provides better yields than the corresponding alkynylalane. The reaction of 26 or 28 with an excess of propenyl magnesium bromide and catalytic CuI provides the ring-opened products 27 and 29 in excellent yield. The reaction, as expected, proceeds with inversion of stereochemistry. A large group, such as a TIPS, is necessary to provide good regioselectivity in the ring opening reaction. When the TIPS group in 26 was replaced with Bn, a 75:25 mixture of regioisomers was obtained.

TIPSO

TIPSO

26

CuI (130 mol%) MgBr (600 mol%)

O

TIPSO

OH 27, 63% TIPSO

28

O

OH

29, 70%

An epoxide ring opening followed by a ring closing has been found to form the important 3-hydroxypyrrolidine ring system . Treatment of amido epoxide 30 with dimethylsulfoxonium methylide initially opens the epoxide ring. The amide anion then closes on the carbon bearing the sulfoxonium group to provide the 3-hydroxypyrrolidine ring 31. Spiro- and bicyclic hydroxypyrrolidines were also prepared from the corresponding cyclic amido epoxides. NHTs

30

O

Me3S(O)I, nBuLi 86%

TsN

31 OH

A Baylis-Hillman type product has been obtained through a ring-opening reaction of an epoxide with an allenoate . The reaction of MgI2 with ethyl propiolate provides the iodo allenoate 32. This nucleophile reacts with an aryl epoxide to provide the homoallylic alcohol 33. The Z iodide is the major product formed.

77


CO2Me

MgO

O

OMe

O

Ar

MgI2

Ar

MeO

•

OH

I

I

Ar = Ph, 78%, 4:1 Z:E Ar = (4-OMe)C6H4, 74%, 5:1 Z:E Ar = 2-Cl-C6H4, 76%, 10:1 Z:E

33

32

The product of the previous reaction provides a Baylis-Hillman type product via an intermolecular addition of an allenoate to an epoxide. The first example of a true MoritaBaylis-Hillman reaction of an epoxide has recently been reported . Treatment of enone 34 with Me3P provides a good yield of the epoxide-opened product 35. The reaction must be carried out at low concentrations in order to avoid the generation of a variety of side products. When the terminal end of the epoxide is substituted (e.g. 34) the exo-mode of cyclization is the only product observed. When the terminal end of the epoxide is unsubstituted (e.g. 36), the endo-mode of cyclization predominates providing 37. O

O

34

OH

O

35, 67%

Me3P, t-BuOH (0.025 M)

O

O

36

O

37, 60%

Epoxides will also participate in radical reactions and this usually results in ring opening of the epoxide. The addition of a radical derived from xanthate 38 to butadiene monoepoxide provides the addition product 39 in good yields as an E/Z mixture of olefins . This reaction presumably proceeds through the addition of the xanthate-derived radical to the olefin, which then opens the epoxide. O

O

O O S

38

OEt

O

O

Et3B, air 82%, E/Z 75:25 39

OH

Epoxides can also be reductively opened to form a radical. An example of an intramolecular cyclization of such a radical has recently been reported . Treatment of 40 with Cp2TiCl generates an intermediate alkoxy radical, which then adds to the carbonyl of the formate ester. The product, 41, is formed as a 2:1 mixture of isomers at the anomeric carbon. This reaction is one of the first examples of a radical addition to an ester. The major byproduct of this reaction is the exo-methylene compound, 42, arising from a β-hydrogen elimination.

78


OH

O Cp2TiCl O 40

OH

OH +

O

H O

O

H

42, 22% O

41, 66%, 2:1 mixture

β-Lactones are highly useful intermediates in organic synthesis and are components of a variety of biologically active molecules. One of the primary routes to β-lactones is the catalytic carbonylation of epoxides. Most carbonylation reactions require fairly high CO pressure (200-900 psi) in order to provide reasonable yields of product. These types of conditions make this reaction not particularly viable in the typical organic laboratory. A Crsalen catalyst has been developed that allows the carbonylation of epoxides to be carried out at only 1 atm. of CO pressure . Catalytic carbonylation of epoxides were performed with only 1 mol % of 43 in 1-2 hours at 100 psi of CO. More impressively, the carbonylation could also be carried out at 1 atm of CO (a balloon) and slightly longer reaction times with 2 mol% of 43. This method was compatible with a number of functional groups including esters, ethers, halides and olefins. THF O

CO (1 atm) 43 (2 mol%) DME

R

O O R

N t-Bu

O

44

R = Me, 96% R = CH2OSiMe2t-Bu, 96% R = (CH2)2CH=CH2, 95%

43

t-Bu

Cr

Co(CO)4

N O

t-Bu

t-Bu THF

Lithiated epoxides have been found to react with a number of different activated electrophiles. A new study examines the reactivity of lithiated epoxides with nitrones to prepare β,γ-epoxyhydroxylamines, 46, and oxazetidine, 47 . Upon deprotonation of styrene oxide, the lithiated reactant was then added to nitrone 45 to form the β,γ-epoxyhydroxylamine 46 in good yield as a single diastereomer. A number of additional nitrones were examined as well and all provided similar yields of the β,γepoxyhydroxylamines. Treatment of 46 with additional base provided the 1,2-oxazetidine ring system 47 in excellent yield. Interestingly, none of the five-membered isoxazolidines from the 5-endo-tet cyclization were formed in this cyclization.

O

Ph

sBuLi, TMEDA THF, -98 °C Ph

NaOH 60 °C 85%

O

Li

Ph

HO O N 47

Ph

t-Bu

t-Bu +

N

Ph 45

O

O 63%

t-Bu

Ph Ph N 46

OH

79


The aza-[2,3] Wittig rearrangement of aziridines is an excellent method for the synthesis of substituted piperidines. The analogous reaction of an epoxide has recently been examined . Reaction of divinyl epoxide 48 with t-butyl diazo acetate provides the ylide intermediate 49, which then undergoes the [2,3] Wittig rearrangement to 50, Several catalysts were examined as catalysts for the formation of 49. It is noteworthy that the copper catalyst performed much better than the more widely used rhodium catalysts. CO2t-Bu

t-BuO2C

O

t-BuO2C

N2

O

O

Cu(hfacac)2 72%

48

49

50

The acid catalyzed rearrangement of an epoxide to an aldehyde or ketone is a useful and widely used reaction. Two useful examples of this rearrangement are reported below. An interesting conversion of a vinyl epoxide to a dihydropyridine has been reported using this rearrangement methodology . Treatment of the ester substituted vinyl epoxide 51 with Sc(OTf)3 catalyzes a ring opening of the epoxide to form an intermediate enol. This enol adds to the imine which subsequently cyclizes to form the dihydropyiridine 53. This reaction is limited by the need for a non-enolizable imine. I

I

O

O

EtO CH3 51

+

Sc(OTf)3 (15 mol%) 5Å MS 51%

N Ph

H

H3C

N Ph CO2Et 53

52

An additional example of an oxonium ion generated via the acid catalyzed rearrangement has been used to prepare a dihydropyran . The oxonium ion 54 generated by the reaction of an epoxide with ZrCl4 can be trapped by a nucleophile such as butynol to prepare dihydropyran 55. A variety of mono- and disubstituted epoxides have been used in this reaction. O

HO

ZrCl4

O

O

ZrCl3

54 Cl

O

67%

O 55

80


3.3

AZIRIDINES

3.3.1

Preparation of Aziridines

Several reviews on the synthesis of aziridines have been published in the previous year. These publications include: a review on the silver catalyzed addition of nitrenes (among other intermediates such as carbene) across a double bond ; a review on sulfur ylide addition to imines to form aziridines ; a review on nitrogen addition across double bonds ; a general review on functionalization of α,β-unsaturated esters with some discussion of aziridination The addition of a nitrogen atom across a carbon-carbon double bond is a powerful method for the synthesis of aziridines in that two bonds are formed in a single step. The large amount of previous knowledge in the stereospecific synthesis of carbon-carbon double bonds also lends great utility to this general route of aziridine synthesis. The reactions of a nitrene, metal nitrene or nitrene equivalent with an olefin continues to attract attention. No doubt due to the potential payoff in terms of a generally universal aziridination method. The use of Rh2(NHCOCF3)4 has been shown to be exceptionally useful in the catalysis of aziridination reactions using trichloroethoxysulfonamide (TcesNH2) as the nitrogen source . The Tces group is readily removed from the final compound. In addition, this aziridination process works well on both styrene as well as aliphatic olefins. This reaction is rare in that similar aziridination methods only work well for styryl olefins. While nitrogen sources such as chloramine-T and PhI=NTs have been used for aziridination reactions, TsNCl2 has not been explored until now. The reaction of TsNCl2 with Pd(OAc)2 and K2CO3 provides the expected N-tosyl aziridines in good yields . This reaction presumably proceeds through an initial amidohalogenation reaction catalyzed by palladium. The chloroamide is then converted to the aziridine via an intramolecular substitution reaction. Gold-based catalysis has attracted considerable attention in recent years. A gold-catalyzed aziridination reaction has recently been reported . A series of gold catalysts were examined for their ability to catalyze the aziridination of styrene with pnitrophenylsulfonamide (NsNH2). Styrene and phenyl-substituted styrenes provided the Nnosyl aziridines in good to excellent yields. Cinnamate however provided the aziridine product in only 25% yield. The use of other sulfonamides (e.g. tosyl, trichloroethyl) gave much lower yields of the aziridine product. Diphenylphosphorylazide (DPPA) has also been shown to be an excellent nitrene source in aziridination reactions . The reaction of styrene and substituted styrenes with DPPA and tetraphenylporphyrin cobalt (CoTPP) provided the N-diphenylphosphinyl aziridines in moderate yields. The use of metal-catalyzed aziridination methods with chiral ligands has also been reported. The copper-based system paired with ligand 56 provides the expected cinnamyl aziridine in good yield and excellent ee . It is interesting to note that the t-butyl ester is obtained with 99% ee while the smaller methyl ester is obtained in only 88% ee. The binaphthyl ruthenium catalyst 57 has been found to aziridinate a number of olefins with moderate enantioselectivity . Both p-nitrophenyl (Ns) and trimethylsilyloxy (SES) sulfonamides work well with this catalytic system. As is usually seen, the aziridination of aliphatic olefins proceeds in only 32% yield and 56% ee.

81


R2

R2 R1

conditions

R3 Conditions

R1

R3

N R4

Yield

Rh2(NHCOCF3)4 (1 mol%), PhI(OAc)2 R1 = Ph, R2 = H, R3 = Me, R4 = Tces, 85% Cl3CCH2OSO2NH2, MgO R1 = Me, R2 = Me, R3 = (CH2)2CH(Me)(CH2)2OH, 70% Pd(OAc)2 (2 mol%), K2CO3, TsNCl2

R1 = Ph, R2, R3 = H, R4 = Ts, 70%

[Au(tBu3Tpy)]OTf (3 mol%), NsNH2

R1 = Ph, R2, R3 = H, R4 = Ns, 88% R1 = Ph, R2 = H, R3 = CO2Me, R4 = Ns, 25%

CoTPP (10 mol%), (PhO)2P(O)N3

R1 = Ph, R2, R3 = H, R4 = P(O)(OPh)2, 50%

[Cu(MeCN)4]ClO4, 56, PhINTs

R1 = Ph, R2 = H, R3 = CO2tBu, R4 = Ts, 99%, 99% ee (2S,3R) R1 = Ph, R2 = H, R3 = CO2Me, R4 = Ts, 97%, 88% ee (2S,3R)

NsN3, 57 (0.1 mol%) NsN3, 57 (2 mol%) SESN3, 57 (0.1 mol%)

R1 = Ph, R2, R3 = H, R4 = Ns, 70%, 81% ee R1 = n-C6H13, R2, R3 = H, R4 = Ns, 32%, 56% ee R1 = Ph, R2, R3 = H, R4 = SES, 26%, 91% ee

O

O Ar = 3,5-Cl2-4-(CH3)3SiC6H2

Cl

N

N

Cl

N CO N Ru O O Ar Ar

Cl

Cl 56

57

Non-metal catalyzed aziridinations have also been reported. These methods are often more broadly applicable than the metal-catalyzed methods. The use of N-methylpyrrolidine-2-one hydrotribromide (MPHT) and chloramine-T is an effective route for the synthesis of N-tosyl aziridines . The aziridination of olefins using t-BuOI and sulfonamides appears to be a general method for aziridination . The t-BuOI is prepared in situ from tBuOCl and NaI. This is a broadly applicable method in that a wide variety of sulfonamides (tosyl, nosyl, SES) can be used with roughly equivalent yields. R2

R2 conditions

R1 Conditions

R1

N R3 Yield

MPHT (10 mol%), Chloramine-T

R1 = Ph, R2, R3 = H, R4 = Ts, 85%

t-BuOCl, NaI, TsNH2 t-BuOCl, NaI, TsNH2 t-BuOCl, NaI, o-NsNH2 t-BuOCl, NaI, SESNH2

R1 = Ph, R2 = Me, R3 = H, R4 = Ts, 81% R1 = n-C6H13, R2, R3 = H, R4 = Ts, 77% R1 = Ph, R2, R3 = H, R4 = o-Ns, 66% R1 = Ph, R2, R3 = H, R4 = SES, 97%

82


The ability to directly prepare N-H aziridines through the addition of nitrogen to an olefin is quite rare. A recent report provides a method for the conversion of chalcones to the corresponding N-H aziridines . The use of the hydrazinium salt 58 as a nitrogen transfer agent in combination with base proved to be a synthetically useful method for the synthesis of aziridine 59. Hydrazinium salt 58 can be readily prepared as either the iodide or nitrate salt, although the iodide synthesis was more convenient. The counterion of the hydrazinium salt as well as the base used were shown to be important factors. For electronrich aryl groups the iodide salt and t-BuOK gave significantly better yields. O

O

O base

Ph

Ar

X

N H2N

CH3 58

Ar Ar Ph Ph p-MeOC6H4 p-MeOC6H4

X I NO3 I NO3

Ph 59 Yield (%) 61 95 56 2

HN

Base t-BuOK NaOH t-BuOK NaOH

Intramolecular aziridination reactions overcome many of the inherent limitations associated with intermolecular aziridinations. The ring strain associated with the resulting bicyclic aziridines leads to increased reactivity and instability. Sulfamate-linked bicyclic aziridines can be readily prepared using rhodium catalysis . Treatment of sulfamate 60 with Rh2(oct)4 and PhIO provides sulfamate-linked fused-ring aziridine 61. The stereoselectivity was moderate in this cyclization and was explained by a chair-like transition state that minimized gauche and A1,3 interactions. Interestingly the seven-membered ring 62 could also be formed in good yield and with improved diastereoselectivity.

O

O2 S

NH2

Me

Rh2(oct)4 (2 mol%) PhI(OAc)2, MgO 84%, 4:1

60 O

O2 S

Me 61

NH2

TBSO

O

O2 S

SiMe3

Rh2(NHCOCF3)4 (2 mol%) PhI(OAc)2, MgO 66%, 10:1

N H

O SO 2 N TBSO

H

SiMe3

62

Allylic carbamates have also been cyclized to carbamate-linked fused-ring aziridines. The cyclization of homoallylic carbamates to the corresponding aziridines has not been successful until a recent report . The reaction of homoallylic carbamate 63 with a rhodium catalyst and iodosobenzene provides moderate yields of the fused-ring aziridine 64. The major byproduct of this reaction is the C-H insertion product 65. The relative amounts of the aziridine to the C-H insertion product could be modulated by the choice of rhodium catalyst. The use of Rh2(OAc)4 provides a 68:14 ratio of aziridine : C-H insertion product, while Rh2(oct)4 provides a slightly better 71:6 ratio.

83


O O

O NH2

O

O NH

N

63

64 Rh2(OAc)4, PhIO Rh2(oct)4, PhIO

O

H

65

68 71

14 6

The conversion of azidoformates to fused-ring aziridines via the thermal generation of a nitrene has previously been reported. More recently, the photolytic conversion of a sugarderived azidoformate has been used to prepare fused-ring aziridines . Photolysis of azidoformate 66 at 254 nm provides aziridine 67 in excellent yield. The resulting bicyclic aziridine was reduced to provide oxazolidinone 68 in 95% yield. Oxazolidinone 68 was subsequently converted to L-daunosamine. OCH3 O

OCH3

O O

hν (254 nm) 79%

O O

N3 66

O

N O

OCH3

O

H2, Pd/C 95%

NH O

67

68

The synthesis of aziridines though an aza-Darzens or Darzens-like approach is a conceptually useful method for the formation of two bonds of an aziridine ring in a single reaction step . There are of course a number of variations on this theme. One very useful approach is the addition of a sulfur ylide to an imine. The addition of S-allyl derived sulfur ylides has been shown to be a good route to diastereomerically pure vinyl aziridines . The reaction of the chiral N-sulfinyl imine 69 with an S-allyl sulfur ylide provides aziridines 70 and 71 in good yield as a 25:75 mixture. The diastereomeric excess of the major isomer (71) was >95%. t-Bu

Me

N Ph

O

S tBu

69

S Me tBuOLi THF 72% ratio 70:71, 25:75

S N

O

t-Bu

Me

S N

O

Ph

Ph 70

71

The intramolecular addition of sulfur ylides to imines (e.g. 72) has proven to be an excellent route to fused-ring aziridines (e.g. 73) . The addition of a sulfonamide to a vinylsulfonium salt leads to the formation of the sulfur ylide 72. The ylide then undergoes an intramolecular addition to form the product fused-ring aziridine 73. This method has also been used for the synthesis of fused-ring epoxides.

84


O

O N S t-Bu

O

S t-Bu NH

SPh2

S t-Bu N NHTs

N Ts

NaH

N

O S

t-Bu

68%

SPh2

N Ts

N Ts 72

73

The addition of halomethyl metal reagents provides another Darzens-like route to aziridines . Reaction of ICH2Cl with MeLi generates a chloromethyllithium reagent, which then adds to the imine 74. A subsequent intramolecular N-alkylation provides the aziridine 75. The isolation of a chloromethyl ketone byproduct demonstrated that the chloromethyllithium reagent is operative as opposed to a carbene.

OMe

N

ICH2Cl, LiBr, MeLi 97%, d.r. 87:13

O

N

OMe

N O

N

74

75

A new methodology for the synthesis of aziridines via an intramolecular cyclization reaction at nitrogen has been reported . Typical ring closing methods for the formation of aziridines rely upon a basic nitrogen displacing a leaving group on a beta-carbon as in the approaches above. The conversion of a hydroxylamine to an O-acyl hydroxylamine renders this nitrogen relatively electrophilic. Formation of the enolate of 76 initiates a 3-exotet ring closure by reaction of the nucleophilic enolate carbon upon the electrophilic Oacylated nitrogen. The yields of this process are quite good. The reaction also proceeds with very good diastereoselectivity, providing 77 and 78 in a 90:10 mixture. The reaction has also been shown to proceed with a chloramine .

Ph

N

76

Ph

OCOtBu LHMDS, -20 °C 93% CO2tBu

Ph N

N CO2tBu

77

90 : 10

CO2tBu 78

One of the most well used methods for the synthesis of aziridines involves a two (or sometimes more) step process in which an epoxide is opened by a nitrogen nucleophile. The resulting β-amino alcohol (e.g. 79) is then converted to an aziridine via a number of different processes. This method is generally not broadly applicable when a variety of different groups on the nitrogen of the aziridine are desired. A useful method to convert an epoxide to a number of different N-sulfonyl aziridines (e.g. 80) has been reported . Simple addition of a sulfonamide to an epoxide provides high yields of 79 which is readily closed to form the aziridine.

85


1.2 equiv. RSO2NH2 0.1 equiv K2CO3 0.1 equiv BnNEt3Cl dioxane, 90 °C

O

OH N H

SO2R

79

R = 4-MeC6H4, 91% R = t-Bu, 83%

1) 5 equiv Pyridine 5 equiv MsCl CH2Cl2, reflux 2) 4 equiv K2CO3 CH3CN, 45 °C R = 4-MeC6H4, 82% R = t-Bu, 77%

N SO2R 80

A rather interesting approach to aziridines involves a reductive ring-opening of an azetidinone followed by ring closure . Treatment of 81 with LiAlH4 leads to an intermediate amino alcohol. This is followed by the subsequent formation of the aziridine ring via displacement of the adjacent halogen to form 82. Cl BnO

OBn

5 equiv LiAlH4

HO

N O

H

R 81

3.3.2

N R

R = i-Pr, 57% R = Bn, 62% R = allyl, 43%

82

Reactions of Aziridines

The reactions of aziridines (like epoxides) are largely dominated by nucleophilic ring opening reactions. In the past year two reviews that cover ring opening reactions of aziridines have been published, including a review on ring opening reaction of aziridines with carbon nucleophiles , and a review on the reactions of N-sulfonylaziridines which includes discussion of their ring opening reactions. The reaction of aziridines with oxygen nucleophiles is a common route to vicinal amino alcohols. The use of aldehydes as oxygen nucleophiles has been reported as a route to acyloxy amines . N-Heterocyclic carbenes (NHC) have also been used to catalyze the ring opening of aziridines by carboxylic acid anhydrides to produce 83 in moderate yields . The same NHC has also been reported to catalyze the opening of aziridines by TMSX reagents where X = N3, Cl, and I . NHTs NHC, RCHO K2CO3 18-crown-6 50 °C, air R = Ph, 70% R = CH3, 75% NHC, (RCO)2O 80 °C R = CH3, 96% R = Ph, 91%

NTs

O O

R

NHC =

N

N

83

Amino sugars are important component of mono- and disaccharides that lend themselves well to synthesis through aziridine opening reactions. Glycal derived aziridines have been found to be useful intermediates for the synthesis of 4-amino-2,3-unsaturated sugars . Epoxide 84 was converted to the trans-dimesylate 85 through a series of standard transformations. Treatment of 85 with base and an excess of a glycosyl acceptor, 87, provides the glycoside 88 in excellent yield. The aziridine 86 was not isolated due to its

86


reactive nature. A number of simply glycosyl acceptors such as MeOH and i-PrOH were examined in this reaction and provided the expected 1,4 addition products in high yield. It is quite impressive that the use of a monosaccharide such as 87 as the glycosyl acceptor also provides the product in very good yields. O

BnO

3 steps

O

BnO

84

85 O

HO

BnO O

O O

73%

MsN

NHMs

O

O

BnO

MsO

O

+

t-BuOK

86 O

O

O

O O

O

MsHN

O

87

88

Typically, the stereospecific formation of quaternary centers is as problematic as selective nucleophilic attack at the more substituted carbon of aziridines. Interestingly, a copper mediated methodology has been reported that does both . Although N-tosyl aziridines show favorable results, N-nosyl aziridines gave the best results. The reaction of 89 with a variety of phenols yielded 90 in moderate yields. O OH N Ns

N H

CO2t-Bu + R

R

O

CuOAc, DBU toluene

O

R = H, 64% R = OMe, 59% R = CHO, 71%

89

N H NHNs

CO2t-Bu

90

Another problem with the reaction of phenols with aziridines is the selectivity between Oalkylation vs C-alkylation. A recent report has identified that the use of (ArO)3B selects for C-alkylation . Most of the examples reported in this paper showed less than 5% of the O-alkylation product. What is interesting about this report is the stereochemistry of the product. While the mechanism is not known, the product is formally an SN1 type product. Generally less than 5% was the product of inversion of configuration (the SN2 product). In addition to the N-tosyl, both the N-Cbz and N-Dpp aziridines gave excellent yields of aziridine-opened product.

NTs Ph

B

O +

3

73% Ph

OH NHTs

Typically in ring-opening reactions of aziridines, the amine functional group is retained in the product molecule. An example of such a reaction where the amine group has been lost has recently been reported . An intramolecular Friedel-Craft reaction of aziridine 91 leads to the expected product as an intermediate. Under the rather drastic reaction conditions, the sulfonamide is lost leading to formation of the naphthalene ring.

87


CO2Me NTs

91

H3C

CO2Me

H2SO4 (300 mol%) benzene, reflux 85%

NHTs

92

H3C CO2Me

CO2Me

NHTs

CH3

93

94

CH3

It has been found that N-tosyl aziridines undergo oxidative addition to palladium complexes to form azapalladacyclobutanes . Reaction of aziridine 95 with Pd2(dba)3 and 1,10-phenanthroline provides the palladacycle 96 in 45% isolated yield. This compound is an air stable solid. Treatment the palladacycle 96 with catalytic CuI is believed to open the palladacycle to form a copper intermediate, which cyclizes to cyclopentyl alkylpalladium intermediate 97. Loss of CuI then provides the product palladacycle 97 as an air stable solid. Several different aziridines were examined in this reaction. Only a limited set of olefin substituted aziridines provided the azapalladacyclobutanes (e.g. 96). NTs 95

(phen) Pd I N Cu Ts

Pd2(dba)3 (50 mol%) 1,10-phenanthroline (phen) 45%

Ts N

Pd(phen)

CuI (20 mol%) 72%

96

Pd(phen) I N Cu Ts

-CuI N Pd(phen) 97 Ts

A novel C-3 functionalization of methylene aziridines has also been reported . Selective deprotonation of 98 to form 99 and the reaction 99 with an electrophile yielded 100 in good yields. In this way, a variety of alkyl groups could be selectively placed on the aziridine. These researchers also found that (S)-α-methylbenzyl substituted methylene aziridines, 101, when deprotonated and reacted with a variety of electrophiles gave 102 in moderate yields and with good diastereoselectivity.

88


Bn N

Bn N

s-BuLi, TMEDA

Bn N

Electrophile

Li

R

98

99

100 MeI PhCHO TMSCl Cl(CH2)4I

Me

H

Ph

Me

N

H

s-BuLi, TMEDA Electrophile

Ph

Electrophile R MeI Me Ph2CO Ph2COH TMSCl TMS

N R

101

R %Yield Me 79 PhCHOH 74 TMS 63 Cl(CH2)4 70

%Yield 47 43 80

%de 80 88 90

102

In an extension of previous work, additional examples of fused-ring aziridines were prepared through the cycloamination of olefins with an aziridine nitrogen . Fused-ring aziridines 104 and 105 were obtained through the cycloamination of aziridine 103. While 104 and 104 were obtained as an ~3:1 mixture, they were converted to exocyclic olefin 106 in excellent yields. These fused-ring aziridines will react with a variety of nucleophiles providing cyclic imine 107 in excellent yields. H O N ( )n 103

Br

Ph

N

H

( )n

N

Br

O

N

O

KOH MeOH/THF

104

105 Ph Ph n = 1, 98%, 104:105 = 74:26 n = 2, 88%, 104:105 = 78:22 O

H

( )n

H

( )n

NBS

Ph

( )n

Nu O H3C

106 Ph n = 1, 99% n = 2, 95%

N H 107

Nu

n = 1, TMSN3, Nu = N3, 99% n = 1, H2, Pd/C, Nu = H, 99% n = 1, MeOH, HBF4, Nu = OMe, 99% n = 2, TMSN3, Nu = N3, 81% n = 2, H2, Pd/C, Nu = H, 82%

In a related example, a cycloamination of an olefin was carried out with an N-t-butyl aziridine to prepare morpholine derivatives . Upon an initial bromoamination reaction an aziridinium ion 110 is formed. This readily undergoes ring opening with bromide to form dibromomorpholine 111. While this is an interesting reaction, it does not appear to be general, as other groups on the nitrogen provided little to no product. Br

Br NBS

N O

N O

O

Br 108

109

N

N

Br

110

43% Br

O 111

89


Researchers have found that the reduction of a variety of aziridine esters yields the corresponding aziridine aldehyde which dimerizes diastereoselectively . The reduction of 112 with excess DIBAL yields the dimer 113, which is in equilibrium with the monomer 114. This molecule reacts as the monomer and both reduction to 115 or reductive amination to 117 proceed in quantitative yields. In a very interesting reaction, treatment of 113 with N-benzyl tryptamine provides the pentacyclic 116 in excellent yield. H N

H N Ph

CO2Et

DIBAL (200 mol%) 83%

Ph

112

H

H

H N

O OH

N

Ph H

113

CHO 114

Ph H N OH

Ph 115

NaBH4 100%

N-benzyltryptamine -20 °C, toluene 94% (20:1, syn:anti) Bn N H

NaCNBH3 aniline 100%

H N NHPh

Ph 117

H Ph

N

H

N H H 116

The reactions of N-acyl aziridines can sometimes involve nucleophilic attack at the acyl group rather than the aziridine ring. This change in the more typical pattern of reactivity is dependent on a number of factors. An example of this type of change in reactivity has recently been reported . Treatment of 118 with benzylamine provided a low yield of 119, the product of nucleophilic attack at the carbonyl. An examination of reaction conditions found that the use of a Lewis acid and a coordinating solvent such as Et2O or THF provided significantly better yields of 119. O

OBn

O BnNH2

N F3C

CO2Et 118

Solvent (temp.) ClCH2CH2Cl (reflux) THF (reflux) Et2O (reflux)

Lewis acid Yield none 25% Yb(OTf)3 (20 mol%) 52% BF3•Et2O (100 mol%) 67%

NHBn N

F3C

CO2Et 119

In a highly unusual reaction, treatment of 120 with an organolithium reagent provides amine substituted homoallylic alcohol 122 . This reaction presumably proceeds via a metalation/ring opening sequence to generate intermediate 121. This then undergoes a beta-elimination to 122. A number of other examples were also reported.

90


Li O

NTs

RLi

R

O NLiTs

120

3.4

121

R HO

NHTs

R = nBu, 82% R = Ph, 69% R = CH2SiMe3, 92%

122

REFERENCES

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92

Chapter 4 Four-membered ring systems Benito Alcaide Departamento de Química Orgánica I. Facultad de Química, Universidad Complutense de Madrid, 28040-Madrid, Spain [email protected] Pedro Almendros Instituto de Química Orgánica General, CSIC, Juan de la Cierva 3, 28006-Madrid, Spain [email protected] ______________________________________________________________

4.1

INTRODUCTION

The importance of four-membered heterocycles in many fields of Science (including Organic Chemistry, Inorganic Chemistry, Medicinal Chemistry, and Material Science) can hardly be overemphasized, and justifies a long lasting effort to work out new synthetic protocols. Condensing the vast amount of published material to less than 20 pages is an extremely demanding task. This, obviously, can only be done by strict selection and by applying a very dense style of writing. Oxygen- and nitrogen-containing heterocycles, in particular β-lactams, dominate the field in terms of the number of publications. This chapter covers selected relevant aspects in this area. 4.2

AZETIDINES, AZETINES, 3-AZETIDINONES, AND DIAZETINES

2-(1-Adamantyl)-2-methyl-azetidines have been synthesized and tested for their antiviral activity against influenza, being markedly active against influenza A H2N2 virus . The biological activities of an aqueous fraction extracted from Polygonatum odoratum of L-2-azetidinecarboxylic acid 1, purified from the extract, on the growth of several types of algae have been tested . Electrophilic amination of ketones and aldehydes in the presence of dibenzyl azodicarboxylate in dichloromethane, using L-2azetidinecarboxylic acid 1 as a catalyst, has been described . The structure of 3fluoroazetidinium hydrochloride 2 has been explored both by X-ray diffraction analysis and DFT calculations, and the conformation of this molecule was shown to be significantly influenced by the through space C–F N+ interaction . Aqueous phosphoric acid (85 wt%) is an effective, environmentally benign reagent for the deprotection of tert-butyl carbamates, including tert-butyl 1-benzhydrylazetidin-3-ylcarbamate 3 . The structure-property relationship of aminonitrofluorenes such as azetidine derivative 4, synthesized by copper-mediated Ullmann-type C–N bond formation between the free amine and the corresponding iodoarene, has been described . tert-Butyl hypoiodite (tBuOI) has been found to be a powerful reagent for the cyclization of N-alkenylamides leading to a variety of N-heterocycles, including 2-(iodomethyl)-1-tosylazetidine 5, under extremely mild conditions .

93


F

CO 2H

BocHN

I N

+

N

N

N H H

1

2

H Cl

3

NO2

Ph

– Ph

N

Ts

5

4

N,N'-Carbonyldiimidazole-mediated cyclization of amino alcohols to substituted azetidines has been developed . N-Tosyl-3-halo-3-butenylamines underwent efficient Ullmann-type coupling with the catalysis of CuI/N,N'-dimethylethylenediamine to afford 2-alkylideneazetidines 6, which could be readily converted into the corresponding βlactams by oxidation with O3 . 6-Vinyl oxazinanones undergo catalytic, diastereoselective, decarboxylative ring contraction to form vinyl azetidines 7 in good yield . N-(Alkylidene or 1-arylmethylidene)-2-propenylamines have been regiospecifically functionalized to novel N-(alkylidene or 1-arylmethylidene)-3-bromo-2fluoropropylamines, which proved to be excellent precursors for 3-fluoroazetidines 8 . The one-pot formation of 1,3-disubstituted azetidines via the reaction of amine nucleophiles with in situ prepared bis-triflates of 2-substituted-1,3-propanediols have been demonstrated . O X

NHTs

Ts

i N

R

R

Ts

N

R2 O

R3

R4

6 (86–99%)

R1

R2

ii

R3

R1

H

R2

F

N

Ts

N

R1

8

R4 7 (60–93%)

o

Key: i) CuI, DMEDA, dioxane, 100 C. ii) 5 mol% Pd(PPh3)4, CH2Cl2, RT. The use of monochloroalane has been shown to be an efficient method for the reduction of 4-aryl-3,3-difluoro- as well as trans-2-aryl-3-chloro-β-lactams to their corresponding azetidines 9 . The resulting chloroazetidines were excellent building blocks for the synthesis of different 3-substituted azetidines through nucleophilic substitution of the chlorine by different carbon, nitrogen, sulfur and oxygen nucleophiles in good to high yields . Azetidine-2-carboxylic acid 10 has been obtained by treating a trichloromethyl ketone-derived Mannich adduct with aqueous NaOH in 1,2-dimethoxyethane. The reaction is considered to proceed via a gem-dichlorooxirane intermediate. Intramolecular ring opening affords the azetidine ring . Enantio- and diastereomerically pure cis-2,3-disubstituted azetidinic amino acid derivatives have been obtained by intramolecular anionic ring-closure . The electroreduction of an aromatic imino ester prepared from (S)-glutamic acid in the presence of chlorotrimethylsilane and triethylamine afforded the four-membered cyclized product 11, a mixed ketal of cis-2,4-disubstituted azetidine-3-one, stereospecifically . The application of N-ferrocenylmethyl azetidin-2-yl(diphenyl)methanol in the asymmetric ethylation and arylation of arylaldehydes has been described . R2

X Y O

N

i Y

R1

O Ph2P

R2

X N

NH

OH

Ph

R1

CCl3

9 (82–97%)

Ph

TMSO

N HO2C

PPh2 O

N Ph

10 (72%) o

o

OMe

CO2Me

ii

Key: i) AlH2Cl, Et2O, 34 C (X = Cl), 0 C (X = F). ii) aq. NaOH, DME, RT.

11

Bz

94

B. Alcaide and P. Almendros

Pyranoid and furanoid spiro-N-mesyl azetidines, a new type of water-soluble spiro-Cnucleoside, have been prepared from easily available sugar spiroacetals . The first results concerning thermally induced and silver-salt-catalyzed [2+2] cycloadditions of imines to (alkoxymethylene)cyclopropanes to afford spirocyclic azetidines 12 have been published . A two-step reaction sequence using a one-pot Į-aminoallylation reaction followed by ring-closing metathesis to make a diverse collection of spirocyclic diamines, including azetidines, has been developed . The dominant secondary fragmentation of a series of 1,3-di- and 1,2,3-trisubstituted N-arylhexahydropyrimidines under electron impact has been described to involve loss of imines or azetidines . The treatment of an oxopiperazino-β-lactam with BH3·SMe2 in THF under reflux gave rise to the bicyclic azetidine 13 as the major product . The crystalline cis,cis,cis,cis-[5.5.5.4]-1-azafenestrane borane adduct 14 has been efficiently isolated using a Mitsunobu reaction as the key cyclization step followed by treatment with BF3·Et2O . Triplet-sensitized irradiation of 8-thia-9-azatricyclo[7.2.1.0]dodeca2,4,6,10-tetraenes in acetone solution gives rise exclusively to tetracyclic sultams bearing a bridgehead azetidine ring . The synthesis of novel 1',2'-azetidine-fused bicyclic pyrimidine nucleosides and their transformations to the corresponding phosphoramidite building blocks for automated solid-phase oligonucleotide synthesis has been reported . It has been shown that the reaction of azetidines with chloroformates gives highly functionalized γ-chloroamines in high yields and selectivities under mild reaction conditions . The ring opening of activated cyclic amines, including fourmembered, followed by an intramolecular expansion of cyclopropanol to cyclobutanone via a carbocation intermediate has been reported. In the case of a N-tosylazetidine ester, the cyclobutanone 15 was formed by treatment of the crude Kulinkovich product with CaSO4 . A formal [4+2] cycloaddition of 2-aryl-N-tosylazetidines with nitriles in the presence of Zn(OTf)2 has been described for the synthesis of substituted tetrahydropyrimidines . N-Activated 2-phenylazetidines have been opened regioselectively at the benzylic carbon with various allylsilanes or propargylsilane in the presence of BF3·Et2O, providing amino olefins . The carbonylative polymerization of azetidines catalyzed by [Co(CH3CO)(CO)3P(o-tol)3], and the participation of the tetrahydrofuran solvent in the polymerization to give ester units in the polymer products has been described

. Insights into the regioselective nucleophilic ring-opening of azetidinium ions has been reported . It has been shown that efficient ring expansions, selectively leading either to pyrrolidines or to azepanes through [1,2] or [2,3] sigmatropic shifts, respectively, can be performed from 2-alkenylazetidinium salts . OR1

OR1

R2 +

H

R4

N

i

N R3

R2

N

OH

N

– BF3 +N

Bn

H

H

R3

ii N Ts

12 (71–97%)

13 o

14

NHTs ( )2

CO 2Et

O 15 (70%)

4

Key: i) 10 mol% Ag(fod), MeCN, 30 C. R = 2,5-Dimethoxyphenyl. ii) (a) ClTi(O-i-Pr)3, EtMgBr, THF, RT; (b) CaSO4, CH2Cl2, RT. The direct, stereoselective conversion of alkynes to N-sulfonylazetidin-2-imines 16 by the initial reaction of copper(I) acetylides with sulfonyl azides, followed, in situ, by the formal [2+2] cycloaddition of a postulated N-sulfonylketenimine intermediate with a range of imines has been described . The synthesis of N-alkylated 2-substituted azetidin-3-ones 17 based on a tandem nucleophilic substitution followed by intramolecular Michael reaction of primary amines with alkyl 5-bromo-4-oxopent-2-enoates has been

95


achieved . 1-Benzhydryl-3,3-difluoroazetidin-2-thione has been prepared and converted into γ-aminodithioesters . The [2+2] cycloaddition of an N-acyl-2azetine to dichloroketene has been described as a new entry to azetidines fused to cyclobutanes . The conversion of 4-vinyl-substituted β-lactams into 4-vinylsubstituted 1-azetines 18 and their subsequent reaction with diphenylcyclopropenone resulted in the formation of a highly functionalized 7-azabicyclo[4.2.1]nonene . The Xray structure of an azetine-containing Ni(II) porphyrin derivative has been elucidated . The preparation of 1,2-diazetidines 19 from 1-(1-hydroxypropan-2yl)hydrazine-1,2-dicarboxylate under very mild conditions has been accomplished . The regioselective acylation reactions of Δ2-1,2-diazetines 20 as well as their rearrangements into 4H-1,3,4-oxadiazines or pyridazines have been reported . It has been proposed that azetine and Δ3-1,2-diazetine intermediates may be involved in the thermolysis of aza-enediynes . A stereoselective synthesis of 4hydroxyalkyl-1,2-oxazetidines 21, based on the addition of α-lithiated aryloxiranes to nitrones and subsequent cyclization of the corresponding intermediates in a 4-exo-tet mode, has been described . NSO2R4

R3 R

2

N

N

R 16

4.3

1

CO2R2

O

17

2

R1

R

N R1 18

HO R1

R2

SEt

1

ArHN

N N R

R

1

19

NHAr

R2 Ph

Ar

N N

O N

20

21

R3

MONOCYCLIC 2-AZETIDINONES (β-LACTAMS)

The polymer-supported and combinatorial synthesis of β-lactams has been reviewed . A review on the synthesis of new classes of heterocyclic C-glycoconjugates including C-glycosyl β-lactams by asymmetric multicomponent reactions has appeared . The asymmetric synthesis of active pharmaceutical ingredients including βlactams such as ezetimibe and SCH 58053 has been reviewed . An overview on recent developments in isocyanide based multicomponent reactions in applied chemistry including β-lactam formation, has appeared . Ketene chemistry including ketene-imine cycloadditions to form β-lactams, has been reviewed . A review on the biocatalytic preparation of β-amino acids including the ring opening of β-lactams, has appeared . A convenient and general method of synthesis of NH-β-lactams via Grubbs’ carbene-promoted isomerization of the respective N-allyl β-lactam followed by RuCl3-catalyzed enamide cleavage has been developed . The [2+2] carbonylative cycloaddition of substituted imines with allyl bromide leading to heteroaryl βlactams has been reported . The reaction of enantiopure 4oxoazetidine-2-carbaldehydes with unmodified ketones catalyzed by L-proline or D-proline has been reported to give the corresponding γ-amino-β-hydroxy ketones 22 . The synthesis of the novel carbapenem precursor (1'R,3S,4S')-3-[1'-(tertbutyldimethylsilyloxy)ethyl]-4-(cyclopropylcarbonyloxy)azetidin-2-one has been described . Ethyl difluoro(trimethylsilyl)acetate and difluoro(trimethylsilyl)acetamides have been used as precursors of 3,3-difluoroazetidinones . The activation of the C–Cl bond of (E)-α-chloroalkylidene-β-lactams via the Suzuki cross-coupling reaction to achieve 2-azetidinones 23 has been reported . The diruthenium-catalyzed formation of β-lactams via carbenoid C–H insertion of α-diazoacetamides has been described . The synthesis of novel N-sulfonyl β-lactams by Staudinger cycloaddition has

96


been achieved . Results on chiral induction during photocyclization within achiral zeolites of α-oxoamides to β-lactams have been presented . A model that explains the relative stereoselectivity in the Staudinger reaction based on a kinetic analysis of the cis/trans ratios of reaction products has been proposed . The effects of solvents, additives, and pathways of ketene generation on the stereoselectivity of the Staudinger reaction have been investigated . Staudinger reaction of ethoxycarbonyl(phenylthio)ketene with various imines and subsequent desulfurization reactions have been employed to synthesize 3-ethoxycarbonyl β-lactams . The γ-heteroatom directed stereocontrolled Staudinger cycloaddition reaction of vinylketenes and imines has been achieved . The diastereoselective synthesis of trans-β-lactams on soluble polymer support has been described . Functionalization of N[(silyl)methyl]-β-lactam carbanions with carbon electrophiles to give 2-azetidinones 24 has been reported . Experimental and theoretical evaluation of the unexpected four-membered (phosphono-β-lactams 25) over six-membered ring formation during the synthesis of azaheterocyclic phosphonates has been documented . 2

R

H H

OH O

Ar 2

R

R3 N O

N

R1

O

22

X

2

R N

R1

E

O

23

O P(OR2)2

O

R1

Cl

1

N

R

Ph i

N

P(OR2)2 O

Ph

24

O

R1

25 (62–90%)

Key: i) NaH, THF, Δ. β-Lactam analogs of combretastatin A-4 have been synthesized and their cytotoxic effects have been evaluated in vitro against L1210 leukemia . The design, synthesis, and antibacterial activity of 4-alkylidene-azetidin-2-ones 26 as new antimicrobial agents against multidrug-resistant pathogens have been reported . (Benzothiazol-2'-yl)azetidin-2-one derivatives have been prepared and screened for antibacterial and antifungal activities . Several pyrimidine-based 2azetidinones have been synthesized and tested for their antibacterial, antifungal and antituberculosis activities against different microorganisms . β-Lactam– dihydrofuran hybrids 27 have been prepared by a novel palladium(II)-catalyzed heterocyclizative cross-coupling of two different α-allenols . The synthesis of 3-(aryl)alkenyl-β-lactams by application of olefin cross-metathesis on solid support has been reported . The synthesis of 3-phenylthio β-lactams has been carried out using α-diazocarbonyl compounds as precursors of ketenes . A Lewis acidmediated method for the C3 epimerization of 3-halo-3-phenylthio-β-lactams has been developed . The stereoselective synthesis of cis- and trans-3-alkoxy-3phenyl/benzylthioazetidin-2-ones has been described . β-Lactams 28 have been isolated as the major products of the reaction of dimethoxycarbene with isocyanates . O MeO

O

O

RO

CO2Bn OMe

MeO OMe

H H 3

2

R

R

N

N H

O

O

26

Key: i) RN=C=O, chlorobenzene, heat.

1

R

27

4

R

N N

O

i

OMe OMe OMe N R O

MeO

28 (49–68%)

97


Azetidin-2,3-diones have been used as synthons for the stereoselective synthesis of cis- and trans-C3-alkyl/aryl azetidin-2-ones . It has been reported that the threecomponent reaction of N-substituted hydroxylamines, aldehydes, and phenylacetylene catalyzed by Cu(I) under neat conditions afforded the corresponding β-lactams 29 . The reactions of nitrones with terminal alkynes (Kinugasa reaction), catalyzed by a chiral iPr-trisoxazoline/Cu(ClO4)2·6H2O complex in air, afforded β-lactams in reasonable yields with up to 85% ee . The direct, palladium-catalyzed, multicomponent synthesis of 3-amido-substituted β-lactams 30 from imines, acid chlorides, and carbon monoxide has been accomplished . 4-Oxoazetidin-2-yl benzoate has been resolved by an inclusion complexation with a chiral host compound, (R,R)-(í)-trans4,5-bis(hydroxydiphenylmethyl)-1,4-dioxaspiro[4.5]decane . The Rh(II)catalyzed intramolecular C–H insertion of diazoacetamides in water to afford β-lactams has been mentioned . The reaction of N-acylimidazoles possessing an electronwithdrawing group in the α position with diarylimines produces β-lactams 31 in high yields . Studies on the effects of the distance between the aromatic rings and the αstereogenic reaction center on the memory of chirality of β-lactams derived from phenylalanine have been performed . The synthesis of C3 unsymmetrically disubstituted azetidin-2-ones by Lewis acid mediated functionalization of β-lactams as well as a mechanistic study have been published . The generation of acyloxyketenes from unstable mesoionic 1,3-dioxolium-4-olates and their reaction with ketenophiles to give [2+2] cycloadducts, including β-lactams has been reported . A strategy for the synthesis of differently C3-substituted β-lactams involving the reaction of β-lactam carbocation equivalents with active substrates in the presence of a Lewis acid has been described . A new route to enantiopure 4-aryl-substituted β-lactams through lipase-catalyzed enantioselective ring cleavage of the corresponding racemic β-lactams has been developed . The enantioselective synthesis of trans-β-lactams using a chiral auxiliary under Reformatsky reaction conditions has been described . A new class of glycoconjugated β-lactams has been accessed by direct glycosidation of a suitable 4alkylidene-azetidin-2-one acceptor with several perbenzylated (N-phenyl)trifluoroacetimidate donors activated by catalytic Yb(OTf)3 . The synthesis and biological evaluation of azido- and aziridino-hydroxy-β-lactams through stereo- and regioselective epoxide ring opening have been reported . O

Ph

+ R1 CHO

i

3

R1

Ph

2 N O

Me

29 (55–95%)

R2

N

+ R 3COCl H

N

R

R1

ii

R1

R2 N O

R2

EWG

R1

O

30 (27–66%)

Ar N Ar 31

Key: i) MeNHOH·HCl, 5 mol % CuCl, 2,2'-bipyridine, KHCO3, NaOAc, neat, 70 oC. ii) 1.4 mol% Pd2(dba)3·CHCl3, iPr2EtN, MeCN/THF (1:1), 55 oC. β-Lactams have been used as a synthon for the preparation of a vast array of compounds. It has been reported that the reduction of 4-(haloalkyl)azetidin-2-ones with LiAlH4 is a powerful method for the synthesis of stereodefined aziridines and azetidines . However, reduction of 4-(haloalkyl)azetidin-2-ones with chloroalane afforded 2-(haloalkyl)azetidines, which were rearranged to 3,4-cis-disubstituted pyrrolidines and piperidines 32 . During these rearrangements, bicyclic azetidinium intermediates were formed which were ring opened by halides. The synthesis of a peptide-

98


deformylase inhibitor has been described using as the key transformation the aminolysis of a β-lactam . Reductive ring opening of 2-azetidinones promoted by sodium borohydride gives 3-aminopropane-1,2-diols . The stereoselective conversion of 2-azabicyclo[2.2.0]hex-5-en-3-one into aminodienes has been described . Using a sodium methoxide/methanol system, an unprecedented domino β-lactam ring opening–allene cyclization reaction gives pyrroles 33 . An enzymatic method has been developed for the synthesis of enantiomeric benzocispentacin and its six- and sevenmembered homologues through the lipase catalyzed enantioselective (E>200) ring opening of bicyclic β-lactams . The ring opening of β-lactam-fused pinenes gave γ-amino alcohols, which have been used as catalysts for the enantioselective addition of diethylzinc to aldehydes . A novel procedure has been developed for the preparation of 2,3disubstituted 4,1-benzothiazepines, via the ring transformation of a β-lactam . X X ( )n

R2O N O

R1

i ii

R2O

2

R ( )n

N R1

N O

OP

R3 H

Ph

iii

R1

32 (44–98%)

R2 MeOOC

Ph

R3 N R1

33 (50–54%)

Key: i) AlH2Cl, Et2O, RT. ii) MeCN, reflux. iii) MeONa, MeOH, RT.

4.4

FUSED AND SPIROCYCLIC β-LACTAMS

A review on antibacterial natural products including β-lactam formation has appeared . β-Lactamase nomenclature has been reviewed . New approaches to the inhibition of metallo-β-lactamases as well as their use as novel weaponry for antibiotic resistance in bacteria have been reviewed . A review on the application of alicyclic β-amino acids in peptide chemistry including enzymecatalyzed ring opening of cycloalkane fused β-lactams has been published . An overview on free radical chemistry including fused β-lactams has appeared . Large-scale oxidations in the pharmaceutical industry including β-lactams have been reviewed . The synthesis and biological activity of spiro β-lactams incorporating quinones have been reported . The Cu(I)-catalyzed coupling of spiranic β-lactams with (E)-2-chlorovinyliodides or (E)-2-bromovinyliodides producing the corresponding β-haloenamides has been accomplished en route to chartellines . In work directed toward a total synthesis of chartelline A, a strategy investigated to construct the 10-membered ring of this marine alkaloid was an intramolecular aldehyde/spiro-β-lactam cyclocondensation to form the macrocyclic enamide functionality . A biosynthetically inspired and strategically designed 10-step sequence synthesis of (±)chartelline C has been reported . The synthesis of spiro-linked β-lactamdihydropyridines 34 through the cyclization of lithiated pyridine carboxamides has been achieved . The utility of the spiro β-lactam 35 in the preparation of peptidomimetics as analogues of melanostatin was demonstrated . The chirospecific synthesis of spirocyclic β-lactams and their characterization as potent type II βturn inducing peptide mimetics have been accomplished . Thermolysis of spiro[β-lactam-4,2'-oxadiazolines] in the presence of aryl isocyanates

99


afforded both N-lactam and O-lactam substituted spiro[azetidine-2-one-4,3'-indol-2'-one] derivatives . O R N

R' Br

N

X

E

O

Cl X

N Br N H

N N

N

But Ph

Y

Ph

i ii

N O

Y

N H O

t

Bu

N

PMP

35

34 (39–91%) R = R' = Br (chartelline A) R = R' = H (chartelline C)

Key: i) LDA, –40 oC. ii) E–Cl. Spiranic β-lactams have been prepared by the reaction of N-protected cyclic keteneN,S-acetals with vinyl isocyanates . The synthesis of spiro-β-lactams through halogen-mediated intrasulfenyl cyclization of cis-3-benzylthio-3-(prop-2-ynyloxy/-enyloxy)β-lactams has been achieved . The one-pot three-component reaction for the direct conversion of certain alkylhydroxylamine hydrochlorides (alkyl = benzyl, pmethoxybenzyl, benzhydryl, tert-butyl), formaldehyde or an alkyl glyoxylate and bicyclopropylidene to furnish the 3-spirocyclopropanated 2-azetidinones 36 has been developed by microwave heating . The acid-catalyzed fragmentative rearrangement of tricyclic isoxazolidines yields cyclopropane-fused β-lactams . The highly diastereoselective synthesis of fused oxopiperazino-ȕ-lactams 37 by Staudinger reaction between functionalized ketenes and 5,6-dihydropyrazin-2(1H)-ones has been carried out .

R 1CHO + R 2 NHOH.HCl +

R1

R1

R2 N O

R2

R2

H

O N

i

N

N O

36 (49–78%)

O

Bn OTBDMS

1

R

37

Key: i) NaOAc, EtOH, MW. The synthesis of a series of macrocyclic bis-β-lactam derivatives via a highly stereoselective [2+2] cycloaddition has been described . Di-exo-3-amino-7oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid, five aldehydes and two isocyanides were reacted both in methanol and in water to prepare a 10-membered ȕ-lactam library via a Ugi4-centre-3-component reaction . 4-Formyl-1-(2- and 3-haloalkyl)azetidin-2-ones have been prepared as valuable starting materials for the synthesis of different optically active bicyclic azetidin-2-ones, such as piperazine and 1,4-diazepane annulated β-lactam derivatives 38 . A synthetic route to β-lactam-fused enediynes involved an intramolecular Kinugasa reaction . A β-lactam-azasugar hybrid (polyhydroxylated carbacephem) has been designed and synthesized as a potent glycosidase inhibitor . 7-Amino- and 2-ethoxycarbonyl-5-dethia-5-oxa-cephams were prepared from 1,3-alkylidene-l-erythritol . Synthetic approaches towards a new class of strained lactenediynes, compounds where a 10-membered enediyne ring is fused with a ȕ-lactam have been described . The stereoselective synthesis of functionalized tricyclic ȕ-lactams via intramolecular nitrilimine cycloaddition has been achieved . Strained tricyclic β-lactams 39 were prepared via intramolecular

100


[2+2] cycloaddition reactions in 2-azetidinone-tethered enallenols with control of the regioselectivity by choice of alkene substitution .

R1 O N O

i

O

R 1O N

ii ( )n

X

N O

R2

R1 O

H H

OH

R2 iii

R 1O

N ( )n

H H

OH

R2

N

O

O

38 (41–87%)

39 (52–57%)

2

Key: i) R NH2, MgSO4, CH2Cl2, RT. ii) NaBH4, MeOH, reflux. iii) Toluene, 220 oC, sealed tube. New C-3' hydroxamate-substituted and more lipophilic cyclic hydroxamate cephalosporin derivatives were preppared as a potential new generation of selective antimicrobial agents . The positive effect of natural and negatively charged cyclodextrins on the stabilization of penicillins towards β-lactamase degradation due to inclusion and external guest–host association has been studied . The first step of the deacylation reaction of benzylpenicillin in the E. coli TEM1 β-lactamase has been modelled . A strategy for the solid-phase synthesis of penicillin derivatives has been reported . Studies on the hydrolysis of oxacillin have been carried out . A theoretical proposal for the synthesis of carbapenems from 4-(2propynyl)azetidinones promoted by [W(CO)5] as an alternative to the Ag+-assisted process has been reported . A stoichiometric molecularly imprinted polymer for the class-selective recognition of β-lactam antibiotics in aqueous media has been described . An amide derived from penicillin V and racemic (R/S)-2-aminobutanol has been prepared and shows significantly higher toxicity than the pure diastereomers . The synthesis and siderophoric activity of conjugates of methyl 6aminopenicillanate with biscatechol-hydroxamate chelators have been reported . An efficient method for the deprotection of tert-butyldimethylsilyl ethers was TiCl4-Lewis base complexes; it was applied in the synthesis of 1β-methylcarbapenems . The reactivity of cephalosporin sulfones has been studied . 4.5 OXETANES, LACTONES)

DIOXETANES,

OXETENES

AND

2-OXETANONES

(β-

Ketene chemistry including ketene-aldehyde cycloaddition to form β-lactones and ketene-alkene cycloaddition to form oxetanes has been reviewed . It has been reported that the attachment of the oxetane motif to molecular scaffolds results in remarkable improvements of key physicochemical characteristics and provides valuable opportunities for property-guided drug discovery . Oxetanes have also been utilized as synthons for the preparation of different compounds. The synthesis of 5-hydroxyfunctionalized 2-trifluoromethyl-1-alkenes was achieved by 1-(trifluoromethyl)vinylation via oxetane ring-opening . A convenient route to tetrahydropyran-based liquid crystals from oxetane precursors has been described . The asymmetric synthesis of γhydroperoxyalkanols involved regiospecific and stereoselective acid-promoted opening of oxetanes with hydrogen peroxide. This was used as the core of the first asymmetric synthesis of 1,2-dioxolane-3-acetic acids 40 . An aniline glycosyl carbamate spacer linked to the 2'-OH of paclitaxel has been obtained . The synthesis of 7- and 10-spermine conjugates of paclitaxel and 10-deacetyl-paclitaxel were synthesised as potential

101


prodrugs . Noncytotoxic taxanes as novel antituberculosis agents have been discovered . A 4-methyl-5-oxo docetaxel analogue was prepared starting from 10-deacetylbaccatin III . Bridging converts the noncytotoxic nor-paclitaxel derivative 41 into the cytotoxic analogue 42 by constraining it to the T-taxol conformation . AcO O R

AcO

O OH

O OH

O O

8 steps

O

R OH

CO2 H

O O

H PhCH 2 OO

40 (12–36%)

O

OH

O

OAc

PhCH 2ON H

H PhCH 2OO

PhCH2 ON H

O O

O

41

42

A C,D-seco-paclitaxel derivative was prepared from taxine and tested for biological activity . A 36-step synthesis has been carried out in automated synthesizers to provide a synthetic key intermediate for taxol . The bicyclic oxetane 43 which was obtained by the [2+2] photocycloaddition (Paternò-Büchi reaction) of a methylthymine derivative with benzaldehyde, showed, in model studies, efficient photosensitized splitting of thymine oxetane units by covalently linked tryptophan in high polarity solvents . The Paternò-Büchi reaction of 1,3-dimethylthymine or 1,3-dimethyluracil with benzophenone and its six 4,4'-disubstituted derivatives generated two series of regioisomeric oxetanes, head-to-head and head-to-tail isomers . The efficient photosensitized splitting of the thymine dimer/oxetane unit on its modifying β-cyclodextrin by a binding electron donor has been reported . Thymine oxetanes have been tested as charge traps for chemical monitoring of nucleic acid mediated transfer of excess electrons . The pathways of excess electron transfer in DNA with flavindonor and oxetane-acceptor modified DNA hairpins 44 has been investigated . A temperature effect on the stereoselectivity in the Paternò–Büchi reaction of 2,3dihydrofuran-3-ol derivatives with benzophenone was noted . A new terpenoid, the tricyclic oxetane amentotaxone, has been isolated from Amentotaxus formosana . The spirocyclic oxetane lactone 45 has been synthetized . An oxetane-fused benzene was proposed as intermediate in the mass spectrometric fragmentation of even-electron negative ions from hydroxyphenyl carbaldehydes and ketones . O

O HN O

i

HN O

N CO2Bn

O N

O

O

Ph H CO2Bn

43 (21%)

NH

O Ph Ph O

N

NH 44 G

O

H NH

G=

N

O

H O

R1O

OR

2

45

O O

Key: i) PhCHO, hν, MeCN, RT. An acid-catalyzed ring-closing ynamide-carbonyl metathesis, which would proceed through ring opening of an amide-substituted oxetene intermediate 46 formed through a stepwise hetero [2+2] cycloaddition pathway, has been described . The synthesis of tetrasubstituted enol ethers by E-selective olefination of esters with ynolates has been reported to occur via lithiated oxetene species . A dioxetane-based selective chemiluminescent probe for singlet oxygen has been employed to detect and

102


quantify singlet oxygen in the reactions of superoxide with organic peroxides . The synthesis and fluoride-induced chemiluminescent decomposition of bicyclic dioxetanes substituted with a 2-hydroxynaphthyl group have been described . The synthesis of dioxetane 47 has been achieved during abortive attempts to synthesize ent-premnalane A . Bicyclic dioxetanes bearing a 2-hydroxy-1,1ƍ-binaphthyl-5-yl moiety are active towards intramolecular charge-transfer-induced chemiluminescent decomposition . Color modulation for intramolecular charge-transfer-induced chemiluminescence of bicyclic dioxetanes bearing a 3-hydroxy-5-naphthylphenyl moiety in the coordination sphere has been reported . 4-(3-tertButyldimethylsilyloxyphenyl)-4-methoxyspiro[1,2-dioxetane-3,2ƍ-adamantane] was synthesised by two different approaches . The dioxetanone intermediate 48 was isolated in studies on the possible biogenetic precursors of pyrrole-2-aminoimidazole alkaloids . A dioxetanone intermediate has been proposed as supporting the bioluminescence mechanism for the chemiexcitation process to generate the singlet-excited state of neutral oxyluciferin . A spirocyclic dioxetanone intermediate was proposed in investigations of the unimolecular reactivities of a range of perbenzoate anions in the gas phase by electrospray ionization tandem mass spectrometry . R 3OC

O

N

O

R2

O

O

H O

O O

i Y

O

N

O O

R1

46

O N H

H

H

47

48

Key: i) O2, hν, CH2Cl2, RT. The structure and absolute configuration of the unusual fused β-lactone-type metabolite vibralactone 49, which was found to inhibit pancreatic lipase with an IC50 of 0.4 μg/mL, from the cultures of the Basidiomycete Boreostereum vibrans have been established by spectroscopic and computational methods . A detailed mechanistic investigation of epoxide carbonylation by the catalyst [(salph)Al(THF)2]+ [Co(CO)4]– (salph = N,N'-o-phenylenebis(3,5-di-tert-butylsalicylideneimine), THF = tetrahydrofuran) to form βlactones has been carried out . A readily prepared Cr–Co bimetallic catalyst is capable of effecting epoxide carbonylation to produce β-lactones at substantially lower CO pressures than previously reported catalyst systems . A chiral oxazaborolidinecatalyzed enantioselective synthesis of β-lactones from ketene and aldehydes has been developed . A catalytic asymmetric synthesis of 3,4-dialkyl-cis-β-lactones, inhibitors of the thioesterase domain of fatty acid synthase, via a sequential ketene dimerization/hydrogenation process has been achieved . 3-Alkylidene-oxetan2-ones 50 have been prepared in good to excellent yields, with high Z-selectivity, by olefin cross metathesis with 3-methyleneoxetan-2-ones in the presence of Ru-based second generation metathesis catalysts . Molecular recognition of lactones, including βlactones, can be achieved by inclusion complexation with optically active hosts derived from tartaric acid . The Walden cycle which interconverts the stereochemical configurations of chlorosuccinic and malic acids involves a β-lactone intermediate rather than an α-lactone intermediate because the Onuc C Cl angle in the transition structure for the former (174°) is more favorable than that for the latter (139°), as determined by a computational study . An efficient chiron approach to the total synthesis of (–)-

103


tetrahydrolipstatin 51 starts from tri-O-acetyl-D-glucal, and uses copper-mediated C–C bond formation, Frater alkylation, and Barton-McCombie deoxygenation . Stereoselective syntheses of (–)-tetrahydrolipstatin have been achieved via two divergent approaches through Prins cyclizations as the key steps . The stereoselective synthesis of (–)-tetrahydrolipstatin via a radical cyclization based strategy has also been reported . An expeditious enantioselective total synthesis of valilactone has been accomplished . Concise syntheses of valilactone and a two-carbon transposed orlistat derivative employed a tandem Mukaiyama aldol-lactonization process as a key step . An efficient protocol has been developed using D-(2R)-Oppolzer sultam as a chiral auxiliary for generating anti/syn diastereomers with high enantiopurity and were utilized in an efficient synthesis of natural product belactosin C 52 and its synthetic congeners . A concise and straightforward 14-step total synthesis of (±)salinosporamide A 53 has been described . Enantioselective total syntheses of lactacystin β-lactone 54 have been achieved . The reaction of acryloyl chloride with an amino ketone in the presence of pyridine produces a bicyclic β-lactone rather than the corresponding acrylamide, which can be the major product under other conditions . A diastereoselective organonucleophile-promoted biscyclization process provides access to bicyclic- and tricyclic-β-lactones bearing tertiary carbinol centers and quaternary carbons and employed keto acid substrates . A synthetic strategy for construction of the novel spiro-bicyclic ȕ-lactone-Ȗ-lactam system present in oxazolomycin has been demonstrated . The ȕ-lactone nucleus has been used as a synthon for the preparation of different compounds such as (–)deoxyharringtonine , the C7–C20 fragment of amphidinolide B , and (–)-pironetin . SN2' Ring opening of a β-lactone has provided the requisite pyrrole-substituted allene for the enantioselective total synthesis of (–)-rhazinilam , while ring opening of amino β-lactones yielded α-amino acids . Yttrium initiators have been used for the polymerization of racemic β-butyrolactone . Different syntheses of functionalized β-keto esters have been carried out starting from 4-methyleneoxetan-2-one . HO

nC6H13 1

R H

O

O

O

O

51 O

N H

H N HO2C

Cl

O NH

NH2 O

52

O

OHCHN

50 (55–94%)

O

O

nC11H23

O O

49

O

R

R2

i

O

O O

R2 +

1

OH

O 53

NH

H

O

OH

O 54

O

Key: i) 5 mol% Ru-based cat., CH2Cl2, reflux. 4.6

THIETANES, β-SULTAMS, AND RELATED SYSTEMS

A stereoselective one-pot synthesis of substituted 1,2-thiazetidine 1,1-dioxides (βsultams) 55 started from heterocyclic pentafluorophenyl (PFP) sulfonates .

104


Thermolysis of the pentacoordinate 1,2-thiazetidine 1-oxide 56, which was synthesized for the first time and characterized by X-ray crystallographic analysis, gave the corresponding aziridine 57 and a cyclic sulfinate almost quantitatively . O

O S

HO O N

PFPO R

H H

i

F3 C

R

F3 C

O S N O 55 (26–58%)

H Ph CF3 CF3 O S N Ph O

F3C F3 C

+ Ph

57 (94%)

56 o

F3C CF 3

Ph N

ii

O S O (quant)

o

Key: i) Mo(CO)6, MeCN–H2O, 90 C. ii) Toluene, 160 C, sealed tube. Four-membered spironucleosides, including the spiroannulated thietane 58 were synthesized . Various D- and L-thietanose nucleosides which have showed moderate anti-HIV activity were synthesized from D- and L-xylose . A synthesis of isothiazolidines 60 via sulfonium ylides formed by the reaction of thietanes 59 and nitrene has been achieved . The 2-(diphenylmethylene)thietan-3-one 61 reacted with 1,2,4,5-tetrazines in KOH/MeOH/THF to give 4H-pyrazolo[5,1-c]thiazines . A model for the prediction of the homolytic bond dissociation enthalpy and adiabatic ionization potential of fused four-membered heterocycles, including benzothiete 62, has been developed using calculations at B3LYP/LANL2DZ level . S

Ph O

O O

BnO 58

Ar

Ar S

+ PhI NTs

59

O

Ph

i N Ts S 60 (56–67%)

S 61

S 62

Key: i) Cu(acac)2, benzene, reflux. 4.7

SILICON AND PHOSPHORUS HETEROCYCLES. MISCELLANEOUS

The preparation and reactivity of heterocyclic compounds with a silicon atom and another non-adjacent different heteroatom including 1,3-oxasiletane, 1,3-azasiletane, 1,3thiasiletane, and 1,3-phosphasiletane have been reviewed . An overview on novel silicon-based reagents for organic synthesis including silacyclobutanes and 1,3disilacyclobutanes has appeared . 3,4-Dibromo-1,2,3,4-tetrakis(di-tertbutylmethylsilyl)cyclotetrasilene 63 was prepared in 81% yield by reduction of the corresponding tetrabromocyclotetrasilane with 2.1 equivalents of KC8 in THF . Calculations on a series of polycyclic silicon molecules confirm that the introduction of a double bond into four-membered cyclic silanes lowers the ring strain by the cyclic delocalization of π-electrons through hyperconjugation with the σ bonds . The first thermally stable four-membered heterocycle chlorosilylene 64 has been synthesised and characterized . The four-membered heterocycle 65 has been prepared and unambiguously identified by multinuclear NMR spectroscopy . Nickel-catalyzed ring opening reaction of silacyclobutanes 66 with aldehydes afforded the corresponding alkoxyallylsilanes 67, while ring expansion of benzodimethylsilacyclobutene with aldehydes occurred under nickel catalysis to give oxasilacyclohexenes . Oxidation of benzylidene acetals that incorporate a siletane ring at the para position creates a deprotection pathway without affecting other important chemical properties of the benzylidene acetal .

105


t-Bu2 MeSi

Si

Si

Br Si t -Bu 2MeSi

SiMet -Bu2

Si Br SiMet -Bu 2

Tip Tip Tip Si Si

Cl

t -Bu N

Si N

Ph

t -Bu

63

64

R3

R2 Si R1 R1 66

Sn Si Tip Tip Tip

+ R 3CHO

65 Tip = 2,4,6-triisopropylphenyl

i

R1 Si R1

O

R2 67 (47–87%)

Key: i) Ni(cod)2, PPh2Me, toluene, 100 oC. The structure of a four-membered phosphapalladacycle has been established by a single-crystal X-ray structural analysis . The thermal conversion of the cyclic carbodiphosphorane 68 into 1,2-λ5-azaphosphete 69 proceeds almost quantitatively and regioselectively . The reaction of aryl nitriles with [1,3,2,4]diselenadiphosphetane (Woollins' reagent) 70, followed by water affords a variety of primary arylselenoamides in 60–100% yield . A single-crystal X-ray diffraction study of a bicyclic four-membered phosphorus-containing product showed the bicycle to adopt envelope-type topology . A 1,3,2-λ5-oxazaphosphetidine reaction intermediate, in which the P–O bond order is 0.47, has been found on studying the aza-Wittig reaction between phosphazenes and aldehydes . It has been postulated that betaine 71 can be formed upon treatment of the corresponding iminophosphorane with phenyl isocyanate through an abnormal aza-Wittig reaction . Various other fourmembered azaphosphaheterocyclic intermediates have also been proposed . The fragmentation of C-amino four-membered phosphorus ylides to carbenes has been proposed . The preparation and characterization of the air-tolerant 1,3diphosphacyclobuten-4-yl radical 72 has been achieved . A fluorous analogue of Lawesson's reagent for thionation of carbonyl compounds has been developed and its use demonstrated on a series of amides, esters, and ketones . Several structures of cationic P–S–halogen cages containing a four-membered heterocycle have been characterized . R N – + – + NR2 P NR N P 2 N R Ph 68

N i

N P R Ph

R NR 2 P NR 2 N 69

Se Se P Ph Ph P Se Se 70

Me Me

CO2 Et

N PPh 3 N Ph O 71

t-Bu

Mes P P

Mes 72

o

Key: i) Benzene, 80 C, 60h. Mes = 2,4,6-t-Bu3C6H2. N-Sulfonyl aziridines underg oxidative addition to palladium(0) complexes resulting in azapalladacyclobutane complexes 73, which after intramolecular carbopalladation in the presence of copper(I) iodide gave azapalladabicyclo[3.2.1]octanes . A titanacyclobutane has been proposed as intermediate in the olefin cyclopropanation with the Ti–Mg–CCl4 system . The existence of oxaarsetanes 74 during an arsa-Wittig reaction has been proved by 1H and 17O NMR spectroscopy . The syntheses, structures, and thermolyses of pentacoordinate 1,2-oxastibetanes, which are considered as formal [2+2]-cycloadducts in the reaction of a stibonium ylide and a carbonyl compound, have been described . A tricyclic intermediate containing a four-membered metallacycle has been proposed for the Rh-catalyzed alkylation-cycloaddition of 3-haloalkyl1,6-enynes . A planar metallacycle bearing a relatively short Hf–Sb bond has been study by X-ray diffraction . Reversible alkene extrusion from platinaoxetanes has been reported . Synthetic and structural studies of germanacycle 75 have been reported . Homogeneus, titanocene-catalyzed

106


dehydrocoupling of amine-borane adducts into four-membered azaboracycles has been accomplished . Formation of (bistriphenylphosphine)-2-(2,2,4,4tetramethylpentan-3-ylidene)-1,3-dithiolato-platinum 76 and its X-ray crystallographic analysis have been carried out . Synthesis and X-ray analysis of the 1,2dialuminacyclobutene 77 have been published . The synthesis of an Nheterocyclic carbene–Pd(II) four-membered complex and its application in the Suzuki and Heck-type cross-coupling reaction have been documented . Intramolecular C–H activation reactions of molybdenacyclobutanes have been performed . Formation of aluminacyclobutenes via carbon monoxide and isocyanide insertion has been accomplished . Experimental results have shown that Ti2 reacts with N2 to give a D2h-symmetric Ti2N2 molecule which has a planar, cyclic structure with alternating Ti and N atoms . Studies on ruthenium metallacycles derived from 14-electron complexes as possible olefin metathesis intermediates have been carried out . The reaction of phosphaalkenes with electrophiles has provided an effective route to 1,3diphosphetanium salts containing a P2C2 ring . Ph Pd(phen) AsPh3 N O R2 R1 Ph 73 74

Dipp N N Ge Dipp Cl 75

phen = 1,10-phenanthroline

Dipp = 2,6-i-Pr2C6H3

4.8

t-Bu

t-Bu

S Pt(PPh3)2 S

Me3Si

Ar Al Al

Me3Si

t-Bu 76

Ar 77

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06JOC9229 06JOC9628 06MI1 06MI49 06MI109 06MI203 06MI370 06MI544 06MI917 06MI1123 06MI2114 06MI2203 06OBC193 06OBC206 06OBC291 06OBC846 06OBC1297 06OBC2576 06OBC2845 06OBC4059 06OBC4178 06OBC4533 06OL7 06OL231 06OL483 06OL753 06OL1093 06OL1101 06OL1105 06OL1323 06OL1717 06OL1779 06OL1983 06OL2139 06OL2301 06OL2421 06OL3121 06OL3211 06OL3709 06OL3335 06OL3923 06OL3927

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110 06OL3983 06OL4335 06OL4363 06OL4497 06OL4625 06OL4783 06OL4943 06OL5251 06OL5325 06OL5365 06OL5501 06OL5513 06OL5749 06PS2483 06S115 06S128 06S514 06S633 06S659 06S1781 06S1829 06S2327 06S2885 06S3297 06S3425 06SL201 06SL781 06SL1113 06SL1125 06SL2039 06SL3179 06SL3443 06SL3888 06T915 06T1565 06T4128 06T4491 06T5054 06T5313 06T5808 06T5831 06T6289 06T6882 06T7747 06T7799 06T7951 06T8291 06T10497 06T10928


S. Tang, C. Yang, P. Brodie, S. Bane, R. Ravindra, S. Sharma, Y. Jiang, J.P. Snyder, D.G.I. Kingston, Org. Lett. 2006, 8, 3983. S. Baktharaman, S. Selvakumar, V.K. Singh, Org. Lett. 2006, 8, 4335. H. Henry-Riyad, C. Lee, V.C. Purohit, Daniel Romo, Org. Lett. 2006, 8, 4363. G. Ma, M. Zancanella, Y. Oyola, R.D. Richardson, J.W. Smith, D. Romo, Org. Lett. 2006, 8, 4497. N. Kano, Y. Daicho, T. Kawashima, Org. Lett. 2006, 8, 4625. S.A. Testero, E.G. Mata, Org. Lett. 2006, 8, 4783. V. Gnanadesikan, E.J. Corey, Org. Lett. 2006, 8, 4943. G. Hua, Y. Li, A.M.Z. Slawin, J.D. Woollins, Org. Lett. 2006, 8, 5251. G. Arnott, J. Clayden, S.D. Hamilton, Org. Lett. 2006, 8, 5325. H. Lu, C. Li, Org. Lett. 2006, 8, 5365. M. Vargas-Sánchez, S. Lakhdar, F. Couty, G. Evano, Org. Lett. 2006, 8, 5501. A.K. de K. Lewis, B.J. Mok, D.A. Tocher, J.D. Wilden, S. Caddick, Org. Lett. 2006, 8, 5513. D.-Z. Liu, F. Wang, T.-G. Liao, J.-G. Tang, W. Steglich, H.-J. Zhu, J.-K. Liu, Org. Lett. 2006, 8, 5749. A.K. Khalafallah, N.A.A. El-Kanzi, H.A. Soleiman, M. Younis, Phosphorus, Sulfur Relat.Elem. 2006, 181, 2483. D.K. Tiwari, V.K. Gumaste, A.R.A.S. Deshmukh, Synthesis 2006, 115. R. Nadano, J. Ichikawa, Synthesis 2006, 128. J. Fleischhauer, R. Beckert, J. Weston, M. Schmidt, H.-J. Flammersheim, H. Görls, Synthesis 2006, 514. R. A. Youcef, C. Boucheron, S. Guillarme, S. Legoupy, D. Dubreuil, F. Huet, Synthesis 2006, 633. L. Jiao, Y. Liang, Q. Zhang, S. Zhang, J. Xu, Synthesis 2006, 659. E.L. Bastos, L.F.M.L. Ciscato, D. Weiss, R. Beckert, W.J. Baader, Synthesis 2006, 1781. S.-Z. Jian, Q. Yuan, Y.-G. Wang, Synthesis 2006, 1829. S. Lacroix, V. Rixhon, J. Marchand-Brynaert, Synthesis 2006, 2327. J. Fleischhauer, R. Beckert, W. Günther, H. Görls, Synthesis 2006, 2885. D.B. Boggián, E.G. Mata, Synthesis 2006, 3297. M. Sarkar, A. Samanta, Synthesis 2006, 3425. A. Zhou, L. Cao, H. Li, Z. Liu, C.U. Pittman Jr, Synlett 2006, 201. M. Sivaprakasam, F. Couty, G. Evano, B. Srinivas, R. Sridhar, K.R. Rao, Synlett 2006, 781. Q. Yuan, S.-Z. Jian, Y.-G. Wang, Synlett 2006, 1113. M. Marradi, A. Brandi, A. de Meijere, Synlett 2006, 1125. W. Van Brabandt, N. De Kimpe, Synlett 2006, 2039. X. Jiang, K. Prasad, M. Prashad, J. Slade, O. Repiþ, T.J. Blacklock, Synlett 2006, 3179. M.-C. Wang, W.-X. Zhao, X.-D. Wang, M.-P. Song, Synlett 2006, 3443. J.S. Yadav, K.V. Rao, A.R. Prasad, Synlett 2006, 3888. F.J. Sayago, M.A. Pradera, C. Gasch, J. Fuentes, Tetrahedron 2006, 62, 915. L. Troisi, L. Ronzini, C. Granito, L. De Vitis, E. Pindinelli, Tetrahedron 2006, 62, 1565. N. Kanomata, S. Yamada, T. Ohhama, A. Fusano, Y. Ochiai, J. Oikawa, M. Yamaguchi, F. Sudo, Tetrahedron 2006, 62, 4128. Y. Naruse, J. Ma, K. Takeuchi, T. Nohara, S. Inagaki, Tetrahedron 2006, 62, 4491. A. Bhalla, S. Madan, P. Venugopalan, S.S. Bari, Tetrahedron 2006, 62, 5054. I. Margaros, T. Montagnon, M. Tofi, E. Pavlakos, G. Vassilikogiannakis, Tetrahedron 2006, 62, 5313. N. Hoshiya, N. Fukuda, H. Maeda, N. Watanabe, M. Matsumoto, Tetrahedron 2006, 62, 5808. A. Liljeblad, L.T. Kanerva, Tetrahedron 2006, 62, 5831. T. Chen, J. Gao, M. Shi, Tetrahedron 2006, 62, 6289. B. Van Driessche, W. Van Brabandt, M. D'hooghe, Y. Dejaegher, N. De Kimpe, Tetrahedron 2006, 62, 6882. F.A. Macías, V.M.I. Viñolo, F.R. Fronczek, G.M. Massanet, J.M.G. Molinillo, Tetrahedron 2006, 62, 7747. R. Schobert, A. Stangl, K. Hannemann, Tetrahedron 2006, 62, 7799. G. Rousseau, L. Blanco, Tetrahedron 2006, 62, 7951. A. Bhalla, P. Venugopalan, S.S. Bari, Tetrahedron 2006, 62, 8291. B.L. Ashfeld, S.F. Martin, Tetrahedron 2006, 62, 10497. T.T. Danh, K. Borsuk, J. Solecka, M. Chmielewski, Tetrahedron 2006, 62, 10928.


06T12064 06T12424 06TA199 06TA1319 06TA1678 06TA2216 06TA2672 06TL425 06TL1019 06TL1109 06TL1117 06TL1737 06TL2205 06TL2209 06TL2527 06TL2667 06TL3701 06TL3875 06TL4393 06TL4601 06TL4995 06TL5255 06TL5257 06TL5393 06TL5665 06TL5883 06TL5993 06TL6031 06TL6057 06TL6377 06TL6835 06TL7893 06TL7923 06TL8407 06TL8503 06TL8855 06TL8911 06TL8977 06TL9113

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Chapter 5.1

Five-membered ring systems: thiophenes and Se/Te analogues Tomasz Janosik and Jan Bergman Department of Biosciences and Nutrition, Karolinska Institute, Novum Research Park, SE141 57 Huddinge, Sweden [email protected] (T. J.), [email protected] (J. B.)

5.1.1 INTRODUCTION This chapter summarizes the advances in the chemistry of thiophenes, selenophenes and tellurophenes reported during the year 2006. The remarkable productivity in this field is manifested not only in all contributions devoted to fundamental reactivity and properties, but also by the numerous papers dealing with applications of thiophene containing molecules, for instance in medicinal chemistry and materials science. With the objective of providing an overview of general interest, selected examples illustrating the progress in these specialized areas will also be discussed briefly. However, the main focus will be directed towards general ring synthesis and reactions of thiophene derivatives. Several useful specialized reviews have appeared during the reporting period of this chapter. The chemistry of thienothiophenes and thienopyrimidines has been discussed in detail, whereas accounts of related interest highlight the field of thiaheterohelicenes as well as similar fused thiophene systems . 5.1.2 THIOPHENE RING SYNTHESIS The boronic ester 1, a useful partner for Suzuki couplings, has been prepared by exposure of the 2-fluorobenzaldehyde 2 to ethyl mercaptoacetate in the presence of a base under microwave irradiation . In addition, base induced reactions between ethyl mercaptoacetate and 2-aryl-1-chloroacrylonitriles , hetarylacetonitriles , or 6-chloropyrimidine-5-carbaldehydes resulted in series of ethyl 3-amino-5-arylthiophenene-2-carboxylates, 2-amino-3-hetaryl-4(5H)oxothiophenes, or thieno[2,3-d]pyrimidine-6-carboxylates, respectively. Annulation of 3-(phenylsulfonyl)pyrazine-2-carbonitrile with ethyl mercaptoacetate gave ethyl 3-aminothieno[2,3-b]pyrazine2-carboxylate in excellent yield . A stepwise sequence involving substitution of electron deficient 2-nitrobenzamides with methyl mercaptoacetate, followed by conversion of

113

Five-membered ring systems: thiophenes and Se/Te analogues

the amide unit to a nitrile and final base induced cyclization gave rise to substituted methyl 3aminobenzo[b]thiophene-2-carboxylates . HS O

O B

CO2Et

K2CO3, MeCN μW, 140 °C, 30 min

CHO

O O B

74%

F

S

2

CO2Et

1

A one-pot variant of the Gewald thiophene synthesis involving aryl alkyl ketones provided a series of 2-amino-4-arylthiophene derivatives , whereas new conditions for the Knoevenagel/Gewald sequence have also been established. This approach utilized hexamethyldisilazane and acetic acid for the condensation step, followed by treatment of the resulting intermediate with sulfur in the presence of NaHCO3, giving for instance 2-amino-3-cyanothiophene derivatives . The Gewald reaction has also been employed for preparation of 2-amino-5-(phosphonomethyl)thiophenes . In addition, a variant using a functional ionic liquid as a soluble support leading to 2aminothiophene-3-carboxylates has been developed . Yet another “classical” thiophene synthesis, namely the reaction of 1,4-diketones with Lawesson’s reagent, has been employed for the construction of the indeno[1,2-b]thiophene skeleton . The precursor 3 served as a starting material for a series of trisubstituted thiophenes in a study towards progesterone receptor modulators, giving for example the product 4 upon reaction with an appropriate bromoketone. The fact that rather complex thiophene derivatives could be prepared in a straightforward manner compensates for the low overall yields . N O N

Br

O

1. Et3N, 65 °C 2. p-TsOH, acetone reflux

S

N

N Cl

21%

Cl

S

N O

O

O O

4

3

An approach to dibenzothiophenes involving a benzyne intermediate has been developed, wherein the required precursor 5, which is available in three steps from 2-fluorothiophenol, underwent lithiation giving the species 6, which could thereafter be treated with various electrophiles rendering the final products 7 . E I

F S 5

t-BuLi (3.3 equiv) THF, -78 °C to 0 °C

Li S 6

E+, -78 °C to 20 °C 75-79% E = H, SPh, Br, 4-MeC6H4C(H)OH

S 7

Electrophilic cyclization of the precursors 8, which are available from 3(methylthio)pyridine by regioselective lithiation, followed by introduction of CBr4, and a subsequent Sonogashira coupling, has resulted in a series of thieno[3,2-b]pyridines 9

114

T. Janosik and J. Bergman

. It should also be mentioned that an isomeric series of thieno[2,3-b]pyridines has been prepared by base induced annulations involving for instance 2-mercaptopyridine-3carbonitrile precursors and ethyl chloroacetate . E+ (I2, Br2, or NBS) CH2Cl2, rt, 30 min

SMe N

E

N

42-88%

S

R

8

E = Br, I R = Ph, TMS

R

9

Intramolecular palladium catalyzed thio-enolate S-arylation has been used in a route to a set of fused benzo[b]thiophenes, as illustrated by the conversion of the substrate 10 into the product 11 . S Pd2(dba)3 (2.5 mol%), DPEphos (6 mol%) Cs2CO3, PhMe, 100 °C 57%

S

Br 10

11

A series of benzo[b]benzo[2,3-d]thiophen-6,9-diones 12 has been prepared in modest yields by palladium mediated cyclization of the precursors 13. However, the necessity to use stoichiometric amounts of the palladium source precludes cost effective preparation of the targets. The required substrates 13 may be constructed by palladium catalyzed reactions between the appropriate phenols with 2,3-dimethylbenzoquinone . O R3

Me Me

R2

S O

13

O

Me Pd(OAc)2, AcOH reflux, 1 d

Me

R2

23-51%

S

O

R1

R3

R1 = H, F R2 = H, Cl R3 = H, Me, OMe, F, Cl

R1

12

Gold catalyzed reactions are currently enjoying considerable interest, and have also found applications in thiophene ring synthesis. A series of (Į-alkoxyalkyl)(o-alkynylphenyl) sulfides 14 was subjected to treatment with catalytic amounts of AuCl, giving the benzo[b]thiophenes 15 in excellent yields. Some additional, more complex examples were also provided . R OMe AuCl (2 mol%), PhMe, 25 °C

S 14

OMe

85%-quant.

S

R

R = Pr, Ph, cyclohexyl, t-Bu, CO2Et, 4-F3CC6H4, 4-MeOC6H4

15

The first gold catalyzed C–S bond formation was demonstrated in a route to the 2,5dihydrothiophene 16 via cycloisomerization of the allene 17 which occurred with high chirality transfer (d.r. > 95:5) .

115


Me

Me

i-Pr

OBn

i-Pr

86%

SH

H

AuCl (5 mol%), CH2Cl2, rt

17

OBn S 16

The intriguing circulene 18 has been prepared from the precursor 19 by initial exhaustive C-2 metalation, followed by introduction of elemental sulfur, and quenching with aqueous hydrochloric acid. This set of operations resulted in a polythiol, which was eventually converted to the target heterocycle 18 by vacuum pyrolysis . S

S

S

S

1. LDA (16 equiv.), Et2O 2. S8, then aq. HCl 3. Vacuum pyrolysis

S

S S

S S

S S

S 19

18

A series of 3-oxothiophene derivatives has been prepared by intramolecular thia-antiMichael addition of a thiol anion to an enone functionality, resulting for instance in preparation of the target 20 by treatment of the precursor 21 with an amine . Cl

O

O

O NHPh

S

O

BnNH2, DMSO, 120 °C, 1 h

NHPh

87%

S

S

Cl

21

NHBn

20

It has been shown that Lewis acid catalyzed isomerization of thionolactones provides access to thiolactones. For example, exposure of the substrate 22 to catalytic amounts of BF3·OEt2 led to efficient conversion to the thiolactone 23. Such transformations were also found to give minor amounts of lactone or dithiolactone side products . Substituted tetrahydrothiophene derivatives have also been obtained from 1,4-dithiane-2,5diol and 2-nitroethyl acetate derivatives by a base induced sequence featuring a Michael addition and a Henry reaction .

S

O

C6H13

22 (98% ee)

BF3 Et2O (10 mol%) PhMe, reflux 70%

O

S

C6H13

23 (97% ee)

A series of functionalized tetrahydrothiophenes has been prepared by acid induced organocatalytic reactions involving Į,ȕ-unsaturated aldehydes and 2-mercapto-1phenylethanone 24. This procedure led to good yields of products displaying useful enantiomeric excess, as illustrated by construction of the target 25 in the presence of the catalyst 26 .

116


O Pr

26 (10 mol%) PhCO2H, PhMe

CHO SH

Ph

74% (95% ee)

Pr

S

24

Ar

OH CHO

25

N H

Ar OTMS

26 Ar = 3,5-(CF3)2-C6H3

Formation of partially saturated thiophene derivatives has also been observed as products resulting from radical reactions of thiophenol with S-4-pentynylcarbamothioates , irradiation of the sultam 27 at 300 nm in hexane, which leads to the fused system 28 as the major product , or photoisomerization of 4-anisyl-4-methyl2,6-diphenyl-4H-thiopyran-1,1-dioxide . Routes to L-ȕ-3ƍ-deoxy-3ƍ,3ƍ-difluoro4ƍ-thionucleosides and a ketone analogue of biotin have also been devised. H N

H S N O O

S O O

27

28

Generation and trapping of tropothione 29 with dienophiles has been utilized in an approach to partially saturated fused thiophene molecules. For example, treatment of tropone with Lawesson’s reagent in benzene, followed by introduction of N-phenylmaleimide gave the adduct 30 in excellent yield . O

S O

Lawesson's reagent PhH, rt

Ph N

S

O

H

N Ph

H 90%

H

29

O

O

30

Heating of the sulfoxide 31 causes a Pummerer rearrangement generating the ylide 32, which could be trapped with dimethyl acetylenedicarboxylate (DMAD) giving the dihydrothiophene derivative 33 . TMS

S O

TMS

DMPU, 100 °C

31

DMAD

S 32

CO2Me

MeO2C

59%

S 33

5.1.3 REACTIONS OF THIOPHENES Again, the ease of bromine–lithium exchange at the 2-position of thiophenes has been demonstrated by conversion of the tetrabrominated trithiophene 34 (available by exhaustive bromination of the parent tricyclic compound) into the system 35, which is a useful building block for extended fused thiophene systems . Regioselective metalation has also been employed en route to 2,3-bis(phosphanyl)benzo[b]thiophene ligands for stereoselective transition metal catalyzed reactions . Metalated thiophenes have

117


also been reacted with aromatic nitriles, followed by reduction with NaBH4, giving 2thienylmethylamine derivatives . Br

Br

Br

Br S

1. BuLi (2.1 equiv.) THF, -78 °C, 3 h 2. TMSCl (2.5 equiv.), -78 °C

TMS

TMS

80%

S

S

Br

Br

S

34

S

S 35

An interesting example of trilithiation has been reported, wherein 3(methylthio)thiophene 36 was exposed to the powerful base system LICKOR (tBuOK/BuLi), giving direct access to the products 37 after quenching of the intermediate 38 with suitable electrophiles. Reactions involving 2-(methylthio)thiophene gave 2,5disubstituted products resulting from a dilithiated intermediate . Li SMe

S LICKOR (6 equiv.) THF, -78 °C

Li

S 36

S

E S

1. E+ (6 equiv.), THF, -78 °C 2. H+

Li

E

48-84% E = Me, allyl, CO2H, CHO, TMS

38

S

E

37

Transition metal catalyzed coupling reactions constitute some of the most powerful and versatile tools for manipulation of thiophene derivatives and are clearly one of the most dominant fields in current thiophene chemistry. Several potentially useful strategies of this type have been elaborated during the past year. An interesting synthesis of 2,3diarylthiophenes has been described, wherein for instance the 3-thiophenemethanol derivative 39 was subjected to treatment with aryl bromides in the presence of a palladium catalyst, leading to the product 40, as well as many similar molecules. The series of events leading to this outcome features cleavage of the C–H and C–C bonds at the 2- and 3-positions of the thiophene substrates . Cl Ph

Ph OH

4-ClC6H4Br Pd(OAc)2, P(biphenyl-2-yl)(t-Bu)2 Cs2CO3, PhMe, reflux 86%

S 39

S

Cl 40

A tandem palladium catalyzed multi-component approach has been devised providing direct access to for instance trisubstituted thiophenes from the simple starting material 3iodothiophene 41. In a representative experiment, the substrate 41 was converted to the product 42 by treatment with ethyl acrylate and iodobutane in the presence of a catalytic system consisting of Pd(OAc)2, tri(2-furyl)phosphine (TFP), norbornene, and a base. A mechanistic rationale accounting for this outcome was also proposed .

118


I

Pd(OAc)2 (10 mol%), TFP (20 mol%) BuI (10 equiv.), methyl acrylate (2 equiv.) norbornene (6 equiv.), Cs2CO3, CH3CN, 80 °C, 1 d

S 40

CO2Et

Bu Bu

S

96%

41

It has been demonstrated that bromothiophenes may undergo palladium catalyzed C–H homocoupling providing a new route to halogenated 2,2ƍ-bithiophenes, an important class of building blocks for oligothiophene synthesis. For example, the alcohol 42 could be converted to the 2,2ƍ-bithiophene derivative 43 in good yield, suggesting useful functional group tolerance . (CH2)4OH

PdCl2(PhCN)2 (3 mol%) AgNO3/KF, DMSO, 60 °C

Br S 42

70%

(CH2)4OH

HO(H2C)4 Br

S

S

Br

43

Exposure of the benzo[b]thiophene derivative 44 to a palladium catalyst in the presence of tri(2-furyl)phosphine (TFP) as the ligand led to the product 45, which incorporated two heterocyclic units from the starting material. The mechanistic aspects of this transformation were also discussed, which appears to involve palladacycle intermediates .

Br S

Pd(OAc)2 (5 mol%), TFP (10 mol%) K2CO3, DMF, 105 °C, 20 h

CONHMe

75%

S

S O

44

N Me 45

The dithienyldienyne 46, which was prepared by sequential palladium catalyzed couplings, underwent intramolecular annulation to compound 47 in excellent yield. Similar cyclizations involving closely related substrates were also studied . S S

Br 46

Pd(OAc)2 (0.2 equiv.), PPh3 (0.4 equiv.) Bu4NBr, K2CO3, DMF, 80 °C 87%

S

S

47

Palladium/copper catalyzed reactions of 3-iodothiophene-2-carboxylic acid 48 with two equivalents of a terminal alkyne gives selective access to 5-substituted 4-alkynylthieno[2,3c]pyran-7-ones, for example the system 49 .


119

OPh OPh (2 equiv.)

I S

OPh

PdCl2(PPh3)2 (cat.), CuI (cat.) Et3N, DMF, 70-80 °C

CO2H

O

75%

S

48

O 49

Other new studies involving thiophenes in transition metal catalyzed couplings encompass generation and coupling of thiophene-3-boronic acid derivatives giving 3,4di(thien-3-yl)maleimides , and Suzuki couplings of 3,4-bis(5-iodo-2methylthien-3-yl)-2,5-dihydrothiophene or benzo[b]thiophene boronic acid . Thiophene boronic esters have also been prepared by iridium catalyzed borylation, and were converted to regioregular poly(alkylthiophenes) using Suzuki reactions . Synthetic sequences featuring Kumada and Suzuki reactions have also been used for construction of thiophenes bearing four thienyl substituents . Negishi coupling involving 2-iodo-(3,4-ethylendioxythiophene) 5-carbaldehyde has been used during synthesis of a thiophene backbone amide linker for solid phase chemistry , whereas Negishi reactions of 2-bromothiophene have found use en route to fused thiophene– phenylene chromophores . Applications of the Sonogashira reaction encompass coupling of brominated 2,2ƍ-bithiophenes leading to two-photon absorption chromophores containing a central 2,2ƍ-bithiophene motif , and preparation of oligo(2,5thienyleneethynylene) materials by repetitive Sonogashira reactions . Sonogashira coupling of halothiophenes may also be conducted in water solution using palladium on charcoal as the catalyst in the presence of PPh3, CuI, and 2-aminoethanol . A study on the reactivity of bromothiophene carboxylates in palladium catalyzed amination with hetaryl amines has also been conducted , whereas copper catalyzed reactions of thienylboronic acids with azo compounds gives rise to thienylhydrazine derivatives . Palladium catalyzed amination of 2,8dibromodibenzothiophene-S,S-dioxide with diarylamines provided access to materials for organic light emitting devices . Several bromothiophenes have also been aminated with various azoles in the presence of CuI in the ionic liquid [Bmim]BF4, as illustrated by the synthesis of compound 50 .

S

Br

benzimidazole CuI/L-proline,K2CO3 [Bmim]BF4, 105-115 °C 76%

S

N N 50

A protocol for palladium catalyzed direct C–H arylation of thieno[2,3-b]thiophenes has been developed . Likewise, 3-cyanobenzo[b]thiophene 51 undergoes coupling with aryl bromides in the presence of a palladium catalyst to provide a series of 2-aryl derivatives, for example the product 52 . Direct C–H arylation catalyzed by palladium acetate has also been carried out employing 3-methoxythiophene, leading to 2aryl-3-methoxythiophene derivatives. Extensions involving 2-bromothiophenes as the coupling partners enabled preparation of new oligothiophene systems Thiophenes may also be arylated using aryl iodides in the presence of a rhodium catalyst .

120


CN

CN

3-(i-PrO)C6H4Br, Pd(OAc)2 (5 mol%) K2CO3, DCH-18-C-6, DMF, 140 °C

Oi-Pr S

82%

S 51

52

Irradiation of the readily available diamide precursor 53 in DMF solution gave the fused system 54 in excellent yield. This material could be subsequently chlorinated using POCl3, and dehalogenated by catalytic hydrogenation to the parent ring system bis[1]benzothieno[2,3-c:3ƍ,2ƍ-i][1,10]phenanthroline . Photocyclization reactions have also been employed in a route to new tetrathia[7]helicenes . Some other related helical aromatics have been prepared by intramolecular coupling of adjacent thiophene units via their 3-positions using FeCl3 in chloroform and nitromethane .

Cl

Cl

S

S NH HN O

hν, DMF 90%

S

S

O

NH HN O

53

O 54

Interconversion of functional groups at the thiophene ring is a common strategy to access further useful derivatives. A set of thiophene-2-isocyanates has been obtained by N-silylation of the corresponding 2-aminothiophenes, followed by treatment of the resulting intermediates with phosgene . Thiophene-2-carbaldehydes may be transformed to their corresponding 1,3-diselenanes or dithioacetals by exposure to propane-1,3-diselenol or ethane-1,2-dithiol, respectively, in the presence of TMSCl. A study of Sharpless asymmetric dihydroxylation of thienyl- and (benzothienyl)acrylates has also been published . Nucleophilic displacement of both bromine atoms in 3,3ƍdibromo-2,2ƍ-bithiophene with NaS(i-Pr), followed by S-dealkylation and oxidative cyclization of the resulting thiol functionalities gave dithieno[3,2-c:2ƍ,3ƍ-e][1,2]dithiin . Studies on a synthesis of 4H-cyclopenta[2,1-b:3,4-bƍ]dithiophen-4-one resulted in isolation of the unexpected product bis[bis(2-iodo-3-thienyl)methyl]ether . Moreover, chiral diamino-thiophene derivatives have been prepared by reduction of imines generated from thiophenecarbaldehydes and (R,R)-1,2-cyclohexanediamine, and were investigated as ligands for asymmetric catalysis . Additional contributions worth mentioning in this context encompass preparation of [n](2,5)thiophenophane-1,n-diones , [3,3]dithiacyclophanes featuring thieno[2,3-b]thiophene motifs , 3,4-dicycloalkoxy-2,5-diethoxycarbonylthiophenes , a thieno analogue of a cooked food mutagen , as well as synthesis of styryl substituted oligothienylenevinylenes using Wittig reactions . Additional studies featuring reactions of thiophene derivatives detail biohydrolysis of (S)3-(thiophen-2-ylthio)butanenitrile , lipase catalyzed resolution of thiotetronic acids , enzymatic kinetic resolution of 1,1-dioxo-2,3-dihydrothiophen-3-ol , and efficient synthesis of 6-methyl-2,3-dihydrothieno[2,3-c]furan 55, a coffee


121

aroma component . A new route to 5-vinyl derivatives of the thiotetronic acid natural product thiolactomycin has also been elaborated using Horner-Wadsworth-Emmons reactions for the key transformations . It should also be mentioned that a study of 1,3-dipolar cycloadditions of benzo[b]thiophene-S,S-dioxide with azomethine ylides has been performed, leading to formation of partially saturated pyrrolo-fused benzo[b]thiophene derivatives, for instance 56, as mixtures of isomers . Cyanation of thiophenes at C-2 has been achieved using TMSCN in combination with a recyclable polyvalent iodine(III) reagent based on an adamantane core . In addition, syntheses of several partially hydrogenated 4,6-dimethyldibenzothiophenes have been reported . H O S

N S

Me 55

H

O

H Ph O 56

Some theoretical aspects of thiophene reactivity and structure have also been discussed, for example the kinetics of proton transfer from 2,3-dihydrobenzo[b]thiophene-2-one , the configuration of imines derived from thiophenecarbaldehydes , and the relative stability of benzo[c]thiophene . The kinetics of nucleophilic aromatic substitution of some 2-substituted-5-nitrothiophenes in room temperature ionic liquids have also been investigated . 5.1.4 NON-POLYMERIC THIOPHENE ORGANIC MATERIALS The field of thiophene containing diarylethenes continues to attract considerable interest. Many of the structures display interesting properties, and could be useful in design of new electronic devices. For example, it has been shown that the photochromic properties of the system 57 may be modulated by addition of fluoride ions, which shifted the absorption maximum from 655 to 490 nm . Diarylethenes featuring thiophene units bearing phenolic and pyridyl substituents have been prepared, and were demonstrated to exhibit pKa changes upon irradiation . Self assembly at different temperatures was observed during studies of dithienylethenes possessing aryl substituents extended with hexaethylene glycol chains in aqueous solution, resulting from different aggregation properties of the open and closed forms of the system . Further extensions involve design of dithienylmaleimide switches incorporating ferrocene moieties controllable by irradiation or electrochemical redox reactions , or molecular switches based on dithienylperfluorocyclopentene bearing imidazo[4,5-f][1,10]phenanthroline units . In addition, it has been demonstrated that photochromic cyclopentenes based on benzo[b]thiophene-S,S-dioxide units display high fatigue resistance . Studies of the photochromic properties of an unsymmetrical perfluorocyclopentene bearing one benzo[b]thiophene system and an indene unit or symmetrical systems with two thiophene units bearing fluorophenyl groups have also been carried out.

122


UV Vis

(Mes)2B

S

B(Mes)2

S

(Mes)2B

S

B(Mes)2

S

57

The unsymmetrical system 58 incorporating donor and acceptor motifs has been prepared by sequential nitration, iodination, and Stille coupling from the parent 1,2-bis(2methylbenzo[b]thiophen-3-yl)perfluorocyclopentene, and was investigated as a device for photo induced electrochemical switching . Upon coordination of the 1,10phenanthroline ligand 59 to a rhenium(I) tricarbonyl complex, a system was obtained where the photochromism was extended from intraligand excitation to metal-to-ligand chargetransfer excitation . The photochromic reactions in single crystals of 1,2-bis(5carboxyl-2-methyl-3-thienyl)perfluorocyclopentene, as well as co-crystals with bipyridines with intermolecular hydrogen bonding networks have also been studied . Intramolecular hydrogen bonding has also been established to play a major role during diastereoselective cyclization of a dithienylhexafluoropentene carrying (R)-N-phenethylamide substituents . The fulvene 60 has been shown to participate in a Diels–Alder reaction with an electron deficient alkene, and the resulting adduct was thereafter locked by closing the dithienylethene unit by irradiation at 313 nm. The reverse reaction occurred upon opening the system by irradiation at wavelengths over 434 nm, whereupon the alkene was released . F

O

F

N

F

F

F

F

O S

S

NO2

S

N

S

58

Cl

S

S

59

S

Cl

60

The benzothieno[3,2-b]benzothiophene 61 is a new semiconductor for air stable organic field effect transistors (FET) . A set of fused benzene–thiophene structures have been included in a study evaluating their vibronic coupling characteristics . Likewise, the molecule 62 and two closely related structures have been investigated as materials for organic thin film transistors . A series of related ring fused thiophenes have been investigated in connection with their solid state properties . S

S Ph

Ph

S

S S

S

S 61

62

The dithieno[3,2-b:2ƍ,3ƍ-d]phosphole 63 has been designed as a very sensitive material for detection of fluoride ions . Cationic dithieno[3,2-b:2ƍ,3ƍ-d]phospholes alkylated at the phosphorus atom have also been prepared for application as building blocks

123


for luminescent conjugated polyelectrolytes . Derivatives of this skeleton bearing SiMe2H groups have also been studied . The impact on the electronic properties of di(2-thienyl)phospholes by modification of the phosphorus substitution has been monitored using Raman spectroscopy . Some other examples of studies concerning thiophene containing materials encompass preparation of the donor–acceptor– donor type liquid crystal 64 , evaluation of the properties of the thienoquinoid system 65 , and probing of the solvatochromic behaviour of some thienylpyrroles, for example 66 .

O

O B

S

S

C12H25

O B O

N N

O

Ph 63

O

64 O NC

NC

C12H25 O

O

O

P O

S

S

S

CN

S

S

CN N Pr

CN

CN 65

66

5.1.5 THIOPHENE OLIGOMERS AND POLYMERS Numerous studies have been devoted to 2,2ƍ-bithiophene based systems. Several diborylated structures, for example 67, have been included in a study investigating electronic communication between the boron centers and binding pyridine rings . The synthesis and evaluation of the electronic properties of the dimer 68, as well as the corresponding trimer have been described . 2,2ƍ-Bithiophenes bearing perfluoroaryl groups have also been prepared and studied as blue light emitting materials . Other studies of related interest encompass push–pull 2,2ƍ-bithiophenes possessing amino and cyanovinyl groups , fluorescent indicators for Ca2+ based on the 2,2ƍ-bithiophene core substituted with the chelator o-aminophenol-N,N,Otriacetic acid , and an octaethylporphyrin–dihexyl-2,2ƍ-bithiophene–pyridine system interlinked with diacetylene units . F5 F5

O B

S S

O

B

S F5

S O

F5

67

O

68

Likewise, a number of terthiophenes have been prepared and studied. For example, radical cations of the system 69 end-capped by bicyclo[2.2.2]octane units have been found to form centrally attracted bent ʌ-dimers . The trimer 70 has been included in a

124


systematic probing of the properties of a series of related molecules . High resolution electronic spectra of several ethylenedioxythiophene oligomers, among others the silyl terminated compound 71, have been recorded and discussed . A thiophene tetramer end-capped with 2-pyridyl units has also been reported in connection with syntheses of several related oligomers . Incorporation of hexafluoropentene units in the system 72 enabled lowering of the LUMO level without disturbing the conjugation efficiency. The construction of this molecule involved preparation and coupling of 1,3dibromohexafluorocyclopenta[c]thiophene . Other studies include Į,Ȧ-capped sexithiophenes bearing fluorenyl or tricyanovinyl units, whereas the self assembly of oligothiophenes with chiral oligoethylene chains attached via ester linkages has been investigated . The parent sexithiophene has also been demonstrated to form inclusion complexes upon mixing with polysaccharides, in which the oligothiophene adapts a twisted conformation in the chiral channel formed by helical wrapping of the polysaccharide hosts . A one pot procedure for construction of symmetric octithiophenes from 4-(alkylthio)-2,2ƍ-bithiophene derivatives has also been described . Finally, several reports of various aspects of quinoid oligothiophene derivatives have appeared .

S S

S

TMS

O

O S

O

F

70

TMS

S O

F F

F

F

S

O

S

F O

S

F

S S

69 O

F

F

F

F

O

71 C6F13

F

F F S

S

F F

F F F

S S

S

S

F

F F C6F13

72

There are also many examples of materials containing thiophenes in combination with other conjugated units, for instance decyl end-capped thiophene–phenylene oligomers with improved oxidation stability for semiconductor applications . A molecule incorporating octithiophene, quaterthiophene, and fullerene units linked by saturated fragments has been investigated as a long distance charge separation system . Liquid crystalline field effect transistors based on 5,5ƍƍ-bis(5-alkyl-2-thienylethynyl)2,2ƍ:5ƍ,2ƍƍ-terthiophenes have been devised . The system 73 has been designed as a molecular wire which displayed electrochemical switching between an insulating and a conducting state . In addition, a synthetic route to monodisperse oligo[1,4-phenyleneethynylene)-alt-(2,5-thiopheneethynylene)] systems has been described .

125


C6H13

C6H13 S

S

S

8

CN

8

C6H13

NC

73

Numerous publications include studies of thiophene containing polymers, for instance materials based on thieno[3,4-b]thiophene units , or the polymer 74 . Visualization of enzymatic cleavage of single-stranded DNA has been achieved using the cationic polythiophene 75 . The popular poly(3,4ethylenedioxythiophene) has been employed for design of transparent, plastic, low-workfunction electrodes . A theoretical study has enabled accurate prediction of HOMO–LUMO gaps for polythiophene and polyselenophene based on extrapolation using long ( > 20-mer) oligomers . The polymer 76 has been developed as a highmobility semiconductor for thin-film transistors . A polymer composed of 1(thiophene-2-yl)benzothieno[2,3-b]benzothiophene units has also been prepared . Additional selected contributions to this field encompass for instance construction of postfunctionalizable phosphole modified polythiophenes , alternating thiophene–perfluoroarene copolymers , regioregular copolymers containing 3-alkoxythiophene units , a thiophene–benzobisthiazole copolymer , and a polythiophene containing cyclobutadiene cobalt cyclopentadiene complexes . The side chain conjugated material 77 displayed a very broad absorption band . C8H17 S

S NEt3 Me

O

Cl

C15H31

S S

S S 74

5.1.6

n

S 75

S

C15H31

n ∗

n

76

S

n

∗

77

THIOPHENE DERIVATIVES IN MEDICINAL CHEMISTRY

As in previous years, the thiophene moiety, which is a common isostere of benzene, has been incorporated in a great number of biologically active compounds targeting a wide variety of potential medical applications. For example, a series of 2-amino-3-(3ƍ,4ƍ,5ƍtrimethoxybenzoyl)-5-arylthiophenes or 3-amino-2-(3ƍ,4ƍ,5ƍ-trimethoxybenzoyl)-5-arylthiophenes has been identified as a new type of antitubulin agents, whereas it was shown that (S)-1-(2-aminocarboxyethyl)-3-(2-carboxythiophene-3ylmethyl)pyrimidine-2,4-dione displayed high potency towards GLUK5-containing kainate receptors . Other studies led to development of the molecule 78 as a hepatitis C virus polymerase inhibitor , 2-aminothiophene-3-carboxylates as adenosine A1 allosteric enhancers , N-glycolsyl-thiophene-2-carboxamides for proliferation of bovine aortic endothelial cells , 5-(pyrazol-5-yl)thiophene2-carboxamides as selective calcium-release-activated calcium channel inhibitors

126


, 2-pyrimidyl-5-amidothiophenes as inhibitors of the kinase AKT , and arylsulfonylthiophene-2-carboxamidine inhibitors of the serine protease C1s . A series of monocyclic thiophenes, for instance 79, displayed activity as tyrosine phosphatase 1B inhibitors . A related set of 5-substituted 3-aryl-4-cyanothiophene-2-carboxylic acids was designed as AMPA receptor allosteric modulators . It should also be mentioned that 2,5-diphenylthiophene derivatives bearing hydroxy and amine substituents have been studied as compounds for ȕamyloid plaque imaging . In addition, a theoretical investigation probing the structure–activity relationships in a series of nitrothiophenes has also appeared . OH N

H N OH

N

S

HO2C

S CO2H

O Br

O

NHCONHCH2(2-ClC6H4)

CO2H

HO2C 79

78

A number of benzo[b]thiophene compounds have also attracted attention. The system 80 has been studied as as a Į7 nicotinic receptor partial agonist , whereas the benzo[b]thiophene derivative 81 displayed antitumor effects < 06JMC3143>. A collection of benzo[b]thiophene-2-carboxamides was evaluated as antagonists of the human H3-receptor . In addition, (arylamino) benzo[b]thiophenes were investigated as antioxidants . It has also been shown that the molecule 82 displayed high affinity for the dopamine D3 receptor . Other related work involves design of benzothieno[2,3-c]pyran derivatives for inhibition of hepatitis C virus NS5B RNA-dependent RNA polymerase , 9-benzylidene-naphtho[2,3-b]thiophen-4-ones as antimicrotubule agents , and some cytotoxic thioaurone based structures . Studies of tetrahydrobenzo[b]thiophene derivatives as inhibitors of hepatitis C virus NS5B polymerase , and 2-acylamino-tetrahydrobenzo[b]thiophene-3carboxamides as FLT3 tyrosine kinase inhibitors have also appeared. MeO O N

O

OMe OH

N

Cl

S

Me

N

O

Cl

N

S

S 80

H N

MeO

81

82

There are also many fused thiophene derivatives incorporating other heterocyclic units which exhibit interesting pharmacological properties. The thieno[2,3-b]pyrrole 83 has been identified as an allosteric inhibitor of hepatitis C virus NS5B polymerase , whereas a series of thienopyrroles has been investigated as glycogen phosphorylase inhibitors . A study on thienopyrazole compounds as kinase inhibitors has also been reported . The thieno[2,3-b]thiophene fragment may be found in the antitumor compound 84 , and protein tyrosine phosphatase 1B inhibitors . Other interesting developments in this context include studies of 2-amino-3-

127


aroyl-thieno[2,3-c]pyridine derivatives as allosteric enhancers at the adenosine A1 receptor , antimicrobial 4-(phenylamino)thieno[2,3-b]pyridines , and 3-aminothieno[2,3-b]pyridine-2-carboxamide kinase inhibitors . The thieno[2,3-b]pyridone 85 represents a series of similar compounds that has been identified as inhibitors of [3H]glycine binding to the NMDA receptor , whereas a set of thieno[2,3-b]pyridine-4-ones has been evaluated as non-peptide luteinizing hormonereleasing receptor antagonists . A nice example of bioisosterism was demonstrated by preparation of the thieno analogue 86 of the alkaloid febrifugine, which displayed potent antimalarial effects . Studies of related interest feature thienopyrimidine structures as melanin concentrating hormone receptor 1 antagonists , 06JMC7095>, antibacterial compounds , or partial agonists for the thyroid stimulating hormone receptor . In addition, the molecule 87 was established to activate ATP-sensitive potassium channels of pancreatic beta cells . CH2CONMe2 N Ph HO2C

S

Cl HO

S S

O Cl

N

H N

HO O Cl

N

S

N H

O

S

S O

86

5.1.7

S

CN

84

83

OPh

NH N H 85

O

H N N

O 87

SELENOPHENES AND TELLUROPHENES

At present, the chemisty of selenophenes and tellurophenes is a relatively scantily studied area. Nevertheless, a number of new valuable contributions dealing with their chemistry have emerged. Electrophilic cyclization of 1-(1-alkynyl)-2-(methylseleno)arenes provides a route to a variety of 2,3-disubstituted benzo[b]selenophenes, as illustrated by the preparation of the system 88. Other useful electrophiles for similar reactions are I2 or NBS . Similar chemistry has also been employed in preparation of 2,3-disubstituted benzo[b]selenophenes on solid phase . In addition, syntheses of 2,3dihydroselenolo[2,3-b]pyridines have been achieved using radical chemistry .

SeMe

SePh

PhSeBr, CH2Cl2, rt 95%

Se

Ph

88

Selenation of the 1,4-dicarbonyl precursor 89 using the reagent (Me2Al)2Se gave the benzo[c]selenophene derivative 90 in good yield . The synthesis and structural studies of 4,7-dimethoxybenzo[c]tellurophene have also been reported .

128


(Me2Al)2Se

Fe

O O

75%

Fe

Se

Fe

89

Fe

90

In similarity to their thiophene counterparts, halogenated selenophenes or tellurophenes are useful substrates for transition metal catalyzed reactions. Apart from a protocol for preparation of 2-arylselenophenes by Suzuki coupling of 2-iodo- or 2-bromoselenophene with aryl boronic acids, a route to 2-aroylselenophenes has been devised. For example, treatment of 2-iodoselenophene 91 with (4-methoxyphenyl)boronic acid under an atmosphere of carbon monoxide gave the product 92 in good yield . A copper mediated amidation protocol involving 2-iodoselenophene has also appeared . Moreover, it has been shown that variants of Sonogashira coupling of 2-bromo- or 2iodotellurophene derivatives offer efficient routes to a variety of 2-alkynyltellurophenes . It has also been demonstrated that homocoupling of 5-aryl or 5heteroaryl-2-bromoselenophenes in the presence of the system (Bu3Sn)2/Pd(PPh3)4 provides excellent yields of the corresponding 5,5ƍ-diaryl-2,2ƍ-diselenophenes and their heteroaryl substituted analogues . OMe

Se

I

4-(MeO)C6H4B(OH)2, Pd(PPh3)4 (cat.) Na2CO3, PhMe, CO

91

80%

Se O 92

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06S2794 06S3670 06S3855 06SC97 06SC3319 06SL737 06SL2016 06SL2423 06SL2559 06SL3161 06SM38 06SM256 06SM784 06T684 06T2190 06T2576 06T4756 06T5855 06T6036 06T6814 06T8467 06T9554 06T10072 06T11124 06T11311 06T11513 06T12204 06TA2919 06TL83 06TL787 06TL795 06TL1267 06TL1551 06TL2179 06TL2887 06TL3167 06TL3447 06TL3365 06TL4635 06TL5143 06TL5139 06TL5273 06TL5375 06TL5585 06TL5599

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135

Chapter 5.2 Five-membered ring systems: pyrroles and benzo analogs Erin T. Pelkey Hobart and William Smith Colleges, Geneva, NY 14456 [email protected] Jonathon S. Russel St. Norbert College, De Pere, WI 54115 [email protected]

5.2.1

INTRODUCTION

The synthesis and chemistry of pyrroles, indoles, and additional fused pyrrole and indole ring systems reported during the past year (2006) are the subjects of this review. Pyrroles and indoles are amongst the most studied heterocyclic ring systems due to their diverse biological activity and materials science applications. Page restrictions limit this review to selected advances. In keeping with the past few years, pyrroles and indoles are treated separately. Review articles will be mentioned at the beginning of the relevant sections.

5.2.2

SYNTHESIS OF PYRROLES

Pyrrole syntheses have been organized systematically into intramolecular (type I) and intermolecular (type II) approaches and classified by the location of the new bonds that describe the pyrrole ring forming step (two examples illustrated below). type Ic N R

5.2.2.1

c d

b e

Intramolecular Approaches

Na R

type IIae Intermolecular Approaches

N R

Intramolecular Approaches

Intramolecular nucleophilic additions by nitrogen functional groups onto pendant alkynes and allenes represent an important class of type Ia approaches to functionalized pyrroles. A platinum-catalyzed (PtCl4) cyclization of homopropargyl azides provided an entry to 2,5disubstituted pyrroles and 4,5,6,7-tetrahydroindoles (fused pyrroles) . The addition of a carbonylation step extended a pyrrole synthesis to pyrrole-2-acetic acid derivatives . Treatment of enyne amine 1 with palladium diiodide in the presence of CO and methanol produced pyrrole-2-acetic ester 2 via a 5-exo-dig cyclization, oxidative carbonylation, and isomerization.

136

E.T. Pelkey and J.S. Russel

Et

Et

PdI2 (cat.), KI CO, O2, MeOH

Et N Bu

63%

NH Bu

Bu

CO2Me

N Bu

Bu

CO2Me Bu

2

1

A ring opening reaction of β-lactams promoted by methoxide generated nitrogen nucleophiles in situ that subsequently added to proximal allenes producing trisubstituted pyrroles . In the event, treatment of β-lactam 3 with MeONa led to pyrrole-2acetic ester 4 after cleavage of the amide bond, 5-exo-dig cyclization, and loss of methanol. The sequence was notable as no metal catalyst was required. OMe

PhO

OMe Ph MeONa

N R

O

MeOH 50%

PhO MeO2C

MeO

Ph NH

PhO

R

Ph

N R

MeO2C

Me

Ph PhO MeO2C

3 (R = p-OMePh)

N R

Me

4

A thermal ring opening reaction of an imine-substituted cyclopropene led to a mixture of 2,3,4-trisubstituted and 3,4,5-trisubstituted pyrroles . Two type Ia syntheses of β-hydroxypyrroles have appeared. An aza-Nazarov cyclization of 1-azapenta-1,4-dien-3-ones produced β-hydroxypyrroles including 2,2’-bipyrroles . A second approach to a β-hydroxypyrrole involved an intramolecular N-H insertion into a rhodium carbene derived from the decomposition of a diazoketone . On the other hand, the photochemical decomposition of the diazoketone led to pyrrolidin-2-ones. Intramolecular condensation reactions of unsaturated γ-aminocarbonyl compounds provide regiospecific methods for the preparation of highly functionalized pyrroles. This strategy was utilized to prepare pyrrole-fused tetrathiafulvenes . In the event, a two-step reductive amination of aldehyde 5 gave sulfonamide 6. Treatment of 6 with Amberlyst 15 promoted an intramolecular condensation leading to fused pyrrole 7. Intramolecular condensation reactions of substituted γ-aminoacetals followed by oxidation with DDQ provided the corresponding pyrroles . The former were prepared by nucleophilic additions of ketene silyl acetals onto imines. An intramolecular aza-Wittig reaction of unsaturated γ-azidoketones provided a regiospecific route to 4-amino- and 4alkyoxy-2-trifluoromethylpyrroles . Similarly, an aza-Wittig sequence involving γ-azido-β-hydroxyketones provided pyrrole-2-acetic esters . OHC

S S

EtO

S OEt

5

NHTs

1. TsNH2, MS, toluene 2. NaBH4, THF, EtOH 75% (2 steps)

S EtO

S OEt

6

S

Amberlyst 15 S

Ts N 99%

S S 7

α-Thioether pyrroles have been prepared utilizing a type Ib condensation . Treatment of ketene N,S-acetal 8 with the Vilsmeier-Haack reagent (POCl3 + DMF) led to 5-

137

Five-membered ring systems: pyrroles and benzo analogs

4-formylpyrrole-2-carboxylate 9 via an iminium-type cyclization. Interestingly, attempts to promote the cyclization with POCl3 alone or different Lewis acids did not yield any pyrrole products. On the other hand, treatment of 8 with the non-nucleophilic base DBU gave the 4unsubstituted pyrrole product 10. In a different study involving a structurally related vinylogous amide (no S), an acid-promoted (p-TsOH, AcOH, or POCl3) intramolecular condensation reaction produced a 2-benzoylpyrrole derivative . Cl

Cl

OHC

POCl3 DMF, 80 °C

EtS

CO2Me

N H

SEt MeO2C

88%

DBU toluene, Δ

N H

EtS

34% O

9

8

CO2Me

N H 10

Cl

A base-mediated type Ib cyclocondensation of imino chlorides, derived from treating the corresponding N-allylamides with triphenylphosphite-chloride, provided 2-aryl- and 2,3diarylpyrroles . A novel intramolecular photocycloaddition involving vinylogous amides and allenes led to an interesting type Ib entry to functionalized pyrroles . For example, photolysis of allene 11 provided fused pyrrole 12 via a [2+2] cycloaddition and retro-Mannich reaction. O

O O

hν N H

87%

N H

HN

11

12

Ring closing metathesis (RCM) continues to enjoy significant attention directed at the preparation of heterocycles including type Ic syntheses of pyrroles. 2-Phosphonopyrroles were prepared utilizing an oxidative RCM as the key step . For example, treatment of 4-aza-1,6-diene 13 with Grubbs’ second-generation catalyst in the presence of the oxidant, tetrachloroquinone (TCQ), produced pyrrole 14. Microwave-assisted RCM reactions involving diallylamines were utilized to provide amino acid pyrrole derivatives (i.e., 15) and N-arylpyrroles . A synthesis of N-(3-fluorophenyl)pyrrole also was reported utilizing a RCM reaction Ph Grubbs 2nd Me TCQ, CH2Cl2

Me N Bn 13

P(OMe)2 O

84%

N N Bn 14

P(OMe)2 O

MeO O 15

138

E.T. Pelkey and J.S. Russel

A McMurry coupling reaction involving 3-aza-1,5-dicarbonyl compounds gave 2,5dihydro-3,4-diarylpyrroles . The latter were converted into the corresponding 3,4-diarylpyrroles by irradiation (Hg lamp, 500 W) in acetonitrile. Intramolecular condensation reactions involving enaminones and carbonyls (or their synthetic equivalents) provides another class of type Ic approaches to pyrroles. Treatment of enaminone 16 with TFA provided fused pyrrole 17 . 16 was prepared utilizing an aza-Wittig reaction between 1,3-cyclohexanedione and 2-azido-1,1-diethyoxyethane. An alternate synthesis of 17 was achieved utilizing an oxidation of a β-hydroxy enaminone promoted by palladium(0) and mesityl bromide . A number of different fused pyrroles were prepared utilizing this methodology. O

O EtO

16

5.2.2.2

OEt

95%

N H

O

Pd(PPh3)4 MesBr, K2CO3, DMF

TFA, CH2Cl2

OH

63%

N H

18

17

N H

Intermolecular Approaches

No type IIab approaches were abstracted. A type IIac synthesis of functionalized pyrroles was developed that adapted the Larock indole synthesis . For example, treatment of iodoacrylate 19 and trimethylsilylphenylacetylene 20 with palladium acetate led to the formation of pyrrole-2carboxylate 21 with excellent regioselectivity. 19 was prepared by iodinating (Niodosuccinimide) the corresponding commercially available dehydroamino ester.

SiMe3

I

Pd(OAc)2 LiCl, K2CO3 DMF, 65 °C

SiMe3

+ MeO2C

NHAc 19

81% Ph 20

MeO2C

N H

Ph

(> 25:1 regioselectivity) 21

A Knorr-type pyrrole synthesis involving the condensation between α-amino-β-ketoesters and β-ketonitriles provided β-cyanopyrroles . The former amine substrates were prepared by reduction of the corresponding α-isonitroso-β-ketoesters with Zn/HOAc. Following the communcation in 2004, a full report appeared that described type IIac cyclocondensation reactions between dihydroisoquinolines and α-nitrocinnamates leading to complex fused pyrroles . The latter were converted into the lamellarin alkaloids and related analogues. An oxidative radical coupling promoted by tetra-n-butylammonium cerium(IV) nitrate (TBACN) between β-aminocinnamate 22 and enamine 23 provided pyrrole-3,4-dicarboxylate 24 . Dimerization of the β-aminocinnamates provided symmetrical pyrroles.

139

Five-membered ring systems: pyrroles and benzo analogs

EtO2C

CO2Et + Ph

EtO2C

NH Ar

H 2N

22

CO2Et

TBACN, CHCl3 Ph

92%

Me 23

Me

N Ar 24

Two unique type IIad syntheses of pyrroles that were reported both involved cyclopropane fragmentations. The first allowed for a synthesis of 2-arylpyrroles . In the event, treatment of stannylcyclopropane 25 with n-BuLi followed by benzonitrile produced 2-phenylpyrrole 26 via tin-lithium exchange, addition to the nitrile, ring fragmentation of ketimine intermediate, intramolecular condensation, and loss of dibenzylamine. 1. n-BuLi 2. PhCN 3. AcOH SnBu3 Bn2N

Ph

80% Bn2N

N H

NLi

25

Ph

26

The second IIad synthesis provided a route to 2,3,4-trisubstituted pyrroles . Mixing cinnamaldehyde 27 with aminocarbene complex 28 in the presence of molecular sieves (MS) gave pyrrole 29. The authors proposed a mechanism that included a cyclopropane intermediate and subsequent fragmentation and intramolecular condensation.

Ph + HN

H

Cr(CO)5

MS 4Å toluene, Δ

Me

94%

Ph

Ph

OHC HN Me

N

proposed intermediate

29

Me

O 27

28

The preparation of 2-aminopyrroles was accomplished with type IIae zinc-catalyzed cyclocondensation reactions between β-cyanoketones and primary amines . Type IIae cyclocondensation reactions between primary amines and 1,4-dicarbonyl compounds (Paal-Knorr) or 2,5-dialkoxytetrahydrofurans (Clauson-Kaas) continue to remain the most utilized de novo approaches to functionalized pyrroles. An investigation into the utility of metal triflates in promoting the Paal-Knorr synthesis identified 1 mol% Sc(OTf)3 to be superior . The preparation of a library of tetra-substituted pyrrole-3carboxamides was accomplished utilizing a Paal-Knorr cyclization within a parallel solutionphase sequence . A few novel approaches for generating 1,4-dicarbonyl compounds appeared in reports aimed at preparing substituted pyrroles. The 1,4carbonylative addition reactions of arylboronic acids to methyl vinyl ketone catalyzed by a Rh(COD)2BF4 provided 1,4-diketones 99% (Ar = Ph) Ar 93% (Ar = 4-OMe-Ph)

N

Ar 45

The Jacobson thioanilide radical cyclization chemistry has been extensively used for the synthesis of benzothiazoles as shown by the preparation of 4-fluoro-2-(3,4-dimethoxyphenyl)benzothiazole 47 . The harsh reaction conditions (K3Fe(CN)6, NaOH,

246

Y.-J. Wu and B.V. Yang

S 46

F

R

Y

N H

48

K3Fe(CN)6 55% NaOH

S Ar

R

Ar

R

N

Ar

N 50

49

O

S

O I OAc AcO OAc DMP

Y N 47 F

N H

.

HS

S

Y = 3,4-di-OMe-Ph

S Ar

R

85-95%

.

R

S Ar N

N 51

52

H2O, EtOH, 90°C) can be overcome by using the Dess-Martin periodinane (DMP) (CH2Cl2, 25°C) . The reaction probably proceeds via thiyl radical 50, which undergoes 1,5-homolytic radical cyclization followed by aromatization of radical 51 to give 2arylthiazole 52. A modified Pictet-Spengler reaction has been applied to the synthesis of thiazoloquinolines 58 . Condensation of anilines 53 with aryl aldehydes 54 followed by endo cyclization results in the formation of thiazoloquinolines 58 under a variety of traditional Pictet-Spengler protocols such as 2% trifluoroacetic acid in dichloromethane. Ar S

ArCHO 54

NH2

R1HN

S R1HN

H S

NH

R1HN

NH

N

N

N

Ar

TFA 53

56

55 Ar S

R1HN

Ar NH

75-85%

S R1HN

N

N

57

58

N R1 = phenyl, benzyl

A novel series of 5H-thiazolo[3,2-a]pyridine-5-ones 64 is prepared by addition of malonic esters 59 to 2-alkynylthiazoles 60 . A plausible reaction mechanism involves an intramolecular cyclization of the initial adduct 61 to give the cyclobutenoxide intermediate 62. Ring-opening of this intermediate and subsequent cyclization lead to 5H-thiazolo[3,2a]pyridine-5-one 64.

247

Five-membered ring systems: with N and S (Se) atoms

R

1

R1

R2

CO2Me

N

+

CO2Me

•

R2

60 61 O R1 R2

R1 OMe

MeO2C

NaH

S

59

O MeO2C

N

R

O OMe

2

N

S

S 62

O

OMe 48-83%

N S CO2Me 63

R1 R

N S

2

R1 = Me, allyl R2 = Ph, n-Bu

CO2Me 64

5.5.2.3 Synthesis of Thiazolines Cyclodehydration of the compounds bearing C(=O)-S-C-C-NH2 moiety is a common approach to thiazolines. This method has been used repetitively to form the thiazoline moiety in a recent synthesis of chiral cyclic oligothiazolines . Exposure of thioester 65 to trifluoroacetic acid results in cyclodehydration to give thiazoline 66, a doubly protected dimer unit. This dimer is converted to carboxylic acid 67 via basic hydrolysis and thiol 68 by the activation of the thiazolidinone ring with a Boc group and subsequent base-induced ring opening. Acid 67 is coupled with thiol 68, and the resulting thioester is treated with trifluoroacetic acid to furnish tetramer 69, which undergoes double deprotection to provide thiocarboxylic acid 70. Di- and tri-merization of this acid in a head-to-tail fashion produce a 1.8 : 1 mixture of macrocyclic thioesters 71a and 71b in 63% yield. Boc deprotection of 71a and 71b and subsequent cyclodehydration give cyclic octathiazoline 72a and dodecathiazoline 72b, respectively.

248


Boc HN Me O H Me CO2Me N S S 65

O

Me N H Me N

TFA 96% O

Me CO2R

S

Boc2O, 91%; NaOMe, 81%

S NaOH 78%

Boc Me N HN HS

CO2Me S

68

66 R = Me 67 R = H Me

67,BOPCl, Et3N, 77%; TFA, 93%

Me N Me N N H Me N

S

Boc Me N HN

Boc2O, 90%; NaOH, 81%

S

S

Me

Me N S

N Me O NHBoc

S

63%

S

S TFA

Me

Me

N Me

N

N

N

S

79% (a) 77% (b)

S

N

N S

S

Me S 71a/b

Me

Me

Me

N

N

Me

S

S

N

S

70

S

N BocHN O Me

CO2H

S

HS

69 S

BOPCl, Et3N

Me N

S

O

Me Me N

CO2Me

S Me S

N

N

Me

Me

S

n a: n = 1; b: n = 2

Me S 72a/b

n

Compounds bearing C(=S)-NH-C-C-OH fragment (β-hydroxy thioamide) can also undergo cyclodehydration to form thiazoline derivatives. The utility of this strategy has been demonstrated in the synthesis of halipeptins A and D . Exposure of 73a/b with (diethylamino)sulfur trifluoride (DAST) brings about intramolecular cyclization to provide thiazolines 74a/b, which are advanced precursors to halipeptins A and D. Me

OMe

O

n-Pr

Me H Me O N

Me S Me O O

Me 73a/b

Me

OH

R

N

N CO2Me DAST Me

OMe

85% N3

Me

Me

n-Pr a: R = (CH2)2OTBDPS b: R = Et

O

Me S Me O O

Me 74a/b

Me O

R

N CO2Me Me

N3

Me

Kelly’s biomimetic methodology, first reported in 2003 , has become one of the most reliable routes to thiazolines. In this approach, the phosphorus-activated amide carbonyl group undergoes nucleophilic attack by the cysteine thiol group to provide the thiazoline moiety (see 76). Kelly’s thiazoline formation has been applied to the total syntheses of three complex natural products: halipeptin A (75 to 77) , apratoxin A (78 to 79) and (R)-telomestatin . The typical protocol in Kelly’s

249


methodology involves triphenylphosphine oxide and triflic anhydride, but the cyclodehydration and deprotection of S-t-Bu group in 80 is carried out with addition of anisole, which drives the reaction to completion. Kelly’s approach is also utilized in the solid-phase synthesis of thiazoline-based peptides 82 from resin-bound dipeptides 81 . Me HN Fmoc

O

Ph3P(O), NH CO2allyl Tf2O Me

Me FmocHN (TfO)Ph3P

STr

75

Me N

CO2allyl

75%

Me

O S Tr

CO2Allyl

N

HN Fmoc

Me

S 77

76 CO2Allyl

Me NH

O

Troc Me

t-Bu O

STr

O

O Me

Ph3P(O), Me Fmoc Tf2O N

N

O

Troc Me

t-Bu O

S

O Me

78

O

HN N

N N

N

Ph3P(O), O Tf2O, Me anisole O

N O

20%

N

N

N

N

N

O

N

N

Me O

Me Ph3P(O), Tf2O

O Me

O telomestatin

80

O

O 81 TrS

O

N

NH

RHN

R

N

Bn

O

O

O

S

O

St-Bu

Fmoc N

79 Bn

O

O N

CO2allyl

O

O N

RHN

O

S

82 R = CBZ, Fmoc

5.5.2.4 Reactions of Thiazoles and Fused Derivatives The first practical, large-scale synthesis of 2-amino-5-fluorothiazole 84 employs the reaction of dilithiated 2-butoxycarbonylaminothiazole 83 with N-fluorobenzenesulfonimide (NFSi) . This reaction generates a 70 : 15 mixture of the desired fluorinated thiazole 84 and the sulphone 85, and after three consecutive recrystallizations thiazole 84 is isolated in 35-40% yield. This procedure has been utilized to prepare multikilogram quantities of 84, which is a heterocyclic amine component of a series of glucokinase inhibitors. BocHN

S N 83

t-BuLi; NFSi 36% (84)

BocHN

S N 84

F

+

BocHN

S

SO2Ph

N 85

A regioselective generation of thiazol-2-yl and benzo[d]thiazol-2-yl magnesium chlorides (87 and 89) uses 2,2,6,6-tetramethylpiperidyl MgCl•LiCl (TMPMgCl•LiCl), readily available by reacting iso-propyl MgCl•LiCl with 2,2,6,6-tetramethylpiperidine

250


. This mixed Mg/Li amide, which has excellent solubility in THF (1.2 M) and is stable for more than six months as THF solution at 25°C, allows the regioselective functionalization of various aromatic and heteroaromatic compounds. Thus, both thiazole and benzothiazole undergo smooth C-2 magnesiation with TMPMgCl•LiCl at 25°C, and the resulting magnesium chlorides are trapped with benzaldehyde and iodine, respectively, to furnish adducts 88 and 90. Me

Me

S + N

N MgCl•LiCl

THF, 25°C

N 87

Me Me TMPMgCl•LiCl 86 S

THF, 25°C

N

S

PhCHO MgCl

S

TMPMgCl•LiCl

N

S

94%

OH

S

I2 MgCl

Ph

N 88

98%

I

N 90

89

A new methodology for direct phosphonation of thiazoles has been developed . Reaction of substituted thiazoles 91 with dimethyl or diethyl phosphates in the presence of manganese (III) acetate dihydrate provides 5-dimethyl or diethylphosphonothiazoles 95. The high C-5 regioselectivity is rationalized by comparing the two intermediates 93 and 94, which result from the attack of phosphonyl radical 92 to the thiazole ring at the C-4 and C-5 position, respectively. The radical in intermediate 94 is next to an imine as opposed to a sulphur as in the case of 93, and therefore, 94 is more stable than 93. As a result, the C-5 phosphonation involving 94 is favored. In the case of unsubstituted thiazole, the C-2 and C-5 phosphonations proceed in a ratio of 78 : 10, indicating that the C-2 position of thiazole is most reactive for phosphonation, followed by the C-5, and the C-4 is the least. R2 5

4

Mn(OAc)3

N

S 2 91

R1

R1 = H R2 = H N

HP(O)(OR)2 • P(O)(OR)2 92

R2 • 1

R

2 XR =H

O O P(OMe)2 + (MeO)2P

S 97 (78%)

O 2 (RO)2P R N • S 93

N

S 98 (10%)

(RO)2P O

R2

80-92%

N R1

S 94

N (RO)2P O

S

R1

95

1

O (MeO)2P

N S 96

R1

R = Me, Et, OMe, OEt, H, acetyl R2 = Me, Ph, H R = Me, Et

A mild and efficient α-heteroarylation of simple esters and amides via nucleophilic aromatic substitution has been described . Treatment of 2-chlorobenzo[d]thiazole 99 with tert-butyl propionate in the presence of NaHMDS under nitrogen furnishes tert-butyl 2-(benzo[d]thiazol-2-yl)propanoate 100. When the same reaction is preformed initially under nitrogen and then exposed to air, the hydroxylation product 101 is obtained. This method offers two desirable features that are either complementary or improvements to the palladium-catalyzed α-arylation reactions. First, heteroaryl chlorides

251


may be used; Second, the reactions can be conducted at ambient temperature as opposed to the elevated temperature usually required by palladium-catalyzed α-arylation reactions. S N 101

CO2t-Bu OH Me

NaHMDS, EtCO2t-Bu,

S Cl

air, 84%

NaHMDS, EtCO2t-Bu, N2, 91%

N 99

S

CO2t-Bu

N 100

Me

The palladium- and copper-mediated C-2 arylation of thiazole with 4-iodoanisole under ligandless and base-free conditions provides 2-(4-methoxyphenyl)thiazole in good yield . However, the scope of this selective C-2 arylation has not been disclosed. N MeO

I

+

Pd(OAc)2 (5 mol%) CuI (2 equiv)

N MeO

84%

S

S

Several palladium-catalyzed C-5 arylations of thiazoles have been reported. For example, 2,5-diarylthiazole 104 is prepared via arylation of thiazole 102 at C-5 with aryl iodide 103 using PdCl2(PPh3)2 as a catalyst and silver(I) fluoride as an activator . The selectivity in the arylation of 4-methylthiazole with biphenyl triflate 105 depends on the choice of base: cesium carbonate favors the C-2 arylation, while the C-5 arylation dominates with potassium carbonate . The C-2 selectivity issue is overcome by using 2trimethylsilylthiazoles, which serve as efficient counterparts for palladium-catalyzed crosscoupling reactions with aromatic triflates (without any fluoride anion source) to afford 2-aryl thiazoles. For example, mono-thiazoles 110a/b are obtained from triflate 108 using 2trimethylsilylthiazoles 109a/b. N S 102

Ar

1

PdCl2(PPh3)2 (3 mol%), AgF Ar2I 103

N Ar2

Ar1 = 4-OMe-Ph; Ar2 = 4-CO2Et-Ph

OTf OH

Pd(OAc)2, PPh3, K2CO3, LiCl R N

S 104

Ar1 46%

108

Pd(OAc)2, PPh3, base

N S

N

OH

TMS

S 109a (R = H) 109b (R = Me)

OTf 105

Ph

110a (71%) 110b (73%)

Ph S 106

N Me

S

Me

+ Me

Ph

S

N

1.6 : 1 (Cs2CO3) 107 1 : 3.5 (K2CO3)

A cobalt-catalyzed method for arylation of heteroarenes including thiazole and benzothiazole was reported in 2003 . According to this report, the direct C-5 arylation of thiazole with iodobenzene was carried out in the presence of cobalt catalyst [Co(OAc)2/IMes] and cesium carbonate, and a complete reversal of arylation from C-5 to C-2 was observed with the bimetallic Co/Cu/IMes system. This report has been retracted as the laboratory of the senior author has not been able to reproduce the key results disclosed in the communication .

252


N Ph

S

Ph-I, IMes (10 mol%) X Co(OAc)2 (5 mol%), Cs2CO3, 64%

Ph-I, IMes (10 mol%) X Co(OAc)2 (5 mol%), CuI, Cs2CO3, 84%

N S

N Ph

S

A parallel synthesis of a library of 2-aryl-6-chlorobenzothiazoles 112 involves a regioselective palladium-catalyzed Suzuki coupling reaction of 2,6-dichlorobenzothiazole 111 with arylboronic acids (1.1 equiv) under microwave irradiation . When excess phenylboronic acid is used, Pd(PPh3)4 still provides 2-phenyl-6-chlorobenzothiazole exclusively, while 2-dicyclohexylphosphinobiphenyl 113 generates 2,6diphenylbenzothiazole as the major product.

Cl

S Cl

Me2N

ArB(OH)2, Pd(PPh3)4, Na2CO3, dioxane/H2O

Cl

S Ar

57-79%

N

N PCy2 113

112

111

The synthesis of 4-bromo-2'-chloro-2,5'-bis(thiazole) 117 from 2-chlorothiazole via palladium-catalyzed cross-coupling reactions has been reported . Among the three coupling methods (Negishi, Suzuki and Stille), the Stille coupling route proves to be the best. Lithiation of 2-chlorothiazole with LDA and subsequent quenching with tributyltin chloride give 2-chloro-5-tributylstannylthiazole 114, which is coupled with 2,4-dibromothiazole 116 to give bis(thiazole) 117. This compound can also be prepared by the Suzuki coupling reaction of 2,4-dibromothiazole with the first known thiazoleboronic acid ester 115, but the yield is much lower. The Negishi coupling protocol suffers from substantial side reactions and results in an inseparable mixture of products. The transition-metal-catalyzed cross-coupling reactions on various azole systems including thiazoles and benzothiazoles have been summarized in a recent review . S

LDA, Bu3SnCl Cl

95%

N

LDA, B(O-iPr)3; pinacol; HOAc 95%

Bu3Sn

Br S

Stille (81%)

Cl N 114 Me O Me B Me O Me 115

Br

N

S N

S

117

N

Cl Br

S 116 S Cl

Suzuki (12%)

N

A synthesis of the eastern fragment of the thiazole peptide GE2270 relies on a regioslective bromine-lithium exchange reaction of thiazoles and Negishi cross-coupling reaction . 2,4-Dibromothiazole 116 undergoes the known regioselective bromine-lithium exchange to give 4-bromo-2-thiazolyl lithium 118, the TBS protected (S)mandelate 119 is added, and the resulting adduct is reduced stereoselectively to provide threo alcohol 120. This alcohol is converted the Boc protected amine 121 in a four step sequence. Bromine-lithium exchange of 121 and subsequent transmetalation to zinc are followed by a regioselective Negishi cross-coupling with 2,4-dibromothiazole 116 to furnish bis(thiazole) 122. This compound could serve as a building block for the synthesis of thiazolyl peptide GE2270.

253


Br

1.

Br N

n-BuLi

N

Br S 116

Li S 118

EtO2C

Ph

119 OTBS 92%

Br N

Ph OTBS

S 2. L-selectride, 86%

OH

120

4 steps

Br N

1. t-BuLi, ZnCl2 Br 2. 116, [PdCl2(PPh3)2]

S N S 122

Ph OTBS NHBoc

44%

N S 121

Ph OTBS NHBoc

The cycloaddition of 2-aminothiazoles with dimethyl acetylenedicarboxylate (DMAD) has been thoroughly investigated . Treatment of thiazoles 123 with DMAD in acetonitrile leads unexpectedly to 6-(dimethylamino)-3,3-pyridinedicarboxylates 128. According to the proposed mechanism, nucleophilic attack of the thiazole at C-5 to DMAD gives the zwitterionic intermediate 124, which cyclizes to the fused cyclobutene 125, the formal [2 + 2] adduct. Thermal disrotatory opening of 125 leads to all-cis 1,3-thiazepine 126, which undergoes a symmetry-allowed disrotatory 6π-electrocyclic ring closure to give 7-thia2-azanorcaradiene 127. Desulfurization of 127 gives rise to pyridine 128. Alternatively, the zwitterionic intermediate 124 could lead to 7-thia-2-azabicyclo[2.2.1]hepta-2,5-diene 129, the formal [4 + 2] cycloadduct, through the attack of its carbanionic center to the C-2 of thiazole moiety. Further sulphur extrusion in 129 would provide the regioisomeric pyridine 130. This pathway proves to be operative, although in low extension, only in rare instances. The zwitterionic intermediates can be trapped when the reactions are carried out in methanol instead of acetonitrile. For example, exposure of thiazole 131 to 1 equiv of DMAD in methanol gives a 24 : 76 mixture of (E)- and (Z)-isomer 132 and 133. In the case of thiazole 134, the fused cyclobutene intermediate 135 is isolated in 52% yield, and it cleanly transforms into pyridine 136 under thermal conditions.

254


NMe2 S 123 N

NMe2 S N

R

R

E

E

N

E

solid arrow

Me

E

N

E

R 125

E

N

N

N

R

E +

N

R = 4-Tol

Me

N 132

R

H 52% Me

S

Me Me

N

E E

R 127 S

Me N

N 133

N

Me 135

R

E

Me

E

Me

90%

E

E

N

Δ

N

N 134

DMAD

N

R

Me

Me2N S

H

E

S

Me

90%

126

S

E

E

N

70-91% Me

128

130 DMAD

E

R

Me

Me R

S

E

N

Me

E

N

R

Me

E = CO2Me; R = CH=CH-Ar, Ar

Me2N

131

S

Me N S

N

E

Me

S

129

Me

Me E

N

[2+2]

dashed arrow

E

Me

E

124 [4+2]

Me

H

N

E

136 Me

Oxidation of thiazoles 137 with HOF•MeCN provides easy access to the family of thiazole N-oxides 138 . The readily made HOF•MeCN complex, considered to be one of the best oxygen transfer agents in chemistry, transfers an oxygen atom directly to thiazole-containing compounds without affecting the double bonds of the thiazole moiety. A small amount of N,S,S-trioxide 139 is also formed in this oxidation. R2

R2 R3

S 137

R1

R2

O N

HOF•MeCN

N

R3

S

O N

R1

138 (78-91%)

+

R3

S

R1

O O 139 (3-10%)

R1 = H, Me R2 = Me, aryl R3 = H, Me, Ac, (CH2)2OAc

5.5.2.5 Thiazole Intermediates in Synthesis An enantioselective synthesis of both (R)- and (S)-α-alkylcysteines 144 and 147 is based on the phase-transfer catalytic alkylation of tert-butyl esters of 2-phenyl-2-thiazoline-4carboxylic acid and 2-ortho-biphenyl-2-thiazoline-4-carboxylic acid, 142 and 145 . Treatment of 142 and 145 with alkyl halides and potassium hydroxide in the presence of chiral catalysts 140 and 141 gives the alkylated products, which are hydrolyzed to (R)- and (S)-α-alkylcysteines 144 and 147, respectively, in high enantioselectivity. This method may have potential for the practical synthesis of chiral α-alkylcysteines.

255


X

Et Br

X

CO2t-Bu

N S

N

CO2t-Bu

S Ph

141

140 (1 mol%), RX, KOH 42-99% yield 67-99% ee

142

O allyl

N

140 X = 3',4',5'-trifluorophenyl

Ph

CO2t-Bu R

N Ph

H

S

143 R = alkyl, allyl, benzyl, propargyl

141 (1 mol%), RX, CsOH

CO2t-Bu R

N

CO2H R

H2N HS

144

CO2H R

H2N

H

S

77-99% yield 68-88% ee

145

N

HS

Ph

147

146

The utility of thiazolidinethione chiral auxiliaries in asymmetric aldol reactions is amply demonstrated in a recent enantioselective synthesis of FD-891, a 16-membered macrolide . This synthesis features four thiazolidinethione propionate aldol reactions for controlling the configuration of 8 of 12 stereogenic centers. For example, addition of aldehyde 149 to the enolate solution of N-propionyl thiazolidinethione 148 produces aldol product 150 with excellent selectivity (dr > 20:1) for the Evans syn isomer. Compound 148 also undergoes diastereoselective aldol addition with 3-butenal to give the non-Evans syn aldol product 152 under different conditions (dr > 15:1). Both aldol products are incorporated into FD-891. Asymmetric aldol reactions using thiazolidinethione chiral auxiliaries are also applied to the synthesis of bistramide , (+)-SCH 351448 and salinomycin . OTBS

Bn Me N

S

TiCl4, (-)-sparteine, NMP, CH2Cl2, 78%

Bn N

S

TiCl4, Me (-)-sparteine, CH2Cl2, 73%

OHC

S

O OH 150

149

OTBS

S

O

148

OHC

151

Bn Me N

S S

O

OH

152

The stereoselective addition of the titanium enolate of N-acetyl-4-phenyl-1,3-thiazolidine2-thione 153 to the cyclic N-acyl iminium ion 154 is utilized in the synthesis of (-)stemoamide, a tricyclic alkaloid . The iminium ion addition product 155 undergoes magnesium bromide-catalyzed anti-aldol reaction with cinnamaldehyde 156 to give adduct 157, which possesses the required stereochemistry of all chiral centers for the synthesis of (-)-stemoamide.

256


Ph

Me

N

S

TiCl4, DIPEA N

Me + AcO

S O 153

O

92%

Me MgBr•Et2O, TMSCl, Et3N; HCl

Ph

S

154

O

N

N

S

O

156 CHO 74%

H 155

Me

N NH

S

Ph

O

Ph

S

O

Ph OH 157

N-(Alkoxy)thiazole-2(3H)-thiones 158 are precursors to alkoxyl radicals which can participate additions, β-fragmentations and remote functionalizations . For example, microwave irradiation of 158 in the presence of tributytin hydride or bromotrichloromethane affords tetrahydrofurans 162a and 162b, respectively. Conceivably, the alkoxyl radical 160, generated under microwave conditions, undergoes 5-exo-trig cyclization to give a cyclized radical 161. Hydrogen (Bu3SnH) or bromine atom transfer (BrCCl3) onto radical 161 leads to tetrahydrofuran derivatives 162a/b. Ar

Ar S Me

N O

S

X-Y μW

Me

N• 159 O•

S

X-Y

S

Ar

S

Me

N O

5-exo-trig

163 •

Ph 158

Ph

Ph 160

161

SY

X -Y = H-SnBu3, Br-CCl3 Ar = 4-OMe-Ph X

64% (X = H) 68% (X = Br)

O Ph 162a (X = H) 162b (X = Br)

The synthesis of a series of piperidine imino-C-glycosides 169 involves a stereoselective addition of 2-thiazolylmagnesium bromide 165 to a N-glycosylhydroxylamine 163, a hidden open-chain sugar nitrone 164 . The resulting N-thiazolylalkylhydroxylamine 166 is reduced to a secondary amine, which, upon mesylation, transforms into a substituted piperidine 167 via a SN2 intramolecular cyclization. Cleavage of the thiazole ring to formyl group is carried out by a one-pot, three-step reaction sequence consisting of microwaveassisted N-methylation of the thiazole ring by methyl iodide, reduction of the Nmethylthiazolium salt with sodium borohydride, and mercury chloride-promoted hydrolysis of the resulting thiazolines. The crude piperidine aldehyde is further reduced to the primary alcohol 168, and removal of the O-Bn and N-Bn groups in 168 affords a pair of 2,6-dideoxy2,6-iminoheptitol hydrochlorides 169.

257


O

BnO

OH NBn

OH BnO BnO

OBn

BnO

BnO

OBn

(ThMgBr) 80%

S

164

H2 N

BnO

N

OBn

OBn 163

Cl

O NBn

OH

Pd(OH)2/C, HCl, H2

BnO

92%

OBn

MgBr 165

BnO

6

BnO

OBn OBn

6S/6R = 3/1

166

1. Cu(OAc)2•H2O, Zn, HOAc (74%) 2. MsCl, Et3N (80%)

Bn N

MeI; NaBH4; OH HgCl2; NaBH4

BnO

56%

OBn

Bn N

BnO BnO

OBn 168

OBn 169

OH NBn

HO Th

Th OBn

OBn 167

6-Nitro-2-benzothiazolyl α-manniside 170 has been identified as an efficient mannosyl donor in the direct β-selective mannosylation of glucosamine derivatives . Mannosylation of 171 with 170 using HB(C6F5)4 as a promoter proceeds smoothly to give a 4 : 1 mixture of β- and α-mannosides 172. This represents the first example of direct βselective mannosylation with the chitobiose acceptor 171. The β-trisaccharide 172 serves as a key building block for the synthesis of the pentasaccharide core commonly present in the Nlinked glycans.

OBn AllylO

OAllyl OBn O

+

HO AllylO

OBn AllylO

N

OBn O PhthN

O S 170 O BnO 171

NO2 HB(C6F5)4 (20 mol%) 5A° MS

OBn O PhthN

N3

OAllyl OBn O O AllylO

OBn O PhthN

O BnO

172 95% (α/β = 1/4)

OBn O PhthN

N3

The Julia olefination reaction involving alkylsulfonyl benzothiazoles remains one of the most effective methods for the stereoselective formation of olefins. The power of Julia olefination is demonstrated in the total synthesis of cystothiazole A and FR901464 . Coupling of sulfone 173 with aldehyde 174 using LHMDS proceeds stereoselectively to give a 14 : 1 mixture of cystothiazole A and its Z-isomer in 64% yield. Epoxyaldehyde 175 also undergoes E-selective Julia olefination with sulfone 176 to give the desired diene 177, which is converted to FR901464 in four steps. The Julia olefination reaction involving alkylsulfonyl benzothiazoles is also applied to the synthesis of phorboxazole A , iejimalide B , (-)-codonopsinine , myxothiazols .

258


O O S N

S N

S

CHO

+

S

R

Me 174

173 Me

O

CHO

MeO 175 O

OTBS

176

Me Me

O

O

MeO

Me OTBS O

Me Me O

E/Z = 14/1 R

Me

O

i-Pr

N

N

R = CO2Me

S O O Me S N

+

OMe OMe

LiHMDS 64%

OMe OMe

i-Pr

N

S

S

cystothiazole A

Me Me O

OTBS

LiHMDS 68%

Me

N H

OTBS

N H

177

There are several new methodologies based on the Julia olefination reaction. For example, 2-(benzo[d]thiazol-2-ylsulfonyl)-N-methoxy-N-methylacetamide 178, prepared in two steps from 2-chloro-N-methoxy-N-methylacetamide, reacts with a variety of aldehydes in the presence of sodium hydride to furnish the α,β-unsaturated Weinreb amides 179 . An efficient synthesis of fluorinated olefins 182 features the Julia olefination of aldehydes or ketones with α-fluoro 1,3-benzothiazol-2-yl sulfones 181, readily available from 1,3-benzothiazol-2-yl sulfones 180 via electrophilic fluorination . A similar strategy has been applied to the synthesis of α-fluoro acrylates 185 . S O O O Me S N N OMe 178 S O O S N Ar 180 S O O S N t-BuO2C 183

NaH, RCHO R 44-72% R = alkyl, aryl, sugar

LDA, NFSi 90% NaH, Selectfluor 73%

S O O S F N Ar 181 S O O S F N t-BuO2C 184

O

Me N OMe 179 LHMDS, R1R2C(O) 62-98%

R1

Ar

R2

F 182

RCHO, DBU

t-BuO2C

R

F

H

70-99% 185

5.5.2.6 Thiazolium-Catalyzed and -Mediated Reactions The thiazolium-catalyzed addition of an aldehyde-derived acyl anion with a Michael acceptor (Stetter reaction) is a well-known synthetic tool leading to the synthesis of highly funtionalized products. Recent developments in this area include the direct nucleophilic addition of acyl anions to nitroalkenes using silyl-protected thiazolium carbinols . In the presence of a fluoride anion, carbinol 186 is not cleaved to an aldehyde

259


and thiazolium zwitterion, but instead, it acts as nucleophlic acyl reagent, thereby selectively accessing carbonyl anion 189 presumably via a 1,2-hydrogen shift of the initial adduct 188. Treatment of carbinol 186 with tetramethylammonium fluoride (TMAF) and thiocarbanilide in the presence of nitroalkenes 187 provides β-nitroketones 190. In the absence of the thiourea additive, the yield is significantly lower. The incorporation of chiral thiourea 193, derived from quinine, into the reaction with (E)-(2-nitrovinyl)cyclohexane 191 produces βnitro ketone 192 in 74% ee. This fluoride-activated acyl anion strategy is divergent from the typical combinations of heteroazolium salts and bases, and therefore reactive nitroalkenes can be used as substrates (nitroalkenes decompose rapidly upon exposure to amine bases). Y

OTES Ar

N I Me Me 186 TMAF 193

Me

NO2

Ar

O 192

Ar

H

Me

N

Me

Ar = 4-Cl-Ph Y = alkyl, aryl

191

OH

188

N Me Me 189

N

F3C

N H

O

OMe

N H 193

Me

56-80%

O

67% yield 74% ee R = cyclohexyl

S

Ar

Me

CF3

NO2

1,2-H shift

S

(PhNH)2C=S

R

R

O

NO2 187 Me4N•F

S

Ar N

NO2 Y 190

H

The conjugate addition of acylsilanes to unsaturated esters and ketones utilizing Nheterocyclic carbenes derived from thiazolium salt 200 (Sila-Stetter reaction), first communicated in 2004 , has been described in full detail . The proposed reaction pathway starts with the deprotonation of the thiazolium salt 200 with DBU to yield thiazol-2-ylidene 201, a nucleophilic carbene. Addition of this carbene to acylsilane 194 generates intermediate 196, which undergoes a 1,2-silyl group migration from carbon to 195 O Ph

Ar TMS

194

N

O

TMS Ph

Ar'

200 (30 mol%) DBU (30 mol%)

Et

Y

Brook

HN

H

P(O)Ph2 Ph

Ar O 203

S Ph

Y

N

50-82%

Y

N Br

Me 200

O 198 RNH2, acid

S

DBU N Et

Ph Ar'

Me 197 acyl anion

S Et

O Ar

Et

Me

196 Y = (CH2)2OH

P(O)Ph2

200 (30 mol%) DBU (30 mol%) 77-94%

OTMS S N

202 Ar

O

Me Br 201

Y

Ph Ar

R N

Ar'

199

to oxygen (Brook rearrangement). This thermodynamically driven migration results in acyl anion equivalent 197, which adds to the α,β-unsaturated ketones 195. This carbonyl anion methodology provides easy access to various 1,4-diketones 198, which are well known precursors to polysubstituted furans and pyrroles. The thiazolium-catalyzed additions of

260


acylsilanes have also been extended to N-phosphinoylimines 202 to give α-aminoketones 203. The N-heterocyclic carbene (NHC) catalyzed carbonyl anion addition reactions have been extensively investigated, but in contrast, the corresponding nucleophilic substitution reactions have received considerably less attention. Recently, NHCs generated in situ from thiazolium salts 205 have been applied to intramolecular nucleophilic substitution reactions . For example, treatment of aldehydes 204 with 205 (25 mol%) and DBU (70 mol%) at 160°C provides benzopyrones 208. In the case of aldehydes 209, benzofuranones 212 are obtained exclusively. Presumably, the reaction involving aldehyde 204 proceeds via SN2 pathway, while aldehyde 209 undergoes SN1 reaction, where the initial carbon cation 210 rearranges to give the more stable intermediate 211, thus leading to benzofuranones 212. Y

Y

Me

Y

Me

S

N Me

S

N Me OH

S Me CHO

205 I

R

X

O

204 Y = (CH2)2OH; X = I, OTs

CHO

X

DBU 48-76%

HO O 206

R

Ar

O R

R

O 208

O 207

Y

Me

Y

Me

S

N Me

S

N Me

205

R O

N Me

O Ar R

OTs DBU 45-86% R

HO O 210

209

R Ar

O

HO Me O Ar 211

Me

212

Benzotetramisole 213 has been identified as an effective catalyst for kinetic resolution of sec-benzylic and propargylic alcohols 214 to give 215 in excellent enantioselectivity . The benzotetramisole-catalyzed kinetic resolution has been extended to 2-oxazolidinone 217 via enantioselective N-acylation . (RCO)2O DIPEA,

OH R1 R2 214 O HN

213 (4 mol%)

OH R1 R2 215

(EtCO)2O, DIPEA, O

Ph 217

213 (4-10 mol%) 15-50%

OC(O)R +

R1

R2 216

R1 = phenyl, propargyl R2 = alkyl R = i-Pr, Et

O

O N

O O

+

HN

S O

Et Ph 218 (92-99% ee)

Ph 219 (17-99% ee)

N 213

N Ph

Asymmetric hydrogenation of trisubstituted aryl alkenes and aryl alkene esters using iridium-phosphine thiazole complexes 220 have been reported . The tetrahydrobenzo[d]thiazole complex (220b) delivers higher enantioselectivity than the cyclopenta[d]thiazole and cyclohepta[d]thiazole counterparts (220a and 220c), and replacement of thiazole moiety with oxazole dramatically reduces the enantioselectivity. The

261


iridium-N-heterocyclic carbene-tetrahydrobenzo[d]thiazole complex 221 is also synthesized, but only moderate enantioselectivity is obtained . Ph BArF

N

Ph2 P Ir

N

N

Ir

R3

R1

H H2, 220 or 221 (0.5 mol%)

>98% ee(220) 34-90% ee (221)

N Ph

Ph

S

S

220a/b/c a: n=0; b: n=1; c: n=2

221

( )n

R2 BArF

R2 H R1

BArF = tetrakis(3,5-di-trifluoromethylphenyl)borate

R3 H H

The C2-symmetric bifunctional tridentate bis(thiazoline) 222 has been shown to promote the zinc(II)-catalyzed asymmetric Michael addition of nitroalkanes to nitroalkenes in high enantioselectivity . The corresponding bis(oxazoline) ligand provides comparable enantioselectivity but higher product yield. The same bis(thiazoline) ligand has also been evaluated in the enantioselective Friedel-Crafts alkylation of indoles, but the enantioselectivity is moderate .

NO2

Ph 223

N H S

N

N

Ph Ph 222

EtNO2 222 (25 mol%) Et2Zn (25 mol%) Ti(Oi-Pr)4

S Zn(OTf)2 (5 mol%) 222 (5 mol%)

Ph Me

NO2

NO2 224 syn/anti = 11.7/1 54% yield, 95% ee Ph *

N H

NO2 N H

99% yield 78% ee

225

5.5.2.7 Thiazole-Containing Natural Products During the past year, there have been numerous reports on the synthesis of thiazolecontaining natural products, including halipeptin A , halipeptin D , obyanamide , tubulysin D , tubulysin U and V , apratoxin A , cystothiazole , myxothiazol A and Z , bistratamide , (R)-telomestatin and GE 2270 . The relative and absolute stereochemistry of antimitotic macrolide archazolid A and B, originally isolated in the early nineties, has been determined on the basis of extensive highfield NMR studies, molecular modelling and chemical derivatization . The proposed structures have yet to be confirmed by total synthesis. The E stereochemistry at Δ14,15 of (-)-mycothiazole has been revised to Z, and a closely related analog, mycothiazole-4,19-diol, has also been isolated from Cacospongia mycofijiensis . Studies on a recent collection of the Red Sea sponge Negombata magnifica have led to the discovery of latrunculin T, a new member of the latrunculin family .

262


Ar

OMe n-Pr Me O

HN

O H

O Me

Me

Me

N

Me

N

NH Me Me N O

Me O Me

S

S

Me

Et

N

N R1

S

i-Pr

N

Me

OMe OMe

Me

O O

NH

O Bn

i-Pr O

N

4

S

S

N H N Me Me N O

MeO 4

O

19

OH OH

N

N

N

N

N N

HN

N

O

telomestatin

Me Me

O O i-Bu

O

mycothiazole-4-19-diol

S

Me

Me MeO

H N

O

O

Me

OH

15

15

Me

Me

O Et

mycothiazole

14

O

N

Me

Me Me R

MeHN

S Me Me

N

O

O OH

S

Me

i-Pr

14

Me Me

19

S CH2OMe i-Pr GE 2270

Me

N

obyanamide

S

NH N

O

myxothiazol A (R = NH2); myxothiazol Z (R = OMe)

O

N S

N

S

MeO

H N

O

Me

OH

O

Me O

N

HN

CO2H

S

S cystothiazole

Ph O

N O

O N

OH

S

Me

O

NH2

S

N

Bn HN

OMe OMe

ROC

N

S

Me t-Bu apratoxin (Ar = 4-MeO-Ph) MeHN

N

O

N

N

OH

tubulysin D (R1 = CH2OC(O)i-Bu, R2 = Ac) tubulysin U (R1 = H, R2 = Ac) tubulysin V (R1 = H, R2 = H)

MeO2C

Me

O

i-Pr OR2

N

N

Et

O

O

O

S

O

O

O

Me

halipeptin A (R = OH) halipeptin D (R = H)

N Me

Me

OO Me N

N

(CH2)2R

H N

O

Me N

N

O

O S archazolid A (R = Me) archazolid B (R = H) OH R Me

Me

latrunculin T (R = CO2H)

5.5.2.8 Thiazole-Containing Drug Candidates A number of biologically important thiazole analogs have been disclosed, including SSR125543 (CRF1 antagonist as antidepressant, phase I) , tebipenem and its prodrug, tebipenem pivoxil (broad-spectrum antibacterial agents, phase II) , BMS-605541 (antitumor agent) , GW610 (antitumor agent) , BAL-4815 (antifungal agent, phase I) , and AF267B (M1 muscarinic receptor

263


agonist for Alzheimer’s disease, phase I) . The discovery of the second generation epothilones as antitumor agents, including fludelone (preclinical), has been reviewed . S

OMe

Me

Me

O

N

fludelone Me

N N

O

Me Me O OH MeO

OMe

F

S GW 610

CN

NMe N H H Me

N

S AF267B

Et S N

S

N

O

CO2R tebipenem (R = H) tebipenem pivoxil (R = OCH2OC(O)t-Bu)

BAL-4815

H N

O

SSR-125543

Me

N F

5.5.3

Cl

HO

S

F

N

N

N

N Me

HO

S

Me

OH Me

Me

F3C

Me F

F

F

S

HN

NH

N H

N

O

BMS-605541

ISOTHIAZOLES

5.5.3.1 Synthesis of Isothiazoles A novel synthesis of alkylsulfanylisothiazoles 230 starts with sodium α-cyanoketene dithiolates 227, obtained by the reaction of cyanoacetamides 226 with carbon disulfide in the presence of sodium ethoxide . Treatment of 227 with sulphur and piperidine acetate generates sodium isothiazole-3,5-dithiolates 229. The formation of 229 is assumed to arise from the addition of anionic sulphur to the nitrile group in 227 to give the intermediate 228, which cyclizes upon elimination of anionic sulphur to yield 229. Salts 229 are readily alkylated to furnish 3,5-bis(alkylthio)isothiazole derivatives 230. Ar HN O 226

NaS

NaOEt, CS2 CN 95%

Ar

SNa

H N

CN O

NaS

piperidine, HOAc sulfur

Ar

N O

227

S 228

-Sn S

RS H N

R = alkyl, aryl Ar

N SR

O 230

S Sn

H N

R-X

NaS

70-85%

H N Ar

75% S

N SNa

O 229

A novel synthesis of isothiazolidines involves sulfonium ylides, formed by the reaction of thietanes and nitrenes . Exposure of N-(p-tolylsulfonyl)imino)phenyliodinane 232 with excess of thietanes 231 (5 equiv) in the presence of a catalytic amount of Cu(II)

264


acetylacetonate affords cis-isothiazolidines 234. One plausible explanation for the cis selectivity is that the cis isomer of the diastereomeric mixture of thietane 231 selectively reacts with 232 to form the sulfimide intermediate 233, which undergoes [1,2]-sigmatropic rearrangement to give the cis product 234. R1 S R2 231

PhI=NTs 232

R1

R1

Cu(acac)2

56-75% R2

S

R2

NTs 233

R1 = aryl, alkyl R2 = aryl, H

S

N Ts 234

A series of benzisothiazolone derivatives 238 has been prepared from methylthiosalicylate 235 . The key cyclization step features the formation of a N-acylnitrenium ion 237, generated by the hypervalent iodine reagent, phenyliodine(III)bis(trifluoroacetate) (PIFA). This ion cyclizes to benzisothiazol-3-one 238 upon intramolecular trapping of the thiol moiety. O OMe

N R H SH

63-95%

SH 235

O

O

AlMe3, RNH2

236

O N R

PIFA

R = aryl, benzyl, Me

60-78% N R S

SH 237

238

Radical cyclization of acyclic sulfinamides 239 provides easy access to cyclic sulfinamides 241 . Conceivably, the reaction pathway involves thiophilic attack by the aryl radical with a concomitant or successive expulsion of the p-tolyl or tertbutyl radical. R1 239

N R2 X S O Y

Bu3SnH, AIBN

31-86% N R2 -Y • S O Y 240 R1 = OMe, F, H; R2 = H, Me; X = Br, I; Y = Ts, t-Bu R1

R1

•

241

N R2 S O

A practical synthesis of the bicyclic dienyl sultam 246 has been reported . The key step of the ring-closing metathesis (RCM) represented by conversion of 243 to 244 has to be implemented prior to the sultam formation (244 to 245). Bicyclic sultam is converted to dienyl sultam 246 in two steps. O O 4 steps S O 242

Cl

H N

S O O 243

RCM

Cl

98% 244

NH S O O

NaOH Et3N 95%

O

O S

2 steps

O

O S

N

N

245

246

An efficient synthesis of N-alkylated-4-substituted isothiazolidine-dioxides (sultams) 251 has been developed utilizing epoxides 248 . Addition of a secondary sulphonamide 247 to epoxide 248 in hot 1,4-dioxane affords the amino alcohol 249, which is

265


converted to the benzensulfonate 250. Treatment of 250 with n-BuLi leads to the formation of N-alkylated-4-substituted sultam 251. Chiral 4-substituted sultams are easily accessed using the chiral epoxide. The chirality is faithfully translated to the product through the inversion at the sulfonate-bearing carbon as a result of cyclization occurring exclusively via a SN2 pathway. O O 247 S 2 Me NHR + O

K2CO3, Et4NCl 86-97%

248

R1

Me O OH S O N 2 R R1 249

PhSO2Cl pyridine

Me O BsO S O N 2 R R1 250

n-BuLi 1 72-83% R (2 steps)

O S O N R2 251

R1 = Ph, alkyl; R2 = Bn, Ph; Bs = PhSO2

An asymmetric synthesis of chiral 3-substituted sultams 256 makes use of a diastereoselective nucleophilic addition reaction . The nucleophilic 1,2addition of various organo-cerium reagents to the C=N double bond of ω-SAMP-hydraznosulfonate 252 gives hydrazines 253 in good to excellent diastereoselectivity. Removal of the chiral auxiliary by reductive N,N-bond cleavage and Cbz protection of the primary amine leads to aminosulfonates 254. After ester hydrolysis and chlorination, the resulting aminosulfonyl chlorides 255 are cyclized under basic conditions to afford 3-substituted sultams 256. MeO N YO

S

O O

MeO

RMgBr or RLi CeCl3

N

78-99%

H

HN YO

S

BH3•THF; CbzCl,K2CO3

N

50-99%

R

O O

NHCbz

EtOH, H2O; NaOAc;

Cl

S O O

COCl2 72-83%

R

O O HN S

HBr, HOAc; Et3N R

255 ee = 78-93%

S O O

R

254 ee = 78-93%

253 de = 78->96%

252

NHCbz YO

Y = cyclohexyl R = alkyl, Ph

256 ee = 78-93%

Chiral N-substituted benzisothiazole-3-one-1,1-dioxide (saccharin) derivatives 258 are synthesized via the direct ortho-lithiation of 3-N-arylsulfonyloxazolidine-2-ones 257 using LDA and HMPA . Compounds 257 are readily prepared from (L)-amino acids. O

O

O

R

S

O S

LDA, HMPA

R N

R1

O R2

257

O

62-71%

OH

1

R

R2

O 258

R = Me, i-Pr, s-Bu, Bn R1, R2 = H, H; or CH=CH-CH=CH

Various saccharin derivatives 260 have been prepared by chromium (VI) oxide catalyzed H5IO6 oxidation of substituted ortho-toluenesulfonamides 259 . The reaction presumably proceeds through a benzylic radical intermediate 261 generated from the

266


abstraction of a benzylic hydrogen by chromium oxo and peroxo species. Subsequent intramolecular hydrogen transfer leads to the formation of the N-centered radical intermediate 262. This radical is easily oxidized to the carbonyl diradical 263 which cyclizes to afford the saccharin skeleton 260. Alternatively, radical 262 can undergo a second hydrogen atom abstraction to give an alkyl diradical 264, which undergoes intramolecular coupling to give sultam intermediate 265. This intermediate can be readily oxidized to 260. The excess H5IO6 used is to regenerate the high-valence chromium species to force the reaction to completion. Further development of this methodology culminates in the direct synthesis of substituted N-tert-butyl saccharin analogs 267 from their corresponding substituted toluene derivatives 266 via a one-pot, three-step sequence: chlorosulfonation with chlorosulfonic acid, trapping the sulfonyl chloride with tert-butyl amine and the oxidative cyclization of the resulting ortho-toluenesulfonamide. O

Cr(n)

O S 2

1

R

259

NHR CH3

Cr(n-1)

O

O S

H5IO6

H-atom transfer

NHR2 • CH2

1

R

R

O [O] R1

N R2

265

ClSO3H; t-BuNH2, Et3N; H5IO6 (7 equiv), CrO3 (10 mol%),

R3

O S NR2 • • CH2 264

R1

N R2

O

260

[O]

-H+, -e O

O S

O

O

O S

R1 •

NR2 •

O 263

O S

R3

NR2 •

CH3 262

R1 = H, halogen, CF3, NO2 etc. R2 = H, alkyl

O S

O S

1

261

O R1

O

-H+, -e

H5IO6 (8 equiv), CrO3 (10 mol%)

12-92%

HIO3

N t-Bu

Me Ac2O (7 equiv), 38-79%

R3 = H, halogen, CF3, t-Bu

267 O

266

5.5.3.2 Reactions of Isothiazoles A highly stereoselective synthesis of the β-substituted β-amino sulfone 271 involves the addition of a sulfonyl anion, derived from N-PMB sultam 268 upon treatment with NaHMDS, to chiral N-sulfinyl imine (S)-269 . Removal of the N-sulfinyl followed by basic workup affords amine 271. The stereochemical outcome of the adduct 270 was established via proton NMR analysis of the Mosher’s amide derived from 271. t-Bu PMB N

S O O

268

N

S (S)-269 O

Ar PMB N

NaHMDS 91% Ar = p-tolyl

S O O 270

H N

S t-Bu O dr >99:1

Ar

TFA; NaHCO3

PMB N

S O O 271

NH2 t-Bu

The Diels-Alder reaction between isothiazole-dioxides and various dienes represents an attractive approach toward a range of bi- and tricyclic derivatives containing the fused

267


heterocyclic nucleus . In all the cycloadditions evaluated, Sc(OTf)3 appears to be the most effective catalyst which affords high yields under mild conditions. The two dienophiles 272a and 272b exhibit different endo/exo selectivity in reactions with cyclopentadiene and furan. The 4-aryl substituted isothiazole-dioxide 272b gives a mixture of exo and endo adducts in all cases, with the latter being preferred (endo/exo: 5/1 with furan and 8/1 with cyclopentadiene, reaction not shown). However, a major selectivity is found with isothiazole-dioxide 272a, and the selectivity depends on the nature of the diene: cyclopentadiene delivers the endo adduct 273 (X = CH2) exclusively, whereas the exo addition product 274 (X = O) is the sole product from furan. X

O O S N

X Sc(OTf)3

70% (X = CH2) NHBn 88% (X = O)

O O S N

X

H OO + S H N

Ar

H NHBn H

BnHN 273

272a

O O S N NEt2 272b

274

Ar = p-MeO-C6H4

endo/exo: 99/1 (X = CH2); 0/100(X = O)

The 1,3-dipolar cycloaddition of diazoalkanes 276 and nitrile oxides 279 to isothiazole dioxides 275 provides an easy entry into fused bicyclic isothiazole systems 277 and 280, respectively . The adducts from 4-bromoisothiazole (R1 = Br) are labile and undergo spontaneous debromination to form the aromatic bicyclic pyrazolo-isothiazoles 278 and isoxazolo-isothiazoles 281. O O S N

R2CH2N2 276 90%

R1 NHBn 275

Ar

Ar C N O 279

N

O O S N

O

R2

R1 = Br -HBr

N H NHBn 278

Ar

R1 = Br -HBr

N

R1 NHBn 280

O O S N

N

74% (from 275) N 2 H R1 NHBn R = CO2Et 277 O O S N

N

85-90%

R2

87% (from 275) Ar = 2,6-diMe-Ph

R1= H, Br R2= CO2Et, Ph Ar = Ph, 2,6-diMe-Ph

O O S N

O NHBn 281

The regioselective ozonation of alkylidene-sultams 282 followed by reaction with diazomethane leads to the formation of highly reactive bicyclic trioxo-isothiazolidine 284 . MeO

CO2Me

MeO

O3 R

SO2 N Me 282

57 -75%

O

CO2Me SO2 N Me 283

MeO

CO2Me

CH2N2 88%

O

SO2 N Me

R = H, Me

284

3,5-Dichloro- and 3,5-dibromoisothiazole-4-carbonitriles 285a/b undergo regioselective Stille, Negishi, Sonogashira coupling reactions at C-5 to provide 3-halo-5-substituted

268


isothiazoles . However, the analogous couplings with 3-chloro- or 3-bromo5-phenylisothiazoles 286a/b at C-3 fail to yield any desired products. To this end, the first 3iodo-5-phenylisothiazole-4-carbonitrile 291 is prepared via Sandmeyer iodination of the 3amino analog 290, available from 3,5-dichloroisothiazole-4-carbonitrile 286a in two steps. This iodide shows sufficient reactivity in the palladium-catalyzed coupling reactions, and the C-3 coupling products 287 and 292 are obtained in good yields. The cross-coupling reactions on azoles with two and more heteroatoms including isothiazoles have been reviewed .

NC X

X

N S 285a/b

Suzuki or Stille

X

N or Negishi Ph S a: X = Cl 286a/b b: X = Br

Sonogashira 69-91% NC

R

NC

X S

N

288a/b

Suzuki X or Stille

BnNH2 (X = Cl)

NC

NHBn

Br2, AIBN

N

90%

S 289

Ph

R

Ph NC

N S 287

Ph

S

Suzuki 80% or Stille 90%

90%

Ph

NC

NC Ph

NH2 N S 290

i-amyl nitrite, I2 85%

N

292

Sonogashira 70-100% NC Ph

I N S 291

5.5.3.3 Isothiazoles as Auxiliaries in Organic Syntheses Oppolzer’s camphor sultam, a well known chiral auxiliary, has been utilized in the asymmetric [2,3]-sigmatropic rearrangement of glycine-derived allyl ammonium ylides. These reactions are known to be highly selective in terms of relative and absolute stereocontrol with substrates bearing acyclic alkene moiety . For example, the [2,3]-rearrangement of N’N’N’-allyldialkyl glycinoyl (2S)-sultam salts 293 gives the allyl glycine derivatives 295 with a high level of diastereoselectivity, in favour of the (2’R)-isomer (dr > 96 : 4). However, when the chiral camphorsultams of the ylides derived from Nmethyltetrahydropyridine (NMTP) undergo rearrangement, the reactions proceed with exclusive cis-stereoselectivity but no absolute stereocontrol as exemplified by the formation of 1 : 1 diastereomers of pyrrolidine carboxylates 297 and 298 from the NMTP (2S)camphorsultam salt 296 . The lack of diastereoselectivity in the cyclic series suggests that the sigmatropic rearrangements of N-chiral ammonium ylides are controlled by nitrogen stereogenicity.

269


Me

Me

Xs

O

NaH

1

R N

2

N

R2 Br

R1 N R2 294

10

S 293 O O

1

2

H

64-99% R1 N R2

H

O

2'

R

NaH S

S

N Me

s

X

O O

+

R

O

53%

N 296

O

Me

O

Br

Xs

2'R/2'S = 96/4 to >99/1

R , R = allyl, Bn, Me; X = (2S)-camphor sultam

N Me

2'

(2'S)-295

(2'R)-295

s

Me

H

Xs + R1 N R2 O

O

S s

X (45 : 55)

297

N Me

298

The camphor sultam auxiliary has been applied to the asymmetric aziridine synthesis via aza-Darzens reaction of N-diphenylphosphinylimines. Reaction of the chiral enolates derived from N-bromoacetyl (2R)-camphorsultam 299 with N-diphenylphosphinyl aryl and tertbutylimines 300 generates (2’R,3’R)-cis-N-diphenylphosphinyl aziridinoyl sultams 301 in high diastereoselectivity . However, the stereoselectivity of this reaction depends on the structure of the imine substituents: arylimines substituted in the ortho-position usually give mixtures of cis- and trans-aziridines, and exclusively trans-configured products 306 are obtained from ortho-bromo, iodo, and trifluoromethylphenylimines . Me

P(O)Ph2

Me R N S O O 299

Br

+

NaHMDS NP(O)Ph2

40-78% dr > 95 : 5

H N H R

X

R O 301 exclusive XR = (2R)-camphor sultam; R = aryl, heteroaryl, vinyl, t-Bu O

Me

300

N O

X

R O

302 none P(O)Ph2

NP(O)Ph2

H N H

H N H LiHMDS

+ S O O 303

H N H R

P(O)Ph2

Me R

Br

P(O)Ph2

69-72%

304 Xs = (2S)-camphor sultam

s

s

X

X

O

R 305 exclusive for R = H, NO2

O

R 306 exclusive for R = Br, I, CF3

An elegant application of Oppolzer’s sultam in the asymmetric [C+NC+CC] coupling reaction provides convenient access to a variety of pyrrolidines 312 in a single step . Simply mixing aldehyde 307, chiral amine derived from glycyl (2R)camphorsultam 308, and electron-deficient alkene 309 in THF in the presence of a catalytic amount of silver acetate results in the clean production of highly functionalized pyrrolidines 312. The reaction proceeds through imine 310 formed from aldehyde 307 and amine 308. The subsequent [3+2] cycloaddition with alkene 309 leads to 2,5-cis disubstituted pyrrolidines, presumably via the intermediacy of a metalated (E, E)-azomethine ylide 311. The Oppolzer’s chiral glycyl sultam serves several important roles: (1) it reduces the nucleophilicity of the amine component, thus preventing unwanted Michael addition; (2) it

270


facilitates azomethine ylide formation by enhancing the α-acidity of the imine; (3) it controls the diastereofacial selectivity of the 1,3-dipolar cycloaddtion in a predicable maner, i.e. alkene approaching from the endo-Re face of the (E,E)-azomethine ylide as depicted by 311. H R2 + H2N

COXR

O AgOAc (5 mol%)

Z

309

X

N R R1

H

Me

R

H 2

H H 308 + H H Y

endo-Re Me

307 CHO

R1

O Ag

N O

63-94% S O

H R2 H N R1 H

XR O

dr: 7:1 to 19:1

Y Z N H R2 312 311 R1 H H R1= Bn, BnO, alkyl; R2 = H, NHBoc; Y = CO2Me, SO2Ph; Z = H, CO2Me or Y, Z = CON(Ph)C(O); XR =(2R)-camphor sultam H

H 310

Other applications of Oppolzer’s sultams include diastereoselective allylation of glyoxylic oxime ethers , asymmetric aldol reactions in the syntheses of macrolide FD-891 and antitumor antibiotic belactosin and its analogs , silver (I) promoted asymmetric halomethoxylation of α, β-unsaturated carboxylic acid derivatives , Lewis acid-catalyzed [4+2] cycloaddition of α, β-unsaturated carboxylic acid derivatives to cyclopentadiene and cyclohexadiene , dialkylboron triflatepromoted anti addition of acylated Oppolzer’s sultam to aldehydes , and BaylisHillman reaction with Oppolzer sultam derived acrylamide . 5.5.3.4 Pharmaceutically interesting isothiazoles Several biologically active isothiazoles and their saturated and/or oxygenated analogs have been reported in 2006. Isothiazoles have been incorporated into TrkA kinase inhibitor 313 and the allosteric MEK1 (MAP kinase/ERK kinase) inhibitor 314 , sultams into the selective TACE (TNFα converting enzyme) inhibitor 315 (IC50: TACE 5.9 nM, MMP-1, 2, 9, 13 > 2128 nM) and human melanocortin subtype-4 receptor (MC4R) selective agonists 316 . Compounds containing isothiazole moiety that are currently in clinical development include STA-5312 (rosabulin), a tubulin binder for the treatment of drug-resistant cancers (Phase I) , and CP-547632, a potent, selective and orally bioavailable vascular endothelial growth factor (VEGF) receptor-2 tyrosine kinase inhibitor for cancer therapy (phase II)

271


OH H2N

N S

O HN O

Me

OH HN

NH OH

O

S O N O

O

NH

S N

H2N

HN

H N

HN O N

S

O Cl

O

313

Cl

Me

314

Cl CN

N

316 R = H, Me

N 315 H N

N

O S

HN

N H N O

S

H2N

N

CP-547632

Me STA-5312

N

F

O O

O

R R S O O

F

Br

5.5.4 THIADIAZOLES A practical α-heteroarylation of simple esters or amides has been developed via nucleophilic aromatic substitution. Exposure of chlorothiadiazoles 317 and 319 to NaHMDS and tert-butyl acetate or N,N-dimethylacetamide leads to the formation of functionalized 1,3,4-thiadiazole 318 and 1,2,4-thiadiazoles 320, respectively . Cl N N

S

CO2t-Bu

MeCO2t-Bu, N NaHMDS N 79%

Ph 317

S

Cl N S

Ph 318

N

MeC(O)R NaHMDS

C(O)R N S

N

69-87%

R = Ot-Bu, NMe2

Ph 320

Ph 319

Direct electrophilic silylation of thiadiazole 321 with bromotrimethylsilane (TMSBr) under basic conditions provides easy access to C-silyl thiadiazole 322, which can serve as a synthetic equivalent of an organometallic intermediate or a silyl-protected azole . N N Ph

S 321

TMSBr, Et3N pyridine-toluene 72%

N N Ph

S 322

TMS

Reaction of N,N-dimethylsulfamoyl aziridines 323 and 325 with primary amines furnishes substituted 1,2,5-thiadiazolidine 1,1-dioxides 324 and 326, respectively, in a regioselective manner . Aziridine 325 is made from (1R,6S,Z)-bicyclo[4.2.1]non3-en-9-one in two steps: N,N-dimethylsulfamoyl imine formation using dimethylsulfamide and subsequent reaction with trimethylsulfoxonium ylide. The product from the reaction with 4-methoxy-benzyl amine can be subsequently manipulated (debenzylation and derivatization) to give the alternative nitrogen substitution pattern in a controlled manner.

272


Cyclic sulfamides 326 serve as key intermediates in the synthesis of a series of potent and selective γ-secretase inhibitors with potential for the treatment of Alzheimer’s disease.

Me2N

O S O

O O S N HN

RNH2

N

O

R

Me2NSO2NH2, Ti(OEt)4, 50%

Me2N

O S O

R

N

RNH2

64-87%

Bn

Bn

323

60-87%

Me3S(O)I, NaH 87%

324

R = alkyl, ArCH2

O N S O NH

325

326

5.5.5 1,3-SELENAZOLES, 1,3-SELENAZOLIDINES AND 1,2,3-SELENADIAZOLES A series of 5-acyl-2-amino-1,3-selenazoles 331 are prepared from selenazadienes 327 upon treatment with α-haloketones 328 in hot methanol or acetonitrile. In the presence of triethylamine, reaction of selenoazadienes 332 with 1,3-dichloro-propan-2-one (5 equiv) affords the bis(selenazoyl) ketones 333 in high yields, whereas the same reaction without base produces the corresponding selenazoles 331 (R3 = CH2Cl) preferentially . R1 R N

R1 R N

O

2

2

X

Se

328

N

R1 R2 N

Se

329

O Se

Et3N 82-91%

NMe2

332

Cl

R1 N R2

Se

N

COR3

330 NMe2

NMe2

Se

Se N

O

Cl

N

COR3

N

X = Br, Cl

NMe2

327

R3

R1 R N 2

N

R1 N 2 R

-Me2NH

68-100%

R1 R2 N

Se COR3

N 331

333

Reaction of N,N-unsubstituted selenoureas 332 with methyl vinyl ketone in the presence of ferric chloride in refluxing ethanol gives 2-amino-5-(1-ethoxy)-1,3-selenazoles 335 . This approach obviates the use of lachrymatory halo carbonyl compounds frequently utilized in the synthesis of 1,3-selenazoles. Me R1 R2 N

Se NH2

332

O FeCl3, EtOH

R1 R N 2

Se N

333 Me

R1 R N 2

Se

R1 77-89% R N 2

334 Me

Se

H -FeCl2 -HCl

N OEt

N

OEt Me 335

A novel synthesis of 1,2,3-selenadiazoles 338 starts with the Michael addition of 2nitropropane to α,β-unsaturated ketones 336 under basic conditions . The resulting adducts are treated with semicarbazide hydrochloride to give semicarbazones 337, which are converted to 1,2,3-selenadiazoles 338 by reaction with selenium dioxide in THF (the choice of the solvent appears to be important in this case).

273


Ar

NH2

H N

1. Me2CHNO2, NaOMe 2. NH2NHC(O)NH2

O

N

NO2

Ar'

Ar Ar'

336

337

N

SeO2

O Me Me

N

Se NO2

Ar

62-73%

Me Me

Ar' 338

Alkylisoselenocyanates 339 are versatile starting materials for the synthesis of various selenium-containing heterocycles. Reaction of 339 with allylamine yields N-allylselenoureas 340 which undergo intramolecular cyclization in the presence of hydrogen chloride to afford 5-methyl imino-selenazolidines 341 . When propargylamines 342 are used instead of allylamine, 5-methylidene-selenazolidines 343 are obtained directly . Addition of 339 with sodium hydroselenide generates the intermediate Nalkyldiselenocarbamates 344, which react with bromoacetylbromide 345 to provide oxoselenazolidines 346 . Se

H2N R-N=C=Se 339

R

N H

89-97%

H N

HCl, EtOAc

N H

81-100%

N Se R 341

Me

340 1 342 NHR

65-97%

R = aryl, cycloalkyl

NaHSe R2 O

R1 N Se 343

3

R

Se

R = aryl, Bn, N cycloalkyl R R1 = H, Me

R

N H

Se

Se

Br Br 345

R

10-37%

O

344

N

Se R3

R2 346

Alkylisoselenocyanates 339 are also used in the synthesis of 2-methylidene-1,3selenazolidine derivatives . Nucleophilic addition of the carbanion derived from malononitrile 347 to 339 leads to an intermediate keten-N, Se-acetal 348, which reacts with 2haloacetate ester and 1,2-dibromoethane to provide 1,3-selenazolidin-4-ones 350 and 1,3selenazolidines 352, respectively. R N

CN

R1 Se 352

Br

Br(CH2)2Br, Et3N

R N Se 351

31-62%

R1CH2CN 347 + R-N=C=Se 339

R = aryl, cycloalkyl R1 = CN, CO2Et

CN R

Br(CH2)2Br

1

Se

34-86%

O

R N

R2

Se 350

2

Et3N R HN

R2CH(X)CO2R3, Et3N

CN R1 348

R = H, Me X = Cl, Br R3 = Me, Et R2CH(X)CO2R3

R3 O

CN R1

R N

CN

Se

R1

O R2

349

5.5.6 ACKNOWLEDGMENT We thank Dr. Richard Hartz of Bristol-Myers Squibb for critical reading of this review.

274


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06JA2995 06JA3128 06JA4460 06JA4932 06JA4936 06JA6536 06JA7418 06JA10513 06JA16018 06JHC149 06JHC1045 06JHC1609 06JMC179 06JMC3766

06JMCAC235 06JNP145 06JNP219 06JOC337 06JOC1802 06JOC3287 06JOC3754 06JOC4599 06JOC5031 06JOC5328 06JOC5715 06JOC6573 06JOC7574 06JOC8261 06JOC8276 06JOC8302 06JOC8329 06N671 06OBC2313 06OBC2906 06OBC3681 03OL3607 06OL527 06OL531 06OL789 06OL1351 06OL1447 06OL1553 06OL1625 06OL2115 06OL2417

275

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276 06OL2695 06OL2887 06OL2899 06OL3057 06OL3647 06OL4165 06OL4457 06OL4637 06OL4751 06OL4811 06OL4859 06OL5291 06OL6043 06OPRD346 06S31 06S1279 06S1289 06S2738 06SC825 06SL460 06SL833 06T66 06T1110 06T1378 06T3201 06T3228 06T3344 06T3681 06T3694 06T7902 06T9548 06T9966 06T11506 06T11592 06TA210 06TA822 06TA1152 06TA1380 06TL239 06TL611 06TL1081 06TL1109 06TL2361 06TL3091 06TL4245 06TL6405 06TL7477 06TL8661


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277

Chapter 5.6 Five-membered ring systems: with O & S (Se, Te) atoms

R. Alan Aitken* and Lynn A. Power University of St. Andrews, UK (e-mail: [email protected])

5.6.1

1,3-DIOXOLES AND DIOXOLANES

The conversion of 1,2-diols into the corresponding 2,2-dimethyl-1,3-dioxolanes has been achieved by reaction with acetone and polymer-supported Ph3P/I2 , while highly stereoselective conversion of trans epoxides 1 into the cis dioxolanes 2 has been reported using acetone with either a Lewis Acid or photocatalytically with a pyridinium salt catalyst . Conversion of non-enolisable aldehydes and ketones, R1R2C=O, into dioxolanes 3 can be carried out in excellent yield by slow addition of KOBut to a mixture of the compound and 2-chloroethanol in DMF . An interesting dioxolane to dioxolane rearrangement is involved in the conversion of 4 into 5 upon acid-catalysed treatment with ethanediol and the stereospecific rearrangement of 6 to give 7 has also been described . Palladium-catalysed coupling of aryl halides with 2-hydroxyethyl vinyl ether gives either of the isomeric dioxolanes 8 or 9 depending on the catalyst and ligands used .

O R1

O R2

R1

1

O

O

R1 R2

O

R2

O

O

68%

S Ph

O

5

O2N

O R

CO2Me

O

10

CO2Me

O O

11

R1 R2

7 R

12

CO2

O

Ar

O

9

8 O

CHR3

Ar

O

O

O

O

6

O

S

4

Ph BF3•Et2O

O2N

O

TsOH

3

2

OH

HO

O

O

O R

O

13

278

R.A. Aitken and L.A. Power

Reaction of substituted catechols with DMAD and 0.1 equiv. DABCO directly gives the benzodioxoles 10 and photochemical addition of 1,3-dioxolan-2-yl radicals to alkynes in acetonitrile affords products 11 . New studies on the industrially important carboxylation of epoxides 12 to give dioxolan-2-ones 13 include catalysis by silica-supported quaternary phosphonium salts , quaternary ammonium saltterminated polyethyleneglycol and tris(dibutylamino)bromomethane with ZnBr2 99% ds, 99% ee

Ph

79

N N N Ce (OTf)4

O

Ph Ph

78

The 1,3-DC of nitrone 80 with maleimide 81 is a new example of recognition-mediated reaction. The association between the urea moiety in 80 and the carboxylate ion in 81c and 81d triggers a pseudointramolecular cycloaddition resulting in increased reaction rate and diastereoselectivity. A slower reaction with essentially no stereocontrol was observed using dipolarophiles lacking the carboxylate recognition site such as 81a and 81b. The recognition site on maleimide could be switched ‘on’ and ‘off’ in situ by the addition of base and acid, respectively . t-Bu HN

Z

t-Bu

O

t-Bu

HN

HN

O

O

HN

O

HN

HN

Z Z + O O d -acetone N O O 6 12.5 mM H O H O N 10 °C Ar O Ar N Ar N N N 36 h 80 81a-d O O Ar = 4-t-BuC6H4 H O 82a-d H O 83a-d Z = a OMe; b OH; c O HNEt3; d O NBu4 a and b: 40-41% conversion; 82/83 = ca. 1: 1 +

c and d: 67-70% conversion; 82/83 = ca. 4: 1

3-O-Allyl carbohydrate nitrones prepared from aldehydes 84 with PhNHOH in aqueous media in the presence of the cationic surfactant cetyltrimethylammonium bromide (CTAB) underwent highly regio- and stereoselective intramolecular cycloaddition at room temperature. In all cases the exclusive formation of a single isomer was observed. In particular, the more substituted prenyl derivatives gave pyran derivatives such as 87, whereas the corresponding allyl and crotyl compounds afforded the bridged isoxazolidines 85 and 86 containing an oxepane ring . No reaction was observed in water without CTAB or under neat conditions, whereas in conventional organic solvents a mixture of isomers was generally obtained. Ph R1 N H H O O H

O

O H O H 85 R1 = H 84% 86 R1 = Me 85%

PhNHOH R1 CTAB 2 H2O, rt R 2

R =H

OHC

O O

O 84

O

PhNHOH CTAB H2O, rt 1

2

R = R = Me

Ph O N H HO H

O H

O O

87 78%

A B3LYP/6-31G* study was performed on both thermal and BH3-catalyzed 1,3-DC of nitrones with methacrolein . A new stereodivergent synthesis of optically pure 4-alkylisoxazolidin-4-ols starting from enantiopure 2-(alkyloxiran-2-yl)methanols has been reported. In particular, the (2R)-glycidyl

298

S. Cicchi, F.M. Cordero, and D. Giomi

tosylate and nosylate R-88 were respectively converted into the enantiomeric isoxazolidines S-91 and R-91. Treatment of the tosyl derivative 88 (R=Ts) with PhthNOH caused the selective opening of the epoxide ring with formation of R-89 that cyclised to S-90 upon addition of methanol and NEt3. On the contrary, the nosyl group in 88 (R=Ns) underwent direct displacement by PhthNOH with conservation of the oxirane ring, which was then opened with HCl. Eventually, chlorohydrin S-92 gave R-90 by treatment with NEt3 in MeOH . HO

HO O c) O b) Cl N N 59% O 75% H Ar PhthN HCl O R-91

R-90

OH R = Ns d), e) O 59%

RO R-88

S-92

HO

R = Ts HO a)

OTs b)

O PhthN

O

HO c)

N

72%

Ar O S-90 41%

R-89

O

N H HCl S-91

Ar = 2-MeO2CC6H4; TsOH = 4-MeC6H4SO3H; NsOH = 3-O2NC6H4SO3H; PhthNH = phthalimide Reagents and conditions: a) PhthNOH, NEt3, 1,4-dioxane, 50 °C, 48 h; b) MeOH, NEt3, 50 °C, 2 h; c) HCl, H2O, 95 °C, 4 h; d) PhthNOH, NEt3, CH2Cl2, 24 h; e) conc HCl, 1 h.

New examples of palladium-catalyzed cyclization of O-homoallylhydroxylamines to isoxazolidines have been reported . 5.7.4 OXAZOLES Several new methods for the synthesis of the oxazole nucleus were published. A new consecutive three-component oxazole synthesis by an amidation-coupling-cycloisomerisation sequence was developed. The synthesis started from propargylamine 92 and acyl chlorides. To extend this process, a four component sequence involving a carbonylative arylation by substitution of one acyl chloride with an aryl iodide and a CO atmosphere was also performed . O Ar

1

+ Cl

O

H2N

+

Ar

2

PdCl2(PPh3)2, CuI

N

Cl NEt3, THF, 0° C

Ar1

92

O

O Ar2

O

O Ar2

NH

Cl

1

Ar

O NH

Ar2

Ar1 Pd(II), Cu(I) 1

O

2

Ar , Ar = Aryl, Heteroaryl 49-75%

Conceptually interesting is the synthesis of the oxazole system 94 through a Beckmann rearrangement of α-formyl ketoxime dimethyl acetals 93 which demonstrated the possibility of a non-amino acid pathway in the biosynthesis of marine derived oxazoles .

299

Five-membered ring systems with O & N atoms

HO

n-Bu

N

n-Bu

n-Bu

N

polyphosphoric acid n-Bu

Beckmann rearrangment MeO

OMe 94

93

O 97%

A new approach to the synthesis of 2,4,5-trisubstituted and 2,5-disubstituted oxazoles, 97 and 98, used 1-(methylthio)acetone 95 with nitriles in the presence of trifluoromethanesulfonic anhydride. The proposed mechanism involves an unstable 1(methylthio)-2-oxopropyl triflate 96 which was detected using NMR spectroscopy . O

O

Tf2O

S

R-CN

S

O

R

Raney-Ni N

95

Base

R-CN

O

N 98 R = alkyl, aryl

97 S

96 OTf

R

70-90%

S

S

O N

N C R

O R

The use of Zn(OTf)2 with a Ru complex, TpRuPPh3(MeCN)2PF6, proved useful for the cyclization of propargyl alcohols 99 with amides. The reaction proceeded through the intermediate 100 which was also isolated from the reaction mixture when only the Zn catalyst was used. Upon heating with the mixture of the two catalysts, compound 100 was completely converted into the final oxazole 101 .

2

R1

Zn(OTf)2 TpRuPPh3(MeCN)2PF6

O

OH R

NH2

99

Toluene, 100° C, 5h

Zn(OTf)2 R1 2

R (O)CHN

O 100

N R1 =aryl R1 101 O 88-95% R2 =aryl, alkyl Zn(OTf)2 TpRuPPh3(MeCN)2PF6

R2

N R2 O 101

R1

Application of the Ritter reaction conditions on γ-hydroxy-α,β-alkynoic esters, 102, produced ethyl 5-oxazoleacetates 103 or γ-N-acylamino-β-keto ester 104 by reaction with aryl or alkyl nitriles respectively. The γ-N-acylamino-β-keto ester 104 can also be transformed into oxazole derivatives using an additional step involving POCl3 .

300


OEt

O Alk-CN

O

Ar OH

Ar

H2SO4, 0° C

102

104

O OEt Alk 55-78%

HN O

POCl3

H2SO4, 0° C ArCN 44-70%OEt Ar O N O

DMF 70° C 84-92%

103 Y Y = aryl, alkyl

A new method for the solid phase synthesis of oxazole-containing peptides 105 was developed, based on cyclodehydration followed or preceded by oxidation in a biomimetic fashion. The oxazole nucleus was obtained starting from threonine or serine and the method is compatible with most protecting groups .

R

Ph

Ph

Ph H N

N H

Dess-Martin Periodinane

O O

O HO

CH2Cl2, 2 h

R

N H

H N O

O

PPh3, I2, DIEA R O

O

N H

O N O

O 105

80-93%

R= Cbz, Fmoc, Alloc, H

A microwave assisted Cornforth rearrangement of oxazole-4-carboxamides 106 efficiently afforded 5-aminooxazole-4-carboxylates 107. This procedure was applied to the formal synthesis of a natural antibiotic derived from pseudomonic acid . O N Ph

O

O

EtO NR2

OEt 106

OEt

O Ph

N

N O

mw R2N

Ph

NR2 107 NR2= primary and secondary alkyl amines 19-99% O

A parallel synthesis of novel pyrrole-oxazole analogues of the insecticide PirateTM was performed through the dehydration of acylaminoketones with POCl3. A multipurpose mesofluidic flow reactor was developed for the automated synthesis of libraries of 4,5-disubstituted oxazoles. The process was based on the known reaction of alkylisocyanoacetates and acylchlorides . Considering the reactivity and the transformations of the oxazole nucleus, some examples of new reactivity were described as well as the application of known reactions to the oxazole nucleus. The ceric ammonium nitrate (CAN) promoted oxidation of oxazoles with various substitution patterns was investigated and yielded the corresponding imides 108 in good yields, tolerating a wide variety of functional groups and substituents on the oxazole moiety .

301


R2

O R

N

R1 N H 108

rt

R3

O

O

CAN

1

R1, R2, R3 = Aryl, Alkyl, Alkenyl

O

+ 2

R3

R

OH

50-90%

An N-heterocyclic carbene 110 catalyzed the rearrangement of the O-acyl carbonates 109 into their corresponding C-acylated isomers 111, generating a C-C bond and a quaternary stereocenter with high efficiency The same reaction can be performed enantioselectively using TADMAP 112 . OR1 O

O

R2

N N

O

110

N R1O N Ph R2

O

N

O

H CPh3 OAc

O

N 67-84% THF, rt, 5 min 111 Ar Ar R1= Me, Bn, Ph R2 = Me, Bn, CHMe2, CH2CHMe2

N

109

TADMAP 112

2-Aryl-4-trifloyloxazoles 113 undergo rapid, microwave assisted coupling with a range of aryl and heteroaryl boronic acids in good to excellent yields. The same procedure is also effective using 4-aryl-2-chlorooxazoles and can be extended to the synthesis of homo- and heterodimeric 4,4'-linked dioxazoles . Analogous results were obtained using oxazol-4-ylboronates with aryl and heteroaryl halides . O Ar1

O Pd(0), Ar2B(OH)2 Ar1 N

mw, dioxane N OTf 113

Ar2

114 75-94%

Ligand and base free conditions for the arylation of azoles were developed, although with a modest yield especially for oxazole, affording 2-substituted oxazoles . With the aim of finding new antagonists for the type 5 metabotropic glutamate receptor (mGluR5) for use in the treatment of drug abuse, two new 4-arylethynyl-2-methyloxazole derivatives 116 and 117 were synthesized starting from 2-methyloxazole-4-carboxaldehyde 115 . I O

1) CBr4, PPh3 (86%) 2) NaHMDS, MeLi, Me3SiCl

N

O

115 H

Y

O N

O

X

N 84%

Y SiMe3

X 116 Y = F X = CH 85% 117 Y = H X = N 52%

A review concerning the cross-coupling reactions of azoles with two and more heteroatoms was published . Several reports on the synthesis of oxazole containing natural compounds or their analogues appeared in 2006. The synthesis of telomestatin 118 was performed as well as several analogues as 119 and others The synthesis of bengazole A 120, a marine bisoxazole natural products with antifungal properties was completed. This synthesis was the first to produce a single stereoisomer . A new synthesis of phorboxazole B was published . Towards the synthesis of diazonamide A a biomimetic approach to the indole bis-oxazole fragment by oxidation of a TyrValTrpTrp tetrapeptide was reported . The first total synthesis of inthomycin B 121 was performed. The synthesis was based on the Stille coupling of a stannyl-diene with an oxazole vinyl iodide . Oxazoles substituted on C-2 with a carbonyl group and a long chain revealed interesting inhibitors of fatty acid amide hydrolase (FAAH) enzymes . N O

S N O

N

N

O N

N

O O

N

N O

O

NH

OH

O

O

O

O

OH OH OH

N

bengazole A 12

N O

N N

N

O O

N

O

O

HN N

O N

N

119

telomestatin 118

O

O

O

O

120

inthomycin B

HO

NH2

121

5.7.5

OXAZOLINES

New simple methodologies for the synthesis of variously substituted 2-oxazolines exploit aldehydes and amino alcohols as starting materials. For instance, the reaction of aromatic or aliphatic aldehydes with amino alcohols in the presence of N-bromosuccinimide as oxidizing agent allowed the one-pot preparation of compounds 122 under mild reaction conditions and in high yields . Analogously, treatment of aromatic aldehydes and 2-aminoethanol with pyridinium hydrobromide perbromide (PHPB) in water led to 2-aryl-4,5dihydrooxazoles 123 . The copper(I)-catalyzed reaction of aldehydes and methyl isocyanoacetate afforded ester derivatives 124 in almost quantitative yields and high diastereoselectivity in favor of the trans diastereomer . 2

R R3 R1 R = Ar, pyridyl, a) stiryl, t-Bu, C9H19 N O 1 2 3 R , R , R = H, Me, R Et, i-Pr, Ph, Bn 122 30-96% NC RCHO +

CO2Me

RCHO +

R1

R2

H2N MeO2C c) R = Ar, i-Pr

N

R3 OH R

b) R = Ar R1= R2= R3= H

N

O

Ar 123 58-95%

trans/cis ratio from 86:14 to >99:1 O 124 >99%

Reagents and conditions: a) 4Å MS, CH2Cl2, rt, 14 h, then NBS, rt, 0.5 h; b) PHPB-H2O, rt; c) 10 mol% iPr2EtN, 5 mol% CuCl, 10 mol% PPh3, CH2Cl2, 40 °C, 2 h.

303


O O R1= Ar, CH3(CH2)n, PhCH2CH2 R2 = H, Me

N

O

R1CO2R2

( )n H2N

a)

R1

OH

a) n = 1-3

125 64->99%

N

O

( )n OH 126 52->99%

Reagents and conditions: a) Zn4(OCOCF3)6O (1.25 mol%), toluene, reflux.

A direct catalytic conversion of esters, lactones, and carboxylic acids to oxazolines was efficiently achieved by treatment with amino alcohols in the presence of the tetranuclear zinc cluster Zn4(OCOCF3)6O as catalyst, essential for condensation and cyclodehydration reactions. For example, the use of (S)-valinol allowed the easy synthesis of oxazolines 125 and 126 in satisfactory yields . A one-pot direct preparation of various 2substituted oxazolines (as well as benzoxazoles and oxadiazoles) was also performed from carboxylic acids and amino alcohols (or aminophenols or benzhydrazide) using Deoxo-Fluor reagent . Bromoamidation of cyclic olefins allowed the synthesis of bicyclic oxazolines. For instance, treatment of cyclohexene with N-bromoacetamide as the halogen source and different nitriles at 0 °C, in the presence of SnCl4 or BF3.Et2O and water, led to oxazolines 128 through intermediate trans-bromoamides 127. The scope of the bromoamidation appears quite broad with regard to olefinic and nitrile components .

Br

a)

CCl3

H O

b)

NHCOR R = t-Bu, Ph 127 75-77%

CCl3 Au[P(C6F5)3]SbF6 (1-2 mol %) NH O N

O R

N H 128 92-93%

ClCH2CH2Cl, 0 °C

R 129

R R = H, c-C6H11, n-C7H15, 130 74-98% i-Pr, t-Bu, Bn

Reagents and conditions: a) MeCONHBr, RCN (15 equiv), H2O (1.2 equiv), BF3.Et2O (0.4 equiv), CH2Cl2, 0 °C; b) NEt3 (2 equiv), DBU (0.2 equiv), DMF, reflux.

Cyclization of N-alkenylamides to 2-oxazolines was achieved in very mild conditions with tert-butyl hypoiodite . The 5-exo-dig gold(I)-catalyzed cyclization of propargylic trichloroacetimidates 129 proceeded with remarkably efficiency under very mild conditions to give 4-methylene-4,5-dihydrooxazoles 130 in good yields. The mildness of the protocol was clearly responsible for the lack of isomerization of the final products to the corresponding, thermodynamically more stable, oxazoles . O R1

F3C 131

NsONHCO2R2 F3C CaO

O 1

CH2Cl2, rt R1 = Ph, OEt R2 = Et, t-Bu

132

F3C

F3C

N R CO2R2

O

N CO R2 2 R1

O

N CO R2 2

R1 133 52-58%

CF3-Enones 131 showed different reactivity in amination reactions to nosyloxycarbamates. In particular, 4-oxazolines 133 were synthesized operating in the

304


presence of CaO or NaH as base probably through a domino sequence involving a fast rearrangement of unstable trifluoroacetyl aziridines 132 . Tripodal oxazolines 136a,b were synthesized from protected (3-hydroxyphenyl)glycinol 134 and tricarboxylic acids 135a,b in a one-pot reaction. Deprotection followed by generation of the corresponding phenoxide ions and subsequent treatment with 4bromomethylpyridine afforded preorganized C3 symmetric pyridyl-oxazolines 137a,b in 62 and 53% overall yields, respectively. Mixing 137b and trans-Pd(OTf)2(PEt3)2 in a 2:3 molar ratio gave homochiral dimeric cage 138b with two well-defined internal binding sites for molecular recognition of ammonium and enantiomeric α-chiral organoammonium ions . Analogous tripodal oxazoline-based artificial receptors were synthesized and exploited for dopamine recognition in water while related bis(oxazolinyl)phenols 139 were applied as fluorescence sensors towards primary amines even capable of enantio-discriminating α-chiral amines . N

R'O HO2C

NH2

R

N

R'O

CO2H

N

OR' OH + OTBS

a) R

R HO2C

134

135a,b

c)

b) R' = TBS R = Me, Et

N

O N O

N R R

R 136a,b Pd

N

N

O

O

O O

O

Et3P PEt3 O

O

d)

6+

O N

O N

O O

N O

138b

O

O

R

137a R = Me 62% R = Et b R = Et 53% e) R

N O

N R R

O N PEt 3 N Pd Pd N Et3P N Et3P PEt3

N O

N

O N

N

O

R O

N

R = Ph, Me HO

N O 139

Reagents and conditions: a) (COCl)2, NEt3, CH2Cl2; b) MsCl, NEt3, DMAP, CH2Cl2; c) aq. NaOH, MeOH, rt; d) NaH, DMF, 4-bromomethylpyridine, CH2Cl2, rt; e) 137b and trans-Pd(OTf)2(PEt3)2 in 2:3 ratio, CH2Cl2, rt.

O

N

N N 1 140a R2 R R3 R3 O

O

N 1

R

140b

N R2

R1

2 R2 R OH O S N

141 R3

O

O

N

O N

O PPh2

N

N 2 R1 R 142

N PAr2 143

R

N PPh2 R 144

305


Great attention is still devoted to the synthesis and applications of enantiopure oxazoline ligands and recent results related to the use of C2-symmetric bis-oxazoline ligands in asymmetric catalysis have been reviewed . Concerning mono-oxazoline derivatives, two libraries of chiral N-heterocyclic carbene-oxazoline ligands 140a,b have been synthesized and their iridium(I) complexes successfully tested in the asymmetric hydrogenation of olefins . A series of enantiopure thiophene mono-oxazoline N,O-ligands 141 with three sites of diversity were also prepared in two steps from the corresponding thiophene carbonitriles and applied to the enantioselective phenyl transfer reaction of aldehydes . A new family of optically active phosphine-oxazoline P,N-ligands 142 has been synthesized and evaluated in asymmetric allylic alkylation (AAA) reactions (ees up to 97%) . Different regioisomers of aromatic-substituted phosphinyl-oxazolinyl-[2.2]paracyclophanes and some aza-paracyclophaneoxazoline N-oxides were prepared and tested in AAA reactions and allylation of aldehydes, respectively. Novel planar chiral PHOX ligands with a pentamethylferrocene backbone were synthesized and applied in Pd-catalyzed AAA reactions (ees up to 94%) while the use of P,N-ferrocenyl-oxazoline ligands with electron-rich or electron-deficient aryl groups on the P atom allowed high diastereoselectivity and excellent enantioselectivity (up to 98%) in Cu(I)-catalyzed asymmetric 1,3-DC of azomethine ylides to nitroalkenes . New chiral phosphine-oxazoline ligands 143 (SIPHOX) with a rigid and bulky spirobiindane scaffold were prepared in four steps in 40-64% overall yields: the corresponding iridium complexes catalyzed the hydrogenation of acyclic N-aryl ketimines (ees up to 97%) . Excellent results (ees up to 99%) in the iridium-catalyzed hydrogenation of imines and olefins were also obtained with 2-aza-norbornane-phosphineoxazoline ligands . Potentially tridentate P,N,N-quinazoline-oxazolinecontaining ligands 144 have been synthesized and applied to Pd(0)-catalyzed AAA reactions .

O t-Bu

N

N

O

O

N

O NH HN

t-Bu

O

O

N

N

Ar O

145

R

146

R

O

O

N

N

R

147

R

Ar O

The synthesis of different C2-symmetric bis-oxazoline ligands, such as 145, with an axialunfixed biaryl backbone has been reported as well as their diastereomeric equilibrium in solution and their application to Cu-catalyzed cyclopropanation of styrene with diazoacetate . A three-step procedure allowed the synthesis of C2-bis-oxazoline-amide ligands 146, tested in Pd-catalyzed AAA (ee’s up to 98%) . Chiral C2- and C1symmetric bis-oxazolines with a cyclopentane backbone have been prepared and studied in transfer hydrogenation, cyclopropanation and Diels-Alder reactions . The synthesis of highly modular N,Y,Z,Y,N-pentadentate bis-oxazolines (Y = N, O, S; Z = N, NO, OH, OMe) such as 147 led to a variety of ligands in diastereo- and enantiomerically pure form exploited for the construction of helical metal complexes with predetermined chirality . Single enantiomer, chiral donor-acceptor metal complexes were synthesized via the self-discriminating Zn(II)-complexation of a pseudoracemic mixture of donor/acceptorsubstituted bis-oxazoline derivatives . Chiral pyridyl-bis-oxazolines (Pybox)

306


were successfully applied in scandium(III)-catalyzed Sakurai additions to glyoxyamide , pyrrole alkylations and cerium(IV)-catalyzed nitrone cycloadditions of α,β-unsaturated 2-acyl imidazoles . Metal-complexes of azabis-oxazolines efficiently catalyzed the addition of indoles to benzylidene malonates and to nitroalkenes (up to 98-99% ee) as well as addition of nitroalkanes to nitroalkenes . Aldol reactions of pyridine N-oxide aldehydes were performed in high yields and diastereoselectivity and in excellent enantioselectivity in the presence of chiral copper(II)-bis(oxazoline) complexes . A novel route to cyclopropane derivatives has been described from 2-(1,1dimethylalkyl)dimethyloxazolines 148a (R1 = Me): conversion into 1,3-diiodides 149 via Pdcatalyzed sequential C-H activation and then radical cyclization led to 2-(1alkylcyclopropyl)dimethyloxazolines 150 in satisfactory yields . The corresponding aryl derivatives 148b (R2 = Ph) were subjected to Pd-catalyzed alkylation of aryl C-H bonds with sp3 organotin reagents using benzoquinone as a crucial promoter to give derivatives 151 . I

R2

I

cat. Pd(OAc)2 R1 R1 (PhCO2)2 IOAc a) N N R2 R2 C6H6, Δ 2 EtOAc, Δ O O R = Ph 148a,b R1 = Me, (CH2)n R1 = Me 149 70-83%

N

O 150 81-91%

R1 R1 N O 151 62-88%

R2= alkyl, CH2X, ester, OTBS, NPhth Reagents and conditions: a) cat. Pd(OAc)2, Me4Sn, Cu(OAc)2, benzoquinone, MeCN, reflux.

Unusual C-2 and C-4 regioselective lithiation of 3-bromo-5-(4,4'dimethyl)oxazolinylpyridine 152 using LTMP versus LDA was observed providing compounds 153 and 154, precursors of highly substituted nicotinic acid derivatives . Bicyclic 2-piperidinones 155 were obtained from 2-(butyn-4-yl)oxazolines through free-radical-mediated carbonylation and 6-endo cyclization of the resultant acyl radicals onto the oxazoline nitrogen . Sugar oxazolines were exploited in the synthesis of glycoproteins and glycosaminoglycans .

N Br R

O N 153 45-77%

1. LTMP, THF, -78 °C 2. Electrophile 3. NH4Cl

N Br

O N

152

1. LDA, THF, -78 °C 2. Electrophile 3. NH4Cl

R = Cl, I, TMS, CO2Et, CH(OH)Ar, CH(NTs)Ar

R Br

N

O O

R R' N

N 154 51-89%

O 155

5.7.6 OXAZOLIDINES Some new methods for the synthesis of the oxazolidine ring were published offering new ways to exploit the rich chemistry of these compounds. In aqueous media α-ketoamides 156 with phenolic substituents (Y = CN, CF3, H) undergo photocleavage and release of the phenol with formation of 5-methyleneoxazolidin-4-ones 158. The zwitterionic intermediate eliminates the phenolate leaving group and the resultant iminium ion 157 undergoes cyclization .

307


O

H

4-YC4H4O

R2 N

156

R1

hν hydrogen transfer

R2 OH

4-YC4H4O

O

O

R2 OH N

R1 - 4-YC H O6 4 157

R2 O N

N R1

R1 158

O

O 17-60 %

R1, R2 = alkyl

Although the synthesis of the oxazolidinone 159 appeared to be well established, the scale-up of the reaction gave poorly reproducible results. The synthesis was much more efficient using diphosgene and a catalytic amount of activated charcoal .

Ph

OH

H2N

Ph Ph

O

ClCO2CCl3 activated charcoal

O

NH 159 Ph

Ph Ph

THF, overnight

25 g, 89%

Another synthesis of 5-methylene-1,3-oxazolidin-3-ones can be achieved using Au(I) to catalyze the cyclization of N-propargyl carbamates 160. The reaction proceeds under very mild conditions and was applied to a large number of compounds . O t-BuO

R3 N 2 1 O R R 160

PPh3AuNTf2

R3 N

5 min-20 h

R2 R1,

O

65-99%

R1 = aryl, alkyl R3 = H, Me

R2

A previously described process – the synthesis of stannylated oxazolidines and their ring opening to afford N-(α-tributylstannylorgano)-(R)-phenylglycinol carbamates 161 – was completed by the transformation of these latter compounds into stannylated oxazolidinones 162. The ring closure of compounds 161 can be achieved by treatment with two equivalents of NaH or by mesylation of the primary alcohol. The applicability of this process was demonstrated by the use of the stannylated oxazolidinones as precursor of organolithium reagents .

O

R22CuLi

Bu3Sn N O

OR1

Ph

OR1

O Bu3Sn 161 R2

O NaH or MsCl

O N

N

OH Ph

Ph Bu3Sn 2 50-93% R 162 1 R = Me, t-Bu R2 = alkyl

The formation of 1,3-oxazolidin-2-ones by the reaction of phosgene or diphosgene with amino alcohols is a well established reaction, proceeding with retention of configuration of the stereocenters of the original amino alcohol. However exceptions were found with substrates containing the (2,3-anti)-3-amino-1,2-diol moiety. As an example, the reaction of amino alcohol 163 with phosgene and diphosgene was described. The two reactions gave

308


different results since for phosgene the major product was the cis-oxazolidinone 164 while with diphosgene the major one was the trans isomer 165 .

Ph

HO

O

OH

Ph

Cl

Cl N

NH 163 HO

NEt3

O

76%

164 O

O NEt3

Cl

OCCl3 HO

Ph N

Ph

OH NEt3

OH OCCl3

OH

Ph O

N O-

OCCl3

N - CCl3O-

O

O

N

O

O45% O

O

165

A high degree of selectivity can be obtained in the base catalysed epimerization of 1,3oxazolidin-2-ones 166 and 167. Through a proper choice of the base and substituents a selectivity up to 99:1 can be obtained for both the trans and cis isomers . CO2Me Bn N

O O

R=H

N LHMDS R

166

CO2Me

CO2Me

R = Bn

O

LHMDS

HN 167

O

dr > 99:1

O O

dr > 99:1

Some reactions in which a preformed 1,3-oxazolidine ring is transformed into another oxazolidine derivative were described. A detailed study of the enantioselective reduction of N-tosyl-4-alkylidene-1,3-oxazolidin-2-ones under the catalysis of Rh salts and chiral ligands, was published . S

O (EtO)2P(S)H O

N

DPSO

AIBN

O O

168

P

OEt OEt

N 75% DPSO

1,3-Oxazolidin-2-ones were employed as nucleophiles in a new multicomponent reaction called UFU (Ullman-Finkelstein-Ullman). This reaction allowed the one-pot synthesis of dissymmetrical para-disubstituted benzene scaffolds from 1-bromo-4-iodobenzene and two nucleophiles . The 1,3-oxazolidin-2-one ring was used as scaffold for a radical cyclization to obtain compound 168, in a synthetic process towards the synthesis of substituted quinuclidines .In a similar way, the 1,3-oxazolidin-4-one ring was used as a scaffold for a ring closing metathesis useful for the synthesis of azepinones and azocinones .

309


Several examples of the use of α,β-unsaturated imides of chiral, or non chiral, 1,3oxazolidin-2-ones were published. These compounds were used in Michael additions and Diels-Alder reactions . (NVinyl)-1,3-oxazolidin-2-ones were used as dipolarophiles in 1,3-DC reactions with nitrones . A fluorinated α-bromo imide was used in a stereoselective Reformatsky-type reaction with imines . Concerning natural and bioactive compounds, a short synthesis of cytoxazene 169 was reported . O HN

O OH cytoxazene 169

MeO

O

H N

O O

N O

O

O

O N H

O

O

H N

N O 170

O

O N

O

O

O N

N H

O

O

OBn O

Three sets of oligomers containing the 4-carboxy-5-methyloxazolidin-2-one moiety, one example is compound 170, were synthesized with the aim of verifying if these systems are able to give a β-bend ribbon spiral . 5.7.7

OXADIAZOLES

5-Alkyl- and 5-aryl-2-amino-1,3,4-oxadiazoles were prepared by tosyl chloride/pyridinemediated cyclization of thiosemicarbazides in good yields (79-99%). Interestingly, thiosemicarbazides exhibited a higher rate of cyclization than the corresponding semicarbazides. For example, 171 (X=S) was converted to oxadiazole 172 within 5 h . O Ph

H N

N H X 171

TsCl (1.2 equiv) Ph pyridine (2.1 equiv) THF, 65-70 °C

H N

N N Ph

O

N H

Ph X = O: 23% conv after 20 h X = S: 99% conv after 5 h

172

O

O

N

N

N N RZ CO2Me

o-Cl2C6H4, 180 °C

O 173

N Me

[4+2] cycloaddition

O N

N O RZ N N RE Me CO2Me

RE

or TIPB, 230 °C 61-94% RZ, RE = H, Me, CH2OTBS, Ph, OBn, CO2Me, CN

O

RZ RE CO2Me

N 174 Me [3+2] cycloaddition

O N

-N2 N Me TIPB = 1,3,5-triisopropylbenzene

O

RZ RE CO2Me

A systematic exploration of a tandem intramolecular [4+2]/[3+2] cycloaddition cascade of 1,3,4-oxadiazoles was conducted in which the tethered initiating dienophile, the tethered

310


dipolarophile, the 1,3,4-oxadiazole C-2 and C-5 substituents, the tether lengths and sites, and the central heterocycle were examined. For instance, derivatives 173, bearing a tethered indole as the dipolarophile trap of the in situ generated carbonyl ylide and different tethered dienophiles, were successfully exploited leading in each case to a single diastereomer of the cycloadducts 174 . Treatment of acylated adenosine-N-oxides with carboxylic acid anhydrides in the presence of thiophenol produced 4-(5-substituted-1,2,4-oxadiazol-3-yl) nucleoside analogues. For example, 175 was converted to 176 by treatment with acetic anhydride followed by deprotection of the amino group at C-5 with I2 (0.5 mol equiv) in hot MeOH . N O AcO AcO

NH2 1. PhSH, (MeCO)2O 2. I2, MeOH

N

OAc 175

N

N

O

3. NEt3, CH2Cl2

N O AcO AcO

N

N

NH2 N O OAc 176 98%

The rearrangement mechanisms of 5-perfluoroalkyl-1,2,4-oxadiazoles such as the five-tosix membered ring-rearrangements by hydrazinolysis and the photoinduced competitive rearrangements have been investigated .

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06EJO3016 06EJO3235 06EJO3283 06EJO4852 06EJO5485 06JA78 06JA925 06JA1452 06JA2410 06JA6626 06JA7418 06JA7712 06JA9644 06JA10589 06JA12886 06JA13662 06JA14004 06JOC38 06JOC345 06JOC1614 06JOC2417 06JOC2480 06JOC2486 06JOC2740 06JOC3026 06JOC3221 06JOC3656 06JOC4206 06JOC4609 06JOC4951 06JOC5008 06JOC6178 06JOC6295 06JOC6451 06JOC8106 06JOC8572 06JOC9319 06JOC9548 06JOC9831 06MM3147 06OL539 06OL927 06OL2115 06OL2249 06OL2309 06OL2417

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312 06OL2495 06OL2701 06OL2759 06OL3081 06OL3335 06OL3351 06OL3537 06OL3679 06OL3785 06OL4165 06OL4565 06OL5109 06OL5157 06OL5231 06OL5513 06OL5669 06OL5685 06OL6071 06OL6099 06PLM3292 06S243 06S706 06S885 06S1021 06S1289 06S1479 06S1975 06S1995 06S2265 06S2293 06S2515 06S2996 06S4151 06SC1247 06SL463 06SL555 06SL1739 06SL2727 06SL3255 06T611 06T1494 06T3095 06T4549 06T6392 06T9237 06T9349 06T9973 06T11470 06T11645


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06T12227 06T12398 06TA292 06TA620 06TA767 06TA1863 06TA2442 06TL549 06TL727 06TL927 06TL1291 06TL1627 06TL3625 06TL4385 06TL4698 06TL4957 06TL4973 06TL6497 06TL7043 06TL7635 06TL7897 06TL8247 06TL8383 06TL8611 06TL8641 06TL8821 06TL9077

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314

Chapter 6.1

Six-membered ring systems: pyridine and benzo derivatives Heidi L. Fraser, Darrin W. Hopper, Kristina M. K. Kutterer, Aimee L. Crombie Chemical and Screening Sciences, Wyeth Research, Pearl River, NY, USA [email protected], [email protected], [email protected], and [email protected]

6.1.1 INTRODUCTION The presence of pyridines in an abundant number of natural products and pharmaceutically active compounds continues to fuel the desire to develop new and improved methods for their synthesis as well as the synthesis of their benzo derivatives. Azacoumarins have been shown to be versatile biodynamic agents . There have also been reviews on quinoline derivatives and their antibiotic properties in multidrug resistant Enterobacter Aerogenes isolates . A number of important reviews highlighting the preparation of pyridines and their benzo derivatives have been published in 2006, including the synthesis of quinolines using the Skraup and Doebner-Miller methods . Fallahpour et al. discussed the utilization of oligopyridines as ligands in coordination chemistry . The reaction of triallylboranes with pyridines and isoquinolines, as well as other heterocycles, was reviewed as a versatile approach to the construction of bicyclic and polycyclic nitrogen heterocycles . This chapter includes a summary of the methods developed for the syntheses and reactions of pyridines, quinolines, isoquinolines, and piperidines that were disclosed in the literature in 2006. It will cover selected advances in the field and will serve as an update to the review published last year in this volume.

6.1.2

PYRIDINES

6.1.2.1 Preparation of Pyridines Cyclocondensations are one of the most widely used methods for preparing pyridines and dihydropyridines. The reaction is routinely employed in the synthesis of biologically important pyridines and those of interest in material sciences . In general, cyclocondensations are catalyzed by base, Brønsted, and Lewis acids (e.g., Yb(OTf)3 , AlCl3 , and Sc(OTf)3 ). Recently, efforts have been focused on employing multicomponent cyclocondensation reactions as one-pot procedures to conveniently synthesize diverse arrays

315

Six-membered ring systems: pyridine and benzo derivatives

of pyridine derivatives in an efficient, cost effective, and often times environmentally friendly manner . For example, a one-step, three-component cyclocondensation procedure for the synthesis of pyridines and 1,4-dihydropyridines has been described . As shown below, structurally diverse aldehydes 1 combine with two equivalents of malononitrile 2 and various thiols 3 to form 2-amino-3,5-dicyano-6-sulfanylpyridines 4 and the corresponding 1,4dihydropyridines 5 in good yields. R1

R1

R1

NC

NC

CN

R2SH

CN

CN

or EtOH reflux, 2 h

H 1

NC

Base

O

H2N

2 3 R1, R2 = Alk, Ar, or HetAr

H2N

R2 N 4 20-48%

N R2 H 5 62-96%

The Hantzsch synthesis of pyridines is a cyclocondensation method of considerable importance. This route traditionally involves the condensation of four components, including two molecules of ȕ-carbonyl compounds, an aldehyde, and ammonia to form 1,4dihydropyridines, which can be aromatized into pyridines . The reaction has conveniently been adapted to solid supported synthesis and liquid-phase synthesis . In a novel solution phase approach, the preparation of dihydropyridine 6 has been achieved by reacting ionic liquid-phase bound ȕ-oxo ester 7 with dimedone 8 and aldehyde 9 in good yields and high purities. Additional adaptations have been made to improve the Hantzsch 1,4-dihydropyridine synthesis. These modified routes generally involve the addition of enones with ȕ-enaminones under conventional thermal conditions and microwave assisted conditions .

IL O

O

O

7

Ar

8 N

Ar 11

H

neat, 90 °C 96%

9

O

MeOH, reflux, 18 h 80% Ar = 3,4-(CH2O2)C6H3

O IL O

Ar 6

O

N

1 equiv NaOMe

HO O

O

H N

1.5 equiv NH4OAc

O

O

O IL O

Ar 10

O

1.1 equiv DDQ CH2Cl2 reflux, 2 h 80%

As improvements in Hantzsch 1,4-dihydropyridine syntheses have occurred, attention has also been focused on advancing the aromatization processes used to produce pyridines from these precursors. The utility of several oxidizing agents has been explored, including DDQ , iodoxybenzoic acid (IBX) , sodium periodate catalyzed by Mn(III)salophen complex or polystyrene-bound Mn(III) porphyrin , molecular oxygen catalyzed by N-hydroxyphthalimide and Cu(OAc)2 , and silica gel-supported bis(trimethylsilyl)chromate . Other improvements in the aromatization process have led to a rapid microwave-assisted reaction using commercially available manganese dioxide (in the absence of an inorganic support) and to a more environmentally friendly, yet effective oxidizing method utilizing methanesulfonic acid

316

H.L. Fraser, D.W. Hopper, K.M.K. Kutterer, and A.L. Crombie

and sodium nitrite in the presence of wet SiO2 under heterogeneous and solvent free conditions . Several related polar cyclization processes have also been reported for the synthesis of pyridines and pyridinones . In some cases, the Vilsmeier reagent is used to effect the cyclization . As shown below, several chloronicotinaldehydes 12 are synthesized via the reaction of enamides 13 with the Vilsmeier reagent, generated by three different methods and at varying concentrations . R2 1

R

13

N R3

O

POCl3 or Triphosgene or Diphosgene

0 °C → rt → 75 °C

R2

88-94%

R1

CHO

DMF N

Cl

R1 = H, Ph, or CO2Me R2 = H, Alk, Ar, or CO2Et R3 = H or Bz

12

In addition to polar cyclization processes, pericyclic reactions are also used to produce pyridines and hydropyridines. Many of the most current strategies employ [4+2] cycloadditions to produce dihydropyridines, which can easily be converted to pyridines in a number of ways including oxidation or elimination processes. The nitrogen of the pyridine ring can be incorporated either via the diene (e.g., 1- or 2-azadienes , oxazoles , 1,2,4-triazines , or pyrazines ) or via the dienophile (activated imine or nitrile ). The utility of this hetero-Diels–Alder approach to pyridines is demonstrated by its application in several syntheses of natural products as the key regioselective step . The scope and efficiency of [4+2] cycloaddition reactions used for the synthesis of pyridines continue to improve. Recently, the collection of dienes participating in aza-Diels– Alder reactions has expanded to include 3-phosphinyl-1-aza-1,3-butadienes, 3-azatrienes, and 1,3-bis(trimethylsiloxy)buta-1,3-dienes (1,3-bis silyl enol ethers), which form phosphorylated, vinyl-substituted, and 2-(arylsulfonyl)-4-hydroxypyridines, respectively . In addition, efforts to improve the synthetic efficiency have been notable, as illustrated with the use of microwave technology. As shown below, a synthesis of highly functionalized pyridine 14 from 3-siloxy-1-aza-1,3-butadiene 15 (conveniently prepared from ȕ-keto oxime 16) and electron-deficient acetylenes utilizes microwave irradiation to reduce reaction times and improve yields . Me 2.5 equiv TBDMSOTf TBDMSO 2.6 equiv EtiPr2N

O Me 16

N OH

CH2Cl2, 0 °C, 5-18 h

Me

2.0 equiv DMAD toluene N OTBDMS μW (180 °C), 2 h 15 56%

TBDMSO Me

CO2Me N 14

CO2Me

Likewise, an efficient one-pot multicomponent synthesis of annelated 2-amino pyridines (e.g., 17) utilizing [4+2] cycloadditions has been described . The process involves the in situ generation of 1-aza-1,3-butadiene from a palladium-catalyzed couplingisomerization reaction of aryl halides (e.g., 18) with propargyl N-tosylamines (e.g., 19). The resulting butadiene then undergoes cycloadditions with N,S-ketene acetals (e.g., 20) to form annelated pyridines (e.g., 17).

317


NHTs

Ar = p-MeOPh

2. 5.0 equiv MeS THF N reflux, 12 h 20 Me 64%

Ar Br 18

CN

1. 2 mol% (Ph3P)2PdCl2 1 mol% CuI Et3N, THF reflux, 24 h

CN

19

Ar

N 17

N Me

Another pericyclic transformation commonly used to synthesize pyridines is the cyclotrimerization reaction . Traditionally, this approach involves a transition metal-catalyzed [2+2+2] cycloaddition of diynes with nitriles. A variety of catalysts are capable of effecting this transformation, including cobalt , ruthenium , rhodium , and nickel complexes and with the appropriate catalyst system (i.e., cationic rhodium(I)/modifiedBINAP complex), the aza-cyclotrimerization can be achieved chemo-, regio-, and enantioselectively . Aza- [2+2+2] cycloadditions of diynes with nitriles can lead to a variety of fused pyridines, including those that are highly substituted and sterically hindered . Additionally, non-fused pyridines can be available via this route, as demonstrated by a solid-supported, cobalt-catalyzed cyclotrimerization shown below . Various alkynes 21 and nitriles 22 were combined with polymer bound propargylic alcohol 23 to rapidly construct libraries of diverse pyridines 25 in good yields and purities. R1

TrtO

CpCo(CO)2 TMAO

R3 N

R2 21

23 1

R = Alk or Ar R2 = H or Alk R3 = Alk or Ar

N

toluene 80 °C, 48 h

22

R1

HO N

R2 3

R 25

R1

TrtO

1% TFA CH2Cl2 rt, 1 h

24

R2 R3

43-85% yield >90% purity

Recently, a method for synthesizing substituted pyridines incorporating 3-azadienynes as substrates in ruthenium-catalyzed cycloisomerizations was described . This route is a two-step process that first converts readily available N-vinyl or N-arylamides (e.g., 26) to the corresponding C-silyl alkynyl imines (e.g., 27) and subsequent rutheniumcatalyzed protodesilylation and cycloisomerization results in the formation of the corresponding substituted pyridines (e.g., 28). 1. 1.2 equiv Tf20 4.0 equiv 2-Cl-pyr CH2Cl2

O Ph

N H 26

O

2. 2.7 equiv TMSC≡CCu Ph THF, -78 °C → 0 °C 99%

O

N

10 mol% CpRu(PPh3)2Cl 10 mol% SPhos 1 equiv NH4PF6 toluene, 105 °C 70%

27

TMS

O

N Ph 28

318


In addition to the examples above, several other interesting methods for synthesizing pyridines, hydropyridines, and pyridinones have recently been described. Routes involving pericyclic reactions as the key step include tandem [2+2] cycloadditions/electrocyclic ring openings , 1,3-dipolar cycloadditions , electrocyclic ring closures , aza-Cope rearrangements , and aza-Wittig reactions . Additionally, palladium-mediated Heck reactions , electrophilic aromatic substitution reactions , and 6-endo N-lithioketimine cyclizations have been employed to produce pyridine derivatives. 6.1.2.2 Reactions of Pyridines Palladium reactions have continued to dominate the reactions of pyridines in the literature of 2006. Material scientists have utilized the palladium chemistry of pyridine to assemble various core structures . Medicinal chemists have also utilized a large assortment of palladium chemistry in the construction of pyridine-containing targets. Many Sonogashira reactions have been performed on halopyridines . While Suzuki reactions use both pyridylboronic acids and halopyridines . Two different groups have examined Suzuki-Miyaura coupling reactions of amino-chloropyridines with various substitution patterns . Stille reactions employ both halo and stannylpyridines in cross-coupling reactions to obtain compounds of interest. Moreover, Heck reactions incorporate vinylpyridines as substrates in addition to halopyridines . All of these palladium reactions may be used in concert to incorporate a large amount of diversity into a heterocycle very efficiently . Scott and Maes separately utilized tandem palladium-catalyzed amination cyclization sequences to prepare imidazopyridiones and dipyridoimidazoles, respectively . Likewise, Cvetovich and Chung synthesized naphthyridinone via palladium-catalyzed Heck-lactamization . Beebe et al. utilized a sequential van Leusen–Heck reaction to prepare a fused imidazopyridine . The regioselectivity of Suzuki cross-coupling reactions of 2,4-dibromopyridine 29 have been examined by Cid et al. . They report two catalytic systems for the Suzuki coupling of 2,4-dibromopyridine 29 and arylboronic acids, which lead to a highly selective method for the preparation of 30 or 31. This illustrates that the C-Br bond at the 2-position of the pyridine ring is more reactive toward palladium insertion than the C-Br bond at the 4position. The scheme below exemplifies how the alteration of ligands, solvent, and additives can modify the major product of this reaction. Anhydrous conditions facilitate high selectivity for preparation of 4-bromo-2-arylpyridine 30. Conversely, for the preparation of the symmetrical 2,4-diarylpyridine 31, the presence of water is instrumental in the optimization of the reaction.

319


Ph

N 31

Br

Ph

.

Pd2dba3, 2-BDBP K3PO4 1.5 H2O PhB(OH)2 82%

N 29

Br

Pd(PPh3)4, TlOH(aq), THF, Pd2dba3/PCy3, K3PO4/dioxane Br PhB(OH)2 43%

N

Ph

30

In addition to being substrates for palladium reactions, pyridines are also utilized as ligands for palladium . Pleixats et al. exploited the complexation of pyridine to palladium to create a silica-bonded, reusable catalysts for Suzuki coupling reactions . Organ and co-workers developed a series of NHC-PdCl2-3-chloropyridine (NHC = N-heterocyclic carbene) complexes that are easily reduced to a highly active Pd0NHC species, readily prepared in large scale and air stable . Yu et al. developed two new types of unsymmetrical pyridyl-supported pyrazolyl-NHC ligands for the assembly of transition metal catalysts . The application of these ligands as palladium complexes was explored; they exhibited good to excellent catalytic activity in the Suzuki–Miyaura reactions. Furthermore, palladium chemistry has also been used to form C-N and C-O bonds on pyridines. The latter has been utilized in the synthesis of oxygen substituted biologically active pyridines . In the formation of C-N bonds this chemistry has also been used to prepare compounds of biological interest that contain amino-pyridine moieties in addition to amino-substituted terpyridines , and pyridines that contain macrocycles . Moreover, a palladium-catalyzed amidation reaction was used in the preparation a 2,3-fused pyridyl urea a potential drug target . Yu and Che reported a catalytic amidation based on a cascade chelation-directed cyclopalladation approach , illustrated in the preparation of amide 32 from 2-phenylpyridine 33 via the cyclic palladium intermediate 34. O 5 mol% Pd(OAc)2

N 33

K2S2O8, H2NCOCF3, DCE 80 °C, 7 h, 92%

HN

N AcO Pd

CF3

N 2

34

32

Some amination reactions, while unsuccessful under palladium conditions, are accomplished via copper-catalyzed reaction . Yu and co-workers capitalized on the extensive literature of pyridyl as a directing group in C-H activation in a copper-catalyzed acetoxylation and halogenation of aryl C-H bonds to yield 35 and 36, respectively . This new reaction can also be applied to cyanation to form 37, amination, esterification, and thioesterification of C-H bonds. Selected examples are shown in the scheme below. The broad scope of this reaction is postulated to be a result of the mechanism. The authors propose a single electron transfer to the pyridine, leading to a radical-cation intermediate. The radical-cation intermediate then reacts with available nucleophiles and facilitates formation of many possible products.

320


OAc 10 mol% Cu(OAc)2 HOAc-Ac2O, O2 130 °C, 48 h, 37%

Br N

1 equiv Cu(OAc)2 Br2CHCHBr2 65%

36

N

1 equiv Cu(OAc)2 CH3CN, TMSCN 42%

33

N 35 CN N 37

Fluorine containing pyridines are of interest in medicinal chemistry due to their unique electronic effects . Two groups over the last year have attempted to improve both electrophilic and nucleophilic fluorination of pyridines. Hoyte et al. enhanced the nucleophilic fluorination of pyridines using microwave conditions . Kinetic experiments showed an average relative rate ratio of 3:1 for microwave versus conventional heating methods. Similarly, Sanford and co-workers describe the development of the first palladium-catalyzed C-H activation/C-F bond-forming reaction with electrophilic fluorine under oxidative conditions, utilizing microwave irradiation . This has been illustrated with the ortho-fluorination of 2-phenylpyridine 38 generating difluoro 39 in good yield. F N

10 mol % Pd(OAc)2 0.5 mL CH3CN in CF3C6H5 μW, 150 °C, 1.5 h F N

38

BF4

N Cl 69%

2

F N F 39

Additional publications from Sanford et al. describe the full exploration of palladiumcatalyzed chelate-directed chlorination, bromination, and iodination of arenes using Nhalosuccinimides as the terminal oxidant . Moreover, an electrophilic fluorination of dihalopyridine-4-carboxaldehydes was reported by Shin et al. . This was accomplished via transmetalation of the bromo derivative, followed by treatment with N-fluorobenzenesulfinimide as the source of electrophilic fluorine. Several groups have studied the free radical chemistry of pyridines. Schiesser and coworkers used a free radical rearrangement of 2-selenopyridines to prepare seleniumcontaining antioxidants . Additionally, Burgos and co-workers examined the radical cyclization and atom transfer reactions of pyridyl radicals in the preparation of annulated pyridines . Pyridylmethyl radicals, prepared by direct selenation of 2methylpyridines, have also been shown to undergo 5-exo-trig and 6-exo-trig cyclization under standard free-radical conditions . Zard et al. presented a more unique free radical reaction of pyridines . An unprecedented radical ring closure onto the pyridine nitrogen was observed when certain protecting groups were present in close proximity to the pyridine nucleus. This result was obtained upon changing the protecting group of the 2-aminopyridine 40 from acetyl to the more versatile t-butoxycarbonyl (Boc) group. Under otherwise identical conditions, alteration of the protecting group resulted in the formation of a different product. It was determined by X-ray and other spectroscopic means that the unexpected product 41, was formed from ring closure onto the pyridine nitrogen followed by electron transfer of the resulting radical to the peroxide generating a radical anion, quenching of the radical anion leads to a tetrahedral intermediate, which then collapses to give the observed pyridone 41.

321


O

Lauroyl peroxide DCE, reflux N R R = Boc; 55% Cl

N O

C(S)OEt S N 40

41

N R

Lauroyl peroxide DCE, reflux R = Ac; 50% Cl

O

N 42

N R

O

Sulfur containing pyridines have been shown to display interesting chemistry. Pyridine disulfides have been used as a sulfenylating agent with a phosphine-promoted desulfurative allylic rearrangement to fuctionalize thiols . Tanaka and co-workers have reported an N-glycosylation, which uses a newly designed glycosyl donor bearing a pyridylmethyl group on the sulfur . This moiety facilitates C-S bond cleavage via bidentate coordination of S and N atoms to Lewis acid activators. N-2-Pyridylmethyl thioamides have been reported to participate in an iodine-mediated oxidative desulfurization cyclization, which is an efficient method for preparation of 2-azaindolizines . Pyridinedithioesters were used as a proficient heterodienophile when complexed with BF3 . A hetero-Diels–Alder reaction using 3-pyridinedithioester 43 was used to generate a key intermediate 44 in the synthesis of racemic Aprikalim 45 as illustrated below. S S N 43

1. BF3 2. CH2Cl2 35 °C, 24 h 91%

N

N S

S

O S S

3:1

S

44

HN

N

Aprikalim 45

Due to their electron deficient character, pyridines are susceptible to nucleophilic attack. Rudler et al. has studied the reaction of pyridines with bis(trimethylsilyl)ketene acetals . In one instance, they examine the reaction of bis(trimethylsilyl)ketene acetals with 2-phenylpyridines activated with chromium tricarbonyl to give pyridine-substituted bicyclic -lactones. This reaction allows for the formation of up to five stereogenic centers in two-steps. A second report describes successive double nucleophilic additions of bis(trimethylsilyl)ketene acetals to pyridines. Modification of substituents on the ketene acetal and starting lactones makes it possible to drive the addition reactions either toward formation of tetrahydropyridines or the formation of highly substituted piperdines stereoselectively. O

O

N

PMP 1. LiHMDS, THF -78 °C, 5 min N 2. CH3OCOCl O 99%, dr = 94/6 O 46 t-Bu

H PMP

N O

OLi

N O

47 t-Bu

O

PMP

O N O

N O

CO2t-Bu 48

Clayden and co-workers reported the dearomatiztion of an electron-deficient pyridine ring via intramolecular cyclization of an enolate shown in the scheme above . Generation of the amino acid derived enolate of 46, with simultaneous activation of the pyridine ring by N-acylation, leads to a stereoselective transition state 47. The authors postulate that the stereoselectivity arises from the manner in which the bulky PMP (p-

322


methoxy phenyl) group controls the approach of the enolate. This results in an enantiomerically enriched diazaspirocyclic amino acid derivative such as 48. 6.1.2.3 Pyridine N-Oxides and Pyridinium Salts Pyridinium salts continue to be targets of interests for several different applications. Bererine derivatives, which originated from Chinese herbal medicine, have been synthesized for examination of their antihyperglycemic activity . These natural products are also of interest for their interactions with G-quadruples DNA structures . The inhibitory activity of pyridinium salts towards acetylcholinesterase was also reported recently . Moreover, Köck reported the first total synthesis of viscosamine, a natural product containing a pyridinium salt moiety . Material science applications of pyridinium salts include non-linear optics and chiral room-temperature ionic liquids . Additionally, their unique physicochemical and photophysical properties make pyridinium salts important compounds for electron transfer sensitizers , photosensitizers , and self-assembled films . Over the past year, the dearomatization of pyridinium salts has been implemented in the synthesis of indoles and less obviously triazolyldienes . Typically, pyridinium salts are prepared through reaction of an intact pyridine with electrophiles. Marazano et al. used a three-component process as entry into 3-substituted pyridinium salts for the preparation of 49 as shown below . O

N R1

O X

O

R2 50

51

R3 LDA X THF 20 - 80%

O O

n-BuNH2 HCl/ MeSO3H MeOH, reflux 60 - 65%

R2 O

52

R2 CH3SO3 N n-Bu 49

R1 = H, Si(CH3)3 R2 = CH3, n-Bu, H R3 = n-Bu, t-Bu X = -C(CH3)2-, -CH2-

3-Substituted pyridinium salts of this nature were difficult to obtain by other methods. This sequence is initiated with condensation of the anions of imine 50 with malonaldehyde monoacetals 51 to access glutaconaldehyde monoacetals 52. The monoacetal-aldehyde was then reacted with primary amines (n-BuNH2) to give 3-substituted pyridinium salts 49. When the silylimino derivative (R1=Si(CH3)3) was used, substantially higher yields of intermediate glutaconaldehydes were obtained. The utilization of solid-support pyridinium salts in the synthesis of bicyclic pyridines has been reported. Yue et al. synthesized 1,2,3,7-tetrasubstituted indolizines using poly(ethyleneglycol)bound pyridinium salts . The PEG-bound pyridinium salts 53 were reacted with alkenes or alkynes in the presence of Et3N, via 1,3-dipolar cycloaddition, to give polymer-bound indolizines 54 and 55, respectively. Liberation of the heterocycle with KCN/MeOH afforded 1,2,3,7-tetrasubstituted indolizines 56 and 57 in good to excellent yield. O

O R1CH=CHR2 Br N 53

O

R1

O

Et3N, TPCD DMF, 90 °C 96-99%

O

R2

N 54

O

R

O KCN/CH3OH rt, overnight O 50-90% R = CH3, Ph R1 = COCH3, CN, COPh R2 = H, aryl, heteroaryl

R1 R2

N 56

O

R

323


O R4

R3

O

Et3N

53

R3 R4

N

DMF, 90 °C 97-99% 55

O

R

O KCN/CH3OH rt, overnight O 62-75% R = CH3, Ph R3 = COCH3, H R4 = COCH3

R3 R4

N 57

R

O

Similarly, Yli-Kauhaluoma and co-workers have studied the 1,3-dipolar cycloaddition of polymer-bound alkynes to azomethine imines, generated in situ from N-aminopyridine iodides, in the synthesis of pyrazolopyridines . Dudley and co-workers have designed pyridinium triflate reagent 58 for the preparation of benzyl ethers . This reagent is easily prepared in two steps with good yield. Since it is also bench-stable and preactivated, the benzylation reaction occurs upon warming 58 in the presence of an alcohol with no need for acidic or basic promoters. R Cl

N

KOH, BnOH 18-c-6, PhMe reflux, 95% BnO

N

MeOTf, PhMe 0 °C to rt 86-91% BnO

N

OTf 58

OH

R

OBn

R = 1°, 2°: Yield> 80% HO R = 3°, aryl: Yield ≤ 80%

OTf

N

A key reaction of pyridinium salts continues to be nucleophilic addition to form dihydropyridines or pyridinones. Specifically, the reaction of Grignard reagents with Nacylpyridinium salts has been used to generate pivotal pyridinone intermediates in the total synthesis of (-)-Barrenazines and (-)-FR901483 . Lavilla et al. examined the addition of isocyanides to pyridinium salts 59 as an efficient entry into substituted nicotinonitrile derivatives 60 . The electron-withdrawing group helps to stabilize the nitrilium intermediate. The carboxamido group also undergoes dehydration in the generation of the observed product 60. CN

H2N(O)C

H2N(O)C

R1Cl N

Br

R1 = Bn, CO2CH3, Fmoc, Alloc R2 =2,6-dimethylphenyl, t-Butyl, Cyclohexyl

N R1 59

R2N=C NaOAc/ MeOH Yield over 2 steps: 60 - 71%

O R1 N NH R2 60

Another classic reaction of pyridinium salts is reduction of the pyridine ring. Donohoe and co-workers reported the partial reduction of N-alkylpyridinium salts , which is accompanied by subsequent alkylation and hydrolysis to furnish a range of 2,3dihydropyrid-4-ones. This sequence has the potential to introduce a variety of functional groups at the C-2 position of 2,3-dihydropyrid-4-ones. Reduction of pyridinium ylides with sodium borohydride has also been reported in fair to good yields . Both pyridinium salts and pyridine N-oxides are of increased interest as chiral catalysts in organic reactions. Connon and Yamada independently designed and examined pyridinium salts as chiral catalysts in the acylation of secondary alcohols . These two catalysts can be used for kinetic resolution of various sec-alcohols and dl-diols in good to moderate enantiomeric excess. Pyridine N-oxides have been utilized as asymmetric catalysts in the allylation of aldehydes and in the Strecker reaction . In the latter, the chiral Noxides played a key role in the initial activation of the Si-C bond by coordinating an O atom to the Si atom of silyl cyanide and stabilizing the three-membered complex proposed by the

324


authors. The preparation of these types of chiral N-oxide catalysts by oxidative dimerization has been examined by Denmark et al. and demonstrated in the synthesis of many chiral pyridine N-oxides . Alternatively, Sanfilippo and co-workers have examined the enzymatic kinetic resolution of pyridine N-oxides to produce several chiral N-oxides . Pro-chiral pyridine N-oxides have also been used as substrates in asymmetric processes. Jørgensen and co-workers explored the catalytic asymmetric Mukaiyama aldol reaction between ketene silyl acetals 61 and pyridine N-oxide carboxaldehydes 62 . The process is catalyzed by a copper(II)-bis(oxazoline) complex 63 which gave good yields and diastereoselectivities with up to 99% enantiomeric excess.

R

catalyst OTMS CH Cl , -40 °C 2 2

H +

N O

OMe

O 62

64 - 92% 77 - 99% ee

61

O

R

O

N O

OH O

O N

t-Bu

Cu

TfO 63

R = H, 6-Br, 6-Ph, 5-Br, 5-Ph

N

OTf

t-Bu

Pyridine N-oxides have been exploited in the reaction with silylaryl triflates 64 to prepare 3-(2-hydroxyphenyl)pyridines 65 regioselectively, as illustrated below . Treatment of the silylaryl triflate 64 with cesium fluoride generates the benzyne intermediate 66, which in turn undergoes 1,3-dipolar cycloaddition with the pyridine N-oxide 67 forming intermediate 68. Rearrangement of 68 to bicyclic 69 occurs rapidly; this intermediate is then deprotonated at the C-3 position to give the 3-phenyl regioisomer 65. Isomer 65 is observed when bicyclic 69 is substituted with electron-donating or electron-neutral group. The influence of electron-withdrawing groups on the pyridine ring (R = CN) facilitates deprotonation at the C-2 carbon resulting in the 2-phenyl isomer 70. N R O N

R

R 67 CH3CN CsF 66

TfO 64

R

fast N O

TMS

H

R = CN, EWG R = CN; 42%

N 68

H O 69

70 HO

R HO R = H, CH3 52 - 80% N 65

Over the past year, two additional methods were reported to reduce pyridine N-oxides to the corresponding pyridines. Sandhu and co-workers have presented an efficient and general method for the deoxygenation of N-oxides using Zn(OTf)2 and Cu(OTf)2 . Similarly, Fernandes et al. have developed a novel reduction method, with wide functional group tolerance, using a silane (PhSiH3) in the presence of a catalytic amount of MoO2Cl2 to produce pyridines in excellent yield.

325


6.1.3

QUINOLINES

6.1.3.1 Preparation of Quinolines The development and use of environmentally friendly methods for the synthesis of quinolines and dihydroquinolines were represented in variety of publications in 2006. Many of the reports incorporated solvent free conditions. Perurnal et al. showed that silicasupported NaHSO4 as a heterogeneous catalyst for the cyclization of 2-amino-chalcones 71 under solvent free microwave conditions results in a variety of 2,3-dihydroquinolin-4-ones 72 in high yields . Lier et al. also utilized a silica supported TaBr5 catalyst to cyclize 2-amino-chalcones 71 forming a variety of 2,3-dihydroquinolin-4-ones 72 under solvent free thermal conditions . The use of silica gel supported TaBr5 under solvent free thermal conditions showed considerable improvement in yield for this cyclization compared to the reaction conducted in organic solvents.

NH2

NaHSO4-SiO2 μW 2 min

O

O

1

Ar R1

71

R = H, 80 - 95% TaBr5-SiO2 140 - 150 °C, 3 - 5 min

R1 72

R1 = H, 70 - 92% Br, 70 - 75%

N H

Ar

Wang et al. reported two different reaction conditions for a solvent free Friedländer quinoline synthesis. Initially, they reported the reaction of 2-acetyl anilines 73 with a variety of β-diketoesters 74 using p-TsOH as the catalyst under microwave conditions to form substituted quinolines 75 . They also reported the same reaction using BiCl3 as the catalyst under thermal conditions . Both sets of conditions afford high yields and simpler experimental procedures. p-TsOH, μW 15 - 60 s

R1 O NH2 73

EtO2C

R1

87 - 96%

+ R2

O 74

BiCl3 74 - 178 °C 2-5h 89 - 96%

CO2Et N

R2

R1 = 4-FC6H4, Me R2 = Me, Et, i-Pr

75

In addition to their work with solvent free systems, Wang and co-workers reported a water mediated Friedländer quinoline synthesis using hydrochloric acid and conventional heating to synthesize a variety of substituted quinolines in high yields . Additionally, Rivkin and co-workers synthesized a variety of 4-hydroxy-3phenylquinolin-2-(1H)-ones under solvent free microwave conditions using an activated arylmalonate . Reacting the desired substituted aniline with di-(2,4,6trichlorophenyl)-2-phenyl-malonate at 250 °C with microwave irradiation for 15 min resulted in a variety of 4-hydroxy-3-phenylquinolin-2-(1H)-ones in good yields. They also demonstrated the utility of this method in the synthesis of type I fatty acid synthase inhibitors . Kumar et al. have reported a variation of the Friedländer quinoline synthesis. They highlight the use of CeCl3•7H2O as a reusable catalyst in the reaction of 2-

326


aminoarylketones 76 with ketones 77 in acetonitrile at room temperature to form a variety of substituted quinolines 78 . R1 R2

O + NH2 O 76

R1

CeCl3·7H2O CH3CN, rt

R2

65 - 95%

R3 77

N

R3

78

R1 = C6H5 R2 = CH3, CO2CH3, CO2CH2CH3, COCH3 R3 = CH3, CH2CH3, CH2OCH2CH2NPht R2 - R3 = COCH2C(CH3)2CH2, (CH2)6, CH2CH(t-butyl) CH2CH2

Xie and co-workers developed a simple route for the synthesis of 3-aryl-1,2,3,4tetrahydroquinolines 79 using a direct intramolecular reductive ring closure strategy . The yields for the key reductive ring closure were moderate; however, the simplicity of their route leads to an efficient synthesis of a variety of tetrahydroquinolines 79. R1 R

R3

R1

1. ArCH2CN Na, C2H5OH 2. NaBH4

O

2

2

R

CN NO2

R3

NO2

R1 H2, Pd/C Ar THF, CH3OH

R4

R2

Ar

R3

7 - 74 %

N H 79

R4

4

R

A novel reaction for the synthesis of 4-amino-substituted quinolines 80 or 4-quinolones 81 was reported. Reaction of various ketones, such as 82 and 83, with o-oxazoline-substituted anilines 84 and 85 in the presence of a catalytic amount of p-toluenesulfonic acid (p-TSA) in dry n-butanol led to 80 and 81, respectively . To the authors’ surprise, the reaction of acetophenones 82 lead to a different outcome than that of the cyclic or acyclic ketones 83 containing more than one carbons α to the ketone. 1

R

R5 O

NH2 N

R2

4

R

O

+ R3

10 mol% p-TSA n-butanol, reflux 24 h

HN HO

75 - 89%

84

82

R5 R6 R6

R4

O

NH2 N

R7

Ph

O

+ 83

85

R6

R2

N 80 O

5

R

R1

10 mol% p-TSA n-butanol, reflux 24 h

R3 R7

88% 81

N H

Ph

The use of cerium(IV) ammonium nitrate (CAN) as a catalyst for an aza-Diels–Alder reaction was reported in two different publications. In one report Perumal and co-workers react a variety of anilines 86 and aldehydes 87 with enamine 88 in the presence of 5 mol% CAN to form a series of tetrahydroquinolines 89. The reactions were performed at room temperature with very short reaction times and in good yields. In addition, the resulting tetrahydroquinolines could be oxidized to the corresponding substituted quinolines using 2.5 eq of CAN in high yields .

327


R1 +

H2N

R2 + O 87

86

N 88

5 mol% CAN H2O or aq CH3CN rt

O

H N

R2

N

O

R1

82 - 86% R1 = H, Cl; R2 = H, Me, OMe

89

Yu and co-workers also used CAN to catalyze an aza-Diels–Alder reaction . Aryl imines were reacted with N-vinylpyrrolidin-2-one or N-methyl-N-vinyl-acetamide in the presence of 10 mol% CAN resulting in the desired 2,4-cis-tetrahydroquinolines in good yields. An efficient high yielding synthesis of 3-substituted 2,3-dihydroquinolin-4-ones 90 was developed by using a one-pot sequential multi-catalytic process . The scheme below shows the one-pot sequential multi-catalytic Stetter reaction of aldehyde 91 and α,βunsaturated esters 92, resulting in the formation of the desired dihydroquinolines 90. Cl O

OH S 20 - 30 mol%

N + NHMs

1

AcO

R 92

91

O R1

5 mol% Pd(OAc)2 12 mol% PPh3, 5 equiv i-Pr2NEt t-BuOH (0.1 M), 50 °C

N Ms

98 - 99%

R1 = CO2Et, CO2t-Bu, CN

90

A novel metal free approach for the synthesis of substituted quinolines 93 was reported using a HCl(cat)-DMSO system . A catalytic amount of HCl in DMSO activates aldehydes 94, which react with benzylideneanilines 95 to form substituted quinolines 93.

1

2

R

94

R O

+

N 95

R3

5 mol% HCl DMSO, air

R

55 - 82%

R1

3

N R2 93

R1 = (CH2)5CH3, (CH2)2Ph, CH2Ph R2 = H, 4-BrPh, 4-OCH3Ph, 4-CO2H, furan, Ph; R3= H, 4-BrPh, 4-OCH3Ph, 4-CO2H, 2-OCH3, Ph

In a similar one-pot synthesis of substituted quinolines, Wang et al. used molecular iodine (1 mol%) to catalyze the reaction between enolizable aldehydes and imines in refluxing benzene. The advantage of this method is that it is metal free, takes place with short reaction times, and produces good yields . Metal-catalyzed methods for the synthesis of quinolines continue to be of interest. In an alternate new strategy, SnCl2 was used to mediate tandem reactions for the synthesis of highly functionalized quinolines 96, derived from Baylis-Hillman adducts . The reduction of the nitro group of 97 initiates a highly regioselective intramolecular cyclization involving the amino and carbonyl group, which is introduced through a SN2 substitution reaction as shown in the scheme below.

328


O R2 + R1

1. DABCO rt, 15 min (80 - 86%) 2. AcCl, pyr, CH2Cl2 2-3 h (78 - 84%)

O

O R1

O

O 3

OAc

R4

R3

2

R

R1

R4 R2

R

DABCO 68 - 85%

NO2 NO2

NO2 97

SnCl2, MeOH reflux

50 - 86% R2

R1 = H, 5-Cl, 3,4-OCH2O R2 = CO2Me, CN R3 = Me, Ph, OEt R4 = Ph, OEt

1

R

O R3

96

N

R4

In another metal-catalyzed quinoline synthesis, NiBr2(dppe) was used to catalyze the reaction of 2-iodoanilines with aroylalkynes in acetonitrile at 80 °C . The resulting 2,4-disubstituted quinolines were synthesized in good yields and this method was reported to tolerate a broad range of functional groups. Konakahara and co-workers reported the first direct synthesis of a quinoline skeleton 99 via homodimerization of ethynylanilines 98 in the presence of InBr3 in refluxing methanol . R1 InBr3, MeOH, reflux, 24 h

1

R

R2 98

NH2

56 - 89% R1 = H, Me, F, CN, NO2 R2 = H, Me

R2 R1

N R2

99

H2N

6.1.3.2 Reactions of Quinolines A novel approach for the direct conversion of quinoline N-oxides to 2-aminoquinolines was developed using an isocyanate intermediate . This regioselective conversion was achieved by treating a primary amide 100 with oxalyl chloride and reacting the resulting isocyanates with quinoline N-oxides 101 to give the desired 2-amidoquinolines 102 in good yield. R1

1. oxalyl chloride CH2Cl2

O NH2

2.

R2

100 N O 101

O R1 N H

N 102

R2 R1 = H, R2 = 3-CN, 91% R1 = H, R2 = 6-CO2Et, 82% R1 = 3-CF3, R2 = H, 81% R1 = 4-OMe, R2 = H, 79%

The synthesis of N-heterocyclic isothiocyanates has been a difficult challenge due to their propensity to oligomerize by autocatalysis. In an attempt to alleviate this issue, silver thiocyanate was used in a novel synthesis of 4-quinolyl isothiocyantes . Reaction of 4-chloroquinoline with silver thiocyanate in refluxing anhydrous toluene for 12 h results in the desired product in quantitative yields and excellent purity. The asymmetric hydrogenation of quinoline continues to be of interest. Li et al. reported the asymmetric hydrogenation of a variety of 2-substituted-quinolines to the corresponding tetrahydroquinolines using an Ir-catalyst with a BINOL-derived diphosphonite ligand

329


. The use of this catalytic system gave enantiomeric excesses ranging from 7396% with conversions of >96% in most cases. In another report involving an asymmetric hydrogenation of 2-substituted-quinolines, a [{IrCl9cod)}2]/(S)-segphos catalyst was used to achieve good enantiomeric excesses . In this reaction, which provides a new approach for the hydrogenation of heteroaromatic systems, the quinoline was first activated with chloroformates forming the N-acylpyridinium salt. Using a metal free Brønsted Acid catalyzed transfer hydrogenation Rueping et al. reported a new organocatalytic reduction of quinolines and its application in the synthesis of alkaloids . 2Substituted quinolines 103 are reduced in the presence of Hantzsch dihydropyridine 104 and catalyst 105 in benzene at 60 °C to give the desired tetrahydroquinolines 106 in good to high yields and high enantiomeric excess. EtO2C

CO2Et N H 104 Ar

R

N 103

N H 106

O O P O OH

R = 2-naphthyl, 93% yield, >99% ee 3-bromophenyl, 92% yield, 98% ee R 1,1'-biphenyl-4-yl, 91% yield, >99% ee 2-furyl, 93% yield, 91% ee n-pentyl, 88% yield,90% ee Ar = 9-phenanthryl

105 Ar

A one-pot synthesis of pyrano[3,2-c]quinolin-2,5(6H)-dione 107 was reported through the condensation reaction of chlorocarbonyl ketenes 108 with 4-hydroxyquinolin-2(1H)-ones 109. This simple procedure was shown to be a convenient synthesis of pharmacologically active compounds in high yields . OH + Cl N 109 R

O

anhyd CHCl3 20 - 30 min, rt

Ph C O

O 108

O

R = Et; 90% Me; 85% Ph; 92%

O Ph

N R

O

OH 107

Kappe and co-workers developed two general microwave methods for the synthesis of symmetrical (hetero)-biaryls 110 from 4-chloroquinolin-2(1H)-one 111 . The two methods include either a Pd(0)- or Ni(0)-mediated homocoupling, as exemplified below. Cl R4 R3 R2

N R1

111

Method 1 O PdCl2(dppf), [B(pin)]2, KOH, BuCl R1 N μW, 130 - 145 °C, 35 min 68 - 91 % R2

R4

Method 2 NiCl2, PPh3, Zn, DMF μW, 205 °C, 25 min 41 - 98%

N

R3 R2

O R3 R4

110

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

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6.1.4 ISOQUINOLINES 6.1.4.1 Preparation of Isoquinolines The Pictet-Spengler reaction continues to be a popular area of research for the synthesis of isoquinolines. In one report it was shown that α-amino acids like L-DOPA can be reacted with benzaldehyde to form the corresponding isoquinoline in quantitative yield . This Pictet-Spengler reaction was conducted under very mild conditions, allowing the reaction to take place in the presence of unstable functional groups. In another version of the Pictet-Spengler reaction, AuCl3/AgOTf was used to catalyze the cyclization of imines 112 to a variety of tetrahydroisoquinolines 113 in good yields . MeO N

MeO 112

R

1 mol% AuCl3, 2 mol% AgOTf,

MeO

1 equiv AcCl, 1 equiv 2,6-lutidine, CH3CN, rt, 12 h

MeO 113

R = CO2Et, 81% p-NO2C6H4,78% N Ac p-MeOC6H4, 82% Ph, 73% R

Chen et al. reported a more environmentally friendly version of the Pictet-Spengler reaction . In this report, a series of 2-phenylsulfonyl-1,2,3,4tetrahydroisoquinoline-1-carboxylic acid ethyl ester derivatives 114 were synthesized in good yields through the cyclization of N-phenylsulfonyl-β-phenethylamines 115 with α-acyl sulfide 116 using phenyliodine(III) bis(trifluoroacetate) (PIFA) in ionic liquid ([bmin]PF6). The use of the ionic liquid allows for a simple purification and [bmin]PF6 can conveniently be recycled. R1 R2

PhO2S CO2Et NH + S

PIFA, [bmin]PF6 50 °C, 1 h [bmin]PF6 = PF6 N

R3

N n-Bu

R1 R2 R3

116

115

114

R1, R2, R3 = H, 88% R1, R2 = H, R3 = OMe, 78% R1= H, R2, R3 = OMe, 85% N SO2Ph 1 2 R , R = H, R3 = Cl, 75% CO2Et

Kobayashi and co-workers have described a new synthesis of a range of 1,4-disubstituted isoquinoline derivatives 117 . Initially, a lithium halogen exchange of 118 was performed to form 119, followed by treatment with a variety of nitriles 120 resulting in 1,4disubstituted isoquinolines 117. R2 R1

R2 OMe

Br 118

n-BuLi R1 Et2O, 0 °C Li 119

R2 3 OMe R CN, 120 0 °C

R1 N

36 - 73% 117

3

R

Kobayashi and co-workers have also reported an alternate synthesis of 1,4-disubstituted isoquinolines and a new synthesis of 1,3,4-dihydroisoquinoline derivatives . The 1,4-disubstituted isoquinolines 121 are synthesized in good yields by reacting a variety of organolithiums 122 with different benzonitriles 123. In addition, a variety of lithium dialkylamides 124 were also reacted with different benzonitriles 123 to form 1-amino-4-substituted isoquinolines 121 in moderate yields.

331


Ph R1

Ph

R2Li 122 or LiNR32 124

OMe

R1 N

-78 °C to rt 41 - 76%

CN 123

R1 = H, OMe R2 = Ph, s-Bu, N(R3)2 R3 = i-Pr, Et

2

121 R

Additionally, Kobayashi and co-workers demonstrated the reaction of 125 with phenyl lithium, followed by treatment with different electrophiles results in 1,3,4-trisubstituted dihydroisoquinolines 126, as shown below . Ar R1

Ar 1. PhLi, -78 °C to 0 °C 2. R1X

N

CN

R1 = H, 69% Me, 59% Bn, 62%

126 Ph

125

Bravo et al. synthesized a series of 1-alkyl- and 1-aryl-3-aminoisoquinolines 127 . Treatment of 2-acylphenyl-acetonitriles 128 with amines 129 and a catalytic amount of trifluoroacetic acid results in the formation of 1-alkyl or 1-aryl-3aminoisoquinolines 127 in a single reaction step and in good yields. CN O + R1

128

NHR2 R1 = Et, R2 = Me, 92% R1 = Et, R2 = Ph, 86% N R1 = Ph, R2 = Ph, 76%

H R2NH2 EtOH, Δ 129 127

R1

An improved method for the synthesis of 4-hydroxy-1-oxo-1,2-dihydroisoquinoline-3carboxylic acid derivatives 130 was presented . This improved three-step method efficiently converts phthalic anhydride 131 to the desired dihydroisoquinolines 130 in high yields over three steps with only one purification. O O 131

O

1. R1NHCH2COR2 2. CH2N2

O O N

R1 = Me, t-Bu R2 = OMe, OEt, NHEt, N(Me)Ph, NEt2

O

R1

O R2

NaOR1 R1OH 64 - 83%

OH O R2 N

R1

130 O

In a facile and rapid stereoselective, three-component, one-pot reaction, a series of cisisoquinolonic acids 132 were synthesized using silica supported sulfuric acid to catalyze the reaction between homophthalic anhydride 133 with different aldehydes 134 and amines 135. This three-component cyclocondensation offers a variety of advantages including high yields, easy experimental work-up, and the use an inexpensive, non-toxic, readily available, and recyclable catalyst . R2CHO 134 R1NH2 135

O O O 133

SiO2·H2SO4 CH3CN, rt 81 - 90%

O N

HO2C

H

R1 H R2 132

R1 = Ph, 4-ClC6H4, 4-MeC6H4, PhCH2, PhCH2CH2, benzimidazole R2 = Ph, 4-ClC6H4, 4-NO2C6H4, 4-BrC6H4, 3-ClC6H4, 2-BrC6H4

332


Chang et al. and Yamamoto et al. reported two notable intramolecular hydroaminations of alkynes to form tetrahydroquinolines. Chang and co-workers were able to synthesize a tetrahydroisoquinoline system using a catalytic one-pot procedure in good yield . In an enantioselective approach, Yamamoto et al. have developed a palladium-catalytic intramolecular asymmetric hydroamination of alkynes using a chiral catalyst derived from Pd2(dba)3•CHCl3 and (R,R)-renorphos to form tetrahydroisoquinolines in high yield and good enantiomeric excess . 6.1.4.2 Reactions of Isoquinolines The asymmetric addition of different types of nucleophiles at the C-1 position of 3,4dihydroisoquinolines were highlighted in a number of publications. Schreiber et al. described an enantioselective addition of terminal alkynes 136 to 3,4-dihydroisoquinolinium bromide 137 in the presence of triethylamine, catalytic copper bromide, and QUINAP . The resulting 1-substituted tetrahydroquinolines 138 were isolated in high yield and high enantiomeric excess in most cases. OMe MeO N

MeO 137

Br

+ R1 Br

136

5 mol% CuBr, 5.5 mol% QUINAP, MeO 1 equiv Et3N, CH2Cl2, -55 °C H MeO 71 - 91% yield 94 - 99% ee

R1 = Ph, Si(Me)3, OEt, CH2OMe

OMe

* N 138

Br

R1

Two recent publications highlight the first catalytic allylation of cyclic imines. In a formal total synthesis of (-)-Emetine, Itoh et al. describe a catalytic asymmetric allylation of 3,4-dihydro-6,7-dimethoxyisoquinoline using CuCl, (R)-tol-BINAP (10 mol%) and TBAT (10 mol%) as the catalyst to achieve moderate to high yields in moderate enantiomeric excess . Chong et al. detailed a general asymmetric methodology for the synthesis of 1-substituted tetrahydroquinolines 139 via an enantioselective allylation of 3,4dihydroquinolines 140 with the allylboronate 141. High yield and high ee were achieved using this method and its utility was highlighted by its application to the synthesis of various known alkaloids (crispine A, coniine•HCl, ent-corynantheidol) . R1

141 N

R2 140

R1

R1, R2 = H, 92%, 95% ee R2 R1, R2 = H, 78%, 98% ee R1, R2 = OCH2O, 86%, 95% ee R1, R2 = Cl, 88%, 95% ee R1 = H, R2 = NO2, 90%, 99% ee

3,5-(CF3)2-C6H3 NH 139

O B O 141 3,5-(CF3)2-C6H3

A Pd(II)-catalyzed asymmetric addition of malonates to dihydroisoquinolines was also reported . This method provides highly optically active C-1-substituted tetrahydroisoquinolines in good yields. An efficient asymmetric hydrocyanation of 6,7dimethoxy-3,4-dihydroisoquinoline to yield 1-cyano-1,2,3,4-tetrahydroisoquinoline was also described . This asymmetric Strecker reaction, which utilizes Jacobsen’s thiourea-containing catalyst, resulted in high yield and high enantiomeric excess of tetrahydroisoquinolines. In another report, the enantioselective addition of vinylzinc reagents

333


to 3,4-dihydroisoquinoline N-oxides were shown to produce the desired 1-substituted 1,2,3,4tetrahydroisoquinolines in good yields and high enantiomeric excess. However, to achieve these high enantiomeric excesses, 1.2 equivalents of chiral ligand must be used . An asymmetric hydrogenation of isoquinolines that were first activated with chloroformates was reported by Zhou and co-workers using an [{IrCl9cod)}2]/(S)-segphos catalyst to synthesize 1,2-dihydroisoquinolines with good enantiomeric excesses . In another asymmetric hydrogenation, 1-substituted-3,4-dihydroisoquinolines were reduced using a water soluble ruthenium(II)complex catalyst in water with sodium formate as the hydrogen source. This environmentally friendly method resulted in high yields and high enantiomeric excess of the desired tetrahydroquinolines . Kundu et al. developed a mild and efficient one-pot protocol for the synthesis of dihydroindazoloisoquinolines 142 via an unprecedented SnCl2-mediated intramolecular cyclization of nitro-aryl substrates 143 . As illustrated below, the cyclization occurs via the hydroxylamines 144 and leads to the formation of dihydroindazoloisoquinolines 142 in high yield and purity. R1O

R1O R2O

R3 143 R4

1. SnCl2·H2O,PhSH, TEA, CH3CN, rt, N 15 min NO2 R1, R2 = CH3, -CH2R3 = H, CH3, OCH3 R4 = H, Cl, OCH3

R1O N OH

R2O

NH R3 144 R4

N

R2O 2. TsCl, rt 15 min 88 - 91 % 142

R3

N

R4

A one-pot procedure was developed by Bai and co-workers for the ring enlargement of αchloromethyl N-containing heterocycles . Chloromethyl tetrahydroisoquinoline 145 was treated with alkylbromides and potassium carbonate in refluxing acetonitrile resulting in good yields of desired 2,3-dihydro-1H-benzo[d]azepine-5-carboxylate 146. The proposed transformation involves the formation of aziridinium salts 147 followed by bond breaking between the nitrogen and the tertiary carbon atom. EtO NH

EtO H3CO2C

Cl

RBr, K2CO3, CH3CN reflux R = Bn, 71% Allyl, 85%

145

EtO

EtO

N R N R

EtO H3CO2C 147

EtO H3CO2C 146

6.1.5 PIPERIDINES There have not been any comprehensive reviews related to piperidines published in the past year. A review on sulfur-nitrogen containing compounds such as sulfinimines (Nsulfinyl imines) and N-sulfonyloxaziridines includes the use of N-sulfinyl imines in the synthesis of di-, tri-, and tetra-substituted 4-piperidones . Another account describes chiral cyclic imide-based synthetic methodologies for the asymmetric synthesis of naturally occurring or pharmaceutically interesting hydroxylated heterocyclic derivatives including (S)-6-alkyl-5-hydroxy-2-piperidinones and 2-alkyl-3-piperidinols .

334


6.1.5.1 Preparation of Piperidines The application of olefin metathesis to the synthesis of piperidines continues to be widely employed. The use of ring closing metathesis (RCM) in the synthesis of fluorovinylcontaining α,β-unsaturated lactams 148 and cyclic amino acid derivatives 149 is shown below. A key improvement in these reactions is the addition of the Grubbs’ 2nd generation catalyst (G2) in small portions during the reaction to compensate for catalyst decomposition that occurs at elevated reaction temperatures . 7 mol% G2, F toluene, Bn 100 °C, 4 h R1 80% - 99% O N F R1 = H or O CH2OC(O)C(F)CH2

N Bn 148

R1

R2

N R

R N Ph

Ru Cl Cy3P

1

R

Cl

N

N R1 O 149

R2

R1 = Boc or Ts, R2 = OMe or substituted benzylamine

F

R = 2,4,6-triMePh

2.5-5 mol% G2, F toluene, 100 °C, O 30-60 min 74% - 99%

Two RCM reactions were employed in a new and efficient route to a key chiral intermediate, isoquinuclidine 150, in the synthesis of alkaloid (+)-catharanthine . The first RCM makes use of chiral enone 151, derived from L-serine, to generate a chiral dihydropyridinone 152. Intramolecular alkene metathesis of dialkenyl piperidine 153 generates 150, which represents the first example of the use of RCM in the generation of an azabicyclo[2.2.2]alkene system. O O O

N 151

O 10 mol% G2, CH2Cl2, reflux, 18 h 87%

O

O

N

MeO2C

O 152

O

N 153

MeO2C N 10 mol% G2, CH2Cl2, reflux, 20 h O 84%, >99% ee 150

O

Additional RCM reactions have been reported for the synthesis of piperidines and related lactams. Pearson et al. have reported the use of RCM as the key step in the generation of the piperidine ring in a synthesis of trans-3,4 iminosugars . A RCM reaction has also been employed in the generation of fused bicyclic derivates from the octahydroquinolizine chemical class of compounds . Grubbs’ first generation Ru catalyst (G1, PhCH=RuCl2(Pcy3)2) was used in the preparation of a lactam structural analogue of the polyketide passifloricin lactone . Niida et al. reported the generation of diastereomeric lactams utilizing mild RCM reactions at room temperature . In the synthesis of cyclic β-amino esters 154 and 155, via RCM, Grubbs’ second-generation catalyst was superior, leading to lower reaction temperature and higher yields compared to those achieved with the first generation catalyst . O HN

CO2Me

5 mol% G1 or G2, CH2Cl2, 2 h O G1 (rt) = 79% G2 (rt) = 85%

O N H

BocN OMe

154

CO2Me

5 mol% G1 O or G2, CH2Cl2, 4 h N OMe G1 (reflux) = 45% Boc 155 G2 (rt) = 92%

Another form of olefin metathesis widely used for piperidine formation is ring-rearrangement metathesis (RRM), as shown below. The versatility of this reaction can be seen in its ability

335


to produce piperidines from different sized cyclo-ene rings (e.g. cyclopentene 156 and cyclooctadiene 157). The RRM reaction proceeds in high conversion and with good diastereomeric ratios . O

O

O

2 mol% A, O

N

ethylene, rt 89%, d.r. = 5:1 156

N

PCy3 Cl Ru Cl

MeO2C

O iPr A IH2Mes Cl Ru Cl Ph Cy3P B

5 mol% B, MeO2C ethylene, Δ TsN 95%, d.r. = 14:1, trans/cis

TsN

157

A new approach to piperidines via cyclization of dienes, such as 158, employs a phosphorus hydride mediated radical addition/cyclization reaction . This reaction proceeds with complete regioselectivity to create the 6-exo-trig product 159, although as an inseparable mixture of two of the four possible diastereomers. O N O 158

O (EtO)2P(S)H, AIBN, cyclohexane, 80 °C O 75% ODPS DPS = tert-butyl diphenylsilane

P(S)(OEt)2

N

ODPS 159

Other radical cyclization approaches to the synthesis of piperidines include a CANmediated stereoselective cyclization of epoxypropyl cinnamyl amines and a cyclization of ¢−trimethylsilylmethylamine radical cation, generated via a photoinduced electron transfer reaction to a tethered -functionality . The scheme below depicts the novel use of a carbonyl ene cyclization (A, Lewis acidcatalyzed) and a closely related Prins cyclization (B, Brønsted acid-catalyzed) to generate predominantly trans (cyclization condition A) or cis (cyclization condition B), di and tri substituted piperidines 160 and 161 . Of note, in the formation of di-substituted derivatives, R1 = H and R2 = Ph, no reaction occurs under cyclization condition B and the cis isomer 160 is obtained exclusively under cyclization condition A. In the case of tri-substituted derivatives, when bulky substituents at the 2-position (R1 = t-Bu or Ph) are present the trans diastereomer 161 is obtained almost exclusively under cyclization condition A, while no diastereoselectivity is seen under cyclization condition B. R1

Ts N R2 O

R2

A. MeAlCl2, CHCl3, 61 °C, 16 -27 h 64 - 84%, up to 2:98 cis:trans B. HCl, CH2Cl2, -78 °C, 16 h 73 - 94%, up to >98:2 cis:trans R1

R2 =

= H; H, CH3, -(CH2)n- [n=2,3,4] R1 = CH3, Bn, i-Pr; R2 = H

R1

Ts N

R1

Ts N R2

R2 OH

R2 160 - cis

OH

R2 161 - trans

Hydroamination of olefins has received considerable attention this year as a route to functionalized piperidines and spiropiperidines, particularly in regard to the investigation of new catalysts. In the synthesis of spiro-piperidines, two new mild and more general intramolecular hydroamination protocols were developed this year. One protocol uses a cationic gold-phosphine complex (Au[P(tBu)2(o-biphenyl)]Cl) as the catalyst

336


and the other makes use of an ytterbium ate complex [Li(THF)n][Yb[(R)C20H12N2(C12H22)]2] , both generating spiro-piperidines in high yield. The utility of a new lanthanide catalyst 162 for hydroamination and hydrosilylation is highlighted below. Application of this new lanthanide catalyst resulted in excellent yields of piperidines such as 163 and 164 with reduced reaction times. NH2

NH2 Ph

2.2 mol% 162 60 °C, 22 h quantitative yield

2 mol% 162 100 °C, 4 h

163 N

164

Ph TMS P N N(SiHMe2)2 La N(SiHMe2)2 P N Ph 162 TMS Ph Ph 2 mol% 162 Ph

NH

Ph

PhSiH3, rt, 4 h 99% yield for 2 steps

N SiH2Ph

Chang et al. reported a mild tandem intramolecular hydroamination of yne amines to form an endo-adduct intermediate, which reacts with electron-deficient azides to produce cyclic amidines . Selected examples of an interesting synthetic route to tropene derivatives 165 via a dual hydroamination strategy is shown below. This one-step reaction makes use of a palladium catalyst and takes place by sequential intermolecular hydroamination of cycloheptatriene with aryl, heteroaryl, and primary alkyl amines to generate intermediate 166, followed by transannular intramolecular hydroamination . H 2 mol% Pd(TFA)2, 4 mol% Xantphos + H2N R RH2N 10 mol% PhCO2H PhMe, 110 °C, 5-48 h 166

N R

PdLn

165

R = Ph, 80% R = 3-pyridyl, 41% R = Bn, 68% R = phenethyl, 72%

Hydroamination of olefins under most catalytic conditions proceed with Markovnikov addition of the N-H bond across the olefin. Shown below is a rhodium-catalyzed intramolecular, anti-Markovnikov, hydroamination developed for the synthesis of 3arylpiperidines 167 . Further evaluation of this reaction as a synthesis of multisubstituted piperidines revealed that substrates with substituents α or γ to the amino group did not produce the expected piperidine, however, substrates with a substituent β to the amino group produce piperidines in high yield. 5 mol% [Rh(COD)(DPPB)]BF4,

β Ar

γ

α

NHMe

THF, 80 °C, 24 h 71 - 83%

N Ar

Ar = Ph, 4-OMePh, 3,4-OMePh, 4-FPh, 3,4-FPh

167

An interesting example of a gold-catalyzed cycloisomerization of β-aminoallene 168 to tetrahydropyridine 169 is depicted below . Patil et al. report a similar goldcatalized hydroamination of allenes to produce 2-vinyl piperidine 170 in good yield .

337


5 mol% AuCl, 5 mol% pyridine nBu HN CH2Cl2, rt, 6 d 76%

nBu H2N 168

5 mol% AuCl, C5H11 THF, rt, 24 h 80% NHCbz

N Cbz

169

C5H11 170

Palladium-catalyzed (PdCl2(PPh3)2) decarboxylative carbonylation reactions for the formation of lactams are known to proceed under carbon monoxide at a pressure of 60 atmospheres. The scheme below highlights a new procedure utilizing a different Pd catalyst, where the formation of lactams 171 from oxazolidinones 172 takes place at atmospheric pressure . O

O

NTs R

172

5 mol% Pd2 (dba)3 10 mol% Ph3P CO (1 atm), benzene, 60 °C, 4 h

R

R = i-Pr, 74% R = Ph, 77% R = Bn, 75% R = CH2OTBDMS, 71%

TsN O 171

A report on a regiospecific 6-exo radical cyclization for the generation of lactams 173 highlights a remarkable halogen-substitution effect on the direct reactions of unsaturated N-H amides on vinylic halogen substituents . O X

NH2

O

Pb (OAc)4 / I2, CH2Cl2, rt hv, 4 h, 70 - 89% X = Cl, Br, I

I

H N

X 173

The following two schemes exemplify the synthesis of piperidines via 1,4-addition of amines. In the first scheme below, a one-pot Stille coupling/double Michael addition, starting from readily available vinyl stannanes, is used to generate piperidinones 174 . An example of the reduction of piperidinone 174 to piperidine 175 is also highlighted. R3

0.5 mol% [allylPdCl]2

R2-NH2, THF 60 °C, 2 h COCl 52 - 70% R3 R1 2 1 R = Me, Ph R = CH2CO2t-Bu, CH2Ph, CH2CH=CH2

Bu3Sn

R1

O 1 mol% PPh3 THF, 60 °C, 3 h

N

R2

R1

HO NaBH4, i-PrOH H2O, rt, 1 d

N

R2

3

R 174 175 R3 = NHPhth, CH(NHTFA)CO2t-Bu

An interesting synthesis of enantiopure cis-decahydroquinolines, which involves enol ether hydrolysis, double bond isomerization, and intramolecular 1,4-addition of an amino group across a cyclohexenone has been reported . The process is stereoselective, with the exclusive formation of both cis-isomers 176 (43% over 3 steps) and 177 (17% over 3 steps) of the decahydroquinoline ring. OH

OH O

Bn2N

O

H2N

H 2N HCl 70 °C, 3.5 h

O

N H H

H

OH 176 O

OH 177

N H H

Other routes to piperidines involving 1,4-addition reactions include the incorporation of a Michael addition reaction as the piperidine ring formation step in the total synthesis of Histrionicotoxin and the use of an intramolecular 1,4-addition, 6-endo-dig ring

338


closure of a nonattenuated amine into a pendant ynone in excellent yields, as demonstrated in the synthesis of enaminones . Bargiggia and Murray reported a novel double 1,4-addition of hydroxylamine to a bis ¢,£-unsaturated diester to afford predominantly the cis isomer of a N-hydroxypiperidine . Another route to the formation of piperidine heterocycles is cyclization via reductive amination utilizing various hydride sources. The scheme below depicts a bis reductive amination, using sodium triacetoxyborohydride as the hydride source, to generate exo-178 and endo-179 azabicyclo[3.2.1]octane amino acids in moderate yields . RO2C OHC

OHC

NHCOMe

RO2C MeOCHN

CHO p-methoxybenzylamine, NaBH(OAc)3, AcOH (cat.), CHO ClCH2CH2Cl, 25 °C CO2R NHCOMe

HN

R = Me; (±)-(1S*,5S*,6S*)-exo-178; 61% R = (-)-8-Phenylmenthyl; (-)-(1S, 5S,6S)-exo-178; 57%

178 NH NHCOMe R = Me; (±)-(1R*,5R*,6S*)-endo-179; 53% CO2R R = (-)-8-Phenylmenthyl; (-)-(1R, 5R,6S)-endo-179; 58% 179

Gheorghe et al. make use of sodium cyanoborohydride as a hydride source in the synthesis of 5-arylpiperidines . Kellehar and Kelly report the formation of a spiro ¥-lactam using sodium borohydride in the key reductive amination step . A number of reports have been published this year that describe the use of hydrogenation over various catalysts as a process to generate the source of hydride ion in reductive amination. Palladium catalysts used in these types of synthesis of various piperidines include Pd/C , Pd/CaCO3 , and Pd(OH)2 . Reductive amination can also be performed via hydrogenation in the absence of catalyst, as reported by Calderón et al. . Finally, a one-pot hydroformylation reductive amination sequence was reported using a rhodium catalyst (HRh(CO)(PPh3)3) and XANTPHOS under microwave irradiation conditions to form cyclic enamides in good yields . Nucleophilic displacement of leaving groups, such as mesylates, tosylates, triflates, or halogens, as well as nucleophilic ring opening of epoxides, cyclic sulfates, cyclic hemiacetals, or lactones is still a common route to piperidine cores. Nucleophilic displacement of mesylates, tosylates, or triflates have been used to generate diverse piperidine containing cores such as imidazolo[1,2-a]-L-arabino-piperidinoses , (S)-3-hydroxypiperidin-2-one , trans-4-hydroxypipecolic acids , 2,3-disubstituted piperidines , 2,3,4,5-substituted piperidines , a bicyclic diamine , iminosugars , bicyclic iminosugars , and a 2'-deoxy-2'-N,4'-C-ethylene-bridged nucleoside , generally in excellent yields. An interesting variation on nucleophilic displacement of halogens includes the use of Nsulfinylamide 180 to generate optically pure 2-(1-hydroxybenzyl)piperidine 181 .

TolOS

Cl TolOS 1. LDA, THF, NH -78 °C 2. -78 °C to rt, 16 h O OTIPS OTIPS TolOS N S Tol ( ) Cl 3 180

TolOS

H

N 2 steps TolOS

OTIPS 66%

N

Ph OH 181

339


An effort to improve the efficiency of the nucleophilic displacement of halogens in a cyclocondensation reaction of primary amines with alkyl dihalides for the synthesis of Nphenylpiperidine through the use of microwave irradiation (80-100 W, 120 °C, 20 min, 96% yield) was reported this year . Stereocontrolled nucleophilic opening at the C1-position of epoxides to furnish substituted piperidine 182 was accomplished through the use of Lewis acids TMSOTf or Sc(OTf)3 . Ts

O Ph

H N

TMSOTf, DCM, rt, 2 d, 98% or Sc(OTf)3, DCM, rt, 3 d, 92%

Ts N

182 OH

Ph

The synthesis of enantiomerically pure D-manno and L-gluco iminosugars 183 and 184, respectively, was achieved via reduction of an isoxazoline to an amine, which subsequently acts as a nucleophile in a spontaneous opening of the cyclic sulfate moiety . O N

O O S O O

1. H2, Pd/C, Na2CO3, MeOH, rt, HO 5 h, 77% OBn 2. H2O, H2SO4, dioxane, 40 °C, HO 36 h, 93%

OBn NH 183

HO HO

OBn NH 184

The scheme below depicts a reduction of an azide on a sugar moiety followed by nucleophilic ring opening of the sugar to obtain either an aza-sugar piperidine 185 or an aza-sugar lactam 186 . HO

HO 1. TFA, H2O, 40 °C, 2 h O 2. H2, PtO2, 20 bar, rt, 12 h O 3. H2, Pd/C, HO O 5 bar, rt, 24 h 80%

N3 H BnO

H H N

EtO2C H OH

N3 O

BnO

OH 185

1. H2 (1 bar), EtO2C O 10% Pd/CaCO3, EtOH, 4 h HO 2. N2, 12 h OBn 65%

H N

O OBn

OBn 186

Other examples of nucleophilic ring opening of a sugar to generate an aza-sugar piperidine include the synthesis of 1-deoxy-homonojirimycin analogues and 1-deoxynojirimycin . Likewise, Kikuchi et al. report the nucleophilic opening of a cyclic hemiacetal to generate a 2,3-substituted piperidine . Amide bond formation as a route to piperidine lactams continues to be widely employed. Formation of the amide bond can be effected through the use of coupling reagents such as dicyclohexylcarbodiimide/4-pyrrolidinopyridine , N-hydroxysuccinimide/EDCI , or by direct cyclization of an amine on a methyl or ethyl ester . Bicyclic lactam 187 was generated via a Staudinger reaction to reduce the azide, followed by thermal cyclization of the amine on the ester . EtO2C OTBS

1. PH3P, H2O, 1,4-dioxane, reflux, 40 h 2. xylene, reflux, 6 h, 95%

N3 Ph

O 187 OTBS

HN Ph

340


Intermolecular or intramolecular cyclizations via alkylation of an enolate with a large variety of electrophiles continues to have widespread usage. One form of these cyclizations involves displacement of a halogen or mesylate. Pu and Ma have reported the use of alkylative cyclization involving displacement of an iodide under mild conditions to generate a bicyclic enone in excellent yield . Kropf et al. report an intramolecular cyclization involving alkylation of an enolate, an ¢-/¢'-unsubstituted cyclohexanone, and a tethered 4-alkyl electrophile to form bicyclo[3.3.1]nonane ring systems in good yields . Double intermolecular alkylation with a dibromide on methyl cyanoacetate or a bis-mesylate on indene was used to generate the piperidine core of ¢,¢-cyclic-£aminohydroxamic acids or spiropiperidine fused indenes , respectively. Other electrophiles used in intramolecular cyclizations with enolates include esters and alkenes. Esters were utilized in the generation of 5,6-dihydro-4-hydroxy-2pyridones and £-keto lactams via Dieckmann condensation . Hanessian et al. report anion cyclization onto a terminal alkene and the formation of a chain extended piperidine through concomitant trapping with allylbromide . Intramolecular Mannich reactions have been used in the synthesis of piperidines. An intramolecular Mannich-type reaction was used as the key step in a highly diastereoselective and concise preparation of novel trifluoro-substituted analogues of di- and trisubstituted piperidine alkaloids . In the scheme below, an intramolecular Mannich reaction is shown as the key step in the asymmetric synthesis of the 2,3,6-trisubstituted piperidine core 188 of the antitumor Nuphar alkaloids . O N O O

TsOH•H2O, benzene, 60 °C, 6 h 76%

188 O

N H

N O

The application of [4+2] cycloaddition reactions for the synthesis of piperidines has received a considerable amount of attention this year. Palacios et al. have reported the hetero-Diels–Alder reaction of 3-azatrienes with enamine pyrrolidinecyclohexanone affording hexahydroisoquinolines in 42% yield . Denmark and Montgomery reported the first [4+2] cycloaddition of an N-vinyl nitrone with a tethered dienophile providing a somewhat unstable tetrahydropyridine N-oxide in 86% yield . Another interesting route to a tetrahydropyridine core enlisted an inverse electron demand Diels–Alder reaction of an electron-deficient N-sulfonyl-1-azabutadiene with an electron-rich dienophile . A number of aza Diels–Alder reactions using imines as azadienes have been reported. Alves et al. reacted 3-(3-(tert-butyl-dimethylsilyloxy)buta-1,3-dienyl)oxazolidin-2-one with 2Hazirines at room temperature for 4-5 days with no catalyst to obtain cycloadducts in moderate to good yield . Venkatraman et al. reported the hetero Diels–Alder reaction of a chiral imine with cyclopentadiene, using catalytic BF3•O(C2H5)2, generating an azabicyclo[2.2.1]heptene derivative . A [4+2] cycloaddition was used in the synthesis of piperidones via a Yb(OTf)3 catalysed reaction of an imine with Danishefsky’s diene . Boglio et al. reported an improved catalyst, a weaker POM-Yb Lewis acid (TBA5H2[¢1-YbP2W17O61]) . An aza Diels–Alder reaction of optically active sulfinimines with the Rawal diene and catalyzed by TMSOTf is reported to lead to enantiomerically enriched dihydropyridones with enantiomeric excesses up to 90% . Dandapani et al. reported a scandium triflate-catalyzed [4+2] aza-annulation

341


in the synthesis of pipecolates . Takasu et al. studied the synthesis of substituted piperidin-4-ones 189 via an imino Diels–Alder reaction catalyzed by triflic imide. They then expanded this reaction to a one-pot multicomponent reaction of 2-siloxy-1,3butadiene 190 with in situ generated aldimines as depicted below . TBSO

R2 NH2

2 mol% Tf2NH, MS 4Å, CH2Cl2, 0 °C, 4 h

O 190 Ph

R1

R1

TBSO N

189

R2

R1 = Ph, R2 = Ph, 78%, trans-cis (80:20) R1 = Bn, R2 = Ph, 74%, trans-cis (80:20) R1 = Bn, R2 = iPr, 16%

Ph

Other multicomponent reactions are exemplified in the following two schemes. A new highly diastereoselective four-component reaction was developed for the synthesis of dihydropyridones 191 substituted with an isocyanide functionality , thereby generating a synthetically useful complex isocyanide for use in further reactions. In this strategy, a phosphonate, a nitrile, and an aldehyde are used to generate an azadiene intermediate 192, which is trapped by an isocyanoacetate in the same pot. R2

O EtO P EtO R1 2

R

n-BuLi, THF CN -78 °C to rt, 5 h CHO

MeO2C R1

R2

R3

N

R1 = Ph, i-Pr, 2-furan R3 2 = aromatic, R NC heteroaromatic, and α,βO unsaturated aldehydes N H R3 = H, Ph, p-chlorophenyl 191

NC R1

32 - 98%

192

Raja and Perumal reported the synthesis of novel 2,6-diaryl-3-(arylthio)piperidin-4-ones via a four-component reaction consisting of arylthioacetones, 2-substituted aromatic aldehydes and methylamine or ammonium acetate . Further elaboration of this four component reaction to a novel five component tandem Mannich-enamine-substitution sequence involving the reaction of ethyl 2-[(2-oxopropyl)sulfanyl]acetate, two equivalents of a substituted aromatic aldehyde, and two equivalents of ammonium acetate is shown below . When this five-component tandem reaction involves para-substituted benzaldehydes, the cis (193) and trans (194) diastereomers of thiazones are obtained. Alternatively, ortho-substituted benzaldehydes form only the trans (194) diastereomer along with an air-oxidized product 195. O

O

O S

O 2 NH4OAc

HN

EtOH, rt, 5-7 d 42 - 74%

2 Ar CHO Ar = Ph, p-Cl-Ph, p-CH3-Ph, p-F-Ph, oCl-Ph, o-CH3-Ph, o-OCH3-Ph

N H 193

HN

HN S

Ar

O

O

Ar

S

S Ar

N H 194

Ar

Ar

N H 195

Ar

Another frequently used method for preparing piperidines is via reduction of the corresponding pyridine. These reductions can be accomplished through catalytic hydrogenation with platinium(IV) oxide . Chong et al. reported the use of rhodium on alumina to generate enantiomerically pure cis-2,6-piperidinedicarboxylic acid from the corresponding 2,6pyridinedicarboxylic acid . Ohigashi reported an improved reduction of 3cyanopyridine to its tetrahydropyridine derivative utilizing a NaBH4-ethanol reduction system .

342


The conversion of pyridines to their tetrahydropyridine or pyridinone derivatives is frequently accomplished via a pyridinium salt intermediate. Bennasar et al. reported the use of a Grignard reaction to generate a pyridinium salt, followed by reduction with NaBH4 producing a substituted tetrahydropyridine in excellent yield . The Grignard reaction of a 4-methoxypyridinium salt, followed by acidic hydrolysis of the intermediate methyl enol ethers, to generate pyridinone derivatives has been reported in three separate instances . Bräckow and Wanner reported the conversion of 4-substituted pyridines to their corresponding 4,4-disubstituted piperidines by trapping 4-substituted N-silylpyridinium ions with dialkylmagnesium reagents, followed by NaCNBH3 reduction . Xu et al. reported a regio- and diastereoselective double dinucleophilic addition of bis(OTMS) ketene acetals to pyridine to generate lactones . The remaining section highlights various other methods of generating piperidine cores. The scheme below depicts a simple route to piperidines heterocycles, such as 196, via an intramolecular Horner–Emmons cyclization of phosphonate 197 . O (EtO)2P 197

O

O N H Ph

Ph

Ph

MeONa, MeOH rt, 16 h 61%

O HN

Ph 196

Thompson et al. reported the use of a [3+2] cycloaddition reaction on an N-alkyl pyridine salt to generate an azabicyclic core with varied substitution on the bridge . A remarkable four-step, one-pot reaction, starting from azide building block 198 and utilizing a Horner–Wadsworth–Emmons [3+2]-1,3-dipolar cycloaddition cascade to generate the pivotal piperidine core 199 in an expeditious stereoselective synthesis of (−)-Cassine 200, is shown in the scheme below . O O O

O

O 1. CH3CN, DIPEA, P rt, 3 d OEt n OEt 2. Rh2(OAc)4, rt, n = 7 OAc 12 h, 74% N3

OAc

O N H

nO

O

O

198

OH

199 n = 7

n

N H 200 n = 9

An elegant synthesis of the spiroaminal containing domain of azaspiracids 201 makes use of a Staudinger-aza-Wittig reaction in a cascade sequence to generate the spiroaminal 202 . N3 O O TES O TBS

Et3P, PhH rt, 6 h 75%

HO TES

O

O

OO N R

TBS

N H TES 202

TES

O 201

R'

Reggelin et al. reported the application of methylated, enantiomerically pure acyclic and cyclic 2-alkenyl sulfoximines 203 for the synthesis of highly substituted aza(poly)cyclic ring systems 204 under complete stereocontrol .

343


O S N

1. n-BuLi, -78 °C 2. ClTi(Oi-Pr)3, -78 °C to 0 °C 3. 205, toluene, 0 °C H OTBS O NPhth 205

H

OH

H

OH

hydrazine NPhth -78 °C to rt S1a

S1a

203

N H 204

A novel route to 3,4-disubstituted piperidines 206 via ring transformation of 2(haloalkyl)azetidines 207 is shown below. During these reactions, bicyclic azetidinium intermediates are formed and then ring opened by a variety of nucleophiles generating stereospecific substituted piperidines in excellent yields . Br

R2O N 1 207 R

CH3CN, Δ, 3h

R2 O

H N R1

OH R2 O N 206 R1

Other routes to piperidines, lactams, and piperidine diones include the conjugate addition of 1,2-ethanedithiol onto a 1,5-amino-ynal, followed by cyclization to a piperidine aminal . Calvet-Vitale et al. reported the formation of new N-substituted ȕ-enamino ester piperidines featuring an exocyclic tetrasubstituted double bond through the intramolecular cyclization of linear amino-ȕ-keto-esters . A biomimetic approach to the pentacyclic substructures of indole alkaloids perophoramidine and communesin has been reported. This approach proceeds via intramolecular cyclopropanation followed by nucleophilic ring opening of the resulting activated cyclopropane ring, with an in situ generated aniline, to form both the tetrahydropyridine and lactam rings of the pentacyclic substructure . Amat and co-workers reported the cyclocondensation of (R)phenylglycinol with racemic methyl 4-formylhexanoate stereoselectively affording a bicyclic cis-lactam derivative in good yield . Chen et al. reported a [3+3] annulation of α-sulfonyl acetamide with α,β-unsaturated esters in the synthesis of bicyclic glutarimides . Lastly, Ge et al. made use of a condensation of a protected amino acid with bromoacrylamide to generate a piperidine dione intermediate .

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06BMCL4788 06BMCL4792 06BMCL5309 06BMCL5378 06BMCL5668 06CC674 06CC874 06CC1313 06CC1766 06CC2071 06CC2156 06CC2159 06CC2586 06CC4422 06CC4744 06CDC843 06CEJ3472 06CEJ4743

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06JOC135 06JOC260 06JOC315 06JOC800 06JOC894 06JOC1009 06JOC1094 06JOC1458 06JOC1707 06JOC1725 06JOC1746 06JOC2000 06JOC2046 06JOC2071 06JOC2460 06JOC2514 06JOC2521 06JOC2715 06JOC2922 06JOC3317 06JOC3494 06JOC3653 06JOC3656 06JOC3923 06JOC4118 06JOC4155 06JOC4222 06JOC4270 06JOC4689 06JOC4862 06JOC4969 06JOC5274 06JOC5328 06JOC5834 06JOC6020 06JOC6211 06JOC6258 06JOC6302 06JOC6562 06JOC6872 06JOC7079 06JOC7322 06JOC7805 06JOC8146 06JOC8384 06JOC8467 06JOC8481 06JOC8565


M.V. Patel, T. Kolasa, K. Mortell, M.A. Matulenko, A.A. Hakeem, J.J. Rohde, S.L. Nelson, M.D. Cowart, M. Nakane, L.N. Miller, M.E. Uchic, M.A. Terranova, O.F. El-Kouhen, D.L. Donnelly-Roberts, M.T. Namovic, P.R. Hollingsworth, R. Chang, B.R. Martino, J.M. Wetter, K.C. Marsh, R. Martin, J.F. Darbyshire, G. Gintant, G.C. Hsieh, R.B. Moreland, J.P. Sullivan, J.D. Brioni, A.O. Stewart, J. Med. Chem. 2006, 49, 7450. Y. Ju, R.S. Varma, J. Org. Chem. 2006, 71, 135. K.T.J. Loones, B.U.W. Maes, C. Meyers, J. Deruytter, J. Org. Chem. 2006, 71, 260. D. Zhang, E.J. Dufek, E.L. Clennan, J. Org. Chem. 2006, 71, 315. S.-y. Tanaka, M. Yasuda, A. Baba, J. Org. Chem. 2006, 71, 800. E. Gallienne, T. Gefflaut, J. Bolte, M. Lemaire, J. Org. Chem. 2006, 71, 894. I. Eryazici, C.N. Moorefield, S. Durmus, G.R. Newkome, J. Org. Chem. 2006, 71, 1009. L. Zhao, F. Liang, X. Bi, S. Sun, Q. Liu, J. Org. Chem. 2006, 71, 1094. L. Pignataro, M. Benaglia, R. Annunziata, M. Cinquini, F. Cozzi, J. Org. Chem. 2006, 71, 1458. J. Hashim, T.N. Glasnov, J.M. Kremsner, C.O. Kappe, J. Org. Chem. 2006, 71, 1707. W. Li, G.S. Wayne, J.E. Lallaman, S.J. Chang, S.J. Wittenberger, J. Org. Chem. 2006, 71, 1725. M.L. Bennasar, T. Roca, F. Ferrando, J. Org. Chem. 2006, 71, 1746. F. Hoffmann-Emery, H. Hilpert, M. Scalone, P. Waldmeier, J. Org. Chem. 2006, 71, 2000. J.E. Kropf, I.C. Meigh, M.W.P. Bebbington, S.M. Weinreb, J. Org. Chem. 2006, 71, 2046. S. Calvet-Vitale, C. Vanucci-Bacque, M.-C. Fargeau-Bellassoued, G. Lhommet, J. Org. Chem. 2006, 71, 2071. J.T. Williams, P.S. Bahia, B.M. Kariuki, N. Spencer, D. Philp, J.S. Snaith, J. Org. Chem. 2006, 71, 2460. D. Riegert, J. Collin, A. Meddour, E. Schulz, A. Trifonov, J. Org. Chem. 2006, 71, 2514. S.W. Youn, J. Org. Chem. 2006, 71, 2521. H.F. Sneddon, A. Van den Heuvel, A.K.H. Hirsch, R.A. Booth, D.M. Shaw, M.J. Gaunt, S.V. Ley, J. Org. Chem. 2006, 71, 2715. Z. Sun, S. Ahmed, L.W. McLaughlin, J. Org. Chem. 2006, 71, 2922. G. Lesma, B. Danieli, A. Sacchetti, A. Silvani, J. Org. Chem. 2006, 71, 3317. O.G. Schramm, N. Dediu, T. Oeser, T.J.J. Mueller, J. Org. Chem. 2006, 71, 3494. N. Sakai, K. Annaka, T. Konakahara, J. Org. Chem. 2006, 71, 3653. T.A. Hunt, A.F. Parsons, R. Pratt, J. Org. Chem. 2006, 71, 3656. K.W.C. Poon, G.B. Dudley, J. Org. Chem. 2006, 71, 3923. A. Niida, M. Mizumoto, T. Narumi, E. Inokuchi, S. Oishi, H. Ohno, A. Otaka, K. Kitaura, N. Fujii, J. Org. Chem. 2006, 71, 4118. H. Jude, D.J. Sinclair, N. Das, M.S. Sherburn, P.J. Stang, J. Org. Chem. 2006, 71, 4155. F.A. Davis, M. Santhanaraman, J. Org. Chem. 2006, 71, 4222. N.T. Patil, L.M. Lutete, H. Wu, N.K. Pahadi, I.D. Gridnev, Y. Yamamoto, J. Org. Chem. 2006, 71, 4270. C. Raminelli, Z. Liu, R.C. Larock, J. Org. Chem. 2006, 71, 4689. A. Winter, J. Hummel, N. Risch, J. Org. Chem. 2006, 71, 4862. Y. Sasaki, A. Niida, T. Tsuji, A. Shigenaga, N. Fujii, A. Otaka, J. Org. Chem. 2006, 71, 4969. F.L. Zeng, Z.K. Yu, J. Org. Chem. 2006, 71, 5274. M. Alajarin, J. Cabrera, A. Pastor, P. Sanchez-Andrada, D. Bautista, J. Org. Chem. 2006, 71, 5328. T.N. Tekavec, G. Zuo, K. Simon, J. Louie, J. Org. Chem. 2006, 71, 5834. F. Palacios, E. Herran, C. Alonso, G. Rubiales, B. Lecea, M. Ayerbe, F.P. Cossio, J. Org. Chem. 2006, 71, 6020. S.E. Denmark, J.I. Montgomery, J. Org. Chem. 2006, 71, 6211. F. Calderon, E.G. Doyagueez, A. Fernandez-Mayoralas, J. Org. Chem. 2006, 71, 6258. C.Y. Chang, H.M. Liu, T.J. Chow, J. Org. Chem. 2006, 71, 6302. X. Pu, D. Ma, J. Org. Chem. 2006, 71, 6562. S. Yamada, T. Misono, Y. Iwai, A. Masumizu, Y. Akiyama, J. Org. Chem. 2006, 71, 6872. R.P. Korivi, C.-H. Cheng, J. Org. Chem. 2006, 71, 7079. M. Urban, R. Pohl, B. Klepetarova, M. Hocek, J. Org. Chem. 2006, 71, 7322. R. Palko, Z. Riedl, O. Egyed, L. Fabian, G. Hajos, J. Org. Chem. 2006, 71, 7805. M. Mascal, S.C. Farmer, J.R. Arnall-Culliford, J. Org. Chem. 2006, 71, 8146. D. Sissouma, L. Maingot, S. Collet, A. Guingant, J. Org. Chem. 2006, 71, 8384. F. Caputo, C. Cattaneo, F. Clerici, M.L. Gelmi, S. Pellegrino, J. Org. Chem. 2006, 71, 8467. G. Pandey, S.G. Dumbre, M.I. Khan, M. Shabab, J. Org. Chem. 2006, 71, 8481. C. Wang, Z. Wang, L. Liu, C. Wang, G. Liu, Z. Xi, J. Org. Chem. 2006, 71, 8565.


06JOC8602 06JOC8610 06JOC8673 06JOC8934 06JOC8993 06JOC9393 06JOC9420 06JOC9857 06JOC9895 06LOC289 06OBC51 06OBC104 06OBC466 06OBC524 06OBC2785 06OBC3664 06OBC3675 06OBC3980 06OBC1071 06OL143 06OL613 06OL899 06OL1033 06OL1105 06OL1295 06OL1525 06OL1569 06OL1653 06OL1787 06OL1929 06OL2123 06OL2187 06OL2309 06OL2611 06OL2647 06OL2985 06OL3033 06OL3473 06OL3489 06OL3549 06OL3565 06OL3593 06OL3725 06OL3979 06OL4051 06OL4485 06OL5325 06OL5325 06OL5369 06OL5789

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350 06OPRD159 06PAC1357 06S227 06S243 06S435 06S451 06S687 06S827 06S1035 06S1141 06S1283 06S1295 06S1664 06S1971 06S2085 06S2224 06S2242 06S2551 06S2580 06S2585 06S2777 06S2855 06S2873 06S2934 06SC77 06SC97 06SC665 06SC1521 06SC1549 06SC1721 06SL53 06SL271 06SL395 06SL487 06SL547 06SL1071 06SL1133 06SL1437 06SL1595 06SL1903 06SL2083 06SL2716 06T968 06T1095 06T2395 06T2465 06T2492 06T2799 06T3095 06T3959 06T4011 06T4071 06T4086 06T4128 06T4756


A. Ohigashi, K. Temmaru, N. Hashimoto, Org. Process Res. Dev. 2006, 10, 159. Y.N. Bubnov, N.Y. Kuznetsov, M.E. Gurskii, A.L. Semenova, G.D. Kolomnikova, T.V. Potapova, Pure Appl. Chem. 2006, 78, 1357. J.G. Knight, I.M. Lawson, C.N. Johnson, Synthesis 2006, 227. Y. Iso, A.P. Kozikowski, Synthesis 2006, 243. H. Sheibani, M.H. Mosslemin, s. Behzadi, M.R. Islami, K. Saidi, Synthesis 2006, 3, 435. J.S. Yadav, B.V.S. Reddy, A.K. Basak, G. Baishya, A.V. Narsaiah, Synthesis 2006, 451. J.L.G. Ruano, J. Aleman, M.B. Cid, Synthesis 2006, 687. P. Maier, S.M. Andersen, I. Lundt, Synthesis 2006, 827. A. Roy, B. Achari, S.B. Mandal, Synthesis 2006, 1035. U.B. Vasconcelos, A.A. Merlo, Synthesis 2006, 1141. M.C. Bagley, M.C. Lubinu, Synthesis 2006, 1283. L.J. Nurkkala, R.O. Steen, S.J. Dunne, Synthesis 2006, 1295. J. Boivin, F. Carpentier, R. Jrad, Synthesis 2006, 1664. M.M. Blanco, M.S. Shmidt, C.B. Schapira, I.A. Perillo, Synthesis 2006, 12, 1971. U. Wittmann, F. Tranel, R. Froehlich, G. Haufe, Synthesis 2006, 2085. M. Reggelin, J. Kuehl, J.P. Kaiser, P. Buehle, Synthesis 2006, 2224. Y.-L. Chen, R. Leguijt, H. Redlich, Synthesis 2006, 2242. T. Emmrich, H. Reinke, P. Langer, Synthesis 2006, 2551. C. Timm, M. Koeck, Synthesis 2006, 2580. O. Johansson, Synthesis 2006, 2585. C. Castera-Ducros, M.D. Crozet, P. Vanelle, Synthesis 2006, 2777. D. Blachut, Z. Czarnocki, K. Wojtasiewicz, Synthesis 2006, 2855. A. Winter, A.M.J. van den Berg, R. Hoogenboom, G. Kickelbick, U.S. Schubert, Synthesis 2006, 2873. K. Kobayashi, K. Hayashi, K. Miyamoto, O. Morikawa, H. Konishi, Synthesis 2006, 17, 2934. M. Heravi, F. Derikvand, H. Oskooie, R. Hekmat Shoar, Synth. Commun. 2006, 36, 77. A. Abdelhamid, A. Al-Atoom, Synth. Commun. 2006, 36, 97. E. Rajanarendar, P. Ramesh, M. Srinivas, K. Ramu, G. Mohan, Synth. Commun. 2006, 36, 665. B.C. Hong, M. Hallur, J.H. Liao, Synth. Commun. 2006, 36, 1521. A. Zheng, W. Zhang, J. Pan, Synth. Commun. 2006, 36, 1549. M. Cooke, J. Wang, I. Theobald, G. Hanan, Synth. Commun. 2006, 36, 1721. T. Cailly, F. Fabis, A. Bouillon, S. Lemaitre, J. Sopkova, O. de Santos, S. Rault, Synlett 2006, 53. P. Raubo, J.J. Kulagowski, G.G. Chicchi, Synlett 2006, 271. A. Saini, S. Kumar, J.S. Sandhu, Synlett 2006, 395. P. Dewi-Wuelfing, J. Gebauer, S. Blechert, Synlett 2006, 487. S. Doerrenbaecher, U. Kazmaier, S. Ruf, Synlett 2006, 547. M. Rueping, T. Theissmann, A.P. Antonchick, Synlett 2006, 7, 1071. P.Q. Huang, Synlett 2006, 1133. N. Nishiwaki, T. Nishimoto, M. Tamura, M. Ariga, Synlett 2006, 1437. T. Kanemitsu, Y. Yamashita, K. Nagata, T. Itoh, Synlett 2006, 10, 1595. N. de la Rifuera, S. Fiol, J.-C. Fernándex, P. Forns, D. Fernándex-Forner, F. Albericio, Synlett 2006, 12, 1903. J.P. Scott, Synlett 2006, 2083. M.E. Popkin, R.K. Bellingham, J.F. Hayes, Synlett 2006, 2716. R. Hrdina, I.G. Stara, L. Dufkova, S. Mitchel, I. Cisarova, M. Kotora, Tetrahedron 2006, 62, 968. F. Palacios, D. Aparicio, Y. Lopez, J.M. de los Santos, J.M. Ezpeleta, Tetrahedron 2006, 62, 1095. J. Brackow, K.T. Wanner, Tetrahedron 2006, 62, 2395. Y. Luo, H. Gao, Y. Li, W. Huang, W. Lu, Z. Zhang, Tetrahedron 2006, 62, 2465. B. Han, Z. Liu, Q. Liu, L. Yang, Z.-L. Liu, W. Yu, Tetrahedron 2006, 62, 2492. A. Herrera, R. Martinez-Alvarez, M. Chioua, R. Chatt, R. Chioua, A. Sanchez, J. Almy, Tetrahedron 2006, 62, 2799. M.J. Alves, A.G. Fortes, F.T. Costa, Tetrahedron 2006, 62, 3095. T. Brunin, L. Legentil, J.-P. Henichart, B. Rigo, Tetrahedron 2006, 62, 3959. R.K. Singh, S. Jain, N. Sinha, A. Mehta, F. Naqvi, N. Anand, Tetrahedron 2006, 62, 4011. Z. Su, C. Hu, S. Qin, X. Feng, Tetrahedron 2006, 62, 4071. W. Cardona, W. Quinones, S. Robledo, I.D. Velez, J. Murga, J. Garcia-Fortanet, M. Carda, D. Cardona, F. Echeverri, Tetrahedron 2006, 62, 4086. N. Kanomata, S. Yamada, T. Ohhama, A. Fusano, Y. Ochiai, J. Oikawa, M. Yamaguchi, F. Sudo, Tetrahedron 2006, 62, 4128. X. Lv, Z. Wang, W. Bao, Tetrahedron 2006, 62, 4756.


06T4892 06T4907 06T5338 06T5454 06T5736 06T5862 06T6222 06T6398 06T6945 06T7266 06T7459 06T7661 06T7817 06T8398 06T8731 06T8740 06T9166 06T9365 06T9650 06T9942 06T10815 06T11063 06T11483 06T11734 06T11900 06TA12 06TA687 06TA1420 06TA1581 06TA2006 06TL553 06TL705 06TL813 06TL837 06TL869 06TL1059 06TL1261 06TL1729 06TL2161 06TL2257 06TL2337 06TL2395 06TL2399 06TL2581 06TL2691 06TL2725 06TL3005 06TL3127 06TL3191 06TL3225 06TL3471 06TL3489

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V.P.A. Raja, S. Perumal, Tetrahedron 2006, 62, 4892. A.S. Paraskar, A. Sudalai, Tetrahedron 2006, 62, 4907. S. Nguyen, J. Xu, C.J. Forsyth, Tetrahedron 2006, 62, 5338. M.D. Fletcher, T.E. Hurst, T.J. Miles, C.J. Moody, Tetrahedron 2006, 62, 5454. T.M. Lipinska, Tetrahedron 2006, 62, 5736. T. Cailly, F. Fabis, S. Rault, Tetrahedron 2006, 62, 5862. M.G. Ferlin, V.B. Di Marco, A. Dean, Tetrahedron 2006, 62, 6222. A. Hamid, H. Oulyadi, A. Daiech, Tetrahedron 2006, 62, 6398. W.T. McElroy, P. DeShong, Tetrahedron 2006, 62, 6945. Z.M. Zhao, P.S. Mariano, Tetrahedron 2006, 62, 7266. C.-G. Feng, J. Chen, J.-L. Ye, Y.-P. Ruan, X. Zheng, P.-Q. Huang, Tetrahedron 2006, 62, 7459. F. Palacios, E. Herran, C. Alonso, G. Rubiales, Tetrahedron 2006, 62, 7661. F. Jara, M. Dominguez, M.C. Rezende, Tetrahedron 2006, 62, 7817. B. Gangadasu, P. Narender, S.B. Kumar, M. Ravinder, B.A. Rao, C. Ramesh, B.C. Raju, V.J. Rao, Tetrahedron 2006, 62, 8398. V. Singh, G.P. Yadav, P.R. Maulik, S. Batra, Tetrahedron 2006, 62, 8731. S. Madapa, V. Singh, S. Batra, Tetrahedron 2006, 62, 8740. M. Mena, N. Valls, M. Borregan, J. Bonjoch, Tetrahedron 2006, 62, 9166. F.-T. Luo, V.K. Ravi, C. Xue, Tetrahedron 2006, 62, 9365. A.C. Fernandes, C.C. Romao, Tetrahedron 2006, 62, 9650. S.R.V. Kandula, P. Kumar, Tetrahedron 2006, 62, 9942. A.-L. Johnson, J. Bergman, Tetrahedron 2006, 62, 10815. C. Sicre, J.L. Alonso-Gomez, M.M. Cid, Tetrahedron 2006, 62, 11063. D. Kalyani, A.R. Dick, W.Q. Anani, M.S. Sanford, Tetrahedron 2006, 62, 11483. A.S. Voisin, A. Bouillon, I. Berenguer, J.-C. Lancelot, A. Lesnard, S. Rault, Tetrahedron 2006, 62, 11734. K. Takasu, N. Shindoh, H. Tokuyama, M. Ihara, Tetrahedron 2006, 62, 11900. C. Sanfilippo, N. D'Antona, G. Nicolosi, Tetrahedron Asymmetry 2006, 17, 12. S.E. Denmark, F. Yu, Tetrahedron Asymmetry 2006, 17, 687. R. Kawecki, Tetrahedron Asymmetry 2006, 17, 1420. M. Amat, C. Escolano, A. Gomez-Esque, O. Lozano, N. Llor, R. Griera, E. Molins, J. Bosch, Tetrahedron Asymmetry 2006, 17, 1581. G. Le Bouc, C. Thomassigny, C. Greck, Tetrahedron Asymmetry 2006, 17, 2006. J. Ward, V. Caprio, Tetrahedron Lett. 2006, 47, 553. V. Nair, K. Mohanan, T.D. Suja, E. Suresh, Tetrahedron Lett. 2006, 47, 705. D.S. Bose, R.K. Kumar, Tetrahedron Lett. 2006, 47, 813. A. Kumar, S. Koul, T.K. Razdan, K.K. Kapoor, Tetrahedron Lett. 2006, 47, 837. D.N. Kozhevnikov, V.N. Kozhevnikov, A.M. Prokhorov, M.M. Ustinova, V.L. Rusinov, O.N. Chupakhin, G.G. Aleksandrov, B. Koenig, Tetrahedron Lett. 2006, 47, 869. G.-W. Wang, C.-S. Jia, Y.-W. Dong, Tetrahedron Lett. 2006, 47, 1059. N. Sakai, D. Aoki, T. Hamajima, T. Konakahara, Tetrahedron Lett. 2006, 47, 1261. O. Dirat, A. Clipson, J.M. Elliott, S. Garrett, A. Brian Jones, M. Reader, D. Shaw, Tetrahedron Lett. 2006, 47, 1729. B. Zhong, R.S. Al-Away, C.Shih, J.H. Grimes Jr., M. Vieth, C. Hamdouchi, Tetrahedron Lett. 2006, 47, 2161. A. Mitchinson, W.P. Blackaby, S. Bourrain, R.W. Carling, R.T. Lewis, Tetrahedron Lett. 2006, 47, 2257. V. Mamane, Y. Fort, Tetrahedron Lett. 2006, 47, 2337. A. Rivkin, B. Adams, Tetrahedron Lett. 2006, 47, 2395. M. Trilla, R. Pleixats, M.W.C. Man, C. Bied, J.J.E. Moreau, Tetrahedron Lett. 2006, 47, 2399. F.H.V. Chau, E.J. Corey, Tetrahedron Lett. 2006, 47, 2581. A.D. Averin, O.A. Ulanovskaya, A.A. Borisenko, M.V. Serebryakova, I.P. Beletskaya, Tetrahedron Lett. 2006, 47, 2691. N. Ahmed, J.E. van Lier, Tetrahedron Lett. 2006, 47, 2725. F. Kelleher, S. Kelly, Tetrahedron Lett. 2006, 47, 3005. X.-F. Lin, S.-L. Cui, Y.-G. Wang, Tetrahedron Lett. 2006, 47, 3127. F.C. Bargiggia, W.V. Murray, Tetrahedron Lett. 2006, 47, 3191. X. Beebe, V. Gracias, S.W. Djuric, Tetrahedron Lett. 2006, 47, 3225. P. Gavina, S. Tatay, Tetrahedron Lett. 2006, 47, 3471. Y. Yoshimura, J. Inoue, N. Yamazaki, S. Aoyagi, C. Kibayashi, Tetrahedron Lett. 2006, 47, 3489.

352 06TL3545 06TL3589 06TL4365 06TL4541 06TL4553 06TL4749 06TL5079 06TL5147 06TL5317 06TL5333 06TL5503 06TL6011 06TL6183 06TL7025 06TL7191 06TL8343 06TL8667 06TL8917


B. Han, X.-D. Jia, Z.-L. Jin, Y.-L. Zhou, L. Yang, Z.-L. Liu, W. Yu, Tetrahedron Lett. 2006, 47, 3545. B. Savitha, P.T. Perumal, Tetrahedron Lett. 2006, 47, 3589. T. Nemoto, T. fukuda, Y. Hamada, Tetrahedron Lett. 2006, 47, 4365. Y. Xu, H. Rudler, B. Denise, A. Parlier, P. Chaquin, P. Herson, Tetrahedron Lett. 2006, 47, 4541. Y. Xu, E. Aldeco-Perez, H. Rudler, A. Parlier, C. Alvarez, Tetrahedron Lett. 2006, 47, 4553. N.T. Patil, L.M. Lutete, N. Nishina, Y. Yamamoto, Tetrahedron Lett. 2006, 47, 4749. J.-D. Cheon, T. Mutai, K. Araki, Tetrahedron Lett. 2006, 47, 5079. K. Mitsudo, W. Matsuda, S. Miyahara, H. Tanaka, Tetrahedron Lett. 2006, 47, 5147. J.M. Andres, R. Pedrosa, A. Perez-Encabo, Tetrahedron Lett. 2006, 47, 5317. P.S. Humphries, S. Bailey, Q.Q.T. Do, J.H. Kellum, G.A. McClellan, D.M. Wilhite, Tetrahedron Lett. 2006, 47, 5333. M.D. Sanchez-Salvatori, A. Lopez-Giral, K. Ben Abdejelil, C. Marazano, Tetrahedron Lett. 2006, 47, 5503. V.S.C. Yeh, P.E. Wiedeman, Tetrahedron Lett. 2006, 47, 6011. S. Hosokawa, S. Kuroda, K. Imamura, K. Tatsuta, Tetrahedron Lett. 2006, 47, 6183. D.N. Kozhevnikov, O.V. Shabunina, D.S. Kopchuk, P.A. Slepukhin, V.N. Kozhevnikov, Tetrahedron Lett. 2006, 47, 7025. W.Chen, B. Liu, C. Yang, Y. Xie, Tetrahedron Lett. 2006, 47, 7191. A. Sanchez, A. Nunez, C. Burgos, J. Alvarez-Builla, Tetrahedron Lett. 2006, 47, 8343. Y.D.V. K. Jayakanthan, Tetrahedron Lett. 2006, 47, 8667. M.-Y. Jang, S. De Jonghe, L.-J. Gao, P. Herdewijn, Tetrahedron Lett. 2006, 47, 8917.

353

Chapter 6.2 (2005)

Six-membered ring systems: diazines and benzo derivatives (2005) Michael P. Groziak California State University East Bay, Hayward, CA, USA [email protected]

__________________________________________________________________________

6.2.1 INTRODUCTION The diazines pyridazine, pyrimidine, pyrazine, and their benzo derivatives cinnoline, phthalazine, quinazoline, quinoxaline, and phenazine once again played a central role in many investigations. Progress was made on the syntheses and reactions of these heterocycles, and their use as intermediates toward broader goals. Some studies relied on solid-phase, microwave irradiation, or metal-assisted synthetic approaches, while others focused attention more on the X-ray, computational, spectroscopic, and natural product and other biological aspects of these heterocycles. Reports with a common flavor have been grouped together whenever possible.

6.2.2 REVIEWS AND GENERAL STUDIES One review covered the functionalizations and synthetic applications of pyridazin-3(2H)ones , while another on the reactions of pyrimido[4,5-c]pyridazine-5,7(6H,8H)diones with nitrogen nucleophiles highlighted their ability to undergo nucleophilic substitution of hydrogen . The synthesis and heterocyclizations of 3-alkynyl6,8-dimethylpyrimido[4,5-c]pyridazine-5,7(6H,8H)-diones and their lumazine analogs was reviewed , as was the synthesis of functionalized compounds containing pyridazine rings . In the medicinal arena, pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidines as A3 adenosine receptors ligands were covered in a review , as were biologically active pyridazinoquinoxalines . Finally, the history of the discovery of the diarylpyrimidine anti-HIV drug Rilpivirine {R278474, 4-[[4-[[4-[(1E)-2cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile} was covered . Homoheteraryl coupling mediated by Pd(OAc)2 was used to form the aryl-aryl bonds in new diazines . The pyrazine alkaloids botryllazine A and B from Botryllus leachi and related compounds (1a-c) were prepared by a regioselective metalation/crosscoupling approach starting from chloropyrazine . The pyridine ring of the

M.P. Groziak

354

pyridin-2-yldiazines 2-4 was used as an ortho-directing group for metalation . The regioselectivity observed was similar to that found for 2H incorporation (percentages shown next to ring positions) after generating the anions with 3-4 eq. LTMP in THF at -78 ˚C for 15 min. The 35Cl NQR and 1H NMR relaxation times in a 1:2 hydrogen-bonded (chloranilic acid)-(1,3-diazine) complex 5 were measured, giving an indication of partial Htransfer to the diazines . Aryl substituted diazines 6 and 7 were obtained by Stille cross-coupling of Bu3Sn-substituted precursors, themselves prepared via nucleophilic substitution of halodiazines with Bu3SnLi . The metalation/functionalization of 2bromopyrazine, 2,4-dibromopyrimidine, and 3-bromo-6-phenylpyridazine was reported, together with an improved preparation of these halodiazine starting materials . The ring metalation of cinnoline, quinazoline, and quinazolinone sulfoxides was found to be effective, but curiously that of a quinoxaline sulfoxide was not . R1

N

R2

21%

O 1a, R = R = H; 1 2 b, R1 = H, R2 = 4-HOC6H4CO; c, R1 = 4-HOC6H4CO, R2=H

N HO

14%

N

N 81%

N

19%

N

N 16%

100%

2

N

N

N 11%

N

89%

3

4

OH N

Cl N H O

O

(N)

N

N O H N

O

N N

N

N

N

N N

N

N

N

Cl

5

7

6

6.2.3 PYRIDAZINES AND BENZO DERIVATIVES X-ray crystallography continued to expand our knowledge of the solid state structures of pyridazines. The crystal structures of 6a-methyl-7-phenylsulfonyl-6-phenylsulfonylmethyl7,7a-dihydro-6aH-cyclopropa[d][1,2,3]triazolo[4,3-b]pyridazine , 3,6-bis(4-methoxybenzyloxy)pyridazine , and ethyl 3-methyl-6-oxo-5-[3-(trifluoromethyl)phenyl]-1,6-dihydro-1-pyridazineacetate were determined. In the organometallics field, neutral Cu4N12 and Ag4N12 metallacycles with a para-cyclophane framework were prepared by treating Cu(I) and Ag(I) pyrazolates with pyridazine, and three of these were solved crystallographically . Finally, [pyridazin-3(2H)-one-6-yl]ferrocenes 8 were prepared and characterized by a wide variety of methods, including IR, 1D and 2D NMR, and X-ray . O Fe

N

N

N

N

O Q 8

Q = -(CH2)n-, (E)-CH=CH-,

(N)

Six-membered ring systems: diazines and benzo derivatives (2005)

355

6.2.3.1 Syntheses Condensation approaches to the synthesis of pyridazines were once again popular. A microwave-assisted cyclocondensation reaction involving -diketones and hydrazine in the presence of DDQ produced 3,4,6-trisubstituted pyridazines . New tricyclic pyrido[3',2':5,6]thiopyrano[4,3-c]pyridazin-3(2H,5H)-ones were prepared from 2,3-dihydrothiopyrano[2,3-b]pyridin-4(4H)-ones via condensation with glyoxylic acid followed by hydrazines. Their binding affinity at the benzodiazepine receptor was studied . Hydrazonoyl halides were used to access many heterocycles, including pyrazolo[3,4-d]pyridazines , pyrrolo[1,2-b]pyridazines were among the many heterocycles accessed using -(cyanomethyl)benzylidene-malononitrile as a starting material , and methyl 3,3,3-trifluoropyruvate was used in a two-step synthesis of 4trifluoromethyl-(2H)-pyridazin-3-ones . Pyridazino[3,4-a]carbazoles 9 were obtained by the reaction of substituted 2-benzylidene-1,2,3,4-tetrahydrocarbazol-1-ones and thiocarbohydrazide or thiosemicarbazide . R

R (H2NNH)2C=S N H

N H

KOH, EtOH

O

N 9

N

A new tetraazaheterocyclic system was accessed when substituted pyridazino[4,5-b][1,8]naphthyridin-6(7H)-ones like 10 were prepared from 1,8-naphthyridine-3-carboxylates . A regioselective synthesis of pyridazines 11 was developed from the cycloaddition of phosphorylated 1,2-diaza-1,3-butadienes with olefins. Cycloadduct formation occurs via an endo transition state with styrene, cyclopentadiene, and dihydrofuran, but via an exo one with norbornadiene . The regioselective cycloaddition of tetrazines and alkynylboronic esters gave highly substituted pyridazine boronic esters 12 . Pyridazine derivatives 13a-c were formed via Diels-Alder reaction of di(benzoyl)acetylene and 1,1,2,2-tetra(cyano)ethylene , and pyridazino[4',3':4,5]thieno[3,2-d]-1,2,3-triazines were prepared along a heterocyclization route . Ph NC EtO

CO2Et N

Br

N

NC EtO

N

Br R1

R1

N

NH N

R2

B(OR)2 N N –N2

B(OR)2 R1

12

O

N

Me

PhOC

CO2Et N O

Me O PPh2

10 R1

N R2 N

N N

CO2Et N N +

O

Ph

O PPh2 11

COPh

N N

+ Ar C N N C Ar H H

Ar PhMe Δ

PhOC

Ar COPh

13a-c, R = Me, OMe, Cl

Some unusual pyridazine syntheses were reported. A dye-sensitized photooxygenation reaction of ribofuranosyl furans gave a new entry to pyridazine C-nucleosides 14

M.P. Groziak

356

, and new pyridazino-psoralens 15 were prepared via a furan ring expansion reaction . The reaction of 3-acetylcoumarins with alloxan followed by NH2NH2 easily produced 3-(2-oxo-2H-chromen-3-yl)-6H,8H-pyrimido[4,5-c]pyridazine-5,7-diones . Furano- and pyrano[2,3-c]pyridazines 17 and 18a,b as well as substituted quinolines were conveniently prepared from pyridazinone 16 and vinyl- and allyltriphenylphosphonium salts . Me Me O

O

1O

1. 2 2. Et2S

N N

O

RO

RO OR

RO

Me

3. NH2NH2•HCl

RO

O

O

Me OR 14 CO2Me N + N

N N

CO2Me N N Δ

O

O 15

CO2Me O

O CN Ph3P

O N

N H

O CN

O N

O

N

+

X

O N

O 17 (39%)

16

O

Me

N O Me 18a, X = NH (13%) b, X = O (19%)

6.2.3.2 Reactions Removal of the MOM group from 5-alkynyl-2-methoxymethylpyridazin-3(2H)-ones 19 with HCl gave, with certain alkynyl substituents, 5-(2-chloroalkenyl)pyridazin-3(2H)-ones like 20a-d . 4-Cyano-5,6-dimethylpyridazine-3(2H)-thione was transformed into thieno[2,3-c]pyridazines and pyrimido[4',5':4,5]thieno[2,3-c]pyridazines . Alkyl/aryl pyridinazinyl ethers were prepared from the corresponding halopyridazinones . O MOM

O HCl

N N Ph

R

HN N

Cl

Ph

20a, R = H, b, R = CH2OH, R c, R = CH(OH)Me, d, R = CH2Cl

19

6.2.3.3 Applications Pyridazines continued to play a central role in the construction of new biologically active compounds. 2,7-Dihydro-3H-pyridazino[5,4,3-kl]acridin-3-ones were synthesized as cytotoxic agents and 6-(5-chloro-3-methylbenzofuran-2-sulfonyl)-2H-


357

pyridazin-3-one and related compounds were prepared as aldose reductase inhibitors . Pyrazolo[1',5':1,6]pyrimido[4,5-d]pyridazin-4(3H)-ones were examined as PDE5 inhibitors , pyrazolo[3,4-c]pyridazines as cyclin-dependent kinase (CDK2) inhibitors , pyrazolo[3,4-d]pyridazines as antibacterials and antifungals , and polyfunctionally substituted pyridazines and their fused derivatives and certain pyrrolopyridazine cycloadducts were all prepared as antimicrobials. Some pyridazines were developed as inhibitors of p38 MAP kinase , others as acyl-CoA:cholesterol acyltransferase (ACAT) inhibitors , and still others as GABA-α receptor ligands . Finally, certain 3(2H)pyridazinones were prepared as fungicides and herbicides .

6.2.4 PYRIMIDINES AND BENZO DERIVATIVES We have learned more about the physicochemical properties of pyrimidines through some detailed investigations. For example, the electronic structures of 15 substituted pyrimidines like 21a-d were studied by computational methods , and mono- and multinuclear Mn(II), Co(II), and Cu(II) complexes of bisazo-dianils containing a pyrimidine moiety were synthesized and examined by a variety of spectroscopic methods (IR, electronic absorption, ESR) . The intramolecular stacked conformation of pyrazolo[3,4-d]1 pyrimidines tethered by a trimethylene linker was documented in solution by H NMR and in the solid state by X-ray , and complexes between the tautomers of the RNA pyrimidine bases and L-leucine were characterized by ab initio computational methods . Tautomerism in N-methyl regioisomers of uracil, 5-fluorouracil, and thymine was also examined this way . 4,5,6,7-Tetrahydro-2-methyl-2,4-diphenyl4,7a,12b-triazadibenzo[e,g]azulene-1,3,8-triones 22 were prepared as members of a pyrimidine-annulated pyrrolobenzodiazepine ring system related to Aspergillus alkaloids , and their prototropic tautomerism was studied by 1H NMR . The 4,9-methanoundecafulvene-related [5-(4,9-methanocycloundeca-2',4',6',8',10'-pentaenylidene)pyrimidine-2,4,6(1,3,5H)-triones] 23 were prepared, and their physical properties were examined by UV-Vis, cyclic voltammetry, and NMR. The rotational barrier about the exocyclic C=C was determined to be 12.55 kcal•mol-1, by a VT-NMR study . In a similar fashion, a set of 5-[bis(1-heteroazulen-3-yl)methylidene]pyrimidine-2,4,6(1,3,5H)triones 24 was prepared by reaction of bis(1-heteroazulen-3-yl)methyl cations with barbituric acid followed by chloranil-mediated oxidation, and these too were extensively characterized by NMR, UV-Vis, cyclic voltammetry, MO computations, and X-ray crystallography . R3

O

R4

R2 N

N

N R1

21a, R1 = H, C≡CH, NH2, NMe2; b, R2 = H, Me, Cl, OH, OMe, NMe2; c, R3 = H, C≡CH, Me, iPr; d, R4 = H, Me, Cl, OMe

N

N Ph

O Me

Ph 22

O

M.P. Groziak

358 O

O

H

O +

O O

H

O

N

N N R

H N

O Ac2O, 120 °C, 1h

O

X

N R

O 23

O

N R

X OO

O O

R N

R N

O OO

O

N R

X

O O 24a, X = O b, X = NMe

N R

X

There was again a large number of X-ray crystallographic determinations of pyrimidinebased structures. 1,3-Bis(pyrimidin-2-ylsulfanyl)propan-2-one (25) , 2,3bis[(pyrimidin-2-ylsulfanyl)methyl]quinoxaline , 2,4,6-tris(pyrimidin-2-ylsulfanyl)-1,3,5-triazine , 4-(2-naphthyl)pyrimidine , and 2-chloro-4-(3,5-dimethyl-1H-pyrazol-1-yl)pyrimidine were among the simpler ones. Others were 3-(4-fluorophenyl)-2-(4-methylphenoxy)-5,8,9-trimethylthieno[3',2':5,6]pyrido[4,3-d]pyrimidin-4(3H)-one , 10''-(4-chlorobenzylidene)5''-(4-chlorophenyl)-4'-(2,4-dichlorophenyl)-1'-methyl-2,3,2'',3'',7'',8'',9'',10''-octahydro-1H, 5''H,6''H-indole-3-spiro-2'-pyrrolidine-3'-spiro-2''-cyclohepteno[1,2-d]thiazolo[3,2-a]pyrimidine-2,3''-dione , 2-diisopropylamino-3-phenylbenzo[4,5]furo[3,2-d]pyrimidin-4(3H)-one , and 10''-(4-methoxybenzylidene)-5'',4'-bis(4methoxyphenyl)-1'-methyl-2,3,2'',3'',7'',8'',9'',10''-octahydro-1H,5''H and 6''H-indole-3-spiro2'-pyrrolidine-3'-spiro-2''-cyclohepteno[1,2-d]thiazolo[3,2-a]pyrimidine-2,3''-dione . Still others were 3-methyl-6,8-di(2-pyridyl)-[1,2,3]triazolo[5',1':6,1]pyrido[2,3-d]pyrimidine , 4-(o-methoxyphenyl)-1,3,4,4a,5,6,7,8a-octahydro-2Hpyrano[2,3-d]pyrimidine-2-thione , 4-(E)-2-[3-(3-[(E)-2-(4-cyanophenyl)1-diazenyl]hexahydro-1-pyrimidinylmethyl)hexahydro-1-pyrimidinyl]-1-diazenylbenzonitrile , 4,7-bis(4-methoxyphenyl)-1,3,7-triphenyl-2,3,5,6,7,7a-hexahydro-1H-pyrrolo[2,3-d]pyrimidine-2,5,6-trione (26) , and the related 4-p-tolyl1,3,4,4a,5,6,7,8a-octahydro-2H-pyrano[2,3-d]pyrimidin-2-one (27) . O N N

Ph

N S

O

O

N

S

N O 25

MeO

Ph

Me

OMe

N

N O

Ph 26

H N

HN O

27

In addition to these, 5-methyl-2-methylsulfanyl-7-phenylpyrazolo[1,5-a]pyrimidine-3carbonitrile , 7''-benzyl-9''-benzylidene-4'-[4-(dimethylamino)phenyl]-1'methyl-5''-phenyl-2'',3'',6'',7'',8'',9''-hexahydro-1H-indole-3(2H)-spiro-2'-pyrrolidine-3'-spiro2''-pyrido[4,3-d]thiazolo[3,2-a]pyrimidine-2,2''-dione , ethyl 3-cyano-7methylpyrazolo[1,5-a]pyrimidine-6-carboxylate , methyl 2-[2-(5,7dimethyl-1,2,4-triazolo[1,5-a]pyrimidin-2-ylsulfanylmethyl)phenyl]-3-methoxyacrylate , and methyl 4-((E)-2-{3-[(3-{(E)-2-[4-(methoxycarbonyl)phenyl]-1-


359

diazenyl}-5,5-dimethylhexahydro-1-pyrimidinyl)methyl]-5,5-dimethylhexahydro-1-pyrimidinyl}-1-diazenyl)benzoate were also analyzed by X-ray crystallography. The isostructural compounds 5-methyl-2-(4-methylphenyl)- (28), 2-(4-chlorophenyl)-5methyl-, and 2-(4-bromophenyl)-5-methyl-7,8-dihydro-6H- cyclopenta[g]pyrazolo[1,5-a]pyrimidines displayed chains linked by a single CH•••π(arene) H bond, but the 5-methyl-2-ptolyl- derivative was found linked by a single CH•••NH bond into chains, which themselves were linked into sheets by a π-π stacking interaction . 7-Hydroxy-3methoxy-4-methyl-5,6,7,8-tetrahydropyrido[1,2-c]pyrimidin-1(9H)-one 29 was shown to have a planar pyrimidine ring involved in three CH•••π interactions . 5-(4Methoxybenzoyl)-4-(4-methoxyphenyl)-1-(1-(4-methoxyphenyl)-ethylideneamino) and 5-(4-methoxybenzoyl)-1-(4-methoxybenzylideneamino)-4-(4methoxyphenyl)- pyrimidin-2(1H)-one (30a and b, respectively) were each solved crystallographically. OMe O N Me

N

Me

N HO

N N

Me

28

O

OMe MeO

N N OMe

N O R

29

30a, R = Me; b, R = H

In the organometallic field, a complicated nonanuclear Ni(II) complex containing the 7,8dihydro-1,2,4-triazolo[4,3-a]pyrimidin-7-one anion 31 as a ligand was characterized by Xray , as were bis(pyrimidine-2-thiolato)bis(triphenylphosphine)ruthenium(II) 32 , cis,cis,trans:N,N;P,P;S,S-[bis(triphenylphosphine)][bis(pyrimidine-2thiolato)]ruthenium(II) , and catena-poly[[[(acetonitrile- N)silver(I)]- bis(pyrimidin-2-ylsulfanyl)methane- 2N1:N1'] tetrafluoroborate] 33 . In the biological-medicinal field, pyrimidines solved crystallographically included 3-bromo-1(2-deoxy- -D-erythro-pentofuranosyl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine 34, a DNA duplex stabilizing nucleoside , the herbicide isopropyl 2-(5,7-dimethyl-1,2,4triazolo[1,5-a]pyrimidin-2-yloxy)benzoate , and 2-methyl-7-oxo-5,6,7,8tetrahydropyrimido-[4,5-d]pyrimidin-3-ium chloride 35, from the thermal decomposition of the HCl salt of nimustine {1-[(4-amino-2-methylpyrimidin-5-yl)methyl]-3-(2-chloroethyl)-3nitrosourea, 36}, an antitumor DNA cross-linker for treating malignant glioma . N

Ph3P PPh3 O

N

N N

Ru

S N

N

N

N

32

Ag

S N

31

N

S

S N

N

CH3CN 33

nBF4– n

360

M.P. Groziak

NH2

Br

Cl

N

N N

N

H NH2

O

OH

N

Me

NH N

34

OH

N H

NH2

H N

Cl

O N N

Me

O

Cl

N

35

HN

O 36, nimustine

6.2.4.1 Syntheses Cyclization routes to pyrimidines continued to be a rather popular approach for preparing these heterocycles. 3,6-Dihydro-7H-1,2,3-triazolo[4,5-d]pyrimidin-7-ones like 37 were prepared via cyclization of guanidine intermediates , and 3-substituted 4-oxo3,4,5,6,7,8-hexahydropyrido[4',3',4,5]thieno[2,3-d]pyrimidine-7-carboxylic acid esters were prepared along a heterocyclization route . A new route to pyrido[4,3-d]pyrimidines like 39 relied upon an intramolecular cyclization of 4-amino-5-(tert-butyliminomethyl)-2(methylthio)-6-(phenylethynyl)pyrimidine 38 , and a regioselective, radical cyclization-based synthesis of pyrimidine-annulated spiro-heterocyclic compounds was reported . Using a photo-induced oxidative cyclization reaction, areno[b]pyrimido[5,4-e]pyran-2,4(1,3H)-dionylium perchlorates and tetrafluoroborates 41 were prepared from alkylidenated barbituric acids 40, and were characterized by NMR, UV-Vis, and X-ray . O N

N

N N Ph

H2N

Ph

CHCl3

38

hν, Ac2O 60% HClO4

N N Me

N N

MeS O

O

N Ph

N

37

Me

H2N AgNO3

NHEt

N

N

40

39

O Me

or 42% HBF4, O aerobic, r.t.

O

N MeS

N N Me

O 41 ClO4(BF4-)

2-Amino-5-methyl-7H-1,3,4-thiadiazolo[3,2-a]pyrimidin-7-ones in a sequence beginning with the condensation of 2-bromo-5-amino-1,3,4-thiadiazole and diketene . A three-component condensation route to 5-aryl-5,8-dihydroazolo[1,5-a]pyrimidine-7carboxylic acids was developed, and the solvent effect on regioisomer production was studied . A condensation approach to pyrrolylthieno[2,3-d]pyrimidines and thieno[2,3-d][4,5-d]dipyrimidines was described , as was the preparation of pyrimidines by condensation of N-substituted lactams and Viehe's salt (dichloromethylenedimethylammonium chloride) . Carbonylative alkynylation followed by cyclocondensation constituted a new four-component pyrimidine synthesis of 42 (variolin B) and 43 (variolin D), tricyclics related to the meridianins 44 , and condensation of


361

6-[(dimethylamino)methylene]aminouracil with aryl isocyanates and isothiocyanates gave pyrimido[4,5-d]pyrimidines upon loss of Me2NH from the initial adduct . The diketo 2-(2-oxocyclohexylcarbonyl)benzoic acid ester was condensed with NH2NH2 to give an indazole, which was subsequently transformed into a fused pyrimidine . H2N OH

N

N

H2N OH

R1 N

N

CO2Me

N

H2N

R3 R4

H2N 42, variolin B

N

R2

N N

N

N

43, variolin D

N H

44, meridianins R1-R4 = H/OH/Br

The use of microwave acceleration in pyrimidine syntheses continued to grow. For example, a microwave assisted synthesis of pyrimidines from ketones and formamide in the presence of HMDS was reported , as was one which generated pyrazolo[1,5-a]pyrimidines from enaminones and 5-amino-1H-pyrazoles . A microwaveassisted Michael addition of pyrimidines to α,β-unsaturated esters generated carbocyclic nucleoside analogs , and a microwave-assisted one-pot synthesis of 2-amino-6,7disubstituted-5-methyl-5,8-dihydropyrido[2,3-d]pyrimidin-4(3H)-one from 2,6-diaminopyrimidin-4-one, aldehydes, and acyclic 1,3-dicarbonyl compounds was found to proceed in very good yields in the absence of a catalyst . Microwaves accelerated the synthesis of imidazo- and pyrimidopyrido[4',3':4,5]thieno[2,3-d]pyrimidines from a thienopyridinecarboxylate and pyridothienopyrimidine , and an improvement in the microwave-assisted synthesis of 1,2,4-triazolo[4,5-a]pyrimidin-5-ones was noted when a paste-like medium was employed . The use of microwave acceleration in combination with solid-phase approaches was used as well. Tetrahydropyrimidinones were obtained via microwave assisted, solid-phase intramolecular cyclization , and a microwave-assisted solid support synthesis of dihydropyrido[2,3-d]pyrimidines was also described . Resin-bound amidines were condensed with -dicarbonyl compounds to give 2-alkyl/aryl-pyrimidines and related 3H-pyrimidin-4-ones . Solid-phase approaches to pyrimidines were used both to generate libraries of compounds and simply for convenience. A combinatorial library of 3,5,6-trisubstituted pyrrolo[3,2-d]pyrimidines (9-deazapurines) was generated by a solid-phase synthetic approach , and the solid phase preparation of pyrido[2,3-d]pyrimidin-7-ones was described . Solid-phase approaches to trisubstituted 1H-pyrido[2,3-d]pyrimidin4-ones , 3-substituted pyrrolo[3,2-d]pyrimidine-6-carboxylates , and 3H-imidazo[1,2-a]pyrimidin-7-ones, 1,3,4,6,7,8-hexahydropyrimido[1,2-a]pyrimidin-2ones, and 3,4,6,7,8,9-hexahydro-1H-pyrimido[1,2-a][1,3]diazepin-2-ones were developed . A solid-phase synthesis of N-(pyrimidin-2-yl)amino acid amides relied upon nucleophilic aromatic substitution using 2-fluoropyrimidine , and a traceless solid-phase sulfone linker approach was used to prepare 3,4-dihydropyrimidin-2-ones . Solid-phase approaches were not solely used to generate libraries, however. A large number of 7-trifluoromethyl-substituted pyrazolo[1,5-a]pyrimidines were prepared via parallel solution-phase synthesis .

362

M.P. Groziak

Efficiency in pyrimidine synthesis was sometimes achieved by the use of metal-catalyzed reactions. 4-Substituted and bicyclic pyrimidines were prepared via a Pd-catalyzed reaction of -Me and -methylene ketones with formamide. Among the products obtained, 5,6dihydrobenzo[h]quinazoline and 4-naphth-2-ylpyrimidine were characterized by X-ray methods . 6-[(Phosphonomethoxy)alkynyl- and alkyl]pyrimidines 45 and 46 were prepared via Sonogashira coupling , and the Pd-C/CuI/PPh3-catalyzed Sonogashira coupling of 3-iodopyrazolo[1,5-a]pyrimidines with propargylic and homopropargylic reagents followed by catalytic hydrogenation gave -functionalized 3-(3dimethylaminopropyl)pyrazolo[1,5-a]pyrimidines . OH (NH2)

OH (NH2)

N H2N

N N

H2N 45

O

n = 1,2

N

PO3H2

46

O n

PO3H2

Often, simply conducting several steps in a one-pot fashion or using more than two components in a reaction was found to generate pyrimidines efficiently. A one-pot preparation of pyrimidines relied on the condensation of α,β-unsaturated imines and amidines or guanidines , and another of 2-arylimidazo[1,2-a]pyrimidines from ketones, [hydroxy(tosyloxy)iodo]benzene, and 2-aminopyrimidine was found to be accelerated by the use of an ionic liquid as solvent . A one-pot synthesis of substituted 1,2,3,4-tetrahydropyrimidines from N,S-acetals, formaldehyde, and diamines was reported , as was a one-pot, three-component, KF/alumina-catalyzed synthesis of pyrido[2,3-d]pyrimidines . A one-step synthesis of 2-amino-7-chlorothiazolo[5,4-d]pyrimidines 48 from 4,6-dichloro-5-aminopyrimidine (47) gave a ready entry to 2,7diaminothiazolo[5,4-d]pyrimidines 49 , and -dicarbonyl compounds were found to add regioselectively to 2-ethoxymethyleneaminonitriles in a one-pot, [5+1]-annulation synthesis of quinazolines and fused pyrimidines . A one-pot synthesis of 3,4dihydropyrimidin-2-(1H)-ones developed using Bi(III) nitrate as catalyst represents an improvement over the classical Biginelli reaction conditions . A three-component, base-mediated reaction of 2-alkyl-4,5-dichloropyridazin-3(2H)-ones 50 with p-cyanophenol and 2-mercaptopyrimidine (51) gave 2,4,5-trisubstituted-pyridazin-3(2H)-ones like 52a-d, together with 5-cyano-5-(pyrimidin-2-yl)-2,7-dialkyl-5H-dipyridazino[4,5-b:4,5-e]4H-thiopyran-1,6-diones . Finally, tri- and tetrasubstituted pyrimidines like 53 were prepared by a four-component coupling reaction involving a silane, two aryl nitriles, and an acetal . Cl

Cl NH2

N N

Cl 47

R1NCS base

NHR2 N

N

R1NH2 NHR1

S

N 48

H+ or base MW, 150 °C

N

N

NHR1 S

N 49

363


Cl

OH

SH

Cl O

N N R 50

+

+

N

Y base

X

CH3CN

O

N

N R

51

CN

52a, X = Cl, Y = SAr; b, X = SAr, Y = OAr; c, X = OAr, Y = SAr; d, X = Y = SAr

N

OR4 R1CH2SiMe3 + BuLi

R2CN

R1

R3CN

R2

NH2 N

R1

(R4O)4C

R3

N N

R2

53 R3

The preparation of 2-substituted thieno[2,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-ones by isomerization of the corresponding [4,3-c] isomers was reported , and was that of pyrido[3',2':4,5]thieno[3,2-d]pyrimidines, pyrido[3'',2'':4',5']thieno[3',2':4,5]pyrimido[1,6-a]benzimidazoles, and related fused polyheterocycles . 2,3Dihydroimidazo[1,2-a]pyrimidin-5(1H)-ones 54a-c were generated by a sterically induced multihetero-retro-ene fragmentation of the 8-alkoxyimidazo[1,2-a]pyrimidin-5(3H)-ones 55a-c initially formed by reacting 2-alkoxyiminoimidazolidines and acetylenedicarboxylates . 3-Formyl- and 3-cyano coumarin N-functionalized amidines were used as starting materials for the preparation of [1]benzopyrano[4,3-b]- and -[4,3-d]pyrimidin-5-ones like 56 , and 6-hydroxy-4H-4-oxo[1]-benzopyran-3-carboxaldehyde was shown to be a versatile starting material for the preparation of pyrimidines like 58a,b when condensed with barbituric or thiobarbituric acid (57a or 57b, respectively) . H N

OCH2R1 R2 N

H N

CO2R3

N or

N R3OH

N H

N

N

R2

O

O

54a-c, R1 = H; R2 = Me, Ph, CO2R O OHC

R1 N

OCH2R1 N R2

55a, R1 = R2 = H; b, R1 = Ph, R2 = H; c, R1 = H, R2 = Me O

O

CH3CO2–

NH4+

PhMe, Δ

N

N R1

O N 56

O O

O HO

NH

O + O

O

N H

O

O

X

57a,b, X = O,S

HO

NH O

O

N H

X

58a,b, X = O,S

A tandem aza-Wittig/heterocumulene-mediated annulation route was developed for the efficient production of 6,7,8,9-tetrahydro-benzothieno[2,3-d]-1,2,4-triazolo[1,5-a]pyrimidin10(3H)-ones , and an amine oxide rearrangement was key to the regioselective preparation of pyrrolo[2,3-d]pyrimidines . Hexahydro-2-phenacylidenepyrimidines gave -lactam fused 8-aroyl-2,3,4,5-tetrahydro-7-hydroxy-6H-pyrrolo[1,2-a]pyrimidine-6-ones when treated with (COCl)2 in the presence of NaH , and methyl

364

M.P. Groziak

N-methyl-N-(6-substituted-5-nitro-4-pyrimidinyl)aminoacetates underwent base-catalyzed ring closure and rearrangement to 6-substituted 4-methylamino-5-nitrosopyrimidines or 9methylpurin-8-ones . Pyrrolo[2,3-d]pyrimidine-2,4-diones were prepared from N-(5-vinyluracil-6-yl)sulfilimines by sunlight-mediated photolysis , and thieno[2,3-d]pyrimidine-6-carboxaldehydes were prepared for the first time by oxidation of thieno[2,3-d]pyrimidin-6-ylmethanols with I2 . A general approach to 1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-ones from 4-amino-1alkyl-3-propylpyrazole-5-carboxamides was developed , a reaction of carbodiimides and secondary amines or alcohols was found to give 5-dialkylamino or 5alkoxy 7H-1,2,3-triazolo[4,5-d]pyrimidin-7-ones , the new ring systems indeno[1,2-d]pyrimidinone, indeno[1,2-e]pyrrolo[1,2-a]pyrimidinone, and indeno[1,2-e]pyrimido[1,2-a]isoindole were accessed via ring expansion of azetidinone and ring closure of amino esters and 1,3-diamines , and substituted pyrazolo[4,3-d]pyrimidin-7ones were prepared from pyrazole-5-carboxylic acid precursors . Enaminones were used to access pyrazolo[1,5-a]pyrimidines , sulfone-containing pyrazolo[1,5-a]pyrimidines were obtained , and tetrahydro2(1H)quinazolinones and cyclopenta[d]-2(1H)pyrimidinones were prepared from alkoxyvinyl trifluoromethyl ketones . Triazolino[4,3-a]pyrimidines were among the various heterocycles prepared using hydrazonoyl halides , and new naphtho[2,1-b]furo[3,2-d]pyrimidines were prepared and examined for biological activity . As for biologically-related pyrimidines, a chemoenzymatic asymmetric total synthesis of the polycyclic pyrazolo[3,4-d]pyrimidine analogs 59 of a phosphodiesterase (PDE) inhibitor was reported , and the conversion of 2-amino-4,6-dichloro-5pyrimidinecarboxaldehyde to methyl 2-amino-4-(methoxy)thieno[2,3-d]pyrimidine-6carboxylate for obtaining antifolates was optimized . Heptadienes containing pyrimidine nucleic acid bases were prepared as building blocks for carbocyclic oligonucleotide analog synthesis , pyrimidine-based 1',3'-anhydro- -D-psicoand -sorbo-furanosyl nucleosides were obtained from O2,3'-anhydro- -D-fructofuranosyluracil , and the total synthesis of N-malayamycin A and related pyrimidine nucleosides 60a-c was achieved .The preparation of 1,3dimethylcyclohepta[4,5]pyrrolo[2,3-d]pyrimidine-2,4(1,3H)-dionylium ions like 62, models for NAD+/NADH, were reported . The dionylium ion 62 can be reduced with NaBH4 to give an NADH-like H– delivery agent (61) effective at reducing ketones to 2˚ alcohols. O

O Ph N

H2N

N

N N

N Bn

59 (and enantiomer)

NH H

O

R1 R2

O H

O N OH

NH O

60a, R1 = OMe, R2 = Me; b, R1 = F, R2 = H; c, R1 = OMe, R2 = H


O Me N

Ph N

H H

Ph N

R1

Me N

O

OH R2

R1

O N

Me

R2

Me N

Ph N +

Me

Me N O

N Me

O

61

Ph N

O

N O

365

N O

O

62

NaBH4

Me

6.2.4.2 Reactions Cyclization reactions of pyrimidines were studied, for instance, the reactivity of tetrahydropyrido[4,3-b]pyrimidines with DMAD leading to dihydropyrimidinylethylamines and pyrimido[4,5-d]pyrimidines obtained efficiently by hetero Diels-Alder cycloaddition of methyl 6-methyl-4-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5carboxylate (64), a Biginelli compound, with N-arylidine-N'-methylformamidines to form 63 and N-arylidine guanidines to form 65. The mechanism of this cycloaddition was probed using semiempirical MO methods . Acetylenic pyrimidines underwent microwave-assisted intramolecular hetero-Diels Alder reactions to form fused bicyclic pyridines . Ar

H Ph N H N CO2Me Me HN Ar Me N N Me 63

S

S

N

HN

H Ph N H

HN

Ar N

H Ph N H CO2Me HN Ar Me HN N 65 NH2

S

H2N

CO2Me Me 64

Nucleophilic addition/substitution reactions of pyrimidines were investigated as well. The selectivity of nucleophilic substitution in 2,4-disulfanyl-substituted thieno[2,3-d]pyrimidin-6carboxylic acids was studied , as was the SN(ANRORC) reactivity of substituted 5-ethoxycarbonylpyrimidines . Selective disubstitution of 2,4-dichloropyrido[2,3-d]pyrimidine with nucleophiles by SNAr and Suzuki and Stille cross-couplings was achieved . The regioselectivity of conjugate additions to 3-(pyridin-3-yl or pyrimidin-2-yl)-propenoates and their N-oxides (66) to give 67a,b was studied by a combination of theoretical and experimental methods , and 4-azido-2pyrimidinone nucleosides 68 were shown to react with nucleophiles at the modified base's C2 position, giving tetrazole nucleosides 69 , contrary to a previous report. N CO2Et

N N N N

CO2Et R1

PrSH O

R2

O N

N 66

NaOEt, EtOH

N

N

O

N

NuH

AcO

68

N NH Nu

O

O

N

AcO

AcO 67a, R1 = H, R2 = SPr b, R1 = SPr, R2 = H

N

AcO

69

O

366

M.P. Groziak

Rearrangements of pyrimidine compounds were also reported. 9H-Cycloalka[1,2-e]oxazolo[3,2-a]pyrimidin-9-ones were found to undergo intramolecular rearrangement in refluxing xylene to give cycloalkyl-fused oxazolo[3,2-a]pyrimidin-7- and -5-ones (70 and 71, respectively) . A regioselective thio-Claisen rearrangement starting from 5-prop2-ynyl/enyl-sulfanyl pyrimidinones generated thienopyrimidinones 72a,b , and O

O N

RCH2 O

CO2Et

+

n = 1, 0

NH2

n

N

RCH2 O

n

N

R3SCH2CO2H N

Me2N

N

N 71

n

N N

S

N

R1 pTsCl, Et3N, anhyd. CH2Cl2 r.t.

O

O

N 70

R2 R2

N

+ RCH2

R1

R

N

O

73a,b, R = H, Me

SR3

72a-b, R3 = CH2C≡CH, CH2CH=CH2

an acid-catalyzed O-N-type Smiles rearrangement reaction was noted in 2-pyrimidinyloxy-Narylbenzylamines, giving the corresponding phenols . Ru(II) complexes containing hemilabile 2-(pyridin-2-ylmethylthio)pyrimidine ligands 73a,b were shown to interconvert between N,S- and N-coordinated species . In the first example of catalytic C-C coupling involving activation of a C-F bond in the presence of a C-Cl one, 5-chloro-2,4,6-trifluoropyrimidine (74) reacted with arylboronic acids in the presence of a Ni(II) catalyst to generate 5-chloro-2-fluoro-4,6-diarylpyrimidines 75 . A theoretical and experimental investigation of the structure and reactivity of 4-(4-chlorophenyl)pyrimidinium ylides was undertaken , and the structure, stability, and reactivity of 4-methyl- and 4-(halophenyl)pyrimidinium (4halobenzoyl)methylides (76a-d and 76e-h, respectively) were examined by theoretical and experimental methods . The Biginelli 3,4-dihydropyrimidin-2(1H)-one 77 was converted in two steps to a variety of multifunctionalized pyrimidines with general structure 78 . In a more biological light, N,N'-bis(3-aminopropyl)-2,7-diamino1,8-naphthyridine was found to stabilize a single pyrimidine bulge in dsDNA . Finally, separate enantioselective microbial reductions of 6-oxo-8-[4-[4-(2pyrimidinyl)-1-piperazinyl]butyl]-8-azaspiro[4.5]decane-7,9-dione 79 generating either of the 2˚ alcohol epimers (80a,b) was reported . N

F 10%

F

R N

N Cl

F N

F

F

Ph3P Ni PPh3 F

N F Cl 74

THF, Cs2CO3 PPh3, PhB(OH)2

N Ph

N

O N

X Ph

Cl 75

76a-d, R = Me, X = F, Cl, Br, I e-h, R = 4-ClC6H4, X = F, Cl, Br, I

367


Ph HN O

N H

Me

CO2Me

N

N PBr PF6

77

O

Ph

1. [O] 2. NuH, base

CO2Me

Nu

NR

Me

N

O

78

3

O NR

[H]

O

HO

O

79, 6-keto Buspirone 80a,b R = 4-(pyrimidin-2-yl)piperazin-1-yl

6.2.4.3 Applications Some interesting non-medical applications were found for pyrimidines. The combination of Pd(OAc)2 and 2-aminopyrimidine-4,6-diol 81 was discovered to form a stable, efficient catalytic system for the Suzuki-Miyaura cross coupling of arylboronic acids and aryl halides , and it rendered the Sonogashira cross-coupling of aryl halides with terminal alkynes efficient and copper-free . New rhodium 1,3-dialkyl-3,4,5,6tetrahydro-2-pyrimidinylidene complexes 82 prepared as aromatic aldehyde arylation catalysts were characterized by multinuclear NMR . Supramolecular systems were constructed from complexes of 2,6-disubstituted 1-oxa-4-thia-3,5-diazine 4,4-dioxides with symmetric triazines . 6-Substituted 2,4-bis(acrylamido)pyrimidines 83 were used as the key pieces in the construction of optically responsive imide receptors , and N-(4-amino-1-methyl-5-nitroso-6-oxo-1,6-dihydropyrimidin-2-yl)-N'[bis(2-aminoethyl)]ethylenediamine 84 was synthesized and characterized by multinuclear NMR methods. It's use as an ion receptor was investigated by assessing it’s ability to adsorb Zn(II) and Cd(II) out of aqueous solution when anchored to activated carbon . A set of 1-dimensional coordination polymers [M(NO3)2(pyrimidine)(H2O)2]∞ (M = Mn, Co, Ni, or Zn) like 85 was prepared and their phase purity was determined . The pressure-sensitive magnetism of guest-tunable weak ferromagnets of the type [Fe{N(CN)2}2(pyrimidine)](guest) (guest = EtOH or pyrimidine) was studied . Metal complexes with the new ditopic ligand 4-[6-(2-pyridyl)-2-pyridyl]-6-(2pyridyl)pyrimidine 86 were shown to self-assemble into 2×2 grid complexes which had encapsulated NO3– ions. These complexes were characterized by X-ray . HO

R R' N N

N cat.

R1 I (Br)

HO

+

O

HN

N R2

NO3N

N N

O

NH2

84

N

N H2O

-O

85

O N H N

N

N N

3N

O

N

N

OH2 Mn2+ N

83

N N R' R 82

1

cat. Pd(OAc)2 CsCO3, CH3CN

R2

Me

NH2 N 81 R

O

N H

N H N

O N

Bn

N 86

N(CH2CH2NH2)2

As for nucleic acid applications, the syntheses and fluorescent properties of the DNA nucleobase replacements like the 1,2,3-triazolo[4,5-d]pyrimidine 2'-deoxyribofuranosides 87

368

M.P. Groziak

were reported . A 4-(2'-pyridyl)-pyrimidinone deoxyriboside was prepared and was shown to form a self-pair in the presence of Ni(II), stabilizing dsDNA as in 88 . Chiral 2-(aminoalkoxy)-substituted 4-(2-thienyl)pyrimidines and 4,6-bis(2thienyl)pyrimidines were prepared as dsDNA intercalators. Their binding constants showed up to a 2.4:1 discrimination of the (S)-enantiomers over the (R)-counterparts . Finally, DNA-intercalating annelated pyrrolo-pyrimidines were prepared from substituted 2-amino-3-cyanopyrroles and 3-amino-4-cyanopyrroles . O N

HN N

Ni2+ N

N

HO

N 87

N

N

N N O

O

O

OH

N

88

1- and 2-Alkyl-4-aminopyrazolo[3,4-d]pyrimidines were developed as adenosine deaminase inhibitors , 2-(2-furanyl)-7-phenyl[1,2,4]triazolo[1,5-c]pyrimidin5-amines were developed as adenosine A2a antagonists , pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidines were prepared as human A3 adenosine receptor antagonists , and 4-substituted 5-phenyl-7-(5-deoxy- -Dribofuranosyl)pyrrolo[2,3-d]pyrimidines (diaryltubercidins) , 6,7-disubstituted 4-aminopyrido[2,3-d]pyrimidines , and 5-(3-bromophenyl)-7-(6-morpholin4-ylpyridin-3-yl)pyrido[2,3-d]pyrimidin-4-ylamine were prepared as inhibitors of adenosine kinase. Pyrimidine-based compounds continue to be of interest as antimalarial agents. Among the ones synthesized for this bioactivity were 2,4,6-trisubstituted pyrimidines and 4-pyrido-6-aryl-2-substituted aminopyrimidines . Libraries of 2,4,6trisubstituted pyrimidines were prepared and screened for antimalarial activity and also for topoisomerase II activity , while other libraries of 6-aryl-2-substituted pyrimidin-4-ylphenols and trisubstituted pyrimidines were prepared and screened for antimalarial and antitubercular activities. 5-Substituted pyrimidine nucleosides were examined as antimycobacterial agents , spiro-pyrazolo-3,3'-thiopyrano[2,3-b]pyridines were prepared as antifungal and antibacterial agents , a set of pyrimidine-based antifungal agents was synthesized , and some unusual [1,2,4]triazolo[1,5-a]pyrimidine-based triorganotin(IV) complexes 89 were prepared and characterized by IR and Mossbauer spectroscopy and quantum chemical calculations . These had good antifungal and antibiofilm activities. Bu

Bu O

O Sn O Bu Bu HN

Sn

O

Bu Bu

N N N

89

N- and O-Substituted terpenyl pyrimidines as well as dihydropyrido[2,3-d]pyrimidines were prepared as antileishmanial agents. 5-Alkynyl- and 6alkyl-furo[2,3-d]pyrimidine acyclic nucleosides , acyclic furo- and

369


pyrrolo[2,3-d]pyrimidine nucleosides , and bicyclic furano pyrimidine nucleosides were synthesized as antiviral agents . Other bioactivities sought were pyrimidine-5-carboxamides as tyrosine kinase inhibiting anti-allergic agents , mono, bi and tricyclic pyrimidines as analgesics and anti-inflammatory agents , and 2,4,6-trisubstituted pyrimidines as pregnancy interceptive agents . Substituted pyrimidines containing a thiazolidinedione moiety were investigated as hypoglycemic and hypolipidemic agents . Pyrimidine heterocycles were examined as receptor site agonists or antagonists. Among these were 2-phenylpyrazolo[1,5-a]pyrimidin-3-yl acetamides for the benzodiazepine receptor , 3-arylpiperazinylalkylpyrrolo[3,2-d]pyrimidine-2,4-diones for the α1-adrenoceptor , bicyclic oxazolino- and thiazolino[3,2-c]pyrimidine-5,7diones, prepared by treating 2-methyloxazolines or -thiazolines with chlorocarbonyl isocyanate, for the hGnRH receptor , piperidinyl- and 1,2,3,6tetrahydropyridinyl-pyrimidines selective for the 5-HT1α receptor , and substituted 3H-pyrimidin-4-ones for the calcium receptor . Pyrimidines were also prepared as enzyme inhibitors. Many of these were kinase inhibitors, including 2anilino-6-phenylpyrido[2,3-d]pyrimidin-7(8H)-ones and pyrido[1',2':1,5]pyrazolo[3,4-d]pyrimidines as kinase inhibitors, 4-aminofuro[2,3-d]pyrimidines as tyrosine kinase inhibitors , pyrazolo[1,5-a]pyrimidines as inhibitors of human cyclin-dependent kinase 2 (CDK2) , pyrido[2,3-d]pyrimidin-7-ones as inhibitors of cyclin-dependent kinase 4 (CDK4) , and substituted aminobenzimidazole pyrimidines as inhibitors of cyclin-dependent kinase . A short synthesis of 3-{4-[2-(3-chlorophenylamino)pyrimidin-4-yl]pyridin-2-ylamino}propanol, a protein kinase C inhibitor, relied on the Negishi crosscoupling reaction of a pyridine zincate and 2,4-dichloropyrimidine (90) to generate the key intermediate 91 . N

ZnI + N

Cl N

F

Cl

90

N Pd[PPh3]4, THF, reflux, 4 h F 90%

N N 91

Cl

2-Amino-3-nitropyrazolo[1,5-a]pyrimidines were prepared as inhibitors of coxsackievirus B3 replication , fused pyrimidines as PDE7 inhibitors , and pyrimidinetriones as inhibitors of MMPs . Methylated 3H-pyrrolo[2,3-d]pyrimidin-2(7H)-one nucleoside analogs 92 incorporated into triplex-forming oligonucleotides were shown to selectively bind CG inversions , and pyrimidine-linked biphenyl anionic RSV fusion inhibitors were found to be less active than their corresponding triazine-linked counterparts . R 92

N

N

Me

N O H

H N H O

N N

N H N N

N O H N H

370

M.P. Groziak

In the anticancer field, 5,6,7,8-tetrahydrobenzothieno[2,3-d]pyrimidin-4(3H)-ones and 6-[1-(2,6-difluorophenyl)ethyl]pyrimidinones were prepared as cytotoxic/antitumor agents, pyrazolo[1,5-a]pyrimidin-7-yl phenyl amides and thieno[2,3-d]pyrimidin-4(1H)-ones were prepared as tumor cell antiproliferative agents, and 5-substituted 2,4-diaminofuro[2,3-d]pyrimidines , trimethylene-bridged 2,4-diaminopyrrolo[2,3-d]pyrimidines , 2,4-diamino-6-methyl-5-substituted pyrrolo[2,3-d]pyrimidines , and pyrrolo[2,3-d]pyrimidines were prepared as dihydrofolate reductase (DHFR) inhibitors. 5-Substituted furo[2,3-d]pyrimidines and 6-substituted pyrrolo[2,3-d]pyrimidines , 2-amino-4-oxo-5-arylthio-substituted pyrrolo[2,3-d]pyrimidines , and 2-amino-4-oxo-5-substituted benzylthiopyrrolo[2,3-d]pyrimidines were all synthesized as antifolate inhibitors of thymidylate synthase.

6.2.5 PYRAZINES AND BENZO DERIVATIVES Our understanding of the physicochemical properties of pyrazines has deepened. The internal rotation and IR spectrum of 2,5-pyrazinedicarboxamide were studied by quantum chemical calculations , and ab initio MO calculations at the MP2/6-31++G(**) level were used to explain the electronic and vibrational properties of complexes of pyrazine and HX linear acids . MM and MO calculations were used to investigate the conformational and electronic properties of odor-active pyrazines , and NMR, IR, X-ray, and DFT methods were used to examine the structures of pyrido[1,2-a]pyrazinium bromide . The amino-imino tautomerism in 2,3-disubstituted pyrazines in both solution and the solid state was investigated by NMR and X-ray methods . Metal complexes containing a pyrazinecarboxamide ligand were investigated by a variety of spectroscopies . Pyrazine-based heterocycles examined by X-ray crystallography included 5,10-dihydroxy-5H,10H-diimidazo[1,2-a:1',2'-d]pyrazine 93 and 7-ethyl-2methyl-4-phenylhexahydropyrazino[1,2-a]pyrazin-3-one . Those within an organometallic complex included a Ca(II) complex with pyrazine-2,3-dicarboxylate ligands , a Ag(I) complex containing the trans-2-(2-phenylethenyl)pyrazine ligand , catena-bis( -pyrazine-2,3-dicarboxylato-N,O,O')zinc(II) , diaqua(pyrazine-2,3-dicarboxylato-N,O:O',O'')calcium(II) , and Ni(II) complexes containing pyrazine-2-carboxylate ligands . In addition, X-ray crystallography was used to examine the one-dimensional coordination polymer 94 of Cu(II) with 2-pyrazinecarboxylate , osmium clusters like 95 containing 2,3-bis(2pyridyl)pyrazine as a chelating ligand , and pyrazine-bridged benzyl dicobaloximes 96a,b, which were also characterized by cyclic voltammetry .

371


R

OH N

R

N O

R

OH N

N O

OH

O N

N

N

N

N

N

OH

OH2

N

N Cu O N 94 O

N

O

93

OC n

R R

N

Os(CO)4

OC Os

CH2Ar O N Co N HO N

Os 95 (CO)4

N O

R

Co

O N

R

N HO CH2Ar

R

96a,b, R = Me, Ph

6.2.5.1 Syntheses A modified Ugi four-component condensation route was used to prepare substituted 4oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-6-carboxamides . Microwaveassisted reactions enhanced the synthesis of substituted 2(1H)-pyrazinones via "click chemistry" , and 6,8-diarylimidazo[1,2-a]pyrazines were prepared from 1-(2aryl-2-oxoethyl)-2-aryloylimidazoles using NH4OAc/AcOH under microwave conditions . A regioselective one-pot synthesis of 9-alkyl-6-chloropyrido[3,2-e][1,2,4]triazolo[4,3-a]pyrazines 98 from 2,3-dichloropyrido[2,3-b]pyrazine (97) was reported , and a solid-phase synthesis of substituted 2(1H)-pyrazinones was developed for future generation of libraries of these heterocycles . Furoxano[3,4-b]pyrazines were prepared by treating 2-alkoxy-3,5-dinitro-6-chloropyrazines with NaN3 . Polyfunctional tetrahydropyrido[3,4-b]pyrazines like 99 were prepared in a one-pot reaction using C5F5N and diamines , while the sequential reaction of C5F5N with sodium phenylsulfinate and a diamine generated polyfunctional tetrahydropyrido[2,3-b]pyrazines like 100 . O N N

N 97

Cl Cl

R

N

NHNH2

Δ

Cl

Me F

N 98

N R

N N

MeO

PhSO2 F

N N N 99

H N

Me

NEt2

F

N

N H

100

Pyrazino[1,2-a]indoles 101 and 102 were prepared by intramolecular cyclization of 2acyl-1-propargylindoles and NH3 . Pyrrolo[1,2-a]pyrazin-1-ones 103 were obtained from 2-acylpyrroles . Pyrazines doubly activated with MeO2CCl in the presence of bis(TMS)ketene acetals generated polycyclic -lactone products . Tetramethylpyrazine reacted with SeO2 to give 2,5-dimethylpyrazine-3,6-dicarboxaldehyde, which in turn reacted with (iPr)2NH to give 2,5-dimethyl-3,6-bis[(2,6-diisopropylphenylimino)methyl]pyrazine, a chelating ligand for transition metal complexes .

372

M.P. Groziak

Finally, trialkyl-substituted pyrazines 104 were prepared in a regiocontrolled manner from nitroketones by reaction with -amino ketones . R N

R

NH3 N

O R'

101 O N H

N R

R +

Pd(OAc)2

N

N CH2R'

O

R1

NO2

N R

R2

O

N CHR'

102 O

R3 octylviologen

R1

N

R2

N

R3

N

NaOAc Bu4NCl DMSO

Na2S4O6 K2CO3

Cl–

H3N

103

104

6.2.5.2 Reactions Palladium-catalyzed reactions on pyrazines were the subject of quite a few investigations. 3,5-Dichloropyrazinones 105 were shown to undergo regioselective Suzuki and Heck reactions to give 3-substituted products, while the less reactive 5-position could be functionalized only after transhalogenation to the corresponding 5-bromo or -iodo derivatives . The Suzuki, Sonogashira, Heck, and Buchwald-Hartwig reactions were explored using 7-bromo-2,3-diphenylpyrido[2,3-b]pyrazine as the key starting material . Functionalized, symmetric bi-2(1H)-pyrazinones were obtained by homocoupling in a Suzuki-type reaction involving an in situ generated boronic acid , while highly substituted bipyrazines like 107 were obtained by a Suzuki cross-coupling approach from 2amino-5-bromopyridazine (106) . The Pd-catalyzed heteroannulation of N-(3chloropyrazin-2-yl)methanesulfonamide with alkynes was used to prepare 6,7-disubstituted5H-pyrrolo[2,3-b]pyrazines . OMe

R Cl

Bn (Ph) O N N 105

Cl

(HO)2B H 2N

N N 106

OMe

B(OH)2

MeO Br Pd[PPh3]4, Na2CO3 THF, reflux, 24 h 56%

N

N

H 2N

NH2 N

N MeO 107

Olefinic pyrazines like 108 were shown to react with C6H6 in the superacid TfOH to give anti-Markovnikov addition products like 109 . The orientation observed is presumed to be due to the multiply charged heterocycle adjacent to the olefin. Pyrazine oquinodimethanes underwent Diels-Alder condensation with meso-tetraarylporphyrins to give new π-extended porphyrins . A one-pot formation of polycyclic - and lactones like 111 was developed using the reaction of pyridine and pyrazine (110) with bis(trimethylsilyl)ketene acetals. Many of them were characterized by X-ray .

373


N

CF3SO3H

N

N

C6H6, 80 ° C 96%

N

108

N

Ph

Me

N MeO2C

O

Me

1. Me2C=C(OSiMe3)2

N 110

109

MeO2C N

2. ClCO2Me

O 111

6.2.5.3 Applications The non-medicinal applications reported for pyrazine-based compounds were extremely diverse. By studying substituent effects, the rate-determining step for chemiluminescence in 6-arylimidazo[1,2-a]pyrazin-3(7H)-ones was indicated to be a single electron transfer from the anion to triplet O2 . Reaction of the diamide ligands N,N'-bis(2pyridylmethyl)pyrazine-2,5-dicarboxamide and N,N'-bis[2-(2-pyridyl)ethyl]pyrazine-2,5dicarboxamide 112 with Cu(BF4)2•4H2O gave dinuclear Cu(II) complexes which were characterized by EPR . The Cu(II) complex [Cu2(pyrazine-2,5dicarboxylato)(1,10-phenanthroline)4](NO3)2•10H2O 113 was examined by X-ray crystallography, and the magnetic exchange through the pyrazine bridge was studied . The colorimetric sensor properties of solvatochromic substituted 2phenylimidazo[1,2-a]pyrazin-3(7H)-ones 114a-e were examined by UV/Vis and SM1COSMO computations . Pyrazine itself was found to bind to the cavities formed in Mn(II), Fe(II), Ni(II), and Cu(II) complexes bridged with squarate molecules, forming a supramolecular network. The X-ray crystal structure of a similar Zn(II) complex was determined . Two axially chiral quinazoline-equipped phosphinamine ligands, 2-(2-pyridyl)quinazolinap 115a and 2-(2-pyrazinyl)quinazolinap 115b, were prepared, resolved, and their diastereomeric palladacycles were examined crystallographically . Other related quinazolines like 116a-f were also prepared. A total of 27 volatile pyrazines such as 117-120 were isolated and characterized from the myxobacterium Chondromyces crocatus and marine bacteria . N O HN O N

N n = 1 or 2

Cu2+ N

N N

O

N Cu2+

N

Me N

N

N

O

N

N

O

N

NH 112

N

O

N

n

O

n

R 114a-e, R = NMe2, OMe, H, Cl, CN

113

N X

N

N N

N

N

N PPh2

MeO

N

R

N

PPh2

N 117

119

MeO N

115a, X = CH; b, X = N

116a-f, R = Ph, Me, Pri, But, H, Bn

Me

N 118

N

Me

N

SMe

120

374

M.P. Groziak

In medicinal applications, [1,2,4]triazolo[1,5-a]pyrazines have been examined as adenosine A2α receptor antagonists , pyrazolo[4,3-e]pyrrolo[1,2-a]pyrazines were prepared from 1-phenyl-5-(pyrrol-1-yl)-1H-pyrazole-3carboxylic acid azide as antibacterials and antifungals , and pyrazinones were examined as inhibitors of the TF/VIIa complex and as non-nucleoside reverse transcriptase inhibitors (NNRTIs) . New thrombin inhibitors were built around a pyrazinone core , pyrazinone monoamides were prepared as ascaspase-3 inhibitors , and 5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazines as dipeptidyl peptidase IV (DPP-IV) inhibitors . A QSAR study on 1,2,3,4tetrahydropyrrolo[1,2-a]pyrazine-4-spiro-3'-pyrrolidine-1,2',3,5'-tetrone as aldose reductase inhibitors was conducted , the synthesis and SAR of pyrazine-pyridine biheteroaryls as vascular endothelial growth factor (VEGF) receptor-2 inhibitors were reported, and the effect of L-pyrazinylalanine as a phenylalanine replacement in a somatostatin was explored . Finally, the susceptibility and resistance of Mycobacterium tuberculosis to pyrazinamide was further investigated.

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376 05BMC4821 05BMC4936 05BMC5475 05BMC6158 05BMC6226 05BMC6663 05BMC6678 05BMCL37 05BMCL47 05BMCL427 05BMCL863

05BMCL1173

05BMCL1407 05BMCL1591 05BMCL1807

05BMCL1829 05BMCL1881 05BMCL1931 05BMCL1973 05BMCL2203 05BMCL2225 05BMCL2381 05BMCL2409 05BMCL2537 05BMCL2720 05BMCL2803 05BMCL2990 05BMCL3006

05BMCL3130

M.P. Groziak

S. Selleri, P. Gratteri, C. Costagli, C. Bonaccini, A. Costanzo, F. Melani, G. Guerrini, G. Ciciani, B. Costa, F. Spinetti, C. Martini, F. Bruni, Bioorg. Med. Chem. 2005, 13, 4821. H. Hisamichi, R. Naito, A. Toyoshima, N. Kawano, A. Ichikawa, A. Orita, M. Orita, N. Hamada, M. Takeuchi, M. Ohta, S.-i. Tsukamoto, Bioorg. Med. Chem. 2005, 13, 4936. A. Gangjee, Y. Zeng, M. Ihnat, L.A. Warnke, D.W. Green, R.L. Kisliuk, F.-T. Lin, Bioorg. Med. Chem. 2005, 13, 5475. S.M. Sondhi, N. Singh, M. Johar, A. Kumar, Bioorg. Med. Chem. 2005, 13, 6158. A. Agarwal, K. Srivastava, S.K. Puri, P.M.S. Chauhan, Bioorg. Med. Chem. 2005, 13, 6226. M. Johar, T. Manning, D.Y. Kunimoto, R. Kumar, Bioorg. Med. Chem. 2005, 13, 6663. A. Agarwal, Ramesh, Ashutosh, N. Goyal, P.M.S. Chauhan, S. Gupta, Bioorg. Med. Chem. 2005, 13, 6678. V.A. Makarov, O.B. Riabova, V.G. Granik, H.-M. Dahse, A. Stelzner, P. Wutzler, M. Schmidtke, Bioorg. Med. Chem. Lett. 2005, 15, 37. S.B. Katiyar, I. Bansal, J.K. Saxena, P.M.S. Chauhan, Bioorg. Med. Chem. Lett. 2005, 15, 47. A. Nikitenko, Y. Raifeld, B. Mitsner, H. Newman, Bioorg. Med. Chem. Lett. 2005, 15, 427. D.S. Williamson, M.J. Parratt, J.F. Bower, J.D. Moore, C.M. Richardson, P. Dokurno, A.D. Cansfield, G.L. Francis, R.J. Hebdon, R. Howes, P.S. Jackson, A.M. Lockie, J.B. Murray, C.L. Nunns, J. Powles, A. Robertson, A.E. Surgenor, C.J. Torrance, Bioorg. Med. Chem. Lett. 2005, 15, 863. Y. Han, A. Giroux, J. Colucci, C.I. Bayly, D.J. McKay, S. Roy, S. Xanthoudakis, J. Vaillancourt, D.M. Rasper, J. Tam, P. Tawa, D.W. Nicholson, R.J. Zamboni, Bioorg. Med. Chem. Lett. 2005, 15, 1173. J. Pontillo, C. Chen, Bioorg. Med. Chem. Lett. 2005, 15, 1407. A. Gopalsamy, H. Yang, J.W. Ellingboe, H.-R. Tsou, N. Zhang, E. Honores, D. Powell, M. Miranda, J.P. McGinnis, S.K. Rabindran, Bioorg. Med. Chem. Lett. 2005, 15, 1591. J.A. Blagg, M.C. Noe, L.A. Wolf-Gouveia, L.A. Reiter, E.R. Laird, S.-P.P. Chang, D.E. Danley, J.T. Downs, N.C. Elliott, J.D. Eskra, R.J. Griffiths, J.R. Hardink, A.I. Haugeto, C.S. Jones, J.L. Liras, L.L. Lopresti-Morrow, P.G. Mitchell, J. Pandit, R.P. Robinson, C. Subramanyam, M.L. Vaughn-Bowser, S.A. Yocum, Bioorg. Med. Chem. Lett. 2005, 15, 1807. J. Kempson, W.J. Pitts, J. Barbosa, J. Guo, O. Omotoso, A. Watson, K. Stebbins, G.C. Starling, J.H. Dodd, J.C. Barrish, R. Felix, K. Fischer, Bioorg. Med. Chem. Lett. 2005, 15, 1829. A. Agarwal, K. Srivastava, S.K. Puri, P.M.S. Chauhan, Bioorg. Med. Chem. Lett. 2005, 15, 1881. B.D. Palmer, J.B. Smaill, G.W. Rewcastle, E.M. Dobrusin, A. Kraker, C.W. Moore, R.W. Steinkampf, W.A. Denny, Bioorg. Med. Chem. Lett. 2005, 15, 1931. S. Verma, D. Nagarathnam, J. Shao, L. Zhang, J. Zhao, Y. Wang, T. Li, E. Mull, I. Enyedy, C. Wang, Q. Zhu, M. Altieri, J. Jordan, T.-T.-A. Dang, S. Reddy, Bioorg. Med. Chem. Lett. 2005, 15, 1973. Y. Miyazaki, S. Matsunaga, J. Tang, Y. Maeda, M. Nakano, R.J. Philippe, M. Shibahara, W. Liu, H. Sato, L. Wang, R.T. Nolte, Bioorg. Med. Chem. Lett. 2005, 15, 2203. A. Gangjee, H.D. Jain, R.L. Kisliuk, Bioorg. Med. Chem. Lett. 2005, 15, 2225. J. Feixas, M. Paola Giovannoni, C. Vergelli, A. Gavalda, N. Cesari, A. Graziano, V. Dal Piaz, Bioorg. Med. Chem. Lett. 2005, 15, 2381. N. Tamayo, L. Liao, M. Goldberg, D. Powers, Y.-Y. Tudor, V. Yu, L.M. Wong, B. Henkle, S. Middleton, R. Syed, T. Harvey, G. Jang, R. Hungate, C. Dominguez, Bioorg. Med. Chem. Lett. 2005, 15, 2409. I. Shcherbakova, G. Huang, O.J. Geoffroy, S.K. Nair, K. Swierczek, M.F. Balandrin, J. Fox, W.L. Heaton, R.L. Conklin, Bioorg. Med. Chem. Lett. 2005, 15, 2537. L. Strekowski, M.T. Cegla, V. Honkan, H. Buczak, W.R. Winkeljohn, A.L. Baumstark, W.D. Wilson, Bioorg. Med. Chem. Lett. 2005, 15, 2720. R.J. Perner, C.-H. Lee, M. Jiang, Y.-G. Gu, S. DiDomenico, E.K. Bayburt, K.M. Alexander, K.L. Kohlhaas, M.F. Jarvis, E.L. Kowaluk, S.S. Bhagwat, Bioorg. Med. Chem. Lett. 2005, 15, 2803. K. Kamei, N. Maeda, R. Katsuragi-Ogino, M. Koyama, M. Nakajima, T. Tatsuoka, T. Ohno, T. Inoue, Bioorg. Med. Chem. Lett. 2005, 15, 2990. B.A. Schweitzer, W.L. Neumann, H.K. Rahman, C.L. Kusturin, K.R. Sample, G.I. Poda, R.G. Kurumbail, A.M. Stevens, R.A. Stegeman, W.C. Stallings, M.S. South, Bioorg. Med. Chem. Lett. 2005, 15, 3006. A. Agarwal, K. Srivastava, S.K. Puri, P.M.S. Chauhan, Bioorg. Med. Chem. Lett. 2005, 15, 3130.


377

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378 05H(65)2321 05H(65)2593 05H(65)2683 05HAC20 05HAC56 05HCA751 05HCA2747 05HEC89 05IJH87 05IJH189 05JCC429 05JCC683 05JCC891 05JCC931 05JCC963 05JCC1241 05JCC1429 05JCO90 05JCO96 05JCO236 05JCO490 05JCO517 05JCO589 05JCO721 05JCO806 05JCO977 05JHC165 05JHC221 05JHC307 05JHC319 05JHC353 05JHC361 05JHC375 05JHC387 05JHC395 05JHC413 05JHC427 05JHC509 05JHC527 05JHC557 05JHC589 05JHC609 05JHC639 05JHC691 05JHC751 05JHC841 05JHC925 05JHC975 05JHC1069 05JHC1085

M.P. Groziak

H. Peng, L. Sha, H.X. Chang, J.T. Vessels, S. Haque, P.R. Conlon, J.E. Dowling, J. Wang, T.M. Engber, G. Kumaravel, D.M. Scott, R.C. Petter, Heterocycles 2005, 65, 2321. T. Ingebrigtsen, I. Helland, T. Lejon, Heterocycles 2005, 65, 2593. T. Nagamatsu, S. Ahmed, Heterocycles 2005, 65, 2683. A.H. Abdel-Rahman, M.A.A. Hammouda, S.I. El-Desoky, Heteroat. Chem. 2005, 16, 20. W.M. Abdou, N.A. Ganoub, A.F. Fahmy, A.M. Shaddy, Heteroat. Chem. 2005, 16, 56. F. Seela, A.M. Jawalekar, I. Muenster, Helv. Chim. Acta 2005, 88, 751. C.C. Moldoveanu, I.I. Mangalagiu, Helv. Chim. Acta 2005, 88, 2747. Y.M. Elkholy, Heterocycl. Commun. 2005, 11, 89. O.M. Singh, M.F. Ahmed, H. Dinesh, Indian J. Heterocycl. Chem. 2005, 15, 87. P. Mathias, V.P. Vaidya, Indian J. Heterocycl. Chem. 2005, 14, 189. T.S. Lobana, P. Kaur, A. Castineiras, J. Coord. Chem. 2005, 58, 429. S.M. Abu-El-Wafa, N.A. El-Wakiel, R.M. Issa, R.A. Mansour, J. Coord. Chem. 2005, 58, 683. W. Starosta, J. Leciejewicz, J. Coord. Chem. 2005, 58, 891. M. Gryz, W. Starosta, J. Leciejewicz, J. Coord. Chem. 2005, 58, 931. W. Starosta, J. Leciejewicz, J. Coord. Chem. 2005, 58, 963. S.M. El-Medani, C.M. Sharaby, R.M. Ramadan, J. Coord. Chem. 2005, 58, 1241. S.M. El-Medani, O.A.M. Ali, H.A. Mohamed, R.M. Ramadan, J. Coord. Chem. 2005, 58, 1429. N. Kaval, W. Dehaen, E. Van der Eycken, J. Comb. Chem. 2005, 7, 90. P. Schell, M.P. Richards, K. Hanson, S.C. Berk, G.M. Makara, J. Comb. Chem. 2005, 7, 96. I.L. Dalinger, I.A. Vatsadse, S.A. Shevelev, A.V. Ivachtchenko, J. Comb. Chem. 2005, 7, 236. N. Kaval, D. Ermolat'ev, P. Appukkuttan, W. Dehaen, C.O. Kappe, E. Van der Eycken, J. Comb. Chem. 2005, 7, 490. J. Cesar, J. Comb. Chem. 2005, 7, 517. F.J.R. Rombouts, G. Fridkin, W.D. Lubell, J. Comb. Chem. 2005, 7, 589. W. Li, Y. Lam, J. Comb. Chem. 2005, 7, 721. A.P. Ilyn, A.S. Trifilenkov, S.A. Tsirulnikov, I.D. Kurashvily, A.V. Ivachtchenko, J. Comb. Chem. 2005, 7, 806. G. Fridkin, W.D. Lubell, J. Comb. Chem. 2005, 7, 977. A. Gangjee, H.D. Jain, J. Phan, R.L. Kisliuk, J. Heterocycl. Chem. 2005, 42, 165. K.M. Dawood, J. Heterocycl. Chem. 2005, 42, 221. F. Al-Omran, A.A. El-Khair, J. Heterocycl. Chem. 2005, 42, 307. S. Demirayak, I. Kayagil, J. Heterocycl. Chem. 2005, 42, 319. S.-K. Kim, D.-H. Kweon, S.-D. Cho, Y.-J. Kang, K.-H. Park, S.-G. Lee, Y.-J. Yoon, J. Heterocycl. Chem. 2005, 42, 353. J. Svete, J. Heterocycl. Chem. 2005, 42, 361. A.F. Pozharskii, A.V. Gulevskaya, J. Heterocycl. Chem. 2005, 42, 375. Y. Kurasawa, H.S. Kim, J. Heterocycl. Chem. 2005, 42, 387. A. Gelain, J. Heterocycl. Chem. 2005, 42, 395. A.V. Gulevskaya, S. Van Dang, A.F. Pozharskii, J. Heterocycl. Chem. 2005, 42, 413. T.M. Stevenson, B.A. Crouse, T.V. Thieu, C. Gebreysus, B.L. Finkelstein, M.R. Sethuraman, C.M. Dubas-Cordery, D.L. Piotrowski, J. Heterocycl. Chem. 2005, 42, 427. L. Decrane, N. Ple, A. Turck, J. Heterocycl. Chem. 2005, 42, 509. A.O. Abdelhamid, M.A.M. Alkhodshi, J. Heterocycl. Chem. 2005, 42, 527. R.S. Vardanyan, V.J. Hruby, G.G. Danagulyan, A.D. Mkrtchyan, J. Heterocycl. Chem. 2005, 42, 557. A. Gangjee, H.D. Jain, S.F. Queener, J. Heterocycl. Chem. 2005, 42, 589. Y.-C. Wu, X.-M. Zou, F.-Z. Hu, H.-Z. Yang, J. Heterocycl. Chem. 2005, 42, 609. H.-A. Chung, J.-J. Kim, H.-K. Kim, D.-H. Kweon, S.-D. Cho, S.-G. Lee, Y.-J. Yoon, J. Heterocycl. Chem. 2005, 42, 639. I.L. Yudin, A.B. Sheremetev, B.B. Averkiev, M.Y. Antipin, J. Heterocycl. Chem. 2005, 42, 691. N.R. Reddy, G.M. Reddy, B.S. Reddy, P.P. Reddy, J. Heterocycl. Chem. 2005, 42, 751. D. Briel, S. Drescher, B. Dobner, J. Heterocycl. Chem. 2005, 42, 841. M. Li, S. Wang, L. Wen, H. Yang, X. Zhang, J. Heterocycl. Chem. 2005, 42, 925. M.C. Dutta, K. Chanda, P. Helissey, J.N. Vishwakarma, J. Heterocycl. Chem. 2005, 42, 975. E.A. Bakhite, A.G. Al-Sehemi, Y. Yamada, J. Heterocycl. Chem. 2005, 42, 1069. K.M. Khan, G.M. Maharvi, M.I. Choudhary, R. Atta ur, S. Perveen, J. Heterocycl. Chem. 2005, 42, 1085.


05JHC1105 05JHC1127 05JHC1223 05JHC1305 05JHC1423 05JMC141

05JMC152 05JMC1886 05JMC1901

05JMC1910

05JMC2371 05JMC2420 05JMC4025 05JMC4690 05JMC4892 05JMC5162 05JMC5329 05JMC6004 05JMC6326 05JMC6776 05JMC6843

05JMC7012 05JMC7089

05JMC7215 05JMC7808 05JMS7 05JMS37

379

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380 05JMS67 05JMS169 05JMS179 05JMS2822 05JOC388 05JOC1957 05JOC1961 05JOC2616 05JOC2729 05JOC2824 05JOC2878 05JOC4088 05JOC5215 05JOC6503 05JOC6721 05JOC7208 05JOC9377 05JOC9780 05JOC10194 05JOM622 05JOM802 05JOM3746 05JOM4773 05JOM5849 05M217 05MI297 05MI307 05MI1319 05OL2505 05OL4705 05OL5529 05OM4057 05PS95 05PS149 05PS163 05PS339 05PS413 05PS591 05PS633 05RJO289 05S131 05S419 05S1083 05S1164

M.P. Groziak

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05S1345 05S1601 05S2544 05S2597 05S2833 05SC249 05SC1003 05SC1741 05SC1921 05SC1961 05SC2251 05SC3055 05SL777 05SL1239 05SL1683 05SL1897 05SL1907 05SL2743 05T1077 05T2897 05T3953 05T4237 05T4453 05T4785 05T4805 05T4919 05T4957 05T5303 05T5389 05T7384 05T8616 05T8924 05T9637 05T9808 05T10073 05T10774 05TA2778 05TC31 05TC73 05TC201 05TL51 05TL1177 05TL1345 05TL1433 05TL1663 05TL1841 05TL1845

381

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382 05TL1975 05TL2189 05TL3423 05TL3449 05TL5289 05TL5551 05TL5747 05TL5851 05TL7701 05TL7889 05TL8749 05ZN(B)22 05ZN(B)221

M.P. Groziak

L.G. Voskressensky, T.N. Borisova, I.S. Kostenev, I.V. Vorobiev, A.V. Varlamov, Tetrahedron Lett. 2005, 46, 1975. S. Zhao, M.G.P.M.S. Neves, A.C. Tome, A.M.S. Silva, J.A.S. Cavaleiro, M.R.M. Domingues, A.J. Ferrer Correia, Tetrahedron Lett. 2005, 46, 2189. B. Shao, Tetrahedron Lett. 2005, 46, 3423. H. Rudler, B. Denise, Y. Xu, J. Vaissermann, Tetrahedron Lett. 2005, 46, 3449. R. Pathak, A.K. Roy, S. Kanojiya, S. Batra, Tetrahedron Lett. 2005, 46, 5289. N. Matsumoto, M. Takahashi, Tetrahedron Lett. 2005, 46, 5551. X. Wang, S. Dixon, N. Yao, M.J. Kurth, K.S. Lam, Tetrahedron Lett. 2005, 46, 5747. G. Lavecchia, S. Berteina-Raboin, G. Guillaumet, Tetrahedron Lett. 2005, 46, 5851. H. Kondo, T. Igarashi, S. Maki, H. Niwa, H. Ikeda, T. Hirano, Tetrahedron Lett. 2005, 46, 7701. S. Tyagarajan, P.K. Chakravarty, Tetrahedron Lett. 2005, 46, 7889. M. Angiolini, D.F. Bassini, M. Gude, M. Menichincheri, Tetrahedron Lett. 2005, 46, 8749. H. Schumann, H.-K. Luo, Z. Naturforsch., B: Chem. Sci. 2005, 60, 22. E.K. Ahmed, M.A. Ameen, F.F. Abdel-Latif, Z. Naturforsch., B: Chem. Sci. 2005, 60, 221.

383

Chapter 6.2 (2006)


Keith Mills Ware, Hertfordshire UK [email protected] ___________________________________________________________________________

6.2.1 INTRODUCTION The chemistry of diazines remains an area of intense interest, both academic and industrial, with applications in many areas, from biomedical to materials science and electronics. They are versatile, having very varied reactivity, giving many opportunities for manipulation of substituents. Nucleophilic substitutions, electrophilic substitution in oxy and amino derivatives, organometallic and transition metal-catalysed coupling reactions are all subjects of substantial research effort. There are obvious similarities in reactivity of the three diazine systems but also many interesting and practically important, often subtle, differences. All three systems are amenable to sequential substitutions, giving opportunities for use as scaffolds and also, particularly for pyrimidines, rapid muticomponent, often “one pot”, ring constructions are possible. Both these features give great potential for combinatorial chemistry and library construction. The main emphasis of this review will be on the synthetic and reactivity aspects of the three diazine systems and their benzo-derivatives, although some other interesting and significant applications will also be covered. Generally one or two representative examples of reactions or syntheses will be given and it is understood that further examples will usually be found in the original paper. However, this is flexible and generic reactions or products may be shown if this is considered more appropriate. 6.2.2

GENERAL STUDIES

The Negishi coupling reactions of a number of amino-chlorodiazines have been reported. The aminopyrazine 1 was used as the substrate for optimisation but examples involving the other diazines were also given. Dialkylzincs and alkylzinc halides reacted successfully and a particularly useful in situ formation of primary alkylzinc halides by exchange of an alkyl halide with diethylzinc could be carried out. Fortuitously, this alkylzinc exchange was catalysed by the nickel catalyst used for the following coupling .

384

K. Mills

N Cl

NH2

N

R = Pr, 92%; cyclopentyl, 46%; PhCH2CH2*, 42%; PhCH2* , 50%

N

RZnX, NiCl2.(dppp) R

N

(* prepared in situ from RBr + Et2Zn)

NH2

1 NH2

similar couplings with (e.g.): N

Cl

Br

N

Me

N

H2N

N

H2N

N

N

Cl

A study of the Į-arylation of diazine mono N-oxides, under Heck-like conditions, also gave emphasis to pyrazines but a number of examples using pyrimidines and pyridazines were also described (Scheme 1). A wide range of aryl chlorides, bromides and iodides was used and the products were easily deoxygenated by catalytic reduction. An interesting feature was the use of a copper additive, which was only required for the pyrimidine reactions, to give a very substantial improvement in yield . Pd(OAc)2, t-Bu3P.HBF4 K2CO3, dioxane, 110 °C

N

N

ArX

N O

N

H2, Pd or HCO2NH4, Pd

N O

N

Ar

Ar

86% yield

75% yield

Ar = 4-tolyl for optimisation studies similarly: N

N N O

N O

68% yield

N

N

N O

Ar

N

Ar

N

N O

73% yield

Ar

N O

standard conditions, 17% yield with 10 mol% CuCN, 61% yield

N O

Scheme 1 A metal-iodine exchange has been carried out on all three diazine systems under very mild conditions using lithium tri-n-butyl magnesate, although only one substrate from each system was used: 3-iodo-6-phenylpyridazine, 4-iodo-2-methylthiopyrimidine and 2-iodopyrazine. The pyridazine example was most problematic, possibly due to solubility problems. Aldehydes, benzophenone and diphenyl disulfide were used as the electrophiles . N N

1) n-Bu3MgLi, THF, −10 °C I 2) PhSSPh, −10 °C to r.t.

N N

SPh

N SPh

86% yield

similarly

MeS

N

85% yield

SPh

Ph

N

N

62% yield

385


The copper-catalysed N-arylation of diazinones by aryl halides, but mainly using 2-fluoro-4iodoaniline, was described as part of a paper devoted primarily to pyridones. Pyrazin-2-one, pyrimidin-4-one and pyridazin-3-one all reacted successfully but pyrimidin-2-one failed to give any product . N

NH2 F

N N H

CuI, 8-hydroxyquinoline, K2CO3, DMSO, 130 °C

N

N O

similarly prepared

O

O

N Ar

O

28%

Me

I

43% yield

F

N

NH2

6.2.3

N Ar

59%

PYRIDAZINES AND BENZO DERIVATIVES

The relatively rare discovery of a new pyridazine natural product – azamerone 2 – has been reported . O

O Cl

N N

O OH

Cl OH

2 azamerone

6.2.3.1 Synthesis A number of pyridazines have been prepared by standard condensations of enediones with hydrazine but a general synthesis of the intermediate enediones is notable. This involved iodine-copper exchange of an iodoenone 3, followed by reaction of the resulting cuprate with acid chlorides. However, only a few of these enediones were actually converted into pyridazines . O O R Ph

I 3

1) Npthyl2CuLi, THF −100 °C 2) O

COCl

Ph

Et

R R O

N2H4.H2O, EtOH reflux

O R = pentyl, 78% yield

Ph

N N O

Me3Si similarly prepared

N N S

96% yield

The one-pot synthesis of the dibromopyridazinone 4 has been optimised up to a 22 kg scale in a process research project. One key feature was the use of hydrobromic acid, rather than

386

K. Mills

hydrochloric acid, for the diazotisation step to avoid partial halide exchange in the final condensation . Br

Br

Br Br

F

F NaNO2, HBr; SnCl2

F

HO

F

O

O

O

N NHNH2

NH2

N

F F

4

82% yield

Useful variations on another standard synthesis of pyridiazines by Inverse-ElectronDemand Diels–Alder reactions included the regioselective reactions of 1,2,4,5-tetrazine sulfoxides with enols, enamines and alkynes (Scheme 2). These sulfoxides have greater reactivity than the previously used sulfides but, more importantly, showed a reversed (complementary) regioselectivity. The reactions of the sulfoxide 5 appeared to be totally regioselective apart from one case (with 2,3-dihydrofuran). The Cbz amine 6 also reacted with high regioselectivity in most cases but there were several exceptions . Ph N Me

S O

N N

SMe Me

N

Ph dioxane, 100 °C, 1 h

or

90% yield

5

Ph NHCbz

S O

94% yield

OTMS

Ph

Me

Ph

CH2Cl2, 25 °C, 1 h

SMe

N

N

Me

OTMS

N

CH2Cl2, 25 °C, 2 h Me

83% yield

S O

S O

NHCbz

N N

N

Me NHCbz

OEt

CH2Cl2, 25 °C, 6 h Me

N

N

6

S O

N

58% yield

N

Me Me

S O

NHCbz N

7% yield

N

The use of an alkynylboronate 7 as the dienophile allowed the synthesis of pyridazin-4ones . Cl O

B

O

7

N N

N N Cl

R R = H, Bu, Ph, TMS

O O xylene reflux

R

B

O

H2O2, Na2CO3 Cl

N Cl N 63% yield, R = H 86% yield, R = TMS

R Cl

Cl N H

N

73-85% yield

387


In a study of the use of microwave irradiation for the preparation of pyridazines by the cycloaddition of alkynes to 3,6-bis-(2-pyridyl)-1,2,4,5-tetrazine 8, it was found incidentally that acetone reacted, via its enol, with this tetrazine, also giving a pyridazine. Aldehydes reacted similarly but with variable yields and other ketones gave mixtures of products derived from both possible enols. In the one example (acetone) where it was tried, conventional heating gave an only marginally lower yield than microwave heating (The room temperature, base-catalysed, addition of aldehydes to tetrazines has previously been reported but this may be mechanistically different ). 2-py

2-py N N

Me2CO

N N

2-py

MW, 150 °C, 30 min; 75% yield

Me

N N

Conventional heating, 150 °C, 30 min; 69% yield

2-py

8

Conversion of other heterocyclic systems into pyridazines has also been used, for example the reaction of 3-aminopyrone 9 with hydrazine, followed by oxidative aromatisation and the more unusual utilisation of a 1,2,4-triazole 10 as the source of the N-N unit . In this latter transformation, the intermediate quaternary salt 11 was isolable. An even more unusual example was the reaction of the diazetidine 12 with enolates . NH2 O

CONHNH2

N2H4.H2O

O

N H 88% yield

9

Cl

N

Li

2) triazole

OH N

N

98% yield

Br

Ar 1) R

O

N

R

Ar

CO2Me

CAN, MeOH

Br2

Ar

N N

R N

NaOH

Ar

N

R N

N

N

10

11

NTol NHTol N N Me

NTol 12

O

R2

LiHMDS, THF

R1

−78 °C to rt

R2

NHTol

N N Me R1 = Me, R2 = H; 93% yield R1

In a paper concerned with the synthesis of fused pyridazines, the isoxazole 13 was used as a masked amino alcohol, which was eventually used to construct a fused pyridine ring. A standard hydrazine reaction, followed by hydrogenolysis of the isoxazole of the intermediate

388

K. Mills

14 gave the required pyridazine amino alcohol. The sequence is interesting, despite the low yield, which was due in part to instability of the bicyclic intermediate 14 . F N N

O OHC N

O

NH2

Ar

N2H4.H2O O

H2, Pd

N

N

O

N 9% yield (2 steps)

14

13

Ph

Ar

HO

N N

N H

Ar

A cyclocondensation involving the carbonyl of a benzoquinone was used for the synthesis of a cinnoline 15 of interest as a potential anti-fungal agent . O

O

CN

Me

Cl

Me

Cl

CO2Me EtOH, NH4OH, rt

O

Cl

Me

Cl

N2H4.H2O, EtOH CO2Me

Me

31% yield

O

HO

CO2Me NH2

Me

N

reflux

CN

Me

N

46% yield

15

Improved conditions for the cyclisation of 2-alkynyl diazonium salts to cinnolines, using aqueous sodium chloride, have been described

6.2.3.2 Reactions A review of the palladium-catalysed reactions of halo-pyridazines has been published . The regioselective O-sulfonylation of 4-bromopyridazine-3,6-dione 16, using a hindered sulfonyl chloride, allowed efficient sequential boronic acid couplings. 2,4,6-Triisopropylbenzenesulfonyl chloride was the only sulfonyl chloride to give essentially complete regioselectivity, whereas the corresponding 4-phenyl pyridazinedione gave a highly selective reaction even with tosyl chloride. . Br

Br O

O

N H

NH

Ar O

ArSO2Cl, py ArSO2O

16

NH

Suzuki

N 90% yield, >95% regioselectivity

ArSO2O

Ar O

N

O

NH Ar'

N

NH

ArSO2 = 2,4,6-triisopropylbenzene sulfonyl

A paper concerned with the synthesis of pyridazino[3,4-b]indoles 18 included a study of various conversions of 4,5-dichloro-2-methylpyridazin-3-one 17 including nucleophilic substitutions, Suzuki reactions and electrophilic substitution (nitration), combined with reductive dehalogenation, and usefully summarised previous work .

389


Cl O N

Cl

Cl

Cl N

N2H4 H2NHN

O

Me

N

N

O

CuSO4 N

Me

N

NH2 O

via Suzuki

Me

79% N

17

N

Me

POCl3 71%

Cl

I O

Cl N

O2N

N

Me

N O2N

N

N

4

3

O

NaI

also prepared 4-Br 3-NO2 compounds

Me

18

N Me

N

The divergence of oxidative addition and nucleophilic substitution was shown by the reaction of the dichloropyridazinone 19 with phenoxide, which displaced the 6-chlorine, vs. a Suzuki coupling, which showed selectivity for the C-3 halide .

O R PhO

O Cl

PhONa, THF

N N CH2Ph

R

O Cl PhB(OH)2, Pd

N N CH2Ph

Cl

Cl

19

70% yield, R = Bu

R

Ph N N CH2Ph

62% yield, R = Bu

The microwave-assisted dipolar cycloaddition of pyridazinyl quaternary salts such as 20 was shown to be substantially better than the reaction using conventional heating. Novel regioselective reactions using monosubstituted dipolarophiles were also included .

N N

MeO2C

CO2Me Et3N, PhH CO2Me

MeO2C

N 20

58% yield 30% yield

N

CO2Me

N N

Et3N, PhH

CO2Me MW, 5min

(previous thermal conditions)

MeO2C

CO2Me CO2Me

59%yield 30% yield

6.2.4 PYRIMIDINES AND BENZO DERIVATIVES A useful discussion of the metallation of pyrimidines is to be found in a more general review on metallation . A full issue of Chemical Reviews was concerned with DNA damage and repair, parts of which may be of interest relating to pyrimidine reactivity

390

K. Mills

. Biginelli compounds were included in an account of heterocyclic glycolconjugates . Other reviews cover the chemistry of quinazoline alkaloids and pyrimidine chemistry in crop protection 6.2.4.1 Synthesis The ever-popular Biginelli synthesis of dihydropyrimidines, by condensation of urea with a keto ester and an aldehyde, and variations on it, has been applied in a number of areas. R'

R'CHO

EtO2C

Biginelli reaction

NH2

R

H 2N

O

EtO2C

O

NH

R

O

N H

New variations in conditions include the use of antimony trichloride as a catalyst for the synthesis of monastrol analogues, with modifications in the aryl ring and replacement of thio by oxo . The use of ionic liquids and microwave enhancement have also been reported. Nanosynthesis (single bead reaction) has been carried out and highly enantioselective reactions have been achieved using the catalyst 21 . 5-Nitro-dihydropyrimidines such as 22 have been prepared using Į-nitroacetophenone in place of the usual keto ester and shown to have potential as antiarrythmic agents .

OH

Ph

N

O P

EtO2C

O O2N

O OH

NH

NH

monastrol Me

N R

S

Ph

Ph 21

N H

O 22

A surprisingly infrequent use of Biginelli compounds to make aromatic pyrimidines has also been reported. Dehydrogenation with ceric ammonium nitrate gave pyrimidinones 23 or pyrimidinediones 24, depending on conditions . Ph EtO2C O 24

CAN, AcOH 80 °C

NH N H

O 61% yield

Ph EtO2C R

NH N H

CAN, aq.Me2CO −5 °C

Ph EtO2C R

O 83% yield

N N H

O 23

A general method for the guanidine analogue of the Biginelli reaction has been developed using the two reagents 25 and 26, which overcome some of the limitations of the direct

391


guanidine condensation. The choice between the two reagents depended on the acid-stability of the substrate . RCHO CO2Et Me

EtO2C

R' NH2

HN

O

R

R

Me

EtO2C

N

Me

R'

N H

NH N

NH2

strong acid for 25 or Boc2O; NH3; TFA for 26

O Me R' HN

N

N

Me or

=

N

NH2

N

25 HN

HN

NH2

N 26 NH2

A number of alternative preparations of Biginelli-type compounds and similar dihydropyrimidines have been described. A route to N-1-substituted compounds 27, which are difficult to make by the standard Biginelli reaction, involved reaction of an Į-chlorobenzyl isocyanate with N-substituted aminocrotonates . EtO2C

ArCHO

EtO2CNH2 H2SO4 cat., 150 °C

ArCH(NHCO2Et)2

PCl3

NCO Ar Cl

Ar = Ph, 68% yield

Ar NHR

EtO2C

CH2Cl2, reflux

Me

Me

NH N R

O 27

Ar = Ph, R = Me, 64% yield Ar = Ph, R = 4-ClC6H4, 63% yield

Another multicomponent synthesis giving N-3-substituted compounds 28 consisted of the sequential reaction of metallated phosphonoacetates, in one pot, with a nitrile then an aldehyde and finally an isocyanate. This was an extensive study of the scope and limitations of the different substituents on all the components. The most important feature was that, for good yields, the isocyanate should bear an electron-withdrawing group – tosyl was the most successful. However, an exchange reaction could be carried out by reaction of the tosyl products with aryl isocyanates under microwave irradiation, giving the N-3-aryl derivatives 29 .

392

K. Mills

R3

1) BuLi 2) R2CN

P(O)(OEt)2

R1

R1

3) R3CHO 4) R4NCO All reactions between -78 and rt

R2

N N H

R4 O

R1 = H, alkyl, aryl, CO2Et, P(O)(OEt)2 R2 = S-alkyl, aryl R3 = (alkyl), aryl R4 = Ts, RCO, (Ar)

28 (R4 = Ts) ArNCO, MW

R3 R1 via R2

N

R3

R4 NH

R1

O

R2

N N H

Ar O

29

The dihydropyrimidinethione 30 has been obtained by microwave-induced rearrangement of a dihydrothiazine, using silicon carbide as a passive heating element . Ph

Ph EtO2C Me

MW, SiC, toluene, 220 °C

S N H

NH

EtO2C Me

NH N H

S 30

68% yield

There has been significant emphasis on the use of pyrimidine thio ethers for further selective functionalisation by nucleophilic displacements of either the alkylthio or alkylsulfone and general syntheses of pyrimidines often include methylthio as one of the representative substituents. The reaction of enolisable ketones with nitriles under the influence of triflic anhydride is a useful general method for the synthesis of 2,4-“symmetrically” substituted pyrimidines. Reaction of 1-tetralone with aryl cyanides or methyl thiocyanate, followed by aromatisation with DDQ gave good yields of benzoquinazolines. The further transformation of the methylthio product 31, via oxidation and selective sequential nucleophilic substitution of the resulting sulfones, illustrates the utility of this substituent. 2-Tetralone reacted similarly but substantial amounts of by-products were formed .

393


O N

Tf2O, MeSCN

SMe

N

DDQ

N

CH2Cl2, rt

SMe N

31

SMe 70% yield

SMe

93% yield mCPBA

N

OMe

NaOMe, MeOH, refl.

NH3, rt

85%

N

N

74%

NH2

SO2Me N

85% yield

SO2Me

The same general method has been applied using N-benzylpiperidone 32 as the ketonic component (note the cleavage of the benzyl group) . O Tf2O, RCN

R

N TfN

N CH2Ph

N

R = Me, Tol, MeS (45-65% yield)

R

32

The use of alkyl esters in place of ketones resulted in the formation of alkoxypyrimidines 33 which could be converted in high yields, via selective sequential nucleophilic substitutions, into amino dialkoxy and trialkoxy pyrimidines 34 . SMe RCH2CO2Et MeSCN

Tf2O

R

Nu 3 steps

N

EtO

N

SMe

33 R = alkyl, Ph (not H)

42-71% yield

R EtO 34

N N

Nu'

e.g. Nu = NH2, OMe; Nu' = OMe

The condensation of anilides or enamides with nitriles was developed as a general method for the synthesis of pyrimidines or quinazolines such as 35 and 36 .

394

K. Mills

Cy MeO

Tf2O NHCOPh

N

Cl

MeO

N

−78 °C to 45 °C

CN

N

Ph

35

90% yield R

similarly

O

O

N Ph N 36

NHCOPh

A process research investigation on p38 MAP kinase inhibitors examined the synthesis (on 7 mol scale) of a group of closely related pyrimidinones such as 37, by condensation of a number of arylacetic esters with 4-cyanopyridine and methyl isothiocyanate. Other nitriles were also examined but were much less successful than 4-cyanopyridine: 3-cyanopyridine gave a much lower yield and both benzonitrile and 2-cyanopyridine failed completely . Me CN

Me

O add KOt-Bu

Ar py

N

CO2Et

Add MeNCS then MeI

N

NH

N

CO2Et

N Reaction carried out on 7 mol scale

Me SMe

37

51% yield

Cyclobutane-fused pyrimidinones 39, precursors to quinone methide intermediates, have been prepared by reaction of amidines with the cyclopropane ester 38 . Cl

38

R

CO2Me

HN

N

Et3N, dioxane, rt NH2

NH 39

R = aryl, MeS

R

O

43-83% yield

PhSO2 175 °C

N

R NH

PhSO2 O

39-84% yield

The synthesis of a pyrimidine 40 by reaction of an amidine with an isoxazole is an interesting example of interconversion of heterocycles . In another heterocycle interconversion, the reaction of 3-amino-5-phenyl-1,2,4-oxadiazole with hexafluoropentane dione gave a mixture of the hydroxaminopyrimidine 41 and aminopyrimidine N-oxide 42. This was in contrast to previous work where pentanedione gave a high yield of only the corresponding amino N-oxide. The mechanism of the reaction was discussed, based on the isolated by-products .

395


Me

Me

Ph HN

N

N

NH2.HCl

N Ph

O

N Ph

N

K2CO3, MeCN

N

Ph N

31% yield Me

N Ph

O

O

NH2 N

Me

O

F3C

CF3

CF3

N

N

CF3 F3C

HClO4, MeCN

40

N

F3C

NHOH

41 39% yield

N O

NH2

42 21% yield

Pyrimidin-2-ones 43 with fluorinated substituents have been prepared by reaction of metallated imines with fluorinated nitriles, followed by cyclisation with triphosgene . O

Rf Me R1

NH2 Cl3CO

LDA, RfCN N R2

R1

Rf OCCl3

N R2

R1 mainly aryl, R2 alkyl or aryl or R1,R2 = (CH2)3 Rf = CF2Ph or C7F15

N R1

N O R2 43 70-94% yield

69-87% yield

A straightforward preparation of pyrimidinones and pyrimidinethiones 45 involved reaction of isocyanates or isothiocyanates with the readily available starting material 44, which had previously been described by the same authors. A particularly interesting application was the use of sugar isothiocyanates to give nucleosides. Nucleophilic displacements of the sulfur groups in the products were also reported . SMe SMe MeS

NH

NMe2 44

RNCX, Et3N

N R = alkyl, aryl, sugar O = S, O

N N R 45

N

S

BzO

X

O

Nu−

including e.g. OBz OBz

Nu N N R

X

The nickel-catalysed co-trimerisation of acetylenes with isocyanates gave good yields of uracils 46, depending on the isocyanate substituents, pyridones being unwanted by-products

396

K. Mills

in some cases. Trimethylsilyl and tri-n-butyltin were favoured as the acetylene substituent, the latter being carried through to an in situ Stille coupling . O Me

TMS

Ni cat.

TMS

N

R

N O R 46 Yields up to 83% Me

RNCO

Me

Similar reaction with

SnBu3

followed by in situ Stille coupling (75% overall, R = Et)

An efficient preparation of 5-cyanouracils started from N-ethoxycarbonylcyanoacetamide 47, the carbonyl of the urethane finally being incorporated into the uracil ring . O O (EtO)3CH, MeCN

O NC

RNH2

NC

NHCO2Et

NC NHCO2Et

Et3N

N O R generally >70% yields overall

RHN

47

NH

Uracil 5-carboxylates 48 were prepared by reaction of aminomethylene malonates with chlorosulfonyl isocyanate. The reaction was greatly accelerated by microwave irradiation (1h vs. 2-3 d in refluxing toluene), although the microwave yields were somewhat lower than those from the thermal reactions. The chlorosulfonyl group was lost during work-up and chromatography. The method was compatible with sugar residues .

O EtO2C

CO2Et NHR

ClSO2NCO

EtO2C

MW, benzene 1 h or toluene reflux 2-3 d

NH N R

R = Ph, yield 60% (thermal), 44% (MW) OAc

O 48

R=

O

AcO OAc

yield 70% (thermal) 58% (MW)

OAc

An improved synthesis of 11C-2 thymine 49, for use in PET scans, was made possible by an efficient and rapid synthesis of 11C-phosgene, previously reported by the same authors. 11C is a particularly interesting challenge due to its very short half life (20 minutes) and the whole sequence and purification from the end of the bombardment took 16 minutes. The scale was necessarily small (0.2 mg) .

397


O

O EtO2C

Me

Me

H2N

3 steps

KOt-Bu, DME

HN C N O H

Me

11

CHO

HN COR

11COCl

2

49

14N

2

+ H2

18 MeV proton beam

11CH

11CCl

4

4

10 min

16 min

A number of new conditions and catalysts have been used for the synthesis of quinazolinones 50 from anthranilic acids, amines and ortho esters, including bismuth trifluoroacetate with an ionic liquid , lanthanum nitrate or tosic acid under solvent-free conditions at room temperature and Nafion-H . O CO2H

R1NH

2 3 2, R C(OR )3

NR1

NH2

N

50

R2

Quinazolines 51 have been prepared by the condensation of N-aryl carbamates with hexamine, followed by aromatisation of the dihydro intermediate. A variety of mono- and disubstituted anilides were used, meta-substituted starting materials giving 7-substituted quinazolines . Benzoquinazolines were also prepared similarly from naphthylamine carbamates .

Me

Me

hexamine, TFA NHCO2Et

N

K3Fe(CN)6, KOH

Me

N 51

reflux

N CO2Et

N 49% yield

The convenient synthesis of dichloroquinazolines 52 from anthranilonitriles by reaction with diphosgene was also applied to fusion of pyrimidine rings onto other heterocyclic aminonitriles . Cl CN NH2

Cl3COCOCl

N

MeCN, 130 °C

N

52 Cl

86% yield Cl CN N N Bn

NH2

Cl3COCOCl MeCN, 100 °C

N

N

N Cl N Bn 51% yield

Yields for 6-substituted compounds range from 41% (CF3) to 80% (Me)

398

K. Mills

The reaction of 2-isothiocyanato benzonitrile with aryl acetonitrile anions was used to prepare quinazoline thione derivatives 53 . NC CN

Ar

ArCH2CN, NaH

NH

NCS

N H

53

S

Quinazoline diones 54 were also available from 2-bromobenzoates via a palladiumcatalysed N-arylation of ureas. O Cl

CO2Me H 2N

Br

NHBu

Pd2(dba)3, Xantphos, Cs2CO3

O

dioxan, 100 °C

Cl

N N H 85% yield

Bu 54

O

Substituted and aza analogues of febrifugine have been prepared in the search, with a certain amount of success, for a better anti-malarial activity/ toxicity balance . A number of analogues of rutaecarpine, including substituents in and fusion onto ring D were prepared by condensation reactions on iminothio ethers 55 . N

HO O N

O

N H

febrifugine

R N SMe

N H 55

CO2H

O AcOH

N

NH2 reflux 24h

N H

N

R

rutaecarpine (R =H) 85% yield

Malayamycin A has been synthesised by a lengthy route, starting with the reaction of a protected ribonolactone with a lithiated pyrimidine . A much shorter synthesis of the fused quinazoline asperlicin D involved direct cyclisation of a diamide .

399


O OMe

O O

O

OMe O

Li

O

N N

O

O NH

O

3 steps

NH

O H OH malayamycin A

N

NH2 O NH

O

NH H

O OMe

H N

H N

H2N MeO

22 steps

MgCl2, DMF CO2Me

O

130 °C

O

NH

N

O

O 35% yield

N H

N H

asperlicin D

The synthesis of both enantiomers of vasicinone has been carried out using almost entirely polymer-supported reagents. The route was based on functionalisation of deoxyvasicinone by a highly selective bromination then via enantioselective reduction of the derived ketone . O

O

O PPh2

N

N

N 98% yield

N3

O

NMe3+Br3−

N

N Br

99% yield

3 steps O

O N

similarly 10S-vasicinone N OH 10R-vasicinone

NaBH4, TMSCl

N

Polymer-supported chiral ligand

N

Me2N

N

OMe

O HN

NH2.HCl

BnHN

N OH

N

N N

N

N

O

.

79% yield

N BnHN

OH

N

variolin B2

N N NH2

N

NH2

NH2

N

N

N H2N

NH2

N

K2CO3

N

N

N

OMe

NH2 NMe2

O

87% yield

N H2N 56

N N NH2

400

K. Mills

Some analogues of the marine alkaloid variolin B2 were prepared as potential cytotoxic agents. The compound 56 is particularly interesting as its synthesis included the simultaneous formation of two pyrimidine rings .6.2.4.2 Reactions Two examples of pyrimidines 57, 58 were included in a study of direct magnesiation of heterocycles. Both of these metallated selectively at C-4 using “inverse addition” i.e. substrate added to the metallating agent .

Br

57

N MgCl.LiCl

N

−55 °C to −40 °C (inverse addition)

N

I

MgCl.LiCl Br

I2

N

Br

67% yield N

N

Ar

MgCl.LiCl

similarly N 58

N

N

OH

4-C6H4CHO

N Cl

N

Cl

N N

68% yield Cl

Conditions for the magnesium-iodine exchange in 5-(4-iodophenyl)pyrimidine with isopropylmagnesium chloride have been optimised. It was found that addition of bis-[2-(N,Ndimethylamino)ethyl] ether greatly inhibited the major side reaction, addition to the pyrimidine ring . Selective halogen exchange at C-5 of 5,6-dibromo-2,4dimethoxypyrimidine 59 was carried out using isopropylmagnesium chloride. The second bromine also exchanged, but much more slowly, allowing a clean “one pot” sequential replacement of both .

OMe Br Br

OMe i-PrMgCl, rt; RCHO then i-PrMgCl; R'COCl

N N

OMe

"one pot conversion"

HO

N

O

N N

59 OMe

69% yield

O

Nucleophilic substitution of leaving groups is probably the most important area in pyrimidine reactivity and, in particular, the differential reactivity of C-2 and C-4 is the most investigated topic. The displacement of 2- and 4-sulfide and sulfone groups is referred to in the synthesis section. The selective hydrolysis of 4-amino-2-chloropyrimidines under acidic conditions has been studied in great detail by a process research group . The selective displacement of the 4-chlorine in 2,4-dichloro compounds can be capricious but a much better result was obtained starting with 4-chloro-2-methylthiopyrimidine 60. A displacement of chlorine was followed by oxidation of the methylthio to sulfone and displacement of sulfone

401


Me

Me HN

Cl RNH2, MW

N

5-azabenzimidazole K2CO3

mCPBA

N N

SMe

N

HN

Ph

N

N N

SMe

N

76% yield

88% yield

60

Ph

N

A number of palladium-catalysed reactions of the triflate 61 have been reported but the nucleophilic displacement with primary aliphatic amines was, surprisingly, very slow in refluxing THF (24-92h). However, under microwave irradiation the reactions were very rapid and gave high yields, although even with microwaves, secondary amines and anilines failed to react . Me N O

N 61

Me N

RNH2, MW

N

5-12 min

OTf

O

N N

NHR

A useful investigation has been published on the comparison of the reactions of 6-aryl-2,4dichloropyrimidines towards nucleophilic substitution with amines vs. palladium-catalysed amination. In many cases, the nucleophilic reactions showed moderate selectivity (ca. 4:1) while the corresponding palladium reactions were highly selective (often 98-99%) for C-4, although this was quite ligand-sensitive, with dppb being the ligand of choice . Another study showed modest selectivity for C-4 in 2,4-dichloropyrimidine 62 using tbutylamine, while the Sonogashira reaction showed high selectivity . TMS Cl Sonogashira

N

N

Cl

N

87% yield

62

N

Cl

NHt-Bu t-BuNH2

Cl

N

N

reflux

N

N

Cl

65% yield

NHt-Bu

26% yield

Another example with the same substrate was a highly C-4-selective Negishi coupling (ArZnCl/ Pd) . Cl

n-BuLi, ZnCl2

I

NHBoc

N

NHBoc ArZnCl

N

62 Cl 75% yield

Pd cat

N N

Cl

402

K. Mills

A detailed study of the regioselectivity of Suzuki couplings on 2,4-dihalo- and 2,4,5trihalopyrimidines and some related substrates under microwave conditions has been reported . In another paper, Sonogashira reactions on the 5-bromo-4-chloropyrimidines 63 were, surprisingly, found to be selective for the chlorine, although for the corresponding 5iodo compounds normal selectivity (I>Cl) returned . Another investigation in this area showed that the Suzuki coupling of 5-bromo-2-chloro-4-piperidinylpyrimidine was selective for the C-5 bromine . R Cl Br Me

N

63

Br

Sonogashira

N

Me

X

N N

X

X = NH2 or MeS

There is always interest in the photochemistry of the pyrimidine nucleic acid bases and related simple pyrimidinones, due to its importance in genetic mutation. In addition to damaging DNA, photo-induced reactions may also repair the damage, as in the reduction, by FADH, of the thymine glycol 64 back to thymine . Another report related to repair of DNA involved a model study, by means of the linked dimer 65, of the involvement of tryptophan in the electron-transfer leading to reversion of thymine oxetane adducts . O O HN O

O

Me OH

N

OH

DNA

64

HN

Me

FADH hν

HN O

N

O N

Me O Ph H R O

HN

DNA

65 MeO2C

RN

Other model studies related to DNA photo damage include the photocyclisation of 5 and 6benzyluracils 66, 67 and the related cyclisation of 5-phenylthio uridine, incorporated into a dinucleotide 68 . O HN O

O Ph

N H 66

hν

HN O

O

O hν

HN N H

O

N H 67

Ph

HN O

N H

403


O

O SPh

HN N

O 68

hν

N

O

O

S

HN

O OH

OH

O

P O HO O dGuanosine

O P O HO O dGuanosine

A computational study was concerned with the effect of solvation on the radical ion involved in CDP photolyase enzyme-catalysed reversion of thymine and uracil cyclobutane dimers stimulated by visible light . Photo-induced conversions are also important synthetically. The photocycloaddition of 5substituted uracils 69 with ethylene has been used for the synthesis of 2aminocyclobutanecarboxylic acids. The addition reaction worked well with carbon and fluorine substituents and also with a Cbz-protected amino. However, uracils with other 5nitrogen substituents (NH2, NHBn and NO2) failed, only starting material being recovered. The sequence also worked for the 6-isomers but somewhat less consistently . O R

H2C CH2

NH N H

O

R

NH

hν aq. Me2CO

69

O

N H R Me Ph F NHCbz CO2H

R

0.5M NaOH

CO2H

r.t.

O

R

NaNO2, HCl

CO2H

NH O

Yield 85% 36% 80% 81% 80%

NH2

NH2

R Yield(2 steps) Me 65% Ph 30% F 74%% NHCbz 36% N.R. CO2H (The CbzNH comound also gave 31% amine)

An unusual C-5-alkylation of 6-chlorouracil occurred on attempted displacement of the chlorine by the aminoindane 70. The reacting species was thought to be the stabilised carbonium ion 71, generated by loss of the amino group .

O NH Cl

N H

O

Me2N Me2N

NH

Et3N, DMSO

O 70

NH2

130 °C-140 °C, 4h

Cl

N H 75% yield

Me2N via

O 71

404

K. Mills

Surprisingly mild conditions, using a multi-component reaction with aldehyde, amine and isocyanide, were sufficient for replacement of oxygen by amine at C-2 or C-4 of pyrimidinones. The reaction was thought to proceed via O-alkylation followed by a Smiles rearrangement 72. The method also works with 2-ones and 2-thiols . A more regular direct replacement of oxygen by amines in uracil and other pyrimidinones used BOP 73 as the activating agent . Cy

Et O

Cy CyNC, R2NH2, EtCHO

N Me

N H

R1

N O

R2 N

MeOH, 60 °C Me

N

N

Et R R1

O NH

via ?

89% yield R1 = Ph; R2 = 4-Cl benzyl

N N

72

O O NH N R1

O

NHR2

RNH2 BOP, DBU rt to 60 °C

N

Br N H

N

(Me2N)3P

N

NH Cl

N N O

N

O

N O R1 e.g. R1=Bn, R2=n-Bu 73% yield

N

NH

similarly with

PF6

O

73 BOP

An efficient method has been developed for the conversion of pyrimidine-2-thiol into the sulfonyl chloride 75, which was reacted in situ with amines. A modified method gave the rather more stable (and storable) sulfonyl fluoride 74 . NaOCl, KHF2

N N 74

SO2F

NaOCl, HCl

N N

SH

−25 °C

RNH2

N N

SO2Cl

N N

SO2NHR

75

The use of more polar solvents (acetonitrile, DMF) improved the N:O ratio Mitsunobu alkylation of 3-benzoyl thymine with cyclopentanol . N selectivity in the alkylation of 2-pyrimidinones has been investigated and the rationalised on the HSAB principle . 2-Phenylthioethyl has been used as a protecting group for N-3 of thymidine manipulation of the sugar. It was removed via oxidation to the sulfone .

in the vs. Oresults during

The reaction of N-methyl nitropyrimidinone 76 with aminocrotonates has been used for the synthesis of 4-aminonicotinates. The only example using a dialkylamino crotonate gave a similar yield, but the equivalent reactions using aminoenones and 4-substituted aminocrotonates gave only very modest yields .

405


O O2N

N

NHR

EtO2C

Me

Me

N

NHR

R Pr Ph CH2CH2OH

CO2Et

MeOH reflux

N

76

Yield 88% 48% 80%

(10 other examples)

6.2.4.3 Applications The 5-anthranylpyrimidinone 77 was designed to be a selective sensor for fluoride ion

O N Me

N H

O N H

N H

n-Bu

77

Amino pyrimidine-terminated oligothiophenes such as 78 were components of donor-acceptor photovoltaic devices . O

NH2 N H 2N

N

N

N

S

S

S

S

S N

H2N

O

H 2N

NH2

N

NH2

78

Some peptide sensors were based on binding to the zinc chelate of ligands such as 79, with specific quenching of the fluorescence of nearby tryptophan residues in the peptide . HO2C HO2C

R N

CO2H

N

H N

R N N H

O

N

H N O

N N H

NHBoc

79

A study of the interaction of 6-pyridinium substituted uracil mesomeric betaines 80 with nucleic acid has been reported .

406

K. Mills

O NH N R2N

O

N 80

2-Amino 4,6-dihydroxypyrimidine is a useful ligand for copper-catalysed arylations of other heterocyclic NH .

6.2.5

PYRAZINES AND BENZO DERIVATIVES

A review discussed the use of 3,5-dichloropyrazin-2-one as a versatile scaffold for synthesis . A feature article was concerned with the synthesis of dragmacidins . 6.2.5.1 Synthesis A variation on the usual synthesis of pyrazines, reaction of 1,2-diones with diamines, was the use of the diazabutadiene 81 in place of the dione . In another paper, the same diaza compound 81 reacted with sarcosine methyl ester, in a complex set of reactions, to produce quite good yields of 5-oxy-pyrazine-2-carboxamides 82. The N-methyl was lost and direct aromatisation occurred, presumably, due to cleavage of the N–N bond . R1 R2O2C

N

R3

NH2

R4

NH2

N

81

Me

dihydropyrazine mixture

benzoquinone or Pd-C

R3

N

R1

R4

N

Me

R1 = CO2Me, CONMe2, P(O)(OEt)2 etc NHMe CO2Me

R1 = CONMe2 R1 R2O

2C

N H

NaOEt

N Me

N Me

CO2Me

THF, reflux

Me2NOC

N 82

Me

O N H 44% yield

The thermal rearrangement of 1,2-dialkynylimidazoles gave intermediate cyclopentapyrazine carbenes 83, which then trapped the solvent (benzene) to give a phenylsubstituted products 84 .

407


Ph N

PhH

N R2

R2 80-100 °C

N

:

N

N

38-88% yields

R2 N

R1 83

R1

84

R1

Quinoxalines 85 have been prepared by the reaction of diols with benzene-1,2-diamines in the presence of a ruthenium catalyst . Iodobenzene diacetate has been suggested as a less toxic alternative to lead tetraacetate for the oxidative cyclisation of iminooximes to quinoxaline N-oxides 86 .

NH2

HO

R

HO

R'

OH N

Ph

N

Ph

R

N

R'

85

Ru cat., KOH

NH2

N

PhI(OAc)2

O N

Ph

CH2Cl2, rt

N

Ph

86

A route to an intermediate 87 containing the core system of dragmacidin has been described, which involved the three-point fusion of an indole onto the seven-membered ring . OTIPS

NTs

OTIPS

NTs

N

N N N I

OMe

OMe

O

BnO

N Ac

87

6.2.5.2 Reactions The reaction of pyrazine and quinoxaline with methyl chloroformate and bis-silyl enol ethers gave fused tetrahydropyrazine lactones 88, in an extension of previous work. There was little consistency with the variation of R in the stereochemistry of the products .

408

K. Mills

OTMS R

N

CO2Me R N

OTMS

CO2Me R N O

O N CO2Me

MeO2CCl

N

O

similarly O N CO2Me

88

An interesting iridium-catalysed 5-CH boronation of 2,3-dimethylpyrazine was reported incidentally in a paper mainly devoted to the reaction of pyridines. The product 89 was used in a Suzuki coupling . Selective mono coupling of 2,6-dichloropyrazine with boronic acids, followed by amine displacement of the second chlorine has been used to prepare potential anti-cancer compounds . A full paper has been published on the chelation-driven selective Suzuki coupling of the pyridinium ylides 90 . N

Me

B2pin2, [Ir(cod)(OMe)]2 (2.5 mol%)

N

Me

N

O

Me

L=

B O

t-Bu

t-Bu

Br

S

L (5 mol%), hexane, rt, 16 h N

Me

Pd

N

Me

N

Me

S 89

34% yield

N

N

N N

N

Br

N

Suzuki Br

N N

N

Ar

N

Br

90

An abnormal (tele) substitution of chlorine in both 2,3- and 2,6-dichloropyrazines 91, 92 occurred on reaction with dithiane anion, while morpholine gave the normal ipso-substitution . Another paper described the highly selective ipso monosubstitution of the 2,3dichloro compound by enolates in toluene . S N N

Li S

S

Cl

−78 °C

Cl

91

N

N

N

Cl

N

N O

S

similarly

S

N

Cl

S morpholine

N

73% yield

Cl

N 92

Cl

N

Cl

69% yield

409


6.2.5.3 Applications and structural studies Quinoxaline bis-N-oxides have been investigated as potential anti-cancer agents 93 and anti-trypanosomal agents 94 . In the latter case, a vanadyl complex was prepared in order to increase bioavailability. O O N N O

N

O N

NH Ar

N O

93

CN NH2 V O

2

94

Several papers were concerned with the synthesis of and mechanism of luminescence of Cypridina luciferin and its analogues . The binding of the diuretic amiloride 95 to DNA has been studied . The chiral camphor-derived pyrazine ligand 96 showed monomeric coordination to Cu and Zn, in contrast to the bidentate polymeric behaviour of related earlier compounds . NH2 HN Cl

N

H2N

N

NH O

N 96

amiloride 95 N

NH2

There has been continued interest in the potential of pyrazines for use in materials science and electronics. Studies of the solid state behaviour have been carried out on pyrazine perchlorate and tetrafluoroborate and of alkyl-substituted pyrazine bis-Noxide-TCNE complexes . The crystallisation and self-assembly of derivatives of hexaazatriphenylene (hat) 97, were also of interest, such as the copper complex 98 and tri-benzo compound 99 . Fluorescent hexakis (biphenyl) derivatives have been investigated as “light-harvesting” systems . CN

CN N

CN

N

N

N

NC

N

N

N

N

NC

N

N

N

97

hexaazatriphenylene (hat)

N

Cu1, EtOH

CN CN

L2Cu

OEt

N

EtO

N

N

NC

N

N

CuL2 L2Cu 98

N

CN OEt

410

K. Mills

R N R

N

O

N R=

N

N

N H

N

n-octyl

R 99

The quinoxaline 100, with self-contained donor-acceptor properties, has potential in optoelectronic . Electroactive dendrimeric bis-quaternary salts have been prepared by direct quaternisation of pyrazine using dendrimeric benzyl bromides . R N N R R = C6H4R' or NMeAr 100

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412 06S2799 06S2885 06S3067 06S3835 06SC1503 06SL65 06SL324 06SL375 06SL804 06SL845 06SL861 06SL1394 06SL1437 06SL1586 06SL2403 06SL2507 06SL2609 06SL3185 06T121 06T1158 06T1444 06T2050 06T2380 06T2799 06T5201 06T6272 06T6490 06T6848 06T7552 06T8966 06T9718 06T9726 06T9787 06T9919 06T11714

06T12084 06T12191 06T12351 06TL31 06TL341 06TL353 06TL693 06TL753 06TL1777 06TL1989 06TL2257 06TL3209

K. Mills

V.G. Pawar, W.M. De Borggraeve, Synthesis 2006, 2799 J. Fleischhauer, R. Beckert, W. Günther, H. Görls, Synthesis 2006, 2885 U. Albrecht, H. Reinke, P. Langer, Synthesis 2006, 3067 C-S. Yu, L-W. Chiang, C-H. Wu, Z-K. Hsu, M-H. Lee, S-D. Pan, K. Pei, Synthesis 2006, 3835 R. Zheng; X. Wang; H. Xu; J. Du, Synth. Commun. 2006, 36, 1503 J. H. Lee, B.S. Lee, H. Shin, D.H. Nam, D.Y. Chi, Synlett 2006, 65 O.R. Ludek, C. Meier, Synlett 2006, 324 V.A. Sukach, A.V. Bol’but, A.D. Sinitsa, M.V. Vovk, Synlett 2006, 375 G.N. Zbancioc, I.I. Mangalagiu, Synlett 2006, 804 J. D’Onofrio, L. De Napoli, G. Di Fabio, D. Montesarchio, Synlett 2006, 845 J.M. Large, M. Clarke, D.M. Williamson, E. McDonald, I. Collins, Synlett 2006, 861 C. Gauzy, B. Saby, E. Pereira, S. Faure, D.J. Aitken, Synlett 2006, 1394 N. Nishiwaki, T. Nishimoto, M. Tamura, M. Ariga, Synlett 2006, 1437 F. Buron, N. Plé, A. Turck, F. Marsais, Synlett 2006, 1586 O.A. Attanasi, L. De Crescentini, P. Filippone, G. Giorgi, F. Mantellini, A. Mazzanti, Synlett 2006, 2403 B.V. Lingaiah, G.E.T. Yakaiah, G.V. Reddy, P.S. Rao, Synlett 2006, 2507 A. Kamal, V. Devaiah, N. Shankaraiah, K.L. Reddy, Synlett 2006, 2609 S. Nara, J. Martinez, C-G. Wermuth, I.Parrot, Synlett 2006, 3185 Z. Riedl, K. Monsieurs, G. Krajsovszky, P. Dunkel, B.U.W. Maes, P. Tapolcsányi, O. Egyed, S. Boros, P. Mátyus, L. Pieters, Tetrahedron 2006, 62, 121 S. Buscemi, A. Pace, A.P. Piccionello, N. Vivona, M. Pani, Tetrahedron 2006, 62, 1158 S. Fustero, J. Piera, J.F. Sanz-Cervera, R. Román, B.H. Brodsky, M. Sánchez-Roselló, J.L. Aceña, C.R. de Arellano, Tetrahedron 2006, 62, 1444 C-H. Huang, N.D. McClenaghan, A. Kuhn, G. Bravic, D.M. Bassani, Tetrahedron 2006, 62, 2050 P. Stanetty, J. Röhrling, M. Schnürch, M.D. Mihovilovic, Tetrahedron 2006, 62, 2380 A. Herrera, R. Martínez-Alvarez, M. Chioua, R. Chatt, R. Chioua, A. Sánchez, J. Almy, Tetrahedron 2006, 62, 2799 S. Hanessian, S. Marcotte, R. Machaalani, G. Huang, J. Pierron, O. Loiseleur, Tetrahedron 2006, 62, 5201 K. Mori, S. Maki, H. Niwa, H. Ikeda, T. Hirano, Tetrahedron 2006, 62, 6272 N.J. Saettel, O. Wiest, Tetrahedron 2006, 62, 6490 A. Gambacorta, D. Tofani, M.A. Loreto, T. Gasperi, R. Bernini, Tetrahedron 2006, 62, 6848 H.A. Duong, J. Louie, Tetrahedron 2006, 62, 7552 P.J. Crowley, S.E. Russell, L.G. Reynolds, Tetrahedron 2006, 62, 8966 F. Požgan, S. Polanc, M. Koþevar, Tetrahedron 2006, 62, 9718 P. Shanmugam and P.T. Perumal , Tetrahedron 2006, 62, 9726 S.B. Mhaske, N.P. Argade, Tetrahedron 2006, 62, 9787 D.S. Chekmarev, S.V. Shorshnev, A.E. Stepanov, A.N. Kasatkin, Tetrahedron 2006, 62, 9919 Y. Lu, T. Xiang, M.D. Bartberger, C. Bernard, T. Bostick, L. Huang, L. Liu, A. Siegmund, G. Sukay, G.Guo, M.S. Elipe, W. Tormos, C.Dominguez, K. Koch, L.E. Burgess, T.C. Basil, P. Ibrahim, C. Hummel, Tetrahedron 2006, 62, 11714 S. Rotzoll, E. Ullah, C. Fischer, D. Michalik, A. Spannenberg, P. Langer, Tetrahedron 2006, 62, 12084 X. Li, S. Miltschitzky, A. Grauer, V. Michlová, B. König, Tetrahedron 2006, 62, 12191 A. Chilin, G. Marzaro, S. Zanatta, V. Barbieri, G. Pastorini, P. Manzini, A. Guiotto, Tetrahedron 2006, 62, 12351 J.E. Torr, J.M. Large, P.N. Horton, M.B. Hursthouse, E. McDonald, Tetrahedron Lett. 2006, 47, 31 I.A.S. Walters, Tetrahedron Lett. 2006, 47, 341 A.K. Nadipuram, S.M. Kerwin, Tetrahedron Lett. 2006, 47, 353 N.H. Al-Said, L.S. Al-Qaisi, Tetrahedron Lett. 2006, 47, 693 C. Wu, K. Kawasaki, S. Ohgiya, Y. Ohmiya, Tetrahedron Lett. 2006, 47, 753 A. Hamid, A. Elomri, A. Daïch, Tetrahedron Lett. 2006, 47, 1777 M. Avalos, R. Babiano, P. Cintas, M.B. Hursthouse, J.L. Jiménez, E. Lerma, M.E. Light, J.C. Palacios, Tetrahedron Lett. 2006, 47, 1989 A. Mitchinson, W.P. Blackaby, S. Bourrain, R.W. Carling, R.T. Lewis, Tetrahedron Lett. 2006, 47, 2257 C.D. Smith, K. Tchabanenko, R.M. Adlington, J.E. Baldwin, Tetrahedron Lett. 2006, 47, 3209


06TL3561 06TL3923 06TL4381 06TL4415 06TL4437 06TL4569 06TL4711 06TL4969 06TL5321 06TL5463 06TL5633 06TL6057 06TL6125 06TL6457 06TL7677

06TL8733

413

A.R. Khosropour, I. Mohammadpoor-Baltork, H. Ghorbankhani, Tetrahedron Lett. 2006, 47, 3561 M. Pal, V.R. Batchu, N.K. Swamy, S. Padakanti, Tetrahedron Lett. 2006, 47, 3923 M. Narasimhulu, K.C. Mahesh, T.S. Reddy, K. Rajesh, Y. Venkateswarlu, Tetrahedron Lett. 2006, 47, 4381 S.C. Ceide, A.G. Montalban, Tetrahedron Lett. 2006, 47, 4415 S. El Kazzouli, G. Lavecchia, S. Berteina-Raboin, G. Guillaumet, Tetrahedron Lett. 2006, 47, 4437 T.J. Kucharski, J.R. Oxsher, S.C. Blackstock, Tetrahedron Lett. 2006, 47, 4569 P. Rajakumar, K. Ganesan, Tetrahedron Lett. 2006, 47, 4711 R. Aggarwal, G. Sumran, A. Saini, S.P. Singh, Tetrahedron Lett. 2006, 47, 4969 K. Ohkura, K. Nishijima, K. Sanoki, Y. Kuge, N. Tamaki, K. Seki, Tetrahedron Lett. 2006, 47, 5321 A. Herrera, R. Martínez-Alvarez, R. Chioua, J. Almy, Tetrahedron Lett. 2006, 47, 5463 C.S. Cho, S.G. Oh, Tetrahedron Lett. 2006, 47, 5633 Y. Takahashi, H. Kondo, S. Maki, H. Niwa, H. Ikeda, T. Hirano, Tetrahedron Lett. 2006, 47, 6057 J.X. de Araújo-Júnior, M. Schmitt, P. Benderitter, J-J. Bourguignon, Tetrahedron Lett. 2006, 47, 6125 M.J. Reyes, R. Castillo, M.L. Izquierdo, J. Alvarez-Builla, Tetrahedron Lett. 2006, 47, 6457 K.J. Filipski, J.T. Kohrt, A. Casimiro-Garcia, C.A. Van Huis, D.A. Dudley, W.L. Cody, C.F. Bigge, S. Desiraju, S. Sun, S.N. Maiti, M.R. Jaber, J.J. Edmunds, Tetrahedron Lett. 2006, 47, 7677 J. Zhang, H.E. Morton, J. Ji, Tetrahedron Lett. 2006, 47, 8733

414

Chapter 6.3

Triazines, tetrazines and fused ring polyaza systems Pilar Goya and Cristina Gómez de la Oliva Instituto de Química Médica (CSIC), Juan de la Cierva, 3, 28006 Madrid, Spain e-mail: [email protected]

6.3.1

TRIAZINES

6.3.1.1 1,2,3-Triazines Computational studies of hydrogen bonding complexes between 1,2,3-triazine and water have been carried out . A theoretical study of 1,2,3-triazine in water has been reported . Ternary complexes of europium(III) ions and triazine have been prepared. A complex containing 5,6-diphenyl-(2-pyridyl)-1,2,3-triazine produced efficient electroluminiscence . Oxidation of 1-(alkylamino)pyrazolones 1 allowed the preparation of monocyclic 1,2,3triazin-4(3H)-ones 2, which are a new class of heterocycles . Ph

O

Me Me

H N N O NHR 1

R=H

Ph

O R

N H

N NH

Cu(OAc)2 , MeOH 60-76%

Me Ph

N 2

N N

R

The reaction of 1,2,3-triazolium-1-aminides 3 with propiolate esters led to fluorescent 2,5-dihydro-1,2,3-triazine derivatives 4 in one pot, involving a Huisgen cycloaddition followed by a sequence of rearrangements . These reactions can be carried out in acetone, in water, or under solvent-free conditions.

415


X X

Ph

Ph O

O

N N N N

H OMe

N

Ph

MeO

30-50%

Ph

N

N N

4

X

X 3

6.3.1.2 1,2,4-Triazines A convenient way to modity calix[4]arenes, based on the direct C-C coupling reactions of their phenol moiety with 1,2,4-triazines has been reported . A theoretical study of the tautomerism of 6-substituted 1,2,4-triazin-3-thion-5-one has been carried out . A new complex derived from 5-methoxy-5,6-diphenyl-4,5-dihydro-2H[1,2,4]triazine-3-thione (LH2OCH3) with methylmercury chloride was synthesized and characterized . Complexes of the types LPtCl2 and [L2Pt]X-2 (L=substituted 3(pyridin-2-yl)-1,2,4-triazine) were synthesized and characterized for the first time by X ray crystallography . A one-pot procedure for preparing 3-pyridyl-5-substituted 1,2,4-triazines 7 from αhydroxyketones 5 and 2-pyridyl amidrazone 6 has been described . R

O

H2N

OH

H2N

5

Py N

R

MnO2, Δ 60-70%

N N

6

Py N

7

Substituted 1,2,4-triazines were conveniently prepared in one pot by the condensation of amides and 1,2-diketones followed by cyclization with hydrazine hydrate . A new class of cyclic dipeptidyl ureas, namely 3-hydroxy-6-oxo[1,2,4]triazin-1-ylalaninamides 12, have been synthesized using the Ugi reaction. This reaction involved an αketo-acid acid 8, an isocyanide 9 and semicarbazones 10 to give the Ugi adducts 11, wich were then stirred with sodium ethoxide . O Ar

O R3NC

HO

O 8

9

HN N

NH2 R2 R1 10

Ugi reaction MeOH 3 days 46-73%

Ar O O HN

O

NH2 O

N NH R2 R1 R3 11

Ar

N

O O

N

EtONa EtOH 12 h 53-84%

HN

OH N R2 R1

R3 12

Several 3-mercapto-1,2,4-trizines have been synthesized through the condensation of thiosemicarbazide with diketones under microwave irradiation in a solventless system . The synthesis and cyclocondensation reactions of 3-substituted-5-(2aminobenzyl)-1H-[1,2,4]triazin-6-ones have been reported .

416

P. Goya and C.G. de la Oliva

The reactivity and use of 1,2,4-triazine 4-oxide have been described . Thus, readily available (3-pyridyl)-1,2,4-triazine 4-oxides 13 were used to prepare 2,2'bipyridines 15. The reaction course involves a nucleophilic substitution of hydrogen and an aza Diels–Alder (DA) reaction . Ar H

N

N

N O

NuH RCOCl 28-56%

Py

Ar

N

Nu

N

Ar

2,5-norbornadiene

N

Nu

82-90%

Py

14

N

Py

15

13

The first case of the use of amino acids as chiral auxiliaries in nucleophilic addition to triazinones was employed in the reaction of C-nucleophiles with 3-aryl-1,2,4-triazin-5(4H)ones 16 and N-protected amino acids 17, to form 1-acyl-6-Nu-3-aryl-1,6-dihydro-1,2,4triazin-5(4H)-ones 18 in high diastereomeric excess .

O

H N N

OH

Ar O

N

H N

R2

R1

16

O

H N

Nu

N

NuH 14-18%

Ar N H N

O

17

R2

1

R 18

Chiral 4-(1-arylpropyl)amino-3-mercapto-6-methyl-4H-1,2,4-triazin-5-ones were synthesized easily through enantioselective diethylzinc addition to the exocyclic C=N double bond of 4-arylidenamino-3-mercapto-6-methyl-4H-1,2,4-triazin-5-ones . The pyrolysis in the gas phase of 4-benzylidenamino- and 6-styryl-1,2,4-triazine-3,5(2H, 4H)-diones and 6-styryl-2,3-dihydro-3-thioxo-1,2,4-triazin-5(4H)-ones has been studied . The DA reaction of 5-acetyl-3-methylthio-1,2,4-triazine with cyclic enamines has been used in the total synthesis of new indazolo[2,3-a]quinolizine alkaloids . Novel agonist 5HT1A receptor position emission tomography (PET) ligands derived form 1,2,4-triazine-3,5-dione 19 have been synthesized and evaluated in vivo .

O

CH 3 O N N

H 3 11 C

N

O

N N 19

6.3.1.3 1,3,5-Triazines The product of an episulfonium ion-mediated cyclotrimerisation previously reported as a 15-membered ring trilactam has now been shown to be a 1,3,5-triazine . The tautomerism of 2,4-di(benzyloxy)-1,3,5-triazin-6(5H)-one has been studied .

417


Theoretical studies on the nonlinear optical properties of octupolar tri-s-triazines have been carried out . The azide-tetrazole isomerism in several polyazido 1,3,5-triazines and diazido-1,2,4,5tetrazines has been investigated by ab initio quantum chemical methods . The tridentate ligand 2,4,6-tri(2-pyridyl)-1,3,5-triazine has continued to be the basis for different complexes, among other with copper , iron , manganese, zinc and cadmium , and with lanthanoids . A novel ligand N,N'di(2-pyridyl)-2,4-diamino-6-phenyl-1,3,5-triazine (dpdapt) has been synthesized and its reactions with CuCl2 studied . A new versatile family of chelating agents based on bis(hydroxyamino)-1,3,5-triazines, BHTS, has been described . The synthesis of 2,4,6-trisubstituted-1,3,5-triazines has been reviewed . Reaction of an activated form of carboxylic acids 20 with zinc dimethyl imidodicarbonimidate 21 led to 4,6-dimethoxy-1,3,5-triazines 22 in high yields . OMe

MeO O

N

NH

R

Zn

R

N

X

NH

74-95%

N

H2O

OMe

MeO

20

1/2 ZnCl2

N

2

22

(0.5 equiv) 21

1,3,5-triazapentadienes have been used as nucleophilic building blocks with different electrophilic reagents. In the case of aldehydes, the corresponding 1,2-dihydrotriazines were obtained whereas with ketones, depending on the substitution of the starting compounds, either 1,3,5-triazahexa-1,3,5-trienes or dihydrotriazines were obtained . The dealkylative functionalization of tertiary amines 23 with electron deficient heteroaryl chlorides including triazinyl chloride 24 has been published . Efficient and practical reaction conditions were determinated for a range of substrates.

R1

N 3

R2

R Ph R 1 = Me, Et, Bn 23

N

N N 24

N Cl

92-96%

Ph

N N 25

N R3

R2

R 1 Cl

Recent applications of 2,4,6-trichloro-1,3,5-triazine and its derivatives in organic synthesis have been reviewed . The selective replacement of chlorine in cyanuric chloride by the 3,7-dioxa-r-1azabicyclo[3,3,0]oct-5-yl-methoxy group through the Williamson method has been described . The reactions of cyanuric chloride with some amine nucleophiles have been described under very mild conditions . Synthetic strategies to generate 2-aryl- 27, 2-alkyl- 28 and 2-acetylenyl- 29 -substituted 4,6-diamino-1,3,5-triazines from the corresponding 2-chloro compound 26 have been reported .

418


Ar

Cl N

N

Cl

R

Cl O O

EtO

diethyl malonate NaH 0 ˚C to 20 ˚C 25%

N

OEt

3-chloroaniline K2CO3, THF

N N

O

EtO OEt

Cl

R

27

N

N N

HN

14%

R

R

28

26 R=N

N N

HN

80 ˚C, 62%

R

O

Cl N

N

Cl

3-chloroaniline, K2CO3 acetone-water 40 ˚C , 94%

N

N N

HN

DME, Pd(PPh3)4 K2CO3, ArB(OH)2

Cl

O

Ph

Ph H toluene, DIPEA CuI, Pd(PPh3)4, 20 ˚C, 71%

Ph

N

3-chloroaniline K2CO3, THF

N

N HN

33% Cl

R

N

N N

R

29 Cl

The base and acid hydrolysis of sym-triazine mononitriles has been studied . The potassium salt of 2-amino-4-methoxy-6-dinitromethyl-1,3,5-triazines 30 with N2O4 afforded the nitroformaldoximes 31 and the 1,2,5-oxadiazole N-oxides 32 . R2

N

N MeO

R1 N

N 30

R2 N 2O 4

N

N C(NO 2) 2K

MeO

R2

R1 N

O N

N N 56-67% 31

N

N MeO

O

R1

R2

N

N

N

N

N N

N

R1

OMe

N O

O 24-32% 32

OH

N-alkyl-2,4-dioxohexahydro-1,3,5-triazines 33 were oxidized easily with oxygen to the corresponding cyanuric acid derivatives 34 . R N

O R

N

O N

33

R

O2 60-85%

R N

O R

N

O N

O 34

R

419


The wide spectrum of potential activity of 1,3,5-triazines is reflected in the number of publications which have again appeared in 2006. Thus, there have been reports dealing with the in silico discovery of -secretase inhibitors among which s-triazine derivatives were promising lead candidates . The socalled ADATS, 6-alkylthio-4-[1-(2,6-difluorophenyl)-alkyl]-1H-[1,3,5]triazin-2-ones, have been identifed as novel regulators of cell differentation , 2,4-diamino- and 2amino-4-alkenyl-1,3,5-triazines have shown antitumor activity . The optimization of triazinyl amines as non-nucleoside inhibitors of HIV-1 reverse transcriptase has been published . 1,3,5-Triazin-2,4,6-trione scaffolds have been employed as templates to incorporate the pharmacophore requirements of cytosolic phospholipase A2α substrate mimetics . Screening of a chemical library in a DNA helicase assay provided the lead for the synthesis of triaminotriazines with antibacterial activity . The synthesis and antibacterial activity of substituted s-triazines and the SAR of novel antibacterial 3,5-diamino-piperidinyl triazines have been described . A series of 2,4,6-trisubstituted triazines has been synthesized and screened for antileishmanial activity . The application of cyanuric chloride in different organic reactions has been the subject of several papers, including a review . It has been used as a dehydrating agent for the synthesis of isomaleimides and for the synthesis of bicyclic isoxazolines and isoxazoles . It has also been employed as catalyst for the synthesis of thiiranes and oxiranes in solvent-free conditions ; together with nBu4NNO2 for the converssion of alcohols, thiols and trimethylsilyl ethers to alkyl nitriles ; for the synthesis of homoallylic alcohols and amines and to generate in situ HCl, used as an efficient catalyst for the solvent-free Hantzsch synthesis of new dihydropyridines . An efficient single-step procedure for the synthesis of 4,6-diarylpyrimidin-2(1H)-ones 35 promoted by cyanuric chloride and Zn(OTf)2 or Bi(OTf)3 under solvent-free microwave irradiation conditions has been developed . Cl N O

O Ar1

H

Ar2

O

N

O Cl CH 3

H 2N

NH 2

N

N

Cl

Zn(OTf ) 2 or Bi(OTf) 3 microwave

NH

Ar1

Ar2 35

64-94%

Fluorous 2,4-dichloro-1,3,5-triazines have been used as nucleophilic scavengers and as amide coupling agents . The preparation of t-butyl 4,6dimethoxy-1,3,5-triazinylcarbonate (Boc-DMT) and 9-fluorenylmethyl 4,6-dimethoxy-1,3,5triazinylcarbonate (Fmoc-DMT) and their usefulness as N-protecting reagents for amines has been rerported . The use of 1,3,5-triazine-based synthons in supramolecular chemistry has been reviewed . The synthesis of bis(triazine) molecules capable of acting as synthetic receptors for barbiturate guest molecules has been described . Two series of triazine-based dendrons were efficiently prepared by a convergent method and their properties studied . A practical syntheis of [1,3,5]triazine dendritic molecules on solid supports has been described .

420


A number of tetraazacalix[2]arene[2]triazines bearing substituents on the bridging atoms were synthesized using a fragment coupling strategy . Nonmesomorphic as well as mesomorphic V-shaped acids with a structure similar to banana liquid crystals, have been complexed to a 2,4,6-triamino-1,3,5-triazine derivative . The organic inclusion compound 2,4,6-tris-(4-bromophenoxy)-1,3,5-triazine was used to create an ordered arrangement of endohedral fullerenes in a crystalline host matrix . Organic-inorganic hybrid gels based on s-triazine have been prepared from chlorosilanes by exchange reactions . 1,3,5-Triazines having oligo(1,4-phenylvinylene) chains in the 2-, 4- and 6-positions have been synthesized and exhibit strong push-pull effects . The synthesis and crystal structures of di- and triorganotin(IV) derivatives with 6-amino1,3,5-triazine-2,4-dithiol have been reported . Self-assembled hexanuclear arene ruthenium metallo-prisms with 2,4,6-tripyridyl-1,3,5triazine (ppt) subunits showed unexpected double helical chirality .

6.3.2

TETRAZINES

A new electrofluorescent switch was prepared with an electroactive fluorescent tetrazine blend of polymer electrolyte . The structure and magnetic properties of the stable oxoverdazyl free radical 6-(4-acetamidophenyl)-1,4,5,6-tetrahydro-2,4-dimethyl1,2,4,5-tetrazin-3(2H)-one has been reported . The synthesis and characterization of two new tetrathiafulvalene (TTF) derivatives bearing pyridine-based substitutents and 1,5'-dimethyl-6-oxoverdazyl radicals have been described . New high-nitrogen materials with 3-amino-6-nitroamino-tetrazine (ANAT) as the anion have been synthesized and their properties studied . The reaction of 3,6-diaryl-1,2,4,5-tetrazines (aryl = phenyl, 2-furyl or 2-thienyl) with 2 equivalents of Ru(acac)2(CH3CN)2 resulted in reductive tetrazine ring opening to yield diruthenium complexes . Complexes involving the 3,6-bis(2-pyridyl)-1,2,4,5-tetrazine (bptz) ligand have been obtained . The unusual reaction of cyanoacetic acid esters with s-triazine monoazides afforded derivatives of a novel coupled heterocyclic system: 2-[1,3,5]triazin-2-yl-1,2dihydro[1,2,3,4]tetrazine-5-carboxylic acid esters . A series of tetrahydro-1,2,4,5-tetrazinan-3-ones have been prepared by the reaction of carbonic acid bis(1-methylhydrazide) with aromatic aldehydes . The synthesis, structure analysis and antitumor activity of 3,6-disubstituted-1,4-dihydro1,2,4,5-tetrazine 36 derivatives have been described . R sulf ur RCN

N 2 H4 x H2 O

EtOH

N HN

NH N

R 32-85% 36

Δ EtOH

N N R

R Cl Cl

N 2 H4 x H2O

421


The inverse electron demand DA reaction of 1,2,4,5-tetrazines has continued to be the most important reaction of this system. The cycloaddition reactions of the novel 3-methylsulfinyl-6-methylthio- 37 and 3(benzyloxycarbonyl)amino-6-methylsulfinyl- 38 -1,2,4,5-tetrazine to afford the corresponding pyridazines 39-40 proceeded with a regioselectivity opposite to expected and complementary to that observed for the corresponding sulfides . O H3 C S

SCH3

SCH3

R 54-96% R 39

R2 N R2 O

R

N N

H3 C S

N N

H3 C S

N N 37 O

O

OR 1

N N

NHCbz

R

N N 38

N N

H3 C S

NHCbz R 34-83% 40

The cycloaddition of acetylenes to 3,6-di(pyridin-2-yl)-1,2,4,5-tetrazines to give the corresponding di(pyridin-2-yl) pyridazines was considerably accelerated under microwave assisted conditions . The [4+2] cycloaddition of dimethyl-1,2,4,5-tetrazine-3,6-dicarboxylate 41 with ketene N,O-acetals or cyanamide yielded tetrafunctionalized pyridazines 42 or 1,2,4-triazine 43 respectively. Treatment of 42-43 with zinc dust in AcOH afforded pyrrole 44 or imidazole 45 derivatives . EWG

CO2 Me N N

N N CO2 Me 41

EtO

NH2

N N

MeO 2C Zn/AcOH

NH 2 CO2 Me

12-98% H2 N

CO2 Me EWG

EWG HN

42

N

44

CO2 Me 93% N N

MeO 2C Zn/AcOH

N

HN NH 2

CO2 Me 43

NH 2

MeO2 C

N

87%

NH 2

MeO2 C 45

Other examples of the use of 1,2,4,5-tetrazine derivatives in [4+2] cycladditions have been reported . Conformationally restricted 6-isoxazol-5-yl-6,7-dihydo-5H-[1,2]diazocin-4-ones were synthesized from 1,2,4,5-tetrazines and isoxazolylcyclobutanone . The reaction of thietan-3-one 46 with 1,2,4,5-tetrazines 47 gave 4H-pyrazolo[5,1c]thiazines 48 via a rare anti-Michael addition .

422


Ph

Ar N N

S

O

Ph

O

Ph

ROH

N N

S

Ar 47

46

S

N N

Ph

KOH

Ph OH

Ph

Ar

Ar

N N Ar 52-56% 48

Ar

The hetaryl displacement in 3,6-disubstituted 1,2,4,5-tetrazines with anhydro bases of Nmethylquinaldiniums has been described .

6.3.3

FUSED [6]+[5] POLYAZA SYSTEMS

6.3.3.1 Triazino and tetrazino [6+5] fused systems The synthesis and biological activity, as vascular endothelial growth factor (VEGF) inhibitors, of a series of substituted pyrrolo[2,1-f][1,2,4]triazine derivatives have been reported . Novel synthetic routes for the preparation of previously inaccesible 2,3,7-trisubstituted pyrazolo[1,5-d][1,2,4]triazines have been described and their affinity for the GABAA benzodiazepine binding site studied . Imidazo[1,2-b][1,2,4]triazines, imidazo[1,2-d][1,2,4]triazin-8-ones and imidazo[2,1f][1,2,4]triazin-8-ones have also been synthesized as agonists of the GABAA benzodiazepine receptor . The synthesis, crystal structure and anticancer activity of derivatives of ethyl and methyl (tetrahydroimidazo[2,1-c][1,2,4]triazin-3-yl) formate and acetate have been reported . The synthesis of the pyrazolo[4,3-e][1,2,4]triazine 52-53 family of natural products, fluvine A, pseudoiodinine and nostocine A have been reported .

N

H N

O

N

CO2Et

H 2N

POCl3, PhNMe2 [PhCH2NMe3]+Cl-

N

MeCN, Δ

N

Cl

N

CO2Et

Boc

H N Boc

N

EtOH, Δ

49

i. CF3CO2H CH2Cl2 ii. KOH, MeOH

N

N

H N NH

N 35% O 51

TMSCHN2 MeOH:MeCN 4:9

N

N

H N N

N

H N NH

CO2Et N 47% 50 Me N N

N OMe 18% 52 Identical to fluviol A and normethylpseudoiodinine

N NH

N O 4% 53 Identical to nostocine A

Pyrazolo[4,3-e][1,2,4]triazine derivatives have been prepared from oximes of 5-aryl- and 5-formyl-1,2,4-triazines . Novel pyrazolo[5,1-c][1,2,4]triazines incorporating an N-(2-oxoethyl)phthalimide moiety have been reported .

423


The synthesis and structures of 6-amino-1,2,4-triazolo[3,4-f][1,2,4]triazin-8(7H)-one derivatives and of dihydrotetrazolo[5,1-c][1,2,4]triazines have been described . Pyrazolo[1,5-a][1,3,5]triazines 58 were obtained by an efficient one-step reaction from iminodithiocarbonates 54 and pyrazole 55, or by an alternative two-step reaction form the aroyl isothiocyanates 56 and pyrazole 55 . O Ar

HN N

SEt N

SEt

54

Me

H 2N

DMF, Δ 61-90%

55

Ar

O Ar

N C S 56

HN N

Δ Me MeCN

H 2N 55

70-96%

N HN H N NH

Ar O

S

N N

N

Me i.NaH, EtBr DMF, rt ii. DMF, Δ

EtS

Me

N 58

75-90%

57

The synthesis and biological activity of 1,2,4-triazolo[1,5-a][1,3,5]triazines (5-azapurines) has been reviewed . Novel three-component reactions of thiazole Schiff bases, ammonium acetate and aromatic aldehydes under solvent-free microwave irradiation conditions yielded diastereoselectively thiazolo-s-triazines . Aminomethylation of 2-amino-5,5-bis(hydroxymethyl)-1,3-thiazol-4(5H)-one and its spiro analogs gave the corresponding [1,3]thiazolo[3,2-a][1,3,5]triazine derivatives . Condensed tetrazolo[1,5-a][1,3,5]triazin-7-ones have been prepared from the corresponding 4-azido-1,3,5-triazines . 6.3.3.2 Purines and related structures The number of publications under this heading is considerable, even through purine nucleosides and related structures have not been included. A general and efficient solid-phase synthesis of N-9-substituted 2,8-diamino purines 62 has been described. The key synthetic transformation uses a carbodiimide-mediated cyclization of a thiourea 60. The reaction was performed using microwave reaction conditions on solid phase .

424


H N

S NH 2

N L

N

N R1

R2

N

CH 2Cl2, 80 ºC microwave

L

N R

N 1

59

N

N L

N H

ArNCS, DMF

N

N

R1

N R2

Ar NH TFA, CH CN 3 HN R1

61

N H

DIC, CH 2Cl2

R2

DMF, EtOH, 25 ºC

60

N

N

25 ºC

Ar

NH

N

Ar NH

N R2

55-81% 62

A regiospecific strategy to N-7-substituted purines 65 and its application to a library of 2,6,8-trisubstituted purines has been reported. The three-step synthetic strategy involves cyclization reactions of suitably substituted pyrimidines 63 with either a carboxylic acid or an aldehyde . SAr N R

N

H N

SAr R1

NH 2

R 2 CO2 H or R 2CHO

N R

64

N

R4

i. mCPBA R2

N

N

61-95%

63

R3

R1 N

N ii. R3 R4 NH

R

R1 N R2 N

N

33-90%

65

A practical synthesis of 2-arylamino-6-alkylaminopurines from 2,6-dichloropurine by base-assisted substitution of the 6-chloro substituent with cyclobutylamine followed by a new trimethylsilyl chloride-catalyzed displacement of the 2-chloro group in the intermediate purine with an aromatic amine has been published . Suzuki-type Pd(0) coupling reactions have been used for the synthesis of 2-arylpurines . A microwave-assisted method to prepare novel 8-mercapto-3-methyl-7-alkyl xanthines 68 has been reported. Compared to conventional synthetic routes, the new method has significantly shortened synthetic steps and reaction time . O

O Br O

NH2 CH3 66

RNH 2 microwave, 120 ºC, 10 min O 71-81%

CH3 67

O NHR

EtOC(O)SK

NH2

microwave, DMF, 120 ºC, 10 min 73-97%

R N SH N

O CH3 68

Direct C–H arylation of purines in position 8 by diverse aryl iodides has been achieved with Pd catalysis in the presence of CuI and Cs2CO3. The methodology is general and efficient and was applied in the consecutive regioselective synthesis of 2,6,8-trisubstituted purines bearing three different C-substituents in combination with two cross-coupling reactions

425


. Treatment of 6-(heteroaryl)purines 69 with NaH followed by alkyl iodides gave regiospecific N9 alkylation derivatives 70 . N X

N X R

N

N ii. R1 I

N H

N

H

N

i. NaH, DMF

N

N Y

R

H

N

Y

N R1

N

83-97%

69

70

The selective magnesiation of chloro-iodo purines which represents an efficient approach to new purine derivatives has been published. Both 6-chloro-2-iodo-purine 71 and 2-chloro-6iodo-purine 72 undergo a selective I/Mg exchange reaction with i-PrMgCl at -80 ºC, thus, 6chloro-2-(phenylhydroxymethyl)-purine 73 and 2-chloro-6-(phenylhydroxymethyl)-purine 74 were synthesized. However, the reaction course at 0 ºC was different. Magnesiation of 6chloro-2-iodo-purine 71 proceeded with the migration of magnesium to the 8 position of the purine nucleus. In the case of 2-chloro-6-iodo-purine 72, substitution of iodine by an alkyl group from the Grignard reagent together with a Cl/Mg exchange reaction took place. Finally, the reaction with aldehydes afforded the corresponding alcohols 6-chloro-8(phenylhydroxymethyl)-purine 75 and 6-alkyl-2-(phenylhydroxymethyl)-purine 76 . Cl N R1

N OH

N R

ii. R1 CHO 48-85%

N N

N 74 R

N

N

N R

N

I

71

OH

N Cl

N

73

R1

Cl

Cl i. i PrMgCl, THF -80 ºC

I i. i PrMgCl, THF -80 ºC ii. R1 CHO 50%

N Cl

N 72

i. i PrMgCl, THF 0 ºC

N

ii. R1 CHO

N

47%

N

i. R 1MgCl, THF -80 ºC to 0 ºC

N R

ii. R2 CHO 54-68%

N

R1

N R

OH

75

R1 N

N HO

N R2

76

N R

The cyclization and rearrangement products from the coupling reactions between terminal O-ethynyl(hydroxymethyl)benzene and 6-halopurines have been described . In a report dealing with the synthesis and anticancer activity of (6'-substituted)-7- and 9(2,3-dihydro-5H-1,4-benzodioxepin-3-yl)purines, transformations of N9'-alkyl-6'-halopurines have been described . Several reports have dealt with biological properties of purine derivatives: a general review ; 2-arylpurines as CdK inhibitors ; 2,6-disubstituted and 2,6,8-trisubstituted purines as adenosine receptor antagonists ; 2,8,9trisubstituted purines as TNF-α inhibitors ; 6-substituted purines as antileishmanial agents ; purine derivatives incorporating metal chelating ligands as HIV integrase inhibitors and purine-based derivatives as inhibitors of the heat schock protein 90 .

426


Several papers dealing with xanthine-based compounds as adenosine A receptor antagonists have been published: 1,3,8- and 9-substituted 9-deazaxanthines as human A2B adenosine receptor antagonists ; 1,3-dipropyl-8-(1-heteroarylmethyl-1Hpyrazol-4-yl)xanthine derivatives as high affinity and selective A2B adenosine receptor antagonists ; norbornyllactone substituted xanthines as adenosine A1 receptor antagonists ; 1- and 3-[1-(2-hydroxy-3-phenoxypropyl)]xanthines as A1 and A2 adenosine receptor antagonists ; tricyclic imidazoline derivatives as potent and selective adenosine A1 receptor antagonists and tricyclic arylo-, imidazo-, pyrimido- and diazepinopurinediones with affinity for the adenosine A2A receptor . A convenient regioselective one-pot approach to pyrazolo[1,5-a]- and imidazolo[1,2a]pyrimidine derivatives 79 from aminoheterocycles 78 and α,β-unsaturated imines 77, generated in situ, has been described .

EtO O P EtO 1

Ar CN

Ar 2

NH Ar

R

Ar2 CHO

1

O

P

H N N

NH 2 78

N

R N

OEt OEt

Ar 2

Ar 1

NH 77

52-76%

N

Ar 1 79

Microwave-assisted regiospecific shyntesis of 2-trifluoromethyl-7-trihalomethylated pyrazolo[1,5-a]pyrimidines has been reported . A one-step synthesis of pyrazolo[1,5-a]pyrimidine via an intermolecular aza-Witting reaction has been achieved . The synthesis of new pyrazolo[3,4-d]pyrimidine derivatives and their activity as potent antiproliferative and proapoptopic agents has been reported . A series of antimicrobial pyrazolo[3,4-d]pyrimidines containing 8(trifluoromethyl)quinoline have been synthesized from 5-amino-1-[8(trifluoromethyl)quinolin-4-yl]-1H-pyrazole-4-carboxylate and 4-carbonitrile . A test library with three novel p38α inhibitory activity has been prepared, among them pyrazolo[3,4-d]pyrimidine and pyrazolo[3,4-b]pyrazine with potent in vivo activity . A convenient route for the synthesis of pyrazolo[3,4-d]pyrimidine involving Friedländer condensation of 5-aminopyrazole-4-carbaldehyde with formamide or benzamide has been reported . A facile synthesis of pyrazolo[3,4-d]pyrimidines and pyrimido[4,5-d]pyrimidin-4-one derivatives has been published . Pyrazolo[4,3-d]pyrimidines have been prepared as inhibitors of coagulation factor Xa , as cannabinoid receptor CB1 antagonists , as selective PDE5 inhibitors and as analogues of myoseverin with antiproliferative activity . Triazolino[4,3-a]pyrimidines, pyrazolo[3,4-d]pyridazines and isozazolo[3,4-d]pyridazines have been synthesized from hydrazonoyl chlorides . A novel tricyclic piperidine-fused pyrazolo[1,5-a]pyrimidin-7-(4H)-one has been synthesized with regioselective formation of the tricyclic core structure .

427


6.3.4

FUSED [6]+[6] POLYAZA SYSTEMS

Molecular orbital calculations have been used to analyze the stabilities of dihydropterins . The photochemistry of 6-(hydromethyl)pterin in aqueous solution has been investigated . A new synthesis of pterins based on the acylation of 4-amino-5-nitrosopyrimidines with dienoic acid chlorides, followed by a high-yielding intramolecular hetero DA cycloaddition and cleavage of the N⎯O bond has been reported . Several new substituted pterins have been obtained in an efficient one-pot procedure using N,N'dimethyldichloromethyleniminium chloride (phosgeniminium chloride) and a suitable pyrazine . Pteridines have been prepared in good yields from 6-amino-5-nitrosouracils with Meldrum’s acid in the presence of piperidine as catalyst under thermolytic conditions . Novel 6-formylpterin derivatives have been synthesized and their neuroprotective effects studied . The synthesis of 4-trifluoromethylpyrimido[4,5-c]pyridazin-5,7-diones from 6hydrazinouracils and 1,1,1-trifluoropropane-2,3-dione monohydrates has been reported . Novel pyrimido[4,5-c]pyridazines have been synthesized and investigated as inhibitors of lymphocyte specific kinase . Reaction of 3-alkylamino-6,8-dimethylpyrimido[4,5-c]pyridazin-5,7-diones 80 with cyclohexyl and cycloheptylamines afforded novel cycloalkano bis(pyrrolo[2,3c]pyrimido[5,4-e]pyridazines 81 . NH2 Me O

Me N O

O

O

H N

N N Me 80

N

N

R

n n = 1,2 AgPy 2MnO4 6-13%

Me

O

Me N

n

N N

N

N R

N R

O N

N

Me

N

81

Electron-rich 6-[(dimethyl(amino)methylene)amino uracil 82 underwent [4+2] cycloaddition reactions with various in situ generated glyoxylate imine and imine oxides to afford novel pyrimido[4,5-d]pyrimidine derivatives 83-84 after elimination of dimethylamine from the (1:1) cycloadducts and oxidative aromatization. This one-pot procedure yielded excellent yields when carried out in the solid state and under microwave irradiation .

428


O

OEt

O

H

O Me

ArNH 2 O Me O

Δ microwave 83-95%

N Me N Me

N Me 82

O

Et

N

N N Me

O

Ar

N 83

Δ microwave

O

Ar

Me N

Pn O 80-90%

O

Ar

N

N N Me

Ph

N 84

Within an SAR study of p38 MAP kinase inhibitors, a series of 3,4-dihydropyrimido[4,5d]pyrimidin-2-ones and 3,4-dihydropyrido[4,3-d]pyrimidin-2-ones were prepared . Coordination frameworks of pyridazino[4,5-d]pyridazine have revealed a pronounced ability for anion π interactions . In a report dealing with novel classes of GABAA receptor benzodiazepine binding site ligands, pyrazino[2,3-d]pyridazines were prepared using an aza Wadsworth-Emmons cyclization as the key step . The formation of pyridazino[4,5-c]pyridazine derivatives upon [4+2] cycloaddition of 4-phenyl-1,2,4-triazoline-3,5-dione to crossconjugated monoferrocenyltrienes has been reported .

6.3.5

MISCELLANEOUS

Pyrimido[3',2':4,5]thieno[3,2-d]pyrimidinones reacted with hydrazonoyl halides in dioxane and triethylamine to give the corresponding tetracyclic fused tetrazines . The electrochemical oxidation of catechols in the presence of 6-methyl-1,2,4-triazin-3thion-5-one and 4-amino-6-methyl-1,2,4-triazin-3-thion-5-one as nucleophiles in aqueous solutions provided an efficient electrosynthesis of thiazolo[3,2-b][1,2,4]triazin-7-one and 1,2,4-triazino[3,4-b]1,3,4-thiadiazine derivatives respectively . Isoindolo[2,1-c]benzo[1,2,4]triazines 85 have been described as a new ring system with antiproliferative activity . R1

O H H O

CN R 4 2

H 2N

R

NaNO 2

KCN R2

N H 2N R

4

CN R 4

R3

R3 NaHSO3 40-95%

H2 N

R1

AcOH 84-98%

R3 R2

N N N 85

R1

Structurally related sets of triazinoquinoline, triazinoisoquinoline and pyridotriazine derivatives have been synthesized and their binding to benzodiazepine receptors studied . Pyridazino[3’,4’:3,4]pyrazolo[5,1-c]-1,2,4-triazines have been prepared and their antimicrobial activity evaluated .


429

An efficient one-pot synthesis of tetracyclic fused 1,2,3triazine[4'',5'':4',5']thieno[3',2':4,5]thieno[3,2-d]-1,2,3-triazines has been described . The synthesis and biological studies of a new series of pyrazolo[4,3-e][1,2,4]triazolo[1,5c]pyrimidines as antagonists of the human A3 adenosine receptor have been reported . The solid phase parallel synthesis of tetrahydroimidazo[1,2-a][1,3,5]triazepin-2-thiones and 2-imines has been reported starting from resin-bound peptides . Pyrazolo[1',5':1,6]pyrimido[4,5-d]pyridazinones with potent and selective phosphodiesterase 5 (PDE5) inhibitory activity have been described

6.3.6

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436

Chapter 6.4 Six-membered ring systems: with O and/or S atoms

Unfortunately, due to unforeseen and unfortunate circumstances, the regular chapter on ‘Six-membered ring systems: with O and/or S atoms’ does not appear in this volume. We apologise for this omission. We anticipate that PHC 20 will include a double chapter on this area, covering the literature of 2006 and 2007.

437

Chapter 7

Seven-membered rings John B. Bremner Department of Chemistry, University of Wollongong, Wollongong, NSW 2522, AUSTRALIA [email protected] Siritron Samosorn Department of Chemistry, Faculty of Science, Srinakharinwirot University, Bangkok 10110, THAILAND [email protected]

7.1

INTRODUCTION

The chemistry and biological activities of seven-membered heterocyclic systems continued to command significant attention in 2006. In this chapter both fused and non-fused heterocycles are addressed with an emphasis on N, O, and S as the heteroatoms in the seven-membered ring components. Reviews which include some treatment of these heterocyclic derivatives have been published covering ring-closing metathesis of heteroatom substituted dienes , and a review of the pyrrolo[1,2-a]azepine-based Stemona alkaloids . A detailed review on synthetic approaches to oxepines has also been published .

7.2

7.2.1

SEVEN-MEMBERED SYSTEMS CONTAINING ONE HETEROATOM

Azepines and derivatives

Detailed computational studies have been reported on 5-azatropolone and 1H-azepine-4,5dione and related isoelectronic homologues and isomers . A novel electrophilic reaction of the 2-methoxyazepinium ion 2, formed in situ from 1 on treatment with TiCl4,was observed in the presence of benzene to give 3, 4 and 5. The kinetics of the isomerisation (k1, k2, k3) of the 4H-azepine 3 to 8 via 6 and 7 were also reported .

438

J.B. Bremner and S. Samosorn

Ph

TiCl4

Ph-H +

iPr

O

N

N

OMe

OMe

N

2

1

OMe

3, 43% Ph

+ N

Ph

N

OMe

4, 49%

Ph

Ph

N

5, 3%

Ph

Ph

k2

k1 N

OMe

k3 N

OMe

N

OMe

7

6

3

OMe

OMe

8

Satake et al. reported further detailed studies on the chemistry of 2H-azepines highlighting a [1,5] sigmatropic hydrogen shift and also an unusual [1,5] sigmatropic propylthio shift on heating 9 to afford 10 and 11 respectively; kinetic measurements were consistent with a concerted process for the propylthio shift . R

R

R

Δ H PrS

N

OMe

PrS

9

SPr

+ N

N

OMe

10

a: R = t-Bu b: R = Me

OMe

11

Access to the 4,4´-disubstituted azepine derivatives 14 was achieved in good yield by ring closing metathesis on the dienes 12 using the Grubbs II catalyst 18; the diene precursors 12 could be made in racemic or optically enriched form from α,α´-disubstituted lactone precursors . Removal of the N-protecting group and reduction of the double bond in 13 by hydrogenation then resulted in the azepanes 14. (i) R2 R1

N CBz

(ii) N CBz

R2 R1

14

13

12 R1 a: Me b: Ph

R2 H Me

NH

R2 R1

75% 83%

R1 a: Me b: Ph

R2 H Me

100% 90%

Reagents: (i), ClCH2CH2Cl, Grubbs II Ru cat., N2, reflux, 82 °C, 5 h; (ii), Pd/C, H2, 50 psi, AcOH, 20 °C, overnight.

439


The power of ring closing metathesis for seven-membered ring synthesis continued to be realised as exemplified by the preparation of the tetrahydroazepines 16 (X = CH2) or 2azepinones 16 (X = CO) from the appropriately substituted precursors 15. Yields were generally good to high (particularly with Grubbs II ruthenium catalyst 18). However, as noted in other 1 2 reactions of this type, amine functionality (15a, R = Bn, R = H, X = CH2) compromised the metathesis process, and a very low yield of 16 was obtained with Grubbs I catalyst 17 and no product at all with the second generation Grubbs catalyst (Table 1); starting material 15 was reisolated in both cases . R1 X N

MeO

(i)

X

MeO

O

O

R2

R2 16

15

P(Cy)3 Cl

R1 N

N

Ru

Cl

N

Cl Ru

Ph

Cl

P(Cy)3 17

Ph P(Cy)3 18

Reagents: (i), Grubbs I or II cat., DCM, 40 °C.

Table 1 Substrate

R

15a 15b

Bn Bn

1

R

2

X

H H

CH2 C=O

Grubbs I cat. 16 yield (%) 8 88

Grubbs II cat. 16 yield (%) 0 90

Inclusion of the amide in oxazolidinone functionality can be used to overcome diene statial disposition issues, for example in the conversion of 19 into 20; yields of 20 were generally high (Table 2). Ring opening of the oxazolidine moiety with or without loss of the mandelic acid moiety then afforded the corresponding azepin-2-ones . TBSO O Ph

5 mol% Grubbs cat.

N O

R

TBSO O Ph

N

CH2Cl2 (abt 10-2 M)

19 Reagents: (i), Grubbs cat. (5 mol %), DCM (ca 10-2 M).

O

R 20

440


Table 2 19 19a 19b

R H i-Bu

Catalyst 17 18

20, Yield (%) 20a, 91 20b, 78

Other N-substituted and reduced 2-azepinone derivatives 22 can also be accessed in high yields (Table 3) by ring closing metathesis on the precursors 21 using Grubbs II catalyst 18. A variety of N-heteroaryl substitutent groups were tolerated in this reaction . O BocHN

O

R1 BocHN

N R3

R3

Grubbs cat.

R2

R2

21

Table 3 R1 O

R1 N

22

R2 H

R3 H

H

H

10

88

H

H

10

92

Grubbs II cat. (mol%) 5

Yield (%) 90

N

A compact synthesis of the azepinones 24 has been developed based on ring closing metathesis reactions of the α-amino enones 23 . High yields of products were 2 1 2 obtained (for example, 24, R = H, R = Boc, 90%) from (23, R =H, R = Me, R = Boc). The 2 azepinone derivative 24 (R = H, R = (2-Pyr)SO2) was converted into a cathepsin K inhibitor. R N P

R1

O

(i)

O

23 Reagents: (i), Grubbs II cat. (2.5-5 mol%), DCM, heat, 12 h.

R

N P 24

Azepanes and azepanones continue to attract attention synthetically because of their incorporation in compounds of biological significance. A new diastereoselective and enantioselective lithiation – addition methodology has been described to provide access to the azepine precursors 25 (Ar1 = p-BrPh, Ar = p-MeOPh)); these were then converted into 27 via 26, and subsequently to the further substituted azepan-2-ones 30 via 28 and 29 .

441


CH3

CH3

H3C

(i)

Ar Boc CO2Et N

Ar

Ar

H3C N

Ar

(ii)

Ar Boc

CH3 N Ar 27

O O

NH 26 Ar

25

CH3

(iii) Ph

CH3

Ph

CH3

ArH2C

(v)

Ph

CH3 CH3

ArH2C

CH3

(iv)

CH3

N O N Ar Ar 30 28 29 Reagents: (i), Me3Al, p-anisidine, DCM, 83%; (ii), HCl (aq.), CHCl3, 86%; (iii), H2, Pd(OH)2, EtOH, benzene, 96%, dr = 94:6; (iv), a. LDA. b. p-BrC6H4CH2Br, THF, 94%, dr = 98:2; (v), CAN, MeCN, H2O, 62%, dr = >99:1. O

N H

O

As part of the development of an efficient synthetic strategy for the synthesis of the little known 3,5- and 3,6-disubstituted tetrahydro-1H-azepines, ring-closing metathesis of the diene 31 to 32 in high yield was reported . Boc N

Boc N

MeO O

(i)

MeO O

OTBS

OTBS

31 Reagents: (i), Grubbs II cat., 2.5 mol%, 90%.

32

The synthesis of the N-protected 7-methylazepine derivative 34 was achieved in 89% yield by a ring-closing metathesis reaction on 33 mediated by Grubbs I ruthenium catalyst. This azepine was an important precursor for the preparation, via epoxidation of the double bond, of a number of 7-methylazepanone derivatives for evaluation as cathepsin K inhibitors . Me

Me

(i)

NCbz

NCbz 33 Reagents: (i), Grubbs I cat., DCM.

34

A two-carbon ring expansion reaction of 5-membered cyclic enamines gave 6,7-dihydro-1Hazepines on reaction with dimethyl acetylenedicarboxylate .

442


The synthesis of the D-gulonolactam 36 was based on an intramolecular cyclisation /ring enlargement strategy involving reduction of the azido group in 35 followed by intramolecular nucleophilic attack on the lactone moiety to afford 36 in excellent yield . H N

OH O

N3 O

(i)

O

O HO

O

O

HO

35 Reagents: (i), 10% Pd/C, HCO2NH4, EtOAc.

7.2.2

O

36

Fused azepines and derivatives

A palladium-catalysed intramolecular hydroamidation (using 39 as the catalyst) with the amido alkyne 37 proceeded regioselectively in the presence of base (KOH or NaOEt) to provide access to the 3-benzazepin-2-one 38. This reaction can also accommodate other alkynes .

(i)

O

N Me O

NHMe

37

38, 82%; KOH 80%; NaOEt

Reagents: (i), Pd(PPh3)2(OAc)2 39, base, DMF, 60 °C, 16 h. CO2Me Et F

N N H 40

CO2Me

F

N Et

CO2Me

Me H O

MeOH

F

δ+

N H

N H B

A

74% MeO2C N

F N H 41

Et

δ+ N Et

443


Reduced fused azepines (e.g. 40) have been used in a new ring expansion strategy to afford fused hexahydroazoninoindoles (e.g. 41) from reaction with methyl propiolate in methanol to give the ylide intermediate A which then ring expanded via the methanol stabilised intermediate B to give 41 . The imidazo-benzazepine 43 was prepared in moderate yield by a combination reaction sequence involving an initial van Leusen reaction to prepare the imidazole 42 followed by a microwave-promoted intramolecular Heck reaction . CN

SO2Tol

Br +

H2N

Br

(i)

+

Ph

CHO

N N 42

(ii) Ph

N N

43 Reagents: (i), K2CO3, DMF, 60%; (ii), Pd(OAc)2, P(o-tolyl)3, CH3CN, NEt3, 125 °C, 1 h, microwave, 66%.

An intramolecular nitrone 1,3-dipolar cycloaddition reaction to give 46 from 45 followed by reductive N-O bond cleavage afforded a stereoselective synthesis of the tetrahydro 1H-1benzazepines 47; the nitrone precursors 44 were prepared in turn by a Claisen rearrangement from an N-allylamine . R

(i), (ii)

R

R2

N H

R1

44

R2

N O

R1

45

H

OH

R

R

R (iii)

O N

46

a b c

N H

R2

R1 47

R2

R1

H H CH3 H Cl H

R2 H H H

R1

Reagents: (i), 30% H2O2 (3–4 mol), Na2WO4·2H2O (4–6 mol%), acetone–H2O (9:1v/v), 25 °C to –5 °C, 40–50 h, then H2O and extraction with CH2Cl2; (ii), toluene, reflux, 3–4 h; (iii), Zn (6 mol), 80% AcOH (excess), 80–85 °C, 2–5 h, 25 °C then 5% NH4OH solution and extraction with EtOAc.

444


Dynamic thermodynamic resolution in a lithiation substitution reaction sequence was used to provide access to the amino ester 48 which could then be converted, via 49 and 50, into the chiral substituted 1-benzazepine derivative 51 . O

CO2CH3 Ph NH2

(i)

HN

Ph

Ph

Ph 49

48 O HN

(ii), (iii)

CH2Ph Ph

CH2Ph HN

(iv)

Ph

Ph Ph

51 50 Reagents: (i), AlEt3, 94%; (ii), n-BuLi; (iii), PhCH2Br, 79%; (iv), BH3, 91%.

Acid catalysed rearrangement of the tetrahydro 1-benzazepine sulfonamides 52 gave the 9substituted sulfone derivatives 53 plus, in the case of 52b, the 7-substituted isomeric derivative 54 . R1

R1 (i)

N H

N O S O R2

O S O R2

+

O NO2

S

O

N H 54

52 53 a: R1 = H; R2 = H a: R1 = H; R2 = H b: R1 = H; R2 = NO2 b: R1 = H; R2 = NO2 Reagents: (i), 98% H2SO4 at 105 °C for 20 min then pour over ice.

A compact approach to the 1-phosphonylated 2-benzazepine 56 was achieved based on a ringclosing metathesis reaction on 55 using Grubbs II catalyst .


445 Ph

(i) N Bn

N Bn

(MeO)2(O)P

P(O)(OMe)2

55 Reagents: (i), DCM, styrene (5 eq.), , 4 h, N2, Grubbs II cat. (10 mol%), 78%.

56

Poly(ethylene glycol) (PEG) was used as a soluble polymeric support in the efficient preparation of the 2-benzazepine 58 via a phosphine-free palladium-catalysed Heck reaction from 57 . Br

COOMe Ph

57

(i)

N R

Ph N

COOMe

R 58

R = PEG-N-(CH2)4-Si(Me)2-CH2CH2SO2 Ts Reagents: (i), Pd(OAc)2, K2CO3, PEG-3400-OH, 80 °C, 12 h, 100%.

The binaphthyl azepinium salt 59 (TT= tris(tetrachlorobenzenediolato)phosphate(V)) and corresponding azepine 60 were developed as effective catalysts for the enantioselective epoxidation of unfunctionalised alkenes, with enantiomeric excesses up to 87% . TTMe

Me N

N

59

7.2.3

60

Oxepines and fused derivatives

The single crystal X-ray structure of the enantiopure tetrahydro oxepin-2-one 61, a mimic of steroidal androgens, has been reported . A new procedure has been described for the synthesis of substituted furano-fused oxepines based on expoxidation of strained fused cyclobutenes followed by thermal rearrangement .

446


O

Me

O H O

Me 61

A new and useful route to the 3-benzoxepin-2-one 64 involved coupling of the Fischer carbene 65 to the epoxy phenylacetylene 62 to give 64 (46%) via 63. An epoxyvinylcarbene complex is proposed for the initiation of the reaction followed by CO insertion and cyclisation . MeO

MeO Me O

O

O

O

63

62 Cr(CO)5

Reagents: Me

Me O

46%

64

OMe 65, dioxane, reflux, 24 h.

A tandem palladium-catalysed ortho-alkylation/intramolecular Heck reaction coupling sequence was used effectively to access in fair yields the tetrahydro 1-benzoxepines 67 from the iodoaryl precursor 66 and the appropriate alkyl bromide. The norbornene plays a relay role in the proposed reaction cycle CO2Et I O 66

R CO2Et

(i) O 67

a: R = (CH2)3Cl, 47% b: R = (CH2)3COOEt, 45% c: R = (CH2)3Ph, 45% Reagents: (i), Pd(OAc)2 (10 mol%), P(2-furyl)3 (20 mol%), norbornene (4 eq.), Cs2CO3 (2 eq.), R(CH2)3Br (6 eq.), CH3CN, 80 °C, 16 h.

A new BF3-induced stereospecific rearrangement of the epoxy ethers 68 gave the enantiopure tetrahydro 2-benzoxepin-4-ols 69a,b in generally good yields . The enantiomerically enriched compounds 69c,d were also produced.

447


O OCH3

O

(i)

O

HO OMe

OCH3

R

OMe

68

69

R

a: R = H b: R = CF3 c: R = Cl d: R = Ph Reagents: (i), BF3.OEt2 (0.3 eq.), DCM, -78 °C, 15 min.

Ring-closing metathesis has been used effectively to prepare the pyrido[3,2-b]oxepine derivative 71 in good yield from the pyridyl diene precursor 70 . O

O

(i)

N

N

70

71

Reagents: (i), Grubbs II cat. (10 mol%), toluene, 70 °C, 16 h, 71%.

The oxepine-fused beta-carboline 73 was synthesized in good yield (71%) from the diene precursor 72 using ring-closing metathesis and Grubbs I catalyst . (i) N H

O

72

N H

O

73

Reagents: (i), Grubbs I cat. (5 mol%), DCM, rt, 24 h.

The synthesis of the fungal natural product ulocladol (from the marine fungus Ulocladium botrytis) was achieved by three routes, including a two-step sequence involving ring enlargement of the 6-membered ring lactone in 74 to the 7-membered ring system in ulocladol 77. Treatment of 74 with methanol in the presence of base give 76 (via 75 and the oxy anion A) in 82% yield; hydrogenolysis to remove the benzyl groups then gave 77 in 63% yield .

448


OH

BnO

OH OMe

MeO

OMe (i)

OBn

MeO

MeO

OBn

O

OH CO2Me

OBn O

O OBn O

OBn 75

74 HO (ii)

76 BnO

OMe

HO

OMe

HO

OMe

HO

MeO

MeO O OH O

O OMe

BnO O

77 Reagents: (i), K2CO3, MeOH, reflux, 82%; (ii), H2, Pd/C, AcOEt, 63%.

A

A palladium-catalysed carbometallation-alkyne cross coupling cascade process has been reported for the stereo- and regio-controlled synthesis of dibenzoxepines with substituted exocyclic alkene functionality . 7.2.4

Thiepines and fused derivatives

A review covering homologation of heterocycles via lithiation-based reductive ring opening, electrophilic substitution, and cyclization includes applications to 2,7-dihydro benzothiepine derivatives . A neat synthesis of the chiral 10,11-dibenzo[b,f]thiepine 79 from the chiral precursor 78 has been described. Cyclisation of the lithiated intermediate was mediated via reaction with sulfur bis(imidazole) . OMe

MeO Br

OMe

(i), (ii) S

OMe Br

N Reagents: (i), t-BuLi; (ii),

N

78 S

79 N

N

449


7.3

SEVEN-MEMBERED SYSTEMS CONTAINING TWO HETEROATOMS

7.3.1

Diazepines and fused derivatives

Although highly reactive, 2H-azirines are of considerable synthetic interest and serve as a source of the 3-fluoro-4H-1,3-diazepines 86. Reaction of 80 with difluorocarbene in the presence of furfural gave 86, rather than the expected furfural-derived products 83. Rearrangement of the initial 1,3-dipolar intermediate 81 to 84 and then cycloaddition of 84 with 80 are proposed as key steps in the reaction; the intermediate cycloadduct 85 gave 86 on base-induced elimination of HF. Nucleophilic displacement of the fluoro group in 86 provided access to further substituted 1,3-diazepines . CHO CF2 N

Ar

N

Ar

O

H N

F F Ar

(i)

82

O

O 83 Ar

CF2

Ar

N

Ar

N

N F N F

Ar

O

O

CF2

81

80

N Ar

Ar 84

85

O N F

Et3N

N Ar

86

a: Ar = Ph (41%) b: Ar = 4-ClC6H4 (18%)

Reagents: (i), CF2Br2, active Pb, Bu4NBr, furfural, CH2Cl2, 40-43 ºC, 6 h

The 1,4-diazepane 87 has been used as a neutral 6-electron ligand for the support of cationic Group 3 metal (Sc,Y) alkyl catalysts . Me N

Me NMe2

N Me 87

Parallel array synthesis was used to access the 3-aryl-tetrahydro-1,2-diazepines 90 (and other related compounds) by cyclisation of the chloro ketones 88 on reaction with hydrazine to give 89 followed by sulfonamide formation; the Si-TrisAmine® was added at the end as a scavenger to remove any unreacted arylsulfonyl chloride remaining .


450

O

(ii), (iii)

(i)

R1

N N O S O R2

N NH

Cl R1

88

R1

89 a: b:

R1 3,4-Cl2 3-F

90 R2 5-Br-2-thienyl 4-Cl-Ph

64% 82%

Reagents: (i), NH2NH2 (4 eq.), i-PrOH, 75 ºC, 16 h; (ii), R2SO2Cl, PS-DMAP, DCM, rt, 16 h; (iii), Si-TrisAmine

In an extension of previous work on conjugated enamine carbonyl derivatives, reaction of the pyrazolone 91 with N,N'-disubstituted hydrazines on heating in an alcohol solvent afforded the hexahydropyrazolo[4,3-d][1,2]diazepine-8-carboxylates 92 in good yields. While the exact mechanism for the formation of 92 is not known, one possibility, namely a Michael-type addition of the alcohol to a pre-formed pyrazolo-diazepine, was excluded . Ph N N

O

Me2N Me2N

(i) COOEt

91

H H COOEt N R1 N N Ph N R1 O a: 92 b: c:

R2O

R1 Me Me Me

R2 Me 74% Et 81% n-Pr 85%

Reagents: (i), R1NHNHR1, R2OH, reflux.

An elegant two-step solution-phase methodology was developed for the synthesis of the benzodiazepine-2,5-diones (93 ; e.g. R1 = PhCH2, R2 = Me, R3 = Me, R4 = H, R5 = Me, 32%). The first step was a Ugi four-component reaction followed in the second step by a palladiummediated intramolecular N-arylation reaction. This methodology has considerable scope for further application in heterocyclic synthesis . R1-NH2 +

O

O R2

+ R5-NC

R3

(i), Ugi 4 component reaction

+ COOH R4 Br

R1 N

R2

R4

R3

(ii), [Pd], N-arylation

O

R5 93

Microwave-promoted reactions continue to extend their reach in heterocyclic synthesis. Regioselective N4-aminoethylation of the 1,4-benzodiazepin-2-one 94 was observed under microwave conditions in DMF/K2CO3 to afford, for example, 96a and 96b in 64% and 67% yield respectively (Table 4). In contrast, the thermal reaction at 80 °C in DMF with K2CO3 as base gave the N1-aminoethylation products (95a, 65%) and (95b, 76%). These results were


451

rationalised using computer-based calculations of the N1 versus N4 alkylation reaction profiles. Microwave irradiation is suggested to facilitate anion production due to a higher change in dipole moment along the deprotonation pathway with a small preference for the N4 anion D over A/B, although the latter is of lower energy, and fast alkylation then proceeds via E or C . K+ H N

O Route A

O

N

N

CH3

K+

O

CH3

NH

CH3

NH

NH

A

94

B RCl

+ K2CO3

Cl δ K+

R N

R N

δ- O

O

CH3

CH3

NH

NH

C H N

O

95 H N

Route B CH3

O

H N

CH3 N K+

NH

O N δ-

9 D

CH3

R

E

Cl

+ K2CO3

H N

δ- K +

O CH3 N

96

R

Table 4 a b

R (CH3)2NCH2CH2 NCH2CH2

Conditions K2CO3, DMF, 80 °C, 6 h K2CO3, DMF, 80 °C, 7 h

Product (%) 95a (65%) 95b (76%)

Conditions K2CO3, DMF, MW, 90 s K2CO3, DMF, MW, 90 s

Product (%) 96a (64%) 96b (67%)

Reagents and methods for the synthesis of 1,5-benzodiazepine derivatives from ophenylenediamine and carbonyl compounds have attracted an unusually high degree of interest in 2006. Illustrative of this, the condensation of two mol equivalents of acetone with ophenylenediamine 97 was reported on simple grinding of the components in the presence of an organic acid catalyst at room temperature resulting in 98. The yields of 98 were


452

dependent upon the acid used, but with trimesic acid (5 mol%) a 97% yield of 98 was obtained after grinding for 10 minutes. Picric acid also gave a high yield of 98 but use of this latter acid should NOT be recommended in view of the potential hazards. Single crystal X-ray data on the trimesic acid and picric acid salts of 98 were also reported . NH2

H N

organic acid

+

2(CH3)2CO

NH2

rt, grinding

N 98

97

A range of other catalysts and conditions for similar cyclisations to the 1,5-benzodiazepine system have included NBS , ultrasound and APPTS , [BPy]HSO4 acidic ionic liquid , Mg(ClO4)2 , ZnCl2 , CAN , (NH4)H2PW12O40 , YbCl3 , and solvent-free conditions at pH 7 . An intramolecular Pictet-Spengler type cyclisation in the intermediates 100, readily prepared in turn from 99, gave the new dihydropyrimido[4,5-b][1,4]benzodiazepines 101. Yields were generally good to excellent (101, R1 = H, R2 = Pr, 65%) . Cl

R2CHO

NH2

N

+H+

R1 N

N CH3

-H2O

N

Cl H N N

Cl R1

N

H N

R2 R1

N N H3C

N CH3 100

99

7.3.2

R2 H

101

Dioxepines, dithiepines and fused derivatives

In the continuing search for new antimalarial agents, a number of spiroperoxy compounds incorporating a dihydro-2,3-benzodioxepine moiety were designed and synthesised. For example, the spiroperoxy derivative 108 was made from 102 via oxidation and the Wittig product 103. Deallylation of 103 then gave a mixture of 104, 105 and 106, and finally peroxidation gave 107 and subsequent cyclisation through an intramolecular Michael-type addition reaction afforded 108 . O

O (i), (ii) OH

102 OH

(iii) OH 103 OH


453

HO MeO

HO

O

O

+

+ O 104

HO

O O

(iv)

107

106 CO2Et

CO2Et

105

CO2Et

O

(v)

O O CO2Et

108

CO2Et

Reagents: (i), (COCl2), DMSO, NEt3; (ii), Ph3P=CHCO2Et, rt, 12 h, 85% from 102; (iii), PdCl2, MeOH, rt, 24 h, then 60 °C, 4 h; (iv), UHP, p-TsOH, DME, rt, 22 h, 71% from 103; (v), HNEt2, CF3CH2OH, rt, 19 h, 59%.

Lewis acid mediated [1,3] rearrangement of the 1,3-dioxepines 109 gave the trisubstituted tetrahydrofurans 110 in high yields and with generally high diastereoselectivities. The Lewis acids used included TiCl2(i-PrO)2 and TBSOTf .

R2

(i)

O O

R1

R2

CHO R1

O

109

110

Reagents: (i), Lewis acid, DCM, -78 °C.

7.3.3

Miscellaneous derivatives with two heteroatoms

Ring expansion based on the Baeyer-Villiger reaction continued to be a valuable methodology for preparing 1,3-oxazepinones, as exemplified by the reaction of 111 with m-CPBA giving 112 in high yield; none of the isomeric 1,4-oxazepan-2-one derivative was observed consistent with some directive influence by the nitrogen . O

O m-CPBA N Ts 111

89%

O N Ts 112


454

Treatment of 112 with an arylmagnesium bromide, followed by dehydration provided access to the substituted alkenes, e.g., 113a and 113b, in moderate yields . Ar

O (i), (ii)

Ar

O NH Ts 110

N Ts 109

a: Ar = Ph, 60% b: Ar = p-MeOC6H4, 43%

Reagents: (i), ArMgBr; (ii), BF3-OEt2.

Ring-closing metathesis on the dienes 116 and 117 with Grubbs ruthenium catalyst II 18 afforded the 7-membered ring sulfones 118 and 119 respectively. The diene precursor 116 was accessed from reaction of the sulfonyl chloride 115 with 3-buten-1-ol 114 .

Cl

O2 S (i)

O O S

O

(ii), (iii)

O O CH3 S

O

115 + HO

116 (v) O O S O

117 (iv) O O S O

CH3

118 119 Reagents: (i), Et3N, CH2Cl2, 0 °C, rt; (ii), n-BuLi, THF, -78 °C; (iii), MeI, 64%; (iv), Grubbs catalyst II (5 mol%), C6H6, 70 °C, 60%; (v), Grubbs catalyst II (5 mol%), C6H6, 70 °C, 100%.

The Pd-based methodology described by Ma et al. has scope for the synthesis of fused 1,3oxazepines . Considerable value would be added to this methodology if it could be adapted to the simpler 1,3-benzazepine system, perhaps via alternative methods for carbinolamine precursor generation. A modified four-component Ugi reaction was used to synthesise a variety of heterocyclic ring fused (ring A) 1,4-oxazepine derivatives 123. For example, starting from 120 O-alkylation gave 121 and then 122 after ester hydrolysis; reaction of 122 with amines and isonitriles on heating afforded 123 in low yields . Other fused rings A included thiophene and thiazole rings.


OH A

O

455

O

(i)

O

(ii) CH3

R A

120, R=CH3

O

O R

R1 = m-Cl-PhCH2 R2 = PhCH2

121, R=CH3, 70% 122, R=H, 60%

(iii)

O

N CH3 R1

123, 25%

O Ring A:

R2 NH

A

O

O

O

Reagents: (i), CH3COCH2Cl, K2CO3, 18-crown-6, CH3CN or NaH, DMF; (ii), R1-NH2, R2-NC, MeOH, 50 °C, 3-8 h; (iii), 5% NaOH, EtOH, H2O.

In a further example of a multicomponent synthesis, dihydrobenz[f][1,4]oxazepin-5-ones were prepared in good yields in two steps by combining an initial three-component Ugi condensation with a subsequent Mitsunobu cyclisation to give (124; e.g. R1 = H, R2 = i-Pr, R3 = cyclohexyl, 65%) . O

R1

N CH CONHR3 O R2 124

The 1,2-benzothiazepine 1,1-dioxides 126 were prepared in fair yields (e.g. 126, R = H, Ar = p-ClC6H4, 52%) by a Heck coupling on the precursors 125, which were obtained in turn from an aza Baylis-Hillman reaction involving the appropriate sulfonamide, aldehyde, and methyl acrylate reactants . O O MeO

Ar

H H2N O S O

R

Br

Ar

MeO O

O S N O Br H

R

125 O

O

(ii)

O

(i)

S NH Ar

R 126

COOMe

Reagents: (i), Ti(i-PrO)4, 2-hydroxyquinuclidine, molecular sieves, i-PrOH; (ii), Pd(OAc)2, P(o-tolyl)3, NEt3, THF, 160 °C, 1 h, microwave

The first observation of the uncommon phenomenon of desmotropy in seven-membered heterocycles was reported for the prototropic annular tautomers 128 and 129. These dihydro-4,1benzothiazepines, which were prepared (via the non-isolated intermediates 130 and 131 from the fused azetidinone 127 on treatment with NaOEt), could be isolated in pure form by column


456

chromatography. However, they equilibrated in solution (acidic chloroform) to give a 3:1 ratio of 128 and 129, as monitored by NMR spectroscopy .

N

S

S

NaOEt, EtOH, rt, 15 min

S

COOEt

+

COOEt N H 129

N

Cl

128

127 O

S+

S N H EtO

ClCOOEt

N H

Cl O

130

131

A number of heteroaryl-fused 3-oxo-1,4-thiazepine-5-carboxamides, for example the indolefused derivatives 133, have been accessed using a modification of the four-component Ugi condensation. In the case of 133, the starting point was the indolic acid 132. The yields of 133 1 2 were moderate to good (for example, R = i-Pr, R = EtO-(CH2)3, 66%) . R2HNOC CHO

R1 N

O

COOH (i), (ii) S

S N Me 132 Reagents: (i), R1NH2, MeOH, rt, 10 min.; (ii), R2NC, MeOH, 50 °C, 2-3 h.

N Me 133

The unexpected 1,5-benzothiazepine derivatives 135, with an exocyclic substituted double bond at the 4-position, were obtained in moderate yields (e.g. 135, R = 4-Me, 51%) on reaction of 134 with the aminothiol 136 in acetic acid. The structure of the products was confirmed by detailed 1D and 2D NMR experiments . SH O

O

R

S

NH2 136

H 134

O

R

N H

AcOH 135

O

O


457

A further neat example of multicomponent reactions in heterocyclic synthesis was reported by Ma et al. . They prepared the furan-fused 1,4-thiazepine 140 in good yield using the three components 137, 138, and 139 in the one reaction. A range of other furan-fused analogues with different substituent groups in the thiazepine ring were also synthesised. O S

CO2Me

C +

N Br- Et

Ph CO2Me

138

137

Ph Ph

(i)

+ Ph

S

139

O

N Et MeO2C

CO2Me

140

Reagents: (i), i-Pr2NEt, DCM, 78%.

7.4 7.4.1

SEVEN-MEMBERED HETEROATOMS

SYSTEMS

CONTAINING

THREE

OR

MORE

Systems with N, S and/or O O HN

O S

O

O

NH

(i)

O

HN

Br

O S

O

N

O

141

142 (ii)

Br O N

O S

O

(iii) Br

N

N

R N

HO

O S

N

S

N

O

Palladium-catalyzed amidation reactions MW, 15-60 min deprotection

144 R

Br

O

O

O

O

O

143

O N

O S

R

N

OH HO OH 146 145 Reagents: (i), AgO2, 2-bromobenzyl bromide, DCM, 100 °C, 60 min, microwave; (ii), K2CO3, 2-bromobenzyl bromide, DMF, 100 °C, 16 h, 99%; (iii), K2CO3, benzyl bromide, DMF, 100 °C, 1 h, 98%; (iv), Pd(dba)2, Xantphos, Cs2CO3, amide, NMP, dioxane, 160 °C, 15 min, microwave.


458

An expeditious route to the cyclic sulfamide HIV-1 protease inhibitors of type 145 and 146 (tetrahydro-1,2,7-thiadiazepine 1,1-dioxide derivatives) from 141 and 142 hinges on palladium-catalysed amidation reactions. These reactions of 144 and 143 were microwave promoted and provided, after removal of the cyclic ketal protecting group, moderate to good yields of (145, 57%) and (146, 66%) for example with R = NHCOCH22-naphthyl . A number of [1,2,3]-oxathiazepane 2,2-dioxides have been prepared in good yields by regioselective nucleophilic ring opening of aziridino[1,2,3]oxathiazinane dioxide precursors . A light-induced ring expansion of the tetrazolo-uracil 147 afforded ready access to the ring expanded 5H-1,3,5-triazepine-2,4-dione nucleoside derivative 148 in 80% yield . O NH

N N N

HN

hν > 290 nm

N N

O

N

O

H2O, CH3CN

O

O OAc AcO

OAc

OAc

148

147

The chiral 1,3,5-triazepane-2,6-dione 149 and its ring fused analogue 150 have been shown to form H-bonded helical molecular tapes with P chirality on self assembly in the solid state. With 149, this self assembly proceeds through aromatic-aromatic ring interactions resulting in hollow tubular structures . O HN

O NH

N Me

HN CH2Ph

O

149

NH CH2Ph

N PhCH2O

O 150

Resin bound dipeptides have been used in the parallel synthesis of 3,4,7-trisubstituted 4,5,8,9tetrahydro-3H-imidazo[1,2-a][1,3,5]triazepine-2(7H)-thiones and N-alkyl-4,5,7,8-tetrahydro-3Himidazo[1,2-a][1,3,5]triazepin-2-amines by ring construction methodology . The single crystal X-ray structures of three new 1,2-dihydro-3H-1,3,4-benzotriazepines has been reported . A compact synthesis of dihydro-1,2,4-benzotriazepin-5-ones has also been described . In connection with studies on antimalarial compounds, simpler mimics of artemisinin based on substituted 1,2,4-trioxepanes were examined. Examples include the 1,2,4-trioxepanes 152, 153 and 154, with the seven-membered ring being made by acid catalysed condensation of the appropriate ketone with the hydroxy hydroperoxide 151. Unfortunately the 1,2,5-trioxepanes were not active as antimalarials in vitro (up to 1000 nM) probably due to their resistance to Fe(II)-mediated degradation .


459

R1 O

ArS

OOH

R2 OH

O

ArS

O

O

H

R1 R2 O

(i)

151 R1 a: (CH2)4 b: (CH2)5 c: Adamantylidene

O

R2 (CH2)4 (CH2)5 Adamantylidene

O

152 a: 72% b: 76% c: 82%

Ar p-ClC6H4 p-ClC6H4 p-ClC6H4

(ii)

O

R1

(iii)

R2

O

ArS

O

O

R1 R2 O

154 a: 87% b: 83% c: 89%

153

a: 87% b: 83% c: 89%

Reagents: (i) ketone, p-toluenesulfonic acid; (ii) m-CPBA (1.0 eq.), DCM, rt, 6 h; (iii) 2,6-lutidine (4.2 eq.), trifluoroacetic acid anhydride (3.8 eq.), acetonitrile, rt.

The chemistry of pentathiepins has been extended to the pyrrolo-fused derivative 155. Reaction of 155 with dimethyl acetylenedicarboxylate (DMAD) and triphenylphosphine at room temperature gave the fused 1,4-dithiin derivative 156 in high yield . It is probable that the triphenylphosphine removes three sulfur atoms from 155 to give a dipolar reactive intermediate for a cycloaddition with DMAD to afford 156.

N Me

S S S S S 155

(i) N Me

S

CO2Me

S

CO2Me

156

Reagents: (i), DMAD, PPh3, DCM, rt, 1 h, 80%.

7.5

SEVEN-MEMBERED SYSTEMS OF PHARMACOLOGICAL SIGNIFICANCE

Pharmacologically active compounds incorporating 7-membered heterocyclic components continue to flourish. Examples include the designed enhancement of pharmacokinetic properties of 1,4-benzodiazepine-2,5-dione antagonists 157 of the Hdm2-p53 protein–protein interaction , the synthesis of enantiomerically pure 1,4-benzodiazepine-2,5-diones and their assessment as Hdm2 antagonists , 1,4-benzodiazepines as inhibitors of respiratory syncytial virus , benzodiazepinone-based cysteine protease inhibitors of type 158 as potential antimalarial compounds , methyl substituted azepan-3ones as cathepsin K inhibitors , novel inhibitors of the epidermal growth factor

460


receptor tyrosine kinase based on pyrimido[4,5-b]-1,4-benzoxazepines (and the corresponding fused thiazepines and diazepines) , and xantheno[9,1-cd] azepines as analogues of clavizepine . Reduced benzo[b]azepin-2-one and -2,5-diones have been assessed as selective dopamine D3-receptor antagonists , and 2H-[1,2,4]triazolo[4,3-a]azepin-3(5H)-ones have moderate herbicidal activity . Other compounds of interest include dibenzo[b,f][1,4]oxazepines for assessing aspects of the histamine H4 receptor site , benzodiazepine-based -turn mimetics with moderate affinity for the AT2 receptor and in one case high affinity for the AT1 receptor , T-cell selective cytotoxic 1,4-benzodiazepine-2,5-diones , achiral 1,3,4-benzotriazepines as selective (over CCK1 receptors) CCK2 receptor antagonists , and 1,5benzodiazepines containing a benzophenone moiety as photoaffinity probes for labelling within the membrane-spanning domain of the cholecystokinin receptor . Further examples include antibody-directed enzyme prodrug therapy (ADEPT) based on pyrrolo[2,1-c][1,4]benzodiazepine prodrugs , novel, orally active vasopressin V2 receptor agonists based on 5,11-dihydropyrido[2,3-b][1,5]benzodiazepines , and 5H-1,4-benzodioxepin-3-yl uracil and purine derivatives as anticancer agents . Interest continues in the design and pharmacological evaluation of dual functional agents and in this context molecular docking and QSAR studies have been described on a number of 4,1benzoxazepinone derivatives as inhibitors of both wild type and mutant (K103N) HIV-1 reverse transcriptases . Pyrrolo-1,5-benzoxazepines, which are potent apoptosis inducers in a number of chemotherapy-resistant human cancer cell lines, have been shown to target tubulin and in one case (PBOX-6) was shown not to bind to the vinblastine or colchicine binding sites . A significant advance in selective 5-HT1A receptor agonists with neuroprotective effects has been detailed ; these compounds are 1,4-benzoxazepine derivatives. A series of moderately potent thiazepines as inhibitors of interleukin-1 converting enzyme has been described , while a new class of antileukemic agents based on pyrrolo[1,2b][1,2,5]benzothiazepines have been reported . Cl

I

Ph

O N

N HO2CH2CH2CH2CH2C

N

CO2H Cl

ArHNCO2

HO

O N O

N H

O O

O 157

158

Using representative 1,3,5-triazepane-2,6-diones, an interesting protein data mining study based on high-throughput docking identified and verified secreted phospholipase A2 as the target for these diones. These diones can be viewed as conformationally restrained dipeptide mimetics , and in another significant paper they have been reported as having inhibitory activity on the liver stage of malaria . Pyrrolo[2,1-b][1,4]benzodiazepine-azepane

461


conjugates (e.g. 159) have been synthesised and their DNA-binding properties assessed . OH Me Me

O N

O

O (CH2)4

HO

N H

MeO

159

7.6

O

O

FUTURE DIRECTIONS

The scope for further developments in the chemistry of seven-membered heterocyclic systems is considerable, particularly with respect to multi-heteroatom component systems. New synthetic methods are needed for these systems and ring-fused derivatives. The demand for such systems is likely to be largely driven by the search for structurally novel drug leads. 7.7

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06JPC(A)1600 06M1349 06MI60 06MI99 06MI281 06OBC2218 06OBC4236 06OL2667 06OL4529 06OL5183 06OL5469 06OL16185 06S1437 06SC355 06SC457 06SC803 06SC817 06SC1645 06SC1661 06SL1009 06SL2275 06SL2771 06T1777 06T2563 06T4671 06T7455 06T7699 06T8126 06T9002 06T9017 06T9301 06T10456 06T11331 06T11724 06T12392 06TA2334 06TL639 06TL2649 06TL3135 06TL3225 06TL3295 06TL3357 06TL3423 06TL3625 06TL3811

463

R.L. Redington, J. Phys. Chem. A 2006, 110, 1600. N.I. Hindawi, J.A. Zahra, M.M. El-Abadelah, B.A. Abu Thaher, K.-P. Zeller, Monatsh. Chem. 2006, 137, 1349. J.M. Mulligan, L.M. Greene, S. Cloonan, M.M. McGee, V. Onnis, G. Campiani, C. Fattorusso, M. Lawler, D.C. Williams, D.M. Zisterer, Mol. Pharmacol. 2006, 70, 60. H. Greger, Planta Medica 2006, 72, 99. Z. Zhang, M. Zheng, L. Du, J. Shen, X. Luo, W. Zhu, H. Jiang, J. Comput. Aided Mol. Des. 2006, 20, 281. P. Wyatt, A. Hudson, J. Charmant, A.G. Orpen, H. Phetmung, Org. Biomol. Chem. 2006, 4, 2218. L. Banfi, A.B.G. Guanti, P. Lecinska, R. Riva, Org. Biomol. Chem., 2006, 4, 4236. Y.S. Park, E.K. Yum, A. Basu, P. Beak, Org. Lett. 2006, 8, 2667. S.A. Amelichev, L.S. Konstantinova, N.V. Obruchnikova, O.A. Rakitin, C.W. Rees, Org. Lett. 2006, 8, 4529. A.J. Leyhane, K.L. Snapper, Org. Lett. 2006, 8, 5183. Y. Kubota, K. Satake, H. Okamoto, M. Kimura, Org. Lett. 2006, 8, 5469. H. Yu, R.N. Richey, M.W. Carson, M.J. Coghlan, Org. Lett. 2006, 8, 1685. L. Delhaye, A. Merschaert, K. Diker, I.N. Houpis, Synthesis 2006, 1437. H. Ren, M. Zanger, J. Mckee, Synth. Commun. 2006, 36, 355. J. Wu, F. Xu, Z. Zhou, Q. Shen, Synth. Commun. 2006, 36, 457. B. Ganai, S. Kumar, C. Andotra, K. Kapoor, Synth. Commun. 2006, 36, 803. M. Kidwai, P. Mothsra, Synth. Commun. 2006, 36, 817. Z.-H. Zhang, S.-T. Yang, J. Lin, Synth. Commun. 2006, 36, 1645. Y. Du, F. Tian, W. Zhao, Synth. Communya Lakshmi, R.B.N. Prasad, N. Lingaiah, P.S. Sai Prasad, Synth. Commun. 2006, 36, 3797. R. Varala, R. Enugala, S. Nuvula, S.R. Adapa, Synlett 2006, 1009. S.L. Gomez Ayala, E. Stashenko, A. Palma, A. Bahsas, J.M. Amaro-Luis, Synlett 2006, 2275. N. Dieltiens, C.V. Stevens, Synlett 2006, 2771. S. Brass, H.-D. Gerber, S. Dorr, W.E. Diederich, Tetrahedron, 2006, 62, 1777. X. Che, L. Zheng, Q. Dang, X. Bai, Tetrahedron 2006, 62, 2563. H. Gold, A. Ax, L. Vrang, B. Samuelsson, A. Karlen, A. Hallberg, M. Larhed, Tetrahedron 2006, 62, 4671. L. Gireaud, L. Chaveriat, I. Stasik, A. Wadouachi, D. Beaupère, Tetrahedron 2006, 62, 7455. H.-X. Jin, Q. Zhang, H.-S. Kim, Y. Wataya, H.-H. Liu, Y. Wu, Tetrahedron 2006, 62, 7699. D. Bevk, U. Groselj, A. Meden, J. Svete, B. Stanovnik, Tetrahedron 2006, 62, 8126. C. Ma, S.-J. Liu, L. Xin, J. R. Falck, D.-S. Shin, Tetrahedron 2006, 62, 9002. A. Le Flohic, C. Meyer, J. Cossy, Tetrahedron 2006, 62, 9017. N.L. Snyder, H.M. Haines, M.W. Peczuh, Tetrahedron 2006, 62, 9301. P. Ribiere, V. Declerck, Y. Nedellec, N. Yadav-Bhatnagar, J. Martinez, F. Lamaty, Tetrahedron 2006, 62, 10456. K. Guthikonda, P.M. Wehn, B.J. Caliando, J. Du Bois, Tetrahedron 2006, 62. 11331. M.C. Nunez, M.G. Pavani, M. Diaz-Gavilan, F. Rodriguez-Serrano, J.A. Gomez-Vidal, J.A. Marchal, A. Aranega, M.A. Gallo, A. Espinosa, J.M. Campos, Tetrahedron 2006, 62, 11724. L.G. Voskressensky, S.V. Akbulatov, T.N. Borisova, A.V. Varlamov, Tetrahedron 2006, 62, 12392. J. Vachon, C. Lauper, K. Ditrich, J. Lacour, Tetrahedron: Asymmetry 2006, 17, 2334. M.S. Novikov, A.A. Amer, A.F. Khlebnikov, Tetrahedron Lett. 2006, 47, 639. A.P. Ilyin, V.Z. Parchinski, J.N. Peregudova, A.S. Trifilenkov, E. B. Poutsykina, S.E. Tkachenko, D.V. Kravchenko, A.V. Ivachtchenko, Tetrahedron Lett. 2006, 47, 2649. H. Thakuria, A. Pramanik, B.M. Borah, G. Das, Tetrahedron Lett. 2006, 47, 3135. X. Beebe, V. Gracias, S.W. Djuric, Tetrahedron Lett. 2006, 47, 3225. G. Liu, W.-Y. Tai, Y.-L. Li, F.-J. Nan, Tetrahedron Lett. 2006, 47, 3295. J.K. Mishra, J.S. Rao, G.N. Sastry, G. Panda, Tetrahedron Lett. 2006, 47, 3357. C. Kalinski, M. Umkehrer, G. Ross, J. Kolb, C. Burdack, W. Hiller, Tetrahedron Lett. 2006, 47, 3423. A. Kamimura, K. Tanaka, T. Hayashi, Y. Omata, Tetrahedron Lett. 2006, 47, 3625. Y. Yu, G.A. Stephenson, D. Mitchell, Tetrahedron Lett. 2006, 47, 3811.

464 06TL5665 06TL6235 06TL6389 06TL6895 06TL8133 06TL8523 06TL8591 06ZN(B)111 06ZN(B)385


P. Csomos, L. Fodor, J. Sinkkonen, K. Pihlaja, G. Bernath, Tetrahedron Lett. 2006, 47, 5665. E. Banaszak, C. Comoy, Y. Fort, Tetrahedron Lett. 2006, 47, 6235. M.-Y. Chang, S.-Y. Wang, C.-L. Pai, Tetrahedron Lett. 2006, 47, 6389. S.K. Chattopadhyay, S.P. Roy, D. Ghosh, G. Biswas, Tetrahedron Lett. 2006, 47, 6895. K.P. Guzen, R. Cella, H.A. Stefani, Tetrahedron Lett. 2006, 47, 8133. C.-W. Kuo, S.V. More, C.-F. Yao, Tetrahedron Lett. 2006, 47, 8523. A. Vasudevan, P-S. Tseng, S.W. Djuric, Tetrahedron Lett. 2006, 47, 8591. B. Kluess, W. Kreiser, T. Sukri, W. Poll, H. Wunderlich, Z. Naturforsch. Teil B, 2006, 61, 111. G. Maas, R. Reinhard, H.-G. Herz, Z. Naturforsch. Teil B, 2006, 61, 385.

465

Chapter 8

Eight-membered and larger rings George R. Newkome The University of Akron, Akron, Ohio USA [email protected]

8.1

INTRODUCTION

Numerous reviews as well as perspectives, feature articles, tutorials, and mini-reviews have appeared throughout 2006 that are of particular interest to the macroheterocyclic enthusiast and those delving into supramolecular chemistry at the macromolecular level, as well as those studying nanoconstructs: switchable rotaxanes ; cyclodextrin rotaxanes and polyrotaxanes ; novel multiple rotaxanes and catenanes ; molecular machines via catenanes and rotaxanes ; supramolecular cyclodextrin hosts for organometallic complexes ; amino acid derived macrocycles ; self-organization of disc-shaped molecules ; palladacycles that are more than precatalysts ; luminescent sensors and switches ; from sub-phthalocyanines to sub-porphyrins ; porphyrin-fullerene systems with rotaxane and catenane architectures ; macromolecular malonates for fullerene encapsulation ; aniontemplated assembly of interpenetrated and interlocked macromolecules ; labeling monoclonal antibodies with macrocyclic radiolabelled complexes ; artificial nanomachines, based on interlocked entities ; ligand design in multimetallic architectures ; metal-mediated multiporphyrin assemblies ; self-assembled nanostructures inspired by photosynthesis ; the dynamics and stereochemistry of interlocked materials ; core-modified porphyrins, as platforms for organometallic chemistry ; metallation of expanded porphyrins ; heteroporphyrins and their analogues ; porphyrincalix[4]arenes ; superphanes to beltenes ; phenylaza- and benzoazacrowns ; macrocyclization via templation ; design of molecular switches and sensors ; H-bondedassembly of synthetic molecular motors and machines ; H-bond-mediated template synthesis of rotaxane, catenanes, and knotanes ; N-confused porphyrins ; microwave irradiation in ring construction ; molecular knots ; amide- and urea-type gelators with tailored properties ; marine polycyclic ether ; resorcarenes ; chelates, pincers, as well as spirocycles ; macrocyclization by ring-closing metathesis ; molecular loops and belts ;

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thiacalixarenes ; sugar-derived crown ethers ; and synthetic routes to porphyrins possessing fused rings . As always, because of space limitations, only meso- and macrocycles possessing heteroatoms and/or subheterocyclic rings have been reviewed; in general, lactones, lactams, and cyclic imides have been excluded. In view of the delayed availability of some articles appearing in previous years, several have been incorporated, where appropriate. I apologize in advance that it is impossible to do justice, to this topic and the numerous researchers that have elegantly contributed to the field, in the allotted twenty pages.

8.2

CARBON–OXYGEN RINGS

The coupling of 1,3-difluoronitrobenzene with resorcinol promoted by CuI with K2CO3 in pyridine under high dilution conditions gave the hexameric product 1 in 25% yield along with the smaller [2+2] cyclophane . Similarly, nucleophilic aromatic substitution of 1,5-difluoro-2,4-dinitrobenzene with 2-propylresorcinol in either Et3N/MeCN or CsF/DMF gave a syn/anti mixture of conformers of the cyclic tetramer and cyclic hexamer . The 3,3',4,4'-tetranitrodibenzo-24/30-crown-8/10 ethers have been made and shown to form organogels with chloroalkanes at 3% w/v . The treatment of 4hydroxybenzaldehyde with triethylene glycol in the presence of K2CO3 in refluxing MeCN gave the desired bis-aldehyde, which was transformed to the bis(ethynyl)ketone intermediate in 84% overall yield, then upon treatment with the known 3-methoxyphenylenaminone under high dilution conditions, macrocyclization to generate 2 was accomplished . The treatment of poly[diphenyl-co-methyl(bromopropyl)]silane with (4-hydroxyphenylazo)dibenzo-18-crown-6 under the traditional Williamson conditions generated the poly[diphenyl-co-methyl(propyloxyphenyl-azodibenzo-18-crown-6]silane, as a brown solid . The reversible acid-catalyzed transacetalation of the cyclophane formal 3 has been shown to undergo a ring-fusion/ring-fission process to generate a mixture of polymer cyclic formaldehyde acetals by means of oxonium ion intermediates . The stepwise O

O

O

O

O

O

O

O

O

O

NO2 O

O NO2 O

O

O

O2N

O

O

1

3 O

OMe

O

2

Br

4

Br

growth of oligo(p-phenylene oxide)s and cyclization via the Ullmann coupling reaction using di(4-iodophenyl) ether and CuI/N,N-dimethylglycine gave the cyclic oligo(p-phenylene oxide)s . The cross-cyclocondensation of ethereal-linked Į,Ȧ-diynes and dimethyl acetylenedicarboxylate in the presence of a Rh(I)/H8-BINAP catalyst gave the [7][21]-polyethereal cyclophanes in good yields . Novel, linear, soluble highmolecular weight, film-forming polymers and copolymers possessing main-chain crown ether

467


units alternating with aliphatic (C10-C16) units has been prepared via electrophilic aromatic substitution, followed by reduction of the carbonyl moieties . Various (a)chiral macrocyclic oligo-malonates were synthesized in a simple one-step process via condensation of malonyl dichloride with Į,Ȧ-diols . Treatment of salicylaldehyde with base in EtOH, followed by the introduction of 1,4-dibromobutane gave (96%) (CH2CH2OC6H4CHO)2, which was subjected to an intramolecular McMurry coupling to generate (95%) the macrocyclic stilbene that when treated with Br2 followed by dehydrobromination gave (90%) the desired macrocyclic alkyne 4 . A novel triptycene-based bis(crown ether) was synthesized in 46% yield from a known tetrahydroxy-triptycene derivative with 1,2-bis[2-[2-(2-tosylethoxy)ethoxy]ethoxy]benzene with Cs2CO3 in DMF at 100 °C; this rigid bis-host can accommodate dibenzylammonium salts to generate a bis[2]pseudorotaxane as well as stable clip-shaped complexes with paraquat derivatives and ammonium salts . The triply crowned 1,3,5-tris(arylalkynyl)mesitylene was prepared by the treatment of triiodomesitylene with 4'-ethynylbenzo-18-crown ether using Sonogashira coupling conditions . The ethynyl derivative of a nickel octaethylporphyrin was coupled with a cone crown calixarene under either Sonogashira or Negishi conditions to give a diphenolic intermediate, which was alkylated to give the desired Pacman-like conformationally frozen cone bisporphyrin 5 in 55% yield . The 1,3-di(2-pyridinylmethyloxy)-p-tert-butyldihomooxacalix[4]arene-crown-6 (6) was synthesized by the reaction of the corresponding N

N

M

N

N

O O

O O

O O

5

O O

N N

t-Bu

N

M N

t-Bu O

EtO2C

RO

X OR

OH HO

O O

6 x = (CH2CH2O)4CH2CH2

R = H or

H 2C

N

or CH3

O

7

OH HO

t-Bu

t-Bu

CO2Et

O

O

EtO2C

O

CO2Et

dihomooxacalix[4]arene-crown-6 with 2-(chloromethyl)pyridine·HCl with NaH in dry DMF at 65 °C for 48h . A complete set of partially O-methylated products of p-tertbutyltetrahomodioxacalix[4]arene has been prepared, thus permitting the tailoring of the

468

G.R. Newkome

cavity for better guest encapsulation . Refluxing ethyl 3,5-di(hydroxymethyl)-4hydroxybenzoate in xylene afforded the known hexahomotrioxacalix[3]arene (48%) and the unknown octahomotetraoxacalix[4]arene (7, 9%) . The acid-catalyzed condensation of furan and pentafluorobenzaldehyde gave very low yields of the 30ʌ and 40ʌ expanded porphyrinoids, in which the furan rings were inverted in an alternating fashion and displayed non-twisted conformations . A methanofullerene derivative possessing an ammonium subunit has been prepared and subsequently shown to form a supramolecular complex with a porphyrin-crown ether conjugate . The synthesis and study of these fullerene-containing supramolecular photoactive devices have also been reported .

8.3

CARBON–NITROGEN RINGS

A series of expanded porphyrins possessing meso-trifluoromethyl moieties, such as Nfused [24]penta-, [28]hexa-, [32]hepta-, [48]deca-, and [56]dodecaphyrins, were prepared by the acid-catalyzed, one-pot condensation of 2-(2,2,2-trifluoro-1-hydroxyethyl)pyrrole . The acid-catalyzed condensation of a pyrrole bisacrylaldehyde with a tripyrrane then oxidation with FeCl3 gave a [22]porphyrin-(3.1.1.3), which displayed a strong diamagnetic current in the NMR as well as a red shifted porphyrin-like UV-vis spectra . The 1,3-dipolar cycloaddition of expanded porphyrins e.g., the mesooctakis(pentafluorophenyl)[36]octaphyrins-(1.1.1.1.1.1.1.1) with an azomethine ylide regioand stereoselectively generated mono- and bis-pyrrolidine-fused octaphyrins . A series of related expanded (4 to 44 pyrrole units) isocorroles was prepared in ca. 50% yields by treatment of the bis(azafulvene) derivative of gem-dimethyldipyrrylmethane with 2,2'bipyrrole under neutral conditions and without a catalyst . Treatment of 4hydroxyisophthaldehyde with excess C6H5MgBr generated a carbinol that was subsequently condensed with pyrrole and aromatic aldehydes in the presence of BF3·Et2O, followed by oxidation with DDQ to afford new tetraarylcarbaporphyrinoids in 10-24% yield . The synthesis of novel [1,2,3]triazolo[4,5-b]porphyrin, from ȕ-nitro-mesotetraarylporphyrins with NaN3 in DMF, and its use in the creation of dimeric and pentameric porphyrins have been reported . The Suzuki coupling of bromoporphyrins, derived from 5,10,15,20-tetraphenylporphyrin, with 2-allyl-4,4,5,5-tetramethyl-1,3,2dioxaborolane was conducted in toluene at 100 °C under an inert gas with anhydrous K2CO3 to give polyallylporphyrins in acceptable yields . Improved methodology for the N-alkylation of N-confused porphyrins has appeared . A different type of confused system recently appeared in which 6,11,16,21-tetra-3-aza-m-benziporphyrin (8), an analog of 5,10,15,20-tetraarylporphyrin in which one of the pyrrole moieties was replaced by a pyridine ring pointing outwards, linked at the ȕ,ȕ'-positions, was formed by condensation of 3,5-bis[phenyl(2-pyrrolyl)methyl]pyridine, pyrrole, and p-tolualdehyde catalyzed by F3CCO2H . The synthesis of 6-methyl-2,6,10-[11]-12,25-phenanthrolinophane possessing a 1,10phenanthroline ring with a 2,9-polyaza-bridge has been reported and characterized . The use of water-soluble pyridinophanes for the two-centered phase-transfer catalysis of N-alkylation of indoles, imidazoles, benzimidazoles, and benzotriazoles has appeared . Macrocycles possessing 3-8 and 10 subunits of N-(p-tolyl)aminopyridine, e.g., the aryl-substituted azacalix[n](2,6)pyridines (9), by a Cu- and Pt-catalyzed aryl amination have been formed ; also see . The reaction of 2,6dibromopyridine with N,N'-di(3-aminopropyl)ethylenediamine with Pd(dba)2/BINAP and NaO-tBu gave the desired polyazamacrocycle 10 in 24% yield ; related 14-

469


2

3 N

H3 C

4

21

6

N

22 19

N

N n-2

N

N 24 H N

18

CH 3

8 9

N

N

HN

N

(n = 3)

11

16

N

H N

NH

H N

14 13

8

CH3

9

10

membered tetraazamacrocycles possessing a pyridine subunit have also appeared . The reaction of N-(3-chloromethyl-5-methylpyrazolyl)-4-methylpyrazolylmethane with 3-aminopropanol gave a tetrapyrazolic intermediate, which with 1,2dibromoethane under high dilution conditions gave the target macrocycle 11 . Various bridged nicotinates 12 possessing a [n](2,5)pyridinophane subunits (n = 8-14) were prepared by a different sequence of events, specifically the reaction of methyl propiolate with a series of formyl-substituted (vinylimino)phosphoranes . An interesting dynamic combinatorial library of macrocyclic oligoimines, starting with enantiopure transcyclohexane-1,2-diamine and 2,6-diformylpyridine, has appeared and these imines were subsequently reduced with borohydride to give the corresponding chiral polyamines in overall high yield and purity . Although lactams are generally not considered in this review, the formation of bowl-shaped cyclic trimers 13 of aromatic amides was reported to occur in high yields by the condensation of meta-substituted 3-(alkylamino)benzoic acid using dichlorotriphenylphosphorane . A series of simple chiral polyazamacrocycles with 12-, 18-, 24-, 27-, and 36-membered rings were easily synthesized using (S)-Į-phenylethylamine, as the chiral source, and 2,6-bis(chloromethyl)pyridine . Trianglamines, a family of macrocyclic heterophanes, have been synthesized through a [3+3] cyclocondensation of (R,R)-1,2-diaminocyclohexane with terephthaldehyde, followed by borohydride reduction and N-alkylation . The reaction of cyclam with 1,2-di(3-bromoprop-2-ynyl)benzene and K2CO3 in DMF at 25 °C for 12h gave a mixture of the mono- and desired bis-eneyne 14 . The improved synthesis of the 1,4,7,10,13,16,21,24-octaazabicyclo[8.8.8]hexacosane (a simple peraza[2.2.2]cryptand) was prepared in 70% yield via a two-step one-pot process by the initial condensation of tris(2-aminoethyl)amine with glyoxal in isopropanol at -78 °C, followed by a Na/liquid NH3 reduction . The equilibrium and rearrangements associated with the two-step synthesis of 1,4,7,10-tetraazacyclododecane from triethylenetetraamine, glyoxal, and diethyl oxalate have been considered . A novel bifunctional octa-coordinate ligand, 1,4,7,10-tetraazacyclododecane-4,7,10-triacetic-1{methyl[4-aminophenyl)methyl]phosphinic acid]}, has been reported . NSubstituted diaza[12]annulenes have been prepared via a one-pot procedure with N-(2,4dinitrophenyl)pyridinium chloride with aryl and alkyl amines in 40-80% yield . Macrocycles possessing two 1,5-diazacyclooctane subunits coupled with two ethylene bridges gave rise to the highly topologically constrained 1,4,8,11-tetraazatricyclo[9.3.3.34,8]eicosane . The novel [2]rotaxanes possessing a tetracationic cyclophane, i.e., cyclobis(paraquat-4,4-biphenylene), and a lumpy molecular thread that incorporated a photoactive diarylcycloheptatriene and photo-active aryl subunits have been created in ca. 30% yields via simply coupling the two halves .

470

G.R. Newkome

H3C

H3C

N

CO2Me

N

N

N N

N

N

H3C

N H3C

N

(CH2)n

12

11 CH3

O H3C

N

OH

N N

O

N

N

N

N

N

13

8.4

O

CH3

14

CARBON–SULFUR RINGS

A novel set of fully conjugated giant macrocyclic oligothiophenes containing 60ʌ, 90ʌ, 120ʌ, 150ʌ, and 180ʌ "frames" possessing butyl-substituents has been synthesized by means of either a Sonogashira or McMurry coupling procedure; the 60–180ʌ macrocycles possess 1.8–6 nm inner cavities and 3.3-7.5 nm outer molecular diameters . Related cyclic oligothiophenes (CnT, n=6-30, even only) in syn- and anti-conformations have been theoretically studied at the B3LYP/6-31G(d) level . The homocoupling of (hetero)aryl halides by electron-transfer oxidation of the Lipshutz cuprates [Ar2Cu(CN)Li2] with organic electron-acceptors has been demonstrated, for example, when bis(3-bromo-2thienyl)methane was treated with two equivalents of BuLi, followed by CuCN and Et3N, followed by oxidation with 1,4-benzoquinone, the desired 10membered ring was generated ; the related bis(3-bromo-2-thienyl)dimethylsilane gave the silicon-bridged 10-membered cyclophane. OH S Under high-dilution conditions, the treatment of S disodium 1,2-dicyanoethene-1,2-dithiolate with OH HO either 1,8-dichloro-3,6-dithiaoctane or 1,9-dichloro3,7-dithianonane gave the corresponding S maleonitrile-tetrathiacrown ethers [mn12S4 or mn13S4; the X-ray data confirmed the structures 15 and it was further shown that mn12S4 is the first preorganized tetradentate thiacrown ether that forms sandwich complexes with the coordination number eight [with silver(I)] . The O-alkylation of 5,11,17,23tetra-tert-butyl-2,8,14,20-tetrathia-calix[4]arene-25,26,27,28-tetraol with bromomethyl acetate gave rise (47%) to the distal-5,11,17,23-tetra-tert-butyl-25,27-bis[(ethoxycarbonyl)methoxy]-26,28-dihydroxy-2,8,14,20-tetracalix[4]arene, which upon treatment with Cs2CO3 in THF, followed by 2-(chloromethyl)pyridine·HCl gave (61%) 5,11,17,23-tetra-tert-butyl25,27-bis[(ethoxycarbonyl)methoxy]-26,28-bis[(2-pyridinylmethyl)oxy]-2,8,14,20-tetrathiacalix-[4]arene possessing an 1,3-alternate configuration . The first synthesis of the C3-symmetrical p-tert-butylhexahomotrithiacalix[3]arene (15) by means of a single-pot procedure by the treatment of 2,6-bis(chloromethyl)-p-tert-butylphenol with Na2S·9H2O under high dilution conditions; other hexahomotrithiacalix[3]arenes were

471


synthesized via a convergent process by a [2+1] cyclization from mono- and bis(chloromethyl)phenol components . Using macrocyclization conditions, e.g., rapidly stirred suspension of Cs2CO3 in DMF in the concentration range of 50-100 mmol/L at 65-100 °C, macrocycles [20]aneS6(OH)6, [13]aneS4(OH), [26]aneS8(OH)2, and [32]aneS8(OH)2 have been prepared via the reaction of 1,3-dichloro-2-hydroxypropane with the appropriate dithiol .

8.5

CARBON–OXYGEN/CARBON–NITROGEN RINGS

A chiral [4]pseudocatenane 16 was synthesized from chiral triptycene-based tris(crown ether) and three equivalents of bis[p-(but-3-enyloxy)benzyl]ammonium salt in CH2Cl2 in the presence of Grubbs II catalyst, followed by reduction . Several novel calix[4]arenocrowns were prepared by a simple one-pot reaction of calix[4]monohydroquinone diacetate with bis-tosylates, e.g. 1,4-bis[2-(2-(2-(2-tosyloxyethoxy)ethoxy)ethoxy)ethoxy)benzene, in dry MeCN in the presence of NaOH; the selfassembly into calix[4]areno[2]catenanes with a dicationic salt and p-bis(bromomethyl)benzene was also demonstrated .

O O

O

N H2

3PF6

O

O

O O

O O O

O

O

O O O O

O

NH2

O O

O O

O

O O

H2N O

O O O

O O

16

8.6

CARBON–NITROGEN–OXYGEN RINGS

A new synthesis of 1,7-bridged cyclens has appeared by reacting bis(2-formylphenyl)ether or 1,8-diformyldibenzofuran with cyclen under reductive amination conditions, e.g., in the presence of 2.8 equimolar amounts of NaBH(OAc)3 in 1,2-dichloroethane at 25 °C . New dioxadiaza-, trioxadiaza-, and hexaaza-macrocycles possessing the rigid dibenzofuran group have been prepared from 1,8-diformylbenzofuran and appropriate Į,Ȧ-

472

G.R. Newkome

diamine, followed by reduction . The treatment of O,O'-bis(2formylphenyl)triethylene glycol with diethyl ketone in the presence of ammonium acetate gave the PEG-bridged 2,6-di(2-oxaphenyl)-3,5-piperidin-4-one in reasonable yield . A variety of macrocyclic phenanthrolines were synthesized from 2,9-bis(4hydroxyphenyl)-1,10-phenanthroline and numerous 1,3-bis(Ȧ-bromoalkoxy)benzenes (alkyl = C6-C16) were used and under specific reaction conditions [K2CO3 in DMSO/H2O (99:1) at 65 °C for 4 h], the C10 connectors were favored . The resultant Cu(I)phenanthroline (with C10 linkages) complex with tris(4-biphenyl)methyl-(CH2)6OC6H4CŁCH generated the [2]rotaxane in 72% yield and thus it was catalyzed by the macrocyclic Cu(I) reagent . The route to oligomeric corroles has been reported in which a monomeric meso-free oxacorrole was treated with AgOTf, instead of the usual AgPF6, the dimer was isolated in ca. 90% yield; this coupling was first observed during an attempt to metallate the oxacorrole with a silver salt . An alternative to forming the meso-meso linkages was reported for the coupling in the related family of 22ʌ smaragdyrins using the AgPF6 (3.7-19.3% yield of dimer); however with n-BuLi, the yield was shown to be 10-30% . Two-photon absorption cross-section values for a series of 22ʌ smaragdyrins possessing phenylacetylenylphenyl- and [(phenylacetylenyl)phenylacetylenyl]phenyl- with meso-links as well as their Rh(I) complexes have been reported . Substituted oxacalix[m]arene[n]pyrimidines have been prepared by SNAr conditions on 4,6dihalopyrimidines; however depending on the reaction conditions, either a mixture of oxacalix[m]arenes (m = 4-12) was obtained or m = 4 could be selectively synthesized in high yield . Oxacalix[2]arene[2]hetarenes were formed by the cyclooligomerization of meta-diphenols with meta-dichlorinated azaheterocycles in a single step . O

O O

O

N

N O

O

N H2 N

O

NH2

O H

O

MeOH/Δ

O

2

N

17

23%

19

PhOCH2COCl Et3N, DCM, 78 ºC

O

O O

O

N

N O

O

18 20 O O

HO

OH

O

HN

NH O

Method a: 10N HCl, H2O, Δ Method b: LiOH, H2O2, 0 ºC

O

Method a: 86%

21 O O

27%

O

Method b: 74% HO

OH

O O

HN

NH O

O

22

Method a: 90% Method b: 74%

473


The synthesis of macrocyclic chiral aminoacids was demonstrated by the initial conversion of a bis-aldehyde 17 with 1,3-diaminopropane to give the corresponding bis-imine 18, which with phenoxyacetyl chloride in the presence of NEt3 gave an ca. equal mixture of bis-ȕ-lactams 19 and 20 that can lastly be ring-opened to afford the desired chiral macrocycles 21 and 22 . Norephedrine and (1R,2S)-ephedrine were initially transformed into the mono-N-protected intermediate, which was then reacted with BrCH2CN, followed by sequential treatment with SOCl2, followed by small PEG reagents, mesylation, deprotection of the N-cyanomethyl group, and lastly intramolecular alkylation gives easy access to chiral azacrown ethers . A chiral N-containing calix[4]arene bearing the chiral 1,2-diphenyl-1,2-oxyamino moiety on the lower rim showed excellent molecular recognition between the mandelic acid enantiomers . A series of chiral C2symmetric 2,2'-bipyridine-containing crown ethers has been reported for the enantiomeric recognition of amino acid derivatives . An aqueous solution of equimolar quantities of 2-[2-(2-aminoethoxy)ethoxy]ethylamine, 1,10-phenanthroline-2,9-dialdehyde, and Cu(I) gave rise to a dimeric, helical macrocycle in quantitative yield ; by alteration of the components, catenanes could be isolated. A new type of molecular motor was demonstrated for [7.7](2,6)pyridinocyclophanes, possessing embedded 1,3-dioxanes within the bridges; the rotation of the central pyridine ring was controlled by the bridge composition and that molecular motion was stopped by the addition of CF3SO3Ag . O

O

O

N

O

N

O

O

O

O

O

O

O N

23

N

O

O N

N

O

O N

N

N

O

O

O

N

N

O 2PF6

RO

O O N

25

24

OR

R = benzyl or methyl

Novel bipyridinocrownophanes 23 possessing two bipyridine moieties were easily prepared by an intramolecular [2+2] photocycloaddition of a linear bis(vinylbipyridine derivative . The synthesis of a tris(crown formazan) from hexakis(actamidophenoxymethyl)benzene has been reported . The 19-membered azoand azoxy-crown ethers have been created by the reductive macrocyclization of the corresponding bis(nitrophenoxy)oxaalkanes . Other new azobenzocrown ethers of different sizes and substitution patterns have also been synthesized . A series of redox-active Wurster's crownophanes were prepared via a macrocyclization process involving N,N'-dimethyl-p-phenylenediamine an various tosylated glycols . A novel example of bis-macrocycle of 2,3,6,7,10,11-hexaphenyl-1,4,5,8,9,12hexaazatriphenylene (24) prepared from a linear tris-benzil system connected by PEG linkages has appeared . In the process of making complexes composed of macrocyclic molecular clips, e.g., 25, the C,N,O-macrocycles were generated from 1,2-bis[2(4-(4-pyridinyl)phenylmethoxy)ethoxy]ethane and Į,Į'-dibromo-p-xylene with added KPF6 . Treatment of diaza-18-crown-6 with a 5,15-o-diamido picket- or a 5,15-

474

G.R. Newkome

diaminophenyl-porphyrin led to the formation of three new macromolecule, specifically a cryptand, a bis-, and a tris-macrocycle . 8.7

CARBON–NITROGEN–SULFUR RINGS

A series of porphyrinoids has been synthesized by the [3+1] strategy starting from tripyrrane analogues (26) with the desired thiophenediol 27 to give 28 and 29; interestingly, when macrocycle 28 was treated with alkoxide in EtOH, conversion to 29 was observed along with decomposition . The synthesis and characterization of a coremodified [26]hexaphyrins(1.1.1.1.0.0) and the related 54ʌ-modified dodecaphyrin have been reported . Dithiaethyneazuliporphyrin (30), the first contracted carbaporphyrinoid, has been prepared by a [3+1] strategy using 1,4-bis[5-(phenyl-hydroxymethyl)thien-2-yl]-1,4-diphenyl-2-butyne and azulene . EtO2C

CO2Et

EtO2C

CO2Et +

N

1) TFA, NH4Cl

OH

HO S

p-Tol

p-Tol

2) DDQ

NH HN

27

26 EtO2C

EtO2C

CO2Et

EtO2C

CO2Et

N NH

HN

EtO2C

CO2Et

N N

N

EtO¯, EtOH

S

S p-Tol

p-Tol

p-Tol

p-Tol

CO2Et

29

28

A simple, nearly quantitative route for the detosylation of mixed azathiacrown ethers using sodium amalgam has appeared . The incorporation of a 2,2'-bisethereal N

N

N

N O

O

O

hν

O

CH2Cl2

31

S

S

O

O

O

O

O

O

N N

S

N

S

30

S

S

32

azobenzene moiety into a 19-membered ring 31 has been reported starting from the commercial 2,2-bishydroxyazobenzene in six-steps; this effort was developed to create a

475


novel photo-triggering device involving the E to Z isomerism . The proof-ofstructure of a tripyridinylthioethereal macrocycle 32 has appeared showing the high degree of molecular distortion . The use of 1,9-dithia-5,13-diazacyclohexadecane in conjunction with orthogonally protected cyclam and aza-18-crown-6 has given rise to a new heterotopic macrocycle incorporating N4-, N2S2-, and NO6-donor sites; the authors also incorporated cyclam and the 1,9-dithia-5,13-diazacyclohexadecane into a cofacial ligand . The N-functionalization of 1,4,10,13-tetrathia-7,16-diazacyclooctadecane with 2-chloro-N-pyren-1-yl-acetamide in MeCN with K2CO3 and KI has been reported . The 1,4,7-trithia-11-azacyclotetradecane has been prepared (62%) from N,Nbis(3-chloropropyl)amine and 2,2'-thiobis(ethanethiol), subsequent treatment with 9(chloromethyl)anthracene generated the desired N-alkylated product (73%) . The novel use of a rhodium(II)-catalyzed double Stevens rearrangement has been applied to the conversion of sulfur-containing heterophane 33 then to the desulfurized cyclophane 34 ; this procedure complements the well-known ring-contraction of these thiaheterophanes. A novel zig-zag polymer has been reported that possesses dithia[3.3](2,6)pyridinophane moieties; the incorporated syn-form of the pyridinophane unit readily complexes palladium to generate a polymeric complex that can catalyze the Heck coupling reaction .

N2 N

N

N E

S R

O

33 R 8.8

N

(EtO)3P hν

E

S

O

S Rh2OAc4 E Xylenes, E Δ

S

R

E

N E E

R

N E

O

E

E R R

34

CARBON–PHOSPHORUS–OXYGEN RINGS

Treatment of (S,S)-bis(2-hydroxypropyl)phenylphosphine oxide with initially base followed by Cl(CH2)2O(CH2)2OTf gave the dichloride intermediate, which with base and either catechol or tosyl amine in DMF and elevated (150 °C) temperatures generated the macrocyclic phosphane oxide 35 in 15% yield or the 1-phospha-10-aza-18-crown-6-ether in 44% yield . 8.9

CARBON– PHOSPHORUS–SULFUR RINGS

A new 2,2'-bipyridine containing phosphadithiamacrocycle 36 has been synthesized (10%) by the treatment of 6,6'-bis(bromomethyl)-2,2'-bipyridine and dilithium 3-phenyl-3phosphapenta-1,5-dithiolate; conversion to the corresponding P-oxide was readily obtained by its simple oxidation in an open atmosphere . The synthesis of calix[1]phosphole[1]thiophene[2]pyrrole (37) was generated in low overall yield by the treatment of 2,5-bis(1-hydroxy-1-methylethyl)phosphole P-sulfide with boron trifluoride etherate in pyrrole to generate the ı4-2,5-bis[(pyrrole-2-yl)methyl]phosphole intermediate , which was similarly condensed with 2,5-bis(1-hydroxy-1-methylethyl)thiophene to give the desired macrocycle 37 . The corresponding calix[1]phosphole[1]furan[2]pyrrole was prepared by the substitution of 2,5-bis(1-hydroxy-1methylethyl)furan in the last step or with 2,5-bis[hydroxy(phenyl)methyl]-

476

G.R. Newkome

thiophene to create a P-containing hybrid porphyrin, which exhibited high aromaticity, as an 18ʌ-electron system .

O

O Ph

P

S O

N P

O

O

O

N

P

S HN

S S

O

36

35

8.10

Ph

Ph NH

37

CARBON–SULFUR–OXYGEN RINGS O R

S

S

S

R

S

S

S

O

O

R = SCH2CH2S or SCH3

S

S

S

SC10H21

S

S

S

SC10H21

O

38

New procedures to the formation of 1,4-dioxa-7,11-dithiacyclotridecan-9-ol and 1,4,7trioxa-10,14-dithiacyclohexadecaen-12-ol utilized 2,3-dibromopropanol with either (CH2OCH2CH2SH)2 or O(CH2CH2OCH2CH2SH)2 with Li2CO3 in aqueous EtOH; the procedure was shown to proceed via an oxirane intermediate . The convenient oxidation of the above tridecan-9-ol to the 1,4-dioxa-7,11-dithiacyclotridecan-9-one was accomplished by a Swern oxidation at low (-70 °C) temperatures; the alkylation and acylation of the ring alcohol moieties were also reported therein. A new amphiphilic bis-tetrathiafulvalene annulated macrocycle 38 that can form redoxactive organogels as well as electrically active nanostructures, e.g., nanowires and sizecontrollable nanodots, has been reported . Thiones that incorporate two different poly(ethylene glycol) chains were prepared from bis(tetraethylammonium)bis(1,3dithiole-2-thione-4,5-dithiol)zincate and subsequent tosylation, followed by reaction with ptert-butylcalix[4]arene to generate 39 . This thioxo reagent did not couple upon reaction with triethyl phosphite, but upon conversion [Hg(OAc)2, CHCl3 and AcOH] of the thioxo moiety to the oxo analog, which was successfully transformed to the desired TTF derivative 40; the final step was the alkylation of the remaining phenolic positions.

8.11

CARBON–NITROGEN–SULFUR–OXYGEN RINGS

The dynamic self-assembly of bis-N,N'-(2-(2-(2-(2-thioacetylethoxy)ethoxy)ethylperylenetetracarboxylic diimide via ʌ-ʌ attraction and disulfide bonds led to the formation of a cyclic perylene dimer as well as the related catenane composed of a threading process . The formation of the N-azo-coupled NO2S2 macrocycle 41 was accomplished by the treatment of N,N'-phenyldiethanolamine with tosyl chloride, followed by thiourea and then bicarbonate to give 2,2'-(phenylazanediyl)diethanethiol, which with 1,2-bis[2(chloromethyl)phenoxy]ethane generated the desired macrocycle in 48% yield . Lastly, treatment of this macrocycle with diazonium salt of 4-nitroaniline gave 41 in 88%

477


But

But

t

Bu tBu

t

Bu tBu

Bu

1) CHCl3, AcOH, Hg(OAc)2

t

Bu

O

CsF, CH3CN, Δ

OH OH O

O

OH

t

OH OH HO S

S

O n

OTs

O

S S

2) P(OEt)3, Δ

O n S

OTs

S O

O

O

O n

n S

S

(n = 0 or 1)

S

39

S

But

t

O But t

Bu

O

O

O S

OH OH

S O

O

S

S

S

S

S

S

40

O

O

O

O

Bu

O HO

t

HO

t

Bu

Bu

O

But

t

Bu

yield; this functionalized NO2S2 macrocycle was shown to a chromoionophore with Hg+2 selectivity.

S N

O N

NO2

N

O S

41 8.12

CARBON-SILICON/SELENIUM/TELLURIUM RINGS

An interesting synthesis of numerous (>40) 4- to 12-membered ring heterocycles containing different combinations of Group 14 and 16 elements [Si, Sn, S, Se, and Te] has been reported from Į,Ȧ-dihalides utilized gem-dialkylsilyl and gem-dialkylstannyl moieties in the precursors ; oxidation of mixed S(Se, Te)/Si eight-membered rings with NOPF6 or Br2 gave the corresponding dications or a bicyclic dibromide.

8.13

CARBON–METAL RINGS

The expeditious stepwise directed assembly of large homochiral metallocycles with up to 38 6,6'-bis(alkynyl)-1,1'-binaphthalene bridging ligands and 38 trans-Pt(PEt3)2 centers as well as possessing cavities as large as 22 nm in diameter has been reported . The reaction of 3,5-diethynylpyridine with [AuCl(SMe2)] and NEt3 gave {Au2[ȝ(CŁC)2Py]}2, which with monodentates or 1,6-bis(diphenylphosphino)hexane gave the neutral complexes of the general formula {(AuL)2[ȝ(CŁC)2Py]} .

478

8.14

G.R. Newkome

CARBON–NITROGEN–METAL RINGS

The treatment of dendritic ligands possessing directed pyridine end-groups with diplatinum acceptors both possessing a 120 ° angles lead to the self-assembled hexameric core (42) of a metallodendritic family . The reaction of a series of di-directed metal-terminated accepters, based on 3,6-bis[trans-Pt(PEt3)2(NO3)]phenanthrene and related extended counterparts with a tridirectional tetrahedral donor [tris(4-pyridinylethynylphenylene)ethane] gave three-dimensional M3L2 trigonal-bipyramidal cages; for related systems, also see . The very unique self-assembly of a 1-perfluoroalkyl-2,6-di(4-diethynylpyridine) with Pd(NO3)2 gave a well-confined molecularscale fluorous "droplet" and has been considered a "inverse dendrimer" . The self-complementary assembly of metallomacrocycles has been accomplished by the mixing of equimolar amounts of N,N'-bis(pyridin-4-yl)pyridine-2,6-dicarboxyamide, [RuCl2(PPh3)2] and 1,3-bis(diphenylphosphino)propane . Treatment of four equivalents of N,N',N"-tris(3-pyridinyl)-1,3,5-benzenetricarboxamide with three equivalents of Pd(NO3)2 in DMSO gave a quantitative yield of a single self-assembled cage, , assigned by a single crystal structure . As a continued effort to prepared hexameric systems based on the self-assembly of directed bis-terpyridine monomers, several interesting in families, e.g. 43, of iron and ruthenium connectivity have appeared . But in the assembly process, the creation of a three-step procedure to the novel first nondendritic fractal 44 entitled the "Sierpinski hexagonal gasket" was reported . O(Gn)

N

O

O

N N

N N

N N

N N

N N

N

Et3P Pt PEt3

Et3P Pt PEt3

N

N

N N

N N

N

N N

= FeII, X = PF6¯ or ZnII, X = BF4¯

N

(Gn)O

42

Et3P N Pt PEt3 O

n=0-3

N N

N N

N N

N

O(Gn) PEt3 Pt Et3P N

8.15

N N

N PEt3 Pt Et3P

Et3P N Pt PEt3

N N

N N

N N

N N

N N

N N

N

43

CARBON–OXYGEN–NITROGEN–METAL RINGS

The treatment of triazacyclononane with TsO(CH2)2OC6H4O(CH2)2OCH2-bpy gave (40%) the desired tris-armed macrocycle, which with Fe(II) gave the red crystalline tricyclic pseudocryptand 45 . The selective formation of a homo- or hetero-cavitand cage of two molecules of tetra(4-pyridinyl)-, tetrakis(4-cyanophenyl)-, or tetrakis(4pyridinylethynyl)cavitands with four molecules of Pd(dppp)(OTf)2 or Pt(dppp)(OTf)2 has been reported .

479


CH3

H3 C

N N N Ru N N N

N N N Ru N N N

N N N Ru N N N

84 PF6-

CH3 N N N Ru N N N

CH3 N N N Ru N N N

H 3C

CH3 N N N Fe N N N

N N N Ru N N N

N N N Ru N N N

N N N Ru N N N

N N N Fe N N N

N N N Ru N N N

N N N Ru N N N

CH3

CH3 N N N Ru N N N

H3C

N N N Ru N N N

N N N Ru N N N

N N N Ru N N N

N N N Ru N N N

N N N Ru N N N

CH3

H3 C

N N N Fe N N N

N N N Ru N N N

H3 C

N N N Ru N N N

N N N Ru N N N

CH3

N N N Fe N N N

N N N Ru N N N

N N N Ru N N N

N N N Ru N N N

N N N Ru N N N

H3 C

CH3

N N N Ru N N N

N N N Ru N N N

CH3 N N N Ru N N N

CH3 H 3C

N N N Ru N N N

N N N Ru N N N

N N N Fe N N N

N N N Ru N N N

N N N Ru N N N

N N N Fe N N N

N N N Ru N N N

CH3

N N N Ru N N N

CH3

CH3 N N N Ru N N N

44

H3C

N N N Ru N N N

N N N Ru N N N

N N N Ru N N N

= RuII = FeII

CH3

CH3

8.16

CARBON–SILICON/GERMANIUM–NITROGEN–METAL RINGS

The self-assembly of di[4-(5-pyrimidyl)phenyl]dimethylsilane and -germane with (ethylenediamine)palladium dinitrate in an 1:2 ratio generated a new octahedral supramolecule containing group 14 elements .

8.17

CARBON-PHOSPHORUS-OXYGEN-METAL RINGS

To a solution of either [Rh(CO)2(Cl)]2 or [Cu(MeCN)4]PF6 in CH2Cl2, a THF solution of [5,15-bis[4-(2-diphenylphosphanylethoxy)phenyl]-10,20-bis(mesityl) porphyrinato]zinc(II) (L) was added to give (94 or 92%) the desired [LRhCl(CO)]2 or [LCu(MeCN)2(PF6)]2 macrocycles 46 or 47, respectively . M e s N

N

O O O O

N N

O

O

O

N

N

N

FeN

8.18 04MI01

L' M

N

L M e s

Ph 2 P

O O O O

N

N

2+ O 2X¯

M e s

L

P Ph 2 M L' P Ph 2

N

N

N

45

Ph 2 P

Z n N

Z n N

N

O

M e s

46 M = RhI, L = CO, L‘ = Cl¯ 47 M = CuI, L = L‘ = CH3CN, X = PF6¯ REFERENCES J. P. Tierney, P. Lidstrom, Microwave Assisted Organic Chemistry, CRC Press, Boca Raton, FL 2004.

480 05ACIE7283 05ACR243 05CCCC1493 05CCR2510 05CEJ4655 05COC337 05COC1167 05EJOC5039 05JOMC5485 05OBC112 05RCR461 05RCR969 05RJOC787 05SL263 05T5363 05T7924 05T8551 05T10738 05T12350 05TCC67 05TCC99 05TCC133 05TCC141 05TCC203 05TCC261 05TCR4314 06AC(E)o4952 06ACIE1364 06ACIE2834 06ACIE4290 06ACIE5487 06ACIE6086 06ACR841 06CC788 06CC2105 06CC2224 06CC2941 06CC3346 06CC3818 06CC3900 06CC4584 06CC5054 06CCR468 06CEJ105 06CEJ865 06CEJ1807 06CEJ1906

G.R. Newkome

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06CEJ4069 06CEJ4594 06CEJ4909 06CEJ5603 06CEJ8566 06CHC125 06CHC206 06COC643 06CR767 06CR782 06CR2527 06CR5274 06CR5291 06CRC862 06CRC1022

06CSR83 06CSR361 06CSR1135 06DMP413 06DT3518 06DT3617 06DT4000 06DT4124 06EJIC2377 06EJIC2997 06EJOC154 06EJOC378 06EJOC516 06EJOC1109 06EJOC1319 06EJOC2296 06EJOC3575 06ICC50 06ICC180 06ICC1063 06JA1531 06JA3488 06JA3530 06JA10014 06JA11150 06JA11286 06JA11760

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482 06JA14949 06JA16286 06JA16740 06JIPMC31 06JIPMC253 06JOC504 06JOC811 06JOC2972 06JOC4155 06JOC4509 06JOC5051 06JOC6110 06JOC6124 06JOC7477 06JOC8614 06JOC8787 06JOC9464 06M4696

06MI1273 06MI1782 04O5707 06OL211 06OL629 06OL1029 06OL1069 06OL1169 06OL1311 06OL1371 06OL1641 06OL1859 06OL2511 06OL2619 06OL2755 06OL3355 06OL3991 06OL4161 06OL4279 06OL4847 06OL4895 06OL5113 06OL5133 06OL5263 06OL5541 06OL5713 06OM3105

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06P599 06P801 06PAC29 06PAC699 06S654 06S756 06S759 06SL87 06T149 06T1979 06T3056 06T3081 06T4128 06T4173 06T6855 06T8550 06T9153 06T10039 06TL117 06TL413 06TL497 06TL1303 06TL1817 06TL2371 06TL3541 06TL4041 06TL4817 06TL6012 06TL6357

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483

484 INDEX N-Acetylneuraminic acid, 295 Adenosine-N-oxides, 310 Aerothionin, 294 Aflatoxin B2, 181 Alkylidenedithiolanes, 202 3-Alkylidenetetrahydrofurans, 191 2-Alkylidenetetrahydrofurans, 191 2-Amino-1,3,4-oxadiazoles, 309 4-Amino-5-nitrosopyrimidines, 427 2-Aminofuran, 179 6-Aminopenicillanate, 100 4-Aminoquinolines, 288 Amphidinolide, 103 Antimalarial agents, 452 4-Aryl-3,3-difluoro-β-lactams, 93 trans-2-Aryl-3-chloro-β-lactams, 93 3-Aryl-furans, 184 N-Arylhexahydropyrimidines, 94 10-Aza-9-thiaphenanthrenes, 27 7-Azabicyclo[4.2.1]nonene, 95 Azacalix[n](2,6)pyridines, 468 1-Azafenestrane, 94 7-Azaindoles, 160 Azapalladabicyclo[3.2.1]octanes, 105 5-Azapurines, 423 1,3-Azasiletane, 104 5-Azatropolone, 437 2-Azatryptophans, 212 Azepanes, 438 1H-Azepine-4,5-dione, 437 Azepinones, 308, 439, 440 Azetidin-2,3-diones, as synthonS, 97 Azetidin-2-thione, 95 Azetidin-2-ones, 96, 97 Azetidin-3-ones, 93, 94 L-2-Azetidinecarboxylic acid, 92 Azetidines, spirocyclic, 94 4-Azido-1,3,5-triazines, 423 Aziridino[1,2,3]oxathiazinane dioxide, 458 2H-Azirines, 449 Azocinones. 308 Bacteriochlorin, 45, 46 Bengazole A, 302 Benz[f][1,4]oxazepin-5-ones, 455

3-Benzazepin-2-one, 442 2-Benzazepine, 1-phosphonylated, 444 1-Benzazepine. 444 Benzazulene, 289 Benzimidazo[1,2-a]quinolines, 225 1,3-Benzimidazoles, 223 1,2-Benzisoxazoles, 290 Benzo[b]benzo[2,3-d]thiophen-6,9diones, 114 Benzo[b]furan-2-aldehyde, 198 Benzo[b]furan-3-one, 197 Benzo[b]furans, 195, 196 Benzo[b]thiophenes, 114, 118, 119, 126 Benzo[c][1,2]thiazines, 21 Benzo[c]carbazoles, 160 Benzo[c]pyrroles, 147 Benzo[c]selenophenes, 127 Benzo[c]tellurophenes, 127 1H-Benzo[d]azepines, 333 Benzo[b]furoisocoumarins , 196 Benzo[d]thiazoles, 250, 260, 261 2H-Benzo[e]indazoles, 226 2H-Benzo[g]indazoles, 226 Benzocispentacin, 98 1,4-Benzodiazepin-2-one, 450 1,5-Benzodiazepine, 451 1,5-Benzodiazepine. 452 1,4-Benzodiazepine-2,5-diones, 450, 460 1,4-Benzodiazepines, 459 Benzodioxoles, 278 Benzodithiole, 280 Benzofurans, aromaticity, 198 Benzonitrile N-oxides, 294 Benzoporphyrins. 44 1,2-Benzothiazepine 1,1-dioxides, 455 1,5-Benzothiazepine, 456 4,1-Benzothiazepines, 98 2,1-Benzothiazines, 1 Benzothieno[2,3-b]benzothiophenes, 125 Benzothieno[3,2-b]benzothiophenes, 122 Benzothiepine, 448 3H-1,3,4-Benzotriazepines, 458 1,3,4-Benzotriazepines, 460 1,4-Benzoxazepine, 460

Index

2-Benzoxepin-4-ols, 446 3-(Benzyloxycarbonyl)amino-6methylsulfinyl-1,2,4,5-tetrazine, 421 9,9’-Binaphtha[2,1-b]furanyl-8,8’-diol, 198 Binaphthyl azepinium salt, 445 Biosynthesis of marine oxazoles, 298 Bipinnatin J, 179 4,4'-Bipyrazole, 179 Bis(pyrrolo[2,3-c]pyrimido[5,4e]pyridazines, 427 Bis[1]benzothieno[2,3-c:3',2'i][1,10]phenanthrolines, 120 Bisnaphthohexaphyrin, 48 2,2'-Bithiophenes, 118, 119, 123, 124 Brevione B, 192 3-Bromofuran, 179 Bromo-γ-hydroxybutenolides, 179 C60, 48-51 Calafianin, 294 Calix[1]phosphole[1]furan[2]pyrroles, 475 Calix[1]phosphole[1]thiophene[2]pyrrol es, 475 Calix[4]arenes, 292, 425, 476 Calix[4]areno[2]catenanes, 471 Calix[4]arenocrowns, 471 Carbapenems, 100 Cathepsin K, 440, 459 Cephalosporin, 100 Chartellines, 98 Chemiluminescence, 101, 102 Chlorins, 44, 45, 58. 63 3-Chloro-4-iodofurans, 185 Chlorophyll a, 44 Cholecystokinin, 460 Cladiella-6,11-dien-3-ol, 190 Colchicines, 460 Combretastatin A-4, 96 Confused isoquinoporphyrin, 48 Cornforth rearrangement, 300 Corrole, 49 Cyclodextrin, 292 Cyclohepta[d]thiazole, 260 4H-Cyclopenta[2,1-b:3,4-b']dithiophen4-ones, 120 Cyclopenta[b]pyrroles, 144 Cyclopenta[c]thiophenes, 124

485 Cyclopenta[d]-2-(1H)pyrimidinones, 364 Cyclopenta[d]thiazole, 260 5H-Cyclopentapyrazines, 223 Cyclotetrasilene, 104 Cytoxazene, 309 1,3-DC, regioselectivity, 291 Deacetoxyalcyonin acetate, 190 Decaturin D, 192 Descurainin, 191 5-Dethia-5-oxa-cephams, 99 N,N'-Di(2-pyridyl)-2,4-diamino-6phenyl-1,3,5-triazine, 417 3,6-Di(pyridin-2-yl)-1,2,4,5-tetrazines, 421 Dialuminacyclobutene, 106 2,8-Diamino purines, 423 4,6-Diamino-1,3,5-triazines, 417 Diaza[12]annulenes, 469 Diazetidines, 387 Δ2-1,2-Diazetines, 95 Diazido-1,2,4,5-tetrazines, 417 Diazirine, 278 5H-[1,2]Diazocin-4-ones, 290 Diazonamide A, 302 10,11-Dibenzo[b,f]thiepine, 448 Dibenzo[c,e][1,2]thiazine 5,5-dioxides, 5 6H-Dibenzo[c,e][1,2]thiazines, 9 7H-Dibenzo[d,f][1,3]thiazepines, 27 Dibenzofurans, 193 Dibenzothiophenes, 121 Dibenzoxepines, 448 Dichloroketene. 279 3,3-Difluoroazetidinone, 95 Difuranylmethane, 184 6,7-Dihydro-1H-azepines on, 441 2,5-Dihydro-2,5-dimethoxyfuran, 179 2,3-Dihydrobenzo[b]furans, 193 Dihydrobenzo[c]furans, 180 5,6-Dihydrobenzo[h]quinazolines, 362 2,3-Dihydrofuran, 181, 192 2,3-Dihydrofuran,, 181 2,5-Dihydrofurans, 182 4,5-Dihydroisoxazoles, 289 5,6-Dihydropyrazin-2(1H)-ones, 99 N,N'-Dimethyldichloromethyleniminium chloride, 427 6-Dinitromethyl-1,3,5-triazines, 418

486 1,4-Dioxaspiro[4.5]decane, 97 1,7-Dioxaspiro[4.5]decanes, 188 1,3-Dioxepines, 453 Dioxetanone, 102 2,4-Dioxohexahydro-1,3,5-triazines, 418 Dioxolanones, 278 1,3-Dioxolium-4-olates, 97 2,5-Diphenylfurans, 179 2,3-Diphenyltetrahydrofurans, 188 Dipyrido[1,2-a:2',3'-d]imidazoles, 225 Dipyrrylmethane, 53 [1,3,2,4]Diselenadiphosphetane, 105 1,2-Diselenolane, 203 Dithia[3.3](2,6)pyridinophanes, 475 1,9-Dithia-5,13-diazacyclohexadecanes, 475 7,11-Dithiaazasteroids, 23 Dithiadiselenafulvalene, 201 Dithieno[3,2-b:2',3'-d]phospholes, 122 1,3-Dithiolane-2,4,5-trithione, 280 1,2-Dithiole-3-thiones, 203 Divinyldioxolanones, 278 Docetaxel, 101 Dpdapt, 417 Episulfonium ion, 416 C-Ethoxycarbonyl nitrene, 295 FAAH, 302 Fatty acid amide hydrolase. 302 Ferrocenyl dioxolane, 278 3-Fluoro-4H-1,3-diazepines, 449 3-Fluoroazetidines, 93 Fluoroazetidinium hydrochloride, 92 Fluorous 1,3,5-triazines, 419 Fluvine A, 422 3-Formytetrahydrofuran, 182 Fucosidase inhibitor, 294 Fullerene. 49, 292 Furan natural products, 176, 177 Furan, cyclopropanation, 180 Furano-1,4-thiazepine, 457 Furano-oxepines, 445 Furanotetrahydroquinolines, 181 Furans froim allenes, 187 Furans from alkynyl cyclopropyl ketones, 186 Furans from alkynyllithiums, 187 Furans from allenones, 186

Index

Furans from enynones, 186 Furans, with SF5, 184 Furfural, 449 Furo[2,3-b]furan, 197 Furo[2,3-b]pyrans, 183 Furo[2,3-b]pyridine-4(1H)-one, 194 Furo[2,3-d]pyrimidines, 370 Furo[2,3-h]chromen-2-one, 193 Furo[3,2-e][1,2,4]triazolo[1,5c]pyrimidines, 233 Furo[3,4-c]coumarins, 188 2-Furylzinc chloride, 184 Galanthamine, 198 Galectins, 291 Glycoproteins, 306 Glycosaminoglycans, 306 D-Gulonolactam, 442 Haloetherification, 188 Heliannuls, 195 1,4,5,8,9,12-Hexaazatriphenylenes, 473 Hexahydroazoninoindoles, 443 Hexaphyrin, 48 [26]Hexaphyrins(1.1.1.1.0.0), 474 4-(3-Hydroxyalkyl)pyrimidine, 182 3H-Imidazo[1,2-a][1,3,5]triazepin-2amines, 458 Imidazo[1,2-a]pyrazines, 371, 373 Imidazo[1,2-a]pyridines, 225, 226 Imidazo[1,2-a]pyrimidines, 222, 225, 362 Imidazo[1,2-a]pyrimidinium salts, 220 3H-Imidazo[1,2-a][1,3,5]triazepine2(7H)-thiones, 458 Imidazo[1,2-b][1,2,4]triazines, 422 Imidazo[1,2-b][1,2,4]triazoles, 233 6H-Imidazo[1,2-b]-1,2,4-triazol-6-ones, 232 Imidazo[1,2-b]pyrazole, 218 Imidazo[1,2-d][1,2,4]triazin-8-ones, 422 Imidazo[1,5-a]pyridines, 225, 226 Imidazo[2,1-f][1,2,4]triazin-8-ones, 422 Imidazo[4,5-f][1,10]phenanthrolines, 121 5H-Imidazo[5,1-a]isoindoles, 225 Imidazo-benzazepine, 443 Imidazoporphyrin-C60, 56 Indazolo[2,3-a]quinolizine, 416 Indeno[1,2-b]thiophenes, 113 Indeno[1,2-d]pyrimidinones, 364

Index

Indeno[1,2-e]pyrrolo[1,2-a]isoindoles, 364 Indeno[1,2-e]pyrrolo[1,2a]pyrimidinones, 364 Indolizines, 322 Inthomycin B, 302 5-Iodoisoxazolines, 291 Isatin, 51 Isobacteriochlorins, 58, 59 Isoindolo[2,1-c]benzo[1,2,4]triazines, 427 Isoxazole-5-carboxylates, 290 4-Isoxazolecarbaldehyde, 289 Isoxazolo[4,3-c][2,1]benzothiazines, 23 Isoxazolo[3,4-d]pyridazines, 426 5H,11H-Isoxazolo[4,5-c]thiopyrano[3,2c][2,1]benzothiazines, 24 Isoxazolylcyclobutanones, 290 Lactacystin β-lactone, 103 β-Lactamase. 98 β-Lactams, 93 β-Lactams, 95, 96 Lactonamycin, 190 Manzamine A, 177 Melanostatin, 98 3-Mercapto-1,2,4-triazines, 415 Metabotropic glutamate receptor. 301 2-Methoxyazepinium ion, 437 2-Methoxyfurans, 180 3-Methylenetetrahydrofurans, 192 N-Methylglycine, 49 3-Methylsulfinyl-6-methylthio-1,2,4,5tetrazine, 421 Molybdenacyclobutanes, 106 Myoseverin, 426 Naphtha[2,3-b]furan, 194 Naphthacene, 49 Naphtho[2,1-b]furo[3,2-d]pyrimidines, 364 Naphtho[2,3-b]furans, 198 Naphtho[a]carbazoles, 160 Naphthohexaphyrin, 48 Naphthoporphyrins. 45, 46 Nitrile oxide 1,3-DC, 65, 291, 292 4-Nitroisoxazoles, 290 3-Nitroisoxazolines, 293 Nitrone 1,3-DC reactions, 296, 443 Norbornadiene, 65

487 Nostocine A, 422 Octaphyrin, 61 Ophirin B, 190 7-Oxabenzo-norbornadienes, 182 7-Oxabicyclo[2.2.1]hept-5-ene, 99 Oxacalix[2]arene[2]hetarenes, 472 Oxacillin, 100 1,2,4-Oxadiazoles, 394 7-Oxa-norbornadienes, 182 1,3-Oxasiletane, 104 [1,2,3]Oxathiazepane 2,2-dioxides, 458 1,3-Oxathiolanones, 202 Oxazaborolidine, 102 1,4-Oxazepan-2-one, 453 1,4-Oxazepine, 454 1,3-Oxazepines, 454 1,2-Oxazetidines, 78 Oxazole-4-carboxaldehyde. 301 Oxazole-4-carboxamides, 300 5-Oxazoleacetates, 299 Oxazole-containing peptides, 300 Oxazolidine, 439 Oxazolidinone, 307, 308, 439 Oxazoline ligands, enantiopure, 305-307 Oxazolo[3,2-a]pyrimidin-5-ones, 366 Oxazolo[3,2-a]pyrimidin-7-ones, 366 Oxazolomycin, 103 Oxepane, 207 Oxepines 437 Oxepino β-carboline, 447 Oxiranes, 419 6-Oxo[1,2,4]triazin-1-yl-alaninamides, 415 4-Oxoazetidine. 95 Ozonide, 203 Paclitaxel, 100 [2.2]Paracyclophanes, 305 Paternò–Büchi reaction, 101 Pentathiepins, 459 Penicillin V, 100 Pentacene, 48 (Pentafluorophenyl)porphyrin, tetrakis, 46, 49, 61 Pentamethylferrocene, 305 [1,2,3,4,5]Pentathienopino[6,7b]pyrroles, 147 Peraza[2.2.2]cryptands, 469

488 Phorboxazole B, 302 Phosgeniminium chloride, 427 1-Phospha-1-aza-18-crown-6-ethers, 475 Phosphaalkenes, 106 Phosphapalladacycle, 105 1,3-Phosphasiletane, 104 Phosphazenes, 105 Photochromism, 198 Photodynamic therapy, 64 PHOX ligands, 305 Phthalocyanin, 201 Phytochlorin-C60 diad, 53 Phytochlorin–C60,, 55 PirateTM, 300 Polyanthellin A, 190 Porphyrin-α-dione, 65 N-(Porphyrin-2-ylmethyl)glycine, 57 Porphyrincalix[4]arenes, 465 Porphyrinic azomethine ylides, 55 Porphyrinic nitrile oxides, 57 Porphyrinic pyridinium ylides, 57 Positron emission tomography, 416 Propargylic dithioacetals, 188 Protoporphyrin IX, 44 Pseudomonic acid, 300 Pseudouridines, 290 Pterins, 427 Purines, magnesiation, 425 Pxycalix[4]arene, 292 Pybox, 305 Pyrano[2,3-c]pyrazol-6-ones, 218 1H,6H-Pyrano[2,3-c]pyrazol-6-ones, 218 Pyrano[2,3-c]pyridazines, 356 Pyrano[3,2-c]quinolin-2,5(6H)-diones, 329 Pyrazin-2-ones, 385 Pyrazino[1,2-a]indoles, 371 2(1H)-Pyrazinones, 371 1H,5H-Pyrazolo[1,2-a][1,2,4]triazoles, 233 Pyrazolo[1',5':1,6]pyrimido[4,5d]pyridazinones, 357, 428 Pyrazolo[1,5-a][1,3,5]triazines, 423 Pyrazolo[1,5-a]pyrimidin-7-(4H)-one, 426 Pyrazolo[1,5-a]pyrimidine, 218, 361, 362, 364, 369, 426

Index

Pyrazolo[1,5-d][1,2,4]triazines, 422 Pyrazolo[3,4-b]pyridines, 218 Pyrazolo[3,4c][1,5,2]diazaphosphinines, 218 Pyrazolo[3,4-c]1,2-thiazines, 20 Pyrazolo[3,4-c]pyridazines, 357 1H-Pyrazolo[3,4-d]pyridazine-3,6diones, 218 Pyrazolo[3,4-d]pyridazines, 357 Pyrazolo[3,4-d]pyridazines, 426 Pyrazolo[3,4-d]pyrimidine, 426 Pyrazolo[3,4-d]pyrimidine, 426 Pyrazolo[3,4-d]pyrimidine, 364, 368, 426 Pyrazolo[4',3':5,6]thiopyranol[4,3b]quinolines, 214 3H-Pyrazolo[4,3-c]thiopyrano[3,2c][2,1]benzothiazines, 24 Pyrazolo[4,3-d][1,2]diazepine-8carboxylates, 450 Pyrazolo[4,3-d]pyrimidin-7-ones, 364 Pyrazolo[4,3-d]pyrimidines, 426 Pyrazolo[4,3-e][1,2,4]triazine, 422 Pyrazolo[4,3-e][1,2,4]triazolo[1,5c]pyrimidines, 353, 368, 428 Pyrazolo[4,3-e]pyrrolo[1,2-a]pyrazines, 374 Pyrazolo[5,1-c]1,2,4-thiadiazines, 20 Pyrazolones, 414 Pyridazin-3-ones, 385 Pyridazin-4-ones, 386 Pyridazine-3,6-diones, 388 Pyridazino[3,4-a]carbazoles, 355 Pyridazino[3,4-b]indoles, 388 Pyridazino[3’,4’:3,4]pyrazolo[5,1-c]1,2,4-triazines, 427 Pyridazino[4',3':4,5]thieno[3,2-d]1,2,3triazines, 355 Pyridazino[4,5-b][1,8]naphthyridin6(7H)-ones, 355 Pyridazino[4,5-c]pyridazine, 428 Pyridazino[4,5-d]pyridazine, 428 3H-Pyridazino[5,4,3-kl]acridin-3-ones, 356 [7.7](2,6)Pyridinocyclophanes, 473 [n](2,5)Pyridinophanes, 469 Pyrido[1',2':1,5]pyrazolo[3,4d]pyrimidines, 369 Pyrido[2,3-b][1,5]benzodiazepines, 460 Pyrido[2,3-b]pyrazines, 372 Pyrido[4,3-d]pyrimidin-2-ones, 428

Index

1H-Pyrido[2,3-d]pyrimidin-4-ones, 361 Pyrido[2,3-d]pyrimidin-7-ones, 361 Pyrido[2,3-d]pyrimidines, 365, 368 Pyrido[3",2":4',5']thieno[3',2':4,5]pyrimi do[1,6-a]benzimidazoles, 363 Pyrido[3',2':4,5]thieno[3,2d]pyrimidines, 363 Pyrido[3',2':5,6]thiopyrano[4,3c]pyridazin-3(2H,5H)-ones, 355 Pyrido[3,2-b]oxepine, 447 Pyrido[3,2-e][1,2,4]triazolo[4,3a]pyrazines, 371 Pyrido[4,3,2-mn]pyrrolo[3,2,1de]acridines, 163 Pyrido[4,3-b]pyrimidines, 365 Pyridotriazine, 427 Pyrimidin-2(1H)-ones, 385, 395, 419 Pyrimidin-4-ones, 385 Pyrimidine-5-carbaldehyde, 290 Pyrimido[3',2':4,5]thieno[3,2d]pyrimidinones, 428 Pyrimido[4',5':4,5]thieno[2,3c]pyridazines, 356 Pyrimido[4,5-b][1,4]benzodiazepines. 452, 460 Pyrimido[4,5-b]-1,4-diazepines, 460 Pyrimido[4,5-b]-1,4-thiazepines, 460 Pyrimido[4,5-c]pyridazin-5,7-diones, 353, 427 Pyrimido[4,5-c]pyridazines, 356, 427 Pyrimido[4,5-d]pyrimidin-2-ones, 427, 428 Pyrimido[4,5-d]pyrimidines, 365 Pyrimidopyrido[4',3':4,5]thieno[2,3d]pyrimidines, 361 Pyrroline N-oxides, 296 Pyrrolo[1,2-a]azepine, 437 Pyrrolo[1,2-b][1,2,5]benzothiazepines, 460 Pyrrolo[1,2-b]pyridazines, 141 Pyrrolo[1,2-b]pyridazines, 355 4H-Pyrrolo[1,2-c][1,2,3]triazoles, 230 Pyrrolo[2,1-a]isoquinolines, 141, 147 Pyrrolo[2,1-b][1,4]benzodiazepineazepane, 460 Pyrrolo[2,1-b]thiazoles, 141 Pyrrolo[2,1-c][1,4]benzodiazepine, 460 Pyrrolo[2,1-f][1,2,4]triazine, 422 Pyrrolo[2,3-b]indol-2-ones, 153 Pyrrolo[2,3-b]indoles, 157

489 3H-Pyrrolo[2,3-d]pyrimidin-2(7H)-ones, 369 Pyrrolo[2,3-d]pyrimidine-2,4-diones, 364 Pyrrolo[2,3-d]pyrimidines, 363, 369, 370 Pyrrolo[3,2,1-hi]indazoles, 158 Pyrrolo[3,2-d]pyrimidines, 361 Pyrrolo-1,5-benzoxazepines, 460 Pyrroloporphyrins, 51 Pyrrolylthieno[2,3-d]pyrimidines, 360 Quinuclidines, 308 Rasfonin, 179 Rhazinilam, 103 Ring closing metathesis, sevenmembered rings, 438 Salinosporamide A, 103 Sapphyrin, 49 1,3-Selenazolidin-4-ones, 273 1,3-Selenazolidines, 273 Silyl nitronate, 293 Silylisoxazoles, 288 Silylmethylisoxazoles, 288 Silylmethylpyrazoles. 288 Silylpyrazoles, 288 Singlet oxygen, 101, 102, 179 SIPHOX, 305 Spirobutenolide, 178 3-Spirocyclopropanated 2-azetidinones, 99 5-Spirocyclopropane isoxazolidines, 295 3-Spirocyclopropane monobactams, 296 3-Spirocyclopropane β-lactam, 295 Spiroisoxazolines, 294 Spironucleosides, 104 Spiro-β-lactams, 99 Stemona alkaloids, 437 N-Sulfinylimines, 279 β-Sultams, 295 TADDOL, 195 Taxol, 101 Telomestatin, 301 Tetraarylporphyrins, 45, 46 Tetraazabacteriochlorin, 49 Tetraazacalix[2]arene[2]triazines, 420 1,4,7,10-Tetraazacyclododecanes, 469 Tetraazaporphine, 49 1,2,4,5-Tetrazine-3,6-dicarboxylate, 421

490 1,4,8,11Tetraazatricyclo[9.3.3.34,8]eicosanes, 469 Tetrahydrofuran synthesis, 189-191 Tetrahydrofuranyl oxonium ions, 183 Tetrahydroimidazo[1,2a][1,3,5]triazepin-2-thiones, 428 Tetrahydrolipstatin, 103 Tetrahydroquinolines, 326 Tetraselenafulvalene, 201 Tetrathiafulvalene, 201 1,2,4,5-Tetrazin-3(2H)-one, 420 [1,2,3,4]Tetrazine-5-carboxylic acid, 410 1,2,4,5-Tetrazines, 387 1,2,4,5-Tetrazines, inverse electron demand DA reactions, 421 Tetrazolo[1,5-a][1,3,5]triazin-7-ones, 234, 423 Tetrazolo[1,5-a]quinoxalines, 234 Tetrazolo[5,1-c][1,2,4]triazines, 423 Tetrazolo-uracil, 458 1,3,4-Thiadiazoles, 271 1,2,4-Thiadiazoles, 271 7H-1,3,4-Thiadiazolo[3,2-a]pyrimidin7-ones, 360 1,3-Thiasiletane, 104 1,4-Thiazepine-5-carboxamides, 456 1,3-Thiazepines, 253 1,2-Thiazetidine 1,1,-dioxides, 103, 295 1,2-Thiazetidine 1-oxide, 104 1,2-Thiazinylium salts, 28 Thiazolino[3,2-c]pyrimidine-5,7-diones, 369 [1,3]Thiazolo[3,2-a][1,3,5]triazine, 423 5H-Thiazolo[3,2-a]pyridine-5-ones, 246 Thiazolo[5,4-d]pyrimidines, 362 Thieno[2,3-b]pyridines, 114, 127 Thieno[2,3-b]pyrroles, 126 Thieno[2,3-b]thiophenes, 119, 120, 126 Thieno[2,3-c]furans, 120 Thieno[2,3-c]pyridazines, 356 Thieno[2,3-d][4,5-d]dipyrimidines, 360 Thieno[2,3-d]pyrimidin-4(1H)-ones, 370 Thieno[2,3-e][1,2,4]triazolo[1,5c]pyrimidin-5(6H)-ones, 363 Thieno[3,2-b]pyridines, 113 Thieno[3,2-c][1λ4,2]thiazines, 22 Thieno[3,4-b]thiophenes, 125 1H-Thieno[3,4-c][1,2]thiazines, 21

Index

Thietan-3-one, 104 Thiiranes, 419 Thiiranethione, 280 Thiocarbonyl ylides, 280 2H,6H-Thiopyrano[3,2c][2,1]benzothiazines, 23 3-Thioxo-1,2,4-triazin-5(4H)-ones, 416 N-Tosyl-3-halo-3-butenylamines. 93 Traversianal, 181 Triazacyclononanes, 478 4,7a,12b-Triazadibenzo[e,g]azulene1,3,8-triones, 357 1,3,5-Triazapentadienes, 417 1,3,5-Triazepane-2,6-dione, 458, 460 5H-1,3,5-Triazepine-2,4-dione, 458 1H-[1,3,5]Triazin-2-ones, 419 1,2,4-Triazin-3-thion-5-one, 415, 427 1,2,4-Triazin-5(4H)-ones. 416 1,2,4-Triazine 4-oxide. 416 1,2,3Triazine[4'',5'':4',5']thieno[3',2':4,5]thien o[3,2-d]-1,2,3-triazines, 428 1,2,4-Triazine-3,5(2H, 4H)-diones, 416 [1,2,4]Triazine-3-thione, 415 1,2,4-Triazines, 316 Triazinoisoquinoline, 427 Triazinoquinoline, 427 1,2,4-Triazoles, 387 1,2,4-Triazoline-3,5-dione, 428 [1,2,4]Triazolo[4,3-a]pyrazines, 374 Triazolino[4,3-a]pyrimidines, 364, 426 Triazolium salts, 289 1,2,4-Triazolo[1,5-a][1,3,5]triazines, 423 [1,2,4]Triazolo[1,5-a]pyrazines, 374 [1,2,3]Triazolo[1,5-a]pyridines, 230 [1,2,4]Triazolo[1,5-a]pyrimidines, 368 [1,2,4]Triazolo[1,5-c]pyrimidin-5amines, 368 1,2,4-Triazolo[3,4-f][1,2,4]triazin8(7H)-one, 423 [1,2,4]Triazolo[4,3-a]pyridines, 233 1,2,4-Triazolo[4,3-a]pyrimidin-7-ones, 359 1,2,4-Triazolo[4,3-a]quinoxalines, 233 1,2,4-Triazolo[4,3-b]pyridazines, 232, 354 1,2,4-Triazolo[4,5-a]pyrimidin-5-ones, 361

Index

[1,2,3]Triazolo[4,5-b]porphyrins, 468 1H-1,2,3-Triazolo[4,5-c]pyridines, 230 1,2,3-Triazolo[4,5-d]-1,2,4-triazolo[1,5a]pyrimidin-9-ones, 230 7H-1,2,3-Triazolo[4,5-d]pyrimidin-7ones, 360 7H-1,2,3-Triazolo[4,5-d]pyrimidin-7ones, 364 3H-1,2,3-Triazolo[4,5-d]pyrimidines, 230 1,2,3-Triazolo[4,5-d]pyrimidines, 367 2,4,6-Trichloro-1,3,5-triazine, 417 4-Trifloyloxazoles, 301 2-Trimethylsilyloxyfuran, 178 1,3,6-Trioxa-7-azacyclopenta[cd]indene, 191 1,2,4-Trioxepanes, 458 Triphenylporphyrin, 54, 64 Tripodal oxazolines, 304 Tripyrrane, 59 1,4,7-Trithia-11-azacyclotetradecanes, 475 1,2,3-Trithiolane. 203 TTF, 201 Ulocladol. 447 Uracil, 427 Uracyl-5-carbaldehyde, 290 Valilactone, 103 (S)-Valinol, 303 Vinblastine, 460 Vinylporphyrins, 44 Williamson ether synthesis, 189 Woollins' reagentm 105 Xanthine, 426 (S)-Xyl-BINAP, 199 Xyloketal A, 182 Zinc porphyrin, 292 3-Zinciobenzo[b]furans, 195

491

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