Heterocyclic Chemistry: v.4 (Specialist Periodical Reports)

Heterocyclic Chemistry Volume 4 A Specialist Periodical Report Heterocyclic Chemistry Volume 4 A Review of the Liter...

Author: H. Suschitzky | O.Meth- Cohn

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Heterocyclic Chemistry Volume 4

A Specialist Periodical Report

Heterocyclic Chemistry Volume 4 A Review of the Literature Abstracted between July 1981 and June 1982

Senior Reporters

H. Suschitzky Department of Chemistry and Applied Chemistry, University of Salford 0 . Meth-Cohn C.S./.R.,Pretoria, South Africa Reporters

G . V. Boyd Chelsea College, London S . D. Carter Queen Elizabeth College, London G . W. H . Cheeseman Queen Elizabeth College, London G . P. Ellis UWIST, Cardiff S. Gronowitz University of Lund, Sweden 0 . Guilloton University of Nantes, France T. V. Lee Brunel University, Middlesex J. R. Malpass University of Leicester T. J. Mason Lanchester Polytechnic, Coventry H. Quiniou University of Nantes, France J. M. E. Quirke Florida International University, USA J. T. Sharp University of Edinburgh

The Royal Society of Chemistry Burlington House, London W I V OBN

ISBN 0-85 186-833-9 ISSN 0144-8773

Copyright 0 1985 The Royal Society of Chemistry

All Rights Reserved No part of this book may be reproduced or transmitted in any form or by any means - graphic, electronic, including photocopying, recording, taping, or information storage and retrieval systems - without written permission from The Royal Society of Chemistry

Printed in Great Britain at the Alden Press, Oxford, London and Northampton

In tr oduc t ion Volume 4 includes the abstracted literature on heterocyclic chemistry between July 1981 and June 1982 (i.e. Volumes 95 and 96 of Chemical Abstracts). The format of previous volumes in respect of chapter arrangement has been retained, to allow the reader to study readily the progress in an area of heterocyclic chemistry through all of the four volumes, helped also by a detailed list of Contents. Our reviewers have again admirably succeeded in distilling out the salient features of several thousand references and have presented them in a concise and readable report. They have also co-operated with skill and patience in a cost-cutting exercise designed by the RSC editors, and have produced diagrams by a new method. I t is hoped that these efforts will ensure the economic survival of the series and eventually bring down the price to a level which will tempt the individual buyer; the only serious and recurring printing mistake, as one illustrious heterocyclic chemist remarked, is the price! Our thanks to all authors for their forbearance in the handling of gridsheets and supplying excellent manuscripts, and to the editorial staff of the Royal Society of Chemistry for smoothing out difficulties.

H. Suschitzky and 0. Meth-Cohn

Contents

Chapter 1 Three-Membered Ring Systems By T. J. Mason

1

1 Reviews General Rings containing Oxygen Rings containing Nitrogen Rings containing Sulphur 1 1

2 Oxirans Preparation Oxidation of Alkenes, using Oxygen or Oxygencontaining Gases Oxidation of Alkenes by Peroxy-acids Oxidation of Alkenes, using Peroxides Synthesis by Halohydrin Cyclizations and Related Reactions Synthesis via Attack of a Carbanion on the Carbonyl Group of Aldehydes and Ketones Synthesis of Chiral Oxirans Synthesis and Reactivities of Aromatic Oxides Miscellaneous Syntheses Spectra and Theoretical Chemistry Reactions Ring-opening Reactions with Electrophiles Cyclization Reactions N ucleophilic Ring-opening Reactions With Oxygen Nucleophiles With Nitrogen Nucleophiles With Sulphur Nucleophiles With Carbanions Reduction and Elimination Reactions Thermal and Photochemical Reactions Reactions with Organometallic Compounds Miscellaneous Reactions

9 11 15 19 21 22 22 23 25 25 28 28 30 33 34 38 39

3 Aziridines Preparation By Direct Insertion

40 40 40

1 3 5 7

Heterocyclic Chemis0

viii

By Cyclization Reactions By Ring-contraction Reactions Synthesis of Chiral Aziridines Spectral and Theoretical Studies Reactions Thermal Reactions Ring-opening to Acyclic Compounds Formation of Other Ring Systems

42 43 43 43 44 44 45 46

4 Azirines Preparation Reactions

47 47 48

5 Thiirans Preparation Reactions The Chemistry of Thiiranium Ions

49 49 50 51

6 Thiirens

51

7 Diaziridines

52

8 Diazirines

53

9 Dioxirans

54

10 Oxaziridines

Chapter 2 Four-Membered Ring Systems By T. V. Lee

54

57

1 Highlights and Reviews

57

2 Systems containing One Nitrogen Atom Azetidines and Azetines Azetidinones

57 57 58

3 Systems containing Two Nitrogen Atoms or One Nitrogen Atom and a Second Heteroatom

63

4 Systems containing Oxygen Oxe tans Dioxetans

65 65 66

5 Systems containing Sulphur

67

6 Miscellaneous Four-Membered Rings

68

Contents

ix

Chapter 3 Five-Membered Ring Systems By G. V. Boyd, S. Gronowitz, 0. Guilloton, and H. Quiniou Part I Thiophens and their Selenium and Tellurium Analogues

71

71

By S. Gronowitz 1 General

71

2 Monocyclic Thiophens Synthesis by Ring-closure Reactions C4 + S Principle C2S + C2 Principle CS 3- C3 Principle Ring-closure of C4S Ring-closure of CzSCz Synthesis from Other Rmgs From Di- and Tetra-hydrothiophens From Other Sulphur Heterocycles From Other Rings Physical Properties of Monocyclic Thiophens Theoretical Calculations Photoelectron and Ultraviolet Spectra Infrared and Raman Spectra Nuclear Magnetic Resonance Mass Spectrometry X-Ray Investigations Miscellaneous Physical Properties Electrophilic Substitution Reactions Electrophilic Ring-closure Reactions Nucleophilic and Radicaloid Substitution Reactions Organometallic Derivatives Lithium Magnesium Mercury, Zinc, and Copper Transition Metals Silicon Photochemistry Cycloaddition Reactions Desulphurization and Hydrogenation of Simple Thiophens Structures and Reactions of Hydroxy-, Mercapto-, and Amino-thiophens Reactivities of Side-Chains Reactions of Thiophen Aldehydes, Ketones, and Carboxylic Acids Reactions of Vinylthiophens and Related Compounds

72 72 72 73 73 74 75 75 75 76 76 77 77 78 78 78 79 79 80 80 83 86 88 88 92 92 92 93 93 95 97 99 101 102 104

Heterocyclic Chemistry

X

Reactions at Benzylic Positions Various Reactions in the Side-Chains of Thiophens Macrocyclic Thiophens Reaction at Sulphur: Thiophen Dioxides Di- and Tetra-hydrothiophens Arylthiophens and Di- and Poly-heterocycles Naturally Occur ring T hio p hens Thiophen Analogues of Steroids Thiophens of Pharmacological Interest Therapy of the Central Nervous System Pharmacodynamic Agents Therapy of Metabolic Diseases Therapy of Infectious Diseases Veterinary and Agricultural Agents Miscellaneous Activities Thiophens of Technical Interest Polymers from Thiophen

104 105 105 106 108 111 113 114 114 114 115 115 116 118 118 119 119

3 Eknzo[ blthiophens and their Benzo-fused Systems Benzo [b] thiophens Synthesis Physical Properties Reactions Benzo [ b ]thiophen S-Oxides Benzo [ c ]thiophens Dibenzothiophens Pharmacologically Active Compounds

120 120 120 12 1 12 1 123 123 124 124

4 Thiophen Analogues of Polycyclic Aromatic Hydrocarbons Analogues of Anthracene and Phenanthrene Polycyclic Thiophens Thiophen Analogues of Indene Various Carbocycle-fused Systems

125 125 125 127 128

5 Thiophen Fused to Five-Membered Heteroaromatic

Rings Thieno-, Furo-, and Pyrrolo-thiophens Thiophen Fused to Various Five-Membered Rings

129 129 131

6 Thiophen Fused to Six-membered Heteroaromatic Rings Thiophen Analogues of Quinoline Thiophen Analogues of Isoquinoline Pyrimidine-fused Systems Miscellaneous Fused Systems

131 131 132 133 135

7 Selenophens and Tellurophens Monocyclic Selenophens

136 136

Contents

xi Condensed Selenophens Tellurophens

Part I I Systems containing Nitrogen and Sulphur, Selenium, or Tellurium By H. Quiniou and 0.Guilloton

137 138

138

1 Introduction and Reviews

138

2 Isothiazoles Synthesis From Dicyanoacetylene and Sulphur Dioxide (Type A: C-C-C-N + S) From 0-Benzoylpropionamides and Th ionyl Chloride (Type A) From 1,3,2-Oxathiazol-5-ones(Type B; S-N-C + C-C) From 3,3’-Disulphanedipropionyl Chloride and Amine (Type H; S-C-C-C + N) From Aqueous Ammonia and Thioamide Vinylogues (Type H) From Ring-Cleavage of 3 -Azidot h io ph ens From Substituted Enamines and Benzyl Isothiocyanate (Type C-C-N + S-C) Physical Properties Chemical Properties N-Qu at er niz at ion o f Isothiazole s Reactions of 5-Aminoisothiazoles A3-Is0thiazolines Chemical Properties of Isothiazoline-5-thiones A4-1sothiazolines Chemical Properties of Isothiazolin-3-ones Isothiazolidines Physical Properties of Isothiazolidine 1,l -Dioxides

139 139

3 1,2-Benzisothiazolesand their 1,l-Dioxides Synthesis From ortho-Halobenzoyl Compounds, Aqueous Ammonia, and Elemental Sulphur Reactions Reduction 3-Chloro-substitution Photochemistry Synthesis of 1,2-Benzisothiazolin-3-ones and their 1,l-Dioxides From 2-(Methylsulphinyl)benzamides and Thionyl Chloride

139 139 139 140 140 140 141 141 141 141 142 143 143 143 143 143 143

144 144 144 144 144 145 145 145 145


xii

From Anilines and 2-Chlorothiobenzoyl Chloride From 2-Aminobenzonitriles and SO2 From 2-(Chlorothio)benzoyl Chloride and Substituted Anilines From Thermal Decomposition of N-Substituted 2-(Me th ylt h io)benzamides Physical Properties of 1,2-Benzisothiazolin-3-ones Chemical Properties of 1,2-Benzisothiazolin-3-ones Hydrolysis, Alcoholysis, and Phenolysis Reactions of 1,2-Benzisothiazolin-3-ones with Amines N-Substitution of 1,2-Benzisothiazolin-3-ones 1,2-Benzisothiazoline-3-thione 1,l -Dioxides 1,2-Benzisothiazolidinesand their 1,l -Dioxides

146 146 147 147 148 148 148 148 149 149 149

4 1,2-Benzisoselenazoles 1,2-Benzisoselenazolin-3-ones

150 150

5 2,l -Benzisothiazoles

150

6 Other Condensed Ring Systems incorporating Isothiazole Thieno [2,3c] isothiazoles Isothiazolo [3,4411pyridines Isothiazolo [5,44] pyrimidines 1,2-Dithiolo [4,3c] isothiazoles Naphtho [ 2 , l d ] isothiazole Thieno [3,441isothiazole 1,l-Dioxides

151 15 1 15 1 15 1 152 152 152

7 Thiazoles Synthesis Hantzsch’s Synthesis (Type A; S-C-N From thioureas From thioamides Type B Syntheses (C-C-N C-S) Type C Syntheses (C-C-N-C + S) Type F Syntheses (C-N-C-S + C) Type H Syntheses (S-C C-N-C) Physical Properties Tautomerism of 2-Aminothiazoles Reactions of Thiazoles Reactions of Thiazolium Salts

152 152 152 152 153 154 154 154 155 155 157 157 158

+

+

8 A2-Thiazolines Synthesis Type B Syntheses (C-C-N + C-S) Type J Syntheses (C-S-C-N-C) Type K Syntheses (C-C-N-C-S) Type E Syntheses (N-C-C-S + C) Reactions

+ C-C)

160 160 160 16 1 16 1 162 162

Conten ts

xiii

9 A3-Thiazolines

10 A4-Thiazolines Synthesis Type A Syntheses (S-C-N Type B Syntheses (C-C-N Physical Properties Reactions

164

+ C-C) + C-S)

11 Thiazolidines Synthesis Type B Syntheses (C-C-N + C-S) Type E Syntheses (N-C-C-S C) By Hydrolysis of Fused-Ring Compounds Physical Proper ties Chemical Properties

+

12 Selenazoles Synthesis and Properties Type A Syntheses (Se-C-N

+ C-C)

13 Benzothiazoles Synthesis From ortho-Aminobenzenethiols (Type A; S46H4-N + C ) Type B (C6H5-N-C-S) Type E (CGH5-N + C-S) Physical Properties Chemical Properties Substitution Reactions on the Thiazole Ring Reactions of 2 -Aminobenzothiazoles Reactions of 2-Mercaptobenzothiazoles Other Reactions of Benzothiazoles Benzo t h iazolines and Benzot h iazolin -2-ones (and -thiones) Benzothiazolium Salts

14 Condensed Ring Systems incorporating Thiazole Structure comprising Two Five-Membered Rings ( 5 3 ) Thiazolo [3,241 te t razoles [CN4-C3NS] Thiazolo[2,3-c][ 1,2,4] thiadiazole [C2N2S-C3NS] Thiazolo [2,3-b][ 1,3,4]thiadiazoles [C2N2S-C3NS] Thiazolo-[2,3-c]-, -[3,2-b]-, and -[3,4-b]-[1,2,4]triazoles [C2N3-C3NS] Thiazolo[4,5-d]-oxazole, -thiazole, and -selenazole [C3NX-C3NS] Imidazo-[2,1-b]-and -[5,1-b]-thiazoles [C3N2-C3NS] Pyrrolo [2,1-b]thiazoles [C4N-C3NS]

165 165 165 167 167 168 169 169 169 169 170 170 17 1 173 173 173 174 174 174 175 175 175 178 178 179 180 180 181 18 1 182 182 182 182 182 182 183 183 184


xiv

Structures comprising One Five-Membered and One Six-Membered Ring (5,6) Thiazolo [3,241- 1,3,5-triazines [C3NS-C3N3] Thiazolo [3,2471pyridazines [C3NS-C4N2] Thiazolo [3,2-a] pyrimidines [C3NS-C4N2] Thiazolo [5,4-b]pyridines [C3NS-CSN] Structures comprising Two Five-Membered Rings and One Six-Membered Ring (5,5,6) Benzo [ 1,2d;4,5dfIbis-thiazoles [C3NS-C3NS-C6] Benzo[d]imidazo[2 ,l-blthiazoles [C3NS-C3N2-C6] Thiazolo [3,44]benzimidazole [C3NS-C3N2-C6] Th iazolo[3',2' :1,2]imidazo [4,5-b]pyrazine [C3NS-C3N2-C4N2] Pyrrolo [2,1-b]benzothiazole [CSNS-C~N-C~] Structures comprising One Five-Membered Ring and Two Six-Membered Rings (5,6,6) 1,2,4-Triazino[3,4-b]benzothiazole [C3NS-C3N 3 -C61 1,3,5-Triazino [2,1-b] benzothiazole [C3NS-C3N3-C6] Thiazolo [2,3-b]quinazolines [C3NS-C4N,-C6] Thiazolo [3,2-a]thiapyrano [4,3-d]pyrimidines [C~NS-C~NZ-C 5x1 1,2-0xathiino[5,6-g]benzothiazoles [C3NS-C4OS-C6] Thiazolo-[2,3-a]- and -[3,4-b]-isoquinolines [C3NS-CSN-CG] Naphtho [2,3d]thiazole [C3NS-C&6] Other Condensed Systems incorporating Thiazole

15 Thiadiazoles and Selenadiazoles 1,2,3-Thiadiazoles Synthesis Physical Properties Chemical Properties 1,2,3-Selenadiazoles 1,2,4-Thiadiazoles Synthesis Physical Properties Chemical Properties 1,3,4-Thiadiazoles Synthesis Physical Properties Chemical Properties Condensed 1,3,4-Thiadiazoles 1,2,5-Thiadiazoles

185 185 185 185 186 186 186 186 187 187 187 187

187 188 188 189 189 189 190 190 190 190 190 19 1 191 19 1 192 192 193 193 194 194 195 195 196 196

Contents

xv Synthesis Physical Properties Chemical Properties 2,1,3-Benzothiadiazoles and 2,1,3-Benzoselenadiazoles

196 197 197 197

16 Dithiazoles and Diselenazoles 1,2,3-Dithiazoles 1,2,4-Dithiazoles 1,4,2-Dithiazoles

198 198 199 200

17 Oxathiazoles and Selenathiazoles 1,3,2-0xathiazoles 1,3,4-Oxathiazoles

200 200 200

18 Miscellaneous Ring Systems 1,3,2,4-Dithiadiazoles

201 201

Part I I I Other Five-Membered Ring Systems By G. V. Boyd

20 1

1 Introduction

201

2 Reviews

202

3 Systems with One Heteroatom and their Benzo-analogues etc. Furans Formation Reactions Benzo furans Isobenzofurans and 0ther Annelated Furans Pyrrole s Form ation Reactions Indoles and Carbazoles Formation Reactions Isoindoles Other Systems containing One Heteroatom

203 203 203 205 209 212 214 214 2 17 22 1 22 1 223 227 228

4 Systems containing Two Identical Heteroatoms Dioxoles Dithioles and Related Systems Tetra t hiafulvalenes and Related Compounds Py razoles Formation Reactions Indazoles

229 229 230 234 236 236 238 240


xvi

Imidazoles Formation Reactions Benzimidazoles and an Imidazoquinoline

5 Systems containing Two Different Heteroatoms Oxathiole s and Selenathioles Isoxazoles Formation Reactions Benzisoxazoles and Other Annelated Isoxazoles Oxazole s Formation Reactions Benz ox az oles Benzoxaiodoles

24 1 24 1 242 244

245 245 248 248 249 250 25 1 25 1 253 258 260

6 Systems containing Three Identical Heteroatoms 1,2,3-Triazoles and Benzotriazoles 1,2,4-Triazoles Other Systems

260 260 26 1 264

7 Other Systems containing Three Heteroatoms Oxadiazoles 1,2,3-0xadiazoles 1,2,4-Oxadiazoles 1,2,5-Oxadiazoles 1,3,4-0xadiazoles Phosphorus Compounds Miscellaneous 0ther Systems

264 264 264 265 266 267 268 269

8 Systems containing Four Heteroatoms Tet razoles Other Systems

270 270 271

9 Compounds containing Two Fused Five-Membered Rings (5,5) Hypervalent Sulphur and Selenium Compounds Nitrogen Systems M onoaza-Comp ounds Diaza- and Triaza-Compounds Other Systems

272 272 273 273 274 275

10 Compounds containing Fused Five- and Six-Membered Rings (5,6) Nitrogen Systems Monoaza- and Diaza-Compounds Triaza-Compounds Tetra-aza-Compounds and a Penta-aza-Compound

276 276 27 6 277 278

Contents

xvii Mixed Oxygen-Nitrogen Systems and a Diselenoloquinoxaline

11 Compounds containing Fused Five- and Seven-Membered and Fused Five- and Eight-Membered Rings [ (5,7), (5,5,7), (5,7,7), and (5,5,8)1

Chapter 4 Six-Membered Ring Systems B y S. D. Carter, G. W. H. Cheeseman, and G. P. Ellis Part I Systems containing Nitrogen By S. D. Carter and G. W. H. Cheeseman

279

282 285

285

1 Introduction

285

2 Reviews

285

3 Azines and their Hydro-and Benzoderivatives Pyridines Synthesis Properties Reduced Pyridines Quinoline, Isoquinoline, and their Benzo- and Hydroderivatives

2 86 286 286 29 1 299

4 Diazines and their Reduced and Fused Derivatives 1,2-Diazines 1,3-Diazines 1,4-Diazines

3 12 3 12 3 14 322

5 Triazines and Tetrazines

326

6 Fused Systems containing One Five- and One Six-Membered Ring (5,6)

329

7 Fused Systems containing Two Six-Membered Rings (6,6)

333

8 Oxazines, Thiazines, and their Fused Derivatives 0x azines Thiazines

336 336 339

9 Other Oxygen- and Sulphur-containing Systems Classified Reference List

34 1 344

Part I I Six-Membered Rings containing Oxygen or Sulphur By G. P. Ellis 1 Reviews

302

345 345

He twocyclic Chemistry

xviii

2 Heterocycles containing One Oxygen Atom Reduced Pyrans Pyrans Pyrylium Salts Pyran-2 -ones Pyran-3- and -4-ones Chromans Isochromans Chromenes Benzopyrylium Salts Chromanones Chromones F lav ans Flavanones Flavones I sofl av one s Dlhydrocoumarins and Dihydroisocoumarins Coumarins Isocoumarins Xanthenes and Xanthones

346 346 348 349 350 355 357 361 363 365 366 367 370 37 1 372 373 373 375 378 378

3 Heterocycles containing One Sulphur Atom T hiopyrans Thiochromans and Thiochromenes Thiochromanones Thiochromones and Thiocoumarins Thioxanthenes and Thioxanthones

380 380 38 1 382 382 383

4 Heterocycles containing One Oxygen and One Sulphur Atom Oxa thiins

383 383

5 Heterocycles containing Two Oxygen Atoms Dioxans

384 384

6 Heterocycles containing Two Sulphur Atoms 1,3-Dithians 1,4-Dithians

385 385 385

7 Heterocycles containing an Oxygen Atom in each of Two or More Rings

386

Chapter 5 Seven-Membered Ring Systems By J. T. Sharp

389

1 Introduction

389

2 Reviews

389

Contents

XiX

3 Azepines and Diazepines Azepines Formation Reactions 1,2-Diazepines Formation Reactions 1,3-Diazepines Formation Reactions 1,4-Diazepines Formation Reactions

389 389 389 394 395 395 397 399 399 40 1 40 1 40 1 403

4 Oxepins and Dioxepins Oxepins Formation Reactions D i ox epins

405 405 405 408 408

5 Thiepins

409

6 Systems containing Two Different Heteroatoms Oxazepines T hiazepines

41 1 41 1 413

7 Systems containing Three Heteroatoms

415

Chapter 6 Eight-Membered and Larger Ring Systems By J. M. E. Quirke

4 19

1 Eight-Membered Rings One Heteroatom Two Heteroatoms

419 419 42 1

2 Nine- and Ten-Membered Heterocycles

422

3 Macrocycles Other than Crown Ethers Systems containing Nitrogen as the only Heteroatom Systems containing Sulphur as the only Heteroatom Systems containing Oxygen as the only Heteroatom Syntheses of Macrocyclic Lactones Other Oxygen-containing Derivatives Other Macrocyclic Systems

423 423 427 427 427 428 429

4 Crown Ethers and Related Compounds Synthesis of Crown Ethers Reactions of Crown Ethers Applications of Crown Ethers in Organic Synthesis

429 429 432 434


xx

Synthesis of Cryptands and Other Polycyclic Systems Host-Guest Complexes of Crown Ethers and Cryptands

Chapter 7 Bridged Systems By J. R. Malpass

43 7 439 44 1

1 General

44 1

2 Physical Methods X-Ray and Electron Diffraction Nuclear Magnetic Resonance Spectroscopy Miscellaneous Methods

44 1 44 1 443 444

3 Nitrogen-containingCompounds Synthesis Cycloadditions 0ther Cyclizations Reactions Bridged Azolkanes

445 445 445 449 450 453

4 Oxygencontaining Compounds Synthesis Cycloadditions Miscellaneous Other Methods Re actions Bridged Peroxides

45 5 45 5 45 5 457 458 460

5 Sulphur-containingCompounds

46 1

6 Silicon- and Germanium-containing Compounds

463

7 Phosphorus-containing Compounds

464

8 Boron-containingCompounds

465

1 Three-Membered Ring Systems BY T. J. MASON

1 Reviews General. - Thermally induced ring-enlargement of vinyl three-membered heterocycles has been reviewed.’ Rings containing Oxygen. - The catalytic epoxidations of alkenes with hydroperoxides have been surveyed,2y3as have transition-metal-catalysed stereocontrolled epoxidations! A major review of oxiran chemistry (956 references) has been published as a chapter in Saul Patai’s series on the Chemistry of Functional Groups (1980).’ Theoretical aspects of the thermal and general chemical reactions of oxirans have been treated by the application of quantum-mechanical methods to the study of the reactions of the triplet states of isomers.6 Rings containing Nitrogen. - The reactions of aziridines with alkylidenephosphoranes and with phosphorus(II1) nucleophiles’ and the reactions of 3 -amino-2H-azirines with NH-acidic compounds have been reviewed.’ Rings containing Sulphur. - The subject of a lecture given in 1980 and published in 1981 was some aspects of the chemistry of episulpho~ides.~ 2 Oxirans Preparation. - Oxidation of Alkenes to Oxirans, using Oxygen or Oxygencontaining Gases. Research into the improvement of the silver catalysts that are used in the commercial oxidation of ethene has resulted in continued interest in the doping of the catalyst with alkali-metal salts, particularly

J . Chuche, Bull. SOC.Chim. Belg., 1981, 9 0 , 535. Ziolkowski, J. Mol. Catal., 1981, 13, 11. R. A. Sheldon, Aspects Homogeneous Catal., 1981, 4, 3. D. Hoppe, Nachr. Chem. Tech. Lab., 1982, 30, 281. M. Bartok and K. L. Lang, in ‘Chemistry of Ethers, Crown Ethers, Hydroxyl Groups, and their Sulphur Analogues’, ed. S. Patai, Wiley, Chichester, U.K., 1980, Vol. 2, p. 6 0 9 . G. R . DeMare, NATO A d v. Study Inst. Ser., Ser. C , 1981, 67 (Comput. Theor. Org. Chem.), 335. M. Vaultier and R. Carrie, ACS Symp. Ser., 1981, 1 7 1 (Phosphorus Chem.), 51. H. Heimgartner, Isr. J. Chem., 1981, 21, 151. G. Maccagnani, Org. Sulfur Chem. Invited Lect. I n t . Syinp., 9 t h, 1980 (publ. 1981), 123.

* J . Sobczak and J . J .

’

’

2

Heterocyclic Chemistly

caesium.1°-12 Spent catalyst may be rejuvenated by treatment with NH3, MeOH, and CsN03.13 Silver powder with a high surface area has been used to determine the reactivity of adsorbed oxygen for the epoxidation of perde~terioethene.'~ The results suggest that the alkene oxide is formed only if both surface and subsurface adsorbed oxygen are present. Two types of adsorbed oxygen were invoked to explain the results obtained when studying the solid-electrolyteaided oxidation of ethene on polycrystalline silver." Solid electrolyte potentiometry (SEP) was used to monitor the chemical potential of the adsorbed oxygen, the activity of which was not affected by the presence of C02. This latter appeared to inhibit only the epoxidation reaction. The same group have also reported that both the selectivity for and the yield of ethylene oxide on polycrystalline silver may be increased by electrochemical pumping of oxygen (023.16 The reaction was studied in the solid electrolyte cell C2H4, C2H40, C 0 2 ,02, AglZr02(Y203)IAg,air, at temperatures around 400 "C and at atmospheric pressure. The cell behaved as a normal epoxidation catalyst under open-circuit conditions. A study has been made of the bond energies between adsorbed oxygen and various supported silver catalysts and of their relationship to the activity of such catalysts for epoxidation of ethene." A linear freeenergy relationship between the mean heat of formation of a monolayer of surface Ago and the catalytic activity was found. Kinetic performance parameters have been calculated for a number of supported-silver epoxidation cata1ysts.l8 Direct oxygenation of alkenes other than ethene and propene is normally achieved in the liquid phase and in the presence of a catalyst or under U.V. irradiation. Thus aryl-oxirans (1; n = 1 or 4) were obtained in 37-71% yields by autoxidation of the corresponding 1-phenyl-cycloalkenes in the presence of cobalt naphthenate at 50°C." Unbranched terminal alkenes yield epoxides during autoxidation in the presence of the soluble catalysts C O Q ~ PrQ3, , TiOQ2, and VOQ2 (Q = pentane-2,4-dionat0).~' The autoxidation of aromatic vinyl ethers proceeds at room temperature even in the dark, but irradiation with U.V. light and the use of a radical generator facilitates the reactions which yield epoxides and carbonyl compounds in significant quantities?l lo

I2

Mitsubishi Petrochemical Co. Ltd., Jpn. Kokai Tokkyo Koho 81 05 471. Nippon Shokubai Kagaku Kogyo Co. Ltd., Jpn. Kokai Tokkyo Koho 81 105 750. Nippon Shokubai Kagaku Kogyo Co. Ltd., Jpn. Kokai Tokkyo Koho 81 108 533. J. Alfranseder, S . Mayer, S. Rebsdat, J . Riedl, and 1. Schaffelhofer, Ger. Offen.

2 938 245. C. Backx, J. Moolhuysen, P. Geenen, and R. A. Van Santen, J. Caral., 1981, 72, 364. I s M. Stoukides and C. G. Vayenas, J. Catal., 1981, 69, 18. l6 M. Stoukides and C. G. Vayenas, J. Caral., 1981, 7 0 , 137. A. Auroux and P. C. Gravelle. J. Calorim. Anal. Therm., 1981, 12, 1NT2,-INT2,. P. Kripylo, L. Moegling, D. Klose, and H. Sueptitz, Chem. Tech. (Leipzig), 1982, 34, 85. I 9 S . C. Sethi, A. D. Natu, and M. S. Wadia, Heterocycles, 1982, 18 (Spec. Issue), p. 221. l4

2o

21

U. Barth, H. Friedler, G. Gross, G. Lauterbach, and D. Schnurpfeil, J. Prakr. Chem., 1981, 323, 887. T. Kanno, M. Hisaoka, H. Sakuragi, and K. Tokumari, Bull. Chem. SOC.Jpn., 1981, 5 4 , 2330.

Three-Membered Ring Systems

3

Photo-epoxidation of alkenes in the presence of benzoins and oxygen has been shown to proceed via the benzoylperoxy radical (2), which is effectively trapped by alkene and subsequently yields predominantly trans-epoxides.22 The same intermediate radical (and, as a result, similar reactivities) has been observed during photo-epoxidation using benzoylformic acid (PhCOCOOH), but the reactivities of the alkenes were different from those obtained using p e r o ~ y - a c i d sA . ~ correction ~ has been published to some previous studies on the efficiency of benzil-sensitized photo-epoxidation of t r i n ~ r b o r n e n eThe .~~ new results indicate a lower yield of < 2 moles of epoxide per mole of diketone that is consumed and thus suggest that a chain mechanism is not involved for such reactions. A new reaction system has been reported in which molecular oxygen oxidizes alkenes to epoxides both thermally and photochemically, in the presence of SO2, under ambient condition^.^' Irradiation of a mixture of propene and SO2 in acetonitrile at 0 "C caused absorption of 02,to yield propene oxide as the sole volatile product. A similar reaction occurred at 25 "C in the dark, in the presence of potassium nitrite. Direct ozonolysis of the parent vinyl sulphide gives (3) (40%), suggesting that oxiran intermediates might be involved more generally in the ozonolysis of vinyl derivatives.26 Ozonolysis of cis- and of trans- 1,2-difluoroethene also yields epoxides with predominantly retained stere~chemistry.~~ Oxidation of Alkenes to Oxirans by Peroxy-acids. An improved procedure for epoxidation using aromatic peroxy-acids has been reported .28 After a normal epoxidation with 3-chloroperoxybenzoic acid (mCPBA) in CH2C12, activated KF is added to the crude mixture, and this results in the precipitation of both mCPBA and the aromatic acid by-product, leaving an acid-free reaction mixture for normal work-up. As an alternative, the insoluble mCPBA-KF complex itself may be used for the epoxidation of alkenes overnight at room temperature. After filtration and treatment of the CH2C12 solution with more KF (to ensure removal of any residual peroxy-acid), normal work-up leads to yields in excess of 95% for cyclohexene and styrene oxides. 22

23 24

25 26

Y. Sawaki and Y . Ogata, J . A m . Chem. SOC., 1981, 103, 2049. Y. Sawaki and Y. Ogata, J. A m . Chem. SOC.,1981, 103,6455. P. D. Bartlett, A. A. M. Roof, and N. Shimizu, J. A m . Chem. SOC.,1982, 104, 3130. T. Sasaki, J. A m . Chem. SOC.,1981, 103, 3882. L. Morin, D. Barillier, M. P. Strobel, and D. Paquer, Tetrahedron L e t t . , 1981, 2 2 , 2267.

27 28

J . W. Agopovich and C. W. Gillies, J . A m . Chem. SOC.,1982, 104, 813. F. Camps, J . Coll, A. Messeguer, and A. M. Pericas, Tetrahedron L e t t . , 1981, 22. 3895.

J$,

Heterocyclic Chemi s t y

4

Ph P \ h 0

-

Ph (4)

1

P Ph h o\ ; ]

@

Fh (5)

CH2

(6)

CH2 (7)

The site-selectivity of oxidations by mCPBA is demonstrated in the conversion of (4; R = Me or Ph) into the corresponding ene epoxide (5).2g The product is sensitive to acid, so that the conversion is accomplished in a basic two-phase medium. Normal epoxidation of (6) with mCPBA leads to (7).30 The stereochemistries for such reactions are shown in the predominant formation of the P-epoxide (8) (81%) from the parent alkene, with 12% of the a - p r ~ d u c t Similar .~~ epoxidation of the cannabinol (9) leads to a less stereospecific isomer distribution of 27.3% and 18.2%.32Remarkable stereoselectivity has been shown in the epoxidation of the 14,15-unsaturated oestratrienes ( Whereas oxidation of 170-esters and 170-ethers gave 14a ,15a-epoxides (< 59%),the 170-urethane derivatives displayed a syn-directive effect to yield 140,15P-epoxides (< 87%).

H

29

30 31

32

R. Y . S. Tan, R . A. Russell, and R. N. Warrender, Aust. J. Chem., 1981, 34,421. H. M. R. Hoffmann and H. Vathke-Ernst, Chem. Ber., 1981, 114, 1182. Meiji Seika Kaisha, Ltd.. Jpn. Kokai Tokkyo Koho 82 0 2 232. I. Yamamoto, S . Narimatsu, K. Watanabe, and H. Yoshimura, Chem. Pharm. Bull., 1981, 2 9 , 3 3 7 8 .

33

K. Ponsold, G. Schubert, M. Wunderwald, and D. Tresselt, J . Prakt. Chem., 1981, 323, 819.


5

The rates of epoxidation of cyclododecene with a series of aliphatic peroxy-acids have been correlated, using the Taft equation.34 The reaction constant ( p * ) was + 2.0 and the steric constant (6) was found to be essentially zero. A two-parameter correlation has been found for the effect of basicity and polarity of the solvent on the rate of epoxidation of propene with peracetic acid.35 Rate constants and activation parameters for the epoxidation of a number of cycloalkenes, including (1 1 ; R = H or COOMe), (12; R = H, Ph, or 2-furyl), (13), (14), and cyclo-octa-1,5-diene, have been measured.36 An isokinetic relationship was demonstrated, with the isokinetic temperature of 3°C. There was only a weak dependence of the rate on the structure of the alkene.

Alkenes have been epoxidized in high yield, using peroxyformic acid (prethus a 90% yield of monopared in situ from formic acid and 85% H202); epoxide has been prepared from trimethylcy~lodecatriene.~~

Oxidation of Alkenes to Oxirans, using Peroxides. The peroxide (1 5; R = OOH) is a useful oxidant for a number of alkenes, giving epoxides in good to moderate yields and generating (15; R = OH).38 The reactivity of this peroxide is two orders of magnitude lower than that of peroxyacetic acid but at least one order of magnitude greater than that of a-peroxy-esters and -nitriles. Its selectivity relative to the structure of the alkene is similar to that for peroxyacetic acid.

34

3s

36 37

38

H. J . Schneider, N. Becker, and K. Philippi, Chem. Ber., 1981, 114,1562. V. N. Sarancha, I. A. Opeida, and R. V. Kucher, Dopov. Akad. Nauk Ukr. RSR, Ser. B , 1981, No. 6,p. 74. A. E. Batog, T. V. Savenko, T. A. Batrak, and R. V. Kucher, Zh. Org. Khim., 1981, 17,2085. G . Kaebisch, R. Truebe, H. Wittmann, S. Raupach, and H. Malitius, Ger. Offen. 3 002 785. A. L. Baumstark and R. S. Pilcher, J. Org. Chem., 1982,47, 1141.

6


A few years ago, hexafluoroacetone was shown to be an effective catalyst for the epoxidation of alkenes by H202.39 The reagent is highly toxic, however, and not commercially available, and so an alternative has been sought. An efficient alternative catalyst has been found to be hexafluoropropan2 - 0 1 , ~but more recently it has been reported that tetrachloroacetone is a useful commercially available alternati~e.~' The reactive species is thought to be (16; R = OOH), the by-product of epoxidation being the hydrate (16; R = OH), which is thermally unstable and from which tetrachloroacetone may be regenerated. The yields are generally good and the selectivity is high, as illustrated by the formation of (17) (60%) from the epoxidation of 4-vinylcyclohexene with only 4% total yield of other possible mono- and di-epoxide products. Two groups have studied the epoxidation of ap-unsaturated ketones with alkaline H202in methanol; a second-order process. Electron-releasing groups attached to the &carbon atom in the alkene reduced the rate whereas electron-attracting groups had the reverse effect !2 In the case of (1 8; R = H or alkyl), the rate constants in 80%aqueous methanol decreased in the order H > Me > Pr > ~ e n t y l Spectral .~~ studies suggested that the origin of this order of reactivity concerned hindrance to delocalization of charge in the intermediate.

Base-catalysed epoxidation of norandrostenone ( 19), using H202 in methanol, produced exclusively the P-epoxide in the A ring.44It was suggested that the conformations of the A ring were such that the hydroperoxide group attached at the 5a- or 50-positions could attain an axial confirmation. cisCyclo-octene oxide (20) has been prepared in 60% yield by epoxidation of 39 40 41 42 43

44

L. Kim, Br. P. 1 399 639. B. Ganem a n d R. P. Heggs, J. A m . Chem. SOC., 1979, 101, 2484. C. J . Stark, Tetrahedron Lett., 1981, 2 2 , 2089. D. S. R. Rao, Indian J. Chem., Sect. B , 1981, 2 0 , 786. I. G. Tishchenko a n d I. F. Revinski, Vestsi Akad. Navuk B S S R , Ser. Khim. Navuk, 1981, No. 1, p. 90. J. R. Hanson, P. B. Hitchcock, a n d H. J . Wadsworth, J. Chem. Soc., Perkin Trans. I , 1981, 3025.


7

cis-cyclo-octene by 30% H 2 0 2 in MeCN at 25-35°C.45 A high yield of epoxide may be obtained by two-phase epoxidation of alkenes, using dichloroethane-water with Na2W04 catalyst and a tetra-alkylammonium salt as the phase-transfer agent.& One of the most commonly used types of catalyst for epoxidations using alkyl hydroperoxides is complexes of molybdenum. The yields can be almost quantitative, as observed when using the n-cyclopentadienyl complex Cp2MoX2 (X = C1 or Br) with t-butyl hydroperoxide, which gives 98.4% of diepoxide from the dimer of cyclopentadiene.'" For the epoxidation of propene by t-butyl hydroperoxide and molybdenum salts of organic acids, the catalytic activity was little affected by the ligand on the A similar insensitivity to ligand (and also to valency) was noted in the epoxidation of cholesteryl acetate with M ~ O ~ ( a c a c MO(CO)~, )~, and MoC15.49 When cyclohexene was treated wtith t-butyl hydroperoxide and molybdenum porphyrins, cyclohexene oxide was obtained with up to 85% selectivity at total peroxide conversion (17-24 hr)." A similar catalyst gave 97% of cis- and 99% of transhex-2-ene oxides from the cis- and trans-alkenes respectively. A number of different catalysts have been used in the epoxidation of monoterpenes with t-butyl hydroperoxide and the conditions ~ptimized.'~ While oxidation of a-pinene in the presence of V(acac)3 gave cis-epoxide (4.4%), campholenic aldehyde was also obtained in the presence of Mo(CO)~. The n.m.r. line-broadening method was applied to the determination of the kinetic parameters of the exchange reactions of cumene hydroperoxide, cumyl alcohol, and cyclohexene in the co-ordination sphere of the complex H2 [ M o ~ O ~ ( C ~ O ~ ) ~ (4H20 H ~ O* (CH3)2C0.52 )~] The results revealed that the first stage of both the decomposition of the hydroperoxide and the epoxidation reaction is the formation of an intermediate compound between a molybdenum(V) complex and the hydroperoxide. *

Synthesis of Oxirans by Halohydrin Cyclizations and Related Reactions. One of the oldest commercial methods for the production of ethene oxide is the chlorohydrin route, involving chlorohydration of ethene followed by dehydrochlorination. An improved procedure for the second stage of this process has been reported in which a basic ion-exchange resin is used to

45

47

48 49 51

52

R. D. Bach and J . W. Knight, Org. Synrh., 1981, 6 0 , 6 3 . E. Alneri and G. Lana, Ger. Offen. 3 027 349. A. 0. Kolmakov, V. M. Fomin, T. N. Aizenshtadt, and Yu. A. Aleksandrov, Zh. Obshch. Khim., 1981, 5 1 , 2805. H. R. Hernandez, P. S. Chow, and A. E. Rico, Rev. Ins?. Mex. Pet., 1981, 13, 6 6 . M. Kimura and T. Muto, Chem. Pharm. Bull., 1981, 29, 35. H. J . Ledon, P. Durbut, and F. Varescon, J. A m . Chem. SOC.,1981, 103, 3601. D. V. Banthrope and S. E. Barrow, Chem. Ind. (London), 1981, 502. A. M. Trzeciak, J . Sobczak, and J . J . Ziolkowski, J. Mol. Catal., 1981, 1 2 , 321.

8

Heterocyclic Chemistry PCH2CH( OAc)CH2Br

H

H

WCWMe OCOMe

4- M e C6H

c1

(25)

remove the HCl that is generated during c y c l i ~ a t i o n The . ~ ~ generation of styrene oxide (2 1; R = Ph) (85%) from PhCH2ClCH2Cl with 99% purity has been achieved by simple hydrolysis followed by elimination of HCl from the intermediate chlorohydrin, using aqueous NaOH.54Other methods for cyclization include the use of sodium methoxide in methanol to generate (21 ;R = CloH70CH2) from (22),55 reduction of (23) with sodium borohydride to yield the cis-epoxide (24),56 or the heating of 0-halogeno-esters with ammonium or phosphonium salts; e.g. , (25) and Bu4P' Br-, when heated at 180 "C for 2 hours, gave (21 ; R = Me) (95%).57

(27)

Reagents: i, LDA, CH,CII; ii, Bu,N+ F-

Scheme 1 The phosphonate epoxide (28) has been prepared in 58% yield from the trimethylsilyl ether (26) via fluoride-ion-induced cyclization of the intermediate (27) (Scheme l).58 The stereochemistry of bromohydrin (31), which yields the oxiran (33) after sequential reduction and treatment with a base, has been proved by the use of a novel oxidative bromocarbonation (Scheme 2).59 Enol (29) of known stereochemistry is converted into the cyclic bromo-carbonate (32) (79%)upon treatment of the lithium alkoxide of (29) with dry C02 followed by Brz. Since (32), on treatment with base, gives 54

'' s6 57

59

T. B. S. Giddey, S. Afr. P. 7 8 0 5 961. Hogyoku C o . Ltd., Jpn. Kokai Tokkyo Koho 81 92 282. Sagami Chemical Research Center, Jpn. Kokai Tokkyo Koho 82 26 6 7 7 . K. S. Bhat and A. S. Rao, Indian J. Chem., Sect. B , 1981, 20, 355. J . M. Renga and A. H. Emmons, U.S. P. 4 261 906. M. Sekine, M. Nakajima, and T. Hata, J. Org. Chem., 1981, 46, 4030. M. F. Haslanger and S. Ahmed, J. Org. Chem., 1981, 46,4808.

9


OH

m

I

A

H

Scheme 2 (33), and the stereochemistry of (32) follows from that of (29), the structure of (3 1) is established. Synthesis of Oxirans via Attack of a Carbanion on the Carbonyl Group of Aldehydes and Ketones. The dibromo-ketones [34; R = 4-MeC6H4, 4-MeOCsH4, 4-ClCsH4, or 3,4-(MeO)zC6H3] cyclized on dissolving in MeONa-MeOH, refluxing, and standing for 10 hours at room temperature to give the compounds (35) (86-95%) by the Darzens mechanism!' A rather useful, mild, and stereoselective synthesis of a,@-epoxyphenylketones (36; R' = Me, R2 = PhCH2CH2, Ph, octyl, or 4-CIC6H4; R' = Et, R2 = Ph or PhCH2CH2)(52-8 1%) involves the reaction of aldehydes R2CH0 with a,adibromo-ketones PhCOCBr2R' in the presence of SnF2.61

Gorc" Br

R

j;r' Ph CO

R

Br (34)

6o 61

COR

(36)

(35)

T-Y. Kao and S. Shang, Nan-ching Ta Hsueh Hsueh Pao, Tzu Jan K ' o Hsueh, 1980, 39. S . Shoda and T. Mukaiyama, Chem. L e t t . , 1 9 8 1 , 7 2 3 .

10

Heterocyclic Chemistry Ph

PhCOCH( B r ) P h (37)

"\T/CN 0

(38)

The use of KCN in the synthesis of oxirans from a-bromo-ketones under phase-transfer conditions has been investigated.62 Treatment of (37) in CH2C12with 40% aqueous KCN and aqueous Et3(PhCH2)N' C1- at 20 "C for 4 hours gave (38) (85%) as a 50 : 50 mixture of the cis- and the trans-isomers. Under homogeneous conditions, using DMF as a solvent, the same mixture was obtained in 61% yield, but the reaction can be made stereoselective for the cis-isomer in the presence of solid adsorb ant^.^^ Owing to the insolubility of KCN, no reaction occurs between (37) and KCN in CH2C12,but when the same substrate is treated with aqueous KCN that is adsorbed on silica gel (CH2C12, at 20 OC, for 4 hours), the oxiran (38) (95%) is produced, comprising 88% of the cis-isomer. A similar result is obtained by using benzene as solvent and alumina as adsorbant. Both silica gel and alumina are thought to facilitate the reaction by virtue of adsorbing the reacting species onto a surface upon which OH groups are plentiful. The combination of adsorption and hydrogen-bonding with OH groups on the surface is thought to explain the stereospecificity. Significantly, both activated carbon and Celite do not promote the epoxidation, neither material being able to participate via surface hy drogen-bonding. The reaction of 1,4-(BrCH2)2C6H4with Me2S gave the sulphonium salt, which, in aqueous NaOH-C6H6 (containing Bu4N+ Br- as a phase-transfer catalyst), gave the ylide (39). The ylide reacted in situ with a number of phenyl-substituted benzaldehydes to give the separable diastereoisomers (40).64Similar reactions were reported for 1,2- and 1,3-~lides.~'

CH=SMe2

Q

CH=SMe2

62

63 64

Ar

K. Takahashi, T. Nishizuka, and H. Iida, Synth. Commun., 1981, 11, 757. K. Takahashi, T. Nishizuka, and H. Iida, Tetrahedron L e t t . , 1981, 22, 2389. L. V. Shubina, I. G. Tishchenko, and S. V. Smatser, Dokl. Akad. Nauk B.SSR, 1982, 26, 148.

65

L. V. Shubina, I. G. Tishchenko, and I. I . Medved, Vestsi Akad. Navuk B S S R , Ser. Khim. Navuk, 1982, No. 1, p. 66.

11

Three-Membered R ing Systems

The sulphonium ylides (42; R4 = R1R2C=CHCH2or R3CH2), derived from tetrahydrothiophen, have been used for the synthesis of the halogenated vinyl epoxides [41; R' R2 = Br, C1, or H (however, either R' or R2 must be halogen); R3 = H, Me, Me2CH, MeCH=CH, H2C=CMe, Me2C=CH, Ph, or PhCH=CH] (23-87%) by reaction with the appropriate aldehydes.66 The more complex salt (43), on reaction with HCO(CH2)3COOMe, gave the ( R ,S)-(all-E)-epoxide (44) as a mixture of cis- and trans-is~mers.~'

COOMe

+

-

Ph S e Me CH (45)

The first examples of reactions of non-stabilized selenium ylides with enolisable carbonyl compounds have been reported.68 Ylide (45) was generated in situ from Me,$ePh MeS04 and NaH in the presence of R'COR2 [R' = Ph, 4-O2NC6H4,Bu, or hexyl; R2 = H, Me, or Et; or R1R2 = (CH2)s] to give the corresponding oxirans (76-94%).68 Synthesis of Chiral Oxirans. The recently introduced Katsuki-Sharpless reagent (titanium alkoxide with tartrate) has proved highly effective for the maiden introduction of chirality into prochiral allylic alcohols. An interesting development of this procedure has afforded the possibility of kinetic resolution of racemic allylic alcohols.69 The basis of the method involves the 66 67

68

69

J . P. Beny, J . C. Pommelet, and J . Chuche, Bull. SOC.Chim. Fr., Part 2 , 1981, 369. M. Rosenberger, Eur. Pat. Appl. 36 663. K. Takaki, M. Yasumura, and K. Negoro, Angew Chem., Znt. Ed. Engl., 1981, 20, 671. V. S. Martin, S. S. Woodard, T. Katsuki, Y. Yamada, M. Ikeda, and K. B. Sharpless, J. A m . Chem. SOC.,1981, 1 0 3 , 6 2 3 7 .


12

difference in rates of epoxidation of the enantiomeric alcohols; in the case of (46)) this difference in rate is 138. Starting with racemic (46), the optical purity of the remaining unreacted alcohol at 60% conversion is greater than 99.999999%. The method promises to be of great synthetic value. The epoxy-alcohol products from such reactions are also of synthetic value. It has been reported that the erythro-threo selectivity is profoundly influenced by the catalyst used; thus, in the case of racemic (47), the Katsuki-Sharpless reagent gives 81:19 erythro selectivity whereas in the absence of diethyl tartrate the ratio swings to 5 :95 in favour of the threo-isomer. In both cases, the erythro- or threo-epoxy-alcohols possess high enantiomeric purity (2 92%e.e.).

In a series of papers, the application of titanium alkoxide catalysts to the synthesis of sugars has been described. Asymmetric epoxidation and kinetic resolution of (48) afforded (+)-(49) (27%; > 95%e.e.) and (-)-(48) (33%; 72%e.e.).70 The ring-opening reactions of the chiral epoxides that are produced, for example, from cis- and from trans-(50) provide new routes to The reagents also find use in the synthesis of pheromones; e.g., (+)-di~parlure~~ and (+)-2,6-dimethylhepta-l,S-dien-3-01 acetate via the epoxide (52), which was obtained from the dienol (51) by using D-(-)70 71

W. R. Roush and R. J . Brown, J . Org. Chern., 1 9 8 2 , 4 7 , 1371. T. Katsuki, A. W. M. Lee, P. Ma, V. S. Martin, S. Masamune, D. Tuddenham, and F. J . Walker, J. Org. Chem., 1982, 47, 1373.

72

P. Ma, V. S. Martin, S. Masamune, K. B. Sharpless, and S . M. Viti, J. Org. Chem.,

73

K. Mori and T. Ebata, Tetrahedron Lett., 1981, 2 2 , 4 2 8 1 .

1982,47,1378.

K. B. Sharpless,


p

Fewo):qcJ Me

13

COOMe

tartrate.74 Under the conditions of such epoxidations it is surprising to note that no decomposition of the iron complex occurred in the formation of (54) from (53) as part of a total synthesis of an analogue of trichothecene.” Leucotrienes are substances that are implicated in asthmatic conditions, and thus their synthesis, or at least the synthesis of their precursors, is of pharmaceutical interest. Two approaches to the synthesis of (56) have been published. The first involves the treatment of the threo-hydroxy-ester lactone ( 5 5 ) with K2C03 in methanol,76 while the second uses LDA to convert (57) into the epoxide (58), which may then be transformed into (56) (Scheme 3).77 0

H Me02S0

PhCOO

H CHZOTs

f

I CH2COOEt ii 0‘

H

HO ‘ (57)

(58)

Reagents i, K,CO,, MeOH; ii, LDA

Scheme 3 74 75 76

77

K. Mori and H. Ueda, Tetrahedron, 1981, 37, 2581.

A. J. Pearson and C. W. Ong, J. Am. Chem. SOC.,1981, 103, 6686. N. Cohen, B. 1. Banner, and R. J . Lopresti, Tetrahedron Lett., 1980, 21, 4163. J. Rokach, C-K. Lau, R. Zamboni, and Y . Guindon, Tetrahedron Lett., 1981, 2 2 , 2763.

14


(59)

Highly stereoselective epoxidations of acyclic homoallylic alcohols have been achieved, using the vanadium(v) t-butyl hydroperoxide method .78 A yield of 90%, with selectivity of > 400 :1, was achieved in the preparation of (60) from (59), and a detailed model of the transition state was proposed. The model involves a cyclic transition state (61), for which the required form is attained by minimizing the steric interactions engendered by the various substituents. The model successfully predicts the stereochemical outcome of a range of such epoxidations.

- I,a,

R~CH=CR~COOH (62)

I

COCR’ =C H R ~ (63)

Scheme 4 An efficient process for the synthesis of a,P-epoxy-aldehydes from a,Punsaturated acids has been rep~rted.~’ The acid (62) is converted into the bromo-lactone [64; R’ = a- or P-Me, R2 = Ph or (CH2)5Me; or R’R2 = (CH2)4 or 2-C,H4(CH2),], via asymmetric bromolactonization of the corresponding acylproline (63; R3 = H or Et). Sequential epoxidation and reductive cleavage of (64) gives the (2R,3S)-epoxy-aldehydes (65) in good yield, with e.e. 84-98% (Scheme 4). The possibility of preparing oxirans via microbial oxidation offers the prospect of considerable stereoselectivity, owing to the enzymes involved in such processes. Thus far, however, such conversions have not been a practical proposition, because of the very low concentrations of alkene that may be used with the cultures (generally, no more than 1% by volume). A good yield has been obtained, however, in the microbial transformation of oct-1-ene, using Pseudomoms oZeovorans.sOThe method employs a two-phase system in 78

79

E. D. Mihelich, K. Daniels, and D. J . Eickhoff, J. Am. Chem. SOC.,1981, 103, 7690. M . Hayashi, S. Terashima, and K. Koga, Tetrahedron, 1981, 37, 2797. M. J . DeSmet, B. Witholt, and H . Wynberg, J. Org. Chem., 1981, 46, 3128.

15

Three-Membered Ring Systems H I

Me a*COOE

t

OR (66)

-

? CH20H

OS03Me (67)

-m H.

Me

Me

0

(68)

Scheme 5 which octene is present in sufficient quantities to serve as the second phase. By this method, 5.6 g (1.4%) of the oxiran, containing 85% of the (R)-isomer, was obtained from 500 cm3 of octene. A useful preparation of (+)-(R)-methyloxiran (68) is shown in Scheme 5.81 The overall yield, based on the readily available (+)-@)-ethyl lactate (66; R = OH), from which (66; R = MeS03) is formed, is 7 1%. The cyclization of (67) involves distillation of the oxiran as it is produced. COOEt

COOEt

The epoxysuccinate (2R ,3R)-(70) (94%) is prepared from (2S,3S)-(69) by treatment with Et3N in CH2C12overnight.82 A number of enantiomerically pure synthetic building blocks have been prepared from hydroxybutanoic, malic, and tartaric acids.83 Examples of those with at least two functional groups are (21; R = CH2CH2Br), (71), and (72; R = H, CH2Ph, CMe20Me, or Ph).

Synthesis and Reactivities of Aromatic Oxides. The synthesis and absolute configurations of benzene and naphthalene ( 1S,2S,3S,4S)-diepoxides, (+)-(73) and (+)-(74), have been reported,84 as have those of the naphthoquinone derivative (2S,3R)-(+)-( 75) .85

82

83 84

L. R. Hillis and R. C. Ronald, J. Org. Chem., 1981, 46, 3348. Taisho Pharmaceutical Co. Ltd., Jpn. Kokai Tokkyo Koho 81 110 683. E. Hungerbuehler, D. Seebach, and D. Wasmuth, Helu. Chim-. A c t a , 1981, 64, 1467. K. Koreeda and M . Yoshihara, J. Chem. SOC.,Chem. Commun., 1981, 974. Y. Harigaya, H. Yamaguchi, and M. Onda, Chem. Pharm. Bull., 1981, 29, 1321.


16

H@

--H

H @\

/

o @

--H

/

/

;

o

:

H

(74IH

o

0

3-Me00CC6H4 O (75)

(73)

The hexahydrophenanthrene 9,lO-oxide (76) has been synthesized, together with its diastereoisomeric isomer (77).& Both isomers are conformationally rigid and give rise to different diol products under acid hydrolysis; (76) yields the cis-diol (75%) at a faster rate than (77), which leads to transdiol exclusively. This reactivity of (76) has been ascribed to the fact that the benzilic C-0 bond of the epoxide ring is aligned nearly parallel to the n-orbitals of the aromatic ring and the epoxide oxygen iscis to the hydrogen at the adjacent ring junction. For the other isomer the benzilic C-0 is not aligned and it has the epoxide oxygen trans to the hydrogen at the adjacent ring junction. Under neutral conditions, (76) gives the rearranged ketone (78) (85%). n

(76)

A possible explanation for the difference in carcinogenicity of K - and bayregion arene oxides has been s~ggested.~' Phenanthrene 9,lO-oxide (79) reacts with the phosphodiester HOP(O)(OEt), to give 9-phenanthrol (80) whereas cyclohexene oxide, under the same conditions, gives the phosphotriester (8 1). If bay-region arene oxides react in the same manner as cyclohexene oxide (to give potentially carcinogenic diol derivatives) then K-region oxides may well be detoxified by conversion into phenols, on approaching a molecule of DNA (or RNA), by the phosphate groups that are present.

'OP( 0 ) ( OEt ) 2

86

87

J. M. Sayer, H. Yagi, J . V. Silverton, S. L. Friedman, D. L. Whalen, and D. M. Jerina, J. Am. Chem. SOC.,1982, 1 0 4 , 1 9 7 2 . P. DiRaddo and T. H. Chan, J, Org. Chem., 1 9 8 2 , 4 7 , 1427.

Three-MemberedRing Systems

17

The first examples of syn stereoselective epoxidation of arene dihydrodiols have been reported with the preparation of (82) and (83) from the corresponding diols.88 Thus unexpected synepoxidation has been interpreted as due to the exertion of steric control by the axial benzylic hydroxy-groups, whereas such control is usually exhibited by equatorial hydroxy-groups. OH

(84)

(85)

The enantiomeric bay-region diol epoxides of benz[a]anthracene (84) and of chrysene (85) have been synthesized and a rather interesting relationship between stereochemistry and turnorigenic activity has emerged.89 It appears that for each of the four metabolically possible bay-region diol epoxides of both of the above fused systems and for the diol epoxides (86) of benzo[a]pyrene, those with the (+)-(R ,S)-diol (S,R)-epoxide trans configuration (87) have practically all of the tumorigenic activity. One attractive explanation for this phenomenon is that the cellular covalent binding site of these ultimate carcinogens is highly chiral and that only these isomers effectively bind to the site. The benz[c]acridine analogues of (84), i.e. (88), have been prepared.g0

(87)

H. Lee and R. G. Harvey, Terrahedron Lett., 1981, 2 2 , 1657. H. Yagi, K. P. Vyas, M. Tanada, D. R. Thakker, and D. M. Jerina, J. Org. Chem., 1982,47,1110.

R. E. Lehr and S. Kumar, J. Org. Chem., 1981, 46, 3675.

18


The optically active benz[a]anthracene oxides (89) and (90) have been synthesi~ed.~' Thermal recemization (at 293-322 K, in CDC13) of the chiral chrysene 3,4-oxide (91) has been shown to occur via first-order kinetics, with an activation energy of 25.2 kcal m01-l.'~ The results are consistent with a reaction mechanism involving an oxepine intermediate (92), as predicted by theory.

The novel bay-region diol epoxide isomers (93) have proved to be remarkably biologically active, despite their relative lack of reactivity towards hydrolysis (as expected from simple PMO calculations).93 Both diastereoisomers prefer the conformation in which the OH groups are quasidiequatorial, and these are the most tumorigenic diol epoxides yet tested on mouse skin. D. R. Boyd, G . S. Fadaginamath, N. D. Sharma, A. F. Drake, S. F. Mason, and D. M. Jerina, J. Chem. SOC.,Perkin Trans. 1, 1981, 2233. 92 D. R. Boyd, M . G. Burnett, and R. M. E. Greene, J. Chem. SOC.,Chem. Commun., 1981, 839. 93 J . M. Sayer, H. Yagi, M. Croisy-Delcey, and D. M. Jerina, J . Am. Chem. SOC.,1981, 103,4970. 91

19

Three-membered Ring Systems

Two bis-imines (94) and (95) have been prepared from the corresponding diepoxides by reaction with NaN3 and subsequent cyclization of the transazido -alcohols .%

Miscellaneous Syntheses of Oxirans. The vinyl-oxirans (97; R' = Ph or phenethyl, R2 = H or Me) were prepared by refluxing the benzimidazole derivatives [96; R3 = CH2CH2(0CH2CH2)20Me]with NaH in THF.95 CR~=CH~ CHR'OH

I

R3

0 (97)

Diazomethane reacts with (98) in the presence of Et3N to give a mixture of (99) and (loo), but, without Et3N, the reaction yields mainly the two oxirans (101) and (102) (Scheme 6).% Trimethylsilyldiazomethane, Me3SiCHN2, reacts with aromatic aldehydes RCHO in the presence of Et3N to give the oxirans (103) and (104), amongst other product^.^'

94 95 96 97

I. Yona and J . Blum, J. Heterocycl. Chem., 1981, 18, 1473. Mitsubishi Chemical Industries Co. Ltd., Jpn. Kokai Tokkyo Koho 81 125 379. H. Meier and A. Binder, Chem.-Ztg., 1981, 105, 149. N. Hashimoto, T. Aoyama, and T. Shioiri, Heterocycles, 1981, 1 5 , 975.


20

CH2C1 PhCOCOCH2N2

PhCOCOCl (98)

/

+

@COPh

(99)

(100)

1 dPh~ 1 : +

0

COCH2NH2

2

( 102)

(101)

Reagents: i, CH,N,, Et,N; ii, CH,N,

Scheme 6

When the valence tautomer of cyclo-octa-1,5-diene (stable below - 20 "C) is treated with O2 under irradiation from a sodium vapour lamp (a street lamp), in the presence of tetraphenylporphyrin as sensitizer, the endoperoxide (105) can be prepared in 85% yield.98 The endoperoxide serves as the starting material for three triepoxides (106), (107), and (108) (Scheme 7). The structures of all three triepoxides have been confirmed by X-ray analysis.

ii

QV

0

0

ii i

Reagents: i, heat, ii, mCPBA; iii, PPh,

Scheme 7 98

W. Adam, 0. Cueto, 0. DeLucchi, K. Peters, E. M. Peters, and H. G . Von Schnering, J. Am. Chem. SOC.,1981,103, 5822.

21

Three-Membered Ring Systems CHO

'H

P 0

Torr gave (1 10) Flash vacuum thermolysis of (109) at 420 "C and 2 x (95%)." The Dewar-furan (1 11; X = 0) has been prepared in six steps from the corresponding Dewar-thiophen (1 1 1; X = S ) because the direct route via photolysis of furan proved

Spectra and Theoretical Chemistry of Oxirans.- The use of conformational analysis, with the aid of torsion-angle notation, permits the interpretation and prediction of regioselective opening of epoxides."' Values for the molar refraction, electron polarization, and permanent electron dipole moments for oxiran and its simple derivatives have been calculated from literature data.lo2 The molar Kerr constants for oxiran and its methyl derivatives in CC14 were also calculated. The pericyclic reactivities of three-membered heterocycles have been rationalized, using the relaxation method.lo3

The 13C n.m.r. spectra for (1 12; X = 0, NH, S , or SO) have been recorded and compared with that for (1 12; X = CH2).lWThe annelation effects of the three-membered rings were determined. Using 350 MHz 'H n.m.r. and dipole moments, ( 1 13; R = H) and (1 13; R = OMe) were shown to adopt a boat conformation, with the 0 of the oxiran ring in a pseudo-axial position.'05 The absolute configuration of alliacolide (1 16) has been established by c.d.

99

100

101 102

103 104

105

A. J. H. Klunder, W. Bos, J . M. M. Verlaak, and B. Zwanenberg, Tetrahedron Lett., 1981, 22,4553. D.Wirth and D. M. Lemal, J. Am. Chem. SOC.,1982,104,847. E. Toromanoff, Tetrahedron, 1981, 37, 3141. D. Pitea, R. Todeschini, and F. Gatti, J. Chem. SOC., Faraday Trans. 1 , 1981, 77, 1611. 0.Henri-Rousseau, P. Pujol, and F. Texier, Bull. SOC.Chim. Fr., Part 2 , 1980,496. M. Christl, H. Leininger, and E. Brunn,J. Org. Chem., 1982,47, 661. J. Huet, Z. Kotkowska-Machnik, and J . Zakrzewski, Org. Magn. Reson., 1981, 16, 236.

wewe

22


MeOOCCHZCH2

Me

Me

(114)

0

OH (115)

Me

Me HO'

measurements on the degradation products (1 14) and (1 15), both of which exhibit positive Cotton curves.1o6 The molecular structure of the perfluoro-oxiran (1 17) has been determined, using gas-phase electron diffracti~n.''~

Reactions of Oxirans. - Ring-opening Reactions with Electrophiles. A ringcontraction resulted from the treatment of the piperidine (118) with BF3. OEt,, to yield (1 19) rather than the expected piperidone (12O).lo8The C-19 group has been shown to have a significant effect on the BF3-catalysed reactions of SP,6P-~teroids.'~~ Thus androstanone (121 ; R = H) reacted with gaseous BF3 in benzene with loss of the hydroxymethyl group as HCHO and subsequent dehydration to give the diene (122), but, for (121; R = OAc), ring-contraction led to ( 1 23). For steroidal Sar,6c~-epoxides,however, an alternative pathway is possible, involving participation of the C-19 group and leading to ring-closed products; eg., chloestanol (121 ; R = H) gives (124) with BF3 log or with HC1O4."'

8 I

COOCH2CC13 (118)

( Y C H O

I

COOCH2CC13 (119)

ho I

COOCH2CC13 ( 120)

A. P. W. Bradshaw, J . R. Hanson, D. N. Kirk, and P. M. Scopes, J. Chem. Soc., Perkin Trans. I , 19 8 1, 17 94. lo' B. Beagley, R. G. Pritchard, and R. E. Banks, J. Fluorine Chem., 1981, 18, 159. F. H. Hershenson and L. Christensen, Synth. Commun., 1981, 11, 61 5. l o g H. Mastalerz and P. Morand, J . Chem. SOC.,Perkin Trans. 1 , 1981, 154. ' l o P. Kocovsky and V. Cerny, Collect. Czech, Chem. Commun., 1980, 45, 3190. lo6

23


The mechanism for the gas-phase reaction of trans-2,3-dideuterioethene oxide with HBr and HCl has been shown to involve anti ring-opening, with the formation of erythro-R(CHD)*OH ( R = C1 or Br)."' The reaction of ethene oxide with HF followed a somewhat different course, affording only 5% of fluorohydrin together with (126) (37%) and oligomers and polymers. A possible mechanism for this reaction is shown (see Scheme 8) in which two moles of oxiran react with HF to give intermediate (125), which is open to polymerization with other oxiran molecules or to ring-expansion, with the subsequent formation of dioxane (1 26).

T7 +O I F-

+

TJ-

[ y7JHIF--[ci>].-- 50%) from (177) has been r e ~ 0 r t e d . lSequential ~~ treatment of (177) in THF at 0 "C with one equivalent each of BuLi, methanesulphonyl chloride, and then BuLi again, to give (17$), may be accomplished in 10 minutes. Terminal yepoxy-sulphones, on treatment with two equivalents of MeMgI , give cis-3-phenylsulphonylcyclobutanols; thus (179) yields (180).13' This reaction contrasts with that of (179) with MeLi or with LiNPr:, which gives derivatives of cyclopropylmethanol. Ph

phso>

phs+h

(179)

OH

The reaction of organomagnesium reagents RMgBr with y ,S -epoxy-ketones, e.g. (181), affords functionalized tetrahydrofurans (182; R = Et, Ph, or CH=CH2) (71-75%).138 The ring-opening of the oxiran by the intermediate alkoxide occurs with inversion of configuration, but, with both organomagnesium and organolithium reagents, the cyclization affords a 1 : 1 mixture of both cis- and trans-tetrahydrofurans (1 82).

M:eAT4:

+T (181)

OH

(182)

The opening of epoxides, e.g. cyclopentene oxide, with the allylic Grignard reagent (1 83), in the presence of CuI , affords (1 84) in high ~ie1d.l~' The allyl-silane (184) may then be converted into the allylic alcohol (185). The overall process demonstrates the use of (1 83) as a hydroxypropenyl synthon. Me3Siw

136

137 138

13'

/

MgBr

Y. Gaoni, Tetrahedron Lett., 1981, 2 2 , 4339. J. M. Decesare, B. Corbel, T. Durst, and J . F. Blount, Can. J. Chem., 1981, 59, 1415. M. Chastrette and G. P. Axiotis, J. Organomet. Chem., 1981, 206, 139. H. Nishiyama, S. Narimatsu, and K. Itoh, Terrahedron Lert., 1981, 2 2 , 5289.

32


Reactions of alkyl-lithiums with isoprene oxide (1 86) yield p,-ydisubstituted allylic alcohols of Z c~nfiguration.'~'The proportion of Z isomer can be increased by using a base; thus the formation of (187) from (186) and BunLi is improved fron an isomer yield of 88% in hexane at 0°C (76% overall yield of allylic alcohols) to an isomer yield of 97% (73% overall) in the presence of Bu"0Li.

I , Enantioselective SN2' reactions of epoxy vinyl sulphones have been rep~rted.'~'The chiral epoxide (-)-( 188) reacts with MeLi in the presence of LiC104 in a 1:1 mixture of CH2C12and Et,O at - 78 "C to yield a 95 : 5 mixture of (+)-(189; R' = Me, R2 = H) and (+)-(189; R' = H, R2 = Me) (81%). Using a mixture of Et3A1 and MeCu, however, the reaction affords solely (+)-(189; R' = Me, R' = H).

In contrast to their reaction with R'R'CuLi (R' = alkyl, R2 = alkyl or CN), the reactions of epoxides with the higher order mixed organocuprates R2Cu(CN)Li2 (R = various alkyl or aryl) give excellent yields of ring-opened products.'42 The trisubstituted oxiran (190), on reaction with Pr"Cu(CN)Li, affords only 23% of (191), but with Prn2Cu(CN)Li2 the yield is increased to 86%.

140

14' 14'

M. Tamura and G. Suzukamo, Tetrahedron Lett., 1981, 2 2 , 577. J . C. Saddler and P. L. Fuchs, J. Am. Chem. SOC.,1981, 103, 2112. B. H. Lipshutz, J . Kozlowski, and R. S. Wilhelm, J. Am. Chem. Soc., 1982, 104, 2305.

33

Three-Mem bered Ring Systems OS iMe

I

OSiMe3

I

Me (193)

The enol ethers of substituted 2,3-epoxycyclohexanones, e.g. (192), react with organocuprates, e.g. MeCu(CN)Li, in a regio- and stereo-specific manner to yield (in most cases) the 1,4-trans-adducts (193) (95%).'43

Reduction and Elimination Reactions of Oxirans. - The liquid-phase hydrogenolysis of the spiro-oxirans (194; X = 0, Y = CH2) and (194; X = CH2, Y = 0) on supported metal catalysts (Pd, Pt,Rh, and Ni) in various solvents leads to preferential cleavage of the more substituted C-0 bond.'@ For Pd and Rh catalysts the major products are aldehydes (60 and 80%respectively) whereas with Pt or Ni the liydrogenoiysis leads mainly to primary alcohols. Catalytic hydrogenolysis of 3,4-epoxybut-l-ene with cationic rhodium complexes at 30°C under 1 atm of hydrogen gives but-2-enal as the major product .14' The hydrogenolysis of methyloxiran on unsupported Pt/C catalysts leads mainly t o Me2CHOH, and to EtCHO, whereas the aldehyde was produced if a supported catalyst was used.14 The interpretation of these results in terms of the role of acidic centres in the isomerization and hydrogenolysis of oxirans has received some criti~ism.'~'

Epoxides may be reduced t o the less substituted alcohol, using a combination of NaBH3CN, BF3. OEt2, and THF. The reaction is both regio- and stereo-~elective;'~~ thus 1-methylcyclohexene oxide gives a 97 : 3 ratio of (195):(196) (overall 87%), with only a trace of trans-(195) being produced. Stereospecific reduction of epoxybutanoic acid (197) with NaBD4 gave (198) (52%).149 The reduction of (+)-(R)-(l99) with A1D3 gives a nearly equal mixture of (+)-(S)-(200) and (-)-(S)-(201),150 The inversion that is involved in 143 144

J. P. Marino and J. C. Jaen, J . A m . Chem. SOC.,1982, 104, 3165. G. Accrombessi, P. Geneste, J. L. Olive, and A. A . Pavia, Bull. SOC.Chim. Fr., Part 2 , 1981, 19.

14' 146

14' 14' 149

H. Fujitsu, E. Matsumura, S. Shirahama, K. Takeshita, and I. Mochida, J . Chem. SOC., Perkin Trans. I , 1982, 855. M. Bartok, F. Notheisz, and J . T. Kiss, J. Catal., 1981, 6 8 , 249. M. Kraus and H. Davidova, J. Catal., 1981, 68, 252. R. 0. Hutchins, I. M. Taffer, and W. Burgoyne, J. Org. Chem., 1981, 46, 5214. J. R. Mohrig, P. J . Vreede, S. C. Schultz, and C. A. Fierke, J . Org. Chem., 1981 46, 46 5 5.

R. L. Elsenbaumer, H. S. Mosher, J. D. Morrison, and J . E. Tomaszewski, J. Org. Chem., 1981, 46,4034.

34


OH

Ph I

D3C+--Ph H

H°CDZ*H

D

the formation of (201) points to a classical s N 2 attack by A1D3 on the benzylic site. Deoxygenation of epoxides to alkenes can be achieved with a number of reagents, including WCls and BuLi,lS1NbCIS and NaA1H4,lS2and Me3SiCl and NaI.’” The last combination of reagents has been shown to react stereoselectively, affording (E)-2,2-dimethylhex-3-ene (95%) from the corresponding (E)-epoxide.

Thermal and Photochemical Reactions of Oxirans. - Isotopic labelling has been used to prove that the thermal rearrangement of phenyloxiran proceeds via a 1,2-shift of hydrogen, and not phenyl migration (Scheme 13).lS4The epoxide (202), labelled with 13C at C-2, gives entirely C(2)-labelled phenylethanol (203) and 3,3-2H2-labelled(202) gives (203) with 2H at both C-1 and C-2. The method does not, however, distinguish between the transfer of H’ and of H-.

wz’

* PhCH-

-0

I

CD2 PhCHD

Ph

1 (202 1

\

+ PhCH-CD2 I

0-

/

-CDO

(203)

Scheme 13 Cycloaddition reactions of the carbonyl ylides derived from the thermolysis of (204; n = 1 , 3 , 5 , or 10) led to annelated products (205;n = 1 , 3 , or 5), but the bridged compound (206) was produced from (204;n = The stereochemistry of 6n and 877 ring-cyclization reactions of 2-oxaheptatrienyl Is’ lS3

M. A. Umbreit and K. B. Sharpless, Org. Synth., 1981, 6 0 , 29. M. Sato and K. Oshima, Chem. Lett., 1982, 157. R. Caputo, L. Mangoni, 0. Neri, and G. Palumbo, Tetrahedron L e n . , 1981, 22, 3 5 5 1 . R. M. Roberts and L. W. Elrod, J . Org. Chem., 1981, 46, 3732. J . Brokatzky and W. Eberback, Tetrahedron Lett., 1980, 2 1 , 4 9 0 9 .

35


ph-a Me

\ /

M

MeOOC

(208)

Mee‘

O

-O

C

b

( 209 1

dipoles has been ~ t u d i e d . ”,15’ ~ The eight-electron cyclization of the conjugated carbonyl ylide (208), generated by thermolysis of (207), gave the dihydro-oxepin (209). The reaction followed the theoretically expected conrotatory process. The thermal decompositions of the three isomers of (210) all yield mixtures of PhCHO, PhOH, C6H6, and furan.lS8It is suggested that two of the decompositions proceed by similar mechanisms; for trans-(210), via (21 l), and for the isomer of cis-(210) in which epoxide rings are anti to cyclobutene, via (212). The first step in the decomposition of the isomer of cis-(210) in which epoxide rings are syn to cyclobutene is thought to involve the formation of (213). The first topologically non-planar molecule (2 15) has been produced by the thermolysis of (214).15’

lS7 158

W. Eberback, E. Haedicke, and U . Trostmann, Tetrahedron Lett., 1981, 22,4953. W. Eberback and U. Trostmann, Chem. Ber., 1981, 114, 2979. H. Prinzbach, M. Mass, H. Fritz, and G . McMullen, Tetrahedron L e t t . , 1980, 21,4897. S . A. Benner, J . E. Maggio, and H. E. Simmons, J. A m . Chem. SOC.,1981, 103, 1581.


36

Direct (457.9 nm) or photosensitized (by benzophenone) irradiation of (216) gives rise to the exclusive formation of (217).l6' In contrast to this, irradiation of the isomer of (216) in which the epoxide oxygen is syn to the benzene ring yields a mixture of products, of which the major constituent is (218) (ca 25%). The difference in reactivities of these isomers was explained in terms of the stereoelectronic effect of the epoxide ring. Pr

Photolysis of a-epoxy-ketones that are excited in their triplet states leads to 0-diketones, a-diketones, or fragmentation products.'61 The reaction pathway depends on the localization of energy for the system; thus (219; Ar' = Ph, Ar2 = 1-naphthyl), on irradiation at 366 nm, at room temperature, in MeCN, gave naphthaldehyde (75%)and the a-diketone (220) (8%)whereas (219; Ar' = 2-naphthyl, Ar2 = Ph), under the same conditions, gave (221) (66%). The absorption spectra of the ylide intermediates in these reactions were reported. 0

0

OH

I6O

C. C. Liao, H. S. Lin, T. H. Hseu, C. P. Tang, and J . L. Wang, J. Am. Chem. Soc.,

16'

P. Hallet, J . Muzart, and J. P. Pete, J. Org. Chem., 1981, 46,4275.

1982,104, 292.


37

Carbonyl ylides that are derived photochemically from symmetrically substituted diaryl-oxirans (222; R = Me, Ar = Ph or 2-naphthyl; R = H, Ar = 2-naphthyl) retain their configuration during cycloaddition reactions with dipolarophiles.'62 Both isomers of (222; R = Me, Ar = Ph) give the same furan products (223) on irradiation in the presence of maleonitrile. This result implies that the same ylide (224) is generated from both oxirans. Adverse interactions of aryl groups would seem to prevent alternative opening of the oxiran ring. The ylides derived from (222; R = Me, Ar = 2naphthyl) do not undergo addition reactions whereas those from (222; R = H, Ar = 2-naphthyl) do; this result may also be explained in terms of steric effects. Another group has concluded that the regioselectivity in cycloaddition reactions of carbonyl ylides is high with electron-rich alkenes but is low with electron-deficient ones.163

A series of papers on photochemical reactions has reached number 122, with ten publications concerning the reactions of various vinyl~xirans;'~~ for example, triplet sensitization of (E)-(225) gave (226) and (227) via cleavage of the C(6)-0 bond.16'

164

J. P. K. Wong, A. A. Fahmi, G. W. Griffin, and N. S. Bhacca, Tetrahedron, 1981, 37, 3345. J. Brokatzky-Geiger and W. Eberbach, Hererocycles, 1981, 16, 1907. N. Bischofberger, G. DeWeck, B. Frei, H. R. Wolf, and 0. Jeger, Helu. Chim. A c t a ,

16'

K. Murato, B. Frei, W. B. Schweizer, H. R. Wolf, and 0. Jeger, Helu. Chim. Acta,

16' 163

1981,64, 1766. 1 9 8 0 , 6 3 , 1856.


38

clD -)/y

PhCH2CO0

Ph CH2 C 1

(228)

PdLm

0

0

li

Ph CH C-P dC l L m

PhCH2!!-ia

Scheme 14 Reactions of Oxirans with Organometallic Compounds. - A general method for the preparation of halohydrin esters via the reaction of organic halides with CO (20atm) in the presence of PhPd(PPh3)21 has been described.'66 In the particular case of benzyl chloride and cyclohexene oxide, (228) (57.5%) was obtained. A possible mechanism for this reaction is shown in Scheme 14. Isomerization of a$-epoxy-ketones in the presence of palladium complexes leads to 1,3-diones; thus heating (229) in toluene that contains Pd(PPh3)4 and (Ph2PCH2)2,at 140°C, for 90 hours gives (230) (94.3%).16' 0

Perilla alcohol (232) (98%) has been prepared by treating 0-pinene epoxide (231) with HgS04 that is suspended in a water-THF mixture, extracting into ether, and treating the ethereal extract with dilute H2S04.16'

( 2 3 11 166

16' 16*

(232) M. Tanaka, M. Koyanagi, and T. Kobayashi, Tetrahedron Lett., 1981,22, 3875. Teijin Ltd., Jpn. Kokai Tokkyo Koho 81 1 5 216. M. Fetizon, J. E. Ecoto, and S. Lazare, Eur. Pat. Appl. 21 952.


39

Miscellaneous Reactions of Oxirans. - Ethylene carbonate (233; R' = R2 = H, X = 0) may be prepared by the reaction of ethylene oxide with C02 under pressure, at 140 OC, in the presence of alkali-metal halide^.'^' The reaction is catalysed by free anion, which is generated by the use of the complex between 18-crown-6 and KI.I7O Using complexes of this type, the compounds (233; X = 0; R' = Me, Ph, or ClCH2; R2 = H or Me) have also been prepared.17' The oxazolidone (233; R' = H, R2 = C1CH2, X = NPr') is prepared by the reaction of (chloromethy1)oxiran with isopropyl isocyanate in the presence of ~ i c 1 . I ~ ~

xKo 0

(233)

O Ph Y O

(234)

The 1,3-dioxolans (234; R = CH2Cl, Me, or Et) have been prepared under neutral conditions by the reactions of the corresponding epoxides with benza 1 d e h ~ d e . IThe ~ ~ reactions are catalysed by halide ion and provide a mixture of cis- and trans-2,4-disubstituted compounds. Using Lewis acid catalysts, the cis-isomer was preferentially formed whereas catalysis by lithium halides favoured the trans-isomer.

Thioamides RCSNH2 react with the chloro-oxiran (235) to yield the thiazoles (236; X = S, R = Me or Ph) (78%).'74 When (235) reacts with selenourea in CH2C12 at O'C, in the dark, and this is followed by treatment with Et3N, the selenazole (236; X = Se, R = NH2) (52%) is produced. Cyclization Of (237; R=4-C1CbH4, 4-NO2C6H4, or 4-MeOC6H4) with the cyclic t h o amides (238; X = HC=CHNMe, HC=CHCH=N, or CH2CH2S) provides a general synthesis of the ring-fused meso-ionic thiazolones (239).17'

169

Nippon Shokubai Kagaku Kogyo Co., Ltd., Jpn. Kokai Tokkyo Koho 8 2 31 682. Nippon Shokubai Kagaku Kogyo Co., Ltd., Jpn Kokai Tokkyo Koho 81 1 2 8 778. 171 K. Naito, H. Koinuma, and H. Hirai, Nippon Kagaku Kaishi, 1982, 290. 17' Seitetsu Kagaku C o . , Ltd., Jpn. Kokai Tokkyo Koho 81 7 3 077. 173 T. Takeda, S. Yasuhara, and S. Watanabe, Yukagaku, 1 9 8 1 , 30,486. 174 J. Gasteiger and C. Herzig, Tetrahedron, 1 9 8 1 , 37, 2607. 17' M. Baudy-Floc 1.1 and A. Robert, Synthesis, 1 9 8 1 , 981. 170

40


Thermal uncatalysed insertion of silicon halides into oxirans normally requires long reaction times and high temperatures. It has been reported, however, that nucleophilic catalysis renders this reaction of greater synthetic importance, providing a regioselective route to @protected vicinal haloh y d r i n ~ . 'The ~ ~ most effective catalysts appear to be Bun4NC1and Ph3P, the latter allowing the conversion of phenyl glycidyl ether into (241) (99%) in CHC13at 0 OC, using (240; X = Cl), after 5 minutes. This should be contrasted with the uncatalysed reaction, which affords only 23% of product after 24 hours at 25 "C. The conversion of epoxides into protected vicinal halohydrins, using (240; X = Br or I) in the presence of Et3N, has been incorporated into a one-pot synthesis of a-bromo- and a-i~do-ketones.'~'The oxidation step is achieved by adding Jones reagent (Cr03-H2S04) to the first-formed 0-halogenosilyl ether. Overall yields of 58-73% have been achieved (based on starting epoxide) for (242; R = alkyl, X = Br or I) and cyclic a-halogenoketones. Trialkylsilyl triflate (240; X = OS02CF3) promotes the ring-opening of oxirans and affords allylic alcohol silyl ethers from tetra-, tri-, and 2,2di-substituted oxirans; thus cyclohexene oxide gives (243).'78

3 Aziridines Preparation. - Direct Insertion. Ethoxycarbonylnitrene (EtOOCN:), generated by the Et3N-induced a-elimination of 4-N02C6H4S03NHCOOEt,adds to vinyl chlorides to give aziridines without appreciable contamination by insertion prod~cts."~The reaction is stereospecific; thus the addition to (244) gives (245), and the a-chloro-aziridines undergo facile rearrangements to alkenylamines, e.g. (246).

177

17' 17'

G. C. An d r e w, T. C. Crawford, and L. G. Contillo, Tetrahedron Lett., 1981, 2 2 , 3803. J. N. Denis and A. Krief, Tetrahedron Lett., 1981, 2 2 , 1429. S. Murata, M. Suzuki, and R. Noyori, Bull. Chem. SOC.Jpn., 1982, 5 5 , 247. L. Pellacani, F. Persia, and P. A. Tardella, Tetrahedron Lett., 1980, 21, 4967.

41

Three-Membered Ring Systems c1

COOEt

I

pr+pr

c1 (244)

Bu

Bu

H (245)

On treatment with Pb(OAc)4 in CHC13, the quinazolone derivative (247) gives (248) stereospecifically, and in good yield, via N-nitrene addition.'" The stereochemistry of these reactions may be explained in terms of a nonconcerted electrophilic addition of nitrene to the double-bond through a seven-membered transition state (249). Oxidation, with Pb(OAc), , of R' ONH2 18' and of RSNH2 lB2 has afforded nitrenes, which add to alkenes to produce the corresponding aziridines, e.g. (250; R' = Et, Pr", Pr', Bun, Bu', or Bus; R2 = R3 = R5 = Me, or R2 = R3 = R4 = Me, R5 = H, or R2 = R4 = Me, R3 = R5 = H, or R2 = R5 = Me, R3 = R4 = H) and [251; R = 2,4(N02)2C6H3].Sulphenyl-aziridines, e.g. (252), have been produced by irradiation of N S F in the presence of perfluor~propene.'~~

"\-&;: R

1

SR

N

I

OR

Fw:3 F

N

I

SNSF2 (252)

180

lS3

R. S. Atkinson, J . R. Malpass, K. L. Skinner, and K. L. Woodthorpe, J. Chem. SOC., Chem. Commun., 1981, 549. B. V. Ioffe and Yu. P. Artsybasheva, Zh. Org. Khim.,1981, 1 7 , 91 1. R. S. Atkinson and B. D. Judkins, J. Chem. SOC.,Perkin Trans. I , 1981, 261 5. W. Bludssus and R. Mews, Chem. Ber., 1981, 114, 1539.

42

Heterocyclic Ch emistry

Preparation by Cyclization Reactions. A new route to 2-cyano-aziridineshas been developed, using the reaction of 2-chloro-ketimines with KCN in methanol.lW Initial nucleophilic attack by cyanide ion on (253; R = Pr', But , or cyclohexyl) gives (254), which is followed by cyclization to form (255) (73-88%). A convenient two-step synthesis of 2-cyano-aziridines has also been reported in which (256; R = Ph, halogenophenyl, 4-MeC6H4, or 4-MeOC6H4) is cyclized t o (257), using NaOH and the phase-transfer catalyst PhCH2NEti Cl-.ls5 The compounds (256) were synthesized by the reaction of the appropriate aromatic amine with CH2CC1(CN), using CU(OAC)~ catalyst. 0

J

iii

\

\

X

N

BHr

R

N R

(258)

Reagents: i, LiAIH, ;ii, Ph,P, Br, ;iii, RNH, ;iv, BuLi

Scheme 15 An jmproved synthesis of the N-substituted isopropylideneaziridines (258;

R = Pr', But, neopentyl, cyclopropyl, Ph, or 1-adamantyl) is shown in Scheme 15.lS6 A method for the preparation of 2-bromo-amines, which are precursors for synthesis of aziridines, has been reported in which DBPA (259) reacts with styrene or with (E)- or (2)-1-phenylpropene to yield (260; R = H or Me), which with HCl in benzene give 2-bromo-amine hydrochlorides (261) in reasonable overall yields.'" R

184

0

N. DeKimpe, L. Moens, R. Verhe, L. DeBuyck, and N. Schamp, J. Chern. SOC.,Chem. Commun., 1982, 19. S. A. Rao, A. Kumar, H. Ila, and H. Junjappa, Synrhesis, 1981, 623. J . B. P. A. Wijnberg, P. G . Wiering, and H. Steinberg, Synthesis, 1981, 901. S. Zawadzki and A. Zwierzak, Tetrahedron, 1981, 37, 2 6 7 5 .

43


F? R1

R2

O Y N R 2

T-7 N R2

hR1

Preparation by Ring-contraction. The phot ofragment ation of oxazolidines, e.g. (262; R' = H or Ph, R2 = aryl), provides a new route to aziridines.'" The reaction proceeds via the elimination of an aldehyde. The vinyl azides [263; R1 = Me, R2 = Ph; R' = H, R2 = Bun; R' = But, R2 = H; or R'R2 = (CH,),], on treatment with dimethylsulphoxonium ylide, give the vinyltriazolines (264) (89-95%).ls9 Flash vacuum pyrolysis of (264) gave the vinylaziridines (265) (91-94%). Preparation of Chiral Aziridines. Asymmetric chlorination of the nitrogen atom of aziridines has been achieved, using Bu'OCl, in the presence of optically active trifluoromethylcarbinols, as chiral solvating agents.'" Thus (266; R' = COOEt or Ph, R2 = H) with Bu*OCl in the presence of (+)-(S)PhCH(OH)CF3 in CH2C12, at - 60°C, for 3 hours gave chiral (266; R' = COOEt or Ph, R2 = Cl). Aziridines of opposite chirality were generated by using (-)-(R)-(C H7)CH(0H)C F 3 . The aziridinecarboxylic acid (267) has been prepared and resolved, using PhMeCHNH2.'"

Spectral and Theoretical Studies of Azkidines. Optically active 2-alkylaziridines (268; R' = H or Me, R2 = Me, Prl, or Bu') have been prepared from their corresponding L-amino-acids and their chiroptical properties recorded.'% From their 0.r.d. and c.d. spectra it was concluded that a negative Cotton

"' 0. Tsuge, K. Oe, and N . Kawaguchi, Chem. Lett., 1981, 1585. A. Hassner, B. A. Belinka, M . Haber, and P. Munger, Tetrahedron Lett., 1981, 2 2 , 1863.

A. Forni, I. Moretti, A. V. Rosyanik, and G. Torre, J . Chem. Soc., Chem. Commun., 1981, 588. l p 1 R. G . Kostyanovskii, G. K. Kadorkina, G . V. Shustov, I. I. Chervin, S. S. Nasibov, and S.V . Var\amov, Izv. Akad. Nauk SSSR, Ser. Khim., 1982, 145. 192 L. Maat and R,W. Wulkan, R e d . Trav. Chim. Pays-Bas, 1981, 100, 204.


44

effect at 200nm was connected with a cis orientation of the lone pair on nitrogen with the 2-alkyl substituent. Circular dichroism spectra have also been reported for benzoylaziridines, allowing configurations to be derived.lg3 The I3C chemical shifts of the unsubstituted carbon in the ring of (268; R' = H; R2 = H, Me, Et, CONH2, CONHNH2, CH2NH2,CN, or COOMe) and of 2,2-dimethylaziridine have been correlated with the "N shifts.'% The 15N shifts were also correlated to Taft inductive and steric constants. The proton-accepting abilities of cis(269; R' = H, Me, or PhCH,; R2 = H or NO2) and of trans-(269; R' = H, Me, or PhCH2; R2 = H, Br, or NO2) have been estimated, using the i.r. spectral shifts that are induced by these aziridines is phenol, 4-bromophenol, and trichloroacetic acid.lg5 The cis-isomers reacted with all three proton donors but trans-isomers only with CC13COOH. The absence of complexation for the trans-isomers was attributed to intramolecular hydrogen-bonding (when R' is H) and to steric hindrance when R' is Me or PhCH2. Two theoretical studies on the structure of aziridine have been published, one relating to the effect of hyperconjugation on the barriers to the inversion of nitrogen" and the other to the structures of aziridine-enarnine~."~The reaction by which (270; R = H, Me, or NH2) are hydrolysed to cis- and to trans-(27 1) has been subjected to ab initio calculations.198Theoretical predictions have been found to agree with experimental results. Reactions of Aziridines. - Thermal. Thermolysis of (272; R', R2, R3 = H or Me) gave (274) and R'CH=CR2R3 (R' and R3 are cis) via the intermediate (27 3).

(272) lg3

(273)

J . M. J. Tronchet, E. Winter-Mihaly, M. A. M. Massoud,and J. Guist, Helv. Chim. Acta, 1981, 64, 2350.

lg5 '91 197

199

E. Liepins, I. Kalvins, and P. T. Trapentsier, Khim. Geterotsikl. Soedin., 1981, 1231. v. D. Orlov, F. G. Yaremenko, N. V. Lishtvan, and Yu. N. Surov, Khim. Gererotsikl. Soedin., 1981, 1641. D. Kost and M. Raban,J. Am. Chem. SOC.,1982,104, 2960. K. Mueller and F. Previdoli, Helv. Chim. Acta, 1981, 64, 2508. A. M. Sapse, Int. J. Quantum Chem., Quanrum Biol. Symp., 1980, 7, 155. H. G. Zoch, E. Kinzel, and G. Szeimies,Chem. Ber., 1981, 114, 968.

45


H

The vinylaziridine (27 5) underwent ring-expansion in refluxing toluene to give (276).200The mechanism involves a [3,3]-sigmatropic shift.

Ring-opening to Acyclic Compounds. The aziridines (277; R1,R2 = B u t , 1-adamantyl) undergo selective cleavage with 2-lithio-1,3-dithian to give the respective compounds (278).201 The A1C13-catalysed addition of 14C-labelled (279; R = Br) to benzene gives (280) with the label almost exclusively in the position shown.202 The mechanism proposed for this conversion involves a primary route via the intermediate (279; R = Ph).

vo

R1

I

R2

RcH23 *

Ph 2CHCH2CH2NHS02Ph

S02Ph

(280 1

(277)

The ring-opening of aziridines by fluorinating agents yields a,P-difluoroamines. The stereochemistry of opening can be controlled by the correct choice of reagent, e.g. anhydrous HF, Olah's reagent, or Et,N.nHF (n = 2, 2.5, or 3).203 Thus (281) with anhydrous HF gives (282) (100%) whereas (283) (92%) is formed with Olah's reagent.

zoo '01

202

203

H. P. Figeys and R. Jammar, Tetrahedron Lett., 1981, 2 2 , 637. E. R. Talaty, A. R. Clague, J . M. Behrens, M. 0. Agho, D. H. Burger, T. L. Hendrixson, K. M. Korst, T. T. Khanh, R. A. Kell, and N. Dibaji, Synth. Commun., 1981, 11,455. W. J . Kensler and S. K. Dheer, J. Org. Chem., 1981,46,4051. G. M. Alvernhe, C. M. Ennakoua, S. M. Lacombe, and A. J . Laurent, J. Org. Chem., 1981.46,4938.

46


Electrochemical oxidation of N-acetyl- and N-formyl-aziridine in methanol at a platinum anode afforded MeCONHCH2CH20Meand HCONHCH2CH2CH(OMe)2 respectively; no cyclic products were obtained.2w The polarographic behaviour of aziridinium salts (284; R = Ph, 4-MeC&, or 3- or 4-BrC6H4) in water has been reported.205

4-RC6H4S02 (284 1 ( 285 1

Formation of Other Ring Systems. A new synthesis of the azetidines (285; n = 2; R = H, Me, or C1) has been reported, based on methylene insertion into the aziridine (285; n = 1 ;R = H, Me, or Cl), using Me2S-OcH2.206 Heating the BF3 adducts of the trans-aziridines (286; R' = 4-Br, 4-C1, 4-Me, H, or %No2; R2 = H, 4-Br, or 4-C1) with MeCN gave the BF3 adducts of the imidazolidines (287) (62-78%).207 With MeONa, (287) isomerized to the trans-imidazolidines. The same aziridines (286) were found to condense with acetone in the presence of Et,N to yield the oxazolidines (288) (55-80%).208 The reaction of (289; R' = OEt, 4-C1C6H4NH,Ph, or Ph2N) with R2CH(COOEt), (R2 = Ph or Me) afforded (290) via ring-opening and subsequent cyclization. 209

N y N M e

Me

'04 '05 207

2. Blum, M. Malmberg, and K. Nyberg, Acra Chem. Scand., Ser. B , 1981, 3 5 , 739. D. R. Crist, A. P. Borsetti, and M. B. Kass, J. Heterocycl. Chem., 1981, 18, 991. U. K. Nadir and V. K. Koul, J. Chem. SOC.,Chem. Commun., 1 9 8 1 , 4 1 7 . I. G. Tishchenko, 0. N. Bubel, and V. A. Konovalov, Khim. Geterorsikl. Soedin., 1981, 952.

208

I. G . Tishchenko, 0. N. Bubel, and V. A. Konovalov, Khim. Gererotsikl. Soedin.,

209

J. Budny and H. Stamm, Arch. Pharm. (Weinheim, Ger.), 1981, 314,657.

1981, 38.


II

H ( 2 9 11

47

Ph

02N

4 Azirines Preparation. - The reaction of (292) with HN3 in 95% acetic acid at room temperature gave a mixture of cis- and trans(296) in the ratio 40: 60.211 Heating cis(296) to 45-50°C gave the azirine (297). The amidoxime (298; R' = 2,4,6-C13C6H2NHC0,R2 = H), prepared from the corresponding nitrile, has been converted into its 0-tosyl derivative (298; R' = same, R2 = COOMe

3

MeOOC

COOMe

'

R CH

NOR^ IICNH

( 296) 210

A. Hassner, R. D'Costa, A. T. McPhail, and W. Butler, Tetrahedron L e t t . , 1981, 2 2 ,

'11

3691. G. L'abbh, J . P. Dekerk, and P. Van Stappen, Bull. SOC.Chim. Belg., 1981, 90, 1073.


48

4-MeC6H4S02)and treated with base to yield (299) as the sole This new variant of the Neber rearrangement provides the first synthesis of unsubstituted amino-azirines and has also been shown to proceed for the formation of (299; R' = PhS02). Kinetic studies have suggested that the thermal isomerization of the isoxazoles (300; R' = Me, R2 = R3 = H, or R' = NH2, R2 =Me, R3 = H) to (302) involves the azirines (301) as reaction intermediate^.^'^ Reactions of Azirines. - A number of reactions of azirines leading to five- and six-membered heterocyclic rings are shown in Scheme 16. Compounds (304) and (305) are formed by addition of MeNCO or R4R5C=C=S (R4, RS = various alkyl groups) to the azirine (303; R' = Ph, R2 = Me, R3 = NMe2).2149215

0: +

(308) H ( 306)

(307)

Reagents: i, MeNCO;ii, R4RsC=C=S, iii, Li,iv, CH,N,; v, Pd(PPh,),

Scheme 16 212

'I3 214 21s

J. A. Hyatt, J. Org. Chem., 1981, 46, 3953. J . D. Perez, G. I. Yranzo, and D. A. Wunderlin, J. Org. Chem., 1982, 47, 982. E. Schaurnann, S. Grabley, and G. Adiwidjaja, Liebigs Ann. Chem., 1981, 264. E. Schaumann, S. Grabley, F. F. Grabley, E. Kausch, and G. Adiwidjaja, Liebigs Ann. Chem., 1981, 277.


49

The reaction of excess lithium in THF with the chloroazirine (303; R' = C1, R2 = R3 = Ph) gave a mixture containing (306) (10%) and (307) and the same azirine, with CH2N2, afforded (308) (10-20%) together with (303; R' = CH2Cl, R2 = R3 = Ph) (45-50%).217 Palladium(0) compounds catalyse the conversion of 2-allyl-azirines into pyridines and pyrroles; thus (303; R' = Me, R2 = CH2CH=CH2, R3 = Ph) with Pd(PPh3)4 gives (309) (18%) together with (3 10) (20%).2'8

The peroxidation of (303; R' = R2 = H, R3 = Ph), using 3-C1C6H4C03H in chlorobenzene, gave PhCON=CH2, and not an o x a b i c y ~ l o b u t a n e . ~The '~ aziridiniminium salt (31 1) was formed quantitatively at - 60°C by the reaction of Ph3C+ BF; with (303; R' = R2 = Me, R3 = NMe2) in CH2C12.220 Using Et4N' CN-, at - 50 O C , the anion attacked the first-formed (31 1) to yield the aziridine (3 12). A theoretical approach t o the photochemical ring-opening reactions of azirines has been published.221

5 Thiirans Preparation. - The syntheses of silylated thiirans from silyl ketones have been reported.222 Anhydrous HC1 and then H2S were bubbled through a solution of (313; X = 0, R' = H or Me) in diethyl ether at - 20°C; subsequent chromatography under N2 afforded (313; X = S), which, used as the crude material, was allowed t o react with (4-R2C6H4)2CN2(R2 = H or MeO) t o yield (3 14) with overall yield 70-90%.

217

'18 219 220

T. C. Gallagher and R. C. Storr, Tetrahedron Lett., 1981, 22, 2905. T, C. Gallagher and R. C. Storr, Tetrahedron Lett., 1981, 22, 2909. T. Izumi and H. Alper, Organometallics (Washington, D . C . ) , 1982, 1, 322. A. Hassner, B. A. Belinka, and A. S. Steinfield, Heterocycles, 1982, 18, 179. C. Bernard-Henriet, P. Hoet, L. Ghosez, and R. Touillaux, Tetrahedron Lett., 1981, 2 2 , 4 7 1 7.

221 222

S. Kato and K. Morokuma, Chem. Lett., 1981, 1021. B. F. Bonini, G. Mazzanti, S. Sarti, P. Zanirato, and G. Maccagnani, J. Chem. SOC., Chem. Commun., 1981, 822.


50

The thiazolidine (315; X = S ) has been synthesized and found to be an. effective sulphur-transfer reagent for the conversion of oxirans into t h i i r a n ~ .Thus ~ ~ ~ cyclohexene oxide was converted into the corresponding thiiran quantitatively [and (315; X = S) into (315; X = O)]. The thiiran (318), of interest for the synthesis of radialene, has been prepared from (316; X = 0) by conversion into (316; X = N2HTs) and pyrolysis of its lithium salt.224The reaction is believed to proceed through the bicyclic sulphur ylide (3 17).

a;>* >K-c

A&

I

H

S

+

H

(316 1

(318)

( 317)

(315)

A 4n-electrocyclization route to (323) is shown in Scheme 17.'" The initial adduct (321) between (319; NR2 = morpholino, pyrrolidino, or piperidino) and a -bromoacetophenone (320) yields a transient carbonylthiocarbonyl ylide (322), which undergoes electrocyclization to the thiiran product (323).

"""& ~

Ph

mJ

Ph

-A2N>d73_ph Ph

Br-

(320)

0

(319)

-"~h?iPh

Ph

0

(322

(323)

Scheme 17 Reactions of Thiirans. - The gas-phase thermolysis of thiiran 1-oxide (324) has been investigated by field-ionization m.s. at 1043-1404 K.226 The decomposition of (324) proceeds via extrusion of 0 (to form thiiran) or of SO (to give ethene) and by rearrangement to 1,2-oxathietan (325). Intermediate (325) is also involved in the fragmentation of (326). Deuterium labelling 223 224 225 226

R. C. Cambie, G. D. Mayer, P. S. Rutledge, and P. D. Woodgate, J. Chem. SOC., Perkin Trans. I , 1981, 52. W. Ando, Y. Haniu, and T. Takata, Tetrahedron Lett., 1981,2 2 , 4815. A. Corsaro, M. Tarantello, and G. Purrello, Tetrahedron Lett., 1981,2 2 , 3 3 0 5 . L. Carlsen and H. Egsgaard, J. Chem. SOC.,Perkin Trans. 2, 1982,279.

51

7%ree-Membered Ring Sys tems

has been used to show that pyrolysis of (324) to ethene in both gas and liquid phases proceeds with more than 90% retention of ~tereochemistry.2~’The results suggest that there is a possible contribution from a biradical mechanism in this reaction. The complex RhCl(PPh3)3 reacts with stilbene episulphoxide in CH2C12to yield a dimeric complex (327) with sulphur monoxide ligand.228 Ion cyclotron resonance has been used to study the ion chemistry of thiiran and a ~ i r i d i n e . ~The ~ ’ main reaction of the molecular ion of thiiran with neutral molecules is transfer of sulphur.

The Chemistry of Thiiranium Ions. - The chemistry of episulphonium ions and the reactions of alkenes with sulphenyl derivatives have been reviewed.230 Stable thiiranium and thiirenium chlorides have been generated in SO2.231 Kinetic studies for the quantitative generation of (329; R’ = R2 = But, X = C1) from the ionization of (328) and the equilibrium between (330) and (331) in SO2 were followed, using n.m.r. spectrometry. Compounds (329; R1 = But , X = SbC15 or BF4) have been isolated as stable salts at room temper atwe. 232

yR2

R1

I

x-

c1

SMe

.sc I

c1-

6 Thiirens Photolysis of the argon-matrix-isolated thiadiazole (332) at 265 nm gave the thiiren (334) via the intermediate (333).233 Electrochemical reduction of (335) at - 1.8 V, followed by methylation, affords trans-stilbene (40%) and (336) (27%).234Similar reduction of (337) produces mainly diphenylacetylene (80%) with benzil (10%). 227

W. G. L. Aalbersberg and K. P. C. Vollhardt, Isr. J. Chem., 1981, 21, 145. K. S. Arulsamy, K. K. Pandey, and U . C. Agarwala, Inorg. Chim. Acra, 1981, 54, L51. 2 2 9 G. Baykut, K. P. Wanczek, and H. Hartmann, Dyn. Mass Spectrom., 1981, 6 , 269. ”O V. A. Smit, N. S. Zefirov, and I. V. Bodrikov, Org. Sulfur Chem., Invited Lecr. Int. Symp., 9th. 1980, (publ. 1981), 159. 231 V. Lucchini, G . Modena, T. Zaupa, and G. Capozzi, J . Org. Chem., 1982,47, 590. 232 V. Lucchini, G . Modena, G. Valle, and G . Capozzi, J. Org. Chem., 1981, 46,4720. M. Torres and 0. P. Strausz, Nouv. J. Chim., 1 9 8 0 , 4 , 703. 234 A . J . Fry, K. Ankner, and V. K. Handa, J. Chem. SOC., Chem. Commun., 1981, 120. 228

”’

52

Heterocyclic Chemistry Me CO

COMe

Ph

5

Me

02

(334) (332)

(333)

( 335

1

Ph

yPh phuso2ph 7 Diaziridines Photolysis of the tetrazolones (338; R = P i or Me) in MeCN or pentane gave the corresponding diaziridinone (339).235Photolysis of (340) gave (341) in a process which is thermally reversible.236

,-y

N-

RN-NMe

..,YNRK 0

0

4 - MeC6H4

The guanidines [342; X = Ts, P(O)(OPh),, P(O)(OEt),, or CN] afforded the diaziridinimines (343) (57-85%) on sequential treatment with Bu’OCl and But

(342)

(343)

Preparative separations or enrichments of the enantiomers of (344) and (345) have been achieved by liquid chromatography on triacetylcellulose.238 Almost pure (+)-(344) and (+)-(345) were isolated. The mass spectra of (346) and related compounds have been reported.239

’” H. Quast and L. Bieber, Chem. Ber., 1981,114,3235. 236 237

G.Tomaschewski, U. Klein, and G. Geissler, Tetrahedron Lett., 1980,21,4877. G. L’abbk, A. Verbruggen, T. Minami, and S. Toppet, J. Org. Chem., 1981,46,4478.

13’

M. Mintas, A. Mannschreck, and L. Klasinc, Tetrahedron, 1981,37, 867.

239

M. Mintas and K. K. Mayer, Org. MarsSpectrom., 1980, 15, 596.


53

8 Diazirines The direct preparation of (347; X = C1 or Br, R = various alkyl or aryl groups) from the reaction of NaOCl (or NaOBr) with amidines or isoureas in aqueous DMSO solution was first reported by Graham.240The reaction mechanism has been investigated and shown to proceed through initial N-halogenation; e.g. , (348) from RC(NH)NH2 (R = Pr' or MeO)?41 A subsequent reaction of (348) leads to (347; R = Pr' or MeO, X = C1) via (349) and the intermediate tight ion-pair (350). The highly explosive (347; R = Ph, X = C1) has been prepared and used as a source of chl~rophenylcarbene.~~~ Treatment of R2C=NOTs ( R = M e , CF3, COOMe, COOEt, or Ph) with R'ONH2 (R' = Me, PhCH2, or Et) affords a single-step synthesis of the diazirines (347; X = R).243

/p 1

N-NC1

-.

R

ClN=CRNHCl

LA J

R

X

c1-

Thermal decomposition of (347; X = C1, R = CF3) produces (trifluoromethyl)chlorocarbene, which, in the presence of cyclic dienes, gives ringexpanded products.244 Thus pyrrole and cyclopentadiene, on treatment with this diazirine, give (351) (35%) and (352) (23%) respectively. The selectivity for the reaction of CF3ClC: (generated by this method) with alkenes has been reported.%' Additions to cis- and to trans-butenes were stereospecific.

(351)

(352)

W. H. Graham, J. A m . Chem. SOC., 1965,87,4396. 241 R. A. Moss, J . Wlostowska, W. Guo, M. Fedorynski, J . P. Springer, and J . M. Hirshfield, J. Org. Chem., 1981,46,5048. 242 A. Padwa, M. J . Pulwer, and T. J. Blacklock, Org. Synth., 1981, 60, 53. 243 G. V. Shustov, N. B. Tavakalyan, A. P. Pleshkova, and R. G . Kostyanovskii, Khim. Geterotsikl. Soedin., 1 98 1, 810. 244 Y. Kobayashi, T. Nakano, H. Iwasaki, and 1. Kumadaki, J. Fluorine Chern., 1981, 18, 533. 2 4 5 R. A. Moss, W. Guo, D. Z. Denney, K. N. Houk, and N. G . Rondam, J. A m . Chem. SOC.,1981,103, 6164. 240


54

Two theoretical treatments of diazirine chemistry have been published, one dealing with gas-phase photolysis of (347; X = C1, R = Me)246and the other with the valence-ionization spectra of diazirine (and of dioxiran, cyclopropene, and thiiran)."

9 Dioxirans The evidence for the existence of dioxirans as intermediates in chemical reactions has been briefly reviewed.248The dioxiran (354) is an intermediate in the tetraphenylporphyrin-sensitized photo-oxygenation of (353), which is quantitatively converted into (3 5 5).249 The unimolecular symmetrical ring-cleavage of dioxiran, leading to the -OCH20.diradical, has been investigated, using ab initio CI calculations.250 0-0

MeCOCH=CHCOOSiMe3 Me HOK ' O(353)

M e 3 x( C354 H =1C H C O M e

(355)

10 Oxaziridines An improved synthesis of 2-sulphonyloxaziridines has been reported.251Oxidation of (356; R' = Ph, R2 = 3-NO2; R' = Ph, R2 = 4-NO2; R' = Me, R2 = H; or R1 = PhCH2, R2 = H) by 3-C1C6H4CO3Hin the presence of a

phase-transfer catalyst gives (357) (80-90%). These compounds epoxidize alkenes in good yield and with retention of stereochemistry; thus transstilbene with (356; R' = Ph, R2 = 4-NO2) gave the trans-stilbene oxide (95%). 252 H R'SO~N=CHC~H~R 2 ( 356 1

(357) R2

The photochemical electrocyclic reaction of CH2N=0 to form oxaziridine has been explored on the basis of the potential-energy surfaces that are obtained by MIND0/3 CI calculations.253 The reactions of oxaziridines with nucleophilic reagents have been 246

14' 14'

14' 15' 252

253

R. Becerra, J . M. Figuera, V. Menendez, A. Tobar, and R. Marinez-Utrilla, An. Quim., Ser. A , 1981, 77, 63. W. Von Niessen, W. P. Kraemer, and J . Schirmer, J . Chem. SOC.. Faraday Trans. 2 , 1981, 77, 1461. W. Adam and R. Curci, Chim. Ind. (Milan), 1981, 6 3 , 20. W. Adam and A. Rodriguez, Tetrahedron Lett., 1981, 2 2 , 3505. R. Cimiraglia, T. K. Ha, R. Meyer, and H. H. Guenthard, Chem. Phys., 1982, 66, 209. F. A. Davis and 0. D. Stringer, J. Org. Chem., 1982, 47, 1774. F. A. Davis, N. F. Abdul-Malik, S. B. Awad, and M. E. Harakal, Tetrahedron Lett., 1981, 22, 917. 0. Kikuchi, K. Morihashi, and K. Suzuki, Bull. Chem. SOC.Jpn., 1982, 55, 11 33.

Three-Membered Ring Sys terns

55

reviewed.254Attack by amines induces the fragmentation of (358) into (359) and (360).255The mechanism for this reaction involves the removal of a proton that is (Y to the nitrogen by base, and not nucleophilic attack at the nitrogen. OH

(361)

Iron(I1) sulphate cleaves oxaziridine rings and, in the case of (36 1 ; X = Hz or 0; R' = But or Ph; R2 = Me, Et, or Ph), it causes a double ring-opening to yield (362).256

254

Y. Hata, Yuki Gosei Kagaku Kyokaishi, 1981,39, 952.

255

W.H. Rastetter, W. R. Wagner, and M. A. Findeis, J. Org. Chem., 1982,47,419. D. St. C. Black and L. M. Johnstone, Angew. Chem., Inr. Ed. Engl., 1981, 2 0 , 669.

256

2 Four-Membered Ring Systems BY T. V. LEE

1 Highlights and Reviews A review on the synthesis of the carbopenam antibiotics has appeared.’ The 1-azabicyclo[2.1.O]pentane skeleton has been reported this year,415as is the first readily performed displacement of 4-acetoxyazetidinone with enolate anion equivalent^.^' Most notable, however, is the preparation and utilization of a series of 1,2-diazetidinium y l i d e ~ ?which ~ appear to have great potential in heterocyclic synthesis. The one ‘missing” cyclo-adduct of singlet oxygen and cycloheptatriene has now been as has the first, highly unstable, benzodithiet .55 2 Systems containing One Nitrogen Atom Azetidines and Azetines. - A new synthesis of azetidine, allowing its preparation on a large scale, has been described.2 The new method involves the addition of sodium azide t o acrolein and reduction of the addition product to 3-azidopropanol (l), whose reaction with triphenylphosphine, followed by distillation, gave azetidine in 30% yield. An improved preparation of 3,3-dimethylazetidine has also been reported, permitting the rate of formation of the enamine (2) to be ~ t u d i e d . ~ Me

H 2C =CHCHO

NaN3

N 3 ( C H 2 ) 30H

NaBH4

3 distil

(1)

Meb

0

1-Azabicyclo[2.1.01pentanes (3) can be readily prepared by the reaction of methyl a-bromoacrylate and imine anions as shown in Scheme 1.4 The elimination of bromide from the anion (4) has been suggested as the pathway

’

T. Kametani, Heterocycles, 1982, 17 (Special Issue), 463. J. Smuskovicz, M . P. Kane, L. G. Laurian, C. G. Chichester, and T. A. Scahill, J. Org. Chem., 1981,46, 3562. H. W. Thompson and J. Swistok, J. Org. Chem., 1981,46,4907. B. Fouchet. M. Joucla. and J . Hamelin, Terrahedron L e t t . , 1981, 22, 3397.

57


58 Me

I

PhCH=NCCOOMe

I Li

+

Me

OK7hMe COOMe

Ph

I

Li (4)

Scheme 1

by which the reaction proceeds. The same skeleton has been described in the patent literature.' a-Keto-azetidines (5) are formed by the photolysis of 2-aminocyclohexanones6 and the new, interesting heterocycle (6) has been prepared and its X-ray structure r e p ~ r t e d . ~ 0

Ph

Azetidinones. - This section only includes novel results on the preparation or reactions of the azetidinone nucleus. The chemistry of p-lactam antibiotics is not included. Readily available azetidine-2-carboxylic acid or the corresponding esters provide the starting point for a new approach to azetidin-2-ones, involving an oxidative decarboxylation. For example, the reaction of the enamino 0-silylated keten acetal(7) (Scheme 2) with singlet oxygen gives the azetidin2-one (8).8 The same authors have applied three of their previous syntheses of azetidinone to the total synthesis of (+)-3-aminocardicinic acid.g By a mixture of chemical and enzymatic methods, Japanese workers have succeeded in preparing (S)- and (R)-4-methoxycarbonylmethylazetidin-2-one (1 2) and (1 1). As shown in Scheme 3 , treatment of dimethyl P-aminoglutarate (9) with pig liver esterase gave the half ester (lo), which, upon cyclization, afforded the (R)-azetidinone ( 1 1). Thus the esterase cleaves the p r o 8 methyl ester group selectively. Alternatively, protection of the free amino-group in (9) results in selective cleavage of the pro-R methyl group and eventual Meija Seika Kaishi Ltd, Jpn. Kokai Tokkyo Koho 81 3 9 0 6 4 (Chern. Abstr., 1981, 9 5 , 11 5 258u). J . C. Arnold, J . Cossy,and J . P. Pete, Tetrahedron, 1981, 37, 1921. E. E. Glover, D. J. Pointer, J. B. Wilford, and M . Elder, J. Chern. SOC., Chern. Cornrnun., 1981,481. H. H. Wasserman, B. H. Lipshutz, A. W. Tremper, and J . S. Wu, J. Org. Chem., 1981, 46, 2991. H. H. Wasserman, C. J . Hlasta, A. W. Tremper, and J . S. Wu, J . Org. Chern., 1981, 46, 2999.

Four-Membered Ring Systems

59

r i,ii ___)

(8)

Reagents: i, lithium di-isopropylamide; ii, Me, Bu'SiCl; iii, singlet oxygen.

Scheme 2

(9)

1

iii

0

PhCH20y I

H2N

H

H

I

\j

i,iv

H

2y/L'~~I

HOOC

COOMe (12)

(S)

Reagents: i, pig liver esterase; ii, Ph,P, PySSPy, MeCN; iii, ClCOOCH,Ph, Et,N; iv, H,, Pd/C.

Scheme 3 formation of the (S)-azetidinone (1 2)." The condensing agent that was used in these cyclizations is itself novel," and is potentially very useful. A Reformatsky type of reaction has been utilized in a novel route to 0-lactams, by allowing carbodi-imides and a-bromo-esters to react in the presence of zinc metal.12 Cyanuric chloride has been shown to activate the la 'l

''

M. Ohno, S. Kobayashi, T. Iimori, Y-F. Wang, and T. Izawa, J. Am. Chem. Suc., 1981,103,2405. S. Kobayashi, T. Iimori, T. Izawa, and M. Ohno, J. Am. Chem. SOC., 1981, 303, 2406. K. Piotrowska and D. Mostowicz, J. Chem. Soc., Chem. Commun., 1981, 41.

60


stereospecific formation of cis-azetidinones from carboxylic acids and imines.13 The same transformation can also be achieved by using NN-bis(2-0x0-3-oxazolidiny1)phosphorodiamidic ch10ride.l~ Phase-transfer catalysis has become highly useful in the synthesis of azetidinones. It facilitates the one-pot synthesis of azetidinones from a-amino-acids and acid chlorides such as (13)." It also promotes the reaction of P-amino-acids and methanesulphonyl chloride to form azetidinones. l6 The reaction of 0-silylated keten acetals and benzyl N-chloromethylcarbamates (14), in the presence of titanium tetrachloride, results in the formation of a-ureidomethylated carboxylates (15), which are readily converted Me

,OS i M e

I BrCH2CCOC1

COOCH2Ph

I

+

I

Br

N\Me

H2,Pd/C -

-

,

base

Me

I

Ha C- NCOOCH2Ph

Me

COOMe

C1 (14)

into azetidinones." The known reaction of 0-silylated keten acetals and imines to form azetidin-2-ones has now been extended to allow the preparation of P-lactams that bear heteroatom-containing substituents.18 As shown in Scheme 4, a new approach to 3-methylene-azetidin-2-ones has been described. The reaction of the acrylamide (16) with n-butyl-lithium, followed by the addition of toluene-4-sulphonyl chloride, gives the azetidinone (17), in 60% yield.lg In the same paper it is reported that lithum phenylethynolate reacts with imines (in a highly stereoselective manner) to form azetidinones, in a promising new approach to functionalized azetibinones. OH

l$3

0

-om OTs

Reagents: i, 2 equiv. of BunLi, THF, at - 7 8 " C ;ii, toluenep-sulphonyl chloride;

iii, 2 5 " C.

Scheme 4 l3

l4 l6 l7 la

M. S. Manhas, A. K. Bose, and M. S. Khajavi, Synthesis, 1981, 209. D. R. Shridar, B. Ram, and V. L. Narayana, Synthesis, 1982,63. T. Okawara, Y. Noguchi, T. Matsuda, and M. Furukawa, Chem. Lett., 1981, 185. Y. Watanabe and T. Mukaiyama, Chem. Lett., 1981,443. K. Ikeda, Y. Terao, and M. Sekiya, Chem. Pharm. Bull., 1981, 29, 1747. I. Ojima, S. Inaba, and M. Nagai, Synthesis, 1981, 545. R. M. Adlington, A. G. M. Barrett, P. Quayle, A. Walker, and M. J . Betts, J. Chem. SOC.,Chem. Commun., 1981,404.


61

The patent literature contains a report of the synthesis of an azetidin-2-one by cyclization of the iron complex (18), which is derived from the iron ester complex (19)." CH,Ph

It has been demonstrated that azetidinones are produced, in good yield, by the oxidative cyclization of fly-unsaturated amidosulphonyl esters as shown in Scheme 5.21

Reagents: i, Br, , NaHCO, ; ii, Bun, SnH.

Scheme 5 Another new approach involves the photolysis of a 2-pyridone to form the bicyclic species (20), ozonolysis of which gives an azetidine that bears a substituent at C-4.22 Workers at the same laboratory have described an improved preparation of the intermediate ( 2 1),23 which is the key intermediate in their synthesis of thienamycin. This route has now been modified to make it an asymmetric synthesis.24

2o

21 22

'' 24

S. V. Ley and E. M. Hebblethwaite, Eur. Pat. Appl. 38661. (Chem. Abstr., 1982, 96, 181 0642). A. J. Biloski, R. D. Wood, and B. Ganem, J . A m . Chem. SOC.,1982, 104,3233. T. Kametani, T. Mochizuki, and T. Honda, Heterocycles, 1982, 19, 89. T. Kametani, T. Nagahara, Y. Suzuki, S. Yokohoma, S-P. Huang, and M . Ihara, Terrahedron, 1981, 37, 715. T. Kametani, T. Nagahara, and M. Ihara, Heterocycles, 1981, 16, 767.

62

Heterocyclic Chemistiy

Some interesting spiro P-lactams (22) are obtained from the reaction of 2-imino-2,5-dihydro-1,3,4-thiadiazoles and ketones.25 The products presumably arise via a [27r + 27r] cycloaddition followed by elimination of a molecule of nitrogen.

Me

$yL

+ Ph

NPh

/Aph-

-#

Me

M e

Me (22)

3-Chloro-4-methylsulphinylazetidin-2-ones (23) have been shown to form highly useful 4-alkoxyazetidinones, stereospecifically, when heated in the presence of an The intermediate (24)has been proposed, in which the chlorine substituent directs the incoming nucleophile to the P-face. 0

t

XSMe ROH

ic

clQoR 0

0

The reaction of 4-acetoxyazetidin-2-one with enolate anions is difficult, but now a high-yield equivalent has been introduced. This involves the react ion of 0-silylated enolat es and 4-acet oxy- 1-trimet hylsilyloxyaze t idin-2one (25) in the presence of trimethylsilyl trifluoromethane~ulphonate.~~ OSiMe

+

Me S i-OT f

&R2

R1

F

~ NSiMe3 ~ O

R

0

Tertiary carbanions such as (26) also react with 4-acetoxyazetidinone to give the carbon-substituted 0-lactam (27).28 The reaction proceeds in high yield, and the product can be oxidized to a sulphoxide and converted into the 4alkylidene derivative by elimination of benzenesulphenic acid .28 Full details of a cyclization reaction of 4-acetoxyazetidin-2-ones have a~peared.~’

’’ 26 21

29

I. Yamamoto, I. Abe, M. Nozawa, J . Motoyoshiya, and H. Gotoh, Synthesis, 1981, 81 3 . M. D. Bachi and A. Gross, J. Chem. SOC.,Chem. Commun., 1981, 959. A. G. M. Barrett and P. Quayle, J . Chem. SOC.,Chem. Commun., 1981, 1076. C . W, Greengrass and D. W. T. Hoople, Tetrahedron Lett., 1981, 2 2 , 1161. T. Kametani, T. Honda, J . Sasaki, H. Terasawa, and K. Fukumoto, J. Chem. SOC., Perkin Trans. I , 1981, 1884.

~


63

Aminolysis of the azetidin-2-one (28) results, via epoxide opening, in cleavage of the amide bond to form the pyrrolidinone (29).30The addition of N-lithio-4-vinylazetidin-2-one to vinyl phosphonates allows ready access to the carbapenam ring-system.”

3 Systems containing Two Nitrogen Atoms or One Nitrogen Atom and a Second Heteroatom In the presence of phosgene, the bis-iminodiazetidine (30) undergoes a ringopening reaction to give, it is believed, the unstable guanidine derivative (31), which cyclizes to a triazine upon addition of an aromatic amine.32 Ph PhNNPh

Ph D C0Cl2

Ph

Ph

(30)

0

PhN

Ph

/k

NPh PhNH2

Ph N ANANPhPh

30 31

32

1

Ph

clKNYNKcl NPh

NPh

0

(31)

S. Kano, S. Shibuya, and T. Ebata, J. Heterocycl. Chem., 1981, 18, 1239. B. Venugopalan, A. B. Hamlet, and T. Durst, Tetrahedron Lerr., 1981, 2 2 , 191. R. Richter and M. Ultich,J. Org. Chem., 1981, 46, 3011.


64

A short series of papers by Taylor and co-workers has highlighted the synthetic utility of 172-diazetidinium ylides, e.g. (32).33-35 For example, its reaction with dimethyl acetylenedicarboxylate forms a 1 : 1 cyclo-adduct (33) at ambient temperature; upon warming, this loses carbon monoxide to form a 2: 1 cyclo-adduct. The intermediacy of the ylide (34) in this process has been indicated.33 C/ph

+N4

'Ph

COOMe + MeOOCCSCCOOMe

c COOMe

0

0

(33)

I

'Ph

COOMe

COOMe

COOMe

N

Ph

MeOOC

COOMe

As one might expect, the addition of carbanions to the ylide (34) results in addition to the iminium bond. Similarly, this bond is reduced to form the diazetidinone (3 5 ) , which displays some interesting chemistry, such as ringexpansion to an oxadiazine upon treatment with acetic anhydride.33 Conversion of the ylide into 3-oxo-1,2-diazetidinium tosylate (36) is achieved by using toluene-p-sulphonic acid. Treating the tosylate with a 173-dicarbonyl compound provides a novel route to p y r a ~ o l e s . ~ ~

Pi

Me C- 0- CMe

Me

0

~i~ (35)

-0Ts +

70% MeOH

Me

0

(36)

CH2COOMe

It has now been shown that the products of the [2n + 2n] cycloaddition of ketimines and sulphur oxides are 172-thiazetidin-3-one 1-oxides (37).36 33 34

35

36

E. C. Taylor, R. J. Clemens, H, M. L. Davies, and N. F. Haley, J. A m . Chem. SOC., 1981, 103, 7659. E. C. Taylor, H. M. L. Davis, R. J. Clemens, H. Yanagisawa, and N. F. Haley, J. A m . Chem. SOC., 1981, 1 0 3 , 7 6 6 0 . E. C. Taylor, N. F. Haley, and R. J . Clemens, J. A m . Chem. SOC., 1981, 103, 7743. A. Dondoni, P. Giorgianni, A. Battaglia, and G. D. Andreetti, J. Chem. SOC.,Chem. Commun., 1981, 3 5 0 .


65

Furthermore, 1,2:thiazetidine 1-oxides are the products from N-sulphinylsulphonamides and dimethylketen N-phenylimine, and not 1,2,4thiadiazetidine 1-oxide, as previously r e p ~ r t e d . ~ ’

*+s-”/

p-toly 1

4 Systems containing Oxygen Oxetans. - A mechanistic investigation of the reaction of methylthiotrimethylsilane (38) and oxetan, in the presence of a catalytic amount of zinc chloride, suggests the involvement of an oxonium cation-methylthiozinc dichloride ion-pair, resulting in the formation of (3-methy1thiopropoxy)trimethylsilane (39).38 A dependence of the stereochemistry of the photoaddition products of aldehydes and alkenes on the concentration of alkene has been ~bserved.~’ Additional examples of the known photo-addition of benzophenone to 2,5-dimethylthiophen to form an oxetan have been reported4’ and the unusual bis(cyanomethy1ene)oxetan (40) has been described ZnC12 +

MeSSiMe3

f

Me OSiMe3

(38)

(39) Me Me.+fCHCN 0%

(40)

CHCN

(41) a ; R 1 = H , R2= Ph b ; R 1= P h , R 2 = H

The oxetans (41a) and (41b) have been shown to be the products of the reaction of benzaldehyde and he~amethylDewarbenzene.~~ An efficient onepot synthesis of oxetan from 1,3-diols has been developed this year.43 37

39 40 41

42

43

G. L’abbt5, A. van Asch, J-P. Dekerk, and T. Minami, Tetrahedron Lett., 1981, 22, 583. H. A. Firgo and W. P. Weber, J. Organometal. Chem., 1981, 2 2 2 , 2 0 1 . G. Jones, 11, Z. H. Khalil, and X . T. Phan, Tetrahedron Lett., 1 9 8 1 , 2 2 , 3823. C . Rivas, D. Pacheco, F. Vargas, and J . Ascanio, J. Heterocycl. Chern., 1 9 8 1 , 1 8 , 1 0 6 5 , Yu. M. Skvortsov, A. G. Mal’kina, A. N. Volkov, B. A. Trofimov, and G. A. Kalabin, USSR P. 8 5 2 870 (Chem. Abstr., 1 9 8 2 , 9 6 , 6 5 5 1 3 ) . M. A. J. Carless and H. S. Trivedi, J. Chem. SOC.,Chern. Cornrnun., 1981, 9 5 0 . P. Picard, D. Leclercq, J-P. Bats, and J . Moulines, Synthesis, 1 9 8 1 , 5 5 0 .


66

The ylide (42) is formed when carbon dioxide and dimethyl acetylenedicarboxylate react in the presence of a trialkyl phosphite (Scheme 6). The reaction of (42) with an aromatic aldehyde afforded the furan (43).44

COOMe

(43)

(42)

Reagents: i, CO,,ii, (RO),P; iii, ArCHO.

Scheme 6 Amongst the few reported reactions of oxetans is their non-stereospecific conversion into oxazines when treated with nit rile^^^,^ and the reaction of the @)-lactone (44) with a Grignard reagent as the key step in a novel synthesis of (R,R)-phytol?’

i

Me

(44)

Dioxetans. - The ‘missing’ cyclo-adduct of cycloheptatriene and singlet oxygen, the 1,2-dioxetan (49, has now been isolated at - 30°C. At ambient temperature it is rapidly converted into benzaldehyde , suggesting that the benzaldehyde that is produced in the oxygenation of cycloheptatriene with singlet oxygen is formed via this intermediate?8 The interesting chemiluminescent dioxetan (46) has also been ~repared.~’

0-0

(45)

44

45

46 47 48 49

Me

(46)

D. V. Griffiths and J . C. Tebby, J. Chem. SOC.,Chem. Commun., 1981,607. T. M. Pavel, Zh. Org. Khim., 1982, 18, 178. 0. N. Chernysh and S. I. Yakimovich, Zh. Org. Khim., 1982,18,181. T. Fujisawa, T. Sato, T. Kawara, and K. Ohashi, Tetrahedron Lett., 1981, 22, 4823. W. Adam and H. Rebello, Tetrahedron Lett., 1981,22,3049. H. Nakamura and T. Goto, Heterocycles, 1981,15,1119.

Four-MemberedRing Systems

67

5 Systems containing Sulphur A novel conversion of chalcones into 2,4-diaryl-thietans has been described, as shown in Scheme 7. The reaction involves a reductive cyclization of the phosphorodithioate (47) and proceeds in excellent yields. This and the fact that the staring chalcones are readily available make this a potentially versatile method.” 0

II

PhCHZCHCPh

-

0

PhCH-CH2!Ph

i

I

ii ,iii

,OEt

S, /p

S’ ‘OEt

S

II

Reagents: i, (EtO),PSH; ii, NaBH,; iii, NaH.

Scheme 7 The thieten 1,l-dioxide (48) has been prepared by cycloaddition of an enamine and sulphene at O°C.51 Mild thermolysis causes a ready retrocycloaddition to occur. Additional stable .P-sultines have been isolated, by the reaction of the anion of a sulphoxide with a ketone and cyclization of the resulting P-hydroxy-sulphoxide with sulphuryl ~hloride.’~Treatment of 2-methylthietan (49) with alumina at 150-350 “C results in the formation of te trahydrothiophen and but -3-enethiol .53

Previously difficult substitution reactions of 1,3-dithietan 1,1,3,3tetroxide (50) are now possible. The formation of the silyl derivative (51) (see Scheme 8), its conversion into the dithieten (52), followed by the addition of electrophiles forms the substitution product^.'^ The dithieten (52) can be considered as the first enol ether of a sulphone. The transient benzothiet (53) has been prepared by the thermolysis of (54), its structure having been confirmed by i.r. and photoelectron s p e c t r o s ~ o p y . ~ ~ so 51 52

53

” 55

Y. Ueno, L. D. S. Yadav, and M. Okawara, Synthesis, 1981,547.

L. N. Koikov, P. B. Terent’ev, and N. S. Kulikov, Zh. Org. Khim., 1981,17, 1087. M. D. Gray, D. R. Russell, D. J . H. Smith, T. Durst, and B. Gimbarzevsky, J. Chem. SOC.,Perkin Trans. 1 , 1981, 1826.

A. K. Yus’kovich, T. A. Danilova, and E. A. Viktorova, Khim. Geterotsikl. Soedin., 1982,184 (Chem. Abstr., 1982,96,162 455m).

U. Rheude and W. Sundermeyer, Chem. Ber., 1981,114,3378. H . Breitenstein, R. Schulz, and A. Schweig, J. Org. Chem., 1982,47, 1979.

Heterocyclic chemistry

68

(50)

(52)

(51)

( R = SiMe3)

Reagents: i, C,H,SO,SiMe,, Et,N; ii, BunLi; iii, D,O.

Scheme 8

(54)

(53)

6 Miscellaneous Four-Membered Rings This year has seen a notable increase in the work being done under this category. A study of the gas-phase pyrolysis of silacyclobutanes has been mades6 and the photoreaction of benzosilacyclobutane with aldehydes and ketones is reported to form 1:l adducts, but not via a o-silaquinone methide ." Irradiation of the silyl-substituted alkyne ( 5 9 , as shown in Scheme 9, results in the formation of the disilacyclobutane (56), indicating the transient formation of a silicon-carbon doubly bonded intermediate.58 The compound (56) is uncharacteristically stable to atmospheric oxygen but it does react with stronger oxidants, such as m-chloroperoxybenzoic acid, to form a Ph RC'C-8i-R

I

Ph

(55)

-

R2C.792

i

ii -R2Cy

fR2

R2C=C=SiPh 2-

Ph,2 Si--SiPh2

( H = SiMe3)

(56)

Ph2Si

iPh 2 (57)

Reagents: i, h v ; ii, rn-chloroperoxybenzoic acid.

Scheme 9 disilacyclopentane (57).58 Furthermore, disilacyclobutanes are the major products that are formed by treating bromotrisilylmethanes, such as (58), with alkyl-lithi~ms.~~ The silaethene (59) was suggested as an intermediate. A 56 57

59

N. Auner and J . Grobe, J. Organometal. Chem., 1 9 8 1 , 2 2 2 , 33. R. Okazaki, K-T. Kang, and N. Inamoto, Tetrahedron Lert., 1 9 8 1 , 2 2 , 2 3 5 . M. Ishikawa, D. Kovar, T. Fuchikama, K. Nishimura, M. Kumada, T. Higuchi, and S. Miyamoto, J. A m . Chem. Soc., 1981, 103, 2324. N. Wiberg, G. Preiner, and 0. Schieda, Chem. Ber., 1981, 114, 2087.

69

Four-Membered Ring Systems SiMeg

I

Me2Si-C(

SiMe3)2

I

I

Br

Br

Me2Si=C(SiMe3)2 (59)

I

(581

SiMeg (60)

silicon-containing bicyclo[ l.l.O]butane (60) has now been prepared and its structure confirmed by X-ray analysis.60 Scheme 10 shows the preparation of the first isolable example of a new heterocyclic ring-system, namely the 3-silaoxetan (6 1).61 Me

Me

Ph

Ph2CHC1

-* (61)

Reagents: i, Mg; ii, Me,SiCl, ;iii, N-bromosuccinimide; iv, H,O.

Scheme 10 A novel preparation of a 4-bromophosphetan (62) has been described; it proceeds by the reaction of l-bromo-3,3-dimethylbut-l-ene with phenylphosphorous dichloride in the presence of aluminium chloride, and subsequent reduction of the oxide.62 Me

I I Me

Me- CCH=CHBr

Me

Me

Me

+

Me Me

PhPC 1

Ph

The short-lived phosphene (63) yields the oxaphosphetan (64) upon [27r 27r] cycloaddition with ap-unsaturated ketones.63 The reaction of sodium phenylacetylide with tellurium metal forms a 1,3-ditelluretan and not, as had previously been reported, a 1,3-ditellurole.@

+

Ph Ph I /Ph O=P=C ' P h (63) 6o

61

63 64

Ph

CI H = C H R ~ (64)

G . Fritz, S. Wartanessian, E. Matern, W. Honle, and H. G . von Schnering, 2. Anorg. Allg. Chem., 1981,475,8 7 . J. V. Swisher, J. Perman, P. D. Weiss, and J . R. Ropchan, J. Organometal. Chem., 1981, 215,373. Mazhar-ul-Haque, W. Horne, S. E. Cremer, P. W. Kremer, and P. K. Kafarski, J. Chem. SOC.,Perkin Trans 2,1981,1138. M. Regitz and H. Eckes, Tetrahedron, 1981, 37, 1039. S.L. Bender, N. F. Haley, and H. R. Luss, Tetrahedron Lett., 1981, 22, 1495.

3 Five-Membered Ring Systems ~~~

~~~

~~

BY G. V. BOYD, S. GRONOWITZ, 0. GUILLOTON & H. QUINIOU

PART I: Thiophens and their Selenium and Tellurium Analogues by S. Gronowitz 1 General Useful reviews on redox transformations of thiophen derivatives (1 79 references),' on the stereochemistry of carbonyl derivatives of five-membered heterocycles (257 references): on synthetic approaches to dihydrothiophens (1 35 reference^),^ and on biosteric thiophens4 have been published. Aspects of thiophen chemistry have been treated in reviews on the synthesis of heterocycles by thermal [2 21 cycloaddition reactions of acetylenes' and on aspects and perspectives of organic heterocyclic A review comparing the chemistry of thieno [2,3-b]- and thieno [3,2-b]-thiophen with that of benzo [ b ]thiophen and quinoline has been published.8 In Advances in HeterocycZic Chemistry, the development of benzo [ b ]thiophen from 1968 to 1980' and of selenophen from 1970 to 1980 was presented." Other aspects of thiophen chemistry are treated in chapters on Dewar Heterocycles," on Cyclizations under Vilsmeier Conditions,12 on Polyfluoroheteroaromatic compound^,'^ and on Reactions of Benzyne with Heterocyclic compound^.'^ Several dissertations treating various aspects of thiophen chemistry have

+

1

2 3

4

L. I. Belen'kii and V. P. Gul'tyai, Khim. Geterotsikl. Soedin., 1981, 723. V. N. Sheinker, A. D. Garnovskii, and 0. A. Osipov, Usp. Khim., 1981, 50, 632. W. G. Blenderman and M. M. JoulliB, Heterocycles, 1982, 19, 11 1.

R. Bdhm, Wiss. Z.

- Martin-Luther-Univ. Halle- Wittenberg, M a t h . - N a t u r e . Reihe,

1981, 30, 3 . 5

6

D. N. Reinhoudt, Bull. SOC. Chim. Belg., 1981, 90, 633. W. Schroth, Wiss. Z. - Martin-Luther-Univ.Halle- Wittenberg, Math.-Naturwiss. Reihe,

I

W. Schroth, Wiss. Z. - Martin-Luther-Univ. Halle- Wittenberg, Math.-Naturwiss. Reihe,

1981, 30, 97. 1981, 30, 29.

8

L. H. Klemm, Heterocycles, 1981, 1 5 , 1285. R . M. Scrowston, Adv. Heterocycl. Chem., 1981, 29, 171. 10 A.-B. Hornfeldt, Adv. Heterocycl. Chem., 1981, 30, 127. 11 Y. Kobayashi and I. Kumadaki, Adv. Heterocycl. Chem., 1982, 31, 169. 12 0. Meth-Cohn and B. Tarnowski, Adv. Heterocycl. Chem., 1982, 31,207. l 3 R. D. Chambers and R. C. Sargent, Adu. Heterocycl. Chem., 1981,28, 1. l 4 M. R. Bryce and J . M. Vernon, Adv. Heterocycl. Chem., 1981, 28, 183. I s C. Y. Lai, DiSs. Abstr. Int. B , 1981,42,2376. l6 W.A. Lindley, Diss. Abstr. Int. B , 1981, 41,4524. '' R. D. Thompson, Diss. Abstr. Int. B , 1981,42, 1900. D. Margosian, Diss. Abstr. Int. B., 1981, 41, 4125. l9 D. L. Singer, Diss. Abstr. Int. B , 1981,42, 1899. 'O V. Lorprayoon, Diss. Abstr. Int. B , 1981,41, 4197. " D. Dell Mazza, Diss. Abstr. Int. B , 1981,41, 3031. '' M. A. Khadim, Diss. Abstr. Int. B, 1981,42, 1457. 9

71

72


2 Monocyclic Thiophens Synthesis of Thiopens by Ring-closure Reactions. - C4 S Principle. The reaction of C6 hydrocarbons with hydrogen sulphide on a chromiumcontaining catalyst led to thiophen derivative^.^^ A 94% yield of thiophen has been obtained in the reaction of diacetylene with hydrated sodium sulphide in KOH-DMS0.24 A number of mono- and di-glycosylthiophens has been prepared by the reaction of mono- and di-glycosylbutadiynes with sodium hydrosulphide, in connection with work on the biological activity of C-glycosyl derivative^.^' The formation of 2,5-diamino-3,4-dicyanothiophen in the reaction of tetracyanoethane with hydrogen sulphide in the presence of pyridine has been confirmed.26 It has been shown that the thiophen that is formed in the reaction of ethyl cyanoacetate with sulphur in the presence of triethylamine is diethyl 2,5-diaminothiophen-3,4-dicarboxylate, and not die thy1 2,4-diaminothiophen-3,5-dicarboxylate as previously claimed.*' The first step in the reaction is most probably oxidative coupling to sym-diethyl dicyanosuccinate, which then reacts by analogy with tetracyanoethane. A patent describes the synthesis of the useful penicillin side-chain 3thienyhnalonic acid through the reaction of sodium sulphide with (l), which was prepared by the A1C13-catalysed addition of chloroacetyl chloride to acetylene followed by condensation with diethyl malonate.28 The reaction of ( 2 ) with alkanesulphenyl chlorides led to a mixture of (3) and (4). Lower reaction temperatures favoured the formation of (3).29 The reaction of vinylidene chloride with hydrogen sulphide at 470-550°C gave 15% of 2-chloro- and 16%of 3-chloro-thiophen as the main product^?^'

+

23

M. A. Ryashentseva, E. P. Belanova, and Kh. M. Minachev, Neftekhimiya, 1982, 22, 231.

l4

M. G. Voronkov, B. A. Trofimov, V. V. Kryuchkov, S. V. Amosova, Yu. M. Skvortsov, A. N. Volkov, A. G . Mal'kina, and R. Ya. Mushii, Khim. Geterotsikl. Soedin., 1981, 1694.

J. M. J . Tronchet and A. P. Bonenfant, Helv. Chim. Acta, 1981, 64, 2322. 26 0. E. Nasakin, V. V. Alekseev, V. K. Promonenkov, I. A. Abramov, and A. Kh. Bulaj, Zh. Org. Khim., 1981, 17, 1958. " K. Gewald and A. Martin, J. Prakt. Chem., 1981, 3 2 3 , 843. 28 K. T. Veal and T. J . Grinter, Eur. Pat. Appl. 38 121, 1981. l9 C. M. Angelov and K. V. Vachkov, Tetrahedron Lett., 1981,22,2517. isa M. G. Voronkov, E. N. Deryagina, V. I. Perevalova, and 0. B. Bannikova, Zh. Org Khim., 1981, 17, 1103. 25

Five-Membered Rings: Thiophens and their Se and Te analogues

73

+

C2S C2 Principle. The reaction of nitroacetonitrile with a-mercaptoketones in the presence of triethylamine yields 4-substituted 2-arnino-3nitrothiophens.30 Various aryl- or heterocycle-substituted acetonitriles, such as p-anisyl-, 2-pyridyl-, or 2-quinolyl-acetonitriles, reacted with esters of thioglycollic acid in the presence of alkoxides to give 3-substituted 2-arnino-4hydroxythiophens, which exist as the 4-keto-ta~torner.~' The reaction of 2,4dichlorophenacyl cyanide with mercaptoacetaldehyde in the presence of triethylamine gave 2-amino-3-(2,6-dichlorobenzoyl)thiophen in 86% yield." Other examples of the use of the Gewald reaction for the synthesis of 2aminothio phen-3-car boxylates , by the modification using the reaction of ketones with cyanoacetates and sulphur in the presence of base, have been published. 33 The lithium salts of 2-arylethenethiolates react with alkyl phenylpropiolates to give alkyl 2,4-diarylth1ophen-3-carboxylates, while the corresponding potassium salts only give conjugate addition to (5). Minor amounts of ( 6 ) are in both cases formed as by-products.% The reaction of ethyl y-chloroacetoacetate with sodium sulphide and ethyl cyanoacetate in the presence of triethylamine was used for the synthesis of 2-amino-4e t hoxy carbonylme t hyl-3-methoxy carb onyl thiophen .34-a Ph

\

RC=C-S

/COOR'

/"="\H (5)

R (6)

CS + C3 Principle. The Fiesselmann reaction between a-formyl arylacetonitriles and methyl thioglycollate has been used for the preparation of methyl 3-amino-4-arylthiophencarboxylates.35 The reaction of (7) with ethyl thioglycollate in the presence of potassium carbonate gave (8) in 70% yield.36

(7)

Nippon Kayaku Co. Ltd., Jpn. Kokai Tokkyo Koho 81 100 780,1981. Yu. M . Volovenko and F. S. Babichev, USSR P. 767 105, 1980 (Otkrytiya, Izobret., Prom. Obraztsy, Tovamye Znaki, 1980, 119). 3 2 D. Binder and P. Stanetty, J. Chem. Res. (s), 1981, 102. 3 3 F. J. Tinney, W. A, Cetenko, J. J . Kerkleski, D. T. Connor, R. J. Sorenson, and D. J . Herzig, J. Med. Chem., 1981, 24, 878. 34 L. S. Rodionova, M. L. Petrov, and A. A. Petrov, Zh. Org. Khim., 1981, 17, 2071. .34aNippon Kayaku Co. Ltd., Jpn. Kokai Tokkyo Koho 81 143 245,1981. 3 5 G. Kirsch, D. Cagniant, and P. Cagniant, J. Heterocycl. Chem., 1982, 19, 443. 36 K. Gewald, U. Hain, and E. Schindler, Ger. (East) P. 146 952, 1981. 30 31


74

From (8a) the thiophencarboxylic acids (8b) were prepared by reaction with thioglycollic acid.36a The reaction of benzylideneaminoacetonitrile with ethyl thioformate and sodium hydride in THF gave the salt (9) in an (E/Z) ratio of 8 : 2. The reaction of (9) with methyl chloroacetate gave (lo), which upon treatment with hydrogen chloride in wet diethyl ether gave methyl 3,4diaminothiophen-2-carboxylate,a key intermediate for biotin ~ynthesis.~’A full study on the formation of compounds of type (1 1) in the reaction of allenylsilver(1) reagents and carbon disulphide, mentioned in the previous Report, has appeared. Through reaction with electrophiles, (1 1) was transformed into (1 2).% c1

Ring-closure of C.S. The reaction of (13) with LDA led to a 2,4-diaminothiophen, which according to n.m.r. exists in the imino-form (14).39 Compounds of type (14a), prepared by the condensation of methyl aryl ketones with phenyl isothiocyanates in the presence of sodium hydroxide followed by alkylation, gave the aminothiophens (14b) if R2 is COPH or COMe, without additional catalysis by a base. On the other hand, if R2 is C02Et or CONH2, the thiazolidones (14c) were obtained; and if R2 is CH2Br, (1 4d) was the product.39a

Ph

Ph

R’CO

’

c=c

H

I \S/CH2

C=C

(14c)

H

\,NCH2

(14d)

36aM.Gosh, R. Mukherjee, B. G . Chatterjee, and J. K. Ray, Indian J. Chem, Sect. B , 1981, 20, 243.

Ph. R o s y , F. G. M. Vogel, W. Hoffmann, J . Paust, and A. Nurrenbach, Tetrahedron Lett., 1981, 22, 3493. J . Meijer, K. Ruitenberg, H. Westmijze, and P. Vermeer, Synthesis, 1981, 551. 39 M. Yokoyama, M. Kurauchi, and T. Imamoto, Tetrahedron Lett., 1981, 22, 2285. 39aN. Ben Mansour, W.-D. Rudorf, and M. Augustin, 2. Chem. 1981, 21,69. 3’

’*


75

Ring-closure of C2SC2.Ally1 1,2,2-trichlorovinyl sulphides ( 15) gave a mixture of (16) and (17) upon heating to 100 - 120°C.40

Synthesis of Thiopens from Other Rings. - From Di- and Tetra-h,ydrothiophens. Compound (18) was prepared by the reaction of ethyl a-bromobutyrate with methyl P-mercaptopropionate followed by base-catalysed cyclization. Treating the oxime of (18) with hydrogen chloride in ether gave the aminothiophen (19a).41 A similar approach was used for the synthesis of (19b). The starting 3-keto-derivative was prepared by Michael addition of methyl thioglycollate to methyl crotonate, followed by Dieckmann c y ~ l i z a t i o n . ~ ~ Treatment of (20) with sulphuryl chloride in methylene chloride at 5"C, followed by treatment with pyridine at room temperature, gave (21).43 Another example of the aromatization of hydrothiophens via chloroderivatives is in the preparation of (23) by the reaction of (22) with N chlorosuccinimide followed by ~ y r i d i n e The . ~ ~ catalytic dehydrogenation of 2- and 3-alkyltetrahydrothiophenshas been in~estigated.~' CN

40

41

E. Nagashima, K. Suzuki, and M. Sekiya, Tetrahedron Lett., 1981,22, 2587. P. N. Confalone, G. Pizzolato, M. R . Uskokovic, and M . Rouge, US P. 4 317 915, 1982.

41

43 44

45

D. Binder, C. R. Noe, and M. Zahora, Arch. Pharm. (Weinheim, Ger.), 1981, 314, 557. P. W. Raynolds, US P. 4 307 239, 1981. J . B. Press, C. M. Hofmann, G. E. Wiegand, and S. R. Safir, J. Heferocycl. Chem., 1982,19,391. M. V. Vagabov, Vestn.Mosk. Univ., Ser. 2: Khim., 1982,23,52.

Heterocyclic Chemi s m

76

From Other Sulphur Heterocycles. The diazo-ketone (24), prepared from 2H-thiopyran-3(6H)-one and phenyl azide, yields (25) upon heating, which apparently is the stable tautomer of 3-hydroxy-4-phenylaminomethylthiophen, and (26). The structures of both compounds were proven by X-ray crystallograph^.^^ The thermal and photochemical reactions of 1,4-dithiin sulphoxides (27) have been re-investigated. In acetonitrile as solvent, 2,4-diarylthiophens (28) and 1,3-dithioles (29) were formed, the proportions depending strongly on the aryl group. In carbon tetrachloride, on the other hand, only (29) was formed, except with (27; Ar = p-chlorophenyl), which yielded 68%of (29) and 32% of (28). Photolysis gave, in addition to (29), (30) and the reduced thiin,and no 2,4-diarylthiophen was formed.47

From Other Rings. Instead of preparing 5-aryl-2-hydroxythiophens (32) by allowing 4-aryl-4-oxobutanoic acid to react with P2S5,it is considered better to prepare first the butenolide (31) by treatment of the acid with acetic anhydride followed by sodium hydrosulphide. The crude (32) can be transformed into (33) in a one-pot procedure by its reaction with an aromatic aldehyde and hydrogen chloride.48 A patent describes the synthesis of more

(31) Y = 0 (32) Y = S

16 47

4a

(33)

K. Skinnemoen and K. Undheirn, Heterocycles, 1981, 16, 929. K. Kobayashi and K. Mutai, Temhedron Lett., 1981, 2 2 , 5201. G. A. Miller, N. D. Heindel, and I . A. Minatelli, J. Heterocycl. Chern., 1981,18,1253.


77

complex 2,5-dialkylthiophens by the reaction of the corresponding furans with hydrogen sulphide in the presence of various strong acids.49 The strange metal-organic heterocycle (34), upon treatment with cerium( IV) salts, gave t etrame thy1 thiophent etracarboxylat e in almost quantitative yield.” MeOOC P-Me

MeOOC

MeOOC

I

Me

Physical Properties of Monocyclic Thiophens. - Theoretical Gzlculations. Calculations by the CNDO/2, ab initio STO-3G7 and ab initio SCF methods of the structure and degree of aromatic character in thiophen, furan, and pyrrole have been carried *52 Enhanced aromaticity of thiophen compared to furan was considered to be primarily due to the delocalization of C(2)-C(3) m-bonds to the vacant d-orbitals of ~ulphur.’~First electron affinities, valence ionization potentials, and photoionization cross-sections of furan, thiophen, selenophen, and tellurophen have been determined .53 Calculations on the C(S) levels in thiophen and other aromatic heterocycles have been carried out by the SSC-MO The 13C n.m.r. shifts, lowest singlet-singlet and singlet-triplet transition energies, and dipole moments for thiophen and its annelated analogues were calculated and compared with experimental results.55 The two low-lying singlet excited states of fourteen monophenylated five-membered heterocycles have been studied with respect to the ordering of their energy levels and the oscillator strengths of the pertinent transition^.'^ Many theoretical calculations on different aspects of the electrophilic reactivity of thiophen derivatives have been performed. The effect of the heteroatom on activity and selectivity in furan, thiophen, and pyrrole has been estimated by CND0/2 calculations of localization energies:’ by the same method, the effect of the electrophilic agents8 has been calculated. Calculations have been carried out on 2-methoxy-5-methylthiothiophen, 2,5-bis(methy1thio)thiophen7and all of their possible C-protonated forms, in V. G. Kharchenko, I. A. Markushina and T. I. Gubina, USSR P. 677 330, 1981 (Otkrytiya, Izobret., From. Obraztsy, Tovamye Znaki, 198 1, 242). E. Lindner, A. Rau, and S. Hoehne, Angew. Chem., 1981,93, 822. F. R. Cordell and J. E. Boggs, J. Mol. Struct., 1981, 85, 163. 5 2 G . Nhray-Szab6 and M. R. Petenon, J. Mol. Struct., 1981,85, 249. 5 3 V. Galasso, J. Mol. Struct., 1982,86, 231. 5 4 Z. B. Maksic and K. Rupnik, N o w . J. Chim., 1981, 5, 515. 55 Yu. B. Vysotskii, B. P. Zemskii, E. A. Zemskaya, and N. N. Alekseev, Zh. Strukt. Khim., 1981, 2 2 , 13. 56 A. Mehlhorn, F. Fratev, and V. Monev, Tetrahedron, 1981, 37, 3627. L. I. Belen’kii and I. A. Abronin, Zh. Org. Khim., 1981, 17, 1129. ” LA. Abronin, L. I. Belen’kii, G . M. Zhidomirov, and Ya. L. Gol’dfarb, Zh. Org. Khim., 1981, 17, 1134.

49

’’

78


order to understand the distribution of isomers in electrophilic substitution of these compound^.'^ Charge-density-activation-energy correlations have been performed for the bromination of 2-halogen0thiophens.~A b initio calculations on the deprotonation at the 2-positions of thiophens have been carried out.61 Photoelectron and Ultraviolet Spectra. The He-I and He-I1 photoelectron spectra and the U.V. absorption spectra of styrylthiophen and a-cyanostyrylthiophen have been interpreted by comparison with the spectra of related compounds, and with the aid of INDOIS-CI calculations.62 The photoelectron spectra of sulphur heterocycles absorbed onto a (1 10) surface of copper have been studied.63964The m.c.d. spectra of thiophen and selenophen have been disc~ssed.~’

Inflared and Raman Spectra. Detailed i.r. and Raman studies of rotational relaxation of furan and thiophen have been carried as well as of the modes of vibrational relaxation of thiophen by isotropic Raman The far4.r. absorption of thiophen in liquid and plastic phases has been studied.% The i.r. and Raman spectra of 2-chloro- and 2-bromo-thiophen and of the corresponding selenophens and tellurophens have been a~signed.~’ Calculated rotational and centrifugal distortion constants for thiophen and tetradeuteriothiophen in the vibrational ground state have been compared with experimental data.72 Hy drogen-bonding in 0-hydroxy-sulphides of the thiophen series has been studied by the i.r. technique.73 The i.r. spectrum of the yttrium salt of thiophen-2-carboxylic acid has been ~tudied.’~ Nuclear Magnetic Resonance. 13C n.m.r. spectra of 39 thiophen and furan chalcones have been reported,” and analysis of the principle components s9 60

Ya. L. Gol’dfarb, I. A. Abronin, M. A. Kalik, and V. K. Zav’yalova, Khim. GeterorsikL Soedin., 1981, 1035. M. J. Nanjan, V. Kannappan, and R. Ganesan, 2. Phys. Chem. (Frankfurt am Main), 1981, 127, 13.

61

G. Seconi, C. Eaborn, and J . G. Stamper, J. Organomef. Chem., 1981, 204, 153. S. Millefiori, G. Scarlata, A. Millefiori, and D. Carbone, 2. Phys. Chem (Frankfurt am Main), 1981, 128, 63. 63 T. M. Thomas, F. A. Grimm, T. A. Carlson, and P. A. Agron,J. Electron Spectrosc, Relnf. Phenom., 1982,25,159. 6 4 N. V. Richardson and J. C. Campuzano, Vacuum, 1981, 31,449. 6 5 J. W. Waluk, E. Vogel, and J. Michl, J. Org. Chem., 1981, 46, 3306. 66 J. P. Pinan-Lucarre, J. Loisel, and L. Vincent-Geisse, Chem. Phys., 1981, 62, 251. 61 J. P. Pinan-Lucarre and T. Nguyen-Tan, Chem. Phys., 1981, 62, 2 6 5 . 68 J. P. Pinan-Lucarre, J. Loisel, and J. Vincent-Geisse, J. Raman Spectrmc., 1981, 69 lo

11, 174. W. Schmitz, Nuovo Cimento SOC.Ital. Fis. B , 1981, 63, 386. J. P. Pinan-Lucarre, D. C. Edewaard, and K. D. Moeller, Spectrochim Acta, PartA, 1981, 37, 977.

” I2

G . Paliani and R. Cataliotti, Spectrochim. Acta, Part A , 1981, 37, 707. F. N. Bolotina, L. N. Gunderova, I. Ya. Zemlyanukhina, A. Kh. Mamleev, V. G. Marutsenko, N. M. Pozdeev, V. F. Pulin, and I. M. Sverdlov, Zh. Smckt. Khim., 1980,

73

S. N. Rustamova, M. M. Seidov, N. Yu. Ibragimov, and S. M. Aliev, Dokl. Akad.

21, 182. 14 75

Nauk Azerb. SSR,1980, 36, 39. M. Singh, B. L. Mathur, and K. S. Gharia, Bull. SOC.Chim. BeZg., 1981, 90, 515. G. Musumarra and F.P. Ballistreri, Org. Magn. Reson., 1980, 14, 384.

Five-MemberedRings: Thiophens and their Se and Te analogues

79

has been used for assignment of the observed chemical shifts.76 The I3C n.m.r. shifts and direct C-H coupling constants for a number of compounds of the types (35)77 and (36)78 have been studied, and the effect of substituents has been discussed. The non-pseudocontact components of the shifts that are induced by [Yb(fod),] in thiophen-2-carbaldehyde have been determined and found to be largest at the carbonyl carbon and at the 3- and 5 -carbons.79 Conformational and dynamic processes of a thiophenoparacyclophane have been studied by dynamic n.m.r.80 The 'H n.m.r. spectra of some aminothiophens have been discussed.81 Metal complexes of thiophen-2carbaldehyde have been studied by 'H and I3C n.m.r. and by i.r. and U.V. spectroscopy.82

Mass Spectrometry. The mass spectra of thiophen-2- and -3-~arboxanilides,8~*~~ of thiophenic chalcone of 2,5-diaryl-substituted thiophens,86 of a t e r t h i e n ~ l ,and ~ ~ of some chromium tricarbonyl c o m p l e x e ~ have ~ ~ * all ~~ been studied. X-Ray Investigations. The crystal structures of 1,1,4,4-tetramethyl-lH,4Hthieno[3,4-c] thiophen,gO of (37):' of (38),92 of triple-layered [2,2] -

I6 I1 78

19

G. Musumarra, S. Wold, and S. Gronowitz, Org. Magn. Reson., 1981, 17, 118. G. Musumarra and F. P . Ballistreri, Chem. Scr., 1981, 18, 209.

F. P. Ballistreri, G. Musumarra, and G. Scarlata, Chem. Scr., 1981, 18, 214. R. J. Abraham, D. J. Chadwick, and F. Sancassan, Tetrahedron Lett., 1981, 22, 2139.

80

83

T. Olsson, D. Tanner, B. Thulin, 0. Wennerstroem, and T . Liljefors, Tetrahedron, 1981, 37, 3473. C. Galvez and F. Garcia, J. Heterocycl. Chem., 1981, 18, 851. S. Burman and D. N. Sathyanarayana, J. Inorg. Nucl. Chem., 1981,43, 1189. S. Fisichella, S. Occhipinti, G. Alberghina, and M. E. Amato, Phosphorus Sulfur,

84

S. Fisichella, S. Occhipinti, G. Alberghina, and M. E. Amato, J. Heterocycl. Chem.,

82

1981, 10, 317. 1981,18,1011.

A. Arcoria, F. P. Ballistreri, G. Musumarra, and S . Occhipinti, Org. MassSpectrom., 1981, 16, 54. 86 81

R. Jimbnez and E. Cortbs, J. Heterocycl. Chem., 1982,19,447. C. D. Gatsonis and P. T. Kosmidis, Pharm. Delt., Epistem. Ekdosis, 1980, 6, 21. 88 V. I. Khvostenko, Yu. S. Nekrasov, I. I. Furlei, N. I. Vasyukova, and G. A. Tolstikov, J. Organomet. Chem., 1981, 212, 369. 89 M. El-Borai and M. F. Abdel-Megeed, Phosphorus Sulfur, 1980, 9, 165. 90 I. Goldberg, M. Freund, and S . Braverman, J. Cryst. Mol. Struct., 1981, 11, 157. 91 R. H. Hall, H. J. den Hertog, Jr., D. N. Reinhoudt, S. Harkema, G. J . van Hummel, and J. W. H. M. Uiterwijk, J. Org. Chem., 1982,47, 977. 92 A. Hordvik, K. Junge and I. Pedersen, Acta Chem. Scand., Ser. A , 1981, 35, 607.

He terocy cIic Chemistry

80

paracyclophanes containing thiophen rings,93 and of some other thiophen derivatives have been Miscellaneous Physical Properties. The microwave spectrum of 2,3-dihydrothiophen shows the molecule to be puckered97 and to have a barrier to inversion of 328 cm-' . The non-planarity of 2-oxotetrahydrothiophen has been demonstrated by microwave s p e c t r o ~ c o p y . ~ ~ The saturated vapour pressures of chloro and chlorosilyl derivatives of thiophen have been determined.99 Liquid vapour isothermal equilibrium for thiophen with benzenelW and with alcohols"' has been measured. The formation constants, extinction coefficients, and total absorption intensities for complexes between thiophens and iodine have been determined. '02 The adsorption of thiophen on montmorillonites'03~104 and on other catalyst^'^^^'^^ has been investigated. Several papers of an analytical nature and on the separation of thiophen from benzene have appeared.lo7- '12

Electrophilic Substitution Reactions of Monocyclic Thiophens. - A careful kinetic investigation of the protodesilylation of substituted trimethylsilylthiophens, either with aqueous HC104 in methanol or aqueous H2S04 in acetic acid, gave values of log k which, except for the nitro-compounds, showed excellent linear correlations with the corresponding ortho-, meta-, or para-substituted trimethylsilylbenzenes. The effect of substituents was larger in the thiophen than in the benzene ~ e r i e s . " ~ * Mixtures "~ of 2- and 393

Ya. Kai, J. Watanabe, N. Yasuoka, and N. Kasai, Acta Crystallogr., Sect. B , 1980, 36, 2276.

94

B. Tinant, B. Coene, J. P. Declercq, G. Germain, and M. van Meerssche, Cryst. Struct. Commun., 1981, 10, 259. 95 A. Carpy, D. Hickel, a n d A. Nuhrich, Cryst. Struct. Commun., 1981, 10, 1387. 96 D. Zobel and G. Ruban, Acta Crystallogr., Sect. B , 1981, 37, 1867. 97 J. R. Durig, T. S. Little and Y. S . Li, J. Chem. Phys., 1982, 76, 3849. 9a J. L. Alonso, J. Chem. SOC.,Chem. Commun., 1981, 577. 99 V. E. Ditsent, I. I. Skorokhodov, M. N. Zolotareva, V. I. Savushkina, and B. M. Tabenko. Zh. Prikl. Khim.. 1981, 54, 1617. 100 M. Diaz Pena,, A. Compostizo, A. Crespo Colin, and I. Escudero, J. Chem. Thermodyn., 1981, 13, 869. 101 0. F. Aguirre, B. R. Inostroza, A. R. Lopez, V. F. Romero, L. J. Triday, and R. E. Trujillo, Scientia (Valpamiso), 1979, 44, 38. 102 S. H. Etajw, G. B. El-Hefnawey, and N. T. Abdel Ghany, Ann. Chim. (Rome), 1982, 72,95. 103

E. K. Varfolomeeva, L. K. Zgadzai, E. Kh. Ivoilova, R. Sh. Kharitonova, and S. S. Sunchaleeva, Kolloidn. Zh., 1981, 43, 6 3 3 . E. K. Varfolomeeva, L. K. Zgadzai, E. Kh. Ivoilova, S. S. Sunchaleeva, and R. Sh. Kharitonova, Kolloidn. Zh., 1981, 43, 962. 105 V. I. Erofeev and I. V. Kalechits, Izv. Akad. Nauk SSSR, Ser. Khim., 1981, 5 0 5 . 106 V. I. Erofeevand I. V. Kalechits, Kinet. Katal., 1982, 23,426. l o 7 L. G. Proskurvakova, V. F. Lisenkov, and L. A. Kogan, Khim. Prom-st., Ser.: Metody Anal. Kontrolya Kach. Prod. Khim. Prom-st., 1981, 9. ' 0 8 A. A. Miroshnichenko and L. G. Fedosyuk, Koks Khim., 1981, No. 9, p. 26. lo9 A. A. Miroshnichenko and L. G. Fedosyuk, Koks Khim., 1981, No. 11, p. 28. ' l o A. E. Habboush, S. M. Farroha, and Z. F. Savaya, J. IraqiChem. SOC.,1980, 5, 81. Ill L. Ya. Kolyandr, V. G. Titarenko, T. G. Shcherbakova, and S. V. Kulyasova, Koks Khim., 1981, No. 6, p. 24. '12 T. D. Zaika, Yu. N. Usenko, and A. A. Motuz, Khim. Tekhnol. (Kiev), 1981, No. 1, 104

113

'I4

p. 21. G. Seconi, C. Eaborn, and J. Stamper, J. Orgunomet. Chem., 1980, 204, 153. G. Seconi and C. Eaborn, J. Chem. SOC.,Perkin Trans. 2, 1981, 931.


81

perfluoroalkylated thiophens have been obtained upon thermolysis of perfluoroalkyl iodides in the presence of thiophen. '15 The Nafion-H-catalysed acylation of thiophen gave acylthiophens only in moderate yields.' l 6 Treatment of thiophen with phenyl isocyanate or phenyl isothiocyanate in the presence of NC13 in nitromethane gave the Nphenylamide and the N-phenylthioamide of thiophen-2-carboxylic acid in high yields."' The reversibility of bromination in the thiophen series is illustrated by the formation of a mixture of acyl derivatives and tetrabromothiophen in the A1C13-catalysed acylation of 2,5-dibromo- and 2,3,5tribromo-thiophen.l18 Another example is the formation of (40) by treatment of (39; X = Br) with PPA. No migration of chlorine occurs during the ring-closure of (39; X = Cl).'19 A very interesting result was obtained in the AICl,-catalysed reaction of (41) with benzene, toluene, or ethylbenzene, which yielded (42) and (43) in 77% and 9% yields, respectively. When half an equivalent of A1Cl3 was used, approximately equal amounts of (42; Ar = Ph) and (43; Ar = Ph) were obtained. Treatment of (43; Ar = Ph) with AlC13 in benzene also yielded (42). The mechanism of this interesting cine-arylation is not clear.12' In connection with this work, the chlorination of 3-benzyl-4phenylthiophen with sulphuryl chloride was undertaken, which gave a mixture of the 2- and 5-chloro-derivatives.120The cations produced by treatment of chlorothiophens in HS03F or AICl3-HC1-CH2CI2 systems have been observed by n.m.r. Protonation occurs exclusively at the a-carbon, both in 2-chloro- and 2,5-dichloro-thiophen." The basicities of the a- and 0positions of thiophen in the gas phase have been studied by ion-cyclotron resonance. a-Protonation was preferred, which was also the case for pyrrole and furan, in accordance with NMDO calculations. '22

*rlgcl CH2Ar

c1 (41) 115

116

(42)

(43)

A. B. Cowell and C. Tamborski, J. Fluorine Chem., 1981,17,345. H. Konishi, K. Setsugu, T. Okano, and J. Kiji, Bull. Chem. SOC. Jpn., 1982, 55, 957.

1I?

E. Jagodzinska, T. Jagodzinski, and Z. Jablonski, Khim. Geterotsikl. Soedin., 1980,

118

M. J. del Agua, A. S. Alvarez-Insda, and S. Conde, J. Heterocycl. Chem., 1981, 18,

119

J. B. Press and N. H. Eudy, J. Heterocycl. Chem., 1981, 18, 1261. T. Sone, H. Kawasaki, S. Nagasawa, N. Takahashi, K. Tate, and K. Sato, Chem. Lett., 1981, 399. Y. Yokoyama, Y. Yamashita, K. Takahashi, and T. Sone, Chem. Lett., 1981, 813. R. Houriet, H. Schwarz, W. Zummack, J. G. Andrade, and P. von Ragu6 Schleyer, Nouv. J. Chim., 1981, 5 , 5 0 5 .

1287. 1345. 120

121 122

Heterocyclic Chemi s t y

82

Hydrogen-deuterium exchange under phase-transfer conditions has been studied with 2-methyl- and 2-nitro-thiophen. No exchange was observed for the latter compound.123 The catalytic deuterium exchange of thiophen over y-alumina has been studied. 124 (Chlorodifluoromethy1thio)thiophen was substituted in the 5position, when it reacted with chlorodifluoromethanesulphenyl chloride in the presence of trifluoromethanesulphonic acid, to yield (44).’” Treatment of 2,3-bis-(4-fluorophenyl) thiophen with trifluor omethylsulphenyl chloride and t rifluoroace tic acid gave the 5-t rifluorome t hy lthio-derivat ive .12’ a Several thiophensulphonyl chlorides have been prepared by the reaction of thiophen or of 5-bromo-3-chloro-, 4,5-dibromo-, or 4-chloro-5-bromo-thiophen with chlorosulphonic acid. The sulphonyl chlorides were transformed into amides and other derivative^.'^^*^^' The Friedel-Crafts reaction between 3-bromothiophen and 2-nitrophenylacetyl chloride gave (45).12’ From 2-t-butylthiophen and pivaloyl chloride, 2-t-butyl-5pivaloylthiophen was obtained by the same rea~ti0n.l~’In connection with work on 2H-, 3H-, and 14C-labelled suprofen 46, bromination was achieved in the 5-position, using A1C13 as a swamping catalyst. The ketone (47) was prepared by Friedel-Crafts acylation of thiophen with 3-bromo-p-toluic carbonyl chloride. 130*131 0

C 1F2CS

lZ3 124

SCF2C1

W. J. Spillane, P. Kavanagh, F. Young, H. J.-M. DOU, and J. Metzger, J. Chem. SOC., Perkin D a m . 1 , 1981, 1763. G. Ya. Katsapov, E. N. Osmanov, and K. Kh. Razikov, React. Kinet. Catal. Lett.,

1981, 17, 227. M. R. C. Gerstenberger, A. Haas, and H. Pauling, Helu. Chim. Acta, 1982, 65,490. C. Cherkofsky, US P. 4 302 461, 1981. I26 R. J. Cremlyn, K. H. Goulding, F. J. Swinbourne, and K.-M. Yung, PhosphorusSulfur, 1981, 10, 111. I27 I. T. Barnish, P. E. Cross, R. P. Dickinson, M. J. Parry, and M. J. Randall, J. Med. Chem., 1981, 24, 959. 1 2 * J. Guillaume, L. NCdClec, M. Cariou, and A. Allais, Heterocycles, 1981, 1 5 , 1227. l Z 9 1. Murata, K. Nishino, S. Yano, Y. Kohashi, and K. Yamamoto, Croat. C h e m Acta, 1980, 53, 615. I 3 O Y. Mori, M. Shibata, K. Toyoshi, S. Baba, M. Horie, Y. Oshika, and K. Ohira, Radioisotopes, 1981, 30, 584. 13’ Y. Mori, M. Shibata, K. Toyoshi, S. Baba, M. Horie, Y. Oshika, and K. Ohira, Radioisotopes, 1981, 30, 590. 12’


83

In connection with developments of new syntheses of biotin, 3-acetylamino2-methoxycarbonylthiophen was nitrated at - 30°C with H N 0 3 in H2S04 to give a mixture of the 4-nitro- and 5-nitro-isomers in a 60:40 ratio. The isomers were easily separated by crystallization from t ~ l u e n e . ~2-Amino-4' ethoxycarbonylmethyl-3-methoxycarbonylthiophenhas been nitrated in the 5 - p o ~ i t i o n . ~The " nitration of 5-bromo- and of 5-methyl-2-cyclopropylthiophen with nitric acid in acetic anhydride has been investigated. With the bromo-derivative, substitution in the 3-position and ipso-substitution to give 5-nitro-2-cyclopropylthiophenwere observed. In the methyl case, it is claimed (without proof) that the 3-nitro-derivative is formed, the main product (44%) being (48).'32 A detailed paper on the nitration of 2,5dime thyl- and 2,5-dimethyl-3,4-dibromo-thiophen, reviewed in last year's Report, has now appeared. 133 2-Formylthiophen, upon nitration with copper and aluminium nitrates in acetic anhydride, gave the 5-isomer as the diacetate, while 2-acetylthiophen gave a mixture of the 4- and 5-nitro-isomers. At 7090" C, 2-formylthiophen was oxidized to thiophen-2-carboxylic acid. 134 The nitration of a,P-unsaturated thiophen ketones has been studied under various conditions, and led to mixtures of ring-nitrated ketones and (49).'34-'36 M e

c ! ON02

R

< j

CH=i!-COMe N02

OH (48)

(49)

Electrophilic Ring-closure Reactions. - In a series of interesting papers, several thienospirans have been described, prepared by cyclization onto thiophen. Thus (50) and (5 1) were converted into ( 5 2 ) and (53), respectively,

13'S. S. Mochalov, T. P. Surikova, F. M. Abdel'razek, V. D. Zakharova, and Yu. S. Shabarov, Khim. Geterotsikl. Soedin., 198 1, 189. 133 H. Suzuki, I. Hidaka, A . Iwasa, T. Mishina, and A. Osuka, Bull, Chem. SOC. Jpn., 1981, 54, 771. 134

13' 136

Yu. D. Churkin, L. V. Panfilova, V. D. Lugovoi, and N. V. Boiko, K h i m Geterotsikl. Soedin., 1981, 913. Yu. D. Churkin, L. V. Panfilova, A. S. Shashkov, and K. Ya. Burshtein, Khirn, Geterotsikl. Soedin., 1981, 325. Yu. D. Churkin, L. V. Panfilova, A. S. Shashkov, and K. Ya. Burshtein, Khirn. Geterotsikl. Soedin., 1981, 753.


84

by treatment with PPA.13' Alternative starting materials were (54),(55), and (56), which led to (57), (58), and (59), re~pective1y.l~'Six-membered fused systems (61) could be prepared by treating (60) with PPS or concentrated phosphoric acid and acetic anhydride. 13' Alternatively, (62), prepared from The Grinard reagent of 2-(bromopropy1)thiophen and cyclohexanone, gave (63) upon treatment with 9ooJo sulphuric acid in ether. Treatment with 50% H2S04 led only to olefm formation.13* When (64) reacted with thiophen under Friedel-Crafts conditions, it gave (65), which, after Wolff-Kishner

(54)

(57)

(58) 0

13' 138

P. Stanetty, J. Chem. Res. (S), 1981, 99. P. Stanetty, J. Chem Res. (S), 1981, 100.

(59)


85

reduction, was ring-closed to (66) with PPA.’39 Treatment of (67) with PPA finally gave (68).13’ Electrophilic ring-closure of 2-geranylthiophens (69) has been studied in great detail. With concentrated H2S04 in nitroethane, at -40°C, it was possible to obtain (72; R = H) in 80% yield; SnC14 gave also (72), but in somewhat lower yield. Trifluoroacetic acid in methylene chloride led only to the formation of (70; R = H) and (71; R = H), in the proportions 4 : 1. When R = C02H, ring-closure was slowed down, and only (70) and (71) were obtained, in various proportions. After treating (69; R = C02H) with SnC14 in methylene chloride for 72 hours at room temperature, a 59% yield of (72) and (73) was obtained, in the proportions 2: 1 . 1 4 0 Treatment of (74)

(72)

139 140

(73)

P. Stanetty, J. Chem. Res. (S), 1981, 139. A. V. Semenovskii and M. M. Emel’yanov, Izv. A kad. Nauk SSSR, Ser. Khim., 1980, 2578.

Heterocyclic Chemi s t v

86

with conc. H2SO4 in a nitromethane-toluene mixture (1 : 1) at - 40°C led to a mixture of (75) and (76).141 The Friedel-Crafts cyclizations of lV-(3theny1)- and of N-(2-thenyl)-glycine, using 80% H2SO4, gave (77) and (78), re~pective1y.l~~ The cyclohepta [ b ]-fused systems (79) and (80) were obtained by treating the appropriate acid chloride with SnC14 in CS2

0

CQ 0

(77)

(79)

Nucleophilic and Radicaloid Substitution Reactions of Monocyclic Thiophens. - The rate constants for the reaction of 5-substituted 2-bromo-3nitrothiophens, in methanol, with various substituted d i n e s to give 5substituted N(3-nitro-2-thienyl)anilines have been measured at various temperatures. It was found that the sensitivity parameters that were obtained from Hammett and Bronsted correlations were practically independent of the starting system.'44 The kinetics of piperidino-substitution of methyl 2methoxy-3-nitrothiophen-5-carboxylateand 5-acetyl-2-methoxy-3-nitrothiophen, in which the methoxy-group is the leaving group, have been investigated and the mechanism has been discussed.145 Six bis(nitrothieny1) sulphides have been prepared by the reaction of appropriate bromonitrothiophens and sodium ~ u 1 p h i d e . lA~ large ~ number of sulphides has also been prepared by nucleophilic substitutions of substituted thiophenolates with substituted 5-bromothiophen-2-sulphonamidesin DMF.'27 With less activated halothiophens, copper-promoted nucleophilic substitution must be used, as in the reaction of 2-chlor0-5-iodothiophen'~~ or of 3-br0mothiophen'~~with substituted thiophenolates, or in the ring14'

A. V. Semenovskii and M. M. Ernel'yanov, Izv. Akad. Nauk SSSR,Ser. Khim.,

1981,

1359. 142 143 144

145

K. Satake, T. Irnai, M. Kirnura, and S. Morosawa, Heterocycles, 1981, 16, 1271. T. Frejd, J. 0. Karlsson, and S. Gronowitz, J. Org. Chem., 1981,46, 3132. G . Consiglio, C. Arnone, D. Spinelli, R. Noto, and V. Frenna, J. Chem. SOC.,Perkin Trans. 2, 1981, 388. G . Consiglio, C. Arnone, D. Spinelli, and R. Noto, J. Chem. Soc., Perkin Trans. 2, 1981,642.

146 147

14'

G. Ronsisvalle and G. Blandino, Farmaco, Ed. Sci., 1981, 36, 785. Z. Polivka, J. Holubek, E. Svitek, J. Metygovd, and M. Protiva, Collect. Czech. Chem. Commun., 1981,46,2222. J. W. H.Watthey and M. Desai, J. Org. Chem., 1982, 47, 1755.


87

closure of (81) to (82). Higher yields and more reproducible results were obtained if the formamide of (81) was used in the reaction with K2CO3 and Cu powder in DMF.'28 Furthermore, phenyl ethers have been prepared by the copper-promoted reaction between 3-bromothiophen, copper bronze, anhydrous K2C03, and substituted phenols. After refluxing for a week, high yields were obtained.I4* The reaction of 2,4-di-iodothiophen in the presence of CuO could be utilized for the preparation of 2-methoxy-4-iodothiophen and 2,4-dimetho~ythiophen,'~' while Ullmann-type coupling between 2iodothiophen and methyl 2-iodobenzoate was used for the preparation of methyl (2-thieny1)benzoate in low yield. Better yields of the desired product were obtained by the reaction of the diazonium salt of methyl anthranilate with t h i ~ p h e n . ' It ~ ~is claimed that the reaction of 3-iodothiophen with diethyl malonate in quinoline in the presence of CuBr gave 69% yield of

diethyl3-thienylmal0nate.'~'

(2)-Dialkenylcuprates were coupled with 2-iodothiophen in the presence of ZnBr and catalytic amounts of Pdo complex to give vinylthiophen~.'~~ Palladium-graphte, prepared by the reduction of PdC12 by C8K, has also been used as a catalyst in the preparation of vinylthiophens from 2iodothiophen. l S 3 The palladium-catalysed reaction of 2,4-dibromothiophen with propargylzinc chloride gave a 70% yield of 4-bromo-2-( 1-propyny1)thiophen, containing small amounts of the 2-bromo-4-( 1-propynyl) isomer. The use of 4-bromo-2-iodothiophen increased the yield to 80% and eliminated the formation of the by-prod~ct."~l-Methy1-2-(3-thienyl)pyrrolehas been synthesized in 73% yield by the palladium-catalysed coupling of 3-bromothiophen with 1-methyl-2-pyrrolylzinc c h l ~ r i d e . ' ~ ~ Halothiophens " have been condensed with terminal acetylenes under carbon monoxide at temperatures of about 120°C and pressures of 80atm, in the presence of triethylamine and a Pdn catalyst, to give acetylenic ketones.'54b I49

Ya. L. Gol'dfarb, M. A. Kalik, and V. K. Zav'yalova, Khim. Geterotsikl. Soedin.., 1981,182.

S. Mataka, T. Ohshima, and M. Tashiro, J. Org. Chem., 1981, 46, 3960. J . P. M. Houbiers and P. G. Mueris, US P. 4 262 129, 1981. l S 2 N. Jabri, A. Alexakis, and J. F. Normant, Tetrahedron Lett., 1981, 2 2 , 3851. I s 3 D. Savoia, C. Trombini, A. Umani-Ronchi, and G. Verardo, J. Chem. SOC.,Chem. Commun., 1981, 541. IS4 J. 0. Karlsson, S. Gronowitz, and T. Frejd, J. Org. Chem., 1982, 47, 374. 154aA. Minato, K. Tamao, T. Hayashi, K. Suzuki, and M. Kumada, Tetrahedron Lett., Is'

1981, 22, 5319.

1s4bT.Kobayashi and M. Tanaka, J. Chem SOC.,Chem Commun., 1981, 333.


88

The scope of the reactions of 5-nitro-3-thienylethyl chloride and acetate with the lithium salt of 2-nitropropane to give (83) (cf.this series, Vol. 2, p. 80) has been investigated. The cyano-group was not found to be sufficiently active, since 4-cyano-2-thienyl-methyl and -ethyl chlorides only gave 0alkylated products by an s N 2 mechanism. The SN(AEAE) reaction also occurred between benzenethiolate and 4-nitro-2-thienylmethyl acetate, and a moderate yield of 4-nitro-2-thienylmethyl phenyl sulphide was obtained.”’

I (83) Me2CN02

The mechanism of the reaction of thiophens with a variety of radicals such as .OH, Cl’, NH,’, and SO2 has been studied in a detailed investigation using the e.s.r. technique. The radicals that were detected were mainly hydroxy adducts, but also included 2-thenyl and thenyloxy radicals. Evidence for the involvement of radical cations was also pre~ented.’’~The rate constants for the reaction of O(3P) with thiophen were determined by using the discharge flow-resonance fluorescence technique. l S 7 Homolytic substitution of thiophen by MeCOcH, and MeCOcHCOMe radicals, generated from acetone and acetylacetone by using Mnm acetate, led regiospecifically to the 2-thienyl ketones.’ 58 The reduction of 2-bromo-5-nitrothiophen and of 2-iodo-5nitrothiophen in DMF has been studied by polarography, e.s.r. spectroscopy, and preparative electrolysis. Further reactions of the radical anions to form nitrothienyl radicals and their dimers were observed and a mechanism was pr~posed.”~

Organometallic Derivatives of Monocyclic Thiophens - Lithium. Numerous a-substituted thiophens have been prepared via metallation of thiophens with organolithium derivatives, Thus 2-thienyl-lithium has been allowed to react with tetraisopropylthiuram disulphide to give S(2-thienyl) N,N-di-isopropyldithiocarbamate in quantitative yield. ‘60 Through the reaction of 2-thienyllithium with tellurium in THF, the tellurolate was obtained, which was converted into various products.16’ The reaction of 2-thienyl-lithium with 1 , l dichloro-2,2-difluoroethene has been developed into a very useful method for

155

lS6

P. J . Newcombe and R. K. Norris, Aust. J. Chem., 1981, 34, 1879. B. C. Gilbert, R. 0. C. Norman, and P. S. Williams, J. Chem. Soc., Perkin Trans. 2 , 1981, 207.

151

Is* Is’

161

J. H. Lee and I. N. Tang, J. Chem. Phys., 1981, 7 5 , 137. R. S. Min, V. S. Aksenov, M. G . Vinogradov, and G. I. Nikishin, Izv. Akad. Nauk SSSR,Ser. Khim., 1981,2315. I. M . Sosonkin, G. N. Stogov, T. K. Ponomareva, A. N. Domarev, A. A. Glushkova, and G. N. Freidlin, Khim. Geterofsikl. Soedin., 1981, 195. K. Y. Jen and M. P. Cava, Tetrahedron Lett., 1982,23,2001. L. Engman and M. P. Cava, Organometallics, 1982, 1,470.


89

the preparation of acetylenic and polyacetylenic derivatives. Thus when (84), formed in this reaction, reacted with excess butyl-lithium followed by dichlorodifluoroethene and trimethylsilyl chloride, 2,5-bis(trimethylsilyL ethyny1)thiophen was produced. Coupling of (85) with cupric acetate in pyridine gave (86).16' The reaction of 2-thienyl-lithium with geranyl bromide and with (E,E)-farnesyl bromide was used for the synthesis of (69a)" and of (7 4) ,14' respectively . Met allation of 2-met h ylthiophen with but yl-lithium, followed by reaction with vinyl azides, was used for the synthesis of 2-amino5-methylthiophen.' 63 The reactions of 2- and of 3-thienyl-lithium with pyridazine are dependent upon the solvent and the temperature that is used. Thus, using THF as cosolvent, at low temperatures, the 4-position of pyridazine is attacked, leading (after hydrolysis and oxidation) t o 4-(2-thienyl)- and 4-(3-thienyl)-pyridazine. If ether is used as the solvent, at O"C, 3-(2-thienyl)- and 3-(3-thienyl)pyridazines were obtained after oxidation. The structures of the initially formed dihydro-derivatives were studied to some extent.'@ The reaction of (87) with butyl-lithium followed by formaldehyde gave (88).16' The reaction of 2-phenylthiophen with butyl-lithium followed by ethyl 2-thienylglyoxylate was used for the synthesis of (89).lM The directing effect of a 3-phenoxyand of a 3-phenylthio-group on metallation with phenyl-lithium has been investigated. While the 3-phenoxy-group almost exclusively directed lithiation to the 2-position, a 1 : 1 mixture of 2- and 5-lithiated derivatives was obtained with 3-(pheny1thio)thiophen. 148 Dilithium derivatives were obtained by treatment of thiophen-2- and -3-carboxylic acids, which reacted with various electrophiles to give 5-substituted thiophen-2-carboxylic acids and 2substituted thiophen-3-carboxylic acids, re~pectively.'~~ The metallation of

(84) R = H (85) R = C s C S i M e 3

Ph R

CH=CHCH2NMe2

HO'

'COOE t

(87) R = H

( 8 8 ) R = CH20H 163

164 165

(89)

K. Okuhara, Bull. Chem. SOC.Jpn., 1981, 54, 2045. A. Hassner, P. Munger, and B. A. Belinka, Jr., Tetrahedron Lett., 1982, 23,699. J . Bourguignon, C. BBcue, and G. QuCguiner, J. Chem. Res. ( S ) , 1981, 104. Yoshtomi Pharmaceutical Industries Ltd., Jpn Kokai Tokkyo Koho 8 1 169 685, 1981. A. T. Jeffries, K. C. Moore, D. M. Ondeyka, A. W. Springsteen, and D. W. H. MacDowell, J. Org. Chem., 1981, 46, 2885. D. W. Knight and A. P. Nott, Tetrahedron Lett., 1980, 21, 5 0 5 1 .

90


3-bromothiophens with LDA followed by trimethylsilyl chloride has been used for the preparation of 3-bromo-2-(trimethylsilyl)thiophens.'68 The reaction of 3-thienyl-lithium, prepared by halogen-metal exchange of 3-bromothiophens, has been used for the synthesis of many geminal 3,3dithienyl derivatives of pharmacological interest. Thus the reactions with ethyl 3-bromopropionate, ethyl cyclopropylcarboxylate, and (90) were used for the synthesis of (91),16' (92),170 and (93),17' respectively. The reaction of 3-thienyl-lithium with quinoxaline has been used for the preparation of 2,3-di(3-thienyl)quinoxaline. 172 The reaction of 3-thienyl-lithium with trialkylboranes gave 'ate' complexes, which upon reaction with bromine or iodine yielded the corresponding 3alkylthi~phens.'~~ Halogen-metal exchange between acetal-protected 5bromothiophen-2-carbaldehyde and butyl-lithium, followed by reaction with nicotinaldehyde, was used for the synthesis of (94) in connection with the preparation of inhibitors of thromboxane ~ynthetase."~Halogen-metal exchange of 3 -bromo-4-phenylthiophen followed by reaction with benzaldehyde gave (99.'"'

'CHMe2

CHO (94)

(95)

168

S . Gronowitz, T. Frejd, J. 0. Karlsson, K. Lawitz, P. Pedaja, and K. Pettersson, Chem. Scr., 1981,18, 192. J. Engel, A. V. Schlichtegroll, and W. S. Scheldrick, Arzneim.-Forsch., 1982, 32,

170

A. Kleemann, J. Heese, and J . Engel, Arzneim.-Forsch., 1981, 31, 1178. F. J. Stiefel, US P. 4 310674, 1982.

174

475.

T. Kauffmann, M. Ghanem, and R. Otter, Chem. Ber., 1982, 115,459. I. Akimoto, M. Sano, and A. Suzuki, Bull. Chem. SOC.Jpn., 1981, 54, 1587. T. Tanouchi, M. Kawamura, I. Ohyama, I. Kajiwara, Y. Iguchi, T. Okada, T. Miyamoto, K. Taniguchi, M. Hayashi, K. Iizuka, and M. Nakazawa, J. Med. Chem., 1981, 24, 1149.


91

The halogen-metal exchange between 4-iodo-2-methoxythiophenand butyl-lithium, followed by reaction with dimethyl disulphide, carbon dioxide, or DMF, was used for the synthesis of various 4-substituted 2-methoxythiophens.14’ In connection with work on optically active 3-(cyclohexeny1)thiophens, substituted 3-thienyl-lithium derivatives were allowed to react with cyclohexanones and cyclohexenones.175 The reaction of 3,4dibromothiophen with two equivalents of butyl-lithium and sulphur, followed by CS2, was used for the synthesis of (96), an intermediate for the synthesis of the ‘organic metals’ (97).176 The synthetic usefulness of the ring-opening reaction of 3-thienyl-lithium derivatives has been further demonstrated. It was found that 2-(trimethylsily1)3-thienyl-lithium ring-opens very fast, in contrast to 3-thienyl-lithium compounds with a free 2 - p o ~ i t i o n This . ~ ~ ~was utilized for the total synthesis of some naturally occurring acetylenic thioenol ethers. Thus (98) was transformed by the reaction with butyl-lithium and methyl iodide into (99), which after desilylation and Pd-catalysed coupling with (2)-methyl 3-bromoacrylate was converted into (100). Another isomer was obtained through coupling with (,!?)-methyl 3-bromoa~ry1ate.l~The ring-opening of cyclo [ b ]-fused systems (10 1) with phenyl-lithium, followed by reactions with electrophiles such as benzyl chloride or ethyl bromoacetate, led to a regio- and stereospecific synthesis of (102).143

(101) n = 1-4

( 1 0 2 ) n = 1-4

R2= CH2COOH or CH2Ph 175 176

A. Svensson and R. Hikansson, Chem. Scr., 1981, 18,202. P. Shu, L. Chiang, T. Emge, D. Holt, T. Kistenmacher, M. Lee, J. Stokes, T. Poehler, A. Bloch, and D. Cowan, J. Chem. SOC.,Chem. Commun., 1981,920.


92

Mugnesium . Metallation of 2,3,4-trichlorothiophen with ethylmagnesium bromide and halogen-metal exchange between tetrachlorothiophen and the same reagent has been achieved, and the resulting Grignard reagents have been characterized by their reactions with C 0 2 and with trimethylsilyl ~hloride."~The reaction of hexabromo-2,2-bithienyl with magnesium under entrainment conditions gave the 5,5'-dimagnesium derivative.'% Ethyl 2thienylglyoxylate has been prepared by the addition of thiophen-2magnesium bromide to diethyl oxalate in THF instead of diethyl ether.'79 Thienyl derivatives of Group IVB elements have been prepared by the reaction of thiophen-2-magnesium bromide with the corresponding silicon, germanium, tin, and lead halides. The electron-acceptor properties of these substituents with the n-electron system of thiophen were investigated by means of 'H, 13C, "'Si, l19Sn, and ""Pb n.m.r. spectroscopy.lg0 The reaction of thiophen-2-magnesium bromide with a-chlorocyclohexanone offered a convenient synthesis of 2-(2-thienyl)cyclohexanone .l 38 Mercury, Zinc, and Copper. The thermal decomposition of 2-thienylmercury thiocyanate, azide, acetate, and trifluoromethylsulphonate has been investigated. lgl Thienylmercury derivatives have been cross-coupled with primary and secondary alkyl- and alkenyl-cuprate reagents.lg2 2-Thienylzinc chloride has been coupled with iodobenzene and vinyl bromide, using Pd ~ata1ysis.l~~ 3,4-Dichloro-2-thienylcopper and trichloro-2-thienylcopper have been coupled with 1,2,A,5-tetrachloro-3-iodobenzene. 184 Damition Metals. A detailed paper on the Pd-assisted alkenylation of thiophen with various olefins to give mono- or di-alkenylated products has been p ~ b 1 i s h e d . l The ~ ~ reaction of the thiophenmercury derivatives (103) with trinorbornenylpalladium chloride and lithium chloride (1 0 : 1 : > 2) in acetonitrile led to the air-stable Pd complex (104). The saturated analogue

'"

M. T. Rahman, J. Indian Chem. SOC.,1981, S8,21. Yu. V. Shklyaev, Yu. P. Dormidontov, and I. I. Lapkin, Khim. Geterotsfkl. Soedin., 1981,468.

L. M. Weinstock, R. B. Currie, and A. V. Lovell, Synth. Commun., 1981, 11, 943. l B 0 E. Lukevits, 0. A. Pudova, Yu. Popelis, and N. P. Erchak, Zh. Obshch. Khim., 1981, 17'

51, 115.

C. A. Obafemi, J. Organomet. Chem., 1981, 219, 1. R. C. Larock and D. R. Leach, Organometallics, 1982, 1, 74. E.-I. Negishi, F.-T. Luo, R. Frisbee, and H. Matsushita, Heterocycles, 1982, 18, 117. M. T. Rahman, Monatsh. Chem., 1982,113, 91. l B 5 Y. Fujiwara, 0. Maruyama, M. Yoshidomi, and A. Taniguchi, J. Org. Chem., 1981, 46, 851.


93

reacted similarly. Subsequent coupling with alkenylcuprates, followed by further reactions, gave (109, and desulphurization with Raney nickel led to bicyclic and tricyclic prostanoic acid analogues such as (1O6).l8(j The cyclometallation of 2(2-thienyl)- and 2-(3-thienyl)-pyridine with Pd", Rh" and Ru" complexes has been in~estigated.'~'The cleavage of (107) with iodine has been studied.'88 7

Silicon. The dehy dr ocondensa t ion of met hyldi-(2-thieny1)silane with various alcohols in the presence of amines has been in~estigated.'~~ The template effect of thiophen in the photochemical chlorination of (108) with sulphuryl chloride has also been studied.'"

J

3

Photochemistry of Monocyclic Thiophens. - The HCCS radical has been identified, by theoretical calculations, as a transient species during the flash photolysis of thiophen.'" Various physical measurements, such as differential scanning calorimetry, thermogravimetry, and mass-spectral studies, have been R. C. Larock, D. R . Leach, and S. M. Bjorge, Tetrahedron Lett., 1982, 2 3 , 7 1 5 . M. Nonoyama and S. Kajita, Transition Met. Chem., 198 1 , 163. N. E. Kolobova and L. 0. Goncharenko, Izv. Akad. Nauk SSSR, Ser. Khim., 1981, 6,6 7. 189 E. Lukevits and M. Dzintara, Zh. Obshch. Khim., 1981,51, 2043. I9O R. Breslow and D. Heyer, J. Am. Chem. SOC., 1982, 104,2045. D. L. Cooper, Chem. Phys. Lett., 1 9 8 1 , 8 1 , 4 7 9 .

187


94

carried out on the photo-products that are derived from the photosensitized cycloaddition reactions between thiophen derivatives and methyl-substituted maleic anhydrides and maleimide~."~The photoaddition of excited benzophenone to 2,3-dimethyl-, 3,4-dimethyl-, and 2,3,5-trimethyl-thiophenhas been attempted. Only the 2,3-dimethyl derivative gave a good yield of the oxetan (109).'93 In a detailed investigation of the photochemistry of 3-aryl2-isoxazolines, the 3-(2-thienyl) derivative was also studied. In the presence of thiophen, cycloaddition products such as (1 10) were formed.'" Photochemical or thermal decomposition of (1 11) gave (1 12), and the structure (1 12a) was proven by X-ray cry~tallography.~~~ Photolysis of (1 13) gave, somewhat unexpectedly, (1 14).196 The photocyclization of (1 15) led to the spiro-annelated product (1 16).19' The photochemical trans-cis isomerization of (1 17) and of the corresponding selenophen analogue has been examined

or

(111) a ; R = Ph

p- MeOOCC6H4

b ; R = Me

( 1 1 0 ) A r = p-NCC6H4

(112) a; R = Ph b ; R = Me

19* 193

194

19' 196

19'

Bra S

R. A. Bolivar, E. Cotte, C. Perez, and C. Rivas, Themzochim. Acta, 1981, 45, 125. C. Rivas, D. Pacheco, F. Vargas, and J. Ascanio, J. Heterocycl. Chem., 1981, 18, 1065.

T. Kumagai, K. Shimizu, Y. Kawamura, and T. Mukai, Tetrahedron, 1981, 37,3365. C. J. Moody, C. W. Rees, S. C. Tsoi, and D. J. Williams, J. Chem. SOC., Chem. Commun., 1981,927. S. Jeganathan and M. Srinivasan, Indian J. Chem., Sect. B y 1980, 19, 1028. J.-C. Gramain, Y. Troin, and D. Vallee, J. Chem. SOC., Chem. Commun., 1981, 832.


95

and quantum yields have been determined.’” Photochemical ring-closure, in the presence of iodine, of (1 18) gave (1 19),’99 and (121) was obtained from (12O).*Oo The isomeric triphenyleno [2,1-b] thiophen was obtained from the 2-thienyl analogue of ( 120).200

Cycloaddition Reactions of Monocyclic Thiophens. - Reviews on sigmatropic additions and cyclosubstitutions in five-membered heterocyclic compounds with exocyclic double bonds201 and on syntheses and reactions of heterocycles under high pressures201ahave been published. Interesting work on the A1C13-catalysed thermal [2 + 21 cycloadditions of but-2-ynedinitrile to alkylthiophens and further reactions of the adduct have been carried out. Thus (122b) gave (123a) in 61% yield, together with 4% of 3,4,5,6-tetramethylphthalonitrile. The unsymmetrical (122c) gave (123b) and (123c) in 44% and 20% yields, respectively, in addition to 6% of the corresponding phthalonitrile. Compound (122d) gave 55% of (123d), together with 5.5% of

R1u:: Me

(122) a; R’= R ~ H = b ; R1= R2= Me c ; R1= But, R2= H d ; R1= R 2 = (cH2)4

(123) a; R1= R2= Me b ; R1= H, R2= But 2 C ; R1= B u t , R = H

d; R1= R2= (CH2)4

M. Reinkhardt, V. G. Mitina, N. S. Pivnenko, and V. F. Lavrushin, Zh. Obshch. Khim., 1980,5 0 , 2770. R. Pratap, Y. Tominaga, M.L. Lee, and R. N. Castle, J. Heferocycl. Chem., 1981, 18,973. 200 R. F’ratap, M. L. Lee, and R. N. Castle, J. Heferocycl. Chem., 1981,18,1457. 201 V. N. Drozd and N. S. Zefirov, SulfurRep., 1981,1, 271. 201uK. Matsumoto, T. Uchida, and R M. Acheson, Heterocycles, 1981, 16, 1367. 19*

199


96

(124). On the other hand, 2,5-dimethylthiophen reacted differently from tri- and tetra-alkylthiophens, and gave the 2 : 1 adduct (1 25) in 26% yield.202 Thermal rearrangements of (122a-c) to (126) occur in high yields at 11014OoC, while photochemical rearrangement occurs to (1 27) via cleavage of the C( 1)-S bond; prolonged irradiation of (127c) leads to (128). Mechanistic suggestions for the rearrangements are given.203 Extrusion of sulphur occurs when the compounds (126) and (127) are heated to 285°C in solution, yielding phthalonitriles. From (1 23d), (37) was also obtained." 2-Thienylthiones (129) react with maleic anhydride to yield (1 30), while their reactions with trinorbornene gave (1 3 l).204Benzyne reacted with various thiophens by addition to the sulphur and 0-carbon and gave, after loss of acetylene, benzo[ b ]thiophens in low (0.5-3.8%) but reproducible yields.205 Evidence for the formation of 2,3-dehydrothiophen by slow vacuum thermolysis of thiophen-2,3-dicarboxylicanhydride has been obtained by trapping it with 2,3-dimethylbu tadiene .206*207 H

"Y'

Me

CN

Me

CN

Me

Me ( 1 2 6 ) a ; R1= R2= M e = H

CN

( 1 2 7 ) a ; R1=

R2= Me

R2= H 1 2 t c; R = H , R = BU

b ; ql= B u t ,

202

R. H. Hall, H. J. den Hertog, Jr., and D. N. Reinhoudt, J. Org. Chem., 1982, 47, 967. R. H. Hall, H. J. den Hertog, Jr., and D. N. Reinhoudt, J. Org. Chem., 1982, 47, 972. '04 H. Ohmura and S. Motoki, Chem. Left., 1981, 2 3 5 . ' 0 5 D. del Mazza and M. G. Reinecke, J. Chem. Soc., Chem. Commun., 1981, 124. 2 0 6 M. G. Reinecke, J . G . Newsom, and K. A. Almqvist, Tetrahedron, 1981, 37,4151. *07 M. G. Reinecke, J . G. Newsom, and L.-J. Chen, J. Am. Chem. Soc., 1981, 103, 2760. 203


97

Carbenoid ring-expansion of thiophen to a 2H-thiopyran has been observed in the rhodium-catalysed reaction with (132), which gave (133) and (134).208 Evidence has been presented that the nitrene intermediate (139, obtained from the corresponding nitro- or azido-derivatives in the usual way, first gives the aziridine intermediate (136), which then leads to interesting heteropolycyclic systems such as 3-(2-thienyl)indole derivative^.^'^

Desulphurization and Hydrogenation of Simple Thiophens. - The reduction of (137) with seven equivalents of lithium in ethylamine at - 20°C gave (138) in 30-75% yield. The same alcohol was, of course, formed from (137d)

(137) a ; b; c; d; e;

R1= R2= H R1= H, R2= Me R1= Me, R2= H R1= R 2= Me ='R H, R ~ =Et

and (137e), but the (E):(Z)ratios were 9:l and 3:2, respectively. Furthermore, the dihydrothiophens (1 39), prepared via electrochemical reduction of thiophen-2-carboxylic acids followed by reduction of the methyl ester with '08

'09

L. Chan and S. A. Matlin, Tetrahedron Lett., 1981, 22, 4025. P. C. Hayes, G. Jones, C. Keates, 1. Kladko, and P. Radley, J. Chem. Res. (S), 1980, 288.


98

LiA1H4, gave (138) upon reaction with five equivalents of lithium,21o9211 A modified method for the synthesis of (139) has been described.212Birch reduction of 2-acylthiophens and of 2-acyl-5-alkylthiophens, followed by alkylation with alkyl halides, gave 2-acyl-, 2-alkyl-, or 2-acyl-2,5-dialkylthiophens in good yields. Oxidation of these compounds to the 1,l-dioxides by MCPBA, followed by thermolysis, offers a convenient route to 1,3dienyl ketones.213 The Birch reduction of 2-t-butyl-5-pivaloylthiophen to the corresponding 2,5-dihydrothiophen was a key procedure in the synthesis of 2,6-di-t-butyl-4-methylthiopyrylium salts.'29 Birch reduction of (140) was used for the synthesis of (141).14' The technical importance of the removal of thiophens from oil and coal has led to a great number of papers on catalytic dehydro sulphur ization ? 4-232

A. V. Lozanova, A. M. Moiseenkov, and A. V. Semenovskii, Izv. Akad. NaukSSSR, Ser. Khim., 1980, 1932. A. V. Lozanova, A. M. Moiseenkov, and A. V. Semenovskii, Izv. Akad. NaukSSSR, Ser. Khim., 198 1, 838. 2 1 2 W. G. Blenderman and M. M. Joullid, Synth. Commun., 1981, 11, 881. '13 K. Kosugi, A. V. Anisimov, H. Yamamoto, R. Yamashiro, K. Shirai, and T. Kumamoto, Chem. Lett., 198 1, 1341. 214 P. Pokornf and M. Zdraiil, Collect. Czech. Chem. Commun., 1981,46,2185. 215 J. Devanneaux and J. Maurin, J. Catal., 1981, 69, 202. 216 M.-A. Apecetche, J. Lemaitre, and B. Delmon, Bull. SOC.Chim. Be@, 1981, 90,419. 2 1 7 Yu. I. Yermakov. A. N. Startsev. V. A. Burmistrov, and B. N. Kuznetsov, React. Kinet. Catal. Lett:, 1980,14, 155.. 21 8 M. R. Blake, M. Eyre, R. B. Moyes, and P.B. Wells, Stud. Surf. Sci. Catal., 1981, 7, 'lo

219

591.

M. Sugioka and K. Aomura, Hokkaido Daigaku Kogakubu Kenkyu Hokoku, 1980, 79.

220

D. H. Broderick, A. V. Sapre, B. C. Gates, H. Kwart, and G. C. A. Schuit, J. Catal.,

221

P. Davidova and P. Kovacheva, Neftekhimiya, 1982, 22,93. Yu. I. Ermakov, B. N. Kuznetsov, A. N. Startsev, P. A. Zhdan, A. P. Shepelin, V. I. Zaikovskii, L. M. Plyasova, and V. A. Burmistrov, J. Mol. Catal., 1981, 11, 205. S. Gultekin, Chim. Acta Turc., 1981, 9, 257. T. W. Matheson and K. C. Pratt, React. Kinet. Cafal. Lett., 1981, 18, 21. F. E. Massoth and K. S. Chung, Stud. Surf. Sci. Catal., 1981, 7 , 629. A. V. Mashkina, V. N. Yakovleva, N. E. Buyanova, and Z. A. Dovbii, Kinet. Katal.,

1982, 73, 45. 222

223 214

22s 226

1982, 23, 58. 227

"* 229

Y. Okamoto, H. Tomioka, T. Imanaka, and S . Teranishi, Stud. Surf. Sci. Catal., 1981, 7, 616.

F. Ruette and E. V. Ludena, J. Catal., 1981, 67, 266. I. Rajca, A. Borowski, and A. Marzec, Erdoel Kohle, Erdgas, Petrochem., 1982, 35, 36.

"O

231

R. Ramachandran and F. E. Massoth, Can. J. Chem. Eng., 1982, 60, 17. A. M. Kuliev, F. A. Teimurova, and I. F. Mustafaeva, Khim. Vys. Energ., 1981, 15, 379.

232

M. Sugioka and K. Aomura, Hokkuido Daigaku Kogakubu Kenkyu Hokoku, 1981, 53.


99

The Structures and Reactions of Hydroxy-,Mercapto-, and Amino-thiophens.A convenient synthesis of the 2-aryl-5-hydroxythiophensystem consists of the reaction of the corresponding butenolides with sodium hydrosulphidehydrogen chloride .48 3-Hydroxy-4-anilinomethylthiophenexists in the stable tautomeric form (25).46 The allyl ether of dimethyl 3-hydroxythiophen2,5-dicarboxylate was prepared in DMF by its reaction with sodium hydride and allyl bromide.233 Thienylthioethanols were obtained in high yields by the reaction of thiophen-2-thiols with ethylene oxide.234 The reaction of 2,4-dinitro-3bromothiophen with sodium dimethylthiocarbamate or sodium t-butyltrithiocarbonate yielded (142). Decomposition of (142b) in glacial acetic acid led to a mixture of (143) and (144) in moderate yield. The reaction of thiophen-3,4-dithiol with phosgene chloride, followed by nitration, gave ( 145).235 The reaction of thiophen-2-thiol with p-(methylsulphonyl)bromobenzene was used for the preparation of 2-thienyl p(me thylsulphony1)phenyl ~u1phide.l~~ A dramatic increase in the number of papers on the synthesis of derivatives of thiophensulphonic acids can be n 0 t e d , ~ 2 ~ - and ~ ~ is~certainly * ~ ~ - con~ ~ ~ nected with the interest in such compounds with bacteriocida1,237,239 -241 or pesticidal activity.lz6*236 The reaction kinetics of substituted thiophen-2-sulphonyl chlorides and of thiophen-3-sulphonyl chloride

NO2

02N

(142) a; R = NMe2 b ; R = SBut

S

233

D. Binder, C. R. Noe, and B. C. Rager, Arch. Pharm. (Weinheim, Ger.), 1981, 314, 751. A. V. h i s i m o v , V. S. Babaitsev, and E. A. Viktorova, Vesfn. Mosk. Univ., Ser. 2: Khim., 1981, 22, 508. 2 3 5 K. Rasheed and J. D. Warkentin, J. Heterocycl. Chem., 1981, 18,1581. 236 R. J. Cremlyn, F. J. Swinbourne, and K.-M. Yung, J. Heterocycl. Chem., 1981, 18,997. 237 C. T. Goralski, US P. 4 264 774, 1981. 238 V. A. Martyushenko and M. M. Kremlev, Vopr. Khim. Khim. Tekhnol., 1980, 60, 3. 239 G. Levitt, Eur. Pat. Appl. 41 404,1981. 240 A. M. El-Naggar, F. S. M. Ahmed, A. M. Abd El-%lam, and T. M. Ibrahim, Egypt. J. Chem., 1981, 23,273. 241 C. T. Goralski, US P. 4 309 554,1982.

234

100


and fluoride with anionic and neutral nucleophiles has been studied in detail, and the reaction mechanism discussed. Hammett- and Taft-type correlations were o b s e r ~ e d . ~The ~ ~ catalytic , ~ ~ ~ effects of silver nitrate and of silver nitrite on the hydrolysis of substituted thiophen-2-sulphonyl chloride were also investigated .244 Methyl 3-amino-4-arylthiophen-2-carboxylates have been hydrolysed and decarboxylated to relatively stable 4-arylaminothiophens. They could also be diazotized and reduced to methyl 4-arylthiophen-2-carbo~ylates.~~ Catalytic reduction of 2-amino-3-nitrothiophen to the unstable 2,3-diaminothiophen, using Raney nickel W2, was achieved; the crude product reacted with biacetyl to give 2,3-dimethylthieno[2,3-b] p y r a ~ i n e .Several ~ ~ ~ aminothiophens have been prepared by Curtius-type reactions. Trimethylsilyl azide, containing trace amounts of potassium azide and 18-crown-6 ethers, is considered to be a safe and stable substitute for hydrazoic acid for the preparation of acyl azides from unreactive acid chlorides, and was used for the preparation of ethyl 4-etho~ythiophen-3-carbamate.~~~ From 2-nitrothiophen-2-carbonyl azide, t-butyl 5-nitrothiophen-2-carbamate and 2-amino-5-nitrothiophenhave been prepared.8' 3-Aminothiophen has been prepared from thiophen-3carboxylic acid via isopropyl 3-thienylcarbamate. It was demonstrated that the instability of 3-aminothiophen was due to polymerization via di(3thieny1)amine and tri(3-thien~l)amine.~~' Selective hydrolysis of (146), followed by Curtius reaction, was used for the preparation of ( 147).233 Some t-butyl 4-methoxy-2-thienylcarbamates have also been prepared.248 From (147) and analogous methoxy derivatives, the hydrazine derivatives were prepared by reaction with o-(p-nitrobenzoy1)hydroxylamine and sodium hydride in DMF.233* 248 N-Alkylated derivatives of acylaminothiophencarboxylic acid appear to be of medicinal interest ?49 * 250

242

243

244 245

A. Arcoria, F. P. Ballistreri, G. Musumarra, and G. A. Tomaselli, J. Chem. Soc.. Perkin Trans. 2, 1981,221. F. P. Ballistreri, k Cantone, E. Maccarone, G. A. Tomaselli, and M. Tripolone, J. Chem. SOC.,Perkin Trans. 2, 1981,438. F. P. Ballistrera and G. A. Tomaselli, J. Heterocycl. Chem., 1981, 18, 1229. D. Binder, C. R. Noe, F. Geissler, and F. Hillebrand, Arch. Pharm. (Weinheim, Ger.), 1981, 314, 564.

246 141 248 249

J. D. Warren and J. B. Press, Synth. Commun., 1980, 10, 107. 'S. Rault, M. Cugnon de Servricourt, and M. Robba, Recl. Trav. Chim. Pays-Bas, 1982, 101, 205. D. Binder, B. C. Prager, and C. R. Noe, J. Chem. Res. (S), 1981, 140. B. P. Clark, W. B. Jamieson, W. J. Ross, A. Todd, and J. P. Verge, Br. P. 1598 900, 1981.

H. H. Lautenschlaeger, H. Betzing, J. Winkelmann, M. Probst, and B. Stoll, Ger. Offen. 3 020 575, 1981.


101

The reaction of (148) with glycol and hydrogen peroxide gave (149).251 Compound (19b) has been reduced with LiAlH4 to the corresponding alcohol, which was converted into the aldehyde and bromomethyl and aminomethyl derivatives that are of pharmaceutical interest.42 A mild method for the hydrolysis and decarboxylation of various amides of methyl 3-aminothiophen2-carboxylates has been developed.252 Thermal decomposition of (1 50) led to cleavage of the thiophen ring, with extrusion of sulphur and formation of the isothiazole (15 1).253

H (148) R = CN or COOEt

H (149)

Reactives of Side-Chains of Monocyclic Thiophens. - The rate constants for the esterification of some 3-, 4-, and 5-substituted thiophen-2-carboxylic and of some 2- and 4-substituted thiophen-3-carboxylic acids2” with diazodiphenylmethane in methanol solution have been measured, and linear correlations gave information about the transmission of substituent effects. The rates of alkaline hydrolysis of ethyl thiophen-2-carboxylate in ethanol-water and DMSO-water media have been measured and compared with those of other heterocyclic esters.256 The kinetics of iodination of 2acetylthiophen in methanol-water, using different carboxylate buffers, have been Basicity constants have been measured for P(2-thienyl)acrylamides and compared with those of the corresponding benzene and furan derivatives .258 The acidity constants of (E)a-phenyl-P-(2 -thieny1)acrylic acids and analogous furan-, selenophen-, and pyridine-substituted compounds have been measured, and have been rationalized by an equation involving separate contributions of polar, conjugative, and steric effects of the heterocycles.259 251 252 253

254

255 256

251

”* 259

H. Wamhoff, G. Hendrikx, and M. Ertas, Liebigs Ann. Chem., 1982,489. I. G. C. Coutts, M. Edwards, and D. J. Richards, Synthesis, 1981,487. C. J. Moody, C. W. Rees, and S. C. Tsoi, J. Chem. SOC.,Chem. Commun., 1981,5 5 0 . R. Noto, S. Buscemi, G. Consiglio, and D. Spinelli, J. He&rucycZ. Chem., 1981, 18, 735. G. Consiglio, D. Spinelli, S. Gronowitz, A-B. Hornfeldt, and R. Noto, Chem. Scr., 1982,19,46. G. V. Rao, M. Balakrishnan, N. Venkatasubramanian, P. V. Subramanian, and V. Subramanian, Indian J. Chem, Sect B , 1981,20, 793. N. Satyanarayana, P. R Rao, and E. V. Sundaram, Indian J. Chem., Sect. B , 1981, 20, 733. G. Alberghina, M. E. Amato, S. Fisichella, and S. Occhipinti, Gazz. Chirn. Ztul., 1981, 111,231. E. Maccarone, A. Mamo, G. Perrini, and M. Torre, J. Heterocycl. Chem., 1981,18,735.

Heterocyclic Chernistry

102

Reactions of Thiophen Aldehydes, Ketones, and Carboxylic Acids. - Numerous anils have been prepared from thiophencarbaldehydes wtih aromatic and heterocyclic amines, and products from their reaction with mercaptoacetic acid and diazomethane have been d e ~ c r i b e d . ~ ~ p-(Phenylsulphony1)'-~~~ benzoic acid, thenylidene hydrazides, and thenylidene hydrazides of p,p'diphenylsulphonyldicarboxylic acids have been synthesized; they show antibacterial activity.266* 267 Thiophen-2-carbaldehyde has been condensed with 2-methyl-3-nitrochromone in connection with work on 242-thienyl)pyrrolo [3,2-b][ 11 benzopyrans,268 and with 2-trimethylsiloxyfuran to give 2-thenylidene-4-b~tenolide.~~' It has been allowed to react with 2-fluoro-3pyridyl-lithium to yield the corresponding carbin01.~~'Further interest has been shown in chalcone-type derivatives that are obtained from thiophen~arbaldehydes~~' -273 and in their use in synthesis; e.g., for 2-amino-4-(2thieny1)pyridines through the reaction with ma lo no nit rile^.^^^ 5-Nitrothiophen-2-carbaldehyde has been condensed with amides of carboxymethanesulphonic acid to give (1 52).275 2-Acetylthiophens were condensed with (153) to give (154).276 Electrochemical hydrodimerization of thiophen-2-carbaldehyde via the anion radicals led only to a 10% yield of the pinacol; the same amount of

260

"'

262 26 3 264 265

266 267 268 269 2 70

M. S. K. Youssef, Croat, C h e m Acta, 1980, 53,453. M. S. K. Youssef, Rev. R o u m Chim., 1981, 26,471. M. S. K. Youssef and'Kh.M. Hassan, Rev. Roum. Chim., 1981, 26,81. W . D. Rudorf and M. Augustin, 2. Chem., 1982, 22, 255. M. S. K. Youssef, J. Chem Technol. Biotechnol., 1981, 31, 363. M. S. K. Youssef, Rev. R o u m C h i m , 1981, 26, 1005. A. Morait and A. Mavrodin, Farmacia (Bucharest), 1980, 28, 159. A. Morait and A. Mavrodin, Farmacia (Bucharest), 1980, 28,229. C. Paparao, K. V. Rao, and V. Sundaramurthy, Synthesis, 1981, 234. M. Asaoka, N. Yanagida, K. Ishibashi, and H. Takei, Tetrahedron L e t t , 1981, 22, 4269.

T. Gungor, F. Marsais, and G. Queguiner, J. Organomef Chem., 1981, 215,139. Yu. D. Churkin and L. V. Panfilova, USSR P. 802 282, 1981 (Otkrytiya, Izobret., Prom Obraztsy, Tovamye Znaki, 1981, 86). 2 7 2 N. Geum, F. Ghozland, J. P. Gorrichon, and P. Maroni, Bull. Soc. Pharm. Bordeaux,

271

1981, 120, 39. 273 274

275

276

E. Degny, S. Z. Zard, R. Pastor, and A. Cambon, Tetrahedron L e a , 1981, 22,2169. N. Latif, N. Mishriky, and N. S. Girgis, Indian J. Chem, Secf B y 1981, 20,147. D. R. Shridhar, C. V. Reddy Sastry, K. B. Lal, A. K. Manvah, G. S. Reddi, K. K. Bhopale, H. N. Tripathi, R. S. Khokhar, K. Tripathi, and G. S. T. !hi,Indian J. Chem, Sect. B, 1981, 20,234. A. I. Pavlyuchenko, E. I. Kovshev, and V. V. Titov, K h i m GeterotsikL Soedin., 1981, 85.


103

(155) was also obtained.277 However, another group found that, by adding small amounts of LiC104 to the reaction medium, the yield of 1,2-di(2thienyl)ethane-l,2-diolcould be increased to 80%.278 Two one-pot procedures for the conversion of thiophencarbaldehydes into the nitriles consist in treatment with nitroethane and pyridine hydrochloride279 or with hydroxylamine hydrochloride and N-methylpyrrolidone.280 2-Thenoylacetonitrile has been allowed to react with CS2 in the presence of sodium hydride to give the disodium salt (156), which was alkylated with various reagents.281 A very convenient method for the synthesis of (1 58) consists in the sidechain bromination of 2-thienyl ethyl ketone followed by reaction with sodium methoxide in methanol and with methanesulphonyl chloride in pyridine, which gave (157) in 88% yield. Treatment of (157) with calcium carbonate led to 1,2-rearrangement of the thienyl group to give (158).282 Metal complexes of ~yn-thiophen-2-aldoxime,~~~ thiophen-2-carbaldehyde 2-benzothia~olylhydrazone,~~~ and thiophen-2-carbaldehyde thiosemicarbahave been studied. The reaction of ethyl thiophen-2-carboxylate with triphenylphosphineCC14 gave (1 59), which upon acidic hydrolysis afforded the dichloromethyl ketone.286 2-Thenoyl chloride reacts with some piperazine derivatives.287 Trimethylsilyldiazomethane has been used as a safe reagent in the ArndtEistert reaction for the transformation of 2-thenoyl chloride into benzyl 2thienylacetate .288 Na'

-S

S- Na+

H OMe (157)

(155)

Me

(158) 277 278

2 79

280 281 282

283 284

28s 286 287

OE t (159)

V. P. Gul'tyai, L. M. Korotaeva, A. P. Rodionov, and A. M. Moiseenkov, Izv. Akad NaukSSSR, Ser. Khim., 1981, 1150. V. P. Gul'tyai, L. M. Korotaeva, A. S. Mendkovich, and I. V. Proskurovskaya, Izv. Akad. NaukSSSR, Ser. Khim., 1981, 834. D. Dauzonne, P. Demerseman, and R. Royer, Synthesis, 1981,739. P. Audoye, A. Gaset, and J. P. Gomchon, Chimia, 1982, 36,4. W.-D. Rudorf and M. Augustin, Phosphorus Sulfur, 1981,9,329. G.-I. Tsuchihashi, K. Kitajima, and S. Mitamura, Tefmhedron Lett., 1981, 22,4305. H. B. Singh, D. Singh, R K. Negi, and V. K. Gupta, J. Inorg. Nucl. Chem., 1981, 43, 1915. T . Odashima and H. Ishii, Nippon Kagaku Kaishi, 1982,425. C. G. R. Nair and K. K. Aravindakshan, J. Inst. Chem. (India), 1981, 53, 295. M. Suda and A. Fukushima, Tetrahedron Lett., 1981, 22, 759. G. Drugarin, I. Jianu, P. Geita, and A. Drugarin, Pharmazie, 1981, 36, 709. T. Aoyama and T. Shioiri, C h e m P h a m Bull., 1981,29, 3249.

104

Heterocyclic Chemisliy

Reactions of Vinylthiophens and Related Compounds.- 2-Aroyl-5-vinylthiophens react with triphenylphosphine, palladium chloride, and carbon monoxide to give 2-(5-aroyl-2-thienyl)propionic acid.289 Cycloaddition of sulphene, from methanesulphonyl chloride and triethylamine, to 2(adimethylaminoviny1)thiophen gave (1 60).290 The synthesis of some substituted 3-(2-thienyl)acryloylamino-acids has been described.291 Some reactions of ~-chloro-~(2-thienyl)vinylphosphonicacid dichlorides have been ~ t u d i e d . 2 ~ ~

Reactions at Benzylic Positions. - The catalytic oxidation, using a cobalt bromide catalyst, of 2,5-dimethylthiophen to the d i a l d e h ~ d e ,of~ ~ 3-methyl~ 2-ethylthiophen to 2-acetyl-3-methylthiophen and 1-(3-methyl-2-thienyl)ethyl a ~ e t a t e , ~ "of the four isomeric methyl acetothienones to the corand of 2-acetoxymethy1thioresponding acetylthiophencarboxylic phen to thiophen-2-carboxylic acid296 has been reported. The Wittig reaction between 2- and 3-thenyltriphenylphosphonium salts and crocetin dialdehyde has been used for the synthesis of carotenoid analogues with terminal thiophen rings.297 The Wittig reaction between diethyl 2-thenylphosphonate and 2-acetylnaphthalene was the first step in the synthesis of pyreno [ b ]t h i 0 ~ h e n s . l ~ ~ 2-Thenyl chloride and 3-thenyl bromide have been allowed to react with ethylglycine to give N-(2-thenyl)- and N-(3-thenyl)-glycine, and have been used for an alternative synthesis of tic10pidine.l~~The reactions of 2-thenyl chloride and of 2,5-dichloro-3-thenyl chloride with the lithium enolate of ethyl cyclohexanecarboxylate gave (50) and (5 1).13' Similarly, (67) was obtained from 2-(2-thienyl)ethyl bromide .139 2-Thenyl ally1 ether, upon treatment with butyl-lithium at - 3OoC, underwent a [2,3] -sigmatropic rearrangement to give 4-(2-thenyl)but- 1-en-4-01.~~' Esters of 3,4,5-trichloro-2-hydroxymethylthiophen have been prepared?99 Jpn. Kokai Tokkyo Koho 82 32 279,1982. L. N. Koikov, P. B. Terent'ev, and N. S. Kulikov, Zh. Org. Khim., 1981, 17, 1087. A. M. El-Naggar, M. N. Aboul-Enein, and A. A. Makhlouf, Glm. Hem. Drus Beograd, 1981,46,545. 2 9 2 G. F. Nazvanova, V. V. Moskva, T. Sh. Sitdikova, and F. A. Kashfarova,Izv. Vyssh. Ucheb. Zaved. K h i m Khim. Tekhnol., 1982, 25,37. 293 I. Iovel, Yu. Sh. Gol'dberg and M. V. Shimanskaya, USSR P. 883041, 1981 (Otkrytiya, Izobref, R o m Obraztsy, Tovamye Znaki, 1981, 102). 294 M. N. Volkov and 0. k Kazakova, Khim Geterotsikl. Soedin., 1981,758. 295 0.A. Kazakova, M. N. Volkov, and P. A. Konstantinov, Zh. Org. Khim., 1981, 17, 511. 296 T. V. Shchedrinskaya, A. A. Leichenko, and M. N. Volkov, Zh. Org. Khim., 1981, 17,2177. 197 H. R. Brahmana, K. Katsuyama, J. Inanaga, T. Katsuki, and M. Yamaguchi, Tetrahedron Lett., 1981, 22, 1695. 298 A. V. Anisimov, L. V. Mozhaeva, and E. A. Viktorova, Zh. Org. Khim., 1981, 17, 1560. 299 S. G. Kon'kova, A. A. Safaryan, and A. N. Akopyan, Arm. Khim Zh., 1981, 34, 790. 291


105

Various Reactions in the Side-Chains of Thiophens. - The preparation of various N-substituted thieno [3,2-fl morphans from 2,5-dimethylthieno [3,2fl morphan has been de~cribed.~" Several thiophen isosteres of protoberberine alkaloids have been prepared, starting from amides between 3thienylacetic acid and substituted 0-phenylethylamine or /3-(3-thienyl)ethylamine, followed by classical cyclization to dihydroisoquinolines, reduction to the tetrahydro system, and Mannich-type reaction with f~rmaldehyde.~'~ A new mild and convenient method for esterification of a-keto-acids has been applied to 2-thienylglyoxylic acid.302 A convenient method for the resolution of &(2-thienyl)alanine has been described.303 Macrocyclic Thiophens. - Novel macrocyclic Schiff-bases (1 6 l), containing thiophen, have been prepared by the non-template condensation of a,wamino-ethers with thiophen-2,5-dicarbaldehyde. Silver complexes were prepared and crystal structures were determined both for some macrocycles and for a silver complex.304 In attempts to prepare bridged thia[l7]annulenes, (1 62) was prepared through the reaction of 2,5-dichloromethylthiophen with p-carb oxyt oluene-cu-t hiol. Transformation of the carb oxyl groups of (162) into bromomethyl, followed by reaction with sodium sulphide, gave (1 63). The Wittig reaction of 3,4-diformyl-2,5-dimethylthiophen

S

T

7-

S

6 b AT-,

(161) (163) 300

J. Bosch, M. Alvarez, and R. Granados, Anal. Quim, 1981, 77,346. 301 S. Jeganathan and M. Srinivasan, Phosphorus Sulfur, 1 981, 11, 12 5. 302 J. M. Domagala, Tetrahedron Lett., 1980, 21,4997. 303 A. W. Lipkowski and G. Fluoret, Pol. J. Chem., 1980, 54,2225. 304 N. A, Bailey, M. M. Eddy, D. E. Fenton, G. Jones, S. Moss, and A. Mukhopadhyay, J. Chem SOC.,Chem. Commun., 1981,628.

Heterocyclic Chemisw

106

with pent-4-ynyltriphenylphosphoniumylide gave (1 64), which by Glazer coupling was transformed into (165). It could not be conclusively established that prototropic rearrangement with potassium t-butoxide in t-butyl alcohol gave (166).305 ~

Melfs]MeJ I - (165)

7'); (CH =CH)

6

(166)

Reaction at Sulphur: Thiophen Dioxides. - The stable S-ylide (167) was formed, in 40% yield, in the reaction of 2-isobutenylthiophen with dimethyl diazomalonate in the presence of rhodium acetate .306 The transient thiophen 1,l -dioxide that is formed on treatment of 3,4-dibromotetrahydrothiophen 1,l-dioxide with base gave mono- and di-adducts such as (168) - (1 72) in the presence of 1,3-dipoles such as N-a-diphenyl nitrone and mesitonitrile oxide. The structures of the adducts were partly proven by X-ray cry~tallography.~~' The reaction of 13C-labelledtransient thiophen 1,l -dioxide with 6-dimethylaminofulvene has been utilized for the preparation of 13C-labelleda ~ u l e n e . ~ ' ~ Rate constants for the reaction of 2,3,4,5-tetrachlorothiophen1,l -dioxide with para-substituted styrenes have been measured, and MO calculations on this type of cycloaddition have been carried The reaction of tetrachlorothiophen 1,l-dioxide with (172) led to (173), having an iceane

T. M. Brown, W. Carruthers, and M. G. Pellatt, J. Chem. Soc., Perkin Trans. 1 , 1982, 483. ' 0 6 V. M. Shostakovskii, A. E. Vasil'vitskii, V. L. Zlatkina, and 0. M. Nefedov, Izv. Akad. NaukSSSR, Ser. Khim., 1980,2180. '07 A. Bened, R. Duran, D. Pioch, P. Geneste, J. P. Declercq, G. Germain, J. Rambaud, and R. Roques, J. Org. Chem., 1981,46,3502. 308 K.-P. Zeller and S. Berger, 2. Namrforsch., Teil. B y1981, 36, 858. 309 K. Kanematsu, K. Harano, and H. Dantsuji, Heterocycles, 1981, 16, 1145.

'05


107

skeleton.310 It was found that 2,5-dimethyl-3-chlorothiophen1,l-dioxide reacted with butyl-lithium via addition to the 4,5-position to give a mixture of the enynes (174a) and (174b), after ring-opening and loss of sulphur dioxide. With the corresponding 3-bromo-derivative, a competing halogenmetal exchange occurs, followed by ring-opening to a vinyl sulphinate, which was trapped as (1 75) with benzyl br~mide.~"Nitration of 3,4-dimethylthiophen 1,l-dioxide with N204in chloroform gave 23% of the 2,5-dinitro-3,4dimethylthiophen 1,l-dioxide, which gave (176) when refluxed in ~ y l e n e . ~ " ~ Theoretical calculations on the barrier to inversion in thiophen 1-oxide have been carried out and compared with results for 1,2,5-thiadiazole 1oxides.312 The addition of dichlorocarbene to 2,Sdihydrothiophen 1,ldioxides has been used for the synthesis of (177), and further reactions of this system have been investigated.313 The photocycloaddition of 2,sdihydro-3-methylthiophen 1,l-dioxide to citraconic anhydride gave (178), which was transformed into the corresponding dimethyl ester. Upon heating, the ester eliminated SOz to give (1 79), which, under the reaction conditions, underwent Cope rearrangement to the geraniol derivative (180).314 Upon

flMe

02NCH=CH-CH=

R1 1

I I

Me

M e f M eSOOCH 2Ph

2

(174) a; R = M e , R = Bu 2 b ; R1= Bu, R = M e

(177)

Me

(176)

(175)

(178)

CHN02

0

Me

(179) 310 31 1

D. P. G. Hamon and P. R. Spurr, J. Chem Soc., Chem. Commun., 1982,372.

J. 0.Karlsson, S. Gronowitz, and A. Hallberg, Actu Chem. Scund., Ser. B, 1982,

36, 341. V. Titova, V. M. Berestovitskaya, and V. V. Perekalin, Metody Sint., Str. Khim. Prevrushch. Nitrosoedin., 1980, 37. 312 J. S. Amato, S. Karady, R. A. Reamer, H. B. Schlegel, J. P. Springer, and L. M. Weinstock, J. A m C h e m SOC.,1982, 104,1375. Y . Gaoni,J. Org. Chem., 1981, 46,4502. 314 J. R. Williams and C. Lin, J. Chem. SOC.,Chem Commun., 1981,752.

' " ' M .

108


treatment of 2,5dihydrothiophen 1-oxide and 2,s-dihydrothiophen 1,ldioxide with strong bases, the resulting anions underwent ring-opening to buta-l,3-dienylsulphenateand buta-l,3-dienylsulphinates,which could be alk~lated.~"Nitration of 3-methyl-4,5-dihydrothiophen 1,l -dioxide occurred in the 2-position, while the 3-phenyl analogue reacted in the p a r a - p ~ s i t i o n . ~ ' ~ The reaction of salts of dithiocarbamic acid with 3-substituted 4J-dihydrothiophen 1,l-dioxides or 3,4-disubstituted thiophen 1,l-dioxides gave (1 82) via (181).317 Treatment of (183) with thionyl chloride gave (184), which underwent cycloaddition with ~yclopentadiene.~'~ The chlorination of cis2,s-diphenyltetrahydrothiophen 1,l-dioxide occurred with inversion to give the trans-2,5-dichloro-2,5-diphenylthiophen 1 , l-dioxide, as proven by X-ray ~rystallography.~'~ Some other aspects of the chemistry and use of dihydroand tetrahydro-thiophen 1,l -dioxide320-326 and of sulphilimine and related derivatives327 - 329 have been published.

Di- and Tetra-hydrothiophens.- Direction control in the preparation of the very useful 3-oxotetrahydrothiophenshas been achieved by using half-thiol 315 316

R. L. Crumbieand D. D. Ridley, Aust. J. Chem., 1981, 34, 1017. M. V. Titova, V. M. Berestovitskaya, and V. V. Perekalin, Zh. Org. Khim., 1981, 17, 1322.

317

T. E. Bezmenova, G. I. Khaskin, V. I. Slutskii, P. G. Dul'nev, L. N. Zakharov, V. I. Kulishov, and Yu. T. Struchkov, Khim. Geteroaikl. Soedin., 1981, 907. 318 G. A. Tolstikov, N. N. Novitskaya, and E. E. Shul'ts, Zh. Org. Khim., 1981, 17, 1111. 319

320

321 322

323

324

32s 326 327

328 329

S. E. Lauritzen, C. RQmmhg, and L. SkattebQl, Acta Chem. Scand., Ser. B , 1981, 35, 263. S. M. Lukashov, P. I. Parkhomenko, Yu. N. Usenko, and T. E. Bezmenova, USSR P. 522 605, 1981 (Otkrytiya, Izobret., Prom. Obraztsy, Tovamye Znaki, 1981, 2 86). P. I. Parkhomenko, Ukr. Khim. Zh. (Russ. E d ) , 1980,46, 1294. P. G. Dul'nev and T. E. Bezmenova, USSR P. 794012, 1981 (Otkrytiya, Izobret, Prom. Obmztsy, Tovamye Znaki, 1981, 95). A. Ts. Malkhasyan, E. M. Asatryan, S. M. Mirakyan, and G. T. Martirosyan, USSR P. 810696, 1981 (Otkrytiya, Izobret, Prom. Obraztsy, Tovamye Znaki, 1981, 92).

R. A. Dorofeeva, T. E. Bezmenova, T. N. Arkhipova, and T. I. Piskunova, USSR P. 787 409,180 (Otkrytiya, Izobret, Prom. Obraztsy, Tovamye Znaki, 1980,96). L. N. Shkaraputa, L. A. Tishchenko, V. T. Sklydr, I. A. Manza, and A. G. Gordienko, Khim TekhnoL (Kiev), 1981, 32. F. Mauer, I. Hammann, and B. Homeyer, Ger. Offen. 3 003 019, 1981. G. Abe and J. M. Shreeve, J. Chem. Soc., Chem. Commun., 1981,242. T. Abe and J. M. Shreeve, Inorg. Chem., 1981, 20, 2432. T. Abe and J. M. Shreeve, Inorg. Chem., 1981, 20,2894.


109

diesters in the Dieckmann c y c l i ~ a t i o n Improved .~~ methods for the synthesis of 3-oxo-4-methoxycarb onyl- and 3-oxo-2-met hoxycarbonyl-te t rahy dr othiophen, by carrying out the reaction of methyl thioglycollate with methyl acrylate under different conditions, have been described.331 The condensation of methyl thioglycollate with cyclohexenone gave (1 SS), and its further chemistry and stereochemistry were investigated.332 The Tic&-catalysed photochemical reaction of (186) in methanol gave ( 187).333The carbene that was generated from (188) by treatment with MeLi gave ( 189).334 Irradiation of (190) in benzene gave 63%of diphenyl disulphide and 49% of (19 1). Brief irradiation of (190) in acetonitrile gave, however, (192) as the main p r ~ d u c t . ~ ~From ' , ~ ~the ~ reactive 1,3-dipole (193), formed in the reaction between diazomethane and thiobenzophenone, the di- and tetra-hydrothiophens (194) - (196) were obtained by reaction with the appropriate d i p ~ l a r o p h i l e .Evidence ~~~ for the existence of 2,2,5,5-tetramethyl-1-thia-

" >r d ) S B

CHMe Me

Me

(189)

(193)

( 194)

OH

Ph

(195) X = 0 , N M e , or N P h Y. Yamada, T. Ishii, M. Kimura, and K. Hosaka, Tetrahedron Lett., 1981, 22, 1353. H.-J. Liu and T. K. Ngooi, Can. J. Chem., 1982, 60,437. P. N. Confalone, E. Baggiolini, B. Hennessy, G. Pizzolato, and M. R. Uskokovik, J. Org. Chem., 1981, 46,4923. 333 K. Saito, H. Yuki, T. Shimada, and T. Sato, Can. J. Chem., 1981, 59, 1722. 3 3 4 M. S. Baird, J. Chem. Res. (S), 1981, 352. 335 T . Sasaki, K. Hayakawa, and S. Nishida, Tetrahedron Lett., 1980, 21, 3903. 336 T. Sasaki, K. Hayakawa, and S. Nishida, Tetrahedron, 1982, 38, 7 5 . 337 I. Kalwinsch, L. Xingva, J. Gottstein, and R. Huisgen, J. Am. Chem. SOC., 1981, 103, 7032. 331

332


110

cyclopent-3-yne as a reactive intermediate has been presented. It was trapped as a cyclo-adduct with phenyl azide and 2 , 5 - d i m e t h y l f ~ r a nThe . ~ ~sulphonium ~ ylide (197) can be isolated, since its [3,2] -sigmatropic rearrangement is inhibited by steric strain. It reacts in a bimolecular fashion to give butadiene, 2,5-dihydrothiophen, and (198).339 Treatment of (199) with base led to (200) via a ring-opening reaction.340 Tetrahydrothiophens have been prepared from dithiotetritols.'' A method for condensing various salicylaldehydes with y-thiobutyrolactone has been described.342 A detailed investigation, by i.r. and n.m.r. spectroscopy, of the tautomerism of 2- and 4-ethoxycarbonylthiolate-3-ones has been carried out .M3 Sulphur analogues of prostaglandins that contain di- and tetra-hydrothiophen rings, such as the sulphur analogue of A6-PGIIm and (52)- and (5@-6,9thiapro~tacycline,~~ have been described. A series of methylated derivatives of 2-thiobiotin has been synthesized and their i.r. and their 'H and I3C n.m.r. spectra have been investigated.% Other aspects of di- and tetrahydrothiophens are discussed in refs. 347 - 350.

+

cdyJMe (199)

338

J. M. Bolster and R. M. Kellogg, J. Am. Chem. SOC., 1981, 103,2868. S. Mageswaran, W. D. Ollis, and I. 0. Sutherland, J. Chem. Soc., Perkin Trans. 1 , 1981,1953. 340 H. J. Federsel and G. Merenyi, J. Org. Chem., 1981, 46,4724. 341 R. A. Sanchez, Synthesis, 1982,148. 3 4 2 G. A. Miller and N. D. Heindel, J. Org. Chem., 1981, 46,4751. 343 F. DUUS,Tetrahedron, 1981, 37,2633. 344 H. Yokomori, Y. Torisawa, M. Shibasaki, and S. Ikegami, Heterocycles, 1982, 18, 251. 34 5 K. C. Nicolaou, W. E. Barnette, and R. L. Magolda, J. Am. Chem. SOC., 1981, 103 3472. 346 H. Haster and H. Kohn, J. HeterocycL Chem., 1981, 18, 1425. 3 4 7 J. Thiem and H. P. Wessel, Liebigs Ann. Chem., 1982, 607. 348 C. F. Service and A. E. Tipping, J. Fluorine Chem., 1982, 20, 135. 349 J. W. Lown, R. R. Koganty, and A. V. Joshua, J. Or& Chem., 1982, 47, 2027. 3 5 0 W. Kunz, Eur. Pat. Appl. 46 138, 1982. 339


111

Arylthiophens and Di- and Poly-heterocycles.- The reaction of (201) with sulphur gave (202) in 45% yield.351 Treatment of the hydrazone (203) with PPA at 110°C gave (204), the structure of which was proven by desulphurization of a degradation product with Raney nickel. From the simple phenylhydrazone of ethyl 2-thienyl glyoxylate, (205) and (206) were obtained in a 7 : 3 ratio. Authentic (206) was prepared via the Friedel-Crafts reaction of 5(p-nitropheny1)thiophen with oxalyl ester 5-Substituted 2,3diarylthi~phens~’~ and 2- [4(3-methyl-:!-thienyl)phenyl] propionic have been synthesized as anti-inflammatory agents. The reactions of bithienyls in the presence of molybdenum and tungsten halides have been in~estigated.~”Some unsaturated bithienyl ketones have been prepared via condensation of 2-formyl-5‘-methyl-2,2’-bithienyl and 2formyl-5’ethyl-2,2’-bithienyl with methyl ketones.356 3,2’: 5‘,3”-Terthiophen and other terthienyls have been prepared by converting the appropriate t hiophencarbaldehyde into et hynylthiophen, followed by coupling to dithienylbutadiyne and ring-closure of the middle ring through reaction with sodium s ~ l p h i d e . ~ ’ ~

(205)

V. Ya. Sosnovskikh, Zh. Org. Khim., 1981, 17, 1777. 3 5 2 R. Fusco and F. Sannicol6, J. Org. Chem., 1982, 47, 1691. 3s3 S. C. Cherkofsky, Eur. Pat. Appl. 24 042, 1981. 3 54 T. Kodama, M. Nakabayashi, I. Watanabe, H. Hirano, N. Abe. K. Tanaka, and H. Arai, US P. 4 230 719,1980. 3 5 5 M. G. Voronkov, V. Z. Annenkova, N. I. Andreeva, V. M. Annenkova, and K. A. Abzaeva, Izv. Sib. Otd. Akad. NaukSSSR, Ser. Khim. Nauk, 1981, No. 3 , p. 147. 356 Yu. D. Churkin, L. V. Panfilova, E. L. Boreko, M. M. Timofeew, and V. I. Votyakov, Khim-Farm. Zh., 1982, 16, 167. 3 5 7 J.-P. Beny, S. N. Dhawan, J. Kagan, and S. Sundlass, J. Org. Chem., 1982,47, 2201. 351

112


The Vilsmeier formylation of 2- and 3(2-pyrrolyl)thiophen occurs in the free a-pyrrolic position. If this position is blocked, as in 2- and 3(5methoxycarbonylpyrrolyl)thiophen,formylation occurs both in the 5 -position of the thiophen ring and the 3-position of the pyrrole ring, and in the 2position of the thiophen ring and the 3-position of the pyrrole ring, respectively .358 Starting from 2-(1-pyrrolyl)thiophen-3-carboxylic acid the corresponding azide gave (207) upon Curtius rearrangement. From the 3amino-derivative, (208) was prepared in several steps.359 Similar work has also been carried out with 3 4 1-pyrrolyl)thiophen-2-carboxylic acid, which also smoothly underwent Vilsmeier formylation in the 2-position of the pyrrole ring.360 Compounds (209), prepared through the reaction of a-acetylenic ketones with p-mercaptoethylamine in the presence of base, gave (210) and (2 1 1), respectively, upon reaction with hydrazine and h y d r ~ x y l a m i n e . ~ ~ ~ Electrophilic nitration of thienylpyridazines has been studied in By the addition of 2- and 3-thienyl-lithium to quinoxaline, mono- and dithienyl-substituted quinoxalines have been preparedl” and their lithiation and self-addition further investigated.362 From 1,s -diketones containing thienyl and fury1 substituents, pyrylium and thiopyrylium salts such as (2 12) have been prepared.363 13C N.m.r. spectra of compounds related to (212) have been i n ~ e s t i g a t e d .1,5-Diketones ~~ were also used for the synthesis of Ph

0

I II S-C=CH-C NH-C=CH

I Ph

-C

II

0

Ph

( 2 1 2 ) X = 0 or S 358 359

360 36 1

362

363 364

J.-P. Boukou-Poba, M. Farnier, and R. Guilard, Can. J. Chem., 1981,59,2962. S. Rault, M. Cugnon de SBvricourt, N.-H.Dung, and M. Robba, J. HeterocycL Chem., 1981, 18,739. Y. Effi, M. Cugnon de S h i c o u r t , S. Rault, and M. Robba, Heterocycles, 1981, 16, 1519. T. E. Glotova, A. S. Nakhmanovish, G. G. Skvortsova, T. N. Komarova, I. D. Kalikhman, and M. G. Voronkov, Zh. Org. Khim., 1981, 17,749. T. Kauffmann and R. Otter, Chem. Ber., 1982, 115, 1825. V. G. Kharchenko, E. V. Burov, and V. A. Sedavkina, Khim. Geterotsikl. Soedin., 1981, 1604. k R. Katritzky, J. M. Lloyd, and R. C. Patel, Chem. Scr., 1981, 18,256.


113

2-(2-thienyl)hydroquinolines and related compounds.365 Several 2 -amino-3cyano-4,6-di(thienyl) -substit ut ed pyridines and 3-cyan04 ,6-di(thieny1)substituted pyridin-2-ones have been prepared by allowing the appropriate propenones to react with malononitrile and ethyl cyanoacetate , respect i ~ e l y Some . ~ ~ ~2(2-thienyl)chromones have been prepared from hydroxyacet ophenones and t hio phen-2 -carbaldehyde through oxidative cy clization ?7 Several 5 ‘(t hienyl) -substituted 3-methyl-4-pyr azolylcarb oxylic acid derivatives have been prepared by closure of the pyrazolyl ring, by the reaction of 2aroyl-3-methylaminobut-2-enoic acid esters with h y d r a ~ i n e Starting . ~ ~ ~ from (213), (214) was prepared by condensation with CS2, followed by alkylation with ethyl bromoacetate and methyl iodide and then r i n g - c l ~ s u r e .Electro~~~ philic substitution reactions of 1-methyl-2-5-[S’-methyl-2‘-(2-thienyl)] benzimidazoles have been studied.370 Ethyl p-alkylphenylthiophen-2carboxylates and some related thienylpyridines have been prepared and their liquid-crystalline properties studied.37’ The mass spectra of some formyl derivatives of 2(2‘-thienyl)indole have been elucidated.372 The electroreduction of 4-(2-thienyl)quinoxaline has been further in~estigated.~’~ The preparation of 2,5-bis(benzoxazolyl)thiophens from thiophen-2,5-dicarboxylic acid has been patented .374- 375

X = NH, N M e , 0 , or S

(214)

Naturally Occurring Thiophens. - A review on the formation of heterocyclic compounds, including thiophen derivatives, by enzymic and non-enzymic browning in relation to food flavour has been Some thiophens have been found as trace constituents in the essential oil from Thymus capitatus.377 From steam-distilled hop oils, 3-(4-methylpent-3-enyl)thiophen T. V. Zabolotnova, V. A. Kaminskii, and M. N. Tilichenko, Khim. Geterotsikl. Soedin., 1981,471. 366 N. Latif, F. M. Asaad, and N. S. Girgis, Indian J. Chem., Sect. B , 1981,20,463. 36 7 D. P. Sarbaggya, K. Rangachari, k K. D. Mazurndar, and K D. Banerji, J. Indian Chem SOC.,1981,58,196. 368 P. Plath and W. Rohr, Synthesis, 1982,318. 36 9 M. Augustin and W. Dolling, 2. Chem., 1981, 21,216. 370 M. M. El’chaninov, A. M. Simonov, V. P. Kosenko, and L. Ya. Oleinikova, Khim. Geterotsikl. Soedin., 1981, 520. 371 L. A. Karamysheva, E. I. Kovshev, A. I. Paviuchenko, K. V. Roitman, V. V. Titov, S. I. Torgova, and M. F. Grebenkin,Mol. Crysf. Liq. Cryst., 1981,67,241. 372 B. S. Holla and S. Y. h b e k a r , J. Indian Chem. SOC.,1981, 58,400. 313 T. P. Devi, C. Kalidas, and C. S. Venkatachalam, Bull. Chem SOC.Jpn., 1982, 5 5 , 286. 3 7 4 W. Schreiber, Eur. Pat. Appl. 31 296, 1981. 375 S. Kell, W. Kipping, B. Noll, W. Rauner, H. Weinelt, H. Krausse, and R. Fischer, Ger. (East) P. 147 667,1981. 376 G. Vernin and J. Metzger, Bull. SOC.Chim. Belg., 1981,90, 553. 377 V. P. Papageorgiou and N. Argyriadou, Phytochemistry, 1981, 20,2295. 365

114

He terocycZic Chemistry

has been isolated.378 The new naturally occurring thiophens (21 5) and (216) have been isolated from Pterocaulon virgatum. 379 Using H-labelled thiophens, the biosynthesis of terthienyl and other naturally occurring thiophens in Tagetes patula was studied.380 The identification and analyses of thiophens from oil and coal have been d e s ~ r i b e d . ~ ~ ' - ~ ~ ~

Thiophen Analogues of Steroids. - A 6a-substituted optically pure steroid with thiophen as the A ring has been prepared via asymmetric induction. The absolute configurations of the precursors and of the cyclized products were determined by c.d.384 Thiophens of Pharmacological Interest. - There has been an almost explosive development in the number of papers and patents in this field, and the space that is available allows only a very brief summary. However, most references will be included, for the benefit of those interested in this field. Therapy of the Central Nervous System. Many new tricyclic neuroleptic thiophens have been prepared,14'* 38s -388 such as (2 17)38s and (2 18).386 Numerous diazepine analogues have been prepared as t ranquillizers ,389 -396

378

J. A. Elvidge, S. P. Jones, and T. L. Peppard, J. Chem. SOC., Perkin Trans. 1 , 1982, 1089. 3 79 F. Bohlmann, W.-R. Abraham, R. M. King, and H. Robinson, Phytochemistry, 1981, 20,825. 380 R. Jente, G.A. Olatunji, and F. Bosold, Phytochemistry, 1981, 20,2169. 381 D. Bodzek, K. Bularz, M. Sobkowiak, and G. Alexander, Koks, Smola, Gaz., 1981, 26, 101. 382 N. K. Lyapina, M. A. Parfenova, V. S. Nikitina, A. A. Vol'tsov, and L. A. Mel'nikova, Khim. TekhnoL Topl Masel, 1982,27. 383 A. Attar and F. Dupuis, Adv. Chem. Ser., 1981, 192,239. 384 A.. k Macco and H. M. Buck, J. Org. Chem., 1981, 46,2655. 385 E. Arribas Mocoroa and S. Vega Noverola, Span. P. 497 896, 1981. 386 V. Figala, R. Riedel, G. Rainer, and K. Klemm, Eur. Pat. Appl. 39 519, 1981. 387 E. Arribas Mocoroa and S. Vega Noverola, Span. P. 497 895,-1981. 388 E. Arribas Mocoroa and S. Vega Noverola, Span. P. 497 898, 1981. 389 Jpn. Kokai Tokkyo Koho 80 143 977,1980. 390 T. Masuko, Jpn. Kokai Tokkyo Koho 80 143 990,1980. 391 J. K. Chakrabarti and D. E. Tupper, Br. P. 1577 743,1980. 392 T. Masuko, Jpn. Kokai Tokkyo Koho 80 143 988,1980. 393 F. Hunziker, R. Fischer, P. Kipfer, J. Schmutz, H. R. Buerki, E. Eichenberger, and T. G. White, Eur. J. Med. Chem. - Chim. Ther., 1981, 16, 391. 394 K H. Weber, A. Bauer, P. Danneberg, and F. J. Kuhn, US P. 4 263 310, 1981. 395 M. Velasco, F. Velasco, C. Cepeda, R. Romo, and M. A. Perez-Toledo, Neurophamacology, 1981, 20,461. 396 W. Sinenberg and 0. Spohn, Ger. Offen. 2 940 737, 1981.


115

and 2-phenylamino-2-imidazolinesas analgesic^;^'^ some thienopyridinopyrazines showed potentiation of p e n t ~ b a r b i t a l . 399 ~~~'

Pharmacodynamic Agents. Compounds that are active as adrenergic receptor blockers and antiarhythmics, such as piperidine derivatives of 3-hydroxythiophen-2-carboxylic acid,400 have been prepared 8 0 ' Basic dithienyl derivatives have been prepared as vasodilator^^^-^^^ and thienylpropanolamine acids as hypotensive agents.'13 Thenoylphenoxyacetic a ~ i d s ~ ~ ~ and other types of thiophen derivative have attracted continued Therapy of Metabolic Diseases. Many very varied thiophen derivatives, such as 2- [4-(2-thenoyl)phenyl] propionic 2,6-di-t-butyl-4-thenoylphenols?23 4H-5,6-dihydro cy clopent a [ b] t hiophen-4-carb oxy lic acid ,424 and

391

H. Staehle, H. Koeppe, W. Kummer, W. Kobinger, and K. Stockhaus, Ger. Offen. 2 951 601,1981. 3 9 8 D. Frehel and J. P. Maffrand, Fr. Demande 2 457 869, 1980. 399 R. Boigegrain and J. P. Maffrand, Fr. Demande 2 463 145, 1981. 400 F. F. Frickel, G. von Philipsborn, C. D. Mueller, and D. Lenke, Ger. Offen. 2 950 064, 1981. 4 0 1 H. Tucker, J. Me& Chem., 1981, 24,1364. 402 S. Carboni, A. da Settimo, P.L. Ferrarini, G. Primofiore, 0. Livi, V. Menichetti, M. del Tacca, E. Martinotti, C. Bernardini, and A. Bertelli, Eur. J. Med Chem. -Chim. Ther., 1982, 17, 159. 403 G. Bobowski and J. M. Gottlieb, J. Heterocycl. Chem., 1982, 19,21. 404 W. L. Matier and W. E. Kreighbaum, U S P. 4 321 398, 1982. 40 5 R. I. Mrongovius, P. Ghosh, A. G. Bolt, and B. Temai, Arzneim.-Fomch., 1981, 31, 1718. 406 J. Buendia and L. Taliani, Fr. Demande 2 646 952, 1981. 407 Belg. P. 886471,1981. 408 S. Kubo, K. Morikawa, M. Yamazaki, I. Matsubara, and H. Kato, Nippon Yukurigaku Zasshi, 1981, 78, 571. 409 F. J. Stiefel, US P. 4275 198, 1981. 410 R. Andreoli Rovat and X. Cirera Dotti, Span. P. 493 741, 1981. 4 1 1 L. M. Brenner, US P. 4 282 227, 1981. 4 1 2 Jpn. Kokai Tokkyo Koho 81 61 373,1981. 413 A. W. Oxford, J. Bradshaw, and I. H. Coates, Eur. Pat. Appl. 21 840, 1981. 4 1 4 W. Liebenow and K. Mannhardt, Ger. Offen. 2 923 345,1980. 4 1 5 W. Liebenow and K. Mannhardt, Ger. Offen. 2 942 643,1981. 416 W. Liebenow and K. Mannhardt, Arch. Pharm (Weinheim, Ger.), 1981, 314,409. 417 G. Thuillier, J. Laforest, B. J. M. Cariou, P. A. R. Bessin, J. S. Bonnet, and J. E. Thuillier, US P. 4 255 585, 1981. 418 E. J. Cragoe, Jr. and W. F. Hoffman, US P. 4 237 130, 1980. 419 W. F. Hoffman, O.W. Woltersdorf, Jr., F. C. Novello, E. J. Cragoe, Jr., J. P. Springer, L. S. Watson, and G. M. Fanelli, Jr., J. Med. Chem., 1981,24, 865. 420 A. Nuhrich, C. Lablanche, G. Devaux, A. Carpy, P. Dufour, C. Nguyen-Ba, and J. Roquebert, Eur. J. Med Chem. -Chim. Ther., 1981, 16,551. 4 2 1 Jpn. Kokai Tokkyo Koho 81 99471,1981. 422 Jpn. Kokai Tokkyo Koho 81 49 376,1981. 4 2 3 Austrian P. 361 467, 1981. 414 J. Barbara Adroher, J. M. Carulla Oliver, S. Julia Arechaga, J. A. Oliva Granell, and J. A. Poch Gabarro, Span. P. 487 841, 1980.

116


many others, have been investigated as anti-inflammatory 13' *425-431 Many analogues of prostaglandin that contain thiophen rings have been re pa red.‘'^^-^^^ Thiophens with antihistaminic activity have been investigated?37--441 The popular antihistamine methapyrilene has been shown to be a potent hepato~arcinogen.4~~ Hypolipidemic thiophensw3--446. and inhibitors of the aggregation of platelets have been d e s ~ r i b e d . ~ ~ , ~ ~ Antidiabetic thiophencarboxylic acidsw9 and s~lphonylureas~~" have been prepared.

Therapy of Infectious Diseases. In connection with side-chains of 0-lactams, several patents on the synthesis and purification of 2-thienylacetic acid~51-455

425 426

427 428

L. A. Koskenniska and R. A. Saxlund, Eur. Pat. Appl. 29 740, 1981. A. E. Sloboda, J. W. Hanifin, and D. N. Ridge, Austrian P. 363930, 1981. A. C. Goudie, R. W. Ward, and H. E. Rosenberg, Eur. Pat. Appl. 35 853, 1980. W. Opitz, M. Schwiertz, S. Raddatz, and P. R. Imberge, Arzneim.-Forsch., 1981, 31,402.

429 430

431 432

B. Lacaze, Fr. Demande 2 461 496, 1981. Jpn. Kokai Tokkyo Koho 82 02 294,1982. R. Boigegrain and J. P. Maffrand, Fr. Demande 2 478 640, 1981. W. Bartmann, G. Beck, 3. Knolle, and R. H. Rupp, Tetrahedron Lett., 1982, 23, 2947.

433 434

G. Beck, U. Lerch, B. Schoelkens, and R. H. Rupp, Ger. Offen. 2 946 116, 1981. E. W. Collington, P. Hallett, C. J. Wallis, and J. Bradshaw, Eur. Pat. Appl. 32 432, 1981.

T. Tamura, N. Inukai, H. Iwamoto, I. Yanagisawa, Y. Ishii, T. Takagi, K. Tomioka, and M. Murakami, YamunouchiSeiyuku Kenkyu Hokoku, 1980,4,16. 436 Jpn. Kokai Tokkyo Koho 81 131 579,1981. 4 3 7 Jpn. Kokai Tokkyo Koho 81 81 578,1981. 438 Jpn. Kokai Tokkyo Koho 81 118080,1981. 4 3 9 D. B. Judd, J. Bradshaw, J. W. Clitherow, B. J. Price, J. W. M. Mackimon, R. Hayes, and L. Carey, Eur. Pat. Appl. 27744, 1981. 440 Jpn. Kokai Tokkyo Koho 80 167 275, 1980. 4 4 1 H. H. Lautenschlaeger, H. Betzing, J. Winkelmann, and M. Probst, Ger. Offen.

435

2 946 810,1981. 442

443

R. Ziegler, B. Ho, and N. Castagnoli, Jr., J. Med. Chem., 1981, 24, 1133. Y. Kawamatsu, T. Sohda, and Y. Imai, Eur. J. Med Chem. - Chim. Ther., 1981, 16, 355.

Jpn. Kokai Tokkyo Koho 81 55 314,1981. 4 4 5 R. A. Parker, Eur. Pat. Appl. 46 595, 1982. 446 J. Courregelongue and J. P. Maffrand, Fr. Demande 2 464 953, 1981. 4 4 7 Jpn. Kokai Tokkyo Koho 81 77 282,1981. 448 I. Imada, H. Sugihara and M. Kawada, Eur. Pat. Appl. 26 000,1981. 449 G. F. Holland, US P. 4 282 246, 1981. 4 5 0 V. Hitzel, R. Weyer, K. Geisen, and G. Regitz, Eur. Pat. Appl. 31 088,1981. 4 5 1 B. P. Fabrichnyi, F. M. Stoyanovich, Yu. B. Vol'kenshtein, S. Z. Taits, Ya.L. Gol'dfarb, A. S. Mezentsev, M. A. Panina, I. B. Karmanova, and V. A. Koval'skaya, USSR P. 677 331, 1981 (Ofkrytiyu, Izobref., From. Obrazfsy, Tovurnye Znuki, 444

1981, 270). 452

B. P. Fabrichnyi, S. Z. Taits, Yu. B. Vol'kenshtein, I. F. Shalavina, I. B. Karmanova, V. A. Koval'skaya, F. M. Stoyanovich, E. P. Zakharov, Ya. L. Gol'dfarb, e f ul., USSR P. 599 508, 1981 (Ofkrytiyu, Izobret., Prom. Obrazfsy, Tovamye Znuki, 1981, 270).

453

454 45s

J. C. Vallejos and Y. Christidis, Fr. Demande 2 470 127, 1981. M. Foa and L. Cassar, US P. 4 287 352,1981. Jpn. Kokai Tokkyo Koho 81 23 429,1981.


117

3-t hie nylmalonic acid ,456 45 and a! -amino-2-t hieny lacet ic a cid458 have appeared, New penicillins and cephalosporins with thiophen in the side-chain have been prepared .459-463 Derivatives of clavulanic acid that include thiophen rings4@ and azeto [ 1 , 2 a ] thieno [3,2-c] ~ y r i d i n e ~ ~also ’ show antibacterial activity. N i t r o t h i o p h e n ~ ~ with ~ ~ - ~antibacterial ~~ and antiparasitic activity, thiophencarbaldehyde thiosemicarbazones with antitubercular and many other structures with antibacterial activity have been s ~ r e e n e d ? ~ l - ~A’ ~large number of patents treat thieno484 and some pyrimidone and related compounds as antifungal other thiophen derivatives with a n t i f ~ n g a l ~ ~ ’and -~~~ antimolluscal

P. C. Harris and J. A. Wilcox, Eur. Pat. Appl. 21 645, 1981. S. H Malik, C. E. Windus, and D. E. Clark, Ew. Pat. Appl. 21 644,1981. 458 B . P. Fabrichnyi, I. F. Shalavina, and Ya. L. Gol’dfarb, USSR P. 771 100, 1980 (Otkrytiya, Izobret., &om. Obraztsy, Tovamye Znaki, 1980, 138). 4 5 4 P. Feyen and W. Schrock, Angew. Chem., Int. Ed. Engl., 1981, 2 0 , 808. 460 C. Palomo-Nicolau and A. L. Palomo-Coll, An. Quim., Ser. C, 1981, 7 7 , 87. 46 1 P. Mazzeo and F. Segnalini, Farmaco, Ed. Sci., 1981, 36,916. 462 J. Colome and C. Ferrer, Belg. P. 886 715, 1981. 4 6 3 J. E. Dolfini, USSR P. 812 184, 1981 (Otkrytiya, Izobref, Prom. Obraztsy, Tovarnye Znaki, 1981,227). 464 P. M. Denerley, Eur. Pat. Appl. 25 287, 1981. 4 6 5 Jpn. Kokai Tokkyo Koho 80 160 779,1980. 466 P. Gavral, M. C. Rigothier, J. C. Gantier, R. C. Coumes, J. P. Gorrichon, and A. Gaset, Eur. J. Med. Chem. -Chim, Ther., 1981, 16,151. 4 6 7 A. Gaset, R. C. Goumes, J. P. Gorrichon, L. Albertini, J. P. Calmon, and G. Michel, Fr. Demande 2 484 784, 1981. 468 H. Dolman and J. Kuipers, Eur. Pat. Appl. 31 173, 1981. 469 Yu. D. Churkin, E. A. Rudzit, L. V. Panfilova, and D. A. Kulikova, USSR P. 770 045, 1981 (Otkrytiya, Izobret., Prom. Obraztsy, Tovamye Znaki, 1981,313). 470 Yu. D. Churkin, E. A. Rudzit, L. V. Panfilova, and D. A. Kulikova, USSR P. 770 044, 1981 (Otkrytiya, Izobret., Prom. Obraztsy, Tovamye Znaki, 1981,313). 4 7 1 Jpn. Kokai Tokkyo Koho 81 95184,1981. 4 7 2 K. A. M. Walter, US P. 4 272 545, 1981. 4 7 3 B. M. Kirichenko, A. V. Vladzimirskaya, and P. M. Steblyuk, Farm. Zh. (Kiev), 1981,61. 474 M . S . K. Youssef, S. R. El-Ezbawy, and A. A. Abdel-Wahab, Acta Pharm. Jugosl., 1981,31,67. 4 7 5 D. R. Shridhar, C. V. Reddy Sastry, B. Lal, G. S . Raddi, K.K. Bhopale, R. S. Khokar, and K. Tripathi, Indian J. Chem., Sect. B, 1980,19, 1065. 476 Jpn. Kokai Tokkyo Koho 81 57 793,1981. 477 T. Kametani, K. Kigasawa, M. Hiiragi, K. Wakisaka, S. Haga, H. Sugi, K. Tanigawa, Y. Suzuki, K. Fukawa, 0. Irino, S. Saita, and S . Yamabe, Heterocycles, 1981, 16, 1205. 4 7 8 Jpn. Kokai Tokkyo Koho 81 08389,1981. 479 Jpn. Kokai‘Tokkyo Koho 81 59 778,1981. 480 Jpn. Kokai Tokkyo Koho 81 53 681,1981. 481 Jpn. Kokai Tokkyo Koho S i 22 789,1981. 482 I. A. Kharizomenova, A. N. Grinev, N. V. Samsonova, E. K. Panisheva, N. V. Kaplina, I. S. Nikolaeva, T. V. Pushkina, and G. N. Pershin, Khim-Farm. Zh., 1981,15,40. 483 Jpn. Kokai Tokkyo Koho 81 34 683,1981. 484 A. R. Burrell, J. M. Cox, N. F. Elmore, J. H. E. Marsden, and M. C. Shephard, S. Afr. P. 80 00 822,1981. 4 8 5 Jpn. Kokai Tokkyo Koho 81 79 604,1981. 486 Jpn. Kokai Tokkyo Koho 81 161 361,1981. 487 H. Boeshagen, K. H. Buechel, W. Draber, 1. Haller, and M. Plempel, Ger. Offen. 3 017 881, 1981. 456

457

118

Heterocyclic Chemis fry

propertiesM8 have been prepared. A thiopheneylnonatetraene has been patented as an antiturnour agent.489

Veterinary and Agricultural Agents. Thiophency clopropanecarboxylic acid4903491 and derivatives of 3,4-dihydro~ythiophen~~~ have been patented as pesticides. Compounds such as (2 19)493 and (220)p94 and others,495-497 have also been suggested as pesticides.

Miscellaneous Activities. Great interest in the synthesis of biotin and intermediates for biotin can be noted.37:498-501Other biological aspects of thiophen derivatives have been treated.502-5'0 G. Madulo-Leblond, P. Gayral, J. Guillaumel, J.-M. Clavel, P. Demerseman, and R. Royer, Eur. J. Med. Chem. -Chim. Ther., 1981, 16,267. 489 M. J. Klaus and B. A. Pawson, US P. 4 256 878, 1981. 490 Jpn. Kokai Tokkyo Koho 81 92 284,1981. 4 9 1 Jpn. Kokai Tokkyo Koho 81 92 285,1981. 492 K. Sato, M. Miyahara, T. Hibi, T. Wada, S. Nagai, Y. Hirota, T. Yorie, and H. Sugiura, Eur. Pat. Appl. 32 748, 1981. 493 G. Levitt, Eur. Pat. Appl. 30 142, 1981. 494 Jpn. Kokai Tokkyo Koho 81 133 282,1981. 4 9 5 Jpn. Kokai Tokkyo KohoSl 167 679,1981. 496 M. T. Clark, Br. P. 1 574429, 1980. 4 9 7 Jpn. Kokai Tokkyo Koho 82 35 579,1982. 498 E. G. Baggiolini, H. L. Lee, and M. R. Uskokovic, Eur. Pat. Appl. 19 788, 1980. 499 E. G. Baggiolini, H. L. Lee, and M. R. Uskokovic, US P. 4 247 704, 1981. P. A. R o s y and F. Vogel, Ger. Offen. 3 018 109, 1981. E. G. Baggiolini, H. L. Lee, and M. R. Uskokovic, US P. 4245 104,1981. A. W.-J. Chow, R. J. Gyurik, and R. C. Parish, Eur. Pat. Appl. 24 842, 1981. G. H. Phillipps, C. Williamson, I. P. Steeples, B. MacDonald Bain, and R. A. Borella, Eur. Pat. Appl. 44 705, 1982. E. Haddock and W. J. Hopwood, Br. Pat. Appl.. 2 078 212, 1982. M. Bayssat, F. Sautel, J. C. Depin, and A. Betbeder-Matibet, USSR P. 795472, 1981 (Otkrytiya, Izobref, Prom Obraztsy, Tovumye ZnaM, 1981,229). G. Grimmer, J. Jacob, and K. W. Naujack, Z. Anal. Chem., 1981, 306,347. M. h i and T. F. Slater, IRCSMed Sci;Libr. Compend., 1981, 9,25. 508 R. Muneyuki, T. Mitsugi, and E. Kondo, Chem. Ind. (London), 1981,159. 509 K. J. Brown, G. W. Tannock, R. B. Elliott, and D. R. Lines, Microbial. Immund., 1980, 24, 603. 'lo P. Staben, A. S. Bhargava, C. Schobel, F. Siegmund, and P. Gunzel, Arzneim.-Forsch., 1981,31-2,1735. 488


119

Thiophens of Technical Interest. - Many patents cover the synthesis of azodyes from aminothiophens such as (22 1),510 (222),'" and others.34a*512-515 Several patents describe solid-state lithium batteries with the iodine-thiophen charge-transfer complex .'16-'19

Polymers from Thiophen. - By the use of sodium t-butoxide, 5-methylthiophen-2-carbaldehyde has been polycondensed in DMF to give poly(thiophen-2,5-diyl)~inylene.~*~ From 4,4' -azodibenzaldehyde and bifunctional Wittig reagents from 2 ,5-dichloromethylthiophen, conjugated polymers with azobenzene units were prepared.521 Polymeric azomethines with azobenzene units have been prepared from 4,4-di-iminoazobenzene and 2,s -diformylthiohen.'^^ The metathesis reaction has been applied to unsaturated polymers that contain thiophen A patent describes the preparation of linear polythiophen-2,s - y l e n e ~ ) , ' ~and ~ the electrical conductivity of their arsenic pentafluoride complexes has been measured ,525 Electrophysical properties of polymeric films that have been prepared from thiophens in a glow discharge have been R. R. Giles and M. A. Weaver, US P. 4 301 068, 1981. D. Mullen, Br. Pat. Appl. 2 0 7 8 7 1 3 , 1982. 513 D. Mullen, Rr. Pat. Appl. 2 041 961,1980. 'I4 Jpn. Kokai Tokkyo Koho 81 120 764,1981. 5 1 5 Jpn. Kokai Tokkyo Koho 81 129 256,1981. S. Saito, S. Kashihara, and G. Takeshima, GS News Tech. Rep., 1981, 40, 8 2 . "'Jpn. Kokai Tokkyo Koho 82 13 670,1982. Jpn. Kokai Tokkyo Koho 82 34 677,1982. 519 L. P. Klemann, G. H. Newman, E. L. Stogryn, T. A. Whitney, and D. Farcasiu, US P. 4 293 623,1981. s20 G. Kossmehl and k Yaridjanian, Makromol. Chem., 1981, 182,3419. 5 2 1 G. Kossmehl and J. Wallis, Makromol. Chem., 1982, 183, 331. 5 2 2 G. Kossmehl and J. Wallis, Makromol. Chem., 1982, 183, 347. 523 K. Hummel and 0. A. Wedam,MakromoZ. Chem., 1981,182, 3041. 5 2 4 Jpn. Kokai Tokkyo Koho 81 47 421,1981. s 2 5 G. Kossmehl and G. Chatzitheodorou, Makromol. Chem., Rapid Commun., 1981, 'I1 'Iz

526

2, 551.

T. A. Starostina, V. L. Materikin, A. B. Gil'man, V. M. Vozzhennikov, and L. F. Rybakova, Vysokomol. Soedin., Ser. B , 1982, 24,269.


120

3 Benzo[ 6J thiophens and their Benzo-fused Systems Benzo[6 J thiophens. - Synthesis. The Michael addition of chalcone to (223) gave (224). The sulphone corresponding to (223) can also be used for the synthesis of benzo [bJ thiophens: using (225) gave (226) in 63% yield.527 Compound (227), easily available by treatment of (228) with base, yields (229) upon reaction with ethyl bromoacetate or phenacyl bromide.528 Methyl 4,7dihydro-4,7-dioxobenzo [ b ]thiophen-2 -carboxylate has been synthesized by the reaction of methyl mercaptoacetate with activated 1 , 4 - b e n ~ o q u i n o n e s . ~ ~ ~ Sub st it ut ed 3-benzylideneb enzo [b ] t hio phen-2 -ones have been prepared .530 Irradiation of methyl 2-phenylthioacetoacetate in benzene-methanol gave methyl 3-methylbenzo[ b ]thiophen-2-carboxylate in 66% yield. Other aryl derivatives reacted similarly.531Dimethyl benzo [ b ]thiophen-2,3-dicarboxylate was formed in the thermal reaction of 3-morpholinosydnone with dimethyl acetylenedicarboxylate (DMAD) .532 The Stobbe condensation between p tolyl 2-thienyl ketone and dimethyl succinate, followed by cyclization, was used for the synthesis of benzo [ b ]t h i o p h e n ~ .3-Bromothiochroman-4-one ~~~ and its S-oxide underwent ring-contraction on heating to give mixtures of products, including t h i ~ i n d i g o .535 ~ ~ Dehydrogenation * of 2,3-dihydrobenzo[bJ thiophens over different types of catalysts has been used for the synthesis of benzo [ b ]t h i ~ p h e n s . ~ ~ Irradiation ~-~~* of 1,2-benzisothiazole in the

CN (228) 521 528

( 229)

R

= COOEt

or COPh

k M. van Leusen and J . W. Terpstra, Tetrahedron Lett., 1981, 22, 5097.

K. Gewald and H. Schafer, 2. Chem., 1981, 21, 183. V. M. Ruiz, R Tapia, J. Valderrama, and J. C. Vega, J. Heterocycl Chem., 1981, 18, 1161. 530 C. Camoutsis, P. Catsoulacos, G. Salem, A. Terzis, and S. E. Filippakis, J. Heterocycl Chem., 1981, 18,1405. 531 T . Sasaki, K. Hayakawa, and H. Ban, Tetrahedron, 1982, 38, 85. 532 H. Gotthardt and F. Reiter, Chem. Ber., 1981, 114, 2450. 533 H. H. Moussa and S. Abdel-Meguid, J. Heterocycl. Chem., 1981, 18, 1519. 534 N. E. MacKenzie and R. H. Thomson, J. Chem SOC.,Perkin Trans. 1 , 1 9 8 2 , 395. 53 5 P. J. Cox, N. E. MacKenzie, and R. H. Thomson, Tetrahedron Lett., 1981, 22,2221. 5 36 T . Yu. Filippova, Kh. M. Minachev, Ya. I. Isakov, M. V. Vagabov, and E. A. Karakhanov, Vestn. Mosk. Univ., Ser. 2: Khim., 1981, 22, 5 1 1 . 531 M. V. Vagabov, E. A. Viktorova, B. I. Liogon'kii, R Z. Aleksanyan, S. K. Dzhamalov, and E. A. Karakhanov, Neftekhimiya, 1980, 20, 887. 538 M. V. Vagabov, Neftekhimiya, 1981, 21, 619. 52Y


121

presence of DMAD gave dimethyl 7-cyanobenzo [b] thiophen-2,3dicarboxylate in addition to mixtures of cis- and trans-substituted phenylthioalkene~.’~~’ Some benzo [b] thiepins have been ring-contracted to benzo [b]t h i ~ p h e n s . ’Prop-2-enyl ~~~ 2,3,4,5 -tetrafluorophenyl sulphide underwent a Claisen rearrangement in N, N-diethylaniline to give 4,5,6,7-tetrafluoro-2,3dihydro-2-methylbenzo [b] t h i ~ p h e n .The ~ ~ ~reaction of 2-methylthiophen with tetrafluoroethylene at 650°C gave (230), in addition to (231).540

(230)

( 231)

Physical Properties of Benzo[b] thiophens. The aromatic electronic delocalization in benzo [b] thiophen has been calc~lated.’~~ The m.c.d. spectra of benzo [b] thiophen and dibenzothiophen have been analy~ed.’~*Chemical thermodynamic properties of benzo [b] thiophen and other condensed systems have been determined.543 The crystal structures of 5 -nitroso-4(phenylethyl)benzo[b] t h i ~ p h e n , ’1,2,3,5-tetramethylbenzo[b] ~~ thiophenium t e t r a f l ~ o r o b o r a t e ,and ~ ~ ~a spiro-benzo[b]thieno [2,1-b] have been determined. Reactions of Benzo[b] thiophens. Photochemical cycloaddition of 2,3dichlorobenzo[b] thiophen with vinyl bromide under benzophenone-sensitized conditions gave a mixture of isomers of (232) in the presence of free-radical inhibitor^.'^^ The products from the photocyclization of DMAD with substituted benzo [b] thiophens are (233) or (234), depending upon the

538aM.Sindler-Kulyk and D. C. Neckers, Tetrahedron Lett., 1981, 2 2 , 525. 538bA.Chatterjea, B. Sen, and S. K. Chatterjee, J. Chem. SOC.,Perkin Trans. 1, 1981, 1707. G. M. Brooke and D. I. Wallis, J. C h e m Soc., Perkin Trans. 1 , 1981, 1659. 540 A. M. Maksimov, V. E. Platonov, G. G. Yakobson, 0. M. Yakhlakova, R. A. Bekker, B. L. Dyatkin, and I. L. Knunyants, Izv. Sib. Otd. A k ad Nauk SSSR, Ser. Khim. Nauk, 1981, No. 6, p. 128. 5 4 1 A. Mehlhorn and J. Fabian, Croat. Chem. Acta, 1981, 54,427. 542 N. Igarashi, A. Tajiri, and M. Hatano, Bull. C h e m SOC.Jpn., 1981, 54, 1511. 543 S. E. Stein and B. D. Barton, Thermochim. Acta, 1981, 44, 265. 544 K. Rou t and F. M. Miao, Acta Crystallogr., Sect. B , 1982, 38, 685. 5 4 5 R. M. Acheson, R. J. hince, G. hocter, J . D. Wallis, and D. J. Watkin, J. Chem. SOC., Perkin Trans. 2, 1981, 266. 546 P. J . Cox and R. A. Howie, Acta Crystallogr., Sect. B, 1982, 38,657. 5 4 7 D. C. Neckers and F. L. Wagenaar, J. Org. Chem., 1981,46,3939. 539

122


irradiating wa ~ e l e n g t h . ’ The ~ ~ photo chemical react ions of 2 -aryl-, 3-aryl-, and 2,3-diaryl-benzo [b] thiophens in neutral solution in the presence of primary and teritary amines have been investigated; they led only to a minor extent to cyclization but gave, in most cases, adducts and d i m e r ~ . ’ ~ ~ In the presence of moist A1C13, aromatic compounds such as benzene, toluene, anisole, phenetole, diphenyl ether, and methylthiobenzene added across the 2,3-double bond of benzo[b]thiophens to give a mixture of 2and 3-(para-substituted aryl)-2,3-dihydrobenzo [ b ]thiophens. It has been suggested that benzo [ b ]thiophen is protonated by moist AlCl,, and that the resulting carbo-cation reacts with a second aromatic compound, which with benzene or chlorobenzene as solvent is the benzo [bJ thiophen itself.5501551 With anisole the formation of a ring-opened product, (E)-4-methoxy-2’methylthiostilbene, was also observed, and is believed to occur via the S methylated benzo [b] t h i ~ p h e n . ’ ~ The ~ addition reactions of benzene and toluene have also been investigated with acetoxy- and hydroxy-benzo [ b ] thiophens. Normal Fries-rearranged products were found for the 4- and 7OAc derivatives, which sometimes react further to produce their dihydroderivatives. Alternatively, benzene can add across the double bond to give the 2- (for 6-OAc) or 3-phenyl-2,3-dihydrobenzo [ b ]thiophens (for 7OAC).”~Isomerization of 2- and 3-methylbenzo [b]thiophen on aluminosilicate catalysts at 300-5OO0C has been inve~tigated.’~~ Ally1 2-benzothienyl sulphide underwent a [3,3] -sigmatropic rearrangement to give 3-allylbenzo[b] thiophen-2-thiol, which ring-closed to a mixture of 2-methyl-2,3-dihydrobenzothieno [2,3-b] thiophen, 2-methylbenzothieno [2,3-b] thiophen, and benzot hieno [2,3-b] dihydro t h i ~ p y r a n . ” ~3-Benzo [b ] t hienyl-lithium reacted with quinoxaline to give 2-benzo- and 2,3-dibenzo-[b] thieny1quinoxaline.ln 6-Fluorobenzo [ b ]thiophen-2(3H)-one has been prepared via diazotization of sodium (2-amino-4-fluoropheny1)acetate followed by reaction with sodium sulphide and ring-clo~ure.’~’ The reaction of 3-amino-2-ethoxycarbonylbenzo [b] thiophen with 2,s -dimethoxytetrahydrofurangave 3(1 -pyrrolyl)2-ethoxycarbonylbenzo [ b ]thiophen, which through Curtius reaction was

548

549

S. R. Ditto, P. D. Davis, and D. C. Neckers, Tetrahedron Lett., 1981, 2 2 , 521. A. Buquet, A. Couture, A. Lablache-Combier, and A. Pollet, Tetrahedron, 1981, 37, 75.

552

P. D. Clark, K. Clarke, D. F. Ewing, R. M. Scrowston, and F. Kerrigan, J. Chem. Res. (S), 1981, 307. P. D. Clark, D. F. Ewing, F. Kerrigan, and R. M. Scrowston, J. Chem. SOC.,Perkin Trans. I , 1982, 615. P. D. Clark, L. K. k Rahman and R. M. Scrowston, J. Chem SOC.,Perkin Trans. I , 1982, 815.

553 554

555

M. V. Vagabov, Neftekhimiya, 1981, 21,658. k V. Anisimov, V. S. Babaitsev, S. Ya. Grobovenko, T. k Danilova, and E. A. Vik orova, Khim. GeterotsikL Soedin., 1981, 615. K. iindeldr, M. Ryska, J. Holubek, E. Svdtek, J. Metys‘ovd, J. Protiva, and M. Protiva, Collect. Czech. Chem Commun., 1981, 46, 118.


123

transformed into (235).556 The reaction of the 6-halogeno-2H,3H-benzo[ b ]thiophen-2,3-diones with alkoxides in the presence of crown ether gave radicals whose e.s.r. spectra indicated that the radical anions of the starting product d i m e r i ~ e .The ~ ~ condensation ~ of 3-methyl-4-phenylcyclobut -3-ene1,2-dione with benzo [b] thiophen-2-carbaldehyde gave the corresponding alkenyl derivative.558 The reaction of 3-bromobenzo [ b ]thiophen with sodium thiosalicylate, followed by ring-closure,gave (236).559

Benzo[b] thiophen S-Oxides.- Mild methods for the oxidation of 2,3dihydrobenzo [ b ]thiophens to the sulphoxide have been d e v e l ~ p e d561 .~~~~ The photochemical reactions of various 2- and 3-substituted benzo [b1thiophen 1-oxides led to different p h o t o d i m e r ~ .From ~ ~ ~ 3-chlorobenzo [ b ]thiophen-2 -carboxylic acid 1,l -dioxide, 1,3-0xazinones of biological interest were obtained through cyclization reactions with cyanamides and carbodii m i d e ~ Secondary .~~~ amines add to 2-phenylbenzo [b] thiophen 1,l -dioxide to give 3-amino-substituted 2,3-dihydro-2-phenylbenzo [ b ]thiophen 1,lBenzo[c ] thiophens. - Compound (237), obtained by isomerization of 1methoxycarbonyl-2,3-benzodithianin methanolic sodium hydroxide at O"C, gives the benzo [c] thiophen (238) upon heating to r e f l ~ x The . ~ ~reaction ~ of o-methylbenzyl alcohol with CS2 at about 500°C in the presence of catalyst yielded up to 80% of dihydrobenzo [c] t h i ~ p h e n . ~ ~ ~ MeOOC

SH

M. Cugnon de Sikicourt, H. EL-Khashef, S. Rault, and M. Robba, Synthesis, 1981, 710. 5 5 7 k Alberti, F. Ciminale, G . F. Pedulli, L. Testaferri, and M. Tiecco, J. Org. Chem., 1981, 46, 751. 5 5 8 W. R e d and M. Vogl, Chem Ber., 1982, 115,403. 5 5 9 K. Grlitzer and D. Holscher, Arch. Pharm. (Weinheim, Ger.), 1982, 315, 193. sf,' Y. Watanabe, T. Numata, and S. Oae, Synthesis, 1981, 204. 5 6 1 S. Oae, Y. Watanabe, and K. Fujimori, Tetrahedron Lett., 1982, 23, 1189. 5 6 2 M. ElFaghi El Amoudi, P. Geneste, and J.-L. Olivd, J. Org. Chem., 1981, 46,4258. 5 6 3 W. X e d , G:Oremek, and R. Pauli, Arch. Pharm (Weinheim, Ger.), 1982, 315, 324. 564 F. Sauter, U. Jordis, P. Stanetty, G. Huttner, and L. Otruba, Arch. Pharm. (Weinheim, Ger.), 1981, 314, 567. 5 6 5 G. Cignarella, A. Nuvole, and M. M. Curzu, Gazn Chim. Ital., 1981, 111, 333. 566 F. Azizian and J. S. Pizey, J. Chem. Tech. Biotechnol., 1981, 31, 163. 556


124

Dibenzo thiophens. - The hydrode sulphur izat ion of dib enzot hi0phen by supported noble metal catalysts has been in~estigated.'~~ Several polyamides have been prepared by condensing dibenzothiophen-2,8diamine with aromatic diacyl dichlorides or dibenzothiophen-2,8 -dicarboxylic acid chlorides with aromatic diamines. The corresponding dibenzothiophen sulphones were also Oxazoline-protected dibenzothiophen-lcarboxylic acid was metallated in the 2-position, and via reaction with ethylene oxide and further reaction was converted into (239), which was studied as a dopamine antagonist.569 Metallation of 4,4'difluorodiphenyl sulphone, followed by reaction with trimethylchlorosilane, gave trimethylsilyl derivatives, which were ring-closed to 2,8-difluorobenzo [b] thiophen 5 5 dioxide and reduced to the corresponding d i b e n z o t h i ~ p h e n .The ~ ~ ~nitrogroup of 2-nitrodibenzo [b] thiophen 5,5-dioxide could be selectively reduced electrochemically.s71 The [7 J -, [9] -, [ 111 -, [ 131-,and [ 151- heterohelicenes with alternant thiophen and benzene rings have been synthesized by photocyclization of precursor olefins and diolefins, and their n.m.r. spectra were investigated.572 Acylation, Mannich reaction, Vilsmeier formylation , and diazo coupling of (240) have been found to occur predominantly in the pyrrolic 0-position, except for acylation , which occurred at the nitrogen, and formylation, which also gave some a - i ~ o m e r . ~ ~ ~ R

(239)

(240)

Pharmacologically Active Compounds. - 2-Aryl-3-alkoxybenzo[bJ thiophens have been shown to possess hypolipidemic activity.574 Alkyl and polyhalophenyl esters of benzo [b] thiophen-3-carbamic acid show antibacterial and antifungal activities.575 Benzo [b] thiophen-3-sulphonamides show herbicidal Derivatives of 2-cyano-3-hydroxybenzo [b J thiophen show sympatholytic E. Dhainaut, H. Charcosset, C. Gachet, and L. de Mourgues, A p p L Catal., 1982, 2, 75. 568 P. R. Srhivasan, V. Mahadevan, and M. Srinivasan, Makromol. Chem., 1981, 182, 1937. 5 6 9 C. R. Ellefson and K. A. ho da n, J. Med Chem., 1981, 24, 1107. 570 M. C. Brirlon, M. M. de Bertorello, and H. E. Bertorello, An. Asoc. Quim. Argent., 1981, 69,247. 5 7 1 L. H. Klemm and Q. N. Porter, J. Org. Chern., 1981, 46,2184. 572 K-I. Yamada, S. Ogashiwa, H. Tanaka, H. Nakagawa, and H. Kawazura, Chem. Lett., 1981, 343. 5 73 L. A. Kintsurashvili, T. E. Khoshtariya, L. N. Kurkovskaya, and N. N. Suvorov, Khim Geterotsikl. Soedin, 1981, 211. F. Sauter, Fr. Demande 2 447 914, 1980. A. Shafiee, M. Vossoghi, J . Wossooghi, and S. Yazdani, J. Pham. Sci., 1981, 7 0 , 5 6 6 . 5 7 6 G. Levitt, Eur. Pat. Appl. 45 196, 1982. 577 R. R. Royer, L. J. A. Rene, and M. E. M. Aurousseau, Eur. Pat. Appl. 20 266, 1980. 567

i::


125

4 Thiophen Analogues of Polycyclic Aromatic Hydrocarbons Analogues of Anthracene and Phenanthrene. - Keto-enol tautomerism in a naphtho- and several anthra-thiophen systems [such as (241) G (242)J has been studied. The system (241) +(242) was obtained via the Friedel-Crafts reaction of thiophen with naphthalene-2,3-dicarboxylic anhydride .followed by ring-closure. A [c] -fused system was similarly obtained by starting from 2,5 -dimethylthiophen. The other [b] -fused system was prepared from 2bromo-3-chloronaphthalene, which was converted into the aldehyde, allowed to react with 2-thienyl-lithium,and then reduced. The chloro-substituent was then transformed into a carboxy-group and the system was r i n g - c l o ~ e d . ~ ~ ~ Aromatic hydrocarbons add across the 1,2-bond of naphtho [2,1-b] thiophen in the presence of AlC& to give 1-aryl-l,2-dihydro-derivativesat room temperature. At higher temperatures, 2-arylnaphtho [2,1 -b]thiophens are obtained. Treatment of the 1-aryl-2,3-dihydrothiophens with DDQ yields 1 arylnaphtho [2,1-b] t h i ~ p h e n s . ~ ’Naphtho ~ [ 1,2-b]thiophens react similarly, although, in addition to 2-aryl-2,3-dihydro-derivatives, 2,3-dihydronaphtho[ 12-b]thiophen was formed.580 Naphtho [ 1,8-bc]thiophen-2-one reacted with dimethyl sulphate to give (243) .581 Treatment of 8 -benzoylmercapto-2naphthol with polyphosphoric acid gave (244) in 63% yield. Treatment of (245) with sodium hydroxide in DMF gave (246) in 82% yield.582

(244)

0

(245)

Polycyclic Thiopens. - In connection with the renewed interest in such compounds as constituents in coal and their potential mutagenic and/or carcinogenic properties, many such compounds have been synthesized by 578 579

W. A. Lindley and D. W. H. MacDowell, J. Org. Chem., 1982, 47,705. P. D. Clark and D. M. McKinnon, Can. J. Chem., 1981, 59,227. P. D. Clark and D. M. McKinnon, Can. J. Chem., 1981, 5 9 , 1297. Yu. I. Rozhinskii and V. L. Plakidin, Zh. Org. Khim., 1981, 17, 1783. R. Neidlein and G. Schafer, Chem.-Ztg., 1981, 105, 89.


126

Castle and co-workers. Thus from (1 19) the pyrenothiophen (247) was prepared by side-chain bromination and further tran~f0rmation.l~~ The last missing pyrenothiophen (248) was prepared from 4-bromopyrene by halogenmetal exchange and reaction with 2,2,2' 2'-tetraethoxydiethyl disulphide, followed - by closure of the thiophen ring.199 Triphenaleno [2,3-b]thiophen (249) was obtained through the reaction of lithiated oxazoline-protected thiophen-3-carboxylic acid with phenanthrene-9-carbaldehyde,followed by ring-closure. The synthesis of the [ 1,241 -isomer (12 1) and the corresponding [2,1-b] -isomer has already been mentioned.200 Using similar synthetic strategy as mentioned above, (250) was prepared via the Wittig reaction of 2-acetylbenzo [b] thiophen and benzyltriphenylphosphonium salt, followed by photochemical ring-closure and side-chain modification of the methyl group. The starting reaction for the synthesis of (251) was metallation of oxazoline-protected benzoic acid with benzo [bj thio~hen-2-carbaldehyde.~~~ All isomers of the parent anthra [b] thiophens and benzo [b] thiophens have been prepared. Some of them were obtained by cycloaddition reactions between 2- or 3-vinylthiophens and 1,4-naphthoq~inone.~~ Benzo [ b ]phenanthreno [ d ]thiophens such as (252) were prepared in a straightfonvard way by the Wittig reaction between benzo [b] thiophen-2-carbaldehyde and diethy 1 2 -naphthy lmet hylpho sphonat e and photochemical ring -closure.585 Starting from phenanthrene-9-thiol, a thiophen ring was elaborated in the

(247)

s83 5.34

R. D. Thompson, M. Iwao, M. L. Lee, and R. N. Castle, J. HeterocycL Chem., 1981, 18,981. Y. Tominaga, M. L. Lee, and R. N. Castle, J. Heferocycl. Chem., 1981, 18,967. R. hatap, M. L. Lee, and R. N. Castle, J. HeterocycL Chem., 1982, 19,219.


127

synthesis of (253). In addition, benzo [ 1,2-b] phenaleno [4,3-bc]thiophen has been ~ynthesized.’~~ Phenaleno [ 1,9-bc]thiophen (254) was prepared, starting from 1 -methylnaphtho [2,1 -b]t h i ~ p h e n . ~ ~ ’ The reaction of malonyl chloride with 2-phenylbenzo [ b ]thiophen led to a mixture of (255) and (256) and their t a u t o m e r ~ .The ~ ~ ~synthesis and reactions of some new thiapseudophenalenone derivatives have been inve~tigated.~~’

(256)

Thiophen Analogues of Indene. - Detailed papers on the reaction of diazoindenothiophens with DMAD and methyl propiolate have now been p~blished.’’~This investigation has been extended to the reaction with mono- and di-benzoylacetylene, which gave similar products, such as (257). However, the benzo-fused indene gave (258) as the main p r o d ~ c t . ’ By ~

HN-

(257)

5 86

N

7 \

’I

\

1

/

R. Pratap, R N. Castle and M. L. Lee, J. HeterocycL Chem., 1982, 19,439.

”’ Y. Tominaga, M. L. Lee, and R. N. Castle, J. Heterocycl. Chem., 1981, 18,977. 588 589

590

R. Neidlein and G. Schafer, Chem.-Ztg., 1981, 105, 91. R. Neidlein and E. A. Varella, Chem. Chron., 1980, 9 , 79. S. Mataka, T. Ohshima, and M. Tashiro, J. Heterocycl. Chem., 1982, 19,65.


128

treatment of the thienylglycollic acids with A1Cl3 in benzene, indenes could be prepared. Thus from (259), (260) was obtained in 79% yield and could be hydrolysed and dicarboxylated to the parent indene.166

Various Carbocycle-fused Systems. - Azuleno [2,1-b]thiophens have been prepared from ethyl 2 -chloro-3-formylazulene-l -carboxylate and ethyl merca~toacetate.~~' The reaction of (261) with sulphur in quinoline gave (262).592 It is claimed that, in the cation of (263), the charge is largely localized on the carbon atom that is flanked by the two thiophen rings.593 An unusual cleavage of a carbon-carbon double bond has been observed in the reaction of (264) with ethanedithiol and toluene-p-sulphonic acid, giving (265) in 40% yield. The structure was proven by X-ray c r y ~ t a l l o g r a p h y . ~ ~ Ph

Me

+

Me

H

591

K. Yamane, K. Fujimori, and T. Takeuchi, Bull. Chem. SOC.Jpn., 1981, 54,2537. Yu. N. Porshnev, T. N. Ivanova, L. V. Efimova, E. M. Tereschenko, M. I. Cherkashin, and K. M. Dyumaev, Zh. Org. Khim., 1982, 18,150. 5 9 3 T. M. Brown and W. Carruthers, J. Chem SOC.,Perkin Trans. 1 , 1981, 2904. 594 B. Hanquet, M. El Borai, R. Guilard, and Y. Dusausoy, Tetrahedron Lett., 1982, 592

23, 2859.

129


5 Thiophen Fused to Five-Membered Heteroaromatic Rings Thieno-, Furo-, and Pyrrolo-thiophens.- Partial rate factors for the detritiation of thieno [2,3-b] thiophen and thieno [3,2-b] thiophen that were specifically labelled with tritium in each position have been measured, along with that for thiophen in either pure trifluoroacetic acid or a mixture of acetic acid and trifluoroacetic acid. Annelation of thiophen by thiophen produced a comparable change in reactivities of the CY- and P-positions, in contrast to annelation by benzene, where the reactivity of the (?-position is markedly increased relative to that of the ~ y - p o s i t i o n . ~ ~ ~ The formation of thienothiophens in connection with attempts to prepare tetrathiafulvalenes has been described in three detailed papers. Attempts to deprotonate (266; X = H) led to (267), together with the trithiones (268) and other products. The mechanisms were discussed. Treatment of (268; R’ = R2 = Ph) or (268; R’ = Ph, R2 = Me) with triethylphosphine in boiling xylene gave the corresponding compound (267). Treatment of (269) with P4S10 also gave (267) together with (268).596 The reductive coupling of (266; X = C1) with zinc of TiC13, which led to the desired 1,1’,2,2’-tetrathiafulvalenes, also gave (268) as a 4,5-Disubstituted 1,2-dithiole-3-thiones reacted with 2,3-diphenylcyclopropenethioneto give thieno [3,2-b] thiophen. Using the 4,5-diphenyl-l,2-dithiole-3-thione gave (270) as a by-product. The reaction of the 1,2-dithiole-3-thiones with cyclopropenones gave thieno [3,2b] fur an^.^^^ 2,7-Diaminobenzo [b] thieno [3,2-b] benzothiophen has been prepared by reduction of 4,4’-diamino-2,2’-stilbenodisulphonyl chloride in 55% HI and subsequent treatment of the product with a dehydrogenating agent .599

€tt--DFt;

J + S R1

‘d’

I

X

’

a s

‘R R2

(267)

r)

R1 R1

s

I

S R2 ( 2 6 6 ) X = H or C 1

l

(269)

(268)

R1=

R2= P h ; R1= R2= (CH=CH)2;

R1=

Ph, R2= H; R1= H, R = P h ;

or R1=

2

P h , R2= M e

Ph Ph

595 596 597 598 599

W. J. Archer and R. Taylor, J. Chem. Soc., Perkin Trans. 2 , 1982, 295. H. Behringer and E. Meinetsberger, Liebigs Ann. Chem., 1981, 1729. H. Behringer and E. Meinetsberger, Liebigs Ann. Chem., 1981, 1928. H. Behringer and E. Meinetsberger, Liebigs Ann. Chem., 1982, 315. S. Yu. Zherdeva, A. Ya. Zheltov, and B. I. Stepanov, Izv. Vyssh. Uchebn. Zaved., K h i m K h i m Tekhnol., 1981, 24,246.


130

The Fischer indole synthesis has been very difficult to carry out in the thiophen series. However, the reaction of (271) with cyclohexanone gave (272) in good yield.248 Attempts to apply the Fischer reaction to (273), which was prepared from (147), led to (274). Compound (275), of interest as a 0-blocker, was instead obtained starting from (272).233 Heating 2- and 3(w-azido)vinylthiophen, prepared via bromoacetylthiophen and azidoacetylthiophen, followed by reduction and dehydration, gave thieno[2,3-b] - and thieno [3,2-b] -pyrrole.600 Thermolysis of (276) gave diethyl thieno[3,2-b] pyrrole-5,6-dicarboxylate in 76% yield.253 The reaction of (277) with methyl chloroacetate followed by ring-closure gave (278), which could be hydrolysed and decarboxylated to the parent compound.6o' A review on [3 13 - and [4 + 11-cycloadditions of isocyanides to dipoles and to nitroalkenes mentions work from a French

+

-om-7MeOOC

"M2

I

COOBut (274)

(273)

H (275) MeHNHC

CHNHMe M

e

I O OI

C

w

)

COOMe

S Me

6oo 601

Me

G. Kumar, K. Rajagopalan, S. Swaminathan, and K. K. Balasubramanian, Indian J. Chem., Sect. B , 1981, 2 0 , 2 7 1 . E. A. Panfdova, I. Ya. Kvitko, A. D. Kuptsov, and k V. El'tsov, Zh. Om. Khim., 1981, 17,1564.


131

thesis, describing the formation of (280) from butyl isocyanide and (279).602 9-Aza-azuleno [2,1-b] thiophen has been prepared from 2-chloro-3-formyl-laza-azulene by annelating the thiophen ring by the Fiesselmann reaction.603 OH

rJyc:l2rfN) I

COOMe

CONHBu

H (279)

(280)

Thiophen Fused to Various Five-Membered Rings. The reaction of ethyl 3-cyano-5,S-diethoxy-2-oxopentanoatewith P4Sl0 gave thieno[2,3-c]isothiazole-3-carboxylic acid, and not, as previously claimed, thieno [3,4d] isothiazole-4-carboxylic acid. The parent compound was obtained by decarboxylation, and also by deamination of thieno [2,3c] isotkiazol-3amine.604 Alkylation of the product of the reaction between sodium 3iminobutyronitrile and CS2 gave (281), which upon oxidation with iodine gave (282), which could be ring-closed to (283). This compound was deaminated, hydrolysed, and decarboxylated to yield 3-methylthieno [3,2d] isothiazole, which underwent bromination and nitration in the 5p~sition.~’’ Lithiation of 3-methylthieno[3,26] isothiazole and its S-bromoderivative led to ring-opening of the isothiazole ring, giving 3-acetyl-2(buty1thio)thiophen and 3-acetyl-2-(butylthio)thiophen-5-carboxylic acid, respecti~ely.~”~ 3-Aminothieno[3,4-d] isothiazole 1,l -dioxides have been prepared by heating thieno [3,4-d] isothiazol-3(2H)-one 1,l-dioxide with the hydrochlorides of primary and secondary aliphatic amines, phosphorus pentoxide, and N,N-dimethylcyclohexylamineat 240”C.606 4,6-Diphenylthieno[3,4c] [ 1,231oxadiazole reacted with trinorbornene to give four stereoisomeric 1 :2 ad duct^.^'^ L

,& CN

Me

SCH2COOEt

SCH2COOEt

NH2

COOEt

s-

(2811

(282)

(283)

6 Thiophen Fused to Six-Membered Heteroaromatic Rings Thiophen Analogues of Quinoline. - Pyrolysis of 3-(2-thienyl)propenal 0methyloxime at 650°C in a silica tube gave a 33% yield of thieno[3,2-b]pyridine.‘08 New methods for the synthesis of 3-cyanopyridine-2-thiones 602

‘03 604 605 606 607

608

A. Foucaud, Bull. SOC.Chim. Belg., 1981, 90,545. K. Yamane, K. Fujimori, and T. Takeuchi, Chem. Lett., 1981, 293. F. C. James and H. D. Krebs, Aust. J. Chem., 1982, 35, 385. F. C. James and H. D. Krebs, Aust. J. Chem., 1982, 35, 393. K. G. Jensen and E. B. Pedersen, 2. Naturforsch., Teil. B, 1981, 36, 1640. 0.Tsuge, T. Takata, and M. Noguchi, Heterocycles, 1981, 16, 789. C. L. Hickson and H. McNab, Synthesis, 1981,464.


132

facilitated the preparation of thieno [2,3-b]pyridines and pyrido [2’,3;2,3] thieno[4,561 pyrimidine^.^" 2-Chloroquinoline-3-carbaldehyde reacts with methyl thioglycollate to give (284); (285) was obtained in a similar way from 2-chloro-6-bromo-3-formylthieno[2,3-b] pyridine.610 Refluxing vinyl quinolinethiones with sodium hydrogen selenide in ethanol gave 2,3-dihydrothieno[2,3-b]quinolines.611 Dimethoxybenzo [b] thieno [2,3-b] quinoline has been synthesized .530 The mass spectra of thieno-pyridines6’’ and thieno [2,341quinoline61 have been analysed. The spectral and magnetic properties of complexes of divalent transition metals with thieno [2,3-b] thiophen have been investigated.614 Detailed investigations of the photolysis of thieno [2,3b] pyridine N-imides have been carried out: (286; X = H) gave (287; X = H), while (286; X = C02Et, Ac, or COPh) gave a mixture of (287) and (288). Similar results were obtained with derivatives of thieno [3,2-b] ~ y r i d i n e . ~ ~ ’

-N-

X

( 286 1

Thiophen Analogues of Isoquinoline. - A catalytic dehydrogenation of 4,5,6,74etrahydrothieno [3,2c] pyridine to thieno [3,2c] pyridine over a chromium catalyst has been patented.616 Oxazolones (289), easily obtained

( 289) ‘09

k A. Krauze, Z. A. Bomika, A. M. Shestopalov, L. A. Rodinovskaya, Yu. E. Pelcher, G. Ya. Dubur, Yu. A. Sharanin, and V. K. Promonenkov, Khim. Geterotsikl. Soedin., 1981, 377.

610

0. Meth-Cohn, B. Narine, B. Tarnowski, R. Hayes, A. Keyzad, S. Rhouati, and A. Robinson, J. Chem SOC.,Perkin Trans. I , 1981, 2509. 6 1 1 I. K. Raja, Curr. Sci., 1981, 5 0 , 364. 6 1 2 L. H. Klemm, J. Shabtai, J . Michaud, and J. N. Louris, J. Heterocycl. Chem., 1981, 18, 1383. 613 N. Soundararajan, R. Palaniappan, V. T. Ramakrishnan, T. K. Thiruvengadam, K. Kanakarajan, K. Natarajan, and P. Shanmugam, Org. Mars Spectrom., 1980, 15, 651.

0.Piovesana, L. Sestili, and C. Troni, J. Inorg. Nucl. Chem., 1981, 43,2321. T. Tsuchiya, M. Enkaku, and S. Okajima, Chem. Pharm. Bull., 1981, 29, 3173. 616 Belg. P. 886470. ‘14

615


133

from thiophen-2-carbaldehyde and N-aroylglycine, gave 4-arylthieno [3,2c] pyridine-6-carboxylic acid by an intramolecular Friedel-Crafts reaction.617 4-Arylthieno [2,3-c] pyridines and 7-arylthieno [3,2-c] pyridines have been prepared by heating 2-(2-thenylamino)- 1-aryl-ethanols or -propanoh and 2, (3-thenylamino)l -aryl-ethanols or -propanols in PPA.618 Starting from 3chloroisonico tinonitrile, 3 -amino-2-et hoxy carbonyl- and 3-amino-:! -phenylthieno [2,3-c]pyridines were obtained by nucleophilic substitution with sodium thioglycollate or toluene-a-thiolate followed by ring-clo~ure.~'~ Benzo [b] thieno[2,3-c] pyrylium perchlorates were obtained in high yields in the acylation of benzo [ b ]thiophen-3-ylacetone with aliphatic acid anhydrides in the presence of 70% perchloric acid. Treatment of the products with ammonia converts them into benzo [b]thieno [2,3-c]pyridines in high yields.620 Irradiation of thieno [2,3-c] pyridine N-imides gave the novel diazepine-fused systems (290) and (29 1) together with (292). Analogous products were obtained from the thieno [3,2-c] -fused systems. The reaction of (290; X = C 0 2 E t ) with acetic acid-ethanol led to (293), which upon reaction with hydrogen chloride ring-closed to (294). The [3,2-c] -fused system similarly gave 4-ethoxycarbonylthieno[3,2-c] pyrrole.62' 1

Pyrimidine-fused Systems. - Owing to their pharmaceutical interest, many new thienopyrimidine derivatives are still being synthesized. The reaction of 2-amino-3-cyanothiophenswith carbonyl sulphide has been used for the preparation of thieno [2,3-d] -2-thio-o~opyrimidine.~~~ The reaction of 2,5 diamino-3,4-diethoxycarbonylthiophen with phenyl isocyanate in the presence 617

618

619 620

621

622

N. F. Eweiss and A. A. Hosni, J. Univ. Kuwait, S c i , 1981, 8, 195. J.-P. Maffrand, R. Boigegrain, J. Courregelongue, G. Ferrand, and D. Frehel, J. Heterocycl. Chem., 1981, 18, 727. J. L. LaMattha and R. L. Taylor, J. Org. Chern., 1981, 46,4179. V. I. Dulenko, S. V. Tolkunov, and N. N. Alekseev, Khim. Gererotsikl. Soedin., 1981,1351.

T . Tsuchiya, H. Sawanishi, M. Enkaku, and T. Hirai, Chem. Pharrn. Bull., 1981, 29, 1539. M. A. Hernandez, F.-L.Chung, R. A. Earl, and L. B. Townsend, J. 0%.Chem., 1981, 46, 3941.


134

of triethylamine gave (295), and with triethyl orthoformate, 3,6-dihydrothieno [2,3-d :5,4-b'] dipyrimidine-4,5-dione was ~ b t a i n e d . ~ ' A series of compounds of the type (296) has been prepared from 2-amino3-ethoxycarbonylthiophens followed by reaction with 6-chloropyridine-3 carboxylic acid or its ester, and the carboxylic function of (296) has been further modified. The compound showed anti-allergic activity.33 A double ring-closure of (297), obtained from (19b), gave (298), of interest as an anti~oagulant.~'Condensation of 2-amino-3-ethoxycarbonylthiophens with a-thiocyanoacetophenone gave (299);623 by its reaction with formamide, 4oxo-(3H)-thieno [2,3-d] pyrimidines, and with benzyl isothiocyanate, 2mercapto-3-benzyl-4-oxothieno[2,3-d]pyrimidines, were obtained.624 NArylthieno [2,3-d] pyrimidin-4-amines have been prepared by heating 2acylaminothiophen-3-carbonitriles with a mixture of phosphorus pentoxide, arylamine hydrochloride, and NN-dimethylcyclohexylamine.625Similarly, thieno [2,3-d] pyrimidin-4(3H)-ones were prepared from ethyl or methyl 2acylaminothiophen-3-carboxylate, using the same reagent .626 They have also been prepared from the same starting materials via the thieno-o~azines.~~' The reaction of 2-amino-3-et hoxy carb onylthiophens with y-halocr ot ononitrile s 0

0

H

H

0

COOMe

623

H. K. Gakhar, S. Bharadwaj, A. Jain, and P. Baveja, J. Indian Chern. SOC., 1981, 58, 1017.

624

625

626 627

V. J. Ram, H. K. Pandey, and A. J. Vlietinck, J. Heterocycl. Chern., 1981, 18, 1277. K. E. Nielsen and E. B. Pedersen, Chem. Scr., 1981, 18,245. K. E. Nielsen and E. B. Pedersen, Chern. Scr., 1981, 18, 135. M. J. Kulshreshtha, S. m a t t , M. Pardasani, and N. M. Khanna, J. Indian Chern. SOC., 1981, 58, 982.


135

gave (300).628Photochemical ringclosure of (301) gave (302).629 Syntheses and reactions of 2-chloro-3,4-dihydrothieno-pyrimidinesand -quinazolines6309631and of 2-substituted 4-chlorothieno[2,3-d] have been studied. Cyclodehydration of 2-carboxymethylmercaptothieno[2,3-d]pyrimidin-4(3H)-ones, leading to derivatives of thiazolo [3,2-a] thieno [2,3d] pyrimidine, has been investigated.633

R2

Miscellaneous Fused Systems. - An elegant synthesis of thieno [2,3-d] pyridazine in 40% yield consists of heating thiophen-2-carbaldehyde azine with A1C13-triethylamine at 170-200°C.634 2,3-Dimethylthieno[3,4-b] pyrazine has been prepared from 2,4-diamin0thiophen.~~'A derivative of the unusual thienopterine (303; R = OH) that was isolated from human urine in 1940, namely (303; R = H), has been synthesized from 2-amino-3,s-dicyano6-chloropyrazine in nine steps. First a thiophen ring is fused by reaction with 1-metcaptopropan-2-oneand then ring-closed to an amino-ketone intermediate, followed by conversion of the amino-group into a methylthio-group via the bromo-derivative, and finally annelation of the pyrimidine ring.635 Double react ion of N-aroylt hioace t amide with a-halogeno carb oxy lic esters gave

(303) 628

629

bH

M. S%se and S. Johne, J. Prakt. Chem., 1981, 3 2 3 , 647. T. Itoh, H. Ogwa, K. A. Watanabe, and N. Kawahara, Chem. Pharm. Bull., 1981, 29, 1039.

630

"'

632 633

H. Yamaguchi and F. Ishikawa, J. Heterocycl. Chem., 1981, 18,67. H. Yamaguchi and F. Ishikawa, Chem. Pharm. Bull., 1982, 30,28. H. Yamaguchi and F. Ishikawa, Chem. Pharm. Bull., 1982, 3 0 , 326. P. €3 Talukdar, S. K. Sengupta, and A. K. Datta, Indian J. Chem., Sect. B y 1981, 20, 538.

634

635

S . K. Robev, Tetrahedron Lett., 1981, 2 2 , 345. E. C. Taylor and L. A. Reiter, J. Org. Chem., 1982, 47, 528.


136

intermediates of the type (304), which spontaneously underwent double cyclization to (305).636 Treatment of 2-acylamino-3-ethoxycarbonylthiophens with t riphenylphosphine-hexachlor oet hane- t riet hylamine gave thieno-fuse d 6H- 1,3-0xazin-6-ones.637 The react ion of 2 -aminothi ophen-3-carboxamide s with SOClz, SClz, or SzCl2 gave thieno-fused 1,2,6-thiadia~ines.~~~ Benzothienothiazines have been obtained by diazotization of 2-aminobenzo [ b ]thiophen-3-carboxylate, followed by the reaction with SO2 to give the sulphon 1 chloride, which was amidated with ethyl glycinate and ringclosed.6 Thieno [2,3-~]coumarins have been re pa red.^^'? 641 Reactions of 5phenylthieno [3,2-b] pyran-7-one, 2-phenylbenzo [b] thieno [3,2-b] pyran-4one, and the corresponding thiones with sodium ethylate, guanidines, hydrazines, and enamines have been investigated.a2 Pyridino [3,2-b] thieno[3,4-c] [ 1,4] diazepines that have potential CNS activity have been prepared from (23)."4

Y

NH P.

1

COOR~

7 Selenophens and Tellurophens Monocyclic Selenophens. - Heating divinyl selenide to 380-45OoC gave a 50% yield of ~ e l e n o p h e n . The ~ ~ reaction of sym-tetracyanoethane with hydrogen selenide in DMF-pyridine gave 92% of 2,5-diamino-3,4-dicyanoselenophen.26 The reaction of lithium phenylethynylselenolate with methyl phenylpropiolate gave, under certain conditions, methyl 2,4-diphenyl~elenophen-3-carboxylate.~ Halogen-metal exchange of 3,4-dibromoselenophen with butyl-lithium at - 7OoC, followed by reaction with dimethyl disulphide, gave 3-bromo-4-(methylthio)selenophen, which upon renewed halogen-metal exchange and reaction with DMF gave 4-(me thy1thio)~elenophen-3-carbaldehyde.~~' The electrochemical reduction of selenophen636

637 638

P. I(rey and H. Dehne, 2. Chem., 1981, 21, 31. D. Achakzi, M. Ertas, R. Appel, and H. Wamhoff, Chem. Ber., 1981, 114, 3188. W. Offermann, K. Eger, and H. J. Roth, Arch. Pharm. (Weinheim, Ger.), 1981, 314, 168.

R. F'fiiter, Eur. Pat. Appl. 2 1 058, 1981. G. k Miller and N. D. Heindell, Synthesis, 1981, 894. 64L M. Trkovnik, R. Djudiic, I. Tabakovic, and M. Kules, Org. Prep. Proced. I n t . , 1982, 14, 21. 642 P. Netchitailo, B. Decroix, and J. Morel, J. Heterocycl. Chem., 1982, 19, 327. 643 M. G. Voronkov, B. A. Trofimov, E. N. Deryagina, E. N. Sukhomazova, N. K. Gusarova, V. A. Potapov, and S. V. Amosova, Zh. Org. Khim., 1982, 18,223. 644 M. L. Petrov, V. Z. Laishev, and A. A. Petrov, Zh. Org.Khim., 1981, 17,667. 6 4 5 A. Konar and V. Litvinov, Chem. Scr., 1982, 19,176.

639 640


137

2-carboxylic acid gave a mixture of three dimeric acids, in contrast to the behaviour of the corresponding furan- and thiophen-carboxylic acids, which give the 2,5-dihydro-deri~atives.@~ Poly(selenien-2,5-ylene)has been prepared by converting 2,5-dibromoselenophen into the Grignard reagent and polymerization with Ni” salt^.^' Condensed Selenophens. - The reaction of lithium phenylacetylide with the complex butyl-lithium-potassium t-butoxide gave the ortho-metallated phenylacetylide, which reacted with selenium to give benzo [b] selenophen.a8 The reaction of benzo [b J selenophen with a-hydroxy-N-benzyloxycarbonylglycine in the presence of sulphuric acid gave, after further modification, benzo [b] ~elenienylglycine;~~ in the text this was claimed to be the 2-isomer, based on n.m.r. data, but in the experimental part and in Chemical Abstracts it is given as the 3 - i s 0 m e r . ~The ~ 77Se n.m.r. spectra of 79 mono- or disubstituted benzo[b] s e l e n ~ p h e n s , ~as ’ ~ well as the 77Se and 13C n.m.r. spectra of thienoisoselenazoles, selenoloisothiazoles, selenoloisoselenazoles, and thienoisothia~oles,~~~ have been published. The synthesis and reactions of new selenapseudophenalenones have been in~estigated.~’~ The reaction of 2-methyl-3-benzoylfuran with NN-diethylseleno propionamide gave 1 -phenylselenolo [ 3,441 furan. The thiophen analogue was obtained similarly, using thioacetamide. Applying the same reaction to phenyl 3-methylindol-2-yl ketone gave 3-phenylselenolo [3,4-b] indole and 3phenylthieno [3,4-b]ind01e.~’~Selenolo [3,4-b]thiophen, the last hitherto unknown ‘classical’ selenolothiophen, has been best synthesized via quaternization of 4-(methylthio)selenophen-3-carbaldehyde with bromoacetate followed by cyclization and decarboxylation. It could also be obtained from methyl 4,5-bis(chloromethyl)thiophen-2-carboxylate by its reaction with sodium hydrogen selenide and aromatization of the ring. The ‘H, I3C, and 77Se n.m.r. spectra were analysed. Similar to its sulphur analogue, but in contrast to the selenium analogue, i.e, selenolo [3,4-b] selenophen, selenolo[3,4-b] thiophen was unstable and polymerized easily.@’ Vilsmeier formylation of selenolo [2,3-c] thiophen gave a mixture of the 4- and 6-formyl derivatives in a 3 :2 ratio. Metallation with butyl-lithium followed by reaction with DMF gave a ring-opened product, 4-($?-butylselenoethenyl)thiophen-3carbaldehyde, together with the 4- and 6-carbaldehydes in a ratio of 1 :4.654 V. P. Gultyai, T. G. Konstantinova, A. M. Moiseenkov, V. P. Litvinov, and A. Konar, Chem. Scr., 1982, 19,95. M. D. Bezoari, P. Kovacic, S. Gronowitz, and A.-B. Hornfeldt, J. Polym. Sci., Polym. Lett. Ed., 1981, 19, 347. 648 H. Hommes, H. D. Verkruijsse, and L. Brandsma, J. Chem. SOC., Chem. Commun., 1981, 366. 6 4 9 T. Sadeh, M. A. Davis, R. Gil, and U. Zoller, J. Heterocycl. Chem., 1981, 18, 1605. 650 M. Baiwir, G. Llabrbs, L. Christiaens, and J.-L. Piette, Org. Magn. Reson., 1981, 16, 14. 651 N. V. Onyamboko, M. Renson, S. Chapelle and P. Granger, Org.Magn. Reson., 1982, 19, 74. 6 5 2 R. Neidlein and E. A. Varella, Chem. Chron., 1980, 9, 91. 6s3 A. Shafiee and S. Sattari, J. Heterocycl. Chem., 1982, 19, 227. 6 5 4 S. Gronowitz, A. Konar, and V. P. Litvinov, Izv. Akud. Nauk SSSR, Ser, Khim., 1981,1363.

646

647

138


Substituent effects in 2-substituted selenolo [3,2-b] selenophens have been studied by ‘H, 13C, and 77Se n.m.r. spectroscopy; good linear correlations between these shifts and those of thieno [3,2-b] thiophens were ~bserved.~” The ‘H, 13C, and 77Se n.m.r spectra of some selenolo[3,2c] thiophens have also been CND0/2 calculations have been carried out on selenophen and on [2,3-b] -, [3,2-b] -,and [3,4-b] -fused ~elenophens.~’~ Tellurophens.- In the reaction of sodium 2-phenylethynyltellurolate with DMAD, dimethyl 4-phenyltellurophen-2,3-dicarboxylate was formed in low yield.658 Di-2-tellurienyl ketone was prepared by allowing tellurophen to react with butyl-lithium and C02.6592,5-Dihydrotellurophen 1,l -dichlorides were obtained through the reaction of butadiene, isoprene, or 2,3-dimethylbutadiene with tellurium tetrachloride in acetonitrile. They were easily reduced to the corresponding 2,5-dihydrotellurophens with aqueous sodium sulphide.660 Reactions of benzotelluracyclopentane di-iodide have been investigated.661

PART 11: Systems containing Nitrogen and Sulphur, Selenium, or Tellurium by H. Quiniou and 0.Guilloton 1 Introduction and Reviews A review describes the pharmacological properties of 1,2-benzisothiazoles.’ In connection with thiazoles, we find several reviews or papers: thiazoles in food aromas;2 patellamides, which are antineoplastic cyclic peptides, from the marine tunicate Lissoclinum pateZZa, which contain an unusual fused oxazoline-thiazole unit;3 and polythiazole-containing peptide antibiotic^.^ An interesting total synthesis of the aglycon of bleomycin A2 should also be mentioned. 655 656

S. Gronowitz, A. Konar, and A.-B. Hornfeldt, Chem. Scr., 1982, 19, 5. S. Gronowitz, A. Konar, I. A. Abronin, and V. P. Litvinov, Izv. Akad. Nauk SSSR, Ser. Khim., 1981, 1285. I. A. Abronin, A. Z. Djumanazarova, V. P. Litvinov, and A. Konar, Chem. Scr., 1982, 19, 75.

658

659 660 661

V. Z. Laishev, M. L. Petrov, and A. A. Petrov, Zh. Org. Khim., 1981, 17, 2064. W. Lohner and K. Praefcke, J. Organomet. Chem., 1981, 208,43. J. Bergman and L. Engman, J. Am. Chem. Soc., 1981, 103,2715. T. N. Srivastava, P. C. Srivastava, and R. Kumar, J. Indian Chem. SOC.,1982, 59, 186.

’ A. De, Prog. Med. Chem., 1981,18,117 (Chem. Abstr., 1982,96,154817). *

G. Vernin, Riv. Ital. EPPOS, 1981, 6 3 , 190 (Chem. Abstr., 1981, 95,132 706). C. M. Ireland, A. R. Durso, Jr., R. A. Newman, and M. P. Hacker, J. Org. Chem., 1982,47,1807.

L. B. Sokolov, L. E. Alekseeva, and E. B. Ratsino, Antibiotiki (Moscow), 1981, 27, 299 (Chem. Abstr., 1982, 96,187 131).

T. Takita, Y. Umezawa, S. Saito, H. Morishima, H. Umezawa, Y. Muraoka, M. Suzuki, M. Otsuka, S. Kobayashi, and M. Ohno, Tetrahedron Lett., 1981, 22,671.

Five-Membered Rings: Systems containing N and S, Se, or Te

139

0the r ring systems reviewed include 3 -acyl-1,3- thiazolidine-2 -thione (monitored aminolysis),6 benzothiazoles in the aquatic environment ,' and 1,2,5-thiadiazole and its selenium analogues.8 Selenium and tellurium compounds that include nitrogen are also described in proceedings published in 1981.9 2 Isothiazoles Synthesis. - From Dicyanoacetylene and Sulphur Dioxide (Type A; C-C-CN S)." Dicyanoacetylene (NCCGCCN) reacts with SOz and HBr t o give 35% of 5-cyano-3,4-dibromoisothiazole (l)."

+

Synthesis of Isothiazoles from P-Benzoylpropionamidesand Thionyl Chloride (Type A ) . N-Phenyl-0-benzoylpropionamide ( 2 ) and SOCl2 give 5 -benzoyl-2phenylisothiaaolin-3-one (3)." 0

II

NcfiBr

PhCO(CH2)2CONHPh

Br

(2)

oQc'hp

(1)

(3)

+

Synthesis of Isothiazoles from I ,3,2-0xathiazol-5-ones (Type B; S-N-C C-C). The thermal reaction of meso-ionic 1,3,2-oxathiazol-5-one [4; R = 2,3,4(Me0)3C6H2] with dimethyl acetylenedicarboxylate (DMAD) at 80°C with C02 evolution gives 80% of isothiazole (5; R the same) (Scheme 1).12

'r + % '

Me00CCECCOOMe

COOMe

MeOOC 0

(4)

(5)

Scheme 1

Y. Nagao and E. Fujita, Heterocycles, 1982,17, 537. B. Brownlee, J. H. Carey, and M. E. Fox, Sci. Sere-Can.,Inland Waters Dir., 1981, 126 (Chem. Abstr., 1982,96,204953). W. S l i m and A. Thomas, Wiad. Chem., 1981, 35, 373 (Chem. Abstr., 1982, 96, 52 194). D. Cagniant and G. Kirsch, Proc. 3rd Int. Symp. Org. Selenium Tellurium Compd., Metz, France, 1979. l o Yu. L. Zborovskii, I. V, Smirnov-Zamkov, and V. I. Staninets, Zh. Org. Khim. 1982, 18,675 (Chem. Abstr., 1982,96,217750). l 1 R. J. S. Beer and D. Wright, Tetrahedron, 1981, 37, 3867. l 2 H. Gottmardt, F. Reiter, and C. Krumer, Liebigs Ann. Chem., 1981, 1025.

* For

definitions of the types A, B, etc. for isothiazoles, see p. 110 of Volume 1 of this series.

140


Visible-light-induced fragmentation of ( 5 ) gives a nitrile sulphide intermediate RCSN-S-, which decays unimolecularly to give S and RCN, or whch can be partially trapped with DMAD to form the isomeric isothiazole (6).

Synthesis of Isothiazoles from 3,3'-DisulphunedipropionylChloride and Amine (Type H; S-C-C-C N ) . 3,3'-Disulphanedipropionylchloride, (SCH2 -CH,COC1)2, reacts with 2,6-MezC6H3NHzto give (SCH2CHzCONHC6H3Me22,6)*.13 This latter compound is treated with S02C12 t o give 4-isothiazolin3-one (7). The oxidation of (7) with 3-C1C6H4CO3Hgives the corresponding 1,l -dioxide (8).

+

a,'

-

MeOOC RyN'ycOOMe

(6)

"/o

"/o ' cs'k O2

Me

0

Me 0

(7)

(8)

Synthesis of Isothiazolesfrom Aqueous Ammonia and Thioamide Vinylogues (Type H). Aqueous ammonia transaminates the thioamide vinyl~gues.'~ In addition, the 3-amino-1-arylpropenethiones, in the presence of elemental sulphur, undergo ring-closure to give 65-95% of 5-arylisothiazoles (9) (Scheme 2). S

II

ArCCH=CHNH2

=

SH

I

sx

ArC=CHCH=NH

Synthesis of Isothiazoles by Ring-Cleavage of 3-Azidothiophens. 3-Azidothiophen-2-carbaldehyde is condensed with N3CH2C02Et to give (10; R = H).lS Thermal decomposition of (10; R = H) in toluene gives cleavage of the thiophen ring and extrusion of acetylene to yield 19% of isothiazole (1 1) together with 17% of the cyclization product (12). The thermolysis of the azide (10; R = C02Et) gives (13). CH=CRCOOE t [R = HI \[R

NC

(11)

= COOEt]

(12)

(13) l3

l4

Meiji Seika Kaisha Ltd., Jpn. P. 81 118 073,1981 (Chem. Abstr., 1982, 96,35 235). H. Quiniou, Phosphorus Sulfur,198 1, 10, 1 . C. J . Moody, C. W. Rees, and S. C. Tsoi, J. Chem. SOC.,Chem. Commun., 1981, 550.

141

Five-Membered Rings: Systems containing Nand S, Se, or Te

Synthesis of Isothiazoles porn Substituted Enamines and Benzyl Isothiocyanate (Type C-C-N S-C). h i d e vinylogues (14; R' = PhCO, 4-C1C6H4C0, 4-MeOC6H4C0,or 4-MeC,H4CO; R2 = SMe or NHEt; R3 = Ph or Et), when treated with PhCONCS, give the intermediates (15), then pyrimidinethiones (1 6) and isothiazoles ( 17).16 The structure of the isothiazoles is further confirmed by subjecting the intermediates (1 5 ) to oxidation by bromine, which also gives isothiazoles (Scheme 3). Similarly, the nitroenamine (14; R' = NO2) gives the intermediate R3NHCR2=C(N02)CSNHCOPh, then the isothiazole (17; R' = NO2), but no pyrimidinethiones.

+

R1CH=CR2NHR3

S

(14)

+

SCNCOPh

:' 6

,COPh

R3P

h

N

I1

R1 \C"S'H

II

,COPh N

RwC\NH

I

R3

(15) (17)

Scheme 3 Physical Properties of Isothiazoles. - The i.r. and U.V. spectra of 3 3 bis(methy1thio)isothiazoles (18; R = H, CN, NH2 etc.) have been studied."

(18)

Chemical Properties. - N-Quaternization of Isothiazoles. 3-Chloroisothiazole is quaternized by FS03Me; the salt is then treated with MeNH2 and passed through an ion-exchanger (Cl-) to give (19; R' = R2 = Me; Z = C1).18 Other

16

17

18

V. Aggarwal, H. Ila, and H. Junjappa, Synthesis, 1982, 65. G. Mille, J. C. Poite, M. Guliano, and J. Chouteau, Spectrosc. Lett., 1981, 14, 271. J. Rokach, C. S. Rooney, and J . E. Cragoe, Jr., U.S.P. 4 2 9 2 4 3 0 , 1981 (Chem. A h * . , l 9 8 2 , 9 6 , 3 5 2 3 6 ) a n d 4 2 6 7 3 4 1 , 1 9 8 1 (Chem. Absstr., 1981,95,132864).


142

salts (19; R1 = H, alkyl, Ph, or PhCH2; R2 = alkyl, Ph, or PhCH,; Z = halide, sulphonate, nitrate, phosphate, or various carboxylates) can also be prepared. 3-Methoxyisothiazole is quaternized as above .l Other 3-alkoxy-2-alkylisothiazolium salts and their derivatives (20; R' = alkyl, or alkenyl; R2 = alkoxy, PhCH20, OCKMe, CH2=CHCH20,or CH2=CMeCH20; R3 = H, C1, or Br; R4 = H or C1; X = counter ion), are similarly prepared, as are 3haloisothiazolium salts (21; R1 = alkyl or alkenyl; R2 = C1 or Br; R3 = H, Me, Et, C02Me, C02Et, C1, Br, NO2, or cyano; R4 = H, Me, Et, C1, Br, cyano, C02Me, or C02Et; X = anion).20

(20)

(21)

Reactions of 5-Aminoisothiazoles. 5-Amino-3-methylisothiazole (22) gives 1 : 1 adducts with nitriles RCN [R = (un)substituted Ph] or EtOCMe=NH to give the thiadiazoles [23; R = (un)substituted Ph or Me] .21 5-Amino-3methylisothiazole-4-carboxylic acid (24), in benzene that contains pyridine, reacts with C1CH2COC1 and then with HNR2 to give 5-dialkylaminoacylamino-3-methyl-4-carboxylic acid derivatives (25; R = Me or Et; n = 1 or 2).22 5-Amino-3-alkylisothiazolium hydrochlorides (26; R' = H or Me) are diazotized and coupled with substituted or annelated anilines to give the free bases, which are quaternized to yield the salts [27; R' = Me, Et, CH2CH20H, CH2CH(OMe)Me,. or CH2CH=CH2; R2, R3 = H or Me; R4 = Me or Et; R5 = H, Me, Et, Pr, Pr', CH2CH20H, or CH2=CHCH2 ; R6 = H, Me, Et, Pr, or Pr'; R4R6 in combination with an amino-ring can form an annelated morpholine residue; X = anion] .23

( 2 2 ) R1= .H ( 2 4 ) R1= COOH

(26)

(23)

(27)

J. A. Vhgilio, M. Manowitz, and E. Heilwell, U.S.P. 4262127, 1981 (Chern. Abstr., 1981,95,62 181). J. A. Virgilio, M. Manowitz, and E. Heilwell, U.S.P. 4281 136, 1981 (Chern. Abstr., 1981,95,203 937). " K. Akiba, A. Noda, K. Ohkata, T. Akiyama, Y. Murata, and Y. Yamamoto, Heferocycles, 1981, 15, 1155. '' Z. Machon, M. Mordawski, and M. Wilimowski, Pol. P. 104 802,1979 (Chern. A bstr., 1981,95,80 942). 23 B. Gertisser, Ger. Offen. 3 029 746,1981 (Chern. Abstr., 1981,9S,26 600). l9

Five-Membered Rings: Systems containing N and S,Se, or Te

143

A?-Isothiazolines.- Chemical Properties of Isothiazoline-5-thiones. By treatment with (EtO),P in benzene, isothiazoline-5-thiones (28) are desulphurized to bis(isothiazoly1idene) (29; R1,R2,R3 = Me, H, Ph; But, H, Ph; Ph, H, Ph; or 4-HOC6H4, H, Ph).24

(29)

A4-1sothiazolines.- Chemical Properties of Isothiazolin-3-ones.

Examples of additions to carbon-carbon double-bonds have been given. Thus 2-octyl-4isothiazolin-3-one 1,l-dioxide (30; R = octyl) is treated with diethyl dithiophosphate to give 4- or 5-(diethyldithiophosphoryl)-2-octylisothiazolidin-3-one 1,l -dioxide (3 1; R = octyl)?' -- - Chloro-5-methyl-4-phenyl-2isothiazolin-3-one with Me2NCS2Na gives substitution products (32). Other derivatives (33), with R3 = CN or polymethyleneimino, were described.26 5-Benzoyl-2-phenylisothiazolin-3-one (34) with (MeC02)2CH2 in MeOH that contains NaOMe, at room temperature, gives the pyrrolinone ( 3 9 , which gives the pyronomaleimide (36) on refluxing in ~ y l e n e . ~ '

88t$ cf~$

(\&

0

O2

Et2PS

R3fs\c

R2

Me 0

0

0

(30)

(31)

0 (33)

(32) 0

PhCO[aO (34)

p

ceM;;

h

~

pho@

~

~

Ph

(35)

0

NPh

0

(36)

Isothiazolidines. - Physical Roperties of Isothiazolidine 1,I -Dioxides. Proton n.m.r. (60, 90, and 250MHz) spectra have been reported for isothiazolidine 1,l-dioxides (sultams) (37; R' = H or Me, R2 = H or substituent) and com-

RENR2 (37)

24

2s

26 27

P. D. Clark and D. M. McKinnon., J. Heferocycl. Chem., 1981, 18,437. G. A. Miller and E. D. Weiler, U.S.P. 4302240, 1981 (Chem. Absfr., 1982, 96, 162 930). R. B. Petigara, Eur. Pdt. Appl. 31 705,1981 (Chem. Abstr., 1981,95, 187 235). R. J. S. Beer and D. Wright, Teimhedron, 1981, 37,3867.

144


pared with those of propane-l,3-~ultone.~~ The paramagnetic shift that is induced by the NH group is smaller than that induced by 0. Low-temperature n.m.r. shows coupling effects with the NH proton. 3 1 ,ZEknzisothiazolesand their 1,l-Dioxides Synthesis. - From ortho-Halobenzoyl Compounds, Aqueous Ammonia, and Elemental Sulphur. Treating a mixture of 2,5-C1(N02)C6H3CHO and sulphur in DMF at 70°C with 25% aqueous NH3 gives 95% of 5-nitro-1,2-benzisothiazole (38) (Scheme 4).29 Other compounds (39; R' = H, aliphatic, cycloaliphatic, optionally annelated aromatic, halo, alkoxy, NO2, or NR2 ;R2-= H, aliphatic, cyclo-aliphatic, arylaliphatic, or aromatic; R3 = H, aromatic or heterocyclic) are similarly prepared by he ter ocyclization.

Scheme 4 Reactions of 1,2-Benzisothiazoles.- Reduction. Thiophenol reduced compounds (41), (42), and (43) to o-mercaptophenylformamidines [40; R' = H, Me, Et, or 4-C1C6H4;R2 = H, Me, or Et; R3 = H, Me, Et, or Ph; R4 = H, 4-C1 or 6-C1; or R1R2 = (CH,),, R3 = Me, R4 = HI with good yields.30 R3N=C-NR1R2

\

NR'

,S

+,R3

\

28

29

30

K. H. Albert, H. Duerr, S. H. Dos, and J. P. Zahra, Org. Mugn. Reson., 1980, 14, 209. H. Hagen, J . Markert, and H. Ziegler, Ger. Offen 3018108, 1981 (Chem. Absstr., 1982, 9 6 , 6 8 980). H. Boeshagen and W. Geiger, Liebigs Ann. Chem., 1982,14.


145

3-Chloro-substitution. 3-Chloro-l,2-benzisothiazole 1,l-dioxide with 3(hydroxymethy1)pyridine in toluene/Et3N gives (44).31Other ethers or thioethers(45; Z = 0 or S ; R = R1,CH2R2 [R' = (un)substitutedimidazolyl, thiazolinyl, etc.; R2 = (un)substituted furyl, imidazolyl, etc.] } are similarly prepared.

Photochemistry. The photochemical reaction of benzisothiazoles (46; R = H) with DMAD gives a mixture of [48;2 (30%), E (50%)] and the substituted benzo thiophen (47) (Scheme 5). 32 5-Chlorobenzisothiazole be haves similarly. A mechanism involving initial cleavage of the thiazole ring to a diradical has

0sLi

MeOOCC%COOMe

R\

MeOOCC =CHCOOMe

I

~

CN

hv

CN (46)

R

(47)

(48)

Scheme 5

been proposed. Irradiation (300 nm) or 3-phenyl-l,2-benzisothiazole (49; R' = R2 = H) in EtOCH=CH2 for 90-150h under N2 gives 80% of 2,3dihydro-l,4-benzothiazepine(50).32* 33 The structure of the latter compound was determined by X-ray analysis. The same reaction has been described for photocycloaddition of other benzisothiazoles (49; R' =Me, R2 = H ; R' = H, R2 = C1) and alkenes. The reaction is regio- and stereo-specific. Ph

Synthesis of 1,2-Benzisothiazolin-3-onesand their 1,l-Dioxides. - From 2(Methy1sulphinyl)benzamides and Thionyl chloride. The reaction of 2(methylsulphiny1)benzamides with thionyl chloride, a novel and convenient 31

32

33

T. Nihon and S. Noyaku, Jpn. P. 81 133 287,1981 (Chem. Abstr., 1982, 96, 759). M. Sindler-Kulyk and D. C. Neckers, Tetmhedron Lett., 1981, 22, 525 and 529. M. Sindler-Kulyk, D.C. Neckers, and J. R. Blount, Tetrahedron, 1981, 37, 3377.

146


method for preparing 2-substituted 1,2-benzisothiazolin-3-ones (51 ; R = Et, Pr, But, C6Hll, PhCH2, Ph, or 4-MeC6H4), has been described (Scheme 6).% 0

C1-

?

Me

-

S-Me

[-HCl]

CNHR

0

II

0

0

Scheme 6 Synthesis from Anilines and 2-Chlorothiobenzoyl Chloride. 2,4-(02N)zC& NH2, when treated with 2-C1C6H4CSC1 and oxidized with H 2 0 2 , gives (52).35

( 5 2 ) R = 2,4-(N02)2C6H3

Synthesis of 1,2-BenzisothiazoEin-3-one I ,I -Dioxides from 2-Aminobenzonitriles and SO2. 2,6-o2N(Meo)C6H3CN is reduced and the 2,6NH2(MeO)C6H3CN is treated with NaNOz followed by SO2 to give 3-amino4-methoxy-l,2-benzisothiazole1,l-dioxide, which underwent demethylation followed by hydrolysis to give (53).36

bP’e OH

\

34

35 36

0

Y. Uchida and S. Kozuka, J. Chem. SOC., Chem. Commun., 1981, 510. Jpn. P. 81 6 5 882 (Chem. Abstr., 1982,96,20089). G. Trummlitz, W. Eberlein, W. Engel, and G. Schmidt, Ger. Offen. 3 01 5 113, 1981 (Chem. Abstr., 1982,96,104 222).


147

Synthesis of 1,2-Benzisothiazolin-3-0ne 1,I -Dioxides from 2-(Ch1orothio)benzoyl Chloride and Substituted Anilines. 2-(C1S)C6H4COCl with 2,4(02N)zC6H3NH2 gives a benzisothiazolinone derivative (54), which is oxidized by H z 0 2 to give [55; R = 2,4-(02N)2C6H3].37 By this method (or other methods), ( 5 5 ; R = fluoro-, nitro-, trifluoromethyl-, cyano-, alkoxycarbonylalkanoyl-, carboxy-, carbamoyl-, acylamino-, alkylsulphonyl-, N,Ndialkylsulphamoyl-, trifluoromethoxy-, trifluoromethylthio-, trifluoromethylsulphonyl-, or trifluoromethylsulphinyl-phenyl) are also prepared.

Synthesis of 1,2-Benzisothiazolin-3-onesfrom Thermal Decomposition of N-Substituted 2-(Methylthio)benzarnides. The compounds 2-MeSC6H4CON(But)OCOR (R = Ph or 4-MeC6H4) are prepared by acylating ButNHOCOR with 2-MeSC6H4COC1in the presence of pyridine.% Compound (56; R = Me, 4-MeC6H4, or 4-C1C6H4) is prepared by treating 2-MeSC6H4CON(OH)But with RCOCl. Thermal decomposition of (56), at 200°C in o-dichlorobenzene, gives (57) as the initial product of the thermolysis. Subsequent decomposition gives the isothiazolinone (58), RC02H, 2-MeSC6H4CONHBut, RC02Me, RCONHBU~, and (59) (Scheme 7).

OCOR

-

SCH20COR

C'

II

It

'But

0

0

(59)

+ other products

Scheme 7

37

H. Jones, R. L. Clark, and M. Zimmerman, U. S. P. 4 276 298, 1981 (Chem. Abstr.,

38

1981,95, 203 929). Y. Uchida, Y. Kobayashi, and S. Kozuka, Bull. Chem. SOC.Jpn., 1981,54,1781.

148


Physical Properties of 1,2-Benzisothiazolin-3-ones. - The infrared spectra of N-substituted isobenzothiazolinone 1,l -dioxides have been measured and characteristic frequencies for the S-N stretching vibration disc~ssed.3~ The medium bands at 819-870cm-1 are assigned to the S-N stretching. Chemical Properties of 1,2-BenzisothiazoIin-3-ones. - Hydrolysis,Alcoholysis, and Phenolysis. Hydrolysis of N-nitro-imides (60) generally involves N-N02 bond cleavage, which is catalysed by the HN03 that is formed in the reaction; in the absence of acid catalysis, (60) is hydrolysed with N-S02 bond cleavage.40 Alcoholysis occurs at the N-CO bond. The effect of solvent on the alcoholysis has been studied. N-Carbamoylsaccharins are split between the N and the CO of the carbamoyl with phenols. Thus 3-(Me02CNH)C6H40H reacts with (61 ; R = Ph) and Et3N, in acetone at 4OoC,to give (62).

Reactions of 1,2-Benzisothiazolin-3-ones with Amines. - N-(Phenylsulphonyl) saccharin (63) with RNH2 (R = Ph, PhCH2, or Bu), in solvents, at room temperature, affords the ringopened adducts (64):l When heated at its melting point, (64; R = Ph) gives 93% of (65 ; R = Ph). With N-unsubstituted saccharins and primary and secondary aliphatic amine hydrochlorides, at 240°C, in the presence of P205 and NN-dimethylcyclohexylamine,there is a single dehydration between the carbonyl and the amino-group to give (65)?2

39 40

41

42

Y. Abe, T. Horii, T. Oka,S. Kawamura, and T. Nakabhayashi, Annu. Rep. Radiat. Cent. Osaka Prefect., 1980, 21,67 (Chem. Abstr., 1982, 96,68 159). I. K. Koslova, 0. A. Luk'yanov, and V. A. Tartakovskii, Izv. Akad. Nauk SSSR. Ser. Khim., 1981,2556 (Chem. Abstr., 1982, 96, 67902). Y. Imai, H. Okunoyama, K. Hirata, and M. Ueda, Nippon Kagaku Kaishi, 1982, 111 (Chem. A bstr., 1982, 96,104 134). K. G. Jensen and E. B. Pedersen, 2. Naturforsch., TeiZ. B , 1981, 36, 1640 (Chem. Abstr., 1982, 96, 122 677).


149

N-Substitution of 1,2-Benzisothiazolin-3-ones. - Saccharin K salt, when stirred with BuOCHC1CH2CC13 in 1 : 10 H20/Me2C0, at room temperature, gives the trichloropropane derivative (66).43

1,2-Benzisothiazoline-3-thione 1 ,l -Dioxides. - The sodium salt of 1,2-benzisothiazoline-3-thione 1,l-dioxide (67), when treated with RX (R = PhCH2, On

PhCH2CH2, PhCH=CHCH2, CH2zCHCH2, CHGCCH2, NCCH2, or Me;X = C1, Br, or I) gives 80-93% of ( 6 Q 4 From the latter, the corresponding thiols RSH are produced with piperidine in almost quantitative yield. Compound (68) is claimed as being an odourless crystalline equivalent of thiols.

1,2-Benzisothiazolidinesand their 1,l-Dioxides. - 2-MeC6H4S02C1, when brominated to 2-BrCH2C6H4SO2C1 and then treated with NH40H, gives (69; R' , R 2 , R3 = H). This compound reacts with C1SCCl2CHCl2 t o give (70; R1 = SCC12CHC12, R2 = H)?' Infrared data indicate that (69; R', R2 = Ph; R3 = NH2) exists in equilibrium with (70); (69) was stabilized when R' = But or ?-IP

43

44

4s 46

Jpn. P. 81 43 265,1981 (Chem. Abstr., 1981,95,97587). K. Inomata, H. Yamada, and H. Kotake, Chem. Lett., 1981, 1457. D. C. K. Chan, U.S.P. 4 253 865,1981 (Chern. Abstr., 1981,95,80935). R. Valters, D. Balode, R. Kampare, and S. Valtere, Khim. Geterotsikl. Soedin., 1981, 1209 (Chern. Abstr., 1981,95,203048).


150

4 1,2-Benzisoselenazoles 1,2-Benzisoselenazolin-3-ones. - p-Toluidine, when treated with 2-ClSeC6H4COC1, gives 90% of (71; R' , R 2 , R3 = H, R4 = 4-Me, n = O).47 Other benzisoselenazolinones (R1, R2 = H, halogen, alkyl, alkoxy, OH, CF3, or NO2; R'R' =R3R4 = OCHZO; R3, R4 = H, halogen, alkyl, alkoxy, OH, CF3, NO2, dialkylamino, cyano, C02H, or alkoxycarbonyl; n = 0-4) were also described.

5 2,l-Benzisothiazoles 2,l -Benzisothiazol-3-ylaceticacid and its methyl and ethyl esters, e.g. (72; R = CH2C02Me), have been prepared.48 Rates of rearrangement of benzisothiazolyl benzoate (73) to benzoxazinone (74) were determined spectrophotometrically at 25 "C. The curves are characteristic of an autocatalytic reaction. Adding sulphur produces a 1000-fold acceleration in the rate.

Derivatives of 3-amino-2,l-benzisothiazoles were described, as well as their coupling to give azo-dyes (75); R' represents an aniline, 1,2,3,4-tetrahydroquinoline, or benzoylmorpholine coupler that contains an N-sulphoalkyl group and a variously substituted benzene ring4' 2,l -Benzisothiazolium salts react with several stabilized carbanions to give products that are derived by attack at the carbon atom of the heterocyclic ring5' Thus the benzisothiazolium iodide (76) reacts with Na+-CH(C02Et), to give the benzisothiazoline derivative (77).

Q""\( N= NR'

R2 (75)

mMj+ Uj \

\

C( COOE t )

1(76)

(77)

A. Welter, L. Christiaens, and Wutz-Peitz, Eur. Pat. Appl. 44453, 1982 (Chem. Abstr., 1982,96,199699). 48 M. Davis and K. C. Tonkin, Aust. J. Chern., 1981, 34, 755. 4 9 M. A. Weaver, C. A. Coats, Jr., and J. C. Fleischer, U.S.P. 4265 812, 1981 (Chern. Abstr., 1981, 95,26606). D. M. McKinnon, K. A. Duncan, and L. M. Millar, Can. J. Chem., 1982,60,440.

47


151

6 Other Condensed Ring Systems incorporating Isothiazole Thieno[ 2 , 3 4 isothiazoles. - The reaction of (78) with Na in liquid NH3 and then H 2 0 gives 5-methoxythieno [2,3-c] isothiazole (79).”

‘CH(

OE t ) (79)

(78)

Isothiazolo[3,4-bJ pyridines - Diazotization of 3-amino-5-cyanoisothiazolo[3,444 pyridines (80) and coupling with m-diethylaminoace tanilide gives the corresponding azo-compounds (8 1).52- Other similar compounds are also de~cribed.’~

( 8 0 ) R = NH2 (81) R = N = N A r

Isothiazolo[ 5,441 pyrimidines. - 5-Formy1-6-mercaptouraci1, when treated with NH20H, gives isothiazolo [5,4d] pyrimidine (82).54 This compound is also prepared by heating the oxime (83) with NaSH. Me

Me

52

Ya. L. Gol’dfarb, M. A. Kalik, and V. K. Zav’yalova, Izv. Akad. Nauk SSSR, Ser, Khim., 1981, 2771. B. R. Fishwick, and T. S. B. Sayer, Eur. Pat. Appl. 26596, 1981 (Chem. Abstr.,

53

P. Gregory and T. S. B. Sayer, Br. P. 2 0 7 4 598, 1981 (Chem. Abstr., 1982, 96,

5’

1981, 95, 82 388). 164 132). 54

K. Hirota, T. Asao, T. Fujioka, and S. Senda, Nippon Kagaku Kaishi, 1981, 721 (Chem. Abstr., 1981, 95,150 597).


152

1,2-Dithiolo[4,3c]isothiazoles. - 3-Aroylamino-6-mercapto1,2-dithiolo [4,3c] isothiazoles (84) are obtained, in good yields, by treating NCCSzM (M = alkali metal or te tra-alkylammonium) with RCOCl.55

s-

s

(84)

Naphtho[ 2,141 isothiazole. - The compound (85) is prepared by the reaction of 1-halo-2-(dihalomethyl)naphthaleneor 1-halo-2-formylnaphthalene with S and NH3, at elevated temperature and pressure, in the presence of an

“hieno[ 3,441 isothiazole 1,l -Dioxides: - 3-Aminothieno [3,4d] isothiazole 1,l-dioxides (86; R = Pr, Me2CHCH2, or EtCHMe) are prepared from thieno[3,4-&Iisothiazolin-3-one 1,l-dioxide and hydrochlorides of primary and secondary aliphatic amines with P 2 0 5 and NN-dimethylcyclohexylamineat 240°C.42

7 Thiazoles Synthesis. - Hantzsch ’s Synthesis (Type A; S-C-N + C-C). * From thioureas. Starting from thioureas, the following compounds have been obtained: 2amino-4-(4-benzyloxyphenyl) thiazoles,” 2 -(2 -amino-5-hydroxythiazol-4-y1)1 -(4-chloro-3-methylpheny1)e thanone,58 2-benzylidenehydrazino-4-( 1,5-dime thyl-2-phenyl-3-pyrazolon-4-y1)-5-e t hylthiazoles, 59 2 -amino-4- [2 -(4-ace taH. u. Kibbel, u. Ohnmacht, and J. Teller, Ger. (East) P. 148341, 1981 (Chem. Abstr., 1982,96,20 092). 56 H. Adolphi, H. Fleig, and H. Hagen, Br. P. 1 579424,1980 (Chem. Abstr., 1981, 95, 37 120). Y. Kawamatsu, T. Sohda, and Y. Imai, Eur. Pat. Appl. 27957,1981 (Chem. Absstr., 1981,95,132 863). M. El-Kadi, M. A. El-Hashash, and M. A. Sayed, Rev. Roum. Chim., 1981, 26,1161. 5 9 H. Amal, 0. Ates, and A. Salman, Dogu, Ser. C, 1980, 4, 13 (Chem. Abstr., 1982, 96,52 232). * For definitions of the types A, By efc., for thiazoles, thiazolines, and thiazolidines, see p. 1 1 9 of Volume 1 of this series ”

’’


153

midophenylsulphonylamido)ethyl] thiaz~les,'~ 2-(2-aminothiazol-4-y1)-2hydroxyiminoacetic acids and substituted derivatives which are useful as intermediates in the manufacture of antibiotic oxime derivatives of 7-aminothiazolylacetamidocephalosporanic acids:' substituted 2-amino-4-phenylthiazole s,6, substituted 4-aryl- or 4-(2 -furyl)-2-(substi tu ted pheny1amino)thiazole s,63 niridazole ,64 4-substi tu t ed 2 -aminothiazole -5-carboxylic acids,65 NN-dimethylJV"'(4-phenylthiazol-2 -yl)thioureas ,66 2-amino-5-isopro yl thiazolyl-4-carboxylic ester and 4-isopropylthiazolyl-5-carboxylicester!7 242aminothiazo1-4-y1)-2-(syn)-methoxyiminoaceticester,68 substituted 2-anilino4-fluoroaryI-thia~oles,~~ 4-substituted 2-aminothia~oles,~~ and 2-amino-4aryl-thia~oles.'~5-Acyl-2-aminothiazoles are also prepared by cleavage of the S-S bond of disulphidocarbamidines, H,NC(=NH)SSC(=NH)NH,, and react ion with &diket ones.

Synthesis from thioamides. Compounds prepared using thioamides include 4(4-chlorophenyl)-2-[4-(hydroxy or acyl)phenyl] thiazol-5-ylacetic a ~ i d s , ' 2~ (hydroxyphenyl)thiazole-4-carboxylic acids and derivatives,% and substituted 2,4,5-triarylthiazole~.~~ From HC( S)NH2 and XCH2CO(CH2)30COMe(X = halo) are formed 5-(2-hydroxyethyl)-4-methylthiazoleas the major product and 4-(3-hydroxypropyl)thiazole as a by-pr~duct.'~Also noted are 2,46o

61

62

63 64

65

0. V. Isakova, A. M. Sipyagin, and V. G. Kartzev, Zh. Org. Khim., 1981, 17, 1522 (Chem. Abstr., 1982,96,6507). J. Martel, J. Tessier, and P. Girault, Fr. Demande 2475 043, 1981 (Chem. Abstr., 1982, 96,6477); Br. P. 1 580 623,1980 (Chem. Abstr., 1981, 95,150 643). Y. Kawamatsu, T. Sohda, and Y. Irnai, Eur. J. Med. Chem.-Chim. Ther., 1981, 16, 355. B. G. Khadse, S. R. Lokhande, and D. G. Kulkarni, Indian J. Chem., Sect. B , 1981, 20,683 (Chem. Abstr., 1981,95,187 140). D. G. Deng and S . X . Lu, Yao Hsueh Hsueh Puo, 1981, 16,14 (Chem. Abstr., 1981, 95, 132 756). R. K. Howe and L. F. Lee, Eur. Pat. Appl. 27108, 1981 (Chem. Abstr., 1981, 95, 115 528).

R. Yoda, Y.Yamarnoto, and Y. Murakami, Kyoritsu Yakka Daigaku Kenkyu Kenkyu Nenpo, 1980,25,37 (Chem. Abstr., 1981, 95,115 369). 6 7 A. Barton, S . P. Breukelrnan, P. T. Kaye, G. D. Meakins, and D. J. Morgan, J. Chem. Soc., Perkin Trans. 1 , 1982 , 159. 6 8 A. Huwiler and L. Tenud, Eur. Pat. Appl. 45005, 1982 (Chem. Abstr., 1982, 96, 66

217 829). 69

R. B. Pathak, B. Jahan, and S . C. Bakel, Bokin Bobai, 1981, 9 , 477 (Chem. Abstr., 1982, 96, 20 018).

M. S. Shingare and D. B. Ingle, Marathwada Univ. J, Sci., Sect. A , 1980, 19, 5 (Chem. Abstr., 1982, 96,181 188). 71 R. C. Joshi and K. A. Thakar, Marathwada Univ. J. ScL, Sect. A , 1980, 19,95 (Chem. Abstr., 1982,96,181 189). 72 A. Kreutzberger and H. Schimmelpfennig, Arch. Phurm. (Weinheim, Ger.), 1981, 314, 385 (Chem. Abstr., 1981,95, 80 800). 73 J. F. Cavalla and R. A. Franklin, Eur. Pat. Appl. 37 710, 1981 (Chem. Abstr., 1982,

70

96, 52 295). '4

E. Draeger and H. Luebbers, Ger. Offen. 3002989, 1981 (Chem. Abstr., 1981, 95, 169 175).

75

K. Matsumoto and K. H. P. Peck, Eur. Pat. Appl. 37 274,1981 (Chem. Abstr., 1982, 96,122 780).

76

T. M. Filippova, A. R. Bekker, T. I. Ozorova, V. M. Belova, V. G. Mairanovskii, and A. M. Yurkevich, Khim. Farm. Zh., 1982, 16, 201 (Chem. Abstr., 1982, 96, 199 570).


154

diaryl-5-~yanothiazoles,~~ 1-(thiazol-2-yl)pyrazolidin-3-ones and derivatives:' and 4-alkoxyaryl-, 4-bromoalkylaryl-, and 4-alkenylaryl-thia~oles.~ Type B Syntheses of Thiazoles (C-C-N C-S). Enamino-esters CF3C(NH2)=CHC02Et, with ClCOSCl, are converted into 2-chloro-4-trifluoromethylthiazole-5-carboxylic esters and derivatives.80 Thioketens and 3dimethylamino-2H-azirines give 2-substituted 4-(NN-dimethylcarbamoyl)-5(NN-dimet hylamino) t hiazoles

+

.'

+

Type C Syntheses of Thiazoles (C-C-N-C S). N-(Cyanomethy1)imines R1COCH(CN)N=CR20Et (R1 = EtO, R2 = Me; R' = NH2, R2 = Me or Ph), when treated with H2S, give thiazoles (87) and imidazoles (88).82 Of the same type, the substituted 2-azabutadiene Me2NCH=C(C02Me)N=C(SMe)2, with H2S , gives 2 -methylt hio t hiazole-4-carboxylic acid methy1 ester (89) .83 Treatment of the imine Me2C=NMe at 400-5OO0C with SOz and a Zr02/ CaOlNaOH catalyst gives 4-methylthia~ole.~ H

(87)

(89)

(88)

Type F Syntheses of Thiazoles (C-N-C-S + C). Substituted N-thiocarbamolyformamidines R2CSN=CR"Me2 react with ally1 bromide to give an azavinamidinium salt, which, upon treatment with a base, gives an ethylideneA2-thiazoline (R1 = R2 = Me2N; R1 = H, R2 = morpholino). This last compound, upon heating or treatment with toluene-p-sulphonic acid, undergoes allylic rearrangement to the thiazole (90) with migration of the NN-dimethylamino-group (Scheme 8) .8s 2,4-Disubstit u t ed 5-benzoyldianilinothiazoles are NMe

I

Scheme 8 A. Corsaro, M. Tarantello, and G. P. Purrello, Tetrahedron Lett., 1981,22,3305. A. M. Richter and E. Fanghaenel, Ger. (East) P. 150 203, 1981 (Chem. Abst., 1982, 96,52 303). 79 T. Hara and J. C. Sheehan, Heterocycles, 1981,16, 1295. R. K. Hoowe and L F. Lee, U.S.P. 4251 261, 1981 (Chem. Absfr., 1981, 95, 62 179). E. Schaumann, S. Grabley, F. F. Grabley, E. Kausch, and G. Adiwidjaja, Liebigs Ann. Chem., 1981,277. 8 2 A. K. Sen and A. K. Mukhopadhyay, Indian. J. Chem., Sect. B , 1981, 20,275 (Chem. Abstr., 1981, 95,97673). 8 3 R. Gompper and U. Heinemann, Angew. Chem., 1981,93,297. 84 S. J. Amato, S. Karady, and L. M. Weinstock, U. S. P. 4 282 364, 1981 (Chem. Abstr., 1981,95,203936). R. Gompper and J. Schelble, Synthesis, 1981,647.

77 78


155

also described, using an analogous The thioamide vinylogues also react with bromoacetone to give 5-a~etyl-2-phenylthiazole.~'

+

Type H Syntheses of Thiazoles (S-C C-AX'). Base-induced cycloadditions of tosylmethyl isocyanide (4-MeC6H4S02CH2NC) and an isothiocyanate RNCS (R = alkyl, allyl, PhCO, aryl, etc.) have been investigated. Depending on the reaction conditions, thiazoles (91) and/or imidazoles (92) are obtained. A high-yield ring-transformation of (91) to (92) occurs in THF/ BuLi."

MeaR;y sl MeaHlyNl R

N

N

O2

O2

(91)

(92)

Physical Properties of Thiazoles. - The mass spectra of the thiazoles [93; R' = Ph, R2 = H, R1R2 = (CH& or (CH2)4, R3 = H; R' = CICH2 , R2 = H, R3 = H or F] and thiazolinone (94) show a major decomposition mechanism involving elimination of PhCN.89 The spectrum of (94) showed a fragment ion (m/z = 90) corresponding to cleavage of an azomethine bond and no loss of PhCN. The U.V. spectra of 2,4-diphenylthiazoles with the 4-phenyl group substituted by a Schiffs base or benzylamine were also recorded.g0 A more important interaction between the two moieties of the Schiff's bases was observed in the case of thiazolyl derivatives. The ionization constants of the hydrazones (95; R' = H, R2 =Me; R1 = R2 =Me; R' = Ph, R2 =Me) and

R2

c"~N-N=cYJ

K. N. Rajasekharan and A. Sulekha, Indian J. Chem., Sect. B , 1981,20, 549 (Chem. Abstr., 1981,95, 187 134). '' M. A. Riahi and J . P. Radhrte, C. R . Hebd. Seances Acad. Sci., Ser. 2, 1981, 293, 671. 88 S. I? J. M. Van Nispen, J. H. Bregman, D. G. Van Engen, A. M. Van Leusen, and H. Saikachi, Red. Trav. Chim. Pays-Bas, 1982, 101,28. 8 9 A. A. Tsurkan, V. M. Adanin, and A. M. Zyakum, Farm. Zh. (Kiev), 1981, 1, 66 (Chem. Abstr., 1981, 9 5 , 60 767). 90 V. Farcasan and A. Donea, Stud. Univ. Babes-Bolyai, Ser. Chem., 1980, 25, 76. 86


156

(96) were determined spectros~opically.~~ Both series of esters (97) and (98) show carbonyl doublets in the i.r. spectrum that are caused by rotational isomerism; the more intense absorptions of the 4-carboxylates are at lower wavenumbers whereas those of the 5-carboxylates are at the higher waven ~ m b e r . ~ In ' both series, the stronger bands arise from the more stable forms; for the 4-carboxylates, these are the carbonyl 0,s-syn-s-trans-rotamers. The 'H n.m.r. spectral assignments of thiazole amides [99; n = 1-3; R = H, MeCONH(CHz), (rn = 2 or 4), Me, or NH2] related to bleomycin A2 have been described.% The polythiazole-containing antibiotics thiocillins I, 11, and I11 were compared with micrococcin P1 by analysis of acid hydrolysates of the native and the reduced antibiotics as well as by means of 'H and 13C n.m.r. s p e c t r o s ~ o p y The . ~ ~ structures of these three compounds were assigned on the basis of the proposed structure of micrococcin P I . The absolute configuration of myxothiazole, an antifungal antibiotic from a gliding bacterium, has been determined by X-ray analysis of its degradation products (loo)." Compound (100) was obtained from myxothiazole by ozonolysis followed by reduction with NaBH4 (MeOH, at - 70°C) and chromatography on silica gel. Extensive analyses of spectral data and results of acid hydrolyses led to the assignment of a cyclic peptide structure to dolastatin 3 (from Dolabella auri~ularia).~~

Me2S( + CH2)$HC

oj-jsyRclII

(99)

91

92

J. Lukasiewicz, D. hfisiuna, S. Bilinski, and L. Bielac; Chem. Anal. (Warsaw), 1981, 26, 207.

J. M. Riordan and T. T. Sakai, J. Heterocycl. Chem., 1981, 1 8 , 1 2 1 3 . 93 J. Shoji, T. Kato, Y. Yoshimura, and K. Tori, J. Antibiot., 1981, 34, 1126. 94 W. Trowitzch, G. Hoefle, and W. S. Sheldrick, Tetrahedron Lett., 1981,22,3829. 9s G. R. Pettit, Y. Kamano, P. Rown, D. Gust, M. Inoue, and C. L. Herald, J. Am. Chem. SOC.,1982, 104,905.

Five-Membered Rings: Systems containing N a n d S, Se, or Te

157

Tautomerism of 2-Aminothiazoles. - The imino-form (1 01) predominates only when the SOzAr group is bonded to the exocyclic nitrogen atom.96 In all other cases the amino-form (102) is prevalent. The 13C and ‘Hn.m.r., i.r., and U.V. spectra of 4- or 5-substituted 4-thiazolin-2-ones and their Nor O-Me derivatives were studied.97 The i.r. and ‘Hn.m.r. spectra show that the parent compounds exist entirely or predominantly in the 2-0x0-form in solution. In contrast, U.V. and 13C n.m.r. spectroscopy did not clearly distinguish between the 2-0x0- and 2-hydroxy-structures. The kinetics and mechanism of spontaneous acid-, base-, and metal-ion-induced hydrolyses of N-salicylidene-2-aminothiazolewere also de~cribed.’~Studies on the polymorphism of sulphathiazole and its crystallographic behaviour under pressure have also been rep0rted.9~

[syNR3R R1LyNso2Ar R1

R2

NH

R2

Reactions of Thiazoles. - 2-Bromothiazole is silylated to give compounds which undergo ipso-substitution with ketens to give, after hydrolysis, two 2acylthiazoles .loo 4,5-Disubstituted 2-chloro thiazoles are obtained by diazotization of the corresponding thiazoles and then ~hlorination.~’ In the limited space available we have only mentioned references concerning the reactions of 4-substituted thia~oles,~’ *lol*lo2 5-substituted t hiazoles, lo3* ‘04 2-aminothiazoles, 21 and, finally, miscellaneous reaction^,^'^'^^ leaving out many patents.

”’-’

’‘ L. Forlani, Gazz. Chim. Ifal., 1981, 111, 159. ”

S. P. Cornwell, P. T. Kaye, A. G. Kent, and G. D. Meakins, J. Chem. SOC., Perkin

Trans. I , 1981, 2340. A. C . Dash, B. Dash, and S. Praharaj, J. Chem. SOC.,Dalton Trans., 1981, 2063. 9 9 H. Kala, H. Moldenhauer, R. Giese, G. Kedvessy, B. Selmeczi, and K. Pintye-Hodi, Pharmazie, 1981, 36, 833. loo A. Medici, P. Pedrini, and A. Dondoni, J. Chem. SOC.,Chem. Commun., 1981, 655. l o ’ Fr. Demande 2 447 380, 1980 (Chem. Abstr., 1981,95, 80 994). lo2 Neth. Appl. 81 00 539,1981 (Chem. Abstr., 1982,96, 52 078). l o 3 R. C. Grabiak, R. K. Howe, and D. E. Schafer, Eur. Pat. Appl. 44 201, 1982 (Chem. Abstr., 1982, 96, 162 687). I. Simiti, A. Muresan, and M. Coman, Arch. Pharm. (Weinheim, Ger.), 1981, 314, 744 (Chem. Absfr., 1982, 96,52 197). 105 F. Kai, H. Takeshita, S. Sukimoto, and K. Tamaoku, J. Inorg. Nucl. Chem., 1981, 43, 3013; I. Liepa, E. Gudriniece, and V. Barkane, Latv. PSR Zinat. Akad. Vestis, Kim. Ser., 1981, 4,477 (Chem. Abstr., 1982, 96,21 268). l o 6 A. Gursoy and D. Gokcek, Doga, Ser. C, 1981, 5 , 27 (Chem. Absa., 1982, 96, 98

52 221). Io7

lo’ Io9 I10

I. M. Bazavova, R. G. Dubenko, and P. S. Pel’kis, Zh. Org. Khim., 1981, 17, 191 (Chem. Abstr., 1981, 95,7129). A. Medici, P. Pedrini, C. Venturoli, and A. Dondoni, J. Org. Chem., 1981,46,2790. R . B. Pathak and S. C. Bahel, Bokin Bobai, 1981, 9, 125 (Chem. Abstr., 1981, 95, 24 899). S. M. M. Zaidi, R . K. Satsangi, P. Nasir, R. Agarwal, and S. S. Tiwari, Pharmazie, 1980, 35,755 (Chem. Abstr., 1981, 95,24 966).

158


Reactions of Thiazolium Salts. - Base-induced attack of thiazolium salts and rearrangement of subsequent 2-hydroxy-A4-thiazoline was studied by U.V. kinetic spectroscopy (two consecutive irreversible steps).123 The first step was the nucleophilic attack of OH- on C-2 of (103; R = H or Me), affording the thiazoline (104), with measured third-order rate constants. The second step was the nucleophilic cyclization of the thiolate (105) to form the thietans (106) (Scheme 9). The mechanism of H-D exchange of H-2 in the thiazolium ions (107) was studied by 'H n.m.r. A tetrahedral intermediate, formed by addition of a nucleophile, is proposed. The effects of solvents and size of the nucleophile on the reaction were studied.'24 However, elsewhere it is claimed that the kinetic data demonstrate that the exchange of H at the 2-position of thiazolium ions cannot occur through a tetrahedral intermediate.12'

L. Forlani, P. de Maria, E. Foresti, and G. hadella, J. Org. Chem., 1981, 46, 3178 M. H. Bahar and B. K. Sabata, Indian J. Chem., Sect. B , 1981, 20,328. S. H. Yang and I. C. Tsai, Kao Teng Hsueh Hsiao Hua Hsueh Pao, 1981, 2 , 188 (Chem. Abstr., 1981, 95,132 726). 114 A. F. Youssef, H. H. Farag, N. M. Omar, M. A. Abdel Kader, and H. H. Awad, Egypt. J. Pham. Sci., 1978 (publ. 1980), 19,247 (Chem. Abstr., 1981,95,80 796). 115 S . P. Srivastava, J. S. Upadhyaya, and M. P. Sharma, Indian J. Chem., Sect. B , 1981, 20, 631; J. S. Upadhyaya and P. K. Srivastava, J. Indian Chem. SOC., 1981, 58,

112

789.

R. Jain, S. Tyagi, and S. Agarwal, J. Indian Chem. SOC.,1981, 58, 1112. Z. Ma, B. Si, and L. Huang, Yaoxue Xuebao, 1981, 16, 793 (Chem. Abstr., 1982,

'I'

96,122 691); Yaoxue Tongbao, 1981, 16,57 (Chem. Abstr., 1982,96,35 162). M. A. El-Maghraby and A. Abou El Ela Hassan, Indian J. Chem., Sect. B , 1981, 20, 256. 119

/

120

I. T. Depeshko, V. I. Treskach, P. A. Bezuglyi, V. P. Chernykh, L. M. Voronina, and

V. 0. Chubenko, Farm. Zh. (Kiev), 1981, 2, 38 (Chem. Abstr., 1981, 95,108536). P. N. Bhargava, S. Prakash, and R. Lakhan; Indian J. Chem., Sect. B , 1981, 20,

927. B. G. Yasnitskii, V. A. Oridoroga, T. V. Medvedeva, and E. B. Dol'berg, Khim.Farm. Zh., 1982, 16, 205 (Chem. Abstr., 1982, 96, 180 546). 122 M. H. Bahar and B. K. Sabata, Indian J. Chem., Sect. B , 1981, 20, 870. 1 2 3 H. J. Federsel and G. Merenyi, J. Org. Chem., 1981, 46, 4724. 124 K. Karimian, I. Ganjian, and M. Askari, Tetrahedron Lett., 1981, 22, 581; K. Karimian, F. Mohtarami, and M. Askari, J. Chem. SOC.,Perkin Trans. 2, 1981, 1538. P . Haake, Tetrahedron Lett., 1981, 22, 2939. I21

159


r\

C1-

Me

NMeCOR

---

( CH2 i

M eI N M e C O R

Scheme 9 Thiazolium bromide (1 08) reacts with keten thioacetals (MeS)2C=C(CN)2,

etc., in the presence of NaH or Et3N, to afford iminothiazolines [109; Z = (NC)2C, Me02CC(CN), or tosylimino] Treating (109) with NaOMe results in cyclization to give imidazo[2,1-b] thiazoles [ 110; R' = C02Me, R2 = CH(CN), or CH2CN; R' = H, R2 = tosylamino] .

CyNCSMe NCH2COOMe

The following have also been described: cationic azo-dyes (1 1l), prepared by diazo-coupling and quaterni~ation,'~'and the effects of alkali128 and of

126

K. Kurata, H. Awaya, Y. Tominaga, Y. Matsuda, and G. Kobayashi, Yakugaku Zasshi, 1981, 101, 991 (Chem. Abstr., 1982, 96, 104 144). 1 2 7 P. Gregory and D. Thorp, Br. Pat. Appl. 2070050, 1981 (C'hem. Abstr., 1982, 96, 201 252).

'21

R. F. W.Hoprnann and G. P. Brugnoni,Angew. Chem., 1981, 93,

1005.

He terocycIic Chemistry

160

alkali that is released from glass containers12' on vitamin B1 (thiamin). We also note the claim of an improved procedure for the synthesis of derivatives of 2-a1kyldihydrothiamin ketones : treating the (pyrimidinylme thy1)thiazolium salt (1 12; R = Me, Et,,!IP Ph, or CH2CHMeCH2CH2CH=CMe2)with KOPr' in P h H gives 78-95% of substituted hexahydrofuro[2,3-d] thiazole (1 13).'30 The synthesis and characterization of thiaminium tribromocadmium(I1) and thiaminium tri-iodocadmium(I1) complexes (1 14; X = Br or I)131 and the luminescence spectra of some thiamin derivatives have also been r e ~ 0 r t e d . l ~ ~

X-

8 A2-Thiazolines

+

Synthesis. - Type B Syntheses (C-C-N C-S). Thiazolines [ 1 15 ;R' = Ph, naphthyl, or biphenyl; R2,R3 = C1-4 alkyl or R2R3= (CH2), (n = 5-8)] have been prepared. Thus Me2C(NH2)CxH, when treated with CS2, gave (115; R' = H, R2 = R3 = Me), which with l-chloro-2,6-dinitro-4-trifluoromethyl-

H2cxT R2

N

SR1

N. N. Rahman and Q. N. Masuda, Dacca Univ. Stud. Part B , 1981, 29, 4 1 (Chem. Abstr., 1982, 96, 168621). 130 K. Karimian, M. Askari, M. Farahani, and N. Sachinvala, Synthesis, 1981,48. 1 3 ' A. Adeyemo, A. Shamin, and T. Williams, J. Chem. SOC.Pak., 1981, 3 , 99 (Chem. Abstr., 1981, 95,231 060). 1 3 ' G. A. Gachko, L. N. Kivach, S. A. Maskevich, A. A. Maskevich, and Yu. M. Ostrovskii, Dokl. Akad. Nauk B. SSR,1981, 25,852 (Chem. Abstr., 1981, 95,202 806). 129


161

benzene gave [ 1 1 5 ; R1 = 2,6,4-(o2N),(F3C)C6H3, R2 = R3 = Me] .133 The complex NaS2CCN.3DMF and NH2CH2CH2C1gave the thiazoline (1 16).lM S

I1

/SyCNH2 (116)

Type J Syntheses of A2 -Thiazolines (C-S-C-N-C). The thiazolines (1 17) are prepared by cyclization of NCN=C(SMe)NHR with (Me2CH)2NLi (THF, at - 3OoC, for 20 min, under nitr~gen).'~'The reaction of Me2NCR'=NCR2 (R' = R2 = Me2N; R' = H, R2 = morpholino) with BrCH2CH=CH2 gives an

(117)

=fi

azavinamidinium salt Me2NCR1 -1CR2(SCH2CH=CH2) Br-, which, upon treatment with NaNH2/NH3 or KOBut, gives the ethylidenethiazolines ( 1 18); the latter, upon heating or treatment with 4-MeC6H4SO3H, rearrange through N-allylic displacement t o the thiazoles (1 19) (Scheme

Type K Syntheses of A2-Thiazolines (C-C-N-C-S). Reactions of the diastereoisomers ClCHPhCHMeNCS with MeONa, Et2NH, or PhNH2 gave stereospecifically cis- and trans-(l20; R = MeO, PhNH, or Et2N).136 Compound (120) reacts with NaSH, yielding cis- and trans-(121), which are converted with (Me0)2S02 into (120; R = MeS). Configurations were determined from the nuclear Overhauser effect.

NH Me

Me (120)

(121)

E. I. Aoyagi, U. S. P. 4272 306,1981 (Chern. Abstr., 1981,95,97786). 1 3 4 H.U. Kibbel, M. Kuecken, E. Peters, and H. Weber, J. Prakt. Chem., 1981, 323,41. 1 3 5 M. Yokoyama, M. Kurauchi, and T. Imamoto, Tetrahedron Lett., 1981, 22,2285. 136 L. Kniezo, P. Kristian, M, Budesinsky, and K. Havrilova, Collect. Czech. Chem. Commun., 1981, 46,71 7. 133

162


+

Type E Syntheses of A2-Thiazolines (N-C-C-S C). PhC02H reacts with NH2(CH2)2SH in the presence of Ph3P, CC14, and tertiary bases to give 45% of A2-thiazoline (1 22).13' In addition, we mention the synthesis of the nitrosothiazoline (123).138

fSIPh (S7.(T N

N

Reactions of A2-Thiazolines.- The photolysis of Me2S2 in cyclopropane that contains the thiazoline (124) gives only the radical (125), by selective abstraction of hydrogen by MeS' radical, whereas H is abstracted from both the 4- and the 5-position in the reaction of (124) with the ButO' radical. The e.s.r. spectrum of (124) with ButO' has been re~0rted.I~' Mercaptoethylamine salts HSCH2CHR'NH2-HX (R' , X = H, C1; H, Br; or Me, C1) are prepared by hydrolysis of aminothiazolines (126; R2 = H or alkyl) with HX (for example, 25% HC1, for 72h).I4' Analogous results are obtained by proceeding in two steps: alkaline hydrolysis, giving HSCH2CHR1NHCONHR2, and then acid h y d r ~ l y s i s . ' ~In~ the hydrolysis of thiazolinium tetrafluoroborates (127), the same scission of the C-S bond is observed under thermodynamic control (KOH, H20, at 45"C), whereas under kinetic control (NaOH, 15-crown-5, PrCN, Ac20, at - 78" C), preferential cleavage of the C-N bond is 0 b ~ e r v e d . l ~ ~ The ability of 2-aminothiazoline (128) to complex metal ions has been investigated: 2-aminothazoline does not form powerful coupling ligands with Ca, Mg, Mn, Ni, Cu, or Zn ions.143 The amino-group is the sole electrondonor that is involved in the complexing of 2-aminothiazoline. 2-HydrazinoA2-thiazoline has been condensed with diethyl oxalate and oxamic acid esters.14 The reaction of 2-hydrazinothiazoline with diethyl oxalate gives

H. Vorbrueggen and K. KrolikieWicz, Tetrahedron Lett., 1981, 22,4471. J. Oiry, J. Martinez, J. L. Imbach, and F. Winternitz, Eur. J. Med. Chern.-Chirn. Ther., 1981, 16, 539. 1 3 9 L. Grossi, L. Linazzi, and G. Placucci, Tetrahedron Lett., 1981, 22,251. 140 Jpn. P. 82 0 9 758,1982 (Chem. Abstr., 1982, 96, 217 230). 14' Jpn. P. 82 1 1 960,1982 (Chern. Abstr., 1982, 96,217232). 1 4 2 L. Khouri and M. K. ploustian, J. Org. Chem., 1981, 46,5052. 143 2. X. Huang, P. M. May, and D. R. Williams, Eur. J. Cancer Clin. Oncol., 1981, 17, 1151 ; Z. X. Huang, P. M. May, D. R. Williams, and M. Gosalvez, Inorg. Chim. Acta, 13'

13*

1981, 56,41. 144

K. H. Ongania,Chem. Ber., 1981, 114, 1200.


163

the thiazolotriazinedione (129) as the only product, whereas with RNHCOC0,Et (R = H or Ph), the hydrazides (130) are obtained. Compound (130; R = H) is cyclized to (131) with NaOEt, whereas (130; R = Ph) gives the thiazolotriazole (13 1; R' = CONHPh); (I 3 1; R' = H) is obtained by treating (129) with NaOH. The thiazolines (132) react with appropriate alkenes by 1,3-dipolar cycloaddition to give, for example, the cyclo-adduct (133; R' = Me, R2 = COMe, R3 = Me).'45 Compound (133; R' = OEt, R2 = C02Et, R3 = H), on treatment with aqueous AgN03 followed by reduction with NaBH4, gives the pyrrolidine (134; R' = H). As regards the syntheses and reactions of A2-thiazolin-4-ones (and -thiones), we have only noted references 100 and 146-155.

G. A. Kraus and J. 0. Nagy, Tetrahedron Lett., 1981, 22,2727. M. A. E. Khalifa, E. M. Zayed, A. A. A. Elbanany, and G. H. Tammam, Chem. Ind. (London), 1981, 35. '41 P. Kutschy, M. Dzurilla, P. Kristian, and K. Kutschyova, Collect. Czech. Chem. Commun., 1981, 46,436. 14' S. M. Ramsh, Y. G. Basova, A. I. Ginak, N. A. Smorygo, and A. A. Rodin, Khim. Geterotsikl. Soedin., 1982, 30 (Chem. Abstr., 1982, 96, 142 747). 149 Yu. G. Basova, S. M. Ramsh, and A. I. Ginak, Khim. Geterotsikl. Soedin., 1981, 1046 (Chem. Abstr., 1982, 96, 68 880). 150 M. T. Omar and M. A. Kasem, J. Heterocycl. Chem., 1981, 18, 1413. M. R. H. Elmoghayar, M. K. A. Ibraheim, A. H. H. Elghandour, and M. H. Elnagdi, Synthesis, 1981,635. 1 5 * M. Muehlstaedt and R. Widera, J. Prakt. Chem., 1981, 323,451. R. Pacura and E. Tarasavicius, Farm. Zh. (Kiev), 1981, 6, 62 (Chem. Abstr., 1982, 14'

146

154

15'

96, 100 783). G. L.'abb&, G. Vermeulen, S. Toppet, G. S. D. King, J. Aerts, and L. Sengier, J. Heterocycl. Chem., 1981, 18, 1309. G.Gattow and W. Eul, 2.Anorg. Allg. Chem., 1981, 483, 121.


164 9 A3-Thiazolines

2-(Alky1thio)alkyl-4,5-dialkyl-A3-thiazolines (135; R' , R2 = H or Me) are prepared by the iminolysis of MeSCHR2CH2CH0 followed by cyclocondensation with MeCOCH(SH)CH2R3.156

Me (135)

MeC(NH2)=C(N=NR2)C02R' (R1 = Me, Et, or But; R2 = Ph or 2,4,6-Me3 CgH2), prepared either from MeC(NH2)=CHCO2R' and R2N,' C1- or from MeCOC(=NNHR2)C02R' and NH3, react with the dithians (1 36) to give the A3-thiazolines (137).lS7 Compounds (137) are acylated at S with (R4CO)20 (R4 = Me or Ph), with ring cleavage, to give (Z)-PhNHN=C(C02R1)CMe= NCH=CHSCOR4. ClCH2CH0 is condensed with NH3, Me2C0, and NaHS in aqueous Me2C0 at 0-10°C to produce the A3-thiazoline (138), which is treated with HCN to give the thiazolidine (139); the latter is hydrolysed by aqueous HC1 to yield racemic c y ~ t e i n e . ' ~ ~ n

COOR

The cyclopropyl azide (140) is smoothly decomposed at 70°C to give a nitrene that can interact not only with the three-membered ring but also with the double bond, leading to the A3-thiazoline (141) and the thiazolidine Me

Me

N

H-C

a

15'

Me (140)

(141)

D. A. Whithycombe, B. D. Mookherjee, C. J. Mussinan, M. H. Vock,and C. Giacino, U.S.P. 4 2 5 5 583, 1981 (Chern. Abstr., 1981, 95, 7268). J. Gasteiger and U. Strauss, Chem. Ber., 1981, 114, 2336. J . Martins, H. Offermanns, and P. Scherberich, Angew. Chern., 1981, 93, 680.


165

(1 42).lS9 The 5-(arylmethylene)-2-piperidino(or morpholino)-2,4-diphenylA3-thiazolines (144; R = p-C1C6H4, X = 0 or CH2; R = Ph, X = 0) are obtained by a Grignard reaction of the A2-thiazolin-4-one (143) with PhBr . 2,2,4-Trimethyl-A3-thiazoline is oximated with NaN02 in HOAc and the oxime is treated with MeNCO to give (145).161 Treatment of 2-amino-A2thiazolin-4-one gives the sodium enolate (146). 149

10 A4-Thiazolines

+

Synthesis. - Type A (S-C-N C-C). 1-Acetyl-4-phenylthiosemicarbazide is condensed with chloroacetone and w-bromacetophenone to give derivatives of A4-thiazolines (147) and (148; R = Me or Ph).'62 Hydrolysis of (147) with boiling 15% HCl yields (149). Compounds (147; R = Me) and (1 48; R = Me), when boiled with 10% NaOH, give (150), but when R = Ph they are stable under these conditions.

A4-Thiazolines (1 5 1; R' , R2 = H, halogen, alkyl, cycloalkyl, thienyl, pyridyl, or variously substituted aromatic; R3 = variously substituted Ph) have been prepared.'63 Thus NCCHzCSNHz is treated with BrCHzCOBut to

16' 16' 16' 163

R. Jorritsma, H. Steinberg, and T. J. De Boer, R e d . Trav. Chim. Pays-Bas, 1984, 100, 307. M.T.Omar, M. M . Habashi, M . E. Shabaan, and M . A. Kasem, Synthesis, 1981,318. C. Luethy and P. Winternitz, Eur. Pat. Appl., 39 520, 1981 ((Chem. Abstr., 1982,96, 104 226). S. Bilinski and B. Marcewicz-Rojewska, Ann. Univ. Mariae Curie-Sklodowska, Sect. D,1979, 34,383 (Chem. Abstr., 1981,95,24898). Neth. A D ~80 . 01 920,1980 (Ctern. Abstr., 1981,95,169174).

Heterocyclic Chemis@

166

give 4-t-butyl-2-cyanomethylthiazole, which was treated with 2,6-Cl(F)C6H3COCl to yield [ 151; R1 = But, R2 = H, R3 = 2,6-Cl(F)C6H3]. The thiazoles (152; R = Ph or p-anisyl) and the A"-thiazolines (153; R' = Ph, R2 = Et or allyl; R1 = p-anisyl, R2 = Et) were prepared by cyclo-condensation of a-bromopropyl antipyryl ketone with thiosemicarbazones R2NHC(S)NHN=CHR' or by the reaction of R2NHC(S)NHNH2 with R'CHO and subsequent cyclo-condensat ion with a-bromoprop yl antipyryl ketone. 59 A4-Thiazolines (154; with a wide variety of substituents) have been prepared.'@ Thus cyclo-condensation of 4,3-Cl(Me2NS02)C6H3COcH2Br with PhNHCSNHMe gives a thiazolidinol which on dehydration with acid yields (154; R' = C1, R2 = R7 = R8 = Me, R3-R6 = H). The reactions of monoprotic thioureas with ethyl chloroacetate, bromomalonate, and bromocyanoacetate have been ~tudied.'~' Thus p-R1C6H4NHCSNHR2 (R1 = Me or H, R2 = Et) with MeCOCHClC0,Et gave Et2NHHCI, p-R1 C6H4NCS, @-R1C6H4NH)2CS, the A4-thiazoline (155), and the oxathiole (156; R' = Me or H). PhNHCSNR2 (R = Me or Et) with BrCH(C02Et), gave R2NH.HBr, PhNCS, the thiazolinone (1 57), and (PhNH)2CS.

Me (153)

02SNR7R8 (154)

0

164

'"

LYNPh NPh

H. J. Lang, B. Sewing, and E. Granzer, Ger. Offen. 2 9 2 6 7 7 1 , 1981 (Chem. Abstr., 1 9 8 1 , 95, 2 5 048). H. Singh, A. S. Ahuja, and N. Malhotra, J. Chem. Soc., Perkin Trans. 1, 1 9 8 2 , 6 5 3 .

Five-Membered Rings: Systems containing N a n d S, Se, or Te

167

+

Type B Syntheses of A4-Thiazolines (C-C-N C-S). CF3C(NH2)=CHC02Et was heated with ClCOSCl in benzene to yield the A4-thiazolin-2-one (1 58)." Compound (158) and POC13 in DMF were refluxed to give the thiazole (159). We also find the cyclo-condensation of MeC(NH,)=CHCN with ClCOSCl, giving 5-cyano-4-methyl-A4-thiazolin-2-one.'66 The A4 -thiazolines (161 ; R1, R2 = alkyl; X = 0, S, or NH) were prepared by the reaction of (160; R3 = H, halogen, or alkoxy) with 2-H2NC6H4XH.I6' Thus (160; R' = R2 = Et, R3 = H) was refluxed with O - ( H ~ N ) & ~ in H ~EtOH to give (161; R' = R2 = Et, X = NH).

(160)

8

(161)

Physical Properties of A4-Thiazolines. - The thiazolinylidene structure of (1 62; R1 = H, R2 = Me) has been proved by u.v., and pK1/pK2 values were determined.'@ The 13C and 'H n.m.r., i.r., and U.V.spectra of 4- or 5-substituted A4-thiazolin-2-ones (163) and their N- or O-methyl derivatives (164) have been studied. The i.r. and 'H n.m.r. spectra show that the parent compounds exist entirely or predominantly in the 2-0x0-form in solution. In contrast, U.V. and I 3 C n.m.r. do not clearly distinguish between the possible 2-0x0-and 2-hydroxy-struct~res.~~~ The barriers t o rotation of the RCH2 groups in the A4-thiazolines (165; R1 = Me, Et, or Pr', R2 = Me or But;

Me3C

R2

R2

('Y'

(165)

169

N

'CH~R~

H. Foenter and V. Mues, Ger. Offen. 3025303, 1982 (Chem. Abstr., 1982, 96, 142 842). K. Peseke and C. Vogel, Ger. (East) P. 143775, 1980 (Chem. Abstr., 1981, 95, 62 178). J. Lukasiewicz, D. Misiuna, S. B i l h k i , and L. Bielak, Chem. Anal. (Warsaw), 1981, 26,207. S. P. Cornwell, P. T. Kaye, A. G. Kent, and G. D. Meakins, J. Chem. Soc., Perkin Trans. I , 1981,2340.


168

R1 = 4-MeOC6H4,. R2 = Bu? and the methylthiothiazolinium ions (166; R = Me, Et, or Pr') were studied by 'H dynamic n.m.r. and molecular orbital calculations."O The barrier to rotation for the But compounds was independent of R, but was caused by strain in the ground state.

'N Me3C

(166)

Reactions of A4-Thiazolines. - By thermal rearrangement with loss of H2S, the imino-A4-thiazolines (167) give 7-substituted 3-phenyl-1H-imidazo [ 1,2a ] benzimidazoles (168; R = H, Me, MeO, EtO, Br, or HO)."l 4-Aminothiazoline-2-thiones (1 69; X = S) were successively treated with Me2S04 and H2NNH2*H20to give the corresponding hydrazones (169; R1 = Ph, R2 = Ph02C, CN, or morpholinocarbonyl; R' =Me, R2 = CN; Rf = H2C=CHCH2, R2 = CONH,; X = NNH2).ln The rearrangement of 4-aminothiazolin-2ylidenemalononitriles [169; R' = Ph, Me, H2C=CHCH2, or PhCH2 ; R2 = H2 NCO or Et02C; X = C(CN)2 ] yields the 2,4-diaminothiophen derivatives (170). The 4-aminothiazolin-2-ylidenecyanamides (169; R' = Ph or CH2= CHCH2, R2 = H2NC0 or Et02C, X = NCN) react to form the substituted 2,4diaminothiazoles (1 71). The reaction of the thiazolinylacetates (1 72; R = C02Et or CN) with Me2S04 and then CH2(CN)2 gives the diaminopyrrolothiazoles (173).

CN

170

H2N

NCH2COOEt

H2N

COOE t

C. Roussel, B. Blaive, R. Gallo, J. Metzger, and J. Sandstroem, Org. Magn. Reson., 1980, 14, 166.

"*

R. P. Soni,Aust. J. Chem., 1981, 34, 1557. K. Gewald, U. Hain, and P. Hartung, Monatsh. Chem., 1981, 112, 1393 (Chem. Abstr., 1982, 96, 217 746); K. Gewald, M. Kleinert, and U. Hain, Ger. (East) P. 151 628,1981 (Chem. Abstr., 1982,96,181 275).


169

The reactions of K2(MX4) (M = Pd or Pt, X = Cl or Br) with the thiazoline (174) and its deuteriated derivatives were studied in aqueous solution at pH 1 and 5.5.'73 Complexes ML2X2=2XH and ML2Xz [L = (174)] were isolated and characterized by elemental analysis, pH titration, and i.r. and 'H and 13C n.m.r. spectra. The ligands are protonated primarily at N-1 of the pyrimidine moiety, whereas the site of metallation is either N-3 or the S atom of the thiazoline ring. With CuI', Ag', Mn", Fe"', and Pd" ions the A4-thiazolines (1 75 ; R = Me, Ph, or 3-or 4-pyridyl) form complexes." Cu" ions form 1 :2 metal-ligand complexes with (174) and a 1 : 1 metal-ligand complex with (1 75 ; R = 4-pyridyl). The proton-donating and -accepting and association constants for the A4-thiazolin-2-one and the oxazolidine-2-thione were determined by i.r. spectroscopy in CC14.17' The proton-donating and -accepting constants are claimed to be useful for selecting pairs of compounds forming hetero-dimers of greater stability than the corresponding homodimers. The use of 3-methyl-2-(2,4-dimethylphenylimino)-A4-thiazoline as copolymer has also been m e n t i ~ n e d . ' ~ ~

m]aMe cyN-N Me

HO

NH

1 1 Thiazolidines Synthesis. - Type B Syntheses (C-C-N + C-S). 2-Arylaminothiazolidines are prepared from R2NHCH2CH2C1and R'NCS (Et3N, CHC13).17'

Type E Syntheses of Thiazolidines (N-C-C-S + C). The nucleophilic displacement by SH- of OS03H from H2NCR3R4CR'R20S03H followed by cyclo-condensation with ketones gave 84% of thiazolidines (1 76 ; R1-R4 = H, R5 = Me, R6 = Et).l% On the other hand, (176) was hydrolysed with 35% HC1 to give HSCR'R2CR3R4NH2.HC1 in good yield. The calcium salt of cysteineglucuronic acid is obtained by using D-glucuronic acid, L-cysteine

173 174

175 176

17' 178

N. Hadjiliadis and J. Markopoulos, J. Chem. SOC.,Dalton Trans., 1981,1635. D. Misiuna and S. Bilinski, Ann. Univ. Mariae Curie-Sklodowska, Sect. D, 1979, 35,143 (Chem. Abstr., 1982, 96,134 799). E. Gentric, J. Lauransan, C. Roussel, and J. Metzger, Nouv. J. Chim., 1980, 4, 743. C. D'Hondt, D. bhrnann, and E. Neuenschwander, Eur. Pat. Appl. 25413, 1981 (Chem. Abstr., 1981, 95,110 182). 0. Ekhner and W. Stendel, Rorn. P. 66 113,1979 (Chem. Abstr., 1981,95,25050). Y. Osawa, M. Itoh, and S. Uchikuga, Ger. Offen. 3025461, 1981 (Chem. Abstr., 1981, 95,6489).


170

.'"

hydrochloride, and CaC03 (s)-Me2C(SH)CH(NHi)C02R1 C1- (R' = Me or Et) with 5,2-R2(HO)C6H3CH0(R2 = H, C1, or NO2) in EtOH-NaOAc gave the corresponding thiazolidines (177; R3 = a-HJ3-H; R4 = H), which with ClCH2COCl yield the corresponding compound (1 77; same substituents, with R4 = COCH2C1).'80 This last compound was cyclized by NaH in HMPT to give derivatives of 2,3-dihydro-l1bH-[3,2-d] [ 1,4] benzoxazepin-5(6H)one.

Me NR

(177)

Synthesis of Thiazolidines by Hydrolysis of Fused-Ring Compounds. With PC15 at 60" C, the methyl 6-phthalimidopenicillinate gives the a-methyl 6-phthalimidopenicilloate ester ( 178).18' COOMe

I

, L NH MeOOC

(178)

Physical Properties of Thiazolidines. - The crystallographic data, bond lengths, and bond angles were determined for 4-ethyl-4-methyl-5-methylene2-p-tolyliminothiazolidine (1 79). In the crystal, (1 79) is associated as a centrosymmetric dimer .lB2 The direct-current and differential-pulse polarographic behaviours of benzylpenicilloic acid (180) have been discussed. The differential-pulse peak current is linearly related to concentration in the range 1-20 x mol i-'.i83 ,CH 2NHCOCH 2Ph

Me Et

HOOC

Jpn. P. 81 150075,1981 (Chem. Abstr., 1982,96,218222). I. Torrini, M. P. Paradisi, and A. Romeo, J. Heterocycl. Chem., 1981, 18,1451. "' M. Kowcevik, J . J. Herak, and B. Gaspert, Croat. Chem. Acta, 1981, 54, 367 (Chem. Abstr., 1982, 96, 181 029). I82 A. A. Espenbetov, A. I. Yanovskii, Yu. T. Struchkov, L. A. Tsoi, and S. T. Cholpankulova, Khim. Geterotsikl. Soedin., 1981, 1617 (Chem. Abstr., 1982, 96, 122 681). U. Forsman and A. Karlsson, Anal. Chim. Acta, 1981, 128, 135 (Chem. Abstr., 1981, 95,121 186). 180


171

Chemical Properties of Thiazolidines. - The me tal-complexing properties of L-thiazolidine-4-carboxylic acid and of 2-amino-A2-thiazoline hydrochloride with Mg2+, Ca2', Ni2+, Mn2+, Cu2+, and Zn2+ have been in~estigated.'~~ Thiazolidine-4-carboxylic acid (1 8 1) was successively converted into 4C02Me, 4-CH20H, 4-CH2Br, 4-NH2, and 4-NHCOR The zinc sulphide complex with thiazolidine-4-carboxylic sodium salt derivatives (1 82) was also de~cribed.'~' Other derivatives of N-acylthiazolidine-4carboxylic acids have also been prepared.'&- lg2 (2RS)-Methylthiazolidine(4R)-carboxylic acid is claimed to be a latent cysteine.'" Acylation of the N-exo-position of 2-iminothiazolidines'" and of 2-spirothia~olidines~~~ has been described. Thermolysis of quaternary salts of 2-arylaminothiazolidines (1 83) and of 2-alkylimino-A2-thiazolines (184) led to (185) and (186), respectively.'% H2NCH2CH2S03Hwas prepared by oxidative (H202) ring-

(183)

(184)

(185)

( 186 1

cleavage of thiazolidine derivatives (187);197 R1R2C(SH)CH(NH2)P(0)(OH)X (R1 = alkyl; R2 = H or alkyl; X = H, OH, alkyl, or aryl) were prepared by hydrolytic ring-cleavage of (188).lg8 The electroreduction of the disulphide gives the corresponding thiol (1 89).lg9 Other N-acylated 2-arylthiazolidines have also been described.200 Jpn. P. 80 81 869,1980 (Chem. Abstr., 1981,95,97781). Jpn. P. 80 167 280,1980 (Chem. Abstr., 1981,95,43090). M. Oya, J . Iwao, and T. Iso, PCT Int. Appl. 81 02 893, 1981 (Chem. Abstr., 1982, 96,123 303). Jpn. P. 81 79 687,1981 (Chem. Abstr., 1981,95,204362). Jpn. P. 81 83419,1981 (Chem. Abstr., 1981,95,181 197). T. Ohashi, K. Shimazaki, K. Kan, H. Kondo, and K. Watanabe, Fr. Demande 2471 975,1981 (Chem. Abstr., 1982,96,7080). I 9 O E. W. Petrillo and M. A. Ondetti, Fr. Demande 2473 517, 1981 (Chem. Abstr., 1982,96,7079). 19' Jpn. P. 81 95 179,1981 (Chem. Abstr., 1982,96,35232). 19' Jpn. P. 81 92 279,1981 (Chem. Abstr., 1982,96,6718). 193 H. T. Nagasawa, D. J . D. Goon, R. T. Zera, and D. L. Yuzon, J. Med. Chem., 1982, 25,489. 1 9 4 Jpn. P. 81 133278,1981 (Chem. Abstr., 1982, 96,104223). 1 9 ' Belg. P. 884 875,1981 (Chem. A bstr., 1981, 95,80936). 19' L. A. Tsoi, S. T. Cholpankulova, G. K. Ryskieva, and A. D. Salimbaeva, Khim. Geterotsikl. Soedin., 1981,917 (Chem. Abstr., 1981, 95,187 137). 19' Jpn. P. 82 26 654,1982 (Chem. Abstr., 1982,96,199089). 19' K. J. M. Andrews, Eur. Pat. Appl. 33 919,1981 (Chem. Abstr., 1982,96,52 498). 1 9 9 Jpn. P. 81 90991,1981 (Chem. Abstr., 1981,95,194476). Jpn. P. 81 87 573,1981 (Chem. Abstr., 1981,95,187240). lB4

186

172


We have noted the following references concerning thiazolidin-2-ones (and -2-thiones and - s e l o n e ~ ) , ' ~ ~ thiazolidin-4-0nes,'~~1 *~~'-~~ 165 *207-228 201

'02

'03

N. E. Plevachuk, B. S. Zimenkovskii, I. I. Gal'kevich, and P. M. Steblyuk, Farm. Zh. (Kiev), 1981,4,40 (Chem. Abstr., 1981,95,160 062). J. F. h c h e r , G. Bourgery, P. Dostert, C. Douzon, P. Guerret, A. Lacour, and M. Langlok, Fr. Demande 2 458 547,1981 (Chem. Abstr., 1981,95,132 868). C. H. Li, Y. H. Yieh, Y. Lin, Y. J. Lu, A. H. Chi, and C. Y. Hsing, Tetrahedron Lett., 1981, 22,3467.

204

205 206

'07

'08

209

210

"I '12

Y. Nagao, T. Miyasaka, K. Seno, M. Yagi, and E. Fujita, Chem. Lett., 1981,463. F. A. Devillanova and G. Verani, Tetrahedron, 1981, 37, 1803. M. V. Andreocci, M. Bossa, F. A. Devillanova, C. Furlani, G. Mattogno, G. Verani, and R. Zanoni, J. Mol, Struct., 1981, 71,227. S. Y. Solov'eva, S. M. Ramsh, and A. I. Ginak, Khim. Geterotsikl. Soedin., 1981, 477 (Chem. Abstr., 1981, 95,80 900). A. M. Osman, M. A. Abbady, and F. M. Atta, Indian J. Chem., Sect. B , 1981, 20, 524 (Chem. Abstr., 1981,95,114964). S . S. Meher, S. Naik, R. K. Behera, and A. Nayak, J. Indian Chem. SOC., 1981, 58, 274 (Chem. Abstr., 1981, 95, 80 817). I. V. Smolanka, N. P. Mano, and T. A. Krasnitskaya, Khim. Geterotsikl. Soedin., 1981,627 (Chem. Abstr., 1981, 95,203 812). T. N. Rao, R. R. Astik, and K. A. Thaker, J. Inst. Chem. (India), 1981, 53, 174 (Chem. Abstr., 1982, 96,68 886). K. Peseke, N. C. Castanedo, and I. Bohn, Ger. (East) P. 147356, 1981 (Chem. Abstr., 1981, 95, 203 938). B. V. Tkachuk and N. M. Turkevich, Farm. Zh. (Kiev), 1981, 1, 24 (Chem. Abstr., 1981, 95,43 370).

'18

'19 220 221

222

H. Aoyama, S. Suzuki, T. Hasegawa, and 0. Yoshimori, J. Chem. SOC.,Perkin Trans. I , 1982, 247. R. Lakhan, Agric. Biol. Chem., 1982, 46, 557 (Chem. Abstr., 1982, 96, 157 185). M. J. Korohoda, Pol. J. Chem., 1981, 55,359 (Chem. Abstr., 1982, 96,20030). N. T. Dang, D. T. Nguyen, T. T. Tran, and H. T. Cao, Tap Chi Hoa HOC, 1981, 19, 14 (Chem. Abstr., 1982, 96, 52 237). M. A. Kaldrikyan and A. V. Khekoyan, Khim. Geterotsikl. Soedin., 1981,41 (Chem. Abstr., 1981, 95,150 520). N. Ben Mansour, W. D. Rudorf, and M. Augustin, 2. Chem., 1981, 21, 69 (Chem. Abstr., 1981, 95,62 071). R. Soliman, Pharmazie, 1981, 36,91 (Chem. Abstr., 1981, 95,62 100). A. J. Cowper, R. R. Astik, and K. A. Thaker, J. Inst. Chem. (India), 1981, 53, 111 (Chem. Abstr., 1982, 96,20 01 7). R. M. Di h r d o and M. G. Bock, Synthesis, 1981,825. K. A. Agaev and M. M. Turkevich, Farm. Zh. (Kiev), 1981, 2 , 43 (Chem. Abstr., 1981, 95,121 044).

Yu. G. Basova, S. M. Ramsh, and A. I. Ginak, Zh. Org. Khim., 1981, 17,663. 2 2 5 S. M. Ramsh, A. I. Ginak, Yu. G. Basova, and L. P. Shamina, Zh. Org. Khim, 1981, 17, 846 and 851 (Chem. Abstr., 1981, 95,96462 and 96463); Yu. G. Basova, S. M. Ramsh, and A. 1. Ginak, ibid., 1981, 17, 986 (Chem. Abstr., 1981, 95, 114 365). 2 2 6 A. J. Cowper, R. R. Astik, and K. A. Thaker, J. Inst, Chem. (India), 1981, 53,224 (Chem. Abstr., 1982, 96, 122 679); B. N. Singh, PhosphorusSulfur, 1981, 11,357. 2 2 7 N. B. Mansour, W. D. Rudorf, and M. Augustin, 2 . Chem., 1981, 21, 284 (Chem. Abstr., 1982,96, 35 149). 228 L. D. Dave, S. K. Thampy, and S. K. Thulasidas, J. Indian Chem SOC.,1981, 58, 1003 (Chem. Abstr., 1981,95,214 331).

2'4

Five-Membered Rings: Systems containing Nand S,Se, or Te

173

and thiazolidinethiazolidine-2,4-diones and 2-thioxothiazolidin-4-0nes,~~'-~~~ 2,5-dione~.~~~

12 Selenazoles Synthesis and Properties. - Type A Syntheses (SE-C-N + C-C). The (+)-p(2-amin0-1,3-selenazol-4-yl)alanine (1 90) has been obtained, starting from H2NC(Se)NH2 and C1CH2COCH2C1.244R1NHCSeNHNHCOR2 (R' = Et or Ph; R2 = Me, Ph, or 2- or 3-pyridyl) were prepared from R'NCSe and R2CONHNH2 by refluxing in EtOH.245 These selenosemicarbazides (R' = Et) react with ClCH2COMe to yield (191), whereas if R' is a phenyl group the A4-selenazolines (1 92) are formed.

H 2NCHCH2

Me

I

COOH ( 190)

229

230

231

232

B. Buchmanand D. N. Hamilton, J. Agric. FoodChem., 1981, 29,1285. S . Satsumabayashi and J. Nakayama, Nippon Shika Daigaku Kiyo, Ippan Kyoikukei, 1981, 10,155 (Chem. Abstr., 1 9 8 1 , 9 5 , 8 0 797). H. Singh, P. Singh, and K. Deep, Chem. Ind. (London), 1981, 252. E. F. Granin, E. D. Sych, V. V. Vyalykh, L. T. Gorb, E. K. Mikitendo, and L. P. Charuiskaya, Fiziol. Akt. Veshchestva, 1980, 12, 60 (Chem. Abstr., 1981, 95, 19 525).

233 2 34

235

236

13'

R. D. Khachikyan, S. M. Atashyan, and S. G. Agbalyan, Arm. Khim. Zh., 1981, 34, 775 (Chem. Abstr., 1982, 9 6 , 6 8 899). M. Valentiny, A. Martvon, and P. Kovac, Collect. Czech. Chem. Commun., 1981, 46, 2197.

H. K. Gakhar, P. Baveja, and N. Kumar, Indian J. Chem., Sect. B , 1982, 21, 64 (Chem. Abstr., 1 9 8 2 , 9 6 , 2 1 7 811). M. S. Fadeeva, T. I. Filaeva, and 0. Ya. Sdobnova, Deposited Document, 1980, VINITI 2987 (Chem. Abstr., 1982, 96, 34 365); M. S. Fadeeva, R. S. Lebedev, T. I. Filaeva, and 0. Ya. Sdobnova, Deposited Document, 1980, VINITI 3380 (Chem. Abstr., 1982, 96,34 366). V. Machacek, V. Sterba, and H. Zahradnickova, Collect. Czech. Chem. Commun., 1981,46,3097.

A. A. Artamonov, L. I. Timoshenko, G. M. Musienko, and L. P. Klimok, Khim. Geterotsikl. Soedin., 1981,1127 (Chem. Abstr., 1981, 95,203 880). 2 3 9 M. T. Omar and F. A. Sherif, Synthesis, 1981, 742. 240 G. Buchbauer and M. Kern, Arch. Pharm. (Weinheim, Ger.), 1980, 313,1043 (Chem. Abstr., 1981, 95,25 275). 241 E. K. Mikitenko and N. N. Romanov, Khim. Geterosikl. Soedin., 1981, 199 (Chem. Abstr., 1981, 95, 7130). 2 4 2 M. T. Omar and F. A. Sherif, Indian J. Chem., Sect. B , 1981, 20, 849 (Chem. Abstr., 1982, 96, 162 578). 243 F. J. Vinick and S. Jung, J. Org. Chem., 1982, 47, 2199. 244 R. N. Hanson and M. A. Davis, J. Heterocycl. Chem., 1981, 18,205. 2 4 5 B. Marcewicz-Rojewska and S. Bilinski, Acta Pol. Phurm., 1980, 37, 159 (Chem. Absrr., 1981, 95, 7160). 238


174

The treatment of oxazolium salts (193; R' = R3 = Ph, R2 = Me; R1-3 = Ph; R' =p-BrC6&, R2 = R3 = Ph; R' =p-tolyl, R2 = Me, R3 = Ph; R' =pMeOC6H4, R2 = R3 = Ph; R' = a-furyl, R2 = R3 = Ph; X = tosyloxy or C104) with HSe- gives R3COCH2NR2C(Se)R', which when treated with HC104 gave selenazolium salts (194).246 Treatment of (194; R'-3 = Ph; R' = p-tolyl, R2 = Me, R3 = Ph) with MeONa gave the A4-selenazolines (195).

R","Y":R '2

No major differences in the mass-spectral behaviour between the sulphurand selenium-containing compounds have been o b s e r ~ e d The . ~ ~predominant form in the tautomerism of A2-thiazolin-4-ones/thiazolidin-4-ones depends in part on the 5 - s u b s t i t ~ e n t . Thus ~ the condensation of 2-amino-A2selenazolin-4-ones (196) with RCHO (R = Ph, 4-C1C6H4, 2,4-C12C6H3, or 4-02Nc&) gave the benzylideneselenazolnones (1 97), whereas the condensation with RCHO [R = 4-MeOC6H4, 2,4-(MeO)2C6H3, or 3,4(Me0)2C6H3] gave the tautomeric iminoselenazolidin-4-ones (1 98). This last structure is also claimed for the imino-N-acylated compounds.249 Sulphoalkylations of selenazoles were also rnenti~ned.~"

1SeYNHz Rcyse7(mz 0

0

Rcxz 0

13 Benzothiazoles

Synthesis. - From ortho-Aminobenzenethiols ( o p e A ; S - C a 4 - N + C). * The cyclization between RNC and o-NH2C6H4SH gives a 2-substituted benzothiaz~le.~~' ~

246 24 1

0. P. Shvaika and V. F. Lipnitzkii, Zh. Obshch. Khim., 1981, 51, 1842 (Chem. Absfr., 1982, 96,20035). G . N. Jham, R. N. Hanson, R. W. Giese, and P. Vouros, J. Heferocycl. Chem., 1981, 18, 1335.

248

249 2 50

251

I. B. Levshin, A. A. Tsurkan, and K. A. V'yunov, Zh. Org. Khim., 1981, 17, 865 (Chem. A bsfr., 1981,95,132 761). I. B. Levshin, A. A. Tsurkan, E. A. Rudzit, and G. N. Neshchadim, Khim.-Farm. Zh., 1981, 15, 27 (Chem. Absfr., 1981, 95, 80 838). H. Kampfer, D. Wendisch, M. Hase, and M. Glass, Eur. Pat. Appl. 34 279, 1981 (Chem. Abstr., 1982, 96, 51 812). I. F. Szabo, I. Farkas, L. Somsak, and R. Bognar, A c f a Chim. Acad. Sci. Hung., 1981, 106,61 (Chem. Abstr., 1981, 95,62 576).

* For definitions of this series.

the types A, B, etc. for benzothiazoles, see p. 133 of Volume 1 of


175

Type B Syntheses of Benzothiazoles (C6H5-N-C-S). Following a known method, arylthioureas were oxidized to give substituted 2-aminobenzot h i a ~ o l e sand ~ ~2~ [(2-thioxoimidazolidin)-3-yl] b e n z ~ t h i a z o l eby ~ ~bromine, ~ and substituted 2-aminobenzothiazoles- by SOC12254 or Br2 (Cl,) and H ~ S ,255 O ~ Type E Syntheses (C6H5-N + C-S). Treatment of substituted anilines with NH4SCN gives substituted 2 - a m i n o t h i a ~ o l e sand ~ ~ ~there are also references concerning the synthesis of b e n z o t h i a ~ o l e s . ~ ~ ' - ~ ~ Physical Properties of Benzothiazoles. - The electronic spectra of some benzothiazole derivatives have been m e a ~ u r e d . ~The ~ ~ -luminescence ~~~ spectra of some benzothiazole derivatives269 and of the benzothiazoline-2thiones2" were also described. The new picosecond laser photolysis system has also been used and gives well-resolved absorption ~pectra.~"The 13C and

I. Ueda, M. Matsuo, S. Satoh, and T. Watanabe, Eur. Pat. Appl. 22 317, 1981 (Chem. Abstr., 1981, 95,7266). 2 5 3 R. J. S. Beer, H. Singh, D. Wright, and L. Kr. Hansen, Tetrahedron, 1981, 37, 2485. 2s4 M. Richter, M. Augustin, W. Kochmann, M. Pallas, W. Schnelle, H. J. Hartmann, M. Sieler, and K. Goetzschel, Ger. (East) P. 147 540, 1981 (Chem. Abstr., 1981, 95,169171). 2 5 5 Jpn. P. 82 09 774,1982 (Chem. Abstr., 1982,96,217832). 2 5 6 A. J. Lin and S. Kasina, J. Heterocycl. Chem., 1981, 18, 759; W. Eberlein, G. Trummlitz, W. Engel, G. Schmidt, G. Engelhardt, and R. Zimmerman, Ger. Offen. 3017976,1981 (Chem. Abstr., 1982, 96,68983). 257 Z.-H. Zhu, %-I. Wang, and J.-D. Wang, Hau-Tung Hua Kung Hsueh Yuan Hsueh Pao, 1981 , No. 1, p. 33 (Chem. Abstr., 1981,95,170 975). 2 58 S. K. Dubey, R. Rastogi, and S. Sharma,Monatsh. Chem., 1981, 112,1387. 2 5 9 G. Rabilloud and B. Sillion, J. Chem. Res. (S), 1981 , 264. 260 R. E. Brown, V. St. Georgiev, and B. Loev, U.S. P. 4 298 742, 1981 (Chem. Abstr., 1982, 96,68972). 261 K. T. Potts, A. J. Elliot, G. R. Titus, D. Al-Hilal, P. F. Lindley, G. V. Boyd, and T. Norris, J. Chem. SOC.,Perkin Trans. 1,1981,2692. 2 6 2 L. Benati and P. C. Montevecchi, J. Org. Chem., 1981,46,4570. 26 3 J. J. Nestor, G. H.Jones, and B. H. Vickery, Eur. Pat. Appl. 42 753, 1981 (Chem. Abstr., 1982, 96,163 214). 264 G. P. Dhareshwar, P. N. Chhaya, and B. D. Hosangadi, Indian J. Chern., Sect. B y 1980, 19,831 (Chem. Abstr., 1981, 95,6745). 2 6 5 D. Shatapathy and P. K . Misra, Indian J. Chem., Sect. B y 1981,20,84 (Chem. Abstr., 1981, 95,23682). 166 N. N. Romanov, Ukr. Khim. Zh. (Russ. Ed.), 1981, 47, 1280 (Chem. Abstr., 1982, 96, 124 505). 267 E. A. Chaika, G. I. Matyushecheva, and L. M. Yagupol'skii, Zh. Org. Khim., 1982, 18, 186 (Chem. Abstr., 1982, 96,201 246). 2 6 8 A. M. Osman and M. S. K. Youssef, Spectrochim. Acta, Part A , 1981,37, 811. 269 Z. Salamon and A. Skibinski, Dyes Pigm., 1981, 2, 239 (Chem. Abstr., 1981, 95, 1 17 044). 2 7 0 M. S. Fadeeva, R. S. Lebedev, T. I. Filaeva, and 0. Ya. Sdobnova, Deposited Document, 1980,VINITI 3380 (Chem. Abstr., 1982,96,34366). 2 7 1 T. Nakayama, S. Tai, K. Hamanoue, and H. Teranishi, Mem. Fac. Ind. Arts, Kyoto Techn. Univ. Sci. Technol., 1980,29,46 (Chem. Abstr., 1981,95,131 926). 252

176


15N n.m.r. spectra of (199) and (200) were measured.2n The largest difference between the (E)- and (2)-isomers was shown by the 13C-1sN coupling constants ( J ) between C-1 of the Ph ring and N-1 of the triazene chain. For [199; ( E ) / ( Z ) ] (, J ) is 0 and 7.7 Hz, respectively; for [200; ( E ) / ( Z ) ] (. J ) is 16.0 and 9.9 Hz, respectively. The 'H n.m.r. spectra of p(benzothiazol-2y1azo)-NN-dimethylanilines with the substituent R at the 6-position of the benzothiazole system were measured and correlated with the Hammett 0constants for R = H, Me, MeO, EtO, H2N, C1, Br, and 02N.273 The substituent effect was primarily of resonance through the .rr-electron system. Other 'H and 13C n.m.r. spectra of acrylic a m i n o - e ~ t e r sand ~ ~ of ~ cyanine dyes,275 respectively, including the benzothiazole system, have also been mentioned. The mass spectra of derivatives of 2-phenylaminobenzothiazole and of its isomers have been recorded.276 The mass spectrum of (201) was used t o determine the ratio of oxime t o nitroso-tautomers as 83.9: 16.1.277 An intense molecular ion and interesting fragmentations are observed in both the positive- and negative-ion mass spectra of nitro-derivatives of 2-aminobenzothiazole (loss of HNCO and H 2 0 re~pectively),~~' A NOz group at position 4 has a pronounced effect on the fragmentation. The separation by thinlayer chromatography of some 1-(benzothiazol-2-yl)-3-methyl-4-arylhydrazonopyrazolin-5-one derivatives has been studied [benzo-fused ring substituted at C-6 (R1); aryl substituted at C-2 (R2), C-3 (R3), C-4 (R4); R' = H, C1, or OMe; R2 = H, C1, Me, or OMe; R3 = H or Me; R4 = H, C1, Me,

"' E.

Fanghaenel, S. Simova, and R. Radeglia, J. Prakt. Chem., 1981,323,239 (Chem. Abstr., 1981, 95,79 681). 273 D. Simov, V. Koleva, A. Penchev, and B. Gulubov, God. Sofii. Univ. Khim. Fak., 1980,71,81 (Chem. Abstr., 1981,95,5940). 2 7 4 E. H. M. Ibrahim, M. 0. Abdel Rahman, and I. M. Abdellah, Egypt. J. Chem., 1979, 22,265 (Chem. Abstr., 1981,95,41675). 2 7 5 C . Reichardt and U. Rust, 2. Naturfomch., Teil. B , 1982, 37,236. 276 Ya. V. Rashkes, R. F. Ambartsumova, V. A. Saprykina, and N. K. Rozhkova, Zh. Org. Khim., 1981,17,614(Chem. Abstr., 1981,95,23703). 2 7 7 N. A. Klyuev, 1. S. Shpileva, L. I. Medvedeva, G. N. Lipunova, and N . P. Bednyagina, Khim. Geterotsikl. Soedin., 1981,1506 (Chem. Abstr., 1982, 9 6 , 51 648). 278 S. Claude, R. Tabacchi, L. DUC,and J. F. Marrel, Helv. Chim. Actu, 1981,64,1545.


177

NO2, or OEt] .279 The best results were obtained with a 40: 15 hexaneethyl acetate mixture. The pK, values were determined for the acid-base equilibrium of N-(2-benzothiazolyl)succinamic acid (202) by potentiometric titration in 60% aqueous dioxan and 50% ethanol.280 H

N

0

COOH

(202)

The protonation of triazenic systems that are bonded at C-2 with 6substituted 3-methylbenzothiazolines occurs on N-1 of the triazene moiety to form (203).281 The rate constants k,(H) and k,(D) were determined for H-D and D-H exchange at C-2 in the benzothiazoles (204; R = H, 6-N02, 543, 5- or 6-Me, 6-NH2, or 6-NME2).282The plots of log k,(H) and log k,(D) against the am + ap values of the substituents, according to the HammettJaffe equations, are slightly curved. The primary hydrogen is0 tope effect k,(H)/k,(D) against the am ap values of the substituents is a more pronounced curve, showing a maximum near the a m a, value of -0.3. The authors conclude that the use of the primary hydrogen isotope effect in the prediction of reaction mechanisms seems unreliable. The kinetics of solvolysis of 2-trimethylsilylbenzothiazole in MeOH, alone or containing NaOMe, and in MeOH/H20 (5 :2) that contains HC104 have been determined; they show first-order rate constants at 25°C.283 The mechanism of solvolysis is discussed in relation to the rate isotope effects in MeOD, and the effects of base and of acid on the rate of solvolysis. The distribution of products of the thermal dissociation of benzothiazolecyanines (205; n = 1-5, R = Et, X = I) that was observed by gas chromato-

+

+

H

279

281

283

V. K. Mahesh, M. Maheshwari, and V. Kumar, Fresenius 2. Anal. Chem., 1981, 309,404 (Chem. Abstr., 1982,96,144 438)., V. P. Chernykh, V. I. Makurina, V. I. Kabachnyi, and P. A. Bezuglyi, Zh. Fiz. Khim., 1981,55,1893 (Chem. Abstr., 1981,95,203080). E. Fanghaenel and J. Hohlfeld, J. B a k f . Chem., 1981, 323, 245 (Chem. Abstr., 1981,95,79443). 0.Attanasi, P. Battistoni, and G. Fan, Phosphorus Sulfur,1981, 10,271. G. Seconi and C. Eaborn, J. Chem. SOC.,Perkin Trans. 2,1981,1051.

178


graphy and mass spectrometry is consistent with atomic charges, bond orders, bond dipole moments, and reactivity indexes that were obtained by M.O. calculations of the ground state by the PPP method.284 The thermolysis of (205; R = Me, Et, Pr, or Bu; X = C1, Br, or I) and of the anhydro-base (206) gives the same volatile products, but ..in different proportions (ethane, ethylene, 2-methylben~othiazole).~~~ The thermolysis data have been explained in terms of a fragmentation scheme that is consistent with the molecular diagrams of electron densities and bond orders that have been calculated for (205; R = Et) and (206) in the PPP approximation. The flash photolysis of benzothiazolino-spirochromenes (207; R1 = Me, CH2Ph, Ph, OMe, SMe, etc.; R2 = Me, Et, or P f ; R3 = H, SMe, NO2, or OMe; R4 = OMe, H, CH20Me, CH20CH2CH20CH2CH2Me, or CH2SEt) was studied.286 The electron-donating substituents decrease the extent of photolysis. Hammett correlations involving inductive, resonance, and steric parameters were established for three compounds; the steric effect is the most important; polar solvents decrease the extent of photolysis. The kinetics of N-methy la tion of substi tu t ed 2-(2-furany1)benz ot hiazoles have be en de termined spectrophotometrically at 80°C.287 The electron-donating methyl group accelerates the reaction, whereas the halogens have the opposite effect.

Chemical Properties of Benzothiazoles. - Substitution Reactions on the Thiazole Ring. 2-Chlorobenzothiazoles are obtained by substitution of 2-NaS(K)-benzothiazoles by C12288 or by reaction of S0C12 with 2-NH2NHb e n z o t h i a z ~ l e s .2-Chlorobenzothiazoles ~~~ are etherified to benzothiazol-2-yl ethers,290 also obtained by displacement of the 2-methylsulphonyl group by 2 84

285

286

287

288

289 290

V. G. Khesin, M. A. Alperovich, P. I. Abramenko, R. D. Raikhina, and T. D. Medvedeva, Khim. Geterotsikl. Soedin., 1982, 188 (Chem. Abstr., 1982, 96, 219 261). V. G. Khesin, M. A. Alperovich, and P. I. Abramenko, Khim. Geterotsikl. Soedin., 1981,1626 (Chem. Abstr., 1982,96,164115). D. Gaude, R. Gautron, R. Guglielmetti, and J. C. Duffy, Bull. SOC.Chim. Fr., Part 2, 1981,14. L. Fiser-Jakic and K. Jackopcic, Croat, Chem. Acta, 1981, 54, 245 (Chem. Abstr., 1981,95,219491). H. Knorr, R. Handte, L. Willms, and T. Tammer, Eur. Pat. Appl. 43 573, 1982 (Chem. Abstr., 1982,96, 142 845). T. Papenfuhs, Ger. Offen. 3 023 227,1982 (Chem. Abstr., 1982,96,104229). S. Kuyama, M. Aya, and J. Saito, Eur. Pat. Appl. 37 524,1981 (Chem. Abstr., 1982, 96, 52 298); 37 525, 1981 (Chem. Abstr., 1982, 96, 52 296); 37 526, 1981 (Chem. Abstr., 1982, 96, 52 297); 37 527, 1981 (Chem. Abstr., 1982, 96, 68978); 37 938, 1981 (Chem. Abstr., 1982, 96, 68984); Jpn. P. 81 29535, 1981 (Chem. Abstr., 1981, 95, 62459); 81 79683, 1981 (Chem. Abstr., 1981, 95, 203934); V. Mues and W. Behrenz, Ew. Pat. Appl. 44008,1982 (Chem. Abstr., 1982,96,199672).


179

phenols.2g1 The substitution (or addition-elimination) of the 2-amino-group of the 2-aminobenzothiazole by itself gives 2,2'-iminobis(benzothiazo1e) compounds [208; R (alike or different) = H, alkyl, halogen, alkoxy, CN, or NO,; n = 1-31 .292 H

Reactions of 2-Aminobenzothiazo2es. (Un)substituted 2-aminobenzothiazoles are diazotized to give dyes293*2" and 2-halo-derivatives. HC1 gives luciferin and its analogues (209; R1 = OH; R2 = H or OH)?" condensed with CS2 (DMF , H, 0, KOH), these give 2-aminobenz othiazol yldithiocarbama tes , which are oxidized to the dimers (210; R = C1, Br, Me, or AcNH).~'~Isocyanates give substituted derivatives of benzothiazolylurea (2 11; R1 = R1

H

H

(211)

L. Willms, R. Handte, and H. Mildenberger, Eur. Pat. Appl. 44497, 1982 (Chem. Abstr., 1982,96,199676). 2 9 2 T. Paoenfuhs, Ger. Offen. 2 947489,1981 (Chem. Abstr., 1981,95,97 784). 2 9 3 K. Nishida, T. Tamura, Y. Ando, T. Morirnoto, T. Katoh,and H. Iwamoto,Arn. Dyest. Rep., 1981, 70,17 (Chem. Abstr., 1981,95,170 969). 294 A. K. Panigrahi, B. K. Panigrahi, P. Mishra, and R. N. Mohanty, J. Inst. Chem. (India), 1981,53, 79 (Chem. Abstr., 1981, 95,188622). 2 9 5 H. G. Batz and K. Wulff, Ger. Offen. 2929115, 1981 (Chem. Abstr., 1981, 95, 196 172). 296 A. Gvozdjakova, T. Goegh, and Z. Odlerova, Czech. P. 192 444,1981 (Chem. A bstr., -1982,96,122782). 291

180


CONHC6H4R3; R3 = H, o- or p-C1; R2 = H, OEt, or OMe);297 3-ClC6H4COCH2Br, for example, gives 2-(3-~hlorophenyl)imidazo [2,1 -b]benzothiazole (2 12).298 Reactions of 2-hydrazinobenzothiazoles with p y r ~ v a l d e h y d e ~ ~ ~ and with 2-substituted pentane-2,4-diones have also been r e p ~ r t e d . ~ ~

Reactions of 2-Mercaptobenzothiuzoles. The (un)subs tituted 2-mercapt obenzothiazoles react with an amine and O2 in the presence of H 2 0 and cobalt phthalocyanine to give high yields of sulphenamide (2 13):" they also react with morpholine in the presence of NaOC1.302 These sulphenamides could be the first step in the conversion into disulphides (214).303 The 2mercaptobenzothiazoles are substituted in alkaline solution with halo-

corn pound^.^^*^^^

Other Reactions of Benzothiuzoles. The regio- and stereo-specific photocycloaddition reaction (4h, under Nz, high- ressure Hg arc) or 2-phenylbenzothiazole with R1RC2=CR3R4 (R1= Rg = R4 = H, R3 = OEt; R' = R4 = H, R2 = R3 = Me; R1 = R3 = Me, R2 = R4 = H) gives the benzothiazepines (219,306 the structure of which was assigned by acidic ringM. K. Lee, B. C. Seoh, Y. G. Chung, K. J. Min, and H. Y. Kang, Yongnam Taehakkyo Nonmunjip Chayon Kwahak Pyon, 1980, 14, 231 (Chem. Abstr., 1982, 96, 142 745). 298 K. Murase, T. Mase, and K. Tomioka, Ger. Offen. 3030982, 1981 (Chem. Abstr., 1982, 96,6724). 2 9 9 C. L. R. Pinto and E. K. Libergott, In$ INT, 1981, 14,12 (Chem. Abstr., 1981,9 5 , 90443). 300 S. N. Sawhney, R. K. Tomer, 0. Prakash, I. Prakash, and S . P. Singh, Indian J. Chem., Sect. 8,1981,20,314 (Chem. Abstr., 1981, 95,62069). 3 0 1 A. S . Cobb and D. J. Williams, Eur. Pat. Appl. 29718, 1981 (Chem. Abstr., 1981, 95, 150 644); H.Zengel and M. Bergfeld, Ger. Offen, 2 944 225 (Chem. Abstr., 1981, 95,26410). ' 0 2 A. M. Herzog, G. Aivanese, and M. F. B. Mavro, Rom. P. 68 398, 1979 (Chem. Abstr., 1981, 95, 25 049); P. Klucovsky, J. Masek, V. Sudek, L. Jozsa, and J. Kollar, Czech. P. 184 052,1980 (Chem. A bsfr., 1981, 95,25046). 303 A. N. Lazovenko, V. A. Ignatov, V. E. Maizlish, and V. F. Borodkin, Izu. Vyssh. Uchebn. Zaved., Khim. Khim. Tekhnol., 1981, 24, 685 (Chem. Abstr., 1981, 9 5 , 219 547). 304 E. Sidoova and Z. Odlerova, Czech. P. 189212, 1981 (Chem. Abstr., 1982, 96, 162 686). 305 T. Doll, E. Schacht, H. E. Radunz, and E. Schulze, Ger. Offen, 2 950 095, 1981 (Chem. Abstr., 1981,95,132865). 306 M. Sindler-Kulyk and D. C. Neckers, Tetrahedron Lett., 1981,22,2081. 297


181

cleavage followed by recyclization. The thermal cyclization of 2-(o-fluorobenzamido)benzothiazole gives 5H-benzothiazolo [3,2421 quinazolin-5-ones (216; R = H, C1, OMe, or OEt).307

Benzothiazolines and Benzothiazolin-2-ones (and -thiones). The syntheses of substituted spiro-2-benzothiazolines308 and 2-methoxycarbonyl-2phenacyl-1 ,3-benzothiazolines30g have been described. By treatment in boiling DMSO, benzothiazolines yield 1,4-benzothiazines, in some cases together with b e n z o t h i a z ~ l e s .Most ~ ~ ~ of the work related to benzothiazolin2-ones (and -thiones) concerns N-alkylation and the modification of the Nalkylated chains.3119312 Benzothiazolium Salts. The benzothiazolium N-phenacylide adds to the endocyclic double bond of methylenecyclopropenes that have no acyl group in the 4-position to give stable [3 + 21 cyclo-adducts (217).313 This is claimed to be the first example of the formation of stable [3 21 cycloadducts in the reaction of 1,3-dipoles with methylenecyclopropenes. Other cycloadditions of benzothiazolium N-phenacylide with olefinic dipolar ophiles from the same team are also mentioned. Various reactions of other benzothiazolium salts have also been d e ~ c r i b e d . ~ ' ~ - ~ l ~

+

Ft l I

"2

D. H. Kim, J. Heferocycl. Chem., 1981, 18, 801. F. Sauter, P. Stanetty, and A. Blaschke, J. Chem. Res. (S),1981, 4, 98; G. Liso, G. Trapani, A. Reho, and A. Latrofa, Tetrahedron Lett., 1981, 22,1641. 309 Yu. S. Andreichikov, S. P. Tendryakova, Ya. A. Nalimova, E. L. Pidemskii, and T. B. Karpova, U.S.S.R. P. 625 392,1981 (Chem. Abstr., 1981,95, 150 646). 3 1 0 G. Liso, G. Trapani, A. Latrofa, and P. Marchini, J. Heterocycl. Chem., 1981, 18, 279. Y. Hamari and K. K. Kogyo, Jpn. P. 81 20 581, 1981 (Chem. Abstr., 1981, 95, 4 3 171) Jpn. P. 81 127 365,1981 (Chern. A h t r . , 1 9 8 2 , 9 6 , 8 5 583). 3 1 2 J. P. Chupp, Fr. Demande 2479221,1981 (Chern. Abstr., 1982,96,181272). 3 1 3 0 . Tsuge, H. Shimoharada, and M. Noguchi, Chem. Lett., l981,1493;Heterocycles, 1981, 1 5 , 807. 314 N. N. Romanov, K. V. Fedotov, and 0. I. Tolmachev, Dopov. Akad. Nauk Ukr. RSR, Ser. B: Geol., Khim. Biol. Nauki, 1980, 11, 59 (Chem. Abstr., 1981, 95, 7191). 3 1 s 0. Tsuge, M. Tanaka, H. Shimoharada, and M. Noguchi, Heterocycles, 1981, 16, 1705. 316 H. Balli, H. Gruener, R. Maul, and H. Schepp, Helv. Chim. A c t a , 1981, 64,648. 317 R. R. Schmidt and H. Hensen, Chem. Ber., 1981, 114, 1723.

307

308

182


14 Condensed Ring Systems incorporating Thiazole Structures comprising Two Five-Membered Rings ( 5 3 ) . - Thiazolof 3,2-d] tetrazoles [CN4-CflS]. 1-Aryl-5-mercaptotetrazoles react with 4-XCsH4 COCH2Br. The resulting derivatives are cyclized to 1,5-diaryl-lH-thiazolo[3,2d] tetrazol-4-ium perchlorates (2 18).318 R1 R2

(YN'i N-

N

c10;

Thiazolor2, 3-cJ/1,2,4] thiadiazole /C2N2S-CflSJ. The molecular and crystal structure of 5,6-dihydrothiazole [2,3-c] [ 1,3,4] thiadiazol-3-one (219) has been determined by X-ray c r y ~ t a l l o g r a p h y . ~ ~ ~

Thiazo10/2,3- bJ [1,3,4/ t hiadiazoles [C2N2S-CflS]. 2 -Amino-5-ally1thi ot hiadiazole is acylated with RCOCl to give amides, which undergo cyclization with NaOH to yield 5-methyl-[ 1,3J thiazolo [2,3-b] [ 1,3,4] thiadiazol-4-ylium2-amidates (220).320 These amidates are alkylated, giving thiazolothiazolium salts.

Thiazolo-f 2,3-c] -, -f3,2-b] -, and -(3,4-b/ -f1,2,4] triazoles [C2N3-CflS]. The hydrazo-derivative (221) was cyclized with NaOEt to the dihydrothiazolotriazole (222; R = CONHPh).'* Compound (222; R = H) was also obtained by opening and re-cyclizing (223) with NaOH. Refluxing [224;

csy$o (221)

318 319

320

0

M. A. Eldawy, I. Chaaban, and A. S. Mehanna, Egypt. J . Pharm. Sci., 1978, 19, 185. A. F. Cameron, I. R. Cameron, and F. D. Duncanson, J. Chem. SOC.,Perkin Trans. 2 , 1981, 789. G. Jaeger and H. Heitzer, Synthesis, 1981, 704.


183

R = Ph or R1C6H4 (R' = 243, 4-C1, 2-Me, 4-MeO)I in NaOMe-MeOH gave the thiazolotriazoles (225).321 2-Substituted 5,6-dihydrothiazolotriazol5-ones were also described.322 Thiazolotriazole-5-thiones(226; R' = Ph, R2 = Ph or Me) and (226; R' = Me, R2 = Ph or Me) have been obtained by heating equimolecular quantities of 5-substituted 3-amino-4-oxothiazolidine2-thiones with PhC(=NR2)C1.323 R1

R2

H C Z CCH S HN-N

Me

N-N

N-N

Thiazolo[4,5-dJ-oxazole,-thiazole, and -selenazole (C3 NX-C3NSJ. The cycloaddition of ethyl 3-p-anisyl-5-bromo-4-oxothiazolidin-2-ylidenecyanoacetate with KOCN gives the 2,3,4,5-tetrahydrothiazolo[4,5-d] oxazol-2-one derivative (227; X = O).324 The sulphur and selenium analogues can be obtained, starting from KSCN and KSeCN, respectively. COOEt

Imidazo-/2,l-b]- and -/S,l-bJ -thiazoles [ C a 2- C a S J . Derivatives of imidazo [2,1 -b]thiazole are obtained by intramolecular Michael addition, followed by elimination of methanethiol, to yield [228; R' = C02Me, R2 = CH(CN)2 or CH2CN; R' = H, R2 = tosylamino] .126 Intramolecular cyclization of 3-aminoethyl-2-iminothiazolines gives 2,3,5,6-tetrahydroimidazo-

V. P. Upadhyaya and V. R. Srinivasan, Indian J. Chem., Sect. B y1981,20, 161. G. Mazzone, F. Bonina, R . R. Arrigo, and G. Blandino, Farmaco, Ed. Sci., 1981, 36, 181 (Chem. Abstr., 1981,95,6695). 323 E. K. Mikitenko and N. N. Romanov, Khim. Geferofsikl.Soedin., 1981, 564 (Chem. Abstr., 1981,95, 80 834). 324 K. Peseke and N. C. Castanedo, Ger. (East) P. 147361, 1981 (Chem. Absfr., 1981, 95,203 939). 321

322


184

[2,1-b] thiazoles (229; R = Ph, 02NC6H4, H2NC6H4, or MeC6H4),325and of substituted 2-imino-3-(2-hydroxyethyl)thiazolidine gives [229; R = 2(3-methylbenzofuranyl)] .326 The thiazole ring is often built in the second step. Imidazolidinethiones and cu-brorno-ketone~,~~' imidazolidinethiones and 2-chlorohydroxamoyl chloride ,328 and imidazole thiol and ethyl bromoacetate329 condense, giving imidazothiazole derivatives. Sometimes the thiazole ring is built in the first step, e.g. condensation of 2-aminothiazole with phenacyl bromides.330 The crystal and molecular structures of a 2,3,5,6tetrahydroimidazo [2 ,1411 thiazole derivative and of a 2,3-dihydroimidazothiazol-6(5H)-one have been described.319 Aminomethylation (with HCHO and piperidine or morpholine), bromination, and nitrosation of (228; R1 = H, R2 = 2-furanyl) and its derivatives were studied.331 Derivatives of the ringsystem (230; R = Ph, 4-MeC6H4, 4-ClCsH4, 4-02NC6H4, or 2- or 3-MeC6H4) were also described.332 'Levamisole' (2,3,5,6-tetrahydro-6-phenylimidazo[2,1-b] thiazole) remains the object of considerable interest (close to 60 references).

Pyrrol0[2,1-b/ thiazoles [CJJ-C&S/. The pyrrolothiazoles (23 1 ; R = H or Et02C) were synthesized from the cycloaddition reaction of imidazothiazole with PhCOC-CCOPh followed by elimination of a nitrile group from the cyclo-adduct .333 COP h

M. E. Menim, U.S.S.R. P. 847 915,1981 (Chem. Abstr., 1982,96,6727). S . Nielek and T. Lesiak, Chem. Ber., 1982, 115, 1247. T. Hara, Y. Kayama, and H. Fukushima, J. Heterocycl. Chem., 1981,18, 1089. 328 D. F. Bushey and T. D. J. D'Silva, Eur. Pat. Appl 43263, 1982 (Chem. Abstr., 1982,96,199666). 329 A. Ali and R. K. Saksena, J. Indian Chem. SOC.,1981,58,1117. S. N. Sawhney, D. R. Kodali, G. S. Dhindsa, and S. P. Singh, Indian J. Chem., Sect. B y1982, 21,134. 331 N. Saldabols, L. L. Zeligman, S. Hillers, and J. Popelis, Org. Soedin. Sery, 1980, 2,220 (Chem. Abstr., 1982,96,122692). 332 A. F. A. Shalaby, M. A. Abdel Aziz, and S. S. M. Boghdadi, 2.Naturforsch., Teil. By 1981,36, 501 (Chem. Abstr., 1981,95,97 667). 333 N. Abe, T. Nishiwaki, T. Omori, and E. Harada, Bull. Chem SOC. Jpn., 1982, 55, 200.

325

326 327


185

Structures comprising One Five-Membered and One Six-Membered Ring (5, 6). - Thiazolo/3,2-a/-l,3,5-triazines (C,NS-C, N3]. Dihydro-3,4-2Hthiazolotriazinones (232; R' = R2 = H, R3 = Me, Ph, etc.) were prepared by Mannich reactions of 2-imino-4-thiazolidin-4-ones with CH20 and R3NH2.207 Thiazolo [3,2-a] triazine-2,4-diones (and 2-thioxo-4-ones) (233 ; X = 0 or S; R1 = H, Me, or halo; R2 = cyclohexyl, Ph, MeC6H4, or 02NC6H4) have been obtained by treating a 2-thiazolylurea derivative with C1C02CC1~.334

(232)

(233

0

ThiazoZo[3,2-b]pyridazines (C3 NS-C4Nz/. Treatment of thiazolo [3,2-b]pyridazin-4-ium perchlorates (234; R' , R2 = H, Ph, or Me) with NzH4 affords the 1,4-bis-(2-vinylpyridazin-3-ylidene)tetrazenes(235) and several other products, depending upon the reaction time, temperature, and substituent .335

Thiazolo[3,2-a]pyrimidines [C3NS-C4N2J. Ethyl 4-chloroacet oacetate condenses with 4-amino-6-hydroxypyrimidine-2-thiol to yield ethyl 7-ami1-102,3-dihydro-3-hydroxy-5(H)-oxothiazolo [3,2a] pyrimidine-3-ace tate (236) (X-ray), and not ethyl 3-hydroxy-5-amino-7-oxothiazolino [3,2a] pyrimidine3-acetate, as previously reported by the authors.336 The cyclization of substi-

334

335 3 36

N. Matsui, K. Maeda, M. Kaeriyama, Y. Yasuda, A. Nakata, and M. Mizuno, Belg. P 889 390,1981 (Chem. Abstr., 1982,96,142898). K. Satoh and T. Miyasaka, Chem. Lett., 1981,1153. E. Campaigne, K. Folting, J. C. Huffman, and T. P. Selby, J. Heterocycl. Chem., 1981, 18,5 7 5 .

186


tuted (2-pyrimidiny1thio)acetic acids in the presence of AcaO gives mesoionic thiazolo [3,2a] pyrimidine derivatives (237).314 Several bicyclic fused compounds of thiazolium salts and perhydropyrimidine, (238) and (239), have been synthesized from halo-ketones and cyclic t h i ~ u r e a s . ~ ~6,7’ Dihydro-5,7-dioxo-8-(2,3,5-tri-0-acetyl-40)-Dribofuranosyl)thiazolopyrimidinium hydroxide inner salts have been described and claimed as the first examples of class 11 meso-ionic xanthine n ~ c l e o s i d e s . ~ ~ ~

Thiazolo/S,4-b/pyridines [CJ?S-C,N/. 2-(Ary1hydrazino)- and 2(ary1amino)-thiazolopyridines (240) were prepared by condensing 2-chloro3-isothiocyanatopyridine with phenylhydrazines or anilines in EtOH .339

(240)

Structures comprising Two Five-Membered Rings and One Six-Membered Ring (5,5,6). - Benzo[lY2-d; 4,5-d’/ -bis-thiazoles (CflSCflS-C, 3. The condensation of 2,3,5,6-tetramethylthiazolo[4,5-f] benzothiazolium diperchlorate with orthoesters RC(OEt), (R = H, Me, Et, or Ph) or with 1,1,3,3tetramethoxypropane gives polymeric cyanines (241) and (242; X = CHCH= CHCH=CH), r e ~ p e c t i v e l y . ~ ~

( 241)

(242)

Benzo[d/ imidazo/2,1-b/ thiazoles [CflSCJ?, -CJ Cyclization of [ ( 5 substituted 2-benzimidazolyl)thio] acetic acids by heating in Dowtherm A or

G. B. Foscolos, G. Tsatsas, and E. Costakis, Chem. Chron., 1980, 9 , 239 (Chem. Abstr., 1981,95,169054). R. A, Glennon, E. Schubert, and R. G. Bass, Tetrahedron Lett., 1981,22,2753. 3 3 9 B. G . Khadse, S. R. Lokhande, P. P. Chaudary, M. B. Bhide, and S. Ghooi, Bull. Haffkine Inst., 1980,8,21 (Chem. Abstr., 1982, 96,35 153). 340 G. Kossmehl and P. Bocionek, Mukromol. Chem., 1981, 182,3427 and 3445 (Chem. Absk., 1982,96,105786 and 105 787).

337 338


187

Ac20/pyridine gave (243; R = NO2, OMe, Me, C1, or C02Me) and (244) in a 1 : 1 ratio in all casesM1 The separation of (243) and (244) was successfully carried out and their structures (the direction of cyclization) were suggested on the basis of n.m.r. spectra.

Thiazolo/3,4-a]benzimidazole [C3NS€f12 -C6j. 1,3-Diphenylthiazolo [3,4a ] benzimidazole (245), containing quadrivalent S, reacts as a thiocarbonyl ylide dipole with fulvene and tropone systems.342 Ph

Thiazolo[3',2' ; 1,2Jirnidazo[4,5,-bJpyrazine [C3NS€3N2€4N2 J. Cyclocondensation of chloropyrazine with urea gives imidazopyrazinol, which is treated with P4Sl0 to give imidaz~pyrazinethiol.~~ Treating this thiol with BrCH2CH2Br gives 2,3-dichloro-7,8-dihydrothiazolo [3',2': 1,2] imidazo [4,5b ]pyrazine (246).

Pyrrolo(2,l -bJ benzothiazole [CflS-C&C, J. is obtained by following a similar method.333

This homologue of (23 1)

Structures comprising One Five-Membered Ring and Two Six-Membered Rings (5,6,6). - 1,2,4-Triazinol[3,4-b]benzothiazole [C3NS-C3N3-C6J. In concentrated HCl, refluxing triazinobenzothiazol-3-one (247) with 4-

(247) 341

342

343

K. Tanaka, M. Ino, and Y. Murakami, Chem. Pharm. Bull., 1981, 29, 1876 (Chem. Abstr., 1981, 95, 220 004). 0. Tsuge, H. Shiraishi, and M. Noguchi, Chem. Lett., 1 9 8 1 , 2 13. Y . C. Tong, J. Heterocycl. Chem., 1981, 18, 751.


188

R'C6H4COR2 (R' = H, NO2, Me, or MeO; R2 = H or Me) gave (248; R3 = H), whereas (248; R3 = Me) was obtained in the presence of MeOH.344

1,3,5-Triazino[2,l-bJ benzothiazole [cfls-cfl3-c6]. MeCON(CH2 C1)2 reacts with 2-benzothiazolamine to give (249);"' 'H and 13C n.m.r. data are given.

f-JSYN> N

#NAc

Thiazol0[2,3-b] quinazolines (CflS-Cfl2 -C6J. The cycloaddition reaction of alkali-metal salts of 2-mercapto-4(3H)-quinazolinones with 3-benzoyl-3bromopropionic acids and esters gives acids (250) and lactones (25 1).346

344

345 346

M. D. Kazanis and P. E. Macheras, Chem. Chron., 1980, 9, 201 (Chem. Abstr., 1981,95, 115475). H.Boehme and J . P. Denis, Arch. Pharm. (Weinheim, Ger.), 1982, 315,227. G.Rovnyak, V. Shu, and J. Schwartz, J. Heterocycl. Chern., 1981, 18,327.


189

Thiazol0[3,2-a] thiapyrano[4,3-d] pyrimidines f C3NS-C4N2-C5XJ. Tricyclic thiazolo [3,2-a]thiapyrano [4,3-d]pyrimidines and related analogues (252 ; X = S, SO2, 0, NMe, NAc, or CH2) are prepared by the cycloaddition reaction of dibenzylidene ketones with 2-aminothiazoline .346

1,2-Oxathino[.5,6-gJ benzothiazoles f C f l s - ~ ~ O The ~ ~polar ~ ] .1,4-addition of CH2 =SOz to benzothiazolones gives oxathiino-benzothia~oles.~’ Thiazolo-/2,3-a] - and -/3,4-b] -isoquinolines ( C ~ ~ S - C S N - CThe ~ ] .fusion of 2,3,5,6-tetrahydrothiazoloisoquinoliniumperchlorate (253) gives the vinyl sulphide (254).348 Thiazoloisoquinolinium salts (255; R1 = C1, alkylthio, or PhCH2S; X = Cl, I, HS04, BF4, or FS03) react with heteroarylamines to give (25 6).349

H C =CH- S (253)

347 348 349

( 254)

L. Mosti, G. Menozzi, and P. Schenone, J. Heferocycl. Chem., 1981, 18, 1069. H. Singhand S. C. Malhotra, Synfh. Commun., 1981, 11, 635. D. Farge, A. Jossin, G. Ponsinet, and D. Reisdorf, Eur. Pat. Appl. 30 198, 1981 (Chem. Abstr., 1982,96,6715).


190

Naphtho[2,3-d] thiazole [C&%c6 -C6]. The 2,3 -dihydro-2-thioxonaphtho[2,3-d] thiazole-4,9-dione (257) is prepared by cyclo-condensation of 2-amino3-chloronaphthoquinone with Na2S and CS2.350

Other Condensed Systems incorporating Thiazole. - Dihydro- and tetrahydrocyclopropa [d] thiazole derivative^,^" cyclenothiazoles,352 hexahydrocycloocta[d] thiazolo [3,2-a] pyrimidines,353 2-amino-10,ll -dihydrophenanthro[ 1 , 2 - d ] t h i a ~ o l e 2-aza-l,3-dimethyl-6-oxa-7,7-diphenyl-4-thiabicyclo[3.2.0],~~~ he~t-2-ene,~” and 4-substituted 2-amino-7-oxochromeno[6,5-d] thiazoles and 4,6,7-trisubstituted 2-amino-9-oxochromeno[4,3-d] thiazoles have also been mentioned.3s6 15 Thiadiazoles and Selenadiazoles

1,2,3-Thiadiazoles. - Synthesis. @-Unsaturated p-tosylhy drazones PhCH= CHCR’=NNHTs (R’ = H, Ts = p-MeC6H4SO2) were treated with SOCl2, SC12, or S2C12 to give 40, 18, and 27% of (258; R1 = H); when R1 = Me, 55 and 18% of (259; R2 = PhCH=CH) were obtained from SC12 or S2C12.357 Saturated substituted hydrazones R’ CH2C(CH2R2)=NNHR3 (R’ = H, alkenyl, etc.; R2 = alkyl, C02Et, C1, S02Ph, Ph, or substituted phenyl; R3 = CONH2, S02C6H4Me-4, or C02Et) cyclize with SOCl2 to give (260) and (261).358 The regioselectivity was discussed in terms of the Z/E equilibrium

350

T. Nakamori, Y. %to, and T. Kasai, Nippon Kagaku Kaishi, 1982, 98 (Chem. Abstr., 1982, 96, 104 156).

P. B. Hitchcock, R. W. McCabe, D. W. Young, and G. M. Davies, J. Chem. SOC., Chem. Commun., 1981,608. 352 H. Eilingsfeld, P. Neumann, G. Seybold, D. Lenke, and L. Friedrich, Eur. Pat. Appl. 44443,1982 (Chem. Abstr., 1982,96,199 675). 353 M. I. Ali, A. El-F. G. Abou, and N. M. Youssef, J. Chem. Eng. Data, 1981, 26, 214 (Chem. Abstr., 1981, 9 5 , 7197). 3 5 4 S. Kumar and K. S. Sharma, Indian J. Chem., Sect. B , 1981, 20, 380. 3 5 5 T. Nakano and A. Martin, Org. Mass. Spectrom., 1981, 16, 5 5 . 3 5 6 J. R. Merchant, G. Martyres, and M. S . Venkatesh, Indian J. Chem., Sect. B, 1981, 20,493. 357

F. Bellesia, R. Grandi, U. M. Pagnoni, and R. Trave, Gazz. Chim. Ital., 1981, 111, 289.

0. Zimmer and H. Meier, Chem. Ber., 1981, 114, 2938.


191

ratio of the starting compound; hydrogens of CH2 are more reactive than those of CH3. Glycosyl isothiocyanates R'NCS react with R2CHN2 (R2 = H or C02Et) to give the corresponding 5-glycosylaminothiadiazoles .359 The reactions of cis-3-(2-furyl)propenoyl isocyanate with PhCH2NH2, piperidine, and CH2N2 gave the corresponding cis thiourea and derivatives of thiadiazo1e .360

Physical Properties of 1,2,3-ThiadiazoZes. Lanthanide-induced shifts have been used for elucidation of the structure of thermally generated monoxides of l72,3-thiadiazo1es (lH and l3C). A calculation has been developed for the evaluation of lanthanide-induced shifts according to the McConnellRobertson equation.=l The 0' ind 0 : parameters of triazoles were also determined by 19F n.m.r. spectroscopy.x2 Chemical properties of 1,2,3-ThiadiazoZes. The pyrolysis of 4- and 5-methyl1,2,3-thiadiazoles gives methylthioketen, MeCH=C=S.363 The photolysis of argon-matrix-isolated 4-acetyl-5-methylthiadiazole at 265 nm gives the thiiren (262) via ring-closure of the carbene (263) that is formed in the s-trans-s-cisc o n f o r r n a t i ~ n The . ~ ~ alkylation of the thiadiazoles (264; R1 = NH or C02Et, R2 = H) and (264; R1 = H or Ph, R2 = NHCOR3) gives the corresponding compounds (265) and (266), r e s p e c t i ~ e l y . ~The ~ meso-ionic compounds (265) and (266), when treated with HC1, give the corresponding 4- and 5 amino-salts.

A,,

Me

R~COR NMe R

1,2,3-!3elenadiazoles. - The substituted hydrazones R' CH2C(CH2R2)= NNHR3 (R1 = H, alkenyl, etc.; R2 = alkyl, C02Et, C1, S02Ph, Ph, or substituted Ph; R3 = CONH2, S02C6H4Me-4, or C02Et) cyclize with H2Se03 H. Ogura, H. Takahashi, and 0. Sato, Chem. Pharm. Bull., 1981, 29, 1843 (Chem. Abstr., 1981, 95, 187 574). P. Kutschy, P. Kristian, M. Dandarova, and J. Kovac, Collect. Czech. Chem. Commun., 1981,46,1160. 3 6 1 U. Pluecken and H. Meier, 2. Nahtrforsch., Teil. B, 1981, 36, 1305. 362 J. Elguero, C. Estopa, and D. Ilavsky, J. Chem. Res. (S), 1981, 364. 363 B. Back, H. Svanholt, and A. Holm, Acta Chem. Scand., Ser. A , 1980, 34, 625. 3 6 4 M. Torres and 0. P. Strausz, N o w . J. Chim.,1980, 4, 703. 3 6 5 K. Masuda, J. Adachi, H. Morita, and K. Nomura, Chem. Pharm. Bull., 1981, 29, 1743 (Chem. Abstr., 1981, 95, 115405); K. Masuda, J. Adachi, H. Nate, H. Takahata, and K. Nomura, J. Chem SOC.,Perkin Trans. 1 , 1981, 1591.

359

360

192


to give (267) and (268).358 Some 'H and 13C n.m.r. spectra of thirty seven 1,2,3-~elenadiazoleshave been recorded.366 Coupling constants ('H-'H, 13C-lH, 77Se-'H, and 77Se-'3C) were discussed. The treatment of 4-phenylselenadiazole with KOH in dioxan gives the 2-phenylethynylselenolate, PhC-CSe- K+.367 Other 4-substituted compounds are similarly treated and then alkylated to give RC-C-SeR', as opposed to PhNCS giving the N-(5substituted 1,3-thiaselenol-2-ylidene)phenylamines (269; R = Ph, p-tolyl, p-anisyl, p-C1C6H4,or But) when treated in this manner.368

1,2,4-Thiadiazoles.- Synthesis. Benzoyl isothiocyanate (PhCONCS) and the aryl-ureas H2NCONHC6H4R (R = H, 2-Me, 3-Me, 2-Me0, 3-Me0, 3-C1, or 4-C1), give PhCONHC(S)CONHC6H4R. These thiobiurets are cyclo-dehydrogenated by H2C)/HCl to the thiadiazoles (270).369 With alkyl or aryl isothiocyanates. N 3 -unsubstituted amidrazone ylides HN-cR -NrNMe3 give N3-thiocarbamoylamidrazone ylides, thermolysis of which gives the 3alkyl(or aryl)-5-alkyl(or aryl)amino-l,2,4-thiadiazoles(27 1; R' = Ph or Me; R2 = Ph, 2-naphthyl, Me, Et, alkyl, or c y c l ~ h e x y l ) . ~ N'-Substituted ~~ thioureas R2NC(S)NH2, when treated with (EtOS),, give thiadiazoles (272; R = Et, Pr, Bu, Ph, NR!,, or m ~ r p h o l i n o ) . ~The ~ ' oxidation of mixtures of thiourea and 1-aryl-3-(2-pyridyl)thioureas also gives t h i a d i a ~ o l e s . ~The ~ bis(p-methoxyphenyl) selenoxide is claimed to function as a mild oxidizing agent for the synthesis of 1,2,4-thiadiazoles from thioureas or t h i ~ a m i d e s . ~ ~ ~ +

366

367 368

369 370

371

372 3 13

H. Meier, J. Zountsas, and 0.Zimmer, 2.Naturforsch., Teil. B, 1981, 36,1017. Y. V. Zachinyaev and D. S. Orlov, Khim. Promst., Ser. Reakt. Osobo Chist. Veshchestva, 1980,6,51 (Chem. Abstr., 1981,95,42 552). V. 2. Laishev, M. L. Petrov, and A. A. Petrov, Otkrytiya, Izobret., Prom. Obraztsy, Tovarnye Snaki, 1981, 32, 114 (Chem. Abstr., 1982, 96, 34 860); ibid,, 1981, 40, 89 (Chem. Abstr., 1982,96,85 563). M. N. Basyouni, A. M. A. El-Khamry, M. M. Habashy, M. E. Shaban, and M. M. ElAdly, Synthesis, 1981,232. R. F. Smith and T. P. Feltz, J. Heterocycl. Chem., 1981, 18,201. H. Kagami, T. Hanzawa, N. Suzuki, S. Yamaguchi, M. Saito, and S. Matoki, Bull. Chem. SOC.Jpn., 1980,53, 3658. P. V. Indukumariand C. P. Joshua, Indian J. Chem., Sect. B , 1981,2 0 , 651. F. Ogura, H. Yamaguchi, T. Otsubo, and H. Tanaka, Bull. Chem. SOC.Jpn., 1982, 55, 641.


193

5-Amino-3-methylisothiazole and nitriles RCN give thiadiazoles [273 ; R = (un)substituted Ph or EtOCMe=NH] .21

Physical Properties of 1,2,4-Thiadiazoles. The X-ray determination of the 1 : 1 adduct between 'Hector's Base' (274; R = H) and methyl isocyanate shows that it forms without a heterocyclic rearrangement; the compound is a 5 -(N-methylthiocarbamoylimino)4-phenyl-3-phenylamino-4H-1,2,4-thiadiazoline [274; R = MeNHC(S)] .374

Chemical Properties of 1,2,4-Thiadiazoles. A "N n.m.r. study indicates that the acylation of (275; R = H) by ClCH,COCl or ClC02Ph involves attack at N-2 of the ring and subsequent rearrangement to (275; R = COCH2Cl or C02Ph).375 The acylation of (275; R = H) by MeNCO to give (275; R = CONHMe) involves attack at the NH2 group. The 5-iminiothiadiazoline salts (276) react with R'CCl=NR2 to give the tetra-azathiapentalenes (277; R' =

MesK lJNHR

R~N-

S-

NR

2

s\N

N

N -

R2 = Ph, e t ~ . ) In . ~the ~ ~presence of base, (276) decomposes into R2NHCR'=NCN. With diphenylketen, (276; R1 = p-MeOC6H4, R2 = Me) gives (278) as a primary product at room ternperature.ls4 Compound (278) rearranges to (279) when it is heated in a polar solvent; the structure of (279) was confirmed by X-ray analysis and shown to be a zwitterion.

374

375

376

A. F. Cuthbertson and C. Glidewell, Acra Crysrallogr., Sect. B , 1981, 37,141.9. A. Reiss, W. Walek, and S. Dietzel, J. Prakr. Chem., 1981, 3 2 3 , 279. G. L'abb6 and G. Vermeulen, Bull. SOC.Chim. Belg., 1981, 90, 89.


194

(278)

(279)

1,3,4-Thiadiazoles. - Synthesis. 1,3,4-Thiadiazoles are obtained by cyclodehydration or by oxidation of 1-acy1-377-379or 1-thioacyl-thiosemicarba~ i d e s . ~ ~Thioacylated ' diaminoguanidines R' CSNHNH-C(=NH)-NH-N= CR2R3 (R' = Ph, R2 = R3 = Me, etc.) are also cyclized by mineral acids, leading to hydrazone-thiadiazole derivatives (280) by elimination of NH3 or to thiadiazoles by elimination of NzH4.381 The cyclo-condensation reaction of H2NNHCSNHR' (R' = H, alkyl, or Ph) with MSC(S)OR2 (M =alkali H

(281)

(280)

metal, R2 = alkyl) by refluxing in water gives the 2-mercaptothiadiazoles (281).382 Amination of (282) by RNH2 (R = H or Ph) gives (283) (Scheme 11y3 N-N

JSYS 0

N\N=C(

Me

SCH2CONHR

SMe)Me

(283)

(282)

0

1

RNH2

s

II It RNHCCH2SCNHN=C(SMe)Me

I]

-

t

[-MeSH]

0

N-

N

II

p 5 C N H R

II

M e l C \ S M e HS'

Scheme 11 The pyrazole-hydrazide (284) has been cyclized by P2S5 to give the 5pyrazolylthiadiazole (285).3&1 The thiadiazinone (286) undergoes thermal 377

378 379 380

382

383

384

D. L. Booth and R. M. Rodebaugh, U.S. P. 4283 543, 1981 (Chem. Abstr., 1981, 95, 187269). M. J. Lavanish, U.S. P. 4 269 983,1981 (Chem. Abstr., 1981,95,62229). S. Singh, L. D. S. Yadav, and H. Singh, Indian J. Chem., Sect. B , 1981, 2 0 , 518. P. V. I. Indukumari, C. P. Joshua, and V. P. Rajan, Indian J. Chem., Sect. B , 1981, 2 0 , 384. F. Kurzer and J. L. Secker, Tetrahedron, 1981, 37, 1429. E. F. Rothgery, U.S. P. 4 252 962,1981 (Chem. Abstr., 1981,95,7295). E. K. Mikitenko, N. N. Romanov, and I. S. Shpileva, K h i m Geterofsikl. Soedin., 1981, 339 (Chem. Abstr., 1981,95,24940). J. C . Lancelot, D. Maume, and M. Robba, J. Heferocycl. Chem., 1981, 18, 1319.


195

fragmentation at 550°C and 0.08Torr, giving PhCN, MezNCN, and the thiadiazole (287).385 H

:

:

Me2N

’N HNCOMe

‘7’

( N N‘

Me2N

/ Ph

f ‘>Ph

-N

N

(287)

Physical Properties of 1,3,4-Thiadiazoles. Ultraviolet spectra of some 2benzylideneamino-5 -phenyl-1,3,4-thiadiazoles have been reported.386 The H n.m.r. spectral properties and conformational preferences of some openchain and cyclic aromatic sulphides that contain 1,3,4-thiadiazole spectroscopic data of metal (Mn, Fe, Co, Ni, Cu, or Zn) chelates of N-(5phenyl-l,3,4-thiadiazol-2-yl)dithiocarbamic conductometric and i.r. and Raman determinations on thirteen complexes of Zn, Cd, or Hg with 2methyl-5-mercapto-l,3,4-thiadiazole,389 and thermogravimetry of some noble- and common-metal chelates of 5-amho-l,3,4-thiadiazole-2-thi01~~~ were also described, as well as the mass-spectral fragmentation of 2-phenyl1,3,4-thiadiazolin-5-0ne.~~~ Chemical Properties of 1,3,4-Thiadiazoles. Thermal decomposition of cis(288) proceeds at 50°C to give (E,E)-ButC=NN=CHBut, but decomposition of trans-(288) proceeds only at 145’ C, giving (E)-ButHC=NNHCOBut and SO, which disproportionates to S and Several reactions of substituted 2-mercaptothiazoles with chloroacetamides~93chlorodiaminotriazines,3~ and ethyl bromoacetate-hydrazine-substituted ben~aldehydes,~” and of 2,5-

385

386

387 388

389

390 391

392 393

394

395

A. E. Baydar, G. V. Boyd, and P. F. Lindley, J. Chem. Soc., Chem. Commun., 1981,1003. M. R. Mahmoud, R. Abdel Hamide, and F. Abdel Goad, 2. Phys. Chem. (Leipzig), 1981,262, 551 (Chem. Abstr., 1981,95,79479). F. Bottino and S. Papalardo, Org. Mugn. Reson., 1981, 16,l. H. Singh, L. D. S. Yadav, and S. B. S. Mishra, J. Inorg. Nucl. Chem., 1981, 43, 1701. A. C. Fabretti, G. C. Franchini, G. Peyronel, and M . Beller, Spectrochim. Actu, Part A , 1981, 37, 5 8 7 . K. N. Johri and B. S. Arora, Thermochim. Acta, 1982, 54,237. G. Bouchoux, Y. Hoppilliard, M . Golfier, and M. G. Guilleriez, Org. Mass.Spectrom., 1981, 16,29. H. Quast and F. Kees, Chem. Ber., 1981, 114,802. A. K. Ramrakhyani, R. S. Shukla, and P. Kumar, J. Indian Chem. Soc., 1981, 5 8 , 307. A. J. Cowper, G . S. Trivedi, R. R. Astik, and K. A. Thaker, J. Inst. Chem (India), 1981, 53,92,141. A. K. S. Gupta and K. Hajela, J. Indian Chem Soc., 1981,58, 690.


196

dimercaptothiadiazole with MoC1, to give the disulphide (289),396 have been described. Substituted 2-aminothiazoles undergo cycloaddition reactions with (C02H), 397 and R02CC-CC02R (R = H or a l k ~ l ) . ~ ’ ~

HN

-N

Condensed 1,3,4-Thiadiazoles. The preparation of 7-0~0-7H-1,3,4-thiadiazolo [3,24] pyrimidine-5-carboxylic compounds has been mentioned above. 1(Acylamino)-l,2,3,4-tetrahydropyrimidine-2-thionesreact with H2S04 to give 7H-1,3,4-thiadiazolo[3,2-a] pyrimidine-6-methanesulphonic acids.399 Cyclo-condensation of derivatives of 1-aminopyrimidine-2-thione with RC02H gives 2,7-disubstituted 5H-1,3,4-thiadiazolo[3,2.a] pyrimidin-5ones.4oo From 1-amino-4,6-diphenylpyridine-2-thione and Ph3P, the resulting iminophosphorane was treated with C 0 2 t o give the thiadiazolopyridiniumolate (290).401 The synthesis of 5-methyl-[ 1,3] thiazolo [2,3-b] [ 1,3,4] thiadiazol-4-ylium-2-amidates (29 1) has also been described.320

Ph

(290)

1,2,5-Thiadiazoles.- Synthesis, The 1,2,5-thiadiazole ring system and its selenium analogue have been reviewed (over 1 17 reference^).^^ 3,4-Diethoxyand 3,4-bis(methylthio)-l,2,5-thiadiazole 1-oxides have been prepared, starting from diethyl di-imino-oxalate and dimethyl di-iminodithio-oxalate, respectively. Alkylthio- and alkoxy-groups are further substituted by amines (292; R’ = R2 = OEt,-SMe, or pyrrolidino; R’ = morpholino, R2 = OEt, SMe, or NHCH2Ph).402 The amino-3-morpholino-4-thiadiazole oxide is converted into ring-N-substituted compounds by allowing it to react with

396 397

398 399 400 40’

402

M. B. Ferrari, G . G. Fava, and C. Pelizzi, Inorg. Chim.Acta, 1981, 55, 167. H. Paul and G . Huschert, Z. Chem., 1981,21, 185. S. Herrling, U.S. P. 4281 120,1981 (Chem. Abstr., 1981,95,187294). D. Heydenhauss, G. Jaenecke, and B. Feuerstein, 2. Chem., 1981,21, 31. T. Tsuji and K. Takenaka, Bull. Chem. SOC.Jpn, 1982,5 5 , 637. P. Molina, M. Alajarin, A. Arques, and R. Benzal, J. Chem. SOC., Perkin Trans. 1 , 1982,351. S. Karady, J. S. Arnato, D. Dortmund, and L. M. Weinstock, Heterocycles, 1981, 16, 1561.

Five-MemberedRings: Systems containing Nand S, Se, or Te

197

0

II

NOs\

fiRl

R211

(292)

PhNCO or CH2=CHC02Me?03 The reaction of N4S4 with various aryl and alkyl benzyl ketones, oxindole, benzyl a-pyridyl ketone, or a-phenacylS

' N

N'

Ph

pyridine affords the corresponding 1,2,5-thiadiazole (293).404 Other derivatives of 1,2,5-thiazole 1-oxide and 1,l-dioxide have been described, being potent histamine H2-recept or antagonists.'"

Physical Properties of I ,2,5-Thiadiazoles. An inversion barrier was theoretically and experimentally investigated for 1,2,5-thiadiazole 1-oxides (pyramidal, SO struct~re).'"~ The crystal and molecular structures of sulfame t role have been determined .406 Chemical Properties of lY2,5-Thiadiazoles. Lithiation and carbonylation of one methyl of 3,4-dimethyl-1,2,5-thiadiazolewere described, followed by subsequent transformation into alcohol, mesylate, and vinyl derivative^.‘"^ The reaction of 2,5-dicyclohexyl-l,2,5-thiadiazole-3,4-dione with RC6H4S02N3 gave the compounds (294; R = 4 M e 0 or 3-02N).408 NS02C6H4R c6Hll\N/

S I'\N/

C 6H 11

2,1,3-Benzothiadiazolesand 2,1,3-Benzoselenadiazoles.- Biologically active substances among benzo-2,1,3-thiadiazole derivatives have been reviewed, with 83 references.The synthesis of 4-bromobenz0-2,1,3-thiadiazole-74u3

404

40 5

406

407 408

409

S. Karady, J. S. Amato, D. Dortmund, R. A. Reamer, and L. M. Weinstock, Heterocycles, 1981, 16, 1565. A. A. Algieri, G. M. Luke, R. T. Standridge, M. Brown, R. A. Partyka, and R. R. Crenshaw, J. Med. Chem., 1982,25, 210. J. S. Amato, S. Karady, R. A. Reamer, H. B. Schlegel, J . P. Springer, and L. M . Weinstock, J. Am. Chem. SOC., 1982, 104,1375. C. H. Koo, Y. J. Chung, H. S. Shin, and J. S . Suh, Bull. Korean Chem. Soc., 1982, 3, 9 (Chem. Abstr., 1982, 96,208 771). D. L. Boger and C. E. Brotherton, J. Heterocycl. Chem., 1981, 18, 1247. R. Neidlein and W. Lehr, Arch. Pharm. (Weinheim, Ger.), 1981, 314, 650. I. A. Belen'kaya and G. P. Krokhina, Deposited Document, 1980, VINITI 384380 (Chem. Abstr., 1 9 8 2 , 9 6 , 6 8 851).

198


sulphonamide was de~cribed.~"K2PdC14 reacts with (295) to give PdLC12 [L = (295), where X = Se, R = 4- or 5-CH2CHNH2C02H or X = S, R = 4CH2CHNH2C02H] and PdL2C12 [L = (295), where X = S, R = 5 CH2CHNH2C02H].411 The complexes were characterized by i.r., u.v., and 'H n.m.r. spectra. The ground- and excited-state configurations of the electrons of 4-substituted benzothiadiazoles (295; X = S; R = H, NH2, or OH) were calculated; the .rr-lo-bonds, total energies, and heats of atomization of (295), their protonated forms, and their tautomers were tabulated. The hydroxyand amino-tautomers are more stable than the 0x0- and imino-tautomers, respectively. Compounds (295) are protonated on N-1 ?12 The linear dichroism and m.c.d. spectra of 2,1,3-benzothiadiazole and 2,1,3-benzoselenadiazole were measured and c.d. spectra reported for the 0-cyclodextrin compound with the heterocycle.413 The kinetics of formation and equilibrium data have been reported for the Meisenheimer complexes of the benzothia- and benzoselena-diazoles (295; X = S, or Se; R = 4-NO2) with MeO- in MeOH/DMS0.414

16 Dithiazoles and Diselenazoles 1,2,3-DithiazoIes. - Amide or carbamate vinylogues H2NCR'=CR2COR3 [R' = R2 = R3 = Me; R'R2 = (CH2)4, R3 = EtO; or R' = Ph, R2 = R3 = Me] react with S2C12,giving (296).415 With R2 = H in MeOH that contains Et3N, it undergoes methoxylation in the 5-position of the 5 H-l,2,3-dithiazole ring (296; R2 = OMe). N-Thiosulphinylamines are otherwise claimed as

4'0

411

412 413

414 415

M. A. Kaldrikyan and L. A. Grigoryan, Khim. Gererotsikl. Soedin., 1981, 7 (Chem. Abstr., 1981, 95, 150 551). S. A. D'yachenko, M. I. Bureneva, M. P. Papirnik, V. G. Pain, N. V. Ostashkova, and A. I. Stetsenko, Zh. Obshch. Khim., 1981, 51, 1912. V. V. Davydov, B. E. Zaitsev, V. G . Sheban, and A. K. Molodkin, Deposited Document, 1980, VINITI 2583-80, 75-83. H. Yamaguchi, A. Uchida, F. Yoneda, and H. Baumann, J. Chem. SOC., Furuduy Tram. 2, 1981, 947. C. Deicha and F. Terrier, J. Chem. Res. ( S ) , 1981, 312. R. Okazaki, K. Inoue, and N. Inamoto, Heterocycles, 1981, 15, 803.


199

intermediates?l6 1,2,3-Dithiazolium salts and stabilized 1,2,3-dithiazolyl radicals of the type (297) are also obtained by treating enamines with S2C12 or S2Br2,or with 33S8 and C12 or Br2, re~pectively.~"

1,2,4-Dithiazoles.- The luminescence spectra of (298) have been discussed in terms of intramolecular charge-transfer from the thione group to the ring. Vibrational frequencies were obtained from the luminescence spectra:36 the structures and energies of mass-spectral fragments that were derived from S-amino-l,2,4-dithiazoline-3-thione were also in~estigated.~~' The reaction of the o-quinonoid 1,2,4-dithiazolidine derivative (299) with (H2NCH2)2 gave 2-HOC6H4CSNH2 and (300; X = NH), whereas the reaction of (299) with HOCH2CH2NH2 gave 2-HOC6H4C(=NH)NH(CH2)20H, which, upon heating, cyclized to (300; X = 0). Heating (299) in triethylene glycol at 180" C gives (301), which is an intermediate in the above reactions.419 Treating the dithiazolium salt (302) with C1Rh(PPh3)3 gives [303 ;M = RhC12(PPh3)2].

s L : A

HN

(298) H

dTb (299)

x-

( 301)

The reaction of Pt(PPh,), with (302) is solvent-dependent: in CHC13, [303; M = Pt(PPh3),] is formed, whereas in C6H6 the product is [303; M = PtCl(PPh3)] ?20 416

417

418 419 4 20

R. Okazaki, K. Inoue, and N. Inamoto, Bull. Chem. SOC.Jpn., 1981,54,3541. R. Mayer, G . Domschke, S. Bleisch, and A. Bartl, 2. Chem., 1981,21, 324. J. R. Bews and C. Glidewell, Theo. Chem., 1982,3, 377. G.Wagner, D. Briel, and S. Lektner, 2. Chem., 1981,21, 261. A. W. Gal, J. W. Gosselink, and F. A. Vollenbroek, Inorg. Chim. Actu, 1980, 32, 235.

Heterocyclic Chemistly

200

174,2-Dithiazoles. - Dithiazolidin-3-ones and -thiones (304; X = 0 or S; R = Ph, 0 - , m-, or p-tolyl, or 0 - , rn-, or p-C1C6H4) are prepared by treating PhN=CClSCl with RNHCOSH.NEt, and RNHCS,H.NEt,, respectively. Treating (304; X = 0 or S) with PhCH2NH2 gives (304; X = NCH2Ph)!21

17 Oxathiazolesand Selenathiazoles l73,2-0xathiazoles. - Meso-ionic oxathiazolones [305 ; R = 2,4-Me2C6H3, 2,4,5-Me3C6H2, or 2,3,4-(Me0)3C6H2] are prepared by the reaction of DL-HSCHRC0,H with EtONO. Compound [305; R = 2,3 ,4-(Me0),C6H2] reacts with DMAD at 80°C, with evolution of C02, to give the isothiazole (306). Photochemical decomposition of (305; R = 2,4,5-Me3C6H2) in the presence of DMAD gives (307).12

1,3,4-0xathiazoles. - Nitrile sulphides, formed by the thermal decarboxylation of oxathiazolones (308; R2R3 = 0),undergo 1,3-dipolar cycloaddition

N-

421

S

R. T. Jadhav, N. M. Nimdeokar, and M. G . Paranjpe, Indian J. Chem, Sect. B , 1980, 19, 970.

Five-Membered Rings: Other systems

201

with activated carbonyl compounds: C13CCH0, (C13C)2C0, and PhCOCF3 give trisubstituted oxathiazoles (308). The structures of (308; R' = Ph, R2 = H, R3 = CC1,; R1 = 4-MeOC6H4,R2 = Ph, R3 = CF3) were determined by X-ray crystallogra hic analysis. The oxathiazole ring is planar, with a localized C=N bond.42P 18 Miscellaneous Ring Systems

1,3,2,4-Dithiadiazoles. - The reaction of S4N4 with Br2 in CS2 yields CS3N2Br2 and the 5-(bromosulphenyl)-1,3,2,4-dithiadiazolium tribromide (309) (X-ray analysis).423

N-

S

PART 111: Other Five-Membered Ring Systems by G. V. Boyd 1 Introduction

This Part deals with the remaining heterocylic compounds that contain fivemembered rings. Monocyclic systems, their benzo-analogues, other annelated heterocycles, and compounds with two or more linked five-membered rings are reviewed first. There follows a survey of those bi- and poly-cyclic systems in which a five-membered ring of the previous type is fused t o a heterocycle containing five, six, seven, or eight atoms. The order in each section is generally that of increasing saturation, so that the fully conjugated 'aromatic' compounds are mentioned first, dihydro- and 0x0-derivatives follow, and completely hydrogenated compounds are discussed last. For some ring systems, e.g. furans, pyrroles, and indoles, it was found convenient t o survey methods of synthesis and reactions in separate sub-sections. As in previous years, the Reporter had t o be severely selective: only about 430 of the nearly 1000 relevant articles are reviewed briefly. However, as in last year's Report, references to other papers are listed at the end of each sub-section, and in order to assist the reader, these are accompanied by appropriate references to Chemical Abstracts.

422

423

A. M. Damas, R. 0. Gould, M. M. Harding, R. M. Paton, J . F. ROSS,and J. Crosby, J. Chem. SOC,,Perkin Trans. I , 1981,2991. G. Wolmerschaeuser, C. JSrueger, and Y. M. Tsay, Chem. Ber., 1982, 115, 1126.


202 2 Reviews

There are general reviews on heterocyclic syntheses by cycloaddition reactions of isocyanates' and on the use of heterocyclic cations in preparative organic chemistry.2 More specific topics are 5-hydroxymethylfuran-2-carbaldehyde ,3 isobenzofurans and related ortho-quinonoid systems,4 the conversion of 2H-cyclohepta [ b ]furan-2-one (1) into derivatives of azulene,' the synthesis of indoles from o-alkylphenyl isocyanides,6 and abnormal Fischer indolization reactions of o-methoxyphenylhydra~ones.~ Two reviews on isoindoles have and a lecture on highly conducting chargetransfer complexes that are based on heterocyclic selenium and tellurium donors has been reprinted." Recent advances in the chemistry of imidazole" and in the use of nitro-imidazoles as radiosensitizers12 have been summarized. There have been reviews on benzimidazole N-oxides13 and on dihydrobenzimidazoles, benzimidazolones, benzimidazolethiones, and related comp o u n d ~ .Other ~ ~ topics are synthetic applications of 1,3-dithiolium and 1,3oxathiolium salts" and of isoxazoles, l6 the chemistry of benzisoxazoles,'7 2-amino-oxazoles,18 5-oxazolones (2)," furoxans, benzofuroxans, and related systems,20921 the synthesis of five-membered meso-ionic comand t e t r a ~ o l e s . ~ ~

A. Foucaud, Bull. SOC.Chem. Belg., 1981,90, 545.

' K. Akiba, Kagaku (Kyo to ) , 1981,36,850 (Chem. Abstr., 1982,96,19 253).

A. Faury, A. Gaset, and J . P. Gorrichon, Inf. Chim., 1981, 2 14,203 (Chem. Abstr., 1981,95, 150 278). U. E. Wiersum, Aldrichimica Acta, 1981, 14,53. K. Takase and M. Yasunami, Yuki Gosei Kagaku Kyokaishi, 1981, 39,1172 (Chem. Abstr., 1982,96,217 283). Y. Ito, Kagaku no Ryoiki, 1982, 36, 91 (Chem. Abstr., 1982,96, 199 436). ' H. Ishii,Acc. Chem. Res., 1981, 14,275. R. Bonnett and S. A. North, Adv. Heterocycl. Chem., 1981,29, 341. F. S. Babichev, V. A. Kovtunenko, and A. K. Tyltin, Usp. Khim., 1981,5 0 , 2073. l o E. M. Engler, Proc. Int. Symp. Org. Selenium Tellurium Compd., 3rd, 1979,357. 11 M. R. Grimmett, Adv. Heterocycl. Chem., 1980, 2 7 , 241. '' H.Monney, J . Parrick, and R. G. Wallace, Pharmacol. Ther., 1981, 14, 197. l 3 D. M. Smith, Chem. Heterocycl. Compd., 1981,40,287. l4 D. M. Smith, Chem. Heterocycl. Compd., 1981,40, 333. l 5 K. Hirai, H. Sugimoto, and T. Ishiba, Yuki Gosei Kagaku, 1981, 39, 192 (Chem. Abstr., 1981,95,42942). l6 A. A. Akhrem, F. A. Lakhvich, and V. A. Khripach, Khim. Geterotsikl. Soedin., 1981,1155. '' R. K. Smalley, Adw. Heterocycl. Chem., 1981, 29, 1. l 8 L. Peshakova, V. Kalcheva, and D. Simov, Khim. Geteerotsikl. Soedin., 1981, 101 1. l 9 A. K. Mukerjee and P. Kumar,.Heterocycles, 1981, 16, 1995. 'O A. J. Boulton, Bull. SOC. Chim. Belg., 1981, 90,645. '' A. Gasco and A. J. Boulton, Adw. Heterocycl. Chem., 1981,29,251. V. G. Yashunskii and V. V. Ogorodnikova, Khim. Geferofsikl.Soedin., 1981,291. 23 G. I. Koldobaskii, V. A. Ostrovskii, and V. S. Poplavskii, Khim. Geterotsikl. Soedin., 1981, 1299.

''


203

3 Systems with One Heteroatom and their Benzo-analogues etc. Furans. - Formation. Treatment of the epoxy-ketones (3; R1,R2, R3 = alkyl) with toluene-p-sulphonic acid yields furans (4).24Phenacyl bromide undergoes electrochemical reduction to give 2,4-diphenylf~ran.~’Tetra-tbutylfuran has been obtained by reductive desulphurization of compound (5).26 Photolysis of the (2)-diazo-ester N2CHCHT(CN)C02Et yields 3cyan0-2-ethoxyfuran.~~ The stabilized ylide PhCH2NMe2-cHCOAr (Ar = 4biphenylyl) reacts with dimethyl acetylenedicarboxylate to form the ester (6) with loss of benzyldimethylamine.28 The thermal isomerization of 1,ldiacetylcyclopropane to the dihydrofuran (7) has been rep~rted.~’The photo-addition of tetramethylethylene to the acetylenic ketone MeCXCOMe results in compound (8).30 The methylenedihydrofuran (9) is formed from acetylacetone and the chloride H C E C C M ~ ~ C ~ . ~ ~

(3)

(4)

L

(7)

(9)

Carbonylation of a mixture of ethylene, ethanol, and diphenylacetylene in the presence of rhodium carbonyl gives the butenolide Another formation of a butenolide, that of compound (12), is by flash vacuum pyrolysis of diphenylmethyl propiolate, Ph2CHO2C=CH. It has been suggested that the ester isomerizes to the methylene-carbene (1 l), which yields the product by intramolecular insertion.33 Ozonization of tetraphenylH :C=CH

\

0

Et Ph (10)

(11)

(12)

A. Cormier and M. D. Francis, Synth. Commun., 1981, 11, 365. Barba, M. D. Velasco, and A. Guirado, Synthesis, 1981,625. 26 Krebs, E. Franken, and S. Muller, Tetrahedron Lett., 1981,22, 1675. 27 Guiborel, R. Danion-Bougot, D. Danion, and R. Carrie, Tetrahedron Lett., 1981, 22,441. 28 R. W. Jemison, S. Mageswaran, W. D. Ollis, I. 0. Sutherland, and Y. Thebtaranonth, J. Chem. SOC.,Perkin Trans. 1 , 1981,1154. 2 9 N. S. Zefirov, S. I. Kozhushkov, and T. S. Kuznetsova, Khirn. Geterotsikl. Soedin., 1981,1285. 30 S . Hussain and W. C. Agosta, Tetrahedron, 1981,37, 3301. 31 R. Chenevert, J . Page, R. Plante, and D. Beaucage, Synthesis, 1982,7 5 . 32 (a) P. Hong, T. Mise, and H. Yamazaki, Chern. Lett., 1981,989;( b ) ibid., p, 993. 33 R. F. C. Brown, F. W. Eastwood, N. Chaichit, B. M. Gatehouse, J . M. Pfeiffer, and D. Woodroffe, Aust. J. Chem., 1981,34, 1467.

24 25

R. F. A. C.


204

cyclopentadienone results in a mixture of the diketone PhCOCHPhCOPh and the butenolide (13).% Bullatenone (14) has been prepared from the acetylenic glycol HOCHPhCGCCMe20H by acetylation, followed by oxidation with silver per~hlorate.~’ A general method for the synthesis of 4ylidenebutenolides (1 6) is the tin(1V)-chloride-catalysed reaction of an aldehyde or ketone R’ R’CO with 2-trimethylsilyloxyfuran and subsequent dehydration of the resulting alcohol (1 5).36 Treatment of mesitoylacrylic acid with acetic anhydride in the presence of a copper(1) salt yields the cisbifuranylidenedione (17; Ar = 2,4,6-Me3C6H2) and the trans-isomer, which crystallize in a blue-black self-charge-transfer form and a scarlet non-chargetransfer form, re~pectively.~’

*

‘

O0 W

’ 0’

Addition of dichloroketen to cyclohexenyl phenyl sulphoxide yields the cis-lactone (18).38 The methylbutanolide (19) is formed by the reaction of but-3-en-1-01 with carbon monoxide in the presence of palladium(I1) chloride, copper( 11) chloride, and triphenylphosphine .39 Palladium( 0)-phosphine complexes catalyse the carboxylation of isopropylidenecyclopropane to give the furanone (20).40

0

34

3s

36

no H2cTto

P. S. Bailey and T. M. Ferrell, J. Org. Chem., 1981, 46, 5028. H. Saimoto, T. Hiyama, and H. Nozaki, J. A m . Chem. SOC.,1981, 103,4975. M. Asaoka, N. Yanagida, K. Ishibashi, and H. Takei, Tetrahedron Lett., 1981, 22, 4269.

37 38 39 40

M. J . Begley, L. Crombie, G. L. Griffiths, R. C. F. Jones, and M. Rahrnani, J. Chem. SOC.,Chem. Commun., 1981,823. J. P. Marino and M. Neisser, J. A m . Chem. SOC., 1981, 103, 7687. J. R. Norton, Prepr. Div. Pet. Chem., A m . Chem. SOC.,1980, 2 5 , 368. Y. Inoue, T. Hibi, M. Sakate, Y. Kamashima, and H. Hashimoto, Nippon Kagaku Kaishi, 1982, 276 (Chem. Abstr., 1982, 96, 217 611).


205

Reactions of Furans. Pyrolysis of the ester (21) yields a mixture of the cyclobutanone (22) and the dimeric compound (23)!l The lactone (25) is produced when octahydrodibenzofuran (24) is oxidized with m-chloroperoxybenzoic acid .42

A mixture of 2-t-butylfuran and 2J-di-t-butylfuran is obtained by the action of t-butyl chloride on furan in the presence of mesitylenemolybdenum tri~arbonyl.4~ The intermediate in the nitration of furan-2-aldehyde in acetic anhydride has been identified as compound (26).* Treatment of 5-bromo-2furoic acid with sulphur tetrafluoride in hydrogen fluoride yields the dihydrofuran (27).45 Bromo-furans are converted into aryl-furans by crosscoupling with aryl Grignard reagents in the presence of nickel(I1jphosphine c ~ m p l e x e s .2-Furoic ~~ acid is lithiated at position 5 , 3-furoic acid at C-2!7 2-Methylfuran yields the 5-methylthio-derivative by lithiation and subsequent treatment with dimethyl disulphide.'@8 The corresponding phenylthiocompound (28) has been converted into a series of 4-substituted 2-methylfurans (29; R = alkyl, Me3Si, C02H, or RCHOH) by the sequence: bromination, lithiation, treatment with the appropriate electrophile, and, finally, desulphurization with Raney nickel!' 2-Lithiofuran reacts with copper( 11)

41

W. S. Trahanovsky, T. J. Cassady, and T. L. Woods, J. Am. Chem. SOC.,1981, 103, 6691.

S. B. Gingerich, W. H. Campbell, C. E. Bricca, P. W. Jennings, and C. F. Campana, J. Org. Chem., 1981, 46, 2589. 43 D. J . Milner, J. Organomet. Chem., 1981, 217, 199. 44 A. Gaset and J . P. Gorichon, Org. Mugn. Reson., 1981, 16, 239. 4 5 V. V. Lyalin, R. V. Grigorash, L. A. Alekseeva, and L. M. Yagupolskii, Zh. Org. Khim., 1981, 17, 1774. 46 L. N. Pridgen and S. S. Jones, J. 0%.Chem., 1982,47,1590. 4 7 D. W. Knight and A. P. Nott, J. Chem. SOC.,Perkin Trans. I , 1981, 1125. 48 C. H. Eugster, M. Balmer, R. Frewo, and J. H. Bieri, Helv. Chim. Actu, 1981, 64,

42

2636. 49

S. M. Nolan and T. Cohen, J. 0%.Chem., 1981,46,2473.


206

chloride to give 2,2'-bifuran (30); lithiation of the latter, followed by the action of copper chloride, yields the quaterfuran (3 l)."

Two unusual cycloaddition reactions of furans are the addition of maleic anhydride to the thioketone (32) to give compound (33)51 and the formation of the intramolecular Diels-Alder adduct (35) from the ester (34).52 Sensitized photo-oxygenation of 2-methoxymethylfuran at - 60°C yields the peroxide (36), which isomerizes to the aldehyde-ester OCHCH=CHC02-

Ph Ph (33)

CH20Me at - 10"C.53 The corresponding photo-adduct (37) of methyl 2,5dimethyl-3-furoate rearranges to the diepoxide (38) on heating.54 The pale 0

T. Kauffmann, H. Lexy, and R. Kriegesmann, Chem. Ber., 1981, 114,3667. H.Ohmura and S. Motoki, Chem. Lett., 1981,2 3 5 . 5 2 H. Kotsuki, A. Kawamura, M. Ochi, and T. Tokoroyama, Chem. Lett., 1981,917. " B. L. Feringa and R. J. Butselaar, Tetrahedron Lett., 1981, 2 2 , 1447. 54 (a) M. L. Graziano, M. R. Iesce, and R. Scarpati, J. Chem. SOC.,Chem. Cornmun., 1981, 720;( b ) M. L. Graziano and R. Scarpati, J. Chem. SOC.,Perkin Trans. I , 1981, 1811. " 51


207

yellow fulgide (39) is suitable for chemical actinometry in near-ultraviolet and visible regions, being reversibly transformed into the deep red dihydrobenzofuran (40).55

Me

=

M

e

m

o

Me

Me

Me

0

Me Me

(39)

0

(40)

The azides (41; R = H, Pr’, or But) decompose at room temperature to nitrogen and the cyano-compounds NCCH=CHCOCOR at different rates, the t-butyl derivative being the least stable. This is attributed to the instability of the intermediate nitrene (42), whose planarity is impeded by the bulky Thermolysis of the azide (43) yields a mixture of the benzindolizine (44) and its 4,5-dihydro-derivative.”

*’

R (41)

COOMe

(43) 5

The synthesis of the diatropic [ 141annuleno [c]furan (45) has been described .58

II But

7I But

H. G. Heller and J . R. Langan, J. Chem. SOC.,Perkin Trans, 2, 1 9 8 1 , 341. Newcornbe and R. K. Norris, Tetrahedron Lett., 1 9 8 1 , 2 2 , 6 9 9 . 5 7 K. Yakushijin, T. Tsuruta, and H. Furukawa, Chem. Pharm. Bull., 1 9 8 2 , 30, 140. H. Ebe, T. Nakagawa, M. Iyoda, and M. Nakagawa, Tetrahedron Lett., 1 9 8 1 , 2 2 , 4441 . ”

’‘ P. J.

208

Heterocyclic Chem istry

Other papers on the f ~ r r n a t i o n ’ ~and - ~ ~reaction^^'-'^ of furans should be noted. 59

R. Dams, M. Malinowski, I. Westdorp, and H. J. Geise, J. Org. Chem., 1981, 46, 2407 (Chem. Abstr., 1981, 95,693).

J. A. Donnelly, P. J. Macken, and S. O’Brien, Isr. J. Chem., 1981, 21, 185 (Chem. Abstr., 1982,96, 52 102). 61 R. Antonioletti, M. D’Auria, G. Piancatelli, and A. Scettri, J. Chem. SOC., Perkin Trans. 1,1981,2398 (Chem. Abstr., 1981, 95,203654). 6 2 M. G. Vinogradov, V. I. Dolinko, and G. I. Nikishin, Izw. Akad. Nuuk SSSR, Ser. Khim., 1981, 700 (Chem. Abstr., 1981, 95, 24673). 6 3 D. W. Knight and A. P. Knott, J. Chem. Soc., Perkin Trans. 1 , 1982, 623 (Chem. Abstr., 1982, 96, 217 547). 64 0. E. Nasakin, V. V. Alekseev, V. K. Promonenkov, A. Kh. Bulai, and S. Yu. Silvestrova, Khim. Geterotsikl. Soedin., 1981, 744 (Chem. Abstr., 1981, 95, 6o

150 302). 65 66

M. G. Vinogradov, M. S. Pogosyan, A. Ya. Shteinshneider, and G. I. Nikishin, Izw. Akud. NaukSSSR, Ser. Khim., 1981,2077 (Chem. Abstr., 1982,96,52 099). J. Benaim and A. L’Honor6, J. Organomet. Chem.,q980, 202, C53 (Chem. Abstr., 1981,95, 60 862).

67

A. Gomez-Sanchez, B. M. Stiefel, R. Fernandez-Fernandez, C. Pascual, and J. Bellanato, J. Chem. SOC., Perkin Trans. I , 1982, 441 (Chem. Abstr., 1982, 96, 199 457).

M. Larcheveque, C. Legueut, A. Debal, and J. Y. Lallemand, Tetrahedron Lett., 1981, 22, 1595 (Chem. Abstr., 1981, 95,96 983). 6 9 Yu. M. Skvortsov, A. G. Malkina, B. A. Trofimov, A. N. Volkov, and V. M. Bzhezovskii, Zh. Org. Khim., 1981, 17, 884 (Chem. Abstr., 1981, 95, 150295). 70 P. J. Babidge and R. A. Massy-Westdropp, Aust. J. Chem., 1981, 34, 1745 (Chem. Abstr., 1981, 95, 219 925). 71 H. Suzuki, H. Yashima, T. Hirose, M. Takahashi, Y. Morooka, and T. Ikawa, Tetrahedron Lett., 1980, 21,4927 (Chem. Abstr., 1981, 95,6931). 72 S. D. Rychnovsky and P. M. Bartlett, J. A m . Chem. SOC., 1981, 103, 3963 (Chem. Abstr., 1981, 95,150 294). 73 S. Gelin and B. Chantegrel, J. Heterocycl. Chem., 1981, 18, 663 (Chem. Abstr., 1981, 95, 132 583).

T. Shono, H. Hamaguchi, I. Nishiguchi, M. Sasaki, T. Miyamoto, M. Miyamoto,and S. Fujita, Chem. Lett., 1981, 1217 (Chem. Abstr., 1981, 95, 219749). 75 Y. Nakada, T. Hata, C. Tamura, T. Iwoka, M. Kondo, and J. Ide, Tetruhedron Lett., 1981, 22,473 (Chem. Abstr., 1981,95, 6696). 76 G. I. Nikitin, V. G. Glukhovtsev, Yu. V. Ilin, and A. V. Ignatenko, Izw. Akud. Nauk SSSR,Ser. Khim., 1982,447 (Chem. Abstr., 1982,96,199465). 77 J. ApSimon, V. S. Srinivasan, M. R. L’Abb6, and R. Seguin, Heterocycles, 1981, 15, 1079 (Chem. Abstr., 1981,95,23 754). 78 T. Shono, Y. Matsumura, K. Tsubata, and J. Takata, Chem. Lett., 1981, 1121 (Chem. Abstr., 1981, 95, 186 969). 7 9 K. Ohno and M. Machida, Tetrahedron Lett., 1981, 22, 4487 (Chem. Abstr., 1982, 74

96, 122 540).

82

K. Yakushijin, M. Kozuka, T. Morishita, and H. Furukawa, Chem. Phurm. Bull., 1981, 29,2420 (Chem. Abstr., 1982, 96,19903). A. Murai, K. Takahashi, H. Taketsuru, and T. Masamune, J. Chem. SOC., Chem. Commun., 1981,221 (Chem. Abstr., 1981,95, 1 1 5 163). H. Kotsuki and H. Nishizawa, Heterocycles, 1981, 16, 1287 (Chem. Abstr., 1981, 95, 219 923).

83

84 85

S. Takano, Y. Oshima, F. Ito, and K. Ogasawara, Yukuguku Zusshi, 1980, 100, 1194 (Chem. Abstr., 1981, 95, 24 871). H. Hart and S. Shamouilian, J. Org. Chem., 1981, 46, 4874 (Chem. Abstr., 1981, 95, 203 613).

R. H. Hall, S. Harkema, H. J. Den Hertog, G. J. Van Hpmmel, and D. N. Reinhoudt, J. R. Neth. Chem. SOC.,1981, 100, 312 (Chem. Abstr., 1982, 96, 6498). 86 H. K. Hall, Jr., P. Nogues, J. W. Rhoades, R. C. Sentman, and M. Detar, J. Org. Chem., 1982,47,1451 (Chem. Abstr., 1982,96, 142 593). 8 7 L. Fisera, J. Kovac, J. Lesko, and V. Smahovsky, Chem. Zvesti, 1981, 35,93 (Chem. Abstr., 1981, 95,42 788).


209

Benzofurans. - Treatment of a mixture of o-dichlorobenzene and cyclohexanone with sodamide and sodium t-but oxide yields tetrahydrobenzofuran by the aryne mechanism outlined in Scheme 1.% The formation of the

Scheme 1 diarylfuran (48) by photolysis of the vinyl bromide (46) proceeds via the vinyl cation (47).” 2-Phenylbenzofuran (50) is obtained by oxidation of the adduct (49) of phenylsulphene, PhHC=S02, to t r ~ p o n e . ’ Pentafluorophenyl ~

oc.(46)

Ph

,so2

(49)

A. P. Cowling, J . Mann, and A. A. Usmani, J. Chem. Soc.. Perkin Trans. 1 , 1981, 2116 (Chem. Abstr., 1981,95,150297). ” N. A. Vaidya, W. J . Nizon, Jr., A. A. Fatmi, and C. de W. Blanton, Jr., J. Org. Chem., 1982,47,2483 (Chem. Abstr., 1982, 96,217 615). 90 P. D. Williams and E. LeGoff, J. Org. Chem., 1981, 46, 4143 (Chem. Abstr., 1981, 95,168 609). y1 K. Hirai, H. Suzuki, H. Kashiwagi, Y. Moro-oka, and T. Ikawa, Chem. Lett., 1982, 23 (Chem. Abstr., 1982, 96,122170). 92 N. Yoneda, A. Suzuki, and Y. Takahashi, Chem. Let?., 1981, 767 (Chem. Abstr., 1981,95,96 977). 93 R. Martinez-Utrilla and M. A. Miranda, Tetrahedron, 1981, 37, 21 1 1 (Chem. A bsrr., 1981,95, 150 300). 94 J. P. Bachelet and P. Caubere, J. Org. Chem., 1982,47,234. 9 5 T. Suzuki, T. Kitamura, T. Sonoda, S. Kobayashi, and H. Taniguchi, J. Org. Chem., 1981,46,5324. 96 B. D. Deanand W. E. Truce, J. Org.Chem., 1981,46, 3575.


210

propargyl ether, C6F50CH2CrCH,is converted into the benzofuran (52) on heating, by way of the Claisen rearrangement product (5 l).” The preparation of 14C-labelled 1,2,7,8- and 2,3,7,8-tetrachlorodibenzofuranshas been de~cribed.’~Free-radical cyclization of the o-allyloxy-diazonium salt (53), induced by tributylstannane, yields 2,3-dihydro-3-methylbpzofuran (54).” The thioether (55) is formed by the action of the salt MeS(SMe)2 SbC1, on o-allylphenol. loo CH=C=CH2

m M e F

-

F \

F

F (51)

(52)

Me

Irradiation Of the ester (56) in methanol leads to the rearranged phthalide (57).”’ The oxonium salt (59) is produced by the action of aluminium chloride on the ester chloride (58).lo2 Me0

OMe (56)

@ c1

COOMe

-Me

a1c14-

c1 0

(58)

(59)

( a ) G. M. Brooke and D. I. Wallis, J. Chem. Soc., Perkin Trans. I , 1981, 1417;( b ) G. M. Brooke, ibid., 1982, 107. 9 8 A. P. Gray, W. J . McClellan, and V. M. Dipinto, J . Labelled Compd. Radiopharm.,

97

99

loo 101 102

1981,18, 507. A. L. J. Beckwith and G. F. Meijs, J. Chem. SOC.,Chem. Commun., 1981,136. G. Capozzi, V. Lucchini, F. Marcuzzi, and G. Modena, J. Chem. SOC.,Perkin Trans. 1, 1981,3106. M. E. Jung and R. B. Blum, J. Chem. SOC., Chem. Commun., 1981,962. M. V. Rao, S. H. E. Ashry, and M. V. Bhatt, Tetmhedron Lett., 1981,22, 145.


211

3-Amino-2-nitrobenzofuran (60) undergoes an astonishing transformation in acetic acid, giving the diazo-compound (6 1).'03 The benzofuranone (62) is converted into the cyclohexadienone ( 6 3 ) on treatment with methyl iodide and sodium methoxide.lW Flash vacuum pyrolysis of methylenephthalide (64) results in the rearranged indanedione (65); the isomer (66), on the other hand, eliminates carbon monoxide to give ben~0furan.l'~Pummerer's ketone

103 lo4

'05

P. Demerseman, S. Risse, and R. Royer, J. Heterocycl. Chem., 1981, 18, 695. J . K. Makrandi and S. K. Grover, J. Chin. Chem. SOC.(Taipei), 1981,28,65 (Chem. Absfr., 1981, 95, 80 609). R. Bloch and P. Orvane, Tetrahedron Lett., 1981, 22, 3597.


212

(67) is converted into a mixture of the azide (68) and the ring-expanded product (69) by the action of hydrazoic acid.lo6 For other work on benzofurans, see references 107-1 12. Me i

f

T

a

e

M

MeaT0

\

0

Me

Isobenzofurans and other Anneiated Furans. - 1-Methoxyisobenzofuran (72 ; R =Me) is formed when the acetal (70) is heated in toluene that contains a trace of acetic acid."3 The acetoxy-analogue (72; R = Ac) has been generated by the action of 3,6-di-2'-pyridyl-l,2,4,5-tetrazine on the adduct

q Me0

OMe

C. W. Bird, Y. P. S. Chauhan, and D. R. Turton, Tetrahedron, 1981,3 7 , 1277. P. Bravo and C. Ticozzi, Heterocycles, 1981, 16, 713 (Chem. Absfr., 1981, 95, 114 324). 108 P. Marshall, B. Mooney, R. Prager, and A. D. Ward, Synthesis, 1981, 197 (Chem. Abstr., 1981,95,132 595). l o 9 K. Kurosawa and Y. Morita, Bull. Chern. SOC. Jpn., 1981, 54,635 (Chem. Abstr., 1981, 95, 6934). 110 L. Fisera, M. Dandarova, J. Kovac, P. Mesko, and A. Krutosikova, Collect. Czech. Chem. Comrnun., 1981,46,2421 (Chem. Abstr., 1982, 96,68873). E. W. Warnhoff and F. W. Yerhoff, Heterocycles, 1981, 15, 777 (Chem. Abstr., 1981, 95,24 678). '12 A. M. Andrievskii, A. N. Poplavskii, and K. M. Dyumaev, Zh. Vses. Khim. 0-ua, 1981, 26,101 (Chem. Abstr., 1981,95,61 886). M. A. Makhlouf and B. Rickborn, J. 0rg. Chem., 1981,46,2734. lo'


213

PY

DP

Scheme 2 (71) of benzyne to 2-acetoxyfuran (Scheme 2).li4 Treatment of compound (73) with methyl vinyl ketone in acetic acid yields the isobenzofuran adduct (74) as a 3 : 2 mixture of endo- and exo-i~omers.'~~ 1-Methylisobenzofuran adds to the quinone acetal (75) to yield solely the endo-adduct (76).l16 The isoindene (77) is oxidized by air to a mixture of acetone and 1,3-diphenylisobenzofuran (78).'17 The stable endo-peroxide (79) is produced by the action

9

Me0

0

(75)

'"

Me0

OMe

OMe

Ph

Ph

Me (76)

But

0

( 7 7 ) X = CMe2 (78) X = 0

(79)

R. A. Russell, D. E. Marsden, M. Sterns, and R. N. Warrener, Aust. J . Chem., 1981, 3 4 , 1223. B. A. Keay, D. K. W. Lee, and R. Rodrigo, Tetrahedron Lett., 1980, 21, 3 6 6 3 . R. N. Warrener, B. C. Hammer, and R. A. Russell, J. Chem. Soc., Chem. Commun., 1981,942. E. Johansson and J. Skramstad, J. Org. Chem., 1981, 46, 3752.

Heterocyclic Chem istr),

214

of singlet oxygen on 1,3-di-t-b~tylisobenzofuran.~~~ The isobenzofuran (78) undergoes a [4n + 4n] cycloaddition to the o-quinone-di-imine (80) to give compound (81).'19 COPh

Ph

COPh

(80)

(81)

A modified mechanism for the formation of the cycloheptafuranone (83) by pyrolysis of phenyl propiolate (82) has been proposed.12* The action of copper(1) phenylacetylide on the azulene ester (84) leads to the azuleno [2,1b ] furan (85).121

Pyrroles. - Formation. A general synthesis of pyrroles is exemplified by the reaction of the nitro-olefin (86) with the enamine (87) to yield the ester Pyrroles (89; R' =Me, Ph, MeO, or MeS; R2 =COPh, CN, or C02Me; R3 = Me or Ph) are formed fromN-(tosylmethy1)imines TosCH2N=C(0Me)R' and electron-deficient ole fins R2CH=CHR3 in a base-catalysed 1,3anionic cycloaddition, followed by elimination of toluene-p-sulphonic acid

I. Saito, A. Nakata, and T. Matsuura, Tetrahedron Lett., 1981, 22, 1695.

W. Friedrichsen, M. Roehe, and T. Debaerdemaeker, 2. Naturforsch., Teil. B, 1981, ''I

'''

36, 632. R. F. C. Brown and F. W. Eastwood, J. Org. Chem., 1981,46,4588. T. Morita, T. Nakadate, and K. Takase, Heterocycles, 1981, 15, 835. H. Meyer, Liebigs Ann. Chem., 1981, 1534.


2 15

and methan01.l~~ The cyclopropane (90) forms 1-t-butyl-3-methylpyrroleby a carbene -+carbene rearrangement .124 Palladium(I1) chloride catalyses the conversion of the amino-alcohol PhCzCH(OH)CH2NH2 into 2-phenylpyrrole12’ and the reaction of buta-1,3-diene with ethylamine to give 1ethyl pyrr ole ?26 1,3,4-Triphenyl-1,2-diazabu t a-1,3-diene (PhN=N CHPh=CHPh) and acetylacetone form the pyrrole (91) under the influence of copper(I1) ~hloride;’~’the 0-chloroazoalkene Me02CN=NCH=CHC1similarly reacts with acetylacetone to yield (92).12* Heating N-formylsarcosine with the acetylene Br

JCNBJ

Me

M AcQcHAc2 e

NHPh

NHCOOMe

PhC=CS02CF3 results in the pyrrole (94) via a munchnone cyclo-adduct (93), shown in Scheme 3 .12’ Tciphenyl-vinylphosphonium bromide reacts with the sodium salt Na+ PhC(CN)NPhCOPh to form 1,2,5-triphenylHOOC OHC N‘

Me

Me

Me

Me

Scheme 3 pyrrole.” The antibiotic pyrrolomycin B has been shown to have the structure (95).131

123 124

12’ 126

12’ 12*

131

c1

c1

H

OH

H. A. Houwing and A. M. Van Leusen, J. Heterocycl. Chem., 1981, 18,1127. J. Arct and L. Skatteboel, Tetrahedron Lett., 1982, 23, 113. K. Utimoto, H. Miwa, and H. Nozaki, Tetruhedron Lett., 1981, 22,4277. J . E. Baeckvall and J . E. Nystroem, J. Chem. SOC.,Chem. Commun., 1981, 59. 0. Attanasi, P. Bonifazi, E. Foresti, and G. hadella, J. Org. Chem., 1982, 47, 684. T. L. Gilchrist, B. Wrton, and J . A. Stevens, Tetrahedron Lett., 1981, 22, 1059. H. C. Berkand J . E. Franz, Synth. Commun., 1981, 11, 267. J. V. Cooney and W. E. McEwen, J. Org. Chem., 1981,46,2570. M. Kaneda, S. Nakamura, N. Ezaki, and Y. Iitaka, J. Antibiot., 1981, 34, 1366.


216

The isopropylidenepyrroline (96) is produced by the action of phosphorus pentoxide on the oxime Me2C=CHCH2CH2CMe=NOH.'32 Reductiomycin, a new antibiotic, is the pyrroline (97).'33 OH

Me

H

(96)

(97)

+

Treatment of the quaternary ammonium salt PhC=CCH2NMe2CH2C0Ph Br- with sodium hydroxide gives, inter alia, the betaine (98)." Controlledpotential electrolysis of y-nitro-ketones on a mercury cathode yields 1 pyrroline 1-oxides, pyrrolines, or pyrrolidines, according to conditions; thus the oxide (99) is obtained from the compound 02NCMe2CHPhCH2COPh.'35 The pyrrolinone (101) results from autoxidation of the furan derivative (1 OO).'36 Irradiation of the amide (1 02) leads to the pyrrolidinone (103) by an unprecedented [ 1,6] shift of hydr~gen.'~'

M:L)Ph COPh Me2

Me

I 0-

(98)

-pJ-==x pho I

Ph

I , ,

HO

0

E

( 100)

( E = COOEt)

(101)

(99)

132

R. E. Gawley, E. J. Termine, and K. D. Onan, J. Chem. SOC., Chem. Commun., 1981,568.

133 134

135

K. Shimizu and G. Tamura, J. Antibiot., 1981, 34, 654. S. Mageswaran, W. D. Ollis, D. A. Southam, I. 0. Sutherland, and Y. Thebtaranonth, J. Chem. SOC.,Perkin Trans. 1 , 1981, 1969. M. Cariou, R. Hazard, M. Jubault, and A. Tallec, Tetrahedron Lett., 1981, 2 2 , 3961.

136

K. Yakushijin, M. Kozuka, and H. Furukawa, Chem. Pharm. Bull., 1980, 2 8 , 2178.

'" H. Aoyama, Y. Inoue, and Y. Omote, J. Org.Chem., 1 9 8 1 , 4 6 , 1965.

Five-MemberedRings: Other systems

217

Reactions of @moles. 1,3-Di-t-butylpyrrole forms the first stable protonated pyrrole, the salt (104).'38 Electrophilic substitution of pyrrole with Me$+ or Me2FC+ in the gas phase occurs mainly at the fl-p~sition,'~'as does nitration and Friedel-Crafts acylation of 1-phenylsulph~nylpyrrole.~~~ Pyrrole-2,5-dialdehyde has been prepared by Vilsrneier-Haack formylation of the ester (1 0 9 , followed by hydr01ysis.l~~ A similar method has been used to convert the di-acetal (1 06) into pyrrole-2,3 ,S-tri~arbaldehyde.'~~ N-Benzoylpyrrole reacts with benzene in the presence of palladium(I1) acetate to yield a mixture of 1 -benzoyl-2,5-diphenylpyrrole:, the bipyrrolyl (107), and compound (108).'43 Treating lithiated N-methylpyrrole with nickel(I1) chloride results in the polypyrrolyls (109; n = 0-4).'44 2-Aryl-1-methylpyrroles are obtained by cross-coupling of 1-methylp:yrrol-2-ylmagnesiurn bromide with aryl halides in the presence of palladium( 0)-phosphine complexes.'4s

Bu Ir

N-Chloropyrrole, prepared from pyrrole and aqueous sodium hypochlorite, rearranges in methanol to a mixture of 2- and 3-chloropyrroles; 2,5dichloropyrrole is also formed.'46 Anodic (oxidation of 1,2,5-trimethylpyrrole in the presence of cyanide ions yields the pyrroline (110) as the primary

Me (110) 138 139

140

141 142

143 144 145

146

R. Gassner, E. Krumbholz, and F. W. Steuber, Liebigs Ann. Chem., 1981, 789. M. Speranza, J. Chem. SOC.,Chem. Commun., 1981,1177. (a) R. X . Xu, H. J . Anderson, N. J . Gogan, C. E. Loader, and R. McDonald, Tetrahedron Lett., 1981, 2 2 , 4899; ( b ) J. Rokach, P. Hamel, M. Kakushima, and G . M. Smith, ibid., p. 4901. R. Miller and K. Olsson, Acta Chem. Scand., Ser. B, 1981, 35, 303. C. E. Loader, G. H. Barnett, and H. J . Anderson, Can. J. Chem., 1982, 60, 383. T. Itahara, J. Chem. SOC.,Chem. Commun., 1981, 254. T. Kauffmann and H. Lexy, Chem. Ber., 1981, 114,3674. A. Minato, K. Tamao, T. Hayashi, K. Suzuki, and M. Kumada, Tetrahedron Lett., 1981, 2 2 , 5319. M. De Rosa, J. Org. Chem., 1982, 47, 1008.

218

Heterocyclic Chernistv

product, which in hot methanol forms mainly 2-cyanomethyl-l,5-dimethylpyrr01e.l~' It has been shown by deuterium labelling and n.m.r. spectroscopy that the conversion of the alcohol (1 1 1) into the chloride (1 13) occurs by randomization of the carbon atoms of the side-chain via the cyclopropane intermediate (1 12).148

The pyrrole (1 14) reacts with dimethyl acetylenedicarboxylate to form the pyrazole (1 16) in a complex process involving an intermediate pyrazoline (1 1 5).149 Nitrosation of the hydroxypyrrole (1 17) results in the ringexpanded product (1 18).lS0 E

1I ,1

I M e -

Me

NMe

(114)

E

17:- :uE Me

Me

(116)

(115) ( E = COOMe) 0

Whereas the reaction of 1 -methyl-2-vinylpyrrole with dimethyl acetylenedicarboxylate at 80°C affords mainly the rearranged Diels-Alder product

14'

L. Eberson, Acta Chem. Scand., Ser. B , 1980,34,747.

14*

K. M. Smith, Z. Martynenko, and H. D. Tabba, Tetrahedron Lett., 1981,2 2 , 1291. A. G . Schultz and R. Ravichandran, Tetrahedron Lett., 1981, 2 2 , 1771. T. Momose, T. Tanaka, T. Yokota, N. Nagamoto, H. Kobayashi, and S. Takano, Heterocycles, 1981, 15, 843.


219

(119), the Michael adducts, cis- and trans-(120), are produced at room temperature.lS1 Treatment of the pyrrole (121) with the acetylenic ester yields the phthalate (123), the bridge of the intermediate cyclo-adduct (122) being extruded as dimethylamin~nitrene.~~~ The 2H-pyrrole (124) functions as a dienophile towards cyclopentadiene but as a diene towards transpiperylene; with cyclohexa- 1,3-diene, both types of adduct are formed.lS3

Me Me

Me

The pyrrolidinone (125) reacts with formic acid to yield the bicyclic ester (127) by way of a [3,3] sigmatropic rearrangement of the cation (126), followed by electrocyclization and addition of formic acid (Scheme 4).'%

Scheme 4 15'

R. A. Jones and J. Sepulveda Arques, Tetrahedron, 1981,37,1597.

15'

A. G. Schultz, M. Shen, and R. Ravichandran, Tetrahedron Lett., 1981,22, 1767. B. K. Rammash, C. M. Gladstone, and J. C. Wong, J. Org. Chern., 1981,46,3036.

153

P. M. M. Nossin and W. N. Speckamp, Tetrahedron Lett., 1981,2 2 , 3289.


220

The product of the action of phosphorus pentachloride on pyrrolidinone is (128), contrary to a previous report.lS5 The ylide (129) undergoes a [2,3] shift to compound (130) under the influence of sodium hydride.lS6

c1 c 1 e J . J (128)

1,1

’

EHE

2 r

-

‘CHZ/C\COPh ( 129) ( E = COOMe)

r2

I

C

EHC

‘CH

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