Heterocyclic Chemistry: v.3 (Specialist Periodical Reports) (Vol 3)

Heterocyclic Chemistry Volume 3 A Specialist Periodical Report Heterocyclic Chemistry Volume 3 A Review of the Lite...

Author: H. Suschitzky | O.Meth- Cohn

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Heterocyclic Chemistry Volume 3

A Specialist Periodical Report

Heterocyclic Chemistry Volume 3

A Review of the Literature Abstracted between July 1980 and June 1981

Senior Reporters H. Suschitzky and 0. Meth-Cohn Department of Chemistry and Applied Chemistry, University of Salford Reporters

G. V. Boyd Chelsea College, London G. M. Brooke University of Durham S. D. Carter Queen Elizabeth College, London G. W. H. Cheeseman Queen Elizabeth College, London J. de Mendoza lnstituto de Quimica Medica, Madrid J. Elguero fnstituto de Quimica Medica, Madrid G. P. Ellis UWIST, Cardiff S. Gronowitz University of Lund, Sweden T. V. Lee Brunel University, Middlesex J. R. Malpass University of Leicester T. J. Mason Lanchester Polytechnic, Coventry J. T. Sharp University of Edinburgh

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

British Library Cataloguing in Publication Data Heterocyclic chemistry.-Vol. 3.-(Specialist periodical report/ Royal Society of Chemistry) 1. Heterocyclic compounds - Periodicals I. Royal Society of Chemistry 547l.58’05 QD339

ISBN 0-85186-823-1 ISSN 0144-8773

Copyright @ 1982 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

Set in Times on Linotron and printed offset by J. W. Arrowsmith Ltd., Bristol, England Madein Great Britain

Introduction

Volume 3 of ‘Heterocyclic Chemistry’ covers literature based essentially on Volumes 93 and 94 (i.e. July 1980-June 1981) of Chemical Abstracts. The arrangement of the Chapters and the extensive ‘Table of Contents’ remain the same as for the previous two volumes, which will facilitate search and back reference. Increasing economic pressure demanded great selectivity from our authors, some of whom, we realize, would have preferred to give more coverage to certain aspects. As editors we are, however, entirely satisfied that our contributors have shown themselves masters in constraint. Another concession to economy is the omission of an author index, which was felt by the majority of our authors, and of those of our readers who were consulted, not to be essential to the purpose of the Report. Judging from the critical reviews and many unsolicited statements by readers, this series is proving a valuable resource for industrial and academic chemists, by virtue of its unrivalled position amongst annual reports. The Society and the editors are constantly striving to reduce production costs to a level which will make acquisition of the report for one’s personal collection feasible. Our thanks go to all authors for supplying manuscripts on schedule for early publication, and to the editorial staff of the Royal Society of Chemistry for their help. H. SUSCHITZKY& 0. METH-COHN

V

Contents Chapter 1 Three-Membered Ring Systems By T. J. Mason 1 Reviews 1 General 1 Rings containing Oxygen 1 Rings containing Nitrogen 2 2 Oxirans 2 Preparation 2 Catalytic Oxidation of Alkenes, using Oxygen or Oxygen-containing Gases 2 Oxidation of Alkenes by Peroxy-acids 4 Oxidation of Alkenes, using Peroxides 5 Halohydrin Cyclizations and Related Reactions 7 Synthesis via Attack of a Carbanion on the Carbonyl Group of Aldehydes and Ketones 8 The Synthesis of Chiral Oxirans 10 The Synthesis and Reactivities of Aromatic Oxides 13 Miscellaneous Syntheses 14 Spectra and Theoretical Chemistry 17 Reactions with Electrophiles 19 Ring-opening 19 Cyclization 20 Nucleophilic Ring-opening Reactions 21 With Oxygen and Nitrogen Nucleophiles 21 With Carbanions 23 Reduction and Elimination Reactions 24 Thermal and Photochemical Reactions 25 Reactions with Organometallic Compounds 28 Miscellaneous Reactions 30 3 Oxirens 30 4 Aziridines 31

Preparation 3 1 By Direct Insertion 31 By Cyclization 32 uia Ring-Contraction 33 vii

1

viii

Heterocyclic Chemistry Chiral Aziridines 33 Reactions 33 Thermal 33 Ring-opening to Acyclic Compounds 34 Formation of Other Ring Systems 35

5 Azirines 36 Preparation 36 Reactions 37

6 Thiirans 40 Preparation 40 Reactions 41 Chemistry of Thiiranium Ions 42 7 Thiirens 43 8 Diaziridines 44 9 Diazirines 44 10 Oxaziridines 46

11 Other Ring Systems 47 Chapter 2 Four-Membered Ring Systems By T. V. Lee

49

1 Highlights and Reviews 49

2 Systems containing One Nitrogen Atom 49 Azetidines and Azetines 49 Azetidinones 50 3 Systems containing Two Nitrogen Atoms or One Nitrogen and a Second Heteroatom 55

4 Systems containing Oxygen 56 Oxetans 56 Dioxetans 59 5 Systems containing Sulphur 59

6 Miscellaneous Four-Membered Rings 6 1

Chapter 3 Five-Membered Ring Systems

63

By G. V. Boyd, J. de Mendoza, J. Elguero, and S. Gronowitz Part I Thiophens and their Selenium and Tellurium Analogues By S. Gronowitz

1 General 63

63

ix

Contents

2 Monocyclic Thiophens 63 Synthesis by Ring-Closure Reactions 63 Synthesis from Other Rings 66 Physical Properties 68 Theoretical Calculations 68 Photoelectron and Ultraviolet Spectra 68 Nuclear Magnetic Resonance 69 Miscellaneous 69 Electrophilic Substitution Reactions 70 Nucleophilic and Radicaloid Substitution Reactions 72 Organometallic Derivatives 73 Photochemistry 76 Desulphurization and Hydrogenation of Simple Thiophens 77 The Structures and Reactions of Hydroxy-, Mercapto-, and Amino-thiophens 79 Reactivities of Side-Chains 82 Reactions of Thiophen Aldehydes and Ketones 83 Reactions of Carboxythiophen and its Derivatives 85 Reactions of Vinylthiophens and Related Compounds 86 Reactions at Benzylic Positions 87 Various Reactions in the Side-Chain 88 Reaction at Sulphur: Thiophen Dioxides 90 Di- and Tetra-hydrothiophens 91 Bi- and Poly-heterocycles 92 Naturally Occurring Thiophens 93 Thiophen Analogues of Steroids 93 Thiophens of Pharmacological Interest 94 Polymers from Thiophens 95 3 Benzothiophens and their Benzo-fused Systems 96 Benzo[b Jthiophens 96 Synthesis 96 Physical Properties 97 Substitution Reactions 97 Reactions of the Side-Chain 98 Benzo[b]thiophen S-Oxides 99 Benzo[c]thiophens 100 Dibenzothiophens 100 Pharmacologically Active Compounds 100

4 Thiophen Analogues of Polycyclic Aromatic Hydrocarbons 101 Analogues of Anthracene and Phenanthrene 101 Various Carbocycle-Fused Systems 101 5 Thiophen Fused to Five-Membered Heteroaromatic Rings Isothiazole-Fused and Related Systems 103

102

Heterocyclic Chemistry

X

6 Thiophen Fused to Six-Membered Heteroaromatic Rings Thiophen Analogues of Quinoline 104 Thiophen Analogues of Isoquinoline 105 Pyrimidine-Fused Systems 105 Miscellaneous Fused Systems 106

104

7 Selenophens and Tellurophens 108 Monocyclic Selenophens 108 Condensed Selenophens 109 Tellurophens 110

Part I I Systems containing Nitrogen and Sulphur, Selenium, or Tel I uriu m By J. Elguero and J. de Mendoza

1 Introduction and Reviews

111

2 Isothiazoles 111 Synthesis 111 From ‘Thiacyanocarbons’ (Type A; C-C-C-N + S) 111 From Nitrile N-Sulphides (Type B; C-C + S-N-C) 111 From Thioenaminones (Type C; S-C-C-C-N) 112 Physical Properties 112 Chemical Properties 113 Alkylation 113 Cycloaddition 113 Other Reactions 113 3 1,2-Benzisothiazoles, their 1-Oxides, and their 1,l-Dioxides 113 Synthesis 113 Chemical Properties 114

4 1,2-Benzisoselenazole and 1,2-Benzisotellurazole 114 5 2,l-Benzisothiazoles 115

6 Other Condensed Ring Systems incorporating Isothiazole 115 Thieno-[2,3-d]-, -[3,2-d]-, and -[2,3-c]-isothiazoles 115 Thieno-[2,3-d]-, - [3,2-d]-, and -[4,3-d]- isoselenazoles, and Selenopheno[3,2-d]isoselenazoles 116 [ l]Benzothien0[2,3-d]isothiazoles 1 16 Isothiazolo[5,4-b]pyridine 116 1,4-Dithiino[c]isothiazole, 1,4-Dithiino[2,3-c ; 6,5-c’]diisothiazole, and Isothiazolo[3,4-f][ 1,2,3,4,5]pentathiepin 1 16 Benzo[c]bisisothiazole and Benzo[c]trisisothiazole 117 Isothiazolo-[3,4-e]-and -[4,3-e]-[2,1,3]benzothiadiazoles 117

xi

Contents

Naphtho[2,1-d]isothiazoles 117 Isothiazolonaphthoquinones and Bis(isothiazo1o)benzoquinones 118 7 Thiazoles 118 Synthesis 118 Hantzsch’s Synthesis (Type A; S-C-N + C-C) 118 Type G (N-C-S-C-C) Type H (S-C + C-N-C) 118 Type K (S-C-N-C-C) 119 Physical Properties 119 Chemical Properties 119 Reactions of 2-Aminothiazoles 120 Reactions of Thiazolium Salts 120 Reactions of Meso-ionic Thiazoles 121 Miscellaneous Reactions 121

118

8 A’-Thiazolines 121 Synthesis 121 Type A (S-C-N + C-C) 121 Type D (C-N + S-C-C) 121 122 Type K (S-C-N-C-C) Physical Properties 122 Chemical Properties 122 9 A3-Thiazolines 122

10 A4-Thiazolines 123 Synthesis 123 Type A (S-C-N + C-C) 123 Type B (S-C + C-C-N) 123 Type E (S-C-C-N + C) 123 123 Type G (N-C-S-C-C) Miscellaneous Methods 123 Chemical Properties 124 11 Thiazolidines 124 Synthesis 124 Type A (S-C-N + C-C) 124 Type D (C-N + C-C-S) 124 Type E (N-C-C-S + C) 125 Type K (S-C-N-C-C) 125 Physical Properties 125 Chemical Properties 126 Rhodanines, Isorhodanines, and Thiorhodanines 126 12 Selenazoles 127 13 Benzothiazoles 127 Synthesis 127

xii

Heterocyclic Chemistry From o-Amino-benzenethiols (Type A; S-C6H4-N Type €3 (C&-N-C-S) 127 Type c (N-C6H4-S-C) 128 Type D (S-C6H4-N-C) 128 128 Type G (C6&-S-C-N) Physical Properties 128 Chemical Properties 129 Substitution Reactions 129 Addition Reactions 130 Alkylation 130 Ring-Cleavage Reactions 130 Rearrangements 130

+ C)

127

14 Condensed Ring Systems incorporating Thiazole or Selenazole 131 Structures comprising Two Five-Membered Rings ( 5 3 ) 131 Thiazolo-[2,3-c]- and -[3,2-b]- [1,2,4]triazoles [C,N,-C,NS] 131 Imidazo-[2,l-b]-, - [3,2-c]-, and -[5,l-b]- thiazoles [C,NS-C,N,] 131 Pyrrolo-[1,2-c]-, -[2,1-b]-, and -[3,2-c]-thiazoles [C,NS-C,N] 132 Thieno[3,2-d]- thiazoles and -selenazoles and Selenopheno[3,2-d]thiazoles [C,NS-C4S] 132 Structures comprising one Five-Membered and One SixMembered Ring (5,6) 132 Thiazolo[3,2-a]pyrimidines [C,NS-C4N2] 132 Thiazolo-[3,2-a]- and -[3,4-a]-pyrazines [C3NS-C4N2] 133 Thiazolo[3,2-~]pyridines[C,NS-C,N] 133 Thiazolo[3,4-~]pyridines[C3NS-C5N] 133 Thiazolo[4,5-b]thiopyran [C3NS-C5S] 133 Structures comprising One Five-Membered and One SevenMembered Ring (5,7) 134 Thiazolo[4,3-~]thiazepine[C3NS-C5NS] 134 Thiazolo[S,4-c]azepines [C3NS-C6N] 134 Structures comprising Two Five-Membered Rings and One SixMembered Ring (5,5,6) 134 1,2,4-Triazolo[3,4 -b]benzothiazoles [C2N3-C3NS-C6] 134 Thiazolo[4,5-g]benzoxazoles [C3NS-C3NO-C6] 134 Thiazolo[2,3-b]benzothiazoles[C3NS-C3NS-C6] 134 Imidazo[2,3-d]thiazolo-[2,3-b]and-[3,2-a]-pyrimidines [C3NS-C,N,-C4N2] 135 Thiazolo[3,2-a]benzimidazoles [c3Ns-c3N2-c6] 135 Thiazolo[3,4-a]benzimidazoles [C3NS-C3N2-C6] 135 Imidazo[2,l-b]benzothiazoles[C3NS-C3N,-C6] 135 Thiazolo[3,2-a Ithieno[2,3-d]p yrimidines [C,NS-C4S-C4N,] 136

xiii

Contents

Structures comprising One Five-Membered Ring and Two SixMembered Rings (5,6,6) 136 Pyrimido[2,1-b]benzothiazoles [C3NS-C4N2-C6] 136 Thiazolo-[2,3-b]-, - [3,2-a ]-, and -[3,2-c ]- quinazolines [C3NS-C4N2-C6] 136 Thiazolo[4,5-b]quinoxalines [C3NS-C4N2-C6] 137 Thiazino[2,3- b lbenzothiazole [C,NS -C4NS-C6] 137 Pyrido-[2,3-d] - and -[3,241- thiazolo[3',2'-a Jpyridines [C,NS-C5N-CSN] 137 Pyrido[2,1-b]benzothiazoles[C3NS-C5N-C6] 137 Thiazolo[3,2-a]quinolines [C3NS-C5N-C6] 138 Thiazolo[2,3-a ]isoquinolines [C3NS-C5N-C6] 138 Naphtho[ 2,3-d]thiazoles [C,NS-C6-C6] 138 Structures comprising Two Five-Membered and Two SixMembered Rings (5,5,6,6) 138 Other Condensed Systems incorporating Thiazole 139

15 Thiadiazoles and Selenadiazoles 139 1,2,3-Thiadiazoles 139 Synthesis 139 Physical Properties 140 Chemical Properties 140 1,2,3-Benzothiadiazoles 140 1,2,3-Selenadiazoles 141 1,2,4-Thiadiazoles 141 Synthesis 141 Physical Properties 142 Chemical Properties 143 1,3,4-Thiadiazoles 143 Synthesis 143 Physical Properties 144 Chemical Properties 144 Condensed 1,3,4-Thiadiazoles 145 1,3,4-Selenadiazoles 146 1,2,5-Thiadiazolesand 1,2,5-Selenadiazoles 146 Synthesis 146 Chemical Properties 146 1,2,3-Benzothiadiazoles 147 Synthesis 147 Physical Properties 147 Chemical Properties 147 Condensed 1,2,5-Thiadiazoles 147 2,1,3-Benzoselenadiazoles 148 14 Dithiazoles and Diselenazoles 148

1,2,3-Dithiazoles 148 1,2,4-DithiazoIes 148

xiv

Heterocyclic Chemistry 1,3,2-Benzodithiazoles 149 1,4,2-Dithiazoles 149

17 Oxathiazoles and Selenathiazoles 149 1,3,4-Oxathiazoles 149 18 Miscellaneous Ring Systems 150 1,2,3,4-Thiatriazoles 150 1,2,3,5-Thiatriazoles 150 1,2,3,5-Dithiadiazoles 150 1,3,2,4-Dithiadiazoles 150 1,2,4,3,5-Trithiadiazoles 150

Part 111 Other Five-Membered Ring Systems ByG. V. Boyd

151

1 Introduction 151

2 Reviews

151

3 Systems with One Heteroatom, and their Benzo-analogues Furans 152 Formation 152 Reactions 154 Benzofurans and Other Annelated Furans 158 Pyrroles 162 Formation 162 Reactions 166 Indoles 171 Formation 171 Reactions 173 Isoindoles 177 Other Systems 178 4 Systems containing Two Identical Heteroatoms 179 Dioxoles 179 Dithioles and Related Systems 180 Tetrathiafulvalenes and Related Compounds 183 Pyrazoles 184 Formation 184 Reactions 185 Indazoles 188 Imidazoles 189 Formation 189 Reactions 190 Benzimidazoles and Other Annelated Imidazoles 193

5 Systems containing Two Different Heteroatoms 195 Oxathioles and Thiaselenoles 195

152

Contents

xv Isoxazoles 196 Formation 196 Reactions 198 Benzisoxazoles 201 Oxazoles 203 Formation 203 Reactions 204 Benzoxazoles and a Thiasilapentane System 208

6 Systems containing Three Identical Heteroatoms 209 1,2,3-Triazoles and Annelated 1,2,3-Triazoles 209 1,2,4-Triazoles and a 1,2,4-TrithioIe 2 11 7 Other Systems containing Three Heteroatoms 214 Oxadiazoles 2 14 1,2,3- and 1,2,4-Oxadiazoles 214 1,2,5-Oxadiazoles 214 1,3,4-Oxadiazoles 215 Phosphorus Compounds 216 Miscellaneous Other Systems 218 8 Systems containing Four Heteroatoms 2 19

Tetrazoles 2 19 Other Systems 219 9 Compounds containing Two Fused Five-Membered Rings (53) 220 Hypervalent Sulphur Compounds 220 Nitrogen Systems 220 Monoaza-Compounds 220 Diaza-Compounds 22 1 Triaza-Compounds 222 Other Systems 223 10 Compounds containing Fused Five- and Six-Membered Rings (5,6) 224 Nitrogen Systems 224 Monoaza-Compounds 224 Diaza-Compounds 225 Triaza-Compounds 226 Tetra-aza-Compounds 228 Penta-aza-Compounds 229 Mixed Oxygen-Nitrogen Systems 23 1

11 Compounds containing Fused Five- and Seven-Membered Rings (5,7)and Three or Four Fused Heterocyclic Rings [(5,5,5),(5,5,6),(5,5,7),(5,6,6),(5,6,8), and (5397,711 233

Heterocyclic Chemistry

xvi

Chapter 4 Six-Membered Ring Systems

237

By S. D. Carter, G, W. H. Cheeseman, and G. P. N i i s

237

Part I Systems containing Nitrogen By S. D. Carter and G. W. H. Cheeseman

1 Introduction 237 2 Reviews 237 3 Azines and their Hydro- and Benzo-derivatives 238 Pyridines 238 Synthesis 238 Properties 242 Reduced Pyridines 250 Quinoline, Isoquinoline, and their Benzo- and Hydroderivatives 253 4 Diazines and their Reduced and Fused Derivatives 261

1,2-Diazines 261 1,3-Diazines 263 1,4-Diazines 27 1 5 Triazines and Tetrazines 275

6 Fused Systems containing One Five- and One SixMembered Ring (5,6) 278 7 Fused Systems containing Two Six-Membered Rings (6,6) 281

8 Oxazines, Thiazines, and their Fused Derivatives 284 Oxazines 284 Thiazines 287 9 Other Oxygen- and Sulphur-containing Systems 289 Classified Reference List 291 Part II Six-Membered Rings containing Oxygen or Sulphur By G. P. Ellis

1 Books and Reviews 293 2 Heterocycles containing One Oxygen Atom

Reduced Pyrans 293 Pyrans and Pyrylium Salts 294 Reduced Pyrones 295 2-Pyrones 296 4-Pyrones 297 Chromans 297 Isochromans and Isochromenes 298 Chromenes 298 Chromanones 299 Chromones 300

293

293

xvii

Contents Flavans 301 Flavanones and Isoflavanones 302 Flavones 302 Isoflavones 303 Dihydroisocoumarins 304 Coumarins 305 Isocoumarins 307 Xanthenes and Xanthones 308

3 Heterocycles containing One Sulphur Atom 308 Thiopyrans 308 Isothiochromans, Thiochromenes, and Isothiochromenes 3 10 Thiocoumarins and Isothiocoumarins 3 10 Thioxanthenes and Thioxanthones 3 11

4 Heterocycles containing One Oxygen and One Sulphur Atom 311 5 Heterocycles containing Two Oxygen Atoms 3 12 1,3-Dioxans 3 12 1,4-Dioxans 3 13

6 Heterocycles containing Two Sulphur Atoms 314 1,3-Dithians 314 1,4-Dithians 315 7 Heterocycles containing an Oxygen or Sulphur Atom in each of Two or Three Rings 3 16

Chapter 5 Seven-Membered Ring Systems By J. T. Sharp 1 Introduction 319 2 Reviews 319 3 Azepines, Diazepines, and Triazepines 3 19 Didehydro-intermediates 319 Monocyclic Azepines 321 Formation 321 Reactions 323 Fused Azepines 324 Formation 324 1-Bemazepines 324 2-Benzazepines 326 3-Benzazepines 326 Hetero-fused azepines 327 Reactions 328 1,2-Diazepines 329 Formation 329 Reactions 332

319

Heterocyclic Chemistry

xviii 1,3-Diazepines 333 1,4-Diazepines 334 Formation 334 Reactions 336 Triazepines 337

4 Oxepins and Dioxepins 337 Oxepins 337 Formation '337 Reactions 340 Dioxepins 340

5 Thiepins and Dithiepins 341 6 Systems containing Two Different Heteroatoms 34 1 Oxazepines 341 Thiazepines 342

7 Other Systems 343

Chapter 6 Eight-Membered and Larger Ring Systems By G.M. Brooke 1 Eight-Membered Rings 345 Rings containing One Heteroatom 345 Rings containing Two Heteroatoms 346 Rings containing Six Heteroatoms 347 2 Nine- and Ten-Membered Heterocycles 347 3 Macrocycles 350 Systems containing Nitrogen as the only Heteroatom 350 One Nitrogen Atom 350 Four Nitrogen Atoms 351 Six or More Nitrogen Atoms 352 Systems containing Heteroatoms other than Nitrogen 353 Crown Ethers and Related Compounds 356 Synthesis 356 Effects on Chemical Reactions 357 Reactions of the Macrocyclic Rings 359 Formation of Host-Guest Complexes 360

Chapter 7 Bridged Systems By J. R. Malpass

1 Reviews 367 2 Physical Methods 367 X-Ray and Electron Diffraction 367 Photoelectron Spectroscopy 368

345

xix

Contents Nuclear Magnetic Resonance Spectroscopy 369 Miscellaneous Methods 370

3 Nitrogen-containing Compounds 37 1 Synthesis 371 Cycloadditions 371 Other Cyclizations 374 Reactions 375 Bridged Annulenes, Cyclazines, and Propellanes Bridged Azoalkanes 378

376

4 Oxygen-containing Compounds 379 Synthesis 379 Cycloadditions 379 Miscellaneous Methods 382 Bridged Peroxides 384 5 Systems that contain Other Heteroatoms 385

Errata for Volume 2

387

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

1 Reviews General.-Recent advances in the synthesis of three-membered-ring heterocycles have been reviewed,' as have the stability and chemistry of the unsatilrated systems oxiren and thiiren together with either azirine2 or ~ilacyclopropane.~ Rings containing Oxygen.-The industrial importance of the oxirans is reflected by the inclusion of two sections in the latest edition of the Kirk-Othmer Encyclopedia of Chemical Technology concerning ethylene oxide4 and perduoroepoxides.' The manufacture of ethylene oxide has also been the subject of three consecutive articles in Catalysis General preparative techniques that have been surveyed include synthetic and mechanistic aspects of metal-catalysed epoxidation with hydroperoxides,' new epoxidation reagents," and new methods for stereo-controlled epoxidation." Articles on specific classes of epoxy-compounds have appeared, dealing with allene oxide (vinyloxiran),'2 cyclic poly-epoxides (mainly five-, six-, seven-, and eight-membered systems),13 long-chain epoxy-acid~,'~and steroid epoxides (their analytical and biological ~ignificance).'~ H. Quast, Heterocycles, 1980,14, 1677. M. Torres, E. M. Lown, H. E. Gunning, and 0. P. Strausz, Pure Appl. Chem., 1980,52, 1623. Y. Oshiro, M. Komatsu, and T. Agawa, Kagaku No Ryoiki, Zokan, 1980, 1 (Chem. Abstr., 1980 93,220 5 11). J. N. Cawse. J. P. Henry, M. W. Swartzlander, and P. H. Wadia, in 'Kirk-Othmer Encyclopedia of Chemical Technology', ed. M. Grayson and D. Eckroth, Wiley, New York, 1980,3rd edn., Vol. 9, p. 432. P. R. Resnick, in 'Kirk-Othmer Encyclopedia of Chemical Technology', ed. M. Grayson and D. Eckroth, Wiley, New York. 1980, 3rd edn., Vol. 10, p. 956. W. M. H. Sachtler, C. Backx, and R. A. Van Santen, Catal. Rev.-Sci. Eng., 1981,23,127. ' J. V. Porcelli, Caral. Rev.-Sci. Eng., 1981, 23, 151. * J. C. Zomerdijk and M. W. Hall, Catal. Rev.-Sci. Eng., 1981, 23, 163. R. A. Sheldon, J. Mol. Catal., 1980, 7, 107. lo J. Rebek, Jr., Heterocycles, 1981,15, 517. l 1 H. Kotsuki and I. Saito, Yuki Gosei Kagaku Kyokai Shi, 1980,38, 936 (Chem. Abstr., 1981,94, 174 740). l2 T. H. Chan and B. S . Ong, Tetrahedron, 1980,36,2269. l 3 W. Adam and M. Balci, Tetrahedron, 1980,36,833. l4 F. D. Gunstone, in 'Fatty Acids', ed. E. H. Pryde, AOCS, Champagne, Ill., 1979, p. 379. H. Breuer, J. Clin. Chem. Clin. Biochem., 1980,18,937.

''

1

2

Heterocyclic Chemistry

Rings containing Nitrogen.-Aziridine chemistry has been included in a review of cyclic imines.I6 Reviews on azirines include their reactions with transition metals,” their use as synthons for other heterocycles,18and the preparations of cyclophanes involving azirine rings.” 2 Oxirans

Preparation.-Catalytic Oxidation of Alkenes to Oxirans, using Oxygen or Oxy gen-containing Gases. It is possible to catalyse the epoxidation of ethene, using simply powdered silver as a suspension in acetic anhydride.20 Using a mixed ethene :oxygen :nitrogen feed of 82 :4 : 15 parts, under pressure, and at 180 “C, 90% conversion of oxygen is achieved in 10 minutes. It has been found that silver carrier catalysts that incorporate a number of combinations of alkali metals (one of which must be caesium) have greater efficiencies for the preparation of ethylene oxide than any such catalyst containing only a single alkali A study of the stereochemistry of the epoxidation of cis-l,2-dideuterioetheneon various silver catalysts, under differing reaction conditions, revealed equilibrations of the deuterium atoms in the product ranging from 57 to 99’/0.~~ A possible explanation for this is based upon the extent of oxidation of the catalyst surface under the particular reaction conditions. The role of the catalyst support in the oxidation of ethene has been investigated by using alumina (a-A1203)that is doped with either GeOz or MgO, making it either an n-type or p-type semiconductor, re~pectively.~~ Compared with silver catalysts on undoped supports, p-type carriers show enhanced reactivity and selectivity whereas n-type have the opposite effect. Styrene has been epoxidized in the liquid phase, using titanium carbide and b ~ r i d e It. ~appears ~ that, during the reaction, an oxygen-containing polymeric film is formed on the catalyst surface which increases its activity but also increases the induction period for the reaction. The latter may be eliminated by the addition of dibenzyl peroxide. Azibenzil (PhCOCPhN2) reacts readily with O2in the presence of transitionmetal-ion catalysts to give an intermediate (probably a metal-carbene-oxygen complex) which can transfer oxygen to alkenes and yield epoxides under very mild c ~ n d i t i o n sThe . ~ ~ reactions are performed at room temperature in CH2C12 that contains azibenzil, Pd(OAc)*, and alkene, with oxygen being simply bubbled through the solution during the reaction. Yields of epoxides up to 87% have been reported, together with benzil, which is the by-product of the reaction. 16

l7

l8 l9 2o

”

G. E. Ham, in ‘Kirk-Othmer Encyclopedia of Chemical Technology’, ed. M. Grayson and D. Eckroth, Wiley, New York, 1980, 3rd edn., Vol. 13, p. 142. T. Sakakibara. Kagoshima Daigaku Rika Hokoku, 1980, 87 (Chem. Abstr., 1981, 94, 174 743). A. Hassner, Heterocycles, 1980, 14, 1517. Y. Sakata, Yuki Gosei Kagaku Kyokai Shi, 1980,38, 164 (Chem. Abstr., 1980,93, 167 990). N. Hiroyuki, Y. Kobayashi, A. Baba, and K. Murayama, Jpn. Kokai Tokkyo Koho 80 15427 (Chem. Abstr., 1980, 93, 150 108). M. M. Bhasin, P. G. Ellgen, and C. B. Hendrix, Ger. Offen. 3 010533 (Chem. Absrr., 1981, 94, 83 916).

22 23 24

25

M. Egashira, R. L. Kuczkowski, and N. W. Cant, J. Catal., 1980,65,297. X . E. Verykios, F. P. Stein, and R. W. Coughlin, J. Catal., 1980,66, 147. S. Yu. Zasedatelev, Yu. M. Shul’ga, E. A. Blyumberg, and Yu. G. Borod’ko Dokl. Akad. Nauk SSSR, 1980,252, 1170 (Chem. Abstr., 1980,93,238 341). H. S. Ryang and C. S. Foote, J. A m . Chem. Soc., 1980,102,2129.

Three-Membered Ring Systems

3

The conversion of cyclic alkenes into epoxy-alcohols may be achieved by using oxygen and the [ V O ( ~ C ~ C ) ~ ] - A Icatalyst B N system.26With dichloroethane as solvent, the yields of epoxy-alcohol (2) and epoxide (3) that were obtained from cyclopentene (1; n = 1) were 41 and 28% respectively (Scheme 1); for cyclohexene (1; n = 2), 10 and 40% were produced, whereas cycloheptene (1; n = 3) gave only the epoxide (3; n = 3) (99O/t).

Reagents: i, [VO(acac),], AIBN, CH,ClCH,Cl, 0,

Scheme 1

Paquette et al., in an ongoing study of electronic control of stereoselectivity, have investigated the direction of addition of singlet oxygen to 1,4-dimethoxynaphthalene derivatives in which bridged bicyclic systems are fused across C-2 and C-3 (Scheme 2).27 Using Rose Bengal as the sensitizer, photochemical oxidation of (4; n = 1) gave mainly the endo-epoxide ( 5 ) (77%) together with 7% of em-epoxide (6), whereas for (4; n = 2) the main product was em-epoxide (6) (77%), with only 13% of ( 5 ) . Each of these epoxidatioris is the reverse of the stereochemistry that is obtained by using alkaline hydroperoxide as the oxidant. While the direction of epoxidation with hydroperoxide can be rationalized in terms of standard steric and kinetic control factors, the direction of photochemical epoxidation is thought to arise from the effect of u-electrons from the bicyclic systems influencing the 7r-orbitals of the aromatic part of the

a--(7)

?Ac I

(14) Reagents: i, 02,hv, Rose Bengal; ;i, hydrolysis of naphthoquinone monoketal; iii, 0,, hv, biacetal; iv, O,, hv, tetraphenylporphyrin; v, 0,, hv, hematoporphyrin.HC1; vi, exo-(13), hv, hernatoporphyrin, argon

Scheme 2

26

”

K. Kaneda, K. Jitsukawa, T. Itoh, and S. Teranishi, J. Org. Chem., 1980,45, 3004. L. A. Paquette, F. Bellarny, M. C. Boehm, and R. Gleiter, J. Org. Chem., 1980 45,4913.

Heterocyclic Chemistry

4

Scheme 2 also illustrates a number of other photochemical oxidations, accomplished with a range of different sensitizers. In a patented process, truns-3,4epoxythujane (8) (42%) is produced from a-thujane (7), using biaceta1.28 Tetraphenylporphyrin sensitizer affords a 6 : 10 ratio of (10) : (11)in the oxygenation of bicyclopropylidene (9).29A porphyrin was also used in the conversion of acetoxycycloheptadiene (12) into a mixture of compounds containing mainly (13) but some diepoxide (14).30The yield of (14) can be increased, however, by further irradiation of (13) under argon. Small quantities of oxirans can be obtained from a number of aromatic alkenes by photo-oxygenation in MeCN, using cyanoanthracene. Thus (16; R = Ph) (15%) is obtained from tetraphenylethene (15; R = Ph).31Suspensions of semiconductors (Ti02 or CdS in CH2C1,) afford small conversions of aromatic a1kene~;~’for example, of (15; R = M e ) into (16; R = M e ) (11’/0). F

F

F (17)

F

0 Ph2C=CR2 (15)

Ph2L1 R2 (16)

F

Irradiation (>200 nm) of a gaseous mixture of hexafluorobenzene in the presence of nitrogen and oxygen rapidly gave Dewar-benzene and, more slowly, yielded the Dewar-benzene oxide (17) (7% after 72 h).33 Oxidation of Alkenes to Oxiruns by Peroxy-acids. For compounds that contain more than one double-bond, epoxidation can clearly lead to a number of possible epoxides. In the case of dienes such as (18;R = alkyl), the use of one equivalent of peracetic acid gives mainly (19) via preferred attack at the more substituted d ~ u b l e - b o n dIt. ~is~ somewhat surprising that 3-CIC6H4C03His so discriminating in its oxidation of (20).35 In this reaction (carried out under nitrogen, at -18 “C, in CH2C12)47% epoxidation occurs at position (a) and 15% at position (b), with 5% of the corresponding diepoxide being formed.

,x””,* (18)

O

(19)

(b)

29

30 31

32 33 34

35

Q 0 (20)

S. Shinpo, H. Toda, H. Saga, K. Suzuki, and Y. Nishida, Jpn. Kokai Tokkyo Koho 80 51 030 (Chem. Abstr., 1980,93,95 443). I. Erden. A. DeMeijere, G . Rousseau, and J. M. Conia, Tetrahedron Lett., 1980,21,2501. D.M.Floyd and C. M. Cimarusti, Tetrahedron Lett., 1979,4129. J. Erikson and C. S. Foote, J. A m . Chem. SOC.,1980,102,6083. T.Kanno, T. Oguchi, H. Sakuragi, and K. Tokumaru. Tetrahedron Lett., 1980, 21,467. M.G.Barlow, R. N. Haszeldine, and C. J. Peck, I. Chem. Soc., Chem. Commun., 1980,158. I. A. Shnyp, V. I. Pansevich-Kolyada, E. E.. Marchik, and L. N. Falaleeva, Vestsi Akad Nauuk BSSR, Ser. Khim.Navuk, 1980,90 (Chem. Abstr., 1981,94,139 517). T. Kato, Jpn. Kokai Tokkyo Koho 80 22 623 (Chem. Abstr., 1980,93,46388).

Three-Membered Ring Systems

5

A co-operative effect by a hydroxyl and ether oxygen has been noted in the stereo-controlled epoxidation of (21) by 3-C1C6H4C03H.36In the case of (21;R' = R2 = H) and (21; R' = CH2Ph,R2 = H), a better than 2 5 : l ratio of oxirans (22):(23) is obtained. This ratio is reduced to 6 : l for (21; R' = H,R2 = CH2Ph) and stereo-control is lost completely for (21;R' = R2 = CH2Ph),where the ratio is 1: 1.A change from hydroxyl to benzoate functionality has no effect, however, on the direction of epoxidation of (24).37The cis-epoxide (25; R = PhCO) (45%) is produced on treatment of (24; R = PhCO) with CF,C03H in sulpholane at 80 "C, in the presence of NaHPO,; attack occurs in the same stereochemical sense as that on the parent trio1 (24; R = H).

'i"-3

'0 OR (24)

(25)

OR

The epoxidation of phospholen oxides that are fused to five- and six-membered carbocyclic rings also proceeds ~tereospecifically.~~ For 3-phospholen oxides, such as (26), the epoxide ring is generated trans to the phosphoryl oxygen (27) whereas for 2-phospholen oxides, such as (28), epoxidation occurs in the other sense (29).

Benzvalene (10)has been converted into the epoxide (31) (54%) directly by reaction with benzoylperoxycarbaminic acid (PhCH2NHC03H).39This relatively new reagent proved successful where both MeC0,H and 3-ClC6H4C03H had failed. Oxidation of Alkenes to Oxirans, using Peroxides. Two investigations into the mechanism of metal-catalysed epoxidations by hydroperoxides have appeared. In the case of catalysis by molybdenum compounds, the reaction involves the '3 38 39

M. R. Johnson and Y. Kishi, Tetrahedron Lett., 1979,4347. M. L. Sinnott and D. Widdows, J. Chem. SOC.,Perkin Trans. 1, 1981,401. L. D. Quin, C. Symmes, Jr., E. D. Middlemas, and H. F. Lawson, J. Org. Chem., 1980, 45, 4688. H. Leininger and M. Christl, Angew. Chem., Znt. Ed. Engl., 1980, 19, 458.

6

Heterocyclic Chemistry

preliminary formation of a complex between the hydroperoxide and catalyst, which then reacts with the alkene. Ligands that are bound to molybdenum have a considerable influence on the rate of epoxidation, as does the particular hydroperoxide (ROOH) that is In general, the order of reactivity of peroxides is R = phenylethyl > cumyl > t-butyl > t-amyl, and the reactivities of both hydroperoxide and alkene follow the Taft equation. Mechanisms involved The in catalysis by Mo, W, Ti, V, Nb, Ta, and Re have also been de~cribed.~' oxidations of cholesteryl acetate by various hydroperoxides in the presence of [ ( A c ~ C H ~ ) or ~ F[Mo(CO),] ~] in different solvents have been For oxidation by H 2 0 2in the presence of the iron catalyst, formation of the epimeric 5,6-epoxides predominated; however, when an organic hydroperoxide or the other catalyst was used, allylic oxidation became a more important route. A Russian group have produced a series of papers dealing with the epoxidation of cyclohexene by organic hydroperoxides, using poly(viny1 alcohol)-supported molybdenum It was concluded that the mechanism for the process using poly(viny1molybdate) did not differ significantly from that using the more traditional unsupported molybdenum catalysts. An alternative polymersupported catalyst for epoxidation of cyclohexene has been developed from oxobis(pentane-2,4-dionato)vanadium(1~) on divinylbenzene-cross-linkedpolystyrene beads.47 Although initially the unsupported catalyst provides a faster reaction than the polymer catalyst, the latter is more stable to the reaction conditions, giving it a longer lifetime and, in the end, it provides a higher yield of cyclohexene oxide. For the oxidation of terminal alkenes using hydroperoxides and molybdenum catalysts it has been shown that stabilization of the peroxide by BaO greatly increases the selectivity for e p ~ x i d a t i o nIn . ~the ~ particular case of the oxidation of oct- 1-ene by cumene hydroperoxide, using molybdenum naphthenate, the selectivity for oct-1-ene oxide was increased from 9% to 95% by using BaO. The epoxidation of aurones, e.g. (32), by means of H202 in the presence of NaOH or KOH affords epoxides in relatively low yields. An improved method of synthesis has been reported in which the base catalyst used is Triton B.49 With this system, the yield of epoxide from (32) was increased from 25% to 60%. Similar methods were used in the synthesis of thioaurone ep~xides.~' A number of novel epoxidation systems have been applied to the conversion of 2,3-dimethylbut-2-ene into (33). When H 2 0 2 is added to a slurry of basic 40

V. N. Sapunov, J. Mol. Catal., 1980,7, 149.

41

J. Kollar, Prep. Div. Pet. Chem., A m . Chem. SOC.,1978, 23, 106.

42 43

44

45

46

47 4*

49

M. Kimura and T. Muto, Chem. Pharm. Bull., 1980,28,1836. V. N. Sapunov, E. A. Riko, I. Yu. Litvintsev, and N. N. Lebedev, Kinet. Katal., 1980, 21, 529 (Chem. Abstr., 1980, 93, 149 431). V. N. Sapunov, E. A. Riko, and N. N. Lebedev, Kinet. Katal., 1980,21,533 (Chem. Abstr., 1980, 93, 11 3 609). V. N. Sapunov, E.A. Riko, and N. N. Lebedev, Kinet. Katal., 1980,21,791 (Chem. Abstr,, 1981, 94,46 466). V. N. Sapunov, E. A. Riko, and I. Yu. Litvintsev, Kinet. Katal., 1980, 21, 794 (Chem. Abstr., 1980,93. 203 691). S. Bhaduri, A. Ghosh, and H. Khwaja, J. Chem. SOC.,Dalton Trans., 1981,447. J. E. Bozik, H. E. Swift, and C.-Y. Wu, U.S.P. 4 217 287 (Chem. Abstr., 1980, 93, 204 060). B. A. Brady, M. Geoghegan, K. D. McMurtrey, and W. I. O'Sullivan, J. Chem. SOC.,Perkin Trans. 1, 1981, 119. L. S. S. Reamonn and W. I. O'Sullivan, J. Chem. SOC., Perkin Trans. I, 1980, 1194.

Three-Membered Ring Systems

7

alumina in ether containing the alkene, low yields of (33) (40%) are obtained.” This low yield has been attributed to further reaction of the product epoxide on the alumina surface. In the same paper, an epoxidation using crystallins Ph3Si02H in CH2C12 at 25°C is described which gave a 70% yield in the formation of (331.”

The uncatalysed reaction of hydroperoxypyrazole (34; R = OH) with 2,3dimethylbut-2-ene led to (33) (70%) together with the by-product (34;R = H).52 The compound (34;R = OH) has increased reactivity toward alkenes (compared to that of alkyl hydroperoxides), and this has been ascribed to intramolecular H-bonding of the peroxo hydrogen to the ring nitrogen atom, together with the slight electron-withdrawing effects of the substituents. A number of a-hydroperoxides of esters, amides, ketones, and nitriles have proved efficient epoxidation reagents; thus (35) provides a quantitative yield of (33) from its parent alkene in CHC13 at 60 “C for 24 h.53

Synthesis of Oxirans by Halohydrin Cyclizations and Related Reactions. One of the mildest techniques for forming a bromohydrin from an alkene is by the use of N-bromosuccinimide (NBS). Epoxide (37) is a cyclic analogue of juvenile hormone 11, and it may be prepared by the reaction of the parent triene (36) with NBS in tetrahydrofuran, isolation of the bromohydrin, and subsequent cyclization, using NaOMe in MeOH, in 80% overall yield.54Epoxide (38) may be prepared from the parent chromene (a potential agent against insect juvenile hormone) in 77% yield by using NBS in dimethoxyethane followed by NaHinduced c y c l i z a t i ~ n . ~ ~

The reaction of P(OSiMe3)3 with a-halogenocarbonyl compounds (R1R2CXCOR3)gives 1: 1 adducts (39; R’, R2, R3 = H or Me; X = C1 or Br); these may be treated with base to yield 1,2-epoxyphosphonates (40) (Scheme 3).56Such derivatives of 1,2-epoxyphosphonic acid are of interest in connection with their relationship to the wide-spectrum antibiotic phosphomycin. A new regioselective synthesis of ap-unsaturated epoxides (43; R = alkyl, cyclohexyl, or aryl) is shown in Scheme 4.” Initial reaction of the acid chloride 51 52

53 54

55 56

”

J. Rebek and R. McCready, Tetrahedron Lett., 1979,4337. A. L. Baumstark, D. R. Chrisope, and M. E. Landis, J. Org. Chem., 1981,46,1964. J. Rebek, Jr., R. McCready, and R. Wolak, J. Chem. SOC.,Chem. Commun., 1980,705. C. Wawrzenczyk and A. Zabza, Tetrahedron, 1980,36,3091. F. Camps, J. Coll., A. Messeguer, and M. A. Pericas., Tetrahedron Lett., 1980,21,2361. M. Sekine, K. Okimoto, K. Yamada, and T. Hata, J. Org. Chem., 1981,46,2097. M. Ochiai and E. Fujita, Tetrahedron Lett., 1980,21,4369.

8

Heterocyclic Chemistry 0

SiMe3

R' X 0 R2

+ P(OSiMe3)3 +

R3

Ry ' Xj P 0,40 R2 R 3

5 RI&P, RZ

(OSiMe3)2

II

RJ

(OSiMeJ2

(39) Reagents: i, NaOMe, MeOH; ii, Me,SiC1

Scheme 3

(42) Reagents: i, A1Cl3, CH,CI,, N,; ii, NaBH, (or LiAlH,); iii, NaOH (as.)

Scheme 4

with allyltrimethylsilane (41) yields the intermediate (42), which is subsequently cyclized to vinyloxiran. For (41; R = Ph) the overall yield is about 50%. A remarkable stereoselective synthesis of ( E ) -or (2)-bromo-epoxides from a common starting material, either (15)or (Z)-pent-3-en-2-01 (44; R', R2 = H, Me), is shown in Scheme 5.58The conversion of (44) into either (45) or (46) depends upon the choice of reaction conditions, but in both cases involves bromination followed by cyclization to the epoxide. Br

Br

OH (44) Reagents: i, Br,, EtOH, at -78 "C; ii, isolate the dibromide, then NaOH (3 mol I-'); (1.5 mol I-'), at O "C

iii, Br,, NaOH

Scheme 5

Synthesis of Oxirans via Attack of a Carbanion on the Carbonyl Group of Aldehydes and Ketones. The synthesis of chromone epoxides (48; R' = Me or Ph, R2 = Ph) from secondary a-bromo-acetophenones has been reported as part of a continuing series of articles on a-halogeno-ket~nes.~~ The reaction is thought to proceed via an intramolecular Darzens condensation (Scheme 6) after treatment of (47) with base. The reactions of (49) or of (47;R' = Me, R2 = CH20Me) in methanolic base to yield (48;R' = Me, R2 = C H 2 0 M ~ ) proceed through a similar mechanism.60 The 'octopus' compound [50; R = SCH2CH2(0CH2CH2)20Me],which can readily be prepared from (50; R = SH), proved an effective catalyst for the two-phase Darzens condensation of R1COR2[R', R2 = (CH2)S; R' = R2 = Me, Et, or Ph; or R1,R2 = Me,Ph] with C1CH2CN to afford the oxirans (51) (23-7 O '/o ) .6 ' M. M. Midland and R. L. Halterman, J. Org. Chem., 1981, 46, 1227.

'' J. A. Donnelly and D. E. Maloney, Tetrahedron, 1979,35, 2875. 6o 61

J. A. Donnelly and D. E. Maloney, Tetrahedron, 1979, 35, 2883. S. Akabori, M. Ohtomi, and S. Yatabe, Bull. Chem. SOC. Jpn., 1980, 53, 1463.

9

J

(47)

(48)

Scheme 6

(49)

Two groups, working independently, have simultaneously published descriptions of epoxyannulation procedures, based on intramolecular reactions of sulphur ylides, that are of considerable synthetic importance. Scheme 7 shows the method for converting cyclic ketones (52; n = 1,2, or 3), via keto-sulphides (53), into bicyclic epoxides (54) (66% for n = 2).62An alternative starting material is a P-keto-ester ( 5 5 ; acyclic, or n = 1 or 2), which, after reaction with o-halogeno-sulphide and decarboxylation, leads to keto-sulphides, analogous to (53), which may be cyclized (Scheme 7) to fused cyclopentane The use of (56) in place of halogeno-sulphide allows for the synthesis of fused cyclohexane oxides; e.g., (57) (50%) from 2-carbethoxycyclohexane ( 5 5 ; n = 2). (

C

g

L (

C

G

-& ( c a s , , (53)

(52)

Ph

Reagents: i,

J, iii

, Me,C(OMe),, H', heat; ii, PhSH, AIBN, heat; iii, Et,0+BF4-; iv, Bu'OK

Scheme 7 62

63

J. K. Crandall, H. S. Magaha, R. K. Widener, and G. A. Tharp, Tetrahedron Lett., 1980, 21,4807. M.E. Garst and A. T. Johnson, Tetrahedron Lett., 1980, 21,4811.

10

Heterocyclic Chemistry

The addition of dimethylsulphonium and dimethyloxosulphonium methylides to the derivative (58) of D-glyceraldehyde gives rise to epimeric epoxides with little stereo~electivity.~~ The ratios of (59) : (60) that were obtained were 60 :40 and 70:30, respectively. In the case of addition of diazomethane, a methyl ketone was formed together with the epoxides.

(58)

(59)

(60)

A selenonium methylide (61), on reaction with aromatic aldehydes ArCHO (Ar = 4-NO2C6H4,Ph, 2-thienyl, %fury& or 2-selenophenyl), gives 27-80% of the epoxides (62).65In the case of addition to salicylaldehyde, subsequent intramolecular cyclization gave benzofuran (63).

(61)

(63)

(62)

In a reaction which is mechanistically analogous to egoxidations of sulphur ylides, unstabilized arsonium ylides react with aldehydes or ketones to yield epoxides.66 The advantage provided by this new route is its high degree of stereochemical direction to trans-epoxides (>50 : 1).In this respect, the addition might be considered to be more nearly analogous to the Wittig reaction. Triphenylarsonium ethylide (64) reacts with octanal to yield a sample of (65) (80%)of which 99% is the trans-isomer. Ph,As=CHCH,

(64)

+ -CHo

-

,.-.'(65)

The Synthesis of Chiral Oxirans. Perhaps the most significant advance in this field for many years has been the development of an efficient chiral epoxidation system for allylic alcohol^.^' The reagent consists of a solution of Ti(OPr'), and L-(+)- or D-(-)-diethy1 tartrate in dry CH2C12.To this solution, at -2O"C, is 64

6s 66

67

S. Hagen, T. Anthonsen, and L. Kilaas, Tetrahedron, 1979,35, 2583. N. N. Magdesieva and N. G. Chovnikova, Zh. Org. Khim., 1979, 15, 2402 (Chem. Abstr., 1980, 93,46 268). W. C. Still and V. J. Novack, J. Am. Chem. SOC.,1981,103,1283. T. Katsuki and K. B. Sharpless, J. A m . Chem. Soc., 1980,102, 5974.

Three-Membered Ring Systems

11

added Bu‘OOH and the ally1 alcohol substrate. Normally, after a period in the freezer overnight, the product may be isolated in good yield. The method possesses two striking features. (i) It gives uniformly high asymmetric inductions throughout a range of substitution patterns in the allylic alcohol substrate; thus geraniol (66) with (+)-tartrate gives 77% yield of a sample of (67) which shows

(66)

(67)

a 95% enantiomeric excess (e.e.) of configuration 2S,3S. (ii) Upon use of a given tartrate enantiomer, the system seems obliged to deliver the epoxide oxygen from the same enantioface of the alkene, regardless of the substitution pattern. This latter characteristic is highlighted in (68),which shows that, when the alkene unit is placed in the plane with the CH20H substituent on the lower right, the use of (.+)-diethy1 tartrate leads to epoxidation from below the plane. When (-)-diethy1 tartrate is used, the epoxide is formed from above. ‘0’ from D-(-)-diethy1 tartrate (unnatural)

1

‘0’ from D-(+)-diethy1 tartrate (natural)

The problem with this original method is that, when the epoxy-alcohol product is fairly soluble in water, poor results were obtained. A modified work-up procedure has now been introduced which allows the isolation of epoxy-alcohols such as (69) and (70) in good yields; these compounds are key intermediates in the synthesis of methymycin and erythromycin.68 Also prepared were (7 1) and (72), intermediates for the synthesis of leukotriene C-1 and disparlure. All four epoxides had e.e. > 95%.

(71)

The major limitation of the Katsuki-Sharpless reagent is, of course, that its use is restricted to allylic alcohol substrates. More traditional asymmetric epoxidation techniques are required for other alkenes. One such method is the use of 30% H 2 0 2 in aqueous NaOH, using benzylquininium chloride as a chiral 68

B. E. Rossiter, T.Katsuki, and K. B. Sharpless, J. A m . Chem. Soc., 1981,103,464.

12

Heterocyclic Chemistry

catalyst. This method has been used for the synthesis of a number of optically active epoxy-naphthaq~inones,~’ in particular vitamin K3 2,3-epoxide (73).70 The enantiomeric excesses for such epoxidations are up to 45% and, furthermore, the absolute configurations of these compounds can be deduced from their c.d. spectra.

n

(74)

Asymmetric epoxidation to produce (3S)-2,3-oxidosqualene (74)in 31o/‘ overall yield and 14% optical purity from the parent alkene was achieved, using Bu‘OOH with [ M ~ ( O ) ~ ( a c a ccatalyst, )~] in the presence of di-isopropyl (+)tartrate.71 A highly efficient synthesis of optically active ap-epoxy-aldehydes from cupunsaturated acids has been d i s ~ l o s e d Proline .~~ bromolactone (76) is prepared from the unsaturated acid (75) in 99% isomeric purity. On treatment with base, (77) is produced, from which the proline moiety can be reductively cleaved to give (78) (95%) with an e.e. of 98%. ON )--CO,Me

Ph

0% (75)

(76)

Ph

Ph (77)

CO,H 0 %

Ph

The useful chiral synthons (-)-(S)-4-iodo-1,2-epoxybutane(80) and its (+)(R)-epimer may each be prepared from the commercially available (-)-(S)-malic acid (79).73 A synthetic enzyme has been employed in the synthesis of (-)-chalcone epoxide from chalcone in optical yields of greater than 90% .74 The method 69

‘O

’’ ’’ 72 7A

H. Pluim and H. Wynberg, J. Org. Chem., 1980,45,2498. G . Snatzke, H. Wynberg, B. Feringa, B. G. Marsman, B. Greydanus, and H. Pluim, J. Org. Chem., 1980,454094. K. Tani, M. Hanafusa, and S. Otsuka, Tetrahedron Lett., 1979, 3017. S.Terashima, M. Hayashi, and K. Koga, Tetrahedron Lett., 1980,21,2733. D.L.Boger and S. J. Panek, J. Org. Chew., 1981,46,1208. S. Julia, J. Masana, and J. C. Vega, Angew. Chem., Int. Ed. Engl., 1980,929.

13

Three-Membered Ring Systems

involves a three-phase system of toluene, water, and the synthetic enzyme poly-(S)-alanine, and it has great promise in that, for the first time, a readily accessible polypeptide has been used to provide epoxide in high optical yield with relatively short reaction time and with only a small amount of the enzyme catalyst needed. The Synthesis and Reactivities of Aromatic Oxides. The kinetic properties of microsomal and purified epoxide hydrolase toward K-region arene oxide substrate have been investigated by a direct spectrophotometric te~hnique.~' The enzyme reactions were studied with phenanthrene 9,lO-oxide (81) and were found to be consistent with a general-base catalysis of the nucleophilic addition of water to epoxide, by a histidine residue on the active site. Non-ionic detergents, which were necessary to solubilize highly lipophilic substrates, were found to inhibit the reactions. A 40-fold difference in the rate of hydration of (+)- and (-)-benzo[a]pyrene 4,5-oxide was thought to be of particular importance in relation to the biological activity of this highly mutagenic K-region arene oxide. A two-step synthesis of (81) has been reported, starting with the reduction of phenanthrene-quinone to -diol ( 6 2 - 6 8 % ) , followed by refluxing with (Me0)2CHNMe2in DMF-THF (58-64'/0).~~ 0

Various amine-substituted arene oxides, e.g. (82), have been suggested as biogenic precursors to fungal metabolites of the epithiadiketopiperazine class (83). Model compounds (84; R', R2, R3 = CH2CH2NH2,H, H) have been synthesized in an attempt to validate this suggestion but, in each case, no biogenetic-type activity was noticed, and aromatization rather than cyclization was It may be that such amine-epoxide cyclizations occur only in vivo under the intervention of an enzyme. The suspected ultimate carcinogenic metabolite of cyclopenta[cd]pyrene (85; R1R2= 0, R3 = H) has been prepared.'" Rearrangement of the epoxide in benzene that contained A1203gave the ketone (85; R' = H, R2R3= 0). Benz[a]anthracene is the member with the lowest molecular weight of the series of polycyclic aromatic hydrocarbons (PAH) to be generally considered a 7s

76 77

78

R. N. Armstrong, W. Levin, and D. M. Jerina, J. Biol. Chem., 1980,255,4698. C. Cortez and R. G. Harvey, Org. Synth., 1978,58,12. W. H. Rastetter and L. J. Nummy, J. Org. Chem., 1980,45,3149. D.J. McCaustland, P. H. Ruehle, and J. C. Wiley, Jr., J. Chem. SOC.,Chem. Commun., 1980,93.

14

Heterocyclic Chemistry

carcinogen. The 8,9-oxide (86), a major initial metabolite of this compound, The major isolated has been synthesized in optically pure (+)- and liver metabolite of (86) is a diol with 8R,9R stereochemistry, and this has been shown to be enzymatically derived from the (+)-isomer. From the same laboratories comes a description of the synthesis of the optically pure forms of benzo[a]pyrene 7,s-oxide (87).80

R'

Attention has been drawn to the potential metabolites of the carcinogenic aza-aromatic hydrocarbons with the synthesis of (88)."This compound is the aza-analogue of the carcinogenic hydrocarbon 7-methylbenzanthracene. Miscellaneous Syntheses of Oxirans. The superoxide anion [02-] became a convenient reagent for laboratory use with the discovery that it could be generated in aprotic solvents by the solubilization of KO2 in organic solvents, using crown ethers.'* Stilbene, acenaphthylene, and a number of chalcones have been epoxidized in the presence of organic sulphur compounds, using the same source of superoxide anion.83The reaction (Scheme 8) is thought to proceed via initial attack by superoxide on the sulphonic acid (89),followed by electron transfer, leading to the nucleophile (90); this adds to substrate to produce an intermediate (91), which then cyclizes to epoxide (92). Acyl halides may also be used for this type of epoxidation rea~tion.'~ Cyclohex-2-enone (93; R' = R2 = Ph) underwent base-catalysed autoxidation in the presence of the same source of superoxide in benzene to give the appropriate 2,3-epoxide (50°/0).85 A similar reaction of (93;R' = R2 = Me) gave a yield of only 20% of epoxide. 79

83 85

D. R. Boyd, K. A. Dawson, G. S. Gadaginamath,J. G. Hamilton, J. F. Malone, and N. D. Sharma, J. Chem. SOC.,Perkin Trans. 1, 1981, 94. D. R. Boyd, G. S. Gadaginamath, A. Kher, J. F. Malone, H. Yagi, and D. M. Jerina, J. Chem. SOC.,Perkin Trans. 1, 1980, 2112. L. J. Boux, H. T. A. Cheung, G. M. Holder, and L. Moldovan, Tetrahedron Lett., 1980, 21, 2923. J. S. Valentine and A. B. Curtis, J. Am. Chem. SOC.,1975, 97, 224. S. Oae and T. Takata, Tetrahedron Lett., 1980,21, 3689. T. Nagano, K. Arakane, and M. Hirobe, Chem. Pharm. Bull., 1980,28, 3719. A. A. Frimer and P. Gilinsky, Tetrahedron Lett., 1979, 4331.

Three-Membered Ring Systems 0

0

II

II

ArSCl -$ ArS-00

II

II

0

0

15

0

II + ArSOO- -$ II

Ph

+P

h 0

0

d Ph

Reagents: i, KOz, 18-crown-6; ii, 0

Scheme 8

0

0

(94)

(95)

Alternative sources of the [02-] species are provided by superoxo-cobalt(II1) complexes, which react with 2,6-di-t-butylbenzoquinonemethides to yield spirooxirans.86Thus epoxides (95; R' = R2 = H or Me), (95; R' = H, R2 = Pr' or Ph), and [95; R'R2 = (CH2)5]were produced, in 37-61% yield, by the reaction of (94) with complexes such as [CO(CN)~O~I-[(P~,P=)~N]'. When the orthoester of oleic acid is treated with H202 in rapidly stirred CH2C12,the epoxide (96)(40%) is ~btained.~' The reaction was shown to be predominantly intramolecular, probably proceeding uia an intermediate such as (97). Me

F3C T : F 3

OH (98)

oc-x (99)

0 (97)

(100)

4

(CH,),Me (101)

Experimental details have been disclosed for a catalytic epoxidation process, involving hexafluoroacetone and 90% H202, which is suitable for large-scale operations.88 The oxidant species (98) is capable of delivering epoxides (99), (loo), and (101) in 83, 92, and 94% yields from their respective alkene precursors. 86

A. Nishinaga, H. Tomita, Y. Tarumi, and T. Matsuura, Tetrahedron Lett., 1980,21,4849.

'' J. Rebek, Jr., and R. McCready, Tetrahedron Lett., 1980,21,2491. A. J. Biloski, R. P. Heggs, and B. Ganem, Synthesis, 1980.810.

Heterocyclic Chemistry

16

The Diels-Alder reaction between 1,4-benzoquinone and dimethylfulvene generates a mixture of exo- and endo-adducts from which the mixed epoxide (102) is obtained by oxidation with H202." This epoxide mixture is the source of quinone epoxide (103) (100%) by a retro-Diels-Alder reaction that takes place in a sealed tube at 160-180°C. Partial reduction of (102) with NaBH, before it is heated in a sealed tube leads to a mixture of cyclohexenones (104) ( 100OO/ ).

A dioxiran intermediate (105) which is capable of epoxidizing alkenes is thought to be formed in KHS04-acetone." This system forms the basis of a new generalized method that is capable of giving high yields of epoxides from either (E)- or (2)-cinnamic acids with retention of configuration. For the oxidation of cyclohexene, a two-phase system was used (water/benzene), with 18-crown-6 as the phase-transfer agent. An easy transformation of ketones into a,P-epoxymethyl ketones involves conversion of the ketone, e.g. (106; R' = Et or Ph, R2 = Me), (106; R' = Bun, R2 = Pr"), (106;R1 = CH2Ph, R2 = Ph), or [106;R'R2 = o-C6H4CH2 or (CHZ)4],into the salt of its Mannich base (107), followed by direct epoxidation to (108) (38-75'/0).~~

Regioselective oxidation of polyisoprenoids to o-epoxides has been achieved by NaBr-promoted electroly~is.~~ When (109) and NaBr are dissolved in MeCN-THF-water and electrolysed in an undivided cell, using platinum foil electrodes, (110) (100%) is formed.

(109)

89

90 91

92

A. Ichihara, M. Kobayashi, K. Oda, S. Sakamura, and R. Sakai, Tetrahedron, 1979, 35,2861.

R. Curci, M. Fiorentino, L. Troisi, J. 0. Edwards, and R. H. Pater, J. Org. Chem., 1980,45,4758. F. Henin and J. P. Pete, Synthesis, 1980, 895. S. Torii, K. Uneyama, M. Ono, H. Tazawa, and S. Matsunami, Tetrahedron Lett., 1979,4661.

Three-Membered Ring Systems

17

If iodosobenzene (PhIO) is used as an oxene-transfer agent to ketens (111;R = Et, Bun, Ph, or CF,), the initial product is an a-lactone (112) which rapidly polymerizes to yield polyester^.^^ Spectra and Theoretical Chemistry of 0xirans.-Predictions as to the reactivities and stabilities of oxirans continue to engage the interest of theoretical chemists. The interconversions of oxirans and carbonyl ylides are electrocyclic reactions for which the effects of substituents have been probed by ab initio SCF calculat i o n ~Theoretical .~~ studies have also been carried out on the rearrangement of oxiranium cation (C2H40')95 and on the attack of amines on a-ethylene ep~xides.~~ The thermodynamic stabilities of the three CzH40isomers have been calculated, and the values show that oxiran is higher in energy than both H2C=CHOH and CH,CHO by 69 and 114 kJ mol-', re~pectively.~'The only stable form of protonated oxiran has proved to be the O-corner-protonated isomer (113).98 In two papers concerning the shape of bicyclo[n.l .O.]-derivatives, quantum and molecular mechanics have been used to show that cycloheptene oxide exists in a b ~ a t - c h a iand r ~ ~cyclohexene oxide in a half-chair'" conformation. Electrondiffraction studies in the gaseous phase also indicate a half-chair shape for cyclohexene oxide, but a conformational mixture of two chair forms is indicated for cycloheptene oxide.lo' Ab initio SCF calculations on syn-(114)and anti-epoxides (115)of benzenediol indicate that intramolecular H-bonding occurs in (114) only.lo2 Hydrogenbonding of this type facilitates opening of the oxiran ring at either carbon atom but particularly affects C-1. Proton n.m.r. spectroscopy has been used to demonstrate the effect of solvent on intramolecular H-bonding of this type.lo3 The coupling constant J(HA-HB) is at a maximum for (116) in Bu'OH, where intramolecular H-bonding predominates. With the addition of the strongly

93

R. M. Moriarty, S. C. Gupta, H. Hu, D. R. Berenschot, and K. B. White, I. A m . Chem. SOC.,

94

K.N . Houk, N. G. Rondan, C. Santiago, C. J. Gallo, R. W. Gandour, and G. W. Griffin, J. A m .

1981,103,686. 9s 96

97 98

99 100 101 102

Chem. SOC.,1980,102,1504. R. Cimiraglia, S. Miertus, and J. Tomasi, J. Mol. Srrucr., 1980.62, 249. R. Lissillour, J. Etrillard, J. Sauleau, and J. Huet, J. Chim. Phys. Phys.-Chim. Biol., 1980, 77, 875. W. J. Bouma, L. Radom, and W. R. Rodwell, Theor. Chim. Actu, 1980, 56,149. R. H. Nobes, W. R. Rodwell, W. J. Bouma, and L. Radom, J. A m . Chem. SOC.,1981,103,1913. R. Todeschini and G. Favini, I. Mol. Struct., 1980,64,47. R. Todeschini, D. Pitea, and G. Favini, J. Mol. Strucf., 1981,71, 279. M. Traetteberg, T. W. Sandnes, and P. Bakken, J, Mol. Struct., 1980,67, 235. P. Politzer, K. C. Daiker, and V. M. Estes, Int. J. Quantum Chem., Quantum Biol. Symp., 1979, 6,47.

103

W. H. Rastetter and J. Adams, J. Org. Chem., 1980,45, 3534.

18

Heterocyclic Chemistry

H-bonding solvent DMSO, however, the coupling constant is reduced, as intermolecular H-bonding with solvent becomes more important, down to a minimum value in 100% DMSO. By using accurate ab initio methods, it has been possible to examine the thermochemistry and the mechanisms of epoxidation and of metathesis of alkenes by complexes such as CrC1202 and M o C ~ ~ The O ~ results . ~ ~ suggest ~ that, in order to activate the metal chlorides, it is essential to have spectator metal-oxo bonds present. A study of the lower electronic states and the oscillator and optical rotatory strengths for the lower electronic transitions of oxiran, 2-methyloxiran, and a number of other three-membered heterocyclic systems has been reported. lo' These calculations of the chiroptical properties of such molecules may be related directly to their observed c.d. spectra. Guanolide (117) has been prepared, in nineteen steps and 7.9% overall yield, from cyclohexane-l,3-dione and its structure determined by X-ray analysis. '06 One unusual aspect of the 'H n.m.r. spectrum of (117) was the chemical shift for one proton at S 2.1, which was assigned, after decoupling experiments, to the P-H that is attached to C-8; this proton is situated close to the oxygen atom and in the plane of the oxiran ring. Two other epoxides whose crystal structures have been determined are (118)'07 and (119).'08

=9 0 0

A

The Raman spectra of vinyl-lo9 and ethyl-oxirans'" have been reported for gaseous, liquid, and solid states. In the former case, three conformations were established in liquid and in vapour, i.e. the s-trans and two nonequivalent gauche forms. Ethyloxiran exists as an equilibrium between two non-equivalent gauche rotameric forms. The relative configuration of the diepoxide side-chain (120) of the antibiotic hedamycin has been established as rel-(14R,16S,17R,18S) by 13Cn.m.r. spectroscopy and by comparison with model compounds."' lo4

lo5 '06

lo'

lo'

'lo

11'

A. K. Rapper and W. A. Goddard, 111, J. A m . Chem. SOC.,1980,102,5114. A. Rauk, J. A m . Chem. SOC.,1981,103,1023. G. H. Posner, K. A. Babiak, G. L. Loomis, W. J. Frazee, R. D. Mittal, and I. L. Karle, J. Am. Chem. SOC.,1980,102,7498. C. H. Charles, R. J. Baker, L. M. Trefonas, and G. W. Griffin, J. Chem. SOC.,Chem. Commun., 1980,1075. H. Ueda, C. Katayarna, and J. Tanaka, Bull. Chem. Soc. Jpn., 1980,53, 1263. V. F. Kalasinky and S. Pechsiri, J. Raman Spectrosc., 1980,9, 120. A. B. Nease and C. J. Wurrey, J. Raman Spectrosc., 1980,9, 107. M. Ceroni and U. Sequin, Tetrahedron Lett., 1979, 3703.

19

Three-Membered Ring Systems

Go

k'

(120)

Chemical ionization mass spectrometry of C2-C4 aliphatic epoxides, using methane as a reagent gas, produces quasi-molecular ions (A4+ 1)+.'12This method may prove useful for the determination of molecular weights of epoxides. Electron-impact and chemical-ionization mass spectra have been recorded for glycidyl ethers (121; R = allyl, Bun, Ph, 4-MeOC6H4,or ~-BU'C,H,).''~

Reactions of Oxirans with E1ectrophiles.-Ring-opening Reactions. Compound (122; R = Me) is the epoxide of a valence tautomer of hexamethyltropone; it undergoes ring-opening followed by rearrangement to give a quantitative yield of (124;R = Me) in CF3C02H, at OoC.ll4 Labelling studies showed that (122; R = CD3) gave a rearrangement product that was specifically labelled at C-4, i.e. (124; R = CD3), which indicates a mechanism proceeding via the dicyclopropylcarbinylintermediate (123; R = CH, or CD,).

' (122)

(123)

(124)

Treatment of (125; R' = H, R2 = Me) with BF3.0Et2,at -20 "C in CH2C12, proceeds normally to give the ketone (126) (70%); however, the same reagent causes a pinacol-type rearrangement in (125; R' = Me, R2 = H) to yield (127) (84O/o ).'

Gf)

0

,

OH (125)

o@

0

HO (126)

(127)

The reactions of a number of steroidal A-ring epoxides with electrophiles have been reported. Ring-contraction of (1281, induced by BF3.0Et2, is influenced by a neighbouring acetoxy-group in that (128; R' = OAc, R2 = H) and (128;R' = H, R2 = OAc) yield ring-contracted compounds (129) in 35 and 50% yields, respectively.116A neighbouring acetoxy-group had a great influence 'I3 'I4

S. Suzuki, Y.Hori, R. C. Das, and 0. Koga, Bull. Chem. SOC. Ipn., 1980,53,1451. R. M. Brown and C. S. Creaser, Org. Mass Specfrom., 1980,15,578. H.Hart, S.-M. Chen, and S. Lee, J. Org. Chem., 1980,45,2096. J. A. Marshall and J. A. Kerschen. Synth. Commun., 1980,10,409. I. Torrini, A.M. Maione, and A. Calcagni, J. Chem. SOC., Perkin Trans. 1, 1980,440.

20

Heterocyclic Chemistry

";CI 1

R'

\ - -

-,

on the ring-opening reactions of the cholestenones (130; R' = H, R2 = OAc) and (130; R' = OAc, R2 = H)."' Using HC10, in THF, a 6p-OAc group completely blocked cleavage of both the a- and p-epoxides, and a 6a-OAc group retarded ring-opening compared with (130; R' = R2 = H). Cholestane derivatives (131)and (132) underwent neighbouring-group participation by the methoxy-groups attached to C-19 on opening with HC104, the former yielding almost entirely the 4~,19-epoxy-compound(133) while (132) gave mainly diol, with 20% of the 4~,19-epoxy-5a-cholestan-5-ol.'18 The Friedel-Crafts reactions of toluene and anisole with epoxypropane and 2,3-dimethyl-2,3-epoxybutanehave been in~estigated."~ The mechanism was found to be SN2-like, with all positional isomers that were formed in the AlC1,-catalysed reaction of epoxypropane having almost completely inverted configurations at the epoxide carbon. Cyclization Reactions of Oxirans. The three mono-epoxides of humulene (134) occur naturaliy, and may well serve as the precursors, in uiuo, of other bicyclic and tricyclic sesquiterpenoids that are of biological significance. The 4,5 -epoxide gives two tricyclic alcohols (135) and (136) on treatment with BF,.OEt, in a 1: 1 ratio (70%), both of which are related to africanol in structure and stereochemistry.120Humulene 8,9-epoxide reacts with SnC1, in CHC1, to give (137).12'

,'5

$-&

8'

(134)

'"

M. Ishigura, H. Saito, Y. Hirano, and N. Ikekawa, J. Chem. SOC.,Perkin Trans. 1, 1980.2503. P. Kocovsky and V. Cerny, Collect. Czech. Chem. Commun., 1980,45,3199. M. Inouhe, K. Chano, 0. Itoh, T. Sugita, and K. Ichikawa, Bull. Chem. SOC.Jpn., 1980,53,458. '*' J. A.Mlotkiewicz, J. Murray-Rust, P. Murray-Rust, W. Parker, F. G. Riddell, J. S. Roberts, and A. Sattar, Tetrahedron Lett., 1979,3887. '*' I. Bryson, J. S. Roberts, and A. Sattar, Tetrahedron Lett., 1980,21,201. '18

Three-Membered Ring Systems

(138)

21

(139)

(140)

A reagent has been found which is capable of differentiating between the epimers of 1,2-epoxylinalool (138) such that cyclizations occur for (138; R' = OH, R2 = H) while (138; R' = H, R2 = OH) is unaffected by this treatment, and may be recovered unchanged (80%).'22 The reaction of (138;R' = OH, R2 = H) with Ti(OPri)4in CH2C12at 25 "C yields a mixture of compounds, from which (139) and (140) (20-30%) may be isolated. The bicyclization reaction of (141) to (142) (36%) is effected by using BC13 at -78°C.'23 The same reagent has also been used in the conversion of (143; R = H or Pr') into (144) and other open-chain

Epoxide (145), on treatment with BF,-OEt, in benzene, gave a mixture of (146; R = a-Me) and (146; R = &Me) (38%) via successive migrations of methyl groups followed by ring-closure.125

Nucleophilic Ring-opening Reactions of 0xirans.-Reactions with Oxygen and Nitrogen Nucleophiles. The kinetics and mechanism of ring-opening reactions of propene oxide with water, under nucleophilic and general catalysis by phosphate,'26 acetic a ~ i d , ' ~and ' chloroacetic acids,'28 have been reported.

"'I

D. J. Morgans, Jr., K. B. Sharpless, and S. G . Traynor, J. A m . Chem. Soc.. 1981,103.462. J. Amupitan and J. K. Sutherland, J. Chem. Sac., Chem. Commun., 1980, 398. D. Nasipuri, A . K. Samaddar, and G . Das, Indian J. Chem., Sect. B, 1980, 19, 727. I. Kitagawa, H. Shibuya, H. Fujioka, Y. Yamamoto, A . Kajiwara, K. Kitamura, A . Miyao, T. Hakoshima, and K. Tomita, Terruhedron Letr., 1980, 21, 1963. Y. Pocker, B. P. Ronald, and L. Ferrin, J. A m . Chem. Soc., 1980, 102, 7725. S. Szakacs, S. Gobolos, and F. Nagy, Magy. Kem. Foly., 1980, 86, 276 (Chem. Abstr., 1980, 93,

'21

185 343). H. Kakiuchi and T. Iijima, Tetrahedron, 1980,36,101 1.

12'

12' 124

lZ5 lZ6

22

Heterocyclic Chemistry

Studies of secondary deuterium isotope effects have revealed details of the methanolysis of 4-nitrostyrene oxide in acidic and basic media.129In acid, the major reaction occurred at the benzilic carbon, C-2, with a large inverse isotope effect at C-3; however, in basic conditions, using methoxide, the situation was reversed, there being a large inverse isotope effect at C-2, with little effect at C-3. These results indicate that there is a large degree of ring-opening in both transition states. A mechanistic switch has been noted in the acid-catalysed opening of 2,3dimethyl-2,3-epoxybutaneunder aqueous conditions, when induced by added NaClO, (Scheme 9).l3' The mechanism, with or without added salt, is initiated by the protonation of substrate to form (147). Nucleophilic opening of this intermediate by H 2 0 leads directly to glycol product (148) (pathway A) and excludes the ring-opening pathway B at low salt concentrations. When [NaClO,] reaches 2 moll-', however, rearrangement to pinacolone (150) is detected, and it increases to 10% at 6 moll-'. High salt concentrations are thought to provide the necessary electrostatic stabilization that is required for the charged intermediate (149), thus rendering pathway B energetically accessible. Cl0,-

H

(148) Scheme 9

A new route to phenoxalanes has been developed, using a-substituted epoxides as bifunctional two-carbon ~ynthons.'~' Thus portionwise addition of (151) to a DMF solution of o-phenylenediamine at 90°C under nitrogen, followed by heating for a further 3 hours, gave (152) (66%).

(151)

(152)

Cartinine (154; R' = R2 = R3 = Me, n = l ) , often referred to as vitamin BT, is involved in the transport of fatty acids across membranes. A synthesis of cartinine analogues (154; R', R2, R3 = various alkyl groups; n = 1 or 2) has been reported'32 in which the key step is the reaction of an epoxy-ester (153) with the appropriate tertiary amine (R'R2R3N) in aqueous ethanol, to effect 130 13'

13*

R. P. Hanzlik and R. B. Westkaemper, J. A m . Chem. SOC.,1980, 102, 2464. Y. Pocker and B. P. Ronald, J. Am. Chem. SOC., 1980,102, 5311. E. C. Taylor, C. A. Maryanoff, and J. S. Skotnicki, J. Org. Chem., 1980,45, 2512. C. R. Degenhardt, J. Org. Chem., 1980,45, 2763.

23

Three-Membered Ring Systems

opening of the epoxide ring and hydrolysis in one step, with yields of 48-70%. Unfortunately, the yield of cartinine itself was only 15%, due to interfering hydrolysis of the ester.

(155)

(157)

(156)

A synthesis of trans-fused y-lactones (157;R'= R2 = H) and (157; R' = Me, R2 = CH=CH2) involves the conversion of cyclohexanone derivative (155) into a mixture of y6-spiro-epoxy-esters (156); subsequent cleavage by PhSNa and further work-up allows the preparation of both the cis- and the trans-fused y-1a~tones.l~~ Stereospecific trans-cleavage of cyclohexene oxide by alcohols, acetic acid, and aniline has been observed, using Woelm alumina at 100°C.'34 The ionexchange resin Wofatit SBW (as its hydroxylated form) has been used as a catalyst for the reaction of phenol with ethene

Nucleophilic Ring-opening Reactions with Carbanions. In 1950 it was reported that the anion of ethyl acetoacetate reacted with styrene oxide to yield (158) This has now been re-investigated and shown to be incorrect; there are two products of the reaction, (158) (45%) and (159) (55%), which are not separable by distillation but have now been isolated by h.p.l.c.13'

Ph (158)

(159)

Copper dienolates derived from a@-unsaturated acids undergo alkylation at the y-carbon atom with high regioselectivity.13* Vinylic epoxides are particularly good alkylating agents for these species, which form 1,5-dienes that are oxygenated at both ends of the skeleton. Tiglic acid (160) can thus be made to react with butadiene oxide to give a mixture of (161) and (162) (93%, ratio 14 :86). 133 13*

13' 136

137

L. Strekowski and M. A. Battiste, Tetrahedron Lett., 1981,22,279. G.H. Posner and M. Hulce, J. Catal., 1980,64,497. R. Boeva, K.Markov, and St. Kotov, J. Catal., 1980,62,231. R.iM. Adams and C. A. VanderWerf, J. A m . Chem. SOC.,1950,72,4368. D.B. Reitz, J. Org. Chem., 1979,44,4707. P. M. Savu and J. A. Katzenellenbogen, J. Org. Chem., 1981,46,239.

24

Heterocyclic Chemistry

(2)-Alkenyl-cuprates react with epoxides to yield enols with cisstereochemistry at the double-bond (50-96'/0).~~~In the particular reaction of (163) with the epoxy-ester (164), ring-opening is followed by cyclization to (165)

Homoallylic alcohols (167; R1 = pentyl, R2 = H), (167; R' = Me,C=CHCH2CH2, R2 = H or Me), and (167;R1 = hexyl, R2 = Me) (71-87%) may be synthesized in what is essentially a single step from terminal alkynes R'CECH (Scheme The formation of the alkenyl-aluminate (166) is catalysed by the zirconium complex. ii, iii

~

Me\_/C~~ R'

R2 (167)

Reagents: i, Me,AI, [Cl,Zr(C,H,),I, CH2ClCH,Cl; ii, evaporate solvent, add BuLi; iii,

Scheme 10

Transition-metal catalysts, particularly NiC12 and NiBr2, greatly accelerate the reaction of tetra-alkyl-aluminates, e.g. NaAlEt, or LiAlBu,, with e p ~ x i d e s . ' ~ ~ The alkylations are regioselective, occurring at either a benzylic C-0 bond (if present) or at the less substituted centre, with the configuration at the alkylated carbon being inverted.

Reduction and Elimination Reactions.-A general procedure for the stereospecific reduction of epoxides to alkenes, using triphenylphosphonium salts, has been de~cribed.',~ The method involves addition of the epoxide to an ice-cold, stirred, mixture of Ph3P.HI and Ph3P12in benzene containing hexane, at 0 "C, with continued stirring over 2 4 4 8 h followed by simple work-up. Yields are >90%, with stereospecificity >98%. Stereospecific reduction of aliphatic epoxides may also be obtained by the very simple procedure of refluxing the epoxide in THF with 2.2 gram atom equivalents of atomized lithium to afford yields of 75-97% .143 The disadvantage of the method is, of course, the potential reactivity of lithium with other functional groups which may be present. 139

I4O

14' '41 143

A. Alexakis, G. Cahiez, and J. F. Norrnant, Tetrahedron, 1980,36, 1961. M.Kobayashi, L. F. Valente, E. I. Negishi, W. Patterson, and A. Silveira, Jr., Synthesis, 1980,1034. G. Boireau, D. Abenhairn, and E. Henry-Basch, Tetrahedron, 1980,36, 3061. P. E.Sonnet, Synthesis, 1980,828. K.N.Gurudutt and B. Ravindranath, Tetrahedron Lett., 1980, 21, 1173.

Three-Membered Ring Systems

25

Attempted reduction of styrene oxide gave polymer. A more complex procedure for the deoxygenation of terminal epoxides involves the use of the tellurium complex (168; M = Li, Na, or K).144This complex is generated, under nitrogen, by the addition of an alkali-metal salt of diethyl phosphite (169) to powdered tellurium; to this solution is added the epoxide, which regenerates tellurium and (169). The reaction may be run with stoicheiometric quantities or under conditions which approach a catalytic nature with respect to tellurium. 0

0

II

II

(EtO),PTe- M+ + Te + (EtO),P-O(168)

M+

(169)

The heterogeneous catalytic hydrogenolysis of cyclohexene oxide on 10% Pd/C has been studied in a range of sol~ents.'~' In each case, the major product was found to be alcohol (82% in cyclohexane to 58% in propan-2-01) together with smaller quantities of cyclohexane and cyclohexanone. The deuteriolysis of cis- and of trans-t-butylcyclohexane oxide, together with kinetic studies, showed that the reaction gave preferentially axial alcohols and trans addition of H after a 'roll-over' of substrate on the catalyst surface. A comparison of the use of platinum and nickel catalysts for the hydrogenolysis of epoxides revealed that, for terminal epoxides, the former catalysts gave secondary alcohols while nickel catalysts led to primary A difference was also noted in their reaction toward cis- and trans-isomers, in that while nickel gave similar rates for both isomers, the platinum catalyst reacted faster with cis-epoxides. Epoxides may be converted into allylic alcohols, using Me3SiI and 1,5diazabicyclo[5.4.0]undec-5-ene (DBN).14'The reaction conditions avoid the use of strong bases, previously used for such conversions, and are thus compatible with the presence of groups such as ester or cyclic ketal on the substrate, allowing the conversion of (170) into (171; R' = Me, R2 = C02Me, n = 1) (70%). A

(170)

(171)

(172)

(173)

similar reaction, using Me3SiI, transformed cyclic epoxides (172; n = 1 or 2) quantitatively into compounds (173).14' Subsequent treatment with 1,8diazabicyclo[5.4.0]undec-7-ene (DBU) gave, after hydrolysis, allylic alcohols (171; R' = R2 = H, n = 1 or 2) in good yields. A more efficient work-up procedure uses (Bun4NFin THF to convert a silyl ether into an Thermal and Photochemical Reactions of 0xirans.-The kinetics and mechanisms for the thermal rearrangements of the isomeric chlorostyrene oxides '41 145

147 148 149

D. I,. J. Clive and S. M. Menchen, J. Org. Chem., 1980, 45, 2347. G. C. Accrombessi, P. Geneste, J-L. Olive, and A . A. Pavia, J. Org. Chem., 1980, 45,4139. M. Bartok and F. Notheisz, J. Chem. SOC.,Chem. Commun., 1980, 667. G. A. Kraus and K. Frazier, J. Org. Chem., 1980,45, 2579. H. Sakurai, K. Sasaki, and A. Hosomi, Tetrahedron Lett., 1980, 21, 2329. M. R. Detty and M. D. Seidler, J. Org. Chern., 1981,46, 1283.

Heterocyclic Chemistry

26

(174; R' = C1, R2 = H, R3 = 4-Me, H, 4-Br, 3-C1, or 4-NO2) and (174; R' = H, R2 = C1, R3 = 4-Me, H, or 4-N02) to (175) and (176), respectively, at 130°C, yielded p values of -3.5 and -0.57.'50 The mechanism involves disrotatory Cp-0 bond heterolysis to yield the corresponding a -keto-carbocation/chloride ion-pairs. CI 0

(174)

Thermolysis of the (3E)-isomers of the butadienyl-oxirans (177; R = Ph, 4-MeOC6H4, or 4-NOzC6H4)gave exclusively the dihydrofurans trans-(178), while (177; R = C02Me) gave trans-(178) (goo/,) together with isomeric cis(178) For the (3Z)-isomers of (177;R = Ph, 4-MeOC6H4, or cis-(178) 4-NOzC6Hs), however, mixtures of trans-(178) (55-61%), (21-26%), and the dihydro-oxepins (179) (18%) were formed.

(177)

(179)

An intramolecular transfer of dimethyl acetylenedicarboxylate occurs in the thermal rearrangement of (180) to (183).lS2The reaction is thought to proceed via initial ring-opening of the oxiran to form the carbonyl ylide (181); this forms the cyclo-adduct (182), cycloreversion of which then gives (183) (Scheme 11).

Scheme 11

lS2

R. N. McDonald and R. C. Cousins, J. Org. Chem., 1980,45,2976. W. Eberbach, G. Koenig, and U. Trostmann, Tetrahedron Lett., 1979,4649. J. Brokatzky and W. Eberbach, Chem. Bet., 1981,114, 384.

Three-Membered Ring Systems

27

In an unsuccessful attempt to produce oxiren via the reverse Diels-Alder reaction of the 'formal' oxiren-isobenzofuran adduct (184), an unusual decomposition was noted wherein a (1: 1)mixture of (185) and (186) was formed.'53

(184)

(186)

(185)

The steroid (187) decarboxylated in refluxing decalin to give a mixture of epimeric alcohols (189) (79%) together with oestrone (9"/0), probably via the intermediate allylic alcohol (188).154

HO 0

A number of papers have been published from a Japanese group investigating the photochemistry of epoxy-quinones. Photolysis of 0.1 M-(190; R' = Me) in benzene gave the primary dimers (191) (65%) and (192) (20%), which underwent photoisomerization under further irradiation to give a mixture of 0

0

@;; \

0

(190) 0 (191)

0 (192)

( E ) - and (2)-isomers of the phthalide (193) in quantitative yield.155Photooxygenation of (190; R' = Me) in benzene, in an oxygen-rich environment, gave (194) (43%) and (195) ( 1 3 Y 0 ) . ' ~The ~ yield of (194) can be increased to 68% by using Rose Bengal as a photosensitizer. Irradiation of (190; R' = Me, Et, or Ph) in the presence of the allylic alcohols H,C=CHCR;OH (R2 = H or Me) in benzene gave the compounds (196; R' = Me, Et, or Ph; R2 = H or Me).157 A photopinacol reaction has been reported for (197) which, using light of wavelength 254 nm, gave (198) as the major product, in CH2C12.15* lS3 lS4 156 157

"*

E. G. Lewars and A. B. Young, Tetrahedron Lett., 1979,4799. H. Mastalerz and P. Morand, J. Org. Chem., 1981,46, 1206. K. Maruyama and A. Osuka, J. Org. Chem., 1980,45, 1898. K. Maruyama and H. Suzuki, J. Chem. Soc., Chem. Commun., 1980,723. K. Maruyama, A. Osuka, and H. Suzuki, Chem. Lett., 1980,919. D. Avnir and J. Blum, J. Heterocycl. Chem., 1980,17,1349.

28

Heterocyclic Chemistry

0

*

(193)

0

(194)

(195)

Irradiation of (199) at 347 nm, in pentane or CC1FZCFCl2,gave a mixture containing (E,Z)-(200),(201), and (E)-(202) through a proposed biradical intermediate that is obtained by simple homolytic fission of the C-C bond of xir ran.'^^ If the shorter wavelength of 254 nm was used, however, the exclusive product was (E)-(200). 0

(199)

(200)

(201)

(202)

The mercury-photosensitized decomposition of ethylene oxide in the gaseous phase proceeds through the biradical OCH2CH2, which rearranges and decomposes to H2, CO, C2H4,and a number of other minor products.160 Reactions of Oxirans with Organometallic Compounds.-Continued interest has been shown in the synthesis of cyclic carbonates (203; R', R2 = various alkyl substituents or H) by direct reaction of COz with oxirans. A microwave study of the insertion of CO, into trans- 1,2-dideuterioethene oxide revealed that retention of configuration occurred if NCCH2COZCuwas the catalyst whereas the catalytic effect of [ N ~ B T ~ ( P Pwas ~ ~non-stereospecific.'61 )~] Quinquevalent organo-antimony compounds, particularly Ph4SbBr and Ph3SbBrz, are novel catalysts for the formation of the compounds (203; R' = H ; R2 = Me, Ph, H, or CH2C1).'62*163 Mixtures of Na, K, or Rb iodides with Mg, Al, Si, Ti, or Zr 160

16'

163

K. Murato, H. R. Wolf, and 0.Jeger, Helu. Chim. Actu, 1980, 63,2212. G. R. DeMare and 0. P. Strausz, Probl. Khim. Kinet., 1979, 38 (Chem. Abstr., 1980,93, 113 546). J . E. Baeckvall, 0. Karlsson, and S. 0. Ljunggren, Tetrahedron Lerr., 1980,21,4985. R. Nomura, A. Ninagawa, and H. Matsuda, J. Org. Chem., 1980,45, 3735. H. Matsuda, Jpn. Kokai Tokkyo Koho 80 122 776 (Chem. Abstr., 1981,94, 13 779).

Three-Membered Ring Systems

29

0

(203)

oxides have been found useful for the synthesis of (203; R1 = R2 = H),164as has an anion-exchange resin, Dowex XF-4155L.16' The normal methods for preparation of P-diketones involve the use of strongly acidic or basic conditionsfor the condensation reactions of carbonyl compounds. A new route for this synthesis has been disclosed which employs neutral conditions and aprotic solvents, using the Pdo-catalysed reactions of cup-epoxyketones.'66 The method consists of heating the epoxy-ketone at 80-140 "C in toluene that contains catalytic quantities of [Pd(PPh,),] and 1,2-bis(dipheny1phosphino)ethanein a sealed tube, under argon. Thus (205) (81o/o) may be obtained from (204), while cyclic diketones (of ring sizes 5 to 8 and 12) (52-94%) are produced from the corresponding cyclic ap-epoxy-ketones. The reactions of the epoxy diazomethyl ketones (206; R' = R2 = H, Me, or Ph; R3 = H or aryl) and (206; R1R2 = cycloalkyl, R3 = H) in R 4 0 H (R4 = Me or Et) gave the corresponding compounds (208) with either activated copper powder or CUSO~.'~'The mechanism for this transformation is thought to proceed via generation of a carbene intermediate, which reacts intramolecularly with the oxiran ring to give the intermediate (207). When (206; R' = H, R2 = Ph, R3 = H) was allowed to react with copper powder in refluxing ethanol for 3 hours, an 80% yield of (208; R4 = Et) was obtained.

The vinyl-oxiran (209), when treated with Fe(CO)', produces a mixture of isomeric tricarbonyliron-lactone complexes (210), from which the lactones (211) and (212) may be obtained on oxidation with (NH4),[Ce(NO3),]in MeCN.I6* 164

165 166

M. C. Annesini, S. Fumasoni, and F. Pochetti, Chim. Ind. (Milan), 1980, 62, 303 (Chem. Abstr., 1980,93, 149 753). D. A. Raines and 0. C. Ainsworth, U.S. P. 4 233 211 (Chem. Absn., 1981, 94, 83 630). M. Suzuki, A . Watanabe, and R. Noyori, J. A m . Chem. SOC.,1980,102,2095. L. Thijs and B. Zwanenburg, Tetrahedron, 1980, 36, 2145. G. D. Annis, S. V. Steven, C. R. Self. and R. Sivararnakrishnan,J. Chern. SOC.,Perkin Trans. 1, 1981,270.

30

Heterocyclic Chemistry

Miscellaneous Reactions of 0xirans.-The rate of eliminative ring-cleavage of (213; R = SO,Et, n = 1)to form (214; R = S0,Et) in EtONa-EtOH is 2.5 x lo6 times faster than the elimination of methoxide ion from the acyclic model compound (215).169This difference has been accounted for in terms of strain in the oxiran ring. Elimination in the relatively unstrained compound (213; R = SO,Et, n = 3) proceeds at only 20 times the rate of that of (215). A Hammett p value of +2.14 was obtained for the conversion of (213; R = variously substituted phenyl, n = 1) into the corresponding ally1 alcohols (214) when using Bu'OK in Bu'OH, indicating that a carbanion develops at the benzilic carbon during the r e a ~ t i 0 n . l ~ '

rZLR

(CH,)"

OMe ).,,SO,Et

HO-R

(213)

(214)

(215)

A synthesis of unsaturated aldehydes from polyene epoxides has been reporConversion of (216), prepared from p-ionone, into (217) was achieved on treatment of the epoxide with MgBr2 in E t 2 0 ;no halohydrins were produced.

(217)

(216)

An interesting, 176-eliminationreaction has been utilized in the synthesis of a human metabolite of ibuprofen.'72 Treatment of the epoxy-acid (218) with Bu'OK, followed by acidic work-up, gave (220), probably by a mechanism involving the intermediate (219) (Scheme 12).

Scheme 12

3 Oxirens A chemical probe has been used to provide evidence for the intermediacy of

oxiren in some ~ e a c t i 0 n s .The l ~ ~method involves establishing an oxiren-oxocar169

I7O

17'

173

R. J . Palmer and C. J. M. Stirling, J. Am. Chem. SOC.,1980, 102, 7888. M. Hassan, A. R. 0. Abdel Nour, A. M. Matti, and I. A. Wakeel, Libyan J. Sci., A, 1979, 9, 49 (Chem. Abstr., 1980,93, 113 470). M. Rosenberger, W. Jackson, and G. Saucy, Helv. Chim. Acta, 1980,63, 1665. R. R. Kurtz and D. J. Houser, J. Org. Chem., 1981, 46, 202. R . A. Cormier, Tetrahrdron L p t t . , 1980, 21, 2021.

Three-Membered Ring Systems

31

bene equilibrium in which the oxiren species possesses different alkyl substituents; such a system appears in Scheme 13. Entry to a particular part of this equilibrium is achieved by the reactions shown, and the distributions of products from each reaction provide firm evidence for the equilibrium, and thus for an oxiren as an intermediate.

t

t i

Reagents: i, hu; ii, 3-C1C,H4CO,H

ii

t i

Scheme 13

The stability and rearrangement of oxirens are of continued theoretical intere~t.'~~"~~

4 Aziridines Preparation.-Direct Insertion. The oxidation of alkoxylamines with Pb(OAc), is a source of nitrenes, and when the reaction is carried out in the presence of a carbon-carbon double-bond the product is an N-alkoxy-aziridine (Scheme 14). Thus (223; R' = Me, R2 = H, R3 = OMe) was produced from the reaction R2 .

R'0NH2

+

(221)

HR3 v

(222)

R

R2 3

OR' (223)

Reagents: i, Pb(OAc),, CH,CI,

Scheme 14

of methoxylamine with Pb(OAc), at -45 "C in CH2C12that contained the vinyl ether (222; R2 = H, R3 = OMe).176An ally1 oxynitrene is produced from (221; R' = H2C=CHCH2) and Pb(OAc), which, with the butenes (222; R2 = Me, R3 = H or Me), gave the corresponding aziridines (223).'77 Me2&=S0 SbCI6

M e , & l SbCI,

(224)

(225)

N-Alkylation of MeN=SO with Me30' SbCli gave (224), which, on treatment with diazomethane, gave the aziridinium salt (225) (19'/0).~~~ 174

K. Tanaka and M. Yoshimine, J. Am. Chem. SOC.,1980,102,7655.

176

Yu. P. Artsybasheva and B. V. Ioffe, Zh. Org. Khim, 1981, 17,436 (Chem. Abstr., 1981, 94,

'71

Yu. P. Artsybasheva, I. V. Suvorova, and B. V. Ioffe, Zh. Org. Khim., 1981, 17,435 (Chem. Abstr., 1981,94,208 079). G . Kresze and M. Roessert, Liebigs Ann. Chem., 1981,58.

"' H.Meier and H. Kolshorn, 2. Nuturforsch., Teil. 8, 1980,35,1040. 192 016).

32

Heterocyclic Chemistry

Preparation of Aziridines by Cyclization. A facile, one-pot, reaction for the direct imination of chalcones involves the generation of the aminimide (226) from 1 , l-dimethylhydrazine and propene oxide and its subsequent reaction with a chalcone to yield (227; Ar' = Ph, Ar2 = Ph), (227; Ar' = Ph, Ar2 = 4-C1C6H4),(227; Ar' = 4-NO&H4, Ar2 = Ph), and (227; Ar' = 2-C1C6H4, Ar2 = Ph) (67-89'/0).~'~ A new route to lH-aziridines is provided by the attack of 2,4,6-Me3C6HzSo3NH2on electrophilic alkenes, e.g. (228), via Michael attack to give an intermediate which cyclizes, in the presence of Et3N, to give (229) (50'/0).'~~ H

OH

Me0,C

C0,Me

MeozcwcozMe C0,Me

(228)

--*

v C 0 , M e H (229)

Two routes to 9,lO-iminophenanthrene (230) have been described. A new synthesis, involving the treatment of phenanthrene with BrN3 followed by LiAlH4, gives (230) (30'/0).'~'An improved synthesis of arene imines involves the cyclization of the corresponding trans-azido-alcohol with (EtO),P in CH2C12; this procedure gave a quantitative yield of (230).18'

A stereospecific synthesis of N-substituted cis-2-phenyl-3-alkyl-aziridines (233; R1 = Me, Et, Pr', But, Ph, or 3-MeC6H,) ( 6 1 4 4 % ) from the phenyl ketone (231) has been ~ e p 0 r t e d .The l ~ ~ method involves the conversion of (231) into its a,a-dichloroalkyl phenyl ketimine (232) followed by its reduction by LiAlH4 in ether.

(234)

(235)

"'I. Ikeda, Y. Machii, and M. Okahara, Synthesis, 1980, 650. P. Metra and J. Hamelin, J. Chem. Soc., Chem. Commun., 1980, 1038. "' J. N. Denis and A. Krief, Tetrahedron, 1979, 35,2901. '*'

lS3

M. Weitzberg, 2. Aizenshtat, P. Jerushalmy, and J. Blum, J. Org. Chem., 1980, 45,4252. N. DeKimpe, R. Verhe, L. DeBuyck, and N. Schamp, J. Org. Chem., 1980,45,5319.

Three-Membered Ring Systems

33

A new method has been described for the preparation of N-substituted a-ethylenic aziridines (235; R' = various alkyl, R2 = H or Me, R3 = various alkyl) by the reaction of the allyl-lithium compound Li(MeCC1CH=CH2) with aldimines and ketimines R1R2C=NR3 at -90°C to give (234), which formed (235) on warming to room temperature.lS4 Preparation of Aziridines via Ring-Contraction. The Dewar-pyrroles (236; X = NR) may be synthesized from the Dewar-thiophen (236; X = S) through photochemical denitrogenation of the 1,3-dipolar azide adduct (237 ; R = Ph, cyclohexyl, But, or H) followed by desulphurization with Ph3P.'85

(238)

(237)

Photolysis of the ozonides of a number of N-substituted h i d e s of diphenylmaleic acid (238; R = H, Me, Pr', or CH2CH2Ph) at 77 K led to benzoic anhydride together with the corresponding aziridine-2,3-dione (239).'86 The unstable dione was identified by its low-temperature i.r. spectra, and it was probably formed uia a biradical intermediate. Chiral Aziridines.-The Michael addition of free sulphimides to unsaturated carbonyl compounds affords a one-step synthesis of aziridines. Optically active aziridines are obtainable by using this technique; thus benzalacetophenone reacts with (+)-(R)-(240) to afford (-)-(241) with 30% optical purity and of relative configuration 2R,3S.lS7The use of (-)-(S)-(240) gave (+)-(241) with 25% optical purity. Ph

N \\7.-COPh

Reactions of Aziridines.-ThermaI. The ease with which the vinyl-aziridines (242; R = aromatic heterocycle) thermally rearrange depends strongly on the nature (electron-deficient or -rich) of the heterocycle;lg8 (242; R = 4-pyridyl) was converted into (243) (90%) in refluxing xylene whereas (242; R = 4-isothiazolyl) yielded the corresponding isothiazolo-azepine (60%)in THF at 25 "C. Thermolysis of (244; R = Me) gave (245) (50%); the reaction of (244; R = Et), however, gave only 10% of the corresponding compound (245; R = Et).'89 184

lS5 186

'sI lS9

B. Mauze, J. Organomet. Chem., 1980,202,233. Y. Kobayashi, A. Ando, K. Kawada, and I. Kumadaki, J. Org. Chem., 1980,45,2966. H.Aoyama, M. Sakamoto, and Y. Omote, J. A m . Chem. SOC.,1980,102,6902. N.Furukawa, T. Yoshimura, M. Ohtsu, T. Akasaka, and S. Oae, Tetrahedron, 1980,36,73. H. P. Figeys and R. Jammar, Tetrahedron Lett., 1980,21,2995. G. K. Bezpal'ko, V. V. Miroshnichenko, A. P. Marchenko, and A. M. Pinchuk, Zh. Obshch. Khim., 1980,50,956(Chem. Abstr., 1980,93,95345).

34

Heterocyclic Chemistry H

1-

I-

(244)

1(245)

Ring-opening of Aziridines to Acyclic Compounds. Hydrogen fluoride, when dissolved in pyridine, combines regiospecifically with aziridines (246; R', R2 = Me, Et, or Ph; R3 = H) to give the 2-fluoro-amines (247) in good yields.'" The attack by fluorine is in all cases completely directed to the most substituted carbon atom of the aziridine ring or to the benzilic carbon (when either R' or R2 is Ph). The advantages of this preparation of fluoro-amines are the ease of handling of the HFapyridine reagent (simple polythene or Teflon flasks) and the high regioselectivity that is achieved. The limitation is that both cis- and trunsaziridines afford the same fluoro-amines; thus cis- and trans-(246; R' = Me, R2 = Ph, R3 = H) give a mixture that contains 70% threo- and 10% erythroPhCHFCH(NH,)Me. Yields and selectivity for this fluorination have been improved by reducing the acidity of Olah's reagent (HFapyridine) by the addition of Et3N and by using the aziridine after it has been activated by N-benzoylation.19' In this way, the fluorination of 2-methylaziridine could be modified to yield (247; R' = H, R2 = Me, R3 = Bz) (85%), compared with the mixture of (247; R' = H, R2 = Me, R3 = H) (65%) and (247; R' = Me, R2 = H, R3 = H) (35%) that is obtained directly with Olah's reagent. Treating the (R)and (S)-benzylaziridines (246; R' = PhCH2,R2 = R3 = H)and (*)-(246; R' = 4-C1C6H4CH2,R2 = R3 = H) with a mixture of H F and KF in pyridine gave the corresponding amphetamine (247) (-50%) that was monofluorinated in the ~ i d e - c h a i n . ' ~ ~

R' N

R3

(246)

(247)

The acetolysis of variously substituted N-(ethoxycarbony1)aziridines (248) in cyclohexane to yield the corresponding N-(2-acetoxyalkyl)carbamates (249) has been shown to follow an A-2 mechanism, where the rate is first-order in aziridine and second-order in acetic acid (Scheme 15).lg3 A convenient synthesis of a -amino-ketones has been reported in which aziridinones (250; R', R2 = 1-adamantyl, But) are allowed to react with I9O 191 '91

T. N. Wade, J. Org. Chern., 1980,45, 5328. G . Alvernhe, S. Lacombe, and A. Laurent, Tetrahedron Lett., 1980,21,289. R. T. Coults, A. Benderly, and A. L. C. Mak, J. Flaorine Chem., 1980,16, 277. H. Takeuchi and K.Koyama, J. Chem. Soc., Perkin Trans. 2, 1981, 121.

Three-Membered Ring Systems

35

AcOH - M M + K

slow

L

fast

N

I

'OAc

N

H

C0,Et

___+

/ \

C0,Et

(248)

HN OAc I C0,Et (249)

Scheme 15

organolithium species (251; R3 = CH2Li) at -78°C for 4 hours, followed by quenching by MeOH, to give [251; R3 = CH=C(OH)CHR'NHR2] (66-72%); these can be hydrolytically cleaved in acid to give a-amino-ketones (252) (60-90 '/o ).194 I R

A new type of lipophilic host oligomer H[CH2CH2N(CONHPh)],H has been prepared by ring-opening oligomerization of 1-(N-phenyl~arbamoyl)aziridine.'~~ This material was found to transport adenine, amino-acids, and simple amine derivatives efficiently through artificial membranes. It behaved similarly to dibenzo-18-crown-6 except that a high specificity was demonstrated towards aromatic amines. Formation of Other Ring Systems from Aziridines. The pyrroles (253) and (254) are obtained from (246; R' = Ph; R2 = CN; R3 = cyclohexyl, PhCH2, Pr', or But) when heated with acetylenes R 4 C ~ C R(R4 5 = C02Me, H, or Ph; R5 = C02Me, Ph, or CN).196A one-step synthesis of the pyrrolidones (255; R4 = various alkyl or aryl, R5 = various alkyl or aryl) involves the smooth reaction of R4R5C=C(OR6)ONa (R6 = Me or Et) with the N-acyl-aziridines (246; R' = R2 = H; R3 = C02Et, CONPh2, COPh, or CONEt2).19' Pyrrolinones (256) are obtained when LiC-CMe reacts with (250; R', R2 = But, 1-adamantyl) in THF, at room temperature, under nitrogen. 19'

phR04 D4

R

Ph N R3 (253)

~

'

c & 5

R3 (254)

H

R2

(255)

(256)

The keten S,N-acetal (257; R' = CN, R2 = PhCO) reacts readily with an excess of aziridine to yield the vinyl-aziridine (258) (87%); this, with KI in acetone, rearranges to the imidazolidine (259) (82'/0).'~~The iodide- (or bromide-)catalysed rearrangements of (260; R = H, alkyl, or aryl) to (261) 194

'91 196

'91 198

199

E. R. Talaty, K. C. Bengtsson, and L. M. Pankow, Synth. Commun., 1980,10,99. K. Maruyama, H. Tsukube, and T. Araki, J. Chem. Soc., Chem. Commun., 1980,1222. B. Merah and F. Texier, Bull. SOC.Chim. Fr., Part2, 1980, 552. H. Stamm, A . Woderer, and W. Wiesert, Chem. Ber., 1981, 114, 3 2 . E. R. Talaty, A . R. Clague, M. 0. Agho, M. N. Deshpande, P. M. Courtney, D. H. Burger. and E. F. Roberts, J. Chem. SOC.,Chem. Commun., 1980,889. W. D. Rudorf, Tetrahedron, 1980,36, 1791.

36

Heterocyclic Chemistry

proceed quantitatively.200This forms the last step in a mild, general method for preparation of oxazolines, starting from the conversion of a wide range of carboxylic acids into their acyl-imidazoles, with subsequent addition of aziridine, to give quantitative yields of the corresponding N-acyl-aziridines (260).

R'R,C=C

/

NHPh

\

SMe (257) PhCH, PhCH,

cf

b N

COR

R

Ph

CH,Ph

i,""j ' N

N

PhCH,

'CH,Ph

(262)

A remarkable electrochemical synthesis of the cyclic tetramer (262) from the anodic oxidation of N-benzylaziridine (246; R' = R2 = H, R3 = CH2Ph) has been reported.201The cell consisted of a platinum anode and a graphite cathode, using Bun4" C104 in MeOH, CH2C12,or MeCN as the electrolyte; yields of up to 80% have been reported, with low consumption of electricity. 5 Azirines

Preparation.-Slow addition of the chloro-enamines (263; R' = H, R2 = alkyl or phenyl, R3 = Me, R4 = Ph), in CC14, to NaN,, in dry MeCN, gave the corresponding amino-azirines (264) (71-74'/0).~'~ Using (263; R' = C02Me, R2 = Me or Ph, R3 = R4 = Me), the product was the corresponding triazole (265); on photolysis, these gave the corresponding compounds (264).203

R=c"'

NR3R4

~2

(263)

-

R'

NO"N

R2*NR3R4 N

(264)

-p

R2

N Me 2

C0,Me (265)

The first reported stereospecific synthesis of 2H-azirine (268) (81%) from the modified Neber reaction of the oxime carbamate (E)-(266) with KMn04 or 3-C1C6H4CO3His thought to proceed as shown (Scheme 16).,04 Initial oxidation of sulphur increased the acidity of the methine proton, allowing cyclization to occur via the intermediate (267). The (2)-isomer only underwent oxidation of sulphur; it did not cyclize. G . S. BGtes and M. A. Varelas, Can. I. Chem., 1980,58,2562. R. Kossai, J. Simonet, and G. Dauphin, Tetrahedron Left., 1980,21, 3575. 'O' M. Henriet, M. Hourtekie, B. Techy, R. Touillaux, and L. Ghosez, Tetrahedron Lett., 1980,21,223. *03 C.Bernard and L. Ghosez, J. Chen. Sac., Chem. Commun., 1980,940. '04 H.G. Corkins, L. Storace, and E. Osgood, J. Org. Chem., 1980,45, 3156. 'O0

Three-Membered Ring Systems

37

MeNHCO,,

MeNHC0,H

+

SMe But

SMe

MeSO,

(266)

(267) Scheme 16

The cycloaddition of benzocylopropene to ArCNO (Ar = 2,4,6-Me,C6H2) gave (269) (27Y0).~" Thermolysis of (269) at 130--135"C, in Me2S0, gave the spiro-azirine (270). 4-MeOC6H4

@;

---*

pi

bMe

4-MeOC6H4

0

N

(271)

(269)

0 (270)

The structure of (271) has been determined by X-ray analysis, and it shows a lop-sided structure for the azirine ring, in which the C-N bond is unusually long.206The length of this bond probably explains the preferential fission of the C-N bond during the thermal reactions of 2H-azirines.

(272)

(273)

The photolysis of 1-azidonaphthalene at 12 K by U.V. light, in an argon or nitrogen matrix, resulted in the formation of the didehydrobenzazepines (272) and (273).207Infrared examination revealed the presence of tricyclic azirine intermediates. Similar reactions were established in the photolysis of 2-azidonaphthalene. R', R3,R4 = Me) undergoes cycloReactions of Azirines.-The azirine (264; R1, addition reactions with allenes and ketens; thus, on reaction with (274), the pyrroline isomers (275) (88%) were formed.'" A more complex product mixture is obtained with the keten (276), consisting of the isomeric compounds (277) (25%), (278) (8%), and benzazepine (279) (14'/0).~'~ These reactions appear to involve cleavage of the 1,2-bond of the azirine precursor and subsequent ring-closure. 205 *06

207 208

M. Nitta. S. Sogo, and T. Nakayama, Chem. Lett., 1979, 1431. N. Kanehisa, N. Yasuoka, N. Kasai, K. Isomura, and H. Taniguchi, J. Chem. SOC.,Chem. Commun,, 1980, 98. I. R. Dunkin and P. C. P. Thornson, J. Chem. SOC.,Chem. Commun., 1980,499. E. Schaumann and H. Mrotzek, Tetrahedron, 1979,35, 1965. E. Schaumann, S. Grabley, M. Henriet, L. Ghosez, R. Touillaux, J. P. Declercq, G. Germain, and M.Van Meerssche, J. Org. Chem., 1980, 45, 2951.

38

Heterocyclic Chemistry

\

FN

/c=c=c

\

Bu' NC

But

(274)

CN

A number of reactions of 2,2-dimethyl-3-phenylazirine(280) are shown in Scheme 17. Carbanions derived from ketones or nitriles give pyrroles; thus acetophenone anion yields (281) (75O/0).~'' The Reformatskii reaction of abromo-esters with azirines give diastereoisomeric addition products, e.g. (282; R' = H, R2 = Me), which, with Olah's reagent, cyclize to amino-lactones, e.g. (283; R' = H, R2 = Me).211With hydroxamic acids RCONHOH (R = Ph or 4-MeOC6H4), good yields of dioxazoles (284) (75%) are obtained.212 The imidazoles (285; R = Me, X = 0) (56%) and (285; R = Me2CH, X = S)

N

Reagents: i, PhCOMe, NaH, DMSO; i i , / \ C o , E t , Zn; iii, HF, pyridine; iv, RCONHOH; v, NH,CO,Et, MeOH for (285; R = M e , X = 0);vi, NH,SCN, Pr'OH for (285 ; R = Pr', X = S)

Scheme 17

*" 212

A . Laurent, P. Mison, A. Nafti, and N. Pellissier, Tetrahedron, 1979, 35, 2285. G . Alvernhe, S. Lacombe, A. Laurent, and B. Marquet, J. Chem. Res. (S), 1980, 54. A. V. Eremeev, R. S. El'kinson, E. Liepins, and V. Imuns, Khim. Geterotsikl. Soedin., 1981, 124 (Chem. Abstr., 1981, 94, 192 237).

Three-Membered Ring Systems

39

(74%) were obtained on treating (280) with NH2C02Et in MeOH and with NH2SCN in Pr'OH, re~pectively.~'~ Just as the addition of HF, in pyridine, to aziridines affords a useful synthesis of p-flu~ro-amines,'~~ so the same reagent reacts with the azirines (286; R' = Ph, R2 = H), (286; R' = Ph, R2 = C02Me), (286; R' = Me, R2 = C02Et), (286; R' = C8H17,R2 = H), (286; R' = R2 = Pr), and [286; R'R2 = (CH,),] to provide a synthesis of P,P-difluoro-amines and esters of P,P-difluoroa-amino-acids (287) (32-67'/0).''~ In the particular case of (286; R' = Ph, R2 = Me), the major product of the reaction was the pyrazine (288) (54%).

A remarkable Pdo-catalysed carbonylation of azirines has been rep~rted."~ When CO was bubbled through a benzene solution of (289; Ar = 4-MeC6H4), in the presence of catalytic amounts of [(PPh,),Pd], for 1 day, at 40°C, the bicyclic lactam (290) (50%) was obtained; its structure has been determined by X-ray analysis. Ar

The intermediary formation of enamines (293) in the course of cyclization of the vinyl-nitrene that is generated from the thermolysis of (291) to the fused pyridine (294) showed that the cyclization did not occur via an insertion reaction.216The key intermediate in the process is thought to be the imine (292), formed by [1,6] hydride shift to the first-formed vinyl-nitrene.

213

214

216

A. V. Eremeev, R. S. El'kinson, E. Liepins, and V. Imuns, Khim. Geterotsikl. Soedin., 1980, 1624 (Chem. Abstr., 1981,94, 156 823). T. N. Wade and R. Kheribet, J. Org. Chem., 1980,45, 5333, H. Alper, C. P. Perera, and F. R. Ahmed, J. Am. Chem. SOC.,1981.103, 1289. K. Isomura, S. Noguchi, M. Saruwatari, S. Hatano and H. Taniguchi, Tetrahedron Lett., 1980, 21, 3879.

Heterocyclic Chemistry

40

Theoretical calculations concerning the stabilities of the azirinyl and diazirinyl cation appear to suggest that the experimentally unknown azirinyl cation could be stable in non-nucleophilic media.,"

6 Thiirans

Preparation.-Photocycloelimination provides a preparative route to (296) through the photolysis of (295).,18 Thiirans may be generated from (297; R' = H or Ph, R' = H or Me, R3 = various alkyl or aryl) by treatment with Me1 and MeN02, followed by EtOH-NaOEt, to give (298) (40-92'/0).'~~ NMe

The reaction of diphenyldiazomethane (Ph2CN2) with ArS0,NCS (Ar = 4-MeC6H4 or 4-C1C6H4) proceeds readily at O"c, with the evolution of nitrogen.''0 The product thiirans (299) were isolated (67-70%) by simply cooling the solution to -30 "C. Because the reaction conditions are so mild, the possibility of a carbene intermediate was discounted in favour of a 1,3-dipolar cycloaddition reaction to form unstable 1,2,3-thiadiazolinimines, which subsequently decompose. The thiiran 1,l-dioxide (301) was formed by the reaction of Bu'CHN, with SO, via zwitterionic addition of the diazoalkane to the sulphene intermediate (300).,,l The thiadiazole (302) was also formed in this reaction.

With the greater commercial availability of oxirans and the wide range of methods for their synthesis, it is not surprising that a prime source of thiirans should be via the conversion of these materials. A new development in this field has been the use of KSCN, supported on silica gel, as a catalyst for this reaction."' When 1,2-epoxydecene is heated at 90 "C, in toluene, for 16 hours, in the presence of powdered KSCN, no thiiran is formed. In contrast, a similar reaction, when carried out with KSCN that had been crushed together with silica gel, gave a 95% yield of thiiran. The method has been used successfully for a range of epoxides, the reaction times being between 13 hours and 22 days. Direct addition of sulphur to carbon-carbon double-bonds may be achieved photolytically, so that (303) could be prepared under mild conditions from 217

'19 220

221 222

K.Krogh-Jerpersen, Tetrahedron Lett., 1980,21,4553. H. Quast and A. Fuss, Angew. Chem., 1981,93,293. D . Hoppe and R. Follmann, Liebigs Ann. Chem., 1980,1779. G.L'abbi, J.-P.Dekerk, C. Martens, and S. Toppet, J. Org. Chem., 1980,45,4366. H.Quast and F. Kees, Chem. Ber., 1981,114,787. M. 0. Brimeyer, A. Mehrota, S. Quici, A. Nigam, and S. L. Regen, J. Org. Chem., 1980,45,4254.

Three-Membered Ring Systems

41

sulphur and the parent sesquiterpene by the action of U.V. light.223Sulphur with ethene, irradiated by a KrF laser, gave a gas mixture that contained 0.3% of thiiran .224

- {&] *& CI

CI

--*

(304)

(305)

(306)

The reaction of (304) with 1.25 molar equivalents of SC12 for 5 minutes, at 25'C, in chloroformal, gave (306; R = H) (80°/~).225 In CH2C12,at O'C, for 80 minutes, the product was (306; R = Cl) (quantitative yield). The difference in the reactions was ascribed to the fate of the addition compound (305), which could decompose with loss of Cl-, to give (305; R = H), or with loss of HCl, to give ring-chlorinated products. Reactions of Thiirans.-Unsaturated thiirans underwent halogenation with halogens, SCl,, and SOCl, to give halogeno-sulphides in good yields; in the case of (307) with 0.5 mole of bromine, the disulphide (308) (95%)was isolated.z26 Further reaction with bromine gave (309). An intramolecular disulphide link is created in some cases; thus (307) with SC12, in CH2C12,at -5O'C, gave (310) (42'/o ).

The ring-opening of terminal thiirans with acid chlorides RCOCl (R = Me or CH2CHMe2)proceeded with predominant attack of C1- on the secondary carbon to yield S-[ 1-(chloromethyl)alkyl]t h i o e ~ t e r s . ~ ~ ' * ~ ~ ~ A detailed kinetic analysis of the acid-catalysed hydrolyses of a number of episulphoxides (311; R = H, Me, or Ph) in aqueous mineral acid has revealed that the reaction occurs by concurrent A-2 and nucleophile-assisted 223 224

225

226

227

228 229

T. L. Peppard, F. R. Sharpe, and J. A. Elvidge, J. Chem. SOC.,Perkin Trans. 1, 1980,311. C.T. Ratcliffe and J. T. Yardley, U.S. P. 4 233 131 (Chem. Abstr., 1981,94,121 294). G.A. Tolstikov, B. M. Lerman, L. I. Umanskaya, Yu. T. Struchkov, A. A. Espenbetov, and A. L. Yanovskii, Tetrahedron Lett., 1980,21,4189. P. H. McCabe and A. Stewart, J. Chem. SOC.,Chem. Commun., 1980,100. K. Byashimov, Z. N. Nudel'man, A. M. Kuliev, and A. S. Shashkov, Izv. Akad. Nauk Turkm. SSR,Ser. Fiz-Tekh., Khim. Geol. Nauk, 1980,116 (Chem. Abstr., 1981,94,30 149). Y.Taguchi and Y. Suhara, Yukagaku, 1980,29,912(Chem. Abstr., 1981,94,174260). A.Saleh and J. G. Tillett, J. Chem. SOC.,Perkin Trans. 2, 1981,132.

42

Heterocyclic Chemistry

Hydrolysis of (311; R = Pr' or But) in H2SO4 occurred by an A-2 mechanism, but in concentrated HClO, their rate profiles passed through a maximum; with a changeover from an A-2 to an A-1 mechanism. cis-Stilbene episulphoxide (312) underwent stereospecific desulphuration with BuLi at 0 ° C in Et20, followed by quenching with MeI, to give (313) (41%) together with Bu2S (41%) and (E)-(314) ( 3 1 Y 0 ) .The ~ ~ ~episulphide of trunsstilbene gave truns-stilbene (97%) together with Bu2S (95%) and a mixture of (2)-and (E)-(314). The desulphuration reactions involved oxysulphurane derivatives (315), the stereochemistry of the phenyl groups being the same as in the episulphoxide precursors.

I1

(313)

0 (312)

II

0 (314)

phvph ; ;. OL' .- .

Bu (315)

Ion cyclotron resonance spectrometry has revealed the kinetics and mechanism for the sulphur-transfer reaction between the molecular ion of thiiran (C2H4S') and a neutral thiiran molecule, to yield C2H4S2+and ethene.231

The Chemistry of Thiiranium Ions.-A method of preparation of the stable thiiranium salts (316; R' = R2 = R5 = Me, R3 = R4 = H), (316; R' = R2 = R3 = Me, R4 = H, R5 = Ph), and (316; R' = R2 = R3 = R4 = R5 = Me) involves treatment of the corresponding sulphide R'R2C(SR')CC1R3R4 with AlC1, in either CD3N02or CD3N02plus CD2C12.232

Ph (319)

The cis-decalin (319) has been prepared via (318) from (317), by reaction with AgC104 in MeN02.233Proton n.m.r. studies have shown that the reactions of the stable ions [320; X = 2,4,6-(N02)3C6H2S03,BF4, or SF6] with various 230

231 232

233

B. F. Bonini, G. Maccagnani, G. Mazzanti, and P. Piccinelli, Tetrahedron Lett., 1979, 3987. G. Baycut, K. P. Wanczek, and H. Hartmann, Adv. Muss Spectrom., Sect. A, 1980,8, 186. E. Akguen, K. Hartke, and T. Kaempchen, Arch. Phurm. (Weinheim, Ger.), 1981,314,72 (Chem. Abstr., 1981, 94, 192 019). W. A. J. DeLoos, A. J. W. Van den Berg-Van Kuijk, H. M. Van Iersel, J. W. De Haan, and H. M. Buck, R e d . Trau. Chim. Pays-Bas,1980,99, 53.

Three-Membered Ring Systems

43

nucleophiles were found to proceed mainly by attack at the carbon atom of the thiiranium ring.234The counter-ion had no effect on the reaction. 7 Thiirens

The preparation and characterization of matrix-isolated thiiren (322; R = H) have been Three pieces of evidence for the existence of thiiren were used. First, the same labelled C2H2Sspecies was formed from the irradiation of the thiadiazoles (321; R = H) that carry a specific 13C label at either of the carbon atoms. Secondly, photoisomerization of the labelled C2H2Sspecies resulted in the formation of HC=CSH and H2C=C=S, each with randomized label, and thirdly, the i.r. spectrum of thiiren was consistent with a cyclopropenol species. An ab initio SCF study of the structure and i.r. spectrum of (322; R = H) indicates an unusually long C-S bond (1.9782 A) and a short C=C bond (1.2509 The calculated i.r. bands are higher than those obtained experimentally, but the v(C-H) and v(C=C) frequencies appear in the correct order, with appropriate relative intensities and symmetry.

Isotopically labelled (321; R = Ph) with 13C at either carbon atom in the heterocyclic ring undergoes photolysis in MeOH, or thermolysis, to yield (323) and the dithiols ( E ) - and (2)-(324).237 Carbon-13 n.m.r. of these products indicates that an intermediate thiiren (322; R = Ph) is formed to a considerable degree during photolysis and almost exclusively in the thermolysis reactions. The thiiren dioxide (325) undergoes reaction with potassium fluoride and 18-crown-6, in MeCN, at 25 "C, to yield diphenylacetylene (35%) and (326) (23%) via initial nucleophilic attack at the sulphur atom of (325).238 Nucleophilic attack by PhSK on (325), in DMF, at 25"C, however, was at a carbon atom in the ring and, after addition of MeI, the final product was (327). Azide ion also attacked at a carbon atom in the ring but gave a variety of products.

Ph Ph

w S

n

Ph

Ph

PhMso2Me Ph

PhS

Diazoalkanes add to (325) to give intermediate cyclo-adducts (328; R' = H; R2 = H, Me, or CH20Me)or (328; R' = R2 = Me), which subsequently decompose.239In the case of (328; R' = R2 = H), the dihydropyrazole (329) is formed. 234

A. S. Gybin, V. A. Smit, M. Z. Krimer, N. S. Zefirov, L. A. Novgorodtseva, and N. K. Sadovaya,

Tetrahedron, 1980,36,1361. 235

236

237 238 239

A. Krantz and J. Laureni, J. A m . Chem. SOC.,1981,103,486. B. A. Hess, Jr., L. J. Schaad, and C. S. Ewig, J. A m . Chem. SOC.,1980,102,2507. U.Timm, U. Merkle, and H. Meier, Chem. Ber., 1980, 113,2519.

B. B.Jarvis and G. P. Stahly, J. Org. Chem., 1980,45,2604. M.Regitz and B. Mathieu, Chem. Ber., 1980, 113,1632.

44

Heterocyclic Chemistry S PhC =N,

Ph N

8 Diaziridines Heating (330; R' = H or OMe; R2 = H, Me, or morpholinoethyl; R3 = aryl) in acid causes ring-contraction to form (332) via (331).240

0

0

(330)

(331)

(332)

Pyrazolidinone derivatives (333; R' = aryl, R2 = Me or Ph, R3 = H or Me) undergo photoreversible conversion into the corresponding diaziridines (334); the difference in A,, between the two forms is 100 nm.241

+p: 4-MeC6H4S0, I (335)

R2NqNso2C6H,Me-4 0 (336)

R [

C1

H

~

-:z

~

]

(338)

Cyclization reactions occurred between (335; R' = Me, Et, or Pr') and R2NC0 (R2 = Ph or PhCO) at 90 "C, under nitrogen, to give the respective compounds (336) (43--85'/0).~~~In the low-temperature reaction of RC(NH2)=NH (R = Ph or 4-pyridyl) with NaOC1, (337) was isolated as an intermediate in the formation of (338).243 9 Diazirines The preparation of (338; R = CD3)has been described, starting from CD3CN.244 This diazirine was needed for the investigation of the reaction of (338; R = Me) 240

24' 242

243 244

M. Flammang and C. G. Wermuth, C.R. Hebd. Seances Acad. Sci., Ser. C,1980,290, 361. G. Tomaschewski, G. Geissler, and G. Schauer, J. Prakt. Chem., 1980, 322, 623. L. S. Lehman, L. M. Baclawski, S. A. Harris, H. W. Heine, J. P. Springer, W. J. A. VandenHeuvel, and B. H. Arison, J. Org. Chem., 1981,46, 320. H. Berneth and S. Huenig, Chem. Ber., 1980, 113,2040. M. T. H. Liu, N. H. Chishti, C. D. Burkholder, W. E. Jones, and J. S. Wasson, J. Org. Chem., 1980,45,4515.

Three-Membered Ring Systems

45

with hydrogen This reaction, studied by mass spectrometry, gives HC1, MeCN, and several other chlorine-containing fragments, and it appears to be initiated by abstraction of H from the methyl group of (338; R = Me), providing further evidence for the apparent lack of reactivity of the diazirine ring. A theoretical approach to this reaction has also been attempted.246 Synthesized A new carbene-generating group (339) has been from 2,2,2-trifluoroacetophenonein 60% overall yield, this material is photolysed rapidly near 350 nm to yield the diazo-compound (340) (35%)and (341) (65%), the latter showing no internal rearrangement of the fluorine atoms. The reactivity of the carbene that was generated either directly or uia (340) is shown in Scheme 18. Photolysis in MeOH gives (342) (95%);in cyclohexane, Ph >N=N

3

Phxy

N F3C (339)

F3c

(340)

1

PhACF3 (341)

Ph

CF3

)/* Ph

U

(343)

Reagents: i, hv, MeOH; ii, hv, cyclohexane

Scheme 18

(343) (50%), i.e. the product from insertion into the C-H bond, was obtained, showing the high reactivity of the carbene species. In the dark, (339) is stable in 1M acid or base and at temperatures as high as 75 "Cfor at least 30 minutes. The use of (339) as a photolabelling species is possible through the synthesis of a derivative that contains the (4-MeC6H4S03CH2CH2) group on the phenyl ring.

It has been shown that irradiation of the diazirine (344) at 310 nm, in a range of solvents, gave the same products in the same ratio.248The main product was the stable diazo-isomer (345) (56%), together with smaller quantities of cyclopropane and alkene derivatives that are formed by intramolecular reaction of the carbene that was generated from (344). There were no intermolecular reactions with solvent for this system. The most significant finding was that (345) could be converted back into (344) by irradiation at 410nm, providing a wavelength-dependent reversible isomerization pathway. 24s

246 247 248

C. D. Burkholder, W. E. Jones, J. S. Wasson, and M. T. H. Liu, J. A m . Chem. Soc., 1980, 102, 2847. C. D. Burkholder, W. E. Jones, K. W. Ling, and J. S. Wasson, Theor. Chim. Actu, 1980,55, 325. J. Brunner, H. Senn, andF. M. Richards, J. Biol. Chem., 1980, 255, 3313. B. Erni and H. G . Khorana, J. A m . Chem. SOC.,1980,102, 3888.

46

Heterocyclic Chemistry

10 Oxaziridines A new class of oxaziridine derivatives (346; R', R2 = Ph, substituted Ph) have been prepared by the oxidation of the corresponding sulphonimines (R'S02N=CHR2) with 3 -C1C6H4C03H.249These compounds are the first stable examples of this ring system to have a substituent other than carbon attached at the nitrogen atom. The oxygen atom in the oxaziridine ring of (346) is highly electrophilic, and such compounds comprise a new class of aprotic oxidizing agents that are capable of selectively oxidizing sulphides and disulphides to sulphoxides and thiosulphinates without over-oxidation. Optically active (346) also provides the possibility of chiral oxidations.

R'

k P0 R 3

R2

(347)

Optically active oxaziridines that are stable at the nitrogen atom have been prepared by the oxidation of imines; thus (347; R' = R2 = Ph, R3 = CHMePh) (95"/0') was obtained from Ph2C=NCHMePh in 24.5% optical yield by reaction with 3-ClC6H4C03Hin the presence of (+)-(S)-F3CCH(OH)Ph.250 The reactions of (347; R'R2 = adamantylidene, R3 = Me), (347; R' = Ph, R2 = H, R3 = various alkyl, or cyclohexyl), and (347; R' = R2 = H, R3 = But) with nucleophilic reagents have been i n v e ~ t i g a t e d A . ~ number ~~ of conclusions were drawn: (i) the nucleophilic reactions for those of the compounds (347) that are without large steric hindrance occur preferentially at nitrogen, followed by fragmentation of the ring to form a carbonyl compound and an ylide; (ii) when bulky substituents are present, the site of reaction shifts from nitrogen to oxygen; (iii) cis-isomers react faster than trans-isomers; and (iv) the carbon atom of the ring is completely inert towards nucleophilic attack. Photoreactions of (348) at low temperatures give a matrix-stabilized oxaziridine intermediate (349),the reactivity of which has been studied (Scheme 19).252At 77 K, (349) was formed in both EtOH and 2-methyltetrahydrofuran (MTHF), but the dark reaction of this intermediate at temperatures that allow thermal reactions with solvent molecules gave (350) and (35 l), respectively. These results are in contrast with the further photoreaction of (349) at 77 K to give (352). A series of papers on the photolysis of oxaziridines has reached ten publications with a report of the thermo- and photo-chemistry of N-(ary1)spiro-oxaziridines, which form lactams r e g i o ~ e l e c t i v e l y . ~ ~ ~ 249

250

251 252

253

F. A. Davis, J. Lamendola, Jr., U. Nadir, E. W. Kluger, T. C. Sedergran, T. W. Panunto, R. Billmers, R. Jenkins, Jr., I. J. Turchi, W. H. Watson, J . S. Chen, and M . Kimura, J. A m . Chem. Soc., 1980,102, 2000. M. Bucciarelli, A. Forni, I. Moretti, and G. Torre, J. Chem. Snc., Perkin Trans. 1, 1980, 2152. Y. Hata and M. Watanabe, J. Org. Chem., 1981, 46, 610. K. Tokumura, H. Goto, H. Kashiwabara, C. Kaneko, and M. Itoh, J. A m . Chem. SOC., 1980, 102, 5643. E. Oliveros, M. Riviere, and A. Lattes, J. Heterocycl. Chem., 1980, 17, 1025.

47

Three-Membered Ring Systems

PIN 1

+

/

0

(349)

(352) Reagents: i, hv, at 77 K, EtOH or MTHF; ii, dark, EtOH, warm to a fluid solution; iii, dark, MTHF, warm to a fluid solution

Scheme 19

11 Other Ring Systems Thiadiaziridine 1,l-dioxides (354;R', RZ = alkyl, phenylalkyl, or 1-adamantyl) have been prepared by the sequential reactions of dialkyl-sulphamides (353) with NaH and B u ' O C ~ . ~ ~ ~ BU'

3

R'NHS02NHR2 + R'N-NR~ (353) (354)

N

/ \

"-N, Et02C

Bu'

The triaziridine (355) has been prepared by photolysis of the azimine that is produced in the reaction of Et0,CN: with (E)-PriN=NPri.255

J. W. Timberlake, J. Alender, A. W. Garner, M. L. Hodges, C. Ozmeral, S. Szilagyi, and J. 0. Jacobus, J. Org. Chem., 1981,46,2082. "' C. Leuenberger, L. Hoesch, and A. S. Dreiding, J. Chem. SOC.,Chem. Commun., 1980, 1197. 254

Four-Membered Ring Systems BY T. V. LEE

1 Highlights and Reviews The [2 + 21 cycloaddition of ketenimines has been reviewed.' Amongst the most notable advances this year was the demonstration of the involvement of a quinone monomethide monoimine in the formation of a benzazetidine,2the use of a chiral imine in azetidinone synthesis,' *,12 and a novel, transition-metalcatalysed conversion of an azirine into an a~etidinone.~' The parent unsubstituted oxet has now been synthesized for the first time" and some stable thiets have also been p~epared.'~ 2 Systems containing One Nitrogen Atom

Azetidines and Azetines.-In an analogous manner to benzocyclobutene chemistry, the sultam (1) has been found to extrude sulphur dioxide, upon heating, to form a benzazetidine (2). When this was done in the presence of trans-chloroacrylic acid, the product (3) was formed, so providing evidence for the intermediacy of a quinone monomethide monoimine (4).2

soz '

N

heat

@

'

NMe

\

Me (2)

(1)

acH

N Me

C1

(3)

'

NMe

(4)

Upon reaction with methyl propiolate, the unstable oxazine oxide (5) forms the adduct (6).3The azetidine is believed to arise by ring-opening of the [3 + 21 cyclo-adduct of the oxazine oxide. 0I

(E = C02Me)

' A. Dondini, Heterocycles, 1980,14, 1547. M. Lancaster and D . J. H. Smith, J. Chem. SOC.,Chem. Commun., 1980,471. M . L. M.Pennings and D. N. Rheinhoudt, Tetrahedron Lett., 1980,21,1781.

49

Heterocyclic Chemistry

50

Further examples of the preparation of functionalized azetidines from primary amines and a,y-dibromocarbonyl compounds have a ~ p e a r e dIt. ~has also been demonstrated that alkyl-lithium reagents react normally with 1-alkyl-azetidine2-carboxylic acids.' The unusual azetidine derivative (7) can be synthesized by allowing an N-(tosy1)ketenimine to react with a Schiff base. This method has been extended to the synthesis of analogues of p -1actam antibiotics.6 Me Ph Me,C=C=NTos

PhCH=NPh A

I Ph

TosN (7)

The new strained amidines (8) were prepared by the sequence shown in Scheme 1. As would be expected, these azetines are readily converted into azetidinones.'

i-iii

Me>CONMe, Me

M e -Me t L c Ph H1

Me,A

Reagents: i, COCl,; ii, PhCH=NCHPh,; iii, NaClO,; iv, H,, Pd/C; v, KOH, MeOH

Scheme 1

Azetidines are the product of irradiation of 2-sulphonamido-methanocyclohexenones' and of the reaction of azomethines and electron-deficient allenes.' Azetidinones.-This section includes only novel results on the preparation or reactions of the azetidinone nucleus. The chemistry of @ -1actam antibiotics is not included.* Cycloaddition reactions continue to be important in the synthesis of azetidinones. For example, in an elegant solution to solving the stereochemical requirements of thienamycin (9), the nitrone (10)is cyclized with methyl crotonate (see Scheme 2). Hydrogenation and protection of the hydroxyl group of the cyclo-adduct gave the amine (ll),which may readily be converted into the azetidinone." In a useful extension of previous work, the reaction of a silylated keten acetal and a chiral imine has been used in a synthesis of an asymmetric @-lactam,as shown in Scheme 3."," * For

this, see Volume 6 of the series of Specialist Periodical Reports on 'Organic Compounds of Sulphur, Selenium, and Tellurium',

lo

''

D. S. Soriano, K. F. Podraza, and N. H. Cromwell, 1.Heterocycl. Chem., 1980,17,1389. N. H.Cromwell, K. F. Podraza, and D. S. Soriano, J. Heterocycl. Chem., 1980,17, 1277. A . Van Camp, D. Goosens, M. M. Portuguez, J. Marchand-Brynaert, and L. Ghosez, Tetrahedron Lett., 1980,21,3081. J. Marchand-Brynaert, M. M. Portuguez, D. Lesuisse, and L. Ghosez, J. Chem. SOC., Chem. Commun., 1980,173 J. C. Arnould, J. Cossy, and J. P. Pete, Tetrahedron,1980,36, 1585. E.Schaumann and H. Mrotzek, Tetrahedron, 1979,35,1965. J. Tufariello and G. E. Lee, Tetrahedron Lett., 1979,4359. I. Ojima, and S. Inaba, Tetrahedron Lett., 1980, 21,2077. I. Ojima and S. Inaba, Tetrahedron Lett., 1980,21,2081.

51

Four-Membered Ring Systems H

TMSO

HH H ++(-J-;&!% Me

4 0-

1

E = C02Me, TMS = SiMe3

(10)

iii

TMSO M

e

<

.

b

0 Reagents: i, H,; ii, hexamethyldisilazane; iii, EtMgBr

Scheme 2

(S)-EtCH=NzHMePh

+

Me2C=C

/OMe

-

dHMeP

Et

e.e. = 54%

i

Me Me

\ OSiMe3 Reagents: i, TiCI,, CH,CI,, at -78 “C

Scheme 3

Other cycloaddition routes have included the reaction of thioketens and isocyanates to afford the 4-thioxo-2-azetidinone ~ y s t e m . ’The ~ reactions of methylketen and various imines give methylated p - l a ~ t a m s , ’and ~ a novel route to a -methylene-,!?-1actams involves the cycloaddition of the (phenylse1eno)keten (12) and an imine. Oxidation and elimination of a selenenic acid forms the a -methylene om pound.'^ PhSe \ /c=c=o + P h ~ e , ,__* H,O, P h d P h Me

(12)

+

O

he

0

CH,

PhCH=NPh

Intramolecular cyclization is still a popular means of forming azetidinones, with numerous examples appearing during the past year. In a continuation of previously reported work, further examples of bond formation between N- 1 and C-4 in azetidinone synthesis have been published.16 Phase-transfer catalysis has been used to aid the cyclization of a ,!?-dibromopropionamide to an azetidin~ne.””~The conversion of /3 -hydroxy-a -amino-acid amides into l3 l4

l6

’*

E. Schaumann, A. Rohr, and G. Adiwidjaja, Tetrahedron Lett., 1980,21,4247. T. Tschamber and J. Streith, Tetrahedron Lett., 1980,21,4503. T. Agawa, M.Ishida, and Y. Ohshiro, Synthesis, 1980,933. R. Abdulla and J. C. Williams, Tetrahedron Lett., 1980,21,997. H. Takahata, Y. Ohnishi, and T. Yamazaki, Heterocycles, 1980,14,467. Y.Hirai, I. Kamide, and T. Yamazaki, Heterocycles, 1981,15,1101.

52

Heterocyclic Chemistry

azetidinones by diethyl azodicdrboxylate and triphenylphosphine has been reported.” A similar approach was used in a study that went some way towards the synthesis of nocardicin A.2o A novel approach to azetidinones (13) that possess an olefinic substituent at C-4 is the reaction (affording low yield) between a p-amino-ester that is derived from the isoxazolone (14) and a Grignard reagent (Scheme 4).21 As part of a synthesis of thienomycin, the azetidinone (15) was prepared from an oxazoline derivative;22more recently, an improved route to the derivative (15) has been described.23

Reagents: i, Na, Pr’OH; ii, MeOH, HCl; iii, (0-toly1)MgBr

Scheme 4

Me

: C0,Me

C0,Me

)-AH 0 (15)

The known preparation of azetidinones utilizing the insertion of carbon monoxide into the bromo-amine (16)has been used in a synthesis of 3-aminocardicinic A novel and elegant synthesis of azetidinones involves the carbonylation of the azirine (17), catalysed by palladium(0). A possible mechanism for this fascinating transformation has been disc~ssed.~’ Other routes to azetidinones include the photolysis of the fused pyrimidone (18),26the ring-contraction of 4-azido-2-pyrrolinones (19),” and the photochemical oxidation of 0-silylated azetidinecarboxylate esters.28 CH2

CO, PPh3

HZC

Pd(OAc),, Bu,N

HNYAr

0

,

C0,CH Ph A. K. Bose, D. P. Sahu, and M. S . Manhas, J. Org. Chem., 1981,46, 1229. P.G. Mattingly and M. J. Miller, J. Org. Chem., 1980, 46, 1557. M. Shibuya and S. Kuhota, Heterocycles, 1980,14,601. 22 T. Kametani, S. P. Huang, S. Yokohama, Y. Suzuki, and M. Ihara, J. A m . Chem. Soc., 1980, 102, 2060. 23 T. Kametani, T. Nagahara, Y. Suzuki, S. Yokohama, S. P. Huang, and M. Ihara, Heterocycles, 1980,14,403. 24 K . Chiba, M. Mori, and Y. Ban, J. Chem. SOC.,Chern. Comrnun., 1980,770. 25 H. Alper, C. P. Perera, and F. R. Ahmed, f. A m . Chem. Soc., 1981,103,1289. 26 T. Kato, N. Katagiri, U. Izumi, and Y. Miura, 1981, 15, 399. ” H. W. Moore, L. Hernandez, Jr., D. M. Kunert, F. Mercer, and A. Sing, J. A m . Chern. Soc., 1981 103, 1769. 28 H. H. Wasserman, B. H. Lipshutz, and J. S. Wu, U.S. P. 4 190 579 (Chem. Absrr., 1980,93,7996). l9

2o

Four-Membered Ring Systems

53

(19)

3-Heteroaryl-1-phenylazetidin-3-01s are the product of photolysis of heteroaryl N-methylanilinomethyl ketones.29 Upon photolysis, succinimides form azetidine-2,4-diones (20),30 and a novel 2-azetidinone-containing nucleus (21) has been ~ y n t h e s i z e d . ~ ~

The interest in synthesizing the penam or carbopenam system has led to various studies involving the nitrogen atom of azetidinones being used in intramolecular cyclizations. Electrophilic cyclization of the olefinic azetidinone (13) to the carbopenam system occurs, in a manner analogous to iodolactonization, by a process which should be widely a p p l i ~ a b l e The . ~ ~ reaction of an a-azo-P-keto-ester (22) has been used to prepare the same ring system by means of a carbene-insertion In a correction of a previous paper,34 Japanese authors have shown, by X-ray analysis, that the product of the copper(1)-mediated oxidative addition of the azetidinone (23) is the isopenem (24), and not, as was thought, the corresponding penem (25).35

Q

0

29

30

31 32 33 34

35

CH,I

M. M. Hesabi, J. Hill, and A. A . El-Hamamy, J. Chem. SOC.,Perkin Trans. 1, 1980, 2371. K. Maruyama, T. Ishitoku, and Y. Kubo, J. Org. Chem., 1981,46, 27. G. M. Bright, M. F. Dee, and M. S. Kellogg, Heterocycles, 1980,14, 1251. T. Aida, R. Legault, D . Dugat, and T. Durst, Tetrahedron Lett., 1979,4993. R. W. Ratcliffe, T. N. Salzmann, and B. G. Christensen, Tetrahedron Lett., 1980, 21, 31, 1193. F. DiNinno, E. V. Linek, and B. G. Christensen, J. A m . Chem. Soc., 1979,101,2210. S. Oida, A. Yoshida, and T. Hayashi, Tetrahedron Lett., 1980,21,619.

Heterocyclic Chemistry

54 C0,PNB LiNPr; CuI, PBu,

0

Br

C0,PNB

(23)

(24)

(PNB

=

p-nitrobenzyl)

The reactions of the a -diazo-azetidinones (26) with allylic sulphides and halides, in the presence of a Lewis acid, allow the synthesis of 6,6-disubstituted penicillinates by means of a [2,3] sigmatropic rearrangement.36However, the reactions of the same azetidinones with bis(acetylacetonato)copper(I) in ethanol result in the formation of the thiazepines (27), and not the expected a-alkoxylOther work on diazo-azetidinones has been reported.38 ated N2

E3

0

XBF,.OE1S-

: 9 - x p e- - &----

0

CO,R

C0,R CO,R (X = MeS, PhS, PhSe, or Br)

(26)

(27)

Stereospecific nucleophilic displacements of the a -amino-azetidinone (28) have been demonstrated, and they are thought to proceed via the imine (29). The specificity is presumably due to the 7 p -amino-compound being thermodynamically more stable because of hydrogen-bonding in structure (30).39Similarly, the a-triflate esters of azetidinones (31) will undergo SN2displacement with a variety of 'soft' nucleophiles, such as iodide and thiols, without affecting the four-membered ring.40 Besides a detailed study of the formation of dihydroquinolines from l-arylazetidinones (by an acid-catalysed Fries-type rearrangement)41 and a report on

36

37 38 3q 40

41

P. J. Giddings, D. I. John, and E. J. Thomas, Tetrahedron Lett., 1980,21, 395. S. A. M a t h and L. Chan, J. Chem. SOC.,Chem. Commun., 1980, 798. J. C. Sheehan, K . Nakajima, and E. Chacko, Heterocycles 1979, 13 (special issue), 227. Y. Sendo and M. Yoshioka, J. Chem. SOC.,Chem. Commun., 1980, 1069. J. E. G . Kemp, M. D. Closier, S. Narayanaswami, and M. H. Stefaniak, Tetrahedron Lett., 1980, 21, 2991. S. Kano, T. Ebata, and S. Shibuya, J. Chem. SOC., Perkin Trans. 1, 1980,2105.

55

Four-Membered Ring Systems

bO,R

CO,R

(31)

the a -alkylation of azetidinones with a -(methylthi~)ketones,~~ the remaining reactions of azetidinones involve displacement reactions at C-4. Allylcopper has been allowed to react with a 4-chloro-azetidinone to form the coupled product, in moderate yield.434-Acetoxy-azetidinones undergo a low-yield displacement reaction with organolithium in a process which has been applied to the synthesis of the benzyl ester of antibiotic PS-5.45 The addition of ethyl diazoacetate to 4-acetoxy-azetidinones is catalysed by rhodium(I1) acetate.46

3 Systems containing Two Nitrogen Atoms or One Nitrogen and a Second Heteroatom Irradiation of the thienodiazepine (32) afforded the diazetothienopyrrole (33) in quantitative yield,47in an analogous fashion to the benzo-anal~gues.~~ The 1,3-diazabicycl0[2.2.O]hexene (34) is formed by photochemically induced cycloaddition of substituted pyrimidine molecules. Thermolysis of (34) leads to 2,4-diphenylq~inoline.~’ Evidence has been presented for a stepwise decomposition of an aryl-substituted diazetine,” and a 1,3-diazetidinone is formed when one allows formamidines and isocyanates to react.” In an effort to determine the extent of its aromatic character, the 1,2-diazetine (35)was successfully synthesized. However, it appears that this thermally labile species does not exhibit any aromatic tendencie~.’~

0 NKNPh

P h u P h

hv

Ph Ph

N--fo

r w N P h Ph (34)

NC0,Me

(35)

S. Kano, T. Ebata, Y. Yuasa, and S. Shibuya, Heterocycles, 1980,14,589. H.Onoue, M. Narisada, S. Uyeo, H. Matsumura, K. Okada, T. Yano, and W. Nagata, Tetrahedron Lett., 1979,3867. 1 . 4 T. Kametani, T. Honda, J. Sasaki, H. Terasawa, Y. Nakayama, and K. Fukumoto, Heterocycles, 1980,14,575. ” T. Kametani, A. Nakayama, and K.Fukumoto, Heterocycles, 1980,14,1967. 4c J. Cuffe and A. E. A. Porter, J. Chem. SOC.,Chem. Commun., 1980,1257. 47 D.P. Munro and J. T. Sharp, J. Chem. SOC., Perkin Trans. 1, 1980,1718. 48 C.D.Anderson and J. T. Sharp, J. Chem. SOC.,Perkin Trans. 1, 1980,1230. 49 T. Nishio. K.Katahira, and Y. Omote, Tetrahedron Lett., 1980,21,2825. J. A. Pincock and L. M. Druet, Tetrahedron Lett., 1980,21,3251. ” M. Tisler and B. Stanovnik, J. Chem. Soc., Chem. Commun., 1980,313. ” R. N.Warrener, E. E. Nunn, and M. N. Paddon-Row, Aust. J. Chem., 1979,32,2659.

42

43

56

Heterocyclic Chemistry

The a-lactam (36) appears to be a useful intermediate in preparing fourmembered-ring heterocycles. If treated with diazomethane, an azetidinone is formed, but it can also form an oxazetidinone (37) with pyridine N - ~ x i d e In .~~ an unusual reaction, an attempt at decarboxylation of the isocyanate (38)resulted in the formation of an o ~ a z e t i d i n o n eAn . ~ ~unusually stable oxazete has been prepared.5 5

ci

Ci I I (MeO,C),C-C-N=C=O I CCI,

H2O ___+

(

(MeO,C),C+NH CCI,

(38)

A novel, stable isothiocyanate dimer, a 1,3-thiazetidinethione, is formed from thiophosgene and a ~yridinamine.’~ The preparation of a 1,3-azaphosphetidine has also been described.57

4 Systems containing Oxygen 0xetans.-The presence of the oxetan function in thromboxane A2 has stimulated a great deal of interest in the synthesis of this heterocycle. For example, the diol (39) is converted into an oxetan by trifluoromethanesulphonic anhydride.58Another novel route to the 6-oxabicyclo[3.1. llheptane skeleton involves the conversion of the exo-epoxide (40) into an oxetan with potassium t-butoxide, followed by a sequence of protection, hydrogenation, and oxidation to furnish the keto-oxetan (4 1). Baeyer-Villiger oxidation, hydrolysis, and methylation gave the required product (42).59 A new synthesis of oxetans from vinyl selenides has been recommended. Thus, the reaction of a phenylselenopropenol (43) with peracid, followed by treatment with base, results in the formation of an oxetan (Scheme 5).60 The photochemically induced [2 + 21 cycloaddition of acetone and dihydrofuran (44) has been shown to proceed smoothly, but with a selectivity opposite to that expected. The analogous intramolecular cycloaddition also readily occurs.61 53

54

55 56

57

58 59

6o

61

D. P. Del’tsova, N. P. Gambaryan, E. I. Mysov, and I. L. Knunyants, Dokf. Akad. Nauk SSSR, 1980,253,886(Chem. Abstr., 1981,94,47 032). V. V. Momot, L. I. Samarai, and N. D. Bodnarchuk, Synthesis, 1980,571. H. G.Corkins, L. Storace, and E. R. Osgood, Tetrahedron Lett., 1980,21, 2025. K.A. Fahrenholtz, W. Benz, J. F. Blount, a n d T . H. Williams, J. Org. Chem., 1980,45,4219. B. A. Arbuzov, 0. A. Erastov, and G. N. Nikonov, Izv. Akad. Nauk SSSR, Ser. Khim., 1980,735 (Chem. Abstr., 1980,93,95 335). K. M. Maxey and G. L. Bundy, Tetrahedron Lett., 1980,21,445. M.Shibasaki, A. Nishida, and S . Ikegami, Tetrahedron Lett., 1980,21,3061. M.Shimizu and I. Kuwajima, 1. Org. Chem., 1980,45,4063. H. A.J. Carless and D. J. Haywood, J. Chem. Soc., Chem. Commun., 1980,1067.

Four-Membered Ring Systems

57

(39)

(40)OH

Ho2caoH ~ 0 B z

Bu'Me,SiO

OSiMe,Bu'

-

0

V

(dl

PhSep~ i,ii

~

OH (43)

J 0
Scheme 5

Other papers on the formation of oxetans include the reaction of 6-ketotosylates with base,62a study of the .P&erno-Buchi reaction of ketones and a variety of heterocycle^,^^ and the autoheterocyclization of cyanoacetylene carbin01s;~~ oxetans have been shown to be the minor products from the The Paterno-Buchi reaction of reaction of chloranil and aryl-dia~ornethanes.~~ (2)-and (E)-l,2-difluoroethylenewith fluoro-ketones has been found to proceed with little stereospecificity.66 62

H. Gerdes, S. Javeri, and H. Marschall, Chem. Ber., 1980,113,1907.

T.Nakano, W.Rodriguez, S. de Roche, J. Larrauri, C. Rivas, and C. Perez, J. Heterocycl. Chem., 64 65

1980,17,1777. Yu. M. Skvortsov, A . G . Mal'kina, B. A. Trofimov, G. A . Kalabin, A . N. Volkov, and V. B. Modonov, Izv. Akad. Nauk. SSSR, Ser. Khim., 1980, 1349 (Chem. Abstr., 1980,93,220634). T.Oshima and T. Nagai, Bull. Chem. SOC.Jpn., 1980,53,726. M.G. Barlow, B. Coles, and R. N. Haszeldine, J. Chem. Soc., Perkin Trans. I . , 1980,2258,2523.

58

Heterocyclic Chemistry

Spirocyclic oxetans are of interest, and the known preparation of oxetans from 1-bromo-3-trialkylstannyl ethers has been applied to the spirocyclic case.67 Upon irradiation, 9,lO-phenanthrenequinone (45) and olefins give the ketooxetans (46).6sSome new derivatives of oxaspiro[2,3]hexanes (47) have been prepared and shown to be useful in the synthesis of cyclopentenone~.~~

+

RiR2 hv --+

R3

R4

R4

AA0

O=P(OMe)2

(47)

A notable achievement has been the isolation of the parent unsubstituted oxet (49; R = H). The method that was used involved the conversion of the known alcohol (48; R = H) into a selenide (48; R = 2-N02C6H4Se),followed As expected, the oxet undergoes by oxidation and selenoxide fragmentati~n.~' facile electrocyclic ring-opening ( t I l 2= 8.4 h). The similarly prepared 3-phenyloxet (49; R = Ph) undergoes an interesting aerial oxidation to phenacyl formate, in a process that has been suggested to involve a radical p a t h ~ a y . ~ ' 02, dark

[R = Ph]

OR (48)

Ph

R (49)

A new terpene synthesis has been developed in which bromomagnesium organocuprates react with p -methyl+ -propiolactone (50). For example, reac, ~ ~shown tion with dihomoprenyl cuprate leads to a synthesis of c i t r ~ n e l l o l as in Scheme 6.

(50)

i, ii

1

citronellol Reagents: i, CH,N,; ii, LiAlH,

Scheme 6 67 68 69 'O

"

A. Odeh, J. Usta, and C. Issidorides, Heterocycles, 1980,14, 189. K. Maruyama, M. Muraoka, and Y. Naruta, J. Org. Chem., 1981,46,983. T.Kato, N. Katagiri, and R. Sato, J. Org. Chem., 1980,45,2587. L. E.Friedrich and P. Lam, J. Org. Chem., 1981,46,306. T.Fujisawa, T. Sato, T. Kawara, A. Noda, and T. Obinata, Tetrahedron Lett., 1980,21, 2553.

59

Four-Membered Ring Systems

Dioxetans.-The reaction of an isolable cyclobutadiene with singlet and triplet oxygen has been studied, resulting in the formation of two isomeric dioxetans. The compound (52) undergoes rapid rearrangement to its more stable isomer (51).72 The dioxetan (53)has been shown to undergo acid-catalysed rearrangement to produce a variety of products, amongst them (54) and ( 5 5 ) , whose distribution varies with the conditions Interestingly, a novel scission of the dioxetan ring, accompanied by phenyl migration and aromatization to the phenol (56), is observed under anhydrous acidic c o n d i t i o n ~ . ~ ~

( J Q Q i @ + ~

0-0 (52) [3O%]

(51) [70%]

(53)

(55)

(54)

Further work on imino-1,2-dioxetans suggests that they decompose via a biradical and that the energy level of the transition state for decomposition is lower than that of simple dioxetans and d i o ~ e t a n o n e s . ~ ~ 5 Systems containing Sulphur

The chemistry of the tetraphenylthietan-2-one (57) has been comprehensively studied. Among the more interesting products is the mixed carboxylic-sulphinic acid anhydride (58), obtained by oxidation of the thietanone with p e r a ~ i d . ~A’ thietan-3-one (60) has been shown to be the product of the thermolysis, in iso-octane, of the a-diazo-ketone (59).76 heat

__*

Ph (57)

(58)

A S

(59)

The selectivity of the 1,2- versus 1,4-cycloaddition of ketenimines and thioketones has been Bis-iminothietans, and their transformation into ring-expanded products, by conventional means, have been Some 72

73 74

75 76

77

78

A. Krebs, H. Schmalstieg, 0.Jarchow, and K.-H. Klaska, Tetrahedron Lett., 1980,21,3171, A.Kawamoto, H. Uda, and N. Harada, Bull. Chem. SOC.Jpn., 1980,53,3279. Y. Ito, H. Yokoya, K. Kyono, S. Yamamura, Y. Yamada, and T. Matsuura, J. Chem. SOC.,Chem. Commun., 1980,898. P. Charumilind and H. Kohn, J. Org. Chem., 1980,45,4359. J. Bolster and R. M. Kellogg, J. Org. Chem., 1980,45,4804. A.Dondini, A. Battaglia, and P. Giorgianni, J. Org. Chem., 1980,45,3766. G.L’abbC, J. P. Dekerk, and M. Mahy, Bull. SOC.Chim. Belg., 1980,89,561.

Heterocyclic Chemistry

60

platinum(0) and palladium(0) complexes of thiet 1,l -dioxides have been described." Further work on the thermal dimerization of a thiobenzil to a 1,3-dithietan and its subsequent photochemical cycloreversion has been described.80 Interestingly, the lachrymatory factor (61) of onion (Allium cepa) has been shown to form, upon dimerization, the first stable 1,2-dithietan derivative (62).81

- tb, Et

H \

C,H,,

c=s-o+

/

at 3 "C

for 7 days

Et

Et'

(61)

(62)

A novel entry into the 2-thietanimine system is by allowing a deprotonated lactone to react with phenyl isothiocyanate (Scheme 7). Hydrolysis results in the formation of the thietanimine and a thioamide. This transformation requires the intermediate (63) to undergo a re-cyclization step which is thought to involve inversion at C-4.82

R - -P o C-NPh Ph

H

NHPh

1:'S'

Reagents: i, LiNPr',; ii, PhN=C=S; iii, H 3 0 +

Scheme 7

Stable thiets (64) are formed by thermolysis of the adduct of azides and tetrakis(trifluoromethy1)Dewarthiophen (65). The reaction has been shown to proceed via a diazo-thiiranimine (66). The stability of these thiets can be attributed to the effect of the trifluoromethyl groups. However, upon reaction in the light or with triphenylphosphine, they are converted into p y r r o l e ~ . ~ ~

2-q +

CF3

F3C F3C

F3c

N2 79

81 a2

83

RN,

--*

R'Z$YAs

(65)

N

\

C. R. Hall, E. R. Hanner, R. D. W. Kemmitt, and D. J. H. Smith, J. Organomet. Chem., 1981, 205,417. C. Bak and K. Praefcke, 2. Naturforsch., Ted. B. 1980, 35, 372. E. Block, A . Bazzi, and L. K. Revelle, J. Am. Chem. Soc., 1980, 102,2490. J. Mulzer and T. Kerkmann, Angew. Chem., Int. Ed. Engl., 1980,19, 466. Y. Kobayashi, A . Ando, K. Kawada, A. Ohsawa, and I. Kumadaki, J. Org. Chem., 1980,45,2962.

61

Four-Membered Ring Systems 6 Miscellaneous Four-Membered Rings

The interest in heterocycles that contain less conventional heteroatoms has continued, notably with many reports on silacy~lobutanes.~~-~* Prominent amongst these is a report concerning prochiral, short-lived silylethylenes. When these species are generated, from silacyclobutanes, in the presence of chiral alcohols, asymmetric induction is observed (Scheme 8).84

-

Ph. Ph'

-%

A

s1

OR*

1

Ph i*-R

R*OH

''Si=CH,

4 R

CH3 up to 30% enantiomeric excess of one diastereoisomer

Scheme 8

Two new procedures for the preparation of silacyclobutanes have been published. The first is by thermolysis of the novel 2-silacyclopentanone (67), at 550 0C,85 whereas the second simply involves treating bis(chloromethy1)dimet hylsilane with potassium hydrosulp hide .86 0 CSiMe.

(67)

55o"cL

oiMe2 EiMe2 +

[4Oo/o]

[4O%]

Contrary to previous results, it has been shown that 3,3-dimethylselenetan (68) is converted into a seleninic acid lactone, rather than a selenone, by hydrogen peroxide.89The product of the reaction of triphenylphospiiine selenide and hexafluoroacetone at 150 "C is tetrakis(trifluoromethyl)-l,3-di~elenetan.~~ The interesting 1,2-diphosphacyclobutene (69) has been reported to be produced from oxalyl chloride and bis(trimethylsily1)phosphines (Scheme 9).91

-

0 PhP(SiMe,),

+ CI%"

0

Me,SiPI

0

Ph

5'"siMe

Ph

1 Me,SiOM

OSiMe,

Me,SiO I

OSiMe, I

PhP-PPh

Scheme 9 84

85 86

87

89

"

G. Bertrand, J. Dubac, P. Mazerolles, and J. Ancelle, J. Chem. SOC., Chem. Commun., 1980, 382. A. Hassner and J. A. Soderquist, Tetrahedron Lett., 1980, 21, 429. M. G. Voronkov, S. K. Kirpichenko, E. N. Suslova, and V. V. Keiko, J. Organomet. Chem., 1981, 204, 13. N. Auner and J. Grobe, J. Organomet. Chem., 1980,188,25. N. Auner and J. Grobe, J. Organomet. Chem., 1980,188, 151. B. Lindgren, Chem. Scr., 1980,16, 24. M. S . Raasch, J. Org. Chem., 1980, 45, 3517. R. Appel and V. Barth, Tetrahedron Lett., 1980, 21, 1923.

3 Five-Membered -Ring Systems BY G. V. BOYD, J. DE MENDOZA, J. ELGUERO & S. GRONOWITZ

PART I: Thiophens and their Selenium and Tellurium Analogues by S. Groptowitz

1 General Reviews on the cyclization of organic sulphur compounds to thiophens,' on activity and selectivity in electrophilic substitution of t h i ~ p h e n s on , ~ ~photochemical rearrangements,' l 8 and on pharmacologically interesting thiophen derivatives299have been published. Great Interesting syntheses of thiophens from allenes have progress in the use of palladium- and other transition-metal-catalysed reactions of thiophen has been reported. 111-"4 Increasing interest in the syntheses of compounds of pharmacological interest can be noted. A revival of interest in selenophens and condensed selenophens has occurred. The increasing use of X-ray crystallography for structure determination is also noticeable in the thiophen field.

2 Monocyclic Thiophens Synthesis of Thiophens by Ring-Closure Reactions.-Reviews on the cyclization of organic sulphur compounds to thiophens' and on catalytic methods for producing thiophens and alkyl-thiophens2 have appeared. Kinetic data for the conversion of several organosulphur compounds into thiophen on different sulphur-containing catalysts gave information about the m e c h a n i ~ m . ~1,2.~ Dichloroethylene reacted with hydrogen sulphide in the gas phase at 420520 "Cto give 2- and 3-chlorothiophens9 2,4-dichlorothiophen, and many other products. The best yield of 2- and 3-chlorothiophens was 25% (ratio 3 : l)? Up to 46% of tetrachlorothiophen was obtained from tetrachloroethylene at 650 0C.6 Thiophen has been prepared from C4 molecules such as n-butanol or crotonaldehyde in 42% and 78% yield, respectively, by reaction with carbon disulphide over a promoted chromium-aluminium oxide catalyst at 500 OC.' Similarly, alkyl-thiophens were prepared from C5-C7 compounds in high yields.' The S. Oae and H. Morita, Kagaku No Ryoiki, Zokan, 1980, 189. M. A. Ryashentseva, Katal. Sint. Org. Soedin. Sery, 1979, 129. T. S. Sukhareva, A. V. Mashkina, L. V. Shepel, and L. S . Zabrodova, Katal. Sint. Org. Soedin. Sery, 1979, 142. T. S.Sukhareva, A. V. Mashkina, and L. V. Shepel, Geterog. Katal., 1979, 4th, Pt. 2, p. 237. V. I. Perevalova, 0. B. Bannikova, E. N. Deryagina, and M. G. Voronkov, Zh. Org. Khim., 1980, 16,399. M. G. Voronkov, E. N. Deryagina, and V. I. Perevalova, Khim. Geterotsikl. Soedin., 1980, 310. F. Azizian and J. S. Pizey, J. Chem. Technol. Biotechnol., 1980, 30, 429. F. Azizian and J. S. Pizey, J. Chem. Technol. Biotechnol., 1980, 30, 648.

63

Heterocyclic Chemistry

64

reaction of phenyl isothiocyanate with ethyl y-chloroacetoacetate gave (l), which, upon reaction with Vilsmeier reagent, gave (2). Upon reaction with thionyl chloride, the interesting (probably tautomeric) system (3) was ~ b t a i n e d . ~ C1

Et0,C PhNH

PhNHI(CH0 S

Et0,C

PhHN

OH

PhN

The phosphonic acid derivative (4) reacted with alkanesulphenyl chlorides to give ( 6 ) ,probably via (9.''

Another example of the use of allenic compounds is the reaction of the t-butylthio-substituted butatriene (7a) with iodine and hydrobromic acid to give (8a) and (8c), respectively. With bromine, a mixture of (8b) and (9) was obtained. The reaction of (7b) with bromine gave either (10) (most probably) or (11). The mechanism of the formation of thiophen is discussed." The reaction of the allenic silver salt (12) with carbon disulphide in THF and HMPT led to (13), which spontaneously ring-closed to (14) and upon treatment with acid gave ( 15).12 The reaction of 2,2,5,5-tetramethyl-3,4-dimethylenehexane(16), obtained by the reaction of 1,4-dichloro-but-2-yne with t-butylmagnesium chloride in the presence of catalytic amounts of copper(x) bromide, with sulphur Its crystal dichloride provides an elegant synthesis of 3,4-di-t-buty1thiophen.l3 structure was determined by X-ray diffra~tion.'~"~ 2,4-Diphenylthiophen was prepared in the reaction of a- and p-bromostyrenes with hydrogen sulphide." The reaction of (17) and sulphur in the presence of diethylamine gave (18).16a

l4

A. W. Faull and R. Hull, J. Chem. SOC.,Perkin Trans. I , 1981,1078. Ch. Angelov, M. Kirilov, K. Vachkov, and S. Spassov, Tetrahedron Lett., 1980,21,3507. A. Roedig and G. Zaby, Chem. Ber., 1980,113,3342. H. Westmijze, K. Ruitenberg, J. Meijer, and P . Vermeer, Tetrahedron Lett., 1980,21, 1771. L. Brandsma, J. Meijer, and H. D. Verkruijsse, J. Chem. Soc., Chem. Commun., 1980,922. G. Bokkers, A. J. M. Duisenberg, J. Kroon, and L. Brandsma, Crysr. Struct. Commun., 1981,10,

l5

M.G.Voronkov, E. N. Deryagina, M. A. Kuznetsova, and V. I. Glukhikh, Zh. Org. Khim., 1980,

lo l1 12 13

361. 16,2450.

65

Five-Membered Rings: Thiophens and their Se and Te analogues Bu'S

SBu'

Bu'S

R

>c=c<

B:;sflu S

(8) a; R = I b; R = Br c; R = H

(7) a; R = SBu' b; R = Ph

SBu'

Br

Bu' S

0

Ph

S

BUS

R'H2C \ ,c=C=C

Br

Bu'S i ( P h S

(9)

R2

H /

~2LiBr

\

R2

Ag

R2

R'H,C \

/FCH R2

CszAgs2LiBr

(13)

(15)

(R' Bu'

I H2C=C-C=CH2 I Bu' (16)

Ph

\

/

=

c=c

/

\

Me

Bu, Pr', or But; R2 = Me)

C02Et

Ph

C02Et

O SN H ,

CN

(17)

Condensation of cyclic ketones with sulphur and ethyl cyanoacetate in the presence of diethylamine yielded (19).16bThe reaction of o-nitrobenzoylacetonitrile with sulphur and propionaldehyde in the presence of triethylamine The reaction of (20) with gave 2-amino-5-methyl-3-(o-nitrobenzoyl)thiophen.17 sodium sulphide gave the corresponding sulphide, which, upon Hinsberg reaction with glyoxal, gave (21). Wolff-Kishner reduction, followed by reaction with hydrogen sulphide under acidic conditions, converted the furan ring into thiophen, yielding (22).lSa The base-catalysed reaction of (23) with biacetyl or benzil gave high yields of (24), rather than the expected 2,5 -diacyl-thiophens, which were obtained upon treatment of (24) with thionyl chloride and pyridine. Phenylglyoxal gave the 2,5-diacyl-thiophen directly."* pBis(thieny1)cyclohexane has been prepared by A1C13-catalysed condensation of hexahydroterephthaloyl chloride with ally1 chloride, followed by reaction with phosphorus pentas~1phide.l~ The spiro-compound (25) gave a 2 :1 adduct (26) ( a ) M. Perrissin, C . L. Duc, G. Narcisse, F. Bakri-Logeais, and F. Huguet, Chim. Ther., 1980, 15,563; ( b ) M.Perrissin, G. Narcisse, F. Bakri-Logeais, and F. Huguet, ibid., p. 413. D. Binder, 0. Hromatka, C. R. Noe, Y. A. Bara, M. Feifel, G. Habison, F. Leierer, and J. E. Blum. Arch. Pharm. (Weinheim, Ger.), 1980,313,636. Y.Miyahara, T. Inazu, and T. Yoshino, (a) Chem. Lett., 1980, 397; ( b ) Bull. Chem. SOC.Jpn., 1980,53,1187. A.G.Ismailov, V. G. Ibragimov, R. D. Goyushov, and I. D. Sadykhov, Azerb. Khim. Zh., 1980, No. 2, p. 47.

66

Heterocyclic Chemistry

0 Y

(19) n = 1 or2, Z = Hor Me

(21) x = Y = 0 (22) X = S , Y = H2

(21))

HO OH

(ArCOCH2)2S (23) Ar = Ph or p-tolyl

fizi

ArOC R1

Ar

S

(24)

R

R

R

NyJh C02R

Ar (26)

with carbon disulphide, the structure of which was determined by X-ray crystallography.20 Michael addition of mercaptoacetic esters to benzylidenebenzoylacetonitriles gave (27)." Synthesis of Thiophens from Other Rings.-Catalytic dehydrogenation of tetrahydrothiophens has been achieved over y-Alz03, activated carbon, or aluminosilicates,22 and over a molybdenum-containing catalyst.23 Upon treatment with an arylamine in boiling xylene, (28) was converted into (29) and small amounts of (30). However, acid- or base-catalysed isomerization of (29) gave (30) in high yields.24 2,3-Dihydrothiophens react with dimethyl acetylenediHO H-C

i

Arl (28) X = OR (29) X = NHAr2 2o 21

22

23 24

CONHAr'

A r ' H 2 SC 0

(30)

G. Ege, K. Gilbert, and F. W. Nader, Chem. Ber., 1981, 114, 1074. S. Kambe, K. Saito, A. Sakurai, and H. Midorikawa, Synthesis, 1980, 839. E. A. Viktorova, M. V. Vagabov, T. A. Danilova, and E. A. Karakhanov, Katal. Sint. Org. Soedin. Sery, 1979, 115. A. R.Kuzyev, Katal. Sint. Org. Soedin. Sery, 1979, 125. R. Jaunin, Helv. Chim. Acta, 1980, 63, 1542.

67

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

carboxylate in boiling benzene, to give alkenes and dimethyl thiophen-2,3dicarboxylate~.~~ Some 2,5-disubstituted furans have been converted into the corresponding thiophens by reaction with hydrogen sulphide in hydrochloric acid or other acidic media at 80-100°C.26 The reaction of (31) with phenyl azide yielded (32) and (33), whose structures were determined by X-ray

~rystallography.~~ Pyrolysis of the 2H-thiopyrans (34) gives, as well as other compounds, the thiophens (35) and (36) and the 2,5-dihydrothiophens (37), the R2

R2

R

a R3

R 0S R 3

R' R'

(35) R = R'&H (36) R = H

R4

R'

composition depending upon substituents." The reaction of (38) with dimethyloxosulphonium methylide gave the thienyl-acetones (39) and (40) and also (41).*'The sulphoxide (42) and its 3-nitro-derivative, upon heating in DMSO at 52 "C, gave 2,4-diphenylthiophen and 2,4-diphenyl-3-nitrothiophen, respect i ~ e l y . ~Compound ' (43) gave the thiophen derivative (44) in almost quantitative yield, with elimination of COS, upon heating in xylene for 15 minute^.^?

;;.Me Ph

S (38)

0

MeCOCH I

XI1 s

Ph (39) R1 = H,R2 = Me (40) R' = Me,R2 = H

hM

Me \ Ph (41)

C-CH

II

0-CH,

Ph

Ph (42) 2s 26 2'

28 29

30

31

(43)

(44)

K. Gollnick and S. Fries, Angew. Chem., 1980, 92,848. V. G . Kharchenko, I. A. Markushina, and T. U. Gubina, Dokl. Akad. Nauk SSSR,1980,255,1144. K.Skinnemoen and T. Ottersen, Acta Chem. Scand., Ser. A, 1980,34,359. K. Praefcke and C. Weichsel, Liebigs Ann. Chem., 1980, 1604. H. Yamaoka, I. Mishima, and T. Hanafusa, Bull. Chem. SOC.Jpn., 1980,53, 1763. C. L.Gajurel and S. R. Vaidya, Indian J. Chem., Sect. B, 1980, 19, 91 1. H. Gotthardt and 0. M. Huss, Liebigs Ann. Chem., 1981, 347.

68

Heterocyclic Chemistry

Physical Properties of Monocyclic Thiophens.- Theoretical Calculations. Electron-density as well as the localized MOs of t h i ~ p h e n , ~ *have ’ been derived from ab initio 4-3 1 G wavefunctions. Semi-empirical calculations of ionization energies with the LHP-RHF open-shell method in the CNDO/INDO formalism has been carried out for t h i ~ p h e n The . ~ ~ r-electron structures of 58 sulphur-containing heterocycles, including thiophen, the bithienyls, and many .condensed thiophens, have been calculated according to the method of Dewar and Harget, with a new parametrization for Simple HMO theory has been used to examine the ease of hydrodesulphurization of t h i ~ p h e n The .~~ conformational preferences of 3,3’-dithienylmethane were investigated by M I N D 0 / 3 calculation^,^^ and those of 2-(2-thienyl)pyrrole using the STO-3G MO method.37 The photoelectron spectra and electronic structure of thiophen were computed by the MSSCFX, method.38 Photoelectron and Ultraviolet Spectra. Ultraviolet photoelectron spectra and Penning-electron spectra, using neon or helium metastable species, have been measured for thiophen and other heterocycles. The usefulness of Penningelectron spectra in assigning r-bands has been demonstrated.39p40 The photoelectron spectra of 2-(2-thienyl)pyrrole have been studied.37 Photoelectron spectroscopy has been used to study the interaction of thiophen with a hydrodesulphurization The threshold photoelectron spectrum of thiophen and the photo-ionization efficiency curves for C4H4S+,C4H3St,C,HS’, C2H2Sf, CHS’, and C3H3+from thiophen have been measured in the range of photon energies of 8-14 eV.42 Correlation of the U.V. spectra of ( E ) - and ( 2 ) - 2 styrylthiophens indicated that the (2)-isomers preferred the S-trans conformation. The (E)-isomers were nearly planar.43 The protonation of some 5 substituted thiophen-2-carboxamides has been studied by U.V. spectroscopy. A plot of p K against u was linear, and confirmed that the thiophen ring is more efficient than the benzene ring in relaying electronic effects of substituents to the reaction Ultraviolet and i.r. spectra of a large number of thiophen-3carboxamides have been in~estigated.~’ The adsorption of thiophen on alumina aluminosilica gel has been studied by the U.V. technique.46

32 33 34

35 36 37

38 39 40 41

42 43

44

*5 46

R. Hilal, J. Comput. Chem., 1980,1, ( a ) p. 348; ( b )p. 358. G. Kluge and M. Scholz, 2. Chem., 1979,19,457. N. K. DasGupta and F. W. Birss, Tetrahedron, 1980, 36, 2711. A. J. Duben, J. Phys. Chem., 1981,85, 245. V. Galasso, E. Montoneri, and G. C. Pappalardo, THEOCHEM., 1981, 1, 43. V. Galasso, L. Klasinc, A. SablijiC, N. TrinajstiE, G. C. Pappalardo, and W. Steglich, J. Chem. SOC.,Perkin Trans. 2, 1981, 127. G. De Alti and P. Decleva, Chem. Phys. Lett., 1981,77, 413. T. Munekata, Y. Harada, and K. Kuchitsu, Koen Yoshishu-Bunshi Kozo Sogo Toronkai, 1979,358. T. Munakata, K. Kuchitsu, and Y. Harada, J. Electron Spectrosc. Relat. Phenom., 1980, 20, 235. P. Dufresne, J. Grimblot, and J.-P. Bonnelle, Bull. SOC.Chim. Fr., Part 1, 1980, 89. J. J. Butler and T. Baer, J. A m . Chem. SOC.,1980, 102, 6764. F. A. Bottino, G. Scarlata, D. Sciotto, and M. Torre, Spectrochim. Acta, Part A, 1980, 36, 205. G. Alberghina, M. E. Amato, S. Fisichella, and S. Occhipinti, J. Chem. SOC.,Perkin Trans. 2, 1980,1721. G. Alberghina, S. Fisichella, and S. Occhipinti, Spectrochim. Acta, Part A, 1980, 36, 349. G. G. Akhmetova, N. A. Zubareva, A. V. Kiselev, and V. I. Lygin, Neftekhimiya, 1980, 20, 285.

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

69

Nuclear Magnetic Resonance. Proton and carbon nuclear magnetic relaxation in 2-bromothiophen has been i n ~ e s t i g a t e dN.m.r. . ~ ~ coherence-transfer experiments have been carried out with 2,3-dibr0mothiophen.~’N.m.r. studies on 2-chloro- and 2-bromo-thiophens when partially oriented by nematic liquid crystals have been carried Carbon-13 and 77Sen.m.r. spectra have been studied for thiophens that contain exocyclic selenium.5oThe 13Cn.m.r. chemical shifts of conjugated heterocyclic nitriles and the i.r. band intensity for the CN stretching vibration were correlated with their total electron density and the n-electron den~ity.~’ Hindered rotation around the aryl-nitrogen bond in (45)

has been studied by dynamic n.m.r.52The proportions of (E)and (2)configurations of isomeric 2-(2-benzimidazolyl)-di-and -tetra-hydrothiophens have been determined by i.r. and n.m.r.

Miscellaneous Physical Properties. The crystal structures of an appreciable number of thiophen derivatives have been determined.s4d1 The mass-spectral fragmentation patterns of thiophensulphonyl derivatives,62 of 5 - and 3-substituted thiophen-2-~arboxamides,~~ and of T -complexes of thiophen with transition have been investigated. The absolute charge-exchange cross-sections, in the gas phase, between thiophen and a large number of positive ions of known ionization potentials have been The molecular stopping cross-

A. Kratochwill and R. L. Vold, J. Magn. Reson., 1980,40, 197. R. Kaiser, J. Magn. Reson., 1980, 40, 439. 49 J. Jokisaari, K. Raisanen, and T. Vaananen, J. Magn. Reson., 1981, 42, 396. P. Granger, S. Chapelle, and C. Paulmier, Org. Magn. Reson., 1980,14, 240. 5 1 T. Saito, M. Yamakawa, Y. Takasu, A. Terui, and T. Honma, Koen Yoshishu-Bunshi Kozo Sogo Toronkai, 1979,422. 5 2 D. Nicole, J.-J. Delpuech, M. Wierzbicki, and D. Cagniant, Tetrahedron, 1980,36, 3233. 53 P. Sohar, G. Manyai, K. Hideg, H. 0. Hankovszky, and L. Lex, Org. Magn. Reson., 1980,14, 125. 54 E. Gutiirrez-Puebla and A. Monge, Acta Crystallogr., Sect. B,1981, 37, 277. 5 5 B. Tinant, B. Coene, J.-P. Declercq, G. Gerrnain, and M. Van Meerssche, Cryst. Sfruct. Commun., 1981, 10, 259. 56 L. V. Panfilova, M. Yu. Antipin, and Yu. T. Struchkov, Zh. Strukt. Khim.,1980, 21, No. 2, p. 190. ” A. Carpy, D. Hickel, and J.-M. Ltger, Cryst. Sfruct. Commun., 1981, 10, 13. ” Y. Kai, J. Watanabe, N. Yasuoka, and N. Kasai, A c f a Crysfallogr., Sect. B, 1980, 36, 2276. 59 F. Mathieu, Acta Crystallogr., Sect. B, 1980, 36, 2715. 6o M. Konno, Y. Saito, K. Yamada, and H. Kawazura, Acta Crystallogr., Sect. B, 1980, 36, 1680. 61 S. Tourk, J. Lapasset, Z. Xicluna, and H. Bodot, A c f a Crysfallogr.,Sect. B,1981, 37, 418. 62 C. A. Obafemi, Phosphorus Sulfur, 1980,8,201. 63 S . Occhipinti, G. Alberghina, S. Fisichella, 0. Puglisi, and L. Ceraulo, Org. Muss Spectrom., 1980, 15, 632. 64 Yu. S. Nekrasov, N. I. Vasyukova, D. V. Zagorevskii, V. F. Sizoi, G. A. Nurgalieva, and L. I. Dyubina, J. Organomet. Chem., 1980, 201, 433. 6’ J. M. Tedder and P. H. Vidaud, J. Chem. SOC.,Faraday Trans. 2, 1980,76, 1516. 47 48

70

Heterocyclic Chemistry

section of thiophen has been measured for He' ions.66 From the microwave spectrum of thiophen and tetradeuteriothiophen, the centrifugal effect, rotation constants, and defects of inertia were c a l c ~ l a t e d The . ~ ~ conformation and the geometry of thiophen-2-sulphonyl chloride have been studied by electron diffraction.68 The fifth overtones of the CH stretching vibrations of thiophen and of 3-methylthiophen have been observed by a thermal lens t e ~ h n i q u eComplexes .~~ of thiophen-2-carboxaldehyde thiocarbohydrazones with various transitionmetal salts have been prepared and characterized by their magnetic moments and U.V. and i.r. ~pectra.~' Dipole moments for methyltelluro-substituted formyland acyl-thiophens have been Electrophilic Substitution Reactions of Monocyclic Thiophens.-A review (with 137 references) on activity and selectivity in electrophilic substitution of fivemembered heterocycles has a ~ p e a r e d . ~ The ' kinetics of the bromination of some substituted thiophens have been i n ~ e s t i g a t e d ,and ~ ~ of the Vilsmeier-Haack f ~ r m y l a t i o n .The ~ ~ *a~ (acy1)methylthiomethyl ~ group has been introduced into thiophen by a Friedel-Crafts reaction.76 Thiophens react with an imidazoletrifluoroacetic anhydride reagent to give . (46).77 5-Substituted 2acetamido thiop hens are converted into 2-acetamido-3 -carbalde hydes with equimolar amounts of DMF and phosphoryl chloride in hot d i ~ h l o r o e t h a n e . ~ ~ 2-Benzoylthiophen was chloromethylated in the 4-position by using paraformaldehyde and an excess of aluminium ~hloride.'~Acyl-thiophens can conveniently be brominated in the ring by using bromine in aqueous sodium acetate.80Nitration of 3-(3-thienyl)acrylic acid and its methyl ester gave a mixture of 2- and 5-nitrated products.81 Nitration of 5-formyl-2-cyclopropylthiophen, prepared by Vilsmeier formylation of 2-~yclopropylthiophen,gave mainly the 3-nitro-derivative, together with small amounts of 2-cyclopropyl-5nitrothiophen.82 Nitration of 2,5-dimethylthiophen with copper(I1) nitrate in acetic anhydride gave 23% of (47) together with 17% of 3-nitro-2,5-dimethylthiophen. Nitration of 3,4-dibromo-2,5-dimethylthiophengave (48) in 50% yield.83

'' H. G . Olson and D. Powers, J. A p p l . Chem., 1981, 52, 564. L. N. Gundarova, A. Kh. Mamleev, V. G . Marutsenko, and N. M. Pozdeev, Deposited Document 1980, VINITI 906. J. Brunvoll, I. Hargittai, T. Szkkely, and G. C. Pappalardo, J. Mol. Sfrucf.,1980,66, 173. " Y. Mizugai and M. Katayama, Chem. Phys. Lett., 1980, 7 3 , 240. 70 S. Barbu and C. G. Macarovici, Rev. Roum. Chim., 1980,25, 339. 7 1 H. Lumbroso, Ch. LiCgeois, N. Dereu, L. Christiaens, and A. Luxen, J. Mol. Sfruct.,1980,67,251. 72 L. I. Belen'kii, Khim. Geterotsikl. Soedin., 1980, 1587. 7 3 V. Kannappan, M. J. Nanjan, and R. Ganesan, Indian J. Chem., Sect. A , 1980, 19, 1183. 74 G. N. Freidlin, N. A. Kuraeva, and K. A. Solop, Khim. Geterotsikl. Soedin., 1980, 315. 7 5 A . Hallberg and S. Gronowitz, Chem. Scr., 1980,16, 38. 76 Y. Tamura, H. Shindo, J. Uenishi, and H. Ishibashi, Tetrahedron Lett., 1980, 21, 3547. 77 J. Bergman, L. Renstrom, and B. Sjoberg, Tetrahedron, 1980,36,2505. 78 0. Meth-Cohn, B. Narine, and B. Tarnowski, J. Chem. SOC.,Perkin Trans. 1, 1981, 1531. 79 G . P. Gromova, L. I. Belen'kii, and Ya. L. Gol'dfarb, Khim. Geterotsikl. Soedin., 1980, 472. 'O 0. Karlsson, Synth. Commun., 1981, 11, 29. '' S. Gronowitz and I. Ander, Chem. Scr., 1980, 15, 145. '* S. S. Mochalov, F. M. Abdel'razek, T. P. Surikova, and Yu. S. Shabarov, Khim. Geterotsikl. Soedin., 1980,455. 8 3 H. Suzuki, 1. Hidaka, A . Osuka, A . Iwasa, andT. Mishina, Chem. Lett., 1980,633. "

''

71

Fiue-Membered Rings: Thiophens and their Se and Te analogues R2 CO

(46) X = H, Br, or Et

(47)

(48)

Treatment of (49) with fluorosulphonic acid in liquid sulphur dioxide gave (50), which could be detosylated with di-isobutylaluminium h ~ d r i d e . *The ~ reaction of (5 1) with phosphorus pentachloride followed by tin tetrachloride in benzene gave (52).*’ The SnC14-catalysed acylation of thiophen with 3-methylglutaric ester chloride gave (53), which, upon Wolff-Kishner reduction, reduction with LiAlH4, and reaction with phthalic anhydride, gave (54). The reaction of (54) with thionyl chloride followed by aluminium chloride yielded (55).86 The reaction of (56) with sulphuric acid in acetic acid gave (57). Similarly, (58) yielded (59).87

Tos

R

q Tos

R

(49)

Me (-)COCH,CHCN,CO,Me I

(53)

(55) 84

85

86

C. G . M. Janssen, P. M. van Lier, P. Shipper, L. H. J. G. Simons, and E. F. Godefroi, J. Org. Chem., 1980,45,3159. K. Satake, M.Kimura, and S. Morosawa, Chem. Lett., 1980,1389. F. D. Alashev, V. N. Bulgakova, S. Z. Taits, and Ya. L. Gol’dfarb, Izv. Akad. Nauk. SSSR, Ser. Khim., 1980,1377. S.Gronowitz and L. Svensson, Chem. Scr., 1980,15,169.

72

Heterocyclic Chemistry

R' P\

R

'

Z

HO (57) R1 = Me,R2 = C1 (59) R' = C1, R2 = Me

0

0

U

(58)

Nucleophilic and Radicaloid SubstitutionReactions of Monocyclic Thiophens.2,5-Dimethyl-3,4-dinitrothiophen reacted with morpholine to give the transdiaminodihydrothiophen (60). The structure of the morpholino-derivative was

proved by X-ray crystallography.88 The kinetics of the substitution reactions of 2,5-dinitrothiophen with piperidine, aniline, and sodium thiophenolate have been found to be se~ond-order.'~E.s.r. data indicated that the reaction of 2-bromo- or of 2-iodo-5-nitrothiophen with tetrabutylammonium hydroxide in DMF produced the anion radical of the starting material of 5,5-dinitro-2,2bithienyl and of 2-nitrothiophen. The SNRlmechanism might therefore not be valid for this reaction." Some very remarkable reactions have been observed between tetracyanothiophen and nucleophiles. It reacted with potassium ethyl xanthate to give (61), which upon treatment with bromine gave (63) via (62). The reaction of tetracyanothiophen with the anion from malononitrile gave (64),which upon acidification ring-closed to (65). With ethyl cyanoacetate and triethylamine, (66) was obtained. Finally, the reaction of tetracyanothiophen with potassium cyanide led to the sulphur-free dipotassium salt (68), probably formed from (67).91 CN

89

90 91

A. Mugnoli, C. Dell'Erba, G. Guanti, and M. Novi, J. Chem. Sac., Perkin Trans. 2,1980, 1764. G.Consiglio, R. Noto, C. Amone, and D. Spinelli, J. Chem. Res. (S),1980,274. I. M. Sosonkin, G. N. Strogov, and N. V. Fedyainov, Dokl. Akad. Nauk SSSR, 1980,253,365. H.E.Simmons, R. D. Vest, S.A. Vladuchick, and 0. W. Webster, J. Org. Chem., 1980,45,5113.

73

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

NC

NC

NC CN

CN C N C N 2K’ (68)

The reactions of the nearly electroneutral methyl radical and of the nucleophilic l-adamantyl radical with 5-nitro-2-methoxycarbonyl-,5-nitro-2formyl-, and 5-nitro-2-phenylsulphonyl-thiophen,and with 3,5-dinitro-2methoxycarbonylthiophen, have been investigated. The adamantyl radical gave exclusively ips0 -substitution, while the methyl radical selectively added at the 4-position. On the other hand, with 4-nitro-2-methoxycarbonylthiophen,both radicals attack the 5-position, and with 4,5-dinitro-2-methoxycarbonylthiophen, both radicals gave ips0 -substitution, displacing the nitro-group at position 5 . Possible reasons for the positional selectivity have been 1Adamantyl radicals reacted with 2,5-diformylthiophen to give 2-( l-adamanty1)3,5-diformylthiophen, showing that the intermediate ipso-radical that was initially formed rearranged by a 1,2-shift of the ipso-s~bstituent,~~ Upon protonation, the thienyliminyl (69) ring-closes to (71) via the radical (70).94

q)

@ 0

N’

(70)

Organometallic Derivatives of Monocyclic Thiophens.-An improved synthesis of thiophen-2,3-dicarboxylicacid consists in halogen-metal exchange of lithium 2-bromothiophen-3-carboxylatefollowed by reaction with carbon dio~ide.’~ An important discovery is that methyl-substituted thiophen-2-carboxylic acids can be readily homologated by treatment with two equivalents of LiNPri2 followed by addition of carbon-containing electrophiles. An exception is 4-methylthiophen-2-carboxylic acid, which is metallated in the 5-position. Dilithiated 92

93 94

”

P. Cogolli, F. Maiolo, L. Testaferri, M. Tiecco, and M. Tingoli, J. Chem. Soc., Perkin Trans. 2, 1980,1331. P. Cogolli, L. Testaferri, M. Tiecco, and M. Tingoli, J. Chem. SOC.,Perkin Trans. 2, 1980, 1336. A. R. Forrester, R. J. Napier, and R. H. Thomson,J. Chem. SOC.,Perkin Trans. 1. 1981,984. M. G . Reinecke, J. G . Newsom, and K. A. Almqvist, Synthesis, 1980,327.

Heterocyclic Chemistry

74

3-methylthiophen-2-carboxylicacid reacts with amyl bromide to give exclusively (72), while acetone gives a mixture of (73) and (74) in the proportions 38 :62. 3,5-Dimethylthiophen-2-carboxylicacid is selectively metallated at the 5-methyl group.96The reactions of (75)-(78) with butyl-lithium and LiNPri2under various conditions have been investigated. Competition between halogen-metal exchange in the benzene ring and metallation of the thiophen ring was observed, and an intramolecular transmetallation reaction was found.97

(75) R1 = R2 = H (76) R' = Br,R2 = H (78) R' = H, R2 = C1

(77)

(79)

Halogen-metal exchange of (79), followed by reaction with trans -chlorovinyl iodosodichloride, gave the iodonium salt, which, upon cleavage with sodium nitrite and then hydrolysis, yielded 3-nitrothiophen-2-carbo~aldehyde.~~ The reaction between 5-alkoxy-2-thienyl-lithium derivatives and l-chloro-2dimethylaminoethane has been found to be useful for the synthesis of 2-alkoxy-5(2-dimethylarnin0ethyl)thiophens.~~ Alkylation or the formation of a sulphone was observed in the reaction between 2-thienyl-lithium derivatives and alkyl tosylates, depending upon the substituent in the thienyl-lithium derivative and upon the alkyl group of the tosylate. The reaction of 3-bromo-2-thienyl-lithium with propane-1,3-diol ditosylate gave (SO), which, upon halogen-metal exchange and coupling with copper(I1) chloride, gave (81)."' The reactions of 2- and of 3-thienyl-lithium with a,cr,a- trifluoro-NN-dimethylacetamide gave the thienyl trifluoromethyl ketone."' The reaction of 3-thienyl-lithium with 2-chlorocyclohexanone gave (82), which was transformed into the cyclohexanone (83) by the action of phenylmagnesium bromide.lo2 The reaction of 5-trimethylsilylthiophen with trifluorochloroethene gave (84). Several other fluorinecontaining vinyl-thiophens were also ~btained.''~ 96 97

98 99

loo

lo'

lo3

N. P. Gould and T.-J. Lee, J. Org. Chem., 1980, 45, 4528. S. Gronowitz, K. Stenhammar, and L. Svensson, Heterocycles, 1981, 15, 947. S. Gronowitz and I. Ander, Chem. Scr., 1980, 15, 135. A . Hallberg and S. Gronowitz, Chem. Scr., 1980, 16, 42. S. Gronowitz and P. Pedaja, Chem. Scr., 1980,15, 187. W. S. DiMenna, Tetrahedron Lett., 1980, 21,2129. D. Binder, C. R. Noe, W. Bilek, and M. Kubjacek, Arch. Pharm. (Weinheim, Ger.), 1981,313,228. T. A . Starostina, L. F. Rybakova, and R. R. Shifrina, Zh. Org. Khim., 1980, 16, 1968.

75

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

(82) R = HorOMe

fl

R S

0

Me,Si(-)CF=CFCI

(83) R = H or OMe

(84)

Metallation of acetal-protected thiophen-2-carboxaldehyde with butyllithium, followed by reaction with dialkyl chlorophosphites, gave (85).'04 2,5Dimethoxythiophen was metallated in the p-position by butyl-lithium at 0 "C to give 2,5-dimethoxy-3-thienyl-lithium, which unexpectedly underwent ringopening. By using 2 equivalents of butyl-lithium followed by dimethyl sulphate, l-methylthio-octa-1,3-diynewas obtained. When 2,5-dimethoxy-3-thienyllithium was prepared at -70 "C from the 3-bromo-derivative by halogen-metal exchange, it was stable enough to react with carbon dioxide to give the carboxylic acid.'" Both 2- and 3-triethoxysilylthiophen have been prepared by the reaction of the corresponding thienyl-lithium with tetrachlorosilane followed by ethanol in pyridine, or through the reaction of 2-thienylmagnesium bromide with tetraethoxysilane.lo6 The reaction of 2-chlorothiophen with trichlorovinylsilane at 600 "Cgave trichloro(2-thieny1)silanein low yield.lo7Some thienyl-containing (amino-alky1)silanes (86) that have psychotropic activity have been synthesized."' Another pharmacologically active compound that contains a thiophensilicon bond is (87), which was prepared via the reaction of 2-thienylmagnesium bromide with (88).lo9

pr- 3 (CH2)n- N

Me

104

10s 106 107

108

109

Ph

1-

0. L. Nevzorova, E. A. Krasilnikova, A. I. Razumov, and S. A. Kuznetsova, Zh. Obshch. Khim., 1980,50, 224. A. Hallberg, T. Frejd, and S. Gronowitz, J. Chem. SOC.,Perkin Trans. 1, 1980, 1390. E. Lukevits, 0. A. Pudova, andN. P. Erchak, Zh. Obshch. Khim., 1980,1348. V. G . Nosenko, V. G. Lakhtin, V. D. Sheludyakov, and V. F. Mironov, Zh. Obshch. Khim., 1980, 50, 1767. E. Lukevits, S. Germane, N. P. Erchak, and 0. A. Pudova, Khim.-Farm. Zh., 1981,15,42. R. Tacke, E. Zimonyi-Hegedus, M. Strecker, E. Heeg, B. Berndt, and R. Langner, Arch. Pharm. (Weinheim, Ger.), 1980, 313, 515.

Heterocyclic Chemistry

76 OMe

I

Ph- SiCH ,CH ,N

I

OMe

l-7 0 W (89) M = P d o r P t

The reaction of trichloro-5-iodothiophenwith copper bronze gave hexachloro2,2'-bithienyl in high yield."' Thienylmercury(I1) chloride reacted with [Pd(PPhJ2Cl2], [Pd(PPh3),], and [Pt(PPh,),] to give compounds (89), with trans stereochemistry."' 2-Bromothiophen underwent oxidative addition with [Pd(PPh,),] and [Pt(PPh3),], probably via a radical mechanism. With [Pd(CO)(PPh,),], a carbonyl-insertion product was obtained. The Schiff base from thiophen-3-carbaldehyde and p-toluidine is directly metallated by [Pd(PhCN),Cl,], in benzene, presumably in the $-position, which is somewhat unexpected. Grignard and organo-zinc reagents derived from dibromothiophens have been selectively mono-alkylated or -arylated, with Pd complexes as catalysts.112Thiophen has been alkenylated with various olefins to give monoand di-alkenylated products, using stoicheiometric amounts of palladium acetate. The process can be made catalytic in palladium by using copper(I1) acetate in the presence of air.", The one-step carboxylation of thiophen has been carried out, in 18% yield, by using carbon monoxide an4 palladium acetate.'14 3,4Dibromothiophen and 3,4-dimethyl-2,5-dibromothiophenhave been coupled with benzylmagnesium chlorides and arylmagnesium bromides by nickel- or palladium-catalysed coupling rea~ti0ns.l'~ The reactions of iodothiophens with triphenylphosphine in the presence of nickel chloride at 160°C gave triphenylphosphonium-substitutedderivatives.l16 In the presence of catalytic amounts of Rh4(CO)12,thiophen adds to diphenylacetylene to give 1-(2-thienyl)1.,2-diphenylethylene. l7 Photochemistry of Monocyclic Thiophens.-A review (with 116 references) on the photochemical rearrangement of five-membered-ring heterocycles has appeared.'18 Irradiation of a benzene-thiophen mixture gave traces of a 1 : l adduct only in the presence of proton donor^.''^ Irradiation of (90) in ether gave (91).12" In the photocycloaddition of (92) with (93), ring-closure to the benzene ring occurs to a minor extent, leading to (94) as the major and (95) as the minor product of such closure.121

'lo

"' 'I3

'I6

'" '18

'I9 120

12'

A. G. Mack, H. Suschitzky, and B. J. Wakefield, J. Chem. SOC.,Perkin Trans. 1, 1980,1682. L.-Y. Chia and W. R. McWhinnie, J. Organomet. Chem., 1980,188,121. A. Minato, K.Tamao, T. Hayashi, K. Suzuki, and M. Kumada, Tetrahedron Lett., 1980,21,845. Y. Fujiwara, 0. Maruyama, M. Yoshidomi, and H. Taniguchi, J. Org. Chem., 1981,46,851. Y. Fujiwara, T. Kawauchi, and H. Taniguchi, J. Chem. SOC.,Chem. Commun., 1980,220. A. Minato, K.Tamao, K. Suzuki, and M. Kumada, Tetrahedron Lett., 1980,21,4017. 0.M. Bukachuk, I. V. Megera, and M. I. Shevchuk, Zh. Obshch. Khim., 1980,50,1730. P.Hong, B.-R. Cho, and H. Yamazaki, Chem. Lett., 1980,507. A.Padwa, Org. Chem. (N.Y.), 1980,42,501. J. C.Berridge, A. Gilberg, and G. N. Taylor, J. Chem. Soc., Perkin Trans. 1, 1980,2174. M. M. Hesabi, J. Hill, and A. A. El-Hamamy, J. Chem. Soc., Perkin Trans. 1, 1980,2371. K. Maruyama, T. Otsuki, K. Mitsui, and M. Tojo, J. Heterocycl. Chem., 1980,17,695.

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

77

rj--CsJ

PhN

194)

(95)

Desulphurization and Hydrogenation of Simple Thiophens.-The thermal decomposition of diphenyliodonium-2-carboxylatein thiophen solution gave naphthalene as the major product, demonstrating the usefulness of thiophen as a trap for benzyne in Thiophen and 2-ethylthiophen were hydrogenated to the corresponding 2,5dihydrothiophens with zinc and trifluoroacetic acid. 123 Indirect reduction of thiophen by electrons, in DMF, in the presence of biphenyl as the electroncarrier, gives 2,5-dihydrothiophen and tetrahydrothiophen in high yields.124 Electrochemical reduction of 2,3,5-tribromothiophen has been suggested for the synthesis of 3-brornothi0phen.'~' Regio- and stereo-specific ring-opening was found to occur for thiophen-2-carboxylic acids upon treatment with lithium and ethanol in liquid ammonia, giving 4-mercapto-(22)- alk-2-enoic acids in preparative yields.'26 The reaction of thiophen with an excess of lithium and trimethylsilyl chloride gave (96) and (97) in 80% and 85% yield, re~pectively.'~~ Desulphurization of (98) and (99) by Raney nickel was used for the synthesis of the lignan skeleton Desulphurization by Raney nickel is the essential step in the synthesis of compounds in which a macrocyclic ring is condensed with a pyrazole ring, as indicated in Scheme 1.lZ8 Desulphurization of ( 5 5 ) in acetone gave (107; R = Me) in 96% yield.86 Desulphurization by Raney nickel was also essential in Wynberg's synthesis of chiral tetra-alkyl-methanes. Addition 122 123

lZ4

126

12'

'*'

D . Del Mazza and M. G. Reinecke, Heterocycles, 1980, 14, 647. Yu. Lyakhovetsky, M. Kalinkin, Z. Parnes, F. Latyopova, and D. Kursanov, J. Chem. Soc., Chem., Commun., 1980,766. S. G. Mairanovskii, L. 1. Kosychenko, and S. Z. Taits, Izv. Akad. Nauk SSSR, Ser. Khim., 1980, 1382. D . Pletcher and M. Razaq, J. Appl. Electrochem., 1980,10, 575. Ya. L. Gol'dfarb, E. P. Zakharov, A. S. Shashokov, and F. M. Stoyanovich, Zh. Org. Khim., 1980.16,1523. M. Laguerre, J. Dunogues, N. Duffaut, and R. Calas, J. Organomet. Chem., 1980,193, C17. Ya. L. Gol'dfarb, S. Z. Taits, and E. A. Krasnyanskaya, Khim. Geterotsikl. Soedin., 1980,920.

78

Heterocyclic Chemistry

of 2-thienylmagnesium bromide to the ap-unsaturated di-(-)-methyl ester (108) gave two diastereoisomeric adducts (109), which were separated. The compounds were then hydrolysed, decarboxylated, and desulphurized to (1lo), which, by reduction (via the alcohol and its tosylate), was transformed into butylethyl-

eN iii

li C0,Et %

(102) R = H ((103) R = Me

~

0

(104) iii

R =H (,(105) (106) R = Met-------

Reagents: i, Raney nickel; ii, PhNHNH,; iii, Me,SO,

Scheme 1

e /

Me

\

Pr

c=c\

/

Me

I

,CO,Men

&'

C0,Men

C0,Men

0

(1071

,CO,Men

Pr-C-CH

(109)

(108) [Men

=

(-)-menthy11

79

Five-Membered Rings: Thiophens and their Se and Te analogues Me I P~-C*-CH,CO,H I

Bu

(-@

Ph 5

Ph

methylpropylmethane of high optical purity.'*' A large number of papers concerning the catalytic hydrodesulphurization of thiophens have a ~ p e a r e d . ' ~ ' - ~ ~ '

The Structures and Reactions of Hydroxy-, Mercapto-, and Amino4hiophens.5-Phenylthiophen-3-one has been condensed with (111) to give (112)? The reaction of 5-bromo-2-thienylmagnesium bromide with 7-methoxycycloheptatriene, followed by thermal isomerization, gave (113). Upon reaction of the Grignard reagent from (113) with t-butyl peroxybenzoate, followed by dealkylation, the interesting system (114) was obtained, which is protonated on oxygen in TFA. From dipole moments and from 'H and 13C n.m.r., u.v., and i.r. spectra, it was concluded that (114) has a highly bond-alternated olefinic character.15* The ionization constants of thiophen-2- and -3-thiols in ethanol have been determined by the U.V. t e c h n i q ~ e . 'Compounds ~~ of the type (115),

129 1I n 131

132 133

134

135

136 137

138 139 140

W. Ten Hoeve and H. Wynberg, J. Org. Chem., 1980,45,2754. E.Baumgarten and H. Hoffkes, Z. Phys. Chem. (Frankfurt am Muin), 1980,121,107. C. S . John, J. G. Williamson, L. V. F. Kennedy, and J. K. Tyler, J. Chem. SOC.,Furuday Trans. 1, 1980,76,1356. Y.Okamoto, H.Tomioka, T. Imanaka, and S.Teranishi, J. Cutal.. 1980,66,93. Y.Okamoto, H.Tomioka, Y. Katoh, T. Imanaka, and S. Teranishi, J. Phys. Chem., 1980,84,1833. J. Bachelier, J. C. Duchet, and D. Cornet, J. Phys. Chem., 1980,84,1925. J. Maternovi and M. Zdraiil, Collect. Czech. Chem. Commun., 1980,45,2532. F. Behbahany, Z.Sheikhrezai, M. Djalali, and S. Salajegheh, J. Cutal., 1980,63,285. B. L. Lebedev, M. S. Khots, T. S. Kostromina, M. N. Kuznetsova, E. D. Radchenko, and A. V Agafonov, Neftekhimiyu, 1980,20,890. F. Olivares, 0.Abrams, and L. Katan, Rev. Port. Quim., 1977,19,208. F.Da Silva, J. Laine, and P. Andreu, Acta Cien?. Venez., 1980,31,17. M. Schmal, M. I. Pais da Silva, and E. Falabella de Sousa Aguiar, Rev. Bras. Technol., 1980,11,

175. 141 142 143 144

K. Fujimoto, K. Akiyoshi, M. Nakagawa, and T. Kunugi, Sekiyu Gakkuishi, 1980,23,203. T. Kabe, Y.Kabe, and T. Sodeyama, Nippon Kugaku Kuishi, 1980,349. T.Kabe, Y.Kabe, and T. Sodeyama, Nippon Kagaku Kaishi, 1980,1898. M. A. Lur'e, T. E. Glotova, I. Z. Kuretz, G. I. Sotnikova, and V. G. Lipovich, Kinet. Kutul.,

1980,21,1074. 145 146 147 148 149 150

151 152 153

V. I. Erofeev, 0. P. Shiryamova, L. M. Koval, and I. V. Kalechits, Kinet. Kafal., 1980,21,983. V. I. Erofeev, V. G. Basov, and I. V. Kalechits, Kinet. Kutul., 1980,21,500. P.Chakraborty and A. K. Kar, Proc. Nutl. Symp. Catal., 4th, 1978,(publ. 1980),p. 410. M.Sugioka and K. Aomura, Hokkaido Daigaku Kogakubu Kenkyu Hokoku, 1980,87. C. S . Brooks, Surf. Technol., 1980,10,379. Yu. I. Ermakov, A. N. Startsev, V. A. Burmistrov, and B. N. Kuznetsov, React. Kinet. Cutul. Lett., 1980,14,155. J.-P. Sauvi and N. Lozac'h, Bull. SOC.Chim. Fr., Part 2, 1980,577. K. Takahashi, T.Sakae, and K. Takase, Chem. Let?., 1980,179. A. V. Anisimov, V. S. Babaitsev, and E. A. Viktorova, Khim. Geterotsikl. Soedin., 1980,1313.

80

Heterocyclic Chemistry

(115) R' = H, alkyl, (CH2)nNR32,(CH2)20H,or (CH&OEt

and some metal chelates from them, which are readily soluble in organic solvents, have been prepared. 154 Some S-derivatives of thiophen-2-thiol have been evaluated as corrosion inhibitors for steel in heterogeneous A review (with 60 references) on thio-Claisen rearrangement in the synthesis of sulphurcontaining heterocyclic compounds has been p ~ b 1 i s h e d . l ~5-Methylsul~ phinylthiophen-2-carbaldehydehas been synthesized, in 80% yield, by oxidation of acet al-pro t ected 5 -(met hylthio)t hiophen -2 -carbalde hyde with 30% hydrogen peroxide in acetic acid.15' Some derivatives of thiophen-2-sulphonic acid have been prepa~ed.'~' The chloroacetylamino- and various aminoacetylamino-derivatives, of pharmacological interest, have been prepared from (18) and (19).16*17The reaction of (116) with dimeric mercaptoacetaldehyde gave (117), which is a useful starting material for thiophen analogues of the benzodiazepine type.159The reaction of a 1,2-diaminobenzene with (118) gave (119; X = NH2), which was aromatized by chloranil to (120; X = NH2, Y = C02Me). The corresponding compound (120; X = NO2, Y = CN) has been prepared in a similar manner.l6' Compounds of the type (120; X = NOz, Y = C02Et)were also obtained through the reaction of ortho-fluorinated nitrobenzenes with 3-amino-4-ethoxycarbonylfhiophens.l6l Curtius rearrangement of 4-ethoxythiophen-3-carbonylazide in the presence of o-nitrobenzoic acid gave (121), which could only be hydrogenated to the hydroxylamine derivative, except under acidic conditions, when the desired amino-derivative could be obtained, but these conditions also led to some cleavage of the amide bond. The condensation of 4-ethoxythiophen-3carbonyl chloride with 4-chloro- or 4-fluoro-l,2-phenylenediamine led to (122).162 The reaction of 4-substituted 3,4-diamino-2-(methylthio)thiophens with 1,3-dicarbonyl compounds gave compounds such as (123).163Ketens react with the compounds (124) to give (125). With p-nitro-styrenes, (126) was obtained from (124; R = Ph).1643-(1-Pyrrolidino)thiophens,such as (124; R = Ya. L. Gol'dfarb, M. A. Kalik, and Z. G. Kozlova, Khim. Geterotsikl. Soedin., 1980,1331. I. F. Mamed'yarova, D. G . Silimkhanova, M. M. Seidov, and S. M. Aliev, Korroz. Zashch. Neftegazov. Prom-sti, 1980,12. lJ6 A, V. Anisimov and E. A . Viktorova, Khim. Geterotsikl. Soedin., 1980,435. E.Kesler and S. Gronowitz, Monatsh. Chem., 1980,111,119. C. A. Obafemi, Phosphorus Sulfur, 1980,8,197. D. Binder, 0.Hromatka, C. R. Noe, F. Hillebrand, W. Veit, and J. E. Blum, Arch. Pharm. (Weinheim, Ger.), 1980,313,587. 16' J. K. Chakrabarti, J. Fairhurst, N. J. A. Gutteridge, L. Horsman, I. A . Pullar, C. W. Smith, D. J. Steggles, D. E. Tupper, and F. C. Wright, J. Med. Chem., 1980,23,884. 16' J. K. Chakrabarti, L. Horsman, T. M. Hotten, I. A. Pullar, D. E. Tupper, and F. C. Wright, J. Med. Chem., 1980,23,878. 16' J. B. Press, C. M. Hofmann, and S. R. Safir, J. Heterocycl. Chem., 1980,17,1361. Y.Tominaga, H.Fujito, H. Norisue, A. Ushirogochi, Y. Matsuda, and G. Kobayashi, Yakuguku Zasshi, 1980,100,699. 164 H. C. Mutreja and D. N. Reinhoudt, Recl. Trav. Chim. Pays-Bas, 1980,99,241. lS5

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

81

Bu'), react as pseudo-enamines with electron-deficient acetylenes, such as dimethyl acetylenedicarboxylate, to give [2 + 23 cyclo-adducts such as (127); these isomerize under the reaction conditions to give (128), which are also thermally unstable and which eliminate sulphur to give (129). In protic solvents, (130) was formed by intramolecular abstraction of hydrogen in the initially formed 1,4-dipolar intermediate.165The structure of (130) was proven by X-ray cry~tallography.'~~ Compound (124 ; R = Ph) reacted with o -phenylene diisocyanate to give a compound which most probably has the structure (131).166 Thiophen derivatives of the type (132) have been prepared from aminot h i o p h e n ~ , 'and ~ ~ compounds (133) via Curtius rearrangement of thiophen-2carbonyl azide and the reaction of the isocyanate with a secondary amine and also via the reaction of amines with secondary amines and phosgene followed by chlorination with carbon tetrach1oride-triphenylphosphine.l6' The reaction

C0,Me R

G

&

S

H (119)

(121)

(122) X = C l o r F

,9 N

q

165

166

lh7

N

Q

R'

R

(124) R = MeorPh

,9

(125) R

=

'COCHY,

9

,N

0

Ph

CHPhCH,NO,

M e o r P h , Y = PhorC1

D. N. Reinhoudt, J. Geevers, W. P. Trompenaars, S. Harkema, and G. J. van Hummel, J. Org. Chem., 1981,46,424. A. W. Faull, D. Griffiths, R. Hull, and T. P. Seden, J. Chem. SOC..Perkin Trans. 1, 1980, 2587. G. Fedgenhauer and R. Moll., J. Prakt. Chem., 1980,322, 826. W. Ried and R. Christ, Liebigs Ann. Chem., 1980, 699.

82

Heterocyclic Chemistry

Bu'

But@ CH,E

Bu' (E

=

C02Me)

(133) R

=

morpholino, pyrrolidino, or piperidino

(134)

NC CN ClSN O N S C l

of (134) with concentrated potassium hydroxide solution yields (135). A selective synthesis of 2,5-diamino-3,4-dicyanothiophenfrom malononitrile and sulphur has been de~cribed.'~'Irradiation of (136) in the presence of oxygen led to the corresponding ~ulphone.'~'2,5-Diamino-3,4-dicyanothiophenreacted with sulphur dichloride to give (137), which can be converted into highly conducting p01ymers."~"~~ Some 3-hydrazinothiophen hydrochlorides have been synthesized from suitably 5-substituted 2-methoxycarbonyl-3-aminothiophens,and some hydrazones were prepared from them.173 Reactivities of Side-Chains of Monocyclic Thiophens.-The rate-constants for the alkaline hydrolysis of eleven methyl esters of 2-substituted thiophen-3carboxylic acids in methanol-water have been determined . When the logarithms of the rate-constants were plotted versus cHand -ApK,, linear free-energy 169

I7O

17'

W. Offermann, K. Eger, and H. J. Roth, Arch. Pharm. (Weinheim, Ger.), 1981,314, 168. R.-L. Sarantaus-Zimmermann, K. Eger, and H. J. Roth, Arch. Pharm. (Weinheim, Ger.), 1981, 314, 127. F. Wudl and E. T. Zellers, J. A m . Chem. Soc., 1980, 102,4283. F. Wudl, E. T. Zellers, and D. Nalewajek, J. Org. Chem., 1980, 45, 3211. P. R.Huddleston, J. M. Barker, and Y. Z. Adamczewaka, J. Chem. Res. (S), 1980, 238.

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

83

ortho-correlations were obtained, thus giving additional evidence for the much smaller steric effects in ortho -like substituted thiophens than in benzenes.174The dissociation constants of some 4-substituted thiophen-3-carboxylic acids in water have been determined and correlated with various kinds of substituent constants. The resulting data have confirmed the hypo-ortho character of the C(3)-C(4) relation in thiophen derivatives as compared to the C(2)-C(3) hyper-ortho re1ati0n.l~' Rates of cleavage of substituted [phenyl(2-thienyl)methyl]trimethylsilanes and analogous furan derivatives by sodium methoxide in methanol have been measured. The results indicate that the 2-thienyl and 2-fury1groups stabilize a carbanionic centre more effectively than a phenyl group, and the following approximate pK, values were derived: Ph2CH2,33.4; Ph(2-thienyl)CH,, 30.0; (2-thieny&CH2, 27.1.176 condensations Reactions of Thiophen Aldehydes and Ketones.-Numerous between thiophen aldehydes and ketones and more or less complex activemethylene derivatives have been carried O U ~ . ~ The ~ , reaction ~ ~ ~ of - thiophen~ ~ ~ 2-carbaldehyde with butanedial in acetic acid-potassium acetate gave (138).18' The condensation of 2-acetyl-5-methylthiophen with (139) gave (140).'86 Schiff bases from thiophen-2-carbaldehydeshave been used for the synthesis of some 88 Schiff bases between amino-furans and some thienylazetidin-2-ones, thiophencarbaldehydes have also been obtained.189 Palladium(I1) complexes from Schiff bases of thiophen-2-carbaldehyde have been characterized by their

0

G. Consiglio, S. Gronowitz, A.-B. Hornfeldt, R. Noto, and D. Spinelli, Chem. Scr., 1980, 15, 49. G. Consiglio, S. Gronowitz, A.-B. Hornfeldt, R. Noto, and D. Spinelli, Chem. Scr., 1980, 16, 117. C. Eaborn, G. Pirazzini, G. Sedoni, and A. Ricci, J. Organomet. Chem., 1980, 192, 339. 177 Y. Yamashita and M. Masumura, Heterocycles, 1980,14, 29. ' 7 1 D. R. Shridhar, C. V. R. Sastry, K. B. Lal, A. K. Marwah, G. S. Reddi, K. K. Bhopale, H. N. Tripathi, R. S. Khokhar, K. Tripathi, and G. S. T. Sai, Indian J. Chem., Sect. B, 1981, 20, 234. 179 H. H. Moussa and B. Haggag, Indian J. Chem., Sect. B, 1980,19, 156. Yu.D. Churkin and L. V. Panfilova, Khim. Geterotsikl. Soedin., 1980, 1048. 18' Yu.D. Churkin, L. V. Panfilova, A. S. Shashkov, and K. Ya. Burshtein, Khim. Geterotsikl. Soedin., 1981,325. ''' T. SzelI, A. Brand, and S. Ratanathanawongs, J. Chem. Eng. Data, 1981, 26, 230. R. Kada, V. Knoppovi, J. KoviE, and M. Balag, Collect. Czech. Chem. Commun., 1980,45, 2360. la' A. M. El-Khawaga, K. M. Hassan, and A. A. Khalaf, Z. Naturforsch., Teil. B, 1981, 36, 119. '*' A. M. El Gendy, A. Mallouli, and Y. Lepage, Synthesis, 1980, 898. la6 Zh. A. Krasnaya, T. S. Stytsenko, E. P. Prokof'ev, and V. F. Kucherov, Izv. Akad. Nauk SSSR, Ser. Khim., 1980, 1362. M. S. K. Youssef, Indian J. Chem., Sect. B, 1980,19,796. la8 M. S. K. Youssef and K. H. M. Hassan, Indian J. Chem., Sect. B, 1980, 19, 361. lS9 J. Prousek, A. Juriiek, and J. KoviE, Collect. Czech. Chem. Commun., 1980,45, 1581. 190 V. K. Gupta, N. C. Jain, and D. K. Sharma, Curr. Sci., 1980, 49,459.

'71

175

176

*''

Heterocyclic Chemistry

84

COR'

OCOCHCe S

CH ,CO,Et

A,

COR~

electrical conductivity and i.r. spectra. 190 The Wittig reaction between thiophen2-carbaldehyde and the appropriate phosphonate gave (141).19' The thiazoliumsalt-catalysed addition of thiophen-2-carbaldehyde to arylidene and alkylidene p -dicarbonyl compounds gave compounds of the type (142).lg2From 2-thenoylacetic acid and 2-hydroxy-l-methylpyrrolidine,(143) was prepared.193 The reaction of thiophen with (144) gave the ketone (145).'94 The reaction of (146) with thiophen-2-carbaldehyde yielded (147).'95 The structures and dynamic conversions of some fluorine-containing /3 -aminovinyl ketones of the type (148) have been Compounds such as (149)19' and (150)198have been synthesized. Physical properties of metal p -diketonates derived from 4,4,4trifluoro-l-(2-thienyl)butane-1,3-dionehave been i n v e ~ t i g a t e d . ' ~ ~ -Oscilla~'~ tion in the rate of reduction of 5-bromo-2-acetylthiophen on mercury has been Transition-metal complexes of thiophen-2-aldoxime have been in~estigated.~~~'~~~

0 (147) 191

S . Linke, J. Kurz, D. Lipinski, and W. Gau, Liebigs Ann. Chem., 1980,542. H. Stetter and F. Jonas, Chem. Ber., 1981,114,564. 193 A.S. Radwan, F. R. Melek, and S. Negm, J. Prakt. Chem., 1980,322,475. 194 D.C. England, J. Urg. Chern., 1981,46, 147. 19' N. N.Magdesieva and N. G. Chovnikova, Zh. Org. Khim., 1979,15,2402. 196 A . Ya. Aizikovich, K. I. Pashkevich, V. V. Gorshkov, M. N. Rudaya, and I. Ya. Postovskii, Zh. Obshch. Khim., 1980,SO.1866. 19' V. 1. Esafov, V. Ya. Sosnovskikh, and V. I. Proshutinskii, Zh. Org. Khim., 1980,16,2008. 19* G.F. Kolyagina, N. P. Glazunova, V. I. Meshcheryakov, L. D. Gavrilov, and L. I. Vereshchagin, Khim.-Farm. Zh., 1981,15.46. 199 K. S. Patel, J. Inorg. Nucl. Chem., 1980,42,1235. 2oo K. S.Patel and A. A . Adimado, J. Inorg. Nucl. Chem., 1980,42,1241. 201 B.Jezowska-Trzebiatowska, Z. Olejnik, and T. Lis, J. Chem. Soc., Dalton Trans., 1981,251. 202 H.G.Brittain, Inorg. Chem., 1980,19, 3473. 203 A. B. Ershler and 1. M. Levinson, Elektrukhirniya, 1981,17,475. *04 N.M. Pradhan and D. N. Patkar, Natl. Acad. Sci. Lett. (India), 1980,3 , 83. 205 M. Mohan, Gazz. Chim. Ital., 1979,109,655. 192

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

Me

85

0 \

II

C=CHCCH=CMe, (150) R' = PhorSEt

(149)

Reactions of Carboxythiophenand its Derivatives.-The ester (151)yields (152) by A1C13-catalysed Fries rearrangement; by alkylation, (152) was transformed into (153), which, in contrast to the 4-(2-thenoyl)isomer, showed no diuretic activity.2MEsters (154) were converted into the ketones (155) by treatment with base; upon reaction with bromine, (155) gave the coumarones (156).207 The 'crown'-type compounds (157) have been prepared from thiophen-2,5dicarbonyl chloride and suitable glycols.2o82-Thenoyl cyanide was prepared

(151)

Cl (152) R = H (153) R = CHzCOzH

0

(154)

R'

0 (156)

(157) n

0

=

3-5

through the reaction of 2-thenoyl chloride with tributyltin cyanide.2092-Thenoyl azide reacted with aromatic and heterocyclic amines to give the corresponding amides. At higher temperatures, NN-disubstituted ureas were Some novel analogues of phthalein dyes have been synthesized from 2-(2-thenoyl)benzoic acid and various phenols.'" Gas-phase thermolysis of thiophen-2,3-dicarboxylic acid anhydride produces thiophen-fused cyclopropenone,which has been trapped by polyfluorocarbonyl compounds.212

*06

207 208

W. Liebenow and K. Mannhardt, Arch. Pharm. (Weinheim, Ger.), 1981,314,409. K. Rangachari, A. K. D. Mazumdar, and K. D. Banerji, J. Indian Chern. Sac., 1980,57, 1014. J. S. Bradshaw, S. L. Baxter, J. D. Lamb, R. M. Izatt, and J. J. Christensen, J. A m . Chem. SOC., 1981,103,1821.

209 210

M. Tanaka, Tetrahedron Lett., 1980, 21, 2959. B. Stanovnik, M. Tibler, V. Golob, I. Hvala, and 0. NikoliE, J. Heterocycl. Chem., 1980, 17, 733.

R. P. Chamoli, S. J. Rai, and P. G. Gupta, Bull. Chem. SOC.Jpn., 1980, 53, 3000. M. G. Reinecke, L.-J. Chen, and A. Almqvist, J. Chem. SOC., Chem. Cornmun., 1980, 585.

Heterocyclic Chemistry

86

Reactions of Vinylthiophens and Related Compounds.-Chalcones that contain thiophen rings have been epoxidized by hypochlorite under phase-transfer conditions.213 3-(2-Thienyl)acrylophenones reacted with malononitrile in the presence of ammonium acetate to give 2-amino-3-cyano-4-thienyl-substituted pyridines214 The conjugate addition of Grignard reagents to (158)has been in~estigated.~" 2-Thienyl-l-methylsulphinyl-l-methylthioethylene, upon treatment with acetic anhydride, gave (159),which is the product of a Pummerer rearrangement; upon acid solvolysis in ethanol, (159)gave methyl 2-thienyldithioacetate, and in the presence of amines it gave the corresponding thioacetamides.2'6 Only (Z)-2-(2-brornovinyl)-5-nitrothiophenwas formed in the debrominative decarboxylation of the alkali-metal salts of 2,3-dibromo-3-(5nitro-2-thieny1)propionic acid in acetone. It reacted with a number of 0-,S-, and N-nucleophiles to give compounds ( 160).217 Some unsaturated thiophen SCH .OAc =CH-X (159)

(160) X

=

OAr, SAr, S02Ar, N3, or NMe2

ketones have been synthesized for pharmacological testing.218 Thiophen-2aldoxime and 2-thienylacrolein aldoxime have been transformed into (161)and (162),respectively, by oxidation with lead t e t r a - a ~ e t a t e . ~1'-(2-Thienyl)-2~ vinylcyclopropanes have been prepared from 2-(diazomethy1)thiophen (obtained

(161) n (162) n

=

0

=

1

by oxidation of the hydrazone) and butadiene or 2,3-dimethylbutadiene. Cope rearrangement led to (163), which was aromatized by acid or base catalysis.220 The three isomeric compounds (164)-(166) were prepared by a combination of bromination of the side-chain, Wittig reactions, and aldehyde synthesis via the Sommelet reaction of metal-organic compounds. Via the hydrazones, the diazo-compounds were prepared, of which the two derived from (164)and (165) cyclized to (168)and (169)upon heating, while the one from (166)did not. A . Arcoria, F. P. Ballistreri, A. Cantone, G. Musumarra, and M. Tripolone, Gazz. Chim. Ital., '1980,110,267. 'I4 N. Latif, N. Mishriky, and N. S. Girgis, Indian J. Chem., Sect. B, 1981, 20,147. 'Is M. L. Haslego and F. X. Smith, Synth. Commun., 1980, 10, 421. 'I6 K. Ogura, Y. Ito, and G.-I; Tsuchihashi, Synthesis, 1980, 736. 'I7 D . VCgh, J. KovaE, and M. DandGrovB, Tetrahedron Lett., 1980, 21,969. '18 D.A . Kulikova, Yu. D . Churkin, and L. V. Panfilova, Khim. Farm. Zh., 1980, 14, 36. 2 1 9 U. Pinder and B. Unterhalt, Arch. Pharm. (Weinheim, Ger.), 1979, 312,282. ''O G.Maas and C. Hummel, Chem. Ber., 1980,113, 3679. 'I3

87

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

Rcph fi S

(165) R' = H, R2 = CHO (166) R' = CHO, R2 = H

(168) X = CPh,Y = N (169) X = N,Y = CPh

S

(167) X (170) X

= =

N , Y = CPh CPh,Y = N

(172)

Treatment with base caused (167) and (168) to isomerize to (169) and (170), while irradiation gave (171) and (172).221 The reduction at a mercury electrode of some [2.4]cyclophanetetraenes that contain two and four thiophen rings has been investigated.222 Reactions at Benzylic Positions.-The cis-trans ratio of the stilbenes formed in Wittig reactions between ylides derived from benzyltri(heteroary1)phosphonium salts with benzaldehyde was found to decrease markedly in the series 2-fury1 > 2-thienyl > phenyl > 1-rnethylpyrr01-2-yl.~*~ Thenyl cyanideswere formylated, and, via the methoxy-derivatives, transformed into (173); upon nitrosation, these gave (174), which were characterized as (175).2242-Thienyl(toluenep-sulphony1)methane was metallated and then allowed to react with ethylene oxide to give (176).84Ethyl 3-thienyl malonate and 3-thienyl acetate have been alkylated in the benzylic position. Alternatively, 3-thenyl cyanide was condensed with ketones and the ap-unsaturated nitriles were reduced with sodium borohydride in order to obtain the desired acids, from which amides of pharmacological interest were prepared.225Fluoride-induced 1,6-eliminationin (177)gave, via the 2,5-dimethylene-2,5-dihydrothiophen, the dimer (178) and the corresponding trimer, in 37% and 14% yield, respectively.226The reaction of 2-thenylmagnesium chloride with 1,3,4-trirnethylpyridinium iodide gave (179),which, in a few steps, was converted into the benzomorphane-related 221 222

223 224 225

226

D. P. Munro and J. T. Sharp, J. Chem. SOC.,Perkin Trans. 1, 1980,1718. K.Ankner, B. Lamm, B. Thulin, and 0.Wennerstrom, J. Chem. SOC.,Perkin Trans. 2, 1980,1301. D.W. Allen and H. Ward, 2. Naturforsch., Teil. B, 1980,35,754. M. Cariou, Bull. SOC.Chim. Fr., Part2, 1979,651. P.de Cointet, P.-J.Grossi, C. Pigerol, M. Broll, and P. Eymard, Chim. Ther., 1980,15, 223. Y. Ito, S. Miyata, M. Nakatsuka, and T. Saegusa, J. Org. Chem., 1981,46,1043.

88

Heterocyclic Chemistry ((Y=C-CN

NMe,

S

compound (180).227 Some amines have been prepared from 2-chloromethyl-3,4,5-tri~hlorothiophen.~~~ The oxidation of 2-(methoxymethy1)thiophen with molecular oxygen in the presence of catalytic amounts of cobalt bromide gave 2-formylthiophen and methyl thiophen-2-carboxylate in a 1 :2 ratio.229 C0,Et

HCI

Me (179)

X

?$Me (180)

&

(181) X

5

=

H or Br

Various Reactions in the Side-Chain of Thiophens.-The amide that is derived from 3-thienylacetic acid and some (alkoxy-P-phenylethy1)amineswere used to prepare (181;X = H);by its reaction with ethyl chloroformate, this was converted into (182).230Compound (181; X = Br) has been prepared (starting from 2,5dibromo-3-thienylacetic acid) and used for the synthesis of (183), which was

Me0

Br

227

228

”*

230

J. Bosch, M. Alvarez, and R. Granados, J. Heterocycl. Chem., 1980,17,745. A. M. Saakyan, A . A . Safaryan, and A. N.Akopyan, Arm. Khim.Zh., 1979,32,826. A. A. Leichenko, T. V. Schedrinskaya, and M. N. Volkov, Khim. Geterotsikl. Soedin., 1980,924. S. Jeganathan and M. Srinivasan, Indian J. Chem., Sect. B, 1980,19,312.

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

89

obtained by the reaction of the dihydro-derivativeof (181; X = Br) with formaldehyde in formic acid; an interesting reaction mechanism has been ~uggested.'~' Photochemical ring-closure of the acetylated dihydro-derivativeof (181;X = Br) gave (184) with debr~minafion.'~~ Starting from 2-(3-thienyl)ethylamine and 3,4-dialkoxybenzoic acids, (185) has been prepared.233Compound (83) was methylated at the benzylic position, and, via the oxime, reduced to the amine; upon reaction with formaldehyde, followed by acetic anhydride, this gave (186).102*234 From 4,5,6,7-tetrahydrothieno[3,2-c]pyridine-4-and -6-carboxylic

OMe

(186)

R

=

H or OMe

acids, (187) and (188) were prepared by diazotization and reaction with acetic anhydride. 1,3-Dipolar cycloaddition of dimethyl acetylenedicarboxylate to these meso-ionic compounds gave (189) and (190).235Starting from 2-amino-l(2-thienyl)ethanols, 2-(2-thienyl)morpholines were prepared, and their pharmacological properties have been e v a l ~ a t e d . ~Phosphorylcholine ~~.~~' esters derived from 2-(2-thienyl)ethanol have been prepared,238 as well as some glycopeptides that contain a thiophen ring.239

0-

(189)

(190)

S. Jeganathan and M. Srinivasan, Synthesis, 1980, 1021. 232 S. Jeganathan and M. Srinivasan, Indian J. Chem., Sect. B, 1980,19, 1028. 233 S. Jeganathan, D. Kuila, and M. Srinivasan, Synthesis, 1980, 469. 234 D. Binder, C. R. Noe, and W. Bilek, Arch. Pharm. (Weinheim, Ger.), 1980, 313, 883. "' J.-P. Maffrand, Heterocycles, 1981, 16, 35. 236 M. Carissimi, G. Icciola, F. Ravenna, G . Carenini, and P. Gentili, Farmaco, Ed. Sci.. 1980,35,812. 237 G. Picciola, F. Ravenna, G. Carenini, S. Manzardo, and P. Gentili, Farmaco, Ed. Sci., 1981, 36, 47. 23a T. F. Spande, J. Org. Chem., 1980, 45, 3081. 239 M. M. Ponpipom, R. L. Bugianesi, and T. Y. Shen, Carbohydrate Res., 1980, 82, 141. 231

90

Heterocyclic Chemistry

Reaction at Sulphur: Thiopheo Dioxides.-Attempts at S-alkylation of some simple thiophen derivatives such as 2-methoxythiophen, 4-(2-thienyl)butyl iodide, and 3-iodopropyl 2-thienyl ketone failed.240 The reaction between thiophen 1,l-dioxide and 6-dimethylamino[6-’3C]fulvenewas used for the synthesis of [4-’3C]azulene.241Some spectral investigations of 2,5- and 4,5-dihydrothiophen 1,l-dioxides have been carried The reactions of the oxides of sulpholen and 3-methylsulpholen with some acid chlorides and chloromethyl ethers have been inve~tigated,’~~ as well as the palladium-catalysed reaction of 3-sulpholen with 1 , 3 - d i e n e ~ . ’The ~ ~ alkylation of 3,4-dimethyl-2,5-dihydrothiophen 1,l-dioxide with acrylonitrile and benzyl chloride has been investigated.245 The reaction of a -halogeno-tetrahydrothiophen 1,l-dioxides with strong bases has been A mixture of cis- and truns-4-[alkyl(or heteraryl or aryl)amino]thiolan-3-01 1,l-dioxides and (3-hydroxy-l,l-dioxothiolan-4y1amino)acetic acids was obtained in the reactions of 2,3-dihydrothiophen-3-01 1,l-dioxide with aliphatic, heterocyclic, and aromatic amines and with gly~ine.’~’ Intramolecular Diels-Alder reactions of suitably substituted 2,5-dihydrothiophen 1,l-dioxides, such as (191), have been used for the synthesis of natural products. Thus, heating (191) at 370-390 “C gave (192), probably via (193). The compound (192) was easily converted into the alkaloid elaeokanine A.248A review covering this synthetic approach has been p ~ b l i s h e d . ’ ~ ~ The reactions of allylsulphenic acids with alkynes yielded derivatives of thiolan of dimethyl acetylenedicarboxylate to 4,5-dihydrol - ~ x i d e . ” Cycloaddition ~ thiophen 1-oxides has been in~estigated.’~’Flash vacuum pyrolysis of compounds such as (194) has offered a new stereospecific synthesis of cis-1,2-divinyl

derivative^.'^' 0

240 241 242 243

R. M. Acheson and M. W. Cooper, J. Chem. SOC., Perkin Trans. 1, 1980,1185. J. Becker, C. Wentrup, E. Katz, and K.-P. Zeller, J. A m . Chem. SOC., 1980,102,5110. G . V. Klimusheva, T. E. Bezmenova, G . M. Soroka, and G . G . Rode, Tetrahedron, 1980,36,1667. L. A.Mukhamedova, L. I. Kursheva, and F. S. Khasyanzyanova, Khim. Geterotsikl. Soedin., 1981,

916. 244

245

246 247 248 249

250

2s 1

252

R. V. Kunakova, F. V. Sharipova, G. A. Tolstikov, L. M. Zelenova, A. A. Panasenko, L. V. Spirikhin, and U. M. Dzhemilev, Izv. Akad. Nauk SSSR, Ser. Khim., 1980,1833. A. Ts. Malkhasyan, E. M. Asatryan, R. T. Grigoryan, A. P. Engoyan, S. M. Mirakyan, and G. T.Martirosyan, Arm. Khim. Zh., 1979,32,678. R.Neidlein and H. Dorr, Liebigs Ann. Chem., 1980,1540. T. E.Bezmenova, P. G. Dul’nev, and M. V. Rybakova, Khim. Geterotsikl. Soedin., 1980,475. H. F.Schmitthenner and S. M. Weinreb, J. Org. Chem., 1980,45,3372. W.Oppolzer, Heterocycles, 1980,14,1615. R. Bell, P. D. Cottam, J. Davies, D . N. Jones, and N. A. Meanwell, Tetrahedron Lett., 1980,21,

4379. K. Gollnick and S. Fries, Angew. Chem., 1980,92,849. J. I. G.Cadogan, I. Gosney, L. M. McLaughlin, and B. J. Hamill, J. Chem. SOC., Chem. Commun., 1980,1242.

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

(194) X

=

91

0,S, or NCH2Ph

Di-and Tetra-hydrothiophens.-Thermal cycloaddition of tetracyanoethylene to 2,3-dihydrothiophens gave the corresponding tetracyanocyclobutane derivat i v e ~ . ~Photolysis ’~ of some acetylenic thiols led to 2,3-dihydrothiophen and other products. 254 A simple synthesis of 2,2-disubstituted tetrahydrothiophens consists of treatment of diethyl 2-(3-mesyloxypropyl)malonate with potassium thioacetate in DMF.2’5 All possible isomers of 4-ureido-3-hydroxy-2-(5-alkoxycarbonylbuty1)tetrahydrothiophen have been synthesized.256Optically active (195) was obtained by an efficient asymmetric synthesis from N-Boc- (S)-methionine ethyl ester, and its absolute configuration was determined by X-ray ~rystallography.~~’ The synthesis and reactions of 3,4-dimethylenetetrahydrothiophenhave been inve~tigated.~’~ The a-diazo-ketone of 2,2,5,5-tetramethylthiolan-3,4-dione underwent both thermally and photochemically induced rearrangement, mainly to a thietanone derivative, which underwent further fragmentati~n,~~’ The baseinduced photo-reactions of thiolan-2,4-dione have been studied.260Some reactions of 2,5-di(chloromethyl)tetrahydrothiophen have been investigated.261 Bis(imin0)thietans gave (196) upon reaction with t-butyl isocyanide.262In an efficient total synthesis of cantharidine, the high-pressure Diels-Alder reaction NHBoc

6 S Me

(195)

253 254

255

256

257 258 259 260

262

Tos-

NC

R’

TosHN

Bu‘Nq ; I P (194)

S. Fries and K. Gollnick, Angew. Chem., 1980,92,848. C.Dupuy, M.-P. Crozet, and J.-M. Surzur, Bull. SOC.Chim. Fr., Part 2, 1980,361. G . H. Hakirnelahi and G. Just, Tetrahedron Lett., 1980,21,2119. S. D. Mikhno, T. M. Filippova, N. S. Kulachkina, I. G. Suchkova, and V. M. Berezovskii, Khim. Geterotsikl. Soedin., 1980,616. K. Tani, S. Otsuka, M. Kido, and I. Miura, J. A m . Chem. SOC.,1980,102,7394. A.G.Talma, J. G. M. Goorhuis, and R. M. Kellogg, J. Org. Chem., 1980,45,2544. J. Bolster and R. M. Kellogg, J. Org. Chem., 1980,45,4804. K. Saito and T. Sato, Bull. Chem. SOC.Jpn., 1979,52,3601. G. A. Tolstikov, R. G. Kantyukova, and L. V. Spirikhin, Zh. Org. Khim., 1980,16,1408. G. L’abbi, J.-P. Dekerk, and M. Mahy, Bull. SOC.Chim. Belg., 1980,89,561.

92

Heterocyclic Chemistry

between 2,5-dihydrothiophen-3,4-dicarboxylic anhydride and furan is the key step. The adducts were desulphurized to cantharidine by using Raney 2-(Tetrahydrothieny1)benzimidazoles have been prepared from 2-(mercaptoalky1)benzimidazoles and p -halogenoalkyl ketones.264Some fused p -1actams that contain a dihydrothiophen ring265and a sulphur analogue of A'-PGI1 have been prepared.266 The rotational constant, moments of inertia, bond lengths, and bond angles of tetrahydrothiophen have been determined by microwave Chemical shifts for 13Cand conformations of tetrahydrothiophen and its methyl derivatives have been studied.268The crystal and molecular structures of the tetrahydrothiophen adduct of niobium bromide sulphide have been determined.269 Bi- and Poly-heterocycles.-The preferred conformations of some bridged 2,2'and 3,3'-bithienyls such as dithieno[c,e]dihydro-azepines, -oxepins, and -thiepins have been studied by U.V. The nitration and bromination of 4-(2-thienyl)pyrazoles and 4-(3-thienyl)pyrazoles have been investigated to evaluate the directing effect of a 4-pyrazolyl group in electrophilicsubstit~tion.~~' 2,5 -Di-(3-indolyl)thiophenhas been synthesized from indolediacetylenicderivat i v e ~ 2,5-Di-(2-thienyl)pyridines .~~~ have been prepared by ring-closure of the pyridine ring273 and 4-(2-thienyl)-3,5-dicyano-1,4-dihydropyridines were obtained by the reaction of thiophen-2-aldehyde with two moles of @-aminocrotononitrile and were oxidized to the corresponding p y r i d i n e ~ .3~-(2~~ Thieny1)pyridazine and some of its 6-substituted derivatives have been prepared.275,276 The reaction of 5-bromo-2-thenylideneacetophenoneswith arylhydrazines gave some 5-(5-bromo-2-thienyl)-1,3-diary1-2-pyrazoline~.~~~ 3-(2Thienyl)-4H-1,4-benzothiazinewas obtained by the lead-tetra-acetate-induced ring-contraction of a thia~ocine.~'~ From (113), the interesting compound (197) was prepared via the aldehyde and the cyanomethyl derivative.279Condensation of 2-thienylglyoxal with some o-aminophenols gave 3-(2-thienyl)-2H-1,4benzoxazines. Electrochemical reduction of 4-(2-thienyl)quinazoline has been

263 264

26s

266 267

268

269 "O

271 272

273 274 275

276 277 278

279

W. G. Dauben, C. R. Kessel, and K. H. Takemura, J. Am. Chem. SOC.,1980,102,6893. H. 0.Hankovszky, K. Hideg, L. Lex, A. Foldesi, and P. Sohar, J. Chem. Soc., Perkin Trans. I , 1980,699. R. J. Ponsford, Tetrahedron Lett., 1980,21,2451. M. Shibasaki, Y. Torisawa, and S. Ikegami, Chem. Lett., 1980,1247. A. Kh. Mamleev and N. M. Pozdeev, Zh. Strukt. Khim., 1979,20, 1114. G. Barbarella and P. Dembech, Org. Magn. Reson., 1980,13,282. M. G. B. Drew, I. B. Baba, D. A. Rice, and D . M. Williams, Znorg. Chim. Acfa, 1980,44,L217. P. Meunier and J, Arriau, J. Heterocycl. Chem., 1980,17,321. S. Liljefors and S. Gronowitz, Chem. Scr., 1980,15,102. A.B. Kamenskii, Yu. 1. Smuchkevich, A. I. Livshits, and N. N. Suvorov, Zh. Org. Khim., 1980, 16,758. R. S. Tewari, S. C. Chaturvedi, and D. K. Nagpal, J. Chem. Eng. Data, 1980,25,293. R. Balicki, H. Blaszczak, and P. Nantka-Namirski, Acta Pol. Pharm., 1980,37, 1. J. Bourguignon, C.BCcue, and G. QuCguiner, J. Heterocycl. Chem., 1981,18,425. G. Steiner, J. Gries, and D. Lenke, J. Med. Chem., 1981,24,59. A . M . Abououf, M. El-Kerdawy, H. Ragab, and M. Moustafa, Pharmazie, 1979,34,798. J. B.Press, N. H. Eudy, F. M. Lovell, and N. A . Perkinson, Tetrahedron Left., 1980,21, 1705. K.Takahashi, K. Takase, and T. Sakae, Chem. Lett., 1980, 1485.

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

93

investigated.280-2822-Phenyl-5-(2-thienyl)thiophen has been found to be a phototoxic

Naturally Occurring Thiophens.-3,4-Dimethyl-2,5-dioxo-2,5-dihydrothiophen has been identified as a new volatile compound in onion and leek.284 2-(Penta-1,3-diynyl)-5-(3,4-dihydroxybut-l -yl)thiophen was extracted from the ~ ~ the compounds (198) from aerial parts root bark of Echinops g i g a n t e ~ s *and of Porophyllum ruderale.286The identification and analyses of thiophens from oil and coal have been

(197)

(198)

R

=

H or OAc

Thiophen Analogues of Steroids.-2’-Aminoandrost-2-eno[2,3-b]thiophens29s and the steroid analogues (199),296 and (201)298have been prepared.

280

( a ) E. Belgodere, R. Bossio, V. Parrini, and R. Pepino, J. Heterocycl. Chem.. 1980,17,1625;(6)

T.P. Devi, C. Kalidas, and C. S . Venkatachalam, J. Electroanal. Chem. Interfacial Electrochem., 281

282 283

284

285 286

287

288 289 290 291

292 293

294 295 296 297 298

1980,113,285. G . Antony, T. P. Devi, M. Srinivasan, and C. S . Venkatachalam, Trans. SOC.Adv. Electrochem. Sci. Technol., 1979,14,213. T.P. Devi, M. S. Gopinathan, and C. S . Venkatachalam, Electrochim. Acta, 1980,25, 1173. J. Kagan, R. Gabriel, and S. P. Singh, Experientiu, 1981,37,80. M.Albrand, P. Dubois, P. Etievant, R. Gelin, and B. Tokarska, J. Agric. Food Chem., 1980,28, 1037. F. Nguimatsia, J. Huet, and L. Girre, Plant. Med. Phytother., 1980,14,170. F.Bohlmann, J. Jakupovic, H. Robinson, and R. M. King, Phytochemistry, 1980,19,2760. N . K. Lyapina, M. A. Parfenova, T. S. Nikitina, E. S. Brodskii, and A. U. Ulendeeva, Neftekhimiya, 1980.20,747. N. K.Lyapina, M. A. Parfenova, and A. D. Ulendeeva, Neftekhimiya, 1980,20,908. E. A. Voitkovskaya, B. F. Voitkovskii, and G. P. Koptev, Koks Khim., 1980,22. A. U. Ulendeeva, A. A. Vol’tsov, N. K. Lyapina, and V. I. Lygin, Neftekhimiya, 1980,20, 131. M.Kuras. Sb. Vys. Sk. Chem.-Technol. Praze, Technol. Paliv, 1980,D42,7. A. A. Miroshnichenko and L. G. Fedosyuk, Zh. Prikl. Khim., 1980,53,1818. C . Willey, M.Iwao, R. N. Castle, and M. L. Lee, Anal. Chem., 1981,53,400. S . M.Farroha, A. E. Habboush, and Z . Savaya, J. Chromatogr. Sci., 1980,18,237. Yu.A. Sharanin and V. K.Promonenkov, Khim. Geterotsikl. Soedin., 1980,1564. S . R. Ramadas and N. S . Chandrakumar, Steroids, 1980,36,593. S. R. Ramadas and P. Ch. Chenchaiah, Steroids, 1981,37,353. T. Terasawa and T. Okada, Steroids, 1981,37,445.

94

Heterocyclic Chemistry

Thiophens of Pharmacological Interest.-A useful review (with 25 1 references) on pharmacologically interesting thiophen derivatives has been The great interest in thiophen-containing tricyclic systems that act on the central nervous system is continuing. Thus, cyclization of (119) and (120) to the sevenmembered amides and further modification led to (202) and (2O3).l6O By an analogous synthetic approach, 45 compounds of the type (204) were prepared.161 Compounds of the type (203), as well as analogous thiepins and oxepins, have been prepared by another group.162*300 Starting from (205), obtained by acylation of 3-bromothiophen with 2-nitrophenylacetyl chloride, the tricyclic system (206) was obtained by protection of the carbonyl group followed by reduction of the nitro-group and nucleophilic ring-cl~sure.~'~ ortho-Substituted 5-phenylthieno[2,3-c][ 1,4]diazepines have been prepared from compounds of the type (117).17,159Compounds of the type (207) show antidepressant Several papers are concerned with a new cerebrally active basic dithienyl derivative (208), called t i n ~ f e d r i n e . ~ ~Another ~ - ~ ~ ' thiophen derivative that is in an advanced stage of clinical testing is the antihypertensive drug (209), called tiamedinine.306 The antiparasitic properties of some derivatives of 5nitrothiophen-2-aldoxime have been compared with those of the corresponding fur an^.^'^ Thiophen derivatives with potential anti-inflammatory,30*~30g analg e ~ i c , ~diuretic,311 ~' a n t i - c a n ~ e r , ~and ~ ~ 'fungicidic314 ~'~ properties have been

(202) X = S , Y = CH (203) X = C H , Y = S 299 300

301

302

303 304

305

306 307

308

309

310

''I 312 313 314

(204)

R. Bohm and G. Zeiger, Pharmazie, 1980,35, 1. J. B. Press, C. M. Hofmann, N. H. Eudy, I. P. Day, E. N. Greenblatt, and S. R. Safir, J. Med. Chem., 1981,24, 154. J. Guillaume, L. Ntdtlec, M. Cariou, and A. Allais, Heterocycles, 1981, 15, 1227. H. H. Ong, J. A. Profitt, V. B. Anderson, H. Kruse, J. C. Wilker, and H. M. Geyer, 111, J. Med. Chem., 1981, 24,74. K. Thiele, K. Posselt, H. Offermanns, and K. Thiemer, Arzneim.-Forsch., 1980, 30, 747. A. Saus and K. Posselt, Arzneim.-Forsch., 1980, 30, 917. K. Thiele, K. Posselt, J. Heese, and J. Engel, Arzneim.-Forsch., 1980, 30, 1057. H. G. Eckert, S. Baudner, K. E. Weimer, and H. Wissmann, Arzneim.-Forsch.,1981, 31,419. Ph. Gayral, M. C. Rigothier, J. C. Gantier, R. C. Cournes, J. P. Gorrichon, A. Gaset, and F. Dusset, Chim. Ther., 1981, 16, 151. W. P. Heilman, R. D. Heilman, J. A. Scozzie, R. J. Wayner, J. M. Gullo, and Z. S. Ariyan, J. Pharm. Sci.,1980,69, 282. R. G. Child, A. C. Osterberg, A. E. Sloboda, and A. S. Tomcufcik, Arzneirn.-Forsch., 1980, 30, 695. R. Span6 and C. Stacchino, Boll. Chim. Farm., 1979,118,567. B. Dartigues, J. Cambar, C. Trebaul, J. Brelivet, and R. Guglielmetti, Chim. Ther., 1980, 15, 405. J. C. Lancelot, D. Maume, and M. Robba, J. Heterocycl. Chem., 1980, 17,625. N. D. Heindel and J. A. Minatelli, J. Pharm. Sci., 1981, 70, 84. G. A. White and G. D. Thorn, Pestic. Biochem. Physiol., 1980, 14, 26.

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

95

(206)

OH i C=CHCH NHCHCHPh

d S

I Me

,uNH 5

prepared. A thiophen analogue of pilocarpine has been ~ynthesized.''~Several publications dealing with different aspects of thiophenic a -amino-acids have appea~ed.''~-~~' Thiophen-2-acetic acid has been used in work on @-lactam

antibiotic^.^^^-'*^ Polymers from Thiophens.-Its synthesis from the Grignard reagent of 2,5dibromothiophen and the properties of poly(2,5-thienylene) have been The nature of the polymers and oligomers obtained from thiophen and a Lewis-acid catalyst has been in~estigated.~~' The structure of a polymer Pyrolysis-mass from a,@-difluoro-@-chlorovinylthiophen has been spectroscopy of some thiophen-derived polymers has been in~estigated.~~' 315

316

317 318

319 320 321 322 323

324 325

326 327 328

329

330

H. Y. Aboul-Enein, A. A. Al-Badr, S. E. Ibrahim, and M. Ismail, Pharm. Acfa Helv., 1980,55, 228. K. J. Brown, B. V. Vesey, G. W. Tannock, E. B. Bell, D. R. Lines, and R. B. Elliott, Med. Microbiol. Immunol., 1980,168,11. K. J. Brown, G. W. Tannock, R. B. Elliott, and D. R. Lines, Microbiol. Immunol., 1980,24,603. S. Shimizu, H. Shimada, S. Takahashi, T. Ohashi, Y. Tani, and H. Yamada, Agric. Biol. Chem., 1980,442233. K. J. Brown, R. B. Elliott, G. W. Tannock, and D. R. Lines, FEMSMicrobiol. Lett., 1980,9,7. W.Optiz, M. Schwiertz, S. Raddatz, and P.-R. Imberge, Arzneim-Forsch., 1981,31,402. T.Sugawara, H.Masuya, T. Matsuo, and T. Miki, Chem. Pharm. Bull., 1980,28,2116. U . Valcavi, A. Brandt, G. B. Corsi, F. Minoja, and G. Pascucci, Gazz. Chim. Ifal., 1980,110,519. T . Sugawara, H.Masuya, Y. Kawano, T. Matsuo, and Y. Kuwada, Chem. Pharm. Bull., 1980,28, 1339. M. Shiozaki, N.Ishida, K. Iino, and T. Hiraoka, Tetrahedron, 1980,36,2735. T. W.Doyle, J. L. Douglas, B. Belleau, T. T. Conway, C. F. Ferrari, D. E. Homing, G. Lim, B.-Y. Luh, A. Martel, M. Menard, L. R. Morris, and M. Misiek, Can. I. Chem., 1980,58,2508. I. Takahashi, T. Sawai, T. Ando, and S . Yamagishi, J. Antibiof., 1980,33,1037. J. W.P. Lin and L. P. Dudek, J. Polym. Sci., Polym. Chem. Ed., 1980,18,2869. P. Kovacic, D.Margosian, and K. N. McFarland, Polym. Prepr., Am. Chem. SOC.,Diu. Polym. Chem., 1979,20,863. T.A. Starostina, A. B. Gil'man, R. R. Shifrina, L. F. Rybakova, and V. M. Kolotyrkin, Vysokomol. Soedin., Ser. B, 1980,22,548. G.Holzmann and G. Kossmehl, Org. Mass Spectrom., 1980,15,336.

96

Heterocyclic Chemistry 3 Benzothiophens and their Benzo-fused Systems

Benzo[b]thiophens.-Synthesis. 2 -Arylthio- 1-chloro-enamines are readily cyclized to 3-(dialky1amino)benzothiophens in the presence of Lewis The reaction of cinnamic acids with thionyl chloride in the presence of catalytic amounts of pyridine has been used for the preparation of 3-chlorobenzo[b]thiophen-2-carbonyl The photocyclization of methyl 2-(ary1thio)acetoacetates in benzene-methanol solution gave benzo[b]thiophens in satisfactory yields.333Irradiation of (210) in acetonitrile gave (21l ) , which was easily dehydrated to the corresponding b e n ~ o [ b ] t h i o p h e n .Heating ~~~ of the dithiolates obtained from o-halogenobenzyl cyanides and carbon disulphide gave 3-~yanobenzo[b]thiophen-2-thiolate.~~~ The reaction of o-chlorobenzaldehydes with sulphur and ammonia gave 1,2-benzisothiazoles, which, upon reaction with base, opened to o -cyano-benzenethiols; upon reaction with chloroacetonitrile and ring-closure, 3-amino-2-cyanobenzo[b]thiophenswere The photoreaction of (212) in the presence of dimethyl acetylenedicarboxylate yielded 2,3-di(carbornethoxy)benzo[b]thiophen, amongst 0-

H

NMe, (212)

other Irradiation of (213) in methanol gave (214), which is the product of a Wolff rearrangement, and a dimeric derivative (215). The latter was the only product if the reaction was carried out in the presence of silver Heating of N-tosylsulphimides that were obtained from the reaction

331

332 333 334

33s 336

337 338

L. Ghosez, P. Notte, C. Bernard-Henriet, and R. Maurin, Heterocycles, 1981,15, 1179.

W.Ried. G. Oremek, and B. Ocakcioglu, Liebigs Ann. Chem., 1980,1424. T.Sasaki and K. Hayakawa, Tetrahedron Lett., 1980,21,1525. T.Sasaki, K. Hayakawa, and S. Nishida, Tetrahedron Lett., 1980,21,3903. W.-D. Rudorf, A. Schierhorn, and M. Augustin, J,Prakt, Chem., 1979,321,1021. J. Markert and H. Hagen, Liebigs Ann. Chem., 1980,768. H. Gotthardt and F. Reiter, Chem. Ber., 1981,114,1737. Y.Tamura, H. Ikeda, C. Mukai, S. M. M. Bayomi, and M. Ikeda, Chem. Pharm. Bull., 1980,28, 3430.

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

97

of thiochroman-4-ones also gave compounds of the type (215).339The reaction of 2,3-dihalogeno-thiochromone S-oxide with sodium acetate in refluxing acetic acid gave t h i ~ i n d i g o . ~Some ~ ' 2,3 -dihydrobenzo[ blthiophens have been aromatized over a poly(pheny1ene)quinone Thio-Claisen rearrangement of (216) gave the psoralene isostere (217).342

Me&o

Me

(217)

(216)

Physical Properties of Benzo[b]thic~phens. The m.c.d. spectrum of benzo[b]thiophen has been a n a l y ~ e d The . ~ ~ 13C ~ chemical shifts of benzo[b]thiophen have been compared with those of the other benzo-fused chalcogen-containing The electronic spectra and acidity of benzo[b]thiophen-2-thiol have been in~estigated.'~~ The influence of steric effects on the deactivation of fluorescence of some aryl-benzo[b]thiophens by aliphatic amines has been studied.345 ~ ~ alkenylati~n~~' ~ Substitution Reactions of Benzo [blthiophens. A l k y l a t i ~ nand of benzo[b]thiophen, catalysed by Lewis acids, has been achieved in the 3position. Palladium-catalysed alkenylation of benzo[ b Ithiophen with acrylonitrile gave a mixture of 2- and 3-substituted products, as well as cis-trans isomers.' l 3 Copper-promoted nucleophilic substitution between 3-bromobenzo[b]thiophen and potassium anthranilate gave (218).348 Irradiation of benzo[b]thiophen and vinyl acetate gave (219). Benzo[b]thiophen 1,l-dioxide gave the corresponding adduct in much higher yield. Hydrolysis and oxidation of (219) gave (220), which underwent Baeyer-Villiger oxidation to (221). The

QyJ qR1 H

R2

@

p

O

H

HO,C

(218) 339

340

341

342

343 344

345

346

347

348

(219) R' = H, R2 = OAC (220) R'R~ =

o

(221)

Y. Tamura, Y. Takebe, S. M. M. Bayomi, C. Mukai, M. Ikeda, M. Murase, and M. Kise, J. Chem. SOC.,Perkin Trans. 1, 1981,1037. N. E. MacKenzie and R. H. Thomson, J. Chem. SOC.,Chem. Commun., 1980,559. M. V. Vagabov, E. A . Viktorova, B. I. Liogon'kii, R. Z. Aleksanyan, S. K. Szhamalov, and E. A . Karakhanov, Neftekhimiya, 1980,20, 887. G.R.Wellman, J. Heterocycl. Chem., 1980,17,911. M. A . Suoto, S. L. Wallace, and 3. Michl, Tetrahedron, 1980,36, 1521. L.Laitem, L. Christiaens, and M. Renson, Org, Mugn. Reson., 1980,13,319. A.Brehon, A . Couture, A . Lablache-Combier, and A. Pollet, Nouv. J. Chim., 1981,s.243. A . V. Anisimov, V. M. Nikolaeva, and E. A. Viktorova, Vestnik Moskov. Univ., Ser. 2: Khim., 1980,21,374. A . V. Anisimov, L. V. Mozhaeva, V. M. Nikolaeva, and E. A . Viktorova, Vestnik Moskov. Univ., Ser. 2: Khim., 1980,21,594. K. Gorlitzer and J. Weber, Arch. Pharm. (Weinheim, Ger.), 1980,314,76.

98

Heterocyclic Chemistry

oxime of (220) gave 2-benzo[b]thienylacetonitrile upon reaction with thienyl Irradiation of 7-azido-3-methylbenzo[b]thiophen in an excess of diethylamine gave 7-amino-3-methylbenzo[b]thiophen and a trace of 3,3'-

dimethyl-7,7'-azobenzo[b]thiophen.350 6-Azido-2,3-dihydrobenzo[b]thiophen 1,l-dioxide gave (222) upon heating in a polyphosphoric acid-acetic acid mixture. This is in contrast to the reaction of 6-azidobenzo[b]thiophen, which has A review on approaches to previously been found to give a linear heterocycles via nitrenes has been

A one-pot procedure for the synthesis of 2-trifluoroacetyl-3-(hydroxymethyl)benzo[b]thiophen consists in halogen-metal exchange of 2,3dibromobenzo[b]thiophen, then reaction with aaa-trifluoro-NN-dimethylacetamide, followed by renewed halogen-metal exchange with butyl-lithium and reaction with formaldehyde. This approach is especially advantageous for the synthesis of (disubstituted aryl) trifluoromethyl ketones, since ketalization of these compounds is not feasible."' 3-Methoxybenzo[b]thiophen, prepared by copper-promoted substitution of 3-bromobenzo[b]thiophen with sodium methoxide, was S-methylated with methyl iodide and silver perchlorate to give l-methyl-3(2H)-oxobenzo[b]thiophen perchlorate, which with diazomethane gave 3-methoxy-1 -methylbenzo[b]thiophenium p e r ~ h l o r a t e . ~ ~ ~ Benzo[b]thiophen has been perchlorated to 2,2,3,3,4,5,6,7-octachloro-2,3-dihydrobenzo[b]thiophen, which could be oxidized to the 1,l-dioxide and aromatized to perchlorobenzo[b]thiophen. Upon oxidation of this compound, (223) was obtained, which gave (224)upon treatment with sodium Reactions of the Side-Chain of Benzo[b]thiophens. The reaction of 3chlorobenzo[b]thiophen-2-carbonyl chlorides with cyanamides led to (225).354 The condensation of 2-acetyl-3-hydroxybenzo[b]thiophen with oxalates gave (226), which could be ring-closed to (227) and then hydrolysed and decarboxylated.355From 3-aminobenzo[b]thiophens with acyl, cyano, or ethoxycarbonyl substituents in the 2-position, tricyclic systems such as benzo[b Jthienyl-fused isothiazoles, pyridones, and thiophens have been prepared.3562,2-Disubstituted benzo[b]thiophen-3 (2H)-ones (228) were prepared by alkylation of the corresponding benzo[b]thiophen-3(2H)-one 1,1-dioxides followed by reduction M. Ikeda, T. Uno, K.-I. Homma, K. Ohno, and Y. Tamura, Synth. Commun., 1980,10,437. P. T. Gallagher, B. Iddon, and H. Suschitzky, J. Chem. Soc., Perkin Trans. 1, 1980,2362. '" P. T. Gallagher, B. Iddon, and H. Suschitzky, J. Chem. Soc., Perkin Trans. 1, 1980, 2358. 352 0. Meth-Cohn, Heterocycles, 1980, 14, 1497. 353 M. S. Raasch, J. Org. Chem., 1980, 45, 2151. 354 W.Ried, G.Oremek, and R. Guryn, Chern. Ber., 1980,113,2583. 35s K. Gorlitzer and E. Engler, Arch. Pharm. (Weinheim, Ger.), 1980,313, 385. 356 K. Clarke, W. R. Fox, and R. M. Scrowston, J. Chem. Res. ( S ) , 1980, 33. 349 350

99

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

with lithium aluminium hydride. Upon S-amination with o-mesitylenesulphonylhydroxylamine followed by base, (229) was ~ b t a i n e d . ’ ~ ” ’The ~~ Meisenheimer rearrangement of the N-oxide of (230)yielded (231). A similar reaction was also carried out with the simple thiophen analogue.359 Starting and (233)361 from 3-(2-aminoethyl)benzo[b]thiophen, systems such as (232)360 (cf.also ref. 362) have been prepared.

W

M

e Ph

Ph

(230)

Q Benzo[b]thiophen S-Oxides. 3-Chlorobenzo[b]thiophen-2-carboxylicacid 1,ldioxides reacted with cyclohexykarbodi-imide to give benzothieno-o~azines.~~~ Reactions of 2,3-dihydrobenzo[b]thiophen-3-one 1,l-dioxide, obtained from 357

358

359

360 361

362 363

Y. Tamura, S. M. Bayomi, C. Mukai, M. Ikeda, M. Murase, and M. Kise, Tetrahedron Lett., 1980, 21,533. Y . Tamura, S. M. M. Bayomi, C. Mukai, M. Ikeda, and M. Kise, J. Chem. SOC.,Perkin Trans. 1, 1980,2830. J. B. Bremner, E. J. Browne, and P. E. Davies, Aust. J. Chem., 1980,33, 1335. G. D . Pandey and K. P. Tiwari, Curr. Sci., 1980,49,261. G. D.Pandey and K. P. Tiwari, Curr. Sci., 1980,49,498. C.Galvez, F. Garcia, J. Ribera, and P. Viladoms, J. Heterocycf. Chem., 1980,17,1355. W.Ried, G. Oremek, and R. Guryn, Liebigs Ann. Chem., 1981,612.

100

Heterocyclic Chemistry

some 2-substituted 3-~hlorobenzo[b]thiophen1,1-dioxides, have been investigated.364Irradiation of 3-acetoxybenzo[b)thiophen 1,1-dioxide in the presence of cycloalkenes gave [2 + 21 cyclo-adducts which underwent ring-expansion to substituted benzo[b]thiepinone~.~~~ The photodimerization of various The benzo[b]thiophen 1,l-dioxides in benzene solution has been ring-expansion of (234) has been

Benzo[c]thiophens.-The rate of oxidation of 1,3-diphenylbenzo[c]thiophen has been measured.3681,3-Dihydronaphtho[2,3-c]thiophen 2-oxide underwent dehydration upon flash vacuum thermolysis to give naphtho[2,3-~]thiophenas a highly reactive yellow solid.369 Dibenzothi0phens.-The conversion of dibenzothiophen into the corresponding sulphoxide and sulphone by the action of chlorine and water has been s t ~ d i e d . ~ ” The desulphurization of condensed thiophens by methanol and a molybdenumcontaining catalyst, with elimination or migration of hydrogen or methyl groups, has also been Electrophilic substitution reactions of (235) have been found to occur in the position indicated by the arrow (called the 5 - or the 6-position, respectively) by different Compounds containing substituted amino-functions in this position have been prepared as potential carcinostatic agents.374 Starting from 2-amino- and from 3-hydrazinodibenzothiophen, prepared from the corresponding amines, several pyrrolefused systems, such as indolo[6,5-d]-, indolo[4,5-d]-, indolo[5,6-d]-, and indolo[5,4-d]-benzo[b]thiophen,were prepared by the Fischer reaction of the hydrazones. 375 Pharmacologically Active Compounds.-3 -Alkylamino-( 3-benzo[ blthienyloxy)propan-2-ols, which are analogues of propranolol, have been prepared.376 364

365 366 367

368 369

370

371

372 373

374

375

376

W. Ried and G . Oremek, Liebigs Ann. Chem., 1981,619. N.V.Kirby and S. T. Reid, J, Chem. SOC.,Chem. Commun., 1980,150. M. S.El Faghi El Amoudi, P. Geneste, and J. L. OlivC, Noun J. Chim., 1981,5,151. Y.Tamura, S. M. Bayomi, M. Ikeda, and M. Kise, Chem. Pharm. Bull., 1980,28,1597. K.-D.Gundermann, M. Steinfatt, P. Witt, C. Paetz, and K.-L. Poppel, J. Chem. Res. ( S ) ,1980,195. J. Bornstein, R. P. Hardy, andD. E. Remy, J. Chem. SOC.,Chem. Commun., 1980,612. N. P. Vasilakos, R. L. Bone, and W. H. Corcoran, Znd. Eng. Chem., Process Des. Dev., 1981,20,

376. M. Nagai and T. Kabe, Sekiyu Gakkaishi, 1980,23, 275. L. H.Klemm, J. J. Karchesy, R. F. Lawrence, and P. Wang, J. Heterocycl. Chem., 1980,17,771. S.Dacka and M. Janczewski, Pol. J. Chem., 1980,54.863. G.Alunni-Bistocchi, G. D e Meo, M. Pedini, A . Ricci, P. Jacquignon, and A. Croisy, J. Heterocycl. Chem., 1980,17,993. L. A. Kintsurashvili, T. E. Khoshtariya, L. N,Kurkovskaya, and N. N. Suvorov, Khirn. Geterotsikl. Soedin., 1980,203. S. Conde, C. Corral, and J. Lissavetzky, J. Heterocycl. Chem., 1980,17,937.

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

101

Several alkyl and polyhalogenophenyl esters of benzo[b]thiophen-3-carbamic acid were synthesized and their antibacterial and antifungal activities investigated.377Some amino-alkyl ketones in the benzo[b]thiophen series, prepared through the Mannich reaction, also showed these types of The effects of benzo[b]thiophen-2-carboxylic acid and dibenzothiophen-4-carboxylicacid on heparin-accelerated osteoporosis have been in~estigated.~~' 4 Thiophen Analogues of Polycyclic Aromatic Hydrocarbons

Analogues of Anthracene and Phenanthrene.-Methyl esters of different types of dichlorobenzodithiophendicarboxylic acid have been prepared by the reactions of the three isomeric phenylenediacrylicacids with thionyl chloride followed by The thiophen isostere of apomorphine (236) was prepared by photochemical ring-closure of (182).230All seven isomeric phenanthro[b]thiophens have been prepared.381Starting with 1- or 2-naphthaldehyde and diethyl 2- or 3-thenylphosphonate, four of the isomers were obtained by Wittig reaction followed by photochemical cyclization. Starting from 2-lithiated oxazolineprotected thiophen-3-carboxylic acid, followed by reaction with 1- or 2-naphthaldehyde, followed by electrophilic ring-closure of the carboxylic acid or the corresponding aldehyde, (237) and (238) were obtained. Finally, (239) was obtained by cyclization of (9-phenanthryl)thioacetaldehyde. 7 -Methoxy -4,s dihydronaphtho[1,2-b]thiophencarboxylic acid has been synthesi~ed.~~' The epoxide from benzo[ 1,2-c :3,4-c']dithiophen has been prepared and transformed into the aziridine (240).383 Various Carbocycle-Fused Systems.-Diazoindenothiophens, upon reaction with dimethyl acetylenedicarboxylate, gave labile spiro-3H-pyrazoles, which rearranged to compounds of the type (241), together with (242).384Derivatives of 4H-5,6-dihydrocyclopenta[c]thiophendicarboxylic acid have been prepared.385 The structure of 9H-cyclohepta[2,1-b :4,5 -b']dithiophen-4-ylium perchlorate has been determined by X-ray ~rystallography.~~~ The i.r. spectra of seven deuteriated derivatives of cyclohepta-[b]- or -[c]- thiophen-6-ones have been analysed and compared with those of the hydrogenated ones.387 A simple synthesis of (243) has been described,js8 and (244) has also been prepared.389 377 378

379 380

383 384

386

389

A . Shafiee, M. Vossoghi, J. Wossooghi, and S. Yazdani, J. Pharm. Sci., 1981,70,566. P. Cagniant, G. Kirsch, M. Wierzbicki, F. Lepage, D. Cagniant, D. Loebenberg, R. Parmegiani, and M. Sherlock, Chim. Ther., 1980,15,439. J. C. Robin, S. D. Sharma, K. Francis, M. Rosenstein, R. Moore, J. A . Vida, C. C. Thomas, Jr., and J. L. Ambrus, J. Med. (Westbury, N.Y.), 1980,11,15. W. Ried, G . Oremek, and R. Guryn, Liebigs Ann. Chem., 1980,1172. M . Iwao, M.L. Lee, and R. N. Castle, J. Heterocycl. Chem., 1980,17,1259. M. Ghosh, R. Mukherjee, B. G. Chatterjee, and J. K. Ray, Indian J. Chem., Sect. B, 1981,20,253. M. Weitzberg, Z. Aizenshtat, P. Jerushalmy, and J. Blum, J. Org. Chem., 1980,45,4252. S. Mataka, K. Takahashi, T. Oshima, and M. Tashiro, Chem. Lett., 1980,915. S . Julia and J. M. Carulla, A n . Quim., 1979,75,904. J.-E. Anderson, Acta Crystallogr., Sect. B, 1981,37,401. Y. Cozien, J. Lauransan, P. Saumagne, R. Guilard, and M. El Borai, Bull. SOC.Chim. Fr., Part 1, 1980,327. R. Neidlein and G. Schafer, Arch. Pharm. (Weinheim, Ger.), 1981,314,91. R. Neidlein and R. Gartner, Arch. Pharm. (Weinheim, Ger.), 1981,314,57.

Heterocyclic Chemistry

102

C0,Me (239)

Q-p Me0,C

SMe

C0,Me SMe (243)

(244)

5 Thiophen Fused to Five-Membered Heteroaromatic Rings C N D 0 / 2 calculations on the reactivity of thienothiophens and selenolothiophens have been carried Thieno[2,3 -b]- and thieno[3,2-b]- thiophens were amongst the products formed in the reaction of 1,2-dichloroethylene with hydrogen sulphide at 420-520 OC.’ 4-Ethoxycarbonyl-3-chloro-5-(phenylamino)thiophen-2-aldehyde was transformed into (245) via the 3-methylthio derivative followed by ring-closure.’ From 2-p-bromophenacylthio-3cyanobenzo[b]thiophen, (246) was obtained upon heating.335 A new method has been developed for the synthesis of 2,5-disubstituted benzothieno[3,2blbenzothiophens by the reaction of 4,4’-disubstituted stilbene-2,2’-disulphonyl chloride with hydriodic acid and subsequent treatment of the reaction products of these systems has with perbromopyridinium b r ~ m i d e . ~ ~ The ~ * ~ nitration ’* been A synthesis of the 4b,9b-dihydro-derivatives has been worked Benzo[b]thieno[3,2-b]benzo[b]thiophen disulphone reacted with 39”

391 392 393 394

I. A. Abronin, C. P. Litvinov, G. M. Zhidomirov, A. 2. Dzhumanazarova, and Ya. L. Gol’dfarb, Khim. Geterotsikl. Soedin., 1980, 199. S. Yu. Zherdeva, A. Ya. Zheltov, T. A. Kozik, and B. I. Stepanov, Zh. Org. Khim., 1980,16,425. S . Yu. Zherdeva, A. Barudi, A. Ya. Zheltov, and B. I. Stepanov, Z h . Org. Khim.,1980, 16, 430. A. Barudi, A. B. Kudryavtsev, A. Ya. Zheltov, and B. I. Stepanov, Zh. Org. Khim., 1980,16,438. A. L. Barudi. A. Ya. Zheltov, and B. I. Stepanov, Zh. Org. Khim., 1980, 16, 2448.

103

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

amines via ring-opening to give (247), the structure of which was determined by X-ray ~rystallography.~~’ A simple and useful synthesis of thieno-[2,3-6]and -[3,2-b]-pyrroles consisted in the reduction of (azidoacety1)thiophens to the corresponding thienyl-substituted ethanol and dehydration to w (azidovinyl)thiophens, followed by thermolysis. 396 The c,c -fused compounds (248)have been prepared by the action of lithium methoxide on y,y-dimethylallenyl thiocyanate and selenocyanate, re~pectively.’~’

(248)

X

=

SorSe

Isothiazole-Fused and Related Systems.-5 -Bromothieno[3,2-d]isothiazole has been prepared from 2,5 -dibromothiophen-3-aldehyde, sulphur, and ammonia.336Treatment of the oximes of o -methylthio-thiophen aldehydes (prepared via double lithiation in the one-pot method) with polyphosphoric acid gave thienoisothiazoles. The corresponding o -methylseleno-thiophen aldehydes gave the thienoselenazoles directly upon treatment with bromine and ammonia.398 Several substituted 4-aminothieno-[2,3-c]- and -[3,2-d]isothiazoles have been prepared by the reaction of 3,5-di(sodiomercapto)isothiazole-4-carbonitrile with appropriate a -chlorocarbonyl derivatives followed by cyclization in basic medium, as described by two different g r o ~ p s . ’ Compounds ~~,~~ (249) have been cyclized to (250) in the presence of mercury oxide. Products from the alkylation of (250) with a -halogeno-ketones have been cyclized to (25 1).401The cycloaddition reaction of the non-classical systems (252) with maleimide,402 and 6,6-diphenylfulvene and 395

396

397 398

399 400 401

402 403

V. E. Udre, E. Ya. Lukevits, A. A. Kemme, and Ya. Ya. Bleidelis, Khim. Gererotsikl. Soedin.,

1980,320. G. Kumar, K. Rajagopalan, S. Swaminathan, and K. K. Balasubramanian, Indian J. Chem., Secf. B, 1981,20,271. S . Braverman, M. Freund, and I. Goldberg, Tetrahedron Lett., 1980,21,3617. N. V. Onyamboko, R. Weber, N. Dereu, M. Renson, and C. Paulmier, Bull. SOC.Chim. Belg., 1980.89.773. B. Tornetta, G. Ronsisvalle, E. Bousquet, F. Guerrera, and M.A. Siracusa, Gazz. Chim. Itul., 1980,110,233. K . Gewald, W. Radke, and U. Hain, J. Prakr. Chem., 1980,322, 1021. E. Fischer, G. Rembarz, and K.-M. Wollin, J. Prakr. Chem., 1980,322,375. 0.Tsuge and T. Takata, Fukusokan Kaguku Toronkai Koen Yoshishu, 12th, 1979,66. 0.Tsuge and T. Takata, J. Org. Chem., 1980,45,2956.

Heterocyclic Chemistry

104

I

t r o p ~ n e ~have " ~ been studied in detail. Some 2-oxohexahydrothieno[3,4dlimidazole derivatives have been prepared by reduction of the corresponding thiophen derivative with triethylsilane in trifluoroacetic

6 Thiophen Fused to Six-Membered Heteroaromatic Rings Thiophen Analogues of Quino1ine.-Treatment of 5-substituted 2acetamidothiophens with DMF and three moles of phosphoryl chloride gave 6-chlorothieno[3,2-b]pyridines.The use of phosphoryl chloride as the solvent (7 moles) with three moles of DMF gave good yields of 6-chlorothieno[2,3blpyridine-5-carbaldehydes.Similarly, thieno-[3,2-b]- and -[3,4-b]-pyridines were obtained from 3-acetamidothiophen and 2,5-dimethyl-3a~etamidothiophen.'~ Derivatives of thieno[3,4-b]pyridine have been prepared by the reaction of 2-amino-3-methoxycarbonylthiophenswith dimethyl acetylenedicarboxylate or pentane-2,4-dione followed by electrophilic ring-closure. Many substituted derivatives, as well as the tricyclic system (253), were prepared.406The reaction of 3-amino-2-(alkoxycarbonyl)thiophenswith diethyl malonate or ethyl cyanoacetate gave amides, which were cyclized to 6-substituted 7-hydroxythieno[3,2-b]pyridine-5(4H)-ones by treatment with sodium hydroxide in DMF. The reactions of this system, especially of its 7-hydroxyand 7-chloro-derivatives,were in~estigated.~'~ The amide (254), upon treatment with polyphosphoric acid, cyclized to (255), which was oxidized to the 1,ldioxide. Its thionation was also inve~tigated.~'~ Condensation of o -nitro-benzaldehydes with thiophens or 5-alkyl-thiophens gave (256), which were converted into the azides via the amines. Deoxygenation of the nitro-compounds or decomposition of the azides led to (257).409Halogenation and nitration of 404

405 406

407

408 409

0.Tsuge, T. Takata, and M. Noguchi, Chem. Lett., 1980, 1031. S. I. Zav'yalov and 0. V. Dorofeeva, Zzv. Akad. Nauk SSSR, Ser. Khim., 1980, 1634. J. M. Barker, P. R. Huddleston, A. W. Jones, and M. Edwards, J. Chem. Res. (S), 1980,4. J. M. Barker, P. R. Huddleston, N. Chadwick, and G. J. Keenan, J. Chem. Res. ( S ) , 1980,6. K. Gorlitzer and J. Weber, Arch. Pharm. (Weinheim, Ger.), 1980,314,76. P. C. Hayes, G. Jones, C. Keates, I. Kladko, and P. Radley, J. Chem. Res. IS),1980,288.

105

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

OcJ 0

-

R

N R

R

R (257)

thieno[2,3-b]quinoline has been in~estigated.~~' Photolysis of pyridine N ethoxycarbonylimides in which thiophen was condensed on the b-side gave 1H-1,2- and 3H-1,3-dia~epines.~" Thiophen Analogues of Isoquinoline.-Benzo[b]thieno[3,2-c]pyridines were prepared from the corresponding pyrylium salts, obtained from benzo[b]thienylacetone and acylium perchlorates, through the reaction with ammonia.412 1,3-Dipolar addition of diazo-compounds and of phenyl azide to 7-methylthieno[2,3-c]pyridine 1,l-dioxide has been investigated. Further reactions of primary products such as (258) have been elucidated.413 In connection with studies on the synthesis of p -1actam antibiotics, (259) has been

C0,Me (259)

Pyrimidine-Fused Systems.-From (133), thieno[2,3 -d]pyrimidines have been prepared.16' The reaction of o -aminocarbonylthiophen with different nitriles has been used for the synthesis of a number of thien0[2,3-dlpyrimidines.~'~ 410

411 412 413

414

415

N. Soundararajan, R. Palaniappan, S. Nagarajan, T. K. Raja, and P. Shanmugam, J. Chem. Res. (S),1980,201. T. Tsuchiya, M. Enkaku, and S. Okajima, J. Chem. Soc., Chem. Commun., 1980,454. N.A. Alekseev and S. V. Tolkunov, Khim. Geterotsikl. Soedin., 1980,848. U.Fischer and F. Schneider, Helu. Chim. Acra, 1980,63,1719. T. Kametani, K. Kigasawa, M. Hiiragi, K. Wakisaka, H. Sugi, and K. Tanigawa, Chem. Pharm. Bull., 1980,28,1196. K. G . Dave, C. J. Shishoo, M. B. Devani, R. Kalyanaraman, S. Ananthan, G. V. Ullas, and V.S. Bhadti, J. Heterocycl. Chem., 1980,17,1497.

106

Heterocyclic Chemistry

Compounds such as (260) have been prepared by the reaction of nitriles that contain active methylene groups with 3-azido-2-substituted thiophens such as 3-azido-2-formylthiophen dimethyl acetaL416Further reactions of (260), which led to 2- and 4-substituted thieno[3,2-d]pyrimidines, have been investigated.417 4-Hydrazinot hieno[:! ,3-d]pyridines were cyclized with trie thyl ort hof ormate and formic acid to give 1,2,4-triazolo derivatives that are isomeric with system (260).4's Compounds (261) have been synthesized by condensation of the 2amino-3-ethoxycarbonylthiophen with ~~-thiocyanoacetophenone.~~~~~~~ 3HBenzothieno[3,2-d]pyrimidin-4-onewas prepared by the reaction of 3-amino-2ethoxycarbonylbenzo[b]thiophen with formamide. Via its thione or hydrazino derivative, the parent benzothieno[3,2-d]pyrimidine was prepared,421 and its nitration and bromination have been investigated.422 Alkaline hydrolysis of 2-amino-3-ethoxycarbonylthiophen, followed by treatment with acetic anhydride, gave oxazines; upon treatment with amines, these gave some substituted t h i e n o p y r i m i d o n e ~ , ~Some ~~ derivatives of 2-amino-4-phenyl3,4-dihydrothieno[2,3-d]pyrimidine, such as (262), have been prepared,424

and other derivatives of this system or of the system in which thiophen is c-fused showed activity as inhibitors of the aggregation of blood Some thieno[2,3-d]pyrimidine nucleosides that are related to cytidine and uridine have been Miscellaneous Fused Systems.-The metallation, chlorination, and nitration of thieno[2,3 -b]pyrazine have been studied and its nitration has been compared with that of thieno[2,3-d]pyrimidine and 2 - t h i e n y l p y r a ~ i n eThe . ~ ~ ~reaction of (263) with phosphorus pentasulphide gave (264),428and the reaction of 2-chloro416 417 418

419

.420 421

422

423 424 425

426

427 428

C. Westerlund, J. Heterocycl. Chem., 1980, 17, 1765. C. Westerlund, J. Heterocycl. Chem., 1980, 17, 1771. C. J. Shishoo, M. B. Devani, G. V. Ullas, S. Ananthan, and V. S. Bhadti, J. Heterocycl. Chem., 1981,18,43. H. K. Gakhar, A . Madan, and N. Kumar, Indian J. Chem., Sect. B, 1980, 19, 250. H. K. Gakhar, A . Madan, and N. Kumar, Indian J. Chem., Sect. B, 1980,19, 965. M. Robba, P. Touzot, and H. El-Kashef, J. Heterocycl. Chem., 1980,17,923. H. El-Kashef, S. Rault, M. Cugnon de SCvricourt, P. Touzot, and M. Robba, J. Heterocycl. Chem., 1980,17,1399. F. A. El-Telbany, Pharmazie, 1980, 35, 326. F. Ishikawa and H. Yarnaguchi, Chem. Pharm. Bull., 1980,28,3172. F. Ishikawa, A . Kosasayama, H. Yamaguchi, Y. Watanabe, J. Saegusa, S. Shibamura, K. Sakuma, S.-I. Ashida, and Y. Abiko, J. Med. Chem., 1981, 24, 376. V. D. Patil, D. S. Wise, and L. B. Townsend, J. Chem. SOC.,Perkin Trans. 1, 1980, 1853. J. Bourguignon, M. Lemarchand, and G. Qutguiner, J. Heterocycl. Chem., 1980,17, 1019. Y. A . Ibrahim. Chem. Ind. (London). 1980. 536.

107

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

3-cyanopyrazine with a -chlorocarbonyl derivatives gave derivatives of 3aminothien0[2,3-b]pyrazine.~~~ A small yield of thieno[3,2-c]pyridazine was obtained via the reaction of 2-vinylthiophen with azodicarbo~ylates.~~~ 2-Aryl-4-oxothieno[2,3-d]oxazineswere synthesized by the action of thionyl chloride on 2-(aroylamino)thiophen-3-carboxylicacid in the presence of DMF. The oxazine ring opened upon treatment with hydrazine to give 2benzamidothiophen-3-carboxylicacid h y d r a ~ i d e , ~ and ~ ' with amino-alcohols to give esters.432From (265), (266) could be prepared by base-catalysed ringclosure.433Starting from (267), the thienotellurochromone (268) was prepared via the Mannich base. The other b-fused and the c-fused system have also been synthesized in an analogous way.4345,4-Borazarobenzo[b]thiophens (269) were and the prepared from 3-amino-2-vinylthiophens and arylboron dichloride~,~~ isomeric 6,7-borazarobenzo[b]thiophens in the same way from derivatives of 2-arnin0-3-vinylthiophen.~~ The thiophen rings were utilized as cis-handles for the ring-closure, and 2,l -borazarenes were obtained by desulphurization with Raney

0 ROC'

429

430

431

433 434

m

SC

0

R

D . Pancechowska-Ksepko, J. Sawlewicz, J. Samulska, and M. Janowiec, Acta Pol. Pharm., 1979, 36,289. G . Jones and P. Rafferty, Tetrahedron, 1979, 35, 2027. I. A. Kharizomenova, N. V. Samsonova, N. V. Kaplina, M. V. Kapustina, and A. N. Grinev, Khim. Geterotsikl. Soedin., 1980, 45. I. A. Kharizomenova, A. N. Grinev, N. V. Samsonova, N. V. Kaplina, M. V. Kapustina, G. N. Pershin, L. M. Polukhina, and E. N. Paceiskaya, Khim.-Farm. Zh., 1980, 1 4 4 2 . W. Ried, B.-I. Podkowik, and G. Oremek, Liebigs Ann. Chem., 1980, 863. N. Dereu and M. Renson, J. Organomet. Chem., 1981,208, 11.

108

Heterocyclic Chemistry 7 Selenophens and Tellurophens

Monocyclic Se1enophens.-Vinylacetylene reacted with the selenium dianion that is generated from elemental selenium in a dimethyl sulphoxide-waterpotassium hydroxide mixture at 100-120 "C to give 24% of selenophen together with 17% of di-(1,3-butadienyl) selenide and 5% of 1-vinyl-2selenabicycl0[3.2.0]hept-3-ene.~~~ A simplified synthesis of 3-bromoselenophen has been Convenient procedures for the bromination of 2- and 3-acetylselenophen have been worked outago The 77Se n.m.r. spectra of some selenophen derivatives with exocyclic selenium-containing substituents have been obtained." The complete structure of selenophen in the nematic phase of a liquid crystal has been obtained by an n.m.r. Irradiation of a mixture of selenophen and 2,3-dimethylmaleicanhydride gave 75% of the mono-adduct (270), together with small amounts of a b i s - a d d u ~ t . ~ ~ ~ Esterification of 3-bromoselenophen-2-carbonylchloride with pyridine-4-thiol gave 43% of (271), in addition to the expected thiolester. Heating of (271) with copper powder in xylene led to (272).439The photo-induced thiolesterthiopyrone transformation of S-aryl selenophenthiocarboxylates gave the ring

systems (273).440The reaction of 2,5-diamino-3,4-dicyanoselenophen(prepared by the reaction of tetracyanoethylene with hydrogen selenide) with sulphur dichloride proceeded differently than in the thiophen series and gave (274), the structure of which was proven by X-ray ~rystallography.~~' 2-(pMethoxypheny1)- and 2-(m-methoxyphenyl)-selenophen were obtained by unsymmetrical coupling of 2-selenienylcopper and p- or rn -iodoanisole, but the yield was much lower than in the thiophen series. Demethylation was achieved with sodium thioethoxide in DMF at 130 "C. The analogous tellurophen compounds could not be obtained from 2-tellurienylcopper, and were instead prepared by the reaction of p -chlorocinnarnaldehydes (from the Vilsmeier-Haack chloroformylation of p- and m -methoxyacetophenones) with sodium telluride and ethyl a-bromoacetate in DMF, which gave (275), followed by hydrolysis and decarboxylation. In contrast to the selenophen case, demethylation, especially that of the meta -derivative, caused difficulties, and was achieved with 43s 436 437

438 439 440

441

B. A. Trofimov, G. K. Musorin, G. A. Kalabin, and S. V. Amosova, Zh. Org. Khim., 1980,16,518. A. Hallberg, S. Liljefors, and P. Pedaja, Synfh. Commun., 1981, 11,25. G. Chidichimo, F. Lelj, M. Longeri, and N. Russo, J. Magn. Reson., 1980, 41, 35. C. Rivas, D. Pacheco, and F. Vargas, J. Heterocycl. Chem., 1980,17,1151. K. Beelitz and K. Praefcke, Liebigs Ann. Chem., 1980, 1620. K. Beelitz, K. Praefcke, and S. Gronowitz,Liebigs Ann. Chern., 1980, 1597; J. Orgunomel. Chem., 1980,194,167. F. Wudle and E. T. Zellers, J. Am. Chem. Soc., 1980,102, 5430.

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

109

boron tribromide in d i ~ h l o r o e t h a n e The . ~ ~ ~n.m.r. spectra and ionization constants for the phenols were determined and u constants for the 2-selenienyl and 2-tellurenienyl group were obtained. They were found to be weakly inductively electron-withdrawing and show a greater ability to delocalize a negative charge by mesomeric The dissociation constants for ( E ) - and (2)-a,P-diarylacrylic acids, and also those for compounds in which one of the rings contains a 2-thienyl or 2-selenienyl ring, have been determined. They are weaker acids than the corresponding benzene derivatives, which has been ascribed to a combination of polar and steric effects, as shown by correlation with a twoparameter equation.443 Both 2- and 3-selenienylalanine have been prepared from 2- and 3-chloromethylselenophen by reaction with diethyl acetamidomalonate and subsequent hydrolysis.444 Condensed Se1enophens.-The reaction of benzoyl isoselenocyanate with phenyldiazomethane at room temperature gave 2-benzoylamino-3-phenylbenz~[b]selenophen.~~~ Friedel-Crafts cyclization of a-(arylse1eno)cinnamic acids with phosphorus pentoxide-methanesulphonic acid gave (276).446The third classical selenophthen, i.e. selenolo[3,4-b]selenophen, has been synthesized by two different routes, using 2,3-bischloromethyl-5-methoxycarbonylselenophen, or, for preference, 4-(methylseleno)selenophen-3-aldehydeas the starting material. In contrast to its thiophen analogue, the bc-fused selenophthen was stable and showed large differences in chemical shift between the two selenium atoms in its 75Se n.m.r. The reaction of 2-(methylseleno)selenophen-3-aldehyde with bromine and ammonia gave selenolo[3,2d ] i ~ o s e l e n a z o l e .The ~ ~ ~reaction of 2-[(triphenylphosphonio)methyl]thiophen chloride with hydrogen selenite in DMF led to the curious diselenide (277), . ~ ~ ~brominthe structure of which was proven by X-ray ~ r y s t a l l o g r a p h y The ation and formylation of selenolo[2,3-b]thiophen and selenolo[3,2-b]thiophen A comparative study of acetylation, formylhave been ation, and chlorination of selenolo[3,2-b]selenophen, selenolo[3,2-b]thiophen, and thieno[3,2-b]thiophen has been carried out. The overall reactivity was found to be: selenolo[3,2-b]selenophen > selenolo[3,2-b]thiophen > 442

443 444

445 446 447

448 449

F. Fringuelli, B. Serena, and A. Taticchi, J. Chem. SOC.,Perkin Trans. 2, 1980,971. E.Maccarone, A. Mamo, D . Sciotto, and M. Torre, J. Chem. SOC.,Perkin Trans. 2, 1980,161. T. Frejd, M. A. Davis, S. Gronowitz, and T. Sadeh, J. Heterocycl. Chem., 1980,17,759. G . L'abb6, J.-P. Dekerk, C. Martens, and S. Toppet, J. Org. Chem., 1980,45,4366. D . H.Wadsworth and M. R. Detty, J. Org. Chem., 1980,45,4611. A.Konar and S. Gronowitz, Tetrahedron, 1980,36,3317. G . Ruban, D . Zobel, G. Kossmehl, and I. Sgustav, Chem. Ber., 1981,114,818. V. P. Litvinov, Ya. L. Gol'dfarb, and I. P. Konyaeva, Izv. Akad. Nauk SSSR,Ser. Khim., 1980,

372.

Heterocy c Zic Chernistry

110

t hieno[3,2 -b]thiophen .450 While (278) reacts normally with butyl-lithium, giving a stable 2-lithium derivative, (279) gives (280) after reaction with butyl-lithium followed by carbon dioxide, while (281) gave (282). The 13C and "Se n.m.r. spectra of (278), (279), and (281) were a n a l y ~ e d . ~ ~ ~

X (278) X, Y = S , Se

CH=CHSeR r n C 0 2 H (280)

(279)

% Se

(281) X

=

X

S or Se

Tellurophens.-The synthesis of some 2-mono- and 2,5-di-substituted tellurophens has been mentioned Several substituted 3-halogenobenzo[b]tellurophens have been synthesized by treating phenylacetylenes with tellurium dioxide in the presence of a lithium halide.4523-Substituted benzo[b]tellurophens have been obtained through Wittig reaction with 2H- benzo[b]teHurophen-3-one and aromatization of the adduct. In this way, various 3monosubstituted derivatives (Me, CHO, CH20H, C02H) were obtained. The reaction of 2H-benzo[b]tellurophen-3-one'with triphenylphosphine and TeX, gave the 3-chloro- and the 3-bromo-derivative, Acetylation of benzo[b]tellurophen with acetic anhydride in trifluoroacetic acid gave a mixture of the 2and the 3-isomer, in the proportions 3 : l.453 The '25Te chemical shifts and 125Te-Hcoupling constants for 1,3-dihydrobenzo[c]tellurophen and its dihalogenated oxidation product have been measured and correlated with the oxidation state of the tellurium and the electronegativity of the halogen s ~ b s t i t u e n t . ~ ~ ~

450 451

4s2 453 4s4

S. Gronowitz, A. Konar, and V. Litvinov, Chem. Scr., 1980, 15, 206. M. Baiwir, G. Llabres, J.-L. Piette, and L. Christiaens, Specfrochim. Acta, Part A, 1980, 36, 819. J. Bergman and L. Engman, J. Organomet. Chem., 1980,199, 377. J.-M. Talbot, J.-L. Piette, and M. Renson, Bull. SOC. Chim.Belg., 1980,89, 763. N. Zumbulyadis and H. J. Gysling, J. Organomet. Chem., 1980, 192, 183.

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

111

PART 11: Systems containing Nitrogen and Sulphur, Selenium, or Tellurium by J. Elguero and J. de Mendoza

1 Introduction and Reviews This section reviews the literature cited in Volumes 93 and 94 of Chemical Abstracts. For earlier reviews, the reader is referred to Volumes 1 and 2 of this Series.’ Other literature sources are to be found in a recent Volume of ‘Advances in Heterocyclic Chemistry’ which features a survey on 4-thia~olidinones.~ Thiazoles, isothiazoles, and other five-membered rings have been reviewed in connection with the synthesis of natural products by ring-opening reaction^.^ Other relevant reviews are on the r-electron structure of heterocyclic molecules that contain ~ u l p h u r ,on ~ the chemistry of the 1,3-thiazolinone S hydroxy1,3-thiazole system^,^ and on the synthesis and reactions of the novel dihydrothiazolo[3,2-a]pyridinium-8-olate system and some closely related molecules.6

2 Isothiazoles Synthesis.-From ‘Thiacyanocarbons ’ (Type A ; C-C-C-N + S),* ‘Thiacyanocarbons’ [which have been defined (see J. Am. Chem. SOC.,1962, 84, 4746) as compounds which contain only carbon, nitrogen, and sulphur, and in which there is a plurality of cyano-groups] are an interesting class of compounds which can be prepared entirely from inorganic sources (namely sodium cyanide, carbon disulphide, and sulphur). They are versatile intermediates in the synthesis of heterocycles. In particular, they give an unusual sulphur-insertionrearrangement reaction which yields bicyclic or polycyclic isothiazole derivatives (see Section 6). The method has been extended to the synthesis of (l), and the reaction is accelerated by the addition of small amounts of tetracyanodithiin (see Section 6).’

Synthesis of Isothiazoles from Nitrile N-Sulphides (Type B ; C-C + S-N-C). Nitrile N-sulphides, generated from 1,3,4-oxathiazol-2-ones (2), react with carbonyl compounds that possess electron-withdrawing substituents to give

* For definitions of the types A, B, etc. for isothiazoles, see p. 110 of Volume 1 of this series. P.A. Lowe, in ‘HeterocyclicChemistry’, ed. H. Suschitzky and 0. Meth-Cohn (SpecialistPeriodical Reports), The Chemical Society, London, 1980, Vol. 1,p. 109, and The Royal Society of Chemistry, London, 1981, Vol. 2, p. 104. G. R. Newkome and A. Nayak, Adv. Heterocycl. Chem., 1979,25, 83. T . Kametani and K. Fukurnoto, Kuguku no Ryoiki, Zokan, 1979, 123, 153 (Chem. Abstr., 1980, 93,204 482). N. K. Das Gupta and F. W. Birss, Tetrahedron, 1980, 36,2711. G. C. Barrett, Tetrahedron, 1980,36,2023. K. Undheirn, Heterocycles, 1981, 15, 1349. S. A. Vladuchick, T. Fukunaga, H. E. Simmons, and 0.W. Webster, J. Org. Chem., 1980,45,5122.

Heterocyclic Chemistry

112

1,3,4-0xathiazoles (3) (Scheme 1). On thermolysis, these substances undergo a 1,3-dipolar cycloreversion to the nitrile sulphide, which may be trapped with alkynes or nitriles, giving isothiazoles (4) and 1,2,4-thiadiazoles ( 5 ) , respectively.' R ' c g O N--S

Scheme 1

Nitrile N- sulphides can also be generated from iminosulphur difluorides (6), and this reaction has been demonstrated to be quite general.' These reagents react with acetylenes and alkenes. For example, N-phenylmaleimide gives compound (7) in 74% yield.

Synthesis of Isothiazoles from Thioenaminones (Type C; S-C-C-C-N). Enaminones and thioenaminones, e.g. (8), react with hydroxylamine-0 sulphonic acid, giving isoxazoles and isothiazoles, e.g. (9), respectively. lo The reaction of N-substituted 3-aroyl-propionamides with excess of thionyl chloride gives the 3-isothiazolones (10; R = Me or Ph)."

On the other hand, 4-isothiazoline-3-thiones result from the ring-opening of 4-isoxazoline-3-thiones and 3-imino-l,2-dithioles with hydrogen sulphide and base, respectively.12 Physical Properties of 1sothiazoles.-Spectroscopic data (u.v., i.r., and 13C n.m.r.), dipole moments, and theoretical calculations of isothiazolium-4-olates (11) have been compared with those for the corresponding 1,2-dithiolium-401ates.l~

lo

l3

R. M. Paton, F. M. Robertson, J. F. Ross, and J. Crosby, J. Chem. SOC., Chem. Commun., 1980,714. M. J. Sanders and J. R. Grunwell, J. Org. Chem., 1980,45, 3753. Y.I. Lin and S. A. Lang, J. Org. Chem., 1980,454857. A. Tsolomitis and C. Sandris, J. Heterocycl. Chem., 1980,17,1645. S . Sugai and K. Tomita, Chem. Pharm. Bull., 1980,28,487. D. Barillier, Phosphorus Sulfur, 1980, 8, 79.

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

113

Chemical Properties of 1sothiazoles.-Alkylation. Alkylation of the 3-isothiazoline-5-thione (12) with CH2N2takes place mainly on the exocyclic sulphur at the 5-position.14 The related compounds (13; R1 = aryl, R2 = alkyl or phenyl) are also alkylated on that position (by CH2N2, MeI, or [Et30]'[BF4]-), giving the corresponding isothiazoles (14; R3 = Me or Et), with a simultaneous thiolester-thiono-ester rearrangement.15 0-

Cycloaddition. Compound (12), when treated with dimethyl acetylenedicarboxylate, undergoes a 1,3-dipolar cycloaddition to form the dithiole (15; R = PhNHCO), with simultaneous ring-0~ening.l~ If the reaction is carried out with (13; R' = Ph), a similar transformation into the compound (15; R = PhCONH) takes place, with a concomitant migration of acyl from S to N.16 Other Reactions. The (isothiazoly1thio)acetamide(16) rearranges in basic media to the corresponding 1,3-dithietancarboxamide(17).17

3 1,2-Benzisothiazoles, their 1-Oxides, and their 1,l-Dioxides

Synthesis.-A novel syi.&esis of 1,2-benzisothiazoles from chlorides, elemental sulphur, and ammonia, has been reported." Thiochroman-4-ones (18; R = H or Me) and benzo[b]thiophen-3(2H)-ones (19; R = Me or Ph) yield the corresponding 1,2-benzisothiazole (20) on treatment with O-mesitylenesulphonylhydroxylamine and aqueous sodium hydroxide. The sulphenamide intermediate (21) has been proposed for the p r o c e ~ s . ' ~ T. Nishiwaki, E. Kawamura, N. Abe, and M. Iori, Heterocycles, 1980,14, 785. T. Nishiwaki, E. Kawarnura, N . Abe, and M. Iori, Chem. Lett., 1980,401. T. Nishiwaki, E. Kawarnura, N. Abe, and M. Iori, J. Chem. SOC.,Perkin Trans. 1, 1980,2693. ''I M. Iwanami, T. Maeda, M. Fujimoto, Y. Nagano, N. Nagano, A. Yamazaki, T. Shibanuma, K. Tamazawa, and K. Yano, Chem. Pharm. Bull., 1980,28,2629. I s J. Markert and H. Hagen, Liebigs Ann. Chem., 1980,768. l9 Y. Tamura, S. M. Bayorni, C. Mukai, M. Ikeda, M. Murase, and M. Kise, Tetrahedron Lett., 1980, 21,533.

l4

l5

Heterocyclic Chemistry

114 H

(19)

O R II 1

I:

Chemical Properties of 1,2-Benzisdhiazoles.-Electrophilic reactions of some derivatives of 3-methyl-l,2-benzisothiazolehave been reported.20 3-Chloro-1,2benzisothiazolium chlorides (22; R1 = H or C1, R2 = ethyl or phenyl) react with aromatic amines to give compounds (23), which are in equilibrium with the isomeric 1,2-benzisothiazolines (24) (Scheme 2). The position of the equilibrium, and the rate of equilibration, depend on the nature of the substituents R2 and R3.21

The 1,2-benzisothiazole 1,1-dioxide (25) has been reported as a new effective condensing agent for the synthesis of peptides.22 Esters of the compound (26) can be easily cleaved to ring-opened products with alkoxides, and to the 1,2benzothiazine derivatives (27) under more drastic condition^.^^ Similarly, 1,2benzisothiazole undergoes ring-cleavage with alkoxides, yielding o-cyanobenzenethiolates."

4 1,2-Benzisoselenazoleand 1,2-Benzisotellurazole

The most interesting result in this series is the reported reaction of 2,1,3benzoselenadiazoles (28) with benzyne, which yields 3-substituted 1,2benzoselenazoles (29).24The crystal structure of (29) has also been reported. 2o 21

22 23 24

K. Clarke, B. Gleadhill, and R. M. Scrowston, J. Chem. Res. ( S ) , 1980,197. H.Boeshagen and W. Geiger, Chem. Ber., 1980,113,2490. A.Ahmed, H: Fukuda, K. Inomata, and H. Kotake, Chem. Lett., 1980,1161. C.B. Schapira, I. A. Perillo, and S . Lamdam, J. Heferocycl. Chem., 1980,17, 1281. M. R. Bryce, C. D. Reynolds, P. Hanson, and J. M. Vernon, J. Chem. Suc., Perkin Trans. 1, 1981, 607.

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

115

5 2,l-Benzisothiazoles

Derivatives of 3-amino-2,1-benzisothiazolehave been prepared from thioanthranilamide~.~’The structure (30), reported in 1979 .-. a ‘new’ bicyclic low-system, is actually a canonical form of the 2,1-benzisoth:,~zole(31).26 The reaction of isocyanates and of isothiocyanates with the 2,1-benzisothiazol-3-ones (32; R’ = H or CI), in the presence of a stoicheiometric amount of an organic base, yields the corresponding derivative of the 3,1-benzoxa~in-4-one (33; R’ = H or C1; X = 0)and of the 3,1-benzothiazin-4-one (33; R’ = H or C1; X = S), respectively (Scheme 3). The extrusion of the heterocyclic sulphur probably takes place through N-carbamoyl or N-thiocarbamoyl intermediates.” 0 R~N=C=X

H (32) Scheme 3

6 Other Condensed Ring Systems incorporating Isothiazole

-

Thieno-[2,3-d] -, [3,2 -d]-,and - [2,3-c] -isothiazoles.-The bicyclic structures (34; X = S) and (35; X = Y = S, R’ = R2 = R3 = H) can beobtainedfrom 2,3substituted thiophens that contain a sulphur function and a carbonyl or nitrile group, by methods often different from those usually employed for the synthesis of benzisothiazoles. Alternatively, compounds of the type (35; X = Y = S) can also be prepared from a methyl 2-mercapto-3-thienyl ketone and chloramine, or from the oxathiazepine (36) in an inert solvent.Z8 Sequential treatment of the dianion (37) with ClCH2COR (R = Me or Ph) and MeI, or in the reverse order, followedby intramolecular cyclization, affords the thieno[2,3-c]isothiazoles (38) and the thieno[3,2-d]isothiazoles (35; X = Y = S, R’ = RCO, R2 = NH2, R3 = SMe), respecti~ely.~~ 25

27 29

.T. Gray and D. R. Waring, J. Heterocycl. Chem., 1980,17,65. M. Davis, 2.Naturforsch., Teil. B, 1980,35, 405. J. Perronet and L. Taliani, J. Heterocycl. Chem., 1980,17,673. K. Clarke, W. R. Fox, and R. M. Scrowston, J. Chem. SOC.,Perkin Trans. I , 1980,1029. B. Tornetta, G. Ronsisvalle, E. Bouquet, F. Guerrera, and M. A. Siracusa, Gazz. Chim. Ital.,

1980,110,233.

Heterocyclic Chemistry

116

-

-

Thieno-[2,3-d] -, [3,2-d] -,and [4,3-d] -isoselenazoles,and Selenopheno[3,2d]isoselenazoles.-The synthesis of these compounds [(34; X = Se), (35; R’ = R2 = R3 = H, X = Y = S or Se), and (39)] from adequately 2,3- or 2,4-disubstituted thiophens or selenophens has been de~cribed.~’

[1]Benzothieno[2,3~d]isothiazoles.-This system (40; R = H) can be obtained in a similar way to the preparation of (35) from (36), starting from the oxathiazepine derivative (41).31Some reactions of (40; R = Me) have also been examined.

Isothiazolo[5,4-6]pyridine.-The reaction of isothiazolyl-5-amines with diethyl ethoxymethylenemalonate gives the compound (42; R = Me or aryl), which can be further saponified and N-alkylated to yield an isothiazolo[5,4-b]pyridine analogue of nalidixic 1,4-Dithiino[c]isothiazole, 1,4-Dithiino[2,3-c;6,5-c’]di-isothiazole, and Isothiazolo[3,4-f][1,2,3,4,5]pentathiepin.-Compounds (43) and (44; R = CN) have been prepared by a sulphur-insertion-rearrangement reaction from a stable tetracyanodithiin (see Scheme 4). On the other hand, the strange and interesting compound ( 4 9 , whose structure has been determined by X-ray analysis, results from the reaction of 5-cyanoisothiazoledithiolate(1)(see Section 2) and sulphur dichloride. Some reactions of these compounds have also been investigated; e.g., the hydrolysis and decarboxylation of (44; R = CN) to the parent compound (44; R = H), and the reactions of this latter with electrophiles and acids. A theoretical study has also been completed for these novel cyclic 7.r-electron systems.’

31

N. V. Onyamboko, R. Weber, N. Dereu, M. Renson, and C. Paulmier, Bull. SOC.Chim. Belg., 1980,89,773. K. Clarke, W. R. Fox, and R. M. Scrowston, J. Chem. Res. (S), 1980, 33.

32

P.M. Gilis, A. Haemers, and W. Bollaert, J. Heterocycl. Chem., 1980,17, 717.

30

117

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

NC

NC

(43)

Scheme 4

Benzo[c]bisisothiazole and Benzo[ c]trisisothiazole.-These compounds, e.g. (46)-(49), can be obtained from 2,l-ben~isothiazoles.~~ Isothiazolo-[3,4-e]- and -[4,3-el-[ 2,1,3] benzothiadiazo1es.-Compound (5 0) can be obtained either from 4,5-diamino-2,1-benzisothiazole and thionyl chloride or from 5-amino-4-methyl-2,1,3-benzothiadiazole and N-sulphinylmethanesulphonamide. Analogously, compound (51; R = H) is produced in a Comsimilar reaction with the isomeric 4-amino-5-methyl-2,1,3-thiadiazole. pound (51; R = Me) is obtained directly, in a few steps, from 4,6-diamino-1,3xy~ene.~~ compound (52) has been prepared18 by a route that is similar to that for 1,2-benzisothiazoles

Naphtho[t,l-d]isothiazoles.-The

ps

N/ \

s -

(49)

S-N

S-N\

\

R

/ (52)

(51)

’’ B. Danylec and M. Davis, J. Heterocycl. Chem., 1980,17,533. 34

B.Danylec and M. Davis, J. Heterocycl. Chem., 1980,17,537.

118

Heterocyclic Chemistry

Isothiazolonaphthoquinonesand Bis(isothiazo1o)benzoquinones.-These compounds, (54) and ( 5 5 ) , are obtained by thermolysis of the oxathiazolones (53; R = Me) and (53;R = Ar) in the presence of the corresponding quinone, through a cycloaddition reaction of the intermediate nitrile ~ u l p h i d e . ~ ~

n

(53)

0 (54)

(55)

7 Thiazoles Synthesis.-Hantzsch's Synthesis (Type A ; S-C-N + C-C)." The vast majority of thiazoles continue to be prepared by this general route, by means of thio~reas,~ thiocarbazone~,~' ~~' and N,S-disubstituted isothiocarba~ones.~~ Type G Syntheses of Thiazoles (N-C-S-C-C). An unconventional and simple synthesis of 2-(o- aminopheny1)thiazoles (56), by a C-2-extrusion reaction from 2-(4-quinazolinylthio)acetophenones (57) with perchloric acid and subsequent SCH,COAr

/ \

basification, has been Compound ( 5 8 ) reacts with phenacyl bromide to give the thiazoles (59; R' = Ph, R2 = ArCO, R3 = Me), as shown in Scheme 5 ; alternatively, (58) reacts with benzyl chloride to give the thiazole' (59; R' = R2 = Ph, R3 = Me) via compound (60).44The use of the intermediate (6-1) affords (59; R' = H, R2 = Ar, R3 = Ar'COCH2).45

Type H Syntheses of Thiazoles (S-C + C-N-C). The synthetic application of tosylmethyl isocyanide (TOSMIC) and its derivatives to the preparation of a variety of pentagonal heterocycles, including thiazole derivatives, has recently * For definitions of the types A, B, etc. for thiazoles, thiazolines, and thiazolidines, see p. 119 of Volume 1 of this series. 35 36

37

38

39 40

41 42 43

44 45

R. M. Paton, J. F. Ross, and J. Crosby, J. Chem. SOC.,Chem. Commun., 1980, 1194. V. G. Kartsev, F. A. Medvedev, and G. N. Voronina, Khim. Geterotsikl. Soedin., 1980, 209 (Chem. Abstr., 1980,93, 26 354). K. Upadhya, B. V. Badami, G. S. Puranik, V. N. Biradar, and S. Nanjappa, Arch. Pharm. (Weinheim, Ger.), 1980, 313, 684. S. P. Singh, D. R. Kodali, and S. N. Sawhney, Indian J. Chem., Sect. B, 1979, 18,424. S. Rajappa, B. G. Advani, and R. Sreenivasan, Indian J. Chem., Sect. B, 1980, 19, 536. E. Campaigne and T. P. Selby, J. Heterocycl. Chem., 1980, 17, 1255. 0. Prakash, D. S. Tyagi, and S.K. Sangal, J. Indian Chem. SOC.,1980, 57, 1136. C. Yamazaki, Bull. Chem. Soc. Jpn., 1980, 53,3289. H. Singh, C. S.Gandhi, and M. S . Bal, Chem. Ind. (London), 1980, 420. M. Agustin, M. Richter, and S. Salas, J. Prakt. Chem., 1980,322, 5 5 . M. Pallas, F. Geissler, and W. Kalkofen, Z. Chem., 1980, 20, 257.

119

Five-Membered Rings: Systems containing N and S, Se, or Te H PhC- N-C-SMe

II

0

$

~

PhC -N=C' II 0 'SCH2Ph (60)

ArCCH,S-C-SCH2CAr'

II

0 I'

NOH (61)

II

0

Scheme 5

been reviewed.46 Ethyl isocyanoacetate reacts with thiono-esters, giving the corresponding 5-substituted 4-(ethoxycarbonyl)thiazoles.47

Type K Syntheses of Thiazoles (S-C-N-C-C). Treatment of N-vinyl-thioamides with morpholine or aryl-mercaptans gives the corresponding thiazoles (62; R = morpholino) and (62; R = arylthi~).~' Physical Properties of Thiazo1es.-Ultraviolet spectra of some thiazolium derivatives have been st~died.~' Ultraviolet and infrared data have been given for thiazole and for its bromo-, methyl-,50and 5-nitro-deri~atives.~'Other studies include the fluorescence and phosphorescence of some thiamine derivatives.'* The tautomerism and site of protonation of dimethylamino-thiazoles have been studied by comparison of their pK, values with those for the 2-unsubstituted analogues, confirming that the protonation centre is the endocyclic nitrogen atom.53 Chemical Properties of Thiazo1es.-The rates of detritiation of thiazole and other azoles and benzazoles, including benzothiazole and benzoselenazole, have been studied ~omparatively.'~ The nitrosation of several 2-hydrazino-substituted thiazole-4-acetates has been shown to occur on the ring, rather than on the a -methylene carbon, as previously reported.55 H "C)Ar

(62)

R2fJN=CHD (63)

_.

R'

H2NCY)NR2

Br;

(64)

A . M. van Leusen, Lect. Heterocycl. Chem., 1980, 5 , S-111. G. D. Hatman and L. M. Weinstock, Org. Synth., 1980, 59, 183. T. K. Vinogradova, A . Martynyuk, and B. S. Drach, Zh. Org. Khim., 1980, 16, 1783 (Chem. Abstr., 1981,94, 30 619). 49 M. R. Mahmoud, H. S. Elkashef, and M. M. Ahmed, Monatsh. Chem., 1980,111, 1213. jU I. T. Depeshko and V. I. Treskach, Farm. Zh. (Kieu),1980,47 (Chem. Abstr., 1981,94, 174 055). '' I. T. Depeshko, V. I. Treskach, and N. M. Turkevich, Farmatsiya (Moscow), 1979,28,30 (Chem. Abstr., 1980, 93,45 339). '* E. P. Gibson and J. H. Turnbull, J. Chem. SOC.,Perkin Trans. 2, 1980, 1288. " L. Forlani, P. D e Maria, and A. Fini, J. Chem. SOC.,Perkin Trans. 2, 1980, 1156. " J. A. Elvidge, J. R. Jones, R. Salih, M. Shandala, and S. E. Taylor, J. Chem. Res. ( S ) , 1980, 172. 55 E. Campaigne and T. P. Selby, J. Heterocycl. Chem., 1980,17, 1249. 4b

47

Heterocyclic Chemistry

120

Reactions of 2-Aminothiazoles. The kinetics of hydrolysis of Schiff bases (63; R' = H or Br, R2 = H or aryl) have been studied.56The new brominating agent 2,4-diaminothiazole hydrotribromide (64; R, R = H, Me) can be prepared by the reaction of the corresponding hydrobromide with bromine in acetic acid or water in the presence of HBr. They are soft brominating reagents for ketones and Reactions of Thiuzolium Salts. The effects of substituent and of solvent on the rates of the reactions of 3-ethyl-2-methyl-4-phenylthiazoliumiodide with substituted benzaldehydes have been e ~ a m i n e d . ' ~The catalytic activities of thiazolium salts in the benzoin condensation,56360 as well as in the addition of aldehydes to activated double-bonds (Michael-Stetter addition),61 continue to be currently investigated. Triethylamine-catalysed Michael additions of benzoins to chalcone can prevail over the expected Michael-Stetter additions when certain thiazolium ion conjugate bases are used as catalysts.61Another catalytic activity of thiazolium ions is the electron-transfer reduction of several organic substrates in methanol by active aldehydes.62The reversible hydrolytic cleavage of thiamine has been studied by a pH-stat method,63whereas its cleavage by ethylene oxide has been followed by d e ~ t e r i a t i o n The . ~ ~ kinetics of the cleavage of thiamine by bisulphite ion support the Zoltewicz-Kauffman (1977) mechanism, in which the second step is an S,2 displacement by bisulphite Thiazole acts as a leaving group in the reaction of 1'-methylthiaminium salts with nucleophiles.66 Some substituted thiazolium salts (65;n = 1, R = Me or Ph) or (65;n = 2 or 3, R = H)give rearranged products (66)on treatment with a base, according to the mechanism of Scheme 6.67

.t

(65)

Me

I Me Scheme 6 A. C. Dash, B. Dash, and M. Patra, Indian J. Chem., Sect. B,1980,19,492. '' L. Forlani, Synthesis, 1980,487. M. R. Mahmoud, H. M. S. El-Kashef, and A. M. El-Nady, Monatsh. Chem., 1980,111,657. 59 W. Tagaki, Y. Tamura, and Y. Yano, Bull. Chem. SOC. Jpn., 1980, 53,478. " Y. Yano, Y. Tamura, and W. Tagaki, Bull. Chem. SOC.Jpn., 1980,53,740. 61 J. Castells, E. Dunach, F. Geijo, F. Lopez-Calahorra, M. Prats, 0. Sanahuja, and L. Villanova, Tetrahedron Lett., 1980,21, 2291. 62 H. Inoue and K. Higashiura, J. Chem. SOC.,Chem. Commun., 1980, 549. 63 J. A. Zoltewicz and G. Uray, J. Org. Chem., 1980,45,2104. " W. M. Polyachenko and A. M. Yurkevich, Bioorg. Khim., 1980, 6, 614 (Chem. Abstr., 1980, 93, 94 428). 65 D . R. Doerge and L. L. Ingraham, J. Am. Chem. SOC.,1980,102,4828. 6b J. A. Zoltewicz, Synthesis, 1980, 218. 67 H. J. Federsel and J. Bergman, Heterocycles, 1980, 14, 33. 56

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

121

Reactions of Meso-ionic Thiazoles. Photo-oxidation of meso-ionic thiazol-4-ones (67; R' = R2 = Ph, X = NPh) and other related meso-ionic structures, e.g. (67; R1 = R2 = Ph, X = S), gives ring-cleavage products whose formation can be rationalized through the formation of the endoperoxides of the meso-ionic ring.68 On the other hand, the oxidation of (67; R' = Ar, R2 = Ph, X = NAr) with m-chloroperoxybenzoic acid in primary alcohols yields (68; R3 = alkyl) and N-aroyl-thiobenzanilide~.~'The meso-ionic compounds (67; R' = R2 = Ar, X = NAr) are desulphurized stereoselectively to the cis -azetidin-2-ones (69); the trans -isomers are obtained in the presence of triphenylpho~phine.~' 4-Hydroxythiazoles (70; R' = H or Ph, R2 = aryl) show similar tautomeric behaviour to azlactones. The mechanisms of their reactions with dipolarophiles differ, h ~ w e v e r . ~ ' R3

Ar

N

(71) X = O (72) X = NCH2Ph

Ar (69)

Miscellaneous Reactions of Thiazoles. Ethyl propiolate (and other acetylenic esters) reacts regioselectively with 2-bromothiazoles in the presence of AlCl, to give N-vinyl-substituted 2-thiazoles (71; 50% with R', R2 = H, C0,Et; 50% with R' = C02Et, R2 = Br). Compound (72; R1 = H, R2 = C02Et)is obtained if the reaction is quenched with b e n ~ y l a m i n e . ~ ~ 8 A2-Thiazolines Synthesis.-Type A (S-C-N + C-C). A2-Thiazolinediones (73; R = alkyl, aryl, or heteroaryl) can be obtained by treating the corresponding thioamides with oxalyl Type D Syntheses of A2-Thiazolines (C-N + S-C-C). Malononitrile reacts with thioglycollic acid to give compounds (74) or (75), depending on the molar ratio of the reactant^.'^

68 69

70

71 72

73 74

H. Kato, K. Tani, H. Kurumisawa, and Y. Tamura, Chem. Lett., 1980,717.

T.Sheradsky and D. Zbaida, J. Org. Chem., 1980,45,4850. T.Sheradsky and D . Zbaida, J. Org. Chem., 1980,45,2165. A. Robert, M. Ferrey, and A. Le Marechal, Tetrahedron, 1980,36, 1571. A. Medici, P. Pedrini, M. Fogagnolo, and A. Dondoni, J. Chem. SOC.,Chem. Commun., 1980,1077 J. Goerdeler and K. Nandi, Chem. Ber., 1981,114,549. M.H.Elnagdi, M. R. H. Elmoghayer, A. E. Hammam, and S. A. Khallaf, J. Heterocycl. Chem.,

1979.16,1541.

122

Heterocyclic Chemistry

Type K Syntheses of A2-Thiazolines (S-C-N-C-C). The reaction of uiciodoisothiocyanates with nucleophiles gives the 2-substituted A’-thiazolines [76; R1 = alkyl or alkoxy, R2 = H or (CH,),] in high ~ield.~’-~’ Physical Properties of A2-Thiazolines.-Mass spectra of derivatives of 2-aminoA2-thiazoline have been ~ t u d i e d .The ~ ~ crystal , ~ ~ structure of compound (77) has been determined.”

(80)

Chemical Properties of A’-ThiazoIines.-The photophysical properties of the derivatives (78) of 2-amino-A2-thiazoline have been investigated by absorption, emission, and phosphorescence spectra, and by studies of intermolecular triplettriplet energy transfer.” The methylene-blue-sensitized photo-oxidation of 4methyl-2-phenyl-A2-thiazolin-5-one (79) gives the dimer (80).’’ 9 A’-Thiazolines

The enamines (81; R = Me, Et, or But) react with 2,5-dihydroxy-1,4-dithian to give the thiazolines (82), which can in turn be cleaved at the 1-5 bond with Ac20, Et,N, or ZnC12.” On the other hand, a variety of A3-thiazolines (83;

’’ P. D. Woodgate, D. Chambers, P. S. Rutledge, and R. C. Cambie, Heterocycles, 1980, 14, 653. 76

R. C. Cambie, D. Chambers, P. S. Rutledge, P. D. Woodgate, and S. D. Woodgate, J. Chem. SOC.,Perkin Trans. 1, 1981, 33.

77

7a 79

81

82

R. C. Cambie, D. Chambers, P. S. Rutledge, and P. D. Woodgate, J. Chem. SOC.,Perkin Trans. 1, 1981, 40. M. P. Viallet, J. Ulrich, and A. Boucherle, Arch. Pharm. (Weinheim, Ger.), 1980, 313, 549. A. E. Lyuts, V. V. Zamkova, L. A. Tsoi, and S. T. Cholpankulova, Zh. Org. Khim., 1980, 16, 1315 (Chem. Absrr., 1980,93, 185 265). S. Stankovic, B. Ribar, A. Kalman, and G. Argay, Acta Crystallogr., Sect. B, 1980, 36, 1235. P. Jardon, M. P. Viallet, A. Boucherle, and R. Gautron, J. Chem. Res. ( S ) , 1980, 353. J. Gasteiger and U. Strauss, Heferocycles, 1981, 16, 199.

123

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

R1 = R2 = aryl, R3 = Me or aryl, R4 = H or Me) can be obtained from the reactions of the N-acyl-thioamides (84) with the appropriate brorno-ket~ne.~~

10 A4-Thiazolines Synthesis.-Type A (S-C-N + C-C). Moderate yields of the A4-thiazolines(85; R = Ph or 4-tolyl) are produced, together with 1,3-oxathioles, in the reaction of adequately trisubstituted acyclic thioureas and ethyl a -chloroa~etoacetate.~~ 1,2-Dithiolimine (86) reacts with alkyl or phenyl ynamines to give the thiazolines (87; R = Me or Ph).85

Type B Syntheses of A4-Thiazolines(S-C + C-C-N). 1-Phenylamino-1-phenylacetonitrile reacts with aryl isothiocyanates, giving the amino-thiazolines (88).86 Type E Syntheses of A4-Thiazolines (S-C-C-N + C). The reaction of carbon has been reported to yield disulphide and a -methylthio-P-imino-sulphoxides the 5-methylthio-A4-thiazoline-2-thiones (89).87 Type G Syntheses of A4-Thiazolines (N-C-S-C-C). A mechanism for the rearrangement of the 2-amino-1,3,4-thiadiazine(90) to the 3-amino-A*-thiazolimine (9l), involving transannular nucleophilic displacements, has been proposed.88

(88)

(89)

(90)

(91)

Miscellaneous Methods of Synthesis of A4-Thiazolines.Thioformanilide reacts with l,l-dicyano-2-phenyl (or -aryl) epoxides (92), giving the corresponding A4-thiazolin-2-ones(93;R = Ph or aryl). Keten and bicyclic intermediates (see Scheme 7) are probably involved.89

’’ P. Krey and H. Dehne, Pharmazie, 1980,35,398. 86

H.Singh and A . S. Ahuja, Indian J. Chem., Sect. B, 1979,18,534. A.Dibo, M. Stavaux, and N. Lozac’h, Bull. SOC.Chim. Fr., Part 2, 1980,530. S. T.Ingle, S. M. Kapley, and M. S. Chande, Proc. Indian Acad. Sci., [Ser.] Chem. Sci., 1980,89,

89

295. M. Muraoka, T. Yamamoto, and T. Takeshima, J. Chem. Res. ( S ) , 1980,356. R. E.Busby and T. W. Dominey, J. Chem. Soc., Perkin Trans. 2, 1980,890. M. Baudy and A. Robert, C.R. Hebd. Seances Acad. Sci., Ser. C, 1980,290,287.

84

”

Heterocyclic Chemistry

y;o

Ar

(92)

1"E""'"

(93)

Ar

T \

/c=c=O ---*

S

\

/

C=NPh

H

H

Scheme 7

Chemical Properties of A'-Thiazo1ines.-The gear effect of alkyl groups in transmitting conformational effects has been examined in the alanine derivatives (94; R', RZ = H, Me; R3 = H, Me, Et, Pr', or Bu'). This effect appears to be a suitable means to modulate the interaction of two active groups, namely the thiocarbonyl and the carboxylic acid functions.90 Similarly, dynamic 'H n.m.r. spectroscopy has been used to determine the barriers to rotation of the 3-substituent in the thiazolinethione (95; R1 = CH,-alkyl, R2 = Me).91 The metallation of the thiazolethiones (95; R' = alkyl, R2 = Me or Ph), followed by reaction with electrophiles, has been reported as a route to diverse 5-substituted analogues of (95).92

Me

\ ; /

H

11 Thiazolidines Synthesis.-Type A (S-C-N + C-C). The condensation of chloro- or bromoacetic acid (or their derivatives) with t h i o u r e a ~continues ~~ to be the method of choice for the preparation of derivatives of thiazolidine-2,4-dione or 2-iminothiazolidin-4-one. Type D Syntheses of Thiazolidines (C-N + C-C-S). The reaction of 2-mercaptoacetic acid with a variety of Schiff bases constitutes the principal method for 90

91 92

93

B. Blake, C. Roussel, J. Metzger, and J. Sandstrom, Can. J. Chem., 1980,58,2212. C.Roussel, R. Gallo, J. Metzger, and J. Sandstrom, Org. Magn. Reson., 1980,14, 120. A. R. Katritzky, D. Winwood, and N. E. Grzeskowiak, Synthesis, 1980,800. K.V. Kale and S.N. Kulkarni, Indian J. Chem., Sect. B, 1980,19,152.

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

125

the synthesis of thiazolidin-4-0nes,~~-~~ but 2,3-disubstituted thiazolidines can be obtained if thiiran is used instead of 2-mercaptoacetic acid.97

Type E Syntheses of Thiazolidines (N-C-C-S + C ) . 2,2-Disubstituted thiazolidines (96; R1 = H or Me; R2 = alkyl, alkenyl, or aikynyl) are obtained by allowing cysteinamine to react with a ketone.98 Type K Syntheses of Thiazolidines (S-C-N-C-C). The intramolecular cyclization of dithiocarbamates to the thiazolidine-2-thiones (97)99 has been reported. Thioureas cyclize in HCl to the thiazolidin-2-imine (98; R', R3 = H, alkyl; R2 = aryl) (Scheme 8).'0° H

CH2NH

I

\

ArCH2CH

I

C=S

----*

I

ArCH

SNa

C1

R2yCH2yH2

R~R'CHN-C

I

1

OH

R3 .N.

- R1R2CHN3(SJ

Scheme 8

Physical Properties of Thiazo1idines.-Studies of the circular dichroism of the n + T* band in (-)-4-alkyl-thiazolidine-2-thiones have established a relationship between the sign and the intensity of the Cotton effect that is observed and the chirality of the ring."' These results confirm the conformations previously attributed by 'H and 13C n.m.r. spectroscopy for other thiazolidine-2t h i o n e ~ . ' ~ ~Other * " ~ 'H and 13Cn.m.r. conformational studies have been performed in this The structure of (d,l)-5,6-dehydropenicillinshas been revised to a thiazolylideneoxazolone structure (99; R = CH2Ph or CH20Ph) rather than a /3 -1actam structure, as previously reported.lo6Mass-spectrometric 94

9s

M. K.Pant, P. C. Joshi, and P. C. Joshi, jr., J. Indian Chem. Soc., 1980,57,826. A. M. A. Abdel-Wahlab, K. M. Hassan, and S. R. El-Ezbawy, Indian J. Chem., Sect. B, 1979,

18,467. %

'' 98

99 100

lo'

M. S. K. Youssef and K. M. Hassan, Rev. Roum. Chim., 1981,26,81. V. V. Sokolov, K. A. Oglobin, and A. A. Potekhin, Khim. Geterotsikl. Soedin., 1980,1569 (Chem. Abstr., 1981,94,121 393). D.Mesnard, L. Miginiac, M. Fatome, J. D. Laval, H. Sentenac-Roumanou, and C.Lion, Eur. J. Med. Chem.-Chim. Ther., 1980,15,247. J. Bernat and M. Ciganikova, Chem. Zvesti, 1979,33,663 (Chem. Abstr., 1980,93,26346). J. Reiter, L.Toldy, I. Schaefer, E. Szondy, J. Borsy, and 1. Lukovits, Euc. J. Med. Chem.-Chim. Ther., 1980,15,41. F. Chanon, M. Chanon, B. Norden, and J. Metzger, C.R. Hebd. Seances Acad. Sci., Ser. C, 1980,

291,161. '02

103

F. Chanon, M. Rajzmann, M. Chanon, J. Metzger, and G. Pouzard, Can. J. Chem., 1980,58,599. F.Chanon, M. Rajzmann, M. Chanon, J. Metzger, G. Pouzard, and T. Drakenberg, Can. J. Chem.,

1980,58,604. 104

lo'

F. A. M. Borremans, W. A. Nachtergaele, M. Budesinsky, M. J. 0. Anteunis, A. Kolodziejczyk, and B. Liberek, Bull. SOC.Chim. Belg., 1980,89,101. W. A. Nachtergaele and M. J. 0. Anteunis, Bull. SOC.Chim. Belg., 1980,89,749. L. Bassignani, A. Brandt, R. Diblasi, E. Mantovani, L. Re, L. Settembri, and R. Mondelli, G a z z . Chim. Ital., 1979,109,709.

126

fragmentation^^^"'^ and X-ray

Heterocyclic Chemistry have been reported for several

thiazolidines.

Chemical Properties of Thiazo1idines.-The synthetic versatility of the thiazolidine-2-thione group as a carboxyl-activating agent has been further demonstrated by the use of its acyl derivatives (100) in the synthesis of amides,'14 aldehydes and alcohols,11sand peptides.l16 Irradiation of (100) in ethanol gives the corresponding e ~ t e r . ' ~The " activation of dicarboxylic acids by this method opens an easy way to the synthesis of monocyclic amides (101; rn = 2, 4, 8, or 12; I? = 2, 3, 4, or 6).'18

Selective N-methylation of cysteamines can be achieved by cleavage of the 1-2 bond of the corresponding Nkubstituted thiazolidine (102; n = 6 or 8) with a b 0 ~ a n e . l ' ~

Rhodanines, Isorhodanines, and Thiorhodanines. The rate ratio of S- and Nmethylation of 5-benzylidenerhodanines has been studied.12'" The effect of substituents in the benzylidene moiety on the rate ratio of S- to N-methylation h'as been correlated with substituent constants, and demonstrated to be exerted about equally at both the N and S reaction centres.120b 107 108

109

110

111

112 113

114

11s 116

117 118 119

'21

H. Remane, R. Widera, and M. Muhlstaedt, J. Prakt. Chem., 1980, 322, 329. B. Tinant, J. P. Declercq, G. Germain, and M. Van Meerssche, Bull. SOC.Chim. Belg., 1980, 89, 113. A. Arte, B. Tinant, J. P. Declercq, G. Germain, and M. Van Meerssche, Bull. SOC.Chim. Belg., 1980,89, 117. R. F. Bryan, P. Hartley, S. Peckler, E. Fujita, Y. Nagao, and K. Seno, Act& Crystallogr., Sect. B, 1980,36,1709. S . Stankovic, B. Ribar, A. Kalman, G. Argay, L. Toldy, I. Toth, and D. N. J. White, Acfa Crystallogr., Sect. B, 1980,36, 2282. A. Kalman and L. Parkanyi, Acta Crystallogr,, Sect. B, 1980,36, 2372. S. Stankovic, B. Ribar, G. Argay, and A. Kalman, Cryst. Struct. Commun., 1980,9, 1147. Y. Nagao, K. Seno, K. Kawabata, T. Miyasaka, S. Takao, and E. Fujita, Tetrahedron Lett., 1980, 21,841. Y . Nagao, K. Kawabata, K. Seno, and E. Fujita, J. Chem. SOC.,Perkin Trans. 1, 1980, 2470. H. Yajima, K. Akaji, Y. Hirota, and N. Fujii, Chem. Pharm. Bull., 1980, 28, 3140. L. P. J. Burton and J. D. White, Tetrahedron Lett., 1980,21, 3147. Y. Nagao, K. Seno, T. Miyasaka, and E. Fujita, Chem. Lett., 1980, 159. C. Melchiorre, D. Giardina, and P. Angeli, J. Heferocycl. Chern., 1980,17, 1215. A. A. Volkova, K. A. V'yunov, A. I.Ginak, S. M. Ramsh, and E. G.Sochilin, Zh. Org. Xhim., 1980,16, ( a )p. 122 (Chem. Abstr., 1980,93,7463);( b ) p. 119 (Chem. Abstr., 1980,93,7186).

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

127

12 Selenazoles The reaction between aryl selenoamides and (ClCH,),CO gives (103; R = CH,Cl), which can be sequentially hydrolysed and oxidized to the aldehyde (103; R = CH0).12' Ring-contraction of selenodiazines gives N-amino-2 -imino-A4-selenazolines, isolated as the Schiff bases (104).122Condensation of arylallyl isothiocyanates and sodium hydroselenide gives the 5 -benzylselenazolidine-2-thiones(105),99 whose structures have been established by n.m.r., i.r., and Raman spectroscopy. A comparative i.r. study of selenazolidine-2-selones (106) and thiazolidine-2selones has been p~b1ished.l~~

13 Benzothiazoles Synthesis.-From ortho-Amino-benzenethiols (Type A ; s-c6H4-N + C).*The amidine (107) is obtained from the corresponding 11itri1e.l~~ The reaction between o-aminobenzenethiol and PhCH=CHCON=C(SMe), gives the benzothiazoles (108).12' 2-(2- or -3-Fury1)benzothiazoleshave been prepared by the oxidative cyclization of the corresponding thioanilides.126

Type B Syntheses of Benzothiazoles ( c6Hs-N-c-s). Cyclization of 1-arylthioureas with S02C12is a general method to obtain the 2-aminobenzothiazoles (109).12' The 5,6-diaminobenzothiazole(110) was prepared by the Pd/C-cataCyclization of lysed oxidative cyclization of 3,4-(H2N)2C6H3NHCSNHMe.'28 the pyrazolidines (111;R', R2,R3,R4, R5 = H, Me,or Ph) under mild conditions (at room temperature, in CF3C02H) yields the imino-derivatives (112) and (113).129Hugerschoff Bases (114) are formed by acid-catalysed rearrangement of thiadiazolidines such as (115).130

* For definitions of the types A, B, etc. for benzothiazoles, see p. 133 of Volume 1 of this series. 12'

lZ2 123

lZ4 lZ5 126

128

129

A. Shafiee, A. Mazloumi, and V. I. Cohen, J. Heterocycl. Chem., 1979, 16,1563. B. Marcewicz-Rojewska and S . Bilinski, Acra Pol. Pharm., 1980, 37, 169 (Chem. Abstr., 1981, 94, 192 229). F. A. Devillanova and G. Verani, Spectrochim. Acta, Part A, 1980,36, 371., G. Wagner and B. Eppner, Pharmarie, 1980,35,285. M. Richter, C. Herrmann, and M. Augustin, J. Prakt. Chem., 1980,322,434. L. Fiser-Jakic, B. Karaman, and K. Jakopcik, Croat. Chem. Acta, 1980, 53, 69. V. H. Patil and D. B. Ingle, Indian J. Chem., Sect B, 1979,17, 519. S.Rajappa and R. Sreenivasan, Tetrahedron, 1980,36, 3087. N. Y.Deeva and A. N. Kost, Khim. Geterotsikl. Soedin, 1980, 228. A. R. Butler and I. Hussain, J. Chem. Res. (S), 1980,407.

128

Heterocyclic Chemistry

Type C Syntheses of Benzothiazoles (N-C6H4-S-C). C-Substituted anilines react with potassium thiocyanate in the presence of an oxidant (e.g. bromine or cupric sulphate) to give 2-aminobenzothiazoles; the a-amino-(4-hydroxy-6benzothiazoly1)propionic acid which is related to the human pigment pheomelanin13* is obtained by nitrous deamination of the 2-amino-group. Type D Syntheses of Benzothiazoles (s-c6H4-N-c). A further example of ring-contraction of benzo-1,2,4-thiadiazine 1-oxides (116; R = H, Me, or Ph) into the benzothiazoles (117)'32 has been observed when (116) are treated with an excess of PBu3.

Type G Syntheses of Benzothiazoles (c6H5-S-c-N). The conversion of 2chloromethyl-5-methoxy-4H-pyran-4-one to 2-amino-5-hydroxy-6-methoxybenzothiazole takes place by treatment with t h i 0 ~ r e a . l ~ ~ Physical Properties of Benzothiazo1es.-Selenation has been used as a diagnostic aid to re-investigate the i.r. spectra of ben~othiazole-2-thiones.'~~ The integrated i.r. intensities of the v(C=N) band of some 2-substituted benzothiazoles are a function of &, the Taft resonance parameter.135The influence 13'

I. A. Ismail, D. E. Sharp, and M. R. Chedekel, J. Org. Chem., 1980,45, 2243. N. Finch, S. Ricca, L. H. Werner, and R. Rodebaugh, J. Org. Chem., 1980,453416.

133

R. L. White, T. J. Schwan, and R. J. Alaimo, J. Hererocycf. Chem., 1980, 17,817.

13'

J. M. Angelelli, J. Chouteau, M. Guiliano, and G. Mille, Spectrosc. Lett., 1980, 13, 741

13'

"'F. A. Devillanova and G. Verani, Aust. J. Chem., 1980, 33, 279.

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

129

of substituents on the basicity of the benzothiazole nucleus in a series of 2-(2or 3-fury1)benzothiazoles has been studied.126The oxime (118) $ nitroso (119) tautomerism has been studied by i.r. and n.m.r. spectroscopy; when X = S, the oxime tautomer predominates in solutions in CHC13 and in Me2S0.'36

(118)

(119)

Mass-spectral studies (positive- and negative-ion spectra) of 2-amino- and 2-acylamino-benzothiazoles have been r e p ~ r t e d ' ~(see ' also ref. 138). A study of electron-impact fragmentation of eighteen benzothiazole derivatives shows that the substituent is rarely lost in the initial fragmentations; instead, a pcleavage with respect to the heterocyclic double-bond is often 0 b ~ e r v e d . The l~~ fragmentation behaviour of some spirobenzothiazoles (120) under electron impact has been st~died.'~'The crystal structures of compounds (lZl),14' (122),'42 and (123)'43 have been described. Compound (122) is formed when 2-mercaptobenzothiazole is treated by SeOz in acetonitrile. Intramolecular proton transfer and excited-state relaxation in (124) have been studied by picosecond

(120) X

Y

=

CH2, S, SOz, or NMe

= CH2, 0,S, NMe, or NBz

Chemical Properties of Benzothiazo1es.-Substitution Reactions. The reaction between copper(1) acetylide and allylic ethers of benzothiazole has been used to prepare 1,4-enynes in a regio- and stereo-selective way.145Sodium benzothiazole-2-thiolate reacts with 2,3-dimethyl-1,4-naphthoquinoneto give the 136 137

13*

139

142 143

'41

L. I. Medvedeva, G. N. Lipunova, N. P. Bednyagina, I. I. Mudretsova, and E. 0. Sidorov, Khim. Geterotsikl. Soedin., 1980, 1101 (Chem. Abstr., 1981, 94, 29 656). S. Claude and R. Tabacchi, Adv. Mass Spectrom., Sect. A, 1980,8,610. Ya. V. Rashkes, R. F. Ambartsumova, V. A. Saprykina, and N. K. Rozhkova, Zh. Org. Khim., 1980, 16, 1744 (Chem. Abstr., 1981, 94, 29 663). S . Claude, R. Tabacchi, L. Duc, R. Fuchs, and K. J. Boosen, Hefu. Chim. Acta, 1980,63,682. U. Herzig, P. Krenmayr, and K. Varmuza, Org. Mass Spectrom., 1980,15, 423. J. Z. Gougoutas, Cryst. Struct. Commun., 1980,9, 529. R. A. Zingaro and E. A. Meyers, Cryst. Struct. Commun., 1980, 9, 1167. T. J. King, R. H. Thomson, and R. D. Worthington, J. Chem. SOC., Chem. Commun., 1980, 777. P. F. Barbara, L. E. Brus, and P. M. Rentzepis, J. A m . Chem. SOC.,1980,102, 5631. V. Calo, L. Lopez, G. Marchese, and G. Pesce, Tetrahedron Lett., 1979, 3873.

130

Heterocyclic Chemistry

expected disulphide, together with 8% of the naphthoquinone (123).'43Kinetic data for reactions of 2-halogeno-6-nitrobenzothiazoleswith aliphatic amines show the presence of a base-catalysed pathway which involves bifunctional c a t a l y s i ~ . ' Thiirans ~~ have been prepared from a-keto-sulphides of benzothia~ole-2-thioI.'~~ H-0

"

R'

2

U

?

j

j

0:' \

I

N-

-

\

(124)

(125) E

=

C02Me

Addition Reactions. Dimethyl acetylenedicarboxylate reacts with l-methyl-2(methy1thio)thiocarbonylimino-1,2-dihydrobenzothiazole to give the interesting spirobenzothiazole (125).'48Michael condensation products are formed by addition of 2-benzylbenzothiazole to a variety of activated double-bonds. 149 Alkylation. N-Methylbenzothiazolines, methylated by Meerwein reagents, give NN-dimethylbenzothiazoliniurn~ a l t s . " ~ Ring-Cleavage Reactions. The reductive ring-cleavage of 4,6-disubstituted benzothiazoles has been proposed as a general synthesis of ortho -amino-thiophenols.'51 The full paper of De Simone et al. concerning the formation of 1,4-benzothiazines from 2,2-disubstituted benzothiazolines and sulphuryl chloride has appeared15* (see Vol. 1 of these Reports, p. 139). The treatment of (125) with butyl-lithium causes a Stevens rearrangement to occur.15o Rearrangements. The preparation of six-, seven-, and eight-membered heterocycles by the base-induced ring-expansion of quaternized benzothiazolium salts has been described.153 Scheme 9 shows the proposed mechanism for the formation of the tetrahydro-1,5-benzothiazepine. CH ,CH ,CH ,C1

yH,CH,CH,CI

CHO

Scheme 9 146

'41 ' 4 1 149

I5O 151

Is*

C1

L. Forlani and P. E. Todesco, Gazz. Chim. Iral., 1980, 110, 561. V. Calo, L. Lopez, and G . Pesce, Gazz. Chim. Ital., 1979, 109, 703. K. Mizuyama, Y. Tomonaga, Y. Matsuda, and G . Kobayashi, Chem. Pharm. Bull., 1979,27,2879. V. Dryanska and C. Ivanov, Synthesis, 1980, 317. Y. Ohara, K. Akiba, and N. Inamoto, Heterocycles, 1979,13,289. M. R. Chedekel, D. E. Sharp, and G. A . Jeffery, Synth. Commun., 1980, 10, 167. F. De Simone, A. Dini, R. A. Nicolaus, E. Ramundo, M. DiRosa, and P. Persico, Farmaco, Ed. Sci., 1980, 35, 333. H. J. Federsel and J. Bergman, Tetrahedron Lett., 1980, 21, 2429.

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

131

The photolysis of 6-azidobenzothiazolesin the presence of secondary amines or of methoxide-methanol mixtures gives thiazol0[5,4-c]azepines.'~~

14 Condensed Ring Systems incorporating Thiazole or Selenazole StructurescomprisingTwo Five-Membered Rings (5,5).-Thiazolo-[2,3-c]- and -[3,2-b]-[ 1,2,4]triazoles [C2N3-C3NS].The cyclization of 2-(rn-nitrobenzoylhydrazino)-4-(p-nitrophenyl)thiazole with POC13 gives the thiazolo[2,3-c][1,2,4]triazole (126).lS5Thiazolo[3,2-b][1,2,4]triazoles (127) have also been prepared,'56 and their mass-spectrometric fragmentation has been studied.'"

Imidazo-[2,1 -b]-, -[3,2-c]-, and -[5,I -b]-thiazoles [C3NS-C3N2].The biological significanceof tetramisole is further demonstrated by the large number of papers published on 2,3,5,6-tetrahydroimidazo[2,1-b]thiazole derivatives (1219, mainly as patents. The unsubstituted derivative has been prepared from imidazoline-2thione and 1,2-dibromoethane, using phase-transfer cataly~is.'~~ On the other hand, the formylation of 6-substituted derivatives of the 5,6-dihydro-structure (129) takes place in the 5-positi0n'~~ whereas methylation takes place in position 7.l6' The 3-acetic acid derivative (129; R = CH2C02H)has been prepared from 4-chloroacetoacetate and imidazolidine-2-thione,followed by hydrolysis in concentrated hydrochloric acid.40 Cycloaddition of imidazo[2,1-b]thiazoles (130) with dialkyl acetylenedicarboxylate affords, depending on the polarity of the solvent, pyrrolo[2,1-b]thiazoles (131)in an aprotic non-polar solvent, or imidazopyridines in an aprotic polar solvent.'61 Meso-ionic derivatives (132) are

IS4 Is'

'sI

Is*

P. T. Gallagher, B. Iddon, and H. Suschitzky, J. Chem. SOC.,Perkin Trans. 1, 1980,2362. R. P. Gupta, M. L. Sachdeva, and H. K. Pujari, Ann. SOC.Sci. Bruxelles, Ser. 1, 1979, 93. 129 (Chem. Abstr., 1980,93,150 206). H. Moskowitz, A. Mignot, and M. Miocque, J. Heterocycl. Chem., 1980,17, 1321. I. Simiti, H. Demian, A. M. N. Palibroda, and N. Palibroda, Org. Mass Spectrom., 1980,15,172. H. J. M. Dou, M. Ludwikow, P. Hassanaly, J. Kister, and J. Metzger, J. Heterocycl. Chem., 1980,

17,393. lS9 160

A.Andreani, D. Bonazzi, M.Rambaldi, and L. Greci, Boll. Chim. Farm, 1979,118,694. R.M. Acheson, M. W. Cooper, and I. R. Cox, J. Chem. SOC.,Perkin Trans. 1, 1980,1773. N. Abe, T. Nishiwaki, and N. Komoto, Bull. Chem. SOC.Jpn., 1980,53,3308.

132

Heterocyclic Chemistry

obtained by the reaction of dicyano-epoxides with l-methylimidazoline-2thione.16’ The meso-ionic imidazo[3,2-c]thiazole (133) has been prepared from 4-amino-2,5-diphenylthiazoleand phenacyl bromide.163 Pyrrolu- [1,2-c]-, -[2,1-b]-, and -[3,2-c]-thiazoles [C3NS-C4N].Pyrrolo[ 1,2-c]thiazole (134),a new non-classical thiazole system, cannot be isolated, but can be trapped with N-phenylmaleimide or dimethyl acetylenedi~arboxylate.~~~ In the latter case, the reaction occurs through the azomethine ylide, affording the new cyclazine system (135). Pyrrolo[2,1-b]thiazolium perchlorates have been prepared from 5-alkylthiopyrrolidinones and a-hal~geno-ketones.~~~ The treatment of (103; R = CHO) with N,CH,CO,Et, affords compound (136),which can by cyclized to the selenazole (137; X = Se). Pyrrolo[3,2-d]thiazoles can be prepared similarly.’21

RHN

NC-X

Q

Thieno[3,2-d]-thiazoles and -selenazoles and Selenopheno[3,2-d]thiazoles [C,NS-C,S]. A general synthesis of this class of compounds (138;X = S, Y = S), (138;X = Se, Y = S), and (138; X = S, Y = Se) with different substituents (H, Me, NHR, or SH) in position 2 has been described, using compound (139) as the starting Structures comprising One Five-Membered and One Six-Membered Ring (5,6).-Thiuzolo[3,2-a]pyrirnidines [C3NS-C4N2].Thiazolopyrimidones (140) can be prepared by the known reaction between 2-aminothiazoles and ethyl acetoacetate; some derivatives show anti-tumour activity in mice.16’ Potts et al.f68have studied the reaction between 2-(methylamino)thiazoleand (chlorocarbony1)phenylketen: the product (80% yield) is the anhydro-7hydroxy-thiazolo[3,2-a]pyrimidinium compound (141),which is a thermally stable betaine. 16’

M. Baudy and A. Robert, Tetrahedron Lett., 1980,21,2517. A. Chuiguk and A. G. Maidannik, Khim. Geterotsikl. Soedin., 1980,1695 (Chem. Abstr., 1981, 94,175 032). J . M.Kane, J. Org. Chem., 1980,45,5396. G.V.Bespalova, V. A. Sedavkina, and V. G. Kharchenko, Khim. Geterotsikl. Soedin., 1979,1648 (Chem. Abstr., 1980,93,168 047). C.Paulmier, Bull. SOC.Chim. Fr., Part. 2, 1980,151. B. Dash, M. Patra, and P. K. Mohapatra, J, Ins$, Chern. (India), 1980, 52, 92 (Chem. Absrp.,

lb3 V. ld4 16’

ld6

16’

1980,93,239353). K.T.Potts, R. Ehlinger, and S . Kanemasa, J. Org. Chem., 1980,45,2474.

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

133

ThiuzoZo-[3,Z-a]- and - [3,4-a]-pyrazines [C3NS-C4N2].A new general synthesis of a 2,5-diketopiperazine that is condensed with a thiazolidine ring involves the use of N-ethoxycarbonyl-2-ethoxy-l,2-dihydroquinoline to form the 2,sdiketopiperazine ring. Compounds (142) and (143) have been prepared by this method. 16’ 0

0

ThiazoZo[3,2-a]pyridines[C3NS-C5N].A new synthesis of perhydro-derivatives by intramolecular cyclization of 2-thiazolidinebutanols has been described, the best yields being obtained when using PPh3 and CCl4.l7’ The crystal structure of the pyridinium tetrafluoroborate (144) has been determined at 123 K.17’ The reactivity and electronic structure of meso-ionic thiazolo[3,2-a]pyridinium 3oxides (145) have been A new synthesis of thiazolo[3,2-a]pyridinium salts has been described.173

Thiazolo[3,4-a]pyridines[C,NS-C,N]. Condensation of tetramethylthiourea with ethyl bromo-2-pyridylacetate gives the pyridinium bromide (146); on acid hydrolysis, this yields 1-ethoxycarbonylthiaz010[3,4-a]pyridin-3-one.”~ Thiazolo[4,5-b]thiopyrun[C3NS-C5S].The compound (147) has been prepared from rhodanines (X = 0)and thiorhodanines (X = S).175

lL9 170

17’ 17*

’” 174

’”

S. Jerumanis and A. Lemieux, J. Heterocycl. Chem., 1980,17,39. D . Barbry, D. Couturier, and G. Ricart, Synthesis, 1980,387. K. Sasvari, L. Parkanyi, G. Hajos, H. Hess, and W. Schwarz, Actu Crystullogr., Sect. B, 1980,36,

1229. G . G . Dyadyusha, N. N. Romanov, A. D . Kachkovskii, and A. I. Tolmachev, Khim. Geterotsikl. Soedin., 1980,1618 (Chem. Abstr., 1981,94,120 683). V. A. Chuiguk and K. V. Fedotov, Ukr. Khim. Zh., 1980, 46, 1306 (Chem. Abstr., 1981, 94, 208 680). J. N.Shah and B. D . Tilak, Indian J. Chem., Sect. B, 1979,18,486 H. A. R, Ead, N. A. L. Kassab, H. Koeppel, W. D. Bloedorn and K. D . Schleinitz, J. Prukt. Chem., 1980,322,155.

Heterocyclic Chemistry

134

Structures comprising One Five-Membered and One Seven-Membered Ring (5,7).-Thiazolo [4,3-clthiazepine [C3NS-CsNS]. A Japanese patent 176 describes the hypotensive activity of lO-aryl-3-methyl-5,8-dithia-l-azabicycle[ 5.3.O]decane-2,6-dione (148). Thiazolo [5,4-c]azepines [C3NS-C6N].Derivatives (149)and (150)have been obtained by photolysis of 6-azidobenzothiazoles.’54

My:
/ s

Meo(-==JN>R N

R 2 N a N > 3

H (149)

S (148) d0 S

5

(150)

Structures comprising Two Five-Membered Rings and One Six-Membered Ring (5,5,6).-1,2,4-Triazolo[3,4-b]benzothiazoles [c2N3-c3Ns-c6].A series of derivatives (15 1) have been prepared from 2-hydrazinoben~othiazole.~~~ When R is CI or SH they inhibit the growth of Xanthomonas maluacearum.

(152)

(151)

Thiazolo[4;5-g]benzoxazoles[C3NS-C3NO-C6]. Thermolysis of 6-azidobenzothiazoles in a polyphosphoric acid-acetic acid mixture yields the title compounds (152; R = H, Me, or SH).17* Thiazolo[Z,3- b]benzothiazoles [c3Ns-c3Ns-c6]. The 1,3-dihydrothiazo10[2,3b]benzothiazolium chloride (153)has been prepared by cyclization of 2-(2hydroxyethy1thio)benzothiazole. Compound (153) reacts with N- and Cnucleophiles, giving the derivatives (154; X = NOH, NNHCONH2, NNHCSNH2, NCH2CH20H,CHN02, or CHC0,Et) of 3-(2-mercaptoethyl)-2benzothiazolinone (Scheme o s > S C H \ N

N I CH ,CH SH

,

,CH ,C1

c1(153)

(154)

Scheme 10

’”

Yoshitomi Pharm. Ind. Ltd., Jpn. Kokai Tokkyo Koho 80 100 393 (Chem.Absrr., 1981,94,103445). 177 D . S. Deshpande, Acta Cienc. Indica, Ser. Chem.. 1980,6, 80 (Chem. Abstr., 1981, 94, 65 568). 17’ P. T. Gallagher, B. Iddon, and H. Suschitzky, J. Chem. SOC.,Perkin Trans. 1, 1980, 2358. 179 V. Sutoris, A. Malivikova, J. Jakubcova, P. Foltinova, and G. Blockinger, Chern. Zuesti, 1979, 33, 558 (Chem. Absrr., 1980, 93, 8072).

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

135

Imidazo [2,3- dlthiazolo-[2,3- b]- and - [3,2-a]-pyrimidines [C3NS-C3Nz-C4N2]. The reaction of 1,2-dibromoethane with 2-mercaptoadenine gives the thiazolopurines (155) and (156).I8OThese bicyclic structures have been identified by their reduction to the corresponding 3- and 1-ethyladeninesby Raney nickel.

ThiazoZo[3,2-a]benzimidazoles [C3NS-C3N2-C6], Benzimidazoline-2-thiones react with a variety of compounds, giving thiazolo[3,2-~]benzimidazoles.For example, the reaction with dimethyl acetylenedicarboxylate affords the thiazolidinone (157),181whereas chloroacetic acid followed by cyclization (using acetic anhydride) gives the 3-methyl derivative ( 158).lg2The 8-aza-derivatives (159) can be prepared from pyrido[2,3-d]imidazoline-2-thioneand phenacyl bromides.

The reactivity of 3-methylthiazolo[3,2-a]benzimidazoletowards dimethyl acetylenedicarboxylate has been studied:16' tetramethyl pyrido[ 1,2-a]benzimidazole-1,2,3,4-tetracarboxylateis formed.

Thiatolo[3,4-a]benzimidazoles[c 3 N s - c 3 N 2 - c 6 ] .This new lo--electron heterocycle (160), containing quadrivalent sulphur, has been prepared by cyclization of 1,2-dibenzoylbenzimidazolewith P2S5in refluxing t01uene.l~~

Imidaz0[2,1- b]benzothiazoles [C3NS-C3N,-c6]. 5,6,7,8-Tetrahydro-derivatives (161) can be classically prepared by condensation of 2-amino-4,5,6,7tetrahydrobenzothiazoles with phenacyl b ~ 0 m i d e s . l ~The ~ reaction of I''

lE4

J. A. Montgomery and H. J. Thomas, J. Heterocycl. Chem., 1980, 17, 583. R. M. Acheson and J. D. Wallis, J. Chem. SOC.,Perkin Trans. 1, 1981,415. R. P. Gupta, R. N. Handa, and H. K. Pujari, Indian J. Chem., Sect. B, 1979,17, 572. M. A. Abdel-Kader, A. M. Abdel-Aleem, and G. S. Al-Karamany, Arch. Pharm. Chemi, Sci. Ed., 1980,8, 153 (Chem. Abstr., 1981,94, 121403). 0. Tsuge, H. Shiraishi, and T. Takata, Chem. Lett., 1980, 1369. M. N. Bake and C. S. Mahajanshetti, Indian J. Chem., Sect. B, 1980,19,263.

136

Heterocyclic Chemistry

2-methylimidazo[2,1 -b]benzothiazole and dimethyl acetylenedicarboxylate in xylene gives dimethyl pyrrolo[2,1 -b]benzothiazole-2,3-dicarboxylate.'61 Th iazolo [3,2- a] thieno [2,3- dlpyrimidines [C3NS-C4S-C4N2]. Derivatives (16 2) of this ring can be prepared by brominating (163) in glacial acetic acid.186 Et0,C H,C=CHCH,N-C-N H II €4

L R 2

-i(s)R1

Structures comprising One Five-Membered Ring and Two Six-Membered Rings (5,6,6).-Pyrimido[2, I - blbenzothiazoles [C3NS-C4N2-C6]. The reaction between 2-aminobenzothiazole and ethyl acetoacetate, followed by aminomethylation, gives the 4-0xopyrimido[2,1 -b]benzothiazole derivatives (164).167 The betaine (165) is readily obtained from 2-(methylamino)benzothiazole and (chlorocarbony1)phenylketen.16' This betaine proved to be stable to aqueous MezSO and does not undergo cycloaddition with a variety of dipolarophiles in boiling toluene.

R 2Q\+JHZNRl2

A

a:-?:-

'Me

Me

(164)

(165)

*

Thiazolo-[2,3- b]-, -[3,2-a]-, and -[3,2-c]-quinazolines [c3Ns-c4N2-c6]. Thiazolo[2,3-b]quinazolinethione (166) has been obtained by the sequence of reactions shown in Scheme 11 S

A

&Ls

K L - ( o M e ) 2 +

H

H

'

S

A?

(166)

Reagents: i, H,NCH,CH(OMe),

Scheme 11

9H-Thiazolo[3,2-a]quinazolines (167) have been obtained in a single step from 2-imino-3,4-diphenyl-A4-thiazolines and paraformaldehyde. A few more well-defined meso-ionic thiazolo[3,2-a]quinazolones, (168) have been prepared 189*190 (see, Vol. 2 of this series, p. 132). Thiazolo[3,2-c]quinazolinium I. V. Smolanka. S. M. Khripak, K. M. Dobosh, A. D. Omel'yanyuk, L. 1. Doinikov, A. A. Dobosh and V. G. Shul'ga, USSR P.767 109, 1980 (Chem. Absrr., 1981, 94, 103418). S. Leistner and G. Wagner, Pharmazie, 1980, 35, 124. S. M. Sondhi, M. P. Mahajan, and N. K. Ralhan, Indian J. Chem., Sect. B, 1979, 17,632. P. B.Talukdar, S. K. Sengupta, and A. K. Datta, Indian J. Chem. Sect. B, 1980,19, 638. V. K. Srivastava, B. R. Pandey, R. C. Gupta, J. P. Barthwal, and K. Kishor, Indian J. Pharrn. Sci., 1980,42,29.

137

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

salts (169) have been prepared from quinazoline-4(3H)-thione and a -bromoketones.lgl

(167)

(169)

(168)

Thiazolo[4,5-b]quinoxalines[c3Ns-c4N2-c6]. The derivatives (170; X = S or NR) and (171) have been obtained by condensing 2,3-dichloroquinoxalinewith RNHCS2- NH4+, thiobarbituric acid, 4-methyl-2-mercapto-A*-imidazoline, or thioamide~.”~

(170)

(171)

Thiazino [2,3 - b]benzothiazole [C3NS-C4NS-C6]. 2(3H)- Benzothiazolethione and (chlorocarbony1)phenylketen react in warm anhydrous benzene to give compound (172)? Dimethyl acetylenedicarboxylatereacts with (172) in boiling toluene. The intermediate cyclo-adduct cannot be isolated, carbonyl sulphide being eliminated, and the tricyclic pyridone (173) is obtained (Scheme 12). Other dipolarophiles, both acetylenic and olefinic, have also been studied. 0

0 (-COS) ___+

(172) Reagents: i, RCGCR

Scheme 12

Pyrido-[2,3- d]- and - [3,2- d]- thiazolo [3 2‘- a] p y ridines [C3NS-CsN- CsN 1. Fusion of P4S10 with 3-hydroxy-2-pyridone gives 50% of 3-hydroxypyridine-2thione and smaller amounts of the unknown betaines (174) and (175), which were identified by ‘H and 13Cn.m.r. ~ p e ~ t r ~ ~ ~ ~ p y . ‘ ~ ~ Pyridoc2, I - bJbentothiazoles [c3Ns-c&c6].The preparation of the 4-0x0derivative (173) has already been described in Scheme 12.’68

19’ 193

H. Singh, C. S. Gandhi, and M. S. Bal, Indian J. Chem., Sect. B, 1981,20,17. V. K. Chadha and V. K. Saxena, J. Indian Chem. SOC.,1980,57,946. J. S.Davies, K. Smith, and J. Turner, Tetrahedron Lett., 1980,21,2191.

138

Heterocyclic Chemistry

Thiazolo [3,2-a]quinolines [c&s-c&-c6]. The meso-ionic compounds (176) have been obtained from 4-substituted quinoline-2-mercaptoacetic acids.194 Thiazolo [2,3-a]isoquinolines [c&!&c&-c6].3-Aryl thiazolo[2,3 -a]isoquinolinium-2-thiolates (177) and the corresponding 5,6-dihydro-derivatives have been prepared and the mechanisms of their formation from 2-benzylisoquinolinium (or 3,4-dihydro) salts elucidated. 195 SS . 4

6

(177)

Naphtho[2,3-d]thiazoles [c&%C6-c,]. The heterocyclic hydrazine (178) has been prepared from 2-arnin0-3-bromonaphthalene.'~~

Structurescomprising Two Five-MemberedRings and Two Six-Membered Rings (5,5,6,6).-A variety of tetracyclic structures, related to those described above, have been studied. Generally they contain an additional benzene ring. Several derivatives of imidazo[2,1-b]thiazoles (179),185(180),19' and (181)15' have been prepared by classical methods. The steroidal analogues (180) have been evaluated for immunological activity. 2-(2-Nitrenophenyl)benzothiazoles, produced by deoxygenation of the corresponding nitro-compounds or by thermolysis or photolysis of the related azides, give indazolo[3,2-b]benzothiazoles (182) by intramolecular attack on the nitrogen in b e n z ~ t h i a z o l e . ' ~ ~

(179)

(180)

L. T. Gorb, A. D. Kachkovskii, N. N. Romanov, I. S. Shpileva, and A. I. Tolrnachev, Khim. Geterotsikl. Soedin., 1980, 621 (Chem. Abstr., 1980, 93, 132 416). 1 9 5 J. A. Duncan, M. L. Bosse, and J. M. Masnovi, J. Org. Chem., 1980, 45, 3176. 196 M. Leymarie-Baljean, M. Pays, and J. C. Richer, J, Heterocycl. Chem., 1980, 17,1175. 19' M. Saito, Y. Kayama, T. Watanabe, H. Fukushirna, T. Hara, K. Koyano, A. Takenaka, and Y. Sasada, J. Med. Chem., 1980,23, 1364. 19* D. Hawkins, J. M. Lindley, I. M. McRobbie, and 0. Meth-Cohn, J. Chem. SOC.,Perkin Trans. 1 , 1980,2387.

194

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

139

Other Condensed Systems incorporating Thiazo1e.-A mass-spectral study of thiazolobenzotriazepines (183; Z = S or H2) has been carried The steroidal molecule (184), i.e. a (5,5,5,6)system, can be prepared from pyrrolo[ 1,2-a Jbenzothiazolinedione and R1NHNH2.200O n the other hand, the pair of isomers (185a) and (185b) is obtained by heating 2-amino-thiazoles with chloranil in ethanol.201

(183)

15 Thiadiazoles and Selenadiazoles

1,2,3=Thiadiazoles.-Synthesis. The reaction of phenyl isothiocyanate and (CH,COCHN,), is a convenient method to obtain 5-anilino-1,2,3-thiadiazoles (186; R2 '-= PhNH).36 In an analogous way, diazoalkanes react with 2-,3-, and 4-pyridyl isothiocyanates to give the corresponding 5-pyridylamino-1,2,3thiadiazoles (186; R2 = NHpyridyl).202Thieno[3,2-d][1,2,3]thiadiazole (187), a new azapentalene, can be conveniently obtained by diazotization of 3-amino-2mercaptothiophen.'66 Electrophilic substitution takes place in the p-position of the thiophen ring. The new meso-ionic system (188; R = Me) has been prepared by the alkylation of 5-methoxycarbonylamino-1,2,3-thiadiazole(189; R =

201 '02

203

S. M. Sondhi, M. P. Mahajan, and N. K. Ralhan, J. Indian Chem. SOC.,1978,55, 1269. T. Kurihara, T. Tani, S.Maeyama, and Y. Sakamoto, J. Heterocycl. Chem., 1980, 17, 945. R. P. Soni and J. P. Saxena, Indian J. Chem., Sect. B, 1979,17, 523. M. Marchalin and A. Martvon, Collect. Czech. Chem. Commun., 1980, 45, 2329. S. Brueckner, G. Fronza, G. L. Malpezzi, V. A. Kozinski, and 0. V. Zelenskaja, Tetrahedron Lett., 1980, 21, 2101.

140

Heterocyclic Chemistry

Physical Properties of 1,2,3 -Thiadiazoles. Proton and 13Cn.m.r. spectra and the X-ray diffraction analysis of compound (188; R = Me) have been used to establish its The same authors have determined the X-ray structure of the related meso-ionic compound 3-methyl-4-phenyl-l,2,3-thiadiazolium-5t h i ~ l a t e . An ~ " ~interesting paper on the mass spectrometry of 1,2,3-thiadiazoles has been Chemical Properties of 1,2,3 -Thiadiazoles. The alkylation of (189) gives different isomers, depending on the experimental conditions (Scheme 13). Compound (190) is obtained with trimethyloxonium tetrafluoroborate, whereas (188) is obtained with dimethyl sulphate, and a mixture of (188) and (191) with diazomethane. L)Me R0,CN

R0,CN

R0,CN Me

H

(189) R = M e o r P h

+ (188)

+

t 190)

(191)

Scheme 13

Two important papers on thiiren have appeared. Thermolysis and photolysis of 13C-labelled 1,2,3-thiadiazoles conclusively proves the formation of an intermediate phenylthiiren from 5-phenyl- but not from 4-phenyl-1,2,3-thiadiazole (186; R' = Ph, R2 = H).'06 A similar approach for thiiren itself is consistent with these Aldothioketens, generated by pyrolysis of 4-alkyl-1,2,3thiadiazoles in the presence of Schiff bases, can be trapped to give p-thiolactams.208Methylation of (186; R' = Ph, R2 = H) gives a 1:2 mixture of (192) and (193). Compound (193) reacts with morpholine to give (194) in high yield, whereas (192) does not react. The crystal structure of (194) has been determined.20g Alkyl-substituted thiadiazoles can be brominated at the a -position of the side-chains at C-4 or at C-5 .'lo

1,2,3-Benzothiadiazoles.-Thermolysis of phenyl azide in the presence of (195) affords phenothiazine, thianthrene, and dibenzo[c,e][ 1,2]dithiin.21' Evidence 204

205 206

'07 *08 209

210 211

S. Auricchio, S. Brueckner, L. M. Giunchi, and V. A . Kozinskii, Heterocycles, 1980, 14, 1757. G . Bouchoux, Y. Hoppilliard, M. Golfier, and D. Rainteau, Org. Mass Spectrom., 1980, 15, 483. U. Timrn, U. Merkle, and H. Meier, Chem. Ber., 1980, 113, 2519. A. Krantz and J. Laureni, J. Am. Chem. Soc., 1981,103, 486. E. Schaumann, J. Ehlers, and F. F. Grabley, Chem. Ber., 1980, 113, 3010. S. Auricchio, S. Brueckner, L. M. Giunchi, V. A. Kozinsky, and 0. V. Zelenskaja, J. Heterocycl. Chem.,1980,17,1217. H. Meier and 0. Zimmer, J. Heterocycl. Chem., 1980, 17, 1639. L. Benati, P. C. Montevecchi, and P. Spagnolo, J. Chem. SOC.,Chem. Commun., 1980,715.

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

141

in favour of an inital attack on the sulphur of (195) by triplet arylnitrenes has been presented. The synthesis and reactivity of 6- and 7-mono- and 6,7-di-substituted derivatives of 1,2,3-benzothiadiazole have been investigated in order to establish their possible behaviour as masked diazo-compounds.212

1,2,3-Selenadiazoles.-Two papers have described a parallel synthesis of 1,2,3thiadiazoles (using SOCl,) and 1,2,3-~elenadiazoles(using Se02)from semicarbazones.213*214 Decomposition of 4-vinyl-l,2,3-selenadiazoleswith base and subsequent addition of CS, affords 5-vinyl-2-thioxo-1,3-thiaselenoles.215 1,2,4-Thiadiazoles.-Synthesis. 1,3-Dipolar cycloaddition of aromatic nitrile sulphides to methyl o-cyanobenzoate gives (196; X = C0,Me). The corresponding nitriles (196; X = CN) are obtained similarly.216The iminothiadiazolines (197) have been obtained by treating (198) with ArC(Cl)=NR.217 The thiadiazoles (199),,18 (200), 219*220 (201),221and (202)222have been prepared from thiourea or its derivatives. Other derivatives, e.g. the 1,l-dioxide (203),

arise from the interaction of R3CONC0 and azomethines in the presence of 3-Hydroxy-5-aryl-l,2,4-thiadiazoleshave been conveniently prepared from trimethylsilyl azide and thiobenzoyl i s ~ c y a n a t e s A .~~ new ~ synthesis of a -amino-sulphonamides (205), based on the Curtius rearrangement, has been described (Scheme 14).’” The same authors have reported the direct cyclization

’”M. Lenic, M. Merslavic,S. Polanc, B. Stanovnik, H. Stavber, D. Struna, and M. Tisler, J. Heterocycl. ’13

’“ *15 ’16 217

*’* ‘19

”*

Chem., 1980,17,1441. A. J. Eid, S. S. Youssef, and A. A . Salama, Egypt J. Pharm. Sci., 1977, 18,339 (Chem. Abstr., 1981,94,121423). R. N. Hanson and M. A . Davis, J. Heterocycl. Chem., 1980,17,1245. A. Shafiee, M. Vosooghi, and I. Lalezari, J. Heterocycl. Chem., 1980,17,545. R. K. Howe and B. R. Shelton, J. Urg. Chem., 1981,46,771. Y.Yamamoto and K. Akiba, Heterocycles, 1979,13,297. M. N. Basyouni and A. M. El-Khamry, Bull. Chem. SOC.Jpn., 1979,52,3728. P. V. Indukumari and C. P. Joshua, Indian J. Chem., Sect. B, 1980,19,667. P.V. Indukumari and C. P. Joshua, Indian J. Chem., Sect. B, 1980,19,672. V. Shankar and S. N. Pandeya, Indian J. Pharm. Sci., 1979,41,218. N.M. Nimdeokar and M. G. Paranjpe, J. Indian Chem. SOC.,1980,57,1123. B. A. Arbuzov, N. N. Zobova, and N. R. Rubinova, Izv. Akad. Nauk SSSR,Ser. Khim., 1980, 1164 (Chem. Abstr., 1980,93,95250). 0. Tsuge, S. Urano, andK. Oe, J. Org. Chem., 1980,45,5130. W.F.Gilmore and H. J. Lin, J. Org. Chem., 1978,43,4535.

’” ’” 222

224

’’’

142

Heterocyclic Chemistry 0

of the intermediates (204) to the 1,2,4-thiadiazolin-3-one 1,l-dioxides (206).226 Condensed 1,2,4-thiadiazoles (207) are formed from o -phenylene diisothiocyanate and sodium azide (R = H) or N-aryl-SS-dimethyl~ulphimide.~~~ 1,2,4-Thiadiazolo[4,5-a]benzimidazole-3-thione(207; R = H) gives SR' derivatives with alkylating agents ('R' = Me, CH2C02Et,etc.). Physical Properties of 1,2,4-Thiadiazoles. The molecular structures of some 1,2,4-thiadiazole derivatives have been determined by X-ray crystallograPhY.228-230 Dendrodoine (208), the first natural compound to be isolated that contains a thiadiazole ring, has been isolated from Dendrodoa grossularia, and ~ ' structure of dendrodoine has been it possesses cytotoxic activity in ~ i t r o . ~The established by X-ray analysis of its N-acetyl derivative. 0

(208)

The geometry and electronic structure of the thiadiazole (209) and the cation Two important (210) have been calculated by ab initio SCF MO papers on the influence of hydrogen bonds (self- and hetero-association) on the structure of thiadiazoles have The most stable tautomer is (21l), since it could be engaged in self-association. Butler's definitive work on Hector's (212), Dost's (213), and Hugerschoff's (114)Bases has been p ~ b l i s h e d . ' ~ ~ * ~ ~ ~

226 227

228 229

230

231 232

233 234

235

W. F. Gilmore, Y. M. Yeh, and R. B. Smith, J. Org. Chem., 1980,45,47g4. D. Griffiths, R. Hull, and T. P. Seden, J. Chem. Soc., Perkin Trans. 1, 1980, 2608. C. Glidewell, H. D. Holden, and D. C. Liles, Acta Crystallogr., Sect. B, 1980,36, 1244. S. Sato, T. Kinoshita, T. Hata, and C. Tamura, Acta Crystallogr., Sect. B, 1980, 36, 2703. F. Iwasaki and K. Y. Akiba, Acta Crystallogr., Sect. B, 1981, 37, 180. S. Heitz, M. Durgeat, M. Guyot, C. Brassy, and B. Bachet, Tetrahedron Lett., 1980, 21, 1457. K. Morokuma and M. Hanamura, Koen Yoshishu-HibenzenkeiHokozoku Kagaku Toronkai, 1979, 197 (Chem. Abstr., 1980,93,45 682). E. Gentric, J. Lauransan, C. Roussel, and J. Metzger, J. Chem. Res. (S), 1980,48. E. Gentric, J. Lauransan, C. Roussel, and J. Metzger, Nouu. J. Chim., 1980,4, 527. A. R. Butler, C. Glidewell, I. Hussain, and P. R. Maw, J. Chem. Res. (S), 1980, 114.

143

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

NHPh HN

NHPh N 9 N PhNHkS/

Chemical Properties of 1,2,4 -Thiadiazoles. The reaction between Hector's Base (212) and X=Y=Z reagents (RNCO, RNCS, and CS,) has been Depending on the nature of X, Y, and Z, two types of isomeric structures are formed, i.e. (214; Y = C, Z = 0 or S, X = NR) and (215; Y = C, Z = S, X = S). However, the product that is formed in the reaction between (216) and Pr'NCS has the structure (217) (X-ray analysis).236Structure (217) differs from (215; Y = C, Z = S, X = NMe) not only in its bicyclic isomerism but in an inverse sense of reaction with the alkyl thiocyanate [(217) corresponds to (215) with Y = C, X = S, Z = NR]. Another compound (218) with a n-hypervalent sulphur atom has been obtained from (197) and ArC(C1)=NR.217 Isocyanates react with N-2 of 1,2,4-thiadiazol-5-ones,giving 1,3,5-triazine-lH,3H-2,4diones with concomitant extrusion of the sulphur atom.27 Ph

2-S

NH,

1,3,4-Thiadiazoles.-Synthesis. A very simple and general synthesis of these compounds has been On the other hand, 2,5-disubstituted thiadiazoles are prepared in one step from aliphatic aldehydes, hydrazine hydrate, and elemental sulphur in methylglycol and ethanol. However, the most widely used method to obtain 1,3,4-thiadiazoles uses thiosemicarbazides or their derivatives (acyl thiosemicarbazides, thiosemicarbazones) as starting materials. In this way, a wide variety of 2-amino-1,2,4-thiadiazoleshave been preThiadiazolines (219) have been obtained in high yields by the

237 238

239

240 241

242

L. Born, Z. Kristallogr., 1980,153,265. H. Hagen, R. D. Kohler, and H. Fleig, Liebigs Ann. Chem., 1980,1216. T. J. Kress and S. M. Costantino, J. Heterocycl. Chem., 1980,17,607. A.Martvon, S. Stankovsky, and M. Uher, Chem. Zvesti, 1980, 34, 118 (Chem. Abstr., 1980,93, 186 246). C. Budeanu, T. Iorga, C. Ciugureanu, and I. Iorga, Rev. Chim. (Bucharest),1979,30,1189. R.Evers, E. Fischer, and M. Pulkenat, 2.Chem., 1980,20,413. W.T. Flowers, J. F. Robinson, D. R. Taylor, and A. E. Tipping, J. Chem. Soc., Perkin Trans. 1, 1981,349.

Heterocyclic Chemistry

144

reaction of methyl alkyl ketones and b e n z ~ t h i o h y d r a z i d ePhenylhydrazones .~~~ react with phenyl thiocyanate or carbon disulphide to give the derivatives (220; X = NPh or S).244

prNxR2 x

S

R’

R ~ N \ ,NHR’

\C

Ar

R

”1 NXCo2Me

A r C ~ CH2C02Me

The reactions of a -nitro- and a -chloro-hydrazones with potassium thiocyanate give iminothiazolines (221).245*246 Thiohydrazides react with dimethyl acetylenedicarboxylate, yielding the thiazolines (222).247The reaction of thiourea and ethylenethiourea (imidazolidine-2-thione)with chlorinated azabutadienes gives the arnidino-1,3,4-thiadiazolines(223; R’ = H) or (223; RIR1= CH2).248

Physical Properties of 1,3,4 -Thiadiazoles. The equilibrium constants of hetero-association of the thiadiazolinethiones (224) have been The electronic spectra and acidity constants of the Schiff bases (225) have been ” amino $ imino determined249and the kinetics of their formation s t ~ d i e d . ~The tautomerism of the sulphanilamides (226) has been studied by mass spectrometry, using fixed derivatives as models.z51The amino-tautomer predominates, but some of the imino-form was also present. The amino-tautomer also predominates in the case of the acylamino-derivative (227).252

Chemical Properties of 1,3,4-Thiadiazoles. The methylation of (227) with CH2N2 gives the isomers (228) and (229).252This last compound has also been prepared unambiguously from 5 -alkyl-3 -methyl-2-imino- 1,3,4-thiadiazoline and 2*3 244

245 246

247

248 249

*” 252

K. N. Zelenin, V. A. Khrustalev, V. V. Pinson, and V. V. Alekseev, Zh. Org. Khim., 1980,16, 2237 (Chem. Abstr., 1981,94,103258). J. Motoyoshiya, M. Nishijima, I. Yamamoto, H. Goto, Y. Katsube, Y. Ohshiro, and T. Agawa, J. Chem. SOC.,Perkin Trans. 1, 1980,574. N. F. Eweiss and A . Osman, J. Heterocycl. Chern., 1980,17,1713. A. S.Shawali, H. M. Hassaneen, and S. M. Sherif, J. Heterocycl. Chem., 1980,17,1745. N. D.Heindel, G. Friedrich, and M. C. Tsai, J. Heterocycl. Chem., 1980,17,191. S . H. Askari, S. F. Moss,and D. R. Taylor, J. Chem. SOC.,Perkin Trans. 1, 1981,360. M.R.Mahmoud, R. Abdel Hamide, and F. Abdel Goad, Indian J. Chem., Sect. A, 1980,19,144. M. R. Mahmoud, A . K. El-Shafei, and F. A . Adam, Gazz. Chim. Ital., 1980,110,221. 0. S. Anisimova and N. Yu. Sheinker, Khim.-Farm. Zh., 1980, 14, 92 (Chem. Abstr., 1980, 93, 238 415). D. Leppard and H. Sauter, J. Heterocycl. Chem., 1980,17,1469.

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

145

R2COCl. The products formed by treatment of the thiazolium salts (230) with base have been identified: open products, dimers, and thiodiazolinethiones are formed.253 Me N

N lc;)NR3COR2

R*rs>NcoR2 (227) R 3 = H

(228) R3=Me

Dialkyl acylphosphonate acts as an acylating agent for the 2-methyl group in 1,3,4-thiadiazolium salts. The reaction of 5-amino-2,3-dimethyl-1,3,4thiadiazolium iodide with (Et0)2P(0)Bzhas been shown to give a complicated mixture of the thiadiazoles (231), (232), (233), and (234).254 Ph Me&“

0(231) R = M e (234) R = CH=CHPh

(232) R = H (233) R = B z

1-Oxidesand 1,l-dioxides of the thiadiazole (235) undergo [4 + 61 cycloaddition with 6-(dimethylamino)fulvene, giving 5,6-diaza-azulenes (236) in good yields. A reasonable mechanism has been proposed for this interesting reaction.255

Condensed 1,3,4=Thiadiazoles.-2-Phenyltetrazolo[4,5 -a][ 1,3,4]thiadiazole (237) exists as a bicyclic compound in the solid state, but isomerizes to the The azide form reacts with dimethyl fumarate, azide (238) in CHC13

(237) 253

(238)

‘*

A . Alemagna and T. Bacchetti, Rend.-Ist. Lomb. Accad. Sci. Lett. A , 1978,112,67(Chem. Abstr., 1980,93,8093).

”‘A . Takamizawa, Y. Matsushita, and H. Harada, Chem. Pharm. Bull., 1980,28,447. 2’5 256

M. Mori and K. Kanematsu, J. Chem. SOC.,Chem. Commun., 1980,873. M.Daneshtalab and K. Motamedi, J. Heterocycl. Chem., 1980.17,785.

146

Heterocyclic Chemistry

giving the thiadiazolo[3,2-a]pyrimidin-5-one(239). The isomeric pyrimidin-7one (240) has been prepared from 2-amino-5-phenyl-1,3,4-thiadiazoleand diethyl acetylenedicarboxylate.

(239)

0ther thiadiazolo[ 3,2 -a]-pyrimidin-5 - o n e ~ ~ ' ~ *and ~ ' ' -pyrimidin-7-0nes~~~ have been described, as well as the condensed 1,2,4-triazolo[3,4-6][1,3,4]thiadia~oles~~~*~~~ and imidazo[2,14][ 1,3,4]thiadiazole~.~~~~~~~ 1,3,4-Selenadiazoles.-The reaction of phenacyl selenocyanate with arenediazonium chlorides affords 2-imino-5-acyl-selenodiazolines.263 2-Iminoselenadiazolines have been transformed into the 2-0x0 analogues through the nitro~amines.~~~ 1,2,5-Thiadiazoles and 1,2,5-Selenadiazoles.-Synthesis. The cyclization of diaminomalononitrile with SO2 gives 3,4-dicyan0-1,2,5-thiadiazole.~~' 1,2,5Thiadiazolidine 1-oxides (241; X = 0 or NR') have been described.2663-Vinyl1,2,5-thiadiazole (242) has been prepared from the thiadiazole (243; R = H) and vinylmagnesium chloride by a Wittig reaction, starting from (243; R = CHO) or (243; R = CH=PPh3), and by the reaction between 3,4-diaminobut-1ene and ditosyl ~ulphurdi-imide.'~~ Analogous reactions have been utilized to prepare 3-vinyl- 1,2,5-~elenadiazole.~~'

N

RKS/ 0 2

(24 1)

/

'S (242) R = CH=CHz (243) R = H, CHO, or CH=PPh3

. RN .i?,R 1 'S (244)

R'N,S/ o G N R 1

II

N R ~ (245)

Chemical Properties of 1,2,5-Thiadiazoles and 1,2,5-Selenadiazoles. The reactivities of 3-vinyl-l,2,5 -thia- and -selena-diazoles towards KMn04, Br,, and CdClZhave been Reactions of (244; R = But) with RC6H4So2N3 2s7

*'*

2s9

260 261

262

263 264 Zb5

266 267

T. Tsuji and Y. Otsuka, Heterocycles, 1980,14, 197. G. Kornis, P. J. Marks, and C. G. Chidester, J. Org. Chem., 1980, 45,4860. S. Singh, L. D. S. Yadav, andH. Singh, Bokin Bobai, 1980,8,385 (Chem.Abstr., 1981,94,103 250). V. K. Chadha and G. R. Sharma, J. Indian Chem. SOC.,1980,57,1112. M. L. Schenetti, F. Taddei, L. Greci, L. Marchetti, G. Milani, G. Andreetti, G. Bocelli, and P. Sgarabotto, J. Chem. SOC.,Perkin Trans. I , 1980,421. H. Paul, R. Wessel, and G. Huschert, Monatsh. Chem., 1981,112, 209. M. Takahashi and M. Kurosawa, Bull. Chem. SOC.Jpn., 1980,53, 1185. H. M. Hassaneen, A. Shetta, and A. S . Shawali, J. Heterocycl. Chem., 1980,17, 1185. J. D. Warren, V. J. Lee, and R. B. Angier, J. Heterocycl. Chem., 1979, 16,1617. R. Beckert and R. Mayer, J. Prakt. Chem., 1980,322, 273. V. Bertini, F. Lucchesini, and A. De Munno, Tetrahedron, 1980, 36, 1245. V. Bertini, F. Lucchesini, and A. De Munno, Synthesis, 1979, 979.

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

147

gave the S-imino-compounds (245).269The X-ray structures of 2,5-di-t-butyl-1( p-tolylsulphonylimino)-1h4,2,5-thiadiazolidine-3,4-dione (245; R1 = But, R2 = MeC6H4SO2) and l-(ethylphenylamino)-3,4-dioxo-2,5-diphenyl-l,2,5-

thiadiazolium tetrafluoroborate have been determined.270

1,2,3=Benzothiadiazoles.-Synthesis.

Treating

3,6-dimethoxy-o-phenylene-

diamine with PhNSO gives (246).265 Physical Properties of 1,2,3-Benzothiadiazoles. The electronic structures (X-ray fluorescence spectra) of 2,1,3-benzothiadiazole and some of its derivatives indicate that compounds (247) exist in the benzenoid rather than in the quinonoid form.27' Chemical Properties of 1,2,3-Benzothiadiazoles. The demethylation of (246) by AlCl, gives (248);the chemistry of the benzologue (249) has also been A family of interesting compounds of general formula (250; X = 0, Y = S), (250; X = S, Y = 0),and (250; X = Y = S) have been prepared from 4,7dibromo-2,1,3-benzothiadiazole.272 The condensation of 2,1,3-benzothiadiazole-4,5-diaminewith aromatic aldehydes gives (25l).273

Condensed 1,2,5=Thiadiazoles.-The reaction of 3,4-diacyl-1,2,5-thiadiazoles with salts of RCH2NH3+ yields the condensed thiadiazolo[3,4-c Jpyridines (25 2).274 4,6-Diphenylthieno[3,4-c][1,2,5]thiadiazole (253) reacts with acetylenes to give 2,1,3-benzothiadiazoles (254) in good yields (Scheme 15).275 The same authors have studied the cycloaddition reaction of (253) with 6,6-diphenylfulvene and t r o p ~ n e . ~ ~ ~ 'Iy

R. Neidlein, P. Leinberger, and W. Lehr, Chem.-Zrg., 1980,104,111.

270

A. Gieren, B. Dederer, and I. Abelein, 2. Anorg. AlIg. Chem., 1980,470,191. G.N. Dolenko, A. V. Zibarev, S. A. Krupoder, and G. G. Furin, I.u.Sib. Otd. Akad. Nauk SSSR, Ser. Khim. Nauk, 1980,No. 2, p. 81 (Chem. Abstr., 1980,93,185 238).

271

272

273 274

275 276

T. Uno, K. Takagi, and M. Tomoeda, Chem. Pharm. Bull., 1980,28,1909. P.S.Rao and V. Veeranagaiah, Indian J. Chem., Sect. B, 1981,20,111. S.Mataka, K. Takahashi, M. Tashiro, and Y.Tsuda, Synthesis, 1980,842. 0.Tsuge and T. Takata, . I Org. Chem., 1980,45,2956. 0.Tsuge, T. Takata, and M. Noguchi, Chem. Left., 1980,1031.

148

Heterocyclic Chemistry Ph

1

N

-

Ph

Ph (254)

Scheme 15

2,1,3-Benzoselenadiazoles.-The reaction between some aromatic orthodiamines and selenious acid, H2Se03, which gives 2,1,3-benzoselenadiazoles such as (255), has been examined; equilibrium and rate constants, as well as ionization constants, have been determined.277The bisquaternary salts (256) have been prepared from A?.'-dimethyl-o -phenylenediamine~.~~~

16 Dithiazoles and Diselenazoles 1,2,3-Dithiazoles.-Phenothiazines have been prepared by hydrolytic fission of 1,2,3-benzodithiazolium salts (257), followed by a Smiles rear~angernenf.~'~ Chloroacetonitrile gives the salt (258) when treated with S,Cl,; this salt can be hydrolysed to (259; X = 0).Derivatives (259; X = S) and (259; X = NAr) have been also described.280The compounds (259; X = NC6H4C1-2)and (259; X = NC6H4CF,-3) are fungicidal against Triclzophyton mertagrophytes.

1,2,4-Dithiazoles.-The reaction of Hector's Base (212) with CS2 gives the 1,2,4-dithiazole (215; Y = C, X = Z = S).23s When (215) is heated with a base, the dithiazole (260) is formed.28' Similarly, (214; Y = C, X = NPh, Z = S) gives (261). The compounds (262) and (263) can be prepared by the oxidative debenzylation and the cyclization with bromine of RC(SCH2Ph)NCSNHAr and R2C=NN=C(SCH2Ph)NCSNHAr, r e ~ p e c t i v e l y . The ~ ~ ~reactivity ' ~ ~ ~ of (264; 277

278

279

281 282

283

J. Neve, M. Hanocq, and L. Molle, Mikrochim. Actu, 1980, 1, 41. G. I. Eremeeva, Yu. I. Akulin, T. N. Timofeeva, B. K. Strelets, and L. S. Efros, Khim. Geterotsikl. Soedin., 1980, 1135 (Chem. Absrr., 1981, 94, 15 649). R. R. Gupta, S. K. Jain, N. K. Goswami, and G . S. Kalwania, Heterocycles, 1980, 14, 831. R. Appel, H. Janssen, I. Haller, and M. Plempel, Ger. Offen. 2 848 221, 1980 (Chem. Abstr., 1980, 93, 186 358).

A. R. Butler and I. Hussain, J. Chern. Res. (S), 1980,266. P. K. Srivastava, S. K. Rai, and V. K. Verma, J. Indian Chem. SOC.,1980, 57, 1125. R. Rai and V. K. Verma, J. Indian Chem. SOC.,1980, 57, 1166.

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

(260) X = S (261) X=NPh

(262) X = N A r (264) X = O

149

(263)

R = 2-pyridyl) towards Ph3P has been studied, providing an interesting entry to thioacyl is~cyanates.'~*~*~ The dithiazole (265) and the dithiazolium salt (266) have been transformed into 1,2,4-0xadiazoles and 1,2,4-triazoles by reaction with hydroxylamine and hydrazine, respectively.'''

1,3,2-Benzodithiazoles.-Two trinorbornyl derivatives that are related to 1,3,2benzodithiazoles have been described. Compound (267) is formed when trithiazyl trichloride is allowed to react with trinorbornene.286Its structure has been established by X-ray analysis. Free radicals (268) are formed from S4N2 and trinorbornene derivatives.287

1,4,2-Dithiazoles.-Dithiazolidines (269) have been obtained by cyclocondensation of Ar'CSCH(CN)COAr* with Ar3COCHBrSCN.'''

17 Oxathiazoles and Selenathiazoles

1,3,4-Oxathiazoles.-2,2-Disubstituted 1,3,4-oxathiazoles (270), on thermolysis, undergo a retro- 1,3-dipolar cycloaddition to give carbonyl compounds and

(270) 284

286

287 288

J. Goerdeler and K.Nandi, Chem. Ber., 1981,114,808. G. Wagner, D. Briel, and S . Leistner, Pharmazie, 1980,35, 48. A. C.Hazell, R. G. Hazell, A. J. Banister, and A. J. Fielder, Acra Crystallogr., Sect. B, 1981,37, 177. S. A.Fairhurst and L. H. Sutcliffe, J. Chem. SOC.,Faraday Trans. 1, 1980,76,1490. H. Dehne and P. Krey, J. Prakt. Chem., 1980,322,407.

150

Heterocyclic Chemistry

nitrile sulphides, which can be trapped by cycloaddition with alkynes and nitriles (see Scheme 1).8 formation of 1,2,4-thiadiazoles from 5-aminoThe crystal and 1,2,3,4-thiatriazole (198) has already been menti~ned.~” molecular structures of (198) have been determined.289

1,2,3,4-Thiatriazoles.-The

1,2,3,5-Thiatriazoles.-The 1-oxides (271) have been prepared ArNHN=C(C02Me)NHR and SOCl, in the absence of base.290 N MeO,C(, NAr RN+ 0

from

(271)

1,2,3,5=Dithiladiazoles.-The reduction of 4-phenyl-l,2,3,5-dithiadiazolium chloride (272) with SCN- gives the dimer (273).29’The two half-molecules are nearly parallel, with one electron pair delocalized at the four sulphur atoms.

(273)

1,3,2,4-Dithiadiazoles.-N-Acyl-S-chlorocarbamoyl chloride reacts with NN’bis(trimethylsily1)sulphurdi-imide to give the dithiazoles (274), which on treatment with FS0,Me give the salts (275).292Methylation of (276) with [MeOSO]’ AsF6- gives the N-methylated salt (277).293

1,2,4,3,5-Trithiadiaoles.-The hypothetical dication (278) has been studied theoretically with respect to its aromaticity and the localization of ~ - o r b i t a l s . * ~ ~

(278) 289

290 291

292

293 294

M. J. Zaworotko, J. L. Atwood, and L. Floch, J. Cryst. Mol. Struct., 1980,9, 173.

G.Heubach, Liebigs Ann. Chem., 1980,1376. A. Vegas, A. Perez-Salazar, A. J. Banister, and R. G. Hey, J. Chem. SOC.,Dalton Trans., 1980,1812. R.Neidlein and W. Lehr, Chem.-Ztg., 1980,104,200. H.W. Roesky, T. Mueller, E. Wehner, and E. Rodek, Chem. Ber., 1980,113,2802. G . Naray-Szabo, Pure Appl. Chem., 1980,52,1565.

151

Five-Membered Rings: Other systems

PART 111: Other Five-Membered Ring Systems by G, V. Boyd 1 Introduction This Part deals with the remaining heterocyclic 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 to a heterocycle containing five, six, or seven 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 to survey methods of synthesis and reactions in separate sub-sections. As in previous years, the Reporter had to be severely selective: only about 500 of the nearly 1000 relevant articles are reviewed briefly. However, a departure has been made from past practice in that 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.

2 Reviews General articles discuss 1,5-electrocyclization reactions,' thermal or photochemical cyclization of hetero-1,3,5-hexatrienes[e.g. (1) + (2)],* and electrophilic substitutions of five-membered heterocyclic c o m p o u n d ~ , ~their reactions with electrophilic ~ l e f i n s ,and ~ their photo rearrangement^,^ while others deal with more specialized subjects: e.g., the chemistry of fur an^,^" their X-ray structures,8 the nitration of fur an^,^ and electrophilic substitution reactions of 2-heteroaryl-furans,'O the use of furans as synthetic building blocks," the synthesis of reduced furans and 3(2H)-dihydrofuranones with 'manipulable CHPh

I1

a r 4 C H P h

- Qyx;h - a> CHPh

CH,Ph

I

(2)

(1)

' R. Huisgen, Angew. Chem., Int. Ed. Engl., 1980,19,947. M. V. George, A. Mitra, and K. B. Sukumaran, Angew. Chem., Int. Ed. Engl., 1980, 19, 973. L. I. Belenkii, Khim. Geterotsikl. Soedin., 1980, 1587. G. V. Grigoryan and S . G. Agbalyan, Arm. Khim. Zh., 1980, 33, 977 (Chem. Abstr., 1981, 94, 174 744). A. Padwa, Org. Chem. (N.Y.),1980,42 (Rearrangements of Ground and Excited States, Vol. 31, 501.

' W. J. McKillip and E. Sherman, Kirk-Othmer Encycl.

' L. H. Klemm, Chem. Lignans, 1978,175. lo

l1

Chem. Technol., 3rd Ed., 1980, 11, 499.

J. Bleidilis, Use. Khim. Furana, 1978, 7 and 231 (Chem. Abstr., 1980,93, 203 429). K.-K. Venter, Use.Khim. Furana, 1978, 134 and 262 (Chem. Abstr., 1980,93,168 026). N. 0. Suldabol, Use. Khim. Furana, 1978, 161 and 270 (Chem. Abstr., 1980,93, 168 027). W. Kreiser, Nachr. Chem. Tech. Lab., 1981, 29, 110.

152

Heterocyclic Chemistry

functionality',12 photo-cycloadditions of aromatic nitriles to furans,13 and benzo[c]furans (3).14There are reviews of the synthesis of pyrroles from acetylenes and ketoxime~,'~substitution reactions of dichloromaleimides,16 the chemistry of indole," abnormal Fischer indolization reactions," electrophilic substitution in the benzene ring of i n d ~ l e s , reactions '~ of 3-substituted indoles,20 3-halogeno-indolenines [e.g. (4)],21halogen derivatives of carbazole (in Polish),22 and electro-oxidation of pyrroles, indoles, and c a r b a z o l e ~ There . ~ ~ are articles on 1 , 2 - d i t h i o l e ~ ,1,4-dithia~~ and 1,4-diselena-fulvenes ( 5 ; X = S or Se)," isoxazoles,26 o x a z o l e ~ ,hypervalent ~~ sulphur compounds, such as (6), (in Japanese),28 a z o - i n d o l e ~ and , ~ ~ on the chemistry and the biological activity of pyrrolobenz~diazepines.~~

3 Systems with One Heteroatom, and their Benzo-analogues Furans.-Formation. The caesium salt of 12-molybdophosphoric acid is an effective catalyst for the vapour-phase oxidation of crotonaldehyde to yield f ~ r a n . Treatment ~' of the cyanhydrin 02NCH2CHPhCMe(OH)CNwith formaldehyde in the presence of triethylamine gives the furan (7).32 Heating a mixture of 0-acetylmandelic acid, dimethyl acetylenedicarboxylate, and acetic anhydride results in the diester (9) by way of the meso-ionic dioxolium oxide (8).33A HOH,C

Ph

QM.

(7) J. E. Semple and M. M. Joullie, Heterocycles, 1980,14, 1825. H. Sakurai and C . Pac., Mem. Inst. Sci. Ind. Res., Osaka Univ., 1980, 37, 59. l4 W. Friedrichsen, Ado. Heterocycl. Chem., 1980, 26, 135. B. A . Trofirnov and A . I. Mikhaleva, Khim. Geterotsikl. Soedin., 1980, 1299. l' M. Augustin and M. Kohler, 2. Chem., 1981, 21, 19. '7 D. W. Bannister, Kirk-Othmer Encycl. Chem. Technol., 3rd Ed., 1981,13, 213. " H. Ishii, Yuki Gosei Kagaku Kyokaishi, 1980,38, 693 (Chem. Abstr., 1981,94, 15 480). l 9 V. A. Budylin, L. G. Yudin, and A. N. Kost, Khim. Geterotsikl. Soedin., 1980, 1181. 2o T. Hino and M. Nakagawa, Kagaku, Zokan (Kyoto), 1980, 57 (Chem. Abstr., 1981,94, 65 394). M. Ikeda and Y. Tarnura, Heterocycles, 1980, 14,867. 22 J. Kyziol and J. Pielichowski, Zesz. Nauk. Politech. Krakow., Chem., 1978, 3 (Chem. Abstr., 1980, 9 3 , 4 6 253). 23 J. M. Bobbitt, C . L. Kulkarni, and J. P. Willis, Heterocycles, 1981, 15, 495. 24 C . T. Pedersen, SulfurRep., 1980, 1, 1. " M. P. Cava and M. V. Lakshrnikantham, Lect. Heterocycl. Chem., 1980, 5, S39. 26 B. J. Wakefield and D. J. Wright, Ado. Heterocycl. Chem., 1979, 25, 147. 27 I. J. Turchi, Ind. Eng. Chem., Prod. Res. Deu., 1981, 20, 32 (Chem. Abstr., 1981, 94, 121 361). K. Akiba and N. Inarnoto, Kagaku no Ryoiki, Zokan, 1980,93 (Chem. Abstr., 1980,93,203 428). 29 L. N. Yakhontov and A . A . Prokopov, Usp. Khim., 1980,49,814. 30 M. Artico, Boll. Chim. Farm., 1980,119,455, 505. 31 M. Ai, T. Tsai, and A. Ozaki, Bull. Chem. SOC.Jpn., 1980, 53,2647. 32 S. A . Ferrino and L. A . Maldonado, Synth. Commun., 1980,10,717. 33 H . C. Berk, K. E. Zwikelrnaier, and J. E. Franz, Synth. Commun., 1980, 10,707. l2

l3

Five-Membered Rings: Other systems

153

mixture of the 4,7-dihydrobenzo[c]furan (11) and the corresponding 4,5,6,7tetrahydro-compound is produced in the catalytic hydrogenation of the dibenHydroxyacetone condenses with malononitrile to zoyl-cyclohexadiene ( form 2-amino-3-cyano-4-methylfuran, which dimerizes spontaneously to the dihydrobifuryl (12).35 The synthesis of [2.2](2,5)furano(3,6)pyridazinophane (13) has been The preparation of dihydrofurans by means of organoselenium compounds is exemplified by the formation of compound (14) from the allenic alcohol Me2C=C=CHCMePr’OH and phenylselenyl chloride3’ and of (15 ) from MeCOCH(CH2CH=CH2)CO2Et and N-phenylseleno~hthalirnide.~’Acetylacetone adds to buta- 1,3-diene in the presence of

(9)

(E = C02Me)

MeOCOPh ‘ Me

‘COPh

manganese(II1) acetate to yield the dihydrofuran ( 16).39The total synthesis of lepiochlorin (17), an antibiotic metabolite of a fungus cultivated by ants, has been de~cribed.~’ The action of lithium di-isopropylamide on the alcohol MeCOCMe20H generates a dianion, whch cyclizes to the tetronic acid (18) on treatment with l,l’-carbonyldi-imidazole.41The bis-diazo-compound

34

” 36

” 38 39

40

A. Sinha and S. Lahiri, Tetrahedron Lett., 1980,21,3717. H.Eilingsfeld, M. Patsch, and E. Hadicke, Liebigs Ann. Chem., 1980,1952. M. D.Bezoari and W. W. Paudler, J. Org. Chem., 1980,45,4584. P. L. Beaulieu, V. M. Morisset, and D. G. Garratt, Tetrahedron Lett., 1980,21, 129. W.P. Jackson, S. V. Ley, and J. A. Morton, J. Chem. SOC.,Chem. Commun., 1980,1026. M. G.Vinogradov, N. L. Radyukina, M. S. Pogosyan, S. P. Verenchikov, A. Ya. Shteinshneider, and G. I. Nikishin, Izv. Akad.Nauk SSSR, Ser. Khim., 1980,1949. J. R. Donaubauer and T. C. McMorris, Tetrahedron Lett., 1980,21,2771. P.J. Jerris, P. M. Wovkulich, and A. B. Smith, 111, Tetrahedron Lett., 1979,4517.

Heterocyclic Chemistry

154

PhCOCN2COCOCN2COPhyields the furanofuran derivative (19)on heating.42 The butanolide (20) results from the reaction of the ally1 ester (MeO2CNH),CHCO2CH2CH=CH2 with methanesulphonic Alkenylsubstituted P-keto-esters cyclize on treatment with PhSe' SbF6-; ethyl The electrochemical y-allylacetoacetate, for instance, yields compound (2l).44 fluorination of methyl a-cyclohexenylbutanoate results in a mixture of the perfluoro-octahydrobenzofuran (22; R = F) and the ketone (22; R = CF3C0).45

c

Me

(22)

Reactions of Furans. 2,5-Bis(trimethylsilyloxy)furan(23), obtained from succinic anhydride, adds dimethyl acetylenedicarboxylate to afford, after hydrolytic work-up, a mixture of the quinone (24)and the corresponding h y d r o q ~ i n o n e . ~ ~ The reactive mixed anhydride AcO2CC~CCO,Ac(from potassium acetylenedicarboxylate and acetyl chloride) yields the 1:2 cyclo-adducts (25) and (26) with f ~ r a nThe . ~ ~formation of, the photo-adducts (27) and (28) of benzene to Me,SiO)\OSiMe3 0 (23)

O Me0,C

C0,Me

P

O

(25)

L$A0 0

ko

0

(26)

(24)

M. B. Rubin, M. Bargurie, M. Kafory, and S. Kosti, J. Chem. SOC.,Perkin Trans. 1, 1980,2670. D.Ben-Ishai, J. Chem. SOC.,Chem. Commun.,1980,687. 44 W.P. Jackson, S. V. Ley, and A. J. Whittle, J. Chem. SOC.,Chem. Commun., 1980, 1173. " T.Abe, E. Hayashi, H. Baba, and S. Nagase, Chem. Lett., 1980, 121. 46 P. Brownbridge and T.-H. Chan, Tetrahedron Lett., 1980,21,3423. 47 G.Maier and W. A. Jung, Tetrahedron Lett., 1980,21,3875. 42 43

Five-Membered Rings: Other systems

155

furan has been described.48Sensitized photo-oxygenation of the furan (29) gives the peroxide (30), which is slowly converted into the epoxide (31).49[3 + 21 Cycloadditions of ally1 cations to furan yield bridged cycloheptenes; thus treatment of the ketones EtCOCHXMe (X = Br or C1) with sodium fluor~borate~' or triethylamine51generates the oxyallyl cation (32), which reacts with furan to form (33), and the reaction of the ester F3CCOzCMe2C(OEt)=CHzwith furan in the presence of ethyldi-isopropylamine and zinc bromide gives compound (34y2 Me02C

Meo2c6 Ph

COMe

P o

PhCO

(29)

(31)

/

I Me (32)

Me (33)

(34)

The furan (35) suffers ring-cleavage on treatment with butyl-lithium to yield the allene MeCOCH2C=C=CHBu.53 The reaction of the silyl ether (23) with anisaldehyde in the presence of titanium(1v) chloride affords the dioxabicyclooctanedione (36).54Flash vacuum pyrolysis of octahydrodibenzofuran (37) at

' (2

Me'

CHBuSePh

(35)

A;

(36) Ar

=

p-MeOC6H4

920 "C affords the radialene (38) by a retro-Diels-Alder rea~tion.'~The furanophane (40) is obtained in moderate yield by the action of tetrabutylammonium fluoride on the quaternary salt (39).56Photo-oxygenation of the esters (41;R',R2,R3 = H or Me) leads to the rearranged pyrrolinones (42).57Irradiation of the pale yellow fulgides (43; R = H or Me) results in reversible electrocyclization to the deep red 7,7aH-dihydrobenzofuran derivatives (44).58 48 49

51

5z

53 54 55

s6 57 58

J. C. Berridge, A. Gilbert, and G. N. Taylor, J. Chem. SOC.,Perkin Trans. 1, 1980,2174. M. L. Graziano, M. R. Iesce, and R. Scarpati, J. Chem. SOC.,Perkin Trans. 1, 1980,1955. J. Mann and A. A. Usmani, J. Chem. SOC.,Chem. Commun., 1980,1119. B. Fohlisch, W. Gottstein, R. Kaiser, and I. Wanner, Tetrahedron Lett., 1980,21,3005. H. M. R. Hoffmann and J. Matthei, Chem. Ber., 1980,113,3837. I. Kuwajima, S. Hoshino, T. Tanaka, and M. Shimizu, Tetrahedron Lett., 1980,21,3209. P. Brownbridge and T.-H. Chan, Tetrahedron Lett., 1980,21,3427. J. Jullien, J. M. Pechine, F. Perez, and J. J. Piade, Tetrahedron Lett., 1980,21,611. Y.Ito, S. Miyata, M. Nakatsuka, and T. Saegusa, J. Org. Chem., 1981,46,1043. K. Yakushijin, M. Komka, Y. Ito, R. Suzuki, and H. Furukawa, Heterocycles, 1980,14,1073. H. G. Heller and S. Oliver, J. Chem. SOC.,Perkin Trans. I , 1981, 197;P, J. Darcy, H. G. Heller, P. J. Strydom, and J. Whittall, ibid., p. 202.

156

Heterocyclic Chemistry M e 3 S i H 2 C0O C H 2 h 4 e ,

I(37)

(39)

(38)

1

(43)

(44)

The methylenebutanolide (45) undergoes palladium(0)-catalysed transposition of the 0-CO moiety to afford the butenolide (46).59 Thermal Cope rearrangement of the cyclbpropane (47) gives the cycloheptafuran (48).60 Tetrakis(tripheny1phosphine)palladium catalyses a [1,3] shift of carbon atom 4 from oxygen to C-3 in the tetrahydrofuran (49)to yield the cyclopentanone derivative (50)."' The [lSJannulenone (51) is protonated below -45 "C to yield the conjugate cation, together with its conformational isomer (52), which changes to (53)at -30 0C.62

(46)

H2C=McCa&C02Et (49)

-

($Me=cH2 0 C02Et (50)

59

6o

61 62

(51) (52) (53) Y. Inoue, T. Hibi, Y. Kawashima, and H. Hashimoto, Chem. Left., 1980,1521. G.Maas and C. Hummel, Chem. Ber., 1980,113,3679. B.M.Trost, T. A. Runge, and L. N. Junjjheim, J. Am. Chem. Soc., 1980,102,2840. H.Ogawa, T. Imoto, H. Kato, and Y. Taniguchi, Fukusokun Kuguku Toronkui Koen Yoshishu, 12th, 1979,6(Chem. Abstr., 1980,93,113 638).

Five-Membered Rings: Other systems

157

Attention is drawn to other papers on the f ~ r r n a t i o n ~and ~ - chemistry7G98 ~~ of furans. J. Brokatzky and W. Eberbach, Chem. Ber., 1981,114,384(Chem. Absrr., 1981,94,120504). G. G. Melikyan, D. A. Mkrtchyan, and Sh. 0. Badanyan, Khim. Geterotsikl. Soedin., 1980, 884 (Chem. Abstr., 1980,93,239112). 65 A. Fabrycy and Z. Wichert, Liebigs Ann. Chem., 1980, 1744 (Chem. Abstr., 1981,94, 139 526). 66 G.Varadi, 1. T. Horvath, J. Palagyi, T. Bak, and G. Palyi, J. Mol. Catal., 1980,9,457 (Chem. Abstr., 1981,94,156 647). 67 H. Schick, E. Griindemann, and D. Ballschuh, J. Prakt. Chem., 1980,322, 559 (Chem. Absti., 1981,94,103 086). S.I. Pennanen, TetrahedronLett.,1980,21,657(Chem. Abstr., 1980,93,114207). 69 K. Leppanen-Lipas, Finn. Chem. Lett., 1980,21(Chem.Abstr., 1980,93,7919). 70 H. J. Bestmann, G. Schade, and G. Schmid, Angew. Chem., Int. Ed. Engl., 1980,19,822 (Chem. Abstr., 1981,94,139 291). 71 S. Nakagawa, T. Naito, and H. Kawaguchi, Heterocycles, 1979,13 (Special Issue), p. 477 (Chem. Abstr., 1980,93,114 349). 72 E. S. Balenkova, E. B. Frolov, and S. N. Anfilogoba, Zh. Org. Khim., 1980, 16, 1780 (Chem. Abstr., 1981,94,47040). 73 C. Phillips, R. Jacobson, B. Abrahams, H. J. Williams, and L. R. Smith, J. Org. Chem., 1980,45, 1920 (Chem.Abstr., 1980,93,7984). 74 K. Venters, A. Kemme, and J. Bleidelis, Latv. PSR Zinat. Akad. Vestis, Kim. Ser., 1980,479 (Chem. Abstr., 1981,94,14 940). 7 5 M. D'Auria, G. Piancatelli, and A. Scettri, Tetrahedron, 1980,36,1877 (Chem. Abstr., 1981,94, 121 195). 76 D. Ranganathan, C. B. Rao, S. Ranganathan, A. K. Mehrotra, and R. Iyengar, J. Org. Chem., 1980,45,1185(Chem.Abstr., 1980,93,7602). 77 P. Hong, B.-R. Cho, and H. Yamazaki, Chem. Lett., 1980,507(Chem.Abstr., 1980,93,132304). 78 A. T. Balaban, A. Bota, and A. Zlota, Synthesis, 1980, 136 (Chem. Abstr., 1980,93,71414). 'I9 N. S. Kozlov, L. I. Moiseenok, and S. I. Kozintsev, Dokl. Akad. Nauk SSSR, 1980,252, 1132 (Chem. Abstr., 1981,94,47 039). 80 S.-C. Kuo, C.-H. Wu, C.-C. Wang, A. Tanaka, and C.-C. Liao, Heterocycles, 1981,16,231(Chem. Abstr., 1981,94,139 530). 81 R. Sjoholm and A. Lundqvist, Acta Chem. Scand., Ser. B, 1980, 34, 446 (Chem. Abstr., 1981, 94,120 486). 82 F. Povazanec, J. Kovac, and D. Hesek, Collect. Czech. Chem. Commun., 1980,45, 150 (Chem. Abstr., 1980,93,7916). 83 W. R. Dolbier, Jr., and C. R. Burkholder, Tetrahedron Lett., 1980,21,785 (Chem. Abstr., 1981, 94,102743). 84 0. M. Nefedov, V. M. Shostakovskii, A. E. Vasilvitskii, and M. 1. Kravchenko, Izv. Akad. Nauk SSSR,Ser. Khim., 1980,607(Chem.Abstr., 1980,93,71417). " G. Weber, K. Monke, and H. Hopf, Chem. Ber., 1980,113,531(Chem. Abstr., 1980,93,46273). 86 L. Fisera, J. Kovac, J. Poliacikova, and J. Lesko, Monatsh. Chem., 1980,111, 909 (Chem. Abstr., 1981,94,14 730). A. Tanaka and T. Usui, Chem. Pharm. Bull., 1979,27,3070(Chem. Abstr., 1980,93,26177). L. M. Gomes and J. Cabares, C. R. Hebd. Seances Acad. Sci.. Ser. C., 1980, 290, 29 (Chem. Abstr., 1980,93,26 178). 89 F. Fournier, S. Altenburger-Combrisson, K. C. Nguyen, and J. J. Basselier, Tetrahedron, 1979, 35,2639(Chem.Abstr., 1980,93,114222). 90 T.Mukaiyama and T. Takenayashi, Chem. Lett., 1980, 1013 (Chem. Abstr., 1981,94, 121 367). 91 S. Bartlett, R. D. Chambers, and N. M.Kelly, Tetrahedron Lett., 1980,21, 1891 (Chem. Abstr., 1980,93,150 066). 92 S. Watanabe, T. Fujita, K. Suga, and K. Kasahara, Yukagaku, 1980,29,689(Chem.Abstr., 1981, 94,65403). 93 0. Simonsen, T. Reffstrup, and P. M. Boll, Tetrahedron, 1980,36,795 (Chem. Absrr., 1980. 93, 71 423). 9* S. Gelin and P. Pollet, Tetrahedron Lett., 1980,21,4491(Chem. Abstr., 1981,94,156 048). 95 N. Ishizuka, S. Miyamura, T. Takeuchi, and K. Achiwa, Heterocycles, 1980, 14, 1123 (Chem. Abstr., 1981,94,47038). % K. Steinbeck, TetrahedronLett.,1980,21,2149 (Chem. Abstr., 1981,94,47034). 97 J. A. Moore and E. M. Partain, 111, Org. Prep. Proced. Int., 1980, 12,305 (Chem. Abstr., 1981, 94,121 197). 98 C. Mohaim, P. A. Carrupt, J. P. Hagenbuch, A. Florey, and P. Vogel, Helv. Chim. Acta, 1980, 63,1149 (Chem.Abstr., 1981,94,47035). 63

Heterocyclic Chemistry

158 Benzofurans and Other Annelated Furans.-The

ethers (54; R' = H or alkyl,

R2 = H) are converted into benzofurans ( 5 5 ) by the action of chlorotrimethylsilane and sodium iodide.99Benzofurans are obtained from o-halogeno-phenols and terminal acetylenes in the presence of copper; thus 4-acetyl-2-iodophenol and the enyne H,C=CMeC=CH yield dehydrotremetone ( 5 5 ; R' = CMe,OH, R2 = Ac). loo Photo-oxygenation of 1-methoxy-2,2-diphenyletheneyields the benzofuran derivatives (57) and (58) by way of the peroxide (56).lo1l-Phenyl-2pyrrolidinoacetylene reacts with 3-nitrobenzo[b]furan to yield, inter alia, the insertion product (59) and the isoxazolobenzofuran (6O).lo2 Ph

~2

/

CH2COR'

+

a O (54) M e

(56)

(55)

OMe (57)

(58)

(59)

Palladium-catalysed carbonylation of o-iodobenzyl alcohol yields the phthalide (61).Io3Enolizable o-hydroxyphenyl ketones react with thallium(II1) acetate in acetic acid to furnish benzofuranones (62; R = H, Me, or COPh).lo4 Manganese(I1) acetate transforms a-phenylcinnamic acids into complex mixtures that contain 2-phenylbenzofurans and spiro-butenolides, such as (63).lo5The

99

loo lo'

lo'

*05

R. Beugelmans and H. Ginsburg, J. Chem. SOC.,Chem. Commun., 1980,508. G . E. Schneiders and R. Stevenson, Synth. Commun., 1980,10, 699. D. S. Steichen and C. S. Foote, Tetrahedron Lett., 1979,4363. A. D. deWit, W. P. Trornpenaars, D. N. Reinhoudt, S. Harkerna, and G. J. Van Hummel, Tetrahedron Lett., 1980, 21, 1779; A. D. deWit, W. P. Trompenaars, M. L. M. Pennings, and D. N. Reinhoudt, J. Org. Chem., 1981, 46, 172. A. Cowell and J. K. Stille, J, Am. Chem. SOC., 1980,102,4193. N . Malaitong and C. Thebtaranonth, Chem. Lett., 1980, 305. K. Oishi and K. Kurosawa, Bull. Chem. SOC.Jpn., 1980, 53, 179.

Five-Membered Rings: Other systems

159

triarylvinyl bromide (64) yields a 1: 1mixture of the benzofurans (66; R = OMe) and (66; R = OEt) on treatment with aqueous ethanolic sodium hydroxide and thiophenol, via the cyclopropene (65).lo6The radialene (67) has been prepared by a three-fold addition of furan to benzyne as outlined in Scheme l.lo7

0 -

iv

Reagents: i, NaNO,, HCI, furan; ii, 2KNH2, 2 x furan; iii, H,, Pd; iv, heat at 550 OC

Scheme 1

Flash vacuum pyrolysis of the condensation product (68) of 2,4,7-trimethylbenzof uran-3 -alde hyde with Meldrum's Acid gave 2- hydroxy-5 &dimethyldibenzofuran, which was acetylated to yield ruscodibenzofuran (69).lo8 The action of potassium iron(II1) cyanide on 2-bromo-4,6-di-t-butylphenol leads to the dimeric product (70).'09 1,4-Naphthoquinone reacts with aluminium chloride to give, inter alia, the dinaphthofuranquinone (71).11"The grisa-2',5'-diene-3,4'dione (73) is produced by intramolecular ipso-acylation of the diphenyl ether

Me

lo6 lo'

(68)

(69)

H. Ohba, T. Ikeda, S. Kobayashi, and H. Taniguchi, J. Chem., SOC.,Chem. Commun.. 1980,988. M. B. Stringer and D. Wege, Tetrahedron Lett., 1980,21,3831. R. F. C . Brown and C . M. Jones, Aust. J. Chem., 1980,33,1817. M . Tashiro, H.Yoshiya, and G . Fukata, Synthesis, 1980,495. R. Buchan and 0. C . Musgrave, J. Chem. SOC.,Perkin Trans. 1, 1980,90.

160

Heterocyclic Chemistry

(72).'11 Radical oxidation of the triarylmethane (74) by PhI(OAc)2 gives the spiro-benzofuran (75) stereospecifically.''2 The absolute configuration of the fungal phenalenone herqueinone (76), isolated from Penicillium herquei, has been determined by X-ray analysis113 and the synthesis of the soil pigment (77) has been de~cribed."~

OMe (73)

(72) E = COzMe

dH

Me \

Me

Ci

(74) Me

HO (77) (76)

Benzo[c]furan (79; R3 = R4 = H) is produced by the action of lithium diisopropylamide on the phthalan (78; R' 5 H, R2 = MeO);"' 1,3-diaryl derivatives (79; R3 = R4 = Ar) are obtained by treatment of the diacyl-cyclohexenes (80; R5 = Et2N, morpholino, Me3Si0, EtO, or AcO) with polyphosphoric

'" M. V. Sargent, J. Chem. SOC.,Chem. Commun.. 1980,285. '12

'13 '14

F. M.Dean, G. A. Herbin, D. A. Matkin, A. W. Price, and M. L. Robinson, J. Chem. Soc., Perkin Trans. 1, 1980, 1986; cf. D. J. Bennett, F. M. Dean, G. A. Herbin, D. A. Matkin, A. W. Price, and M. L. Robinson, ibid., p. 1978. A.Quick and R. Thomas,J. Chem. SOC.,Chem. Commun., 1980,1051. D. W. Cameron, G. I. Feutrill, and L. J. H. Pannan, Tetrahedron Lett., 1980, 21, 1385; Aust. J. Chem., 1980,33,2531. K. Naito and B . Rickborn, J. Org. Chem., 1980,45,4061.

Five-Membered Rings: Other systems

161

acid.116 The formation of the naphthol (81), which occurs when 1 , l diethoxyphthalan (78; R1 = R2 = OEt) is heated with dimethyl acetylenedicarboxylate, proceeds via the isobenzofuran (79; R3 = H, R4 = OEt)."'

1,3-Diphenylisobenzofuran(79; R3 = R4 = Ph) reacts with alkali metals to yield a dianion, which, on protonation, methylation, or carboxylation, gives mainly cis-phthalans, e.g. (82).'18 When cycloheptatrienylidene (83) is generated from the sodium salt of tropone tosylhydrazone in the presence of diphenylisobenzofuran, there is obtained a mixture of the cyclo-adducts (84) and ( 8 5 ) and the heptafulvene (86).'19 The synthesis of furo[b]tropylium fluoroborate (87) has been described."' Cyclohepta[b]furan-2-one (88) affords the azulenes (89; R', R2 = H, Me, Et, or Ph) on treatment with enamines.'2'

n

11*

'I9

T. Oida, S. Tanimoto, T. Sugimoto, and M. Okano, Synthesis, 1980,131. L. Contreras and D. B. MacLean, Can. J. Chem., 1980,58, 2573. J. G.Smith and R. B. McCall, J. Org. Chem., 1980,45,3982. K. Saito, Y. Omura, and T. Mukai, Chem. Letr., 1980,349. M. Kato, H.Kobayashi, and T. Miwa, Tetrahedron Lett., 1980,21,3373. M.Yasunami, A. Chen, P. W. Yang, and K. Takase, Chem. Lett., 1980,579.

Heterocyclic Chemistry

162

Other articles on benzofurans etc. are in references 122-140.

Pyrro1es.-Furmation. A new pyrrole synthesis is exemplified by the reaction of the ketol acetate (90) with benzylamine in the presence of tetrakis(triphenylph0sphine)palladium to yield compound (91).141 Methyl isocyanoacetate and methyl p-aryl-a-isocyanoacrylates, ArCH=C(NC)C02Me, form pyrrole esters (92).14’ Treatment of dimethyl (methy1amino)fumarate with lead tetra-acetate results in a mixture of the pyrrole (93), the pyrrolopyrrole (94), and the pyridone (95),143New methods for preparing 2-aminopyrroles

c

N H (92)

u

(90)

(93) 122 123

124

125 126

127 128

129

130

131 132

133

134

135

136

137

138

139

140

141 142

143

(94)

(E = COzMe)

-

A.

(95)

K. Maruyama and T. Kozuka, Chem. Lett., 1980,341 (Chem. Abstr., 1980,93,70473). S . Hirotani and S. Zen, Kokagaku Toronkai Koen Yoshishu, 1979, 200 (Chem. Abstr., 1980, 93, 45 537). V. P. Makovetskii, I. B. Dzvinchuk, Yu. M. Volovenko, and A. A. Svishchuk, Khim. Geterotsikl. Soedin., 1980, 164 (Chem. Abstr., 1980,93,26 340). P. M. Dewick and J. L. Ingham, Phytochemistry, 1980, 19, 289 (Chem. Abstr., 1980, 93, 26 186). Y. Kobayashi and I. Kumadaki, J. Chem., SOC., Perkin Trans. 1, 1980, 661 (Chem. Abstr., 1980, 93, 132 311). H.-J. Liu and W. H. Chan, Can. J. Chem., 1980,58,2196 (Chem. Abstr., 1981,94, 3888). R. W. Saalfrank, E. Ackermann, H. Winkler, W. Paul, and R. Bohme, Chem. Ber., 1980, 113, 2950 (Chem. Abstr., 1981, 94, 14 950). T. Keumi, C. Murata, Y. Sasaki, and H. Kitajima, Synthesis, 1980, 634 (Chem. Abstr., 1981, 94, 46 872). W. Stadlbauer, 0. Schmut, and T. Kappe, Monutsh. Chem., 1980,111, 1005 (Chem. Abstr., 1981, 94, 139 531). A. Prewysz-Kwinto, J. Prakt. Chem., 1980,322,487 (Chem. Abstr., 1981,94, 30 454). K. Imafuku, K. Yamaguchi, and H. Matsumura, Bull. Chem. SOC.Jpn., 1980, 53, 745 (Chem. Absrr., 1980, 93, 186 062). H. N. C. Wong and F. Sondheimer, Tetrahedron Lett., 1980, 21, 983 (Chem. Abstr., 1980, 93, 95 052). F. Toda and K. Tanaka, Chem. Lett., 1979,1451 (Chem. Abstr., 1980,93,7933). T. Horaguchi, R. Yamazaki, and T. Abe, Bull. Chem. SOC.Jpn., 1980, 53, 494 (Chem. Abstr., 1980,93,46 302). J. Bergman and B. Egestad, A c f a Chem. Scand., Ser. B, 1980, 34, 177 (Chem. Abstr., 1980, 93, 239 116). J. P. Cateau, P. Karafiloglou, and A. Lablache-Combier, J. Chem. Res. ( S ) , 1980, 305 (Chem. Abstr., 1981, 94, 15 465). T. I. Gray, A. Pelter, and R. S. Ward, Tetrahedron, 1979, 35, 2539 (Chem. Abstr., 1980, 93, 132 309). V. B. Voleva, I. A. Novikova, G. D. Ostapets-Sveshnikova, I. S. Belostotskaya, and V. V. Ershov, IZV. Akad. Nuuk. SSSR, Ser. Khim., 1980, 2416 (Chem. Abstr., 1981, 94, 174 547). J. E. Baldwin, W. A. Dupont, and M. F. Ming, J. Chem. SOC., Chem. Commun., 1980, 1042 (Chem. Abstr., 1981,94, 83 865). B. M. Trost and E. Keinan, J. Org. Chem., 1980,45, 2741. K . Sakai, M. Suzuki, K. Nunami, N. Yoneda, Y. Onoda, and Y. Iwasawa, Chem. Pharm. Bull., 1980,28,2384. R. M. Carr, R. 0. C. Norman, and J. M. Vernon, I. Chem. SOC., Perkin Trans. 1, 1980, 156.

Fiue-Membered Rings: Other systems

163

include the formation of 2-amino-3,4-dicyanopyrrole (96) from 1,1,2,2tetracyanoefhane and hyd+liodic the condensation of the dimorpholinium salt OC4HsN=CHCH=NC4H80 2Br- with Schiff -bases R’CH2CR2=NR3 (R’, RZ = Me or Ph, R3 = H or alkyl) to yield the pyrroles (97),14’ and the synthesis of compound (98) by sequential treatment of the a-ketoketen SS-acetal PhCOC(CH2CN)=C(SMe)2with methylamine and benzoyl ch10ride.l~~ NC

CN

PhCO

((NH, N

MeSONHCOPh N

H (96)

Me (97)

(98)

Aromatic lY2-diketones ArCOCOAr react with acetonitrile and sodium hydride and undergo a benzilic acid rearrangement to yield 2-pyrrolin-5-ones (99).14’ The 3-pyrrolin-5-one (100) is produced by the action of diphenylcyclopropenone on the enamine H2NCMe=CHCOMe. 14’ Treatment of chloroacetonitrile with aromatic amines results in dimerization to ClCHzC(NH2)=CClCN,followed by condensation to give the iminopyrrolines (101).’49A series of pyrrole analogues of indigo, e.g. (102),has been prepared.’” The nitrile ylide (F3C)2c-k=CPh, generated by thermolysis of the phosphorus compound (103), adds to 1,l-diphenylethene to form a mixture of the 1,3-cycloadducts (104) and (105).”’ A regio- and stereo-specific syntht .is of a 1-pyrroline NC MeCOH,C M e H V0

H

Cl

QNH Ar

x-Y N>Ph

MeMMe (MeO),P-0

Me

Me

N

H

O

(cF3)k.N>Ph

(cF3)2(

(104) X = CH2, Y = CPhz (105) X = CPh2, Y = CH2

consists of the 1,3-anionic cycloaddition of the salt (106) to ethyl crotonate to give (107), followed by elimination of a phosphite to yield the product (108).’52 Reductive cyclization of the nitro-olefin (109; Py = 4-pyridyl) leads to the pyrroline oxide (1 144

14’ 14‘

lo’ lo9 150

15* lS3

0. E. Nasakin, V. V. Alekseev, V. K. Promonenkov, and I. A. Abramov, Khim. Geterotsikl. Soedin., 1981, 121. S. Baroni. R. Stradi, and M. L. Saccarello, J. Heterocycl. Chem., 1980,17, 1221. S. Apparao, H. Ila, and H. Junjappa, Synthesis, 1981,65. S . Akabori, M. Ohtomi, K. Takahashi, Y. Sakamoto, and Y. Ichinohe, Synthesis, 1980, 900. C. Kascheres, A. Kascheres, and P. S. H. Pilli, J. Org, Chem., 1980,45,5340. H. J. Teuber, G. Schiitz, and F. Erkenbrecher, Arch. Phann. (Weinheim, Ger.), 1980,313,851. G . Pfeiffer and H. Bauer, Liebigs Ann. Chem., 1980, 564. K. Burger, H. Goth, and W. D. Roth, 2.Naturforsch., Teil. B, 1980,35, 1426. A. Dehnel and G. Labielle, Tetrahedron Lett., 1980, 21, 1315. K. H. Pfoertner and J. Foricher, Heh. Chim. Acta, 1980,63,658.

164

Heterocyclic Chemistry

(EtO),P-CH=NCMePh

II

M e H ~ ' " H-(EtO),P

Li+

0 (106)

II

Ph Me

\

H

0

(107)

NO, 0 ( 109)

The fulvene (11l), obtai7ed from t-butylcyclopentadiene and the phosgeneimmonium salt C12C=NMe2 C1-, condenses with ammonia to give the azapentalene (112), and this adds dimethyl acetylenedicarboxylate to yield the ring-enlarged aza-azulene that is The formation of the pyrrolidinone (114) by the action of manganese dioxide on the hydrazide EtCH=CHCH,CH,CONHNHCO,Et represents an intramolecular ene reaction of the intermediate azo-compound (113).1552,2,6,6-Tetramethylpiperidin4-one (115) reacts with dichlorocarbene, under phase-transfer conditions, with N Me,

Bu' CI-

Me,N

Me P H,N

o

C0,Et (113)

-

Me f?o HNI C0,Et (114)

ring-contraction to yield the pyrrolidinone (116), as outlined in Scheme 2.156 Three examples of 1,3-anionic cycloadditions of 2-aza-ally1 anions to yield pyrrolidines are the reaction of styrene with the anion (117), generated in the two-phase system benzylidenebenzylamine/aqueous sodium hydroxidebenzyltriethylammonium chloride, to give (118),15' the formation of the ethylene 154

155

'51

15'

K. Hafner and H. P. Krimmer, Angew. Chem., Inr. Ed. Engt., 1980, 19, 199;K. Hafner, H.G. Klis, and M. C. Bohm, Tetrahedron Lett., 1980,21,41. E. Vedejs and G. P. Meier, Tetrahedron Lett., 1979,4185. H. Lind and T. Winkler, Tetrahedron Lett., 1980,21, 119. A. Ts. Malkhasyan, E. M. Nazaryan, S. M. Mirakyan, and G. T. Martirosyan, Arm. Khim. Zh., 1979,32,952 (Chern. Abstr., 1980,93, 132 318).

165

Fiue-Membered Rings: Other systems Ty

ACH2

Scheme 2

adduct (119) when benzylidenebenzylamine is treated with butyl-lithium in tetrahydrofuran (which is cleaved to form ethylene ),15* and the reaction of the anion (117) with phenylallene to afford, after hydrolysis, solely the compound ( 120).'59Diethylaluminium chloride catalyses the intramolecular ene reaction of the triester (121) to give the pyrrolidine (122).16"The quinone methide (124) is produced by the action of N-bromosuccinimide on the naphthol (123).161 Ph \ ,C<.:->C, H N

/Ph

Ph PhCH=CH2

PhCH=CH2

H I

CH,CH Ph

-fHk (1 18)

Me

4

N

I

E

(E = C02Me)

H MeN-

(123) lS9 160 16'

Me

(1 24)

K. Kamata and M. Terashirna, Heterocycles, 1980,14, 205. L. Vo-Quang and Y. Vo-Quang, Tetrahedron Lett., 1980,21,939. W.Oppolzer and C. Robbiani, Helv. Chim., Acta, 1980,63, 2010. D.Berney and K. Schuh, Helv. Chim. Actu, 1979,62,1268.

N I

E

166

Heterocyclic Chemistry

Reactions of Pyrroles. The chemistry of the valence-bond isomers (126) of pyrroles (125) has been studied in order to elucidate the mechanism of the photochemical transformation of five-membered heterocycles. It was found that compounds (126) do not rearrange at temperatures at which pyrroles undergo photoisomerization. 16' Successive treatment of pyrrole with oxalyl chloride dimethylformamide and hydroxylamine hydrochloride yields 2-cyanopyrrole. 163 2-Cyanopyrroles are obtained by the action of triphenylphosphine-thiocyanogen on pyrroles; indoles gives 3-cyano-derivatives in this ~ e a c t i 0 n . IN-Alkyl~~ pyrroles are trifluoroacetylated at position 2 if the alkyl group is small, e.g. methyl, but at position 3 if it is bulky, e.g. l-adamantyl; N-isopropylpyrrole represents an intermediate case, yielding a mixture of 2- and 3-trifluoroacetyl-lis~propylpyrroles.'~~ N-Substituted 2- or 3-acyl-pyrroles form equilibrium mixtures in strong acids.'66 2-Phenylsulphinylpyrrole (127), prepared by the action

of phenylsulphinyl chloride on pyrrole, undergoes an acid-catalysed rearrangement to the 3-is0mer.'~~ The intermediate (128) in the Vilsmeier-Haack formylation of pyrrole can be acylated under Friedel-Crafts conditions; hydrolytic work-up then yields 4-acyl-2-formylpyrroles, e.g. (129)? The 2,2'-bipyrrole (130) is produced by the action of palladium(I1) acetate on N-benz~ylpyrrole.'~~ MeCO

(128)

(129)

(130)

The reaction of 1-alkyl-3,4-dinitropyrroles with secondary amines yields mainly products of cine-substitution, e.g. compound (131) from 1-methyl-3,4dinilropyrrole and piperidine; however, with primary amines the reaction is complicated by a multi-step mechanism involving ring-opening and re-cyclization. Thus 1-methyl-3,4-dinitropyrrole and isopropylamine give a mixture of (132), (133), and (134).'76 The stable dipyrryldiazene (136) is formed by the action of lead tetra-acetate on the aminopyrrole (135).171 16*

lti3 16'

165 166

167

"* 169 ' 7 1

17*

Y. Kobayashi, A . Ando, K. Kawada, and I. Kurnadaki, J. Org. Chem., 1980, 45, 2968. G. H. Barnett, H. J. Anderson, and C. E. Loader, Can. J. Chem., 1980, 58,409. Y. Tarnura, M. Adachi, T. Kawasaki, H. Yasuda, and Y. Kita, J. Chem. SOC.,Perkin Trans. 1, 1980,1132. D. J. Chadwick, G. D. Meakins, and C. A . Rhodes, J. Chem. Res. ( S ) , 1980,42. J. R. Carson and N. M. Davis, J. Org. Chem., 1981, 46, 839. 0. Carmona, R. Greenhouse, R. Landeros, and J. M. Muchowski, J. Org. Chem., 1980,45, 5336. H. J. Anderson, C . E. Loader, and A. Foster, Can. J. Chem., 1980,58,2527. T. Itahara, J , Chem, SOC.,Chem. Commun., 1980,49. P. Mencarelli and F. Stegel, J. Chem. Suc., Chem. Commun., 1980,123. M. Scotton and L. R. Lampariello, Chim. Ind. (Milan), 1980,62,843.

167

Five-Membered Rings: Other systems NHR~

O,N

O*N

QNG Me

(131)

-

E ~ lN - N , , Me

0

N R' (132) R' = Me, R2 = Pr' (133) R' = Prl, R2 = Me (134) R' = R2 = Pr' Me 'cN--N=N-Na \ E

E

H E

l Me

Me

(135)

(136)

(E = COZEt)

The endo-peroxide (137),obtained by photo-oxygenation of N-methyoxycarbhylpyrrole at low temperatures, reacts with 1-trimethylsilyloxybuta-1,3-diene in the presence of tin(I1) chloride to give the aldehyde (138), which cyclizes to the indole (139).'72The reaction of several pyrroles with dimethyl acetylenedicarboxylate has been studied. Pyrroles with a free a-position, e.g. 1-

a

N

0-0 + (137)

SnC'4*

E

p J J (139)

(138) (E = C02Me)

acetyl-3-methylpyrrole, yield a mixture of Michael adducts (140)and (141) and the Diels-Alder product (142).The latter is unstable: it (a) reverts to (140) and (141),( b )reacts further to give (143),(c) cleaves to give the pyrrole diester (144),and (d) eliminates the bridging group to afford the phthalate (145)(see The Diels-Alder adduct (146)of dimethyl acetylenedicarboxylate Scheme 3).173

;gJe

E

NH 0"' +@Ac

+

/"

E

(140) +

E

N

Ac

E

(142)

E Ac

(14')

E (E = C02Me) Scheme 3

M. Natsume and H. Muratake, Tetrahedron Lett., 1979,3477. W . E. Noland and C. K. Lee. J. Org. Chem., 1980, 45,4573.

l

E (143) Ac

0 \ 0 E

E

(144)

E E (145)

168

Heterocyclic Chemistry

to 1 -methyl-2-vinylpyrrole undergoes a spontaneous [1,3] shift of hydrogen to yield the dihydroindole (147);on the other hand, the reaction of the 3-vinylpyrrole (148) with methyl propiolate affords a mixture of the primary adduct (149) and its rearrangement product (150).’74

E H Bu‘

Bu‘

E

But

(E = C02Me)

The pentachloro-2H-pyrrole (15 1) appears to exist in equilibrium with the 3H-isomer (152), since it affords the Diels-Alder adduct (153) with vinyl acetate.175 Treatment of compound (15 1) with dimethyl(trimethylsilyl)amine, Me,NSiMe,, gives the salt (154); this yields the azafulvene (155), of ‘inverse polarity’, by the action of methyl ~ y a n 0 a c e t a t e . The I ~ ~ pyrrolone N-oxide (156) is reduced by zinc and acetic acid to the dimeric compound (157),contrary to a previous r e p ~ r t . ”Dimethyl ~ acetylenedicarboxylate reacts with the N-oxide (156) to yield a mixture of the 3H-pyridin-4-one (158) and the pyridine OAc

‘c1 CI

NMez

M e 2 N h c N

c1(154)

174

17’

177

C02Me

(155)

R. A. Jones, M. T. P. Mariott, W. P. Rosentha1;and J. Sepulveda Arques, J. Org. Chem., 1980, 45,4515. M. E. Jung and J. J. Shapiro, I. Am. Chem. SOC.,1980,102,7862. R. Gompper and M. Junius, Tetrahedron Lett., 1980,21,2883. J. P.Freeman and M. J. Haddadin, Tetrahedron Lett., 1979,4813.

Five-Membered Rings: Other systems

169

(159);17' with the pyrroline oxide (160), compound (162) is obtained, which results by migration of a phenyl group in the initial 1,3-cyclo-adduct (161)."' Ph

Me:? N

Ph

I

o&\E

E =

C02Me) (162)

The pyrrolinedione (163; Ar = p-MeOC6H,) undergoes a reversible cycloaddition to phenyl isocyanide to yield the furanopyrrole (164)."' Photolysis of the ozonide (165) of N-methyldiphenylmaleimide at -78 "C yields the aziridine-2,3-dione (166), which decomposes to carbon monoxide and methyl isocyanate.lS1The azetidine-2,4-dione (168) is formed by irradiation of Nmethylhexahydrophthalimide (167).lS2Thermal or photolytic decomposition of the pyrrolinone (169) results in the azetidinone (17O).la3The photochemical ring-contraction of the pyrrolinone (171) to the cyclopropyl isocyanate (172) 0 '

V O Ph N

O

la*

+

PhNC

O N M e , N (171)

G==

- x

OCN NMe, (172)

J. P. Freeman and M. J. Haddadin, J. Org. Chem., 1980,454898. H. Bender and D. Dopp, Tetrahedron Lett., 1980,21,1837. G. Kollenz, W. Ott, E. Ziegler, K. Peters, H. G. von Schnering, and H. Quast, Liebigs Ann. Chem.. 1980,1801. H.Aoyama, M. Sakamoto, and Y. Omote, J. A m . Chem. SOC.,1980,102,6902. K. Maruyama, T. Ishitoku, Y. Kubo, and T. Ogawa, Fukusokan Kagaku Toronkai Koen Yoshishu, 12th, 1979,46(Chem. Abstr., 1980,93,203617). H. W.Moore, L. Hernandez, Jr., D. M. Kunert, F. Mercer, and A . Sing, J. A m . Chem. SOC.,1981,

103,1769.

Heterocyclic Chemistry

170

has been reported.lg4Irradiation of 2-aryl-pyrrolinium salts (173; R' = H or Me) in the presence of methanol affords the pyrrolidines (174);lS5with methyl acrylate, the cyclo-adducts (175; R2 = F, C1, Br, or Me) are obtained.186 Dehydration of the N-oxide (176; R = H) with toluene-p-sulphonic acid yields the 2H-pyrrole (177), whereas compound (176; R = Ph) gives the benzylidene derivative (178).lg7The adducts (179; X = F or C1) of polyhalogeno-benzynes to N-methylpyrrole are cleanly deaminated by dichlorocarbene to give the corresponding naphthalenes.lg8 N-Aminopyrrolidine (180) undergoes oxidative ring-enlargement to the diazepine (181) on silica gel.189

N R' (173)

aR2

x-

R' C02Me (175)

(174)

0 N

(3 N

H

Other articles on the f ~ r m a t i o n ' ~and ~ - ~reaction^^^^-^'^ ~~ of pyrroles should be noted. B. J. Swanson, G. C. Crockett, andT. H. Koch, J. Org. Chem., 1981,46,1082. J. Stavinoha, E. Bay, A. Leone, and P. S. Mariano, Tetrahedron Lett., 1980,21,3455, P. S. Mariano and A. Leone, Tetrahedron Lett., 1980,21,4581. "' D. St. C. Black, N. A. Blackman, and L. M. Johnstone, Ausr. J. Chem., 1979,32,2025. G.W.Gribble, R. W. Allen, C. S. LeHoullier, J. T. Eaton, N. R. Easton, Jr., R. I. Slayton, and M. P. Sibi, J. Org. Chem.. 1981,46,1025. 189 N. Viswanathan and A. R. Sidhaye, Tetrahedron Lett., 1979,5025. 190 R. Verhe, N. DeKimpe, L. DeBuyck, M. Tilley, and N. Schamp, Tetrahedron, 1980,36., 131 (Chem. Abstr., 1980,93,113 864). 19' H. Stamm and J. Budny, Arch. Pharm. (Weinheim, Ger.), 1980, 313,967 (Chem. Abstr., 1981, la4

la5

94,65414).

R. Grigg, J. Kemp, J. Malone, and A. Tangthongkum, J. Chem. SOC.,Chem. Commun., 1980, 193

194

195

648 (Chem. Abstr., 1981,94,30465). W. Bartmann, G. Beck, J. Knolle, and R. H. Rupp, Angew. Chem., Int. Ed. Engl., 1980,19,819 (Chem. Abstr., 1981,94,30 466). I. Hasan, E. R. Marinelli, L.-C. C. Lin, F. W. Fowler, and A. B. Levy, J. Org. Chem., 1981,46, 157 (Chem. Abstr., 1981,94,47 067). K. M. Smith, G. W. Craig, F. Eivazi, and Z . Martynenko, Synthesis, 1980,493 (Chem. Abstr., 1980,93,186 075).

Five-Membered Rings: Other systems

171

1ndoles.-Formation. The preparation of the acids (182),labelled with 14C at C,, at C,, and at both C, and C,, has been described.203Fischer indolization of the 2-ethyld-methylphenylhydrazone of cyclohexanone gives, after dehydrogenation, the carbazole (183), which arises by a [1,5] shift of either the methyl or the ethyl group, followed by [1,2] migration of the latter.2" Polyphosphoric acid converts N- ( p -bromophenacyl)-3,5-dimethoxyanilineinto a mixture of 2and 3-( p-bromophenyl)-3,4-dimethoxyindoles.205The reaction of fluorophenacyl-pyridinium salts (184) with analine yields 2-(fluorophenyl)ind01es.~~~ N-Allyl-2-bromoaniline cyclizes to 3-methylindole under palladium(0) Irradiation of the enamine ketone PhMeNCMe=CHCOMe affords 2-acetyl-1,2-dimethylindole(185).208The chloromaleimide (186) reacts with sodium azide at room temperature to yield the indole (187).209The N-hydroxyindole (188) is produced by the action of t-butyl isocyanide on the nitro-olefin PhCH=CMeN02.21"

a H

QQ -E H

(187) 197

198

199

2oo

201

'O'

203 204

2os

207

'08 '09

*lo

(188)

M. T. Giardi and G. Sleiter, Garz. Chim. Ital., 1980,110,361 (Chem. Abstr., 1981,94,30463). T.Tanaka, T. Oba, N. Okamura, K. Watanabe, S. Kurozumi, and T. Naruchi, Synth. Commun., 1980,10,773 (Chem. Abstr., 1981,94,139 537). W.E.Noland, K. J. Kim, C. K. Lee, S. K. Bae, and C. S . Hahn, J. Org. Chem., 1980,45,4582 (Chem. Abstr., 1980,93,239141). H. 0.Hankovszky, K. Hideg, and L. Lex, Synthesis, 1980,914(Chem. Abstr., 1981,94,121218). B. P. Wijnberg and W. N. Speckamp, Tetrahedron Lett., 1980,21,1987 (Chem. Abstr., 1981,94, 65 435). H. E. Schoemaker, T. Boer-Terpstra, J. Dijkink, and W. N. Speckamp, Tetrahedron, 1980,36, 143 (Chem. Abstr., 1980,93,168049). P. M.M. Nossin and W. N. Speckamp, Tetrahedron Lett., 1980,21, 1991 (Chem. Abstr., 1981, 94,103 125). K . V. Viswanathan and T. V. Ramamurthy, J. Labelled Compd. Radiopharm., 1980,17,727. B. Miller and E. R. Matjeka, J. A m . Chem. SOC.,1980,102,4772. D.St. C. Black, B. M. K. C. Gatehouse, F. Theobald, and L. C. H. Wong, Aust. J. Chem., 1980, 33,343. R. K.Bansal and G. Bhagchandani, Indian J. Chem., Sect. B, 1980,19,801. R. Odle, B. Blevins, M. Ratcliff, and L. S . Hegedus, J. Org. Chem., 1980,45,2709. D.Watson and D. R. Dillin, Tetrahedron Lett., 1980,21,3969. M.Augustin, M. Kohler, J. Faust, and M. M. Al-Holly. Tetrahedron, 1980,36,1801. H.Person, M. Del Aguila Pardo, and A. Foucaud, Tetrahedron Lett., 1980,21,281.

172

Heterocyclic Chemistry

P-Nitrostyrene cyclizes to the oxindole (189; R' = H, R2 = C1) on treatment with acetyl chloride and iron(II1) chloride.21' Oxindoles (189; R', R2 = H or alkyl) are produced by irradiating the lithium salts of acyl-o-chloroanilines o-ClC6H4NR'COCH2R2.2'2 The action of potassium hydroxide on oazidoisobutyrophenone, o-N3C6H4COCHMe2,leads to the indoxyl ( 190).213 +

Diphenylketen adds to the nitrone, Ph2C=NPh-O- to yield the oxindole (191); in contrast, the fluorenylidene-nitrone (192)forms the oxazolidinone (193) with di~henylketen.~'~ The oxindole (195) is produced by the action of copper(1) iodide and sodium hydride on the amide (194).2'5

do R'

(189)

,CPh2 OCCHPh,

It 0 (191)

&Me.

2FPh (190)

\

0-

(193)

Irradiation of the enamine PhNHC(C02Me)=CH2 yields the indoline (196).'16 The complex isocyanide (197) cyclizes to the indoline (198) in the

'*' J. Guillaumel, P. Demerseman, J. M. Clavel, R. Royer, N. Platzer, and C. Brevard, Tetrahedron, 1980,36,2459. ''' J. F. Wolfe, M. C. Sleevi, and R. R. Goehring, J. Am. Chem. SOC.,1980, 102, 3646. '13 '14

'I5 'I6

M. A . Ardakani and R. K. Smalley, Tetrahedron Lett., 1979,4769. M. Hafiz and G. A . Taylor, J. Chem. Soc., Perkin Trans. I , 1980, 1700. T. Kametani, T. Ohsawa, and M. Ihara, Heterocycles, 1980,14, 277; J. Chem. Soc., Perkin Trans. 1, 1981, 290. A . G. Schultz and C.-K. Sha, Tetrahedron, 1980, 36, 1757.

Five-Membered Rings: Other systems

173

presence of Lewis acid^.^" Thermoylsis of aryl o-azidobenzoates (199; R = H, Me, C1, Br, or C02Et) yield carbazoles (200) by way of the spiro-intermediates 0

Reactions of Indoles. Tetrabutylammoniurn borohydride reduces indoles to ind01ines.~~’ 2-Lithio-1-methylindole reacts successively with triethylborane and methyl iodide to yield 2-ethyl-1,3-dimethylindole via the salt (201).220 Trifluoroacetic anhydride reacts with 2,3-dimethylindole to give the methyleneindoline (202);221with 1,2,3-trimethylindole, compound (203) is obtained.222 Me m ‘

B

E N

Me

t

3

Lj+

@CH2 ‘ N

COCF, @CH2COCF3 \ N

COCF,

Me

Bromine converts 2,3-dimethylindole into the 3H-indole derivative (204), which .~~~ reacts with caris stable in the presence of t r i e t h ~ l a m i n e N-Benzoylindole boxylic acids RC02H (R = Me, Ph, or PhCH,) in the presence of N-iodosuccinimide to afford the trans-indolines (205).224Acetone condenses with indole under the influence of boron trifluoride to furnish a number of products, which include (206) and (207).2253-Acetoxy-1 -methylindole is converted into the

Q)5c:2cr? COPh (205)

’” Y. Ito, K. Kobayashi, N. Seko, M. Maeno, and T. Saegusa, Fukusokan Kagaku Toronkai Koen ’I9 220

221

’” 223 224

Yoshishu, 12th, 1979, 116 (Chem. Abstr., 1980,93,71456). M. G. Clancy, M. M. Hesabi, and 0. Meth-Cohn, J. Chem. SOC.,Chem. Commun., 1980, 1112. T. Wakamatsu, H. Inaki, A. Ogawa, M. Watanabe, and Y. Ban, Heterocycles, 1980, 14, 1441. A. B. Levy, Tetrahedron Lett., 1979, 4021. S. Clementi, G. Marino, G. Savelli, andP. Linda, J. Chem. SOC., Chem. Commun., 1980, 794. A. S. Bailey, J. B. Haxby, A. N. Hilton, J. M. Peach, and M. H. Vandrevala, J. Chem. Soc., Perkin Trans. 1, 1981, 382. G. I. Dmitrienko, E. A. Gross, and S. F. Vice, Can. J. Chem., 1980, 58, 808. S . Kwon and N. Kuroki, Chem. Lett., 1980, 237.

He te roc y c Zic Chern istry

174

tri-indolobenzene (208) in boiling trifluoroacetic acid.226The azabenzofulvenes (209; R2N = Me2N, Et2N, or pyrrolidino), obtained from indole-3-aldehyde and the appropriate amine, are stable, whereas the piperidino- and morpholinoderivatives dimerize readily.227

The stereochemistry of the reduction of the nitroxide radicals (210; R = Me, Et, or Ph) by sodium borohydride to the hydroxylamine compounds (211) has been examined.228Isatins (212; R = H or MeO) react with phenacyl bromide and alkali to yield the carboxylic acids (213).229 The spiro-indoline (215) results from the action of chlorobenzene-p-sulphonyl azide on the P-carboline (214).230

I 0'

(210)

OH (211)

NO,SC,H,Cl-p

Me

225

J. Banerji, A. Chatterjee, S. Manna, C . Pascard, T. Prange, and J. N. Shoolery, Heterocycles,

1981, 15, 325; J. Chem. Sac., Perkin Trans. 1, 1980, 553. J. Bergman and N. Eklund, Tetrahedron, 1980, 36, 1445. 227 T. Moriya, K. Hagio, and N. Yoneda, Chem. Pharm. Bull., 1980,28, 1711. "* C. Berti, L. Greci, and M. Poloni, J. Chem. SOC.,Perkin Trans. 2, 1980, 710. 229 G. I. Zhungietu, V. I. Gorgos, M. A. Rekhter, and A. I. Korpan, Izv. Akad. Nauk Mold. SSR, Ser. Biol. Khim. Nauk, 1980, 61 (Chem. Abstr., 1980, 93, 239 138); D. St. C. Black and L. C . H. Wong, J. Chem. SOC.,Chem. Commun., 1980,100. 230 A. S. Bailey and M. H. Vandraleva, J. Chem. SOC., Perkin Trans. 1, 1980, 1512. 226

175

Five-Membered Rings: Other systems

Indolines are dehydrogenated to indoles by catalytic amounts of bis(salicy1idene)ethylenediaminatocobalt(~~).~~~ Treatment of the azo-compound (216) with zinc and acetic anhydride affords the rearranged diamino-derivative (217), which is oxidized to the quinone imine (218) by copper(I1) The PhN2

0

AcNH C0,Et

Meo&Me \

4

PhNH

Me

NPh

N-acetylindolinone (219) undergoes ring-opening and re-cyclization in aqueous acetic acid to yield the hexahydrofuranofuranone (220).233The hydroperoxide (221) undergoes an unusual reaction in methanol in the presence of bases to give the 6-methyoxyindole (222).234Photochemical ring-closure of the indole (223) results in a mixture of the tricyclic compounds (224) and (225).235 One-electron photo-oxidation of carbazole in ethanol-carbon tetrachloride G

Z Me2 O

P

&

Ph

h

- - P I

\

N

Ac

\

-

NHAc (220)

(219)

__*

qo+E L

N

H

CH2CH2NHCOCH2Cl (223)

(224)

O

N H (225)

231 232

233 234 235

A . Inada, Y. Nakamura, and Y.&lorita, Chem. Lett., 1980, 1287. G.N. Kurilo, N. I. Rostova, A . A. Cherkasova, K. F. Turchin, L. M. Alekseeva, and A . N. Grinev, Khim. Geterotsikl. Soedin., 1980, 1374. G. Tacconi, L. D. Maggi, F. A . Marinone, P. Righetti, and R. Oberti, J. Chem. Res. ( S ) , 1980,22. C.Amsterdamsky and J. Rigaudy, Tetrahedron Lett., 1980,21,3187. S . Naruto and 0. Yonemitsu, Chem. Pharm. Bull., 1980,28,900.

176

Heterocyclic Chemistry

gives ethyl carbazole-1- and - 3 - c a ~ b o x y l a t e s .The ~ ~ ~ cyclobuta-indole (226) rearranges at 270°C to a mixture of the benzazepine (227) and N-benzoyl-lna~hthylamine.~~~

of indoles have Other articles on the f ~ r r n a t i o n ~ ~and * - ~reaction^^^^-*^^ ~~ appeared. 236

237

23s

239 240

241

242

243

244

245 246

247 248

249

2s1

252

2s3

254

255 256

257

258

259

260

26' 262

263

B. Zelent and G. Durocher, J. Org. Chem., 1981,46, 1496. M. Ikeda, T. Uno, K. Ohno, and Y. Tamura, Fukusokan Kagaku Toronkai Koen Yoshishu, 12th, 1979, 201 (Chem. Abstr., 1980,93, 114 241). Y . Watanabe, M. Yamamoto, S. C. Shim, S. Miyanaga, and T. Mitsudo, Chem. Lett., 1980, 603 (Chem. Abstr., 1980,93, 150 077). J. B. Patrick and E. K. Saunders, Tetrahedron Lett., 1979, 4009 (Chem. Abstr., 1980, 93, 26 201). R. K. Bansal and G. Bhagchandani, Bull. Chem. SOC.Jpn., 1980,53, 2423 (Chem.-Abstr., 1981, 94,47 060). M. Natsume and H. Muratake, Fukusokan Kagaku Toronkai Koen Yoshishu, 12th, 1979, 96 (Chem. Abstr., 1980,93,71455). R. Kreher and P. H. Wagner, Chem. Ber., 1980,113, 3675 (Chem. Abstr., 1981, 94, 65 418). J. E. Nordlander, D. B. Catalane, K. D. Kotian, R. M. Stevens, and J. E. Haky, J. Org. Chem., 1981,46,773(Chem. Abstr., 1981,94, 103 112). M. Somei, F. Yamada, and C. Kaneko, Fukusokan Kagaku Toronkai Koen Yoshishu, 12th, 1979, 91 (Chem. Abstr., 1980,93, 26 206). A. Taylor, J. Chem. Res. (S), 1980, 347 (Chem. Abstr., 1981, 94, 30474). J. Iriarte, C. Camargo, and P. CrabbC, J. Chem. SOC.,Perkin Trans. 1, 1980, 2077 (Chem. Abstr., 1980,93,239 085). B. D. Dean and W. E. Truce, J. Org. Chem., 1980, 45, 5429 (Chem. Abstr., 1980, 93, 238 988). D. P. Chakraborty, M. Sarkar, and A. Islam, J. Indian Chem. SOC.,1979,56, 1217 (Chem. Abstr., 1980,93, 71 459). K. Imafuku, M. Sumio, and H. Matsumura, J. Heterocycl. Chem., 1980, 17, 1057 (Chem. Abstr., 1981, 94, 103 309). K. Sakano and S. Nakamura, J. Antibiot., 1980,33, 961 (Chem. Abstr., 1981,94,47 046). H. Iida, Y. Yuasa, and C. Kibayashi, J. Org. Chem., 1980, 45, 2938 (Chem. Abstr., 1980, 93, 71 461). V. V. Mezheritskii, A. L. Pikus, L. G. Minyaeva, and G. N. Dorofeenko, Zh. Org. Khim., 1980, 16, 1958 (Chem. Abstr., 1981,94, 121 225). R. Neidlein and F. Moller, Arch. Pharm. (Weinheim, Ger.), 1980, 313, 971 (Chem. Abstr., 1981, 94, 121 232). N . K. Genkina, V. N. Eraksina, and N. N. Suvorov, Zh. Org. Khim., 1980, 16, 2154 (Chem. Abstr., 1981,94, 65 419). A. P. Kozikowski and H. Ishida, Heterocycles, 1980, 14, 5 5 (Chem. Abstr., 1980, 93, 26 208). D. S. Farlow, M. E. Flaugh, S. D. Horvath, E. R. Lavagnino, and P. Pranc, Org. Prep. Proced. Int., 1981, 13, 39 (Chem. Abstr., 1981, 94, 121 229). J. Bergman, L. Renstroem, and B. Sjoerberg, Tetrahedron, 1980, 36, 2505 (Chem. Abstr., 1981, 94, 156 678). J. C. Halle, F. Terrier, M. J. Pouet, and M. P. Simonnin, J. Chem. Res. (S), 1980, 360 (Chem. Abstr., 1981, 94, 156 677). E. Bisagni, C. Ducrocq, and C. H. Nguyen, Tetrahedron, 1980, 36, 1327 (Chem. Abstr., 1981, 94, 139 545). H. J. Teuber, A. Gholami, and U. Reinehr, Liebigs Ann. Chem., 1981, 152 (Chem. Abstr., 1981, 94, 156 690). W . Grahn, Liebigs Ann. Chem., 1981, 107 (Chem. Abstr., 1981, 94, 156 689). T. V. Stupnikova, L. A. Rybenko, A. N. Kost, R. S. Sagitullin, A. I. Kolodin, and V. P. Marshtupa, Khim. Geterotsikl. Soedin., 1980, 761 (Chem. Abstr., 1980, 93, 186 118). T. V. Stupnikova, B. P. Zemskii, Yu. B. Vysotskii, R. S. Sagitullin, and Kh. Ya. Lopatinskaya, Khim. Geterotsikl. Soedin., 1980, 959 (Chem. Abstr., 1981, 94, 15 512).

177

Five-Membered Rings: Other systems

1soindoIes.-The Diels-Alder adduct (228 ; R1 = C02Bu') of N-t-butoxycarbonylpyrrole to benzyne reacts with 3,6-di-(2-pyridyl)-1,2,4,5-tetrazine(229; R2 = 2-pyridyl) to yield the isoindole (230).27' The purple lithium salt (231), obtained by the action of lithium in liquid ammonia on N-phenylphthalimide,

gives a mixture of compounds (232) and (233) on treatment with 1,3dibr~mopropane.~~' When the nitrile (234) is dissolved in concentrated sulphuric acid, it undergoes demethylation and rearrangement with elimination of ammonia to form the cyclohepta[c]pyrrolone (235).273

"'"0 Me0 \

264

26s 266 267 268 269

270

271 2f2

3'2

CH,NMeCHPhCN

-0

T. V. Stupnikova, V. N. Kalafat, N. A. Klyuev, V. P. Marshtupa, and R. S. Sagitullin, Khim. Geterotsikl. Soedin., 1980, 1360 (Chem. Abstr., 1981,94, 64 937). V. S . Velezheva, Yu. V. Erofeev, and N. N. Suvorov, Zh. Org. Khim., 1980, 16, 2157 (Chem. Abstr., 1981,94,64 827). A. N. Grinev, S. Yu. Ryabova, G. N. Kurilo, and K. F. Turchin, Khim. Geterotsikl. Soedin., 1980, 1068 (Chem. Abstr., 1981,94,30 469). R. Neidlein and F. Moller, Liebigs Ann. Chem., 1980, 971 (Chem. Abstr., 1980, 93, 220 531). T. Moriya, K. Hagio, and N. Yoneda, Synthesis, 1980, 728. A. S. Bailey, M. H. Vandrevala, and J. V. Greenhill, Tetrahedron Lett., 1979,4407 (Chem. Abstr., 1980,93,45 777). C . Berti, L. Greci, M. Poloni, G. D. Andreetti, G. Bocelli, and P. Sgarabotto, J. Chem. SOC., Perkin Trans. 2, 1980, 339 (Chem. Abstr., 1980, 93, 7312). T . Sasaki, T. Manabe, and S. Nishida, J. Org. Chem., 1980, 45,476. G. A. Flynn, J. Chem. SOC.,Chem. Commun., 1980, 862. R. D. Waigh, J. Chem. SOC.,Chem. Commun., 1980,1164.

He te roc y c lic Chemistry

178

N-t-Butylisoindole (229; R' = But) reacts with triethyloxonium fluoroborate to yield the salt (236); coupling with p-nitrobenzenediazonium fluoroborate affords the hydrazone (237).274Isoindoles react with diethyl azocarboxylate to give either 1: 1- or 1 :2-adducts, e.g. (238), depending on the degree of substitution in the benzene ring.275 There are several other r e p ~ r t s * ' ~on - ~derivatives ~~ of isoindole. EtO,C,

/

NNH CO, Et

Et0,C' (238)

Other Systems.-The silacyclopentane (239) undergoes a stereospecific freeradical chlorination to give the dichloride (240).281Treatment of pentaphenylgermole (241) with di-iron enneacarbonyl results in ring-cleavage and the formation of the germanium-iron heterocycle (242).282 The U.V. and mass spectra of Mannicii's arsindole (243)283and the X-ray structure of the tetramethyldistibolyl (244)284have been determined.

'As

Cl

Ph Ph P h n P h Ge

H

274

275 276

277

278 279

280

283 284

/

\

-

Ph

Ph

R. Kreher and G. Use, Angew. Chem., Int. Ed. Engl., 1980,19,320. R. Kreher, D. Schmitt, and K. J. Herd, Tetrahedron Lett., 1980, 21, 3471. S. G. Tadevosyan, E. N. Telerhov, I. V. Vasileva, and A. N. Pravednikov, Zh. Org. Khim., 1980, 16, 353 (Chem. Abstr., 1980, 93, 7209). G . Karlivans, V. Ciekure, and R. Valters, Latv. PSR Zinat. Akad. Vestis, Kim. Ser., 1980, 732 (Chem. Abstr., 1981,94, 138 959). G . Karlivans and R. Valters, Khim. Geterotsikl. Soedin., 1980,335 (Chem. Abstr., 1980,93,70 620). M. Machida, K. Oda, K. Maruyama, Y. Kubo, and Y. Kanaoka, Heterocycles, 1980, 14, 779 (Chem. Abstr., 1980, 93, 3432). T. Sasaki, T. Manabe. and E. Wakabayashi, Tetrahedron, 1980, 36, 2119 (Chem. Abstr., 1981, 94, 103 101). P. R. Wells and F. P. Franke, Tetrahedron Lett., 1979,481. M. D. Curtis, W. M. Butler, and J. Scibelli, J. Organomet. Chem., 1980, 192, 209. D. W. Allen, J. Heterocycl. Chem., 1980,17, 1341. A. J. Ashe, 111, W. Butler, andT. R. Diephouse, J. A m . Chem., SOC.,1981, 103, 207.

179

Five-Membered Rings: Other systems 4 Systems containing Two Identical Heteroatoms

Dioxo1es.-Irradiation of the peroxide (245) yields pinacolone and minor amounts of tetramethyloxiran (246).285Oxygenation of a mixture of thiophenol and octa-l,3,6-triene in the presence of a free-radical initiator yields the peroxide (247) regio- and stereo-specifically.286Ethyl diazopyruvate (N2CHCOC02Et) reacts with acetone+under copper catalysis to afford the dioxole (248) by way of the 1,3-dipole HC=C(C0,Et)-O-.287 Dioxolenium fluoroborates (249) are produced by the action of acylium salts ArCH2CO+BF4-on 2,3-dimethylbutane1,3-di01.~"Dichlorocarbene, generated by phase-transfer catalysis, undergoes insertion into the dioxolan (250; R = H) to yield (250; R = CHC12).289 The mechanism of the transformation of the cyclic carbonates (251; R = Me, Ph, or C02Me)into benzene derivatives (252) has been in~estigated.~~' Other relevant articles291-296 should be noted. Me

/

(245)

285

286

288

289

291 292

293

294 295

*%

W. Adam, 0. Cueto, and L. N. Guedes, J. A m . Chem. SOC.,1980,102,2106. A . L. J. Beckwith and R. D. Wagner, J. Chem. SOC.,Chem. Commun., 1980,485. M. E. Alonso and P. Jano, J. Heterocycl. Chem., 1980,17,721. L. V. Mezheritskaya, E. S. Matskovskaya, and G. N. Dorofeenko, Zh. Org. Khim., 1980,16, 183. K. Steinbeck and J. Klein, J. Chem. Res. (S),1980, 94; K. Steinbeck, ibid., p. 95. E. A. Harrison, Jr., Heterocycles, 1980, 14, 51. A. J. Bloodworth and J. A. Khan, J. Chcm. Soc., Perkin Trans. 1. 1980, 2450 (Chem. Abstr., 1981,94, 139 663). R. P. Houghton and A . D . Morgan, J. Chem. SOC.,Perkin Trans. 1, 1980, 756 (Chem. Abstr., 1980,93, 113 888). E. R. Cole, G. Crank, and H. T. H. Minh, Aust. J. Chem., 1980, 33, 675 (Chem. Abstr,, 1980, 93, 186 217). N. Latif, I. Zeid, and R. El-Masry, Egypt. J. Chem., 1980,20,617 (Chem. Absfr., 1981,94,65 508). E. R. Cole, G. Crank, and H. T. H. Minh, Ausf. J. Chem., 1980, 33, 527 (Chem. Abstr., 1980, 93, 186 216). W. Ott, C. Kratky, and P. Seiler, Liebigs Ann. Chem., 1980,1711 (Chem. Abstr., 1981,94,103 212).

180

Heterocyclic Chemistry

Dithioles and Related System.-The dimethylaminothiolate (253; R = Me2N) forms the 1,2-dithiole-3-thione (254) on treatment with carbon disulphide, whereas the analogous reaction of the methoxy-derivative (253; R = MeO) yields the spiro(dithio1e) (255).297The diselenolone (256) is produced by the action of sodium hydrogen selenide on diphenylcycl~propenone.~~~ The imines (257) are converted into the dithiolodithioles (258) in ~ y r i d i n eOther . ~ ~ ~remarkable transformations of the 1,2-dithiole system are exemplified by the photochemical reaction of the thione (259; R = Me) with cyclopentadiene to yield the 1,3-dithiolan (260)300and with diphenylacetylene to give the trithiapentalene (261),301by the oxidative rearrangement of the dithiolium salt (262) to the thienothiapyran (263),302and by the conversion of the diphenyldithiolethione

(254)

AcS

NCOAr

CN

s

ArCN II 0

z NCOAr

(257)

(258)

Me P

Ph

h m P S' 'S

h

Ph

(263)

(242)

(259; R = Ph) into the 1,3-dithiole (264) in the reaction with the ynamine Et2NC=CMe.303 The dilithioacenaphthylene (265) reacts with elemental sulphur, selenium, or tellurium to form the corresponding heterocycles (266; X = S, Se, or Te).304 297 298 299

300

301

302 303 304

N. A. Bunina, M. L. Petrov, and A. A. Petrov, Zh. Org. Khim., 1980, 16, 13. M. Takahashi, S. Watanabe, and T. Kasai, Heterocycles, 1980, 14, 1921. H. U. Kibbel, J . Teller, P. Hansen, and A. Reiter, J. Prukt. Chem., 1980, 322, 769. V. N. Drozd, Yu. M. Udachin, V. V. Sergeichuk, and G. S. Bogomolova, Zh. Org. Khim., 1980, 16,443. V. N. Drozd, Yu. M. Udachin, G. S. Bogomolova, and V. V. Sergeichuk, Zh. Org. Khim., 1980; 16, 883.

J. P.Sauve and N. Lozach, Bull. SOC.Chim. Fr., Part2, 1980, 577. A. Dibo, M. Stavaux, and N. Lozach, Bull. Soc. Chim. Fr., PartZ, 1980, 530. L.-Y. Chiang and J. Meinwald, Tetrahedron Lett., 1980, 21, 4565.

181

Five-Membered Rings: Other systems Ph

\C-PhC=(

S

4

s

S

3 NEt2

Li

Li

(264)

(265)

x-x (266)

The reaction of benzoyl isothiocyanate with the carbene :C(CO,Et),, generated from diethyl diazomalonate or diethyl bromomalonate, yields the 1,3dithiole-imine (267), or the oxathiole (268), or the oxazole (269), depending on The dithiolanone (270) results from the action of iodine on ally1 ethcyl xanthate, H2C=CHCH2SC(S)OEt.306Treatment of the sulphones RS02CH=CC12 (R = alkyl or Ph) with potassium ethyl xanthate affords the 1,4-dithiafulvenes (271)as mixtures of geometrical Dimethyl acetylenedicarboxylate adds to benzyl dithiobenzoate to yield the rearranged product (272);3"8the dithiolan (273) is formed from dithioacetic acid and the enyne H,C=CM~CECH.~~~

IH,C

RSOz

(273)

(272)

Photo-oxygenation of the meso-ionic dithiolium oxide (274) in methanol affords dibenzoyl disulphide and methyl benzoylformate by fragmentation of the initial cyclo-adduct (275).310Treatment of the dithiolium salts (276; R = Me Ph

Ph

(274) 305

'07

308

309 310

(275)

L. Capuano, M. Bronder, W. Hell, P. Morsdorf, and R. Hoge, Monatsh. Chem., 1980, 111, 899. N. F. Haley and M. W. Fichtner, J. Org. Chem., 1980,45, 2959.

A. N. Mirskova, G . G. Levkovskaya, A. V. Martynov, I. D . Kalikhman, and M. G. Voronkov, Izv. Akad. NaukSSSR, Ser. Khim., 1980,368. V. N. Drozd and 0. A. Popova, Zh. Org. Khim., 1980,16,2047. G. Levesque and A. Mahjoub, Tetrahedron Lett., 1980, 21, 2247. H:Gotthardt, 0. M. HUSS,and S. Schoy-Tribbensee, Chem. Ber., 1981, 114, 285; H. Kato, K. Tani, H. Kurumisawa, and Y. Tamura, Chem. Lett., 1980,717.

Heterocyclic Chemistry

182

or Ph) with bases produces carbenes (277), which react with benzaldehyde in sifu to afford the dimeric products (278).311The hydroxycyclopentaphenalenone (279) condenses with 2-methylthio-1,3-dithiolium iodide to yield the dithiafulvene (280).312The X-ray structure of the cyclohexanetrione derivative (28 1) has been The salts (282; R = H or Me, m = 2 or 6, n = 2, 3, or 4) exhibit semiconducting b e h a v i o ~ r . ~ ~ ~

ox

@ \ /

0

0

0

(282)

The trithiocarbonate (283) cyclizes to the benzodithiolone (284) in hot acetic The ortho-thioquinone methide (286) is obtained by the action of 1,2-di(methylamino)ethaneon 1,3-benzodithiole-2-thione(285).316The reaction of 1,3-benzodithiolium fluoroborate with indole yields the salt (287), which affords the azabenzofulvene (288) on d e p r o f o n a t i ~ n2-Azidobenzodithioles .~~~

*0

2

N

a

s

>

S0

CF, (2i(4)

NEt3

NH

BF4(287) 311 312

313

314 315 316

317

D. Buza and W. Gradowska, Pol. J. Chem., 1980,54,717. R. Neidlein and R. Gartner, Chem.-Ztg., 1980, 104, 304. M. Kimura, W. H. Watson, and J. Nakayama, J. Org. Chem., 1980, 45, 3719. Y. Yumoto, R. Nishioka, and T. Tanaka, Bull. Chem. SOC.Jpn., 1980, 53, 1247. K. Rasheed and J. D. Warkentin, J. Org. Chem., 1980,45,4041. K.-T. Kang, R. Okazaki, and N. Inamoto, Bull. Chem. SOC. Jpn., 1979, 52, 3640. J. Nakayama, M. Imura, and M. Hoshino, Bull. Chem. SOC. Jpn., 1980, 53, 1661.

Five-Membered Rings: Other systems

183

(289; R = H or Ph) undergo thermal ring-expansion to the 1,4,2-benzodithiazines (290).3 l8

(289)

(290)-

Other work on dithioles will be found in references 319-327. Tetrathiafulvalenes and Related Compounds.-The simplest synthesis of a tetrathiafulvalene derivative yet reported is that of compound (291; R’ = R2 = C02Me) by the reaction of dimethyl acetylenedicarboxylate with carbon disulphide under high pressure.328Tetrathiafulvalenes (291; R’ = R2 = H, Me, Ph, or C02Me) are obtained from the corresponding dithiolethiones (292) by irradia t i ~ n or ~ ~under ’ the influence of dicobalt o ~ t a c a r b o n y land , ~ ~by ~ dimerization of the carbenes (277).331 The di(decylpheny1)-derivative (291; R’ = R2 = H), which is obtained by reductive coupling of 4-(pdecylphenyl)l,3-dithiol-2-one with triethyl phosphite, shows a transition to a smectic phase at 102 “C; the butyl analogue (291; R’ = p-BuC6H4, R2 = H) becomes nematic at 134 0C.332The action of trimethyl phosphite on a mixture of 4,5-dicyano-1,3-dithiol-2-oneand the dithiolodithiole (293) leads to the tetracyclic compound (294).333The synthesis of the tetrathiafulvalene analogue

Y

(294) ’I8

’I9 320

321 322

”’ 324

325 326

”’ ”*

329

330

331 332

333

J. Nakayama, M. Ochiai, K. Kawada, and M. Hoshino, J. Chem. SOC.,Perkin Trans. 1, 1981,618. T. P. Vasileva, M. G. Linkova, 0. V. Kildisheva, and I. L. Knunyants, Izu. Akad. Nauk SSSR, Ser. Khim., 1980, 2111 (Chem. Abstr., 1981, 94, 65 510). T. P. Vasileva, M. G. Linkova, 0. V. Kildisheva, and I. L. Knunyants, Izu. Akad. Nauk SSSR, Ser. Khim., 1980,2108 (Chem. Abstr., 1981,94,65 509). S . Tamagaki, K. Hotta, and S . Kozuka, Chem. Lett., 1980,619 (Chem. Abstr., 1980,93,204 506). J. Nakayama, K. Fujiwara, and M. Hoshino, J. Org. Chem., 1980, 45, 2024 (Chem. Abstr., 1980, 93,8661). V. N. Drozd and 0. A. Popova, Zh. Org. Khim., 1980,16,2616 (Chem.Abstr., 1981,94,156 794). V. A. Lokshin, N. S. Trofimova, N. A. Voloshin, Yu. V. Revinskii, N. E. Shelepin, Kh. A. Kurdanov, and V. I. Minkin, Khim. Geterotsikl. Soedin., 1980,47 (Chem. Abstr., 1980, 93, 8059). J. Nakayama, T. Takemasa, and M. Hoshino, Bull. Chem. SOC.Jpn., 1980,53,2281 (Chem. Abstr., 1981,94,47 190). S. R. Wilson, G. M. Georgiadis, H. N. Khatri, and J. E. Bartmess, J. A m . Chem. SOC.,1980, 102, 3577 (Chem. Abstr., 1980,93,95 161). G. A. Olah, S. S. Narang, and G. F. Salem, Synthesis, 1980,659 (Chem. Absk., 1981,94,65 261). J. E. Rice and Y. Okamoto, J. Org. Chem., 1981,46,446. S . Yamada, N. Mino, K. Tsujimoto, and M. Ohashi, Kokagaku Toronkai Koen Yoshishu, 1979, 166 (Chem. Abstr., 1980, 93, 45 536). G. LeCoustumer and Y. Mollier, J. Chem. SOC.,Chem. Commun., 1980, 38. D. Buza and W. Gradowska, Pol. J. Chem., 1980,54,145. U . T. Miiller-Westerhoff, A. Nazzal, R. J. Cox, and A. M. Giroud, J. Chem. SOC.,Chem. Commun., 1980,497. R. R. Shumaker and E. M. Engler, J. A m . Chem. SOC.,1980,102,6651.

Heterocyclic Chemistry

184

(295) from 2,7-dibromo-1,6-methano[ 101annulene and toluene-3,4-dithiol has been described.334

M e G C + f j + s B -

s

’

Me

(295)

syn-Diselenadithiafulvalene (296) and the anti-isomer have been obtained as an inseparable Reductive coupling of+the diselenoleselone (297; X = Se)336or the immonium salt (297; X = Me2N)337yields the tetraselenafulvalene (298).

Pyrazoles.-Formation. l-Phenyl-2-(phenylazo)acetylene reacts with the enamine PhSCH=CHNMe2 to yield the pyrazole (300) via the intermediate (299).338Thermolysis of the azine (F3C)2C=N-N=C(CF3)2 in the presence of phenylacetylene and tetrahydrofuran results in compound (301).399 The diazomethane derivative Me,As(Me,Sn)CN, adds to dimethyl acetylenedicarboxylate to give the pyrazole (302) by a ‘metallotropic’ shift of the trimethylstannyl group from carbon to Perfluoro-2-methylpent-2-ene and 1,l-dimethylhydrazine form the zwitterion (303).341

(299)

(301)

The formation of a 7.4: 1 mixture of 3- and 4-methylpyrazolines in the cycloaddition of diazomethane to propene is claimed342to support a diradical 334

335 336

337 338 339 14n

341 342

R. Neidlein and H. Zeiner, Angew. Chem., Znt. Ed. Engl., 1980, 19, 204. M. V. Lakshmikantham and M. P. Cava, J. Org. Chem., 1980,45, 2632. L. Y . Chiang, T. 0. Poehler, A. N. Bloch, and D. 0 . Cowan, J. Chem. SOC.,Chem. Commun., 1980,866. F. Wudl and D. Nalewajek, J. Chem. SOC.,Chem. Commun., 1980, 866. T. Agawa, M. Ishikawa, M. Komatsu, and Y. Ohshiro, Chem. Lett., 1980,335. K . Burger and C. Zettl, Chem.-Ztg., 1980, 104, 71. M. Birkhahn, R. Hohlfeld, W. Massa, R. Schmidt, and J. Lorberth, J. Orgunomet. Chem., 1980, 192,47. I. Ikeda, T. Tsukamoto, and N. Okahara, Chem. Lett., 1980,583. R. A. Firestone, Tetrahedron Lett., 1980, 21, 2209.

Five-Membered Rings: Other systems

185

mechanism for the reaction. The diazo-alkenes (304; R = Me or Ph) undergo a stereospecific intramolecular cycloaddition to yield the aziridinopyrazolines (305);343o-allylphenyldiazomethane forms compound (306) in this type of reaction.344 Me0,C

AsMe,

Me02C)\NN I

N

Me, (303)

d H

R*

H

R YR

H

Ph/?

&

H H

P

h N’d

Rearrangement of the toluene-p-sulphonylhydrazonesof 1-acyl-oxirans (307 ; R = Et or Ph) yields the hydroxy-pyrazolines (308) as mixtures of Treatment of acetophenone phenylhydrazone with lithium di-isopropylamide produces the dilithio-derivative LiCH2PhC=N-NPhLi, which reacts with diethyl carbonate to furnish the pyrazolinone (309).346The 3H-pyrazole N-oxide (310) is formed from the dioxime HON=CPhCMe2CPh=NOH under the conditions of the Beckmann rear~angernent.~~’ HO

R

MR e F N N (307)

oc? N Ph (309)

N I 0(310)

Reactions of Pyruzoles. Nitration of 4,5-dibromo-1,3-dimethylpyrazole(311; R’ = RZ = Br) gives a mixture of the bromonitropyrazole (311; R’ = Br, R2 = NO,) and the debrominated compound (311; R’ = H,R2 = N02).348Oxidative coupling of the dilithio-derivative (312) of p-phenylenedipyrazole leads to compound (313), in which the benzene rings are rigidly held face-to-face, causing an upfield shift of the aromatic The chromium-nitrogen-platinum 343

344 34s

346 347 348

349

A. Padwa and A. Rodriguez, Tetrahedron Lett., 1981, 22, 187; T. Miyashi, Y. Fujii, Y. Nishizawa, and T. Mukai, J. Am. Chem. SOC.,1981,103,725. A . Padwa and H. Ku, J. Org. Chem., 1980,453756. W. H. Pirkle and D. J. Hoover, J. Org. Chem., 1980, 45, 3407. J. D. Wilson, T. D . Fulmer, L. P. Dasher, and C. F. Beam, J. Heterocycl. Chem., 1980,17, 389.

H. Gnichtel and U. Bohringer, Chem. Ber., 1980,113, 1507. M. A. Andreeva, M. I. Bolotov, Sh. G. Isaev, V. P. Perevalov, and B. I. Stepanov, Khim. Geterotsikl. Soedin., 1980, 1561. H. Lexy and T. Kauffmann, Chern. Ber., 1980,113,2749,2755.

186

Heterocyclic Chemistry

Li P

M

N

N-N

N'

N-N

heterocycle (315) is prepared by irradiating a mixture of the complex (314) and chromium h e x a c a r b ~ n y lSeveral . ~ ~ ~ interesting ring-expansions of pyrazoles have been described. The formation of 1,2,3-triazines (317; R1,R2,R3= H or Me) by the action of lead tetra-acetate on N-amino-pyrazoles (316) is especially others are the base-induced rearrangements (318)+ (319),352 (320) + (321),3s3and (322) --+(323).354

ph(-j;' N CH ,Ph (318)

Me c ? P h

___* NaNH,

Ph

-A

N

H Na+

(319)

3,5-Diphenyl-4H-pyrazol-4-one (324) forms the endu-[2 + 4]-cyclo-adducts (325 ; X = NC02Et or 0) with N-ethoxycarbonylazepine or oxepin, respect i ~ e l y . ~ "The 3H-pyrazole (326) undergoes acid-catalysed [ 1,5] sigmatropic 350

351 352 353

354 355

S. R. Stobart, K. R. Dixon, D. T. Eadie, J. L. Atwood, and M. D . Zaworotko, Angew. Chem., Int. Ed. Engl., 1980, 19, 931. A. Ohsawa, H. Arai, H. Ohnishi, and H. Igeta, J. Chem. SOC., Chem. Commun., 1980, 1182. B. A. Tertov and Yu. G. Bogachev, Khim. Geterotsikl. Soedin., 1981, 119. K. Burger, F. Hein, and G. Jannitsopoulos, Chem. Ber., 1980, 113, 3396. T. Ueda, N. Oda, and I. Ito, Chem. Pharm. Bull., 1980, 28, 2144. K. Harano, M. Yasuda, T. Ban, and K. Kanematsu, J. Org. Chem., 1980, 45, 4455; T. Ban and K. Kanematsu, Heterocycles, 1981, 15, 373.

Five-Membered Rings:Other systems

187

rearrangement to give a mixture of the pyrazoles (327) and (328).3s6The pyrazoline (329) forms stable diazonium The reversible photochemical conversion of the azomethine imines (330) into diaziridinopyrazolidinones (331) has been The generation of (1,3-diradicals from A'-pyrazolines continues to attract interest: photolysis of the diphenyl-derivative (332) yields a mixture of cis- and truns-1,2-diphenylcyclopropane (333) uiu 1,3-diphenylpr0pane-1,3-diyl;~'~ the triplet biradical(335), obtained from the bicyclic azo-compound (334), has been trapped as the peroxide (336);360the tetracyclic pyrazoline (337) forms mainly the condensed cyclopropane (338) on irradiati01-1;~~' and the ketone (339) decomposes above 400 "C to tetramethylcyclop r ~ p a n o n e The .~~~ spiro-3H-pyrazole (340) reacts differently, depending on

\--

(337) 356

357 358

359

360 361 362

-,

(338)

(339)

P. Schiess and H. Stalder, Tetrahedron Lett., 1980, 21, 1413, 1417. M. V. Gorelik, S. P. Titova, and V. I. Rybinov, Zh. Org. Khim., 1980, 16, 1322. G. Tomaschewski, G. Geissler, and G. Schauer, J. Prakt. Chem., 1980, 322,623. M. P. Schneider, H. Bippi, H. Rau, D. Ufermann, and M. Hormann, J. Chem. SOC., Chem., Commun., 1980,957. R. M. Wilson and J. W. Rekers, J. A m . Chem. SOC., 1981,103,206. W. Adam and 0. De Lucchi, J. Am. Chem. SOC.,1980,102,2109. W. Adam, A. Fuss, F. P. Mazenod, and H. Quast, J. A m . Chem. SOC., 1981,103,998.

He teroc y cEic Chemistry 188 the polarity of the solvent: warming in benzene produces the cyclopropene (341), while rearrangement to a phenanthropyrazole (342) is observed if it is in a ~ e t o n i t r i l eThe . ~ ~ ~thermal rearrangement of the complex cyclopropane (343) to the furanopyrazole (344) has been reported.364

(340)

(342)

(E

=

C02Me)

F-yPh

N-NPh

(343)

(344)

Other articles on the f ~ r m a t i o n ~ ~ ' -and ~~' appeared.

of pyrazoles have

Indazoles.-2-Phenylindazolin-3 -one (346) is formed by the action of sodium or by heating the anilinobenzohydride on N- (o-a~idobenzoyl)aniline~~~ 363 364

365 366

367 368

369

370

371

372

373

374

375

376

S. Makata and M. Tashiro, J. Org. Chem., 1981, 46, 1929. G. Mann, L. Hennig, H. Wilde, S. Hauptmann, S. Behrendt, and M. Kretschmer, Tetrahedron Lett., 1979,4645. H. Abdallah and R. Gree, Tetrahedron Lett., 1980, 21, 2239 (Chem. Abstr., 1980, 93, 204 529). G . Saito, R. Onoda, and N. Abe, Akita Daigaku Kyoikugakubu Kenkyu Kiyo, Shizen Kagaku, 1980,15 (Chem. Abstr., 1981,94,103 232). T. Sasaki, S. Eguchi, and Y .Tanaka, Tetrahedron, 1980,36,1565 (Chem.Abstr., 1980,93,239 306). V. G . Yusupov, S. I. Yakimovich, S. D. Nasirdinov, and N. A. Parpiev, Zh. Org. Khim., 1980, 16,415 (Chem. Abstr., 1980,93, 26 335). V. K. Upadhyay and S. K. Wadhwa, Agra Uniu. J. Res., Sci., 1978, 27,'77 (Chem. Abstr., 1980, 93, 26 334). J. Knabe and W. Wunn, Arch. Pharm. (Weinheim, Ger.), 1980, 313, 577 (Chem. Abstr., 1981, 94, 3960). T. Axenrod, P. Mangiaracina, C. M. Watnick, M. J. Wieder, and S. Bulusu, Org. Magn. Reson., 1980,13, 197 (Chem. Abstr., 1980,93, 70 321). B. Cross, R. L. Arotin, and C. F. Ruopp, J. Heterocycl. Chem., 1980, 17, 905 (Chem. Abstr., 1981, 94,65 537). A. Steigel and R. Fey, Chem. Ber., 1980, 113, 3910 (Chem. Abstr., 1981, 94, 121 397). R. K. Huff and E. G. Savins, J. Chem. SOC., Chem. Commun., 1980, 742 (Chem. Abstr., 1981, 94, 15 674). A . L. Baumstark, D. R. Chrisope, and M. E. Landis, J. Org. Chem., 1981, 46, 1964 (Chem.Abstr., 1981, 94, 208 764). E. D. Laganis and D. M. Lemal, J. A m . Chem. SOC.,1980, 102, 6634 (Chem. Abstr., 1981, 94,

30 628). 377

M. A . Ardakani and R. K. Smalley, Tetrahedron Lett., 1979, 4765.

Five-Membered Rings: Other systems 189 triazinone (345).378The spiro-indazole (347) yields the hydroxyfluoranthene (348) on thermolysi~.~’~

(345)

p -

(347)

For other papers, see references 380-383. +

1midazoles.-Formation. Treatment of the nitrone ArCH=NMe -0- (Ar = p-tolyl) with potassium cyanide gives the imidazole (350) via the cyano-imine (349).384X-Ray crystallography has shown that the product of the reaction of NN’-dimethylurea with diacetyl is (351)385and that the action of phenyl isocyanate on bis(dimethylamino)acetonitrile, (Me2N)2CHCN,yields the imidazolidinedione (352).386 Isothioureas PhNHC(SR’)=NH (R’ = alkyl) are converted into trans-imidazolines+ (353) on treatment with the ~’ dimorpholinium salt R2,k=CHCH=NR2’ 2Br- (NR22= m ~ r p h o l i n o ) . ~The enamine PhCMe=CHNC4H80 reacts with N-chloro-N’-aroyl-amidines PhC(NHCOAr)=NCl to give imidazolidines (354) in low yields.388Fluorination 0

II

Me

Me,NCNPh Me,NHC=N NPh

o Y - - - Me cH2~~

/ MeN Me

(351) 378

379 380

381

382 383 384

385

386

387 388

OL

(352)

N

O

Ph

T. McC. Paterson and R. K. Smalley, J. Chem. Res. ( S ) , 1980,246. K. Hirakawa, T. Toki, K. Yamazaki, and S. Nakazawa, J. Chem. Soc., Perkin Trans. 1,1980,1944. A. Atmani, J. L. Aubagnac, and V. Pellegrin, Org. Mass Spectrom., 1980, 15, 533 (Chem. Abstr.. 1981,94, 155 910). C. Ruchardt and V. Hassmann. Liebigs Ann. Chem., 1980,908 (Chem. Abstr., 1981,94,3959). F. M. Dean, L E. Houghton, R. Nayyir-Mashir, and C. Thebtaranonth, J. Chem. SOC.,Perkin Trans. 1, 1980, 1994 (Chem. Abstr., 1981, 94, 30411). G. F. Bannikov, G. A. Nikiforov, K. DeJonge, and V. V. Ershov, fzu. Akad. Nauk SSSR, Ser. Khim., 1980, 1921 (Chem. Abstr., 1981,94, 15 634). E. Cawkill and N. G. Clark, J. Chem. Soc., Perkin Trans. 1, 1980, 244. C. Glidewell, H. D. Holden, and D. C. Liles, J. Mol. Sfruct., 1980,66, 325. K. Seckinger, Helv. Chim. Acta, 1980,63, 1,958. S. Meola, E. Rivera, R. Stradi, and B. Gioih, J. Heterocycl. Chem., 1980,17, 1041. L. Citerio, D. Pocar, M. L. Saccarello, and R. Stradi, Tetrahedron, 1979, 35,2453.

190

Heterocyclic Chemistry

of trirnethylamine with cobalt(rI1) fluoride gave a mixture of eleven products, including the irnidazolidine (355).389The dimer of the radical anion PhCH-NPh, which is produced by the action of sodium on benzylideneaniline, has been trapped as a mixture of meso- and DL-imidazolidinones (356) by reaction with ethyl c h l o r ~ f o r m a t e .C,N-Diphenylnitrone ~~~ and metallated isocyanides, e.g. CN-CH, Li', form irnidazolidinones, such as (358), via an intermediate dihydro- 1,2,5-0xadiazine (357).391

(353)

ph,

(354)

Ph

(355) Ph

(356)

Reactions of Imidazoles. 2-Substituted imidazoles are readily prepared by lithiation of the acetal (359) (prepared from imidazole and triethyl orthoformate) and treatment of the resulting 2-lithio-derivative with various electrophiles, such as carbon dioxide, butyl bromide, acetyl chloride, or benzaldehyde; the protecting group is then removed under mild acidic or neutral 4,5Dimethylimidazole (360) reacts with chloroform in a flow system at 5500C to give a mixture of the pyrimidines (361) and (362) and the pyrazine (363).393

H

(360)

(361)

(362)

(363)

The photochemical addition of oxygen to the imidazoles (364; R',R2 = alkyl) to yield hydroperoxides (365)394and of benzophenone to 1-acyl-imidazoles to yield oxetans (366; R = Ac or COPh)395has been reported. Chlorosulphinylirnidazole (367), prepared from imidazole and thionyl chloride, reacts with 389 390 391

392 393

394 395

R. W. Rendell and B. Wright, Tetrahedron, 1979, 35, 2405. G. Prasad, G. Singh, and K. N. Mehrotra, Zndian J. Chem., Sect. B, 1980,19,653. U. Schollkopf, H. H. Lau, K. H..Scheunamann, E. Blume, and K. Madawinata, Liebigs Ann. Chem., 1980,600. N. J. Curtis and R. S. Brown, J. Org. Chem., 1980, 45, 4038. R. E. Busby, M. A. Khan, M. R. Khan, J. Parrick, C. J. G. Shaw, and M. Iqbal, J. Chem. Soc., Perkin Trans. 1, 1980, 1427; R. E. Busby, M. A. Khan, M. R. Khan, J. Parrick, and C. J. G. Shaw, ibid., p. 1431. M. L. Graziano, G. Curato, and R. Scarpati, J. Heterocycl. Chem., 1979,16, 1571. T. Nakano, W. Rodriguez, S. Z. DeRoche, J . M. Larrauri, C. Rivas, and C. Perez, J. Heterocycl. Cheni., 1980, 17, 1777.

Five-Membered Rings: Other systems

191

certain phenyl ketones PhCOR' (R2= C02Et,CN, or COPh) to yield compounds (368) with elimination of sulphur the action of thionyldi-imidazole (369) on acetophenone produces a mixture of the di-imidazole (370) and the elimination product (37f).3972,4,5-Triphenylimidazole(lophyl) forms photochromic dimers (372) and (373), which are interconvertible by irradiation; these and the thermochromic dimer (374) equilibrate at 100 0C.398 RZ Ph[>R1 N H (364)

Ph Na Ph N_z Ph Phy N 3 P h Ph k1 N (372)

R'_N

N-

P h c x " ' OOH (365)

N

R

(366)

bNR'

(367) R1 = SOCl (368) R' = PhCR2Cl

Ph ~ " \ ~ p hN.Ph p h Phb

x 2 Ph

(373)

Ph (374)

Treatment of the salt (37S), which possesses four welectrons, with sodium ethoxide yields the 4H-imidazole (376); the latter condenses with dimethyl malonate to form (377), which is a diaza-fulvene with 'inverse polarity'.399

(375)

(376)

(377)

2,5-Diazacyclopentadienylidene (379), generated thermally or photochemically from the diazo-2H-imidazole (378), exhibits much greater biradical character than the carbon analogue; it reacts with arenes C6HSRto give mainly mixtures of ortho-, meta-, and para-substituted 2-aryl-imida~oles.~~~ The meso-ionic imidazolium oxide (380) forms the [4 + 41 cyclo-adduct (381) with tetrachloro-ob e n z o q ~ i n o n eThe . ~ ~ ~imidazolinethione (382) reacts with the dicyano-oxiran (383; Ar = p-N02C6H4)to yield the irnidazothiazolium oxide (385)by way of the isolated spiro-intermediate (384).402 396

H. Matsumoto, Synth. Commun., 1980,10,733.

397

M. Ogata, H. Matsumoto, S. Kida, and S. Shimizu, Tetrahedron Lett., 1979, 5011; Fukusokan

398 399 400

401 402

Kagaku Toronkai Koen Yoshishu, IZth, 1979,71 (Chem. Abstr., 1980,93,71 640). T. Goto, H. Tanino, and T. Kondo, Chem. Lett., 1980,431. R.Gompper and K. P. Bichlmayer, Tetrahedron Lett., 1980,21,2879. N.Bru and J. Vilarrasa, Chem. Lett., 1980,1489. W.Friedrichsen, W. D. Schroer, and T. Debaerdemaeker, Liebigs Ann.Chem., 1980,180. M. Baudy and A. Robert, Tetrahedron Lett., 1980,21,2517.

Heterocyclic Chemistry

192

Me

0-

H

Ar

N Me

N S Me

NC

Ar COAr (386) (387) (R2N = morpholino)

The imidazoline (386; Ar = p-BrC6H4)undergoes ring-enlargement to the pyrimidine (387) in boiling ~ y l e n e . ~The ' ~ imine (388) is in tautomeric equilibrium with the 1,3-dipole (389); it dimerizes to the imidazolidine (390), which, in the presence of N-phenylmaleimide, forms the cyclo-adduct (391) (see Scheme 4).404The cross-conjugated betaine (393) is obtained by the action of

Ph '{rrh

[+

H E2C' H

N

*CHPh

-HN,+

E2C

(38x

H 'CHE, (390)

(388)]

(389)

a,

9'k0h

CHPh

(388)

O (E = C02Et) Scheme 4 403

404

N

N Ph (391)

L. Citerio, M. L. Saccarello, R. Stradi, and B. Gioia, J. Chem. SOC.,Perkin Trans. 1, 1980, 722. K. Amornraksa and R. Grigg, Tetrahedron Lett., 1980, 21, 2197; cf. R. Grigg, M. Jordan, and J. F. Malone, ibid., 1979, 3677.

Fiue-Membered Rings: Other systems

193

carbon disulphide on the bi-imidazolidinylidene (392).405The stable nitroxide (394) undergoes photocyclization to the oxiran (395); treatment of the imidazolidine nitroxide (396) with phosgene yields the acid chloride (397).406 Ph

Ph

Ph N

Ph

N Ph

N Ph

(392)

(393)

0-

1 0. (394)

I

0. (395)

Other references to the should be noted.

0. (396)

and

of imidazoles

Benzimidazoles and Other Annelated 1midazoles.-Heating o-nitroaniline with benzylamine produces a mixture of 2-phenylbenzimidazole (398; R = H) and its benzyl derivative (398; R = PhCH,); the process is thought to involve the formation of o-phenylenediamine and benzylideneimine by a redox reaction.416 The Schiff -base (399) forms 2-phenylbenzimidazole under the influence of hot fluoroboric 1,3-Dimethyl-2- phenylbenzimidazolium nitrite (401; X = NOz) results from an intramolecular nucleophilic replacement reaction of the amidine (400).418The action of o-phenylenediamineon 1-ethoxy-2,3-diphenylcyclopropenylium fluoroborate yields the salt (402); on deprotonation, this 405 406

407 408

409

410 411

412

413 414

415

416 417 418

W. S. Sheldrick, A. Schonberg, E. Singer, and P. Eckert, Chem. Ber., 1980,113,3605. G. I. Shchukin, I. A. Grigorev, and L. B. Volodarskii, Izv. Akad. Nauk SSSR,Ser. Khim., 1980, 1421; V . A. Reznikov and L. B. Volodarskii, Izv. Sib. Otd. Akad. Nauk SSSR,Ser. Khim. Nauk, 1980,109 (Chcm. Abstr., 1981,94,156 817); cf. A. B. Shapiro, L. B. Volodarskii, 0.N. Krasochka, and L. 0.Atovmyan, Dokl. Akad. Nauk SSSR, 1980,254,1140; L. B. Volodarskii, I. A. Grigorev, and R. Z. Sagdeev, Biol.Magn. Reson., 1980,2, 169. C . J. Harris, J. Chem. SOC.,Perkin Trans. 1, 1980, 2497 (Chem. Abstr., 1981, 94, 15 642). I. Jurgevica and E. Kupce, Khim. Geterotsikl. Soedin., 1980, 1474 (Chem. Abstr., 1981, 94, 103 241). J. Moskal, A. Moskal, and W. Pietrzycki, Tetrahedron, 1979, 35, 1883 (Chem. Abstr., 1980, 93, 8113). C. P. Whittle, Aust. J. Chem., 1980,33, 1545 (Chem. Abstr., 1981,94, 65 549). G. Lindgren, K. E. Stensioe, and K. Wahlberg, J. Heterocycl. Chem., 1980, 17,679 (Chem. Abstr., 1981,94, 15 638). N. Matsumura, Y. Sakaguchi, T. Ohba, and H. Inoue, J. Chem. SOC.,Chem. Commun., 1980,326 (Chem. Abstr., 1980,93, 149 942). M. J. Korohoda, Pol. J. Chem., 1980, 54, 683 (Chem. Abstr., 1981,94, 30646). H. J. M. Dou, P. Hassanaly, and J. Metzger, Chim. Acra Turc., 1979, 7, 291 (Chem. Abstr., 1981, 94, 15 639). H. Sakurai, A. Shirahata, and A. Hosomi, Tetrahedron Lett., 1980, 21, 1967 (Chem. Abstr., 1980, 93,167 575). C. V. C. Rao, K. K. Reddy, and N. V. S. Rao, Indian J. Chem., Sect. B, 1980,19,655. R. Kreher and U. Bergmann, Heterocycles, 1980, 14, 1725. H. M. Wollf and K. Hartke, Arch. Pharm. (Weinheim, Ger.), 1980,313,266.

Heterocyclic Chemistry

194

affords the rearranged benzimidazole (403).4'9Manganese dioxide transforms the sulphonamide (404)into the quinone imine (405).420

UNl0Q -+o~ H

H

Tos

(405)

(404)

The 2 : 1 adduct of diphenylketen to 1-methylbenzimidazole is (406),contrary to a previous r e p ~ r t . ~ 'E.s.r. ' spectroscopy indicates that atomic hydrogen reacts with the salts (401)to form the radical cation (407).422 The total synthesis of Me-IQ (408),a potent mutagen isolated from broiled fish, has been The dibromo(methoxy)tropone (409)condenses with guanidine to yield the treatment of 2,4-dichloro-5-rnethoxytropone(411) 193-diaza-azulene (410);424

Br \

Br (409) 419 420

421 422

423

424

\

-

N

Me0

Br (4 10)

(411)

T. Eicher and D. Lerch, Tetrahedron Lett., 1980,21,3751. I. G.C. Coutts and M. R. Hamblin, J. Chem. Sac., Chem. Commun., 1980,949. M. J. Haddadin and H. H. N. Murad, J. Org. Chem., 1980,45,2518. N. T.Berberova, E. P. Ivakhnenko, N. N. Bubnov, and 0. Yu. Okhlobystin, Khim. Geterotsikl. Soedin., 1980,1568. H. Kasai, Z . Yamaizumi, K. Wakabayashi, M. Nagao, T. Sugimura, S. Yokoyama, T.Miyazawa, and S. Nishimura, Chem. Lett., 1980, 1391;H. Kasai, S. Nishimura, K. Wakabayashi, M. Nagao, and T. Sugimura, Proc. Jpn. Acad., Ser. B,1980,56,382 (Chem. Abstr., 1981,94,30 643). M. Yasunami, Y. Sasagawa, and K. Takase, Chem. Lett., 1980,205.

Five-Membered Rings: Other systems

195

with acetamidine furnishes a mixture of the tricyclic compound (412) and the isomer (413); the latter arises from a cine-rea~tion.~~’

(413)

Other material on benzimidazoles can be found in references 4 2 6 4 3 4 . 5 Systems containing Two Different Heteroatoms

Oxathioles and Thiaseleno1es.-The 1,2-0xathiolan-5-one 2-oxide (414) has been prepared by the action of oxalyl chloride on the salt 2Na’ -02SCHMeCH2C02-.435Two previously reported syntheses of the episulphide (415) actually yielded the 1,3-oxathiole (416).436The chelated lithium compound (417) reacts with aldehydes or ketones to give the oxathiole-imines (418; R’ = H, Me, or Et; R2 = Me, Et, or Ph).437Photolysis of 1,3-benzoxathiol2-one (419) in an argon matrix yields the ketocarbene (420), which undergoes a spontaneous Wolff rearrangement to the keten (421).438 A mixture of

425 426

427

428

429

430

431

432

433

434

435

436 437 438

H. Takeshita. A. Mori, T. Minami, and H. Kondo, Heterocycles, 1980,14, 793. T. Mukaiyama, M. Murakami, and M. Yamaguchi, Chem. Lett., 1980, 529 (Chem. Abstr., 1980, 93, 166 993). K. El-Bayouki and M. Hammad, E g y p t . J. Chem., 1978, 21, 171 (Chem. Abstr., 1981, 94, 3962). J. Schulze, H. Tanneberg, and H. Matschiner, Z . Chem., 1980, 20, 436 (Chem. Abstr., 1981, 94, 156 822). A. Mitra, S. M. S. Chauhan, and M. V. George, J. Org. Chem., 1980, 45, 3182 (Chem. Abstr., 1980,93, 114 394). M. Augustin, M. Richter, and S. Salas, J. Prakt. Chem., 1980, 322, 5 5 (Chem. Abstr., 1980, 93, 26 307). M. Ogata and H. Matsumoto, Synth. Commun., 1980, 10, 559, (Chem. Abstr., 1981, 94, 30 647). R. A. Kozak, N. K. Rozhkova, and M. M. Yusupov, Uzb. Khim. Zh., 1980, 81 (Chem. Abstr., 1981,94, 30 638). R. A. Sogomonova, S. N. Kolodyazhnaya, A. M. Simonov, and L. N. Divaeva, Khim. Geterotsikl. Soedin., 1980. 1428 (Chem. Abstr., 1981,94, 103 240). T. V. Stupnikova, L. A. Rybenko, and S. N. Baranov, Dopou. Akad. Naulc Ukr. RSR, Ser. B: Geol., Khim. Biol. Nauki, 1980, 5 3 (Chem. Abstr., 1980,93,46 524). T. P. Vasileva, N. V. Kalyuzhnaya, V. M. Bystrova, M. G. Linkova, 0. V. Kildisheva, and 1. L. Knunyants, Izv. Akad. Nauk SSSR, Ser. Khim., 1980, 2187. A. Senning, Bull. SOC.Chim. Belg., 1980, 89, 781. D . Hoppe, R. Follmann, and L. Beckmann, Liebigs Ann. Chem., 1980, 1765. M. Torres, A. Clement, and 0. P. Strausz, J. Org. Chem., 1980, 45, 2271.

He te rocy c Eic Chemistry

196

thiaselenolethiones (423; 4-C0,Et) and (423; 5-CO2Et) and the dithioleselone (424) was isolated from the reaction of the thione (422) with ethyl p r ~ p i o l a t e .The ~ ~ ~thiaselenafulvene (426) has been synthesized from benzaldehyde and the phosphonium salt (425).440Treatment of the acetylenic sulphide PhCEC-S -CH,Cl with alkali-metal sulphides, selenides, or tellurides yields the respective heterocycles (427; X = S,.Se, or Te).441

For other papers on oxathioles and thiaselenoles, see references 442-446.

1soxazoles.-Curmation. The reaction of the propargyl bromide PhCECCHMeBr with sodium nitrite yields the nitro-isoxazole (428).447NIodosuccinimide is a useful reagent for oxidative cyclization: it effects the conversion of the oxime of benzylideneacetone into the isoxazole (429) and of the dioxime HON=CPhCPh=NOH into the N-oxide (430).448Electrochemical reduction of cyanonitro-compounds PhC(CN)=CRNO, (R = H, Me, or Ph) generates a-cyano-oximes, which cyclize to the 5-aminoisoxazoles (431).449 The 5-amino-isoxazoles (432) are also formed by the action of thiols on Ph Ph P h 0' p ; (428) R = NO2 (429) R = H 439 440 44 1

442

443

444

445 446

447

448 449

m+

"O/N,O-

(430)

Ph R

WVN (431)

A. Shafiee and F. Assadi, J. Heterocycl. Chem., 1980, 17, 549. M. V. Lakshmikantham and M. P. Cava, Heterocycles, 1980,14, 271. R. S. Sukhai, W. Verboom, J. Meijer, M. J. M. Schoufs, and L. Brandsma, Recl. Trav. Chim. PUYS-BUS, 1981,100, 10. K. T. Tanatarova and K. B. Erzhanov, Deposited Document 1979, VINITI 3478 (Chem. Absa., 1981, 94, 191 604). I. Kapovits, J. Rabai, F. Ruff, A. Kucsman, and B. Tanacs, Tetrahedron, 1979, 35, 1875 (Chem. Abstr., 1980,93, 26 323). I. Kapovits, J. Rabai, F. Ruff, and A. Kucsman, Tetrahedron, 1979, 35, 1869 (Chem. Abstr., 1980, 93, 26 322). I. Degani, M. Dolci, and R. Fochi, Synth.Commun., 1980,10, 161 (Chem. Abstr., 1980,93, 8660). A. Shafiee, M. Vosoogh, and R. Asgharian, J. Heterocycl. Chem., 1980, 17, 117 (Chem. Abstr., 1980, 93, 71 651). Ts. D. Mechkov, I. G. Sulimov, N. V. Usik, I. Mladenov, and V. V. Perekalin, Zh. Org. Khim., 1980,16,1328. S . K. Talapatra, P. Chaudhuri, and B. Talapatra, Heterocycles, 1980, 14, 1279. C. Bellec, D. Berth, R. Colau, S. Deswarte, P. Maitte, and C. Viel, J. Hererocycl. Chem., 1979, 16, 1611.

Five-Membered Rings: Other systems

197

a-cyano-P-nitrostyrenes Ar'C(N02)=CAr2CN.450 The cyano-oxime Et02C(CN)=NOCH2C02Etis transformed into the 4-aminoisoxazole (433) on treatment with lithium hydro~ide.~'' H 2 N C0,Et

Ar2 Ar'

H 2 N c N

E t 0 2 C0'p N

(432)

(433)

The synthesis of the anti-tumour agent AT-125 (434) has been The condensation product of benzaldehyde with methyl nitroacetate forms the nitronate anion (433, which undergoes an intramolecular nucleophilic substitution reaction to yield the isoxazoline N-oxide (436).453The adduct (438) of the ynamine (437) to 1-nitrocyclopentene readily rearranges to the cyclopentaisoxazoline (439).454There has been the usual spate of reports on 1,3-dipolar cycloaddition reactions of nitrile oxides and nitrones, of which only a brief selection can be presented. Of special interest is the generation of aliphatic nitrile oxides (441; R = Me or Et) by the action of acetyl chloride on the nitroalkanes (440); trapping with dimethyl fumarate gives the isoxazolines

H-' I CO, H (434)

Ph

\ C

\A/

H H R

-0

450

451 452 453

A55

A56

457 458

I - , N /+Xo

H

R

II

N

-

(-AcOH)

R I Ill N+ I

c

0-

R. Colau and C. Viel, Bull. SOC.Chim. Fr., Part 2, 1980, 163. K. Gewald, P. Bellmann, and H. J. Jaensch, Liebigs Ann. Chem., 1980, 1623. J. E. Baldwin, L. I. Kruse, and J.-K. Cha, J. A m . Chem. SOC.,1981, 103, 942. E. Kaji and S. Zen, Chem. Pharm. Bull., 1980, 28,479. M. L. M. Penning and D. N. Reinhoudt, Tetrahedron Lett., 1980,21, 1781. K. Harada, E. Kaji, and S. Zen, Fukusokan Kagaku Toronkai Koen Yoshishu, 12th, 1979, 271 (Chem. Abstr., 1980, 93, 26 351). M. Nitta, S. Sogo, and T. Nakayama, Chem. Lett., 1979,1431; Fukusokan Kagaku Toronkai Koen Yoshishu, 12th, 1979,266 (Chem. Abstr., 1980,93,95 163). L. Garanti and G. Zecchi, J. Heterocycl. Chem., 1980, 17, 609. R. H. Wollenberg and J. E. Goldstein, Synthesis, 1980, 757.

Heterocyclic Chemistry

198

(442).455Benzocyclopropene and benzonitrile oxide, PhCNO, yield the cycloadduct (443).456Treatment of the chloro-oxime (444) with triethylamine results in the lactone (449, formed by intramolecular cycloaddition of a transient nitrile a series of similar cyclizations (446)+(447; n = 1-4) has been

A

SMe

Reactions of Isoxazoles. Attempted alkylation of the phenylazo-isoxazole (448) resulted in its rearrangement to the triazole (449).459The azido-isoxazoles (450; n = 1 or 2) decompose thermally to the acyl cyanides (451).460Deprotonation of the perchlorate (452) is accompanied by ring-enlargement to yield the 2H-1,3-oxazine (453).461The formation of the thiol (456) in the reaction of the isoxazolium salt (454) with thiophenol is thought to proceed via an intermediate benzoylketenimine (455).462

c;

Ph (CH =C H),,

C104P h F r

0’ ‘CHMe,

(450)

1

CN

(452)

--*

P h f i O V N Me2 (453)

/

Ph(CH=CH), (451)

Ch

Ph’

!NMe

CI (454) 459 460

461

462

AO

*

CH=C=NMe / Ph-C

\b (455)

/

* Ph-C

SPh

FH=‘NHMe \b \

(456)

J. Wrubel and R. Mayer, 2. Chem., 1979,19,446. G . Kumar, K. Rajagopalan, S. Swaminathan, and K. K. Balasubramanian, Tetrahedron Lett., 1979, 4685. C . Kashima, Y. Tsuda, S. Imada, and T. Nishio, J. Chem. SOC.,Perkin Trans. 1, 1980, 1866. S. Sugai and K. Tomita, Chem. Pharrn. Bull., 1979,27,2787.

Five-Membered Rings: Other systems

199

Treatment of the bromo-isoxazoline (457) with silver nitrate gives the rearranged isoxazole (458).463The hydroxy-isoxazolinone (459) undergoes successive reversible reactions with mesityl oxide and alcohols to afford the isoxazolo[3,2-b][ 1,310xazines (460).464The indoline N-oxide (462) is produced by the action of boron trifluoride etherate on the isoxazoline oxide (461).465 Photolysis of 2,3-dimethyl-4-(phenylthio)isoxazolin-5-one(463) leads to the imino-carbene (464).466Interesting observations on the flash vacuum pyrolysis of isoxazolin-5-ones that contain an exocyclic double-bond at C-4 have been recorded by Wentrup and his colleagues: the enamine (465) decomposes to anilinoacetylene, which rearranges to keten N-phenylimine (466).467The styrylmethylene derivative (467) yields a mixture of styrylacetylene,naphthalene, and

”6 Br

----*

Ph Ph M e0 p’ N

Me Ph OH

o ffi oi $oM) eM e.ROHh

0

ofl>Me Ph

0”

OR

0”

(459)

(E = C02Me)

PhS

Me (-CO,)

C N M e O O

PhHNCH

(465) 463

PhN

II

(466) \ . - - I

--+

PhS

NMe

fir

PhCHZHC-CH O O (467)

0’ 0’

J. F. Hansen, Y. I. Kim, S. E. McCrotty, S. A. Strong, and D. E. Zimmer, J. Heterocycl. Chem., 1980,17,475.

464 465

466 467

G. Zvilichovsky, M. David, and E. Nemes, J. Heterocycl. Chem., 1980, 17, 299. E. Kaj and S. Zen, Heterocycles, 1979, 13 (Special Issue), p. 187. T. Sasaki, K. Hayakawa, andS. Nishida, J. Chem. SOC.,Chem. Commun., 1980, 1054. H. W. Winter and C. Wentrup, Angew. Chem., Int. Ed. Engl., 1980,19,720.

Heterocyclic Chemistry

200

azulene, and there is evidence that one of the paths connecting azulene with naphthalene leads via the carbene :C=CH-CH=CHPh.468 The indene (468) fragments to the carbene (469), which rearranges to 2-eth~nylindene.~~’ Phenyl fulminate, PhONC, is generated from the oxime (470),470and the hydrazone (47 1) yields the isocyano-amine PhNH-NC, which was characterized by lowtemperature Pyrolysis of the isoxazoline-3-thione (472) produces a mixture of isomeric 1,4-dithiins (474) and (475), presumably by way of the thiiren (473).472

(470) R (471) R

= =

OPh NHPh

(469)

Other work on the formation4734g1and be noted. 468

469 470

471 472

473

474

475

476

477

478 479

480

481

482

483

484 485

486

of isoxazoles should

J. Becker, C. Wentrup, E. Katz, and K. P. Zeller, J. A m . Chem. SOC., 1980, 102, 5110. C. Wentrup, E. Wentrup-Byrne, P. Muller, and J. Becker, Tetrahedron Lett., 1979,4249. C. Wentrup, B. Gerecht, D. Laqua, H. Briehl, H. W. Winter, H. P. Reisenauer, and M. Winnewisser, J. Org. Chem., 1981,46, 1046. C. Wentrup and H. W. Winter, J. Org. Chem., 1981, 46, 1045. S. Sugai and K. Tomita, Chem. Pharm. Buff.,1980,28, 103. C. Kashima, S. Shirai, and N. Yoshiwara, J. Chem. SOC.,Chem. Commun., 1980, 826 (Chem. Abstr., 1981, 94, 15 623). E. Oehler and E. Zbiral, Chem. Ber., 1980, 113, 2852 (Chem. Abstr., 1981, 94, 15 635). T. D. Fulmer, L. P. Dasher, B. L. Bobb, J. D. Wilson, K. L. Sides, and C. F. Beam, J. Heterocycf. Chem., 1980,17,799 (Chem. Abstr., 1981,94, 30 626). C. Bellec, D. Berth, R. Colau, S. Deswarte, P. Maitte, and C. Viel, J. Heterocycf. Chem., 1979, 16, 1657 (Chem. Abstr., 1980,93, 26 329). J. Perronnet, P. Girault, and J. P. Dernoute, J. Heferocycl. Chem., 1980, 17, 727 (Chem. Abstr., 1981,94,3953). A. S. Asrof, P. A. Senaratne, C. R. Illig, H. Meckler, and J. J. Tufariello, Tetrahedron Lett., 1979, 4167 (Chem. Abstr., 1980,93, 113 780). D. Pocar, L. M. Rossi, P. Trimarco, and L. Vago, J. Heterocycf. Chem., 1980, 17, 881 (Chem. Abstr., 1981, 94, 65 515). D. N. Nicolaides, M. A. Kanetakis, and K. E. Litinas, Chem. Chron., 1979, 8, 187 (Chem. Abstr., 1980,93,71608). N. A. Akmanova, Kh. F. Sagitdinova, R. F. Talipov, V. N. Domrachev, and V. P. Yurev, Zh. Org. Khim., 1980,16, 2309 (Chem. Abstr., 1981,94, 139 672). R. Nesi, S. Chimichi, M. Scotton, A. Degl’Innocenti, and G. Adembri, J. Chem. SOC.,Perkin Trans. 1, 1980, 1667 (Chem. Abstr., 1981,94,47 252). P. Sarti-Fantoni, D. Donati, M. Fiorenza, E. Moschi, and V. Dal Piaz, J. Heterocycl. Chem., 1980, 17,621 (Chem. Abstr., 1980,93, 167 819). S. A. Tischler and L. Weiler, Tetrahedron Lett., 1979, 4903 (Chem. Abstr., 1980, 93, 46 485). G. Tacconi, P. P. Righetti, and G. Desimoni, J. Prakt. Chem., 1980, 322, 679 (Chem. Abstr., 1981, 94,65 541). V. Jaeger, V. Buss, and W. Schwab, Liebigs Ann. Chem., 1980, 122 (Chem. Abstr., 1980, 93, 131 952).

20 1

Five-Membered Rings: Other systems

Benzisoxazo1es.-Lead tetra-acetate effects oxidative ring-closure of the oxime (476) to the 1,2-benzisoxazole N-oxide (477).487Lithio-dithioketals (478; R = alkyl or aryl) react with benzonitrile oxide to yield oximes (479), which are converted into benzisoxazoles (480) under the influence of potassium The reaction of the acetal (481) with t-butoxyl radicals affords the nitroxyl (482), whose e.s.r. spectrum has been determined.489Treatment of the quinone (483) with sodium azide leads to 3,7-dimethoxybenzo[ 1,2-c: 4,5-c’]diisoxazole-4,8-dione (484), which is cleaved by potassium hydroxide to give potassium dimethyl cyanomalonate and which condenses with malononitrile in the presence of alkali to yield the coloured salt (485).490The 2,l -benzisoxazoles Me

Li

OH

(478)

(479)

0

Me0

- 0 0

NC

2Kt <485)

487 4B8

489

490

A. J. Boulton and P. G. Tsoungas, J. Chem. Sac., Chem. Commun., 1980,421. T. Yamamori and I. Adachi, Fukusokan Kagaku ToronkaiKoen Yoshishu, 12th, 1979,121 (Chem. Abstr., 1981, 94, 65 513). E. G. Janzen, C. C. Lai, and R. V. Shetty, Tetrahedron Letr., 1980, 21, 1201. R. Neidlein and S. Throm, Arch. Pharm. (Weinheim, Ger.), 1980, 313, 572, 891; Chimia, 1981, 35,14.

202

Heterocyclic Chemistry

(486; X=CH or N) rearrange thermally to the quinazoline (487; X = CH) or benzotriazinone (487; X = N), respectively, as The azidoanthraquinone (488) gives the condensed isoxazole (489) if heated; this is converted into the oxazine (490) on further heating.492 The benzisoxazolone (491) is transformed (under basic conditions) into the biphenyl derivative (493), which arises by a ‘benzidine’ rearrangement of the intermediate hydroxylamine (492); acids, on the other hand, cause cleavage of the N - 0 bond in (491) and subsequent re-cyclization to the benzoxazolone (494) (see Scheme 5),493 on benzisoxazoles. Attention is drawn to two other

o-”‘.

X=NPh

X=Wh

\

_+

o L + o

.N’

N:

+ ,x@

‘

(486)

N-NPh

J ’‘-N -X

0 (490) 491

492 A93 A94

A95

R. K. Smalley, R. H. Smith, and H. Suschitzky, Tetrahedron Lett., 1979, 4687. L. M. Gornostaev and V. A. Levdanskii, Zh. Org. Khim., 1980,16,2209. T. Sheradsky and S. Avramovici-Grisaru, J. Heterocycl. Chem., 1980, 17, 189. S. S. Mochalov, A. N. Fedotov, and Yu. S. Shabarov, Zh. Org. Khim. 1980, 16, 462 (Chem. Abstr., 1980,93, 46 489). L. M. Gornostaev and V. T. Sakilidi, Khim. Geterotsikl. Soedin., 1980, 1471 (Chem. Abstr., 1981, 94, 120 471).

Five-Membered Rings: Other systems

QyNPh oo\

203

o

NO2

(491)

\

?

''kph

NO2

[1,2]shif;

Ph

U " & o

'

NO2

Scheme 5

0-

Ph

----*

aNFo '

0

NO2

(494)

0xazoles.-Furmation. Diazocarbonyl compounds (495) react with nitriles in the presence of boron trifluoride to yield oxazoles (496; R',R2,R3 = alkyl, aryl, C02Me, e t ~ . Various ) . ~ ~ ~oxazoles (496; R' = H, Me, or Et, R2 = H, R3 = Ph, Ar, or 4-pyridyl) have been prepared from amino-ketone hydrochlorides R3COCH2NH2 HCl and orthoesters R1C(OEt)3.4972-Amino-4,5-diphenyloxazole (497) is produced from a-bromobenzyl phenyl ketone (PhCHBrCOPh) and cyanamide.498 The cyclization of N-rnethylisocyanoacetanilide, CNCH2CONMePh, to the oxazole (496; R' = R2 = H, R3 = NMePh) is a particular instance of a general reaction of cu-i~ocyano-arnides.~~~ The methylthio-oxazole (498) +is one of the products obtained by irradiating the nitrone PhCOCPh=N(CH2SMe)-O-.soo l-Chloro-2-formamidoethane, HCONHCH2CH2Cl, yields 2-oxazoline (499) on treatment with sodium hydride."' The a-metallated isocyanide (500; Fu = 2-furyl) reacts with benzaldehyde or benzophenone at -10 "C to yield the furyloxazolines (501; R = H) and (501; R = Ph), respectively.s02

T. Ibata and R. Sato, Bull. Chem. SOC.Jpn., 1979,52, 3597;M. P. Doyle, W. E. Buhro, J. G. Davidson, R. C. Elliott, J. W. Hoekstra, and M. Oppenhuizen, J. Org. Chem., 1980,45,3567. 497 J. L.LaMattina, J. Org. Chem., 1980,45,2261. 498 Yu.A.Sharanin, Zh. Org. Khim., 1980,16,2185. 499 J. P. Chupp and K. L. Leschinsky, J. Heterocycf. Chem., 1980,17,705,711. 500 N.S.Ooi and D. A. Wilson, J. Chem. Res. ( S ) , 1980,366. F. Franco and J. M. Muchowski, J. Heterocycl. Chem., 1980,17,1613. 502 U. Schollkopf and W. Frieben, Liebigs Ann. Chem., 1980,1722. 496

204

Heterocyclic Chemistry

Treatment of the keto-aldehyde PhCOCHPhCHO with N-phenylhydroxylamine leads to the phenylimino-oxazoline (502), presumably via the benzoylketenimine PhCOCPh=C=NPh.503 The action of trifluoroacetic anhydride on the amino-acids R'CH2CH(NHMe)C02H results in the methyleneoxazolines (503;R' = Ph or Pr', R2 = H) or their trifluoroacetyl derivatives (503; R' = H, Me, or n-C5H11; R2 = CF3CO), depending on the steric demand of the group R1.504The iminothione (504) is formed from acetone and the thiocyanate MeNHCSCN.505 a-Bromoisobutyrylbenzylamide (505) affords the oxazolidinone (507)on treatment with sodium hydride; the reaction represents a cycloaddition of the 1,3-dipole (506)to the amide carbonyl group of (505).506 3-Nitroso-5 -0xazo1idinones (508) are produced by the action of nitrosonium fluoroborate (NOBF,) on the salts ArCH=NCH2C02Na.507 R'

/

NO

(509) py

Reactions of Oxazoles. 2,4,5-Trimethyloxazole is lithiated at the 2-methyl group.5o8The Diels-Alder reaction of 2,4-dimethyloxazole with 2-vinylpyridine yields the adduct (509; Py = 2-pyridyl), whose orientation is as predicted by Frontier Molecular Orbital Benzyne reacts with 4-methyl-2,5diphenyloxazole to give the bridged dihydroanthracene ( 5 11) by way of the primary cyclo-adduct (5 Maleimide and 5-diethylamino-2,4-dimethyloxazole afford the rearranged adduct ( 5 12)? Treatment of 2-t-butyl-5-ethoxyoxazole with acrylonitrile yields the pyridinol (514) [via (513)],which has been F. D e Sarlo, J. Chem. SOC.,Perkin Trans. 1, 1980, 385. U. Hess and W. A. Konig, Liebigs Ann. Chem., 1980,611. 505 R. Ketcham, E. Schaumann, and T. Niemer, Synthesis, 1980, 869. 506 G. Zanotti, F. Filira, A . Del Pra, G. Cavicchioni, A. C. Veronese, and F. D'Angeli, J. Chem. SOC., Perkin Trans. 1, 1980, 2249. 507 M. A . Barton and B. R. Brown, J. Chem. SOC.,Chem. Commun., 1980, 59. B. H. Lipshutz and R. W. Hungate, J. Org. Chem., 1981, 46, 1410. 509 P. B. Terente, N. P. Lomakina, M. I. Rahimi, K. D. Riad, Ya. B. Zelikhover, and A . N. Kost, Khim. Geterotsikl. Soedin., 1980, 1255. 'lo G. S. Reddy and M. V. Bhatt, Tetrahedron Lett., 1980, 21, 3627. '*'V. S. Bogdanov, G. Ya. Kondrateva, and M. A. Aktzhanova, Izu. Akad. Nauk SSSR, Ser. Khim., 1980,1017.

503 504

Five-Membered Rings: Other systems

205

transformed (in several steps) into the saluretic agent (515).”* The use of the chiral oxazoline (516) for the preparation of optically active a-hydroxy-acids and lactones has been described.’13

@ Me

\

(-MeCN! (+benzyne)

&

0,

‘‘

Me ~ N\

/

\

Ph

Ph (510)

,NEt2

N

Me

(511)

0

(512)

MeOC,H, Ph /&OPh 0 ( 5 16)

The flash vacuum pyrolysis of oxazolinones has been investigated. The A3oxazolinone ( 5 17) extrudes carbon dioxide to yield the 2-azabuta-1,3-diene (519) via the nitrile ylide (518);’14 A2-oxazolinones(520) and (522) fragment to give carbon monoxide plus the acylimine (521) and the ketenimine (523), Ph

Ph \

O?>Me2 O

+

+

CrN

Me \-/ C

I

\ +

H

I1

CH3

(517)

CH2 (519)

(518)

Ph

Me

/C=N\C/

Ph

OH t >O P h

I

H- C \C

Ph,

\N

4

\C--Ph

C=N

H

’

II

//

0 (521)

”* 513 ’14

‘C-Ph

0

(523)

G. E. Stokker, R. L. Smith, E. J. Cragoe, Jr., C. T. Ludden, H. F. Russo, C. S. Sweet, and L. S. Watson, J. Med. Chem., 1981, 24, 115. A. I. Meyers and J. Slade, J. Org. Chem., 1980, 45, 2785; A. I. Meyers, Y. Yamamoto, E. D. Mihelich, and R. A. Bell, ibid., 1980, 45, 2792; A. I. Meyers and J. Slade, ibid., p. 2912. H. M. Berstermann, K. P. Netsch, and C. Wentrup, J. Chem. Soc., Chem. Commun., 1980, 503.

H

Heterocyclic Chemistry

206

re~pectively.~ l 5 The protonated oxazolinone (524) possesses a reactive methyl group at C-2 and condenses with aromatic aldehydes.516The free-radical reaction of 3-acetyloxazolin-2-one (525) with carbon tetrachloride leads to a mixture of the adduct (526) and the isomeric coupling products (527) and (52Q517 2Methyl-A’-oxazolin-5-one (529; R = H) forms the substitution product (529; R = 2-quinolinyl) on treatment with quinoline N-oxide in acetic anhydride.’I8 The azlactone (522) reacts with the ylide PhCOCH=SMe2 to yield the spirocyclopropane derivative (530).”’

(527) X = 0, Y = NAc (528) X = NAc,.Y = 0

0

Ph

The meso-ionic oxazolone (531; Ar = pNO2C6H4)forms the 1,3-adduct (532) with ethanol; the corresponding adduct with water cleaves to the amide (533).520The miinchnone derivative (534) adds tetrachloro-o-benzoquinoneto yield the lactone (535).521Treatment of C-phenylglycine with acetic anhydride

rye

O / IC-N,

Ar

-0

’._. 0

(531)

Ph

HfYPh 0

Ar,

OEt

(532)

I

HAo’c

Me

/

Ph

$0

(533)

’” H. M. Berstermann, R. Harder, H. W. Winter, and C. Wentrup, Angew. Chem., Int. Ed. Engl., ’I6 517

519

’*’

1980,19, 564. V . G . Kulnevich, T. P. Kosulina, F. U. Luebke, and Z. I. Zelikman, Khim. Geterotsikl. Soedin., 1980, 30. Y. Abe and T. Kunieda, Fukusokan Kagaku Toronkai Koen Yoshishu, 12th, 1979, 76 (Chem. Abstr., 1980,93, 114 365). M. M. Yousif, S. Saeki, and M. Hamana, J. Heterocycl. Chem., 1980, 17, 1029. 0.Tsuge, M.Noguchi, and H.Moriyama, Heterocycles, 1981,16,209. M. Hamaguchi and T. Ibata, J. Chem. SOC.,Chem. Commun., 1980,230. W. Friedrichsen, W. D. Schroer, and T. Debaerdemaeker, Liebigs Ann. Chew., 1980, 1836.

207

Five-Membered Rings: Other systems

generates the transient oxazolium oxide (536), which reacts with 1,2-dicyanocyclobutene in situ to form the dihydro-1H-azepine (537).522 The regioselectivity of the intramolecular cycloaddition of miinchnones depends on the nature of substituents: the methyl derivative (538;.R = Me) affords solely compound (539;R = Me;, whereas the phenyl analogue (538;R = Ph) yields a mixture of (539;R = Ph) and (540).523

Ph

GMe G:* R

v

\

\

*R

0-

Ph

0

(538)

0

(540)

(539)

+

The ring-chain tautomerism (541) (542), and that of the corresponding imidazolidine, has been studied by ‘H n.m.r. ~pectro~copy.’~~ The vinyloxazolidine (543)undergoes an acid-catalysed rearrangement to the pyrrolidine (544).525Pyrolysis of the stable nitroxide radical (545) results in a mixture of the corresponding N-hydroxylated compound, 4-t-butylcyclohexanone,and 4-tbutylcyclohexanone ~ x i m e . ’ ~ ~

0 CH2

(541)

H

Me

(542)

0’

Me<\ (545) O (544) (543) szz I. J. Turchi, C. A. Maryanoff, and A. R. Mastrocola, J. Heterocycl. Chem., 1980,17, 1593. 523 A. Padwa, H. L. Gingrich, and R. Lim, Tetrahedron Lett., 1980,21,3419. 524 J. B. Lambert and M. W. Majchrzak, J. A m . Chem. SOC.,1980,102,3588. 525 L. E. Ovennan, M. Kakimoto, and M. Okawara, Tetrahedron Lett., 1979,4041. 526 J. Michon and A. Rassat, Tetrahedron Lett., 1980, 21, 1949; cf C. Morat and A. Rassat, ibid., 1979,4561.

208

Heterocyclic Chemistry

Other work on the f o r m a t i ~ n ~ ~and ’ - ~c ~h ~ e m i ~ t r y ~ ~of~ oxazoles - ’ ~ ~ has been described.

Benzoxazoles and a Thiasilapentane System.-The photochemical conversion of o-nitroanisole into benzoxazole has been Oxidative cyclization of the quinone (546) yields the benzobi-oxazole (547).543The proportion of the open form in the equilibrium mixture (548) S (549) decreases from 100 to 40% in the series R = 2-thienyl > 2-fury1 > 3 - t h i e n ~ l . ’ ~The ~ action of dimethyl acetylenedicarboxylate on benzoxazole results in compound (552) by way of the observed intermediates (550) and (55 1).545 Nucleophilic substitution reactions of the chiral thiasilaptentane (553; Ar = l-naphthyl, X = S) proceed mainly with inversion of configuration, whereas the oxygen analogue (553 ; X = 0)usually reacts with retention.546

PhHC=N (546)

+P h ( a N > p h N ‘ 0 (547) H

527 528

529 530 531

532 533

534

535

536

s37

538

539 540

s41

542 543

544 545 546

M. V. Bhatt and G. S. Reddy, Tetrahedron Lett., 1980,21,2359 (Chem. Abstr., 1980,93, 204 512). 0. N. Bubel, I. G. Tishchenko, 0. A. Grinkevich, and A. F. Abramov, Khim. Geterotsikl. Soedin., 1980,468 (Chem. Abstr., 1980,93,71613). D. Geffken, Arch. Pharm. (Weinheim, Ger.), 1980, 313, 817 (Chem. Abstr., 1981, 94, 103 215). H. Kozuka, Eisei Kagaku, 1980,26, 112 (Chem. Abstr., 1981,94,47 197). J. W. McFarland, C. E. Hayes, E. B. Blair, and K. R. Stuhlmacher, J Heterocycl. Chem., 1980, 17,271 (Chem. Abstr., 1980,93, 114 368). M. Miihlstaedt and R. Widera, J. Prakt. Chem., 1980, 322, 139 (Chem. Abstr., 1980,93, 8068). T. Kunieda, T. Higuchi, Y. Abe, and M. Hirobe, Tetrahedron Lett., 1980, 21, 3065 (Chem. Abstr., 1981,94, 3954). F. S. Guziec, Jr., and E. T. Tewes, J. Heterocycl. Chem., 1980, 17, 1807 (Chem. Abstr., 1981, 94, 173 921). B. Sain, G. Thyawajan, and J. S. Sandhu, Can. J. Chem., 1980, 58, 2034 (Chem. Abstr., 1981, 94, 15 620). K. T. Potts, D. Bhattacharjee, and S. Kanemasa, J. Org. Chem., 1980, 45, 4985 (Chem. Abstr., 1981, 94, 3955). G. Schulz, T. Andries, and W. Steglich, Synth. Commun., 1980, 10, 405 (Chem. Abstr., 1980, 93, 94 933). H. D. Stachel, K. K. Harigel, H. Poschenrieder, and H. Burghard, J. Heterocycl. Chem., 1980, 17, 1195 (Chem. Abstr., 1981,94, 15 476). A. Forestiere and B. Sillion, J. Heterocycl. Chem., 1980,17,1381 (Chem.Abstr., 1981,94,103219). J. Diago-Meseguer, A. L. Palomo-Coll, J. R. Fernandez-Lizarbe, and A. Zugaza-Bilbao, Synthesis, 1980, 547 (Chem. Abstr., 1981,94, 103 214). J. CabrC-Castellvi and A. L. Palomo-Coll, Tetrahedron Lett., 1980, 21, 4179 (Chem. Abstr., 1981, 94, 174 579). S. Oguchi and H. Torizuka, Bull. Chem. SOC.Jpn., 1980, 53, 2425. C.-H. Kao, Y.-M. Zhou, M.-Z. Wang, J.-X. Pan, and X.-J. Fan, Kao Teng Hsueh Hsiao Hua Hsueh Hsueh Pao, 1980,1,61 (Chem. Abstr., 1981,94, 174 948). E. Belgodere, R. Bossio, V. Parrini, and R. Pepino, J. Heterocycl. Chem., 1980, 17, 1629. N. Kawahara, M. Katsuyama, T. Itoh, and H. Ogura, Heterocycles, 1980, 14, 15. R. J. P. Corriu, J. M. Fernandez, C. Guerin, and A. Kpoton, Bull. SOC.Chim. Belg., 1980,89,783.

209

Five-Membered Rings: Other systems

H

(550)

fEC-CE

(551)

(E = C02Me)

6 Systems containing Three Identical Heteroatoms 1,2,3-Triazoles and Annelated 1,2,3=Triazoles.-The action of amines RNH2 on the aliphatic diazonium salt (EtO),C=CHN,' SbC16- results in the formation of 5-ethoxy-1,2,3-triazoles(554).547 The a-chloro-enamines (R = Me or Ph) react with sodium azide to yield MeO,C-CR=CCINMe, the 4H-triazoles ( 5 5 3 , which decompose to the azirines (556)when heated.548 1-Aryl-3-(cyanomethyl)triazenes, ArN=NNHCH2CN (Ar = u- or pN02C6H4),undergo a Lewis-base-catalysed cyclization to the triazoles (557); in protic solvents, these compounds undergo a Dimroth rearrangement to the isomers (558).549Treatment of the unsaturated ester E2C=CHAc (E = C02Me) with phenyl azide affords a mixture of the cyclo-adduct (559) and the diazocompound E2C(NHPh)-CACN,.~~'

(557) R1 = Ar, R2 = NH2 ( 5 5 8 ) R1 = H, R2 = NHAr 547 548

549

(559)

R. W. Saalfrank and E. Ackermann, Liebig3 Ann. Chem., 1981, 7. C. Bernard and L. Ghosez, J. Chem. SOC.,Chem. Commun., 1980, 940; M. Henriet, M. Houtekie, B. Techy, R. Touillaux, and L. Ghosez, Tetrahedron Lett., 1980,21, 223. K. M. Baines, T. W. Rourke, K. Vaughan, and D. L. Hooper, J. Org. Chem.. 1981,46, 856. M. S. Ouali, M. Vaultier, and R. Carrie, Tetrahedron, 1980, 36, 1821.

Heterocyclic Chemistry

210

Pyrolysis of l-cyano-5-methyl-4-phenyl-1,2,3-triazole (560) generates the 1,3-dipole (561), which forms the cyclo-adduct (562) with benzene.551The carbene that is produced thermally from the diazomethyl-triazole (563) adds to p-xylene to yield the cycloheptatriene (564).552 2,4,6-Triaryl-1,3,4,5oxatriazines (566), which are derivatives of a new heterocyclic system, are obtained by irradiation of the triazole N-oxides (565).553

2

Ph

Ph Me C’N N’

Me

N I

I

+

M

e

m

I H

1-Benzyloxybenzotriazole (567; R = PhCH20)decomposes photolytically to a mixture of benzaldehyde and a ~ o b e n z e n e .The ~ ~ ~action of iodobenzene diacetate on 1-aminobenzotriazole (567; R = NH2) results in a mixture of the 2-aryl-benzotriazoles (569; R’ = H, R2 = Ph) and (569; R’ = R2 = Ph); these are formed via the benzyne adduct (568), which undergoes ring-cleavage to (569; R’ = R2 = H), followed by phenylation with b e n ~ y n e . ~4,5-Dehy’~ drotropone (571), generated in the reaction of the condensed triazole (570) with lead tetra-acetate, forms the cyclo-adduct (572) with ~ x e p i n . ~ ~ ~

a) a>yJO:>Q / \

R (567)

N

H2

NR’R~ (569)

(568)

(571) 551 552

”’ 554 555

’”

D . Danion, B. Arnold, and M. Regitz, Angew. Chem., Int. Ed. Engl., 1981, 20, 113. C. D. Bedford, E. M. Bruckmann, and P. A. S. Smith, J. Org. Chem., 1981,46,679. G. J. Gainsford and A. D . Woolhouse, Aust. J. Chem.. 1980, 33, 2447. W. A. Feld, R. Paessun, and M. P. Serve, J. Heterocycl. Chem., 1980,17, 1309. P. G. Houghton and C. W. Rees, J. Chem. Res. (S),1980,303. T. Nakazawa, M. Kubo, and I. Murata, Angew. Chem., Int. Ed. Engl,, 1981,20, 189.

Five-Membered Rings: Other systems

211

For other papers that describe 1,2,3-triazoles, see references 557-560. 1,2,4=Triazoles and a 1,2,4=Trithiole.-The dioxime HO -N=CHN=NCH=N-OH cyclizes in water to 4-hydroxy-1,2,4-triazole(573).56’ Treatment of the azine PhCCl=N-N=CClPh with potassium cyanate affords the triazolinone (574).562A mixture of the triazolidinone (575; R=H) and its 1phenylcarbamoyl derivative (575; R = PhNHCO) is obtained by the action of phenyl isocyanate on acetone phenylhydra~one.~~~ Thiocarbonyl-bis-1,2,4triazol-l-yl (576) functions as a dienophile; with cyclopentadiene, for example, the cyclo-adduct (577) is formed.564 The use of 3-methylthio-1,4-

R

N

(577)

OH (573)

diphenyl-l,2,4-triazolium chloride (578) for the homologation of aliphatic aldehydes is illustrated in Scheme 6, in which the key step is the addition of the aldehyde to the nucleophilic carbene (579).565The reverse reaction (see Scheme 7) can be used for the degradation of carboxylic acids to aldehydes that contain

OHCCH2Pri

-

Ph

/

N.+ A,:,+

MeS

N I

1-

CH2Pri

Ph Reagents: i, Et,N; ii, Pr’CHO; iii, SOCl,; iv, KI, NaHSO,;

V,

NaBH,; Vi, H@+, HCHO

Scheme 6 557

558

559

560

565

J. Svetlik, J. Lesko, and A. Martvon, Monatsh. Chem., 1980, 111,635 (Chem. Abstr., 1981,94,

15 643). R. G. Kostyanovskii, A. V. Prosyanik, A. I. Mishchenko. N. L. Zaichenko, I. I. Chervin, and V. I. Markov, Izv. Akad. Nauk SSSR, Ser. Khim., 1980,882 (Chem. Abstr., 1980,93,71405). S . Cilloni, D. Pocar, L. M. Rossi, and P. Trimarco, J. Chem. Res. ( S ) , 1980,14 (Chem. Abstr., 1980,93,132 423). W. A. Feld and M. P. Serve, J. Heterocycl. Chem., 1980,17,825(Chem.Abstr,, 1980,93,167 239). J. Armand and P. Bassinet, J. Chem. Res. (S), 1980,304. W. T. Flowers, J. F. Robinson, D. R. Taylor, and A. E. Tipping, J. Chem. SOC.,Perkin Trans. 1, 1981,356. M.Heitmann and G. Zinner, Chem.-Ztg., 1980,104,239. C. Lanen and D. N. Harpp, J. Org. Chem., 1980,45,3713. G. Doleschall, Tetrahedron Lett., 1980,21,4183.

Heterocyclic Chemistry

212

MeS

FNHPh > NHPh

Ph

I

Ph

N7.N

N-NPh

MeS(

N Ph (579)

+

/R /

'

Ph

N,N'

MeS

I-

/

A,N+.A /R CH \

I

RCHO

\

I

Y

OAc

Ph

0-

Ph

Reagents: i, KI; ii, Pb(OAc),; iii, MeONa

Scheme 7

one less carbon atom.566Benzonitrile N-phenylimide, PhCGfi-RPh, adds to iron complexes (580; R = alkyl or aryl) or tropone imines to form spirotriazolines (581), which rearrange to mixtures of the [47r + 8~]-cyclo-adducts (582) and their 4 a H - i ~ o r n e r s Treatment .~~~ of the betaine (583) with ethanolic ammonia yields diphenylamine, the azides Et02CNPhCON3and H2NCONPhCON3, and the urea Et02CNPhCONH2.568

-a oNR

pNz

0 : T P h

/

\

Nj p h

\ R WCO),

Fe(CO)3

R

(582)

(581)

(580)

The mechanism of ene-reactions of 4-phenyl-1,2,4-triazoline-3,5-dione (584) has been The compound adds to the silane H2C=CHCH2SiMe3 to yield the ene-product (585), together with the rearranged cyclo-adduct The reagent (586);570with heptalene (587), cis- and truns-(588)are forms the [27r + 87r]-cyclo-adduct (590) with the 3aH-indene derivative

,N -N

0

x

N

<-;N*>

A,

Ph

(583) 566

s67 568

s69 "O

s71

NPh2

N=N

A0

O A N Ph

(584)

O

\

SiMe,

Z-?0 N

Ph

n

SiMe,

CH=CH

/ C\H2

N-N

A0

O AN Ph

(585) (586) G. Doleschall and G.Toth, Terruhedron, 1980,36, 1649. R.Gandolfi and L. Toma, Tetrahedron, 1980,36, 935. E. Fahr, M. J. Richter, W. Schmitt-Sody, and R. Elbert, Tetrahedron Lett., 1980,21,3269. C.A.Seymour and F. D. Greene, J. A m . Chem. SOC.,1980,102,6384. S. Ohashi, W. E. Ruch, and G. B. Butler, J. Org. Chem., 1981,46,614. K.A.Horn, A. R. Brown, and L. A. Paquette, J. Org. Chem., 1980,45,5381.

213

Five-Membered Rings: Other systems

(589),572 and with 1,2-homoheptafulvene (591) it forms a mixture of [27r + 4 ~ 1 and - [27r + 67r + 2a]-cyclo-adducts, (592)and (593)respectively.573 The combined action of the triazolidinedione and triphenylphosphine on the cyclopropene (594) produces the doubly bridged heterocycle (595).574The unstable (benzoy1oxy)enamine H2C=C(02CPh)NMe2 has been trapped by Nphenyltriazolinedione as the adduct (596), in which the acyl group has been transferred from oxygen to a-angelica lactone (597) similarly furnishes compound (598).576

OCPh \

/

CH,CONMe,

oqLo Ph

Ph

(596)

(595)

The dithiolate (599; Ar = p-ClC6H,) forms the trithiole derivative (600) on treatment with phosgene at -78 0C.577 SAr (597) 572 573

574

57s 576

577

O

N

Ph (598)

2Et4Nt (599)

Ar2CL i x C A r (600)

r. L. Giichrist, C. W. Rees, and D. Tuddenham, J. Chem. SOC., Chem. Commun., 1980,689. M.Oda, N. Morita, and T. Asao, Tetrahedron Lett., 1980,21,471. Y . Kobayashi, T. Nakano, K. Shirahashi, A . Takeda, and I. Kumadaki, Tetrahedron Lett., 1980, 21,4615. W.E.Bottomley and G. V. Boyd, J. Chem. SOC., Chem. Commun., 1980,790. W.E.Bottomley, G. V. Boyd, and R. L. Monteil, J. Chem. SOC., Perkin Trans. I , 1980,843. E.Schaurnann, U.Wriede, and J. Ehlers, Synthesis, 1980,907.

214

Heterocyclic Chemistry

A number of other papers on 1,2,4-triazoles have a p p e a ~ e d . ~ ~ ~ - ~ ~ ’ 7 Other Systems containing Three Heteroatoms Oxadiazoles.-l,2,3- and 1,2,4-Oxadiazoles. N- Butylsydnone (601) reacts with tetracyanoethylene to yield, surprisingly, the car-onyl cyanide hydrazone B u N H N = C ( C N ) ~ . ~The ~ ~ glyoxal dinitrone AdN(O-)=CHCH=$(O-)Ad (Ad = 1-adamantyl) and phenyl. isocyanate form mainly the mono-cycloadduct (602).592

1,2,5-Oxadiazoles. The furoxan (604) is produced by the action of nitrosonium fluoroborate on the norbornane derivative (603), presumably by way of an intermediate n i t r o a ~ e t y l e n e .Flash ~ ~ ~ vacuum pyrolysis of the furoxans (605 ;

578

F. Anzani, P. Dalla Croce, and R. Stradi, J. Heterocycl. Chem., 1980, 17, 311 (Chem. Abstr.,

1980,93, 113 458). T. Bany and M. Santus, Ann. Univ. Mariae Curie-Sklodowska, Sect. A A : Chem., 1976-77,31-32, 247 (Chem. Abstr., 1981, 94, 103 248). V. A. Khrustalev, K. N. Zelenin, V. P. Sergutina, and V. V. Pinson, Khim. Geterotsikl. Soedin., 1980, 1138 (Chem. Abstr., 1981,94, 14 675). 581 K. N. Zelenin, V. A. Khrustalev, and V. P. Sergutina, Zh. Org. Khim., 1980, 16, 942 (Chem. Abstr., 1981, 94, 65 532). 582 A. Ikizler and R. Un, Chim. Acta Turc., 1979,7, 269 (Chem. Abstr., 1981,94, 15 645). 583 R. V. Venkataratnam and K. Mohan, Indian J. Chem., Sect. B, 1979, 18, 455 (Chem. Abstr., 1980, 93,26 330). 584 G. Barnikow and D. Richter, 2. Chem., 1980,20, 97 (Chem. Abstr., 1980,93,71 230). s85 G. Zinner, M. Heitmann, and R. Vollrath, Arch. Pharm. (Weinheim, Ger., ), 1981, 314, 94 (Chem. Abstr., 1981, 94, 173 887). 586 K. S. Lehman, L. M. Baclawski, S. A. Harris, H. W. Heine, J. P. Springer, W. J. A. VandenHeuvel, and B. H. Arison, J. Org. Chem., 1981, 46, 320 (Chem. Abstr., 1981, 94,65 547). ”’H. J. Timpe, W. Schroder, and R. Worschech, Rev. Roum. Chim., 1980, 25, 407 (Chem. Abstr., 1980,93, 239 318). 588 S. D. Ziman, J. Heterocycf. Chem., 1980,17,1319 (Chem. Abstr., 1981,94, 15 652). s89 T. R. Hoye, K. J. Bottorff, A. J. Caruso, and J. F. Dellaria, J. Org. Chem., 1980, 45, 4287 (Chem. Abstr., 1980,93, 203 934). 590 V. S. Pilipenko and N. P. Shusherina, Zh. Org. Khim., 1980, 16, 2444 (Chem. Abstr., 1981, 94, 139 695). ”* H. C. Berk and J. E. Franz, Synrh. Commun., 1980,10, 189. 592 G. Zinner, H. Blass, E. Eghtessad, and J. Schmidt, Chem.-Ztg., 1980,104, 145. 593 D. R. Britelli and G. A. Boswell, Jr., J. Org. Chem., 1981,46, 312. 5’9

Five-Membered Rings: Other systems

215

R = Ph or 2-acetoxybornane-2-carbonyl) generates the nitrile oxides RCN0.594 4-Nitrobenzofuroxan (606; R = NO,) affords the condensed norcaradiene (607) on treatment with dia~omethane;~~’ the parent compound (606; R = H) reacts with methyl isopropyl ketone and ammonia to yield the dihydroquinoxaline NN’-dioxide (608),596and with cinnamaldehyde to give a mixture of 2phenylquinoxaline 1-oxide (609) and the corresponding 4-0xide.~”

0-

I

1,3,4-OxadiatoZes. Nitration of 2,5-diphenyl-1,3,4-oxadiazole(610) gives all six possible 2,5-bis(nitrophenyl)-derivatives.598Flash vacuum pyrolysis of 3benzyl-5-phenyl-l,3,4-oxadiazolin-2-one(611) generates the nitrile imine PhCG6 -NCH2Ph as the p r i m a r y p r o d u ~ tThe . ~ ~meso-ionic ~ oxadiazoliumoxide (612) functions as the isocyanate valence tautomer (613) in its reaction with the azomethine ylide (614; Ar = pNO2C6H4)to yield the triazoloisoquinoline (615).600

598

W. R. Mitchell and R. M. Paton, Chem. Znd. (London), 1980,665; D.R. Britelli and G. A. Boswell, Jr., J. Org. Chem., 1981,46,316. R. C. Boruah, P. Devi, and J. S. Sandhu, J. Heterocycl. Chem., 1979,16,1555. K.Heyns, E. Behse, and W. Francke, Chem. Ber., 1981,114,246. A.F. Kluge, M. L. Maddox, and G. S. Lewis, J. Org. Chem., 1980,45,1909. A. Blackhall, D. L. Brydon, A. J. G. Sagar, and D. M. Smith, J. Chem. SOC.,Perkin Trans. 2,

599

A. Padwa, T. Caruso, and D. Plache, J. Chem. SOC.,Chem. Commun., 1980,1229;cf. A.Padwa,

‘O0

T. Caruso, and S. Nahm, J. Org. Chem., 1980,45,4065. R. Brashey and E. Janchen, Chem.-Ztg., 1980,104,240.

594

595 596 597

1980,773.

216

Heterocyclic Chemistry

For other articles on oxadiazoles, see references 601-609.

Phosphorus Compounds.-2,4-Dichloro-5 -methyl-2-oxo- 1,3,2h ’-dioxaphospholen (616), prepared by the action of phosphorus pentachloride and triethylamine on lactic acid, reacts stepwise with alcohols R’OH and R20H, first at the P-C1 bond and then by ring-opening, to yield eventually the phosphates (617).610The unstable dioxaphospholan (618) is produced by treatment of l,l,l-trifluoroacetone with trimethyl phosphite.611Phosphorus-31 n.m.r. spectroscopy indicates that the phosphite (619) exists in equilibrium with the triethylammonium phosphoranide (620)612and that dioxaphospholans (621; R = Me, But, or Ph) dimerize reversibly to the ten-membered-ring compounds (622).613

601

602

603

604

605

606

607

608

‘09

610

612

A. Corsaro, U. Chiacchio, A. Compagnini, and G. Purello, J. Chem. Soc., Perkin Trans. 1, 1980, 1635 (Chem. Absrr., 1981, 94, 15 359). C. V. Greco and J. R. Mehta, J. Chem. SOC.,Perkin Trans. 1, 1980, 20 (Chem. Abstr., 1980, 93, 95 192). J. W. Tilley, H. Ramuz, P. Levitan, and J. F. Blount, Helv. Chim. Acra, 1980, 63, 841 (Chem. Abstr., 1981, 94, 3508). C. Schenk, M. L. Beekes, J. A. M. Van der Drift, and T. J. De Boer, Red. Trav. Chim. Pays-Bas, 1980,99, 278 (Chem. Absrr., 1981,94, 15 309). U. Pliicken, W. Winter, and H. Meier, Liebigs Ann. Chem., 1980, 1557 (Chem. Abstr., 1981, 94, 65 576). F. Terrier, A. P. Chatrousse, and F. Millot, J. Org. Chem., 1980 45, 2660 (Chem. Abstr., 1980, 93,45 487). M. Neitzel and G. Zinner, Arch. Pharm. (Weinheim, Ger.), 1980, 313, 867 (Chem. Absrr., 1981, 94, 65 569). R. Evers, E. Fischer, and M. Pulkenat, Z. Chern., 1980,20,371 (Chem. Abstr., 1981,94,121413). L. Farkas, J. Keuler, and H. Wamhoff, Chem. Ber., 1980, 113, 2566 (Chem. Absrr., 1980, 93, 149 407). P. Lemmen, Tetrahedron Lett., 1979, 4461. A. M. Kibardin, T. Kh. Gazizov, Yu. Ya. Efremov, V. N. Zinin, R. Z. Musin, and A. N. Pudovik, Izv. Akad. NaukSSSR, Ser. Khim., 1980,910. B. Garrigues, M. Koenig, and A. Munoz, Tetrahedron Lett., 1979, 4205. J. P. Dutasta, J. Martin, and J. B. Robert, Heterocycles, 1980,14, 1631.

Five-Membered Rings: Other systems

217

Successive treatment of the phosphite (623; R = Et) with chlorine and antimony pentachloride affords the phosphonium salts (624);614the phenoxy-analogue (623; R = Ph) is converted into the phosphorane (625) by the action of br~rnine.~"The reaction of the quinoline derivative (623; R = 8-quinolinyl) with benzil results in an equilibrium mixture of five- and six-co-ordinated phosphorus compounds (626) and (627), in which the former predominates616 The dithiaphospholan (628) and diethyl azodicarboxylate form the unstable adduct (629), which yields compound (630) on treatment with glyc01.~''

(625) R = Ph (626) R = 8-quinolyl

NMe, [S\ [>PNMe, (628)

----*

P(PJOE'

s'

\N/N C0,Et (629)

NMe,

- [ IP1 s\ /p\ s o (630)

The phosphonium-metal complex [631; R = Mo(q5-C5H,)(CO),]has been prepared by the action of sodium molybdenum(cyclopentadieny1)tricarbonyl on the fluorophosphine (631; R = F).6'8 The X-ray structure of the first phosphorus(v)-phosphorus(v) compound (632) has been determined.619 The 1,3,2benzoxazaphosphole (633) exists as a dynamic equilibrium mixture of two conformational isomers, in which the methyl group occupies axial and equatorial positions.620The kinetics of the interconversion of the two diastereoisomers of the spiro-compound (634) have been measured.62'

'14

'lS 616 617

619

620

621

J. Michalski, M. Pakulski, and A. Skowronska, J. Chem. SOC.,Perkin Trans. I, 1980,833. J. Gloede and H. Gross, J. Prakt. Chem., 1979,321,1029 (Chem. Abstr., 1980,93,7774). Chanh Bui Cong, G. Gence, B. Garrigues, M. Koenig, and A. Munoz, Tetrahedron, 1979,35,1825. J. P. Majoral, R. Kraemer, T. N'Gando M'Pondo, and J. Navech, Tetrahedron Letr., 1980,211307. L. D. Hutchins, R. T. Paine, and C. F. Campana, J. A m . Chem. SOC., 1980,102,4521. J. E. Richman, R. 0. Day, and R. R. Holmes, J. A m . Chem. SOC.,1980,102,3955. R. Haller, K. Scheffler, H. B. Stegmann, and W. Winter, Chem. Ber., 1981, 114, 447; H. B. Stegmann, R. Haller, A. Burmester, and K. Schefller, ibid., p. 14. B. Garrigues, A. Klaebe, and A. Munoz, Phosphorus Sulfur, 1980,8,153.

218

Heterocyclic Chemistry

For other papers on phosphorus systems, see references 622-635. Miscellaneous Other Systems containing Three Heteroatoms.-l-Aza-2-bora3-oxacyclopentanes (635; R’ = F or C1, R2 = Pr’ or Ph) are formed in the reaction of halogenoboranes with disilylated e t h a n ~ l a m i n e sThe . ~ ~ X-ray ~ structure of the spiro-germole (636) has been determined.637Monoacyl derivatives of butane-2,3-diol, e.g. MeCH(OH)CHMe02CPh, are obtained by the action of acyl chlorides on the tin compound (637).638The dioxazole (638)results when dec-l-ene is ozonized in the presence of ammonia.639Ethylene glycol is converted into the tellurium heterocycle (639) under the influence of tellurium tetra~hloride.~~’

r

C1

1-

(638)

For other papers on these systems, see references 641-643. 622

623

624

625

626 627

629

630

631 632

633

634

635

636

637 638

639 640 641

642

643

G. Meggendorfer, R. Schwarz, and I. Ugi, Tetrahedron Lett., 1980, 21, 2493 (Chem. Abstr., 1981, 94,46 702). M. A. Pudovik, N. A. Muslimova, and A. N. Pudovik, Izv. Akad. Nauk SSSR, Ser. Khim., 1980, 1183 (Chem. Abstr., 1980,93, 114408). V, A. Gilyarov, N. A. Tikhonina, T. M. Shcherbina, and M. I. Kabachnik, Zh. Obshch. Khim., 1980, 50, 1438 (Chem. Abstr.. 1981, 94, 3994). R. Burgada, Y. Leroux, and Y. 0. El Khoshnieh, Tetrahedron Lett., 1980, 21, 925 (Chem. Abstr., 1980,93, 113 455). J. Gloede and H. Gross, Sint. Geterotsikl. Soedin., 1979, 11, 59 (Chem. Abstr., 1981, 94, 30 666). V. V. Ragulin, V. I. Zakharov, A. A. Petrov, and N. A. Razumova, Zh. Obshch. Khim., 1981, 51, 34 (Chem. Abstr., 1981,94, 191 365). H. Fauduet and R.Burgada, C.R. Hebd. Seances Acad. Sci., Ser. C, 1980. 291, 81 (Chem. Abstr., 1981,94, 83 351). K. Burger, S. Penninger, and S. Tremmel, Z . Naturforsch., Ted. B, 1980, 35, 749 (Chem. Abstr., 1980,93, 220 666). A. Schmidpeter and H. Tautz, 2. Naturforsch., Teil. B, 1980, 35, 1222 (Chem. Abstr., 1981, 94, 29 896). M. Mulliez and M. Wakselman, Phosphorus Sulfur, 1980,8,41 (Chem. Absfr., 1980,93,149 284). M. S. R. Naidu, C. D. Reddy, and P. S. Reddy, Indian J. Chem., Sect. B, 1979, 17, 458 (Chem. Abstr., 1981, 94, 3965). Yu. G. Gololobov and L. I. Nesterova, Zh. Obshch. Khim., 1980, 50, 683 (Chem. Abstr., 1980, 93. 186 250). Yu.V. Balitskii and Yu. G. Gololobov, Zh. Obshch. Khim., 1980, 50, 1204 (Chem. Abstr., 1980, 93, 114 409). C . D. Reddy, P. S. Reddy, and M. S. R. Naidu, Synthesis, 1980, 1004 (Chem. Abstr., 1981, 94, 139 698). H.-G. Koehn and A. Meller, Z . Naturforsch., Ted. B, 1980, 35, 447. A. C. Sau, R. 0. Day, and R. R. Holmes, J. A m . Chem. SOC.,1980,102,7923. A. Shanzer, Tetrahedron Lett., 1980,21, 221. G. G. Filina, T. A. Bortyan, A. T. Menyailo, and M. V. Pospelov, Zh. Org. Khim., 1980, 16, 782. D. B. Denney, D. Z. Denney, P. J. Hammond, and Y. F. Hsu, J. A m . Chem. Soc., 1981,103,2340. D. S. Matteson and D. Majumdar, J. Chem. SOC.,Chem. Commun., 1980, 39 (Chem. Abstr., 1980,93,45 885). V. F. Rudchenko, V. G. Shtamburg, Sh. S. Nasibov, I. I. Chervin, and R. G. Kostyanovskii, Izu. Akad. Nauk SSSR, Ser. Khim., 1980,2181 (Chem. Abstr., 1981,94,30 669). Q.-C. Mir and J. M. Shreeve, Znorg. Chem., 1980, 19, 1510 (Chem. Abstr., 1980, 93,70 938).

219

Five-Membered Rings: Other systems 8 Systems containing Four Heteroatoms

Tetrazoles.-5-Methoxytetrazole (640; R = H) undergoes an unusual acylation reaction at N- 1 on treatment with methanesulphonyl chloride; the product (640; R = MeS02) opens spontaneously to the azide MeOC(N3)=NS02Me.644 Irradiation of 2-acetyltetrazole (641) affords, infer alia, 2-methyl-1,3,4oxadiazole (642);6451,3,4-0xadiazoles also result when 2-acyl-5-aryl-tetrazoles are heated in The ditetrazolylmethane derivative (643), prepared by the action of sodium azide on the imidoyl chloride Cl,C(CCl=NHPh),, reacts with copper to yield the rearranged triazolyltetrazole (644).647 The lowtemperature matrix photolysis of 2,5-diphenyltetrazole to yield spectroscopically characterized benzonitrile phenylimide, PhC&-NPh, has been announced from two l a b o r a t o r i e ~ . ~ ~ ~

N-N

N-N

$N&xN)\N Ph C1, Ph

- %F N-N

N-N

N )" Ph

NPh

(643)

(644)

on tetrazoles should be noted.

Other

Other Systems.-2,3,5-Triphenyl-1,3,4-triazaborole (645) is transformed into the triazole (646) on treatment with acetic anhydride and sulphuric The amide oxime PhC(NHPh)=NOH reacts with triethyl borate to give the 1,3,5,2oxadiazaborole (647).656 N-NPh PhCN)\BPh

H (645) 644 645

646 647

'*' 649

650 65 1

652

653 654

655 656

-

N-NPh PhCN>#e (646)

N-? PhCN,B

- OEt

Ph (647)

0. S. Rao and W. Lwowski, J. Heterocycl. Chem., 1980,17, 187. K. Murato, T. Yatsunami, and S. Iwasaki, Helv. Chim. Acta, 1980, 63,588. F. Povazanec, J. Kovac, and J. Svoboda, Collect. Czech. Chem. Commun., 1980,45,1299. A. F. Shivanyuk and M. 0. Lozinskii, Zh. Org. Khim., 1980, 16, 2623. H. Meier, W. Heinzelmann, and H. Heimgartner, Chimia, 1980, 34, 504; N. H. Toubro and A. Holm, J. Am. Chem. SOC.,1980,102,2093. 0. Tsuge, S. Urano, and K. Oe, J. Org. CHem., 1980,45, 5130 (Chem. Abstr., 1981,94, 30 668). M. M. Krayushkin, A. M. Beskopylnyi, S. G. Zlotin, 0. A. Lukyanov, and V. M. Zhulin, Izv. Akad. Nauk SSSR, Ser. Khim., 1980,2668 (Chem. Abstr., 1981,94,103 260). N. A. Klyuev, Yu. V. Shurukhin, V. A. Konchits, I. I. Grandberg, V. L. Rusinov, V. A. Zyryanov, and I. Ya. Postovskii, Khim. Geterotsikl. Soedin., 1980, 265 (Chem. Abstr., 1980,93,25 627). F. A. Neugebauer and H. Fischer, Chem. Ber., 1980,113,1226 (Chem. Abstr., 1980,93,46 089). A. F. Hegarty and E. P. Ahern, J. Org. Chem., 1981,46, 1342 (Chem. Abstr., 1981,94,155 948). S. Fischer and C. Wentrup, J. Chem. SOC.,Chem. Commun., 1980, 502 (Chem. Abstr., 1980, 93, 203 762). Z. V. Bezuglaya, G. V. Avramenko, and B. I. Stepanov, Zh. Obshch. Khim., 1980,50,2811. L. Nigam, V. D. Gupta, and R.C. Mehrotra, Synth. React. Inorg. Metal.-Org. Chem., 1980,10,491.

220

He term yclic Chemistry

9 Compounds containing Two Fused Five-Membered Rings (53) Hypervalent Sulphur Compounds.-The trithiapentalene (649) is produced by the combined action of 1-diethylaminopropyne and hydrogen sulphide on the dithiole (64Q6" 1,3-Diacyl-thioureas, R'CONHCSNHCOR2 (R',R2 = Me or Ph), react with bromine to yield 1,6-dioxa-6ah 4-thia-3,4-diazapentalenes (650).658Successive treatment of the thiatriazole (65 1)with two imidoyl chlorides leads to the thiatetra-azapentalenes (652).6s9The synthesis of the condensed trithiapentalene (653) by the action of sodium sulphide on 1,8-dichloro-9,10anthraquinone has been reported.660 +

IY

Me

Me

Me

Me (652)

s-s-s (653)

Nitrogen Systems.--Monoaza-Compounds. Acid-catalysed cyclization of the ester (654), prepared from potassium pyrrole and ethyl benzylidenecyanoacetate, yields the pyrrolopyrrole (655).661 An 0x0-derivative of this ring system, i.e. compound (656), is formed by the intramolecular Wittig reaction of benzyl pyrrole-2-carboxylate with the keten Ph3P=C=C0.662 Treatment of the Nchloro-amine (657) with methanolic silver nitrate results in the rearranged ether (658).663The allylphthalimide (659) cyclizes to a mixture of stereoisomers (660)

\

657

6s8 659

661 663

0 Ph (656) (655) A . Dibo, M. Stavaux, and N. Lozach, Bull. SOC.Chim. Fr., Part2, 1980, 539. J. 0. Gardner, J. Org. Chem., 1980, 45, 3909. Y. Yamamoto and K. Akiba, Heterocycles, 1979, 13 (Special Issue), p. 297. S. Davidson, T. J. Grinter, D. Leaver, and J. H. Steven, J. Chem. Res. (S), 1980, 221. R. Neidlein and G. Jeromin, J. Chem. Res. ( S ) , 1980, 232. K. Nickisch, W. Klose, E. Nordhoff, and F. Bohlmann, Chem. Ber., 1980, 113, 3086. F. M. Schell, R. N. Ganguly, K. S. Percell, and J. E. Parker, 111, Tetrahedron Lett., 1979, 4925.

22 1

Five-Membered Rings: Other systems

Full details of the transformations of the azulene when irradiated in derivative (661) have appeared.665(See these Reports, Volume 2, p. 205).

Diaza-Compounds. Three papers666deal with the synthesis and chemistry of derivatives of syn- and anti-l,5-diazabicyclo[3.3.O]octadienediones (662) and (663), i.e. the ‘bimanes’. Pyrazole reacts with (chlorocarbony1)phenylketen to yield the deeply coloured pyrazolopyrazolium oxide (664; R = H), which is a . ~ ~ ~dimethyl representative of a new class of betaines, named ‘ p a r a i ~ n i c ’ The derivative (664; R = Me) forms the adduct (665) with tetrachloro-o-benzoquinone.668The pyrroloindole (667) is produced by the action of iron and acetic

(663)

(666)

666

667

(667)

K. Maruyama, Y. Kubo, and T. Ogawa, Kokagaku Toronkai Koen Yoshishw, 1979, 268 (Chem.. Abstr., 1980,93, 70 456). N. Abe, and T. Nishiwaki, Bull. Chem. SOC. Jpn., 1980, 53, 1406; Fukusokan Kagaku Toronkai Koen Yoshishu, 12th. 1979,241 (Chem. Abstr., 1980,93,71442). E. M. Kosower and B. Pazhenchevsky, J. Am. Chem. SOC., 1980, 102,4983; E. M. Kosower, B. Pazhenchevsky, H. Dodiuk, H. Kanety, and D. Faust, J. Org. Chem., 1981, 46, 1666; E. M. Kosower, B. Pazhenchevsky, H. Dodiuk, M. Ben-Shoshan, and H. Kanety, ibid., p. 1673. K. T. Potts, S. Kanemasa, and G. Zvilichovsky, J. Am. Chem. SOC., 1980,102, 3971. W. Friedrichsen, 2. Naturforsch., Teil. B, 1980, 35, 1002.

He te roc y c lie Chemistry

222

acid on the pyrrole (666).669Thermolysis of the DL-diamino-diarylethane (668) gives the indoloindole (669).670

4

Triaza-Compounds. The diazo-amide (670) undergoes spontaneous intramolecular 1,3-dipolar cycloaddition to give the pyrrolopyrazole (67 The thermolysis of the azide (672) affords the triazapentalene (673; R = Me),672 which is converted into the epoxide (674) by p h o t o - ~ x y g e n a t i o n The . ~ ~ ~parent compound (673; R = H) reacts with dimethyl acetylenedicarboxylate to yield a mixture of the cyclo-adduct (675) and the rearranged adduct (676).674 NJ

N'!

0

NMe + N ' x N M e 4-J

(670)

(671)

For other articles on these compounds, see references 675-683. E. Aiello, G. Dattolo, and G. Cirrincione, J. Chem. SOC.,Perkin Trans. 1, 1981, 1. E. von Angerer, A. K. Taneja, R. Ringshandl, and H. Schonenberger, Liebigs Ann. Chem., 1980, 409. 671 H. Sturm, K. H. Ongania, J. J. Daly, and W. Klotzer, Chem. Ber., 1981,114, 190. 672 A. Albini, G. F. Bettinetti, and G . Minoli, J. Chem. SOC.,Perkin Trans. 1, 1981,4. 6'3 A. Albini, G. F. Bettinetti, G. Minoli, and S. Pietra, J. Chem. SOC.,Perkin Trans. 1, 1980, 2904. 674 A. Albini, G. F. Bettinetti, G. Minoli, and R. Oberti, J. Chem. Res. ( S ) , 1980, 404. J. Ackrell, F. Franco, R. Greenhouse, A. Guzman, and J. M. Muchowski, J. Heterocycl. Chem., 1980,17, 1081 (Chem. Abstr., 1981,94,47 058). 676 R. Neidlein and G. Jeromin, J. Chem. Res. ( S ) , 1980, 233 (Chem. Abstr., 1980, 93,204 394). 677 A. S. Bailey, P. W. Scott, and M. H. Vandrevala, J. Chem. SOC.,Perkin Trans. 1, 1980, 97 (Chem. Abstr., 1980,93, 26 204). 678 T. C. G. Kazembe and D. A. Taylor, Tetrahedron, 1980,36,2152 (Chem.Abstr., 1981,94,83 873). 679 R. M. Acheson, R. M. Letcher, and G. Procter, J. Chem. SOC.,Perkin Trans. 1, 1980, 535 (Chem. Absfr., 1980,93, 168 048). 680 J. D. Coyle, J. F. Challiner, E. J. Haws, and G. L. Newport, J. Heterocycl. Chem., 1980, 17, 1131 (Chem. Abstr., 1980, 93, 204 431). "' D. Pocar, L. M. Rossi, and P. Trimarco, J. Heterocycl. Chem., 1980, 17,267 (Chem. Absfr., 1980, 93,114 401). F. M. Albini, D. Vitali, R. Oberti, and P. Caramella, J. Chem. Res. ( S ) , 1980, 348 (Chem. Abstr., 1981,94, 15 625). 683 R. Milcent and C. Redeuilh, J. Heterocycl. Chem., 1980,17,1691 (Chem.Absrr., 1981,94,175 000). 669 670

Five-MemberedRings: Other systems

223

Other Systems.-The preparation and conformational analysis of the perhydrofuro[2,3-b]furan (677) have been Tetra-acetylethylene is converted into the spiro-compound (678) in refluxing benzene.6851-Methyl-2,4-dithia-8oxabicyclo[3.3.0]octane (679), which is a degradation product of thiamine, has been synthesized.686The X-ray structures of the bicyclic sulphurane (680), the spiro-sulphurane (68l),and the persulphurane (682) have been determined.687 The structures of several phosphoranes, such as (683) and (684), in solution have been investigated by n.m.r. spectroscopy.688The first organobrominane, compound (686), has been prepared by the action of bromine trifluoride on the alcohol (685).689

*

Me

HO

0

(680)

Y. Kojima, N. Kato, and Y. Terada, Tetrahedron Lett., 1979,4667. G.Adembri, D. Donati, R. Chi, R. Nesi, and M. Scotton, Can. J. Chem., 1980.58,1645. 686 P. Gygax, J. Agric. Food Chem., 1981,29,172. "' W . Y.Lam and J. C. Martin,J. Am. Chem. SOC.,1981,103,120;W.Y.Lam,E. N. Duesler, and J. C . Martin, ibid., p. 127. 688 D.B. Denney, D. Z. Denney, P. J. Hammond, C. Huang, and K . 4 . Tseng, J. Am. Chem. SOC., 684 '13'

689

1980,102,5073. T. T. Nguyen and J. C;Martin, J. Am. Chem. SOC.,1980,102,7382.

224

Heterocyclic Chemistry 10 Compounds containing Fused Five- and Six-membered Rings (5,6)

Nitrogen Systems.-Monoaza-Compounds. The picolinium bromides (687 ; R = Me or Ph) are converted into indolizines (688) in alkaline media.690The diketone (689) cyclizes to compound (690) under the influence of acetic anhydride.691 3-Diethylaminoindolizine is formed in one step from 2-bromopyridine, propargyl alcohol, and diethylamine in the presence of bis(tripheny1phosphine)palladium(I1) chloride and copper iodide.692 The salt (69 1) reacts with carbon disulphide and sodium hydride, folllowed by dimethyl sulphate, to give the ester (692).693Treatment of pyridinium N-dicyanomethylide (693) with triphenylThe benzoindolizine (694) is cyclopropene affords 1,2,3-triphenylindoli~ine.~~~ produced by the action of dibromo-N-methyImaleimideon N-phenylpyrr~le.~~’ The indeno-thione (695) is transformed into the ester (696) by its reaction with p-benzoquinone in

- LqcoMe Me

O

/

(694) 690

691 692

693

694

695

696

p

(496)

W. Schliemann and A. Buge, Pharmazie, 1980, 35, 203. E. K. Pohjala, Acta Chem. Scand., Ser. B, 1980, 34, 79. A. Osawa, Y. Abe, and H. Igeta, Bull. Chem. SOC.Jpn., 1980, 53, 3273. K. Kurata, Y. Tajima, H. Awaya, Y. Tominaga, Y. Matsuda, and G. Kobayashi, Fukusokan Kagaku Toronkai Koen Yoshishu, 12th, 1979,106 (Chem.Abstr., 1980,93,71509); cf. A. Kakehi, S. Ito, K. Nakanishi, K. Watanabe, and M. Kitagawa, Fukusokan Kagaku Toronkai Kocn Yoshishu, 12th, 1979, 111 (Chem. Abstr., 1980, 93, 71 600). K. Matsumoto and T. Uchida, J. Chem. SOC.,Perkin Trans. 1, 1981, 73. K. M. Wald, A. A. Nada, G. Szilagyi, and H. Wamhoff, Chem. Ber., 1980, 113, 2884. K. Buggle and J. Power, J. Chem. SOC.,Perkin Trans. 1, 1980, 1070.

Fiue-Membered Rings: Other systems

225

3-Alkylthio-2-methylindolizinesare produced by the action of alkyl 2,4dinitrophenyl disulphides on 2-methylindoli~ine.~~~ 3-Cyanoindolizine reacts with dimethyl acetylenedicarboxylate to form the cyclazine (697), while 7methylindolizine yields the 1:2 adduct (698).698

(E = C02Me)

Diaza-Compounds. Treatment of the pyrazolinone (699) with lead tetra-acetate generates 2,3-diazacyclopentadienone,which has been trapped as the DielsAlder adduct (700) with 2,3-dimethylb~ta-l,3-diene.~~' Methylation of the pyrrolopyridine (701)yields the pseudoazulene (702).7"03-(Ethylthio)imidazo[1,5-a]pyridine (703)is lithiated at position 5.701 Treatment of the imidazo[ 1,2-a]pyridine (704)with bromine leads to the dimeric product (705).'"* The pyrrolopyridine (706) forms the 1: 1cyclo-adduct (707) with one equivalent of diethyl acetylenedicarboxylate; with an excess, a mixture of the rearranged 1:2 adducts (708) and (709) is Pyridinium N-benzoylimide (710)

(E = COzEt) 697

698 699

'0° 701

' 0 2 703

M. Cardellini, G. M. Cingolani, F. Claudi, U. Gulini, and S. Martelli, Synthesis, 1980, 886. T. Uchida and K. Matsumoto, Chem. Lett., 1980, 149. M. F. Brana, J. M. Castellano, E. Gonzalez, M. Lora-Tamayo, and J. L. Soto, An. Quim., 1979, 75,927. H. J. Timpe, U. Miiller, and R. Worschech, J. Prakt. Chem., 1980,322, 517. P. Blatcher and D. Middlemiss, Tetrahedron Lett., 1980, 21, 2195. E. S. Hand and W. W. Paudler, J. Org. Chem., 1980,45,3738. J. Duflos and G. Queguiner, J. Org. Chem., 1981,46,1195.

226

Heterocyclic Chemistry

reacts with benzyne to yield pyrido[l,2-b]indazole (71o 7 O 4 The phthalimide (7 12) is transformed into compound (7 13) by irradiati~n.~"trans-P-Carbolines (715; R = alkyl) are produced stereoselectively by the action of aldehydes RCHO on the tryptamine derivative (714).706A remarkable photochemical ring-reorganization [(716) + (717)] has been

L+j)

'NCOPh

Triaza-Compounds. The triazolopyridine (719) is one of the products of the The betaine reaction of pyridinium N-imide (718) with trifluoroa~etonitrile.~~~ (720), generated by the action of pyridine on a-chlorobenzylidene benzenesulphonylhydrazine, cyclizes to 3-phenyl-1,2,4-triazolo[4,3-a]pyridine(721) in the presence of chl0rani1.~~~ Pyrazolo[3,4-~]pyridines(723; R = Me, MeO, C1, efc.) are obtained from the acetamido-pyridines (722) by nitrosation, followed by hydrolysi~.~"2-(2-Pyrrolyl)-1,3,4-oxadiazole(724) rearranges to the pyrrolotriazine (725) under the influence of alkali.711The product of the reaction of p-tolyl isocyanate with the furandione (726) has the structure (727; Ar = p-MeCsHd), contrary to a previous The adduct (729) of tetrachlorocyclopropene to pyridazinium N- acetylimide (728) is converted into the pyrazolopyridazine (730) on heating;'13 the cyclopropapyrazolo[ 15-a]704 '05 '06

707

70n

' 0 9 710 711

'12 713

Y . Yamashita, T. Hayashi, and M. Masumura, Chem. Lett., 1980, 1133. M. Machida, H. Takechi, and Y . Kanaoka, Heterocycles, 1980, 14, 1255. F. Ungemach, M. DiPierro, R. Weber, and J. M. Cook, J. Org. Chem., 1981,46, 164.

Y. Yamashita and M. Masumara, Chem. Lett., 1980,621. R. E. Banks and S. M. Hitchen, J. Fluorine Chem., 1980, 15, 179. S. Ito, A. Kakehi, T. Matsuno, and J. Yoshida, Bull. Chem. SOC.Jpn., 1980,53,2007. D. Chapman and J. Hurst, J. Chem. SOC.,Perkin Trans. 1, 1980, 2398. J. C. Lancelot, D. Maume, and M. Robba, J. Heterocycl. Chem., 1980,17, 631. K. Peters and G. Kollenz, Chem. Ber., 1981,114, 1206. A. Ohsawa, I. Wada, and H. Igeta, Heterocycles, 1981, 15, 753; A. Ohsawa, I. Wada, H. Igeta, T. Akimoto, and A. Tsuji, Fukusokan Kagaku Toronkai Koen Yoshishu, 12th, 1979,256 (Chem. Absfr., 1980,93, 71 680).

Five-Membered Rings: Other systems

227

pyrimidine (731) rearranges to yield a complex mixture, which contains the pyrazolodiazepine (732).’14 1,2,3-Triazolo[1,5-a]pyridine (733) decomposes to 2-(dibromomethy1)pyridineon treatment with bromine, whereas nitric acid gives the 1-nitro-derivative.”’ The angular heterocycle (734) is transformed into the linear isomer (735) by the action of 1,2-diamin0ethane.”~ Diphenylcyclopropenone adds to 4-phenyl-1,2,3-benzotriazine(736) to yield a mixture of

(733)

’I4 ’I5 ’I6

T. Kurihara T. Tani, and K. Nasu,Heterocycles, 1981,15,265. G. Jones, D. R. Sliskovic, B. Foster, J. Rogers, A. K. Smith, M. Y. Wong, and A. C. Yarham, J. Chem. SOC.,Perkin Trans. 1, 1981,7 8 . S. Leistner, G. Wagner, and K. Hentschel, 2. Chem., 1980,20,143.

228

Heterocyclic Chemistry

the pyrazolobenzotriazine (737) and the rearranged compound (738), for which the betaines (739) or (740) have been suggested as possible precursors.717

0

\

(736)

O (737)

Ph

N

(739)

Ph

(738)

4

Ph

Tetru-uta-Compounds.Condensation of pyrazole-3-diazonium nitrate with ethyl nitroacetate affords the pyrazolotriazinone (741).718The triazolotriazinium salt (743) is produced by the action of trifluoroacetic anhydride on a mixture of 1-amino-4-phenyl-1,2,3-triazole(742) and a~etylacetone.~’~ Treatment of the hydrazone (744) with lead tetra-acetate leads to the triazolopyridazine (745).720 The preparation of the novel betaines (746) from 3-methylpyrazole-5-carboxylic acid alkylhydrazides has been de~cribed.~” The cyclic carbodi-imide (748), which is stable at -196”C, is formed by flash vacuum pyrolysis of the tetrazolopyridine (747).’” cis-o-Azidocinnamonitrile,N3C6H4CH=CHCN, cyclizes to H

0 (7411

(743)

Me

. I

(744)

(745)

0-

(746)

N -

(747)

(748)

”’ D . E. Davies, D . L. R. Reeves, R. C. Storr, C. W. Rees, and D. J. Williams, J. Chem. Soc., Chem. 718

’19

720

”’

”’

Commun., 1980,808. V. L. Rusinov, A. Yu. Petrov, and I. Ya. Postovskii, Khim. Geterotsikl. Soedin., 1980,1283. V. A. Chuiguk, G. N. Poshtaruk, and V. A. Goroshko, Ukr. Khim. Zh. (Russ. Ed.), 1981,47,76. J. Kosary, Magy. Kem. Foly., 1980,86, 564 (Chem. Abstr., 1981,94, 175 021). E.Tihanyi, P. Sohar, 0. Feher, and M. Gal, Heterocycles, 1980,14, 1291. C. WentruD and H. W. Winter, J. Am. Chem. SOC., 1980, 102,6159.

Five-Membered Rings: Other systems

229

tetrazolo[1,5-u]quinoline (749) on heating, whereas the trans-isomer affords 2-cyan0indole.~~~ The hydrazone (750) forms the tricyclic cation (751) on protona t i ~ nThe . ~ tetrazolopyridinium ~~ salt (752; Ar = p-ClC6H4)is cleaved to the tetrazole (753) by the action of sodium ethoxide, contrary to a previous Photolysis of the triazolopyridine (754) results in the pyrrolopyridoisoquinoline (755).726

N=N

MeN-N H

(749)

(751)

(752)

1 (754)

Pentu-uzu-Compounds. 3-Hydrazino-l,2,4-triazine1-oxide (756) reacts with the acetal AcOCH(OEt), to yield the triazolotriazine oxide (757).727The diazopyrazole (758) functions as a 1,7-dipole in the cycloaddition to phenyl isocyanate, forming the pyrazolotetrazinederivative (759).728The photochemical transformation of the N-phenyltriazolopyrimidine(760) to the indolopyrimidine 0-

Ph + N 5 N m M e

Ph

N

-+

N-N (756)

(758)

(759)

1 (757) 723 724

72s 726 727 728

0

Ph (760)

H (761)

L. Garantiand G. Zecchi, J. Org. Chem., 1980,45,4767. B. I. Buzykin, A. P. Stolyarov, and N. N. Bystrykh, Tetrahedron Lett., 1980, 21, 209. A. Gelleri, A. Messmer, S. Nagy, and L. Radics, Tetrahedron Lett., 1980, 21, 663. C. Rivalle, L. Ducrocq, J. M. Lhoste, and E. Bisagni, J. Org. Chem., 1980, 45, 2176. W. W. Paudler and R. M. Sheets, J. Org. Chem., 1980,45, 5421. G. Ege and K. Gilbert, Tetrahedron Lett., 1979,4253.

230

Heterocyclic Chemistry

(761)has been described.729The cyclic carbodi-imide (764)is a common intermediate in the thermolysis of the isomeric heterocycles (762)and (763)to yield, inter alia, 1-cyano-2-phenylbenzimidazole(765).730 N-N

/

(764)

(765)

N =N

I

\

(763)

For other papers on these penta-aza-compounds, see references 731-753. 729

730

731 732

733

734

735 736

737

738

739

740

741

742 743

744

745 746

747

T. Higashino, E. Hayashi, H. Matsuda, and T. Katori, Heterocycles, 1981,15,483. C . Wentrup, C. Thetaz, E. Tagliaferri, H. J. Lindner, B. Kitschke, H. W. Winter, and H. P. Reisenauer, Angew. Chem., Int. Ed. Engl., 1980,19, 566. K. B. Soroka and J. A. Soroka, Tetrahedron Lett., 1980,21,4631 (Chem. Abstr., 1981,94,174 797). A. Kakehi, S. Ito, K. Watanabe, T. Ono, and T. Miyazima, J. Chem. Res. ( S ) , 1980, 18 (Chem. Abstr., 1980, 93, 132 417). A. R. Katritzky, M. Michalska, R. L. Harlow, and S. H. Simonsen, J. Chem. SOC., Perkin Trans. 1,1980,354 (Chem. Abstr., 1980,93,132 420). V. B. Ivanov, V. S. Reznik, B. E. Ivanov, A. A. Musina, and Yu.Ya. Efremov, Izu. Akad. Nauk SSSR,Ser. Khim., 1980,2428 (Chem. Abstr., 1981,94,47 265). V . A. Anisimova, N. I. Avdyunina, A. F. Pozharskii, A. M. Simonov, and L. N. Talanova, Khim. Geterotsikl. Soedin., 1980, 528 (Chem. Abstr., 1980, 93, 149 290). A. V. Azimov and L. N. Yakhontov, Khim. Geterotsikl. Soedin., 1980, 1562 (Chem. Abstr., 1981, 94, 103 208). N. F. Kucherova, N. M. Sipilina, N. N. Novikova, I. D. Silenko, S. G. Rozenberg, and V. A. Zagorevskii, Khim. Geterotsikl. Soedin., 1980, 1383 (Chem. Abstr., 1981,94, 121 372). H. Bieraugel, R. Plemp, H. C. Hiemstra, and U. K. Pandit, Heterocycles, 1979, 13 (Special Issue), p. 221 (Chem. Abstr., 1980,93,26318). E. Georgescu, I. Druta, and M. Petrovanu, Rev. Roum. Chim., 1981, 26, 109 (Chem. Abstr., 1981,94, 208 802). J. Grimshaw and A. P. De Silva, J. Chem. SOC.,Chem. Commun., 1980, 1236 (Chem. Abstr., 1981,94, 138 888). H. Ogura, S. Mineo, and K. Nakagawa, Heterocycles, 1980, 14, 1125 (Chem. Abstr., 1981, 94, 47 224). H. Dorn and R. Ozegowski, J. Prakt. Chem., 1979,321,881 (Chem. Abstr., 1980,93, 8078). M. M. Abbasi, M. Nasr, and H. H. Zoorob, Monatsh. Chem., 1980, 111, 963 (Chem. Abstr., 1981, 94,47 216). M. Gal, 0. Feher, E. Tihanyi, G. Horvath, G. Jerkovich, G. Argay, and A. Kalman, Tetrahedron Lett., 1980,21, 1567 (Chem. Abstr., 1980,93, 204 524). M. Santus, Pol. J. Chem., 1980, 54, 661 (Chem. Abstr., 1981, 94, 65 565). C. R. Hardy and J. Parrick, J. Chem. SOC.,Perkin Trans. 1, 1980, 506 (Chem. Abstr., 1980, 93, 132 395). B. Stanovnik, M. Tisler, D. Gabrijelcic, M. Kunaver, and J. Zmitek, J. Heterocycl. Chem., 1979, 16, 1567 (Chem. Abstr., 1980,93,46 525).

23 1

Five-Membered Rings: Other systems

Mixed Oxygen-Nitrogen Systems.-Thermal oligomerization of methacraldehyde oxime gives the perhydroisoxazolo[2,3-a]pyridine (766),which exists as two conformational isomers. The X-ray structure of the ‘a-form’ has been determined.754The oxazolo[2,3-a]isoquinoline (767) forms the rearranged methanobenzoxazonine (768) in the presence of methanolic cyanogen Details of the thermolysis of the oxadiazolopyridine (769)to yield the condensed triazinedione (770)have appeared.756The reaction of pyridine N-oxide with phenyl isocyanate has been re-examined. The initial cyclo-adduct (771) readily rearranges to (772),which is converted into 2-anilinopyridine on heating.757The pyridylurea (773)eliminates aniline at 250°C to form the meso-ionic compound (774).758 Thermolysis of the azide (775)(or deoxygenaMe

v

-

(771)

(770) 0 NHPh

c=o (773)

-

(774)

V. A. Zyryanov, V. L. Rusinov, and 1. Ya. Postovskii, Khim. Geterotsikl. Soedin., 1980, 1690 (Chem. Abstr., 1981,94,156 834). 749 A. Messmer and G. Hajos, J. Org. Chem., 1981,46,843 (Chem. Absrr.. 1981,94,138997). ‘Is0W. A. Romanchick and M. M. Joullie, Heterocycles, 1980,14, 1139 (Chem. Abstr., 1981,94, 748

41 276). K. Imafuku, M. Sumio, and H. Matsumura, Synthesis, 1980,331(Chem.Abstr., 1980,93,114458). W. E. Hull, M. Kiinstlinger, and E. Breitmaier, Angew. Chem., In!. Ed. Engl., 1980, 19, 924 (Chem. Abstr., 1981,94,102 419). 7 5 3 R. I. Trust, J. D. Albright, F. M. Lovell, and N. A. Perkinson, J. Heterocycl. Chem., 1979, 16, 1393 (Chem. Abstr., 1981,94,15 682). 754 T.Ota, S. Masuda, and M. Kido, Bull. Chem. SOC.Jpn., 1980,53,3240. Is’ J. B. Bremner and K. N. Winzenberg, Heterocycles, 1980,14,1085. 756 A. Ohsawa, H. Arai, and H. Igeta, Chem. Pharm. Bull., 1980,28, 3570;cf. Heterocycles, 1979, 12,917. 757 T.Hisano, T. Matsuoka, M. Ichikawa, and M. Hamana, Heterocycles, 1980,14,19. 758 M. Alajarin and P. Molina, Tetrahedron Lett., 1980,21,4025. 751

’”

232

Heterocyclic Chemistry

tion of the corresponding nitro-compound) yields the indazolobenzopyran (776), which rearranges to the indazoloindazole (777) in acetic anhydride.759 The condensed furoxan (778) reacts with a-methylene-ketones to form pyridopyrazine dioxides; butan-2-one, for instance, affords compound (779).760 Oxidation of benzhydroxamic acid generates the nitrosocarbonyl derivative PhCONO, which has been trapped by .2,5 -dimethylfuran as the Diels-Alder adduct (780).761

0-

1

0(779)

Other work on related systems has been d e s ~ r i b e d . ~ ~ * - ’ ~ *

759

760

761

762

763

764

765

766

767

768 769

770

771

772

M. Alkhader, R. K. Smalley, and B. Mohajerani, Synthesis, 1980, 381. D. Binder, C. R. Noe, J. Nussbaumer, and B. C. Prager, Monatsh. Chem., 1980, 111, 407; cf. L. E. Crane, G. P. Beardsley, and Y. Maki, J. Org. Chem., 1980,45, 3827; F. Yoneda, T. Tachibana, J. Tanoue, T. Yano, and Y. Sakuma, Heterocycles, 1981, 15, 341. D. Mackay, H. L. Dao, and J. M. Dust, J. Chem. Soc., Perkin Trans. 1, 1980, 2408. G. Daidone, S. Plescia, and J. Fabra, J. Heterocycl. Chem., 1980, 17, 1409 (Chem. Abstr., 1981, 94, 121 395). E. Tighineanu, F. Chiralev, and D. Raileanu, Tetrahedron, 1980, 36, 1385 (Chem. Abstr., 1981, 94, 15 618). Y. Kanaoka and K. San-nohe, Tetrahedron Lett., 1980,21,3893 (Chem. Abstr., 1981,94,156 654). L. G. Sharanina, V. P. Marshtupa, and Yu. A. Sharanin, Khim. Geterotsikl. Soedin., 1980, 1420 (Chem. Abstr., 1981, 94, 47 212). G. Tacconi, G. Gatti, and G. Desimoni, J. Prakt. Chem., 1980, 322, 831 (Chem. Abstr., 1981, 94, 174962). H. Junek, B. Thierrichter, and G. Lukas, Chem. Ber., 1980, 113, 1195 (Chem. Abstr., 1980, 93, 8069). H. H. Otto and H. Schmelz, Monatsh. Chem., 1980, 111, 5 3 (Chem. Abstr., 1980,93,71629). T. Shimizu, Y. Hayashi, Y. Nagano, and K. Teramura, Bull. Chem. SOC.Jpn., 1980, 53, 429 (Chem. Abstr., 1980,93, 114 385). T. Sakamoto, H. Yamanaka, A. Shiozawa, W. Tanaka, and H. Miyazaki, Chem. Pharm. Bull., 1980, 28, 1832 (Chem. Abstr., 1981, 94, 30 693). I. P. Bachkovskii, A. P. Mikhailovskii, and V. A. Chuiguk, Ukr, Khim. Zh. (Russ.Ed.), 1980, 46,639 (Chem. Abstr., 1980,93,168 222). B. R. Rao and K. Ahmed, Curr. Sci., 1980, 49, 310 (Chem. Abstr., 1980, 93, 150220).

Fiue-Membered Rings: Other systems

233

11 Compounds containing Fused Five- and Seven-Membered Rings (5,7) and Three or Four Fused Heterocyclic Rings [(5,5,5), (5959% (5,597)9 (59694)9 (5,6,8), and (5,5,7,7)1 Treatment of the pyrroloazepinone (781) with the Wittig reagent Ph3P=CHCOPh affords the bridged compound (782) by sequential Michael addition, intramolecular attack at the benzoyl carbonyl group, and elimination of triphenylphosphine Thermolysis of the diphenylmethane derivative (783) yields the azepinoindole (784) with expansion of the electron-deficient benzene ring.774The pyrazolinodiazepine (785) loses nitrogen at 105 “Cto yield a mixture of N-benzoyl-5 -isopropyl- 1,2-diazepine, N-benzoyl-5 -isopropenyl1,2-diazepine, the cyclopropadiazepine (786), and the tricyclic compound (787).775

The dipyrrolo[ 1,2-c : 2’,1’-elimidazole (788) has been prepared from di(pyrro1-

1-yl)methane by lithiation, followed by treatment with copper(I1) The boratriazatricyclodecane (789; n = 1) exists only as a dimer, whereas the homologue (789; IZ = 2) is dimeric in solution but monomeric in the vapour phase.777The lithium compound (790) reacts with benzonitrile to yield the diazacycl[3.2.2]azine (791) with elimination of lithium ethylthi~late.~~’

773 774

775 776

”’

”*

W. Flitsch and E. R. Gesing, Tetrahedron Lett., 1979, 4529. P. C. Hayes and G. Jones, J. Chem. SOC.,Chem. Commun., 1980,844. P. Gesche, F. Klinger, J. Streith, and H. Strub, Tetrahedron Lett., 1980,21,4507. U. Burger and F. Dreier, Helu. Chim. Acta, 1980, 63, 1190. J. E. Richman, N. C. Yang, and L. L. Andersen, J. A m . Chem. SOC.,1980,102,5796. P. Blatcher, D. Middlemiss, P.Murray-Rust, and J. Murray-Rust, Tetrahedron Lett., 1980,21,4193.

Heterocyclic Chemistry

234

The 1,2-di(methoxycarbonyl)cyc1[3.2.2]azine [cf. (793)] is formed by treating the adduct (792) of diethyl azodicarboxylate to indolizine with dimethyl acetylenedi~arboxylate;~’~ the isomer, in which the ester groups are in positions 5 and 6, has been prepared from pyrrolo[l,2-a]pyrrole (794) by a Vilsmeier-Haack reaction, followed by dipolar cycloaddition of the product to the acetylenic ester.78”Compound (794) reacts with the fulvene salt (795) to yield the cyclopentacycl[4.2.2]azine (796), whole electronic spectrum resembles that of azulene.781The synthesis of the 1,4-diazepino[1,7-u]benzimidazole (797) has been

NC0,Et

I

NHC0,Et (792)

yCE

Q

E2

E

E

(E = C02Me)

NMe,

C’

clod-

+NMe2

(796) (797)

(795)

1-Benzyl-3-cyanopyridinium chloride forms the dimeric compound (798) under the influence of hydroxylamine and potassium t - b u t o ~ i d e . 2~~~ Chloroquinoxaline reacts with heterocyclic compounds that contain active

Ph (798) 779 780

”’

782

783

(799)

W. Flitsch and J. Heinrich, Tetrahedron Lett., 1980, 21, 3673. M. A. Jessep and D. Leaver, J. Chem. SOC.,Perkin Trans. 1, 1980, 1319. M. A. Jessep and D. Leaver, J. Chem. SOC.,Perkin Trans. 1, 1980, 1324. H. Stahle, H. Koppe, H. Daniel, K. H. Pook, H. J. Forster, H. J. Hecht, and W. Steglich, Chem. Ber., 1980, 113,2841. W. H. Gundel, 2. Naturforsch., Teil.B, 1980,35, 896.

Five-Membered Rings: Other systems

235

methyl groups; with 2-methyl-3-phenoxyquinoxaline,for example, the condensed heterocycle (799) is The betaine (800), prepared from 8-aminoquinoline and phenacyl bromide, reacts with dimethyl acetylenedicarboxylate to form the dehydro-adduct (801).785Novel macroheterocycles have been synthesized, starting with phthalodinitrile; thus condensation with two equivalents of anthranilamide gave compound (802).786The dipyrryl-dialdehyde (803) has been converted into the bright-red bridged [14]annulenedione (804) by treatment with benzyl cyanide and boron t r i f l u ~ r i d e . ’ ~ ~

O NC H O

I

Several other r e p ~ r t on ~ ~bi-~ and ~ -poly-cyclic ~ ~ ~ systems should be noted. 784 785 786

787 788 789 790

791

792

793

794 795

796 191

798

799

800

R. K. Anderson, S. D. Carter, and G. W. H. Cheeseman, Tetrahedron, 1979,35, 2463. S . Kanemasa, S. Kobira, and S. Kajigaeshi, Heterocycles, 1980, 14, 1107. I. I. Ponomarev, N. I. Vasyukova, S. A. Siling, B. V. Lokshin, S. V. Vinogradova, and V. V. Korshak. Izu. Akad. Nuuk SSSR, Ser. Khim., 1980, 1866; cf. S. A. Siling, I. I. Ponomarev, N. I. Vasyukova, V. V. Korshak, and S . V. Vinogradova, ibid., 1980,2335. W. Flitsch and W. Schulten, Chem. Ber., 1981,114,620. F. A. Carey and R. M. Giuliano, J. Org. Chem., 1981,46,1366 (Chem. Abstr., 1981,94,208 829). T. C. McKenzie, J. Heterocycl. Chem., 1980,17, 657 (Chem. Abstr., 1980,93, 168 157). K. Jurkschat, C. Miigge, A. Tzschach, A. Zschunke, and G. W. Fischer, Z. Anorg. Allg. Chem., 1980,463,123 (Chem. Abstr., 1980,93,238 456). A. S. Medvedeva, M. M. Demina, N. I. Protsuk, I. D. Kalikh-man,E. I. Brodskaya, G. A. Kalabin, and N. S. Vyazankin, Zh. Obshch. Khim., 1980,50, 1775 (Chem. Abstr., 1981,94, 30 630). J. P. Dirlam, R. B. James, and E. V. Shoop, J. Heterocycl. Chem., 1980, 17, 409 (Chem. Abstr., 1980,93, 132 421). V. M. Dziomko, B. K. Berestevich, A. V, Kessenikh, R. S. Kuzanyan, and L. V. Shmelev, Khim. Geterotsikl. Soedin., 1980, 1524 (Chem. Abstr., 1981,94, 103 233). D. J. Brown and K. Shinozuka, Aust. J. Chem., 1980, 33, 1141 (Chem. Abstr., 1981, 94, 30 690). M. A. Khan and A. C. C. Freitas, J. Heterocycl. Chem., 1980, 17, 1603 (Chem. Abstr., 1981,94, 103 295). K. C. Joshi and P. Chand, Heterocycles, 1981,16,43 (Chem. Abstr., 1981,94, 175 062). A. Konnecke, R. Dorre, E. Kleinpeter, and E. Lippmann, Tetrahedron, 1979, 35, 1957 (Chem. Abstr.. 1980, 93, 7144). J. Schmidt and G. Zinner, Arch. Pharm. (Weinheim, Ger.), 1980, 313, 174 (Chem. Abstr., 1980, 93,26 385). V. A. Chuiguk and T. I. Glukhova, Ukr. Khim. Zh. (Russ. Ed.), 1980, 46, 835 (Chem. Abstr., 1981,94,65 605). A. Kakehi, S. Ito, K. Watanabe, M. Kitagawa, S. Takeuchi, and T. Hashimoto, J. Org. Chem., 1980,45, 5100 (Chem. Abstr., 1981,94,30471).

4 Six-Membered Ring Systems BY S. D. CARTER, G. W. H. CHEESEMAN & G. P. ELLIS

PART I: Systems containing Nitrogen by S. D. Carter and G. W.H.Cheeseman 1 Introduction In the hope of alerting readers to some interesting papers which it has not been possible to include in the text, a classified reference list is added at the end of this article. With this exception, the format is similar to that of the previous review in this series.

2 Reviews In the past year, the first part of a monograph on isoquinolines' has appeared. Books on organophosphorus reagents in organic synthesis2 and on thermal electrocyclic reactions3 contain much interesting reading on the synthesis of six-membered rings that contain nitrogen. Reviews on 1,7-na~hthyridines,~ acridizinium salts,5 and 1,3-oxazines6 have been published. Other specialist reviews are devoted to heterocyclic betaine derivatives of alternant hydrocarb o n ~ 3-oxidopyridinium ,~ betaines,' the reactions of aryl-pyridines,' the cycloaddition reactions of pyridines," aminimides (N-aminoazine ylides)," the thermal and photochemical additions of dienophiles to arenes and to their vinylogues and hetero-analogues,'2 heteroaromatic radical^,'^ heterocyclic p s e ~ d o - b a s e s , ~ ~ the Bischler-Napieralski and related reaction^,'^ the reactions of 9-substituted acridines,16 the conversion of simple pyrimidines into derivatives with a Cfunctional group,17 naturally occurring pyrazines and their mass-spectrometric Chem. Heterocycl. Compd., Vol. 38, Pt. 1, ed. G. Grethe, Wiley, New York, 1981. 'Organophosphorus Reagents in Organic Synthesis', ed. J. I. G. Cadogan, Academic Press, New York, 1979. E. N. Marvell, 'Thermal Electrocyclic Reactions', Academic Press, New York, 1980. W. Czuba, Wiad. Chem., 1980,34,263. '. S.-D. Saraf, Heterocycles, 1980,14, 2047. T. Kato, N. Katagiri, and Y. Yamamoto, Heterocycles, 1980, 14, 1333. C. A. Ramsden, Adv. Heterocycl. Chem., 1980, 26, 1. A. R. Katritzky and N. Dennis, 'New Trends in Heterocyclic Chemistry', Elsevier, Amsterdam, 1979, p. 290. H. B. Degussa, Aldrichirnica Acta, 1981, 14, 13. W. Sliwa, Heterocycles, 1980, 14, 1793. S . Wawzonek, Ind. Eng. Chem., Prod. Res. Dev., 1980,19, 338. T. Wagner-Jauregg, Synthesis, 1980, 165. l3 P. Hanson, Adv. Heterocycl. Chem., 1979,25, 208; 1980, 27, 31. l4 J. W. Bunting, Adv. Heterocycl. Chem., 1979, 25, 2. G. Fodor and S. Nagubandi, Tetrahedron, 1980,36, 1279. l 6 S. Skonieczny, Heterocycles, 1980,14, 985. l7 T. Sakamoto and H. Yamanaka, Heterocycles, 1981, 15, 583.

237

238

Heterocyclic Chemistry

characterization,18 and the transformation of diazoquinone adducts. l 9 The synthetic utility of nitrenes,20isoureas,21glutaconaldehyde, and 5 -amino-penta-2,4and orfho-amino-benz~phenones~~ has been dienals,22orfho-amino-aldehyde~,~~ reviewed; in addition, reviews have appeared on l-azabicyclo[3.2. l l h e ~ a n e s , ~ ~ 2-azabicyclo[3.3. l l n ~ n a n e s ,and ~ ~ ring-syntheses of heteroaromatic nitrocompounds2’.

3 Azines and their Hydro- and Benzo-derivatives Pyridines.-Synthesis. Improved yields in the synthesis of pyridines from propargylic alcohols and N-cyano-amines have been obtained by using the N-cyanoderivative of N-methylaniline rather than that from the more basic secondary amine pyrrolidineZs (cf. ref. 29). 2-Pyridones have been prepared in yields varying from 13 to 76% by the polyphosphoric-acid-catalysedcondensation of ketones with acetoacetamide (Scheme 1). This method could sometimes (in Me

Me

H Scheme 1

principle) lead to two isomeric products, but no comment is made on the apparent regioselectivity of the process.3o 4-Amino-2-azabutadienes (l), prepared by reaction of azomethines with dimethylformamide diethyl acetal, give pyridines (2) on reaction with dimethyl acetylenedicarboxylate (Scheme 2).31 M e z N y N y A r

E

+ ECECE

(-Me * NH)

,

H

(1)

E o : r (2) [154I0/o]

(Ar = Ph, p-C1C6H4,or p-MeC6H4; E=C02Me) Scheme 2

1,2,4-Triazine (4) yields 3,4-disubstituted pyridines, e.g. ( 5 ) , on reaction with electron-rich alkenes, e.g. (3); these additions are regiospecific (Scheme 3).32

’’ J. J. Brophy and G. W. K. Cavill, Heterocycles, 1980,14, 477. F. G. Contreras and M. Lora-Tamayo, Heterocycles, 1979, 13, 389. ’’ 0.Meth-Cohn, Heterocycles, 1980,14, 1497. l9

”

’*

23 24

” 26 27 28 29

30 31

’’

L. J . Mathias, Org. Prep. Proced. Znt., 1980, 12, 309. J. Becher, Synthesis, 1980, 589. P. Caluwe, Tetrahedron, 1980, 36, 2359. D. A. Walsh, Synthesis, 1980, 677. D. St. C. Black and J. E. Doyle, A d v . Heterocycl. Chem., 1980, 27, 1. J. Bosch and J. Bonjoch, Heterocycles, 1980, 14, 505. S. Rajappa and M. D. Nair, A d v . Heterocycl. Chem., 1979, 25, 113. L. E. Overman and J. P. Roos, J. Org. Chem., 1981,46, 811. R. K. Smalley, in ‘Aromatic and Heteroaromatic Chemistry’, ed. H. Suschitzky and 0. Meth-Cohn (Specialist Periodical Reports), The Chemical Society, London, 1979, Vol. 7, Ch. 4. T. Kato, M. Sato, M. Noda, and I. Itoh, Chem. Pharm. Bull., 1980,28, 2244. R. Gompper and U. Heinemann, Angew. Chern., Znt. Ed. Engl., 1981, 20, 296. D. L. Boger and J. S. Panek, J. Org. Chem., 1981,46, 2179.

239

Six-Membered Rings: Systems containing nitrogen

(4)

Scheme 3

2-Amino-3,4,5-tricyanopyridines(7) are formed simply by heating iminonitriles (6) with tetracyanoethylene (Scheme 4).33

R

NH L C

(-HCN)

N

-k

(Nc)2c=c(cN)2

NC

CN \'CN

R QNH2

N (7)

(6)

(R = Me,Ph, or p-C1C6H4) Scheme 4

Fused pyridones result from Horner-Wittig reaction of heteroaromatic carboxaldehydes with phosphonate esters, as illustrated by the formation of the pyridone (10) from pyrimidine-4-carboxaldehyde (8) and the phosphonate (9) (Scheme 5).34The intermediate alkene may sometimes be isolated. 0

Scheme 5

A new series of 4,6-diaryl-3,5-dicyano-2-pyridones (13) has been prepared, in excellent overall yields, by the reactions of the a -benzoylcinnamonitriles (11) with cyanoacetamide, followed by treatment of the resulting hydroxypiperidones (12) with sodium nitrite and sulphuric acid (Scheme 6).35

0

Reagents: i, H,NCOCH,CN, piperidine, MeOH, at r.t.; ii, NaNO,, H,SO,

Scheme 6 33 34

35

H.-W. Schmidt, G. Zacharias, and H. Junek, Synthesis, 1980,471. S. Linke, J. Kurz, D. Lipinski, and W. Gau, Liebigs Ann. Chem., 1980, 542. C. Sloane, J. L. Soto, and M. P. Zamorano, Heterocycles, 1980,14,639.

Ph

Heterocyclic Chemistry

240

4,5-Unsubstituted pyridinediols (14) result from the base-promoted cyclization of substituted acetamides with ethyl propiolate (Scheme 7). The reaction of phenylsulphonylacetamide with diethyl malonate similarly yields a pyridinetriol (15).364-Pyridone-3-carboxylates(16) have been prepared by the . ..

I, 11

CO2Et

6-2ph

HO

CONH,

Reagents: i, NaOMe;(R=CN ii, aq. HCI or PhS02)

HO\

(14)

Scheme 7

OH

(15)

reaction of 4-substituted ethyl acetoacetates with 1,3,5-triazine. Although this reaction was first reported in 1962, a greatly extended range of 4-pyridones has now been prepared. Yields vary from 6.7 to 98% (Scheme 8h3'

Scheme 8

The reaction of the enamine (17; X=OEt) with ethyl propiolate in a molecular ratio of 2 : 1 yields the dihydropyridine (18; X = OEt), which undergoes basecatalysed elimination to give the pyridine-3,5-dicarboxylate (19; X = OEt). When the enamine (17; X = NH2) is allowed to react with ethyl propiolate, in the presence of sodium ethoxide, the corresponding pyridine (19; X = NH2) is obtained directly (Scheme 9).38 2H,N\ C=CHCO,Et

X

/

+

'1'

CH,CO,Et

&E

t

~

2

~

x

~

~

~

t

C0,Et

Reagents: i, heat at 100 "C,for 1 h; ii, NaOEt

Scheme 9

2,4,6-Triaryl-pyridines (22) have been prepared by the reaction of phenacylidene dimethylsulphurane (20) with a/3-unsaturated ketones (21) and ammonium acetate (Scheme Previously, the corresponding quinolinium ylides had been used as substrates in this reaction (see ref. 167). 3h 37

38

39

W. Jiinemann, H.-J. Opgenorth, and H. Scheuermann, Angew. Chem., Int. Ed. Engl., 1980,19,388. M. Balogh, I. Hermecz, Z. M&sziiros,K. Simon, L. Pusztay, G. Horvath, and P. DvortsLk, J. Heterocycl. Chem., 1980,17, 359. D. K. Dantchev and I. C. Ivanov, Synthesis, 1981, 227. (a)R. S. Tewari and A. K. Awasthi, Synthesis, 1981, 314; ( b ) R. S. Tewari and A. K. Dubey, J. Chem. Eng.Data, 1980,25, 91; ( c ) U.S. P. 4 196 287 (Chem. Abstr., 1980,93, 114 337).

24 1

Six-Membered Rings: Systems containing nitrogen

Further cobalt-catalysed co-oligomerizations of alkynes with nitriles have been reported, using a~rylonitrile~' and thiocyanate~~' as the nitrile components (Scheme 11).

(R = H2C=CH or R'S) Reagents: i, cyclopentadienyl-octadienylcobalt complex

(21)

(20)

Reagents: i, NH40Ac, HOAc

Scheme 10

Scheme 11

A one-pot synthesis of 2-amino-4-aryl-3-cyanopyridines(23)involves heating a mixture of malononitrile, an aryl aldehyde, an alkyl ketone, and an excess of ammonium acetate in boiling benzene (Scheme 12).42 4-Pyridone-3-carboxylic acids (25) are formed by treatment of 3(aminomethy1ene)pyrandiones (24) with aqueous dimethylamine (Scheme 13).43

+ ArCHO . + A

R 'COCH2R2

0

0

CH2(CN),

R()C02H

R'ficN R' /NH2 N (23) [3 5 - 6 7 '10]

Reagents: i, N H 4 0 A c

0

N H

0

(24)

(25)

Reagents: i, aq. Me,NH, at 40-50

Scheme 12

"C, for 2 h

Scheme 13

The fused pyridines (28), obtained by thermal rearrangement of 2H-azirines of the type (26), are formed by cyclization of an intermediate 1-azahexatriene (27) rather than by a nitrene-insertion reaction (Scheme 14).44

w

R.2 \

co2Et

N

(R', R2, R3 = H or Me) 40 41

42 43 44

\r

(27) Scheme 14

H. Boennemann and M. Samson, Ger. P. 2 840 460 (Chem. Abstr., 1980,93,95 136). H . Boennemann and G. S. Natarajan, Erdoel, Kohle, Erdgas, Petrochem., 1980, 33, 328 (Chem. Abstr., 1981, 94, 30 432). S. Kambe, K. Saito, A. Sakurai, and H. Midorikawa, Synthesis, 1980, 366. J. Synth. Methods, 1980, 6 , 75 826V. K. Isomura, S. Noguchi, M. Saruwatari, S. Hatano, and S. Taniguchi, TetrahedronLett., 1980,21, 3879.

Heterocyclic Chemistry

242

Properties of Pyridines. Variable-temperature 'H n.m.r. studies on penta-arylpyridines suggest that the lone pair on nitrogen has a smaller steric requirement than does hydrogen.45 A comprehensive study has been made of the 15N n.m.r. spectra of aminopyridines, aminopyrimidines, and some diazine N-oxides. A linear correlation (0=0.9985) is observed between the substituent effects of amino-groups [AS(15N)]on the nitrogen atom that is in the ring in aminopyridines and the corresponding values. of AS(I3C) in aminobenzenes. The slope of the linear correlation is indicative of a stronger conjugation of an amino-group with a pyridine ring than with a benzene ring.46 The N(1s) binding energies for 36 monosubstitued pyridines have been determined by X-ray photoelectron spectroscopy. There is a good correlation between these energies and the basicities in the gas phase.47 A comprehensive study of the efficiency of drying agents for pyridines has been The photoreactions of pyridine with aliphatic amines and ethers give 2- and 4-substituted pyridines; reaction takes place at the a-CH2 of the amine or ether. For example, the compounds (29) and (30) are formed, in a ratio of 1 :0.85, if a mixture of pyridine and diethylamine is irradiated with light of wavelength 254 nm.49 CH(Me)NHEt

(29)

(30)

4,4'-Bipyridyl and 3,4-dibromo-N-methylmaleimideundergo a photo-initiated dehydrohalogenative cyclization reaction (Scheme 15).50

8 +

N'

Scheme 15

(E)-(2-Alkenyl)pyridines(33)are obtained by the reaction of 2-(trimethylsilylmethy1)pyridine (31)with the aldimines (32) (Scheme 16).51Treatment of 2,6-lutidine, in ether, with an excess of phenyl-lithium, followed by deuterium oxide, yields only monodeuteriated The preparation, reactions, and spectral characterization (i.r., n,m.r., and m.s.) of an extensive range of derivaD. Gust and M. W. Fagan, J. Org. Chem., 1980,45,2511. W.Stadeli, W. von Philipsborn, A. Wick, and I. KompiS, Helv. Chim. Acta, 1980,63,504. " R.S. Brown and A. Tse, Can. J. Chem., 1980,58,694. 48 D.R. Barfield, R. H. Srnithers, and A. S. C. Tan, J. @g. Chem., 1981,46,629. 4q A. Gilbert and S. Krestonosich, J. Chem. SOC.,Perkin Trans. 1, 1980,2531. 5 0 K. M.Wald, A. A. Nada, G. Szilagyi, and H. Wamhoff, Chem. Ber., 1980,113,2884. 5 1 T. Konokahara and Y. Takagi, Tetrahedron Left., 1980,21,2073. 5 2 Ya.S.Karpman, V. A . Azirnov, 0. S. Anisimova, and L. N. Yakhontov, Chern. Heterocycl. Compd. (Engl. Trans/.),1980,16,89. 45

46

243

Six-Membered Rings: Systems containing nitrogen

+ Ar\C=N H/

oCH2SiMe3 (31)

i,ii

R

~

H

\R

H

(32)

Ar

+

RNH, + Me,SiOH

(33)

Reagents: i, LiNPr',, THF, at -75 "C;ii, aq. NH4Cl

Scheme 16

tives of quinolinic acid (pyridine-2,3-dicarboxylicacid) have been reported. Treatment of the diacid chloride with aqueous ammonia gives 2-cyanopyridine3-carboxylic acid, and not, as previously supposed, the isomeric 3-cyano-2carboxylic Irradiation of a solution of methyl pyridine-2-carboxylate in acidified methanol gives methyl 6-methoxypyridine-2-carboxylate in 88% yield; in the absence of acid, only methyl 5 -methylpyridine-2-carboxylate is obtained, in low (15%) yield.54Further studies on the site-specific lithiation of pyridines have appeared; for example, pyridine-2-carboxamides undergo directed lithia t i ~ nThus . ~ ~2,3-disubstituted pyridines are formed from the di-lithio-derivative of N-methyl(or N-benzyl)pyridine-2-carboxamideby reactions with electrophiles. 3-Chloropyridine yields a 4-lithio-derivative (using LiNPrI2 in THF, at -78"C), and this has been allowed to react with a number of electrophiles to give 4-substituted 3-chloropyridines. The tendency of 3-halogeno-4lithiopyridines to give 3-pyridyne is greatest with the 3-iodo- and least with the 3-fluoro-compo~nd.~~ An efficient method for preparing 4-cyanopyridine (36) involves the reaction of pyridine with bromine and benzophenone phenylhydrazone, followed by treatment of the resulting salt (34) with potassium cyanide and then treatment of the adduct (35) with a catalytic amount of base (Scheme 17)."

1

--*

\

5 Ph

PhN=N-C

I/

Ph

(34)

L 11

\

Ph

(36) [75'/;]

(35)

Reagents: i, aq. KCN; ii, NaOEt

Scheme 17

The photoreaction of 4-cyanopyridine and cyclopentene in acetonitrile is effected by irradiation with light of wavelength 254nm, and this procedure yields 60% of 4-(cyclopent-2-enyl)pyridine;2-(cyclopent-2-enyl)pyridine is L. I. M. Spiessens and M. 0. Anteunis, Bull. SOC.Chim. Belg., 1980, 89, 205. T. Sugiyama, E. Tobita, K. Takagi, M. Sato, Y. Kumugai, G. P. Sato, and A. Sugimora, Chern. Lett., 1980, 131. 5 5 ( a ) A. R. Katritzky, S. Rahimi-Rastgoo, and N. K. Ponkshe, Synthesis, 1981, 127; ( b )J. Epsztajn, Z . Berski, J. Z. Brzezinski and A. Jozwiak, Tetrahedron Lett., 1980, 21,4739. 56 G. W. Gribble and M. G. Saulnier, Tetrahedron Lett., 1980, 21,4137. " J. Schantl and H. Gstach, Synthesis, 1980, 694. s3 54

244

Heterocyclic Chemistry

formed in 23 % yield, under similar conditions, from 2-cyan0pyridine.~~ Protodecyanation of 4-cyanopyridine is simply achieved, in quantitative yield, by treatment with titanium trichloride followed by base. The reaction is less favourable (30% yield) with 2-cyanopyridine, and 3-cyanopyridine is inert under these condition^.^^ Pyridine-2-carboxaldehydes (37) have been prepared from triazolo[1,5-a]pyridines. The key step is fission of the ring by reaction with bromine (Scheme 18).60

Reagents: i, Br,; ii, AgNO,

Scheme 18

2,3,5,6-Tetrachloropyridinehas been prepared from 2,6-diaminopyridine by controlled chlorination (by HCl and H202)to give the 3,5-dichloro-derivative, followed by diazotization (using NaNO, and HC1).6*2,3,5,6-Tetrachloropyridine is also available, in excellent yield, from the reduction of pentachloropyridine with zinc dust, dimethyl methylphosphonate, and ammonium chloride. Under these conditions the specific reduction of the 4-chlorine in 2,3,4,5-tetrachloropyridine has also been achieved.62In the phase-transfer-mediated reaction of 2-chloro-3-cyanopyridinewith alkoxides, primary alkoxides are more reactive than secondary alkoxides, and t-butoxide is inert.63The novel use of the acetylenic alcohol (38) as an equivalent of ethyne in the conversion of 2-bromo- into 2-ethynyl-pyridine is illustrated in Scheme 19.64

I

X-C-OH I

Reagentg: i, [(PPh,),PdCl,], CuI; ii, NaOH

Scheme 19

-2,4,5,6-Tetrafluoro-3-pyridyl prop-2-enyl ether (39), on prolonged heating at 185 "C, gives the tricyclic product (41) in excellent yield. This is formed as a result of site-specific Claisen rearrangement and trapping of the intermediate (40) by an internal Diels-Alder addition (Scheme 20).65 The photoreaction of enolate anions with 3-amino-2-chloropyridine occurs by an SNRlmechanism, and results in a one-pot synthesis of the 4-azaindoles

'* 59

60 61

62 63 64

65

R. Bernardi, T. Caronna, S. Morrocchi, and P. Traldi, Tetrahedron Lett., 1981,22, 155. A. Clerici and 0. Porta, Tetrahedron Lett., 1980,21,1675. G.Jones and D. R. Sliskovic, Tetrahedron Lett., 1980,21,4529. T.K.Chen and W. T. Flowers, J. Chem. SOC.,Chem. Commun., 1980,1139. P.Sutter and C. D. Weis, J. Heterocycl. Chem., 1980,17,493. A.J. Serio Duggan, E. J. J. Grabowski, and W. K. Russ, Synthesis, 1980, 573. D. E. Ames, D. Bull, and C. Takunda, Synthesis, 1981,364. G . M.Brooke, R. S. Matthews, and N. S. Robson, J. Chem. SOC., Perkin Trans. 1, 1980,102.

245

Six-Membered Rings: Systems containing nitrogen

.Fo:CH2CH=CH2 (39)

fy+

+ F

dF

NF&F

(40)

0

(41) [Sl%]

Scheme 20

(42); a quantitative yield is obtained when R is t-butyl (Scheme 21).66 An increasing number of reactions of this type are being reported in the literature (see, for exgmme, page 262).

Scheme 21

A new procedure, developed for the arylation of alkenes with aromatic amines, is illustrated in Scheme 22. This supplements the classical diazonium-salt method.67

+ PhCH=CH2 & I QH=CHPh [69%] Reagents: i, Bu'ONO, bis(dibenzylideneacetone)palladium,AcOH, CICH,CO,H

Scheme 22

The well-known rearrangement of 2-nitraminopyridine to 3-nitro- and 5nitro-2-aminopyridines in concentrated sulphuric acid has been shown to be intermolecular in nature, in contrast to the analogous rearrangement of N nitroanilines, which is almost always intramolecular in character.68 An unexpecwas ted decarbalkoxylation occurred when ethyl 2-ethoxypyridine-3-carboxylate heated at 280 "C, N-ethylpyridone being formed in 95% yield.69A number of activated aromatic substrates have been acylated, in high yield, by their reaction with 2-(acy1oxy)pyridinesin trifluoroacetic acid; for example, 2-benzoylthiophen is obtained in 98% yield by this procedure. The latter compound cannot be obtained by a traditional Friedel-Crafts rea~tion.~' 4-Acetoxy- and 4-alkoxy-2pyridones (43)form bicyclic products (44)on irradiation (A 3300 nm), in excellent yields. On heating compound (44; R = Me), a mixture of 4- and 6methoxypyridones, (43;R = Me) and ( 4 3 , is obtained. Compound (44; R = Ac), however, reverts solely to the starting material (43;R = Ac) on heating.71 66

R. Beuglemans, B. Boudet, and L. Quintero, Tetrahedron Lett., 1980,21, 1943.

K.Kikukawa, K. Maemura, K. Nagira, F. Wada, and T. Matsuda, Chem. Lett., 1980,551. '* L.W. Deady, M. R. Grimmett, and C. H. Potts, Tetrahedron, 1979,35,2895. 67

69

G . R. Newkome, D. K. Kohli, and T. Kawato, J. Org. Chem., 1980,45,4508.

'' T . Keumi, R. Taniguchi, and H. Kitajima, Synthesis, 1980,139.

71

C. Kaneko, K. Shiba, H. Fujii, and Y. Momose, J. Chem. Soc., Chem. Commun., 1980,1177.

Go a.

246

Heterocyclic Chemistry

M

H (44)

H (43)

e NO

nO

H (45)

(R = Me or Ac) The mechanism of a similar rearrangement of oxazines is discussed on page 285. Thermolysis of the 1-phenethoxy-2-pyridone (46) at 220 "C yields, in addition to phenylacetaldehyde (49%) and 4,6-diphenyl-2-pyridone,26% of 3-benzyl-4,6-diphenyl-2-pyridone(47).72 Potassium dimsylaw Converts 1benzyl-4,6-diphenyl-2-pyridone(48) into its 3-methyl derivative. The anion that is derived from 1-(a-methylbenzyl)-4,6-diphenyl-2-pyridone (49) rapidly rearranges to the azepinone (50) (Scheme 23).73

P (46) R' (47) R' (48) R'

= = =

hR' o

fi0 - phQ:e

Ph N

i

PhMeCH (49)

OCH2CH2PhYpR2 = H H, R2 = CHzPh CHZPh, R2 = H

H Ph (50)

Reagents: i, LiNPr',, THF, at -78 "C

Scheme 23

1-Alkyl-4,6-diphenyl-2-pyridones ( 5 l),on reaction with alkyl-lithiums and subsequent reaction with electrophiles, form products (52), in which an alkyl carbanion has added to the 3-position and then an electrophile to the 4-position (Scheme 24). The mechanism of this reaction, and similar ones, has been Ph

Et

Ph

E

Ph CH ,R

N 0CH,R

N CH,R

Reagents: i, EtLi, THF, at -78 " C ; ii, Me1 or p-CIC,H,COCI

Scheme 24

Only N -acyl-4-pyridones are obtained from the acylation of 4-pyridone with aliphatic carboxylic anhydrides or chlorides, or from the free acids in the presence of dicyclohexylcarbodi-imide.The factors governing the N- or 0-acylation of pyridones have been i n ~ e s t i g a t e d .N-Methyl-3,5-dinitro-4-pyridone ~~ (53) 72 73

74

74

A. R. Katritzky, A. V. Chapman, M. J. Cook, and G . H. Millet, J. Chem. Soc:, Perkin Trans. 1, 1980,2743. A. R. Katritzky, J. Arrowsmith, Z. bin Bahari, C. Jayaram, T. Siddiqui, and S. Vassilatos, J. Chem. SOC.,Perkin Trans. 1, 1980, 2851. A. R. Katritzky, N. E. Grzeskowiak, H. J. Salgado, and Z. bin Bahari, Tetrahedron Lett., 1980, 21,4451. ( a ) F. Effenberger, A. 0. Muck, and E. Bessey, Chem. Ber., 1980,113, 2086; ( b ) F. Effenberger and E. Bessey, ibid., p. 2100; ( c ) F. Effenberger, M. Keil, and E. Bessey, ibid.,p. 2110.

247

Six-Membered Rings: Systems containing nitrogen

reacts with the sodium salt of diethyl3-oxopentanedioate (54) to give N-methyl3,5-bis(ethoxycarbony1)-4-pyridone( 5 5 ) in 85Oh yield (Scheme 25).76 0

0 0 2 , h N 0 2 N Me

E t o 2 c ~ C 0 2 E t

II

(53)

N Me

-

+ EtO,CCH,C-CHC0,Et

+

Na'

(55)

(5 4)

+ 0

II

-

O,NCH,C-CHNO,

Na'

Scheme 25

Dichloroketen and a series of aryl(bromo)ketens react with various 1substituted 3-oxidopyridiniums to give bicyclic compounds by addition across the C(4)-0 and C(2)-0 positions.77 Reduction of the pyridinium salt (56)with sodium borohydride gives mainly the tetrahydropyridine (57); this, on cyclization (induced by polyphosphoric acid) yields the benzomorphan homologue ( 5 8) (Scheme 26).78

& o."f'-QNMe N +/

Me

1._

I-

N

Me

(57)

(56)

Me (58)

Reagents: i, NaBH,; ii, polyphosphoric acid

Scheme 26

The reaction of the anion of ethyl cyclopentanecarboxylate with N-benzylnicotinamide bromide (59) leads to the spirotricyclic skeleton of the antileukaemic alkaloid sesbanine (Scheme 27).79

Reagents: i, LiNPr',, THF, at -30 "C

Scheme 27 76

77

78 79

E. Matsumura, M. Ariga, and Y . Tohda, Bull. Chern. SOC.Jpn., 1980, 53, 2891. A. R. Katritzky, A. T. Cutler, N. Dennis, G. J. Sabongi, S. Rahimi-Rastgoo, G. W. Fisher, and I. J. Fletcher, J. Chem. SOC.,Perkin Trans. 1, 1980, 1176. F. J. Smith and G. R. Proctor, J. Chem. SOC.,Perkin Trans. 1, 1980, 2141. M. J. Wanner, G.-J. Koomen, and U. K. Pandit, Heterocycles, 1980, 14, 643.

Heterocyclic Chemistry

248

Papers continue to appear on the synthetic uses of triphenylpyridinium and related salts; thus azides," bromides," fluorides,'' and nitrate esterss3 have been prepared by thermolysis of the appropriate pyridinium salts. On treatment of 1-alkyl(or 1-aryl)-2,4,6-triphenylpyridiniumsalts (60) with potassium ferricyanide, the corresponding 2-benzoylpyrroles (6 1) are formed (Scheme 28).s4 Ph P h i g COPh N

Ph f N i P h

R

Scheme 28

The oxidation of the pyridinium betaine (62) with hydrogen peroxide also gives a pyrrolic product (63), together with the pyridinium 3-olate (64) (Scheme 29).85 Ph

boPh$-(h

P h o P h \

(62)

+

__* H~O,

b

O

H

(63) [20%]

Ph

h0+/

Ph

b\ O

H

(64) [26%]

Scheme 29

The synthetic applications of N-N-linked heterocycles have been further explored for the preparation of 4-substituted pyridines,s6 and the use of N nitropyridinium and N-nitroquinolinium salts as nitrating agents for aromatic substrates has been investigated. For example, nitration of mesitylene with N-nitro-2,4,6-collidinium tetrafluoroborate yields 93% of nitr~mesitylene.~~ Irradiation of pyridine N-oxides in the presence of secondary amines produces mixtures of geometrically isomeric 5,5 -di (substituted amino)penta-2,4-diene nitriles in preparatively useful amounts," and the irradiation of 2-azidopyridine 1-oxide (65) yields 6-cyano-1,2-oxazine (66). The latter is converted into 2-cyano-1 -hydroxypyrrole (67) if heated in toluene (Scheme 30)." A. R. Katritzky, G. Liso, E. Lunt, R. C. Patel, S . S. Thind, and A. Zia, J. Chem. SOC.,Perkin Trans. 1, 1980, 849. A. R. Katritzky, F. Al-Oram, R. C. Patel, and S. S. Thind, J. Chem. Soc., Perkin Trans. I , 1980,

'* 83 84

8s 86

1890.

A. R. Katritzky, A. Chermprapai, and R. C. Patel, J. Chem. SOC.,Perkin Trans. 1, 1980, 2901. A. R. Katritzky and L. Marzorati, J. Org. Chem., 1980,45, 2515. P. Nesvadba and J. Kuthan, Tetrahedron Lett., 1980, 21, 3727. A. R. Katritzky, A. Ramsden, Z. Zakaria, R. I., Harlow, and S. H. Simonsen, J. Chem. SOC., Perkin Trans. 1, 1980, 1870. ( a ) A. R. Katritzky, J. G. Keay, D. N. Rogers, M. P. Sammes, and C. W. F. Leung, J. Chem. Soc., Perkin Trans. 1, 1981, 588; ( b ) C. M. Lee, M. P. Sammes, and A. R. Katritzky, ibid., 1980, 2458.

'' G. A. Olah, S. C. Narang, J. A. Olah, R. L. Pearson, and C. A. Cupas, J. A m . Chem. SOC.,1980, 102,3501.

'' J. Becher, L. Finsen, I. Winckelmann, R. R. Koganty, and 0.Buchardt, Tetrahedron, 1981,37,789. n9

R. A. Abramovitch and C. Dupuy, J. Chem. SOC.,Chem. Commun., 1981,36.

249

Six -Membered Rings: Systems containing nitrogen

U

(65)

(66)

(67)

Reagents: i, irradiate a 0.1Msolution in benzene, at r.t., for 1 h ( A = 350 nm); ii, heat

Scheme 30

2-Chloropyridine 1-oxide (68) is converted into 6-amino-2-chloropyridine (69), in excellent overall yield, as shown in Scheme 31.90

Reagents: i, CH,Cl,, heat; ii, hydrolysis

Scheme 31

Treatment of the pyridine N-oxide (70) with acetic anhydride surprisingly gives a dimeric product (7 1) (Scheme 32).” 2-Carboxypyridine I-oxides (74) are formed by the reaction of a pyridine N-oxide with a 3-aryl-rhodanine (72) followed by oxidative cleavage of the intermediate (73) (Scheme 33).”

0-

(7 1)

(70) Scheme 32

Reagents: i, Ac,O, NaOAc, heat; ii, 30%H,O,, HOAc, reflux

Scheme 33

’” 91

92

K. Wachi and A. Terada, Chem. Pharm. Bull., 1980,28,465. M. F. Brana and M. L. Lopez Rodriguez, Tetrahedron Lett., 1980, 21, 3923. M.M. Yousif, S. Saeki, and M. Hamana, J. Heterocycl. Chem., 1980, 17, 305.

250

Heterocyclic Chem'istry

A novel route to 2,5-disubstituted pyridines is illustrated by the conversion of 2-chloromethyl-5-ethoxypyridine 1-oxide (75) into the pyridine (76) (Scheme 34).93

1

(75)

ii

EtO

FN (76)

0

Reagents: i, AgBF,, CH,CI,, 1-substituted cyclohexene; ii, DBU

Scheme 34

Diphosphorus tetraiodide (formed in situ by the disproportionation of phosphorus tri-iodide) has been recommended as a mild reagent for the deoxygenation of pyridine N-oxides; yields are generally very good.94

Reduced Pyridines.-A modified procedure for the preparation of 1-methyl- 1,4dihydropyridines involves the treatment of 1 -methylpyridinium salts with ethanol, liquid ammonia, and lithium at -33 "C. These air-sensitive compounds can be stored at -20 "C. The most striking feature of their 'H n.m.r. spectra is the six-bond 'H-'H coupling between the N-methyl protons and those in position 4 of the ring.95Zinc iodide has been shown to catalyse the reduction of ketones by 1,2-dimethyl-1,4-dihydropyridinein cyclohexane at 20 "C. This observation was prompted by the known involvement of zinc in biological NADH redox The selective reducing properties of polymer-linked 1,4-dihydropyridines are illustrated by the reduction of m-nitrobenzaldehyde to m-nitrobenzyl alcohol.97 The 1,4-dihydropyridines (77) that result from addition of alkyl (or aryl) thiols to 1-methylpyridinium salts readily yield thioesters (78) on reaction with activated derivatives of acids (Scheme 35).98

yocl

?5

lCOY N Me (77)

+R2COX

94 y5

96

97 98

N +/

Me (7 8)

(Y y3

-yococoy

=

OEt 6r NHEt; X Scheme 35

=

+ R~COSR'

X-

C1)

M. Riediker and W. Graf, Chimia, 1980, 34, 461. H. Suzuki, N. Sato, and A. Osuka, Chem. Lett., 1980, 459. A. J. de Koning, P. H. M. Budzelaar, L. Brandsma, M. J. A. de Bie, and J. Boersma, Tetrahedron Lett., 1980, 21,2105. A. J. de Koning, H. J. Alberts-Jansen, J. Boersma, and G. J. M. van der Kerk, Red. Trav. Chim. PUYS-BUS, 1980, 99, 316. R. Mathis, G. Dupas, A. Decormeille, and G. Queguiner, Tetrahedron Lett., 1981, 22, 59. 0. Piepers and R. M. Kellogg, J. Chem. SOC.,Chem. Commun., 1980, 1147.

25 1

Six-Membered Rings: Systems containing nitrogen

2,5-Dihydropyridines (79), which are a relatively rare class of reduced pyridines, are formed as shown in Scheme 36. Addition of an imine to the activated double-bond, followed by Thorpe cyclization, has been postulated as a likelv mechanism for ring formation.99

(79) (cis and trans) Scheme 36

A 3,4-dihydropyridine (82) is obtained by the reaction of the 1,2,4-triazine (80) with 3,3-dimethylcyclopropene (81; R=Me) (Scheme 37).looThe product from the corresponding reaction with cyclopropene exists in the monocyclic form (83) rather than the bicyclic form (82).looThe adduct formed from pentachloropyrrole (84) and styrene has been reformulated as the 2-azabicyclo[2.2. llheptane (85), the pyrrole thus functioning as a 2-aza- rather than as a 1-aza-butadiene (Scheme 38)."'

R Ph

(81) R = H or Me

Ph

Ph

Scheme 38

The anion generated from 2-methyl-3,4,5,6-tetrahydropyridineis methylated ( 2 9 5 % ) on exocyclic carbon rather than at C-3 of the ring.''*

Azabicyclo-octanones (87) are obtained by the sodium-ethoxide-promoted reaction of 1,3-dicarbonyl compounds with the reduced pyridinones (86; R3 = C02Me or S02Me). However, Robinson-type cyclization to an azabicyclononanone (88) was achieved by their condensation with dimethyl acetonedicarboxylate. Azabicyclo[2.2.2]octanones can be isomerized to azabicycloyy

loo

'" lo'

S . K. Robev, Tetrahedron Lett., 1980, 21, 2097. U. Gockel, U. Hartmannsgruber, A. Stiegel, and J. Sauer, Tetrahedron Lett., 1980,21, 599. P. H. Daniels, J. H. Wong, J. L. Atwood, L. G. Canada, and R. D. Rogers, J. Org. Chem., 1980, 45,435. K. N. Houk, R. W. Strozier, N. G. Rondan, R. R. Fraser, and N. Chaqui-Offermanns, J. Am. Chem. SOC.,1980,102, 1426.

252

Heterocyclic Chemistry

r3.3.1Inonanones on treatment with acid (Scheme 39).lo3A piperidine derivative (90) is formed by the unusual endo-cyclization of the chloramine (89) that is induced by titanium trichloride (Scheme 40).lo4

Reagents: i, R2COCH,COCH,R' ; ii, (MeO,CCH,),CO

Scheme 39

Scheme 40

A novel method of annelation of a piperidine ring is illustrated by the formation of the cis-2-allyldecahydroquinolines(92). The immonium salt (9 1) that is initially formed undergoes a [ 3 , 3 ] sigmatropic rearrangement and subsequent hydrolytic loss of benzaldehyde (Scheme 41).'05

(Bz= PhCH2)

(91)

Reagents: i, ( d ) -10-carnphorsulphonic acid, H 2 0 , PhH, reflux; ii, NaBH,, MeOH

Scheme 41

Analogues of thalidomide with an indane-1,3-dione system in place of the phthalimide one show greater teratogenic activity than thalidomide (93) itself. This observation casts doubt upon the suggestion that transacylation is the cause of the teratogenicity of thalidomide.lo6 The reductive denitrosation of N-nitrosopiperidines and N-nitrosotetrahydroquinolines and -isoquinolines is achieved by treatment with either titanium tetrachloride and sodium borohydride or nickel dichloride and sodium borohydride."' A new mild procedure for the a-cyanation of tertiary amines involves successive treatment with aqueous hydrogen peroxide, trifluoroacetic anhydride, lo3

'06 lo'

T. Imanishi, H. Shin, M. Kanaoka, T. Momose, and I. Imanishi, Heterocycles, 1980, 14, 1111. J.-L. Stein, L. Stella, and J.-M. Surzur, TefraahedronLett., 1980, 21, 287. L. E. Overman and T. Yokomatsu, J. Org. Chem., 1980,45, 5229. K. Fickentscher, U. Halfmann, and F. Kohler, Arch. Pharm. ( Weinheim, Ger.), 1980,313,481. S . Kano, Y. Tanaka, E. Sugino, S. Shibuya, and S. Hibino, Synthesis, 1980, 741.

253

Six-Membered Rings: Systems containing nitrogen

and aqueous potassium cyanide. Using this method, the a-cyanopiperidine (94) has been prepared in 73% overall yield from the parent tertiary amine."' The reaction of N-aminopiperidine with diethyl azodicarboxylate yields N-ethoxycarbonylpiperidine (81%) and ethyl azidoformate (79%) via an unstable aminonitrene intermediate."'

Quinoline, Isoquinoline, and their Benzo- and Hydro-derivatives.-An improved method for the selective reduction of nitro- to amino-groups, using phthalocyaninecobalt(1) anion, is the basis for improved yields in the Friedlander synthesis of quinolines from ortho -nitrobenzaldehydes."O A much less used route to quinolines, involving ring-closure of a 2,3 -disubstituted pyridine, is illustrated by the preparation of 6-0~0-5,6,7,8-tetrahydroquinoline(95) (Scheme 42).'"

0

0

\ CH2SO2Ph i ,

N/ CH2Br

\ CH2SO2Ph /

N

CH,CH,CO,Et

ii,iii

,

mo (95)

Reagents: i, PhSCH,CO,Et, LiNPr',, Raney nickel; ii, NaH; iii, Raney nickel

Scheme 42

A novel synthesis of 2,4-diphenylquinolines (98) involves the thermolysis of the bicyclic photoproducts (97) that are obtained from the l-aryl-4,6-diphenyl2(1H)-pyrimidin-2-ones (96) (Scheme 43).'12

phcyoph$x:(a'ap \

NAr

Ph (96)

be2:ne

(97)

(98) R

=

H, Me, or M e 0

Scheme 43

Reduction of quinoline and of isoquinoline with sodium borohydride in a 1:3 mixture of acetic anhydride and acetic acid gives mainly 1,2-dihydro-N-acetyl derivatives.l13 1,2,3,4-Tetrahydro-derivativesare obtained from these substrates (and from quinoxaline) by reduction with diborane. However, quinaldine, '09

'lo ''I

'I2

W. C. Groutas, M. Essawi, and P. S . Portoghese, Synrh. Commun., 1980,10;495. E. Fahr and K.-H. Koch, Liebigs Ann. Chem., 1980,219. H.Eckert, Angew. Chem., Int. Ed. Engl., 1981,20, 208. E.Ghera, Y.B. David, and H. Rapoport, J. Org. Chem., 1981,46,2059. T.Nishio, K.Katahira, and Y. Omote, Tetrahedron Lett., 1980,21, 2825. H. Katayama, M. Ohkoshi, and M. Yasue, Chem. Pharm. Bull., 1980,28,2226.

254

Heterocyclic Chemistry

lepidine, and 3-methylisoquinoline cannot be reduced by this method.' l 4 The photoinitiated dimerization of quinoline-2-carbonitrile in aqueous isopropyl alcohol gives compound (99) as the major The photo-adduct (100) of 4-methoxy-2( 1H)-quinolinone and ethylene has been transformed into 1,2-dihydrocyclobuta[c]quinoline (101) (Scheme 44).lI6

Reagents: i, KOH, MeOH; ii, POCI,; iii, Zn, aq. H,SO,,

Scheme 44

Compounds of this type can act as diene precursors, and they undergo DielsAlder additions upon heating with electron-deficient alkenes.l1' Addition of cyanide to N-methylquinoliniurn ion occurs at position 2 at low temperatures (-70 to -30 "C); above 20 "C, addition takes place at position 4."* An interesting tetracyclic product (103) is formed by the reaction of the anion of ethyl bromocyanoacetate with N-methylquinolinium iodide; the postulated intermediate (102) is thought to undergo intramolecular nucleophilic attack (Scheme 45).lI9

A number of 1,2-dihydroquinolines have been prepared in excellent yield by the reaction of 1-methyl-2-methylthioquinolinium iodide with active-methylene compounds.12o Photolysis of quinoline N-imides (104) that have an electrondonating substituent in the 6- or 8-position affords 3H-l,3-benzodiazepines (10 9 , whereas quinolines having an electron-donating group in the other positions, or an electron-withdrawing group, give no diazepines (Scheme 46).121 '14 l1' 116

'17

120 121

A. Nose and T. Kudo, Yakugaku Zasshi, 1979,99, 1240 (Chem. Abstr., 1980, 93, 26 237). T. Caronna, S. Morrocchi, and B. M. Vittimberga, J. Org. Chem., 1981,46, 34. C. Kaneko, T. Naito, and N. Nakayama, Chem. Pharm. Bull., 1981, 29, 593; H. Fujii, K. Shiba, and C. Kaneko, J. Chem. SOC.,Chem. Commun., 1980,537. C. Kaneko, T. Naito, and M. Ito, Tetrahedron Lett., 1980, 21, 1645. A. I. Matern, E. 0. Sidorov, and 0. N. Chupakhin, Zh. Org. Khim., 1980,16, 671 (Chem. Abstr., 1980,93,95 107). S. Saeki, Y. Kaku, M. Hamana, and H. Noda, Heterocycles, 1980, 14, 809. H. Tomisawa, T. Tanbara, H. Kato, H. Hongo, and R. Fujita, Heterocycles, 1981, 15, 277. T. Tsuchiya, S. Okajima, M. Enkaku, and J. Kurita, J. Chem. SOC., Chem. Commun., 1981, 211.

255

Six-Membered Rings: Systems containing nitrogen

-NCO,Et

(1051

( 104)

(R' = H or Me, R2 = OMe or NMe2, R3 = H or Me) Scheme 46

4-(Hydroxyamino)quinoline N-oxide, in contrast to its monocyclic analogue, has been shown to exist predominantly as the 1,4-dihydroquinoline (106) by n.m.r. spectroscopy.122 N

,OH

The photo-products obtained from methoxy-substituted quinoline and isoquinoline N-oxides have been investigated. The major product obtained from 2-methoxyquinoline 1-oxide is the 3,l -benzoxazepine (107), which is readily hydrolysed to compound ( 108).123Reissert compounds are oxidized (in basic solution, under phase-transfer conditions) to give quinoline- and isoquinolinecarbonitriles. Under the same conditions, dihydroisoquinoline Reissert compounds, e.g. (log), undergo oxidative decyanation to dihydroisocarbostyrils, e.g. (llo), as shown in Scheme 47.'24 N'COPh

W

-

w

N

CN

0 (1 10)

(109) Reagents: i, PhH, aq. NaOH, Et,(PhCH,)N'

H

C1-, air

Scheme 41

Sulphonyl- and acyl-hydrazones of 2-(substituted ethyny1)benzaldehydes (11l).cyclizein the presence of base to give isoquinoline N-imines (112) (Scheme 48).125

a::::NHR2 mR' (111)

\

/N,-

(112)

N R ~

Reagents: i, K,C03 or DBU

H or Ph; R2 = S02C6H4Me,S02Me, or COPh) Scheme 48 Y.Kawazoe, 0. Ogawa, and G.-F. Huang, Tetrahedron, 1980,36,2933. (R'

lZ2 lZ3 lZ4 lZs

=

A. Albini, E. Fasani, and L. M. Dacrema, J. Chem. SOC.,Perkin Trans. 1, 1980, 2738. M. D. Rozwadowska and D. Brozda, Can. J. Chem., 1980,58,1239. P. N. Anderson and J. T. Sharp, J. Chem. SOC.,Perkin Trans. I , 1980, 1331.

256

Heterocyclic Chemistry

A mild two-step procedure for carrying out the Bischler-Napieralski synthesis of dihydroisoquinolines from amides involves the formation of the intermediate imidoyl chloride followed by cyclization in the presence of stannic chloride. 126 Treatment of the benzylamino-acetals (113) with chlorosulphonic acid results in the formation of fully aromatized isoquinolines (114)(Scheme 49).127 CISO,H,

Rza R' \

1 R3

R3 (114) [ 15-75°/o]

(R' = H or OMe, R2

=

H or OMe, R3 = H or alkyl)

Scheme 49

The urethane acetals (115) cyclize, under mild acidic conditions, to the stereoisomeric 4-hydroxytetrahydroisoquinolines(116). Under more acidic conditions, further intramolecular cyclization occurs to give compounds of the type (117), i.e. isopavines (Scheme 50).128 OH

CH,Ar (115)

(R

=

C02Et, Ar

=

CH,Ar (116) y

-

d

3-benzyloxy-4-methoxyphenyl)

\

Me / BzO \

e

/OBz

(117) Reagents: i, HC02H, Me,CO; ii, 3M-H,S04, Me,CO; iii, HC0,H

Scheme 50

A series of halogen-substituted N-acetyl- 1,2-dihydroisoquinolines (119) has been prepared by cyclization of the benzylamino-acetals (118) (Scheme 5 1),'29 and tetrahydroisoquinolines (121) that bear halogen substituents in the

(R'

=

H or C1; R2 = H, C1, or F;R3 = H or C1)

Reagents: i, AlCl,, ClCH,CH,Cl, at ambient temperature

Scheme 51 lZ6 lZ7

12*

lZ9

S. Nagubandi and G. Fodor, J. Heterocycl. Chem., 1980,17,1457. K. Kid0 and Y. Watanabe, Heterocycles, 1980,14,1151. R.Elliot, F. Hewgill, E. McDonald, and P.McKenna, Tetrahedron Lett., 1980,21,4633. C. D.Perchonock, I. Lantos, J. A. Finkelstein, and K. G. Holden, J. Org. Chem., 1980,45, 1950.

257

Six-Membered Rings: Systems containing nitrogen

benzenoid ring are conveniently obtained by the cyclization (promoted by aluminium trihalide) of the appropriately constituted (hydroxy- or halogenoethy1)benzylamines(120) (Scheme 52).l3'

(120) (121) ( Z = OH or halogen, R = halogen) Reagents: i, AlX3, NH,X, at 185 "C

Scheme 52

The reaction of the Schiff bases (122) with butyl-lithium at low temperatures yields the l-pheny1-1,2,3,4-tetrahydroisoquinolines(123) (Scheme 53).13' 1,4Diphenylisoquinolines have been prepared by condensation of o -dibenzoylbenzene and derivatives of methylamine in the presence of a base. The mineral-acid

I

Ph (123)

(R = H or OMe) Reagents: i, BuLi, THF, hexane, at -100 "C Scheme 53

salts of amines that bear' electron-withdrawing groups (e.g.NCCH2NH3+HSO,-) condense with o-dibenzoylbenzene in boiling n-butanol without needing catalysis by a base.'32 A number of isoquinolines have been prepared from indenes in a one-pot procedure, by ozonolysis and the reaction of the resulting dialdehydes with aqueous ammonia (Scheme 54).133

(X = H, Me, NOz, or halogen) Reagents: i, 0,, MeOH, at -78 "C; ii, Me$, NaHCO,; iii, aq. NH,

[60-80%]

Scheme 54

The anion that is derived by treatment of the phthalide (124) with lithium di-isopropylamide can be added to Schiff bases to give mainly cis-2,3-diaryl-3,4dihydro-4-hydroxy-l(2H)-isoquinolones(125). The latter undergo dehydration and rearrangement, on treatment with trifluoroacetic acid, to give 2,4-diaryl1(2H)-isoquinolones (126) (Scheme 55).134 130

13*

W. L. Mendelson, C. B. Spainhour, S. S. Jones, B. L. 'Lam, and K. L. Wert, Tetrahedron Lett., 1980,21,1393. C.K.Bradsher and D. A. Hunt, J. Org. Chem., 1981,46,327. S. Mataka, K. Takahashi, Y.Tsuda, and M. Tashiro, Heterocycles, 1980,14,789. R. B. Miller and J. M. Frincke, J. Org. Chem., 1980,45,5312. D.J. Dodsworth, M.-P. Caliagno, U. E. Ehrrnann, and P. G. Samrnes, Tetrahedron Lett., 1980, 21,5075.

Heterocyclic Chemistry

258

Reagents: i, LiNPr',, ArCH=NAr; ii, H,O';

iii, CF,CO,H

Scheme 55

3-Substituted 1-indanones (127) react with butyl nitrite in the presence of sodium methoxide to give exclusively 2-hydroxyisocarbostyrils (128) (Scheme

56).13'

Reagents: i, BuONO, NaOMe, Et,O, at 0 "C

Scheme 56

An unusual approach to tetrahydroisoquinolines involves the annelation of a carbocyclic ring to N-benzoyl-4-piperidone (Scheme 57). 13' O

P + i,ii NCOPh

__* iii-v

NCOPh

o(>

+NH

R\

cr

R ~~

Reagents: i, H,C=CHMgBr, THF; ii, 12, PhMe; iii, RCECR; iv, SeO,; v, HCI

Scheme 57

Singlet oxygen regiospecifically oxidizes 1-benzyl-3,4-dihydroisoquinolines to 1-benzoyl-3,4-dihydroisoquinolines.137 The high nucleophilicity of the lithium derivative of N-pivaloyltetrahydroisoquinolinepermits alkylation at C- 1by using primary alkyl chlorides, secondary alkyl iodides, and ketones. The protecting group in the products can be reductively removed with the aluminate Na[AlH2(0CH2CH20Me)2].'38 Bromo- and chloro-isoquinolines are converted into arylisoquinolines by their reaction with arylmagnesium halides in the presence of dichloro-[ 1,3-bis(diphenylphosphino)propane]nickel(11) (DPPP).139 A novel route to quinolizidines (and indolizines) is illustrated in Scheme 58; it involves the intramolecular trapping of a substituted 1-azabutadiene.14' 135

136 137 138

139 140

J. N. Chatterjea, C. Bhakta, A. K.Sinha, H. C. Jha, and F. ZilIiken, Liebigs Ann. Chem., 1981, 52. J. A. Finkelstein and C. D. Perchonock, Tetrahedron Lett., 1980, 21, 3323. N. H. Martin, S. L. Champion, and P. B. Belt, Tetrahedron Lett., 1980, 21, 2613. J.-J. Lohmann, D. Seebach, M. A. Syfrig, and M. Yoshifuji, Angew. Chem., Int. Ed. Engl., 1981, 20, 128. L. N. Pridgen, J. Heterocycl. Chem., 1980,17, 1289. Y.-S.Cheng, F. W. Fowler, and A. T. Lupo, Jr., J. Am. Chem. Soc., 1981,103, 2090.

259

Six-Membered Rings: Systems containing nitrogen

( n = 1 or 2) Reagents: i, Heat, in the gas phase

Scheme 58

Systematic studies of the synthesis and deuteriation of halogeno-quinolizinium and of the Chichibabin amination of 1,X-naphthyridines have been made. Amination of 1,5-naphthyridine occurs at position 2 at low temperatures; at higher temperatures, amination takes place at the 4-position. The amination of 1,7-naphthyridine, unlike that of the 1,6- and 1,8-isomers, is also temperaturedependent.142 Treatment of 2-allyl-3-aminocyclohex-2-enone(129) with [PdC12(MeCN)2] yields the acridinedione (130) (Scheme 59).14' New n.m.r. data (13C and 'H) have been reported for 9-substituted acridines and arnino-acridine~.'~~*'~~ The thermally stable 4nr-anion (132) has been obtained by deprotonation of the dihydroacridine (131) (Scheme 60). The relatively high-field signals of the

Scheme 59

Me (132) Reagents: i, KNH,, liq. NH,

Scheme 60

benzenoid and the N-methyl protons in (132) reveal the presence of a paramagnetic ring-current. 146 The photo-initiated reaction of acridine and acetaldehyde and the phase-transfer alkylation and yields 9-acety1-9,10-dihydroa~ridine,'~~ acylation of thioacridones gives 9-thioalkyl- and 9-thioacyl-acridines in very high yield.'48 3-Hydroxy- 10-methylacridinium iodide has been investigated as a model for NAD' and shown to dehydrogenate benzyl alcohol and cyclohexanol 14' 142 143 144

145

146

'41 14'

G. M. Sanders, M. van Dijk, and H. C. van der Plas, Heterocycles, 1981,15, 213. H.J. W. van den Haak, H. C. van der Plas, and B. van Veldhuizen, J. Org. Chem., 1981,46,2134. H.Iida, Y. Yuasa, and C. Kibayashi, J. Chem. SOC.,Chem. Cornmun., 1981,114. P. Faure, J.-P. Galy, E. J. Vincent, J. Elguero, A.-M. Galy, and J. Barbe, Chem. Scr., 1980,15, 62. R. F. Martin and D. P. Kelly, Aust. J. Chem., 1979,32,2637. A. G. Anastassiou, H. S. Kasmai, and M. R. Saadein, Tetrahedron Lett., 1980,21,3743. M. Takagi, S. Goto, and T. Matsuda, Bull. Chem. SOC.Jpn., 1980,53,1777. M.Vlassa, M. Kezdi, and I. Goia, Synthesis, 1980,850.

260

Heterocyclic Chemistry

in 82 and 96% yield, respe~tive1y.l~~ There have been two of the preparation of phenanthridones (134) by the photochemical dehydrohalogenation of the o-halogeno-benzanilides (133) (Scheme 61).

R

(X = CI, Br, or I; R

=

(134) H, CF3, C02Et, C1, Me, OMe, or OH) Scheme 61

6-Cyanophenanthridine (135) gives [2 + 21 cyclo-adducts (136) with electronrich alkenes, on irradiation; these are transformed into azocines (137) on further reaction (Scheme 62).152

Reagents: i, R'CH=CHR2, EtOH, hv

Scheme 62

6-Azidophenanthridine (138), on heating to 490 "C, yields the carbodi-imide (139), which is characterized by strong absorption at 2010 cm-' and which forms a crystalline dimer on warming above -40 "C.153 Perhydro-3a,6a,9atriazaphenalene (140) has been synthesized. Its hydrochloride and its

149

15'

"* 153

S. Shinkai, H. Hamada, H. Kuroda, and 0.Manabe, Chem. Lett., 1980,1235. J. Grimshaw and A. P. de Silva, J. Chem. SOC.,Chem. Commun., 1980,302. B. R. Pai, H. Sunguna, B. Geetha, and K. Sarada, Indian J. Chem., Sect. B,1979,17,503(Chem. Abstr., 1980,93,168 093). S.Futamara, H. Ohta, and Y. Kamiya, Chem. Lett., 1980,655. C. Wentrup and H.-W. Winter, J. A m . Chem. SOC.,1980,102,6159.

26 1

Six-Membered Rings: Systems containing nitrogen

tetrafluoroborate lose hydrogen on heating; this can be quantitatively captured by stilbene in the presence of a 10% palladium-on-carbon ~ a t a 1 y s t . l ~ ~ 4 Diazines and their Reduced and Fused Derivatives

1,2-Diazines.-Good yields of pyridazinones (142; R = Me, Ph, or MeO) are obtained by treating phosphacumulene ylides (Ph,P=C=C=X) with the a -oxohydrazones (141) (Scheme 63);lSs the use of these ylides in the synthesis of pyrimidines, 1,3-oxazines, and 1,3-thiazines has also been reported (see p. 285).

( 144)

ClO, (143) Reagents: i, Ph,P=C=C=X

(X = 0 or NPh)

Reagents: i, Na,CO,, CH,N,

Scheme 64

Scheme 63

The reaction of a three-membered ring with a 1,3-dipole has proved to be a useful route to certain six-membered heterocycles (see also p. 275); illustrative of this is the formation of 3,4-diaminopyridazines (144) from diazomethane and diaminocyclopropenium salts (143) (Scheme 64).lS6 In the absence of base, this reaction has been reported to give pyridazinium salts of the type (145).15’

e\ +N ,N . 2 ClO, Me (145)

Q C O p h

@NCOPh \ COPh

CN (146)

(147)

have appeared on the reactions of the reagent system Several Me,SiCN-PhCOC1-A1Cl3 with diazines, and the first example of a Reissert compound that is derived from a monocyclic azine has been obtained (see also p. 265). 3-Methylpyridazine gives a mono-adduct (146) (41’/0), as does phthalazine (88%),whereas cinnoline affords (147), which is presumably formed by loss of HCN from a di-adduct. The SRNlreactions of four chloro-diazines with ketone enolates in liquid ammonia have been studied and an order of reactivity has been established; thus, in the dark, the potassium enolate of pinacolone reacts with 2chloropyrazine (rapidly) and with 3-chloro-6-methoxypyridazine(less rapidly), lS4

15’

lS6 lS7

J. M. Erhardt and J. D. Wuest, J. A m . Chem. Soc., 1980,102,6323; J. M. Erhardt, E. R. Grover, and J. D. Wuest, ibid., p. 6365. H. J. Bestmann, G. Schmid, and D. Sandmeier, Tetrahedron Lett., 1980, 21, 2939. J. Synth. Methods, 1980,6, 75 924V. R. K. Smalley, in ‘Aromatic and Heteroaromatic Chemistry’ ed. H. Suschitzky and 0. Meth-Cohn (Specialist Periodical Reports), The Chemical Society, London, 1978, Vol. 6, Ch. 3. (a) S. Veeraraghavan, D. Bhattacharjee, and F. D. Popp, J. Heterocycl. Chern., 1981, 18, 443; ( b ) D. Bhattacharjee and F. D. Popp, ibid., 1980, 17,433; (c) ibid., p. 1211.

262

Heterocyclic Chemistry

but photostimulation (350 nm) is required for the reactions with 4-chloro-2,6dimethoxypyrimidine and with 2-chloropyrimidine to occur. The yields obtained in these reactions can be e ~ c e l 1 e n t . l ~ ~ The reaction of phenyl-lithium with 2,6-diphenylpyridazin-3-oneoccurs at the 6-position whereas the corresponding Grignard reagent attacks the 4position (Scheme 65)l6' (see also p. 267).

ePh

Ph\

,NPh

Ph\

iii,ii

___*

NPh

ph2n: N' H

Reagents: i, PhMgBr; ii, aqueous NH,Cl; iii, PhLi

Scheme 65

The dichloropyridazinone (149) has been obtained from the aminochloropyridazinone (148) by the route shown in Scheme 66.16*

(148)

(149)

Reagents: i, NaNO,, HCl, at -10 "C; ii, SOCI,, DMF, at 70-75 "C

Scheme 66

The principal product (33%) that is obtained upon irradiation of the N-imide (150) in acetone is the pyrrole (151); analogous pyrimidine and pyrazine ylides both give pyrazoles of the type (152). The formation of triazepines, e.g. (153), may well be involved (by analogy with the corresponding reactions of monoazine ylides), but neither they nor any valence tautomers, e.g. (154), have been isolated. 162

N'

I

-NC02Et (150)

C0,Et (151) X = CH (152) X = N

(153)

(154)

Two decahydrocinnolines, e.g. (155), have been shown to possess substantially stronger analgesic properties than morphine. 163 Oxidative cyclization of the diphenyl-diazadiene (156) to 1-phenylphthalazine proceeds in good yield upon heating (at 170-200 "C)with a 2 : 1 mixture of lSq

16' 163

D.R. Carver, A. P. Komin, J. S. Hubbard, and J. F. Wolfe, J. Org. Chem., 1981, 46, 294.

A. K. Fateen, A. H. Moustafa, A. h.Kaddah, and N. A. Shams, Synthesis, 1980,457. J. Synth. Methods, 1980,6, 76 125V. T.Tsuchiya, J. Kurita, and K. T. Takayama, Chem. Pharm. Bull., 1980, 28,2676. T. Kametani, K. Kigasawa, M. Hiiragi, H. Ishimaru, N. Wagatsuma, T. Kohagisawa, and T. Nakamura, Heterocycles, 1980, 14, 449.

263

Six-Membered Rings: Systems containing nitrogen

aluminium chloride and triethylamine ; other aromatic aldazines ArCH=NN=CHAr react similarly, and the use of aluminium chloride alone results in the loss of one of the arene moieties, with the formation of phthalazine: (157) that are unsubstituted in the heterocyclic ring.'64 Yields of 18-65% are obtained.

""0

6 *'

N I N Me

Ph

~

/N

\

(156)

ey

R2\

/N

(157)

(155)

The unstable (4H)-phthalazin-1-ones (158) have been prepared for the first time (Scheme 67). Attempts to form cyclo-adducts with dienes were fruitless (contrast the known reactivity of benzopyrazolone), and possible reasons for this are touched upon; on warming to room temperature in TFA, 1,2-migration of aryl groups occurs, giving the phthalazinium betaines (159).16' Ar'

K\

'Ar2

E Y Ar'

Ar2

NH H i ,\

Y

N

.o

0

(158) Reagents: i, Pb(OAc),, Et,N, CH,Cl,, at -78 "C

0(159)

Scheme 67

1,3-Diazines.-6-Phenylpyrimidines (I60) have been prepared, in good overall yields, by the reaction sequence depicted in Scheme 68; the generality of the reaction appears to be limited in that the analogous 6-ethylpyrimidines (161) could not be obtained by the same route.166

Reagents: i, Me,NCH(OMe),, reflux; ii, RZNH2,DMF, heat

(160) R' = Ph (161) R' = Et

Scheme 68

The P-iminoyl-enamines (163) that were mentioned last year'67 have been further investigated for use in pyrimidine synthesis. Treatment with isocyanates IL4

16'

S. A . Robev, Tetrahedron Lett., 1981,22,345. M. Kuzuya, F. Miyake, and T. Okuda, Tetrahedron Lett., 1980,21,2729. M. Mittelbach and H. Junek, J. Heterocycl. Chem., 1980,17,1385. S. D. Carter and G. W. H. Cheeseman, in 'Heterocyclic Chemistry', ed. H. Suschitzky and 0. Meth-Cohn (Specialist Periodical Reports), The Royal Society of Chemistry, London, 1981,Vol. 2,Ch. 4.

Heterocyclic Chemistry

264

R2NC0 gives the pyrimidinones (162 and/or 164), the product ratio depending on the nature of R' and of R2;thus mixtures are obtained when both are aromatic, while aliphatic isocyanates lead solely to (164) (Scheme 69). Pyrimidinethiones have also been prepared, using isothiocyanates.16*

Reagents: i, R'NCO, at 80 "C, THF

Scheme 69

Amidines and guanidines continue to be much used in the classical N-C-N + C-C-C pyrimidine synthesis, with the interest usually residing in the nature of the C-C-C component; thus the aminals (165) and (166) have been used to furnish a variety of 4-(dimethylamino)pyrimidines (Schemes 70 and 7 1).169a NMe, NCfNMez H,C OMe

- Ecj;

NMe,

- phcj;

ph+Me2 OMe OMe (166)

(165) Reagents: RC(=NH)NH2 (R = H or NHJ

Reagents: RC(=NH)NH, (R = Me or NC,H,)

Scheme 70

Scheme 71

The closely related p-acyl-enamines (167) and (168) give 2,4-diaminopyrimidines (169) and (170) upon base-catalysed reaction with guanidine; this is a continuation of earlier studies on structurally similar keten d i t h i ~ a c e t a l s . ' ~ ~ ~

Tt""' rFjNH2 fjNH* NR;

N

(167) R2 = OEt (168) R2 = Ar

H (169)

N

(170)

The 2,4-diamino-5-(alkylthio)pyrimidines(172), of interest as possible antimalarials, have been prepared from @-bromo-acrylonitriles (171) as shown in Scheme 72.169c Condensation of N-phenylurea with benzoylacetone gives both (173) and (174),with the former isomer predominating (17 :2); interestingly, this selectivity '68 lti9

J. Barluenga, V. Rubio, and V. Gotor, J. Org. Chem., 1980, 45, 2592. (a) W. Kantlehner, I. C. Ivanov, W. W. Mergen, and H. Bredereck, Liebigs Ann. Chem., 1980, 372; ( b ) A. Kumar, V. Aggarwal, H. lla, and H. Junjappa, Synthesis, 1980, 748; ( c ) F. Pochat, ibid.,p. 379.

265

Six-Membered Rings: Systems containing nitrogen

is completely reversed in the case of N-phenylthiourea, and only the 1,6-diphenyl isomer (175) is obtained (82'/0).~~'

(173) X = 0

(171)

(174) X = 0 (175) X = S

Reagents: i, (H,N),C=NH

Scheme 72

Depending on the conditions, reactions of di-imines, e.g. (176), with carbon acids such as malononitrile can give either perhydropyrimidines or perhydropyridines as the major product, as exemplified in Scheme 73.*'l

fGH

Ph & .. P h j l

NC

,CPh

P:xPh

NYN Ph

Ph [53%]

HNYNH Ph [4I0/o]

(176)

Reagents: i, CH,(CN),, NH,OAc, EtOH, at r.t.; ii, CH,(CN),, NH,OAc, EtOH, reflux

Scheme 73

Natural-abundance "N n.m.r. spectroscopy has been used to investigate the azidoazine-tetrazoloazine equilibrium that is depicted in Scheme 74; the tetrazoles predominate (ca 95%) in [2H6]DMS0.'72

R/

+ N [5 6-77

'/O

N

]

Scheme 74

Treatment of pyrimidine with Me,SiCN, PhCOCl, and AlCl, (see also p. 261) gives a di-adduct (177); quinazoline reacts like~ise.'~*"

C

Y

Z

h

COPh (177) 170 17' 17'

C. Kashima and A. Katoh, J. Heterocycl. Chem., 1980, 17, 913. T. Tayajo and S . Kambe, Synthesis, 1980, 833. W. E. Hull, M. Kiinstlinger, and E. Breitmaier, Angew. Chem., Int. Ed. Engl., 1980,19, 924.

Heterocyclic Chemistry

266

The photoisomerization of 4-aryl-dihydropyrimidines to 5-aryl-dihydropyrimidines, mentioned last year, was thought to proceed via a di-.rr-methane rearrangement; spectroscopic ('H and 13Cn.m.r.) evidence has now been reported for the formation of a bicyclic intermediate (Scheme 75) of the expected type. 173

H Scheme 75

Preliminary studies on the coupling reactions of amino- and mercaptopyrimidines with diazonium salts show that different reactions occur, depending on the conditions, on the substituents on the pyrimidine, and on the diazonium salt; illustrative of this last point are the reactions undergone by 2-amino-4methylpyrimidine (Scheme 76).174

N-L

j

A N N H

2

tM

/ N e G NN H 2

ii

/ N M e cNA N = N /

C6H4CI-p

/

N H C , H ,NO 2 -p Reagents: i, p-NO,C,H,N,+;

ii, p-ClC6H,N,'

Scheme 76

Irradiation of 1,2,4-trimethylpyrimidin-6-one '(178) (v = 1665 cm-') at low temperatures gives the valence isomer (180) ( v = 1750cm-l; for similar 'Dewar heterocycles', see pp. 253 and 285); this may be converted into the monocyclic p-lactam (181) on treatment with methanol (Scheme 77). The carbacepham (182) has been similarly prepared, starting from the fused pyrimidine (179).175

0 (178) R' = R2 = Me (179) R'R2 = (CH2)4

0 (180)

(181) R1 = R2 = Me (182) R'R2 = ( C H h

Reagents: i, hv, in NH,-Et,O, at -40 "C; ii, MeOH

Scheme 77 R. E. van der Stoel, H. C. van der Plas, and G. Geurtsen, J. Hererocycl. Chem., 1980,17, 1617.

",D. T. Hurst, A. D. Stacey, and D. K. Weerasinghe, Heterocycles, 1980,14, 1753.

"*

S. Hirokami, T. Takahashi, M. Nagata, Y. Hirai, and T. Yamazaki, J. Org. Chem., 1981, 46, 1769.

267

Six-Membered Rings: Systems containing nitrogen

As has already been noted (p. 262), organolithium and organomagnesium reagents can react quite differently with heterocycles; thus methyl-lithium reacts with the pyrimidinone (184) to give mainly the product (185), resulting from 1,2-addition, whereas MeMgI gives exclusively (183),from attack at the conjugate position (Scheme 78).176 Me iii,ii ___*

Ph

Ph

Ph

Reagents: i, MeMgI; ii, H,O; iii, MeLi

Scheme 78

Several reports have appeared on the alkylation of nucleosides (see also p. 280). Cytidine has been converted into 3-methylcytidine in 81% yield by heating it with trimethyl phosphate in DMF,'77 and the parent base (cytosine) has been selectively methylated at the 1-position by a route (Scheme 79) which is .a substantial advance on other published methods.'78 Trimethylsulphonium N=CHNMe2

J-qJLo~> 0

H

A ..

Me

17

O

N Me

Reagents: i, Me,NCH(OMe),; ii, aq. NH,

Scheme 79

fluoride has been used to methylate a number of pyrimidine and purine nucleosides; thus uridine gives 3-methyluridine in 90% yield. The contrasting patterns of reactivity of trimethylsulphonium fluoride and iodide (which does not react with uridine) are most interesting; with guanosine, the former gives the 1-methyl derivative (loo%), and the 7-methyl isomer is obtained (90%) by using the i~dide."~ L-Selectride (lithium tri-s-butylborohydride) is reported to be a mild reagent for the reduction of N-blocked uracils to 5,6-dihydrouracils; the intermediate anions may be intercepted by alkyl halides as well as by water (Scheme 80), and yields are generally quite good.'80 Phenobarbital (5-ethyl-5-phenylbarbituric acid) is formed quantitatively by phenylating 5 -ethylbarbituric acid with phenyllead triacetate.I8'

'" 178

180

C. Kashima, A. Katoh, Y. Yokota, and Y. Omote, J. Chem. SOC.,Perkin Trans. 1, 1981,489. M. Hayashi, K. Yamauchi, and M. Kinoshita, Bull. Chem. SOC.Jpn., 1980,53,277. R. S.Hosmane and N. J. Leonard, Synthesis, 1981,118. K. Yamauchi, Y. Hisanaga, and M. Kinoshita, Synthesis, 1980,852. S.J. Hannon, N. G. Kundu, R. P. Hertzberg, R. S. Bhatt, and C. Heidelberger, Tetrahedron Lett.,

1980,21,1105. J . Pinhey and B. A. Rowe, Tetrahedron Lett., 1980,21,965.

268

Heterocyclic Chemistry

(X = H, 5-CSCSiMe3, 5-F,or 6-C02Et; R = H, Me, Et, Bz, or HCECCH2) Reagents: i, L-Selectride, THF, at -78 "C; ii, H,O or. RX

Scheme 80

Coupling of terminal acetylenes with 0'-protected 5-iodouracil nucleosides has been effected, in excellent yields, with dichlorobis(tripheny1phosphine)palladium and cuprous iodide in triethylamine (see also p. 274)."* Boi1in.g an aqueous solution of 6-aminouracil with p-aminobenzylamine gave the 5-substituted derivative (187) rather than the desired product (186). An investigation into this reaction has shown that the benzylamine (186) (which was independently prepared) rearranges in boiling NN-dimethylaniline to its 5-(p-aminobenzyl) isomer (187) (80%)by an intermolecular reaction; the suggested mechanism is depicted in Scheme 81.lS3 0

Scheme 81

The photochemistry of uracils continues to attract attention; ultraviolet irradiation of aqueous solutions of pyrimidine nucleosides (and the corresponding pyrimidines) in the presence of air has been shown to produce carbon monoxide, and it has been suggested that similar photochemical elimination of CO from nucleic acids may be a means whereby higher plants release this gas to the atmosphere.lS4 Irradiation of 6-cyano- 1,3-dimethyluracil(188)in the presence of isopentene results in a novel type of photoaddition, the cyanopentyl derivative (189) being formed (60%). Hex-1-yne reacts similarly, affording (190) [ E : Z = 1: 13; phenylacetylenes PhCECR give either the cyclo-adducts (191) or benzo[h]MeN%HIDI

oAN Me (188) le2

lS3

'

: N k N c 4 H 9

CN

Me (189)

N'

Me

(190)

M. J. Robins and P. J. Barr, Tetrahedron Lett., 1981, 22, 421. G . E.Wright, J. Org. Chem., 1980, 45, 3128. E. Fahr, P. Fecher, G. Roth, and P. Wustenfeld, Angew. Chem., Int. Ed. Engf., 1980, 19, 829.

269

Six -Membered Rings :Systems contain ing nitrogen

quinazolinediones (192), depending on the wavelength of the light that is employed (Scheme 82).lg5 MeN Ph (191)

Scheme 82

Reagents: i, hv (Pyrex-filtered),PhCGCR (R

=

(192)

Me or Ph); ii, hv (254 nm), PhCECR (R

=

Me or Ph)

In a paper on the utility of the trimethylsilyl function as an easily removable directing group, the photoadditions of alkenes to 5-trimethylsilyluracil have been examined. In the cases studied, good yields of 'head-to-tail' adducts are obtained (Scheme 83); the silyl moiety is easily removed with potassium fluoride.lg6

R2

H Reagents: i, R1R2C=CH,, hv, acetone; ii, KF.2H20, DMSO

Scheme 83

Further work has been described on the reactions of uracils with 1,3-bisnu~leophiles.'~~ 1,3-Dimethy1-5-formyluracil(194) gives p-hydroxybenzoates (195) on reaction with substituted acetones, and a pyridone (193) with cyanoacetamide (Scheme 84). In a closely related reaction, deaza-pteridines (197) have been synthesized, using 6-aminouracils, e.g. (196), as the nucleophile (Scheme 85). 0

(193)

(195) R = Ac, CONH2, Ph, or CO&t Reagents: i, NCCH,CONH2, EtONa, EtOH; ii, RCH,COMe, EtONa, EtOH, reflux

Scheme 84

186

( a ) I. Saito, K. Shimozono, and T. Matsuura, J. A m . Chem. Soc., 1980, 102, 3948; (6) I. Saito, K. Shimozono, S.Miyazaki, and T. Matsuura, Tetrahedron Lett., 1980,21,2317. C. Shih, E. L. Fritzen, and J. S. Swenton, J. Org. Chem., 1980, 45,4462. K. Hirota, Y. Kitadc. and S . Senda, ( a ) J. Heterocycl. Chem., 1980, 17, 413; ( 6 ) ibid., p. 143; ( c ) Heterocycles, 1980, 14,407.

Heterocyclic Chemistry

270

(X Reagents: i, EtONa, EtOH, heat

=

H, CN, NO2, or COMe)

(197) [3 3-65 O h ]

Scheme 85

A number of d-fused pyrimidines have been prepared by passing dry hydrogen chloride through a mixture of a nitrile and an ortho-substituted arylamine (Scheme 86); the method is fairly general, and yields are quite good.188

Z X R

= = =

(inter alia) C02Et, CN, or COPh OH, NH2, or Ph alkyl, aryl, o r alkenyl

Scheme 86

The use of chlorosulphonyl isocyanate in the formation of 4-phenylquinazolin2-ones from o -aminobenzophenones is reported to give better yields than previously used reagents (e.g. urea).189 A quantitative yield of 3-methyl-2phenylquinazolin-4-one is obtained ypon treating 0-aminobenzamide with Nmethylbenzonitrilium triflate (PhCENMe CF,SO,-) in nitr~methane."~ Excellent yields of quinazolin-4-ones are also obtained, in a one-pot procedure, by condensing aldehydes with o -aminobenzamide in the presence of one equivalent of sodium bisulphite. The same procedure has been used to prepare benzo[dl[ 1,2,4]thiadiazine 1,1-dioxide from o -aminobenzenesulphonamide. 19' Flash vacuum thermolysis (FVT) of 4-azido-2-phenylquinazoline(198) gives the benzimidazole (200) (100%); a labelling experiment lent support to the intermediacy of a cyclic carbodi-imide (199), and this could be observed (Y = 2010cm-') upon irradiation of the azide (198) (v = 2150 and 2120cm-') at a low temperature (10K) in an argon matrix (Scheme 87). The same benzimidazole (200) is obtained upon FVT of 2-a~ido-3-phenylquinoxaline.'~~

Scheme 87

190 19' 192

K. G. Dare, C. J. Shishoo, M. B. Devani, R. Kalyanaraman, S. Ananthan, G. V. Ullas, and V. S . Bhadti, J. Heterocycl. Chem., 1980, 17,1497. A. Kamal, K. R. Rao, and P. B. Sattur, Synth. Commun., 1980, 10, 799. B. L. Booth, K. 0. Jibodu, and M. F. ProenGa, J. Chem. SOC.,Chem. Commun., 1980, 1151. Y. Imai, S. Sato, R. Takasawa, and M. Ueda, Synthesis, 1981, 35. C. Wentrup, C. Thktaz, E. Tagliaferri, H. J. Lindner, B. Kitschke, H.-C. Winter, and H. P. Reisenauer, Angew. Chem., Int. Ed. Engl., 1980, 19, 566.

27 1

Six-Membered Rings: Systems containing nitrogen

have appeared on the synthesis of 2-amino-31,4-Diazines.-Two cyanopyrazine-5-carboxaldehyde[as an acetal(202)], which is a key intermediate in the preparation of folic acid and its analogues. In the first, the N-tosyl-imine (201), which has previously been advocated as a useful synthon for the preparation of pyrazines, is the starting point for a two-step synthesis of (202) (overall yield is 39%) (Scheme 88).193aIn the preparation of 5-substituted 2-amino-3cyanopyrazines (204) from (Y -ketoximes and aminomalononitrile, it has been OTs I

N I ,

CN

Me,N (202) R

CN (201)

=

CH(0Et)Z

Reagents: i, RCH=CHNMe,, ether, at r.t,; ii, NH,, CH2Cl,, at r.t.

Scheme 88

pointed out that it may be advantageous to decarbalkoxylate after ring-closure (Scheme 89) rather than initially converting the ketoxime (203) into an aldoxime

(203) +

I

0[R' = CH(OMe2),R2

=

Me]

Reagents: i, NH3CH(CN)2 Ts-; ii, Me,NCH(OMe),; iii, LiI, aq. pyridine; iv, toluene-p-sulphonic acid; v, (MeO),P

Scheme 89

Glyoxals (R2COCHO)react with 2-hydroxyamino-acetamides(205) to afford 6-substituted pyrazin-2-one 4-oxides (206); the reaction of phenylglyoxal with 2-(hydroxyamino)acetamide to give a 6-phenyl derivative contrasts with its reaction with glycinamide, which gives 5-phenylpyrazin-2-one. Some of the pyrazinones that have been prepared exhibit potent anticoccidial activity.194 OH

I

0-

I

iNH NH -oI:]R.

I

R' (205)

t

R'

(206)

xN c') OH

0-

I

I

+

NH,

(207)

R\

N

Me

(208)

(R = D -arubino-tetrahydroxybutyl)

Regioselective condensation is also observed when the oxime of 2-amino-2deoxyglucose (207) reacts with pyruvaldehyde, the 2,6-dialkyl-pyrazine 4-oxide (208) being formed in greater yield than the 2,Sdialkyl derivative (82 : 18).lg5 193

( a ) J.-P.Mayer and J.-P. Fleury, Tetrahedron Lett., 1980, 21, 3759; (b) E. C. Taylor and D. J.

Dumas, J. Org. Chem., 1980,45, 2485. 194

'91

M. Mano, T. Seo, and K.-I. Imai, Chem. Pharm. Bull., 1980, 28,2720. S. Fujii, M. Matsumoto, and H. Kobatako, J. Org. Chem., 1980, 45, 1693.

272

Heterocyclic Chemistry

Good yields of 2,5-disubstituted pyrazines (209) have been obtained by catalytic (Pd/C) hydrogenation of azidomethyl ketones RCOCH2N3;in one case (R=But), the intermediate dihydropyrazine was is01ated.l~~ The 13C n.m.r. spectra of some 40 alkyl- and phenyl-pyrazines and their N-oxides have been studied and the chemical shifts compared with calculated (CND0/2) charge densities. 19'

Electrochemical reduction of pyrazine while the catholyte is being saturated with carbon dioxide, followed by treatment with ethyl bromide, gives the dihydropyrazine (210) (76o/' ). 198 Coupling of alkyl-pyrazine anions to give a 1,2-bis-(2-pyrazinyl)ethane,e.g. (21l), has been effected with iodine.'99 Photoinduced protodecyanation (see also p. 244) of the dinitrile (212) proceeds selectively to give an excellent yield of the mononitrile (213) (Scheme 90).200Derivatives of 3-metlioxypyrazine-2-

Reagents: i, hv, MeCN, Et,N

Scheme 90

carboxylic acid are known to possess powerful antimicrobial activity; in the search for useful analogues, the dinitriles (214) have been converted into the alkoxy-nitriles (215) (Scheme 91).201

(2 14)

(215) [30-90%]

Reagents: i, R'OH, DMF, Et,N, reflux

I

CN (216)

Scheme 91 196

'97

19'

'99 'On *01

M. Nakajima, C. A. Loeschom, W. E. Cimbrelo, and J.-P. Anselme, Org. Prep. Proced. Int., 1980, 12,265. T. Matsuo, S. Matsumoto, T. Kurihara, Y. Akita, T. Watanabe, and A. Ohta, Org. Magn. Reson., 1980,13, 172. D. Michelet, Fr. Demande 2 444 030 (Chern. Abstr., 1981, 94, 164 821). Y. Houminer and E. B. Sanders, J. Heterocycl. Chem., 1980,17,647. M. Tada, H. Hamazaki, and H. Hirano, Chern. Lett., 1980, 921. T. Kojima, F. Nagasaki, and Y. Ohtsuka, J. Heterocycl. Chern., 1980, 17,455.

Six-Membered Rings: Systems containing nitrogen

273

Pyrolysis (at 220 "C)of 2-azido-3,5-diphenylpyrazinegives the N-cyanoimidazole (216)quantitatively, other azidopyrazines behaving similarly; the reaction is said to proceed with 'an explosive generation of nitrogen'! (see also p. 270).202

The 3,5-dihydroxypyrazine (217)reacts readily with acetylenes and electrondeficient alkenes to give 3,8-diazabicyclo[3.2.l]octane-2,4-diones,e.g. (218); the pyrazine is thus reacting across positions 2 and 6 as a 47r component in very similar fashion to the well-known cycloadditions of 3-hydroxypyridine deriva-

(218)

Styrene oxides (219)give good yields of quinoxalines when treated with o-phenylenediamines in hot DMF; depending on the substituents on the epoxide (219)' either 1,2,3,4-tetrahydroquinoxalines,e.g. (220),or fully aromatic derivatives (221)are obtained, the latter being isolated when (219;X=g-tosyl) is H

The reaction of benzofurazan N-oxide (222)with an enone in the presence of an amine takes a course which depends on the type of amine (Scheme 92); although the reaction is usually specific, the synthetic utility of the procedure is limited by the poor yields that are obtained (<35'/0). The mechanisms are discussed and the I3C spectra of a number of quinoxaline N-oxides and NNdioxides are reported.20s

(222) Reagents: i, R2CH=CHCOR', secondary amine; ii, R2CH=CHCOR', primary amine

Scheme 92

The synthesis of a substituted 5,6,7,8-tetrahydroquinoxalinethat is shown in Scheme 93 embodies an uncommon approach in that the carbocyclic ring is 202

' 0 3 204 '05

A. Ohta, T. Watanabe, J. Nishiyama, K. Uehura, and R. Hirate, Heterocycles, 1980,14, 1963. M. E. K. Cartoon, G . W. H. Cheeseman, H. Dowlatshahi, and P. Sharma, J. Chem. Soc., Perkin Trans. 1, 1980, 1603. E. C. Taylor, C. A. Maryanoff, and J. S. Skotnicki, J. Org. Chem., 1980,45, 2512. A. F. Kluge, M. L. Maddox, and G. S. Lewis, J. Org. Chem., 1980,45, 1909.

Heterocyclic Chemistry

274

built onto a pre-formed pyrazine. The ability to perform stepwise transformations of the methyl groups of 2,3-dimethylpyrazine makes this a route of some potential versatility for the synthesis of quinoxalines that are variously substituted on the carbocyclic ring.'06 C0,Et C0,Et

-

f NG

H

coo"

0

N

Reagents: i, LiNPr',, BrCH,CH(OEt),; ii, LiNPr',, (EtO),CO; iii, H,O; iv, NaH; v, work-up at 0°C

Scheme 93

A Pd"-Cu' catalyst system (see also p. 268) has been successfully employed to couple alk-1-ynes with 2-chloro- and 2,3-dichloro-quinoxalines,giving monoand di-alkynyl deriyatives in good yields.207 The 1,4-ethanoquinoxaline (223) has been prepared by the route shown in Scheme 94; this system was claimed in 1921, but apparently erroneously. The mechanism of the cyclization step has been investigated.208 COMe

0-1

COMe

ON) LaN)

Reagents: i,

\ O

N

\ CH,CH,OH N H HOAc; ii, 48% HBr, reflux; iii, NaOMe

u,

(223) N

Scheme 94

In an attempt to form the cyanhydrin, quinoxaline-2-carboxaldehydeNNdioxide was treated with an aqueous solution of acetone cyanhydrin and triethylamine; the product isolated, however, was the carboxylic acid (224) (66%). The suggested mechanism involves loss of water from the initially formed cyanhydrin to give the quinoxaline acylcyanide 4-oxide (225), which, under the reaction conditions, is hydrolysed to the carboxylic acid (224); when the reaction takes place in methanol, the methyl ester (226) is obtained (74'/0).~'~ 0-

I

O N ; # N

(224) X = OH (225) X = CN (226) X = OMe

N e N (227)

Acid-catalysed condensation of 2-chloroquinoxaline with 4-methylquinazoline gives the novel condensed pyrrole (227); several other new ring systems have been prepared in similar fashion.210 '06 '07 *08

Y. Houmaner, J. Heterocycl. Chem., 1981, 18,15. D. E. Ames and M. I. Brohi, J. Chem. SOC.,Perkin Trans. 1, 1980, 1384. ( a ) G . V. Shishkin and A. A. Gall', Chem. Heterocycl. Compd., (Engl. Transl.), 1980, 16, 645; ( b ) ibid., p. 648. A. F. Kluge and M. L. Maddox, J. Heterocycl. Chem., 1980, 17, 1107. R. K. Anderson, S. D. Carter, and G. W. H. Cheeseman, Tetrahedron, 1979, 35, 2463.

Six-Membered Rings: Systems containing nitrogen

275

5 Triazines and Tetrazines Thermal rearrangement of the styrylbenzisoxazole (228) to the quinolone (231) is a known process; this reaction has now been extended to certain heteroanalogues, with the azo-compound (229) giving a benzotriazinone (232) and the imine (230) giving the quinazolinone (233) (Scheme 95).211

T d

NHR

(228) X = * Y = CH (229) X = Y = N (230) X = CH, Y = N

(231) X = Y = CH (232) X = Y = N [SO%] (233) x = CH, y = N [25y0] Scheme95

(234)

Thermolysis (at 180-200 “C) of the aminotriazinones (235; R = Me, Ph, or Ac) gives exclusively 2-substituted indazolinones (237); this supports the thesis that the formation of indazolinone (which is known for R = H) occurs via the azetidinone (236) (see Scheme 96), and not by direct ring-closure of an acyclic intermediate such as (234), which would give 1-substituted indazolinones.212

[62-88

(236)

O/O

3

Scheme 96

The reaction of hydrazine with an isocyanoacetate (238) gives 1,4,5,6tetrahydro-172,4-triazin-6-ones(240) via the (isolable) hydrazides (239) (Scheme 97); using this procedure, the parent compound (240; R’ = R2 = H) has been prepared for the first time.*13

Scheme 97

Two publication^^'^ have appeared on the synthesis+of -1,2,4-triazines by the reaction of an imine with diphenylnitrilimine (PhCGN-”Ph). Thus treatment of the azaspiro[2.2]pentene (241) with this 173-dipolegives a nearly quantitative

214

R. K. Smalley, R. H. Smith, and H. Suschitzky, Tetrahedron Lett., 1979,4687. T. M. Patterson and R. K. Smalley, J. Chem. Res. ( S ) , 1980, 246. K. L. Leschinsky and J. P. Chupp, J. Heterocycl. Chem., 1980, 17, 1621. ( a ) 0.Tsuge, H. Watanabe, and Y. Kirgu, Bull. Chem. Sac. Jpn., 1979, 52, 3654; ( b )R. Gandolfi and L. Toma, Tetrahedron, 1980, 36, 935.

276

Heterocyclic Chemistry

yield of the cyclobutatriazine (242); in the presence of silica gel, this 4,6-system undergoes hydration and rearrangement to the 5,5 system (243).214aThe tropone imine (244) reacts with diphenylnitrilimine (generated in situ) to give the two protomeric fused triazines (245) and (246) in excellent overall yield. These two products do not interconvert under the reaction conditions (in MeCN, at r.t.), and the authors therefore suggest that the isolation of the 4 a H isomer (246) is evidence for the intermediacy of a [4 + 21 spiro-adduct (247), which rearranges to (246); the 9 a H isomer (245) might also be formed via (247).2146

(R = p-ClGjH4)

An unusually facile cleavage of a pyridine ring occurs when the hydrazone (249) is treated with methyl 1-methylhydrazinecarbodithioate (NH2NMeCS2Me),the resultant triazine (250) being formed in 67% yield; the action of dimethylamine on (249) gives the pyridotriazine (248) (40%) (Scheme 98). These investigations owed their genesis to the observation that 2-acetylpyridine and the carbodithioate give only the triazine (250), none of the desired Schiff -base (249) being isolated; 6-blocked pyridines (2-acetyl-6-methylpyridine and 2-acetylquinoline) give only the expected Schiff-bases.215 S

Reagents: i, MeS,CNMeNH,; ii, Me,NH, MeCN, H,O, at r.t.

Scheme 98

A good yield of 2-chloro-4,6-diphenyl-l,3,5-triazine(253) is obtained when N-cyanobenzamidine (252) is treated with the amide chloride of NN-dimethylbenzamide (25 1) (Scheme 99); amino- and mercapto-triazines can also be ’15

J. P. Scovill and J. V. Silverton, J. Org. Chem., 1980, 45, 4372.

Six-Membered Rings: Systems containing nitrogen

277

prepared, in similar fashion; thus S-methyl NN-dimethyldithiocarbamate (Me,NCSSMe) and the aforementioned amidine lead to 2-chloro-4-methylthio6-phenyl- 1,3,5-tria~ine.~l~

c1

x(251) X

= C1 or

(252)

(253)

POCl2 Scheme 99

Thermolysis (at 120°C) of the iminoylhydrazine inner salt (254) gives a dihydrotriazine (256), together with some aromatized material. It has been suggested that a Stevens rearrangement, followed by loss of dimethylamine, gives the diaza-diene (255), which then dimerizes, with loss of p-tolylideneimine (see also p. 290), as outlined in Scheme

phYNH

(-Me,NH)

N< + NMe2CH2Ar (254)

PhYNH

Ph(

(-ArCH=NH)

N YPh

NYNH Ar

Ar

(256) Ar = p-tolyl

(255)

Scheme 100

Good yields of triazinediones, e.g. (258), are obtained by treatment of thiadiazolones, e.g. (257),with isocyanates (Scheme 101).2'8 0 0 N

4

Phk,/' H (257)

NANR

Ph"A0 H (258)

N-N

Ph( /

/)Ph N-N

c 6F5

Reagents: i, RNCO, Et,N, THF

(259)

Scheme 101

Investigations continue into the synthetic uses of cyanuric halides;219 thus lactones of ring size up to 19 have been formed from o-hydroxy-acids, using cyanuric chloride-triethylamine in acetone, at room temperature, and sulphoxides have been deoxygenated in good yields by cyanuric fluoride. 3,6-Diaryl-1,2,4,5-tetrazineshave been obtained (in yields of 7 4 6 % ) by treating aroyl-hydrazines ArCONHNH2 with triphenylphosphine, hexachloroethane, and triethylamine, followed by oxidation with N-bromosuccin'16 217

218

R. L. N. Harris, Synthesis, 1980,841. R. F.Smith, A. S. Craig, L. A. Buckley, and R. R. Soelch, Tetrahedron Lett., 1979,4193. J. Perronnet and L. Taiiani, J. Heterocycl. Chem., 1980,17,673. ( a ) K. Venkataraman and D. R. Wayle, Tetrahedron Letr., 1980,21, 1893;(6) G. A.Olah, A. P. Fung, B. G . B. Gupta, and S. C. Narang, Synthesis, 1980,221.

Heterocyclic Chemistry

278

imide.220 A better yield (75%) of the dihydrotetrazine (259) is obtained by refluxing 2-(perfluoropheny1)benzhydrazidein thionyl chloride 221a Two reports221on verdazyl radicals (260) have appeared, and the syntheses are outlined in Scheme 102; these radicals are stable crystalline solids, and some e.s.r. spectra in aqueous solution have been recorded. /

Me

Me

R

\

R

(260) X=CH2 or C=O Reagents: i, (CH,O),, BF,.Et,O; ii, NaOH; iii, K,[Fe(CN),]; iv, PhCHO; v, Ag,O

Scheme 102

Cycloaddition reactions of triazines and tetrazines continue to be much employed in the synthesis of other cyclic systems (see also pp. 238 and 251). Noteworthy is the synthesis of substituted semibullvalenes that is depl'cted in Scheme 103; the intermediate diazanorcaradienes are, in two cases (where R is Me and Ph), sufficientIy stable to be observed by n.m.r. spectroscopy.222 R R

[3 8 4 8 Yo 3

Scheme 103

Irradiation of cis-diazidobis(triphenylphosphine)platinum(Ir) at 77 K in = 380 nm) which disappears on warming, ethanol produces a yellow colour (A,, with simultaneous evolution of nitrogen; this absorption, which may also be observed upon flash photolysis at room temperature, exhibits first-order decay ( k l = 1.66 x s-'), and it has been suggested that it may be attributable to he~a-azabenzene.~~~ 6 Fused Systems containing One Five- and One Six-Membered Ring (5,6)

6-Azapurines (263) have been prepared by oxidative cyclization of azahexatrienes (262) with diethyl azodicarboxylate (DAD). Starting materials (261) by are prepared from 6-arylidenehydrazino-3-methyl-5-nitrosouracils 220

L. Farkas, J. Keuler, and H. Wamhoff, Chem. Ber., 1980,113,2566. I. G. Ryabokon', and L. N. Markovskii, Chem. Heterocycl. Compd. (Engl. Trunsl.), 1980, 16, 882; (b) F. A. Neugebauer and H. Fischer, Angew. Chem., Znt. Ed. Engl., 1980,19,724. D. Paske, R. Ringshandl, I. Sellner, H. Sickert, and J. Sauer, Angew. Chem., Int. Ed. Engl., 1980, 19,456. A. Vogler, R. E. Wright, and H . Kunkely, Angew. Chem., Znr. Ed. Engl., 1980,19, 717.

'" ( a ) 0. M. Polumbrik, *', 223

279

Six-Membered Rings: Systems containing nitrogen

sequential treatment with alkali and an alkylating reagent (Scheme 104).224

0 (261)

(262) R = Me or Et

Reagents: i, 10%KOH; ii, RI, K,CO,, DMF; iii, DAD, at 175 "C

Scheme 104

The pharmacologically active agent from the marine sponge Tedania digitata has been shown to be 1-methylisoguanosine (264);225it was shown to exist in the 2-keto-6-amino-form by measuring its 13C n.m.r. spin-lattice relaxation

HO OH (264)

times.226 1-Substituted 4-cyano-5-aminoimidazoleshave been converted into purines in the search for Ara-A p r o - d r ~ g s . ~An ~ ' alternative approach to purine synthesis is illustrated by the preparation of 9-substituted 8-phenyltheophyllines (265) from oxazolopyrimidines (Scheme 105).228

Me (265) R

=

Me, CHzPh, (CH2)5,or Ar

Reagents: i, RNH,; ii, SOCl, or POCl,

Scheme 105

The reduction (by NaBH4 or by Hzand Pd) of 8-trifluoromethyl-9-methylpurine is unusual in that it gives the 7,8-dihydro-derivative in addition to the When 2-chloro-, 2-fluoro-, or 2expected 1,6-dihydro-compound (2 : l).229 thiomethyl-purine is allowed to react with "N-labelled potassium amide in liquid 224 225 226

227 228

229

T. Kametani, M. Higuchi, M. Noguchi, Y. Hashiguchi, and F. Yoneda, Heterocycles, 1980,14,1295. A. F. Cook, R. T. Bartlett, R. P. Gregson, and R. J. Quinn, J. Org. Chem., 1980, 45,4020. R. S. Norton, R. P. Gregson, and R. J. Quinn, J. Chem. SOC.,Chem. Commun., 1980, 339. K.Kadir, G. Shaw, and D. Wright, J. Chem. SOC.,Perkin Trans. 1, 1980,2728. S. Nishigaki, J. Sato, K. Shimizu, and K. Senga, Chem. Pharm. Bull., 1980, 28, 1905. A. Albert, Abstr. Fifth Lakeland Heterocycl. Symp., 1981, p. 21.

280

Heterocyclic Chemistry

ammonia, the resulting 2-aminopurine incorporates the label at N-1 of the ring.23oIn contrast, 6-chloro- and 6-thiomethyl-purine yield 6-aminopurine that is labelled at the exocyclic nitrogen atom.231 Permethylation of adenosine and guanosine, i.e. the formation of pentamethyl and hexamethyl derivatives, is achieved by their reaction with trimethylanilinium m e t h o ~ i d e Benzylation .~~~ of adenine under phase-transfer conditions yields mainly the 9-benzyl derivative; it was previously necessary to use strictly anhydrous conditions to achieve this 3-Benzyladenine is debenzylated on treatment with 96% sulphuric acid at 50 "C, but 9-benzyladenine is unchanged under these conditions; this differential reactivity has been used to remove the 3-isomer from mixtures of benzylated adenines.234 The replacement of the 6-amino-group in purines by hydrogen, chlorine, bromine, or iodine has been carried out by the generation of purinyl radicals in an appropriate Pyrimidine and purine nucleosides have been methylated by methyl radicals, these being generated by homolysis of t-butyl peracetate. At pH 1-4, mainly C-methylation is observed, but, at pH 4-10, the extent of C-methylation decreases and the amount of N-methylation on nitrogen that is in the ring and/or exocyclic increases. Purine nucleosides are more reactive at low pH and pyrimidine nucleosides at higher pH. This work is relevant to the study of radical-induced c a r c i n o g e n e s i ~The . ~ ~use ~ of pivaloyloxymethyl (Me3CC02CHz) as a protecting group in the synthesis of dimethylated xanthines has been demonstrated; it can be removed by treatment with sodium The photochemical reaction of caffeine and stilbene gives a complex mixture of products arising from both [2 + 21 and [4+ 21 cycloadditions. Carbons 4 and 5 , and 4 and 8 of the caffeine molecule, are involved in these reactions.238 Pyrrolopyrimidines (deazapurines) continue to be investigated because of their potentially interesting biological proper tie^.^^^^^^^ For example, 7-deaza-Ara-A, in contrast to Ara-A, is not deaminated by adenosine deaminase. 9-Deazaadenosine is reported to have exceptional cytotoxicity to several lines of mouse and human l e u k a e r n i a ~ . 9-Deazatheophyllines ~~* (267) have been prepared by the reaction of the arylidene-nitrouracils (266) with sodium dithionite and formic acid (Scheme 106).242 C-5-Substituted pyrrolo[2,3-d]pyrimidine nucleosides (268) have been synthesized via the organopalladium intermediates derived from 5 m e r c ~ r i t u b e r c i d i n .Analogues ~~~ of dideazapurine have also been synthesized; 23n

231 232

233

234

23s 236 237 238

239 240

241 242

243

N. J. Kos and H. C. van der Plas, J. Org. Chem., 1980,45, 2942. N. J. Kos, H. C . van der Plas, and A. van Veldhuizen, Recl. Trav.Chim. Pays Bas, 1980, 99, 267. G . R. Pettit, R. M Blazer, J. J. Einck, and K. Yamauchi, J. Org. Chem., 1980,45,4073. I. Shinkai, M. C. van der Zwan, F. W. Hartner, R. A. Reamer, R. J. Tull, and L. M. Weinstock, J. Heterocycl. Chem., 1981, 18, 197. L. M. Weinstock, R. J. Tull, A. W. Douglas, and I. Shinkai, J. Org. Chem., 1980, 45, 5419. V. Nair and S. G . Richardson, J. Org. Chem., 1980,45, 3969. M. F. Zady and J. L. Wong, J. Org. Chem., 1980,45,2373. M. W. Hu, P. Singh, and E. F. Ullman, J. Org. Chem., 1980, 45, 1711. G . Kaupp and H.-W. Griiber, Angew. Chem., Inr. Ed. Engl., 1980,19,714. H.-D. Winkeler and F. Seela, Chem. Ber., 1980,113, 2069. F. Seela and D . Hasselmann, Chem. Ber., 1980,113,3389. M.-I. Lim and R. S. Klein, Tetrahedron Lett., 1981, 22, 25. S. Nishigaki, Y. Kanamori, and K. Senga, Chem. Pharm. Bull., 1980, 28, 1636. D . E. Bergstrom, A. J. Brattesani, M. K. Ogawa, and M. J. Schweickert, J. Org. Chem., 1981, 46, 1423.

28 1

Six-Membered Rings: Systems containing nitrogen 0 MeN?No2 NO '

'

CH=CHAr

-

MeNQ oAN

Ar Me

Me (266)

(267) [35--65'/0] Scheme 106

0

HO

OH

(268) R = H,NOCCH=CH or NCCH=CH

thus pyrrolopyridines that are structurally related to the naturally occurring purines have been r e p ~ r t e d . ~ ~ ~ , ~ ~ ~

7 Fused Systems containing Two Six-Membered Rings (6,6) The pyrimidotriazines (269;R = H) and (269;R = Me) have been synthesized and tested as potential inhibitors of hydroxymethyldihydropterin pyrophosphokinase. Surprisingly, they had little enzyme-inhibiting activity, despite their close structural similarity to the normal pteridine A novel synthesis of the pyrimidinotriazines (3-substituted fervenulins) (272) involves the reaction of 6-azido-1,3-dimethyluracil(270) with C-substituted tetrazoles (271).(Scheme 107).247 0 M e N 5 oAN N3 Me (270)

+

'

N 5 N/)R HN"

DMF,reflux

(271) R = Ar,PhCH2, or MeS

~

M e N k N x NO '

N' Me (272) [40-85 %]

Scheme 107

Cyclization of the (alky1hydrazino)isocytosines (273) with bromo-ketones has been reported to yield the pyrimidotriazines (274) rather than pyridazinopyrimidine~.~~' The pyrimidopyridazines (275) act as hydrogen acceptors, and they oxidize both alcohols and amines (in weakly basic conditions) to 244 245

246 247 248

S. W. Schneller, J.-K. Luo, and R. S . Hosmane, Tetrahedron Lett., 1980,21,3135. S. W.Schneller and J.-K. Luo, J. Org. Chem., 1980,45,4045. S. S.Al-Hassan, I. Stirling, and H. C. S . Wood, J. Chem. Res. ( S ) , 1980,278. K. Hirota, M. Maruhashi, T. Asao, and S . Senda, Heterocycles, 1981,15,285. W.R. Mallory and R. W. Morrison, J. Ore. Chem., 1980,45,3919.

282

Heterocyclic Chemistry

the corresponding carbonyl and iminyl compounds. The resulting dihydrocompounds (276) are readily re-oxidized (Scheme 108).249

{R 1{R} 2 ~ o (275)

(276)

R1R2C0 or

PhCHzNH2

PhCH=NH Scheme 108

An unusual pterin, i.e. euglenapterin (277), with a 2-dimethylamino-group has been isolated from Euglena grucilis; its structure has been confirmed by The reaction of 6-amino- 1,3-dimethyl-5 -(phenylazo)uracil (278)

HN5N, ' HO H C-C-CH20H I I

OH

Me2NkN

(277)

with dimethyl acetylenedicarboxylate yields the 6,7-bis(methoxycarbonyl)pteridine (279) (Scheme 109).251The catalytic reduction of 7-methylpterin in neutral solution occurs first at the 7,8-bond; in acidic solution, the 5,6-bond

(278)

(279)

Scheme 109 249

250

F. Yoneda, and K. Nakagawa, J. Chem. SOC., Chem. Commun., 1980,878. M. Bohme, W. Pfleiderer, E. F. Elstner, and W. R. Richter, Angew. Chem., Int. Ed. Engl., 1980, 19, 473.

251

S . Nishigaki, K. Fukami, M. Ichiba, H. Kanazawa, K. Matsuyama, S. Ogusu, K. Senga, F. Yoneda, R. Koga, and T. Ueno, Heterocycles, 1981, 1 5 , 7 5 7 .

Six-Membered Rings: Systems containing nitrogen

283

is reduced first and the dihydro-intermediate then undergoes rearrangement to Xanthothe thermodynamically more stable 7-meth~l-7,8-dihydropterin.~~~ pterin-7-carboxylic acid (280) is converted into 7-aminoxanthopterin (281) by the prolonged action of aqueous ammonia and manganese dioxide (Scheme 110).~53

(280) Reagents: i, 25% aq. NH3, MnO,, for 5 days, at r.t.

Scheme 110

Pyrido[3,2-d]pyrimidines (284) have been prepared by the reaction of the (arylideneamino) trimethyluracils (282) with dimethylf ormamide dimethy1 acetal. The intermediate azahexatriene (283) undergoes intramolecular cyclization, subsequent loss of dimethylamine giving the aromatic product (Scheme 11l).254

MeN5(N=cHAr o A N Me

Me

\.L

(282)

Reagents: i, (MeO),CHNMe,, at 130 "C, for 7 h

Scheme 111

The reaction of 6-amino-1,3-dimethyluracil(285) with NN-dimethylphosgenimmonium chloride gives the 5 -substituted 6-aminouracil (286); on ringclosure with malononitrile, this yields the pyridopyrimidine (287) (Scheme 1 12).255

(285)

+

Reagents: i, Me,N=CCl,

(286) C1-; ii, CH,(CN),; iii, OH-, H 2 0

Scheme 112 252

253 254 255

A. N. Ganguly, P. K. Sengupta, J. H. Bieri, and M. Viscontini, Helv. Chim. Acta, 1980, 63,395.

K. Baumgartner and J. H. Bieri, Helv. Chim.Acta, 1980, 63, 1805. K. Senga, K. Furukawa, and S. Nishigaki, Synthesis, 1980, 479. B. Kokel, C. Lespagnol, and H. G. Viehe, Bull. SOC.Chim. Belg., 1980,89,651.

Heterocyclic Chemistry

284

Rate data on the acetate-promoted loss of protons from dimethyl-5-deazalumazines suggest that the C-7-methyl group in (288) is activated by the methyl group attached to position 6. The C-7-methyl group is also an activated site in lumazines and in f l a v i n ~ . ~ ’ ~ 0

(288)

8-Acetoxyflavins (290) are formed by the reaction of flavin 5-oxides (289) with acetic anhydride (Scheme 113).257 The reaction of 6-arylamino-1,3dimethyluracils with one-carbon synthons (e.g. DMF dimethyl acetal, Vilsmeier

(289)

(290)

Scheme 113

reagent, triethyl orthoformate, and carbon disulphide) yields 5-deazaalloxazines (pyrimidoq~inolines).~~~~~~~ Analogous ring-closure of the 6-aryloxyl-methyluracils (291; X=O) yields 5-deaza-10-oxaflavins (292; X = 0),which oxidize benzyl alcohols under neutral (aerobic) conditions [the thia-analogue (292; X = S) is known to perform this oxidation under strongly basic condition~].~~~

H

(291)

(292)

8 Oxazines, Thiazines, and their Fused Derivatives 0xazines.-Treatment of the triazoles (293) with aromatic nitrile oxides affords 6H-1,2-oxazines (294) (Scheme 114); the structure of one of these products was confirmed by X-ray crystallography.261 A benzyl-oxazinone (296; one 25h 257 258

259

260 261

R. Stewart, S. J. Gumbley, and R. Srinivasan, J. A m . Chem. SOC.,1980, 102,6168. F. Yoneda, Y. Sakuma, and K. Hiromatsu, Chem. Lett., 1980, 235. S. Nishigaki, J. Sato, K. Shimizu, K. Furukawa, K. Senga, and F. Yoneda, Chem. Pharm. Bull., 1980, 28, 142. Y. Tominaga, H. Okuda, M. Tochiki, Y. Matsuda, and G. Kobayashi, Heterocycles, 1981, 15,679. F. Yoneda, R. Hirayami, and M. Yamashita, Chem. Lett., 1980, 1157. D. D’Oria, D. Pocar, L. M. Rossi, and P. Trimarco, J. Chem. Res. ( S ) , 1980, 242.

285

Six-Membered Rings: Systems containing nitrogen

isomer) is the product that is isolated when the cyclopropane (295) is condensed with hydroxylamine in pyridine.262

COPh

Ar (293)

Ph

ph4 Bz
(294) [30-7 5 "/o ]

0

Reagents: i, Ar2CN0, MeCN, at r.t.

Scheme 114

6-Carboxyalkyl-6H-l,2-oxazines, e.g. (297), are formed in good yields by the as exemplified in acid-catalysed rearrangement of 2-alkoxy-5-oximinoylfurans, Scheme 115.263These oxazines undergo base-induced transformation into 2oxopyrrolines [e.g. (298); see Scheme 1151; it is interesting to compare these rearrangements with the previously mentioned (see p. 248) thermal ones of 6-cyano-6H- 1,2-oxazines, which give 2-cyano-N-hydroxypyrroles.

Reagents: i, toluene-p-sulphonic acid, PhH, reflux; ii, Et,N, PhH, reflux

Scheme 115

The cycloaddition reactions of ap-unsaturated heterocumulenes (e.g. acyl isocyanates) with phosphacumulene ylides Ph,P=C=C=X (see also p. 261) have been explored; good yields of [2 + 41 adducts can be obtained, as exemplified by the synthesis of a 1,3-0xazine shown in Scheme 116. Pyrimidines and 1,3-thiazines have also been prepared, by similar types of c y ~ l o a d d i t i o n . ~ ~ ~ 0

Scheme 116

Two reports have appeared on the photochemistry of 1,3-0xazin-6-ones.~~~ In the first, the possibility of using these oxazinones as precursors of azetes was 262 2c3

26* 265

I. E.-S. El-Kholy, H. M. Fuid-Alla, and M. M. Mishrikey, J. Heterocycl. Chem., 1980,17,541. Y . Nakada, T. Hata, C. Tamura, T. Iwaoka, M. Kondo, and J. Ide, Tetrahedron Lett., 1981,22,473. H.Bestmann, G. Schmid, D. Sandmeier, and C. Geismann, Tetrahedron Lett., 1980,21,2401. ( a ) G.Maier and U. Schafer, Liebigs Ann. Chem., 1980, 798; (6) P. de Mayo, A. C. Weedon, and R. W. Zabel, J. Chem. SOC.,Chem. Commun., 1980,881.

286

Heterocyclic Chemistry

investigated by irradiation at low temperatures. At -78"C, in THF, the oxazinone (299) gives its bicyclic valence isomer (301) (v = 1820cm-'), and irradiation in an organic glass (MeOPr) at -185 "C enables the keten (300) ( v = 2140cm-') to be detected. Prolonged irradiation gave, in addition to C 0 2 , a mixture of the four products (Bu'CECH, ButCN, MeCECH, and MeCN) that would be expected from fragmentation of an azete (302), were such a compound being formed. The photochemical interconversion of the oxazinones (303) and (306) has been shown to proceed by way of the bicyclic isomers (304) Bu'

B u'

*n

(300)

"

and (305); thus irradiation of (303) at -78 "C in [*H8]toluene gives its valence isomer (304), which, on warming to -40 "C, gives the isomeric p-lactone (305); this in turn gives a mixture of the two oxazinones (303) and (306) when warmed to room temperature. It is suggested that the interconversion of the two bicyclic compounds (304) and (305) occurs by heterolysis of the bridgehead carbonoxygen bonds, the carboxylate moiety being able to re-cyclize at either end of the resulting aza-ally1 cation (307).

Carbonylation of the aryl-thallium compounds ArTl(O,CCF,), can be performed at room temperature and pressure, using PdCl, as a catalyst; thus the reaction of acetanilide with Tl(O,CCF,),, followed by carbonylation of the resulting metallated derivative, gives the benzoxazinone (308) (40'/0),,~~ A synthesis of fused oxazines from o -chlorocarboxylic acids and cyanamides is depicted in Scheme 117. Mixtures such as (310) and (311) do not always result; thus the oxazine (309) is obtained in 73"/0 yield from 2-chloro-3,5dinitrobenzoic acid and N-cyanopyrr~lidine.~~' 2h6 267

R. C. Larock and C. A. Fellows, J. Org. Chem., 1980,45, 363. W. Reid, G . Oremek, R. Guryri, and H.-E. Erle, Chem. Ber., 1980, 113,2818.

Six-Membered Rings: Systems containing nitrogen

287

(310) [2 parts]

(311) [ l part]

Reagents: i, Me,NCN, at 80 "C

Scheme 117

Thiazines.-The thiazinium salt (313) gives a cyanopyridine (314) upon treatment with base and methyl cyanoacetate; this ring transformation does not occur with other carbon acids such as diethyl malonate, which gives the adduct (312) (Scheme 118).268 Ph

Ph (312)

Ph

Ph

(313)

CN (314)

Reagents: i, MeO,CCH,CN; ii, CH,(CO,Et),

Scheme 118

Good yields of benzothiazines are obtained by addition of diary1 thioketones to N-aryl-ketenimines (Scheme 119). Kinetic studies indicate that this reaction exhibits the standard features of a concerted process; the formation of heterocycles by the cycloaddition reactions of ketenimines has been reviewed.269

- .

Scheme 119

An interesting reaction occurs when the cephem (315; R=PhOCH2CONH) is treated with N203in dichloromethane at room temperature, the a-nitro-oxime (317) being isolated, in 67% yield. It has been suggested that the oxime is formed by loss of CO, from the intermediate adduct (316); this 'retro-ene' reaction is analogous to the facile decarboxylation of P-keto-acid~.~'~

R

R

(-cot)

0 \ C ' . - X N 0 2'Me

Me CO,H (315) 268

26q

"O

N\ (317)

OH

I. Shibuya, Bull. Chem. SOC.Jpn., 1979,532,3767. (a) A. Dondoni, A. Battaglia, and P. Giorgianni, J. Org. Chem., 1980,453,3766;( b )A.Dondoni, A. Battaglia, F. Bernardi, and P. Giorgianni, ibid., p. 3773;(c) A. Dondoni, Heterocycles, 1980, 14,1547. M. M. Campbell and S. J. Ray, J. Chem. Soc., Chem. Commun., 1980,665.

288

Heterocyclic Chemistry

The fused thiazine (318) is formed by the reaction of NN-diethylpropynamine with the now readily available o-di-isothiocyanatobenzene; other nucleophiles which give similar products are enamines and the malononitrile anion.271 Benzalanilines cyclo-add to sulphene (H2C=S02; generated from mesyl chloride and triethylamine) to afford dihydrobenzothiazines (3 19)(52--70'/0).~~*

The formation of a ca 1: 1 mixture of the benzothiazoline (321) and benzothiazine (322) upon treatment of the disulphide of o-aminobenzenethiol with methyl phenylethynyl ketone (PhC-CCOMe) is accounted for by invoking the intermediacy of a b%-adduct (320), as shown in Scheme 120.273"A related

askcoMe \

N f

I'

Ph (322)

H (320)

Scheme 120

mechanism has been proposed for the oxidative ring-expansion of benzothiazolines which occurs on refluxing in DMSO, as shown in Scheme 121; yields of the thiazines are generally low (8-46%).273b Related 2-acyl-benzothiazines have been formed directly from o -aminobenzenethiol and fluorinated 6diketones by heating in DMSO, as exemplified in Scheme 122; yields are quite good, and, in the light of the previous reference, it would be interesting to know whether benzothiazolines are formed as i n t e r r n e d i a t e ~ . ~ ~ ~ ~ OH I M e - y y Me

H Scheme 121 271

272 273

A. W. Faul, D. Griffiths, R. Hull, and T. M. Seden, J. Chem. SOC.,Perkin Trans. 1, 1980, 2587. M. Rai, S. Kumar, K. Krishna, and A. Singh, Chem. Ind. (London), 1979, 26. ( a ) G . Liso, G . Trapani, V. Berardi, and P. Marchini, J. Heterocycl. Chem., 1980, 17, 377; ( b ) G. Liso, G. Trapani. A. Latrofa, and P. Marchini, ibid., 1981, 18, 279; (c) R. P. Soni and M. L. Jain, Tetrahedron Lett., 1980, 21,3795.

289

Six-Membered Rings: Systems containing nitrogen 0

Scheme 122

9 Other Oxygen- and Sulphur-containing Systems Benzoylsulphene (PhCOCH=SO,) cyclo-adds regiospecifically to the azirines (323) to afford 1,4,3-oxathiazines (324) (ca 60%). The structures of the products follow from the formation of sulphonamides (325) upon acid hydrolysis,274 U

A new procedure for the preparation of 1,2,3-benzoxathiazine 2,2-dioxides (327) involves heating o-acyl-phenols (326) with chlorosulphonyl isocyanate (CSI) in this is in distinct contrast to the reactions of CSI with o-acyl-anilines (329) (see p. 270), which give quinazolinones (328), only traces of thiadiazines (330) being formed (Scheme 123). Chlorosulphonyl isocyanate is a 1,3-bis-electrophile, and the differing reactions that are observed with this reagent may depend upon which site (C or S ) undergoes initial attack.

(328) X = NH [66-81%]

(326) X = 0 (329) X = NH

(327) X = 0 [66-83%] (330) X = NH [ 5 4 % ]

Reagents: i, C10,SNCO

Scheme 123

The 1,2,3-oxasilazine (332) (80%)has been formed by successive treatment of the aminosilane (331)with butyl-lithium and methacrolein (Scheme 124).276 Trifluoromethyl-substituted hetero-dienes continue to be much used in the formation of six-membered heterocycles (uide infru); thus nearly quantitative yields of 1,3,2,5-dioxathiazines (334) can be obtained by the reaction of the N-acyl-imines (333) with dimethyl sulphoxide (Scheme 125).277The tetrakis(trifluoromethyl)-1,3,5-oxadiazines (339, prepared from amidines and hexafluoroacetone, undergo retro-Diels-Alder reactions on vacuum thermolysis, 274

275 276 277

0. Tsuge and M. Noguchi, Heterocycles, 1978,9,423. A. Kamal and P. B. Sattur, Synthesis, 1981, 272. J. Neeman and U. Klingebiel, Liebigs Ann. Chem., 1980, 1978. J. Synth. Methods, 1980,6, 75 779V.

Heterocyclic Chemistry

290

,H

But,

But

N I ,Si\

R

Bu\

I N+/F3

Bu\

iu,F

\ C+ 0

Si , 0 Bu' ' (332) . ,

-

/0'7h'fe2

DMSO

"x"

F3C CF3 (334)

I

(331) (333)

Reagents: i, BuLi; ii, H,C=C(Me)CHO

Scheme 125

Scheme 124

and the resultant diazabutadienes (336) give either triazines (338) (see p. 277) or quinazolines (337), depending on the substituents on the diaza-diene (Scheme 126); yields can be very

x x

x x x =

iii

(337)

R' (335)

(X = CF3) Reagents: i, (CF,),CO; ii, POCl,, pyridine; iii, at 170-220 "C, at 15-80 Torr

Scheme 126

The 1,3-thiaza-dienes (339) give 1,3,5-thiadiazines (340) on reaction with tetracyanoethylene (TCNE); this is apparently the first reported case of this much-used dienophile adding a diene to one of its nitrile groups rather than across its C=C d o ~ b l e - b o n d . ~ ~ ~ TCNE __I+

at 120OC

(339)

(340)

A new route to benzothiadiazine S-oxides (342) has been reported; the key step is the quantitative reduction of the sulphonyl chloride (341) to the corresponding sulphinic acid ArS02H (Scheme 127). Yields are variable, but the generality of the procedure is greater than that of the one previously reported route.280 278 279 280

K. Burger, S. Penninger, and M. Greisel, J. Fluorine Chem., 1980,15,1. K. Burger and H. Goth, A n g e w . Chem., Int. Ed. Engl., 1980,19, 810. N. Finch, S. Ricca, and L. H. Werner, J. Org. Chem., 1980,45, 3410.

29 1

Six-Membered Rings: Systems containing nitrogen H

(341)

(342) R

=

0 H, Me, or Ph

Reagents: i, aq. Na,SO,, at S40 "C; ii, SO.Cl,; iii, NH,; iv, RC(OEt),

Scheme 127

The first members of the novel oxatriazine system (344) have been prepared by irradiation of triaryl-2H-l,2,3-triazole 1-oxides (343). These highly coloured solids are stable to mild hydrolytic:conditions (acidic or basic) and are unaffected by attempted reduction with LiAlH, or with HZand Pd on

(343)

(344)

The thiatriazine (346), obtained by ozonolytic cleavage of the stilbenyl precursor (343, undergoes an extremely facile anionic electrocyclization, with extrusion of sulphur dioxide, to give a 1,2,3-triazole (347) as the only product (Scheme 128).282 PhB/Ph NkN/N

i,ii

3>Ph KN"

Ph(

_3

(APh

H

Ph

(346)

P h y I P h "N, (347)

(345) Reagents: i, 0,; ii, Et,N, MeOH, at -5 "C;iii, Et,N, MeOH, at r.t., for 10 minutes

Scheme 128

Classified Reference List Synthesis of Pyridines.-D. R. Walt, V. M. Rios-Mercadillo, J. AugC, and G. M. Whitesides, J. A m . Chem. SOC.,1980,102,7804. A. E. Sausin, B. S. Chekavichus, V. K. Lusis, and G. Ya. Dubur, Chem. Heterocycl. Compd. (Engl. Transl.), 1980,16,377. Properties of Pyridines.-G. Maas and C. Hummel, Chem. Ber., 1980,113,3679. C . S. Giam and K. Kikukawa, J. Chem. SOC.,Chem. Commun., 1980,756. M.Hirota, T. Sekiya, A. Hishikura, H. Endo, Y. Hamada, and Y. Ito, Bull. Chem. SOC.Jpn., 1980,

53,717. S. Tono-oka, Y. Sasahara, A. Sasaki, H. Shirahama, T. Matsumoto, and S. Kakimoto, Bull. Chem. SOC.Jpn., 1981,54,212. 281 282

G. J. Gainsford and A. D. Woolhouse, Aust. J. Chem., 1980,33,2447. B. B. Jarvis and G. P. Stahly, J. Org. Chem., 1980,45,2604.

292

Heterocyclic Chemistry

J. S. Davies, K. Smith, and J. Turner, Tetrahedron Lett., 1980, 21, 2191. L. W. Deady and W. L. Finlayson, Synth. Commun., 1980,10,947. Y. Mizuno, T. Endo, Y. Inoue, H. Tampo, A. Takahashi, M. Iigo, A. Hoshi, and K. Kuretani, Chem. Pharm. Bull., 1980,28, 1584. Quinolines, Isoquinolines, and their Benzo- and Hydro-derivatives.-Y. Watanabe, N. Suzuki, S. C. Shim. M. Yamamoto, T.-A. Mitsudo, and Y . Takegami, Chem. Lett., 1980,429. I. Ninomiya, T. Kiguchi, S. Yamauchi. and T. Naito, J. Chem. SOC.,Perkin Trans. 1, 1980, 197. W. Zielinski, Pol. J. Chem., 1980, 54,2209. K. Matsumoto and T. Uchida, J. Chem. SOC.,Perkin Trans. 1, 1980, 73. H. Inoue and K. Higashiura, J. Chem. SOC.,Chem. Commun., 1980, 549. 0 .Meth-Cohn and B. Tarnowski, Tetrahedron Lett., 1980, 21, 3721. 1,2-Diazines.-C. Degrand, P.-L. Compagnon, G . Belot, and D. Jacquin, J. Org. Chem., 1980,45,1189. H. Heydt, K.-H. Busch, and M. Regitz, Liebigs Ann. Chem., 1980, 590. S . Polanc, B. Stanovnik, and M. Tisler, Synthesis, 1980, 830. I. V. Barinov, T. 1. Voevodskaya, and Yu. A. Ustynyuk, Vestn. Mosk. Univ., Ser. 2: Khim., 1980, 21, 72 (Chem. Abstr., 1980, 93,46 558). 1,3-Dinzines.-H. Meyer, Liebigs Ann. Chem., 1980,673. J. Gallucci, M. LeBlanc, and J. G. Riess, J. Fluorine Chem., 1980, 15, 333. S. Robev, Dokl. Bolg. Akad. Nauk, 1979,32, 1235 (Chem. Abstr., 1980, 93, 8129). K. Burger, F. Hein, and G. Jannitsopoulos, Chem. Ber., 1980, 113, 3396. L. Citerio, M. L. Saccarello, R. Stradi, and B. Giria, J. Chem. SOC.,Perkin Trans. 1, 1980, 722. Y. Kobayashi, I. Kumadaki, and A. Nakazato, Tetrahedron Lett., 1980, 21, 4605. H. Singh and P. Singh, J. Chem. SOC.,Perkin-Trans. 1, 1980, 1013. K. Hirota, Y. Kitade, S. Senda, M. J. Halat, K. A. Watanabe and J. J. Fox, J. Org. Chem., 1981, 46, 846. T. Sakamoto, T. Ono, T. Sakasai, and H. Yamanaka, Chem. Pharm. Bull., 1980,28,202. I. Saito, H. Sugiyama, S. Ito, N. Furukawa, and T. Matsuura, J. A m . Chem. SOC.,1981, 103, 1598. K.-I. Ozaki, Y. Yamada, and T. Oine, Chem. Pharm. Bull., 1980,28,702. K. E. Nielsen and E. B. Pedersen, Acta Chem. Scand., Ser. B, 1980,34,637. 1,4-Diazines.-J. H. Zhao and M. H. Wang, Chung Ts’ov Yao, 1980, 11, 199 (Chem. Abstr., 1981, 94,65 623). P. R. Buckland, J. Heterocycl. Chem., 1980, 17, 397. R. E. van der Stoel, H. C. van der Plas, H. Jongejan, and L. Hoere, R e d . Trau. Chim. Pays-Bas, 1980, 99, 234. T. Nishio, N. Nakayima, and Y. Omote, Tetrahedron Lett., 1981, 22, 753. J. D. M. Herscheid, R. J. F. Nivard, M. W. Tijhuis, and H. C. J. Ottenheijm, J. Org. Chem., 1980, 45, 1885. Triazines and Tetrazines.-A. Oksawa, H. Arai, H. Ohnishi, and H. Igeta, J. Chem. SOC.,Chem. Commun., 1980,1182. T. M. Paterson, R. K. Smalley, H. Suschitzky, and A. J. Barker, J. Chem. SOC.,Perkin Trans. 1, 1980, 633. M. M. Davtyan, S. P. Krubovskii, and V. A. Ponomarenko, Izu. Akad. Nauk SSSR, Ser. Khim., 1980,425 (Chem. Abstr., 1980,93,46610). H. Mohrle and U. Scharf, Arch. Pharm. (Weinheim, Ger.), 1980,313, 435. Fused Systems with One Five- and One Six-Membered Ring.-R. H. Foster and N. J. Leonard, J. Org. Chem., 1980, 45, 3072. E. Curry, F. W. Lichtenthaler, and A. Moser, Tetrahedron Lett., 1980, 21, 3029. Fused Systems with Two Six-Membered Rings.-P. 113,1514.

H. Boyle and W. Pfleiderer, Chem. Ber., 1980,

Oxazines, Thiazines, and their Fused Derivatives.-M. L. M. Pennings and D. N. Reinhoudt, Tetrahedron Lett., 1980, 21, 1781. M. A. Leoni, G. F. Bettinetti, G. Minoli, and A. Albini, J. Org. Chem., 1980. 45. 2331. H.-J. Federsel and J. Bergman, Tetrahedron Lett., 1980, 21, 2429. I. A. Silberg and M. V. Diudea, Rev. Roum. Chim., 1980,25, 1229. M. Takahashi, S.-I. Watanabe, and T. Kasai, Heterocycles, 1980, 14, 1921. Other Oxygen- and Sulphur-containing Systems.-A. J. Elliott and M. S. Gibson, J. Org. Chem., 1980, 45, 3677. J. Beger, C. Thielemann, and P. D. Thong, J. Prakt. Chem., 1979, 321, 959.

Six-Membered Rings: Systems containing oxygen or sulphur

293

PART 11: Six-Membered Rings containing Oxygen or Sulphur by G. P. Ellis The selection of material for this Part has been more difficult than usual because of the voluminous literature and the limited amount of space available. Most of the phytochemical work has therefore been omitted.

1 Books and Reviews The reactions of polysubstituted thiopyrans with protonic acids and structural studies on the resulting products have been reviewed.' The biosynthesis of isochromanquinone antibiotics2 and the chemistry of flavanols3 have been surveyed. Reviews on the intriguing relationships between chemical structure and taste in the flavonoids4 and the latter's effect on the taste and quality of citrus fruits' emphasize the importance of these compounds. Reviews of the chemistry and biological activity of naturally occurring coumarins6 and of the chemistry of thioco~marins~ give detailed coverage of these compounds. Naturally occurring anth hones^*^ have been extensively reviewed and a survey of the toxicity of chlorinated dioxin derivatives, especially the dreaded TCDD, is timely.'' A comprehensive book on chromans and tocopherols has been published.''

2 Heterocycles containing One Oxygen Atom

Reduced Pyrans.-A total synthesis of pederin, a potent insecticide isolated from Puederus fuscipes,12 has been achieved from (+)-pederic acid.13 Diglycollic aldehyde [O(CH2CH0)2]reacts with diethyl malonate or pentane-2,4-dione to form the tetrahydropyran-3,5-diols(1; R = C02Et) and (1; R = Ac), which give a positive Tollens reaction, indicative of alkali-induced ring-~pening.'~

*

' lo

*' '*

13

l4

V. G. Kharchenko, N. I. Kozhevnikova, A. A. Shcherbakov, G. G. Aleksandrov, and Yu. T. Struchkov, Khim. Geterotsikl. Soedin., 1980, 324. F. G. Heinz, Antibiotics (New York), 1981, 4 (Biosynthesis), p. 215. Y.L. Liu, Yao Hsueh Hseuh Pao, 1980,15,50. R. M . Horowitz and B. Gentili, Dev. Food Sci., 1979,2,384. R. L. Rouseff, A.C.S. Symp. Ser., 1980, No. 143, p. 83. A. S. Chawla, V. K. Kapoor and J. Kumar, Pharmacos, 1980,24,63. 0. Meth-Cohn and B. Tarnowski, Adv. Heterocycl. Chem., 1980, 26, 115. M. U.S. Sultanbawa, Tetrahedron, 1980, 36, 1465. M. Afzal and J. M. A1:Hassan. Heterocycles, 1980, 14, 1173. D. Kriebel, Environment, 1981, 23,6. 'Chromans and Tocopherols', ed. G. P. Ellis and I. M. Lockhart, Wiley, New York, 1981. G. P. Ellis, in 'Heterocyclic Chemistry', ed. H. Suschitzky and 0.Meth-Cohn (Specialist Periodical Reports), The Royal Society of Chemistry, London, 1981, Vol. 2, p. 283. M. Yanagiya, K. Tsuzuki, T. Watanabe, Y.Nakajima, F. Matsuda, K. Hasegawa, and T. Matsumoto, Koen Yoshishu-Tennen Yuki Kagobutsu Toronkai, 22nd, 1979,635(Chem.Abstr., 1980,93,7943). F. J. L. Aparicio, M. G. Mezo, and U. A. Espinosa, A n . Quim., 1979, 75, 916 (Chem. Abstr., 1980,93,26 359).

294

Heterocyclic Chemistry

An analogue of thromboxane A2 in which there is a 2,4-methylene bridge has been synthesized in a multi-stage process, from trans-penta-2,4-dien- 1-01 and the bridged pyran (2).” Tetrahydropyrans that are spiro-annulated at C-4 have been prepared from tetrahydropyran-4-carboxaldehyde,acrylonitrile, and methylmagnesium iodide.16 Three short papers have described the synthesis of the antibiotic monensin (3) from stereoselectively synthesized fragment^.^' The methyl ester dibenzoate (4) of another antibiotic, ambruticin, upon ozonolysis in CH2C12at -78 “C, gave a mixture of alcohols which included the diol ( 5 ) and the trio1 (6), both of which (as their perbenzoates) were separately and unambiguously synthesized.l8

3:

Me0

CH,OH

Me

HO,C

Me

(3)

OCOPh

A

PhOCO

(5)

Meo OCOPh

Me

...,,

OCOPh

‘‘OCOPh OCOPh (6)

Pyrans and Pyrylium Salts.-1 -(Trifluoromethyl)ethenyl phenyl sulphide has been condensed with ethyl acetoacetate to give the pyran (7) in 69% yield.’’ Another synthesis of a 4H-pyran (8) employed arylidene-malononitriles and oxaloacetic ester.” Diphenylpyryliurn salts, e.g. (9), have been prepared in a one-step reaction of acetophenone with RCHClOAc in the presence of a Lewis acid. When R is l5

l6

l7

’’ l9

2o

E. J. Corey, J. W. Ponder, and P. Ulrich, Tetrahedron Lett., 1980, 21, 137. R. A. Kuroyan, N. S. Arutyunyan, and S . A. Vartanyan, Arm. Khim. Zh., 1980, 33,415. D. B. Collum, J. H. McDonald, and W. C. Still, J. A m . Chem. Soc., 1980,102, 2117, 2118, 2120. G. Just and P. Potvin, Can. J. Chem., 1980, 58, 2173. A. E. Feiring, J. Org. Chem., 1980, 45, 1962. Yu. A. Sharanin, Zh. Org. Khim., 1980, 16, 2188.

Foe

Six-Membered Rings: Systems containing oxygen or sulphur CF,C=CH, I SPh

+ AcCH,CO,Et

%

295

CO2Et

PhS

(7)

Me or Ph, a mixture of 2,6- and 2,4-diphenylpyrylium salts is formed.21 The reactions of pyrylium salts continue to be exploited in synthesis; e.g., electrochemical reduction of 2,4,6-triaryl-pyrylium salts in the presence of alkyl halides (RX) gave the 4-alkyl-pyran (lO),’’” while the formation of the spiran (11) in 92% yield is one of several reactions of 2,6,2’,6‘-tetra-t-butyl-4,4’bispyrylium diperchlorate.’”

The versatility of 2,4,6-triphenylpyrylium salts in synthesis23 has been extended to that of sulphur-containing Advantages of trifluoromethanesulphonates over perchlorates and tetrafluoroborates have been dem~nstrated,~’and replacement of one or two of the phenyl rings by heterocycles has been studied for both the pyrylium and pyridinium salts.26

Reduced Pyrones.-Good yields of 3,4-dihydropyran-2-ones,e.g. (12), were obtained from enaminones such as PriCOCH=CHNPh2 and dichloroketen; dehydrochlorination with DBN yielded the corresponding pyran-2-0nes.~’*~* Photolytic degradation of the two isomers [ ( S , R )and ( S , S ) ]of the dipyran (13) in benzene at 80 “C gave tetrahydropyran-3-one and S-valer~lactone.~~

A number of partially reduced pyran-2-ones of biological importance have been studied; for example, the absolute stereochemistry at C-2 and C-3 of 21

22

23 24 25

26 27

** 29

S. M. Luk’yanov, S. V. Borodaev, and G. N. Dorofeenko, Zh. Org. Khim., 1981, 17,208. ( a ) L. Yu. Ukhin, V. V. Bessonov, A. I. Yanovskii, T. V. Timofeeva, N. G. Furmanova, and Yu. T. Struchkov, Khim. Geterotsikl. Soedin., 1980, 461; ( 6 ) F. Pragst, M. Janda, and I. Stibor, Electrochim. Ada, 1980,25, 779. Ref. 12, p. 290. A. R. Katritzky, M. C. Rezande, and S. S. Thind, J. Chem. Res. (S),1980, 309. A. R. Katritzky, A. M. El-Mowafy, L. M. Marzorati, R. C. Patel, and S. S . Thind, J. Chem. Res. (S), 1980, 310. A. R. Katritzky and M. C. Rezande, J. Chem. Res. (S), 1980,312. A. Bargagna, S. Cafaggi, and P. Schenone, J. Heterocycl. Chem., 1980,17,507. A. Bargagna, P. Schenone, F. Bondavalli, and M. Longobardi, J. Heterocycl. Chem., 1980,17,1201. C. Bernasconi, L. Cottier, G. Descotes, M. F. Grenier, and F. Metras, J. Heterocycf. Chem., 1980, 17,45.

296

Heterocyclic Chemistry

stegobinone, which is the sex pheromone of the drugstore beetle,30 has been determined,3*and the pheromone (14) of the carpenter bee has been synthesized from triacetic acid l a ~ t o n e . ~ The * total synthesis of (*)-pentalenolactone (15), a lipophilic anti-tumour antibiotic, has been achieved from the vinologous ester 3-met hoxy - 2-methylcyclopent-2-enone. 33 Bae yer-Villiger oxidation of bren d a n - 4 - 0 n e ~gave ~ two lactones, one of which, i.e. (16; R = H), has now been synthesized from an iodo-lactone (16; R = I) by treatment with tri-n-butyltin and NaBH4.35

Malyngolide (17), an antibiotic of marine origin, has been synthesized by two routes, one of which should be applicable to the synthesis of similar lac tone^.^^'^'

2-Pyrones.-4-t-Butyl-3-methoxycatechol reacts with an excess of methoxy(pyridine)copper(II) chloride under anaerobic conditions to give methyl 4-t-butyl-2-oxopyran-6-carboxylate in very high yield. This conversion is compared with that effected aerobically by copper-containing enzymes3* An inhibitor of elastase called elasnin (18) has been synthesized from (E)- 2-butyl0ct-2-enal.~~ The pyrones (19; R' = H) and (19; R1 = 4-R2C6H4C0,where R2 is Bu, MeO, BuO, etc.) have been synthesized by acylation of the phenol (whose synthesis is described), and they showed an enantiotropic smectic phase and a nematic mesophase of high thermal ~tability.~'

OH (18)

Kojic acid has been benzoylated, phenylacetylated, and benzylated under a variety of conditions; some of these showed selectivity towards one of the two 30

31 32 33 34

35 36 37

38 39 40

G. P. Ellis, in 'Heterocyclic Chemistry', ed. H. Suschitzky and 0. Meth-Cohn (Specialist Periodical Reports), The Royal Society of Chemistry, London, 1980, Volume 1, p. 336. R. W. Hoffmann and W. Ladner, Tetrahedron Lett., 1979,4653. R. Bacardit and M. Moreno-Manas, Tetrahedron Lett., 1980, 21, 551. W. H. Parsons, R. H. Schlessinger, and M. L. Quesada, J. A m . Chem. SOC.,1980,102,889. A. Nickon, H. R. Kwasnick, C. T. Matthew, T. D. Schwart, R. 0. Williams, and J. B. Di Giorgio, J. Org. Chem., 1978,43, 3904. S. P. Briggs, D . I. Davies, and R. F. Kenyon, J. Urg. Chem., 1980, 45, 2531. Y. Sakito, S. Tanaka, M. Asami, and T. Mukaiyama, Chem. Lett., 1980, 1223. J. H. Babler, B. J. Invergo, and S. J. Sarussi, J. Urg. Chem., 1980, 45,4241. T. R. Demmin and M. M. Rogic, J. Urg. Chem., 1980,45,4210. J. R. Pfister, Tetrahedron Lett., 1980, 21, 1281. T. I. Zverkova, N . F. Lynkmanov, and E. I. Koshev, Zh. Org. Khim., 1980,16,645.

297

Six-Membered Rings: Systems containing oxygen or sulphur

hydroxyl group^.^' When 4,6-diphenylpyran-2-one was heated with morpholine or piperidine, 1,3-dipheny1-5-oxopent-2-enoicmorpholide or piperidide was formed in high yield. Some thiopyran-2-ones behaved similarly.42 4-Pyrones.-C-Acylation of the potassium salt of 2-hydroxy-4-methoxybutane1,3-dione with acyl chlorides (e.g. benzoyl chloride) or anhydrides, followed by cyclization, gave 4-pyrones (e.g. 2-phenylpyran-4-one, in 82% yield).43Another by treatefficient synthesis yielded 2-acetyl-3-hydroxy-6-methylpyran-4-one ment of octane-2,4,5,7-tetraone with iodo~obenzene.~~ A new and unexpected rearrangement of a 4-pyrone was observed when the chloromethyl compound (21; R = Me) was heated with thiourea in ethanol to give the benzothiazole (22);the hydroxypyrone (21; R = H) behaved predictably to produce the isothiuronium salt (20).4s H o Q c H 2 s ~ N HNH*HCI 2

0

+ R o ~ c H 2 c 1 4MHO e 0 0\1 > N H 2 * I - I C l 0

(20)

(22) (21)

Chromans.-Phenoxypropyl bromides have been cyclized (at - 100 "C, by butyllithium) in high yields to the c h r o m a n ~when ; ~ ~ a dihydric phenol is treated with phytyl chloride in the presence of complexes of cation-exchange resins with metal ions, tocopherol-like compounds are produced in good yield^.^' An intermediate (23) in the synthesis of trichothecene antibiotics has been synthesized from a reduced indanone (24).48Treatment of the cannabinol7-ester (25; R' = equatorial C02Me, R2 = Ac) with NaOMe caused irreversible isomerization to the axial isomer (25; R' = axial C02Me, R2 = Ac); the axial methyl ether (25; R' = axial C02Me, R2 = Me) gave the equatorial isomer (25; R' = equatorial CO,Me, R2 = Me).49 Several spiro[2H-l-benzopyran2,l',cycloheptanes] have been synthesized from dihydrocoumarins and the

R'

41

42 43

44 45

46 47 48

49

N. S. Poonia, A . K. Arora, and A. V. Bajaj, Bull. Chem. Soc. Jpn., 1980,53,569. I. E.S. El-Kholy, M. M. Mishrikey, and H. M. Feid-Allah, J. Heterocycl. Chem., 1981,18,105. T. A.Morgan and B. Ganem, Tetrahedron Lett., 1980,21,2773. M. Poje, Tetrahedron Lett., 1980,21,1575. R.L. White, T. J. Swan, and R. J. Alaimo, J. Heterocycl. Chem., 1980,17,817. C.K.Bradsher and D. C . Reames, J. Org. Chem., 1981,46,1384. Y.Tachibana, Bull. Chem. Soc. Jpn., 1980,53, 5 5 5 . C-M. Chen and D. Fullerton, Proc. Nut. Sci. Counc., Repub. China, 1979,3, 388 (Chem. Abstr., 1980,93,7951). R. Mechoulam, N. Landef, I. Tamir, Z. Ben-Zvi, and Y. Kimmel, Angew. Chem., Int. Ed. Engl., 1980,19,543.

298

Heterocyclic Chemistry

Grignard reagent from 1,6-dibromoheptane in THF via opening and closing of the pyran ring.50" Several products have been identified in the bromination of P-lapachone and lapachol with N-bromo~uccinimide.~~~ Isochromans and 1sochromenes.-A Diels-Alder reaction of 2-acetylcyclohex2-enone with vinyl ethers at 25 "C gave a 75% yield of the isochromene (26; R = P-OEt) and about 5% of the em-isomer (26; R = a-OEt)? Descriptions of total syntheses of several naphthoquinone antibiotics have been published: (k)-f renolicin, (k) -nanaomycin A, (k) -kalaf ungin, and (k)-deoxyfrenolicin.5 2

Substituents attached at C- 1 of isochromans are easily displaced; for example, an ethoxy--grouphas been replaced by a benzyloxy-group (on heating with benzyl alcohol), by OCHMeC0,Et [with (*)-ethyl lactate], by 2- and 4-hydroxyphenyl (with phenol), by 1-(2,4-dimethoxyphenyl) (with 1,3-dimethoxybenzene), and by a 4-methoxycarbonyl-2-hydroxyphenylgroup (with methyl 4-hydroxybenzate.^^ The isochromene (27) has been converted into the aglycons of several iridoids, such as that of (*)-1-0-methylsweroside (28).54 Chromenes.-2H-Chromenes have been synthesized by cyclo-condensation of a phosphonium salt such as (29) with a 2-chloro-ketone, e.g., (30; R' = Me or aryl; R2 = H, Me, or Ph).55Several natural 2H-chromenes, e.g. 2,2-dimethyl-7methoxy-6-acetyl-2H-chromene, have been synthesized from acetylenic ethers of 4- hydroxy acetophenone. 56

Fluorine-containing analogues of natural chromenes have been synthesized; for example, the 2-trifluoromethyl analogue of the insect anti-juvenile hormone, precocene 11,57 was prepared from 3,4-dimethoxyphenol and 3 -hydroxy-3trifluoromethylbutanal dimethyl a ~ e t a l and , ~ ~3-fluoro-analogues of both pre50

51 52

53 54 55

56 57

58

( a ) P. Canone, D. BBlanger, and G . Lemay, Heterocycles, 1981, 15, 455; ( b ) R. B. Gupta and R. N. Khauna, Indian J. Chem., Sect. B., 1980, 19, 13, 17. B. B. Snider, Tetrahedron Lett., 1980, 21, 1133. A. Ichihara, M. Obukata, H. Oikawa, K. Murakami, and S. Sakamura, Koen Yoshishu-Tennen Yuki Kagobutsu Toronkai, 22nd, 1979, 440 (Chem. Abstr., 1980, 93, 46 466); Tetrahedron Lett., 1980,21,4469. M. Yamato, T. Ishikawa, and T. Kobayashi, Chem. Pharm. Bull., 1980,28, 2967. M. Nakane and C. R. Hutchinson, J. Org. Chem., 1980,454233. B. Begasse and M. LeCorre, Tetrahedron,1980, 36, 3409. F. Bohlmann and F. M. Stohr, Liebigs Ann. Chem., 1980, 185. Ref. 12, p. 296. F. Camps, J. Coll, A. Messeguer, and M. A. Pericas, J. Heterocycl. Chem., 1980,17, 207.

Six-Membered Rings: Systems containing oxygen or sulphur

299

cocene I and I1 (among other chromenes) were obtained from a phenol and 1,1-dimethoxy-2-fluoro-3-methylbut-3-ene.59 Several linear and angular furochromenes have been synthesized as potential photosensitizers.60 2H-Chromene undergoes cycloaddition with 1,3-dipoles to give tricyclic products; e.g., with mesitonitrile oxide, (31) is the main product.61

Me

Chromanones.-A synthesis of 2,2-dimethyl-4-chromanonesis provided by condensation of a reactive phenol with 3-methylbut-2-enoic acid in the presence of MeS03H.62 When the oxime of 4-chromanone was reduced with sodium bis-(2-methoxyethoxy)aluminohydride, 2,3,4,5-tetrahydro-l,5-benzoxazepinewas formed.63Attempts to oxidize compounds such as (32;R' = H, R2 = H2, R3 = Me) to the 3,4-dione failed, but the dione was obtained by first protecting the 5-hydroxy-group and then oxidizing this ether with pentyl nitrite. The resulting oxime (32; R' = OCH2Ph, R2 = NOH, R3 = Me) gave the dione (32; R' = OCH,Ph, R2 = 0, R3 = Me), which was condensed with various reagents to form a third ring before removing the 0-protecting group. The corresponding 7-hydroxychromans were also oxidized to the d i ~ n e N,N-Disubstituted .~~ 3aminomethylenechromanones [such as (32; R' = R3 = H, R2 = CHNPh,)] undergo cyclization with dichloroketen to form (after dehydrochlorination) SH-pyran0[3,2-c][ llbenzopyran-2-ones [such as (33)] which are related to the fungal metabolite c i t r ~ m y c e t i n . ~ ~ 0

Concentrated sulphuric acid caused the polymerization of 4-chromanone in the presence of formaldehyde, but, when the reaction was conducted in dioxan or acetic acid-benzene, and a lower concentration of sulphuric acid was used, rather low yields of compounds of the type (34) or (35) were obtained. The

'' F. Camps, J. Coll, A. Messeguer, and M. A. Pericas, J. Heterocycl. Chem., 1980,17, 1377. 6o

62

64 65

L. Rene, M. Faulques, and R.Royer, J. Heterocycl. Chem., 1980,17, 1149. T. Shimizu, Y. Hayashi, K. Yamada, T. Nishio, and K. Teramura, Bull. Chem. SOC.Jpn., 1981, 54,217. F. Camps, J. Coll, A. Messeguer, M. A. Pericas, S. Ricart, W. S. Bowers, and D. M. Soderland, Synthesis, 1980, 725. L. M. Meshcheryakov, V. A. Zagorevskii, and E. K. Orlova, Khim. Geterotsikl. Soedin., 1980,853. L. Chiodini, M. Di Ciommo, and L. Merlini, J. Heterocycl. Chem., 1981, 18, 23. L. Mosti, P. Schenone, and G. Menozzi, J. Heterocycl. Chem., 1980, 17, 61.

300

Heterocyclic Chemistry

concentration of acid also has an effect on the regioselectivity of bromination of 6,8-dibromochromanone: in 96% acid, the 5-bromo-compound was obtained, but the 3-isomer was produced in acetic acid-sulphuric acid.66

c1-

Chromones.-A convenient synthesis of the rather inaccessible 2-methylchromone-3-carboxylic acid has been achieved by the reaction of salicylyl chloride and the morpholine enamine of ethyl acetoacetate. The intermediate salt (36) cyclized, on heating, to give a 36% yield of the ester, which was then hydrolysed to the carboxylic Syntheses of chromones with C1 or C2 alkyl side-chains at C-3 are readily available but usually fail when long side-chains are required. By modifying the Baker-Ollis and Kostanecki-Robinson methods, good yields of 3-(higher alky1)chromones have been obtained.68 A further example of the direct formation of a phenylhydrazone of a chromone has been recorded in the reaction of 8-methylchromone in methanol at 18 *C.69 Much improved syntheses of 2-methylchromone-3-carboxaldehydeand of 3-methylchromone-2-carboxaldehyde from 2-methylchromone and 2,3dimethylchromone, respectively, are now a~ailable.~' The fragmentation of several 2-styrylchromone-6-carboxylic acids in the mass spectrometer has been studied7' and the relative stereochemistry of the epoxide side-chain of the antibiotic hedamycin has been shown (by 13C n.m.r. and by comparison with model compounds) to be (14R,16S,17S,18S).722-Methylchromone has been condensed with phthalic anhydride in the presence of sodium acetate to give the furanone (37), which rearranged with base to the indanedione (38).73

Qo &

H CJJ - f

\

0

I

I

0 (37)

(38)

A. Ninagawa, R. Nomura, and H. Matsuda, Bull. Chem. SOC.Jpn., 1979,52, 1169. J. L. Charlton, G. Lypka, and V. Sayeed, J, Heterocycl. Chem., 1980,17, 593. 68 T. Buggy and G. P. Ellis, J. Chem. Res. ( S ) , 1980, 317. 69 K. Kostka and J. Nawrot, Pol. J. Chem., 1980, 54, 15. 'O T. Buggy and G . P. Ellis, I. Chem. Res. ( S ) , 1980, 159. 7 1 R. Tonani, Org. Mass Spectrom., 1980, 15, 275. '* M. Ceroni and U. Sequin, Tetrahedron Lett., 1979, 3703. 7 3 A. A. Sayed, S. M. Sami, and S. S. Ibrahim, Egypt. J. Chem., 1977,20, 225 (Chem. Abstr., 1980, 93, 46 331). 66

67

Six-Membered Rings: Systems containing oxygen or sulphur

301

Several reactions have been described in which a chromone has been converted into a tricyclic analogue. When chromone-3-carboxaldehyde was condensed with guanidine, a benzopyranopyrimidine (39) was obtained, but the corresponding oxime and guanidine sulphate gave 5-(3-hydroxyphenyl)isoxazole-4~arboxaldehyde.~~ Diazomethane adds on to 3-nitrochromone to give the cyclopropa[l]benzopyran (40) as the main product, and this reacts with water or alcohols to give the l-benzoxepinone derivatives (41;R = H or alkyl). Other diazo-alkanes, however, behave diff e ~ e n t l y .2-Aminochromone-3 ~~ -carboxaldehyde, on treatment with 1,2-diamines or acetylglycine, gave several products, some of which contained an imidazole, diazepine, or oxazolone ring.76

The reaction of 6-methylchromone-3-carbonitrilewith diazo-alkanes results in alkylation of the 2-position in high yield; the corresponding 3-acetylchromone behaved similarly. On the other hand, 2-carbonitriles yield 2-(2-methyl-1,2,3triazol-4-y1)chromones and the 2-carboxaldehyde gives the corresponding 2and related compounds, when subjec~ x i r a n7-Methoxy-2-methylchromones .~~ ted to reduction by metal in liquid ammonia, were degraded to the corresponding 2-hydroxy-4-methoxybutyrophenones(42).78 Chromone-3-carboxaldehydes are readily available, but their conversion into carboxylic acids proceeded in only moderate yields. A new method79utilizes N-bromosuccinimide (NBS), a solvent, and either azobisisobutyronitrile or irradiation with tungsten light to effect oxidation in high yield.

F1avans.-Cyclization of 2-cinnamylphenols with iodine and H202 gave 3iodoflavans in 77-96% yield. Dehydrohalogenation of the iodo-compounds with base yielded 2H-fla~enes.~' Spectroscopic and X-ray crystallographic techniques have been used to study the conformation of 3-substituted flavans that contain bulky groups.81 74 75

76 77 78 79

C. Pene and M. Hubert-Habart, J. Heterocycl. Chem., 1980, 17, 329. F. M. Dean and R. S. Johnson, J. Chem. Soc., Perkin Trans. 1, 1980, 2049. C. Ghosh and N. Tewari, J. Org. Chem., 1980,45, 1964. F. M. Dean and R. S. Johnson, J. Chem. Soc., Perkin Trans. 1, 1981, 224. A. Major, Z . Nagy, and M. Nogradi, Acta Chim. Acad. Sci. Hung., 1980,104, 8 5 . Y. Machida, S. Nomoto, S. Negi, H. Ikuta, and I. Saito, Synrh. Commun., 1980, 10, 889. L. Jurd and G. D. Manners, Synthesis, 1980,618. F. Baert, R. Fouret, M. Sliwa, and H. Sliwa, Tetrahedron, 1980,36, 2765.

302

Heterocyclic Chemistry

Flavanones and 1soflavanones.-The presence of 18-crown-6 ether in the reaction of 2-hydroxyacetophenone (converted into its silyl ether) with benzaldehyde at 37°C facilitated the formation of flavanone,82 and the synthesis of isoflavanones is expedited by the presence of a phase-transfer catalyst such as tetrabutylammonium hydrogen ~ u l p h a t e .3-Chloroflavanones ~~ are initially formed by thermal elimination of hydrogen chloride from 2’-hydroxychalcone dichlorides at 200”C, but, at 210--220”C, the corresponding flavone is formed in 90% yield. Pyrolysis of the dibromides was also studied.84 The structure of melanervin (43), the first natural triphenylmethane derivative, has been confirmed by its synthesis.85 3-Aroyl-flavanones have been oxidized with SeOz in dioxan to 3-aroyl-flavones. Both types of compounds reacted with hydroxylamine hydrochloride in pyridine to give the isoxazolines (44; R = H) and the isoxazole (44; RR = a bond) respectively.86A study of the U.V. spectra of 3-hydroxy- and 3 -amino-flavanones in buffered solution showed that irreversible base-catalysed oxidation to the flavones O C C U ~ S . ~Flavanones, ’ when treated with copper(I1) chloride, gave 3-mono- and 3,3-di-chloro-derivatives,depending on other substituents present. Dehydrochlorination of some dichlorides led to 3-chloroflavones, while reduction of the 3-chloroflavanones with NaBH4 gave flavanols with inversion of configuration at C-3 The (E)-oxime of substituted flavanones, on heating with trifluoroacetic acid, is rearranged to the 2-isoxazoline (45);s9 this reaction is reminiscent of the recently reported rearrangement of the oxime of dihydropyr~nes.’~ Me

Me OH

v

F1avones.-Lithiation of 2-hydroxyacetophenones and reaction with a benzoyl chloride at -78 “C gave 1,3-diaryl-propane-l,3-dionesr mineral acids caused these to cyclize to flavones in high yield.” When lieated in pyridine for a short time, chalcone dibromides gave low to moderate yields of mono- or dibromoflavones; for example, 6-bromoflavone from 2‘-hydroxychalcone R2

83 84

85

86 87

a8 89

90 91

T. Katagi, T. Shirota, M. Kashiwagi, and K. Hayashi, Heterocycles, 1981, 15, 493. P. K. Jain, J. K. Makrandi, S. K. Grover, and M. Nogradi, Curr. Sci., 1980,49, 664. J. A . Donnelly and K. Quigley, J. Chem. SOC.,Perkin Trans. 1, 1980, 1299. E. Schindlbeck, S. Ahmad, 0. Seligmann, H. Wagner, and S. Antus, Tetrahedron Lett., 1980, 21, 1189. M. M. Chincholkar and V. S . Jamode, Indian J. Chem., Sect. B, 1979,17, 510. E. R. David, M. Rakosi, G . B. Szabo, and R. Bognar, Acta Chim. Acad. Sci. Hung., 1979, 102, 187. F. G . Weber, E. Birkner, and H. Koeppel, Pharmazie, 1 9 8 0 , 3 5 3 2 8 . J. M. Paris, J. M. Couquelet, and J. D. Couquelet, Bull. SOC.Chim. Fr., Part2, 1979, 299. Z. Witczak, Heterocycles, 1980, 14, 1319. A . Banerji and N. C. Goomer, Synthesis, 1980, 874.

Six-Membered Rings: Systems containing oxygen or sulphur

303

(5,7,3',4'-tetrahydroxyflavone)has been synthesized by d i b r ~ m i d e Luteolin .~~ treatment of the partly 0-methylated chalcone with Se02 and demethylation of the An improved method of preparing 3-chloroflavones in good yield consists of refluxing 2-hydroxydibenzoylmethaneswith S02C12in dioxan for one 5-Hydroxy-7,8,3',4'-tetramethoxyflavoneis present in bergamot oil, and has been synthesized from 2,6-dihydroxy-3,4-dimethoxyacetophenone and 3,4dimethoxybenzoyl chloride. A synthesis of the corresponding flavanone has also been de~cribed.~' The absorptions of .several flavones, isoflavones, and chromones in the U.V. region have been used to determine their rates of hydrolysis in aqueous alkali. Fluorescence of the compounds was also A study of the 13C n.m.r. spectra of 61 flavones in dimethyl sulphoxide showed that this technique gave valuable information which enabled the structure of unknown polysubstituted flavones to be determined.97 When flavone was treated with PhHgCBr3 in benzene, at 60 "C,it gave a 40% yield of (46; RR = CBr2) and 10% of (46; R = Br).98The Claisen rearrangement of several 7-prenyloxyflavones (and of the corresponding isoflavones) in

(46)

NN-dimethylaniline was found to give the 8-CHMeCMe=CH2 derivative as well as the expected products (such as the 8-CH2CH=CMe2 c o r n p ~ u n d ) . ~ ~ Analogues of P-adrenergic blocking agents, in which the benzenoid ring is that of flavone, have been synthesized by treatment of a 5-, 6-, 7-, or 4'hydroxyflavone successively with epichlorhydrin and an amine. loo 1soflavones.-Isoflavones in which the 3-aryl ring has been replaced by a heterocycle (e.g.furan, pyridine, or benzimidazole) have been synthesized from the relevant ketone.'" The structure originally assigned to derrugenin (from Derris robusta)lo2has been shown by an unambiguous synthesis to be incorrect; the compound is 5,4'-dihydroxy-7,2',5'-trimethoxyisoflavone.'03 N. J. Reddy, M. Bokadia, T. Sharma, and J. A. Donnelly, J. Org. Chem., 1981, 46, 638. Y-H. Lu, Z. Ji, J-X. Qi, C-P. Du, R-C. Chan, and S. C. Wu, Yao Hsueh Hsueh Pao, 1980,15,477. 94 H. L. Gaggad and K.N. Wadodkar, Indian J. Chem., Sect. B, 1979,17,641. '' M. Stefanolic, L. Krstic, A. Jokic, B. Rihter, and S. Mladenovic, Glas-Srp. Akad. Nauka Umet., Od. Prir.-Mat. Nauka, 1979,46, 7, 13 (Chem. Abstr., 1980,93,95 094, 95 095). 96 G. M. Huitink, Talanta, 1980,27, 977. 97 M. Iinuma, S. Matsuura, and K.Kusuda, Chem. Pharm. Bull., 1980,28,708. 98 J. Iqbal and W. Rahman, Chem. Ind. (London),1980,198. 99 K.V. Subba Raju, K.Sudha, and G . Srimannarayana, Indian J. Chem., Sect. B, 1980,19,866. loo D. Wang, Q.-W. Song, and H.-Z. Kiu, Yao Hsueh Hsueh Pao, 1980,15,253 (Chem. Absrr., 1981, 94,65 430). lo' V. P. Khilya, L. G. Grishko, T. I. Zhirova, N. A. Gorchakova, I. P. Kupcheoskaya, and G . M. Colubushina, Khim.-Farm. Zh., 1980, 14, 24. lo2 Ref. 12, p. 310. 103 M. Tsukayama, T. Horie, Y. Yamashita, M. Masumura, and M. Nakayama, Heterocycles, 1980, 14. 1283. 92

93

304

Heterocyclic Chemistry

The 13Cn.m.r. spectra of 35 isoflavones (and of a few chromones) have been ana1y~ed.l'~Sulphuryl chloride reacts with isoflavone in boiling CCl, to give 2,3-dichloroisoflavanone in moderate yield and with 7-hydroxyisoflavone similarly to produce two products in approximately equal amounts, i.e. 7hydroxy-2,3,6,8 -tetrachloroisoflavanone and 6,8-dichloro-7 -hydroxyisoflavone. Thionyl chloride reacted with 7-hydroxyisoflavone in boiling benzene to give 7-chloroisoflavone.105 Lead tetra-acetate oxidized 2'-hydroxy-7-methoxy-2methylisoflavone to the quinone (47) and the tetracycle (48) in 46% and 25% yields, respectively. Similar results were obtained with other isoflavones.lo6 The 2,3-epoxides of several isoflavones, flavones, and a chromone have been synthesized and some of their reactions studied."'

(47)

(48)

Dihydroisocoumarins.-o-Allylbenzoic acids undergo palladium-assisted cyclization-carbonylation to give dihydroisocoumarinacetic acid esters in high yield. log Condensation of ortho-lithio-N-methylbenzamides with propylene oxide gave 3-methyldihydroisocoumarins, and the method has been used to synthesize (&)-5 -methylmellein ( 3 3-dimethyl4 -hydroxyisocoumarin). '09 The quinone (49) has been synthesized as a means of developing a synthesis of a naturally occurring quinonoid pigment, xylindein. One important step was the photorearrangement of the carboxylic acid (50) into the lactone (51),which was then oxidatively demethylated."' Multi-stage syntheses have appeared of (*)-phyllodulcin (52) from 4-(3 -benzyloxy-4-methoxyphenyl)b~ut-3 -en-2-one1" and from 3-(3benzyloxy-4-methoxyphenyl)-2-propenal."2 trans-Cinnamaldehyde has been in a biomimetic converted into 3,4-dihydro-8-hydroxy-3-phenylisocoumarin eight-stage

H. C. Jha, F. Zilliken, and E. Breitmaier, Can. J. Chem., 1980, 58, 1211. J. R. Merchant and G. Martyres, J. Heterocycl. Chem., 1980, 17, 1331. '06 K. Kurosawa and F. Araki, Bull. Chem. SOC.Jpn., 1979, 52, 529. In' J. A. Donnelly and D. E. Maloney, Tetrahedron, 1979,35, 2875, 2883. Ins L. S. Hegedus, G. F. Allen, and D. J. Olsen, J. A m . Chem. SOC.,1980,102, 3583. B. H. Bhide and K. K. Shah, Indian J. Chem., Sect. B, 1980, 19, 9. "'R. G. F. Giles, M. K. Reuben, and G. H. P. Roos, S. Afr. J. Chem., 1979, 32, 127. N. Takeuchi, K. Ochi, M. Murase, and S. Tobinaga, J. Chem. SOC., Chem. Commun., 1980, 593. ''* N. Takeuchi, M. Murase, K. Ochi,.and S. Tobinaga, Chem. Pharm. Bull., 1980,28, 3013. 'I3 N. Takeuchi and S. Tobinaga, Chem. Pharm. Bull., 1980,28,3007. *05

'"

Six-Membered Rings: Systems containing oxygen or sulphur

305

When 8-hydroxy- or 8-acetoxy-3-aryl-dihydroisocoumarinswere reduced with LiA1H4,they gave the 1,8-dihydroxy-derivativesin addition to the expected is~chromans.~'~ Coumarins.-Methods of synthesizing coumarins are numerous, but continue to multiply. ortho-Hydroxy-aldehydes have recently been converted into coumarins with three reagents: ( a ) NN-dimethylacetamide and P0Cl3, followed by aqueous perchloric acid, gave the pyrylium salt (53), which yielded coumarin on addition of aqueous carbonate;'l5 (b) glycine in acetic anhydride-sodium acetate gave 3-acetamidocoumarin7 the 3-aminocoumarin that was obtained on hydrolysis being shown to exist as the 3-amino tautomer;116 (c) cyclization of 4-hydroxybenzo[b]thiophen-5-carboxaldehydes with cyanomethylene compounds gave variable yields of the thienocoumarin (54;R = CN, CONH2, or CSNH,)."' Several a-methylene lactones [such as (5 5 ) ] have been synthesized from cyclohexane-1 ,3-dione.11' The natural anti-tumour compound geiparvarin (56) has been synthesized and its stereochemistry determined;"' medicinal interest in furocoumarins has resulted in a new synthesis of methoxalen from 1,2,3-trimethoxyben~ene.~~~ Mass spectral fragmentation of a number of coumarins has been studied.1217122

(56)

'15

117

lZ1 12'

M. Yamato, T. Ishikawa, T. Nagamatsu, S. Yoshikawa, and T. Koyama, Chem. Pharm. Bull., 1980,28,723. M. A. Kira and K. Z. Gadalla, Egypt. J. Chem., 1978,21,395. M. A . Khan, M. Lucia, and B. Morley, Bol. SOC.Quim. Peru, 1979,45,42 (Chem. Abstr., 1981, 94,30 483). C.M. Asprou, J. S. A . Brunskill, H. Jeffrey, and A . De, J. Heterocycf. Chem., 1980,17,87. W.C . Groutas, D. Felker, D. Magnin, G . Meitzner, and T. Gaynor, Synth. Commun., 1980,10, 1. P.J. Jerris and A. B. Smith, J. Org. Chem., 1981,46,577. P. Nore and E. Honkanen, J. Heterocycl. Chem., 1980,17,985. L. S. Shibryaeva, A . I. Mikaya, and V. G. Zaikin, Zh. Obshch. Khim., 1980,50,940. G . Saint-Ruf, A. De, J. S. A . Brunskill, and H. Jeffrey, J. Heterocycl. Chem., 1980,17,81.

306

Heterocyclic Chemistry

When osthole (7-methoxy-8-prenylcoumarin)was photolysed, two products in which two coumarin rings were joined through a cyclobutane ring were and revised structures have been established for the mononitration products of sth hole;'^^ 6- and 8-fluorocoumarins (prepared by the Schiemann reaction) gave a mixture of 5 - and 'I-nitro-deri~atives.'~~ Bromination of 5,7dimethylcoumarin with NBS yielded 7-bromomethyl-5-methylcoumarin, which was converted into several other derivatives.126 A photo-induced Fries rearrangement of 3-benzoyloxy-6,7-dimethoxycoumaringave two products; these were shown to be the 4- and 5-acyl derivatives, but the 2-chlorobenzoyl analogue, on treatment with acetic acid and boron trifluoride, gave a 71% yield of the tetracycle (57).1273-Cinnamoyloxycoumarin undergoes a Claisen rearrangement to give 3-hydroxy-4-( 1-phenylprop- 1-enyl)coumarin and the furocoumarin (58). Cinnamoylation products vary with the solvent used.'28

& m \

0

0

0

(59)

(57)

Substituted 4-hydroxycoumarins have been condensed with o-benzoquinone to produce the 3-(3,4-dihydroxyphenyl)-4-hydroxycoumarin,which cyclized to the dihydrocoumestans ( 5 9 ; R = H, Me, or Cl) on treatment with K,[Fe(CN),] and sodium acetate.129In acetic acid solution, 4-hydroxycoumarin reacts with quinones to give 3-substituted coumarins, e.g. (6O);l3O the enamine that is formed from 4-hydroxycoumarin and aniline cyclized to give the pyrano[3,2c]benzopyran-2,5-diones (61; R' = H or electron-releasing group; R2 = aryl, heteroaryl, or CN) on reaction with a nitrile and DMF.131 0

A. Z . Abyshev, Khim. Prir. Soedin., 1980, 165 (Chem. Abstr., 1980, 93, 150 082). S. K. Kaul, K. L. Dhar, and C . K. Atal, Indian J. Chem., Sect. B, 1979,18, 510. l Z 5 F. M. E. Megeid, M. A. F. El-Kaschef, and A. A. G. Ghattas, Egypt. J. Chem., 1977,20,453. 126 P. Gewande and S. Sethna, J. Inst. Chem. (India), 1980, 52, 130. lZ7 V. G. S. Box and Y.A. Jackson, Heterocycles, 1980,14, 1265. l Z 8 V. K. Ahluwalia, M. C . Gupta, and S. Mehta, Indian J. Chem., Sect. B, 1979, 17, 333. lZ9 K. Srihari and V: Sundaramurthy, Proc. Indian Acad. Sci. (Ser). Chem. Sci., 1980,89,405. 13' L. Jurd, Aust. J. Chem., 1980, 33, 1603. 13' A. Knierzinger and 0. S. Wolfbeis, J. Heterocycl. Chem., 1980, 17, 225. 123

124

Six-Membered Rings: Systems containing oxygen or sulphur

307

P-Deprotonation occurred when 4-methoxycoumarin (and other pyrones) was treated with lithium di-isopropylamide and the resulting carbanion was carbox~ 1 a t e d . I3-Acyl-4-hydroxycoumarins ~~ were reduced by sodium cyanoborohydride in acetic acid, in high yield, to the corresponding 3-alkyl compound; dehydroacetic acid was similarly reduced.133Reduction of coumarins with B2H6, followed by oxidation with Cr03, yielded 4 - c h r o m a n o n e ~but , ~ ~catalytic ~ hydrogenation (Ni or Pd/C) at 100 "C and moderate pressures gave dihydrocoumarins and ethyl 4-(2-hydroxyphenyl)butanoatesas the main Grignard reactions on N-aryl-coumarin-3-carboxamidesproceeded by 1,2and 1,4-addition to give 4-substituted N-aryl-coumarin-3-carboxamidesand 2-substituted N-aryl-2-hydroxy-2H-chromen-3-carboxamides(62).136When dihydrocoumarins were treated with reagents of the type BrMg(CH2),MgBr and the resulting diol was treated with mineral acid, spiro[chroman-2-cycloalkanes] (63; R = H or Me, n = 4 or 5) were ~btained.'~'The pyrone ring of coumarin and that of its 3-acetyl- and 3-nitro-derivatives have been converted into the corresponding o-hydroxycinnamic acid amides in good yields, but 3bromocoumarin yielded the amide of benzofuran-2-carboxylic

I

R (63)

1socoumarins.-Pyridine-catalysed acylation of homophthalic acids with alkanoic anhydrides has produced isocoumarins. In this way, a new synthesis of tetrahydrocapillarine (3-butylisocoumarin) has been a~hieved.'~'A revised structure (64) has been proposed for the antibiotic thermorubin on the grounds of X-ray a n a 1 ~ s i s . l5-Nitro~~ and 5 -amino-isocoumarins (and their dihydroderivatives) have been synthesized from 2-methyl-3-nitrobenzoic acid and the dimethyl acetal of DMF.14' OH

OH

0

OMe OMe OH

0

C02H

(64) 132

A. M. B. S. Costa, F. M. Dean, M. A. Jones, D . A. Smith, and R. S. Varrna, J. Chem. Soc.,

Chem. Commun., 1980,1224. C. F. Nutaitis, R. A. Schultz, J. Obaza, and F. X. Smith, J. Org. Chem., 1980,45,4606. 134 B. S.Kirkiacharian, C . R . Hebd. Seances Acad. Sci., Ser. C, 1980,291,73. 13' F.D.Mills, J. Heterocycl. Chem., 1980,17, 1597. 136 A. M. Islam, A. M. S. El-Sharief, A. H. Bedair, E. H. Ibrahirn, F. M. Aly, and F. M. El-Masry, Indian J. Chem., Sect. B, 1979,17,630. 13' P. Canone, D. Belanger, and G . Lernay, Synthesis, 1980,301. J. N. Chatterjea, S. K. Mukherjee, C. Bhakta, H. C. Jha, and F. Zilliken, Chem. Ber., 1980,113, 3927. 139 F. Johnson, B. Chandra, C. R. Iden, P. Naiksatarn, R. Kahen, Y. Okaya, and S-Y. Lin, J. A m . Chem. SOC.,1980,102,5580. 140 M. Somei, Y. Karasawa, T. Skoda, and C. Kaneko, Chem. Pharm. Bull., 1981,29,249. 133

308

Heterocyclic Chemistry

When 3-methyl-5,6,7-trimethoxyisocoumarin was heated with SeO, in dioxan, the corresponding 3-carboxaldehyde was obtained in good yield, and it was oxidized to the 3-carboxylic acid, in moderate yield, by treatment with hydrogen peroxide in acetic acid.141 Xanthenes and Xanthones.-The reactivity of the hydroxyl group of xanthen-901 is well known, and is further illustrated in its reaction with the active methylene group of ethyl acetoacetate and of 5-amino- and 5-methyl-2,4-dihydro-2phenyl-3N-pyrazol-3-0nes.’~~ A study of the 13C n.m.r. spectra of 136 polyhydroxy-xanthones, with the aid of a computer, has led to a method of rapidly identifying any of the Some corrections have been made to earlier assignments of 13Cchemical shifts of a number of oxygenated xanthones. 144 The products of the reaction of 1,3,5-trihydroxyxanthen-9-one with 2methylbut-3-en-2-01 in the presence of boron trifluoride etherate have been investigated and related to the possible biogenesis of 6-deoxyisojacareubin and 6 -deoxyj acareubin. 145

3 Heterocycles containing One Sulphur Atom Thiopyrans.-Irradiation of 3-dimethylamino- 1-phenylprop-2-ene- 1-thione in the presence of various dienophiles has given thiopyrans in 20-95% yield (Scheme l).146 Cyclization of 2-(ally1thio)propanoyl chloride with aluminium chloride gave a mixture of three products in approximately equal amounts.

[20%]

I iii

NMe,

Reagents: i, H,C=CHCN; ii, HCECC0,Me; iii, maleic anhydride

Scheme 1

These were shown to be the three dihydro-2H- thiopyran-3-ones ( 6 5 ) ,(66), and (68), but a single product (67) was obtained in 64% yield when propargylthioacetyl chloride was warmed with aluminium chloride. 14’ The 14’ 14* 143 144

14’

14’

U. C. Mashelkar and R. N. Usgaonkar, Indian J. Chem., Sect. B, 1979, 17, 642. I. Okabayashi, J. Heterocycl. Chem., 1980, 17, 1339. H. Hambloch and A. W. Frahm, Tetrahedron, 1980,36, 3273. A. W. Frahm and R. K. Chaudhuri, Tetrahedron, 1979,35, 2 ~ 3 5 . V. Gujral and S . R. Gupta, Bull. Chem. Sac. Jpn., 1979, 52, 3679. T. Nishio, N. Nakajima, and Y. Omote, J. Heterocycl. Chem., 1980,17,405. K. Ichikawa, S. Inoue, and K. Sato, J. Heterocycl. Chem., 1980, 17, 289.

a1

0

Six-Membered Rings: Systems containing oxygen or sulphur O

M

e

O

R2\

0

(66) R"= Me,R2 = H (67) R' = H, R2 = C1

(65)

M

e

#

0

C1

309

COCH2C02Me (69)

(68)

thiopyran-4-ylpropanoic ester (69) has been synthesized from 2,2-dimethyl-4ethynyl-5,6-dihydr0thiopyran.'~' ap-Unsaturated ketones react with carbon disulphide and secondary amines to give the thiopyran-2-thiones (70; R3 = 5or 6 - a l k ~ l ) . The ' ~ ~ reaction of dithioesters (e.g. EtCS,Me) with dienes (such as butadiene) at 160 "C has given good yields of thiopyrans; e.g., 2,3-dihydro-2ethyl-2-(methylthio)thi0pyran.~~~ Ring-expansion of the 3-(methylthio)dithioIylium iodides (71; R = H, alkyl, or aryl) on treatment with MeC=CNEt, and hydrogen sulphide gave the corresponding thiopyran-2-thiones (72; R = alkyl or aryl), but, when hydrogen sulphide was replaced by sodium bisulphide, the aminothiopyran-2-thione (73) was formed.'51 Thiopyran 1,l-dioxides [such as (76)] have been synthesized in high yield by cyclization of the sulphone (74) uia the anion (75) that is produced by lithium di-i~opropy1amide.l~~ A bicyclic thiopyran-4-one (77) was prepared by treatment of cyclohepta-2,6-dienone with sodium ~ u 1 p h i d e . l ~ ~

..t%"

M e S o s

@ .-, SMe

/

R

NR 'R*

PhCH2S02CH

II

H ,C=CHCMe (74)

E t 2 N ( 3 s

Me

/

R

R

-

g2

Phv\

Phy.$ W

(75)

M

e

(76)

Deprotonation and methylation of 2H-thieno[2,3-b]thiopyransunder various conditions occur at different positions, according to the medium; the role of hexamethylphosphoric triamide has been inve~tigated.'~~ Methylation of cyclic thianium salts, e.g. (78; R2 = H or Me), proceeded stereoselectively at a low temperature while that of the five-membered homologues showed no selectivity.15' The epoxysulphones (79) have been isomerized (by base catalysis) to the alcohols (80).156 Thiopyran-2-thiones react with a-bromo-ketones to produce thiopyrylium bromides; e.g. (8l),which is decomposed by boiling acetic acid or ethanol to give the dithiopyran (82).157 149

lS1

153

154

R. S. Vartanyan, Z . V. Kazaryan, and A. P. Engoyan, Arm. Khim. Zh., 1979,32, 966. K. Schweiger, Monatsh. Chem., 1980, 111, 1175. P. Beslin and P. Metzner, Tetrahedron Lett., 1980, 21, 4657. A. Dibo, M. Stavaux, and N. Lozac'h, Bull. SOC.Chim. Fr., Part 2, 1980, 539. J. J. Burger, T. B. R. A. Chen, E. R. D e Waard, and H. 0.Huisman, Heterocycles, 1980, 14, 1739. T. Sasaki, S. Eguchi, and T. Hioki, Heterocycles, 1979, 1 3 (Special issue), p. 293. R. Graefing and L. Brandsma, Recl. Trav. Chim. Pays-Bas, 1980,99, 23. A. Garbesi, Tetrahedron Lett., 1980,21, 547. J. Polakova, M. Palecek, and M. Prochazka, Collect. Czech. Chem. Commun., 1979, 44, 3705. S. J. Sauve and N. Lozac'h, Bull. SOC.Chim. Fr., Part 2, 1980,427.

Heterocyclic Chemistry

310

(82)

(81)

Isothiochromans, Thiochromenes, and 1sothiochromenes.-A new cyclization of methyl styryl sulphone with lithium ketone enolates has produced very good yields of sulphones such as (83) at low temperatures.15' X-Ray analysis of a 2-thianaphthalene derivative (84) has shown that the hetero-ring has a half-boat conformation, with an apex at S.I5' Thiobenzophenone and dimethyl acetylenedicarboxylate react at room temperature to give a 92% yield of the isothiochromene (85).I6O OH

COPh

Thiocoumarins and 1sothiocoumarins.-A new type of heterocycle (86) was formed when phenethyl alcohol was warmed with benzoyl chloride, carbon disulphide, and aluminium chloride.16' Thiocoumarins have been reduced with lithium aluminium hydride at 18 "C to give a dimeric thiopyrylium salt, which was isolated as its perchlorate [e.g. (87)]. 2-Thioxothiocoumarins for this study were prepared by the action of P,S, on thiocoumarins.162

'" I6O

16' 162

K. Takaki, K. Nakagawa, and K. Negoro, J. Org. Chem., 1980,45,4789. M. Hori, T. Kataoka, H. Shimizu, S. Ohno, K. Narita, H. Takayanagi, H. Ogura, and Y. Iitaka, Tetrahedron Lett., 1979,4315. H. Gotthardt and S. Nieberl, Liebigs Ann. Chern., 1980, 867. M. Czarniecki and R. Q. Klutz, Tetrahedron Lett., 1979,4893. H. Nakagumi and T. Kitao, Bull. Chem. SOC. Jpn., 1980, 53,2415.

Six-Membered Rings: Systems containing oxygen or sulphur

311

Thioxanthenes and Thioxanthones.-Benzophenone reacts with SO, to give a 30% yield of thioxanthone ~u1phone.l~~ A multi-stage synthesis from 2-chloro-5methoxythiophenolhas produced 6-thiatetracycline (88), which has a high order of antibacterial a ~ t i v i t y ;its '~~ conformation has been elucidated with the aid of high-resolution X-ray ana~ysis.'~' OH CONH,

Isomerization of thioxanthene N-tosylsulphimides to the 9-(N-tosylamido)xanthenes has been demonstrated,'66 and it has recently been shown that the related thioxanthenio(bis-methoxycarbony1)methanides (89) similarly rearrange to the 9-[bis(methoxycarbonyl)methyl]thioxanthene (90) in good ~ie1d.l~'

R

CH(CO,Me),

When 9-(3-iodopropyl)thioxanthene (91; R = I) was treated with silver tetrafluoroborate, 9,10-propanothioxanthylium tetrafluoroborate (92) was obtained in high yield; it reacted with nucleophiles to give the thioxanthenes (91; R = n~cleophile).'~~

4 Heterocycles containing One Oxygen and One Sulphur Atom Divinyl ethers (RCH=CH)20, where R is H or Me, react with SC4 to give the 1,4-0xathians (93); these are dehydrochlorinated by base to the oxathiins (94).168 1,2-Oxathiin 2,2-dioxides (95) are formed in 33--83% yields by the cyclization of the enaminones R2COCPh=CHN(Alk)2 and R'COCH=CH-

16'

W. Ried and G. Oremek, Chem. Ztg., 1980,104,12. R. Kirchleckner and W. Rogalski, TefruhedronLett., 1980,21,247. R. Prewo and J. J. Stezowski, Tetrahedron Lett., 1980,21,251. Ref. 12, p. 319. Y.Tamura, C. Mukai, N. Nakajima, M. Ikeda, and M. Kido, J. Chem. SOC.,Perkin Trans. 1, 1981,

la.'

M.Schoufs, J. Meijer, and L. Brandsma, Red. Trav. Chim. Pays-Bas, 1980,99,12.

lb3 164

'61

212.

Heterocyclic Chemistry

312

N(AIk)2, respectively, with ~ u 1 p h e n e . I2,l-Benzoxathiin ~~ 1,l-dioxides (97) have been synthesized from the nitrile (96) and sulphuric acid and shown to possess depressant activity towards the central nervous ~ystem.’~’1,4-0xathiins, e.g. (98), rearrange to the pyrimidine-2-thione, e.g. (99), when treated with aqueous alkali. 17’ 2,4-Dimethylfuran was obtained, in low yield, as the sole product of irradiation of 4,6-dimethyl-l,2-oxathiin 2,2-dioxide in ~entane.~~~

(93)

(98)

(99) [80°/o]

5 Heterocycles containing Two Oxygen Atoms 1,3-Dioxans.-The synthesis of 5,5-disubstituted 1,3-dioxans from ketones, formaldehyde, and a cati~n-exchangerl~~ has been extended to ketones that carry nitro- and c y a n o - g r o u p ~ .In~ ~order ~ to avoid competing reactions, the synthesis of a 5-alkylidene-4,6-dioxo-1,3-dioxan (100; R = alkyl) was effected by a Grignard reaction on a vinylogous carbamafe (100; R = NMe,), followed by treatment with When a substituted phenol is treated with an aliphatic aldehyde and titanium(1v) chloride, a good yield of the 1,3-benzodioxin (101) is formed.’765-Aminomethylene-4,6-dioxo-1,3-dioxans (100; R = NHPh) have been synthesized, in high yield, by heating the 5-unsubstituted dioxan with triethyl orthoformate and an a ~ y 1 a m i n e . l ~ ~ De-ethoxycarbonylation of gem-diesters of 2-isopropyl-1,3-dioxan-5,5dicarboxylic acids (102) by treatment with lithium in DMSO gave predominantly A. Bargagna, F. Evangelisti, and P. Schenone, J. Heterocycl. Chem., 1981, 18, 111. W. Popel, G. Laban, G. Faust, and G. Dietz, Pharmazie, 1980, 35, 266. 17‘ M. Kulka, Can. J. Chem., 1980, 58, 2044. 17’ H. Itokawa, T. Tazaki, and S. Mihashi, Heterocycles, 1981, 15,1105. 173 Ref. 12, p. 321. 174 M. Delmas, A. Denis, J. P. Gorrichon, and H. Gaset, Synrh. Commun., 1980, 10,517. 17’ F. E. Ziegler, T. Guenther, and R. V. Nelson, Synrh. Commun., 1980,10, 661. 176 F. Bigi, G. Casiraghi, G. Casnati, and G. Sartori, Synthesis, 1980, 724. 177 G. Bouillon and K. Schank, Chem. Ber., 1980, 113,2630. 16’

170

313

Six-Membered Rings: Systems containing oxygen or sulphur

oqo Me

Me

w

0

(101)

Et0,C

(100)

C02Et (102)

the cis-monoe~ter.'~~ The replacement of C-2 by silicon in 1,3-dioxans, in high yield, was achieved by their reaction with tin(1v) chloride and dimethoxydimethylsilane (Scheme 2).179 When the diphenyl ether (103) was treated with Me2

+ Me,Si(OMe),

Me Me

o, si, d

--+

M

Me

Me

e Me

Scheme 2

triethylamine, the Meisenheimer complex (104) was obtained in quantitative yield.'80 4,4-Dimethyl-1,3-dioxan has been used as a solvent in the Favorskii reaction, with good results.'81

. ,

0,N 0 .-0\02 NO, (104)

(103)

1,4-Dioxans.-Diglycolic aldehyde reacted with acetoacetanilide to give the Several benzo-l,4-dioxan-2-carboxylic dioxan (105 ; R = CHACCONHP~).'~ acids (106; R = CO,H), which are of pharmacological interest, have been synthesized by oxidation of the corresponding hydroxymethyl compound (106;

8

alye ( 106)

X C lPh l'O"

/

PhSeCH,

C H ,Se Ph (108)

(107) '71

179

"O

lS1

H. D. Banks, J. Org. Chem., 1981,46,1743. V. I. Larionov, R. S. Musavirom, E. A. Kantor, S. S. Zlotskii, D. L. Rakhmankulov, and R. A., Karakhanov, Dokl. Akad. Nauk SSSR, 1980,255,579. V. N. Knyazev, V. N. Drozd, and T. Ya. Mozhaeva, Zh. Org. Khim., 1980,16,2012. A . A. Gevorkyan, P. I. Kazaryan, S. V. Avakyan, and A. S. Melikyan, Arm. Khim. Zh., 1980, 33,176.

3 14

Heterocyclic Chemistry

R = CH20H) (which was prepared from a substituted catechol and 3-chloro-2methyl- 1,2-epoxypropane) by perrnanganate.IB2Phenanthrenequinone and cinnamyl alcohol underwent photocycloaddition in benzene to give a mixture of cis- and trans-forms of the dioxin (1O7).IB3 2,6-Disubstituted 1,4-dioxans, e.g. (log), have been synthesized in good yield by cyclization of diallyl ethers with phenylselenyl ch10ride.l~~ When 2-methoxy-1,4-dioxans were heated with phosphoric acid and pyridine, dioxans such as 2,3-dihydro-5-methyl-l,4-dioxin were obtained in high yield.IBSElectrochemical fluorination of dioxan produced a number of acyclic perfluorinated ethers as well as perfluorinated dioxan.lg6 6 Heterocycles containing Two Sulphur Atoms 1,3-Dithians.-These heterocycles are sometimes of value as synthetic intermediates, and they undergo some interesting selective reactions. Alkylation of the lithium salt of 2-(prop-l-enyl)-1,3-dithian(109; R = Me) occurred solely at the a-carbon atom, but both a- and P-alkylation occurred in the 2-styryl analogue (109; R = Ph).lg7Useful intermediates, e.g. (110; R = Li), have been synthesized by treatment of 1,3-dithians with carbon disulphide and two equivalents of butyl-lithium. Alkylation of the resulting carbodithioate gave high yields of products such as [110; R = Me or (CH2)2].188Alkenylation of 1,3-dithian-2-carboxaldehyde(formed in situ from the 2-lithium derivative and DMF) gave good yields of compounds such as (11l),which were formed in poor

yield by formylation of the cyclohexenyldithian. 18’ 1,3-Dithian anions add on to ap-unsaturated ketones, and the adducts undergo a [1,3] rearrangement on treatment with KH. This has been applied to a two-carbon ring-expansion . ~ ~unexpected ~ ring-cleavage and rearrangement of leading to D L - m ~ s c o n e An hydroxydithians, e.g. (112), has been brought about by lead tetra-acetate, and this procedure enables such compounds as queen’s substance [methyl (E)9oxodec-2-enoate] to be ~ynthesized.”~ A. Salimbeni and E. Manghisi, J. Heterocycl. Chem., 1980,17,489. P. Kertesz and J. Reisch, Arch. Pharm. (Weinheim, Ger.), 1980,313,476. S. Uernura, A . Toshimitsu, T. Aoai, and M. Okano, Tetrahedron Lett., 1980,21, 1533. C.Bacquet, J. Einhorn, and D . Lelandais, J. Heterocycl. Chem., 1980,17,831. V.V.Berenblit, Yu. P. Dolnakov, G. A. Davidov, and S. V. Sokolov, Zh. Prikl. Khim. (Leningrad), 1980,53,858. W. S. Murphy and S. Wattanasin, J. Chem. SOC.,Perkin Trans. 1, 1980,2678. D. M.Baird and R. D. Bereman, J. Org. Chem., 1981,46,458. l E 9 S.R.Wilson and J. Mathew, Synthesis, 1980, 625. 190 S. R. Wilson, R. N. Misra, and G. M. Georgiadis, J. Org. Chem., 1980,45,2460. B. M. Trost, K. Hiroi, and J. N. Jungheim, J. Org. Chem., 1980,45,1839.

lE3

*’’ ’*’ ”’

Six-Membered Rings: Systems containing oxygen or sulphur

315

Proton and 13Cn.m.r. spectroscopy of 1,3-dithians that are substituted at C-2 with trimethylsilyl, stannyl, or plumbyl groups showed that they had a greater preference for an equatorial position in this ring than in c y c l o h e ~ a n eIf. ~used ~~ as a protecting group, 1,3-dithianyl may be removed under mild conditions by indirect electrochemical

1,4-Dithians.-l,l-Dichloroethene reacts with benzene-1,2-dithiols in liquid ammonia to give 1,4-benzodithiins [e.g, (113), in 74% yield].'94 The reactions of tetracyano-l,4-dithiin have been studied; heating at 60 "C in the presence of caesium fluoride resulted in extrusion of sulphur to give tetracyanothiophen. Stirring with potassium ethylxanthate gave bis-(2-mercapto-1,2-dicyanovinyl) sulphide and the anhydride (EtOCS),S. Thiocyanate ion converts the dithiin into the trinitriles (114) and (115).195 o-Benzenedithiol reacted with hexa-

chlorobutadiene in the presence of a tertiary amine to produce several compounds, according to the conditions. The isomeric dichlorides (116) and (117) and the dithiin (118) were thus obtained; the reduction of (116) with zinc and aqueous ethanol removed the halogens.196

192

193 194

19' 196

G. M. Drew and W. Kitching, J. Org. Chem., 1981, 46, 558. M. Platen and E. Steckham, Tetrahedron Lett., 1980, 21, 511. W. Schroth and L. Moegel, Z . Chem., 1981, 21, 30. H. E. Simmons, R. D. Vest, S. A. Vladuchick, and 0. W. Webster, J. Org. Chem., 1980, 45, 5 113. M. Mizuno and M. P. Cava, Heterocycles, 1980, 14, 415.

316

Heterocyclic Chemistry 7 Heterocycles containing an Oxygen or Sulphur Atom in each of Two or Three Rings

Several 4-aminopyrano[3,2-c][l]benzopyran-2-ones (120; R' = C1, R2 = H) that are related to citromycetin have been synthesized from the enaminones (119). Dehydrochlorination of (120; R' = C1, R2 = H) with triethylamine gave the pyranones (120; R1R2 = a bond).197Self-condensation of ethyl acetoacetate in the presence of sodium bicarbonate has given dehydroacetic acid and a new pyranopyran (121) in 40% yield. The latter was formed from dehydroacetic acid.'98 Several pyranoisoflavans which occur naturally have been synthesized from 2,4-di(methoxymethoxy)acetophenone and an aromatic a 1 d e h ~ d e . l ~ ~

Bromination of 7-methoxy-4-methylcoumaringave 3-bromo-4-bromomethy17-methoxycoumarin, which reacted with 1-naphthol to give the ether (122). The latter rearranged to the dipyran (123) on heating with diethylaniline.200Linear pyranocoumarins such as (124) have been synthesized by a more convenient

., 19'

19*

201 '02 203 204

-

-,

(125)

L. Mosti, P. Schenone, and G. Menozzi, J. Heterocycl. Chem., 1980,17, 61. S. K. Talapatra, A. Basak, B. C. Maiti, and B. Talapatra, Indian J. Chem., Sect. B, 1980, 19, 546. F. R. VanHeerden, E. V. Brandt, and D. G. Roux, J. Chem. SOC.,Perkin Trans. 1, 1980,2463. V. G. S, Box and C. G. Holmes, Heterocycles, 1980,14, 1775. V. K. Ahluwalia, K. Bhat, C. Prakash, and S. Bala, Bull. Chem. SOC.Jpn., 1980, 53, 1070. F. M. Hauser and D. W. Coombs, J. Org. Chem., 1980, 45,4071. Ref. 30, p. 372. T. Nomura, T. Fukai, and J. Matsumoto, J. Heterocycl. Chem., 1980,17, 641.

Six-Membered Rings: Systems containing oxygen or sulphur

317

route than hitherto available, from 7-hydroxy-8-iodocoumarin and 3-chloro-3methylbut-l-yne.201A regiospecific total synthesis of the aglycon (125) of the antibiotic chartreusin is also of more general application to analogues.202Photooxidation of morusin has been investigated203and has been followed by oxidative cyclization with permanganate or silver oxide. A mechanism for the photooxidation emerged from this Wessely-Moser rearrangements are usually acid-catalysed, but a high yield has been reported for the base-catalysed rearrangement205 shown in Scheme 3.

'

%ph

OH

Me

KOH,EtOH,

\

'Me

/

OH

0

0

[80%]

Scheme 3

A general synthesis of 6a,l2a-dehydro-rotenoidshas been developed in which ethyl 3-oxochroman-4-carboxylate was condensed with 2-hydroxyacetophenone.206Homopterocarpans (126; R1 = R4 = H or OMe; R2 = H or Ph; R3 = H or OH) have been synthesized by epoxidation of benzylidenec h r o m a n ~ n e s . ~Photocoloration ~' of spirans such as (127) proceeds through the triplet state.208When the tripyran (128) was catalytically reduced, the corresponding dihydropyran-4-ones and dihydropyrans were obtained.*Og2,10,11Trioxatricyclo[4.4.4.01~6]tetradecane(129) has been synthesized, in 88% yield, from (H2C=CHCH2)2CHC02Et.210

@

0

\ o

205

206

207

208

209

210

A. C . Jain, R. C . Gupta, and A. Gupta, Indian J. Chem., Sect. B, 1980,19, 101. R. Verhe, N. D e Kimpe, L. D e Buyck, W. Steurbaut, M. Sadones, R. Willaert, J. P. Verbeek,

and N. Schamp, Bull. SOC.Chim. Belg., 1980,89,459. P. Valenti, P. Montanari, P. L. Barili, and P. Da Re, Arch. Pharm. (Weinheim, Ger.), 1980, 313, 289. Yu. P. Stokach, V. F. Mandzhikov, V. A. Barachevskii, N. D. Dmitrieva, and R. M. Liberzon, Opt. Spektrosk., 1980,49, 1195 (Chem. Abstr., 1981,94,102454). C. Schmiz and F. Eiden, Liebigs Ann. Chem., 1980,2021. N. Beaulieu and P. Deslongchamps, Can. J. Chem., 1980, 58, 875.

318

Heterocyclic Chemistry

The Wittig-Horner and Wittig reactions have been applied to the synthesis of unsymmetrical bipyranylidenes such as (130; X = 0 or S) and (13 1; X = 0 or S), respectively. The former reaction has also been adapted to the synthesis of the tetraphenyls (132), including their mono- and di-benzo-derivatives.21'*212

Interest in hetero-steroids continues to expand,*13 and the synthesis of the thiopyrano[3,2-c][ llbenzothiopyran dioxide (133) ring-system from thiochroman-4-one 1,l-dioxide and mercaptopropionic acid is significant.*14

213 214

G. A. Reynolds and C. H. Chen, J. Org. Chem., 1980, 45, 2458. C. H. Chen and G . A. Reynolds, J. Org. Chem., 1980,452449,2453. For a review, see H. Singh, V. K. Kapoor, and D. Paul, Prog. Med. Chem., 1979,16, 37. A. Fravolini, F. Schiaffella, C. Brunelli, and B. Cecchetti, J. Heterocycl. Chem., 1980, 17, 125.

5 Seven-Membered Ring Systems BY J. T. SHARP

1 Introduction The combined effects of reduced length and more publications (>600) have required greater selectivity this year and, regrettably, the rather brief treatment of much interesting chemistry.

2 Reviews There are general reviews on the use of nitrenes in heterocyclic synthesis,’.* the synthesis of saturated system^,^ and the cyclization and cycloaddition reactions4 of seven-membered rings; more specific reviews on ben~azepines,~ benzindenoazepines,6 benzodiazepines,’ natural and synthetic pyrrolobenzodiazepines;’ and a paper on a new approach to the conformationalanalysis of seven-membered rings.’

3 Azepines, Diazepines, and Triazepines Didehydro-intermediates.-Recent mechanistic interest in the photochemical ring-expansion of aryl azides to azepines has centred on the nature of the intermediates and whether or not the ring-expansion involves direct rearrangement to didehydro-azepines, e.g. (l),or proceeds via strained bicyclic azirines, e.g, (2). Chapman” recently obtained direct i.r. evidence for (l),but not for

(1)

’ H. Suschitzky, Lect. Heterocycl. Chem., 1980,5, S1-S14.

’ 0. Meth-Cohn, Heterocycles, 1980, 14, 1497.

W. J. Ross, Gen. Synth. Methods, 1980, 3, 265. T. Mukai, T. Kumagai, and Y. Yamashita, Heterocycles, 1981, 15, 1569. K.Orito, Mem. Fac. Eng., Hokkaido Univ., 1979,15, 223. K.Orito and M. Itoh, Mem. Fac. Eng., Hokkaido Univ., 1979, 15, 235. ’ ‘Benzodiazepines Today and Tomorrow’ [Proceedings of the 1st International Symposium on Benzodiazepines in Rio de Janeiro, 27-30 September 19791, ed R. G. Priest, U. Vianna Filho, R.Amrein, and M. Skreta, University Park Press, Baltimore, 1980. M. Artico, Boll. Chim. Farm., 1980,119,455,505. F. Sauriol-Lord and T. B. Grindley, J. Am. Chem. SOC.,1981,103,936. lo 0. L. Chapman, R.S. Sheridan, and J.-P. LeRoux, Recl. Trav. Chim.Pays-Bas, 1979,98, 334.

319

320

Heterocyclic Chemistry

(2), in the matrix photolysis of phenyl azide, but now it has been shown'' that the irradiation of azidonaphthalenes, e.g. (3),in a nitrogen matrix leads first to the formation of azirines, e.g. (4), and that these rearrange further to didehydroazepines, e.g. (3,on continued irradiation.

(3)

(4)

(5)

-

Wentrup has demonstrated the presence of similar 1,3-diazepine intermediates in the decomposition of heterocyclic azides, but there is no evidence for the intermediate formation of strained azirines.l* Using an apparatus in which the products of flash vacuum pyrolysis were condensed on a KBr disc at -196 "C, it was shown that the decomposition of (6) at 150-200°C gave the azide (7), and that increasing the pyrolysis temperature led to the formation of (8). Similarly, the pyrolyses of tetrazolo[5,1-a]- and tetrazolo[ 1,5-a]-isoquinolines go vip compounds (9) and (11) through a common intermediate (10).13 In all these f.v.p. decompositions the seven-membered ring is disrupted in the subsequent product-forming steps, but the pyrolysis of tetrazolo[ 1,5-c]quinazoline in solution, which apparently goes via (12) and (13), gave a substantial yield of the dimer (14), in which the triazepine ring is preserved, as well as some 2-phenylbenzimidazole- 1-carbonitrile, which is the sole product of the f .v.p. Direct i.r. evidence for (13)was also obtained in a matrix photolysis experiment.

'' I. R. Dunkin and P. C. P. Thomson, J. Chem. SOC.,Chem. Commun., 1980,499. l3

C. Wentrup and H.-W. Winter, J. A m . Chem. SOC.,1980, 102,6159. C. Wentrup, C. ThBtaz, E. Tagliaferri, H. J. Lindner, B. Kitschke, H.-W. Winter, and H. P. Reisenauer, Angew. Chem., Int. Ed. Engl., 1980,19, 566.

Seven-Membered Ring Systems

321

The intermediacy of the perfluorinated analogue of (1) in the thermolysis of azidopentafluorobenzene has been confirmed by the crystal structure of its carbene-carbene-type dimer.14 Monocyclic Azepines.-Formation. 1H-Azepine (15 ) is a highly reactive species which readily tautomerizes to the 3H-isomer. The improved preparative method that is shown in Scheme 1 has now allowed a more detailed study of its spectroscopic and chemical ~ r 0 p e r t i e s . Its l ~ 'H and 13C n.m.r. spectra confirm the theoretical prediction that the azepine form is strongly thermodynamically C N C O 2 S i M e , -+ C N/C 0 2 H

-

C

N

/

H

0\N I - f (16) [<1%]

(15) Reagents: i, MeOH, at -78 "C; ii, warm to room temperature

Scheme 1

favoured over (16). Compound (17), also an N-unsubstituted 1H-azepine, was prepared as a precursor for syn-l,6-imin0-8,13-methano[l4]annulene.'~ It was stable up to 75 "C, but, surprisingly, it isomerized on alumina to the anti-isomer (18), via prototropy involving the 3H-azepine tautomer (19). This reversal of the usual order of stability of 3H- > 1H-azepine has been attributed to the violation of Bredt's rule in (19). H

H

(19)

(18)

(17)

The reaction between 1,2,4-triazines and cyclopropenes provides a good route to 4H-azepines, e.g. (20).17 Those with two hydrogen atoms on the saturated carbon readily tautomerize to 3H-azepines [e.g. (21)] by a sigmatropic hydrogen shift.

Ph Ph

l4 15

l6 l7

R. E. Banks, N. D. Venayak, andT. A. Hamor, J. Chem. SOC.,Chem. Commun., 1980,900. E. Vogel, H . 4 . Altenbach, J.-M. Drossard, H. Schmickler, and H. Stegelmeier, Angew. Chem., Znt. Ed. EngL, 1980, i9, 1016. E. Vogel, U. Brocker, qnd H. Junglas, Angew. Chem., Int. Ed. Engl., 1980,19, 1015. U. Goeckel, U. Hartmannsgruber, A. Steigel, and J. Sauer, Tetrahedron Lett., 1980, 21, 595.

Heterocyclic Chemistry

322

The position of the valence-tautomeric equilibrium between 4H-azepines and azanorcaradienes is strongly dependent on the substituents; compounds of the latter class, e.g. (22), may be trapped by reaction with cyclopropenes.18

(22) E = C02Me

The pyridone carbanion (23) is much less stable when R=Me than when R = H, owing to steric crowding which reduces the effective co-ordination of lithium by the oxygen atom. Thus while (23; R = H) reacts with electrophiles, (23; R = Me) rearranges rapidly to give (after quenching with water) the azepin-3-one (24).” In a formally similar rearrangement, the aminocyclohexadienone (25) undergoes thermally induced ring-expansion to the azepin-2one (26).*’ Ph

0 0

-[

phQOLi

I P h C - Li

R

Ph Me

- phb= H Ph (24)

(23)

The Beckmann or Schmidt rearrangements of cyclohex-2-enones provide routes to hexahydroazepin-2-ones that have alkyl or aryl substituents at C-4 and C-6 which are not easily obtained by modification of the pre-formed azepinone ring.2’ There is a full report on the synthetic studies on ‘meptazinol’ (27). The key step in the best route is shown, and it is of interest to note that this is only viable when the Hauser base, bromomagnesium di-isopropylamide,

l9

’* ”

U. Goeckel, U. Hartmannsgruber, A. Steigel, and J. Sauer, Terrahedron Lerr., 1980, 21, 599. A. R. Katritzky, J. Arrowsmith, Z. bin Bahari, C. Jayaram, T. Siddiqui, and S. Vassilatos, J. Chem. SOC.,Perkin Trans. 1, 1980, 2851. H. H. Eckhardt, H. Perst, and M. Marsch, TetrahedronLett., 1979,4975. G . I. Hutchison, R. H. Prager, and A. D. Ward, Ausr. J. Chem., 1980,33,2477.

323

Seven-Membered Ring Systems

is used. Use of lithium di-isopropylamide allows a rapid retro-reaction, leading to an unidentified 'thermodynamic' product.22 a,o-Diamines can be converted into heterocyclic amines with the elimination of ammonia by the homogeneous catalyst [RuCl,(Ph,P),]; for example, 1,6diaminohexane gives perhydroazepine (ca 70'/0).~~ New, high-yielding general ~ ~ omethods have also been reported for the cyclization of ~ - a m i n o -and h y d r ~ x y carboxylic -~~ acids to lactones and lactams.

Reactions of Monocyclic Arepines. The course of the reaction between the dihydroazepine (28) and dimethyl acetylenedicarboxylate (DMAD) has been shown to depend strongly on the nature of the solvent. In non-polar solvents (e.g. carbon tetrachloride), the [4+2] adduct is the only product, but the reaction goes via the dipolar species (29) in polar solvents. In aprotic polar solvents (e.g. acetonitrile) this closes to give (31), which rapidly ring-opens to give an azacyclononatriene, but, in protic solvents (e.g. methanol), it gives the Michael adduct (30) via protonation-deprotonation.26

)-$

E

(y

E -

E

-

+

E (28)

E

@ E

E J J /

-

(30)

-

-

E E

\

R

(29)

(E

=

C02Me,R

=

CH2Ph)

The reaction of N-ethoxycarbonylazepine with nitrosobenzene has previously been reported to give (32); it has now been shown that the adduct (34) is also formed.27 Concerted formation of (34) would require an unlikely (7r6s + 7r2a) transition state, and it has been suggested that both adducts may be formed in stepwise reactions via (33). The full papers on the cycloaddition and subsequent

C0,Et (32)

*'

(33)

C0,Et (34)

G. Bradley, J. F. Cavalla, T. Edington, R. G. Shepherd, and A. C. White, Eur. J. Med. Chem., Chim. Ther., 1980,15,375. 23 Bui-The-Khai, C. Concilio, and G. Porzi, J. Org. Chem., 1981,46,1759. 24 K. Steliou, A. Szczygielska-Nowosielska, A. Favre, M. A. Poupart, and S. Hanessian, J. A m . Chem. SOC.,1980,102,7578. 25 H. Ogura and K. Takeda, Heterocycles, 1981,15,467. " W.Eberbach and J. C. CarrC, Tetrahedron Lett., 1980,21,1145. 27 W. S.Murphy and K. P. Raman, Tetrahedron Lett., 1980,21,319.

Heterocyclic Chemistry

324

rearrangement reactions of N-ethoxycarbonylazepine with phencyclone2* and other cycl~pentadienones~~ have now appeared. As with many related sevenmembered heterocycles, the diene unit in (35) readily photoisomerizes to a cyclobutene, but in this case, only in non-polar solvents. In methanol, the system shows reactivity typical of a py-unsaturated ketone, and it undergoes a 1,3-acyl migration to give (36) and (37).30 Me

(35)

Me

(37)

The rearrangement of N-ethoxycarbonylazepine to N-ethoxycarbonylaniline takes place quantitatively at room temperature in the presence of boron trifluoride ether ate.31

Fused Azepines.-Formation. The full paper on the synthesis of the 1 4 ~ indeno[l,2-d]azepine system has now been published,32 and the same workers have used a bromination-dehydrobromination sequence to synthesize the new cyclopent[d]azepine system (38).33This compound was blue, and its n.m.r. and U.V.spectra resembled tliose of azulene. Another new azulene analogue, the green crystalline cyclopenta[h][2.2.4]cyclazine (40), has been synthesized by the addition of (39) to cyclopentadiene. It too resembles azulene in its visible and near-u.v. spectrum, and also in its high reactivity to electrophilic attack in the carbocyclic ring at positions 6 and 8.34

1-Bentazepines. A useful synthesis of the 1H-1-benzazepine system is provided by the ring-expansion of the cyclobut[b]indoles (41).35A number of N-acylated derivatives (41; R=acyl) have been prepared uia the photocycloaddition of methyl acrylate to 1-benzoylindole, followed by hydrolysis and oxidative decarboxylation with lead tetra-acetate; these decomposed at 250-280 "C to 2'

29 3"

31 32

33 34

35

M. Yasuda, K. Harano, and K. Kanematsu, J. Org. Chem., 1980.45, 2368. K. Harano, M. Yasuda, T. Ban, and K. Kanematsu, J. Org. Chem., 1980,45,4455. H.-D. Becker and A. B. Turner, Tetrahedron Lett., 1979,4871. W. S. Murphy and K. P. Raman, J. Chem. SOC.,Perkin Trans. 1, 1981,441. M. Kimura, K. Satake, S. Yonemori, and S. Morosawa, Bull. Chem. SOC.Jpn., 1980, 53, 3232. M. Kimura and S. Tai, J. Chem. SOC.,Chem. Commun., 1980,974. M. A. Jessep and D. Leaver, J. Chem. Soc., Perkin Trans. 1, 1980, 1324. M. Ikeda, K. Ohno, T. Uno, and Y. Tamura, Tetrahedron Lett., 1980, 21, 3403; Heterocycles, 1980,14, 123 (Chem. Abstr., 1980, 93, 114 241).

Seven-Membered Ring Systems

325

give (42) as a major product. Interestingly, catalysis by silver fluoroborate much reduced the rearrangement temperature, and promoted the reverse reaction, so that equilibria between (41) and (42) were set up in refluxing xylene. More heavily substituted N-methyl analogues (43) have been prepared directly by the

4

\

R (41)

N

Me (43)

R

(42) - -

photocycloaddition of dimethyl acetylenedicarboxylate (DMAD) to N-methylated indoles; it was shown that these undergo both thermal and photochemical rearrangements to b e n ~ a z e p i n e sbut , ~ ~that the rearrangement may be prevented by a methylene bridge across the fusion positions; e.g., [43; R1R2= (CH2),,].A similar intermediate (45) has been postulated in the formation of (46) by the reaction of (44) with DMAD at 0 "C. The surprising absence of products resulting

Bu' NMe2

NMe, (45)

(44)

Bu' (E = C0,Me)

Me,N

from electrophilic attack of DMAD at the nitrogen atom in the ring has been rationalized by calculations which show that the course of the reaction is dominated by frontier-orbital interactions rather than by charge contr01.~' o -Lithiomethylphenyl isocyanide (47), which has previously been used in indole synthesis, may also be used for the preparation of 1-benzazepin-2-ones [e.g. (48)] via 1,4-addition to @unsaturated carboxylic esters and subsequent hydrolysis and c y c l i z a t i ~ n . ~ ~

aNc CH,Li

(47)

36

37

+

MeCH=CHCO,Me

+

qM N H (48)

P. D . Davis and D. C. Neckers, J. Org. Chem., 1980,45,456,462. K.Hafner, H.-G. Klas, and M. C. Bohm, Tetrahedron Left.,1980,21,41. Y.1to;K. Kobayashi, M. hlaeno, and T. Saegusa, Chem. Lett., 1980,487.

\ O

326

Heterocyclic Chemistry

and 2-benzazepines4' have been pre2-Benzazepines. 2-Benza~epinones~~ pared by the decomposition of isoquinoline derivatives in which dichlorocarbene has been added across the 3,4-double-bond; e.g., (50) from (49).

Cl-

NMe 0

0 (50)

0

(49)

The 2-benzazepin-5-ones (52) have been prepared from (51).41 0

NHOH

f l J ) H+

Ar

(5 1)

(52)

3-Benzazepines. Oxindoles, isoquinolines, and benzazepinones [e.g. (53); see Scheme 21 have been prepared, in good yields, by intramolecular amidoalkylation, using aromatic amides of bis(methoxycarbonyl)aminoacetic

0

CH,CH,NHCOCH(NHCO,Me),

+ 1

q

O

H

\

Me0,CNH Reagents: i, methanesulphonic acid

(53) Scheme 2

The 5H -oxazolo[2,3-a]isoquinoline (54) underwent an unexpected conversion into (56) on treatment with cyanogen bromide in methanol, probably via (55). Treatment of (56) with acid gave the 3-(2-hydroxyethyl) d e r i ~ a t i v e . ~ ~

The benz[d]indeno[ 1,2-b]azepine system ( 5 8 ) has been synthesized by treatment of (57) with phosphoryl The oxidative cleavage of the doublebond in such systems provides a synthetic approach to the ten-membered ring of the protopine alkaloid 39 40 41 42

43 44

45

H. P. Soetens and U. K. Pandit, Red. Trav. Chim. Pays-Bas, 1980,99, 271. C. D. Perchonock, I. Lantos, J. A. Finkelstein, and K. G. Holden, J. Om.Chem., 1980, 45, 1950. E. J. Trybulski, Eur. Pat. Appl. 14 454 (Chem. Abstr., 1981, 94, 30 587).

a. Ben-Ishai, N. Peled, and I. Sataty, Tetrahedron Lett., 1980, 21, 569.

J. B. Bremner and K. N. Winzenberg, Heterocycles, 1980, 14, 1085. K. Orito, H. Kaga, M. Ito, S. Osmand d t Silva, R. H. Manske, and R. Rodrigo, J. Heterocyc/. Chem., 1980,17,417. K. Orito, Y. Kurokawa, and M. Itoh, Tetrahedron,1980, 36, 617.

Seven-Membered Ring Systems

327

Hetero-fused azepines. The Dieckmann reaction has now been applied to the synthesis of pyrrolo[2,3-b]azepin-4-ones[e.g. (60) from (59)46].

Me (59)

(60)

(E = COZEt)

The photo-reactions of seven isomeric N-(chloroacetyl)indolylethylamines, e.g. (61), have been studied; they undergo cyclization at ortho- and/or peripositions to give, in some cases, useful yields of azepino-in dole^.^' The azepinoindole system (62) has been prepared by the cyclization and ring-expansion of

the nitrenes derived from 4-(2-azidobenzyl)-methoxycarbonylbenzenes;this is the first such reaction of an electron-deficient benzene ring.48In a continuation of their study of the decomposition of polycyclic azides, workers at Salford have shown that the photolysis of 6-azidobenzothiazolesgives thiazolo[5,4-~]azepines, e.g. (65), in moderate yield, most probably via (63) and (64).49The thermal isomerization of 2-vinyl-N-heteroaromatic-aziridines provides a route to a 46

M. M. Vora, C. S. Yi, and C. D e Witt Blanton, Heterocycles, 1981,16, 399;J. Heterocycl. Chem.,

47

S. Naruto and 0. Yonemitsu, Chem. Pharm. Bull., 1980,28,900.

1981,18,507. 48 49

G.Jones and P. C. Hayes, J. Chem. SOC.,Chem.'Commun., 1980,844. P.T.Gallagher, B. Iddon, and H. Suschitzky, J. Chem. SOC.,Perkin Trans. 1, 1980,2362.

328

Heterocyclic Chemistry

PJN%

N

-

/

N / (66)

variety of fused azepines, e.g. (66); isothiazolo- and thieno-azepines were similarly prepared." The condensation of cis- and of trans-2-aminocyclohexane- 1-carboxylic acids with lactim ethers provides a good route to the azepinoquinazolinones (67).5'

ace'" NH2

+

J-2

Me0 1

(CHd,

- d,n (67)

Reactions of Fused Atepines. A one-pot three-step reaction of an acylmethylenetriphenylphosphorane with electron-deficient dienes gives what is formally a Diels-Alder adduct of the diene to a simple alkene; for example, (68) gives (69) in ca 50% yield.52 0

HC - PPh,

Ph .3 PO

4

COMe (68)

Me (69)

The azepino[4,5-b]indole carboxylate (70) reacts with aldehydes to give the bridged azepines (71).Quaternization of (71) and treatment with base generates the intermediate (72), which cyclizes to give the A, B, C , E ring-system of the vincadiff ormine-type alkaloids.53

51

52

53

(71) (70) (E = C02Me) H. P. Figeys and R. Jammar, Tetrahedron Lett., 1980, 21, 2995. G . Bernath, G. Toth, F. Fulop, G. Gondos, and L. Gera, Magy. Kem. Foly., 1980,86, 232 (Chem. Absrr., 1981, 94, 15 667). W. Flitsch and E. R. Gesing, Tetrahedron Lett., 1979, 4529. M. E. Kuehne, T. H. Matsko, J. C. Bohnert, L. Motyka, and D. Oliver-Smith, J. Org. Chem., 1981,46,2002.

3 29

Seven-Membered Ring Systems

1,2-Diazepines.-Formation. Further work on the reactions of orthoalkenylphenyl-substitutedchloroglyoxylate phenylhydrazones, e.g. (73), with bases (see last year’s Report) has produced interesting results. It is clear that the reaction with triethylamine at 80 “C generates the nitrilimine (74), which can either be trapped with added alkenes or which, in their absence, gives the 1,2-benzodiazepine (75). However, new work has shown that different results are obtained at room temperature; thus triethylamine then gives the chlorocompound (76), while silver carbonate gives only the cyclopropa[c]cinnoline (77).54The latter was readily converted into (75) by thermolysis at 80°C. It is not yet clear whether the primary step in these reactions is 177-cyclizationto give (78), which either collapses to (77) at a low temperature or undergoes hydrogen migration to give (75) at a higher temperature, or whether it is a concerted 1,l-cycloaddition of the ‘carbene’ form of (74) to give (77) directly. Reactions with and (2)-propenyl analogues of (73) have shown that the cylization to cyclopropacinnolines is stereospecific for short periods but that the initially formed isomers then epimerize slowly, probably via an intermediate like (78). It has also been shown that similar reactions, carried out in the presence of anionic nucleophiles (X = OH-, W3-, CN-, or OAc-), give the 5-substituted diazepines (79).55

(a-

P 1

I

c1

(77)

(E = COZEt) 54

A. Padwa and S. Nahm, J. Org. Chern., 1979,44,4746; 1981,46,1402

’’ L.Garanti and G. Zecchi, J. Chem. Soc., Perkin Trans. 1, 1980, 116.

(79)

330

Heterocyclic Chemistry

The cyclization reactions of (ortho-alkenylaryl)diazoalkanes,e . g (81), are formally similar to those of (74). It was shown previously that these provide a high-yielding route to 2,3-benzodiazepines, e.g. (82), but further work has now shown that this path is completely inhibited when R' is Me or Ph.56Thus the (E)-propenyl compound (81; R'=H, R2 = Me) gives (82) in high yield, but (81; R' = Me, R2 = H) gives only products that are derived from the carbene (80). This shows an interesting difference from the (2)-propenyl analogue of (74), which cyclizes at room temperature to give a cyclopropa[c]cinnoline that readily isomerizes to a 1,2-benzodiazepine on heating [cf. (77) + (75)]. This could be taken as further evidence for different primary steps in the reactions of these two formally similar dipolar species.

The diazoalkene ring-closure (81) + (82) has been extended to the synthesis of the thienodiazepines (83) and (84). It is interesting that the 3-alkenyl-4diazomethylthiophen (85) did not undergo a similar reaction, presumably due to the inhibition of 1,7-electrocyclization by the lack of double-bond character across the 3,4-position of the thiophen ring.57 Diazo-compounds with 76-aryl

N

(83)

(84)

(85)

unsaturation aiso undergo 1,7-cyclization to give, in this case, 1,2benzodiazepines. A study of substituent effects on this reaction has shown that, for (86), the cyclization is under kinetic control at 80°C and is preferentially directed to the ortho-position when R is alkyl, alkoxy, or chloro; e.g., when R is Me, [(87)]/[(88)] = 4.3. However, when R is an alkoxy-group, the orthoproduct (87) rearranges to the more stable (88) at higher temperatures, most probably via a retro-cyclization

N

(87)

(88)

(86) 56

" 58

D. P. Munro and J. T. Sharp, Tetrahedron Lett., 1980,21,4109. D. P. Munro and J. T. Sharp, J. Chem. SOC., Perkin Trans. 1, 1980, 1718. T.K.Miller, J. T. Sharp, H. R. Sood, and E. Stefaniuk, Tetrahedron Lett., 1980, 21, 1379.

33 1

Seven-Membered Ring Systems

The photochemical ring-expansion of pyridinium N-imides and their polycyclic analogues is a major route to the 172-diazepinesystem. Streith has now extended its range to provide a route to 1,2-diazepin-3-ones (91) from (89).59As expected from earlier work, the methoxy-group induced high regioselectivity in the primary ring-closure, giving only the 3-methoxydiazepine (90). Steric constraints can, however, induce ring-closure to occur at the more hindered a-carbon.60

(90)

(89)

(91)

It has recently been shown that, in some cases, these ring-expansions can involve a further rearrangement step to give 1,3-diazepines7 and the full paper on the conversion of 1-substituted isoquinoline N-acyl-imines into 1H-1,3benzodiazepines has now appeared.6' In an extension of this work it is also reported that pyridine N-imides that are condensed with five-membered heteroaromatic rings on the b side similarly give thieno-, furo-, and pyrrolo-fused 1,3-diazepines, e.g. (94).62The ratio of (93) to (94) is sensitive to the nature of R; thus (92; R = C0,Et) gave ca 10% of (93) and 60% of (94) while (92; R = H) gave only (93), in 60% yield.

A number of 172-diazepines(95) with a cis-azo-linkage have been synthesized but, interestingly, the by the oxidation of cyclic hydrazines by mercuric oxidation of (96) with iodine in ether gave the trans-thiadiazepine (97). Irradiation of (97) in benzene at room temperature produced a precipitate of the cis-isomer (98), but irradiation of the latter gave only isobutene, sulphur dioxide, and

02

n n

(95)

f9fA \ / -1

(97)

T. Kiguchi, J.-L. Schuppiser, J.-C. Schwaller, and J. Streith, JyOrg. Chem., 1980, 45, 5095. Y. Yamashita and M. Masumura, Chem. Lett., 1980, 621. 6 1 T. Tsuchiya, M. Enkaku, and S. Okajima, Chem. Pharm. Bull., 1980,28,2602. T. Tsuchiya, M. Enkaku, and S. Okajima, J. Chem. SOC.,Chem. Commun., 1980, 454 (See also Chem. Abstr., 1980,93,46 621 and 1981,94, 139 856). C. G. Overberger and T. F. Merkel, J. Org. Chem., 1981,46,442. '' H. Lind, G. Rihs, and G. Rist, TetrahedronLett., 1980, 21, 339. 59

332

Heterocyclic Chemistry

In a full account of work on the reaction of pyrylium salts with hydrazines, Snieckus has further delineated the scope and limitations of the reaction as a route to 1,2-diazepines. In contrast to the 2-aryl-pyrylium salts, which give mostly diazepines on reaction with hydrazine, those with 2-methyl substituents give N-aminopyridinium salts, and reactions with methylhydrazine generally lead mainly to ring-contracted Attempts to prepare the little-known 3H-2,3-benzodiazepine system (100) by the cyclization of anions of 2(alkyny1)benzaldehyde hydrazone, e.g. (99), gave only isoquinoline N-imides (101). These may be produced by rearrangement of (100) or directly by nucleophilic attack by the neutral nitrogen atom in (99).66 The thieno-analogue of (100) has, however, recently been prepared, but there is no information on its propensity for ring-c~ntraction.~'The reported synthesis of 5,6-diazaazulenes by the cycloaddition of thiazole 1,1-dioxides to 6-dimethylaminofulvene68has been shown to be

Reactions of 1,2-Diazepines. The products of the thermal decomposition of the lH-1,2-diazepines (102) depend strongly on the nature and position of the substituents. If there is an electron-donating group in the 4-or in the 6-position (R' or R2=Me, MeO, NHAc, or NEt,), these diazepines rearrange at 90-140 "C to the 1,3-diazepines (105) in the 30-70°/~ yields. However, analogous compounds with halogens or acyl groups in the 4-or the 6-position give only their parent pyridine N-imides and aminopyridines. It has been suggested that donation of electrons by R2 favours N-N cleavage in (103) and the formation of (104) while withdrawal of electrons favours C-N ~leavage.~'

(E

=

CO2Et)

3H-1,2-Diazepines, e.g. (106), undergo a virtually quantitative photoisomerization to diazeto[1,4-a]pyrroles (107), which is a completely different reaction path to that taken in their thermal decomp~sition.~' 65

66

67 68

69 70

71

D. J. Harris, G. Y.-P. Kan, T. Tschamber, and V. Snieckus, Can. J. Chem., 1980, 58, 494. P. N. Anderson and J. T. Sharp, J. Chem. SOC.,Perkin Trans. 1, 1980, 1331. T. Tsuchiya, M. Enkaku, and H. Sawanishi, Heterocycles, 1979,12, 1471. M. Mori and K. Kanematsu, J. Chem. SOC.,Chem. Commun., 1980,873. A. J. Boulton and A. K. A. Chong, J. Chem. SOC.,Chem. Commun., 1981,736. T. Tsuchiya, J. Kurita, and H. Kojima, J. Chem. SOC., Chem. Commun., 1980,444. C. D. Anderson and J. T. Sharp, J. Chem. SOC.,Perkin Trans. 1, 1980, 1230.

Seven-Membered Ring Systems Me

MecN '& 333

Me

QN

(heat

Me

5

Me (107)

N (106)

N' H

Me

Me

eN

Treatment of (108) with base, followed by acetic anhydride, produces (110) and (11l), as shown in Scheme 3; (111)is formed via electrocyclic ring-closure at the termini of the delocalized 6 ~ e l e c t r o n system of i c ' A c V H NCOR -+

NAc

:'?

---.-N

-N

(109)

(108)

+

-N

N' H H Ac (111)

(110)

Reagents: i, Bu'OK, benzene; ii, Ac,O

Scheme 3

The thermal decomposition of pyrazolino[5,4-dJ[1,2]diazepines is rather complex, and leads to compounds of the type (log), pyridines, 2-aminopyridines, pyridinium N-imides, and other The full paper on the oxidation of lH-1,2-benzodiazepines with lead tetrahas now appeared.74 acetate to give 5-acetoxy-SH-1,2-benzodiazepines 1,3-Diazepines.-The hydroxy-1,3-diazepinone (112) has been prepared in high yield by the route shown in Scheme 4; a similar technique was used to synthesize

~2

0

YJoH

4 : L sH e p h

H

H

0

Reagents: i, N-(phenylseleny1)phthalimide;ii, m-chloroperoxybenzoic acid

(112)

Scheme 4

the 1-p-D-ribofuranosyl nucleosides (113), which are of interest as inhibitors of the transition state of cytidine d e a m i n a ~ e . ~In~ connection .~~ with related work, it has been shown that the natural product squamalone, previously reported to be the 1,3-diazepine-2,4-dione (114), is in fact (115); both materials have been svnthesi~ed.~~

oy-JoH N

0

0 HO OH (113)

0

I

H

CONH,

(114)

(115)

P. Gesche, F. Klinger, H. Strub, and J. Streith, Tetrahedron Lett., 1980, 21, 1223. 73 P. Gesche, F. Klinger, J. Streith, and H. Strub, Tetrahedron Lett., 1980, 21,4507. " T. Tsuchiya and J. Kurita, Chem. Pharm. Bull., 1980, 28, 1842. 7s P. S. Liu, V. E. Marquez, J. A. Kelley, and J. S.Driscoll, J. Org. Chern., 1980, 45, 5225. 76 P. S. Liu, V. E. Marquez, J. A. Kelley, J. S. Driscoll, and J. J. McCormack, 1. Med. Chem., 1980, 23,713. 77 V. E. Marquez, J. A. Kelley, and J. A. Driscoll, J. O g . Chem., 1980, 45, 5308. 72

334

Heterocyclic Chemistry

Routes to the following systems have been described: pyrazolo[ 1,5-a]imid[1,3]dia~epines,'~ imidazo[2,1-6]-[1,3]- and -[2,4]-benzodiazepin-2-ones, azo[l,2-a][l,3]benzodiazepin-2-ones,79 indeno[l,2-d]-5H- 1,3-diazepines,*" 81 and isoindolo[ 1,2-~][2,4]benzodiazepines. 1,4=Diazepines.-Formation. The diamine (116) reacts with ketones and with chloroform in the presence of a phase-transfer catalyst to give the 1,4-diazepin-2ones (117), possibly via attack of the amine on the intermediate (118).82

The reaction of the dianion of benzil dibenzylimine with carbon disulphide gives (119; X = S) and that with ethyl chloroformate gives (119; X = O).83 1,4-Diazepinyl nitroxides have been prepared by Beckmann-type ringexpansions of piperidone n i t r ~ x i d e s . ~ ~ * * ~

In an extension of the study on the use of keten thioacetals in heterocyclic synthesis it has now been shown that a -0xoketen dithioacetals (120) react with o-phenylenediamines to give 1,5benzodiazepines in good yields.86 13Benzodiazepines are also produced by reactions of o-phenylenediamine with (12l y 7 and with (buty1thio)cyclopropeniumSalk8*

T. Kurihara, T. Tani, and K. Nasu, Heterocycles, 1980, 15, 265. F. Ishikawa and Y . Watanabe, Chem. Pharm. Bull., 1980,28, 1307. so P. V. Padmanabhan, K. J. J. Rao, D. V. Ramana, and S. R. Ramadas, Heterocycles, 1981, 16, 1. J. D. Coyle, P. L. Addison, J. L. Farmer, E. J. Haws, and P. W. Small, Synthesis, 1980,403. 82 P. Son and J. T. Lai, J. Org. Chem., 1981,46, 323. 83 K. N. Mehrotra and G. Singh, Synthesis, 1980, 1001. 84 Y.-C. Liu, C.-C. Chiang, and H.-K. Lei, Chem. Abstr., 1981, 94, 30 515 and 175 074. 85 E. G . Rozantsev, A. V. Chudinov, and V. D. Siholle, Izv. Akad. Nauk SSSR,Ser. Khim., 1980, 79

86

87

2114 (Chem. Abstr., 1981,94, 30 720). A. Ushirogochi, Y. Tominaga, Y. Matsuda, and G. Kobayashi, Heterocycles, 1980, 14, 7. T. Kato, N. Katagiri, and R. Sato, J. Org. Chem., 1980, 45, 2587. S. Yoneda, H. Hirai, Y. Katsuro, and Z. Yoshida, Fukusokan Kagaku Toronkai Koen Yoshishu lZth, 1979, 206 (Chem. Abstr., 1980,93, 95 252).

335

Seven-Membered Ring Systems

Detailed studies have been reported on the conversion of 2-(2ha1ogenoacetamido)benzophenones into 2-0~0~1,4-benzodiazepines by reaction with ammoniag9 and with hexamine and in the latter case, a new mechanism has been propo~ed.'~Dinitroso-1,3,5,7-tetra-azabicyclo[3.3.1]nonane has been found to be an excellent reagent for this r e a ~ t i o n . ~The ' reductive cyclization of (122) provides a new route to the dibenzo[b,e][1,4]diazepin-11-one system (123).92

(122) (123) A synthetic route to 7,9-di-O-methyl-ll-oxosibiromycinone (124) has been developed; this compound is potentially a key intermediate in the synthesis of the anti-tumour antibiotic ~ i b i r o m y c i nThe . ~ ~ activity of the latter is dependent on its N-10, C-11 carbinolamine function, but attempts to introduce this in model compounds by reduction of the carbonyl group that includes C-11 have

Me

0 H (124)

so far resulted in preferential reduction at C-5. A high level of interest continues to be shown in the synthesis and pharmacological properties of 1,4-diazepines that are fused to other heterocyclic rings, and new routes to the following systems have been described: aminomethyl-substituted imidazo[ 1,2-a][1,4]ben~odiazepines,~~ s-triazolo[4,3-a][ 1,4]benzodiazepine~,~~ 7H-pyrrolo[1,2-d][ 1,4]benzodiazepin-6-0nes,~~pyrrolo[ 1,2-a][ 1,4]benzodia~epines,~'-~~ thieno-[3,4-b]-[1,4]and -[1,5]-benzodiazepine~,~~ pyrrolo[1,2-a]thieno[3,2-fl[1,4]diazepines,'OO pyrrolo[l,2,3-ef][l,5]benzodiazepin-6(7H)-one~,~~~

*'

G. M. Clarke, J. B. Lee, F. J. Swinbourne, and B. Williamson, J. Chem. Res. ( S ) , 1980,398, 399, and 400. ' O T. KovaE, B. Belin, T. Fajdiga, and V. Sunjik, J. Heterocycl. Chem., 1981, 18, 59. M. Japelj, V. Tiiler, B. Novak, and D. BabiE, Vestn. Slov. Kem. Drus., 1979, 26, 215. 92 C. W. Bird and M. Latif, Tetrahedron, 1980, 36, 1813. 93 F. A. Carey and R. M. Giuliano, J. Org. Chem., 1981,46, 1366. 94 M. Gall and B. V. Kamdar, J. Org Chem., 1981,46, 1575. 95 J. B.,Hester, Jr., J. Heterocycf. Chem., 1980, 17, 575. 96 G. Dattolo, G. Cirrincione, and E. Aiello, J. Heterocycf. Chern., 1980,17, 701. '' S. Vomero, R. Guiliano, M. Artico, and G. Stefancick, Farrnaco, Ed. Sci., 1980, 35, 110. '' H. Stetter and P. Lappe, Liebigs Ann. Chem., 1980,703. " J. B. Press, C. M. Hofmann, and S. R. Safir, J. Heterocycf. Chem., 1980,17, 1361. loo S. Rault, M. Cugnon de SCvricourt, H. El Khashef, and M. Robba, C.R. Hebd. Seances Acad. Sci., Ser. C., 1980, 290, 169. lo' A. V. Bogatskii, R. Yu. Ivanov, S. A. Andronati, Z. I. Zhilina, Y. I. Vikhlyaev, T. A. Klygul, and E. I. Ivanov, USSR P. 726 098 (Chern. Abstr., 1981,94,4049).

''

336

Heterocyclic Chemistry

imidazo[4,5 -el[ 1,4]dia~epine-5,8(6H)-diones,~~~benzimidazo[2,1 -el[ 1,4]benz~diazepines,"~ 7-oxo-7H-[l]benzopyrano[2,3-~][l,5]benzodiazepine~,~~~ 4H-pyrido[3,4-b][ 1,5]benzodiazepin-4-0nes,''~ quinoxalino[2,1 -el[ 1,4]benzodiazepines,'06 and pyrimido[ 1,2-a][ 1,4]ben~odiazepines.~'~

Reactions of 1,4-Diazepines. The reactivity of 2,3-dihydro-1,4-diazepinium cations to electrochemical reduction depends strongly on the nature and position of substituents. The reduction of the 5,7-diphenyl derivative (125a) proceeds in two steps, giving first the radical (126), which disproportionates to give the dihydrodiazepine base and a tetrahydrodiazepine, and at the second wave the anion (127). However, the 6-phenyl analogues (125b) are reduced less readily, and the initially formed radicals, which are less hindered, dimerize and undergo subsequent rearrangement and fragmentation to give the pyrrolodiazepines

b; R' = Me or H, R2 = Ph The,diazepine ring in (129) is opened by attack of hydroxylamines to give (130).lo9 H NH2OH,

f-Jy;2'Hc'

O \

H (129)

N

T NH,

0'6

NH; C

N

CH=NOH

\

NH,

0-N

(130)

Acylation of (131) at low temperatures gives (132), but the rearrangement product (133) is obtained at 100 'C.ll'

g T o H ~7 R'

CI \

Io2

lo3

lo'

lo6 lo'

lo9 'lo

RZCoc:

cl\

.N

Ph

Ph

(131)

(132)

R' NOCOR' c

l

~

~

(133)

A. V. Bogatskii and E. I. Ivanov, Ukr. Khim. Zh. (Russ.Ed.), 1980, 46, 1074 (Chem. Abstr., 1981, 94,47 288). A. V. Bogatskii, E. I. Ivanov, G . L. Kamalov, and T. V. Babilina, Ukr. Khim. Zh. (Russ.Ed.), 1980, 46, 1076 (Chem. Abstr., 1981, 94,47 289). C. K. Ghosh and S. Khan, Synthesis, 1980,701; C . K. Ghosh and N . Tewari, J. Org. Chem., 1980, 45, 1964. Y . Tamura, L. C. Chen, M. Fujita, and Y. Kita, J. Heterocycl. Chem., 1980,17, 1. S. Massa, F. Corelli, G. Stefancick, and G . de Martino, J. Heterocycl. Chem., 1980, 17, 1781. H. Natsugari, K. Meguro, and Y. Kuwada, Chem. Pharm. Bull., 1979,27,2927. D. Lloyd, C . A. Vincent, and D. J. Walton, J. Chem. SOC.,Perkin Trans. 2, 1980, 668; D. Lloyd, C. Nyns, C. A. Vincent, and D. J. Walton, ibid., p. 1441. Y.Okamoto, K. Takagi, andT. Ueda, Chem. Pharm. Bull., 1980,28,567. H.-G. Schecker and G . Zinner, Arch. Pharm. (Weinheim, Ger.), 1980,313, 926.

~

Seven-Membered Ring Systems

337

Kinetic studies have confirmed that 3-hydroxy-substituted 1,4-benzodiazepin2-ones lose the configurational identity of the chiral centre at C-3 by both direct nucleophilic substitution and by ring-chain tautomerization. Triazepines.-The photolyses of various diazine N-ethoxycarbonylimides have been studied; these proceed probably via photochemically unstable triazepines, to give pyrazoles or pyrroles; e.g., (134) gives (135).l12 The condensation of p- dicarbonyl compounds with thiosemicarbazides can give triazepinones, triazepines, 1,2,4-triazolines, or pyrazoles, depending on the reagents and the experimental conditions.' l 3

(134)

(E = CO2Et)

4 Oxepins and Dioxepins

0xepins.-Formation. The position of the equilibrium between the benzene oxide (136) and the oxepin (137) is strongly affected by the size of the annelated ring; when n =3, (136) predominates, while the opposite is true if n = 2.1i4

(136)

(137)

(E = C02Me)

Further work on the thermal transformations of ap,yS- unsaturated oxirans has shown that the y,S-bond participates only when the @-bond has Z stereochemistry, so that (138), for example, gives both (140) and (141) uia (respectively) 8 ~ and - 6~-electrocyclizationof the carbonyl ylide (139)."'

C0,Me (138) V. Sunjii., M. Ohlc)hdLija,

(139)

C02Me (140)

A. Lisini, A. Scga, F. Kajfez, D. Srzic, and L. Klasinc, Tetrahedron, 1979,35,2531. T. Tsuchija, J. Kurita, and K. Takayama, Chem. Pharm. Bull., 1980,28,2676. ' 1 3 A. Hasnaoui, J.-P. Lavergne, and P. Viallefont, Reel. Trav. Chim. Pays-Bas, @80,99, 301. 'I4 B. Epe, P. Rosner, and W. Tochtermann, Liebigs Ann. Chem., 1980, 1889. "'W. Eberbach, G. Konig, and U. Trostmann, Tetrahedron Lett., 1979,4649. 111

338

Heterocyclic Chemistry

The propargyl anion (143), generated by the deprotonation of (142), cyclizes to give mainly (144) (52%)and a little (145) (4'/0).''~ a C H =NCH, CHMe, 0 OCH, C (142)

CPh (143)

ah J

NHCHMe,

(144)

(145)

Alkenyl-substituted p -dicarbonyl compounds can be cyclized, using N-phenylselenophthalimide; for example, (146) gives (147) in ca 50% yield.'"

(146)

(147)

The reactions of diazo-compounds with coumarins and chromones provide interesting chemistry and, in some cases, routes to 1-benzoxepins. Thus the cyclopropabenzopyran (148; R' = H), formed by the reaction of diazomethane with 3-nitrochromone, is readily converted into the benzoxepin (149) by water or alcohols. However, in (148; R' = Me) the small ring opens in a different sense to give, for example, (150)."*

The further reactions of the pyrazolines (151), produced by the addition of diazo-alkanes to cournarins with electron-withdrawing 3-substituents (X), are strongly dependent on both the nature of X and on the bulk of the diazo-alkane. Moderate bulk in the diazo-alkane is required to force the pyrazoline ring into 0. Tsuge, K. Ueno, and K. Oe, Chem. Let?., 1981, 135. W. P. Jackson, S. V. Ley, and J. A. Morton, J. Chem. SOC.,Chem. Commun., 1980, 1028. F. M. Dean and R. S. Johnson, J. Chem. SOC.,Perkin Trans. 1, 1980, 2049; see also Y. Masuda, M. Hoshi, and A. Arase, Chem. Lett., 1980,413.

Seven-Membered Ring Systems

339

the correct conformation for ring-expansion to a benzoxepin, e.g. ( 152).1'9

Benzoxepins are similarly produced by the rearrangement of some diazocompound-2-acyl-chromone adducts (153), but only via sigmatropic migration of the carbonyl group.12' Me

0-m \

c=o

COMe

\

\

Q 0 (153)

0

Oxepinium cations have previously been postulated as intermediates in the trifluoroacetic-acid-catalysedconversion of peroxy-esters (154) into derivatives of 4-oxacyclopent-2-enone, but now it has been shown that the reactions of (154) with trifluoroacetic anhydride give (156) via (155).'**

R h % ' CF3 H

trifluoroaceticanhydride

'

0

(R = But)

The photorearrangement product (158) of the cyclo-octyne adduct (157) ring-opens thermally to give the bridged oxepin (159).'22

n

-b

(E = CO2Et) 'I9 12'

"*

F. M. Dean and B. K. Park, J. Chem. SOC.,Perkin Trans. 1, 1980,2937. F. M. Dean and R.S . Johnson, J. Chem. SOC.,Perkin Trans. 1 , 1981,224. A. Nishinaga, K. Nakamura, and T. Matsuura, Tefrahedron Lett., 1980, 21, 1269. W. Tochtermann and P. Rosner, Tetrahedron Lett., 1980, 21,4905.

340

Heterocyclic Chemistry

Reactions of Oxepins. Oxepin reacts with the cyclopentadienone (160) at room the end042 + 41r-adducts temperature to give both the eno-[6 + 4 1 ~ and (161) and (162). The former is quite stable, but the latter is readily transformed into (163) in boiling benzene by successive Cope rearrangements. This contrasts with the analogous compound in which COzMe is replaced by Me (prepared earlier), which decomposes thermally only via cyclorever~ion.'~~ However, with (164), only the anti-endo[4 + 2]n-adduct (165) was obtained as a primary product, in ca 5 : 1 equilibrium with (166), at room t e m p e r a t ~ r e . ' ~ ~ 0

H

E

0

CHO

Ph

Ph ph& E'

:*hp

Ph

0

Ph

(162) (E = C02Me)

H

/N

P h,?

+ph

N-N

CHO

/N

0 Ph

Ph

(166)

(165)

(164)

Oxepin reacts via its benzene oxide valence tautomer in [4 + 2]n cycloadditions with some dienophiles, but with p-chloronitrosobenzene it gave only the nitrone (167), formed via r i n g - ~ l e a v a g e . ~ ~ ~ 0-

OHC(CH=CH)lCH

I

=?-

C6H4Cl-p

(167)

An efficient method has been described which effects a 1,2-transposition of a carbonyl group to convert seven-membered-ring lactones into p -ketoethers.126

Dioxepins.-l,3-Dioxepan-4-ylium ions, prepared by the protonation of 4,5 dihydro- 173-dioxepins(168), undergo thermal fragmentation and re-cyclization to give tetrahydrofuran-3-aldehydes on a preparative scale.'27 The use of boron

(168) 124 125

12'

T. Ban, Y. Wakita, and K. Kanematsu, J. Am. Chem. Soc., 1980, 102, 5415. T. Ban and K. Kanematsu, Heterocycles, 1981, 15, 373. G . Kresze and W. Dittel, Liebigs Ann. Chem., 1980, 1630. V. V. Kane, D. L. Doyle, and P. C. Ostrowski, Tetrahedron Lett., 1980, 21, 2643. H.-D. Scharf and H. Frauenrath, Chem. Ber., 1980,113, 1472.

34 1

Seven-Membered Ring Systems

trifluoride etherate as a catalyst is said to bring the advantages of better yield, a simpler procedure, and higher stereoselectivity.'*' 5 Thiepins and Dithiepins

The photocyclo-adducts of 3-acetoxybenzo[b]thiophen 1,l-dioxide with cycloalkenes, e.g. (169), readily undergo a retro-aldol cleavage to provide a useful route to benzo[b]thiepinone~.'~~

Earlier suggestions that the 1,3-dithiepinylanion has some degree of aromatic; stability are supported by some 'H shift data from the n.m.r. spectrum of (170). Comparison with 2H-1,3-dithiepin and its anion-suggests that the dipolar form is stabilized by delocalization of the negative charge.13'

6 Systems containing Two Different Heteroatoms 0xazepines.-The reactions of the benzopyranone (171)with some 1,3-dipoles have been investigated. It reacted with diphenylnitrilimine by 1,3-~ycloaddition in typical enamine manner, but, with benzonitrile oxide, a new reaction path gave the new benzoxazepinone system (172). A similar reaction was given by the nitrone N-benzylideneaniline N - 0 ~ i d e . A l ~systematic ~ study of the application of the Meisenheimer rearrangement in heterocyclic synthesis has produced 0

p

o

N

R

2 0

0 (171)

0

CONR2

0 (172) '21

H. Suzuki, H. Yashima, T. Hirose, M. Takahashi, Y. Moro-Oka, and T. Ikawa, Tetrahedron Lett.,

131

1980,21,4927. N.V. Kirby and S. T. Reid, J. Chem. SOC.,Chem. Commun., 1980,150. Y. Sugihara, Y.Fujiyama, and I. Murata, Chem. Lett., 1980,1427. G. V. Boyd and R. L. Monteil, J. Chem. SOC.,Perkin Trans. 1, 1980,846.

342

Heterocyclic Chemistry

effective routes to 2,3-benzo~azepines,'~~ e.g. (173), [1,2]oxazepino[6,5-b]indoles, thieno[2,3-e][1,2]oxazepine, and [l)benzothieno[3,2-e][1,2]oxazepines.133 M MeoQN/oe0 \

--*

M e 0e \o q y 0 M e

\

~1

R~ Me

R' RZ (173)

Further work on the synthesis of seven-membered rings by 1,5-cycloadditions has led to the preparation of 1,4-oxazepinesand 1,4-diazepinesby the reactions of, respectively, 1,3-0xazolidinesand irnidazolidines with enamines in the presence of acid.' 34 Various 1,5-benzo-diazepines, -oxazepines, and -dioxepines have been synthesized by the reaction of ortho-difunctional benzenes with fluorinated a1kenes.13' The primary step in the photochemical ring-contraction of 3,l -benzoxazepines (174) to indoles is the formation of the labile 3H-indole intermediate (175). The subsequent fate of this intermediate depends on the nature of R1;when R1 is H, a clean conversion into (176) is obtained by a hydrogen shift, but various substituted indoles are formed if R1is C1, C02H, or C02Me, via several reaction paths which include migration of halogen or an acyl group, decarboxylation, and de~arbony1ation.l~~

Thiazepines.-A nova1 base-induced ring-expansion of quaternized oxazolium, thiazolium, and selenazolium salts offers routes to a variety of heterocyclic systems, e.g. of (178) from (177).13' N-Tosylsulphimines, e.g. (179), are conCHO

(CH2)3C1

1

I

CHO

A/

1

(178) 133 134

135 136

13'

J. B. Bremner, E. J. Browne, P. E. Davies, and Le van Thuc, Aust. J. Chem., 1980,33,833. J. B. Bremner, E. J. Browne, and P. E. Davies, Aust. J. Chem., 1980,33, 1335. H.Griengl, G. Prischl, and A. Bleikolm, Lidigs Ann. Chem., 1980,1573. M.Maruta, S. Kubota, N. Yoshimura, T. Kitazume, and N. Ishikawa, J. Fluorine Chem., 1980, 16,75. C.Kaneko, H.Fujui, S. Kawai, A. Yamamoto, K. Hashiba, T. Kimata, R. Hayashi, and M. Somei, Chem. Pharm. Bull., 1980,28,1157. H.-J. Federsel and J. Bergman, Tetrahedron Lett., 1980, 21,2429.

Seven Membered Ring Systems

343

verted into 1,2-benzothiazepines in high yield when treated with triethylamine in benzene under reflux. In the absence of the base, the intermediate (180) can be isolated.138It was recently shown that a 6-diazopenicillanateester reacts with alcohols in the presence of BF3-Et,0 catalyst to give the 6a-alkoxy-derivatives,

e.g. (181). Now it appears that the course of the reaction is much affected by the nature of the catalyst; thus copper and rhodium catalysts give thiazepines, e.g. (183), as the major product. Both products may be formed via the oxonium ylide intermediate (182).139 R'O,

jx> -

0

,'R

IH

CO2R'

(181)

+

?0% CO2R' (182)

..i;. H

C0,R'

(183)

7 Other Systems Annelated 1,3,4,6-thiatriazepines (185) have been prepared for the first time by the route shown; acyclic thioureas lead to an alternative path in which (184) eliminates a carbodi-imide to give 1,3,4-thiadia~olines.~~"

''13

139

loo

Y.Tamura, S. M. Bayomi, C. Mukai, M. Ikeda, M. Murase, and M. Kise, Tetrahedron Lett., 1980, 21,533;J. Chem. Soc., Perkin Trans. 1, 1980,2830. S . A. Matlin and L. Chan, J. Chem. SOC.,Chem. Commun., 1980, 798; see also J. C. Sheehan, K. Nakajirna, and E. Chacko, Heterocycles, 1979, 13,227. S.F. Moss and D. R. Taylor, J. Chem. SOC.,Chem. Commun., 1980, 156.

344

Heterocyclic Chemistry

8-Aryl- 1,2,4-triazol0[3,4-b]- 1,3,44hiadiazepines can be conveniently prepared by the reaction of the aminomercaptotriazole (186) with alkynyl aldehydes.14' N-N N-N RCNJSH

+

ArCfCCHO

-

I

The reaction of syn- ( E )- (benzy1amino)propiophenoneoxime with formaldehyde gave 6-benzyl-3-phenyl-4,5,6,7-tetrahydro-1,2,6-oxadiazepine ( 187).14* The reaction of a primary amine with a 1,2-diol and paraformaldehyde is a new general route to 1,5,3-perhydrodio~azepines.'~~

nAr HCHO+

PhCH,NH

HO

'*' 143

N

/

PhCH,N

L0' (187)

N. D. Heindel and J. R. Reid, J. Heterocycf. Chem., 1980, 17, 1087. M. Gnichtel, K. Hirte, and R. Wagner, Chem. Ber., 1980,113,3373. H. Kapnang and G. Charles, TefruhedronLeft., 1980, 21, 2949.

Eight-Membered and Larger Ring Systems BY G. M. BROOKE

1 Eight-Membered Rings One Heteroatom.-l,2,3,4-Tetrahydroazocine derivatives (1) are obtained by the reaction of the enamine (2) with methyl propynoate in MeCN.' However, the cyclic thioenol ether 1-oxide (3) and dimethyl acetylenedicarboxylate, in the formation of which was rationalized boiling toluene, unexpectedly gave (4),2 by invoking an initial [2,3]cyclo-adduct ( 5 ) , followed by an intramolecular Michael addition to give the tricyclic sulphonium ylide S-oxide (6), which then rearranged. The photochemically induced cycloaddition of 2-methylpropene to (7) gave (8), the four-membered ring of which opened on treatment with NaHC03 in MeOH to form the benzazocine derivative (9).3

0

QMe

QJR2

/ C02Me

&co2Me 0

N H

(7)

O

2 C 0M, M ee

II 0

S

(2)

(3)

0 (4)

COzMe

$Me 0

(5)

a

O

R'

R'

(1)

0

(6)

R&

N H (8)

O

II

-', .

OMe

i>

67 H o

R

(9)

R. M. Acheson and G. Paglietti, Studi Sassar., Sez. 2, 1979,57, 451 (Chem. Abstr., 1980,93,

220 565). K. Gollnick and S . Fries, Angew. Chern., int. Ed. Engl., 1980,19,833. T.Naito and C. Kaneko. Chem. Pharm. Bull., 1980,28,3150(Chem. Abstr., 1981,94,139591).

345

346

Heterocyclic Chemistry

The 'H n.m.r. spectrum of the anion derived from 10H-dibenz[b,g]oxocin (10) with KNH3 in liquid ammonia shows all the characteristics of a simple allylic species (11) rather than a fully delocalized (4n+2).rr aromatic oxo~ a r b a n i o nMolecular .~ models of (11)show that the heterocyclic ring is heavily buckled, a concept which is supported by some coupling-constant data for (C-lO)-H and (C-11)-H.

(10)

(11)

Trost has developed a very useful synthesis of lactones from esters via C-C bond f ~ r m a t i o n The . ~ principle involved is shown in Scheme 1. Interestingly, for (12; R = H, x = 2, y = 0), the eight-membered ring is formed in preference to the six-membered lactone, even though the ease of formation of the smaller ring is usually favoured by a factor of -lo4.

4

Reagents: i, NaH, THF, [Pd(PPh,),]

Scheme 1

Eight-Membered Rings containing Two Heteroatoms.-Novel C-C bond formations occur during the oxidative cyclodimerization of substituted (electrondonating)NN-dimethylanilinecompounds to 1,4-diazocine derivatives (13) with Pd(OAc)2.6The NN'-disubstituted 'cis-benzenetri-imine' compound (14; R2 = H), on treatment with NOBF, at < -30 "C, and loss of N 2 0 , gave (15), which, S u 2 s + u2s] cycloreversion to at -30 to -lO"C, rapidly underwent a [ T ~ + the 1,4-disubstituted 1,4-dihydro-l,4-diazocines( 16),7 the structures of which were presented in last year's Report (p. 360).

A. G. Anastassiou and H. S. Kasmai, Angew. Chem., Int. E d . Engl., 1980, 19, 393. B. M. Trost and T. R. Verhoeven, J. A m . Chem. SOC.,1980,102,4743. T. Sakakibara and H. Matsuyama, Chem. Lett., 1980, 1331 (Chem. Abstr., 1 9 8 1 , 9 4 , 4 7 287).

' M. Breuninger, R. Schwesinger, B. Gallenkamp, K. H. Mueller, H. Fritz, D. Hunkler, and H. Prinzbach, Chem. Ber., 1980, 113, 3161.

Eight-Membered and Larger Ring Systems

347

(17) Br-

The quaternized heterocycles (17;X= 0, S, or Se), on treatment with aqueous sodium hydroxide, undergo novel ring-expansion reactions to produce (18) via an initial attack by HQ- on the imino carbon of the heterocycle.8 On the other hand, the benzothiazocine compound (19; Ar = 2-thienyl) undergoes ) ~ .enamine ~ tautomer of (19) a ring-contraction to form (20) with P ~ ( O A C An and the species (21) were invoked as intermediates along the reaction path. The propelfane derivative (22) was obtained from the reaction of thiocatechol with the vicinal pairs of CH2Br groups in 1,1,2,2-tetrakis(bromomethyl)cyclopropane," even though the seven-membered heterocycle was formed by its reaction with 1,l-bis(bromomethy1)cyclopropane.

Eight-Membered Rings containing Six Heteroatoms.-Two compounds that incorporate nitrogen and sulphur in the ring and which superficially should have the same structure (23; R = Ph) or (23; R = Me2N) have been prepared from benzamidine and NN-dimethylguanidine, respectively, with SC12 and diazabicycloundecene." An X-ray crystal study on these products, however, showed that they were entirely different. The diphenyl compound had a planar heterocyclic ring, which suggested a delocalized aromatic l0v-electron system (24), whereas the guanidine derivative indicated partial bonding between the two sulphur atoms, which also formed the axis about which the whole molecule was folded (25).

2 Nine- and Ten-Membered Heterocycles The product that is formed in the reaction of dihydroazepine (26) and dimethyl acetylenedicarboxylate is strongly dependent on the nature of the solvent. In H. J. Federsel and J. Bergman, Tetrahedron Left., 1980,21,2429.

J. B.Press, N. H. Eudy, F. M. Lovell, and N. A. Perkinson, Tetruhedron Lett., 1980,21, 1705. lo

J. Jarnrozik, J. Prukt. Chem., 1980,322,909 (Chem. Abstr., 1981,94,156 898). I. Ernest, W. Holick, G . Rihs, D. Schomburg, G. Shoham, D. Wenkert, and R. B. Woodward, J. Am. Chem. Sac., 1981,103,1540.

348

Heterocyclic Chemistry

(23)

(25)

(24)

acetronitrile, the reactants undergo an overall [2 + 2lcycloaddition process via a dipolar intermediate prior to ring expansion, to give the azacyclononatriene (27).l 2 A closely related reaction involves the NaOMe-catalysed reaction of the P-keto-ester (28) with dimethyl acetylenedicarboxylate to form (29).13 The photosolvolytic ring-opening of compounds of type (30;X = CH2 or CH20; R = H , o r Me) in methanol has been used to prepare (31).14 Azacycloalkanes CH2Ph

mE E

(26)

HO

E

C' \

E R

E

(281

(27)

Me0

N

'R (29) (E = C02Me)

(30)

(32)

(31)

(33)

having eight-, nine-, ten-, and eleven-membered rings have been obtained by intramolecular Hofmann elimination reactions (Me1 and HO-) on appropriate spiropyrrolidine compounds [e.g. (32) -+ (33)I.l' The temperature at which isomerization of NN'N"-trisubstituted 'cisbenzenetri-imine' compounds (14; R' = R2) to the 4,7-dihydro-lH- 1,4,7triazonine derivatives (34) occurs depends on the substituents R' (200 "C for R' = CH,S02; 90 "C for R' = Me).16 Kinetic data suggest a trishomobenzenoid transition state (35) for the 3 u -+ 37r transformation. l2 l3

l4

*'

l6

W. Eberbach and J. C. Carre, Tetrahedron Lett., 1980,21. 1145. A.J. Frew, G. R. Proctor, and J. V. Silverton, J. Chem. Soc., Perkin Trans. 1, 1980,1251. J. B. Bremner and K. N. Winzenberg, Chem. Ind. (London), 1980,421. D.Berney and K. Schuh, Helv. Chim. Acta, 1980.63,1785. R.Schwesinger, M. Breuninger, B. Gallenkarnp, K. H. Mueller, D. Hunkler, and H. Prinzbach, Chem. Ber., 1980,113,3127.

349

Eight-Membered and Larger Ring Systems

R' (34)

(37)

(36)

(35)

The rupture of the C-C bridge in (36) by NaH in benzene at high dilution gives the lactone (37)." The Eschenmoser sulphide-contraction, applied to the synthesis of macrocyclic lactones and shown in principle in Scheme 2, has been used to synthesize the ten-membered lactone (*)-diplodialide A."

Reagents: i, B- (B = base); ii, R*,P; iii, H 3 0 +

Scheme 2

The quinodimethane intermediate (38) that is obtained from (39) by a fluorideion-induced 1,6-elimination reaction with Bun4" F- in boiling MeCN dimerizes to form (40; X = 0 or S).I9Some cyclic trimer is also formed with X = S.

(40)

Both cis- and the fascinating trans-doubly-bridged ethenes ('betweenanenes') that contain nine-membered-ring sulphur heterocycles have been prepared via stereospecific [2,3] sigmatropic rearrangements, the 'cis' spirocyclic sulphonium ylide (41) giving the cis-alkene (42) and the 'trans' ylide (43)giving the 'thiabetweenane' (44).*'

(41) "

'' 19

(42)

J. R. Mahajan and I. S. Resck, Synthesis, 1980,998;see also P.W. Scott, I. T. Harrison, and S. Bittner, J. Org. Chem., 1981,46,1914. R. E. Ireland and F. R. Brown, Jr., J. Org. Chem., 1980,45,1868. Y.Ito, S. Miyata, M. Nakatsuka, and T. Saegusa, J. Org. Chem., 1981,46,1043. V. Cere, C. Paolucci, S. Pollicino, E. Sandri, and A. Fava, J. Org. Chem., 1981,46,486.

Heterocyclic Chemistry

350

2

QPR

H2C

+S

(CH2)io (43)

(44)

3 Macrocycles Systems containing Nitrogen as the only Heteroatom.-One Nitrogen Atom. A new type of isomerism, termed translational isomerism, has been observed in a compound made up of three rings (a [3]catenane) in which the central ring contains two bulky groups:21 the isomer ( 4 3 , in which the lateral rings are separated by the bulky aromatic ring; and (46) and (47), in which the lateral rings are arranged next to each other. The isomers were prepared from (48) by the following sequence of reactions: (i) acid cleavage of the ketals; (ii) dehydrogenation of the resulting 1,2-quinols to 4-(disubstituted amino)-1,2-benzoquinone, using Fe,(SO,), and HzSO4, and the subsequent hydrolysis of the quinone C-N bond; and (iii) reduction of the quinones to quinols and the acetylation of all 0 - H and N-H bonds, using Zn and AczO and NaOH. Compound (45) was Ac

LC

A.C

Ac

AcO

I Ac

(45)

(46) R' = OAc,R2 = H (47) R1 = H,R2 = OAc

G. Schill, K. R i d e r , H. Fritz, and W. Vetter, Angew. Chem., Int. Ed. Engl., 1981, 20, 187.

Eight-Membered and Larger Ring Systems

35 1

separated by chromatography from the mixture of (46)and (47)(themselves inseparable), and the identities of the isomers were deduced from 'H and 13C n.m.r. spectra. The isomers are only interconvertible by translation of the 26-membered nitrogen-containing rings across the high steric barrier, a process which did not occur below the decomposition temperature (200 "C). The intramolecular cyclization of H2N(CH2),C02H( n = 10 or 11) is promoted by Bun2Sn0(see p. 355).22

Macrocycles containing Four Nitrogen Atoms. N-Benzylaziridine undergoes tetramerization in various solvents (MeOH, CH2C12, and MeCN; containing Bun4N'C104-) at a platinum anode to form [N(CH2Ph)(CH2)2]4by a radicalcation chain p r o ~ e s s . ~Di-imine ' tetra-aza-macrocycles with a wide range of ring sizes have been prepared from (49) and am-diamino-compounds without recourse to a metal-ion template catalyst or to high-dilution condition^.^^ An important structural prerequisite in the product, responsible in part for the success of the syntheses, is the stabilization of the two imine bonds by intramolecular hydrogen-bonding (50), which effectively reduces lone-pair interactions in the centres of the rings.

I

Mn

(50)

The paracyclophane compound [51; R = (CH2)4],which is soluble in mineral acids at pH < 2, forms a 1:l complex with the non-polar molecule durene, indicating the importance of hydrophobic interactions in the binding process.25 The same host niolecule has been shown by 'H n.m.r studies to form an inclusion complex with 2,7-dihydroxynaphthalenein DC1 in D20, at pD 1.2, which has a particular geometry.*6 A more strongly bonded complex (80-fold increase in the dissociation constant) is formed between 1-anilinonaphthalene-8-sulphonate and [51; R = 1,4-CH2-cyclohexylidene-CH2-] than with [51; R = (CH,),] as the 22

23 24

25

26

27

K. Steliou, A . Szczygielska-Nowosielska, A . Favre, M. A . Poupart, and S. Hanessian, J. A m . Chem. SOC.,1980,102,7578. R. Kossai, J. Simonet, and G . Dauphin, Tetrahedron Lett., 1980,21,3575. P. G. Owston, R. Peters, E. Ramsammy, P. A . Tasker, and J. Trotter, J. Chem. Soc., Chem. Commun., 1980,1218. K. Odashima, A . Itai, Y. Iitaka, and K. Koga, J. Am. Chem. Soc., 1980,102,2504. K. Odashima, A . Itai, Y. Iitaka, Y. Arata, and K. Koga, Tetrahedron Lett., 1980,21,4347. T.Soga, K. Odashima, and K. Koga, Tetrahedron Lett., 1980,21,4351.

Heterocyclic Chemistry

352

The aliphatic bridge in [52;M = Fe02CMe] is oxidized by air in DMF, at 80°C, to (53), and a similar process occurs if M is CU.~’Complex formation between the parent ligand (52; -M= -H H-), and Mg(C104)2is unsuccessful, though the incorporation of magnesium to form (52;M = Mg) did take place with PhMgBr or EtMgBr.” These magnesium complexes underwent transmetallation reactions [e.g.with VO(acac)J to give complexes [e.g. (52; M = VO)] which were not accessible by the more direct route. The nickel complex (54; R = H) undergoes electrophilic substitution at both methine C-H bonds in these [14]aza-annulene derivatives to give (54; R = Hal, CHzC02Et, or

R (54)

CH,CN), using N-halogeno-succinimide, BrCH2C02Et,and BrCH2CN, respect i ~ e l y . ~Co-ordination ’ of a metal ion protects the potentially nucleophilic N-centres from attack, since the metal-free ligand is decomposed by BrCH2C02Et.

Macrocycles containing Six or More Nitrogen Atoms. 6,6‘-Dichloro-2,2’-bipyridyl undergoes template cyclization with (NH&ZnC14, the demetallation of which gives a mixture of tautomers (55), which is preferred in non-polar solvents, and (56),which is preferrred in polar Interest in polyammonium compounds stems from the property of natural polyamines (spermidine and spermine) to bind nucleotides strongly and to participate in the synthesis of nucleic acids and of proteins, and in cell growth. The polycations ( 5 7 ; n = 1 or 3) form strong and selective complexes with both inorganic and organic polyanions in aqueous The selective complexa29

30

31 32

S. Gozen, R. Peters, P. G. Owston, and P. A. Tasker, J. Chern. Soc., Chern. Cornrnun., 1980,1199. A. J. Greenwood, K. Henrick, P. G . Owston, and P. A. Tasker, J. Chern. SOC.,Chern. Cornmun.,

1980,88. D.A.Place, G . P. Ferrara, J. J. Harland, and J. C. Dabrowiak, J. Hererocycl. Chern., 1980,17,439. S . Ogawa and S. Shiraishi, J. Chem. SOC.,Perkin Trans. 1, 1980,2521. B. Dietrich, M. W. Hosseini, J. M. Lehn, and R. B. Sessions, J. Am. Chern. SOC.,1981,103,1282.

353

Eight-Membered and Larger Ring Systems

(55)

(57) X = N H 2

(56)

tion of biologically important anions (AMP, ADP, ATP, citrate, and other carboxylates) is of particular interest; complexes of complex ions, e.g. [Fe(CN)4]4-,are also formed. The transport of the anions S- (e.g. nitrophenolates, picrate, nitrobenzoates, phosphates, and sulphonates) from one aqueous solution (Aq. 1) to another (Aq. 2) through a CH2C12'membrane' can be performed with the lipophilic ion-pair complex [L --+ Cu2+ X-]X-,where L is (58) and X is HO-, C1-, C104-, or SCN-; the principle of this is shown in Scheme 3.33Compound (59) has been

A x-'

E

[L+ Cu'+.x-]+xS-

compared with dibenzo-18-crown-6 in its ability to form complexes with biologiAnilinium-type cally important adenine, amino-acid, and simple amine salts, ArNH3', are extracted highly selectively in comparison with monoalkylammonium salts (the crown ether extracts both); compound (59), but not the crown ether, extracted the amidinium cation that is derived from adenine; the phenylalanine derivative PhCH2CH(C02Et)NH3' was hardly extracted by (59) compared with the crown ether, but the replacement of the para-hydrogen by OH, i.e. 4-H0-C6H4CH2CH(CO2Et)NH3+,resulted in the tyrosine derivative being readily extracted.

(58) (59)

X

=

S

x=0

Systems containing Heteroatoms other than Nitrogen.-The Pdo-catalysed C-C bond formation that was mentioned earlier has been used to prepare

CYO

33 34

K. Maruyama, H. Tsukube, and T. Araki, J. Chem. SOC.,Chem. Cornrnun., 1980,966. K. Maruyama, H. Tsukube, andT. Araki, J. Chem. SOC.,Chrm. Cornmun.. 1980,1222.

354

Heterocyclic Chemistry

ten-, twelve-, fourteen-, and sixteen-membered lac tone^.^ The olefin-metathesis reaction has been exploited to convert the esters (60) into (61), using WC16 and Me4Sn3’ or else wOc1, (or WC16) and Cp2TiMe236as catalysts which tolerate the -CO-0group. Fragmentation of the a-alkoxy-hydroperoxide derivative (62) [from (63) + H 2 0 2in AcOH] with FeSO, in MeOH that is saturated with Cu(OAc), gave the cyclic (2)-unsaturated ester (=I=)-recifeiolide(64) (96’/0).~’ A recent synthesis of 14-tetradecanolide entails the cyclization of the o-hydroxyynamine HO(CH2)12CrCNPhMe with BF3 E t 2 0 and hydrolysis of the product (65);38 the kinetics of formation of this macrolide from 2[HO(CH2)13C(0)S]C5H3N(X) derivatives showed that high r a t e of cyclization could be attained with ring substituents X which were electron-donating (render-

-a2

0

0

OOH

RHC

CHR .Me,

,Ph N

S-

a+

ing the terminal O H group more nucleophilic) (-0 * * H * * - N), or electronattracting (2-substituted-pyridyl-S-, being a better leaving group).39 Further work with compounds of type (66; n = 1 or 2) and EtSCO(CH2),oO-K’ (for comparison) has established that the particularly efficient cyclization of (66 ; n = 2) (mentioned in last year’s Report, p. 365) arises from the transition state approximating to (67) (both oxygen atoms are capable of close approach

(66) 35

36

’’ 38 39

D. Villemin, Tetrahedron Lett.,, 1980. 21, 1715. J. Tsuji and S. Hlshiguchi, Tetrahedron Lett., 1980, 21, 2955. S. L. Schreiber, J. Am. Chem. SOC.,1980,102,6163. J. P. Genet and P. Kahn, Tetrahedron Lett., 1980,21,, 1521. R. H. Wollenberg, J. S. Nimitz, and D. Y. Gokcek, Tetrahedron Lett., 1980, 21, 2791.

355

Eight-Membered and Larger Ring Systems

to the K ' to optimize the ~tabilization).~'Tin compounds have been used to promote ester formation. Thus the intramolecularcyclization of HO(CH2),C02H is catalysed by Bun2Sn0in reactions which possibly involve species such as (68) as intermediates.22Small amounts of dilactones are formed in these reactions, though, surprisingly, none of these compounds is formed from ethylene glycol that has been treated with Bun2S0followed by reaction with ao-diacyl chlorides: only tetralactones are formed.41The formation of six-co-ordinated tin species (69) involving the cyclic stannoxane was suggested as a plausible transition state in these reactions. Treatment of ethane-1,2-dithiol with Me2SiClz and the subsequent reaction of the resulting five-membered heterocycle with ao-diacyl chlorides gave exclusive formation of tetrathiolactones rather than of dithiolactones, a reaction which illustrates the guiding and activating unit of the metalloid.42

(68) (69)

Double Wittig reactions of compound (70; n = 0 or 1) with S(CH6Ph3)2, followed by intramolecular oxidative coupling [using Cu(OAc), and pyridine] of the terminal acetylene units, provides a route to dehydrothia-[131- and -[171annulene derivatives (71).43Doughnut-shaped macrocyclophanes have been prepared by joining pairs of 1,4-dihydro~ybenzene~~ or 2,fi-dihydroxynaphthalene units4' through their oxygen atoms with hexa-2,4-diyn-1,6-diyl spacers. Relatively large quantities of cyclic sulphides can be prepared from awchloroiodo-alkanesby treatment with thiourea (1equivalent), followed by hydrolysis of the S-thiouronium iodide (not isolated) and cyclization with aqueous sodium hydroxide.46Thus, from Cl(CH2)61there is obtained [S(CH2)6]2(8%) accompanying 1-thiacycloheptane (34%). Ferrocene units have been incorporated in some polyoxathia- and p~lythia-ethers.~~

a

(CH=CH),CHO

C=CH (70) W. H. Rastetter and D. P. Phillion ,J. Org. Chem., 1980,45. 1535. A. Shanzer and N. Mayer-Shochet, J. Chem. SOC.,Chem. Commun., 1980,176;see also A. Shanzar and E. Berman, ibid, p. 259. 42 A. Shanzer and E. Schwartz, Tetrahedron Lett., 1979,5019. 43. J. Ojima, K. Kusaki, K. Wada, and Y. Nakagawa, Bull. Chem. Soc. Jpn., 1980,53,1127. 44 E.T.Jarvi and H. W. Whitlock, Jr., J. A m . Chem. SOC.,1980,102,657. 45 B. J. Whitlock, E. T. Jarvi, and H. W. Whitlock, Jr., J. Org. Chem., 1981,46,1832. 46 R. L. Cumbie and D. D. Ridley, Aust. J. Chem., 1979,32,2777. " B. Czech and RatajczaK, Pol. J. Chem., 1980,54,767(Chem. Abstr., 1981,94,65803). 40

41

356

Heterocyclic Chemistry

A number of air-stable three-carbon-bridged crown arsanes have been prepared for use as multi-electron ligands for transitioa Crown Ethers and Related Compounds.-Synthesis. Williamson-type syntheses have been carried out, using ao-dihalides and the dithallium alcoholates of ( R , R ) -(+)-tartaric acid derivative^,^ and the caesium salts of aw-dithiols in DMF.” Tetrafluorobenzo-15-crown-5and -18-crown-6 are readily accessible from the overall substitution of two ortho-fluorine atoms in C6F6 and the bis-alkoxides derived from HO(CH2CH20),H for n = 4 and 5, re~pectively.~’ The transetherification of ethyl orthoformate with aw-diols, followed by reaction of the product with alkanones, provides a simple route to cyclic acetal~.’~ An alternative route to cyclic ketals of benzophenone under very mild conditions utilizes diphenyldiazomethane (PhzCNz) and ao-diols in the presence of 2,3-

dichloro-5,6-dicyano-1,4-benzoquinone.53 A novel approach to crown ethers is based on the solvomercuriation-demercuriation reaction of alkenes. Treatment of diallyl ether with Hg(OAc)zand KClO, and HClO, in HO(CH2CH20),H as solvent, followed by rupture of the The C-Hg bonds in the product with NaBH, and NaOH, gave (72) (ll’/~).’~ diester (73), on treatment initially with Na-K alloy in benzene at high dilution, followed by hydrolysis and decarboxylation, gave the intermolecular Dieckmann-cyclized product (74).5s However, the expected acyloin type of product, in which no carbon was lost, was obtained in another reaction.

coh 0

e

O W 0

In addition to the synthetic methods described in this section, a wide variety of polyethers containing other functional groups or atoms in addition to oxygen atoms bridged by two carbon atoms have been prepared by well-established methods. Some of these include bis-benzo-crown ethers that are linked through J. Ennen and T. Kauffmann, Angew. Chem., In?. Ed. Engl., 1981, 20, 118; see also E. P. Kyba and S . 4 . P. Chou, J. A m . Chem. SOC.,1980,102,7012. 49 J. P. Behr, J. M. Girodeau, R. C. Hayward, J. M. Lehn, and J. P. Sauvage, Helv. Chim. Acta, 1980,63,2096. J. Buter and R. M. Kellogg, J. Chem. SOC.,Chem. Commun., 1980,466. A. H. Haines, Tetrahedron Lett., 1980, 21, 285. 5 2 J . Einhorn, C. Bacquet, and D. Lelandais, J. Heterocycl. Chem., 1980, 17, 1345. s3 T. Oshima, R. Nishioka, and T. Nagai, Tetrahedron Lett., 1980, 21, 3919. ” A. J. Bloodworth, D. J. Lapham, and R. A. Savva, J. Chem. SOC.,Chem. Commun., 1980,925. J. H. P. Tyman, J. Grundy, and G . R. Brown, J. Chem. SOC.,Perkin Trans. I , 1981, 336.

48

’’

357

Eight-Membered and Larger Ring Systems

polyethylene ether chains;56 ethers containing mal0ny1,~~ 1,5- and 1,8-naphth~ridine,~* thiourea,59 and amino-acid6' subunits; as well as cyclic sulphites61 and methylphosphony162and phosphorus63 subunits. Efects of Crown Ethers on Chemical Reactions. Substitution reactions at the saturated carbon atom of alkyl halides have been promoted in the presence of 18-crown-4 polyether (18-C-6). Thus treatment of heterocycles bearing an acidic N-H (e.g. pyrazole, imidazole, benzotriazole, carbazole, and indole) in diethyl ether in the presence of KOBu' generally give only N-alkylated phosphinic acid salts R,P(O)O- K ' are converted into R2P(0)OAlk;6s and displacement of chloride ion by fluoride ion, using KF, can be conducted at 100 "C with epichlorohydrin and 3,3-bis(chloromethyl)oxetan.66In this last reaction it was demonstrated unequivocally, by deuterium-labelling experiments, that the oxetan ring was not opened during the substitution process. Forcing the (2)-cyclopropyl bromide (75) to react, under SN2conditions, with KOAc in DMSO at 85 "C with added 18-C-6 gave the (2)-cinnamoyl ethanoate (74), the stereochemical course being interpreted in terms of a disrotatory ringopening of the ring, the LUMO of the incipient ally1 cation interacting with the HOMO of the ethanoate ion (77).67The rate of displacement of bromide ion from n-C8HI7Br by various nucleophiles (e.g. I-, CN-, and PhS-) in aqueous solution in the presence of a polymer resin that incorporates a pendant 18-C-4 ring is proportional to the concentration of the catalyst added, but the rates for these polymeric materials were almost the same as for 'free' crown ethers.68

Ar&Br (75)

(77) K. H. Wong and H. L. Ng, Tetrahedron Lett., 1979,4295. '' J. S. Bradshaw, S. T. Jolley, and B. A. Jones, J. Heterocycl. Chem., 1980, 17, 1317. G. R. Newkome, S. J. Garbis, V. K. Majestic, F. R. Fronczek, and G. Chiari, J. Org. Chem., 1981, "

"

6o 61

62

63

65

66 67

68

46, 833. A. V. Bogatskii, N. G . Lukyanenko, and T. I. Kirichenko, Tetrahedron Lett., 1980, 21, 313; see also A. V. Bogatskii, N. G. Lukyanenko, and T. I. Kirichenko, Zh. Org. Khim., 1980, 16, 1301 (Chem. Abstr., 1980,93,204 611). M. Zinic, B. Bosnic-Kasnar, and D. Kolbah, Tetrahedron Lett., 1980, 21, 1365. A. C. Guimaraes, J. B. Robert, L. Cazaux, C. Picard, and P. Tisnes, Tetrahedron Lett., 1980, 21, 1039. A. V. Kirsanov, T. N. Kudrya, and A. S. Shtepanek, Zh. Obshch. Khim., 1980,50, 2452 (Chem. Abstr., 1981, 94, 121 648). M. Ciampolini, P. Dapporto, N. Nardi, and F. Zanobini, J. Chem. SOC.,Chem. Commun., 1980,177. W. C. Guida and D. J. Mathre, J. Org. Chem., 1980,45, 3172. Z. E. Golubski, Synthesis, 1980, 632. Y . Kawakami and Y. Yamashita, J. Org. Chem., 1980,45, 3930. D. H. Buchanan and G. McComas, Tetrahedron Lett., 1980,21,4317. F. Montanari and P. Tundo, J. Org. Chem., 1981,46, 2125.

358

Heterocyclic Chemistry

Some polymers incorporating dibenzo-18-C-6 units in the main chain, however, did show some high activating effects in tri-phase The selective acylation of secondary over primary ammonium salts in the presence of two molar proportions of 18-C-6 relies on the selective complexation of RNH3+over R2NH2+,leaving the secondary amine derivative free for functiona l i ~ a t i o n . ~This ' property hastnow been +applied to the selective acylations of diammonium salts, e.g. MeNH2(CH2)2NH32TosO-, which, on successive treatment first with PhCOCl and Et3N and then with TosCl and Et3N, gives MeN(COPh)(CH2),NHTos. However, the stabilities of RNH3+ complexes d o decrease with increasing steric congestion in R, to such an extent that, in the presence of N-benzylmonoaza-18-C-6, in an equimolar mixture of 3P- and 3a-amino-5a-cholestanes and CF3C02H, only the axially disposed amine ( 3 a ) compound was functionalized, because the unhindered 3P-amino-compound complexed strongly with the crown ether. The effectiveness of nucleophiles is enhanced by the presence of 18-C-6 in the substitution reactions of c h l o r o b e n z e n e ~ .Even ~ ~ when electron-donating groups were present in the aromatic ring, activation by the formation of complexes with Cr(C0)3 and treatment with KOMe brought about smooth replacement of chlorine.72O n the other hand, the initial rate of electrophilic substitution of N-ethylcarbazole by 4-NO2C6H4N2+ C1- in CH2C12-H20 was inhibited by a factor of c a . 4 upon the addition of 18-C-6, presumably because of the low coupling ability of the complexed e l e ~ t r o p h i l e The . ~ ~ decarboxylation of the potassium salts of the ethyl half-esters of malonic acid derivatives, i.e. R2C(C02Et)C02-K', in the presence of 18-C-6 is much faster than the conventional thermal decarboxylation of the dicarboxylic acids (by a factor of lo"), and provides a simple route to the esters RCHC02Et, the reactions being conducted at d 100 0C.74 The alkali metals form blue solutions in 12-C-6 as an aprotic solvent, the colour being due to metal anions M- (produced by the reaction: 2M M' + M-); the relative stabilities of the solutions are in the order Na- > K- > Rb- > C S - . ~ For ' sodium, the addition of LiCl brings about a marked increase in the intensity of the blue colour, because the lithium cation is complexed strongly by the crown ether and the Na' comes out of solution as precipitated NaC1, thereby increasing the concentration of Na- (to >0.1 moll-'). This solution, when added t o benzene followed by EtOH, gave cyclohexa-2,4-diene (60%). In THF that contained a catalytic amount of 18-C-6, the Na-K alloy again formed intense blue solutions, due to Na-/K-, which were decomposed only ~ alcoholic solution partially slowly at 0 "C upon the addition of B u ' O H . ~This

+

69 70

"

'* 73 74

75

76

K. Fukunishi, B. Czech, and S. L. Regen, J. O r g . Chem., 1981, 46, 1218. A. G. M. Barrett, J. C. A. Lana, and S. Tograie, J. Chem. SOC.,Chem. Commun., 1980, 300. W. Rasshofer, G . Oepen, and F. Voegtle, Isr. J. Chern., 1979, 18, 249 (Chem. Absrr., 1980, 93, 132 456). M. Fukui, Y. Endo, and T. Oishi, Chem. Pharm. Bull., 1980, 28, 3639 (Chem. Abstr., 1981, 94, 191 195). M. Ellwood, F. Griffiths, and P. Gregory, J. Chem. SOC.,Chem. Commun., 1980, 181. D . H. Hunter, V . Patel, and R. A. Perry, Can. J. Chem., 1980,58,2271. R. R. Dewald, S. R. Jones, and B. S. Schwartz, J. Chem. SOC., Chem. Commun., 1980, 272. D. J. Mathre and W. C. Guida, Tetrahedron Lett., 1980, 21, 4773.

359

Eight-Membered and Larger Ring Systems

reduced a C-C bond to form ( E ) - and (2)-alkenes over short times, but complete conversion into alkanes took place over longer periods. Interestingly, benzoic acid suffered complete reduction of the aromatic ring by the reagent, to give C6HllC02H.Contact ion-pairs of aromatic radical anions and 18-C-6' that are of sufficient stability to be observable by e m . spectroscopy complexed K can be obtained from hydrocarbons of low electron affinity; e.g., mesitylene with Potassium hydroxide in 1,2-dimethoxyethane containing 18-C-6 is sufficiently basic to form carbanions from Ph3CH and Ph2CH2.78It has been reported that the addition of dibenzo-18-C-6 increases the selectivity for abstraction of chlorine from CC1, by C11H2,.by forming a complex with the

Reactions of the Macrocyclic Rings of Crown Ethers and Related Compounds. The presence of ether oxygen atoms in the bridge X of the chiral 1,4-dihydropyridine (78), which is a reducing agent, has very little effect on raising or lowering the enantiomeric excess of R1CH(OH)R2that is formed by transfer of a hydride ion to the ketone R1COR2 in the presence of Mg(C104)2 (see last year's Report, p. 371).80Consequently, the magnesium cation does not bind to the bridge in the [(1,4-DHP)Mg2+]complex. Using PhCOC0,Et as the substrate, 90% of the (S)-alcohol was obtained in the reaction with [78; R = Me,CH; X = (CH2)J. Compound (79) was reduced by 1-benzyl-[4,4-*H2]-1,4-dihydronicotinamide to (80) in a reaction which was >go% stereoselective, and which mimicks the hydride-transfer properties that are displayed by the NADNADH couple under enzymatic conditions.81 Interestingly, the 3,5-bridged dihydropyridine crown ether (81; n = 3) does not undergo a hydride-transfer reaction with the pyridinium salt (82) [though transfer does occur if n = 1 or 21, but forms a bright red charge-transfer complex, in which the salt is encapsulated by the 24-membered ring, but in an orientation which does not permit 4,4'- transf er of hydride. 82

77 78

79

''

Me

CH7Ph

(78)

(79)-

CH2Ph

(80) P. Belser, G. Desbiolles, U. Ochsenbein, and A. von Zelewsky, Helv. Chim. Acta, 1980,63, 523. G. A. Artamkina, A. A. Grinfel'd, and I. P. Beletskaya, Zzv. Akad. Nauk SSSR, Ser. Khim., 1980, 2431 (Chem. Abstr., 1981,94,46863). V. V. Zorin, N. A. Batyrbaev, S. S. Zlotskii, D. L. Rakhmankulov, and R. A. Karakhanov, Dokl. Akad. Nauk SSSR,1980,255,626(Chem. Abstr., 1981,94,120 543). P.Jouin, C.B. Troostwijk, and R. M. Kellogg, J. A m . Chem. Soc., 1981,103,2091. F. Rob, H. J. van Ramesdonk, J. W. Verhoeven, U. K. Pandit, and Th. J. de Boer, Tftrahedron Lett., 1980,21, 1549. 0.Piepers and R. M. Kellogg, J. Chem. Sac., Chem. Commun., 1980,1154.

360

Heterocyclic Chemistry

The rate constants for the acylation of piperidine by (83) are increased by the presence of metal cations. Thus Na’ acts as a catalyst for (83; n = 0), while K’ is effective for (83; n = l).83 The effects of guest cations on the photochemical behaviour of acetyl-benzocrown ether oximes have been syn-anti isomerization of the 15-C-5 derivative was stimulated by the formation of a complex with the sodium ion, whereas the photolysis of the oximes to give the parent ketones and products of a Beckmann rearrangement via an oxaziridine intermediate was depressed by host-guest complexation. Formation of Host-Guest Complexes. A diastereoisomeric pair of macrocyclic polyethers based on two ( R , R ) -tartaric acid residues has been prepared which have interesting symmetry properties.*’ Compound (84), the syn-isomer, has different faces but identical sides, so that the possibility arises of performing reactions separately on the ‘top’ and on the ‘bottom’ of the macrocycle. The anti-isomer (85) has identical faces, but is ‘side discriminated’.

(84) R’ = R3 = COz-,R2 = R4 = CONHAr

(85) R’

=

R4

=

COz-,R2

=

R3

=

CONHAr

The transport of cations from one aqueous phase through an immiscible organic phase (a ‘membrane’) that contains a carrier into a second aqueous phase (a process akin to the passage of polar molecules through lipophilic barriers in biological systems) continues to be of great interest. The rates of transport 83

84

85

J. P. Dix, A. Wittenbrink-Dix, and F. Voegtle, Naturwhsenschaften, 1980, 67, 91 (Chern. Abstr., 1980, 93,7439). M. Tada, H. Hirano, and A. Suzuki, Bull. Chern. SOC.Jpn., 1980, 53,2304. J. P. Behr, J. M. Lehn, D. Moras, and J . C. Thierry, J. A m . Chern. SOC.,1981, 103, 701.

Eight-Membered and Larger Ring Systems

361

of metal cations through membranes containing crown ethers have been examined as a function of the concentration of the salt and the nature of the anion.86For the maximum transport of cations, an optimum range in the value of the stability of the cation complex has been shown to exist, the rate of transport decreasing rapidly at stability constants higher or lower than this range.87 Dicyclohexano- and 2,6-diketopyridino-l8-C-6 ethers show a remarkable selectivity for Pb2' over the biologically important cations Na', K', Ca2', Fe3', Cu2+,and Zn", and they are very effective carriers of Pb2+ even when This finding is presumably a the ratio of [Pb2']: [other cation] is < 1 : reflection of the relative values of the stability constants for the ions involved, and it has clear implications for the removal of lead from the environment and from biological systems. The transport of primary ammonium salts that are based on 2-phenylethylamine in a mixture of MeOH and H,O (95 :5 v/v) through a CHC13 membrane that contains dicyclohexyl- 18-C-6 has been i n ~ e s t i g a t e d . ~ ~ The selectivity of RNH3' compounds over RNH,Me' compounds is about 15 : 1, reflecting the superior complexing ability of the crown ether with the primary ammonium salt. Substitution of the a-CH, by one or two methyl groups and of a P-CH by OH decreases the transport rate by factors of ca. 2, 7 , and 7, respectively. An intriguing approach towards the control of the extraction and transport of ions employs the trans-azo-compound (86). Under the influence of U.V. light, this compound isomerizes to the cis-compound (87), which in turn reverts (under O r . )

thermal conditions) to the trans-compound, the interconversions being such as is found in the motion of a butterfly." It was found that, of the alkali-metal cations, Na' is extracted the most efficiently from an aqueous phase to an organic phase (o-C6H4C12)with the trans-isomer because it forms a 1: 1 cation-benzocrown [i.e. 2 : 1 cation-(86)] complex, whereas K', Rb', and Cs' are extracted efficiently (compared with Na*) by the cis-isomer, as the 1:2 cation-benzo-crown [i.e. 1: 1 cation-(87)] complex, which is a sandwich complex. The transport of 86

87

89

90

J. D. Lamb, J. J. Christensen, S. R. Izatt, K. Bedke, M. S. Astin, and R. M. Izatt, J. A m . Chem. SOC.,1980,102,3399. J. D, Lamb, J. J. Christensen, J. L. Oscarson, B. L. Nielsen, B. W. Asay, and R. M. Izatt, J. Am. Chem. SOC.,1980,102,6820. J. D.Lamb, R. M. Izatt, P. A . Robertson, and J. J. Christensen, J. A m . Chem. SOC.,1980,102,2452.

E.Bacon, L. Jung, and J. M. Lehn, J. Chem. Res. ( S ) , 1980,136. S. Shinkai, T. Nakaji, T. Ogawa, K., Shigematsu, and 0. Manabe, J. A m . Chem. SOC.,1981,103, 111.

362

Heterocyclic Chemistry

K' across a membrane of O-C&Clz is suppressed by light when a hydrophobic counter-anion is used (e.g. 1.9-fold by picrate), whereas it is accelerated by.light when a relatively hydrophilic counter-anion is used. The increase in hydrophobicity of the counter-anions shifts the rate-limiting step from the ion-complexation site to the ion-releasing site, so that photoisomerized cis-(87) would further suppress the release of 'K' to the 'outside' aqueous phase. However, when only one fifth of the liquid membrane that was in contact with the 'inside' aqueous phase was irradiated, the transport of potassium picrate was accelerated by a factor of 1.3. It was presumed that the cis-(87) that was formed in the membrane rapidly extracted K', and the resulting sandwich complex then thermally isomerized in the non-irradiated portion of the membrane to the less stable trans-(86)K' complex, which finally released K' at the 'outside' aqueous phase. Closely related to compound (87) is (88), containing one benzo-18-C-6 unit, formed by photoirradiation of the analogous truns-isomer with U.V.light." No alkali-metal ions were extracted from- aqueous solution by the trans-isomer in O-C6H,CI,, and only K' (ca. 5 % ) was extracted by (88) on photoirradiation. The observation that alkali-metal cations reduce the rate of isomerization of (88) to the transisomer by factors of 12-32 compared with that for the undissociated ciscarboxylic acid from which (88) is derived implies that the crown ether is tied to the carboxylate ion through a metal ion. The incorporation of a crown ether unit and an azobenzene unit into a polymer chain (89) enabled the ability of

(88)

this polymer to extract alkali-metal cations to be evaluated with the azo-group in either the trans configuration or the cis configuration (produced by photoisomerization with U.V. light).92The extractability for K' increased by 1.7, but the affinity of the crown ether for Na' ion, which was greatest amongst the alkali metals with (89), was lost when the azo-group adopted the cis configuration. Polymer (89) extracts the dipotassium salt of phthalic acid from aqueous solution, but not the salts of iso- and tere-phthalic acids. Photoirradiation of (89) had very little effect on the relative extractabilities of these isomers. 92

S. Shinkai, K. Shigematsu, T. Ogawa, T. Minami, and 0.Manabe, TetrahedronLett., 1980,21,4463. S . Shinkai, T. Nakaji, Y. Nishida, T. Ogawa, and 0. Manabe, J. A m . Chem. Suc., 1980,102,5860.

363

Eight-Membered and Larger Ring Systems

The half-life of (90) [obtained by U.V. irradiation of (91)] at 30 "C is prolonged in the presence of an alkali-metal ion, compared to that of the ion-free case, in the order Na' > K' > Li'; this is understandable, since the parent 15-C-6 forms the most stable alkali-metal complex with Na'.93 However, the complexation of (91) by metal ions has no influence on the rate of photochemical cyclization.

(91)

Variable-temperature 'H n.m.r. spectroscopy has shown that the barrier to racemization of the 2,2'-bipyridyl compounds (92; n = 0, 1, or 2; no M) is not surmounted at 165 "C (for n = 0); this puts a minimum value of 24 kcal mol-' for the energy barrier AG+.94However, if M = PdC1, and n = 0, AG' is lowered by at least 8.4 kcal mol-', representing a rate enhancement of lo6 at room temperature. The binding reaches a maximum when the two pyridine rings are coplanar -the transition state for racemization. The change in the conformation of the ring of the crown ether, depending on the absence or presence of binding of a transition metal at the bipyridyl unit, is reflected in the relative value of the transport selectivity for the alkali-metal ion through a chloroform membrane. For compound (92; n = 0; no M), K':Na' = 3.8, but for [92; n = 0, M = W(CO),], K':Na' = 0.8.95 Molecular models show that, in the absence of a transition metal, both benzylic oxygens are involved in complexation with the cation, but that in the transition-metal-complexed compound the rapid racemization of the 2,2'-bipyridyl unit forces the benzylic oxygens into conformations in which only one can participate in the formation of an ether cavity, so that stronger complexation occurs with the Na' cation. The diminished affinity of (93) relative to the transition-metal-free macrocycle for Na' (by a factor of 11 with NaBPhJ can be attributed to either or both of the following factors: the reduced number of conformations available to the crown ether, thereby limiting the effective size of the cavity; and electronic factors that are transmitted to the aryl ~ x y g e n sThe . ~ ~bis-crown ether (94) forms both 1: 1 and 1: 2 com-. plexes with Hg(CF,)2.97 The statistically corrected association constants are equal, so that the two complexing sites act independently. It was proposed that 93

I. Yarnashita, M. Fujii, T. Kaneda, S. Misurni, and T. Otsubo, Tetrahedron Lett., 1980,21,541.

J. Rebek, Jr., T. Costello, and R. V. Wattley, Tetrahedron Lett., 1980,21,2379. " J. Rebek, Jr., and R. V. Wattley, J. A m . Chem. Soc., 1980,102,4853. '' J. Rebek, Jr., and R. V. Wattley, I. Heterocycl. Chem., 1980,17,749. 97 J. Rebek, Jr., R. V. Wattley, T. Costello, R . Gadwood, and L. Marshall, J. A m . Chem. SOL, 1980, 94

102,7398.

Heterocyclic Chemistry

364

(92)

(93)

(94)

binding at one site fixes only one of the many rotational degrees of freedom that are enjoyed by the remote polyether ring. Biologically important donor-acceptor interactions between indole and pyridinium moieties have been studied by examining the U.V. and visible absorption spectra of complexes that are formed between an 18-C-6 compound and a primary ammonium salt substrate which incorporate these units as substituents mobile arm, on the host and guest molecules, r e ~ p e c t i v e l yA . ~conformationally ~ attached to a 15-C-5 ring in the form of a 1,2-CH20-C6H40Meunit, offers a complexed Na' ion an additional axially directed binding site (the methoxyloxygen atom), since the extraction constant for this macrocycle is two-fold greater than the isomeric ether bearing the 1,4-CH20-C6H40Me The treatment of 0x0-12-C-3 (95; n = 1) or 0x0-18-C-5 (95; n = 3) with one molar equivalent of benzylamine did not result in any complex formation which could have arisen by an intermolecular interaction of the type shown in (96).looHowever, 1: 1 complexes were formed between these hosts and RNH3+ and R2NH2+salts. Dynamic proton-decoupled 13Cn.m.r. spectroscopy demonstrated an equilibrium between two complexes formed from (95; n = 3) and 0-

99

loo

J. P. Behr and J. M. Lehn, Helv. Chim. Acta, 1980, 63, 2112. G . W. Gokel, D . M. Dishong, and C. J. Diamond, J. Chem. Soc., Chem. Commun., 1980, 1053. G. D. Beresford and J. F. Stoddart, Tetrahedron Lett., 1980, 21, 867.

365

Eight-Membered and Larger Ring Systems

(S)-PhCHMeNH3' C104- in which the guest and the carbonyl group of the host are orientated syn and anti to each other. An X-ray structure determination of the complex formed between NN'-dimethyl-l,7-diaza-4,10-dioxacyclododecane and PhCH2NH3+C104- identified the twp-point binding structure (97; R = Ph), with syn stereochemistry, (stronger N-H * N bonding than N-H * 0 bonding)."' Dynamic I3C n.m.r. spectroscopic measurements in CH2C12, at low temperatures, on [97; R = (S)-PhCHMeNH3'], however, revealed the occurrence of conformational isomerism with the host species. In a comparative study with three eighteen-membered macrocyclic ligands, the triaza-trioxo-compound (98) has been shown to display the highest stability and selectivity for binding the RNH3+ion.'02 The stability of the complex of RNH3+ with (98) was greater than with 18-C-6 by a factor of ca. 30 while the selectivity (measured by the ratio of the stability c o n s t p RNH,'/K') increased from ca. 0.01 with 18-C-6 to ca. 10 for (98). Three N-H - N hydrogen-bonds and six electrostatic interactions (99) account for these properties. No transprotonations occur in the complexes.

-

Me

Me

(97) [* these are s y n ]

Macrocyclic compounds incorporating the ferrocene subunit in ether-amide or -amine systems have been prepared.lo3Their weak (if any) ability to complex alkali-metal cations was accounted for by the rigidity of the molecule and the smallness of the cavity of the macrocycle. The 1: 1 macro-ligand that has been prepared from 6,6'-bis(chloromethyl)2,2'-bipyridyl and hexaethyleneglycol forms a pentaco-ordinated cobalt(I1) chloride complex that contains a novel Co"-0 (ether) bond.lo4 The 2 :2 macroligand, also isolated along with the 1: 1ligand, formed a binuclear complex with copper(I1) ch10ride.l'~ Compound (100) can be converted into a bis-copper(1) (C10& complex which, in MeCN, rapidly absorbs one mole of oxygen; the resulting bis-copper(I1) complex undergoes a slower anaerobic oxidative dehydrogenation of the ligand by the bound oxygen, to regenerate the Cu' centres, with imino-nitrogen ligands. The cycle can be repeated at least once again, although more slowly.'o6 lo'

'02

lo3 lo'

lo'

'06

J. C. Metcalfe, J. F. Stoddart, G. Jones, W. E. Hull, A. Atkinson, I. S. Kerr, and D. J. Williams, J. Chem. SOC.,Chem. Commun., 1980,540. J. M. Lehn and P. Vierling, Tetrahedron Len., 1980,21, 1323. A. P. Bell and C. D. Hall, J. Chem. SOC.,Chem. Commun., 1980,163. G.R.Newkome, C. K. Kohli, and F. Fronczek, J. Chem. SOC.,Chem. Commun., 1980,9. G.R. Newkome, D. K. Kohli, F. R. Fronczek, B. J. Hales, E. E. Case, and G. Chiari, J. A m . Chem. SOC., 1980,102,7608. M. G. Burnett, V. McKee, S. M. Nelson, and M. G. B. Drew, J. Chem. SOC., Chem. Commun., 1980,829.

366

Heterocyclic Chemistry

Further examples of complexes between crown ethers and neutral molecules have been published. Compound (101) forms 1: 1 crystalline complexes with another crown ether, 12-C-4, and with molecules that contain potentially acidic C-H bonds, i.e. MeCN, MeNO,, Me,SO, HCONH,, HCONMe,, and MeCONMe2.'07 Hydrazine derivatives RNHNH, form stable 1 : 1 complexes with 18-C-6.'"'

'07

F. Voegtle, W. M. Mueller, and E. Weber, Chem. Ber., 1980,113, 1130. F. Voegtle and W. M. Mueller, Chem. Ber., 1980, 113,2081.

7 Bridged Systems BY J. R. MALPASS

This chapter covers the period July 1980 to June 1981. The increased interest in bridged oxygen compounds, noted in last year's Report, has been maintained. Cycloaddition reactions remain of major concern in this chapter; current interest in stereoelectronic control and in intramolecular cycloaddition reactions continues. Pressure of space demands a selective coverage of synthetic and mechanistic studies in the wide area of bridged systems, so that topics such as heterocyclophanes, cryptates, prostanoids, and bridged systems that have physiological activity receive only passing mention.

1 Reviews Reviews of the synthetic applications of singlet oxygen' and of bicyclic endoperoxides2 have appeared, together with a comprehensive account of the synthesis of unusual molecules from a~oalkanes.~ Intramolecular cycloadditions have been reviewed by O p p ~ l z e r and , ~ Mukais has covered cycloadditions of hetero-epins. Articles which contain details of bridged systems include one on cyclization of aminium radicals,6 another on one-electron oxidation of tetraalkyl-hydrazines,' and an authoritative review of inversion barriers in sixmembered-ring compounds.8 Details of both nitrogen- and oxygen-insertion reactions of bridged bicyclic ketones have been collatedg and a review by Gleiter takes a detailed theoretical view of the structural multiplicity of S/N rings." 2 Physical Methods

X-Ray and Electron Diffraction.-X-Ray studies have been reported for lO-bromo-1,6-methano-2-aza[ 10]annulene1' and for the phosphatrane (l),in which the transannular N + P interaction brings the phosphorus atom into a

' lo

H. H. Wasserman and J. L. Ives, Tetrahedron, 1981,37, 1825. M. Balci, Chem. Rev., 1981, 81, 91. W. Adam and 0. D e Lucchi, Angew. Chem., Int. Ed. Engl., 1980,19, 762. W. Oppolzer, Heterocycles, 1980, 14, 1615. T. Mukai, T. Kumagi, and Y. Yamashita, Heterocycles, 1981, 15, 1569. Y. L. Chow, React. Intermed., 1980, 1, 151. S. F. Nelsen, Acc. Chern. Res., 1981, 14, 131. A. R. Katritzky, R. C. Patel, andF. G. Riddell, Angew. Chem., Znt. Ed. Engl., 1981, 20, 521. G. R. Krow, Tetrahedron, 1981, 37, 1283, 2697. R. Gleiter, Angew. Chem., Int. Ed. Engl., 1981, 20, 444. R. Destro, M. Simonetta, and E. Vogel, J. A m . Chem. Soc., 1981, 103,2863.

367

Heterocyclic Chemistry

368

trigonal-bipyramidal configuration.** Gas-phase electron-diffraction results on methylsilatrane (2) indicate the absence of an N -P Si intera~tion,'~" in contrast to many X-ray studies on s o l i d ~ . * ~ ~ X -studies R a y of the dimers of 3,4-dimethylphospholes that are obtained in the presence of metal carbonyl chelating agents, e.g. (3), confirm the unexpected exo configuration and the strained nature of the phosphorus bridge (LCPC = 79.40).14An X-ray structure of (4) indicates that it possesses a stable, planar BN3 array, unlike smaller members of this family, which exist as tight d i m e r ~ . ~Homoconjugative ' and hyperconjugative effects have been invoked to explain distortions in (5).16 X-Ray studies have been used to define the structure of the adduct (6), which is derived from intramolecular 1,3-cycloaddition of an N- (0-allylphenyl)munchnone," and of the adduct (7), which is one of the epimeric products from the trapping of a strained bicyclic enone by furan." A report" of differences between the crystal structure and the conformation in solution (determined by using lanthanide shift reagents) of a bicyclic lactam emphasizes that such discrepancies may be common where interconversion barriers are low.

R-M +

(1) M-R (2) M-R

= =

PEt BFi SiMe

0 (6)

Photoelectron Spectroscopy.-An efficient interaction is observed between the v(NN) and .rr(CC)bonds in (8)and related compounds.20Photoelectron-spectroscopic and cyclic-voltammetric studies on (9) show that the radical cation has a short lifetime, in contrast to other 'Bredt's-Rule-protected' systems.'l Results

'' l4 l5 16

"

'*

l9 20

*'

D. Van Aken, I. I. Merkelbach, A . S. Koster, and H. M. Buck, J. Chem. SOC.,Chem. Commun., 1980, 1045. ( a ) Q. Shen and R. L. Hilderbrandt, J. Mol. Struct., 1980, 64, 257; ( b ) e.g. J. Bleidelis and A . Kernrne, Int. Semin. Cryst. Chem. Coord. Organomet. Compd. [Proc.],3rd, 1977, 116 C. C. Santini, J. Fisher, F. Mathey, and A . Mitschler, J. A m . Chem. SOC.,1980, 102, 5809. J. E. Richrnan, N. C . Young, and L. L. Andersen, J. Am. Chem. SOC.,1980,102, 5790. A . A . Pinkerton, D. Schwarzenbach, J. H. A . Stibbard, P.-A. Carrupt, and P. Vogel, J. A m . Chem. SOC.,1981,103, 2095. A. Padwa, H. L. Gingrich, and R. Lim, Tetrahedron Lett., 1980, 21, 3419. H. 0. House, M. B. D e Tar, R. F. Sieloff, and D. VanDerveer, J. Org. Chem., 1980,45, 3545. H. L. Ammon, P. H. Mazzocchi, and L. Liu, Chem. Lett., 1980, 897. B. Albert, W. Berning, C. Burschka, S. Hunig, H.-D. Martin, and F. Prokschy, Chem. Ber., 1981, 114, 423. S. F. Nelsen, C. R. Kessel, D. J. Brien, and F. Weinhold, J. Org. Chem., 1980, 45, 2116, see also S. F. Nelsen, C. R. Kessel, L. A. Grezzo, and D. J. Steffek, J. A m . Chem. SOC., 1980, 102, 5482.

Bridged Systems

369

from photoelectron spectroscopy have been related to the question of the conformation of 3,7-dimethyl-3,7-diazabicyclo[3.3. llnonane in the gas phase.22a A chair/chair conformation predominates here and in other derivatives;22bn.m.r. studies on 9-keto- and 9-hydroxy-analogues are consistent with a chair/boat configuration.22C

(8)

(9)

Nuclear Magnetic Resonance Spectroscopy.-A chair/ boat conformation has been proposed for the new N-bridgehead lactam The compound is only moderately reactive in hydrolysis, in contrast to the rapid hydrolysis of ( l l ) , which is a result of significant torsional distortion of the amide.24 Carbon-13 studies of lactams, including (12), have formed the basis for conformational studies of pep tide^.^^ A linear correlation is found between chemical shifts of "0 in (13) and (14) and of 13C for C-7 in the corresponding hydrocarbons.26 The syn-7-phosphorus atom in (15) has been reported to be in resonance at the lowest field ever recorded for a tertiary ph~sphine;~' variation in the values of 1J(31P-13C)occurs in (16) as the substituents (and hence the steric interactions) are altered.28 Examination of 1J(13C-1H)in the three-unit p - ~ system of (17) shows that there is no detectable bicycloconjugation (in contrast to the parent

2s

( a ) P. Livant, K. A. Roberts, M. D. Eggers, and S. D. Worley, Tetrahedron, 1981, 37, 1853; ( b ) H. Quast and B. Muller, Chem. Ber., 1980,113,2959; ( c ) P. Scheiber and K. Nador, Acta Chim. Acad. Sci. Hung., 1979, 102, 297. H. K.Hall, Jr., R. G. Shaw, Jr., and A. Deutschmann, J. Org. Chem., 1980, 45, 3722. G. M. Blackburn, C. J. Skaife, and I. T. Kay, J. Chem. Res. ( S ) , 1980, 294. M. T. Cung, G. Boussard, B. Vitoux, and M. Marraud, C.R. Hebd. Seances Acad. Sci., Ser. C,

26

T. T-T. Nguyen, C. Delseth, J.-P. Kintzinger, P-A. Carrupt, and P. Vogel, Tetrahedron, 1980, 36,

22

23 24

1980,290,291.

27 28

29

2793. L. D.Quin and K. A. Mesch, J. Chem. SOC.,Chem. Commun., 1980,959. A. Zschunke and H. Meyer, Phosphorus Sulfur, 1980, 9, 117. A. G. Anastassiou, H. S. Kasmai, and R. Badri, Angew. Chem., Int. Ed. Engl., 1980, 19, 639.

370

Heterocyclic Chemistry

Carbon-13 and/or proton n.m.r. data have also been employed in conformational studies on tropane (and related) ~pirohydantoins,~'3-borabicyc10[3.3.l]nonanes,~~ 3-azabicycl0[3.2.2]nonanes,~~ the dioxa-bicycle (18),33 and the cyclazines (19).34nThe tricyclic integrity of (19; x = y = z = 1) is maintained on dialkylation to give the corresponding d i ~ a t i o n Replacement .~~~ of X = CH by X = N in (20) surprisingly favours conformation (20a) rather than (20b) by some 1.3-1.4 kcal m01-l.~~ Double isotope labelling studies,

(19) x, y , z

=

1, 1, 1 ; 1, 1 , 2 ; 1 , 2 , 2 ; or 2 , 2 , 2

based on the perturbation of chemical shifts of 13Cby isotopes of oxygen, were used in the elucidation of the rearrangement shown in Scheme 1, giving the first topologically non-planar molecule.36 Examples of topologically spherical molecules are provided by dihomodioxatrisecododecahedranes.37

-@ Hforheat

Scheme 1

Miscellaneous Methods.-Mass-spectroscopic studies have been reported of derivatives of the 7-azabicyclo[2.2.l]heptane and 2-azabicyclo[2.2.2]octane and of the 4-alkyl derivatives of 2,6,7-trioxa-l -phosphabicycl0[2.2.2]octanes~~~and the corresponding 1-oxides, 1-sulphides, and 1 - ~ e l e n i d e s . ~ ~Previously ' unnoticed electronic transitions occur in cycl[ 3.3.31a~ines.~~

30

31

32 33

34

35

36

37 38

39

G. G. Trigo, M. Martinez, and E. Galvez, J. Pharm. Sci., 1981,70, 87.See also G.G. Trigo, C. Avendano, E. Santos, H. N. Christensen, and M. Handlogten, Can. J. Chem., 1980,58, 2295. M. E.Gursky, A. S. Shashkov, and B. M. Mikhailov, J. Organomet. Chem., 1980,199,171. I. Yavari, J. Mol. Struct., 1980,67, 293. G.Domburgs, I. Berzina, E. Kupce, and I. Z. Kirshbaum, Khim. Dreu., 1980,No. 3,p. 99 (Chem. Abstr., 1980,93,132 705). ( a ) G. R. Weisman, V. Johnson, and R. E. Fiala, Tetrahedron Lett., 1980, 21, 3635; ( b ) T. J. Atkins, J. A m . Chem. SOC.,1980,102,6364. S. F. Nelsen, P. M. Gannett, and D. J. Steffek, J. Org. Chem., 1980,45,3857. S.A. Benner, J. E. Maggio, and H. E. Simmons, 111, J. A m . Chem. Soc., 1981,103,1581. D . W. Balogh and L. A. Paquette, J. Org. Chem., 1980,45,3038. ( a ) A . Marchand and R. W. Allen, Org. Muss Spectrom., 1980,15, 487;( b ) R. S. Edmundson and C. I. Forth, Phosphorus Sulfur, 1980, 8, 3 1 5 ; ( c ) H. Kenttamaa and J. Enqvist, Org. Muss Spectrom., 1980,15,520. W. Leupin and J. Wirz, J. A m . Chem. SOC.,1980,102,6068.

37 1

Bridged Systems

3 Nitrogen-containing Compounds Synthesis.-Cycloadditions. Reports of [4 + 21 additions of nitroso-compounds to cyclohexa-1,3-diene include the formation of (21)40 and (22).4' The 2 : 1 adduct (23) from trifluoronitrosomethane and cyclohexa-1,4-diene is formed via an intermediate 'ene'-adduct (24).41Nitrosobenzene adds regiospecifically to N-acyl-l,2-dihydropyridines,giving (25),42"and cycloaddition reactions of OH

I

R A < I:'

1$J

&NPh (24)

(21) R' = C(Me)2CI,R2 = H (22) R' = CF3,R2 = H (23) R' = CF3,R2 = N(OH)CF3

(25) R' = Meor C02Me R2 = H or Ph

N-methyl-l,2-dihydropyridineshave been Cycloadditions of a variety of dienophiles to azepines, isoindoles, and related systems are shown in Schemes 2,433,444,45and 5.46 [4 + 21-Additions of oxazoles and vinylpyridine~~' and of 5-amino-oxazoles and m a l e i m i d e ~together ,~~ with further cycloadditions of oxidopyridini~rns,~~ are noted. Me

XCGCX

x\

ax N

(X = C02R) Scheme 2

Scheme 3 E. Kessler, J. Heterocycl. Chem., 1980, 17, 113. 41 M. G. Barlow, R. N. Haszeldine, and K. W. Murray, J. Chem. SOC.,Perkin Trans. 1, 1980, 1960. 4 2 ( a ) E. E. Knaus. K. Avasthi, and C. S . Giam, Can. J. Chem., 1980, 58, 2447; ( b ) B. Weinstein, L-C. C. Lin, and F. W. Fowler, J. Org. Chem., 1980,45, 1657. 4 3 J. Duflos and G. Queguiner, J. Org. Chem., 1981,46, 1195. " G. W. Gribble and C. S. LeHoullier, Tetrahedron Lett., 1981, 22,903. 45 W. Eberbach and J. C. Carri, Tetrahedron Lett., 1980,21, 1145. 46 K. Harano, M. Yasuda, T. Ban, and K. Kanematsu, J. Org. Chem., 1980, 45, 4455. 47 P. B. Terent'ev, N. P. Lomakina, M. I. Rahimi, and K. D. Riad, Khim. Geterotsikl. Soedin., 1980, 1255. 48 V. S. Bogdanov, G. Ya. Kondrat'eva, and M. A. Aitzhanova, Izv. Akad. Nauk. SSSR,Ser. Khim., 1980,1017. 49 A. R. Katritzky, M. Abdullah, A. T. Cutler, N. Dennis, S. K. Parton, S. Rahimi-Rastgoo, G . J. Sabongi, H. J. Salgado Zamora, and E.-U. Wurthwein, J. Chem. Res. ( S ) , 1980,249;J. A. Lepoivre, R. A. Dommisse, E. L. Esmans, J. J. Van Luppen, E. M. Merckx, and F. C. Alderweireldt, Bull. SOC.Chim. Belg., 1981,90, 49. 4"

372

ox-

Heterocyclic Chemistry

CH,Ph I

XCrCX

+ X

-

0

'x

X (X = C02R) Scheme 4

x

0

0

Scheme 5

N- Phenyltriazolinediones add straightforwardly to substituted cyclohexa- 1,3dienes,so to 1,2-homoheptafulvene {to give (26) and the [67r + 2 a + 2773 adduct (27)},51 and to tris(trifluoromethy1)cyclopropyl trifluoromethyl ketone and The unstable hydrocartriphenylphosphine to give the interesting adduct (28).52 bon (29) (the formal adduct of benzene and naphthalene) has been intercepted Ph

(26)

(28)

(29)

by N-ethyltriazolinedi~ne~~ and optically active triazolinediones have been found to have limited ability to discriminate between diastereoisomeric transition states with optically active d i e n e ~The . ~ ~formation of a 2-azabicyclo[2.2.l]hept2-ene derivative, rather than the expected 1-aza-product, is shown in Scheme 6,s5together with a conversion of a tetrazene into a triazene.s6 5o 51

52

53 54

55 56

K. B. Becker, Synthesis, 1980, 238. M. Oda, N. Morita, and T. Asao, Tetrahedron Lett., 1980, 21, 471. Y. Kobayashi, T. Nakano, K. Shirahashi, A. Takeda, and I. Kumadaki, Tetrahedron Lett., 1980, 21. 4615. W. Grimme and H. G. Koser, Angew. Chem., Int. Ed. Engl., 1980,19, 307. L. A. Paquette and R. F. Doehner, Jr., J. Org. Chem., 1980, 45, 5105. M. E. Jung and J. J. Shapiro, J. Am. Chem. SOC.,1980,102, 7863. H. P. Figeys and A. Mathy, Tetrahedron Lett., 1981, 22, 1393.

373

Bridged Systems CI,

,c1

Scheme 6

A photochemical [2 + 21 addition produces a 2,4-methanoproline derivative (Scheme 7).57Variations in the ratios of cis- and trans-photodimers of N - ( 0 carboxyalkyl)-2-pyridonesin micellar and reversed micellar systems have been C02Et

AAN-COMe

\N-COMe -?02Et

Scheme 7

observed; in the 4-alkyl derivatives, only cis-dimers (30) and (31) were

X

R

0

’ N,o

R’ 0

R

(30)

NR’

(31)

[R’ = (CH2)2C02H,R2

=

alkyl]

Martin has reported the first (intramolecular) examples of cycloaddition of enamines and enamides to unactivated dienessga(Scheme 8).A route to Aspidosperma alkaloids has been developed from a closely related intramolecular [4 + 21 addition.59b

wgx CH2

0 2 s

57

/

(-sod

[2+21

sx [4heat + 21 \

Qx

(X = H2or 0) Scheme 8

M. Pirrung, Tetrahedron Lett., 1980,21,4577;P.Hughes, M. Martin, and J. Clardy, ibid., p. 4579.

’* Y.Nakamura, T. Kato, and Y. Morita, Tetrahedron Lett., 1981,22,1025. 59

(a) S. F. Martin, C. Tu, and T. Chou, J. Am. Chem. Soc., 1980,102,5274;( b ) S. F.Martin, S. R. Desai, G. W. Phillips, and A. C. Miller, ibid., p. 3294.

374

Heterocyclic Chemistry

Intramolecular cycloaddition of nitrile oxides has been utilized in the annulation procedure shown in Scheme 9,60and an intramolecular nitrone cycloaddition is a key step in a synthesis of adaline (32).6’

Reagents: i, PhNCO, NEt,, PhH; ii, hydrogenolysis; iii, hydrolysis; iv, (-H,O)

Scheme 9

Synthesis by Other Cyclizations. Approaches to derivatives of azabicyclo[2.2.2]octane, based on intramolecular anionic addition6’ and a$’a n n ~ l a t i o n are , ~ ~shown in Scheme 10 and an example of an intramolecular cationic [3 + 23 cycloaddition is in Scheme 1leb4A novel diazanonane system

(R’= Me, OMe, or NHPh; R2

= C02Et)

Reagents: i, LiNEt,, HNEt,, THF; ii, Michael addition

Scheme 10

v

(-7p &) HC02H+

NHPh

HN-NPh

Scheme 11

(33) results from treatment of quinoline methiodide with derivatives of bromoacetonitrile in the presence of trieth~lamine.~’ Syntheses of 3-azawurtzitane (34), of 3(4 5)abeo-3-wurtzitane (35),66and of 3-heterodiamantanes6’ are noted.

~I

6o 61 h2 63 64

”

67

<X3

= a bond, R3 = H =

a bond, R2

R. H. Wollenberg and J. E. Goldstein, Synthesis, 1980, 757. E. Gossinger and B. Witkop, Monatsh. Chem., 1980, 111,803. R. A. Farr, J. E. Dolfini, and A. A. Carr, J. Org. Chem., 1981, 46, 1212. T. Imanishi, H. Shin, M. Hanaoka, T. Momose, and I. Imanishi, Heterocycles, 1980, 14, 1111. B. Fouchet, M. Joucla, and J. Hamelin, Tetrahedron Lett., 1981, 22, 1333. S. Saeki, Y. Kaku, M. Hamana, and H. Noda, Heterocycles, 1980, 14, 809. R. D. Klaus and C. Ganter, Helv. Chim. Acta, 1980,63, 2559. V. V. Krishnamurthy and R. C. Fort, Jr., J. Org. Chem., 1981, 46, 1388.

=

H

Bridged Systems

375

Reactions of Nitrogen-containing Compounds.-Cheletropic elimination of amino-nitrenes from bridged N-amino-compounds has been explored6' and the dichlorocarbene-induced deamination of naphthalene- 1,4-imines and of anthracene-9,lO-imines provides a simple route to naphthalenes and to a n t h r a c e n e ~Benzocyclobutanedione .~~ and the corresponding naphthalene and pyridine derivatives result from flash vacuum pyrolysis of adducts such as (36) (Scheme 12).70X-Ray analysis confirms the structure of the [2 + 41 adduct (37)

qx., 0

1 ,

(36) Reagents: i, Pb(OAc),, anthracene; ii, flash vacuum pyrolysis

Scheme 12

that results from the ready isomerization of the initially formed [4 + 21 adduct (38) from N-ethoxycarbonylazepine and a cyclopentadienone d e r i ~ a t i v e . ~ ~ Silver-fluoroborate-inducedrearrangement of the N-chloramine (39) gives an isolable immonium intermediate, which, upon reduction by a hydride, gives a 92% yield of 8-coniceine (40).72 The endo-tosylates (41) fragment some

(37)

69

70

71

72

A. G. Schultz, M. Shen, and R. Ravichandran, Tetrahedron Lett., 1981,22, 1767. G. W. Gribble, R. W. Allen, C. S. LeHoullier, J. T. Eaton, N. R. Easton, Jr., R. I. Slayton, and M. P. Sibi, J. Org. Chem., 1981,46,1025. K. J. Gould, N. P. Hacker, J. F. W. McOmie, and D. H. Perry, J. Chem. SOC.,Perkin Truns. I ,

1980,1834. M. Yasuda, K. Harano, and K. Kanematsu, J. Org. Chem., 1980,45,2368. F. M. Schell and R. N. Ganguly, J. Org. Chem., 1980,45,4069.

376

Heterocyclic Chemistry

lo3-l O4 times faster than the corresponding carbocyclic tosylates because the anti-periplanar arrangement of the C(4)-OTs bond and the electron pair at nitrogen [relative to the C(2)-C(3) bond] allows synchronous fragmentation and a resulting increase in reactivity (a frangomeric effect). The importance of C-C hyperconjugative and inductive effects in determining the relative reactivity of analogues, including the corresponding exo -tosylates, is discussed by G r ~ b . ~ ~ Bridged Annulenes, Cyclazines, and Propel1anes.-Vogel has reviewed the area of bridged a n n ~ l e n e and s ~ ~has ~ prepared the bridged [14lannulene (42).74bThis work includes the observation of the intriguing irreversible isomerization of the dihydro-[14]annulene shown in Scheme 13, which is catalysed by alumina. One of the products isolated from addition of arylnitrile oxides to benzocyclopropene has the structure (43) [which is preferred to the 'open' tautomer (44)].75 H

H

Scheme 13 H

Synthesis and substitution reactions of the N-bridged v-systems (45) and (46)76have been described and other cycl[3.2.2]azines result from cyclization of dimethyl acetylenedicarboxylateto indolizine~.~~ Perhydroboraphenalene (47) has been converted into hippodamine (48)and related amines and amine oxide~;'~" isopropyleine (49)has been found to equilibrate rapidly with propyleine Routes to systems that contain additional heteroatoms, e.g. ( 5 1),79

8 X/ R

(45a) X = CR,R = NO2 (45b) X = N, R = H 73 74

75 76

77

78

7q

(46)

Hp

(47) X (48)X

= B, R = = N, R = C . A. Grob, M. Bolleter, and W. Kunz, Angew. Chem., Int. Ed. Engl., 1980, 19, 709.

H

Me

( a ) E. Vogel, Isr. J. Chem., 1980, 20, 215; (6) E. Vogel, U. Brocker, and M. Junglas, Angew. Chem., Int. Ed. Engl., 1980, 19,1015. M. Nitta, S. Sogo, and T. Nakayama, Fukusokan Kagaku Toronkai Koen Yoshishu 12th, 1979,266. M. A. Jessep and D. Leaver, J. Chem. SOC., Perkin Trans. 1, 1980, 1319 and 1324. T. Uchida and K. Matsurnoto, Chem. Lett., 1980, 149; K. Matsumoto, Y. Ikerni-Kono, T. Uchida, and L. A. Paquette, Fukusokan Kagaku Toronkai Koen Yoshishu 12th, 1979, 101. R. H. Mueller and M. E. Thompson, Tetrahedron Lett., 1980, 21, ( a )p. 1093; (6) p. 1097. E. Gossinger, Monatsh. Chem., 1980,111, 783.

377

Bridged Systems

(49) R' (50)

=

H; A3a,4

(52)

R2 = H; A3v3a

X

= NH, N-alkyl, N-aryl,

C(CO~R)Z, or C C N h (52),80and (53)," are recorded. The cycloaddition products which result from interception of the unstable pyrrolo[l,2-c]thiazole (54) depend on the choice of dienophile (Scheme 14).'*

E

E

Me

Me (54)

E

E

L

(E = COZMe)

E&TJ-.$h Me

Reagents: i, Ac,O; ii, EC=CE; iii, N-phenylmaleimide

0

Scheme 14 Et

R (53) R

=

(55)

CN or C02Me

The 3-aza[4.4.4]propellane (55) is formed by rearrangement of a bridged isoquinolineE3and the dianion of N-methylphthalimide is employed in an attractive synthesis of (56) (Scheme 15).84 The stereoselectivity for syn- and anti-

Reagents: i, Li, NH,, at -78 "C; ii, BrCH2CH2CH2Br

Scheme 15 E. M. Kosower, B. Pazhenchevsky, H. Dodiuk, M. Ben-Shoshan, and H. Kanety, J. Org. Chem., 1981,46,1673. 'I S. Kanemasa, S. Nakamura, and S. Kajigaeshi, Chem. Lerr., 1980, 947. '' J. M. Kane, J. Org. Chem., 1980, 45, 5396. 83 B. C. Uff, M. J. Powell, and A . C. W.Curran, J. Chem. Sue., Chem. Cummun., 1980, 1059. 84 G. A. Flynn, J. Chem. Soc., Chem. Cummun., 1980, 862. 80

378

Heterocyclic Chemistry

isomers in the Diels-Alder reactions of a series of propellanes, e.g. (57), has been rationalized, using a frontier M.O. approach, substantiated by extended Hiickel calculations.*’ Cyclic oligomers of propellanes and bridyd annulenes with (58) have been made86abut an attempt at dehydrogenation of (59) was Azapropellanes have been proposed as potential chiral phasetransfer catalysts.87 0

Bridged Azoa1kanes.-A wide range of bridged azoalkanes continues to be made, usually via cycloaddition of triazolinediones to bicyclic alkenes.88 Intramolecular [2 + 23 addition of (60) gives the cage compound (61).89Major interest remains focussed on thermal and photochemical decomposition of azoalkanes3and the behaviour of the resulting biradicals; the decomposition of (62),90of (63),9’of (64),92of (65),93of (66) and related and of ‘reluctant’ diazoalkanes (67)95is recorded. A ‘one-pot’ synthesis of semibullvalenes has been achieved which involves (68) as an intermediate.96 Time-

+Yfg

”

Np4 N

(62)N

(61)

(60)

N

II

/

A? (63)

@

--

\

(64) 85

(65)

(66)

M. C. Bohm and R. Gleiter, Tetrahedron, 1980, 36, 3209. ( a ) P. Ashkenazi, R. D. Macfarlane, W. A. Oertling, H. Wamhoff, K. M. Wald, and D. Ginsburg, Angew. Chem., Znt. Ed. Engl., 1980, 19, 933, 936; ( 6 ) M. Peled, J. Kalo, and D. Ginsburg, Heterocycles, 1981, 15, 459. 87 J. W. McIntosh. Can. J. Chem., 1980, SS, 2604. 88 W. Adam, 0. DeLucchi, and I. Erden, J. A m . Chem. SOC.,1980,102,4806. 89 L. A. Paquette, R. V. C. Carr, P. Charumilind, and J. F. Blount, J. Org. Chem., 1980, 45, 4922. 90 D. A. Chichra, C. D. Duncan, and J. A. Berson, J. A m . Chem. SOC.,1980, 102, 6527. 91 P. S. Engel and C. J. Nalepa, Pure Appl. Chem., 1980, 52, 2621. ” J. W. Wilt and R. Niinemae, J. Org. Chem., 1980, 45, 5402. 93 W. Adam and 0. DeLucchi, Angew. Chem., Int. Ed. Engl., 1981,20,400. y4 R. Jose1 and G. Schroder, Liebigs Ann. Chem., 1980, 1428. 95 W. Adam and F. Mazenod, J. A m . Chem. SOC.,1980,102,7131. 96 D. Paske, R. Ringshandl, I. Sellner, H. Sichert, and J. Sauer, Angew. Chem., Znt. Ed. Engl., 1980, 19,456. 86

Bridged Systems

379

resolved and polarization e.s.r. studies of the biradical from (69) have been made. ’’

4 Oxygen-containing Compounds Synthesis.-Cycluadditions. Examples of intramolecular photochemical [2 + 21 additions of alkenes to carbonyl groups are selected in Scheme 16,98-101together with a route to the tetracyclic ether (70). The efficiency of the intramolecular

@

hv_

88 +

Ref.98

Ref. 99

(R = H or Me)

Ref. 100

(R = H or Me)

Ref. 101

(70) Scheme 16 97

98

99 loo

W. P. Chisholm, S. I. Weissman, M. N. Burnett, and R. M. Pagni, J. Am. Chern. SOC.,1980,102,

7103. ( a ) J. Kossanyi, P. Jost, B. Furth, G . Daccord, and P. Chaquin, J. Chem. Res. ( S ) , 1980,368; ( b ) P.Jost, P. Chaquin, and 3. Kossanyi, TetrahedronLett., 1980,21,465. M. Yoshika, K. Ishii, and H. R. Wolf, Helv. Chirn. Actu, 1980,63, 571. T. Sasaki, S. Eguchi, and T. Suzuki, J. Org. Chem., 1980,45,3824. A. Gilbert and G. N. Taylor, J. Chern. Soc., Perkin Trans. 1, 1980,1761.

He terocy c 1ic Chemistry

380

toluene reflux

___*

addition to the furan nucleus of (71) is highly dependent on the presence of intramolecular hydrogen-bonding.'02 An intriguing cycloaddition/cycloreversion sequence is shown in Scheme 17 in which thermal ring-opening of the oxiran yields a carbonyl ylide; intramolecular addition gives (72), which breaks apart to give a p r o d u ~ t . " ~

at

120 "C

o x

CN

(72) X = C02Me

Scheme 17

A synthesis of cantharidin (73)Io4 uses a furan cycloaddition as a key step, and the hexano-oxepin (74)Io5has furanoid origins (Scheme 18). Adducts of furans with fluoroallene,lo6with bistrimethylsilyl allenedicarb~xylate,'~~ with di-t-butyl acetylenedicarboxylate,108with mixed anhydrides of acetylenedicarb ~ x y l a t e , "with ~ spiropentene,l10and with oxoallyls"' are noted, together with photochemical addition of furan to benzene1I2 and the efficient conversion of

+$044@o 0

S 0 102

'07

S

0 (73)

T. Mukaiyama and T. Takebayashi, Chem. Lett., 1980, 1013. J. Brokatzky and W. Eberbach, Chem. Ber., 1981,114,384. W. G.Dauben, C. R. Kessel, and K. H. Takemura, J. A m . Chem. SOC., 1980,102,6893. W.Tochtermann and P. Rosner, Tetrahedron Lett., 1980,21,4905. W.R.Dolbier, Jr., and C. R. Burkholder, Tetrahedron Lett., 1980,21,7 8 5 . T. Suzuki, S. Kagaya, A. Tomino, K. Unno, and T. Kametani, J. Chem. SOC.,Perkin Trans. 1,

1980,2801.

G.Weber, K.Menke, and H. Hopf, Chem. Ber., 1980,113,531. G.Maier and W. A. Jung, Tetrahedron Lett., 1980,21,3875. 'lo

'I1

'I2

R. Bloch and J.-M. Denis, Angew. Chem., Int. Ed. Engl., 1980,19,928. Commun., 1980, 1119;M.

J. Mann and A. A, Usmani, J. Chem. SOC.,Chem. H. M. R. Hoffmann, Org. Synth., 1978,58,17.

R. Ashcroft and

J. C. Berridge, A. Gilbert, and G. N. Taylor, J. Chem. SOC.,Perkin Trans. 1, 1980,2174.

38 1

Bridged Systems

Scheme 18

furan into the synthon (75)."' Interest continues in the synthesis of C-nucleosides from fur an^."^ Factors that control stereoselectivity in the cycloaddition of isobenzofurans to cycl~propenes'~~ and to 7-isopropylideneben~onorbornadienes~'~ have been discussed. Cycloheptatrienylidene"' and a benzocyclo-octatrienyne"' have been intercepted by 1,3-diphenylisobenzofuranto give the adducts (76) and (77) respectively; isobenzofuran derivatives have also been of value in the stereo- and regio-controlled synthesis of Podophyllum 1ignar1s.l'~The adducts (78) from benzyne and oxazoles lose MeCN, and the resulting isobenzofurans react with a secwd benzyne to give (79).120

0

(77)

Ph (78)

(79)

Control by frontier orbitals has been invoked in the formation of endo-[2 + 41 and exo-[6 + 41 adducts from oxepin and derivatives of cyclopentadienone.12' Oxepins have also been allowed to react with pyrazolones.l** ortho-Quinones act as hetero-dienes in additions to quadricyclanes, 123 and the a@ -unsaturated aldehyde unit in 2,6-dimethylocta-2,7-dienal plays the role

'14

'IS '16

'la

'Iy 120 121

123

C. Mahairn, P.-A. Carrupt, J.-P.Hagenbuch, A. Florey, and P. Vogel, Helv. Chim. Actu, 1980, 63, 1149. T. Sat0 and R. Noyori, Bull. Chem. SOC.Jpn., 1980, 53, 1195; T. Sato, M. Watanabe, and R. Noyori, Chem. Lett., 1980,679;Heterocycles, 1980,14,761; T. Sato, H. Kobayashi, and R. Noyori, ibid., 1981, 15, 321. V. V. Plernenkov, Kh. Z. Giniyatov, Ya. Ya. Villern, N. V. Villern, L. S. Surrnina, and I. G. Bolesov, Dokl. Akud. Nuuk SSSR,1980,254, 895. T. Sasaki, K. Hayakawa, T. Manabe, and S. Nishida, J. A m . Chem. SOC.,1981,103,565. K. Saito, Y. Omura, and T. Mukai, Chem. Lett.. 1980, 349. H. N. C. Wong and F. Sondheirner, Tetrahedron Lett., 1980, 21, 983. R. Rodrigo, J. Org. Chem., 1980, 45,4538. G. S. Reddy and M. V. Bhatt, Tetrahedron Lett., 1980, 21, 3627. T. Ban, Y.Wakita, and K. Kanernatsu, J. A m . Chem. SOC.,1980,102,5415. T. Ban and K. Kanematsu, Heterocycles, 1981, 15, 373. E. Biildt, T. Debaerdemaeker, and W. Friedrichsen, Tetrahedron, 1980,36,267.

Heterocyclic Chern is try

382

of diene in a Lewis-acid-catalysed intramolecular Diels-Alder reaction which yields (80).124An aryl aldehyde is the 277 component in an intramolecular addition to an o-xylylene moiety (formed in situ) which results in formation of the ketal (81).'*'

(81) R = !%Me3

3-Oxidopyrylium is the key intermediate in the synthesis of (82),126a and the oxidopyrylium trimer (83) rearranges thermally to the doubly oxygen-bridged cyclodecadienedione (84)126b (Scheme 19).

Scheme 19

Synthesis by Miscellaneous Other Methods. A general method for the preparation of a-lithio-ethers forms the basis of a short, practical synthesis of brevicomin (85).127 Hydroxymercuration of non-conjugated dienes in aqueous micelles gives cyclic ethers, e.g. (86).12*Two approaches to lineatin (87) have been described,129

12'

12Y

B. B. Snider and J. V. Duncia, J. Org. Chem., 1980, 45, 3461. R. L. Funk and K. P. C. Vollhardt, J. A m . Chem. SOC., 1980,102, 5245. J. B. Hendrickson and J. S. Farina, J. Org. Chem., 1980, 45, ( a )p. 3359; ( b )p. 3361. T. Cohen and J. R. Matz, J. A m . Chem. SOC.,1980, 102, 6900. See also E. Murayama, K. Nagayoshi, and T. Sato, Kokagaku Toronkai Koen Yoshishu, 1979,196, for another synthesis. C. M. Link, D. K. Jansen, and C. N. Sukenik, J. A m . Chem. SOC., 1980, 102, 7798. K. N. Slessor, A. C. Oehlschlager, B. D. Johnston, H. D. Pierce, Jr., S. K. Grewal, and L. K. G . Wickremesinghe, J. Org. Chem., 1980, 45, 2290; K. Mori and M. Sasaki, Tetrahedron, 1980, 36, 2197.

Bridged Systems

383

syntheses of the trichothecane-like compounds (88)”’ and (89)”’ have been reported, and Still’s total synthesis of trichodermol (90) has a biomimetic theme. 32

A number of syntheses based on cyclization of nucleophilic oxygen are shown in Scheme 20. There is evidence in favour of early participation of oxygen in the formation of (91).13’

a A 2

Ref. 133

SbFi

0

-

P H +

iii

CO,H

H

0 Ref. 134

(91)

Ref. 135

Reagents: i, AgSbF,, CH2C12,at -20 “C; ii, MeMgI; iii, PhSeC1, Et,O; iv, HCl, THF

Scheme 20

Mechanistic studies of the hydrolysis of bicyclic acetals (92),136and of the bicyclic orthoesters (93a) and (94),13’ are noted, as is the use of (93b) as a carboxy function in the synthesis of alkyl-cobaloxime derivatives.13’

(92) 130 13’ 13’ 133

134

13’

13’

13*

(93a) R = aryl (93b) R = various groups

(94)

W. R. Rousch and T. E. D’Ambra, J. Org. Chem., 1980,453921. D. J. Goldsmith, T. K. John, C. D. Kwong, and G. R. Painter, 111, J. Org. Chem., 1980, 45, 3989. W. C. Still and M.-Y. Tsai, J. A m . Chem. SOC.,1980,102,3654. 3. P. BBguC, M. Charpentier-Morize, D. Bonnet-Delpon, and J. Sansoulet, J. Org. Chem., 1980, 45, 3357. D. L. J. Clive, C. G. Russell, G. Chittattu, and A. Singh, Terrahedron, 1980, 36, 1399. C. W. Doecke and P. J. Garratt, Tetrahedron Lett., 1981, 22, 1051. S. R. Wann and M. M. Kreevoy, J. Org. Chem., 1981,46,419. ( a ) R. A. McClelland, S. Gedge, and J. Bohonek, J. Org. Chem., 1981,46,886; ( b )P. W. K.Lam and R. A. McClelland, J. Chem. SOC.,Chem. Commun., 1980,883. M. P. Atkins, B. T. Golding, D. A. Howes, and P. J. Sellars, J. Chem. SOC.,Chem. Commun., 1980,207.

Heterocyclic Chemistry

384

Bridged Peroxides.-Paquette's comprehensive studies of stereoselectivity of capture of singlet oxygen continue, with investigations into the behaviour of (95)139a and related and into factors controlling the reactivity of (96) towards ozone and singlet and triplet oxygen.14oAddition of singlet oxygen to an enol ether of methyl phenylpyruvate affords the adduct (97);141primary [4 + 21 addition followed by an ene reaction gives (98)from hexamethylbenzene.'42

& 4

RH

(95a) R = H (95b) R = H; A".'

p 2 Y e O'O

H

(97)

(96)

Autoxidation of methyl linoleate is selective, giving only two major isomers of (99) in the bicyclic endoperoxide fraction;143 studies on prostaglandin endoperoxides ~ 0 n t i n u e . Thermal, l~~ reductive, and oxidative transformations of endoperoxides that are derived from cycloheptatrienes and from various n o r - ~ a r a d i e n e s l ~and ~ ~ from bicycl0[4.2.0]octa-2,4,7-triene~~~~ have been reported. Thermal decomposition of (100) gives the oxiran (101),146aand an unstable aziridinedione results from photolysis of (102) at 77 K.'46" Selective cleavage of the C-0 bond of the peroxide bridge occurs when (103) decomposes in the presence of chlorosulphonic although the pentaoxa-

OOH

OOH (99)

(102) R 139

'41

14' 142

143

144 145

'41

'41

=

H or alkyl

( a ) L. A. Paquette, R. V. C. Carr, E. Arnold, and J. Clardy, J. Org. Chem., 1980, 45, 4907; ( 6 ) L. A. Paquette, F. Bellamy, M. C. Bohm, and R. Gleiter, ibid., p. 4913. L. A. Paquette and R. V. C. Carr, J. A m . Chem. SOC.,1980,102,7553. H. Kotsuki, I. Saito, and T. Matsuura, Tetrahedron Lett., 1981, 22, 469. C. J. M. van den Heuvel, A. Hofland, H. Steinberg, and Th. J. de Boer, Red. Trav. Chim. Pays-Bas., 1980, 99, 275. D. E. O'Connor, E. D. Mihelich, and M. C. Coleman, J. A m . Chem. SOC.,1981, 103,223. e.g. M. G. Zagorski and R. G. Salomon, J. A m . Chem. SOC., 1980, 102, 2501. ( a ) W . Adam, M . Balci, B. Pietrzak, and H. Rebollo, Synthesis, 1980, 820; ( 6 ) W. Adam, 0. Cueto, and 0. D e Lucchi, J, O r g . Chem., 1980, 45, 5520. ( a ) M. L. Graziano, M. R. Iesce, and R. Scarpati, J. Chem. Soc., Perkin Trans. 1, 1980, 1955; (6) H. Aoyama, M. Sakamoto, and Y. Omoto, J. Am. Chem. SOC., 1980,102,6903. ( a ) M. Miura, M. Nojima, and S. Kusabayashi, J. Chem. Soc., Perkin Trans. 1, 1980, 2909; (6) M. Miura, A. Ikekami, M. Ikekami, M. Nojima, and S. Kusabayashi, J. Chem. SOC.,Chem. Commun., 1980, 1279.

Bridged Systems

385

bicyclo[5.3. llundecane (104) is amongst the products when aryl aldehydes are present.'476 Studies of the thermal, p h o t o ~ h e m i c a l , ~and ~ ~ "hydrolyti~'~~' behaviour of endoperoxide derivatives of polycyclic benzenoid hydrocarbons are noted. The compound (105) is a convenient, water-soluble source of singlet oxygen under mild condition^.'^^ I

The endoperoxide (106) arises either from catalysed cyclization of 6-methylhept-6-en-2-one and H 2 0 2or from interception with O2 of the triplet biradical that is generated by laser-photosensitized decomposition of (107); frontalin (108) is formed exclusively when (106) is photolysed under conditions of triplet sensitization.'so Isomerization of (109) in the presence of catalytic amounts of natural bases, e.g. (+)-quinidine, provides chiral y-hydroxy-ap-unsaturated aldehydes (110) with enantiomeric excesses of up to 46%?

Bridged Systems that contain Other Heteroatoms

1,l'-Thiocarbonylbis-( 1,2,4-triazole) adds to a variety of dienes, affording good yields of bicyclic sulphides, e.g. (lll).152 Synthesis of the fungal metabolite hyalodendrin (112) and related compounds has been described153 and naphtho[2,3-~]thiophen(113) has been prepared and trapped with N-phenylrnaleimide.ls4

phcH2Y?--?- oH 0

MeN S--

R& (111) R

=

S 1,2,4-triazol-l-yl

\ \ - - -

0

(1 13)

(112) 14*

149

150 151

15*

15'

( a ) A. Lopp and M. Gubergrits, Zh. Obshch. Khim., 1981,51,225; R. Schmidt and H. D. Brauer, J. Photochem., 1981, 15, 85; D. Sparfel, F. Gobert, and J. Rigaudy, Tetrahedron, 1980, 36, 2225;

( b )J. Santamaria and J. Rigaudy, ibid.,p. 2453. I. Saito, T. Matsuura, and K. Inoue, J. A m . Chem. SOC.,1981,103, 188. R. M. Wilson and J. W. Rekers, J. A m . Chem. SOC.,1981,103, 206. J. P. Hagenbuch and P. Vogel, J. Chem. SOC.,Chem. Commun., 1980,1062. C. Larsen and D. N. Harpp, J. Org. Chem., 1980,45,3713. R. M. Williams and W. H. Rastetter, J. Org. Chem., 1980, 45, 2625; J. D. M. Herscheid, R. J. F. Nivard, M. W. Tijhuis, and H. C. J. Ottenheijm, ibid., p. 1885. J. Bornstein, R. P. Hardy, and D. E. Remy, J. Chem. Soc., Chem. Commun., 1980,612.

386

Heterocyclic Chemistry

A number of germanium-bridged adducts (114) have been added to the examples in last year’s Report;”’ thermal decomposition gives naphthalenes and polygermanes. Photolysis of the adduct (115) yields the strained diphosphabenzvalene (116) via an intermediate 1,4-diphosphabenzene. lS6 0-Arylated phospholans, e.g. (117), are obtained with surprising ease by treating phospholens, e.g. (118),with benzene or chlorobenzene, in the presence of A1Cl3, at ambient temperat~re.’~’

R

*h p Ph

\

Ph

/

R

X

‘

R

(114) R

=

H o r alkyl

x

X >P$Me

y! X

(115)

X

(X

=

CF3)

)..IX X

(116)

9-Borabicyclo[3.3. llnonanes have been used in the stereospecific synthesis of conjugated enyne~,l’*~ of methylenecycloalkanes from c y ~ l o a l k e n e s , ~and ’~~ in the hydroboration of styrenes15’ and the synthesis of methoxycyclopropanes.160 The 9-pinanyll6la and 3-pinanyl161bderivatives have seen use as asymmetric reducing agents, and a new procedure for making 1,4-dienes and monoalkenes involves methylcopper-induced cross-coupling of 9-alkenyl-9borabicyclo[3.3. llnonanes. 162

155 156

15’

159

‘‘I

162

W. P. Neumann and M. Schriewer, Tetrahedron Letf.,1980, 21, 3273.

Y. Kobayashi, S. Fujino, H. Hamana, Y. Hanzawa, S. Morita, and I. Kumadaki, J. Org. Chem., 1980,45,4683. J. E. MacDiarmid and L. D. Quin, J. Org. Chem., 1981, 46, 1451. ( a )H. C. Brown and G. A. Molander, J. Org. Chem., 1981, 46, 645; ( b ) H. C. Brown and T. M. Ford, ibid., p. 647. L. C. Vishwakarma and A. Fry, J. Org. Chem., 1980,45, 5306. N. Miyaura, T. Yoshinari, M. Itoh, and A. Suzuki, Tetrahedron Lett., 1980, 21, 537. ( a )M. M. Midland, D. C . McDowell, R. L. Hatch, and A. Tramontano, J. Am. Chem. Soc., 1980, 102, 869; ( b ) M. M. Midland and A. Tramontano, Tetrahedron Lett., 1980, 21, 3549. H. Yatagai, J. Org. Chem., 1980, 45, 1640.

Errata

Volume 2 p. 166: formulae (227), (228), and (229) should all have been shown to be the products obtained from (226). The key ‘Ar = p-C1CsH4’ applies to all three products. p. 184: The compound obtained from (431) should have been labelled ‘(432)’. p, 220: both (861) and (862) were obtained from (860), as should have been shown by a ‘ + ’ sign between them. p. 295: the reagents that effected the conversion of (117) into (118) should have been shown as HCHO, H’. p. 393: the reaction that is effected by reagent v of Scheme 12 is described in Ref. 83.

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