Heterocyclic Chemistry (v. 1)

Heterocyclic Chemistry Volume 1

A Specialist Periodical Report ~~

Heterocyclic Chemistry Volume 1

A Review of the Literature Abstracted between July 1978 and June 1979

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 G. P. Ellis UWIST, Cardiff S. Gronowitz University of Lund, Sweden D. Le Count ICI Pharmaceuticals, Macclesfield, Cheshire P. A. Lowe University of Salford T. J. Mason Lanchester Polytechnic, Coventry J. M. Mellor University of Southampton F. G. Riddell University of Stirling R. K. Smalley University of Salford R. C. Storr University of Fiverpool

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

British Library Cataloguing in Publication Data Heterocyclic chemistry.(Royal Society of Chemistry. Specialist periodical reports). VOl. 1 1. Heterocyclic compounds I. Suschitzky, Hans 11. Meth-Cohn, Otto 111. Series 547'.59 QD400

ISBN 0-85 186-970-X ISSN 0144-8773 RSC Members copy ISBN 0-85404-970-3

Copyright @ 1980 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 Made in Great Britain

In trod uction

Heterocyclic Chemistry represents a vast and important area of research which is of interest to a wide spectrum of chemists. This is amply documented by the fact that various journals, societies, and interest groups have sprung up entirely devoted to the pursuit of heterocyclic chemistry. Surprisingly though, there exists to our knowledge no single periodical review alerting the reader on an annual basis to important developments of the subject. We have now been able to persuade the Royal Society of Chemistry to allow us to remedy this omission with the help of eleven specialists. This new series of Specialist Periodical Reports, apart from making economic sense, will facilitate the finding of information on heterocyclic topics since it combines the material previously reviewed in a piecemeal way in three different series of volumes. These were ‘Saturated Heterocyclic Chemistry’, ‘Aromatic and Heteroaromatic Chemistry’ (both of which are now discontinued), and the still thriving volume on ‘Organic Compounds of Sulphur, Selenium, and Tellurium’, which has surrendered its heterocyclic parts but will continue to report on P-lactam antibiotic chemistry. The literature coverage is essentially based on volumes 89 and 90 (i.e.July 1978 to June 1979) of Chemical Abstracts, but, in order to provide continuity between this new series and previous (now deleted) reports, the period covered in certain chapters was extended accordingly. Our authors have endeavoured to include all significant contributions in a selective and concise rather than an encyclopaedic manner. We have retained the newly introduced format of Volume 7 of the series ‘Aromatic and Heteroaromatic Chemistry’, i.e. proceeding from small to large rings and giving preference to the smaller heterocycle in fused systems. Exceptionally, if the smaller ring is trivial to the chemistry of the annelated system, the larger ring is given priority. In cases of uncertainty, both ring-chapters will carry the information, as we felt this to be a justified overlap. Articles on ‘Bridged Systems’ and ‘Conformation’ have been added because of their relevance to the chemistry of saturated heterocycles. Review references are mostly quoted at the beginning of each chapter, and the contents list has been drawn up with the aim of serving as a broad index for easy location of points of interest. In future issues it is hoped to follow similar schemes in each chapter as far as possible. We intend to include reviews on specific topics of current interest from time to time. Our authors provided us with the manuscripts in good time and we thank them and the editorial staff of the Royal Society of Chemistry for their efficiency, which made our own task a pleasure.

vi

Introduction

The Senior Reporters, as always, would welcome comments, criticism, and suggestions concerning this new venture.

H. SUSCHITZKY& 0. METH-COHN

Postscript: Owing to a printers’ dispute, the publishing date of this volume was considerably delayed. This is much regretted. Volumes in this series are normally scheduled to appear in the early Summer.

H.S. & 0.M.-C.

Contents ~

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

1 Oxirans Preparation Catalytic Oxidation of Alkenes, using Oxygen or Oxygen-containing Gases Oxidation of Alkenes by Peroxy-acids Catalytic Oxidation of Alkenes, using Peroxides Halohydrin Cyclizations and Related Reactions Syntheses Related to the Darzens Reaction Synthesis of Chiral Oxirans Synthesis of Fused Aromatic Oxides Miscellaneous Syntheses Spectra and Theoretical Chemistry Reactions Electrophilic Ring-opening Kinetic studies Cyclization reactions Miscellaneous reactions Nucleophilic Ring-opening With oxygen and nitrogen nucleophiles With carbanions Reduction and Elimination Thermal and Photochemical With Organometallic Compounds Miscellaneous

1 1 1 1 3 4

6 7 8 10 11 12 13 14 14 14 16 17 17 18 19 21 22 24

2 Oxirens

25

3 Aziridines Preparation Direct Insertion Cyclizations via Ring Contraction Spectroscopic and Theoretical Studies Reactions Retention of the Aziridine Ring Ring-opening to Acyclic Compounds Formation of other Ring Systems

26 26 26 27 28 29 30 30 31 32

4 Azirines Preparation

34 34

...

Heterocyclic Chemistry

Vlll

Reactions Photochemical and Thermal Cyclization to Five- and Six-membered Heterocyclic Systems With Metal Carbonyls

35

35 36 37

5 Thiirans Preparation Reactions Chemistry of Thiiranium Ions

38 38 39 39

6 Thiirens

40

7 Diaziridines

41

8 Diazirines

42

9 Oxaziridines

42

10 Thiazirines Chapter 2 Four-membered Ring Systems By R. C. Storr

44 45

1 Reviews

45

2 Systems containing One Nitrogen Atom Azetidines and Azetines Azetidinones

45 45 47

3 Systems containing Two Nitrogen Atoms

53

4 Systems containing One Oxygen Atom Oxetans 2-Oxetanones (p-Lactones)

56

5 Systems containing Two Oxygen Atoms Dioxetans

59 59

6 Systems containing Sulphur

63

7 Miscellaneous

66

Chapter 3 Five-membered Ring Systems

56 58

67

By G. V. Boyd, P. A. Lowe, and S. Gronowitz Part I Thiophens and their Selenium and Tellurium Analogues By S. Grono wit2

67

1 General

67

2 Monocyclic Thiophens Synthesis by Ring-closure Reactions

68 68

ix

Contents

Physical Properties Electrophilic Substitution Electrophilic Ring-closure Reactions Nucleophilic Substitution Organometallic Derivatives Cycloadditions and Photochemistry The Structure and Reactions of Hydroxy-, Mercapto-, and Amino-thiophens Side-chain Reactivities Carbene and Nitrene Reactions ‘Benzylic’ Reactivity Reactions of Thiophen Aldehydes and Ketones Reactions of Carboxy- and Cyano-thiophens Various Side-chain Reactions Reaction at Sulphur: Thiophen Dioxides Di- and Tetra-hydrothiophens Bi- and Poly-heterocycles Naturally Occurring Thiophens Thiophen Analogues of Steroids Thiophens of Pharmacological Interest

3 Benzothiophens and their Benzo-fused Systems Synthesis of Benzothiophens Physical Properties Substitution Reactions Side-chain Reactions Benzo[b]thiophen S-Oxides Benzo[c]thiophens Dibenzothiophens Pharmacologically Active Compounds

4 Thiophen Analogues of Polycyclic Aromatic Hydrocarbons Analogues of Phenanthrene Analogues of Phenalenes and Phenalenium Ions Thiophen-fused Tropylium Ions and Related Compounds 5 Thiophens Fused to Five-membered Heteroaromatic Rings Thiophen- and Pyrrole-fused Thiophcns, and Related Compounds Pyrazole-, Thiazole-, and Isothiazole-fused Thiophens and Related Systems 6 Thiophens Fused to Six-membered Aromatic Heterocyclic Rings Thiophen Analogues of Quinoline Thiophen Analogues of Isoquinoline

73 74 75 76 77 78 79 81 82 84 85 86 87 87 88 90 93 93 95 97 97 97 97 99 100 100 100 101 101

101 102 103 103 103 104

105 105 105

Heterocyclic Chemistry

X

Pyrimidine-fused Systems Pyrazine- and Triazine-fused Systems Miscellaneous Fused Systems

7 Selenophens and Tellurophens Monocyclic Selenophens Benzoselenophens and their Benzo-fused Derivatives Selenophens Fused to Five-membered Aromatic Rings Selenophens Fused to Six-membered Aromatic Rings Tellurophens Part II Systems containing Nitrogen and Sulphur, Selenium, or TelIur ium ByP. A. Lowe

106 107 107 107 107 108 108 109 109 109

1 Introduction and Reviews

109

2 Isothiazoles Synthesis From Oxathiazolones (Type B) (Type B) From Meso-ionic 1,3,2-0xathiazolium-5-olates From P- Amino-cinnamates (Type C) From Enamines and Isothiocyanates (Type C) From Benzothiazolyldithioazetidinone(Type C) From Thione-S-imides (Type D) From Enamines and Perchloromethanethiol (Type E) From y- Hydroxy-alkenesulphonamides(Type F) Physical Properties Chemical Properties Alk ylation Nucleophilic Reactions Cycloaddition

110 110 110 111 111 111 112 112 112 112 113 113 113 113 113

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

114 114 115

4 1,2-Benzisoselenazoleand 1,2-Benzisotellurazole

116

5 2,l-Benzisothiazoles

116 117 117

6 Other Condensed Ring Systems incorporating Isothiazole Thieno[3,4-c]isothiazoles Furano-, Thieno-, Pyrrolo-, and Pyrazolo[4,5 -d]isothiazoles Thiazolo[4,5 -c]isothiazole Isothiazolo[4,5-b]pyrazines Cyclohept a[ c ]is0t hiazole Pyrido[3’, 2’ :4,5]thieno[3,2-c ]is0 thiazole Isothiazolo[4,3-c]quinolines

117 117 117 117 118 118

Contents

xi Isothiazolo[5,4-b]quinoline Naphtho[ 1,2-d]isothiazoIe Naph tho[ 2,l -d]isothiazole Miscellaneous 7 Thiazoles Synthesis Hantzsch's Synthesis (Type A; S-C-N + S) Type C Syntheses (C-C-N-C Type F Syntheses (C-N-C-S + C) Type G Syntheses (N-C-S-C-C) Type J Syntheses (C-S-C-N-C) Type K Syntheses (C-C-N-C-S) Synthesis of Meso-ionic Thiazoles Miscellaneous Physical Properties Chemical Properties Electrophilic Reactions Nucleophilic Reactions Homolytic Reactions Photochemistry Reactions of 2-Amino-thiazoles Reactions of Thiazolium Salts Reactions of Meso-ionic Thiazoles Miscellaneous

118 118 118 119

+ C-C)

119 119 119 120 120 121 121 121 121 122 122 123 123 123 123 123 124 125 125 125

8 A'-Thiazolines Synthesis + C-S) Type B Syntheses (C-C-N Type E Syntheses (N-C-C-S + C) Type K Syntheses (C-C-N-C-S) Physical Properties Chemical Properties

125 125 125 126 126 126 126

9 A3-Thiazolines

127

10 A4-Thiazolines Synthesis Reactions

127 127 127

11 Thiazolidines Synthesis Type A Syntheses (S-C-N + C-C) Type B Syntheses (C-C-N + C-S) + S) Type C Syntheses (C-C-N-C Type D Syntheses (C-C-S + C-N) Type E Syntheses (N-C-C-S + C) Type G Syntheses (C-C-S-C-N) Physical Properties

128 128 128 128 128 128 129 129 129

xii

Heterocyclic Chemistry Chemical Properties Rhodanines, Isorhodanines, and Thiorhodanines

130 131

12 Selenazoles

132

13 Benzothiazoles Synthesis From ortho-Amino-benzenethiols (Type A; S-C6H4-N + C) Type B Syntheses (C6Hs-N-C-S) Type C Syntheses (NhC6H4-S-C) Type G Syntheses (C6H5-s-c-N) + S Syntheses Type C6Hs-N-c Physical Properties Chemical Properties Substitution Reactions Addition Reactions Alkylation Reactions of Thiazolium Salts Ring-cleavage Reactions

133 133 133 134 134 134 135 135 136 136 137 138 138 139

14 Condensed Ring Systems incorporating Thiazole Structures comprising Two Five-membered Rings ( 5 3 ) Thiazolo[2,3-e]tetrazoles [CN4-C3NS] Thiazolo-[2,3-c]- and -[3,2-b]-[1,2,4]triazoles [C~NJ-CWI Thiazolo[3,4,-c]oxazole [C3NO-C3NS] Thiazolo[4,5-d]thiazoles [C3NS-C3NS] Pyrazolo[3,4-d]thiazole [C3NS-C3N2] Imidazo[2,1-b]thiazoles [C3NS-C3Nz] Pyrrolo[2,1-b]thiazoles [C,NS-C4N] Furano[2,3-d]thiazoles [C3NS-C40] Cyclopentenothiazol-6-one[C3NS-C,] Structures comprising One Five-membered and One Six-membered Ring (5,6) Thiazolo[3,2-a]- 1,3,5-triazines [C3NS-C3N3] Thiazolo[4,5 -d]pyridazines [C3NS-C4Nz] Thiazolo[3,2-~]pyrimidines[C3NS-C4N2] Thiazolo-[4,5 -d] - and -[5,441-pyrimidines [C3NS-C4N2] Thiazolo[3,4-a]pyrazines [C3NS-C4N,] Thiazolo[4,5-b]pyrazines [C3NS-C4N2] Thiazolo[3,2-a Ipyridines [C3NS-C5N] Thiazolo[3,4-a]pyridines [C3NS-CSN] Thiazolo[5,4-b]pyridines [C3NS-CSN] Pyrano[4,3-d]thiazoles [C3NS-C50] Structures comprising One Five-membered Ring and One Seven-membered Ring (5,7) Thiazolor4.5-claze~inesTC,NS-C,Nl ~

L

I

2

1

L

a

"

>

139 139 139 139 140 140 140 140 141 141 142 142 142 142 142 143 143 143 143 145 145 145 145 145

...

Contents

Xlll

Structures comprising Two Five-membered Rings and One Six-membered Ring (5,5,6) 1,2,4-Triazolo[3,4- blbenzothiazole [C3N3-C3NS-C6] Thiazolo[2,3-b]benzothiazoles [C3NS-C3NS-C6] Thiazolo[4,5-d]indazole [C3NS-C3N2-C6] Benzo[ 1,2-d ; 3,4-d’]-bis-thiazoles [C3NS-C3NS-C6] Thiazolo[3,2-a]benzimidazoles [C3NS-C3N2-C6] Thiazolo[5,4-c]benzimidazoles [C3NS-C3N2-C6] Imidazo[2,1-b]benzothiazoles [C3NS-C3N2-C6] Thiazolo[3,4-a]indoles [C3NS-C4N-C6] Thia~olo[5,4-b lindoles [C3NS-C4N-C6] Pyrrolo[2,1-b]benzothiazoles [C3NS-C4N-C6] Benzo[b]furano[2,3-d]thiazole [c3Ns-C40-c6] Structures comprising One Five-membered Ring and Two Six-membered Rings (5,6,6) 1,3,5-Triazino[2,1-b]benzothiazole [C3NS-C3N3-C6] 8-Thia-l,4-diazacyc1[3.3.2]azines[C3NS-C4N2-C4N2] Pyrano[4,3-d]thiazolo[3,2-a]pyrimidines [C3NS-C4N2-C50] Pyrimido[2,1-b ]benzothiazoles [c3Ns-c4N2-c6] Thiazolo-[2,3-b]-, - [3,2-a I-, and -[3,2-c]-quinazolines [C,NS-C,N -C6] Thiazolo[4,5- b]&inoxalines [C3NS-C4N2-C6] Thiazolo-[3,2-a]-, -[4,5-g]-, -[5,4-g]-, -[4,5-h]-, and -[5,4-h]-quinolines [c3Ns-c5N-c6] Thiazolo-[2,3-a]- and -[3,4-b]- isoquinolines [C3NS-CSN-CJ Naphtho-[1,2-d]- and -[2,1-d]-thiazoles [C3NS-C6-C6] Other Condensed Systems incorporating Thiazole 15 Thiadiazoles and Selenadiazoles 1,2,3-Thiadiazoles Synthesis Physical Properties Chemical Properties 1,2,3-Selenadiazoles 1,2,4-Thiadiazoles Synthesis Physical Properties Chemical Properties 1,2,4-Selenadiazoles 1,3,4-Thiadiazoles Synthesis Physical Properties Chemical Properties Condensed 1,3,4-Thiadiazoles 1,3,4-Selenadiazoles

145 145 146 146 146 146 147 147 147 147 148 148 148 148 148 149 149 149 150 150 151 152 152 153 153 153 153 154 155 155 155 156 157 158 158 158 159 159 160 160

xiv

Heterocyclic Chemistry 1,2,5-Thiadiazoles Synthesis Physical Properties 2,1,3-Benzothiadiazoles and 2,1,3-Benzoselenadiazoles Physical Properties Chemical Properties 1,2,5-Thiadiazol0[3,4-g]benzofurazan

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

17 Oxathiazoles and Selenathiazoles 1,2,3-0xathiazoles 1,3,2-Oxathiazoles 1,2,4-0xathiazoles 1,3,4-Oxathiazoles 1,3,5-Oxathiazoles 1,2,4-Thiaselenazoles

18 Miscellaneous Ring Systems 1,2,3,4-Thiatriazoles 1,2,3,5-Dithiadiazoles 1,3,2,4-Dioxathiazoles Part Ill Other Five-membered Ring Systems ByG. K Boyd

161 161 161 162 162 162 163 163 163 163 164 164 164 165 165 165 165 166 166 166 166 166 167 167 167

1 Introduction

167

2 Reviews

168

3 Systems with One Heteroatom, and their Benzo-analogues Furans Formation Reactions Benzofurans Formation Reactions Pyrroles Formation Reactions Indoles and Carbazoles Formation Reactions Isoindoles Other Heterocyclic Systems

168 168 168 172 174 174 177 178 178 181 184 184 187 192 193

xv

Contents

4 Systems containing Two Identical Heteroatoms Dioxoles 1,2-Dithioles 1,3-Dithioles Tetrathiaf ulvalenes A Diselenole Pyrazoles Formation Reactions Indazoles Imidazoles Formation Reactions Benzimidazoles and other Annelated Imidazoles

193 193 194 197 199 200 20 1 201 201 204 205 205 205 208

5 Systems containing Two Different Heteroatoms Oxathioles and Oxaselenoles Isoxazoles Formation Reactions Benzisoxazoles Oxazoles Formation Reactions Benzoxazoles Other Systems

209 209 211 211 213 215 2 16 216 217 219 220

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

220 220 220 222

7 Other Systems containing Three Heteroatoms Oxadiazoles 1,2,3-0xadiazoles 1,2,4-0xadiazoles 1,2,5-0xadiazoles 1,3,4-Oxadiazoles Thiadiazoles 1,2,3-Thiadiazoles 1,2,4-Thiadiazoles A 2,1,3-Benzothiadiazole 1,3,4-Thiadiazoles Selenadiazoles 1,2,3-Selenadiazoles Other Selenadiazoles Other Systems in which Two of the Three Heteroatoms are Identical Systems containing Three Different Heteroatoms

223 223 223 224 225 226 226 226 227 228 228 228 228 229 229 232

xvi

Heterocyclic Chemistry

8 Systems containing Four Heteroatoms Tetrazoles 1,2,3,4-ThiatriazoIes Miscellaneous Systems

232 232 233 234

9 Compounds containing Two Fused Five-membered Rings (5,5) Systems containing Oxygen and/or Sulphur Nitrogen Systems Monoaza-compounds Diaza-compounds Triaza-compounds Tetra-aza-compounds Penta- and Hexa-aza-compounds Mixed Oxygen, Nitrogen Systems Other Mixed Systems

235 235 236 236 237 239 239 239 240 241

10 Compounds containing Fused Five- and Six-membered Rings (5,6) Nitrogen Systems Monoaza-compounds Diaza-compounds Triaza-compounds Tetra-aza-compounds Penta- and Poly-aza-compounds Compounds containing Oxygen and Nitrogen Other Mixed Systems

242 242 242 243 245 247 249 250 252

11 Compounds containing Fused Five- and Sevenmembered Rings (5,7) Nitrogen Systems Monoaza-compounds Diaza-compounds Triaza-compounds Tetra- and Penta-aza-compounds Other Systems

252 252 252 253 254 254 255

Chapter 4 Six-membered Ring Systems By G.P. Ellis and R. K. Smalley Part I Azines, Oxazines, and Thiazines By R. K. Smalley

257 257

1 Reviews

257

2 Azines and their Hydro- and Benzo-derivatives Pyridines Synthesis Reactions

258 258 258 263

Conten fs

xvii Hydro-p yridines Quinoline, Isoquinoline, and their Benzo- and Hydroderivatives

3 Diazines and their Hydro- and Benzo-derivatives Pyridazines, Cinnolines, and Phthalazines Pyrimidines and Quinazolines Pyrazines and Quinoxalines Purines, Pteridines, and Related Systems Other Systems with Two Nitrogen Atoms

275 282 293 293 296 304 308 316

4 Triazines and Tetrazines

320

5 Oxazines, Thiazines, and their Benzo-derivatives

323

6 Oxa- and Thia-diazines and Related Systems

327

Part II Other Six-membered Ring Systems By G.P. Ellis

329

1 Books and Reviews

329

2 Systems containing One Oxygen or Sulphur Atom Reduced Pyrans Pyrans Pyrones Preparation Properties Pyrylium salts Thiopyrans Synthesis Reactions Chromans Isochromans Chromenes Chromanones Chromones Thiochromans, Thiochromenes, Thiochromanones, and Thiochromones Flavans and Isoflavans Isoflavenes Flavanones Isoflavanones Flavones Isoflavones Dihydrocoumarins Coumarins Isocoumarins Thiocoumarins Xanthenes

330 330 332 333 333 336 337 340 340 34 1 34 1 343 344 345 346 349 350 350 351 352 353 356 358 358 362 363 363

xviii

Heterocyclic Chemistry

Thioxanthenes Xanthones

364 365

3 Systems containing Two or More Oxygen or Sulphur Atoms Oxathians and their Benzo-derivatives Dioxans and Benzodioxans Dithians and Related Compounds Systems consisting of Two or More Oxygen-containing Rings Cannabinoids Rotenoids Other Natural Compounds Synthetic Compounds Systemscontaining Oxygen and Sulphur in Different Rings

370 370 371 372 374 374

4 Systems containing Phosphorus as a Heteroatom

375

5 Systems containing Silicon or Selenium as Heteroatoms

375

Chapter 5 Seven-membered Ring Systems By D. J. Le Count

367 367 368 370

377

1 Introduction

377

2 Reviews

377

3 Systems containing One Heteroatom One Nitrogen Atom One Oxygen Atom One Sulphur Atom Other Systems

377 377 389 392 395

4 Systems containing Two Heteroatoms Two Nitrogen Atoms Nitrogen and another Heteroatom 0t her Systems

395 395 405 408

5 Systems containing Three or More Heteroatoms

410

Chapter 6 Eight-membered and Larger Ring Systems By G.M. Brooke 1 Eight-membered Rings One Heteroatom Two Heteroatoms

Three or More Heteroatoms 2 Nine- and Ten-membered Heterocycles

411 411 41 1 412 414 416

xix

Contents

3 Macrocycles Systems containing Nitrogen only One Nitrogen Atom Two or Three Nitrogen Atoms Four Nitrogen Atoms Five or More Nitrogen Atoms Systems containing Nitrogen and Other Heteroatoms Systems containing Heteroatoms other than Nitrogen Crown Ethers and Related Compounds Syntheses Effects on Chemical Reactions Reactions of the Macrocyclic Rings Formation of Host-Guest Complexes

Chapter 7 Bridged Systems By J. M.Mellor

419 419 419 420 422 424 425 426 429 429 430 432 434

439

1 Introduction

439

2 Reviews

439

3 Physical Methods X-Ray and Neutron Diffraction Photoelectron Spectroscopy and Related Electrochemical Studies Nuclear Magnetic Resonance Spectroscopy Electron Spin Resonance Spectroscopy Miscellaneous

440 440

4 Nitrogen Compounds Synthesis Tropane Derivatives and Related Azabicyclo[3.2. lloctanes Other Alkaloid Syntheses Cycloadditions Cyclizations with Nucleophilic Nitrogen Cyclization via Radical Intermediates Cyclization via Electrophilic Nitrogen Reactions Bridged Azoalkanes

445 445 446 449 450 455 456 456 457 458

5 Oxygen Compounds Cycloadditions Miscellaneous Syntheses Bridged Peroxides

459 459 461 462

6 Sulphur Compounds Cycloadditions Miscellaneous Syntheses

463 463 464

442 444 445 445

Heterocyclic Chemistry

xx 7 Bridged Annulenes and Related Systems

464

8 Cyclophanes

464

9 Cryptands and Cryptates

466

Chapter 8 Conformational Analysis By F. G. Riddell

469

1 Introduction

469

2 Four-membered Rings

469

3 Five-membered Rings

470

4 Six-membered Rings Oxygen-containing Rings Nitrogen-containing Rings Sulphur-containing Rings Phosphorus-containing Rings Boron- and Silicon-containing Rings

470 470 472 476 478 480

5 Seven-membered Rings

481

6 Eight-membered Rings

48 1

7 Nine-membered and Larger Rings

482

8 Polycyclic Systems

484

Author Index

489

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

The last Report on three-membered heterocyclic rings to appear in one of the Specialist Periodical Reports series concerned only saturated systems and covered material published in 1975.l The scope of this Report has been extended to include unsaturated systems, and some articles published between 1975 and the current review have been included here to attempt to bridge the gap in coverage.

1 Oxirans Preparation.-Catalytic Oxidation of Alkenes to Oxirans, using Oxygen or O x y gen-containing Gases. The use of supported silver catalysts for the gas-phase epoxidation of ethene continues as an area of active investigation. Improvements in the selectivity of the reaction may be attained by doping the silver with trace quantities of other metals; e.g., 0.2 atom O/O of Na or K, or 0.003% of Cs or Rb, . ~ may also be improved by the increase selectivity to around ~ O O / O Selectivity addition of 1,2-dichloroethane to the gases; this retards the formation of CO, and H 2 0 . It is reported that HCI (produced by the dehydrochlorination of the chloro-alkane) reacts with chemisorbed atomic oxygen on the silver catalyst to form chemisorbed atomic ~ h l o r i n e .The ~ kinetics of such a reaction, in the presence of dichloroethane, have been reported, and rates of both oxidation and epoxidation depend on the concentrations of ethene and ~ x y g e n . ~ The palladium complex [PdCl,{P(C,F,),},] has been found to give a selectivity of more than 60% in the epoxidation of ~ r o p e n eA . ~mixtiire of 43.1% propene, 54.4% hydrogen, and 2.5% oxygen was passed through the catalyst in 1,2dichlorobenzene and water at 67 “C and 15.8 atm pressure; no carbon dioxide was formed. Photosensitized epoxidation has received considerable attention over the past few years. Since 1974, many cases have been reported in which photo-epoxida-

’

T. J. Mason, in ‘Saturated Heterocyclic Chemistry’, ed. G. Pattenden, (Specialist Periodical Reports), The Chemical Society, London, 1978, Vol. 5, p. 1. W. D. Mross, E. Titzenthaler, M. Schwarzmann, and J. Koopman, Ger. Offen. 2 704 197 (Chem. Ah.,1978,89, 163 381). P. Kripylo, L. Gerber, P. Muench, D. Klose, and L. Beck, Chem. Tech. (Leiprig) 1978, 30, 630 (Chern. Abs., 1979,90,103 080). A. Gawdzik and J. Wasilewski, Chem. Stosow., 1978,22,13 (Chem. Abs., 1978,89 89 924). P. N. Dyer, Ger. Offen. 2 746 812 (Chem. Abs., 1978,89,43 091).

1

2

Heterocyclic Chemistry

tion competes with the usual reactions of singlet oxygen,6 the reaction being influenced by, among other factors, the nature of the photosensitizer.' An example is the reaction of bisadamantyl with oxygen in acetone solvent; sensitization by methylene blue yields more than 95% of 1,2-dioxetan whereas more than 95% of the epoxide is formed with rose bengal as sensitizer. The photooxygenation of a-pyronene (1)with tungsten lamps using methylene blue yields peroxide (2), which may be reduced by Ph3P, in a low-yield reaction, to the epoxide (3).8 The epoxide (4) is directly produced by oxidation of (1) with perbenzoic acid. Dimethylstyrene (5) and tetraphenylporphine (a dye photosensitizer), when irradiated in CCl, using sodium lamps, react with oxygen to give a mixture of products containing 30% of the diperoxide (6),which on refluxing in benzene gave epoxide (7) (65%).'

r7J-f \

om 0°0

0

The cleanest photo-epoxidations occur using a-diketones as sensitizers. lo The for the mechanism of the reaction has been investigated by Bartlett, using epoxidation of norbornene." With benzil or biacetyl as sensitizers, the results suggested the intermediacy of a diradical species such as (8;R = Me or Ph) in the reaction. Attempted photo-epoxidation of vinyl-allenes using biacetyl as sensitizer yielded little or no epoxide, but resulted in a good and efficient method of converting such compounds into cyclopentenones.12 The yields of cyclopentenones (10)isolatedfrom the allenes (9; R1 = But, R2 = H), (9; R' = C5Hll, R2 = H), and (9; R' = C4H9,R2 = H) being 40, 55, and 6O%, respectively. A mechanistic investigation of the acenaphthenequinone-sensitized photoepoxidation of alkenes has been r e p 0 ~ t e d . lPhotolysis ~ of the quinone in dichloromethane that was continuously saturated in oxygen generated 1,snaphthalic anhydride in 80% isolated yield. When cyclohexene was included in

lo

P. D. Bartlett and M. S. Ho, J. A m . Chem. SOC.,1974,96,627. C . W. Jefford and A. F. Boschung, Helu. Chim. Ada, 1977,60, 2673. W. Cocker, K. J. Crowley, and K. Srinivasan, J. Chem. Soc., Perkin Trans. 1, 1978, 159. M. Matsumoto and K. Kuroda, Japan. Kokai 78 68 789 (Chem. Abs., 1978,89, 197 559) N. Shimizu and P. D. Bartlett, J. A m . Chem. SOC., 1976,98, 4193.

l1

P. D. Bartlett and 3. Becherer, Tetrahedron Lett., 1978,2983.

l2

l3

M. Malacria and J. Gore, J. Org. Chem.. 1979,44,885. J-Y. Koo and G. B. Schuster, J. Org. Chem., 1979,44, 847.

3

Three-membered Ring Systems

the reaction solution it was converted into a mixture of oxidized products consisting mainly of allylic hydroperoxide (40%) and epoxide (33%). A possible

(8)

(9)

(10)

mechanism was proposed (Scheme 1) involving the diradical intermediate (11) obtained by either C- or O-oxidation. It was suggested that this intermediate could yield O3by further reaction with O2and thus account for the small amount of adipaldehyde formed in the reaction.

a* a I

4%

0' /

0

\

/

\

.?I

/

0-0'

Scheme 1

Oxidation of Alkenes to Oxirans by Peroxy-acids. The use of peroxy-acids in the Vinyloxiran (12) epoxidation of unsaturated compounds has been re~iewed.'~ was prepared in 95% yield by the reaction of peroxypropanoic acid with butadiene in benzene at 40 OC.15The same peroxy-acid, continuously generated by the reaction of propanoic acid with hydrogen peroxide, has been used in the

'* l5

E. L. Gershanova, E. I. Stratonova, M. F. Sorokin, and Z. A. Mikhitarova, Deposited Document 1976, VINITI 792 (Chem. Ah., 1978,88,61683). G. Rauleder, H. Seifert, H. Waldmann, W. Schwerdtel, and W. Swodenk. Ger. Offen. 2 734 242 (Chem. A h . , 1979,90, 168 429).

4

Heterocyclic Chemistry

epoxidation of propene in tetrachloroethene and 1,2-dichloropropane. l6 The epoxides of a variety of cyclohex-2-enyl halogenoacetates (13; R = Me, ClCH2, C12CH, C13C, or BrCH2)may be prepared in 53-75% yield by the reaction of the corresponding alkenes with peroxyacetic acid." For these epoxidations, a correlation exists between log k and T * . Substituents (R' and R2) have been shown to have a marked effect on the rate of epoxidation of (14) to (15), even though

(12)

(13)

(14)

(15)

they are separated from the alkene double bond by four 0-bonds." If the rate of epoxidation of the unsubstituted alkene (14; R1 = R2 = H) by peroxy-mchlorobenzoic acid at 22 "C in dichloromethane is taken as unity, then the relative rates of epoxidation of (14; R'R2 = 0),(14; R' = OMe, R2 = H), and (14; R' = H, R2 = OMe) are 0.04, 13.2, and 0.36, respectively. These results are in accord with predictions based on the concept of orbital interactions through space

(o ITs ) .~ ~ A useful crystalline substitute for peroxytrifluoroacetic acid has been found to be 3,5-dinitroperoxybenzoicacid.*' The major advantages are that ( a )no buffers are needed and ( b ) the crystalline material may be stored for up to 1 year at -10 "C without noticeable loss of reactivity. Though perhaps not quite so reactive as peroxytrifluoroacetic acid, the yields of epoxides from both peroxy-acids are comparable. Catalytic Oxidation of Alkenes to Oxirans, using Peroxides. The kinetics and mechanisms of epoxidation of alkenes by organic hydroperoxides have been reviewed,*l as have the prospects for the large-scale use of such methods.22 The stereochemistry of [VO(a~ac)~]-catalysed epoxidation of cyclic allylic alcohols with Bu'OOH has been examined and compared with that obtained This investigatiori followed an earlier using m -CIC6H4C03H as observation that the former system showed high cis selectivity for allylic alcohols witH a medium-sized ring whereas the latter showed predominantly trans selectivity with such In the case of the cyclonon-2-enols (16) (2)and (17) ( E ) , both gave an 83% epoxide yield, consisting of >90% cis-isomer, using Bu'OOH and [ V O ( a ~ a c ) whereas ~] a 90% epoxide yield was obtained with l6

l7

Is

l9

*'

21

22

23 24

A. M. Hildon, T. D. Manly, and A. J. Jaggers, Ger. Offen. 2 747 762; and A. M. Hildon and P. F. Greenhalgh, Ger. Offen. 2 747 761 (Chem. A h . , 1978,89,24 123 and 24 124). I. L. Osipenko, D. V. Lopatik, N. G . Bulatskaya, and I. P. Prokopovich, Vestsi Akad. Navuk BSSR, Ser. Khim. Nuuuk, 1978,118 (Chem. A h . , 1978,89,24060). M. N. Paddon-Row, H. K. Patney, and R. N. Warrener, J. Chem. SOC.,Chem. Commun., 1978,296. M. N. Paddon-Row, Tetrahedron Lett., 1972, 1409. W. H. Rastetter, T. J. Richard, and M. D. Lewis, J. Org. Chem., 1978, 43, 3163. S. B. Grinenko and V. M. Belousov, Metallokompleksnyi Katal., 1977,40 (Chem. Abs., 1978,89, 23 239). M. I. Farberov, Khim. Prom-st. (Moscow), 1979, No. 1, p. 8 (Chem. A h . , 1979,90, 203 777). T. Itoh, K. Jitsukawa, K. Kaneda, and S. Teranishi, J. A m . Chem. SOC.,1979, 101, 159. T. Itoh, K. Kaneda, and S. Teranishi, J. Chem. SOC.,Chem. Commun., 1976,421.

Three-membered Ring Systems

5

rn-C1C6H4CO3Hin each case, consisting of 99.8 and 90% trans-isomer respectively. For five- and six-membered-ring allylic alcohols, both reagents gave predominantly cis-products.

The product distributions in the [MO(C0)6]-CatalySed epoxidation of esters of farnesol (18) and geranylgeraniol by ButOOH are influenced by phenyldimethylcarbinol tern plate^.^^ Thus the ratio of 6,7- to 10,ll-epoxides may be changed from 40 :60 for a para- to 17 : 83 for a meta-dimethylcarbinol substituent. Together with the results from other templates, the authors have concluded that the simplest terpene conformation consistent with the data is one in which the carbon chain is U-shaped; the template is thought to fold back along one of the legs of the U, as shown in (19). The hydroxy-group of the aromatic substituent serves to co-ordinate with the catalyst (20).

Me I

mc-0:.

Ae

/

H /

“

Bu‘

Mo .- .O,

‘OH

Molybdenum powder has been used as a catalyst to provide highly selective epoxidations of hex- 1-ene, oct- 1-ene, and cyclohexene with B u ~ O O H . *The ~ kinetics and mechanism for the reaction were reported; the rates correlated with the ionization potentials of the alkenes. Kinetic studies have also appeared for the epoxidation, by cumene hydroperoxide, of styrene, using (RO)3Bcatalysts (R = Pr or Bu),*’ and of isobutene, using [ M ~ ( a c a c )catalyst.28 ~] 25 26

27

’*

R. Breslow and L. M. Maresca, Tetrahedron Lett., 1978, 887. Y.Kurusu, R. Kaya, and N. Ishii, Nippon Kagaku Kaishi, 1978, 9, 1262 (Chem. Abs., 1978,89, 196 678). A. Badev, D. Mondeshka, and D. Dimitrov, Khim. Ind. (Sofia),1978,435 (Chem. Abs., 1979,90, 186 058). E. Costa Novella, P. J. Martinez de la Cuesta, E. Rus Martinez, and G. Galleja Pardo, A n . Quim., 1977,73,1192,1198 (Chem. A h . , 1978,89,129 000,128 828).

6

Heterocyclic Chemistry

Hydrogen peroxide has been used to epoxidize cyclohexene in >85% yield and 87% selectivity, using either [Mo(CO)~]or B2O3 as catalyst.29Seleninic acids RSe(O)(OH) [R = Ph, 2-N02C,&, or 2,4-(N02)2C6H3]have also proved effective catalysts with this ~xidant.~' Thus (21; R = H) a'id (21; R = Me) were prepared in 91-94% yield and cyclodecene oxide in 87% yield. The novel stereochemical feature of [Fe(a~ac)~]-catalysed oxidatioi- a€ either cis- or trwcsstilbene by H202is the production of the truns-epoxide (22) from either.31This catalyst system, when applied to the methyl esters of higher unsaturated fatty acids, also consistently gave trans-epoxides.

R Me Y

Me C

H ,CH Ph

Halohydrin Cyclizations and Related.Reactions. A general synthesis of oxirans has been described which involves a cyclization of P-hydroxydimethylsulphonium salts (24) with base.32 The method applied to the synthesis of phenyldimethyloxiran (25) in 68% yield is shown in Scheme 2, starting from the a-sulphenylated ketone (23). For a number of such syntheses the yields are in the range 64-70%, and the method has also been applied successfully to the syntheses of cyclopentene and cyclohexene oxides.

Reagents: i, NaBH,; ii, MeI; iii, Bu'OK, DMSO Scheme 2

The oxiran (28) was prepared from the alcohol (26) by sequential reaction with C C 4 and azobisisobutyronitrile, and after heating for 15 hours this gave (27) (72%),which was dehydrochlorinated with NaOH in methan01.~~ The reaction of R'Br (R' = Ph, p-tolyl, benzyl, a-naphthyl, or p-anisyl) with Mg and Se gave

29

30

31 32 33

J. P. Schirmann and S. Y. Delavarenne, Ger. Offen. 2 752 626 and 2 803 791 (Chem.Abs., 1978,89, 59 832 and 163 380). H. J. Reich, F. Chow,and S. L. Peake, Synthesis, 1978, 299. T. Yamamatu and M. Kamura, J. Chem. SOC.,Chem. Commun., 1977,948. S. Kano, T. Yokomatzu, and S. Shibuya, J. Chem. SOC.,Chem. Commun., 1978,785. N. Itaya and F. Fujita, Japan. Kokai 78 23 912 (Chem. Abs., 1978, 89, 109 031).

Three-membered Ring Systems

7

R'SeMgBr, which reacted with epichlorohydrin to form (29); this, with KOH in diethyl ether, gave the corresponding selenyl epoxide (30): (31) was prepared from 2-methylepi~hlorohydrin.~~~~~ A number of 2-halogeno-ketones (32; R' = Me, Pr', or Ph; R2 = H, Me, or Ph; R3 = Me or Ph; X = Cl or Br) reacted with Et4N'CN- in CHzC12 (or MeCN) at 40-80°C to give the oxirans (33).36The &

0 R ' S e Y CH $1 OH (29)

C R1/

0

R3

NC

II

RISe<

'

RZ

Rl)a(Rz

/

+x

(30) R2 = H (31) R2 = Me

R3

(32)

(33)

reagent 2,4,4,6-tetrabromocyclohexadienone (TBCO) selectively bromohydroxylated squalene to yield, by reaction with NaOH, the 2,3-epoxide and the The technique has also been applied to the epoxidation of 2,3 :22,23-diepo~ide.~' methyl farnesate, farnesyl acetate, and farnesol.

Syntheses Related to the Darzens Reaction. The chromone epoxide (37) has been prepared from the bromo-ketone (34) by reaction in aqueous methanolis NaOH.38 The reaction proceeds through a Darzens-type mechanism via the anion ( 3 9 , followed by subsequent elimination of bromide ion by the oxy-anion in (36) (Scheme 3).

?3

WOMe fJO-';-Me COCHBrPh (34)

'

C-E-Ph

8 8, (35)

- aozz ' Me

c \

II LBr

J

0 (36)

0 (37)

Scheme 3

A new strategy for the formation of ap-epoxy-esters has been reported which gives a remarkably stereochemically pure product; the least-hindered ~xiran.~' F. G. Casanov, I. M. Akhmedov, S. B. Kurbanov, and M. M. Guseinov, Azerb. Khim. Zh., 1978,3, 50 (Chem. Abs., 1979,90,22 697). " I. M. Akhmedov, F. G. Gasanov, S. B. Kurbanov, and M. M. Guseinov, Zh. Org, Khim., 1978,14, 881 (Chem.Ah.,1978,89,24 061). '' H. Kobler, K. H. Schuster, and G. Simchen, JusfusLiebigs Ann. Chem., 1978, 1946. " I. Ichinose, T. Hosogai, and T. Kato, Synthesis, 1978,605. J. A. Donnelly, M. J. Fox, and D. E. Maloney, Tetrahedron Lett., 1978,4691. 39 G . A. Kraus and M. J. Taschner, Tetrahedron Lett., 1977,4575. 34

8

Heterocyclic Chemistry

Thus a P-hydroxy-ester, e.g. (38), reacts with PriNLi and iodine in THF at -78 "C to give (39) (48%). A possible explanation for the stereospecificity lies in the addition of iodine to the least hindered side of an intermediate complex (40) followed by elimination of LiI.

PhwCo2Et

Ph OH &C02Et Ph

Ph

EtO

0

,O

(39)

(38)

I..

Li

Li

(40)

Carbanions derived from a-chloro sulphur compounds may be used in condensation reactions with carbonyl compounds. Thus the epoxy-sulphimines (42) may be synthesized from the reaction of the chloro-sulphoximine (41),using R'R2C0 [R', R2 = Me, Me or H, Ph; R1R2 = (CH2)5or (CH2)2CHB~f(CH2)2J in the presence of KOBU'.~' The epoxyalkane-sulphonamides (44; R1 = R2 = various alkyl and aryl groups) are prepared by the reaction of sulphonylmorpholines (43; R' = H, Ph, or Pr) with the corresponding carbonyl

R1 \O

R2

/-

0

+ Ph-S-CH2Cl

RCHS02-N

cI1

I1

It

NMe

-

Ph

R2

S02-N

BU'OK

A

\p

MeN

A

0

R')acR3

Synthesis of Chiral Oxiruns. A general method for the synthesis of chiral epoxides of high enantiomeric purity is outlined in Scheme 4.42The method starts with the

(45)

Scheme 4

opening of racemic epoxides with sodium thiophenoxide to produce P-hydroxysulphides (45; R', R2, R3 = alkyl or aryl), followed by chromatographic separation (on neutral or basic alumina) of the diastereomeric carbamates derived by the 40 41

42

H.G. Corkins, L. Veenstra, and C.R.Johnson, J. Org. Chem., 1978,43,4233. J. Golinski and M. Makosza, Synthesis, 1978, 823. W. H. Pirkle and P. L. Rinaldi, J. Org. Chem., 1978,43, 3803; ibid., 1979,44, 1025.

9

Three-membered Ring Systems

reaction of (45) with enantiomericallypure l-(l-naphthy1)ethyl isocyanate. After cleavage by silanolysis (80-90%), the pure P-hydroxy-sulphides are converted into chiral oxirans upon treatment with [Me,O]' BF4- followed by alkaline hydrolysis. The method has been applied to the synthesis of (+)-disparlure (46), the sex pheromone of the gypsy moth.

(46)

Catalytic asymmetric syntheses of epoxides have been briefly re~iewed.~' Attempts have been made to introduce chirality by the use of an optically active catalyst, e.g. dioxo(acetylacetonato)[(-)-N-methylephedrinato]molybdenum, in the oxidation of 3-methylbut-2-en-1-01to epoxide (47) by cumene hydroperoxide in 50% chemical and 17o/' asymmetric yield.44Alternatively, an optically active alcohol, e.g. (-)-menthol, may be introduced into a system, as in the epoxidation of cis- or trans-oct-2-ene with Bu'OOH, using vanadium cataly~ts.~' * Wynberg has developed a technique for producing both enantiomers of a variety of oxirans under phase-transfer conditions, using salts of the Cinchona alkaloid^.^^,^^ Chiral oxirans were obtained using the followingmethods: (a)28% hypochlorite, ( b )Darzens, (cj racemic halohydrin cyclization, and ( d )addition of cyanide to a-halogeno-ketones, using quinininium benzyl chloride (QUIBEC) (48) as the catalyst. In the phase-transfer chiral epoxidation of (49) with H 2 0 2in the presence of (48), the enantiomeric excess (Ee) fell from 54% in benzene to 10% in nitrobenzene in a manner which was inversely related to the dielectric constant of the

CH,Ph

(47)

OMe

(49) 43 44

45

46

47

48

K. Hermann, Nachr. Chem. Tech. Lab., 1977,25,301,303(Chem. Abs., 1977,87,134852). S.Yamada, S. Terashima, and T. Masuko, Japan. Kokai 78 50 11 1 (Chem. A h . , 1978,89,109035). R.Curci, F. Furia, J. 0.Edwards, and G. Modena, Chim. Ind. (Milan),1978 60,597(Chem. Abs., 1978,89,214797). R.Helder, J. C. Hummelen, R. W. P. M. Laane, J. S. Wiering, and H. Wynberg, Tetrahedron Letr., 1976,1831. J. C. Hummelen and H. Wynberg, Tetrahedron Lett., 1978, 1089. H.Wynberg and B. Greijdanus, J. Chem. Soc., Chem. Commun., 1978,427.

10

Heterocyclic Chemistry

Partial asymmetric synthesis of substituted truns-2,3-diaryl-oxiranshas been achieved, using chiral arsonium ylide~.~’ For (R,R)-diphenyloxiran, Ee was in the range 5-17%, depending on conditions; an Ee of 38% was achieved for (R,R)di-(2-methoxyphenyl)oxiran. Complexation chromatography has been used in the estimation of the enantiomeric purity of samples of ( + ) - ( R )and - (-)-(S)-1,2epoxypropane prepared from L-alanine and ethyl (-)-(S)-lactate, re~pectively.~’ Synthesis ofFused Aromatic Oxides. The interest in both the synthesis and the biological activity of fused aromatic oxides continues, although only synthetic aspects will be reviewed in this Report.” A new route to naphthalene oxides (51) and (52) has appeared, starting from the adduct of benzyne with trans,truns-1,4diacetoxybutadiene (50).’* The chrysene bay-region anti-diol-epoxide (53) has been synthesized from c h r y ~ e n e The . ~ ~ diol-epoxides (54) and (55) have been synthesized and the stereochemistry of the OH groups is diaxial, in contrast to the analogous derivatives of benzo[a]pyrene, e.g. (56), where the preferred conformation of the OH groups is d i e q ~ a t o r i a l . ~ ~

49

51

52

53 54

D. G. Allen, N. K. Roberts, and S. B. Wild, J. Chern. SOC.,Chem. Comrnun., 1978,346. V. Schurig, B. Koppenhoefer, and W. Buerkle, Angew Chem., 1978,90, 993. S. C. Agarwal and B. L. Van Duuren, in ‘Carcinogenesis-A Comprehensive Survey, Vol. 3, Poiynuclear Aromatic Hydrocarbons, 1978, p. 109 (Chem. Abs., 1978,89, 146 793). R. R. Schmidt and R. Angerbauer, Angew. Chem., 1979,91,325. P. P. Fu and R. G. Harvey, J. Chem. SOC.,Chern. Comrnun., 1978,585. R. G. Harvey, H. M. Lee, andN. Shyamasundar, J. Org. Chem., 1979,44,78.

Three-membered Ring Systems

11

Miscellaneous Syntheses. The biosyntheses of epoxy-terpenes and epoxyfatty-acids have been re~iewed,~’ as has the epoxidation of alkenes under enzyme-simulated conditions.56 Terminal alkenes are oxidized biochemically by Corynebacterium equi to give the corresponding optically pure (+)-(R)-epoxides5’ Two-phase fermentation has been used to produce 7,8-epoxyoct-l-ene and 1,2 :7,8-diepoxyoctane from octane and octa- 1,7-diene, using Pseudomonas oleo~orans.~~ Corey’s reagent, dimethylsulphonium methylide, has been used in the synthesis of aryl-oxirans, e.g. 2-naphthyloxiran (%YO),and under phase-transfer catalysis Stereospecific addition of the conditions, e.g. 9-phenanthryloxiran (90Y0).~~ reagent to 9,lO-anthraquinone affords the diepoxide (57) (94y0).~’The sulphur ylide (58) was prepared by treating cis- and trans-l-thioniabicyclo[4.4.0]decane bromides with NaH in THF at reflux.61The ylides reacted with carbonyl compounds to give epoxides; e.g., with acetone to yield (59) (74%).

(57)

(59)

(58)

Garst has reported a new annelation procedure in which l-butadienyldimethylsulphoniurnfluoroborate reacts with some ketone and aldehyde enolates to give dihydro-arene oxides as major products.62Thus (60) (58%) may be prepared from cyclohexanone. Epoxidation using selenium compounds has been reviewed.63A new reagent, MeSeOH, has been used for the conversion of alkenes into P-hydroxy~ e l e n i d e s .This ~ ~ has allowed the synthesis of (61; R’ = H, R2 = Me) and (61; R’ = Me, R2 = H) with >95% stereochemical purity from (2)-and (E)-oct-2-ene respectively.

R,’

(,CHAMe

R1-H H (60) ” 56 57

59

6o

62 63

64

(61)

S. Voigt and M. Luckner, Pharmazie, 1978,33,632. Z. Yoshida, Kagaku No Ryoiki, Zokan, 1976, 113, 1 (Chem. Abs., 1977, !6,42 532). H. Ohta and H. Tetsukawa, J. Chem. SOC.,Chem. Commun., 1978,849. C. J. McCoy and R. D. Schwartz, Ger. Offen. 2 756 287 (Chem. Abs., 1978,89,127 778). N-C. C. Yang, W-L. Chiang, D. Leonov, E. Leonov, I. Bilyk, and K. Bongsub, J. Org. Chem., 1978, 43,3425. T. J. McCarthy, W. F. Connor, and S. M. Rosenfeld, Synth. Commun., 1978, 379. K. Tokuno, F. Miyoshi, Y. Arata, Y. Itatani, Y. Arakawa, and T. Ohashi, Yakugaku Zasshi, 1978, 98, 1005 (Chems.Abs., 1979,90, 6195). M. E. Garst, J. Org. Chem., 1979, 44 1578. Y. Tatsumo, S. Otsuka, K. Saigo, T. Mukaiyama, A. Yasuda, H. Yamamoto, and N. Sonoda, Kagaku No Ryoiki, Zokan, 1977,117,329 (Chem. Abs., 1978,89, 128 540). D. Labar, A. Krief, and L. Hevesi, Tetrahedron Lett., 1978, 3967.

12

Heterocyclic Chemistry

A new approach to substituted arene oxides (63) is outlined in Scheme 5.65A variety of substituents in (62) may be introduced uia alkylation of dilithio-1,4dihydrobenzoate. This method has been incorporated in the total synthesis of the shikimate-derived metabolites senepoxide and seneol from (63; R = CHZOCOPh).

4

HO,C\ R

(62) Reagents: i, Br,, NaHCO, (aq.); ii, CF,CO,H; iii, D B U , benzene; iv, heat

Scheme 5

Iron-porphine complexes have been used as catalysts in epoxidations using iodosylbenzene as the oxygen source.66 Using chloro-apy&tetraphenylporphinatoiron(III), cyclohexene yielded 55 OO/ oxide while cyclohexadiene gave 74% mono-epoxide. It is interesting to note that cis- (but not trans-)stilbene was epoxidized with this catalyst, whereas both isomers were epoxidized using chlorodimethylferriprotoporphyrin, with complete retention of configuration. Iodine(II1) trifluoroacetate has been shown to epoxidize a number of steroidal alkene~.~’ Spectra and Theoretical Chemistry of 0xirans.-Bonding and bond-bending in small ring compounds (64; Z = CH2,0,S, or NH) have been examined, using a b initio FSGO calculations.68Attempts have been made to predict the reactivity of oxirans towards thermal and photochemical ring-opening and also towards fragrnentati~n.~’ The first hundred mono- and di-excited states of ethene oxide were used to provide the basis for a semi-quantitative rationale of the main reactivity trends by ab initio SCF calculations. Predictions of the properties of arene oxides with relation to their biological importance have been The steric course of the 1,4-opening of cisnid and transoid diene mono-epoxides incorporated into ring systems has been analysed and interpreted, using torsionangle notation and assuming the maintenance of orbital overlap during the rea~tion.~’

6s 66 67 68

69 70

’’ 72

B. Ganem, G. W. Holbert, L. B. Weiss, and K. Ishizumi, J. Am. Chem. SOC.,1978,100, 6483. J. T. Groves, T. E. Nemo, and R. S. Myers, J. Am. Chem. SOC.,1979,101, 1032. M. Linskeseder and E. Zbiral, Justus Liebigs Ann. Chem., 1978, 1076. E. R. Talaty and G. Simons, Theor. Chim. Acta, 1978,48, 331. B. Bigot, A. Sevin, and A. Devanquet, J. Am. Chem. SOC.,1979,101, 1095, 1101. P. P. Fu, R. G. Harvey, and F. A. Beland, Tetrahedron,1978, 34, 857. M. M. Marsh and D. M. Jerina, J. Med. Chem., 1978,21, 1298. E. Toromanoff, Tetrahedron,1978, 34, 1461.

Three-membered Ring Systems

13

An ion cyclotron resonance study of the reaction of CzH40+'ion, from ethene oxide or 1,3-dioxolan and their deuteriated derivatives, provides support for the existence of the open oxiran ion (65) as a stable entity in the gaseous phase, in agreement with theoretical prediction^.^^ Microwave studies of (66) involving assignments of the normal and the monodeuterio-, dideuterio-, and "0 and 13C isotopic species have given a complete The dipole was found to be 2.89D. A study of the polarizability of oxiran and thiiran has resulted in refinements to the anisotropy of polarizability of the exocyclic C-C bonds in methyl- and tetramethyl-~xiran.~' The conformations of the cis- and trans-isomers of 3,4-epoxybicyclo[4.1.0]heptane (67) and 1,2 :4,5-diepoxycyclohexane (68) have been investigated by 'H n.m.r., using [ E ~ ( d p r n )as ~ ]shift reagent.76Results indicate that the cyclohexane ring in both isomers of (67) and in cis-(68) exists in a predominantly planar conformation; the results for trans-(68) were inconclusive. A novel application of the study of the oxiran ring-current effect is in the determination of the configuration and conformation of certain epoxy-bicycloalkanones in which the epoxide is on a five-membered ring.77Thus two epoxides may be obtained when the unsaturated @-lactam(69) is epoxidized. The oxiran ring in (70) shields proton Ha,which is transannular to and coaxial with it, whereas no such shielding occurs for Ha in (71).

q0

X f J O (67)X (68) X

O

=

=

CH2

0

MeN (69)

q

MeN (70)

0

do MeN (71)

The conformations of cis,& 1,3- cyclo-octadiene and its mono- and di-epoxides have been determined, using variable-temperature 'H and 13Cn.m.r. studies together with iterative force-field calculation^.^^ The 13C n.m.r. spectra for a number of 5,6-epoxy-steroids have been reported, with the result that the published spectra for several 5a,6a- epoxides require re-a~signment.~' Reactions of 0xirans.-The chemical reactivity of epoxides,80.81the solution chemistry of arene oxides,82 and the hydrosilylation of epoxy unsaturated have been reviewed. "

74

'' 76

77

79

83

W. J. Bouma, J. K. Macleod, and L. Radom, Nouu. J. Chim., 1978 2,439; J. Chem. SOC.,Chem. Commun., 1978,724. C . W. Gillies, J. Mol. Spectrosc., 1978, 71, 85. B. A. Arbuzov, L. K. Novikova-Aleksandrova, S. G. Vul'fson, and A. N. Vereshchagin,Izv. Akad. Nauk. SSSR, Ser. Khim., 1978,1932 (Chem. Abs., 1978,79,179 377). A. Aumelas, E. Casadevall, and A. Casadevall, Tetrahedron, 1978 34, 2481. A. S. Mubarik, J. M. Berge, N. W. Crossland, and S. M. Roberts, J. Chem. SOC.,Perkin Trans. 2. 1978,1205. F. A. AnetandI. Yavari, J. A m . Chem. SOC.,1978,100,7814. H. L. Holland, P. R. P. Diakow, and G. R. Taylor, Can. J. Chem., 1978,56,3121. S. G. Wilkinson, Int. Rev. Sci., Org. Chem., Ser. Two, 1975, 2, 111. R. Oda, Kagaku (Kyoto),1975,30,968 (Chem. Abs., 1 9 7 6 , 8 5 2 0 955). T. C. Bruice and P. Y. Bruice, Acc. Chem. Res., 1976, 9, 378. S. I. Sadykhzade and R. A. Sultanov, in 'Epoksidne Monomery Epoksidne Smoly', ed. M. S. Salakhov, Baku (USSR),1975, p. 8. (Chem. Abs., 1976,85, 5712).

Heterocyclic Chemistry

14

Electrophilic Ring-opening Reactions. Kinetic studies. A detailed n.m.r. study of the rates of hydrolysis of tetramethyloxiran to pinacol in aqueous buffers has been The mechanism which was suggested for acid-catalysed ring-opening involves an equilibrium protonation of the oxygen atom, which weakens and lengthens (but does not break) the C - 0 bonds and facilitates attack by water at either tertiary carbon centre. The transition state (72) thus obtained includes the H

b+

M e A M e Me Me

(72)

conjugate base (A-) of the proton-acid catalyst, which assists in the breaking of a water O-H bond. A number of publications have been concerned with the kinetics and mechanism of the hydrolysis of arene oxides.” It is thought that the rates of hydrolysis of the oxides or, perhaps more likely, the diol epoxides may act as a guide to the carcinogenicity or mutagenicity of this family of compounds. Linked to this topic have been two theoretical papers on the hydrolysis of ethene oxide86 and benzene oxide.” Cyclization reactions. Decalone derivatives (74) (30%)and (75) (25 YO) may be prepared from the epoxycyclohexanone (73; R = CH=CH2) by treatment with strong Lewis acids, e.g. TiC14 in CH2C12.88Similar cyclizations occurred using (73; R = CH=CHMe) and (73; R = p-anisyl), the latter producing a 1: 1 mixture of (76; X = H, Y = OMe) and (76; X = OMe, Y = H) (90°/0).A

(73)

(74)

(75)

(76)

related ring closure is that for the acetylenic epoxide (73; R = CGCH) to (77) (>90%).89An unexpected cyclization, however, was observed when (73; R = CH=CMe2) was treated with Lewis acids, giving (78) as a kinetic product that was 84 85

86

87

89

Y. Pocker and B. P. Ronald, J. A m . Chem. SOC.,1978,100,3122. T. Okarnoto, K. Shudo, N. Miyata, Y. Kitahara, and S. Nagata, Chem. Pharm. Bull., 1978,26,2014; A. R. Becker, J. M. Janusz, R. Z. Rogers, and T. C. Bruice, J. A m . Chem. Soc., 1978,100,2244;D. L. Whalen, A. W. Ross, H. Yagi, J. M. Karle, and D. M. Jerina, ibid., p. 5218; J. M. Janusz, A. R. Becker, and T. C. Bruice, ibid., p. 8269. P. Politzer, K. C. Daiker, V. M. Estes, and M. Baughman, Int. J. Quantum Chem., Quantum Biol. Symp.. 1978,5, 291. J. E. Ferrell and G . H. Loew, J. Am. Chem. Soc., 1979,101,1385. E. Huq, M. Mellor, and E. G. Scovell, J. Chem. Soc., Chem. Commun., 1978,526. M. Mellor, A. Santos, E. G. Scovell, and J. K. Sutherland, J. Chem. SOC.,Chem. Commun., 1978, 528.

Three-membered Ring Systems

15

readily converted into bicyclononane (79).90The vinyl ether epoxides (80; = R3 = H, R2 = Me) and (80; R' = H, R2= R3 = Me) cyclized to (81) and (82) respectively on treatment with BF,.Et,O .91 Hydrolysis or cleavage by singlet oxygen of the cyclized products affords a new stereospecific route to carbocyclic ketones and lactones with a medium-sized ring respectively.

R'

&

( &(+) 0 OH

OH

(77)

CMe=CH,

(81)

(80)

0 OH CMe=CH, (79)

(78)

(82)

Cyclizationsfrom ring D epoxy-steroids have been reported; e.g., treatment of the epoxy-dinorcholenedione enol acetate (83) with AcOH containing H2S04 gave the steroidal furanone (84) and the pyranone (85). Lactone (87)was obtained when the epoxy-norcholenoate (86)was similarly treated with acid.92A 19-methoxy-group has been found to be a sufficiently good internal nucleophile to compete with water in the HCIO,-catalysed cleavage of the A- and B-ring gCFH=CHOCOMe

OAc

\

AcO

(83)

90 91

q2

(84)

E. G. Scovell and J. K. Sutherland J. Chem. SOC.,Chem. Commun., 1978,529. R. J. Boeckman, K. J. Bruza, and G. R. Heinrich, J. Am. Chem. Soc., 1978, 100,7101. A. V. Kamernitskii, I. G. Reshetova, and K. Yu. Chernyuk, Izv. Akad. Nauk SSSR,Ser. Khim., 1978, 184; A. V. Kamernitskii, V. A. Krivoruchko, and I. G. Reshetova, ibid., p. 188 (Chern. Abs., 1978,89,43 945, 43 946).

Heterocyclic Chemistry

16

a-epoxides (88)and (89).93Adjacent acetate groups have also proved effective as internal nucleophiles in ring-cleavage reactions of steroidal e p ~ x i d e s . ~ ~

& *m 17

0::

8H

H30+

HO'*

AcO

OH

* L$iEt (89)

Bartlett has reported a highly stereoselective synthesis of (*)-a-multistriatin (91) which, in the last step, involves the Lewis-acid-catalysed cyclization of (90) in >95% Me

Me

0

Me

(90)

(91)

Miscellaneous reactions. The acid-catalysed ethanolysis of trans-stilbene oxide has been examined in a variety of binary ethanolic The steric course could be controlled between the extremes of 85% retention (MeN02:EtOH = 10: 1) and 90% inversion (HMPA:EtOH = 10: 12). In an effort to identify the type of norbornyl cation that is generated on acid-catalysed opening of (92) (ex0 and endo), the products have been compared with those obtained on treatment of nortricyclanol with acid.97For a common nonclassical carbenium ion intermediate, the products from all three compounds would be identical, and in the same ratio. Since this was not found, and the ratio of the diols R' R2

v

93 94 95 96

97

(93) R'

=

(94) R'

=

H , R 2 = OH OH,R2 = H

P. Kocovsky and V. Cerny, Collect. Czech. Chem. Commun., 1979,44, 226. E. Glotter and P. Krinsky, J. Chem. SOC.,Perkin Trans. 1, 1978,413. P. A. Bartlett and J. Myerson, J. Org. Chem., 1979, 44, 1625. M. Inoue, Y. Taguchi, T. Sugita, and K. Ichikawa, Bull. Chem. SOC.Jpn., 1978, 51,2098. H. Christol, J. Coste, F. Pietrasanta, F. Plenat, and G. Renard, J. Chem. Res. ( S ) , 1978, 62.

Three-membered Ring Systems

17

(93) and (94) was reversed from exo- and from endo-(92), the authors have suggested that a secondary carbenium ion is the intermediate involved. Olah has reported a useful reagent, pyridinium poly-hydrogen fluoride, for the preparation of fluorohydrins from e p o x i d e ~The . ~ ~ reaction can be carried out under mild conditions without recourse to heating, and is applicable to both aliphatic and aromatic epoxides. Nucleophilic Ring-opening Reactions. New aspects of the nucleophilic ring opening of oxirans have been re~iewed.'~ 1 With oxygen and nitrogen nucleophilks. The hydrolyses of a number of chloro-oxirans have been studied, at 37"C, in aqueous solution buffered at pH 7.4, the conditionsbeing chosen to mirror the reactivity of an epoxide towards cellular nucleophiles in uivo.looThe reactions obeyed pseudo-first-order kinetics and yielded a-chlorocarbonyl compounds via chlorine migration; thus both cis and trans-l,3-dichloropropeneoxide gave a-chloroacrylaldehyde. The presence of chlorine greatly increases the hydrolytic reactivity of aliphatic epoxides, the rate for trichloroethene oxide being 2 x lo4 times faster than that for ethene oxide itself. For the reaction of benzoic acid with ethene oxide in the presence of mines, kinetic data and the isolation of intermediates indicate that the catalyst for the reaction is a quaternary salt formed from all three compounds.'o' A Hammett plot for the esterification of (95;R1 = MeO, Me, H, C1, or NO,) to (96) gave a positive value for p, suggesting that hydrogen-bonding between the epoxide and acid in the transition state has an important accelerating effect. The esterification of terephthalic acid with ethene oxide has also been investigated.lo2 Isoquinoline reacts with ethene oxide in acetic acid to yield the unstable oxazolidine (98; R = H) via the zwitterion (97).lo3Using 1-(3-methoxy-2nitrobenzyl)isoquinoline, the stable oxazolidine (98; R = 3-MeO-,2-N02CaH3CH2)was obtained (69%).lo4Similar treatment of quinoline gave the novel labile compound (99). R'QCO*RZ -

m;) qNl

(95) R2 = H (96) R2 = CHzCHzOH

\

-0 (97)

0 (98)

(99)

Linear free-energy relationship (LFER) studies of the ring-opening reactions of chalcone epoxides (100; R1 = H; R2 = H, OMe, Me, or Br) and (100; R' = OMe, Me, Br, or Cl; R2 = H) with morpholine have shown that, for G. A. Olah and D. Meidar, Isr. J. Chem., 1978, 17, (1-2), p. 148. N. S. Enikolopiyan, Pure Appl. Chem., 1976,48, 317. S. A. Kline, J. J. Solomon, and B. L. Van Duuren J. Org. Chem., 1978,43, 3596. lo' H. Kamatani, Nippon Kuguku Kaishi, 1978,850 (Chem. Ah., 1978,89,107 290). H. Kamatani, Nippon KagukuKuishi, 1978,1271 (Chem.Abs., 1978,89,214 595);T. I. Samsonova, G. D. Mikhailov, V. A. Malykh, and A. S. Chegolya, Khim. Volokna, 1978, 15 (Chem. Abs., 1978, 89,41849). lo3 C.N. Filer, F. E. Granchelli, A. H. Soloway, and J. L. Neumeyer, J. Org. Chem., 1978,43, 672. C. N. Filer, F. E. Granchelli, P. Ferri, and J. L. Neumeyer, J. Org. Chem., 1979,44,285. 98

99

loo

Heterocyclic Chemistry

18

variable R1 and R2, p values of -0.64 (50 "C) and +0.455 (70 "C) are obtained, respectively.105These results are consistent with the expected nucleophilic attack at the position B to the carbonyl group. A number of other reactions of (100; R1 = H, R2 = C1) and (100; R' = NOz or C1,R2 = Me) with Grignard reagents, A1Cl3, thioureas, and hydrazines have been reported.lo6

/ \

R J 1 -T (" Q -R 2

(100)

Two detailed mechanisms occurring in the reaction of ethene oxide with NMe3.HCI to give [Me3NCH2CH20H]+C1- have been reported.lo7 Rate constants for four separate stages of the process have been determined, the first step being the dissociation of the amine salt. The tetrahydroquinoline derivative (101) reacted with NEt, to give the betaine (102), which underwent thermal rearrangement to (103).lo'

&

@: 0-7

--*

&H2ht3

----*

Ph

Ph

(101)

(102)

Ph (103)

With carbanions. The epoxides (104; R = H, Me, Ph, OMe, or Cl), derived from o-bromophenyl ally1ethers, undergo Br-Li exchange with BuLi at -100 OC, and the resulting lithium compounds cyclize to (105).'09 The attack on the epoxide ring is e m , as predicted by the Baldwin rules. Carbanion-induced cyclization of (106; n = 2 or 3) to (107) is achieved by reaction with MeMgI in

(106) lo5

'06

lo' log lo9

(107)

S. N. Sernenova, S. K. El-Sadana, V. S. Karavan, and T. J. Ternnikova, Zh. Org. Khim., 1978, 14, 1268 (Chem. Ah., 1978,89,107 686). A. A. Hamed, A. Essawy, and M. A. Salem, Indian J. Chem., Sect. B, 1978, 16,693. N. A. Uring, G. F. Tereshchenko, and L. A. Lavrent'eva, Zh. Obshch. Khim., 1979,49,466(Chern. A h . , 1979 90,203 144). H. Wittmann and H. Siegel, Z. Naturforsch., Teil B, 1978,33,429. C. K. Bradsher and D. C. Reames, J. Org. Chem., 1978,43,3800.

Three-membered Ring Systems

19

THF.' l o The a-lithiation of cycloalkene epoxides gave products arising from carbene intermediates."' Cycloheptane oxide gave cycloheptanone (84%), whereas cyclo-octene oxide gave the bicyclic alcohol (108) (99%). The sealed-tube reaction of the anion of a-(00-diethy1phosphono)-y-butyrolactone with epoxides in benzene produces isomeric spiro-lactones (40-60%); e.g., (109) and (110) (2 : 1ratio) from propene oxide.'12 A convenient synthesis of

R2 H

(108)

(109) R' = H , R 2 = Me (110) R' = Me,R2 = H

bifunctional vicinal cyclopropanes is provided by carbanion opening of (chloromethy1)o~iran."~Treatment of Bu'COMe with NaNH2 followed by the oxiran gave a 50% yield of (111) (95% trans), and similar treatment of PhCH2CN followed by hydrolysis gave (112) (cisltrans mixture). The 2-lithio-2-alkyl-l,3-benzodithioles(113; R' = H, Me, or Pr"; R2 = Li) act as equivalentsof an acyl carbanion in a number of reaction^."^ The reaction of (113; R' = Pr", R2 = Li) with propene oxide gave [113; R1 = Pr", R2 = CH2CH(OH)Me](92%), which was converted into (114) by standard methods.

The stannylated 1,3-dithian (115) reacted with halogeno-epoxides to give cyclized products; e.g., (116) from epichlorohydrin, and a mixture of (117) and (118) from l-brorn0-4,5-epoxypentane.l'~

~

1

(115)

~

c)GH~OH ~ 7 (1 16)

3

C@ CQ CH20H (117)

OH (118)

Reduction and Elimination Reactions. In order to clarify the stereospecificity of A12H3and A1Cl2H as reducing agents for epoxides, the reductions of optically active styrene oxides have been investigated. A12H3reduces (-)-(S)-styrene oxide to a 2:13 mixture of (119):(120) whereas AlC12H produces 2-phenylethanol from (+)-(R)-styrene oxide in a 3 : 1 ratio of [1-2H,2-2H]-:[l,l-2H2]'lo

''' '13

'14 '15 '16

B. Corbel, J. M. Decesare, and T. Durst, Can. J. Chem., 1978,56,505. R. K. Boeckman, Tetrahedron Lett., 1977,4281. T. Minami, M. Matsumoto, H. Suganuma, and T. Agawa, J. Org. Chem., 1978,43,2149. G. Mouzin, H. Cousse, and B. Bonnaud, Synthesis, 1978,304. S . Ncube, A. Pelter, K. Smith, P. Blatcher, and S. Warren, Tetrahedron Lett., 1978,2345. D.Seebach, I. Willert, and A. K. Beck, Helu. Chim. Actu, 1978,612510. U.Sankawa and T. Sato, Tetrahedron Lett., 1978,981.

20

Heterocyclic Chemistry

compounds. The optical purity of the enantiotopic methylene groups was determined enzymatically, and showed that the reduction by A12H3proceeded with inversion and 32% stereospecificity whereas reduction by AlC12H resulted in complete racemization. *H

OH Phi(.

H

A I ~ H Ph+H ~

CH;H

H

+ Ph4-H CH,OH

(119)

(120)

The epoxide ring in steroidal trans-ap- and -py-epoxy-alcohols is cleaved by NaBH4 in refluxing MeOH to produce the corresponding methoxyhydrins, in contrast to the cis-epoxy-alcohols, which are inert under these condition^."^ Reduction of aliphatic ap-unsaturated epoxides by B2H6 in THF gave the cis-alcohol with high stereoselectivity; e.g., (121) gave (122) (64Y0).~~* The increase in the rate of reduction of epoxides to alcohols by B2H6 that is induced by adding LiCl has been ascribed to the presence of Li' ClBH3- as the reducing species."'

Two reagents that are useful for the conversion of epoxides into alkenes are WCl6-LiA1H4 (1 : 1)120 and TiCl3-LiA1H4 (4: 1).121Neither reagent is stereospecific, and both are used in THF, at room temperature, under nitrogen. A series of papers have appeared which concern the reactions of lithium amides with epoxides in hexamethylphosphoric triamide (HMPA).'22Using this system, it is possible to prepare allylic alcohols in good yields; e.g., PrI2NLiin E t 2 0reacts with cyclo-octene oxide to give (123) (2%) and (124) (98%), but in HMPA it yields only the ally1 alcohol (123) (lOOo/~). A number of ?,&unsaturated epoxides gave thus (126) (95YO)was obtained high yields of 1-hydroxy-2-vinyl-cyclopropanes; from cyclo-octadiene oxide (125).

(123) '17

12'

lZ2

(124)

(125)

(126)

M. Weissenberg, P. Krinsky, and E. Cilotter, J. Chem. SOC.,Perkin Trans. I , 1978, 565. M. Zaidlewicz, A . Uzarewicz, and R. Sarnowski, Synthesis, 1979, 62. N. M. Yoon and J. S. Cha, Taehan Hwahak Hoechi, 1978,22,37 (Chem. Abs., 1978,89,106935). Y. Fujiwara, R. Ishikawa, F. Akiyama, and S. Teranishi, J. Org. Chem., 1978,43,2417. J. E. McMurry, M. G. Silvestri, M. P. Fleming, T. Hoz, and M. W. Grayston, J. Org. Chem., 1978,43, 3249. M. Apparu and M. Barelle, Tetrahedron, 1978, 34, 1541; ibid., p. 1691; ibid., p. 1818.

Three-membered Ring Systems

21

The mechanism for the conversion of epoxides into ally1 alcohols has been investigated for (127; R = H, p-C1, p-F, p-Me, p-Bu', p-MeO, m-C1, or rn-Me), using ButOK in Bu'OH at 60 0C,123A Taft LFER plot yields a p value of +0.81, suggestingthat there is a carbanion intermediate followed by a concerted reaction to form (128), in accord with an Elcb-type mechanism. Such a mechanism also applies to the conversion of (129) into (130) in EtONa-EtOH, which proceeds 2 x lo6 times faster than the analogous elimination reaction of EtSO,CH,CH(Me)OMe to form (E)-EtS02CH=CHMe.124The massive rate difference has been ascribed to the strain in the epoxide ring of (129).

Thermal and Photochemical Reactions. Electrocyclic ring-~pening'~~ and the gas-phase combustion of oxirans126have been reviewed. A versatile conversion of ketones into enones is illustrated by the condensation of 4-methylcyclohexanone with MeClCS(0)Ph to give the sulphinyl epoxide (131), which readily rearranges, on thermolysis at 150 "C, to the enone (132).12' A thermolysis route may be used to convert cyclic ap-epoxy-ketones into acetylenic carbonyl compounds.128 The conversion of 3,5,5-trimethyl-2,3epoxycyclohexanone into (133; Z = 0 or NPh), followed by heating in polar solvents, gave (134); the method failed, however, when using acyclic epoxyketones. SOPh

-

Thermal isomerization of the tropone oxide (135) gave the bicyclic compound (136), whereas the dibenzotropone oxide (137) was converted into (138).12' 123

124

12' 126

12' 12*

M. Hassan, A . R. 0. Abdel Nour, and A. M. Satti, Rev. Roum. Chim., 1978,23,747(Chem. Abs.,

1978,89,128 756). R. J. Palmer and C. J. M. Stirling, J. Chem. SOC.,Chem. Commun., 1978,338. R.Huisgen, Angew. Chem., Int. Ed. Engl., 1977, 16,572. J. A . Barnard, in 'Comprehensive Chemical Kinetics', ed. C. H. Bamford and C. F. H. Tipper, Elsevier, Amsterdam, 1977,Vol. 17,p. 441. D. F. Taber and B. P. G u m , J. Org. Chem., 1979,44,450. G . A. MacAlpine and J. Warkentin, Can. J. Chem., 1978,56, 308. T. Tezuka, M. Shinba, T. Abe, R. Miyamoto, and T.Mukai, Heterocycles, 1978,11, 149.

22

Heterocyclic Chemistry

Photolysis of the naphthaquinone oxide (139; R' = Ph) in the presence of norbornadiene in benzene solvent gave a mixture of products including the primary adduct (141) formed by addition of the carbonyl ylide intermediate (140) to the diene.13' Similar irradiation of (139; R' = Me) in the presence of aldehydes or ketones gave [142; R' = H, R2 = Me or Et; or R'R2 = (CH2)4 or (CH,),] through a similar interrnediate.l3l

0

Reactions with Organometallic Compounds. A review of the reactions of organometallic (Mg, Zn, Cd, and Al) compounds with epoxides has been published,13*as have some synthetic applications of organo-copper reagents and their reactions with epoxy-compounds. '33 The reaction of RZCuLi [R2 = EtCH=CH, Me2C=CH, or CH2=CMe(CH2)4] with epoxides (143; R' = H or Me) gave (144).'34 The reaction proceeds with unchanged stereochemistry of the R2 group and a high selectivity for the trans-isomer of the newly formed bond. An extension of these syntheses of 1,4- and 1,5-alkadienes has led to the highly stereoselective pre~ ~stereoselective paration of the insect sex pheromone (145) and p r o p y l ~ r e . 'A synthesis of homoallylic alcohols containing trisubstituted double bonds, e.g. 130

13'

133 134

135

H. Kato, H. Tezuka, K. Yamaguchi, K. Nowada, and Y. Nakamura, J. Chem. SOC.,Perkin Trans. I , 1978,1029. K. Maruyama and A. Osuka, Chem. Lett., 1979,77. G. Boireau, D. Abenhaim, J. L. Namy, andE. Henry-Basch,Zh. Org.Khim., 1976,12,1841 (Chem. Abs., 1977, 86, 29 065). R. Noyori, Yuki Gosei Kagaku Kyokai Shi, 1976, 34,675 (Chem. Abs., 1977,86,42 527). C. Cahiez, A. Alexakis, and J. F. Normant, Synthesis, 1978, 528. A. Alexakis, G. Cahiez, and J. F. Normant, Tetrahedron Lett., 1978, 2027.

Three-membered Ring Systems

23

(CH,),OAc M e ( C H z P Bun

(145)

(146)R (147)R

=

=

Cu CH2CH20H

(147), has been ~ e p 0 r t e d . An l ~ ~organocopper reagent (146), prepared from PfMgBr with [CuBr(Me2S)]followed by treatment with Bu"C=CH, reacted with ethene oxide in the presence of LiCECPr (which renders the mixed cuprate more reactive). The use of 10% CuI as a catalyst in the reaction of allylic Grignard reagents with epoxides has a marked effect upon product distrib~ti0n.l~~ In the case of the 'isoprenyl' reagent Me2C=CHCH2MgCl, its reaction with [148; R' = H, R2 = H or Me; or R'R2 = (CH2)4]leads to y-products (149) containing only a trace of a-product (150). In the presence of 10% CuI, however, the product distribution is reversed, to yield (150) as the almost exclusive product (97-99%).

In the presence of [Pd(PPh,),] catalyst, 1,3-diene-1,2-epoxides undergo site'~~ specific isomerization to give dienols; e.g., (151) to (152) ( ~ O Y O ) . Epoxides derived from simple 1,3-dienes in five- to eight-membered rings give the corresponding By-unsaturated ketones, thus providing ready access to cyclopent-2enone (154) (77%) from cyclopentadiene oxide (153).

*hCH2OH (151)

(152)

li'c.+ryo (153)

(154)

The complexed dialkylgermylene Et,Ge.NEt3 reacts with styrene oxide to Ethene oxide, form (Et2GeO), and (155) uia the intermediate german01-1e.l~~ with PhClGe, gave Ph(ClCH2CH20)Ge,which, with excess of epoxide, produced (156); this dimerized to (157).I4O

(155) 136

'31

140

(156)

(157)

P. R. McGuirk, A. Marfat, and P. Helquist, Tetrahedron Lett., 1978,2465. G. Linstrumelle, R. Lome, and H. P. Dang, TetrahedronLeft., 1978,4069. M. Suzuki, Y. Oda, and R. Noyori, J. Am. Chem. SOC.,1979,101,1625. J. Barrau, M. Bouchaut, H. Lavayssiere, G. Dousse, and J. Satgk, Helv. Chim. Actu, 1979,62, 152. A. Castel, P. Riviere, J. Satge, and A. Cazes, C.R. Hebd. Seances Acad. Sci. Ser. C. 1978,281,205.

24

Heterocyclic Chemistry

A novel synthesis of carboxylic esters, e.g. (159), is via the dimerization of terminal epoxides (158), induced by Rh' or Ru" catalyst^.'^' The reaction of two different epoxides gave a mixture of all four possible esters.

Miscellaneous Reactions of Oxirans. Epichlorohydrin (160; X = Cl) is some 3 times more reactive than cyclopropylcarbinyl chloride and 100 times more reactive than ally1 ctloride towards a c e t o l y s i ~Recent . ~ ~ ~ results indicate that this acetolysis does not involve initial ionization at the carbinyl position but rather occurs by initial opening of the oxiran ring by Strong evidence for this conclusion was obtained by comparing the rates of acetolysis of (160; X = C1) and (160; X = p-BrC6H4S03);there was only a marginally faster rate for the latter. If initial ionization at carbinyl carbon were rate-controlling, one would have expected a rate ratio of 102-105 in favour of the latter. Assistance to ionization at a secondary centre by a neighbouring oxiranyl ring has been shown to be of small magnitude (<15-fold) in the hydrolysis of a series of methylsubstituted but-3-en-2-yi-toluene-p-sulphonates(161).'44 A neighbouring oxiranyl group has a minor effect on the stability of an adjacent developing tertiary cationic centre compared with that of a cyclopropyl This conclusion was drawn from comparisons of the rate of solvolysis of (162; X = p-NO2C6H4CO2)with that of the model system (163); the strained bonds of the oxiran increase the rate by a factor of 10, which is far less than the anchimeric assistance to solvolysis afforded by a neighbouring cyclopropyl group.

In the presence of Et4NBr, PhNCO reacts with (160; X = CH2C02Bu")to yield ( 164).'46 More generally, 5-substituted 2-oxazolidinones are formed, The independent of the type of catalyst (nucleophilic or electrophilic) new heterocyclic system (165; R = H, C1, MeO, or NOz) is prepared by the reaction of gem-dicyano-epoxides with KSeCN in acetic anhydride.148 Analogous reactions occur with KSCN. These same gem-dicyano-epoxides undergo ready 141

14* 143 144

145

146

14' '41

J. Blum, B. Zinger, D. Milstein, and 0. Buchman, J. Org. Chem., 1978, 43, 2961. H. Monta and S. Oae, Tetrahedron Lett., 1969, 1347. D. L. Whalen, Tetrahedron Lett., 1978,4973. M. Santelli and J. Viala, Tetrahedron, 1978, 34, 2327. E. N. Peters, J. Org. Chem., 1978,43,4006. T . Ishikawa and H. Hidaka, Meisei Daigaku Kenkyu Kiyo, Rikogakubu, 1978,14,59 (Chem. Abs., 1979,90.6155). D. Braun and J. Weinert, Justus Liebigs Ann. Chem., 1979, 200. A. Robert and A. Le Marechal, J. Chem. SOC., Chem. Commun., 1978,447.

Three-mem bered Ring Systems

25

reaction under neutral conditions with N-substituted thioamides R1C(S)NHR2to give a new synthetic route to anhydro-4-hydroxythiazolium hydroxides (166; R = H, C1, MeO, or NO2; R1 = Ph, p-N02CsH4, Me, Me2N, PhS, or CN; R2 = Ph, PhCH2, or Et) (30-96Y0).'~'Heating aryl-oxirans (167) with urea in DMF gave 4- and 5-aryl-2-oxazolidinones (168; R = H, or 4-N02, -C1, -F, -Ph, or -MeO, or 2- or 4-Me). Electrcn-withdrawing and -donating substituents favoured the formation of the 5- and the 4-isomers, respectively.

Surface-doped active alumina may be used to control epoxide rearrangem e n t ~ The . ~ ~method ~ simply involves shaking the substrate with a slurry of alkali-metal-doped alumina in hexane under nitrogen. By this technique, the epoxy-pinane (169) could be converted into (170) (93%)or (171) (84%) by using AI2O3-NaOH or Al2O3-LiC1, respectively.

2 Oxirens

The intermediacy of oxirens in the photochemical Wolff rearrangement of (172; R' = R2 = H or Ph), (172; R1 = Ph, R2 = Me), and (172; R' = Me, R2 = Ph) was verified by 13C-labellingof the CO group.1529153 Oxiren formation increased with decreasing migratory aptitude of R1. Oxirens were also involved in the '41

lS1 lS2

M. Baudy, A. Robert, and A. Foucaud, J. Org. Chem., 1978,43,3732. A Huth and F. Neubauer, Justus Liebigs Ann. Chem., 1979,56. V.S.Joshi and S. Dev., Tetrahedron, 1977,33,2955. K. P. Zeller, Chem. Ber., 1979,112,678. H. Meier and K. P. Zeller, in Proceedings of the Seventh IUPAC Symposium on Photochemistry, Katholieke Universiteit Leuven, Louvain, Belgium, 1978,p. 234.

26

Heterocyclic Chemistry

formation of (176) and (177) from the photolytic or thermal reactions of (173) via a-oxo-carbenes (174) and (175).'54 A theoretical study of the structures and relative energies of the lowest closed-shell states of the isomers keten, oxiren, and ethynol has revealed that oxiren is about 335 kJ mol-' less stable than keten, which itself is only 146 kJ mol-' less stable than ethyn01.l~~ 0

(173)

(175)

3 Aziridines A study of secondary aziridines has been described,156 and reviews have appeared on aziridines and azetidines (alkyleneimine~)'~'*'~~ and bridged aziridine~.'~~

Preparation.-Direct Insertion. Ethoxycarbonylnitrene (generated upon exposure of benzenesulphonoxyurethane to tetramethylguanidine, in CH2C12,at 8 "C) adds to the bicyclic triene (178; R1 = H, R2 = C1) to yield a mixture from which crystalline (179) and (180) were isolated.16' Similar treatment of (178; R' = Cl, R2 = H) gave a mixture, from which (179; R' = C1, R2 = H) was isolated as

an oil. Addition of Pb(OAc)4to N-aminophthalimide (in CH2C12,at 0-50 "C)in the presence of a large excess of tropone gave (181) (52%); this may be formally regarded as the addition of phthalimidonitrene to the C-4-C-5 bond of tro15'

lS5 lS6 157

158 159

160

U . Timm, K. P. Zeller, andH. Meier, Chem. Ber., 1978, 111, 1549. C.E. Dykstra, J. Chem. Phys., 1978,68, 4244. R. Bartnik, Ph.D. thesis, 1977, Universytet Lodzki, Lodz, Poland (Chem. A h . , 1979,89, 146 747). B. Cervinka, in 'Methodicum Chimicum', ed. F. Zymalkowski, Academic Press, New York, 1975, Vol. 6, p. 591. N.Cromwell, Lect. Heterocycl. Chem., 1976,3, 1. W. Nagata, Lect. Heterocycl. Chem., 1972, 1,29. A. G. Anastassiou and R. L. Mahaffey, J. Chem. SOC.,Chem. Commun., 1978,915.

Three-membered Ring Systems

27

pone.161Decomposition of an azide has afforded syntheses of (182; R = H, Me, C1, or Ph), from norbornene and N3SOZAr,l6'and (183), from 2-methylpropene and N3CN.163

Cyclizations. A new synthesis of aziridines from oxirans by treatment with NaN3 (to form the azido-alcohol) followed by addition of tertiary phosphine (e.g. Ph3P) was used for the conversion of styrene oxide into (184) ( 6 3 Y 0 ) .The ~ ~ ~greatest advantage of this method would seem to be in the syntheses of unsubstituted arene imines such as (185; X = NH) from (185; X = 0). R

Rivc02

b N

N

1

H

(184) R (194) R

R'CHPh

*

=

Ph

=

SiMe3

t 186) (185)

The syntheses of enantiomeric N-benzyl-aziridines, e.g. (186), were accomplished from the corresponding alkyl2,3-dibromopropanoates or dimethyl 2,3In a similar dibromosuccinates by treatment with chiral benzylamine~.'~~.'~~ manner, 2,3-cis-(189) was prepared either from erythro-(187) or from cis- or trans- (188) by reaction with ben~ylarnine.'~~ Optically active ~-aziridine-2carboxylic acid (191; R1 = H, R2 = CH,Ph) was prepared from the serine derivative (190) by sequential 0-tosylation and cyc1ization.l6* PhCHBrCHBrCOzMe (187)

PhCH=CBrCOzMe (188)

phwco2Me N

I

CH,Ph (189)

CHzOH

I

Ph3CNHCHCOZCHzPh (190)

dCo2Ri N R (191)

D. W. Jones, J. Chem. Sac., Chem. Commun., 1978,404. M. Hedayatullah and A. Guy, J. Heterocycl. Chem., 1979,16,201. 163 F. D. Marsh, U.S.P. 4 115 384 (Chem. A h . , 1979,90, 87 239). 164 Y. Ittah, Y. Sasson, I. Shahak, S. Tzaroom, and J. Blum, J. Org. Chem., 1978, 43,4271. K. Harada and I. Nakamura, J. Chem. SOC.,Chem. Commun., 1978,522. K. Harada and I. Nakamura, Chem. Lett., 1978,1171. 1. Nakamura and K. Harada, Heterocycles, 1978,9,473. 16* K. Nakajima, F. Takai, T. Tanaka and K. Okawa, Bull. Chem. Soc. Jpn., 1978, 51, 1577. 16'

28

Heterocyclic Chemistry

The 3-N-aziridinylcyclohex-2-en-1-one (192) was obtained by treating cyclohexa-1,3-diene with NH2CH2CH2R (R = C1 or Br) and cyclizing the product in base.169Fatty acid esters (193; n = 0-8) were prepared (73432%) by the reaction of CH3(CH2),C 0 2 K with HN(CH2CH2C1)2followed by cyclization.17' 2-Trimethylsilylaziridine (194) was produced on reduction of Me3SiCHN3CH2Brwith LiAlH4.17'

via Ring Contraction. Addition of diazoacetonitrile to the para-substituted N-benzylideneanilines (195; R' = H or NMe2,R2 = OMe), (195; R' = H, R2 = NMe2, H, or NO2), or (195; R' = NO2, R2 = Hj in the dark and at In some cases the triazolines decomroom temperature gave triazolines ( 196).172 posed spontaneously to aziridines; e.g., the cis- and trans-isomers (197) and (l-98)in yields of 18% and 2% (R2= H) or 28% and 3% (R2 = NO2).

p-R'C6H4CH=NC6H4R2-p (195)

NCCH2N2

,

:--I;;

P-R'C& (194)

p-R27 G H 4

*-ACN B

C6H4R2-p (197) A (198) A

H

=

ph,B

=

H, B

=H =

Ph

The 'Dewar' thiophen (199) reacts with RN3 (R = H, phenyl, or cyclohexyl) in CH2C12at room temperature to give the adduct (200). This adduct, on irradiation in pentane, gave (201),which was desulphurized with Ph3P to the 'Dewar' pyrrole (202).'73~174

(202) X = NR (200) (201) Cycloaddition of PhC=CH to the indole N-oxide (203), in hot benzene, gave the unstable isoxazolo-indole (204), which isomerized to (205) (57%). ' 7 5 Yields in the range 57-97% were obtained for variously substituted alkynes and indole oxides. 169

170

17'

172 173 174

17'

H. Iida, Y. Yuasa, and C, Kibayashi, Heterocycles, 1978, 9, 1745. I. Manolov and A. Iovchev, Dokl. Bolg. Akad. Nauk, 1978, 31, 311 (Chem. Abs., 1978, 89, 197 233). F. Duboudin and 0 Laports, J. Organomet. Chem., 1978,156, C25. F. Roelants and A. Bruylants, Tetrahedron, 1978,34, 2229. Y. Kobayashi, I. Kumadaki, A. Ohsawa, and A. Ando, J. A m . Chem. SOC.1977,98,7350. Y. Kobayashi, A. Ando, and I. Kumadaki, J. Chem. SOC., Chem. Commun., 1978,509. D . Doepp and A. M. Nour-el-Din, Tetrahedron Lett., 1978, 1463.

29

Three-rnembered Ring Systems

Spectroscopic and Theoretical Studies of Aziridines.-The use of n.m.r. spectroscopy to study compounds with an aziridine ring has been reviewed.'76 Nitrogen inversion in (206) was investigated by 'H n.m.r. spectroscopy; there were two superimposed ABC patterns at room temperature and below, and these were assigned to the pair of invertomer~.'~~ A single pattern was observed at 158.9 "C,and thermodynamic data for the cis-trans equilibrium were calculated. Long-range coupling has been used to show that (207) and (208; R' = H, R2 = Me) exist as a mixture of interconverting conformers whereas (209) and (208; R' = Me, R2 = H) and (208; R'R2 = CH2)adopt single rigid c~nformations.'~~ The 13C n.m.r. spectra of a number of N- (para-substituted pheny1)-aziridines (210) and (211) have been r e ~ 0 r t e d . l ~ ~

0 fiR1 H

H

dCN NI CD3 (206)

'

(207)

H

R2

Me (208)

Me (209)

N

I

(210) R (211) R

= =

H C6H4R-p

Calculated (INDO) structural parameters, electron densities, and bond orders for (212) have been reported.'80 Values determined for the rotational barriers of the aziridine ring about the C-N bond (<29 kJ mol-') were in agreement with experimental results from dynamic 'H n.m.r. studies of the system.'81 Ab initio calculations for anhydrous and hydrated aziridine have revealed barrier heights for proton inversion that are in agreement with those determined by microwave spectroscopy.'82It was found that a dihydrate was responsible for the singlet 'H n.m.r. signal for the hydrated aziridine. The difference in anhydrous (multiplet)and hydrated (singlet) 'H n.m.r. signals for unsubstituted aziridine has been used to show that the organic phase remains essentially anhydrous during a phase-transfer alkylation of aziridine.183 The rate of inversion of the nitrogen atom N" in (213) has been calculated (CND0/2) to be significantly lowered because the lone pair of the nitrogen atom in the ring can conjugate, in the transition state, with the v-electrons of the double bond.184Several types of 176

177

' 7 1 179

180

lS1 lS3

E. Liepins, Larv. PSR Zinat. Akad. Vestis, 1976, 32 (Chem. Abs., 1977, 86,42 564). D. Hoefner, I. Tamir, and G. Binsch, Org. Magn. Reson., 1978, 11, 172. M. Rouillard, L. Ferrero, S. Geribaldi, and M. Azzaro, Org. Magn. Reson., 1978, 11, 133. E. Liepins, A. V. Eremeev, D. A. Tikhomirov, and R. S. El'kinson, Khim. Geterotsikl.Soedin., 1978, 338 (Chem. A h . , 1978,89,41721). R. Osman, A. Zunger, and Y. Shvo, Tetrahedron, 1978,34,2315. R. Osman and S. Youval, Tetrahedron,1978, 34, 2321. J. Catalan, A. Macias, 0.Mo, and M. Yanez, Mol. Phys., 1977,34, 1429. A. Lopez, M. T. Maurette'-Ft?Ma,tino, and A. Lattes, Tetrahedron Lett., 1978, 2013. A. V. Eremeev and M. A. Shokhen, Khim. Geterotsikl. Soedin., 1978, 480 (Chem. Abs., 1978,89, 59 597).

Heterocyclic Chemistry

30

calculation (CND0/2, INDO, and MIND0/3) have been carried out for Nacetylaziridine (214).18' Conformations with Q, = k60" and 150" existed in equilibrium.

Reactions of -dines.-Detention of the Aziridine Ring. Aziridine attacks conjugated ynones to give 1,3-type addition compounds ( 7 8 4 5 % ) ; thus with (215) the N-substituted aziridine (216) (80%) is formed.186Chloroformates are attacked by 2-cyanoaziridines to form (217; R = alkyl, cycloalkyl, or ary1).18' With the isocyanate (218), 2-cyanoaziridine in PhMe gave (219); this reaction was possible for a wide variety of 2-cyanoaziridines and also for isothiocyanates. lS8 T-7 N PhC =CCOPh (215)

I

dCN

PhC=CHCOPh (216)

N CO,R (217)

dCN BU'C(O)NCO (2 18)

N OCNHCOBu' (219)

The alkenyl-triphenylphosphonium bromide derivatives of aziridine [22 1; R1 = R2 = H; R1R2 = (CH2)4; R1 = Ph,R2 = H ; and R' = Bz, R2 = 4N02C6H4]were prepared directly by the reaction of aziridines with (220) at low temperatures, the isomer (222) being obtained at higher t e m p e r a t ~ r e s . ~These ~' derivatives were useful for the synthesis of other heterocyclic systems via rearrangement reactions; e.g., (223) from (222; R' = R2 = H) by heating in MeCN. Vinylaziridine (224), with (220), gave (225).

lS5

lS6

18'

lS8

lS9

N. A. Tarasenko, V. G. Avakyan, and A. V. Belik, Zh. Strukt. Khim., 1978,541 (Chems.Abs., 1978, 89, 196 788). M. G. Voronkov, V. I. Knutov, L. M. Churdesova, and 0.B. Bannikova, Khim. Geterotsikl. Soedin., 1979,55 (Chem. Abs., 1979,90,203 781). E. Bosies, R. Heerdt, R. Gall, U. Bicker, and A. E. Ziegler, Ger. Offen. 2 740 248 (Chem. Abs., 1979,90,203 849). H. Berger, R. Gall, W. Kampe, U. Bicker, and G. Hebold, Ger. Offen. 2 727 550 (Chem.A h . , 1979, 90, 121 395). M. A. Calcagno and E. E. Schweizer, J. Org. Chem., 1978, 43,4207.

Three-membered Ring Systems

31

Ozonation of (226; R = Ph or 4-MeC6H4) in CH2C12 at -78°C gave a colourless solution which, on treatment with excess NaBH4, afforded (227)

phvp

Ph

Me

v C H = C H , H

N R

phoC::Ph

Me

H (225)

(224)

(226) R (227) R

= =

aryl or alkyl H

(>80Y0).'~~ Similar treatment of (226; R = Bu") gave (227) (37%). It was concluded that the C-H bonds in an aziridine ring are remarkably resistant to attack by ozone.

Ring-opening to Acyclic Compounds. A new ring-opening reaction for threemembered heterocycles has been reported.'" Thus aziridine (228; R = H) reacted with phenyl acetate in the presence of a base to yield (229); with (228; R = Me) the product was (230).

N H

AcNHCH~CH~OP~ (229)

AcNHCH2CH(Me)OPh (230)

(228)

Attempts to reproduce the reported reaction192 of 1,3-di-t-butylaziridinone (231) with MeMgI to give (232) have failed.'93 The principal set of products was found to consist of (233) and compounds derived from it. Bu'CH~CH~CONHBU'++ (232)

Bu'wo + MeMgI + BU~CHICONHBU' N (233)

Bu' (231)

Treatment of (234)with 70% H F in xylene gave fluorinated amine (235); this is one of a series of reactions of H F with C-substituted aziridines, affording a new general synthesis of fluoro-amine homologues of phenylethylamine. 194 Aziridinium fluorosulphonates (236; R' = Me or But; R2 = C02Et, C02Me, CN, COPh, or CH20H; R3 = R4 = H or Me) are cleaved with LiCl to p-chloroamine~.~ The ~ ' chloro-amines, with AgS03F, AgC104, or NaBPh,, gave (236) or

R3

Ph Ph +Et H

EtC N H ,

R ' k R '

R' (234)

dCH2 N

F

(235)

/ \

Me (236)

FSO;

/ \

H

Me (237)

(238)

Y. Ito, H. Ida, and T. Matsuura, TetrahedronLett., 1978, 3119. K. Funahashi. Chem. Lett., 1978, 1043. lg2 J. C. Sheehan and M. M. Nafissi-V, J. Am. Chem. SOC.,1969,91,4596. lg3 E. R. Talary, L. M. Pankow, M. B. Deshpande, K. E. Garrett, and A. L. Edwards, TetrahedronLett., 1978,3665. 194 T. N. Wade and R. Guedj, TetrahedronLett., 1978, 3247. J. L. Pierre, P. Baret, and E. M. Rivoirard, J. Heterocycl. Chem., 1978,15, 817.

190

32

Heterocyclic Chemistry

the respective aziridinium perchlorates or tetraphenylborates. A kinetic study has shown that the aziridinium ion (237) rearranges in a first-order reaction to the ring-opened enammonium ion (238).196At 80 "C this process takes place via an intermediate cyclopropaniminium ion. Formation of other Ring Systems.The 2-alkoxycarbonyl-aziridines(239; R = Ph, cyclohexyl, or Pr') react with isocyanates R1C6H4NC0(R' = H, 3-C1, or 4-N02) to form the epimeric imidazolidones (241; R2 = H, R3 = C02Me) and (241; R2 = C02Me, R3 = H) via ring-cleavage to the azomethine ylides (24O).lg7The Ph-C0,Me

Ph

phenyl-aziridines (242; R' = cyclohexyl; R2 = H, C1, Br, Me, or MeO) and (242; R' = Me,R2 = H) underwent 1,3-dipolar cycloadditions with 1,2,3-triphenylcyclopropeneto give the azabicyclohexanes (243) (13-65 A detailed study of the reaction of N-aryl cis-2,3-diphenylaziridines with dimethyl acetylenedicarboxylate and other dipolarophiles provides evidence for the direct generation of azomethine ylides by conrotatory opening of the aziridine followed by stereospecific &,cis -cycloaddition to the dipolarophile.199 Ph

Ph

R' N

COC, H,R2 - p

tjC0c6H4R2-p N R' Ph (243)

*:

lH

H v C O , C H , C H = C HI D ri I L

C0,Me

Intramolecular cycloaddition reactions were observed when cis- or trans -(244) was heated in benzene to yield (245).200The presence of an electron-withdrawing group on the double bond was essential for this reaction, but isomerization of the cis-ylide to the trans-form competed with it. In the presence of benzoic acid, the aziridine (246) reacted with NaNO, to give the oxadiazoline (249).*01A possible 196 '91

19' 199

'01

E. Jongejan, H. Steinberg, and T. J. DeBoer, R e d . Truv. Chim. Pays-Bas, 1979,98, 66. H. Benhaoua, F. Texier, P. Guenot, J. Martelli, and R. Carrie, Tetrahedron, 1978, 34, 1153. T. Uchida, J. Chem. SOC.,Perkin Trans. 1, 1978, 1315. A. C. Oehlschlager, A. S. Yim, and M. H. Akhtar, Can. J. Chem., 1978 56, 273. A. Padwa and H. Ku, J. Org. Chem., 1979,44,255. M. Vaultier and R. Carrie, J. Chem. SOC.,Chem. Commun., 1978, 356.

Three-membered Ring Systems

33

mechanism (Scheme 6) involves initial formation of the iminium salt (247) by addition of benzoic acid to the azomethine ylide from (246), which then reacts with NO2- to form the anion (248). Subsequent cyclization and demethoxycarbonylation of (248) leads to (2433. PIh

CO,Me

%CO,Me EL

[

i ,PhCH=N-CH(C02Me)2 I Ph

(247)

/

0-N

(248)

PhAN'C02Me Ph Reagents: i, PhC0,H; ii, NaNO,

(249)

Scheme 6

Fluorenyl sodium, with N-acyl-aziridines (250; R' = OEt, NPh2, NEt2, or Ph), under N2, in THF, gave a mixture of (251; R2 = H) and (251; R2 = CH2CH2NHCOR')whereas with an excess (>2 equivalents) of (250) the spirocompound (252) was the major product.202Steric hindrance by the bulky t-butyl group of (253; R = But) may account for the low yield of pyrrolidone (254) (31%) on reaction of the aziridine with di-t-butyl malonate, since (253; R = cyclohexyl) gave (254) (75%).203 *

Ph t j C 0 C 6 H 4 R - p N 'ONHR (253)

N CONHR (254)

C6H 11

(255)

R\

NHC6H11

Ph (256)

The unique rearrangement-dehydration reaction which occurs when cis-alkyl2-aryl-3-aroyl-aziridines (255; R = H, Ph, Me, or Br) are treated with a lithium amide to yield indenones (256) has been shown to be H. Stamm and W. Wiesert, Chem. Ber., 1978,111,2665. H.Stamm and J. Budny, Arch. Pharm. (Weinheim, Gel.), 1979,312, 69 (Chem. Abs., 1979,90, 168 395). 204 P.Tarburton, D. K. Wall, and N. H. Cromwell, J. Heterocycl. Chem., 1978,15,1281.

202

' 0 3

34

Heterocyclic Chemistry

The ring conformations of the cyclic tetramers of N-benzyl-aziridines have been investigated by 13Cand 'H n.m.r. spectroscopy.2o5 4 Azirines

The ring chemistry,206the p h o t o c h e m i ~ t r y , ~and ~ ~the * ~ ~thermal ~ reactions of azirines209have been reviewed. Preparation.-The thermolysis or photolysis of isoxazole derivatives yields azirines. The isoxazole (257) isomerizes to an equilibrium mixture of itself and the oxazole (258) at 500 "C, but at higher temperatures either isomer forms azirine (259), which is also the photoproduct of (258)."O Ring contraction of (260; R = H, Br, C1, Me, or MeO) to azirine (261) has been accomplished at 60 "C in the presence of catalytic copper(1) stearate; this is a new method of azirine synthesis.211Solvent and substituent effects on the kinetics suggest a biradical mechanism for the reaction. Estimations of the heats of isomerization of 21 isoxazoles (262; R' and R2 are alkyl or aryl groups; R3 = Me2N, MeO, MeS, or NH2) to azirines have been The reactivities were found to decrease in the order R3 = Me2N > NH2 > M e 0 > MeS.

'Me

N

O

Photochemical or thermal treatment of (263), formed by the addition of 2 equivalents of BrN3 to (Z)-RC(N02)=CHC02Et (R = Me, Et, or Ph), gave

205

206 207 '08

'09 210

'11

"*

K. Tsuboyama, S. Tsuboyama, J. Uzawa, K. Kobayashi, and T. Sakurai, Tetrahedron Lett., 1977, 4603. V. Nair and K. H. Kim, Heterocycles, 1977, 353. A. Padwa, Acc. Chem. Res., 1976,9, 371. P. Gilgen, H. Heimgartner, H. Schmid, and H. J. Hansen, Heterocycles, 1977,6, 143. H. Taniguchi, K. Isomura, and T. Tanaka, Heferocycles, 1977,6, 1563. D . A. Murature, J. D . Perez, M. M.'DeBertorello, and H. E. Bertorello, An. Asoc. Quim. Argent., 1976,64,337 (Chem. A h . , 1978,89,128 847).

R. R. Bekmukhametov, Tezisy DokL-Resp. Konf. Molodykh Uch.-Khim., 2nd, 1977, 49 (Chem. Ah., 1978,89, 162 830). M. I. Komendantov, R. R. Bekmukhametov, and R. R. Kostikov, Khim. Geterotsikl. Soedin., 1978, 1053 (Chein. A h . , 1978,89,214 685).

Three-membered Ring Systems

35

(264).213 Azidobutadiene (265), on heating at 60-80 "C, lost nitrogen to yield the vinyl-azirines (266; R = CN) (goo/,) or (266; R = C02Me)( ~ O Y O ) . ~ ~ ~ The synthesis of optically active azirines (268; R' = Me, Et, Pr", Pr', or CH=CHPh) is accomplished by the esterification of (267) with the respective Optical rotations of anhydride in the presence of 0.25 equivalents of br~cine.~" +47.1, +56.7, +59.8, +5.3, and +8.4" were obtained.

(267) R = H (268) R = OCOR'

Reactions of Azirines.-Photochemical and Thermal Reactions. Some thermal reactions of azirines have been reviewed.216Theoretical calculation^^^^ have confirmed that the preferred photochemicalpath to ring-opening in azirines is via C-C bond rupture whereas thermal opening proceeds via C-N bond rupture. Padwa and his co-workers have been active in the study of the photochemical behaviour of a ~ i r i n e s . ~The ' ~ allyl-substituted azirines (E)-(269; R = Ph), on irradiation in cyclohexane, gave exclusively (270), which, on standing or during chromatography, gave the pyridine (271).218With the electron-withdrawing carbomethoxy-group on the double bond, (E)-or (2)-(269;R = C02Me)gave the same mixture of epimeric compounds (272). These, in turn, were readily transformed into (273) (60%)and (274) (40%) by chromatography on silica gel. p h v M e Me

Ph

phoM R\

(271) R = Ph

H

Meo2c%Me (272)

R (274) R = C02Me

Stern-Volmer analysis of the reactions revealed a rate ratio for (E)-(269; R = Ph) :(2)-(269;R = C02Me):(E)-(269;R = C02Me)of 1:2.7 :30.8. The results were consistent with reaction via a nitrile ylide intermediate, the reaction 213 '14 '15 216

C-G. Shin, Y. Yonezawa, K. Suzuki, and J. Yoshimura, BUR. Chem. SOC.Jpn., 1978,51,2614. K.Freidrich, G. Boech, and H. Fritz, Tetrahedron Lett., 1978,3327. W.Stegmann, P. Uebelhart, H. Heimgartner, and H. Schmid, Tetrahedron Lett., 1978,3091. H. Taniguchi, K. Isomura, and T. Tanaka, Symp. Heterocycl., (Pap.),1977,65 (Chem.A h . , 1978,89,

145 941). 217

21*

B. Bigot, A. Sevin, and A. Devaquet, J. Am. Chem. SOC.,1978,100,6924. A.Padwa and P. H. J. Carlsen, J. Org. Chem., 1978,43,3757.

Heterocyclic Chemistry

36

being cvntrolled by the HOMO of the dipole and the LUMO of the dipolarophile. Thermolysis of (E)-(269; R = C02Me) yields (276) and (277) by a different mechanism, possibly involving a vinylnitrene and the intermediate (275).219At the (269;R

=

C02Me) ? A

Ph@co2Me Me

- I%u N,

C0,Me

+

H

P h W 0 , M e Me

time of writing, the series of papers entitled 'Photochemical Transformations of Small Ring Heterocyclic Compounds' had reached Part 99, which deals with the production of azabutadienes (280) by the photolysis of hydroxymethyl-azirine derivatives (278).220The observation that the rearrangement of the nitrile ylide derived from the azirine (278; R = F) proceeds at a 200-fold faster rate than that derived from (278; R = H) provides support for the intermediacy of an ion-pair (279) in the reaction. If the 1,4-shift of the substituent had occurred by means of neighbouring-group participation, the rate ratio would have been reversed, since (278; R = H) would have given the more stable bridged intermediate (281).

Irradiation of a 1 : 1 mixture of (282) with dimethylfulvene (283) gave a 3 : 1 mixture of the [6 + 41 and [4 + 21 cyclo-adducts (284) and (285) respectively.221 A molecular orbital analysis was used to rationalize product formation.

Cyclization to Fiue- and Six-membered Heterocyclic Systems. The azirine (286 ; R = Me or Ph) reacts with (287; X = 0 or S) to give the pyridinones or pyridinethiones (288).222,223 '19

220 'I 222

223

A. Padwa and P. ti.J. Carlsen, TeirahedronLett., 1978, 433. A. Padwa, P. H. J. Carlsen, and A. Tremper, J. A m . Chem. Soc., 1978,100,4481. A. Padwa and F. Nobs, TetrahedronLett., 1978, 93. S. Chaloupka and H. Heimgartner, Chimia, 1978, 32,468. S. Chaloupka and H. Heimgartner, Helu. Chim. Acta, 1979,62, 86.

37

Threemembered Ring Systems

On regction with aroyl hydrazides RCONHNH, (R = Ph, 4-NO&Hs, or The 4-pyridyl), (286; R = Me) gave the corresponding oxadiazoles (289).224*225 same reaction with the cyclic hydrazide (290) gave (291).226

R Me,N

I

(291)

R

(292) X = S (293) X = NPh

Two similar zwitterionic species (292) and (293) are obtained on treating (286; = Me) with CS2227 or PhNCS,”’ respectively.

Reactions with Metal Carbonyls. The azirine derivative (294) reacts with one equivalent of [Mo(CO)~]in anhydrous THF (30 h, at room temperature, under nitrogen atmosphere) to give a mixture of compounds from which the oxazepine (295) and the pyrroles (296; R’ = H, R2 = H or COPh) and (296; R1 = COPh, R2 = H) were isolated.229The formation of (295) is a purely thermal process involving C-C bond cleavage [on thermolysis at 100°C, (294) yields (295) ( ~ O Y O ) ~Pyrrole ~ ~ ] . formation, however, is believed to involve [M~(Co)~]-induced C-N cleavage and rearrangement of (294). An identical set of compounds was formed when the same azirine was treated with [Fe2(C0)9]in dry benzene, but, in this case, an additional product, i.e. tetraphenylpyridine (297) (8-lO%), was

::a:: N

Ph

CH==CPh(COPh) (294)

Ph

Ph

(295)

R’ (296)

An insertion product (299) was formed as one component of the mixture obtained from the reaction of (298) with [Fe2(C0)9].232 224

225

H. Link, Helv. Chim. Acta, 1978,61,2419. S.Chaloupka and H. Heimgartner, Chimia, 1978,32,332. H. Link, K. Bernauer, S. Chaloupka, H. Heimgartner, and H. Schmid, Helu. Chim. Acta, 1978,61, 2116. E. Schaumann, E. Kausch, S. Grabley, and H. Behr, Chem. Ber., 1978 111,1486. U.Schmid, H. Heimgartner, and H. Schmid, Helu. Chim. Acta, 1979 62,160. F.Bellamy, Tetrahedron Lett., 1978,4577. J. P. LeRoux, J. C. Cherton, andP. L. Desbene, C.R. Hebd. Seances Acad. Sci., Ser. C, 1975,280,37. F.Bellamy, J. Chem. SOC.,Chem. Commun., 1978,998. Y.Nakamura, K. Backmann, H. Heimgartner, H. Schmid, and J. J. Daly, Helu. Chim. Acra, 1978, 61,589.

’” ”*

229

230

231 232

38

Heterocyclic Chemistry Ph

Ph

(CO),Fe -Fe(CO), (299)

5 Thiirans Preparation.-An X-ray crystal structure determination has confirmed that (301) is the product formed when compound (300) is heated with Cu The reaction of azibenzils (302) with thiofluorenone (303), on refluxing in benzene, gave the thiirans (305) (20-86%), probably via the ions (304).234

+s Ar N2 (302) Ar = C6H4R-p R = H, Me, MeO, or C1

8 (303)

ArCOC-S

I

Ar

fj ---*

Ar

\ / (305)

(304)

The cyclic carbonate (306), prepared from bis-(1-hydroxycyclopropyl) sulphide and COCl2, was pyrolysed at 500 "C (0.5 mmHg) to yield methylenethiiran (307).235The thiirans (308) and (309) cleanly decompose to (307) at 600-700 "C with no detectable formation of the isomeric propanethione, suggesting that (307) has the greater thermodynamic stability.236

(306) X = O (308) X = S 233

234 235

236

(309)

W. Wond-Ng and S. C. Nyburg, J. Chem. SOC.,Chem. Commun, 1978,556. S . Mataka, S . Ishii, and M.Tashiro, J. Org. Chem., 1978,43, 3730. E. Jongejan, T. S. V. Buys, H. Steinberg, and T. J. DeBoer, Red. Trav. Chim. Pays-Bas, 1978,97, 214. E. Block, R. E. Penn, M. D. Ennis, T. A. Owens, and S. L. Yu, J. A m . Chem. Soc., 1978,100,7436.

39

Three-membered Ring Systems

Oxirans [310; X = 0,R1 = R2 = €3, R3 = Me or CH2Cl;or R'R2 = (CH2)4, = S) (6068%) by reaction with KCNS in the presence of perhydrobenzo-18-cr0wn-6.~~' Thiocyanate was also used in the preparation of cis- and trans -divinylthiiran (311).2'8

R3 = H] may be converted into the corresponding thiirans (310; X

R2wR1 x

R3

Reactions of Thiirans.-The reactivity of thiirans has been reviewed.239The dithiiran (312) reacts with 25% aqueous MeNH2, in aqueous alcohol containing AgN03, to give a mixture (85%) of the pyrrolidines (313) and (314).240 H

H H

H

Me ( C H 2 ) , V CH, h$(CH2),C02Me

HS Me(cH2)4$~~H2)7C02Me

The Chemistry of Thiiranium Ions.-Reactions which involve intermediate thiiranium and thiirenium ions have been r_e~iewed.~~' Thiiranium salts (316) have been assumed to be intermediates in the addition of sulphenyl halides (315; R = alkyl or aryl, X = halogen) to alkenes, the product being generated by subsequent nucleophilic attack of the halide ion to give trans-addition products (317).242With non-nucleophilic X groups, stable salts may be prepared; e.g., (318; X = Clod,Br3, C1, or C13).243 The reactions of nucleophiles with (318) have

237

238 239

240

241

242 243

I. M. Abdullabekov, F. K. Agaev, A . L. Shabanov, and M. M. Movsumzade, Dokl. Akad. Nauk A z . SSR,1978,6,30 (Chem. Abs., 1979,90,6157). M. P. Schneider and M. Schnaithmann, J. Am. Chem. SOC.,1979,101, 254. A , V. Fokin and A. F. Kolomiets, Usp. Khim., 1976, 4 5 7 1 . I. L. Kuranova and E. V. Snetkova, Zh. Org. Khim., 1978, 14, 2460 (Chem. Abs., 1979, 90, 137 612). G. H. Schmid, Top. Sulfur Chem., 1977, 3 , 101. P. Sammes, Chem. Rev., 1976,76,117. J. Bolster and R. M. Kellogg, J. Chem. Soc., Chem. Commun., 1978, 14.

40

Heterocyclic Chemistry

been studied, and it has been suggested that three modes of nucleophilic opening of thiiranium ions are possible: ( a )ring opening by SN2or E 2 reaction; ( b )attack at the S' atom, leading to desulphuration; or (c) in the case of highly hindered ions, such as (318), dealkylation to afford the parent thiiran together with the a1kylated nucleophile. The species (319; R' = H or Me, R2 = aryl, X = SbF6) reacted stereoselectively with AcO-, HO-, MeO-, F-, and BzNH- in liquid SO, or MeNO, to give mainly the Markovnikov These results contrast sharply with the mainly anti-Markovnikov mode of addition of sulphenyl halides to the same alkenes. This marked difference has been used as evidence against the involvement of thiiranium ions as intermediates in such additions in non-polar solvents.

(319)

(320)

(321)

(322)

A study of the solvolyses of the p-nitrobenzoate (OPNB)esters (320; R = H or Me) and (321; R = H or Me) in 80% aqueous acetone has revealed a four-fold faster rate of reaction for (321; R = Me) than for (320; R = Me).245Since both (320) and (321) give similar ratios of alcohol products, it has been suggested that the common intermediate involved in these solvolyses is (322). 6 Thiirens The detection and properties of thiirens have been reviewed.246Evidence for a methylthiiren intermediate (324; R1 = H, R2 = Me) has been obtained from the gas-phase reactions of 192,3-thiadiazoles (323; R1 = Me,R2 = H) and (323: R' = H, R2 = Me).247 Photolysis of either isomer in the presence of hexafluorobut-2-yne yields the same adduct (325), clearly implicating the common thiiren intermediate (324). Several thiirens, i.e. (324; R1 = R2 = H), (324; R' = CF,, R2 = H), (324; R1R2= CH=CHCH=CH), and (324; R' = Me, R2 = CO,Et), have been prepared by photolysis of the corresponding thiadiazole (323) in an argon matrix and then identified by i.r.

A comparative ab initio and valence-electron study of unsaturated threemembered ring systems includes the first ab initio data on thiiren l-oxide and 244

245 246

247 248

W. A. Smit, A. S. Gybin, V. S. Bogdanov, M. Z. Krimer, and E. A. Vorobieva, Tetrahedron Lett., 1978,1085. J. Ohishi and S. Ikegarni, C h e m ~ ~ ~ ~ - B u l 1 , , , 1 9 7 8 , 2 6 , 3 2 1 1 . M. Torres, E. M. Lown, and 0. P. Strausz, Heterocycles, 1978,11,697. J. Font, M. Torres, H. E. Gunning, and 0. P. Strausz, J. Org. Chem., 1978, 43, 2487. M. Torres, A. Clement, J. E. Bertie, H. E. Gunning, and 0.P. Strausz, J. Org. Chem., 1978,43,2490.

Three-membered Ring Systems

41

l , l - d i ~ x i d eDiphenylthiiren .~~~ 1-oxide (327) has been prepared from (326) by cyclization in refluxing CH2CI2containing Et3N.250A number of reactions of (327) were reported, including photolysis (to PhCECPh), thermolysis (to PhCOCOPh), and treatment with PhCHN2 [to yield (328)l. Examination of the 19F n.m.r. spectra of (329; Z = SO), (329; Z = SO2), and (329; Z = CO) provides evidence for an increase in conjugative effects in the order thiiren 1-oxide < thiiren 1,l-dioxide < cyclopropenone. 0 II

(326)

(327)

(328)

(329)

The thiiren 1,l-dioxide (330; R = Me) reacts with a-metallated nitriles containingno a-proton, (33 1;R = Ph or Me, M = Na or Li), to give two types of cyclic product, (332) and (333), in moderate yields.251Products (332) were derived from attack by a carbanion at the ring carbon whereas (333) came from the initial attack at the sulphur atom. Lithium azide reacts with (330; R1 = Ph) in MeCN at room temperature to give a mixture of products each derived from the common intermediate (334).252Amongst these products was the novel heterocycle (335) (20%).

Ph

Ph

s 0 2

(334)

N3

Ph

Ph (335)

7 Diaziridines

Diaziridines (337; A review of diaziridine chemistry has been R' = H, Pr", Pri, or CH2CH20H)(56-95%) have been prepared from the condensation of amines R'NH2 with oxime esters (336; R = Bu, Ph, or p -

'"H. L. Hase, C. Mueller, and A. Schweig, Tetrahedron, 1978,34, 2983. 251 252

253

254

L. A . Carpino and H-W. Chen, J. A m . Chem. SOC.,1979,101,390. Y. Yoshida, M. Komatsu, Y. Oshiro, and T. Agawa, J. Org. Chem., 1979 44,830. B. B. Jarvis, P. G. Stahly, and H. L. Ammon, Tetrahedron Lett., 1978,3781. S. M. A . Hai, A. W. Qureshi, and A. Begum, Pak. J. Sci. Ind. Res., 1975,18,116 (Chem.Abs., 1977, 86,89 644). A. N. Mikhailyuk, N. N. Makhova, A . E. Bova, L. I. Khmel'nitskii, and S. S. Novikov, Izu. Akad. Nauk SSSR, Ser. Khim.,1978,1566 (Chem. Abs., 1978,89,215 263).

42

Heterocyclic Chemistry

8 Diazirines State-correlation diagrams have been constructed for the conversion of CH2N2 and a theoretical investigation of into diazirine, using natural MO the photochemistry of this system has been attempted.256 Me

Me

>="\ 0,SR

(336)

c1

Me

R

Me (337)

(338) R = OMe (339) R = cyclopropyl

Methoxychlorocarbene may be generated by the decomposition of diazirine (338), prepared from 0-methylisourea toluene-p-~ulphonate.~~~~~~~ The carbene was identified through its capture by alkenes. Similarly, cyclopropylchlorocarbene may be generated from (339).259 A reversible photochemical valence isomerism has been observed between an CY -keto-diazirine and an a-diazoketone.260 When a solution of the diazoketone (340), in aqueous dioxan, was irradiated (>290 nm, for 3 h) the endo carboxylic acid (342) (42.5%) and the diazirine (341) (16%) were isolated, together with recovered (340) (11.4'/0). Irradiation of (341) gave (340) and (342) under the same conditions.

A new class of nitrogen-containing radicals has been identified as the diazirinyl ~ ~ radicals ~ were generated by the radical (343; R = Me, Et, But, Ph, or B z ) . The photolysis of the corresponding azirinyl bromides in the presence of Sn2Bu6.The principal e.p.r. parameters were determined, and INDO calculations gave 14N and I3C hyperfine splittings in good agreement with experiment. Diazirinyls are type I1 radicals, and decay with second-order kinetics to yield the corresponding nitriles. 9 Oxaziridines

Theoretical studies of the acid-catalysed ring-opening of oxaziridines have shown that, for the N-methyl derivatives (344; R = Me) and (344; R = Ph), pro255

2S6

257

B. Bigot, A Sevin, and A. Devaquet, in 'Proceedings of the Seventh IUPAC Symposium on Photochemistry', Katholieke Universiteit Leuven, Louvain, Belgium, 1978, p. 46. B. Bigot, R. Ponec, A. Sevin, and A. Devaquet, J. A m . Chem. SOC.,1978,100,6575. N. P. Smith and I. D. R. Stevens, Tetrahedron Lett., 1978, 1931.

R. A. Moss and W-C. Shieh, Tetrahedron Lett., 1978, 1935. 259 260

261

R. A. Moss and M. E. Fantina, J. A m . Chem. SOC.,1978,100,6788. T. Miyashi, T. Nakajo, and T. Mukai, J. Chem. SOC.,Chem. Commun., 1978,442. Y. Maeda and K. U. Ingold, J. A m . Chem. SOC.,1979,101,837.

Three-membered Ring Systems

43

tonation occurs at 0, independent of the nature of R.262Calculations using MIND0/3, however, while agreeing with the fact that N-methyl derivatives are protonated at 0, suggest that N-protonation is favoured for C-phenyl derivat i v e ~The . ~ ~thermal ~ and photochemical rearrangements of (345) to amide (346) have been explored through ab initio calculations.264Breaking of the N-0 bond is the first step for both reactions, and the regioselectivity of the reactions may be due to a barrier to the subsequent migration of the H atom that is syn to the lone 1air of electrons on nitrogen.

A new fragmentation reaction of aziridinones has been reported in which (347; R = But) is converted quantitatively into (349) by a vigorous reaction with m-chloroperbenzoic For (347; R = Ph), a 6O-7O0,h yield was obtained (with added Li2C03,to neutralize the acid formed in the reaction). The proposed intermediate for this reaction is the N-oxide (348).

Oxaziridines are interesting species in that they show a high barrier to inversion, and asymmetry at N.266Optically active oxaziridines have been prepared in 1-19% optical yields by the oxidation of Ph2C=NR (R = Me or But) with m-chloroperbenzoic acid in the presence of chiral alcohols, e.g. (-)-(I?)menthol, or (-)-(I?)- or (+)-(S)-octan-2-01, in CH2C12at -40 "Cfor 8 h.267The first assignments of absolute configurations for oxaziridines have been reported that are based on X-ray structure analysis.268z269 Simultaneous determinations of the enantiomeric composition and the absolute configuration of chiral oxaziridines have been accomplished by n.m.r. spectroscopy and by using a chiral solvating agent.270*271 Addition of the chiral fluoro-alcohol (350; R = phenyl, 9-anthryl, or l-naphthyl) to the mixture of 262

F. Sanz e Cameras, Afinidud, 1978,35, 193 (Chem. Abs., 1978,89, 128 753).

263

J. F. Garvey and J. A. Hashmall, J. Org. Chem., 1978, 43,2380.

' a E. Oliveros, M. Riviere, J. P. Malrieu, and Ch. Teichteil, J. A m . Chem. SOC.,1979, 101, 318. 265

266

267 268

269

270

271

Y. Hata and M. Watanabe, J. A m . Chem. SOC.,1979,101,1323. W. H. Pirkle and P. L. Rinaldi, J. Org Chem., 1977,42, 3217, and references sited therein. A. Forni, I. Moretti, and G. Torre, J. Chem. SOC.,Chem. Commun, 1977, 731. M. Bucciarelli, I. Moretti, G. Torre, G. D . Andreetti, G. Brocelli, and P. Sgarabotto, J. Chem. SOC., Chem. Commun., 1976,60. M. Bogueka-Ledochowsk, A . Konitz, A. Hempel, Z. Dauter, E. Borowski, C. Belzecki, and D. Mostowin, Tetrahedron Lett., 1976, 1025. W. H. Pirkle and P. L. Rinaldi, J. Org. Chem., 1978,43, 4475. A. Forni, I. Moretti, and G. Torre, Tetrahedron Left., 1978, 2941.

Heterocyclic Chemistry

44

isomers causes the oxaziridine enantiomers to have non-identical n.m.r. spectra. Thermal epimerization of (-)-(2S)-(35 1)and (+)-(2R)-(352) has been studied The results suggest that the by polarimetry and ‘H n.m.r. reaction proceeds solely by a nitrogen-inversion mechanism.

10 Thiazirines A book has been published concerning the search for nitrile sulphides and thiazirine~.~~~ Thiazirines have never been isolated, but strong evidence for the existence of phenylthiazirine (354) as a reaction intermediate has recently been Photolysis of phenyl-substituted five-membered heterocyclic compounds, e.g. (353), embedded in PVC, at 10-15 K, generated a species, believed to be (354), which was stable for several hours. On warming, the thermally labile nitrile sulphide (355) was formed; it was identified by U.V. spectroscopy. Ph

N-N As,k *

Ph

\

C=N \ /

S (354)

-+

PhCNS

(355)

’’’ A. Forni, G. Garuti, I. Moretti, G. Torre, and G. D. Andreetti,J. Chem. SOC.,Perkin Trans. 2,1978, 273 274

401. A. Holm, ‘On the Trail of Nitrile Sulphides, Thioacylnitrenes and Thiazirines’, 1978. A. Holm, N. Harrit, and I. Trabjerg, J. Chem. SOC.,Perkin Trans. 1 , 1978, 746.

2 Four-membered Ring Systems ~

~

~~~

BY R. C.STORR

1 Reviews An extensive survey of the development of p-lactam chemistry' and a review of the chemistry of the 1,2-dioxetan ring system have appeared.2 A general review of saturated heterocyclic chemistry contains sections on four-membered rings.3 2 Systems containing One Nitrogen Atom

Azetidines and Azetines.-It had previously been shown that further photorearrangement of oxaziridines produced from pyrroline 1-oxides leads to both azetidines and pyrrolidinones, in proportions that depend upon the substituents. However, 2-cyano- 1-pyrroline 1-oxides undergo clean photorearrangement at 254 nm in benzene to give only the cyanoformyl-a~etidines.~ A streamlined route to azetidine nitroxides involves addition of chlorosulphonyl isocyanate to an alkene, hydrolysis, and O-methylation, followed by reaction with two equivalents of Grignard reagent and finally N-oxidation.' The synthesis of biazetidinyl has completed the series of cyclic hydrazones (1; n = 2-5). The molecule exists predominantly in the s-trans conformation, in line with the general gradation from s-trans to gauche as strain is decreased. The key step in the formation of biazetidinyl involved steady-state photolysis of tetrazene (2).Flow pyrolysis of (2) at 300 "C gave (l-azetidinyl)acetonitrile.6

The aziridine (3) exists as the open azomethine ylide in acetonitrile in the presence of LiC104,and, by virtue of this activation, reaction with the carbanions from bromomalonate and bromomalononitrile to give azetidines occurs at low A. K. Mukerjee and A. K. Singh, Tetrahedron,1978,34, 1731.

' K. A. Horn, J-Y.Koo, S. P. Schmidt, and G. B. Schuster, Mol. Photochem., 1978-9,9,1. N. F. Elmore, Gen. Synth. Methods, 1978, 1, 197. D. St. C. Black, N. A. Blackman, and A. B. Boscacci, Tetrahedron Lett., 1978, 175. J. C. Espie, R. Ramasseul, and A. Rassat, Tetrahedron Lett., 1978, 795. K. Kirste, W. Luettke, and P. Rademacher, Angew. Chem., Int. Ed. Engl. 1978, 17, 680.

45

46

Heterocyclic Chemistry

temperature^.^ The combined reagent PPh,-CCl,-NEt, provides a convenient 'one-pot' route to 1-methyl-azetidines from the corresponding 3-amino-alco-hols.' Methylene imine has been observed directly, and ttapped at low temperature, in the gas-phase pyrolysis of azetidine.' The perfluorinated methyleneazetidine (4) has been reported to be produced from the reaction of perfluoroisobutene and

(4)

thionyl amines (RNSO)." The ketenimine (9,with ethyl vinyl ether, also gives a methyleneazetidine (6);this undergoes ring expansion with cyclohexyl isocyanide to give (7). With phenylacetylene, the ketenimine ( 5 ) is reported to give both the methyleneazetine (8) and iminocyclobutene (9).'

\

OEt

(6)

,-N SO, Ph F 3 E b Ph

-

The azetine (12) is observed as a product of thermolysis of the iminocyclobutanes (11)during isolation of the latter from photolysis of (10).l2

Me2CH-C-

II

C-CH2CHMe2 hV,

II

O N 'OEt

""c:;

rN--OEt

- - + 7T

COCHMe,

A

Me Me (11)

Me Me (12)

(10)

* 10

l1 l2

M. Vaultier and R. Carrie, Tetrahedron Lett., 1978, 1195. V. Stoilova, L. S. Trifonov, and A. Orahovats, Synthesis, 1979, 105. V. V. Volkova, L. E. Gusel'nikov, V. N. Perchenko, V. G. Zaikin, E. I. Eremina, and N. S. Nametkin, Tetrahedron Lett., 1978, 577. Y. V. Zeifman, E. G . Ter-Gabrielyan, D . P. Del'tsova, and N. P. Gambaryan, Izu. A k a d . Nauk SSSR, Ser. Khim., 1979, 396. D. P. Del'tsova and N. P. Gambaryan, Izv. A k a d . Nauk SSSR, Ser. Khirn., 1978, 880. P. Baas and H. Cerfontain, Tetrahedron Lett., 1978, 1501.

Four-membered Ring Systems

47

Several N-phenyl-benzazetines have been obtained, together with dihydrophenanthridines, by intramolecular cyclization of the arynes (13) formed by

elimination from 2- or 3-halogeno-N-phenyl-benzylamines.The method was only successful when R’ and R2 were alkoxy-groups, and it failed when the N-phenyl group was replaced by methyl.13 The high reactivity of the fused benzazetines produced by 1,3-dipolar cycloaddition to benzazetes has been further exploited. Thus the cycloaddition of nitrile imines to 2-phenylbenzazete (14) gives the novel 1,3,5-benzotriazepines (15) by spontaneous rearrangement of the initial cyclo-adduct (Scheme 1).With diazomethane, the primary adduct

Ph

(17) Reagents: i, PhN-AGCAr; ii, CH,N,; iii, H’

Scheme 1

(16) undergoes thermal cleavage to the azidostyrene (17), but, in the presence of acidic catalysts, rapid loss of nitrogen occurs, giving the indoles (18) and (19) and the ketone (20).14 Azetidinones.-There has again been considerable activity in the area of plactams. Much of this work is highly specialized, and is concerned with compounds of pharmaceutical interest such as penicillins, cephalosporins, and related analogues; these fall outside the scope of this review. While selected l3 l4

K. Krohn, D. Carboo, and U. Puttfarcken, Justus Liebigs Ann. Chem., 1978,608. P. W. Manley, R. Somanathan, D. L. R. Reeves, and R. C. Storr, J. Chem. SOC.,Chem. Commun., 1978,396.

48

Heterocyclic Chemistry

highlights from this area are mentioned, this section is mainly limited to simple azetidinone chemistry involving the formation and the transformations of this four-membered ring system. The c.d. spectra of a series of polysubstituted p-lactams of known configuration all show an n,-+ r * Cotton effect, centred about 225 nm, whose sign best fits with the Ogura lactam rule.I5 A novel ring contraction to a p-lactam is observed in the desulphurization (Raney nickel and MeOH) of the thiazolones (21).16 The reaction of CNdiphenylnitrone with hexafluoropropene gives 2-azetidinones (22) in low yield. l7 Simple procedares for the N-alkylation of p-lactams (alkyl halide and powdered KOH in THF contaigng 10% Bu4N+Br-)18and for the oxidative decarboxylation Q€ azetidinecarboxylic acids to give azetidinones” have been described. The reaction of ketens or acid chlorides with imines is one of the most important routes to azetidinones,%nd recent applications are numerous.2oFor example, addition of halogeno-cyanoketens to formimidates and thioformimidates gives p-lactams in which the 3-cyano-group and 4-H are trans; these can be elaborated further by virtue of the 3-hal0gen.’~A new route to a-amino-p-lactams involves what is formally the addition of enamido-ketens (23) to imines, followed by hydrolysis.22

8 R

RCOCH=C

w s R’ (21)

(22)

/ \

Me NHCH=C=O

(23) R

=

OEtorMe

The scope of the reaction of conjugated imines with azidoacetyl chloride to give cis-p-lactams as precursors to 1-carba-cephams has been further explored, using a series of cinnamylideneanilines and azidoacetyl chloride. cis-&Lactams are formed in high yield with relatively electron-rich aniline derivatives, but for others, mixtures of cis and trans or only trans products are formed, in lower yield. This is attributed to intervention of keten [2 + 21 addition, rather than nucleophilic attack on the azido-acid chloride, as the nucleophilicity of the nitrogen of the Schiff base falls.23Recent applications of this method include syntheses of the tricyclic p-lactam (24)24and of the azetidinone (25), in which it was hoped that the l5 l6

l7

l9

2”

’’ ” 23 24

R.Busson, E. Roets, and H. Vanderhaeghe, J. Org. Chem., 1978,43,4434. T . Sheradsky and D. Zbaida, Tetrahedron Lett., 1978, 2037. K. Tada and F. Toda, Tetrahedron Lett., 1978, 563. D. Reuschling, H. Pietsch, and A. Linkies, Tetrahedron Lett., 1978, 615. H. H. Wasserman and B. H. Lipshutz, Ger Offen. 2 747 494 (Chem. Abs., 1978,89,129 384). See, for example, H. Hoberg and J. Korff, Justus Liebigs Ann. Chem., 1978, 11 11 ;T. Kametani, S. Yokohama, Y. Shiratori,S. Aihara, K. Fukumoto, and F. Satoh, Heterocycles, 1979,12,405;M. Rai, K. Krishnan, and A. Singh, Indian J. Chem., Sect. B, 1978,16,832; K. M. Hassan, 2.Naturforsch., Ted B, 1978,33,1508; and A. M. Osman, K. M. Hassan, M. A. El-Maghraby, H. S. El-Kashev, and A. M. Abdel-Mawgoud, J. Prakt. Chem., 1978,320,482. D. M. Kunert, R.Chambers, F. Merier, L. Hernandez, and H. W. Moore, Tetrahedron Lett., 1978, 929; R. Chambers, D. M. Kunert, L. Hernandez, F. Merier, and H. W. Moore, ibid., p. 933. S. D. Sharma and P. K. Gupta, Tetrahedron Lett., 1978,4587. G . Just, A. Ugolini, and R.Zamboni, Synth. Commun., 1979, 9, 117. G. Just and R. Zamboni, Can. J. Chem., 1978, 56, 2720, 2725; G. Just, G. H. Hakimelahi, A. Ugolini, and R. Zamboni, Synth. Commun., 1979, 9, 113.

Four-membered Ring Systems

49

electron-withdrawing group on the nitrogen of the p-lactam would provide electronic activation towards nucleophilic

C0,Me

\

1

R = Bu‘Me,SiO>

H

I

C0,Me I

(25)

The previously reported photochemical synthesis of N-substituted 3-hydroxyazetidin-2-onesfrom NN-disubstituted a-oxamides (26) has been extended to give an N-unsubstituted derivative, but only in the case of (26; R’ = H, R1 R2COCONCH2R3 (26)

R2 = R3 = Ph).26Reductive dechlorination of 3-phenoxyacetamido-4-chloroazetidinones has been achieved with Bu3SnH-AIBN. With the phthalimido analogues, reduction of the phthalomido-group or of the four-membered ring occurred in prefe~ence.~’ Trichloroethyl-6-diazopenicillinate has been used as the starting point for Other work preparing spiro-penicillins28and 6-0x0- and 6-thio-peni~illanates.~~ of interest includes a total synthesis of n o ~ a r d i c i nan , ~ ~alternative route from penicillin to the nocardicin ~ k e l e t o n ,syntheses ~~ of (&)-3-aminocardicinic ” 26

*’ ’*

29 30

31

G. Just and T-J. Liak, Can. J. Chem., 1978, 56, 211. M. Shiozaki and T. Hiraoka, Synth. Commun., 1979,9, 179. C. A. Whitesitt and D. K. Herron, Tetrahedron Lett., 1978, 1737. J. C. Sheehan, E. Chacko, Y. S. Lo, D. R. Ponzi, and E. Sato, J. Org. Chem., 1978,43,4856. P. J. Giddings, D. I. John, and E. J. Thomas, Tetrahedron Lett., 1978, 995. G. A. Koppel, L. McShane, F. Jose, and R. D. G. Cooper, J. Am. Chem. SOC.,1978,100,3933. M. Foglio, G . Franceschi, P. Lombardi, C. Scarafile, and F. Arcamone, J. Chem. SOC., Chem. Commun., 1978,1101.

50

Heterocyclic Chemistry

t h i e n a m y ~ i n ,and ~ ~ clavulanic acid analogues,34 a new route for the conversion of penicillin derivatives into optically active 4-acyloxy-azetidinone~,~~ and a simple preparation of the 4-mercapto-azetidinone (28) from the penicillinderived p-lactam (27).36Interestingly, (28) is converted into the thiazole (29) on

phocH2Yo

N6SCH,OPh

HN

I X ;

HB-&

0

--+

0

CO,CH,Ph

CO,CH,Ph (28)

(27)

CH20Ph

\

phocH2\r" HNrsH HN

phocH2Yo 0

+

4

7

0

H

*

C0,CH ,Ph

H

CO,CH,Ph

CO ,CH Ph

heating, not via the thiazoline (27) but possibly as shown. Kinetic evidence has been presented for a tetrahedral intermediate in the aminolysis of benzylpenicillin,37 and further procedures of dephthaloylation of phthalimido-azetidinones3* have appeared.

. .. I, I1

PNPh 0

R2 Me,Si

. ...

Z

0

P

h

"$Nph

0

Reagents: i, LiNPr;; ii, Me3SiC1;iii, R1COR2

Scheme 2

Methyleneazetidinones have been prepared as shown in Schemes 239and 3,40 the methylthiophenylketen (30) being of interest as an equivalent of methylH. H. Wasserman and J. D. Hlasta, J. A m . Chem. SOC.,1978, 100, 6780. L. D. Cama and B. G. Christensen, J. A m . Chem. SOC., 1978,100,8006. 34 P. H. Bentley, G. Brooks, M. L. Gilpen, and E. Hunt, J. Chem. SOC., Chem. Commun., 1977,905, 906; P. H. Bentley and E. Hunt, ibid., 1978,439, 518. 35 A. Suarato, P. Lombardi, C. Galliani, and F. Giovanni, Tetrahedron Lett., 1978, 4059. 36 J. E. Baldwin and M. A. Christie, J. Chem. SOC., Chem. Commun., 1978, 239. 37 N. P. Gensmantel and M. I. Page, J. Chem. SOC., Chem. Commun., 1978,374. ji3W .D. Kingsbury, Ger. Offen. 2 748 258 (Chem. Abs., 1978,89,43 094); S . Kukolja, S.R. Lamrnert, and I. Ellis, Croat. Chem. Acta, 1977, 49, 779. 39 S. Kano, T. Ebata, E. Funaki, and S . Shibuya, Synthesis, 1978, 746. 40 T. Minami, M. Ishida, and T. Agawa, J. Chem. SOC., Chem. Commun., 1978, 12. 32

33

Four-membered Ring Systems

51

RN=CHPh Scheme 3

eneketen. Another new, simple approach to the system involves treatment of (BrCH2)*CHCONHR with base under conditions of phase-transfer catalysis.41 The product of photolysis of the pyridopyrimidine (31)in methanol or ethanol has also been assigned the methylene-p-lactam structure (32).42The bicyclic plactams (34; R = H or Ph) are formed by the action of hydrazine and phenyl-

0

ArN=N RNHNH,,

O w N R

PhN

---‘hf I .

C0,Et

hydrazine on the azo-compound (33).43Photolysis of the diazo-compound (35) gives the novel amino-ketenimine (36), which with benzylideneaniline gives the imino-azetidine (37).44 Ph2N-C-CHN2 II NCN

(35)

hu

--+ PhZN-C-eH II

NCN

__*

Ph&JCH=C=NCN (36) PhCH=NPh

Ph

(37)

Four delicately balanced reaction pathways have been identified for the diazabicyclic ketone (38), as shown in Scheme 4. Thermal transformations 41 42

43 44

S. R. Fletcher and I. T. Kay, J. Chem. Soc., Chem. Commun., 1978,903. T. Yamazaki, M. Nagata, S. Hirokami, Y. Hirai, and T. Date, Heterocycles, 1978,9, 505. F. A. Amer, A. H. Harbash, and M. L. Awad, 2.Naturforsch., Teil B, 1978,33,660. B. Arnold and M. Regitz, Angew. Chem. Int. Ed. Engl., 1979,18,320.

52

Heterocyclic Chemistry

proceed through the diazepinium betaine (39); in acid solution the products can be accounted for by protonation at N-1 and attack by nucleophiles at C-3 of (38), followed by further transformations. In methanol, the unstable carbinolamine (41),formed by methanolysis of the azztinone (40),has been detected as the precursor to the observed products. Finally, in aqueous methanolic base there is evidence that initial attack by base on the carbonyl group of (38; R = Ph) can occur, leading in this case to glycine and (42) as the major

RCO

RCO (38)

J P h Men o \+

iiI

P f l

RCO

phi&yo NH

Nuc

N-N I

ii\

N-N

I H

RCO

I

RCO

(40)

(39)

1 1

1

1 1

NH

OMe

I

RCO

OMe Reagents: i, A; ii, H', Nuc; iii, MeOH, at 50 "C;iv, MeO-

RCO (41)

Scheme 4

45

J. A. Moore and B. Staskun, J. Org. Chem., 1978,43,4021.

Four-membered Ring Systems

53

The meso-ionic 1,2,3-triazines (43) are formed from chloroformyl-ketens and triazenes in ether. On heating, triazine (43) loses nitrogen and azobenzene to give the 3,3’-biazetidine tetraone (44).46Malonimides (45)give 1,4-diazepines (46) with amino-azirines in 2-propanol at room temperat~re.~’ PhN=N-NHR’

+ ClCO

>c=o

R2

-

6

0 P hI: N Y ’ A PhN$h N*:.‘0 R’ = R2 = Ph ‘N 0 R‘ (43)

“Ph

Ph

0 (44)

3 Systems containing Two Nitrogen Atoms Conformational studies on 1,2-diazetidines have Photoelectron spectra for (47) show that the molecule exists overwhelmingly in the diequatorial trans-conformation for R = Me, whereas a significant amount of the trans-diaxial conformer is detected for R = CHMe2.48N.m.r. studies also indicate that the diequatorial conformation is preferred for small R but that the di-t-butyl compound exists in the diaxial form. Variab:e-temperature n.m.r. data indicate that double inversion about the nitrogen atoms in (47)is slow, but that ring flipping is fast.49 The 1,4,5,6-tetrahydro-u-tetrazine(48), readily obtained from a-lithiated N-alkyl-nitrosamines via the N-oxide, does not give a diazetidine on pyrolysis or photolysis; the trimer of N-methylmethyleneimine is produced instead.”

R

(49)

(48)

Thermal decomposition of the stereoisomeric diazetines (49) is cis stereospecific and does not give an electronically excited product in spite of the high exothermicity of the reaction. Rapid loss of nitrogen from a diradical inter46

47 48

49

T. Kappe, W. Golser, and W. Stadlbauer, Chem. Ber., 1978, 111,2173. B. Scholl, J. H. Bieri, and H. Heimgartner, Helv. Chim. Actu, 1978,61, 3050. S. F. Nelson, V. E. Peacock, G. R. Weisman, M. E. Landis, and J. A. Spencer, J. Am. Chem. Soc., 1978,100,2806. J. H. Hall and W. S. Bigard, J. Org. Chem., 1978, 43, 2785. D. Seebach, R. Dach, D. Enders, B. Renger, M. Jansen, and G. Bracktel, Helv. Chim. Actu, 1978, 61, 1622.

Heterocyclic Chemistry

56 4 Systems containing One Oxygen Atom

0xetans.-The mass spectral cleavage of oxetans has been studied in some detail .67 The Paterno-Buchi reaction continues to be employed widely as a route to oxetans. Examples of intcrest include the rarely applied addition of a fluorinated carbonyl compound to a normal alkene68and the reaction of 3-chloro-2-methyll-propene with aryl aldehydes, which leads to diastereoisomeric chloromethylsubstituted oxetans; this gives potential access to other functionalized ~ x e t a n s . ~ ~ Several examples of additions involving the carbonyl group of imides have a ~ p e a r e d ; ~for ' , ~ example, ~ N-methylsuccinimide and isobutene give (67). With N-methylphthalimide, ring insertion to give (68) occurs, rather than cycloadditi~n.~'

Photoaddition,of phenanthraquinone to a series of cyclic alkenes gives (69) and (72) in addition to the expected dihydrodioxin (70) and the keto-oxetan (71), the proportions of products being very dependent on the structure of the alkene. Compound (72) arises by further photorearrangement of the oxetan (71), and the products can be accommodated as shown in Scheme 5.72 Photolysis of 6-acetyluracil (73) gives the oxetan dimer (74) as the major product from the singlet state. A double dioxetan is considered as a possible intermediate.73 Several examples of intramolecular formation of oxetans from 3,4-epoxyalcohols, e.g. ( 7 9 , and base have appeared, and the factors responsible for directing this reaction to give oxetan rather than oxolan have been Further studies of the competing modes of reaction (fragmentation, cyclization, substitution, and elimination) of 3-halogeno-propanols with base show that, for unstrained tertiary halides, fragmentation competes with elimination, and oxetan formation is only observed to a small Quadricyclane and its 3-substituted derivatives give both cyclobutanones and diphenylmethylene-oxetans with d i ~ h e n y l k e t e nThe . ~ ~ketone (76) and tetrafluoroethene, in the presence of SbF5, G. Jones and L. P. McDonnell-Bushnell, J. Org. Chern., 1978,43, 2184. 0. Paleta, J. Svoboda, and D. Vaclav, Collect Czech. Chern. Comrnun., 1978, 43, 2932. 69 H. Ruotsalainen, Acta Chern. Scand., Ser. B, 1978,32,417. 70 K. Maruyama and Y. Kubo, Chem. Lett., 1978, 769; P. H. Mazzocchi, S . Minamikawa, and M. Bowen, Heterocycles, 1978, 9, 1713. 71 Y. Kanaoka, K. Yoshida, and Y. Hatanaka, J. Org. Chern., 1979,44664. '' K. Maruyama, T. Iwai, Y. Naruta, T. Otsuki, and T. Miyagi, Bull Chern. SOC.Jpn., 1978,51,2052. 73 A. Sarpotdar and J. G. Burr, Photochem. Photobiol., 1978, 28,401. 74 T. Masamune, M. Ono, S. Sato, and A. Murai, Tetrahedron Lett., 1978,371. 7s W. Fischer and C. A. Grob, Helv. Chim. Acta, 1978,61, 2336. 76 J. Becherer, N. Havel, and R. W. Hoffmann, Justus Liebigs Ann. Chem., 1978, 312. 67

Four-membered Ring Systems

57

\

(71)

Scheme 5

give the ketone (77) and the oxetan (78).77Methylenephosphoranes react with oxirans and oxetans to give cyclic phosphoranes, and this has been applied to 77

G. G. Belen’kii, G. I. Savicheva, E. P. Lur’e, and L. S. German, Izv. Akad. Nauk SSSR, Ser. Khim., 1978,1430.

Heterocyclic Chemistry

58

make spiro-dcrivatives, e.g. (79).78Several other papers in which oxetans receive attention have appeared.79 FC1,zE;

F C=CF

FZClCCOCC12CF2CF3 +

F2CCICOCC12F (76)

F

(77)

F (78)

(79)

n = 4or5

2-Oxetanones (P-Lactones).-A p-lactone structure has been established for the

esterase inhibitor esterastin." Addition of the rather unreactive compound trimethylsilylketen to saturated aldehydes occurs readily, with BF,.Et20 catalysis, to give cis- and trans-2oxetanones, which are thermally stable towards decarboxylation up to 150 "C. With @-unsaturated aldehydes, e.g. cinnamaldehyde, the esters (80) are RCH RCH=CHCHO

+

-

11

-

rLo

---+ RCH=CHCH=CHCOzSiMe3 (80)

produced by rearrangement of 2-oxetanones, whereas decarboxylation to 1,3butadienes occurs with other ketens.'l Consecutive elimination of HBr and CO, from cyclohexane-bromo-P-lactone epoxides provides a versatile route to arene oxides.82 The reaction of 3,3diphenyl-l-oxaspiro[3,5]nona-5,8-diene-277-diones(81) with nucleophiles proceeds via p-quinone methides and 1 This contrasts with the X 0

8

p& \

KCN,

MeLi or MeMgI

0

0

OH X = CN or Me

H. Schmidbaur and P. Hall, Chem. Ber., 1979,112, 501. W. Dmowski and R. A. Kolinska, Pol. J. Chem., 1978, 52, 71; R. Cizmarikova and J. Heger, 2. Chem., 1978,18,380; F . Notheisz and M. Bartok, Acta Chim. Acad. Sci. Hung., 1977,95,335; N. A. Kusnetsov and I. I. Krasavtsev, Ukr. Khim. Zh., 1978,44, 744; K. Baum and P. T. Berkowitz, U.S. P. Appl. 933 364 (Chem.Abs., 1979,90, 186 768); J. Jokisaari, Org. Mugn. Reson., 1978,11, 157. *" H. Umezawa, J. Anfibid., 1978, 31, 797. W. T. Brady and K. Saidi, J. Org. Chem., 1979,44,733. ** B. Ganern, G . W. Holbert, L, B. Weiss, and K. Ishizumi, J. Am. Chem. Soc., 1978, 100,6483. 83 K. Ogino, K. Yoshida, and S. Kozuka, J. Chem. SOC., Chem., Commun., 1978,312. 78

"

Four-membered Ring Systems

59

behaviour of the 3,3-dimethyl analogues (82), where nucleophilic attack at the cyclohexadienone ring is observed.83

0 (82)

Photolysis (A > 2800 A) of the py-epoxy-ketone (83) gives (84) and (85) as the primary products; this parallels the mode of reaction of p y-cyclopropyl-

oHcLPCH=C (85)

The formation of anhydrides by ozonolysis of enol esters has been applied to diketens to produce monomeric malonic anhydrides which undergo fragmentation to CO,and keten at ca. 0 0C.85 a-Methylglycidaldehyde unexpectedly gives the epoxy-p-propiolactones (86) on treatment with aluminium alkoxides.86

5 Systems containing Two Oxygen Atoms

Dioxetans.-Because of their central importance in chemiluminescence, large numbers of papers concerning dioxetans continue to appear. MIND0/3 calculations of the conformations and bond strengths of substituted 1,2-dioxetans indicate that the 0-0 bond is strengthened by increasing alkyl substitution. In principle, this should stabilize the molecule and increase the 84

a6

S. Ayral-Kaloustian, S. Wolff, and W. C. Agosta, J. Org. Chem., 1978,43,3314. C. L. Perrin and T. Arrhenius, J. Am. Chem. SOC.,1978,100,5249. Z.Jedlinski and M. Kowalczak, J. Org. Chem., 1979,44,222.

Heterocyclic Chemistry

60

concerted nature of the fragmentation. Substituents such as alkoxy and fluorine (with lone pairs) tend to weaken the C-C bond such that fragmentation to ground-state products begins with cleavage of the C-C bond.87 The actual mechanism of fragmentation of dioxetan has been the subject of considerable investigation and debate. In general, triplet products predominate considerably over singlet products, and the reaction is insensitive to substituents on carbon. This has led to an increasing acceptance of a stepwise mechanism involving initial homolytic cleavage of the 0-0 bond rather than a concerted fragmentation. Several detailed studies this year support such a mechanism, and the general consensus of opinion can be summarized in Scheme 6.88-91The

Scheme 6

singlet-triplet efficiencies are determined by partitioning of the singlet diradical (87) between singlet carbonyl products and the triplet diradical(88) that leads to triplet carbonyl product. Even for triphenyldioxetan, the most highly phenylsubstituted dioxetan yet produced, evidence is in favour of the reaction proceeding via a diradical resulting from 0-0 bond cleavage, in spite of the fact that resonance stabilization of the developing v b o n d s in a concerted fragmentation should be relatively favourable.9‘ In addition to this ‘normal’ type of dioxetan decomposition, it has been observed that dioxetans bearing strongly electron-donating substituents tend to give very high yields of singlet excited products. This has led to the proposal of an alternative mechanism for such cases,92793for which it is suggested that

88

89 90 91

92

93

P. Lechtken, Chem. Ber., 1978,111, 1413. W. H. Richardson, J. H. Burns, M. E. Price, R. Crawford,M. Foster, P. Slusser, and J. H. Anderegg, J. Am. Chem. SOC.,1978,100,7596. C. Neidl and J. Stauff, 2.Naturforsch., Teil B, 1978, 33, 763. K. A. HornandG. B. Schuster, J. Am. Chem. SOC.,1978,100,6649. W. H. Richardson, J. H. Anderegg, M. E. Price, W. A. Tappen, and H. E. O’Neal, J. Org. Chem., 1978,43,2236. F. McCapra, I. Beheshti, A. Burford, R. Hann, and K. A. Zaklika, J. Chem. SOC.,Chem. Commun., 1977,944; F. McCapra, ibid., p. 946. K. A. Zaklika, A. L. Thayer, and A. P. Schaap, J. A m . Chem. SOC.,1978,100,4916.

61

Four-membered Ring Systems

decomposition proceeds via radical ions and excitation occurs by electron transfer, as illustrated for the dioxetan (89).92 Me

Me

0

+ PhCHO

Also of considerable interest is the observation that the above chemiluminescent reaction is considerably catalysed by surf aces such as A1203 and SOz, although this is not general for all dioxetans. It is suggested that enzyme binding could have a similar effect in natural systems. In recent years, doubts had been cast on the role of dioxetans in bright chemiluminescence and bioluminescence, since this requires rapid decay of singlet states, whereas most dioxetans lead to excited triplets. The above observations, however, re-establish dioxetans as viable species.92 Examination of the activation parameters for decomposition of dimethyldioxetanone reveals two pathways, one leading to excited acetone and carbon dioxide, and the other, a dark reaction, leading to ground-state products. It is not clear whether these two modes are separate reactions or result from branching of an intermediate.94 Full details of the evidence for the intermediacy of zwitterionic peroxides, either open (90) or cyclic (91), in the reaction of norbornenyl ethers with singlet oxygen have appeared. These intermediates can be intercepted with methanol, but, in the absence of such interception, collapse to isolable dioxetans (92)

&Me OMe

Intramolecular interception of the endo-perepoxide intermediate by the adjacent double bond is observed in the case of 7,7-dimethylnorbornadienol A similar perepoxide intermediate is believed to be involved in the 94 95

96

S. P. Schmidt and G. B. Schuster, J. A m . Chem. Soc., 1978,100,5559. C.W.Jefford and C. G. Rimbault, J. A m . Chem. SOC.,1978,100,6437. C.W.Jefford and C. G. Rimbault, J. A m . Chem. Soc., 1978,100,6515.

62

Heterocyclic Chemistry

formation of both hydroperoxide- and dioxetan-derived products from cis- and truns- 1-cyclopropyl-2-methoxyethenes and singlet oxygen. The preferential formation of hydroperoxide from the cis-isomer and dioxetan from the trunsisomer is attributed to an anomeric effect in the intermediate which tends to hold the perepoxide 0- such that it can readily abstract hydrogen from a cyclopropyl group that is cis to the m e t h ~ x y l . ~ ~ A novel intramolecular peroxymercuriation is involved in the formation of the mercuriated dioxetans (94)and (95) on treatment of 2,3-dimethyl-3-hydroperoxy-1-butene (93) in CDC13 with Hg(CF3C02),. The dioxetans were not isolated, since they decomposed to acetone with chemiluminescence, but they could be trapped by bromination. Formation of (95) involves an initial allylic merc~riation.'~

OH

(95)

(94)

HO

\

T

(93)

Fluorescence from excited singlet 9-isobutyrylanthracene- 10-carboxylic acid in the aerial oxidation of 9,lO-di-isobutyrylanthracenelends support to the belief that dioxetans can lead to excited singlet The yields of excited singlet and triplet states from a number of alkyl-dioxetans have been determined. Surprisingly, the dioxetan (96) is very inefficient compared with other rigid tricyclic dioxetans."' The triplet-ketone-sensitized di-v-methane rearrangement of benzonorbornadiene provides a simple, reliable, and general method for the chemical titration of chemically generated triplets in the decomposition of dioxetans.lO1

Photoreduction of dioxetans to cis-l,2-glycols with relatively large amounts of xanthine dyes in protic solvents in visible light has been observed. This occurs in the dye-sensitized reaction of the vinylcyclopropane (97) with lo2,thus supporting the suggestion that dioxetans can be involved in such reactions.102A number G. Rousseau, A. Lechevallier, F. Huet, and J. M. Conia, Tetrahedron Lett., 1978, 3287. W. Adam and K. Sakanishi, J. Am. Chem. SOC.,1978,100,3935. I. Kamiya and T. Sugimoto, Chem. Lett., 1978, 335. loo K. R. Kopecky and J. E. Filby, Can. J. Chem., 1979,57, 283. lo' W. Adam, C. C. Cheng, 0.Ceuto, K. Sakanishi, and K. Zinner, J. Am. Chem. Soc., 1979,101,1324. lo' H. Takeshita and T. Hatsui, J. Org. Chem., 1978, 43, 3080. 97

98

99

Four-membered Ring Systems

63

of other papers concerned with aspects of dioxetan chemistry have also appeared.lo3

6 Systems containing Sulphur The mass spectra of thietan and of its mono- and di-S-oxides have been ana1y~ed.l'~ Ab initio SCF calculations for thiacyclobutadiene (98) indicate that the most stable conformation for the molecule is planar except for the hydrogen that is bonded to the sulphur, which is pyramidal, with a high (estimated) barrier to inversion. The molecule would appear to be essentially non-aromatic.lo'

Di-t-butylthione undergoes addition to electron-rich or -deficient alkenes on + 7r* excitation by irradiation with light of short wavelength. With unactivated alkenes, products arise from H-abstraction by the excited thione followed by combination of the resulting radicals. In contrast, irradiation at long wavelength ( n + 7r* excitation) and triplet sensitization led to no reaction.'06 Other photoadditions have been reported for xanthione and 2-thiaparabonate (99),'07 and spiro-thiets have been produced by photoaddltions of xanthionelo8and (99) to acetyIenes.lo9 The first example of the C3N, C3S-4,4 ring system (101) has been reported in the reaction of the penicillin derivative (100) with triphenylphosphine and v

PPh, EN=NE

ENH

CO,CH,Ph (100)

N-S

HCO,CH,Ph (101) 103

104

105

106 107 108

109

P. D. Bartlett and A. A. Frimer, Heterocycles, 1978, 11, 419; K. T. Alben, A. Auerbach, M. W. Ollison, J. Weiner, and R. J. Cross, J. A m . Chem. SOC.,1978, 100, 3274; C. W. Jefford, A. F. Boschung, and C. G. Rimbault, Singlet Oxygen. Org. Compd. Polym. 1976, ed. B. Ranby and J. F. Rabek, Wiley, New York, 1978, p. 182; N. J. Turro, M. F. Chow, and Y. Ito, ibid., p. 174; M. J. Mirbach, A. Henne, and K. Schaffner, Roc. IUPAC Symp. Photochem., 7th, 1978, 240; P. D. Bartlett, A. L. Baumstark, and M. E. Landis, Reel. Trav. Chim. Puys-Bas, 1979, 98, 104; E. A. Halevi and C. Trindle, Israel J. Chem., 1977,16, 283. A. A. Scala and I. Colon, J. Heterocyclic Chem., 1978,15,421. F. Bernardi, N. D. Epiotis, S. Shaik, and K. Mislow, Tetrahedron, 1977,33, 3061. R. Rajee and V. Ramamurthy, Tetrahedron Lett., 1978, 3463. H. Gotthardt and S . Nieberl, Chem. Ber., 1978, 111, 1471. A. C. Brouwer, A. V. E. George, D. Seykens, and H. J. T. Bos, Tetrahedron Lett., 1978,4839. H. Gotthardt and 0. M. Huss, Tetrahedron Lett., 1978, 3617.

64

Heterocyclic Chemistry

azodicarboxylic ester. 'lo 3-Hydroxy-2-phenylthietanand 3-hydroxy-3-phenylthietan are produced by treatment of 3-chloro- 1-phenylpropylene oxide and 3-chloro-2-phenylpropylene oxide, respectively, with H2S and base. These thietans can be oxidized and dehydrated to give thiet di-S-oxides, although with mineral acid the sulphone (102) unexpectedly gave benzyl methyl ketone (Scheme 7).'11 Addition of an excess of nitrile imine to thiet 1,l-dioxide gave the

i, i i l

ArCH2COCH3

S

-

1 ArCH2COCH2S02H

G.2

Reagents: i, BzS0,CI; ii, NEt,; iii, H,PO,

Scheme 7

pyrazoles (104) by opening of the four-membered ring of the initial cyclo-adduct (103) by a second molecule of the 1,3-dip0le.~~' 2-Halogeno-3-dimethylaminothietan 1,l-dioxides (105) are produced stereoselectively from halogen-substituted methanesulphonyl chlorides and (E)-P-dimethylaminostyrene.Cope elimination gave only the 2-halogeno-thiet dioxide, which could not be converted

-

RI/so2 Nh Ph

(103)

R Ni-,JIC,,,,

Ph

Ph

NNHPh (104)

(105)

into the 2-0x0-derivative by further halogenation and oxidation. l 3 Further studies of the addition of ester-substituted sulphenes to enamines have a~peared.''~ Photolysis of 2-phenylthietan di-S-oxides has been developed as a route to substituted 1-phenylcyclopropanes. l5 Replacement of sulphur by oxygen in a variety of thiocarbonyl compounds can be effected by reaction with bistrifluoromethyl- and diphenyl-ketens. This proceeds via cycloaddition to an oxathietan followed by cycloreversion.116*1l7 With ethylene thiocarbonate and dimethylthioformamide, alkenes are produced via 'lo

F. DiNinno, J. A m . Chem. Soc., 1978,100,3251.

'" F. S. Abbott and K. Haya, Can. J. Chem., 1978 56, 71.

P.D.Croce, P. D. Buttero, S. Maiorana, and R. Vistocco, J. Heterocycl. Chem., 1978,15,515. W. Ried and H. Bopp, Chem. Ber., 1978,111,1527. ' I A A . Etienne and B. Desrnazieres, J. Chem. Res. ( S ) , 1978,484. J. D. Finlay, D. J. H. Smith, and T. Durst, Synthesis, 1978,579. H.Kohn, Y.Gopichand, and P. Charurnilind, J. Org. Chem., 1978,43,4955. 'I7 H. Kohn, P. Charurnilind, and Y. Gopichand, J. Org. Chem., 1978,43,4961. 'I2

Four-membered Ring Systems

65

unstable thietan-2-ones. A stable thietan-2-one structure (106), rather than the previously suggested thietan-3-one, has been assigned to the adduct from diphenylketen and diary1thioketone~."~ Pyrolysis of the tosyl hydrazide (107) led to allene episulphide, and not cyclopropanethione.ll'

(106)

(107)

(108)

The reaction of the dithiet (108) with tervalent phosphorus compounds has been inve~tigated."~ 1,3-Dithietans (109; R = C0,Et or Ph) are formed in excellent yield, presumably via dimerization of the thiocarbonyl compound, by treatment of a-chlorosulphenyl chlorides (110) with triphenylphosphine.12'

C02Et (109)

C02Et Cl+SCl R (110)

The first stable fluorine-containing disulphur(v1) compound (111) has been reported in the chlorofluorination of tetrafluoro-1,3-dithietan. This is converted into the five-co-ordinate sulphur(v1) derivatives (112) and (113) on treatment with the nucleophiles LiN=C(CFJ, and MeN(SiMe3), respectively.12' The vibrational spectrum of tetrafluoro- 1,3-dithietan has also been discussed.12'

(112) R = CF(CF& (113) R = Me

Oxathietanone (114) has been detected at low temperature in the matrix photolysis of SO, and keten.123A more convenient procedure for the synthesis of N-phenyl-1,2-thiazetidin-3-one1-oxide (115) from keten and N-sulphinylaniline has been reported. With arylamines, (115) readily gives the sulphinamides (116), which can be oxidized to the corresponding sulphonamides.'24 In the course of calculations for the potential surfaces for the transformations between sulphene, a-sultine, and singlet carbene and SO2,the possibility was raised that a 118 119

120

121 122 123 124

E. Block, R. E. Penn, M. D . Ennis, T. A. Owens, and S-L.Yu, J. A m . Chem. Soc., 1978,100,7436. B. C. Burros, N. J. De'ath, D. B, Denney, D . Z . Denney, and I. J. Kipnis, J. A m . Chem. SOC.,1978, 100,7300. K. Oka, J. Org. Chem., 1979,44, 1736. T. Kitazume and J. M. Shreeve, J. Chem. SOC.,Chem. Commun., 1978, 154. P. Klaboe and Z. Smith, Spectrochim. Acta, Part A, 1978, 34, 489. I. R. Dunkin and G. J. MacDonald, J. Chem. SOC.,Chem. Commun., 1978, 1020. J. E. Semple and M. M. Joulli6, J. Org. Chem., 1978,43, 3066.

66

Heterocyclic Chemistry

Gyclic sulphoxylate ester (117) may be involved in some of the observed transformations. '*'

PhNHSOCH2CONHAr (116)

7 Miscellaneous

A number of papers have been concerned with silacyclobutane derivatives. 126 The vibrational spectrum of 1,3-disilacyclobutane indicates that it is puckered in the liquid and vapour phases but planar in the s01id.l~' The formation of the sila-cyclic phosphorus ylide (118),12' of the disilacyclobutenes (119; R = Ph or SiMe3),'29and of the silathietane (l2O)l3Ohas been reported. The novel selenathietane (121) has been obtained from divinyl sulphone and SeBr4.l3l

[2 + 2]-Cyclo-adducts, for example (122), have been isolated from cyclic phosphinimines and i s o c y a n a t e ~ . ' ~Both ~ phosphetan (123) and bicyclo[3.1.0]hexane (124) are formed from 3,4-dimethyl-1,4-pentadienewith PhPC12 and A1C13.133

126

''' 12'

I3O

13'

13*

13'

L. Carlsen and J. P. Snyder, J. Org. Chem., 1978,43, 2216. C. S. Cundy, M. F. Lappert, and C-K. Yuen, J. Chem. SOC.,Dalton Trans., 1978,427; N. V. Ushakov and V. M. Vdovin, Izu. Akad. Nauk SSSR,Ser. Khim., 1978,1686; S . Tokach, P. Boudjouk, and R. D. Koob, J. Phys. Chem., 1978,82,1203. R. M. Irwin and J. Lanne, J. Phys. Chem., 1978,82, 2845. H. Sohmidbaur and M. Heimann, Chem. Ber., 1978,111,2696. H. Sakurai, T. Kobayashi, and Y. Nakadaira, J. Organometal. Chem., 1978,162, C43. M. G. Voronkov, S. V. Kirpichenko, T. D. Barton, V. V. Keiko, V. V. Pestunovich, and B. A. Trofimov, Tezisy Dokl. Nauchn. Sess. Khim. Tekhnol., 14th, 1975, p. 147 (Chem. Abs., 1978, 89, 43 569). Yu. V. Migalina, V. G. Lend'el, A. S. Koz'min, and N. S. Zefirov, Khim. Geterotsikl. Soedin., 1978, 708 (Chem. Abs., 1978,89,109 182). A. Schmidpeter and T. von Criegern, J. Chem. SOC., Chem. Commun., 1978,470. M. Rotem and Y. Kashman, Tetrahedron Lett., 1978, 6 3 .

3 Five-membered Ring Systems BY G. V. BOYD, S. GRONOWITZ & P. A. LOWE

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

1 General This Report covers the period April 1978 to June 1979, so as to maintain continuity of the coverage of the literature on thiophen and related compounds, which has previously been reviewed in the Specialist Periodical Reports on Organic Compounds of Sulphur, Selenium, and Tellurium. Important progress has been made in the synthesis of thiophens by ring-closure reactions. An elegant route to diethyl 3-thienylmalonate7an important penicillin side-chain, has been worked out, as well as a new synthesis of 2-methylthio-3,4disubstituted thiophens based on regioselective deprotonation of SS-dimethyl-a, oxoketen dithioacetals. Much progress has been reported in the synthesis of biotin analogues. In the spectroscopic field, a detailed study of the m.c.d. spectra of the parent five-membered heterocycles has been carried out. Quantitative investigations of nucleophilic aromatic substitution in the thiophen field are continuing. The preparative usefulness of Pd-catalysed reactions of bromo-thiophens with allylic alcohols is becoming evident. It has been shown that thiophen itself undergoes the Diels-Alder reaction at high pressure. Important investigations on the chemistry of 2- and 3-thienylmzthylenes as well as on thiophen-substituted nitrenes have been carried out. Work on astropisomeric bithienyls is continuing; in particular, compounds with known conformations have been investigated. Many elegant syntheses of thiophen analogues of various steroids have been reported. Isomer distributions in electrophilic substitutions have been determined for a range of 4-and 6-substituted benzo[b]thiophens. An important contribution to the understanding of side-chain reactivities in benzo[b]thiophens is the investigation of the rates of gas-phase elimination of all six 1-benzo[b]thienylethyl acetates. In the field of condensed thiophens, a method for the synthesis of all six dithiophen analogues of phenanthrene has been worked out and the chemistry of these compounds has been studied. The chemistry of thieno[3,2-c]pyrazoles has been studied extensively. A new non-classical relatively stable condensed thiophen, 3,4,6-triphenylthieno[3,4c]isothiazole, has been studied. The reaction of acetamido-thiophens with the Vilsmeier reagent has been developed into a versatile synthesis for thiophen analogues of quinoline.

67

Heterocyclic Chemistry

68

2 Monocyclic Thiophens reaction of vinyl Synthesis of Thiophens by Ring-closure Reactions.-The chloride with an excess of hydrogen sulphide in the gas phase at 530-550 "C gave a 67% yield of vinyl hydrosulphide and a 24% yield of thiophen, based on the amount of vinyl chloride that reacted.' Ethyl phenyl ketone reacts with thionyl chloride in the presence of pyridine to produce 3,4-dibenzoylthiophen in 34% yield. The reaction path has been discussed.2 The reaction of (1)with hydrogen sulphide gave diethyl3-thienylmalonate (2), an important penicillin ~ i d e - c h a i n , ~ and 3-keto-4-chlorobutyronitriles (3) with sodium hydrosulphide in alcohol yielded the 2-amino-4-hydroxythiophensystem, which exists predominantly in the tautomeric 0x0-form (4).4 The acid-catalysed reaction of diethyl acetyl-

C1

H (1)

RCHCOCH2CI I CN (3)

succinate with hydrogen sulphide in ethanol gave a mixture of (9,(6), and (7). The thiophen derivatives were formed by an intramolecular cyclization condensation of (8) (not observed). In an appropriate acidic medium, (5) could be Me

\

S:

c=c\/

CH ,CO,Et O

Et0,C

(61

(9

S

E

(7)

CO2Et

Me \

HS

cc)o

Me

Me

,,C-OEt H.e.0

/

c=c

'CH2C02Et

M. G. Voronkov, E. N. Deryagina, M. A. Kuznetsova, and I. D . Kalikhman, Zh. Org. Khim.,1978, 14, 185. K. Oka, Heterocycles, 1979, 12,461. Beecham Group Ltd., Jpn. Kokai Tokkyo Koho 79 24 867 (Chem. A h . , 1979,90, 186 778). Yu. M.Volovenko and F. S. Babichev, Khim. Geterotsikl. Soedin.,1977, 1425.

Five-membered Rings : Thiophens and their Se and Te Analogues

69

c1 I

R~COCH~C-CH~CI I R2

(9)

completely converted into (6) and (7).5The products (9) obtained by electrophilic addition of acid chlorides such as cyclopentane-, 1-chlorocyclopentane-, cyclohexane-, and 1- and 4-chlorocyclohexane-carboxylicacid chlorides to ally1 and methallyl chlorides reacted with phosphorus pentasulphide in DMF or dioxan to give 2-cycloalkyl- and 2-cycloalkyl-4-methyl-thiophensin good yields.6 The reaction of alkali-metal salts of acetylenethiols (obtained through treatment of 1,2,3-thiadiazoles with base) with acetylenedicarboxylic esters gives derivatives of thiophen-2,3-dicarboxylicacids. The reaction mechanism has been discussed.' In the reaction of (1 0) with dimethyl acetylenedicarboxylate, the reaction stopped at the dihydro-derivative (11).8 Me

Thiodiacetonitrile reacted with a -diketo-esters to give 3-hydroxythiophen2,5-dicarbonitriles in a modified Hinsberg reaction.' This reaction was also the key step in a synthesis of thiophenophanes in which compounds (12) were transformed into (13) through the reaction with sodium sulphide, whereupon (14) was obtained through reaction with glyoxal."

(14) n = 3-8, or 10

F. Duus, J. Chem. SOC.,Perkin Trans. 1, 1978, 292.

' A. G. Ismailov, E. I. Marnedov, and V. G. Ibragimov, Zh. Org. Khim., 1977,13,2612. lo

L. S. Rodinova, M. L. Petrov, and A. A. Petrov, Zh. Org. Khim., 1978,14, 2050. M. L. Petrov, N. A. Bunina, and A. A. Petrov, Zh. Org. Khim., 1978, 14, 2619. D. A. Crombie, J. R. Kiely, and C. J. Ryan, J. Heterocycl. Chem., 1979,16, 381. Y. Miyahara, T. Inazu, and T. Yoshino, Chem. Lett., 1978, 563.

Heterocyclic Chemistry

70

A very convenient new synthesis of 2-methylthio-3,4-disubstituted thiophens consists in the regioselective deprotonation of SS-dimethyl-a -0xoketen dithioacetals (15) with LDA and HMPA at - 78"C, followed by ringclosure.",''

Through the reaction of enamines (16) with the amide chlorides (17), the vinamidinium salts (18) were prepared. When (18)was treated with sodium amide in liquid ammonia, (19) was obtained via the 5-ylide, in 74% yield. With some other similar vinamidinium salts, however, non-separable mixtures of allenes and thiophens were ~ b t a i n e d . 'In ~ further development of the use of adducts of

MeC=C

'

H2N

/

COR ' MeC-C

'CNHR2

II

SCH2N02

S

(22) R1 = R' = Me R' = OEt,R' = Me R' = OEt, R2 = COPh

(23) R' = OEt, R2 = Ph R' = OEt, R2 = p-anisyl R' = Me, R2 = Ph

enamine isothiocyanate (20) for thiophen synthesis, they were treated with bromonitromethane, which gave the 2-nitro-thiophens (22) in low yield. This was due to a competing ring-closure of the intermediate (21) to the isothiazoles (23). By using enamines with dialkylamino-groups to give isothiocyanato adducts (24), isothiazole formation could be hindered, and the nitrothiophen derivative (25) was obtained in 45% yield upon reaction with bromonitromethane. Starting " l3

J. P. Marino and J. L. Kostusyk, Tetrahedron Lett., 1979, 2489. J. P. Marino and J. L. Kostusyk, Tetrahedron Lett., 1979, 2493. R. Gompper and C . S. Schneider, Synthesis, 1979, 213.

Five-membered Rings : Thiophens and their Se and Te Analogues CO,Et / MeC=C' RIl32A 'CNHR3

71

Me,NFN02

s//

Me2N

from the nitroketen aminal (26), reaction with phenyl isothiocyanate and bromonitromethane gave the diaminodinitrothiophen (27) in 58% yield.14In the reaction of 3-thietanone with methanolic sodium hydrogen sulphide, 2,4dimethylthiophen-3-thiol and its disulphide, together with other products, are formed. l5 Heterocyclic ketones (28) have been used in the Gewald reaction with aroylacetonitriles and sulphur to prepare (29).16

(28)

X = OorS

(29)

From (30) and dimeric mercaptoacetaldehyde, (31) was obtained.17 The chloroformylation of cyclo-octane-l,5-dione followed by base-catalysed condensation with methyl thioglycolate gave (32), the chemical properties of which were further studied."" Ethyl 5-anilino-3-aryl-4-cyanothiophen-2carboxylates were obtained from suitably substituted thiazolidin-4-ones. l g b CONHCH,CN NCCH2NHCOCH2CN (30) (31)

vc

Me02C

(32)

The gas-phase reaction of 1,2,3-thiadiazole and its methyl derivatives gives reactive thiirens, which were trapped with hexafluorobut-2-yne, giving 2,3bis(trifluoromethy1)thiophen and its 5-methyl derivative.lga Upon treatment of a photodimer of 2,5-diphenyl-l,4-dithiin with hydrogen peroxide, 2,4-diphenylthiophen were obtained."" l4 l5 16

l7 l8

l9

S. Rajappa and R. Sreenivasan, Indian J. Chem., Sect. B, 1978, 16, 752. B. Fohlisch and B. Czauderna, Phosphorus Sulfur, 1978,4, 167. A. S. Noravyan, A. P. Mkrtchyan, I. A. Dzhagatspanyan, and S. A. Vartanyan, Khim.-Farm. Zh., 1977,11,62. K.-H. Weber and H. Daniel, Justus Liebigs Ann. Chem., 1979, 328. ( a )J.-M. Magar, J.-F. Muller, and D. Cagniant, C. R. Hebd. Seances Acad. Sci. Ser. C, 1978, 286, 241; ( b ) H. Dehne and P. Krey, Pharmazie, 1978,33, 687. ( a ) J. Font, M. Torres, H. E. Gunning, and 0. P. Strausz, J. Org. Chem., 1978, 43, 2487; ( b ) K. Kobayashi and T. Ohi, Chem. Lett., 1973, 645.

Heterocyclic Chemistry

72

The reaction of the easily prepared vinylphosphonates (33) with LY -mercaptocarbonyl compounds gave substituted 3-carbomethoxy-2,5-dihydrothiophens (34) in excellent yield, which sometimes, in air, were aromatized to the corresponding thiophens.20The compounds (34) could be oxidized to the sulphones, which decomposed thermally to sulphur dioxide and conjugated dienes.’l A new synthesis of dehydrobiotin starts from adipaldehydic acid methyl ester (35); this, by condensation with nitromethane followed by Michael addition of thioglycolic acid, gave (36), which was resolved. Base-catalysed ring-closure of the phenyl ester of (36) gave the dehydrothiophen (37). Reduction of the nitro-group and reaction of the amino-ketone hydrochloride with potassium cyanate at pH 5-6 gave (38), which was dehydrated to dehydrobiotin (39). It was also shown that a compound previously claimed to be the (dl)-form of (39) was instead (40), owing to dehydration and aromatization of the amino-ketone derived from (37) upon treatment with mineral acids.22 Pyrolysis of 2,2,5,5-tetrafluoro-3-thiolen gives 3-Ketotetrahydrothiophen has been 2,5-difluorothiophen as the main used in the synthesis of (41).24 0

I1

(EtO),P,,CO,Me

?

R l L 1 C 0 2Me

R2

AsIR

H

w

C

0

2

M

e

(37)

0

0

,NHCONH,

’‘’ 21

22

23 24

J. M. McIntosh and R. A. Sieler, Can. J. Chem., 1978, 56, 226. J. M. McIntosh and R. A . Sieler, J. Org. Chem., 1978,43, 4431. J. Vasilevskis, J. A . Gualtieri, S. D. Hutchings, R. C. West, J. W. Scott, D. R. Parrish, F. T. Bizzarro, and G. F. Field, J. A m . Chem. Soc., 1978,100,7423. J. Burdon and I. W. Parsons, J. Fluorine Chem., 1979, 13, 159. M. Alvarez, J. Bosch, R. Granados, and F. Lbpez, J. Heterocycl. Chem., 1978, 15, 193.

Five-membered Rings : Thiophens and their Se and Te Analogues

73

Physical Properties.-In connection with an examination of rotational isomerism in alkyl thiophen-2-carboxylates, the i.r. v(C=O) region of derivatives of (38) in various solvents was examined at high dispersion. Twenty-six of them show doublets in carbon tetrachloride; this was shown to be due to rotational isomerism between syn +trans and anti-s-trans The m.c.d spectra of thiophen and of pyrrole, furan, selenophen, and tellurophen and some of their derivatives have been reported, and the corresponding energies, oscillator strengths, direction of the transition moment, and m.c.d. terms were calculated from semi-empirical quantum mechanical calculations in the 7r -electron approximation.26 The assignment of some I3C chemical shifts in 2-thienyl-stannanes has been reversed. Proton-coupled '19Sn n.m.r. spectra were shown to be useful for the detection of long-range couplings in thienyl-stannane~.~'"Carbon- 13 chemical shifts for some thiophen derivatives (42)have been The conformational behaviour of the cyclophane (43)and of some of its deuteriated derivatives was studied by 2H n.m.r. In the latter compounds the energy barriers associated with ring and chain flipping were found to be 16.0 and 11.4 kcal mol-', respectively.28 The analysis of the 'H n.m.r. spectrum of (44) and its c-fused analogue has been carried out by deuterium labelling and LAOCN3 iterative calculations. Whether the configuration of the compounds is cis or trans could not be established from these The conformational behaviour of the radical anions of several biand ter-thienyls has been investigated by e.~.r.~O The liquid-crystalline properties of trans-2-(5-alffyl-2-thienyl)acrylicacids31a and of other thiophen derivatives, such as (45),316 have been investigated. The use

25

26 27

28

29

30

(45) D. J. Chadwick, R. D. Chambers, G. D. Meakins, W. K. R. Musgrave, and R. L. Snowden, J. Chem. Res. ( M ) ,1977, 385. B. Nordkn, R. HAkansson, P. B. Pedersen, and E. W. Thulstrup, Chem. Phys., 1978,33, 355. ( a )B. Wrackmeyer, 2.Naturforsch.,Teil B., 1979,34,235; ( b )S. R. Ramadas and S. Padrnanabhan, Org. Magn. Reson., 1978, 11,471. A. W. Lee, P. M. Keehn, S. M. Ramos, and S. M. Rosenfeld, Heterocycles, 1977, 7, 81. B. Hanquet and R. Guilard, C. R . Hebd. Seances Acad. Sci., Ser. C, 1978,287, 515. G. F. Pedulli, M. Tiecco, M. Guerra, G . Martelli, and P. Zanirato, J. Chem. SOC.,Perkin Trans. 2,

1978,212. 31

( a )I. A. Sagitdinov and H. Schubert, Zh. Obshch. Khim., 1979,49,476; ( b )Zh. Org. Khim., 1978, 14, 1060.

74

Heterocyclic Chemistry

of N-p-chlorophenyl-2-thenoylhydroxamic acid for solvent extraction of metal ions such as CeIV, Fe”, Fe”’, TirV,Uvl, Vv, and ZrIVhas been studied.’* The behaviour of solutions of thenoyltrifluoroacetone in alcoholic solvents has been investigated.”

Electrophilic Substitution.-2,3,4-Trichlorothiophen, obtained from the reaction between 1,1,2,3-tetrachlorobuta-1,3-dieneand sulphur, was acylated with a variety of acid chlorides derived from mono- and di-carboxylic acids, using AlCl, as catalyst.’, Some 3-amino- and 3-methoxy-thiophens have been thiocyanated and selenocyanated in the 2-position by treatment with ammonium thiocyanate or potassium selenocyanate and bromine in methanol.’’ The anti-inflammatory compounds (46) were obtained by SnC1,-catalysed acylation of thiophen with (47).36 The AlCl,-catalysed reaction of 2-thienylchlorosilane with adamantyl chloride led to 5-adamantyl-2-thienylchlorosilane and to a disubstituted product. 37

The reaction of glyoxylic acid with amides, carbamates, or ureas led to N-acyl-hemiaminals, which gave a-substituted N-acyl-glycines via electrophilic substitution. With thiophen, a 45 YO yield of N-acyl-2-thienylglycine was obtained.38 2 -C hloro- 5 -methy1thiop hen has been benzoylated in the 4-position , using benzoyl chloride in CS2, and AlCl, as catalyst.’” An isomerization of 2,5-bis-alkylthio-thiophens upon C-protonation has been discovered. The products were the 2,4-isomers formed by intermolecular d i s p r o p o r t i ~ n a t i o nIt. ~ ~ has been found that 2-chlorothiophen was converted into dimer-type products by Amberlyst 15 or 100% orthophosphoric acid, the products being 4- and 5-(5chloro-2-thienyl)tetrahydro-2-thiophenones, and 4-(2-thienyl)-2(5H)-thiophenone, as well as 5-chlor0-2,2’-bithienyl.~~ Electrophilic bromination and nitration of 1,l-diphenyl-2-(2-thienyl)ethenehas been studied. Nitration occurs in the 5-position of the thiophen ring, while bromination gave the 3,5dibrominated It has been found that ionic hydrogenation of 2,532 33

34

35

16

37

3R 19 40

41

42

R. Pande and S. G . Tandon, J. Indian Chem. SOC.,1977,54, 990. H. Shibuya, H . Watarai, and N. Suzuki, Bull. Chem. SOC.Jpn., 1978, 51, 2932. S. G. Kon’kova, A. A. Safaryan, and A. N. Akopyan, Zh. Org. Khim., 1977, 13, 2428; ibid., 1078, 14, 2162. C. Paulmier, Tetrahedron Lett., 1978, 1797. T. Aono, M. Imanishi, Y. Kawano, S. Kishimoto, and S. Noguchi, Chem. Pharm. Bull., 1978, 26, 2475. V. F. Mironov, N. S. Fedotov, G. E. Evert, M. G . Kuznetsova, and A. B. Kisin, Z h . Obshch. Khim., 1979,49, 361. A. Schouteeten, Y. Christidis, and G. Mattioda, Bull. SOC. Chim. Fr., Part 2, 1978, 248. D. R. Arnold and C. P. Hadjiantoniou, Can. J. Chem., 1978, 56,1970. A. P. Yakubov, N . V. Grigor’eva, and L. I. Belen’kii, Zh. Org. Khim., 1978, 14, 641. T. Sone, 0.Shiromaru, S. Igarashi, E. Kato, and M. Sawara, Bull. Chem. SOC.Jpn., 1979,52, 1126. F. A. Bottino, G. C. Pappalardo, G . Scarlata, D. Sciotto, and M. Torre, Cun. J. Chem., 1978, 56, 2755.

75

Five-membered Rings : Thiophens and their Se and Te Analogues

dimethylthiophenium and 2,3,5-trimethylthiophenium tetrachloroaluminates with triethylsilane and diphenylsilane in the presence of hydrogen chloride gave the corresponding t h i ~ p h e n s . ~ ~ Electrophilic Ring-closure Reactions.-Ring-closure of (48) led to the tricyclic ketones (49). Polyphosphoric acid (PPA) is successful as catalyst when X is sulphur. When X is oxygen, ring-closure was first achieved with the acid chloride, using AlCl, as catalyst. With PPA, (50)was obtained instead. In the case of ( 5 1; X = 0),the AlCl, method also gave the rearranged product (52), while the corresponding sulphur analogue (51; X = S) behaved normally, yielding (53; X = S) with PPA. Attempts to prepare (53; X = 0)by other methods were unsuccessful. Thus, for instance, (54) did not give (53; X = 0),but (55) was obtained It has been claimed that (56)cyclizes, with rearrangement, to (57) upon treatment with PPA.45This has recently been shown to be incorrect, as the claim was based on the erroneous interpretation of n.m.r. data.46Compounds (58) have been ring-closed to (59).47

Qp

* 0

0

(48)

X

=

OorS

(49)

0

(50)

X

(51)X

=

OorS

(53)

0

(57) 43

44 45

46 47

(59)

Z. N. Parnes, Yu. I. Lyakhovetsky, M. I. Kalinkin, D. N. Kursanov, and L. I. Belen’kii, Tetrahedron, 1978,34,1703. H. Tagawa and K. Ueno, Chem. Pharm. Bull., 1978,26,1384. M. H. Palmer, D. S. Leitch, and C. W. Greenhalgh, Tetrahedron, 1978, 34, 1015. T. Frejd and 0. Karlsson, Tetrahedron, 1979, 35, 2155. P. K. Sen, B. Kundu, and T. K. Das, J. Indian Chem. Soc., 1978, 55, 847.

76

Heterocyclic Chemistry

In connection with work on thiophen derivatives of protoberberine alkaloids, (60)was ring-closed to (61);this, through reduction with sodium borohydride and acid-catalysed reaction with formaldehyde, was transformed into (62).48

Nucleophilic Substitution.-In a search for evidence of primary steric effects in thiophen derivatives, the rates of substitution by piperidine and benzenethiolate of some 2-L-3-R-5-nitro-thiophens (L = Br or S0,Ph; R = Et, Pr", Hx", Pr', or But)were measured in ethanol. For substitution by piperidine, when a linear alkyl group is ortho to the site of substitution, there is no primary steric effect if the leaving group is bromine. On the other hand, large primary steric effects occur with branched alkyl The rates of anilino-debromination of 2-bromo3,5-dinitrothiophen, in methanol, by some ortho-substituted anilines have been measured. The kinetic results were treated according to the multi-parameter analysis of ortho-effects proposed by Fujita and Ni~hioka.~' The reactions of lithium and tetra-alkylammonium salts of 2-nitrothiophen, 2,5-dinitrothiophen, 2-iodo-5-nitrothiophen,2,4-dinitrothiophen, and 2-( 1-methyl- 1-nitroethyl)-5nitrothiophen have been studied. 2-Nitro- and 2,4-dinitro-thiophen gave Meisenheimer adducts, whose n.m.r. data were discussed. Possible reaction mechanisms were discussed and evidence for an SRNlmechanism was presented." The mechanism of cine-substitution of 3,4-dinitrothiophen with sodium arenethiolates in methanol, which yields 2-arylthio-4-nitrothiophens, has been el~cidated.~~ The nucleophilic substitution reaction between ortho-bromo-nitro-thiophens and anthranilic acids has been used for the synthesis of substituted 2-(o-nitrothieny1amino)-substituted benzoic acids such as (63).53With sodium disulphide, 3-bromo-2-nitrothiophen gave bis-(2-nitro-3-thienyl) d i ~ u l p h i d e . ~ ~ Descriptions of the Pd-catalysed reactions of allylic alcohols with 2- and 3-bromothiophen have appeared, and confirm the usefulness of this reaction for the synthesis of 3-(thieny1)-aldehydes and -ketones such as (64). The reaction 48 49

50

51 52 53

54

S. Jeganathan and M. Srinavasan, Synthesis, 1979, 195. G . Consiglio, S. Gronowitz, A.-B. Hornfeldt, B. Maltesson, R. Noto, and D. Spinelli, Chem. Scr., 1977. 11. 175. G. Consiglio, R. Noto, D. Spinelli, and C. Arnone, J Chem. Soc., Perkin Trans. 2, 1979, 219. P. J. Newcombeand R. K. Norris, Aust. J. Chem., 1978,31,2463. M. Novi, G. Guanti, F. Sancassan, and C. Dell'Erba, J. Chem. Soc., Perkin Trans. 1, 1978, 1140. J. K. Chakrabarti, T. M. Hotten, D. J. Steggles, and D. E. Tupper, J. Chem. Res. ( M ) ,1978,5101. N. I. Astrakhantseva, V. G. Zhiryakov, and P. I. Abramenko, Khim. Geterotsikl. Soedin., 1976, 1355.

Five-membered Rings : Thiophens and their Se and Te Analogues

77

mechanism is The Pd-catalysed reaction of 2-bromothiophen with 4-vinylpyridine gave a 57% yield of (65).56

Organometallic Derivatives.-The thienyl-lithium derivatives maintain their synthetic importance. The reaction of substituted thienyl-lithium derivatives with cupric chloride has been extensively used for the synthesis of b i t h i e n y l ~ .The ~~,~~ reaction of the 1,2-di(o-bromothienyl)ethenes with butyl-lithium, followed by treatment with cupric chloride, provided a convenient method for the synthesis of all six benzodithiophen analogues of ~henanthrene.~' Carboxylic acids have been prepared from the lithium derivatives and C02.60The reaction of 3-thienyllithium with o -methylbenzonitrile4* and with 2-cyano-pyridine~~~ was used for the synthesis of 3-(2-methylbenzoyl)thiophenand 2-pyridyl 3-thienyl ketones. Several azido-thiophens have been prepared by treatment of thienyl-lithium derivatives with toluene-p-sulphonyl azide and subsequent fragmentation of the intermediate triazenelithium salts. High yields were obtained with 3-thienyllithiums, while the yield was low with the 2-is0mers.~'The reaction of 2-thienyllithium, 2-thienylcalcium bromide, and 2-thienylstrontium iodide with trifluorochloroethylene, which yields ap-difluoro-p -chlorovinylthiophen, has been investigated.62 2-Thienylmagnesium bromide reacts with partially brominated 1,4-~0lybutadiene.~~ Phenyl-2-thienyl-acetylenehas been metallated in the 5position with butyl-lithium, and some derivatives have been prepared.64 2Alkylthio-5-alkyl-thiophen-3-carboxaldehydediethyl acetals are metallated by butyl-lithium in the remaining p-position. 5-Ethylthiophen-2-carboxaldehyde diethyl acetal is also metallated by butyl-lithium in the 3-position, but the yield is 1-(2'-Thieny1)silatranes have been prepared through transesterification of 2-thienyltrialkoxysilaneswith triethanolamine.66 The thienyl-tellurium derivative (66) was prepared from the diazonium salt of anthranilic acid and 3,3'dithienyl ditelluride. The reaction of dichloromethyl butyl ether and ZnClz gave Y. Tamaru, Y. Yamada, and Z . Yoshida, Tetrahedron, 1979,35, 329. W. C . Frank, Y. C . Kim, and R. F. Heck, J. Org. Chem., 1978,43, 2947. 57 A. Almqvist and R. Hhkansson, Chem. Scr., 1977,11, 186. 58 S. Gronowitz and P. Pedaja, Tetrahedron, 1978, 34, 587. 59 S. Gronowitz and T. Dahlgren, Chem. Scr., 1977, 12, 57. 6o A. Almqvist and R. Hikansson, Chem. Scr., 1977,11, 180. " P. Spagnolo and P. Zanirato, J. Org. Chem., 1978, 43, 3539. '' T. A . Starostina, I. E. Paleeva, L. F. Kozhemyakina, L. F. Rybakova, R. R. Shifrina, V. A. Chernoplekova, and K. A. Kocheshkov, Zh. Org. Khim., 1978,14,2600. 6 3 K. Hummel, 0. A . Wedam, W. Kathan, and H. Demel, Makromol. Chem., 1978,179, 1159. 64 A. Siege1 and M. D. Rausch, Synth. React. Inorg. Metal-Org. Chem., 1978,8, 209. '' Ya. L. Gol'dfarb and M. A . Kalik, Zh. Org. Khim., 1978,14, 2603. '' M. G . Voronkov, G. I. Zelchan, V. I. Savushkina, B. M. Tabenko, and E. A . Chernyshev, Khim. Geterotsikl. Soedin., 1976, 772. "

56

Heterocyclic Chemistry

78

(67).672,2'-Dithienyl ditelluride has been prepared through the reaction of 2-thienylmercuric chloride with tellurium tetrachloride in dioxan, and its complexes with Pd" and Pt" were studied and characterized.68 0

Te

TeCl

A review on ring-opening reactions of 3-thienyl-lithium and 3-selenienyllithium derivatives has been published.69 Cycloadditions and Photochemistry of Thiophens.-The Diels-Alder reaction of thiophen with maleic anhydride at 100 "C in methylene chloride and at the high pressure of 15 kbar yields the e ~ o - a d d u c t . ~ ~ ~ ~ ~ The highly reactive thiophen endoperoxide (68),obtained in the reaction with singlet oxygen, reacts with di-imine at - 78°C to give (69).72Thiophen and

(68) R = MeorBu'

(69)

2-methylthiophen undergo [4 + 21 cycloaddition with negatively substituted tetrazines (70) to give (71). 2-Chlorothiophen reacts much more slowly. If both a -positions are blocked, as in 2,5-dimethylthiophen, the reaction stops at the dihydro-derivative (72). The analogous furans and pyrroles react differently ;with 2,5-dimethylfuran, (73) was Thiophen adds benzo- and rnesito-nitrile oxides, yielding mainly the cyclo-adducts (74),in very low yield, or else products derived from them. Frontier orbital considerations, using EH and MIND0/3 calculations, predict the observed regio~electivity.~~ The isoindene analogue (75) has been demonstrated to be in slow equilibrium with (76). The fluorescent (75) Me0,C " N' \2 T M e

MeO,C Me (72) 67

69

7" 71

72 73 74

'p

Me0,C

cd

Ar,FJs)

N\ Me0,C

N,

(73)

1

s

0 (74)

Ph

(75)

J.-L. Piette, P. Thibaut, and M. Renson, Tetrahedron, 1978, 34, 6 5 5 . L. Y. Chia and W. R. McWhinnie, J. Organomet. Chem., 1978,148, 165. S. Gronowitz and T. Frejd, Khim. Geterotsikl. Soedin., 1978, 435. H. Kotsuki, S. Kitagawa, H. Nishizawa, and T. Tokoroyama, J. Org. Chem., 1978, 43, 1471. H. Kotsuki, H. Nishizawa, S. Kitagawa, M. Ochi, N. Yamasaki, K. Matsuoka, and T. Tokoroyama, Bull. Chem. SOC.Jpn., 1979, 5 2 , 544. W. Adam and H. J. Eggelte, Angew. Chem., 1978,90,811. G . Seitz and T. Kampchen, Arch. Pharm. (Weinheim, Ger.), 1978,311,728. P. Caramella, G. Cellerino, P. Griinanger, F. Marinone Albini, and M. R. Re Cellerino, Tetrahedron, 1978,34,3545.

Five-membered Rings ; Thiophens and their Se and Te Analogues

79

reacted rapidly with dimethyl acetylenedicarboxylate and maleic anhydride to give (77) and (78),respectively. The reaction was so fast that the amount (81%)of (75) in equilibrium could be determined by ‘titration’ with maleic anhydride, using the disappearance of fluorescence as the end-point. However, (76) also slowly underwent cycloaddition with dimethyl acetylenedicarboxylate, yielding (79). 5 -Methyl-6-phenyl-4N-cyclopenta[b]thiophen also underwent cycloaddition with dimethyl acetylenedi~arboxylate.’~

The electronic absorption spectra and phosphorescence emission spectra, as well as the photochemical reactivities, of several methyl-3-benzoyl-thiophens have been studied. Photocycloaddition of dimethyl acetylenedicarboxylateto the thiophen ring to give (80) was

R‘ (80) R’,R2,R3 = H or Me

(79)

The Structure and Reactions.of Hydroxy-, Mercapto-, and Amino-thiophens.The 4-thiolen-2-one form (81)was found to be more stable than the 3-thiolen-2one form (82); Keg = 0.09 in CS, was found by n.m.r. spectroscopy. The enol Et0,C

Po= .Do

Et02C

Me

Me

(81)

(82)

form could not be d e t e ~ t e d .Using ~ phase-transfer catalysis, the 2-hydroxythiophen system could be O-alkylated with ethyl 2-bromoacetate, ethyl 2bromopropionate, ethyl 2-bromobutyrate, and ethyl 2-bromo-2-methylpropionate in about 10% yield. The low yield was due to predominant C alkylation, but these acidic products could easily be removed. On the other hand, thiophen-2-thi&, under the same conditions, gave exclusively S-alkylation with the above-mentioned alkylating agents, yielding 90% of ethyl 2-(2-thienylthio)2-methyIpropi0nate.’~ 2-Acetoxythiophen, upon treatment with boron 75 76

J. Skramstad and T. Midthaug, Acta Chem. Scand., Ser. B, 1978,32,413. S. Gronowitz, R. Svenson, G. Bondesson, 0.Magnusson, and N. E. Stjernstrom, Acra Pharm. Suec., 1978,15,361.

80

Heterocyclic Chemistry

trifluoride etherate, gave a mixture of 3-thiolen-2-one and 5-acetyl-2-acetoxythiophen, while 2-acetoxy-5-methylthiophen gave 5-methyl-3-thiolen-2-one and 3-acety1-5-methyl-2-hydro~ythiophen.~~ The reaction of 2,5-dithiocyanatothiophen with equimolar amounts of the dipotassium salt of cyclo-octatetraene dianion in THF gave potassium 2-thiocyanato-5-thienylmercaptide.The latter was converted into a cyclic tetramer with disulphide bonds, the structure of which was determined by X-ray cry~tallography.~~ It has been shown that allyl 2-thienyl and allyl 3-thienyl sulphides rearrange in various solvents at 89-136 "C to give the corresponding allylthiophen-thiols, which can subsequently undergo transallylation with the starting sulphide and cyclization to thienodihydrothiopyrans and methyldihydrothienothiophens. The energy of activation of the rearrangement of both isomeric sulphides was found to be 19 kcal m 0 1 - I . ~The ~ reaction of (83) with butyl-lithium, sulphur, and propargyl bromide gave (84), which upon heating ring-closed to (86), probably uia (85)."

(84) R = SCH,CrCH

(85)

(86)

Through Michae! addition of thioglycolic acid to acrylic acids, (87) was prepared, which was ring-closed to (88) in acetic anhydride, using lithium acetate as catalyst. Condensation with pyrrolidine followed by aromatization with diisopentyl disulphide gave the 3-amino-derivatives (89).'l

(87)

2-Amino-thiophens react with diethyl ethoxymethylenemalonate to give (90)82 and with ethyl aminocrotonate to give (91).83 From the reaction with p-isothiocyanato-ketones, (92) was For pharmacological testing, a series of oxamic acid derivatives (93) was prepared from 2-arnino-thi0phens.'~ Through the reaction of 2- and 3-amino-thiophens with N-acyl isothiocyanates, several G . A. Kraus and B. Roth, J. Org. Chem., 1978,43, 2072. Z. V. Todres, N. G. Furmanova, S. P. Avagyan, Yu. T. Struchkov, and D. N. Kursanov, Phosphorus Sulfur, 1979, 5, 309. 79 A. V. Anisimov, V. F. Ionova, and E. A. Viktorova, Zh. Org. Khim., 1977, 13, 2624; Khim. Geterorsikl. Soedin., 1978, 186. '"R. Grafing and L. Brandsma, Synthesis, 1978, 578. 81 D. N. Reinhoudt, W. P. Trompenaars, and J. Geevers, Synthesis, 1978, 368. 82 P. M. Gilis, A. Haemers, and W. Bollaert, Chim. Ther., 1978, 13, 265. 83 I. Lalezari, J. Heterocycl. Chem., 1979,16, 603. 84 H. K. Gakhar, A. Khanna, and P. Baveja, Indian J. Chem., Sect. B, 1 9 7 8 , 1 6 , 3 0 5 . F. H. Briggs, W. T. Pelletier, and C . D. Blanton, J. Pharm. Sci., 1978,67, 735. 77

78

Fioe-membered Rings Thiophens and their Se and Te Analogues

81

thienylthioureas were prepared.86 The reaction of 3-amino-2-carbomethoxythiophen with dimethyl acetylenedicarboxylate gave (94).87The reaction of the 3,4-diamino-thiophen (95) with ethyl acetoacetate gave (96).'* The reaction of acetamido-thiophens with the Vilsmeier-Haack reagent has been developed to a versatile synthesis of thien~pyridines.~~

C0,Et

H

R' CH2COR3

H

(96) R = C(Me)=CHCO,Et

Side-chain Reactivities.-The acid dissociation constants of some 2-substituted thiophen-3-carboxylic acids in water at 25 "C have been measured and correlated by means of the Yukawa-Tsuno equation (crt 1.80, r f 0.32, R 0.996), confirming the difference from the situation observed for ortho-substituted benzoic acids." The reaction kinetics of thiophen-2-sulphonyl chloride with anions and with neutral nucleophiles were studied in protic and aprotic solvents, at 25 "C.Solvent effects on nucleophilic reactivities were discussed in terms of S parameters and by the approach of multi-parameter empirical correlations. The data show that solvation plays a large role in the determination of nucleophilic order." The reaction rates of cinnamoyl, 0 -2-furylacryloyl, and p- 2- thienylacryloyl chlorides with substituted anilines in benzene have been measured, at different temperatures. The results confirm that, when a vinyl group is interposed between the reaction centre and the heteroaromatic ring, the heteroaromatic nuclei behave as the benzene nucleus. The Hammett treatment of the data showed the variability 86

88

89 90

L. Grehn, J. Heterocycl. Chem., 1978, 15, 81. J. M. Barker, P. R. Huddleston, and A . W. Jones, J. Chem. Rex ( M ) ,1978,4701. Y . Tominaga, H. Fujito, Y . Matsuda, and G. Kobayashi, Heterocycles, 1979, 12,401. 0. Meth-Cohn and B. Narine, Tetrahedron Lett., 1978, 2045. G. Consiglio, S. Gronowitz, A.-B. Hornfeldt, R. Noto, K. Pettersson, and D. Spinelli, Chern. Scr., 1978-79,13,20. A. Arcoria, F. P. Ballistreri, and G. A . Tomaselli, Tetrahedron, 1978, 34, 2545.

Heterocyclic Chemistry

82

of (Thet values.92Rates of reduction by sodium borohydride have been measured for the 2-fury1 and 2-thienyl ketones 2-(XC,H4CO)C4H2YE (E = 0 or S) for a range of X groups with Y = H, and of Y groups with X = H. The results permitted direct comparison of transmission of substituent effects through the various aromatic rings to the same reaction centre. It was concluded that the substituent effects were transmitted to virtually identical extents through the two heterocyclic rings, but markedly less effectively through the benzene ring. Some of the data have been used to derive ~ 5 , and 2 ~ 4 . constants 2 for thiophen and furan Both benzyltri-(3-furyl)- and benzyltri-(3-thienyl)-phosphonium bromides underwent alkaline hydrolysis with preferential loss of the benzyl group, indicating that the latter is better able to support the forming carbanionic centre than are the 3-heteroaryl groups, in contrast to the corresponding 2heteroaryl systems. A comparison of the rates of hydrolysis of a series of methyltri(heteroary1)phosphonium salts showed that the relative reactivities were in the order 2-fury1 (lo9) > 2-thienyl (3 x lo6) > 3-fury1 (46) > 3-thienyl (33) > phenyl (1 x lo-'), confirming the much smaller electron-withdrawing nature of the 3- than the 2-heteroaryl groups. An interesting difference was observed in the decomposition of the betaine derived from the reaction of tri-(3-furyl)phosphine and of tri-(3-thienyl)phosphine and styrene oxide. While the former decomposes to styrene and phosphine oxide, the latter yields (97) and (98).94The kinetics of the selenium-catalysed cis-trans isomerization of (99) in dehydronaphthalene at 150-190 "C have been studied. The reaction mechanism

(97) R = CH=CHPh

(98) R

=

CHCH2Ph

b

(99) X

=

0or S

S

was discussed. The effect of heteroaromatic nuclei linked to the a -carbon atom on the isomerization rate (phenyl > 2-fury1 > 2-thienyl) indicates a lack of conjugation from the heteroatom to the side-chain in the rate-determining Carbene and Nitrene Reactions.-An important investigation of the chemistry of (2- and 3-thieny1)methylenes and analogous furan derivatives has been carried out. Diazo-(2-thienyl)methanes (100) decompose thermally, in part with ringopening to form compounds (101)and polymers derived from them. This route is 92

93

94

95

G. Alberghina, A. Arcoria, and S . Fisichella, J. Org. Chem., 1978, 43, 1122. M. Fiorenza, A. Ricci, G. Sbrana, G. Pirazzini, C. Eaborn, and J. G. Stamper, J. Chem. SOC., Perkin Trans. 2, 1978, 1232. D. W. Allen and B. G. Hutley, J. Chem. SOC., Perkin Trans. 1, 1978, 675. E. Maccarone, A. Mamo, G. Scarlata, and M. Torre, Tetrahedron, 1978,34, 3531.

Five-membered Rings Thiophens and their Se and Te Analogues

83

the main path for the diazo-(2-thienyl)methanes7 giving the corresponding ketones. The principal process for (100) is the formation of the corresponding H

H

1,2-di-(2-thienyl)ethenes.The greater resistance of 2-thienylmethylenes than 2-furylmethylenes to ring-opening was rationalized on the basis of the greater resonance energy of the thiophen ring and the lower stability of its ring-opened products. Diazo-(3-thienyl)methane gave only cis- and trans- 1,2-di-(3thieny1)ethene at 300 "C. Ring-opening or ring-expansion to the corresponding y-thiopyranylides was not observed. Diazo-(3-furyl)methane behaved completely a n a l o g o ~ s l y .Very ~ ~ interesting results have been obtained in an investigation of the thermal and photochemical decomposition of 2-azidophenyl sulphides. The nitrene (102) gave (in most cases) the pyrrolo[2,1-b]benzothiazoles (106) in good yields, probably via the intermediates (103)-(105).

-R

2 -Azidophenyl 3,5-dimethyl-2- thienyl sulphide gave 2-(3-thienyl)benzothiazole, in addition to a pyrrolo[2,1-b]benzothiazole. The influence of various solvents and the presence of various dienophiles, of added triethyl phosphite, and of photosensitization with acetophenone were also The nitrenoid (107), derived from the anils formed from 2-nitrothiophen-3-carboxaldehyde by reaction with triethyl phosphite, ring-opens via (108)to (109), which ring-closes to the pyrrole (110)with elimination of sulphur. The nitrenoid from 3-nitrothio-

96

97

R. V. Hoffman, G.G. Orphanides, and H. Shechter, J. A m . Chem. Soc., 1978,100,7927. J. M. Lindley, 0. Meth-Cohn, and H. Suschitzky, J. Chem. Soc., Perkin Trans. I, 1978, 1198,

Heterocyclic Chemistry

84

phen-2-carboxaldehyde anils behaved as expected, and ring-closed to a thien0[3,2-~]pyrrole.~~ Such compounds were also obtained by thermal decomposition of 3-azidothiophen-2-carboxaldehydea d ~ The . ~reaction ~ of 3azidothiophen with acetic anhydride under reflux gave 2-acetoxy-3-acetylaminothiophen in 52% yield; with PPA in acetic acid, 3-acetylamino-3-thiolen-2-one was obtained.6' 'Benzylic' Reactivity.-The reactions of 2- and 3-bromomethylthiophens with the potassium salt of the alanine derivative (111)in THF-DMSO at - 30 "C give (112); this was hydrolysed to the thiophen analogues of a-methyldopa.'OO I(~CH,-~-CO I ,Me HC-C0,Me

I

S

Me

Me

(111)

The macrocyc ic polythioether (1 ) has been prepared by allowing tile dilit--io salt of propane-1,3-dithiol to react with 2,5-bis(chloromethyl)thiophen.'01 2Thenyl cyanide has been doubly alkylated in the benzylic position, using sodium amide in liquid ammonia as the base, in connection with the synthesis of thienylaminobutyronitriles (114) that have spasmolytic activity."*" The compounds (114) were aroylated to (115) by Friedel-Crafts acylation."*') The reaction of 2-ethylthiophen with tellurium dioxide in acetic acid at 160 "C gave (116) and (117).'03 2-Vinylthiophen oxide reacts with [RhC12(PPh3)3]in the

X

C: 3 S

J l - SJ I I S/ (117) 98

R' (114) X = H (115) X = ArCO

cJ---+/Q 0 (118)

V. M. Colburn, B. Iddon, H. Suschitzky, and P. T. Gallagher, J. Chem. Soc., Chem. Commun., 1978,

453. 99 loo

lo*

lo3

S . Gronowitz, C. Westerlund, and A.-B. Hornfeldt, Chem. Scr., 1977,12, 1. J. W. Tilley, P. Levitan, and R. W. Kierstead, J. Heterocycl. Chem., 1979, 16, 333. A. Bhattacharjya and A. G. Hortmann, J. Heterocycl. Chem., 1978, 15, 1223. ( a )H. Tron-Loisel, P. Brossier, 0. Compagnon, N. Grosjean, P.-L. Compagnon, and D. Branceni, Chim. Ther., 1977, 12, 379; ( b ) H. Tron-Loisel, P. Brossier, P.-L. Compagnon, and D. Branceni, ibid., 1978, 13, 351. J. Bergman and L. Engman, Tetrahedron Lett., 1978, 3279.

Five-membered Rings : Thiophens and their Se and Te Analogues

85

presence of traces of [RhCl(PPh3)3],which efficientlydecarbonylates the inhibitor thiophen-2-carboxaldehyde,to give (118).lo4 Reactions of Thiophen Aldehydes and Ketones.-Through the Wittig reaction between ortho- bromoformyl-thiophens and ortho- bromothenyl-triphenylphosphoranes, all six cis- 1,2-di-(o-bromothienyl)ethenes have been synthesi~ed.’~ The phosphonate modification was applied to thiophen-2-carboxaldehyde and 3-acetylthiophen with triethyl phosphonoacetate, in connection with the synthesis of (119);105a with diethyl methylsulphonylmethylphosphonate, thiophen-2-carboxaldehyde gave (120).1056 The cycloaddition reaction of dichloroketen to thiophen-2-carboxaldehyde gave (121). Furfural behaved similarly, while benzaldehyde, and especially its derivatives that have electronwithdrawing groups, gave (122).’06 The reaction of thiophen-2-carboxaldehyde and morpholine with sodium cyanide in the presence of toluene-p-sulphonic acid gave (123), which by Michael addition to ethyl acrylate gave (124); this, through reaction with hydrazine, was converted into ( 125).’07 Thiophen-2-carboxaldehyde has been condensed with (126) to give (127).’08 The reaction of thiophen-2-carboxaldehydewith methyl isocyanoacetate in the presence of secondary amines such as piperidine and pyrrolidine gave only one stereoisomer of ( 128),’09Thiophen analogues of chloro-amphetamines have been prepared by

CQHCO

,Et

I

I

CH=CHSO,Me CI

Ac1

(123) R = H (124) R = (CH2)2C02H

,C02Me

104

10.5

106 107

108 109

J. Blum, B. Zinger, D. Milstein, and 0. Buchman, J. Org. Chem., 1978,43,2961. ( a )A. A . Macco, R. J. de Brouwer, P. M. M. Nossin, E. F. Godefroi, and H. M. Buck, J. Org. Chern., 1978,43,1591; (b)H. Fillion, M.-H. PCra, J.-L. Rappa, andC. Luu-Duc, J. Heferocycl. Chem., 1978, 15, 753. H. 0. Krabbenhoft, J. Org. Chem., 1978,43, 1305. J. D. Albright, F. J. McEvoy, and D. B. Moran, J. Hererocycl. Chem., 1978, 15, 881. T. Zimaity, E. Afsah, and M. Abbas, Zndian J. Chem., Sect. B, 1978,16, 876. M. Suzuki, K. Nunami, T. Moriya, K. Matsumoto, and N. Yoneda, J. Org. Chem., 1978,43,4933.

86

Heterocyclic Chemistry

condensation of chlorothiophen-2-carboxaldehydeswith nitroethane followed by reduction with LiAIH4.'" Various Schiff bases have been prepared from thiophen-2-carboxaldehydeand its 5-nitro-derivative in connection with antibacterial screening. "' The Ugi method for the synthesis of a-amino-acids has been applied to thiophen-2-carboxaldehyde,which reacted with a -methylbenzylamine, benzoic acid, and cyclohexyl isocyanide to give (129) in 68% yield. The Schiff base with a -methylbenzylamine could also be used successfully.' '' The factors influencing the reactivity of 2-thienylglyoxal monosemicarbazones with cyclizing reagents have been investigated. At room temperature, bromine-sodium acetate in acetic acid gave (1301, which ring-closed to (131),sometimes spontaneously or else after treatment with triethylamine. In some cases, thienyl-l,2,4-triazines (132) were obtained. ''

The gem dimorpholine derivative of 2-thienylglyoxal reacts with thiols to give dithioacetals.' l 4 The kinetics and mechanism of vapour-phase ammonoxidation of thiophen-2-carboxaldehydeto 2-cyanothiophen over a Mo-Bi-Sb catalyst at 400 "C have been ~ t u d i e d . " ~ A simple synthesis of 2- and 3-thienylacetylenes from the corresponding thiophencarboxaldehydes has been described.' l 6 The condensation of thiophencarboxaldehyde with co-dimers from malononitrile and cyanoacetate has been in~estigated."~

Reactions of Carboxy- and Cyano-thiophens.-N-Aryl-thiophen-2-hydroxamic acids have been prepared.'" While 2-cyanothiophen reacts with sodium borohydride to give the corresponding imino-ether, 3-cyanothiophen does not react. Both 2- and 3-cyanothiophens react with hydrogen chloride in the Pinner reaction to give the imino-ether hydrochlorides.' l 9 The Pinner reaction has also 110

'12

'16 'I7

'I9

S. Conde, R. Madroiiero, M. P. Fernandez-Tom&, and J. del Rio, J. Med. Chem., 1978,21,978. R.-C. Coumes, A. Gaset, J.-P. Gorrichon, and G. Michel, Chim. Ther., 1978, 13,527. H. R. Divanfard, Z. Lysenko, P.-C. Wang, and M. M. Joullit, Synth. Commun., 1978,8, 269. G. Werber, F. Buccheri, N. Vivona, and M. Gentile, J. Heterocycl. Chem., 1978, 15,1393. Y. Le Floc'h, Bull. SOC.Chim. Fr., Part 2, 1978, 595. P. Singh, Y. Miwa, and J. Okada, Chem. Pharm. Bull., 1978,26, 2838. C. Wentrup and H.-W. Winter, Angew. Chem., 1978,90,643. H. Junek, B.Thierrichter, and P. Wibmer, Monatsh. Chem., 1979, 110,483. R. Pande and S. G. Tandon, J. Chem. Eng. Data, 1979,24,72. B. Decroix and P. Pastour, J. Chem. Res. ( M ) ,1978, 1812.

Fiue-membered Rings : Thiophens and their Se and Te Analogues

87

been studied with various dicyano-thiophens. When equivalent amounts of alcohol were used with 2,3- and 2,4-dicyanothiophen, a mixture of cyano-imidate salts was obtained, depending upon the position of the cyano-group and the Various Side-chain Reactions.-Some 1-(2-thienyl)propen-3-ones have been nitrated in the 2-position of the side-chain.121 Some bis-derivatives of p-(2thieny1)ethylamine and p -(2-thienyl)isopropylamine have been synthesized. 122

CL4

3

2

CH=CHC=O

1

I

a,J4 3

2 1

CH=CH-CN

Me

(134)

(133)

The silylation of (133) and (134) using the Me3SiC1-Mg-HMPA system occurs in the 1,4- and 1,2-positions7 respectively. 123 A series of 5-styryl-2-thienylacetic acids has been synthesized, starting with the Friedel-Crafts acylation of 2-thenyl cyanide with phenylacetyl ch10ride.l~~ The reaction of the 2-thienyltropane (135) with diethyl azidocarboxylate gave (136), which ring-closed to (137) upon

H NI - ZIE - J ) C0,Et

p

C02Me

treatment with 2-Thienylglycine has been oxidized to the corresponding sulphonimine derivative by mild treatment with toluene-p-sulphenyl chloride in the presence of acid Reaction at Sulphur: Thiophen Dioxides.-Irradiation of 3,4-dibromo-, 3,4dichloro-, and 3-chloro-2,5-dimethyl-thiophen1,l-dioxides in the presence of pentacarbonyliron caused successive reductive dehalogenation of the substrates and Ir-complexation of the parent compounds.'26 The reaction of thiiren 1,ldioxides with a-metallated nitriles yielded the sulpholens (138) and (139).'*' Flash vapour-phase pyrolysis of 2,5- or of 2,4- and 2,5-diphenylthiophen 1,ldioxides at temperatures above 800 "C, at low2mmHg pressure, yielded the corresponding furans. 12* B. Decroix, J. Morel, and P. Pastour, J. Chem. Res. ( M ) ,1978, 1848. A. I. Sitkin, V. I. Klimenko, and A. L. Fridman, Zh. Org. Khim., 1977,13, 2623. lZ2 T, J. Burakowski, E, Muszyhski, and A. Petruczenko, Acta Pol. Pharm., 1978,35, 175. 123 M. Bolourtchian and A. Saednya, Bull. SOC.Chim. Fr., Part 2, 1978, 170. 124 S . Yoshimura, S. Takahashi, A. Kawamata, K. Kikugawa, H. Suehiro, and A. Aoki, Chem. Pharm. Bull., 1978, 26, 685. '" ( a ) R. L. Clarke, A. J. Gambino, and M. L. Heckeler, J. Org. Chem., 1978, 43, 4589; ( 6 ) E. M. Gordon and J. PluSEec, ibid., 1979, 44, 1218. lZ6 V. Usieli, S. Gronowitz, and I. Andersson, J. Organomet. Chem., 1979, 165,357. lZ7 Y. Yoshida, M. Komatsu, Y. Ohshiro, and T. Agawa, J. Org. Chem., 1979, 44, 830. '*' W. J. M. van Tilborg and R. Plomp, R e d . Trav. Chim. Pays-Bas, 1977,96282. lZ1

88

Heterocyclic Chemistry Ph

(139)

The recently reported azulene synthesis through [6 + 41 cycloaddition of thiophen 1,l-dioxides and 6-aminofulvenes has been used for the synthesis of guaiazulene and c h a m a z ~ l e n e . ' ~ ~ Wolff-Kishner reduction of (14) followed by desulphurization with Raney nickel has been used for the synthesis of (140)." Starting from (64), a new synthesis of queen substance, in which desulphurization by Raney nickel is a key step, has been worked

Di- and Tetra-hydrothiophens.-A synthesis of 2,5 -dihydro thiophen from vinylacetylene and sodium hydrosulphide has been described.13' 2,5-Dihydrothiophen is probably an intermediate in a novel 1,2- and 1,4-diacetoxylation of buta-1,3-diene, promoted by sulphur d i 0 ~ i d e . IThe ~ ~ reaction of (141) with hydrogen bromide and trichloroacetic acid led to a mixture of (142) and (143).'32The rate of solvolysis in 80% aqueous acetone of the p-nitrobenzoate of 5'

SH

1l

w

(

C

H

2

)

7

c

0

2

Me

SH (142)

(143)

2 -me thy1te tra hydro thiop hen-2 -methanol has been determined. '33 2-Tetrahydrothienyl diphenylacetate, a stable crystalline compound, prepared from 2-chlorotetrahydrothiophen,has been introduced as a reagent for the protection of Compound (144)has been used for the synthesis of activated carboxy-groups in peptide ~ y n t h e s i s . 'Photolysis ~~ of dihydrothiophen-3(2H)ones in methanol proceeds via p -cleavage to give 5,6-dithiadecane-2,9-

'3n

132

133 134

D. Mukherjee, L. C. Dunn, and K. N. Houk, J. Am. Chem. Soc., 1979,101,251. B. A. Trofimov, S. V. Amosova, G. K. Musorin, and M. G. Voronkov, Zh. Org. Khim., 1978,14, 667. E. Tempesti and L. Giuffre, J. Heterocycl. Chem., 1979,16, 533. I. L. Kuranova and E. V. Snetkova, Zh. Org. Khim., 1978,14, 2165. J. Ohishi and S. Ikegami, Chem. Pharm. Bull., 1978,26, 321 1. C. G. Kruse, E. K. Poels, F. L. Jonkers, and A. van der Gen, J. Org. Chem., 1978,43, 3548. G. Schnorrenberg and W. Steglich, Angew. Chem., 1979,91, 326.

Five-membered Rings: Thiophens and their Se and Te Analogues

89

diones. 136 Upon base-induced photolysis of 3-acetyl-2,4-dioxothiolan,reductive ring-cleavage or two types of fragmentation with carbon-skeleton rearrangement were observed, depending upon the irradiation In connection with work on anti-inflammatory compounds, various sulpholan derivatives such as (145) and (146) have been prepared.138 l-Hydroxy-3,3-dimethyl-l-aryl-thiophthalans and their methyl ethers were synthesized and their spectroscopic properties studied. 139 Me OC0,R

I

HO,CC=HC

' jSICH=cc

Me

Ph 0 2

0 2

0 2

Several papers concerned with the synthesis of biotin and its analogues have appeared. A total synthesis of biotin was based on stereoselective alkylation of sulphoxides. Starting from dibromosuccinic acid, the imidazolone ring was first constructed and (147) was then ring-closed with sodium sulphide and oxidized with periodate to (148). This compound was treated with methyl-lithium and t-butyl w-iodovalerate to give (149). Reduction of the sulphoxide with TiC13and

1-

HM--H

- -H

H--

MsOCH,

CH20Ms

R = PhCH2 or H2C=CHCH2

Bu'O,C(H,C)~

II

(147)

0

II

0

(148)

(149)

debenzylation or deallylation then gave (dl)-bi~tin.'~' Dehydrobiotin (40) has been synthesized.22A new synthesis of (dZ)-epiallobiotin,starting from (lSO), and going via (151) and (152), has been carried The monobenzyl PhCONH

NHCOPh

NH,.HBr

BrH*NH2

R (150)R

=

(CH2)4C02Me

(151)Phth

=

phthalimido

(152)

P. Yates and Y. C. Toong, J. Chem. SOC.,Chem. Commun., 1978,205. K. Saito and T. Sato, Chem. Letters, 1978, 307. 138 G. A. Tolstikov, N. N. Novitskaya, B. V. Flekhter, D. N. Lazareva, V. A. Davydova, and E. G . Kamalova, Khim.-Farm. Zh., 1978, 12, 33. 13' D . A. Oparin, T. G. Melent'eva, and L. A. Pavlova, Zh. Org. Khim., 1978, 14, 628. lQo S. Lavielle, S. Bory, B. Moreau, M. J. Luche, and A. Marquet, J. Am. Chem. SOC.,1978,100, 1558. 14' S. D. Mikhno, T. M. Filippova, N. S. Kulachkina, I. G. Suchkova, and V. M. Berezovskii, Zh. Org. Khim., 1978,14, 1706. 136 137

90

Heterocyclic Chemistry

derivative (153)has been metallated on nitrogen and converted into 3’-Nmethylbiotin by reactions analogous to those used in the synthesis of biotin itself .14’ 0

P h C H ,I N K NIH

Bi- and Poly-heterocycles.-More work on the synthesis and properties of 2-thienylcyclopropenium ions has appeared.’43 5-Aryl-2-acetylthiophens were prepared by Friedel-Crafts acetylation and condensed with benzaldehyde in connection with a study of proton-acceptor capacities.144 Some new direct azo-dyes were obtained by diazo-coupling of 2-( p - aminophenyl)thiophen, 2,5bis- ( p -aminophen yl)thiophen, and 2,5 -bis- ( p -aminostyryl)thiophens with naphtholsulphonic, naphthalenesulphonic, and naphtholaminosulphonic The reaction of thenoylmethane with amines and hydroximino-p acids dicarbonyl compounds led to ( 154).’46Some 5-aryl-thiophen-2-carboxylic have been prepared for studies of biological activity. 147 The condensation product (155)from 2-phenyl-1,3-dithiolone and styrene gave 2,3-diphenylthiophen upon dehydrogenative cleavage on a Pd c a t a 1 y ~ t . lSimilarly, ~~ the adduct mixture from 2,5-diphenyl-l,3-dithiolylium-4-olatewith N-phenylmaleimide gives (156) upon deh~drogenati0n.l~~

An experimental and theoretical study of the U.V. spectra of some bithienyls indicates that non-planar conformations are predominant in the vapour phase and in non-polar solvents. 150In connection with continued work on atropisomeric was prepared from 3,3’-bithienyls, 2,2‘-dicarboxy-4,4’-dichloro-3,3’-bithienyl 2,2’-dibromo-4,4’-dichloro-3,3’-bithienyl via bromolithium exchange and reaction with carbon dioxide and then resolved into antipodes with dehydroabietylG . F. Field, J. Org. Chem., 1978, 43, 1084. G.Martelli, P. Spagnolo, L. Testaferri, and M. Tiecco, Tetrahedron Left.,1979, 281. 144 V. K. Polyakov, Z. P. Zaplyuisvechka, L. P. Pivovarevich, Yu. N. Surov, and S. V. Tsukerman, Khim. Geterotsikl. Soedin., 1976, 1196. 14’ A . Arcoria, V. Librando, M. Longo, and M. Torre, Chim. Ind. (Milan),1978,60,981. 146 E. Yu. Belyaev, G. A. Suboch, and A. V. El’tsov, Zh. Org. Khim., 1978, 14, 1506. 14’ V. I. Shvedov and 0. A . Safonova, Khim.-Farm. Zh., 1978,12, 5 3 . 14’ H. Gotthardt, C. M. Weisshuhn, and B. Christl, Justus Liebigs Ann. Chem., 1979, 360. 149 H. Gotthardt and B. Christl, Chem. Ber., 1978, 111,3029. P. Meunier, M. Coustale, and J. Arriau, Bull. SOC.Chim. Belg., 1978, 87, 27. 14’

143

Five-membered Rings : Thiophens and their Se and Te Analogues

91

amine. Its rate of racemization was measured and the absolute configuration determined by ~ . d . ~In’ order to study derivatives with locked configuration, it was transformed into (157). The AG? value for (157; X = 0)was found to be 17.8 kcal mol-’. The compound (158) was prepared from 2,2’,4,4’-tetrabromo3,3’-bithienyl in five steps, and the ( + )-form of (158) was obtained in a second-order asymmetric transformation through formation of a salt with quinine. The barrier to inversion was determined to be 22.5 kcalmol-’, and the c.d. spectrum was studied.60 A number of dihydrodithieno[c,e]-oxepins, -thiepins, and -azepines have been synthe~ized.’~’ 3,3’-DimethyL2,2’-bithienyl has been brominated in the side-chain and transformed into the dinitrile, and then, by Thorpe-Ziegler cyclization, transformed into (159). Malonate synthesis

a s

(163)

s

(159)

(158)

(157)X = O o r S

Rf-JJ

SJCH(SCH2CO2H), (165)

S (164)

with 3,3’-di(bromomethyl)-2,2’-bithienyl and 2,2‘-di(bromomethyl)-3,3’bithienyl gave (160) and (161), r e s p e ~ t i v e l y .The ~ ~ reaction of hexa(bromomethy1)benzene with sodium sulphide gave a trisulphide, which was aromatized with DDQ to (162). In contrast to benzo[c]thiophen, (162) does not readily add dienophiles. It gave intensely coloured air- and moisture-stable crystalline 1 : 1 charge-transfer complexes with TCNG, DDQ, and TCNQ, and showed very interesting protonation behaviour in FS0,H-S0,CIF at - 20 to - 78 “C,giving a single species.’52 From 2,2’-dibromo-3,3’-bithienyl and 3,3‘-dibromo-2,2’bithienyl, with butyl-lithium and CuC1, or Feel,, the compounds (163) were prepared. Similarly, (164) was obtained from 4,4’-dibrom0-3,3’-bithienyl.’~~ 15’

P. Meunier, J. Heterocycl. Chem., 1978, 15, 593.

153

H. Hart and M. Sasaoka, J. A m . Chem. SOC.,1978,100,4326. T. Kauffmann, B. Greving, R. Kriegesmann, A. Mitschker, and A. Woltermann, Chem. Ber., 1978, 111,1330.

92

Heterocyclic Chemistry

Azomethine derivatives derived from 5-formyl-2,2'-bithienyls gave (165) with thioglycolic acid. The compound (165) showed antibacterial p r o p e r t i e ~ . ~ ' ~ 2,2'-Thienyl-pyrroles have been prepared through the reaction of methyl 2-thienyl ketoxime with acetylene in the presence of potassium hydroxide at 100-140 0C.155Formylation of N-(3-cyano-2-thienyl)pyrrole gave N - ( 3 cyano-2-thienyl)pyrrole-2-carboxaldehyde,which upon heating with hydrazine gave (166).156Nitration of 2-(2-thienyl)indole occurs in the 5-position of the benzenoid ring. 15' The reaction of tosylmethyl isocyanide with thiophen-2-carboxaldehydewas From 2- and 3-azidothiophen, used for the synthesis of 5-(2-thienyl)oxa~ole.~~~ l-(thienyl)-l,2,3-triazoleshave been prepared by reaction with acetylenes.61The synthesis of (167) as a p -adrenergic blocking agent, from 2-bromoacetylthiophen-5-carboxamide, has been d e ~ c r i b e d .From ' ~ ~ the easily available (168), a convenient synthesis of 4-(2-thienyl)pyrazole-3-carboxylic acid and other aryl-pyrazoles through the reaction with hydrazine has been worked out. 160 2-Thienyl-substituted benzimidazoles, benzoxazoles, and benzothiazoles have been prepared through the reaction of 2-thienylselenocarboxamide with o phenylenediamine, o -aminophenol, or o -aminothiophenol. l 6 I In connection with the synthesis of 2-arylthiazolo[3,2-a]pyridinium salts for the investigation of their hypoglycaemic activity, the 2-thienyl derivative has been prepared.I6*

Y'

SCH,CHCH,NHBu'

C0,Et

CI (168)

Thiophen amidines have been transformed into l-amino-2,5-bis(thienyl)1,3,4-triazoles through reaction with hydrazine, and, through reaction with various active-methylene derivatives, into substituted 2-(thienyl)-pyrimidines. l 9 '51

lS5

157

16'

162

A. E. Lipkin, K. I. Vakhreeva, P. I . Buchin, D. A. Kulikova, and E. A. Rudzit, Khim.-Farm. Zh., 1977,11,46. B. A. Trofimov, A. I. Mikhaleva, R. N . Nesterenko, A. N. Vasil'ev, A. S. Nakhmanovich, and M. G. Voronkov, Khim. Geterotsikl. Soedin., 1977, 1136. S . Rault, M. Cugnon de Skvricourt, and M. Robba, C. R. Hebd. Seances Acad. Sci., Ser. C, 1978,287, 117. B. S. Holla and S. Y. Ambekar, Indian J. Chem., Sect. B, 1978,16, 240. H. Saikachi, T. Kitagawa, H. Sasaki, and A . M. van Leusen, Chem. Pharm. Bull., 1979,27, 793. Y. Hara, E. Sato, A. Miyagishi, A . Aisaka, and T. Hibino, J. Pharm. Sci., 1978,67, 1334. S. Liljefors and A. Hallberg, Tetrahedron Lett., 1978, 4573. V. I. Cohen, J. Heterocycl. Chem., 1979,16, 13. B. Blank, N. W. DiTullio, A. J. Krog, and H. L. Saunders, J. Med. Chem., 1978, 2 1 , 4 8 9 .

Five-membered Rings : Thiophens and their Se and Te Analogues

93

With 3- (N-methylani1ino)acrylaldehyde, the parent 2 -(thieny1)pyrimidines were obtained; their nitration and reaction with butyl-lithium were inve~tigated.'~~ 5-(2-Thienyl)pyrimidine has been prepared via the reaction of 5-chloro-2thienylacetic acid with DMF and POCl, followed by ring-closure of the resulting 1-dimet hylamino-3 -dimet hylimonio-2-( 5 -chloro- 2 -thieny1)prop- 1-ene perchlorate to 5-(5-chloro-2-thieny1)pyrimidine7and dechlorination. An alternative synthesis consisted of the reduction of 2-thienylmalonaldehydonitrileto 2thienyl-3-aminopropenal followed by ring-closure. 5 -(3-Thienyl)pyrimidine was prepared analogously. Isomer distributions in nitration and bromination of the 5-(thienyl)pyrimidines were determined and the directing properties of the 5 -pyrimidyl group in electrophilic substitution were analysed. 164 Naturally Occurring Thiophens.-Two new natural substances, cardopatine (169) and its stereoisomer, have been isolated from the roots of Cardopatium

p)J$ S

c o r y r n b ~ s u mThe . ~ ~ ~origin of the carbon skeleton of the C8 thiophenacetylene junipal has been elucidated.166Many simple alkyl-thiophens and thiophen aldehydes and ketones have been detected as constituents of meat aroma.167 marked interest in this field has been Thiophen Analogues of Steroids.-A noticeable during the period. Compound (170) was prepared analogously to the [1,2-b]-fused system mentioned in the previous Report (in volume 5 of the Specialist Periodical Reports on Organic Compounds of Sulphur, Selenium, and Tellurium), and both systems were further transformed into the oestrogen-like compounds (171) and (172).16' The high asymmetric induction in the olefinic

163 164

165

16' 16'

J. Pankiewicz, B. Decroix, C. Fugier, J. Morel, and P. Pastour, J. Chem. Res. ( M ) ,1978, 1832. S. Gronowitz and S. Liljefors, Chem. Scr., 1978-79, 13, 39. A . Selva, A . Arnone, R. Mondelli, V. Sprio, L. Ceraulo, S. Petruso, S. Plescia, and L. Lamartina, Phytochemistry, 1978, 17, 2097. E. R. H. Jones, C. M. Piggin, V. Thaller, and J. L. Turner, J. Chem. Res. ( M ) ,1977,744. G. Ohloff and I. Flament, Heterocycles, 1978, 11, 663. A. Corvers, P. C. H. Scheers, J. W. de Haan, and H. M. Buck, Recl. Trav. Chim. Pays-Bas, 1977,96, 279.

94

Heterocyclic Chemistry

cyclization to thiophen-containing steroid-like molecules has been further investigated, and strong evidence for pre-coiling of the initially formed allylic cation was obtained. Treatment of (173) with SnC14gave (174),which consisted of 97% of the LY- and 3% of the p-form. Some ring-closure also occurred to the thiophenic p -position, and the product in this case was 79% diastereomerically pure.'05" The ring-closure led to thiophen-containing steroids with cis fusion of the B and c rings if the (E)-polyene was substituted at pro-C-7 or at pro-C-6 and

H0,C'

(175)

(173)

0 OorR

P-OH, a-H

pro-C-7 ( t h r e ~ ) .The ' ~ ~Grignard reaction of optically active (175) with 2- and 3-thienylmagnesium bromide followed by lactonization gave (17 6 ) . These compounds were converted, through multi-step reactions, into a number of A-thieno-steroids, such as (177) and (178).17' Starting from (179), the aza-system (180) was prepared.171 When (181) was refluxed with laevulinic acid in a high-boiling solvent, (182) was obtained.17

170

A. A. Macco, J. M. G . Driesen-Engels, M. L. M. Pennings, J. W. de Haan, and H. M. Buck, J. Chem. SOC.,Chem. Commun., 1978,1103. T. Komeno, H. Iwakura, and K. Takeda, Heterocycles, 1978,10, 207. I. R. Trehan, B. S. Ahluwalia, and M. Vig, Indian J. Chem., Sect. B,1978, 16, 210.

Five-membered Rings : Thiophens and their Se and Te Analogues

95

Thiophens of Pharmacological Interest.-Several papers describe the pharmacological properties of a new anti-anxiety drug (183) of the thienodiazepine type. 172-174 The synthesis of (183) and many analogues, as well as structureactivity relationships, have been p~b1ished.l~~ From (29), the compounds (184) have been prepared.16 Cyclization of (31)gave (185), which in several steps was transformed into (186).17Thieno-[2,3-b][1,5]-, -[3,2-b][1,5]-, and -[3,4-b][1,5]benzodiazepinoneshave been synthesized,for evaluation as antipsychoticagents. Thus, (187) gave (188) upon intramolecular cyclization using dirnsylsodi~m.'~~ The analogous thieno[ 1,4]benzodiazepinone was prepared, starting from, for instance, (189), which was reduced and ring-closed to (190).53

RQ

&lNH H

&l)Me N-N

Thiophen derivatives continue to play an important role in the development of non-steroidal anti-inflammatory agents, and acetic acid derivatives of tricyclic systems such as (49), (50), (53),44and analogous compounds have been studied extensively.177~178 172 173

174

175 176

177

178

M. S. Manhas, M. Sugiura, and H. P. S. Chawla, J. Heterocycl. Chem., 1978, 15, 949. M. Setoguchi, S. Takehara, A. Nakajima, T. Tsumagari, and Y. Takigawa, Arzneim.-Forsch., 1978, 28, 1165; T. Tsumagari, A. Nakajima, T. Fukuda, S. Shuto, T. Kenjo, Y. Morimoto, and Y . Takigawa, ibid., p. 1158. Y. Kato and H. Nishimine, Arzneim.-Forsch., 1978, 28, 1170. T. Tahara, K. Araki, M. Shiroki, H. Matsuo, and T. Munakata, Arzneim.-Forsch., 1978,28, 1153. J. K. Chakrabarti, T. A. Hicks, T. M. Hotten, and D. E. Tupper, J. Chem. SOC.,Perkin Trans. 1,1978, 937. T. Yoshioka, M. Kitagawa, M. Oki, S.Kubo, H. Tagawa, K. Ueno, W. Tsukada, M. Tsubokawa, and A. Kasahara, J. Med. Chem., 1978,21,633. J. Ackrell, Y. Antonio, F. Franco, R. Landeros, A. Leon, J. M. Muchowski, M. L. Maddox, P. H. Nelson, W. H. Rooks, A. P. Roszkowski, and M. B. Wallach, J. Med. Chem., 1978, 21, 1035.

Heterocyclic Chemistry

96

5-Substituted thienylacetic acids have been investigated for inhibition of platelet aggregation. 124 The hypolipidaemic activities of the thiophen analogues of clofibrate and procetopen have been studied. In addition, a number of thiophens with a thioisobutyrate side-chain have been prepared, and ethyl 2-(5-chloro-2-thienylthio)-2-methylpropionate exhibited hypocholesteremic and hypoglyceridemic activities which by far exceed those of lof fib rate.^^ 5-Aryl-2-azabicyclo[3.2. llnonanes containing the 2-thienyl group,179as well as compounds of type (135),lgohave been studied for analgesic activity. The latter also have hypoglycaemic activity. H.p.1.c. has been used for assaying suprofen (191), a potent new analgesic.'*l Methods for the quantitative determination of tiamenidine hydrochloride (192), a new central antihypertensive agent that is under clinical trial, have been worked out.lg2

Q

Me

I

OH

I

C=CHCH,NHCH-CHPh

(193)

The synthesis of tinofedrin (193) has been de~cribed."~ In connection with a study of chemotherapeutically active 5-nitro-imidazoles, more than 170 compounds were synthesized, some containing thiophen rings. lS4 Some thiophen analogues of amidinomycin were synthesized, but showed no antiviral a~tivity."~ The 16- and 17-thienylprostaglandins FZa (194) and (195)Ig6

(194) X

lg3

lS4 lS5

=

0, CH2, o r S

OH (195)

"S'

H. H. Ong, V. B. Anderson, and J. C. Wilker, J. Med. Chem., 1978, 21, 758. R. L. Clarke, M. L. Heckeler, A . J. Gambino, S. J. Daum, H. R. Harding, A . K. Pierson, D . G . Teiger, J. Pearl, L. D. Shargel, and T. J. Goehl, J. Med. Chem., 1978,21, 1243. K. B. Alton and J. E. Patrick, J. Pharm. Sci., 1978,67, 985. H. W. Fehlhaber, K. Metternich, D. Tripier, and M. Uihlein, Biomed. Mass Spectrom., 1978,5, 188. K. Thiele, K. Posselt, and H. Offermanns, Arzneim.-Forsch., 1978, 28, 2047. E. Winkelmann, W. Raether, and A . Sinharay, Arzneim.-Forsch., 1978, 28, 351. H. Paul and H. Migulla, Arch. Pharm. (Weinheim, Ger.),1978, 311, 679. W. Bartmann, G. Beck, U . Lerch, H. Teufel, and B. Scholkens, Prostaglandins, 1979, 17, 301.

Five-membered Rings : Thiophens and their Se and Te Analogues

97

have been synthesized. Analogues of the thyrotropin-releasing hormone that contain 2-thienylalanine have been synthesized and The effects of acetylated,propionylated, chloroacetylated, and trifluoroacetylatedamino-acids, including the thienylalanines, on a microbial anti-tumour screen have been A keto-analogue of acetylcholine, i.e. (3-thenoylpropy1)trimethylammonium chloride, has been synthesized for studies of the inhibition of human placental choline acetyltransferase.190 Thienylglycine derivatives have been used as side-chains in cephalosporins.191~192In connection with studies on the synthesis and chemistry of penicillin and cephalosporin antibiotics, thiophen2-acetic acid has been used as a ~ i d e - c h a i n . ' ~ ~ - ' ~ ~

3 Benzothiophens and their Benzo-fused Systems Synthesis of Benzothiophens.-A facile and rapid synthesis of 2-phenylbenzo[b]thiophen-3-amine and its S-oxides, starting from o-nitrobenzonitrile, has been Derivatives of 5,6-disubstituted 3-benzo[b]thienylacetic acids have been obtained uia ring-closure of the appropriate methyl and ethyl phenylthioacetoacetates. They were used for the synthesis of melatonin and harmaline analogues.l g g b The reaction of 3-bromothiocoumarin with nitrogen bases was used for the synthesis of amides of benzo[b]thiophen-2-carboxylic acid.200Heating of [5-chloro-2-(phenylthio)phenyl]acetothiomorpholide with polyphosphoric acid led to a new benzo[b]thiophen synthesis, giving 5-chloro-2morpholinobenzo[b]thiophen in 72% yield.*" Physical Properties.-The electronic structure of benzo[b]thiophen and some of its substituted derivatives was examined by photoelectron spectroscopy in conjunction with semi-empirical calculations (EHT, CNDO/S). A qualitative correlation between nucleophilic reactivity and the energies of frontier orbitals was obtained.*'* Substitution Reactions.-The reaction of benzothiophen with ally1 halides in the presence of silver trichloroacetate in chlorine-containing hydrocarbons yielded

187

190 191 192

193 194

195 196

197 198

'01 'O'

S. Castensson, S. Bjorkman, H. Sievertsson, and C. Y. Bowers, Acta Pharm. Suec., 1977,14, 505. T. T. Otani and M. R. Briley, J. Pharm. Sci., 1979,68, 496. T. T. Otani and M. R. Briley, J. Pharm. Sci., 1978,67, 520. A. K. Chaturvedi, P. P. Rowell, and B. V. Rama Sastry, J. Pharm. Sci., 1978,67, 657. H. Breuer, U. D. Treuner, H. J. Schneider, M. G. Young, and H. I. Basch,J. Antibiot., 1978,31,546. H. E. Applegate, C. M. Cimarusti, J. E. Dolfini, W. H. Koster, M. A. Ondetti, W. A. Slusarchyk, M. G. Young, H. Breuer, and U. D. Treuner, J. Antibiot., 1978, 31, 561. J. C. Sheehan and T. J. Commons, J. Org. Chem., 1978,43,2203. T. Hashimoto, Y. Kawano, S.Natsume, T. Tanaka, T. Watanabe, M. Nagano, S. Sugawara, and T. Miyadera, Chem. Pharm. Bull., 1978, 26, 1803. M. Narisada, H. Onoue, and W. Nagata, Heterocycles, 1977,7, 839. W. F. Huffman, R. F. Hall, J. A. Grant, and K. G. Holden, J. Med. Chem., 1978,21,413. P. R. Bontchev and P. Papazova, Pharmazie, 1978,33, 346. J. V. Uri, P. Actor, L. Phillips, and J. A. Weisbach, J. Antibiot., 1978, 31, 580. (a)J. R. Beck, J. Heterocycl. Chem., 1978,15,513; ( b )E. Campaigne, E. Homfeld, and D. E. Mais, ibid., p. 1351. V. L. Savel'ev, T. G. Afanas'eva, and V. A. Zagorevskii, Khim. Geterotsikl. Soedin., 1978, 1340. M. RajSner, F. MikSik, and M. Protiva, Collect. Czech. Chem. Commun., 1978, 43, 1276. C. Guimon, M. F. Guimon, G. Pfister-Guillouzo, P. Geneste, J. L. Olive, and S. N. Ung, Phosphorus Sulfur, 1979, 5 , 341.

98

Heterocyclic Chemistry

Acylation of benzo[b]thiophen with 3-allyl- and diallyl-benz~[b]thiophen.~~~ ferric chloride as catalyst gave a 1:4 mixture of 2- and 3-acylbenzo[b]thiophens.*04Electrophilic substitutions such as nitration, bromination, and FriedelCrafts acetylation, under varying conditions, with a range of 4- and 6-substituted benzo[b]thiophens have been carried out. Substitution usually took place in the 2- and/or 3-position, except for 6-acetamido- and 6-hydroxy-benzo[b]thiophen, where bromination and nitration also took place in the 5 - and 7-positions. Also, for 4-chloro-3-methylbenzo[b]thiophen,one of the nitration products was due to ipso-substitution, and bromination was confined to the ~ i d e - c h a i n . ~ ~ ~ ~ Benzo[b]thiophen has been acylated with succinic acid ester chloride in connection with work on the synthesis of tri- and tetra-cyclic sulphur analogues of ind~le.~~~' The attempted oxidative demethylation of a series of ortho-dihydroxybenzo[b]thiophen methyl ethers failed. However, with ceric ammonium nitrate, nitration in the 2-position was observed, while aqueous periodate or thallate gave oxidative hydroxylation in the 7-po~ition.~'~ Friedel-Crafts acylations of 2- and 3-methoxy- and 2- and 3-methylthiobenzo[b]thiophen with arylacrylic acid chlorides were key steps in the synthesis of flavones and xanthones of the benzo[b]thiophen series. Compounds such as (196)-(199) were thus prepared.207

0

0

From 2- and 3-lithiobenzo[b]thiophen, the azido-compounds were prepared. The reaction of the 3-azido derivative with refluxing acetic anhydride gave a low yield of 3-diacetylamino-2-acetoxybenzo[b]thiophen.61Electrochemical oxidation of benzo[b]thiophen and some methyl derivatives gave the corresponding 2,3-dirnethoxy-2,3-dihydrobenzo[b]thiophen~.~~~ The reactions of benzo[b]thiophen and 3-methylbenzo[b]thiophen with cyclic secondary amines 203

204 '05

206 207 208

A. V. Anisimov, Yu. N. Luzikov, V. M. Nikolaeva, Yu. N. Radyukin, E. A. Karakhanov, and E. A.

Viktorova, Khim. Geterotsikl. Soedin.,1977, 1625. Kh. Yu. Yuldashev, Khim. Geterotsikl. Soedin., 1978, 1039. ( a )P. D. Clark, K. Clarke, R. M. Scrowston, and T. M. Sutton, J. Chem. Res. ( M ) ,1978,368; ( b ) R. Neidlein and N. Kolb, Arch. Pharm. (Weinheim, Ger.), 1979, 312,338. E. Campaigne and E. Homfeld, J. Heterocycl. Chem., 1979, 16,231. P. Netchitailo, B. Decroix, J. Morel, and P. Pastour, J. Heterocycl. Chem., 1978, 15, 337. J. Srogl, M. Janda, I. Stibor, J. Kos, and V. VyskoEil, Collect. Czech. Chem. Commun., 1978, 43, 201s.

Five-membered Rings Thiophens and their Se and Te Analogues

99

in the presence of dispersed sodium, or with alkali-metal salts of the amine, gave addition across the 2,3-bond to yield, for instance, 2-piperidino-2,3-dihydrobenzo[b]thiophen. No addition was observed with 2-methyl- and 2,3dimethyl-benzo[b]thiophen, benzo[b]furan, or benzo[b]selenophen. With primary amines of low molecular weight, reduction to ethylbenzene and other compounds was The reactions of 5-halogeno-2H,3Hbenzo[b]thiophen-2,3-diones with several nucleophiles have been studied by e.s.r. spectroscopy.210Benzo[b]thiophen underwent cycloaddition with benzoand mesito-nitrile oxides, but the regioselectivity is lower than with thi~phen.’~ Side-chain Reactions.-All six 1-(benzo[b]thienyl)ethyl acetates, 1(benzo[b]furan-2-yl)ethyl acetate, and 1-(benzo[b]furan-3-yl)ethyl acetate have been prepared and their rates of gas-phase elimination of acetic acid measured. The positional order of reactivity in benzo[b]thiophen is 3 > 2 > 6 > 5 > 4 > 7, which is both theoretically predicted and observed in the solvolysis of 1(benzo[b]thienyl)ethyl chlorides and (in part) in electrophilic aromatic substitutiom211 3-Vinylbenzo[b]thiophen and three simple homologues were shown to give normal Diels-Alder adducts with tetracyanoethylene, whereas 3-methyl-2vinyl- and 2-methyl-3-prop-l-enyl-benzo[b]thiophengave cyclobutanes.212 Direct and sensitized irradiation of (200) led to the unrearranged intramolecular cycloaddition product (201), which upon extended photolysis could rearrange to (202).213 The intramolecular photo-arylation of amides of 3-chlorobenzo[b]thiophencarboxylic acid has been investigated.*14Three classes of dyes

(202)

have been obtained by condensation of 4-bromo-3-hydroxybenzo[b]thiophen with acenaphthenequinones, phenanthrenequinones, and ben~aldehydes.~”3Benzo[b]thiophencarboxaldehyde reacts with methylated pyrylium and thiopyrylium salts.216 ’09

’lo 211

212 *I3

’14

215 216

P. Grandclaudon and A. Lablache-Cornbier,J. Org. Chem., 1978,43,4379. F. Ciminale, G. Bruno, L. Testaferri, M. Tiecco, and G. Martelli, J. Org. Chem., 1978,43, 4509. H. B. Amin and R. Taylor, J. Chem. Soc., Perkin Trans. 2, 1978, 1053. W. H. Cherry, J. T. Craig, and Q. N. Porter, Aust. J. Chem., 1979,32, 133. A. H. A. Tinnemans and D. C. Neckers, J. Org. Chern., 1978,43,2493. M. Terashima,K. Seki, K. Itoh, and Y. Kanaoka, Heterocycles, 1977,8,421; S. Kano, T. Ozaki, and S. Hibino, ibid., 1979, 12,489. K. D. Banerji, A. K. D. Mazumdar, and S. K. Guha, J. Indian Chem. Soc., 1977,54,969. R. Neidlein and I. Korber, Arch. Pharm. (Weinheim, Ger.), 1978,311, 256.

100

Heterocyclic Chemistry

Benzo[b]thiophen S-Oxides.-2-Phenyland 2-methyl-3-methoxybenzo[b]thiophen 1 , l-dioxide underwent ring-opening to ortho-sulphonylsubstituted benzamides on treatment with morpholine and with piperidine, but reacted with pyrrolidine to yield enamines. 3-Methoxybenzo[b]thiophen 1 , l dioxide gave ring-cleavage with all three a m i n e ~ .2-Benzoyl-3-chloro~~~ benzo[b]thiophen 1,l-dioxide reacted with salts of active methylene compounds such as malononitrile to give nucleophilic substitution of the chlorine.218The photodimerization of 3-methylbenzo[b]thiophen 1-oxide has been investigated.219

of some new ortho-dibenzylated aromatic compounds with sulphur gave benzo[c]thiophens and naphtho[2,3-c]thiophens.220 1,3-Dithiolylium-3-0lates reacted with cyclohexadiene to give the cyclo-adduct (203) and the other cyclohexene isomer, which upon dehydrogenation with Pd on carbon gave 1,3-diphenylbenzo[~]thiophen.~~~

Benzo[c]thiophens.-Treatment

S

0

Dibenzothi0phens.-The procedure for metallation of dibenzothiophen with butyl-lithium has been improved, and better methods for the synthesis of all four isomeric hydroxydibenzothiophens and some of their chlorine and methoxysubstituted derivatives have been developed.222The benzoylation and p -chlorobenzoylation of dibenzothiophen in the presence of the FeC13 complex with nitromethane led to the corresponding 3 -acyl-dibenzothiophens in good yields.223 Rieche formylation of dibenzothiophen, using AlC1, and dichloromethyl ether, has been investigated.224Among the products obtained upon thermolysis of biphenyl-2-thiol over various catalysts was dibenzothiophen. The desulphurization of dibenzothiophen and biphenylthiols was Aryl radicals (204) afforded dihalogenodibenzothiophens as a result of intramolecular homolytic aromatic i p s o - s u b ~ t i t u t i o nFrom . ~ ~ ~ l-aminodibenzothiophen, several benzothienoquinolinecarboxylic acids were prepared, which were tested for anti-allergic Dibenzothiophen 5,5-dioxide analogues K. Buggle, P. McManus, and D. O’Sullivan, J. Chem. SOC.,Perkin Trans. 1, 1978, 1136. W. Ried, J. B. Mavunkal, and G. Oremek, Justus Liebigs Ann. Chem., 1978, 1274. ’lY M. S. El Faghiel Amoudi, P. Geneste, and J. L. OlivC, Tetrahedron Lett., 1978, 999. ”” L. Lepage and Y. Lepage, J. Heterocycl. Chem., 1978,15, 118.5. H. Gotthardt, C. M. Weisshuhn, and B. Christl, Chem. Ber., 1978, 111, 3037. 222 S. Gronowitz, M. Herslof, R. Svenson, G. Bondesson, 0.Magnusson, and N. E. Stjernstrom, Acta Pharm. Suec., 1978, 15, 337. 2 2 3 A. G . Khaitbaeva, Kh. Yu. Yuldashev, and N. G. Sidorova, Khim. Geterotsikl. Soedin., 1978, 620. 224 J. N. Chatterjea and R. S. Gandhi, J. Indian Chem. SOC.,1977, 54, 1151. L. H. Klemm and J. J. Karchesy, J. Heterocycl. Chem., 1978, 15, 281. L. Benati, P. C. Montevecchi, and A. Tundo, J. Chem. SOC.,Chem. Commun., 1978, 530. 227 J. J. Wade, E. H. Erickson, R. F. Hegel, L. R. Lappi, a n d T . K . Rice, J. Med. Chem., 1978,21,941. 217

218

’”

‘” ’“

Five-membered Rings : Thiophens and their Se and Te Analogues

(204)X = C l o r B r

(205) R

=

101

O(CH&NEt,

(205) of tilorone dihydrochloride have been prepared through the reaction of 3,7-dihydroxydibenzothiophen 5,5-dioxide and NN-diethylaminoethyl chloride.228Electrophilic substitution in benzo[ blthiophenanthrene has been investigated.229 Pharmacologically Active Compounds.-Some 5-chloro-2-phenyl- 1benzo[b]thiophen-3-alkanamides have been synthesized, starting from the 3methyl derivative, as potential antipsychotic The synthesis of benzo[b]thieno-[2,3-f]- and -[3,2-f]-morphans by the Grewe method has been described.2312-Benzo[b]thienyl-substituted thiazoles have been synthesized as thiabendazole Progress towards the synthesis of the sulphur analogue of lysergic acid, which involved the isosteric substitution of sulphur for the Plasma-lipid-lowering compounds belonging to the indole NH, was 2-(dibenzothiophenoxy)-2-methylpropionate series have been prepared.222The highly active 4-isomer was labelled with 4 Thiophen Analogues of Polycyclic Aromatic Hydrocarbons

Thiophen Analogues of Phenanthrene.-When 1-isopropenylnaphthalene was heated at 190 "C with sulphur, l-methylnaphtho[2,1-b]thiophen was formed, together with other products. It was converted into the 2-bromo-derivative, which was used for the synthesis of other derivatives. Similarly, derivatives of 3-methylnaphtho[l,2-b]thiophen were obtained, starting from 2-isopr~penylnaphthalene.~~~ Photocyclization of (206) gave (207), which was aromatized with DDQ to the corresponding naphth0[2,1-b]thiophen.~~~

asq I

228

229 "O

''' 232

233 234

235 236

l S I

H. M. Burke and M. M. Joullik, J. Med. Chem., 1978,21, 1084. J. N. Chatterjea and R. S. Gandhi, J. Indian Chem. SOC.,1977,54, 719. M. J. Kukla, C. M. Woo, J. R. Kehr, and A. Miller, J. Med. Chem., 1978, 21, 348. M. Alvarez, J. Bosch, and M. Feliz, J. Heterocycl. Chem., 1978, 15, 1089. G . Sarodnick and G. Kempter, Z. Chem., 1979,19, 21. J. Cymerman Craig and S. D. Hurt, J. Org. Chem., 1979, 44, 1113. T. Gosztonyi, G. Bondesson, K. E. Domeij, and N. E. Stjernstrom, J. Labelled Compd. Radiopharm., 1978,14,231. K. Adachi and J. Tanaka, Kogyo Kagaku Zasshi, 1978,1666. A. G. Schultz, W. Y. Fu, R. D. Lucci, B. G. Kurr, K. M. Lo, and M. Boxer, J. A m . Chem. SOC.,1978, 100,2140.

102

Heterocyclic Chemistry

Halogen-metal exchange of all six isomeric cis- 1,2-di-(o-bromothieny1)ethenes with butyl-lithium, followed by reaction with cupric chloride, gave all six benzodithiophens which are analogous to phenanthrene. The [bcl-fused systems, although relatively stable in solution, could not be isolated owing to dimerization and polymerization. They could be characterized by reaction with dimethyl acetylenedicarboxylate. After extrusion of sulphur, 7,8 -dicarbome thoxynaphtho[ 2,l- blthiophen and the corresponding naphtho[ 1,2-b]thiophen were obtained. The other four benzodithiophens did not undergo cycloaddition. The I3C n.m.r. spectra were a n a l y ~ e d Electrophilic .~~ nitration and bromination of benzo[l,2-b ;4,3-b']dithiophen and benzo[2,1-b ; 3,4-b']dithiophen have been carried out, and isomer distributions determined.237 has Thiophen Analogues of Phenalenes and Phenalenium Ions.-Neidlein continued his extensive work on this class of compounds. Thus, (208) was alkylated with triethyloxonium fluoroborate to give the phenalenium salt (209). Also, (2 10) has been prepared.238 The Friedel-Crafts reaction of 2-ethyl-

0

OEt

(212) R (213) R

= =

OEt

0 CR'R2

benzo[ blthiophen with cinnamoyl chloride gave (21l),which, upon treatment with A1C13, gave (212) with elimination of benzene.239The 'H n.m.r., ix., and mass spectra of these types of compounds have been studied.240The reduction of (212) and similar compounds has been studied, as well as its reaction with ketens, Some dichloro-derivatives of (2 12) reacted with Grigwhich gives (213).2417242 nard reagents (RMgX) to give (214).243The hitherto unknown dicyanoketen was synthesized from 2,5-diazido-3,6-dicyanobenzoquinone,and it reacted with compounds of types (208) and (212) to give compounds analogous to (213).244 237 238 239 240

241 242

243 244

S. Gronowitz and T. Dahlgren, Chem. Scr., 1977,12, 97. R. Neidlein and H. Seel, Arch. Pharm. (Weinheim, Ger.), 1978, 311, 324. R. Neidlein and L. Seguil-Camargo, Arch. Pharm. (Weinheim, Ger.), 1978, 311, 710. R. Neidlein, K. F. Cepera, and A. Hotzel, Arch. Pharm. (Weinheim, Ger.), 1978, 311, 861. R. Neidlein and K. F. Cepera, Chem. Ber., 1978,111, 1824. R. Neidlein and G. Humburg, Justus Liebigs Ann. Chem., 1978, 1974. R. Neidlein and G. Humburg, Chem. Ber., 1979,112, 349. R. Neidlein and E. Bernhard, Angew. Chem., 1978,90, 395.

Five-membered Rings : Thiophens and their Se and Te Analogues

103

Thiophen-fused Tropylium Ions and Related Compounds.-From (160) and (161), the very stable dithienotropylium ions (215) and (216) have been ~ynthesized.’~ Cyclohepta[c]thiophen-6-one gave, with 4,5-dichlorocyclopentene-1,3-dione and indane-1,3-dione in the presence of acetic anhydride, (217) and (218), respectively.245The condensation of cyclohepta[c]thiophen-6-one with malononitrile was also investigated.246

&& S

S (216)

(217) R = C1 (218) R-R=

3

5 Thiophens Fused to Five-membered Heteroaromatic Rings

Thiophen- and Pyrrole-fused Thiophens, and Related Compounds.-Some potential a1kyl- and aryl-substituted 2,5 -dihydroxythieno[3,2-b]thiophens have been prepared and their tautomeric structures determined by n.m.r. spectroscopy. The preferred structure was in all cases the dilactonic thieno[3,2b]thiophen-2,5(6H,7H)-dione structure. Only in the unsubstituted compound could the thieno[3,2-b]thiophen-2,5(3H,6H)-dione structure be Treatment of 2-acetamido-3-hydroxythieno[3,2-b]thiophen with phosphorus pentasulphide gave the thiazole-fused compound 2-methylthieno[3,2b]thien0[2,3-d]thiazole.~~~ In connection with work on potential hypolipidemic agents, more convenient syntheses of thieno[2,3-b]thiophencarboxylic acid and thieno[3,2-b]thiophencarboxylic acid and some halogen-substituted derivatives have been described. Thieno[2,3-b][l]benzothiophen-2-carboxylic acid and the [3,2-b]-fused isomer have been synthesized.249 The synthesis of derivatives of 4-thieno[2,3-b]pyrroleaceticacid via Fischer indole cyclization of t-butoxycarbonyl-protected 2-hydrazinothiophens has been described.250The reaction of ethyl azidoacetate with thiophen-2- and

245

246

247 248 249

250

G. Seitz, R. A. Olsen, and H. Monnighoff, Arch. Pharm. (Weinheim, Ger.), 1979,312, 120. H. Monnighoff, R. A. Olsen, R. Matusch, T. Kampchen, and G. Seitz, Chem.-Ztg., 1978,102,404. L. Testaferri, M. Tiecco, P. Zanirato, and G. Martelli, J. Org. Chem., 1978, 43, 2197. P. I. Abramenko and V. G. Zhiryakov, Khim. Geterotsikl. Soedin., 1976, 1039. S. Gronowitz, M. Herslof, R. Svenson, G. Bondesson, 0. Magnusson, and N. E. Stjernstrom, Acta Pharm. Suec., 1978,15, 368. D. Binder, C. R. Noe, G. Habison, and J. Chocholous, Arch. Pharm. (Weinheim, Ger.),1979, 312, 169.

104

Heterocyclic Chemistry

-3-aldehydes gave thieno[3,2-b]- and thien0[2,34]-pyrroles, respectively.251A new non-classical thiophen system (219) has been synthesized from 1,2-dibenzoyldibenzo[e,g]pyrrolo[ 1,2-a]pyridine and phosphorus p e n t a ~ u l p h i d e . ~ ~ ~

Pyrazole-, Thiazole-, and Isothiazole-fused Thiophens and Related Systems.Unsubstituted thieno[3,2-~]pyrazoleshave been prepared by the reaction of 3-azido-2-formylthiophen with hydrazine hydrate or by diazotization and subsequent reduction of 3-amino-2-formylthiophen. Some amino- and phenylsubstituted thieno[3,2-c]pyrazoles have been prepared by thermal decomposition of suitably 2-substituted 3-azido-thiophens. Electrophilic substitution of thieno[3,2-~]pyrazolehas been extensively i n ~ e s t i g a t e dAnils . ~ ~ derived from 3-nitrothiophen-2-carboxaldehyde underwent reductive cyclization with triethyl phosphite to give 2-aryl-thien0[3,2-c]pyrazoles.~~ Photolysis of 3H-thieno-l,2diazepines gave 3-vinyl-thienopyrazoles, whereas their thermolysis led to t hien yl-pyrazoles. 253 1-Acyl-3-(3-thienyl)-2-thioureas have been cyclized to 2-acylaminothieno[3,2-d]thiazoles with bromine in acetic acid. The parent thieno[3,2-d]thiazole was obtained by hydrolysis and deamination of the 2-benzoylaminoderivative, and some electrophilic substitution reactions were studied.86 2Mercaptothieno[2,3-d]thiazole was obtained in low yield from bis-(2-nitro-3thienyl) disulphide by selective reduction with sodium hydrogen sulphide to produce the sodium salt of 2-nitrothiophen-3-thio1, followed by reaction with sodium hydrosulphite and carbon disulphide. 2-Mercaptobenzo[b]thieno[3,2dlthiazole has been prepared by the reaction of 3-aminobenzo[b]thiophen hydrochloride with sulphur monochloride and cleavage of the resulting benzo[b]thienothiazolthionium chloride with sodium sulphide in the presence of carbon d i ~ u l p h i d e . ~ ~ 2-Acylamino-thieno[3,2-d]thiazoles have also been 3-acylamino-2-thiocyanato-thiophens.35 2-Methylobtained from benzothieno[2,3-d]thiazole has been prepared by the oxidation of 2-thioacetamidobenzo[b]thiophen with potassium ferricyanide in alkaline medium.254 Starting from readily available aryl2-substituted-4-methyl-5-thiazolyl ketones, a series of 2,6-disubstituted thieno[3,4-d]thiazoles was prepared through bromination of the side-chain with NBS followed by reaction with thioacetamide .255 Cleavage of the disulphide bond of bis-(3-formyl-5-phenyl-2-thienyl) disulphide in the presence of ammonia led to an isothiazole-fused thiophen.2s6A new non-classical condensed thiophen, 3,4,6-triphenylthieno[3,4-c]isothiazole, has been prepared in the following way. The reaction of 4-phenyl-1,3,2-oxathiazuiyiium-5-olate with dibenzoylacetylene gave 3,5-dibenzoyl-5-phenylisothiazole, which upon treatment with phosphorus pentasulphide gave the desired purple non-classical compound. Its photoelectron and U.V.spectra were S. Soth, M. Farnier, and C. Paulmier, Can. J. Chem., 1978,56, 1429. K. T. Potts and S. Yao, J. Org. Chem., 1979,44, 977. 253 T. Tsuchiya, M. Enkaku, and H. Sawanishi, J. Chem. Soc., Chem. Commun., 1978, 568. 254 P. I. Abramenko and V. G. Zhiryakov, Khim. Geterotsikl. Soedin., 1977, 1495. "' A. Shafiee and A. Mazloumi, J. Heterocycl. Chem., 1978, 15, 1455. 256 L. V. Alam and I. Ya. Kvitko, Khim. Geterotsikl. Soedin., 1978, 561. 251

252

Five-membered Rings ; Thiophens and their Se and Te Analogues

105

measured and the experimental data compared with P.P.P.-C.I. c a l c ~ l a t i o n s . ~ ~ ~ Its thermal cycloadditions to alkynes and alkenes have been inve~tigated.~~'

6 Thiophens Fused to Six-membered Aromatic Heterocyclic Rings Thiophen Analogues of Quino1ine.-Treatment of 5-substituted 2-acetamidothiophens with Vilsmeier reagent (POCl, in DMF) under defined conditions gave The correspondeither 2-chloro- or 2-chloro-3-formyl-thieno[2,3-b]pyridine. ing thieno[3,2-b]pyridines were obtained from 3-acetamidothiophen, and the corresponding thieno[ 3,4-c]pyridine was obtained from 2,5-dimethyl-3acetamidothiophen. Substitution reactions and halogen-metal exchange have been carried out with these quinoline analogues.89Starting from products derived from 2-amino-3-cyanothiophen and ethyl aminocrotonate, 4-aminothieno[2,3blpyridine-5-carboxylic acid was ~repared.'~ The Gould-Jacobs reaction was used for the synthesis of 4,7-dihydro-4-oxothieno[2,3-b]pyridine-5-carboxylic acids, for evaluation of their antibacterial properties.82The product from the Michael addition of 3-amino-2-methoxycarbonylthiophen to dimethyl acetylenedicarboxylate has been smoothly cyclized to 5,6-bismethoxycarbonylthieno[3,2- b]pyridin-7(4H)-one by sodium hydride in DMF. This compound was transformed into a variety of thieno[3,2-b]thiophens, including thiophen analogues of echinorine and e~hinopsine.'~The novel ring systems thienolH-1,2-diazepines were obtained by amination of thieno[2,3-b]- and thieno[3,2-b]-pyridine with 0-mesitylenesulphonylhydroxylamine to give the corresponding N-iminopyridinium ylides, which, upon photolysis, gave the dia~epines.~'~ The reaction of 3-formyl-2(1H)-pyridinethione with LY -bromocarbonyl compounds gave thien0[3,2-b]pyridine.~~'Tetracyclic systems such as (220)261and pentacyclic systems such as (221) have been synthesized.262

Thiophen Analogues of 1soquinoline.-Starting from tetrachloropyridine-4carboxaldehyde, 4,5,7-trichlorothieno[2,3-c]pyridine-2-carboxylic acid was prepared by condensation with rhodanine followed by hydrolysis and ringNew thieno[3,2-~]pyridineshave been prepared by condensation, in acid medium, of mercaptoacetates with 3-alkoxycarbonyl-4-piperidones, 257

259 260

261

262 263

H. Gotthardt, F. Reiter, R. Gleiter, and R. Bartetzko, Chem. Ber., 1979, 112,260. H. Gotthardt and F. Reiter, Chem. Ber., 1979,112,266. T. Tsuchiya, M. Enkaku, and H. Sawanishi, Heterocycles, 1978,9,621. J. Becher, C. Dreier, E. G. Frandsen, and A. S. Wengel, Tetrahedron,1978, 34, 989. M. A. Khan and A. M. Coimbrarolim, Heterocycles, 1979, 12,701. G. N. Dorofeenko, V. I. Volbushko, V. I. Dulenko, and 8.N. Kornilova, Khim. Geterotsikl.Soedin., 1976,1181. B. Iddon, H. Suschitzky, A. W. Thompson, B. J. Wakefield, and D . J. Wright, J. Chem. Res. ( M ) , 1978,2038.

106

Heterocyclic Chemistry

followed by a Dieckmann reaction.264 Thien0[3,2-c]pyridin-3-01~have been synthesized from 4-chloro-3-alkoxycarbonyl-pyridinesthrough reaction with ethyl m e r ~ a p t o a c e t a t e . Tetracyclic ~,~ systems such as (222) and (223) have been

R

(222) R

=

0 H, Me, OMe, COMe, or C 0 2 E t

(223) R

=

0 H or Me

obtained through photocyclization reactions.214Rate constants for deuteriodeprotonation in D2S04at the 2- and 3-positions of the four isomeric thieno[2,3b]-, thieno[2,3-c]-, thieno[3;2-b]-, and thieno[3,2-~]-pyridines have been measured. The slopes of the rate profiles gave evidence that all the substrates undergo exchange as protonated species. The relative reactivities, given as standard rates, were compared with those for furo[3,2-b]- and selenolo[3,2-b]pyridine and discussed in terms of electronic effects in heteroaromatic systems.266 Pyrimidine-fused Systems.-3 -Meth ylthieno[ 2,3-d]pyrimidin -4 (3H)-ones have been obtained by heating phenyl NN’-dimethylphosphordiamidateand methyl 2-acylaminothiophen-3-carboxylates to 250 0C.267A series of new thieno[3,2dlpyrimidine derivatives that have a carbocyclic ring fused at positions 5 and 6 has been synthesized in order to study their pesticidal activity.268 Some tetrahydro[ l]benzothieno[2,3-d]pyrimidines have been synthesized by the condensation of ethyl 2-amino-4,5,6,7-tetrahydrobenzothiophen-3-carbonitrile or its amide with acetonitrile, benzonitrile, urea, or f o ~ m a m i d eCompounds .~~~ such as (224) have been synthesized as potential antifertility Benzothieno[2,3d]thiazolo[3,2-a]pyrimidines have been synthesized for antibacterial evaluati or^.'^^ Compounds in which imidazo- and diazino-rings have been fused to the (l)-benzothieno[2,3-d]pyrimidine ring, such as (225) and (226), have been

264

205 266

267

268

269

”‘’ ”’

J.-P. Maffrand, D . Frehel, M. Miquel, and M. Roc, Bull. SOC.Chim. Fr., Part 2, 1978, 48. G . Horlein, B. Kiibel, A. Studeneer, and G. Salbeck, Justus Liebigs Ann. Chem., 1979, 387. S. Clementi, S. Lepri, G. V. Sebastiani, S. Gronowitz, C . Westerlund, and A.-B. Hornfeldt, J. Chem. Soc., Perkin Trans. 2, 1978, 861. K. E. Nielsen and E. B. Pedersen, Acta Chem. Scand., Ser. B, 1978,32, 303. V. J. Ram, Arch. Pharm. (Weinheim, Ger.), 1979,312, 19. H. K. Gakhar, P. M. Singh, A . Madan, and N. Kumar, Indian J. Chem., Seer. B, 1978,16, 940. M. S. Manhas, S. G. Amin, S. D. Sharma, B. Dayal, and A . K. Bose, J. Heterocycl. Chem., 1979,16, 371. H . K . Gakhar, A. Madan, A . Khanna, and N. Kumar, J. Indian Chem. SOC.,1 9 7 8 , 5 5 , 7 0 5 .

Five-membered Rings : Thiophens and their Se and Te Analogues

107

prepared.272Tricyclic systems such as 3 -aminopyrido[3’,2’:4,5]thieno[3,2-~]thiazoles and pyrido[3’,2’:4,5]thieno[3,2-d]pyrimidineshave been prepared and their n.m.r. spectra described.273 Pyrazine- and Triazine-fused Systems.-2-Substituted thieno[2,3-b]pyrazines have been obtained by the reaction of (227) with 2 equivalents of butyl-lithium, followed by esters, to give (228); these, upon acidification, r i n g - c l o ~ e d . ~ ~ ~ Treatment of (229) with P2S5in pyridine gave (230).275

Miscellaneous Fused Systems.-Thieno[3,4-b][ 1,4] diazepin-2-ones have been prepared by the condensation of 3,4-diamino-thiophens with 1,3-dicarbonyl compounds.88Compounds of type (231)have been prepared by the condensation of 2-amino-3-carbethoxy-4,5-dimethylthiophen with various p -isothiocyanatoAnother synthesis of (232) by the reaction of N-(3-cyano-2-thienyl)2-formylpyrrole with an appropriate ketone and alkaline hydrogen peroxide has

A-

NHS0,Ar

(23 I

been described, along with its X-ray A series of thieno-[2,3-f]-, -[3,2-f]-, and -[3,4-f]-morphans has been prepared by the Grewe synthesis.24 Sulphonamides from the borazarothienopyridines (233) have been synthesized. 277 7 Selenophens and Tellurophens

Monocyclic Se1enophens.-Phosphorus pentaselenide, prepared from red amorphous selenium, was shown to be sufficiently reactive towards 1,4-diketones to effect their cyclization to 2,5-disubstituted selenophens. From tetrabenzoylFrom ethane, a 40% yield of the cis-trans mixture of (234) was 272

273 274

275

276

277 27g

F. Sauter, P. Stanetty, E. Schrom, and G. Sengstschmid, Monatsh. Chem., 1978,109, 53. B. Tornetta, M. A. Siracusa, G. Ronsisvalle, and F. Guerrera, Gazz. Chim. Itul., 1978,108, 57. P. B. M. W. M. Timmermans, C. G. Kurse, and A. van der Gen, R e d . Trav. Chim. Pays-Bas, 1978, 97,81. Y . A. Ibrahim, Chem. Ind. (London), 1978,585. S . Rault, M. Cugnon de Sevricourt, M. Robba, and N. H. Dung, Tetrahedron Lett., 1979, 643. S. Gronowitz and C. Glennow, Acta Pharm. Suec., 1978, 15, 287. S. Gronowitz and A. Konar, Chem. Scr., 1977, 12, 11.

108

Heterocyclic Chemistry

the allenic selenide (235), cyclo-aromatization led to (236).279In connection with work on 75Se-marked compounds, 2-selenienylalanine was prepared by the reaction of (237) with sodium hydrogen selenide.280

NHCOMe I M~~S~CEC-CECCH~CHCO~H (237)

3-Acylamino- and 3-methoxy-selenophen have been thiocyanated and selenocyanated in the 2 - p o ~ i t i o n From . ~ ~ 2- and 3-cyanoselenophen, amidines have been prepared, which were then converted into selenienyl-pyrimidines. '19 Benzoselenophens and their Benzo-fused Derivatives.-2,3-Disubstituted 2,3dihydrobenzo[b]selenophens have been obtained in the form of trans- isomers by the action of selenium tetrabromide on dibenzal- and benzal-acetone in benzene.281The Friedel-Crafts acylation of 2,3-dimethylbenzo[b]selenophen gave 6-substituted ketones.282 3-(l-Pyrrolidinyl)benzo[b]selenophen reacted with cup -unsaturated ketones to give stereospecific Robinson-Stork a n n e l a t i ~ n . ~ ~ ~ The aminomethylation of 2H-benzo[b]selenophen-3-one has been investigated.284In a study of carcinogenic nitrogen compounds, a large number of selenoquinolines and other derivatives of aminobenzo[ blselenophens, such as (238) and (239), were prepared.285

Selenophens Fused to Five-membered Aromatic Rings.-The reaction of ethyl azidoacetate with selenophen-2- and -3-carboxaldehydes yielded selenolo-[2,3b ] - and -[3,2-b]-pyrrole~.*~' Unsubstituted selenolo[3,2-c]pyrazoleswere pre279

280

281

283 284

S. Braverman and Y. Duar, Tetrahedron Lett., 1978, 1493. P. M. Jacobs and M. A. Davis, J. Org. Chem., 1979,44, 178. V. L. Lendel, Yu. V. Migalina, S. V. Galla, A. S. Koz'min, and N. S. Zefirov, Khirn. Geterotsikl. Soedin., 1977, 1340. P. Cagniant, G. Kirsch, and L. Christiaens, C. R. Hebd. Seances Acad. Sci.,Ser. C, 1978,287, 333. M. Schaefer, J. Weber, and P. Faller, Synthesis, 1979, 122. M. Schaefer, J. Weber, and P. Faller, Bull. SOC.Chim. Fr., Part 2, 1978, 241. G. Markchal, L. Christiaens, M. Renson, and P. Jacquignon, Collect. Czech. Chem. Commun., 1978, 43,2916.

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

109

pared from 3-azido-2-formylselenophenin the same way as the thiophen analogues mentioned p r e v i o ~ s l y Starting .~~ from 2-substituted 4-methyl-5-thiazolyl ketones, a series of 2,6-disubstituted selenolo[3,4-d]thiazoles was prepared.255 Heating 2-ace tylamino-3 -bromobenzo[ b Iselenophen with P2S5 gave 2-me thylbenzo[ blselenop heno[ 2,3 -d]thiazole .254 Starting from aryl 3-me thyl-2 benzo[b]furyl ketones, 3-substituted selenolo[3,4-b]benzofuranswere prepared in high yields.286 Selenophens Fused to Si-membered Aromatic Rings.-Rate constants for deuteriodeprotonation at the 2- and 3-positions of selenolo[3,2-b]pyridine have been determined.266The synthesis of selenolo[2,3-b]quinolines, starting from 2-chloro-3-( 1’,2’-dibromomethyl)quinolines, has been The reaction of 2-chloro-3 -vinylquinoline with disodium diselenide has led to a convenient synthesis of the selenolo[2,3-b]quinoline system.288 Tellurophens.-An improved synthesis of tellurophen has been described, utilizing the reaction of bis(trimethylsilyl)buta-1,3-diyne and sodium telluride, generated in situ from tellurium and sodium formaldehydesulphoxylate.289 Tetraphenyl-2 ,1-telluro - 2,3-t hiaporp hyrin has been synthesized, starting from 2,5-bis(phenylhydroxymethyl)tellurophen, which was prepared from 1,6-diphenylhexa-2,4-diyne-1,6-diol and sodium hydrogen telluride.2g0 1,4-Dihalogeno-substituted tellurolans have been obtained by the reaction of tellurium tetrabromide and tetrachloride with h e ~ a - l , 5 - d i e n e . ~Elemental ~’ tellurium reacted with a&’-dichloro-o-xylene and sodium iodide in 2in high methoxyethanol to form l,l-di-iodo-3,4-benzo-l-tellurocyclopentane yield.292

PART 11: Systems containing Nitrogen and Sulphur, Selenium, or Tellurium by P.A . Lowe

1 Introduction and Reviews This section reviews the literature abstracted in Chemical Abstracts, Volumes 88 (second half), 89, and 90. Earlier reviews appeared in the Specialist Periodical

286 287

288

289 290

291

292

A. Shafiee and E. Behnam, J. Heterocycl. Chem., 1978,15, 589. T. K. Raja, N. Soundararajan, V. Bakthavachalam, and P. Shanmugam, Z. Naturforsch., Teil B, 1978,33, 228. T. K. Raja, S. Nagarajan, and P. Shanmugam, Chem. Scr., 1977,12,44. W. Lohner and K. Praefcke, Chem. Ber., 1978,111, 3745. A. Ulman, J. Manassen, F. Frolow, and D. Rabinovich, Tetrahedron Lett., 1978, 1885. Yu. V. Migalina, I. M. Balog, V. G. Lendel, A. S. Koz’min, and N. S . Zefirov, Khim. Geterotsikl. Soedin., 1978, 1212. R. F. Ziolo and W. H. H. Giinther, J. Organomet. Chem., 1978,146, 245.

110

Heterocyclic Chemistry

Reports on 'Organic Compounds of Sulphur, Selenium, and Tellurium', Volumes 1 to 5.' The chemistry of thiazole and its derivatives is thoroughly surveyed in Volume 34 (in three parts) of the Weissberger series on the chemistry of heterocyclic compounds, covering the literature of approximately one century.2 Isothiazoles are included in a review on advances in the chemistry of 1,2-az0les,~and the of 2-thioxothiazolidin-4-ones, the toxicological and preparation4" and antifungal properties of thiabenda~ole,~ the benefits of saccharin,6 mesomeric betaine derivatives of heter~pentalenes,~ and modern organoselenium chemistry' (including a section on 1,2,3-~elenadiazole)have also been reviewed.

2 Isothiazoles Synthesis.*-From Oxathiazolones (Type B ) . The nitrile sulphides obtained by thermolysis of 1,3,4-oxathiazol-2-ones (1; R = alkyl, cycloalkyl, or aryl) can be trapped with dimethyl acetylenedicarboxylate to give good yields of dimethyl 3-substituted-4,5-isothiazoledicarboxylates(2; R as before). The 3-aryl-4-isothiazole- and 3-aryl-5-isothiazole-carboxylates are obtained in nearly equivalent amounts from benzonitrile sulphides and ethyl propargylate.' Activated alkenes (e.g. dimethyl fumarate) react analogously." * The syntheses of isothiazoles, of thiazoles, thiazolines, and thiazolidines, and of benzothiazoles have been classified according to the fragments that are condensed (see ref. 56). The syntheses of isothiazoles are classified as follows: c-c

c-c

c-c

c

c

Type D

c-c

k c .

lo

Type E Type F Type G Type H 'Organic Compounds of Sulphur, Selenium, and Tellurium' (Specialist Periodical Reports), The Chemical Society, London, 1970, 1973, 1975, 1977, 1979, ed. D. H. Reid (Vols. 1-3) and D. R. Hogg (Vols. 4, 5): ( a ) Vol. 1, F. Kurzer (Isothiazoles; Thiazoles and Related Compounds; Benzothiazoles; Condensed Ring Systems incorporating Thiazole; Thiadiazoles); (b) Vol. 2, F. Kurzer (Isothiazoles; Thiazoles; Condensed Ring Systems incorporating Thiazole; Thiadiazoles and Selenadiazoles); (c) Vol. 3, F. Kurzer (Isothiazoles; Thiazoles and Related Compounds; Condensed Ring Systems incorporating Thiazole; Thiadiazoles and Selenadiazoles); ( d ) Vol. 4, F. Kurzer (Isothiazoles and Related Compounds; Thiadiazoles and Selenadiazoles), B. Iddon and P. A. Lowe (Thiazoles and Related Compounds; Condensed Ring Systems incorporating Thiazole); ( e ) Vol. 5, M. Davis (Isothiazoles and Related Compounds; Thiadiazoles and Selenadiazoles), B. Iddon and P. A. Lowe (Thiazoles and Related Compounds; Condensed Ring Systems incorporating Thiazole). 'The Chemistry of Heterocyclic Compounds', Vol. 34, Pt. 1, 'Thiazole and its Derivatives', ed. J. V. Metzger, Wiley-Interscience, New York, 1979. S. D. Sokolov, Usp. Khim., 1979, 48, 533 (Chem. Abs., 1979,90, 203 896). ( a )G. Danilo, Rev. Chim. (Bucharest),1978,29,1152 (Chem.Abs., 1979,90,152 037); (6) ibid., p. 820 (Chem. Abs., 1979,90,72 086). H. J. Robinson, H. F. Phares, and 0. E. Graessle, Ecotoxicol. Enuiron. Suf., 1978, 1,471 (Chem. A h . , 1978,89, 158 586). K. Rosenman, Environ. Res., 1978, 15,70. C. A. Ramsden, Tetrahedron, 1977, 33,3203. D. L. J. Clive, Tetrahedron, 1978, 34, 1049. R. K. Howe, T. A. Gruner, L. G. Carter, L. L. Black, and J. E. Franz, J. Org. Chem., 1978,43,3736. R. K. Howe and J. E. Franz, J. Org. Chem., 1978,43,3742.

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

111

From Meso-ionic 1,3,2-Oxathiazolium- 5 -0lates (Type B ) . Cycloaddition of 4phenyl-1,3,2-oxathiazolylium-5-olate( 3 ) with dibenzoylacetylene gives 3,4dibenzoyl-5-phenylisothiazole(18%), which is converted into the thieno[3,4-c]isothiazole (4) with phosphorus pentasulphide."

(1)

(2)

(3)

(4)

From P-Amino-cinnamates (Type C ) . The ethyl p-aminocinnamates RC,H,C(NH,)=CHCO,Et (R = H, m-Me2CH, m-Me, m-F3C, or p-F3C) have been converted into the isothiazoles (5) via a Vilsmeier-Haack reaction, thiation, and oxidation." From Enamines and Isothiocyanates (Type C ) . 4-Nitroisothiazolines ( 6 ) are obtained by oxidation (bromine in acetic acid) of the adducts formed from nitroketen aminals (MeNH)2C=CHN02 and isothiocyanates RNCS (R = Ph or

PhCH2) (cf.ref. l e , p. 345).However, the unsymmetrical aminal l-methylamino1-pyrrolidino-2-nitroethylene gives only the benzothiazole (7). The adducts from carbethoxy isothiocyanate and the nitroketen aminals (8; n = 1 or 2) and the nitrovinyl-amines (9; n = 1, 3, or 4) are oxidized to the 4-nitro-isothiazoline derivatives ( 1 0) and (11) respectively. l 3 The unsaturated thioamide H2NC(NMe2)=C(CN)CSNHzhas been oxidized in a similar manner to give 5-amino-4-cyano-3-dimethylaminoisothiazole.14 H. Gotthardt, F. Reiter, R. Gleiter, and R. Bartetzko, Chem. Ber., 1979,112,260.

*' R.K. Howe, T. A. Gruner, L. G. Carter, and J. E. Franz, J. Heterocycl. Chem., 1978,15,1001. l3

l4

D.Rajappa, B. G. Advani, and R. Sreenivasan, Indian J. Chem., Sect. B, 1977,15,886. L.K.Gibbons, U S . P.4 075 001/1978(Chem. A h . , 1978,88,170135).

112

Heterocyclic Chemistry

From Benzothiazolyldithioazetidinone (Type C). Thermolysis of the 4-benzothiazolyldithioazetidinone derivative (12) gives 2-mercaptobenzothiazole and a mixture of the isomeric isothiazolones (13) and the isomeric thiazoles (14), whereas the photolysis of (12) gives two cephams only.15 ~ ~ > s - s T J 0 c H 2 P h

Me0,CHC

/

o

I

(13) R = -CHC02Me or -C=CMe2

H2C=CMe

1

(12)

MeC=CH2

1

C02Me

R N
II

CMe2 or -CONHCHC02Me

I

CMe=CH2

From Thione-S-imides (Type D ) .The reaction of 9-fluorenethione S-toluene-psulphonimide with vinyl ethers CH2=CHOR (R = Et, Bun, or Bu') gives the (3 + 2) cyclo-adducts (15; R' = H, R2 = O R ) and (15; R' = OR, R2 = H).16 From Enamines and Perchlorornethanethiol (Type E ) . Examples of the synthesis of 3-substituted-4-(5-nitro-2-furyl)-5-chloro-isothiazoles by means of this previously described method (cf. ref. lc, p. 545) have been r e p ~ r t e d . ' ~ From y-Hydroxy-alkenesulphonamides (Type F ) . The synthesis of the sultam analogue of ll-deoxy-PGE2 (16), which involves the cyclization of the yhydroxy-alkenesulphonamide (17) to give the isothiazolidine 1 , l -dioxide (18), has been accomplished, using tosyl chloride in pyridine followed by K,CO, in DMF? OH

PhCH20CH2CH(OH)(CH2)2SOZNHz (17) l5 l6 l7

Is

M. Sako and T. Maki, Chem. Pharm. Bull., 1978,26,1236. T. Saito and S. Motoki, Chem. Lett., 1978, 591. A. TanakaandT. Usui, Chem. Pharm. Bull., 1978, 26,3576. J. H. Jones, J. B. Bicking, and E. J. Cragoe, Prostaglandins, 1979,17,223;U.S. P. 4 087 435/1978 (Chem. Abs., 1978, 89, 163 134).

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

113

Physical Properties.-Thioketens R1R2C=CS (R' = H, R2 = NO, or Me; or R1 = NO2 or Me, R2 = H) are formed (63--87'/0) in the gas phase by thermolysis (590°C) of the isothiazoles (19; R' = H, R2 = NO, or Me) and (19; R' = NO2 or Me, R2 = H). Kinetic experiments have shown that the decomposition is not a radical process. MIND0/3 and NDDO calculations suggest that the thioketens are formed by rearrangement of the fragment R'CSCR2 (R', R2 as before).lg Comparison of the asymmetry parameters and the coupling constants obtained from the 14N n.q.r. spectra (at 77 K) of isothiazole, thiazole, and the isomeric thiadiazoles and those produced by ab initio molecular orbital calculations indicates that there is a high level of agreement in both magnitude and direction.20 Photoelectron spectra and quantum mechanical calculations (STO-3G, CNDO/S, and EHT) have been used to compare the electronic structures of isothiazole and thiazole. In the case of the former, there is an inversion of the two highest occupied molecular orbitals between the STO-3G and the CNDO/S calculations.2' Chemical Properties.-Alkylation. 4-(1-Pyrrolidino)isothiazole has been prepared by NN-dialkylation of 4-aminoisothiazole with Br(CH2)4Br as part of a programme on the synthesis of various heteroaromatic compounds having enamine activity for use in (2 + 2) cyclo-additions.22 Nucleophilic Reactions. Isothiazoline-3-thiones have been converted into the 3-thiophenacylidene derivatives by reaction with PhCOCH2Br in pyridine followed by thionation with P2S5.23A novel and generally high-yield (72-95%) method for the formation of new 3-alkylamino- and 3-arylamino-isothiazoles (20; R = Me, Et, Ph, PhCH2, or cyclohexyl) by amination of 3-chloro(or -methoxy)-2-alkyl-isothiazolium salts (21; R as before, R' = C1 or MeO, X = C1 or FSO,) with excess of ammonia in acetonitrile at 25°C has been reported. The mechanism involves nucleophilic attack at sulphur (giving ringopening) followed by r e - c y c l i z a t i ~ n . ~ ~ * ~ ~

Cycloaddition. Diels-Alder adducts, e.g. (22; R1 = H, Me, or C1; R2 = H, Me, Bu, or octyl; X = -, CH2,or CH2CH2;n = 1or 2), of isothiazolin-2-one 1-oxide and 1,l-dioxide with 1,3-dienes have been obtained in 21-97% yields.26

2o

21

22

23 24

2s

26

G. E. Castillo and H. E. Bertorello, J. Chem. SOC.,Perkin Trans. 1, 1978, 325. M. Redshaw, M. H. Palmer, and R. H. Findlay, 2. Naturforsch., Teil A , 1979, 34, 220. G . Salmona, R. Faure, E. J. Vincent, C. Guimon, and G . Pfister-Guillouzo, J. Mol. Strucf., 1978,48, 205. D. N. Reinhoudt, W. P. Trompenaars, and J. Geevers, Synthesis, 1978, 368. D. M. McKinnon, M. E. Hassan, and M. S. Chauhan, Can. J. Chem., 1979,57,207. J. Rokach and P. Hamel, J. Heterocycl. Chem., 1978, 15, 695. J. Rokach, P. Hamel, Y. Girard, and G. Reader, J. Org. Chem., 1979,44, 1118. E. D. Weiler and J. J. Brennan, J. Heterocycl. Chem., 1978, 15, 1299.

Heterocyclic Chemistry

114

3 1,2-Benzisothiazoles, their 1-Oxides, and their 1,l-Dioxides Synthesis.-A novel synthesis of 3-chloro- 1,2-benzisothiazole (23) involves the oxidation of 2,2'-dithiobis(benzonitri1e)(24a) by ~hlorine.~' Treatment of the disulphide (24b) with chlorine followed by ethanolamine produces N-(2hydroxyethyl)-l,2-benzisothiazolone(25).28

(23)

(24) a; R = C N b; R=COCI

Oxidation of bis-[2-(N-isopropylcarbamoyl)phenyI] sulphide (26) with Me,COCl gives the chlorazasulphurane (27); this, on treatment with potassium hydride, yields the novel diazasulphurane (28), whose structure has been confirmed crystallographically. The sulphoxide 'of (26) reacts with thionyl chloride to give (28)

, reacts The di-acid chloride (29) can be cyclized to (30; X = C12,Y = 0 ) which with ammonia to give both (30; X = Y = NH) and (30; X = 0, Y = NH). Treatment of (29) with aniline gives (30; X = 0,Y = NPh).30A novel method of formation of 1,2-benzisothiazole involves treatment of the sulphoxide (31)with sodium azide and sulphuric acid to give the sulphoximine, which cyclizes with alkali to l-methyl-1H,3H-1,2-benzisothiazole1-oxide (32). Thermolysis of (32) hydrochloride gives 1,2-benzisothiazole in 94% yield.31 27

28 29 'O

31

J. R. Beck and J. A. Yahner, J. Org. Chem., 1978,43, 1604. K. H. Baggaley, Ger. Offen. 2 753 391/1978 (Chem. Abs., 1978,89, 109 455). L. J. Adzima, C. C. Chiang, I. C. Paul, and J. C. Martin, J. A m . Chem. Soc., 1978,100,953. V. N. Klyuev, A. B. Korzhenevskii, and B. D. Berezin, Izu. Vyssh. Uchebn. Zaved., Khim. Khim. Tekhnol., 1978, 21,31 (Chem. A h . , 1978, 88, 170041). R. H. Rynbrandt and D. P. Balgoyen, J. Org. Chem., 1978,43,1824.

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

115

Reactions.-The conversion of 4-chloro- 1,2-benzisothiazole into isothiazole4,5-dicarboxylic acid involves nitration, hydrolyiis to the 4-hydroxy-7-nitrocompound, and then oxidation by KMn04. Isothiazole-4-carboxylicacid may be 1,2-Benzisothiazole-3-aceticacid is obtained by subsequent decarb~xylation.~~ similar to the corresponding 1,2-benzisoxazole in reacting at the 3a-position with electrophilic reagents.33 1,2-Benzisothiazolin-3-oneundergoes chlorination in a similar manner to an N-aroyl-sulphenamide, giving 1-chloro- 1,2-benzisothiazol-3 -one (33).34 N-Monosubstituted-2-cyanobenzenesulphonamidesexist in tautomeric equilibrium with (34; R = alkyl or aryl; X = NH) in dioxan containing Et3N. The equilibrium is attained more rapidly when R is aryl than when R is alkyl, and electron-donating groups in the former increase the proportion of the 1,2benzisothiazole 1,l-dioxide in the A free-radical mechanism has been proposed for the reaction between Nchloro-1,2-benzisothiazol-3-one1,l-dioxide and arenethiols to give (34; R = Ar, X = O).36 Investigation of the reaction between N-(alkoxycarbony1)-saccharins and various nucleophiles shows that with MeO- and EtS-, attack takes place at the ring carbonyl group to give sulphonamides, whereas PhO- and PhS- react at the COzMe group to give saccharin. Amines react at both carbonyl groups.37

(34)

0 2

The reaction of 3-(2-hydroxyethylamino)-1,2-benzisothiazole 1,l-dioxide (35 ; X = OH) with thionyl chloride gives a mixture of the chloroethyl derivative (35; X = C1) and the rearranged product (36). Treatment of (35; X = C1) with dilute alkali gives the imidazo[ 1,2-b][ 1,2]benzisothiazole derivative (37); acidification of the remaining liquors gives the benzo[g]-1,2,5-thiadiazocine (38). Treatment of (37) with hydrochloric acid gives (36), which with alkali then gives (38). The 32

33 34

35

36

37

P. V. Plazzi, M. Vitto, and M. Impicciatore, Ateneo Parmense, Acta Nut., 1977,13,593 (Chem.Abs., 1978,89,43 213). H. Uno and M. Kurokawa, Chem. Pharm. Bull., 1978,26,3888. E. S. Levchenko and T. N. Dubinina, J. Org. Chem. USSR (Engl. Transl.), 1978,14, 798. D. Balode, R. Valters, and S. Valtere, Khim. Geterotsikl. Soedin., 1978, 1632 (Chem. Abs., 1979, 90,120 792). Y. Abe, K. Oka, R. Kiritani, R. Akaki, and T. Fukumoto, Annu. Rep. Radiat. Cent. Osaka Prefect., 1977,18,77 (Chem. Abs., 1978,89,146823). N. Matsumura, Y. Matsuyama, Y. Otsuji, and E. Imoto, Nippon Kuguku Kaishi, 1978,582 (Chem. Abs., 1978, 89,_197385).

116

Heterocyclic Chemistry

various chemical interconversions can only be accounted for if two separate cyclic intermediates are involved.38 3-Aryloxy(and -arylthio)-l,2-benzisothiazole 1,l-dioxides are readily obtained on heating 3-chloro-1,2-benzisothiazole1,l-dioxide with the appropriate n ~ c l e o p h i l e s . ~ ~

4 1,2=Benzisoselenazoleand 1,2=Benzisotellurazole Unlike the corresponding 1,2-benzisothiazole, which reacts with hydrogen peroxide to produce saccharin, 1,2-benzisoselenazole is converted into the whose structure was confirmed ammonium salt of 2-~arboxybenzeneselenonate, by X-ray ~rystallography.~'The first syntheses of 1,2-benzisotellurazole have been reported, by the reaction of 2-butyltellurobenzaldehyde with ammonia (74% yield), and by conversion of the aldehyde into its oxime, which cyclizes with polyphosphoric acid (PPA).41The crystal structures of both the benzisoselenazole and the benzisotellurazole have been described.42

5 2,l-Benzisothiazoles The 2,l-benzisothiazole derivatives (39;R1,R2 = CO,Me), (39; R' = C02Me, R2 = H), and (39;R' = H, R2 = C02Me) have been obtained from cycloaddition reactions between the novel thieno[3,4-c]isothiazole (4) and acetylenic esters. Olefinic esters will also react, in this case giving adducts (40; R', R2,R3, R4 = H, CN, or C0,Me) as exo,endo isomeric pairs.43The 2,l-benzisothiazole (41) is obtained in 70% yield by treating lithiated N-(fluorodimethylsily1)-2,4,6trime thylaniline with bis(trime thylsily1)sulphurdi-imide. The reaction of (4 1)with F3CC02H gives the salt (42).44

2,1-Benzisothiazolin-3-ones (43;R = H, Me, or PhCH2),which are available through the oxidation of thioanthranilic acid derivatives (cf. ref. lc, p. 5 5 8 ) , 38

" 4"

41

42

J. Ashby, D. Griffiths, and D. Paton, J. Heterocyci. Chem., 1978,15,1009. G.L.Bachman, J. W. Baker, and D. P. Roman, J. Pharm. Sci., 1978,67,1323. L.Dupont, 0. Dideberg, J. Lamotte, M. Baiwir, and R. Weber, Tetrahedron, 1977,33,3083. R. Weber, J. L. Piette, and M. Renson, J. Heterocycl. Chem., 1978,15,865. H.Campsteyn, L. Dupont, J. Lamotte-Brasseur, and M. Vermeire, J. Heterocycl. Chem., 1978,15,

745. H. Gotthardt and F. Reiter, Chem. Ber., 1979,112,266. " U.Klingebiel and D. Bentmann, 2.Naturforsch., Ted B, 1979,34, 123. O3

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

117

undergo electrophilic substitution at position 5. Treatment of (43; R = H) with POCl, yields the 3-chloro-compound (44), whose chlorine atom is replaceable by nu~leophiles.~~

6 Other Condensed Ring Systems incorporating Isothiazole Thieno[3,4-c]isothiazoles.-The formation of this novel ring system (4)," which reacts as a thiocarbonyl ylide, forming adducts with acetylenes and olefins, is referred to above.43

-

-

- -

Furano , Thieno Pyrr010 , and Pyrazolo [4,5 aJis0thiazo1es.-These compounds (46) are formed (in 4 0 4 8 % yields) by the reaction of the disulphides (45; R = Me, X = NPh, Z = N) and (45; R = H, X = NMe, 0,or S; 2 = CPh) with methanolic ammonia.46 9,

Thiazolo[4,5-c]isothiazole. - The reaction of 2-substituted-4-amino-5-cyanothiazoles with H2S, followed by dehydrative cyclization with BrZ and aqueous NH3, gives the product (47).47

isothiazolo[4,5- b]p yrazines, e.g. (48), have been prepared by conventional routes, starting from 3-methyl(or -methylmercapto)-4-nitroso-5-acetamidoisothiazole; these compounds react further to give the pyrido[2,3-b]isothiaolo[4,5-e]pyrazine (49)and the isothiazolo[4,5glpteridine (50).48

Isothiazolo[4,5-b]pyrazines.-Several

Cyclohepta[c]isothiazole.-Cycloaddition of 8-azaheptafulvenes (5 1) to sulphenes (52; R = Ph) takes place stereoselectively to give the cis-(8 + 2)cyclo45

46 47

A. H. Albert, D. E. O'Brien, and R. K. Robins, J. Heterocycl. Chem., 1978,15,529. L. V. Alam and I. Ya. Kvitko, Khim. Geterotsikl. Soedin., 1978,561 (Chem.Abs., 1978,89,59 858). H. Eilingsfeld and G. Swybold, Ger. Offen. 2 713 57311978 (Chem. Abs., 1979,90,23 035). E. C. Taylor and E. Wachsen, J. Org. Chem., 1978,43,4154.

118

Heterocyclic Chemistry

adducts (53) as sole products, whilst with (52; R = Bz) the trans-adducts are obtained, by epimerization of the intermediate ~ i s - a d d u c t s . ~ ~ reaction of 3-amino-2-cyanothieno[2,3-b]pyridine with hydrogen sulphide gives the thioamide; this cyclizes to (54) when treated with hydrogen p e r ~ x i d e . ~ '

Pyrido[3',2':4,5]thieno[3,2-~]isothiazole.-The

Isothiazolo[4,3-c]quinolines.-In a similar series of reactions, 3-amino-2-cyanoquinolines have been converted into isothiazolo[4,3-c]quinolines (55).51 ;c

of 3-formylquinoline-2-thiol with ammoniacal sodium hypochlorite gives (56) in high yield, probably via the sulphenamide. The 3-amino-derivative of (56) is obtained by base-induced ring-opening to 3-cyanoquinoline-2-thio1, oxidation to the sulphenamide, and re-closure of the isothiazole ring, using sodium e t h ~ x i d e . ~ ~

Isothiazolo[5,4-6]quinoline.-Treatment

(57)

(58)

(59)

(60)

Naphtho[1,2-dJisothiazole.-The reaction of ethyl 2-(2,3-dihydro-3-oxonaphtho[ 1,2-d]isothiazole)acetate 1,l-dioxide (57) with sodium ethoxide causes a ring expansion that produces the naphtho[2,1 -el[ 1,2]thiazine derivative (58).53

Naphtho[2,1-dJisothiazole.-This compound (59) is obtained in 74% yield by the treatment of 1-chloro-2-naphthaldehydewith sulphur and ammonia.54 49

51 52

53 54

T. Iwasaki, S. Kajigaeshi, and S. Kanemasa, Bull. Chem. SOC.Jpn., 1978,51, 229. B. Tornetta, M. A . Siracusa, G. Ronsisvalle, and F. Guerrera, Gazz. Chim. Itul., 1978, 108, 57. H. Schaefer and K. Gewald, Monarsh. Chem., 1978,109,527. I. Iijima and K. C. Rice, J. Heterocycl. Chem., 1978,15, 1527. G. Steiner, Justus Liebigs Ann. Chem., 1978, 635. H. Adolphi, H. Fleig, and H. Hagen, Ger. Offen. 2 626 967/1977 (Chem. A h . , 1978,88,136608).

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

119

Miscellaneous.-The azathiathiophthen (60) (an isothiazolo[5,1-e]isothiazole derivative), prepared from 178-dinitro-4,5-dihydroxyanthraquinone and sodium sulphide, has been investigated as a possible azo-dye i~~termediate.’~

7 Thiazoles Synthesis.”-The bulk of the preparative work in the thiazole field continues to be based on Hantzsch’s synthesis.

Hantzsch’s Synthesis (Type A ; S-C--N + C-C). Compounds prepared util2-alkyl-4-( p izing thioamides include 2-methyl-4-dihydro~yphenyl-thiazoles,~~ nitropheny1)-thiazoles,” 4-acetylthiazole ~ x i m e , ~ 2-alkyl-4-diethyl~ phosphonomethylthiazoles,60 2-[2-(N-rnethylindolyl)]-4-alkyl-thiazole~,~~ several bithiazolyls,62and the compounds (61; R = H) and (61; R = Me), which are precursors of heterocyclic prostaglandin^;^^ those formed from thioureas include 2-amino-4-dihydroxyphenyl-thiazoles,57 2-amino-4-fluoroarylt h i a ~ o l e s , ~ ~ 2-amino-4-halogenoaryl-thiazoles,65 2-arylamino-4-aryl2-arylamino-4-(4-pyrathiazoles,66-68 2-amino-4-(4-isothiazolyl)-thiazoles,69 zolono)-thia~oles,~~ 2-amino-4-(4-hydroxy-3 co~marinyl)-thiazoles,~~ and some

* The syntheses of thiazoles, thiazolines, and thiazolidines are classified as

s-c

6, N d

S-C

s-c

SF:

CXN/C

C,”C

LN/C

S-C

& b,

”

N

Type G Type H Type J Type K Type N N. R. Ayyangar, S. R. Purao, and B. D. Tilak, Indian J. Chem., Sect. B., 1978,16,67. 56 For the system of classification,see J. M. Sprague and H. Land, in ‘Heterocyclic Compounds’, ed. R. C. Elderfield, Wiley, New York, 1957, Vol. 5, pp. 484, 496. ST J. Shukri, Wiss. Z. Martin-Luther-Univ. Halle- Wittenberg, Math.-Naturwiss. Reihe, 1977, 26, 59 (Chem. Abs., 1978,88, 190 663). 5 8 R. I. Plugina and I. Ya. Kvitko, Deposited Document, 1977, VINITI 543-77,59 (Chem. Abs., 1979, 90, 123 049). 59 G . Sarodnick and G. Kempter, Wiss. 2.Paedagog. Hochsch. “Karl Liebknecht” Potsdam, 1977,21, 19 (Chem. Abs., 1978,89,197 387). 6o M. Baboulene and G. Sturtz, Phosphorus Sulfur, 1978,5,87. N. A. Kogan and E. P. Chernova, Tezisy Doklady Nauchn. Sess. Khim. Tekhnol. Org. Soedin., Sery. Sernistykh Neftei, 14th, 1975, 209 (Chem. Abs., 1978, 89, 43 176). 62 S. N. Sawhney, S. P. Singh, and S. K. Arora, Indian J. Chem., Sect. B, 1977,15,727. 63 G . Arnbrus, I. Barta, G. Horvath, Z. Mehesfalvi, and P. Sohar, Acta Chim. Acad. Sci. Hung., 1978, 97,413. 64 K. C. Joshi, V. N. Pathak, and P. Arya, Agric. Biol. Chem., 1979,43, 199. 65 S. R. Choudhari, D. D. Goswami, and K. A. Thakar, J. Indian Chem. Soc., 1978,55,401. 66 S. N. Sawhney, S. K. Arora, and S. P. Singh, Indian J. Chem., Sect. B, 1978,16, 521. 67 K. A. Thakar, D. D. Goswami, and S. R. Choudhari, J. Pharm. Sci., 1978,67,587. 68 M. S. Shingare and D. B. Ingle, J. Indian Chem. Soc., 1977,54, 705. 69 V. P. Arya, J. David, S. Rajappa, and P. K. Talwalker, Indian J. Chem., Sect. B , 1978, 16,402. ” S. Rao and A. S. Mittra, Indian 3. Chem., Sect. B, 1977,15, 1062. M. Trkovnik, N. Zivkovic, M. Kules, and R. Djudjic, Org. Prep. Proced. Int., 1978, 10, 215. ”

120

Heterocyclic Chemistry

4,4'-diary1-2,2'-iminobis(thia~oles).~~ Starting from ammonium dithiocarbamate, some 2-mercapto-4,5-dialkyl-thiazoles73 and 2-mercapto-4-(2-benzothiazolyl)-thia~oles~~ have been obtained. The bithiazolyl (62) is formed from dithio-oxamide in 50% yield,75whilst some 2-(NN-dimethylaminothiocarbonyl)4-aryl-thiazoles have been prepared from the unsymmetrical d i t h i o - ~ x a m i d e . ~ ~ Thiosemicarbazides have been used to prepare some 2-substituted hydrazino-4thiazolyl acetate^'^*^^ and 2-substituted hydrazino-4-methyl(or -phenyl)-thiazoles. 7 9

Type C Syntheses ( C - C - N - C + S ) . Treatment of the enamide Cl2C=C(NHCOAr)P(0)Ph2 with phosphorus pentachloride followed by sodium hydrosulphide gives the phosphorylated thiazoles (63) in 82-9 1YO yields."

Type F Syntheses ( C - N - C - S + C ) . Salts of cyanodithioiminocarbonates react with y-bromocrotonic acid derivatives in the presence of base to give the substituted 4-amino-thiazoles (64; R' = C02Me, C02Et, or CN; R2 = SMe, SEt, SCH,Ph, SCH2CH=CHC02Me, or SCH,CH=CHCN) (cf. ref. l c , p. 569, and ref. le, p. 362). Starting from the cyanothiourea PhN(Me)C(SNa)=NCN, the 2-aralkylamino-thiazole (64; R' as before, R2 = NMePh) is obtained, whilst with the cyanothiourea R2NHC(SNa)=NCN (R2 = Me or Ph) the thiazolidine (65; R1 as before, R2 = Me or Ph) is formed instead." R'H2C N R ~
Ph N S O2N[>NI-IR

S. R. Choudhari, D. D. Goswami, and K.A. Thakar, J. Indian Chem. Soc., 1978,55,48. J. Beger and Pham Dac Thong, East Ger. P. 127 812/1977 (Chem. Abs., 1978,88, 152 605). S. P. Singh, S. N. Sawhney, and R. K. Tomer, Indian J. Chem., Sect. B, 1978, 16, 334. '' V. P. Arya, Indian J. Pharm., 1978, 40, 5 . 76 H. U. Kibbel, E. Peters, and M. Michalik, 2. Chem., 1979,19, 19. 77 H. Johne, K. Seifert, S. Johne, and E. Bulka, Pharmazie, 1978, 33, 259. 7 8 E. Campaigne and T. P. Selby, J. Heterocycl. Chem., 1978, 15, 401. 79 S. Bilinski, L. Bielak, J. Gospodarek, and T. Urban, Ann. Univ. Mariae Curie-Sklodowska, Sect. D, 1976,31,45,61 (Chem. Abs., 1978,89,146 222, 107 635). 8o B. S. Drach and 0.P. Lobanov, Zh. Obshch. Khim., 1978,48,1994 (Chem. Abs., 1979,90,6471). *' D. Wobig, Justus Liebigs Ann. Chem., 1978, 11 18. 72

73

74

Five-membered Rings : Systems containingN a n d S, Se, or Te

121

Whilst the benzamidine H,NC(Ph)=NC(S)NHPh reacts with bromonitromethane to give mainly the 1,2,4-thiadiazole (66) and only 8.6% of the thiazole (67; R = Ph), a similar reaction using Et,NC(Ph)=NC(S)NHPh gives a 37% yield of (67; R = Ph). Other thiazoles (67; R = 4-C1C6H4,Me, PhCH2, alkyl, But, cyclohexyl, or C02Et)were also prepared.82 Type G Syntheses (N-C-S-C-C). Further details (cf.ref. 16, p. 591) of the reaction between N- (5-aryl-1,3-oxathiol-2-ylidene tertiary iminium salts (68; R2N = piperidino, morpholino, or dimethylamino) and ammonia to give 2amino-4-phenylthiazoles have appea~ed.'~ The reaction between (68) and hydroxylamine followed by 10% methanolic hydrogen chloride gives 6 5 4 7 % yields of the thiazole N-oxide salts (69; R2N as before).84 Type J Syntheses (C-S-C-N-CC). The reaction between the guanidine (Me2N),C=NH and the salt RClC=NMe2' C1- (R = MeS or EtS) gives the 2-azavinamidinium salts (Me2N)*C=N=C(SMe)NMe2' X- (X = C1 or clod-), which cyclize with sodamide to give 2,4-dimethylamino-5-methyl(or-ethyl)mercaptothiazole in 65-68'/0 yields.85

N-Thiobenzoyl-a-amino-acids(or their Type K Syntheses (C-C-N-C-S). amides) will cyclize, using trifluoroacetic anhydride, to give 2-phenylthiazole derivatives (70; R = OCOCHRlNHCOPh or NHCOCF3).86 Partially fluorinated thiazoles (71) may be prepared by heating 4,4-bis(trifluoromethyl)2H-l-thia-3-azabuta-1,3-diene with anhydrous stannous Synthesis of Meso-ionic Thiazoles. Full details (cf. ref. Id, p. 359) of the preparation of anhydro-4-hydroxythiazolium hydroxides (72; R' = Ph, Me, Me2N, PhS, CN, or 4-02NC6H4; R2 = Ph, PhCH,, or Et; R3 = Ph, 4-02NCd-b, 4-MeC6H4, or 4-C1C6H4)by the reaction of a thioamide R'C(S)NHR2 with a gem-dicyano-epoxide have appeared.88Treatment of the meso-ionic dithiolium -0

-0

Ph

__ S

82

83 84

86

S. Rajappa and B. G. Advani, Indian J. Chem., Sect. B, 1978,16,749. K. Hirai and T. Ishiba, Chem. Pharrn. Bull., 1978,26, 3017. K. Hirai and T. Ishiba, Heterocycles, 1978, 9, 1223. R. Gompper and C. S. Schneider, Synthesis, 1979,215. G. C. Barrett, Tetrahedron, 1978, 34, 611. R. Ottlinger, K. Burger, H. Goth, and J. Firl, Tetrahedron Lett., 1978, 5003. M. Baudy, A. Robert, and A. Foucaud, J. Org. Chem., 1978,43,3732.

122

Heterocyclic Chemistry

salt (73) with aniline gives a 76% yield of (72; R’ = R2 = R3 = Ph).89Further examples of the formation of anhydro -5-hydroxythiazolium hydroxides (74; R’ = 2- or 4-MeC6H4, 2- or 4-MeOC6H4,or 3- or 4-C1C6H4;R2 = H, Ac, or Br) by cyclization of ArN(CH,CO,H)C(S)Ph have been reported.”

Miscellaneous. A computer-assisted approach to the synthesis of thiazoles has so far yielded one experimental verification (cf. ref. 2, p. 310). Details of the main features of this non-interactive program, which proposes further new pathways for the synthesis of 2,4-dialkyl-thiazoles, have been described.” Physical Properties.-The structure of dimethyl sulphomycinamate, a degradation product of the sulphur-containing antibiotic sulphomycin I, has been confirmed by X-ray ~rystallography,~~ whilst the total structure of micrococcin P, a polythiazoIe-containing antibiotic, has been elucidated by means of a I3Cn.m.r. The crystal structure of a non-steroidal anti-inflammatory drug, 2-phenyl-4-(4-chlorophenyl)-5-thiazolylacetic acid,94 of 5-benzyl-2-phenyl4 -t ~ l y l t h i a z o l e , ~and ~ of anhydro - 3-benzyl-4- hydroxy-5 - (4-nitrophenyl) 2-phenylthia~ole~~ have also been determined by X-ray crystallography. Comparison of the structures of thiazole and isothiazole, using a combination of quantum-mechanical calculations and photoelectron2’ or I4N n.q.r. spectroscopy,2o and a 13C n.m.r. study of variously substituted phenylthia~oles,~’ have been reported. Molecular orbital calculations have also been used in studies of the quenching or sensitizing of the photo-Fries rearrangement by a variety of heterocycles, including thiazoleYg8of thiazolium salts99 and of variously substituted thiazoles.lo0 The kinetic acidities of the 2-methyl group of some 3substituted-2,4-dimethylthiazoliumsalts have been studied by ‘H n.m.r. spectroscopy,”’ dynamic n.m.r. studies have indicated the presence of some restricted rotation in 2-(NN-dimethylamino)thiazoles,102 and hindrance to free rotation in certain alkyl-nitrothiazoles has been examined by e.p.r.lo3 Investigation of the H-D exchange kinetics of various substituted thiazoles in (2H6)DMSO-CD30D indicated that the C-2 and C-5 positions have nearly identical reactivity, and that the proton at C-4 does not exchange.lo4 89 90

91

92

93

94

95

96 97 98

99 loo

lo*

lo4

H. Gotthardt and C. M. Weisshuhn, Chem. Ber., 1978,111, 3178. M. A . Elgendy and M. A . Eldawy, Egypt. J. Pharm. Sci., 1976 (publ. 1978), 17, 35 (Chem. Abs., 1979,90, 152 061). R. Barone, M. Chanon, and J. Metzger, Chimia, 1978, 32, 216. H. Abe, T. Takaishi, T. Okuda, K. Aoe, and T. Date, Tetrahedron Lett., 1978, 2791. J. Walker, A . Olesker, L. Valente, R. Rabanal, and G. Lukacs, J. Chem. Soc., Chem. Commun., 1977,706. R. Destro, Acta Crystallogr., Sect. B, 1978, 34, 959. J. C. Bart, I. W. Bassi, C. Benedicenti, M. Calcaterra, and R. Intrito, Acta Crystalfogr., Sect. B, 1978,34,3639. Y. Delugeard, J. C. Messager, and L. Toupet, Acta Crystallogr., Sect. B, 1978, 34, 2887. R. Faure, A . Assaf, E. J. Vincent, and J. P. Aune, J. Chim. Phys. Phys.-Chim. Biof., 1978,75,727. A. Melhorn, B. Schwenzer, H. J. Brueckner, and K. Schwetlick, Tetrahedron, 1 9 7 8 , 3 4 , 4 8 1 . H. S. Aldrich, W. L. Alworth, and N. R. Clement, J. A m . Chem. Soc., 1978,100,2362. I. Schwartz, R. D. Pop, and I. Simiti, Acta Chim. Acad. Sci. Hung., 1977,94, 141. J. A , Zoltewicz and S. Sridharan, J. Org. Chem., 1978, 43, 3785. L. Forlani, L. Lunazzi, and A. Medici, Tetrahedron Lett., 1977, 4525. P. Tordo, G . Pouzard, A . Babadjamian, H. J. M. Dou, and J. Metzger, Nouv. J. Chim., 1977,1,493 (Chem. Abs., 1978,88, 135 891). L. Forlani, M. Magagni, and P. E. Todesco, Chim. Ind. (Milan),1 9 7 8 , 6 0 , 3 4 8 (Chem. Abs., 1978, 89, 179 289).

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

123

Tautomerism in the 2-hydrazino-4-phenylthiazoleS 4-phenylthiazol-2-one hydrazone system has been investigated by means of U.V. ~ p e ~ t r ~and ~ the ~ ~ p y , 2-azidothiazole G= thiazolo[2,3-e]tetrazole tautomerism has been further examined, using 'H n.m.r.lo6 and I3C n.m.r. ~ p e ~ t r ~ ~ ~ ~ p i e ~ . ~ ~ ~

(75) R' (76) R'

= H, R2 = NO2

= NO2, R2 = H

Chemical Properties.-Electrophilic Reactions. Halogenation of 2-aminothiazoles to give 2-amino-5-halogeno-thiazolesproceeds via an addition-elimination mechanism, the intermediate A2-thiazolines having been isolated and characterized by n.m.r. The addition step is highly regio- and stereo-specific, the C-4-C-5 double bond behaving similarly to an ethylenic bond.lo8The nitramide rearrangement of 1-(2'-thiazolyl)-3-nitroureaderivatives, e.g. of (75)to give (76), appears to be partly intermolecular and partly intramolecular, as shown by kinetic and n.m.r. meas~rernents.'~~ Nucleophilic Reactions. 2,5-Dipicrylthiazole (77; Pi = 2,4,6-trinitrophenyl) is obtained (59% yield) by the Ullmann reaction between 2,5-dibromothiazole and picryl bromide. The 4-nitro-derivative is obtained (73%) by nitration of (77).'" Nucleophilic substitution of 2- and 4-chloro(and -bromo)thiazoles takes place via an addition-elimination mechanism; the k4 : kZ ratios are very sensitive to the experimental conditions, in some cases the 4-halogeno-thiazoles reacting faster than the 2-is0mers.''~ The fluorine at C-5 in (71) is replaceable by nucleophiles (e.g. CN-, EtO-).87 Homolytic Reactions. The reaction of thiazole with phenylazotriphenylmethane at 75 "C for 24 hours gives 2-phenyl-5-triphenylmethylthiazole(15%).'12 Photochemistry. The photo-rearrangement of eleven phenylthiazoles (78;R'. R2,

R3 = H, Ph, 4-MeC6H4) containing not more than two aryl groups, to give a mixure of phenyl-thiazoles and -isothiazoles, appears to take place by two pathways, A and B. Path A involves formal exchange of positions 2 and 4 or of 3 and 5, whereas path B involves interchange of positions 2 and 3 with concomitant inversion of positions 4 and 5. A proposed mechanism, which is supported by

lo'

'06

lo' lo' lo9 'lo '11

S. Bilinski, D. Misiuna, L. Bielak, and B. Marcewicz,Ann. Univ. Mariae Curie-Sklodowska, Sect. D, 1977,32,221 (Chem. Abs., 1978,89, 107 524). R. Faure, J.-P. Galy, E.-J. Vincent, and J. Elguero, Org. Magn. Reson., 1977,10, 249. R. Faure, J.-P. Galy, E.-J. Vincent, and J. Elguero, Can. J. Chem., 1978, 56,46. L. Forlani and A. Medici. J. Chem. SOC., Perkin Trans. 1, 1978, 1169. A. Nemes, G. Toth, and 0. Fuchs, Actu Chim. Acad. Sci. Hung., 1977,95. 295. J. C . Dacons and M. E. Sitzmann, J. Heterocycl. Chem., 1977,14, 1151. L. Forlani, P. E.Todesco, and L. Troisi, J. Chem. SOC.,Perkin Trans. 2, 1978, 1016. G. Fenech, A. Chimirri, and R. Ficarra, J. Pharm. Sci.,1978, 67, 1432.

124

Heterocyclic Chemistry R2

R2

% ) q3 ) q -

R3

R'

R3

" 1

R'

1

\i

1

1

1

R2 R1R$N2

R 3 c S5 R '

S'

S'

Scheme 1

labelling studies, involves a cyclic sulphonium cation rearranging to a more stable bicyclic intermediate, which then leads to the products (Scheme l).'13

Reactions of 2-Amino-thiazoles. As part of a study of the reactions of heterocyclic amidines, the cyanoethylation (using acrylonitrile) of 2-amino-4-phenylthiazole gives the bis-(2-cyanoethyl) derivative, whereas 2-amino-5-phenyl-1,3,4-thiadiazole gave only the mono-N-(2-~yanoethyl) Treatment of the diquinone (79) with (78; R1 = NH2, R2 = Ph or Me, R3 = H or Me), (78; R' = NH2, R2 = 4-MeOC& or 4-BrC6H4,R3 = H), or (78; R' = NHZ,R2 = Me, R3 = C 0 2 H or C0,Et) gives the thiazolocarbazoloquinones (80; R2 and R3 as before) in 70--100% ~ie1ds.l'~ Some novel N-(2-thiazolo) p-lactams have been obtained by cycloaddition of phthaIimidoacy1 chlorides to N-(2-thiazolyl)azomethines."6 Significant amounts of ethyl N-(2-thiazolyl)carbamatehave been

'13

'14

'Is

M. Maeda and M. Kojima, J. Chem. SOC.,Perkin Trans. 1, 1978, 685. S. M. Fahmy, E. M. Kandeel, E . F. R. Elsayed, and M. H. Elnagdi, J. Heferocycl. Chem., 1978, 15, 1291. A. S. Hammam and H. S. El-Kashef, Rev. Roum. Chim.,1978, 23, 587 (Chem. Abs., 1978, 89, 163 481). A . M. Osman, K. M. Hassan, M. A. Maghraby, H. S. El-Kashef, and A. M. Abdel-Mawgoud, J. Prakt. Chem., 1978, 320,482.

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

125

obtained as a by-product when the peptide-coupling reagent N-ethoxycarbonyl2-ethoxy-1,2-dihydroquinoline(EEDQ) is used to couple 2-aminothiazole to thiophen-2-carboxylic acid."7

Reactions of ThiazoliupnSalts. Further work on the catalytic effect of thiazolium salts on the benzoin reaction"sa3118band on the reaction between benzaldehyde and quinones,118b and the participation of these salts, which undergo ring cleavage in the conversion of cystine to cysteine,"8c has been reported. Prolonged treatment of the thiazolium salts (81; R = 2-fury1 or 5-nitro-2-furyl) with DMSO at room temperature gives the imidazo-thiazoles (83; R = 2-furyl, X = Br) and (82; R = 5-nitro-2-fury1, X = H), in 43--60% yields.'lg ,CH,COR

cb,

I

.

(82)

Reactions of Meso-ionic Thiazoles. Meso-ionic thiazol-4-ones (72; R1 = R2 = R3 = aryl) are desulphurized by Raney nickel, giving the cis-p-lactams (83) stereospecifically. The reaction proceeds uiu a dipolar intermediate, and in the case of (83; R' = R3 = Ph, R2 = 4-C1C6H4),isomerization to the trans-isomer takes place at 90-100 0C,120 Miscellaneous.Formation of oximes from acyl-thiazoles (78; R' = PhCH2,R2 = Ac, R3 = H) has been shown to give products having the anti configuration exclusively, whereas the thiazoles (78; R' = Bz, R2 = C02Me, R3 = H) give products having mainly the syn configuration.12' Oxidation of the thiazoles (78; R' = R2 = R3 = alkyl), prepared by alkylation of A'-thiazoline-2-thiones under phase-transfer conditions, with 3-ClC6H4CO3H gives the corresponding sulphoxides or sulphones, depending on the experimental conditions, in good to excellent yields.122

8 A'-Thiazolines Synthesis.-Type B Syntheses (C-C--N + C - S ) . The 1,l-adducts (84; NR2 = NMe2 or morpholino) of 2,2-dimethyl-3-dimethylamino-2H-azirine and carbon disulphide, which exist in the crystalline state as a A2-thiazolinebut which on melting become the open-chain valence tautomer, are converted (on prolonged heating) into the isomeric thiazolines (85; NR2 = NMe2 or morpholino); (84; NR2 = NEt2) is cleaved to HNCS and MeC(=CH2)CSNEt2.123 'I8

'19 120 12'

123

J. G. Lombardino, S. L. Anderson, and C. P. Noris, J. Heterocycl. Chem., 1978, 15, 655. ( a )A . I. Vovk, A . H. Babicheva, and A. A. Yasnikov, Dopov. Akad. Nauk Ukr.RSR, Ser. B, 1977, 1089; ( b )ibid., 1978, 1097; (c) ibid.,1979,25 (Chem. A h . , 1978,88,104 391; 1979,90,120 665; 1979,90, 138 171). N. Saldabols and 0. E. Lando, Khim. Geterotsikl. Soedin., 1978, 258 (Chem. Abs., 1978, 88, 190 733). T. Sheradsky and D. Zbaida, Tetrahedron Lett., 1978, 2037. I. Simiti and G. Hintz, Arch. Pharm. (Weinheim, Ger.), 1979, 312, 198. G. Vernin, C. Siv, and J. Metzger, J. Heterocycl. Chem., 1978,15, 1361. E. Schaumann, E. Kausch, S. Grabley, and H. Behr., Chem. Ber., 1978, 111, 1486.

Heterocyclic Chemistry

126

Type E Syntheses ( N - C - C - S + C ) .The slow addition of hydrogen chloride to NS-diacetylglutathione diethyl ester in 5 % EtOH-CHCl, solution over a 24 hour period leads to the A2-thiazoline (86).124

Type K Syntheses ( C - C - N - C - S ) . Further investigations into the solvolytic conversion of dihydrothiazines into A2-thiazolines (cf. ref. l e , p. 375) have been reported. 12' A variant of the Perkin reaction between phthalic anhydride and thioaroyl-glycines gives the A2-thiazolin-5-one derivatives (87; R = Ph, 4MeC6H4, 4-C1C6H4,4-MeOC6H4, PhCH2S, or EtS).126Dehydrative cyclization of thioacetamido-monosaccharidesleads to the formation of A2-thiazoline whilst similar treatment of the, dithio-oxamide (88) gives the bis-(A2-thiazoline) (89).75

Ph&& S

S

[PhCH(OH)CH2NHCS]2 (88)

Physical Properties.-The 2-amino-A2-thiazoline $ 2-iminothiazolidine tautomerism is discussed under thiazolidines. Raman and i.r. spectroscopy studies of A2-thiazoline and its 2-alkyl derivatives indicate that the ring is almost planar,'29 but an X-ray crystallographic study of 2-(2'-chlorobenzoylamino)thiazoline shows the thiazoline ring to be p~ckered.'~' Chemical Properties.-A2-Thiazolines may be converted into the corresponding thiazoles on treatment with nickel peroxide at room temperat~re,'~'a more efficient reagent than manganese dioxide when other functional groups are D. K. Minster, U. Jordis, D. L. Evans, and S. M. Hecht, J. Org. Chem., 1978,43, 1624. V. M. Fedoseev, V. S. Churilin, S. E. Tkachenko, and A. V. Kamaev, Tezisy Doklady Nauchn. Sess. Khim. Tekhnol. Org. Soedin., Sery. Sernistykh Neftei, 14th, 1975 (pub]. 1976), 200 (Chem. Abs., 1978,88,189 729); V. M. Fedoseev, A. A. Mandrugin, and S. V. Volkova, Muter. Resp. NauchnoTekh. Konf. Molodykh, Uch. Pererab. Nefti Neftekhim, 3rd, 1976, 98 (Chem. Abs., 1978, 89, 162 728); V. M. Fedoseev, V. S. Churilin, S. E. Tkachenko, and A. V. Kamaev, Khirn. Geterotsikl. Soedin., 1978,997 (Chem. Abs., 1978,89, 163 523). 126 A. M. Khalil, I. I. Abdel-Gawad, and M. H. El-Metwally, Indian J. Chem., Sect. B, 1977,15, 1029. 127 P. Herczegh and R. Bognor, Acta Chim. Acad. Sci. Hung., 1978,98, 321. "* G. S. Bedi, R. H. Shah, and 0.P. Bahl, Carbohydr. Res., 1978,62,253. lZ9 G . Mille, J. L. Meyer, and J. Chouteau, J. Mol. Struct., 1978, 50, 247. 130 C. Cohen-Addad and M. P. Viallet, Cryst. Struct. Commun., 1978, 7 , 341. 13' D. L. Evans, D. K. Minster, U. Jordis, S. M. Hecht, A. L. Mazzu, and A. I. Meyers, J. Org. Chem., 1979,44,497. lZ5

Five-membered Rings 1 Systems containing N and S, Se, or Te

127

present; e.g., for oxidation of the A2-thiazolines derived from cysteinyl

pep tide^.'^^ 9 A3-Thiazolines

The A3-thiazoline-2-thiones (90; R = Me or Ph) are decomposed thermally, photochemically, or by treatment with trimethyl phosphite to give vinyl isothiocyanates R,C=C(Ph)NCS.132 Addition of liquid hydrogen cyanide to 2,2-disubstituted A3-thiazolines(91; R = H, alkyl, alkenyl, aryl, aralkyl, alkylene, or alkenylene) gives the corresponding 4-cyano-thiazolidines, which are intermediates in the formation of cysteine ana10gues.l~~

10 A*-Thiazolines Synthesis.-Thiosemicarbazides R'NHCSNHNHz (R' = alkyl or aryl) react with a-halogeno-ketones R2COCHR3X to give A4-thiazolin-2-one hydrazones, e.g. (92; R1 = R2 = Me, R3 = H).'34 However, when R' is Me2CH, the main product is the isomer (93; R' = Me2CH, R2 = R3 = Ph).13' 2-Imino-3-aminoderivatives may also be formed from thiosemicarbazide and ethyl 4-chloroa c e t ~ a c e t a t e . ~The ~ reaction between p-imino-sulphones R'C(=NH)CHzS02R2, carbon disulphide, and sodium alkoxides gives a mixture of 1,3-thiazine-2,6-dithiones, 1,2-dithiole-3-thiones, and A4- thiazoline-2t h i ~ n e sChlorocarbonylsulphenyl .~~~ chloride reacts with substituted enamines to give A4-thiazolin-2-ones, e.g. (94).17

Reactions.-2-Thiophenacylidene-A4-thiazolines may be prepared from the thiazoline-2-thiones by reaction with phenacyl bromide and pyridine, then thionation with phosphorus pentasulphide. They react with dimethyl acetylenedicarboxylate to give both mono- and d i - a d d ~ c t sA4-Thiazoline-2-thiones .~~

"*

A. Q. Hussein, A. Abu-Taha, and J. C. Jochims, Chem. Ber., 1978,111, 3750. P. Scherberich, Ger. Offen. 2 645 69211978 (Chem. Abs., 1978,89,43 396). 134 W. J. Humphlett, Res. D i d , 1978,17442 (Chem. Abs., 1979,90, 54 871). 135 E. Bulka, W. D. Pfeiffer, C. Troeltsch, E. Dilk, H. Gaertner, and D. Daniel, Collect. Czech. Chem. Commun., 1978,43,1227 (Chem. Abs., 1978,89,146 872). 136 M. Muraoka, T. Yamamoto, T. Ebisawa, W. Kobayashi, and T. Takeshima, J. Chem. SOC., Perkin Trans. 1, 1978, 1017. 133

128

Heterocyclic Chemistry

are alkylated under phase-transfer conditions to give excellent yields of 2alkylthio-thia~oles.~~~ Acetylation of the 4-amino-2-iminothiazoline (95 ; R' = R3 = H, R2 = Ar, R4 = CN or C02Et), using acetic anhydride and triethyl orthoformate, gives (95; R' = Ac, R3 = H, R2 and R4 as before), and not the isomer (95; R1 = H, R3 = Ac, R2and R4as before), as shown by u.v., by n.m.r., and by chemical t r a n s f o r m a t i o n ~ . ~ ~ ~ Photolysis, in dioxan or pyridine, of the dehydrovaline acrylamide [96; R = CONHC(=CMe2)C02Me] gives the novel p-lactam (97).139

11 Thiazolidines Synthesis.-Type A Syntheses ( S - C - N + C- C). 2-Iminothiazolidin-4-ones continue to be prepared by the reaction between chloroacetic acid (or its derivatives) and f h i o ~ r e a s , ~ thiosemi~arbazones,'~~~'~~ ~' or biguanides. 143 Chloroacetic acid has been replaced by 1-(alkoxycarbonyl)alkyl p h o s p h a t e ~ , ' ~ ~ y-bromocrotonic acid derivatives," and phenyl (trichloromethyl)carbinol'45 in this reaction. Type B Syntheses ( C - C - N + C - S ) . The reaction of phenylglycine with thiophosgene gives 4-phenylthia~olidine-2,5-dione,'~~ and 2-acylamino-thiazolidines, which are rather unstable compounds and which may rearrange to thiazine derivatives, are formed from acyl thiocyanates and acetylenic amines. 147 Type C Syntheses (C-C-N-C + S ) . A novel method of formation of 3substituted 5,5-dialkyl-thiazolidin-2-ones(98; R' = Me, Et, CHMe2, Ph, or cyclohexyl; R2 = Me) involves the reaction between esters of unsaturated thiocarbamic acids, i.e. H2C=CMeCH2NR1C(S)OEt (R' as for 98), and sulphur dichloride. 1,2,4-Dithiazinones, e.g. (99; R = cyclohexyl), may also be formed in the Type D Syntheses ( C - C - S + C - N ) . Reactions between 2-mercaptoacetic acid and a variety of Schiff's bases (R'CH=NR2) to give thiazolidin-4-ones 2-benz0thiazoly1,'~~ continue to be described [R' = Ar, R2 = 2-thia~oly1,'~~

13'

13* 139 140

14'

144

145 146

I47

14'

149

H. J. M. Dou, P. Hassanaly, J . Kister, G. Vernin, and J. Metzger, Helu. Chim. Acta, 1978,61,3143. A. Singh and A. S. Uppal, Indian J. Chem., Sect. B, 1978,16,779; J. Indian Chem. SOC., 1978,55, 1040. P. K. Sen, C. J. Veal, and D. W. Young, J. Chem. SOC.,Chem. Commun., 1977,678. L. I, Mizrakh, L. Yu. Polonskaya, B. I. Bryantsev, andT. M. Ivanova, Zh. Org. Khim., 1978, 14, 1553 (Chem. Abs., 1978,89, 163 482). A . K. Dimri and S. S. Parmar, J. Heterocycl. Chem., 1978, 15, 335. A . K. Agrawal, V. K. Rastogi, and S. S. Parmar, J. Heterocycl. Chem., 1978, 15, 677. M. Furukawa, T. Okawara, Y. Noguchi, and R. Miyazaki, Chem. Pharm. Bull., 1978, 26, 314. L. I. Mizrakh, L. Yu. Polonskaya, B. I. Bryantsev, and T. N . Doronchenkova, Zh. Obshch. Khim., 1978,48, 568 (Chem. Abs., 1 9 7 8 , 8 9 , 4 3 255). W. Reeve and W. R. Coley, Can. J. Chem., 1 9 7 9 , 5 7 , 4 4 4 . M. Japelj, N. Vitezic, M. Hohnjec, M. Pokorny, and M. Globokar, Vestn. Slou. Kem. Drus., 1978,25, 13 (Chem. Abs., 1 9 7 8 , 8 9 , 5 9 866). I. N . Azerbaev, L. A . Tsoi, L. T. Kalkabaeva, S. T. Cholpankulova, and M. Zh. Aitkhozhaeva, Tezisy Doklady Vses, Konf. Khim. Atsetilena, 5th, 1975, 307 (Chem. Abs., 1978, 89, 59 865). M. Muehlstaedt and R. Widera, J. Prakt. Chem., 1978, 320, 123. A. K. El-Shafei, K. M. Hassan, and H. S. El-Kashef, J. Indian Chem. SOC., 1977, 5 4 , 7 4 3 . K. M. Hassan, A. M. Mahmoud, and H. A. El-Sherief, 2.Naturforsch., Teil B, 1978, 33, 1005.

Fiue-membered Rings ; Systems containing N a n d S, Se, or Te

129

4-phenyls~lphonopheny1,~~~~~~~ 2-alkyl(or -aryl)-thi~ethyl,'~~ or 2-aryloxyR' = adamantyl, R2 = Ar or h e t e r ~ a r y l ; ' R' ~ ~ = ferrocenyl, R2 = heteroaryl or substituted when the anils are formed from cyclic ketones, the products are spiro-thiazolidinones.'57~'s8The condensation of activated nitriles R1R2CHCN(R' = H or Ph; R2 = C02Et,CONH,, CN, Bz, Ph, pyridyl, or indolyl) with 2-mercaptoacetic acid derivatives yields the corresponding thiazolidin-4-ones (loo), each of which exists as a tautomeric mixture with the A2-thiazolin-4-one.'59 0 %-NH

(99)

Type E Syntheses ( N - C - C - S + C ) .A convenient synthesis of thiazolidin-4ones entails the acid-catalysed reaction between 2-mercaptoacetamides and aldehydes.16' Partially deuteriated thiazolidines have been prepared, using the reaction between ethyleneimine, formaldehyde, and hydrogen sulphide.16' A spiro-thiazolidine has been obtained by condensation between N-benzylpiperidin-3-one and cysteine hydrochloride,162and the possibility of stereoselectivity in reactions between cysteine and aldehydes has been Type G Syntheses ( C - C - S - C - N ) . Cyclocondensation of methyl 2-thiocyanatoacetates R1R2C(SCN)C02Me(R1 = H; R2 = H, Me, Et, Bu, cyclohexyl, PhCH2, Ph, 4-N02C6H4,4-C1C6H4,ClCH2CH2,or MeCHBrCH,; or R' = R2 = Me) with hydroxylamine produces the corresponding 2-hydroxyimino-thiazolidin-4-ones in 12-71% ~ i e 1 d s . l ~ ~ Physical Properties.-Conformational analysis of various alkyl-thiazolidines, using photoelectron spectroscopy combined with molecular orbital calculations, suggests the predominance of certain conformer^,'^^ whilst i.r. spectral analysis of the isomeric monoethyl-thiazolidines confirms an equilibrium at ambient K. J. Mehta and A. R. Parikh, J. Znst. Chem. (India),1978, 50, 67. M. H. Goghari and A. R. Parikh, Indian Chem. J., 1977,12, 17. lS3 A. M. Kuliev, A. Kh. Mamedova, K. Z. Guseinov, and A. K. Ibad-Zade, Zh. Org. Khim., 1978,14, 513 (Chem. Abs., 1978,89,43 212). lS4 P. B. Patel and J. J. Trivedi, J. Indian Chem. SOC.,1977, 54, 765. lS5 G. Fenech, P. Monforte, A. Chimirri, and S. Grasso, J. Heterocycl. Chem., 1979,16, 347. lS6 K. M. Hassan, 2 . Naturforsch., Teil B, 1978, 33, 1508. lS7 K. J. Mehta and A. R. Parikh, Indian J. Chem., Sect. B, 1978, 16, 836. K. M. Hassan,,A. K. El-Shafei, and H. S. El-Kashef, 2. Nuturforsch., Teil B, 1978, 33, 1515. lS9 G. Satzinger, Justus Liebigs Ann. Chem., 1978,473. 16' T. Kametani, Heterocycles, 1978, 9, 831. 16' M. Guiliano, G. Mille, J. Chouteau, J. L. Larice, and J. P. Roggero, J. Labelled Compd. Radiopharm., 1978.14,59 (Chem. Abs.. 1978.89. 197427). 16' Z. Ozdowska, Pol. J. Chem., 1978,52,385 (Chem. Abs . 1978,89,43 214). 163 L. Szilagyi and Z. Gyorgydeak, J. A m . Chem. SOC.,1979,101,427. 164 G. Entenmann. E. Eckle, and J. J. Stezowski, Phosphorus Sulfur, 1978,4, 303. 16' C. Guimon, G. Pfister-Guillouzo, and J. L. Larice, J. Chim. Phys. Phys.-Chim. Biof., 1977,74,109?. lS1 lS2

130

Heterocyclic Chemistry

temperatures between various half-chain conformers.'66 1.r. and Raman spectroscopy, when combined with theoretical calculations, have allowed a complete assignment of the various vibrations of thiazolidine and five of its deuteriated derivative^,'^^ and an i.r. study of the molecular self-association of thiazolidine in various solvents by comparison of the spectrum with those of pyrrolidine and piperidine has been reported. 1.r. studies of 4-imino-5-arylidene-thiazolidin2 - 0 n e s , l ~and, ~ together with 'H n.m.r. studies, of some 3-benzylideneaminothiazolidin-4-ones have been made.170The 13Cn.m.r.17' and dynamic 'H n.m.r. of some 2-arylamino-thiazoline-2-arylimino-thiazolidineisomeric pairs have been used to establish unambiguously the structures of some Nunsubstituted tautomers, the tautomerism of 2-iminothiazolidin-4-0ne'~~ and of some 2-arylirnino-thiazolidin-4-0nes'~~.'~~ has been investigated using U.V.spectroscopy, whilst C-H coupling constants have been shown to be of considerable importance in distinguishing between possible structures for the addition products of acetylenedicarboxylic esters with thioureas. '76 X-Ray data have been reported for 2-(2,6-dimethylphenyl)imino-3-mesylthiaz01idine.l~~ A study of the kinetics of hydrolysis of 2-(substituted phenyl) thiazolidines shows that electron-donating substituents increase the rate, whilst it is lowered considerably by the introduction of a 3-methyl

Chemical Properties.-Alkylation of thiazolidine-2,4-diones, as their sodium or triethylamine salts, using ethyl iodide in solvents of low polarity, takes place at the N-3 centre of the ambient 0-C-2-N-3-C-4-0 system; increasing either the solvent polarity or the activity of the alkylating agent increases the yield of the 2-ethoxy-derivatives. 179 The alkaline hydrolysis of thiazolidines appears to take

(101) 166

167 16'

169

170

17'

'71 173

174 175

'71

'71

(102)

M. Guiliano, G. Mille, and J. Chouteau, J. Mol. Struct., 1978, 50, 233. M. Guiliano, G. Mille, T. Avignon, and J. Chouteau, J, Raman. Spectrosc., 1978, 7, 214. M. Guiliano, G. Mille, and J. Chouteau, C.R. Hebd. Seances Acad. Sci., Ser. B, 1979,288, 131. N. A. Kassab, Y. M. Issa, S. H. Etaiw, and A. A. El-Deken, Egypt. J. Chem., 1978,18,863 (Chem. Abs., 1978,89, 179 079). M. G. Vigorita, A. Chimirri, S. Grasso, and G. Fenech, AttiSoc. Peloritana Sci. Fis.,Mat. Nut., 1976, 22, 109 (Chem. Abs., 1979,90,54 387). P. Sohar, G. Feher, and L. Toldy, Org, Magn. Reson., 1978, 11, 9. G. Toth and J. Hemela, Acta Chim. Acad. Sci. Hung., 1977, 95, 71. S. M. Ramsh, A. I. Ginak, N. A. Smorygo, Yu. G. Basova, and E. G. Sochilin, Zh. Org. Khim., 1978, 14,1327 (Chem. A h . , 1978,89, 107 688). S. M. Ramsh, A. I. Ginak, E. G . Sochilin, andT. G. Skachko, Zh. Org. Khim., 1978,14,1070(Chem. Abs., 1978,89, 107 640). A. P. Engoyan, E. M. Pereslini, T. F, Vlasova, I. I. Chizhevskaya, and Yu. N. Sheinker, Khim. Geterotsikl. .Soedin.,1978, 190 (Chem. Abs., 1978, 89, 5750). U. Voegeli, W. Philipsborn, K. Nagarajan, and M. D . Nair, Helv. Chim. Actu, 1978,61, 607. A. Kalman and G. Argay, Cryst. Struct. Commun., 1978,7, 659. A. Terol, J. P. Fernandez, Y. Robbe, J. P. Chapat, R. Granger, and H. Sentenac-Roumanou, Eur. J. Med. Chem., Chim. Ther., 1978,13, 153 (Chem. Abs., 1978,89,99735). K. A. Vsyunov, A. 1. Ginak, and E. G. Sochilin, Zh. Org. Khim., 1978,14,1075 (Chem.Abs., 1978, 89, 107 257).

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

(103)

131

( 104)

place via two intermediates; a zwitterion and a Schiff's base.'80 Hydrolysis of the spirochromene (101) cleaves the thiazolidine ring to give the coumarin, whereas treatment of (101) with hydrogen sulphide opens the pyran ring, giving the substituted thiazolidine (1O2).lg1 The 2-alkylidene-3-aryl-thiazolidin-4-ones (103; R' = C1, R2 = H, C1, or Me) rearrange in ethanolic sodium ethoxide to the thiophens (104; R', R2as before).'" An interestingring-enlargement of 3-acetylthiazolidine l-oxides [105; R' = H, R2 = Me or R1R2= (CH&] and their benzo-analogues takes place on refluxing with a solution of toluene-4-sulphonic acid in toluene, to give the 1,4-thiazines (or benzothiazines); see Scheme 2.183

Scheme 2

The sodium salt of thiazolidine-2,4-dione reacts with acetyl, benzoyl, and tosyl halides and with maleic and succinic anhydrides to give the 3-acyl-derivatives, but with phthalic anhydride it gives the tricyclic product (106).'84Further details of the reduction of 3-acyl-thiazolidine-2-thioneswith di-isobutylaluminium hydride and with lithium tri-t-butoxyaluminium hydride have appeared (cf. ref. le, p. 388).'"

Rhodanines, Isorhodanines, and Thiorhodanines. Condensation of chloroacetic acid with the dithiocarbamate derived from isonicotinoyl hydrazide and carbon disulphide gives the 3-(isonicotinoy1amino)rhodanine (107).1865-Arylidenerhodanines react with diazomethane to give mixtures of N-methyl and S-methyl derivatives. Increasing the dielectric constant of the solvent increases the relative yield of the N-methyl compounds, but in basic solvents, e.g. triethylamine, only lS2 lS3

lS5 lS6

R. Luhowy and F. Meneghini, J. Am. Chem. SOC.,1979,101,420. M. Maguet and R. Guglielmetti, J. Heterocycl. Chem., 1978, 15, 1439. H. Dehne and P. Krey, Pharmarie, 1978,33,687. F. Chioccara, L. Oliva, G. Prota, and E. Novellino, Synthesis, 1978, 744. M. A. Pergal and K. M. Popov-Pergal, Glas. Hem. Drus., Beograd, 1977,42,663 (Chem.Abs., 1978, 88, 105 202); 1978, 43, 9 (Chem. Abs., 1978, 89, 24 268); 1978, 43, 13 (Chenr. Abs., 1978,89, 24 209). T. Izawa and T. Mukaiyama, Bull. Chem. SOC.Jpn., 1979, 52, 555. G. Danila, Rev. Chim. (Bucharest), 1978, 29,623 (Chem. Abs., 1979,90,22 939).

132

Heterocyclic Chemistry

the S-methyl compounds are obtained. lS7 Aryl-amines react with 3-aryl-5arylidene-rhodanines to give the corresponding arylimino-thiazolidinones (108).lg8

A recent molecular orbital treatment of the electronic structures of thiazolidine-2,4-dione, rhodanine, isorhodanine, and thiorhodanine can account for the origin of the electronic absorption transitions and the effect of replacing oxygen by sulphur atoms on the coplanarity of the rn01ecules.~~~ Isorhodanine reacts with o-phenylenediamine to give the benzimidazole (109) via an intermediate Schiff's base,"' and thiorhodanine is converted into the A4-thiazolines (110; R = CH2C02H, COMe, or 2-benzoxazolyl) on treatment with the corresponding chlorides RCl, and into the thiazolium salt (111) with dimethyl ~ulphate.'~'

12 Selenazoles The reactions between a-halogeno-ketones and aryl- or heteroaryl-selenoamides to give selenazoles [112; R' = ClCH2, Me, or Ph; R2 = Ph, 4-MeCsH4, 4ClC6H4, 4-BrCsH4, 4-MeOC&, 3,4-(Me0)2C6H3,or 2 - t h i e n ~ l - jand ~ ~ ~with selenosemicarbazides to give 2-arylimino-A4-selenazolineshave been reported.79,193 The tautomeric A2-selenazolines (113, R1,R2 = alkyl, R3 = aryl) and the selenazolidines (114; R1, R2 = alkyl, R3 = benzyl) are obtained (53-93%) by cyclocondensation of R'R2C(NH2)C=CH with R3NCSe. The N-aryl derivatives have structure (113) and the N-benzyl compounds have structure (114).194 "*

19'

19' 193

194

A. Ginak and E. G. Sochilin, Zh. Org. Khim., 1978, 14,1065 (Chem. Abs., 1978,89, 107 256). A.M. Khalil, A. A. Fadda, andM. M. Yousif, Rev. Roum. Chim., 1978,23,935 (Chem. Abs., 1978, 89, 146 825). R. Hilal, H. Ead, and A. Osman, Appl. Spectrosc., 1978, 32, 557. V. F. Lipnitskii, 0.P. Shvaika, V. I. Fomenko, and S. N. Baranov, Khim. Geterotsikl. Soedin., 1978, 666 (Chem. Abs., 1978,89,109 240). E. D. Sych and E. K. Mikitenko, Khim. Geterotsikl. Soedin., 1978, 560 (Chem. Abs., 1978, 89, 59 851). V. I. Cohen, Synthesis, 1979, 66. S. Bilinski and J. Chmielewski, Ann. Univ. Mariae Curie-Sklodowska, Sect. 0, 1977, 32, 231, 249 (Chem. Abs., 1978,89,109 265,107 056). I. N. Azerbaev, L. A. Tsoi, S. T. Cholpankulova, A. B. Asmanova, and V. I. Artyukhin, Khim. Geterotsikl. Soedin., 1978, 917 (Chem. Abs., 1978, 89, 197 415).

Fiue-membered Rings : Systems containing N and S, Se, or Te

133

Condensation of the alkyl isothiocyanates RCHClCH,NCS (R = H, Me, Ph, 4-MeC6H,, or 4-C1C&) with sodium hydroselenide gives selenazolidine-2thiones (1 l5).lgs The mass spectra of some 2-amino-selenazolines show fragmentation patterns similar to those of the corresponding thiazolines.lg6

13 Benzothiazoles Synthesis.*-From ortho-Amino-benzenethiols (Type A ; S-C6H4-N 3. C). The condensation of o-aminobenzenethiol and carboxylic acids RC0,H [R = Me, Me(CH2)9,PhCH,, 3-pyridylmethyl, cyclohexyl, Me2CH, 3-MeOC6H4,or 2-furyl1, catalysed by P205plus MeS03H (1 : lo), gives substituted benzothiazoles (84-96%), but lower yields are obtained with ap-unsaturated or a-trialkylated acids.lg7 Starting from aryl or heteroaryl selenoamides RC(Se)NH2, the corresponding 2-aryl- and 2-heteroaryl-benzothiazoles are conveniently prepared (40-85°/~).'98 Whereas the reaction between perfluoropropene and o-aminobenzenethiol gives the S-alkylated compound (1 16) only, perfluoro-2-methylpropene gives the benzothiazole [117; R = CH(CF,),] under similar condition^.'^^ Benzothiazoles [117; R = CF(CF,)OPr or C6H5]may be prepared either by direct acylation of o-aminobenzenethiol with the appropriate acyl halide or by reduction of NN'-diacyL2,2'-diaminodiphenyl disulphides followed by cyclization. The intermediates in the former case are N-acylaminobenzenethiolsrather than the S-acyl derivatives.200The reaction between o-aminobenzenethiol and aryl methyl ketones gives the benzothiazolines (1 18; R' = H, R2 = Ar);'O1 with ethyl acetoacetate the product obtained at room temperature is (118; R1 = H, R2 = CH2C0,Et), but at 130 "C the compounds (117; R = CH2COMe or Me) predominate; starting from acetylketen, compound (117; R = CH2COMe) is obtained.202The 2-substituted benzo* The syntheses of benzothiazoles are classified as follows:

Type B Type c Type D Type G Type A P. Kristian and L. Kniezo, Collect. Czech. Chem. Commun., 1978,43,2298 (Chem. Abs., 1979,90, 38 842). 196 V. V. Zamkova, A. E. Lyuts, L. A. Tsoi, and S. T. Cholpankulova,Izu. Akad. Nauk. Kaz. SSR, Ser. Khim., 1979,29,55 (Chem. Abs., 1979,90,203 073). '91 D. L. Boger, J, Org. Chem., 1978,43, 2296. ' 9 1 V. I. Cohen, J. Heterocycl. Chem., 1979, 16, 13. 199 H. Harada, S. Mizutaki, S. Hayashi, and N. Ishikawa, J. Fluorine Chem., 1978,12,211. zoo K. C. Eapen and C. Tamborski, J. Fluorine Chem., 1978,12,271. '01 F. DeSimone, A. Dini, E. Ramundo, and G. La Bella, Rend. Accad. Sci. Fis. Mat., Naples, 1977, (publ. 1978), 44,387 (Chem. Abs., 1979,90, 54 891). ' 0 2 V. I. Avramenko, V. S. Fendenko, Z. F. Solomko, and N. Y. Bozhanova, Khim. Geterotsikl. Soedin., 1978,1049 (Chem. Abs., 1979,90,6290). 195

134

Heterocyclic Chemistry

thiazole (119) is obtained by a novel ring-opening reaction of the benzo[b]thiophen 1,l-dioxide (120),using o - a m i n o b e n ~ e n e t h i o l . ~ ~ ~ Type B Syntheses (C6H5-N-C-s). Further examples have been reported of the formation of substituted 2-aminobenzothiazoles by cyclization (with PPA) of 1-aryl-thiosemicarbazides (cf. ref. le, p, 395).204Oxidative cyclization, using a bromine-chlorine (1: 12) mixture, of 1-aryl-thioureas gives excellent yields of substituted 2-aminobenzothiazoles.20sTetrafluorobenzothiazoles (121; R = NH2, NEt2, OH, CF3, Me, or Ph) may be obtained either by cyclization (thermal) of the thioamides C6FsNHCSR (R as before) or by the reaction of the amides C6FsNHCOR with phosphorus pen tasulphide .*06 Type C Syntheses (N-c&-S-c). o-Chloroaniline reacts with sodium thiocyanate under photochemical conditions to give 2-aminobenzothiazole (117 ; R = NH2).207 Type G Syntheses ( C 6 H s - s - c - N ) . A modification of the reaction between p-benzoquinone and thiourea, giving 2-amino-6-hydroxybenzothiazole(cf. ref. lb, p. 658), has been reported, in which replacement of the thiourea with thioacetamide gives 3a-hydroxy-2-methylbenzothiazol-6(3aH)-one (122) together with other sulphur-containing products, depending on the reactant ratio and the solvent. 2-(Acetimidoy1thio)hydroquinone appears to be an intermediate in the reaction.208

'03 2v4

'05

W. Reid and J. B. Mavunkal, Chem. Ber., 1978, 111, 1521. A. N. Kost, N. Yu. Lebedenko, L. A. Sviridova, and V. N. Torocheshnikov, Khim. Geterotsikl. Soedin., 1978,467 (Chem. Abs., 1978, 89,43 216). H. J. Opgenorth and H. Scheuermann, Ger. Offen. 2631 163/1978 (Chem. A h . , 1978, 88, 136 609).

206

*07 '08

F. E. Herkes, J. Fluorine Chem., 1979, 13,1. K. Fujiki, T. Nishio, and Y. Omote, Bull. Chem. SOC.Jpn., 1979, 52, 614. W. B. Manning and V. Horak, J. Org. Chem., 1979, 44, 120.

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

135

Type CsH5-N--C + SSyntheses. p-Benzoquinone diacetimide (123; R = Me) or dibenzimide (123; R = Ph) react with thiolacetic acid, MeC(O)SH, to give 6-amino-2 -met hyl(or -phen y1)benzothiazole.209 Physical Properties.-The Hiickel M.O. method has been used to calculate the 7r-electron densities in 2,6-disubstituted benzothiazoles; the perturbation on the sulphur atom results in a decrease in the r-electron density at sulphur.210A comparison of the electronic structures of benzothiazole and its N,O, and Se homologues, as obtained by M.O. calculations (STO-3G and EHT), agrees with the observed relative bond-intensity differences determined by photoelectron spectroscopy (He I and He I1 spectra).211 Dipole-moment studies on benzothiazole-2-thione,*'* on various 2-substituted benzofhiazole~,~'~ and on the complexes formed between benzothiazole and phenols in dioxan solution have been spectroscopic investigations of the thiol-thione tautomerism of benzothiazole-2-thiol (using u.v., i.r., and Raman spectroscopy) indicate that the thione form is to be preferreda215The Raman v(C=N) frequencies of 21 metaand pura-substituted 2-phenyl-benzothiazoles show a linear correlation with the Hammett paru-substituent constants but are almost independent of metu-substituent constants.216 Recent 'H n.m.r. studies on the transfer of substituent effects in 2-dibenzoylmethylene-3-ethyl-benzothiazolinesand the corresponding selenazolines give information on the conformations of these and the use of lanthanide shift reagents has enabled the configurations of some benzothiazol-2-one hydrazones to be determined.218 The influence of Z / E isomerism on chemical shifts in some 2-hydrazino-benzothiazolines has been studied by 'H and 13C r~.m.r.,~ and l ~ the use of 13Cn.m.r. to study the transmission of substituent effects in 57 benzothiazoles has been described.220 Mass spectral studies on 2-aminobenzothiazole/2-iminobenzothiazoline derivatives,221 on benzothiazol-2-one hydrazones,222 on some 2-phenacylbenzothiazoles and -benzo~elenazoles,~~~ and on various 3-alkyl-benzothiazolium (and -selenazolium) iodides have been Detailed studies of W. B. Manning and V. Horak, Synthesis, 1978, 363. M. K. Mahanti, Indian1 Chem., Sect. B, 1977, 15, 1049. '1 C. Guimon, G. Pfister-Guillouzo, G. Salmona, and E. J. Vincent, J. Chim. Phys. Phys.-Chim. Biol., 1978,75,859. "'Dipti, R. S. Varma, and P. P. Rastogi, Nut. Acad. Sci. Lett. (India),1978,1,61 (Chem.Abs., 1978, 89, 179 332). 'I3 A. M. Galy, J. Llinares, J. P. Galy, and J. Barbe, C.R. Hebd. Seances Acad. Sci., Ser. C, 1978,287, 459. 214 S. B. Bulgarevich, V. S. Bolotnikov, D. Ya. Movshovich, V. N. Sheinker, 0. A. Osipov, and A. D . Garnovskii, Zh. Obshch. Khim., 1978,48, 1824 (Chem. Abs., 1978,89, 162 886). '15 M. Uher, S. Kovac, A . Martvon, and M. Jezek, Chem. Zuesti, 1978,32,486 (Chem.Abs., 1979,90, 167 746). '16 A. Brembilla and P. Lochon, C.R. Hebd. Seances Acad. Sci., Ser. C, 1978,286, 557. '"M. Holik, A. Mistr, and V. Laznicka, Collect. Czech. Chem. Commun., 1978,43, 739. 218 J. C. Richer, M. Beljean, and M. Pays, Org. Magn. Reson., 1977, 10, 226. *19 M. Naulet, M. Beljean, and G. J. Martin, Org. Maxn. Reson., 1978, 11, 16. ''O S. N. Sawhney and D. W. Boykin, J. Org. Chem., 1979,44, 1136. ''' Ya. V. Rashkes, R. F. Ambartsurnova,V. A . Saprykina, and N. K. Rozhkova, Zh. Org. Khim., 1978, 14,1980 (Chem. A h . , 1979,90,21 763). "'J. C. Richer, M. Beljean, and M. Pays, Org. Mass Spectrom., 1977, 12,689. 223 G. Ciurdaru, Z. Moldovan, and I. Oprean, Monatsh. Chem., 1978,109, 379. 224 M. Bologa, N. Palibroda, Z . Moldovan, and G. Ciurdaru, Org. Mass Spectrom., 1977,12, 562. '09

"*

136

Heterocyclic Chemistry

the cis-trans isomerism (both thermal and photochemical) of 1-aryl-3-(3methylbenzothiazolin-2-ylidene)-triazenes and -triazinium salts, using ‘H, I3C, and 15Nn.m.r. and U.V. spectroscopic techniques, and flash photolysis, have been carried An investigation of the effect of hydrogen-bonding on the luminescent behaviour of 2-(2-hydroxyphenyl)benzothiazole at different temperatures has been described.226 Further detailed studies of various photochromic benzothiazolinic spiro-pyrans and their open-chain merocyanine derivatives have been made, using u.v., i.r., Raman, and 13C and ‘H n.m.r. spectroscopy and dipolemoment techniques (cf. ref. le, p. 397).227Charge-transfer complexing in the course of quenching of the triplet state of carbocyanine dyes by the nitroxyl radical has been observed.228 The kinetics and mechanism of oxidation of heteroaromatic diols (e.g. 4,7-dihydroxybenzothiazole)by means of a series of monoelectron-acceptor iron(II1) complexes has been investigated, using a stopped-flow spectrophotometric t e ~ h n i q u e , ” and ~ a combination of spectrophotometry and electrophoresis allows the identification of the various products formed by polarographic reduction of a benzothiazole a~o-dye.’~’ The crystal structures of 2-(4-morpholinothio)benzothiazole,which exhibits p~lymorphisrn,~~’ and of 3-ethyl-2-methyl-6-nitro(and -methoxy)benzothiazolium tetrafluoroborate~’~~ have been described.

Chemical Properties.-Substitution Reactions. The reaction between benzothiazol-2-yl allylic sulphides, Grignard reagents, and cuprous iodide leads to the formation of alkenes in a regioselective manner, dependent on the solvent; e.g., benzothiazol-2-yl cinnamyl sulphide and BuMgBr plus CuI in ether gives a 97 : 3 mixture of (E)-H2C=C(H)CHPhBu and (E)-BuCH,CH=CHPh, whilst in ether-THF (2 : 1) the latter product predominate^.^^^ A similar rearrangement occurs when benzothiazol-2-yl propargylic sulphides react with Bu3SnH under thermal or photochemical conditions, giving, for example, B u ~ S ~ C H = C = C H ~ 2-Halogeno-benzothiazoles .~~~ react with lithium dimethylcuprate by metal-halogen exchange, decomposition of the product then being induced by reaction with acids, oxygen, or methyl iodide, yielding benzo22s

226

227

228 229

230 231 232

233 234

E. Fanghaenel, H. Poleschner, R. Radeglia, and R. Haensel, J. Prakt. Chem., 1977, 319,813; E. Fanghaenel, W. Ortmann, B. Tyszkiewicz, and M. Tyszkiewicz, ibid., 1978,320,422;E. Fanghaenel, W. Ortmann, and K. Hirsch, ibid., p. 607; E. Fanghaenel, R. Radeglia, D. Hauptmann, B. Tyszkiewicz, and M. Tyszkiewicz, ibid., p. 618. R. Nakagaki, T. Kobayashi, S. Nagakura, and J. Nakamura, Bull. Chem. SOC.Jpn., 1977,50, 1909; R. Nakagaki, T. Kobayashi, and S. Nagakura, ibid., 1978,51, 1671. J. Kister and J. Metzger, C.R. Hebd. Seances Acad. Sci., Ser. C , 1978, 287, 281; A. LeBeuze, A. Samat, A. Botrel, P. Appriou, and R. Guglielmetti, J. Chim. Phys. Phys.-Chim. Biol., 1978,75,46, 255,267;P. Appriou, A. Samat, R. Guglielmetti, and J. Y. Le Gall, Org. Magn. Reson., 1977,10,39; M. Guiliano, E. Davin-Pretelli, G. Mille, J. Chouteau, and R. Guglielmetti, Helv. Chim. Acta, 1978, 61. 1072. V. A . Kuzmin, A. S. Tatikolov, and Yu. E. Borisevich, Chem. Phys. Lett., 1978, 53,52. E.Pelizzetti, E. Mentasti, and E. Barni, J. Chem. SOC.,Perkin Trans. 2,1978, 623. V. Zelenska, V. Madajova, and I. Zelensky, Collect. Czech. Chem. Commun., 1978, 43,2289. J. Guzman and J. Largo-Cabrerizo, J. Heterocycl. Chem., 1978, 15, 1531. E. Srenger and F. Robert, Acta Crystallogr., Sect. B,1978, 34,585; E. Srenger, C. Storer, and T. Avignon, ibid., p. 1221. P. Barsanti, V. Calo, L. Lopez, G. Marchese, F. Naso, and G. Pesce, J. Chem. SOC.,Chem. Commun., 1978.1085. Y. Ueno and M. Okawara, J. A m . Chem. SOC.,1979,101, 1893.

Five-membered Rings; Systems containing N and S, Se, or Te

137

t hiazole or 2-methylbenzo t hiazole. 235 2-Hydroxyimino-3 -me thyl-benzothiazoline derivatives (124; R' = tosyloxy, OSiMe,, or OMe; R2 = Me) react with EtMgBr to give (124; R' = H or Et, R2 = Me) as the major and (125; Diazotization of 6-amino-2-ethylR = H or CN) as the minor benzothiazole in aprotic solvents generates 2-ethyl-6-benzothiazolyl radicals, which exhibit a weak electrophilic character, being converted into 6-aryl(or -heteroaryl)-2-ethyl-benzothiazoles,and subsequently into the corresponding quaternary salts and ~ p i r o - p y r a n s Aliphatic .~~~ Mannich bases RCH2CH2NMe2 (R = 2-benzothiazolyl or other heterocyclic group) will react with aromatic amines by amine exchange to give the otherwise inaccessible aromatic analog u e ~ . ~An ~ *efficient preparation of 2-benzothiazolyl-sulphenamidesby electrolytic cross-coupling of benzothiazole-2-thiol (or the disulphide) with amines in DMF (81-96% yields)239and their conversion into a-(2-benzothiazolylthio)alkanoates (117; R = SCHR1C02R2)by reaction with P-keto-esters have been described.200 Addition Reactions. Benzothiazole reacts with aryl isocyanates in boiling nitrobenzene to form benzothiazole-2-carboxamides (117; R = CONHAr),241and benzothiazole-2-thiol will add to ketens (e.g.,Ph2C=C=O), giving 1:2 adducts (126), although 3-methylbenzothiazole-2-thionegives 3-methylbenzothiazol-2one with the same reagent.242Benzothiazol-2-one will add to activated double bonds; e.g., H2C=CHCN or Cl,CCH=NCOMe, forming RCH2CH2CN and C1,CCHRNHCOMe (R = 2-oxo-3-benzothiazoly1).243 The addition of 2,6-xylyl isocyanide to 2-(cyclohexyldithio)benzothiazoleresults in the formation of two isomeric cyclohexylthio-esters, (127) and ( 128).244 CPh, II

/

C(SR2)=NR'

(1 28) R' 235 236

237

238 239 240 241

242 243

244

= 2,6-xylyl,

R2 = cyclohexyl

F. Babudri, L. DiNunno, S. Florio, G. Marchese, andF. Naso, J. Organomet. Chem., 1979,166,265. K. Y. Akiba, H. Shiraishi, and N. Inamoto, Bull. Chem. SOC. Jpn., 1979, 52, 263. G. Vernin, J. Kister, and J. Metzger, Helu. Chim. Acta, 1979,62, 21. H. Kamogawa, K. Kubota, and M. Nanasawa, Bull Chem. Soc. Jpn., 1978, 51, 1571. S. Torii, H. Tanaka, and M. Ukida, J. Org. Chem., 1978,43, 3223. S. Torii, H. Tanaka, and H. Okumoto, Bull. Chem. SOC. Jpn., 1979, 52, 267. E. P. Papadopoulos and C. M. Schupbach, J. Org. Chem., 1979,44, 99. H. Kohn, P. Charumilind, and Y. Gopichand, J. Org. Chem., 1978,43,4961. H. Zinner and G . Zinner, Wiss. 2. Wilhelm-Pieck-Uniu.,Rostock, Math.-Naturwiss. Reihe, 1977, 26,799 (Chem. Abs., 1979,90, 121 471). J. P. Chupp, J. J. D'Amico, and K. L. Leschinsky, J. Org. Chem., 1978,43, 3 5 5 3 .

138

Heterocyclic Chemistry

Alkylation. Further investigation of the reductive C-alkylation of 6-nitrobenzothiazole with alkyl Grignard reagents has been reported [cf. ref. le, p. 404 and 'Aromatic and Heteroaromatic Chemistry' (Specialist Periodical Reports), Vol. 7, p. 671. It appears that the addition of cuprous iodide to the reactants both accelerates the reaction and gives much cleaner Benzothiazole-2thione is readily alkylated with 2-chloroacetamide and its higher homologues to study ~ ~ of the methylation of 2-arylgive (117; R = SCH,CONH,, e t ~ . )A. ~ idenehydrazino-5,6,7,8-tetrahydrobenzothiazoles and the corresponding benzoselenazoles (129; X = S or Se) shows that modification of the reaction conditions leads to methylation of the NH group at C-2 or of the ring nitrogen atom.247

(129)

Reactions of Thiazolium Salts. Benzothiazoline derivatives may conveniently be prepared by reduction of benzothiazolium salts with sodium borohydride or by treatment of these salts with Grignard regents.248The benzothiazolium salt (130) has been used to invert optically active alcohols or thiols, as shown in Scheme 3, and it will also catalyse the cyclization of unsaturated alcohols, e.g. farnesol, more efficiently than conventional reagents.249The condensation under basic conditions of 2,3-dimethylbenzothiazolium salts with salicylaldehyde does not give

Dl

Et

R' fHOCLR2 \

BF,-

+/

Et

5 R3

R3

(130)

ii

R '.

1

]

X-

€2l.

RZ-COH /

R3

_lil R~-COC(O)CCI, R3/

Reagents: i, Et,N; ii, CI,CC02H, Et,N; iii, HO-

Scheme 3

either a spiro-pyran or a merocyanine, but gives instead the bi-condensed product (13 1). With salicylaldehydes containing electron-withdrawing groups, condensation gives non-cyclizable merocyanines.*'" 24' 246

247

248

249

G. Bartoli, A. Medici, G. Rosini, and D. Tavernari, Synthesis, 1978, 436. D . J. Brown, W. C. Dunlap, G. W. Grigg, and L. Danckwerts, Aust. J. Chem., 1978, 31, 447. A, A. Tsurkan and N. A. Platonova, Dokl. Akud. Nuuk. A z . SSR, 1978,34,67 (Chem.Abs., 1979, 90, 203 968). M. Hori, T. Kataoka, H. Shimizu, Y. Imai, and H. Fujimura, Yukrrguku Zusshi, 1978, 98, 1019 (Chem. Abs., 1979, 90, 22 877). T. Mukaiyama, Symp. Heterocycl. [Pup.], 1977, 11 (Chem. A h . , 1978, 89, 214 454). A . Samat, C. Riou, J. Robillard, and R. Guglielmetti, J. Phorogr. Sci.,1978, 26, 34.

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

139

Ring-cleavage Reactions. The reaction between the benzothiazoline (118; R' = Ac, R2 = Arj and sulphuryl chloride gives a chlorosulphonium salt which rearranges to the benzo-1,4-thiazine (132; R' and R2 as before),201whilst the addition of chloroacetyl chloride to a mixture of (118; R' = H, R2 = Me) and anhydrous potassium carbonate gives a mixture of (118; R1 = COCH2Cl, R2 = Me), (117; R = CH2Cl), (133; R = H) and (133; R = COCH,Cl). It is possible that compound (118; R' = H, R2 = Me) initially tautomerizes to HSC6H4N=CMe2, which is then chloroacetylated and subsequently re-cy~lizes.~~'

Photochemical irradiation of a mixture of 3-phenylbenzothiazol-2-oneand ethyl vinyl ether leads to the formation of (134), probably via cycloaddition of the ether to an intermediate quinoid (135).252Diborane reacts with benzothiazole or 2-methylbenzothiazole to give the benzothiazaboroles (136; R = H or Me) via a rearrangement in which the formation of a BH3 adduct is the first A similar reaction takes place with 2-methylbenzoselenazole and with benzo x a z 0 1 e . ~A~ ~simple and general procedure for the preparation of cis-3-acylamino-4-mercapto-azetidin-2-ones involves acid hydrolysis of the thiazolinoazetidinones (137).254

14 Condensed Ring Systems incorporating Thiazole Structures comprising Two Five-membered Rings (5,5).-Thiazolo[2,3e]tetrazoZes [CN4-C3NS]. The 2-azidothiazole $ thiazolo[2,3-e]tetrazole equilibrium has been further studied, using 'H n.m.r. spectroscopy to determine the protonation sites'06 and 13C n.m.r. spectroscopy to ascertain the effect of substituents on the tautomeri~rn.'~' Thiazolo- [2,3-c]- and - [3,2- b]- [1,2,4]triazoles [C2N3-C3NS]. The reaction of (138; R' = Et, 2-C1C6H4, or 33-ethyl(or -aryl)-5-mercapto-l,2,4-triazoles O2NC6H4;R2 = H) with a-halogenated ketones gives products (138; R' = Et, 251

252

253 254

M. Hori, T. Kataoka, H. Shirnizu, and Y. Irnai, Heterocycles, 1978,9, 1413. L. R. Sousa and J. G. Bucher, Tetrahedron Lett., 1978,2267. K. K. Knapp, P. C. Keller, and J. V. Rund, J. Chem. SOC.,Chem. Commun., 1978, 971. M. Narisada, H. Onoue, M. Ohtani, F. Watanabe, T. Okada, and W. Nagata, TetrahedronLett., 1978, 17.55.

140

Heterocyclic Chemistry

R2 = 4-C1C&, 4-02NC6H4, 3-OzNC6H4; R' = 2-ClC6H4 Or 3-02NC6H4, R2 = Ph, 4-BrC&, 4-C1C6H4, 4-02NC6H4, or 3-02NC,H4); these, on treatment with polyphosphoric acid or POC13, cyclize to give the substituted thiazolo[3,2-b][1,2,4]triazoles (139; R', R2 as and not the thiaz010[2,3-c][ 1,2,4]triazoles (140; R', R2 as before), as reported previou~ly.~~'

Compounds (140; R' = Et or 2-C1C6H4,R2 = 4-BrC6H4)can be unequivocally synthesized by cyclization (with POC1,) of the corresponding 2-acylhydrazino-4aryl-thia~oles.~ Other ~ ~ * ~derivatives ~~ of these two systems (139; R' = aryl, R2 = Me) and (140; R' and R2 as before) may be obtained by cyclization of the 2-aryl-5-propynylthio- 1,2,4-triazoles, using mercuric acetate258or acidic or basic conditions,259compound (139) being the main product in each case. Thiazolo[3,4-c]oxazole [C3NO-C3NS]. The perhydro-compound (141) is obtained in 40% overall yield in a four-stage synthesis starting from cysteine.26"

Thiazolo[4,5-d]thiazoles[C3NS-C3NS]. Derivates of this ring system (142; R1 = aryl, R2 = NH2or substituted amino) can be obtained by the condensation of 3-aryl-5-bromorhodanine with thioureas.261 Pyrazolo[3,4-d]thiazole [C3NS-C3N2].The reaction between 2-amino-pyrazoles and benzoyl isothiocyanate gives the compounds ( 143).262 Imidazo[2,I-b]thiazoles [C3NS-C3N2].The reaction of 2-amino-thiazoles with chloroacetic or with substituted phenacyl gives the 2-iminoA4-thiazolines, which cyclize on treatment with acetic anhydride and ~ y r i d i n e , ~ ~ ~ or on heating in to give the imidazo[2,1-b]thiazoles (144; R' = OH, R. P. Gupta, M. L. Sachdeva, and H. K. Pujari, Indian J. Chem., Sect. B, 1977,15, 1143. A. Singh, R. N. Honda, and H. K. Pujari, Indian J. Chem., Sect. B, 1978,16,475. 257 K. T. Potts and S. Husain, J. Org. Chem., 1971, 36, 10. 258 V. P. Upadhyaya, T. G . S. Nath, and V. R. Srinivasan, Synthesis, 1978, 288. 259 A. Mignot, H. Moskowitz, and M. Miocque, Synthesis, 1979, 52. G. G . Habermehl and W. Ecsy, Heterocycles, 1977,7, 1027. '" S. K. Mahapatra, M. Patra, and B. Dash, Cum. Sci., 1978, 47,411. 262 M. H. Elnagdi, S. M. Fahmy, M. R. H. Elmoghayar, and E. M. Kandeel, J. Heterocycf.Chem., 1979, 16, 61. 263 A. N. Krasovskii, N. Grins, A. K. Sheinkman, N. A. Klyuev, and A. B. Belikov, Khim. Geterotsikl. Soedin., 1978,476 (Chem. Abs., 1978,89,43 217). 264 S. N. Sawhney, S. K. Arora, and S. P. Singh, Indian J. Chem., Sect. B, 1978,16, 523. 255

256

Five-membered Rings ; Systems containing Nand S, Se, or Te

141

R2 = Ac, R3 = H) and (144; R' = Ar, R2 = H, R3 = CH2C02Et).4,S-Diaryl2-mercaptoimidazole condenses with chloroacetic acid to give the imidazo[2,1-b]thiazol-3(2H)-one (145; R' = R2 = H, R3 = 4-MeOC6H4),265with hexafluoro-1,2-epoxypropaneto give (145; R1 = F, R2 = CF3,R3 = Ph),266and with 1,2-dibromoethane to give (146; R' = R2 = 4-MeOC6H4).267

Heating the imidazo[2,1-b]thiazole (82; R = 2-furoyl, X = Br)l'' with HBr in DMF leads to debromination of the imidazo ring and bromination of the furan ring at position 5, a mixture of products containingone, two, or no bromine atoms being obtained, depending upon the duration of heating.268The thiazole ring of 2,3,5,6-tetrahydro-6-phenylimidazo[2,l-b]thiazole (tetramisole) (147) is ruptured on treatment with lithium di-isopropylamidein THF, to give, following the addition of alkyl halides, 1-(2-alkylthio)ethyl-4-phenyl-imidazoles. Conclusive evidence for this was obtained by X-ray crystallography of the 2- (4-bromobenzylthio)ethyl derivative.269 PyrroZo[Z, I-b]thiuzoZes [C3NS-Cfl].An elegant conversion of the peptide (148) into the penicillin (150) takes place via the intermediate (149), as shown in Scheme 4. The CA-S bond of (149) is selectively cleaved rather than the CB-S bond, and the reaction only occurs if ring A is fi~e-mernbered.~~' The overall conversion had previously been achieved only by a rather lengthy procedure. 0

0

S

Me

BzO (149) Reagents: i, NaH; ii, Bu'OCl

Scheme 4

Fu rano [2,3-d]thiatoles [C&S- C401. Treatment of substituted 2-furanyl-t hioureas with bromine in acetic acid or with triethyl phosphate gives the furano[2,3dthiazoles (151; R'=H or C0,Et; R2 = Me or C0,Et; R3 = EtO, Ph, 2-thienyl, 26s 266 267

269

*''

R. P. Gupta and H. K. Pujari, Indian J. Chem., Sect. B, 1978, 16, 329. H. A. Hammouda and N. Ishikawa, Bull. Chem. SOC.Jpn., 1978,51, 3091. P. E. Bender, Ger. Offen. 2 742 725/1978 (Chem. Abs., 1978,89,24 305). N. 0. Saldabol and 0.E. Lando, Zh. Org. Khim., 1977,13,2626 (Chem. Abs., 1978,88,136 573). R. F. Fibiger, A. R. Banks, T. Jones, R. C. Haltiwanger, and D. S. Watt, J. Heterocycl. Chem., 1978, 15,307. J. E. Baldwin and M. A. Christie, J. Am. Chem. SOC.,1978, 100,4597.

142

Heterocyclic Chemistry

or 2-furanyl)in 10--82% yields.271An improved procedure for the cyclization of a thiamine derivative [152; R = CH(OH)Me] gives the perhydrofurano[2,3dthiazole (153; R'=COMe, RZ = H),272and a y-radiation-induced reaction of thiamine hydrochloridewith di-l-adamantyl tetrasulphide (AdSSSSAd)gives the perhydrofurano[2,3-d]thiazoles (153; R1=H or CH20H, R2 = SSAd).273

Cyclopentenothiazol-6 -one [C3NS-C5]. Treatment of 5-acetyl-4-formyl-3phenylthiazole with 10% sodium hydroxide solution gives the cyclopentenothiazol-6-one (154) (65YO).274

Structures comprising One Five-membered and One Six-membered Ring (5,6).-~hiazo~o[3,2-a]-I,3,5-triuzines[CflS-C3N3]. Two equivalents of diphenylcarbodi-imide react with one equivalent of the iminophosphorane Ph3P=NR (R = 2-thiazolyl) in a cycloaddition reaction to give 2,4-diphenylimino~3-phenylthiazolo[3,2-a]-1,3,5-triazine (155), probably via the intermediate (156).275 NPh

fl:)

0

(1 54)

csYpE I


PhN (156)

Thiuzolo[4,5-d]pyriduzines [C3NS-CY,].5-Acetyl-4-formyl-2-phenylthiazole condenses with hydrazine to give 7-methyl-2-phenylthiazolo[4,5-d]pyridazine (157) (88'Y0).~~~ Thiazolo[3,2-alpyrimidines [CaS-CY,]. Condensation between 2-aminothiazole (or 2-amino-A2-thiazoline) and the acetylenic ester PhC=CCOzEt gives the thiazolo[3,2-a]pyrimidin-7-one (158) (or the 2,3-dihydro-derivat i ~ e )A. series ~ ~ ~of meso-ionic xanthine analogues (159; R' = H or Et; R2 = Bu, CH2CHMez, pentyl, CH2CHzCHMez, CH2CMe3, or benzyl) have been obtained by treatment of 2-(substituted amino)-thiazoles with malonic Unsymmetrical derivatives of malondiamide may be prepared by the 271 272

273 274 275

276

277

L. Grehn and H. Lindberg, Chem. Scr., 1977,11,199. K. Karimian and G. E. Risinger, Org. Prep. Proced. Int., 1978,10,45. N.Hayashi and S . Kato, Chem. Lett., 1978,149. I. Simiti and M. Coman, Arch. Pharm. (Weinheim, Ger.), 1978,311,480. J. Boedeker, P. Koeckritz, and K. Courault, 2.Chem., 1979,19,59. H.N.Al-Jallo and M. A. Muniem, J. Heterocycl. Chem., 1978,15,849. R. A. Glennon, M. E. Rogers, R. G. Bass, and S. B. Ryan, J. Pharm. Sci., 1978,67,1762.

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

143

reaction of thiazolo[3,2-a]pyrimidine-5,7-dione with amines in non-aqueous s01vents.*'~

(157)

(158)

(159)

Thiuzolo-[4,5-d]- and - [5,4- d]-pyrimidines [CaS-CY,]. Cyclocondensation of 2-acylimino-A4-thiazolines(95;R' = Ac, R2 = Ph Or 4-MeCsH4, R3 = H, R4 = CN or CONH2) in polyphosphoric acid gives the thiazolo[4,5-dlpyrimidines (160; R = Ph or 4-MeC6H4),138whilst the reactions of 4-bromothiouracil derivatives with thioureas give the thiazolo[4,5-d]pyrimidin-7-one-5-thiones (161; R' = NH2 or substituted amino, R2 = ary1).261

Oxazolo[S,4-dJpyrimidines (162; X = Y = Z = 0) are converted into the corresponding thiazolo[5,4-dJpyrimidines (162; X = Z = S, Y = 0)on treatment with phosphorus pentasulphide, which may be oxidized to the corresponding 4,6-diones (162; X = s, Y = Z = 0),using 30% hydrogen Thiuzolo[3,4-a]pyrazines [C,NS-CJV,]. The synthesis of sulphomycinine (163), a degradation product of the sulphur-containing antibiotic sulphomycin, by the reaction between thiazole-4-carbonyl chloride and threonine, followed by bromination and cyclization, has been described.280 Thiuzolo[4,5-b]pyruzines [C a S -CY, 3. The reaction between 2-amino-5,6dichloro-3-mercaptopyrazine and chloroacetic anhydride gives 2-chloromethyl5,6-dichlorothiazolo[4,5- blpyrazine (164) Me

0

0 (163) ThiuzoloC3,2-a]pyri~ines[C'S-C,N). The reaction between acetylenic esters and 2-substituted-A*-thiazolinesto give compounds (165; R' = CN, COPh, 278

27q 280

281

L. B. Dashkevich, Yu. Khodzhibaev, and M. M. Samoletov, Org. Khim. (U.S.S.R.), 1976, 105 (Chem. A h . , 1978,88,136 505). K. Senga, J. Sato, and S. Nishigaki, Chem. Pharm. Bull., 1978,26,765. H.Abe, T. Takaishi, Y. Ito, and T. Okuda, Heterocycles, 1977,8,461. Y . C.Tong, US.P. 4 075 20711978 (Chem. A h . , 1978,88,190 900).

144

Heterocyclic Chemistry

C02Me, or C02Et; R2 = H or C02Me) has been further investigated (cf.ref. le, p. 416).282The esters RCH=C(COMe)CO,Et (R = alkyl or aryl) condense with 2-(alkoxycarbonylmethylene)-thiazolines to give compounds (166; R' = Me or Et, R2 = alkyl or aryl) in what appears to be a modified Hantzsch dihydropyridine Acid-catalysed ring closure of 1-phenacylpyridine-2thiones gives the 2-arylthiazolo[3,2-a]pyridinium salts (167; R' = aryl, R2 = H),284and nitration of the salt (167; R' = Me, R2 = H, X = Clo,) with nitricsulphuric acid gives (167; R1 = Me, R2 = NO2)? The reaction between pyridine-2-thione and ethyl bromocyanoacetate gives compound ( 168).286The 2pyridylthioacetic acid derivatives (169; R' = Me, R2 = H) and [169; R' = H, R2 = 2-(5-nitropyridylamino)] cyclize on heating with acetic anhydride287or xylene288to give the products (170; R', R2 as before). Condensation of thiazolo[3,2-a]pyridinium 3-oxide with 4-dimethylaminobenzaldehydeand perchloric acid gives compound (17 l).2873-Hydroxypyridine-2-thionereacts with the

2-bromoacetal BrCH2CH(OMe), to give compound (172; R=OMe),289and with tetrabromoethane, Br2CHCHBr2, to give (173; R = Br), which cannot be formed by halogenation of (173; R = H). Treatment of (172; R = OMe) with potassium t-butoxide gives (173; R = H).289 282 283 284

*" 286 287

288 289

C. Rocheville-Divorne and J. P. Roggero, C.R. Hebd. Seances Acad. Sci., Ser. C , 1978, 287, 385. H. Meyer, F. Bossert, and H. Horstrnann, Justus Liebigs Ann. Chem., 1977, 1888. B. Blank, N. W. DiTullio, A. J. Krog, and H. J. Saunders, J. Med. Chem., 1978, 21, 489. V. P. Martynova, E. R. Zakhs, and A. V. El'tsov, Zh. Org. Khim., 1978,14,216(Chem. Abs., 1978, 88, 170 022). H. Singh and C. S. Gandhi, J. Chem. Res., 1978, ( S ) 407; ( M )4930. L. T. Gorb, N. N. Rornanov, E. D. Sych, and A. I. Tolmachev, Dopou. Akud. Nuuk Ukr. RSR, Ser. B, 1978,894 (Chem. Abs., 1979,90,38 831). D. Tavernier, J. C. Jamoulle, and C . L. Lapiere, Can. J. Chem., 1978,56, 2109. G. A. Ulsaker, T. Laerum, and K. Undheim, Acta Chem. Scand., Ser. B, 1978, 32,460, 651.

Five-membered Rings : Systems containingN a n d S, Se, or Te

145

Thiazolo[3,4- alpyridines [C3NS-C5N].The reaction of the piperidinyl-thiourea (174) with thionyl chloride gives a mixture of the saturated thiazolo[3,4-a]pyridine (175) and the oxazolo[3,4-a Jpyridine (176). The cyclizations take place stereospecifically, with inversion of configuration giving (175) and retention giving (176).290 MeN

C(S)NHMe (174)

(175) X = S (176) X = O

Thiazolo[5,4-blpyridines [C3NS-CsN]. 3-Amino-2-chloropyridine cyclizes with ethoxycarbonyl isocyanate to give compound (177; R = C02Et), which on hydrolysis and decarboxylation gives (177; R = H).291The 3-oxide of (177; R = H) can be obtained by catalytic hydrogenation (Pd/C) of 3-nitro-2-thiocyanatopyridine, and it may be further hydrogenated to (177; R = H).291 Pyrano [4,3-dJ thiazoles [C3NS-CsO]. 2- Aryl-4- (2-hydroxyethyl) -thiazoles will react with ketones RCO(CH2),C02Et (R = Me or Et; n = 1 or 2) to give the tetrahydropyrano[4,3-d]thiazoles (178; R, n as before).292

Structures comprising One Five-membered Ring and One Seven-membered Ring (5,7).--Thiazolo [4,5-c]azepines [C3NS-CJV]. The reaction between 4bromo-3,3-dihydroxyhexahydroazepin-2-one and thiourea gives (179) (75°h).293

Structures comprising Two Five-membered Rings and One Six-membered Ring (5,5,6).--1,2,4-Triazolo[3,4-b]benzothiazole[C2N3-C3NS-C6].The 3-chloroderivative (180) reacts with o-aminobenzenethio1 to give the novel pentacyclic system (18 290

291

H. Wollweber, U.Pohl, and K. Stoepel, Eur. J. Med. Chem. Chim. Ther., 1978,13,141(Chem.Abs., 1978,89,109 203). A. Petric, B. Stanovnik, M.Tisler, andB. Vercek, Vestn. Slou. Kem. Drus., 1978,25,31(Chem.Abs.,

1978,89,109 200). 292

293

294

A. H. Philipp, L. G. Humber, and R. R. Martel, J. Heterocycl. Chem., 1978,15,413. R. G. Glushkov, V. G. Smirnova, I. M. Zasosova, T. V. Stezhko, I. M. Ovcharova, andT. F. Vlasova, Khim. Geterotsikl. Soedin., 1978,374 (Chem. Abs., 1978,89,43 306). D. S. Deshpande and S. T. Jannawar, Marathwada Univ. J. Sci., Nut. Sci.,1975,14,13(Chem. Abs.,

1978,89,43351).

146

Heterocyclic Chemistry

Thiazolo [2,3-blbenzo thiazoles [C3NS-C3NS-C6].The 3-ary Ithiazolo[ 2,3 - b 1benzothiazolium perchlorates (182; R' = Ar, R2 = H) (cf. ref. le, p. 421) will react with 1-morpholinocyclohex-1-ene to give the isoindolo[ 1,2-b]benzothiazole derivatives [183; R'R1 = (CH2)4,R2 = Ar].295The isomeric anhydro 2and 3-hydroxythiazolo[2,3-b]benzothiazoliumhydroxides (182; R' = 0-,R2 = H) and (182; R' = H, R2 = 0-)are convenient substrates for annelation of a five- and six-membered ring to benzothiazole, yielding the pyrrolo[2,1 -b]benzothiazole (183; R' = C02Me, R2 = H) from (182; R' = 0-, R2 = H) and the pyrrolo[2,1-b]benzothiazol-l-one (184; R' = C02Me, R2 = Ph) from (182; R' = Ph, R2 = 0-)respectively.296

Thiazolo[4,5-d]indazole [C3NS-C3Nz-C6].The reaction of 5-aminoindazole with cupric thiocyanate in acetic acid gives the compound (185), which has been diazotized and coupled with amines to give disperse Benzo[ 1,2-d;3,4-df]-bis-thiuzoles[C3NS-C3NS-C6]. Condensation of 6-amino2-methylbenzothiazole-7-thiolwith carboxylic acids or acid chlorides gives the title compounds (186), which have been converted into cyanine dyes by standard reactions.298

Q

Thiazolo[3,2-a]benzimidazoles [C3NS-C3Nz-C6].The reaction between 5bromobenzimidazole-2-thiol and chloroacetic acid, followed by cyclization using acetic anhydride, gives the bromothiazolo[3,2-a]benzimidazole (187; R' = Br, R2 = H), and not the isomer (187; R' = H, R2 = Br); similar products are obtained starting from a-halogeno-ketones and 1,3-dibr0mopropane.~~~ The cyclocondensation between benzimidazoline-2-thione and dimethyl acetylenedicarboxylate (DMAD) gives compound (188) as the major product together with the isomer (189). The structure of (188)was confirmed by X-ray crystallo295 296

297

298 299

S. Sawada, T. Miyasaka, and K. Arakawa, Chem. Pharm. Bull., 1978,26, 275. K. T. Potts and D. R. Choudhury, J. Org. Chem., 1978, 43,2697. C. Tarabasanu-Mihaila, F. Urseanu, L. Floru, and B. Marculescu, Rev. Roum. Chim., 1978,23,977 (Chem. Abs., 1979,90, 7566). S. G. Fridman and L. I. Kotova, Ukr. Khim. Zh., 1978,44, 637 (Chem. Abs., 1978,89, 148 132). A . Singh, R. N. Handa, and H. K . Pujari, Indian J. Chem., Sect. B, 1978, 16, 478.

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

144

graphy and by an unambiguous ~ynthesis.~"The crystal structures of two 9-phenacyl thiazolo[ 3,2-a Ibenzimidazole derivatives have been described.301

(188)

(189)

Thiuzul0[5,4c]benzirniduzoles [C3NS-C3N2-C6].The title compounds can be obtained in a similar manner to the benzo[ 1,2-d ;3,4-d']- bis-thiazoles described above, starting from 5-amino-2-methyl- 1-phenylbenzimidazole-4-thio1.298 Irniduzo[2,1-b]benzothiazoles [c&s-c3N2-c6].Members of this class of compound have been prepared from N-acetyliminobenzothiazolinesby a similar and also from the procedure to that used to prepare imidaz0[2,l-b]thiazoles,~~~ reaction between cyclic thioureas (190; n = 2) and dimedone in the presence of N-bromosuccinimide, e.g. (191; n = 2, 3, or 4).302 Thiazolo[3,4-a]indolees [c&s-C&-c6]. The reaction between (2-indoly1)methanol sulphates and carbon disulphide, followed by methylation, gives the quaternary salts of the title compounds, e.g. (192).303

Thiuzolo[~,#-b]indolees [C3NS-C4N-C6].The conversion of the acetamido-

indoles (193; R1 = Me or Et; R2 = H, 5-Br, 5,'7-C12, or 4,6-Me2) into the thiazolo[5,4-b]indoles (194; R1,-R2as before) is accomplished by using phosphorus pentasulphide.304 300

301 302

303

304

A. McKillop, G. C. A. Bellinger, P. N. Preston, A. Davidson, andT. J. King, Tetrahedron Lett., 1978, 2621. W. Schuckrnann, H. Fuess, S. W. Park, and W. Reid, Acta Crystallogr., Sect. B, 1979, 35, 96. V. K. Chadha, Ann. Soc. Sci. Bruxelles, Ser. 1, 1977, 91, 101 (Chem. Abs., 1978,88, 121 121); J. Indian Chem. SOC.,1977, 54, 878. D. Farge, A. Jossin, G. Ponsinet, and D. Reisdorf, Ger. Offen. 2 802 520/1978 (Chem. Abs., 1978, 89, 197 532). P. I. Abrarnenko, T. K. Ponornareva, and G. I. Priklonskikh, Zh. Vses. Khim. 0-ua., 1978,23, 71 1 (Chem. Abs., 1979,90, 152 060).

Heterocyclic Chemistry

148

Pyrrolo[Z, 1-blbenzothiazoles [C3NS-C4N-C6].The thermal and photochemical decomposition of 2-azidophenyl thienyl sulphides (195; R = H,3-Me,5-Me, or 3,5-Me2) gives up to 68% of the pyrrolo[2,1-b]benzothiazoles (196; R as before), as shown in Scheme 5.305

1

(195)

Scheme 5

Benzo[blfurano[2,3-d]thiazole[C3NS-C40-C6]. Cyclization of 2-acetylamino3-bromobenzo[b]furan, using phosphorus pentasulphide, gives compound (197) in low yield.306 Structures comprising One Five-membered Ring and Two Six-membered Rings (5,6,6).-1,3,5-Triazino[Z, 1- blbenzothiazole [C3NS-C3N3-C6]. 2-Aminobenzothiazole reacts with Cl,CCH(Cl)N=C=O, 1,2,2,2-tetrachloroethylisocyanate, to give 2,3-dihydr0-1,3,5-triazino[2,1 -b]benzothiazole ( 198).307

OH

8-Thia-1,4-diazacycl[3.3.2]azines[C3NS-C4N2-C4Nz].The condensation between 4,6-diaminopyrimidine-6-thioland ethyl 4-chloroacetoacetate gives, after treatment with hydrochloric acid, the cyclazine ( 199).308 305 306

307 308

J. M. Lindley, 0. Meth-Cohn, and H. Suschitzky, J. Chem. Soc., Perkin Trans. 1, 1978, 1198. P. I. Abramenko and V. G. Zhiryakov, Khim. Geterotsikl. Soedin., 1977, 1495 (Chem. Abs., 1978, 88, 105 203). H. Zinner, U. Rosenthal, H. P. Kruse, S. Rosenthal, and M. Schnell, J. Prakt. Chem., 1978,320,625. E. Campaigne and T. P. Selby, J. Heterocycl. Chem., 1979, 16, 151.

149

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

Pyrano[43- dlthiazolo[3,2- alpyrimidines [C3NS-C4N2-CsO]. The reaction between 2-amino-A'-thiazoline and tetrahydro-3,5-bis(arylmethylene)-4Hpyran-4-one gives intermediate pyranols which cyclize with titanium tetrachloride to give the compounds (200).309 2-Aminobenzothiazole [C3NS-C4N2- C, 1. condenses with acetylenic esters, e.g. PhC=CCO,Et, to give compound (201),276 and the cyclic thiourea (190; n = 3) reacts with dimedone in the presence of N-bromosuccinimide to give (191; n = 3).302

Py rimido[2,I - b] benzoth iazoles

(205)

(207)

JJ

Thiazolo-[2,3-b]-,-[3,2- a]-, and - [3,2-c]-quinazolines [C3NS-CY,-C,]. The 5,6,7,8-tetrahydroquinazoline-2,4-dithiones [202; R = (CH,),OH, (CH2),0H, or CH2CH=CH2] cyclize under acidic conditions to give a mixture of the thiazolo-[2,3-b]- and -[3,2-c]-quinazolines (203; R = H or Me) and (204; R = H or Me).310Halogenated derivatives of (205; X = F)311 or (205; X = Br)312are obtained by cyclocondensation of the quinazolones (206; X = F or Br). Reduction of (206; X = F) with sodium borohydride followed by cyclization gives the isomeric thiazolo[3,2-a]quinazoline (207; X = F).311 2,6-Bis(arylmethylene)cyclohexanones react with thiourea to give the quinazolines (208), which cyclize with a-halogenated acids RCH(C1)CO2H (R = H or Me) to give the G. C. Rovnyak, U.S. P. 4 128 64811978 (Chem. Abs., 1979,90,121643). S. Leistner, A. P. Giro, and G. Wagner, Pharmazie, 1978, 33, 185. 3 1 1 V. K. Singh and K. C. Joshi, J. Indian Chem. SOC.,1978,55, 928. 312 R. P. Gupta, M. L. Sachdeva, R. N. Handa, and H. K. Pujari, Indian J. Chem., Sect. B, 1978,16,537. 3uy

310

150

Heterocyclic Chemistry

thiazolo[2,3-b]quinazolin-3-ones (209; R = H or Me).313The meso-ionic thiazolo[3,2-a]quinazolin-4-ones(2lo), previously described in ref. 1e, p. 426, have surprisingly different colours, depending on the substituent R; when R is Ar, the compounds are deep blue, becoming yellow with alkalis.314The thiazolo[3,2c]quinazolinium salt (2 11)is obtained by allowing sodium quinazoline-4-thiolate to react with c h l o r ~ a c e t o n i t r i l e and , ~ ~ ~a similar reaction with ethyl bromomalonate gives the meso-ionic compound (212) in almost quantitative yield.316

ThiazoZo[4,5-b]quinoxaZines [C3NS-C4N2-C6].The reaction between 2,3dichloroquinoxaline and thiourea gives, in addition to the thiazolo[4,5 b]quinoxaline (213), the compound (2 14),317 Thiazolo-[3,2-a]-, -[4,5-g]-, -[5,4-g]-, -[4,5-h]-, and -[5,4-h]-quinolines [C,NS-C,N-C,]. Condensation of 2-hydroxyquinoline with a-bromophenylacetic acid gives the meso-ionic compound (21S ) , which reacts with acetylenic esters to give the pyrrolo[l,2-a]quinolines (216; R1 = R2 = C02Me) and (216; 313 314

316

317

M. I. Ali and A. E. G. Hammam, J. Chem. Eng. Data, 1978,23,351. P. B. Talukdar, S. K. Sengupta, and A. K. Datta, Indian J. Chem., Sect. B, 1978, 16, 678. H. Singh, S. S. Narula, and C. S. Gandhi, J. Chem. Res., 1978, (S) 324; ( M ) 3957. H. Singh and C. S. Gandhi, Indian J. Chem., Sect. B,1978, 16, 331. I. M. Ismail and W. Sauer, Indian J. Chem., Sect. B, 1978, 16, 683.

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

151

R' = H, R2 = C 0 2 E t ) following loss of carbon oxysulphide from the intermediate addition compound, and with fumaronitrile to give the pyrido[ 1,2alquinoline (217).3'8Substituted thiazolo-[4,5 -g]- (21S), - [5,4-g]- (219), - [4,5 h]- (220), and -[5,4-h]-quinolines (221) are obtained by condensation of benzothiazoles (substituted with amino- and chloro-groups in the benzene ring) with ethyl ethoxymethylenemalonate followed by cyclization and N-alkylation, or by condensation of quinolines (substituted in the benzene ring with amino- and chloro-groups, arranged ortho) with carbon disulphide or hydrogen ~ u l p h i d e . ~ ~ ~

m2 ep 0

Eto2 c

/

/

Et0,C

Et

0

(218)

(219)

0

c1

(222)

(223)

Thiazolo- [2,3-a]- and - [3,4-b]-isoquinolines [C3NS-C5N-C6].Sodium isoquinolinyl- 1-thiolate condenses with ethyl bromocyanoacetate to give the salt (222)286 and with ethyl bromomalonate to give the meso-ionic compound (223).316(3-Isoquinolinyl)methanolsulphates react with carbon disulphide to give, after methylation, the thiazolo[3,4-b]isoquinolinium salts (224),303and the isoquinolinyl-thioureas (225) cyclize in acidic media to give compounds (226).320 The kinetics of the acid hydrolysis of meso-ionic thiazolo[2,3-a]isoquinolines have been i n ~ e s t i g a t e d . ~ ~ ' '18 319 320

321

K. T. Potts and D. R. Choudhury, J. Org. Chem., 1978, 43, 2700. N. Suzuki,Y. Tanaka, and R. Dohmohri, Chem. Pharm. Bull., 1979,27, 1. Rhone-Poulenc Industries S.A., Belg. P. 851 146/1977 (Chem. Abs., 1978,89,6316);Austrian P. 347 953/1979 (Chem. Abs., 1979,90,186 929). P. B. Talukdar and A . Chakraborty, Indian J. Chem., Sect. B, 1978, 16, 310.

152

Heterocyclic Chemistry

and - [2,1-d]-thiazoles [C3NS-C6-C6]. 2-ArylazoNaphtho- [ 1,2-d]naphthalene-1-sulphenyl bromides react with compounds containing active methylene groups to give the naphtho[2,1-d]thiazoles (227; R=COMe, C 0 2 E t , et~.),~’*and U.V. irradiation of 1- and 2-naphthylthioureas gives the title compounds (228; R = Me) and (227; R = Me) in good yield.323The hydrazononaphtho[2,l-d]thiazoles (227; R = NHN=CHAr) cyclize on heating to give the 3-aryl-1,2,4-triazolo[5,4-b]naphtho[2, 1-dlthiazoles (229).324 The imidazo[3,2-b]naphtho[ 1,2-d]thiazolium salt (230) is obtained by allowing N(1-naphthyl)ethylenediamine to react with carbon disulphide and subsequent cyclization (using bromine) of the intermediate 1-(l-naphthyl)-4,5-dihydroimidazole-2 -thiol.325

(233)

(234)

Other Condensed Systems incorporating Thiazo1e.-Condensation of 4-aryl-2imino-3-(2-naphthy1)-A4-thiazolines with paraformaldehyde gives the naphtho[ l ,2 -e]thiazolo[3,2-a]pyrimidines

(23l ).326 The benzo[g]thiazolo[3,2 -a]quinazolines (232) are obtained by the reaction of 3-amino-2-naphthoic acid with the thiocyanates ArCOCH,SCN, whilst the condensation of the aminonaphthoic acid with 4-aryl-2-chloro-thiazolesgives the isomeric benzo[g]thiazolo[2,3-b]quinazolines (233).327The reaction of the appropriate benzocycloheptenopyridine-2-thionewith chloroacetic acid gives (234).328 322

323 324 325 326

327 328

A. Chaudhuri, S. K.Bhattacharjee, and S. K. Dasgupta, J. Indian Chem. SOC.,1978, 5 5 , 702. M. Kimura, S. Morosawa, and T. Emoto, Japan. Kokai 79 19 973 (Chem.Abs., 1979,90,204 256). A. P. Kulkarni, S. T. Jannawar, and D. S. Deshpande, J. Indian Chem. SOC., 1978,55, 922. K. C. Liu, C. Y. Shih, J. Y. Tuan, and S. F. Chen., Arch. Pharm. (Weinheim, Ger.), 1978,311,267. S . M. Sondhi and N. K. Ralhan, Indian J. Chem., Sect. B, 1977,15,697. H. K. Gakhar, R. Gupta, and N. Kumar, Indian J. Chem., Sect. B, 1977, 15, 1115. M. I. Ali and A. E. G. Hammam, J. Chem. Eng. Data, 1978,23,91.

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

153

15 Thiadiazoles and Selenadiazoles 1,2,3-Thiadiazoles.-Synthesis. The reaction between ethyl 2-(ethoxythiocarbony1)propionate and diazomethane gives the 1,2,3-thiadiazole (235; R = CHMeC02Et).329The determining factor in the type of product formed in the reaction of carbon disulphide and a-diazo-ketones R1COCN2R2is the nature of R2;when R2is Ph, 1,3-dithiolans, e.g. (236), are the sole products; when R2is Me, both 1,3-dithiolansand 1,3-dithietans, e.g. (237), are obtained; whilst when R' is H, a 1,2,3-thiadiazole, e.g. (238), is formed.3301,2,3-Thiadiazoleslabelled at C-4 and C-5 with 13C and with 13C and 2H have been prepared as precursors to labelled thiirens, ( a )by the reaction between Me13COC02Naand NH2NHC02Et

R'

R SO2NsN , 0

Rz,fS/NMe ,'R N\ Me R3S0,NH

0

to give the hydrazone, which condenses with thionyl chloride to give 4-carboxy1,2,3-[4-'3C]thiadiazole; this decarboxylates to the 4-13C-labelled parent compound (235; R = H), which after 2H20exchange and decarboxylation gives the 4-13C, 2H-labelled compound (235; R = H), and (b) by the reaction of the hydrazone 13CH3CH=NNHC02Et with thionyl chloride to give [5-13C]-(235; R = H), which exchanges with 2 H 2 0 to give [5-"C, 'H]-(235; R = H).331 Ring-contraction of the dihydrothiatriazine 1-oxides [239; R1 = Me, R2 = Me or PhNHCO, R3 = 4-MeC6H4;or R1R2 = (CH2)4,R3 = Me] to the A3-1,2,3thiadiazoline 1-oxides (240; R1,RZ,R3as before) occurs on treatment with trifluoroacetic acid, whereas (239; R1 = Me, R2 = H, R3 = 4-MeC6H4 or Me) gives the 1,2,3-thiadiazoline (241; R = 4-MeC6H4 or Me), by loss of water.332

Physical Properties. Microwave and 14N n.q.r. spectra of 1,2,3-thiadiazole (and other thiazoles and thiadiazoles) have been reported and the results correlated with M.O. calculations,20and the 13Cn.m.r. spectra of some 1,2,3-thiadiazoles (and 1,3,4-thiadiazoIes) have been X-Ray crystallography of the 329

330

331

332 333

J. Nyitrai, G. Domany, G. Sirnig, J. Fetter, K. Zauer, and K. Lempert, Acru Chim. Acad. Sci. Hung., 1978, 97, 91. P. Yates and J. A. Eenkhorn, Heterocycles, 1977, 7, 961. A. Krantz and J. Laureni, J. Labelled Compd. Radiopharm., 1978, 15 (Suppl.), 697 (Chem. Abs., 1979,90, 186 864). S. Somrner and U. Schubert, Chem. Ber., 1978, 111, 1989. J. H. Looker, N. A. Khatri, R. B. Patterson, and C. A. Kingsbury, J. Heterocycl. Chem., 1978, 15, 1383.

154

Heterocyclic Chemistry

N-oxide obtained either thermally or photochemically from 4-phenyl-1,2,3thiadiazole indicates that it is the 3 - 0 x i d e . ~ ~ ~ Chemical Properties. The photolysis and pyrolysis of 1,2,3-thiadiazoles continue to attract interest, and a report surveys the attempts to observe thiiren interm e d i a t e ~ Photolysis .~~~ of the 1,2,3-thiadiazoles (242; R' = R2 = H), (242; R' = CF3, R2 = H), (242; R'R2 = CH=CHCH=CH), and (242; R' = Me, R2 = C0,Et) in an argon matrix at 8 K gives the thiirens (243; R', R2as before); all are highly unstable, and were identified from their i.r. spectra. Electronwithdrawing substituents exert a marked stabilizing effect, such that (243; R' = Me, R2 = C02Et) is stable up to 73 K.336Photolysis of the compounds (242; R' = R2 = H), (242; R' = Me, R2 = H), and (242; R' = H, R2 = Me) and trapping of the intermediates with C F 3 C ~ C C F ,gives the thiophens (244; R' = R2 = CF3, R3 = H) and (244; R' = R2 = CF3, R3 = Me).337Whilst the photolysis of [242; R1R2 = (CH2)4]in benzene gives the expected mixture of products, thermolysis of this compound in ethylene glycol gives the glycol ester (245) in almost quantitative yield.338The labelled 1,2,3-thiadiazoles mentioned above331have been pyrolysed to give labelled thioketens, whose microwave spectra have been

(242)

(243)

(244)

(245)

The reaction of 5-chloro-4-substituted-l,2,3-thiadiazoleswith KS2COEt followed by KOH gives the stable potassium salts of (242; R' = COAr, R2 = SH) and (242; R' = C02Et, R2 = SH).3403-Methyl-4,5-diphenyl-l,2,3-thiadiazolium fluorosulphonate, which is obtained by methylation of (242; R' = R2 = Ph) with Me03SF, and whose structure was confirmed by X-ray crystallography, can be demethylated with a variety of nucleophiles (e.g. EtO-, Et3N, or PhCH2NH2)without ring cleavage, unlike the corresponding N-methyl-l,2,4thiadiazolium salts, which undergo ring cleavage extremely readily.341The oxidation of 4,7- and 5,6-dihydroxybenzo-l,2,3-thiadiazoles, using Fe"' complexes of 1,lO-phenanthroline and related compounds, has been investigated.229 The reaction between 6-hydrazino- 1,3-dimethyluracil and thionyl chloride gives the 1,2,3-thiadiazolo[4,5-d]pyrimidine(246; R = Me), whereas a similar reaction of 6-hydrazino-3 -methyluracil gives the 1,2,3,5 - thiatriazolino[5,4clpyrimidine (247), which rearranges to (246; R = H).342Treatment of 3methyl-6-( 1-methylhydrazino)uracil with thionyl chloride gives the meso-ionic 334

335 336

337 338

339

340

341 342

W. Winter, U. Pluecken, and H. Meier, 2. Naturforsch., Teil B, 1978, 33, 316. H. Meier and K . P. Zeller, Proc. I.U.P.A.C. Sym. Photochem., 7th, 1978, 234. M. Torres, A. Clement, J. E. Bertie, H. E. Gunning, andP. 0.Strausz,J. Org. Chem., 1978,43,2490. J. Font, M. Torres, H. E. Gunning, and 0. P. Strausz, J. Org. Chem., 1978,43, 2487. U.Timm, H. Buehl, and H. Meier, J. Heterocycf. Chem., 1978, 15, 697. B. Bak, 0.J . Nielsen, H. Svanholt, A. Holm, N. H. Toubro, A. Krantz, and J. Laureni, Acfa Chem. Scand., Ser. A, 1979, 33, 161. P. Demaree, M. C. Doria, and J. M. Muchowski, J. Heterocycl. Chem., 1978, 15, 1295. S. Crook, P. G. Jones, 0. Kennard, and P. Sykes, Chem. Ind. (London), 1977,840. K . Senga, M. Ichiba, and S. Nishigaki, J. Org. Chem., 1978, 43, 1677.

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

155

compound (248).342A similar reaction between 2,3,4,5-tetrahydro-l-tosylbenz[ llazepin-5-one semicarbazone and thionyl chloride gives the 1,2,3-thiazolo[5,4-d]benz[ llazepine (249).343

H YN\

Me

Me

Me

NO-N

\,A.

Ph

Ph

Me

'

N Ph

Partial desulp hurization of 3,4-dimethyl- 1-phenyl-6,6a-dithia- 1,2-diazapentalene (250; X = S) [cf. 'Aromatic and Heteroaromatic Chemistry' (Specialist Periodical Reports) Vol. 7, p. 861 with mercuric acetate gives the 6-oxa-analogue (250; X = 0),which couples with benzenediazonium tetrafluoroborate (with deformylation) to give 3,4-dimethyl-1,6-diphenyl-6a-thia-1,2,5,6-tetraazapentalene (25 l ) , probably via a 172,3-thiadiazoliumintermediate (252).344

1,2,3-Selenadiazoles.-The oxidation of the semicarbazones H2NCONHN=CR1CH2SO2R2(R' = H or aryl, R2 = aryl) with selenium dioxide gives the 1,2,3-selenadiazole (253; R', R2as before), but the semicarbazones HZNCONHN=CMeCH2S02Argive a mixture of (253; R' = Me, R2 = aryl) and (254).345 Treatment of 5-hydroxycyclo-octanone semicarbazone with selenium dioxide gives the cyclo-octa-l,2,3-selenadiazole(255), which can be decomposed thermally to the 5-hydroxycyclo-octyne346"and converted into the tricyclic 1,2,3-selenadiazoline derivatives (256).346b

Oxidation of the 4-quinazolinyl-thioureas (257 ; R = Me, Ph, or Ar), using iodine in chloroform, gives the 3,5-bis-(4-quinazolinylimino)-1,2,4-thiadiazolidines(258; R as before) in 70-91% yields,347and

1,2,4-Thiadiazoles.-Synthesis.

343 344

34s

'06

347

G. R. Proctor and B. M. L. Smith, J. Chem. SOC.,Perkin Trans. 1, 1978,862. R. M. Christie, D. H. Reid, R. Walker, and R. G . Webster, J. Chem. SOC.,Perkin Trans 1,1978,195. I. Lalezari, A. Shafiee, J. Khorrami, and A. Soltani, J. Pharm. Sci., 1978,67, 1336. ( a )H. Meier and-H2 Petersen, Synthesis, 1978,596; ( 6 )H. Peterson and H. Meier, Chem. Ber., 1978, 111,3423. W. Reid, 0. Moesinger, and W. Schuckmann, Justus Liebigs Ann. Chem., 1977, 1817.

156

Heterocyclic Chemistry

the action of iodine plus triethylamine on the thioamide PhC(OH)=C(CN)NHMe gives the 3,5 -bis(benzoylcyanomethyleno) - 1,2,4-t hiadiazolidine (259) (42°/0).348The structure of compound (258; R = 4-BrC&) has been confirmed by X-ray ~ r y s t a l l o g r a p h y .Oxidation ~~~ of 1-aroyl-2-thiobiurets, ArC(0)NHC(S)NHCONH2 (Ar = Ph, 2-C1C6H4, or 4-MeOC6H4), using hydrogen peroxide, gives the 1,2,4-thiadiazo1-3-ones (260; Ar as before).350The formation of the thiadiazole (66) in the reaction between the thiourea H,NC(Ph)=NC(S)NHPh and bromonitromethane has been described earlier (p. 121).82

NHPh 3

__ .i

.A T

N 4 *

PhN-

HN

Ph

,N,

-c

\

L

II

NPh

s-

Physical Properties. The 89-year-long controversy concerning the structure of ‘Hector’s Base’ has finally been resolved by means of X-ray crystallography. It has been shown to be 5-imino-4-phenyl-3-phenylamino-4H-l,2,4-thiadiazoline (261) in the crystalline state; in solution there could be a prototropic shift.”’ The structure of the 1: 1 adduct of ‘Hector’s Base’ with carbon disulphide (cf.ref, le, p. 438) has also been determined by this method, and shown to be a 1,2,4dithiazole-3-thione (262).352An investigation of the differences of the ‘H n.m.r. chemical shifts of a series of 2,4-disubstituted-3,5-dialkyl-or di-(ary1imino)1,2,4-thiadiazolidines in different solvents (e.g. C6D6, Ccl,) indicates that there is a linear correlation with either the Hammett or the Taft 348

349

3s* 351

352

353

H. Kunzek, E. Nesener, and J. Voigt, Z. Chem.. 1978. 18, 172. W. Schuckmann, H. Fuess, 0. Moesinger, and W. Reid, Cryst. Struct. Cummun., 1978, 7,571.

M. N. Basyouni and A. M. A. El-Khamry, Chem. Ind. (London), 1978,670. A. R. Butler, C. Glidewell, and D. C. Liles, J. Chem. Suc., Chem. Cummun., 1978, 652; Acta Crystallogr., Sect. B,1978, 34, 3241. A. R. Butler, C. Glidewell, and D. C. Liles, Acta Crystallogr., Sect. B, 1978,34, 2570. T. Kinoshita, S. Sato, Y. Furukawa, and C. Tamura, Nippun Kagaku Kaishi, 1978, 1256 (Chem. Abs., 1979, 90, 5735).

157

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

Chemical Properties. The cycloaddition reactions between 5-imino-A3-1,2,4thiadiazolines (263; R' = Me, Et, Me,CH, or Ph; R2 = Me, Me2CH, or Ph) and a series of heterocumulenes [CS,, R3NCS, R3NC0, R4C(0)NCS, and R3NCNR51all result in ring cleavage of (263) to give dithiazolidines (264) or thiadiazolidines (265).354Alkylation (using trialkyloxonium tetrafluoroborates) Ph

R'

R2N (264) Z

=S

or NCOR4

(265) Z = S, 0, or NR5

Me MetTN)R1 "S. N H R2

BF;

Me

MetT>CMe N" NH,

BF;

X-NH

H A 4S (273)

of the 1: 1 adducts of 5-imino-A2-1,2,4-thiadiazolines with nitriles, e.g. (266; R' = Me or Ph) gives the 5-imino-A2-1,2,4-thiadiazolines (267; R' as before, R2 = Me) via a bond switch at the .rr-hypervalent sulphur of the intermediate (268; R', R2as before). Further alkylation of (267) with R;0' BF4- (R3= Me or Et) gives the meso-ionic salts (269; R' = Me or Ph, R2 = Me, R3 = Me or Et).355"A similar bond switch occurs on treatment of the 5-imino-A2-1,2,4thiadiazolines (270; R' = Me) with imino-ethers R2C(OEt)=NH (R2 = Me or Et), giving (266; R' = Me or Et). Protonation of (266; R' = Me) with HBF, is followed by tautomerism to the thermodynamically more stable salt (27 1).355b Nucleophilic substitution of 5-chloro-3-methylmercapto-1,2,4-thiadiazole, using tetra-acetylthioglucose, followed by deacetylation, gives the 5 -p-D-glucopyranosylmercapto-derivative (272).356 Condensed 1,2,4-thiadiazoles are obtained on treating the thiones (273; X = o-C6H4, CH=CMe, CMe=CHCO, or N=CMe) with aryl cyanates; e.g., 354 355

3s6

J. Goerdeler and W. Loebach, Chem. Ber., 1979,112, 517. ( a ) K. Akiba, S. Arai, and F. Iwasaki, Tetrahedron Lett., 1978, 4117; ( b ) K. Akiba, S. Arai, T. Tsuchiya, Y. Yamamoto, and F. Iwasaki, Angew. Chem., Int. Ed. Engl., 1979, 18, 166. G . Wagner and B. Dietzsch, Pharmazie, 1978,33, 764.

158

Heterocyclic Chernistry

benzimidazoline-2-thionereacts with phenyl cyanate to give 3-phenoxybenzimidazo[ 1,2-d]-1,2,4-thiadiazolidine(274).357 Oxidation of the 1-(2-pyridyl)-thioureas (275; R = OH, OEt, or NH2) with bromine gives the 1,2,4-thiadiazolo[2,3-a]pyridines (276; R as before).358

1,2,4-Selenadiazoles.-A facile synthesis of 3,5 -diaryl- and 3,5-bis(heteroaryl)1,2,4-selenadiazoles (277; R = aryl or heteroaryl) is by oxidation (by iodine in methanol) of the selenoamides RCSeNH2.359 1,3,4-Thiadiazoles.-Synthesis. Further examples of the formation of 1,3,4thiadiazoles by acid cyclization of acyl-thiosemicarbazides have been reported,360 and compounds (278; R’ = R2 = NHAr) are obtained as the sole products in the acid-catalysed reaction of the hydrazone 4(NH2S02)C6H4NHN=C(COMe)2 with aryl-thiosemicarbazides, due to the preferred autocondensation of the latter.361

(281)

(282)

(283)

The amine-catalysed reaction of NN’-thiocarbonyl-di-imidazole(279) with diazomethane gives 2-(l-imidoyl)-l,3,4-thiadiazole(278; R’=H, R2 = 1i m i d ~ y l )The . ~ ~reaction ~ of methyl dithiocarbazates (280) with cyanogen iodide gives 2-alkylmercapto-5-imino-A2-1,3,4-thiadiazolines (281; R = l-s-tria ~ i n y l ) and , ~ ~ the ~ thiosemicarbazides (282; R = Me or Ph) react with diiodomethane to give the A2-1 ,3,4-thiadiazolinium salt (283; R as before).364 357

358

359 “O

361

362 363

364

D. Martin, A. Wenzel, and R. Bacaloglu, J. Prakt. Chem., 1978, 320, 677. B. Vercek, B. Stanovnik, and M. Tisler, Heterocycles, 1978,11, 313. V. I. Cohen, Synthesis, 1978, 768. ( a )L. I. Shevchenko, A. D. Grabenko, and P. S. Pel’kis, Ukr.Khim. Zh., 1978,44,840 (Chem.Abs., 1979,90, 6057); ( b ) P. K. Sengupta, M. R. Ray, and S . S. Chakravorti, Indian J. Chem., Sect. B, 1978,16,231;( c )S. Giri, H. Singh, L. D. S. Yadav, and R. K. Khare, J. Zndiun Chem. Soc., 1978,55, 168. R. M. Shafik, A. A. B. Hazzaa, and F. S. G . Solirnan, Pharmazie, 1978,33,237. A. Martvon, L. Floch, and S. Sekretar, Tetrahedron, 1978, 34, 453, V. V. Dovlatyan and R. A. Gevorkyan, Arm. Khim. Zh., 1978, 31, 85 (Chem. Abs., 1979, 90, 152 131). W. Reid and 0. Moesinger, Chem. Ber., 1978, 111, 155.

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

159

A detailed account of the cycloaddition reactions of sulphines Ar,C=S=O and diphenylnitrilimine Phc=N-NPh, giving A2- 1,3,4-thiadiazoline S-oxides (284), has appeared (cfi ref. lc, p. 693). There is a high degree of regiospecificity (in the case of thiofluorene S-oxide, a A3-1,2,3-thiadiazoline S-oxide was obtained as a by-product), but the reactions are non-stereospecific, due to equilibration of the adducts via a ring-opening-ring-closure mechanism (Scheme 6).365 Ph

+

. / Ph

t/

PhC =N-NPh

N”

+

Ar,SO (284)

-0

Scheme 6

Physical Properties. The dipole moments of 14 classes of meso-ionic heterocycles (including 2-imino- 1,3,4-thiadiazolines) have been measured; vector analyses of these support the formulations for the The 15Nn.m.r. spectra of some 1,3,4-thiadiazoles and A*-1,3,4-thiadiazoline-5-thioneshave been d e ~ c r i b e d , ~as ~ ’ has the crystal structure of 5,5’-dithiobis-(3-methyl-1,3,4thiadiazoline-2- thione).368 Chemical Properties. 2-Amino-l,3,4-thiadiazoles react with acrylonitrile to give the 2-(2-~yanoethyl)aminoderivatives;’ l4 with 2-arylbenzoxazin-4-ones to give the quinazolin-4(3H)-ones (285);369with 2-hydroxymethylene-3-0x0-steroids and 16-hydroxymethylene- 17-0x0-steroids to give a 2’-thiocyanatopyrimidine ring fused to the 2,3 or 16,17 positions of the steroid nucleus, e.g. (286);370with methoxycarbonyl isocyanate to give thioureas that, after S-alkylation, may be thermalized to give 1,3,4-thiadiazolo[3,2-a]-1,3,5-triazin-5 -ones (287);371and with arenesulphonyl halides to give the corresponding s ~ l p h o n a m i d e s . ~ ~ ~

365 366

367 368

369 370 371

372

B. F. Bonini, G. Maccagnani, G . Mazzanti, L. Thijs, G . E. Veenstra, and B. Zwanenburg, J. Chem. SOC.,Perkin Trans. 1, 1978, 1218. R. N. Hanley, W. D. Ollis, C. A. Ramsden, G . Rowlands, and L. E. Sutton, J. Chem. SOC.,Perkin Trans. 1, 1978,600. K. L. Williamson and J. D. Roberts, Heterocycles, 1978, 11, 121. S. Larsen, Acta Crystallogr,, Sect. B,1978,34, 3803. S. S. Tiwari and R. K. Satsangi, J. Indian Chem. SOC.,1978, 55,477. J. S. Bajwa and P. J. Sykes, J. Chem. SOC.,Perkin Trans. 1, 1978, 1618. F. Russo, M. Santagati, and A. Santagati, Farmaco, Ed, Sci., 1978, 33, 26 (Chem. Abs., 1978, 88, 152 506). K. C. Joshi and V. K. Singh, Pharmazie, 1978,33, 254.

160

Heterocyclic Chemistry

Thermolysis of A3-1 ,3,4-thiadiazolines (288) gives the corresponding thiirans, which may be converted into ~ e c o - s t e r o i d s ,and ~ ~ ~the A3-1,3,4-thiadiazoline (289), prepared by the reaction of the pyrazoline (290; X = S) with (290; X = N2), decomposes thermally and gives, after desulphurization, the highly crowded alkene (291).374

1,3,4-Thiadiazolium salts containing electron-withdrawing groups at C-2, e.g. (292; R' = 4-N02C6H4,R2 = Ar, X = Cl), react with alcohols or amines to give 5-substituted-A2-1,3,4-thiadiazolines(293; R', R2 as before, R3 = OR or NR2),375and (292; R' = Ar, R2 = Me, X = I or MeS04) reacts with aldehydes to give acyloins, via the intermediates (293; R1, R2 as before, R3 = COAr), in a similar manner to thiazolium

Condensed 1,3,4-Thiadiazoles.-The reactions of 2-amino- 1,3,4-thiadiazoles with alkyl or aryl i ~ o c y a n a t e or s ~i~s o~ t h i ~ c y a n a t e sgive ~ ~ ~1,3,4-thiadiazolo[3,2a]-l,3,5-triazine derivatives, e.g. (294), and with DMAD378or malonic esters379 give 1,3,4-thiadiazolo[3,2-a]pyrimidin-5-ones,e.g. (295). 1,3,4-Thiadiazolo[3,2-a]pyrimidines are also formed by the reaction of 3-amino-6-substituted2-thiouracils with ~ r t h o e s t e r s ,or ~ ~by ~ cyclodehydration of 3-acylamino-2thiouracils. 38'

1,3,4-!3elenadiazoles.-2,5 -Diaryl- and 2,5 -diheteroaryl- 1,3,4-~elenadiazoles are readily obtained on treatment of selenoamides RC(Se)NH2with hydrazine, but not from the selenone esters RC(Se)OEt, the products in this case being the azines RC(OEt)=N-N=C(OEt)R.382 373

374

37s 376

377

378

379 380

381 382

D. J. Humphreys, C. E. Newall, G. H. Phillipps, and G. A. Smith, J. Chem. Soc., Perkin Trans. 1, 1978, 45. R. J. Bushby, M. D. Pollard, and W. S. McDonald, Tetrahedron Lett., 1978, 3851. G. Scherowsky and H. Matloubi, Justus Liebigs Ann. Chem., 1978, 98. A. Alemagna and T. Bacchetti, Gazz. Chim. Ital., 1978, 108, 77; J. Heterocycl. Chem., 1978, 15, 1515. F. Russo, M. Santagati, A . Santagati, and R. Arrigo Reina, Farmaco, Ed. Sci., 1978,33,972 (Chem. Abs., 1979,90, 103 925). S. Herrling, Ger. Offen. 2 712 932/1978 (Chem. Abs., 1979,90, 38 957). F. S. G. Solirnan, A . A. B. Hazzaa, and S. A . Shams El-Dine, Pharmazie, 1978,33, 713. T . Tsuji and Y.Otsuka, Chem. Pharm. Bull., 1978,26, 2765. D. Heydenhauss, G. Jaenecke, H. Voigt, and F. Hofmann, 2. Chem., 1 9 7 8 , 1 8 , 6 6 . V. I. Cohen, J. Heterocycl. Chem., 1979, 16, 365.

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

161

1,2,5=Thiadiazoles.-Synthesis. 1,2-Bis(trimethylsilyl)imines, A r c (=NSiMe3)C(=NSiMe3)Ph (Ar = 4-C1C6H4or 4-MeOC6H4),which are obtained by the reaction of aryl a-diketones with sodium di-(trimethylsilyl)amide, react with sulphur dichloride to give the 1,2,5-thiadiazoles (296; Ar as above).383 The formation of 3-(substituted amino)-isothiazoles by the reaction of 3-methoxy- or 3-chloro-isothiazolium salts with ammonia has been extended to the 1,2,5thiadiazole Treatment of the amine hydrochlorides NH2CH2CONHR.HCl (R = Me, Pr", Ph, PhCH2, or n-dodecyl) with disulphur dichloride gives compounds (297; R as before) which react with methyl fluorosulphonate or phosphorus oxychloride to give the salts (298; R as before, R' = OMe or Cl); these, with excess of ammonia, undergo ring-opening-ringclosure, giving the products (299; R as b e f ~ r e ) . ~ '

The optimum yield (16%) of the 1,2,5-thiadiazolidine 1,l-dioxide (300; = R2 = But) is obtained when Bu'NH(CH~)~NHBU' and sulphuryl chloride react at -50°C. The t-butyl groups may be removed on treatment with trifluoroacetic acid at room temperature, giving the mono- and un-substituted compounds (300; R1 = H, R2 = But) and (300; R' = R2 = H).384

R'

Physical Properties. Nitrogen-14 n.m.r. studies on 1,2,5-thiadia~ole,~~' and on have been described. Doublesome of its derivatives, including 1 resonance modulation microwave spectroscopy has yielded structural informaA mass spectral tion on 1,2,5-thiadiazole and its 3,4-dideuterio-analog~e.~~' investigation of 2,5 -diaryl-1 -(arylimino)- 1A 4,2,5-thiadiazoline-3,4-diones(301; R' = R2 = Ph, 4-MeC6H4, 4-ClC&, or 4-BrC6H4; X = NR') suggests that some rearrangement to (302) and (303) occurs prior to fragmentation,388nand the same investigators observed that (301; R' = R2 = But; R' = But, R2 = Ph; X = 0 or absent) fragmented by loss of the t-butyl group(s) prior to cleavage of the heterocyclic ring.3886

Y .s' \\

X (302) X = N R ' , Y = 0 (303) x = 0, Y = NR' 383 384

385

386

H. Buchwald and K. Ruehlmann, J. Organomet. Chem., 1979,166,25. M. Preiss, Chern. Ber., 1978, 111, 1915. 0. L. Stiefvater, 2.Naturforsch., Teil A , 1978,33, 1518. M. Witanowski, L. Stefaniak, A. Grabowska, and G . A. Webb, Spectrochim. Acta, PartA, 1978,34,

877. 387

388

0. L. Stiefvater, 2.Naturforsch., Teil A , 1978, 33, 1511. ( a )R. Neidlein, P. Leinberger, and A. Hotzel, Org. Mass Spectrorn., 1977,12,628; ( b )Arch. Pharm. (Weinheim, Ger.), 1978, 311, 520.

He teroc y cZic Chemistry

162

2,1,3-Benzothiadiazolesand 2,1,3=Benzoselenadiazoles.-PhysicaZ Properties. The polarized electronic and electric field absorption spectra (So + S,) of 2,1,3benzothiadiazole at 4.2 K have been obtained; they indicate that the S1 state has B2 symmetry, similar to the selenium analogue.389The I5N n.m.r. spectra of benzofurazan and its sulphur and selenium analogues have been recorded, and the high-field 15N resonance of the sulphur heterocycle has been discussed in terms of significant contributions of sulphur-di-imide-type resonance struct u r e ~Positive. ~ ~ ~ and negative-ion mass spectra of the oxa-, thia-, and selena2,1,3-benzo-diazoles have been obtained, and the influence of the Group VI heteroatom on the fragmentation modes of these heterocycles is Chemical Properties. Photolysis of 2,1,3-benzothiadiazole 2-oxide (304) in ethanolic solution produces 2,1,3-benzothiadiazoline1,l-dioxide (305),via the 2,1,3-benzothiadiazole l-oxide (306). There is some spectral evidence for the reversible formation of the short-lived intermediate (307).392

2,1,3-Benzoselenadiazole reacts with benzyne to give the benzisoselenazole (308; R = cis,cis- and cis,trans-CH=CHCH=CHCN) whereas with DMAD it gives dimethyl quinoxaline-2,3-dicarboxylatetogether with selenium. The sulphur analogue gives similar products in low yields. Possible mechanisms for the formation of (308) are shown in Scheme 7.393

q 1

e

\

Scheme 7 389

390 391 392

393

T. S.Lin and J. R. Braun, Chem. Phys., 1978,28,379. I. Yavari, R. E. Botto, and J. D. Roberts, J. Org. Chem., 1978, 43, 2542. M. R. Arshadi, Org. MassSpectrom., 1978,13, 379. C. L. Pedersen, C. Lohse, and M. Poliakoff, Acta Chem. Scand., Ser. B, 1978,32,625. C. D. Campbell, C. W. Rees, M. R. Bryce, M. D. Cooke, P. Hanson, and J. M. Vernon, J. Chern. Soc., Perkin Trans. 1, 1978, 1006.

163

Fiue-membered Rings ; Systems containing N and S, Se, or Te

A novel insertion of a platinum atom into one of the N-S bonds of 5,6dimethyl-2,1,3-benzothiadiazoleon reaction with [(Ph3P)2Pt(C2H4)]gives the complex (309), whose crystal structure has been determined. The bond distances in the six-membered heterocyclic ring indicate considerable delocalization of

1,2,5-Thiadiazolo[3,4-g]benzofurazan.-This compound (310) has been obtained in a four-step synthesis starting from 4,7-dibromo-5-nitro-2,1,3benzothiadiazole.395 16 Dithiazoles and Diselenazoles

1,2,3-Dithiazoles.-l,2,3-Benzodithiazolium salts are obtained on allowing aromatic amines to react with disulphur dichloride; e.g., aniline gives compound (311).396 The 1,2,3-benzodithiazole derivative (312) equilibrates in benzene solution with the open-chain compound 2,4,6-tri-t-butyl-N-thiosulphinylaniline(313; Z = S); dipole-moment studies of the equilibrium mixture and of (313; 2 = S)(1.5 D) enabled the dipole moment of (312) (3.0 D) to .be determined.397" Oxidation of the equilibrium mixture with 3-chloroperbenzoic acid gives the S(1)-oxideof (312), (313; Z = 0),and (314);the last appears to be formed via a retro-ene reaction of the S(2)-oxideof (312), whose intermediacycan be detected using n.m.r.

c1(313)

(3 14)

1,2,4-Dithiazoles.-The oxidation of thiobenzamide by iodine or the addition of hydrogen sulphide to an iodine-benzonitrile mixture gives the 3,5-diphenyl1,2,4-dithiazolium salt (31 9 , probably via the intermediate (316).398The 3,5-di(substituted imino)-1,2,4-dithiazolidines(317; R = Et or Ar) are prepared by 394

395 396 397

398

R. Meij, D. J. Stufkens, K. Vrieze, A. M. F. Brouwers, and A. R. Overbeek, J. Orgunornet. Chem., 1978,155,123. .f.. Uno, K. Takagi, and M. Tomoeda, Chem. Pharm. Bull., 1978,26,3896. R. Mayer, S. Bleisch, and G. Domschke, 2.Chem., 1978,18, 323. ( a ) Y. Inagaki, R. Okazaki, and N. Inamoto, Heterocycles, 1978,9, 1613; ( 6 ) Chem. Lett., 1978, 1095. I. Shibuya, Nippon Kagaku Kaishi, 1979,389 (Chem, Abs., 1979,90,186 869).

164

Heterocyclic Chemistry

the oxidative debenzylation (by Br2) and simultaneous ring closure of isodithiobiurets, ArCH,SC(=NPh)NHC(S)NHR (R as before),399 whilst N-aryl derivatives of (317; R = Ar) are obtained on allowing symmetrical diarylthioureas to react with the imine C1C(SC1)=NPh.400 The 1,l-adduct of 'Hector's Base' with carbon disulphide has been shown to be a 172,4-dithiazol-3-thione (262).352 The 1,2,4-dithiazolium salt (315) reacts with ammonia to give 3,s-diphenyl1,2,4-thiadia~ole,"~with hydroxylamine to give 3,s -diphenyl- 1,2,4-0xadiaz01e,~~' with hydrazine to give 3,5-diphenyl-1,2,4-tria~ole,~~* and with arylhydrazines to give 1-ary1-3,5-diphenyl-l,2,4-tria~oles.~~'

1,3,2-Benzodithiazoles.-The reaction between toluene-3,4-bis(sulphenyl chloride) and amines under high-dilution conditions gives compounds (318; R = Ph, PhCH2, Me& anisyl, or 2 - b e n ~ o t h i a z o l y l ) . ~ ~ ~

NR

Ph PhC (=NH) S -SC(=NH)P h (316)

H N 4

PhN

1,4,2-Dithiazoles.-Compounds of this class may be obtained either by the reaction of 2-aryl-acetylene-1 -sulphonamides ArC=CSO2NH2 with carbon disulphide under strongly basic conditions, followed by subsequent methylation to give (319; R' = SMe, R2 = Ar), or by treatment of 2-bromostyrene to give (319; R' = SMe, R2 = Ar),or by treatment of 2-bromostyrene-2-sulphonamide with isothiocyanates under similar conditions, giving (319; R1 = NHR, where R = alkyl or aryl, R2 = Ph).403 1,2,4-Dise1enazoles.-A3-1,2,4-Diselenazolines (320; R = NMe2 or Ar) are obtained on heating N-perfluoroisopropylideneureas or carboxamides with diphosphorus pentaselenide or by the reaction of perfluoroacetone with

399

4nn 4n1 4n2 403

R . Singh and V. K. Verma, J. Indian Chem. SOC.,1977, 54, 908. N. M. Nimdeoka and M. G. Paranjpe, Indian J. Chem., Sect. B, 1977,15, 1068. J. Liebscher, East Ger. P. 129 908/1978 (Chem. A h . , 1978,89, 109 514). C. H. Chen and B. A. Donatelli, J. Heterocycl. Chem., 1979, 16, 183. K. Hasegawa, S. Hirooka, H. Kawahara, A. Nakayama, K. Ishikawa, N. Takeda, and H. Mukai, Bull. Chem. SOC.Jpn., 1978,51, 1805.

165

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

selenoamides RSeNH2. The reaction of (320; R = NMe2)with t-butyl isocyanide gives the selenazoline (321), and with the acetylene MeC=CNEt2 it gives the selenazine (322).404

17 Oxathiazoles and Selenathiazoles 1,2,3-Oxathiazoles.-The reaction between methanesulphonyl azide and ketenimines Me2C=C=NAr gives the oxathiazolines (323), and not the diaziridines (324), as reported previously.4o5 ArN

ArN-NS0,Me

K

CMe,

H S RZ N > 0O

N

The biotin analogues [325; R = H, C02Me, or (CH2)4C02Me]have been prepared by the reaction of 4-amino-2-hydroxy-thiophaneswith thionyl 13CN.m.r. spectroscopy of some 3-aryl-l,2,3-oxathiazoline2-oxides indicates that some of the 13Cchemical shifts are appreciably influenced by the conformation of the heterocyclic ring.4o71,2,3-0xathiazolo[4,5-d]-1,2,3-oxathiazole 2,2,5,5-tetroxide (326) has been obtained by the cycloaddition of sulphur trioxide to dicyanogen. Its structure has been determined by X-ray crystallo-

graph^.^" 1,3,2-Oxathiazoles.~-Phenyl-1,3,2-oxathiazolylium-5-olate (3) reacts with dibenzoylacetylene to give 3,4-dibenzoyl-5-phenylisothiazole.” Photolysis, at 10-15 K, of (3) (and of 5-phenyl-1,3,4-oxathiazol-2-one, of 5-phenyl-1,3,4dithiazole-2-thione, and of 5-phenyl- 1,2,3,4-thiatriazole) gives phenylthiazirine; this is stable at this temperature but, on warming, it rearranges to phenyl isothiocyanate, which then decomposes to benzonitrile and Photolysis in the presence of DMAD gives the isothiazole (2; R = Ph) as evidence of the formation of phenyl i ~ o t h i o c y a n a t e . ~ ~ ~ ’ 1,2,4-Oxathiazoles.-The 1,2,4-oxathiazolidines (327), obtained from the 1,3dipolar cyloaddition of thioketen S-oxides to azomethines, can be obtained crystalline, but they are unstable, and rearrange to the oxazolidine-thiones (328).41 404 405

406

407 408

409

410

K. Burger and R. Ottlinger, Tetrahedron Lett., 1978, 973. G . L’AbbC, C. C. Yu, J. P. Declercq, G . Germain, and M. Van Meerssche, Angew. Chem., Int. Ed. Engl., 1978, 17,352. T. M. Filippova, S. D. Mikhno, N. S. Kulachkina, I. G. Suchkova, and V. M. Berezovskii, Tezisy Doklady Vses. Konf. Stereo Khim. Konform. Anal., Org. Neftekhim. Sint., 3rd, 1976,97 (Chem. Abs., 1978, 89, 24 201). T. Nishiyama, T. Mizuno, and F. Yamada, Bull. Chem. SOC.Jpn., 1978, 51, 323. H. W. Roesky, N. Amin, G. Remmers, A. Gieren, U. Riemann, and B. Dederer, Angew. Chem., Inr. Ed. Engl., 1979, 18, 223. ( a ) A. Holm,N. Harrit, and 1. Trabjerg, J. Chem. SOC.,Perkin Trans. 1, 1978,746; ( b )A. Holm and N. H. Toubro, ibid., 1978, 1445. E. Schaumann, J. Ehlers, and U. Behrens, Angew. Chem., Int. Ed. Engl., 1978, 17,455.

166

Heterocyclic Chemistry

1,3,4-Oxathiazoles.-Physical chemical experiments (microwave, i.r. and Raman spectroscopy, and electron diffraction) have established that gaseous 1,3,4oxathiazol-2-one (329) is essentially planar.411

1,3,5-Oxathiazoles.-The reaction between sulphonyl isothiocyanates RS02NCS and aryl cyanates ArCNO gives 1,3,5-oxathiazolines (330) in good yields.412 NckCF3

1,2,4-Thiaselenazo1es.-A4- 1,2,4-thiaselenazolines(33 1) may be obtained (7 186%) on treatment of the thiazetes (332) with diphosphorus p e n t a ~ e l e n i d e . ~ ' ~ The reaction of (331) with trimethyl phosphite gives the thiazaphospholines (333); with the acetylene MeCECNEt,, (33 1) gives the 1,3-thiazines (334).4'3 18 Miscellaneous Ring Systems

1,2,3,4-Thiatriazoles.-5-Arylimino- 1,2,3,4-thiatriazoles (335; R = ArNH) are obtained when aryl-thiosemicarbazides ArNHC(S)NHNH2 react with nitrous acid414 and with benzenediazonium f l u o r ~ b o r a t e ,or~ ~on ~ treatment of trimethylsilyl azide with aryl i s o t h i ~ c y a n a t e sThe . ~ ~5-(l-imidoyl)-derivative ~ (335; R = 1-imidoyl) is obtained quantitatively when compound (279) reacts with trimethylsilyl azide and t h i ~ p h o s g e n eThe .~~~ thermal decomposition of (335; R = Ph) has been investigated further; at 50--60°C the products are benzonitrile, sulphur, and nitrogen, whilst phenyl isothiocyanate is obtained above

Rr-.\ N s

N,Y

Rk 41 1

412

413 414 415 416

R2N

Nk-;

c1-

N-9 A r k o/so2

B. Bak, 0. Nielsen, H. Svanholt, A. Almenningen, 0.Bastiansen, L. Fernholt, G. Gundersen, C. J. Nielsen, B. N. Cyvin, and S. J. Cyvin, Actu Chem. Scand., Ser. A, 1978, 32, 1005. K. Agihara, M. Mizuno, and A . Nakata, Japan. Kokai 77 148 076 (Chem.Abs., 1978,88,1.52625). K. Burger and R. Ottlinger, Synthesis, 1978,44. A . Wahab and R. P. Rao, Boll. Chim.Farm., 1978,117, 107 (Chem. Abs., 1 9 7 8 , 8 9 , 2 1 5 306.). B. Stanovnik, M. Tisler, and B. Valencic, Org. Prep. Proced. Int., 1978, 10, 59. H. Vorbrueggen and K. Krolikiewicz, Synthesis, 1979, 35.

Five-membered Rings : Other Systems

167

100 “C, by rearrangement of the intermediate thiobenzoyl azide PhCSN3.417 Alkylation of the thiatriazoles (335; R = MeNH, EtNH, or 4-MeC6H4S02NH) with trialkyloxonium tetrafluoroborates gives the previously unknown 4-alkyl-5alkylimino-1,2,3,4-thiatriazolines(336; R’ = Me or Et; R2 = Me, Et, or 4MeC6H4S02),which decompose thermally to give carbodi-imides R’N=C=NR2 (R’, R2 as before).418The compounds (336; R1 = Me or Et, R2 = alkyl or aryl) act as masked 1,3-dipoles, and undergo cycloaddition reactions with electron-rich a1kenes or he t e r o a n n u l e n e ~8*41 .~~

1,2,3,5-DithiadiazoIes.-The reaction between trichlorotrithiatriazine and the azines RCH=N-N=CHR (R = Ph or Me3C) gives the 1,2,3,5-dithiadiazolium salts (337; R as b e f ~ r e ) . ~ ”

1,3,2,4-Dioxathiazoles.-The cycloaddition reaction between aryl cyanates and sulphur trioxide at -15 “C gives the dioxathiazoles 2,2-dioxides (338).421

PART 111: Other Five-membered Ring Systems by G. V. Boyd

1 Introduction This Part deals with the remaining heterocyclic compounds containing fivemembered rings. Monocyclic systems, their benzo-analogues, and other annelated heterocycles, such as cyclohepteno-compounds 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 oxo-derivatives follow, and completely hydrogenated compounds are discussed at the end. 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. The scope of the present Part is so great that the Reporter had to be severely selective: only two-thirds of the more than 900 interesting articles noted initially are mentioned, and these only briefly. The reader is referred to the original sources, where he will find further information and a wealth of fine chemistry. 417 418

‘19

420

421

A. Holm, L. Carlsen, and E. Larsen, J. Org. Chem., 1978, 43,4816. N. H. Toubro and A. Holm, J. Chem. SOC.,Perkin Trans. I, 1978, 1440. (a)G. L’AbbC, A. Timmerman, C. Martens, and S.Toppet, J. Org. Chem., 1978,43,4951; ( 6 ) G. L’Abb6, A. Van Asch, J. P. Declercq, G. Germain, and M. Van Meerssche, Bull. SOC. Chim.Belg., 1978, 87, 285. H. W. Roesky and T. Mueller, Chem. Ber., 1978,111, 2960. I. V. Bodrikov, V. L. Krasnov, and N. K. Tulegenova, Zh. Org. Khim., 1978,14,2231 (Chem. Abs., 1979,90, 87 359).

Heterocyclic Chemistry

168

2 Reviews There have been reviews on the base-induced ring-opening of five-membered heterocyclic compounds,1 the chemistry of isobenzufurans,*the use of A2-1 ,2,3triazolines as synthetic intermediate^,^ the mechanism of the Fischer indole ~ y n t h e s i sisatogens ,~ and in do lone^,^ indazol-3-01s and 1,2-dihydro-3H-indazol3-ones ( 1),6 five-membered meso-ionic system^,^ and the synthesis of heterocyclic compounds containing one nitrogen atom via nitrenes.' Three reviews are general, concern heterocyclic analogues of pentalene (2); the first while the third" is restricted to dipolar systems such as (3) and (4). The chemistry of pyrrolo[ 2,3-c]quinoline (5),' p yrrolo[ 3,4- blquinoline ( 6 ) , te trahydro- y~ a r b o l i n e , and ' ~ 1,2,4-tria~ino-indoles~~ has been surveyed.

(3)

(4)

' 'N 3 Systems with One Heteroatom, and their Benzo-analogues

Furans.-Formation. The perfluorinated furan derivative (7) has been prepared from the olefin C,F,C(CF,) =C( CF,)CF( OMe)CF3.l 6 Treatment of 1,2,3,4-te traphenylbut-2-ene-1,4-dione,PhCOCPh=CPhCOPh, with triethyl phosphite yields tetraphenylf~ran.'~ New syntheses of acyl-furans are the formation of the

' S. Gronowitz and T. Frejd, Khim. Geterotsikl. Soedin., 1978, 435. M. J. Haddadin, Heterocycles, 1978,9, 865. J. Bourgeois, M. Bourgeois, and F. Texier, Bull. SOC.Chim. Fr. Part 2, 1978, 485. ( a ) R. Fusco and F. Sannicolo, Khim. Geterotsikl. Soedin., 1978, 200; ( b ) R. Fusco, Chim. Ind. (Milan), 1978,60, 903. S . P. Kiremath and M. Hooper, Adu. Heterocycl. Chem., 1978, 22, 123. ' L. bdiocchl, Ci. Corsi, and G. Palazzo, Synthesis, 1978,633. K. T. Potts, Lect. Heterocycl. Chem., 1978,4, 35 (J. Heterocycl. Chem., 1978,15, S-35). V. P. Semenov, A. N. Studenikov, and A. A. Potekhin, Khim. Geterotsikl. Soedin., 1978, 291. ' H. Volz and H. Kowarsch, Heterocycles, 1977,7, 1319. J. Elguero, R. Claramunt, and A. J. H. Summers, Ado. Heterocycl. Chem., 1978, 22, 183. '' C. A. Ramsden, Tetrahedron, 1977,33, 3203. '* M. A. Khan and J. Ferreira da Rocha, Heterocycles, 1978, 9, 1617. l 3 M. A. Khan and J. Ferreira da Rocha, Heterocycles, 1978, 9, 1059. l4 A. N. Kost, M. A. Yurovskaya, and F. A. Trofimov, Usp. Khim. Geterotsikl., 1976, 171. l5 W. A. Romanchick and M. M. Joullie, Heterocycles, 1978,9, 1631. l 6 R. D. Chambers, A. A. Lindley, P. D. Philpot, H. C. Fielding, J. Hutchinson, and G. Whittaker, J. Chem. SOC.,Chem. Commun., 1978,431. " M. J. Haddadin, B. J. Agha, and R. F. Tabri, J. Org. Chem., 1979,44,494.

169

Five-membered Rings : Other Systems

3-acetyl derivative (8)from acetylacetone and 2-nitropropene in the presence of potassium fluoride" or by heating the bromo-olefin (MeCO),C=CHCHBrMe," and the conversion of 2,4,6-trimethylpyrylium fluoroborate (9) into 2-acetyl-3,5dimethylfuran (10) by the action of superoxide ion (Oj).'" The sodium enolate of Me

F3C

CF,

R O 0W ,

Me@:' 0

(8) R' R' (10) R' R'

(7) R = C F 3 (15) R = F

0

Me\+

(13)

o

BF; (11)

=Me = AC =Ac = Me

1 M e 0 2 C Ac

CN Et02CCH

Meo2CHA Ac CN

Me

M e O0 N H ,

2

R/C,, 0 (14) R=CF3 (16) R = F

cyanoacetone, obtained by the action of sodium ethoxide on 5-methylisoxazole, reacts with ethyl a-chloroacetoacetate to form the cyano-dione (1l ) , which cyclizes spontaneously to the 2-amino-furan (12);'l the amino-cyano-furan (13) is similarly formed by the action of ethyl y-chloroacetoacetate on malononitrile in the presence of triethylamine.22 The cyclopropenyl ketone (14) isomerizes to tetrakis(trifluoromethy1)furan(7) when heated to 250 "C with a trace of the reverse reaction (15) + (16) occurs on irradiati~n.'~Tetra-acetylcyclopropane (18) is similarly formed by photolysis of the triacetyldihydrofuran (17)." A detailed discussion of the vinyloxiran -+ dihydrofuran isomerization, e.g. (19) + (20), has been presented.26

Electrolysis of the acyl chloride PrCHMeCOCl in hydrogen fluoride yields, inter alia, the perfluorinated tetrahydrofuran (2l)." 1,4-Diols, such as

l9

'' 22 23 24 25

26

27

( a )T. Yanami, A . Ballatore, M. Miyashita, M. Kato, and A . Yoshikoshi, J. Chem. SOC.,Perkin Trans. 1,1978,1144;( b )M. Miyashita, T. Kumazawa, and A. Yoshikoshi, J. Chem. SOC.,Chem. Commun., 1978,362. R. A . Kretchmer and R. A . Laitar, J. Org. Chem., 1978,43,4596. S. Kobayashi and W. Ando, Chem. Lett., 1978, 1159. J. F. Blount, D. L. Coffen, and D. A. Katonak, J. Org. Chem., 1978,43,3821. T. Kato, H. Kimura, and K. Tanji, Chem. Pharm. Bull., 1978, 26,3880. C. J. Boriack, E. D. Laganis, and D. M. Lemal, Tetrahedron Lett., 1978, 1015. R. D. Chambers, A. A. Lindley, and H. C. Fielding, J. Fluorine Chem., 1978,12, 337. T. Sakai, Y. Kubo, andT. Hanafusa, J. Org. Chem., 1978, 43,3076. W. Eberbach and B. Burchardt, Chem. Ber., 1978,111,3665. T. Abe, K. Kodaira, H. Baba, and S. Nagase, J. Fluorine Chem., 1978, 12, 1.

170

Heterocyclic Chemistry

HOCBu2CH2CH2CH20H,give tetrahydrofurans, e.g. (22), on treatment with

NN-diethylphosphoramidic dichloride, Et2NPOC12.28The allenic ether (23) cyclizes to the spiro-compound (24) in the presence of crown The oxonium salt (25) is obtained by the action of pivaloyl fluoroborate on the olefin Bu'CMe=CH2 in a general reaction of acyl fluoroborates with a l k e n e ~ . ~The ' thermal rearrangement of 2,7-diphenyltropone 2.3-oxide (26) to the oxabicyclooctadienone (27) has been reported.3' F

F +M

Me% 'HO

e

o

w

MeO+Me

(31)

(32)

Quantitative yields of y-methylenebutyrolactones (28) are obtained by heating acetylenic acids R1CzCCHR2CR2R3CO2Hwith a catalytic amount of mercury(I1) Graminin A, a new toxic metabolite isolated from Cephalosporium gramineum Nisikado et Ikata, has structure (29).33 The combined action of nickel(cyc1o-octa-1,5-diene)2and pyridine on diphenylketen results in the complex [Ni(pyridine),(Ph,C=CO),], which is transformed into compound (30) by carbon monoxide.34Lactides (31; R1, R2,R3 = alkyl) undergo ring-contraction to the furan-diones (32) on treatment with sodium h ~ d r i d e . ~ ~

*' 29

3n

31

32 33 34

3s

H.-J. Liu, W. H . Chan, and S. P. Lee, Heterocycles, 1978,11, 261. D. Gange and P. Magnus, J. A m . Chem. SOC.,1978,100,7746. 0 . V. Lyubinskaya, V. A. h i t , A. S. Shashkov, V. A. Chertkov, M. L. Kanishchev, and V. F. Kucherov, Izu. Akad. Nauk SSSR, Ser. Khim., 1978,397. T. Tezuka, M. Shinba, T. Abe, R. Miyamoto, and T. Mukai, Heterocycles, 1978,11, 149. M. Yamamoto, J. Chem. Soc., Chem. Commun., 1978,649. K. KobayashiandT. Ui, J. Chem. SOC., Chem. Commun., 1977,774. H. Hoberg and J. Korff, J. Organomet. Chem., 1978,152, C39. U. Schollkopf, W. Hartwig, U . Sprotte, and W. Jung, Angew. Chem. Int. Ed. Engl., 1979,18, 310.

171

Five-membered Rings : Other Systems

The cyclo-co-oIigomerization of 1,3-butadiene with N-methylfurfuraldimine in the presence of nickel complexes affords an 8 i 2 mixture of compound (33) and the macrocycle (34).36The synthesis of the diamides (36; n = 2, 3, or 6) from X-Ray diamines H2N(CH2),NH2and the acid chloride (35) has been de~cribed.~' structure analysis of [2.2][2,5]furano( 1,4)naphthalenophane (37) reveals that ~~ the quaternary hydroxide (38) generates the ring A is b o a t - ~ h a p e d .Heating transient intermediate (39), which dimerizes in a head-to-head and head-to-tail fashion; hydrogenation leads to [6.2](2,5)- and [4.4](2,5)-furanophanes (40) and (41), re~pectively.~~ The 'cross-breeding' co-dimerization of the intermediates (42) and (43) yielded a mixture of compounds (44)-(46); the last isomerized to the furanophane (45) above 135 "C. The furan compounds were converted into the corresponding pyrrolophanes by hydrolysis and subsequent treatment with ammonia.4o

S (33) R = 2-fury1

(34) R = 2-fury1

(35) R=C1 (36) R-R =-NH(CHz),NH-

(37)

(40) n = 2, rn = 6 (41) n = r n = 4

(44)

U. M. Dzhemilev, L. Yu. Gubaidullin, and G . A. Tolstikov, Im. Akad. Nauk SSSR, Ser. Khim., 1978,2557. s7 S . A. Vartanyan, T. R. Akopyan, and E. G. Paronilfyan, Arm. Khim. Zh., 1978,31,349 (Chem.Abs., 1978, 89, 109 427). ' M. Corson, B. M. Foxman, and P. M. Keehn, Teiahedron, 1978,34, 1641. ' S. H. Kuesefoglu and D. T. Longone, Tetrahedroh Lett., 1978, 2391. 'O P. S. Hammond and D. T. Longone, Tetruhedrori Lett., 1978,415. '6

Heterocyclic Chemistry

172

Reactions. Methyl 5-bromo-2-furoate (47) reacts with ally1 alcohol in the presence of palladium acetate to give the aldehyde (48), together with a little of the isomer (49).413,4-Dimethoxyfuran forms the adducts (50) when treated with arenediazonium chlorides in ~ y r i d i n eArylation .~~ of the furan nucleus occurs in the reaction of furan with 2,4-dinitrobenzenediazonium salts in acetic anhydride - acetic acid; in aqueous acetic acid, however, the pyrrolone (5 1)is formed.43The rates and equilibrium constants for the formation of Meisenheimer adducts of 2-nitro- and 4-cyano-2-nitro-furan have been determined.44 The thermal and light-induced decompositions of furyldiazomethanes (52) yield y&acetylenic ap-olefinic carbonyl compounds R10C-HC=CH-CrCR2 by way of singlet carbenes (53).45 M e 0 OMe Me0,C Q

R

(47) R = B r

c1

0+H :

(48) R=(CH&CHO

(49) R = CH(Me)CHO

The fury phenyl ketone (54) is transformed into the pyrazole (55) by the action of h y d r a ~ i n eThe . ~ ~ morpholino-butenolide (56)reacts with aromatic aldehydes ArCHO and carbon disulphide to give the adducts (57) and ( 5 8 ) , re~pectively.~’ Contrary to previous reports, irradiation of tetracyanoethylene in THF yields 37% of the mono-adduct (59) and 3% of the ‘di-adduct’ (60).48Atomic carbon, 41

42 43

** 45

46

47 48

Y. Tamaru, Y. Yamada, and Z . Yoshida, Chem. Lett., 1978, 529. P. X. Iten and C . H. Eugster, Heh. Chim. Actu, 1978,61, 1033. M. G. Bartle, S. T. Gore, R. K Mackie, S. Mhatre, and J. M. Tedder, J. Chem. Sac., Perkin Trans. I , 1978,401. G. Doddi, F. Stegel, and M. T. Tanasi, J. Org. Chem., 1978,43, 4303. (a)R. V. Hoffman, G. G. Orphanides, and H. Shechter, J. A m . Chem. Soc., 1978,100,7927;( b )R. V. Hoffman and H. Shechter, ibid., p. 7934. G. Menichi and M. Hubert-Habart, Bull. Sac. Chim. Fr., 1977, 1235. A. E. Baydar and G. V. Boyd, J. Chem. Sac., Perkin Trans. I , 1978, 1360. M. Ohashi, S. Suwa, and Y. Osawa, J. Chem. Soc., Chem. Commun., 1977,884.

173

Five-membered Rings : Other Systems

generated by heating 5-diazotetrazole, reacts with furan to yield the aldehyde cis-HC=C-CCH=CHCHO, presumably via the carbenic adduct (61).49 The sensitized photo-oxygenation of 2,5-dimethylfuran gives the non-isolable peroxide (62);50analogous photo-adducts are thought to be intermediates in the conversion of the furylcarbamates (63; R = alkyl) into pyrrolinones (64).” H

Me F3C

0

CF3

Me F3C

CF,

0

The perfluorinated furan (7) adds but-2-yne to give a mixture of compounds (65) and (66).’*Photo-addition of indene to furan in the presence of l-cyanonaphthalene affords a mixture of the Diels-Alder product (67) and compounds (68) and (69).53The Diels-Alder reaction of 2,3-dehydronaphthalene with the spiro-acetal (70) constitutes a method for preparing functionalized partially hydrogenated benz[a]anthraquinones (7 l).54 Partial hydrogenation of the adduct 49

” 52

’3 54

S. F. Dyer and P. B. Shevlin, J. A m . Chem. SOC.,1979,101, 1303. W. Adam and K. Takayama, J. Org. Chem., 1979,44,1727. K. Ito and K. K. Yakushijin, Heterocycles, 1978, 9, 1603. Y . Kobayashi and Y. Hanzawa, Tetrahedron Lett., 1978,4301. K. Mizuno, R. Kaji, H. Okada, and Y. Otsuji, J. Chem. SOC.,Chem. Commun., 1978,594. W. Tochtermann, A. Malchow, and H. Timm, Chern. Ber., 1978,111, 1233.

Heterocyclic Chemistry

174

(72) of dimethyl acetylenedicarboxylate to 2-furylacetone and subsequent retroDiels-Alder reaction yields ethylene and the di-ester (73), which has been converted into the furo[3,2-c]pyranone (74).5sTreatment of the principal diadduct (75) of dimethyl acetylenedicarboxylate to 3,4-dimethoxyfuran with rhodium carbonyl chloride, [Rh(CO),Cl],, in methanol gives compound (76).s6 The ally1oxide (77) is generated by the action of silver perchlorate on the silyl enol ether Me2CC1C(OSiMe3)=CH,; it is trapped by furan as the 1,3-cyclo-adduct (78).57The amides (79) and (81; n = 1-3) form the intramolecular Diels-Alder adducts (80)5sand (82),” respectively.

Me

0

(75)

NU

(cH,),-N’

MP

‘x

Benzofurans.-Formation. 2,3-Diphenylbenzofuran (84) is produced by the action of potassium hydroxide on the nitro-ketone (83).60 The synthesis of DL-tremetone (85) has been described.61 Oxymercuration of o-allyl-phenols 55 56

57 5R

J9

6o 61

L. M. Gomes, J..Cabares, and M. Aicart, C. R. Hebd. Seances Acad. Sci.,Ser. C, 1978, 287,381. P. X. Iten and C. H. Eugster, Helv. Chim. Actu, 1978,61, 1133. N. Shimizu and Y. Tsuno, Chem. Lett., 1979, 103. T. R. Melikyan, G. 0.Torosyan, R. S. Mkrtchyan, and K. Ts. Tagmazyan, Arm. Khim. Zh., 1977,30, 981 (Chem. Abs., 1978, 8 9 , 7 5 356). K. A. Parker and M. R. Adamchuk, Tetrahedron Lett., 1978, 1689. M. Jawdosiuk, I. Kmiotek-Skarzynska, and E. Czarnecka, Pol. J. Chem., 1978,52, 1837. Y. Kawase, S. Yamaguchi, S. Kondo, and K. Shimokawa, Chem. Lett., 1978, 253.

Five-membered Rings : Other Systems

175

yields solely dihydrobenzofurans, but those with a substituent at the terminal carbon atom, e.g. (86),form mixtures of dihydrobenzofurans and chromans.62 The asymmetric palladium-acetate-catalysed cyclization of the phenol (86)in the presence of (-)-P-pinene gives the (S)-vinyldihydrobenzofuran (87) in 12% optical yield.63The cyclohexenylphenol(88)yields a mixture of the double-bond isomers (89) and (90) on treatment with palladium acetate.64The condensation product of maleic anhydride with resorcinol has been shown to be (91).65The azirine (92) reacts with phenol in the presence of tin(Iv) chloride to give the imine (93).66Photocyclization of the enol ether (94) results in the tetrahydrodibenzofuran-1-one (95).67A re-investigation of the reaction of ethyl acetoacetate with p-benzoquinone has shown that a mixture of the benzofuran (96) and the linear benzodifuran (97) is produced.68

Me

V. Speziale, Dao Huy Giao, and A. Lattes, J. Heterocycl. Chem., 1978,15, 225. T. Hosokawa, S. Miyagi, S. Murahashi, and A. Sonoda, J. Chem. Sac., Chem. Commun., 1978,687. T. Hosokawa, S. Miyagi, S. Murahashi, and A. Sonoda, J. Org. Chem., 1978,43,2752. 65 R. J. Molyneux, J. Org. Chem., 1978, 43, 2730. “ M. Seno, S. Shiraishi, H. Kise, and Y. Suzuki, J. Org. Chem., 1978,43,3402. A. G. Schultz, R. D . Lucci, W. Y. Fu, M. H. Berger, J. Erhardt, and W. K. Hagmann, J.A m . Chem. SOC.,1978,100,2150. H. L. McPherson and B. W. Ponder, J. Heterocycl. Chem., 1978,15,43. 62

63 64

‘’

Heterocyclic Chemistry

176

Irradiation of the dibenzodioxepinone (98) gives d i b e n ~ o f u r a n The . ~ ~ ketone (101) is obtained by treatment of the oxepin (99) with methanol, presumably by way of the ring-contracted intermediate ( The combined action of aromatic aldehydes, triethyl orthoformate, and perchloric acid on the ketone (102) leads to the naphthofurylium salts ( 103).71The photo-cyclization of the nitrocompound (104) to the phenanthrofuran (106) is thoughout to proceed via the oxazine N-oxide (105).72The complex reaction of sulphuric acid with the adduct (107) of dimethyl acetylenedicarboxylate to 2-acetonyl-5-benzylfuran affords a mixture of the anthra[2,3-b]furan derivative (108) and its methyl ester.73The

Me (104)

6q

7n

"

'' 73

-O (105)

S. R. Lele and B. D. Hosangadi, Indian J. Chem., Sect. B, 1978, 16,415. H. P. Schneider, W. Winter, and A. Rieker, J. Chern. Res. ( S ) , 1978, 336. V. V. Mezheritskii, V. V. Tkachenko, 0.N. Zhukovskaya, and G. N. Dorofeenko, Zh. Org. Khirn., 1978,14, 1986. R. A. Humphry-Baker, K. Salisbury, and G. P. Wood, J. Chern. Soc., Perkin Trans. 2, 1978, 659. L. Mavoungou-Gornes and J. Cabares, C. R . Hebd. Seances Acad. Sci., Ser. C, 1978, 287, 73.

Five-membered Rings : Other Systems

177

polychloro-pigment (log), isolated from green soils associated with stringy-bark eucalypts, is the first naturally occurring example of this ring When the o-quinone methide (1 10)is irradiated, the benzocycloheptafuran (111)is formed, with ring-enlargement of the phenyl group.75Zinc-induced debromination of the isobenzofuran derivative (112) yields the cyclobutadiene (113) as stable orangered

Ac

Reactions. Aryl radicals, produced by the action of pentyl nitrite on 1,3-diaryltriazenes ArNH-N=NAr, attack benzofuran at C-2, in agreement with theoretical prediction^.^^ The anomalous reaction of 3-acetamido-2-acetylbenzofuran with sulphuryl chloride yields 3-acetamido-2-chlorobenzofuran.78 Treatment of benzofuran with iodine azide gives a mixture of cis- and trunsdiazidodihydrobenzofurans (114), both of which are converted into 3-azidobenzofuran on treatment with alkali.79The Friedel-Crafts reaction of 2,3-dimethylbenzofuran with acetic anhydride yields, besides the 4- and 6-acetyl-derivatives, 2-acetyl-3-ethylbenzofuran(117) by way of the proposed intermediates (115) and (116)." The adducts (118) and (119) of trifluoromethyl hypofluorite to 74

D. W. Cameron and M. D. Sidell, Aust. J. Chem., 1978,31, 1323.

'' W. Verboom and H. J. T. Box, Tetrahedron Lett., 1978, 1229.

H. Firouzabadi and N. Maleki, Tetrahedron Lett., 1978, 3153. G. Vernin, S. Coen, J. Metzger, and C. Parkanyi, J. Heterocycl. Chem., 1979,16,97. '' S . Jordan and R. E. Markwell, J. Chem. SOC.,Perkin Trans. 1, 1978,419. 79 Y. Tarnura, M. W. Chun, S. Kwon, S. M. Bayomi, T. Okada, and M. Ikeda, Chem. Pharm. Bull., 1978,26.3515. E. Baciocchi, A. Cipiciani, S. Clementi, and G. V.Sebastiani, J. Chem. SOC.,Chem. Commun., 1978, 597. 76

77

Heterocyclic Chemistry

178

benzofuran give 3-trifluoromethoxybenzofuran on treatment with bases.'l The oxime (120) rearranges to the 3-aminobenzofuran (121) under the influence of ethanolic hydrochloric acid.82 The photo-isomerization (122) -+ (123) is stereo~pecific.'~

-% '

(124)

(121)

QSOzMe C0,Me

I

zb R' (128) 30) R ' = R 3 = H

COMe R'QMe

R' (129)

O2N QMe

n02

&""' PhMe

(127)

Whereas benzofuran reacts with benzonitrile oxide to form the adducts (124) and (125; R=Ph) in the ratio 7 : 3, the regiochemistry is reversed in the reaction with mesitonitrile oxide, (125; R = 2,4,6-Me3C6H2)being the major p r o d u ~ t . ' ~ Diphenylisobenzofuran yields mainly the [477 + 27r] cyclo-adduct (126) in the photo-reaction with 1,4-diphenylbuta-1,3-diene,while the [4.rr+4~]cycloadduct (127) is the predominant product of the reaction with the ester MeCH=CHCH=CHC02Me.85 Pyrro1es.-Formation. The reaction of acetophenone oxime with acetylene in DMSO in the presence of lithium hydroxide gives 2-phenylpyrrole, while 2 phenyl-1-vinylpyrrole is produced with potassium hydroxide.86 Pyrroles (128) 81 82

83 84

D. H. R. Barton, R. H. Hesse, and G. P. Jackman, J. Chem. Soc., Perkin Trans. I , 1977, 2604. V. A . Zagorevskii, L. A . Samarina, and L. M. Sharkova, Khim. Geterotsikl. Soedin., 1978, 850. A. G. Schultz, J. J. Napier, and R. Lea, J. Org. Chem., 1979,44, 663. P . Caramella, G. Cellerino, K. N. Houk, F. M. Albini, and C. Santiago, J. Org. Chem., 1978, 43,

3006. 85

86

G. Kaupp and E. Teufel, J. Chem. Res. ( S ) , 1978, 100. B. A . Trofimov, S. E. Korostova, L. N. Balabanova, and A . I. Mikhaleva, Khim. Geterotsikl. Soedin., 1978,489.

Five-membered Rings : Other Systems

179

are formed from a-chloroacrylonitrile and imines R'N=CHR2CH2R2 (R1 = alkyl or aryl, R2 = a l k ~ l ) ; ~ 'the condensation of a-amino-aldimines R'NH-CHR2CH=NR1 (R', R2 = alkyl) with acetylacetone yields 3-acetylpyrroles (129)." N-Allyl-imidoyl chlorides R2CCl=NCH2CH=CH2 (R2 = But, Ph, 2-furyl, or 2-thienyl) cyclize to the pyrroles (130) in the presence of potassium t - b u t o ~ i d e .The ~ ~ dinitropyrrole (13l), which inhibits bacterial growth, is produced when sorbic acid is gently warmed with aqueous sodium nitrite." Treatment of acetophenone azine (132) with lithium di-isopropylamide gives a

Scheme 1

mixture of 2,5-diphenylpyrrole and the tetrahydropyridazine (135); the former arises by Cope rearrangement of the dilithium compound (133), while the key step in the formation of the latter is the electrocyclization of the dianion (134) (see Scheme l).91 The pyrrolophane (136) is obtained from cyclohexadeca-1,3-diyne and aniline.92

0 (CH2II2

MeQMe OH (137)

o C H 2 S e P h Et0,C (138)

(136)

Aryl cyclopropyl ketones react with formamide to yield 2-aryl-pyrr01idines.~' The &-unsaturated hydroxylamine derivative HONHCHMeCH2CH2CH=CH2 cyclizes spontaneously to the 1-hydroxy-pyrrolidine (137).94A general synthesis of nitrogen heterocycles is exemplified by the formation of the pyrrolidine derivative (138) when the olefinic urethane H2C=CH(CH2),NHC02Et is treated with benzeneselenyl chloride, PhSeC1.95The condensation products of aldehydes with a-amino-carboxylic esters behave as tautomeric azomethine ylides in

'' S. 0. Olesen, J. 0.Madsen, and S. 0. Lawesson, Bull. Soc. Chim. Belg., 1978,87, 535. 88 89

90 91

92 93 94

95

J. Y. Valnot, Synthesis, 1978, 590. N. Engel and W. Steglich, Angew. Chem., Int. Ed. Engl., 1978, 17,676. Y. Kito, M. Namiki, and K. Tsuji, Tetrahedron, 1978, 34, 505. Y. Tamaru, T. Harada, and Z. Yoshida, J. Org. Chem., 1978,43, 3370. A. Stiitz and H. Reinshagen, Tetrahedron Lett., 1978, 2821. J. W. ApSimon, D. G. Durham, and A. H. Rees, J. Chem. SOC., Perkin Trans. 1, 1978, 1588. D. St. C. Black and J. E. Doyle, Aust. J. Chem., 1978,31, 2317. D. L. J. Clive, C. K.Wong, W. A . Kiel, and S. M. Menchen, J. Chem. Soc., Chem. Commun., 1978, 379.

Heterocyclic Chemistry

180

cycloaddition reactions; thus the imine (139; R = 2-furyl) yields the pyrrolidine (140) with N-phenylmaleimide.96 Heating the azirine (141; Ar = 4-biphenylyl) generates the 1,3-dipole (142),which undergoes an intramolecular cycloaddition to give the condensed pyrrolidine ( 143).97The trisquaternary ammonium salt (144) is produced by the action of dimethylamine on hexakis(bromomethy1)ben~ e n e . ~ ~

OZH Ph

H

I

R/

c,N' /cH\,CO,Me

-

H

R- -

Ph

N H

H

(139)

--C0,Me Ph

(140)

H

C0,Me \

AT N

H-C=C

0

+ Meo2c*o

H-Ar

\'

l i H

Pr

Pr'

Pr'

Me

COAr (145) \

Me

H

h& +(0 I.

I

Me

/

3Br-

Me (144)

Me

(1 46)

PhP G A r PhP G R l

R3 (147)

R2

R

H

-A--r

(148) R = N=C / (149) R = H

R2 (150)

H '

Condensation of N-phenylglycine esters with benzyl cyanide yields the aminopyrrolinone ( 145).99N-Acyl-pyrrolinones (146) are formed when mixtures of aroyl azides and diketen are irradiated.loOTreatment of imines R1R2C=NR3with diphenylcyclopropenone affords the adducts (147);"' azines ArCH=N-N=CHAr similarly yield the hydrazones (148), which readily eliminate aryl cyanides to give pyrrolinones ( 149).lo2Phenanthrapyrrolines (150; R. Grigg, J. Kemp, G. Sheldrick, and J. Trotter, J. Chern. SOC.,Chern. Comrnun., 1978, 109. A. Padwa and H. Ku, J. Org. Chern., 1979,44,255. 98 J. Ciric, S. L. Lawton, G. T. Kokotailo, and G. W. Griffin, J. A m . Chern. SOC.,1978, 100, 2173. 99 Yu. M. Volovenko, L. V. Gofman, and F. S. Babichev, Dopov. Akad. Nauk Ukr.RSR, Ser. B, 1978, 619 (Chern.Abs., 1978,89,163 331). loo T. Kato, Y . Suzuki, and M. Sato, Chem. Lett., 1978,697. '" T. Eicher, J. L. Weber, and G. Chatila, Justus Liebigs Ann. Chem., 1978, 1203. lo* M. Takahashi, N. Inaba, H. Kirihara, and S. Watanabe, Bull. Chem. SOC.Jpn., 1978, 51, 3312. 96

97

181

Five-membered Rings : Other Systems

R', R2 = H, Me, or Ph) are obtained when phenthraquinone is treated with a mixture of an a-methylene ketone R'CH2COR2 and concentrated aqueous ammonia.'o3 The action of strong bases on the deuteriated hydrazide (151) yields a mixture of deuteriated and non-deuteriated condensed pyrrolinones (152) and (153) (R = CH, or CD,);these are produced by Cope rearrangement, followed by elimination of either CD3NH2or CH3NH2.104

+

mMie N R

0 2 v o"OMe Me

Me (156)

-

(154)

'

OyJ 'OMe

Me (157)

0-0 (155)

H (158)

O

@ \ I

\ OMe

(159)

Reactions. The equilibrium mixture of the bis(cyanomethy1)-pyrrole (154) in acid solution contains 12% of the pyrroline isomer (155) when R is methyl, but only 3% when R is ~ h e n y l . " ~Conditions for exclusive C- or N-alkylation of the pyrrole anion have been worked out;106 2-amino-pyrroles are selectively methylated at the ring nitrogen atom in the system sodium hydrideTHF-dimethyl sulphate. lo' The kinetics of the reaction of N-methylpyrrole and 2,5-dimethylpyrrole with arenediazonium fluoroborates in the presence of dicyclohexyl-18-crown-6 have been determined."' N-Methyl-3,4-dinitropyrrole yields compound (156) on treatment with methanolic sodium methoxide; subsequent elimination of methanol gives (157), the product of a formal cine -substitution. lo9 0 -Acetyl-N- benzoyl-N-p -methoxyphenylhydroxylamine, AcON(C6H40Me-p)-COPh,reacts with pyrrole to give compound (158).'" The conformation of 1,l'-dipyrryls has been studied by photoelectron spectroscopy; in the parent molecule the pyrrole rings are perpendicular, while in the bridged compound (159) they are coplanar.'" M. Constenla and J. Aguilar, Rev. Latinoam. Quim., 1978, 9, 22 (Chem. Abs., 1978, 89, 108 930). C. von Rohrscheidt and H. Fritz, Justus Liebigs Ann. Chem., 1978, 680. W. Flitsch and F. Kappenberg, Chem. Ber., 1978, 111, 2401. lo6 N.-C. Wang, K.-E.Teo, and H. J. Anderson, Can. J. Chem., 1977,55,4112. lo7 R. J. Mattson and, J. W. Sowell, jr., Synthesis, 1979, 217. lo* A. R. Butler and P. T. Shepherd, J. Chem. Res. ( S ) , 1978, 339. P. Mencarelli and F. Stegel, J. Chem. SOC.,Chem. Commun., 1978, 564. 'lo T. Ohta, K. Shudo, and T. Okamoto, Tetrahedron Lett., 1978, 1983. W. Flitsch, H. Peeters, W. Schulten, and P. Rademacher, Tetrahedron, 1978,34, 2301. lo3

lo4

Heterocyclic Chemistry

182

The proposed intermediate (16 1) in the photo-transposition of the 2-cyanopyrrole (160) to the 3-cyano-isomer has been intercepted by furan as a mixture of cyclo-adducts (162) and (163) (Scheme 2).l12 The product (165) of the thio-

Scheme 2

Claisen rearrangement of the ally1 thioether (164) has been isolated as the A mixture of spiro- and annelated pyrrolines (167) and S-acetyl derivati~e."~ (168) is obtained when the alcohol (166; n = 4) is treated with trifluoromethanesulphonic anhydride; the homologue (166; n = 9, however, affords solely a ~ p i r ~ - ~ ~ m p The ~ ~ reaction n d . " ~of pyrroles with carbon monoxide and ethanolic sodium ethoxide yields a variety of products: compound (169) gives a mixture of the 2-formyl derivative and the triester (170), while the pyrrole (171) affords the pyrrolo-indole (172).'15

H (164) R1 = H, R2= SCH2CH=CH2 (165) R1 = CHzCH=CHz, R2= SH

+ H (166)

Me

Et0,C

Me C0,Et

M

MemEI-,()MN e

H

I

H

C0,Et (170) '12 '14

'I5

Et02C R

e

0

Me0,C M

e

H (169) R = M e (171) R = H

w CO,Ete C02Et

(172)

J. A. Barltrop, A. C. Day, and R. W. Ward, J. Chem. SOC.,Chem. Commun., 1978, 131. K.-E. Teo, G. H. Barnett, and H. J. Anderson, Can. J. Chem., 1978,56, 221. K. Hosaka, A. P. Johnson, and A. W. Johnson, Tetrahedron Lett., 1978, 2953. A. Treibs and R. Wilhelm, Justus LiebiRs Ann. Chem., 1979, 11.

183

Five-membered Rings : Other Systems

2-t-Butyl-5-methylpyrrole, when treated with phenyl(trichloromethy1)mercury (PhHgCCl,; a precursor of dichlorocarbene) and sodium iodide, gives a mixture of the intermediate (173) and the carbene products (174)--(178).ll6 The N-unsubstituted Dewar-pyrrole (179), prepared from the corresponding thiophen compound, yields the Diels-Alder adduct (180) with furan.'17 The types of products formed from nitrones and cyclic phosphonates depend on the size of the rings in the latter: thus 5,5-dimethyl-A1-pyrroline N-oxide (181) yields the fused azirine (183) on reaction with compound (182), but the pyrrolidine derivative (185) by the action of the six-membered phosphonate (184).l18Irradiation of 2-cyanopyrrolineN-oxides (186; R = H, Me, or Ph) leads to azetidines (188) via intermediate oxaziridines (187).'19 In the presence of

(173)R=HgPh (174)R = H

'I6

?HO

(175)

(176)R1= C1, R2 = Me,R3= H (177)R' = Me,R2= C1, R3= H (178)R' = Me,R2= H,R3= C1

A. Gambacorta, R. Nicoletti, S. Cerrini, W. Fedeli, and E. Gavuzzo, Tetrahedron Lett., 1978,2439.

"'Y. Kobayashi, A. Ando, and I. Kumadaki, J. Chem. SOC.,Chem. Commun., 1978,509. 'la

S . Zbaida and E. Breuer, J. Chem. SOC.,Chem. Commun., 1978,6. D. St. C. Black, N. A. Blackman, and A. B. Bosacci, Tetrahedron Lett., 1978,175.

184

Heterocyclic Chemistry

diazabicycloundecane, the pyrrolinone (189; Ar = p-ClC6H4)decomposes to the nitrile ylide (190), which undergoes intramolecular 1,3-dipolar cycloaddition to yield the aziridino-pyrroline (191) as a mixture of endo- and exo-isomers.120

-CH,CO __3

+/

PhCrN

C

\

Ar

Indoles and Carbazoles.-~~rmation. Carbon- 13 Fourier-transform n.m.r. spectroscopy has been used to detect intermediates in the Fischer indole synthesis.121 The direction of cyclization of unsymmetrical ketone phenylhydrazones has been examined; higher acidities and temperatures cause cyclization towards the less substituted position.'22 The 2,3-dimethylphenylhydrazoneof cyclohexanone yields not only 7,8-dimethyltetrahydrocarbazole(192), but also the rearranged 5,6- and 5,8-dimethyl-i~omers.'~~ The action of hot polyphosphoric acid on the phenylhydrazone of p-methoxyacetophenone leads to the biphenyl derivative (193) in competition with the Fischer indole Treatment of o-allylanilines with palladium(11)chloride yields 2-methyl-indoles and/or quinolines. 125 Specific ortho-substitution occurs in the reaction of anilines with chloroacetonitrile in the presence of boron trichloride; the products are transformed into 2,3-unsubstituted indoles by reductive cyclization.126 The action of phenacyltriphenylarsonium bromide on o-toluidine furnishes the indole (194) via the ylide PhCOCH-LsPh,; naphthylamines similarly yield benzindoles, e.g. compound (195) from 2-naphthylamine. 127 Thionium ions function as reactive carbonyl equivalents in cyclization reactions; thus compound (196) is transformed into the indole (197) by the action of toluene-p-sulphinic acid.128 Copper(1) oxide catalyses the conversion of o-cyanomethylphenyl isocyanide (198) into 3-cyanoindole (199).'29 The reaction of allenic nitriles with phenylhydrazine affords a mixture of N-phenyl-pyrazoles and indolines (Scheme 3).l3'

J. Fischer and W. Steglich, Angew. Chem., Int. Ed. Engl., 1979, 18, 167. A . W. Douglas, J. A m . Chem. SOC.,1978, 100, 6463. lZ2 F. M. Miller and W. N. Schinske, J. Org. Chem., 1978, 43, 3384. 123 R. Fusco and F. Sannicolo, Tetrahedron Lett., 1978,4827. 124 R. Fusco and F. Sannicolo, Tetrahedron Lett., 1978, 1233. L. S. Hegedus, G . F. Allen, J. J. Bozell, and E. L. Waterman, J. A m . Chem. SOC.,1978,100,5800. lZ6 T. Sugasawa, M. Adachi, K. Sasakura, and A. Kitagawa, J. Org. Chem., 1979, 44, 578. 127 R. K. Bansal and S. K. Sharma, J. Organomet. Chem., 1978,149,309. lZ8 B. M. Trost, M. Reiffen, and M. Crimmin, J. A m . Chem. SOC.,1979, 101,257. lZ9 Y . Ito, Y .Inubushi, T. Sugaya, K. Kobayashi, and T. Saegusa, Bull. Chem. SOC. Jpn., 1978,51,1186. 13' S . R. Landor, P. D . Landor, Z . T. Fomum, and G. M. Mpango, Tetrahedron Lett., 1977, 3743. 12'

"'

Five-membered Rings : Other Systems

185

,CH,CN

MeEtC=C 'NHNHPh

CHCN

Scheme 3

N-Methylindole-7-aldehyde (201) is formed by the action of methylammonium bisulphite on nicotyrine methiodide (200).131 The reduction of onitrophenylacetaldehyde affords 1-hydroxyindole, isolated as the acetate (202).'32Photocyclization of the diphenylamine derivative (203) gives a mixture

13'

13'

A. N. Kost, L. G. Yudin, R. S. Sagitullin, and A. Muminov, Khim. Geterotsikl. Soedin., 1978,1566; cf. A.N.Kost, T. V. Stupnikova, R. S . Sagitullin, B . P. Zemskii, and A. K. Sheinkman, Dokl. Akad. NaukSSSR,Ser. Khim., 1979,244,103. R.M. Acheson, P. G. Hunt, D. M. Littlewood, B. A. Murrer, and H. E. Rosenberg, J. Chem. Soc., Perkin Trans. 1, 1978,1117.

Heterocyclic Chemistry

186

of the tetrafluoromethoxycarbazoles (204) and (205).133 p-Benzoquinone and methylamine give the carbazole quinone (206), contrary to a previous The main products of the Nenitzescu reaction of the aminocrotonic esters (207; R = H, Me, Ph, or PhCH,) with 2-acetoxy-1,4-naphthaquinoneare the benzindoles (208).13’ The formation of the indoline (210) from the enamino-ketone (209) is an example of a general synthesis of heterocycles of various ring sizes by intramolecular photochemical arylation. 136 The photochemical conversion of the Reissert compound (211) into the cycloprop[b]indole (212) has been ~ e p 0 r t e d . l ~ ~ The stringent spatial requirements for intramolecular 1,3-cycloadditions are illustrated by the observation that whereas the nitrile ylide (213) forms compound (214), the ylide (215) does not undergo an analogous reaction.13*

Me (203) (204) R’= OMe, R2 = H (205) R1 = H, R2 = OMe

(206)

C0,Et Me

NHR

C0,Me &Me

(211)

13’

134

13’

‘36

C0,Et

I

(212)

Co2Et

E. P. Fokin, T. N. Gerasimova, T. V. Fomenko, and N. V. Semikolenova, Zh. Org. Khim., 1978,14, 834. R. Ott, E. Pinter, and P. Kajtna, Monarsh. Chem., 1979, 110, 51. U. Kucklander, Jusrus Liebigs Ann. Chem., 1978, 129. H. Iida, Y. Yuasa, and C . Kibayashi, J. Org. Chem., 1979,44, 1236. M. Ikeda, S. Matsugashita, and Y. Tamura, Heterocycles, 1978, 9, 28. A. Padwa, and A. Ku, J. A m . Chem. SOC.,1978,100,2181.

187

Five-membered Rings : Other Systems

The adduct (216) of the allenic ester Et02CCH=C=CHC02Et to N-acetylpyrrole is converted into the indolinone (217) by the action of potassium h~dride.'~'N-Phenyl-a-chloro-ca-diphenylacetimidoylchloride, PhN=CClCClPh2, forms the indolinone (218) by the action of sulphuric acid.14' Attempted addition of CN-diphenylnitrone to the ketenimine PhN=C=C(CF3)C02Et resulted in the cyclized product (219).14' The a-lactam (221) is thought.to be an intermediate in the conversion of the hydroxamic acid derivative (220) into l-ethoxy-3-phenylindolin-2-one(222).142Acid-catalysed condensation of 2-methylindole with ethyl acetoacetate yields (223), which cyclizes to 2-hydroxy-4-methylcarbazole (224) in the presence of sodium h~dride.'~~ Ac

&C02Et

+

fi 0

CHC0,Et (216)

(217)

N H

Q+; N

R3

(218) R' (219) R'

= R2 = Ph,

R3 = H

= CF3,R2 = COZEt, R3= H

N H f224)

Reactions. N-Chloroindole and the 3H-indole (225) have been identified as intermediates in the chlorination of indole to give 3-chloroindole. 144 3-Halogenoindoles are obtained by treatment of 3-indolyl phenyliodonium trifluoroacetate (226) with the appropriate metal halide.145Acylation of 3-alkyl-indoles yields 2-acyl-3-alkyl-indoles by initial attack at C-3, followed by migration of the acyl 139

I4O 14'

142

143 144

'41

A . P. Kozikowski and M. P. Kuniak, J. Org. Chem., 1978, 43,2083. M. Seno, S. Shiraishi, Y. Suzuki, and T. Asahara, Bull. Chem. SOC. Jpn., 1978,51, 1433. D. P. Deltsova, Z . V. Safronova, N. P. Gambaryan, M. Yu. Antipin, and Yu. T. Struchkov, luz. Akad. Nauk SSSR,Ser. Khtm., 1978,1881. K. Ogino, S. Itoh, and S. Kozuka, Mem. Fac. Eng. Osaka City Univ., 1977, 18, 95 (Chem. Abs., 1979, 90,22 733). J. Bergman and R. Carlsson, Tetrahedron Lett., 1978,4051. M. De Rosa and J. L. Triana Alonso, J. Org. Chem., 1978, 43, 2639. M. S. Ermolenko, V. A . Budylin, and A. N. Kost, Khim. Geterotsikl. Soedin., 1978, 933.

188

Heterocyclic Chemistry

group. 146 Similarly, the boron-trifluoride-induced cyclization of compound (227) to the tetrahydrocarbazole (229) proceeds mainly by way of the spiro-cation (228).14' A mixture of trifluoroacetyl derivatives (231) and (232) is produced, via the intermediate methyleneindoline (230), when 1,2,3-trimethylindole is treated with trifluoroacetic anhydride.14* Whereas thiocyanogen attacks indole and 2substituted indoles mainly at position 2, 2,3-diphenyl- and 3-methyl-2-phenylindole form 6-thiocyanato-derivatives.14' Nucleophilic substitution of Nmethylindoletricarbonylchromium(o) by 2-lithio-l,3-dithian affords compound (233).l5O The sensitized irradiation of N-methylindole in methanolic sodium cyanide gives a mixture of 2- and 3-cyano-derivatives. 15'

Me0

-

\ (227)

H

M

e

OH

0 (228)

Q

Y

-

M

H

e

o

m

N

(229)

H

COCF,

N (230) Me

(231) Me

(232) Me

>

OOH

-0

'N' (237) H

ii

N

I

Me t,N

/ P\

NEt,

(235) R = P(0R)z (236) R = (CH2)zOH (238) R=COPh

0

IjQ \N

The phosphorylated indole (234) forms the rearranged compounds (235) by treatment with aliphatic alcohols ROH.152The sensitized photo-oxygenatioh of tryptophol(236) at -70 "Cleads to the hydroperoxide (237).153Palladium acetate induces the oxidative cyclization of the ketone (238) to the tetracyclic compound (239),154One of the products of the reaction of the oxobutenyl-indole (240) with 146

147

14* 149

lS1 15'

153 154

A. H. Jackson, B. Naidoo, A. E. Smith, A. S. Bailey, and M. H. Vandrevala, J. Chem. SOC.,Chem.

Commun., 1978,779. J. S. L. Ibaceta-Lizana, R. Iyer, A. H. Jackson, and P. V. R. Shannon, J. Chem. SOC.,Perkin Trans. 2, 1978,733. A. S. Bailey, J. M. Peach, and M. H. Vandrevala, J. Chem. SOC.,Chem. Commun., 1978, 845. Y. Tamura, S. Kwon, M. W. Chun, and M. Ikeda, J. Heterocycl. Chem., 1 9 7 8 , 1 5 , 4 2 5 . A. P. Kozikowski and K. Isobe, J. Chem. SOC.,Chem. Commun., 1978, 1076. K. Yoshida, J. Chem. SOC.,Chem. Commun., 1978, 1108. P. A. Gurevich, A. I. Razurnov, S. A. Muslirnov, and T. V. Komina, Zh. Obshch. Khim., 1978,48, 1655. I. Saito, M. Imuta, A. Nakada, S. Matsugo, and T. Matsuura, Photochem. Photobiol., 1978,28,531. T. Itahara and T. Sakakibara, Synthesis, 1978, 607.

189

Five-membered Rings : Other Systems

methanolic hydrogen chloride is the propellane (24 1)? Intramolecular anodic coupling of the indole (242) gives an almost quantitative yield of the rearranged heterocycle (243),156A mixture of the alkylated indoles (244; R' = H, R2 = CH2CH=CMe2) and (244; R1 = R2 = CH2CH=CMe2) and the dimeric compound (245; R = CH2CH=CMe2) is produced when indole is treated with 3,3-dimethylallyl

y; Q8 I

(241)

CH=CHCOCH,

Me

-

RJQ -

N

"

/

N

R

(247) R = 3-indolyl

H

& I '

N H (244)

H

0

H

M

'

p

H

0

Thallium(II1)acetate brings about oxidative coupling of 2,3-dimethylindole to the indolo-carbazole (246).15*Carbazole forms 3,3'-bicarbazolyl in the presence of palladium acetate.lS9 Indole is oxidized in the soil to yield mainly the diindolylindolinone (247).160 The black polymers formed by the action of hydrochloric acid on 4,7-dimethoxyindole arise from an intermediate dimeric compound (248).161 Treatment of a mixture of indole and 2-methylfuran with 155

lS6

15' 15' 15'

160

16*

H. J. Teuber, A. Gholami, H. J. Bader, and U. Reinehr, Tetrahedron Lett., 1978, 3089. M. Sainsbury, Heterocycles, 1978,9, 1349. V. Bocchi, G. Casnati, and R. Marchelli, Tetrahedron,1978, 34, 929. A. Banerji and R. Ray, Indian J. Chem., Sect. B, 1978,16,422. I. V. Kozhevnikov, S. A. Tuzovskaya, V. P. Lopatinskii, V. M. Sutyagin, 0. V. Rotar, and K. I. Matveev, React. Kinet. Catal. Lett., 1978,9, 287. A. K. Sheinkman, N. A. Klyuev, L. A. Rybenko, and E. Kh. Dank, Khim. Geterotsikl.Soedin., 1978, 1490. G. Malesani, F. Galiano, A. Pietrogrande, and G. Rodighiero, Tetrahedron,1978, 34, 2355.

190

Heterocyclic Chemistry

acetyl chloride gives the indoline (250), which is produced by nucleophilic attack on the cation (249).'62 1-Aminoindole yields a mixture of 1,4-dihydrocinnoline (25 1)and cinnoline in acidic media.'63 3-Azido-3H-indoles (252; R' = H or C0,Et; R2 = Me, Et, Ph, or CO,Et), prepared by the action of iodine azide on the corresponding indoles, form quinoxalines (253) and quinazolines (254) on irradiati011.l~~The nitrone (255) isomerizes to the indolinone (256) in the presence of tetra~yanoethylene.'~~ Oxidation of 3,3-dimethyI-3H-indole with rn-chloroperbenzoic acid gives the unstable oxiran (257), which rearranges spontaneously to a mixture of the isocyanate (258) and the indolinone (259).'66The oxidative rearrangement of the hydroxy-indoline (260) to the indolinone (261) has been reported.lh7The 3Hindole (262; Ar=o-HOC,H,) is converted into the indolin-3-one (263) on heating.16*

162 163 164

166 16' 16'

A. K. Sheinkman, T . V. Stupnikova, and L. A. Rybenko, Khim. Geterotsikl. Soedin., 1978, 561. ( a )M. Somei and K. Ura, Chem. Lett., 1978, 707; ( b )M. Somei and Y. Kurizuka, ibid., 1979, 127. Y. Tamura, M. W. Chun, H. Nishida, S. Kwon, and M. Ikeda, Chem. Pharm. Bull., 1978,26,2866. D. Dopp and A. M. Nour-el-Din, Chem. Ber., 1978, 111, 3952. D. Dopp and H. Weiler, Chem. Ber., 1978,111, 3806. A. G. Schultz and W. K. Hagmann, J. Urg. Chem., 1978,43,4231. B. Robinson and M. Uppal Zubair, Pak. J. Sci. Ind. Res., 1976, 19, 214.

191

Five-membered Rings : Other Systems

Treatment of 1,2-dimethylindole with diketen, followed by polyphosphoric acid, gives the nitrogen analogue (264) of phenalen-1-one, which forms the salt (265) by the action of triethyloxonium f l ~ o r o b o r a t e Ring-opening .~~~ of the thermochromic spiro-pyran (266) is catalysed by p-nitrobenzenesulphonic acid to give (267).170

7 L

(264)

(266) O2N colourless

Me

1

(270)

(271)

coloured

(272)

(273)

The Diels-Alder adduct (269) of benzoquinone to 1-methyl-3-vinylindole (268) has been described.17' (Alkoxycarbonylmethy1ene)-indolinones (270; R' = Me or Et) function as dienophiles in the reaction with butadienes R2CH=CH-CH=CH2 (R2 = Me or OAc) to yield compounds (271) as mixtures of ~ t e r e o i s o m e r s and , ~ ~ ~as dipolarophiles with diazomethane and benzonitrile oxide to give the spiro-indolinones (272) and (273), respectively.173 An unusual ring-expansion occurs in the formation of the quinolinone (276) in the reaction of the (cyanomethy1ene)indolinone (274) with diazomethane; the C0,Et

Q--p N

CO,Et

W

$ HC

H (274)

169 170

17'

173

R. Neidlein and F. Moller, Synthesis, 1978, 685. F. M. Menger and M. Perinis, Tetrahedron Lett., 1978,4653. R. Bergamasco, Q. N. Porter, and C. Yap, Aust. J. Chem., 1978,31, 1841. K. Okada, H. Sakuma, M. Kondo, and S. Inoue, Chem. Lett., 1979,213. A. Franke, Justus Liebigs Ann. Chem., 1978, 717.

N

Heterocyclic Chemistry

192

authors have suggested the 1,3-dipclar species (275) as the key intermediate (see Scheme 4).174 The photochemical cycloaddition of dimethyl acetylenedicarboxylate to Nmethylindole in the presence of acetophenone as a sensitizer gives the cyclobutindole (277), which isomerizes reversibly to the benzazepine (278).175

E Me H (277)

C1

C1

c1

E

CI

Bu'

1soindoles.-Stable 2H-isoindoles (280; Me, = 4,7-Me,, 5,6-Me2, or 4,5,6,7Me4) are obtained by thermal elimination of methanesulphinic acid from the isoindolines (279).176 The 'fluorogenic' reaction of phthalaldehyde with mercaptans and amino-acids yields alkylthio-isoindoles, e.g. (281).177 Treatment of N-t-butylpyrrole with tetrachlorobenzyne yields a mixture of 1,2- and 1,4adducts (282) and (283); the latter decomposes on heating to afford a mixture of acetylene and the isoindole (284).'78 Synthetic routes to 9,10-dihydro-9,10iminoanthracenes (285) from benzynes and isoindoles have been examined in detail.179 Flash vacuum pyrolysis of the hydrogenated 2,3-naphtha1yne-N-

174

'71 177

17' 179

G. B. Bennett, R. B. Mason, and M. J. Shapiro, J. Org. Chem., 1978,43,4383. P. D . Davis and D. C. Neckers, Tetrahedron Lett., 1978, 2979. R. Kreher and K. J. Herd, Heterocycles, 1978, 11, 409. S. S. Simons, jr. and D. F. Johnson, J. Org. Chern., 1978, 43, 2886. J. M. Vernon, M. Ahmed, and L. J. Kricka, J. Chem. SOC.,Perkin Trans. 1, 1978, 837. P. S. Anderson, M. E. Christy, C. D. Colton, W. Halczenko, G. S. Ponticello, and K. L. Shepard, J. Org. Chem., 1979,44, 1519.

193

Five-membered Rings : Other Systems

methylpyrrole cyclo-adduct (286) affords a 2-methylbenz[f]isoindole (287; R = Me).lgOThe parent compound exists predominantly in the form (288); however, the existence of the 2H-tautomer (287; R = H) in the equilibrium mixture is shown by the formation of the Diels-Alder adduct (289) in the reaction with N-phenylmaleimide.

m m R (286)

(289;

d

\R

(292) M = Si, R = Me (293) M = G e

a

(287)

N (288)

v

(294)

(295) R1 = H (296) R' = CHClz

ClO,(297) R = A r (298) R = CH=CHAr

Other Heterocyclic Systems.-The steric course of replacement reactions of ( E ) and (2)1-chloro- 1,2-dimethylsilacyclopentanes(290) has been investigated; alcoholysis catalysed by transition metals results in inversion of configuration.lg2 The 29Si n.m.r. spectra of numerous 1-silacyclopent-2-enes and -3-enes, e.g. (291) and (292), have been d e t e ~ m i n e d . 'Infrared ~~ and Raman spectroscopy of the 1-germacyclopent-3-enes (293; R = C1 or OMe) indicate that the compounds possess a planar ring.lg4 Evidence has been presented that the silver-assisted acetolysis of ( E , Z )- 1- bromo-4-chloro-l,4-diphenylbuta-l,3diene proceeds partially through the chloronium ion (294).lS5 4 Systems containing Two Identical Heteroatoms

Dioxo1es.-Dichiorocarbene, generated by the phase-transfer-catalysed reaction of chloroform with aqueous sodium hydroxide, reacts with the dioxolans (295; R2 = Pr or Ph) to give high yields of the insertion products (296).lg62-Aryl-1,3dioxolanium perchlorates (297) are formed by the combined action of aroyl J. Bornstein, S. E. Hunt, J. D. Mineck, and D . E. Remy, J. Org. Chem., 1 9 7 9 , 4 , 8 0 5 . D. E. Remy and F. H. Bissett, J. Org. Chem., 1978, 43,4469. (a)F. K. Cartledge, J. M. Wolcott, J. Dubac, P. Mazerolles, and M. Joly, J. Orgunornet.Chem., 1978, 154, 187; ( b ) ibid., p. 203. lS3 M. L. Filleux-Blanchard, Nguyen Dinh An, and G . Manuel, Org. Mugn. Reson., 1978, 11,150. la4 P. W. Jagodzinski, J. Laane, and G . Manuel, J. Mol. Struct., 1978,49,239. I. L. Reich, C. L. Haile, and H. J. Reich, J. Org. Chem., 1978, 43, 2402. K. Steinbeck, Tetrahedron Lett., 1978, 1103. la'

Heterocyclic Chemistry

194

chlorides and silver perchlorate on pinacol. '*' The pinacol esters Me2C(OH)CMe20,CCH2CHAr, are similarly cyclized to the vinyldioxolanium salts (298) in the presence of acetic anhydride and perchloric acid.'88 The photochemical reaction of dioxole (299) with benzene results in a mixture of the 1?2-, 1?3-?and 1,4-cyclo-adducts (300)-(302), respe~tively.~'~ The p-benzoquinone mono-ethylene acetal (304) is produced by oxidation of the ether (303) with mercury(I1) Treatment of 6-substituted 2-naphthols with tetrachloro-o-benzoquinone generally leads to a mixture of the spiro-acetals (305) and (306).'" The trinitro-compound (307) forms the double Meisenheimer complex (308) in the presence of sodium r n e t h 0 ~ i d e . l ~ ~

n

0

0

02N-@--

NO? (308)

2Na'

1,2-Dithioles.4-Acetoxy-1,2-dithioliumsalts (309; R = But or Ar), prepared by the combined action of tetraphosphorus decasulphide and perchloric acid on the 1,3-diketones RCOCH(OAc)COR, form meso-ionic dithiolium oxides (310) on treatment with ~ y r i d i n e . A ' ~general ~ reaction of 3-methylthio-l,2-dithiolium la'

189

190 19' 192

193

E. S. Matskovskaya, L. V. Mezheritskaya, and G. N. Dorofeenko, Zh. Org. Khim., 1978,14,1119. L. V. Mezheritskaya, E. S. Matskovskaya, and G. N. Dorofeenko, Zh. Org. Khim., 1977,13,2608. J. Mattay, H. Leismann, and H. D. Scharf, Chem. Ber., 1979,112, 577. A. Goosen and C. W. McCleland, J. Chem. SOC.,Perkin Trans. 1, 1978,646. T. R. Kasturi and R. Sivaramakrishnan, Indian J. Chem., Sect. B, 1 9 7 8 , 1 6 , 6 6 8 . S. S. Gitis, A. Ya. Kaminskii, A. 1. Melnikov, and N. R. Nikitin, Zh. Org. Khim., 1978, 14, 1343. D. Barillier, Phosphorus Sulfur, 1978, 5 , 251.

195

Five-membered Rings : Other Systems

salts is exemplified by the conversion of the salt (311) into compound (312) by reaction with acetonedicarboxylic anhydride, followed by acidic hydr01ysis.l~~ Phenalenor 1,9-cd]dithiolium hexafluorophosphate (313)has been reduced to the corresponding monomeric radical by chemical or electrochemical means. lg5

(311)

I-

Q s-s : I.\

.

+: *-

*.I.*

I-

,

,

0

.1

. . ,

.

. -: *

(313)

Me SAr Ph

Ph

s'

(314) X = S (315) X = C H A r , R = H ( 317) X = NCOAr

Br(316)

The dithiole-thione (314; R = H ) yields thiafulvenes (315) when treated with the Wittig reagents ArCH=PPh3.'96 Photochemical arylation of the thione (314; R = Me) with aryl bromides leads to the arylthio-dithiolium salts (316).'97 NN-Dichloro-amides ArCONCl, [Ar = 0-NO2C6H4,2,4-(N02)2C6H3,or 2,6Cl,C,H,J condense with the dithiole-thione (314; R = H) to give mixtures of imines (317; R = H) and (317; R = Cl).lg81-Pyrrolidinocyclohexene and other cyclic enamines react with 1,2-dithiole-3-thiones to give thiapyran-2-thiones by the mechanism outlined in Scheme 5.l"

J NR2 = pyrrolidino Scheme 5 lg4 lg5

lg6 lg7 19'

lg9

E. G. Frandsen, Tetrahedron, 1978,34, 2175. ( a ) R. C. Haddon, F. Wudl, M. L. Kaplan, J. H. Marshall, R. E. Cais, and F. B. Bramwell, J. A m . Chem. SOC., 1978,100,7629; ( 6 ) R. C. Haddon, F. Wudl, M. L. Kaplan, J. H. Marshall, and F. B. Bramwell, J. Chem. SOC., Chem. Commun., 1978,429. R. S. Tewari and K. C. Gupta, Synrh. Commun., 1978, 8, 315. V. N. Drozd, G . S. Bogomolova, and Yu. M. Udachin, Zh. Org. Khim., 1978,14,894. G . J. Wentrup and F. Boberg, Jusfus Liebigs Ann. Chem., 1978,387. F. Ishii, M. Stavaux, and N. Lozach, Bull. SOC.Chim. Fr., 1977, 1142.

196

Heterocyclic Chemistry

X-Ray analysis confirms that the dithiole-thione (318; Ar = p-MeC,H,) does not possess a symmetrical structure.200The ten-membered heterocycle (320) is formed by treatment of the benzodithiolethione (319) with lithium aluminium hydride."l rn-Chloroperbenzoic acid oxidizes the thiol (321) to the benzodithiole 2,2-dioxide (322); photo-desulphonylation of the latter produced othiobenzoquinone methide (323), which was trapped by N-phenylmaleimide as the adduct (324).202The stable ortho-quinonoid thioacetals (325; n = 3,4, or 6) and the aminal(326) are obtained by treatment of benzodithiolethione (319) with cycloalkenes and NN'-dimethylethylenediamine, respe~tively.'~~These compounds yield Diels-Alder adducts, e.g. (327), with electron-poor olefins and acetylenes and with ketens and i~ocyanates.~'~ Bromine oxidizes arylhydrazones of dithiomesoxalic acid diamides to the diamino-dithioles (328).'05

ArN=N

CSNH, A~NH-N<

--b

CSNH,

H2N

tJ

NH,

(328) P.-T. Cheng and S. C. Nyburg, J. Chem. SOC.,Perkin Trans. 2, 1977, 1854. 201 R. T. Parfitt, D. E. Games, R. F. Cookson, R. C. Richards, and N. Lynaugh, Org. Mass Spectrom., 1978,13, 341. '"'A . G. Hortmann, A . J. Aron, and A. K. Bhattacharya, J. Org. Chem., 1978, 43, 3374. 2"3 R. Okazaki, K. Sunagawa, K.-T. Kang, and N. Inamoto, Bull. Chem. SOC.Jpn., 1979,52,496. '04 R. Okazaki, K.-T. Kang, and N. Inamoto, Heterocycles, 1978, 9, 1741. ' 0 5 L. N. Kuiaeva, A. D. Grabenko, and P. S. Pelkis, Khim. Geterotsikl. Soedin., 1978, 909. 200

Five-membered Rings : Other Systems

197

1,3=Dithioles.-The dithiolium salt (329) forms a mixture of mono- (330) and bis-(dithioly1)-compounds (331) on treatment with furan.2062-Methylthio-1,3dithiolium salts (332) condense with 2-naphthol and pyrrole to give the naphthaquinone methide (333)207and the stable orange azafulvene (334),208respectively. The electrical conductivities of the radical-anion salts (335; R = alkyl or aryl) of 1,3-dithiolan-2-iminiumhave been Treatment of dichloroolefinic ketones RCOCH=CC12 (R = alkyl or aryl) with sodium sulphide is reported to yield a mixture of cis- and trans-dithioles (336) and dithietans (337).210Acetylenes are converted into 173-dithiole-2-thiones(338; R1,R2 = H, Me, Ph, or C02Me)by the action of carbon disulphide and amine disulphides211 or by irradiation with ethylene trithiocarbonate.212 Ph Ph

The chemistry of meso-ionic 173-dithiolium4-oxides (339) has been studied by Gotthardt and his colleagues. These compounds are obtained by cyclization of a-carboxy-dithioesters RCS2CHArC02H(R = Ph, EtS, piperidino, e t ~ . ) . * ~ ~ * * ' ~ 206 207 '08

'09

'lo

211 212 '13

'14

D. Buza and W. Gradowska, Pol. J. Chem., 1978,52,2071. E. Fanghanel, W. John, H. Fricke, and G. Kempe, 2.Chem., 1978,18,385. J. Nakayama, Y. Watabe, and M. Hoshino, Bull. Chem. SOC.Jpn., 1978, 51, 1427. S. Araki and T. Tanaka, Bull. Chem. SOC.Jpn., 1978,51, 131 1. A. N. Mirskova, G. G. Levkovskaya, I. D. Kalikhman, T. I. Vakulskaya, V. A. Pestunovich, and M. G. Voronkov, Tezisy Dokl. Nauchn. Sess. Khim. Tekhnol. Org. Soedin. Sery Sernistykh Neftei, 14th. 1975,150 (Chem. A h . , 1978,89,90 176). F. M. Benitez and J. R. Grunwell, J. Org. Chem., 1978,43, 2917. M. Ohashi, N. Mino, N. Nakayama, and S. Yamada, Chem. Lett., 1978, 1189. H. Gotthardt and C. M. Weisshuhn, Chem. Ber., 1978,111, 3178. H. Gotthardt and C. M. Weisshuhn, Chem. Ber., 1978, 111, 2021.

Heterocyclic Chemistry

198

The diphenyl-derivative is converted into the meso-ionic thiazole (340) by the action of aniline;2131,3-dipolar cyclo-adducts (341), (342), and (343) are formed by treatment of the appropriate meso-ionic compound with dimethyl maleate,215 formaldehyde,216and cy~lopropene,~~' respectively. Methyl propiolate undergoes a regiospecific reaction with compound (339; R = piperidino, Ar = Ph) to yield solely the thiophen (345) via the initial adduct (344), but the addition of the acetylenic ester to diaryl-dithiolium oxides containing two different aryl substituents affords mixtures of isomeric thiophens, e.g. (346) and (347).218The methylphenyldithiolium oxide (339; R = Me, Ar = Ph) dimerizes spontaneously to compound (348).219

(340)

MeO,CT

kO,Me (341)

(343)

0

Ph

P h\ o / R

NCSHlO C0,Me (344)

C0,Me (345) R = NC5H10 (346) R = C6H40Me-p

(349)

(348)

Me0,C (347) R = C6H40Me-p

(350) R 2 = L i (351) R 2 = M e

Treatment of o-benzenedithiol with carboxylic acids, esters, anhydrides, or nitriles in the presence of boron trifluoride etherate yields the benzo-l,3dithiolium salts (349), which afford hydrocarbons RCH3 by reduction with sodium in liquid ammonia.22o 2-Lithio-1,3-benzodithioles(350) function as acyl-anion equivalents; methyl iodide, for instance, gives compounds (35l), which

*I6

H. Gotthardt and B. Christl, Chem. Ber., 1978,111, 3029. H. Gotthardt and C. M. Weisshuhn, Chem. Ber., 1978, 111, 3171.

217

H. Gotthardt, C. M. Weisshuhn, and B. Christl, Chem. Ber., 1978,111, 3037.

21s

*I8

'I9 220

H. Gotthardt and C. M. Weisshuhn, Chem. Ber., 1978,111, 2028. H. Gotthardt, C. M. Weisshuhn, 0. M. Huss, and D. J. Brauer, Tetrahedron Lett., 1978, 671. I. Degani and R. Fochi, J. Chem. Sac., Perkin Trans. I , 1978, 1133.

Five-membered Rings : Other Systems

199

are readily hydrolysed to the ketones R1COMee2*l(Hydroxyalky1)benzodithioles, such as compound (352),obtained by the action of cyclohexanone on the propyl derivative (350; R' = Pr), undergo ring-expansion to 1,4-benzodithians, e.g. (353), on treatment with thionyl chloride and triethylamine.222 4-Nitrobenzo-1,3-dithiol-2-one (355) is formed by heating the dinitrophenyl dithiocarbamate (354).223The tribenzodithiafulvalene (356)is obtained by the action of fluorenone on lithium 2-dimethoxyphosphinyl-l,3-benzodithiole.224

Tetrathiafulva1enes.-Tetrathiafulvalene (357;R = H) has been obtained by decarboxylation of the corresponding tetracarboxylic it forms a monolithium derivative, from which a variety of substituted tetrathiafulvalenes (357; R = Me, CH20H, CHO, or C02Et) have been prepared.226 rn-Chloroperbenzoic acid produces tetrathiafulvalene mono-S-oxide, the first example of this type of The 7'-carbon disulphide complex [Fe(CS2)(CO),(P(OMe),},] reacts with activated alkynes to give dithiolium compounds; dimethyl acetylenedicarboxylate, for example, yields the complex (358),which is converted into the tetrathiafulvalene (359;R = C02Me) in air.228Tetrakis(alky1thio)thiafulvalenes (359; R = alkylthio), formed by the action of triethyl phosphite on the corresponding bis(alky1thio)dithiolethiones (360), yield 1: 1 complexes with tetracyano-p-quinodimethane; the tetrakis(methy1thio)-complex has a very low conductivity at room temperature, owing to the rotation of the 221

222

223 224 225

226

227 228

S. Ncube, A . Pelter, K. Smith, P. Blatcher, and S. Warren, Tetrahedron Lett., 1978, 2345. P. Blatcher, S. Warren, S. Ncube, A . Pelter, and k. Smith, Tetrahedron Lett., 1978, 2349. K. Rasheed and J. D. Warkentin, J. Org. Chem., 1979,44267. K . Akiba, K. Ishikawa, and N. Inamoto, Bull. Chem. SOC.Jpn., 1978, 51, 2674. S. Yoneda, T. Kawase, Y.Yasuda, and Z. Yoshida, J. Org. Chem., 1979,44, 1728. D. C. Green, J. Org. Chem., 1979, 44, 1476. M. V. Lakshmikantham, A . F. Garito, and M. P. Cava, J. Org. Chem., 1978,43,4394. H. LeBozec, A . Gorques, and P. H. Dixneuf, J. Am. Chem. SOC.,1978,100,3946.

200

Heterocyclic Chemistry

m e t h y l t h i o - g r ~ u p s .Diazotization ~~~ of substituted anthranilic acids with isopentyl nitrite in the presence of carbon disulphide and isopentyl alcohol yields the benzo-1,3-dithiole ethers (361), which have been converted into isomeric dibenzotetrathiafulvalenes (363) by way of the salts (362).230The action of dimethyl acetylenedicarboxylate on the adduct of carbon disulphide with tributylphosphine leads to the unstable phosphorane (364), which can be used in Wittig reactions; with cyclohexane-1,4-dione, for example, the bis-dithiole (365) is The synthesis of the p-quinobis(benzo-1,3-dithioles)(366; R = H)232and (366; R = Me),233the first isolable p-quinodimethane derivatives containing electron-donating groups, has been described. Benzobisdithiolium salts (367) have been prepared from piperidinium tetrathioterephthalate by successive treatment with 3-chlorobutan-2-one and perchloric or sulphuric The diphenyl-derivative forms a non-stoicheiometric iodine complex (368) by the action of lithium iodide.235 x ~ s > o C H * c H 2 P r '

\

s

(.a

x+fJ;> BF4(362)

(36 1)

(363)

a Se -Se

Ph[)-Q=0-(pPh

\

12.8

(368)

\

\

\

Se -Se (369)

A Diseleno1e.-The bis(diseleno1e) (369) is prepared by the action of disodium diselenide on 5,6,11,12-tetra~hlorotetracene;~~~ it forms a range of non-stoicheiometric complexes with iodine.237 229

230 231

232 233 234

23s 236 237

M. Mizuno, A. F. Garito, and M. P. Cava, J. Chem. SOC.,Chem. Commun., 1978, 18. J. Nakayama, F. Seki, and M. Hoshino, J. Chem. SOC.,Perkin Trans. 1, 1978,468. M. Sato, N . C. Gonnella, and M. P. Cava, J. Org. Chem., 1979, 4 4 , 9 3 0 . M. Sato, M. V. Lakshmikantham, M. P. Cava, and A. F. Garito, J. Org. Chem., 1978,43, 2084. Y. Ueno, A. Nakayama, and M. Okawara, J. Chem. Soc., Chem. Commun., 1978, 74. J. M. Fabre, E. Torreilles, and L. Giral, Tetrahedron Lett., 1978, 3703. Y. Ueno, M. Bahry, and M. Okawara, Tetrahedron Lett., 1977,4607. K. Balodis, A. Livdane, R. Medne, and 0. Neilands, Zh. Org. Khim., 1979,15, 391. S. P. Zolotukhin, V. F. Kaminskii, A. I. Kotov, M. L. Khidekel, R. P. Shibaeva, and E. B. Yagubskii, Izv. Akad. Nauk SSSR, Ser. Khim., 1978, 1816.

201

Five-membered Rings : Other Systems

Pyrazo1es.-Formation. Treatment of the acetal MeCOCH2CH(OMe)2 with The methylhydrazine gives a mixture of 1,3- and 1,5-dimethylpyra~ole.~~~ furanone esters (370; R = alkyl or aryl) are transformed into pyrazoles (371) by (372) similarly yield the pyrathe action of h y d r a ~ i n e ; ~dihydropyranones ~' zoles (373).240The addition of benzonitrile N-phenylimine, P h C r N-NPh, to acetylallene leads to a mixture of the regio-isomers (374) and (373, together with the bis-adduct (376).241Allenic esters and ketones add diazomethane at the substituted double bond, whereas allenic ethers and thioethers react at the terminal double bond.242The pyrazoline (377) is produced from diazomethane and methyl angelate with virtually complete retention of c ~ n f i g u r a t i o n .4~~~ Dialkylamino-pyrazolines have been isolated from the action of diazocarbonyl compounds on enamines; thus methyl diazoacetate and 2-methyl-1-pyrrolidinopropene (378) give compound (379).244Benzaldehyde phenylhydrazone functions as the 1,3-dipolar tautomer (380) in the reaction with N-phenylmaleimide to give the pyrazolidine (38 1).245

Eto2c 0

R

(371) n = 1 (373) n = 2

Me

R2 P h Q

N Ph (374) R' = Me, R2 = Ac (375) R' = Ac, R2 = M e

Me0,C Ac

Me Ph

(377)

(376)

Ph

IH pz2Me 'E H

Me

Me

-+

Me Me

(378) R = 1-pyrrolidinyl (379)

ph&l;,$hH

(380)

OYNYO

'E

Ph H p L h (381)

Reactions. The interconversion of the tautomeric 3(5)-methyl-5(3)-phenylpyrazoles has been studied by temperature-jump s p e c t r o p h ~ t o m e t r y .N~~~ Alkyl-pyrazolium halides are de-quaternized by triphenylphosphine in DMF or 238 239 240

241 242 243 244

245 246

R. Lazaro, D. Mathieu, R. Phan Tan Luu, and J. Elguero, Bull. SOC.Chim.Fr., 1977, 1163. S. Gelin and M. Chabannet, Synthesis, 1978, 448. S. Gelin and C. Deshayes, Synthesis, 1978, 900. P. Battioni, L. Vo-Quang, and Vo-Quang Yen, Bull. SOC. Chim. Fr., Part 2, 1978, 415. P. Battioni, L. Vo-Quang, and Vo-Quang Yen, Bull. SOC.Chim. Fr., Part 2, 1978,401. W. Bihlmaier, J. Geittner, R. Huisgen, and H. U. Reissig, Heterocycles, 1978,10, 147. R. Huisgen and H. U. Reissig, Angew. Chem., Int. Ed. Engl., 1979, 18, 330. R. Grigg, J. Kemp, and N. Thompson, Tetrahedron Lett., 1978, 2827. 0. Bensaude, M. Chewier, and J. E. Dubois, Tetrahedron, 1978,34, 2259.

202

Heterocyclic Chemistry

by the action of thiophenol in benzene-aqueous sodium The isopyrazole (382) yields the 1,4-adduct (383) with acetic anhydride; acetyl chloride, on the other hand, gives the benzisoxazole derivative (384) by initial 1,7-addition. 248

p h f l C N

-

Ph C N C N

- eN N-“

kN C02Me

C0,Me

N

1

Me0,C’ (393)

(394)

(395)

The pyrazole (387) is formed when the pyrazolidine (385) is heated with chloranil; the intermediate A3-pyrazoline (386) can be isolated.249The action of pyridinium hexachloroantimonate on the A*-pyrazoline (388) yields a radical cation which dimerizes to (389) under the influence of zinc 1,l-Dicyano2-methyl-4-phenylbuta- 1,3-diene (390) reacts with two molecules of diazomethane to yield the cyclopropyl-pyrazoline (392) via the non-isolable bis-pyrazoline (391).”l The bis-adduct (394) of 2-diazopropane to the diester (393) similarly decomposes to the biscyclopropyl (395).252Pyrolysis of the 247 248 249

*” 252

J. Elguero and M. Espada, C. R. Hebd. Seances Acad. Sci., Ser. C., 1978,287, 439. T. Kurihara, Y. Sakamoto, T. Sakaguchi, and H. Hirano, Chem. Pharm. Bull., 1978,26, 1141. G. Le Ftvre and J. Hamelin, Tetrahedron Lett., 1978,4503. A. S. Morkovnik and 0. Yu. Okhlobystin, Khim. Geterotsikl. Soedin., 1979, 128. J. Martelli and R. Carrie, Tetrahedron,1978,34, 1163. H. D. Scharf and J. Mattay, Chem. Ber., 1978,111, 2206.

203

Five-membered Rings : Other Systems

pyrazolobenzoxepinones (396; R = COBu', COPh, or NO2) yields cycloThe propabenzoxepinones (397) with complete retention of c~nfiguration.'~~ 3H-pyrazole (398) is photolysed to a mixture of the cyclopropene (399) and the indene (400);254the isomeric pyrazole (401) yields the same cyclopropene, together with the indene (402).255The severely crowded bis-pyrazolinylidene (406) has been prepared by heating the adduct (405) of the diazopyrazoline (403) to the thione (404) with trimethyl p h ~ s p h i t e . *The ~ ~ stable azomethine imine (407) adds nitrosyl chloride to yield compound (408).257

qN."iM Me H

N I1

Me H (397)

Me

(396)

w w \

N2

s +

(404)

(398) R'Ph = COzMe, N R2 = Ph (401) R' = Ph, R2= C02Me

IN--N

N=N

N ---*

R' R2 w

X

Ph Ph

I .

(406)

(405) ---+

F

3

F3C

c

".

CF,

p

N

I

/

c-cl \

NO

CF3

R3 (400) R' = COZMe, R2 = R3 =Ph (402) R1= R2 = Ph, R3 = C02Me

(408)

(410) Ar

The kinetics of the Diels-Alder reaction of isopropoxyethylene with various N-aryl-benzylidenepyrazolinones(409) to yield cis- and trans-pyrazolo-pyrans (410) have been The hydrazone (411) rearranges to the hydrazide 253

254 255 256 257

258

M. J. Begley, F. M. Dean, L. E. Houghton, R. S. Johnson, and B. K. Park, J. Chem. Soc., Chem. Commun., 1978,461. M. I. Komendantov, R. R. Bekmukhametov, and I. N. Domnin, Zh. Org. Khim., 1978,14, 759. C . L. Leach, jr. and J. W. Wilson, J. Org. Chem., 1978, 43,4880. R. J. Bushby, M. D . Pollard, and W. S. McDonald, Tetrahedron Lett., 1978, 3851. D. Bell and A. E. Tipping, J. Fluorine Chem., 1978,11, 567. G . Desimoni, P. P. Righetti, E. Selva, G. Tacconi, V. Riganti, and M. Specchiarello, Tetrahedron, 1977,33,2829.

204

Heterocyclic Chemistry

(412) in acid media.259 Methylation of 4-cyclohexylidene-l,2-diphenylpyrazolidine-3,5-dione (413) yields compound (414).260

Ph

Ph

N' Ph

(411)

.NAr

NAr I/

YPh Ph

1F-N

1ndazoles.-Diphenylcarbamoyl azide, Ph,NCON,, decomposes, on heating, to the labile isocyanate Ph,NNCO, which gives the indazolone (415),261together with 0- and N-acyl derivatives (416) and (417).262Ultraviolet and "N n.m.r. spectroscopy show that the products obtained by treatment of diazotized ortho-aminobenzophenoneswith sodium bisulphite are 3-hydroxy-3H-indazoles (418).263Dipolar benz[cd]indazoles (420) are formed by thermolysis or photolysis of the azido-arylazonaphthalenes(419).264The kinetics of the nitration of indazole to give the 5-nitro-derivative have been determined.265There is evidence from mass spectrometry that the formation of 3-azidoindazole by the action of azide ion on 3-diazoindazole (421)involves a spectacular intermediate: the indazolylpentazole (422).266The 1,3-dipolar adduct (424) of 2-diazo-1,3259 260

261 262 263

264 265 266

J. Elguero, E. Gonzalez, and R. Sarlin, A n . Quim., 1978, 74, 527. B. L. Moldaver and M. E. Aronzon, Khim. Geterotsikl. Soedin., 1979, 254. M. Kurz and W. Reichen, Tetrahedron Lett., 1978, 1433. R. Richter, H. Ulrich, and D. J. Duchamp, J. Org. Chem., 1978,43, 3060. A. J. Boulton, J. S. Khosrowshahi, and K.-W. Thoe, J. Chem. SOC.,Chem. Commun., 1978, 1052 P.Spagnolo, A. Tundo, and P. Zanirato, J. Org. Chem., 1978,43, 2508. ( a ) M. W. Austin, Chem. Ind. (London), 1978,40; ( b )J. Chem. SOC.,Perkin Trans. 2, 1978, 632. B. Stanovnik, M. Tigler, S. Polanc, and D. Janezic, J. Heterocycl. Chem., 1978, 15, 349.

205

Five-membered Rings : Other Systems

diphenylcyclopentadiene (423) to benzyne decomposes to 3 -phenyl- 1H-cyclopenta[ZJphenanthrene (425)on irradiation.267

Ph' PhP

P

'Ph

h N$

N2 (423)

(424)

Ph N

Et0,C

PhF>Ph N Ph (430) R = 4-morpholino

PhHNQ

(-,!hMe N Ph

(431)

1

N=CHPh (432)

H (433)

1midazoles.-Formation. a-Acylamino-ketimines (426; R', R2,R3 = alkyl or aryl) are cyclized to imidazoles (427) under the influence of phosphorus pentachloride or triphenylphosphine-hexachloroethane-triethylamine.268 The '2-azavinamidinium salts' (428;R = But or NMe,) form 4-dimethylamino-imidazoles (429)by the action of sodium amide.269The 4-morpholino-imidazole (430) is obtained when @-morpholinostyrene is treated with the N-chloro-amidine

CIN=CPhNHPh.270NN'-Diphenyl-C-methylthio-formamidine,PhN=C(SMe)NHPh, condenses with the potassium salt of ethyl isocyanoacetate in hexamethylphosphoric triamide in the presence of copper(1) chloride to give the anilino-imidazole ester (431).*'l The benzaldehyde derivative (432) of 1-amino2-methylthio-4-phenylimidazole is produced by the action of phenacyl bromide

on benzylidene-S-methylisosemicarbazone.272 The sterically hindered A3-imidazolidine 3-oxide (433) is formed from the amino-oxime Me2C(NH2)CMe=NOH and Irradiation of a solution of N-benzylidenebenzylamine in isopropyl alcohol affords, inter a h , the 267 268

270

271 272

273

H. Diirr and A. Hackenberger, Synthesis, 1978,594. N.Engel and W. Steglich, Justus Liebigs Ann. Chirn., 1978,1916. R. Gompper and C. S. Schneider, Synthesis, 1979,215. L. Citerio, D. Pocar, R. Stradi, and B. Gioia, J. Chern. SOC.,Perkin Trans. 1, 1978,309. J. T.Hunt and P. A. Bartlett, Synthesis, 1978,741. C.Yamazaki, Bull. Chem. SOC.Jpn., 1978,51, 1846. V. V.Martin and L. B. Volodarskii, Khirn. Geterotsikl. Soedin., 1979,103.

Heterocyclic Chemistry

206

imidazolidine (434).274Methyl propiolate reacts with alkyl and aryl isocyanates in the presence of bi~-(q~-cyclopentadienyl)cobalt(~~) to yield the hydantoins (435) . ~ ~thiohydantoins ~ (437) are obtained by as mixtures of ( E ) -and ( Z ) - i ~ o m e r sThe the action of primary amines RNH2 (R = Me, Pr', or Ar) on the isothiocyanates ( E ) - and (2)-(436), which, in turn, are produced from thiocyanic acid and dimethyl acetylenedi~arboxylate.~~~ Alkyl-cyanamides condense with oxalyl chloride to yield the imidazolidinetriones (438; R = But, 2-adamantyl, e t ~ . ) . ~ ~ ~

NH,

(441)

(442)

(443)

Reactions. Imidazole-2-aldehydes are deformylated in hot The photoisomerization of 1-valerylimidazole to a mixture of 2- and 4-valerylimidazole has been A variety of 2-substituted imidazoles has been prepared by treating 2-lithio-l-triphenylmethylimidazolewith the appropriate electrophile, chlorine, bromine, methyl iodide, ethyl chloroformate, etc., followed by detritylation with an acid.280Mass, i.r., and 'H, 13C, and "B n.m.r. spectroscopy indicate that l-imidazolyldiethylboraneexists as a chain-polymer.281 1,3-Dimethylimidazolidine exists as an equilibrium mixture of cyclic and open-chain tautomers (439) $ (440) in trifluoroacetic acid.282Treatment of 1,2-diamino-irnidazoles (441) with manganese dioxide yields mixtures containing variable amounts of 1,2,3-triazoles (442), 1,2,4-triazines (443), diazocompounds ArCHN,, ketones ArCOCH3, and aryl cyanides.283 The thione 274 275

K. N. Mehrotra and B. P. Giri, Indian J. Chem., Sect. B., 1977, 15, 1106. P. Hong and H. Yamazaki, Nippon Kagaku Kaishi, 1978, 737 (Chem. Abs., 1978,89, 109 236).

'" P. C. Thieme and E. Hadicke, Justus Liebigs Ann. Chem., 1978, 227. 277 278

279

282 283

G . Zinner and V. Kleinau, Arch. Pharm. (Weinheim, Ger.), 1978, 311, 704. I. Antonini, G. Cristalli, P. Franchetti, M. Grifantini, U. Gulini, and S. Martelli,J. Heterocycl. Chem., 1978,15,1201. T. Yatsunami and S. Iwasaki, Helv. Chim. Acta, 1978, 61, 2823. K. L. Kirk, J. Org. Chem., 1978, 4 3 , 4381. K. D. Mueller, L. Komorowski, and K. Niedenzu, Synth. React. Inorg. Met.-Org. Chem., 1978,8,149 (Chem A h . , 1978,89, 75 199). J. B. Lambert and M. W. Majchrzak, J. Am. Chem. SOC.,1979,101, 1048. M. Nakajima, R. Hisada, and J. P. Anselme, J. Org. Chem., 1978, 43, 2693.

Five-membered Rings : Other Systems

207

S-methylide (444), generated from the corresponding hydrofluoroborate, functions as a Wittig reagent in the reaction with aliphatic, aromatic, and unsaturated aldehydes RCHO to yield unsaturated esters RCH=CHC02Me.284 The 2H-imidazole N-oxide (445) and 1-hydroxy-imidazoles, e.g. (446), are deoxygenated by hexachlorodi~ilane.~~~ The N-oxides (447)are cleaved photolytically to di-imines (448)via intermediate fused oxirans.286The photochemical reaction of 1-methyl-2,4,5-triphenylimidazole(449)with acrylonitrile in ethanol affords the cyclobutene (450);in acetonitrile, however, the oxygenated rearrangement product (45 1) is Thermolysis of the 4H-imidazole (452; Ar = p-ClC,H,) results in the bi-imidazolyl (453) by a free-radical mechanism.288The deep-blue quinodimethane derivative (454)adds ethanol in the presence of bases to give compound (455);the reaction is reversed on irradiation.**’

Ph NAr2

N PhCJAr’

I

-

NAr2

c% NA r l

-

SPh phLNAr

‘0

0-

I

COAr’

(452) (453)

(454) E. M. Burgess and M. S. Pulcrano, J. Am. Chem. SOC.,1978, 100, 6538. 285 A. G. Hortmann, J.-Y. Koo, and C.-C. Yu, J. Org. Chem., 1978,43, 2289. 286 G. J. Gainsford and A. D. Woolhouse, J. Chem. SOC., Chem. Commun., 1978,857. Y. Ito and T. Matsuura, J. Org. Chem., 1979,44,41. ’” G . Domany, J. Nyitrai, K. Lempert, W. Volter, and H. Horn, Chem. Ber., 1978,111, 1464. 289 Y. Sakaino, H. Kakisawa, T. Kusumi, and K. Maeda, J. Org. Chem., 1979,44,1241. 284

’”

208

Heterocyclic Chemistry

Benzimidazoles and other Annelated Imidazoles.-2-a-Pyridylbenzimidazole (457) is formed by the action of sodium hypochlorite on the amidine (456).290The benzimidazole oxides (459; R = Me or Ph), produced by hydrogenation of the diphenylamine derivatives (458), form stable nitroxide radicals (460) on treatment with p h e n y l - l i t h i ~ m .The ~ ~ ~acid-catalysed condensation of acetone with o-benzoquinone dioxime gives the 2H-benzimidazole NN’-dioxide (46 1).292 Treatment of the o-benzoquinone bis(benzenesulphony1imine) (462) with 6-pmethoxyphenyl-6-methylfulvene yields the [ 4 ~ + 6 ~adduct ] (463; Ar = pMeOC6H4),which rearranges, on heating, to the benzimidazoline (464).293The phenanthra-imidazole (465) is formed from phenanthraquinone and butylbiguanidine. 294

PhSO,

MecxNso2ph Me\

NS0,Ph

(462)

The complex reaction of benzamidine with 4-methylthio-tropone yields 2phenyl- 1,3-diaza-azulene (466).295The tetra-azacyclopent[e]azulene (467) has 290

291

292 293

M. Ichikawa, S. Nabeya, K. Muraoka, andT. Hisano, Org. Prep. Proced. Int., 1978,10, 205. C. Berti, M. Colonna, L. Greci, and L. Marchetti, J. Heterocycl. Chem., 1979, 16,17. L. B. Volodarskii and V. A. Samsonov, Zzv. Akad. Nauk SSSR, Ser. Khim.,1978,971. W. Friedrichsen and H. G. Oeser, Justus Liebigs Ann. Chem., 1978, 1146.

294

S. Tanabe and T. Sakaguchi, Chem. Pharm. Bull., 1978,26,423.

295

M. Cavazza, R. Cabrino, F. Del Cima, and F. Pietra, J. Chem. SOC.,Perkin Trans. 1, 1978, 609.

Five-membered Rings : Other Systems

209

been isolated from bathyal marine organisms of a species of P a r a ~ o a n t h u s . ~ ~ ~ Syntheses of the related, highly fluorescent marine natural products pseudozoanthoxanthin A (468) and parazoanthoxanthin A (469) have been described.297

(467) R = M e (468) R = H

M

e

Q N T

,

2-Benzoyl-1,3-dimethylbenzimidazoliumiodide is debenzoylated in hot water.298Tri-1 -benzimidazolylmethane is produced by the action of dichlorocarbene on benzimidazole. Irradiation of benzimidazole in air yields a mixture of the 2,4’-bibenzimidazolyl (470) and the 2,5‘-is0mer.~~~ Photo-Fries rearrangement of the diacetylbenzimidazolinone (471) causes the acetyl group at N-1 to migrate to C-5 or to C-7.301The hydroxybenzimidazole N-oxide (472) rearranges to o-nitrosoacetanilide (473) in sunlight.302 5 Systems containing Two Different Heteroatoms

Oxathioles and 0xaselenoles.-The 1,3-0xathioles (474; R = Ph)303and (474; R = B2)304are produced by the reaction of azibenzil, PhCOC(N2)Ph, with thiobenzophenone and monothiobenzil, respectively. The dihydrothiophen ylide (475) undergoes a complex reaction on heating to give 2-benzoyl-5-phenyl-l,3oxathiole (476), which on further heating decomposes to 1,2-dibenzoylethy(477)is formed by the action of 1ene.305l,l-Dichloro-2,1-benzoxathiol-3-one

296 297 298

299

300 301 302

303 304

30s

R. E. Schwartz, M. B. Yunker, P. J. Scheuer, and T. Ottersen, Tetrahedron Lett., 1978,2235. M. Braun, G. Buechi, and D. F. Bushey, J. A m . Chem. SOC.,1978,100,4208. J. Glowczyk and B. Serafin, Pol. J. Chem., 1978, 52, 1467. H. Singh and P. Singh, Chem. Ind. (London), 1978, 126. E. R. Cole, G. Crank, and E. Lye, Aust. J. Chem., 1978,31, 2675. P. Bouchet, G. Joncheray, R. Jacquier, and J. Elguero, J. Heterocycl. Chem., 1978, 15, 625. M. J. Haddadin. A. A. Hawi. and M. Z . Nazer. Tetrahedron Lett.. 1978,4581. S . Mataka, S. Ishii, and M. Tashiro, J. Org. Chem., 1978, 43, 3730. C. Bak and K. Praefcke, Chem.-Ztg., 1978,102,456. U . J. Kempe, T. Kempe, and T. Norin, J. Chem. SOC.,Perkin Trans. 1, 1978, 1547.

210

Heterocyclic Chemistry

chlorine on thiosalicylic 2-(Benzylsulphinyl)isophthalicacid rearranges to the benzoxathiolone (478) in acetic anhydride-acetic 2-Morpholino-5-phenyl-l,3-oxathiolium perchlorate (479) forms the thiazole (480) on treatment with ammonia; the imines (481) or open-chain compounds are obtained from the reactions with primary aromatic a m i n e ~ . ~Non-isolable '~ 1,3-oxathiolium 4-oxides (482; R = SMe or morpholino), generated by the action of acetic anhydride on the acids RC(S)OCHPhCO,H, react with dimethyl acetylenedicarboxylate in situ to form furans (484) via the 1,3-dipolar cycloadducts (483).309The y-sultine (485) decomposes photolytically to 1 -methyl-2phenylcyclopropaneby a free-radical chain mechanism.310The X-ray structure of the sulphurane (486; R = perfluoropivaloyl) has been

(485)

2-Acetylimino-1,3-0xaselenoles (488),representatives of a new heterocyclic system, are prepared by the action of potassium selenocyanate and acetic anhydride on the dicyano-oxirans (487).312A mixture of the 1,3-0xaselenolen (489) and the oxaselenolenone (490) results when the dibromo-ketone ArCOCBr,Ph (Ar = p-MeOC6H,) is treated with potassium ethyl diselenocarbonate. l 3 V. N. Klyuev, A. B. Korzhenevskii, and B. D. Berezin, Izu. Vyssh. Uchebn. Zaued., Khim. Khim. Tekhnol., 1978,21, 189 (Chem. Abs., 1978,89,24 223). W. Walter, B. Krische, G . Adiwidjaja, and J. Voss, Chem. Ber., 1978, 111, 1685. jog K. Hirai and T. Ishiba, Chem. Pharm. Bull., 1978,26, 3017. 309 H. Gotthardt, C. M. Weisshuhn, and K. Dorhofer, Chem. Ber., 1978,111, 3336. 310 T. Durst, J. C. Huang, N. K. Sharma, a n d D . J. H. Smith, Can.J. Chem., 1978, 56, 512. 311 E. F. Peroui and J. C. Martin, J. Am. Chem. SOC.,1979,101, 1155. 312 A. Robert and A. Le Marechal, J. Chem. SOC.,Chem. Commun., 1978,447. 3'3 C . Bak, K. Praefcke, and L. Henriksen, Chem.-Ztg., 1978, 102, 361. 306

307

Five-membered Rings : Other Systems

21 1

1soxazoles.-Formation. syn- 1,4-Dilithio-oximes are formed regiospecifically by the action of butyl-lithium on oximes; subsequent treatment with amides, followed by hydrolysis, yields isoxazoles. In this way, 3-(2-phenylethyl)isoxazole (492), uncontaminated by the 4-benzyl-3-methyl isomer, is obtained from the reaction between the di-lithio-derivative (491) of 4-phenylbutan-2-one oxime and dimethylf~rmarnide.~~~ Thermolysis of p-azido-ap-unsaturated ketones R'COR2C=CR3N3 (R', RZ,R3 = H, Me, or Ph) yields isoxazoles (494) via intermediate acyl-azirines (493).315The formation of 4-nitro-isoxazoles (495) by the action of dinitrogen trioxide on unsaturated ketones Ar'COCH=CHAr* has been r e p ~ r t e d . Nitrosyl ~'~ chloride reacts with diethyl acetonedicarboxylate to yield the 4-hydroxy-isoxazole (496).317The phosgene-iminium chloride (497) condenses with NN-dimethylfluoroacetamide to give the salt (498), which is converted into the isoxazole derivative (499) when it reacts with hydr~xylamine.~~~

H O C0,Et E t 0 2 CO/p N

Me02C

Me

MeO,Clj\jN 0' (500)

1,3-Dipolar cycloaddition reactions of olefins and acetylenes to nitrile oxides and nitrones continue to be a field of active research. Treatment of nitroethane with an acyl chloride gives an unstable O-acyl intermediate CH3CH2h(0)OCOR Cl-, which fragments to acetonitrile oxide, CH,C&-O; in the presence of dimethyl acetylenedicarboxylate, the adduct (500) is formed.319The effect of G. N. Barber and R. A. Olofson, J. Org. Chem., 1978,43, 3015. K. Isomura, Y. Hirose, H. Shuyama, S. Abe, G. Ayabe, and H. Taniguchi, Heterocycles, 1978, 9, 1207. 316 J. P. Hauff, J. Tuaillon, and R. Perrot, Helv. Chim. Acta, 1978,61, 1207. 317 R. B. Silverman, J. Heterocycl. Chem., 1978, 15, 1519. 318 J. Gorissen and H. G. Viehe, Bull. SOC.Chim. Belg., 1978,87, 391. 319 E. Kaji, K. Harada, and S. Zen, Chem. Pharm. Bull., 1978,26, 3254. 31*

31s

Heterocyclic Chemistry

212

temperature on the ratio of the isomeric endo- and exo-adducts of benzoyl cyanide oxide to n~rbornadiene,~~' the stereochemistry of the products (501) from styrene and the chiral nitrone PhMeCHN(0)=CHPh,321and the kinetics of the non-synchronous addition of a series of ethyl arylmethylenecyanoacetates ArCH=C(CN)CO,Et to the highly polarized N-phenyl-C-a-pyridylnitrone PhN(O)=CHPy (Py = a-pyridyl) to yield the isoxazolidines (502)322have been investigated. 2-Phenylsulphonyl-2-azabicyclo[3.2.l]octa-3,6-diene(503) reacts with benzonitrile oxide at the 6,7-double bond to yield a mixture of the exo-regioisomers (504) and (505).323 Benzonitrile oxide adds to the less substituted double bonds of both the bicyclo[2.2.2]octadiene (506) and the bicyclo[3.2.2]nonadiene (508); but whereas the former reaction affords only the endo-product (507), the latter results in the corresponding exo-isomer (509).324The regiospecific cycloaddition of benzonitrile oxide to the isoxazoline (5 10)yields the fused heterocycle (5 11).32s

(511)

1,5-Diphenylpenta- 1,4-dien-3-one oxime is autoxidized to the hydroxy-isoxazoline (512) in the presence of copper(II), cobalt(II), or manganese(I1) 320

32'

322

323 324

325 326

H. Taniguchi and E. Imoto, Bull, Chem. SOC.Jpn., 1978, 51, 2405. C . Belzecki and I. Panfil, J. Org. Chem., 1979, 44, 1212. D. St. C . Black, R. F. Crozier, and I. D. Rae, Aust. J. Chem., 1978, 31, 2239. H. Taniguchi, T.Ikeda, and E. Imoto, Bull. Chem. SOC.Jpn., 1978,51, 1859. H. Taniguchi, T. Ikeda, and E. Imoto, Bull. Chem. SOC.Jpn., 1978,51, 1495. J. P. Gibert, C. Petrus, and F. Petrus, J. Chem. Res. ( S ) , 1978, 164. K. Kikuchi, Y. Maki, M. Hayashi, and N. Murakoshi, Heterocycles, 1978,11, 187

213

Five-membered Rings : Other Systems

Heating acetophenone with urea or thiourea yields the amino-isoxazoline ( 5 13).3274-Nitro-isoxazoline N-oxides (5 14) are produced from a@-dinitrostyrene, PhC(N02)=CHN02, and diaryl-diaz~methanes.~~~ 0-Cinnamoyl-Nmethylhydroxylamine (5 15) cyclizes to the isoxazolidinone (5 16),329contrary to Baldwin’s rules.33o

(5 1 3)

(514)

(516)

(515)

Reactions. Lithium phenylethynolate (5 17) has been generated by treatment of 3,4-diphenylisoxazole with butyl-lithium; dilithioketen (5 18) is similarly obtained from 3-phenylisoxazole (Scheme 6).3315-o-Hydroxyphenyl-isoxazole Ph

I C 111

Li+ C

+

PhCN

IR=Ph

R

Ph

- R=H

Li+

I

H

Li

C‘

c

111

c

I 0-

I

111

C Li+

I 0-

(518)

Scheme 6

(5 19) rearranges thermally to 4-hydroxy-24minochromene (521) via the nitrile (520).332Irradiation of the isoxazolyl-acetamidine (522) yields a mixture of the imidazole (523) and the pyrimidine (524) by way of open-chain intermediate^.^^^ NH

327 328 329

330

331

332 333

L. N. Volovelskii, S. A. Korotkov, N. V. Popova, and Z . P. Shchechenko, Zh. Org. Khim., 1978,14, 2000. F. A. Gabitov, 0. B. Kremleva, and A. L. Fridman, Khim. Geterotsikl. Soedin., 1978,324. K . R. Fountain and G. Gerhardt, Tetrahedron Lett., 1978, 3985. J. E. Baldwin, J. Chem. SOC., Chem. Commun., 1976, 734; J. E. Baldwin, J. Cutting, W. Dupont, L. Kruse, L. Silberman, and R. C. Thomas, ibid., p. 736. I. Hoppe and U. Schollkopf, Justus Liebigs Ann. Chem., 1979, 219. Z. Jerzmanowska and W. Basinski, Rocz. Chem., 1977,51,2283. G .Adembri, A. Camparini, D. Donati, F. Ponticelli, and P. Tedeschi, Tetrahedron Lett., 1978,4439.

214

Heterocyclic Chemistry

The kinetics of the reversible thermal isoxazole-azirine isomerization (525) $ (526) (R’, R2, R3 = H, Me, or Ph) have been determined.334The azirine (526; R1 = R3 = Me, R2 = H) is thought to be an intermediate in the rearrangement of 3,5-dimethylisoxazole to 2,5-dimethyloxazole at 500 0C.335 R2

R’

R 3 c N =

R2

B:

R3

0

2,3-Dimethyl-5 -phenylisoxazolium iodide (5 27) yields 5 -methyl-3 -phenylisoxazole (530) on treatment with hydroxylamine via the adducts (528) and (529).336 The action of acetic anhydride on the condensed isoxazolium bromide (531) results in a complex rearrangement to afford a mixture of the pyrazole (532) and the pyrrolinone (533).337 The meso-ionic isoxazolium oxide (534) is formed by deprotonation of 4hydroxy-2-methyl-3,5-diphenylisoxazoliump e r c h l ~ r a t e Deuteriation .~~~ or alkylation of 4-lithio-5-methyl-3-phenyl-A2-isoxazoline results predominantly in the trans-isomers (535; R = 2H or a l k ~ l )Heterocyclic .~~~ acetylenes RCECH 334

335

336

337 338 339

( a ) R. R. Bekmukhametov, Tezisy Dok1.-Resp. Konf. Molodykh Uch.-Khim., 2nd, 1977, 1, 49 (Chem. Abs., 1978, 89, 162830); ( b ) M. I. Komendantov, R. R. Bekmukhametov, and R. R. Kostikov, Khim. Geterotsikl. Soedin., 1978, 1053. D. A. Murature, J. D. Perez, M. M. D e Bertorello, and H. E. D e Bertorello, A n . Asoc. Quim. Argent., 1976,64, 337 (Chem. Abs., 1978,89, 128 847). C. Kashima, K. Arai, S. Imada, and Y. Tsuda, Bull. Chem. SOC.Jpn., 1978, 51, 1844. G . Jones, J. R. Phipps, and P. Rafferty, Tetrahedron, 1978,34, 1581. W. Friedrichsen and R. Schmidt, Justus Liebigs Ann. Chem., 1978, 1540. V. Jager and W. Schwab, Tetrahedron Lett., 1978, 3129.

215

Five-membered Rings : Other Systems

(R = 2-pyrrolyl, 3-indolyl, 5-methyl-2-fury1, etc.) are formed in good yield by flash photolysis of the (heteroarylmethy1ene)isoxazolones (536);340 the iminoisoxazolones (537;R = aryl or heteroaryl) similarly decompose to isocyanides RNC on heating.341Photoelectron spectroscopyof a series of isoxazolidines (538; R = H,Me, or But) reveals an increasing tendency for the N-substituent to occupy an equatorial position as its bulk increases.342The complexed isoxazolidine (539)undergoes 1,3-dipolar cycloreversion to tropone-iron carbonyl (540)and the nitrone (541)even at room temperature, due to the conjugated nature of the t r ~ p o n e . ~ ~ ~ RN

RHC

(5 38)

(537)

~

~

-

B u 1 a1 c H 2

(540)

-0'

0

H

-Buts \

\

\

But N O

Bu'

(541)

NOH

~

/

Bu'

- 0

0 (544)

0 (545)

Benzisoxazo1es.-Thermolysis of the nitroso-compound (542)yields the dihydrobenzisoxazole (543)by an initial [1,5] shift of hydrogen.344The diazidobenzoquinone (544) is transformed into the isoxazolo-benzisoxazole (545)on 340 341 342

343 344

C. Wentrup and H.-W. Winter, Angew. Chem., Znt. Ed. Engl., 1978,17,609. C . Wentrup, U. Stutz, and H. T. Wollweber, Angew. Chem., Int. Ed. Engl., 1978,17,688. P. Rademacher and B. Freckmann, Tetrahedron Lett., 1978,841. R.Gandolfi, L. Toma, and C. D e Micheli, Heterocycles, 1979,12,5. R. Okazaki, M. Watanabe, Y. Inagaki, and N. Inamoto, Tetrahedron Lett., 1978,3439.

~

Heterocyclic Chemistry

216

heating.345 3-(4-Methoxystyry1)-2,1-benzisoxazole (546; Ar = p -MeOC6H4), obtained by heating p-methoxybenzylidene-o-azidoacetophenoneat 110 "C, rearranges to the indoxyl(548) at 155 "C; at higher temperatures the quinolinone (549) is formed. The nitrene (547) is the key intermediate in these reactions.346 Irradiation of 1,2-benzisoxazoles (550; R = H or Me) in sulphuric acid generates the aryl-oxenium ions (551) as singlets, which are attacked by water to give a mixture of the o- and p-dihydroxy-compounds (552) and (553).3472,lBenzisoxazoles (554; R = Me or Ph) yield the analogous nitrenium ions ( 5 5 5 ) ; these are captured by water or chloride ion as the hydroxy- or chloro-ketones (556) and (557) (X = OH or C1, r e s p e c t i ~ e l y ) . Photolysis ~~~*~~~ of a solution of indazole in dilute sulphuric acid similarly affords the nitrenium cation (558).350

(549) H

H (554)

(555)

(559)

(556) 3-x (557) 5-x

(560) R' = F, R2 = CF3, R3 = Ph

0xazoles.-Formation. Numerous oxazoles (559; R', R2,R3 = H, alkyl, or aryl) have been obtained by the Lewis-acid-catalysed decomposition of a-diazoThe imine ketones R'COCR2N2 in the presence of nitriles R3CN.351*352 345

346 347

348

349 350

352

R. Neidlein, G. Humburg, A. Gieren, and C. Hahn, Chem. Ber., 1978, 111,3346. R. K. Smalley, R. H. Smith, and H. Suschitzky, Tetrahedron Lett., 1978, 2309. T. Doppler, H. Schmid, and H. J. Hansen, Helv. Chim. Acta, 1979,62, 314. ( a )T. Doppler, H. Schmid, and H. J. Hansen, Helu. Chim. Acta, 1979, 62, 271; ( b )ibid., p. 304. ( a )E. Giovannini and 8 . F. S. E. De Sousa, Helv. Chim. Acta, 1979,62, 198; ( b ) ibid., p. 185. E. Georgarakis, H. Schmid, and H. J. Hansen, Helv. Chim. Acta, 1979,62, 234. T. Ibata and R. Sato, Chem. Lett., 1978, 1129. M. P. Doyle, M. Oppenhuizen, R. C. Elliott, and M. R. Boelkins, Tetrahedron Lett., 1978, 2247.

217

Five-membered Rings : Other Systems

(CF&C=NBz cyclizes to the fluorinated oxazole (560) on heating with tin(I1) Derivatives of 4-methoxycarbonyl-oxazole are formed from methyl isocyanoacetate and cyclic anhydrides; phthalic anhydride, for instance, yields compound (561).354

?!I/

.+To

-0

0

(565) R = H (566) R = Ph; 5-Ar

R2

\ / R'_N R3@H

-

Et02C

--*

R30

Et02C

Prolonged heating of the imidate hydrochloride PhC(OEt)=NH,' C1- with 2-aminoethanol affords the oxazoline (562).355Phenyl isocyanide reacts with hexafluoroacetone N-ethoxycarbonylimine to give the phenylimino-oxazoline (563).356Treatment of aryl-oxirans (564)with urea leads to a mixture of 4- and 5 -aryl-oxazolidinones (565);357with phenyl isocyanate, only the 5 -substituted compounds (566)are The salt (567) is formed by the action of acetic .~~~ formation of the anhydride and perchloric acid on acetone ~ y a n h y d r i n The rearranged adducts (569) of t-butylcyanoketen to the N- aryl-nitrones (568) has been

Reactions. Photo-oxygenation of the oxazoles (570; R1 = Me, Ph, or OMe; R2 = H or Ph; R3 = Ph or OMe) produces the unstable peroxides (571).3h' The Diels-Alder adducts (572) of ethyl propiolate to oxazoles (570; R' = H; R2, 353 354

355

356

357

358 359

360

361

R. Ottlinger, K. Burger, H. Goth, and J. Firl, Tetrahedron Letr., 1978, 5003. M. Suzuki, K. Nunami, K. Matsumoto, N. Yoneda, and M. Miyoshi, Synthesis, 1978,461. M. I. Butt, D. G. Neilson, K. M. Watson, and U. Zakir, J. Chem. Soc., Perkin Trans. 1,1977,2328. E. G. Ter-Gabrielyan, N. P. Gambaryan, and Yu. V. Zeifman, Izv. Akad. Nauk SSSR,Ser. Khim., 1978,1888. A. Huth and F. Neubauer, Justus Liebigs Ann. Chem., 1979,56. D. Braun and J. Weinhert, Justus Liebigs Ann. Chem., 1979,200. ( a )G. N. Dorofeenko, V. D. Karpenko, and Yu. I. Ryabukhin, Zh. Org. Khim., 1978,14,1905; ( 6 ) A. T. Balaban, A. Bota, G. N. Dorofeenko, V. D. Karpenko, and Yu. I. Ryabukhin, Tetrahedron,. 1978,34,2035. M. A. Abou-Gharbia, M. M. Joullie, and I. Miura, Heterocycles, 1978, 9,457. ( a ) M. L. Graziano, M. R. Iesce, and R. Scarpati, J. Heterocycl. Chem., 1978, 15, 1205; ( b ) ibid., 1979, 16, 129.

Heterocyclic Chemistry

218

R3 = H, alkyl, aryl, or C02Et) decompose spontaneously to nitriles R2CN and the furan-esters (573).362 The fluorine atom in compound (574)is activated by the oxazoline substituent in displacement reactions with Grignard reagents and organo-lithium The transformation of the N-acetyl-oxazolin-2-one (575;R = Ph) into the oxazole (576)in sulphuric acid represents a nitrogen analogue of the a-acyl-lactone rearrangement.364 Sensitized photo-addition of ethylene to the oxazolinone (575;R = Me)produces the cyclobutane (577)in high yield.365 A comprehensive article deals with the dipole moments of representatives of fourteen classes of meso-ionic compounds, including oxazolium 5 -oxides, 5 sulphides, and 5-imidates (578; X = 0, S, or NR).3662,3-Diphenyloxazoliurn 4-oxide (579;R = Ph), generated by the catalysed decomposition of the diazoamide PhCONPhCOCHN2, gives the 1,3-dipolar cyclo-adduct (580; Ar = pClC6H4) with p-chl~robenzaldehyde.~~’ The formation of the furan (583) when 2-phenyl-A2-oxazolin-4-one(581) is treated with dimethyl acetylenedicarboxylate proceeds by way of the meso-ionic tautomer (579;R = H) and the labile adduct ( 5 82).368 Me

(579)

362

364

365

366 367 368

G. Ya. Kondrateva and L. B. Medvedskaya, Tezisy Dok1.-Vses. Konf. Khim. Atsetilena, Sth, 1975, 304 (Chem. Abs., 1978,89,90 148). A. I. Meyers and B. E. Williams, Tetrahedron Lett., 1978, 223. H. Lautenschlager, Justus Liebigs Ann. Chem., 1978, 566. K. H. Scholz, H. G. Heine, and W. Hartmann, Tetrahedron Lett., 1978, 1467. R. N. Hanley, W. D. Ollis, C. A. Ramsden, G. Rowlands, and L. E. Sutton, J. Chem. SOC.,Perkin Trans. 1, 1978, 600. M. Hamaguchi, J. Chem. SOC., Chem. Commun., 1978,247. K. T. Potts and J. L. Marshall, J. Org. Chem., 1979, 44, 626.

219

Five-membered Rings : Other Systems

Benzoxazo1es.-The phenolic Schiff's bases (584; R = alkyl or aryl) are con5-Bromo-2verted into benzoxazoles (585) by the action of silver

-+

0

)

R

(585)

(584)

phenylbenzoxazole (587) is obtained by treatment of a-bromobenzylidene-o nitrophenylhydrazone (586) with sodium ethoxide; the mechanism outlined in Scheme 7 has been proposed to account for this surprising reaction.370 Anodic oxidation of p-methoxy-N-methylacetanilidein the presence of sodium perchlorate yields the benzoxazolium salt (588).371 OH

J

(587)

Scheme 7

Alcohols R'OH are efficiently phosphorylated by condensation with 2-fluorobenzoxazole and treatment of the resulting ethers (585; R = OR') with diphenylphosphoric The reaction of N-phenyl-N-salicoylhydroxylamine (589) with thionyl chloride yields the benzoxazolone (591) rather than the benzisoxazolone (592),as was claimed previously; the acylnitrenium ion (590)is a likely intermediate in the ~onversion.3~~

0;" - ON>0 Ph

I

Ph

4 Z h J-f

' (589) 369 370

371

372 373

(590)

0 (591)

M. Yoshifuji, R. Nagase, T. Kawashima, and N. Inamoto, Heterocycles, 1978, 10,57. S. Sunders and N. P. Peet, J. Heterocycl. Chern., 1979, 16, 33. M. Masui, C. Ueda, and H. Ohmori, Chern. Pharrn. Bull., 1978, 26, 1953. Y. Watanabe and T. Mukaiyama, Chem. Lett., 1978,349. T. Sheradsky and S. Avramovici-Grisaru, Tetrahedron Lett., 1978, 2325.

220

Heterocyclic Chemistry

Other Systems.-The allenic phosphonate Me,C=C=CH-P(0)(OMe)2 cyclizes to the 1,2-oxaphospholen (593) in hydrochloric [27r + 27~1 Cyclo-adducts (595) are formed from azaphospholes (594; R = Me, Ph, or NMe2) and phenyl isocyanate.375Dehydrochlorination of compound (596) yields the 1,2-benziodazol-3-one (597).376

6 Systems containing Three Identical Heteroatoms Trithio1ans.-X-Ray analysis of the product obtained from sulphur and tricyclopentadiene shows that it is the 1,2,3-trithiolan derivative (598).’77 Reductive dimerization and cyclization of ClSCClMe gives 3,5-dimethyl- 1,2,4-trithiolan (599).37g

1,2,3-Triazoles and Benzotriazo1es.-Benzil toluene-p-sulphonylhydrazone, TosNH-N=CPhCPh=N-NHTos, undergoes oxidative cyclization to the N(tosylamino)-1,2,3-triazole (600) under the influence of mercury(I1) acetate.379 374

375 376 377

378 379

T. S. Mikhailova, V. M. Ignatev, B. I. Ionin, and A. A. Petrov, Zh. Obshch. Khim., 1978, 48, 701. A. Schmidpeter and T. von Criegern, J. Chem. SOC., Chem. Commun., 1978,470. T. M. Balthazor, D. E. Godar, and B. R. Stults, J. Org. Chem., 1979,44, 1447. J. Emsley, D. W. Griffiths, and R. Osborn, J. Chem. SOC., Chem. Commun., 1978,658. P. Dubs and M. Joho, Helv. Chim. Acta, 1978,61, 1404. R . N. Butler, A. B. Hanahoe, and W. B. King, J. Chem. Soc., Perkin Trans. I, 1978, 881.

22 1

Five-membered Rings : Other Systems

Diazodihydromethoxyuracil (601; R = OMe) is transformed into the triazole (602) by the action of butylamine; the intermediate butylamino-derivative (601; R = NHBu) cannot be The reaction of aromatic Schiff's bases Ar'CH=NAr* with diazoacetonitrile results in a mixture of cis- and trans-A21,2,3- triazolines (603), their decomposition products [the cis- and trans- azirines The triazatricyclodecenes (607), (604)], and the rearranged enamines (605).381 obtained from the alcohol (606) and aryl azides, form 3-azatricycloC3.2.1. 0 2 p 4 ] ~ ~ t a(608) n e ~ on thermolysis or photolysi~.~** The azide (609) undergoes a spontaneous intramolecular 1,3-dipolar cycloaddition to yield the condensed triazoline (610).383Aza-ally1 cations (61l ) , formed from arenediazonium salts and 2-methylaminoethanol, cyclize to the triazenium salts (612), a 5-Amino-l-methyl-1,2,3-triazole (613) is attacked new class of by the Vilsmeier-Haack reagent at both carbon and nitrogen to yield compound (614); in contrast, the 4-amino-1-methyl isomer is substituted only at the amino-group. 385

OHC \

Me (613)

Me

Me,N (614)

S. Romani and W. Klotzer, J. Heterocycl. Chem., 1978,15, 1349. F. Roelants and A. Bruylants, Tetrahedron, 1978, 34, 2229. 382 P. G. Gassman and 3. G. Schaffhausen, J. Org. Chem., 1978,43,3214. 383. P. Kolsaker, P. 0. Ellingsen, and G. Woeien, Acta Chem. Scand., Ser. B, 1978, 32, 683. 384 H. Hansen, S. Hunig, and K. Kishi, Chem. Ber., 1979,112, 445. 38s A. Albert and C. J. Lin, J. Chem. SOC.,Perkin Trans. 1, 1978,427. 380

381

HeterucycZic Chemistry

222

The kinetics of the thermal conversion of various u-azido-azobenzenes (615) into 2-aryl-benzotriazoles (616) have been The quinonoid character of 2-substituted benzotriazoles is shown by the formation of a mixture of geometrically isomeric addition compounds (617)when (616; Ar = 2-acetoxy-5methylphenyl) is treated with chlorine.387The action of iodine or bromine on 1-chlorobenzotriazole (618) affords the corresponding iodo- or bromo-derivatives; the latter is an active oxidant; e.g., for the conversion of benzyl alcohol into b e n ~ a l d e h y d e .The ~ ~ ~ reaction of 1-chlorobenzotriazole with benzophenone hydrazone surprisingly yields the substituted methylenecyclohexadiene (6 19).389 CI

HN-N Me2& NJCHCI, (621)

/

H2C=CMe \ N-N

R1kN

N

M e U &

JSR2

(622)

0 (623)

(624)

1,2,4-Triazoles.-Two new syntheses of the 172,4-triazole nucleus are the formation of 3,4-diaryl-triazoles (620) from imidoyl chlorides Ar'N=CC1Ar2 and lithio-dia~omethane,~~~ and that of the dichloromethyl-derivative (621) by the action of hydrazine on the (trichloroviny1)imidoyl chloride C12C=CClN=CClNMe2.391Ten triazole thioethers (622) have been prepared by heating isothiosemicarbazones R'CH=N-N=C(NH2)SR2 (R', R2 = alkyl or aryl) with c h l o r o a ~ e t o n eTreatment .~~~ of 6-methyl-2-phenyl- 173-oxazin-4-one (623) with hydrazine results in ring-contraction to yield compound (624).393 386

387 388 389

390 391

392

393

J. H. Hall and F. W. Dolan, J. Org. Chem., 1978,43, 4608. T. Norris, A . Payne, and D. T. Southby, J. Chem. Soc., Chem. Commun., 1978, 932. M. J. Sasse and R. C. Storr, J. Chem. Soc., Perkin Trans. 1, 1978,909. M. Keating, M. J. Sasse, and R. C. Storr, J. Chem. Soc., Perkin Trans. 1, 1978, 905, D. N. Kevill and M.-G. A . Park, Tetrahedron Lett., 1978, 4629. D. Van Broeck, Z. Janousek, R. MerCnyi, and H. G . Viehe, Angew. Chem., Int. Ed. Engl., 1979,18, 333. C. Yamazaki, Tetrahedron Lett., 1978, 1295. ( a )Y. Yarnarnoto, Y. Azuma, andT. Kato, Symp. Heterocycl. (Pupua),1977,112;( b )Y. Yamamoto, Y. Azuma, and K. Miyakawa, Chem. Pharm. Bull., 1978,26, 1825.

223

Fiue-membered Rings : Other Systems

Contrary to a previous report, the triazinedione (625) is transformed into 5-hydroxy-1,2,4-triazole-3-carboxylic acid (626) in acid media.394Oxidative cyclization ,of isopropylideneiminoguanidine with lead(1v) acetate affords the triazoline (627).395 1,6-Dimethyl-2,5-dithiobiurea, MeHNC(S)NHNHC(S)NHMe, yields a mixture of the triazolidinedithione (628)and the triazolinethione (629)when treated with a base.396A method for converting primary aliphatic amines into aldehydes with the same number of carbon atoms is shown in Scheme

8.397

RCHO

+

'\

Ph Nr.N I : '!\ Aq.'..;)SMe +H,N N Ph

I

A.

/E

Ph N-N

E

41 ..1 H\ c1-

E

E = CO,Et

I /N C-H I

A

JSMe N Ph

R

Reagents: i, EtO,CN=NCO,Et (i.e. EN=NE); ii, HzO,HCI

Scheme 8

7 Other Systems containing Three Heteroatoms

Oxadiazoles.-l,2,3-Oxadiazoles. A series of sydnone N-carbamoyl-imines (630;R = alkyl) has been prepared by treating the corresponding sydnone T. J. Schwan, T. J. Sanford, R. L. White, jr., and N. J. Miles, J. Heterocycl. Chem., 1979, 16, 199. L. M. Cabelkova-Taguchi and J. Warkentin, Can. J. Chem., 1978,56,2194. "'H . W. Altland and P. A. Graham, J. Heterocycl. Chem., 1978.15, 377. 397 G. Doleschall, Tetrahedron Lett., 1978, 2131. 394

395

224

Heterocyclic Chemistry

imines with aryl iso~yanates.~~' Photolysis of diphenylsydnone (631) affords the triazole (633), while l-acetyl-2-benzoyl-1 -phenylhydrazine (634) is formed in the presence of acetic acid; both reactions are thought to proceed via the nitrile imine (632).399An unusual photo-isomerization, that of the N-morpholinosydnone (635) to the dipolar triazole N-oxide (636), has been

Phd,,

Ph \

N ,NPh

Ph

I

OMe

(634)

(637)

H,E

N Ef:

1,2,4-Oxadiazoles. Treatment of benzamide oxime, PhC(NH2)=NOH, with the lactam acetal(637) yields the 1,2,4-oxadiazole derivative (638).401The formation of 3-aryl-1,2,4-oxadiazoles(640) from nitrile oxides ArCNO and 1,3,5-triazine (639) in the presence of boron trifluoride involves azomethine radicals.402The combined action of sodium nitrite and benzoic acid o n the azirine (641) gives the nitrite (642), which cyclizes to the oxadiazoline (643); irradiation of the latter affords 2-methoxycarbonyl-benzimidazole (644).403 The kinetics of the

398

399

400

402 403

Z. A. Olovyanishnikova, T. M. Ivanova, V. E. Sviridova, and V. G. Yashunskii, Khim. Geterotsikl. Soedin., 1978, 170. M. Marky, H. Meier, A. Wunderli, H . Heimgartner, H. Schmid, and H. J. Hansen, Helu. Chim. Acta, 1978,61,1477. H. Gotthardt, F. Reiter, A. Gieren, and V. Lamrn, TetrahedronLeft., 1978, 2331. A. Botta, Justus Liebigs Ann. Chem., 1978, 306. M. Kurabayashi and C. Grundmann, Bull. Chem. SOC.Jpn., 1978,51, 1484. M. Vaultier and R. Carrie, J. Chem. SOC.,Chem. Commun., 1978, 356.

225

Fiue-membered Rings : Other Systems

oxadiazole --+ triazole rearrangement (645) --+ (646) (Ar = Ph, p-MeOC6H4, m-N02C6H4,etc.) have been determined.404

(647)

1,2,5-Oxadiazoles. The furoxan (647) is formed when l-nitrosohex-l-yne, BuCGC-NO, is treated with aniline and nitrosyl ~hloride.~"The reaction of bromine azide with ethyl 3-nitro-2-alkenoates RC(NO,)=CHCO,Et (R = Me, Et, or Ph) leads to the furoxans (648).406Various fused heterocyclic systems are accessiblefrom diaminofurazan (649); benzoylacetaldehyde,for example, affords the furazano-pyrazine (650),4" while ethyl acetoacetate gives the furazanodiazepinone (65 l).408 Treatment of dibenzoylfuroxan (652) with isopropylamine results in ring transformation to the isoxazole derivative (653).409 The nitrobenzoxadiazole derivative (654) forms the Meisenheimer complex (655) in DMSO; the corresponding l-oxide yields an analogous complex, but much more slowly.41o'Benzotrifuroxan' has structure (656), as shown by 13C n.m.r. spectro~copy.~" 404

405 406

407 408 409

410 411

D. Spinelli, V. Frenna, A. Corrao, N. Vivona, and M. Ruccia, J. Heterocycl. Chem., 1979,16,359. J . M. Tedder and D. J. Woodcock, J. Chem. Res. ( S ) , 1978, 356. C.-G. Shin, Y. Yonezawa, K. Suzuki, and J. Yoshimura, Bull. Chem. SOC.Jpn., 1978,51,2614. A. V. Eremeev, V. G . Andrianov, and I. P. Piskunova, Khim. Geterotsikl. Soedin., 1978,613. A. V. Eremeev, V. G . Andrianov, and 1. P. Piskunova, Khim. Geterotsikl. Soedin., 1978,1196. A. V. Eremeev, V. G. Andrianov, and I. P. Piskunova, Khim. Geterotsikl. Soedin., 1978,618. G. Ah-Kow, F. Terrier, and F. Lxssard, J. Org. Chem., 1978,43,3578. L. Stefaniak, M. Witanowski, and G . A. Webb, Bull. Acad. Pol. Sci., Ser. Sci. Chim., 1978,26,281 (Chem. A h . , 1978,89,128 704).

226

Heterocydic Chemistry

1,3,4-Oxadiazoles.Treatment of the aziridine (657) with benzhydrazide yields the oxadiazole (658).412The formation of 1,3,4-oxadiazolines from diazocompounds has been reported from three laboratories: diphenyldiazomethane and hexafluoroacetone yield compound (659), which decomposes at room temperature to the oxiran (660);4’3under the influence of lead(1v) acetate, benzil semicarbazone cyclizes to the imino-A3-oxadiazoline(66l),which fragments to azibenzil and cyanic and the reaction of 2-diazocyclopentanone with diethyl azodicarboxylate affords the spiro-A2-oxadiazoline (662).4’5 Heating 2-ethoxy-5-phenyl-l,3,4-oxadiazole(663) with benzoic anhydride gives the N-benzoyloxadiazolinone (664), which on further heating is converted into 2,5-diphenyloxadiazole (665).416The kinetics of the acid-catalysed hydrolysis of ‘isosydnones’ (666) have been

y

N- NMe,

(668) R = ’ H (669) R = 2 H

-

N-N

Ph

Ph( O>CMe,NH,

(670)

Ph

(671) R = ‘H (672) R = 2 H

3

(673)

(674)

Thiadiazo1es.- 1,2,3- Thiadiaroles. The first 1,2,3-t hiadiazole- 5 -thiolate has been obtained as the potassium salt (667; Ar = p-CIC6H4)from the corresponding chlor~thiadiazole.~~~ The labelled thiadiazoles (668)-(672) have been prepared as precursors for labelled thiirens (673), into which they are converted on phot~lysis.~ ~ A’ number of unstable substituted thiirens, including benzothiiren (674), were produced from 1,2,3-thiadiazoles by irradiation in an argon matrix at 412

413 414

415 416

417 418

419

H. Link, Helv. Chim. Acta, 1978,61, 2419. N. Shimizu and P. D. Bartlett, J. Am. Chem. SOC.,1978,100,4260. D. Daniil, U. Merkle, and H. Meier, Synthesis, 1978, 535. L. L. Rodina, A. G. Osman, and I. K. Korobitsyna, Zh. Org. Khim., 1978,14, 610. R. B. Mitra, G. H. Kulkarni, and G. S. Shirwaiker, Indian J. Chem., Sect. B, 1978, 16, 146. E. A. Isukul and J. G. Tillett, 3. Chem. SOC.,Perkin Trans. 2, 1978, 908. P. Demaree, M. C. Doria, and J. M. Muchowski, J. Heterocycl. Chem., 1978,15, 1295. A. Krantz and J. Laureni, J. Labelled Compd. Radiopharm., 1978, 15 (Suppl. Vol.), p. 697 (Chem. Abs., 1979,90, 186 864).

Five-membered Rings : Other Systems

227

8 K.420 Photolysis of both 4-methyl- and 5-methyl-1,2,3-thiadiazole[cf. (675)] in the presence of perfluorobut-2-yne yields only 2-methyl-4,5-bis(trifluoromethy1)thiophen (677); it has been suggested that the reactions proceed via the common intermediate (676), which adds the acetylene at the less hindered site to give the observed The cyclohexeno-thiadiazole (678) affords a mixture of the dithiole (679), the dithiin (680),and the thiophen (681) on i~radiation.~~’

’

0

(677)

(675)

+

Me H N N “/)Me

s“ (682)

Me N + Me<

N /)Me

N ’\N (683)

Me +M e t T N ) M e

N# N ‘ (684) Me

Me N --*

Me<

N

‘r” ,>Me

N” N (685) Me

l,Z,4-ThiadiazoZes. Methylation of the condensation product (683) of S-methyl-

imino-3-methyl-l,2,4-thiadiazoline (682) with ethyl acetimidate yields compound (685) by ‘bond-switching’ in the intermediate cation (684).423A similar rearrangement occurs on p r ~ t o n a t i o n .The ~ ~ ~ ‘ring-cleaving’ cycloaddition of carbon disulphide to the thiadiazoline (686) results in the dithiazole derivative (687).425X-Ray analysis shows that, contrary to previous assignments, Hector’s base has structure (688).426It reacts with carbon disulphide to yield the triazadithiapentalene (689).427 420 421

422 423 424

425 426

427

M. Torres, A. Clement, J. E. Bertie, H. E. Gunning, and 0.P. Strausz,J. Org. Chem., 1978,43,2490. J. Font, M. Torres, H. E. Gunning, and 0. P. Strausz, J. Org. Chem., 1978, 43, 2487. U. Timm, H. Buhl, and H. Meier, J. Heterocycl. Chem., 1978,15, 697. K. Akiba, S. Arai, and F. Iwasaki, Tetrahedron Lett., 1978,4117. K. Akiba, S. Arai, T. Tsuchiya, Y. Yamamoto, and F. Iwasaki, Angew. Chem., Int. Ed. Engl., 1979, 18, 166. J. Gordeler and W. Liibach, Chem. Ber., 1979,112, 112. A. R. Butler, C. Glidewell, and D. C. Liles, J. Chem. SOC., G e m . Cornmun., 1978, 652. A. R. Butler, J. Chem. Rex (S), 1978, 50.

228

Heterocyclic Chemistry

A 2,1,3-Benzothiadiatole.Irradiation of the N-oxide (690) yields o-nitrosothionitrosobenzene (69 1) as a short-lived intermediate.42s

1,3,4-Thiadiazoles.Cycloaddition of the sulphine Ph,C=SO to benzonitrile N-phenylimine yields the S-oxide (692).429 3-Methyl-5 -phenyl- 1,3,4-thiadiazolium iodide (693) catalyses the acyloin condensation of aliphatic, aromatic, and heteroaromatic aldehydes;43ointermediate acyl-thiadiazolines, e.g. (694), have been isolated.431 N-NPh

)cph

ph(( II

Ph

N-T.NMe

Ph(:) S

0-

(696) R = O (700) R = H, OH

(697)

Selenadiazoles.-1,2,3-Selenadiatoles. The geometry of deuterioselenoketen, HDC=C=Se, generated by heating the deuterioselenadiazole (695), has been investigated by microwave spectroscopy.432Cyclo-oct-4-ynone (697) has been prepared by heating the oxocyclo-octenoselenadiazole (696).433Thermolysis of cyclo-octatrieno-l,2,3-sclenadiazole(698) similarly yields cyclo-octa-1,5-dien3-yne (699), which readily rearranges to c y ~ l o - o c t a t e t r a e n e .The ~ ~ ~ bridged compound (701) is formed by the action of acetyl chloride on the alcohol (700).435 Dibenzocyclo-octenoselenadiazole (702) decomposes to dibenzocyclo-octyne (703) in the presence of b ~ t y l - l i t h i u r n Treatment .~~~ of the semicarbazone of 428

429

41n 431

432

433 434 435

436

C . L. Pedersen, C . Lohse, and M. Poliakoff, Actu Chem. Scand., Ser. B, 1978,32,625. B. F. Bonini, G. Maccagnani, G. Mazzanti, L. Thijs, G. E. Veenstra, and B. Zwanenburg, J. Chern. SOC.,Perkin Trans. 1, 1978, 1218. A. Alemagna and T. Bacchetti, Gazz. Chim. Ital., 1978, 108, 77. A. Alemagna and T. Bacchetti, J. Heterocyc:. Chem., 1978, 15, 1515. B. Bak, 0.J. Nielsen, H. Svanholt, and A. Holm, Chem. Phys. Lett., 1978,55, 36. H. Meier and H. Petersen, Synthesis, 1978, 596. H. Meier, T. Echter, and H. Petersen, Angew. Chem., Int. Ed. Engl., 1978,17,942. H. Petersen and H. Meier, Chem. Ser., 1978, 111, 3423. H. Buhl, H. Gugel, H. Kolshorn, and H. Meier, Synthesis, 1978, 536.

229

Five-membered Rings : Other Systems

1,2,3,4-tetrahydrophenanthren-1-one with selenium dioxide gives the dihydrophenanthraselenadiazole (704), which has been pyrolysed to the 1,4-diselenine (705).437

Se (704)

(705)

Other Selenadiazoles. Aromatic seleno-arnides ArC(Se)NH2 are converted into 3,5-diaryl-1,2,4-selenadiazoles (706)438 or into 2,5-diaryl-1,3,4-selenadiazoles (707)439by the action of iodine or hydrazine, respectively. Treatment of 2,1,3benzoselenadiazole (708) with dirnethyl acetylenedicarboxylate results in 2,3dimethoxycarbonylquinoxaline (709); the reaction with benzyne is more complex, giving mainly the 1,2-benzselenazole derivative (710). Two plausible explanations have been given.44o

(708)

+

Other Systems containing Three Heteroatoms, Two of which are Identical.Catechol condenses with m-nitrophenylboronic acid to yield the benzoboradioxole (71l);441with sulphur tetrafluoride, the tetraoxysulphurane (712) is

(71 1) 437 43u 439 440

441

(712)

I. Lalezari and S. Sadeghi-Milani, J. Heterocycl. Chem., 1978, 15, 501. V. I. Cohen, Synthesis, 1978, 768. V. I. Cohen, J. Heterocycl. Chem., 1979,16, 365. C. D. Campbell, C. W. Rees,.M. R. Bryce, M. D. Cooke, P. Hanson, and J. M. Vernon, J. Chem. Soc., Perkin Trans. 1, 1978, 1006. M. F. El-Shazly, J. Electroanal. Chem. Interfacial Electrochem., 1978, 89, 199.

230

Heterocyclic Chemistry

which undergoes intramolecular ligand reorganization on heating, as shown by variable-temperature 13Cn.m.r. The I3C n.m.r. specThe trum of the tetraoxyselenurane (7 13) is likewise temperat~re-dependent.~~~ reaction of mesitonitrile oxide with tetramethyl-p-benzoquinone affords the spiro-dioxazole (714).445The dioxaphosphole (7 15) reacts with various difunctional compounds in the presence of N-chlorodi-isopropylamine;monothiocatechol, for instance, yields the quinquevalent phosphorus derivative (716).446 Successive treatment of the phosphorochloridate (7 17) with an alcohol ROH

(R = Bu', octadecyl, or cholesteryl), HOCH2CH2NMe3Cl-, and triethylamine in aqueous acetonitrile affords the phosphorylcholines (718), which are analogues of the natural phospholipid lecithin.447 The spiro-phosphorane (719) deoxygenates aliphatic and aromatic s u l p h ~ x i d e s . ~ ~ ~

Ph

2,4,6-Tri-t-butyl-N-thiosulphinylaniline (720) exists in equilibrium with the

5H-1,2,3-dithiazole (721).4493,5-Diphenyl-1,2,4-dithiazolium tri-iodide (722) 442 443

444

44s 446

447 448 449

G. E. Wilson, jr. and B. A. Belkind, J. A m . Chem. SOC.,1978, 100,8124. B. A. Belkind, D . B. Denney, D. Z. Denney, Y. F. Hsu, and G. E. Wilson jr., J. A m . Chem. SOC., 1978,100,6327. D . B. Denney, D . Z. Denney, and Y. F. Hsu, J. A m . Chem. soc., 1978,100,5982. S. Shiraishi, S. Ikeuchi, M. Seno, and T. Asahara, Bull. Chem. SOC.Jpn., 1978,51, 921. S. Singh, M. Swindles, S. Trippett, and R. E. L. Waddling, J. Chem. SOC.,Perkin Trans. 1,1978,1438. F. Ramirez, H. Okazaki, and J. F. Marecek, J. Org. Chem., 1978,43, 2331. P. Savignac, A. Breque, B. Bartet, and R. Wolf, C.R.Hebd. SeancesAcad. Sci., Ser. C, 1978,287,13. ( a ) Y. Inagaki, R. Okazaki, and N. Inamoto, Chern. Lerf., 1978, 1095; ( b ) Heterocycles, 1978, 9, 1613.

23 1

Fiue-membered Rings : Other Systems

is prepared by the combined action of iodine and hydrogen sulphide on benzonitrile.450Oxidation of the thiourea derivatives (723) results in cyclization and concomitant loss of the p-chlorobenzyl group to yield the di-imino- 1,2,4-dithiazolidines (724).451The novel 1,3,2-benzodithiazoles (726; R = alkyl or aryl) are formed by the reaction of amines RNH, with the dichloride (725) under conditions of high Successive treatment of 2-phenylacetylene-lsulphonamide, PhCECS02NH2,with carbon disulphide and dimethyl sulphate leads to the dithiazole dioxide (727).453

Ph

a ' s <

F3C N-\ NMe, AX/Se F3C (729) X = S e (730) X = C=NBu'

CI

/

/

(731)

Ph

Si

\

CI

(732)

2-Chloro-1,3,2-dithiaphosphole (728) is formed by the action of phosphorus The A3- 1,2,4-diselenazoline trichloride on the dithiol c~s-HSCH=CHSH.~'~ (729), obtained from hexafluoroacetone and the selenourea H2NC(Se)NMe2,is transformed into the iminoselenazoline (730) on treatment with t-butyl isocyanide.455Some 'H, 13C,I4N,"N, and 31Pn.m.r. data for 1,2,3-diazaphosphole (731) and its derivatives have been The 2-oxa- 1,3-disilaindane derivative (732) gives polymers on hydrolysis.457 450 451

452 453

454

455 456

457

I. Shibuya, Nippon Kagaku Kaishi, 1979, 389 (Chem. Abs., 1979,90, 186 869). R. Singh and V. K.Verma, J. Indian Chem. SOC.,1977, 54,908. C. H. Chen and B. A. Donatelli, J. Heterocycl. Chem., 1979,16, 183. K. Hasegawa, S.Hirooka, H. Kawahara, A. Nakayama, K. Ishikawa, N. Takeda, and H. Mukai, Bull. Chem. SOC.Jpn., 1978,51,1805. C. H. Chen, B. A. Donatelli, and N. Zumbulyadis, Synthesis, 1978, 667. K. Burger and R. Ottlinger, Tetrahedron Lett., 1978,973. ( a ) V. V. Negrebetskii, L. Ya. Bogelfer, A. V. Vasilev, R. G. Bobkova, N. P. Ignatova, N. 1. Shvetsov-Shilovskii, and N. N. Melnikov, Zh. Strukt. Khim., 1978, 532; ( b )V. V. Negrebetskii, L. Ya. Bogelfer, R. G. Bobkova, N. P. Ignatova, and N. I. Shvetsov-Shilovskii, ibid., p. 64. E. A. Chernyshev, T. V. Belkina, V. S. Nikitin, N. G. Komalenkova, A. S. Shapatin, and D. Ya. Zhinkin, Zh. Obshch. Khim., 1978,48, 630.

Heterocyclic Chemistry

232

Systems containing Three Different Heteroatoms.-Contrary to a previous report, the reaction of methanesulphonyl azide with N-aryl-dimethylketenimines, Me,C=C=NAr, results in the oxathiazolines (733).458Treatment of acetonyl thiocyanate with EtP(0)ClOEt yields the 1,3,2-oxathiaphospholen (734).459The trigonal-bipyramidal oxazaphospholes (736; R = Ph or OMe) are formed from the azido-oxiran (735) and triphenylphosphine or trimethyl phosphite, respectively.46*The oxazaphosphole (737) serves as a precursor of the nitrile ylide (738), which undergoes intramolecular cycloaddition to yield the pyrrolobenzopyran (739).461

(734)

(733)

R

(735)

(736)

(737)

8 Systems containing Four Heteroatoms Tetrazo1es.-Treatment of the ketenimine Me,C=C=NPh with hydrazoic acid in air yields three types of products, the isopropyltetrazole (740; R = H), the amine (740; R = NH2),and the hydroperoxide (740; R = OOH).462The rates of the thermal cyclization of various azido-azines (741) to the tetrazoles (742) have been The azido-oxime PhCOC(N,)=NOH is converted into 1acetoxy-5-benzoyltetrazole (743) under the influence of acetyl OxiN3 A+&

(740) 458

A59 460

461 462

463 4b4

N

I

N=CHAr2 (741)

R (742) R = N=CHAr2 (743) Ar’ = COPh, R = OAc

G. L’Abbb, C.-C. Yu,J. P. Declerq, G. Germain, and M. Van Meerssche, Angew. Chern., Inr. Ed. Engl., 1978,17, 352. Zh. M. Ivanova, T. V. Kim, and Yu.G. Gololobov, Zh. Obshch. Khim., 1978, 48, 2376. E. P. Kyba and D. C. Alexander, J. Chem. Soc., Chem. Commun., 1977, 934. A. Padwa, P. H. J. Carlsen, and A. Ku, J. A m . Chem. Soc., 1978, 100, 3494. G. L’Abbe, J. P. Declerq, A. Verbruggen, S. Toppet, J. P. Dekerk, G. Gerrnain, and M. Van Meerssche, J. Org. Chem., 1978,43,3042. A. F. Hegarty, K. Brady, and M. Muilane, J. Chem. SOC.,Chem. Comrnun., 1978, 871. J. Plenkiewicz and E. Osuchowska, Pol. J. Chem., 1978, 5 2 , 1597.

233

Five-membered Rings : Other Systems

dation of the tetrahydrotetrazine derivative (744) with potassium permanganate yields the tetrazolinone N-oxide (745).465

N-N R((,,!h

(754)

N=T

F3C+S,NPh

+

F3C

(755)

Ph

YP S

(7 5 6)

The tautomerism (746) (747) (R = Me, Ph, C1, or NHJ of various tetrazoles has been studied by I3Cn.m.r. Pyrolysis of 2-benzoyl-5-onitrophenyltetrazole (748) generates the nitrile imine (749), which undergoes 1,Sdipolar cyclization to the oxadiazole (750).467 The nitrile imine (752), produced from the tetrazole (75 l),rearranges to the benzoyloxybenzotriazole (753) .468

1,2,3,4-Thiatriazoles.-Treatment of thiosemicarbazidewith benzenediazonium fluoroborate yields 5-amino-1,2,3,4-thiatriazole(754; R=NH2) by 'aza-transfer'.469The imidazoyl-thiatriazole (754; R = l-imidazolyl) is obtained by the action of hydrazoic acid or trimethylsilyl azide on NN'- thiocarbonyldiimida~ole.~~' Addition of bis(trifluoromethyl)thioketen, (CF3)2C=C=S, to phenyl azide gives the thiatriazoline (755).47' Low-temperature photolysis of 5-phenylthiatriazole (754; R = Ph) yields a species, probably phenylthiazirine (756), which decomposes progressively to benzonitrile sulphide and benzo465

*" 467

468 469

470 471

D. Seebach, R. Dach, D. Enders, B. Renger, M. Jansen, and G. Brachtel, Helv. Chim. Acta, 1978, 61, 1622. R. N. Butler and T. M. McEvoy, Proc. R. Ir. Acad., Sect. B., 1977,77,359 (Chem Abs., 1978,89, 128 843). A. Konnecke, R. Dorre, and E. Lippmann, TetrahedronLeft., 1978,2071. A. Konnecke, P. Lepom, and E. LFppmann, 2. Chem., 1978,18,214. B. Stanovnik, M. TiSler, and B. Valencic, Org. Prep. Proced. Int., 1978, 10, 59. A. Martvon, L. Roch, and S. Sekretar, Tetrahedron, 1978, 34, 453, M. S. Raasch, J. Org. Chem., 1978,43,2500.

Heterocyclic Chemistry

234

~ ~ i t r i l eThe . ~ ~ methyliminothiatriazoline * (757), obtained by the action of triethyloxonium fluoroborate on 5-methylaminothiatriazole (754; R = MeHN), fragments, on heating, to N-ethyl-N’-methylcarbodi-imide(EtN=C=NMe), sulphur, and nitrogen .473 4-Met hyl- 5-phen yliminot hiatriazoline (758) functions as a masked dipole (759), yielding the dithiazolidines (760) with aroyl isocyanate~.~~~

(757) R’ = Et, R2= M e (758) R’=Me, R2 = Ph

N-9 Phc

0’

SOz

(762)

(759)

(760) Me \ ,OPh PhJ-Np+ EtO I s

N-? A r c ,PCl 0 (763)

(764)

PhCH,

(766)

c1

(765)

PhCH, \

”’

-Ph(

N-N I

TosN (767)

PhCH,

I

\\

--*

N

/ L

&S

Me N-N \ /OPh P, 0’ \s

+

\

N-SO

(769)

Miscellaneous Systems.-The crystal structure of diphenylboron N-methylacethydroxamate (761) has been described.475The dioxathiazole SS-dioxide (762) is formed from benzonitrile oxide and sulphur t r i o ~ i d e .Aromatic ~~~ hydroxamic acids ArC(0)NHOH react with phosphorus pentachloride to give 1,3,4,2-dioxazaphospholes(763).477The action of the phosphorohydrazidic chloride PhOP(S)ClNMeNH, on triethyl orthobenzoate yields the hydrazone (764), which cyclizes to the novel phosphorus heterocycle (765).4784-Phenyl1,2,3,5-dithiadiazolium chloride (766) is obtained by treatment of benzaldehyde azine with trichl~rotrithiatriazine.~~~ 4-Benzyl-5-tosylimino-l,2,3,4-thiatriazoline (767) reacts with sulphinylaniline, PhN=S=O, to form the dithiadiazoline oxide (769) via the presumed intermediate (768).480 The 3-sila-l,2,4-tri-

472

473 474 475 476 477 478

479 480

( a ) A. Holm, L. Carlsen, and E. Larsen, J. Org. Chem., 1978, 43, 4816; (b) A . Holm and N. H. Toubro, J. Chem. SOC.,Perkin Trans. 1, 1978, 1445; (c) A . Holm, N. Harrit, and I. Trabjerg, ibid., p. 746. N. H. Toubro and A. Holm, J. Chem. SOC., Perkin Trans. 1, 1978, 1440. G. L’AbbC, A. Timmerman, C . Martens, and S. Toppet, J. Org. Chem., 1978,43,4951. S . J. Rettig, J. Trotter, W. Kliegel, and D. Nanninga, Can. J. Chem., 1978, 56, 1676. I. V. Bodrikov, V. L. Krasnov, and N. K. Tulegenova, Zh. Org. Khim., 1978,14,2231. E. von Hinrichs and I. Ugi, J. Chem. Res. ( S ) , 1978, 338. 3. P. Majoral, M. Revel, and J. Navech, Phosphorus Sulfur, 1978,4, 3 . H. W. Roesky and T. Muller, Chem. Ber., 1978,111, 2960. G. L‘AbbC, A . Van Asch, J. P. Declerq, G . Germain, and M. Van Meerssche, Bull. SOC.Chim. Belg., 1978.87, 285.

23 5

Five-membered Rings : Other Systems

azolidine-5-thione (770) is transformed into the thiatriazolidine (77 1) by the action of sulphur d i ~ h l o r i d e . ~ ~ ~ S YYMe PhN, NMe X' (770) X = SiMe2 (771) X = S

9 Compounds containing Two Fused Five-membered Rings ( 5 3 ) Systems containing Oxygen and/or Sulphur.-The dioxabicyclo-octanedione (772; Ar = p-MeOC6H4) is produced by the action of thallium(II1) trifluoroacetate on p-methoxycinnamic The furobenzofuran (774) is an intermediate in the formation of the bridged compound (775) from 2-benzoyl-3bromomethylbenzofuran (773) and dimethyl acetylenedi~arboxylate.~~~ 1,4-Bis(p-methoxyphenyl)but-2-yneyields the benzofuro[2,3-b]benzofuran (776) by a two-fold Claisen ~earrangement.~'~ The benzofuro[3,2-b]benzofuran (778) is formed when the endo-peroxide (777) is irradiated.48s Photo-addition of diphenylacetylene to the dithiole-thione (779) yields, inter alia, the trithiapentalene (780).4862-(Arylsulphinyl)isophthalic acids (78 1) are converted into the bicyclic sulphuranes (782) in acetic acid.487The hypervalent

Ph

Ph (777)

-

phM&'

phM@Ph

S' (779) 481 482 483 484

485

486

487

HO2C qArSO \C 0 2 H (781)

(780)

- ofi 0-yo

0

Ar

(782)

H. Buchwald and K. Riihlrnann, Z. Chem., 1978,18,336. E. C. Taylor, J. G. Andrade, G. J. H. Rall, and A. McKillop, Tetrahedron Lett., 1978, 3623. A. Shafiee and E. Behnarn, J. Heterocycl. Chem., 1978,15, 1459. D. K. Bates and M. C. Jones, J. Ore. G e m . , 1978,43,3856. J. Rigaudy, C. Brelikre, and P. Scribe, Tetrahedron Lett., 1978,687; cf. M. K. Logani, W. A. Austin, and R. E. Davies, ibid., p. 511. V. N. Drozd, G. S. Bogornolova, and Yu.M. Udachin, Zh. Org. Khim., 1978,14,2459. W. Walter, B. Krische, and J. Voss, J. Chem. Res. ( S ) , 1978, 332.

236

Heterocyclic Chemistry

tri-co-ordinate sulphur species (784) has been produced from the y-sultene

(783).488

But

,Me

Me

-+

Me

Me

Me

Et0,C--

NHAc

K+ (783)

(784)

(789)

Nitrogen Systems.-Monoaza-compounds. A4‘8’-Dehydropyrrolizidinium(786) has been prepared from N-(3-carboxypropyl)pyrrolidin-2-oneby heating with soda lime and then acidifying the resulting base (785).4891-Azacyclo-oct-4-ene (787) undergoes stereospecific transannular cyclization to yield compounds (788 ; R = Br, I, HgCl, PhS, or PhSe) when treated with the appropriate electrophilic l-Aryl-pyrrolizidine-3,5,7-triones(789) are formed stereoselectively from (arylmethy1ene)malonic esters and ethyl a~etamidoacetate.~’~ The reaction of dimethyl acetylenedicarboxylate with pyrrolidine enamines in polar solvents yields pyrrolizines in addition to the usual rearranged pyrrolidinodienes, e.g. (79), as illustrated in Scheme 9 for the case of pyrrolidinocyclo~entene.~~*

+ ECGCE

E

=

E

C02Me

up.

Scheme 9 488

489 490

491 492

P. H. W. Lau and J. C. Martin, J. Am. Chem. SOC.,1978,100,7077. S. Miyano, T. Somehara, M. Nakao, and K. Sumoto, Synthesis, 1978,701. S. R. Wilson and R. A. Sawicki, J, Org. Chem., 1979,44, 287. P. PachaIy and H. P. Westfeld, Arch. Pharm. (Weinheim, Ger.), 1978, 311,629. D. N. Reinhoudt, J. Geevers, and W. P. Trornpenaars, Tetrahedron Lett, 1978, 1351.

237

Fiue-membered Rings : Other Systems

Irradiation of N- (3,3- dimethylally1)phthalimide(791)in methanol leads to the The isoindolo[2,1tricyclic alcohol (792) as a mixture of diastere~isomers.~~~ alindol-6-one (793) is produced by the action of lead(1v) acetate on N-(2,4dimethy1ben~oyl)indole.~~~ The strained hexahydropyrrolo[3,2,1-jk]carbazole (794) reacts with dimethyl acetylenedicarboxylatein moist acetic acid to afford a mixture of compounds (796)-(799); the intermediate (795) has been proposed as a common precursor.495

(791) ‘O

(792)

!!?

‘0

(793)

(794)

0

(795)

(796)

(799)

(798)

E = C02Me

(797)

Diuzu-compounds. The pyrrolo-imidazole (801) is produced by the action of benzenediazonium fluoroborate on the pyrrolidine enamine (800) by the process shown in Scheme Reductive cyclization of the pyrrolidinones (802) with NHPh

H (800) Scheme 10 493

494

495 496

K. Maruyama, Y. Kubo, M. Machida, K. Oda, Y. Kanaoka, and K. Fukuyama, J. Org. Chem., 1978, 43,2303. T. Itahara, Synthesis, 1979, 151. R. M. Acheson, R. M. Letcher, and G. Procter, J. Chem. SOC.,Chem. Commun., 1978,332. C . P. Kanner and U. K. Pandit, Heterocycles, 1978,9, 757.

Heterocyclic Chemistry

238

di-isobutylaluminium hydride leads to mixtures of diastereoisomers (803).497 The strongly fluorescent 1,5-diazabicyclo[3.3.0]octadiene-2,8-dione(804)is the main product of the reaction of chlorodimethylpyrazolinone with weak bases.498 ‘Criss-cross’ cycloaddition of ethoxyacetylene to hexafluoroacetone azine (805) yields the pyrazolo-pyrazole (807) via the intermediate azomethine imine (806).499The interesting reaction of the dipolar 3a,6a-diazapentalene (808)with two molecules of dimethyl acetylenedicarboxylate to afford the bridged pyrazole (809) proceeds with scission of the unsubstituted ring.*’’ The pyrrolo-benzimidazole (810) is produced by treatment of N-o-aminophenylpyrrolidinewith mercury(I1) ethylenediaminetetra-acetate.501The thermal rearrangement of the N-diphenylamino-pyrrolidinedione(811)to the pyrrolo-indole (812)represents a variant of the Fischer indole

COPh

(808)

w E

E

(809) E = COzMe

(811) 497

498 499 500

501 502

(8 12)

E. D. Thorsett, E. E. Harris, and A. A. Patchett, J. Org. Chem., 1978, 43, 4276. E. M. Kosower, B. Pazhenchevsky, and E. Hershkowitz, J. Am. Chem. SOC.,1978,100,6516. K. Burger and F. Hein, Chem.-Zfg., 1978, 102, 152. K. Matsumoto and T. Uchida, Chem. Lett., 1978, 1093. H. Mohrle and J. Gerloff, Arch. Pharm. (Weinheim, Ger.), 1978,311, 381. G. Kollenz, Monatsh. Chem., 1978, 109, 249.

239

Five-membered Rings : Other Systems

Triaza-compounds. The pyrazolo-triazole (813) is obtained by cycloaddition of ethyl cyanoformate to the C-methyl derivative of the dipolar compound (806).503 2-Phenyl-l,3a,6a-triazapentalene(814) yields the tricyclic adduct (815) with dimethyl acetylenedicarb~xylate.~~~ Me0,C N

c > P h

C0,Me

--*

\ N.4

"N (814)

(815)

(813)

Ph Ph N

NLQf

\

I

Ac Ac (822)

NPh

NPh AcCzNNHPh (823)

R'

~2

(824) R1= H. R2= AcC=NNHPh (825j R' = ~2 = Me

-

Tetra-aza-compounds. Ethyl 6-methylpyrazolo[3,2-c ]- 1,2,4-triazole-7-carboxylate (817) is obtained by the photochemical Wolff rearrangement of the diazo-ketone (816) in ethanol.505Aromatic aldazines ArCH=N-N=CHAr yield the triazolo-triazoles (818) and the tetracyclic compounds (819) by the action of benzoyl and N-phenylmaleimide,507respectively. Penta- and Hexa-aza-compounds. The X-ray structure of the pyrazolo[ 1,5-d]tetrazole (820) has been reported.508Treatment of pyrrole with the nitrile imine AcCH=&-NPh results in a mixture of isomeric bis-adducts (821) and (822) and tris-adducts (823) and (824);509 1,2-dimethylpyrrole gives the bis503 '04 505

507

508 509

K. Burger and F. Hein, Justus Liebigs Ann. Chern., 1979, 133. H. Koga, M. Hirobe, and T. Okamoto, Tetrahedron Lett., 1978, 1291. B. Stanovnik, M. TiSler, B. Kirn, and I. Kovac, J. Heterocycl. Chem., 1979, 16, 195. B. A. Arbuzov, N. N. Zobova, and N. R. Rubinova, Izu. Akad. Nauk SSSR,Ser. Khim., 1978,2784. A. Sammour, A. F. M. Fahmy, and G. H. Sayed, Egypt. J. Chem., 1975,18,445 (Chem.Abs., 1978, 89, 163 492). E. Alcalde, R. M. Claramunt, J. Elguero, and C. P. S. Huber, J. Heterocycl. Chem., 1978,15, 395. M. Ruccia, N.Vivona, G. Cusmano, and G . Macaluso, J. Heterocycl. Chem., 1978, 15, 1485.

240

Heterocyclic Chemistry

adducts (825) and (826), together with the spiro-compound (827) and the substitution product (828).510The azido-triazole-triazolotetrazoleequilibrium in the anionic system (829) $ (830) is shifted in favour of the azide form with increasing t e m p e r a t ~ r e . ~ ' ~ /

NHPh

Mixed Oxygen, Nitrogen Systems.-The adduct (832) of phenylacetylene to the 3H-indole 1-oxide (831) isomerizes to the azirino[ 1,2-a]indole (833).512The pyrrolo[ 1,2-a]indoloquinone (835) results from the thermal decomposition of the tosylhydrazone (834).513 The major product of the oxidation of dibenzoylethylene dioxime with lead tetra-acetate is the isoxazolo-isoxazole (836).514 1,3-Diphenylfuro[3,2-c Jpyrazole (837) undergoes formylation at C-2, whereas nitration takes place at the paru-position of the N-phenyl group.515The formation

"" 511 *I2

'I3 '14 515

M. Ruccia, N. Vivona, and G. Cusmano, J. Heterocycl. Chem., 1978,15, 293. R. M. Claramunt, J. Elguero, A. Fruchier, and M. J. Nye, Afinidad,1977, 34, 545. D. Dopp and A. M. Nour-El-Din, Tetrahedron Lerr., 1978, 1463. M. Akiba, Y. Kosugi, and T. Takada, J. Org. Chem., 1978,43,4472. A. Ohsawa, H. Arai, and H. Igeta, Heterocycles, 1978, 9, 1367. S. Yoshina, A. Tanaka, and S.-C. Kuo, Yakagaku Zasshi, 1978,98, 204.

Fiue-membered Rings : Other Systems

24 1

of the tetrahydropyrrolo[3,4-c]isoxazole (839) by the action of allylamine on C-benzoyl-N-phenylnitrone involves an intramolecular 1,3-dipolar cycloaddition of the intermediate imine (838).516The imidazolo[4,5-d]oxazolidinone (840; Ar = p-MeOC6H4)decomposes, on heating, to the imidazolinone (842) by loss of phenyl isocyanate and rearrangement of the intermediate (841).5'7The valence-bond isomer (844) of hexakis(trifluoromethy1)oxepin (843) reacts with diazomethane to yield the cyclobuteno-furopyrazole (845); thermolysis of the latter affords a mixture of the furan (846) and the pyrazole (847).5'8

Other Mixed Systems.-The bis-tetrafluoroborate (849) is produced by treatment of 5-methyl-l-thia-5-azacyclo-octane(848) with nitrosyl f l u ~ r o b o r a t e . ~ ~ ~ The action of phenyl cyanate on the imidazolinethione(850) yields the condensed thiadiazole (851);an example of a general reaction of heterocyclic thione~.~~'The '16

'I8 '19

'*'

D. St. C. Black, R. F. Crozier, and-1. D. Rae, Aust. J. Chem., 1978,31,2013. Y . Goto and N. Honjo, Chem. Pharm. Bull., 1978,26,3798. Y. Kobayashi, Y. Hanzawa, Y. Nakanishi, and T. Kashiwagi, Tetrahedron Letr., 1978,1019. W.K. Musker,'A. S. Hirschon, and J. T. Doi, J. A m . Chem. Suc., 1978,100,7754. D.Martin, A . Wenzel, and R. Bacaloglu, J. Prakt. Chem., 1978,320,677.

Heterocyclic Chemistry

242

crystal structure of the azadithiapentalene (852) has been reported, and the i.r. and "N n.m.r. spectra and dipole moments of this and other hypervalent sulphur compounds have been The 6-oxa-6ah 4-thia-1,2-diazapentalene (853) reacts with arenediazonium salts to afford thiatetra-azapentalenes ( 8 5 5 ) via the suggested intermediates (854).522Dicyanogen adds two molecules of sulphur The tetrasilapentalene (857)is trioxide to give the complex heterocycle (856).523 formed by pyrolysis of methyltrichl~rosilane.~~~ There is evidence from 31Pn.m.r. spectroscopy that hydrolysis of the phosphorane (858) proceeds by way of the hydrate (859).525

~m% Me

P

h m P h S' 'N Ph (852)

Me

N' '0 Ph (853)

N Ph (854)Ar

Me

Me

Ph Ar (855)

10 Compounds containing Fused Five- and Six-membered Rings (5,6)

Nitrogen Systems.--Monoata-compounds. The indolizine ring is formed by the reaction of the pyridinium dicyanomethylide (860) with 1,2,3-triphenylcyclopropene [which yields the triphenyl-derivative (861)],526 by the thermal cyclization of the dihydropyridine (862) to give (863),527and by the

521 522 523

524 525 526 527

M. M. Borel, A. Leclaire, G. Le Coustumer, and Y. Mollier, J. Mol. Struct., 1978,48, 227. R. C. Christie, D. H. Reid, R. Walker, and R. G. Webster, J. Chem. Soc., Perkin Trans. 1,1978,195. H. W. Roesky, N. Amin, G. Remmers, A. Gieren, U. Riemann, and D. Dederer, Angew. Chem., Int. Ed. Engl., 1979,18,223. G. Fritz, E. Matern, H. Bock, and G. Brahler, 2. Anorg. Allg. Chem., 1978,439, 173. D . Houalla, M. Sanchez, R. Wolf, and F. H. Osman, Tetrahedron Left.,1978,4675. K. Matsumoto and T. Uchida, Synthesis, 1978, 207. A. Kakehi, S. Ito, T. Maeda, R. Takeda, M. Nishimura, M. Tamashima, and T. Yamaguchi, J. Org. Chem., 1978,43,4837.

Five-membered Rings : Other Systems

243

cyclocondensation of the pyridinium salt (864) to the ketone (865)in the presence of alkali.5282-Methyl-A’-pyrroline (866) adds two molecules of dimethyl acetylenedicarboxylate to form the tetrahydroindolizine (867).”’ The action of acetic anhydride on piperidine-2-carboxylic acid yields the meso-ionic oxazolium oxide (868), which, in the presence of dibenzoylacetylene, forms the isolable 1,3dipolar cyclo-adduct (869) and thence the tetrahydroindolizine (870).530The salt (872) is produced by transannular cyclization of the dibenzo-azacyclononene (871).531

_c

Me0,C

c1-

‘OzMe (874)

(875)

(876)

(877)

Treatment of indolizine with tetracyanoethylene yields a mixture of 1- and 3-tricyanovinyl-derivatives[cf. (873)].532The pyrrolo[2,1,5-cd]indolizine(874) is produced by the reaction of 1-acetoxy-3-methylindolizine with dimethyl acetylenedicarboxylate.533

Diaza-compounds. The chloroallyl-pyridine derivative (875) cyclizes to 2methylimidazo[l,2-a]pyridine (876) by the action of sodium The parent compound of this ring system yields the dehydro-dimer (877) under the

’** ’29 530

s31

532

533 534

A. Kakehi, S. Ito, K. Nakanishi, and M. Kitagawa, Chem. Lett., 1979, 297. G. Dannhardt and R. Obergrusberger, Arch. Pharm. (Weinheim, Ger.), 1978,311,977. T. Uchida, S. Tsubokawa, K. Harihara, and K. Matsumoto, J. Heterocycl. Chem., 1978,15, 1303.

D. J. Brickwood, A. M. Hassan, W. D. Ollis, J. Stephanatou, and J. F. Stoddart, J. Chem. SOC.,Perkin Trans. 1, 1978, 1393. 0. Ceder and B. Hall, J. Heterocycl. Chem., 1978,15, 1471. E. Pohjala, J. Heterocycl. Chem., 1978, 15, 955. V. Klusis and J. Tamosiunas, Chem. Chem. Technol., Tech. Mokslu Isvystymo Resp. Ju Rezult. Panaudojimo Konf. Medziaga, 1975, 85 (Chem. Abs., 1978,89,6191).

244

Heterocyclic Chemistry

influence of potassium amide.535Treatment of pyridinium N-imine (878; R = H) with ketenimines Ph,C=C=NAr gives the rearranged pyrrolo[3,2-b]pyridines (879).536Another unexpected reaction is the formation of the dihydropyridobenzimidazole (881) when the enamino-ketone (880) is heated with toluene-psulphonic The picryl derivative of pyridinium imine [878; R = 2,4,6(NO,),C,H,] cyclizes to compound (882) in the presence of ~ i p e r i d i n e . ~ ~ ~

Allenyl-azines (883; R’, R2,R3, R4 = H or Ph) cyclize readily to dihydropyrazolo[l,5-b]isoquinolines (884) and/or pyrazolo[5,l-c][1,4]oxazines (885), depending on the nature of the substituents R3 and R4.539The optical resolution of several pyrrolo[3,2-fJindolizines (886; R = alkyl) has been described.540Irradiation of isatin with light of wavelength 10.6 pm from a laser produces the indoloquinazoline (887).541Deoxygenation of 1-a-nitrophenyl-3,4535

536 537

s38 s39

541

E. S. Hand and W. W. Paudler, J. Org. Chem., 1978, 43, 2900. M. V. Barker and W. E. McHenry, J. Org. Chem., 1979,44, 1175. S. Miyano, N. Abe, S. Takeda, and K. Sumoto, Synthesis, 1978,451. C . Leonte and E. Carp, Rev. Roum. Chim., 1978,23, 1461. E. E. Schweizer and S. Evans, J. Org. Chem., 1978,43,4328. A . F. Mironov, T. V. Abramenko, and R. P. Evstigneeva, DokL Akad. Nauk SSSR, 1978,241,1093. H. Karpf and H . Junek, Tetrahedron Lett., 1978, 3007.

Five-membered Rings ; Other Systems

245

dihydroisoquinoline (888) with trimethyl phosphite or thermolysis of the corresponding o-azidophenyl-compound furnishes the dihydroindazolo[3,2-a]isoquinoline (889) by nitrene c y c l i z a t i ~ nTreatment .~~~ of the indoloquinolizidinone (890) with methanolic potassium hydroxide yields, inter alia, the rearranged spiro-compound (891).543 The diperchlorate (892) reacts with dimethyl acetylenedicarboxylate in the presence of sodium hydride to give the pyrazinodiindolizine (893).544

Triaza-compounds. Thermolysis of the pyridyltetrazole (894) yields the triazolopyridine (896) by cyclization of the transient intermediate 2-diazomethylpyridine (895).545The isomeric 1,2,4-triazolo[ 1,5-a]pyridine (898) is obtained by heating the 0-acetyl-oxime (897).546The pyridazinium imine (899) forms the cyclo-adduct (900)-with tetrachlorocyclopropene.547 Treatment of S-amino-l,3542 543 544 545 546

547

Y. P. Reddy, G . S-Reddy, and K. K. Reddy, Indian J. Chem., Sect. B, 1977,15,1133. J. Y. Laronze, J. Laronze, D. Royer, J. Levy, and J. Le Men, Bull. SOC.Chim. Fr., 1977, 1215. G . C. Abbot, D. Leaver, and K. C. Mathur, J. Chem. Res. ( S ) , 1978,224. C. Wentrup, Helv. Chim. Acta, 1978,61, 1755. B. Vercek, B. Stanovnik, M. TiSler, and Z. Zrimsek, Org. Prep. Proced. Int., 1978, 10, 293. A. Ohsawa, I. Wada, H. Igeta, T. Akimoto, A. Tsuji, and Y. Iitaka, Tetrahedron Lett., 1978,4121.

Heterocyclic Chemistry

246

dimethylpyrazole (901) with acetic anhydride and sulphuric acid results in the substituted p yrazolo[3,441pyridine (902).548 Pyrazolo[ 3,441pyridine-3diazonium fluoroborate (903) functions as a dienophile, and yields the dehydrogenated Diels-Alder adduct (904) with 2,3-dimethylbuta-1 ,3-diene.549 Me-

Me

Me

Me

A derivative (906) of the novel dipolar pyrrolo[3,4-~]pyrazolesystem has been prepared by the action of triethyl phosphite on the nitro-pyrrole (905).550 Treatment of phthalazinedione (907) with the azirine (908) results in the betaine (909).5517-Chloroimidazo[ 1,241- 1,2,4-triazolo[4,3-a]pyridine (911) is formed by condensation of the amine (910) with bromoacetaldehyde d i m e t h y l a ~ e t a l . ~ ~ ~ The pyridinium salt (912) reacts with ethyl (ethoxymethy1ene)cyanoacetate to yield the pyrazolo-pyridine (913), which is converted into the tricyclic compound (914) in the presence of potassium t - b u t o ~ i d eThe . ~ ~trione ~ (915) undergoes ring s48 549

551

552 553

E. Gonzalez, R. Sarlin, and J. Elguero, Tetrahedron, 1978,34, 1175. M. KoEevar, B. Stanovnik, and M. Tiher, J. Heterocycl. Chem., 1978, 15, 1175. K. T. Potts, S. K. Datta, and J. C . Marshall, J. Org. Chem., 1979, 44, 622. H. Link, K. Bernauer, S. Chaloupka, H. Heirngartner, and H, Schrnid, Helv. Chim. A m , 1978,61, 2116. S. W. Schneiler and D . G. Bartholomew, J. Heterocycl. Chem., 1978, 15,439. A. Kakehi, S. Ito, K. Watanabe, T. Ono, and T. Miyazima, Chem. Lett., 1979, 205.

247

Five-membered Rings : Other Systems

contraction when treated with 2-aminopyridine, giving the spiro-compound (916).554Indolo[2,3-b]quinoxaline (917) is one of the products of the reaction of 2-chloroquinoxaline with aniline.555The indazole derivative (9 18), obtained by the action of benzonitrile N-phenylimine on indazole, is rearranged by acids to the aminophenyl-triazole (919), which has been converted into the 1,2,4-triazolo[ 1,5-f]phenanthridine (920) by d i a z ~ t i z a t i o n . ~ ~ ~

-+

(915)

H

Ar2

Tetra-aza-compounds. A number of 3,6-diaryl- 1,2,4-triazolo[4,3 -b ]p yridazines (922) have been obtained by oxidative cyclization of the hydrazones (921).557The electron-poor tetrazine (923) adds to N-methylimidazole in a Diels-Alder reaction with inverse electron-demand to yield a bridged intermediate, which fragments to the imidazo-pyridazine (924).558 The novel heterocycle 1,2,3-triazolo[l,5-~]pyrimidine(926) is produced by the action of lead(1v) acetate on the 554

555 556

557 558

H. Wittmann and F. Gunzl, 2.Naturforsch., Teil B, 1978,33,1540. S.D.Carter and G. W. H. Cheeseman, Tetrahedron, 1978,34,981. M.Ruccia, N. Vivona, G. Cusmano, and A . M. Almerico, Heterocycles, 1978,9,1577. K. R. Rao and P. B. Sattur, Indian J. Chem., Sect. B, 1978,16,163. G. Seitz and T. Kampchen, Arch. Pharm. (Weinheim, Ger.), 1978,311,728.

248

Heterocyclic Chemistry

hydrazone (925).559The triazolo[4,3-c]pyrimidine (927) rearranges in acetic acid to the isomeric triazolo[ 1,s-clpyrimidine (929) by way of acylaminovinyltriazole (928).560The pyrazolo-pyrimidine N-oxide (930) undergoes ring-expansion to the pyrimidino-pyrimidine (931) under the influence of sodium e t h ~ x i d e . ~ ~ ~ Treatment of the pyrimidonethione (932) with chlorotrimethylsilane yields the rearranged imidazotriazine derivative (933).562Cycloaddition of the ynamine Et,NC_CMe to 3-diazoindazole (934) affords the indazolo-triazine (935).563 The condensed heterocycles (936) and (937) are formed by the action of S-methylisothiourea hydrogen sulphate on 1-hydrazinophthalazine and 2-hydrazino-3-methylquinoxaline, respectively.564 The synthesis of the triazoloquinoxaline N-oxide (938) has been

(937)

0-

I+

(933)

(934) 559

560

562

563 564

56J

(935)

G. Maury, J. P. Paugam, and R. Paugam, J. Heterocycl. Chem., 1978, 15, 1041. D. J. Brown and T. Nagamatsu, Aust. J. Chem., 1978,31, 2505. S. Senda, K. Hirota, T. Asao, and Y. Yamada, Tetrahedron Lett., 1978, 2295. B. Golankiewicz, J. B. Holtwick, B. N. Holmes, E. N. Duesler, and N. J. Leonard, J. Ore. Chem.,

1979,41740. H . Durr and H. Schmitz, Chem. Ber., 1978,111, 2258. Y.-I. Lin, T. L. Fields, and S. A. Lang, jr., J. Heterocycl. Chem., 1978, 15, 311. B. W. Cue, jr., L. J. Czube, and J. P. Dirlam, J. Org. Chem., 1978, 43, 4125.

249

Five-membered Rings : Other Systems

Penta- and Poly-aza-compounds. The oxadiazolium salt (939) is transformed into the dihydrotriazolotriazine (940) on treatment with ben~ylhydrazine.'~~ The p-hydroxyphenyl-tetrazoloquinoxaline(941; Ar = p-HOC6H4)loses nitrogen, on heating, to yield a transient nitrene, which cyclizes to compound (942).567The A3-imidazolin-2-one (944), generated by heating the methoxy-imidazolidinone (943), trimerizes spontaneously to the tri-imidazotriazinetrione (945).568The polyazacycl[2.3.3]azine (947) is obtained by pyrolysis of the azide (946).569 Azide-tetrazole valence isomerism has been studied for the complex systems (948) $ (949)570and (950) S (951).571

(945)

566 567

568

569

s70 571

N-N

N=N

(946)

(947)

(951) A. Hetzheim, D. Schneider, and J. Singelmann, 2.Chem., 1978, 18, 136. A. Konnecke, R. Dorre, and E. Lippmann, 2. Chem., 1978,18,257. R. VerhC, N. De Kimpe, L. De Buyck, N. Schamp,J. P. Declerq, G. Germain, and M. Van Meersshe, J. Org. Chem., 1978,43, 5022. A. Konnecke, E. Lippmann, R. Dorre, and P. Lepom, Tetrahedron Lett., 1978, 3687. A. Konnecke, R. Dorre, E. Kleinpeter, and E. Lippmann, Tetrahedron Lett., 1978, 1311. A. Konnecke and E. Lippmann, 2.Chem., 1978,18,92.

250

Heterocyclic Chemistry

Compounds containing Oxygen and Nitrogen.-3-Hydroxypyridine 1-oxide (952) reacts with ethyl cyanoacetate in acetic anhydride to yield the substituted pyridine (953), which is converted into the amino-furopyridine (954) in strong The pyridinium 3-oxides (955; R = Ph, PhCH2, etc.) yield mixtures of isomeric 0x0-furopyridines (956) and (957) by the action of phenylbromoketen, PhCBr=C=0.573 Thermolysis of the isoxazolopyridinium salt (958) yields the nitrobenzofuropyridine (959) via an intermediate aryloxenium The condensed oxazolidinone (961) is obtained by the action of benzaldehyde on the Reissert compound (960).575Thermolysis of the perhydroisoxazolo-oxazines (962; R = CN, Ac, or C0,Et) results in the spiro-isoxazolines (963) with loss of the angular n i t r o - g r o ~ pThe . ~ ~ reaction ~ of 3-substituted indoles with o-benzoquinone is exemplified by the formation of compound (964) from 3-methyli n d 0 1 e . ~The ~ ~ X-ray structures of the isomeric adducts (966) and (967) (Ar = p ClC6H,) of p-chlorophenyl isocyanate to P-picoline N-oxide (965) have been

(953)

(955)

W N C CN O 2 E t (960) 572 513

574 575

576

577 5510

(956)

-

NC (961) Ph

Yo

0

0(965)

(966) R' =Me, R2= H (967) R' = H, R2= M e

M. L. Stein, F. Manna, and C. C. Lombardi, J. Heterocycl. Chem., 1978, 15, 1411. A. R. Katritzky, A. T. Cutler, N. Dennis, S. Rahimi-Rastgoo, G. J. Sabongi, I. J. Fletcher, and G. W. Fischer, 2. Chem., 1979, 19, 20. R. A. Abramovitch and M. N. Inbasekaran, J. Chem. Soc., Chem. Commun., 1978, 149. M. D. Rozwadowska and D. Brozda, Bull. Acad. Pol. Sci., Ser. Sci. Chim., 1978,26,33 (Chem.Abs., 1978, 89,42 035). I. E. Chlenov, I. M. Petrova, B. N. Khasapov,N. F. Karpenko, A. U. Stepanyants, 0.S. Chizhov, and V. A. Tartakovskii, Zzv. Akad. Nauk SSSR, Ser. Khim., 1978,2551. T. Komatsu, T. Nishio, and Y. Omote, Chem. Ind. (London), 1978,95. T. Hisano, T. Matsuoka, M. Ichikawa, K. Muraoka, T. Komori, K. Harano, Y. Ida, and A. T. Christensen, Org. Prep. Proced. Znt., 1978,10, 300.

25 1

Five-membered Rings : Other Systems

Treatment of the iodopyrazolecarboxylic acid (968) with copper(1) pent-lynide in boiling pyridine affords the pyrazolopyrone (969).579The condensed oxadiazinone (970) is obtained by the reaction of urea with ~-phthalaldehyde.~~' The hydroxylamino-uracil (971) condenses with aromatic aldehydes to give isoxazolo[3,4-d]pyrimidines (972);581 these compounds undergo ring-enlargement on treatment with benzylamine, yielding pyrimidinopyrimidine-diones (974) via intermediate imines (973).582The benzofuran derivative (977), formed from the quinone (975) and 2-cyanomethylbenzimidazole (976), is converted into the complex heterocycle (978) in boiling acetic anhydride.583 0

OH

Me (974)

1 NH2 579

580 581

s82 583

(977)

S . F. Vasilevskii, E. M. Rubenshtein, and M. S. Shvartsberg, Zzv. Akad. Nauk SSSR,Ser. Khim., 1978,1175. R. D. Reynolds, D. F. Guanci, C. B. Neynaber, and R. J. Conboy, J. Org. Chem., 1978,43,3838. S . Nishigaki, Y. Kanamori, and K. Senga, Chem. Pharm. Bull., 1978,26,2497. F.Yoneda, T. Yano, M. Higuchi, and A. Koshiro, Chem. Lett., 1979,155. V.P.Makovetskii, I. B. Dzvinchuk, Yu. M. Volovenko, and A. A. Svishchuk, Dopov. Akad. Nauk Ukr. RSR, Ser. B, 1978,626 (Chem. Abs., 1978,89,146 841).

Heteruc yclic Chemistry

252

Other Mixed Systems.-N-a-pyridylthiourea-”acetic acid (979) cyclizes to the 1,2,4-thiadiazolo[2,3-a]pyridine(980) on treatment with The Namino-triazolethiol (981) condenses with a-halogeno-cycloalkanones to yield condensed triazolothiadiazines (982; n = 3, 4, 5, or 6);585the reaction with chloranil results in the novel heterocycle (983).’86 The X-ray structure of the quinquevalent phosphorus compound (984) has been d e t e ~ m i n e d . ~ ”

11 Compounds containing Fused Five- and Seven-membered Rings (5,7) Nitrogen Systems.-Munoaza-compounds. 2-Acetylpyrrole condenses with the + vinylogous amidinium salt Me2NCH=CHCH=NMe2 C10,- to yield compound (985), which cyclizes to the aza-azulenone (986) on heating.588 A mixture of

I

NMe,

(986)

(985) 584 585

587

B. Vercek, B. Stanovnik, and M. TiSier, Heterocycles, 1978, 11, 313. W. L. Albrecht, W. D. Jones, jr., and F. W. Sweet, J. Heterocycl. Chem., 1978, 15, 209. V. K. Chadha, J. Indian Chem. Soc., 1978,55, 817. F. Ramirez, J. S. Ricci, jr., J. F. Marecek, H. Okazaki, and M. Pike, J. Org. Chem., 1978,43,4996. W. Flitsch, F. Kappenberg, and H. Schmitt, Chem. Ber., 1978,111, 2407.

Five-membered Rings : Other Systems

253

adducts (988) and (989) is formed by the reaction of 2-chloro-l-aza-azulene (987) with dimethyl acetylenedi~arboxylate.~~~ The azepino[ 1,2-a]indole (991) is one of the products of the thermolysis of o-azidotriphenylmethane (990).590

(987) (988)

E=

Ph

NHBz

NHBz

(998) (999)

Diaza-compounds. The dihydrodiaza-azulene (993), produced by heating the toluene-p-sulphonylhydrazone (992), isomerizes to a mixture of cyclopropaindazoles (994) and (995) on irradiation.591Ethyl 3-formylindole-2-carboxylate (996) reacts with cyanoacetic ester to give the azepino[3,4-b]indole (997), in addition to the expected Knoevenagel The pyrrolo-1,4-benzodiazepinedione (999) is formed by pyrolysis of benzyol-DL-kynurenylglycine (998).593 589 "O

591

592

593

N. Abe, Y. Tanaka, and T. Nishiwaki, JChem. SOC.,Perkin Trans. 1, 1978,429. R. N. Carde, G. Jones, W. H. McKinley, and C. Price, J. Chem. Soc., Perkin Trans. 1, 1978, 121 1. T. Miyashi, Y. Nishizawa, and T. Mukai, Heterocycles, 1978,11,293. J. Pigulla and E. Roder, Arch. Pharm (Weinheim, Ger.), 1978,311, 822. F. H. C. Stewart and D.'E.Rivett, Chem. Ind. (London), 1978, 347.

254

Heterocyclic Chemistry

Triara-compounds. The benzimidazole derivative (1000) cyclizes to compound (1001) in sulphuric Pyrolysis of the pyrazolodibenzazepine (1002) yields N-methyldibenzo[b,f]cyclopr~p[d]azepine ( 1003).595

CH,CH,CO,Me (1000)

1 Me aN\Y--toN H (1002)

(1001) N

(1004)

(1008)

U

(1003)

O

Me

(1005)

(1006)

Me

(1011)

( 1007)

S (1012)

(1009) X = C R (1010) X = N

Tetra- and Penta-aza-compounds. The imidazo[ 1,s-b][1,2,4]triazepinone (1005) is one of the products of the reaction of the diamino-imidazole (1004)with ethyl a ~ e t o a c e t a t e The . ~ ~ ~triazolo-isoindole (1006) is converted into the triazoloThe benzodiazepine (1007) on treatment with hexarneth~lenetetramine.~~~ action of acid anhydrides on 5-hydrazino-l-methyl-l,4-benzodiazepine(1008) leads to the fused triazoles (1009; R = Me, Et, or Ph), while nitrous acid gives the The thermal Dimroth rearrangetetrazolo[l,5-a][ 1,4]benzodiazepine ( 1010).598 ment in the triazolotriazepine system (1011) -+ (1012) proceeds by fission of the indicated bond and re-cyclization onto N-3.599 594

595

596

597

598 599

B. Serafin and L. Konopski, Pol. J. Chem., 1 9 7 8 , 5 2 , 5 1 . K. Kawashima and Y. Kawano, Takeda Kenkyusho Ho, 1978, 37, 6 (Chem. Abs., 1979, 90, 121 387). A. Bernardini, P. Viallefont, and R. Zniber, J. Heterocycl. Chem., 1978, 15, 937. P. C. Wade, T. P. Kissick, B. R. Vogt, and B. Toeplitz, J. Org. Chem., 1979, 44, 84. R. Madronero and S. Vega, J. Heterocycl. Chem., 1978,15, 1127. A. Hasnaoui, J. P. Lavergne, and P. Viallefont, J. Chem. Res. ( S ) , 1978, 190.

255

Five-membered Rings : Other Systems

Other Systems.-1,3-Dimethylallyl 2-oxide (1013), generated by the action of copper and potassium iodide on 2,4-dibromopentan-3-one, reacts with the furotropone (1014) to yield the cyclo-adduct (1015); hydrolysisof the latter gives 2,4-dimethylheptalene-3,8-dione (1016).600.A derivative (1018) of the new [l]benzofuro[3,2-e]- 1,4-diazepin-2-one ring system has been prepared by the action of ammonia on the benzofuran (1017).60*The benzophenone imine (1019; Ar = o-C1C6H4) has been transformed into the oxazolo-benzodiazepine (1020)?02

-oj Me

+

I

Me (1013)

--*

c,

(1014)

:mo /

Me

(1015) I

1 (1016)

(1017)

(1018)

w - - rl \ ~

Ar

'CHMe HOCH,

~-

I

. 0 /&Me (1020)

(1019)

'O0

601 602

K. Kato, M. Oda, S. Kuroda, N. Morita, and T. Asao, Chem. k t t . , 1979,43. J. Ashby and E M . Ramage, J. Heterocycl. Chem., 1979,16, 189. R. Tachikawa, T. Miyadera, C. Tamura, A . Terada, S. Naruto, and E. Nagamatsu, J. Chem. SOC., Perkin Trans. 1, 1978, 1524.

Six-membered Ring Systems BY

G. P. ELLIS & R. K. SMALLEY

PART I: Azines, Oxazines, and Thiazines by R. K. Smalley

1 Reviews Specificring systems reviewed during the current year include 1,5-, 1,6-, 1,7-, and 1,8-naphthyridines,' tetrahydro-y-carbolines,2 acridine and its derivative^,^ 1,2,4-tria~ino-indoles,~ 3H-pyrrolo-[2,3-c]- 5 u and -[3,4-b]-q~inolines,'~1,2,4triazines, tetrazines, and pentazines,6 and 1,3-0xazine derivative^.^ Also reviewed are the syntheses of substituted pyrazines and their olfactive properties,' cobalt-catalysed syntheses of pyridines from alkynes and nitriles,' advances in indolizine chemistry," the chemistry of pteridine N-oxides, and the synthesis of 8-mercaptoquinoline and its derivatives. l 2 Reviews of more general nature on biologically active heterocyclic analogues of thiourea,13 heterocyclo-polyaromatic cornp~unds,'~ the chemistry of diazaq~inones,'~ and heterobenzenes containing elements of Group V16 have also appeared. In addition, accounts of fused heterocyclic systems having a nitrogen atom in common to two or more rings,"= systems containing two fused five- or six-membered heterocyclic rings, each with one heter~atom,'~'and oxazines, thiazines, and their analogues'' have been presented. The reactions of 2,3-cycloalkeno-pyridines,'' of heteroaromatic and aromatic amine N-oxides with acylating agents," of sulphur nucleophiles with halogenated pyrimidines,21 and of aromatic and heteroaromatic trifluoromethyl compounds

W. Czuba, Khim. Geterotsikl. Soedin., 1979, 3. A. N. Kost, M. A. Yurovskaya, and F. A. Trofimov, Usp. Khim. Geterotsikl., 1976, 171. N. Campbell, Rodd's Chem. Carbon Compd., 2nd. edn., 1978, IVG, p. 1. W. A. Romanchick and M. M. Joullik, Heterocycles, 1978,9, 1631. M. A. Khan and J. F. da Rocha, Heterocycles, 1978,9, (a) p. 1617; ( b )p. 1059. H. Neunhoeffer, Chem. Heterocycl. Compd., 1978, Vol. 33. Z. Eckstein and T. Urbanski, Adv:Heterocycl. Chem., 1978, 23, 1. P. J. Calabretta, Perfum. Flavor, 1978,3,33. ' H. Bonnemann, Angew. Chem., Int. Ed. Engl., 1978, 17,505. 10 F. J. Swinbourne, J. H. Hunt, and G. Klinkert, Adv. Heterocycl. Chem., 1978,23, 103. W . Pfleiderer, Usp. Khim. Geterotsikl., 1976, 87. l2 Yu. A. Bankovskii, M. Cirule, D. Zaruma, and J. Lejejs, Latv. PSR Zinat. Akad. Vestis, 1978, 109. l3 L. Toldy, Khim. Geterotsikl. Soedin., 1978, 878. l4 T. Kauffmann, Angew. Chem., Int. Ed. EngL, 1979,18, 1. M.Quinteiro, C. Seoane, and J. L. Soto, Heterocycles, 1978,9, 1771. l6 A. J. Ashe, 111, Acc. Chem. Res., 1978, 11,153. l7 N. Campbell, Rodd's Chem. Carbon Compd., 2nd. edn., 1978, IVH, (a) p. 259; ( b ) p. 343. M. Sainsbury, Rodd's Chem. Carbon Compd., 2nd. edn., 1978, IVH, p. 427. H. Beschke, Aldrichimica Acta, 1978, 11, 13. 2o S . Oae, Lect. Heterocycl. Chem., 1978, 4, 69. E. G. Sander, Bioorg. Chem., 1978,2,273.

257

258

Heterocyclic Chemistry

with nucleophilic reagents22 have been collated. The use of y-piperidinones in organic and that of 4-dialkylamino-pyridines as highly activating catalysts24have been appraised. Evidence for a spiroindolenine intermediate in the Pictet-Spengler synthesis of 1,2,3,4-tetrahydro-p-carbolines has been reviewed,25 as has the cyclotrimerization of N-C-containing compounds to 1,3,5-tria~ines.’~Also of a mechanistic nature are accounts on the degenerative transformation of the pyrimidine ring in N-methyl- and N- amino-pyrimidinium and ‘S,(ANRORC) - a new mechanism for nucleophilic substit~tion’.~~’ Finally, an up-to-date account of the reactions of acetylenedicarboxylic esters with nitrogencontaining heterocycles28is most welcome, in view of the recent re-formulation” of some of the earlier products.

2 Azines and their Hydro- and Benzo-derivatives Pyridines-Synthesis. A full report on the thermal rearrangement of 2-allyl-2Hazirines (1) to pyridines, noted last year,3o has appeared.31QThese rearrangements, for which only a tentative mechanistic rationale has been advanced, show marked substituent effects. For example, the unsubstituted ally1 derivative (1; R’ = Ph, R2 = Me, R3 = H) in toluene at 180-195 “C gives mainly (90%)the 3-azabicyclo[3.l.0]hex-2-ene (2; R’ = Ph, R2 = Me, R3 = H) along with 3methyl-2-phenylpyridine, whereas the phenyl derivative (1; R’ = R3 = Ph, R2 = Me) yields 3-methyl-2,6-diphenylpyridine(49%)as the sole identifiable

Me

Reagents: i, A, PhMe, 180-195 “C;ii, A > 250 nm.

Scheme 1 22 23 24 25

26

27 28 29

30

31

Y. Kobayashi and 1. Kumadaki, Acc. Chem. Res., 1978,11,197. N.S. Prostakov and L. A. Gaivoronskaya, Usp. Khim., 1978,47,859. G . Hofle, W.Steglich, and H. Vorbriiggen, Angew. Chem., Int. Ed. Engl., 1978,17,569. F.Ungemach and J. M. Cook, Heterocycles, 1978,9, 1089. D.Martin, M. Bauer, and V. A. Ponkratov, Usp, Khim., 1978,47,1814. H.C.van der Plas, (a) Khirn. Geterotsikl. Soedin., 1978,1155; ( b ) ACC.Chem. Res., 1978,11,462. R . M.Acheson and N. F. Elmore, Adv. Heterocycl. Chem., 1978,23,263. 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,p. 170. See ref. 29,p. 145. A. Padwa and P. H. J. Carlsen, J. Org. Chem., 1978,43,( a )p. 2029;( 6 ) p. 3757.

259

Six-membered Rings: Azines, Oxazines, and Thiazines product. However, interchange of the alkyl and aryl groups, i.e. (1; R'

=

Me,

R2 = Ph, R3 = H), results in formation of a mixture of the azabicyclohexene (2; R' = Me, R2 = Ph, R' = H) (31%), 2-methyl-3-phenylpyridine(5%), and 2methyl-3-allylindole (58%). In contrast, photo-rearrangements (A > 250 nm) of allyl-azirines, e.g. (1; R' = R3 = Ph, R2 = Me), in general yield the 2-azabicyclo[3.1 .O]hex-2-enes, e.g. (4), by intramolecular cycloaddition of the initially formed dipolar species (3)! I h (see Scheme 1). The bicyclohexene (4) undergoes quantitative, oxidative rearrangement to 2-methyl-5,6-diphenylpyridine(5). 2,3,5,6-Tetraphenylpyridine has been isolated in low yield (8-lO%) along with various substituted pyrroles from the di-iron-nonacarbonyl-inducedrearrangement of the azirine (6) in dry benzene .32 p-Tosylisonitrosomalonodinitrile, (NC),C=NOTs, undergoes regioselective, cis-stereospecificcycloadditions with b u t a d i e n e ~In . ~boiling ~ ethanol the resulting cyclo-adducts (7) readily eliminate HCN and toluene-p-sulphonic acid, and so this provides an easy route to the 2-cyano-pyridines (8).Cycloaddition of the isonitrosodinitrileto cyclohexadiene yields 2-azabicyclo[2.2.21octene (9).

2-Oxazolin-5-ones generally enter into cycloaddition reactions as the 1,3dipolar form (10) rather than as the hydroxy-diene tautomer (11; R3 = H). However, their silyl ethers (11; R3 = SiMe,) do undergo Diels-Alder reaction with common dienophiles, e.g. dimethyl maleate, to give ultimately the vitamin Bs analogues, e.g. (12), in high yield (>80%)34(Scheme 2).

R1(Ao* R1[S0 R2

HI;

R2

-

N

R2

R i ( ,0 30R3

0

C02Me Q ;2 M :; e

-

(12) Reagent: i, MeO,CCH=CHCO,Me

Scheme 2 32 33 34

F. Bellamy, J. Chem. Soc., Chem. Commun., 1978,998. J-P. Fleury, M. Desbois, and J. See, Bull. SOC.Chim. Fr., Part 2, 1978, 147. H. Takagaki, N. Yasuda, M. Asoka, and H. Takei, Chem. Lett., 1979, 183.

Heterocyclic Chemistry

260

The condensation products of malononitriles, e.g. Me,C=C(CN)CO,Et, or of cyanoacetates, e.g. (13), with either dimethylformamide dimethyl acetal or ethyl orthoformate behave as py-unsaturated aldehyde equivalents, and as such are useful precursors of 2-halogeno-nicotinic acid derivatives (e.g. as shown in Scheme 3).35a Triethyl orthoformate is the superior reagent, as condensations with dimethylformamide dimethyl acetal are accompanied by the production of dimeric by-products. /

H

\ /

,CO,Et

c=c

CI4 3CH 2

\

C0,Et

C0,Et

I

/

4MeCH CN

\

/‘*CH

(13)

uct

Reagents: i, HC(OEt),; ii, HBr, AcOH

Scheme 3

A preliminary indicates that electron-deficient heteroaromatic ketones, in the presence of sodium hydride, undergo a remarkably facile decarbonylation to biheteroaryls. For example, the dipyridyl ketone (14), with ethylene glycol and sodium hydride in boiling xylene, yields the bipyridyl(l5) (40%) along with only a trace of the expected macrocycle. A similar reaction is observed in the absence of ethylene glycol, whereas with sodium methoxide in place of sodium hydride only trace amounts of bipyridyl are formed.

(14)

(15)

(16)

Two useful methods for the preparation of cyano-2-pyridones have appeared. The first involves the condensation of 2-cyano-cinnamates ArCH=C(CN)CO,R in the presence of an alkoxide (RONa).376-Alkoxy-3,5-dicyano-2-pyridones (16) are obtained in 78-92% yield. The second is an extension of some earlier work on the alkoxide-induced condensation of a -acyl- and a-cyano-keten 35

36 37

( a )J. J. Baldwin, A. W. Raab, and G. S. Ponticello, J. Org. Chem., 1978,43,2529; (b)J. J. Baldwin, K. Mender, and G. S. Ponticello, ibid.,p. 4878. G. R. Newkome and H. C. R. Taylor, J. Org. Chem., 1979,44, 1363. H-H. Otto, 0. Rinus, and H. Schmelz, Synthesis, 1978,681.

Six-membered Rings : Azines, Oxazines, and Thiazines

26 1

dithioacetals (17) with cyano-acetamides (Scheme 4).38" With an excess of the cyanoacetamide the cyano-pyridones react further to give 8-amino-5-cyano-2,7naphthyridine-l,6-diones( 18).38b

R' , -(R

\C=C(SMe), /

i

= CNorPh)

(R2= CN)

R2

H 60%

-@ = Bz) p h (Rz= H)

(R'

0

H 82O/O

(17)

li 0

N g : H 2 Ph

N

O

Reagents: i, NCCH,CONH,, Pr'ONa; ii, excess of reagents i

Scheme 4

Interestingly, with the a-methylketen dithioacetal(l7; R1= Bz,R2 = Me) the product is not the 4-methylthio-pyridone but the isomeric 5-methylthiomethyl derivative (19), formed as outlined in Scheme 5.380 SMe

-.

(R'= Bz)

(17)

MeS

-

M e SH C HH e 1,3H shift

1

(R2 = Me)

PhAC*O

MeSCH2

A

HQ

Ph

0

-H,O

Ph

0 H (19)

Reagent: i, NCCH,CONH, Pr'ONa

Scheme 5

Oxazoles and isoxazoles feature in two new syntheses of 2- and 4-pyridones, respectively. Ring opening of maleic anhydride with methyl isocyanoacetate in the presence of 1,8-diazabicyclo[5.4.O]undec-7-ene(DBU) yields the oxazole carboxylate (20),which in methanolic hydrogen chloride undergoes ring-opening and then ring-closure to the 5-hydroxy-2-pyridone-6-carboxylate(2 l).39A

39

R. R. Rastogi, A. Kumar, H. Ila, and H. Junjappa, J. Chem. Soc., Perkin Trans. 1, 1978, (a)p. 549; ( b ) p. 554: M.Suzuki, K-I. Nunami, K. Matsumoto, N. Yoneda, and M. Miyoshi, Synthesis, 1978,461.

Heterocyclic Chemistry

262

similar reaction with phthalic anhydride furnishes the corresponding 1-isoquinolone-3-carboxylate (21). Treatment of 5-methylisoxazole with two equivalents of lithium di-isopropylamide in THF at -10 "C provides access to the new dianion CH,COCHCN, which on prolonged heating (for 18 h) with an aryl cyanide gives a 6-aryl-2-cyano-4-pyridone(22) in practicable yield (4867Y0).~"Shorter reaction times (30 min) provide non-cyclic products, e.g. ArC(NH,) =CHCOCH,CN.

2H-Azirines have often featured30z31 in the synthesis of pyridines. A report4' now indicates that 4-pyridones (23) are obtainable by addition of 3-dialkylamino2H-azirines to diphenylcyclopropenone, as outlined in Scheme 6.

Ph (23) R

"Me, =

H or Me

Reagent: i, diphenylcyclopropenone

Scheme 6

General methods for the synthesis of 1-substituted vinyl-2-pyridones are lacking. However, three approaches have now been formulated,42anamely (a) direct nucleophilic substitution of halogeno-alkanes that contain an activating

40 41

42

F. J. Vinick, Y.Pan, and H. U'.Gschwend, Tetrahedron Lett., 1978, 4221. S. Chaloupka and H. Heimgartner, Chirnia, 1978, 32,468. ( a ) P. S . Mariano, E. Krochmal, R. Beamer, P. L. Huesmann, and D . Dunaway-Mariano, Tetrahedron, 1978,34,2609; ( b )P. S. Mariano, R. Beamer, P. L. Huesmann, and D. Dunaway-Mariano, ibid., p. 2617.

Six-membered Rings : Azines, Oxazines, and Thiazines

263

P-group by 2-pyridone (Scheme 7, path a), (b) elimination reactions of 2pyridonylethanols (path b), and (c) base-catalysed (K0Bu'-DMSO) isomerization of N-allyl-2-pyridones.

Me-C

oo

*C-H

I

COMe 46%

iii, iv

-Qo

I

CH ,CHPh

I

I

CH,=CHPh 9 3 '/o

OH

Reagents: i, MeCOCH=C(Cl)Me, NaH, THF; ii, NaBH,; iii, Ac,O; iv, p-TsOH in boiling xylene

Scheme 7

Reactions. Good yields of cyclic perfluoroalkyl-azadienes are obtained by direct fluorination of perfluoroalkyl-pyridines, using a mixture of cobalt trifluoride and calcium fluoride (Scheme 8).43aOn photolysis, the perfluoropropyl derivative [24; RF = CF(CF,)2] undergoes electrocyclic ring-opening to the perfluoropropyl-hexatriene (25).436

(24) 60% (26%)

28% (26%)

FzC=C(RF)CF=CFN=CF2 (25) Reagents: i, CoF,, 118°C; ii, hu (A = 253.7 nm)

Scheme 8

A detailed study of the nitration of 2-pyridone and its simpla N-alkyl (Et, *) derivatives has shown that an increase in reaction temperature always increases the ratio of 5-N02:3-N02 isomer (1.17 : 1.OO at 90 "C),whereas increasing the concentration of nitric acid has little effect on the isomer ratio but increases the 43

( a )R. D. Chambers, R. D. Hercliffe,and W. K. R. Musgrave,J. Chem. SOC.,Chem. Commun., 1978, 304; (b) R. D. Chambers, R.D. Hercliffe, and R. Middleton, ibid., p. 305.

Heterocyclic Chemistry

264

amount of dinitro-derivative formed.44Only a few heterocyclic sulphenyl halides are known, and all are unstable. Noteworthy, therefore, is the formation (100%) and isolation of the stable 3-nitropyridyl-2-sulphenyl chloride (26) from the chlorination of bis-(3-nitro-2-pyridyl) disulphide in cold (0-10 "C) di~hloromethane.~' Also new are the 2-, 3-, and 4-pyridylpropiolic acid esters (27),which have been isolated in good yields (58--80%), as unstable liquids, from the thermolysis (250 "C)of the Wittig reagents (28).46 X

(27) X (28) X

= =

C=CCO,R COC(C02R)=PPh3

3-Mercaptopyrido-2-thione (29), prepared as indicated in Scheme 9, is only the third of the six possible isomeric dimercaptopyridines to be synthesi~ed.~' On standing in air it decomposes to an as yet uncharacterized yellow powder.

Reagents: i, NO+; ii, CS,, 200 "C; iii, NH,NH,

Scheme 9

Direct chlorination of the three isomeric isopropylpyridines to the corresponding 2-chloro-2-(pyridyl)-propanes has been achieved, using t-butyl hypoChlorination of 2- and of 4-methylpyridine with phosphorus halides to the corresponding trichloromethyl derivatives is well documented; 4- and 6methyl-3-nitropyridines react similarly. However, the isomeric 2-methyl-3nitropyridine undergoes phosphorylation to dichloro-(3-nitro-2-pyridyl)methyl phosphoric dichloride (30).49Mechanistic explanation of this unique direct phosphorylation process is as yet purely tentative. Regioselective oxoalkylation of the pyridine nucleus has been achieved by the palladium-acetate-catalysed reaction of 4-bromo-2,6-dimethylpyridinewith an The 3-oxoallyl ally1 alcohol, R3CH=C(R2)CH(R')OH, in DMF derivatives (31) are the major products (70-95%), only a little 2-oxoallyl derivative being formed. Similar reactions are reported" with 3-bromo-pyridines, whereas 4-chloro- and 2-bromo-pyridine yield only their respective bipyridyl~.~' Regioselective metallation of the pyridine ring at the 3-position via a 44

45

4d 47 48 4y

''

N. P. Shusherina, T. I. Likhomanova, and E. V. Adamskaya, Khim. Geterotsikl. Soedin., 1978, 72. R. Matsueda and K. Aiba, Chem. Lett., 1978,951. Won Nam Lok and A. D. Ward, Ausr. J. Chem., 1978,31,617. K. Krowicki, Pol. J. Chem., 1978,52, 2039. H. Feuer and J. K. Doty, J. Hererocycl. Chern., 1978,15, 1517. T. Kato, N. Katagiri, and A . Wagai, Tetrahedron, 1978, 34, 3445. Y. Tamaru, Y. Yamada, T. Arimoto, and Z-I. Yoshida, Chern. Lett., 1978,975. Y. Tamaru, Y. Yamada, and Z-I. Yoshida, J. Org. Chem., 1978, 43, 3396.

Six-membered Rings : Azines, Oxazines, and Thiazines

265

2-(4'-pyridy1)isoxazoline derivative was noted last year.52It is now reported53that the isomeric 2-(3'-pyridy1)isoxazoline (32; R = H) undergoes regioselective addition of phenyl- and alkyl-lithiums at the 1,4-positions to give stable 1,4dihydropyridines (33), which, on oxidation with KMnO, in acetone, provide access to the 4-substituted pyridines (32; R = Ph, Me, Bun,or Bu'). P r e p a ~ a t i o n ~ ~ of ~(2-pyridyl)ketones by the acylation of 2-picolyl-lithium and 2,6-lutidyllithium with NN-dimethylcarboxyamides is reckoned to be superior to the more usual reaction of heteroaryl-lithiumswith esters. However, one notable failure of this new process is the reaction with dimethylformamide, which gives not, as expected, the 2-pyridylacetaldehyde7but an unstable yellow oil, tentatively identified (mass spectrum) as the aminovinylpyridine (34). 2-Substituted pyridines undergo a new type of metallation with dicyclopentadienylmethyltitanium (Cp,TiMe; Cp = ~yclopentadienyl).~~ The complexes (35; R = Me, Ph, or vinyl) so formed probably contain a three-membered titanocycle in which the ligands act as bidentate three-electron donors. Quinoline is metallated similarly at the 2-position.

I

\

QCH=CHNMe, N

N

R

8,

(34)

N +TiCp,

(35)

(33)

N-Formyl-N-methyl-2-aminopyridine (36) is a useful reagent for the direct formylation of Grignard The reactions are carried out in tetrahydrofuran at 0 "C,and with aryl, vinyl, allyl, and alkyl Grignards the yields are good (>70%). 4-Dimethylaminopyridine is an efficient and selective catalyst for the silylation of alcohol^.^' For example, 1-phenylethane-1,2-diol gives mainly the

'' See ref. 29, p. 151. '' C. S. Giam and A. E. Hauck, J. Chem. SOC.,Chem. Commun., 1978,615. R. P. Cassity, L. T. Taylor, and J. F. Wolfe, J. Org. Chem., 1978,43,2286. B. Klei and J. H. Teuben, J. G e m . SOC.,Chem. Commun., 1978,659. 56 D. Comins and A. I. Meyers, Synthesis, 1978,403. '' S . K. Chaudhary and 0.Hernandez, Tetrahedron Lett., 1979,99.

54 55

Heterocyclic Chemistry

266

primary silyl ether, and no secondary silyl ether, when treated with t-butyldimethylchlorosilane, Bu'Me,SiCl. Possibly, the silylpyridinium chloride (37) (the effective silylating agent) is sterically too demanding for silylation to occur at the secondary alcohol function. 2- and 4-Dialkylamino-pyridines are now accessible by heating the appropriate pyridone with a mixture of phosphorus pentoxide and a secondary dialkylamix~e.'~ Although yields are only moderate, the simplicity of the method is to be noted. 1-Vinyl-2-pyridones, prepared as described earlier,42uon treatment with simple dienophiles (e.g. dimethyl acetylenedicarboxylate), furnish modest yields of N-vinyl-isoquinuclidienones, e.g. (38),42bwhich on thermolysis undergo a retro-Diels-Alder reaction to form vinyl isocyanates RCH=CHNCO and, in the case of the cyclo-adduct (38), dimethyl phthalate also. The isoquinuclidienones derived from maleic anhydride yield pyridones by elimination of an ethylene unit. Still more examplessy illustrating the use of quaternized 2-halogeno-pyridines for the preparation of simple aliphatic compounds have been announced, and include the synthesis of sulphinic acid esters,60 the formation of allenes from propargyl alcohols (Scheme and the preparation of primary amines from N-benzylhydroxylamine and 2-fluoro-N-methylpyridinium tosylate.61b

OF [Mefi ] A

Me

Et

BF4-

+/ OCH(R~)C=CR~ &

R2CH=C=CR1R3 77-99%

N Et

Reagents: i, RZCH(OH)C=CR', Et,N, CH,Cl,, 0 "C; ii, R3MgBr, CuI, THF, at -20 "C

Scheme 10

The latter reagent also features in a new process for the oxidation of secondary alcohols to ketones,62uwhile N-ethylpyridinium tetrafluoroborates (39) are key intermediates in the stereospecific synthesis of alkenes from P-hydroxysulphides, as outlined in Scheme 11.62b In addition, the use of these pyridinium

Reagents: i, R'CH(SPh)CH(OH)R'; ii, LiI

Scheme 11 E. B. Pedersen and D. Carlsen, Synthesis, 1978, 844. See ref. 29, pp. 153-4. M. Furukawa, T. Okawara, Y. Noguchi, and M. Nishikawa, Synthesis, 1978,441. 6' (a) T. Mukaiyama and K. Kawata, Chem. Lett, 1978, 785; ( b ) T. Mukaiyama, T. Tsuji, and Y. Watanabe, ibid., p. 1057. " ( a ) K. Hojo and T. Mukaiyama, Chem. Lett.,1978,369; ( b )T. Mukaiyama and M. Imaoka, ibid., p. 413; (c) K. Narasaka, K. Maruyama, and T. Mukaiyama, ibid., p. 885. 58 59

60

267

Six-membered Rings: Azines, Oxazines, and Thiazines

salts for the synthesis of macrocyclic lactones, noted last year,59 has been extended successfully to the synthesis of prostaglandin FZa 1,9- and 1,15lactones.62c N-Nitro-2,4,6-trimethylpyridinium tetrafluoroborate is useful for effecting the transfer nitration of alcohols and polyols, and so provides a safe and convenient ~~ method for the preparation of alkyl ,nitrates and p ~ l y n i t r a t e s .N-Methoxypyridinium iodide, on treatment with a primary nitroalkane (RCH,NO,) and sodium ethoxide, suffers cleavage of the pyridine ring to give l-methoxyimino-6nitrohexa-2,4-diene (40), rather than a nitr~alkyl-pyridine.~~

I

UNa

OMe

Me

The phase-transfer-catalysed methylation of quaternized alkyl-pyridines has been successful for the preparation of 2- (36%) and 4-isopropylpyridine (37%), 2,6-di-isopropylpyridine (40°/0),and 2,6-di-isopropyl-4- t- butylpyridine (20%) from 2-methyl-, 4-methyl-, 2,6-dimethyl-, and 2,4,6:trimethyl-pyridines, re~pectively.~’ 3-Cyanopyridinium salts (41), on treatment with hydroxide ion, undergo a double rearrangement to 2-alkylamino-3-acylpyridines, as outlined in Scheme 12.66The cyano-aldehyde intermediate (42), rather than ring-closing at the aldehyde function, suffers intramolecular nucleophilic addition at the cyanogroup. Further ring-transformation via a Dimroth-type rearrangement yields the acyl-pyridine (43).

li Reagent: i, OH-

Scheme 12

64

6s

G . A. Olah, S. C. Narong, R. L. Pearson, and C. A. Cupas, Synthesis, 1978,452. H. Takayama and T. Okamoto, Chem. Pharm. Bull., 1978,26,2422. L. S. Hart, C. R. J. Killen, and K. D. Saunders, J. Chem. SOC.,Chem. Commun., 1979,24. S. P. Gromov, A. N. Kost, and R-S.Sagitullin, J. Urg. Chem. USSR (Engl. TransL), 1978, 1218.

Heterocyclic Chemistry

268

A 5-methoxy substituent increases greatly the 1,3-dipolar reactivity of the otherwise unreactive 1-methyl-3-oxidopyridinium For example, addition of singlet oxygen yields ultimately the trione (44). Once again, investigations into the chemistry of pyridine N-oxides have produced interesting results. Completely unexpected is the formation of 3chloro-4-cyanopyridine ( 4 3 , rather than the 2-chloro-isomer, by the action of phosphorus o:.ychloride plus phosphorus pentachloride on 4-cyanopyridine Noxide.68 It has been suggested that the strong electron-withdrawing effect of the cyano-group renders the 4-position most susceptible to initial nucleophilic attack, as outlined in Scheme 13.

q p - i k L (yyQCI NC

Cl

NC @I

CN

N

0I

cbPC1*

(45)

Reagent: i, POCl,, PCI,

Scheme 13

Attempts to improve the yield of pyrrole-2-aldehydes from the photorearrangement of pyridine N-oxides by-complexing what is thought to be the key intermediate, i.e. the vinylnitrene :NCH=CHCH=CHCHO, with a transition metal have been u n ~ u c c e ~ ~ fOfu lthe . ~ variety ~ of metal cations tried, substantial increases in yield (4% to >30%) are brought about only by Cu2' ions. Experiments suggest that the increase is not due to stabilization of the nitrene but to the operation of a reversible redox process involving an electron transfer. The measurement of activation volumes has been suggested as a means of distinguishing between concerted and stepwise rearrangement^.^' It is argued that, since concerted sigmatropic rearrangements involve primarily the formation of a new bond, they should experience a volume contraction and hence be accelerated by an increase in reaction pressure. Conversely, a stepwise diradical process involves bond cleavage, i.e. a volume expansion, and should be retarded by increasing the pressure. The thermal rearrangement of 2-alkoxy-pyridine N-oxides to 1-alkoxy-2-pyridones provides a useful system on which to test these ideas, as the rearrangement can be either concerted or diradical, depending on the nature of the alkoxy-group. Over a pressure range of 4 kbar it is found that, for a concerted 1,4-alkyl shift, e.g. in 2-benzyloxypyridine N-oxide, the activation volume is -30 5 cm-3 mol-l, whereas for the 2-benzhydryloxy N-oxide (a diradical process) the value is +10 f 2 cm-3 mol-'. The success of these experiments has led the authors to suggest that a negative activation volume constitutes a new criterion for concertedness in sigmatropic shifts.

*

67

Y. Tamura, M. Akita, H. Kiyokawa, L.-C. Chen, and H. I. Ishibashi, TetrahedronLett., 1978,1751. J. Rokach and Y. Girard, J. Heterocycl. Chem., 1978, 15, 683. " F. Bellamy and J. Streith, J. Chem. Res. ( S ) , 1979, 18. 7" W. J. le Noble and M. R. Daka, J. A m . Chem. SOC.,1978,100,5961. "

269

Six-membered Rings : Azines, Oxazines, and Thiazines

To the list of interesting transformations of N-aryloxy-pyridinium salts reported last year71 may be added their azide-catalysed rearrangements to 3-(0hydroxypheny1)pyridines (Scheme 14).72 The rearrangement is also catalysed by CN-, I-, and AcO-, but not by other common anions such as NO3-, C1-, Br-, and

s2-.

X

X [3,5]shift or diradical

O ' O

'@

X

=

H, o r 45-Br, - M e 0S M e , 5-Ph,

Reagent: i, NaN,, MeCN

Scheme 14

There is continuing activity in the studies of the synthesis and complexing properties of crown macrocycles, particularly those based on pyridine units. 1,3,5-Tri[2,6]pyridacyclohexaphane-2,4,6-trione(46)is the first example of a pyridine-containing xanthoporphinogen-type model and possesses an unusual 6nelectron-rich cavity which is ideally suited to act as a 'perfect proton ~ponge'.'~ Bis-(6-bromo-2-pyridyl)phenylphosphine, prepared by the action of dichlorophenylphosphine on 6-bromo-2-lithiopyridine, is oxidized readily by Condensation of the dipyhydrogen peroxide to the phosphine oxide (47).74 ridylphosphine with hexaethylene glycol in the presence of sodium hydride is also accompanied by oxidation, so that the phosphine oxide macrocycle (48)(47%), rather than the phosphine crown ether, is obtained. However, attempts to prepare macrocycle (48)by direct condensation of phosphine oxide (47)with hexaethylene glycol under a variety of conditions (e.g. NaH, or NaOEt in hot toluene) resulted in a novel phosphorus-expulsion reaction and the formation of the bipyridyl(50) in practicable yield (5040%).This reaction is reminiscent of the decarbonylation process reported earlier (p. 260), and is thought to proceed uia a bipyramidal phosphorane intermediate (49),which undergoes a benzylic-acidtype rearrangement as illustrated in Scheme 15. The macrocycle (48),with sodium hydride and hexaethylene glycol at 90-100 "C, dephosphorylates to the corresponding bipyridyl crown ether. 71 72

73 74

See ref. 29, p. 157. R. A.Abramovitch, A. L. Miller, T. A. Radzikowska, and P. Tomasik, J. Org, Chem., 1979,44,465. G. R.Newkome, J. D. Sauer, P. K. Mattschei, and A. Nayak, Heterocycles, 1978,9, 1555. G. R. Newkome and D. C. Hager, J. Am. Chem. Soc., 1978,100,5567.

He terocy c Zic Chemistry

270

1 (49)

Reagent: i, NaOEt, PhMe

Scheme 15

Several macrocycles based on 2,6-dioxypyridyl units have been r e p ~ r t e d . ~ ' However, the synthesis of their thioether analogues has proved to be much more difficult.76For example, condensation of 2,6-dihalogeno-pyridineswith 2,2'-bismercaptoethyl ether, (HSCH2CH2),0, gives only trace amounts of the macrocycle (5l),together with numerous complex by-products, while the corresponding thioether (HSCH,CH,),S yields no macrocycle at all! 2,6-Bis(aminomethyl)pyridine, which itself forms complexes with, for example, CuCl,, Mg(C10J2, and Ni(BF,),, has been prepared,77and is a useful intermediate for the synthesis of other new cyclic and acyclic crown-type molecules, e.g. (52). The hydride-donating ability of crown ethers based on Hantzsch-type 1,4dihydropyridine-3,5-dicarboxylateswas noted last year.75 The development of other systems of this nature has been hindered by synthetic problems. However, the authors now that crown ethers of type (53)are obtainable in high yield (80--90%) by treating the dicaesium salts of the corresponding pyridine3,5-dicarboxylic acids with the requisite ww 'dibromo-polyether in hot DMF. 75

76

77 78

See ref. 29, p. 160. G . R . Newkome, F. Danesh-Khoshboo, A. Nayak, and W . H . Benton, J. Org. Chem., 1978, 43,

2685. E. Buhleier, W. Wehner, an: F. Vogtle, Justus Liebigs Ann. Chem., 1978, 537. (a) 0.Piepers and R . M. Kellogg, J. Chem. SOC.,Chem. Commun., 1978, 383; (b) R. H. van der Veen, R. M. Kellogg, A. Vos, and T. J. van Bergen, ibid., p. 923.

27 1

Six-membered Rings : Azines, Oxazines, and Thiazines

The method is also applicable to benzenedicarboxylic acids and for the synthesis of linear polyethers, e.g. (54).

(54) (55) (-)- 15-Aminomethyl-14-hydroxy-2,8-dithia[9](2,5)pyridinophane (55), a chiral pyridoxamine analogue, is successful in effecting stereoselective transamination of cu-kefo-a~ids.~~For example, P-phenylpyruvic acid (PhCH,COCO,H) and (55), when stirred for 20 h at room temperature in acetonitrile, in the presence of zinc perchlorate, yields a sample of the a-aminoacid PhCH,CH(NH,)CO,H that is enriched by up to 26% of one enantiomer. Spectral ('H and 13Cn.m.r., and u.v.) along with other data (e.g. basicity) have been measuredsonfor the cyclobutapyridines reported last year.81[2,3:5,6]Dicyclobutapyridine (57) (pK, 4.40)has been prepared in 15% yield by flash vacuum pyrolysis of the bis-chloromethyl-lutidine (56), as outlined in Scheme 16.806

Reagent: i, FVP, 750 "C, NaOH, 0.1 mmHg

Scheme 16

In addition to the known trans-anti- (4 + 4) cyclo-adduct from the photodimerization of N-methy1-2-pyridone,'* three new (4 + 4) cycloaddition products, identified as the trans-syn, cis-unti-, and cis-syn-isomers, have been isolated in minor amounts (0.6, 11.2, and 6.8%,respectively). 79

H. Kuzuhara, T. Komatsu, and S. Emo'7, Tetrahedron Lett., 1978, 3563. R. P.Thummel1 and D. K. Kohli, ( a )J. Org. Chem., 1978,43,4882; ( b ) TetrahedronLett., 1979,143. See ref. 29, p. 161. Y. Nakamura, T. Kato, and Y. Morita, J. Chem. SOC.,Chem. Cornrnun., 1978,620.

Heterocyclic Chemistry

272

Recent suggest that simple aryl-imines are in thermal tautomeric equilibrium with their 173-dipolar species. This raises the intriguing possibility that important enzyme transformations involving the aldimines of pyridoxal (or its phosphate) with a-amino-acids, e.g. (58), may also feature 173-dipolarspecies, e.g. (59), particularly as the aldimine (58),with N-phenylmaleimide in boiling xylene, gives the cyclo-adduct (60) in 84% yield.83b C0,Me

C0,Me

I

I

CH=&HCCH ,Ph

CH=NCHCH,Ph

- HOCH, A

0:

(58)

P h N q : : 2 M e CH,Ph

(59)

0

0

(60)

5H-Pyrano- and 5H-thiopyrano-[2,3-b:6,5-b’]dipyridin-5-one, (61; X = 0) and (6 1;X = S) respectively, have been prepared,84 and are the first examples of xanthone-like heterocycles possessing two pyridine rings fused to the 4-pyrone ring. The rearrangement of 4-pyridyl propargyl ether at high temperature (550 “C) to a mixture of cyclobutapyridines was reported last year.81 A completely different sequence of reactions, however, is undergone by 3-pyridyl propargyl ether (62; R = H) in hot (208°C) DMF or n-decane (Scheme 17).85 The furo-pyridines (63) and (64) arise via cyclization of the appropriate allene, e.g. (66), whereas the pyranopyridine (65) forms by electrocyclization of (67). The 2-methylpyridyl ether (62; R = Me) behaves similarly, whereas if both orthopositions to the ether are blocked, intramolecular Diels-Alder cycloaddition of the intermediate allene (68) (Scheme 18) yields the tetracycle (69) as a diastereoisomeric mixture. A full report on the synthesis of indolizines by cyclization of allylidenedihydropyridines, described last year,86 has a p p e a ~ e d . ” The ~ method has been 83

84

’’ ’’ a6

( a )R. Grigg, J. Kemp, G. Sheldrick, and J. Trotter, J. Chem. SOC.,Chem. Commun., 1978, 109; ( b ) R. Grigg and J. Kemp, Tetrahedron Lett., 1978,2823. F. Trtcourt, J. Morel, and G. Qutguiner, J. Chem. Rex ( S ) , 1979,46. J. Bruhn, J. Zsindely, H. Schmid, and G. Frater, Helv. Chim. Actu, 1978, 61, 2542. See ref. 29, p. 163. (a) A. Kakehi, S. Ito, T. Maeda, R. Takeda, M. Nishimura, M. Tamashima, and T. Yamaguchi, J. Org. Chem., 1978,43, 4837; ( b ) A. Kakehi, S. Ito, K. Uchiyama, and K. Kondo, ibid., p. 2896.

273

Six-membered Rings : Azines, Oxazines, and Thiazines

Reagents: i, DMF, 208 "C;ii, decane, 208 "C

Scheme 17

Scheme 18

I? MeNC0,Et

xH+

Reagent: i, A, xylene

(70) Scheme 19

extended to the synthesis of ethenyl-pyrazolo[1,5-a]pyridines (70), as outlined in Scheme 19,*'* and of 1,2-dihydropyrazolo[1,5-a]pyridin-2-ones (72; X = C0,Et or CN)'* from 1-acylimino-pyridinium ylides (71). A. Kakehi, S. Ito, Y.Konno, and T. Maeda, Bull. Chem. SOC.Jpn., 1978, 51, 251.

Heterocyclic Chemistry

274

1,2,3,5,6,10b-Hexahydropyrido[2,3-g]indolizine(74) (79%), a bridged-nicotine derivative, has been prepared by the method shown in Scheme 20.89 Reduction of lactone (73)with lithium aluminium hydride gave the indolizidine in only 30% yield.

Reagents: i, Bu"Li; ii, CO,; iii, BH,-THF

Scheme 20

A one-step, metal-catalysed synthesis of 3-dialkylamino-indolizines and their 5-aza-analogues from a-halogeno-aza-aromatics has been described;" e.g., Scheme 21.

li oC=CCH20H

1

T

0,

-+

N

CH

II

H' C 'CHO

Reagent: i, HC=CCH,OH, R,NH, [Pd(PPh,)Cl,], CuI, 80 "C, 16 h

Scheme 21

'' T. E. Catka and E. Leete, J. Org. Chem., 1978,43,2125.

'' A. Ohsawa, Y. Abe, and H. Igeta, Chem. Lett., 1979,241.

-

Six-membered Rings: Azines, Oxazines, and Thiazines

275

Rare examples of nucleophilic displacement of halogen from aza-indolizines have been noted9' in the reactions of 5-chloro-6-aza- (75) and 7-chloro-8-azaindolizine (76) with sodium methoxide. The chloro-compounds are, however, inert towards sodium hydroxide, ammonia, and sodium amide.

2-Halogeno-pyridines are not sufficiently nucleophilic to react with dimethyl acetylenedicarboxylate under normal conditions. However, in diethyl ether, at room temperature, and under high pressure (10 kbar), over a period of several days, 2-chloro- and 2-bromo-pyridine give 1:2 (pyridine :ester) adducts; these were identified as the quinolizines (77; X = C1 or Br).92The 9aH-quinolizine (78) may also be isolated from the latter reaction. 2-Fluoropyridine gives an uncharacterized 1:3 adduct. The base-catalysed condensation of a-cyano-o-toluonitrile with 2-halogenopyridines forms the basis of a new route to benzoquinolizine (79) and benzoquinolizinium (80) derivatives (Scheme 22).93 CN I

-L

ii or iii,

0 N

\

/

X

9

(79) x = (80) X = NH2BF4Reagents: i, 2-BrC,H4N, NaH, glyrne; ii, HBr, HBF,; iii, Al,O,, MeOH

Scheme 22

Hydro-pyridines.-A comprehensive MIND0/3 study of the formation, stability, and protonation of dihydropyridines has been carried It was concluded that the stability of the dihydropyridine isomers decreases in the series 1,4- > 3,4- > 1,2- > 2,5- > 2,3- >> bicyclo-isomers, e.g. (81). The greater stability of 1,4-dihydropyridine over its 1,2-dihydro-isomer has been attributed to the greater hyperconjugation of the CH, group and the enhanced contribution of the nitrogen lone-pair to its HOMO. The calculations also indicate that protonation 91

R. Buchan, M. Fraser, and C. Shand, J. Org. Chem., 1978,43,3544.

93

K.Matsumoto, Y. Ikemi-Kono, and T. Uchida, J. Chem. SOC.,Chem. Commun., 1978.543. C . K.Bradsher and I. J . Westerman, J. Org. Chem., 1978,43,3536.

94

N . Bodor and R. Pearlman, J. Am. Chem. SOC., 1978,100,4946.

"

Heterocyclic Chemistry

276

of 1,4-dihydropyridine (a process of biological importance) takes place pref erentially at carbon, to yield enamine salt (82),which is a more stable system than the quaternary nitrogen structure (83). It has also been estimated that protonation of 1,2-dihydropyridine will give initially the kinetically more favourable 2,5-dihydro-derivative (84) which, on the basis of A H measurements, should equilibrate to the thermodynamically more stable 2,3-dihydro-form (85).X-Ray analysis has established that all the dihydro-pyridines, except for the bicycloderivatives, e.g. (81), are planar.

The adaptation of the Hantzsch dihydropyridine synthesis noted last year95has been expanded to include the preparation of 2-amino-6-dialkylamino-4,5-dihydropyridines, e.g. (86),96aand 2-amin0-6-0~0-1,4,5,6-tetrahydropyridine3,5-dicarboxylates (87)."* The former arise by condensing an aldehyde (R'CHO) (1 mole) with a molar excess of amidinoacetic ester, HN=C(NH2)CH2C02R2, whereas the latter are formed by ring-closure of the product of Michael addition of the amidinoacetic ester and a dialkyl aryl-alkylidenemalonate, e.g. ArCH=C(CO,Et),. N-Acyl- 1,4-dihydropyridines, e.g. (88), are accessible in good yield (75%) by acid-catalysed (toluene-p-sulphonic acid, TSA) condensation of cudialdehydes, e.g. Me,C(CH,CHO),, with amides RCONH, (R = Me or Ph) in boiling benzene.97 The products are stable if kept at -10°C. An improvement on the Wenkert reduction (Pd/C and Et3N)of 1-methylpyridinium ' modification, salts to 1,4,5,6-tetrahydropyridixleshas been e l a b ~ r a t e d . ~The which uses 10% palladium-charcoal in methanol that also contains a suspension of disodium hydrogen phosphate and sodium dihydrogen phosphate, produces the tetrahydropyridine, e.g. (89), in good yield, along with minor amounts of the corresponding piperidine.

"'":ON.,0 Me

C02R2

R

2

0

2

c

~

~

~

Me

2

QC0,EtMe

0

(86)

H (87)

COR (88)

Me (89)

Proton n.m.r. and i.r. data indicate that 2,5dihydropyridines (90; R' = Bu", But, or Ph; R2 = Me or Et) are intermediates in the alkylation of 2-alkyl- or 2-aryl-l-lithio-l,2-dihydropyridines with alkyl halides R2X (R2 = Me or Et).99 95 y6 97

98 yy

See ref. 29, p. 149. H. Meyer, F. Bossert, and H. Horstmann,Jushrs Liebigs Ann. Chem., 1978, (a) p. 1476; ( b )p. 1483. J. S. Foos, W. Killian, S. Q. A. Rizvi, M. Unger, and G. Fraenkel, Tetrahedron Lett., 1978, 1407. L. Chevolot and H-P. Hussan, J. Heterocycf. Chem., 1978,15, 1509. R. F. Francis, C. D. Crews, and B. S. Scott, J. Org. Chem., 1978,43,3227.

Six-membered Rings : Azines, Oxazines, and Thiazines

277

Surprisingly,no 1,2-dialkyl-1,2-dihydropyridineswere detected. Direct work-up of the reaction produces a mixture of 2,5-dialkyl-pyridine and 2,Sdialkyl1,2,5,6-tetrahydropyridine(91), whereas reduction of the reaction mixture with lithium aluminium hydride produces (in certain cases; see Scheme 23) a single

0 N Li

L .

R'

'*n Ro' +R'o 9

\

N

/

N

R'

or R' = Ph,

R'

R'

H

R2 = Me or Et

Reagents: i, R2X; ii, LiAIH,

Scheme 23

tetrahydropyridine (91), in practicable yield. However, with (90; R' = But, = Bu", R2 = Me), mixtures of stereoisomeric tetrahydropyridines are obtained. Also of potential preparative value are the reactions of 2-alkyl-1-lithio-pyridines with ethyl isocyanate.100aThe n-butyl derivative (92; R' = Bun, R2 = Li), as anticipated on the basis of mesomeric interactions (and also in accord with the theoretical prediction^^^ noted on p. 275), suffers electrophilic attack at the 1- and 3-positions to give the dihydropyridines (92; R' = Bun, R2 = CONHEt) (51.6%) and (93) (11.8y0),along with the pyridine (94) (14.6%). In contrast, the 2-phenyl derivative (92; R' = Ph, R2 = Li) undergoes exclusive N-substitution to the 1,2-dihydropyridine (92; R' = Ph, R2 = CONHEt) (61%).

R2 = Et) and (90; R'

(92)

CONHEt (93)

Reduction of 1,3-dimethylpyridiniurn iodide (95) with sodium borohydride in strongly alkaline medium has been the subject of some controversy, with dihydro-, tetrahydro-, and hexahydro-pyridines being claimed as products. A careful re-investigation'" has clarified the position and shows that the nature of the reduction products depends on the reaction time. For example, 'H n.m.r. analysis of the reaction mixture after only three minutes reveals the presence of a complex mixture of hydro-derivatives (96)-( loo), in the quantities shown loo

( a )T. A. Ondrus, F. M. Pasutto, E. E. Knaus, and C. S. Giam, Can. J. Chem., 1978,56,1913; ( b )T . A. Ondrus, E. E. Knaus, and C. S. Giam, ibid., p. 1026. A. Casini, B. di Rienzo, F. M. Moracci, S. Tortorella, and F. Liberatore, Tetruhedron Lett.,1978, 2139.

Heterocyclic Chemistry

278

(Scheme 24). On allowing the reaction mixture to stand (or on distillation), the 1,2-dihydro-derivative (96) disappears, with concomitant formation of the dimeric species (100). The high ratio of (96) : [(97) + (98)] is surprising, since it indicates attack by the borohydride at the most sterically hindered ring site (i.e. the 2-position). Labelling experiments with NaBD, exclude the possibility of forming (96) by rearrangement of (97) or (98). They do show, however, that the enamine systems present in structures (96), (97), and (98) are capable of direct and complete reduction to hexahydropyridines by borohydride in alkaline solution.

(-ye

+ QMe

+

QMe Me

&

62 % +

(96)

N Me

Me

11% (97)

1 1O/O (98)

Me

Me

(95)

(99 Reagent: i, 0.8N-NaOH, MeOH, NaBH,, light petrol, 3 min

Scheme 24

Reduction of N-iminopyridinium ylides with sodium borohydride yields their tetrahydro-derivatives (101), which are readily converted into the N-imino1,2,5,6-tetrahydropyridiniumylides (102); see Scheme 25.'"

oR oR i,ii

I

NHC0,Et

/

Me

\-

NC0,Et

(102)

101) Reagents: i, MeI; ii, OH

Scheme 25

Several new severely Andered nitrogen bases have been prepared by reduction of 2,6-di-t-butylpyridine with lithium meta1.lo3For example, with lithium (2-7 equivalents) and a large excess of t-butyl alcohol, in liquid ammonia, a mixture of the 1,4- and 3,4-dihydro-derivatives is obtained, in 60% overall yield. On 102

T. Tsuchiya, H. Sashida, and H. Sawanishi, Chem. Pham. Bull., 1978,26,2880. J. C . Day, J. Org. Chem., 1978,43,3646.

279

Six-membered Rings; Arines, Oxazines, and Thiazines

standing, the 1,4-dihydro-derivative tautomerizes quantitatively to the 3,4dihydro-isomer. In contrast, with lithium (5 equivalents) and a seven-molar excess of t-butyl alcohol, the tetrahydro-derivative (103) is formed, in 46% yield. Complete reduction to hexahydro-cisdi-t-butylpiperidine(104) (86%) is possible if one uses an excess of lithium (18 equivalents) in 1,2-diaminoethane and t-butyl alcohol.

Me

rC) CO,Et

(107)

The reaction of 2-picoline with ethyl chloroformate gives not, as was supposed (105) but a mixture of the 1,2previously, the 2-methyleno-1,2-dihydropyridine and 1,4-dihydropyridines(106) and (107).'04 The efficiency of light-induced and dye-accelerated reductions of phenacylsulphonium salts by crown ether 1,4-dihydropyridines, e.g. (108), reported last year75 is increased by visible light.lo5 X-Ray crystallographic studies on the sodium perchlorate-acetone complex of (108) reveal that the dihydropyridine ring is in a pronounced boat c ~ n f o r m a t i o nThe . ~ ~simple ~ Hantzsch intermediate (log), (possibly because of steric factors) resists the photodimerization usually undergone by 1,4-dihydropyridines,and is an ideal NAD(P)H model for effecting the photo-induced reduction of imines.Io6 For example, benzylideneanilines RC6H4CH=N4 (R = H or MeO; Ar = Ph, p-MeOC&, or P-naphthyl) are reduced to the correspondingbenzylamines RC6H4CH,NHArin 60-92% yield.

(108) '04

lo' '06

J . P. Lenders and C. Hootelt, Bull SOC.Chirn. Belg., 1978,87,553.

D.M. Hedstrand, W. H. Kruizinga, and R. M. Kellogg, Tetrahedron Lett., 1978, 1255. S. Singh, A. K. Trehan, and V. K. Sharma, Tetrahedron Lett.,1978,5029.

280

Heterocyclic Chemistry

The cyclo-adducts (110)from cyanogen azide and 2-alkyl-1-methoxycarbonyl1,2-dihydropyridines extrude nitrogen easily to give a stereoisomeric mixture of the tetrahydropyridylidene-4-cyanoamides(111).loo' However, when cyanogen azide reacts with l-acetyl-2-n-butyl-l,2-dihydropyridifie,2,7-diazabicycloC4.1.0]hept14-ene (112) (19.7%) and 2-diazo-172,3,6-tetrahydropyridylidene3-cyanoamide (1 13) (11.4%) are isolated, in addition to the syn- and anti-forms of the imine (111; R' = Bun,R2 = Ac) (36.5%), suggesting that there is a competing 1,3-dipolar cycloaddition of cyanogen azide at the 5,6-bond, as illustrated in Scheme 26. CN I

(92)&

2

-N, (R' = H, Ph, or Bu') (R2= CO,Me)

CN

bR1 R2

1 N

C

N

N

n Bu"

Reagent: i, NCN,

Scheme 26

Unlike N-imino-pyridinium ylides themselves, which undergo thermal ringexpansion to 1,2-diazepines7 their 1,2,5,6-tetrahydro-derivatives (102) are transformed into ring-contraction products, e.g. 3-vinyl-tetrahydropyrazoles (114) (10-12%), and ring-opened products, e.g. the pentadienyl-hydrazines (115) (20-25%) at 150-160 'C.'02 Minor amounts (10-15%) of the 1,2,5,6-

28 1

Six-membered Rings 1 Azines, Oxazines, and Thiazines tetrahydropyridines (116; R3 = NHC0,Et) produced.

and (116; R3 = Me) are also

Thermolysis of N- (hex-l-eny1)-1,2-dihydropyridine (117) gives not the expected intramolecular (4 + 2) cyclo-adduct but 9-azabicyclo[5.2.2.01~5]undec8-ene (120).'07 The formation of (120), which is isolated as a mixture of two isomers, the major one having the C-5-proton ex0 to the C=N bridge, is best explained in terms of an initial ring-opening to an acyclic triene; this, by a series of [1,7] and [1,5] hydrogen shifts, isomerizes to the N-(pent- l-enyl)-3,4-dihydropyridine (119); see Scheme 27. Intramolecular (4 + 2) cycloaddition of (119) yields the azabicycloundecene. This mechanism is supported by deuteriumlabelling studies and also by the fact that the pentenyl-dihydropyridine (118) has been detected during flash vacuum photolysis of the hexenyl-pyridine (117). This result has led the authors to speculate that, contrary to general opinion (see for example ref. 94), 2,3-dihydropyridines are more stable than their more extensively conjugated 1,2-dihydro-isomersa

,

N=CH

H2C

Scheme 27

'07

kH2-CH2

1

(117)

I. Hasan and F.W. Fowler, J. Am. Chem. SOC.,1978,100, 6696.

282

Heterocyclic Chemistry

The first 3,4-dihydropyrido[1,2-a]benzimidazo1es7e.g. (12 l),have been prepared oia the reaction sequence outlined in Scheme 28.'08 1

0

H

H

J

(121)

Reagent: i, p-TsOH, A

Scheme 28

Schmidt rearrangement of tertiary cycloalkyl azides provides direct access to simple 2-alkyl- and 2,6-dialkyl-piperidine alkaloid^.'^^ For example, 1-azido-1n-propylpyrrolidine ring-expands to a-n-propylpiperideine (93%), catalytic hydrogenation of which yields (*)-coniine (122) in 63% overall yield. 1and 4-substituted 2-aza-1,3-butadienes, e.g. Surprisingly, Me2C=CHN=CHCHMe2, do not undergo Diels-Alder reaction with acrylonitrile, but instead they yield the Michael adducts, e.g. Me,C=CHN=CHC(Me),CH,CH,CN.' l o However, reduction of these adducts with palladium-charcoal and hydrogen results in hydrogenative cyclization to N-alkyl-3,3-dialkyl-piperidines (123) in practicable yields (70-90%). Perfluoro-N-perfluorophenylpiperidine ( 124) is obtained in quantitative yield by treating the corresponding perfluoro-2,6-dioxopiperidinewith a mixture of sulphur tetrafluoride and hydrogen fluoride at 125°C for 24 hours."' The method appears to be a general one for the conversion of cyclic tertiary amides into perfluorinated tertiary amines. Direct conversion of perfluoropiperidine and perfluoromorpholine into the respective perfluoro secondary amines, i.e. (125; X = GF,) and (125 ;X = 0),has been achieved, using hydrogen iodide in the presence of a Type 4A molecular sieve. Mydrodefluorination of perfluoromorpholine is also accompaniedby dehydrofluorination to the perfluoro- 1,4-oxazine (126; X = 0, R = F). A variety of 2-substituted perfluoro-1-azacyclohexenes (126; X = CF,; R = NMe,, OC4H8N,or OC,Cl,) are accessible by controlled nucleophilic displacement reactions on the perfluoro- 1-azacyclohexene (126; X = CF,, R = F).112b

Quinoline, Isoquinoline, and their Benzo- and Hydro-derivatives-pMethoxyacetanilidefails to formylate under normal Vilsmeier-Haack conditions, lo9 110

'11

l2

S. Miyano, N. Abe, K. Takeda, and K. Sumoto, Synthesis, 1978, 451. A. Astier and M. M. Plat, Tetrahedron Lett., 1478, 2051. H. Feichtinger, W. Payer, and B. Cornils, Chem. Ber., 1978, 111, 1721. R. J. De Pasquale, J. Org. Chem., 1978, 43, 1727. ( a )R. E. Banks and R. Hatton, J. Fluorine Chem., 1978,11,563; ( 6 )R. E. Banks and C. Oppenheim, ibid., p. 27.

283

Six-membered Rings : Azines, Oxazines, and Thiazines

whereas rn-methoxy-, rn-methyl-, 3,4-dimethoxy-, and 3,4,5-trimethoxyacetanilides yield a mixture of the 2-chloro- and 2-chloro-3-formyl-quinolines."3 Careful control of the reaction conditions enables either of these two products to be generated exclusively. For example, rn-methoxyacetanilide with a 1:3 mixture of dimethylformamide and phosphorus oxychloride in 1,1,2,2-tetrachloroethane yields 7-methoxy-2-chloroquinoline(127; R = H) (73%) whereas with a 3 :7 DMF-POC1, mixture and no solvent, 2-chloro-3-formyl-7-methoxyquinoline (127; R = CHO) becomes the sole product (89%). Similarly, formylation of the appropriate acetamido-thiophens provide useful syntheses of thieno-[3,2-b]-, -[3,4-c]-, and -[2,3-b]-chloroquinolines,e.g. (128; R = H) and their formyl derivatives, e.g. (128; R = CHO).

Me0 \ (128)

(127)

A full account of the palladium(I1)-catalysed ring-closure of o-allyl-anilines to 2-methyl-indoles and quinolines, noted last year,"" has appeared.'15 Metal complexes also feature in two other new quinoline syntheses. o-Nitrocinnamaldehyde suffers quantitative reductive cyclization to quinoline with alcoholic potassium tetracarbonylhydridoferrate, (KHFe(CO),].' l 6 Mixtures of onitrobenzaldehyde and methyl ketones (e.g. acetone) yield 2-substituted quinolines (e.g. quinaldine), but in lesser yields (55%). It is likely that the reaction goes via the ortho-amine, although reduction of the pre-formed o-amino-aldehydes produces quinolines in much reduced yields. Attempts to extend the method to other o-nitro-cup-unsubstitutedsystems were disappointing. Of greater synthetic potential is the formation of quinolines and their 1,2,3,4-tetrahydroderivatives from aryl-amines and alkenes by the route outlined in Scheme 29."'

t iii

\

N

/

Me

a Me

\

H

0

CH,CH,CH=CH,

\

N H *.............Rh,

X

Reagents: i, RhC13-3H,0, Ph3P, 200 "C, 100 atm, 72 h; ii, CH,=CH,; iii, RhCI,.3H20, CH2=CH2

Scheme 29 114

'15 116

'"

0.Meth-Cohn and B. Narine, Tetrahedron Lett., 1978, 2045. R. K. Smalley, in 'Aromatic and Heteroaromatic Chemistry',ed. H. Suschitzkyand 0.Meth-Cohn (Specialist Periodical Reports), The Chemical Society, London, 1978, Vol. 6, p. 31. L. S. Hegedus, G . F. Allen, J. J. Bozell, and E. L. Waterman, J. Am. Chem. Soc.,1978,100,5800. Y. Watanabe, K. Takatsuki, S. C. Shim;T. Mitsudo, and Y. Takegami, Bull. Chem. SOC.,Jpn., 1978, 51,3397. S. E. Diamond, A. Szalkiewia, and F. Mares, J. Am. Chem. Soc., 1979,101,490.

Heterocyclic Chemistry

284

This reaction sequence, which is specific to complexes with Group VIII metals, is unique in having five consecutive metal-catalysed steps. The tetrahydroquinoline :quinoline ratio can be varied by changing either the reaction conditions or the Group VIII metal catalyst. Good evidence for some of the intermediates proposed in Scheme 29 is presented. Benzo[c][2]pyrindine, prepared as indicated in Scheme 30 from the cyclopenta[c]quinoline (129), is stable under nitrogen at
(132)

(131)

Reagents: i, Peracid; ii, Ac,O; iii, NaOH, MeOH; iv, conc. H,SO,

Scheme 30

1,2-Diphenyl-3-azanaphtho[b]cyclobutadiene (133), prepared as outlined in Scheme 31, is claimed to be the first example of a cyclobutadiene fused to a

uo

Ph-0

; ii, Fe,(CO),,

Reagents: i,

Ph

'"

(134) 13%

Scheme 31

J. J. Eisch, H. Gopal, and C. T. Kuo, J. Org. Chem., 1978, 43, 2190.

(133) 16.5%

Six-membered Rings : Azines, Oxazines, and Thiazines

285

nitrogen-containing heteroaromatic system.ll9 Also formed is the [Fe(CO),] complex of (134) (12.5%). As expected, the cyclobutadiene (133) is oxidized readily to 2,3-dibenzoylquinoline, and undergoes Diels-Alder cycloadditions with the usual dienes. A Friedlander synthesis with o-aminobenzaldehyde and 3-phenyl-2-isoxazolin-5-one yields the new heterocyclic system 3-phenylisoxazolo[5,4-bJquinoline (135) in 70% yield.12' Ph I

2-Quinolones are available in variable yields (30-70%) by the palladiumacetate-catalysed condensation of activated alkenes with o-iodo-anilines, as exemplified in Scheme 32. 12' 4-Phenyl-2-quinolone is produced (60%) from o-iodoaniline and cinnamanilide under similar conditions, but can be obtained in better yield by a-arylation of o-aminocinnamic acid with iodobenzene and a palladium acetate catalyst. The resulting amino-acid (136) cyclizes in situ to the quinolone in 71% yield. Attempts to extend the process to the synthesis of coumarins from o-iodo-phenols failed. Other quinolone syntheses that have been announced include the production of 4-chloro-3-methyl-2-quinolone (79%)by Vilsmeier reaction on l-methyl-2-ind0linone'~~ and of 4-quinolone-3-carboxylates (and 3-substituted 4-amino-quinolines) by intramolecular FriedelArNHCH=C(CN)CO,Et Crafts reaction on arylaminomethylene-cyanoacetates and -malononitriles ArNHCH=C(CN)X (X = CN, CONH2, or Bz), respectively.123

Reagent: i, cis-MeO,CCH=CHCO,Me, Pd(OAc),, Et,N, 100 "C

Scheme 32

In addition, 2,3-disubstituted 4-quinolones (137), useful precursors of 2,3,4trisubstituted quinolines, are produced in practicable yields (4&75%) by 'I9

122

123

A. A. Ardakani, N. Maleki, and M. R. Saadein, J. Org. Chem., 1978,43,4128. C. Skotsch and E. Breitmaier, Chem.-Ztg., 1978, 102, 264. N. A. Cortese, C. B. Ziegler, B. J. Hrnjez, and R. F. Heck, J. Org. Chem., 1978,43, 2952. A. Andreani, D. Bonazzi, and M. Rambaldi, Boll. Chim. Farm., 1976, 115, 732. H. Schafer and K. Gewald, Monatsh. Chem., 1978,109,527.

286

Heterocyclic Chemistry

condensing ethyl 2-ethoxycarbonylacetimidate hydrochloride with o-aminobenzoates, as outlined in Scheme 33.124 0

\

OMe

(137)

H

Reagents: i, XCH,C(OMe)=NH.HCl (X = C0,Et or CN), EtOH, 50 "C, 2 h; ii, base

Scheme 33

The action of diazomethanes RCHfi2on oxindole-acrylates (138) does not give the expected 1,3-dipolar cyclo-adducts, but results in an unusual ring-expansion (Scheme 34) to produce the 2-quinolones (139).12' At ambient temperature, in DMSO, the 2-quinolone (139; R = H) slowly equilibrates to the furo[2,3-b]quinoline (140). 70,Et 1

--*

R

/

C02E

-H2

+-

H

(140) -

Reagent: i, RCHN, (R

=

H or Ph)

Scheme 34

In hot nitrobenzene the vinyl-propargyl-amine (141; n = 1) undergoes an amino-Claisen rearrangement to the allenic enamine (142), which by [1,5]-H shift and electrocyclization yields 5,6,7,8-tetrahydroquinolin-5-one(143) in 50%

Scheme 35 Iz4 125

J. Y. Merour and F. Tatibouet, Synthesis, 1978, 698. G. B. Bennett, R. B. Mason, and M. J. Shapiro, J. Org. Chem., 1978,43, 4383.

Six-membered Rings : Azines, Oxazines, and Thiazines

287

yield (Scheme 35).126A similar reaction on the 3-oxocyclopentenyl-amine (141; n = 0)yields 6,7-dihydro-l-pyrindin-5-one (68%). 2-Chloroquinoline is reduced quantitatively to 1,2,3,4-tetrahydroquinoline when it reacts with calcium in methan01.'~' Pyridine-borane, C5HSN*BH3, does not reduce aza-heteroaromatics in benzene or pyridine solution, whereas in acetic acid at room temperature it reduces quinoline to 1,2,3,4-tetrahydroquinolinein 7 1% yield.128However, care is needed, as acetylation of the tetrahydroquinoline occurs at higher temperatures (boiling acetic acid), followed by reduction of the N-acetyl compound to N-ethyl- 1,2,3,4-tetrahydroquinoline(63%). Both the above methods have been applied successfully to the reduction of other azaheteroaromatic systems, such as pyrazines, quinoxalines, and phthalazines. Alkynyl-quinolines are available, generally in good yields, by the coupling of iodo-(and sometimes bromo-)quinolines with monosubstituted alkynes in the presence of the palladium complex [Pd(PPh,),Cl,], cupric iodide, and trimeth~1amine.l~~ Alkenylation of iodo-pyrimidines under similar conditions was reported last year.',' Generally, quinoline N-oxide reacts with active methylene groups in the presence of acylating agents to give 2- and 4-substituted quinolines. However, with ethyl cyanoacetate and acetic anhydride in DMF or DMSO at 0 "C,the major product is the quinolinium ethoxycarbonylcyanomethylide (145) (53.6%),along with lesser amounts (32% and 7% respectively) of the expected ethyl 2- (146; R = CN) and 4-quinolylcyanoacetates.'31 A likely reactioapathway is uiu ringopening of the aziridine intermediate (144)(Scheme 36). Ylides also result from the reaction of quinoline N-oxide with malononitrile and a-cyanoacetophenone, but not with cyanoacetamide, diethyl malonate, ethyl acetoacetate, or acetylacetone, and not at all with pyridine and isoquinoline N-oxides.

Scheme 36

The keto-ester (146; R = Ac), obtained by treating quinoline N-oxide with ethyl acetoacetate in acetic anhydride, sufferspreferential loss of the acetyl group on mild hydrolysis with 10% hydrochloric acid, so providing a practicable synthesis of 2-quinolyl The method is of general application, and has K. Berg-Nielsen and L. Skattabd, Acta Chem. Scand., Ser. B, 1978, 553. H. Neunhoeffer and G. Kohler, Tetrahedron Lett., 1978,4879. '** Y. Kikugawa, K . Saito, and S-I. Yamada, Synthesis, 1978, 447. 129 H. Yamanaka, M. Shiraiwa, K. Edo, and T. Sakamoto, Chem. Phann. Bull., 1979,27, 270. See ref. 29, p. 187. 13' K. Funakoshi, H. Sonoda, Y. Sonoda, and M. Hamana, Chem. Phann. Bull., 1978,26,3504. 13' M. Iwao and T. Kuraishi, J. Heterocycl. Chem., 1978, 15, 1425. '21 '21

288

Heterocyclic Chemistry

been used to prepare 4-pyridyl- (48%), 2-methyl-4-pyridyl- (45%), 1-isoquinolyl- (69%), and 6-methoxy-3-pyridazinyl-acetic esters (67%). An alternative and well-established method of functionalizing the 2-position of the quinoline ring is by treating quinoline N-oxide with an enamine in the presence of an acyl halide. If 5-amino-isoxazoles are used as the enamine component then the 2-(4-isoxazolyl)-quinolines(147; R = NH, or NHMe) are obtained in moderate yields (14-35Y0).~~~ In a similar manner, 3-methylisoxazolin-5-one yields the 2-(substituted 4-isoxazolyl)quinoline (147; R = OH), which is a useful precursor of other 2-substituted quinolines. For example, reduction (by Ni and H,) results in ring-opening and loss of CO, to give the 2-aminopropyl derivative (148). l-(4-Isoxazolyl)-isoquinolines have been prepared similarly. 4-Nitroquinoline and its N-oxide, with potassium cyanide in hot (80 "C)DMF, undergo unusual, and as yet unexplained, hydroxy-denitrations and cyanations to produce 3-cyano4-hydroxyquinoline in 8 1.4% and 62.7% yield, r e s p e ~ t i v e l y . ' ~ ~

Photolysis of 4-nitropyridine and 4-nitroquinoline N-oxides in the presence of trimethyl phosphite is r e c ~ m m e n d e d las ~ ~a useful method of deoxygenation without loss of the nitro-group, such as occurs using phosphorus halides. The rearrangements and ring-expansions of quinoline (and isoquinoline) N-oxides to quinolones (1-isoquinolones) and oxazepines are known to be reactions involving the excited singlet state, whereas photo-deoxygenation is a process in which the triplet state takes part. Previously, it was ~ h o w n ' ~that " the yield of isoquinolone from the photo-rearrangement of isoquinoline N-oxide varies with the strength of an externally applied magnetic field, and from this result it was suggested that there is perturbation of the inter-system singlet-triplet crossing by the magnetic field. New inve~tigafions,~~' however, have failed to corroborate these findings. For example, irradiation of 2-cyanoquinoline N-oxide produces mainly (>90%) cyano-oxazepine along with a small amount of deoxygenated (i.e. triplet-state) material. Plots of the yields of oxazepine and cyanoquinoline as a function of field strength over a range of 0-17 kG show that there is no variation, and demonstrate unequivocally that inter-system crossing is unaffected by an external magnetic field. Further, evidence has been presented to show that the variation in yield of the lactam previously observed is due to the formation of an excited radical ion-pair, and it is this initial process that is sensitive to variations in the magnetic field. 133 134

135

13' 13'

H. Yamanaka, H. Egawa, and T. Sakamoto, Chem. Pharm. Bull., 1978,26,2759. M. Hamana and S. Kumadaki, Chem. Pharm. Bull., 1978,12,3856. C. Kaneko, A. Yamamoto, and M. Gomi, Heterocycles, 1979, 12, 227. See ref. 114, p. 102. N. Hata, Chem. Lett., 1978, 1359.

Six-membered Rings: Azines, Oxazines, and Thiazines

289

A high-yield (>9O%) photochemical decarboxylation of quinoline-4-carboxylic acids has been a n n 0 ~ n c e d . The l ~ ~ photolyses, which are carried out in isopropyl alcohol, are sensitized by Michlers ketone but quenched totally by oxygen, suggestingthat the decarboxylationproceeds by way of the excited triplet state of the carboxylic acid. 3-Azidoquinoline, on photolysis in potassium methoxide-methanol-dioxan mixture, ring-expands to benzo-1,4-diazepinone (149) (43'/0),l~~ whereas in the presence of amines only 3-aminoquinoline is obtained. In contrast, 4-azido-7-chloroquinoline undergoes photo-induced ringexpansion in the presence of amines to yield 5-aminobenzo- 1,4-diazepines(150) in practicable yields (20-55%).

Unlike quinoline, which is unreactive, 6- and 7-methoxyquinoline undergo photocyanation (at the 5- and 8-positions, respectively) with sodium cyanide in aqueous acetonitrile.140 Likewise, under similar conditions isoquinoline gives only a poor yield (11%) of 3-cyanoisoquinoline, whereas its 6- and 7-methoxyderivatives give the respective 5- and 8-cyano-compounds in enhanced yield. Detailed photochemicai studies of the cyanation process reveal that it is a reaction that involves the excited singlet state, and that the increase of reactivity shown by the methoxy-heterocycles is related to the enhanced basicity of the excited singlet state. Estimates of the pK, values of these excited singlet states have been presented. 3,4-Dihydro-2-quinolone, with thionyl chloride in DMF at 0-10 "C, yields not the anticipated imidoyl chloride but a mixture of 2-chloro-3-quinolyl disulphide, 2-chloro-3-mercaptoquinoline, and bis-3-(2-chloroquinolyl) ~u1phide.l~~ At 80°C the disulphide is formed, together with the isomeric polycyclic products (151)and (152). A speculative mechanistic rationale of these reactions has been given.

13' 139 140

G. A. Epling, N. K. N. Ayengar, A. Lopes, and U. C. Yoon, J. Org. Chem., 1978,43,2929. F . Hollywood, E. F. V. Scriven, H. Suschitzky, D. R. Thomas, and R. Hull, J. Chem. Soc., Chem. Commun., 1978,806. N. Numao and 0.Yonemitsu, Heterocycles, 1979,12, 21. B. A. Dreikorn, A. F. Elsasser, and G. P. Jourdan, J. Org, Chem., 1979,44,877.

290

Heterocyclic Chemistry

The iodonium ylide (153; X = iPh), prepared from 4-hydroxy-2-quinolone and phenyliodonium diacetate, PhI(OAc),, in hot pyridine, rearranges to 3-iodo4-phenoxy-2-quinolone (154), whereas in pyridine with an acid catalyst the pyridinium ylide (153; X = C,H,6) is Hydrochloric acid converts the iodonium ylide into 3-chloro-4-hydroxy-2-quinolone.

Isoquinolines have been prepared by Diels-Alder reaction for the first time (Scheme 37).143At higher temperatures (190°C) and with R = CN the trunstetrahydro-adduct (7.5%) and the fully aromatized isoquinolone (156) (17.6%) are formed, in addition to the cis-adduct (155; R = CN) (31%).

Mew NMe

Me \

0

a

N Me

o

MeQNMe Me H O (155) cis

(156)

Reagents: CH,=C(Me)C(Me)=CH,,

--* i

R = CN, 71.6% R = CO,Et, 85% that is i, at 170 "C, for 96 h; ii, at 190 "C

Scheme 37

Cyclization of N-benzyl diethoxyacetamides ArCH2N(R)COCH(OEt), (157) in sulphuric acid provides a new synthesis of 3-isoquinolones.144 The reaction, which is a variation of the Pomeranz-Fritsch isoquinoline synthesis, is also

Reagents: i, HOCH2CH20H,p-TsOH; ii, B,H,, THF; iii, MeOH, HCl; iv, I,

Scheme 38 142 143

144

T. Kappe, G. Korbuly, and W. Stadlbauer, Chem. Ber., 1978, 111,3857. H. Kato, R. Fujita, H. Hongo, and H. Tomisawa, Heterucycles, 1979, 12, 1. H. Fukumi and H.Kurihara, Heterocycles, 1978,9, 1197.

Six-membered Rings : Azines, Oxazines, and Thiazines

29 1

successful with N-alkyl-N-benzyl-derivatives(157; R = alkyl), the N-alkyl-3isoquinolones (158; R = alkyl) being formed generally in 80%yield. Also new is the synthesis of 3-substituted isoquinolines from a-acyl-o-toluonitriles, as outlined in Scheme 38.'45Noteworthy is the use of diborane in THF, which proves to be a better reagent than lithium aluminium hydride for reducing the cyano function to the benzylamine (159). Unlike some of the dinitro-compounds reported last year,'46 3,5-dinitrobenzonitrile does not give a 1,3-bridged zwitterion with benzylamidine but instead the o-mmplex (160), which in warm (50-60"C) DMSO cyclizes to the 1,3diamino-isoquinoline (161).147a The isoquinoline most probably arises by dissociation of the o-complex to the original reactants, followed by attack of the amidine at the cyano-group. The structure of (161) was confirmed by 13Cn.m.r. spectroscopy. 0 2 N v -Ph IN < + NMe,

CN

NH2

NH2

N+ (161)

-0/ \ 0(160)

Free-radical phenylation of isoquinoline has been effected by photodecomposition of phenylthallium(II1)bis-trifluoroacetate, PhTl(CF,CO,),, and by the action of pentyl nitrite on ani1ine.l4*Analysis of the products by g.1.c. and h.p.1.c. has established a reactivity order for the isoquinoline nucleus towards radical attack of 1 > 5 > 8 > 4 > 3,6,7; a result in disagreement with several theoretical predictions. Alkylations of isoquinoline Reissert compounds, often a key step in the synthesis of benzyl-isoquinolines and aporphine alkaloids, using sodium

Reagent: i, I,

Scheme 39 145

'41 14'

'41

C. K. Bradsher and T. G. Wallis, J. Org. Chem., 1978,43,3817. See ref. 29, p. 150. (a)M. J. Strauss and R. R. Bard, J. Org. Chem., 1978,43,3600; ( b ) M. J. Strauss, D. C. Palmer, and R. R. Bard, ibid., p. 2041. L. K. Dyall and C. J. Pullin, Aus?.J. Chem., 1979,32, 345.

Heterocyclic Chemistry

292

hydride in DMF, are often irreproducible, and tend also to give low yields. It has now been that a much more reliable alkylating system is a mixture of potassium hydroxide in benzene containing dicyclohexyl- 18-crown-6, or (better) 50% sodium hydroxide in benzene (or acetonitrile) and the phase-transfer catalyst cetyltrimethylammonium bromide. A facile new photolytic route to benzo[k]phenanthridines (162) has been described (Scheme 39). lSo Photolysis in the absence of iodine produces the dihydro-derivative (163). An improved phenanthridine synthesis, involving the photocyclization of boron complexes of N-phenylbenzohydroxamic acids (164), has been announced (Scheme 4O).ls1 The process is superior to the direct photocyclization of benzanilides, which, because of unfavourable geometry in the anilides, generally furnishes only moderate yields of phenanthridines.

Reagents: i, hv, Pyrex, C6H6, 2-8

h; ii, LiAIH,, THF, 72 h, room temperature

Scheme 40

The Schmidt reaction on 2-formylbiphenyl-2'-dicarboxylicacid (165; X = CHO), using an excess of sodium azide in concentrated sulphuric acid, proceeds regiospecifically at the formyl group to yield phenanthridone in almost quantitative yield (96%).'s2 Equimolar quantities of sodium azide and the biphenylcarboxylic acid yield the amide intermediate (165; X = CONH2). Apparently, earlier reports that reduction of 4,6'-dinitrodiphenic acid with tin and hydrochloric acid yields the 4,6'-diamino-derivative are erroneous. The actual product is the 8-amino-5-hydroxyphenanthridone-1-carboxylic acid ( 166).153

0 (166)

150 I51 152

153

J. W. Skiles and M. P. Cava, Heterocycles, 1978, 9, 6 5 3 . K. Veeramani, K. Paramasivam, S. Ramakrishnasubramanian, and P. Shanmugam, Synthesis, 1978, 855. S. Prabhakar, A . M. Lobo, and M. R. Tavares, J. Chem. Soc., Chem. Commun., 1978, 884. G . I. Magachev, A . N. Poplavskii, and K. M. Dyumaev, J. Gen. Chem. USSR (Engl. Transl.),1978, 48,1526. N. S. Dokunikhin, G. I. Migachev, and A . M. Andrievskii, J. Org. Chem. USSR (Engl. Transl.), 1978, 14, 830.

293

Six-membered Rings : Azines, Oxazines, and Thiazines

Photolysis ( A > 300 nm) of 6-cyanophenanthridine N-oxide in methylene chloride containing triphenylphosphine results in almost quantitative (95%) deoxygenation to 6-cyanophenanthridine.154 However, similar irradiation in the absence of the phosphorus compound yields a mixture of N-cyanophenanthridone (13%), 6-cyanophenanthridone (3%), and, as the mr jor product, 6-cyano-[d,fl[ 1,3]-oxazepine (167) (78%). Electroreductive addition of alkyl halides to immonium salts is the basis of a new annelation procedure for formingheter0-rir1gs.l~'The process is particularly useful for alkaloid systems, as exemplified in Scheme 41.

Reagents: i, e-, DMF; ii, NaBH,

Scheme 41

3 Diazines and their Hydro- and Benzo-derivatives Pyridazines, Cinnolines, and Phtha1azines.-Unlike the perfluoroalkyl-pyridines described earlier (p. 263), the perfluoropyridazine [168; R' = R3 = F, R2 = CF(CF,),], on treatment with cobalt trifluoride at 163 "C, fragments to the cis- and trans-perfluoroalkenes (CF3),CFC(CF,)=C(CF3)CF(CF3), (53%) and the perfluoroalkanes (CF,),CFC(CF,)FCF(CF,)CF(CF,), (9"/0) and (CF,),CFC(CF,)FCF,CF, (12% ).43a The sensitivity of the pyridazine ring towards metallation makes alkylation of the side-chain via the metallated alkyl derivativesdifficult. However, the problem has now been resolved by using lithium di-isopropylamide as the lithiating agent (Scheme 42).156a 4

(168)

R R

=

=

Me 40%

PhCH2 57%

15% 6 'Yo

Reagents: i, Pr',N- Li+; ii, RX

Scheme 42 154 155

C. Kaneko, M.Yamamori, A. Yamamoto, and R. Hayashi, Tetrahedron Lett., 1978,2799. T. Shono, K. Yoshida, K. Ando, Y. Usui, and H. Hamaguchi, Tetrahedron Lett.,-1978,4819. ( a )A. Ohsawa, T. Uezu, and H. Igeta, Chem. Pharm. Bull., 1978,26,2428; ( b )A. Ohsawa, Y. Abe, and H.Igeta, ibid., p. 2550.

294

Heterocyclic Chemistry

The cross-coupling of chloro-pyridazines with alkyl and aryl Grignard reagents in the presence of nickel-phosphine complexes (see also p. 299) constitutes a useful general synthesis of alkyl- and aryl-pyridazines. 1 5 6 b Nucleophilic acyl radicals, generated as indicated in Scheme 43, attack the protonated pyridazine nucleus at the C-4 and C-5 positions, to yield 4,5-diacyl-pyridazines, e.g. (169), which are useful precursors of the pyridazino[4,5-d]pyridazine ring system (170).ls7 If the acyl radicals possess a-hydrogens (e.g. R = CHMe,), then cyclopenta[d]pyridazines, e.g. (17 l), can be produced by intramolecular aldol condensation as shown in Scheme 43.

&+N H

‘9 ‘‘q Me

N”\

R O C F % ..

N’” (169)

I

R

Me,CH

” ‘ N

(170) iii (R = Me,CH)

N’”

(171)

t

Reagents: i, RCHO, FeSO,, Bu’OOH; ii, NH,NH,; iii, base

Scheme 43

Last year it was reported,”’ on the basis of measurements of ionization constants and U.V. spectral data, that pyridazine-3,4,5-trithiolexists as the N(2)H-3,4-dimercapto-5-thioneform. Similar studies on pyridazine-3,4,6-trithiol are not as conclusive, and although the trithiol, the 3,4-dimercapto-6-( 1H)thione, and the 4,6-dimercapto-3(2H)-thione structures have been eliminated, the actual tautomeric form of this trimercapto-derivative has not yet been resolved.’ 5 9 Two useful routes to cinnolines have been announced. The first involves the coupling of arenediazonium tetrafluoroborates with enamine esters or amides followed by cyclization of the resulting iminium hydrazones (172) (see Scheme 44). I6O ,COR2

Reagent: i, ArN,+ BF,-

Scheme 44

lS9 160

M. Braun, G. Hanel, and G. Heinisch, Monatsh. Chem., 1978, 109,63. See ref. 29, p. 184. G. B. Barlin and P. Lakshminarayana, Aust. J. Chem., 1978,31, 389. C. B. Kanner and U. K. Pandit, Heterocycles, 1978,9, 1381.

Six-membered Rings: Azines, Oxazines, and Thiazines

295

The second method consists of the acid-catalysed ring-expansion of 2-substituted-1-amino-indoles in the presence of an oxidizing agent (e.g. PhNO,), as exemplified in Scheme 45.161a In the absence of oxidizing agent, or with oxidizing agents other than nitrobenzene, yields are poor. Further investigation has shown*61b that, in the absence of oxidizing agent and with a shorter reaction time (13 h), 1-amino-3-methylindole yields a mixture of 3-methylcinnoline (174; R' = Me, R2 = H) (24.3%) and its 1,4-dihydro-derivative (173; R' = Me, R2 = H) (56%).

+NH3

1

R2

H Reagents: i, 3% HCI, MeOH, reflux for 42 h; ii, PhNO,

Scheme 45

Benzo[3,4]cyclobuta[1,2-a]biphenylene (176) has been prepared in low yield (9.5%) by flash vacuum pyrolysis (800 "C; 0.04 Torr) of benzo[l,2-c: 4,3c'ldicinnoline (175).162Also formed are biphenylene[2,1-~]cinnoline (177) (13.7%) and a third product, thought to be phenanthro[l,l0,9-cde]cinnoline (178) (6.5%). Uranocenes, e.g. (179), have been used to effect the reduction of nit~0-arenes.l~~ 2,2'-Dinitrobiphenyl and (179), in THF, at room temperature, yield benzo[c]cinnoline (180) (44%), whereas 1,s-dinitronaphthalene gives intractable tars rather than the elusive benz[cd]indazole. Also noteworthy is the

162

(a)M. Somei and Y. Kurizuka, Chem. Left., 1979,127; ( b )M.Somai and K. Ura, ibid., 1978,707. J. W. Barton and R. B. Walker, Tetrahedron Left., 1978,1005.

163

C . B. Grant and A. Streitwieser, jun., J. Am. Chem. Soc., 1978,100,2433.

16'

296

Heterocyclic Chemistry

absence of carbazole in the reduction of o-nitrobiphenyl, 2-aminobiphenyl(14%) and 2,2'-azobiphenyl (24%) being the only products.

QBun I U

(179)

Pyrimidines and Quinazo1ines.-Several new synthetic approaches to the pyrimidine ring have been announced. 1,2-Diarnino- 1,2-dicyanoethylene can be condensed sequentially with aldehydes ArCHO and isocyanates R'NCO to give the anil-ureas (181; X = N=CHAr), which with triethylamine undergo basecatalysed isomerization to the trans-nitriles (182) and then cyclization to the cytosines (183), as outlined in Scheme 46.'64 In the presence of base, aldehydes R 2 C H 0 condense with the amino-urea (181; X = NH,) to give pyrimido[5,4dlpyrimidines (184)directly.

ArCH=N NC

H (183) Reagents: i, ArCHO; ii, R'NCO; iii, Et,N

Scheme 46

3-(Substituted amino)-3-cyanimino-propionitriles( 1 8 3 , readily prepared by condensing the corresponding imidate NCCH,(OEt)=NCN with ap amine R,NH in methanol or THF, are useful precursors of triaminopyrimidine N-oxides and chlorodiaminopyrimidines.'65For example, condensation of (185; R = Et) with hydroxylamine yields the pyrimidine N-oxide (186; R = Et) (57%),whereas with a mixture of hydrochloric and acetic acids the 2-chloro-4,6-diaminopyrimidines (187) are .obtained in excellent yields (83-95%). 164

Y.Ohtsuka, J. Org. Chem., 1978, 43, 3231. J. M. McCaIl and R. E. ten Brink, Synthesis, 1978, 673.

297

Six-membered Rings : Azines, Oxazines, and Thiazines

HN

I

(185)

-0 (186)

(184)

(187)

l-Aroyl-4,5-diamino-4,5-dihydroimidazoles (188), prepared as indicated in Scheme 47, undergo a novel ring-expansion to 5,6-diamino-pyrimidines (190) in boiling xylene, via the isolable diaza-diene intermediates (189).166The 2-methylimidazole (188; Me in place of Ph) yields a 50: 50 mixture of the isomeric 2-methyl-4-aryl- and 2-aryl-4-methyl-5,6-diamino-pyrimidines under similar conditions. R2N

\

H/

/

H

c=c

\ NR2

NR* --3

+ ArCONHC(Ph)=NCl

c > p h R2N I COAr

R2N'fNyPh R 2 N c P h --3

CH2 N

/ R2N

\

R2N'

COAr

3

Ar

Reagent: i, A, xylene, 130°C

Scheme 47

Carbamoylaspartic acids NH2CONHCH(C02H)CH2C02Meundergo novel electrochemical oxidative decarboxylations to give (ultimately) uracil, in high yield (94%).167Ethoxycarbonylasparagine, EtO,CNHCH(CO,H)CH,CONH,, behaves similarly. Cycloaddition of formimidates to the 1,$-dipolar zwitterion (191) (prepared by the variety of methods illustrated in Scheme 48) constitutes a

CI(CN)C=C=O Reagent: i, HC(ORZ)=NR'

Scheme 48 166 16'

L. Citerio, M. Garufi, and R. Stradi, Tetrahedron Lett., 1978, 2175. T. Iwasaki, H. Horikawa, K.Matsumoto, and M. Miyoshi, Tetrahedron Lett., 1978, 4799.

Heterocyclic Chemistry

298

convenient synthetic route to the hitherto rare meso-ionic pyrimidine systems (192). A variety of 2-substituted 4,6-diaryl-pyrimidines are available by allowing pyrylium perchlorates to react with amidines in boiling Acid- or base-catalysed Mannich condensation of nitro-alkanes R'CH,NO, with formaldehyde and a-amino-acids R2CH(NH2)C02Hat room temperature yields hexahydropyrimidine- 173-dicarboxylicacids of type (193).

(CF3),CF

'I

(194)

(197)

(198)

Photo-cleavage of the perfluoroalkyl-perfluoro-1,4-diazacyclohexadiene (194), obtained by the action of cobalt trifluoride on the corresponding perflu~ropyrimidine,~~" yields a mixture of perfluoroisopropyl cyanide, the perfluoroazabutadiene (193, and the perfluorodiazahexatriene ( 196).43bThe first two products are rare examples of a photochemically induced retro-DielsAlder reaction, whereas the formation of the triene (196) must involve a fluorine migration. Last year the regioselective nitrosation of 2,4- and 2,4,6-trimethyl heterocycles at the 4-methyl group was noted."l The same authors now an unexpected regioselective nitrosation of 1,2,4-trimethyl-6-0~0-1,6-dihydropyrimidine at the 2-methyl group with amyl nitrite and potassium amide in liquid ammonia. In trifluoroacetic acid the cations of pyrimidine and 5-methylpyrimidine behave as electrophiles, and will substitute activated aromatic nuclei, e.g. re~orcinol."~ The 3,4-dihydropyrimidinium salts [197; Ar = 2,4-(HO),C,H,] are formed in high yields (>90%) and with alkali they yield the dihydro-derivatives [198; Ar = 2,4(HO),C,H,], which are easily oxidized to 4-aryl-pyrimidines by potassium ferricyanide. Homolytic acylation of 2- and 4-unsubstituted pyrimidines under Minisci conditions ( i e . RCHO, FeSO,, Bu'OOH, and H2S04) is regioselective, furnishing only the 4-acyl derivatives. 174 Polyalkyl-pyrimidines, which are not 168

169

I7O 172

174

F. Mercer, L. Hernandez, jnr., and H. W. Moore, Heterocycles, 1979, 12, 45. M. P. Zhdanova, E. A. Zvezdina, and G. N. Dorofeenko, ( a )Khim. Geterotsikl.Soedin., 1978,456; ( b ) J. Gen. Chem. USSR (Engl. Transl.), 1978, 48, 859. H. J. Roth and K. Ergenzinger, Arch. Pharrn. (Weinheirn, Ger.), 1978, 311, 492. See ref. 29, p. 152. H. Yamanaka, H. Abe, H. Hiranuma, and T. Sakamoto, Chern. Pharm. Bull., 1978,26,842. W. D. K. Girke, Chem. Ber., 1979, 112, 1. T. Sakamoto, T. Sakasai, and H. Yamanaka, Heterocycles, 1978,9, 481.

299

Six-membered Rings : Azines, Oxazines, and Thiazines

generally available by standard procedures, are now accessible by the coupling (catalysed by nickel-phosphine complexes) of mono-, di-, and tri-chloropyrimidines with Grignard reagents.175(See also p. 294). Examples are given in Scheme 49. Me

P

Ph

N

86 O/o

56%

Reagents: i, excess MeMgI, [Ni{(Ph,PCH,),CH,}C12]; ii, excess PhMgBr, [Ni{(Ph,PCH,),CH,}Clz]

Scheme 49

In a similar manner to the halogeno-quinolines mentioned earlier (p. 287), 2-, 4-, and 5iodopyrimidines and 2,4- and 4,6-di-iodopyrimidines couple with alkynes in the presence of the palladium complex [Pd(PPh,)Cl,], copper iodide, and triethylamine to give the corresponding mono- and di-alkynyl-pyrimidines, respectively, in excellent (70-100%) yields.'76" A similar alkenylation of 5halogeno-pyrimidines provides a useful synthesis of 5-alkenyl-pyrimidines (199; R = CO,Et, CN, or Ph).17hbUnlike the alkynylation process, alkenylation is specific to the 5-halogeno-derivatives, there being no reaction with 2- and 4-iodo-pyrimidines. Alkenylation is, however, successful with 3-iodopyridine, 3-bromoquinoline, and 4-bromoisoquinoline; results which suggest that coupling is specific to halogens p to the heteroatom. The 4,5-didehydropyrimidine (201), generated by oxidation of the 1-amino-triazolopyrimidine(200) with lead tetraacetate, has been trapped (as the furan adduct) for the first time.'77

A full report on the intramolecular cycloaddition reactions of mono- and di-hydroxy-pyrimidines, noted l a 3 year,178has appeared. 179 Further examples of S,(ANRORC) reactions have been uncovered. The aminodemethoxylation of 4,6-dimethoxy-pyrimidineswith potassium amide in liquid ammonia has been shownlgonto proceed exclusively by an open-chain intermediate, and is the first 175

176

177 178

'71

"*

H. Yamanaka, K. Edo, F. Shoji, S. Konno, T. Sakamoto, and M. Mizugaki, Chem. Pharm. Bull., 1978,26,2160. K . Edo, T. Sakamoto, and H. Yamanaka, Chem. Pharm. Bull., ( a )1978,26,3843; ( b )1979,27,193. D. Christophe, R. Promel, and M. Maeck, Tetrahedron Lett., 1978,4435. See ref. 29, p. 186. L. B. Davies, 0.A. Leci, P. G. Sammes, and R. A. Watt, J. Chem. SOC.,Perkin Trans. 1,1978,1293. C . A. H. Rasmussen and H. C. van der Plas, ( a )Tetrahedron Lett., 1978,3841; ( b )R e d . Truu. Chim. Pays-Bas, 1979,98, 5.

300

Heterocyclic Chemistry

example of aminodemethoxylation by an ANRORC process. Careful "N-labelling experiments have shown*sobthat ANRORC aminodehalogenations of 4substituted-6-halogeno-pyrimidines by potassium amide in liquid ammonia are dependent on several factors, the main ones being (a) the ready accessibility of the C-2 position and (b) the absence of an acidic C-H function in the substituent at C-4, adjacent to the pyrimidine nucleus. Reaction temperatures are also important. 5-Nitropyrimidine undergoes novel ring-transformations to nitro-pyridines and nitro-arenes.'s' For example, in dilute acetic acid, 3,5-dinitropyridine is formed via the reaction sequence outlined in Scheme 50. In basic solution (KOEt

r

li

T

i i (4

OH

+ 2)

I

Reagents: i, H,O, AcOH; ii, (202) + (203)

Scheme 50

or Et,N) and in the presence of a ketone R'CH2COR2, 5,6-dialkyl-3-nitropyridines and (depending on the nature of the base and the ketone) p-nitrophenols are produced.'s2 A mechanistic rationale for these rare transformations is presented (Scheme 5l),Apparently, with strong base, e.g. OEt-, the intermediate (204) forms a carbanion, which then cyclizes to the phenol via path a, whereas path b is preferred with a weak base. However, with the more acidic benzyl ketones (Le. R2 = Ph), phenols are formed even with weak bases. The atropisomers of several l-aryl-4,6-dimethyl-2( 1H)-pyrimidinones (205) have been separated by recrystallization of their salts of &camphor- 10-sulphonic acid.ls3 The barrier to rotation between the two rings has been calculated to be ca. 30 kcal mol-'. 4-(Pyrimidiny1)-cyanoacetateshave been shown by 'H n.m.r. to exist solely as the intramolecular hydrogen-bonded oquinonoid tautomers (206; R = Me or CF3).lS4However, in solution in DMSO the hydrogen bonding is destroyed, and the pquinonoid tautomers (207; R = Me or CF,) prevail. Both tautomeric forms have been isolated and characterized. In addition, a pyrimidine-pyrimidylidene equilibrium (208) (209) has been detected for the first time in a pyrimidyl-2-methane system. The percentage of pyrimidylidene

+

181

lS4

H. C. van der Plas, H. Jongejan, and A. Koudijs, J. Heterocycl. Chem., 1978, 15, 485. P. Barczynski and H. C. van der Plas, Recl. Trav. Chim. Pays-Bas, 1978, 97, 256. C. Kashima, A . Katoh, Y. Omote, and Y. Nakata, Heterocycles, 1978,9,469. V. V. Lapachov, 0.A . Zaguiayeva, S. F. Bichkov, and V. P. Mamaev, TetrahedronLett., 1978,3055.

Six-membered Rings: Azines, Oxazines, and Thiazines

301

0

/

/ iii

R2CH2NaNo2 R’

-

(204)

path b

HF=CH

ii

1

path a

HN

..,\

- *.CH ‘I

\

Reagents: i, R’CH2COCH2R2,base (Et,N or KOMe); ii, OEt-; iii, Et,N

Scheme 51

tautomer (in CHC1, solution) varies from 1% (R’ = R2 = H) to 3 0 4 0 % (R1 = H, R2 = NMe,), depending on the nature of R2. In view of the amount of work published on 2-pyridones, it is surprising that relatively little is known about the photochemistry of their aza-analogues. However, it has now been that 4,6-dimethylpyrimidin-2-ones(210), on irradiation (A > 300 nm), yield the bicyclic valence tautomers (21l),which, OEt I

(205) X = Me, Et, C1, MeO, or EtO

lS5

T. Nishio, A. Katoh, Y. Omote, and C. Kashima, Tetrahedron Lett., 1978, 1543.

302

Heterocyclic Chemistry

although stable at room temperature, on heating or on irradiation with light of shorter wavelength (A = 253.7nm) revert to the pyrimidinones. The bicycles (2 11) are of synthetic interest as potential precursors of the azacyclobutadiene system. N

M

'e

.Me, Nyo

NR

A > 300nm

w Me

A = 253.7 nm

(2 10)

KN

Me \

(211) R

=

R

=

0

R

Ph; 67% Me; 33%

HN

NHMe H Me (212)

Me

(214) (2 13)

Apparently the photochemistry of cytosine has also been neglected relative to the other commonly occurring nucleic acid bases. However, it has now been demonstrated'86 that photolysis (A > 260nm) of cytosines, e.g. (212), in isopropyl alcohol yields -photo-adducts, e.g. (213). Photolysis of 6-acetyluracil produces the oxetane (214) as the major 6-(2-Dimethylaminovinyl)5-nitro-(or cyano)uracils (2 15), in aqueous sodium hydroxide, rearrange to 2-pyridones (216) by an ANRORC process (Scheme 52)."'

(216)

(215) X = NO2 or CN Reagent: i, NaOH, H,O

Scheme 52

Unlike quinoline and isoquinoline N-oxides, 4,6-dimethylpyrimidine 1-oxide reacts with active-methylene compounds (e.g. malononitrile and ethyl acetoacetate) in the presence of acylating agents (e.g. acetic anhydride) to give only ring-opened product^.^^^ However, with 5-amino-3-methylisoxazole(as the active-methylene component) and benzoyl chloride, the 2-(4-isoxazolyl)-pyrimidine (217) is obtained, albeit in poor yield (7%).

lag

K. I. Ekpenyong, R. B. Meyer, jun., and M. D. Shetlar, Tetrahedron Lett., 1978, 1619. J. G. Burr, Photochem. Photobiol., 1978,28,401. S . Senda, K. Hirota, T. Asao, and Y. Abe, Heterocycles, 1978,9, 739. H. Yamanaka, T. Sakamoto, Y. Bannai, and S. Ogawa, Chem. Pharm. Bull., 1978,26,3404.

Six-membered Rings : Azines, Oxazines, and Thiazines

303

Macrocycles incorporating 2,4-pyrimidino sub-units and C-0 and C-S linkages have been prepared from 2,6-dichloropyrimidine by standard proc e d u r e ~On . ~ strong ~ ~ heating (250 "C),the crown ether (218), prepared from the dichloropyrimidine and triethylene glycol, undergoes rearrangement to the isomeric macrocyclic lactam (2 19).

0-Ethylsuccinimide (220), a hitherto scarcely used reagent, features in a one-pot synthesis of ethyl p- (2-quinazolyl)-propanoates (221) and (222) (Scheme 53).191 r

CH,CH,CO,Et

NAN

"'4

1

-

ii (R = OMe)

ii

(R

=

___*

Me or Ph)

-MeOH

\

(222)

Reagents: i, 140 "C,2 h; ii, NaOMe

Scheme 53

Hexafluoro- 1,2-epoxypropane, whose use for the synthesis of trifluoromethylsubstituted heterocycles was mentioned last year,19*isomerizes to perfluoropropionyl fluoride, CF,CF,COF, in the presence of triethylamine. Isomerization in the presence of o-aminobenzamide yields the perfluoropropionyl-derivative (223) (74%); this, in hot DMF, cyclizes to 2-perfluoroethylquinazolin-4-one (224; R = C,F,) ( 7 6 Y 0 ) . l Aryl ~ ~ cyanates and ethyl anthranilate in the presence of a mild acid catalyst (PhC0,H) provide a simple, general synthetic route to I9O 191 192

193

G. R. Newkome, A. Nayak, J. Otemaa, D. A. Van, and W. H. Benton, J. Org. Chem., 1978,43,3362. T. Nagasaka, F. Hamaguchi, N . Ozawa, and S. Ohki, Heterocycles, 1978,9, 1375. See ref. 29, p. 210. H. A. Hammouda and N. Ishikawa, Bull Chem. SOC.Jpn., 1978,51,3091.

Heterocyclic Chemistry

304

2-aryloxy-quinazolin-4-ones (224; R = OAr). 194 Sodium borohydride in trifluoroacetic acid reduces quinazoline to the 172-dihydro-derivative in 85% yield.'95

(223)

(224) 0

Quinazolin-2-ones have been prepared by the route outlined in Scheme 54.196

Reagents: i, Clz, hv; ii, NH,, toluene; iii, A, >120 "C, or H,O, HCl, or hot EtOH, or base

Scheme 54

Pyrazines and Quinoxa1ines.-The versatility of ethyl amidinoacetates in the synthesis of heterocyclic systems has already been n ~ t e d , ' ~and ' ~ ~is further demonstrated in the formation of 3-aminopyrazine-2-carboxylateswith 1,2dicarbonyl Pyrazines and quinoxalines (225; R' = aryl, R2 = H or Me) are available in good yields (70%) by condensing either 172-diaminoethenes or o-phenylenediamines with P-keto-sulphoxides MeSOCH(R2)COR' under neutral conditions. 198 The neutral reduction of nitro-enamines to amines is well known. However, under acid conditions (MeOH-AcOH), with a palladium/charcoal catalyst, the nitro-enamine (226) suffers a novel reductive cyclodimerization to the 2,5-bis-w-aminoalkyl-pyrazines (227; n = 3, 4, 5, or 6).19' Yields vary from 8% (n = 4)to 67% (n = 5). 3-Phenyl-2,2-dimethy1-2Hazirine and 172-dimethylhydrazine yield 2,5-dihydro-2,2,5,5-tetramethyl-3,6diphenylpyrazine.200

M. Hedayatullah and J. Pailler, J. Heterocycl. Chem., 1978, 15, 1033. R. C. Bugle and R. A. Osteryoung, J. Org. Chem., 1979,44, 1719. 196 K. Sasse, Synthesis, 1978, 379. '91 W. F. Keir, A. H. MacLennan, and H. C. S. Wood, J. Chem. SOC., Perkin Trans. 1, 1978, 1002. 198 S. Kano, Y . Takahagi, and S. Shibuya, Synthesis, 1978,372. 199 S. Rajappa and R. Sreenivasan, Tetrahedron Lett., 1978,2217. zoo A. V. Eremeev, R. S. El'kinson, and E. Liepins, Khim. Geterotsikl. Soedin., 1978, 342. lY4

195

Six-membered Rings: Azines, Oxazines, and Thiazines

305

An elegant method for the conversion of 5-heteroaryl-tetrazoles into 1,2,3triazolo[ 1,5-a]azines has been formulated201and is exemplified in Scheme 5 5 . The basis of the process is that the tetrazoles, prepared by addition of hydrazoic acid to the heteroaryl nitrile, eliminate nitrogen in the vapour phase to give 2-(diazomethy1)-azine intermediates, e.g. (228), which cyclize spontaneously to the more stable triazole tautomers, e.g. the 1,2,3-triazolo[ 1,5-a]pyrazine (229).

Flash vacuum pyrolysis of the tetrazolo-quinazoline (230) produces 1,2,3-triazolo[ 1,5-c]quinazoline (23 1)in only poor yield, whereas prolonged heating (for 78 h) of (230) in mesitylene at 160 "C furnishes (231) in 75% yield.

In a similar manner to the perfluoroalkyl-pyrimidines reported earlier (p. 298), perfluoroalkyl-pyrazines, e.g. (232), with cobalt trifluoride, at 150 "C, yield perfluoro- 1,4-diazacyclohexadienes, e.g. (233);43" these, on photolysis (A = 253.7 nm), fragment by a retro-Diels-Alder reaction to perfluoroisopropyl cyanide and the perfluoro-imine (195). Oxidation of 2-chloro-pyrazines with peracetic acid is usually regioselective, and yields mainly the 4 - 0 x i d e s . ~ ~ ~ However, in some instances, with peroxysulphuric acid, this regioselectivity is changed and the 1-oxides become the main products. The oxidations, however, are not consistent; for example, 2-chloro-6-phenylpyrazineis oxidized by peracetic acid to the 4-oxide, but not at all by peroxysulphuric acid. The action of 20 1 '02

C . Wentrup, Helv. Chim. Acta, 1978,61, 1755. N.Sato, J. Org. Chem., 1978,43, 3367.

306

Heterocyclic Chemistry

hot hexamethylphosphoric triamide on 2-halogeno-azaheteroaromatics, e.g. 2chloropyrazine, provides an alternative synthesis of their 2-dimethylaminoYields are generally very good (>70%).

Reagent: i, PhCH2C(NH,)=NH

Scheme 56

The metu-bridging of o-nitro-halogeno-aromatics by amidines has been discussed a-Phenyl-acetamidines and o-nitro-halogenocompounds, however, display an alternative bridging in which the amidine is annelated across the ring carbon at which initial nucleophilic displacement of halogen occurs and the nitrogen of an adjacent nitro-gr~up~~’’ (Scheme 56). The reaction provides a useful one-step synthesis of quinoxaline, and, if cyclic amidines are used, e.g. (235), of imidazo-quinoxaline N-oxides, e.g. (234) and (236),respectively. Interestingly, when ethyl 2-chloro-3,5-dinitrobenzoatereacts

*03

A. Ohta, N. Takahashi, T. Ohwada, M. Matsunaga, and Y. Akita, Chem. Pharm. Bull., 1978,26, 1322.

Six-membered Rings : Azines, Oxazines, and Thiazines

307

with the imidazolidine (235), it suffers regioselective annelation at the ester function to yield the imidazo[ 1,2-a]quinoline (237). NN'-Dibenzoyl- (238; R = Bz) and NN'-bis(phenylsulphony1)- o-benzoquinone di-imines (238; R = PhSO,) are reactive dienes, and with electron-rich alkenes they give tetrahydroquinoxalines, e.g. (239).'040 The dibenzoyl derivative (238; R = Bz) reacts similarly with fulvenes to yield cyclopenta[b]quinoxalines (240).204bHowever, the bis-sulphonyl derivative (238;R = PhSO,), with fulvenes, forms not only the (4 + 2) adducts (240; R = PhSO,) but also the (6 + 4) adducts, i.e. the tetrahydrobenzo[b]cyclopenta[e][ 1,5]diazepines (241;R = PhS0,).204 Solvent and substituent effects on the photoisomerization of quinoxaline N-oxides have been correlated and are detailed in Scheme 57.,OS The hydroxyimidazolidine (242) is the product of hydrolysis of the 3,1,5-benzoxadiazepine (243; X = Y = Me).

X X

Y

I

H; 65% = H, Y = MeO; 80% =

=

-0

a!xoH '-.

N

\

Me

Ac

(243)

(242)

X = Y = Me; 90% X = H, Y = Me; 70% X = Me, Y = H; 85%

Reagents: i, hv, H,O; ii, hv, C,H,,

Scheme 57

Quinoxaline is reduced to the 1,2,3,4-tetrahydro-derivativeby sodium borohydride in trifluoroacetic acid.195In a similar manner, pyrido[2,3-b]pyrazine suffers regiospecific reduction of the pyrazine ring to give the tetrahydroderivative (244) in 75% yield. In contrast, under the same conditions, pteridine yields a mixture of the 1,2,3,4-tetrahydro- and 5,6,7,8-tetrahydro-derivatives,in

'04

*05

( a )W. Friedrichsen and R. Schmidt, Justus Liebigs Ann. Chern., 1978,1129; ( b )W. Friedrichsenand H-G. Oeser, ibid., p. 1139. A. Albini, R. Colombi, and G. Minoli, J. Chem. SOC.,Perkin Trans. 1, 1978, 924.

308

Heterocyclic Chemistry

the ratio of 35:58. Apparently this is the first direct route to these hydroderivatives. The reaction between 2-chloroquinoxaline and an excess of aniline is unexpectedly complex and yields, besides 2-anilinoquinoxaline, 6H-indolo[2,3blquinoxaline (245) and traces of 2,3-dianilinoquinoxaline and 3-( p-aminophenyl)-2-anilinoq~inoxaline.~~~ Experiments with 2-anilinoquinoxaline show that C-C bond formation at the 3-position occurs after the initial condensation, nucleophilic attack by the para-position of the arylamine giving the 3 - ( p aminopheny1)-derivative,whereas attack by the ortho-position of the aniline leads ultimately to the indoloquinoxaline. 2,3-Dichloroquinoxaline condenses normally with aniline. This sub-section finishes on a high note with the report that precipitation of dichloro(pyrazine)zinc(II) (prepared by adding zinc chloride to an aqueous solution of pyrazine) is accompanied by ‘acoustic emission’, i.e. strong cracking sounds are heard.*” These sounds are also generated when the mixture is shaken, even after several hours. Investigation reveals that the sound intensity is proportional to the concentration of reagents and that the sound pressure level of a single crack is most intense in the range outside that of the human ear, i.e. >20 kHz. Purines, Pteridines, and Related Systems.-This year has seen considerable activity in the synthesis of pyrrolo-pyrimidines. Pyrrolo[3,2-d]pyrimidines,e.g. (246), have been prepared by 1,3-dipolar cycloaddition of dimethyl acetylby an unusual enedicarboxylate to fervenulin 4-oxides in hot toluene (95 0C):208 ring-contraction, accompanied by extrusion of sulphur, of pyrimido[4,5-b 1[1,4]thiazines (247) in boiling DMF or xylene;209and more simply, by cyclization of 3-aminopyrrole-2-carboxyamides(248) by formic acid.210The amino-pyrroles (248) are obtained by sodium-ethoxide-catalysed cyclization of enamino-nitriles, e.g. (249), which are useful precursors of other pyrrolo-azines; for example, lH-pyrrolo[3,2-b]pyridines (250) and 6H-pyrrolo[3,4-d]pyrimidines (251; R’ = R2 = Me, R3 = Me or Ph).’1°

R

H

0 (247)

(248)

H Me

H

R3

(249) X = NHR or OBu‘ S. D. Carter and G . W. H. Cheeseman, Tetrahedron,1978,34,981. J. A. C. van Ooijen, E. van Tooren, and J. Reedijk, J. Am. Chem. SOC.,1978,100, 5569. 208 K.Senga, M. Ichiba, and S. Nishigaki, Heterocycles, 1978, 9, 793. *09 H. Fenner and A. Motscall, Arch. Pharrn. (Weinheim, Ger.), 1978,311, 153. ‘lo T. Murata, T. Sugawara, and K. Ukawa, Chern. Phann. Bull., 1978, 26, 3080. *06 207

Six-membered Rings: Azines, Oxazines, and Thiazines

309

Condensation of 2,6-diaminopyrimidin-4-one with chloroacetone in DMF at 55 "Cyields a mixture of 2-amino-&me t hylpyrrolo[ 2,3-dlp yrimidin-4-one (25 2) (55%) and 2,4-diamino-5-methylfuro[2,3-d]pyrimidine(253) (20%)." In several examples, annelation is regioselective. For example, ethyl 4-bromo-3oxobutanoate gives only the pyrrolo-pyrimidine, whereas 1,3-dichloroacetone and 2-chlorocyclohexanone yield only furo-pyrimidines. Pyrrolo[3,4-d]pyrimidines (251; R2 = H, R3 = Me) are available by condensing the bromomethyl aldehyde (254; X = 0)with amines (R1NH2).'12 Analogous condensation with acetohydrazide yields the acylhydrazone (254; X = NNHAc), which with hydrazine ring-closes to the aminopyrrolo-pyrimidine (251; R' = NH2, R2 = H, R3 = Me). Direct treatment of (254; X = 0) with hydrazines (RNHNH,) produces pyrimido[4,5- dlpyridazines (255 ) .

H

t-Butoxy-bis-dimethylaminomethane (BBDM), a substitute for dimethylformamide dimethyl acetal, is used in a new synthesis of SH-pyrrol0[3,2-d]pyrimidines (Scheme 58).*13Reduction of the initially formed pyrimido[5,4-c]-

Reagents: i, BBDM, DMF; ii, Pd/C, AcOH

Scheme 58 212

213

J. A. Secrist, 111, and P. S. Liu, J. Org. Chem., 1978, 43, 3937. S. Senda, K. Hirota, T. Asao, and Y. Yamada, Synthesis, 1978,463. R. S. Klein, M. I. Lim, S. Y-K. Tam, and J. J. Fox,J. Org. Chem., 1978, 43,2536.

Heterocyclic Chemistry

310

pyridazine (256) with palladium/charcoal in acetic acid effects ring-contraction to the pyrrolo-pyrimidine (257) in good yields (78%). Several interesting ring-transformations of azolo- and oxazolo-pyrimidines have been reported. For example, isoxazolo[3,4-d]pyrimidine (258; X = 0), prepared as shown in Scheme 59,214ais a useful precursor of various other fused pyrimidine systems (Scheme 59). Noteworthy is its reaction with phosphorus pentasulphide in pyridine, which yields the thione (258; X = S) rather than the isothiazolo[3,4-d]pyrimidine.

0

Me

N Me

Me

Me

1

iii

Me 29-65% Reagents: i, DMF, POCl,, 95 "C, 1 h; ii, NH,OAc, sulpholane; iii, ArCHO, DMF

Scheme 59

Ring-expansions of isoxazolo[3,4-d]pyrimidines (259) to pyrimido[4,5-d]pyrimidines (261) proceed via 1,5-diazahexatriene intermediates (260) (Scheme 60), and are brought about by heating the isoxazolo-systems strongly with an alkylamine R2CH2NH2.215 In contrast to the isoxazolo-pyrimidine (258), oxazolo[5,4-d]pyrimidines(262; X = 0)(reported last yea?), on treatment with phosphorus pentasulphide in pyridine, yield the thiazolo[5,4-d]pyrimidinethiones (262; X = S) in excellent yields (>90%)."" Pyrazolo[4,3-d]pyrimidine 1-oxides (263), also noted last year,217that bear active methylene groups at the N-2 position undergo basecatalysed ring expansion to pyrimido[5,4-d]pyrimidines (264) by the route indicated in Scheme 61.'18 Full reports on the synthesis and reactions of purines and related systems that were noted in preliminary form in previous years have appeared. These include 'I4

'I5 '16 'I7

'la

( a )K. Senga, S. Nishigaki, and Y . Kanamori, Chem. Pharm. Bull., 1978,26,2497; ( b )K. Senga, J. Sato, and S. Nishigaki, ibid., p. 765. F. Yoneda, T. Yano, M. Higuchi, and K. Koshiro, Chem. Lett., 1979, 155. See ref. 29, p. 194. See ref. 29, p. 196. S. Senda, K. Hirota, and T. Asao, Tetrahedron Lett., 1978, 2295.

Six-membered Rings: Azines, Oxazines, and Thiazines

Me

(261) Reagent: i, R2CH2NH,, 200-280 "C,2-3 h Scheme 60

(263) M e

(264) Me

Reagent: i, NaOEt, EtOH or NaH, diglyme Scheme 61

311

Heterocyclic Chemistry

312

the preparation of 8-aryl-xanthine~~'~ and 9-substituted-8-aryl-theophyllines216 by the dehydrogenative cyclization of 6-amino-5-benzylideneamino-uracils by diethyl azodicarboxylate2'" and thionyl chloride;221" the synthesis of 8-arylamino- theophyllines' l6 from 6-amino-5 -arylazo-ur acils ;222 and the acidcatalysed rearrangement of 9 - b e n ~ y l - x a n t h i n e to s ~the ~ ~ 7-benzyl In addition, a new synthesis of 9-aryl-theophyllines (265) and their 8-aza-analogues (266), from 6-arylamino-5-arylazo-uracils, by the simple route outlined in Scheme 62, has been recorded.221b 0

MeN?

OAN NHArMe

i

h4eN%N=NAr Me iii, iv

NHAr

1

Me Ar (265)

Reagents: i, PhN2+ X-;ii, Na2S204,HC0,H; iii, Pd/C, H,; iv, NaNO,, HCI

Scheme 62

A general synthetic route (Scheme 63) to 3,9-dialkyl-adenine hydrochlorides (267) has been developed.224However, attempts to isolate the free bases were unsuccessful and gave only the ring-opened products, i.e. the amidino-indazoles (268) [see p. 3111.

(267) Reagents: i, H 2 0 ; ii, MeI, K2C0,, DMF, 25 "C; iii, HCl; iv, Ni, H,; v, Et,N, E t O H or H', MeOH 219

220

22 1

222

223 224

Scheme 63 See ref. 114, p. 132. F. Yoneda, M. Higuchi, K. Mori, K. Senga, Y. Kanamori, K. Shimuzu, and S. Nishigaki, Chem. Pharm. Bull., 1978,26, 2905. K. Senga, Y.Kanamori, and S . Nishigaki, ( a )Chem. Pharm. Bull., 1978,26,3240; ( b )Heterocycles, 1978,9, 1437. K. Senga, M. Ichiba, H. Kanazawa, S. Nishigaki, M. Higuchi, and F. Yoneda, J. Heterocycl. Chem., 1978,15, 641. J . H. Lister, Aust. J. Chem., 1979, 32, 387. T. Fujii, T. Saito, and M. Kawanishi, TetrahedronLeft., 1978, 5007.

313

Six-membered Rings: Azines, Oxazines, and Thiazines

Direct methylation of caffeine at C-8 is possible by photolysing ( A > 300 nm) Oxithe heterocycle in the presence of t-butyl peracetate, CH3C020CMe3.225" dation of 6- and 8-hydrazinopurine with 30% aqueous ferric chloride at room temperature furnishes the corresponding chloro-derivatives in practicable yields (66-70%).225b 1,3-Disubstituted uracils react with thionyl chloride to yield 1,2,3-thiadiazolo[4,5-d]pyrimidines(270; R = Me) as depicted in Scheme 64,226

1

Reagent: i, SOC1,

Scheme 64

the initially formed thiadiazoline S-oxide (269) undergoing dehydration by a Pumrnerer reaction. If, however, the N-1 position is unsubstituted, then an alternative cyclization to thiatriazolino[5,4-c]pyrimidine-5,7-diones (27 1) takes place; on prolonged treatment with thionyl chloride, these yield the thiadiazolo[4,5-d]pyrimidines (270; R = H)via the sulphinylamine (272). The Nmethyl thiatriazolinopyrimidine (27 1; R2=Me), prepared from the appropriate hydrazine, reacts with an excess of thionyl chloride to yield the meso-ionic system (273). Synthetic routes to the rare 1-alkyl-8-azapurines, e.g. (274; R = Me), have been describedzz7and include the direct methylation of 9-benzyl-u-triazolo[5,422s 226

227

( a )M. F. Zady and J. L. Wong, in 'Nucleic Acid Chemistry', ed. L. B. Townsend and R. S. Tipson, J. Wiley and Sons, New York, 1978, Vol. 1, p. 29; (b) A . Giner-Sorolla and J. T. Segarra, ibid.,p. 19. K. Senga, M. Ichiba, and S. Nishigaki, J. Org. Chem., 1978, 43, 1677. A . Albert, J. Chem. SOC.,Perkin Trans. 1, 1978, 513.

Heterocyclic Chemistry

314

dlpyrimidine (274;R = H)and the ring-closure of 5-amino- 1-benzyl-v-triazole4-carboxyamide (275)with formamide. On the basis of I3C- and l5N-labe1ling studies, a rationalization for the formation of purine from hydrogen cyanide and formamide has been proposed228(Scheme 65). HCONH2 + H 2 0

+ HC02NH4% HC02H + NH3

2HCONH2 % H,NCH(OH)NHCHO % H,NCH=NCHO

li

Reagents: i, 2HI3Cl5N;ii, HCONH,

Scheme 65

0

Two new syntheses of pyrimido[4,5-b]quinoline-2,4-diones(i.e.deazaflavins) (277)and (280)have been formulated. The first, which is the more general, involves oxidative coupling of 5-benzylidene-6-alkyl-(or -aryl-)amino-uracils (276;R' = alkyl or aryl) with diethyl azodicarboxylate.229"The second route commences with the l-alkyl-3-cyano-5,6,7,8-tetrahydro-2-quinolone imines (279),prepared, as indicated in Scheme 66,from the enamine (278).230

228

229

230

H. Yamada, M. Hirobe, K. Higashiyama, H. Takahashi, and K. T. Suzuki, Tetruhedron Lett., 1978, 4039. ( a )K. Mori, K. Shinozuka, Y. Sakuma, and F. Yoneda, J. Chem. SOC.,Chem. Commun., 1978,764; ( b )F. Yoneda, Y. Sakuma, and Y. Matsushita, ibid., p. 398. A. Lacroix and J-P. Fleury, Tetrahedron Lett., 1978, 3469,

Six-membered Rings : Azines, Oxazines, and Thiazines

.

,

315

aa R

R

\

"-I

/

(280)

,

NPh

iv,v

NH

0

Reagents: i, RNH,, MeOH; ii, PhNCO; iii, Et,N, MeOH; iv, HCl; v, Pd/C, decalin

Scheme 66

5-Deaza-10-thiaflavin (281; X = S), a new ring system that is isosteric and isoelectronic with 5-deazaflavin, has been synthesized (Scheme 67).231In the presence of potassium t-butoxide and benzyl alcohol, reduction to the 1,5dihydro-derivative (282; X = S) takes place, whereas in 20% potassium hydroxide the system disproportionates to the 1,5-dihydro-derivative and 10thiaflavin-5-one (283; X = S).

(282)

(283)

Reagents: i, PhSH, EtOH, KOH; ii, DMF, POCI,, 90 "C, 2 h; iii, PPA, 120 "C, 2 h; iv, 20% KOH; v, K ' Bu'O-, PhCHzOH

Scheme 67

In concentrated potassium hydroxide, 5-deazaflavins (28 1;X = NR) undergo similar disproportionations to form 1,5-dihydro-5-deazaflavins(282; X = NR) and 1,5-dihydro-5-deazaflavin-5-ones(283; X = NR) by an intramolecular 231

F. Yoneda, M. Kawazoe, and Y.Sakuma, Tetrahedron Lett., 1978,2803.

316

Heterocyclic Chemistry

oxidation-reduction between the initially formed 5-hydroxy- 175-dihydroderivatives and unchanged d e a z a f l a v i n ~ . ~In~ ~dilute ' potassium hydroxide the reverse oxidation-reduction takes place between the 175-dihydro-flavins and -flavones to give the original deazaflavins and the 5-hydroxy- 1,5-dihydro-5deazaflavins, these latter products undergoing further oxidation in air to the flavin-5-ones. This ease of oxidation of 175-dihydro-5-deazaflavins is apparent in their ability to reduce compounds containing inactive carbonyl groups to alcohols. For example, in acetic or hydrochloric acid solution, N-ethyl- 175-dihydro-5deazaflavin (282; X = NEt) reduces cyclohexanone and benzaldehyde to the respective alcohols, itself being oxidized to the deazaflavin (281; X = NEt).232 Pyrimidyl-adiazopropionates, e.g. (284; R2 = Cl), with triphenylphosphine in di-isopropyl ether, at room temperature, yield pyrimido[4,5-~]pyridazines(286) via the phosphazine intermediates (285; X = N=PPh3).233 In the case of the 4-methoxy-derivative (284; R2 = MeO), careful hydrolysis of the phosphazine permits isolation of the hydrazone (285; X = NH2).

The cyclization of the 6-arylamino-5-nitrouracils (287) to 8-chloro-flavins in phosphorus oxychloride and DMF was described last year.234However, attempts to prepare 8-bromo-flavins7using phosphorus oxybromide in place of phosphorus oxychloride, have failed.235 At 80°C, isoalloxazines (288) are formed by an intramolecular dehydration-deoxygenation process, whereas at 130 "C only 5deazaflavins (281; X = N-alkyl) are produced, apparently by denitration and then formylation at the 5-position of the pyrimidine ring. Other Systems with Two Nitrogen Atoms.-Condensation of dimethylformamide dimethyl acetal with 3-cyano-4-methylpyridine in DMF produces the enamine (289); this, in a mixture of 30% hydrobromic and acetic acids, cyclizes to l-hydroxy-2,7-naphthyridine(290) in 41% yield.35b Similar treatment of 3cyano-2-methyl- and of 2-cyano-3-methyl-pyridine yields 5-hydroxy- 1,6-naphthyridine (46%) and 8-hydroxy- 1,7-naphthyridine ( 5 % ) respectively. Under 232

F. Yoneda, Y. Sakuma, and Y. Nitta, Chem. Lett., 1978,1177.

233

T.Miyamoto, Y. Kimura, J-I. Matsumoto, and S. Minami, Chem. Pharm. Bull., 1978,26,14.

234 235

See ref. 29, p. 201. Y.Sakuma, Y. Matsushita, and F. Yoneda, Heterocycles, 1978,9,1767.

317

Six-membered Rings Azines, Oxazines, and Thiazines

normal conditions, oxidation of 1,8-phenanthroline produces only the N(8)oxide, the N-1 position being sterically screened. However, the N ( 1)-oxides are available by quaternizing the N-8 position (as the p-nitrophenyl salt) prior to oxidation with peroxytrifluoroacetic Ammonolysis of the p-nitrophenylphenanthrolinium salt (291; Ar =p-NO2C,H,) liberates the free N ( 1)-oxide (292).

3H-Pyrido[ 1,2-b]pyridazin-3-0nes (296) are formed by the reaction of pyridinium-imines with cyclopropenones in the presence of base (Scheme 68)."' The reaction may proceed either by the 1,3-dipolar adduct (293) (path a ) or by the 1,6-dipolar species (294) (path b). Both routes lead to the dihydro-systems (295); in certain cases, these are isolable. R2

N I

-NH

L

I

R2

(293)

1

/

i(b

R2

0 Reagent: i,

(295)

(296)

, CH,Cl,, base

Scheme 68

Moderate yields (10-25%) of tetrahydro-pyrido[3,2-c]- (297) and -pyrid0[3,4-~]-pyridazines are obtained from the addition of dialkyl azodicarboxylates to 2- and 4-vinylpyridine re~pectively.~~' Hydrolysis and decarboxylation (by CF,CO,H) followed by oxidation (with HgO) yields

236

237 238

F. Hordnejewicz and Z . Skrowaczewska, Synthesis, 1978,583. A. Kascheres, D. Marchi, jun., and J. A. R. Rodrigues, J. Org. Chem., 1978,43,2892. G . Jones and P. Rafferty, Tetrahedron Lett., 1978,2731.

318

Heterocyclic Chemistry

pyrido[3,2-c]- (298) and pyrido[3,4-~]-pyridazine.Also formed in the initial cycloaddition are small amounts of tetrahydropyridotriazines,e.g. (299).

The previously inaccessible v-triazolo[1,5-a]-, s-triazolo[4,3-c]- (300; X = CH), and tetrazolo[ 1,s-a]-quinoxaline 5-oxides (300; X = 'N) have been prepared directly from quinoxaline 4-oxide precursors, as indicated in Scheme 69.239

0-

0-

0-

1

1

X=N

(300) Reagents: i, NH,NH,; ii, NaNO,; iii, HC(OEt),

Scheme 69

Heterocyclic penamino-esters, e.g. (30 l),are particularly useful precursors for a variety of partially reduced heterocycles such as the tetrahydro-1,80

0

c-x02Et

vi

N

a: (303)

NH

o$Co H

H

Reagents: i, RNCO; ii, KOH; iii, CH2(C02Et),,NaOEt; iv, PhCH,CO,Et, NaOEt; v, CH,=C(R)CO,Et; vi, R1C=CCO2R2; vii, RC(OEt)=NH

Scheme 70 239

B. w.Cue, jun., L. J. Czuba, and J. P.Dirlam, J. Org. Chem.. 1978. 43,1125.

319

Six-membered Rings : Azines, Oxazines, and Thiazines

naphthyridines (302), (303), and (304)240nand the pyrido-[1,2-a]- (305)240aand -[2,3-d]-pyrimidines (306) and (307)240b(Scheme 70). The hexahydro-1,8-naphthyridine(308)has been synthesized and is potentially a useful reagent for preparing proton complexes of carboxylic acids and other similar bidentate l i g a n d ~ . ~An ~ ~ improved synthesis of 1,4diazacycl[3.3.3]azine hydrobromide (309) has been announced.242However, the free base is unstable, and comparison of its 'H n.m.r. spectrum with those of other cyclazines suggests that it has a paramagnetic ring-current and may be antiaromatic. Similar paramagnetic contributions to the ring-current are evident in the 'H n.m.r. spectrum of pyrazino[2,1,6-cd; 5,4,3-c'd']di-indolizines (310; R' = R2 = C0,Me) and (310; R' = Me, R2 = H).243The ring protons of these [16]annulene-type structures are 0.7-1.2 p.p.m. more shielded than those in the corresponding indolizines.

(308)

(310)

Treatment of 5-0~0-5,6,7,8-tetrahydrocoumarin (311) (readily obtained by condensing cyclohexane-1,3-dione with dimethyl P-ketoglutarate at pH 5.4) with

I

(311)

I

HO

+

(312a)

0-

ii, iii

\

iv

--*

H

(312b)-

Reagents: i, NH,OH (3 mole), EtOH, H20; ii, NH,, MeOH; iii, NH,OH (1 mole), EtOH, H,O; iv, 10% HCl

Scheme 71 240 24 1 242

243

H. Wamhoff and L. Lichtenthaler, Chem. Ber., 1978,111, (a) p. 2813; ( b ) p. 2297. F. Heinzer, M. Soukup, and A. Eschenmoser, Helv. Chim. Acta, 1978,61, 2851. M. Kuya, K. Kurata, H. Awaya, Y. Tominaga, Y . Matsuda, and G. Kobayashi, Chem. Phann. Bull., 1978,26,680. G. G. Abbot, D. Leaver, and K. C. Mathur, J. Chem. Res. (S), 1978,224.

320

Heterocyclic Chemistry

an excess of hydroxylamine hydrochloride, as outlined in Scheme 7 1, provides a simple method of entry into the 1,6-diazaphenalene ring-system (312).244

4 Triazines and Tetrazines A full account of the formation of lumazines and fervenulins by phototransformation reactions of 6-azido- 1,3-dimethyl-uracils, noted last year,245 has appeared,246nand the process has been to the synthesis of other uracils, that are functionalized at the 5- and 6-positions. For example, photolysis (A > 300 nm) of the azide (313; R' = H, R2 = N3)in THF in the presence of an acyl halide RCOCI produces the 5-acylamino-6-chloro-uracils (3 13; R' = NHCOR, R2 = Cl); these, with ethanolic hydrazine, ring-close to 3-substituted fervenulins (314) in high yields (80%). The synthesis of imidazo[4,5-c]-as-triazines,i.e. 6-azapurines, from 6-amino5-nitroso-uracils (313; R' = NO, R2 = NH2) has been noted p r e v i ~ u s l y . ~A~ ' more detailed account of this work has now been and the aminonitroso-uracil provides the starting material for a new synthesis of isofervenulins (315) (Scheme 72).248b 8-Azapurino[7,8-f]-6-azapteridines (316) are 'byproducts (1-36%). Reduction of the isofervenulin with sodium dithionite in formic acid brings about ring-contraction to the %substituted theophylline (317), whereas with dithionite in DMSO the pyrimido-pteridinone (318) is produced.

(313; R' = NO, R2 = NH2)

Me

Me

N

Me

Me

Me

( 3 18) Reagents: i, RCONH.NH,, DMF or DMSO, boil; ii, Na,S,O,,

(317) DMSO; iii, Na,S204, HCO,H

Scheme 72 244

245 246

247 248

M. I. El-Sheikh, J-C. Chang, and J. M. Cook, Heterocycles, 1978, 9, 1561. See ref. 29, pp. 198-9. S. Senda, K. Hirota, T. Asao, and K. Maruhashi, (a) J. Am. Chem. Soc., 1978,100, 7661; (6) J. Chem. Soc., Chem. Commun., 1978,367. See ref. 114, p. 143. (a)F. Yoneda, M. Noguchi, M. Noda, and Y. Nitta, Chem. Pharm. Bull., 1978,26, 3155; (b) F. Yoneda, T. Nagarnatsu, K. Ogiwara, K. Kanahori, S. Nishigaki, and E. C. Taylor, ibid., p. 367.

Six-membered Rings : Azines, Oxazines, and Thiazines

32 1

The condensation of 6-amino-5-arylazo-uracils (versatile purine precursors;216 also see p. 312) with urea constitutes a new synthesis of 6-azalumazin-7-ones (319); on treatment with hot potassium hydroxide, these fragment to l-aryl-6azauracil-5-carboxylic acids (320; R = C02H).249 Decarboxylation in diphenyl 0 Me?.:

A

O

N Me

(313)

0 M e N k N y R

A

O

N Me

4N

N

A Me

(314)

(319)

Ar (320)

ether at 200-220 "C yields the 1-aryl-6-azauracils(320; R = H). Equally simple is the preparation of 7-azaxanthopterin (322)from the 6-acylhydrazino-2-aminopyrimidine (321; R = Ac) and diethyl azodicarboxylate (Scheme 73).250Prior acetylation of the hydrazine appears to be essential, as the free hydrazine (321; R = H) and diethyl azodicarboxylate give only tars.

Reagents: i, EtO,CN=NCO,Et; ii, NaOEt, EtOH

Scheme 73

Steric crowding, which prevents effective resonance stabilization of the N-0 function, is thought to be responsible for the remarkably mild (in boiling 50% w/v H,O-EtOH) deoxygenation of naphtho[ 1,2-el[ 1,2,4]triazin-2-one 1-oxide (323).251The 4-oxide behaves normally and requires forcing conditions in order to effect deoxygenation. 2-Aryl- 1,2,3-benzotriazinium 1-oxides (324) have been isolated as intermediates in the photorearrangement of N-aryl-2-nitrobenzhydrazonoyl bromides o-NO,C,H,C(Br)=NNHAr to 3-aryl-1,2,3-benzotriazin4-0nes.'~' Ring-transformation of 1,2,4,5-tetrazines to pyridazines is effected 249

"' 252

F. Yoneda and M. Higuchi, Heterocycles, 1978,9, 1387. E. C. Taylor and A. J. Cocuzza, J. Org. Chem., 1979,44, 1125. F. J. Lalor, F. L. Scott, G. Ferguson, and W. C. Marsh, J. Chem. SOC.,Perkin Trans. 1, 1978,789. Y. Maki and T. Furuta, Synthesis, 1978,382.

Heterocyclic Chemistry

322

simply and in high yield (60--80°/~) by ketones of type R'CH,COR2 in methanolic potassium The reaction probably proceeds in a stepwise manner (Scheme 74),although a Diels-Alder addition between the tetrazine and the enol tautomer of the ketone cannot be excluded. Ph

R'

CHCOR'

Ph --*

N Ph

Ph Reagent: i, R'CH2COR2, MeOH, KOH

Scheme 74

1,4,5,6-Tetrahydro-u-tetrazines(326) are obtained by th low-temp rat (-73 "C)dimerization of a-lithio-N-alkyl-nitrosamines. Cyclization is thought to involve head-to-head dimerization of the radical anion (325), as illustrated in Scheme 75.254Photodecomposition or thermal decomposition of the tetrazine produces the hexahydro-sym-triazine (327) (a trimer of N-methylimine), and not a diazetidine.

MeN(NO)CH,Li

.

N710 I:-a Me-N-CH,

Me N-N-O-

/ ----r""

Li'

--*

HZ7 H,C\

2Li+

N-N-OMe- - -i - ---

(325)

1 Me t

Me

N Me

Me

(326) Reagents: i, -73 "C;ii, (MeO),P or LiAlH,

Scheme 75 253 254

M. J. Haddadin, S. J. Firsan, and B. S. Nader, J. Org. Chem., 1979,44, 629. D. Seebach, R. Dach, D. Enders, B. Renger, M. Jansen, and G. Brachtel, Helu. Chim. Acta, 1978, 61, 1622.

Six-membered Rings : Azines, Oxazines, and Thiazines

323

5 Oxazines, Thiazines, and their Benzo-derivatives 3-Nitrosobut-3-en-2-one, MeCOC(NO)=CH,, generated in situ by the action of potassium carbonate on the chloro-oxime MeCOC(CH,Cl)=NOH, has pronounced dienophilic character, and adds to simple alkenes R’CH=CHR2 (and electron-rich heterocycles, e.g. furan) in a highly regioselective manner to give 5,6-dihydro-4H- 1,2-0xazines (328).255Similar adducts result with 4-nitroa-nitrosostyrene, and, although yields are higher, there is less regioselectivity. Me

fN7

MeN-NMe

(327)

N.m.r. studies show that the 1,2-oxazine N-oxide (329), a cyclic nitronic ester (prepared as shown in Scheme 76), is in equilibrium with the enamine (330).256 The equilibrium is solvent-dependent; for example, in chloroform the ratios of oxazine to enamine are 1: 1 and 3 :2 (X = 0 and CH2, respectively) whereas in benzene or carbon tetrachloride only the enamine species (330) are present.

Reagent: i, PhCH=C(NO,)Me

Scheme 76

Attempts to synthesize the highly functionalized lactam (333) by intramolecular (4 + 2) cycloaddition of the acylnitroso-compound H,C=CHCH=CHCH(OH)CH,CONO (331)have been thwarted by the inaccessibilityof the p- hydroxyhydrpxamic acid precursor. However, the problem has been circumvented by the elegant approach outlined in Scheme 77, which employs an intramolecular dienophile-transfer process.2s7 Addition of the acyl-nitrosodienophile to the anthracene, followed. by condensation with the appropriate unsaturatedddehyde, yields the adduct (332) in excellent yield (85%). In boiling benzene (332) undergoes a quantitative retro-DieIs-Alder reaction to produce

256 257

T. L. Gilchrist and T. G. Roberts, J. Chem. SOC.,Chem. Commun., 1978, 847. G. Pitacco and E. Valentin, Tetrahedron Lett., 1978, 2339. G. E. Keck, Tetrahedron Lett., 1978,4767.

324

Heterocyclic Chemistry

the dimethylanthracene and a stereoisomeric mixture of the intramolecular (4 2) cycloaddition product (333). N-Alkyl-dipropenyl-aminesand aliphatic aldehydes, in the presence of phosphoric acid, yield 1,2-dihydro- 1,3-oxazines (334).25* However, tripropenylamines, under similar conditions, yield alkyl-pyridines (335) by the route outlined in Scheme 78.

+

OH

HO 111

t-

Me

H

(332)

(333)

Reagents: i, MeCONHOH, Prn4N+1 0 4 - , 23 "C; ii, Pr',N- Li', MeCH=CHCH=CHCHO; iii, C6&, 5 h reflux

Scheme 77

Me\

,Me CH

II

HC

II

HC,

,CH

(R'

=

CHyCHMe)

R' iii

1

Me\

,Me

Me,

CH

HC

II

HC,

II

N H

CH,CH,

CH 7

,CH

II

HC\

I

N

,/CH

p i

(R' = alkyl)

(334)

OH

Men;;

Me\ ,&HR' HC I

HC:

CHEt NH

N

(335) Reagents: i, H,PO,; ii, H', R2CHO; iii, H,PO,, R 2 C H 0

Scheme 78 258

B. Adler, C. Burtzlaff, C. Duschek, J. Ohl, H. Schmidt, and W. Zech, J. Prakt. Chem., 1978, 320, 905.

Six-membered Rings : Azines, Oxazines, and Thiazines

325

6-Amino- 1,3-oxazin-2-ones, e.g. (336),259are attractive precursors of azetes. However, they are photo-stable, and on flash vacuum pyrolysis (650°C; 0.007 Torr) they undergo electrocyclic ring-opening to vinyl isocyanates (337), rather than fragmentation.2601,3-0xazin-6-ones, e.g. (338), are equally odd in that, on FVP, they yield evidence neither of fragmentation to an azete nor of electrocyclic ring-opening to the vinyl-keten PhCON=C(Ph)C(Ph)= C= 0. Instead, diphenylacetylene and benzonitrile are the major products.

(336)

(337)

(338)

have been made on the use of acyl-ketensfor the synthesis of Further 2H-1,3-oxazine-2,4-dionesand pyrimidine-2,4-dione~.~~l Also, the preparation of five-membered heterocycles by ring-contraction of 1,3-oxazin-4-ones(339) in the presence of bidentate nucleophiles, noted last year,262has been extended to the synthesis of 1,2,4-triazoles and pyrazoles, as exemplified in Scheme 79.263

X RN-N R = H, X = NNH2; 91% R = Me, X = 0;52% R = Ph, X = NNHPh; 76.5%

(339) [ii

- [MeTrTop] OH

0 MeCJPh

I

M eN-NR fiNHCOPh

NHNHR

R R R

= = =

H; 74.4% Me; 61% Ph; 42%

Reagents: i, RNHNH,; ii, RNHNH,, H,SO,

Scheme 79

The synthesis of 6-0x0-6H- 1,3-0xazin-3-ium-4-olates (340) from malonyl dichlorides and secondaryamides has been On the basis of solvolysis experiments and CND0/2 calculations there appears to be no delocalization of 2s9 260

262

263 264

See ref. 114, p. 136. P. W. Manley, R. C. Storr, A. E.Baydar, and G .V. Boyd, J. Chem. SOC.,Chem. Commun., 1978,902. L. Capuano, W. Fischer, H. Scheidt, and M. Schneider, Chem. Ber., 1978,111, 2497. See ref. 29, p. 207. Y. Yamamoto, Y. Azuma, and K. Miyakawa, Chem. Pharm. Bull., 1978,26,1825. W. Friedrichsen, E. Kujath, G. Liebezeit, R. Schmidt, and 1. Schwarz, Justus Liebigs Ann. Chem., 1978,1655.

326

Heterocyclic Chemistry

the positive charge at C-2. The ring-opening of 2-substituted benzo-3, l-oxazin4-ones, e.g. (341), to o-acylamido- or o-amidino-acids is dependent on the nature of the 2-substituent and on the steric bulk and basic strength of the attacking a~nine.'~'Further studies have now revealed that the nature of the ring-opened product depends also on the chain-length of the attacking aliphatic amine, and in particular on the nature of the substituent at C-4. For example, with alkyl-amines NH,(CH,),R (n < 4, R = H), normal, rapid ring-opening to the amidines (342) is observed. However, if n b 4 and R = H, only the o-acylamido-acids (343) This curious change in reaction pathway has been attributed to steric hindrance, brought about by the alkyl-amines for which n 3 4 being held in a' coiled configuration (344) by intramolecular van der Waals forces. Support for this idea comes from studies on the alkyl-amines NH,(CH,),R in which R = OH or C 0 2 H ; intermolecular hydrogen-bonding overcomes the weaker van der Waals forces, and as a result the expected ring-cleavage of the benzoxazinone to the amidines (342; R = OH or C0,H) is experienced.265bIn addition, if the alkyl-amine has no 8-carbon centre, e.g. NH,(CH,),Si(OEt),, then 'coiling' is prevented, and amidines once again become the only 0-

0

(342)

o:H2c'

(344)

(345)

2-Amino-4H- 3,l -benzoxazines (346) result from the addition of alkyl-amines R'R'NH to o-isocyanatobenzyl chloride (345; X = NCO), followed by basecatalysed cyclization of the resulting 0-(chloromethy1)-ureas (345; X = NHCONR'R2).266Sodium in DMF is a superior reagent for cyclizing 2- and 4-(2'-hydroxyanilino)-3-nitro-pyridinesto 1-aza-, 3-aza-, and 4-aza-phenoxa~ines.~~'

2b6

2b7

( a )L. A. Errede, J. Org. Chcm., 1978,43,1880;( 6 )L.A.Errede and J. J. McBrady, ibid., p. 1884; (c) L.A.Errede and G. V. D. Tiers, ibid., p. 1887. W. Gauss and H-J. Kabbe, Synthesis, 1978,377. Y.Ito and Y. Hamada, Chem. Pharm. Bull., 1978,26,1375.

327

Six-membered Rings: Azines, Oxazines, and Thiazines

A new synthesis of 4H- 1,4-benzothiazines (348) by ring-expansion of 2,3dihydro-1,3-benzothiazolel-oxides (347) is outlined in Scheme 80.268

0

1

(347)

II

+OH

1

Reagents: i, mClC,H,CO,OH; ii, p-TsOH, PhMe, boil

Scheme 80

The preparation of 1,2-thiazin-5(6H)-one 1,l-dioxides (350)by addition of alkyl-sulphonylamines RN=SO, to activated dienes is not a concerted (4 + 2) process but a stepwise reaction involving a diketo-sulphonamide intermediate (349) (Scheme 81).269

He,,

N,

CIH I

OMe

R /

Scheme 81

6 Oxa- and Thia-diazines and Related Systems 5,6-Dihydro-oxadiazines (351; X = H), obtained as unstable adducts of azodicarboxylates and keten acetals, undergo thermal ring-opening to hydrazinylketen acetals (R2O),C=CHN(CO2R')NHCO2R1, which may react further with the azodicarboxylate to give the substituted oxadiazines [351; X = R'02CNHN(C02R')].270 The more stable 6-chloro- 1,3,4-0xadiazin-5-ones 268 269 270

F. Chioccara, L. Oliva, and G. Prota, Synthesis, 1978, 744. J. A. Kloek and K. L. Leschinsky, J. Org. Chem., 1979,44,305. J. H. Hall and M. Wojciechowska, J. Org. Chem., 1978,43, 3348.

328

Heterocyclic Chemistry

(352) may be prepared by condensing dichloroacetyl chloride with P-N-benzoylphenylhydrazine, P ~ N H N H B z . 'The ~ ~ lH-4,1,2-benzothiadiazine(354) is the product of the base-catalysed cyclization of the 1-(2-nitrophenylthio)pyruvaldehyde hydrazone (353).272

A modified one-pot synthesis of 4H- 1,3,5-dithiazines (355) has been noted (Scheme S2).273

(355) Reagents: i, H,S; ii, R3CH0

Scheme 82

A new synthesis of l(h 4),2,4-benzothiadiazines(356), which contain the relatively scarce sulphur(1v)-nitrogen ylide system as part of a heterocyclic ring, has been e l a b ~ r a t e d . ~The ' ~ process involves condensing a sulphenyl chloride R3SCl (generated in situ) with an N-aryl-benzamidine ArN=C(Ph)NH, at -20 "C in dichloromethane. Yields of (356) are in the region 30-80%. 2-Arylacetylene- 1-sulphonamides ArCrCSO,NH, are useful precursors of 1,4,3oxathiazine 4,4-dioxides (357) and 1,4,2-dithiazine 1,l-dioxides (358), as outlined in Scheme 83.275The dithiazines (358), on treatment with strong base (e.g. NaOH in DMF), ring-contract to 1,4,2-dithiazole 1,l-dioxides (359). 1,3,4,5-Thiatriazine 1,l-dioxide (361), a new class of heterocycle, has been synthesized by treating diphenylthiiran 1,l-dioxide (360) with lithium azide in acetonitrile at room t e m p e r a t ~ r e . ' Also ~ ~ formed are 2,3-diphenyl-2H-azirine

*" 272 273 '14 215

276

G. Westphal and T. Miiller, J. Prakt. Chem., 1978, 320,452. D. E. Ames, S. Chandrasekhar, and K. J. Hansen, J. Chem. SOC.,Perkin Trans. 1, 1978, 539. C. Giordano, A. Belli, and V. Bellotti, Synthesis, 1978, 443. T. L. Gilchrist, C. W. Rees, and D. Vaughan, J. Chem. SOC.,Chem. Commun., 1978, 1049. K. Hasegawa, S. Hirooka, H. Kawahara, A. Nakayama, K. Ishikawa, N. Takeda, and H. Mukai, Bull. Chem. SOC.Jpn., 1978,51, 1805. B. B. Jarvis, G. P. Stahly, and H. L. Ammon, Tetruhedron Lett., 1978, 3781.

Six-membered Rings: Other Systems

329

NHPh

NHPh

ArCH

Reagents: i, PhNCX; ii, K,CO,; iii, K,CO,, Me,CO; iv, NaOH, DMF

Scheme 83

(11YO),and 4,5-diphenyl-1,2,3-triazole (7%). The structure of the thiatriazine, which arises by the reaction sequence outlined in Scheme 84, was confirmed by X-ray analysis.

+ PhfiPh (360)

+ Ph<

>Ph N‘s. -,:N N ‘‘

N;;--*i;N N

Ph(($Ph N\”N

so

c-- Phl(

-so,

-

so

j P h

YN’N

Ph Ph (361)

Ph

Reagents: i, LiN,, MeCN, 25 “C, 20 h; ii, (360) Scheme 84

PART 11: Other Six-membered Ring Systems by G. P. Ellis

1 Books and Reviews The proceedings of a symposium on ‘Flavonoids and Bioflavonoids’ have been published.’ The chemistry of pyrans is surveyed in a chapter of a book on synthetic methods,* and an extensive review of the reactions of a- and p-alkyl groups in mono- and bi-cyclic pyrylium salts has a ~ p e a r e d . ~

’ ‘Flavonoids and Bioflavonoids; Proceedings of the 5th Hungarian Bioflavonoid Symposium’,ed. L. *

’

Farkas, M. Gabor, and F. Kallay, Elsevier, Amsterdam, 1977. T. Goto and S. Yamamura, in ‘Methodicum Chimicum’, ed. F. Korte, Vol. 11, Academic Press, New York, 1978, pp. 134-141. V. V. Mezheritskii, A. L. Wasserman, and G. N. Dorofeenko, Heferocycles, 1979,12, 1.

330

Heterocyclic Chemistry

Thiochromenes and hydrothiochromenes are the subject of a review in R ~ s s i a nVarious .~ aspects of flavonoid chemistry have been reviewed; for example, naturally occurring f l a v o n e ~ , ~photocherni~try,~ '~ and the relationship between taste and the structure of flavonoids and their precursors.8.9 Natural isoflavonoids," homoisoflavonoids, l 1 and plant coumarins, furocoumarins, and pyranocoumarins l 2 have been surveyed in some detail. Partial alkylation of polyhydroxy-coumarins has been reviewed. l 3 The u.v.14 and 'H n.m.r.15 spectra of phytoxanthones have been discussed and are tabulated. A chapter in a multi-volume work covers the chemistry of dioxans, oxathians, and dithians.I6 The chemistry, biotransformation, and biology of r~tenone,~ as' well as recent developments in the chemistry of rotenoids," have been reviewed. 2 Systems containing One Oxygen or Sulphur Atom

Reduced Pyrans.-Cyclization of substituted 175-diols by heating the monotosylate in hexamethylphosphortriamide (HMPA) provides a synthesis of 2alkyl-tetrahydropyrans. l9 Their 3-alkyl analogues have been synthesized by the method" shown in Scheme 1. Several 2-, 4-, and 6-alkyl- and 6-phenyl-3,4dihydropyrans have been prepared, and the reactivity of the double bond of each

RCH(CO,Et),

+

Br(CH2),C02Et

-!+ RC(CO,Et),

I

ii, iii

(CH2)2C02Et

RCHCH20H

I

-

(CH2120H

Reagents: i, NaH, DMF; ii, OH-; iii, LiAIH,; iv, TsCI; v, HMPA

Scheme 1

compound towards Bu'OCl in MeOH has been correlated with the position and nature of the substituent. 3,4-Dihydropyrans have been used to synthesize S. K. Klimenko, V. G. Kharchenko, and T. V. Stolbova, Khim. Geterotsikl. Soedin., 1978, 3.

' D. G . Roux, Chemsa, 1978,90. G . J. Niemann, Acta Bot. Neerl., 1979, 28,73. ' A. C. Jain, H. R. Saini, and R. C. Gupta, J. Sci. Ind. Res., 1978, 37,264. ' R. E. Wingard, G. A. Crosby, and G. E. DuBois, Chemtech., 1978,8,616.

' R. W. Bragg, Y. Chow, L. Dennis, L. N. Ferguson, S. Howell, G. Morga, C. Ogino, H. Pugh, and M. lo

" l2 l3

I' 16

17

I* l9

Winters, J. Chem. Educ., 1978,55, 281. V. A. Bandyukova and A. L. Kazakov, Khim. Prirod. Soedin., 1978,669. A. C. Jain and R.Khazanchi, J. Sci. Ind. Res., 1978, 37, 408. R. D. H. Murray, Fortschr. Chem. Org. Naturst., 1978, 35, 199. V. K. Ahluwalia and N. Rani, J. Chem. Sci., 1977, 3, 1 M. Afzal, J. M. Al-Hassam, and F. N. Al-Masad, Heterocycles, 1979, 12,269. M. Afzal and J. M. Al-Hassam, Heterocycles, 1979, 12,421. M. Sainsbury, in 'Rodd's Chemistry of Carbon Compounds', Vol. 4H, ed. S. Coffey, Elsevier, Amsterdam, 1978, pp. 375-426. T. J. Haley, J. Environ. Pathol. Toxicol., 1978, 1,315. A. C. Jain, A. Kumar, and A. K. Kohli, J. Sci. Znd. Res., 1978, 37, 606. E. Montaudon, J. Thepenier, and R. Lalande, J. Heterocycl. Chem., 1979,16, 113.

33 1

Six-membered Rings: Other Systems

MzoMe OMe Me

+ CCI,

Me

Scheme 2

dichloronorcaranes of known stereochemistry (Scheme 2).20 When Diels-Alder reactions of 1-methoxybutadiene with ketones are conducted under pressure, 2,3-dihydro-6H-pyrans are obtained in good yield (Scheme 3)." MeOCH

II

HC,

&H,

-

+ R'COR~

C H

Scheme 3

A new stereospecific synthesis of genipin (1; R' or R2 = OH) has been reported22and the stereochemistry of xylomollin (2) has been revised.23 When 2,3-dihydropyran was subjected to three pulses of a laser beam, with or without SiF, as sensitizer, 33% of it decomposed to acrolein and ethylene. The conversion increased to 65% when 100 flashes were applied, and this promises to be a useful means of effecting a retro-Diels-Alder reaction.24Two norlignans, sequirins A and E, which occur in some members of the Coniferae, have been synthesized as their di- and tri-methyl ethers (3) and (4)respectively, by a series of reactions from 4-metho~yacetophenone.~~ R ' R2

.qA r*

HOCH

H C02Me

'OMe

HO.

C0,Me

Antibiotics containing a reduced pyran ring have been investigated by several workers. 5,6-Dihydroxypolyangioic acid and its epimer (5) have been isolated from Polyangium celldosum var. fulzmm.26 Salinomycin ( 6 ) and SY-1 (7) are produced by Streptomyces albus, and the structure of the latter compound has now 2o 22

23 24 25

26

G. F. Weber and S. S. Hall, J. Org. Chem., 1979, 44, 364,447. J. Juraak and M. Chmielewski, Synthesis, 1979,41. G. Buyuk, Tetrahedron Lett., 1978,3803. M. Nakane, C. R. Hutchinson, D. Van Eugen, and J. Clardy, J. A m . Chem. SOC.,1978,100,7079. D. Garcia and P. M. Keehn, J. A m . G e m . SOC.,1978, 100, 6111. A. P. Beracierta and D. A. Whiting, J. Chem. SOC.,Perkin Trans. 1, 1978, 1257. D. T. Connor and M. von Strandtmann, J. Org. Chem., 1978,43,4606.

Heterocyclic Chemistry

332

been dete~mined.~' The stereochemistry of the double bond of pseudomonic acid A (8) has been shown to be (E). Chemical synthesis of the methyl ester of the (2)-isomer, n.m.r., and X-ray analysis were employed in this study.28The acid (8) undergoes rearrangements in acidic and basic media.29In an attempt to reduce the extent to which the acid (8) binds to protein, the allylic acid of which pseudomonic acid A is an ester was converted into other H 0 2 C C H 2 0 C H = C H - ~- CH=CH I CHMe

I

Me

'OH

HC=CMe..

OH (5)

H0,CHC

I

,H

Me

Et

Meoc)Et

(6) R = O H (7) R = H

Me

OH

Pyrans.-Full details have been published of a previously mentioned method of preparing 6-amino-2,4-diaryl-4H-pyrans (9) from a -benzoylcinnamonitrile and malononitrile under basic c ~ n d i t i o n s . ~ ~

Ar'CH=CCOAr2

I

+ CH2(CN)2

-D

CN (9) 27 28

29

30 31

Y. Miyazaki, A. Shibata, K. Tsuda, H. Kinashi, and N. Otake, Agric. Biol. Chem., 1978,42,2129. R. G.Alexander, J. P. Clayton, K. Luk, N. H. Rogers, andT. J. King, J. Chem. SOC.,Perkin Trans. 1, 1978,561. J. P.Clayton, R. S. Oliver, N. H. Rogers, and T. J. King, J. Chem. SOC.,Perkin Trans. I , 1979,838. J. P.Clayton, K.Luk, and N. H. Rogers, J. Chem. Soc., Perkin Trans. 1, 1979,308. M. Quinteiro, C. Seoane, and J. L. Soto, J. Heterocycl. Chem., 1978,15,57.

Six-membered Rings: Other Systems

333

Pyrones.-Preparution. 5,6-Dihydro-2-pyrones have been synthesized from an for example, the 6-cinnamyl aldehyde and the dianion of 2-butynoic derivative (10) is prepared in 27% yield. The 1,4-addition of dichloroketen to has been extended to ketones NN-disubstituted 2-aminomethylene bearing aliphatic and mono- and di-arylamino-gr~ups.~~ Cyclization of ketones containing sterically hindered nitrogen-containing groups (e.g. NPri) was not achieved, but pyrones such as (1 1)were obtained in good yield. In another route to 2-pyrones, dimethyl 2,4-diacetylglutaconate (12), which in solution exists largely in the cyclic form, gave several products under the influence of various alkoxides, including methyl 3-acetyl-6-methyl-2-oxo-2H-pyran-5-carboxylate (13). Chelation of magnesium from the alkoxide played an important role in this reaction. A number of xanthyrones (16) [6-(propenyl)-2-pyrones] were synthesized from the pyrandicarboxylic ester (14) and 6-methoxyhex-5-ene-2,4dione (15).35*36 When methyl methoxymethyleneacetoacetate (17) reacts with

RCHO

+ CH,CZCC=O I 0-

CH2N2b

RCHCH2C=CCO2Me

I

OH

-

ooczMe +

Me0,C \

32 33 34

35 36

O ~ C H = C H ; '

MeOCH=CH

I

AcCH,CO

-

Me0,C \

C0,Me

k c-0'

Me/

H.H. Meyer, Justus Liebigs Ann. Chem., 1978,337. L. Mosti, P. Schenone, and G. Menozzi, J. Heterocycl. Chem., 1978,15, 181. A. Bargagna, F. Evangelisti, and P. Schenone, J. Heterocycl. Chem., 1979, 16, 1.93. L. Crombie, D. E. Games, and A. W. G. James, J. Chem. SOC.,Perkin Trans. 1, 1979,464. L. Crombie, M. Eskins, D. E. Games, and C. Loader, J. Chem. SOC.,Perkin Trans. 1,1979,472,478.

334

Heterocyclic Chemistry

methyl cyanoacetate and sodium methoxide, the product may be the pyrone (14), the pyridone (18), or a mixture of t h e ~ e . ~ ’ H

MeOCH=CH

I

MeO,CCH,CO

M e 0‘2 oC :\i 2 M e

(17)

(18)

3,4-Dihydro-2-pyrones (20) are prepared in high yield by heating 1,3-diarylprop-2-en-1-ones (19) with ethyl phenylacetate and sodium acetate (Scheme 4).” In a synthesis of (*)-mevalonolactone (22), the 1,3-dioxan (21) is hydrolysed ArCH=CHCOPh (19)

+

i

P

h

u

P

H h

v

90%

88%

PhCH,CO,Et

Ph Ar

Reagents: i, EtO-, 80 “C; ii, N,H,.H,O

ii

Ph Ar

(20) Scheme 4

and treated with KCN and then aqueous alkali.” The kinetics of the formation of 2-pyrones (24) from aryl-substituted derivatives of 2,3-dioxofuran (23) have been studied under various condition~.~’

Among 2-pyrones of biological importance which have been synthesized are (*)-pestalotin (25) and its 6-epimer from 2-benzyloxyhexanoic acid and diketen.41Two of the fragrant constituents of jasmine oil, (*)-tuberolactone (26) and (*)-jasmine lactone (27), have been totally synthesized from butane- 1,2,4tri01.~~ ,Bu

OMe (25) 37

38

’’

40

41 42

S. R. Baker, L. Crombie, R. V. Dove, and D. A. Slack, J. Chem. SOC.,Perkin Trans. 1, 1979, 677. Y.A. Al-Farkh, F. H. Al-Hajjar, and €3. S. Harnoud, J. Heterocycl. Chem., 1979, 16, 1 . H. Ohmichi, T. Miyakoshi, and K. Saito, Yuki Gosei Kugaku Kyokaishi, 1978, 36, 874. y u . S. Andreichikov, Yu. A. Nalimova, A . P.Xozlov, and I. A. Rusakov, Z h . Org. Khim., 1978,14, 2436. T. Izawa and T. Mukaiyama, Chem. Lett., 1978,409. P. D e Clercq and R. Mijngheer, Bull. SOC.Chim. Berg. 1978,87,495.

335

Six-membered Rings : Other Systems

A four-stage synthesis of 5,6-dihydro-6-methoxy-2H-5-pyrone in 36% yield from 2-methoxytetrahydro-3-pyroneis an improvement on earlier Ethyl 4-phenoxyacetoacetate reacts with diketen in hexamethylphosphortriamide under basic conditions to produce the 4-pyrone (28) in 28% yield, but when the triamide is replaced by THF, no pyrone is PhOCH ,CO

'

no

H2C

EtO,CCH, -I-

PhOCH2vcH2

+ PhocH2QMe Et0,C

Et0,C

0

0

Me$OMe,

ii 89%

M

e

u

/ OAc

0 Reagents: i, Ac,O, OH-; ii, [Me,O]' BF,-, H30'

Scheme 5

Triacetic acid lactone (29) has been converted into 2-alkoxy-4-pyrones in high yield (Scheme 5).45Oxidation of tetra-aryl-bipyranidenes (30) gave 2,6-diaryl-4pyrones in 2 0 4 5 % yield.46A novel biosynthetic route to lankacidin C diacetate (31) has been demonstrated, by the addition of enriched CH,13C0,Na,

0 (32) 43 44 45

46

A. Saroli, D . Deswurs, D . Anker, and H. Pachew, J. Heterocycl. Chem., 1978, 15, 765. T. Kato, M. Sato, and H. Kimura, J. Chem. Soc., Perkin Trans. 1, 1979, 529. T. D. Cyr and G. A. Poulton, Can. J. Chem., 1978,56, 1796. E. V. Kuznetsov, D. V. Pruchkin, A. I. Pyschev, and G. N. Dorofeenko, Khim. Geterotsikl. Soedin., 1978, 1320.

Heterocyclic Chemistry

336

'3CH3'3C02Na, NH2CH213C02H, "CH,S(CH2)2CH(NH2)C02H7 and 'SNH2CH2C02Hto cultures of Streptornyces species.47The sex pheromone of the drugstore beetle (Stegubiumpaniceum)has been shown to be the 4-pyrone (32).48

Properties. The electrostatic effects of the heteroatom and the conformation of the molecule have been studied, using 13C n.m.r. spectroscopy, for tetrahydrothiopyran-3 - and -4-ones and their 1,1-dioxides. The compounds were shown to have a chair conformation, and evidence of transannular electron transfer was obtained in the chemical shifts of the carbonyl carbon of the thiopyran-3-0ne.~~ Both 'H and 13C n.m.r. were used to study the stereochemistry of 2-alkoxytetrahydro-3-pyrones, and the results were used to interpret their photolytic behaviour in several Photochemical rearrangement of the 4-pyrones (33) to 2-pyrones (34) has been

0 (33)

(34)

Reduction of pyrones by various reagents and the effect of these on the stereochemistry of the pyranols continues to be investigated; for example, reduction of 2,6-diaryI-3-methyltetrahydro-4-pyroneswith several reagents,53 and of 2-methyltetrahydro-4-pyrone and of its 2-C2H3-2,6,6-2H3analogue by metal h y d r i d e ~The . ~ ~latter gave a mixture of isomers, but L-Selectride reduced the 2-methyl-pyrone to give 73% of the 4-equatorial alcohol. 3,4-Dihydro-2pyrones are reduced by lithium aluminium hydride at -10 "C to the unstable 2-pyranols7 but, when the reaction is done in methanol, the 2-methoxy-2,3dihydropyrans and 2,6-dimethoxytetrahydropyrans are Selective hydrogenation of 2-pyrones (35) gives high yields of di- or tetra-hydro-2pyrones, according to the conditions (see Scheme 6).56 M

e

u

-

M

e

83%

u

I,

85%

OH

M

e

0 /

OH

(35) Reagents: i, H,, Pd/C, CuSO,; ii, H,, Pd/C

Scheme 6 47 48

4y 50

'' 52

53 54 55

M. Uramoto, N. Otake, L. Cary, and M. Tanabe, J. A m . Chem. SOC.,1978,100,3616. Y. Kuwahara, H. Fukami, R. Howard, S. Ishii, F. Matsumura, and W. E. Burkholder, Tetrahedron, 1978,34,1769. J. A. Hirsch and A. A. Jarmas, J. Org. Chem., 1978,43,4106. C. Bernasconi, L.Cottier, G. Descotes, M. F. Grenier, and F. Metras, Nouu. J. Chem., 1977,2,79. N. Ishibe and S. Yutaka, J. Org. Chem., 1978,43,2138. N. Ishibe, S. Yutaka, J. Masui, and N. Ihda, J. Org. Chem., 1978,43,2144. V. Baliah and G. Mangalam, Indian J. Chem., Sect. B, 1978,16, 213. D . C.Wigfield and S. Feiner, Can. J. Chem., 1978,56,789. R.Semet and R. Longeray, Bull. SOC.Chim. Fr., Part2, 1978,185. B. Nedjar, M. Hamdi, J. Perie, and V. Herault, J. Heterocycl. Chem., 1978,15, 1153.

337

Six-membered Rings: Other Systems

When kojic acid is methylated with dimethyl sulphate and alkali, a mixture of a di- and two mono-methyl ethers is usually obtained. A study of the role of alkalis in various proportions has shown that, when the reactants and conditions are carefully chosen, each of the three possible products may be obtained singly and in good yield.57 The conversion of pyrones into pyridones is well known;56 for example, 3,6-dihydro-2-pyronesgive good yields of pyridones by heating for several hours at 140 "C,but at room temperature the ring was cleaved; on heating with amines, recyclization occ~rred.'~ Heating the 2-pyrone (20) with hydrazine hydrate gave a yield of 87--90% of 4-ary1-3,4-dihydr0-3,6-diphenyl-2-pyridone.~~ When reactive groups are attached to the pyrone ring, they sometimes react preferentially with the amine and the pyrone ring remains; for example, the reaction of the diester (17) with methylamine gives the monomethyl amide (36).59 O D M e Me0,C

C0,Me

MeNH,,

'0"'

*cI

\

NHMe

C0,Me

(34)

Pyrylium Salts.-One of the most useful properties of pyrylium salts is the susceptibility of substituents or hydrogen to nucleophilic displacement. Methoxide ion reacts with 2,6-diphenylpyrylium perchlorate in CD,CN and methanol to give 2,6-diphenyl-4-methoxy-4H-pyran(37). In methanol alone, (37) is formed rapidly, but it soon disappears, with the formation of the dienone (38).602,4,6Trimethylpyryhm perchlorate (39) condenses at the $-methyl group with 4pyrones (Scheme 7).61When 2,6-diphenylpyrylium perchlorate (40) is treated with water and a base, the product is the diketone (41), and not the previously suggested dipyran.62Compounds in which two pyrone rings are joined to a carbon atom are of interest as dyes. Such a compound (42) is prepared in 85% yield from 4,6-diphenyl-2-pyrone and acetophenone (Scheme 8) with simultaneous loss of the benzoyl

57 58

59 60 61 62

63

N. S. Poonia and B. P. Yadav, J. Org. Chem., 1978, 43, 2842. A. A. Avetisyan, S. K. Karayez, and M. T. Dangyan, Khim. Geterotsikl. Soedin., 1978,452. L. Crombie and R. V. Dove, J. Chem. Soc., Perkin Trans. 1, 1979,686. S . Bersani, G. Doddi, S. Fornarini, and F. Stegel, J. Org. Chem., 1978,43,4112. R. Neidlein and I. Koerber, Arch. Pharm. (Weinheim, Ger.), 1978,311, 236. A. I. Pyschev, N. G. Bokii, and Yu. T. Struchkov, Tetrahedron, 1978,34, 2131. G. A. Reynolds and J. A. Van Allan, J. Heterocycl. Chem., 1978, 15, 1225.

338

Heterocyclic Che rnisrry

MeoMe +

Me

j/

(39)

\L

Reagents: i, 2,6-dimethylpyran-4-one; ii, flavone

Scheme 7

Ph

Ph (42)

Reagents: i, POC1,; ii, HClO,

Scheme 8

Conversion of pyrylium salts into pyridinium ~ a l t s ~continues ' , ~ ~ to attract attention as a versatile reaction. Pyrylium salts react with alkyl-amines such as 2-chloro- or 2-hydroxy-ethylamine to form N-substituted pyridinium salts (43)in good yield.65 Synthetic use has been made of this type of reaction with 2,4,6triphenylpyrylium perchlorate; for example, in the synthesis of halides, amines,

b4

65

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, p. 106. A. R. Katritzky, J. B. Bapat, R.M. Claramunt-Elghero, F. S. Yates, A. Dinculescu, A. T. Balaban, and F. Chiraleu, J. Chem. Res., 1978, (S) 395, (M) 4783.

339

Six-membered Rings: Other Systems

and esters. Scheme 9 shows a few of the many examples described by the workers at the University of East Acyl-hydrazines react with 2,4,6-triphenylpyrylium perchlorate to give the N-acyl-imine (44); this, on pyrolysis, yields the isocyanate (45).71

pho F7HZCH 2y

+

+ Y(CH2)ZNHz + Ph

Y = C1 or OH

ClO4

Ph

(43)

R'CH,NR;

k

R'CH2Y

Ph Reagents: i, 2,4,6-triphenylpyrylium perchlorate; ii, pyridine (X= (210,); iii secondary amine (X = '20,) iv,;R3CH2C02Na(X = BF,); v, A (X = Y = C1, Br, or I); vi, NaBH, (X = CIO,).

Scheme 9

phoph+

RCOAr I

+ ArCONHNH,

Ph

c10,-

Superoxide ion causes ring contraction of trimethylpyrylium borofluoride to give a mixture of fur an^.^^ 66

67

68

69

70 71 72

A. R. Katritzky, M. F. Abdel-Megeed, G. Lhommet, and C. A. Ramsden, J. Chem. Soc., Perkin Trans. 1, 1979,426. A. R. Katritzky, U. Gruntz, D. H. Kenny, M. C. Rezende, and H. Sheikh, J. Chem. SOC.,Perkin Trans. 1, 1979,430. A. R. Katritzky, N. F. Eweiss, and P. L. Nie, J. Chem. Soc., Perkin Trans. 1, 1979,433. A. R. Katritzky, U. Gruntz, A. A. Ikizler, D. H. Kenny, and B. P. Leddy, 1.Chem. Soc., Perkin Trans. 1, 1979,436. A. R. Katritzky, J. Lewis, and P. L. Nie, J. Chem. SOC.,Perkin Trans. 1, 1979, 442. A. R. Katritzky, J. Lewis, and P. L. Nie, J. Chem. Soc., Perkin Trans. 1, 1979, 446. S. Kobayashi and W. Ando, Chem. Lett., 1978, ,1159.

Heterocyclic Chemistry

340

Thiopyrans.-Synthesis. Chalcones (46), on standing with P,Sl0 in carbon disulphide and triethylamine, dimerize to give thiopyrans (47); these, on heating with acrylonitrile, give the nitriles (48), as shown in Scheme Thiopyran-4ones have been prepared74by the reaction of penta- 1,4-dien-3-ones with H,S. In 2ArCOCHzCHAr

A .

A r o A r

--+ ii

A

r

u

CSAr

(46)

r CN

dr

Ar

(48)

(47) Reagents: i, P4S,,,Et,N; ii, H,C=CHCN

Scheme 10

light, ethylene sulphide and octenylmagnesium bromide react to give a 47% yield of 4-pen tylte trah ydrothiop yran. 7 5 Thermal dimerization of 3-aryl-2-cyanothioacrylamides is regioselective and stereoselective, and leads to 3,4-dihydro2 H - t h i o ~ y r a n s for , ~ ~one of which the activation parameters for ring inversion have been dete~rnined.~'Treatment of 4,6-diphenylpyridine-2-thionewith hydroxylamine hydrochloride gave the oxime of 4,6-diphenylthiopyran-2-0ne.~* A one-step synthesis of a bithiopyran (50) from an acyclic precursor uses the diester (49), H2S, and HC1 under pressure.79 An efficient route has been developed for the synthesis of 2,6-diaryl-5,6-dihydro-2H-thiopyrans (52) from tetrahydro-4H-thiopyran-4-01 (51) by 0-mesylation and elimination with alumina at ambient temperature." U.V.

CH2COCO2Et

co I

+H2S

CHzCOCO2Et (49)

I

OH

Et0,C

C02Et

S

--*

Et0,C

m (50)

C02Et

I

OS0,Me

(51) 73

74

75 76

77

78 79

T. Karakasa and S. Motoki, J. Org. Chem., 1978, 43, 4147. K. Ramalingam, K.D. Berlin, R. A. Loghry, D. van der Helm, and N. Satyamurthy, J. Org. Chem., 1979, 44, 477. V. P. Krivonogov, V. I. Dronov, and R. F. Nigmatullina, Khim. Geterotsikl. Soedin., 1977, 1622. J. S. A . Brunskill, A. De, and D. F. Ewing, J. Chem. SOC.,Perkin Trans. 1, 1978, 629. J. S. A . Brunskill, A. De, and D. F. Ewing, Org. Magn. Reson., 1979,12, 257. P.M. Fresneda, P.Molina, and A . Soler, A n . Univ. Murcia, Cienc., 1975, 32, 5 (publ. 1978). D. J. Sandman, T. J. Holmes, and D. E. Warner, J. Org. Chem., 1979,44, 880. C. H. Chen, G. A . Reynolds, N. Zumbulyadis, and J. A . Van Allan, J. Heterocycl. Chem., 1978,15, 289.

34 1

Six-membered Rings: Other Systems

ReaEh'ons. Tetrahydro-2-vinylthiopyranis readily S-alkylated, and the salt undergoes ring expansion on treatment with 1,5-diazabicyclo[5.4.0]undec-5ene; €or example, with CF,SO,OCH,CO,Et the thiopyran gives the ester (53).81

aco2 (54)

The thiopyrans (54)'also undergo ring expansion when the phenyl groups are at C-2 and C-6, but ring contraction occurs with the 3,5-diphenyl isomer.82These and other thiopyrans have been h a l ~ g e n a t e d2H-Thiopyran .~~ is lithiated at C-6, and the product reacts normally with Me1 and MeSCN.84 The anion of 2Hthiopyran reacts with Bu'Br to give the 2-t-butyl derivative, but cyclohexyl bromide gives a mixture of 2- and 4-substituted Reduction of 2,6-disubstituted tetrahydro-1-thiopyran-4-one oxime with LiAlH, gives the 4e-amine when the substituents are 2,6-truns but the 4e- and 4a-amines from the 2,6-ci~-isorner.~~ 2-Bromo-3,5-dimethyl-4H-thiopyran-4-one (55) can give either a pyran-2-thione (56) or a 1-thiopyran-2-one (57) according to the conditions (see Scheme 11);mechanisms have been ~ u g g e s t e d . ~ ~

Reagents: i, OH-, DMSO, MeOH; ii, OH-, DMSO, H,O

Scheme 11

Chromans.-Unambiguous syntheses have been described of 4-hydroxy-a - (59) and 4-hydroxy-P-lapachone (61) by treating a- (58)or P-lapachone (60) with E. Vedejs, M. J. Arw, D. W. Powell, J. M. Renga, and S. P. Singer, J. Org. Chem., 1978,43,4831. W. Ried and H. Bopp, Synthesis, 1978, 211. W. Ried and H. Bopp, Justus Liebigs Ann. Chem., 1978,1280. 84 R. H. Everhardus, R. Grafing, and L. Brandsma, Red. Trav. Chim. Pays-Bas, 1978,97, 69. 85 R. Grafing, H. D. Verkruijsse, and L. Brandsma, J. Chem. Soc., Chem. Commun., 1978, 596. 86 V. Baliah and N. Bhavani, Indian J. Chem., Sect. B, 1978, 16, 776. " F. H. Greenberg and Y. Gaoni, J. Org. Chem., 1978,43,4966. 81

**

83

Heterocyclic Chemistry

342

NBS and lead tetra-acetate (Scheme 12). Dehydration of (61) was accompanied by isomerization to yield the same chromene (62) as from the a-isomer.88 An efficient synthesis of 2-(hydroxymethy1)-chromans is by oxidative cyclization of alkenes (63) with rn-chloroperbenzoic acid.89 The use of an organocopper 0

0 (58)

(60) 0 Reagents: i, NBS, Pb(OAc),; ii, HCl

Scheme 12

compound has led to a synthesis in 20% yield of (*)-3,4-~is-A'~~-tetrahydrocannabinol from dehydrolinalool acetate and olivetol bis(tetrahydropyrany1) ether." (-)-A9-6a, l0a-trans-Tetrahydrocannabinol is converted into three monohydroxy-derivatives by a fungus isolated from the same plant." Cannabinoids containing two pyran rings are mentioned in a later section of this Chapter. A useful and simple method of converting phenols into 2,2-dimethylchromans is to heat them, their potassium salts, AlCl,, and isoprene in benzene.92 " YO y1

92

R. B. Gupta and R. N. Khama, IndianJ. Chem., Sect. B, 1978,16, 35. P. Bravo and C. Ticozzi, J. Heterocycl. Chem., 1978,15, 1051. J. M. Luteijn and H. J. W. Spronck, J. Chem. SOC.,Perkin Trans. 1, 1979, 201. R. M. Christie, R. W. Rickards, and W. P. Watson, Aust. J. Chem., 1978,31, 1737. L. Bolzoni, G. Casiraghi, G. Casnati, and G . Sartori, Angew. Chern., Znt. Ed. Engl., 1978, 17,684.

Six-membered Rings: Other Systems

343

The epoxy-dihydropyran (64) cyclizes to a 6-hydroxy-hexahydrochroman (65) under mild conditions to give a regio- and stereo-specific product (Scheme 13).93 Progress has been made in unravelling the structures of a group of related pigments that are present in some mushrooms. In this work, several new chromans were synthesized; for example, the 0-methyltetronic acid (66).94 X-Ray crystallography was used to determine the structure of some of the and related compoundswhich are present in lichens and fungi were st~died.'~ A tetrahydrochroman, dactyloxene A (67), has been isolated from the sea hare, Aplysia d a c ~ l o r n e l a . ~ ~

rn 0

(64)

Reagent: i, BF,.Et,O, at -25 "C

Scheme 13

Stereoselective[3,3]sigmatropic Claisen rearrangement is a valuable technique in the synthesis of (2R,4'R,8'R)-a- tocopheryl a~etate.~' Homologues of atocopherol in which the OH is replaced by C1 have been ~ynthesized.~~ Photooxidation of simpler analogues of tocopherols gave the Saldehyde, or, where one position ortho to the 6-OH is free, coupled products."' Carbon-13 n.m.r. spectroscopy enabled the structures of several aspulvinones to be established.'" 1sochromans.-The trimethylsilyl ether of acetaldehyde iodohydrin reacts with 2-phenylethyl trimethylsilyl ether at 50°C to give a 50% yield of l-methylisochroman.lo' 2-Benzopyrylium perchlorates have been converted into several

'' R. K. Boeckman, K. J. Bruza, and G. R. Heinrich, J. Am. Chem. SOC.,1978,100,7101. 94

95

96 97 98 99

lo" lo'

lo*

D. W. Knight and G. Pattenden, J. Chem. SOC.,Perkin Trans. 1, 1979, 70. M. J. Begley, D. R. Gedge, D. W. Knight, and G. Pattenden, J. Chem. SOC.,Perkin Trans. 1,1979,77. D. W. Knight and G. Pattenden, J. Chem. SOC.,Perkin Trans. 1, 1979, 84, 89. F. J. Schmitz, F. J. McDonald, and D. J. Vanderah, J. Org. Chem., 1978,43,4220. K.K. Chan, A. C. Specian, and G. Saucy, J. Org. Chem., 1978,43,3435. E. D. Basalkevich and A. A. Svishchuk, Ukr. Khim. Zh. (Russ. Ed.), 1978, 44,407. S. Minami and S. Kijima, Yakugaku Zasshi, 1978,98, 426. H. Sugiyama, N. Ojima, M. Kobayashi, Y. Senda, J. Ishiyama, and S. Seto, Agric. Biol. Chem., 1979, 43,403. M. E. Yung, A. B. Mossman, and M. A. Lyster, J. Org. Chem., 1978,43,3698.

Heterocyclic Chemistry

344

isochroman derivative^,^^ and stereoselective total syntheses of the racemic forms of antibiotics kalafungin and nanaomycin A have been r e p ~ r t e d . "The ~ effect of restraining the stereochemistry of catecholamine-like compounds was studied by synthesizing several isochromans such as (629, which showed some hypotensive effect .'O4

Chromenes.-Compounds containing a 2-nitrovinyl group (such as w-nitrostyrene) condense with salicylaldehyde to give a 3-nitro-2H-chromene (69)and a trans,trans-3-nitrochroman-4-ol(70)as a by-pr~duct."~ Diethers of type (7 1)are converted into 4-aryloxymethyl-2H-chromenes (72) under mild conditions (Scheme 14); when the ring is activated, further cyclization to a furan occurs.106

(69) 38%

OH (70) 31%

(71) H)

(R = M e O x

Reagent: i, AgBF,

Scheme 14 103 104 105 I06

T. T. Li and R. H. Ellison, J. Am. Chern. Soc., 1978,100,6263. A . Kumar, J. M. Khanna, P. C. Jain, and N. Anand, Indian J. Chern., Sect. B, 1978,16, 793. T. Sakakibara, M. Koczuka, and R. Sudoh, Bull. Chern. SOC.Jpn., 1978, 51, 3095. D. K. Bates and M. C. Jones, J. Org. Chem., 1978,43, 3856.

Six-membered Rings : Other Systems

345

Metal phenoxides react with ap-unsaturated aldehydes and ketones to give 2H-chromenes. Io7 Encecalin (6-acetyl-2,2-dimethyl-7 -methoxy-2H-chromene) has been synthesized1" by a new route, as has cannabichr~rnene.~'~ Two new derivatives (74) and (75) of edulan (73) have been isolated from the fruit of the purple passion flower."' A few flavonoids containing a sugar residue attached to ring B are known, and synthetic analogues of these have recently been described."'

(73) R = H (74)R = O H

(77)

(75)

(78)

(76)

Benzopyrylium perchlorates (76) react with nucleophiles at C-2, are oxidized to coumarins (77), and are reduced to 2H-chromenes (78).'12 Hydroxylation of 2H-naphtho[2,3-b]pyrans with OsO, and NaC10, gave a mixture of products, some of which showed antibacterial acti~ity.''~ The main product was truns-3hydroxy-2-me thyl-2,3 -dihydropyran-4-one, but some of the cis-isomer was also present. Chromanones.-Interaction of a substituted 2-hydroxyacetophenone with a ketone and pyrrolidine or the enamine provides a simple synthesis of chromanones. A natural benzodipyran [graveolone (79)] has been synthesized

(79)

0

from 7-benzyloxy-2,2-dimethylchromanone.1 l 5 Chromanone (and flavanone) oximes react with lithium tetrachloropalladate and AcONa to give a palladium lo'

Io9 110

111

'I2

'I4 'I5

S. Giovanni, G. Casiraghi, L. Bolzoni, and G. Casnati, J. Org. Chem., 1979,44803. C. Stelink and G. P. Marshall, J. Org. Chem., 1979, 44, 1429. M. A. El Sohly, E. G. Boeren, and C. E. Turner, J. Heterocycl. Chem., 1978,15,699. M. Winter, K. H. Schulte-Elte, A. Velluz, J. Limacher, W. Pickenhagen, and G. Ohloff, Helv. Chim. Acra, 1979, 62, 131. S. Yamada, F. Ono, T. Katagiri, and J. Tanaka, Bull. Chem. SOC.Jpn., 1978,51, 3399. P. Bouvier, A. Jean, H. Cunha, and D. Molho, Bull. SOC.Chim. Fr., 1977, 1187. K. Krohn, G. Brueckner, and H. P. Tietjen, Chem. Ber., 1978,111, 1284. H. J. Kabbe, Synthesis, 1978, 886. A. G. Shinde and R. N. Usgaonkar, Indian J. Chem., Sect. B, 1978,16,570.

Heterocyclic Chemistry

346

complex (80); this reacted with CO and MeOH to give the 5-ester (81); see Scheme 15.116The presence of TiCl, or FeCl, raised the yields of 4-aminochromans obtained by the reduction of the oximes of chromanones and 4thiochromanones with LiAIH,.’ *’ Numerous products have been obtained from the reaction of 6,8-dimethylchromanone and HCHO. I8

(80) Reagents: i, PPh,; ii, CO, MeOH

Scheme 15

Chromones.-New methods of synthesizing chromones continue to appear; for example, chromone-2-carboxylic acids from a phenol and dichloromaleic anhydride, l9 3 -aminochromones from the corresponding 3- b r o m ~ c h r o m a n o n e s ~ ~ ~ or from the 3-bromochromone~,~*~ and 3-chlorochromones frdm 3,4-dichIorocoumarins.”’ A previously described procedure123has been modified so as to extend its usefulness to the synthesis of cbromone and naphtho[2,1-b]pyran-lone. 124 l-Methyl-2-naphthol(82) reacted with the half amide of malonic acid and POCl, to give 2-aminonaphthopyrones (83),lZ5and naphthopyrans containing NN-di(chloroethy1)amino substituents in the pyran ring were synthesized as potential anti-tumour agents.126 Cyclization of 2,3,6-triacetoxyacetophenone under prolonged Kostanecki-Robinson conditions gave a mixture of substituted 3-acetyl-2 -methylchromones. 27 3-Substituted chromones (85) are conveniently synthesized from the appropriate 2-hydroxyphenacyl derivative (84) in one of

@OH

+

TH2CONR2 C02Et

116

T. Izumi, T. Katou, A. Kasahara, and K. Hanaya, Bull. Chem. SOC.Jpn., 1978, 51, 3407. L.M.Meshcheryakova, V. A. Zagorevskii,and E. K. Orlova, Khim. Geterotsikl.Soedin., 1978,1694. ‘18 A. Ninigawa and H. Matsuda, Bull. G e m . SOC. Jpn., 1978, 51, 1874. G. Roberge and P. Brassard, Synth. Commun., 1979,9, 129. 120 V. Szabo and L. Nemeth, Magy. Kem. Foly., 1978,84, 164. M. K. Rastogi, C. Kamla, R. P.Kapoor, and C. P. Garg, Indian J. Chem., Sect. B, 1978,16,895. 122 C. Kamla, M. K. Rastogi, R. P. Kapoor, and C. P. Garg, Indian J. Chem., Sect. B, 1978,16,417. 123 G. A. Reynolds and J. A. Van Allan, J. Heterocycl. Chem., 1969,6, 29. lZ4 G. A. Reynolds, J. A. Van Allan, and A. K. Seidel, J. Heterocycl. Chem., 1979,16, 369. 125 G. Roma, E. Vigevani, M. Mazzei, A. Ermili, A. Ambrosini, and N. Passerini, Fannaco, Ed. Sci., 1978, 33, 822. 126 M. Mazzei, G. Roma, and A. Ermili, Farmaco, Ed. Sci., 1979,34, 5 2 . 127 J. Rybertt and J. Valderrama, Rev. Latinoam. Quim., 1978, 9, 220. 11’

Six-membered Rings: Other Systems

347

two ways, depending on the electronic nature of the w-substituent (Scheme 16). Electron-withdrawing substituents, as in (84a), require condensation with aceticformic anhydride, while electron-releasing groups, i.e. (84b), enable the phenacyl derivative to be condensed with triethyl orthoformate.'2s

R 2 G O H

(84a)

R

2

q

R

l

2(84b)

COCH2R1 (84a) R' = OH, OMe, Me, or Ph (84b) R' = Ac, PhCO, NO2, SOMe, or S0,Me

0 (85)

Reagents: i, HC(OEt),; ii, AcOCHO

Scheme 16

Analogues of khellin in which a homocyclic ring is fused to the 2,3-positions have been synthesized from 6-ace toxy-4,7 -dime thoxybenzofuran-5 -carbony1 chloride and the lithium enolate of a cy~loalkanone.'~~ Medicinal interest in tetrazolylchromones'30 continues to encourage the study of their synthesis, spectra, reactions, and metabolism. ' 3 1 * 1 3 2 Chromone N-(5-tetrazolyl)carboxamides have also shown promise as anti-allergic compounds. 133 The anthropyranone kidamycinone (86), which is the aglycone of the antibiotic kidamycin, has been synthesized as its methyl ether.'34 A reduced chromone, agarotetrol (87), has been identified in a fungus-infected a g a r w o ~ d , 'and ~~ a chromone-5-carboxylic ester (lapidosin) is a metabolite of Penicillium lapidosum.'36 Extraction of root bark of Schumanniophyton problematicum with MeOH-AcOH gave several compounds, including two new piperidine-

12' 129

130

132 133

134

'31

G. J. P. Becket, G. P. Ellis, and M. I. U. Trindade, J. Chem. Res., 1978, ( S ) 47, (M) 0865. T. Watanabe, S. Katayama, Y. Nakashita, and M. Yamauchi, J. Chem. SOC.,Perkin Trans. 1, 1978, 726. G. P. Ellis and D. Shaw, J. Chem. SOC.,1972,779. A. Nohara, H. Kuriki, T. Ishiguro, T. Saijo, S. Ukawa, Y. Maki, and Y. Sanno,J. Med. Chem., 1979, 22, 290. T. Kato, A. Nohara, T. Kawarasaki, and Y. Sawa, J. Tukeda Res. Lab., 1978,37, 195. G. P. Ellis, G. J. P. Becket, D. Shaw, H. K. Wilson, C. J. Vardey, and I. F. Skidmore, J. Med. Chem., 1978,21,1120. F. M. Hauser and R. P. Rhee, J. Am. Chem. SOC.,1979,101, 1628. E. Yoshii, T. Koizumi, T. Oribe, F. Takeuchi, and K. Kubo, Tetrahedron Lett.,1978,3921. W. B. Turner, J. Chem. Soc., Perkin Trans. 1, 1978, 1621.

Heterocyclic Chemistry

348

chromones (88) and (89).13’ Soon after this discovery, a positional analogue, rohitukine (90), was isolated f‘rom Amooru rohituku, and its structure was confirmed by X-ray analysis. 138 Me

(89) R = M e

(90)

The tautomerism between 2-hydroxy-chromones and 4-hydro~y-coumarins’~’ has been studied, using i.r. spectroscopy; the chromone is favoured by 7-OH, 7-OMe, or 5-OH substitution and the coumarin by 3- or 5-OMe groups.’4o Irradiation of 2-methyl- or of 2,3-dimethyl-chromone in methanol containing 5% HCl produced the corresponding 2-hydroxymethyl-2-methyl-chromone, but chromone or its 3-methyl derivative was methylated a’t C-2 by similar treatment.I4l An attempt to effect a Pummerer reaction on a chromone-3-methylsulphoxide (9 1) gave a mixture of intermolecularly reduced-oxidized products (92) and (93), the former ~ r e d 0 m i n a t i n g .The l ~ ~ reaction of (91) with SOCl, alone or with acetic anhydride resulted in addition across the 2,3- double bond,143as shown in Scheme 17.

0

0 (92)

0 (93) 11

t

Reagents: i, HCI; ii, rn-ClC,H,CO,H; iii, Ac,O, SOCl,; iv, SOCl,

Scheme 17 137 13’ 13’

140

14’ 142

L43

E. Schlittler and U. Spitaler, Tefrahedron Lett., 1978, 2911. A. D. Harmon, U. Weiss, and J. V. Silverton, Tetrahedron Lett., 1979, 721. For a review see, G. P. Ellis, ‘Chromenes,Chromanones and Chromones’,John Wiley, New York, 1977, p. 488. S. S. Chibber and R. P. Sharma, Cum. Sci., 1978, 47, 730. I. Yokoe, Y. Shirataki, and M. Komatsu, Chem. Pharm. Bull., 1978,26,2277. D. T. Connor and M. Von Strandtmann, J. Heterocycl. Chem., 1978,15, 113. D. T. Connor, P. A, Young, and M. Von Strandtmann, J. Heterocycl. Chem., 1978, 15, 115.

Six-membered Rings: Other Systems

349

The reactions of 3-aminochromone have been and 2-( y- t-aminoalky1)-chromones have been found to possess neuroleptic activity. 145 Thiochromans, Thiochromenes, Thiochromanones, and Thiochromones.-2Thiadecalins (95) have been synthesized by cyclization of a 2-substituted cyclohexanone (94). Their stereochemistry has been studied by spectral and chemical methods, including deacetoxylation to the sulphone (96).146Thiochromans with a nitrogenous substituent at C-4 have been synthesized for antimalarial screening.14’ Tricyclic thioisochromans, such as (97),have been synthesized under mild Diels-Alder The triketone (98) has been cyclized, by treatment with H,S and a strong acid, to give the naphthothiopyran (98a) in excellent yield.’49 2-Amino- l-thiochromones’50 and similar have been synthesized.

Ph

Ph (97)

Ph

An attempt to fluorinate 3-bromo-1-thiochromanonewith XeF, gave 3bromo-1-thiochromone, but 3,3-dibromo- 1-thiochromanone was fluorinated”* 144

14’

146

14’

14’ 149

lS1

V. Szabo and L. Nemeth, Magy. Kem. Foly., 1978,84,453. P. Da Re, P. Valenti, P. Montanari, L. Cima, and P. Giusti, Eur. J. Med. Gem.-Chim. mer., 1978, 13,387. S . Fabrissin, S. Fatutta, and A. Risaliti, J. Chem. SOC.,Perkin Trans. 1, 1978, 1321. R. K. Razdan, R. J. BNni, A. C. Mehta, K. K. Weinhardt, and Z. B. Papanastassiou, J. Med. Chem., 1978,21,643. M. S . Raasch, J. Org. Chem., 1978,43,2500. 0 .V. Fedotova, A. P. Kriven’ko, and V. G. Kharchenko, Zh. Org. Khim., 1978, 14, 1782. L. A. Zhmurenko, 0.M. Glozman, and V. A. Zagorevskii, Khim. Geterotsikl. Soedin., 1978, 182. H. Nakazumi and T. Kitao, Chem. Lett., 1978,929. M. Zupan and B. Zajc, J. Chem. SOC.,Perkin Trans. 1, 1978,965.

350

Heterocyclic Chemistry

normally at C-2. The thiochromanone (99)has been converted, in good yield, into the 1-benzothiepin (loo), which is a versatile intermediate.'53 Dimeric benzothio-analogues of (42) have been obtained from 2-methyl-l-thiochromone.'54

a'

-' HCl

0

R'C1

(99)

Flavans and 1soflavans.-The substance that is present in the grain of sorghum (a grain that is used as a food source in some countries) which inhibits some enzymes and reduces the brewing quality of the grain is thought to be a polymer called procyanidin. This is produced in the grain from the flavanol cation (101) and ( + ) - c a t e c h i r ~ .The ~ ~ ~proanthocyanidins present in leaves of crown vetch and flowering currants are based on bis(hexahydr0flavans). The structural units of natural polymers have been shown to be flavans by trapping them as their phloroglucinol adducts. lS6 The stereochemistry of 8-bromotetra- 0-methyl-(+)catechin has been studied by means of X-ray c r y s t a l l ~ g r a p h yMore . ~ ~ ~ synthetic, stereochemical, and degradative studies on the flavanols of tannins have been described. 1587159 Several flavans have been isolated from Glycyrrhiza glubru L. and shown to have potent antibacterial activity.'" Amongst the constituents of the heartwood of Machaerium opucum are two isoflavans, (-)-duartin (102) and (-)-mueronulatol (103)?

(102) R = H (103) R = M e O

1soflavenes.-A biomimetic synthesis of biflavenes (104) employed an isoflavylium perchlorate and a 1,3-diarylpropene in acid solution under mild conditions (Scheme 18).162 153

155

157

lS8 159 I6O

'" 16'

V. J. Traynelis, J. A. Schield, W. A. Lindley, and D. W. H. MacDowell, J. Org. Chem., 1978, 43, 3379. H. Nakazumi and T. Kitao, Bull. Chem. SOC.Jpn., 1979, 52, 160. R.K. Gupta and E. Haslam, J. Chem. SOC.,Perkin Trans. 1, 1978, 892. L. Y. Foo and L. J. Porter, J. Chem. SOC.,Perkin Trans. 1, 1978, 1186. D. W. Engel, M. Hattingh, H. K. L. Hundt, and D. G. Roux,J. Chem. SOC.,Chem. Commun., 1978, 695. H. K. L. Hundt and D. G. Roux, J. Chem. SOC.,Chem. Commun., 1978,696. J. J. Botha, D. Ferreira, and D. G. Roux,J. Chem. SOC.,Chern. Commun., 1978, 698, 700. L. A. Mitscher, Y. H. Park, S. Omoto, G. W. Clark, and D. Clark, Heterocycles, 1978,9, 1533. W. D . Ollis, I. 0. Sutherland, H. M. Alves, and 0. R. Gottlieb, Phyrochemistry, 1978, 17, 1401. J. 0.Oluwadiya and W. B. Whalley, J. Chem. SOC.,Perkin Trans. 1, 1978, 88.

Six-membered Rings: Other Systems

35 1

UoMe +

ClO, Scheme 18

Havanones.-Most of the recent work is about the flavanones present in plants, but it has been shown that 3-azido-flavanones are useful intermediates in the synthesis of 3-amino-flavanones,'63 and Q -azido-2'-hydroxy-chalcones(105) react with triphenylphosphine to yield flavanones (106).164 Several examples of prenylflavanones have been identified in plants: sophoraflavanone B (107; R' = H, R2 = CH,CH=CMe,) is present in a Chinese plant, Sophora fornenfosa, 16' together with two known analogues, sophoronol and isobavachin. The 8,8'-biflavanone mesuaferrone A (108) has been obtained from the stamens of Mesua ferrea. '66 Lupinifolin (109) has been synthesized by oxidative cyclization

aoH g";e" + PPh,

+ \

COC=CHPh

I

(105)

N3

N=PPh3

0 (106)

(107; R' = R2 = CH,CH=CMe,)

(109) 163 164

166

T. Patonay, M. Rakosi, G. Litkei, and R. Bognar, Justus Liebigs Ann. Chem., 1979,162. G. Litkei, T.Mester, T. Patonay, and R. Bognar, Jusfus Liebigs Ann. Chem., 1979,174. M.Komatsu, I. Yokoe, and Y. Shirataki, Chem. Phann. Bull., 1978,26,3863. M.S.Raju, G. Snmannarayana, and N. V. S. Rao, Indian J. Chem., Sect. B,1978,16,167.

352

Heterocyclic Chemistry

of the flavone (107; R ' = R2 = CH2CH=CMe2) with DDQ.'"' Confirmation of the structure suggested earlier168for silychristin has been obtained from its 13C n.m.r. but the structure of two isomeric flavanones isolated from hydrolysis of carthamin, the red colouring matter of safflower should be interchanged according to an independent synthesis of the two compounds carthamidin (110) and isocarthamidin (11l).17' Two glucosyloxyflavanones (112) and (113) have been identified in Hoppea dichotorna, an Indian medicinal plant.'72 A new biflavanone (1 14)called kolaflavanone has been isolated from the HR' \O

W

O

H

H

\ O

GlucO

OH 0 (110) R' =OH, R2= H (I 11) R~= H, R~ = OH

w

O

M

e

0 (112) R=OMe (113) R = H

(114)

false kola nut, Garcinia k ~ l a . * In ' ~ a study of the relationship between chemical structure and the sweet taste of flavanones, a 5-OH, a 3'-OH, and a 4'-OMe are found to be essential for sweetness. 5,3'-Dihydroxy-4'-methoxyflavanonewas found to be 350 times as sweet as sucrose.174Bavachinin (6-dimethylallyl-4'hydroxy-7-methoxyilavanone), obtained from the seeds of Psoralea eurylifulia, has anti-inflammatory and antipyretic activity when given orally to animals. 175

1soflavanones.-An interesting synthesis of a 2-methyleneisoflavanone was observed when the a-bromo-ketone (115) was treated with aqueous methanolic sodium hydroxide. The initially formed epoxide was rearranged by acid.''" A new isoflavanone, sophoraisoflavanone A (116),which has a prenyl group attached to ring c, was identified in Sophura turnentus~.~"~ A revision of the original structure 167 168

169

'" 17' 172

173 174

'71 176

A. Nagar, V. K. Gujral, and S. R. Gupta, Tetrahedron Lett., 1978, 2031. H. Wagner, 0. Seligman, L. Horhammer, M. Seitz, and J. Sonnenbichler, Tetrahedron Lett., 1971, 1895. A. Pelter, R. Haensel, and M.Kaloga, Tetrahedron Lett., 1977, 4547. C. Kuroda, Nippon Kagaku Zasshi, 1930,51, 237. H. Obara, J. Onodera, Y. Kurihara, and F. Yamamoto, Buff. Chem. SOC.Jpn., 1978,51, 3627. S . Ghosal, D. K. Jaiswal, and K. Biswas, Phytochemistiy, 1978,17, 2119. P. J. Cotterill, F. Scheinmann, and I. A. Stenhouse, J. Chem. SOC.,Perkin Trans. 1, 1978, 532. M. Yamato, K. Hashigaki, K. Mito, and T. Koyama, Chem. Phann. Bull., 1978, 26, 2321. K. K. Anand, M. L. Sharma, B. Singh, and B. J. R. Ghatiak, Indian J. Exp. Biol., 1978,16, 1216. J. A. Donnelly, M. J. Fox, and D. E. Maloney, Tetrahedron Lert., 1978, 4691.

353

Six-membered Rings : Other Systems

(1 17)for cajanol(l18) (from Cajanus cajan) has been suggested as a result of the oxidation of its ethyl ether with p e r ~ x i d e . ' ~ ~

R

\ ' O

a

o

R

4

OH 0 (1 16) R' = R4 = H, R2 =Me, R3 = CH2CH=CMe2 (117) R ' = R 4 = M e , R 2 = R 3 = H (118) R 1 = R 2 = M e , R 3 = R 4 = H

F1avones.-Oxidation of 4H-flavene with KMnO, under mild conditions gave good yields of a number of flavones by a little-used m e t h ~ d . "Improvement ~ of a much more widely used method - the Kostanecki-Robinson reaction - has been effected by replacing the sodium salt of an acid by the minimum quantity of a tertiary amine that is necessary to solubilize the reactants. Several flavones were thus prepared in high yield.'79 Flavylium salts have been prepared from phloroglucinol or pyrogallol and dibenzoylmethane with acetic acid. These were nitrated in the 2-phenyl ring.'8o Such flavylium salts may be converted, in good yields, into the corresponding flavones by means of thallium(m) nitrate.'" Flavone-6-acetic acid (119)has been prepared by condensation of methyl 4-hydroxyphenylacetate with methyl phenylpropiolate, followed by hydrolysis and cyclization of the acid with PPA,'82as shown in Scheme 19.

+ PhCECC0,Me ii,flo%

(119)

0

OCPh=CHCO,Me

Reagents: i, Triton B; ii, H,O+; iii, PPA

Scheme 19 J. L. Ingham, 2. Naturforsch., Teil C, 1979,34, 159. K. Kurosawa and Y. Ashihara, Bull. G e m . SOC.Jpn., 1978,51,1175. "'J. H. Looker, J. H. McMechan, and J. W. Mader, J. Org Chem., 1978,43.2344. N . L.Olenovich, G. F. Tantsyura, Z . G. Galanets, and A. I. Gavril'chenko, Ukr. Khim. Zh. (Russ. Ed.), 1977,43,885. l n l M. Meyer-Dayan, B. Bodo, C. Deschamps-Vallet, and D . Molho, Tefrahedron Leu., 1978, 3359. D . R. Shridher, C. R. Sharrna, R. R. Krishna, R. S. Prasad, and Y. P. Sachdeva, Org. Prep. Proced. Int., 1978,10,163. '77 1-18

354

Heterocyclic Chemistry

Amino-alkyl ethers of oximes of flavones have been synthesized for pharmacological screening.'83 Many flavones have been reported to be present in plants; the following is a selection of these. Four new flavones containing a prenyl side-chain have been isolated from the root bark of the mulberry tree; compounds (120) and (121) are examples. lS4 The first allose-containing flavonoid has been isolated from the Japanese fern Osmundu usiuticu, and is named asiaticalin (122). lS5 Gomphrenol (123), the first flavonol to be found in the leaves of Gomphrenu globosu, is of interest because the methylenedioxy-group is uncommon in natural flavonols. New flavones, e.g. (124) and (125),have been identified in the leaves of Solunum citrullifolium, S. gruyi, S. heterodoxum, and S. tenuipes ;18' in Tephrociu semiglubru, glabratephrin (126) is a minor constituent.lss Several tetra- and pentahydroxy-flavones (e.g. syringetine and mearnsetin) have been found in the leguminous plants Dorycnium sufiuticosum and Tetrugonolobus s i l i q u o s u ~ . ~ ~ ~ 5,3',4'-Trihydroxy-6,7,8-trimethoxyAavoneis a new flavone extracted, together with 5,4'-dihydroxy-6,7,8,3'-tetramethoxyflavone,from Sideritis l e u c u n t h ~ . ~ ~ ~ The excretion from fronds of Costa Rican Notholuenu ufinis contained four flavones not previously found in Nature; they have the fully substituted benzopyran system (127; R', RZ = OH or OMe).lgl Several novel flavonoids have been identified in the petroleum extract of an African bush, Popowia caulflora; for example, 5-hydroxy-6,7-dime thoxyflavone and 5,7,8-trimet hoxyflavanone . 92 Flavonolignans obtained from the seeds of Hydnocarpus wightiunu have been studied, using 13Cn.m.r. ~ p e ~ t r ~ ~and ~ the ~ papplication y , ' ~ ~ of this technique to several complex natural flavones (e.g. mulberrin and mulberrochromene) has resulted in the revision of their structures.194 Tissue cultures of Androgruphispuniculutu which had been serially cultured for seven months produced three new flavones (128a)-(128c) which are not normally present in this specie~.'~'Flavonyl- 0-glycosides have been found in several The less common flavonyl C-glycosides have been identified in the bark of Almeidu guyunensis2" and in the seeds of Zizyphus 183

L. M. Meshcheryakova, E. K. Orlova, Z. P. Senova, 0. A. Mochalova, N. P. Speranskaya, Y. V. Burov, and V. A. Zagorevskii, Khim.-Farm. Zh., 1978, 12, 50. T. Nomura, T. Fukai, and M. Katayanagi, Chem. Pharm. Bull., 1978,26, 1453. T. Okutama, K. Hosoyama, Y. Hiraga, G. Kurono, and T. Takemoto, Chem. Pharm. Bufl.,1978,26, 3071. M. L. Bouillant, P. Redolfi, A. Cantisant, and J. Chopin, Phytochemistry, 1978, 17, 2138. M. D. Whalen and T. J. Mabry, Phytochemistry, 1979,18, 263. 188 R. Vleggaar, G. J. Kruger, T. M. Smalberger, and A. J. van den Berg, Tefrahedron, 1978,34,1405. lS9 M. Jay, A.Hasan, B. Voirin, J. Fabre-Bonvin, and M. R. Viricel, Phytochemistry, 1978, 17, 1196. F. Tomas, F. Ferreres, and A. Guirado, Phytochemistry, 1979, 18, 185. 191 M. Jay, E. Wollenweber, and J. Favre-Bonvin, Phytochemistry, 1979,18, 153. 192 K. Panichpol and P. G. Waterman, Phytochemistry, 1978,17, 1363. 193 M. R.Parthasarathy, K. R. Ranganathan, and D. K. Sharma, Phytochemistty, 1979, 18, 506. 194 V. M.Chari, S. Ahmed, and B. G. Oesterdahl, Z. Nafurforsch., Teil B, 1978, 33, 1547. 195 M. A. F. Jalal, K. H. Overton, and D. S . Rycroft, Phytochemistry, 1979,18, 149. '91 K. R.Markham, H. D. Zinsmeister, and R. Mues, Phytochemistry, 1978,17, 1601. 197 J. D. Bacon, L. E. Urbatsch, L. H. Bragg, T. J. Mabry, P. Newman, and D. W. Jackson, Phytochemistry, 1978,17,1939. 198 M.W.Bierner, Phytochemistry, 1979,18,358. 199 C. N. Lin, M. Arisawa, M. Shimizu, and N. Morita, Chem. Pharm. Bull., 1978,26,2036. 200 P.K. Jauhari, S. C. Charma, J. S. Tandon, and M. M. Dhar, Phytochemistry, 1979, IS, 359. 20 1 M. Jay, J. Glaye, M.L.Bouillant, E. Stanislav, and C. Moretti, Phytochemistry, 1979, 18, 184.

355

Six-membered Rings: Other Systems

CH2CH=CMe2 0

(122) R' = allosyl, R2 = H, R3 = OH (123) R' = H, R2R3= OCH20

(126)

M

e

o

(124) R' = OMe, R2 = R4 =Me, R3= H, R5 = O H (125) R ' = R 2 = R 4 = R 5 = H , R 3 = M e

0

w

0 (128a) R = OMe (128b) R = O H (128c) R = H

(129a) R' = R2= H, R3 = OMe

(129b) R'

a

p

= (CH2)2Pr1,R2 =Me,

R3 = H

h

NNMeSO,C,H,-4-Me (130)

vulgaris var. spinosus.202Spinosin, from the latter, has a mild sedative action. The fruits of poison ivy (Toxicodendron radicans) contain the biflavone amentoflavone and the biflavanone 3',8"-binaringenin,the latter being previously unknown in W. S . Woo, S. S. Kang, S. H. Shim, H. Wagner, V. M. Chari, 0. Seligmann, and G. Obermeier, Phytochemistry, 1979,18,353. *03 M. A. El Sohly, J. C. Craig, C. W. Waller, and C. E. Turner, Phytochemistry, 1978,17,2140. 'O'

356

Heterocyclic Chemistry

Amongst flavones previously known, several have been synthesized; for example, tabularin ( 129a)204 and tetrahydrokuwanon tetramethyl ether ( 129b).205It is possible to differentiate several hydroxy-polymethoxy-flavones by the relative abundances of their M' and [M - 151' ions in their mass spectra.206 Some interesting reactions of flavones have been described; for example, 3-flavonols and their methyl ethers are reduced with sodium in liquid ammonia to CY -hydroxyor CY -methoxy-dihydrochalcones as the main Demethylation of poly(methoxy)flavones with AlCl,-MeCN has been shown to be selective.208The halogen of 3-chloroflavone may be replaced by secondary amines on heating in a sealed tube.209The sites of Mannich reactions in hydroxyflavones have been determined: 5-hydroxyflavone gives the 6 - and 8-Me2NCH2and the 6,8-(Me,NCH,),-derivatives, and 7-hydroxyflavone yields only the 8-Me,NCH,-deri~ative.~~~ The conversion of 4-thionoflavone into its Nmethyltosylhydrazone is catalysed by Ag' and Hg2+salts, so that a high yield was obtained of (130) in the presence of silver nitrate.211In the synthesis of tabularin ( 129a),'04 the simultaneous removal of the 7-0-benzyl and 5- 0-methyl grohps was achieved with BCl, in CH2C12at 0 "C.

1soflavones.-Deoxybenzoins react with dimethylformamide dimethyl acetal in the presence of BF,-Et20 to give good yields of isoflavones;212for example, biochanin A (131) is obtained in 61% yield. Salicylaldehydes are converted into isoflavylium perchlorate by condensation with the dimethyl acetal of phenylacetaldehyde in perchloric Several natural isoflavones have been synthesized to confirm their structures; for example, neobavaisoflavone (132a)214 and luteone (132b).215The 13Cn.m.r. spectra of a number of isoflavones have been published, and some of the chemical shifts are relatively insensitive to alterations in substituents.2'h Further examples of cleavage of the pyrone ring of isoflavones by hydroxylamineZ1' and hydrazines2I8 have been reported. Kinetic measurements show that methoxy or 2-alkyl substituents increase but that CF, decreases the stability of the ring towards aqueous alkali.219

'04

205

206 207 *08

'lo

'I'

2'2

*I3 214

*I5 216

'I7

218 219

S.Ahmad, H.Wagner, and S. Razaq, Tetrahedron, 1978, 34, 1593. T. Nomura, Y. Sawaura, T. Fukai, S. Yamada, and S. Tamura, Heterocycles, 1978,9, 1355. M. Goudard, J. Favre-Bonvin, J. Strelisky, M. Nogradi, and J. Chopin, Phytochemisny, 1979, 18, 186. J. G. Sweeney, T. Radford, and G. A. Iacobucci, J. Org. Chem., 1979, 44, 1494. T. Horie, Nippon Kagaku Kaishi, 1978, 748. M. K. Rastogi, R. P. Kapoor, and C. P. Garg, Indian J. Chem., Sect. B,1978,16, 245. N. A. Tyukavkina, G. A. Kalabin, V. V. Kononova, and D. F. Kushnarev, Khim. Geterotsikl. Soedin., 1978,609. S . Cacchi, F. La Torre, and D. Misiti, Chem. Znd. (London), 1978, 669. A. Pelter, R. S. Ward, and D. H. J. Ashdown, Synthesis, 1978, 843. J. B. Ilotse, C. Deschamps-Vallet, and D. Molho, Bull. Mus. Nut. Hist. Nar. Phys. Chim., 1977,17, 97.

M. Nakayama, S. Eguchi, S. Hayashi, M. Tsukayama, T. Horie, T. Yamada, and M. MaSumura, Bull. Chem. SOC.Jpn., 1978,51, 2398. A. C. Jain, A. Kumar, and R. C. Gupta, J. Chem. SOC.,Perkin Trans. I , 1979, 279. A. Pelter, K.S. Ward, and R. J. Bass, J. Chem. SOC.,Perkin Trans. 1, 1978,666. V. Szabo, J. Borda, and L. Losonczi, Acta Chim. Acad. Sci. Hung., 1978,97, 69. V. Szabo, J. Borda, and V. Vegh, Acta Chim. Acad. Sci. Hung., 1978,98,457. V. Szabo and M. Zsuga, Acta Chim. Acad. Sci. Hung., 1978,97,451.

Six-membered Rings : Other Systems

357

(132a) R1 = R2= H, R3 = CH2CH=CMe2 (132b) R' = OH, R2 = CH2CH=CMe2, R3 = H

Using I4C-labelledisoflavones (whose synthesis is described), it was shown in feeding experiments on red clover and other plants that these compounds are good precursors of the pterocarpan maackiain (133).220The presence of isoflavones such as calycosin (134) and pseudobaptigenin (135) in pasture legumes has been reported,221and this observation supports the theory of the origin of pterocarpans. An isoflavone (7-methoxy-2-methylisoflavone)that is present in Glycyrrhiza glabra has been synthesized from an Q -methyl-chafcone and thallium(II1)nitrate by a method which is biogenetically significant.222 A high yield of a C-glycosyl-isoflavone,7,4'-di- 0-methylpuerarin (137), was obtained when an acetylated C-glycosyl-chalcone (136) was treated with thallium(II1) nitrate in triethyl orthoformate and Retusin (7,8-dihydroxy-4'-

(133)

(134)R' =Me, R2 = H (135) R'R2 = CH2

I\ 0

0 (136)

R' = Ac4-1 - C-glucosyl 'O

(137)

R2= 1-C-glucosyl

P. M. Dewick and D. Ward, Phytochemistry, 1978,17,1751.

'"D.R.Biggs and G. A. Lane, Phytochemistry, 1978,17,1683.

''' A.C.Jain, R. Khazanchi, and R. C. Gupta, Bioorg. Chem., 1978,7,493.

223

R.A.Eade, F. J. McDonald, and H. P. Pham, Aust. J. Chem., 1978,31,2699.

358

Heterocyclic Chemistry

m e t h o x y i s ~ f l a v o n eand ) ~ ~its ~ 8-methyl ether occur in the heartwood of Dalbergiu and iriskumaonin (5,4’-dimethoxy-3’-hydroxy-6,7-methylretusa, enedioxyisoflavone) is present as its glycoside in Iris k ~ m a o n e n s i s . ~ ~ ~ Dihydrocoumarins.-A new dihydrocoumarin, dihydromammea (138), as well as four coumarins are present in the seeds of the African evergreen tree Mummea ufricanu.226Configurational and conformational changes which occur when 3,4-diaryl-3,4-dihydrocoumarinsare heated have been followed by n.m.r. spectros~opyA . ~ new, ~ ~ instantaneous, and attractive synthesis of bz-di- and trimethoxy-dihydrocoumarins (139) from 3-arylpropanoic acids, thallium(II1)

How COCHMeEt

\

O7138) Bu

r

+

R

R (139a)

(139)

trifluoroacetate, and BF,.Et,O points the way to higher productivity for synthetic organic chemists.228aThe spirodienone (139a) is a likely intermediate. 3-Aryl3,4-dihydro-isocoumarins undergo cleavage of the pyrone ring when irradiated in methanol to give the cis-stilbene-2-carboxylic acid.228b Coumarins.-Self-condensation of diethyl acetonedicarboxylate (140) in the presence of sodium ethoxide gave a good yield of the two isomeric coumarins (14 1) and ( 142).229A new four-stage synthesis of 6-allylumbelliferone230uses resorcinol, acrylonitrile, and ZnC1,.

(141) 224

.225 226 227

”* 229

(142)

M. Gregson, W. D. Ollis, B. T. Redman, I. 0. Sutherland, H. H. Dietrichs, and 0. R. Gottlieb, Phytochemistry, 1978,17, 1395. A. K. Kalla, M. K. Bhan, and K. L. Dhar, Phytochemistry, 1978, 17, 1441. E. G. Crichton and P. G. Waterman, Phytochemistry, 1978,17, 1783. M. Prashad, R. Prasad, M. Seth, P. Kole, S. Ray, and A. P. Bhaduri, Indian J. Chem., Sect. B, 1978, 16, 819. ( a )E. C . Taylor, J. G. Andrade, G. J. H. Rall, and A. McKillop, J. Org. Chem., 1978,43,3632; ( b ) M. Yamato, K. Sato, A. Tanoguchi, A. Miyaki, and T. Koyama, Chem. Pharm. Bull., 1978,26,1990. M . Yamato, J. Uenishi, and K. Hashigaki, Chem. Pharm. Bull., 1978, 26, 1459, 1973. A. Ray, A. D. Gupta, and K. Sen, IndianJ. Chem., Sect. B,1978, 16,929.

Six-membered Rings: Other Systems

359

The spiro-compound (144)[prepared from diketen (143)and urethane] reacts with resorcinol or phloroglucinol to give the coumarin (145)231 in 60% (R = H) or 83% (R = OH)yield. The spirothiazolidine (146)is hydrolysed by boiling aqueous ethanol, the yields of the coumarins varying considerably according to the alkyl group R2;when R2 is a bulky group such as But, the yield of coumarin is 68%. Dehydrochlorination of the hexahydrocoumarins (147)with collidine, triethylamine, or 1,5-diazabicycl0[3.4.0]non-5-ene gave good yields of the tetrahydrocoumarins ( 148),232 which are not otherwise easily obtained. Similar compounds have been synthesized in six steps from 2-methylcyclohexanone and diethyl o ~ a l a t e . ~ ~ ~ C02Et "'CQ

.--*

---*

0 (143)

0 ( 144)

H

o \

R

r

n

/

(CH&CO2Et (145)

(147)NR2

The conversion of 2-benzyloxy-4-methoxy-6-methylbenzoylacetoneinto (149)and (150)with HBr and Ac20 has been Several isomeric benzofurans carrying benzoyl and hydroxy groups placed ortho to one another have been cyclized with Ac20 to 4-phenylcoumarins by a modification of the Kostanecki-Robinson reaction (which often leads to c h r o m o n e ~ ~in~which ~) 1,8-diazabicyclo[5.4.0]undec-7-enereplaced sodium acetate (the phenol acetate was produced by this base).236Pyronanthrone (151)has been synthesized and 7-(Aryloxyalkyloxy)-4-hydroxy-3some of its properties have been n i t r o c ~ u m a r i n sand ~ ~ coumarin-3 ~ -thiocarb~xamides*~~ have been synthesized. 231 232 233 234

235 236

237 238

239

T. Kato, N. Katagiri, and R. Sato, J. Chem. Soc., Perkin Trans. 1, 1979, 525. M. Maguet and R. Guglielmetti, J. Heterocycl. Chem., 1978,15, 1439. G. I. Feutrill and R. N. Mirrington, J. Heterocycl. Chem., 1978, 15, 693. V. K. Ahluwalia, D. Kumar, and M. C. Gupta, Indian J. Chem., Sect. B, 1978, 16, 292. Ref. 139, p. 515. Y. Kawase, S. Yamaguchi, K. Aoyama, and M. Matsuda, Bull. Chem. SOC.Jpn., 1978,51, 1907. M. V. Gorelik, M. V. Kazankov, and M. I. Bernadskii, Zh. Org. Khim., 1978, 14, 1535. D. R. Buckle, D. J. Outred, J. W. Ross, H. Smith, R. J. Smith, B. A. Spicer, and B . C. Gasson, J. Med. Chem., 1979,22, 158. J. S. A. Brunskill, A. De, 2.Elagbar, H. Jeffrey, and D. F. Ewing, Synth. Commun., 1978,8, 533.

360

Heterocyclic Chemistry

The natural coumarins avicennol (152) and dipetaline (153) have been synthesized and their structures thus Natural quassinoids have antineoplastic activity, and recent work shows that certain features of the complex molecule holacanthone (154), such as the epoxymethano bridge, are essential for Among the numerous coumarins which have been identified in plants ~~~ (156) from are isofraxetin (155) from Fraxinus m a n d c h ~ r i c a ,umckalin Pelurgonium r e i n f ~ r m e kuhlmannin ,~~~ (157) from trunkwood of Machaerium kuhlmannii and M. n i ~ t i t a n sindicolactonediol(l58) ,~~~ from Cluusena i n d i ~ a , ~ ~ ~ and sesebrin (159), sesebrinol (160), and sibiricol (161) from the Indian herb Seseli s i b i ~ i c u mA. ~new ~ ~ metabolite of warfarin (162) has been shown to be the cis- or trans-form of the 9,lO-dehydro-derivative ( 163).246

Mem& 0

\

OM^

/ Me

\

(149)R = PhCH2 (150) R = H

\

0

(151)

0 0&Me

R

(152) R = trans-CH=CHCMe,OH (153) R = CH,CH=CMe,

(154)

H O CH C Me (0H)CH

I

~

3

CH2

0

R2

R'

(If;;) &' = R'= R'= R5 = H, R4= Me (156) R ' = R 4 = R 5 = H , R2=OMe, R 3 = M e (157) R'=Ph, R 2 = R 3 = H , R 4 = R 5 = M e 240 241

242 243 244

245 246

R. D. H. Murray and I. T. Forbes, Tetrahedron, 1978,34, 1411. M. E. Wall and M. C. Wani, J. Med. Chem., 1978,21, 1186. A. K. Ahluwalia, C. Prakash, and M. C. Gupta, Indian J. Chem., Sect. B, 1978, 16, 286. W. D. Ollis, B. T. Redman, R. J. Roberts, I. 0. Sutherland, 0.R. Gottlieb, and M. T. Magalhaes, Phytochernistry, 1978,17, 1383. D. Prakash, K. Raj, R. S. Kapil, and S. P. Popli, Phytochemistry, 1978, 17, 1194. R. Kumar, B. D. Gupta, S. K. Banerjee, and C. K. Atal, Phytochemistry, 1978, 17, 2111. M. J. Fasco, P. P. Dymerski, J. D . Wos, and L. S. Kaminsky, J. Med. Chem., 1978, 21, 1054.

Six-membered Rings : Other Systems

36 1

(159) R' = CH2CH=CMe2, R2 = Ch-kMe, (160) R' = CH2CH=CMe2, R2= CHCHOHMe,

I

(161) R' = H, R2= CH=CMe2

a*

OH

OH

HC

2

(162) R = CHPhCH,Ac (163) R = CPh=CHAc

Several interesting reactions of coumarins have been described recently. For example, aryl radicals react with coumarin to form 3-arylcoumarins. Calculations of the free-radical reactivity index for coumarin by HMO and SCF-MO treatments give different conclusions; the HMO shows C-4 to be the most reactive but the SCF-MO correctly predicts C-3 to be the site of When 4-hydroxycoumarin is boiled with benzoyl peroxide (1mol) in CHC13, 4-hydroxy3-phenylcoumarin is obtained, blzt 6-hydroxy-4-methylcoumarin gives the ethylene derivative ( 164).248Other reactions of 4-hydroxycoumarin include its ring cleavage by butylamine and the simultaneous formation of 4-(substituted amino)-coumarins on reaction with benzylamine and some other a m i n e ~ ; ~ ~ ' reductive detosylation of 4-(tosy1oxy)-coumarins with Zn and HCl removes the OH Similar removal of hydroxy-groups (uia their tosylates) has been achieved by reduction with Raney nickel.251 Photocycloaddition of 5,7-dimethoxycoumarin and 2,3-dimethylbut-2-ene gave a 1: 1 C, c y c l o - a d d ~ c t An . ~ ~intramolecular ~ cycloaddition of a coumarin ester (165) to form a naphthoic acid lactone (166) is by heating in a

(165) 247 248

249

250

251 252 253

G. Vernin, S. &en, and J. Metzger, J. Heterocycl. Chem., 1979,16,97. Y . S. Chanhan and K. B. L. Mathur, Indian J. Chem., Sect. B, 1978.16.292. 0. H. Hishmat, A. K. M. Gohar, M. E. Wassef, M. R. Shalash, and I. Ismail, Pharm. Acta Helv., 1977,52, 252. V. K. Ahluwalia, C. Prakash, and R. P. Singh, Indian J. Chem., Sect. B, 1978, 16, 587; V. K. Ahluwalia, R. Gupta, and N. Rani, Nut. Acad. Sci. India, Letters, 1978, 1,369. V. Narayanan, S. Neelakantan, N. Padmanaban, and P. V. Raman, Cum. Sci., 1979,48, 108. S. C. Shim and D. Y. Chi, Chem. Lett., 1978,1229. G. A. Kraus, J. 0. Pezzanite, and H. Sugimoto, TetrahedronLett., 1978,853.

Heterocyclic Chemistry

362

sealed tube, and gives yields of 47-61%. Esters (167) of coumarin-3-carboxylic acid, on treatment with an anhydride and a base, are rearranged to the coumarin4-acetates ( 168).254Alkali causes ring contraction of the fully substituted coumarin (169) to the benzofuran-2-carboxylic acid ( 170).255Prenylation of coumarins followed by cyclization with dimethylaniline gives p y r a n o c o ~ m a r i n s . ~ ~ ~

+ (Et@O),O

-P

\

(167)

Me (168)

H

O

m Br

Ac \

OH

-

CH2C02R

HO&cooH Ac \

Me

OH

Me

1socoumarins.-The reaction of 2-(aroylmethy1)-benzonitriles (17 1) with HBr gave a high yield of l-amino-3-aryl-2-benzopyryliumbromide (172), which was hydrolysed with water to the isocoumarin ( 173).257 'NH

,CAr (171)

0

Fusamarin (174), the (+)-dihydro-derivative of a metabolite of a Fusarium species, has been synthesized,258and so has 9-deoxykalafungin (175).259Several 254 255

256

257 258

259

K. Ivanova and A. Bozhilova, Chem. Ber., 1978,111,5755. T. Zawadowski and J. Kossakowski, Pol. J. Chem., 1978,52, 377. V. K. Ahluwalia, C. Prakash, and R. P. Singh, Indian J. Chem., Sect. B, 1978,16, 1033. C. K. Bradsher and T. G. Wallis, J. Org. Chem., 1978,43,3817. S. M. Afzai, R. Pike, N. H. Rama, I. R. Smith, E. S. Turner, and W. B. Whalley, J. Chem. SOC.,Perkin Trans. 1, 1978, 81. G. A . Kraus and B. Roth, J. Org. Chem., 1978,43,4923.

Six-membered Rings: Other Systems

363

isocoumarins of phytochemical interest have been synthesized from homophthalic anhydride.260*261 Three new derivatives (176)-(178) of 8-hydroxy-6methoxyisocoumarin have been isolated from the fermentation of an unidentified fungus,262and the structure of griseorhodin C (179) has been demonstrated by n.m.r. and its chemical

HO

Bu (174)

(175)

Me

(176) R = (CH0H)zCHzCI (177) R = CH2CH(OH)COMe (178) R = CH=CHCQ2H

Thiocoumarins.-There are few general methods of synthesis for this class of compounds, and so the conversion of 2-(t-butylthio)-benzaldehyde(180) into a 1-thiocoumarin is very welcome. The aldehyde is prepared in 96% yield from 2-nitrobenzaldehyde7 t-butylthiol, DMF, and KzCO3, and it reacts with an active-methylene compound to give the styrene, which is cyclized by polyphosphoric acid (PPA) in high yield; for example, to 1-thiocoumarin-3-nitrile (18 1).264

Me (182j (183)

Xantbenes.-Benzoxanthenes (182) related to those obtained from redwoods have been synthesized from isoflavylium perchlorate and 1,3-diaryIpropenes.'61 2MI 261 262

263 264

D. R. Nadkarni and R. N. Usgaonkar, Indian J. Chem., Sect. B, 1978,16,320. B. N. Sarkhel and J. N. Snvastava, J. Indian G e m . SOC.,1 9 7 7 , 5 4 9 2 5 . G. A. Ellstead, F. M. Lovell, N. A. Perkinson, R. T. Hargreaves,and W. J. McGahren, J. Org. Chem., 1978,43,233. K. Eckardt, D. Tresselt, and W. Ihn, J. Anfibiot., 1978, 31,970. 0. Meth-Cohn and B. Tarnowski, Synthesis, 1978,56.

364

Heterocyclic Chemistry

Amongst several quinonoid compounds isolated from a sponge (Stelospongia conulutu) were the xanthene dehydrocyclospongiaquin-1-one (183) and its dihydro-deri~ative.’~~ Irradiation of the sulphone (184) (prepared from dimedone aldehyde and SCl’, followed by oxidation) in benzene gave a high yield of the octahydroxanthenedione (185)?

Me

a /

\

0

.. (190a)

WMe /

Ar

(189)

(188)

\

R (186) i = C N (187) R = A r

/

(1 92)

Thioxanthenes.-The first crystalline 1,4-ylide, a thioxanthen (186), has been described, and converted into the thioxanthone (188) in high yield.267The 9-aryl ylide (187) rearranges to the thioxanthene (189).268Other reactions have been described.269Photolysis of 9-diazothioxanthene (190) in THF generates thioxanthylidene (190a), as shown by the photolysis in the presence of cyclohexene to 265

266 267 268 269

R. Kazlauskas, P. T. Murphy, R. G. Warren, R. J. Walls, and J. F. Blount, Ausr. I. Chem., 1978,31, 2685. S . Ito and J. Mori, Bull. Chem. Soc. Jpn., 1978, 51, 3403. M. Hori, T. Kataoka, H. Shimizu, S. Ohno, and K. Narita, Tetruhedron Lett., 1978, 251. M. Hori, T. Kataoka, H. Shimizu, and S. Ohno, Tetrahedron Lett., 1978,255. M. Hori, T. Kataoka, H. Shimizu, and S. Ohno, Heterocycles, 1977,7,863.

365

Six-membered Rings: Other Systems

give compound (192); three compounds were formed, the major product being dithioxanthenylene (19l),derived from the reaction of the diazo-compound and (190a).Z70 NS02C,H,-4-Me I

(193) CH2'I

R (194)

When 2-chlorodibenzo[ b,f]thiepin was acylated under Friedel-Crafts reaction conditions, simultaneous addition of HCl and ring contraction gave the thioxanthene (193), which was subjected to further The synthesis, stereochemistry, and rearrangement of the N- tosylsulphilimines (194) of 9alkyl-xanthenes have been Fluorine-containing analogues of the tranquillizer chlorprothixin have been synthesized but were less active than the parent.273 Xanthones.-A one-step synthesis of xanthones is achieved, in good yields, by heating ethyl 2-hydroxybenzoates with phenols, for example 5-methylresorcinol (195).274 Some xanthone derivatives are known to have promising pharmacological activity, and many more xanthone-2-carboxylic acids have been synthesized, for this r e a ~ o n . ~ ~ ' - * ~ ~

+

Mef-J-JrJ OH

/

0

The 13C n.m.r. spectra of 36 natural anth hones'^^ and of mono- and polymethoxy-~anthones~'~ have been obtained. Dynamic n.m.r. spectroscopy has 270

*"

272

273

274 275 276

277 278

279

T. B. Patrick, M. A. Dorton, and J. G. Dolan, J. Org. Chem., 1978, 43, 3303. K. Sindeler, J. 0.Jilek, J. Pomykacek, Z. Sedivy, and M. Protiva, Collect. Czech. Chem. Commun., 1978,43,471. Y.Tamura, Y.Nishikawa, C. Mukai, K. Sumoto, M. Ikeda, and M. Kise, J. Org. Chem., 1979,44, 1684. M. Protiva, I. Cervena, M. Rajsner, J. Metysova, and M. Hrubantaova, Collect. Czech. Chem. Commun., 1978,43,2656. R. J. Patolia and K. N. Trivedi, Chem. Ind. (London), 1978, 235. J. A. Bristol, R. Alekel, J. Y.Fukunaga, and M. Steinman, J. Med. Chem., 1978, 21, 1327. J. R. Pfister, R. W. Ferraresi, I. T. Harrison, W. H. Rooks, and J. A. Fried, J. Med. Chem., 1978,21, 669. R. Graham and J. R. Lewis, J. Chem. Soc., Perkin Trans. 1, 1978, 876. P. W. Westerman, S. P. Gunasekera, M. Uvais, S. Sultanbawa, and R. Kazlauskas, Org. Magn. Reson., 1977,9, 631. R. K. Chaudhuri, F. Zymalkowski, and A. W. Frahm, Tetrahedron, 1978,34, 1837.

Heterocyclic Chemistry

366

been used to study the geometrical isomerism and conformation of 9,9'-dixanthylenes .280 Many natural xanthones have been studied; for example, the structure of secalonic acid G (196) (from Pyrenochaeta terrestris) has been determined;28' athyriol (3-methoxy- 1,6,7-trihydroxyxanthone) has been synthesized by condensation of 2,4,5-trihydroxybenzoic acid and phloroglucinol dimethyl ether and subsequent selective 1-demethylation;282revised structures have been proposed for several xanthones present in lichens.283A new xanthone isolated from Lawsonia inermis has been shown to be 6-acetoxy-3,7-dimethoxy-l -hyd r o ~ y x a n t h o n e The . ~ ~ ~aerial parts of Gentiana germanica and G. ramosa contain xanthones with oxygen functions at positions l y3,5, and 8 or at 1 , 3 , 4 , 5 , . ~ ~ ~ 1,3,7,8-0xygenated and 8; some of the compounds are O - g l u c ~ s i d e sFifteen

M e 0 , C OH

OH

xanthones have been isolated from the leaves of G. ciliata L.286A plant used medicinally in India, Hoppea dichotoma, has been shown to contain a large number of O-heterocycles, including eleven xanthones, three of which are new glucosylxanthones containing four other oxygen A reduced xanthone, diversonol (197), has been isolated from Penicillium lapidosum. 136 The chemical reactions of bikaverin (198) have been studied; for example, ozonolysis of the monomethyl ether (199) gives the lactone (200).288 Iodination of various hydroxyxanthones with iodine and HIO, or with iodine and NH,OH gave mono- or di-iodo-derivatives, and their methyl ethers underwent Rosenmund-von Braun conversion into nit rile^.'^^ Selective demethylation of poly-

Me0 \

/

OR2 (198) R' = M e , R2= H (199) R' = R2= Me 281

282

283 284 285

287 288 289

a

OR'

Me0 \

'

Me0 (200)

HO

C0,Me

I. Agranat and Y. Tapuhi, J. Am. Chem. SOC.,1979,101,665. I. Kurobane, L. C. Vining, and A . G. McInnes, Tetrahedron Letr., 1978,4633. D. K. Bhardwaj, S. C. Jain, and R. Singh, Indian J. Chem., Sect. B,1978, 16, 150. E. G. Sundholm, Tetrahedron, 1978,34,577. D. K. Bhardwaj, R. K. Jain, B. C. Jain, and C. K. Mehta, Tetrahedron, 1978, 34, 1837. M. Hostettmann-Kaldas and A . Jacot-Guillarmod, Phytochemistry, 1978, 17, 2083. M. Goetz, F. Maniliho, and A. Jacot-Guillarmod, Helu. Chirn. Acra, 1978,61, 1549. S. Ghosal, D. K. Jaiswal, and K. Biswas, Phytochemistry, 1978, 17, 2119. T. Kato, M. Sato, N. Katagiri, T, Awaji, and J. Nakano, Chem. Pharm. Bull., 1978, 26, 209. Y . G. Gackwad and S. Sethna, J. Indian Chem. SOC.,1978,55, 794.

Six-membered Rings : Other Systems

367

(methoxy)-xanthones, using aqueous piperidine, has been described and dis3 Systems containing Two or More Oxygen or Sulphur Atoms

Oxathians and their Benzo-derivatives.-Mono- and bi-cyclic 1,2-0xathiin 2,2dioxides (201) have been synthesized from enamino-ketones and a sulphene PhC=O HC,I

FH

+

MeS0,Cl

+

I

--*

phooz \

Et,N

NR2

NR* (201)

(from methanesulphonyl chloride and Et,N).29' The synthesis of 1,2-oxathiin 2,2-dioxides (202) from isoprene and SO, in DMF has been described (Scheme 20), occurring with overall yield of about 8% .292

ooz

x

i, ii

---+

---*

17%

91%

Me

Br Qo2 Br Me

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

Scheme 20

The mass spectra of 2-mono-, 2,3-di-, and a 2,2,3-tri-substituted 1,4-benzoxathians (203) have a characteristic ion (204), of m / z 137.293In an almost

(203)

-

(204)

complete asymmetric synthesis (see Scheme 21) of 0-methyl (+)-(S)-atrolactic acid (206) from (-)-4,6,4'-trimethyl- 1,3-oxathian (205), the key step is the electrophilic attack on a 2-lithio salt, which leads exclusively to an equatorial

Me MeEoTrh el -%

Me

Me

PhCHMeC02H I

OMe

(205) Reagents: i, BuLi, PhCHO; ii, several steps

Scheme 21 290

29' 292 293

R. K. Chaudhuri, F. Zymalkowski, and S. Ghosal, J. Pharm. Sci., 1978, 67, 1321. F. Evangelisti, P. Schenone, and A. Bargagna, J. Heterocycl. Chem., 1979,16, 217. T. Akiyama, M. Sugihara, T. Imagawa, and M.Kawanisi, Bull. Chem. Soc. Jpn., 1978, 51, 1251. J. F. Caputo and H. R. Martin, J. Heterocycl. Chem., 1978, 15, 1403.

Heterocyclic Chemistry

368

Conflicting reports on the sites of disubstitution by electrophiles in phenoxathiin (207) have been clarified. The major product is a 2,7-disubstituted compound (208), and a small amount of the 2,8-isomer (209) is also formed.295

(208) R' = H, R2 = Ac (209) R' = Ac, R2= H

Dioxans and Benzodioxans.-1 , l -Diarylethylenes are converted into 3,3,6,6tetra-aryl-l,2-dioxans (210) in high yields on irradiation. The peroxides are crystalline solids and are reduced to 1,4-diols by LiA1H4.296The Diels-Alder reaction of hexafluoroacetone with CH,=CHCOR under pressure gave the 4-R-2,2-bis(trifluoromethyl)- 1,3-dioxins in high yield.2971,4-Benzodioxins have been prepared from 1,4-benzodioxans by conversion into the 2,3-dibromide followed by treatment with NaI.298Anodic oxidation of ethylene acetals (21 1)in methanol provides a good route to 2-methoxy- 1 , 4 - d i 0 x a n s . ~Ethynyl ~~ aryl ketones react with salicylic acid and related compounds (212; X = 0 or S) to give

aXH + ArCC-CH

CO,H

I1

0

CH,CAr

II 0

-+

0

(2 12)

heterocycles containing two oxygen atoms or an oxygen and a sulphur atom.300In a short communication, the first characterization of a 4,5-benzo- 1,2-dioxan is described. The intermediate (2 14)was probably produced in a chemiluminescent thermal decomposition of the endoperoxide (213) in boiling benzene.30' It was trapped as shown in Scheme 22. 294 295

29h 297 298

299

E. L. Eliel, J. K. Koshimie, and B. Lohri, J. A m . Chem. SOC.,1978, 100, 1614. J. P. Coic and G. Saint-Ruf, J. Heterocycl. Chem., 1978, 15, 769. R. K. Haynes, M. K. S. Probert, and I. D. Wilmot, Aust. J. Chem., 1978,31, 1737. A. V. Fokin, A. F. Kolomiets, and A. A. Krolevets, Izv. Akad. Nauk. SSSR, Ser. Khim., 1978,976. G . Coudert, G. Guillaumet, and B. Loubinoux, Tetrahedron Le#.,1978, 1059. D. Lelandais, C. Bacquet, and J. Einhorn, J. Chem. SOC.,Chem. Commun., 1978, 194. V. K. Tripathi, P. S. Venkataramani, and G. Mehta, J. Chem. SOC.,Perkin Trans. 1, 1979, 36. J. P. Smith and G. B. Schuster, J. Am. Chem. Soc., 1978,100,2564.

Six-membered Rings: Other Systems

369

Reagent: i, maleic anhydride

Scheme 22

Further derivatives of the antibiotic spectinomycin (215; R = NMeC02CH2Ph)have been as also has a pentacyclic analogue (216) of the highly toxic dibenzodioxin (217a). The former was so insoluble that chemical modification and biological assessment were very difficult to effect.303a The pharmacological activity of the phenothiazines is well known, and a comparison of the bond angles of the parent with those of the isosteric dibenzodioxin (217b) and related compounds has led to a new antipsychotic agent.3o3b

cIfJo)-JoyJcI

RfJOyJe OH

c-1 \ OO

k0

0

0

/

c1

(2 16)

(215)

HC (217a) R=C1 (217b) R = H

\I

\.

CHCHO

OH

(218)

Americanin (2 18) has been found in Phytolacca americana, being extracted with The mass spectral fragmentation patterns of a number of 1,4-benzodioxans have been described,305and calorimetric studies on 2-alkylated 4,6-dimethyl-2-phenyl- 1,3-dioxans have been applied to the determination of their conformational equilibria.306A convenient method of protecting carbonyl groups by their conversion into the 1,3-dioxans is effected under mild conditions by passing the carbonyl compound and ethanediol through a column of Amberlyst 15.307 302

303

'04

305 '06

307

W. Rosenbrook, R. E. Carney, R. S. Egan, R. S. Stanaszek, M. Cirovic, T. Nishinaga, K. Mochida, and Y. Mori, J. Antibiot., 1978,31,451. ( a )J. E . Oliver and W. R. Lusby, J. Heterocycl. Chem., 1978,15,689; ( b )G.E. Martin, J. D. Korp, J. C . Turley, and I. Bernal, ibid., p. 721. W. S. Woo, S. S. Kang, H. Wagner, and V. M. Chari, Tetrahedron Lett., 1978,3239. J. F. Caputo and A. R. Martin, J. Heterocycl. Chem., 1978,15,777. W. F. Bailey, H. Connon, E. L. Eliel, and K. B. Wiberg, J. Am. Chem. Soc., 1978,100,2202. A.E. Dann, J. B. Davis, and M. J. Nagler, J. Chem. Soc., Perkin Trans. 1, 1979,158.

370

Heterocyclic Chemistry

Dithians and Related Compounds.-l,3-Dithian is protonated in FS0,H to give both mono- (85%) and di-protonated (15%)ions. The former is predominantly equatorial (2 19) whereas the latter is a mixture of isomers.3o8Photochemical breakdown of the reduced thiadiazole (220), with expulsion of N2,yields the reduced thianthrene (220a) as one of the 2-t-Butyl-5-hydroxy- and

-5-mercapto- 1,3-dithians have been synthesized, and their cis- and trans-isomers were separated by chromatography. The stereochemistry of their 0-and S methyl derivatives has a greater preference for an equatorial alignment of the 5-substituent than is predicted by calculation.3102,5-Diphenyl- 1,4-dithiin 1,ldioxide (22 1) underwent a cycloaddition-elimination with benzyne or dimethyl acetylenedicarboxylate to give 2-phenylthiophen or a thiophen derivative, respectively (Scheme 23).31

PPh + +

(22 1) (60%)

Reagents: i, CC0,Me; ii.

111

CC0,Me

Scheme 23

Systems consisting of Two or More Oxygen-containing Rings.-Cannabinoids. Several derivatives of tetrahydrocannabinol (THC) carrying different substituents at C-9 have been synthesized from 9-nor-9-oxohexahydrocannabinol.312 Two new cannabinols, (*)-9,lO- and (*)-8,9-dihydro~y-A~""~"'-THC, have been isolated from hexane extracts of Cannabis s a t i ~ al 3. ~Conversion of 3,4-cis- into 3,4-trans-cannabinoids is effected by treatment at low temperature with BBr,. Epimerization occurs at C-4 and/or C-3; for example, that of 3,4-cis- into 3,4- trans-hexahydrocannabinols proceeds only by epimerization at C-4.314 Several new cannabinoids have been detected in extracts of cannabis by gas chromatography-mass ~ p e c t r o m e t r y ,and ~ ' ~ others have been synthesized from 308

3"9 310 311

312 313 314 315

J. B. Lambert, E. Vulgaris, S . I. Featherrnan, and M. Majchrzak, J. A m . Chem. SOC.,1978, 100, 3269. U . Tirnrn, H. Buhl, and H. Meier, J. Heterocycf. Chem., 1978, 15, 697. E. L. Eliel and E. Juaristic, J. A m . Chem. Soc., 1978, 100, 61 14. K. Kobayashi and K. Mutai, Tetrahedron Lett., 1978,905. W. A. Skinner, G. Rackur, and E. Uyeno, J. Pharm. Sci., 1979,68, 330. M. A. El Sohly, E. G. Boeren, and C. E. Turner, Experienh'a, 1978,34, 1127. D. B. Uliss, G . R. Handrick, H. C. Dalzell, and R. K. Razdan, Tetrahedron, 1978,34, 1885. H. Grote and G. Spiteller, J. Chromatogr., 1978, 154, 13.

Six-membered Rings : Other Systems

371

the 1,3-dithian (222) and an Amongs the products of pyrolysis of cannabidiol was 2,2-dimethyl-5-hydroxy-7-pentylchromene,which was synthesized by two Cyclocondensation of 4-hydroxycoumarin or 4-hydroxythiocoumarin with citral or citronella1 gave several new tetra- or hexa-hydrocannabinoids, for example (223a) and (223b) . 3 l 8

Me

(223b)

(223a)

MeC=CH,

O

H

MeC=CH,

N(224) O

M OMe

e

H,C=CCH OH

h2

Rotenoids. (-)-Tuba-aldehyde, a key intermediate in the synthesis of (-)rotenone, has been synthesized by decarboxylation and Vilsmeier formylation of (-)-tubaic acid. The aldehyde was converted into (-)-rotenone in four Several rotenoids from Tephrosia villosa have been photolysed, and one A new compound, (224), gave an almost quantitative yield of a single 12a-hydroxyrotenoid named dalbinol (225) has been identified in the seeds of Indian rosewood, Dalbergia l a t i f ~ l i a . ~ ~ '

320

C . G. Pitt, H. H. Seltzman, Y. Sayed, C. E. Twine, and D. L. Williams, J. Org. Chem., 1979,44,677. J. M. Luteyn, H. J. W. Spronck, and C. A. Salemink, Recl. Trav. Chim. Pays-Bas, 1978,97, 187. S. Y. Dike and J. R. Merchant, Bull. Chem. Soc. Jpn., 1978,51,2145. I. Sasaki and K. Yamashita, Agnc. Biol. Chem., 1979, 43, 137. G. L. D. Krupadanam, G. Srimannarayana, and N. V. S. Rao, Indian J. Chem., Sect. B, 1978,16,

321

S. S. Chibber and U. Khera, Phytochernisfry, 1978, 17, 1442.

316 317 318

3'9

770.

372

Heterocyclic Chemistry

Other Natural Compounds. The deep purple'heartwood of Acacia peuce F.Muel1. contains the stereochemically rare 2,3-cis-3,4-cis-dipyran (226), which has also been obtained by epimerization of (*)-peltogynol (227).322Several coumarins were identified in the Mediterranean plant Cneorum fricoccum ; for example, bethancorin (228).323 Pyrano[2,3-h]flavanones were isolated from several leguminous plants.324Three new prenyl flavonoids have been discovered in the root bark of the cultivated mulberry tree, Moms alba, and two of them are morusin (229) and cyclomorusin (230) Photo-oxidation of (229) has been studied.'"

CMeC0,Me

0fJJy OH

0

CH,CH=CMe,

(230)

Pomiferin, auriculasin (from the fruit of the osaje orange tree), and related pyrano-[2,3-g]- and -[2,3-h]-isoflavones haire been ~ y n t h e s i z e d . Several ~'~~~~~ analogues of the yellow light-stable compound arthraxin (from the grass Arthraxon hispidus) have been synthesized by a double Allan-Robinson reaction on 2,4-diacetylphloroglucino1.327 The bark and wood of the creeper Dalbergia 322 323

324

325

E. V. Brandt and D. G. Roux, J. Chem. SOC.,Perkin Trans. 1, 1979, 777. A. G. Gonzalez, B. M. Fraga, M. G. Hernandez, 0.Pino, and A. G. Ravelo, Rev. Latinoam. Quim., 1978, 9, 205. F. Delle Monache, L. E. C. Suarez, and G. B. Marini-Bettolo, Phytochemisfry, 1978,17, 1812. T. Nomura, T. Fukai, S. Yamada, and M. Katayanagi, Chem. Pharm. Bull., 1978,26,( a ) 394; ( b ) 1431.

326 327

A. C. Jain, D. K. Tuli, and R. C. Gupta, J. Org. Chem., 1978, 43, 3446. M. Kaneta, H. Hikichi, S. Endo, and N. Sugiyama, Bull. Chem. SOC.Jpn., 1978, 51, 1784.

Six-membered Rings: Other Systems

373

; ~ ~example, ~ variabilis and of D. spruceana have yielded several f l a v o n o i d ~for (+)-medicarpin (23 1) and the methylenedioxy-analogue (232), which has been synthesized from 6 - h y d r o ~ y p i p e r o n a lThe .~~~ absolute configurations of some of the compounds have been determined, using ~ . r . d . ~Several ~' flavanoids from the wood of Machaerium species have also been Chemical and spectral evidence supports the pyranoisocoumarin structure and X-ray crystal analysis of the (233) for. the antibiotic griseorhodin A,333 antibiotic striatin A (produced by Cyathus striatus) shows its structure to be (234).334Pyrano[3,2-c]chromans related to a stimulant of seed germination335 have been and an extension of this work is an attractive route to 6,ll-dioxa-steroids such as (235).337

Me

Me0

(233)

328 329 330

331

332

333 334

335 336 337

K. Kurosawa, W. D. Ollis, I. 0.Sutherland, and 0. R. Gottlieb, Phytochemistry, 1978,17, 1417. J. T. Cook, W. D. Ollis, I. 0. Sutherland, and 0. R. Gottlieb, Phytochemistry, 1978,17, 1419. K. Kurosawa, W. D. Ollis, B. T. Redman, I. 0. Sutherland, H. M. Alves, and 0. R. Gottlieb, Phytochemistry, 1978,17, 1423. K. Kurosawa, W. D. Ollis, I. 0.Sutherland, 0. R. Gottlieb, and A. B. de Oliveira, Phytochemistry, 1978,17, 1405. K. Kurosawa, W. D. Ollis, B. T. Redman, 1. 0. Sutherland, and 0. R. Gottlieb, Phytochemistry, 1978,17,1413. D. Tresselt, K. Eckardt, and W. Ihn, Tetrahedron, 1978,34, 2693. H. J. Hecht, G. Hofle, W. Steglich, T. Anke, and F. Obenvinkler, J. Chem. Soc., Chem. Commun., 1978,665. M. Davis, M. Pettett, D. B. Scanlon, and V. Ferrito, Am?.J. Chem., 1977, 30, 2289. M. Davis, M. Pettett,*b.B. Scanlon, and V. Ferrito, Aus?. J. Chem., 1978,31, 1053. M . Davis and M.Pettett, Aust. J. Chem., 1979, 32, 369.

Heterocyclic Chemistry

374

Synthetic Compounds. Two new ring systems, containing two and three heterooxygen rings respectively, have been described. Alkylation of pyrrolidine enamines with 2,5-bis(dimethylaminomethyl)hydroquinone(236) followed by hydrolysis and cyclization gave 2,3 :7,8-bis(polymethylene)-4H,9H-benzo[ 1,2p :4,5-b’]dipyrans in good yield.338A new hexacyclic ring system (238) was formed, in high yield, by cyclization of the methylenebisbenzopyran (237) with acetic acid. Oxidation of the product (238) gave the tripyrone (239).339Several benzopyrano[4,3 - g][ 1Ibenzopyrans have been synthesized for pharmacological screening.34o

MeINCH2no 3 ‘ n

+

HO

\Nj

3steps

CH,NMe,

/

0

-3

(238) X=H, (239) X = O

R’

(237)

Systems containing Oxygen and Sulphur in Different Rings.-Cycloaddition of dichloroketen to 1-thiochromanones gives, on dehydrochlorination, the benzothiopyrano[4,3-b]pyran-2-ones (240). Yields are high when bulky groups are attached to the nitrogen atom.33 A similar reaction on the 1-thiopyran-4-one produces the thiopyrano[4,3-b]pyran-2-ones(241).33

a \

+ CI,C=CO

-3

CHNR,

9 NR*

0

c1

(240)

+ Cl,C=CO

0

- m: S

NR2

(24 1) 338

339

340

J. R. Mahajan and M. B. Monteiro, Bull. Chem. SOC.Jpn., 1978,51, 1207. M. Mazzei, G. Roma, and A. Ermili, J. Heterocycl. Chem., 1978, 15,605. J. P. Devlin, A. Bauen, G. J. Possanza, and P. B. Stewart, J. Med. Chem., 1978, 21,480.

375

Six-membered Rings: Other Systems 4 Systems containing Phosphorus as a Heteroatom

The synthesis and reactions of a phosphorus analogue (242) of 2-pyrone have been described.341 2-Phosphorus analogues (244) of coumarins have been synthesized342by cyclization of phosphates (243) with PPA or P2OS. PhO-P=O

R'C

II

(242)

R'(CHJ2OCH

OR2 (244)

CH $3

(245)

The pyramidal inversion at phosphorus in cis- and trans-4-t-butyl- l-phenylphosphorinans has been studied by means of 13C and 31P n.m.r. and X-ray analysis.343Nucleophilic substitution at phosphorus in compounds such as (245) gives a mixture of isomers in a ratio which depends on the degree of anion-cation association, the nature of the cation, and the solvent. The presence of 18-crown-6 ether had a marked effect.344Configurational equilibria of 1,3,2-dioxaphosphorinans have been determined by means of i.r. and Raman spectra.34s

5 Systems containing Silicon or Selenium as Heteroatoms An a b initio molecular orbital calculation, using Gaussian 70 and Force programs, has been made of silabenzene, which is suggested to be highly 1-Allyl-1-methyl- l-silacyclohexa-2,4-diene(247) has been synthesized from 1-chloro- 1-methyl- 1-silacyclohexadiene (246). Acetylene reacts with the ally1 compound (247) to give the adduct (249), probably via l-methyl-l-silacyclohexa-1,3,5-triene (248), as shown in Scheme 24.347Reduction of several cyclic silicon compounds with LiAlH, has been and the stereochemistry of the reaction is dependent on the ionic interaction between Li' and AlH,-. A new ring system, 9H-cyclopenta[b][ llbenzoselenin (25 l), was formed in 14% yield as one of the products of a photorearrangement of the selenol ester 341

342

343

344 345 346

347 348

I. Segal and L. h e w , J. Am. Chem. SOC.,1978,100,6394. K. A. Petrov, V. A. Chauzov, S. M. Kostrova, and N. Yu. Lebedeva, Zh. Obshch. Khim., 1978,48, 2667. G. D. Macdonnell, K. D. Berlin, J. R. Baker, S. E. Ealick, D. van der Helm, and K. L. Marsi, J. Am. Chem. Soc., 1978,100,4535. M. Bauman and W. S. Wadsworth, J. Am. Chem. SOC.,1978,100,6388. I. K. Shakirov and R. R. Shagidullin, Zh. Obshch. Khim., .1978, 48, 508. H. B. Schlegel, B. Coleman, and M. Jones, J. Am. Chem. Soc., 1978,100,6499. T. J. Barton and G. T. Burns, J. Am. Chem. Soc., 1978,100,5246. R. J. P. Corriu, J. M. Fernandez, and C. Guerin, Tetrahedron Lett., 1978, 3391.

He te roc y c 1ic Chemistry

376 Me

C1

Me

CH,CH=CH,

0q.J \

/

\ /

(246)

(247)

r

1. Me1

Reagents: i, CH,=CHCH,MgCI; ii, HCGCH

(250).349A 2,6-diphenyl-selenacyclohexenehas been synthesized in the same way as its sulphur analogue (52)." Selenium-75, incorporatedin 1 -selenaflavone, has been introduced into isolated leaves of Brussica oleruceu in a study of

insecticide^.^^^

349 350

K . Praefcke and D. Schmidt, J. Heterocycl. Chem., 1979, 16,47. A. Breccia, E. Gattavecchia, A. M. Di Petra, and G. Albonetti, J. Enuiron. Sci. Health, Part B, 1978, 13, 361.

5 Seven-membered Ring Systems BY D. J. LE COUNT

1 Introduction Any review of seven-membered heterocyclic systems is complicated by the extensive literature, mostly patent literature, on the pharmacologically interesting 1,4-benzodiazepinesand tricyclic antidepressants which has appeared during the period covered. To keep the chapter to the prescribed length and to achieve what is hopefully a reasonably balanced review, most of this work has had to be omitted. The arrangement of the sectionsfollowsthe conventionallines of structure (one N, one 0, two N’s, etc) rather than reaction type, except where close analogy of reaction makes the discussion more complete to combine, for example, azepine and diazepine systems. 2 Reviews

A review’ of the literature covering 1973-1977 on 2,3-dihydro-1,4-diazepines has appeared. The ‘Benzodiazepine Story’ has been published’ (twice, for those who missed it first time round) and an extensive review3 on benzodiazepines condensed with heterocyclic rings has also appeared.

3 Systems containing One Heteroatom One Nitrogen Atom.-Photolysis of derivatives of o-azidobenzoic acid4 in the presence of methanol gives entry into 3H-azepine derivatives. Thus (2) is prepared in 66% yield from (1).Thermal decomposition of toluene-p-sulphonyl azide in the presence of dimethyl terephthalate is reported5 to give the azepine (3)

‘ D. Lloyd and H. McNab, Heterocycles, 1978,11, 549. L. H. Sternbach, DnigRes., 1978,22, 229; L. H. Sternbach, J. Med. Chem., 1979, 22, 1. ’ A. Nawojski, Wiad. Chem., 1977, 31, 753. R.Purvis, R. K. Smalley, W. A. Strachan, and H. Suschitzky, J. Chem. SOC.,Perkin Trans. 1, 1978, 191. N. R. Ayyangar, M. V. Phatak, and B. D. Tilak, Indian J. Chem., Sect. B, 1978,16, 547.

377

378

Heterocyclic Chemistry

in low yield, and thermal cleavage6 of the azabicycloheptanones (4) yields the azatropolones (5), the chemical and spectral properties of which have been investigated. Analogous to the carbocyclic series, hydrolysis yields pyridine-2carboxylates. Further photo-valence-isomer studies' on the 2H-azepin-2-ones (6; R' = H or Me) have led to the isolation of (7; R' = R3 = H, R2 = Me) and ( 7 ; R ' = R2 = Me,R3 = H).

(4)

(5)

(6)

(7)

Vinyl-aziridines (8) react with acetylenic phosphonium bromides to give partially reduced azepinephosphonium bromides (9) and (10) via a hetero-Cope rearrangement.* The derivatives, under Wittig conditions, react in the normal manner (Scheme 1).

Reagents: i, HCGCCH,6Ph3 Br-; ii, R 4 C ~ C $ P h ,Br- (R4 = Me or Ph).

Scheme 1

1-Ethoxycarbonylazepine reacts with 2,5-dimethoxycarbonyl-3,4-diphenylcyclopenta-2,4-dien-l-oneto yield the e m [ 6 7 ~+ 47c]cyclo-adduct (11)and the anti-endo [ 4 +~2 ~ adduct 1 (12).9 Kinetic measurements have allowed the mechanism of this reaction to be elucidated. Whereas the e m [67~+ 47~1adduct T. Sano, Y. Horiguchi, and Y. Tsuda, Heterocycles, 1978,9, 731.

' J. W. Pavlik and C. A. Seymour, Tetrahedron Lett., 1977,2555.

' M. A, Calcagno and E. E. Schweizer, J. Org. Chem., 1978,43,4207. K. Harano, T. Ban, M. Yasuda, and K. K. Kanematsu, Tetrahedron Lett., 1979, 1599.

Seven-membered Ring Systems

379

(11) arises directly, the anti-endo [4n + 2 n ] adduct is formed via the rearrangement of the intermediate enda [ 4 +~2 n ] adduct (13). !4 similar Me0,C

I

CO2Et (11)

mechanism is presumably responsible for the formation of (14) from 1-acetyl- 1H1,2-diazepine and 2,5-dimethyl-3,4-diphenylcyclopenta-2,4-dien-l-0ne.~~ In this reaction the intermediate adduct (14) is transformed photochemically into the cage structure (15 ) . The structure of the cyclo-adduct of N-ethoxycarbonylazepine and phencyclone has been amended" to (16). [47r + 27r] Cycloadditions of ethoxycarbonyl-azepines and 1,2-diazepines with the s-cis-azine system of 3,6-dimethoxycarbonyl-l,2,4,5-tetrazine give, after loss of nitrogen, the derivatives (17; X = CH or N) (Scheme 2).12

i

C N -C 0 , E t

----*

M He 0 C y N, Me0,C

x NC0,Et /

ii

y s , , ,

Me0,C

N\ Me0,C

I

Reagents: i, 3,6-dimethoxycarbonyl- 1,2,4,5-tetrazine; ii, chloranil

Scheme 2

In

l2

T. Mukai, Jpn. Kokai Tokkyo Koho 7 8 121 778 (Chem Abs., 1979,90,121672). K. Harano, T. Ban, M. Yasuda, and K. Kanematsu, Tetrahedron Lett., 1978,4037. G. Seitz, T. Kaempchen, and W. Overheu, Arch. Pharm. (Weinheim, Ger.), 1978,311,786.

380

Heterocyclic Chemistry OH

R2si I

C N C O ,Et

R,SiCI,

NC02Et

* R,Si I

OH

(18) R = MeorPh

Chloro-silanes add in a trans manner across the 4,5-double-bond of 1e thoxycarbonylazepine to give (18). 4-Amino- 1,5-die thoxycar bonyl-2 ,3,6,7 tetrahydroazepine (19) has been c o n ~ e r t e d into ' ~ the tetrahydropyridoazepine (20); this, on conversion into (21) with phosphorus oxychloride in the presence of NN-diethylaniline and subsequent hydrogenolysis, gave (22) (Scheme 3). The tetrahydropyrimidinoazepine(23) has been successfully dehydrogenated to (24) in a stepwise p r 0 ~ e d u r e . l ~

(21)R = C1 (22)R = H Reagents: i, CH,(CO,Et),, NaOEt; ii, POCl,, PhNEt,; iii, H,, Pd/C.

Scheme 3

The Schmidt reaction and the Beckmann rearrangement still serve as useful methods for the preparation of azepine ring systems. The oximes from 1,5,6,7tetrahydro-4H-indol-4-ones (25) undergo the Beckmann rearrangement on treatment with polyphosphoric acid to produce (26).16The Schmidt reaction and Beckmann rearrangement of the oxime tosylates give (27). Other 3-substituted l3 14

Is l6

K. Saito and K. Takahashi, Heterocycles, 1979, 12, 263. H. Yamamoto, H. Kawamoto, S. Morosawa, and A. Yokoo, Heterocycles, 1978, 1 1 , 2 6 7 . H. Yamamoto, T. Komazawa, K. Nakaue, and A. Yakoo, Heterocycles, 1978, 11, 275. V. Bardakas and W. Sucrow, Chem. Ber., 1978,111, 1780.

Seven-memberedRing Systems

381

derivatives are described. The spiro-derivatives (28; R = H or Me) are converted into the triazaspiro[5,6]dodecane-1,3,5,lO-tetraones (29) by Beckmann rearrangement of their oximes.” The steroid field too continues to provide examples of these reactions.”

a

N

Me (25)X-Y

=

CO

(26)X = N H , Y = CO (27)X

=

C0,Y

=

(28)X = C O (29)X = CONH

NH

Photoaddition of dimethyl acetylenedicarboxylate to a number of 2,3-dialkylindoles proceeds in a [27r + 27r] fashion to yield the cyclobutenes (30);19unlike the analogous benzothiophens and benzofurans, these are stable to further photochemical transformation. Heat converts the non-fused bridgehead cyclobutenes into the valence tautomers (31), which are reconverted into (30) upon irradiation. The rates of each reaction are substituent-dependent.

R’ (30)

Michael addition of chalcones to 3,5-dimethyl-4-nitroisoxazole,20 followed by reductive cyclization, yields the isoxazolo[4,5- blazepines (32).

The problem of whether y-keto-acids form 1-benzazepinone derivatives with aniline and aniline hydrochloride has been further investigated.21 It has been shown that, as predicted, rn-anisidine gives increased yields of benzazepinones (33; R’ = Me or Ph, R2 = H or OMe) in the reaction with laevulinic or 3-benzoylpropionic acids.

l9

*’ 21

H. H. Otto and J. Triepel, Justus Liebigs Ann. Chern., 1978, 1809. H. Singh and K. K. Bhutani, Indian J. Chem., Sect. B, 1978,16, 95; H. Singh and T. R. Bhardwaj, ibid., p. 617; H. Singh, K. K. Bhutani, R. K. Malhotra, and D. Paul, Experientia, 1978,34, 557; K. Oka and S. Hara, J. Org. Chem., 1978, 43, 3790. P. D. Davis and D. C. Neckers, Tetrahedron Lett., 1978,2979. C. J. Rao and K. Murthy, Indian J. Chem., Sect. B, 1978,16,636. V. Candeloro and J. H. Bowie, Aust. I. Chem., 1978,31, 203.

Heterocyclic Chemistry

382

A number of annelated systems have been prepared from suitably substituted 1,2,3,4-tetrahydro-l-benzazepin-5-0nes.~~ These include the pyrimidinobenzazepine (34), the pyrazolobenzazepine (35), and the isoxazoles (36) and (37).

R2a R'

H

o

(33) (34)

(35) R (36) R

=

=

H, X = N, Y = NH Tosyl, X = N, Y = 0

(37)

The synthesis of isoquinolones by acid-catalysed cyclization of a-benzylmethoxybenzylamino-acetonitrile has been extended to a-phenethyl homolog ~ e s , giving '~ access to 3-substituted 2-benzazepines (39). Here too the products are consistent with a mechanism involving a spiro-intermediate (38). A further entry into the 2-benzazepine molecule is afforded24 by the dichlorocarbene adduct (40) of N-methylisoquinolin- 1-one. Whereas the adduct gives the isoindolone (41) with water, the reaction with alcohols gives the 2-benzodiazepine (42). +a

ROH

NMe

Further have appeared on the photochemical behaviour of cyclic imides in the presence of unsaturated systems. Phthalimides react with olefins to produce 4-alkylated 2H-3,4-dihydro-2-benzazepine- 1,5-diones, e.g. (43). The reaction only takes place with alkenes having an ionization potential above 9 eV,25no reaction occurring with alkenes of lower ionization potentials, suggesting that the reaction may not proceed via an electron-transfer process. In 22

23 24

25

G . R.Proctor and B. M.L. Smith, J. Chem. SOC.,Perkin Trans. 1, 1978, 862. D. N. Harcourt, N. Taylor, and R. D. Waigh, J. Chem. Soc., Perkin Trans. I, 1978, 1330. H. P. Seotens and U. K. Pandit, Heterocycles, 1978,11, 75. P. H. Mazzocchi, S. Minamikawa, and M. J. Bowen, J. Org. Chem., 1978,43, 3079.

383

Seven-membered Ring Systems

comparison, succinimides yield oxetans; no azepine derivatives are observed.26 2H-2-Benzazepine-173-dionehas been prepared*' in a two-step procedure from 2-(chloroformyl)-cis-cinnamonitrile.Both the dione and its N-methyl derivative each give a photodimer of related structure. These two products have been assigned the parallel and antiparallel structures (44) and (45) on the basis of an analysis of the coupling constants in the n.m.r. spectra.

(43)

0

0

The Knoevenagel condensation of ethyl 3-formylindole-2-carboxylateleads to derivatives of indoleacrylic When cyanoacetamide or malondiamide are used, the intermediate condensation products react further to give the azepino[3,4-b]indole (46; R = CONH, or CN). The related 1,5-diones (48) are prepared,29in moderate yield, from the P-carboxamide (47) by cyclization with polyphosphoric acid. CH=CCONH,

@& H

(47) 26

*'

28

29

K. Maruyama and Y. Kubo, Chem. Lett., 1978,769. M. S. Puar and B. R. Vogt, Tetrahedron, 1978,34,2887. J. Pigulla and E. Roder, Arch. Pharm. (Weinheim, Ger.), 1978,311,822. J. Pigulla and E. Roder, Justus Liebigs Ann. Chem., 1978, 1390.

384

Heterocyclic Chemistry

The acid-catalysed cyclization of a number of N-benzyl-propynamines has been disc~ssed.~' Cyclization of NN-dibenzyl-3-phenylpropynamine(49) with triflic acid gives rise to the 2-benzazepine derivative (50) whereas N-[a-phenylphenethyll-2-propynamine (51) affords the bridged compound (52). The azabicyclononadiene (53),prepared by quaternization of the product from the acid-catalysed ring closure of NN-dibenzylaminoacetaldehyde diethyl acetal, rearranges31 in the presence of potassium t-butoxide to give the isomeric (54).

I Me

(54)

(53)

Derivatives of a-oxocaprolactam have been useful in the preparation of a number of heterocyclic derivatives. Treatment of the phenyl oxime (55)with acid and then methyl iodide gave (56),32 which was dehydrated by trifluoroaceticacid to give the benzofurano-azepine derivative (57). The bromo-compound (58) condensed33with orfho-amino-thiophenols to give (59). The pyrimidinopyrroloazepines (60; R' = Me or H, R"= Me) and (60; R' = Me, R2 = H) were

(55) 30

31 32

33

(54)

(57)

H. Takayama, T. Suzuki, and T. Nomoto, Chem. Len., 1978,865. H.Takayama, T. Nomoto, T. Suzuki, and M. Takamoto, Heterocycles, 1978,9,1545.

R. G. Glushkov, I. M. Zasosova, I. M. Ovcharova, N. P. Solov'evd, D. S. Anisimova, and Yu. N. Sheinker, Khim. Geterotsikl. Soedin., 1978,1504. R. G.Glushkov, V. G. Smirnova,I. M. Zasosova, T. V. Stezhko, I. M. Ovcharova, and T. F. Vlasova, Khim. Geterotsikl. Soedin., 1978,374.

Seven-membered Ring Systems

385

obtained in low to moderate yield by condensation of (58)with the corresponding amino-uracils, and condensation of (58) with thiourea and ethyl acetoacetate gave (61)and (62)respectively (see Scheme 4).The oxime (63)was prepared34by

CQJH 0

(59)

\

J

Scheme 4

the reaction of 2,3-dioxo-4-(NN-dimethylaminomethylene)-hexahydroazepine with hydroxylamine in acetic acid at 20°C. When the reaction solution was heated, the isoxazole (64)was isolated. Treatment of (63)with triethylamine or of (64)with methoxide gave (65),from which (66)and (67) were prepared by treatment with anilines and hydrazine respectively, as shown in Scheme 5. The

N

(65)X = 0 (66)X = NAr Reagents: i, AcOH, heat; ii, NaOMe; iii, Et,N; iv, ArNH,; v, H,NNH,

Scheme 5 34

R. G. Glushkov and T. V. Stezhko, Khim. Geterotsikl. Soedin., 1978, 1252.

Heterocyclic Chemistry

386

triazolo[4,5-c]azepine derivative (69) was obtained3' by thermal cyclization of (68).

phNHNp -7QH H

NH

p-MeC,H,S02NHN

0 (68)

0 (69)

Cyclization of N-phenethyl-enaminones can follow two paths.36Treatment of the bromo-derivative (70) with lithium diethylamide gives the indoline (7 1) whereas the benzazepine system (72) is the product of photochemical cyclization.

As part of the synthetic sequence for vincadifformine, the chloro-indolenine (73) has been transformed3' (by thallium t-butyl methyl malonate) into the indolo-azepine (74), the structure of which was confirmed by independent synthesis of its decarboxylated derivative.

(74)

The aza-azulene (75) has been prepared38 by the reaction of 2-acetylpyrrole with 1-dimethylamino-3-dimethyliminoprop- 1-ene . The reaction of 1,2,6,7,8,9hexahydropyrrolo[3,2,1-jk]carbazole (76) with dimethyl acetylenedicarboxylate is complex, and X-ray crystallography has had to be employed39in the elucidation of the reaction products. One of the products thus identified is (77). The reaction of the cycloheptapyrroles(78; R = H or C0,Et) and the cycloheptimidazole (79) with dimethyl acetylenedicarboxylatehas also been st~died.~' In each case, 1 + 2 35 36

37 38

39

40

R. G. Glushkov, I. M. Zasosova, and 1. M. Ovcharova, Khim. Geterotsikl. Soedin., 1978, 1429. H. Iida, Y. Yuasa, and C. Kibayashi, Tetrahedron Lett., 1978,3817. M. E. Kuehne, D. M. Roland, and R. Hafter, J. Org. Chem., 1978,43,3705. W. Flitsch, F. Kappenberg, and H. Schmitt, Chem. Ber., 1978,111,2407. P. J. Abbott, R. M. Acheson, G. Proctor, and D. J. Watkin, Acra. Crystallogr., Sect. B, 1978, 34, 2165. N. Abe, Y. Tanaka, and N. Nishiwaki, J. Chem. SOC.,Perkin Trans. 1, 1978,429.

Seven-membered Ring Systems

387

adducts are formed viu the intermediate (80; X = CH or N) to afford (81) and (83). With (78) a small amount of (82) is formed by a 1,s-dipolar addition.

/

(75) (76)

(77)

H

(78) X = CR,Y = C1 (79)X= N,Y = H

Me02C

(80)

C0,Me

Me02C (82)

Studies on nitrene-insertion reactions of phenyl-methanes have been extended4' to triphenylmethanes containing an ortho-azido-group as the nitrene source. Where the phenyl rings are otherwise unsubstituted, equal amounts of indoloazepine (84), 9 , l O-dihydro-9-phenylacridine, and the corresponding acridine are formed. The presence of a methoxy-group favours acridine formation; the tetracyclic (85) is also formed, and it may be transformed into the indolo-azepinone (86). Ph

-f7J---T&

J f? $ \

(85) 41

-

'OMe (86)

0

R. N. Carde, G. Jones, W. H. McKinley, and C. Price, J. Chem. Soc., Perkin Trans. 1, 1978, 12 11.

Heterocyclic Chemistry

388

(87)

A new heterocyclic ring system, the azepino[3,2,l-kl]phenothiazine ring system, is e ~ e m p l i f i e dby~ ~ (87). The isomeric system (89)has been prepared43by ring expansion of the ketone (88) (Scheme 6). Ho CH,0S02C,H,Me

+ \

/

(88) +

Reagents: i, Ph,PMe Br-; ii, OsO,; iii, p-MeC,H,SO,CI; iv, LiClO,

Scheme 6

A retro-Hofmann elimination is r e ~ p o n s i b l efor ~ ~the formation of the bridged ~ enamino-ketone (91)affords the system (90). Photochemical c y ~ l i z a t i o nof~ the azepino-system (92), which undergoes ring opening with acid to yield (93). Alkali reverses the ring-opening process. I r r a d i a t i ~ nof~ ~ N-substituted succinimides, e. g. (94), affords the lactams (95) with retention of exo-endo stereochemistry .

42 43 44

45 46

S. H. Kim and A. R. Martin, J. Heterocycl. Chem., 1978, 15, 1503. S. H. Kim and A. R. Martin, J. Heterocycl. Chem., 1978,15, 1507. D. J. Brickwood, A. M. Hassan, W. D. Ollis, J. S. Stephanatou, and J . F. Stoddart, J. Chem. SOC., Perkin Trans. 1, 1978, 1393. F. M. Shell and P. M. Cook, J. Org. Chem., 1978, 43,4420. Y . Kanaoka, H. Okajima, Y. Hatanaka, and M. Terashima, Heterocycles, 1978, 11, 455.

Seven -membered Ring Systems

389

One Oxygen Atom.-2-Carboxyoxepin and its methyl ester have been prepared,47and their ring-contraction behaviour uia the valence tautomer benzene oxide has been studied, as they are possible models for the NIH shift pathway of metabolic hydroxylation, aided by deuterium labelling at C-7. The acid rearranges to phenol (100% retention of deuterium) and salicylic acid (72% retention), the proportions being dependent on pH. The methyl ester rearranges to methyl salicylate with 55% retention of deuterium. The possible mechanisms are discussed. 4,5-Dimethyloxepin (96) is converted4' into the diepoxide (97) by way of its Diels-Alder adduct with bis(trich1oroethyl) azodicarboxylate and epoxidation. Extrusion of nitrogen yields the transient species (98), which rearranges to (99) in the presence of acid. In the absence of acid, (98) rearranges rapidly to (loo), which likewise undergoes a Cope rearrangement to (101). 2,7Dimethyloxepin reacts in a different manner.49 In this case the Diels-Alder adducts with azodicarboxylates are not formed with the valence tautomer 1,2dimethylbenzene oxide but with the oxepin itself. Subsequent Claisen rearrangement of the postulated adduct (102) affords the ketone (103). If the two methyl groups are incorporated into a ring system,'' as in (104), the DielsAlder/azocarboxylate sequence yields (103, which does not undergo a Cope rearrangement, presumably because of its inability to interconvert into (106).

MeQMe H

47 48 49

t-

CHO

MeoMe 6 f-

0

- I

Me

o

Me

I

Me COMe

D. R. Boyd and G. A. Berchtold, J. A m . Chem. SOC.,1978,100,3958. W. H. Rastetter and T. J. Richard, Tetrahedron Lett., 1978, 2995. W. H. Rastetter and T. J. Richard, Tetrahedron Lett., 1978, 2999. W. H. Rastetter, T. J. Richard, and N. D. Jones, J. Chem. Soc., Chem. Commun., 1978, 377.

Heterocyclic Chemistry

390

Me

The benzoxepinium ylide (107) is formed5' as a transient species in the photolysis of 2,3-diphenylnaphthaquinone 2,3-epoxide. When photolysis is carried out in the presence of a dipolarophile, adducts such as (108) and (109) are formed. The thermolysis product (110) from (108) represents the formal acetylene adduct of (107).

0

*CO2Me

CO,Me

0 PhH

(107)

+

% \

0 Ph

1

C02Me C02Me

A new route to l-benzoxepin-S(2H)-ones by a three-step sequence has been described, and is shown in Scheme 7.52 51

H. Kato, H. Tezuka, K. Yamaguchi, K. Nowada, and Y. Nakamura, J. Chem. SOC.,Perkin Trans. 1,

'*

1978, 1029. J. K. Holroyde, A. F. Om, and V. Thaller, J. Chem. SOC.,Pirkin Trans. I , 1978, 1490.

Seven-membered Ring Systems

Ho2c!

39 1

Ho23

M e U 2 C 0 r )

d ii

C02Me

C02Me

C02Me

Reagents: i, NBS; ii, pMe02CC,H40H, KOH, H20; iii, S0C12;iv, AICI,, CH,CI,

Scheme 7

The structure of the product obtained from the oxidation of the bisphenol(ll1) with lead tetra-acetate has been to (112). Treatments3of (1 12) with acid yields the isomeric benzofuranones (1 13) and (1 14), whereas alcohols give54 the benzofurans (115).

MeoQ-i Bu'

(113)

I

0

0

53

54

F. C. Hewgill, D. G. Hewitt, H. B. Graeme, C. L. Raston, R. J. Webb, and A. H. White, J. Chem. Soc., Perkin Trans. 1, 1979, 290. H. P. Schreider, W. Winter, and A. Rieker, J. Chem. Res. ( S ) , 1978, 336.

392

Heterocyclic Chemistry

The photochemical behaviour of benzo[a]phenazine 7-oxide (116) has been unravelled by X-ray ~rystallography.~~ The initial product is the benzoxadiazepine (117), which is stable to irradiation at 366 nm but undergoes photochemical sigmatropic rearrangement at 254 nm to afford the benzoxepinoquinoxalines (118) and (119).

One Sulphur Atom.-Attempts to prepare a stable thiepin still attract attention. To investigate the possible stabilizing effects of bulky substituents in the 2,7positions of a thiepin, (120) was treated56with 7r-allylpalladium chloride, but it yielded, however, only the sulphur-extrusion product ethyl 2,4-di-isopropyl-5methylbenzoate. Similar failures are reported5’ in the reactions of 3-pyrrolidinylthiophens with acetylenic diesters, although in this case sulphur-containing products were isolated. Perhaps the simplest thiepin reported is the 1,l-dioxide (12 l),prepared58by the reaction of divinyl sulphone with phenylalkyne-cobalt complexes.

S

R. Oberti, A. Coda, L. Incoccia, and F. Comin, Acta Crystallogr., Sect. B, 1978, 34, 1544 S. Yano, K. Nishino, K. Nakasuji, and I. Murata, Chem. Lett., 1978,723. ’’ D. N. Reinhoudt, G. Okay, and W. P. Trompendaars, Tetrahedron Lett., 1979, 1529. 5 8 I. V. Khand and P. L. Pauson, Heterocycles, 1978, 11, 59. 55

56

Seven-membered Ring Systems

393

3,3,6,6-Tetramethyl- 1-thiacyclohept-4-yne has found a useful application in cyclobutadiene chemistry.59 Its reaction with PdCl, gave the complex (122), which upon treatment with ethylenebis(dipheny1phosphane) gave the tricyclic cyclobutadiene (123), the first cyclobutadiene derivative sufficientlystabilized by steric effects to be isolated at room temperature. Ring-expansion methods for the preparation of 1-benzothiepins have been more successful. The three-step procedure for the preparation of 1-benzothiepin itself and its chloro-analogues, starting from 7a-chlorocyclopropan[b][l]benzothiopyran-7-one, has been extended6' to the preparation of 5-aryl- and 5-alkyl-substituted derivatives by replacing the initial borohydride-reduction step by a Grignard reaction. Apparently, increasing the substitution by electrondonating substituents stabilizes the thiepin ring against extrusion of sulphur. A further contribution to studies on the stability of 1-benzothiepins is supplied6' by the preparation of all four thiepin-ring ethoxycarbonyl derivatives by the diazoester ring-enlargement method. The electron-withdrawing substituents in positions 3, 4, and 5 reduce the stability of the thiepin ring. 2-Ethoxycarbonyl-lbenzothiepin is substantially more stable. A combination of steric and electronic effects has been put forward as an explanation. The availability of 2,3-dihydro- l-benzothiepin-4(5H)one (124) has made the preparation of new fused-ring derivatives possible.62 Fischer indole synthesis gives the indole (125), and a Friedlander synthesis the quinolines (126; R = H or Me).

A number of dibenzo[b,f]thiepins have been prepared as potential psychotropic agents.63 In this work it was found that, during Friedel-Crafts acetylation, 2-chlorodibenzo[b,flthiepin (127) undergoes ring contraction to the thioxanthene (128). Generatiod4 of the anion (129) with sodium hydride in 59

A. Krebs, H. Kimling, and R. Kemper, Justus Liebigs Ann. Chem., 1978,431.

6o

V. J. Traynelis, J. A. Schield, W. A. Lindley, and D. W. H. MacDowell, J. Org. Chem., 1978, 43,

61

62 63

64

3379. K. Nishino, K. Kazuhiro, and I. Murata, TetrahedronLett., 1978, 3567. R. Pellicciari, B. Natalini, A. Ricci, G. Alunnibistocchi, and G. Demeo, J. Heferoeycl. Chem., 1978, 15, 927. K. Sindelar, J. 0.Jilek, J. Pomykacek, Z . Sedivy, and M. Protiva, Collect. Czech. Chem. Commun., 1978,43,471. J. Ackrell, J. Ore. Chem., 1978,43, 4892.

394

Heterocyclic Chemistry

N-methylpyrrolidine at a little below 0 "C, followed by treatment with methyl iodide, gives only a minor amount of the methyl derivative (130), the major reaction products being (13 1) and (132). Substantially lower temperatures and reverse-addition techniques are necessary to prevent ring contraction.

SMe i131)

Ph

Me 'SMe (132)

R'

R2 (133)

Cyclization reactions of 11-phenyl-6,ll -dihydrodibenzo[b,e]thiepins have given rise to a number of novel cyclized products. The carbinol(l33; R' = OH, R2 = H) c y ~ l i z e to s ~the ~ pentacyclic derivative (134) in the presence of an excess of antimony pentachloride. Treatment of (133; R' = R2 = C1) with water or ammonia yields66the bridged systems (135; X = 0 or NH). The epoxide (135; X = 0)was also preparedh7from the sulphoxide of (133; R' = OH, R2 = H) under a variety of acidic conditions. Thermolysis" of (133; R' = RZ = Cl) and of (133; R' = H, R2 = Cl) resulted in a new cyclization, yielding the bridged compounds (136; R' = C1) and (136; R' = H).

'' M. Hori, T. Kataoka, H. Shimizu, and K. Onogi, Yukuguku Zasshi, 1978, 98, 1189.

hh

M. Hori, T. Kataoka, H. Shimizu, and K. Onogi, Chem. Pharm. Bull., 1978,26, 2170

Seven-membered Ring Systems

395

Other Systems.- 1,2-Bis(hydroxymethyl)benzene reacts68 with hexame thylcyclotrisilazane and dichlorodiphenylsilane to yield the dioxabenzosilepins (137; R = Me *or Ph). Tetramethoxysilane yields the spiro-product (138). 3,3Dichloro-3H-3-benzosilepin and its 172,4,5-tetrahydro-derivativeform69 the spiro-benzosilepins (139) and (140) by reaction with 1,2-bis-(2-bromoe thy1)benzene.

(138)X = 0 (140) X = CHZ

(139)

4 Systems containing Two Heteroatoms

Two Nitrogen Atoms.-3,5,7-Triphenyl- 172-4H-diazepines readily form an anion with lithium di-isopropylamide. When the anion is generated in tetrarnethylethylenediamine the anion undergoes a number of reactions with electrophiles to form 4-substituted derivative^.^^ In this way 4-alkyl, -alkylthio, and -acyl derivatives have been formed. 1,2-Diazepines undergo a number of ring-contraction reactions. The peroxides (141; R = H or Me) undergo photolytic ring-contraction7’ to yield the 1,3,4oxadiazoles (142) together with minor amounts of acyclic products. A reinvestigation7’ of the formation of complexes of iron tricarbonyl with 1-acyl or 1-arylsuphonyl- 1H-diazepines (143) has shown that the diazepines are capable of isomerization to the pyrroles (144). An iron tricarbonyl-vinylnitrene complex is thought to be the most likely intermediate. 3H-Thieno-[3,2-c]- and -[2,3-c][ 1,2]diazepines both thermal and photochemical rearrangement. Deuterium-labelling studies show that the thermolytic rearrangement probably involves a [1,5] hydrogen shift.

61 68 69 70

72 l3

M. Hori, T. Kataoka, H. Shimizu, and K. Onogi, Chem. Pharm. Bull., 1978,26,2811. L. Birkoffer and 0. Stuhl, J. Organometal. Chem., 1979,164, C1. L. Birkoffer and H. Haddad, J. Organometal. Chem., 1979,164, C17. L. Bemi, M. T. Thomas, and V. Snieckus, Synthesis, 1979, 130. T. Tsuchiya, H. Arai, H. Hasegawa, and H. Igeta, Chem. Pharm. Bull., 1978,26, 2205. F. Bellamy, J. L. Schuppiser, and J. Streith, Heterocycles, 1978, 11, 461. T. Tsuchiya, M. Enkaku, and H. Sawanishi, J. Chem. SOC.,Chem. Commun., 1978, 568.

396

Heterocyclic Chemistry

Syntheses of 3-substituted- 1,2-benzodiazepines have been reported (Scheme S).74 Starting from the known 1H-tautomer (145; R = H or Me), the 3H-

tautomer (146) was prepared by a hydrogenation-dehydrogenation sequence. The 2-oxide of (146) reacts with a number of nucleophiles to give 3-substituted derivatives, e.g. (147). The energy barriers to ring inversion of (146) have been calculated, from n.m.r. studies, to be 11.7 kcal mol-’ (R = H) and 13.8 kcal mol-’ (R = Me). Photo-oxygenation7’ of (145) gives a number of ring-contraction and nitrogen-extrusion products, formed from the 3- and 5hydroperoxides. 1-Methyl analogues give the benzodiazepinones (148) as sole R

R

R

I)

Me

(147)

(148) Reagents: i, LiAlH,; ii,

R

R

PhN

yo iii, m-ClC,H,CO,H;

O&NH H

;

iv, NaCN

Scheme 8

products. Further examples of the formation of 3-substituted- 1H-1,2-benzodiazepines by direct synthesis have been Coupling of the diazocomponent (149) with, e.g., 3-chloroacetylacetone followed by dehydration and dechlorination affords the benzodiazepine (150) (Scheme 9). Other examples are quoted. If the coupling agent is the sodio-derivative of a nitroalkane, the method can be modified to prepare 3-alkyl derivatives.

Reagents: i, MeCOCHClCOMe; ii, P,O,; iii, Et,N

Scheme 9 74

75 76

T. Tsuchiya and J. Kurita, Chem. Pharm. Bull., 1978,26, 1890, 1896. T. Tsuchiya, J. Kurita, and K. Takayama, Heterocycles, 1978,9, 1549. L. Chiodini, L. Garanti, and G. Zecchi, Synthesis, 1978,603; L. Garanti, G. Testoni, and G. Zecchi, ibid., 1979, 380.

Seven -membered Ring Systems

397

A number of heterocyclic analogues have been synthesized. One applicable to a large number of examples, utilizes a photolytic insertion [(151) + (152)]. The 3H-tautomers can be prepared by the previously described reduction-dehydrogenation sequence.74The pyrimidone analogues (€54; R = alkyl) are p~epared'~ from the hydrazine (153) as shown in Scheme €0. Cycloaddition onto the 4,5-double-bond of 1H-1,2-diazepines has proved a useful method for

I

H

(151) -NH

(152)

0 (153)

(154)

Reagent: i, RCH[CH(OEt),], or RICH =CRCHO (R'

=

OEt or NH,)

Scheme 10

the preparation of heterocyclic fused diazepines. Diazomethane gives792,3,3a,6tetrahydropyrazolo[3,4-dl[1,2]diazepines (M),and Tosmic gives the corresponding 3,7-dihydropyrrolo-diazepines(156)." Bridgehead diazepines (158) are prepared" from complexes of the pyrazole derivative (€57) (Scheme 11). N,3:O2Me (157) C0,Me

Me02:r$?ph Ph

Me02C

N- Fe(CO), A5 ke(CO),

MeOzC

"5 1ii

Me02C

Ph

Ph

Ph Ph Ph M

e

O

z N-Fe a p

MeO,C

(158) 0 Reagents: i, Fe(CO),; ii, PhCECPh; iii, Br, 77 78 79

Scheme 11 T. Takashi, M. Enkaku, and H. Sawanishi, Heterocycles, 1978,9,621. K. Waid and E. Breitmaier, Synthesis, 1978, 748. J. R. Frost and J. Streith, J. Chem. SOC.,Perkin Trans. 1, 1978, 1297. D. Harris, S . Syren, and J. Streith, Tetrahedron Lett., 1978,4093. B. Ulbrich and H. Kisch, Angew. Chem., 1978,90,388.

T

(CO),

:

398

Heterocyclic Chemistry

Treatments2 of succinoyl chloride with NN'-diphenylacetamidine and triethylamine gives 1,3-diphenyl-173-diazepine-4,7-dione.Substitution of phthaloyl chloride for succinoyl chloride affords the corresponding benzo-2,4diazepine. Treatmentx3of the imidazole (159) with triethyl orthoformate gives the imidazo[4,5 -4[1,3]diazepine (160). An alternative method for this ring system is provided84 by the base-catalysed ring-expansion of the imidazopyrimidine (161), giving (162). A synthesis of the triazolo[5,1-a][2,4]benzodiazepine ring system has been reported.85In this synthesis of (164) the diazepine ring is formed last, by treatment of (163) with hexamethylenetetramine and acid.

r l

HO OH

Ph

NH,

Ph (164)

The ever popular lactam formation has been used to prepare the diazepinones (165) and (166) by cyclization of their respective w-amino-esters.86 The application and limitations of the use of 1,5-diaza- and 5-aza-1-pentadienium salts in the preparation of 2,3-dihydro- 1,4-diazepinium salts are discussedx7in detail. Electrolytic reduction8' of 6-phenyl-2,3-dihydro- 174-diazepinium salts gave, unexpectedly, the pyrrolodiazepine (167). The reaction of imides with 3dimethylamino-2,2-dimethyl-2H-azirinehas been extendeds9 to the preparation H. W. Heine and C. Tintel, Tetrahedron Len., 1978, 23. D. C. Baker and R. S. Putt, U.S. P. 4 117 229 (Chem. Abs., 1979, 90, 87 527). 84 H. Umesawa, T. Takeuchi, S. Kondo, and M. Shimazaki,Jpn. Kokai Tokkyo Koho 78 34 796 (Chem. Abs., 1978,89, 75 438). '' P. C. Wade, T. P. Kisshick, R. B. Vogt, and B. Toeplitz, J. Org. Chem., 1979,44, 84. " M. Majchrzak, A. Kotelko, and R. Guryn, Pol. J. Chem., 1978,52, 1023; F. Herold, Arch. Pharm. (Weinheim, Ger.), 1979,312, 154. '' D. Lloyd, H. McNab, and D. R. Marshall, J. Chem. Soc., Perkin Trans. 1, 1978, 1453. 88 D. Lloyd, C. A. Vincent, D . J. Walton, J. P. Declercq, G. Germain, and M. Van Meerssche, J. Chem. SOC.,Chem. Commun., 1978, 499. 89 B. Scholl, J. H. Bieri, and H. Heimgartner, Helv. Chim. Ada, 1978, 61, 3050. 82

83

Seven-membered Ring Systems

399

R (165)

(166)

(167)

of 1,4-diazepinediones (168) from malonimides. Imidazolidines react" with cyclic enol ethers to give fused diazepines (169). In contrast to similar addition reactions of oxazolidine, the imidazolidines give little or no diazepine with acyclic enol ethers. 0. H X T

R2 0

J

A new route to 1,4-benzodiazepines has been reported.'' Photolysis of 3azidoquinoline in the presence of methoxide gives moderate yields of 4,5dihydro- 1,4-benzodiazepin-3-0ne,presumably by hydrolysis of the intermediate 3-methoxy-derivative. Similarly, photolysis of 4-azido-7-chloroquinoline gives 8-chloro-5-methoxy- 1,4-benzodiazepine, and its hydrolysis produced the benzodiazepin-5-one. If the latter photolysis is undertaken in the presence of amines, a number of 5-amino-8-chloro- 1,4-benzodiazepines are prepared. O z o n ~ l y s i sof~ ~the azides (170) gives (1-azidoacetamid0)-benzophenones (171), which cyclize in the presence of triphenylphosphine to yield the benzodiazepinones (172) (Scheme 12). The pyrrolo-benzodiazepinone(173) has been Ph

(170) Reagents: i, 0,;ii, PPh,

Scheme 12 90

91

92

H.Griengl, G. Prischl, and A. Bleikolm, Justus Liebigs Ann. Chem., 1979,400;H. Griengl, A. Bleikoim, W. Grubbauer, and H. Soellradl, ibid., p. 392. F. Hollywood, E. F. V. Scriven, H. Suschitzky, D. R. Thomas,and R. Hull, J. Chern. Soc., Chern. Commun., 1978,806. Y. Tamura, M. W. Chun, K. Ohno, S. Kwon, and I. Masazumi, Chern. Pharrn. Bull., 1978,26,2874.

He te rocy c 1ic Chemistry

400 NHCOPh

H0,CCH ,N 40

N

(174)

(173)

preparedy3 by thermolysis of benzoyl-DL-kynurenyl-glycine.The reaction is considered to proceed by initial cyclization to the pyrrolone (174). A new synthesis of the pyrrolobenzo- 1,4-diazepinone system (175) has been reported94 (Scheme 13).

Reagents: i, P,O,; ii, FeSO,, NH,OH; iii, KOH

Scheme 13

It is inevitable that the value of 1,4-benzodiazepines as pharmaceutical agents should lead to an increasing interest in systems where the phenyl ring is replaced by a heterocyclic system, and the period under review is no exception. The thienotriazolo-derivatives (177) are prepared95 via a ring-cleavage reaction of the oxepins (176) (Scheme 14).

ti,

iii

(177)

Ar

Ar

Reagents: i, HBr; ii, SOCl, or PBr,; iii, NH,; iv, Br,

Scheme 14 93 94

95

F. H. C. Stewart and D. E. Rivett, Chem. Ind. (London), 1978, 347. G. De Martino, S. Massa, and F. Corelli, Farmaco, Ed. Sci., 1978, 33,604. K. H. Weber, A. Bauer, A. Langbein, and H. Daniel, Justus Liebigs Ann. Chem., 1978,1257

Seven-membered Ring Systems

40 1

The reaction of mercaptoacetaldehyde with 2-cyano-N-(cyanomethy1)acetamideyields96the thiophen (178); this is converted by base into the thienodiazepinone (179), from which the triazine (180) may be prepared. Further transformations aimed at preparing the desired product (18 1) were without success. The benzofuran (182) has yielded97the furanobenzodiazepinone (183). Starting from the known benzodiazepinones (184), a number of imidazothienoand imidazopyrazolo-diazepines (185) have been prepared in multi-step

and the view that conformation plays an important role in the activities of the benzodiazepines has led9' to the preparation of a number of 1,2,4-triazolo- and 1,2,5-triazino-[4,3-d][1,4]benzodiazepinones (186), (187), and (188)in order to study the energetics of the ring-inversion (189) + (190) by 96 97

98 99

K. H. Weber and H. Daniel, Justus Liebigs Ann. Chem., 1979, 328. J. Ashby and E . M. Ramage, J. Heterocycl. Chem., 1979, 16, 189. I. R. Fryer, J. V. Earley, and A. Walser, J. Heterocycl. Chem., 1978, 15, 619. P. C. Wade, B. R. Vogt, B. Toeplitz, M. S. Puar, and J. Z. Gougoutas, J. Org. Chem., 1979,44,88.

Heterocyclic Chemistry

402

dynamic n.m.r. The triazoles and triazolones exhibit a clearly defined quartet for the -CH2-group at low temperature which becomes a singlet at higher temperatures; by using the coalescence temperature [-8 to -10°C for the triazoles (186)], the barriers to ring inversion have been calculated. Replacement of the triazole or triazolone ring by a triazinedione ring leads to greater rigidity. Conformational inversion of the non-annelated benzodiazepine (19 1) is dependent upon the substituent in the 5-phenyl ring.'"

7 L

c1

H (190)

A convenient procedure of aerial oxidation for 3-hydroxylation of benzodiazepinones has been developed,'" and a number of zinc and cadmium complexes of nitrazepam (192) and diazepam (193) have been isolated.102 Spectroscopic studies support the assignment of tetrahedral symmetry to the majority of the complexes. Hydrogenation of the benzodiazepinone (194) giveszo3the cis-dihydro-product (195). Tosylation failed to give the expected N-tosyl derivative but gave the tetracycle (196), thermolysis of which led to (197), i.e. a rearrangement involving a 1,3-migration of the sulphonyl group (Scheme 15). If reduction by zinc and acetic acid is substituted for hydrogenation in the initial step of the sequence, the trans-isomer of (195) is isolated, which behaves similarly towards tosylation and thermolysis. The role of phosgeniminium salts in the synthesis of heterocyclic systems has been extendedzo4to the preparation of the fluoro- 1,s-benzodiazepine (198). Other applications of activated unsaturated systems in the preparation of 1,5benzodiazepines are exemplified by the preparation of (199)'05 and (200),'06 as shown in Scheme 16. 100

A. V. Bogatskii, S. A. Andronati, T. I. Korotenkb, L. N. Yakubovskaya, V. I. Minkin, and V. S. Yur'eva, Vopr. Stereokhim., 1977,6, 74. lo' M. Gall, B. Kamdar, and R. J. Collins,.J. Med. Chem., 1978, 21, 1290. lo2 C. Preti and G. Tosi, Transition Met. Chem., 1978, 3, 246. R. I. Fryer, J. Blount, E. Reeder, E. J. Trybulski, and A. Walser, J. Org. Chem., 1978,43,4480. 104 J . Gorissen and H. G. Viehe, Bull. Soc. Chim. Belg., 1978, 87, 391. lo' W. Ried and R. Teubner, Justus Liebigs Ann.Chem., 1978,741. M. Maruta, T. Kitazume, S. Kubota, N. Yoshimura, and N. Ishihawa, Chem. Lett., 1979,291.

Seven-membered Ring Systems

403

(194)

iii

t-

c1

(197)

0'

Reagents: i, HJPtO,; ii, CIOzS

Scheme 15

( 199) +

Reagents: i, Me,NCCl=C(F)CCl=NMe,Cl-; ii, PhC=CCOR3; iii, (F,C),C=C(F)C,F,

Scheme 16

The cycloaddition reactions of o -benzoquinonedi-imines have been extendedlo7to the reactions of NN'-di(arylsulphony1)-o-benzoquinonedi-imines with fulvenes. Three adducts may be isolated from the reaction; the [27r + 4 ~ 1 the , [47r + 4 ~ 1and , the [67r + 4 ~ 1depending , upon the substituents. By variation of lo'

W. Friedrichsen and G. G. Oeser, Justus Liebigs Ann. Chem., 1978, 1161.

He terocy c1ic Chemistry

404

the substituents it emerges that the [ 6 n + 4 n ] adduct (201) is the primary product, with the other apparent primary product, i.e. the [ 2 n + 4 n ] adduct (203), arisingfrom (201) via the [ 4 n + 4?r] adduct (202). In most cases (201) has no more than a transitory existence, detectable only by n.m.r. spectroscopy. In addition to the rearrangement of (201) to (202), a [1,5] hydride shift results in the formation of (204); this, on heating, enters into equilibrium with (205).

R R3 \ 2 a :

a-R2afP r'502

SOzR'

+

S0,R'

R3 \

R4

S02R'

I R4 R 'SO2

R5

R4

I

R'SO,

I

R'SO,

R'SO,

R4

I

R'SO,

R4

The benzodiazepine (206; X = NH) is preparedlo8 by the reaction of ophenylenediamine with 3-formyl-chromones. The corresponding oxazines (206; X = 0) and thiazepines (206; X = S) are similarly prepared from o-aminophenol and o-aminothiophenol. Sodium methylsulphinylmethanide has been 'On

A. D. Fitton, P. G . Houghton, and H. Suschitzky, Synthesis, 1979, 337.

Seven-membered Ring Systems

405

employedloYin the cyclizations of the amino-esters (207) and (209) to (208) and (210), respectively.

C02Et

H

-

(209)

The electro-reduction of some 3H- 1,5-benzodiazepines has been studied.' l o Two main reduction waves were obtained, which correspond to the consecutive reduction of the imine double-bonds. The mass spectra of a number of 1,5benzodiazepines have also been reported. ' The main fragmentation processes involve skeletal rearrangements to give benzimidazole, indole, and quinoxaline ions.

Nitrogen and another Heteroatom.-l,3-Oxazolidin-5-ones (211) undergo'12 a ring-expansion reaction with NN-diethyl- 1-propynylamine via a postulated 1,7dipolar intermediate. The products (2 12) undergo a ring-contraction upon thermolysis. A similar reaction sequence has also been observed with the dioxolones (2 13), the ring-contraction reaction involving, in this case, an elimination of hexafluoroacetone. A further ring-enlargement to 1,3-0xazepines is

'lo

'"

'''

J. K. Chakrabarti, T. M. Hotten, D. J. Steggles, and D. E. Tupper, J. Chem. Res., 1978, 5105. K.Butkiewia, J. Electroanai. Chem. Interfacial Electrochem., 1978,90, 271. A. Trka, A. Frigerio, D. Nardi, A. Tajana, and U. Rapp, Furmaco, Ed. Sci., 1978, 33, 885. K. Burger, A. Meffert, and A. Gieren, Justus Liebigs Ann. Chem., 1978, 1037; R.Burger and A. Meffert, ibid., p 1052.

406

Heterocyclic Chemistry

e~emplified"~ by the preparation of (215) by the action of sodium azide on (214). Steric constraints permitting, the oxazapines react with N-phenyltriazoline-3,5dione, yielding (216), as shown in Scheme 17. Ph 0%

R

(214) BF4-

(2 15)

0

(216)

0

N-+ Reagents: i, NaN,; ii, 11 N$Nph

0

Scheme 17

Cuprous oxide acts as a catalyst in the synthesis'14 of the dihydrobenzoxazepine (217), and the dibenzoxazepine (219) is ~ r e p a r e d ' 'by ~ the photolysis of the N-oxide (218). The medicinal interest in benzodiazepinones and their hetero-analogues has spilled over116into the oxazepines and thiazepines (220), where the ring labelled het is a triazole, a pyrazole, or a thiophen moiety. Further reactions in the examples of photocyclization117 and ring-enlargement' preparation of benzoxazepines are given by the preparation of (221), (222), and (223). A dihydrobenzo-analogue (225) is provided by cleavage12oof the vinylogous amide (224) and re-cyclization.

Ar

(220) X

115

'I6 117

'I8 119

I2O

=

0 or S

T.,Toda, T. Takase, T. Mukai, and Y. Suzuki, Heterocycles, 1978,11, 331. Y. Ito, K..Kobayashi, and T. Saegusa, Tetrahedron Lett., 1978, 2087. C . Kaneko, R. Hayashi, M. Yamarnori, K. Tokumura, and M. Itoh, Chem. Pharm. Bull., 1978,26, 2508. K. H. Weber, A. Langbein, and H. Daniel, Justus Liebigs Ann. Chem., 1978,1241;K. H. Weber, A. Bauer, A. Langbein, and H. Daniel, ibid., p. 1250. K. Mutai, S.Kanno, and K. Kobayashi, Chem. Lett., 1978,931. C. K. Ghosh and K. K. Mukhopadhyay, Synthesis, 1978,779. A. Levai and R. Bognar, Acta Chim. Acad. Sci. Hung., 1978,97,77. H. Iida, S.Aoyagi, K. Kawano, and C. Kibayashi, Chem. Pharm. Bull., 1978.26, 3229.

Seven-membered Ring Systems

407 Ph hv

Qco2H

HzNoH+

0

q - c NoH 2 . 0

m

0

0

0

~ e ~ H o ~ H~ ~H ” s; ” N H 2

TCE = trichloroethyl

0

-

Me

(228) Co2TCE

Epoxidation of the exocyclic double-bond of the diene sulphoxide (226) gave121the expected epoxide (227), the epimer obtained being dependent upon the oxidant used. The reaction of either epoxide with thiourea gave the ringexpanded cephem (228). D. 0.Spry, TetrahedronLett., 1978,4751.

408

Heterocyclic Chemistry

A simple synthesis of annelated dibenzo[ b,f]thiazepines (230) has been developed.12' The critical stage in this synthesis is the Smiles rearrangement of the intermediate (229). In a manner which is reminiscent of the behaviour of certain dihydro-dibenzo[b, elthiepins previously discussed, the dibenzorb, el[ l, 4lthiazepine (23 l) readily the transannular product (232), and ring-contraction reactions are a feature of the oxidation of (233) by halogens. Thus, with iodine in methanol or ethanol, the products (234) are is01afed.I~~

0

CHO (23 1)

0

OEt (232)

0 CH,OR

Other Systems.-The structure of the ozonide prepared from 2-(4-nitrobenzyl)3-phenylindanone has been by X-ray crystallography to have the benzodioxepinone structure (235). 2-Alkyl-4,7-dihydro-2H-1,3-dioxepins undergo hetero-diene cyclizations with oxazoles; 4-methyl-5-propoxyoxazole 122

124

125

J. U. Bliesender, Justus Liebigs Ann. Chem., 1978, 259. H. L. Yale, J. Heterocycl. Chern., 1978, 15, 331. T. Hiramitsu, Y.Maki, and S. Senda, J. Chem. SOC.,Perkin Trans. 1, 1978, 716. J. Karban, J. L. Mcatee, J. S. Belew, D. F. Muliica, W. 0.Milligan, and J. Korp, J. Chem. SOC.,Chem. Commun., 1978,729.

Seven - membered Ring Systems

409

gives (236)'26 whereas the 5-cyano-4-methyl derivative gives (237).12' The conformational dynamic properties of a series of 3-substituted 2,4-benzodioxepins have been discussedf28in terms of the structures (238) and (239). The 3-unsubstituted compound exists as a mixture, with (238) predominating. Monoalkyl substitution results in transformation into (239).

Ph

1RxO &= - (

R2

Base-catalysed ring closure of the alcohol (240) gave'29 the Meisenheimer complex (241), which rearranged in refluxing dimethyl sulphoxide to yield the benzodioxepin (242). Further depsidone syntheses, using benzophenone oxidative coupling of benzophenone, have been reported. 130 Evidence supporting the involvement of a grisadiendione intermediate has been presented,l3' as has evidence the involvement of a keten intermediate in the base-catalysed grisadiendionedepsidone rearrangement. The parent tricyclic system has been to lose carbon dioxide upon irradiation in benzene solution, yielding dibenzofuran. 126 127

12'

12'

I3O 13' 13'

S. D. L'vova, Z . I. Itov, and V. I. Gunar, Khim. Farm. Zh., 1978, 12, 106. D. Szlompek-Nesteruk, A . Rudnicki, K. Wojsa, S. Stanislawa, and M. Adamus, Pol. P. 93 375 (Chem. Abs., 1978,89, 109 108). A. Blanchette, F. Sauriollord, and M. St. Jacques, J. Am. Chem. SOC.,1978, 100,4055. V. N. Knyazev, V. N. Drozd, and V. M,Minov, Zh. Org. Khim., 1978,14, 105. P. Djura and M. V. Sargent, J. Chem. SOC.,e r k i n Trans. 1, 1978, 395. T. Sala and M. V. Sargent, J. Chem. SOC.,Chem. Commun., 1978, 1043. S. R. Lele and B. D. Hosangadi, Indian J. Chem., Sect. B, 1978, 16,415.

410

Heterocyclic Chemistry

A synthesis of 4,7-dihydro-2H- 173-dithiepin from cis-2-butene- 1,4-diol has been r e ~ 0 r t e d . Treatment I~~ of the phosphorine (243) with base has given134the ring-expanded product (244).

(243)

(244)

5 Systems containing Three or More Heteroatoms Photolysis of azides has found another application in the preparation13' of the triazepinediones (246) from the pyrimidine (245). When the methyl group is replaced by nitrile, the alkoxy-derivatives (247) are isolated (Scheme 18).

-

0

11

+--(R = Me)

(R

=

CN)

Reagents: i, hv, R'R'NH; ii, hv, R'OH

Scheme 18

The synthetic potential of benzazetes in 1,3-dipolar addition is well illust ~ a t e d by ' ~ the ~ reaction with diaryl-nitrilimines, when the benzotriazines (248) are formed. Photochemical addition of nitriles to the silacyclopropene (249) gives13' the adduct (250). The reaction is considered to proceed via a [ZT + 2 w ] cycloaddition followed by a [ 4 +~ 27~1reaction of the intermediate product. Ph

(249) 133 134 135 136

137

(250)

D. N. Harpp, K. Steliou, and B. T. Friedlander, Org. Prep. Proced. Int., 1978,10, 133. F. Mathey and D. Thavard, Can. J. Chem., 1978,56, 1952. S . Senda, K.Hirota, T. Asao, K. Muruhashi, and N. Kitamura, Tetrahedron Lett., 1978,1531. W.P.Manley, R. Somanathan, D. L. R. Reeves, and R. C. Storr, J. Chem. SOC.,Chem. Commun., 1978,396. H. Sakurai, Y. Kamiyama, and Y. Nakadaira, J. Chem. SOC.,Chem. Commun., 1978,80.

Eight-membered and Larger Ring Systems BY G. M. BROOKE

This report covers literature abstracted in Volumes 87-90, Abstracts.

inclusive, of Chemical

1 Eight-membered Rings One Heteroatom-The double electrophilic cyclization of NN-dibenzyl derivatives of aminoacetaldehyde diethyl acetal is an efficient route to compounds (l), which in turn can be transformed into dibenz[c,flazocine derivatives (2) and (3), using Me2S04plus HO- and BrCN, respectively.’ The last reagent,’ and also CICOzEtand Ac’O,~have been used to effect ring-opening of the indolines (4) to 1-benzazocines. Dimethyl acetylenedicarboxylateadds to (5; X = NMe) to form (6; X = NMe),4presumably by a preliminary addition across the 3,4-bond to give

xq-yy CH,Br

&’..

CN (3)

(4)

C0,Me

(6)

0

H. Takayama, M. Takamoto, and T. Okamoto, Tetruhedron Lett., 1978,1307. T . Kametani, K. Takahashi, M. Ihara, and K. Fukumoto, J. Chem. SOC., Perkin Trans. 1, 1978,662. T. Kametani, K. Takahashi, M. Ihara, and K. Fukumoto, Heterocycles, 1978,9,435. ‘ D. J. Haywood and S. T. Reid, J. Chem. SOC.,Perkin Trans. 1 , 1977,2457.

41 1

412

Heterocyclic Chemistry

a cyclobutene derivative, which then undergoes a thermally allowed ring-opening reaction. Certain vinyltetrahydroisoquinoline derivatives (7; R = Me) undergo an overall 1,3-sigmatropic shift on heating to give (8);' with MeI, compound (7) gives the methiodide of (8). The first example of an intramolecular 1,3-dipolar cycloaddition reaction of an azide across a C=C bond has been reported, using (9):6thermal elimination of nitrogen from the product (10) gave the corresponding aziridine, which formed (11) on treatment with HCl. N-Substituted glutarimides undergo a photochemical ring-expansion reaction to form keto-lactam systems 1e.g. (12) + ( ~ 1 . ~ [2,3]Sigmatropic shifts have been used extensively in ring-expansion reactions The Nfor nitrogen,* and especially for sulphur-containing alkylation of 2-vinyl-N-benzyltetrahydropyrrolewith CF3S03CH2C02Etgives separable diastereomeric salts, either of which, on deprotonation with KOBu', yields comparable amounts of the (2)-and (E)-heterocyclic alkenes (14) and (15).* These arise from diastereomeric ylides (16) and (17) respectively, which must be able to interconvert. With sulphur-containing compounds, stereospecific S-alkylation of 2-vinyltetrahydrothiophenwith CF3S03CH2C02Etgives (18; R = C02Et, X = CF3S03); this, with KOBu', gives only the (2)-thiocyclooctene (19; R = C02Et).8However, with (18; R = COPh, X = Clod), proton abstraction with the non-nucleophilic base 1,5-diazabicyclo[5.4.O]undec-5-ene (DBU) gives 67% of the (2)-isomer (19; R = COPh) and 7% of the (E)-isomer (20).8Models show that the formation of the (2)-isomers has to come from (21), so it is again necessary to invoke one diastereomeric interconversion between (18) and (21). The use of CH2=CHCH20S02CF3 followed by DBU,' or of CH2=CHCH2Br followed by KOH,'" with 2-vinyltetrahydrothiophengives (19; R = CH2CH=CH2), which is suitable for further ring-expansion reactions [see later]. An unusual ring contraction takes place when (22) is heated with sulphur in hexamethylphosphoramide at 100-1 20 "C for 3 hours: the pyrrole derivative (23) is formed." Compound (5; X = 0), with dimethyl acetylenedicarboxylate, gives the benzoxocin derivative (6; X = O).4

Two Heteroatoms.-Photolysis of (24) provides a route to the 1,2-diaza-analogue of cyclo-octatetraene (25), the 'H n.m.r. spectrum of which shows the presence of the structural feature =N-N= (and nut -N=N-) and the conformation shown. l 3

* lo

l3

W. H. Bersch, D. Hoff, and D. Schon, Arch. Pharm. (Weinheim, Ger.), 1978,311,1029 (Chem. A h . , 1979, 90, 121 374). A. Padwa, A. Ku, H. Ku, and A. Mazzu, Tetrahedron Lett., 1977, 551. Y . Kanaoka, H. Okajima, and Y. Hatanaka, Heterocycles, 1977,8, 339. E. Vedejs, J. P. Hagen, B. L. Roach, and K. L. Spear, J. Org. Chem., 1978,43, 1185. E. Vedejs, M. J. Mullins, J. M. Renga, and S. P. Singer, Tetrahedron Lett., 1978, 519. R. Schmid and H. Schmid, Helv. Chim. Acta, 1977,60, 1361. V. Cere, A. Fava, S. Pallicino, and E. Sandri, Chim. Ind. (Milan), 1977,59,459 (Chem. Abs., 1978, 88,22 582). J. Perregaard, S. Sheibye, H. J. Meyer, I. Thomsen, and S.-0. Lawesson, Bull. SOC.Chim. Belg., 1977,86,679 (Chem. Abs., 1978,88,61734). B. M. Trost, P. H. Scudder, R. M. Cory, N. J. Turro, V. Ramamurthy,and T. J. Katz, J. Org. Chem., 1979,44,1264.

Eight-membered and Larger Ring Systems

413

(7)

C02Et CH,Ph (15)

CHR (21)

414

Heterocyclic Chemistry

Derivatives of 1,5-diazacyclo-octane have been prepared by a variety of synthetic approaches: e.g., the use of SN2-type reactions to prepare (26) from CH2=C(CH2Hal)2 and RNH2 or from CH2=C(CH2NHR)* and CH2=C(CH21),.14 An alternative method involves ring-opening (using BH3 in THF) and reduction of (27) to give (28).15 The starting materials (27)are readily made by the NaOEt-catalysed condensation of derivatives of diethyl malonate with hydrazine. The formation of (29) from 3-(1-imidazolyl)quinoline,on treatment with LiNPri followed by oxidation with KMn04, can be rationalized in terms of a double Chichibabin reaction.16 Phthalimide reacts with the azirine derivative (30) at 0-20 "C to give (31; X = CO)." The dibenzo[b,f][l,4]diazocine (32)is tub-shaped and chiral, and it has been resolved via a reaction with l-ephedrine.'* The N-alkenyl-phthalimide (33) undergoes a photochemical/solventincorporated cyclization reaction in methanol to give (34) via a proposed one-electron transfer from the N-alkenyl group to carbonyl; rings with up to fifteen members have been prepared by this method.lg An intramolecular cyclization reaction based upon the Cu20-catalysed insertion reaction of isocyanides into the 0-H bond of alcohols enables (35)to be converted into (36).,' The 1,4-dioxocin compound (37)is formed in the photochemical addition of diphenylacetylene to (38)followed by an electrocyclic disrotatory ring-opening of the cis-fused ring system.21A related dithiocin (39) is formed by the thermolysis of (40),presumably by a non-concerted process.22 The reduction of 1,5-dithiacyclo-octane 1-oxide by iodide in aqueous acid . ~ ~kinetics of proceeds ca. lo6times more rapidly than for simple s u l p h ~ x i d e sThe the reaction indicate that the accelerated rate of reduction is due to participation by the transannular thioether group displacing HO-, with the formation of an intermediate dithioether dication (41);this is then ring-opened by attack by Iand de-iodinated by attack by a second iodide ion. Three or More Heteroatoms.-Saccharin (42) reacts with (30) to give (31; X = SO,)." Tetaco-ordinated arsatranes (43) are formed when HOCHR'CH2NR2CRqCHR40His treated with M ~ A S ( N M ~ ~ ) ~ . ~ ~ Tetrameric thioformaldehyde (CH2S)4,in the presence of Et20-BF3,reacts with (CH2S), under mild conditions to give a polymeric product (CH2S),, and with elemental sulphur to give a polymer The possibility that a highly reactive l4

l5 l6

l7 l8 l9 2o

22 23 24

25

K. Schulze, A. Vetter, W. Dietrich, and M. Muehlstaedt, Z. Chem., 1977, 17, 174 (Chem. Abs., 1977,87, 102 295). D. S. Kemp, J. C. Chabala, and S. A. Marson, Tetrahedron Lett., 1978, 543. T. Kauffmann, D. Tigler, and A. Wolterrnann, Tetrahedron Lett., 1977, 741. S. Chaloupka, P. Vittorelli, H. Heirngartner, H. Schrnid, H. Link, K. Bernauer, and W. E. Oberhaensli, Helv. Chim. Acra, 1977,60,2476. J.-M. Ruxer and G. Solladie, J. Chem. Res. ( S ) , 1978, 408. K. Maruyama and Y. Kubo, J. A m . Chem. SOC.,1978,100,7772. Y. Ito, K. Kobayashi, and T. Saegusa, Tetrahedron Lett., 1978, 2087. G. Kaupp and M. Stark, Angew. Chem., Int. Ed. Engl., 1977,16,552. W. Schroth and L. Moegel, 2. Chem., 1977,17,441 (Chem. Abs., 1978,88,89 645). J. K. Doi and W. K.Musker, J. A m . Chem. SOC., 1978,100, 3533. P. Maroni, M. Holeman, and J. G . Wolf, Bull. SOC.Chim. Belg., 1977,86,199 (Chem.Abs., 1977,87, 22 202). M. Schmidt and E. Weissflog, Angew. Chem., Int. Ed. Engl., 1978,17, 51.

Eight-membered and Larger Ring Systems

0'""
-N

415

0

(33)

Go MeO,

\

O (34)

,Yc2CHR

'CHR2OH

(35)

P'

0,

R2N+AsMe R 3 * '

R4 (43)

Heterocyclic Chemistry

416

intermediate CH2SCH2SCH2SCH2SBF4(diradical or zwitterion?) is formed has been proposed.

2 Nine- and Ten-membered Heterocycles Subtle changes in the substitution pattern of quaternized piperidine compounds can influence the geometry of 2,3-sigmatropic ring-expansion processes. In compounds (44),26 (45),27 and (46)26 the substituents involved in the reaction with the vinyl group are all on the same side of the six-membered ring. Treatment of (44)with LiNPri gives the (2)-azacyclononene (47), and the conformationally fixed compound (45)is also converted into the (a-isomer (48)with DBU, via the sterically favourable cisoid vinyl rotamer (49). However, the reaction of (46)and DBU gives the (E)-azacyclononene (50). BU‘

BU‘

q-2 PhCH,

(48)

CHC0,Et I

Q02Et

(49)

(50)

S-Alkylation of (51) with CF3S03CH2C02Et is assumed to put the SCH2C02Etand a-vinyl groups in adjacent equatorial positions; on treatment with DBU, the (E)-thiacyclononene (52) is formed:26in this case, only a transoid vinyl rotamer (53) can achieve effective five-centre overlap without significant distortion of the ring. The ten-membered (I?)-thiacycloalkene (54)has been prepared by an analogous reaction sequence from 2 - v i n ~ l t h i e p a n . ~ ~ Thermolyses of the cis-tris-cr-homobenzene derivatives (55 ; X = NTos) and (55; X = 0) give the 4,7-dihydroazonine (56;X = NH) and the 4,7-dihydrooxonin (56;X = 0), respectively.28 N-Chlorosulphonyl isocyanate reacts as the electrophilic species ClS0,N-60 with the cisoid and transoid conformers (57) and (58) by overall conjugative cycloaddition reactions to give, after reductive removal of the chlorosulphonyl group by Na,S03 (a reagent which also caused migration of double-bonds), a ”

E. Vedejs, M. J. Arco, D. W. Powell, J. M. Renga, and S. P.Singer, J. Org. Chem., 1978,43,4831.

28

H. Prinzbach, H.-P. Bohm, S. Kagabu, V. Wessely, and H. V. Rivera, Tetrahedron Lerr., 1978,1243.

’’ E. Vedejs, M. J. Arco, and J. M. Renga, Tetrahedron Lett., 1978, 523.

Eight-membered and Larger Ring Systems

417

mixture of products which contained (59; n = 2) (45%), (59; n = 3) ( 5 5 % ) , (60; n = 2) (12%) and (60; n = 3) ( l l , / ~ ) . Structure ~~ (61) shows the zwitterionic intermediate that has been proposed as the species initially formed prior to its collapse to cyclized material en route to (59). N-Methyl-3,4-dihydroisoquinolinium salts undergo a two-fold insertion of PhCECNMe, to give (62).30Molecular oxygen converts cyclic imines (63; R' = H) into the keto-amides (64) in non-catalysed reactions that proceed through the unstable a-imino-hydroperoxides (63; R' = OOH).31

Rl?&JIR (55)

&-A \

1

(58)

An isolated but unusual example of the formation of the 1,5-diazonine derivative (65) involves treatment of (66) with silica gel at 25 "C for eighteen hours, presumably to form (67), which then undergoes another 175-sigmatropic 29 30

31

M. Langbeheim and S. Sarel, TetrahedronLett., 1978, 2613. R. Fuks, R. Merenyi, and H. G. Viehe, Bull. SOC.Chim. Belg., 1976,85892 (Chem.Abs., 1977,87, 5780). D. Schumann, A. Naumann, and K.-P. Wirtz, Chem. Ber., 1979,112, 734.

418

Heterocyclic Chemistry

shift to form (65).32The meso-ionic 3a,6a-diazapentalenes (68) react with two equimolar amounts of MeOzCCrCC02Meto give (69; X = C02Me)when R’is PhCO and R2is Ph, thou h a compound containing an eight-membered ring is formed if R’ = R2 = H.3 f Varieties of approach for the synthesis of ten-membered cyclic lactones have been reported. The cyclization step in a route to naturally occurring diplodialides utilizes a modified Reformatski reaction, using Et,AICI and Z n with (70).34 Another process involves an overall transesterification reaction: compound (71) is first converted into the S-(2-pyridyl) thioester, by its reaction with 2,2’dipyridyl disulphide and Ph3P; the thioester is then cyclized, using AgC104.3sA Claisen ester rearrangement converts (72) into a mixture of the (2)-(7 parts) and ( E ) - (2 parts) ten-membered lactone (73).36The formation of (72) as an intermediate (not isolated) involves a crucial selenium-assistedformation of the acetal (74; X = PhSe) from ( 7 9 , using PhSeBr, followed by oxidation with periodate [to give (74; X = PhSeO)] and finally thermal elimination of PhSeOH. Conversion of the 2-vinylpyran (76) into (77) with CI2C=C=O (made by

X’ (74)

(75)

P. Aeberli and W. Houlihan, J. Heterocycl. Chem., 1978, 15, 1141. M. Matsumoto and T. Uchida, Chem. Lett., 1978, 1093 (Chem. Abs., 1979,90, 103 891). ’‘ J. Tsuji and T. Mandai, TetrahedronLett., 1978, 1817. ” H. Gerlach, P. Kunzler, and K. Oertle, Helv. Chim. A m , 1978, 61, 1226. 36 M. Petrzilka, Helv. Chim. Acta, 1978, 61, 3075. 32 33

Eight-membered and Larger Ring Systems

419

dechlorination of CC1,COCl with Zn/Cu) proceeds under mild conditions (in ether, at 25 "C) by a 3,3-sigmatropic shift from the initially formed 1,3-dipolar intermediate that is produced by the oxygen of pyran attacking the carbonyl carbon.37 Cleavage of cis-cyclohexane-1,2-diolby iodine(1) acetate into hexane-l,6-dial is accompanied by the formation of the stable crystalline peroxide (78); this suggests that a radical process is occurring.38 The reversal of the Hofmann elimination reaction has been studied with cycloa~a-nonene,~~ -decene,*' and - ~ n d e c e n ecompounds. ~~ With (79), cyclization at 25 "C occurs under the influence of EtOH and HI, of aqueous MeOH, or of MeOH and NI-LOH (at pH 10) to give (80; X = I), (80; X = OH), and (80; X = MeO), respectively.

(83)

3 Macrocycles Systems containing Nitrogen only.-One Nitrogen Atom. Synthesis of some monoaza-annulenes have been reported. The 1H-1-aza[l7]annulene (81; X = NH), a higher homologue in the series of which pyrrole is the first member, has nitrogen occupying an internal position. It is formed by the sequence of reactions that involves photolysing (82; Y m =NC0,Et) in pentane at -105 to -7OoC, treatment of the derivative (83) with KOBu', and protonation of the aza[l7]annulenyl anion (in which the nitrogen also occupies an internal posit i ~ n ) . However, ~* irradiation of (82; R = NH) with U.V. light gives an isomer of 37 38

39

40 41

R. Malherbe and D. Bellus, Helv. Chim. Acta, 1978,61, 3096. R. C. Cambie, D. Chambers, P. S. Rutledge, and P. D. Woodgate, J. Chem. SOC.,Perkin Trans. 1, 1978,1483. D. J. Brickwood, A. M. Hassan, W. D. Ollis, J. S. Stephanatou, and J. F. Stoddart, J. Chem. Soc., Perkin Trans. 1, 1978, 1393. A. J. Kirby and C. J. Logan, J. Chem. SOC.,Perkin Trans. 2, 1978,642. H. Roettele, G. Heil, and G. Schroeder, Chem. Ber., 1978,111, 84.

420

Heterocyclic Chemistry

(81) that has an external arrangement of the NH group. Aza[lS]annulene, which is similarly a Huckel (4n + 2 ) ~ e l e c t r o ncompound, and a higher homologue of pyridine, has been synthesized by the photochemical decomposition of (84) in pentane at -80°C; it has been shown, by 'H n.m.r. spectroscopy, to have the structure (85), in which the nitrogen occupies an internal position.42The darkgreen solid forms a black/violet hydrochloride, which contains an equilibrium mixture of (86) and (87) in the ratio of 1:4, respectively.

Butadiene

H

(85) X =

(84)

(86) X

undergoes

=

nickel-catalysed

NH

cyclization

(87)

reactions

with and with methylfurfuraldimine, forming (89).44 The dialkyne compound HCEC(CH,)~,C=CH and amines RNH2 (R = Ph or PhCH2), with Cu'Cl, at 170 "C, give the heterophanes (90).45

(RCH2)2C=CHN=CHCH(CH2R)2, to give (88) as one of the

The formation of [2]-[azacyclohexacosane]-[cyclo-octacosane]-catenane has been described.46 Two or Three Nitrogen Atoms. A particularly intriguing transamidation reaction involves cyclic amides bearing a -(CH2)3NH2 group on the nitrogen. When such a compound is treated with H2N(CH&NH K+,in H2N(CH2)3NH2[KAPA], followed by quenching with water, the ring of the cyclic amide is expanded by four atoms (-CH2CH2CH2NH-), as shown in Scheme 1. In this way, the eightmembered heterocycle with one nitrogen [Le. @-1-N] (91) is converted into

*' 43 44

45 46

W. Gilb and G. Schroeder, Angew. Chem., Int. Ed. Engl., 1979, 18, 312. D. Reinehr, Helv. Chim. Acta, 1978, 61, 1122. U. M. Dzhemilev, L. Yu. Gubaidullin, and G. A. Tolstikov, Izu. Akad. Nauk. SSSR, Ser. Khirn., 1978,2557 (Chep. Abs., 1979,90, 121 386). A. Stutz and H. Reinshagen, Tetrahedron Lett., 1978,2821. E. Logemann, G. Schill, and W. Vetter, Chem. Ber., 1978,111, 2615.

Eight-membered and Larger Ring Systems

n

F?

42 1

KAPA

NH2

0 - 2 - N (92; R = H) (the minimum ring size which can be formed by the pr~cedure),~’ and analogous reactions can be carried out with the compounds @-1-N, @-1-N, and 0 - 1 - N . A stepwise sequence of reactions may be carried out :48 0-1-N + 0-2-N + 0-3-N but this double expansion may be effected in one experiment, using [93; R = (CH2)3NH(CH2)3NH2]and KAPA; an example of what is now called the ‘ziprea~tion’.~’

(91)

(93)

\

/

(94)

0 (95)

The photochemically induced cyclizations of N-(wmethylani1ino)alkylphthalimides give (94; n = 1-6, 10, or l2).” The macrocyclic ring system (95) has been synthesized and is of interest for two reasons: (i) it possesses a particularly electron-rich cavity; and (ii) because of the electronic and/or steric 47

48 49

5o

A. Guggisberg,U. Krarner, C. Heidelberger, R. Charubala, E. Stephanou, M. Hesse, and H. Schrnid, Helv. Chirn. Acta, 1978, 61, 1050 U. Kramer, A. Guggisberg, M. Hesse, and H. Schmid, Helv. Chim. Acra, 1978,61, 1342. U. Kramer, A. Guggisberg, M. Hesse, and H. Schmid, Angew. Chem., Inr. Ed. Engl., 1977,16,861. M. Machida, H. Takeuchi, and Y . Kanaoka, Heterocycles, 1977, 7, 273 (Chem. Abs., 1978, 88, 50 823).

Heterocyclic Chemistry

422

electronic repulsion within the cavity, which should cause deviation from planarity, two conformations should be po~sible.'~

Four Nitrogen Atoms. Ring systems with four nitrogen atoms bridged by two- and three-carbon units (having a 2-3-2-3 or a 2-2-3-3 sequence) are of special interest for their ability to complex certain metal ions, ions which are often necessary to facilitate the formation of the ring in the first instance (the metal-template effect). The reaction of EtOCH=C(R)CHO with (96)in the presence of M2+ions having ionic radii of ca. 70 pm (e.g.Ni2'; 69 pm) gives high yields of (97) because of the favourable arrangement of the enediamine groups in the complex (98) and because of the high stability of (97).52Often the removal of the metal ion to give the free heterocycle is accomplished only with difficulty, but an ingenious use of metal ions that are either considerably smaller (Mg2'; 66 pm) or considerably larger (M2'; 80 pm) than the ionic radius of 70 pm that is required for a good fit of the cavity in (97) enables complexes (98) to be formed prior to the condensation reaction; upon completion of the macrocyclic ring, the cations are readily

R

The enthalpy of formation of tetra-aza-macrocyclic complexes with metal ions, which significantly contributes to their high stability in solution, strictly depends on the fitting of the metal ion into the ligand cavity. The value for the Cu" complex from (99) is more favourable than that from the isomeric unsymmetrical complex (loo), and the values for both of these fourteen-membered systems are more favourable than any other in the twelve- to fifteen-membered systems.54 The thermodynamics of protonation of some tetra-aza-macrocycles related to and including (99) have been Important factors at work in comparison with closely related open-chain tetra-amines include the formation of

'' 52

53 54

55 56

G. R. Newkome, J. D. Sauer, P. K. Mattschei, and A. Nayak, Heterocycles, 1978, 9, 1555 (Chem. Abs., 1979, 90, 38 896). I. Kohlmeyer, E. Lorch, G. Bauer, and E. Breitmaier, Chem. Ber., 1978,111, 2919. G. Miihmel and E. Breitmaier, Angew. Chem., Inr. Ed. Engl., 1978,17,772. L. Fabbrizzi, M. Micheloni, and P. Paoletti, J. Chem. Sac., Chem. Commun., 1978, 833. M. Micheloni, A. Sabatini, and P. Paoletti, J. Chem. SOC.,Perkin Trans. 2, 1978, 828. M. Micheloni,P. Paoletti, and A. Vacca, J. Chem. SOC.,Perkin Trans. 2, 1978, 945.

Eight-membered and Larger Ring Systems

423 +

favourable intra-cation hydrogen bonds N:.-.H-N in the ring compounds for the first two protonations; but, due to the high electrostatic repulsion among the,four positively charged nitrogen atoms, the overall basicity, utilizing all the heteroatoms, is lower than that of each corresponding open-chain tetra-amine. Two intermediates (101; R' = H, R2 = Tos) and (101; R' = Tos, R2 = H) have been synthesized which are accessible to alkylation of the secondary N-H group, thereby enabling an additional ligating function to be introduced; the tosylate groups are then removed electrochemically or by 40% HBr in HOAC.'~ 2,6-Diacetylpyridine and Y(CH2)2N[(CH2)3NH2]2 (Y = OH or NMe2)undergo a condensation reaction in the presence of Ni2+salts to form (102), which has the additional ligating function [(CH,),Y] in the m a ~ r 0 ~ y ~ 1 e . ' ~

Y (102)

cf. (105)

P Self-coupling of the dilithio-compound (103) with CuCl, gives (104), the first cyclohexa-aromatic compound to be synthesized which has a face-to-face arrangement of the two benzene rings." The 'H n.m.r. spectrum shows an upfield shift for the benzenoid protons, resulting from the anisotropic effect of the neighbouring benzene ring, and since they give only a sharp singlet, despite having different magnetic environments, (104) and its mirror image must be undergoing fast interconversion. The attempt to produce the macrocyclic tetra-aza-compound (109, which has an annulene perimeter, by the reaction of (106) with 1,2-cyclohexanedione resulted in the tautomer (107) being produced.60 Glyoxal undergoes a novel

'' M. Hediger and T. A. Kaden, J. Chem. SOC.,Chem. Commun., 1978,14. 59

T. J. Lotz and T. A. Kaden, Helv. Chim. Acta, 1978,61, 1376. T . Kauffmann and H. Lexy, Angew. Chem., Int. Ed. Engl., 1978,17,755. C.P.Ehrensperger, M. Heberlein, and P. Skrabal, Helv. Chim. Acta, 1978,61,2813.

424

Heterocyclic Chemistry

condensation reaction with the macrocycle (108) to form the tetra-azapyrene (109).61The exchange reaction between (110; R1 = R2 = H) and P(NMe2), gave a product which indicated that the phosphorane tautomer (111; R = H) predominated rather than the tricyclic phosphorus triamide, whereas ethylenediamine derivatives have not yielded phosphorus(v) compounds.62 Similarly, in the reaction of (110; R' = SiMe,, R2 = H) with PF5, all four nitrogen atoms participate in forming (111; R = F), in contrast to the reaction of simple dialkylamino-compounds R2NSiMe3, which effect only two displacements of fluorine, giving (R2N)zPF3.63 The cyclic tetramine (110; R1 = H, R2 = n-CI4Hz9),which has a long hydrophobic chain, catalyses phase-transf er reactions in which both cations and anions are

NR' R'N

n

n

u

U

Five or More Nitrogen Atoms. A spectacular example of the 'zip-reaction' (see page 421) has been reported, i.e. the conversion of the thirteen-membered, one-nitrogen-containing macrocycle (93; R = (CH2)3[NH(CH2)3]9NH2) into the fifty-three-membered, eleven-nitrogen-containingcompound (112).65 61

62

64 65

P. W. R. Caulkett, D. Greatbanks, R. W. Turner, and J. A. Jarvis, J. Chem. Soc., Chem. Commun., 1977,150. J. E. Richman and T. Atkins, Tetrahedron Lett., 1978, 4333. J. E. Richman, Tetrahedron Lett., 1977, 559. P. Tundo, Tetrahedron Len., 1978,4693. U . Kramer, A. Guggisberg,M. Hesse, and H. Schmid, Angew. Chem., Int. Ed. Engl., 1978,17,200.

Eight-membered and Larger Ring Systems

425

The synthesis of union -receptor molecules has received little attention compared with cation-co-ordinating species. A method has been developed to introduce guanidinium groups into macrocycles, and the stability constants for the 1:1complexes which are formed with have been measured. The value for (1 13) and Pod3-in MeOH-H20 (9 : 1) is 4.3, indicating that the effect is relatively weak.66

Systems containing Nitrogen and Other Heteroatoms.-A chiral [( - )-enantiomer] pyridoxal analogue (114; R = CHO) has been synthesized and its capacity to act as a potential catalyst for non-enzymic reactions has been dem~nstrated:~' a modest rate enhancement over (115) (by a factor of 1.67) has been observed in the presence of Cu2' ions for the rate of racemization of Lglutamic acid, and it exhibits a modest stereospecificity in that L-glutamic acid reacts faster than the D-enantiomer by a factor of 1.24. The chiral ( - )pyridoxamine compound (114; R = CHzNHz) undergoes a non-enzymatic stereoselective transamination reaction with PhCH2C(O)COZ- Na' and

*

ZnClz.6Hz0 to give PhCH2CH(NH2)C02H in which the (+)-enantiomer predominates in aprotic solvents and the (-)-enantiomer predominates in protic media.68 The phosphorus-containing macrocycle (116) is formed by the alcoholysis (by ROH) of compounds of structure (117).69 66

67 68 69

B. Dietrich, T. M. Fyles, J-M. Lehn, L. G. Pease, and D. L. Fyles, J. Chem. SOC.,Chem. Commun., 1978,934. H. Kuzuhara, M. Iwata, and S . Emoto, J. A m . Chem. SOC.,1977,99,4173. H. Kuzuhara, T. Komatsu, and S . Emoto, Tetrahedron Lett., 1978, 3563. H. Sliwa and J. P. Picavet, Tetrahedron Lett., 1977, 1583.

Heterocyclic Chemistry

426

Systems containing Heteroatoms other than Nitrogen.-Epoxidation of dimeric cyclo-octatetraene and photolysis of the product (82; Y = 0) gives oxa[ 17lannulene (81 ;X = 0),a higher homologue in the series of which furan is the first member.” The [24]annulene tetrasulphide derivative (118; X = S) and the oxygen-containing compound (118; X = 0)have been prepared via Wittig

reaction^.^^

(119)

(120)

The cyclic acetylacetone host (119) is synthesized from the magnesium salt, specifically, of (120) (and not from the calcium salt, which works in a related synthesis, thereby demonstrating a template effect) by treatment with LiNPr; and reaction with 1,3-bis(bromomethyl)benzene.72Interestingly, removal of a proton from the monoanion derived from (119) to produce the dianion is so slow that its course can be observed on a pH meter. Molecular models show that the proton in the monoanion is locked in a tetrahedrally arranged cage of four oxygen atoms that carry one negative charge overall. Macrocyclic lactones have been synthesized from a variety of functionalized acyclic esters. The modified Reformatski reaction using RCHBrCOO(CH2), CHO and Et,AICI plus Zn gives aldol-type products containing 13, 15, and 16 atoms in the ring.73A double Wittig reaction has been used to prepare the sixteen-membered bis-lactone (-)-vermiculine, a cytotoxic antibiotic having a C, axis of ~ y m r n e t r y . ~ ~ The photochemical (2 + 2) cycloaddition reactions of aw-dicinnamates are effective for the formation of eighteen-75and 22-, 28-, 32-, and 36-membered76 70 71

72

73 74

7s 76

G. Schroeder, G. Plinke, and J. F. M. Oth, Chem. Ber., 1978,111,99. S . Strand, B. Thulin, and 0. Wennerstrom, Actu Chem. Scund., Ser. B, 1977,31,521 (Chem. A h . , 1977,87,201496). A. H. Alberts and D. J. Cram, J. Am. Chem. SOC.,1977,99,3880. K. Maruoka, S. Hashimoto, Y. Kitagawa, H. Yamamoto, and H. Nozaki, J. Am. Chem. SOC.,1977, 99,7705. K. F. Burri, R. A. Cardone, W. Y. Chen, and P. Rosen, J. Am. Chem. SOC.,1978,100,7069. J. A. Ors and R. Srinivasan, J. Am. Chem. Soc., 1978, 100, 315. J. A . Ors and R. Srinivasan, J. Chem. SOC., Chem. Commun., 1978,400.

Eight-membered and Larger Ring Systems

427

ring systems, e.g. the conversion of (121) into (122). A point of interest is the stereochemistry of the product: only the &addition compound is formed. 0

0

II

II

0

0

Ph

II 0

0 (121)

0

0 (122)

An internal Diels-Alder reaction occurs stereoselectively with (1 23) in boiling toluene under high dilution to give (124) (27%),and only 5% of the alternative regio-is~mer.~~ Intramolecular Williamson’ssyntheses have been performed on ortho-w-bromoalkyl- and ortho-w-bromoalkyloxy-phenols,using NaOH in Me2S0, and the kinetics of the ring-closure reaction for these as well as for reactions using Br(CH2),-2C02Hhave been examined.” In the last study, a factor of ca. lo6separates the rate constant for formation of the three-membered ring from that for the formation of the least reactive system (the eight-membered ring). Reactivities vary within a factor of 2 for n = 13-23. Comparisons of reactivity data of different cyclization reaction series, when considered in terms of effective molarities [defined as k(intramolecu1ar reaction)/k(intermolecular reaction) for a properly chosen model reaction] suggest that the ease of formation of large rings is independent of (i) the nature of the functional groups involved in the cyclization process, (ii) the length of the chain, and (iii) the presence of structural moieties other than methylene groups.

Thiomacrolides (125; n = 4, 5, 6, or 10) are formed by the photochemical oxygenation of the bicyclic thioenol ethers (126) produced by the reaction of (127) with acids.80 77

S. J. Bailey,E. J. Thomas, W. B. Turner,and J. A. Jarvis, J. Chem. SOC.,Chem. Commun., 1978,474.

’‘ G. Illuminati, L. Mandolini, and B: Masci, J. A m . Chern. SOC.,1977,99,6308. 79

C. Galli, G . Illuminati, L. Mandolini, and P. Tamborra, I. Am. Chem. SOC.,1977,99,2591. H. C. Araujo and J. R. Mahajan, Synthesis, 1978, 228.

428

Heterocyclic Chemistry

A novel xylylene-like intermediate (128) is formed by a Hofmann-type 1,selimination reaction when (129) is heated.*l Head-to-head and head-to-tail dimers are formed which, after hydrogenation, give the furanophanes (130) and (131) respectively. The cross-cyclization of (128) with p-xylylene expands the scope of the syntheses.

(130)

(131)

Consecutive 2,3- ring-expansions on the eight-membered sulphur heterocycle (19; R = CH=CH2), using prop-2-enyl bromide" (see also ref. 9) followed by proton abstraction with DBU and then rearrangement, give first an elevenmembered sulphur heterocycle (132), then a fourteen-membered compound (133), and finally two seventeen-membered rings (134) and (135). A similar sequence of reactions, involving S-alkylation with prop-2-enyl triflate, converts a six-membered cyclic sulphide into a twelve-membered compound via a ninemembered one.' An unusual macrocyclic polydisulphide (136) is reported to be formed by treatment of the adduct of Me2C=CH2 and S2CI2with ethanolic NaSHeE2

I

1

S-CH2-C-S-S

/\

Me Me

'' S. H. KusefogIu and D. T. Longone, Tetrahedron Lett., 1978,2391. 82

M. Braid, G. T. Kokotailo, P. S. Landis, S. L. Lawton, and A. 0.M. Okorodudu, J. A m . Chem. Soc., 1978,100,6160.

Eight-membered and Larger Ring Systems

429

Crown Ethers and Related Compounds.-Syntheses. Double- and triple-loop crown ethers linked through spiro carbon atoms have now been synthesized, and they exhibit di- and tri-functional cation-receptor properties, re~pectively.~~ Some investigations have been conducted on their use for the separation of cations according to their charge. Thus a 1:1 mixture of NaSCN and Ca(SCN)*, when mixed with the ‘ 5 3 ’ ligand (137), gives a precipitate of the 1: 2 Na’ complex in almost quantitative yield, whereas 15-crown-5, under the same conditions, selectively forms the 1: 1 complex incorporating Ca2’. Macrocycles that contain 2,4-pyrimidino subunits connected by C-0 and/or C-S linkages have been ~ y n t h e s i z e d .When ~~ compound (138) is heated at 250°C for-20 hours, rearrangement to the uracil macrocycle (139) occurs by analogy with a transformation first reported in 1930. In another ring-contractive process a 2,2’-bipyridyl unit is formed by a benzilic-acid-type rearrangement of (140) with an alkoxide (sodium he~aethyleneglycolate).~~

Pyrolysis of sodium chloroacetate has been shown to give, in addition to the diglycolide (141; n = 2), small amounts of the penta- (141; n = 5 ) (0.16%) and hexa-glycolides (141; n = 6) (0.03%), but no ring compounds in which n = 3 or 4.86 The alkali-metal ion acts as a template in the formation of substituted and unsubstituted 15-crown-5 and 18-crown-6 polyethers from equimolar amounts of polyethylene glycols (having suitable ethyleneoxy-groups), toluene-psulphonyl chloride, and powdered NaOH or KOH, in dioxan or m~noglyme,~’ and the process has been adapted for the synthesis of N-alkyl monoaza crown

’’ E. Weber, Angew. Chem., Inf. Ed. Engl., 1979,18,219. a4

” 86

’’

G.R.Newkome, A. Nayak, J. Otemaa, D. A. Van, and W. H. Benton, J. Org. Chem., 1978,43,3362. G . R. Newkome and D . C. Hager, J. A m . Chem. SOC.,1978,100,5568. J. Dale, 0.Sevaldsen, and K. Titlestad, Actu Chem. Scund., Ser. B, 1978,32,307(Chem.A h . , 1978, 89,108 036). K. Ping-Lin, M. Miki, and M. Okahara, J. Chem. SOC.,Chem. Commun., 1978,504.

430

Heterocyclic Chemistry

ethersg8Lead(I1) [as Pb(SCN),] also acts as a template in the cyclo-condensations of 2,6-diformyl- or 2,6-diacetyl-pyridine and H2N(CH2CH20)3CH2CH2NH2.89 An intriguing intramolecular photochemical reaction involves the dimerization of anthracene units linked through their C-9 positions in C14H90CH2(CH20CH2)2CH20C14H9 to give a thermally unstable product.g0 However, in the presence of excess LiC104, the cation locks the 12-crown-4 derivative as the complex (142); this is stable at 201-210 "C, but it reverts to the acyclic precursor on the addition of a cation-solvating medium such as acetonitrile.

Effects of Crown Ethers on Chemical Reactions. Potassium hydride in THF abstracts the methine proton in triphenylmethane only in the presence of 18-crown-6 polyether (18-C-6); this is the first reported use of a crown ether to affect an acid-base equilibrium." The same polyether enhances the nucleophiliwhile dicyclohexyl-18-crown-6, city of KOBu' in reactions with benzyl used as a phase-transfer agent, enables 4-NO2-C,H4CO2- K' in water to react with benzyl bromide; a process which occurs by simultaneous S N 1 and SN2 mechanisms, though predominantly by the SN2 Polymer-supported crown ethers can be used as phase-transfer catalysts in the halogen-exchange reaction of n-octyl bromide with KI.94A 300-fold increase in the rate constant for the reaction between l-chloro-2,4-dinitrobenzenein 99% benzene-1 o/' MeOH with KOMe upon the addition of an equivalent amount of 18-C-6 is due to the ability of the crown ether to dissociate ion pairs.9s The role of 18-C-6 in promoting the decarboxylation of sodium carboxylates has been

'* '93* 94

95

96

P.-L. Kuo, M. Miki, I. Ikeda, and M. Okahara, Tetrahedron Lett., 1978,4273. D. E. Fenton, D. H. Cook, and I. W. Nowell, J. Chem. SOC.,Chem. Commun., 1977,274. J.-P. Desvergne and H. Bouas-Laurent. J. Chem. Soc., Chem. Commun., 1978,403. E. Buncel and B. Menon, J. Am. Chem. SOC.,1977,99,4457. S. A. DiBiase and G. W. Gokel, J. Org. Chem., 1978, 43,447. K.-H. Wong, J. Chem. SOC.,Chem. Commun., 1978,286. M. Tomoi,0. Abe, M. Ikeda, K. Kihara, and H. Kakiuchi, Tetrahedron Lett., 1978, 3031. C. Mariani, G. Modena, and G. Scorrano, J. Chem. Res. (S), 1978,392. D . H. Hunter, M. Hanity, V. Patel, and R. A. Perry, Can. J. Chem., 1978, 56, 104.

Eight-membered and Larger Ring Systems

43 1

Poly(vinylbenzo)-18-crown-6 (143), dissolved in water, catalyses the decarboxylation of (144) to the 2-cyano-hitrophenate by a factor of 2300 at 25 "C, but by convertingthe polymer (which acts as a neutral polysoap) into apolycation, the intrinsicbinding constant is vastly increased, and the catalyticactivity is raised accordingly by a factor of 14 000 for the very effective polymer/Cs'ClThe aromatic hydrocarbon environment and the high charge density of the polysoap have been suggested as the main factors contributing to the high catalytic activity of the system. The stereochemistry of the cyclopropane derivatives formed via the initial Michael addition of R1CClCO2Me (from R'CHC1C02Me and NaH) to H2C=CR2C02Me changes from the predominantly cis-product (145) to a mixture which usually contains mainly the trans-isomer when 18-C-6 is pre~ent.~' Cyclization of the enantiomer (146) with 0.1 M-KOBu' in chlorobenzene at -40 "C gives a product that contains 62% of the isomer having the ( S ) configuration at C-6 (147) and 38% of that with the (R) configuration; but, when the same reaction is carried out in the presence of 0.1M-18-C-6, the diastereaselectivity is almost exactly revesed for this asymmetric reaction.99

-(YH-CH,), -

R2 R' Na' or

Of i C N0 2 M e

Secondary dialkyl-ammonium salts are less effectively complexed than primary alkyl-ammonium salts with 18-C-6, a property which has been exploited in their selective acylations.loOThus PhCH2NH2,PhCH2NH2Et' C1-, and 18-C-6 in the molar proportions 1: 1: 1, on treatment with (CF3C0)20and Et3N, give a mole fraction of secondary amide of 0.79; this is increased to 0.95 in the presence of two molar proportions of crown ether (cf. a mole fraction of only 0.20 in the absence of crown ether). Thermodynamic parameters have been measured by titration calorimetry for complexes formed between 18-C-6 and various ArN2' S. C. Shah and J. Schmid, J. A m . Chem. Soc., 1978,100,1426. S. Akabori and T. Yoshii, Tetrahedron Lett., 1978,4523. 99 T. Wakabayashi and Y. Kato, Tetrahedron Lett., 1977, 1235. loo A. G. M. Barrett and J. C. A. Lana, J. Chem. Soc., Chem. Commun., 1978,471. 97

98

Heterocyclic Chemistry

432

salts and related ArNH3' salts."' The aryl group is expected to be closer to the macrocyclic ligand in the -N2+ salts than in the corresponding anilinium salts, and it is indeed found that an ortho methyl group eliminates complexation completely with the diazonium salt, while reducing the stability of ArNH,' by a factor of ten. A substituent such as a para Et2N group delocalizes the charge on the diazonium group, causing almost total loss of stability of the complex. The rate of photochemical formation of fluorobenzene from solid PhN2+BF,- is dramatically retarded with the 1: 1 solid complex between the solid aryl diazonium compound and 18-C-6.102On the other hand, 15-crown-5 does not provide the specific complexation with this salt (the cavity is too small), and actually accelerates the rate of photochemical decomposition in the early stages.

Reactions of the Macrocyclic Rings of Crown Ethers and Related Compounds. Synthetic molecular catalysts which embody both a receptor site for substrate binding and a reactive site for transformation of the bound substrate are of interest as enzyme models. Considerable progress has been made in this area, though the final stage in imitating enzyme catalysis, i.e. the automatic release of the substrate from the host after it has reacted, has not been achieved. Crown ethers containing (or attached to) 1,4-dihydropyridine rings, i.e. (148) and (149a), respectively, have been synthesized; they show enhanced rates of donation of hydride to positively charged substrates that can complex with the + crown-ether portion of the molecule. Thus (148) reduces PhCOCH2S(Me)Phto PhCOCH, and PhSMe with a rate constant that is 2700 times greater than that for reduction by (150), at 75 OC.lo3 Moreover, sodium ions strongly inhibit the transfer of hydride, and an X-ray structure determination has confirmed that Na' fits very neatly into the ring of the m a c r ~ c y c l eCompound .~~~ (149a) has been used with primary alkyl-ammonium salts as guests; e.g., (15 1).'05

CONHBu"

(149)

X

=

X'

=

-CONH(CH2),N

(b) X

=

X'

=

-CONH(L)CHCO*Me

=

CH2SH H; X' = CH,SH, (CH,),SH, or CH20(CH2)2SH

(a)

Me

I

(c) lo'

lo'

lo3 lo4 '05

X

R. M. Izatt, J. D. Lamb, B. E. Rossiter, N. E. Izatt, J. J. Christensen, and B. L. Haymore, J. Chem. SOC.,Chem. Commun., 1978, 386. R. A. Bartsch, N. F. Haddock, and D. W. McCann, Tetrahedron Lett., 1977, 3779. T. J. Van Bergen and R. M. Kellogg, J. A m . Chem. SOC.,1977,99,3882. R. H. van der Veen, R. M. Kellogg, and A. Vos, J. Chem. SOC., Chem. Commun., 1978,923. J.-P.Behr and J.-M. Lehn, J. €'hem. SOC., Chem. Commun., 1978, 143.

Eight-membered and Larger Ring Systems

433

(151)

The host (149b) forms complexes with primary amino-ester salts which display enhanced rates of intramolecular thiolysis, giving internally complexed S-aryl derivatives.lo6 High chiral discrimination is found in the reaction with enantiomeric dipeptide ester salts &H3CH2CONHEH(CH2Ph)COOC6H4NO2-p Br- : the L-species reacts ca. 50-90 times faster with (149b) than does its D-antipode, enabling a kinetic resolution of the non-consumed D-ester from the racemic ester to be achieved. Other workers have studied the kinetics of transacylation +

Br- (n = 1,2,3, or 5) with hosts reactions of guests NH3(CH2)nC02C6H4N02-p (149c) and have showed the feasibility of getting regioselectivity in the reactions that are catalysed by functionalized crown ethers.lo7 The photochemical reaction of PhCOR compounds with 18-crown-6 in benzene brings about the overall replacement of hydrogen in the ether by PhC(OH)R.lo8 With acetophenone (R = Me), only 9% of the substituted product is formed, but with compounds which are known to complex with the macrocycle (e.g. when R is CH2CH2CNor CH2CH2C02-K+),the yields are of the order of 20%. It is presumed that, in these cases, Ph(C-O)(R) abstracts H from the ether, and the two radicals thus formed, being held together more tightly by complexation (or by a loose ion-pair interaction) than in a simple radical pair, collapse to give the cross-coupled product. The acylation of benzo-crown ethers can be carried out, using RCOCl and BF3 or R C 0 2 Hwith P205and MeSO3H.lo9 The efficiency of photoelimination of propene from the pentanoyl crown ether derivative (152) to give the acetyl derivative is increased by complexation with Na' and with K ' by factors of 5 and 10 respectively.'"

lo6

J.-M. Lehn and C. W i n , J. Chem. SOC., Chem. Commun., 1978,949.

T. Matsui and K. Koga, Tetrahedron Lett., 1978, 1115. M. Tada and H. Hirano, Tetrahedron Lett., 1978, 5111. lop W. W. Parish, P. E. Stott, C. W. McCausland, and J. S. Bradshaw, J. Org. Chem., 1978, 43,4577. 'lo R. R. Hautala and R. H. Hastings, J. A m . Chem. SOC., 1978, 100, 648. lo'

434

Heterocyclic Chemistry

Monoaza-18-crown-6, with KH in THF, forms an anionic base (153)"' in which the nitrogen remains unassociated with the counter-ion, even in toluene (a solvent of low polarity).ll2 This was demonstrated by the formation of a low proportion of but-1-ene in its reaction with 2-iodobutane compared with the same reaction using KOBu', which is an associated base that has a high steric requirement.

The stabilities of macrocyclic ether acetals (154) towards acid-catalysed ringopening are increased markedly by the addition of some alkali-metal cations. '13 The results are consistent with the assumption that the basicity of the acetal oxygen atoms (the protonation of which occurs in the first step of the hydrolysis) is lowered, to an extent that is determined by the degree of complexation of the metal ion by the cyclic ether. The ozonolysis of dibenzo-18-crown-6 polyether gives the simple eighteenmembered-ring tetralactone.'14

Formation of Host-Guest complexes. Cram and co-workers have published thirteen papers in a series entitled 'Host-Guest Complexation', in which a very full account of some of the work previously published as 'Communications' is included. A selection of this work is given here. Special emphasis has been given to the design and synthesis of hosts for complexing organic guests that contain the -NH3' group as well as for metal cation guests. A good set of molecular models has proved invaluable in this work in evaluating potentially complementary host-guest relationships: matching sizes and shapes, as well as the electronic properties of the binding portions of the hosts and guests, are a necessary requisite to strong binding. Chiral hosts of type (155) and (156) have been synthesized in which the substituents A and A' project on opposite sides of the macrocyclic ring, and these substituents, when terminated with appropriate functional groups, can provide additional ligands for cationic guests, and in some cases counter-ions for the g ~ e s t s . ~ With '' [156; A = CH2N(CH2CH2)20,A' = CH20CH2C02-], the complexed K ' salt is stable enough to be detected as the parent ion in a mass spectrometer, and two molecules of (156) are utilized in forming the complex with Ba2'. The barium is presumed to be totally encapsulated since it cannot be removed with sulphuric acid. 'I1 'I2 '13

'Is

G. W. Gokel and B. J. Garcia, Tetrahedron Lett., 1977, 317. R. A. Bartsch and D. K. Roberts, Tetrahedron Lett., 1977, 321. V. Gold and C. M. Sghibartz, J. Chem. SOC.,Chem. Commun., 1978, 507. W. KogeI and G. Schroder, Tetrahedron Lett., 1978,623. D. J. Cram, R. C. Helgeson, K. Koga, E. P. Kyba, K. Madan, L. R. Soma, M. G. Spiegel, P. Moreau, G. W. Gokel, J. M. Timko, and G. D. Y. Sogah, J. Org. Chem., 1978,43,2758.

Eight-membered and Larger Ring Systems

435

(155) ( R ) configuration

(156) (S) configuration

(157)

The relative stabilities of the complexes formed between the enantiomers of a host and an optically pure guest are of particular interest, and give a measure of what has been termed 'thermodynamic chiral recognition'. '16 L-Valine is a readily available guest, and molecular models were first constructed of complexes from hosts (155) and (156) in which the protonated amine group of the guest forms a '16

J. M. Timko, R.C. Helgeson, and D. J. Cram, J. Am. Chem. Soc., 1978,100,2828.

436

Heterocyclic Chemistry +

basic tripod arrangement with the host, using three 0 -..H-N hydrogen bonds. For the particular case where A = A' = CH20CH2C02H,the configuration of the -C02H group of A was arranged so that it hydrogen-bonded specificallywith the -C02H group of the valine guest, while the other group, A', actually +

terminating in -C02-, was arranged to form a contact ionic pair with the -NH, group. Inspection of these models showed that the chiral elements were sterically complementary in the (S)-(L)-complex (157; R = Me) but non-complementary in the (R)-(L)-complex. Experiments bore out these predictions, and a liquidliquid chromatography experiment was devised which enabled racemic host [(155) + (156)] to be resolved. The best model for the host containing bis-dinaphthyl units (158) in the (SS) *

+

configuration and the chiral guest BMTC-NH, X- is shown in (159), with the largest group, B, occupying the least sterically hindered position, the smallest group, T, contacting one naphthalene wall, and the medium-sized group, M, orieiitated along the second upper naphthalene This model satisfactorily accounts for the preferred complexation between the host (SS)-(l58;A = H) + and the PF6- salts of the amino-acid derivatives L-PhCH(C02Me)NH3[shown in (160; A = H, R = Ph)]," L - P ~ C H ( C O ~ P ~ ' ) &L-PhCH(CO,Bu')&H,, H~, and L - ~ - H O C ~ H ~ ( C ~ ~ M ~In) & these H ~ .examples " there is no ambiguity in the sequence of the relative sizes of the groups attached to the chiral carbon centre, but this is not the case with REH(CO2Me)hH3PF6- if R is Me2CH, PhCH2, or MeS(CH&, when the preferred complex with the (SS) host involves the Damino-acid derivatives. From X-ray workcarried out on the complex between (SS)-(158; A = H) and D-PhCH(CO2Me)NH3 PF6- and from 'H n.m.r. data of the diastyeomeric complexes, it was proposed that, in addition to the three 0-m.H-N bonds involving the macrocyclic ring, a fourth binding site exists between the guest and host which involves the C02Me group acting as a rr-acid and a naphthalene unit acting as a rr-base, providing another reason for the stability of (160; A = H) in addition to that advanced on stereochemical grounds, which places the COzMe group adjacent to the naphthalene ring. In (161)b [i.e. the complex between* (SS)-(158; A = H) and the D-amino-acid derivatives], rotation about the C-R bond can give conformations in which steric interactions between the groups in R and the upper naphthalene group are not serious. Additional substituents at the 3- and 3'-positions of the naphthalene rings produce a more discriminating host, e.g. (158; A = Me):"* complex (160; (A = Me) is alwfys more stable than (161; A = Me). With the enantiomers of PhCH(C02Me)NH3PF6-, the difference between the stabilities of the complex l1

'I8

E. P. Kyba, J. M. Timko, L. J. Kaplan, F. de Jong, G. W. Gokel, and D. J. Cram, J. A m . Chem. Soc., 1978,100,4555. S. C. Peacock, L. A. Domeier, F. C. A, Gaeta, R. C. Helgeson, J. M. Timko, and D. J. Cram, J. Am. Chem. Soc., 1978,100,8190. L. R. Sousa, G . D. Y. Sogah, D. H. Hoffman, and D. J. Cram, J. A m . Chem. Soc., 1978,100,4569.

a These experiments were actually performed using the ( R R ) host, which preferentially complexed with the D-amino-acid derivatives. These experiments were actually performed with the ( R R )host, which preferentially complexed with the L-amino-acid derivatives.

431

Eight-membered and Larger Ring Systems

-N=N

(160; A = Me, R = Ph) [(SS)-L]and the diastereomeric (SS)-D-complex is AAG* = -1.9 kcal mo1-l at 0 "C,compared with -0.56 kcal mol-1 at 2 "Cfor the case where (158; A = H) is the host.'" The total optical resolution of racemic amine and amino-ester salts has been achieved, using an optically pure host as the mobile phase in liquid-liquid chromatography experiments and by liquid-solid chromatography experiments in which an optically pure host had been bonded to the surface of silica gel.119 The downfield shift in the aromatic protons in the 'H n.m.r. spectrum of (162; X = 0)that occurs on complexation with alkali metals shows that the aromatic ring acts as a w-donor in the complexation process,12oand variable-temperature 'H n.m.r. measurements carried out on the complexes formed between (162; X = NMe) and primary alkyl-ammonium salts reveal a similar effect, which causes hindered rotation of the phenylene ring.'*l Proton n.m.r. studies with polyethers incorporating the nicotinamide nucleus in conjunction with europium(II1) shift reagents have given information about the availability of competi120 12*

N. Kawashima, T. Kawashima, T. Otsubo, and S. Misumi, TetrahedronLett., 1978, 5025. H. F. Beckford, R. M. King, J. F. Stoddart, and R. F. Newton, TetrahedronLett., 1978, 171.

438

Heterocyclic Chemistry

tive sites for complexation of metal ions and about the potential location of complexation of metal prior to a chemical reaction.122 The U.V. spectra of the chromophore in N-substituted monoaza- 18-crown-6 (163) have been used to monitor the degree of interaction between complexed metal ions and the lone pair of electrons on the nitrogen in the macrocyclic ring.123

lZ2 lZ3

G. R. Newkome and T. Kawato, Tetrahedron Lett., 1978,4643. J. P.Dix and F. Vogtle, Angew. Chem., Int. Ed. Engl., 1978,17,857.

7 Bridged Systems BY J. M. MELLOR

1 Introduction This chapter covers not only the period July 1978-June 1979 but also the important developments since the last coverage of this topic.’ As a consequence of this longer timescale, many interesting publications are either very briefly mentioned, or, because of the acute pressure on space, not reported. 2 Reviews

Some topics are discussed briefly in the new series ‘Comprehensive Organic Chemistry’. Peripheral reference is made to macrocyclic polyethers,2to bridged amines, hydrazines, and ph~sphines,~ and to sulphides,selenides, and s ~ l p h o n e s . ~ Further volumes of ‘Rodd’ review bridged heterocyclic compoundss and morphine alkaloids.6 Later, we report many examples of addition of singlet oxygen to dienes. Some of this work, and much of the background, is discussed in A further monograph8concerns ozonolysis, and the more limited a m~nograph.~ topics of dioxetan chemistrygand the photo-oxidation of tryptophan” have been reviewed. Preparation of 9-borabicyclo[3.3.llnonane is described in Organic Syntheses” and the use of such boranes has been reviewed.12In this Report we devote little space to the chemistry of these bridged boranes or of silanes, which

’ ‘Saturated Heterocyclic Chemistry’, ed. G. Pattenden (SpecialistPeriodical Reports), The Chemical Society, London, 1978,Vol. 5, p. 261.

’ ‘ComprehensiveOrganic Chemistry’,ed. D. H. R. Barton and W. D. Ollis, Pergamon, Oxford, 1979, Vol. 1, p. 853. ‘Comprehensive Organic Chemistry’, ed. D. H. R. Barton and W. D. Ollis, Pergamon, Oxford, 1979, Vol. 2,pp. 2,61,219,and 1127. ‘Comprehensive Organic Chemistry’,ed. D. H. R. Barton and W. D. Ollis, Pergamon, Oxford, 1979, Vol. 3,pp. 55, 197,and 491. “Rodd’s Chemistry of Carbon Compounds”, ed. S. Coffey, Elsevier, Amsterdam, 1978, Vol. 4H, p. 278. “Rodd’s Chemistry of Carbon Compounds”, ed. S. Coffey, Elsevier, Amsterdam, 1978, Vol. 4G,p. 268. ’I ‘Singlet Oxygen’, ed. B. Ranby and J. F. Rabek, Wiley, New York, 1978. P. S. Bailey, ‘Ozonation in Organic Chemistry’, Wiley, New York, 1978. W. Adam, Adu. Heterocycl. Chem., 1977,21,438. lo I. Saito, T. Matsuua, M. Nakagawa, and T. Hino, Acc. Chem. Res., 1977,10,346. ‘Organic Syntheses’, ed. W. A. Sheppard, Wiley, New York, 1978,Vol. 58,p. 24. l2 H.C.Brown, ‘Organic Syntheses via Boranes’, Wiley, New York, 1975;K. Avasthi, D.Devaprabhakara, and A. Suzuki, Organometal. Chem. Rev., 1979,7, 1.

439

Heterocyclic Chemistry

440

are reviewed elsewhere. l 3 Similarly, organoselenium chemistry is more fully discussed in a recent report.14 Reviews concern two important areas where rapid and exciting progress is being made. Until recently, bridged heterocyclic annulenes were neglected. Now some reference is made to such systems in a more general review of medium-large hetero-annulenes," and the chemistry of cyclazines and related nitrogen-bridged annulenes16 has been reviewed. Recent milestones in this area are reported later. A second area concerning cryptands and their cryptate complexes has passed from a subject of potential to one of established utility. Hence many studies report minor improvements of established methods, and concern cryptands of structure closely related to earlier examples; at the same time, innovatory work is being reported in this area. Highlights are briefly reported later, and aspects17 have recently been reviewed. Reviews concern heterocyclic compounds with an adamantane skeleton" and, more specifically, hexamethylenetetramine. l9 A full account of the Ramberg-Backlund2' rearrangement, important in the construction of cyclophanes, has been given, and two very useful synthetic procedures, i.e. the Noyori use of iron carbonyl in [4 + 31 cycloadditions,21 and intramolecular [4 + 21 and [3 + 21 cycloadditions,22 have been reviewed. Addition of acetylenecarboxylic esters to nitrogen-containing heterocycle^^^ and s ~ ~ been discussed. cycloaddition reactions of d i a z a q ~ i n o n e have Many groups are studying the chemistry of trimethylenemethanes, a subject recently re~iewed,'~and this chemistry frequently requires the synthesis of unusual bridged diazenes. Examples are given later. Aminium radicals, used with moderate success in synthesis, are reviewed;26 in discussing the conformation of hexahydropyridazine derivatives, N e l ~ e nreports ~~ on the interesting use of photoelectron spectroscopy and electroanalytical techniques to solve conformational problems.

3 Physical Methods X-Ray and Neutron Diffraction.-Both techniques have been used2*to show that 9-thiabicyclo[3.3.1]nonane-2,6-dione(1)is skewed. The skeletally related (2) is l3 l4

l6 l7

l9 2o 21 22 23 24

25 26

27 28

J. Y.Corey, Organometal. Chem. Rev., 1979,8,1; P.R.Jones, ibid., p. 203. D. L. J. Clive, Tetrahedron, 1978,34,1049. A. G . Anastassiou, Adv. Heterocycl. Chem., 1978,23,5 5 . W. Flitsch and U. Kramer, Adv. Heterocycl. Chem., 1978,22,321. D.J. Cram and J. M. Cram. Acc. Chem. Rex, 1978,11,8; J. M.Lehn, ibid., p. 49;Top. Curr. Chem., 1978,74,1. Z.Kafka and V. Galik, Chem. Listy, 1978,72,509. N. Blazevic, D. Kolbah, B. Belin, V. Sunjic, and F. Kajfez, Synrhesis, 1979,161. L. A . Paquette, Org. React., 1977,25, 1. R.Noyori, Acc. Chem. Res., 1979,12,61. W.Oppolzer, New Synth. Methods, 1979,6,1. R. M. Acheson and N. F. Elmore, Adv. Heterocycl. Chem., 1478,23,263. M. Quinteiro, C. Seoane, and J. L. Soto, Heterocycles, 1978,9, 1771. J. A.Berson, Acc. Chem. Res., 1978,11,446. Y.L.Chow, W. C. Danen, S. F. Nelsen, and D. H. Rosenblatt, Chem. Rev., 1978,78,243. S.F.Nelsen, Ace. Chem. Res., 1978,11,14. M. J. Bovill, P. J. Cox, H. P. Flitrnan, M. H. P. Guy, A. D. V. Hardy, P. H. McCabe, M. A. MacDonald, G. A. Sim, and D. N. J. White, Acta Crystallogr., Sect. B, 1979,35,669.

Bridged Systems

44 1

also severely distorted.*' Both X-ray and photoelectron studies have been reported for (3),30 and X-ray studies for propellane adducts with tria~olinedione,~' for benzotropine methane~ulphonate~~ and tropane derivative^,^^ for 11-methyl-1 l-azabicyclo[5.3.1)undecan-4-one,34 for the diaza-dioxides (4) and (5)35and the monoxide (6),36for the bridged lactam (7),37 for the bridged hydrazine (8) and the related cation radical salt (9), which has surprisingly large differences in geometry from (8),38 for the product of reaction of phenylmagnesium bromide with the methyl vinyl ketone dimer, for the 3,6-dimethyl4,5-dihydropyridazine dimer (11),40for the phosphonium salt ( 12),41in which the

& S

0 CO,Et

(10) 29

30

31 32

33 34

35 36

37

38 39 40

41

(11)

(12)

J. S. Chen, W. H. Watson, J. Kagan, D. A. Agdeppa, and S. A. Chen, Acta Crystallogr., Sect. B, 1978, 34,3627. R. Gleiter, N. S.Zefirov, V. A. Palyulin, K. A. Potekhin, E. N. Kurkutova, Yu. T. Struchkov, and M. Ya. Antipin, Zh. Org. Khim., 1978,14, 1630. M. Kaftory, Acta Crystallogr., Sect. B, 1978, 34, 300, 303. P. G. Jones, 0. Kennard, and A. S . Horn, Acta Crystallogr., Sect. B, 1978,34, 3125. P. Chananont and T. A. Hamor, J. Chem. Res. ( S ) , 1978,414. E. Bye and J. D. Dunitz, Acta Crystallogr., Sect. B, 1978, 34, 3245. K. Prout, V. P. Stothard, and D. J. Watkin, Acta Crystallogr., Sect. B,1978,34,2602. S . Larsen and J. P. Snyder, Acta Chem. Scand., Ser. B, 1979 33,31. K. Blaha, P. Malon, M. Tichy, I. Fric, R. Usha, S.Ramakumar, and K. Venkatesan, Collect. Czech. Chem. Commun., 1978,43,3241. S . F. Nelsen, W. C. Hollinsed, C. R. Kessel, and J. C. Calabrese, J. A m . Chem. SOC.,1978,100,7876. B. P. Mundy, G. W. Dirks, R. D. Larsen, and C. N. Laughlan, J. Org. Chem., 1978,43,2347. J. Dodge, W. Hedges, J. W. Timberlake, L. M. Trefonas, and R. J. Majeste, J. Org. Chem., 1978,43, 3615. Mazhar-ul-Haque, M. Rashid, and S. E. Cremer, J. Chem. SOC.,Perkin Trans. 2, 1978, 1115.

442

Heterocyclic Chemistry

heteroatom is contained in a four-membered ring, for the strained bridgehead diene ( 13)42and related bromination for the epimeric alcohols (14) and (15),44for 13-thiabic yclo[ 7.3.11 tridecene and 13-t hiabicyclo[ 8.2.11 tridecene derivative^,^^ for the monoborohydride of 1,7-diaza-4,10,15-trioxa[5.5.5]bicy~ l o h e p t a d e c a n e ,and ~ ~ for the triarsine (16).47Structure (17)has been characterized by electron d i f f r a ~ t i o nX-Ray4’ .~~ analysis required a revision of structure of the phencyclone-N-ethoxycarbonylazepine adduct from the previously suggested [6 + 21 adduct to a [4 + 21 adduct. Further X-ray analyses are reported in later references (52, 114, 148, 152, 192, 194, 214, 226, and 227).

Me

Photoelectron Spectroscopy and Related Electrochemical Studies.-Nelsen and his group in Wisconsin have used this technique, in combination with other m e a s u r e m e n t ~to , ~probe ~ the ground-state conformation of bridged amines and hydrazines, and have made interesting comparisons with the geometries of the respective cation radicals. Now,an analysis’’ of the four-membered-ring hydrazines (18) and (19) has established the overwhelming preference for a single conformer. The rates for double inversion of nitrogen for (18) and (19) were measured by ‘H n.m.r. spectroscopy. Photoelectron spectroscopy (PES) of the tetra-amine (20) from the vibrational splittings, that the ion radical is produced with little structural reorganization, and hence it must have effectively 42 43

44

45

46 47

48

49 50

51

W. H. Rastetter, T. J. Richard, J. Bordner, and G. L. A. Hennessee, J. Org. Chem., 1979,44,999. W. H. Rastetter, T. J. Richard, N. D. Jones, and M. 0. Chaney, J. Chem. Soc., Chem. Commun., 1978,377. A. A. Usol’tsev, E. S. Karavlov, M. N. Tilichenko, M. Ya. Antipin, S. G. Ilin, and Yu. T. Struchkov, Khim. Geterotsikl. Soedin., 1978, 1044, L. A. Aslanov, V. M. Ionov, V. I. Andrianov, Z.Sh. Safina, and A. Yu. Shashkov, Khim. Geterotsikl. Soedin., 1977, 1628. B. Metz and R. Weiss, Nouu. J. Chim., 1978, 2,615. B. J. McKerley, K. Reinhardt, J. L. Mills, G. M. Reisner, J. D. Korp, and I. Bernal, Inorg. Chim. Actu, 1978,31, U 1 1 . S. A. Shaidulin, V. A. Naumov, and N. A. Makarova, Zh. Strukt. Khim., 1978, 19, 942. K. Harano, T. Ban, M. Yasuda, and K. Kanematsu, Tetrahedron Lett., 1978,4037. S . F. Nelsen, V. E. Peacock, G. R. Weisman. M. E. Landis, and J. A. Spencer, J. Am. Chem. SOC., 1978,100,2806. S . F. Nelsen, E. Haselbach, R. Gschwind, U. Klemrn, and S. Lanyova, J. Am. Chem. Soc., 1978,100, 4367.

Bridged Systems

443

Dad symmetry. In contrast, e.s.r. studies show that, in solution, (20) has the different C2"symmetry. MIND0/3 calculations accord with the experimental observations. Following the o b s e r ~ a t i o nof~ ~the remarkably low ionization potential (6.90 eV) of (21), the spectrum of the parent 1,5-diazabicyclo[3.3.3]undecane has been recorded.53A lowest ionization potential at 6.86 eV and a second band at 7.80 eV suggest an unusual p-character in the lone pairs in these diamines, and that the odd electron is in an antisymmetric N-N orbital in the cation radical. Reasonably stable cation radicals may be prepared electrochemically from both 1,5-diazabicycl0[3.3.3]undecane and 1,6-diazabicyclo[4.3.3]dode~ane.~~ The constraints of Bredt's Rule prevent loss of a proton from such cation radicals, and this feaaure has been used to observe electrochemical reversibility in the one-electron oxidation of hydrazine (8) to the and in the oxidation of the amine (22).55This is the first cation-radical (9)38*54 report" of a saturated amine having an electrochemically reversible oxidation. Nelson and his c o - w ~ r k e r have s ~ ~ measured the standard oxidation potentials for a large series of o-phenylenediaminederivatives,including bridged examples, and E; data from some strained heterocyclic are available. The latter data are based on irreversible systems and therefore are less meaningful. Photoelectron spectra are also reported for cycl[3.3.3]azine and cyc1[3.3.2]a~ine,~~ some thia[4.4.3]propellane~,~~ further 3,7,9-trihetero-derivatives of bicycloc3.3. l]nonane6' (see also ref. 30), peroxide (23) and related homologues,61 ozonides (24) and (25),62and bicyclic phosphites and phosphines, e.g. (26).63

52

53

54

s5 56

57 58 59 60

61 62 63

R. W. Alder, N. C. Goode, T. J. King, J. M. Mellor, and B. W. Miller, J. Chem. Soc., Chem. Commun., 1976,173. R. W. Alder, R. B. Sessions, J. M. Mellor, andM. F. Rawlins, J. Chem. SOC.,Chem. Commun., 1977, 747. S . F. Nelsen and C. R. Kessel, J. A m . Chem. Soc., 1977,99, 2392. S. F. Nelsen and C. R. Kessel, J. Chem. SOC.,Chem. Commun.. 1977,490. S . F. Nelsen, E. L. Clennan, L. Echegoyan, and L. A. Grezzo, J. Org. Chem., 1978,43,2621. P . G. Gassman, R. Yamaguchi, and G. F. Koser, J. Org. Chem., 1978,43,4392. M. H. Palmer, D. Leaver, J. D. Nisbet, R. W. Millar, and R. Egdell, J. Mol. Struct., 1977,42, 85. M. C. Bohm and R. Gleiter, Terrahedron, 1979, 35, 675. R. Gleiter, M. Kobayashi, N. S. Zefirov, and V. A. Palyulin, Dokl. Akad, Nauk SSSR,1977,235, 347. D. J. Coughlin, R. S. Brown, and R. G. Salomon, J. A m . Chem. SOC.,1979,101,1533. R. S. Brown and R. W. Marcinko, J. A m . Chem. SOC.,1978,100,5584. A. H. Cowley, D. W. Goodman, N. A. Kuebler, M. Sanchez, and J. G. Verkade, Inorg. Chem., 1977, 16,854; L. W. Yarbrough and M. B. Hall, J. Chem. SOC.,Chem. Commun., 1978,161.

444

Heterocyclic Chemistry

Nuclear Magnetic Resonance Spectroscopy.-The greater availability of probes for heteroatoms is reflected in the recent publication of results for 29Sispectra in 3 n.m.r. spectra have been reported65for twentybridged ~ i l a t r a n e sCarbon-1 .~~ six S-phosphabicyclo[3.2. lloctanes, and 13C-31P coupling constants are given. Routine 13Cn.m.r. spectra have been published for 2,3-dimethylene-7-oxabicycl0[2.2. l l h e p t a n e ~ ,substituted ~~ q u i n ~ c l i d i n e sand ~ ~ their salts, and cocaine derivatives.68 Routine 'H n.m.r. spectra have been reported for azabicyclo[3.3.1]nonane~.~~ Both 'H and 13C n.m.r. spectra have been reported for the atropine and scopolamine cations7' in aqueous solution. The calculated chemical shifts, based on ring-current effects, have been compared with the experimental results to give the conformations in solution. Both 'H and 13Cdata are available for further azabicyc10[3.3.l]nonanes,~~*~~ azabicyclo[4,2, llnonanes, and oxabicyclo-[3.3.1]- and -[4.2. l l - n o n a n e ~ Normal .~~ and ''N-decoupled 'H n.m.r. spectra have been measured, to give 14N--'H in various bridged ammonium salts, and 13C n.m.r. spectra have been for protonated N-alkyl-2-azabicyclo[2.2.l]heptanes in order to assess possible steric destabilization of a 2-endo-alkyl substituent. In a conceptually related study, N-chloroderivatives of 2-azabicyclo[2.2.l]hept-5-ene, 2-azabicyclo[2.2.l]heptane, and 2-azabicyclo[2.2.2]oct-5-ene's have been studied at low temperatures by 'H n.m.r. spectroscopy. The separate invertomers were characterized, and both kinetic and thermodynamic data were obtained for the inversion process. The double-inversion process in (27) has been by variable-temperature 15 N n.m.r., and the results agree well with earlier 'H and I3Cstudies. Inversion of nitrogen has been studied in (28) and related compounds by 13Cn . m ~ . ~ ~

R. K.Harris, J. Jones, and S. Ng., J. Magn. Reson., 1978,30,521;V. A. Pestunovich, S. N. Tandura, M. G. Voronkov, G. Engelhardt, E. Lippmaa, T. Pehk, V. F. Sidorkin, G. Zelcans, and V. P. Baryshok, Dokl. Akad. Nauk SSSR, 1978, 240, 914. 65 A. Rudi and Y. Kashman, Org. Magn. Reson., 1977,10, 245. 66 D. Quarroz, J.-M. Sonney, A. Chollet, A. Florey, and P. Vogel, Org. Magn. Reson., 1977, 9, 611. " K. B. Becker and C. A. Grob, Helu. Chim. Acta, 1978,61, 2596. 68 J. K. Baker and R. F. Borne, J. Heterocycl. Chem., 1978,15, 165. 69 G. G. Trigo, C. Avendano, P. Ballesteros, and A. Gonzalez, J. Heterocycl. Chem., 1978,15,833; G. G. Trigo, E. Galvez, and C. Avendano, ibid., p. 907; T. Momose and S. Atarashi, Heterocycles, 1978, 9,631; T. R. Bok and W. N. Speckamp, Tetrahedron,1979,35, 267. 70 J. Feeney, R. Foster, and E. A. Piper, J. Chem. SOC., Perkin Trans. 2, 1977, 2016. 'I' P. C. Ruenitz, J. Org. Chem., 1978,43, 2910. 7 2 M. Barrelle, M. Apparu, and C. Gey, Can. J. Chem., 1978,56, 85. 73 M. J. 0. Anteunis, F. A. M. Borremans, J. Gelan, A. P. Marchand, and R. W. Allen, J. A m . Chem. SOC.,1978,100,4050. 74 F. M. Menger, M. Perinis, J. M. Jerkunica, and L. E. Glass, J. Am. Chem. SOC.,1978, 100, 1503. 7s J. R. Malpass and N. J. Tweddle, J. Chem. Soc., Perkin Trans. 2, 1978, 120. 76 Y. Nomura and Y . Takeuchi, J. Chem. Soc., Chem. Commun., 1979,295. " F. G. Riddell, E. S. Turner, and A. Boyd, Tetrahedron, 1979,35,259. 64

Bridged Systems

445

Electron Spin Resonance Spectroscopy.-E.s.r. spectra of cation r a d i ~ a l s ~ ” ~ ~ - ~ ~ have been noted. Spectra of heterocyclophane anion-radical~’~are also well described. Routine e.s.r. spectra have been reported for nitroxides of some 9-azabicyclo[3.3.l l n o n a n e ~ ,and ~ ~ for a number of 170-labelled bridged compounds.80 Miscellaneous.-Mass spectra have been reported for a series of 9-azabicyelo[3.3.l l n o n a n e ~ , ~ ~ ~ 9-oxabicyclo[3.3.1]nonanes,s1b and 2,4,6&tetrathiaadamantane~.~~ The resonance Raman of the 1,4-diazabicyclo[2.2.2]octane cation-radical has been described. 7-Thiabicyclo[2.2.1]heptan-2-one and 7-thiabicyclo[2.2.1]heptane-2,5-dione have been ~ynthesized;’~ the band at 260nm has been assigned to a chargetransfer absorption. 4 Nitrogen Compounds

Synthesis.-The impetus of synthesis of bridged anlines having physiological activity has led to the development of a number of important reactions. We describe these highlights below, note a number of papers” that are mainly concerned with the physiological activity of such compounds, and recommend reference elsewheres6to the chemistry of alkaloids. ” 79

82

83

84

86

F. Gerson, W. Huber, and 0. Wennerstrom, Helv. Chim. Acra, 1978,61,2763. R. M. Dupeyre and A. Rassat, Bull. SOC.Chim. Fr., Part 2, 1978,612. H. G. Aurich and H. Czepluch, Tetrahedron Lett., 1978,1187. ( a ) H. 0.Krabbenhoft, J. Org. Chem., 1978,43,47;fb) H. 0. Krabblnhoft and W. V. Ligon, ibid., p. 51. V. I. Khvostenko, E. G. Galkin, E. M. Vyrypaev, B. M. Lerman, and G. A. Tolstikov, Khim. Geterotsikl. Soedin., 1978,748. E.E.Ernstbrunner, R. B. Girling, W. E. Grossman, and R. E. Hester, J. Chem. SOC.,Faraday Trans. 2, 1978,74,501. 1. Tabushi, Y. Tamaru, and Z. Yoshida, Bull Chem. SOC.Jpn., 1978,51,1178. Benzomorphans:N.Yokoyama, P. I. Almaula, F. B. Block, F. R. Grant, N. Gottfried, R. T. Hill, E. H. McMahon, W. F. Munch, H. Rachlin, J. K. Saelens, M. G. Siegel, H. C. Tomaselli, and F. H. Clarke, J. Med. Chem., 1979,22,537;A.E. Jacobson, K. C. Rice, J. Reden, L. Lupinacci, A. Brossi, R. A. Streaty, and W. A. Klee, ibid., p. 328;J. Reden, M. F. Reich, K. C. Rice, A. E. Jacobson, A. Brossi, R. A. Streaty, and W. A. Klee, ibid., p. 256;T. Kametani and S. Shiotani, ibid., 1978,21, 1105. Benzazocines: P. H. Mazzocchi and A. M. Harrison, J. Med. Chem., 1978,21,238;see also P. H. Mazzocchi and B. C. Stahly, ibid., 1979,22,455;W.F.Michne, ibid., 1978,21,1325. Dibenzazocines: H. Takayama, M. Takamoto, and T. Okamoto, Tetrahedron Lett., 1978,1307. Tropane derivatives: J. L. Wallace, M. R. Kidd, S. E. Cauthen, and J. D. Woodyard, J. Heterocycl. Chem., 1978,15,315;R.L. Clarke, A. J. Gambino, A. K. Pierson, and S. J. Daum, J. Med. Chem., 1978,21, 1235;R. L. Clarke, M. L. Heckeler, A. J. Gambino, S. J. Daum, H. R. Harding, A. K. Pierson, D. G. Teiger, J. Pearl, L. D. Shargel, and T. J. Goehl, ibid., p. 1243;R. L. Clarke and M. L. Heckeler, J. Org. Chem., 1978,43,4586. 2-Azabicydo[2.2.2]octanes: S.-J. Law, D. H. Lewis, and R. F. Borne, J. Heterocycl. Chem., 1978, 15,273. 2-Azabicyclo[3.2.l]octanes: H.H.Ong, V. B. Anderson, and J. C. Walker, J.Med. Chem., 1978,21, 758. 6,7-Diazabicyclo[3.2.2]nonanes: S.Cherkez, H. Yellin, Y. Kashman, B. Yaavetz, and M. Sokolovsky, J. Med. Chem., 1979,22,18. 5,ll-Diazaditwistanes:M. A. Kozlowski, J. ten Broeke, and E. J. J. Grabowski, J. Heterocycl. Chem., 1979,16,609; M.H. Fisher, E. J. J. Grabowski, A. A. Patchett, J. ten Broeke, L. M. Flataker, V. J. Lotti, and F. M. Robinson, J. Med. Chem., 1977,20,63. ‘The Alkaloids’, ed. M. F. Grundon (Specialist Periodical Reports), The Chemical Society, London, 1979,Vol. 9.

Heterocyclic Chemistry

446

Tropane Derivatives and Related Azabicyclo[3.2. lloctanes. The reaction of aa'dibromo-ketones and iron carbonyls with pyrrole derivatives affords the tropane skeleton conveniently, in moderate to good yields. The method has been reviewed,21many details of the reactions with other dienes" are given (both for the iron-cabonyl method and for the related Hofmann procedure" for generation of oxyallyl cations), and full detailss9have now been published for the route to tropine, pseudotropine, and 6,7-dehydrotropine. Using the Hofmann method to generate oxyallyl intermediates, Cowling and Mann9' have made successful cycloadditions to N-methylpyrrole; a reaction not possible with the Noyori method. Intramolecular cycloadditions involvingnitrones are good methods of synthesis of nitrogen heterocycles, have already been used as an entry to the tropane skeleton, and are now used in elegant stereospecific syntheses of ( d l ) - ~ o c a i n e ~ ' * ~ ~ and p s e ~ d o t r o p i n e(Schemes ~~ 1 and 2). The procedure of Scheme 2 gives intermediate (29) in 40% overall yield from methyl 3-butenoate, and therefore the approach leads to (dl)-cocaine stereospecifically, in high yield.

E E

Me

= C02Me

Me

1

iii

\

\

ocoPh

OH

Reagents: i, NaOMe, H,C=CHCHO; ii, Zn, NH,CI, MeOCH2CH20Me, H 2 0 ; iii, H', A; iv, MeI; v, Zn, AcOH; vi, PhCOCl

Scheme 1

Anodic oxidation of tropane derivative^^^ leads to dealkylation, but offers no synthetic advantage over non-electrochemical methods, e.g. trichloroethyl chl~roforrnate.~~ Diethyl azodicarboxylate has been allowed to react with tropane derivatives9' (Scheme 3).

88 89

90 91

92

93 94 95

R. Noyori, Y. Hayakawa, H. Takaya, S. Murai, R. Kobayashi, and N. Sonoda, J. A m . Chem. SOC., 1978,100,1759; H. Takaya, S. Makino, Y. Hayakawa, and R. Noyori, ibid., p. 1765; H. Takaya, Y. Hayakawa, S. Makino, and R. Noyori, ibid., p. 1778. D. 1. Rawson, B. K. Carpenter, and H. M. R. Hoffmann, J. A m . Chem. SOC.,1979,101,1786. Y. Hayakawa, Y:Baba, S. Makino, and R. Noyori, J. A m . Chem. SOC.,1978,100,1786. A. P. Cowling and J. Mann, J. Chem. SOC.,Perkin Trans. 1, 1978, 1564. J. J. Tufariello, J. J. Tegeler, S. C. Wong, and S . A. Ali, Tetrahedron Lett., 1978,1733; J. J. Tufariello and G. B. Mullen, J. A m . Chem. SOC.,1978,100,3638. J. J. Tufariello, G. B. Mullen, 3. J. Tegeler, E. J. Trybulski, 9. C. Wong, and S. A. Ali, J. Am. Chem. SOC.,1979,101, 2435. B. L. Laube, M. R. Asirvatham, and C. K. Mann, J. Org. Chem., 1977,42,670. J. R. Pfister, J. Org. Chem., 1978,43,4373. R. L. Clarke, A. J. Gambino, and M. L. Heckeler, J. Org. Chem., 1978,43,4589.

Bridged Systems

447

0-

E

=

C02Me

(29)

E

E Reagents: i, MCPBA; ii, H,C=CHCO,Me; iii, A

Scheme 2

M &

C0,Me Scheme 3

In a series of now over 40 papers, Katritzky and his group have mainly been concerned with the 1,3-dipolar addition reactions of six-membered aromatic betaines, which can provide a very effective synthesis of the tropane skeleton. It is claimed96that the application of this procedure with the simple betaine (30) is quite limited, because of insufficient reactivity of the betaine. One method” of activation is by choice of substituent at nitrogen [e.g. (31)]. An a l t e r n a t i ~ is e ~to~

no-noN

N

Me

I

(30)

+J(

/

NO2 (31)

use (32) (see Scheme 4). In order to use the azabicyclo[3.2.l]octenones as synthons for tropones and tropolones, a key step is subsequent N-methylation to permit Hofmann degradation. In a search for improved 1-substituents, cycloadducts of a further range of 3-hydroxpyridinium b e t a i n e ~have ~ ~ been prepared. More precise calculation^^^ compare kinetic rates with the peri-, site, regio-, and % 97

9a 99

Y. Tamura, M. Akita, H. Kiyokawa, L.-C. Chen, and H. Ishibashi, Tetrahedron Lea., 1978,1751. N. Dennis, A. R. Katritzky, and Y. Takeuchi, Angew. Chem., Int. Ed. Engl., 1976,15, 1. A. R. Katritzky, J. Banerji, A. Boonyarakvanich, A. T. Cutler, N. Dennis, S. Q. A. Rizvi, G . J. Sabongi, and H. Wilde, J. Chem. SOC., Perkin Trans. 1, 1979, 399. A. R. Katritzky, N. Dennis, M. Chaillet, C. Larrieu, and M. El Mouhtadi, J. Chem. SOC.,Perkin Trans. 1, 1979,408.

Heterocyclic Chemistry

448

X

o

6

,

OMe

MeoQo-

Reagents: i, PhCH=CH,; ii, PhC=CH; iii, cyclopentadiene; iv, EtO,CN=NCO,Et

Scheme 4

stereo-selectivities of the reactions. Good correlations are observed except for additions involving fulvenes. Further kinetic data'" are available, and other synthetic aspectslol are noted. Although 2-oxabicyclo[3.2.l]octa-3,6-diene is a well-studied compound, less work has been reported with the aza- or thia-analogues. Now, the parent 2-azabicyclo[3.2.l]octa-3,6-diene (33) has been prepared,lo2 but not fully characterized. There is some suggestion of equilibration to diene (34).N-Alkyl derivatives were prepared. Their increased stqbility permitted the of 'H, and 13C n.m.r. and photoelectron spectra, but the evidence for the claimed homoconjugative effects in an extensive series of 2-heterobicyclo[3.2.l]octa-3,6dienes is meagre. The ~ynthesis"~ of other 2-azabicyclo[3.2.l]octa-3,6-dienes, and the t r a n ~ f o r m a t i o nof'benzylnorteloidinone ~~~ (35) to a monocyclic product (36) that is related to the water-soluble betalains, is noted. ,NHCONH,

L

A. R. Katritzky, B. El-Osta, G. Musumarra, and C. Ogretir, J. Chem. Res. ( S ) , 1979, 322. A. R. Katritzky, N. Dennis, and H. A. Dowlatshahi, J. Chem. Soc., Chem. Commun., 1978,316; N. Dennis, H. A. Dowlatshahi and A. R. Katritzky, J. Chem. Res. ( S ) , 1978, 102; A. R. Katritzky, N. Dennis, G. J. Sabongi, and L. Turker, J. Chem. SOC.,Perkin Trans. I , 1979, 1525. ln2 P. Barraclough, S. Bilgic, and D. W. Young, Tetrahedron, 1979, 35, 91. lo3 P. Barraclough, S.Bilgic, J. B. Pedley, A. J. Rogers, and D. W. Young, Tetrahedron, 1979, 35, 99. K. Umano, H. Taniguchi, H. Inoue, and E. Imoto, Tetrahedron Lett., 1979, 247. Ins G. Buchi, H. Fliri, and R. Shapiro, J. Org. Chem., 1978,43,4765. loo 101

Bridged Systems

449

Other Alkaloid Syntheses. We highlight here a number of procedures which have been used successfully in target synthesis. Their success suggests that these methods will have considerable generality. Trost has earlier shownlo6 that palladium-catalysed cyclizations are most efficient in the construction of the isoquinuclidine skeleton (Scheme 5 ) and in the

R = Ph, 65% R = CH2Ph, 56% Reagents: i, [(PPh,),Pd], Et,N, MeCN

Scheme 5

subsequent formation of desethylibogamine (37; R = H) by similar cyclization of (38).The method has been developed to permit synthesis of ibogamine (37; R = Et),lo7and, in a most significant development, the catalysis by palladium has been

achieved, using supported catalysts. This permitslo8 reaction using a flow system, without appreciable loss of catalyst activity, and also affords enhanced selectivity in cyclization (Schemes 6 and 7).

(65%)

OAC Reagents: i, Polymer

-

I \Ph

Pd, PhH, PhCHzNHz

Scheme 6

The use of intramolecular cycloaddition, using nitrones, has been n~fed.’~’’~ In a further illustration’09 of the high selectivity possible in such reactions, the alkaloid luciduline (39) has been synthesized by the key transformation (40) + (41) (87%), followed by high-yield methylation and reductive cleavage, to give (42). In 1971 the structure (43) was assigned to the alkaloid cannivonine. Now two groups have reported the unambiguous total synthesis of (43), and have shown the B. M. Trost and J. P. Genet, J. A m . Chem. SOC.,1976,98,8516. B. M. Trost, S. A. Godleski, and J. P. Genet, J. A m . Chem. SOC., 1978, 100, 3930. lo* B. M. Trost and E. Keinan, J. A m . Chem. SOC.,1978, 100,7779. W. Oppolzer and M. Petrzilka, Helv. Chim. Acta, 1978,61, 2755. ‘06 lo’

Heterocyclic Chemistry

450

I

CH,R

1

ii (76%)

I

Reagents: i, Polymer

-

Me

CH,R Pd, RCH,NH,; ii, 5%KOH, MeOH, A; iii, Ph,PBr,, MeCN, Et,N, A

Scheme 7

&.NHOH

eM@'

R'

Me

R2 (39) R ~ R = *o

H

(4 0)

(42) R1= OH, R2= H

non-identity of the synthetic material with the natural alkaloid. In both cases, nucleophilic opening''o of an epoxide (e.g. Scheme 8) was the key step.

Reagents: i, K2C03, MeOH, H 2 0 , A

Scheme 8

Anatoxin-a (44) has recently been isolated,"' and synthesized112from cocaine. A route to related compounds is provided113by cyclization of the iminium salt (45) to give (46) in 47% yield.

Cycloadditions. Few important developments are to be noted. A n area of interest has concerned the cycloaddition of nitrosobenzenes and acylnitroso-compounds

"1

'I2

A. P. Kozikowski and R. Schmiesing,J. Chem. SOC.,Chem. Commun., 1979,106; D. A. Evans, A. M. Golob, N. S. Mandel, and G. S . Mandel, J. Am. Chem. SOC.,1978,100,8170. J. P. Devlin, 0.E. Edwards, P. R. Gorham, N. R. Hunter, R. K. Pike, andB. Stavric, Can. J. Chem., 1977,55,1367. H. F. Cambell, 0. E. Edwards, and R. Kolt, Can. J. Chem., 1977, 55, 1372. H. A. Bates and H. Rapoport, J. Am. Chem. Soc., 1979,101,1259.

Bridged Systems

45 1

with dienes, and the chemistry of the adducts. Products of cycloaddition are shown in Scheme 9.'14-'16 Thermal decomposition of (47)permits detection of nitroxyl, HNO. Reactions of [Fe2(C0)J with the adducts of nitrosobenzene with cyclohepta-1,3-diene,''' cycloheptatriene, ''' and cyclohexa-1,3-diene1'* have been reported. /

C0,Et

NPh

Ref. 114

C0,Et

Ref. 116

Ph Reagents: i, PhNO; ii, MeCON(H)OH, Pr4N+ 10;

Scheme 9

A simple route to 2-azabicyclo[2.2.2]octanes is by Diels-Alder addition of imines with cyclohexa-1,3-diene. Further aspects of this route concern the BF3-catalysedaddition'" of iminoacetate (48) to give an intermediate (49) that is used to construct Prosopis alkaloids via Baeyer-Villiger oxidation. The '14

'16

11'

W. S. Murphy, K. P. Raman, and B. J. Hathaway, J. Chem. SOC.,Perkin Trans. I, 1977,2521. G. E. Keck, Tetrahedron Lett., 1978, 4767;J. E. T.Corrie, G. W. Kirby, A. E. Laird, L. W. MacKinnon, and J. K. Tyler, J. Chem. SOC.,Chem. Commun., 1978,275. H. Hart, S. K.Ramaswami, and R. Willer, J. Org. Chem., 1979,44,1. Y.Becker, A. Eisenstadt, and Y. Shvo,J. Organometal. Chem., 1978,155,63. Y.Becker, A. Eisenstadt, and Y. Shvo, Tetrahedron, 1978,34,799. A.J. G.Baxter and A. B. Holmes, J. Chem. SOC.,Perkin Trans. 1,1977,2343;see also G.R. Krow and C. Johnson, Synthesis, 1979,50;T. Momose, S.Atarashi, and C. H. Eugster, Heterocycles, 1979,

12,41.

452

Heterocyclic Chemistry

stereoselectivity of this acid-catalysed cycloaddition12' has been further studied. The alternative cycloaddition of dimethyl fumarate with N-carbomethoxy-1,2dihydropyridine121 has been used to afford (50),which, via anodic oxidation, gives the unstable (51) in 17% yield. Both Diels-Alder routes to 2-azabicyclo[2.2.2]octenes, using cyclohexa-1,3-diene and N-carboethoxy-l,2-dihydropyridine, have been used to construct N-viny1-isoquinuclidinesl2' that are capable of amino-Claisen rearrangement to afford hydro-isoquinolines. Examples of intramolecular cycloaddition via 1,2-dihydropyridine~~~.'~~ [e.g. ( 5 2 ) + (53)]are known. Wagner-Meerwein rearrangement of 2-azabicyclo[2.2.2]oct-5-enes to l-azabicyclo[3.2. lloctenes has been ~ e p 0 r t e d . l ~ ~

PhCH,OCO,

Me0,C

x

Meo2cy& I N

H

(48)

C0,Me

OCOCH,Ph (49)

(50)

Me0,C

&

Other [4 + 21 cycloadditions, affording a variety of heterocyclic skeletons, are collected in Scheme 10.125-130With appropriate substitution, cycloaddition can Other thermal be directed to give adducts of either type (54) or (55).131,132 cycloadditions are shown in Scheme 11133-136and some photoadditions in Scheme 12.137-141 G. R. Krow, C. Johnson, and M. Boyle, Tetrahedron Lett., 1978, 1971. H. Sliwa and Y. le Bot, Tetrahedron Lett., 1977, 4129. l Z 2 P. S. Mariano, D. Dunaway-Mariano, and P. L. Huesmann, J. Org. Chem., 1979, 44, 124. 123 I. Hasan and F. W. Fowler, J. A m . Chem. SOC., 1978, 100, 6696. 124 J.-P. Fleury and M. Desbois, J. Heterocycl. Chem., 1978, 15, 1005. J. Duflos, G. Queguiner, and P. Pastour, J. Chem. Res. ( S ) , 1978, 39. T. Sasaki, K. Minamoto, and K. Harada, Heterocycles, 1978, 10, 93. 127 J. Bornstein, S. E. Hunt, J. D. Mineck, and D. E. Remy, J. Org. Chem., 1979,44,805; D. E. Remy, F. H. Bissett, and J. Bornstein, ibid., 1978, 43,4469. 12* R. Kreher and G. Use, Tetrahedron Lett., 1978,4671. lZ9 P. S. Anderson, M. E. Christy, C. D. Colton, W. Halczenko, G. S. Ponticello, and K. L. Shepard, J. Org. Chem., 1979,44, 1519. C. K. Bradsher, G. L. B. Carlson, and M. G. Adams, J. Org. Chem., 1979,44,1199;I. J. Westerman and C. K. Bradsher, ibid., p. 727 and 1978,43, 3002. 13' D. R. Boyd and G. A. Berchtold, J. Org. Chem., 1979,44,468. 132 W. H. Rastetter and T. J. Richard, Tetrahedron Lett., 1978, 2995, 2999. 133 A. R. Browne and L. A. Paquette, J. Org. Chem., 1978,43,4522. 134 J. C. Jagt and A. M. van Leusen, R e d . Trav. Chim. Pays-Bas, 1977, 96, 145. 13' K. T. Potts and D. R. Choudhury, J. Org. Chem., 1978,43,2697. 136 K. T. Potts and D. R. Choudhury J. Org. Chem., 1978, 43, 2700. 13' E. Chamot and L. A. Paquette, J. Org. Chem., 1978,43,4527. 13* W. Berning and S . Hunig, Angew. Chem., Int. E d . Engl., 1977, 16, 777. 139 N. G. Anderson and R. G. Lawton, Tetrahedron Lett., 1977, 1843. 140 D. Bryce-Smith, A. Gilbert, and B. Halton, J. Chem. SOC.,Perkin Trans. I , 1978, 1172. 14' Y. Nakamura, T. Kato, and Y. Morita, J. Chem. SOC., Chem. Commun., 1978,620. 120

12'

Bridged Systems R'

N'

\

'R' (Ref. 129)

453

e:Rl - (x=c})

R'

R3

~

benzyne

' { ! ! R

e O

\

_____*

R2

0

X= Me R' = M e , R 2 = R 3 = P h (Ref. 125)

R'=Me,R2=H,R3=Ph (Ref. 127)

R'=Bu',R2=H,R3=Me (Ref. 128)

E Ref. 126 I

Me (E = C02Me)

Me

Cyclopropene

Ref. 130

Scheme 10

SiMe,

R2

Go R'

e

SiMe3 R

2

Q

,

l(R1=Me, RZ= H)

Me

SiMe,

(54)

(55)

R'

Heterocyclic Chemistry

454

N-Phenylmaleimide

y-N

=& 0

Ref.133

/&SR

-t

Ref.134

NC

NH

Ref. 135

- co

Ref. 136 Scheme 11

hv

>

%

Ref. 137

Ref. 138

Scheme 12 ( p a r t )

Bridged Systems

455

Ref. 139

Ref. 140

Maleimide, kv

Me0

NH 0

0: Me all four isomers Scheme 12 (part)

Cyclirations with Nucleophilic Nitrogen. Further standard Mannich reactions are reported to give 1,3-diaza-adamantanes,14* 3-azabicyclo[3.3.llnonanes, 143 and 1,3,5-triaza-adamantanesand related polyaza-adamantane~.'~~ Reduction of the dinitrile (56) gives (57) in 10% yield,'45 and reduction of dioxime derivatives of (58) affords hexacyclic a m i n e ~ . ' ~ ~

I*'

P. F. Yakushev, A . I. Kuznetsov, V. V. Tolstikov, and B.V. Unkovskii, Zh. Org. Khim., 1977,13, 2452.

143

'41 146

V. Baliah and G .Mangalam, Indian J. Chem., Sect. B,1978,16,237;T . Momose, M. Kinoshita, and T. Imanishi, Heterocycles, 1979, 12, 243. A. Edwards and G. A. Webb, Org. Magn. Reson., 1978,11,103;A. T. Nielsen, D. W. Moore, M. D. Ogan, and R. L. Atkins, J. Org, Chem., 1979, 44, 1678. A . G. Anderson and P. C. Wade, J. Org. Chem., 1978,43,54. P. Singh, I. Org. Chem., 1979, 44, 843.

456

Heterocyclic Chemistry

of substituted azabicyclo[3.3, llnonenes and l-azaAn interesting adamantanes from a-pinene is shown in Scheme 13.

OH Reagents: i, HgN03, MeCN; ii, NaBH,; iii, CH20, H'

Scheme 13

The reaction'4s of (59) with amines RNH2, followed by treatment with acid (to eliminate the t-butyl group), led to (60) in good yields.

oro But

Cyclization via Radical Intermediates. Waegell and his group have reported149on the synthetic utility of the peroxide-initiated decomposition of olefinic N-chloroamides, which leads to cyclization. Reactions proceeding in moderate yield are shown in Scheme 14. In general, better yields are obtainedI5'by cyclization that is promoted by chromous chloride (see also Scheme 14).

R1= H , R2= A c or RIR1= 0,R2= M e

M,e

c1

Scheme 14

Cyclization via Electrophilic Nitrogen. Olefinic N-chloro-amines can be cyclized in the presence of Lewis acids. Some evidencel'l for intermediacy of nitrenium 1 4 '

'41 14'

B. Delpech and Q. Khuong-Huu, J. Org. Chem., 1978,43,4898. J. Becher, C. Dreier, and 0. Simonsen, Tetrahedron, 1979, 35, 869; see also M. F. Corrigan, J. D. Rae, and B. 0.West, Aust. J. Chem., 1978,31, 587. P. Mackiewicz, R. Furstoss, B. Waegell, R. Cote, and J. Lessard, J. Org. Chem., 1978, 43, 3746. J. Lessard, R. Cote, P. Mackiewicz, R. Furstoss, and B. Waegell, J. Org. Chem., 1978, 43, 3750. J. Lacrampe, A. Heumann, R. Furstoss, and B. Waegell, J. Chem. Res. ( S ) , 1978, 334.

457

Bridged Systems

ions or that cyclization proceeds via addition of a chlorenium ion has now been of the related cyclization provided. Further synthetic and mechanistic of aminium radicals are discussed. The reaction of 2-methyl-2-hydroxyadamantane with sodium azide in methanesulphonic acid gives (61) in 79% yield. Transformation~'~~ of (61) have now been reported. Reactions.-The effect of a proximate nitrogen atom on the solvolytic reactivity of compounds substituted at a bridgehead has been well studied. Now Kovacic the solvolysis of (62). Related halides show high and his group have solvolytic reactivity. A series of a z a - n ~ r a d a m a n t a n e shas ~ ~ ~been prepared by acid-catalysed cyclization [e.g. (63)--+(64)]. The basicity of (64) and related compounds is compared with that of 1-aza-adamantane.

Treatment of (65) with potassium t-butoxide leads to rearrangement and the formation of (66).156Similarly, Stevens rear~angement'~'of (67) gives (68), and 13 C labelling confirms that there are diradical intermediates.

q-p I Me (65)

x-

Me

P-CHCOPh k

PqY (68) 'OPh

We also note a study of the regio~electivity'~~ of di-v-methane rearrangement in (69), the formation of (70) via carbonylation of the reaction product of (71)

R. W. Lockhart, M. Kitadani, F. W. B. Einstein, and Y. L. Chow, Can. J. Chem., 1978,56.2897;R. A. Perry, R. W. Lockhart, M. Kitadani, and Y. L. Chow, ibid., p. 2906. IS3 T.Sasaki, S. Eguchi, and N. Toi, J. Org. Chem., 1978,43,3811;T. Sasaki, S. Eguchi, and N. Toi, Heterocycles, 1977,7,315. lJ4 P. M. Starewicz, G. E. Breigwieser, E. A. Hill, and P.Kovacic, Tetrahedron, 1979,35,819. T. R. Bok and W. N. Speckamp, Heterocycles, 1979,12,343. H. Takayama, T. Nomoto, T. Suzuki, M. Takamoto, and T. Okamoto, Heterocycles, 1978,9,1545. W.D.Ollis, M. Rey, and I. 0. Sutherland, J. Chem. Soc., Chem. Commun., 1978,675. Is* M. Kuzuya, M. Ishikawa, T. Okuda, and H. Hart, Tetrahedron Lerr., 1979,523. 15*

Heterocyclic Chemistry

458

with iron penta~arbonyl,’~’similar carbonylation of 2,3-homotropilidenes (72),16* and the formation161of transition-metal complexes of 1,4-diazabicyclo[2.2.2]octane. Bridged AzoaIkanes.-Intere~t~~in the behaviour of diradicals has led to a number of investigations directed to the synthesis and analysis of both thermal and photochemical decomposition of bridged azoalkanes. New synthetic routes are shown in Scheme 15. Photodecomposition162-166of compounds (73)-(76)

-&yo YNPh 0 f i p y o

$

NP N P h

(73)

Q2

%

Ref.162

Ref.163

N

N “CUCI

(74)

0

b-viii,

ix

&

Ref.164

Ref. 165

II

C0,Me

MeO,C (76)

Reagents: i, N-Phenylmaleimide, MeCOMe, at -50 “C; ii, H,, Pd/C, MeOH; iii, Bu‘OK, DMSO, H,O; iv, CuCl,, H,O, EtOH; v, KOH; vi, MeOK; vii, NH40H; viii, [C4H4-Fe(CO),l; ix, Ce4+;x, C3H4

Scheme 15

lS9 160

16’ 163 164

16’ 166

R. Aumann and J. Knecht, Chem. Ber., 1978,111,3429. R.Aumann and J. Knecht, Chem. Ber., 1978,111,3927. H. Yokobayashi, K. Nagase, and K. Sone, Bull Chem. SOC.Jpn., 1978,51,2569. D. Kaufmann and A. de Meijere, Tetrahedron Lett., 1979,779. N.J. Turro, K. C. Liu, W. Cherry, J.-M. Liu, and B. Jacobson, Tetrahedron Lett., 1978,5 5 5 . H.-D. Martin and M. Hekman, Tetrahedron Lett., 1978, 1183. H.D.Fuhlhuber, C. Gousetis, T. Troll, and J. Sauer, Tetrahedron Lett., 1978,3903. R. Dyllick-Brenzinger, J. F. M. Oth, H. D. Fuhlhuber, C. Gousetis, T. Troll, and J. Sauer, Tetrahedron Lett., 1978,3907.

459

Bridged Systems

and of related a z o a l k a n e ~ lhas ~ ~ been described, and thermal extrusion of has also been studied. A detailed analysis of azoalkane photochemistry16' has been based on spectroscopic data (absorption, emission, and photoelectron) and the measurement of fluorescence quantum yields and lifetimes. Thermal decomp~sition'~~ in the presence of ap-unsaturated ketones provides a novel entry to unusual skeletons (Scheme 16). The aviation of 2,3-diazabicycle[ 2.2.2Ioct-2-ene"O to give 2,3-diphen yl-2,3-diazabicyclo[2.2.2 ]octane has been described.

0

Scheme 16

5 Oxygen Compounds

Cyc1oadditions.-Of dominant interest are the applications of the Noyori cycloaddition2' of aa'-dibromo-ketones to furans, and the use of intramolecular Diels-Alder reactions in the construction of cyclic ethers. Both concepts are in the intramolecular cyclization that is shown in Scheme 17 to generate

fb 0

Me

Br

0 Scheme 17

an important sesquiterpene skeleton. The use of the Noyori method in the synthesis of carbohydrate^'^^ is illustrated by the key transformations of Scheme 18. Using the same approach, but with ring expansion via a Beckmann 167

16'

169

17'

172

R. Siemionko, A. Shaw, G. O'Connell, R. D. Little, B. K. Carpenter, L. Shen, and J. A. Berson, TetrahedronLett., 1978,3529; P. S . Engel, R. A. Hayes, L. Keifer, S. Szilagyi, and J. W. Timberlake, J. A m . Chem. SOC.,1978,100,1876; J. P. Snyder and H. Olsen, ibid., p. 2566; N. J. Turro and V. Ramamurthy, R e d . Trav. Chim. Pays-Bas, 1979,98,173; N. J. Turro, W. R. Cherry, M. J. Mirbach, M. F. Mirbach, and V. Ramamurthy, Mol. Phorochem., 1978,9,111; M. Gisin, E. Rommel, J. Win, M. N. Burnett, and R. M. Pagni,J. Am. Chem. SOC.,1979,101,2216; N. J. Turro, M. J. Mirbach, N. Harrit, J. A. Berson, and M. J. Platz, ibid., 1978, 100,7653. M. J. Mirbach, K . 4 . Liu, M. F. Mirbach, W. R. Cherry, N. J. Turro, and P. S. Engel, J. Am. Chem. SOC.,1978, 100, 5122. R. D. Little, A. Bukhari, and M. G. Venegas, Tetrahedron Lett., 1979, 305. F. A. Neugebauer and H. Weger, Chem. Ber., 1979,112,1075. R. Noyori, M. Nishizawa, F. Shimizu, Y. Hayakawa, K. Maruoka, S.Hashimoto, H. Yamamoto, and H. Nozaki, J. A m . Chem. SOC.,1979,101,221. T. Sato, M. Watanabe, and R. Noyori, Tetrahedron Lett., 1978, 4403; R. Noyori, T. Sato, and Y. Hayakawa, J. Am. Chem. SOC.,1978,100,2561.

Heterocyclic Chemistry

460

ii, iii

v-vii

A

Reagents: i, 1,1,3-Tribromo-3-methylbutan-2-one; ii, H202, OsO,; iii, p-TsOH, CuSO,, MeCOMe; iv, CF,CO,H; v, Bu‘OCH(NMe,),; vi, Urea; vii, H’

Scheme 18

rearrangement, 173 leads to a stereoselective synthesis of various alkaloids. Full details of the alternative Hofmann method of cycloaddition are a ~ a i 1 a b l e . l ~ ~ Examples of synthesis via intramolecular addition are shown in Scheme 19.175,176 In the conventional intermolecular [4 + 21 addition with furans, further studies concern reaction with allenes,17’ the effect of high pressure”* on exo-/endoratios, and trapping of a 4,5-didehydr0pyrimidine~~’ with furan.

Ref. 175

Ref. 176

Scheme 19 173

’, 17’ 176

17’

R. S. Glass, D. R. Deardorff, and L. H. Gains, Tetrahedron Lett., 1978,2965;S . R. Wilson and R. A. Sawicki, ibid., p. 2969. ‘Organic Syntheses’, ed. W. A. Sheppard, Wiley, New York, 1978,Vol. 58,p. 17. K.A. Parker and M. R. Adamchuk, Tetrahedron Lett., 1978,1689. J. D.White, B. G. Sheldon, B. A. Solheim, and J. Clardy, Tetrahedron Lett., 1978,5189. M.Bertrand, J.-L. Gras, and B. S. Galledou, Tetrahedron Lett., 1978,2873. J. Rimmelin, G. Jenner, and P. Rimmelin, Bull. SOC.Chim. Fr., Part 2, 1978,461. D.Christophe, R.Promel, and M. Maeck, Tetrahedron Lett., 1978,4435.

Bridged Systems

46 1

ArCOCOCOCOAr

Ar$Ar O'

Ref.183

COCOAr CF,

Scheme 20

Photoaddition to 1,3-diphenylisoben~ofuran'~~ and to furan'" are noted. Other photoadditions are shown in Scheme 20.'82-'84 Stetter and Miscellaneous Syntheses.-From bicyclo[3.3.l]nonane-3,7,9-trione, L e n n a r t ~ have ' ~ ~ described cyclizationsto give a series of 1,3,6-trisubstituted-2oxa-adamantanes; from substituted bicyclo[3.3. llnonenes, Goff and Murray have given a route186to 2-substituted-4-oxa-homoadamantanes. The interesting base-catalysed formation of an ether, used by Ganter's group, in Zurich, has been further studied. In cyclizations of the type (77)+(78), both proximity and electronic eff ectsl" are important in determining the yield. Metal complexes of (79)have previously been isolated from acetylacetone; now the free ether has been isolated and The reaction of 3-0xaquadricyclane'~~with organometallic reagents has been described. The continued interest in' the

(77)

lS3 lS4

lS6 lS7

(79)

G. Kaupp and E. Teufel, J. Chem. Res. ( S ) , 1978,100. K. Mizuno, R. Kaji, H. Okada, and Y. Otsuji, J. Chem. SOC.,Chem. Commun., 1978, 594. A. Gilbert and G. Taylor, J. Chem. SOC.,Chem. Commun., 1978, 129. M. B. Rubin, E. C. Krochmal, and M. Kaftory, Red. Trau. Chim. Pays-Bas, 1979,98,85. Y. Kobayashi and Y. Hanzawa, Tetrahedron Lett., 1978,4301. H. Stetter and J. Lennartz, Justus Liebigs Ann. Chem., 1978, 1807. D. L. Goff and R. K. Murray, J. Ore. Chem., 1978,43,3179. R. A. Pfund and C.Ganter, Helu. Chim. Acta, 1979,62,228. A. de Renzi, A. Panunzi, L. Paolillo, and A. Vitagliano, J. Organometal. Chem., 1977,124,221. H. Hogeveen and B. J. Nusse, J. Am. Chem. SOC.,1978,100,3110.

Heterocyclic Chemistry

462

pheromonal activity of dioxabicycloalkanes has stimulated further syntheses (Scheme 2l””), and other bridged diethers”’ have been obtained from carbohydrate sources.

I

‘CHO

”xScheme 21

An unusual SbF5-promoted addition of sulphur dioxide to cyclohexa-1,3diene’” gives (80),the structure being confirmed by X-ray analysis. Less surprisingly, s u l p h ~ n a t i o n of ’ ~9-t-butylanthracene ~ gives (81). The reaction of phenylacetaldehyde with FS03H gives (82) (incorrectlynamed) directly,lg4in moderate yield. Alternatively, (82) may be ~ b t a i n e d , ~in’ ~similar yield, by the direct reaction of phenylacetaldehyde with trimethylsilyl iodide. We also note oxygen analogues of (60).148

Bridged Peroxides.-Improved procedures for the formation of cyclic peroxides, using singlet ~xygen,’.~ have been noted earlier. Routine extension to cyclohe~tatriene’’~ gives the [4 + 21 and [2 + 61 adducts and a little of the [4 + 21 adduct of norcaradiene. 7-Cyanocycloheptatriene gives the [4 + 21 adduct of the norcaradiene i~orner.’~’ In these studies, a key feature of the structural elucidation is the reduction198of isolated double bonds by di-imide, permitting the transformation of the adducts into saturated peroxides. The method has been used successfully with a variety of peroxide^,'^^-'^* including 2,3-dioxabicyclo[2.2. llheptenes, 199 2,3-dioxa-7-thiabicyclo[2.2.1]heptenes,200 2,3,7 -trioxabicyclo[2.2. l]heptenesZo1(i.e. ozonides), 2,3-dioxabicyclo[2.2.2]0~tane~,~~~ Y. Yamada, H. Sanjoh, and K. Iguchi, Tetruhedron Lett., 1979,423. P. Koll and F. S. Tayman, Chem. Ber., 1979,112,2296; P. Koll, S. Deyhim, and K. Heyns, ibid., p. 2909; P. Koll and S. Deyhim, ibid., p. 2913; P. Koll, F. S. Tayman, and K. Heyns, ibid., p. 2305. 19’ K. S. Fongers and H. Hogeveen, Tetrahedron Lett., 1979,275. 193 F. van de Griendt and H. Cerfontain, Tetrahedron Lett., 1978, 3263. 194 J. Kagan, S-Y. Chen, D. A. Agdeppa, W. H. Watson, and V. Zabel, Tetrahedron LeR, 1977,4469. 195 M. E. Jung, A. B. Mossman, and M. A. Lyster, J. Org. Chem., 1978,43, 3698. 196 T. Asao, M. Yagihara, and Y . Kitahara, Bull Chem. SOC.Jpn., 1978, 51, 2131; W. Adam and M. Balci, Angew. Chem., 1978,90, 1014. 19’ W. Adam and M. Balci, J. Org. Chem., 1979,44, 1189. 19’ D. J. Coughlin and R. G. Salomon, J. A m . Chem. SOC.,1977, 99,655. ‘99 W. Adam and H. J. Eggelte, J. Org. Chem., 1977,42,3987; W. Adam and I. Erden, ibid., 1978,43, 2737. zoo W. Adam and H. J. Eggelte, Angew. Chem., 1978,90,811. *01 W. Adam, H. J. Eggelte, and A. Rodriguez, Synthesis, 1979, 383; W. Adam and K. Takayama, J. Org. Chem., 1979,44, 1727. ’O’ W. Adam and H. J. Eggelte, Angew. Chem., 1977, 89, 762. 190 19’

Bridged Systems

463

oxygen adducts of f ~ l v e n e sand ,~~ a -~p y r ~ n e . We ~ ' ~note other aspects of addition of oxygen to olefinsZo5and to aromatics.206The important role of prostaglandin endoperoxides as biosynthetic precursors of prostacyclins and related compounds has led to interest in other methods of synthesis of simple model peroxides. A number of non-photolytic are available. 6 Sulphur Compounds

Cyc1oadditions.-Although maleic anhydride does not react with thiophen at normal pressures, use of high pressure,'08 at 100 "C,permits successful cycloaddition. Thermo1ysisZo9of cis- and trans-2,3-divinylthiiran gives a mixture of dihydrothiepins,two of which readily give adducts (83)and (84). Bridged adducts are reported of cyanothioformamides210and of bistrifluoromethylthioketen.'" A series of papers212concern [3 + 21 cycloaddition to meso-ionic 173-dithiolones, Treatment of (87) giving, for example, (85). Dimers (86) can also be with base, surprisingly, gives (88)in good yield214(structure confirmed by X-ray analysis).

(86) ' 0 3 '04

'05

(87)

W. Adam and I. Erden, Angew. Chem., 1978,90,223. W.Adam and I. Erden, Angew. Chem., 1978,90,223. I. Landheer and D. Ginsburg, R e d . Trav. Chim. Pays-Bas, 1979,98,70;C. W . Jefford and C. G. 1978,100,6515;J-P. Hagenbuch and P. Vogel, Tetrahedron Lett., Rimbault, J. Am. Chem. SOC.,

1979,561. M. Laguerre, J. Dunogues, and R. Calas, J. Chem. Res. (S), 1978,295; G. Aksnes and B. H. Vagstad, Acta Chem. Scand., Ser. B, 1979,33,47;A.Defoin, J. Baranne-Lafont, J. Rigaudy, and J. Guilhem, Tetrahedron, 1978,34,83;J. Rigaudy and D. Sparfel, Tetrahedron, 1978,34,113;N. J. Turro, M. F. Chow, and J. Rigaudy, J. A m . Chem. SOC.,1979,101,1300. 'O' A.J. Bloodworth and J. A. Khan, Tetrahedron Lett., 1978,3075;A. J. Bloodworth and B. P. Leddy, ibid., 1979,729;R. G. Salomon and M. F. Salomon,J. A m . Chem. Soc., 1977,99,3501;N. A.Porter and D. W. Gilmore, ibid., p. 3503. "* H. Kotsuki, S. Kitagawa, H. Nishizawa, and T. Tokoroyama, J. Org. Chem., 1978,43,1471. '09 M.P. Schneider and M. Schnaithmann, J. A m . Chem. SOC.,1979,101,254. 'lo K. Friedrich and M. Zamkanei, Chem. Ber., 1979,112,1867. '11 M . S. Raasch, J. Org. Chem., 1978,43,2500. '"H. Gotthardt, C. M. Weisshuhn, and B. Christl, Justus Liebigs Ann. Chem., 1979, 360, and references therein. '13 H.Gotthardt, 0.M. Huss, and C. M. Weisshuhn, Chem. Ber., 1979,112,1650. S. Braverman, D. Reisman, M. Sprecher, D. Rabinovich, and F. Frolow, Tetrahedron Lett., 1979, 901. '06

464

Heterocyclic Chemistry

Miscellaneous Syntheses.-Michael addition of Na2S to cyclo-octa-2,7d i e n ~ n e followed , ~ ~ ~ by transannular carbene insertion via the tosylhydrazone, leads to 9-thianoradamantane (89). Michael addition216 of Na2S to 4,4dimethoxycyclohexa-2,5-dienonegives (90). Amine adducts (9 1)of a-mercaptoketones217and of bridged thians218from dithioacetic acid are noted. S o l v o l y ~ i s ~ ~ ~ of 2-thiabicycl0[2.2.1]heptan-6-01 esters, obtained via addition of thiophosgene to cyclopentadiene, has been reported.

7 Bridged Annulenes and Related Systems Although the chemistry of bridged annulenes incorporating pyrrole, furan, or thiophen units, and particularly the chemistry of cyclophanes, has made interesting progress, the major breakthrough in this area is the successful synthesis of simple bridged heterocyclic annulenes (Scheme 22220*221). The aza[ 1Olannulene (92) is a stable compound, forming a stable hydrochloride, and has been well characterized by n.m.r. as an aromatic annulene. Photolysis of (93) is reported222 to give (94). The structure (94)has been assigned with little supporting evidence. Routes to singly and doubly bridged porphyrins have been the first and novel bridged platyrin (95) (a 22~-electronsystem) has been benzodiazepines (96) have been 8 Cyclophanes

New synthetic routes to cyclophanes and studies in which various spectroscopic techniques were used to probe intramolecular interactions have been reported. X-Ray analysis of the heterocyclophanes (97),226(98),227and (99)*?.'and the

217

'19

220 22 1

222

223 224

225 226

227

T. Sasaki, S. Eguchi, and T. Hioki, J. Org. Chem., 1978,43, 3808. C . H. Foster and D. A. Payne, J. Am. Chem. SOC.,1978,100,2834. F. Asinger, A . Saus, and M. Bahr-Wirtz, Justus Liebigs Ann. Chem., 1979, 708, G. Levesque, A. Mahjoub, and A. Thuillier, Tetrahedron Lett., 1978, 3847. J. Ohishi, K. Tsuneoka, S. Ikegami, and S. Akaboshi, J. Org. Chem., 1978,43, 4013. W. J. Lipa, H. T. Crawford, P. C. Radlick, and G . K. Helmkamp, J. Org. Chem., 1978,43,3813;see also H. J. Golz, J. M. Muchowski, and M. L. Maddox, Angew. Chem., 1978,90, 896. M. Schafer-Ridder, A. Wagner, M. Schwamborn, H. Schreiner, E. Devrout, and E. Vogel, Angew. Chem., 1978,90,894. J. Kawata, S. Niizuma, and H. Kokubun, J. Photochem., 1978,9, 463. A . R. Battersby, S. G. Hartley, and M. D. Turnbull, Tetrahedron Lett., 1978, 3169. R. A . Berger and E. LeGoff, Tetrahedron Lett., 1978,4225. J. M. Mellor, M. F. Rawlins, and J. H. A . Stibbard, J. Chem. SOC., Chem. Commun., 1978, 557. M. Corson, B. M. Foxman, and P. M. Keehn, Tetrahedron, 1978, 34, 1641. N. B. Pahor, M. Calligaris, and L. Randaccio, J. Chem. SOC.,Perkin Trans. 2, 1978,42.

Bridged Systems

465 i, ii

-NOT

1

iii-vi

Reagents: i, TsCl; ii, 2,6-Dimethylpyridine, at 40 "C; iii, HMPA, THF, PriNH, BuLi; iv, MeSSMe; v, MCPBA; vi, Me,O'BF,-; vii, KOBu', BuOH; viii, Ph,PCH,; ix, Ago; x, NaN, on acid chloride; xi, llO°C, for 30min; xii, hot PhMe, for 12 h; xiii, TsCl on Ksalt; xiv, LiAlH,; xv, D D Q

Scheme 22

0(93)

0(94)

Heterocyclic Chemistry

466

I - -

(97)

(98) X = 0 (99)X= s

(100)

photoelectron spectra of (98), (99) and related compounds,228and (loo)”’ are noted. The syntheses of (101) and (102)230and their reduction products, of many pyridino-paracy~lophanes,~~~ and of cyclophanes with sulphur bridges232 are noted.

9 Cryptands and Cryptates Lack of space dictates the limited coverage and absence of structural formulae in this section. Many varied cryptands have been synthesized, notably by the groups working at Bonn,233Liverpo01,~~~ S t r a s b o ~ r g , ~and ~ ’ Utah.236A recent objective in the work at Strasbourg has been the design of a cryptand that is capable of forming cryptates with inclusion of linear triatomic anions; e.g., azide ion. In the Liverpool work, inclusion complexes incorporating simple (primary alky1)-ammonium salts and bis(primary alky1)-ammonium salts have been formed. Other related with primary alkylammonium and secondary dialkylammonium salts are noted. The development of chiral recognition, noted earlier, is now being aimed at esters of amino-acids, with increasing s o p h i s t i ~ a t i o n . ~ ~ ~ U. Folli, P. Vivarelli, F. Bernardi, A. Bottoni, F. P. Colonna, and G. Distefano, Z. Naturforsch., Teil A , 1978,33,959. 229 W. FIitsch, H. Peeters, W. Schulten, and P. Rademacher, Tetrahedron, 1978, 34, 2301. 230 S. H. Kusefoglu and D. T. Longone, Tetrahedron Lett., 1978, 2391. 231 I. D. Reingold, W. Schmidt, and V. Boekelheide, J. A m . Chem. SOC.,1979,101, 2121. 232 A. Bhattacharjya and A. G. Hortmann, J. Heferocycl. Chem., 1978,15, 1223; F. Bottino, S. Foti, S. Pappalardo, P. Finocchiaro, and M. Ferrugia, J. Chem. SOC.,Perkin Trans. 1, 1979, 198; Y. Fukuzawa, M. Aoyagi, and S . Ito, Tetrahedron Lett., 1979, 1055; N. Kato, Y. Fukuzawa, and S.Ito, ibid., p. 1113; F. Bottino, S. Foti, S.Pappalardo, and N. Bresciani-Pahor, ibid., p. 1171; F. Vogtle and K. Bockmann, Chem. Ber., 1979,112, 1400. 233 U. Heimann, M. Herzhoff, and F. Vogtle, Chem. Ber., 1979,112, 1392, and references therein. 234 M. R. Johnson, I. 0.Sutherland, and R. F. Newton, J. Chem. SOC.,Chem. Commun., 1979,307,309; S . J. Leigh and I. 0. Sutherland, J. Chem. Soc., Perkin Trans. 1, 1979, 1089. 235 J. M. Lehn, E. Sonveaux, and A. K. Willard, J. Am. Chem. SOC.,1978,100,4914; J-M. Lehn, Pure Appl. Chem., 1977,49,857. 236 J. S . Bradshaw, R. E. Asay, G. E. Maas, R. M. Izatt, and J. J. Christensen, J. Heterocycl. Chem., 1978, 15, 825. 237 J. C. Metcalfe, J. F. Stoddart, and G. Jones, J. A m . Chem. SOC.,1977,99,8317. 238 S . C. Peacock, L. A. Domeier, F. C. A. Gaeta, R. C. Helgeson, J. M. Timko, and D. J. Cram, J. A m . 1978,100,8190. Chem. SOC., 228

Bridged Systems

467

An important new application239is the use of cations to control the photochemistry of possible photochromic materials. Polyether (103), on irradiation, gives the expected photo-adduct (104), but this is not thermally stable, and it rapidly (ti ca. 3 min) reverts to (103). In marked contrast, in the presence of LiClO4, complete conversion of (103) becomes possible by the formation of the stable (up to 210 "C)compound (104) as the lithium complex.

With a Schroder and Witt have reported the first 'breathing crown polyether periphery attached to a bullvalene skeleton, a ring size of 11 or 13 in one case or of 20 or 22 in another case is possible by variation of the bullvalene isomers. The flexibility of such a cryptand for cation complexation has yet to be tested.

239

240

J. P. Desvergne and H. Bouas-Laurent, J. Chem. SOC., Chem. Commun., 1978,403; A.Castellan,J. M.Lacoste, and H. Bouas-Laurent, J. Chem. SOC.,Perkin Trans. 1, 1979,411. G. Schroder and W. Witt, Angew. Chem., Int. Ed. Engl., 1979,18,311.

8 Conformational Analysis BY F. G. RIDDELL

1 Introduction This chapter departs slightly in its content from that of most others in this volume in that it covers the literature appearing in Chemical Abstracts during the period May 1978 to May 1979. The ordering of material is firstly by ring size, and secondly by the nature of the heteroatoms. The heteroatoms are introduced in an order of ‘strangeness’: oxygen, nitrogen, sulphur, phosphorus, boron, and silicon, with the ‘strangest’ atom in the ring determining its position in the text. Features of note emerging from the preparation of this Report include the increasing attention being given to rings containing phosphorus, increasing numbers of publications dealing with medium and larger rings, the greater use of 13 C n.m.r. due to its more widespread availability, and an increase in papers dealing with conformational analysis coming from the Soviet Union. 2 Four-membered Rings

An ab inih’o calculation of the molecular structure of azetidine has appeared’ which agrees with the observed structure except that the puckering angle is larger. This work indicates that the previous postulation that the equatorial N-H is more stable in this molecule is correct. Two groups have reported work on 1,2-diazetidines, in which the principal interest is the double nitrogen-inversion Hall and Bigard2 examined the coalescence of the AA’BB’ spectra of the ring hydrogens in several 1,Zdialkyl-l,2-diazetidines,and Nelsen’s group, pursuing their detailed investigation of conformations of hydrazine, have also looked at mono- and poly-cyclic derivatives of this ring.3 Free energies, enthalpies, and entropies of activation and free-energy differences between conformations are reported. A vibrational spectroscopic investigation of 1,3-disilacyclobutane suggests that the molecules have a bent ring conformation in the vapour and liquid phase, but a planar conformation in the solid.4

’ ‘

J. Catalan, 0. Mo, and M. Yanez, J. Mol. Struct., 1978, 43, 251 J. H. Hall and W. S . Bigard, J. Org. Chem., 1978, 43, 2785. S. F. Nelsen, V. E. Peacock, G. R. Weisman, M. E. Landis, and J. A. Spencer, J. Am. Chem. Soc., 1978,100,2806. R. M. Irwin and J. Laane, J. Phys. Chem., 1978,82,2845.

469

Heterocyclic Chemistry

470

3 Five-membered Rings A timely review of the conformations of five-membered heterocyclic rings has appeared.' A detailed n.m.r. investigation of the conformations of 2- and 4-nicotines, using n.m.r. methods, has appeared.6 Envelope conformations for the pyrrolidine rings and a perpendicular arrangement between both rings are deduced. Anteunis et al. have investigated the conformations of proline and hydroxyproline in linear and cyclic pep tide^.^ Ab initio calculations on the five possible envelope conformations of 1,3oxazolidine suggest that the N-envelope is the most stable.' The 1,3-thiazolidine ring has been studied by vibrational spectroscopy9 and by n.m.r. methods." A report has appeared of a dipole moment/Kerr constant investigation of some 2 -chloro- 1,3,2-dioxaphospholans. '' Delmas and Maire have published results on the dithiastannacyclopentane system, e.g. (1).l2Ultraviolet photoelectron spectra and 'H n.m.r. spectra indicate non-planarity of the ring and flexibility of the S-Sn-S intracyclic angle.

5

(1) R' = Me,Et, or Bu R2 = H o r Me

4 Six-membered Rings

Oxygen-containing Rings.-The conformational equilibria in 4-halogenotetrahydropyrans (2) have been investigated by 'H and 13Cn.m.r. spectroscopy above and below coalescence. l3 The equatorial preferences of the halogens were less pronounced than in the cyclohexane series, and increased with increasing electronegativity of the halogen.

X

B. Fuchs, in 'Topics in Stereochemistry', ed. E. L. Eliel and N. L. Allinger, Wiley Interscience, New York, 1978,Vol. 10,pp.1-94. J. F. Whidby, W. B. Edwards, and T. P. Pitner, J. Org. Chem., 1979,44794. ' M. J. 0.Anteunis, R. Callens, V. Asher, and J. Sleeckx, Bull. SOC.Chim. Belg., 1978,87,41. a M. Hotokka and P. Pyykko, J. Mol. Struct., 1979,51,133. M. Guiliano, G. Mille, T. Avignon, and J. Chouteau, J. Raman Spectrosc., 1978,7,214. lo F.Piriou, K. Lintner, Lam Thanh Hung, F. Toma, and S. Fermandjian, Tetrahedron,1978,34,553. l 1 R. P. Arshinova, E. T. Mukmenev, L. I. Gurarii, and B. A. Arbuzov, Izv. Akad. Nauk SSSR, Ser. Khim., 1978,609. M.A . Delmas and J. C. Maire, J. Organomet. Chem., 1978,161,13, l3 R. Schrooten, F. Borremans, and M. Anteunis, Spectrochim. Acta, Part A, 1978,34, 297.

Conformational Analysis

47 1

The conformations of alkyl-substituted di- and tetra-hydropyrans have been studied by means of 13Cn.m.r. ~ p e c t r a .The ' ~ series (3)prefers the 2-equatorial-4axial conformation.

The stereochemistry and conformations of the reduction products of 2methyltetrahydropyran-4-one have been investigated by Wigfield and Feiner. l5 Proton n.m.r. data have been used to study the conformations of 2,3,4-tri-0aCetyl-D-XylOnO-1,5-lactone (4).l6 AcOQO OAc

(4)

A configurational and conformationalstudy of some 2,5-dimethyl dihydro- and tetrahydro-pyran-6,6-dicarboxylateshas been r e p ~ r t e d . ' ~ A microwave and n.m.r. study of the structure and the ring-inversion process in 3,6-dihydro-1,2-dioxin ( 5 ) shows a half chair conformation and a possibly nearly planar transition state."

The by now well studied 1,3-dioxan ring continues to attract investigations.19-" The two most notable contributions come from Kalo~stian'~ and Pihlaja.20The former reports a larger preference for an equatorial 5-iodogroup in 1,3-dioxan than in cyclohexane.20The latter finds that the 2,2-disubstituted derivatives (6) prefer chair conformations, with the methyl group axial.21 l4 Is l6 I'

l8 l9 'O

E. Kleinpeter, C. Duschek, and M. Muehlstaedt, J. Prakt. Chem., 1978, 320, 303. D. C. Wigfield and S..Feiner, Can. J. Chem., 1978, 56, 789. C. R. Nelson, Carbohydr. Res., 1979,68,55. K. Jankowski and J. Couturier, Pol. J. Chem., 1978,52,413. T. Kondo, M. Matsumoto, and M. Tanimoto, Tetrahedron, 1978,3819. N . J. Kotite, M. Harris, and M. K. Kaloustian, J. Chem. SOC.,Chem. Commun., 1977, 911. K.Pihlaja and T. Harkonen, Acta Chem. Scand., Ser. B, 1978,32,769. B. 'A.Arbuzov, V. E. Kataev, S. G. Vul'fson, and A. N. Vereshchagin, Izv. Akad. Nauk SSSR, Ser. Khim., 1978, 2441.

Heterocyclic Chemistry

472 Me

R

O X 0

U

(6) R

=

Et, Pr”, Pri, Me2CHCH2, or EtCHMe

An infrared spectroscopic investigation of trans -2,3 -dichloro- 1,4-dioxan3*and a 13C n.m.r. investigation of 1,4-dio~an-2,3-diols~~ have been reported. Nitrogen-containing Rings.-Booth et al. have reinvestigated the classical work on the thermal decomposition of some quaternary hydroxides derived from piperidine, morpholine, and decahydr~quinoline.~~ Their results confirm the validity of the previous measurements and show the importance of conformational factors in /3-elimination reactions. Duthaler and Roberts have reported the 15Nnatural-abundance chemical shifts for a number of closely related C- and N-methyl-substituted piperidine and decahydroquinoline hydrochloride^.^^ The 15Nshifts give linear correlations with 13 C shifts in hydrocarbon analogues, and additive shift parameters were deduced. These parameters are of potential use for conformational studies. Proton-transfer reactions and nitrogen inversion in cis- 1,2,6-trimethylpiperidine in aqueous and in anhydrous acidic dimethyl s ~ l p h o x i d have e~~ been investigated by Delpuech. In aqueous solutions, proton transfer is far more rapid and nitrogen inversion is far slower than in the non-aqueous medium. N.m.r. studies of 4-nitropiperidine derivatives indicate a preference for an equatorial 4 - n i t r o - g r o ~ p . ~ ~

22 23 24

25 26

2’ 28 29

30

31

32 33 34

35 36

37 38

L. Cazaux, J. P. Gorrichon, P. Maroni, a n d M . Perry, Can. J. Chem., 1978, 56, 2998. L. Cazaux, J. P. Gorrichon, Y. Koudsi, and P. Maroni. Can. J. Chem., 1978, 56, 3006. N. S. Zefirov, E. G. Chalenko, I. G. Mursakulov, M. M. Guseinov, N. K. Kasumov, and E. L. Ramazanov, Zh. Org. Khim., 1978, 14, 1560. L. Cazaux, J. P. Gorrichon, and P. Maroni, Can. J. Chem., 1978,56, 3016. Yu. Yu. Samitov, R. S. Musavirov, F. Kh. Karataeva, E. A. Kantor, D. L. Rakhmankulov, and N. A. Nikiforova, Zh. Org. Khim., 1978,14, 2483. V. E. Kataev, Tezisy Dok1.-Vses. Konf. ‘Stereokhim. Konform. Anal. Org. Neftekhim, Sint’, 3rd, 1976, p. 74 (Chem. A h . , 1978,88, 169 492). Z. I. Zelikman, Yu. Yu. Samitov, T. P. Kosulina, V. G. Kulnevich, and B. A. Tertov, Khim. Geterotsikl. Soedin., 1978, 1172. Ya. B. Yasman, N. A. Nikiforova, R. S. Musavirov, E. A. Kantor, R. A. Karakhanov, and D. L. Rakhmankulov, Tezisy Dok1.- Vses.Konf.‘ Stereokhim. Konform, Anal. Org. Neftekhim. Sint.’, 3rd, 1976, p.50 (Chem. Abs., 1978,89,43 268). E. Santoro and M. Chiavarini, J. Chem. SOC.,Perkin Trans. 2, 1978, 189. D. Jeremic, I. Gutman, R. Petrovic, and S. Milosavljevic, Glus. Hem. Drus., Beograd, 1978,43, 1 (Chem. Abs., 1978,89,42 201). K. Fukushima and S. Takeda, J. Mol. Struct., 1978, 49, 259. P. Ayras, Org. Magn. Reson., 1978, 11, 152. H. Booth, A. H. Bostock, N. C. Franklin, D. V. Griffiths, and J. H. Little, J. Chem. SOC.,Perkin Trans.

2, 1978, 899. R. 0. Duthaler and J. D. Roberts, J. A m . Chem. Soe., 1978,100,3882. J. J. Delpuech and M. N. Deschamps, Nouu. J. Chim., 1978, 2, 563. J. J. Delpuech and B. Bianchin, J. A m . Chem. SOC.,1979,101, 383. H. Piotrowska, W. Sas, and J. Winiarski, Bull. Acad. Pol. Sci., Ser. Sci. Chim., 1978, 26, 277.

ConformationalAnalysis

473

X-Ray crystallography on the piperidine nitroxide radical (7)shows a somewhat deformed chair conformation, and the N-0 bond at 19.8" from the CNC plane.39 H C

Buchanan and Morin have reported a study of the structure and bonding in cyclic phosphoramidates, e.g. (8), of ring size from four to nine.40 For sixmembered and larger rings there appears to be nearly complete delocalization of the lone pair and a trigonal planar nitrogen atom. In the azetidine derivatives the lone pair of nitrogen appears to be localized, whilst an intermediate situation pertains in the five-membered rings. 0 II ,OMe

M e o - P ,

OMe

(8)

Recent 13Cn.m.r. studies of sterically hindered derivatives of 4-piperidone and the corresponding oximes41and of 1-hetera-3-cyclohexanonesystems4*(9) have been reported.

4

X (9) X

=

NCOMe,S, SOz, etc.

A conformational study of some 1,4-dihydropyridines has been reported.43 Anet and Yavari have examined the 13C n.m.r. spectrum of NN'-dichloropiperazine (10) at -45 "C and found a population ratio for ee :(ea + ae)

c1 I

("I N

39 40

41 42

43

M. Cygler, Acra Crystallogr., Sect. B, 1979, 35, 195. G. W. Buchanan and F. G. Morin, Can. J. Chem., 1979,57,21. P. Geneste, J. M. Kamenka, and C. Brevard, Org. M a p . Reson., 1977,10, 31. J. A. Hirsch and A. A. Jarmas, J. Org. Chem., 1978,43,4106. I. Sekacis, E. Liepins, and G. Duburs, Latv. PSR Zinat. Akad. Vestis, Kim. Ser., 1979, 11 1.

474

Heterocyclic Chemistry

conformations of 3 : 1, as compared with the value for N-chloropiperidine of ca. 15 : l.44 The origin of this unexpected effect is discussed. Binsch et al. have recorded the 'Hn.m.r. spectra of 1,4-dinitrosopiperazine (ll),its cis-2,6- and trans-2,5-dimethyl derivatives (12) and (13), and 1,3,5trinitrosohexahydro-1,3,5-triazine(14) at varying t e m p e r a t u r e ~ .The ~ ~ results

reveal a complicated variety of conformational rate processes arising from rotation about the N-N bonds. One rate process is observed in (11)and (12) and there are two in (13) and three in (14). X-Ray studies on NN'-bis-( 1-chloro-2-methylpropenyl)piperazine(15 ) reveal a chair conformation for the piperazine ring.46 Me

The group at the University of East Anglia (at Norwich) have published a report of the conformations and conformational processes in perhydro- 1,2,4triazines (16)and perhydro-1,3,4-thiadiazines(17).47

R

AX MeN MeA.J (16) X = NMe (17) X = S

A conformational study of 4,4,6-trimethyltetrahydro-1,3-oxazinehas appeared.48 Carbon- 13 n.m.r. spectra have been reported for twenty-four methyl-substituted morpholines. The chemical shifts of the carbon atoms in the ring are 44 45

46 47

48

F. A. L. Anet and I. Yavari, J. Chem. SOC.,Chem. Commun., 1978, 58. D. Hoefner, D. S. Stephenson, and G. Binsch, J. Magn. Reson., 1978.32, 131. M. van Meerssche, G. Germain, J. P. Declerq, and N. Molhant, Cryst. Struct. Commun., 1979,8,45. A. R. Katritzky, R. C. Patel, and D. M. Read, Tetrahedron Lett., 1977, 3803. S. G. Klepikova, L. P. Krasnomolova, 0. V. Agashkin, B. V. Unkovskii, I. P. Boiko, and Yu. F. Malina, Izu. Akad. Nauk Kaz. SSR,Ser. Khim., 1978, 28, 70.

Conformational Analysis

475

additive with respect to the methyl substituents, and a good correlation was found between observed and predicted shiftsa4' The derived parameters enabled the authors to assign the conformation of the all-cis-2,3,5,6-tetramethyl derivative as (18).

N.m.r. results indicate that the N-alkyl chain in 4-alkyl-morpholine N-oxides prefers to be e q ~ a t o r i a l . ~ ~ The ring-chain tautomerism in 3,4-dimethyltetrahydro-l,3,4-oxadiazines, and their conformations, have been investigated by a Russian group."

The groups in Norwich and at the University of Stirling have reported their results on the conformations and conformational rate processes of tetrahydro1,2,4- and 1,2,5-0xadiazines.~*-~~ For the 1,2,5-oxadiazine (19) a careful kinetic study by n.m.r. shows A H * to be 14.4 f 0.1 kcal mol-' and AS* to be -1.2 f 0.4 cal K-'mol-' for inversion of N-2.54 For the 1,2,4-oxadiazine system (20), measurements of the coalescence temperature give values of AG' of 12.7 kcal mol-', again presumed to arise from inversion of N-zS3 The Norwich group has also reported further studies on 1,3,5-oxadiazines, 1,3,5 -dioxazines, and 1,3, S - t r i a ~ i n e s . ~ ~ Riddell et al. have published an extensive survey of the conformations of tetrahydro-1,4,2-dioxazines(21), using 'H and I3C n.m.r.56 A study of model compounds allows the assignment of the ring- and N-methyl-inversion processes

R4

49 50 51 52

53 54 55

56

B. Nilsson and S. Hernestam, Org. Magn. Reson., 1978, 11, 116. F. Devinsky, I. Lacko, A. Nagy, and L. Krasnec, Chem. Zvesti, 1978,32, 106. A. A. Potekhin, and S. M. Shevchenko, Khim. Geterotsikl. Soedin., 1978, 1203. A. R. Katritzky and R. Patel, Heterocycles, 1978,9, 263. F. G . Riddell and E. S. Turner, Heterocycles, 1978, 9, 267. F. G. Riddell and E. S. Turner, J. Chem. Res. ( S ) , 1978,476. V. J. Baker, I. J. Ferguson, A. R. Katritzky, R. Patel, and S. Rahimi-Rastgoo, J. Chem. SOC.,Perkin Trans. 2, 1978, 377. F. G . Riddell, M. H. Berry, and E. S. Turner, Terrahedron, 1978, 34, 1415.

476

Heterocyclic Chemistry

as being those for which AG’ is 10.9 and 11.4 kcal mol-’, respectively. The differences in conformational free energies of N-methyl- and N-ethyl groups are also measured and discussed. Sulphur-containing Rings.-The barrier to ring inversion in thian-4-one dimethyl ketal has been measured,” and found to be 10.2 kcal mol-’. N.m.r. data indicate that the conformations of the cis- and trans-thianium ions (22) in solution are strongly solvent-dependent ; a result reminiscent of the analogous piperidinium Me I

Three papers dealing with conformations of thian oxides have appeared. 5941

In thian-3-one and in 3-dicyanomethylenethian oxides the S-0 bond is preferentially axial.” Introduction of a sulphur atom into these rings p to the sulphinyl group increases the amount of the equatorial conformer present. A configurational and conformational study of N-aryl-sulphimides derived from thians and thiadecalins has been reported,62 as has some work on 3,4dihydro thiapyrans. 63 1,3-Dithian continues to attract attention.64d7 Several macrocyclic compounds, e.g. (23), have been prepared to study the competition between aryl and benzyl groups for the equatorial 2-position in 1,3-dithia11.~~ The benzylic bond goes equatorial, with the aryl group axial. Analogous results were obtained for a 1,3-dioxan derivative.

(23)

The gauche repulsive effect has been investigated in 5-methoxy- and 5 methylthio-1,3-dithians (24) by Eliel and Juaristi.6s The cis-trans equilibria in 57

59

6o 62

64

65

R. Borsdorf, E. Kleinpeter, S. Agurakis, and H. Jancke, J. Prakt. Chem., 1978, 320, 309. G. Lambrecht, Arch. Pharm. (Weinheim, Ger.), 1978,311,636. K. Bergesen, B. M. Carden, andM. J. Cook, J. Chem. SOC.,Perkin Trans. 2, 1978, 1001. R. Lett and G. Chassaing, Tetrahedron, 1978, 34, 2705. G. Chassaing, R. Lett, and A. Marquet, Tetrahedron Lett., 1978,471. P. K. Claus, W. Rieder, and F. W. Vierhapper, Monatsh. Chem., 1978,109, 609. J. P. Pradere and G. Hadjukovic, C. R. Hebd. Seances Acad. Sci.,Ser. C , 1978,286, 553. E. Langer, H. Lehner, and M. J. 0. Anteunis, Monatsh. Chem., 1978,109,719. E. L. ElieI and E. Juaristi, J. A m . Chem. SOC.,1978, 100,6114.

Conformationa 1 A na1ysis

477 Bu‘

R (24) R = M e 0 or MeS

(24) show greater equatorial preferences than would be expected on the basis of van der Waals and dipolar forces, indicating that extra S/S and S/O gauche repulsions exist. Other studies include those of protonated 1 , 3 - d i t h i a n ~and ~ ~ 2-lithio-2-phenyl1,3-dithiam6’ Free energies of activation for inversion of the ring of 1,4-dithian and for the configurational inversion of its dihalogen complexes with bromine and chlorine have been reported.68 The conformations of N-(2- and N-(4-chlorophenyl)-3,6-dithiacyclohexene1,2-dicarboximide have been investigated by X-ray ~rystallography.~~ X-Ray crystallography has also been used to show a chair conformation for the 1,2,3-trithian (25), the side-chain being equatorial.70

The conformations of the mixed trithians and hexathia-adamantane formed from thioacetic acid have been examined.71 Infrared spectra show that 1,3,5-trithian 1-oxide has a chair conformation, with an equatorial sulphinyl group, in the solid phase.72 and of 1,4-oxathian The conformations of some 2,5,5-trialkyl-1,3-0xathians~~ 4 - 0 x i d e ~have ~ been studied. The latter compound has its sulphinyl group Work on the conformations of 5,6-dihydro-2-methyl-1,4-oxathiins (26)75and 1,4-ben~oxathiins~~ has been reported. on 3-chloromethyl-2,3-dihydroX-Ray crystallography shows that cis,cis-4,6-dimethyl-trimethylenesulphite has the all-equatorial conformation (27).77 66

67 68 69 70 71

72 73 74 75

76

77

J. B. Lambert, E. Vulgaris, S. I. Featherman, and M. Majchrzak, J. A m . Chem. SOC.,1978, 100, 3269. L. F. Kuyper and E. L. Eliel, J. Organomet. Chem., 1978,156,245. G. Hunter, R. F. Jameson, and M. Shiralian, J. Chem. SOC.,Perkin Trans. 2, 1978, 712. M. Bukowska-Strzyzewska and B. Priewska, Acta Crystallogr., Sect. B,1979,35,633,640. A. Kato and Y. Mashimoto, Chem. Lett., 1978, 1219. G. Levesque, A. Mahjoub, and A. Thuillier, Tetrahedron Lett., 1978,3847. M. Asai and K. Noda, Spectrochim. Acta, Part A, 1978,34,695. A. I. Gren, A. M. Turyanskaya, V. I. Sidorov, and A. Weigt, Vopr. Stereokhim., 1977,6,87. Y. Hase and Y. Kawano, Spectrosc. Lett., 1978,11, 151. M. J. McGlinchey, B. G. Sayer, F. I. Onuska, and M. E. Comba, J. Chem. SOC.,Perkin Trans. 2,1978, 1267. E. Kleinpeter, M. Muehlstaedt, and P. Kuhl, Org. Magn. Reson., 1977,9,661. G. Petit, A. T. H. Lenstra, and H. J. Geise, Bull. SOC.Chim. Belg., 1978,87, 659.

Heterocyclic Chemistry

478

(26) n

=

0, 1, or 2

(27)

Buchanan et al. have shown that both isomers of 4-phenyl-trimethylene sulphite exist in chair conformations, and not the previously reported twist onf formation.^^ Further work by the same group indicates that chair conformations predominate in this series except for truns-4,6-disubstituted derivative~.~~ Two studies of perhydro-1,3,4-thiadiazineshave appeared.47380 Phosphorus-containing Rings.-Heating 4- t- butyl- 1-phenylphosphorinan (28) at 417 K causes cis-trans equilibration via pyramidal inversion at phosphorus." The trans-isomer with both groups equatorial is more stable (AG* = -0.30 kcal mol-'), and the activation energy for the inversion process was found to be 35.7 kcal mol-'. Ph

I

D

0 Bu'

In a study of cis- and trans-1,3- and 1,4-dimethylphosphorinans,Quin and Lee have shown that the methyl on carbon prefers the equatorial position. The same result has been found for the 1-oxides and the l-sulphides.82 Conformational equilibria in l-phenyl-3-carbomethoxyphosphorinan-4-one and some derivatives have been i n ~ e s t i g a t e d . ~ ~ Dipole-moment and Kerr-eff ect data have been used to investigate 2-alkoxyand 2-phenoxy-2-0x0- 1,2-0xaphosphorinans.~~ A configurational and conformational investigation of 1,3-0xaphosphorinans has been reported.85The conformational equilibria seem to be mainly controlled by the 2-substituent, and in the trans, trans-isomer of 2,3-diphenyl-4,4,6-tri" 79

81

** 83

84

85

G. W. Buchanan, C. M. E. Cousineau, and T. C. Mundell, Tetrahedron Letr., 1978,2775. G . W. Buchanan, C. M. E. Cousineau, andT. C. Mundell, Can. J. Chem., 1978,56,2019. A. A. Potekhin, S. M. Shevchenko, T. Ya. Vakhitov, and V. A. Gindin, Khim. Geterotsikl. Soedin., 1978,1568. G. D. Macdonell, K. D. Berlin, J. R. Baker, S. E. Ealick, D. Van der Helm, and K.L. Marsi, J. A m . 1978,100,4535. Chem. SOC., L. D. Quin and S. 0. Lee, J. Org. Chem., 1978,43, 1424. B. A. Arbuzov, 0. A. Erastov, S. N. Ignat'eva, T. A. Zyablikova, and E. I. Gol'dfarb, Izu. Akad. Nauk SSSR, Ser. Khim., 1978,1533. B. A. Arbuzov, R. P. Arshinova, and T. D. Sorokina, Izu. Akad. Nauk SSSR, Ser. Khim., 1978. 2010. A. Zschunke, H. Meyer, E. Leissring, H. Oehme, and K. Issleib, Phosphorus Sulfur, 1978, 5 , 81.

Conformationa1A na1ysis

479 Ph

methyl- 1,3-oxaphosphorinan (29) a participation of twist-boat conformations has been proposed. The synthesis and the conformational analysis of some 1,4-heterophosphorinanium salts (30), using ‘H and 13Cn.m.r., have been reported.86 R

Ph \+/

Xca,

Me

(30) Y = 0, S, NH, NMe, etc

The 1,3,2-dioxaphosphorinan system continues to attract considerable particularly from workers in P ~ I a n d ~ ’and , ~ ~ the Soviet Union.89-94 Of particular interest are the following: the crystallographic determination of a twist-boat conformation in cis-2-t-butylamino-2-seleno-4,4,6trimethyl-1,3,2-oxaphosphorinan,88 and a study by Mosbo of the 220 MHz ‘H n.m.r. spectra of 2-substituted-2-oxo-4-methyl-1,3,2-dioxaphosphorinan~.~~ An investigation of 2,4,6-tri-isopropyl-1,3,5-dioxaphosphorinanand its sulphide showed that the molecules have the chair conformation (31), with axial P-H.96

(31) X = electron pair or S,

89 90

91

92 93 94

95

96

S. Samaan, Chem. Ber., 1978,111,579. B. Zielinska and W.J. Stec, Org. Mass Spectrom., 1978,13,65. R. Kinas, W.J. Stec, and C. Krueger, Phosphorus Sulfur, 1 9 7 8 , 4 2 9 5 . R. P. Arshinova, Dokl. Akad. Nauk SSSR, 1978,238,858. R. P. Arshinova, V. E. Kataev, and B. A . Arbuzov, Izv. Akad. Nauk SSSR,Ser. Khim., 1978,835. E . A. Ishmaeva, V. V. Ovchinnikov, and A . N. Pudovik, Izv. Akad. Nauk SSSR, Ser Khim., 1978, 2164. R. P. Arshinova, Phosphorus Sulfur, 1978,5, 131. B. A. Arbuzov, V. E. Kataev, R. P. Arshinova, and R. N. Gubaidullin, Izv. Akad. Nauk SSSR, Ser. Khim., 1978,2450. A. A . Borisenko, S. F. Sorokina, A. I. Zavalishina, and E. E. Nifant’ev, Dokl. Akad. Nauk SSSR, 1978,241,842. J. A. Mosbo, Org. Magn. Reson., 1978, 11, 281. B. A . Arbuzov, 0. A . Erastov, S. N. Ignat’eva, T. A. Zyablikova, R. P. Arshinova, and I. K. Skakirov, Dokl. Akad. Nauk SSSR, 1978,240,331.

Heterocyclic Chemistry

480

Two papers reporting conformational work on 1,3,2-oxazaphosphorinansthat are closely related to the anti-cancer drug cyclophosphamide have appeared.97398 Crystallographic and n.m.r. data show that the cis-2-0x0-2-dimethylamino-3phenyl-5-t-butyl derivative (32) exists in a twist conformation in both solid and solution.98

A study of some 1,4,2-oxazaphosphorinans,using 'H and 31Pn.m.r. spectra, suggests that this ring exists primarily in a chair c o n f ~ r m a t i o n . ~ ~ Two conformational investigations of 1,3,2-dithiaphosphorinanshave been reported. loo,lol

Boron- and Silicon-containing Rings.-Alkyl-substituted (33) have been investigated by n.m.r. spectroscopy.'02

1,3,2-dioxaborinans

R4 I

(33)

Dipole-moment and infrared data have led to a suggestion that 2,2-dimethyl-5alkyl- 1,3,2,5-dioxasilaphosphorinans (34) exist in boat conformations, with equatorial alkyl groups.'o3 Me

\ /

Me

I R (34) 97 98

99

loo lo'

lo3

R. P. Arshinova, R. Kraemer, and J. Navech, Phosphorus Sulfur, 1977,3, 281. G. S. Bajwa, W. G. Bentrude, N. S. Pantaleo, M. G. Newton, and J. H. Hargis, J. A m . Chem. Soc., 1979,101, 1602. M. V. Sigalov, V. A. Pestunovich, V. M. Nikitin, A. S. Atavin, and B. F. Kukharev, Izv. Akad. Nauk SSSR, Ser. Khim., 1978, 1544. J. Martin and J. B. Robert, Org. Magn. Reson., 1977, 9, 637. A. A. Borisenko, S. F. Sorokina, A. I. Zavalishina, N. M. Sergeev, and E. E. Nifant'ev, Zh. Obshch. Khim., 1978,48, 1251. V. V. Kuznetsov, A. I. Gren, A. V. Bogatskii, S. P. Egorova, and V. I. Sidorov, Khim. Geterotsikl. Soedin., 1978, 26. 0. A. Varnavskaya, E. A. Ishmaeva, V. M. D'yakov, and N. M. Kudyakov, Izv. Akad. Nauk SSSR, Ser. Khim., 1978,2129.

Conformational Analysis

48 1

5 Seven-membered Rings St-Jacques and co-workers have shown, from a low-temperature 13C and 'H n.m.r. spectral study, that 2,4-benzodioxepin (35)has chair (79%) and twist-boat (21%) conformation^.^^^

Two reports of the ring-inversion process in benzodiazepinones have appeared.105~106Variable-temperature n.m.r. studies show that the barrier is lower (13.0-14.2 kcal mol-') in the triazolo derivatives (36) than in the diazepam (37)(18.1 kcal mol-'), whilst the barrier in the triazinediones (38)is greater still (19.9-20.7 kcal mo1-1).'06 Me

N (36)

(37)

(38)

Aspects of the conformational analysis of 1,3,2-dioxaphosphepans have been discussed by J. B. Robert's group.1o7 A study of the conformational inversion in benzannelated spiranes with central rings of from seven members [e.g. (39)] upwards has been reported."'

6 Eight-membered Rings The vibrational spectra of 2,4-bis(trichloromethyl)-1,3,5,7-tetraoxocanhave been examined; they indicate that there is a crown conformation, with equatorial ~ubstituents.'~~ A. Blanchette, F. Sauriol-Lord, and M. St-Jacques, J. A m . Chem. SOC.,1978,100,4055. A. V. Bogatskii, S. A. Andronati, T. I. Korotenko, L. N. Yakubovskaya, V. 1. Minkin, V. S. Yur'eva, and L. E. Nivorozhkin, Vopr. Stereokhim., 1977,6, 74. lo6 P. C. Wade, B. R. Vogt, B. Toeplitz, M. S. Puar, and J. Z. Gougoutas, J. Org. Chem., 1979,4488. lo' A. C. Guimaraes, J. B. Robert, C. Taieb, and J. Tabony, Org. Magn. Reson., 1978,11, 411. S . Smolinski and M. Paluchowska, Zesr. Nauk. Uniw. Jagiellon., Pr. Chem., 1978, 23, 29 (Chem. Abs., 1979, 90, 5797). lo9 J. F. Rey Boero and 0.Brieux de Mandirola, An. Asoc. Quim. Argent., 1976,64,305 (Chem. Abs., 1978,89, 107 863).

'04

lo5

Heterocyclic Chemistry

482

Anet has reported a careful 'H and 13C n.m.r. reinvestigation of azocane (azacyclo-octane).'" The predominant conformation is a boat-chair, minor amounts (3% at -112 "C)of a crown family being present. Ring inversion of the boat-chair conformation has AG* = 7.3 f 0.2 kcal mol-' at ca. -120 "C. The thermodynamic and kinetic parameters for the process of inversion from boatchair to crown are AG* = 1.2 0.1 and AG* = 10.5 f 0.2 kcal mol-'. Other results on the conformations of eight-membered nitrogen-containing rings have been reported. '1'~112 trans-2-Methylthiacyclo-oct-4-ene exists in two diastereoisomeric forms (40) (41), which interconvert by an inversion process of the eight-membered ring. Activation parameters for this process have been measured and found to be AH* = 29.7 f 0.4 kcal mol-' and AS* = -1 f 1 cal K-' n~ol-~.'~~

*

N.m.r. data indicate that the phosphorus-containing rings (42) have a rigid chair-chair conformation, with a transannular 0-P intera~tion."~

(42) X = electron pair or S

7 Nine-membered and Larger Rings Ollis's group have continued with their studies of benzannelated medium-sized rings. The interest in these compounds is that the annelation introduces a 'rigid group' into the ring, thus reducing its conformational complexity. They have studied the conformations of nine-,'15 ten-,'15 and twelve-membered''6 rings (43)-(45) by this method. In cis-anfi-cis-bis-cyclohexano-1,3,6,8-tetraoxecan the central ten-membered ring is found to have a boat-chair-boat c~nformation.''~ A similar conformation 'lo

F. A. L. Anet, P. J. Degen, and I. Yavari, J. Org. Chem., 1978,43,3021.

"' M . Kihara, S. Kobayashi, and T. Shingu, Yakugaku Zasshi, 1978,98,593. ''' J. M.Ruxer, A. Solladie-Cavallo, G. Solladie, and D. Olliero, Org. Magn. Reson., 1977,10,105. '"

V. Cere, S. Pollicino, E. Sandri, and A. Fava, J. Am. Chem. SOC., 1978,100,1516. J. P. Dutasta and J. B. Robert, J. Am. Chem. SOC.,1978,100,1925. D.J. Brickwood, W. D. Ollis, and J. F. Stoddart, J. Chem. SOC.,Perkin Trans. I , 1978. 1385. W.D.Ollis, J. S. Stephanatou,J. F. Stoddart, and M. Nogradi, J. Chem. Soc., Perkin Trans. 1,1978,

'I'

A. Terzis, J. B. Faught, and T. B. Grindley, Can. J. Chem., 1978,56,1705.

'14

'''

1421.

ConformationalAnalysis

483

S

ksb (45)

\ /

o \ /

(43)X = 0,NMe, or NTos

(44)

has been found for the ten-membered ring in 1,1,6,6-tetraphenyl-1,6-distannacylodecane.118 Recently, 13Cand 'H n.m.r. spectra have been used to show that four isomers of (46; R = CH2Ph)have a square [3333] conformation, with methylene groups at the corners. This result has been confirmed for (46; R = H) by X-ray crystallography.'lg

+ A d RE t

Et

N-R

R-N F Et

N

I

+

Et

R (46)

Reports have appeared of the conformations and conformational processes in tricyclic thirteen-membered heterocyclic compounds with the central ring annelated by benzene and azulene moieties.120 Dale's group have continued to investigate medium-sized and large ring polyethers, and have published results for some tetraoxacyclotetradecanes and tetraoxacyclohexadecanes.'2' Both the 1,4,7,11- and 1,4,8,11-oxygenatedfourteen-membered rings, in solution in CS2and in CC14,have similar non-diamondlattice-like conformations to that found for the solids by X-ray crystallography. However, in the more polar solvent CHC12Fthe diamond-lattice conformation increases in population on lowering the temperature. Paoletti's group have reported conformational results on 1,4,8,1l-tetraazacyclotetradecanes and 1,4,8,12-tetra- azacyclopent adecanes.12* Conformational results on benzannelated fourteen- and sixteen-membered suphur-containing rings have a~peared."~ '18

'19

I2O 12' lZ2 lZ3

A. G. Davies, M-W. Tse, J. D . Kennedy, W. McFarlane, G . S. Pyne, M. F. C. Ladd, and D . C. Povey, J. Chem. SOC.,Chem. Commun., 1978,791. K. Tsuboyama, S. Tsuboyama, J. Uzawa, K. Kobayashi, and T. Sakurai, Tetrahedron Lett., 1977, 4603. ( a )M. Atzmueller and F. Voegtle, Chem. Ber., 1979,112,138; ( b )Y. Fukazawa, M. Aoyagi, and S. Ito, Tetrahedron Lett., 1978,1067. G. Borgen, J. Dale, and G. Teien, Acta Chem. Scand., Ser. B, 1979,33, 15. M. Micheloni, P. Paoletti, and A. Vacca, J. Chem. SOC.,Perkin Trans. 2, 1978, 945. M. W. Haenel and A. Flatow, Chem. Ber., 1979,112,249.

He te roc y c 1ic Chernis try

484 8 Polycyclic Systems

The material in this section is ordered into spiro- and then other systems. Within this arrangement, compounds are ordered according to increasing ring size. Proton n.m.r. data indicate that (47) prefers the conformation with oxygen axial to that with CH2 A similar result has been obtained for other l-oxaspiro[ n. 5]alkanes. l Z 5 0

X-Ray crystallography shows that the dioxa-spiro-compound (48) has chair rings, with equatorial substituents. Each oxygen atom is axial with respect to the other tetrahydropyran ring, to minimize anomeric interactions. 126

The conformations of some 1,3-dioxa-9-azaspiro[S .5]undecanes have been investigated. The main conformation detected is (49).lZ7 0

Conformational equilibria in 2-azanorbornane derivatives in strong acid solution have been investigated.’28 Approximately equal amounts of endo- and exo-N-methyl, -ethyl, and -isopropyl groups are found, and it was concluded that each of these alkyl groups and the solvated NH are equally hindered in either location. Although the authors implicitly claim their results as those of ther-

lZ5 126

lZ8

D. J. O’Donnell, K. Ramalingam, K. D. Berlin, S. E. Ealick, and D. Van der Helm, J. Org. Chem., 1978,43,4259. P. Picard and J. Moulines, Tetrahedron, 1978, 34,671. D. L. Hughes Tetrahedron Lett., 1978, 3959. J. Bassus, D. Anker, H. Pacheco, M. Chareire, and J. C. Duplan, J. Heterocycl. Chem., 1978,15,449. F. M. Menger, M. Perinis, J. M. Jerkunica, and L. E. Glass, J. Am. Chem. Soc., 1978, 100, 1503.

Conformational Analysis

485

modynamic equilibria, it is not clear that they have ruled out the possibility that they are kinetic artefacts of the protonation reaction. Several bicyclic ammonium salts have been used by Anteunis in a study of vicinal 14N-C-C-H coupling constants, to obtain a Karplus re1ation~hip.l~~ Similarly, Berger has used "N-enriched materials, including bicyclo[2.2.2]- and homo-adamantane systems, to study the conformational dependence of lSN-l3C coupling constants. 130 Two studies, by different groups at the State University of Ghent, of the conformations of 2-oxabicyclo[3.3.0loctan-3 -ones have appeared. 131~132 Variable-temperature n.m.r. spectra show an equilibrium between chair and boat forms for the bicyclic structure of 5-aza-2,8-dioxa-l -stannacyclo-octanes (50).133

R

Ten papers have appeared dealing with the conformations of oxygen- and nitrogen-containing derivatives of bicyclo[3.3. llnonane. 134-143 These reports all agree with the established literature in assigning double-chair conformations to the molecules studied, with several exceptions. Speckamp et al. have shown that the equilibria between the double-chair and chair-boat conformations can be detected when the boat ring is held in a hemi-acetal or hemi-acylal form; e.g., (51) (52).'39,'40Evidence is also presented that a bulky substituent adjacent to

+

YH (51)

X = CH20rNTos Y = OorC02

(52)

M. J. 0.Anteunis, F. A. M. Borremans, J. Gelan, A. P. Marchand, and R. W. Allen, J. Am. Chem. Soc.. 1978,100,4050. 130 S. Berger, Tetrahedron, 1978,34, 3133. 13' A. De Bruyn, M. Van Audenhove, and M. J. 0. Anteunis, Bull. SOC.Chim. Belg., 1978,87, 195. 132 P. De Clercq and M. G. Samson, Org. Magn. Reson., 1978,11, 262. 133 M. Zeldin and R. Gsell, J. Inorg. Nucl. Chem., 1978, 40, 597. 134 J. A. Peters, P. E. J. Peters-Van Cranenburgh, J. M. Van der Toorn, T. M. Wortel, and H. Van Bekkum, Tetrahedron, 1978, 34, 2217. 13' M. Barrelle, M. Apparu, and C. Gey, Can. J. Chem., 1978,56,85. I G. G. Trigo, E. Galvez, and C. Avendano, J. Heterocycl. Chem., 1978,15,907. 13' G. G. Trigo, C. Avendano, P. Ballesteros, and A. Gonzalez, J. Heterocycl. Chem., 1978, 15,833. 13* T. Momose and S. Atarashi, Heterocycles, 1978,9,631. 139 T. R. Bok, C. Kruk, and W. N. Speckamp, Tetrahedron Left., 1978,657. 140 H. Van Oosterhout, C. Kruk, and W. N. Speckamp, Tetrahedron Lett., 1978, 653. 129

Heterocyclic Chemistry

486

Ar

nitrogen in systems such as (53) and (54) causes the piperidine ring to go into a boat conformation (53; R = Pri) or (54; Ar = ~ - M e o P h ) . ' ~ ' - ' ~ ~ The stereochemistry and conformations of some bicyclo[3.2.2.]-systems that are acetals of cis-l,4-cyclohexanediol have been investigated.*44 The microwave spectrum and dipole moment of 7-oxabicyclo[4.l.0]hept-3ene indicate that the molecule has a boat c ~ n f o r m a t i o n . ' ~ ~ Heterocyclic derivatives of bicyclo[4.4.0]decane (decalin) continue to attract attention, including systems containing oxygen,'46 n i t r ~ g e n , ~ ~ ~and -"~ sulphur. 53-' 5 5 Of these, four publications merit a closer look. The acid-catalysed condensation of meso- and ~,~-2,3-dimethylbutane-1,2,3,4-tetrol and paraformaldehyde has been examined by a Danish group.'46 Two of the bicyclic acetals formed, (55) and (56), then had their conformations examined by n.m.r. and dipole-moment techniques. The cis-decalin analogue follows literature precedent in having an O-inside conformation (56). Me

Me

Vierhapper and Eliel have investigated some 8-t-butyl-trans-decahydroquinolines and related compounds (57).147It is suggested that the hydrogen on nitrogen is preferentially equatorial in most cases but can be forced into a predominantly axial position by an equatorial 8-t-butyl group, as in (57; R2=tbutyl).

14' ' 4 1

144

P. C. Ruenitz, J. Org. Chem., 1978,43,2910. V. Baliah and R. Jeyaraman, Indian J. Chem., Sect. B, 1978,16,597. V. Baliah and R. Jeyaraman, Indian J. Chem., Sect. B, 1977,15,852. S.Mager, I. Hopartean, and V. Cristian, Stud. Univ. Babes-Bolyai, Ser. Chem., 1978,23,28(Chem.

Abs., 1979,90,167 932). 146

S.Chao, R. L. Cook, and T. B. Malloy, Jr., J. Chem. Phys., 1978,68,4027. N.Frederiksen, R. B. Jensen, S. E. Joergensen, J. U. R. Nielsen, L. Noerskov, and G. Schroll, Actu

14'

Chem. Scand., Ser. B, 1977,31,694. F. W. Vierhapper and E. L. Eliel, J. Org. Chem., 1979,44,1081.

14'

Conformational Analysis

487

Nelsen’s group have investigated the conformations of bridgehead diazatechniques. decalins of general form (58), using n.m.r.14* and electro~hemical~~~ Detailed results on preferred conformations and their interconversion pathways are reported.

The conformation and crystal structure of the oxygen-containing bispirotricyclic compound (59) have been investigated by X-ray ~rystallography.~~~ Me

X-Ray crystallography shows the amide ring in (60) to be almost ~1anar.l~’ Benzo-annelated quinolizidine158-160 and phenanthridine161derivatives have been investigated.

14* 149

150

Is* lS3 154

’” 156

lS9 160

S. F. Nelsen and E. L. Clennan, J. Am. Chem. SOC.,1978,100,4004. S. F. Nelsen, E. L. Clennan, and D. H. Evans, J. Am. Chem. SOC.,1978,100,4012. V. G. Zaikin, Izu. Akad Nauk SSSR, Ser. Khim., 1978, 1471. H. J. Furrer, J. H. Bieri, and M. Viscontini, Helv. Chim. A d a , 1978,61, 2744. M. Sugiura, N. Takao, K. Iwasa, and Y. Sasaki, Chem. Pharm. Bull., 1978, 26, 1901. P. K. Claus, W. Rieder, and F. W. Vierhapper, Monatsh. Chem., 1978,109,631. L. M. Petrova, S. G. Vul’fson, and Sh. S . Bikeev, Tezisy Dok1.-Vses. Konf ‘Stereokhim.Konform. Anal. Org. Neftekhim. Sint.’, 3rd, 1976, p.116 (Chem. Abs., 1978,88, 151 928). 0. M. Tsyguleva, L. A. Sleta, and I. V. Krivoshei, Zh. Strukt. Khim., 1978,19, 720. A. Conde, E. Moreno, and R. Morquez, Acta. Crystallogr., Sect. B, 1979,35, 652. K. Blaha, P. Malon, M. Tichy, I. Fric, R. Usha, S. Ramakumar, and K. Venkatesan, Collect. Czech. Chem. Commun., 1978,43,3241. D. Tourwe, W. Van den Brandt, and G. Van Binst, Bull. SOC.Chim. Belg., 1978,87,427. M. Sugiura, N. Takao, H. Fujiwara, and Y. Sasaki, Chem. Pharm. Bull., 1978,26,2555. K. Nagarajan, R. K. Shah, H. Fuhrer, R. T. Puckett, M. R. Naraimhamurthy, and K. Venkatesan, Helv. Chim. Acta, 1978,61, 1246. G . Van Binst, G. Laus, and D. Tourwe, Org. Mugn. Reson., 1977, 10, 10.

488

Heterocyclic Chemistry

Katritzky et al.,using X-ray and n.m.r. techniques, have shown that the tricyclic dioxazine (61) exists in the tetra-equatorial conformation both in the solid and in so1ution.16*

N.m.r. spectroscopy was used to show that aza-tricyclic nitroxides (62) have a non-planar and rapidly inverting nitroxide group. 163 0'

I

N

(62) n

16*

163

=

0 or 1

A. R. Katritzky, R. Patel, S. Saba, R. L. Harlow, and S. H. Simonsen, J. Chem. SOC.,Perkin Trans. 2, 1978,818. R. M. Dupeyre and A. Rassat, Tetrahedron, 1978, 34, 1501.

Author Index Abbas, M., 85 Abbot, G. G., 245, 319 Abbott, F. S., 64 Abbott, P. J., 386 Abdel-Gawad, I. I., 126 Abdel-Megeed, M. F., 339 Abdel-Mawgoud, A. M., 48, 124 Abdel Nour, A. R. O., 21 Abdullabekov, I. M., 39 Abe, H., 122, 143, 298 Abe, N., 244, 253, 282, 386 Abe, O., 430 Abe, S., 211 Abe, T., 21, 169, 170 Abe, Y.,115, 274, 293, 302 Abenhaim, D., 22 Abou-Gharbia, M. A., 217 Abramenko, P. I., 76, 103, 104, 147, 148 Abramenko, T. V., 244 Abramovitch, R. A., 250, 269 Abu-Taha, A., 127 Acheson, R. M., 185, 237, 258, 386,440 Ackrell, J., 95, 393 Actor, P., 97 Adachi, K., 101 Adachi, M., 184 Adam, W., 62, 78, 173,439, 462,463 Adamchuk, M. R., 174,460 Adams, M. G., 452 Adamskaya, E. V., 264 Adamus, M., 409 Adembri, G., 213 Adiwidjaja, G., 210 Adler, B., 324 Adolphi, H., 118 Advani, B. G., 11, 121 Adzima, L. J., 114 Aeberli. P., 418 Afanas'eva, T. G., 97 Afsah, E., 85 Afzai, S. M., 362 Afzal, M., 330 Agaev, F. K., 39 Agarwal, S. C., 10 Agashkin, 0. V., 474 Agawa, T., 19, 41, 50, 87 Agdeppa, D. A., 441, 462 Agha, B. J., 168 Agihara, K., 166 Agosta, W. C., 59 Agranat, I., 366

Agrawal, A. K., 128 Aguilar, J., 181 Agurakis, S., 476 Ah-Kow, G., 225 Ahluwalia, B. S., 94 Ahluwalia, V. K., 330, 359, 360,361, 362 Ahmad, S., 356 Ahmed, M., 192 Ahmed, S., 354 Aiba, K., 264 Aicart, M., 174 Aihara, S., 48 Aisaka, A., 92 Aitkhozhaeva, M. Zh., 128 Akabori, S., 431 Akaboshi, S., 464 Akaki, R., 115 Akhmedov, I. M., 7 Akhtar, M. H., 32 Akiba, K. Y.,137, 157, 199, 227 Akiba, M., 240 Akimoto, T., 245 Akita, M., 268, 447 Akita, Y.,306 Akiyama, F., 20. Akiyama, T., 367 Akopyan, A. N., 74 Akopyan, T. R., 171 Aksnes, G., 463 Alam, L. V., 104, 117 Alben, K. T., 63 Alberghina, G., 82 Albert, A., 221, 313 Albert, A. H.,117 Alberts, A. H., 426 Albini, A., 307 Albini, F. M., 178 Albonetti, G., 376 Albrecht, W. L., 252 Albright, J. D., 85 Alcalde, E., 239 Alder, R. W., 443 Aldrich, H. S., 122 Alekel, R., 365 Alemagna, A., 160, 228 Alexakis, A., 22 Alexander, D. C., 232 Alexander, R. G., 332 Al-Farkh, Y. A., 334 Al-Hajjar, F. H., 334 Al-Hassam, J. M., 330 Ali, M. I., 150, 152 Ali, S. A., 446

489

Al-Jallo, H. N., 142 Allen, D. G., 10 Allen, D. W., 82 Allen, G. F., 184, 283 Allen, R. W., 444, 485 Al-Masad, F. N., 330 Almaula, P. I., 445 Almenningen, A., 166 Almerico, A. M., 247 Almqvist, A., 77 Altland, H. W., 223 Alton, K. B., 96 Alunnibistocchi, G., 393 Alworth, W. L., 122 Alvarez, M., 72, 101 Alves, H. M., 350, 373 Ambartsumova, R. F., 135 Ambekar, S . Y.,92 Ambrosini, A., 346 Ambrosius, K., 55 Ambrus, G., 119 Amer, F. A., 51 Ames, D. E., 328 Amin, H. B., 99 Amin, N., 165, 242 Amin, S. G., 106 Ammon, H. L., 41,328 Amosova, S. V., 88 Anand, K. K., 352 Anand, N., 344 Anastassiou, A. G., 26, 440 Anderegg, J. H., 60 Anderson, A. G., 455 Anderson, H. J., 181, 182 Anderson, N. G., 452 Anderson, P. S., 192, 452 Anderson, S. L., 125 Anderson, V. B., 96, 445 Anderson, I., 87 Ando, A., 28, 183 Ando, K., 293 Ando, W., 169, 339 Andrade, J. G., 235, 358 Andreani, A., 285 Andreetti, G. D., 43,'44 Andreichikov, Y.S., 334 Andrianov, V. .G.,225 Andrianov, V. I., 442 Andrievskii, A. M., 292 Andronati, S. A., 402, 481 Anet, F. A., 13 Anet, F. A. L., 474, 482 Angerbauer, R., 10 Anisimov, A. V., 80, 98 Anisimova, D. S.,384

490 Anke, T., 373 Anker, D., 335, 484 Anselme, J. P., 206 Anteunis, M. J. O., 444, 470, 476,485 Antipin, M. Yu., 187, 441, 442 Antonini, I., 206 Antonio, Y., 95 Aoe, K., 122 Aoki, A., 87 Aono, T., 74 Aoyagi, M., 466, 483 Aoyagi, S., 406 Aoyama, K., 359 Apparu, M., 20, 444, 485 Applegate, H. E., 97 Appriou, P., 136 ApSimon, J. W., 179 Arai, H., 240, 395 Arai, K., 214 Arai, S., 157 Arakawa, K., 146 Arakawa, Y., 11 Araki, K., 95 Araki, S., 197 Arata, Y., 11 Araujo, H. C., 427 Arbuzov, B. A., 13, 239, 470, 471,478,479 Arcamone, F., 49 Arco, M. J., 341, 416 Arcoria, A., 81, 82, 90 Ardakani, A. A., 285 Argay, G., 130 Aria, S.,227 Arimoto, T., 264 Arisawa, M., 354 Arnone, C., 76 Aron, A. J., 196 Aronzon, M. E., 204 Arora, S. K., 119, 140 Arnold, B., 51 Arnold, D. R., 74 Arnone, A., 93 Arrhenius, T., 59 Arriau, J., 90 Arrigo Reina, R., 160 Arshadi, M. R., 162 Arshinova, R. P., 470, 478, 479, 480 Artyukhin, V. I., 132 Arya, P., 119 Arya, V. P., 119, 120 Asahara, T., 187, 230 Asai, M., 471 Asao, T., 248, 255, 302, 309, 310, 320,410,462 Asay, R. E., 466 Ashby, J., 116, 255, 401 Ashdown, D. H. J., 356 Ashe, A. J. tert., 257 Asher, V., 470 Ashihara, Y., 353

Author Index Asinger, F., 464 Asirvatham, M. R., 446 Aslanov, L. A., 442 Asmanova, A. B., 132 Asoka, M., 259 Assaf, A., 122 Astier, A., 282 Astrakhantseva, N. I., 76 Atal, C. K., 360 Atarashi, S., 444, 451, 485 Atavin, A. S., 480 Atkins, R. L., 455 Atkins, T., 424 Atzmueller, M., 483 Auerbach, A., 63 Aumann, R., 458 Aumelas, A., 13 Aune, J. P., 122 Aurich, H. G., 445 Austin, M. W., 204 Austin, W. A., 235 Avagyan, S. P., 80 Avakyan, V. G., 30 Avasthi, K., 439 Avendano, C., 444, 485 Avetisyan, A. A., 337 Avignon, T., 130, 136, 470 Avramenko, V. I., 133 Avramovici-Grisaru, S., 219 Awad, M. L., 51 Awaji, T., 366 Awaya, H., 319 Ayabe, G., 211 Ayengar, N. K. N., 289 Ayral-Kaloustian, S., 59 Ayras, P., 472 Ayyangar, N. R., 119, 377 Azerbaev, I. N., 128, 132 Azuma, Y., 222, 325 Azzaro, M., 29 Baas, P., 46 Baba, H., 169 Baba, Y., 446 Babadjamian, A., 122 Babichev, F. S., 68, 180 Babicheva, A. F., 125 Baboulene, M., 119 Babudri, F., 137 Bacaloglu, R., 158, 241 Bacchetti, T., 160, 228 Bachman, G. L., 116 Baciocchi, E., 177 Backmann, K., 37 Bacon, J. D., 354 Bacquet, C., 368 Bader, H. J., 189 Badev, A., 5 Baggaley, K. H., 114 Bahl, 0. P., 126 Bahr-Wirtz, M., 464 Bahry, M., 200 Bailey, A. S., 188 Bailey, P. S., 439

Bailey, S. J., 427 Bailey, W. F., 369 Baiocchi, L., 168 Baird, N. C., 54 Baiwir, M., 116 Bajwa, G. S., 480 Bajwa, J. S., 159 Bak, B., 154, 166, 228 Bak, C., 209, 210 Baker, D. C., 398 Baker, J. K., 444 Baker, J. R., 375, 478 Baker, J. W., 116 Baker, S. R., 334 Baker, V. J., 475 Bakthavachalam, V., 109 Balaban, A. T., 217, 338 Balabanova, L. N., 178 Balci, M., 462 Baldwin, J. E., 50, 141, 213 Baldwin, J. J., 260 Balgoyen, D. P., 114 Baliah, V., 336, 341, 455, 486 Ballatore, A,, 169 Ballesteros, P., 444, 485 Ballistreri, F. P., 81 Balode, D., 115 Balodis, K., 200 Balog, I. M., 109 Balthazor, T. M., 220 Ban, T., 378, 379, 442 Bandynkova, V. A., 330 Banerjee, S. K., 360 Banerji, A., 189 Banerji, J., 447 Banerji, K. D., 99 Bankovskii, Yu. A., 257 Banks, A. R., 141 Banks, R. E., 282 Bannai, Y., 302 Bannikova, 0. B., 30 Bansal, R. K., 184 Bapat, J. B., 338 Baranne-Lafont, J., 463 Baranov, S. N., 132 Barbe, J., 135 Barber, G. N., 211 Barczynski, P.,300 Bard, R. R., 291 Bardakas, V., 380 Barelle, M., 20 Baret, P., 31 Bargagna, A., 333, 367 Barillier, D., 194 Barker, J. M., 81 Barker, M. V., 244 Barlin, G. B., 294 Barltrop, J. A., 182 Barnard, J. A., 21 Barnett, G. H., 182 Barni, E., 136 Barone, R., 122 Barraclough, P., 448 Barrau, J., 23

Author Index Barrelle, M., 444, 485 Barrett, A. G. M., 431 Barrett, G. C., 121 Barsanti, P., 136 Bart, J. C. J., 122 Barta, I., 119 Bartet, B., 230 Bartetzko, R., 105, 111 Bartholomew, D. G., 246 Bartle, M. G., 172 Bartlett, P. A., 205 Bartlett, P. D., 2, 16, 63, 226 Bartmann, W., 96 Bartnik, R., 26 Bartok, M., 58 Bartoli, G., 138 Barton, D. H. R., 178 Barton, J. W., 295 Barton, T. D., 66 Barton, T. J., 375 Bartsch, R. A,, 432, 434 Baryshok, V. P., 444 Basalkevich, E. D., 343 Basch, H. I., 97 Basinski, W., 213 Basova, Yu. G., 130 Bass, R. G., 142 Bass, R. J., 357 Bassi, I. W., 122 Bassus, J., 484 Bastiansen, O., 166 Basyouni, M. N., 156 Bates, D. K., 235, 344 Bates, H. A., 450 Battersby, A. R., 464 Battioni, P., 201 Baudy, M., 25, 121 Bauen, A., 374 Bauer, A., 400, 406 Bauer, G., 422 Bauer, M., 258 Baughman, M., 14 Baum, K.,58 Bauman, M., 375 Baumstark, A. L., 63 Baveja, P., 80 Baxter, A. J. G., 451 Baydar, A. E., 172, 325 Bayomi, S. M., 177 Beamer, R., 262 Becher, J., 105, 456 Becherer, J., 2, 56 Beck, A. K., 19 Beck, G., 96 Beck, J. R., 97, 114 Beck, L., 1 Becker, A. R., 14 Becker, K. B., 444 Becker, Y.,451 Becket, G. J. P., 347 Beckford, H. F., 437 Bedi, G. S., 126 Beger, J., 120 Begley, M. J., 203, 343

49 1 Begum, A., 41 Beheshti, I., 60 Behnam, E., 109, 235 Behr, H., 37, 125 Behr, J.-P., 432 Behrens, U., 165 Bekmukhametov, R. R., 34, 203,214 Beland, F. A., 12 Belen’kii, G. G., 57 Belen’kii, L. I., 74, 75 Belew, J. S., 408 Belik, A. V., 30 Belikov, A. B., 140 Belin, B., 440 Beljean, M., 135 Belkina, T. V., 231 Belkind, B. A., 230 Bell, D., 203 Bellamy, F., 37, 259, 268, 395 Belli, A., 328 Bellinger, G. C. A., 147 Bellotti, V., 328 Bellus, D., 419 Belousov, V. M., 4 Belyaev, E. Yu., 90 Belzecki, C., 43, 212 Bemi, L., 395 Benardi, F., 466 Benati, L., 100 Bender, P. E., 141 Benedicenti, C., 122 Benhaoua, H., 32 Benitez, F. M., 197 Bennett, G. B., 192, 286 Bensaude, O., 201 Bentley, P . H., 50 Bentmann, D., 116 Benton, W. H., 270, 303, 429 Bentrude, W. G., 480 Beracierta, A. P., 331 Berchtold, G. A., 389, 452 Berezin, B. D., 114, 210 Berezovskii, V. M., 89, 165 Bergamasco, R., 191 Berge, J. M., 13 Berger, H., 30 Berger, M. H., 175 Berger, R. A., 464 Berger, S., 485 Bergesen, K., 476 Bergman, J., 84, 187 Berg-Nielsen, K., 287 Berkowitz, P. T., 58 Berlin, K. D., 340, 375, 478, 484 Bernadskii, M. I., 359 Bernal, I., 369, 442 Bernardi, F., 63 Bernardini, A., 254 Bernasconi, C., 336 Bernauer, K., 37, 246, 414 Bernhard, E., 102 Berning, W., 452

Berry, M. H., 475 Bersani, S., 337 Bersch, W. H., 412 Berson, J. A., 440, 459 Berti, C., 208 Bertie, J. E., 40, 154, 227 Bertorello, H. E., 34, 113 Bertrand, M., 460 Beschke, H., 257 Bhaduri, A. P., 358 Bhan, M. K., 358 Bhardwaj, D. K., 366 Bhardwaj, T. R., 381 Bhattacharjee, S. K., 152 Bhattacharjya, A., 84, 466 Bhattacharya, A. K., 196 Bhavani, N., 341 Bhutani, K. K., 381 Bianchin, B., 472 Bichkov, S. F., 300 Bicker, U., 30 Bicking, J. B., 112 Bielak, L., 120, 123 Bieri, J. H., 53, 398, 487 Bierner, M. W., 354 Bigard, W. S., 53, 469 Biggs, D. R., 357 Bigot, B., 12, 35, 42 Bihlmaier, W., 201 Bikeev, Sh. S., 487 Bilgic, S., 448 Bilinski, S., 120, 123, 132 Bilyk, I., 11 Binder, D., 103 Binsch, G., 29, 474 Birkoffer, L., 395 Bissett, F. H., 193, 452 Biswas, K., 352, 366 Bizzarro, F. T., 72 Bjorkman, S., 97 Black, D. St. C., 45, 179, 183, 212,241 Black, L. L., 110 Blackman, N. A., 45, 183 Blaha, K.,441, 487 Blanchette, A., 409, 481 Blank, B., 92, 144 Blanton, C. D., 80 Blatcher, P., 19, 199 Blazevic, N., 440 Bleikolm, A., 399 Bleisch, S., 163 Bliesender, J. U., 408 Block, E., 38,65 Block, F. B., 445 Bloodworth, A. J., 463 Blount, J., 402 Blount, J. F., 169, 364 Blum, J., 24, 27, 85 Boberg, F., 195 Bobkova, R. G., 231 Bocchi, V., 189 Bock, H., 242 Bockmann, K., 466

492 Bodo, B., 353 Bodor, N., 275 Bodrikov, I. V., 167, 234 Boech, G., 35 Boeckman, R. K., 15, 19, 343 Boedeker, J., 55, 142 Bohm, H.-P., 416 Boekelheide, V., 466 Boelkins, M. R., 216 Bonnemann, H., 257 Boeren, E. G., 345, 370 Bogatskii, A. V., 402, 480, 48 1 Bogdanov, V. S.,40 Bogelfer, L. Ya., 231 Boger, D. L., 133 Bognar, R., 351, 406 Bognor, R., 126 Bogomolova, G. S., 195, 235 Bogueka-Ledochowsk, M., 43 Bohm, M. C., 443 Boiko, I. P., 474 Boireau, G., 22 Bok, T. R., 444, 457, 485 Bokii, N. G., 337 Bollaert, W., 80 Bologa, M., 135 Bolotnikov, V. S., 135 Bolourtchian, M., 87 Bolster, J., 39 Bolzoni, L., 342, 345 Bbnazzi, D., 285 Bondesson, G., 79, 100, 101, 103 Bongsub, K., 11 Bonini, B. F., 159, 228 Bonnaud, B., 19 Bontchev, P. R., 97 Boonyarakvanich, A., 447 Booth, H., 472 Bopp, H., 64, 341 Borda, J., 357 Bordner, J., 442 Borel, M. M., 242 Borgen, G., 483 Boriack, C. J., 169 Borisenko, A. A., 479, 480 Borisevich, Yu. E., 136 Borne, R. F., 444, 445 Bornstein, J., 193, 452 Borowski, E., 43 Borremans, F. A. M., 444, 470,485 Borsdorf, R., 476 Bory, S., 89 Bos, H. J. T., 63 Boscacci, A. B., 45, 183 Bosch, J., 72, 101 Boschung, A. F., 2, 63 Bose, A. K., 106 Bosies, E., 30 Bossert, F., 144, 276 Bostock, A. H., 472 Bota, A., 217

Author Index Botha, J. J., 350 Botrel, A., 136 Botta, A., 224 Bottino, F., 466 Bottino, F. A., 74 Botto, R. E., 162 Bottoni, A., 466 Bouas-Laurent, H., 430, 467 Bouchaut, M., 23 Bouchet, P., 209 Boudjouk, P., 66 Bouillant, M. L., 354 Boulton, A. J., 204 Bouma, W. J., 13 Bourgeois, J., 168 Bourgeois, M., 168 Bouvier, P., 345 Bova, A. E., 41 Bovill, M. J., 440 Bowen, M. J., 56, 382 Bowers, C. Y., 97 Bowie, J. H., 381 Box, H. J. T., 177 Boxer, M., 101 Boyd, A., 444 Boyd, D. R., 389, 452 Boyd, G. V., 172, 325 Boykin, D. W., 135 Boyle, M., 452 Bozell, J. J., 184, 283 Bozhanova, N. Y., 133 Bozhilova, A., 362 Brachtel, G., 233, 322 Bracktel, G., 53 Bradshaw, J. S., 433, 466 Bradsher, C. K., 18, 275, 291, 362,452 Brady, K., 232 Brady, W. T., 58 Brahler, G., 242 Bragg, L. H., 354 Bragg, R. W., 330 Braid, M., 428 Bramwell, F. B., 195 Branceni, D., 84 Brandsma, L., 80, 341 Brandt, E. V., 372 Brassard, P., 346 Brauer, D. J., 198 Braun, D., 24, 217 Braun, J. R., 162 Braun, M., 209, 294 Braverman, S., 108, 463 Bravo, P., 342 Breccia, A., 376 Breigwieser, G. E., 457 Breitmaier, E., 285, 397, 422 Brelikre, C., 235 Brembilla, A., 135 Brennan, J. J., 113 Breque, A., 230 Bresciani-Pahor, N., 466 Breslow, R., 5 Breuer, E., 183

'

Breuer, H., 97 Brevard, C., 473 Brickwood, D. J., 243, 388, 419,482 Brieux de Mandirola, O., 481 Briggs, F. H., 80 Briley, M. R., 97 Bristol, J. A., 365 Brocelli, G., 43 Brooks, G., 50 Brossi, A., 445 Brossier, P., 84 Brouwer, A. C., 63 Brouwers, A. M. F., 163 Brown, D. J., 138, 248 Brown, H. C., 439 Brown, R. S.,443 Browne, A. R., 452 Brozda, D., 250 Brueckner, G., 345 Brueckner, H. J., 122 Bruhn, J., 272 Bruice, P. Y.,13 Bruice, T. C., 13, 14 Bruni, R. J., 349 Bruiio, G . , 99 Brunskill, J. S. A., 340, 359 Bruylants, A., 28, 221 Bruza, K. J., 15, 343 Bryantsev, B. I., 128 Bryce, M. R., 162, 229 Bryce-Smith, D., 452 Buccheri, F., 86 Bucciarelli, M., 43 Buchan, R., 275 Buchanan, G. W., 473, 478 Bucher, J. G., 139 Buchi, G., 448 Buchin, P. I., 92 Buchman, O., 24, 85 Buchwald, H., 161, 235 Buck, H. M., 85, 93, 94 Buckle, D. R., 359 Budny, J., 33 Budylin, V. A., 187 Buechi, G., 209 Buhl. H., 154, 227, 228 Buerkle, W., 10 Buggle, K., 100 Bugle, R. C., 304 Buhl, H., 370 Buhleier, E., 270 Bukhari, A., 459 Bukowska-Strzyzewska, M., 477 Bulatskaya, N. G., 4 Bulgarevich, S. B., 135 Bulka, E., 120, 127 Buncel, E., 430 Bunina, N. A., 69 Burakowski, T. J., 87 Burchardt, B., 169 Burdon, J., 72 Burford, A., 60

493

Author Index Burger, K., 121, 165, 166, 217,231, 238, 239,405 Burgess, E. M., 207 Burke, H. M., 101 Burkholder, W. E., 336 Burnaeva, L. A., 55 Burnett, M. N., 459 Burns, G. T., 375 Burns, J. H., 60 Burov, Y. V., 354 Burr, J. G., 56, 302 Burri, K. F., 426 Burros, B. C., 65 Burtzlaff, C., 324 Bushby, R. J., 160, 203 Bushey, D. F., 209 Busson, R., 4 8 Butkiewicz, K., 405 Butler, A. R., 156, 181, 227 Butler, R. N., 220, 233 Butt, M. I., 217 Buttero, P. D., 64 Buys, T. S. V., 38 Buyuk, G., 331 Buza. D., 197 Bye, E., 441 Cabares, J., 174, 176 Cabelkova-Taguchi, L. M., 223 Cabrino, R., 208 Cacchi, S., 356 Cagniant, D., 71, 108 Cahiez, C., 22 Cais, R. E., 195 Calabrese, J. C., 441 Calabretta, P. J., 257 Calas, R., 463 Calcagno, M. A., 30, 378 Calcaterra, M., 122 Callens, R., 470 Calligaris, M., 464 Calo, V., 136 Cama, L. D., 50 Cambell, H. F., 450 Cambie, R. C., 419 Cameron, D. W., 177 Campaigne, E., 97, 98, 120, 148 Camparini, A., 213 Campbell, C. D., 162, 229 Campbell, N., 257 Campsteyn, H., 116 Candeloro, V., 381 Cantisant, A., 354 Capuano, L., 325 Caputo, J. F., 367, 369 Caramella, P., 78, 178 Carboo, D., 47 Carde, R. N., 253, 387 Carden, B. M., 476 Cardone, R. A., 426 Carlsen, D., 266 Carlsen, L., 66, 167, 234

Carlsen, P. H. J., 35, 36, 232, 258 Carlson, G. L. B., 452 Carlsson, R., 187 Carney, R. E., 369 Carp, E., 244 Carpenter, B. K., 54, 446, 459 Carpino, L. A., 41 Carrie, R., 32, 46, 202, 224 Carter, L. G., 110, 111 Carter, S. D., 247, 308 Cartledge, F. K., 193 Cary, L., 336 Casadevall, A., 13 Casadevall, E., 13 Casini, A., 277 Casiraghi, G., 342, 345 Casnati, G., 189, 342, 345 Cassity, R. P., 265 Castel, A., 23 Castellan, A., 467 Castensson, S.,97 Castillo, G. E., 113 Catalan, J., 29, 469 Catka, T. E., 274 Caulkett, P. W. R., 424 Cauthen, S. E., 445 Cava, M. P., 199, 200, 292 Cavazza, M., 208 Cazaux, L., 472 Cazes, A., 23 Ceder, O., 243 Cellerino, G., 78, 178 Cepera, K. F., 102 Ceraulo, L., 93 Cere, V., 412, 482 Cerfontain, H., 46, 462 Cerny, V., 16 Cerrini, S., 183 Cervena, I., 365 Cervinka, B., 26 Ceuto, O., 62 Cha, J. S., 20 Chabala, J. C., 414 Chabannet, M., 201 Chacko, E., 49 Chadha, V. K., 147, 252 Chadwick, D. J., 73 Chaillet, M., 447 Chakrabarti, J. K., 76, 95, 405 Chakraborty, A., 151 Chakravorti, S. S., 158 Chalenko, E. G., 472 Chaloupka, S., 36, 37, 246, 262,414 Chambers, D., 419 Chambers, R., 48 Chambers, R. D., 73, 168, 169, 263 Chamot, E., 452 Chan, K. K., 343 Chan, W. H., 170

Chananont, P., 441 Chandrasekhar, S., 328 Chaney, M. O., 442 Chang, J.-C., 320 Chanhan, Y. S., 361 Chanon, M., 122 Chao, S., 486 Chapat, J. P., 130 Chareire, M., 484 Chari, V. M., 354, 355, 369 Charma, S. C., 354 Charubala, R., 421 Charumilind, P., 64, 137 Chassaing, G., 476 Chatila, G., 180 Chatterjea, J. N., 100, 101 Chaturvedi, A. K., 97 Chaudhari, R. K., 365, 367 Chaudhary, S. K., 265 Chaudhuri, A., 152 Chauhan, M. S., 113 Chauzov, V. A., 375 Chawla, H. P. S., 95 Cheeseman, G. W. H., 247, 308 Chegolya, A. S., 17 Chen, C. H., 164, 231, 340 Chen, H.-W., 41 Chen, J. S., 441 Chen, L.-C., 268, 447 Chen, S. A., 441 Chen, S. F., 152 Chen, S.-Y., 462 Chen, W. Y., 426 Cheng, C. C., 62 Cheng, P.-T., 196 Cherkez, S., 445 Chernoplekova, V. A., 77 Chernova, E. P., 119 Chernyshev, E. A., 77, 231 Chernyuk, K. Yu., 15 Cherry, W. H., 99 Cherry, W.R., 54, 458, 459 Chertkov, V. A., 170 Cherton, J. C., 37 Chevolot, L., 276 Chevrier, M., 201 Chi, D. Y., 361 Chia, L. Y., 78 Chiang, C. C., 114 Chiang, W.-L., 11 Chiavarini, M., 472 Chibber, S. S., 348, 371 Chimirri, A., 123, 129, 130 Chioccara, F., 131, 327 Chiodini, L., 396 Chiraleu, F., 338 Chizhevskaya, I. I., 130 Chizhov, 0. S., 250 Chlenov, I. E., 250 Chmielewski, J., 132 Chmielewski, M., 331 Chocholous, J., 103 Chollet, A., 444

Author Index

494 Cholpankulova, S. T., 128, 132, 133 Chopin, J., 354, 356 Choudhari, S. R., 119, 120 Choudhury, D. R., 146, 151, 452 Chouteau, J., 126, 129, 130, 136,470 Chow, F., 6 Chow, M. F., 63, 463 Chow, Y., 330 Chow, Y. L., 440,457 Christensen, A. T., 250 Christensen, B. G., 50 Christensen, J. J., 432, 466 Christiaens, L., 108 Christidis, Y.,74 Christie, M. A., 50, 141 Christie, R. C.. 242 Christie, R. M., 155, 342 Christl, B., 90, 100, 198, 463 Christol, H., 16 Christophe, D., 299, 460 Christy, M. E., 192, 452 Chun, M. W., 177, 188, 190, 399 Chupp, J. P., 137 Churdesova, L. M., 30 Churilin, V. S., 126 Cima, L., 349 Cimarusti, C. M., 97 Ciminale, F., 99 Cipiciani, A., 177 Ciric, J., 180 Cirovic, M., 369 Cirule, M., 257 Citerio, L., 205, 297 Ciurdaru, G., 135 Cizmarikova, R., 58 Claramunt, R. M., 168, 239, 240 Claramunt-Elguero, R. M., 338 Clardy, J., 331, 460 Clark, D., 350 Clark, G. W., 350 Clark, P. D., 98 Clarke, F. H., 445 Clarke. K.. 98 Clarke; R.’L., 87, 96, 445, 446 Claus, P. K., 476, 487 Clayton, J. P., 332 Clement, A., 40, 154, 227 Clement, N. R., 122 Clementi, S., 106, 177 Clennan, E. L., 443, 487 Clive, D. L. J., 110, 179, 440 Cocker, W., 2 Cocuua. A. J., 321 Coda, A., 392 Coen, S., 177, 361 Coffen, D. L., 169 Cohen, V. I., 92, 132, 133, 158,160, 229

Cohen-Addad, C., 126 Coic, J. P., 368 Coimbrarolim, A. M., 105 Colburn, V. M., 84 Cole, E. R., 209 Coleman, B., 375 Coley, W. R., 128 Collins, R. J., 402 Colombi, R., 307 Colon, I., 63 Colonna, F. P., 466 Colonna, M., 208 Colton, C. D., 192, 452 Coman, M., 142 Comba, M. E., 477 Comin, F., 392 Comins, D., 265 Commons, T. J., 97 Compagnon, O., 84 Compagnon, P. L., 84 Conboy, R. J., 251 Conde, A., 487 Conde, S., 86 Conia, J. M., 62 Connon, H., 369 Connor, D. T., 331, 348 Connor, W. F., 11 Consiglio, G., 76, 81 Constenla, M., 181 Cook, D. H., 430 Cook, J. M., 258, 320 Cook, J. T., 373 Cook, M. J., 476 Cook, P. M., 388 Cook, R. L., 486 Cooke, M. D., 162,229 Cookson, R. F., 196 Cooper, R. D. G., 49 Corbel, B., 19 Corelli, F., 400 Corey, J. Y.,440 Corkins, H. G., 8 Cornils, B., 282 Corrao, A., 225 Corrie, J. E. T., 451 Corrigan, M. F., 456 Corriu, R. J. P., 375 Corsi, G., 168 Corson, M., 171, 464 Cortese, N. A., 285 Cowers, A., 93 Cory, R. M., 412 Costa Novella, E., 5 Coste, J., 16 Cote, R., 456 Cotterill, P. J., 352 Cottier, L., 336 Coudert, G., 368 Coughlin, D. J., 443, 462 Coumes, R.-C., 86 Courault, K., 5 5 , 142 Cousineau, C. M. E., 478 Cousse, H., 19 Coustale, M., 90 Couturier, J., 471

Cowley, A. H., 443 Cowling, A. P,, 446 Cox, P. J., 440 Cragoe, E. J., 112 Craig, J. C., 355 Craig, J. T., 99 Cram, D. J., 426, 434, 435, 436,440,466 Cram, J. M., 440 Crank, G., 209 Crawford, H. T., 464 Crawford, R., 60 Cremer, S. E., 441 Crews, C. D., 276 Crichton, E. G., 358 Crimmin, M., 184 Cristalli, G., 206 Cristian, V., 486 Croce, P. D., 64 Crombie, D. A., 69 Crombie, L., 333, 334, 337 Cromwell, N., 26 Cromwell, N. H., 33 Crook, S., 154 Crosby, G. A., 330 Cross, R. J., 63 Crossland, N. W., 13 Crowley, K. J., 2 Crozier, R. F., 212, 241 Cue, B. W., jun., 248, 318 Cugnon de Skvricourt, M., 92, 107 Cundy, C. S., 66 Cunha, H., 345 Cupas, C. A., 267 Curci, R., 9 Cusmano, G., 239, 240, 247 Cutler, A. T., 250, 447 Cutting, J., 213 Cygler, M., 473 Cymerman Craig, J., 101 Cyr, T. D., 335 Cyvin, B. N., 166 Cyvin, S. J., 166 Czarnecka, E., 174 Czauderna, B., 71 Czepluch, H., 445 Czuba, W., 257 Czube, L. J., 248, 318 Dach, R., 53, 233, 322 Dacons, J. C., 123 Dahlgren, T., 77, 102 Daiker, K. C., 14 Daka, M. R., 268 Dale, J.. 429, 483 Daly, J. J., 37 Dalzell, H. C., 370 D’Amico, J. J,, 137 Danckwerts, L., 138 Danen, W. C., 440 Danesh-Khoshboo, F., 270 Dang, H. P., 23 Dangyan, M. T., 337

Author Index Daniel, D., 127 Daniel, H., 71, 400, 401, 406 Daniil, D., 226 Danila, G., 110, 131 Dank, E. Kh., 189 Dann, A. E., 369 Dannhardt, G., 243 Dao Huy Giao., 175 Da Re, P., 349 da Rocha, J. F., 257 Das, T. K., 75 Dasgupta, S. K., 152 Dash, B., 140 Dashkevich, L. B., 143 Date, T., 51, 122 Datta, A. K., 150 Datta, S. K., 246 Daum, S.J., 96, 445 Dauter, Z., 43 David, J., 119 Davidson, A., 147 Davies, A. G., 483 Davies, L. B., 299 Davies, R. E., 235 Davin-Pretelli, E., 136 Davis, J. B., 369 Davis, M., 373 Davis, M. A., 108 Davis, P. D., 192, 381 Davydova, V. A., 89 Day, A. C., 182 Day, J. C., 278 Dayal, B., 106 De, A., 340,359 Dean, F. M., 203 Deardorff, D. R., 460 De’Ath, N. J., 65 De Bertorello, H.E..214 De Bertorello, M. M., 34, 214 De Boer, T. J., 32, 38 de Brouwer, R. J., 85 De Bruyn, A., 485 De Buyck, L., 249 Decesare, J. M., 19 Declerq, J. P., 167, 232, 234, 249,398,474 De Clercq, P., 334, 485 Decleron, J. P., 165 Decroix, B., 86, 87, 93, 98 Dederer, B., 165, 242 Defoin, A., 463 Degani, I., 198 Degen, P. J., 482 de Haan, J. W.,93,94 Dehne, H., 71,131 de Jong, F., 436 Dekerk, J. P., 232 De Kimpe, N., 249 Delavarenne, S. Y., 6 Del Cima, F.,208 Delle Monache, F., 372 Dell’Erba, C., 76 Delmas, M A,, 410 Delpech, B., 456 Delpuech, J. J., 472

495 del Rio, J., 86 Delltsova, D. P., 46, 187 Delugeard, Y., 122 Demaree, P., 154, 226 De Martino, G., 400 de Meijere, A., 458 Demel, H., 77 Demeo, G., 393 De Micheli, C., 215 Denney, D. B., 65, 230 Denney, D. Z., 65, 230 Dennis, L., 330 Dennis, N., 250, 447, 448 de Oliveira, A. B., 373 De Pasquale, R.J., 282 de Renzi, A., 461 De Rosa, M., 187 Deryagina, E. N., 68 Desbene, P. L., 37 Desbois, M., 259, 452 Deschamps, M. N., 472 Deschamps-Vallet, C., 353, 356 Descotes, G. 336 Descours, D., 335 Deshayes, C., 201 Deshpande, D. S., 145, 152 Deshpande, M. B., 31 De Simone, F., 133 Desimoni, G., 203 Desmazieres, B., 64 De Sousa, B. F. S. E.,216 Destro, R., 122 Desvergne, J.-P., 430, 467 Dev, S., 25 Devaprabhakara, D., 439 Devaquet, A., 12, 35, 42 Devinsky, F., 475 Devlin, J. P., 374, 450 Devrout, E., 464 Dewick, P. M., 357 Deyhim, S., 462 Dhar, K. L., 358 Dhar, M. M., 354 Diakow, P. R. P., 13 Diamond, S. E., 283 Di Biase, S. A., 430 Dideberg, O., 116 Dietrich, B., 425 Dietrich, W., 414 Dietrichs, H. H., 358 Dietzsch, B., 157 Dike, S. Y.,371 Dilk, E., 127 Dimitrov, D., 5 Dimri, A. K., 128 Dinculescu, A., 338 Dini, A., 133 Di Ninno, F., 64 Di Nunno, L., 137 Di Pietra, A. M., 376 Dipti, 135 Di Rienzo, B., 277 Dirks, G. W., 441 Dirlam, J. P., 248, 318

Distefano, G., 466 Di Tullio, N. W.,92, 144 Divanfard, H. R., 86 Dix, J. P., 438 Dixneuf, P. H., 199 Djudjic, R., 119 Djura, P., 409 Dmowski, W.,58 Doddi, G., 172, 337 Dodge, J., 441 Dopp, K., 28, 190,240 Dorhofer, K., 210 Dorre, R., 233, 249 Dohmohri, R., 151 Doi, J. T., 241, 414 Dokunikhin, N. S., 292 Dolan, F. W.,222 Dolan, J. G., 365 Doleschall, G., 223 Dolfini, J. E., 97 Domany, G., 153, 207 Domeier, L. A., 436, 466 Domeij, K. E., 101 Domnin, I. N., 203 Domschke, G., 163 Donatelli, B. A., 164, 231 Donati, D., 213 Donnelly, J. A.. 7, 352 Doppler, T.,216 Doria, M. C., 154, 226 Dorofeenko, G. N., 105, 176, 194,217,298,329, 335 Doronchenkova, T. N., 128 Dorton, M. A., 365 Doty, G. K., 264 DOU,H. J. M., 122, 128 Douglas, A. W.,184 Dousse, G., 23 Dove, R. V., 334, 337 Dovlatyan, V. V., 158 Dowlatshahi, H. A., 448 Doyle, J. E., 179 Doyle, M. P., 216 Drach, B. S., 120 Dreier, C., 105, 456 Dreikorn, B. A., 289 Driesen-Engels, J. M. G., 94 Dronov, V. I., 340 Drozd, V. N., 195, 235,409 Duar, Y., 108 Dubac, J.. 193 Dubinina, T. N., 115 DuBois, G. E.,330 Dubois, J. E., 201 Duboudin. F.,28 Dubs, P., 220 Duburs, G., 473 Duchamp, D. J., 204 Durr, H., 205, 248 Duesler, E. N., 248 Duflos, J., 452 Dulenko, V. I., 105 Dunaway-Mariano, I., 262, 452 Dung, N. H., 107

Author Index

496 Dunitz, J. D., 441 Dunkin, I. R., 65 Dunlap, W.C . , 138 Dunogues, J., 463 Dunn, L. C., 88 Dupeyre, R. M., 445, 488 Duplan, J. C., 484 Dupont, L., 116 Dupont, W., 213 Durham, D. G., 179 Durst, T., 19, 64, 210 Duschek, C., 324,471 Dutasta, J. P.,482 Duthaler, R. O., 472 Duus, F., 69 D’yakov, V. M., 480 Dyall, L. K., 291 Dyer, P. N., 1 Dyer, S. F., 173 Dykstra, C. E., 26 Dyllick-Brenzinger, R., 458 Dymerski, P. P.,360 Dyurnaev, K. M., 292 Dzhagatspanyan, I. A., 71 Dzhemilev, U. M., 171, 420 Dzvinchuk, I. R., 251 Eaborn, C., 82 Ead, H., 132 Eade, R. A., 357 Ealick, S. E., 375, 478, 484 Eapen, K. C., 133 Earley, J. V., 401 Ebata, T., 50 Eberbach, W., 169 Ebisawa, T., 127 Echegoyan, L., 443 Echter, T., 228 Eckardt, K., 363, 373 Eckle, E., 129 Eckstein, Z., 257 Ecsy, W., 140 Edo, K., 287, 299 Edwards, A., 455 Edwards, A. L., 31 Edwards, J. O., 9 Edwards, 0. E., 450 Edwards, W. B., 470 Eenkhorn, J. A., 153 Egan, R. S., 369 Egawa, H., 288 Egdell, R., 443 Eggelte, H. J., 78, 462 Egorova, S. P., 480 Eguchi, S., 357, 457, 464 Ehlers, J., 165 Ehrensperger, C. P., 423 Eicher, T., 180 Eilingsfeld, H., 117 Einhorn, J., 368 Einstein, F. W. B., 457 Eisch, J. J., 284 Eisenstadt, A., 451

Ekpenyong, K. I., 302 Elagbar, Z., 359 Eldawy, M. A., 122 El-Deken, A. A., 130 El Faghiel Amoudi, M. S., 100 Elgendy, M. A., 122 Elguero, J., 123, 168, 201, 202, 204, 209, 239, 240, 246 Eliel, E. L., 368, 369, 370, 476,477,486 El-Kashev, H. S., 48, 124, 128, 129 El-Khamry, A. M. A., 156 El’kinson, R. S., 29, 304 Ellingsen, P. 0.. 221 Elliott, R. C., 216 Ellis, G. P., 347 Ellis, I., 50 Ellison, R. H., 344 Ellstead, G. A., 363 El-Maghraby, M. A., 48 El-Metwally, M. H., 126 Elmoghayar, M. R. H., 140 Elmore, N. F., 45, 258, 440 El Mouhtadi, M., 447 El-Osta, B., 448 Elnagdi, M. H., 124, 140 El-Sadana, S. K., 18 Elsasser, A. F., 289 Elsayed, E. F. R., 124 El-Shafei, A. K., 128, 129 El-Shaly, M. F., 229 El-Sheikh, M. I., 320 El-Sherief, H. A., 128 El Sohly, M. A., 345, 355, 370El’tsov, A. V., 90, 144 Emoto, S., 271, 425 Emoto, T., 152 Emsley, J., 220 Enders, D., 53, 233, 322 Endo, S., 372 Engel, D. W., 350 Engel, N., 179, 205 Engel, P. S., 459 Engelhardt, G., 444 Engman, L., 84 Engoyan, A. P., 130 Enikolopiyan, N. S., 17 Enkaku, M., 104, 105, 395, 397 Ennis, M. D., 38, 65 Entenmann, G., 129 Epiotis, N. D., 63 Epling, G. A., 289 Erastov, 0. A., 478, 479 Eremeev, A. V., 29, 225, 304 Eremina, E. I., 46 Erden, I., 462, 463 Ergenzinger, K., 298 Erhardt, J., 175 Erickson, E. H., 100

Ermili, A., 346, 374 Errnolenko, M. S., 187 Ernstbrunner, E. E., 445 Errede, L. A., 326 Eschenmoser, A., 319 Eskins, M., 333 Espada, M., 202 Espie, J. C., 45 Essawy, A., 18 Estes, V. M., 14 Etaiw, S. H., 130 Etienne, A., 64 Eugster, C. H., 172, 174, 451 Evangelisti, F., 333, 367 Evans, D. A., 450 Evans, D. H., 487 Evans, D. L., 126 Evans, S., 244 Everhardus, R. H., 341 Evert, G. E., 74 Evstigneeva, R. P., 244 Eweiss, N. F., 339 Ewing, D. F., 340, 359 Fabbrizzi, L., 422 Fabre, J. M., 200 Fabrissin, S., 349 Fadda, A. A., 132 Fahmy, A. F. M., 239 Fahmy, S. M., 124, 140 Faller, P., 108 Fanghaenel, E., 136, 197 Fantina, M. E., 42 Farberov, M. I., 4 Farge, D., 147 Farnier, M., 104 Fasco, M. J., 360 Fatutta, S., 349 Faught, J. B., 482 Faure, R., 113, 122, 123 Fava, A., 412, 482 Favre-Bonvin, J., 354, 356 Featherman, S. I., 370, 477 Fedeli, W., 183 Fedoseev, V. M., 126 Fedotov, N. S., 74 Fedotova, 0. V., 349 Feeney, J., 444 Feher, G., 130 Fehlhaber, H.-W., 96 Feichtinger, H., 282 Feiner, S., 336, 471 Feliz, M., 101 Fendenko, V. S., 133 Fenech, G., 123, 129, 130 Fenner, H., 308 Fenton, D. E., 430 Ferguson, G., 321 Ferguson, I. J., 475 Ferguson, L. N., 330 Ferrnandjian, S., 470 Fernandez, J. M., 375 Fernandez, J. P., 130 FernLndez-Tom&,M. P., 86

Author Index Fernholt, L., 166 Ferraresi, R. W., 365 Ferreira, D., 350 Ferreira da Rocha, J., 168 Ferrell, J. E., 14 Ferreres, F., 354 Ferrero, L., 29 Ferrito, V., 373 Ferrugia, M., 466 Fetter, J., 153 Feuer, H., 264 Feutrill, G. I., 359 Fibiger, R. F., 141 Ficarra, R., 123 Field, G. F., 72, 90 Fielding, H. C., 168, 169 Fields, T. L., 248 Filby, J. E., 62 Filer, C. N., 17 Filippova, T. M., 89, 165 Filleux-Blanchard, M. L., 193 Fillion, H., 85 Findlay, R. H., 113 Finlay, J. D., 64 Finocchiaro, P., 466 Fiorenza, M., 82 Firl, J., 121, 217 Firouzabadi, H., 177 Firsan, S. J., 322 Fischer, G. W., 250 Fischer, J., 184 Fischer, W., 56, 325 Fisher, M. H., 445 Fisichella, S., 82 Fitton, A. D., 404 Flament, I., 93 Flataker, L. M., 445 Flatow, A., 483 Fleig, H., 118 Flekhter, B. V., 89 Fleming, M. P., 20 Fletcher, I. J., 250 Fletcher, S. R., 51 Fleury, J.-P., 259, 314, 452 Fliri, H., 448 Flitman, H. P., 440 Flitsch, W., 181, 252, 386, 440,466 Floch, L., 158, 233 Florey, A., 444 Florio, S., 137 Floru, L., 146 Fochi, R., 198 Fohlisch, B., 71 Foglio, M., 49 Fokin, A. V., 39, 368 Fokin, E. P., 186 Folli, O., 466 Fomenko, T. V., 186 Fomenko, V. I., 132 Fomum, Z. T., 184 Fongers, K. S., 462 Font, J., 40, 71, 154, 227 Foo, L. Y.,350

497 Foos, J. S., 276 Forbes, I. T., 360 Forlani, L., 122, 123 Fornarini, S., 337 Forni, A., 43, 44 Foster, C. H., 464 Foster, M., 60 Foster, R., 444 Foti, S., 466 Foucaud, A., 25, 121 Fountain, K. R., 213 Fowler, F. W., 281, 452 Fox, J. J., 309 Fox, M. J., 7, 352 Foxrnan, B. M., 171, 464 Fraenkel, G., 276 Fraga, B. M., 372 Frahm, A. W., 365 Franceschi, G., 49 Franchetti, P., 206 Francis, R. F., 276 Franco, F., 95 Frandsen, E. G., 105, 195 Frank, W. C., 77 Franke, A., 191 Franklin, N. C., 472 Franz, J. E., 110, 111 Fraser, M., 275 Frater, G., 272 Freckmann, B., 215 Frederiksen, N., 486 Frehel, D., 106 Freidrich, K., 35 Frejd, T., 75, 78, 168 Frenna, V., 225 Fresneda, P. M., 340 Fric, I., 441, 487 Fricke, H., 197 Fridman, A. L., 87, 213 Fridman, S. G., 146 Fried, J. A., 365 Friedlander, B. T., 410 Friedrich, K., 463 Friedrichsen, W., 208, 214, 307, 325,403 Frigerio, A., 405 Frimer, A. A., 63 Fritz, G., 242 Fritz, H., 35, 181 Frolow, F., 109, 463 Frost, J. R., 397 Fruchier, A., 240 Fryer, R. I., 401, 402 Fu, P. P., 10, 12 Fu, W. Y., 101, 175 Fuchs, B., 470 Fuchs, O., 123 Fuess, H., 147, 156 Fugazawa, Y.,466 Fugier, C., 93 Fuhlhuber, H. I., 458 Fuhrer, H., 487 Fujii, T., 312 Fujiki, K., 134

Fujimura, H., 138 Fujita, F., 6 Fujita, R., 290 Fujito, H., 81 Fujiwara, H., 487 Fujiwara, Y., 20 Fukai, T., 354, 356, 372 Fukami, H., 336 Fukazawa, Y., 466,483 Fuks, R., 417 Fukuda, T., 95 Fukumi, H., 290 Fukumoto, K., 48, 411 Fukumoto, T., 115 Fukunaga, J. Y., 365 Fukushima, K., 472 Fukuyama, K.,237 Funahashi, K., 31 Funaki, K., 50 Funakoshi, K., 287 Furia, F., 9 Furmanova, N. G., 80 Furrer, H. J., 487 Furstoss, R., 456 Furukawa, M., 128, 266 Furukawa, Y., 156 Furuta, T., 321 Fusco, R., 168, 184 Fyles, D. L.,425 Fyles, T. M., 425 Gabitov, F. A., 213 Gackwad. Y. G., 366 Gaertner, H., 127 Gaeta, F. C. A., 436, 466 Gains, L. H., 460 Gainsford, G. J., 207 Gaivoronskaya, L. A., 258 Gakhar, H. K., 80, 106, 152 Galanets, Z. G., 353 Galiano, F., 189 Galik, V., 440 Galkin, E. G., 445 Gall, C., 402 Gall, R., 30 Galla, S . V., 108 Gallagher, P. T., 84 Galledou, B. S., 460 Galleja, Pardo, G., 5 Galli, C., 427 Galliani, C., 50 Galvez, E., 444, 485 Galy, A. M., 135 Galy, J.-P., 123, 135 Gambacorta, A., 183 Garnbaryan, N. P., 46, 187, 217 Gambino, A. J., 87, 96, 445, 446 Games, D. E., 196,333 Gandhi, C. S., 144, 150 Gandhi, R. S., 100, 101 Gandolfi, R., 215 Ganem, B., 12,58

Author Index

498 Gange, D., 170 Ganter, C., 461 Gaoni, Y., 341 Garanti, L., 396 Garcia, B. J., 434 Garcia, D., 331 Gareev, R. D., 55 Garg, C. P., 346, 356 Garito, A. F., 199, 200 Garnovskii, A. D., 135 Garrett, K. E., 31 Garst, M. E., 11 Garufi, M., 297 Garuti, G., 44 Garvey, J. F., 43 Gasanov, F. G., 7 Gaset, A., 86 Gassman, P. G., 221, 443 Gasson, B. C., 359 Gattavecchia, E., 376 Gauss, W., 326 Gavril’chenko, A. I., 353 Gavuzzo, E., 183 Gawdzik, A., 1 Gedge, D. R., 343 Geevers, J., 80, 113, 236 Geise, H. J., 477 Geittner, J., 201 Gelan, J., 444, 485 Gelin, S., 201 Geneste, P., 97, 100, 473 Genet, J. P., 449 Gensmantel, N. P., 50 Gentile, M., 86 Georgarakis, E., 216 George, A. V. E., 63 Gerasimova, T. N., 186 Gerber, L., 1 Gerhardt, G., 213 Geribaldi, S., 29 Gerlach, H., 418 Gerloff, J., 238 Germain, G., 165, 167, 232, 234, 249, 398,474 German, L. S., 57 Gershanova, E. L., 3 Gerson, F., 445 Gevorkyan, R. A., 158 Gewald, K., 118, 285 Gey, C., 444, 485 Ghatiak, B. J. R., 352 Gholami, A., 189 Ghosal, S., 352, 366, 367 Ghosh, C. K., 406 Giam, C. S., 265, 277 Gibert, J. P., 212 Gibbons, L. K., 111 Giddings, P. J., 49 Gieren, A., 165, 216, 224, 242, 405 Gilb, W., 420 Gilbert, A., 452, 461 Gilchrist, T. L., 323, 328 Gilis, P. M., 80

Gilgen, P., 34 Gillies, C. W., 13 Gilmore, D. W., 463 Gilpen, M. L., 50 Ginak, A. I., 130, 132 Gindin, V. A., 478 Giner-Sorolla, A., 313 Ginsburg, D., 463 Gioia, B., 205 Giordano, C., 328 Giovanni, F., 50 Giovanni, S., 345 Giovannini, E., 216 Giral, L., 200 Girard, Y., 113, 268 Giri, B. P., 206 Giri, S., 158 Girke, W. D. K., 298 Girling, R. B., 445 Giro, A. P., 149 Gisin, M., 459 Gitis, S. S., 194 Giuffrk, L., 88 Giusti, P., 349 Glass, L. E., 444, 484 Glass, R. S., 460 Glaye, J., 354 Gleiter, R., 105, 111, 441, 443 Glennon, R. A., 142 Glennow, C., 107 Glidewell, C., 156, 227 Globokar, M., 128 Glotter, E., 16, 20 Glowczyk, J., 209 Glozman, 0. M., 349 Glushkov, R. G., 145, 384, 385, 386 Godar, D. E., 220 Godefroi, E. F., 85 Godleski, S. A., 449 Goehl, T. J., 96, 445 Goerdeler, J., 157, 227 Goetz, M., 366 Goff, D. L., 461 Gofman, L. V., 180 Goghari, M. H., 129 Gohar, A. K. M., 361 Gokel, G. W., 430, 434, 436 Golankiewicz, B., 248 Gold, V., 434 Gol’dfarb, E. I., 478 Gol’dfarb, Ya. L., 77 Golinski, J., 8 Golob, A. M., 450 Gololobov, Yu. G., 232 Golser, W., 53 Golz, H. J., 464 Gomes, L. M., 174, 176 Gomi, M., 288 Gompper, R., 70, 121, 205 Gonnella, N. C., 200 Gonzalez, A., 444, 485 Gonzalez, A. G., 372

Ganzalez, E., 204, 246 Goode, N. C., 443 Goodman, D. W., 443 Goosen, A., 194 Gopal, H., 284 Gopichand, Y., 64, 137 Gorb, L. T., 144 Gordon, E. M., 87 Gore, J., 2 Gore, S. T., 172 Gorelik, M. V., 359 Gorham, P. R., 450 Gorissen, J., 211, 402 Gorques, A., 199 Gorrichon, J.-P., 86, 472 Gospodarek, J., 120 Goswami, D. D., 119, 120 Gosztonyi, T., 101 Goth, H., 121, 217 Goto, T., 329 Goto, Y., 241 Gottfried, N., 445 Gotthardt, H., 63, 90, 100, 105, 111, 116, 122, 197, 198, 210,224,463 Gottlieb, 0. R., 350, 358, 360, 373 Goudard, M., 356 Gougoutas, J. Z., 401, 481 Gousetis, C., 458 Grabenko, A. D., 158, 161, 196 Grabley, S., 37, 125 Grabowski, E. J. J., 445 Gradowska, W., 197 Grafing, R., 80, 341 Graeme, H. B., 391 Graessle, 0. E., 110 Graham, P. A., 223 Graham, R., 365 Granados, R., 75 Granchelli, F. E., 17 Grandclaudon, P., 99 Granger, R., 130 Grant, C. B., 295 Grant, F. R., 445 Grant, J. A., 97 Gras, J.-L., 460 Grasso, S., 129, 130 Grayston, M. W., 20 Graziano, M. L., 217 Greatbanks, D., 424 Greci, L., 208 Green, D. C., 199 Greenberg, F. H., 341 Greene, F. D., 54 Greenhalgh, C. W., 75 Greenhalgh, P. F., 4 Gregson, M., 358 Grehn, L., 81, 142 Greijdanus, B., 9 Gren, A. I., 477, 480 Grenier, M. F., 336 Greving, B., 91

Author Index Grezzo, L. A., 443 Griengl, H., 399 Grifantini, M., 206 Griffin, G. W., 180 Griffiths, D., 116 Griffiths, D. W., 220 Griffiths, D. V., 472 Grigg, G. W., 138 Grigg, R., 180, 201, 272 Grigor'eva, N. V., 74 Grindley, T. B., 482 Grinenko, S. B., 4 Grins, N., 140 Grob, C. A., 56, 444 Gromov, S. P., 267 Gronowitz, S., 76, 77, 78, 79, 81, 84, 87, 93, 100, 102, 103, 106, 107, 168 Grosjean, N., 84 Grossman, W. E., 445 Grote, H., 370 Groves, J. T., 12 Grubbauer, W., 399 Grunanger, P.,78 Grundmann, C., 224 Gruner, T. A., 110, 111 Gruntz, U., 339 Grunwell, J. R., 197 Gschwend, H. W., 262 Gschwind, R., 442 Gsell, R., 485 Gualtieri, J. A., 72 Guanci, D. F.. 251 Guanti, G., 76 Gubaidullin, L. Yu., 171, 420 Gubaidullin, R. N., 479 Guedj, R., 31 Guenot, P., 32 Giinther, W. H. H., 109 Giinzl, F., 247 Guerin, C., 375 Guerra, M., 73 Guerrera, G., 107, 118 Gugel, H., 228 Guggisberg, A., 421, 424 Guglielmetti, R., 131, 136, 138, 359 Guha, S. K.,99 Guilard, R., 73 Guilhem, J., 463 Guiliano, M., 129, 130, 136, 470 Guillaumet, G., 368 Guimaraes, A. C., 481 Guimon, C., 97, 113, 129, 135 Guimon, M. F., 97 Guirado, A., 354 Gujral, V. K., 352 Gulini, U., 206 Gunar, V. I., 409 Gunasekera, S. P.,365 Gundersen, G., 166 Gunn, B. P., 21

499 Gunning, H. E., 40, 71, 154, 227 Gupta, A. D., 358 Gupta, B. D., 360 Gupta, K. C., 195 Gupta, M. C., 359, 360 Gupta, P. K., 48 Gupta, R., 152, 361 Gupta, R. B., 342 Gupta, R. C., 330, 357, 372 Gupta, R. K.,350 Gupta, R. P., 140, 141, 149 Gupta, S. R., 352 Gurarii, L. I., 470 Gurevich, P. A., 288 Guryn, R., 398 Guseinov, K. Z., 129 Guseinov, M. M., 7, 472 Gusel'nikov, L. E., 46 Gutman, I., 472 Guy, A., 27 Guy, M. H. P., 440 Guzman, J., 136 Gybin, A. S., 40 Gyorgydeak, Z., 129 '

Habermehl, G. G., 140 Habison, G., 103 Hackenberger, A., 205 Haddad, H., 395 Haddadin, M. J., 168, 209, 322 Haddock, N. F., 432 Haddon, R. C., 195 Hadjiantoniou, C. P., 74 Hadjukovic, G., 476 Hadicke, E., 206 Haemers, A., 80 Haenel, M. W., 483 Haensel, R., 136, 352 Hafter, R., 386 Hagen, H., 118 Hagen, J. P., 412 Hagenbuch, J.-P., 463 Hager, D. C., 269, 429 Hagmann, W. K., 175, 190 Hahn, C., 216 Hai, S. M. A., 41 Haile, C. L., 193 Hakimelahi, G. H., 48 HHkansson, R., 73,77 Halczenko, W., 192, 452 Halevi, E. A., 63 Haley, T. J., 330 Hall, B., 243 Hall, J. H., 53, 222, 327, 469 Hall, M. B., 443 Hall, P., 58 Hall, R. F., 97 Hall, S. S., 331 Hallberg, A., 92 Haltiwanger, R. C., 141 Halton, B., 452 Hamada, Y., 326

Hamaguchi, F., 303 Hamaguchi, H., 293 Hamaguchi, M., 218 Hamana, M., 287, 288 Hamdi, M., 336 Hamed, A. A., 18 Hamel, P., 113 Hamelin, J., 202 Hammam, A. E. G., 150, 152 Hammam, A. S., 124 Hammond, P. S., 171 Hammouda, H. A., 141, 303 Hamor, T. A., 441 Hamoud, H. S., 334 Hanafusa, T., 169 Hanahoe, A. B., 220 Hanaya, K., 346 Hand, E. S., 244 Handa, R. N., 146, 149 Handrick, G. R., 370 Hanel, G., 294 Hanity, M., 430 Hanley, R. N., 159, 218 Hann, R., 60 Hanquet, B., 73 Hansen, H.-J., 34, 216, 221, 224 Hansen, K.J., 328 Hanson, P., 162, 229 Hanzawa, Y., 173, 241,461 Hara, S., 381 Hara, Y., 92 Harada, H., 133, 179 Harada, K.,27, 211, 452 Harano, K., 250, 378, 379, 442 Harbush, A. H., 51 Harcourt, D. N., 382 Harding, H. R., 96, 445 Hardy, A. D. V., 440 Hargis, J. H., 480 Hargreaves, R. T., 363 Harihara, K., 243 Harkonen, T., 471 Harlow, R. L., 488 Harmon, A. D., 348 Harpp, D. N., 410 Harris, D., 397 Harris, E. E., 238 Harris, M., 471 Harris, R. K., 444 Harrison, A. M., 445 Harrison, I. T., 365 Harrit, N., 44, 165, 234, 459 Hart, H., 91, 451, 457 Hart, L. S.,267 Hartley, S. G., 464 Hartmann, W., 218 Hartwig, W., 170 Harvey, R. G., 10, 12 Hasan, A., 354 Hasan, I., 281, 452 Hase, H. L., 41 Hase, Y., 471

Author Index

500 Hasegawa, H., 395 Hasegawa, K., 164, 231, 328 Haselbach, E., 442 Hashigaki, K., 352, 358 Hashimoto, S., 426, 459 Hashimoto, T., 97 Hashmall, J. A., 43 Haslam, E., 350 Hasnaoui, A,, 254 Hassan, A. M., 243, 388, 419 Hassan, K. M., 48, 124, 128, 129 Hassan, M,., 21 Hassan, M. E., 113 Hassanaly, P., 128 Hastings, R. H., 433 Hata, N., 288 Hata, Y., 43 Hatanaka, Y., 56, 388, 412 Hathaway, B. J., 451 Hatsui, T., 62 Hattingh, M., 350 Hatton, R., 282 Hauck, A. E., 265 Hauff, J. P., 211 Hauptmann, D., 136 Hauser, F. M., 347 Hautala, R. R., 433 Havel, N., 56 Hawi, A. A., 209 Haya, K., 64 Hayakawa, Y.,446, 459 Hayashi, M., 212 Hayashi, N., 142 Hayashi, R., 293, 406 Hayashi, S., 133, 357 Hayes, R. A., 459 Haymore, B. L., 432 Haynes, R. K., 368 Haywood, D. J., 411 Hazzaa, A. A. B., 158, 160 Heberlein, M., 423 Hebold, G., 30 Hecht, H. J., 373 Hecht, S. M., 126 Heck, R. F., 77, 285 Heckeler, M. L., 87, 96, 445, 446 Hedayatullah, M., 27, 304 Hedges, W., 441 Hediger, M., 423 Hedstrand, D. M., 279 Heerdt, R., 30 Hegarty, A. F., 232 Hegedus, L. S., 184, 283 Hegel, R. F.,100 Heger, J., 58 Heidelberger, C., 421 Heil, G., 419 Heimann, M., 66 Heimann, U., 466 Heimgartner, H., 34, 35, 36, 37, 53, 224, 246, 262, 398, 414

Hein, F., 238, 239 Heine, H. G., 218 Heine, H. W., 398 Heinisch, G., 294 Heinrich, G. R., 15, 343 Heinzer, F., 319 Hekman, M., 458 Helder, R., 9 Helgeson, R. C., 434, 435, 436,466 Helmkamp, G. K., 464 Helquist, P., 23 Hemela, J., 130 Hempel, A., 43 Henne, A., 63 Hennessee, G. L. A., 442 Henriksen, L., 210 Henry-Basch, E., 22 Herault, V., 336 Hercliffe, R. D., 263 Herczegh, P., 126 Herd, K. J., 192 Herkes, F. E., 134 Hermann, K., 9 Hernandez, L., jun., 48, 298 Hernandez, M. G., 372 Hernandez, O., 265 Hernestam, S., 475 Herrling, S., 160 Herron, D. K., 49 Hershkowitz, E., 238 Herslof, M., 100, 103 Herzhoff, M., 466 Hesse, M., 421, 424 Hesse, R. H., 178 Hester, R. E., 445 Hetzheim, A., 249 Heumann, A., 456 Hevesi, L., 11 Hewgill, F. C., 391 Hewitt, D. G., 391 Heydenhauss, D., 160 Heyns, K., 462 Hibino, S., 99 Hibino, T., 92 Hicks, T. A., 95 Hidaka, H., 24 Higashiyarna, K., 314 Higuchi, M., 251, 310, 312, 321 Hikichi, H., 372 Hilal, R., 132 Hildon, A. M., 4 Hill, E. A., 457 Hill, R. T., 445 Hino, T., 439 Hintz, G., 125 Hioki, T., 464 Hiraga, Y., 354 Hirai, K., 121, 210 Hirai, Y., 51 Hiramitsu, T., 408 Hirano, H., 202, 433 Hiranurna, H., 298

Hiraoka, T., 49 Hirobe, M., 239, 314 Hirokami, S., 51 Hirooka, S., 164, 231, 328 Hirose, Y., 211 Hirota, K., 248, 302, 309, 310, 320,410 Hirsch, J. A., 336, 473 Hirsch, K., 136 Hirschon, A. S., 241 Hisada, R., 206 Hisano, T., 208, 250 Hishmat, 0. H., 361 Hlasta, J. D., 50 Ho, M. S., 2 Hoberg, H., 48, 170 Hofle, G., 258, 373 Hoefner, D., 29, 474 Horlein, G., 106 Hornfeldt, A.-B., 76, 81, 84, 106 Hoff, D., 412 Hoffman, D. H., 436 Hoffman, R. V., 83, 172 Hoffmann, H. M. R., 446 Hoffmann, R. W., 56 Hofmann, F., 160 Hogeveen, H., 461, 462 Hohnjec, M., 128 Hojo, K., 266 Holbert, G. W., 12, 58 Holden, K. G., 97 Holeman, M., 414 Holik, M., 135 Hollinsed, W. C., 441 Holla, B. S., 92 Holland, H. L., 13 Hollywood, F., 289, 399 Holm, A., 44, 154, 165, 167, 228, 234 Holmes, A. B., 451 Holmes, B. N., 248 Holmes, T. J., 340 Holroyde, J. K., 390 Holtwick, J. B., 248 Homfeld, E., 97, 98 Honda, R. N., 140 Hong, P., 206 Hongo, H., 290 Honjo, N., 241 Hooper, M., 168 Hootelk, C., 279 Hopartean, I., 486 Hoppe, I., 213 Horak, V., 134, 135 Hordziejewicz, F., 317 Horhammer, L., 352 Hori, M., 138, 139, 364, 394, 395 Horie, T., 356, 357 Horiguchi, Y.,378 Horikawa, H., 297 Horn, A. S., 441 Horn, H., 207

Author Index Horn, K. A., 45, 60 Horstmann, H., 144, 276 Hortmann, A. G., 84, 196, 207,466 Horvath, G., 119 Hosaka, K., 182 Hosangadi, B. D., 176, 409 Hoshino, M., 197, 200 Hosogai, T., 7 Hosokawa, T., 175 Hosoyarna, K., 354 Hostettmann-Kaldas, M., 366 Hotokka, M.,470 Hotten, T. M., 76, 95, 405 Hotzel, A., 102, 161 Houalla. D., 242 Houghton, P. G., 404 Hougton, L. E., 203 Houk, K. N., 88, 178 Houlihan, W., 418 Howard, R., 336 Howe, R. K., 110, 111 Howell, S., 330 Hoz, T., 20 Hrnjez. B. J., 285 Hrubantova, M., 365 Hsu, Y. F., 230 Huang, J. C., 210 Huber, C. P. S., 239 Huber, W., 445 Hubert-Habart, M., 172 Huddleston, P. R., 81 Hunig, S., 221, 452 Huesmann, P. L., 262, 452 Huet, F., 62 Huffman, W. F., 97 Hughes, D. L., 484 Huisgen, R., 21, 201 Hull, R., 289, 399 Humber, L. G., 145 Humburg, G., 102, 216 Hummel, K., 77 Hummelen, J. C., 9 Humphlett, W. J., 127 Hurnphreys, D. J., 160 Humphry-Baker, R. A., 176 Hundt, H. K. L., 350 Hunt, E., 50 Hunt, J. H., 257 Hunt, J. T., 205 Hunt, P. G., 185 Hunt, S. E., 193,452 Hunter, D. H., 430 Hunter, G., 477 Hunter, N. R., 450 Huq, E., 14 Hurt, S. D., 101 Husain, S., 140 Huss, 0. M., 63, 198, 463 Hussan, H.-P., 276 Hussein, A. Q., 127 Hutchings, S. D., 72 Hutchinson, C.R., 331 Hutchinson, J., 168

501 Huth, A., 25, 217 Hutley, B. G., 82 Iacobucci, G. A., 356 Ibaceta-Lizana, J. S. L., 188 Ibad-Zade, A. K.,129 Ibata, M. P., 216 Ibragimov, V. G., 69 Ibrahim, Y. A., 107 Ichiba, M., 154, 308, 312, 313 Ichikawa, K., 16 Ichikawa, M., 208, 250 Ichinose, I., 7 Ida, H., 31 Ida, Y., 250 Iddon, B., 84, 105 Iesce, M. R., 217 Igarashi, S., 74 Igeta, H., 240, 245, 274, 293, 395 Ignatev, V. M., 220 Ignat’eva, S. N., 478, 479 Ignatova, N. P., 231 Iguchi, K., 462 Ihara, M., 411 Ihda, N., 336 Ihn, W., 363, 373 Iida, H., 28, 186, 386, 406 Iijima, I., 118 Iitaka, Y., 245 Ikeda, I., 430 Ikeda, M., 177, 186, 188, 190, 365,430 Ikeda, T., 212 Ikegami, S., 40, 88, 464 Ikemi-Kono, Y., 275 Ikeuchi, S., 230 Ikizler, A. A., 339 Ila, H., 261 Ilin, S. G., 442 Illuminati, G., 427 Ilotse, J. B., 356 Imada, S., 214 Imagawa, T., 367 Irnai, Y.,138, 139 Irnanishi, M., 74 Imanishi, T., 455 Imaoka, M., 266 Imoto, E., 115, 212, 448 Irnpicciatore, M., 115 Imuta, M., 188 Inabe, N., 180 Inagaki, Y.,163, 215, 230 Inamoto, N., 137, 163, 196, 199, 215, 219,230 Inazu, T., 69 Inbasekaran, M. N., 250 Incoccia, L., 392 Ingham, J. L., 353 Ingle, D. B., 119 Ingold, K. U., 42 Inoue, H., 448 Inoue, M., 16 Inoue, S., 191

Intrito, R., 122 Inubushi, Y., 184 Ionon, B. I., 220 Ionov, V. M.. 442 Ionova, V. F., 80 Iovchev, A., 28 Irwin, R. M., 66, 469 Ishiba, T., 121, 210 Ishibashi, H.,268, 447 Ishibe, N., 336 Ishida, M., 50 Ishiguro, T., 347 Ishii, F., 195 Ishii, N., 5 Ishii, S.. 38, 209, 336 Ishihawa, N., 402 Ishikawa, K., 164, 199, 231, 328 Ishikawa, M., 457 Ishikawa, N., 133, 141, 303 Ishikawa, R.,20 Ishikawa, T., 24 Ishiyama, J., 343 Ishizumi, K., 12, 58 Ishmaeva, E. A., 479, 480 Ismail, I., 361 Ismail, I. M., 150 Ismailov, A. G., 69 Isobe, K., 188 Isomura, K., 34, 35, 211 Issa, Y. M., 130 Issleib, K., 478 Isukul, E. A., 226 Itahara, T., 188, 237 Itatani, Y., 11 Itaya, N., 6 Iten, P. X.,172, 174 Ito, K., 173 Ito, S., 242, 243, 246, 272, 273,364,466,483 Ito, Y., 31, 63, 143, 184, 207, 326,406,414 Itoh, K., 99 Itoh, M., 406 Itoh, S., 187 Itoh, T., 4 Itov, Z. I., 409 Ittah, Y.,27 Iwai, T., 56 Iwakura, H., 94 Iwao, M., 287 Iwasa, K., 487 Iwasaki, F., 157, 227 Iwasaki, S., 206 Iwasaki, T., 118, 297 Iwata, M., 425 Ivanova, K.,362 Ivanova, T. M., 128, 224 Ivanova, Zh. M.. 232 Iyer, R., 188 Izatt, N. E., 432 Izatt, R. M., 432, 466 Izawa, T., 131, 334 Izumi, T., 346

Author Index

502 Jackman, G. P., 178 Jackson, A. H., 188 Jackson, D. W., 354 Jacobs, P. M., 108 Jacobsen, B., 458 Jacobson, A. E., 445 Jacot-Guillarmod, A., 366 Jacquignon, P., 108 Jacquier, R., 209 Jager, V., 214 Jaenecke, G., 160 Jaggers, A. J., 4 Jagodzinski, P. W., 193 Jagt, J. C., 452 Jain, A. C., 330, 357, 372 Jain, B. C., 366 Jain, P. C., 344 Jain, R. K., 366 Jain, S. C., 366 Jaiswal, D. K., 352, 366 Jalal, M. A. F., 354 James, A. W. G., 333 Jameson, R. F., 477 Jamoulle, J. C., 144 Jancke, H., 476 Janda, M., 98 Janezic, D., 204 Jankowski, K., 471 Jannawar, S. T., 145, 152 Janousek, Z., 222 Jansen, M., 53, 233, 322 Janusz, J. M., 14 Japelj, M., 128 Jarmas, A. A., 336, 473 Jarvis, B. B., 41, 328 Jarvis, J. A,, 424, 427 Jauhari, P. K., 354 Jawdosiuk, M., 174 Jay, M., 354 Jean, A., 345 Jedlifiski, Z., 59 Jefford, C. W., 2, 61, 63, 463 Jeffrey, H., 359 Jeganathan, S., 76 Jenner, G., 460 Jensen, R. B., 486 Jeremic, D., 472 Jerina, D. M., 12, 14 Jerkunica, J. M., 444, 484 Jerzmanowska, Z., 213 Jeyaraman, R., 486 Jezek, M., 135 Jilek, J. O., 365, 393 Jitsukawa, K., 4 Jochims, J. C., 127 Joergensen, S. E., 486 John, D. I., 49 John, W., 197 Johne, H., 120 Johne, S., 120 Johnson, A. P., 182 Johnson, A. W., 182 Johnson, C., 451, 452

Johnson, C. R., 8 Johnson, D. F., 192 Johnson, M. R., 466 Johnson, R. S., 203 Joho, M., 220 Jokisaari, J., 58 Joly, M., 193 Joncheray, G., 209 Jones, A. W., 81 Jones, D. W., 27 Jones, E. R. H., 93 Jones, G., 56, 214, 253, 317, 387,466 Jones, J., 444 Jones, J. H., 112 Jones, M., 375 Jones, M. C., 235, 344 Jones, N. D., 389, 442 Jones, P. G., 154, 441 Jones, P. R.,440 Jones, T., 141 Jones, W. D., jun., 252 Jongejan, E., 32, 38 Jongejan, H., 300 Jonkers, F. L., 88 Jordan, S., 177 Jordis, U., 126 Jose, F., 49 Joshi, K. C., 119, 149, 159 Joshi, V. S., 25 Jossin, A., 147 Joullik, M. M., 65, 86, 101, 168, 217, 257 Jourdan, G. P., 289 Juaristic. E., 370, 476 Junek, H., 87, 244 Jung, M. E., 462 Jung, W., 170 Junjappa, H., 261 Jurczak, J., 331 Just, G., 48, 49 Kabbe, H.-J., 326, 345 Kaden, T. A., 423 Karnpchen, T., 78, 103, 247, 379 Kafka, Z., 440 Kaftory, M., 441, 461 Kagabu, S., 416 Kagan, J., 441, 462 Kajfez, F., 440 Kaji, E., 211 Kaji, R., 173, 461 Kajigaeshi, S., 118 Kajtna, P., 186 Kakehi, A., 242, 243, 246, 272, 273 Kakisawa, H., 207 Kakiuchi, H., 430 Kalabin, G. A., 356 Kalik, M. A., 77 Kalikhman, I. D., 68, 197 Kalinkin, M. I., 75

Kalkabaeva, L. T., 128 Kalla, A. K., 358 Kalman, A., 130 Kaloga, M., 352 Kaloustian, M. K., 471 Kamaev, A. V., 126 Kamalova, E. G., 89 Kamatani, H., 17 Kamdar, B., 402 Kamenka, J. M., 473 Kamernitskii, A. V., 15 Kametani, T., 48, 129, 411, 445 Kaminskii, A. Ya., 194 Kaminskii, V. F., 200 Kaminsky, L. S., 360 Kamiya, I., 62 Kamiyama, Y., 410 Kamla, C., 346 Kamogawa, H., 137 Kampe, W., 30 Kamura, M., 6 Kanahori, K., 320 Kanamori, Y., 251, 310, 312 Kanaoka, Y., 56, 99, 237, 388,412,421 Kanazawa, H., 312 Kandeel, E. M., 124, 140 Kaneda, K., 4 Kaneko, C., 288, 293, 406 Kanemasa, S., 118 Kanematsu, K. K., 378, 379, 442 Kaneta, M., 372 Kang, K.-T., 196 Kang, S. S., 355, 369 Kanishchev, M. L., 170 Kanner, C. B., 237, 294 Kanno, S., 406 Kano, S., 6, 50, 99, 304 Kantor, E. A., 472 Kapil, R. S., 360 Kaplan, L. J., 436 Kaplan, M. L., 195 Kapoor, R. P., 346, 356 Kappe, T., 53, 290 Kappenberg, F., 181, 252, 386 Karakasa, T., 340 Karakhanov, E. A., 98 Karakhanov, R. A., 472 Karataeva, F. Kh., 472 Karavan, V. S., 18 Karavlov, E. S., 44f Karayez, S. K., 337 Karban, J., 40% Karchesy, J. J., 100 Karimian, K., 142 Karle, J. M., 14 Karlsson, O., 75 Karpenko, N. F., 250 Karpenko, V. D., 217 Karpf, H., 244 Kasahara, A., 95, 346

Author Index Kascheres, A., 317 Kashima, C., 55, 214, 300, 301 Kashiwagi, T., 241 Kashman, Y., 66, 444, 445 Kassab, N. A., 130 Kasturi, T. R., 194 Kasumov, N. K., 472 Kataev, V. E., 471, 472, 479 Katagiri, N., 264, 359, 366 Katagiri, T., 345 Kataoka, T., 138, 139, 364, 394, 395 Katayanagi, M., 354, 372 Katayama, S., 347 Kathan, W., 77 Kato, A., 477 Kato, E., 7 4 Kato, H., 22, 290, 390 Kato, K., 255 Kato, M., 169 Kato, N., 466 Kato, S., 142 Kato, T., 7, 169, 180, 222, 264, 271, 335, 347, 359, 366,452 Kato, Y., 95, 431 Katoh, A., 55, 300, 301 Katonak, D. A., 169 Katou, T., 346 Katritzky, A. R., 250, 338, 339, 447, 448, 474, 475, 488 Katz, T. J., 412 Kaufmann, D., 458 Kauffmann, T., 91, 257, 414, 423 Kaupp, G., 178, 414, 461 Kausch, E., 37, 125 Kawahara, H., 164, 231, 328 Kawamata, A., 87 Kawamoto, H., 380 Kawanishi, M., 312 Kawanisi, M., 367 Kawano, K., 406 Kawano, Y., 7 4 , 9 7 , 254,477 Kawarasaki, T., 347 Kawase, T., 199 Kawase, Y., 174, 359 Kawashima, K., 254 Kawashima, N., 437 Kawashima, T., 219, 437 Kawata, H., 464 Kawata, K., 266 Kawato, T., 438 Kawazoe, M., 315 Kay, I. T., 51 Kaya, R., 5 Kazakov, A. L., 330 Kazankov, M. V., 359 Kazlauskas, R., 364, 365 Kazuhiro, K., 393 Keating, M., 222 Keck, G. E., 323, 451 ,

503 Keehn, P. M., 73, 171, 331, 464 Kehr, J. R., 101 Keifer, L., 459 Keiko, V. V., 6 6 Keinan, E., 449 Keir, W. F., 304 Keller, P. C., 139 Kellogg, R. M., 39, 270, 279, 432 Kemp, D. S., 414 Kemp, J., 180, 201, 272 Kempe, G., 197 Kempe, T., 209 Kempe, U. J., 209 Kemper, R., 393 Kempter, G., 101, 119 Kenjo, T., 95 Kennard, O., 154, 441 Kennedy, J. D., 483 Kenny, D. H., 339 Kessel, C. R., 441, 443 Kevill, D. N., 222 Khaitbaeva, A. G., 100 Khalil, A. M., 126, 132 Khama, R. N., 342 Khan, J. A., 463 Khan, M. A., 105, 168, 257 Khand, I. V., 392 Khanna, A., 80, 106 Khanna, J. M., 344 Kharchenko, V. G . , 330, 349 Khare, R. K., 158 Khasapov, B. N., 250 Khatri, N. A., 153 Khazanchi, R., 330, 357 Khera, U., 371 Khidekel, M. L., 200 Khmel’nitskii, L. I., 41 Khodzhibaev, Yu.,143 Khorrami, J., 155 Khosrowshahi, J. S., 204 Khuong-Huu, Q., 456 Khvostenko, V. I., 445 Kibayashi, C., 28, 186, 386, 406 Kibbel, H. U., 120 Kidd, M. R., 445 Kiel, W. A., 179 Kiely, J. R., 69 Kierstead, R. W., 8 4 Kihara, K., 430 Kihara, M., 482 Kijima, S., 343 Kikuchi, K., 212 Kikugawa, K., 8 7 Kikugawa, Y., 287 Killen, C. R. J., 267 Killian, W., 276 Kim, K. H., 3 4 Kim, S. H., 388 Kim, T. V., 232 Kim, Y. C., 77 Kimling, H., 393

Kimura, H., 169, 335 Kimura, M., 152 Kimura, Y., 316 Kinas, R., 479 Kinashi, H., 332 King, R. M., 437 King, R. J., 147, 332, 443 King, W. B., 220 Kingsbury, C. A., 153 Kingsbury, W. D., 5 0 Kinoshita, M., 455 Kinoshita, T., 156 Kipnis, I. J., 6 5 Kirby, A. J., 419 Kirby, G. W., 451 Kiremath, S. P., 168 Kirihara, H., 180 Kiritani, R., 115 Kirk, K. L., 206 Kirn, B., 239 Kirpichenko, S. V., 6 6 Kirsch, G., 108 Kirste, K., 4 5 Kisch, H., 397 Kise, H., 175 Kise, M.. 365 Kishi, K., 221 Kishimoto, S., 7 4 Kisin, A. B., 7 4 Kissick, T. P., 254, 398 Kister, J., 128, 136, 137 Kitadani, M., 457 Kitagawa, A., 184 Kitagawa, M., 95, 243 Kitagawa, S.,78, 463 Kitagawa, T., 92 Kitagawa, Y., 426 Kitahara, Y., 14, 462 Kitamura, N., 410 Kitao, T., 349, 350 Kitazume, T., 65, 402 Kito, Y., 179 Kiyokawa, H., 268, 447 Klaboe, P., 6 5 Klee, W. A., 445 Klei, B., 265 Klein, R. S., 309 Kleinau, V., 206 Kleinpeter, E., 249, 471, 476, 477 Klemm, L. H., 100 Klemm, U., 442 Klepikova, S. G., 474 Kliegel, W., 234 Klimenko, S. K., 330 Klimenko, V. I., 8 7 Kline, S. A., 1 7 Klingebiel, U., 116 Klinkert, G., 257 Kloek, J. A., 327 Klotzer, W., 221 Klose, D., 1 Klusis, V., 243 Klyuev, N. A., 140, 189

Author Index

5 04 Klyuev, V. N., 114, 210 Kmiotek-Skarzynska, I., 174 Knapp, K. K., 139 Knaus, E. E., 277 Knecht, J., 458 Kniezo, L., 133 Knight, D. W., 343 Knutov, V. I., 30 Knyazev, V. N., 409 Kobayashi, G., 81, 319 Kobayashi, K., 34, 71, 170, 184, 3 7 0 , 4 0 6 , 4 1 4 , 4 8 3 Kobayashi, M., 343, 443 Kobayashi, R., 446 Kobayashi, S., 169, 339, 482 Kobayashi, T., 66, 136 Kobayashi, W., 127 Kobayashi, Y., 28, 173, 183, 241, 2 5 8 , 4 6 1 Kobler, H., 7 KoEevar, M., 246 Kocheshkov, K. A., 7 7 Kocovsky, P., 16 Koczuka, M., 344 Kodaira, K., 169 Koechritz, P., 55, 142 Kogel, W., 434 Kohler, G., 287 Konnecke, A., 233, 249 Korber, I., 99, 337 Kohli, A. K., 330 Kohli, D. K., 271 Kohlmeyer, I., 422 Kohn, H., 64, 137 Koizumi, T., 347 Kojima, M., 124 Kokotailo, G. T., 180, 428 Kokubun, H., 464 Koga, H., 239 Koga, K., 4 3 3 , 4 3 4 Kogan, N. A., 119 Kolb, N., 9 8 Kolbah, D., 440 Kole, P., 358 Kolinska, R. A,, 58 Koll, P., 462 Kollenz, G., 238 Kolomiets, A. F., 39, 368 Kolsaker, P., 221 Kolshorn, H., 228 Kolt, R., 450 Komalenkova, N. G., 231 Komatsu, M., 41, 87, 348, 351 Komatsu, T., 250, 271, 425 Komazawa, T., 380 Komendantov, M. I., 34, 203, 214 Komeno, T., 9 4 Komina, T. V., 188 Komori, T., 250 Komorowski, L., 206 Konar, A., 107 Kondo, K., 272

Kondo, M., 191 Kondo, S., 174, 398 Kondo, T., 471 Kondrateva, G. Ya., 218 Konitz, A., 4 3 Kon’kova, S. G., 7 4 Kononova, V. V., 356 Konopski, L., 254 Konovalo, I. V., 55 Konno, S., 299 Konno, Y., 273 KOO, J.-Y., 2, 45, 207 Koob, R. D., 66 Koopman, J., 1 Kopecky, K. R., 6 2 Koppel, G. A., 49 Koppenhoefer, B., 10 Korbuly, G., 290 Korff, J., 48, 170 Kornilova, E. N., 105 Korobitsyna, I. K., 226 Korostova, S. E., 178 Korotenko, T. I., 402, 481 Korotkov, S. A., 213 Korp, J., 408 Korp, J. D., 369, 442 Korzhenevskii, A. B., 114, 210 Kos, J., 9 8 Koser, G. F., 443 Koshimie, J. K., 368 Koshiro, A., 251 Koshiro, K., 310 Kosower, E. M., 238 Kossakowski, J., 362 Kost, A. N., 134, 168, 185, 187, 257, 267 Koster, W. H., 97 Kostikov, R. R., 34, 214 Kostrova, S. M., 375 Kostusyk, J. L., 7 0 Kosugi, Y., 240 Kosulina, T. P., 472 Kotelko, A., 398 Kotite, N. J., 471 Kotov, A. I., 200 Kotova, L. I., 146 Kotsuki, H., 78, 463 Koudijs, A., 300 Koudsi, Y., 472 Kovac, I., 239 Kovac, S., 135 Kovacic, P., 457 Kowalczak, M., 5 9 Kowarsch, H., 168 Koyama, T., 352, 358 Kozhemyakina, L. F., 77 Kozhevnikov, I. V., 189 Kozikowski, A. P., 187, 188, 450 Kozlowski, M. A., 445 Kozlov, A. P., 334 Koz’min, A. S., 66, 108, 109 Kozuka, S., 58, 187

Krabbenhoft, H. O., 85, 445 Kraemer, R., 480 Kramer, U., 421, 424, 440 Krantz, A., 153, 154, 226 Krasavtsev, I. I., 58 Krasnec, L., 475 Krasnomolova, L. P., 474 Krasnov, V. L., 167, 234 Krasovskii, A. N., 140 Kraus, G. A., 7, 80, 361, 362 Krebs, A., 393 Krebs, B., 55 Kreher, R., 192, 452 Kremleva, 0. B., 213 Kretchmer, R. A., 169 Krey, P., 71, 131 Kricka, L. J., 192 Krief, A., 11 Kriegesmann, R., 91 Krimer, M. Z., 4 0 Krinsky, P., 16, 20 Kriplo, P., 1 Krische, B., 210, 235 Krishna, R. R., 353 Krishnan, K., 48 Kristian, P., 133 Kriven’ko, A. P., 349 Krivonogov, V. P., 340 Krivoruchko, V. A., 1 5 Krivoshei, I. V., 487 Krochmal, E., 262, 461 Krog, A. J., 92, 144 Krohn, K., 47, 345 Krolevets, A. A., 368 Krolikiewicz, K., 166 Krow, G. R., 4 5 1 , 4 5 2 Krowicki, K., 264 Krueger, C., 479 Kruger, G. J., 354 Kruizinga, W. H., 279 Kruk, C., 485 Krupadanam, G. L. D., 371 Kruse, C. G., 88 Kruse, H. P., 148 Kruse, L., 213 Ku, A., 1 8 6 , 2 3 2 , 4 1 2 Ku, H., 32, 180, 412 Kubo, K., 347 Kubo, S., 95 Kubo, Y., 56, 169, 237, 383, 414 Kubota, K., 137 Kubota, S., 402 Kucherov, V. F., 170 Kucklander, U., 186 Kudyakov, N. M., 480 Kiibel, B., 106 Kuebler, N. A., 443 Kuehne, M. E., 386 Kiinzler, P., 418 Kuesefoglu, S. H., 171, 428, 466 Kuhl, P., 477 Kujath, E., 325

505

Author Index Kukhar, V. P., 54 Kukharev, B. F.,480 Kukla, M.J., 101 Kukolja, S., 50 Kulachkina, N. S.,89, 165 Kulaeva, L. N.,196 Kules, M.,119 Kuliev, A. M.,129 Kulikova, D.A.,92 Kulkarni, A. P., 152 Kulkarni, G. H.,226 Kulnevich, V. G., 472 Kumadaki, I., 28, 183,258 Kumadaki, S.,288 Kumar, A., 261,330,344,

357 Kumar, D., 359 Kumar, N.,106,152 Kumar, R.,360 Kumazawa, T.,169 Kundu, B., 75 Kunert, D. M.,48 Kuniak, M.P., 187 Kunzek, H., 156 Kuo, C. T.,284 KUO,P.-L., 430 KUO,S.-C., 240 Kurabayashi, M., 224 Kuraishi, T.,287 Kuranova, I. L., 39,88 Kurata, K.,319 Kurbanov, S. B., 7 Kurihara, H., 290 Kurihara, T.,202 Kurihara, Y., 352 Kuriki, H., 347 Kurita. J., 396 Kurizuka, Y., 190,295 Kurkutova, E.N.,441 Kurobane, I., 366 Kuroda, C.,352 Kuroda, K.,2 Kuroda, S., 255 Kurokawa, M.,11 5 Kurono, G., 354 Kurosawa, K.,353, 373 Kurr, B. G.,101 Kursanov, D.N.,75,80 Kurse, C.G.,107 Kurusu, Y., 5 Kurz, M., 54, 204 Kushnarev, D.F., 356 Kusnetsov, N. A.,58 Kusumi, T.,207 Kuwahara, Y., 336 Kuya, M., 319 Kuyper, L. F., 477 Kuzmin, V. A., 136 Kuznetsov, A. I., 455 Kuznetsov, E. V., 335 Kuznetsov, V.V.,480 Kuznetsova, M.A., 68 Kuznetsova, M. G., 74 Kuzuhara, H., 271,425

Kuzuya, M., 457 Kvitko, I. Ya., 104,117,119 Kwon, S., 177,188,190,399 Kyba, E. P.,232,434,436 Laane, J., 193,469 Laane, R. W.P. M., 9 Labar, D.,11 L’Abbe, G., 165,167, 232,

234 La Bella, G., 133 Lablache-Combier, A., 99 Lacko, I., 475 Lacoste, J. M.,467 Lacrampe, J., 456 Lacroix, A.,314 Ladd, M.F.C., 483 Laerum, T.,144 Laganis, E. D.,169 Laguerre, M.,463 Laird, A. E.,451 Laitar, R. A., 169 Lakshmikantham, M.V.,199,

200 Lakshminarayana, P., 294 Lalande, R., 330 Lalezari, I., 80, 155, 229 Lalor, F.J., 321 Lamartina, L., 93 Lamb, J. D.,432 Lambert, J. B., 206,370,477 Lambrecht, G., 476 Lamm, V., 224 Lammert, S. R.,50 Lamotte, J., 116 Lamotte-Brasseur, J., 116 Lam Thanh Hung, 470 Lana, J. C.A., 431 Land, H., 119 Landeros, R.,95 Landheer, I., 463 Landis, M.E.,53,63,442,

469 Landis, P. S., 428 Lando, 0.E.,125,141 Landor, P. D.,184 Landor, S. R.,184 Lane, G. A., 357 Lang, S. A. jun., 248 Langbeheim, M., 417 Langbein, A., 400,406 Langer, E.,476 Lanne, J., 66 Lanyova, S., 442 Lapachov, V. V.,300 Lapiere, C. L., 144 Laports, O., 28 Lappert, M. F.,66 Lappi, L.R.,100 Largo-Cabrerizo, J., 136 Larice, J. L., 129 Laronze, J., 245 Laronze, J. Y., 245 Larrieu, C., 447

Larsen, E., 167,234 Larsen, R.D.,441 Larsen. S.,159,441 La Torre, F., 356 Lattes, A., 29, 175 Lau, P. H.W., 236 Laube, B. L., 446 Laughlan, C. N.,441 Laureni, J., 153,154,226 Laus, G., 487 Lautenschlager, H.,218 Lavayssiere, H.,23 Lavergne, J. P., 254 Lavielle, S.. 89 Lavrent’eva, L. A., 18 Law, S-J., 445 Lawesson, S.O.,179,412 Lawton, R. G., 452 Lawton, S. L., 180,428 Lazareva, D.N.,89 Lazaro, R.,201 Laznicka, V., 135 Lea, R.,178 Leach, C. L. jun., 203 Leaver, D., 245, 319,443 Lebedenko, N.Yu., 134 Lebedeva, N. Yu., 375 Le B e u e , A., 136 le Bot, Y., 452 Le Bozec, H.,199 Lechevallier, A., 62 Lechtken, P., 60 Leci, 0. A., 299 Leclaire, A., 242 Le Coustumer, G., 242 Leddy, B. P., 339,463 Lee, A. W.,73 Lee, H.M.,10 Lee, S. O.,478 Lee, S. P., 170 Leete, E.,274 Le Fkvre, G., 202 Le Floc’h, Y.,86 Le Gall, J. Y., 136 Le Goff, E.,464 Lehn, J.-M., 425,432,433,

440,466 Lehner, H., 476 Leigh, S.J., 466 Leinberger, P., 161 Leismann, H., 194 Leissring, E., 478 Leistner, S., 149 Leitch, D.S., 75 Lejejs, J., 257 Lelandais, D.,368 Lele, S. R., 176,409 Lemal, D.M.,169 Le Marechal, A., 24, 210 Le Men, J., 245 Lernpert, K.,153, 207 Lend’el, V. G.,66, 108, 109 Lenders, J. P.. 279 Lennartz, J., 461

Author Index

506 le Noble, W. J., 268 Lenstra, A. T. H., 477 Leon, A., 95 Leonard, N. J., 248 Leonov, D., 11 Leonov, E.,11 Leonte, C., 244 Lepage, L., 100 Lepom, P., 233,249 Lepri, S., 106 Lerch, U., 96 Lerman, B. M., 445 Le ROUX,J. P., 37 Leschinsky, K. L., 137, 327 Lessard, F., 225 Lessard, J., 456 Letcher, R. M., 237 Lett, R., 476 Levai, A,, 406 Levchenko, E. S., 115 Levesque, G., 464, 477 Levitan, P., 84 Levkovskaya, G. G., 197 Levy, J., 245 Lewis, D. H., 445 Lewis, J., 339 Lewis, J. R., 365 Lewis, M. D., 4 Lexy, H., 423 Lhommet, G., 339 Li, T. T., 344 Liak, T.-J., 49 Liberatore, F., 277 Librando, V., 90 Lichtenthaler, L., 319 Liebezeit, G., 325 Liebscher, J., 164 Liepins, E., 29, 304, 473 Ligon, W. V., 445 Likhomanova, T. I., 264 Liles, D. C.. 156, 227 Liljefors, S.,92, 93 Lim, M. I., 309 Limacher, J., 345 Lin, C. J., 221 Lin, C. N., 354 Lin, T. S., 162 Lin, Y.-I., 248 Lindberg, H., 142 Lindley, A. A., 168, 169 Lindley, J. M., 83, 148 Lindley, W. A., 350, 393 Link, H., 37, 226, 246, 414 Linkies, A,, 48 Linskeseder, M., 12 Linstrumelk, G., 23 Lintner, K.,470 Lipa, W. J., 464 Lipkin, A. E., 92 Lipnitskii, V. F., 132 Lippmaa, E., 444 Lippmann, E., 233, 249 Lipshutz, B. H., 48 Lister, J. H., 312

Litkei, G., 351 Little, J. H., 472 Little, R. D., 459 Littlewood, D. M., 185 Liu, H.-J., 170 Liu, J.-M., 458 Liu, K. C., 152, 458, 459 Liu, P. S., 309 Livdane, A., 200 Llinares, J., 135 Lloyd, D., 377, 398 Lo, K. M., 101 Lo, Y. s., 49 Loader, C., 333 Lobanov, 0. P., 120 Lobo, A. M., 292 Lochon, P., 135 Lockhart, R. W., 457 Loebach, W., 157, 227 Loew, G. H., 14 Loew, L., 375 Logan, C. J., 419 Logani, M. K., 235 Logemann, E., 420 Loghry, R. A., 340 Lohner, W., 109 Lohri, B., 368 Lohse, C., 162, 228 Lombardi, C. C., 250 Lombardi, P., 49, 50 Lombardino, J. G., 125 Longeray, R.,336 Longo, M., 90 Longone, D. T., 171,428, 466 Looker, J. H., 153, 353 Lopatik, D. V., 4 Lopatinskii, V. P., 189 Lopes, A., 289 Lopez, A., 29 Lbpez, F., 72 Lopez, L., 136 Lorch, E., 422 Lorne, R.,23 Losonczi, L., 357 Lotti, V. J., 445 Lotz, T. J., 423 Loubinoux, B., 368 Lovell, F. M., 363 Lown, E. M., 40 Lozach, N., 195 Lucci, R. D., 101, 175 Luche, M. J., 89 Luckner, M., 11 Luettke, W., 45 Luhowy, R.,131 Luk, K.,332 Lukacs, G., 122 Lunazzi, L., 122 Lupinacci, L., 445 Lur'e, E. P., 57 Lusby, W,R., 369 Luteijn, J. M., 342, 371 LUU-DUC, C., 85

Luzikov, Yu. N., 98 L'vova, S. D., 409 Lyakhovetsky, Yu. I., 75 Lye, E., 209 Lynaugh, N., 196 Lysenko, Z., 86 Lyster, M. A., 343, 462 Lyubinskaya, 0. V., 170 Lyuts, A. E., 133 Maas, G. E., 466 Mabry, T. J., 354 MacAlpine, G. A., 21 Macaluso, G., 239 McBrady, J. J., 326 McCabe, P. H.. 440 Maccagnani, G., 159, 228 McCall, J. M., 296 McCann, D. W., 432 McCapra, F., 60 Maccarone, E., 82 McCarthy, T. J., 11 McCausland, C. W., 433 McCleland, C. W., 194 Macco, A. A., 85, 94 McCoy, C. J., 11 McDonald, F. J., 343, 357 MacDonald, G. J., 65 MacDonald, M. A., 440 McDonald, W. S., 160, 203 Macdonell, G. D., 375, 478 McDonnell-Bushnell, L. P., 56 MacDowell, D. W. H., 350, 393 McEvoy, F. J., 85, 233 McFarlane, W., 483 McGahren, W. J., 363 McGlinchey, M. J., 477 McGuirk, P. R.,23 McHenry, W. E., 244 Machida, M., 237, 421 Macias, A., 29 McInnes, A. G., 366 McIntosh, J. M., 72 McKerley, B. J., 442 Mackie, R. K., 172 Mackiewicz, P., 456 McKillop, A., 147, 235, 358 McKinley, W. H., 253, 387 McKinnon, D. M., 113 MacKinnon, L. W., 451 MacLennan, A. H., 304 Macleod, J. K., 13 McMahon, E. H., 445 McManus, P., 100 McMechan, J. H., 353 McMurry, J. E., 20 McNab, H., 377, 398 McPherson, H. L., 175 McShane, L., 49 McWhinnie, W. R.,78 Madajova, V., 136 Madan, A., 106 Madan, K.,434

Author Index Maddox, M. L., 95,464 Mader, J. W., 353 Madrofiero, R., 86, 254 Madsen, J. O., 179 Maeda, K., 207 Maeda, M., 124,299,460 Maeda, T., 242, 272, 213 Maeda, Y.,42 Mirky, M., 224 Mafirand, J.-P., 106 Magachev, G. I., 292 Magagni, M., 122 Magalhaes, M. T., 360 Magar, J.-M., 71 Mager, S., 486 Maghraby, M. A.. 124 Magnus, P., 170 Magnusson, 0.. 79, 100, 103 Maguet, M., 131, 359 Mahafiey, R. L., 26 Mahajan, J. R., 374,427 Mahanti, M. K., 135 Mahapatra, S. K., 140 Mahjoub, A.. 464, 477 Mahmoud, A. M., 128 Maiorana, S., 64 Maire, J. C., 470 Mais, D. E.,94 Majchrzak, M., 310, 398, 477 Majchrzak, M. W., 206 Majeste, R. J., 441 Majoral, J. P., 234 Makarova, N. A., 442 Makhova, N. N., 41 Maki, Y., 112, 212, 321, 347, 408 Makino, S., 446 Makosza, M., 8 Makovetskii, V. P., 251 Malacria, M., 2 Malchow, A., 173 Maleki, N., 177, 285 Malesani, G., 189 Malherbe, R., 419 Malhotra, R. K., 381 Malina, Y. F., 474 Malloy, T. B. jun., 486 Malon, P., 441, 487 Maloney, D. E., 7, 352 Malpass, J. R., 444 Malrieu, J. P., 43 Maltesson, B., 76 Malykh, V. A., 17 Mamaev, V. P., 300 Mamedov, E. I., 69 Mamedova, A. Kh., 129 Mamo, A., 82 Manassen, J., 109 Mandai, T., 418 Mandel, G. S., 450 Mandel. N. S., 450 Mandolini, L., 427 Mandrugin, A. A., 126 Mangalam, G., 336,455

507 Manhas. M. S., 95, 106 Maniliho, F., 366 Manley, P. W., 47, 325, 410 Manly, T. D., 4 Mann, C. K., 446 Mann, J., 446 Manna, F., 250 Manning, W. B., 134, 135 Manolov, I., 28 Manuel, G., 193 Marcewicz, B., 123 Marchand, A. P., 444, 485 Marchelli, R., 189 Marchese, G., 136, 137 Marchetti, L., 208 Marchi, D. jun., 317 Marcinko, R. W., 443 Marculescu, B., 146 Marecek, J. F., 230, 252 MarCchal, G., 108 Mares, F., 283 Maresca, L. M., 5 Marfat, A., 23 Mariani, C., 430 Mariano, P. S., 262, 452 Marini-Bettolo, G. B., 372 Marino, J. P., 70 Marinone Albini, F., 78 Markham, K. R., 354 Markwell, R. E., 177 Maroni, P., 414, 472 Marquet, A., 89, 476 Marsh, F. D., 27 Marsh, M. M., 12 Marsh, W. C., 321 Marshall, D. R., 398 Marshall, G. P., 345 Marshall, 3. C., 246 Marshall, J. H., 195 Marshall, J. L., 218 Marsi, K. L., 375,478 Marson, S. A., 414 Martel, R. R., 145 Martelli, G., 73, 90, 99, 103 Martelli, J., 32, 202 Martelli, S., 206 Martens, C., 167, 234 Martin, A. R., 369, 388 Martin, D., 158, 241, 258 Martin, G. E.,369 Martin, G. J., 135 Martin, H.-D., 458 Martin, H. R., 367 Martin, J., 480 Martin, J. C.. 114, 210, 236 Martin, V. V., 205 Martinez de la Cuesta, P. J., 5 Martino, R., 29 Maruhashi, K., 320, 410 Maruoka, K., 426, 459 Maruta, M., 402 Maruyama, K., 22, 56, 237, 266, 383,414 Martvon, A,, 135, 158, 233

Martynova, V. P., 144 Masamune, T., 56 Masazumi, T., 399 Masci, B., 427 Mashimoto, Y..477 Mason, R. B., 192, 286 Mason, T. J., 1 Massa, S., 400 Masui, J., 336 Masui, M., 219 Masuko, T., 9 Masumura, M., 357 Mataka, S., 38, 209 Matern, E.,242 Mathey, F., 410 Mathieu, D., 201 Mathur, K. B. L., 361 Mathur, K. C., 245, 319 Matloubi, H., 160 Matskovskaya, E.S., 194 Matsuda, H., 346 Matsuda, M., 359 Matsuda, Y.,81, 319 Matsueda, R., 264 Matsugashita, S., 186 Matsugo, S., 188 Matsui, T., 433 Matsumoto, J.-I., 316 Matsumoto, K., 85, 217, 238, 242,243,261,275,297 Matsumoto, M., 2, 19, 418, 47 1 Matsumura, F., 336 Matsumura, N., 115 Matsunaga, M., 306 Matsuo, H., 95 Matsuoka, K.,78 Matsuoka, T., 250 Matsushita, Y.,314, 316 Matsuura. T., 31, 188, 207, 439 Matsuyama, Y.,115 Mattay, J., 194, 202 Mattioda, G., 74 Mattschei. P. K., 269, 422 Mattson, R. J., 181 Matusch, R., 103 Matveev, K. I., 189 Maurette, M. T., 29 Maury, G., 248 Mavunkal, J. B., 100, 134 Mayer, R.,163 Mazerolles, P., 193 Mazhar-ul-Haque, 441 Mazloumi, A., 104 Mazumdar, A. K. D., 99 Mazzanti, G., 159, 228 Mazzei, M., 346, 374 Mazzocchi, P. H., 56, 382, 445 Mazzu, A., 412 Mazzu, A. L., 126 Mcatee, J. L., 408 Meakins, G. D., 73

508 Medici, A., 122, 123, 138 Medne, R., 200 Medvedskaya, L. B., 218 Meffert, A., 405 Mehesfalvi, Z., 119 Mehrotra, K. N., 206 Mehta, A. C., 349 Mehta, C. K., 366 Mehta, G., 368 Mehta, K. J., 129 Meidar, D., 17 Meier, H., 25, 26, 142, 154, 155, 224, 226, 227, 228, 370 Meij, R., 163 Melent’eva, T. G., 89 Melhorn, A., 122 Melikyan, T. R., 174 Mellor, J. M., 443, 464 Mellor, M., 14 Melnikov, A. I., 194 Melnikov, N. N., 231 Mencarelli, P., 181 Menchen, S. M., 179 Meneghini, F., 131 Menger, F. M., 191, 444, 484 Menichi, G., 172 Menon, B., 430 Menozzi, G., 333 Mender, K., 260 Mentasti, E., 136 Mercer, F., 298 Merchant, J. R., 371 MerCnyi, R., 222, 417 Merier, F., 48 Merkle, U., 226 Merour, J. Y., 286 Meshcheryakova, L. M., 346, 354 Messager, J. C., 122 Mester, T., 351 Metcalfe, J. C., 466 Meth-Cohn, O., 81, 83, 148, 283,363 Metras, F., 336 Metternich, K., 96 Metysova, J., 365 Metz, B., 442 Metzger, J., 122, 125, 128, 136, 137, 177,361 Meunier, P., 90, 91 Mews, R., 55 Meyer, H., 144, 276, 478 Meyer, H. H., 333 Meyer, H. J., 412 Meyer, J. L., 126 Meyer, R. B. jun., 302 Meyer-Dayan, M., 353 Meyers, A. I., 126, 218, 265 Mezheritskaya, L. V., 194 Mezheritskii, V. V.. 176, 329 Mhatre, S., 172 Michalik, M., 120 Michel, G., 8 6

Author Index Micheloni, M., 422, 483 Michne, W. F., 445 Middleton, R., 263 Midthaug, T., 79 Migachev, G. I., 292 Migalina, Yu. V., 66, 108, 109 Mignot, A., 140 Migulla, H., 96 Mijngheer, R., 334 Mikhailov, G. D., 17 Mikhailova, N. V., 55 Mikhailova, T. S., 220 Mikhailyuk, A. N., 41 Mikhaleva, A. I., 92, 178 Mikhitarova, Z. A., 3 Mikhno, S. D., 89, 165 Miki, M., 429, 430 Mikitenko, E. K., 132 MikBik, F., 97 Miles, N. J., 223 Millar, R. W., 443 Miller, A., 101 Miller, A. L., 269 Miller, B. W., 443 Miller, F. M., 184 Mille, G., 126, 129, 130, 136, 470 Milligan, W. O., 408 Mills, J. L., 442 Milosavljevic, S., 472 Milstein, D., 24, 85 Minami, S.,316, 343 Minarni, T., 19, 50 Minamikawa, S., 56, 382 Minamoto, K., 452 Mineck, J. D., 193, 452 Minkin, V. I., 402, 481 Mino, N., 197 Minoli, G., 307 Minov, V. M., 409 Minster, D. K., 126 Miocque, M., 140 Miquel, M., 106 Mirbach, M. F., 54, 459 Mirbach, M. J., 54, 63, 459 Miranov, A, F., 244 Mironov, V. F., 74 Mirrington, R. N., 359 Mirskova, A. N., 197 Misiti, D., 356 Misiuna, D., 123 Mislow, K., 63 Mistr, A., 135 Misumi, S., 437 Mito, K., 352 Mitra, R. B., 226 Mitscher, L. A., 350 Mitschker, A., 91 Mitsudo, T., 283 Mittra, A. S., 119 Miura, I., 217 Miwa, Y., 86 Miyadera, T., 97, 255

Miyagi, S., 175 Miyagi, Y., 56 Miyagishi, A., 92 Miyahara, Y., 69 MiyEkawa, K., 222, 325 Miyaki, A,, 358 Miyakoshi, T., 334 Miyamoto, R., 21, 170 Miyamoto, T., 316 Miyano, S., 236, 244, 282 Miyasaka, T., 146 Miyashi, T., 42, 253 Miyashita, M., 169 Miyata, N., 14 Miyazaki, R., 128 Miyazaki, Y., 332 Miyazima, T., 246 Miyoshi, F., 11 Miyoshi, M., 217, 261, 297 Mizrakh, L. I., 128 Mizugaki, M., 299 Mizuno, K., 173,461 Mizuno, M., 166, 200 Mizuno, T., 165 Mizutaki, S., 133 Mkrtchyan, A. P., 71 Mkrtchyan, R. S., 174 Mo, O., 29, 469 Mochalova, 0. A., 354 Mochida, K., 369 Modena, G., 9 , 4 3 0 Moegel, L., 414 Mohrle, H., 238 Monnighoff, H., 103 Moesinger, O., 155, 156, 158 Moldaver, B. L., 204 Moldovan, Z., 135 Molhant, N., 474 Molho, D., 345, 353, 356 Molina, P., 340 Moller, F., 191 Mollier, Y., 242 Molyneux, R. J., 175 Momose, T., 444, 451, 455, 485 Mondelli, R., 93 Mondeshka, D., 5 Monforte, P., 129 Monta, H., 24 Montanari, P., 349 Montaudon, E., 330 Monteiro, M. B., 374 Montevecchi, P. C., 100 Moore, D. W., 455 Moore, H. W., 48, 298 Moore, J. A., 52 Moracci, F. M., 277 Moran, D. B., 85 Moreau, B., 89 Moreau, P., 434 Morel, J., 87, 93, 98, 272 Moreno, E., 487 Moretti, C., 354 Moretti, I., 43, 44

509

Author Index Morga, G., 330 Mori, J., 364 Mod, K., 312, 314 Mori, Y.. 369 Morimoto, Y., 95 Morin, F. G., 473 Morita, N., 255, 354 Morita, Y., 271,452 Moriya, T., 85 Morkovnik, A. S., 202 Morquez, R., 487 Morosawa, S., 152, 380 Mosbo, J. A., 479 Moskowitz, H., 140 Moss, R. A., 42 Mossman, A. B., 343,462 Mosti, L., 333 Mostowin, D., 43 Motoki, S., 112, 340 Motscall, A., 308 Moulines, J., 484 Mouzin, G., 19 Movshovich, D. Ya., 135 Movsumzade, M. M., 39 Mpango, G. M., 184 Mross, W. D., 1 Mubarik, A. S., 1 3 Muchowski, J. M., 95, 154, 226,464 Muehlstaedt, M., 128, 414, 471,477 Muhmel, G., 422 Mueller, C., 41 Mueller, K. D., 206 Muller, T., 167, 234, 328 Muench, P., 1 Mues, R., 354 Mukai, C., 365 Mukai, H., 164, 231, 328 Mukai, T., 21, 42, 170, 253, 379,406 Mukaiyama, T., 11, 131, 138, 219,266,334 Mukerjee, A. K., 45, 88 Mukhopadhyay, K. K., 406 Mukmenev, E. T., 470 Mullane, M., 232 Mullen, G. B., 446 Muller, J.-F., 71 Mullica, D. F., 408 Mullins, M. J., 412 Muminov, A., 185 Munakata, T., 95 Munch, W. F., 445 Mundell, T. C., 478 Mundy, B. P., 441 Muniem, M. A., 142 Murahashi, S., 175 Murai, A., 56 Murai, S., 446 Murakoshi, N., 212 Muraoka, K.,208, 250 Muraoka, M., 127 Murata, I., 392, 393

Murata, T., 308 Murature, D. A., 34, 214 Murphy, P. T., 364 Murphy, W. S., 451 Murrer, B. A., 185 Murray, R. D. H., 330, 360 Murray, R. K., 461 Mursakulov, I. G., 472 Musavirov, R. S., 472 Musgrave, W. K. C., 73 Musker, W. K., 241, 263, 414 Muslimov, S. A., 188 Musorin, G. K., 88 Musumarra, G., 448 Muszyhski, E., 87 Mutai, K., 370, 406 Murthy, K., 381 Myers, R. S., 12 Myerson, J., 16 Nabeya, S., 208 Nader, B. S., 322 Nadkarni, D. R., 363 Nafissi-V, M. M., 31 Nagakura, S., 136 Nagamatsu, E., 255 Nagamatsu, T., 248, 320 Nagano, M., 97 Nagar, A., 352 Nagarajan, K.,130, 487 Nagarajan, S., 109 Nagasaka, T., 303 Nagase, K.,458 Nagase, R., 219 Nagase, S., 169 Nagata, M., 51 Nagata, S., 14 Nagata, W., 26, 97, 139 Nagler, M. J., 369 Nagy, A., 475 Naidoo, B., 188 Nair, M. D., 130 Nair, V., 34 Nakada, A., 188 Nakadaira, Y., 66, 410 Nakagaki, R., 136 Nakagawa, M., 439 Nakajima, A., 95 Nakajima, K., 27 Nakajima, M., 206 Nakajo, T., 42 Nakamura, J., 136 Nakamura, I., 27 Nakamura, Y., 22, 37, 271, 390,452 Nakane, M., 331 Nakanishi, K.,243 Nakanishi, Y., 241 Nakano, J., 366 Nakao, M., 236 Nakashita, Y., 347 Nakasuji, K., 392 Nakata, A., 166 Nakata, Y., 300

Nakaue, K.,380 Nakayama, A., 164, 200, 231, 328 Nakayama, J., 197, 200 Nakayama, M., 357 Nakayama, N., 197 Nakazumi, H., 349, 350 Nakhmanovich, A. S., 92 Nalimova, Y. A,, ?34 Nametkin, N. S., 46 Namiki, M., 179 Namy, J. L., 22 Nanasawa, M., 137 Nanninga, D., 234 Napier, J. J., 178 Narasaka, K., 266 Narasimhamurthy, M. R., 487 Narayanan, V., 361 Nardi, D., 405 Narine, B., 81, 283 Narisada, M., 97, 139 Narita, K.,364 Narong, S. C., 267 Narula, S. S., 150 Naruta, Y., 56 Naruto, S.,255 Naso, F., 136, 137 Natalini, B., 393 Nath, T. G. S., 140 Natsume, S., 97 Naulet, M., 135 Naumann, A., 417 Naumov, V. A,, 442 Navech, J., 234,480 Nawojski, A., 377 Nayak, A,, 269, 270, 303, 422,429 Nazer, M. Z.. 209 Ncube, S., 19, 199 Neckers, D. C., 99, 192, 381 Nedjar, B., 336 Neelakantan, S., 361 Negrebetskii, V. V., 231 Neidl, C., 60 Neidlein, R., 98, 99, 102, 161, 191, 216, 337 200 Neilands, 0.. Neilson, D. G., 217 Nelsen, S. F., 440, 441, 442, 443,469,487 Nelson, C. R., 471 Nelson, P. H., 95 Nelson, S. F., 53 Nemes, A., 123 Nemeth, L., 346, 349 Nemo, T. E., 12 Nesener, E., 156 Nesterenko. R. N., 92 Netchitailo, P., 98 Neubauer, F., 25, 217 Neugebauer, F. A., 459 Neumeyer, J. L., 17 Neunhoeffer, H., 257,287 Newall, C. E., 160

Author Index

510 Newcombe, P. J., 76 Newkome, G. R., 260,269, 270, 303,422,429,438 Newman, P., 354 Newton, M. G., 480 Newton, R. F., 437, 466 Neynaber, C. B., 251 Ng, S., 444 Nguyen Dinh An, 193 Nicoletti, R., 183 Nie, P. L., 339 Nieberl, S., 63 Niedenzu, K.,206 Nielsen, A. T., 455 Nielsen, C. J., 166 Nielsen, J. U. R., 486 Nielsen, K. E., 106 Nielsen, 0. J.. 154, 166, 228 Niemann, G. J., 330 Nifant’ev, E. E., 479, 480 Nigmatullina, R. F., 340 Niizuma, S., 464 Nikiforova, N. A., 472 Nikitin, N. R., 194 Nikitin, V. M., 480 Nikitin, V. S., 231 Nikolaeva, V. M., 98 Nilsson, B., 475 Nimdeoka, N. M., 164 Ninigawa, A., 346 Nisbet, J. D., 443 Nishida, H., 190 Nishigaki, S., 143, 154, 251, 308,310, 312, 313, 320 Nishikawa, M., 266 Nishikawa, Y., 365 Nishimine, H., 95 Nishimura, M., 242, 272 Nishinaga, T., 369 Nishino, K., 392, 393 Nishio, T., 55, 134, 250, 301 Nishiwaki, N., 386 Nishiwaki, T., 253 Nishiyama, T., 165 Nishizawa, H., 78, 463 Nishizawa, M., 459 Nishizawa, Y.,253 Nitta, Y., 316, 320 Nivorozhkin, L. E., 481 Nobs, F., 36 Noda, K., 477 Noda, M., 320 Noe, C. R., 103 Noerskov, L., 486 Nogradi, M., 356, 482 Noguchi, M., 320 Noguchi, S., 74 Noguchi, Y., 128, 266 Nohara, A., 347 Nomoto, T., 384, 457 Nomura, T., 354, 356, 372 Nomura, Y., 444 Noravyan, A. S., 71

Norden, B., 73 Norin, T., 209 Noris, C. P., 125 Normant, J. F., 22 Norris, R. K.,76 Norris, T., 222 Nossin, P. M. M., 85 Notheisz, F., 58 Noto, R., 76, 81 Nour-el-Din, A. M., 28, 190, 240 Novellino, E., 131 Novi, M., 76 Novikov, S. S., 41 Novikova, N. K.,55 Novikova-Aleksandrova, L. K.,13 Novitskaya, N. N., 89 Nowada, K., 22, 390 Nowell, I. W., 430 Noyori, R., 22, 23, 440, 446, 459 Nozaki, H.. 426, 459 Nunami, K.-I., 85, 217, 261 Numao, N., 289 Nusse, B. J., 461 Nyburg, S. C., 38, 196 Nye, M. J., 240 Nyitrai, J., 153, 207 Oae, S., 24, 257 Obara, H., 352 Obergrusberger, R., 243 Oberhaensli, W. E., 414 Obermeier, G., 355 Oberti, R., 392 Oberwinkler, F., 373 O’Brien, D. E., 117 Ochi, M., 78 O’Connell, G., 459 Oda, K., 237 Oda, M., 255 Oda, R., 13 Oda, Y., 23 O’Donnell, D. J., 484 Oehlschlager, A. C., 32 Oehme, H., 478 Oertle, K.,418 Oeser, H. G., 208, 307, 403 Oesterdahl, B. G., 354 Offermanns, H., 96 Ogan, M. D., 455 Ogawa, S., 302 Ogino, C., 330 Ogino, K.,58, 187 Ogiwara, K., 320 Ogretir, C., 448 Ohashi, M., 172, 197 Ohashi, T., 11 Ohi, T., 71 Ohishi, J., 40, 88, 464 Ohki, S., 303 Ohl, J., 324 Ohloff, G., 93, 345

Ohmichi, H., 334 Ohmori, H., 219 Ohno, K.,399 Ohno, S., 364 Ohsawa, A., 28, 240, 245, 274,293 Ohshiro, Y., 87 Ohta, A., 306 Ohta, H., 11 Ohta, T., 181 Ohtani, M., 139 Ohtsuka, Y., 296 Ohwada, T., 306 Ojima, N., 343 Oka, K.,65, 68, 115, 381 Okada, H., 173,461 Okada, J., 86 Okada, K., 191 Okada, T., 139, 177 Okahara, M., 429, 430 Okajima, H., 388, 412 Okamoto, T., 14, 181, 239, 267,411,445,457 Okawa, K., 27 Okawara, M., 136, 200 Okawara, T., 128, 266 Okay, G., 392 Okazaki, H., 230, 252 Okazaki, R., 163, 196, 215, 230 Okhlobystin, 0. Yu., 202 Oki, M., 95 Okorodudu, A. 0. M., 428 Okuda, T., 122, 143, 457 Okumoto, H., 137 Okutama, T., 354 Olah, G. A., 17, 267 Olenovich, N. L., 353 Olesen, S. O., 179 Olesker, A., 122 Oliva, L., 131, 327 OlivC, J. L., 97, 100 Oliver, J. E., 369 Oliver, R. S., 332 Oliveros, E., 43 Olliero, D., 482 Ollis, W. D., 159, 218, 243, 350, 358, 360, 373, 388, 419,457,482 Ollison, M. W., 63 Olofson, R. A., 211 Olovyanishnikova, Z. A., 224 Olsen, H., 459 Olsen, R. A., 103 Oluwadiya, J. O., 350 Omoto, S., 350 Omote, Y., 55, 134, 250, 300, 301 Ondetti, M. A., 97 Ondrus, T. A., 277 O’Neal, H. E., 60 Ong, H. H., 96,445 Ono, F., 345 Ono, M., 56

Author Index Ono, T., 246 Onodera, J., 352 Onogi, K., 394, 395 Onoue, H., 97, 139 Onuska, F. I., 477 Oparin, D. A., 89 Opgenorth, H. J., 134 Oppenheim, C., 282 Oppenhuizen, M., 216 Oppolzer, W.,440, 449 Oprean, I., 135 Orahovats, A,, 46 Oremek, G., 100 Oribe, T., 347 Orlova, E. K.,346, 354 Orphanides, G. G., 83, 172 Orr, A. F., 390 Ors, J. A., 426 Ortmann, W., 136 Osawa, Y.,172 Osborn, R., 220 Oshiro, Y., 41 Osipenko, I. L., 4 Osipov, 0. A., 135 Osman, A., 132 Osman, A. G., 226 Osman, A. M., 48, 124 Osman, F. H., 242 Osman, R., 29 Osteryoung, R. A., 304 Osuchowska, E., 232 Osuka, A., 22 O’Sullivan, D.. 100 Otake, N., 332, 336 Otani, T. T., 97 Otemaa, J., 303, 429 Oth, J. F. M., 426, 458 Otsubo, T., 437 Otsuji, Y.,115, 173, 461 Otsuka, S., 11 Otsuka, Y., 160 Otsuki, T., 56 Ott, R., 186 Ottersen, T., 209 Ottlinger, R., 121, 165, 166, 217,231 Otto, H.-H., 260, 381 Outred, D. J., 359 Ovcharova, I. M., 145, 384, 386 Ovchinnikov, V. V., 479 Overbeek, A. R., 163 Overheu, W.,379 Overton, K. H.,354. Owens, T. A., 38, 65 Ozaki, T., 99 Ozawa, N., 303 Ozdowska, Z., 129 Pachaly, P., 236 Pacheco, H.,335, 484 Paddon-Row, M. N., 4 Padmanaban, N., 361 Padmanabhan, S., 73

511 Padwa, A., 32, 34, 35, 36, 180, 186,232, 258,412 Page, M. I., 50 Pagni, R. M., 459 Pahor, N. B., 464 Pailler, J., 304 Palazzo, G., 168 Paleeva, 1. E., 77 Paleta, O., 56 Palibroda, N., 135 Pallicino, S., 412 Palmer, D. C., 291 Palmer, M. H., 75, 113,443 Palmer, R. J., 21 Paluchowska, M., 481 Palyulin, V. A., 441, 443 Pan, Y., 262 Pande, R., 74, 86 Pandit, U. K.,237, 294, 382 Panfil, I., 212 Panichpol, K.,354 Pankiewicz, J., 93 Pankow, L. M., 31 Pantaleo, N. S., 480 Panunzi, A., 461 Paoletti, P., 422, 483 Paolillo, L., 461 Papadopoulos, E. P., 137 Papanastassiou, Z. B., 349 Papazova, P., 97 Pappalardo, G. C., 74 Pappalardo, S., 466 Paquette, L. A,, 440, 452 Paramasivam, K.,292 Paranjpe, M. G., 164 Parfitt, R. T., 196 Parikh, A. R., 129 Parish, W. W., 433 Park, B. K.,203 Park, M.-G. A., 222 Park, S. W.,147 Park, Y.H., 350 Parkanyi, C., 177 Parker, K. A., 174, 460 Parmar, S. S., 128 Parnes, Z. N., 75 Paronikyan, E. G., 171 Parrish, D. R., 72 Parsons, I. W., 72 Parthasarathy, M. R., 354 Passerini, N., 346 Pasternak, V. I., 54 Pastour, P., 86, 87, 93, 98, 452 Pasutto, F. M., 277 Patchett, A. A., 238, 445 Patel, P. B., 129 Patel, R. C., 474, 475, 488 Patel, V., 430 Pathak, V. N., 119 Patney, H. K.,4 Patolia, R. J., 365 Paton, D., 116 Patonay. T., 351

Patra, M., 140 Patrick, J. E., 96 Patrick, T. B., 365 Pattenden, G., 343 Patterson, R. B., 153 Paudler, W. W., 244 Paugam, J. P., 248 Paugam, R., 248 Paul, D., 381 Paul, H., 96 Paul, I. C., 114 Paulmier, C., 74, 104 Pauson, P. L., 392 Pavlik, J. W.,378 Pavlova, L. A., 89 Payer, W., 282 Payne, A., 222 Payne, D. A., 464 Pays, M., 135 Pazhenchevsky, B., 238 Peach, J. M., 188 Peacock, S. C., 436,466 Peacock, V. E., 53, 442, 469 Peake, S. L., 6 Pearl, J., 96, 445 Pearlman, R., 275 Pearson, R. L., 267 Pease, L. G., 425 Pedaja, P., 77 Pederson, C. L., 162, 228 Pedersen, E. B., 106,266 Pedersen, P. B., 73 Pedley, J. B., 448 Pedulli, G. F., 73 Peet, N. P., 219 Peeters, H., 181, 466 Pehk, T., 444 Pelizzetti, E., 136 Pel’kis, P. S., 158, 196 Pelletier, W. T., 80 Pellicciari, R., 393 Pelter, A., 19, 199, 352, 356, 357 Penn, R. E., 38,65 Pennings, M. L. M., 94 Pkra, M.-H., 85 Perchenko, V. N., 46 Pereslini. E. M., 130 Perez, J. D., 34, 214 Pergal, M. A., 131 Perie, J., 336 Perinis, M., 191, 444, 484 Perkinson, N. A., 363 Perozzi, E. F., 210 Perregaard, J., 412 Perri, P., 17 Perrin, C. L., 59 Perrot, R., 211 Perry, M., 472 Perry, R. A., 430, 457 Pesce, G., 136 Pestunovich, V. A., 197, 444, 480 Pestunovich, V. V., 66

512 Peters, E. N., 24, 120 Peters, J. A., 485 Petersen, H., 155, 228 Pettersson, K., 81 Peters-Van Cranenburgh, P. E. J., 485 Petit, G., 477 Petric, A., 145 Petrov, A. A., 69, 220 Petrov, K. A., 375 Petrov, M. L., 69 Petrova, I. M., 250 Petrova, L. M., 487 Petrovic, R., 472 Petruczenko, A., 87 Petrus, C., 212 Petrus, F., 212 Petruso, S., 93 Petrzilka, M., 418, 449 Pettett, M., 373 Pezzanite, J. O., 361 Pfeiffer, W. D.. 127 Pfister, J. R., 365, 446 Pfister-Guillouzo, G., 97, 113, 129, 135 Pfleiderer, W., 257 Pfund, R. A., 461 Pham, H. P., 357 Pham Dac Thong, 120 Phan Tan Luu, R., 201 Phares, H. F., 110 Phatak, M. V., 377 Philipp, A. H., 145 Philipsborn, W., 130 Phillips, L., 97 Phillipps, G. H., 160 Philpot, P. D., 168 Phipps, J. R., 214 Picard, P., 484 Picavet, J. P., 425 Pickenhagen, W., 345 Piepers, O., 270 Pierre, J. L., 31 Pierson, A. K., 96, 445 Pietra, F., 208 Pietrasanta, F., 16 Pietrogrande, A., 189 Pietsch, H., 48 Piette, J.-L., 78, 116 Piggin, C. M., 93 Pigulla, J., 253, 383 Pihlaja, K., 471 Pike, M., 252 Pike, R., 362 Pike, R. K., 450 Ping-Lin, K., 429 Pino, O., 372 Pinter, E., 186 Piotrowska, H., 472 Piper, E. A., 444 Pirazzini, G., 82 Piriou, F., 470 Pirkle, W. H., 8, 43 Piskunova, I. P., 225

Author Index Pitacco, G., 323 Pitner, T. P., 470 Pitt, C. G., 371 Pivovarevich, L. P., 90 Plat, M. M., 282 Platonova, N. A., 138 Platz, M. J., 459 Plazzi, P. V., 115 Plenat, F., 16 Plenkiewicz, J., 232 Plescia, S., 93 Plinke, G., 426 Plomp, R., 87 Pluecken, U., 142 Plugina, R. I., 119 PluSEec, J., 87 Pocar, D., 205 Pocker, Y., 14 Poels, E. K., 88 Pohjala, E., 243 Pohl, U., 145 Pokorny, M., 128 Polanc, S., 204 Poleschner, H., 136 Poliakoff, M., 162, 228 Politzer, P., 14 Pollard, M. D., 160, 203 Pollicino, S., 482 Polonskaya, L. Yu.,128 Polyakov, V. K.,90 Pomykacek, J., 365, 393 Ponder, B. W., 175 Ponec, R., 42 Ponkratov, V. A., 258 Ponomareva, T. K., 147 Ponsinet, G., 147 Ponticelli, F., 213 Ponticello, G. S., 192, 260, 452 Ponzi, D. R., 49 Poonia, N. S., 337 Pop, R. D., 122 Poplavskii, A. N., 292 Popli, S. P., 360 Popov-Pergal, K. M., 131 Popova, N. V., 213 Porter, L. J., 350 Porter, N. A., 463 Porter, Q. N., 99, 191 Possanza, G. J., 374 Posselt, K., 96 Potekhin, A. A., 168, 475, 478 Potekhin, K. A., 441 Potts, K. T., 104, 140, 146, 151, 168, 218, 246, 452 Poulton, G. A., 335 Pouzard, G., 122 Povey, D. C., 483 Powell, D. W., 341, 416 Prabhakar, S., 292 Pradere, J. P., 476 Praefcke, K., 109, 209, 210, 376

Prakash, C., 360, 361, 362 Prakash, D., 360 Prasad, R. S., 353, 358 Prashad, M., 358 Preiss,-M., 161 Preston, P. N., 147 Preti, C., 402 Price, C., 253, 387 Price, M. E., 60 Priewska, B., 477 Priklonskikh, G. I., 147 Prinzbach, H., 416 Prischl, G., 399 Probert, M. K. S., 368 Proctor, G., 237, 386 Proctor, G. R., 155, 382 Prokopovich, I. P., 4 Promel, R., 299, 460 Prostakov, N. S., 258 Prota, G., 131, 327 Protiva, 97, 365, 393 Prout, K., 441 Puar, M. S., 383, 401, 481 Pruchkin, D. V., 335 Puckett, R. T., 487 Pudovik, A. N., 55, 479 Pugh, H., 330 Pujari, H. K., 140, 141, 146, 149 Pulcrano, M. S., 207 Pullin, C. J., 291 Purao, S. R., 119 Purvis, R., 377 Putt, R. S., 398 Puttfarcken, U., 47 Pyne, G. S., 483 Pyschev, A. I., 335, 337 Pyykko, P., 470 Quarroz, D., 444 QuCguiner, G., 272, 452 Quin, L. D., 478 Quinteiro, M., 257, 332, 440 Qureshi, A. W., 41 Raab, A. W., 260 Raasch, M. S., 233, 349, 463 Rabanal, R., 122 Rabek, J. F., 63 Rabinovich, D., 109, 463 Rachlin, H., 445 Rackur, G., 370 Radeglia, R., 136 Rademacher, P., 45, 181, 215, 466 Radford, T., 356 Radlick, P. C., 464 Radom, L., 13 Radyukin, Yu.N., 98 Radzikowska, T. A., 269 Rae, I. D., 212, 241, 456 Raether, W., 96 Rafferty, P., 214, 317 Rahimi-Rastgoo, S., 250, 475

Author Index Rai, M., 48 Raj, K., 360 Raja, T. K., 109 Rajappa, S., 71, 111, 119, 121, 304 Rajee, R., 63 RajSner, M., 97, 365 Raju, M. S., 351 Rakhmankulov, D. L., 472 Rakosi, M., 351 Ralhan, N. K., 152 Rall, G. J. H., 235, 358 Ram, V. J., 106 Rama, N. H., 362 Ramadas, S. R., 73 Ramage, E. M., 255, 401 Ramakrishnasubramanian, S., 292 Ramakumar, S., 441, 487 Ramalingarn, K., 340,484 Ramamurthy, V., 54, 63, 412, 459 Raman, K. P., 451 Rarnan, P. V., 361 Rama Sastry, B. V., 97 Ramasseul, R., 45 Rarnaswami, S. K., 451 Ramazanov, E. L., 472 Rambaldi, M.,285 Ramirez, F., 230, 252 Ramos, S. M., 73 Ramsden, C. A., 110, 159, 168,218,339 Ramsh, S. M., 130 Ramundo, E., 133 Ranby, Ed. B., 63 Randaccio, L., 464 Ranganathan, K. R.,354 Rani, N., 330, 361 Rao, C. J., 381 Rao, K. R., 247 Rao, N. V. S., 351, 371 Rao, R. P., 166 Rao, S., 119 Rapoport, H., 450 Rapp, U., 405 Rappe, J.-L., 85 Rasheed, K.. 199 Rashid, M., 441 Rashkes, Ya. V., 135 Rasmussen, C. A. H., 299 Rassat, A., 45, 445, 488 Rastetter, W. H., 4, 389, 442, 452 Rastogi, M. K., 346, 356 Rastogi, P. P., 135 Rastogi, R. R., 261 Rastogi, V. K., 128 Raston, C. L., 391 Rauleder, G., 3 Rault, S., 92, 107 Rausch, M. D., 77 Ravelo, A. G., 372 Rawlins, M. F., 443, 464

513 Rawson, D. I., 446 Ray, A., 358 Ray, M. R., 158 Ray, R., 189 Ray, S., 358 Razaq, S., 356 Razdan, R. K., 349, 370 Razumov, A. I., 188 Read, D. M., 474 Reader, G., 113 Reames, D. C., 18 Re Cellerino, M. R., 78 Reddy, G. S., 245 Reddy, K. K., 245 Reddy. Y. P., 245 Reden, J., 445 Redman, B. T., 358, 360, 373 Redolfi, P., 354 Redshaw, M., 113 Reeder, E., 402 Reedijk, J., 308 Rees, A. H., 179 Rees, C. W., 162, 229, 328 Reeve, W., 128 Reeves, D. L. R., 47, 410 Regitz, M., 51 Reich, H. J., 6, 193 Reich, I. L., 193 Reich, M. F., 445 Reichen, W., 54, 204 Reid, D. H., 155, 242 Reid, S. T., 411 Reid, W., 134, 147, 155, 156, 158 Reiffen, M., 184 Reinehr, D., 420 Reinehr, U., 189 Reingold, I. D., 466 Reinhardt, K., 442 Reinhoudt, D. N., 80, 113, 236, 392 Reinshagen, H., 179, 420 Reisdorf, D., 147 Reisman, D., 463 Reisner, G. M., 442 Reissig, H. U., 201 Reiter, F., 105, 111, 116, 224 Remmers, G., 165, 242 Rerny, D. E., 193, 452 Renard, G., 16 Renga, J. M., 341, 412, 416 Reneger, B., 53, 233, 322 Renson, M., 78, 108, 116 Reshetova, I. G., 15 Rettig, S. J., 234 Reuschling, D., 48 Revel, M., 234 Rey, M., 457 Rey Boero, J. F., 481 Reynolds, G. A., 337, 340, 346 Reynolds, R. D., 251 Rezende, M. C., 339 Rhee, R. P., 347

Ricci, A., 82, 393 Ricci, J. S. jun., 252 Rice, K. C., 118, 445 Rice, T. K., 100 Richard, T. J., 4, 389, 442, 452 Richards, R. C., 196 Richardson, W. H., 60 Richer, J. C., 135 Richman, J. E., 424 Richter, R., 204 Rickards, R. W., 342 Riddell, F. G., 444, 475 Ried, W., 64, 100, 341, 402 Rieder, W., 476, 487 Rieker, A., 176, 391 Riernann, U., 165, 242 Riganti, V., 203 Rigaudy, J., 235, 463 Righetti, P. P., 203 Rimbault, C. G., 61, 63, 463 Rimmelin, J., 460 Rimmelin, P., 460 Rinaldi, P. L., 8, 43 Rinus, O., 260 Riou, C., 138 Risalite, A., 349 Risinger, G. E., 142 Rivera, H. V., 416 Rivett, D. E., 253, 400 Riviere, M., 43 Riviere, P., 23, 55 Riviere-Baudet, M., 55 Rivoirard, E. M., 31 Rizvi, S. Q. A., 276, 447 Roach, B. L., 412 Robba, M., 92, 107 Robbe, Y., 130 Roberge, G., 346 Robert, A., 24, 25, 121, 210 Robert, F., 136 Robert, J. B., 480, 481, 482 Roberts, D. K., 434 Roberts, J. D., 159, 162, 472 Roberts, N. K.,10 Roberts, R. J., 360 Roberts, S. M., 13 Roberts, T. G., 323 Robillard, J., 138 Robins, R. K., 117 Robinson, B., 190 Robinson, F. M., 445 Robinson, H. J., 110 Roc, M., 106 Rocheville-Divorne, C., 144 Roder, E., 383 Rodighiero, G., 189 Rodina, L. L., 226 Rodinova, L. S., 69 Rodrigues, J. A. R., 317 Rodriguez, A., 462 Roder, E., 253 Roelants, F., 28, 221

Author Index

5 14 Roesky, H. W., 55, 165, 167, 234, 242 Roets, E., 48 Roettele, H., 419 Rogers, A. J., 448 Rogers, M. E., 142 Rogers, N. H., 332 Rogers, R. Z., 14 Roggero, J. P., 129, 144 Rokach, J., 113, 268 Roland, D. M., 386 Roma, G., 346, 374 Roman, D. P., 116 Romanchick, W. A., 168, 257 Romani, S., 221 Romanov, N. N., 144 Rommel, E., 459 Ronald, B. P., 14 Ronsisvalle, G., 107, 118 Rooks, W. H., 95, 365 Rosen, P., 426 Rosenberg, H. E., 185 Rosenblatt, D. H., 440 Rosenbrook, W., 369 Rosenfeld, S. M., 11, 73 Rosenman, K., 110 Rosenthal, S., 148 Rosenthal, U., 148 Rosini, G., 138 Ross, A. W., 14 Ross, J. W., 359 Rossiter, B. E., 432 Roszkowski, A. P., 95 Rotar, 0. V., 189 Rotem, M., 66 Roth, B., 80, 362 Roth, H. J., 298 Rouillard, M., 29 Rousseau, G., 62 Roux, D. G., 330, 350,372 Rovnyak, G. C., 149 Rowell, P. P., 97 Rowlands, G., 159, 218 Royer, D., 245 Rozhkova, N. K., 135 Rozwadowska, M. D., 250 Rubin, M. B., 461 Rubinova, N. R., 239 Rubinshtein, E. M., 251 Ruccia, M., 225, 239, 240, 247 Rudi, A., 444 Rudnicki, A., 409 Rudzit, E. A., 92 Ruehlmann, K., 161, 235 Ruenitz, P. C., 444, 486 Rund, J. V., 139 Ruotsalainen, H., 56 Rusakov, 1. A., 334 Rus Martinez, E., 5 Russo, F., 159, 160 Rutledge, P. S., 419 Ruxer, J.-M., 414, 482 Ryabukhin, Yu. I., 217

Ryan, C. J., 69 Ryan, S. B., 142 Rybakova, L. F., 77 Rybenko, L. A., 189, 190 Rybertt, J., 346 Rycroft, D. S., 354 Rynbrandt, R. H., 114 Saadein, M. R., 285 Saba, S., 488 Sabatini, A., 422 Sabongi, G. J., 250,447,448 Sachdeva, M. L., 140, 149 Sachdeva, Y. P., 353 Sadeghi-Milani, S., 229 Sadykhzade, S. I., 13 Saegusa, T., 184, 406, 414 Saednya, A., 87 Saelens, J. K., 445 Safaryan, A. A., 74 Safina, Z. Sh., 442 Safonova, 0. A., 90 Safronova, Z. V., 187 Sagitdinov, 1. A., 73 Sagitullin, R. S., 185, 267 Saidi, K., 58 Saigo, K., 11 Saijo, T., 347 Saikachi, H., 92 Saini, H. R., 330 Sainsbury, M., 189, 257, 330 St-Jacques, M., 409, 481 Saint-Ruf, G., 368 Saito, I., 188, 439 Saito, K., 89, 287, 334, 380 Saito, T., 112, 312 Sakaguchi, T., 202, 208 Sakai, T., 169 Sakaino, Y., 207 Sakakibara, T., 188, 344 Sakamoto, T., 287, 288, 298, 299, 302 Sakamoto, Y., 202 Sakanishi, K., 62 Sakasai, T., 298 Sako, M., 112 Sakuma, H., 191 Sakuma, Y., 314,315, 316 Sakurai, H., 66, 410 Sakurai, T., 34,483 Sala, T., 409 Salbeck, G., 106 Saldabol, N. O., 141 Saldabols, N., 125 Salem, M. A., 18 Salemink, C. A., 371 Salisbury, K., 176 Salornon, M. F., 463 Salomon, R. G., 443, 462, 463 Salmona, G., 113, 135 Samaan, S., 479 Samarina, L. A., 178 Samat, A., 136, 138

Samitov, Yu. Yu., 472 Sammes, P. G., 39, 299 Sammour, A., 239 Samoletov, M. M., 143 Samson, M. G., 485 Samsonova, T. I., 17 Samsonov, V. A., 208 Sancassan, F., 76 Sanchez, M., 242,443 Sander, E. G., 257 Sandman, D. J., 340 Sandri, E., 412,482 Sanford, T. J., 223 Sanjoh, H., 462 Sankawa, U., 19 Sannicolo, F., 168, 184 Sanno, Y., 347 Sano, T., 378 Santagati, A., 159, 160 Santagati, M., 159, 160 Santelli, M., 24 Santiago, C., 178 Santos, A., 14 Santoro, E., 472 Sanz e Carreras, F., 43 Saprykina, V. A., 135 Sarel, S., 417 Sargent, M. V., 409 Sarkhel, B. N., 363 Sarlin, R., 204, 246 Sarnowski, R., 20 Sarodnick, G., 101, 119 Saroli, A., 335 Sarpotdar, A., 56 Sartori, G., 342 Sas, W., 472 Sasaki, H., 92 Sasaki, I., 371 Sasaki, T., 452, 457, 464 Sasaki, Y., 487 Sasakura, K., 184 Sasaoka, M., 91 Sashida, H., 278 Sasse, K., 304 Sasse, M. J., 222 Sasson, Y., 27 Satgk, J., 23, 55 Sato, E., 49, 92 Sato, J., 143, 310 Sato, K., 358 Sato, M., 180, 200, 335, 366 Sato, N., 305 Sato, R., 216, 359 Sato, S., 56, 156 Sato, T., 19, 89, 459 Satoh, F., 48 Satsangi, R. K., 159 Satti, A. M., 21 Sattur, P. B., 247 Satyamurthy, N., 340 Satzinger, G., 129 Saucy, G., 343 Sauer, J. D., 269, 422, 458 Sauer, W., 150

Author Index Saunders, H. J., 144 Saunders, H. L., 92 Saunders, K. D., 267 Sauriol-Lord, F., 409,481 Saus, A., 464 Sauter, F., 107 Savel’ev, V. L., 97 Savicheva, G. I., 57 Savignac, P., 230 Savushkina, V. I., 77 Sawa, Y., 347 Sawada, S., 146 Sawanishi, H., 104, 105, 278, 395,397 Sawara, M., 74 Sawaura, Y., 356 Sawhney, S. N., 119, 120, 135, 140 Sawicki, R. A., 236, 460 Sayed, G. H., 239 Sayed, Y.,371 Sayer, B. G., 477 Sbrana, G., 82 Scala, A. A., 63 Scanlon, D. B., 373 Scarafile, C., 49 Scarlata, G., 74, 82 Scarpati, R., 217 Schaap, A. P., 60 Schaefer. H.. 118, 285 Schaefer, M., 108 Schafer-Ridder, M., 464 Schaffhausen, J. G., 221 Schaffner, K.,63 Schamp, N., 249 Scharf, H. D., 194, 202 Schaumann, E., 37, 125, 165 Scheers, P. C. H., 93 Scheidt, H., 325 Scheinmann, F., 352 Schenone, P., 333,367 Scherberich, P., 127 Scherowsky, G., 160 Scheuer, P. J., 209 Scheuermann, H., 134 Schield, J. A., 350, 393 Schill, G., 420 Schinske, W. N., 184 Schirmann, J. P., 6 Schlegel, H. B., 375 Schlittler, E., 348 Schmelz, H., 260 Schmid, G. H., 39 Schmid, H., 34, 37, 216, 224, 246, 272, 412, 414, 420, 424 Schmid, J., 43 1 Schmid, R., 412 Schmid, U., 37 Schmidpeter, A., 66, 220 Schmidt, D., 376 Schmidt, H., 324 Schmidt, M., 414 Schmidt, R., 214, 307, 325

515 Schmidt, R. R., 10 Schmidt, S. P., 45, 61 Schmidt, W., 466 Schmidbauer, H., 58 Schmiesing, R., 450 Schmitt, H., 252, 386 Schmitz, F. J., 343 Schmitz, H., 248 Schnaithmann, M., 39,463 Schnell, M., 148 Schneller, S. W., 246 Schneider, C. S., 70, 121, 205 Schneider, D., 249 Schneider, H. J., 97 Schneider, H. P., 176 Schneider, M. P., 39, 325, 463 Schnorrenberg, G., 88 Scholkens, B., 96 Schollkopf, U., 170, 213 Scholl, B., 53, 398 Scholz, K.H., 218 Schon, D., 412 Schouteeten, A., 74 Schreider, H. P., 391 Schreiner, H., 464 Schroeder, G., 419, 420,426, 434,467 Schroll, G., 486 Schrom, E., 107 Schrooten, R., 470 Schroth, W., 414 Schubert, H., 73 Schubert, U., 153 Schuckmann, W., 147, 155, 156 Scudder, P. H., 412 Schulte-Eke, K. H., 345 Schulten, W., 181, 466 Schulze, K.,414 Schultz, A. G., 101, 175, 178, 190 Schumann, D., 417 Schupbach, C. M., 137 Schuppiser, J. L., 395 Schurig, V., 10 Schuster, G. B., 2, 45, 60, 61, 368 Schuster, K. H., 7 Schwab, W., 214 Schwamborn, M., 464 Schwan, T. J., 223 Schwartz, I., 122 Schwarz, I., 325 Schwartz, R. D., 11 Schwartz, R. E., 209 Schwarzmann, M., 1 Schweig, A., 41 Schweizer, E. E., 30, 244, 378 Schwenzer, B., 122 Schwerdtel, W., 3 Schwetlick, K.,122 Sciotto, D., 74 Scribe, P., 235 Scriven, E. F. V., 289, 399

Scrowston, R. M., 98 Scorrano, G., 430 Scott, B. S., 276 Scott, F. L., 321 Scott, J. W.,72 Scovell, E. G., 14, 15 Sebastiani, G. V., 106, 177 Secrist, J. A., tert., 309 Sedivy, Z., 365, 393 See, J., 259 Seebach. D., 19, 53, 233, 322 Seel, H., 102 Segal, I., 375 Segarra, J. T., 313 Seguil-Camargo, L., 102 Seidel, A. K.,346 Seifert, H., 3 Seifert, K., 120 Seitz, G., 78, 103, 247, 379 Seitz, M., 352 Sekacis, I., 473 Seki, F., 200 Seki, K.,99 Sekretar, S., 158, 233 Selby, T. P., 120, 148 Seligmann, O., 352, 355 Seltzman, H. H., 371 Selva, A., 93 Selva, E., 203 Semenov, V. P., 168 Semenova, S. N., 18 Semet, R., 336 Semikolenova, N. V., 186 Semple, J. E., 65 Sen, P. K.,75, 128, 358 Senda, S., 248, 302, 309, 310, 320,408,410 Sengupta, P. K.,158 Sengupta, S. K., 150 Senda, Y., 343 Senga, K.,143, 154,251, 308, 310, 312, 313 Sengstschmid, G., 107 Seno, M., 175, 187, 230 Senova, 2. P., 354 Sentenac-Roumanou, H., 130 Seoane, C., 257, 332, 440 Seotens, H. P., 382 Serafin, B., 209, 254 Sergeev, N. M.,480 Sessions, R. B., 443 Seth, M., 358 Sethna, S., 366 Seto, S., 343 Setoguchi, M., 95 Sevaldsen, O., 429 Sevin, A., 12, 35, 42 Seykens, D., 63 Seymour, C. A., 378 Sgarabotto, P., 43 Sghibartz, C. M., 434 Shabanov, A. L., 39 Shafiee, A., 104, 109, 155, 235

Author Index

5 16 Shafik, R. M., 158 Shagidullin, R. R., 375 Shah, R. H., 126 Shah, R. K., 487 Shah, S. C., 431 Shahak, I., 27 Shaidulin, S. A., 442 Shaik, S., 63 Shakirov, I. K., 375 Shalash, M. R., 361 Shams El-Dine, S. A., 160 Shand, C., 275 Shanmugam, P., 109, 292 Shannon, P. V. R., 188 Shapatin, A. S., 231 Shapiro, M. J., 192, 286 Shapiro, R., 448 Shargel, L. D., 96, 445 Sharkova, L. M., 178 Sharma, C. R., 353 Sharma, D. K., 354 Sharma, M. L., 352 Sharma, N. K., 210 Sharma, R. P., 348 Sharma, S. D., 48, 106 Sharma, S. K., 184 Sharma, V. K., 279 Shashkov, A. S., 170 Shashkov, A. Yu., 442 Shaw, A., 459 Shaw, D., 347 Shchechenko, 2. P., 213 Shechter, H., 83, 172 Sheehan, J. C., 31,49, 97 Sheibye, S., 412 Sheikh, H., 339 Sheinker, V. N., 135 Sheinker, Yu. N., 130, 384 Sheinkman, A. K., 140, 185, 189, 190 Sheldon, B. G., 460 Sheldrick, G., 180, 272 Shell, F. M., 388 Shen, L., 459 Shepard, K. L., 192, 452 Shepherd, P. T., 181 Sheradsky, T., 48, 125, 219 Shetlar, M. D., 302 Shevchenko, L. I., 158 Shevchenko, M. V., 54 Shevchenko, S. M., 475, 478 Shevlin, P. B., 173 Shibaeva, R. P., 200 Shibata, A., 332 Shibuya, H., 74 Shibuya, I., 163, 231 Shibuya, S., 6, 50, 304 Shieh, W.-C., 42 Shifrina, R. R., 77 Shih, C. Y., 152 Shim, S. C., 283, 355, 361 Shimazaki, M., 398 Shimizu, F., 459 Shimizu, H., 138, 139, 364, 394,395

Shimuzu, K., 312 Shimizu, M., 354 Shimizu, N., 2, 174, 226 Shimokawa, K., 174 Shin, C.-G., 35, 225 Shinba, M., 21, 170 Shinde, A. G., 345 Shingare, M. S., 119 Shingu, T., 482 Shinozuka, K., 314 Shiotani, S., 445 Shiozaki, M., 49 Shiraishi, H., 137 Shiraishi, S., 175, 187, 230 Shiraiwa, M., 287 Shiralian, M., 477 Shirataki, Y.,348, 351 Shiratori, Y., 48 Shiroki, M., 95 Shiromaru, O., 74 Shirwaiker, G. S., 226 Shoji, F., 299 Shokhen, M. A., 29 Shono, T., 293 Shreeve, J. M., 65 Shridher, D. R., 353 Shudo, K., 14, 181 Shukri, J., 119 Shusherina, N. P.,264 Shuto, S., 95 Shuyama, H., 211 Shvaika, 0. P., 132 Shvartsberg, M. S., 251 Shvedov, V. I., 90 Shvetsov-Shilovskii, N. I., 231 Shvo, Y., 29,451 Shyamasundar, N., 10 Sidell, M. D., 177 Sidiropoulos, G., 55 Sidorkin, V. F., 444 Sidorov, V. I., 477, 480 Sidorova, N. G., 100 Siegel, A., 77 Siegel, H., 18 Siegel, M. G., 445 Sieler, R. A., 72 Siemionko, R., 459 Sievertsson, H., 97 Sigalov, M. V., 480 Silberman, L., 213 Silverman, R. B., 211 Silverton, J. V., 348 Silvestri, M. G., 20 Sim, G. A,, 440 Simchen, G., 7 Simig, G., 153 Simiti, I., 122, 125, 142 Simons, G., 12 Simons, S. S., jun., 192 Simonsen, O., 456 Simonsen, S. H., 488 Sindeler, K., 365, 393 Singelmann, J., 249 Singer, S. P., 341, 412, 416 Singh, A,, 48, 128, 140, 146

Singh, A. K., 45 Singh, B., 352 Singh, H., 144, 150, 158, 209, 381 Singh, P., 86, 209, 455 Singh, P. M., 106 Singh, R., 164, 231, 366 Singh, R. P., 361, 362 Singh, S., 230, 279 Singh, S. P., 119, 120, 140 Singh, V. K., 149, 159 Sinharay, A., 96 Siracusa, M. A., 107, 118 Sirlin, C., 433 Sitkin, A. I., 87 Sitzmann, M. E., 123 Siv, C., 125 Sivaramakrishnan, R., 194 Skachko, T. G., 130 Skakirov, I. K., 479 Skattabdl, L., 287 Skidmore, I. F., 347 Skiles, J. W., 292 Skinner, W. A., 370 Skotsch, C., 285 Skrabal, P., 423 Skramstad, J., 79 Skrowaczewska, Z., 317 Slack, D. A., 334 Sleeckx, J., 470 Sleta, L. A., 487 Sliwa, H., 425, 452 Slusarchyk, W. A., 97 Slusser, P., 60 Smalberger, T. M., 354 Smalley, R. K., 216, 258, 283, 338, 377 Smirnova, V. G., 145, 384 Smit, V. A., 170 Smit, W. A., 40 Smith, A. E., 188 Smith, B. M. L., 155, 382 Smith, D. J. H., 64, 210 Smith, G. A., 160 Smith, H., 359 Smith, 1. R., 362 Smith, J. P., 368 Smith, K., 19, 199 Smith, N. P., 42 Smith, R. H., 216 Smith, R. J., 359 Smith, Z., 65 Smolinski, S., 481 Smorygo, N. A., 130 Snetkova, E. V., 39, 88 Snieckus, V., 395 Snowden, R. L., 73 Snyder, J. P., 66, 441, 459 Sochilin, E. G., 130, 132 Soellradl, H., 399 Sogah, G. D. Y., 434, 436 Sohar, P., 119, 130 Sokolov, S. D., 110 Sokolovsky, M., 445 Soler, A., 340

517

Author Index Solheim, B. A., 460 Soliman, F. S. G., 158, 160 Solladie, G., 414, 482 Solladie-Cavallo, A., 482 Soloman, J. J., 17 Solomko, Z. F., 133 Solov'evd, N. P., 384 Soloway, A. H., 17 Soltani, A., 155 Somanathan, R., 47, 410 Somehara, T., 236 Somei, M., 190, 295 Sommer, S., 153 Sondhi, S. M., 152 Sone, K., 458 Sone, T., 74 Sonnenbichler, J., 352 Sonney, J.-M., 444 Sonoda, A., 175 Sonoda, H., 287 Sonoda, N., 11, 446 Sonoda, Y.,287 Sonveaux, E., 466 Sorokin, M. F., 3 Sorokina, S. F., 479, 480 Sorokina, T. D., 478 Soth, S., 104 Soto, J. L., 257, 332, 440 Soukup, M., 319 Soundararajan, N., 109 Sousa, L. R., 139, 434, 436 Southby, D. T., 222 Sowell, J. W., jun., 181 Spagnolo, P., 77, 90, 204 Sparfel, D., 463 Spear, K. L., 412 Specchiarello, M., 203 Specian, A. C., 343 Speckamp, W. N., 444,457, 485 Spencer, J. A., 53, 442, 469 Speranskaya, N. P., 354 Speziale, V., 175 Spicer, B. A., 359 Spiegel, M. G., 434 Spinelli, D., 76, 81, 225 Spitaler, U., 348 Spiteller, G., 370 Sprague, J. M., 119 Sprecher, M., 463 Spiro, V., 93 Spronck, H. J. W., 342, 371 Sprotte, U., 170 Spry, D. O., 407 Sreenivasan, R., 71, 111, 304 Srenger, E., 136 Sridharan, S., 122 Srimannarayana, G., 351, 371 Srinivasan, K., 2 Srinivasan, M., 76 Srinivasan, R., 426 Srinivasan, V. R., 140 Srivastava, J. N., 363 Srogl, J., 98 Stadlbauer, W., 53, 290

Stahly, B. C., 445 Stahly, G. P.,41, 328 Stamm, H., 33 Stamper, J. G., 82 Stanaszek, R. S., 369 Stanetty, P., 107 Stanislav, E., 354 Stanislawa, S., 409 Stanovnik, B., 145, 158, 166, 204, 233, 239, 245, 246, 252 Starewicz, P. M., 457 Stark, M., 414 Starostina, T. A., 77 Staskun, B., 52 Stauff, J., 60 Stavaux, M., 195 Stavric, B., 450 Stec, W. J., 479 Stefaniak, L., 161, 225 Stegel, F., 172, 181, 337 Steggles, D. J., 76, 405 Steglich, W., 88, 179, 184, 205,258, 373 Stegmann, W., 35 Stein, M. L., 250 Steinbeck, K., 193 Steinberg, H., 32, 38 Steiner, G., 118 Steinman, M., 365 Stelink, C., 345 Steliou, K., 410 Stenhouse, I. A., 352 Stephanatou, J., 243, 388, 419,482 Stephanou, E., 421 Stepanyants, A. U., 250 Stephenson, D. S., 474 Sternbach, L. H., 377 Stetter, H., 461 Stevens, I. D. R., 42 Stewart, F. H. C., 253, 400 Stewart, P. B., 374 Stezhko, T. V., 145, 384, 385 Stezowski, J. J., 129 Stibbard, J. H. A., 464 Stibor, I., 98 Stiefvater, 0. L., 161 Stirling, C. J. M., 21 Stjernstrom, N. E., 79, 100, 101, 103 Stoddart, J. F., 243, 388, 419, 437,466,482 Stoepel, K., 145 Stoilova, V., 46 Stolbova, T. V., 330 Storer, C., 136 Storr, R. C., 47, 222, 325, 410 Stothard, V. P., 441 Stott, P. E., 433 Strachen, W. A., 377 Stradi, R., 205, 297 Strand, S., 426 Stratonova, E. I., 3

Strauss, M. J., 291 Strausz, 0. P., 40, 71, 154, 227 Streaty, R. A., 445 Streith. J., 268, 395, 397 Streitwieser, A., jun., 295 Strelisky, J., 356 Struchkov, Yu.T., 80, 187, 337,441,442 Studeneer, A., 106 Studenikov, A. N., 168 Stutz, A., 179,420 Stufkens, D. J., 163 Stuhl, O., 395 Stults, B. R., 220 Stupnikova, T. V., 185, 190 Sturtz, G., 119 Stutz, U., 215 Suarato, A., 50 Suarez, L. E. C., 372 Suboch, G. A., 90 Suchkova, I. G., 89, 165 Sucrow, W., 380 Sudoh, R., 344 Suehiro, H., 87 Suganuma, H.. 19 Sugasawa, T., 184 Sugawara, S., 97 Sugawara, T., 308 Sugaya, T., 184 Sugihara, M., 367 Sugimoto, H., 361 Sugimoto, T., 62 Sugita, T., 16 Sugiura, M., 95, 487 Sugiyama, H., 343 Sugiyama, N., 372 Sultanbawa, S., 365 Sultanov, R. A., 13 Sumoto, K., 236, 244, 282, 365 Summers, A. J. H., 168 Sunagawa, K., 196 Sunders, S., 219 Sundholm, E. G., 366 Sunjic, V., 440 Surov, Yu.N., 90 Suschitzky, H., 83, 84, 105, 148, 216, 289, 377, 399, 404 Sutherland, I. O., 350, 358, 360, 373,457,466 Sutherland, J. K.. 14, 15 Sutton, L. E., 159, 218 Sutton, T. M., 98 Sutyagin, V. M., 189 Suwa, S., 172 Suzuki, A., 439 Suzuki, K., 35, 225 Suzuki, K.T., 314 Suzuki, M., 23, 85, 217, 261 Suzuki, N., 74, 151 Suzuki, T., 384,457 Suzuki, Y.,175, 180, 187, 406

518 Svanholt, H., 154, 166, 228 Svenson, R., 79, 100, 103 Sviridova, L. A., 134 Sviridova, V. E., 224 Svishchuk, A. A., 251, 343 Svoboda, J., 56 Sweeney, J. G., 356 Sweet, F. W., 252 Swinbourne, F. J., 257 Swindles, M., 230 Swodenk. W., 3 Swybold, G., 117 Sych, E. D., 132, 144 Sykes, P., 154 Sykes, P. J., 159 Syren, S., 397 Szabo, V., 346, 349, 357 Szalkiewicz, A., 283 Szilagyi, L., 129 Szilagyi, S., 459 Szlompek-Nesteruk, D., 409 Tabenko, B. M., 77 Taber, D. F., 21 Tabony, J., 481 Tabri, R. F., 168 Tabushi, I., 445 Tacconi, G., 203 Tachikawa, R., 255 Tada, K., 48 Tada, M., 433 Tagawa, H., 75, 95 Tagmazyan, K. Ts., 174 Taguchi, Y.,16 Tahara, T., 95 Taieb, C., 481 Tajana, A., 405 Takada, T., 240 Takagi, K., 163 Takagaki, H., 259 Takahagi, Y.,304 Takahashi, H., 314 Takahashi, K., 380, 411 Takahashi, M., 180 Takahashi, N., 306 Takahashi, S., 87 Takai, F., 27 Takaishi, T., 122, 143 Takamoto, M., 384, 411, 445, 457 Takao, N., 487 Takase, T., 406 Takashi, T., 397 Takatsuki, K., 283 Takaya, H., 446 Takayama, H., 267, 384,411, 445,457 Takayama, K., 173, 396, 462 Takechi, H., 421 Takeda, K., 94, 282 Takeda, N., 164,231, 328 Takeda, R., 242, 272 Takeda, S., 244, 472

Author Index Takegami, Y., 283 Takehara, S., 95 Takei, H., 259 Takemoto, T., 354 Takeshima, T., 127 Takeshita, H., 62 Takeuchi, F., 347 Takeuchi, T., 398 Takeuchi, Y., 444,447 Takigawa, Y.,95 Talary, E. R., 31 Talaty, E. R., 12 Talukdar, P. B., 150, 151 Talwalker, P. K., 119 Tam, S. Y-K., 309 Tamaru, Y., 77, 172, 179, 264, 445 Tamashima, M., 242, 272 Tamborra, P., 427 Tamborski, C., 133 Tamir, I., 29 Tamosiunas, J., 243 Tamura, C., 156, 255 Tamura, S., 356 Tamura, Y., 177, 186, 188, 190, 268,365, 399,447 Tanabe, M., 336 Tanabe, S., 208 Tanaka, A., 112, 240 Tanaka, H., 137 Tanaka, J., 101, 345 Tanaka, T., 27, 34, 35, 97 Tanaka, Y.,151, 253, 386 Tanasi, M. T., 172 Tandon, J. S., 354 Tandon, S. G., 74, 86 Tandura, S. N., 444 Taniguchi, H., 34, 35, 211, 212,448 Tanimoto, M., 471 Tanji, K., 169 Tanoguchi, A., 358 Tantsyura, G. F., 353 Tappen, W. A,, 60 Tapuhi, Y., 366 Tarabasanu-Mihaila, C., 146 Tarasenko, N. A., 30 Tarburton, P., 33 Tarnowski, B., 363 Tartakovskii, V. A., 250 Taschner, M. J., 7 Tashiro, M., 38, 209 Tatibouet, F., 286 Tatikolov, A. S., 136 Tatsumo, Y.,11 Tavares, M. R., 292 Tavernari, D., 138 Tavernier, D., 144 Taylor, E. C., 117, 235, 320, 321, 358 Taylor, G., 461 Taylor, G. R., 13 Taylor, H. C. R., 260

Taylor, L. T., 265 Taylor, N., 382 Taylor, R., 99 Tayman, F. S., 462 Tedder, J. M., 172, 225 Tedeschi, P., 213 Tegeler, J. J., 446 Teichteil, Ch., 43 Teien, G., 483 Teiger, D. G., 96. 445 Temnikova, T. J., 18 Tempesti, E., 88 ten Brink, R. E., 296 ten Broeke, J., 445 Teo, K.-E., 181, 182 Terada, A., 255 Teranishi, S., 4, 20 Terashima, M., 99, 388 Terashima, S., 9 Tereshchenko, G. F., 18 Ter-Gabrielyan, E. G., 46, 217 Terol, A., 130 Terrier, F., 225 Tertov, B. A., 472 Terzis, A., 482 Tesky, F. M., 55 Testaferri, L., 90, 99, 103 Testoni, G., 396 Tetsukawa, H., 11 Teuben, J. H., 265 Teuber, H. J., 189 Teubner, R., 402 Teufel, E., 178, 461 Teufel, H., 96 Tewari, R. S., 195 Texier, F., 32, 168 Tezuka, H., 22, 390 Tezuka, T., 21, 170 Thakar, K. A., 119, 120 Thaller, V., 93, 390 Thavard, D., 410 Thayer, A. L., 60 Thepenier, J., 330 Thibaut, P., 78 Thiele, K., 96 Thieme, P. C., 206 Thierrichter, B., 86 Thijs, L., 159, 228 Thoe, K.-W., 204 Thomas, D. R., 289, 399 Thomas, E. J., 49, 427 Thomas, M. T., 395 Thomas, R. C., 213 Thompson, A. W., 105 Thompson, N., 201 Thomsen, I., 412 Thorsett, E. D., 238 Thuillier, A,, 464, 477 Thulin, B., 426 Thulstrup, E. W., 73 Thummell, R. P., 271 Tichy, M., 441, 487 Ticozzi, C., 342

Author Index Tiecco, M., 73, 90, 99, 103 Tiers, G. V. D., 326 Tietjen, H. P., 345 Tigler, D., 414 Tikhomirov, D. A., 29 Tilak, B. D., 119, 377 Tilichenko, M. N., 442 Tillett, J. G., 226 Tilley, J. W., 84 Timberlake, J. W., 441, 459 Timko, J. M., 434, 435, 436, 466 Timm, H., 173 Timm, U., 26, 154,227, 370 Timmerman, A., 167, 234 Timmermans, P. B. M. W. M., 107 Tinnemans, A. H. A., 99 Tintel, C., 398 Tipping, A. E., 203 TiSler, M., 145, 158, 166, 204, 233, 239, 245, 246, 252 Titlestad, K.,429 Titzenthaler, E., 1 Tiwari, S. S., 159 Tkachenko, S. E., 126 Tkachenko, V. V., 176 Tochtermann, W., 173 Toda, F., 48 Toda, T., 406 Todesco, P. E., 122, 123 Todres, Z. V., 80 Toeplitz, B., 254, 398, 401, 48 1 Toi, N., 457 Tokach, S.,66 Tokoroyama, T., 78, 463 Tokumura, K.,406 Tokuno, K.,11 Toldy, L., 130, 257 Tolmachev, A. I., 144 Tolstikov, G. A., 89, 171, 420, 445 Tolstikov, V. V., 455 Toma, F, 470 Toma, L., 215 Tomas, F., 354 Tomaselli, G. A., 81 Tomaselli, H. C., 445 Tomasik, P., 269 Tomer, R. K., 120 Tominaga, Y.,81, 319 Tomisawa, H., 290 Tomoeda, M., 163 Tomoi, M., 430 Tong, Y.C., 143 Toong, Y.C., 89 Toppet, S.,167, 232, 234 Tordo, P., 122 Torii, S., 137 Tornetta, B., 107, 118 Torocheshnikov, V. N., 134 Toromanoff, E., 12

519 Torosyan, G. O., 174 Torre, M., 74, 82, 90 Torre, G., 43, 44 Torres, M., 40, 71, 154, 227 Torreilles, E., 200 Tortorella, S., 277 Tosi, G., 402 Toth, G., 130 Toubro, N. H., 154, 165, 167, 234 Toupet, L., 122 Tourwe, D., 487 Trabjerg, I., 44, 165, 234 Traynelis, V. J., 350, 393 Trtcourt, F., 272 Trefonas, L. M., 441 Trehan, A. K., 279 Trehan, I. R., 94 Treibs, A., 182 Tremper, A., 36 Tresselt, D., 363 Treuner, U. D., 97 Triana Alonso, J. L., 187 Triepel, J., 381 Trifonov, L. S.,46 Trigo, G. G., 444, 485 Trindade, M. 1. U., 347 Trindle, C., 63 Tripathi, V. K.,368 Tripier, D., 96 Trippett, S., 230 Trivedi, J. J., 129 Trivedi, K. N., 365 Trka, A., 405 Trkovnik, M., 119 Troeltsch, C., 127 Trofimov, B. A., 66, 88, 92, 178 Trofimov, F. A., 168, 257 Troisi, L., 123 Troll, T., 458 Trompenaars, W. P., 80, 113, 236, 392 Tron-Loisel, H., 84 Trost, B. M., 184, 412, 449 Trotter, J., 180, 234, 272 Trybulski, E. J., 402, 446 Tse, M.-W., 483 Tsoi, L. A., 128, 132, 133 Tsubokawa, M., 95 Tsubokawa, S., 243 Tsuboyama, K., 34,483 Tsuboyarna, S., 34, 483 Tsuchiya, T., 104, 105, 157, 227,278, 395,396 Tsuda, K.,332 Tsuda, Y.,214, 378 Tsuji, A., 245 Tsuji, J., 418 Tsuji, K.,179 Tsuji, T., 160, 266 Tsukada. W., 95 Tsukayama, M., 357 Tsukerman, S. V., 90

Tsumagari, T., 95 Tsuneoka, K.,464 Tsuno, Y.,174 Tsurkan, A. A., 138 Tsyguleva, 0. M., 487 Tuaillon, J., 21 1 Tuan, J. Y.,152 Tufariello, J. J., 446 Tulegenova, N. K.,167, 234 Tuli, D. K.,372 Tundo, A., 100, 204 Tundo. P., 424 Tupper, D. E., 76, 95,405 Turker, L., 448 Turley, J. C.. 369 Turnbull, M. D., 464 Turner, C. E., 345, 355, 370 Turner, E. S., 362, 444,475 Turner, J. L., 93 Turner, R. W., 424 Turner, W. B., 347, 427 Turro, N. J., 54, 63, 412,458, 459,463 Turyanskaya, A. M., 477 Tuzovskaya, S. A., 189 Tweddle, N. J., 444 Twine, C. E., 371 Tyler, J. K.,451 Tyszkiewics, B., 136 Tyszkiewics, M., 136 Tyukavkina, N. A., 356 Tzaroom, S., 27 Uchida, T., 32, 238, 242, 243, 275,418 Uchiyama, K.,272 Udachin, Yu.M., 195, 235 Udupa, M. R., 55 Uebelhart, P., 35 Ueda, C., 219 Uenishi, J., 358 Ueno, K.,75, 95 Ueno, Y.,136, 200 Uezu, T., 293 Ugi. I., 234 Ugolini, A., 48 Uher, M., 135 Ui, T., 170 Uihlein, M., 96 Ukawa, K.,308 Ukawa, S., 347 Ukida, M., 137 Ulbrich, B., 397 Uliss, D. B., 370 Ulman, A., 109 Ulrich, H., 204 Ulsaker, G. A., 144 Urnano, K., 448 Umezawa, H., 58, 398 Undheim, K.,144 Ung, S. N., 97 Ungernach, F., 258 Unger, M., 276 Unkovskii, B. V., 455, 474

Author Index

5 20 Uno, H., 115 Uno, T., 163 Upadhyaya, V. P., 140 Uppal, A. S., 128 Uppal Zubair, M., 190 Ura, K., 190, 295 Uramoto, M., 336 Urban, T., 120 Urbariski, T., 257 Urbatsch, L. E., 354 Uri, J. V., 97 Uring, N. A., 18 Urseanu, F., 146 Use, G., 452 Usgaonkar, R. N., 345, 363 Usha, R., 441, 487 Ushakov, N. V., 66 Usieli, V., 87 Usol’tsev, A. A., 442 Usui, T., 112 Usui, Y., 293 Uvais, M., 365 Uyeno, E., 370 Uzarewicz, A., 20 Uzawa, J., 34, 483 Vacca, A., 422, 483 Vaclav, D., 56 Vagstad, B. H., 463 Vakhitov, T. Y., 478 Vakhreeva, K. I., 92 Vakulskaya, T. I., 197 Valderrama, J., 346 Valencic, B., 166, 233 Valente, L., 122 Valenti, P., 349 Valentin, E., 323 Valnot, J. Y., 179 Valtere, S., 115 Valters, R., 115 Van, D. A., 303,429 Van Allan, J. A., 337, 340, 346 Van Asch, A., 167, 234 Van Audenhove, M., 485 Van Bekkum, H., 485 van Bergen, T. J., 270, 432 Van Binst, G., 487 Van Broeck, D., 222 Vandrevala, M. H., 188 van de Griendt, F., 462 van den Berg, A. J., 354 Van den Brandt, W., 487 Vanderah, D. J., 343 Vanderhaeghe, H., 48 van der Helm, D., 340, 375, 478, 484 van der Gen, A., 88, 107 van der Plas, H. C., 258, 299, 300 Van der Toorn, J. M., 485 van der Veen, R. H., 270,432 Van Duuren, B. L., 10, 17 Van Eugen, D., 331

van Leusen, A. M., 92, 452 Van Meerssche, M., 165, 167, 232,234, 249, 398,474 van Ooijen, J. A. C., 308 Van Oosterhout, H., 485 van Tilborg, W. J. M., 87 van Tooren, E., 308 Vardey, C. J., 347 Varma, R. S., 135 Varnavskaya, D. A., 480 Viirtanyan, S. A., 71, 171 Vasilev, A. V., 231 Vasil’ev, A. N., 92 Vasilevskii, S. F., 251 Vasilevskis, J., 72 Vaughan, D., 328 Vaultier, M., 32, 46, 224 Vdovin, V. M., 66 Veal, C. J., 128 Vedejs, E., 341, 412, 416 Veenstra, G. E., 159, 228 Veenstra, L., 8 Veeramani, K., 292 Vega, S., 254 Vegh, V., 357 Velluz, A., 345 Venegas, M. G., 459 Venkataramani, P. S., 368 Venkatesan, K., 441, 487 Verboom, W., 177 Verbruggen, A., 232 Vercek, B., 145, 158, 245, 252 Vereshchagin, A. N., 13, 471 Verht, R., 249 Verkade, J. G., 443 Verkruijsse, H. D., 341 Verma, V. K., 164, 231 Vermeire, M., 116 Vernin, G., 125, 128, 137, 177, 361 Vernon, J. M., 162, 192, 229 Vetter, A., 414 Vetter, W., 420 Viala, J., 24 Viallet, M. P., 126 Viallefont, P., 254 Viehe, H. G., 211, 222, 402, 417 Vierhapper, F. W., 476, 486, 487 Vig, M., 94 Vigevani, E., 346 Vigorita, M. G., 130 Viktorova, E. A., 80, 98 Vincent, C. A., 398 Vincent, E. J., 113, 122, 123, 135 Vinick, F. J., 262 Vining, L. C., 366 Viricel, M. R., 354 Viscontini, M., 487 Vistocco, R., 64 Vitagliano, A., 461 Vitezic, N., 128

Vitto, M., 115 Vittorelli, P., 414 Vivarelli, P.,466 Vivona, N., 86, 225, 239, 240, 247 Vlasova, T. F., 130, 145, 384 Vleggaar, R., 354 Voegeli, U., 130 Vogtle, F., 270,438,466, 48 3 Volter, W., 207 Vogel, E., 464 Vogel, P., 444, 463 Vogt, B. R., 254, 383, 398, 401,481 Voight, H., 160 Voight, S., 11 Voigt, J., 156 Voirin, B., 354 Volbushko, V. I., 105 Volkova, S. V., 126 Volkova, V. V., 46 Volodarskii, L. B., 205, 208 Volovelskii, L. N., 213 Volovenko, Yu. M., 68, 180, 25 1 Volz, H., 168 von Griegern, T., 66, 220 von Hinrichs, E., 234 von Rohrscheidt, C., 181 Von Strandtmann, M., 331, 348 Vo-Quang, L., 201 Vo-Quang, Yen., 201 Vorbrueggen, H., 166, 258 Vorobieva, E. A., 40 Voronkov, M. G., 30, 66, 68, 77, 88, 92, 197, 444 Vos, A., 270, 432 Voss, J., 210, 235 Vovk, A. I., 125 Vrieze, K., 163 Vsyunov, K. A., 130 Vulgaris, E., 370, 477 Vul’fson, S. G., 13, 471, 487 Vyrvpaev, E. M., 445 VyskoEil, V., 98

Wachsen, E., 117 Wada, I., 245 Waddling, R. E. L., 230 Wade, J. J., 100 Wade, P. C., 254, 398, 401, 455,481 Wade, T. N., 31 Wadsworth, W. S., 375 Waegell, B., 456 Wagai, A., 264 Wagner, A., 464 Wagner, G., 149, 157 Wagner, H., 352, 355, 356, 369 Wahab, A,, 166

Author Index Waid, K.,397 Waigh, R. D., 382 Wakabayashi, T., 431 Wakefield, B. J., 105 Waldmann, H., 3 Walker, J., 122 Walker, J. C., 445 Walker, R., 155, 242 Walker, R. B., 295 Wall, D. K., 33 Wall, M. E., 360 Wallace, J. L., 445 Wallach, M. B., 95 Waller, C.W., 355 Wallis, T. G., 291, 362 Walls, R. J., 364 Walser, A., 401, 402 Walter, W., 210, 235 Walton, D. J., 398 Wamhoff, H., 319 Wanatabe, M., 43 Wang, N.-C., 181 Wang, P.-C., 86 Wani, M. C., 360 Ward, A. D., 264 Ward, D., 357 Ward, R. S., 356, 357 Ward, R. W., 182 Warkentin, J., 21, 223 Warkentin, J. D., 199 Warner, D. E., 340 Warren, R. G., 364 Warren, S., 19, 199 Warrener, R. N., 4 Wassef, M. E., 361 Wasserman, A. L., 329 Wasserman, H. H., 48, 50 Wasilewski, J., 1 Watabe, Y., 197 Watanabe, F.. 139 Watanabe, K., 246 Watanabe, M., 215, 459 Watanabe, S., 180 Watanabe, T., 97, 347 Watanabe, Y.,219, 266, 283 Watarai, H., 74 Waterman, E. L., 184, 283 Waterman, P. G., 354, 358 Watkin, D. J., 386, 441 Watson, K. M., 217 Watson, W. H., 441, 462 Watson, W. P., 342 Watt, D. S., 141 Watt, R. A., 299 Webb, G. A., 161, 225,455 Webb, R. J., 391 Weber, E., 429 Weber, G. F., 331 Weber, J., 108 Weber, J. L., 180 Weber, K.-H., 71, 400, 401, 406 Weber, R., 116 Webster, R. G., 155, 242 Wedam, 0. A,, 77

521 Weger, H.,459 Wehner, W., 270 Weigt, A., 477 Weiler, E. D., 113 Weiler, H., 190 Weiner, J., 63 Weinert, J., 24, 217 Weinhardt, K. K., 349 Weisbach, J. A., 97 Weisman, G. R., 53, 442, 469 Weiss, L. B., 12, 58 Weiss, R., 442 Weiss, U.,348 Weissenberg, M., 20 Weissflog, E., 414 Weisshuhn, C. M., 90, 100, 122, 197, 198,210,463 Wengel, A. S.,105 Wennerstrorn, O., 426, 445 Wentrup, C., 86, 215, 245, 305 Wentrup, G. J., 195 Wenzel, A., 158, 241 Werber, G., 86 Wessely, V., 416 West, B. 0..456 West, R. C., 1 2 Westerlund, C., 84, 106 Westerman, I. J., 275, 452 Westerman, P. W., 365 Westfield, H.P., 236 Westphal, G., 328 Whalen, D. L., 14, 24 Whalen, M. D., 354 Whalley, W. B., 350, 362 Whidby, J. F., 470 White, A. H., 391 White, D. K., 54 White, D. N. J., 440 White, J. D., 460 White, R. L., jun., 223 Whitesitt, C. A., 49 Whiting, D. A., 331 Whittaker, G., 168 Wiberg, K. B., 369 Wibmer, P., 86 Widera, R., 128 Wiering. J. S., 9 Wiesert, W., 33 Wigfield, D. C., 336, 471 Wild, S. B., 10 Wilde, H., 447 Wildi, E. A,, 54 Wilhelm, R., 182 Wilker, J. C., 96 Wilkinson, S. G., 13 Willard, A. K., 466 Willer, R., 451 Willert, I., 19 Williams, B. E., 218 Williams, D. L., 371 Williamson, K. L., 159 Wilmot, I. D., 368 Wilson, G. E., jun., 230 Wilson, H. K., 347

Wilson, J. W., 203 Wilson, S. R., 236, 460 Wingard, R. E., 330 Winiarski, J., 472 Winkelmann, E.,96 Winter, H.-W., 86, 215 Winter, M., 345 Winter, W., 154, 176, 391 Winters, M., 330 417 Wirtz, K.-P., Wirz, J., 459 Witanowski, M., 161, 225 Witt, W., 467 Wittmann, H., 18, 247 Wobig, D., 120 Woeien, G., 221 Wojciechowska, M., 327 Wojsa, K., 409 Wolcott, J. M., 193 Wolf, J. G., 414 Wolf, R., 230, 242 Wolfe, J. F., 265 Wolff, s., 59 Wollenweber, E., 354 Wollweber, H.,145 Wollweber, H. T., 215 Woltermann, A., 91, 414 Won Nam Lok, 264 Wond-Ng. W., 38 Wong, C. K., 179 Wong, J. L., 313 Wong, K.-H., 430 Wong, S. C., 446 Woo, C. M., 101 Woo, W. S., 355, 369 Wood, G. P., 176 Wood, H. C. S., 304 Woodcock, D. J., 225 Woodgate, P. D., 419 Woodyard, J. D., 445 Woolhouse, A. D., 207 Wortel, T. M., 485 Wos, J. D., 360 Wrackmeyer, B., 73 Wright, D. J., 105 Wudl, F., 195 Wunderli, A.. 224 Wynberg, H., 9 Yaavetz, B., 445 Yadav, B. P., 337 Yadav, L. D. S., 158 Yagi, H., 14 Yagihara, M., 462 Yagubskii, E. B., 200 Yahner, J. A., 114 Yakoo, A,, 380 Yakubov, A. P.,74 Yakubovskaya, L. N., 402, 48 1 Yakushev, P. F., 455 Yakushijin, K., 173 Yale, H.L., 408 Yarnada. F., 165 Yarnada, H., 314

522 Yamada, S., 9, 197, 345, 356, 372 Yamada, S.-I., 287 Yamada, T., 357 Yamada, Y., 77, 172, 248, 264, 309, ,462 Yamaguchi, K., 22, 390 Yamaguchi, R., 443 Yamaguchi, S., 174, 359 Yamaguchi, T., 242, 272 Yamamatu, T., 6 Yamamori, M., 293, 406 Yamamoto, A., 288, 293 Yamamoto, F.. 352 Yamamoto, H., 11, 380, 426, 459 Yamamoto, M., 170 Yamamoto, T., 127 Yamamoto, Y., 222, 227, 325 Yamamura, S., 329 Yamanaka, H., 287, 288, 298, 299, 302 Yamasaki, N., 7 8 Yamashita, K., 371 Yamato, M., 352, 358 Yamauchi, M., 347 Yamazaki, C., 205, 222 Yamazaki, H., 206 Yamazaki, T., 51 Yamomoto, Y., 157 Yanami, T., 169 Yanez, M., 29, 469 Yang, N.-C. C., 11 Yano, S., 392 Yano, T., 251, 310 Yao, S., 104 Yap, C., 191 Yarbrough, L. W., 443 Yashunskii, V. G., 224 Yasman, Y. B., 472 Yasnikov, A. A., 125 Yasuda, A., 11 Yasuda, M., 378, 379, 442 Yasuda, N., 259 Yasuda, Y., 199 Yates, F. S.,338 Yates, P., 89, 1 5 3 Yatsunami, T., 206 Yavari, I., 13, 162, 474,482 Yellin, H., 445 Yim, A. S., 32 Yohsida, K., 56 Yokobayashi, H., 458 Yokoe, I., 348, 351 Yokohama, S.,48 Yokomatzu, T., 6 Yokoo, A., 380

Author Index Yokoyama, N., 445 Yoneda, F., 251, 310, 312, 314,315, 3 1 6 , 3 2 0 , 3 2 1 Yoneda, N., 85, 2 1 7 , 2 6 1 Yoneda, S., 199 Yonemitsu, O., 289 Yonezawa, Y., 35, 225 Yoon, N. M., 20 Yoon, U. C., 289 Yoshida, K., 58, 188, 293 Yoshida, Y., 41, 8 7 Yoshida, Z., 11, 77, 172, 179, 199,445 Yoshida, Z.-I., 264 Yoshifuji, M., 219 Yoshii, E., 347 Yoshii, T., 431 Yoshikoshi, A., 169 Yoshimura, J., 35, 225 Yoshimura, N., 402 Yoshimura, S., 8 7 Yoshina, S.,240 Yoshino, T., 6 9 Yoshioka, T., 9 5 Young, D. W., 1 2 8 , 4 4 8 Young, M. G., 97 Young, P. A., 348 Yousif, M. M., 132 YouvaI, S., 29 Yu, C. C., 165, 207, 232 Yu, S. L., 38, 65 Yuasa, Y., 28, 186, 386 Yudin, L. G., 185 Yuen, C.-K., 66 Yuldashev, Kh. Yu., 98, 100 Yunker, M. B., 209 Yung, M. E., 343 Yur’eva, V. S., 402, 481 Yurovskaya, M. A., 168, 257 Yutaka, S., 336

Zabel, V., 462 Zady, M. F., 313 Zagorevskii, V. A., 97, 178, 346, 349, 354 Zagulayeva, 0. A., 300 Zaidlewicz, M., 20 Zaikin, V. G., 46, 487 Zajc, B., 349 Zakhs, E. R., 144 Zaklika, K. A., 60 Zakir, U., 217 Zamboni, R., 48 Zamkanei, M., 463 Zamkova, V. V., 133

Zanirato, P., 73, 77, 103, 204 Zaplyuisvechka, Z. P., 9 0 Zaruma, D., 257 Zasosova, I. M., 145, 384, 386 Zauer, K., 153 Zavalishina, A. I., 479, 480 Zawadowski, T., 362 Zbaida, D., 48, 125 Zbaida, S., 183 Zbiral, E., 12 Zecchi, G., 396 Zech, W., 324 Zefirov, N. S., 66, 108, 109, 441,443,472 Zeifman, Yu V., 46, 217 Zelcans, G., 444 Zelchan, G. I., 7 7 Zeldin, M., 485 Zelenska, V., 136 Zelensky, I., 136 Zelikman, Z. I., 472 Zeller, K. P., 25, 26, 154 Zemskii, B. P., 185 Zen, S., 211 Zhdanova, M.P., 298 Zhinkin, D. Ya., 231 Zhiryakov, V. G., 76, 103, 104, 148 Zhmurenko, L. A., 349 Zhukovskaya, 0. N., 176 Ziegler, A. E., 30 Ziegler, C. B., 285 Zielinska, B., 479 Zimaity, T., 8 5 Zinger, B., 24, 8 5 Zinner, G., 137, 206 Zinner, H., 137, 148 Zinner, K., 6 2 Zinsmeister, H. D., 354 Ziolo, R. F., 109 Zivkovic, N., 119 Zniber, R., 254 Zobova, N. N., 239 Zolotukhin, S. P.,200 Zoltewicz, J. A., 122 Zrimsek, Z., 245 Zschunke, A., 478 Zsindely, J., 272 Zsuga, M., 357 Zumbulyadis, N., 231, 340 Zunger, A., 29 Zupan, M., 349 Zvezdina, E. A., 298 Zwanenburg, B., 159, 228 Zyablikova, T. A., 478, 479 Zymalkowski, F., 365, 367