Heterocyclic Chemistry (v. 1)

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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


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


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


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


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


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%).'

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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


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.


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


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).


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
="\ 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.


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.


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


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


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.


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


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


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


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.


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.


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


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.


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

"


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.


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


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


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


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


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


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


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


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.


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.


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.


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


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


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


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.


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


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


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.


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,


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.


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


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


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


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


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 .


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


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.


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.


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.


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


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


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

’”

‘” ’“


(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


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.


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


-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


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 .


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


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


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


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.


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


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


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


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 ~

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


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


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


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


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'


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


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


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
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.


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.


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.


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.


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.


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


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.


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


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


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.


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


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.


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.

-


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.

"


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.


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.


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


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


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


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.


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 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.


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


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.


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.


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


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


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.


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


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


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.


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


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


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.


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


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.


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.


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


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


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.


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


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


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.


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.


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


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


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.


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,


.

,

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


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


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


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


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.


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.


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.


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


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.


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


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


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


(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


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


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.


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.


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


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.


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


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


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.


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


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


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.


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.


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.


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.


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’


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.


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.


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


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.


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


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


(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


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


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


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.


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


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.


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


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.


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.


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.


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


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


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.


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.


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.


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.


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


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.


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


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.


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.


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


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.


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


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


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.


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.


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.


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.


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.


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.


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


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


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


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


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


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


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


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


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.


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.


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.


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


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.


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


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


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


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


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'""

Heterocyclic Chemistry (v. 1)

Saturated Heterocyclic Chemistry (v. 3)

Heterocyclic Chemistry: v.4 (Specialist Periodical Reports)

Advances in Heterocyclic Chemistry: v. 18