AZEPINES Part 1

Authors:

Burt Renfroe CIBA-GEIGY CORPORATION

ARDSLEY, NEW YORK

Clinton Harrington

George R. Proctor

DOW CHEMICAL COMPANY MIDLAND, MICHIGAN

UNIVERSITY OF STRATHCLYDE GLASGOW, SCOTLAND

Editor:

Andre Rosowsky DANA-FARBER CANCER INSTITUTE

BOSTON, MASSACHUSETTS

AN INTERSCIENCE@ PUBLICATION

JOHN WILEY AND SONS NEW YORK CHICHESTER BRISBANE TORONTO SINGAPORE

AZEPINES-PART 1

This is the forry-third volume in rhe series

T H E CHEMISTRY OF HETEROCYCLIC COMPOUNDS

THE CHEMISTRY OF HETEROCYCLIC COMPOUNDS

A SERIES OF MONOGRAPHS

ARNOLD WEISSBERGER AND EDWARD C. TAYLOR

Editors

AZEPINES Part 1

Authors:

Burt Renfroe CIBA-GEIGY CORPORATION

ARDSLEY, NEW YORK

Clinton Harrington

George R. Proctor

DOW CHEMICAL COMPANY MIDLAND, MICHIGAN

UNIVERSITY OF STRATHCLYDE GLASGOW, SCOTLAND

Editor:

Andre Rosowsky DANA-FARBER CANCER INSTITUTE

BOSTON, MASSACHUSETTS

AN INTERSCIENCE@ PUBLICATION

JOHN WILEY AND SONS NEW YORK CHICHESTER BRISBANE TORONTO SINGAPORE

An InterscienceB Publication Copyright 0 1984 by John Wiley & Sons, Inc.

All rights reserved. Published simultaneously in Canada.

Reproduction or translation of any part of this work beyond that permitted by Section 107 or 108 of the 1976 United States Copyright Act without the permission of the copyright owner is unlawful. Requests for permission or further information should be addressed to the Permissions Department, John Wiley & Sons, Inc.

Library of Congress Cataloging in Publication Data:

Renfroe, Burt. Azepines.

(Chemistry of heterocyclic compounds, ISSN 0069-3154

“An Interscience publication.” Bibliography: p. Includes index. 1. Azepines. I . Harrington, Clinton. 11. Proctor,

George. 111. Rosowsky, Andre. IV. Title. V . Series.

QD401.R43 1984 547’.593 83-3497 ISBN 0-471-01878-3 (v. 1)

v. 43)

The Chemistry of Heterocyclic Compounds

The chemistry of heterocyclic compounds is one of the most complex branches of organic chemistry. It is equally interesting for its theoretical implications, for the diversity of its synthetic procedures, and for the physiological and industrial significance of heterocyclic compounds.

A field of such importance and intrinsic difficulty should be made as readily accessible as possible, and the lack of a modern detailed and comprehensive presentation of heterocyclic chemistry is therefore keenly felt. It is the in- tention of the present series to fill this gap by expert presentations of the various branches of heterocyclic chemistry. The subdivisions have been designed to cover the field in its entirety by monographs which reflect the importance and the interrelations of the various compounds, and accom- modate the specific interests of the authors.

In order to continue to make heterocyclic chemistry as readily accessible as possible new editions are planned for those areas where the respective volumes in the first edition have become obsolete by overwhelming progress. If, however, the changes are not too great so that the first editions can be brought up-to-date by supplementary volumes, supplements to the respective volumes will be published in the first edition.

ARNOLD WEISSBERGER

Reseurch Luhorurories Eustman Koduk Coinpuny Rochester , N e w York

EDWARD C. TAYLOR

Princeton University Princeton, N e w Jersey

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Preface

Heterocyclic systems with seven atoms, once considered chemical oddities, are today just as easily obtained as their five- and six-membered cousins, thanks to the very substantial advances in synthetic art that have been made in this field over the past 20 years. In a previous volume of the Heterocyclic Compounds series (Volume 26), seven-membered oxygen ring systems (ox- epins) and sulfur ring systems (thiepins) were reviewed. The present two- part volume extends this coverage to the seven-membered nitrogen hetero- cycles (azepines).

As with the oxepins and thiepins, interest in the azepines encompasses a broad spectrum of theoretical and applied disciplines. At the theoretical level, chemists are fascinated by these compounds from the molecular orbital standpoint. Of particular importance in this regard are the azulenoid cyclo- pentazepine ring systems, the bridgehead nitrogen benz[a]azepinium cation, the bridged annulene system 1 1-azabicyclo[4.4. I]undeca-l,3,5,7,9-pentaene (“ 1,6-azirino[ lO]annulene”), and the still unknown cyc1[4.4.3]azine. At the “applied” end of the spectrum, one hardly need be reminded of the enormous amount of research that has been conducted in pharmaceutical laboratories since the early 1960s on tranquilizers, antidepressants, and other psycho- tropic drugs of the benzodiazepine and dibenzazepine class. Probably more than any other factor, the vast commercial success of these medicinal agents and their benefit to society have caused the chemistry of condensed azepines to evolve into a major area of research in heterocyclic chemistry. One of the consequences of this effort has been the appearance, on the chemical scene, of a host of new ring systems which collectively form a dazzling array of structural types. It is the purpose of this two-part volume to give an account of the current state of knowledge concerning the synthesis, chemical reactions, and physical properties of some-though by no means all-of these systems, with particular emphasis on those facets that pertain to the “seven-memberedness” of the azepine ring.

Part 1 consists of two chapters. Chapter I (Renfroe and Harrington) is devoted to tricyclic systems containing an azepine ring along with two other rings that can be either carbocyclic or heterocyclic. This category includes no fewer than 150 different heterocylic systems, ranging from oxi- reno[d][2]benzazepines (a 3,6,7-system) to benzo[e]cyclooct[b]azepines (a 6,7,8-system). The largest single family, the dibenz[b,flazepines, has as its most famous members the antidepressant imipramine and its congeners, such as carbamazepine. Other dibenzazepines of pharmaceutical interest are the dibenz[c,elazepines, a number of which possess hypotensive activity. Cer- tain tricyclic azepine ring systems are also noteworthy because they appear in natural products. Here may be cited certain alkaloids of the rheadan family (1,3-dioxolo[4,5-h1[31benzazepines) and at least three groups of indole al-

vii

... Vl l l Preface

kaloids, the erythroidine and tuberostemonine family (azepino[3,2,1- hilindoles), the naucladerine family (azepino[4,5-b]indoles), and the ergot family (azepino[5,4,3-cd]indoles). Additionally, fused tricylic azepine sys- tems have been generated from tricyclic terpene ketones (e.g., santonin) via ring enlargement. The identification and characterization of the products from these reactions have played an important role in increasing our un- derstanding of the mechanism of the Schmidt and Beckmann rearrangements and in providing model systems for the synthesis of ring-enlarged azasteroid analogues.

Chapter I1 (Proctor) presents a review of the chemistry of bicyclic, as opposed to tricyclic, azepine derivatives. Here again a substantial number of fused, bridged, and spiran systems are covered, with emphasis being placed again on the seven-membered ring. Among these compounds the I - , 2-, and 3-benzazepines are of interest because of their potential psycho- pharmacologic activity. A novel class of antiviral agents also cited in this chapter consists of compounds belonging to the bridged 1,6-azirino [ IOIannulene ring system. The development of these compounds represents an intriguing blend of “pure” and “applied” heterocyclic chemistry.

Part 2 also consists of two chapters. Chapter I (Watthey and Stanton) covers the tricyclic diazepine systems, a number of which have attracted attention because of the pharmaceutical importance of some of their mem- bers. Here may be cited anxiolytic agents such as benzazepam, oxazolam, and triazolam; antidepressants such as dibenzopin; and antipsychotic agents such as clozapine. All these tricyclic azepine derivatives have contributed in a major way to the modern treatment of mental illness. Another example of a biologically important class of tricyclic azepine derivatives is provided by the anthramycin antibiotics (pyrrolo[2,l-c][ I ,4]benzodiazepines), which have shown impressive activity as antineoplastic agents.

The practical importance of azepine derivatives is by no means limited to medical applications. For example, among the ring systems discussed by Dr. Peet in Chapter I1 are the 1,2,5-triazepines, some of which have found use in the agricultural field as pesticidal plant protectants. Other triazepines, of the 1,3,5-type with N-nitro substituents, have been investigated as high explosives.

In summary, the two-part volume for which this Preface is written bears witness to the fact that seven-membered heterocyclic compounds are no longer the esoteric species they were once considered to be. Quite to the contrary, the pace of research and development in this area is accelerating, and there seems to be virtually no limit to the number of interesting ring systems that can be created in the laboratory by a combination of ingenuity and perseverance. The future should bring rich rewards not only in terms of new academic knowledge but also in terms of practical applications that will benefit us all, chemists and nonchemists alike. I wish to graciously thank the several authors who have joined me in preparing this review. Their

Preface ix

thoroughness and limitless patience cannot be sufficiently praised. Thanks are due, as well, to Drs. Arnold Weissberger and Edward C. Taylor for their encouragement and support of the project, and to the capable staff at John Wiley & Sons for their expeditious handling of these chapters as they were received.

ANDRE ROSOWSKY Boston, Massachusetts Junuary 1984

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Contents

CHAPTER I. AZEPINES

Burt Renfroe and Clinton Harrington

DIBENZAZEPINES AND OTHER TRICYCLIC

I. Introduction

11. 3,6,7-Systems

1. Oxireno[d][2]benzazepines 2. Benzo[6]cycloprop[d]azepines 3. Benzo[d]cycloprop[6]azepines

111. 5,5,7-Systems

1. Cyclopenta[cJtetrazolo[ 1,5-a]azepines 2. 2,2a,3-Trithia(2a-S’V)-4a-azacyclopent[cd]azulenes 3. Dipyrazolo[4,3-c:3’,4’-e]azepines 4. Thiazolol2’ ,3’:2,3]imidazo[ 1,5-a]azepines 5 . DipyrroloC 1,2-~:2’,3’-d]azepines 6. Azepino[2,1,7-cd]pyrrolizines 7. Furo[3,2-c]pyrrolo[l,2-aJazepines 8. Dithieno[2,3-c:3 ’,2‘-e]azepines

IV. 5,6,7-Systems

1. Tetrazolo[5, I-u][2lbenzazepines 2. Tetrazolo[S, 1 -6][3]benzazepines 3. 1,2,4-Triazolo[3,4-6][3lbenzazepines 4. Azepinol2, I-b]benzoxazoles 5. Oxazolo[2,3-~][2]benzazepines 6. Isothiazolo[5’ ,4’:4,5]pyrimido[ 1,2-a]azepines 7. AzepinoC2, I-b]benzothiazoles 8. Isothiazol0[3,2,-6][3]benzazepines 9. Thiazol0[2,3-~][2]benzazepines

10. Thiazolo[2,3-b][3lbenzazepines 11. Thiazolo[3,2-6][2]benzazepines 12. Thiazolo[ 3,2-a] [ 1 lbenzazepines 13. AzepinolZ, l-b]benzoselenazoles 14. Azepino[ 1,2-e]purines 15. Azepino[2,1-flpurines 16. Pyrazolo[3‘,4‘:4,5]pyrirnido[ 1,2-aJazepines

xi

1

1

6

6 6 9 9

11 13 14 15

16

16 17 18 20 22 23 23 27 28 29 29 32 32 34 35 36

xii Contents

17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62.

2a,4,9a-Triazabenz[c, dlazulenes Pyrido[3’ ,2’:4,5]imidazo[ 1,2-a]azepines Pyridol3’ ,4’:4,5]imidazo[ 1,2-a]azepines Azepino[ 1 ,2-a]benzimidazoles Imidazo[2, l-a][2]benzazepines Imidazo[2,l-b][3]benzazepines Imidazo[4,5-jk]benzazepines Pyrazolo[3,4-b]benzazepines Pyrazolo[3,4-c][ llbenzazepines Pyrazolo[3,4-c][2]benzazepines Pyrazolo[4,3-d][2]benzazepines 1,3-Dioxolo[4,5-h][2] benzazepines 1,3-Dioxolo[4,5-h][3]benzazepines [ 1,3]0xazino[3,2-a]pyrrolo[2,3-flazepines Azepino[2,1,7-cd]indolizines Pyrido[3 ’ ,2‘:4,5]pyrrolo[2,3-c]azepines Pyrido[3 ‘ ,4‘:4,5]pyrrolo[2,3-~]azepines Azepino[ 1,2-a]indoles Azepino[2, I-ilindoles Azepino[2,3-b]indoles Azepino[3 ,2-b]indoles Azepino[3,4-b]indoles Azepino[3,2, l-hilindoles Azepino[3,4,5-cd]indoles Azepino[4,3-b]indoles Azepino[4,3,2-cdjindoles Azepino[4,5-b]indoles Azepino[5,4,3-~dlindoles Azepino[4,5-e]indoles Azepino[4,5-flindoles Azepino[ 4,5-g] indole s Azepino[2, I-a]isoindoles Pyrrolo[ 1,2-a][ llbenzazepines Pyrrolo[ 1,2-b][2]benzazepines Pyrrolo[2,1 -b][3]benzazepines Furo[2’ ,3’:4,5]pyrimido[l,2-~]azepines Benzofuro[2,3-b]azepines Benzofuro[2,3-c]azepines Benzofuro[3,2-b]azepines Benzofuro[3,2-c]azepines Furo[2,3-g] [3]benzazepines Furo[3,2-g][ l]benzazepines Furo[3,2-g][2]benzazepines Furo[3,2-i][ llbenzazepines Furo[3,2-i][2]benzazepines Furo[3,4-c][ llbenzazepines

37 37 37 39 61 61 62 65 66 67 68 73 73 88 89 91 91 92 105 106 109 111 117 131 133 135 138 160 168 168 168 170 171 173 173 182 182 183 183 184 185 188 188 189 189 191

63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80.

Contents

ThienoI2’ ,3’:4,5]pyrimido[ 1,2-alazepines Thieno[4,3,2-4[ I]benzazepines [ 1 lBenzothieno[2,3-c]azepines [I]Benzothieno[3,2-b]azepines [ l]Benzothien0[3,2-c]azepines Thieno[2,3-c] [ 1 Ibenzazepines Thieno[3,2-b][ Ilbenzazepines Thieno[3,2-c][ Ilbenzazepines Benzo[e]cyclopent[b]azepines Cyclopenta[d][ Ilbenzazepines Indeno[ 1,241azepines Indeno[1,2-c]azepines Indeno[ 1,2-d]azepines Indeno[ 1,7-bc]azepines Indeno[2,1 -c]azepines Indeno[5 ,4-c]azepines Indeno[7,1 -belazepines Indenot7, I-cdlazepines

V. 5,7,7-Systems

1. Cyclohepta[4,5]thieno[3,2-b]azepines 2. Azuleno[l,8-cdlazepines

VI. 6,6,7-Systems

1. 2. 3. 4. 5 . 6. 7. 8. 9.

10. 1 1 . 12. 13. 14. 15. 16. 17. 18. 19. 20.

Azepino[ 1,2-b][ 1,2,4]benzothiadiazine Azepino[2, I-cl[ 1,2,4]benzothiadiazines Azepino[2,1-b][ 1,3]benzoxazines [ 1,3]0xazino[2,3-a][2]benzazepines Azepino[2, I-bI[ 1,3]benzothiazines AzepinoI2, I-blpteridines Dipyrimido[S ,4-c:4’ ,5’-e]azepines Pyrimido[4’ ,5’:4,5]pyrimido[ 1,2-a]azepines 2,3a,6a-Triazacyclohepta[de]naphthalenes Pyrido[2’ ,3‘:4,5]pyrimido[ I ,2-a]azepines Pyrido[3’ ,2’ :4,5]pyrimido[ 1,2-a]azepines Azepino[ 1,2-a]quinazolines Azepino[ 1,2-c]quinazolines Azepino[2,1 -b]quinazolines Azepino[ 1,2-a]quinoxalines Azepino[2,3-b]quinoxalines Azepino[4,5-b]quinoxalines Pyrimido[4,5-b][ llbenzazepines Pyrimido[4,5-c] [2]benzazepines Dipyrido[2,3-b:4’ ,3’-elazepines

... x111

192 192 194 197 197 198 199 206 207 208 210 210 212 212 213 215 222 223

223

223 224

225

225 226 228 230 23 1 234 234 235 236 236 236 237 240 240 248 250 25 1 256 257 259

xiv Contents

21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52.

Dipyrido[4,3-b:3’ ,4’-flazepines Azepino[ 1,2-b]isoquinolines Azepino[2,l-u]isoquinolines Azepino[ 1,2-u]quinolines Azepino[2,3-b]quinolines Azepino[ 3,2-b]quinolines Azepino[4,3-b]quinolines Azepino[4,5-b]quinolines Pyrido[l,2-6][2]benzazepines Pyrido[2,1 -a] [2]benzazepines Pyrido[2, l-b ][3]benzazepines Pyrido[2,3-b][ l]benzazepines Pyrido[2,3-c J [2]benzazepines Pyrido[3,2-~][2]benzazepines Pyrido[3,4-~][2Ibenzazepines Pyrido[3,2,ljk][ llbenzazepines Dibenz[b,d]azepines Dibenz[b,e]azepines Dibenz[b,f lazepines Dibenz[c, elazepines Naphth[ 1,241azepines Naphth[ 1,2-c]azepines Naphth[l,2,-d]azepines Naphth[ 1,8,-bc]azepines Naphth[ 1,8-cd]azepines Naphth[2,1 -blazepines Napht h[2,1 -c] azepines Naphth[2,3-b]azepines Naphth[2,3-c]azepines Naphth[2,3-d]azepines Pyrazino[ 1,2-bJbenzazepines Pyrazino[2,1 -b][3]benzazepines

VII. 6,7,7-Systems

1. Pyrazino[ 1,2-~:4,5-a]bisazepines 2. 1 Ib-Azabenzo[e,f Iheptalenes 3. Azepino[3,2,l-jk][l,4]benzodiazepines

VIII. .6,7,8-Systems

1. Cycloocta[4,5]pyrimido[ 1,2-u]azepines 2. Benzo[e]cyclooct[blazepines

260 26 1 262 264 266 270 27 1 27 1 283 285 288 290 29 1 294 294 295 297 306 368 545 582 584 589 590 593 594 595 597 598 600 602 602

604

604 604 605

606

606 606

References 608

Contents xv

CHAPTER 11. TWO RINGS

George R . Proctor

AZEPINE RING SYSTEMS CONTAINING

I. Introduction

11. Fused Ring Systems

A. Synthesis B. Reactions

1. 3,7-Systems

2. 4,7-Systems 3. 5,7-Systems

A, Cyclopentazepines B . Furoazepines C. Isoxazoloazepines D. Oxazoloazepines E. Pyrazoloazepines F. Pyrroloazepines G. Thiazoloazepines H. Thienoazepines

A. 1-Benzazepines B. 2-Benzazepines C. 3-Benzazepines D. Pyranoazepines E. Pyridoazepines F. Pyrimidoazepines G , Pyridazinoazepines 7,7 and Higher Ring Systems

4. 6,7-Systems

5.

111. Bridged Bicyclic Ring Systems

1. Azabicylooctanes 2. Azubicyclononanes

A. 2-Azabicyclo[ 3.2.21nonanes B. 3-Azabicyclo[3.2.2]nonanes C. 6-Azabicyclo[3.2.2]nonanes D. 2-Azabicyclo[4.2. Ilnonanes E. 3-Azabicyclo[4.2.l]nonanes F. 9-Azabicycl0[4.2.1 Inonanes G. 6-Oxa-3-azabicyclo[3.2.2]nonanes H. 8-0xa-3-azabicyclo[4.2. llnonanes I. 7-Oxa-8,9-diazabicyclo[4.2. llnonanes J. 7,8,9-Triazabicyclo[4.2. llnonanes

637

637

637

637 638 639 639 640 640 644 645 646 647 648 649 650 652 65 2 67 1 696 738 738 74 I 743 744

744

744 745 745 747 753 753 754 755 757 757 758 75 8

xvi Contents

3. Azabicyclodecanes A. 3-Azabicyclo[3.3.2]decanes B. 9-Azabicyclo[3.3.2]decanes C. 2-Azabicyclo[4.3. Ildecanes D. 3-Azabicyclo[4.3. Ildecanes E. IO-Azabicyclo[4.3. Ildecanes

A. 10-Azabicyclo[4.3.2]undecanes B. 1 I-Azabicyclo[4.4. I]undecanes C. 2-Azabicyclo[4.4. llundecanes D. 3-Azabicyclo[4.4.1 Iundecanes E. 3,1 I-Diazabicyclo[4.4. llundecanes

4. Azabicycloundecanes

IV. Spiro Systems

1 . 6-Azaspiro[3.6]decanes 2. 6-Azaspiro[4.6]undecanes 3. 7-Azaspiro [4.6] undecane s 4. 9-Azaspiro[S .6]dodecanes 5. 2-0xa-7-azaspiro[4.6]undecanes

References

AUTHOR INDEX

759 759 760 76 1 76 1 762 763 763 763 764 765 765

766

766 766 767 767 768

768

785

SUBJECT INDEX 805

CHAPTER I

DIBENZAZEPINES AND OTHER TRICYCLIC AZEPINES

BURTRENFROE

CIBA-Geigy Corporation Ardsley, New York

CLINTON HARRINGTON

Dow Chemical Company Midland, Michigan

I. INTRODUCTION

This chapter reviews the synthesis and chemistry of the 148 tricyclic azepine ring systems that have appeared in the chemical literature through Volume 86 of Chemical Abstracts. Ring systems have been arranged in ascending order of ring size according to the rules of Chemical Abstracts.

The chemistry in this survey ranges from isolated investigations of purely academic interest in heterocyclic chemistry to numerous patents generated by industrial research organizations in their vigorous efforts to uncover new classes of pharmacologically active agents. The largest single system, con- sisting of the dibenz[b,f]azepines (Section VI. 39), reflects the especially intense interest of the pharmaceutical industry in structural modifications of the clinically important antidepressant imipramine. It must be noted that the patent literature does not always provide melting points or other physical data. In this review, only those compounds which were supported by a melting point or boiling point in a patent or journal article are tabulated or discussed in the text.

A common method of forming azepine rings that is reported frequently in the literature is the Beckmann or Schmidt-type ring expansion of a six- membered ketone to a seven-membered lactam. Unfortunately, the struc- tures of the lactams generated in this way are not always firmly established, and the reader should bear this in mind.

A recent review of the reactions of acetylenecarboxylic esters and nitro-

2 Dibenzazepines and Other Tricyclic Azepines

gen heterocycles by Acheson and Elmore (Section VI.24) offers new struc- tural assignments for several ring systems previously thought to contain azepine rings. The tricyclic systems affected, in addition to azepino[ 1,2-a]- quinolines are: azepino[ 1,2-a]- and [ 1,2-c]quinazolines (Sections VI. 12 and VI. 13), azepino[ 1,2-a]quinoxalines (Section VI. 1 3 , azepino[2,1-6]- benzoxazoles (Section IV.4), azepino[ 1,2-a]benzimidazoles (Section IV. 20), and-quite possibly-azepino[2,1-a]isoquinolines (Section VI.23), aze- pino[2,1-blbenzothiazoles (Section IV.7), and azepino[2, I-h Jbenzoselenazoles (Section IV. 13).

11. 3,6,7-SYSTEMS

1. Oxireno[d][ 2lbenzazepines

The only study of derivatives of the oxireno[d][ 2lbenzazepine ring system was reported in 1974 by Hassner and Anderson (l), who found that rear- rangement of the azirine-isobenzofuran adducts l a and l b on neutral alumina gave the 2H-oxireno[d]benzazepines 2a and 2b. Treatment of 2b with HCl/ HOAc under reflux (Eq. 1) gave the diketone 3, and nmr spectra of 2a and 2b closely resembled those of the benzazepines 4a and 4b. These data were

\ ph Ph

la, R = H l b , R = Me

Ph \

'R

Za, R = H Zb, R = Me

HCliHOAc

(R = Me) -

Ph

3

11. 3,6,7-Systems 3

consistent with either the N-oxide 6, arising via 5 (Eq. 2), or the oxide 2b, arising by direct rearrangement of l b (Eq. 3). An authentic sample of 6, prepared by oxidation of 4b with rn-chloroperbenzoic acid (Eq. 4), proved to be different from the rearrangement product of lb. Treatment of 4b with excess rn-chloroperbenzoic acid in refluxing chloroform gave a substance (7) that was identical to the product of room temperature oxidation of 2b.

G I 11

Ph 'ph Ph Fd'Ph

lh 2b

Ph \

m-CIC6H4C07H reflux +

aH m-CIC,HXO,H+ room temp.

R I 'Ph

Ph 4a, R = H 4h, R = Me

2b m-CIC6HoCOlH

Me

7

(3)

(4)

4 Dibenzazepines and Other Tricyclic Azepines

The 2H-oxireno[dJ[2lbenzazepines 2a and 2b were resistant to acid, base, and lithium aluminum hydride (cf. the resistance of tetraphenylethylene ox- ide to these reagents). However, prolonged treatment of 2a with neutral alumina gave the pinacol rearrangement product 8a. The structure was for- mulated as 8a rather than the isomeric ketone 8b on the basis of its infrared absorption at 1710 cm-’.

Ph \

Ph \

8a 8b

2. Benzo[ b]cycloprop[d]azepines

I Ts

I Ts

I Ts

9 10 11, mp 148-149°C

/ Ts 13

I Ts 14

11. 3,6,7-Systems 5

Ross and Proctor (2) have generated an example of the benzo[hl- cycloprop[d]azepine ring system by addition of dibromocarbene to the enol ether 10, as shown in Eq. 5. The dibromo adduct 11 (51-60% yield) can be ring-expanded with silver ion to the benzazocinone 14 (48% yield) or to the bromo ether 13 in refluxing aqueous pyridine (81% yield). The adduct 12, prepared similarly from the corresponding olefin (Eq. 6), did not undergo ring expansion to a benzazocine (as did 11) on treatment with silver ion. Since the isomeric adduct 16 (Section 11.3) also did not undergo ring ex- pansion, it is clear that the ether oxygen is required for this process.

I Ts

I Ts 12

3. Benzo[ d]cycloprop[ blazepines

A single example of the benzo[d]cycloprop[ blazepine ring system is found in the work of Proctor and Ross ( 2 ) , who treated the N-tosylenamine 15 with dibrornocarbene to form 16 in 40% yield (Eq. 7). In a similar manner to 12, compound 16 failed to undergo ring expansion by reaction with silver ion (see Section 11.2).

15 16

6 Dibenzazepines and Other Tricyclic Azepines

111. 5,5,7-SYSTEMS

1. Cyclopenta[ c]tetrazolo[ l,S-a]azepines

2 "-N, 3

9 :-l.'-F 7

The only example to date of cyclopenta[ c]tetrazolo[ 1,5-u]azepines is found in ferrocene chemistry (3). Treatment of 17 with hydrazoic acid (Eq. 8) yields a mixture of 18 (27%) and 19 (10-20%).

18

17

+

19

2. 2,2a,3-Trithia(2a-S'V)-4a-azacyclopent[c~]azulenes

111. 5,5,7-Systems 7

The sodium tert-amylate-catalyzed condensation of two equivalents of carbon disulfide with caprolactam, when quenched with excess methyl io- dide, gave rise to the adduct 20. Replacement of caprolactam with pyrroli- dinone afforded the homolog 21. When 20 and 21 were treated with phos- phorous pentasulfide followed by perchloric acid (Eq. 9), the tricyclic products 22 and 23 were formed in 60 and 41% yields, respectively. Treatment of 22 and 23 with ethanolic ammonia produced 24 and 25 (Eq. lOa), but reaction with aniline (Fig. I) took a different course; compound 22 afforded 26-28, whereas 23 generated 29-31 (4).

In principle, reaction of 22 with ammonia might be expected to give 32 instead of its isomer 24, and 23 could give rise to 33 and not 25 (Eq. lob). Furthermore, 22 and 23 with aniline could give 34 and 35 instead of 26 and 29 (Fig. 1). In order to differentiate between these possibilities, the tricyclic analog 36 was prepared from 37 (Eq. 1 1 ) . Loss of the ethyl signals in the nmr spectrum on reaction of 36 with ammonia was consistent with structure 25 as the reaction product. Likewise, 36 and p-toluidine produced 30 as the

8

path b

Dibenzazepines and Other Tricyclic Azepines

path u

L -

i i

34, n = 4; X = H 26, n = 4 ; X = H 29, n = 2 ; X = H 35, n = 2 ; X = H 27, n = 4; X = Me 30, n = 2; X = Me

28, n = 4; X = OMe 31, n = 2; X = OMe

Figure 1

MeS MesL& 37

36

TABLE 1 . 2,2a,3-TRITHIA(2a-S'")-4a-AZACYCLOPENT[~~]AZULENES

Product mp ("C) Spectra

22 24 26 27 28

190- 193 159-162

154- 156 147-149

168- I70

"Ref. 4.

111. 5,5,7-Systems 9

sole product. These results strongly supported the assignment of the tricyclic structures 24 and 25 to the reaction products obtained from 22 and 23. Table 1 summarizes the physical data for representatives of this system.

3. Dipyrazolo[4,3-~:3’,4’-e]azepines

5

Two examples of the dipyrazolo[4,3-~:3’,4‘-e]azepine system have been reported by Treibs and Lange ( S ) , who prepared the dicyanoazepinone 38 in 63% yield. Treatment of 38 with hydrazine hydrate or phenylhydrazine in SO% aqueous HOAc gave 39a and 39b, respectively (Eq. 12).

haw RNHNM, HN(CH2CH2CN)2 + (COzEt), -

I H 38

I H

39a, R = H; mp 146-147°C 39b, R = Ph; mp 130-131°C

4. Thiazolo[2’,3’ :2,3]imidazo[ 1,5-a]azepines

10 Dibenzazepines and Other Tricyclic Azepines

Only one example of the thiazolo[2',3':2,3]imidazo[ 1,5-a]azepine ring sys- tem has been described in the literature. Condensation of the imino ether of caprolactam 40 with nitromethane (Fig. 2) yielded the nitrovinyl derivative 41. Catalytic reduction afforded the diamine 42, which on reaction with carbon disulfide gave the imidazo[3,4-a]azepine thione 43. Condensation of 43 with phenacyl bromide (Fig. 3 ) gave a single product (69% yield), which was formulated as the tricyclic structure 44 (6).

H21Pt021MeOH P

QOMe = Q I CHN02

H 40 41

H

42

100°C. 6 hr

43

Figure 2

0 I/

( 1 ) PhCCH-Br. r-PrOH 2 hr, reRux

(2) Amberlite IRA-400 (CI 1

Ph

c1-

44, mp 208-210°C

H 45

Pterobiline, Biliverdine IV v

Figure 3

111. 5,5,7-Systems

MeOH. H +

H 46

Phorcabiline, Neobiliverdine v

N

H 48

Figure 3 (continued)

5. Dipyrrolo[ 1,2-a:2’,3’-d]azepines

French workers have studied the structure and biosynthesis of the main bile pigments of Lepidoptera and-by employing field desorption mass spec- troscopy and high-resolution nmr of the natural compounds and of degra-

12 Dibenzazepines and Other Tricyclic Azepines

dation products obtained from thick-layer chromatography-have discov- ered two examples of the dipyrrolo[ 1,2-a:2’,3’-d]azepine ring system in phorcabiline (46) and neobiliverdine 6 (50) (7). It was found that the pigment pterobiline (45) is converted to phorcabiline (46) in vivo and can also be cyclized to 46 on heating (Fig. 3). In similar fashion, biliverdine 6 (49) is converted to neobiliverdine 6 (50) (Fig. 4). Pigment 46 was distinguished from 50 by analysis of mass spectral and nmr patterns and by its conversion to 47 and 48 on treatment with methanol. Neobiliverdine 6, on chromic acid oxidation, yielded fragments 51, 52, and 53, which were isolated from tlc plates and identified by mass spectrometry. More recently, the conversions of 45 to 46 and of 49 to 50 have been carried out photochemically (8).

MeOH. A A

0 0 I

H I

H 49

Biliverdine IV S

H 50

Neobiliverdine S

+ x 2 ) 2 C 0 2 M e

0 q $ ( C H 2 ) 2 C 0 2 h 4 e H 52 H N I 0 53 I H

51

Figure 4