Bicyclic Diazepines: Diazepines with an Additional Ring
Edited by R. Ian Fryer
JOHN WILEY & SONS
This Page Intentionally Left Blank
BICYCLIC DIAZEPINES
This is the Fftieth Volume in the Series
THE CHEMISTRY OF HETEROCYCLIC COMPOUNDS
~~
THE CHEMISTRY OF HETEROCYCLIC COMPOUNDS A SERIES OF MONOGRAPHS
EDWARD C. TAYLOR, Editor ARNOLD WEISSBERGER, Founding Editor
BICYCLIC DIAZEPINES Diazepines with an Additional Ring Edited by
R. Ian Fryer Department of Chemistry, Rutgers, State University of New Jersey, Newark, New Jersey
AN INTERSCIENCE@PUBLICATION
John Wiley & Sons, Inc. NEW YORK / CHICHESTER / BRISBANE / TORONTO / SINGAPORE
In recognition of the importance of preserving what has been written, it is a policy of John Wiley & Sons, Inc., to have books of enduring value published in the United States printed on acid-free paper, and we exert our best efforts to that end. An Interscience@Publication Copyright
0 1991 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 Sections 107 or 108 of the 1976 United States Copyright Act without the permission of the copyright owner is unlawful.
Library of Congress Cataloging-in-Publication Data
Bicyclic diazepines: diazepines with an additional ring 1 edited by R. Ian Fryer. p. cm.--(Chemistry of heterocyclic compounds, ISSN 0069-3154; v. 50) “An Interscience publication.” Includes bibliographical references. ISBN 0471-52148-5 1. Bicyclic diazepines. I. Fryer, R. Ian. 11. Series. RS431.B49B53 1991 547.594~20 89-24943 CIP
Contributions R. Ian Fryer, Department of Chemistry, Rutgers University, Newark, New Jersey 07 102
A. Walser, Chemical Research Department, Hoffmann-La Roche, Inc., Nutley, New Jersey 07 1 10
V
This Page Intentionally Left Blank
The Chemistry of Heterocyclic Compounds Introduction to the Series The chemistry of heterocyclic compounds constitutes one of the broadest and most complex branches of chemistry. The diversity of synthetic methods utilized in this field, coupled with the immense physiological and industrial significance of heterocycles, combine to make the general heterocyclic arena of central importance to organic chemistry. The Chemistry of Heterocyclic Compounds, published since 1950 under the initial editorship of Arnold Weissberger, and later, until Dr. Weissberger’s death in 1984, under our joint editorship, has attempted to make the extraordinarily complex and diverse field of heterocyclic chemistry as organized and readily accessible as possible. Each volume has dealt with syntheses, reactions, properties, structure, physical chemistry, and utility of compounds belonging to a specific ring system or class (e.g., pyridines, thiophenes, pyrimidines, threemembered ring systems). This series has become the basic reference collection for information on heterocyclic compounds. Many broader aspects of heterocyclic chemistry are recognized as disciplines of general significance which impinge on almost all aspects of modern organic and medicinal chemistry, and for this reason we initiated several years ago a parallel series entitled General Heterocyclic Chemistry, which treated such topics as nuclear magnetic resonance, mass spectra, and photochemistry of heterocyclic compounds, the utility of heterocyclic compounds in organic synthesis, and the synthesis of heterocyclic compounds by means of 1,3-dipolar cycloaddition reactions. These volumes are of interest to all organic and medicinal chemists, as well as to those whose particular concern is heterocyclic chemistry. It has become increasingly clear that this arbitrary distinction created as many problems as it solved, and we have therefore elected to discontinue the more recently initiated series General Heterocyclic Chemistry and to publish all forthcoming volumes in the general area of heterocyclic chemistry in The Chemistry of Heterocyclic Compounds series. EDWARD Department of Chemistry Princeton University Princeton, N e w Jersey
vii
C. TAYLOR
This Page Intentionally Left Blank
Preface The completion of this book has been greatly facilitated by the assistance of many people, too numerous to list by name, and the authors acknowledge their generous contributions of time and helpful advice. Special thanks are due to Andre Rosowsky, who, because of the unfortunate delays that occurred in the writing of the book, had to withdraw as editor. His editorial assistance in the early versions of the first few chapters was of inestimable value and provided a guide for the remainder of the work. Special thanks are also due Norman W. Gilman for his critical reading of the manuscript, his numerous helpful suggestions, and his ability to catch typographical mistakes. After completion of the last chapter, it became necessary to update the first four chapters with new material published through 1985. This work was incorporated into the body of these chapters, and the additional references have been included in the numbered reference lists. Our thanks are due to Zi-Qiang Gu and to Julia C . Pinto, who carried out a great portion of these revisions and additions. The format generally followed for the presentation of these bicyclic diazepine compounds has been to discuss each system, first in order of ring fusion (i.e., [a]fused before [b]-fused, etc.) and then by increasing size of the fused ring, least degree of saturation first, with discussions of carbocyclic fused rings preceding those of heterocyclic fused rings. In instances where the benzene annelated ring system was the most important, this ring system was given preference over other fused ring systems. The volume of material to be covered for the [el-fused[1,4]benzodiazepines was too great to allow use of this format and still retain some sense of clarity and ease of reading. It was therefore decided to divide these structures into five chapters. The first four of these, Chapters V-VIII, cover benzodiazepines, dihydrobenzodiazepines, dihydrobenzodiazepinones and -thiones, and tetrahydrobenzodiazepines. The literature was surveyed through 1983 for Chapters V and VI, and through 1984 for Chapters VII and VIII. Chapter IX covers other fused[e] [ 1,4]-diazepine ring systems, the literature being surveyed through 1985. Previous reviews of bicyclic diazepines have been noted and the material covered in such reviews has been incorporated in related chapters. 1,5Benzodiazepine compounds are discussed in Chapter IV, under 1,4-diazepines with [bl-fused rings. The literature subsequent to the cutoff dates for the bicyclic benzodiazepines has been largely due to the finding that, by appropriately substituting 1,4benzodiazepine derivatives in the 3-position, it is possible to prepare compounds that are biologically active as cholecystokinin (CCK) receptor antagonists [see e.g., B. E. Evans et al., J . Med. Chem. 30,1229 (1987)l. No attempt has been made to summarize this work. Most other 1,4-benzodiazepine chemistry ix
X
Preface
currently reported relates to either tricyclic or tetracyclic ring systems and is beyond the scope of this review. Bridged diazepines are also considered to be beyond the scope of this review and are therefore excluded from discussion. Finally, the authors express their gratitude to Professor E. C. Taylor, whose patience and understanding has been very much appreciated. R. IAN FRYER A. WALSER Newark, N e w Jersey Nutley, N e w Jersey June 1989
Contents
........... ..........
1
. ....................
89
.....
183
..........
209
. ...... .. ., ..........
431
I. BICYCLIC-1,2-DIAZEPINES R. IANFRYER and A. WALSER 11. BICYCLIC-1,3-DIAZEPINES
R. IANFRYER and A. WALSER 111. 1,CDIAZEPINES WITH [a]- OR [&FUSED RINGS. R. IANFRYER and A. WALSER
IV. [1,4]DIAZEPINES WITH [bl-FUSED RINGS R. IANFRYER and A. WALSER
V. 1,CBENZODIAZEPINES . . A. WALSER and R. IANFRYER
.. . . ..... ...-
--
545
VII. DIHYDRO-1,4-BENZODIAZEPINONES AND THIONES A. WALSER and R. IANFRYER
..
631
VI. DIHYDRO-1,CBENZODIAZEPINES. A. WALSER and R. IANFRYER
VIII. TETRAHYDRO- AND POLYHYDRO-1,4-BENZODIAZEPINES ................................... 849 A. WALSER and R. IANFRYER IX. HETERO RING[e][1,4]DIAZEPINES A. WALSER and R. IANFRYER
...... . . . .. .. ..
947
. . . . . . . . . . . . . . . . . . . . . . . . . . . 1053 SUBJECT INDEX. . . . . . . . . . . . . . . . . . . . . . . . . . . . l o 9 1 AUTHOR INDEX.
xi
This Page Intentionally Left Blank
CHAPTER I
Bicyclic 1.2.Diazepines R . Ian Fryer Department of Chemistry. Rutgers. State University of New Jersey. Newark. New Jersey
and
.
A Walser Chemical Research Department. Hoffmann-La Roche Inc., Nutley. New Jersey
A . [a].Fused[l. 2ldiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4
1. Pyrazolo[l. 2.a] 11.2ldiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4
2. Pyridazino[l. 2.a] [l.2ldiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6
3. [1.2.4]-Triazolo[l. 2.a] [l.23diazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7
B. [b]-Fused[1.2]diazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9
1. Azetoll. 2-b] [l.Zldiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9
2. 1.2.4-0xadiazolo[4. 5 4 1 [l.Z]diazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10
3. Pyrrolo[l. 2 4 1 [l.Zldiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
11
4. ThiazoloC3.2.b] [l.Zldiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
12
C . [c]-Fused[1.2]diazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Benzo[c] 11.2ldiazepines (1.2.benzodiazepines) . . . . . . . . . . . . . . . . . . . . . . . . . .
12 13
1.1. lH.l. 2-Benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
13
1.1.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1.2. Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1.2.1. Reactions with electrophiles . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1.2.2. Reactions with nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1.2.3. Oxidation reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1.2.4. Acylation reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
13 18 18 20 20 21
1.2. 3H.1. 2.Benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2.2. Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2.3. Spectral data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1
21 21 22 23
Bicyclic 1.2.Diazepines
2
1.3. 5H.1,2.Benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
23
1.3.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.3.2. Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
23 24
1.4. Dihydro-1, 2-benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
24
1.4.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.4.2. Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
24 26
1.5. Tetrahydro-1, 2-benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
26
1.5.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
26
1.6. Hexahydro-1,2-benzodiazepines .................................
27
1.6.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.6.2. Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
27 28
2. Cyclopenta[c] [I, 2ldiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
28
3. Cyclopropa[c] [l, 2ldiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
29
3.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
29
4. Heterolc] [1,2]diazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
29
D . Id]-FusedCl, 2ldiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Benzo[d] [1. 2ldiazepines (2.3.benzodiazepines) . . . . . . . . . . . . . 1.1. 1H.2, 3.Benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . .
33
. . 33 . . 33
1.1.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1.2. Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2. 3H-2,3-Benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
33 34 35
1.2.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
35
1.3. 5H-2,3-Benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
36
1.3.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.3.2. Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.3.3. Spectral data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
36 36 39
1.4. Dihydro-2, 3-benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
41
......................... 1.4.1. 4,5-Dihydro-lH-2,3-benzodiazepines. .......................... 1.4.2. 4,5-Dihydro-311-2,3-benzodiazepines 1.4.3. Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
41 41 43
1.5. Dihydro-2,3.benzodiazepinones. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
44
2,3.Dihydro.2,3.benzodiazepin.l(lH ).ones . . . . . . . . . . . . . . . . . . . . . . 2,5.Dihydro.2,3.benzodiazepin.l(lH ).ones . . . . . . . . . . . . . . . . . . . . . . 3,5.Dihydro.2,3.benzodiazepin.4(4H ).ones . . . . . . . . . . . . . . . . . . . . . . Reactions . . . . . . . . . . . . . . . . . . . . ...................... 1.5.4.1. Reactions with electrophiles . . . . . . . . . . . . . . . . . . . . . . . . . . 1.5.4.2. Reactions with nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . 1.5.5. Tetrahydro.2,3.benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.5.6. Tetrahydro.2, 3.benzodiazepinones . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 . Cyclopenta[d] [1,2]diazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
44 44 45 47 47 48 49 50
3. Cyclopropa[d] [1.2]diazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
52
4 . Oxireno[d] [1.2]diazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
52
5 . Pyrazolo[3, 4-d] [I. 2ldiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
54 54
5.2. Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
54
1.5.1. 1.5.2. 1.5.3. 1.5.4.
51
Introduction
3
6. Pyrido[3,2-d] [1,2]diazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
56
7. Thieno and Other HeteroCd] [l,Z]diazepines . . . . . . . . . . . . . . . . . . . . . . . . . . .
56
7.1. Synthesis.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2. Reactions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
56 58
E. Tables of Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
59
F. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
86
INTRODUCTION This chapter reviews the synthesis and chemistry of 1,2-diazepines of structure 1, with an additional carbocyclic or heterocyclic ring, of any size, fused to bonds a-d. Sections A to D of the chapter correspond to the site of annelation. These sections are subdivided according to the nature of the added ring. When necessary, compounds are arranged in groups according to the degree of saturation, with fully unsaturated species taking precedence.
For both the [ c l - and [dl-fused ring systems, benzannelated compounds represent the largest class and are given preference over other systems. In some instances, the small amount of published data does not warrant a separate section for the reactions of the compounds under discussion. Bridged sevenmembered rings are not covered. All compounds are named and numbered according to current Chemical Abstracts practice. 1,2-Diazepines have been reviewed previously by M. Nastasi [Heterocycles, 4, 1509 (1976)l; F. D. Popp and A. C . Noble (in Advances in Heterocyclic Chemistry, Vol. 8, A. R. Katritzky and A. J. Boulton, Eds., Academic Press, New York and London, 1967, p. 21); J. A. Moore and E. Mitchell (in Heterocyclic Compounds, Vol. 9, R. C . Elderfield, Ed., Wiley, New York, 1967, p. 224); G. A. Archer and L. H. Sternbach [Chem. Rev., 68, 747 (1968)l; and A. Nawojski [ Wiadomoici Chemi, 12,673 (1964)l. A review of 1,2-diazepines [V. Snieckus and J. Streith, Acc. Chern. Res., 14, 348 (1981)] also includes some bicyclic derivatives. One additional review article, covering 1,2-benzodiazepines and related compounds by T. Tsuchiya, appeared in Yuki Gosei Kagaku Kyokashi [39, 99 (1981); in Japanese].
Bicyclic 1,2-Diazepines
4
A. [a]-FUSED [1,2]DIAZEPINES This section is devoted to bicyclic systems of general structure 2. The few representatives of this system which are described in the literature are discussed in alphabetical order.
1. PYRAZOLO[1,2-a] [1,2]DIAZEPINES None of the three possible tautomeric forms 3a-3c of the unsaturated ring system has been reported in the literature. Only the synthesis of either partially o r fully saturated compounds, which are named and numbered as derivatives of 1,7-diazabicyclo[5.3.O]decane (4), has been described.
lH,SH-Pyrazolo[1,2-a] [ 1,2]diazepine
3b 1H.7H-Pyrazolo[ 1,241 [1,2]diazepine
3c
1H9H-Pyrazolo11,241 [l,Z]diazepine
4
1,7-Diazabicyclo[S.3.O]decane
The highly substituted 2,3-dihydro- 1H,SH-pyrazolo[ 1,2-a] [1,2]diazepines 8 were synthesized by Ulbrich and Kisch.' Photoinduced addition of iron pentacarbonyl to the pyrazolines 5 led to the complexes 6, which were then allowed to react with diphenylacetylene (Eq. 1) to form new complexes formulated as 7. Oxidative cleavage of the latter with bromine gave the diazepines 8. The structures of 8 were assigned on the basis of analytical and spectral data and were supported by a few reactions. Thus 2 mol of bromine added to 8 (R = i-Pr) to yield the tetrabromo derivative 12, which was not fully characterized but could be reconverted to the starting material by reduction with zinc in dimethyl sulfoxide. Thermolysis of 8 (R = Ph) gave the fragments 9,10, and 11, which can be derived from the assigned structure.
1. Pyrazolo[ 1,2-a] [1,2]Diazepines
5
R Ph Br,
c
P
h\
/ Ph
/
Ph
GN 2 COOMe R 0 COOMe 8
I
/
+ COOMe 9
10
0
Ph
COOMe
11
12
(1)
A pyrazolodiazepine with a saturated seven-membered ring, compound 16, was obtained' by thermolysis of the pyrazolium chloride 14 via the chloropentylpyrazolone 15. The pyrazolium salt was accessible by the reaction of N-aminopiperidine with methyl propiolate (Eq. 2) followed, by treatment of the resultant spirane 13 with hydrochloric acid. The structure assigned for 16 is supported by physical data, including I3C-nmr spectra.
c1-
16
Bicyclic 1,2-Diazepines
6
The one-pot preparation of the fully saturated parent compound 17 by condensation of pyrazolidine with glutaraldehyde, followed by reduction with .~ sodium cyanoborohydride (Eq. 3) was reported by Nelsen and W e i ~ m a nThis compound and the homologous pyridazino[ 1,2-a] [ 1,2]diazepine 194 were used with other tetrasubstituted hydrazines in physicochemical studies. In an attempt to determine the conformations of mono and bicyclic hydrazines, Nelsen and Buschek' applied photoelectron spectroscopy and estimated the dihedral angle of the lone pairs of electrons on the two nitrogens in the predominant conformer of compound 17 to be 138". This value lies between the angles found for the two possible trans conformations of the monocyclic pyrazolidines. In a later study6 13C-nmr spectroscopy was used to determine the conformations of 17 and 19 and the equatorialkquatorial confirmation was found to predominate, although the spectra were not too informative due to a broadening at low temperatures (down to - 127°C). This was attributed to the flexibility of the seven-membered ring. The same compounds were compared with other tetraalkylhydrazines in an investigation4 of single-electron oxidation equilibria. On the basis of these experiments, it was concluded that the formation of the radical cation occurs preferentially in the seven-membered ring rather than in either the five- or six-membered ring.
17
2. PYRIDAZIN0[1,2-a] [1,2]DIAZEPINES
I8a 6H-Pyridazino[1,2-a][1,2]diazepine
I8b 8H-PyridazinoC1,241[1,Z]diazepine
The parent ring system may exist formally as either of the tautomeric forms 18a or 18b. The only reported compounds belonging to this class are the fully saturated octahydropyridazino[ 1,2-a] [1,2]diazepines related to 19. The unsubstituted derivative was prepared by reductive condensation of hexahydropyridazine with glutaraldehyde in the presence of sodium cyanoborohydride (Eq. 4).4Compound 19 may also be named 1,7-diazabicyclo[5.4.O]undecane.
I
3. [ 1,2,4]Triazolo[ 1,241 [1,2]Diazepines
19
The synthesis of other a-fused derivatives has been reported in a U.S. patent.76 In general, the synthesis starts from the known benzyloxycarbonylprotected hexahydropyridazine (20), which is acylated by a 2-substituted 1,Spentandioic acid chloride ester. Deprotection of the amine and ester 21 followed by cyclization affords the diazepine 22. Removal of the t-Bu ester group at C-1 followed by conversion of the acid, Q = C1 to the corresponding Q = phthalimido derivative and finally to the amine 23 completes the synthetic scheme (Eq. 5). The patent further describes substitution of the primary amine. n
I ? ?
BzOC(CH2)>CHCOCI
c
COOt-Bu
Q
20
21
i tt-
COOH 23
t-BuOH
4
~
cq ~
J
0
Q
~
COOt-Bu
22
3. [1,2,4]TRIAZOLO[1,2-a] [1,2]DIAZEPINES Compounds belonging to the fully saturated parent ring system were first prepared by Zinner and D e ~ c k e r .A~ double alkylation of the dipotassium salt 25 with 1,5-dibromopentane in dimethylformamide (Eq. 6 ) gave the triazolodiazepines 26. More recently, a number of compounds of general structure 26, where R represents a substituted phenyl moiety, appeared in the patent literature.8 These compounds were prepared by the same alkylation process or by the cyclization of the carbamates 27 (X = 0). The dithione 28 (Y = S and R = 4-ClC6H,) was accessible either by reaction of the dione 26 with phosphorus pentasulfide or by condensation of the
~
~
8
Bicyclic 1,2-Diazepines
24b IH,7H-[ 1,2,4]Triazolo[1,2-a] [1,2]diazepine
24a 1H,SH-[ 1,2,4]Triazolo[ 1,2-a] [ 1,2]diazepine
24r lH,9H-[ 1,2,4]Triazolo[1,2-a] [1,2]diazepine
3
K +-N K + -N(,
X
n Br(CH,),
N-R
0 25
I
28
(from 26, Y = S) (from 27, Y = 0)
thiocarbazide 29 with carbon disulfide.8b. Various monothiones were prepared by thermal cyclization of the urethanes 27 (X = S) in boiling cumene.8a3b In what appears to be a typographical error, the structures of the 1,2,6,7,8,9hexahydro-5H-[1,2,4]triazolo[ 1,2-a] [1,2]diazepinium salts, 30, have been assigned to compounds derived from the treatment of an azomethine with a diazonium s a k g These compounds probably should be redrawn as the more likely [1,2,3]triazolo[3,4-a]azepinium salts 31.
BF, 31
9
1. Azeto[1,2-b] [1,2]Diazepines
B. [bl-FUSED [1,2]DIAZEPINES
32
Only four known bicyclic systems with the general structure 32 have been reported in the literature; these are discussed in alphabetical order in this section.
1. AZETO[l,Zb] [1,2]DIAZEPINES
33
34 1,2-Diazabicyclo[5.2.O]nonane
Representatives of ring system 33 were synthesized by Streith and coworkers", b y the cycloaddition of ketenes to l-acyl-lH-l,2-diazepines (Eq. 7). The compounds were named as derivatives of 1,2-diazabicyclo[5.2.O]nonane 34. Thus, the reaction of a chloroketene generated in situ with 35 (R, = Ph) gave the adduct 36 (R, = H, R, = C1) with a trans configuration. The cycloaddition of methylchloroketene led to a mixture of two diastereomers whose configurations were assigned on the basis of spectral data including nuclear Overhauser effects.
.ti, 35
I
R1 36
Although yields were given for several analogs, the initial publication" gave the spectral data and melting point only for 36 (R, = Ph, R, = H, R, = Cl). A later publication' reported the addition of phthalimidoacetyl chloride to 35 (R, = EtO), which led to 36 (R, = EtO, R, = H, R, = 2-phthalimido) in 91% yield. Removal of the phthalimido protecting group afforded the corres-
10
Bicyclic 1,2-Diazepines
ponding amine 36 (R, = EtO, R, = H, R, = NH,), which was reacylated with various aromatic carboxylic acids in the presence of dicyclohexylcarbodiimide. Evidence for the assignment of the diene structure as shown in 36 included the formation of a Diels-Alder adduct between 36 and tetracyanoethylene. X-Ray analysisI2 of 36 furnished the final proof of structure. Additional work by Streith et al. has expanded the use of these 2 + 2 cycloadditi~ns.'~~
2. 1,2,4-OXADIAZOLO[4,5-6] [1,2]DIAZEPINES
37
Although the parent ring system 37 is still unknown, substituted derivatives of the 5,9a-dihydro analog 39 were preparedI3 in good yields by a 1,3-dipolar addition of nitrile oxides to the acylated 1,2-diazepines 38 (Eq. 8). The site of cycloaddition was derived from spectroscopic data, including l3C-nmr spectra, and is in agreement with Huisgen's rule for 1,3-dipolar additions. The addition of mesitylnitrile oxide to 38 usually gave crystalline adducts, while the products obtained by the cycloaddition of benzonitrile oxide were described as unstable oils and were characterized only by spectroscopic data. In one case (starting with 38, R, = EtO; R, = Me) a 1:2 adduct with benzonitrile oxide was isolated
38
N 0' \\Ph
M8h 'Y
COOEt 40
41
3. Pyrrolo[1,2-b] [1,2]Diazepines
11
in low yield and assigned structure 41. Since this compound could not be prepared from 39 (R, = EtO; R, = Me; R, = Ph) under the same cycloaddition conditions, the authors concluded that 41 probably is formed from an initial slow addition of benzonitrile oxide to the d-bond of 38, leading to the intermediate 40, followed by a fast reaction of 40 with a second molecule of nitrile oxide to yield the isolated product, 41.
3. PYRROLO [1,2-b] [1,2]DIAZEPINES
A 42b 3H-PyrroloC1,2-b][1,2]diazepine
42a
1H-PyrroloC1,2-b]-
[1,2]diazepine
42c SH-Pyrrolo[ 1,2-b][1,2]diazepine
p i 42d
6H-Pyrrolo[ 1,2-b][1.2ldiazepine
42e
SH-Pyrrolo[ 1,2-b][ 1,2]diazepine
None of the five possible tautomers 42a-42e of the parent ring system has been described in the literature. 2,5-Disubstituted 3H-pyrrolo [1,241 [1,2]diazepines (44) were obtained by Flitsch and coworker^'^ by the acidcatalyzed condensation of 1-aminopyrrole 43 with lP-diketones (Eq. 9). The 1,l-bipyrryls 45 were also isolated as major by-products.
44
The structures of compounds 44 were compatible with spectroscopic data. Other, energetically less favored tautomers, were excluded on the basis of nmr data.
12
Bicyclic 1,2-Diazepines
4. THIAZOLO[3,2-b] [1,2]DIAZEPINES
46
Representatives of the parent ring system 46 have been claimed incorrectly to be accessible by addition of dimethylacetylene dicarboxylate to N-aminothiazolium salts 47 (Eq. 10).15Potts and Choudhury'6 reinvestigated this reaction and found that the products were not thiazolodiazepines, but rather the pyrazoles 49.
MSO-
+ 41
COOMe I C Ill * MeOOC
7COOMe
COOMe
COOMe
Meoocn 48
COOMe
"
MeOOC
sd~ "COOMe 49
C. [C] -F USED [1,2] -DIAZEPINES
50
This section is concerned with bicyclic systems of general structure 50. The benzo[c] [ 1,2]diazepines, which constitute the largest group of compounds within this structural class, are discussed first. Other [cl-fused [1,2]diazepines ring systems follow in alphabetical order in Sections 2 4 .
13
1. Benzo[c] [1,2]Diazepines (1,2-Benzodiazepines)
1. BENZO[c] [1,2]DIAZEPINES (1,2-BENZODIAZEPINES)
51a
1 N -1,2-Benzodiazepine
51b
3H- 1.2-Benzodiazepine
51c
SH-1,2-Benzodiazepine
If the energetically less favored quinoidal tautomers are disregarded, 1,2benzodiazepines can occur in the three possible tautomeric forms 51a-51c. No report of the synthesis of the parent ring system for 5H-1,2-benzodiazepine (51c) was found during our literature search. 1.1. 1H-1,ZBenzodiazepines
1.1.1. Synthesis The parent ring system 51a together with substituted analogs were first synthesized in 1977 by Tsuchiya and coworkers." Photolysis of N-iminoquinolinium dimers of type 54 in a mixture of methylene chloride and acetic acid (Eq. 11) led to the diazepines 55 in yields of 5-80%. The parent quinolines 52 and 2-aminoquinolines 57 were minor by-products of this reaction. The dimers were synthesized by carbonate treatment of the intermediate N-aminoquinolinium mesitylenesulfonates 53, which were prepared by N-amination of the corresponding quinolines 52 with 0-mesitylenesulfonylhydroxylamine. The authors reported that nmr spectra of the dimers 54 recorded in the solvents used for photolysis indicated the presence of an equilibrium mixture of both 54 and the monomeric ylide 56. A mechanism for the ring expansion of the ylide via the corresponding diaziridine followed by valence tautomerization was proposed in analogy with previously reported ring expansions of N-amino heterocycles (See Section 1.4.1 and Ref. 24). The structures of the benzodiazepines were established both by spectroscopic data and by chemical transformations. While the synthetic utility of this method was not extensively investigated, the approach appears to be limited by the accessibility of the ylide dimers 54. Thus, although a number of substituted N-aminoquinolinium salts 53 were prepared, not all these compounds formed the dimers 54. Attempts to obtain benzodiazepines by treatment of the salts 53 with aqueous sodium carbonate and methylene chloride followed by direct irradiation of the organic phase were not successful. Another synthesis of 1H - 1,2-benzodiazepines, reported by Garanti and coworkers." involves the intramolecular addition of a nitrile imide to an olefin
14
Bicyclic 1,2-Diazepines
and is especially useful for the preparation of 1H - 1,2-benzodiazepines with substituents in the 3- and 4-positions. Treatment of the phenylhydrazoyl chlorides 60 (R3 = H) with triethylamine in boiling benzene led to HCl elimination and generated a transient nitrile imide, which cyclized immediately to the benzodiazepines 61 in good yields (Eq. 12). Compounds 60 were prepared by coupling of the diazonium salt 58 with ethyl 2-chloroacetoacetate or, in some instances, by dehydration of the carbinol59 in the presence of catalytic amounts of p-toluenesulfonic acid. By introducing the olefinic bond after the coupling reaction, the cyclization of the diazonium salt 58 to a cinnoline by-product was suppressed. Compound 60 (R, = Me; R,, R, = H) gave, in addition to the corresponding benzodiazepine 61, the isomer 62 (R2, R, = H) with the exocyclic double bond. The latter did not isomerize to 61 under the reaction conditions, implying that 62 was formed by a competing reaction pathway. Compounds 60 with a terminally djsubstituted styrene (R,, R, # H) yielded the cyclopropa[clcinnolines 63 under the same conditions. The tetrasubstituted olefin 60 (Rl, R,, R, = Me) gave the cinnoline 63 together with a 10% yield of the benzodiazepine 62 (R,, R, = Me).
1. BenzoCc] [1,2]Diazepines (1,2-Benzodiazepines)
15
58 59
It was found that 3-carbethoxy compounds related to 61 (e.g., 64) could be hydrolyzed with ethanolic sodium hydroxide to give the corresponding acids 65 in high yield. Thermal decomposition of these acids did not lead to the characterized decarboxylated products (Eq. 13).77
peon .o$:500H H
OH
R1
R2
64
R1
R2
65
lA
(1 3)
mainly ring-open derived products The authors explained the mechanism of formation of the products as proceeding by an intramolecular nucleophilic attack of the double bond on the electron-deficient carbon atom of the generated nitrile imide (Eq. 14). This would result in the formation of the dipole 66, which is a valence tautomer of the tricyclic compound 67 and also of the 4H- 1,2-benzodiazepine 68. These high
Bicyclic 1,2-Diazepines
16
61-63
*
I f’ 68
energy intermediates would then be stabilized by prototropic shifts or by electrocyclic reactions to form the observed products 6143. This synthetic method is not limited to the benzodiazepine-3-carboxylates 61, as was later demonstrated by the same group.lg Several 7-chloro-5-phenyllH-l,2-benzodiazepines with electron-withdrawing substituents other than carbethoxy in the 3-position were prepared in good yields. Also reported by the Garanti group was the use of 1-nitrohydrazones 69 as precursors rather than the 1-chloro compounds 60. These intermediates allowed the preparation of 3-unsubstituted (or 3-alkyl-substituted) 1H-1,2benzodiazepines 70 (Eq. 15).78
69
70
The acid-catalyzed rearrangement of cyclopropa[c]cinnolines (63) to give 1,2-benzodiazepines 71 seems to be of limited utility, since yields vary widely depending on the nature of the substitution of the fused cyclopropane ring. Besides the ring-expanded compound, varying amounts of fragmentation products were also obtained.79 Oxidation of the 5-hydroxy compound 72 with activated MnO, led to the ketone 73 (Eq. 16). In closely related work, Padwa and Nahm treated the N-substituted o-vinyl phenylhydrazone 60 (Rl, R,, R, = H) with base at 80°C and obtained the corresponding diazepine 63 in 91% yield.80 If the reaction was carried out at room temperature in the presence of silver carbonate, the only product obtained was the cinnoline 63 ( R l , R,, R, = H) in 92% yield. Compound 63 could be
17
1. Benzorc] [1,2]Diazepines (1,2-Benzodiazepines)
H COOEt COOEt
QCOOEt R H z COOEt
OH 71
63
R = Me, Ph-
(16)
72
OOEt 73
61
(17)
thermally converted at 80°C to the 1,2-benzodiazepine 61. This ring expansion is readily explained in terms of an initial electrocyclic ring opening of the cyclopropane ring, followed by a 1,5-sigmatropic shift to give the more stable 1H tautomer. Further mechanistic studies on these cycloadditions and rearrangements* were carried out in which the proposed o-quinoidal intermediate 75 was captured as the acetate 76 (Eq. 18). Thus treatment of either the endo or exo
_____) A
[edlg
OOMe]
Me Me
75
74
(18)
iHOAC
H
H
-0OMe
G
OAk 77
Me
O OAc 76
O
M Me
e
18
Bicyclic 1,2-Diazepines
form of the cinnoline 74 with acetic acid gave 76 in high yield. A I3C-nmr spectrum of 76 showed a signal at 142.6 ppm, consistent with structure 76. Heating this compound in toluene with a trace of acid afforded the thermodynamically more stable isomer 77 (Eq. 18).The formation of the cis isomer was explained on the basis of kinetic attack of acetate on 75 from the least hindered position. A variety of 3-substituted lH-1,2-benzodiazepines were also accessible” by the reaction of 3H- 1,Zbenzodiazepine 2-oxides 78 with nucleophiles under both acidic and basic conditions (Eq. 19).Treatment of 78 with dry hydrogen chloride in ether gave the 3-chlorobenzodiazepines 79 (X = C1) in about 90% yield. While sodium methoxide in methanol converted 78 to the 3-methoxy derivatives 79 (X = MeO), the stronger base, ethoxide in ethanol, gave mainly the quinolines 80 together with small amounts of 79 (X = EtO). Reaction of 78 with a cyanide in methanol resulted in mixtures containing the nitrile 79 (X = CN), the corresponding amide (X = CONH,) and the ester (X = COOMe). Dimethyl malonate anion converted 78 to the malonyl derivatives 79 [X = CH(COOMe),], although these compounds were not obtained in a crystalline state. The structures of these 3-substituted benzodiazepines were assigned on the basis of spectroscopic data. The authors rationalized their findings by proposing mechanisms for both the acid- and base-promoted reactions.
78
19
80
Since the lH-l,2-benzodiazepine appears to be the thermodynamically most stable tautomer, this compound can also be prepared by isomerization of the corresponding 3H tautomer. The 3H-172-benzodiazepines 81 (R = H, Me) were foundz1 to rearrange almost quantitatively to the corresponding 1H tautomer 82 under the influence of either basic or acidic catalysts (Eq. 20). The reaction of tropone tosylhydrazone sodium salt (85) with acetylenes (e.g., 86a-86c) afforded the benzodiazepines 89a-89c in 33-52%0 yield. The cyclo-addition and rearrangement most probably proceeds via the norcaradiene intermediate 88.*’
1.I .2. Reactions 1.1.2.1. Reactions with Electrophiles Methylation of 82 to the 1-methyl derivatives 83 was achieved in high yield2’ by using butyllithium and methyl iodide at low temperature (Eq. 20).
I
R
/
1
R
I . BuLi
81
2 . Mcl
Me
@ /
;;.;dye
0"" \
&ooR1 \
R
R I = H , Me
83
i
hv. 02.dye
Me I
& d; OCH,
N
N
H
from 82 (R = Me)
Qf-JO
R, = CHO, from 82 (R= H ) R , =Me, from 82 ( R = Me)
R
84
i WN\ + R 86, c = c R ~ - [ ~
Na N-N-TS 85
R, = R, = COOEt 86b. R, = Rj = C O O M e 86c. R, = H,RZ = COOEt 86%
WRl H
89
19
87
i 88
Bicyclic 1,2-Diazepines
20
Dye-sensitized photooxidation of compounds 82 (R = H, Me) gave an array of productss3 containing either benzaldehyde (27%) or acetophenone (30%), cinnamic acids (lo%), and their corresponding esters (20%). In addition, compound 82 (R = H) yielded 2-3% of indazole-3-carboxaldehyde,while the 5-methyl derivative 82 (R = Me) gave 6% of 3-methy1-3-(2-methoxyethen-l-y1)3H-indazole and 3% of 3-methylindazole. These products are believed to arise from 3H-benzodiazepine-3-hydroperoxidesand 5H-benzodiazepine-5-hydroperoxides. Similar oxidation of the 1-methyl derivatives 83 gave the 3-ones 84 in good yield. 1.1.2.2. Reactions with Nucleophiles Treatment of 82 with sodium ethoxide in ethanol'7b resulted in conversion to the 2-aminoquinolines 92 in high yield (Eq. 22). This ring contraction has been postulated to proceed via the ring-opened nitrile 90 formed by an initial proton abstraction from the 3-position followed by N-N bond cleavage. Recyclization of the nitrile intermediate would then lead to 92.
R
90
82
R
R 91
92
Another reductive ring contraction with loss of ammonia was observed'7b during the hydrogenation of 82 over palladium on carbon. The formation of the quinoline 91 under these conditions may be explained by a reductive cleavage of the N-N bond to form an aminoimine, which could then cyclize with the elimination of ammonia.
1.1.2.3. Oxidation Reactions Treatment with lead tetraacetate of lH-l,2,-benzodiazepines 93, having an electron-withdrawing group such as methoxycarbonyl or cyano in the 3-position, resulted in the formation of the corresponding 5-acetoxy-SH-1,2benzodiazepines 94 in 68% yield. These compounds were the first examples of 5H-1,2-benzodiazepines reported by Tsuchiya and Kurita.'"
21
1. Benzo[c] [1,2]Diazepines (1,2-Benzodiazepines)
H OAc Pb(OAc),
-
m R N" H
R
=
*
O
R
(23)
94
93 COOMe, CN
1.1.2.4. Acylation Reactions (95; R = H) with ethyl The reaction of 3-methyl-lH-l,2-benzodiazepine chloroformate in benzene at room temperature, gave the exo-methylene compound 96 and 2-methylquinoline N-ethoxycarbonylimide (97) as products. The formation of a 1,3-diazepine (98) was not observed. However, when the R group in the 7-position of 95 was an electron-donating group such as a methyl or methoxy group, the formation of 3-ethoxycarbonyl-lH-1,3benzo[d]diazepines (98) was obtained in addition to the em-methylene compound 96 and the quinoline N-imides 97 (Eq. 24).88,l o 3
Rm"m
+
+
Me
N" H
H
N
- N-COOEt 97
%
95
R
96
H Me
52 50 22
OMe
\COOEt
Yield (%)98 97 6 21 8
' r A N C 0 O E t
N'
Me
98
2-3 10 (24)
1.2. 3H-1,2-Benzodiazepines
I .2.1. Synthesis The parent compound 81 (R = H) and its 5-methyl derivative (R = Me) were prepared in almost quantitative yield by Tsuchiya and Kuritaz1Sz3 b Y dehydrogenation of the corresponding 2,3-dihydro- 1H-1,2-benzodiazepines 99 with 4-phenyl-1,2,4-triazoline-3,5-dione (Eq. 26).
Bicyclic 1,2-Diazepines
22
q H
,qN-,, 0 (25)
R
R
99
81
(R = H, Me)
The 3-acetoxy-3H-l,2-benzodiazepines 100 (R, = Ac) were obtained by oxidation of 82 with lead tetraacetate in methylene chloride” or by treatment of the 2-oxide 78 with acetic acid.’Ob Compounds 100 (R, = Me) were prepared’, from 82 by an oxidative addition of methanol using cupric nitrate in methanol (Eq. 26).
I .2.2. Reactions Since the 3H-benzodiazepines are thermodynamically less stable than the corresponding 1H tautomers, the treatment of 81 with acid, base, or heat resulted in conversion to 82 (Section 1.1.1). Oxidation of 81 with m-chloroperbenzoic acid (Eq. 27) led to a 3 : 1 mixture of the 2-oxides 78 and the 1-oxides 101. The products were separated by chromatography and the structures assigned on the basis of ‘proton-nmr Irradiation of the diazepine 81 (R = H) in methylene chloride solution with a high pressure mercury lamp gave 90% of 3-vinylindazole 103 and 1-2% of the indene 104 (R = H).’7a The 5-methyl analog 81 (R = Me) yielded no indazole under similar conditions, but gave instead a 70% yield of the 3-methylindene 104 (R = Me). This apparent discrepancy may be rationalized by the following mechanistic considerations. Thus, when R = H, the intermediate 102 can be stabilized by a 1,3-proton shift to form the indazole 103. When R = Me, however, the intermediate can eliminate nitrogen and recyclize to the observed indene 104.
1. Benzo[c] [1,2]Diazepines (1,2-Benzodiazepines)
102
23
103
R = n,
R I04
1.2.3. Spectral Data References to characteristic spectral features are given in the tables of compounds (Section E). Kurita and T ~ u c h i y a ” ~recorded the temperaturedependent proton-nmr spectra of compounds 81 (R = H, Me) and determined the energies of activation for the inversion of the seven-membered ring. At the temperature of coalescence, the energy of activation was calculated to be 11.7 kcal/mol for 81 (R = H) and 13.8 kcal/mol for the 5-methyl analog. The higher rigidity of the latter may be due to interaction of the 5-methyl group with the 6-proton.
1.3. 5H-l.,2-Benzodiazepines
1.3.1. Synthesis Treatment of the IH-l,2-benzodiazepines 93 with Pb(OAc), to give the 5H1,2-benzodiazepines 94,84 was discussed under oxidation reactions of the 1H compounds (Section 1.1.2.3.).Also, isolated from this type of oxidation was the 3-vinyl indazole 106. Since 3H- 1,2-benzodiazepines are known to be susceptible to heat- and light-induced rearrangement^,^^ the diazepines 105 are believed to be intermediates (Eq. 28). Oxidation of compounds 93 (R = H, C1, or OMe) gave only the corresponding 3H tautomers 105 and/or the indazoles 106. None of the 5H compounds were found.
Bicyclic 1,2-Diazepines
24
dAc
93
105
94
106
1.3.2. Reactions In analogy to the 3H-benzodiazepines, the 5H compounds 94 readily tautomerized into the corresponding 1H derivatives 103 by treatment with base (Et3N).85Treatment of 94 with either acetic acid or methanol gave the adducts 108 by 1,Cadditions. Irradiation of 94 gave the indole derivative 110 (75%), believed to have been formed via the intermediate valence tautomer 109 (Eq. 29).
OAc OAc 107
+
-_
H
109 I
4
WR, OAc
108
R'=OAc, OMe
a OAc
(29)
H
110
1.4. Dihydro-l,2-benzodiazepines
1.4.1. Synthesis Except for one 4,5-dihydro-l H-l,2-benzodiazepine substituted by a 3-carbethoxy and a 5-methylene group (viz., 62), all the reported dihydro-1,2-
1. BenzoCc] [1,2]Diazepines (1,2-Benzodiazepines)
25
benzodiazepines are 2,3-dihydro-1H derivatives. No examples of either the 1,2ring system were found. dihydro-5H- or the 4,5-dihydro-3H-1,2-benzodiazepine 2,3-Dihydro-1 H-1,2-benzodiazepines 99 were prepared by reduction of compounds of type 82 with lithium aluminum hydride.17",b Reductive acylation of 82 with sodium borohydride in the presence of methyl chloroformate (Eq. 30) led to the 2-methoxycarbonyl derivatives 111 (R, = Me0).'7b The same compounds were also formed, but in better yield, by the reaction of 82 with methyl chloroformate and sodium borohydride. Acetic anhydride at room temperature converted 99 to the 2-acetyl derivatives 111 (R, = Me), which could be further acetylated under more vigorous conditions to the diacetyl derivative 112.
R
R 82
a' w' I
NaBH, ClCOOMe
H
4"
COR,
' /
Ac
___) A O ;
I
R
R 112
111
2-Acyl-2,3-dihydro-1,2-benzodiazepines bearing an alkoxy substituent in the 3-position 114, were formed by photolysis of solutions of N-acyliminoquinolinium ylides 113 in alcohols (Eq. 31). While 114 (R,, R, = Me) was isolated only in low yield and was not fully ~haracterized,,~ the carbamate 114 (R, = EtO, R, = Et) was accessible in 60% yield.25 COR
H
N" . hv. R,OH
113
COR, (31)
114
Two l-methyl-1,2-dihydro-1,2-benzodiazepin-3(3H)-ones (84) were prepared by dye-sensitized photooxidation of the corresponding 1H-L2-benzodiazepine (see Section i.i.2.i).23
Bicyclic 1,2-Diazepines
26
1.4.2. Reactions Compound 114 (R, = EtO, R, = Et) was reconverted to the acetylimino quinolinium ylide 113 (R, = Me) upon heating in acetic acid." Examples of the acylation of 2,3-dihydro-lH-l,2-benzodiazepines and of oxidations leading to 3 H - 1,2-benzodiazepines were mentioned above. 1.5. Tetrahydro-1,2-benzodiazepines
I .5.I . Synthesis The 2,3,4,5-tetrahydro-lH-1,2-benzodiazepines 116 were ~ y n t h e s i z e d from '~~ the corresponding 2,3-dihydro-IH-derivatives 115, by catalytic hydrogenation over palladium on carbon (Eq. 32). Fission of the N-N bond was not observed under these conditions.
R3
R3
115
116
Selective acetylation of the more basic nitrogen of 116 (Rl, R, = H) with acetic anhydride at room temperature led in high yields to the 2-acetyl derivatives. The same compounds were obtained almost quantitatively by hydrogenation of the 2-acetyl-2,3-dihydro-1H-l,2-benzodiazepines 115 (R, = Ac). The diacetyl derivatives 116 (R,, R, = Ac) were prepared analogously by hydrogenation of the appropriately substituted 115 or by acetylation of 116 (Rl, R, = H) with acetic anhydride under more vigorous conditions. Streith and coworkers26 prepared the 2-acyl-6,7,8,9-tetrahydro-2H-1,2-benzodiazepines 119 by photolytic ring expansion (Eq. 33) of the N-acyliminotetrahydroquinolinium ylides 117. The high regioselectivity of this reaction may be due to the
?OR
r
COR1
h"
\ 117
118
119
(33)
21
1. Benzo[c] [1,2JDiazepines (1,2-Benzodiazepines)
preferential formation of the intermediate diaziridine 118,which can rearrange thermally to the diazepine. The 1,2-diazepine 119 (R = EtO) was obtained as an oil in almost quantitative yield, whereas the corresponding acetyl derivative (R = Me), accessible in much lower yield, was crystalline. The latter compound formed an orange, crystalline iron tricarbonyl complex upon treatment with iron pentacarbonyl. Although Fischer and Kuzel” synthesized 121 in 1883, most reported 1,2benzodiazepines are of very recent origin. l-Ethyl-1,2,4,5-tetrahydro-1,2benzodiazepine-3(3H)-one 121, which appears to be the first benzodiazepine ever prepared, was obtained by evaporating an aqueous acetic acid solution of the o-hydrazinophenylpropionic acid (120).Compound 120 was prepared by reduction of the corresponding nitrosoaniline with zinc and acetic acid. This ring closure is limited to the synthesis of monosubstituted compounds, since the preferred cyclization is that which leads to the 1-aminoquinolone derivative 122.Acid hydrolysis of 121 resultedz7 in ring cleavage to the starting hydrazino acid 120. NH2
Et
120
121
122
(34)
1.6. Hexahydro-1,2-benzodiazepines 1.6.1. Synthesis The structures 124 were a s ~ i g n e dto~ compounds ~,~~ obtained by reaction of the 1,5-diketones 123 with hydrazine in ethanol/acetic acid (Eq. 35). Since the compounds were apparently characterized by microanalysis alone, the structural assignment must be considered to be tentative. Structure 125 was similarly assigned to the reaction product obtained by reaction of 123 (R, = H,R, = COOH) with methylhydra~ine.~’No spectral data for 125 were reported. Based on the paucity of the available evidence, these two compounds (124and 125)might equally well be assigned as N-aminoquinoline derivatives-that is, structures represented by the proposed intermediate
126.
28
Bicyclic 1,2-Diazepines
+
lH
Me
COOH 125
/
126
I27
1.6.2. Reactions It has been reported that treatment of 124 (Rl, R, = H) with strong acid, in the presence or absence of solvent, results in ring contraction to the tetrahydroquinoline 127.28 The authors postulate that this reaction is most likely to proceed via the intermediate 126.
,a
2. CYCLOPENTA[c] [1,2]DIAZEPINES 1
3 6
5
128
The parent compound 128 is as yet unknown although a few hexahydro derivatives 13028and 13130reportedly have been obtained by the reaction of the cyclopentanones 129 with hydrazine and methylhydrazine, respectively (Eq. 36). The correct assignment of these structures is doubtful (see Sections 1.6.1. and 1.6.2.).
29
4. HeteroCc] [1,2]Diazepines
R
130
129 RNHNH,
132
131
The structure of 130 is based solely on microanalytical data and on its ability to be converted to 132 under acidic conditions. The assignment of structure 131 (R = H, Me) was based on infrared spectral data.
3. CYCLOPROPA[c] [l,Z]DIAZEPINES
H
6
134
133
Cyclopropa[c] [ 1,2]diazepine
2,3-DiazabIcyclo[S.l.O]octane
3.1. Synthesis The only known example of the bicyclic system 133 or the corresponding reduced system 134 is the highly substituted compound 138, which was prepared by Sasaki and coworkers3' in 25% yield by a Diels-Alder type of addition (Eq. 37) of the cyclopropenone 136 to the 4H-pyrazole 138. The postulated intermediate adduct 137 is believed to rearrange to the diazepine 138 as indicated. The structure of the product is supported by spectral data.
4. HETERO[c] [l,Z]DIAZEPINES Tsuchiya and coworkers extended their synthesis of 1,2-ben~odiazepines'~ to 86 Thus, the 1H the preparation of several heterocyclo[c] [1,2]diazepine~.~~.
Bicyclic 1,2-Diazepines
30
Ph
Ph 135
136
137
(37)
0 138
pyrido[3,2-c] [1,2]diazepine 141 was accessible in 25% yield by photolysis of the ylide dimer 140, believed to exist in equilibrium with the monomer 139 under the reaction conditions (Eq. 38). The isomeric 1H-pyrido[2,3-c] [1,2]diazepine 143 was obtained analogously (Eq. 39) from the l-amino-l&naphthyridinium ylide 142. NH-
H
@-
141
139
(38)
140
NH\
H
\ 142
143
144
(39)
As in the benzodiazepine series, compound 141 was converted to the 3H tautomer 144 by reduction with lithium aluminum hydride followed by dehydrogenation with 4-phenyl-1,2,4-triazolin-3,5-dione. Treatment of 144 with sodium methoxide in methanol resulted in isomerization back to 141, the thermodynamically more stable tautomer. The same type of photochemical synthesis was used for the preparation of the 1H-pyrrolo[2,3-c] [ 1,2]dia~epine.~~ Irradiation of the 2-methylpyridine N-acylimides 145 that were condensed with a thiophene, furan, or pyrrole ring on the b-side of the pyridine ring gave the corresponding fused 1H-1,2 and
4. HeteroCc] [1,2]Diazepines
R.
R
31
R, +
Me
+ I
-NCOOEt
COOEt
145
147
146
(40) 3H- 1,3-diazepines 146 and 147, whereas the N-unsubstituted N-imide gave only the lH-1,2-diazepine 146 and no 1,3-diazepine (Eq. 40). In this ring expansion reaction, the initial photoinduced rearrangement may take place on either side of the pyridine nitrogen to give two kinds of diaziridine intermediates, 148 and 149; compound 148 may give 1,2-diazepines directly, whereas 149 may further rearrange to the aziridine intermediate 150, followed by ring expansion to give the 1,3-diazepines 147 (Eq. 41). R
r
R
X 145
148 X=HI
150
J
149 IX=H
R
i
Similarly 1H-thieno[3,2-c] [I1,2]diazepine 152 was prepared by photochemical synthesis from 4,6-dimethylthieno[3,2-c]pyridine N-imide 151 (Eq. 42).
151
152
Bicyclic 1,2-Diazepines
32
Treatment of N-unsubstituted compound 152 with ethyl chloroformate in anhydrous benzene resulted in a rearrangement with ring conversion to give the 3-ethoxycarbonyl-3H-1,3-thieno[3,2-c]diazepine 153 as the only product (Eq. 43).
Me
)=\ (43)
ClCOOEt
153
But treatment of the N-unsubstituted compound with ethyl chloroformate in pyridine instead of benzene afforded only the l-ethoxycarbonyl-1H-1,2thieno[3,2-c]diazepine 154. Conversely, treatment of the N-substituted compound 154 with ethyl chloroformate in benzene resulted in the formation of the 1,2-diethoxycarbony1-3-exo-methylenecompound 155 instead of 153 (Eq. 44). 152
1
ClCOOEt pyridine
(44) COOEt 154
N' 'COOEt COOEt 155
Morrison and coworkers reported the synthesis (Eq. 45) of the substituted lH-pyrimid0[4,5-c] [1,2]diazepines 158 by condensation of the hydrazine 156 with 1,3-diketones 157.33a,b,89
Compounds 158 were found to be susceptible to ring opening and closing rearrangements leading to either pyrido[2,3-d]pyrimidines, pyrimido[4,5-c]pyridazines, or pyrazolo[2,3-d]pyrimidines.
33
1. Benzo [ d ] [1,2]Diazepines (2,3-Benzodiazepines)
D. [d]FUSED [l,Z]DIAZEPINES This section describes the synthesis and properties of bicyclic systems of general formula 159, beginning with the best known members of this class, the benzo[d] [1,2]diazepines.
159
1. BENZOCd] [1,2]DIAZEPINES (2,3-BENZODIAZEPINES)
160a
1H-2,3Benzodiazepine
160b 38-2,3Benzodiazepine
160c
58-2,3Benzodiazepine
The 2,3-benzodiazepine ring system may theoretically exist in any of the three tautomeric forms 160a-160c (the energetically less favored quinonoidal forms being disregarded). 1.1. lH-2,3-Benzodiazepines
1.1.1. Synthesis Sharp and T h o r ~ g o o dfound ~ ~ that the thermal decomposition of the sodium salts of tosylhydrazones in aprotic solvents (Eq. 46) led in good yields to variously substituted 1H-2,3-benzodiazepines. The preliminary account of the work by these authors was followed by a full paper35 that gave a number of additional examples, including compounds with substituents in the benzene ring. Compounds 164 are most likely formed by an electrocyclic ring closure of the intermediate diazo compound 162 to yield the 4H tautomer 163. A [1,5]-sigmatropic proton shift would then lead to the observed products. It would appear that the 1H compounds must form by a kinetically controlled route since, in general, the thermodynamically more stable 5H tautomers were obtained only in the presence of excess base. The structures of 164 were firmly established by spectral data and by an X-ray crystallographic
Bicyclic 1,2-Diazepines
34
R
3
K
R
I.lc:,":]
2
-N= N
R, ~ N - NN-aT+S 161
I___/
162 R 1
164
163
165
(46) analysis of 1-methyl-4-phenyl-lH-2,3-benzodiazepine (164: R , = Me, R, = Ph, R, = H).36 This synthesis was later applied by Benda11,37who claimed to have obtained the 4H tautomer 165, which rearranged to the 1H isomer upon standing in methanol solution for 2 days. Sharp and coworkers35 showed that the compound claimed to be 165 was in fact the 1H tautomer 164 (R, = Ph; R,, R, = H). The rearranged product Bendall believed to be the 1H tautomer was undoubtedly a photoproduct related to 166 as discussed below.
1.I .2. Reactions Base-catalyzed or thermal isomerization (Eq. 47) of the 1H-2,3benzodiazepines 164 leads to the thermodynamically more stable 5H tautomers 167.35The sensitivity to light of 164 prompted the study of their photochemical trans for ma ti or^.^^^^^.^^ These compounds were found to undergo a rapid and virtually quantitative isomerization to the [1,2]diazeto[4,1-~]isoindoles 166.
(47)
164
167
1. Benzord] [1,2JDiazepines (2,3-Benzodiazepines)
35
1.2. 3H-2,3-Benzodiazepines
1.2.1. Synthesis Lida and Mukai were able to induce the diazepine 168 to undergo a (4 + 2) cycloaddition reaction with a pyrone activated by a methoxycarbonyl group." Thus upon heating the pyrone 169 with the diazepine 168 at 80-110°C for 7 days, the benzodiazepines 171 were obtained in low yield. The reaction was postulated to proceed via the intermediate 170, which would then decarboxylate and dehydrogenate to give 171 (Eq. 48).
170
(48) Kurita et al. reported that acetylating the benzodiazepines 172 (R = H or Me) afforded the 3H derivatives 173. The acetate could be removed in either acid or base and original starting material recovered (Eq. 49).91
QAc,
n i 01 n-
Me 172
(49) Me 173
Photolysis of isoquinoline N-imides 174 under basic conditions gave the ringexpanded SH-2,3-benzodiazepines 175 in yields of between 25 and 60%.91392 A reasonable mechanism was given, which proceeds via the photoinduced
174
175
36
Bicyclic 1,2-Diazepines
formation of a diaziridine followed by ring expansion and tautomerisation to the 5H product through the 1H intermediate (Eq. 50).
1.3. 5H-2,3-Benzodiazepines
1.3.1. Synthesis As mentioned above, the tautomers 167 may be prepared by treatment of the lH-2,3-benzodiazepines 164 with base or heat. If excess base is used during thermal decomposition of the sodium salts 161, the 5H tautomers are obtained directly.35 Small amounts of 5H-2,3-benzodiazepines were detected during pyrolysis of the photoproducts 166.39 The rather obvious route to these compounds (i.e., condensation of a 1,5-diketone with hydrazine) has not been widely used and seems to be exemplified4' only by the synthesis of analogs of the 5H-2,3-benzodiazepine 180 by treatment of the 1,5-diketone 176 with hydrazine under acid catalysis (Eq. 51). If 176 was condensed with hydrazine hydrate below 100°C, the intermediate hydrazine 178 could be isolated in high yield and subsequently ring closed under acidic conditions. Reaction of the pyrylium salt 177 with hydrazine led to the alternative hydrazone 179, which was found to be more labile than 178 and could be characterized only by spectroscopic methods. It was converted in good yield to 180 by heating in solution. Compound 178 was initially thought to be the N-iminoisoquinolinium ylide 181,41 but detailed spectroscopic analysis4' including 3C-nmr spectroscopy established the correct structure. The same synthetic method was later applied43 for the preparation of 14C derivatives of 180 with the label in the ethyl and 8-methoxy groups.
1.3.2. Reactions Acylation of 180 with p-nitrobenzoyl chloride or with acetic anhydride (Eq. 52) has been reported44 to give the exocyclic double-bonded compounds 182 in 38 and 67% yield. The products obtained from the acylation of 5H-2,3-benzodiazepines are strongly dependent on the nature of the acylating agent and the reaction conditions. The reaction of 183 with acetic anhydride in benzene was rapid at room temperature and gave reactive intermediate 184. Quenching of 184 with water gave 185, and when 185 was reacted with a ra.ige of 0 or S nucleophiles, products 186 and 187 were formed. It is noted that the diazepine ring of 186 and 187 was retained (Eq. 53).97,98 However, reaction of 183 with acyl halides in benzene or toluene induced a ring transformation that gave either 3-phenylisoquinoline N-imine salts 189 or
&;;
MeoqM , Et
OMe
Me0
Me0
HX
Me0
Et
bMe 176
I
177
NH2NH,
Nn,Nn,.n,o, RT
-90°C
B'
Et
Me0
I
/
OMe
OMe 179
178
OMe
(yMe M
e
,-' Me Et
Me0
Et 180
a NH
O
Me
181
\__\\ \ \ '**(4., ..,
or
$OMe
(52)
M
e
O
Et 182
37
v
mph
Bicyclic 1,2-Diazepines
38
2 PhH OAc_
'
-N
183 /GOH
187
186
(53) the formation of the acylated dimers 191 and 192 via a dehydrochlorinated intermediate 190 (Eq. 54).99 Ph --N 183
188
189
1
< O C RCOCI
COR 190
NCOR 191 192
Similarly, as shown in Eq. 49, acylation of the 1-methyl and lP-dimethyl(SH)-2,3-benzodiazepines gave the corresponding 3-acetyl derivatives 173. Hydrolysis of the acetyl derivatives to recover starting material could be effected
1. BenzoCd] [1,2]Diazepines (2,3-Benzodiazepines)
39
with either acid or base (Eq. 49).91 For these compounds, however, 3H structures were assigned. Analogs without a 1-substituent gave only complex mixtures upon acylation. Stepwise reduction of the seven-membered ring with sodium borohydride could be effected by the choice of solvent. Thus, use of ethanol at room temperature afforded the 3,4-dihydro compound 193, while treatment in acetic acid gave the tetrahydro derivative 194. 1,3-Dipolar cycloaddition of imines with nitrite oxides is well known, but it was interesting to observe that only a single product was obtained [viz., 195: (R = H) 60-65%] when the unsubstituted analog 172 (R = H) was treated with mesitylnitrile oxide. This would indicate a hifference in reactivity for the two imines (Eq. 55)."
Q -N
Me 172
Me 193
I
Me 194
i
maitylnitrik
oxide
195
(for R = H or Me) Similar borohydride reductions have been reported by Kovosi et al. in the patent literature (Eq. 56).93
1.3.3. Spectral Data The flexibility of the seven-membered ring was studied in 1H- and the 58-2,3benzodiazepines by means of temperature-dependent nmr s p e c t r o ~ c o p y . ~ ~ The protons at the 1-position of lH-2,3-benzodiazepine give rise to an AB system with J = 9 Hz, which coalesces at 60 k 20°C. The free energy of activa-
Bicyclic 1,2-Diazepines
40
tion for ring inversion at the coalescence temperature was determined to be 15 t- 1 kcal/mol. If the carbon atom at the 1-position is substituted, no temperature dependence is observed, indicating a preference for one conformation. The free energy of activation for ring inversion was also determined3' for four differently substituted SH-2,3-benzodiazepines 198 in which the C-5-protons appear as an AB system with J = 12.5 Hz. The coalescence temperature T, and free energies of activation for ring inversion at the coalescence temperature AGI are listed below. Rl
&& '
R3
R, 198
Ph Me 4-MeC,H4
R2
R,
T,("C)
AGI (kcal/mol)
H H Ph Ph
H Me0 H H
120 & 5 110 -t 5 137 k 5 180 k 5
19.5 f 0.3 19.0 0.3 19.9 f 0.3 22.1 f 0.3
Proton and l3C-nmr spectra4' of the 5H-2,3-benzodiazepine 175 showed the presence of two conformational isomers in solution, whereas only one conformation was observed in the solid state. In solution, conformational equilibrium was reached with a half-time of about 10 hours at room temperature. From the temperature dependence of this equilibrium, the difference between the free energies of the two conformations was estimated to be about 1 kcal/mol. The major conformer was assigned the configuration in which the ethyl group at the 5-position is pseudo equatorial. Several salts of the l-(3,4-dimethoxyphenyl)-7,8-dimethyl-5-ethyl-5~-2,3benzodiazepin-3-ium iodide hydrate (1%) were prepared for pmr investi g a t i ~ n , ~to, establish which of the two ring nitrogens was protonated. The authors concluded that only the N-3 atom could be protonated by strong acids. Quarternization with methyl iodide gave only the 3-methyl analog 199.
6 O M e
I99
1. BenzoCd] [1,2]Diazepines (2,3-Benzodiazepines)
41
1.4. Dihydro-2,3-benzodiazepines
I .4.1. 4,s-Dihydro-1H-2,3-benzodiazepines The only representative of these cyclic azo compounds reported in the literature appears to be compound 201, which was prepared by Schmitz and Ohme45 in 20% yield by oxidation of the tetrahydro derivative 200 with hydrogen peroxide (Eq. 57).
1.4.2. 4 5 Dihydro-3H-2,3-benzodiuzepines The same investigators4$ obtained the dihydrobenzodiazepine 203 in 40% yield by thermal decomposition of the dimer 202 of the N-imino-3,4dihydroisoquinolinium ylide (Eq. 58). Since this pyrolysis also led to the formation of isoquinoline, the latter was used as the solvent. The structure of 203 was confirmed by chemical transformations (see below). The cyclic hydrazone 203 was also accessible by acid-catalyzed rearrangement of the azo compound 201.
HN’ N w
A
UH \
cNH cN ~
203
H’
201
202
(58) Tamura and coworkers46 prepared 3-aryl-4,5-dihydro-3H-2,3-benzodiazepines 212 by reaction of N-aryl-o-formylphenethylamines 204 with hydroxylamine-0-sulfonic acid (Eq. 59). Compounds 204, which may exist in equilibrium with the cyclic form 205,are obtained by treatment of the N-phenyl3,4-dihydroisoquinolinium salts 206 with hydroxide. The authors assumed that N-amination of 204 would lead to the hydrazone 211,which then cyclizes to 212. Streith and Fizet4’ showed, however, that N-amination of the phenethylamine is not involved; rather, a nucleophilic attack of the hydroxylamine, most likely on compound 206, better explains the observed reaction products. The intermediate 208 formed in this manner may either lead to the diaziridinium salt 210,
42
Bicyclic 1,2-Diazepines
204
206
205
I
1
HINOR
H,NOA
4
c
208
[QAr 207
a-
1
I
i
Ar
\
209
210
21 1
212
I
or via the ring-opened compound 207, to the nitrile 209 (the major by-product). The benzodiazepine 212 would arise from 210 by the indicated ring expansion. This mechanism is in agreement with the observations that the ease of formation of the benzodiazepine is related to the basicity of the aniline functionality in intermediate 208. As the nucleophilicity of the aniline nitrogen decreased, the relative yields of benzodiazepines also decreased and the proportion of the nitrile by-products increased. The 1-phenyl-substituted analogs 214 were reportedly synthesized (Eq. 60) by the reaction of the 2-(2-bromoethyl)benzophenones 213 with hydrazines at elevated temperat~re.~' The structures of these compounds were supported by microanalytical data only. Dimers of a type related to compound 202 cannot be excluded from consideration. 216 was reported to be The 4-phenyl-4,5-dihydro-3H-2,3-benzodiazepine accessible (Eq. 61) by partial catalytic hydrogenation of 215.37This compound was characterized only by its melting point and by its infrared absorption band in the region of N-H bonds. Other structures, especially the tautomer 217, cannot be excluded on the basis of the reported data.
1. Benzo[d] [1,2]Diazepines (2,3-Benzodiazepines)
215
216
43
(61)
217
1.4.3. Reactions The acid-catalyzed rearrangement of the azo compound 201 to the hydrazone 203 was mentioned above. Treatment of 203 with aqueous sulfuric acid4’ followed by alkaline workup (Eq. 62) led in almost quantitative yield to the H,O ’
* 203
mcNH \
218
202
Bicyclic 1,2-Diazepines
44
dimer 202, possibly via the N-amino-3,4-dihydroisoquinoliniumsalt 218.Acylafforded the 3-(N-phenyl)carboxamide ation of 203 with phenyli~ocyanate~~
219. 1.5. Dihydro-2,3-benzodiazepinones
1S.1, 2,3-Dihydro-2,3-benzodiazepin-l(lH-)-ones Treatment of the isocoumarin 220 with hydrazine in boiling ethanol (Eq. 63) led to the formation of the benzodiazepinone 221 as the major product and the N-aminoisoquinolone 222 as the minor product.49 If the condensation was carried out in the presence of glacial acetic acid, the isoquinolone was the only product isolated. The structural assignment for 221 was based on its infrared spectrum (broad N-H) and its inability to react with aldehydes and isocyanates. This lack of reactivity was attributed to the weak basicity of the enamine nitrogen. No evidence to exclude the possibility that 221 is in fact a 2,5-dihydro derivative was given (see Section 1.5.2).
@ \
/
=>;;;YI
&H \
/
COOMe
NH
f
QJyNH2
COOMe
220
(63)
COOMe
221
222
Among the many 4-aryl-substituted 2,Sdihydro analogs prepared in the same fashion, only the nitro-substituted compound 223 was observed to exist in the 2,3-dihydro tautomeric form, which has the double bond in conjugation with the two benzene rings.54
N
0
2
S
OH Me 223
1.5.2.2,5-Dihydro-2,3-benzodiazepin-l(1 H - )-ones The synthesis of these compounds was first reported in the nineteenth century. Gottlieb” described the preparation of the benzodiazepine 225
45
1. Benzo[d] [1,2]Diazepines (2,3-Benzodiazepines)
(R, = Ph, R, = Me) by reaction of the isocoumarin 226 (X = 0,R, = Me) with phenylhydrazine (Eq. 64). The same compound was obtained also from the condensation of the corresponding ketoacid 224 with phenylhydrazine. The analogous reaction of 2-(benzoylmethyl)benzoic acid 224 (R, = Ph) or the corresponding isocoumarin with hydrazine was subsequently studied by Wolbling,51 L i e ~ k , ~and ' B ~ u - H o i .A~ ~number of 4-aryl-2,5-dihydro-2,3benzodiazepin- 1(1H)-ones were more recently prepared in high yield from the corresponding isocoumarins with h y d r a ~ i n eand ~ ~ with monosubstituted hyd r a ~ i n e s The . ~ ~ 2-thioisocoumarins 226 (X = S, R, = Ar) reacted in the same fashion56 with hydrazine to yield the benzodiazepines 225. The extension of this method to the synthesis of the 5-phenyl analog 230 failed,57 and the reaction of the isocoumarin 227 with methylhydrazine (Eq. 65) led exclusively to the ~ ~displacement isoquinolone 228. Compound 230 was, however, ~ y n t h e s i z e dby of bromide in 229 with phenylmagnesium bromide (Eq. 66).
R AcOH ,NHNH,
& '
&f'
L RNHNH
'R,
\ R2
224
226
225
8 Ph
Ph 227
229
228
230
I S.3. 3,S-Dihydro-2,3-benzodiazepin-4 (4H) -ones Halford and coworkers5* obtained the first compounds of this type (Eq. 67) by thermal dehydration of the phenylhydrazone of o-acetylphenylacetic acid (231, R , = Me, R, = Ph). The parent compound 233 (R,, R,, R, = H) and the
46
Bicyclic 1,2-Diazepines
COOH COOH
NH,NHR, R3
Rl
234
235
(67)
1-methyl analog 232 (R, = Me, R,, R, = H) were accessible by pyrolysis of the semicarbazones 231 (R, = H, Me, R, = CONH,; R, = H). Pyrolysis of the azine 233 (R, = Me; R, = H) also led to the benzodiazepine 232 (R, = Me; R,, R, = H) in low yield. Thermal cyclodehydration was later used successfully also for the preparation of 1-aryl-substituted benzodiazepines 232 (R, = Ph).59Wermuth and Flammang6'2 61 simplified and improved this synthesis and obtained good yields of benzodiazepines by heating under reflux a solution of the ketoacids 234 and a hydrazine in an inert solvent. The water formed in the reaction was removed azeotropically. The superiority of this modified method was evident from the preparation6, of the 5,Sdimethyl derivative 235 (R, = Ph, R, = 2morpholinoethyl, R, = H). Previous attempt to prepare a 5,5-dimethyl analog (235, R, = Me, R, = Ph, R, = H) by the pyrolysis procedure failed.58 An alternate method for the cyclodehydration of arylhydrazones 231 (R, = aryl) to the corresponding benzodiazepines 232 was demonstrated by the use of dicyclohexylcarbodiimide.62The 1-benzyl derivative 237 was not accessible by this approach but could be ~ y n t h e s i z e dfrom ~ ~ the 1-bromomethyl compound 236 by reaction with phenylmagnesium bromide (Eq. 68). CH,Br
236
CHzPh
231
1. BenzoCd] [1,2]Diazepines (2,3-Benzodiazepines)
47
1S . 4 . Reactions 1.5.4.1. Reactions with Electrophiles Ring contraction of dihydro-2,3-benzodiazepinones to N-aminoisoand quinolones 238 and 239 (R, = H) occurs with both the I-ones 22549,51,55,56 the 4-ones 232 (R, = H)58,60under the influence of acid catalysts (Eqs. 69 and 70). The same isoquinolones are, in general, by-products in the preparation of the benzodiazepines and may be the predominant or exclusive products, particularly under acidic conditions.49. 5 7
ci
5 5 3
R,
O
&R2
HX
\
R,
0
R2
225
N,
NHR,
(69)
238
R3&N-R2
(70)
R3 0
239
232
Reaction of compound 240 (R = Me) with N-bromosuccinimide in the presence of a peroxide catalyst (Eq. 71) afforded the 5-bromo derivative 229.57
R=Me
Ph 240
229
0 241
Ph 242
Flammang has studied the utility of a number of 1,3-disubstituted 4-oxo-3,5-
dihydro-(4H)-2,3-benzodiazepinesfor the synthesis of 2-aminoisoquinolin-3ones.95The starting materials were prepared by reacting the appropriate o-acyl
Bicyclic 1,2-Diazepines
48
or aroylphenylacetic acid with a substituted hydrazine. Heating the 2,3benzodiazepine 243 thus obtained in H,SO,/HOAc at 100°C for 12 hours afforded the ring contraction product 244 in 0-30% yields. Best yields were obtained when R and R, are alkyl and aryl (Eq. 72). Most if not all of the compounds used in this study have been reported elsewhere. No spectra or physical characteristics were reported. A similar study was also reported for the ring contraction of 2,3-benzodiazepin- 1-ones 243.96 These compounds underwent ring contraction in much higher yield (7&90%) when the starting diazepine was a secondary amide. Again, all the compounds used have been described elsewhere, therefore neither spectra nor physical characteristics are reported.
W~H" ; " '
N-R1
NH,NHR,+
\
c=o
qo \
H'
N-NR,
-N
R
I
R 243
244
(72) Wolbling51 reported the conversion of the diazepinone 240 (R = H) to the 4-nitroisoquinolone 241 by treatment of 240 with nitric acid (Eq. 71). He also described the formation of an unstable nitroso derivative, to which he assigned structure 242, as a result of the action of nitrogen oxides on a suspension of 240 (R = H) in acetic acid. Alkylation of 240 (R = H) with methyl iodide and ethyl iodide led to the respective 2-alkyl derivative^.^^ Reaction of the 4-ones 232 (R, = H) with various alkyl halides was reported to yield the corresponding 3-alkyl
derivative^.'^' 6 1 Bromination of compound 245 with N-bromosuccinimide in the presence of a peroxide catalyst or with phenyltrimethylammonium perbromide (Eq. 73) gave the 1-bromomethyl derivative 236 in 15 and 40% yields.63 Me
245
CH2Br
236
1S.4.2. Reactions with Nucleophiles Reduction of 246 (R = H) with zinc and hydrochloric acid afforded the isoquinolone 247?l Reaction of the benzodiazepin-1-one 246 (R = Me) with phosphorus pentasulfide in boiling pyridine (Eq. 74) gave the thione 248.56In
49
1. Benzo[d] [1,2]Diazepines (2,3-Benzodiazepines)
Zn/HCI
%
h& :
247
246
(74)
Me 248
contrast to the corresponding ketone, this thione was founds6 to be resistant to ring contraction. Cleavage of the hydrazide bond in 249 to give the open phenylhydrazone 250 could be effected (Eq. 75) by treatment with sodium hydroxide in boiling ethylene
OH-
- Q&
COOH /N-NH-Ph
(75)
Me 249
250
1S . 5 . Tetrahydro-2,3-benzodiazepines The tetrahydrobenzodiazepine 200 (R = H) was prepared4' by catalytic hydrogenation of the dihydrobenzodiazepine 203 over palladium on carbon (Eq. 76) and was characterized as a hydrochloride salt. The structure of 200 (R = H) was confirmed by an alternative synthesis via the alkaline hydrolysis of the phthaloyl derivative 253. The latter was obtained by doubly alkylating phthalhydrazide with the dichloride 252. Tetrahydrobenzodiazepines are also accessible by reduction of tetrahydrobenzodiazepinones with lithium aluminum hydride, exemplified by the conversion of 251 to 200 (R = Me), which formed a crystalline p i ~ r a t e . ~ ~
Bicyclic 1,2-Diazepines
50
203
200
HN
0
\ 252
253
1S.6. Tetrahydro-2,3-henzodiazepinones The tetrahydro-2,3-benzodiazepin-4-ones 256 (R = Me, Ph) were recently reported by Cignarella and coworker^.^^ Condensation of the bromide 254 with a monosubstituted hydrazine (Eq. 77) led to the intermediates 255, which were isolated and characterized. Compounds 255 slowly cyclized to the benzodiazepinones 256 at room temperature, or were more readily converted in high yield to compounds 256 by refluxing in acetic acid. COOMe @N/"
COOMe 254
\
eN COOMe
COOMe A
NH, COOMe
~
H ~
\
0
256
255
(77)
According to Rosen," tetrahydrobenzodiazepinones of structure 258 could be obtained by the reaction of phenylacetic acid hydrazides 257 with formaldehyde under acidic conditions (Eq. 78). The structures assigned to these products
257
258
2. Cyclopenta[d] [1,2]Diazepines
51
are doubtful, since the chemistry performed to establish the structures gave conflicting results. Rosen and P ~ p reinvestigated p ~ ~ the reaction of homophthalic anhydride 259 with hydrazine (Eq. 79) and disproved much earlier reports67 that this reaction leads to the tetrahydrobenzodiazepin- 1,Cdione 260 (R = H). Only in the case of 1,2-dimethylhydrazine did this condensation lead to the benzodiazepine 260 (R = Me).
0
/
259
0
Me J
0 H
G
‘0 260
Br,/hv
i Br - M
e
Me
(79)
* G o - M e \
(11
261
262
Bromination of 260 (R = Me) with bromine in the presence of light afforded66 the 5-bromo derivative 261, which reacted with morpholine to give what appears to be the 5-morpholino compound 262. According to the analytical data, it seems that the latter compound was not properly purified.66a
2. CYCLOPENTACd ] [1,2]DIAZEPINES
263
The only reported representative of ring system 263 is the 1,Cdiphenyl derivative 267.68This compound was formed in 40% yield (Eq. 80) by cycloaddition of the fulvene 264 and the 1,2,4,5-tetrazine 265 to give, presumably, the intermediate 266. ‘Loss of nitrogen and dimethylamine from this bridged intermediate would then lead to 267. The structure of 267 is based on microanalysis, the mass spectrum and a characteristic ultraviolet absorption spectrum that resembles that of another diazaazulene.
52
Bicyclic 1,2-Diazepines
+
-
Ph
Ph
266
267
265
3. CYCLOPROPACd] [l,Z]DIAZEPINES
*c:i4
43;.
7
'4
h
5
269
268
Cyclopropa[d] [1,2]diazepine
3,4-Diazabicyclo[S. 1 .O]octane
Compounds derived from the ring parent 268 have usually been named as 3,Cdiazabicyclo[S. 1.0loctanes 269 or trivially as homodiazepines. Streith and coworkers69 obtained tetrahydrocyclopropa[dl [1,2]diazepines 272 by thermal or, in much lower yield, by photochemical extrusion of nitrogen (Eq. 81) from the pyrazolo[3,4-4 [ 1,2]diazepines 270 and 271. N-- MeN EtOOC-d
H a
M Me 270
Me
e
J
G
H Me Me
\
\
J
I8O"C
:CN-cOo 170'C
271
(81)
R 272
(R
=
H, Me)
4. OXIRENOCd C1,ZIDIAZEPINES 1,2-Diazepine epoxides of structure 277, which are derivatives of the parent ring systems 273 or 274, were synthesized by Tsuchiya and coworker^'^ by
4. Oxireno[d] [1,2]Diazepines
53
274
laH-OxirenoCd] [1,2]diazepine
3,4-Diaza-8-oxabicyclo[ 5.1.O]octane
rearrangement of the endoperoxide 276 with potassium hydroxide in methanol at 0°C (Eq. 82). The endoperoxides 276 were prepared in 3&60% yields by dye-sensitized photooxygenation of the corresponding ethoxycarbonyl-1,2diazepines 275.
275
276
277
The same sequence of reactions carried out on the 2,3-dihydrodiazepine 278 led to the 2,3,4,5,6,6a-hexahydro-6a-methyl-1aH-oxireno[d] [1,2]diazepine 281. In this case the intermediate 280 was isolated in 80% yield after treatment of the endoperoxide 279 with aluminum oxide in methylene chloride (Eq. 83). Interestingly, the attempted isolation of a corresponding intermediate in the conversion of 276 to 277 failed because treatment of 276 with either alumina or methanolic triethylamine converted the endoperoxide back to starting material 275. The reactivity of these endoperoxides and the course of their rearrangement appear to depend on the nature of their substituents.
YOOEt N-NH %,dye hv
*
FOOEt N-NH
v y
*
YOOEt
Me
Me
Me
278
279
280
COOEt 281
54
Bicyclic 1,2-Diazepines
5. PYRAZOL0[3,4-(II [l,Z]DIAZEPINES 8
1
282
5.1. Synthesis
The parent compound 282 is still unknown. Tetrahydro derivatives with various substituents were synthesized by Streith and coworkers69 by the cycloaddition of diazoalkanes to 1-acyl- 1,2-diazepines. Diazomethane was inert toward most of these 1,2-diazepines and reacted only with compounds having a strongly electron-withdrawing substituent at the 1-position, such as the l-benzenesulfony1-1,2-diazepine283 (R, = SO,Ph, R, = H). 2Diazopropane was found to be much more reactive, and it added regioselectively (Eq. 84) to yield the adducts 284 (R3= Me). The azo function undergoes rearrangement to the hydrazone form 285 if a 1,3-hydrogen shift is possible (R, = H). Because of the limited stability of some of these adducts, they were characterized spectroscopically only. Detailed nmr studies7’ revealed an unusually large coupling between the vinylic proton at the 5-position with the allylic proton in the 3a-position. The coupling constant ranged from 2.5 to 3.5 Hz, depending on the substitution in 284 and 285. This phenomenon was attributed to the conformational rigidity of this ring system, with the allylic proton being nearly perpendicular to the plane of the 4,5-olefinic bond. The structure of the pyrazolo[3,4-d] [1,2]diazepine 287 was assigned to the product obtained7’ in moderate yield by condensation of the pyrone 286 with hydrazine (Eq. 85). The reported infrared absorption data would not exclude possible alternative structures. 5.2. Reactions
The thermal or photolytic extrusion of nitrogen from compounds of type 284 or 285 leading to cyclopropa[d] [1,2]diazepines was discussed for compounds 270 and 271 (Section 3). Oxidation of 288 (R, = Me, R, = COOEt, R, = H) with lead tetraacetate (Eq. 86) gave a 40% yield of an acetoxy derivative to which structure 289 (R = Me) was assigned and confirmed by X-ray analysis of the p-bromobenzoate (R = ~-BI-C,H,).~, A more recent paper7, described the acylation of the labile pyrazolodiazepines 288 (R, = H) to various stable 2-acyl derivatives 290. The
5. Pyrazolo[3,4-d] [1,2]Diazepines
283
55
284
285
286
287
2-methoxymethyl derivative 291 was obtained by reaction of 288 (R, = H, R, = Ts, R, = H) with methanolic formaldehyde followed by workup with sodium borohydride (Eq. 86). Depending on the nature of the R, R,, and R, groups, compounds 290 underwent conversions to 292 by shift of the double bond, to 293 by elimination of RH, and to 294 by elimination of RH accompanied by ring opening. Treatment of the methoxymethyl derivative 291 with F3
R 2-N N
z
N
H
PbIOAc),
EtOOC-N
1
RI
R1
MeOH. Na,CO,
N-R 292
+
R2-N
H 293 294
Bicyclic 1,2-Diazepines
56
sodium carbonate in boiling methanol, for example, gave a 53% yield of 294 (R, = Ts, R, = H) and a 21% yield of 292 (R = CH,OMe, R, = Ts, R, = H). Mechanisms for these conversions were proposed and supported by deuterium labeling experiments. The initial step appears to be the removal of the doubly allylic proton at the 3a-position.
6. PYRID0[3,2-d] [1,2]DIAZEPINES
295
Of the four possible pyrido[d] [1,2]diazepine ring systems, only derivatives of the pyrido[3,2-d] [1,2]diazepine 295 are known in the liter at~ re. ~In' a manner analogous to the synthesis of 2,3-benzodiazepines (Section 1.5.2), compounds 297 were prepared by condensation of the ketoacids 296 with methylhydrazine in boiling ethanol (Eq. 87). The structures of 297 were supported by spectral data. In particular, nmr spectroscopy allowed differentiation from other tautomeric forms.
R MeNHNH,
296 297
7. THIENO AND OTHER HETEROCd] [1,2] DIAZEPINES 7.1. Synthesis Munro and Sharp reported the first route to synthesize thieno[3,2-d] 300 and thieno[2,3-d] [ 1,2]diazepines 303 by cyclization of the cr-(2-alkenylthienyl) diazoalkanes 298 and 301 (Eq. 88).loo In contrast, 3-diazomethyl-4-(trans-2phenyletheny1)thiophene 304 did not cyclize but gave carbene-derived products. The 1H-thieno[d][ 1,2]diazepines 300 and 303 were readily isomerized to the SH-thieno[d][ 1,2]diazepines 305 and 306 by sodium ethoxide in ethanol.
7. Thieno and Other HeteroCd] [1,2]Diazepines
298
299
57
300
(88)
303 301
302
305
306
Tsuchiya et al. reported that the methylpyridine N-imides (307b307e) that were condensed with a thiophene, furan, or pyrrole ring on the c-side of the pyridine ring gave, upon irradiation, the corresponding novel fused 3H-[1,2]diazepines (308b308e) and products 309 and 310 as well (Eq. 89).16'
q /N<
-
*
0
x +q 4 N
"
NX
x
Me
307b307e
308b308e
308 b e
309 b e
310 b e
35% 45yo 67 Yo
10%
6 Yo 5 yo 6 Yo
17%
-
15%
Me
309b-309e
Yield (YO)
12%
+
4 yo
qN /N
Me 310b-310e
Bicyclic 1,2-Diazepines
58
This photolysis can proceed by rearrangement to form two kinds of diaziridine intermediates, 311 and 312. The latter can give 308b-30% by ring expansion, whereas the former can further rearrange, followed by ring expansion, to give other products (Eq. 90).
Q
y R
Me 307b307e
N X
NHX
31 I
V
\N N'
X
-
qN 309
QX
-N
R
and
/N
R
R
312
310
308b-308e
7.2. Reactions The reduction of the [1,2]diazepine 313 with sodium borohydride in the presence of aqueous alkali gave the 1,Zdihydro (314) and 4,5-dihydro (315) compounds, whereas treatment of 313 with sodium borohydride in acetic acid gave the 1,Zdihydro compound 314 as the sole product in high yield. Acetylation of the dihydro compounds 314 and 315 with acetic anhydride gave the corresponding acetates 316 and 317 in high yields (Eq. 91)."'
313
314
316
QH -
Me 315
Me 317
(91)
vl W
Y
n
5 2+ wCA
59
Y
bv m rU -i
TABLE 1-1. -3contd.)
Substituent
mp ("C); rbp (" C/torr)]
Solvent of Crystallization
Yield (YO)
None
Spectra
32
Refs. 3
Pyridazino[I,2-a][1,2]diazepines
m
Octahydro-6H-pyridazino[l,2-a][1,2]diarepine
0
None
I(S)-C00tB~-6,10-( = O),-9(S)-PhthN l(S)-COOH-6,10-(= 0),-9(S)-PhthN l(S)-COOH-6,10-( = O),-9(S)-NH2
26
182-185 307-310d 195-200d
EtAc/Et,O Me,CO/H,O EtOH/H,O
[a];0 [a];' [a];'
~
80.0 (C = 0.5;MeOH) 139 (C = 0.5; DMF) - 174.6 (C = 0.5; 3N HCI)
-
l3C-nrnr
4
16 76 16
Triazolo[I,Z-a] [I,Z]diazepines
Tetrahydro[I ,2,4]triazolo[l,2-a] [ I ,2]diazepin-l,3-(2H,5H)-diones
2-Bu 2-Ph 2-(4-BrC,H,) 2-(4-C1C6H4) 2-[4-(4-C1C6H4CH20)C6H4] 2-(4-MeOC,H4) 2-(4-NO,C,H,) 2-(3-CF,C,H,) 2-(3,4-C1,C,H,) 2-(3,5-CI,C,H,)
2-(4-BrC6H,) 2-(4-C1C,H,) 2-(4-MeOC6H,) 2-(4-MeC6H,) 2-(3,5-CIC,H,)
20 21 70 74
[lOcrl05/0.5]
148 134-135 118-119.5 168-170 134135 168-169 103-104 133-1 34 124125
150-152
154.5-155 185-1 87 208-210 168-170
75 74
95 95 92 84 77
8b 8b 8b 8b 8a, b
75
8b, c
70 72
EtOH EtOH EtOH EtOH EtOH
i
7 8b 8b 8b 8b 8b 8b 8b 8a, b
Tetrahydro[I ,2,4ltriazolo[I ,2-a] [ I ,2]diazepin-l,3 (2H,SH)-dithione
2-(4-CIC,H,)
2w201
TABLE 1-2. [b]-FUSED [1,2]DIAZEPINES
Substituent
mp YC); [bp ("C/torr)]
Solvent of Crystallization
Yield (YO)
Spectra
Refs.
Azeto[l,2-h] [ I ,2]diazepines
l-C1-4-COPh, trans l-C1-4-COOEt, trans 1-C1-4-COOPr-i, trans 1-Ph-4-COOEt l-NH2-4-COOEt-7-Me, trans 1,l-Clz-4-COPh 1-C1-1-Me-COOEt, cis l-CI-l-Me-4-COOEt, trans l-NHCOPh-4-COOEt-7-Me, trans 1-(4-NO,C,H,CONH)-4-COOEt-7-Me, trans
144145
110
EtOH
70 70 80 56
ir, pmr, uv
10 10 10 10
84
ir. uv
11 10
80 43 6 93 77
ir, uv ir, uv
10 10 11 11
158 151 145
90 92 91
ir, pmr, uv ir, pmr, I3C-nmr, uv ir, pmr, I3C-nmr, uv
11 11 11
165 137 Oil Oil Oil Oil Oil
90 92 61 56 15 68
ir, pmr, uv ir, uv ir, uv, ms, pmr ir, uv, ms, pmr ir, uv, ms, pmr ir, uv, ms, pmr ir, uv, ms, pmr
50
1-NHC0(2-COOH-C,H,)-4-COOEt-7-Me, trans
l-NHCOOPh-4-COOEt-7-Me, trans l-Phthalimido-4-COOEt-7-Me, trans I-N-[3-iminoisobenzofuranl-one]-4-COOEt-7-Me, trans
l-NHC0(2-thienyl)-4-COOEt-7-Me, trans 1-CI-4-COOEt-6-Me
1-Br-CCOOEt-6-Me I-Me-4-COOEt l-p-CITs-4-COOEt-6-Me l-MeC00-4-COOEt-6-Me
95
11 11 104 104 104 104 104
1-PhCH,OCONH-4-COOEt-6-Me I-N, -4-COOEt-6-Me 1-Br-4-COPh 1-p-CITs-5-COPh 1-MeCO0-4-COPh-h-Me 1-N3-4-COPh 4-COOEt-6-Me 4-CONH2-6-Me I-Cl-4-COOEt-8-COOEt 1,1-Cl2-4-COPh I-Me-1 -CI-4-COPh l,l-Me2-5-COOEt 4-COOEt-1,1,6-Me3
m w
134 Oil Oil 133-134 120 114 77-78 175 Oil Oil Oil 79 Oil
Et,O/Petr ether
CHCI,/Et,O CHCI,/Petr ether EtOH Hexane EtOAc
Et,O/Petr ether
40 86 33 81 79 55
44 69 60 80 31 29
ir, uv, pmr ir, uv, ms, pmr ir, uv, ms, prnr ir, uv, ms, pmr ir, uv, pmi ir, uv, ms, pmr ir, uv, ms, pmr ir, uv, ms, pmr, ir, uv, ms, pmr ir, uv, ms, pmr ir, uv, ms, pmr ir, uv, prnr ir, uv, ms, pmr
104 104 104
ir, uv, pmr ir, uv, pmr
104 104
104
104 104 104 104 104 104
104 104 104
5-Carbethoxy-7-dimethyhmonium-8,8-dimethyla~eto[l,2-b~ [I ,2]diazepines Et
None 2,8,8-Me3
84
85
I .2,4-0xadiazolo[4.5-b] [ I ,2]diazepines
TABLE 1-2. 4 c o n t d . )
Substituent
mp ("C); [bp rC/torr)]
3-(2,4,6-Me3C,H,)-5-COOEt 3-Ph-5-COPh-8-Me 3-Ph-5-COOEt-8-Me 3,8-(Ph),-5-COOEt
[70/0.01]
3-(2,4,6-Me,C,H,)-5-COPh-8-Me
159 122 157
3-(2,4,6-Me,C,H, )-5-COOEt-8-Me
3-(2,4,6-Me3C6H,)-5-COOEt-8-Ph
E
Solvent of Crystallization
Yield (YO)
Spectra
Et,O/Petr ether Et,O/Petr ether Et,O/Petr ether
50 58 60 62 61 11.5 64
ir, pmr, uv ir, pmr, uv ir, pmr, uv ir, pmr, uv ir, pmr, uv ir, pmr, uv ir, pmr, uv
13 13 13 13 13 13 13
pmr, uv pmr, uv pmr, uv pmr, uv
14 14 14 14
Refs.
Pyrrolo[I,Z-b] [I,Z]diazepines
[79/0.4] 93 118 [17G180/0.5]
Petr ether EtOH/H,O
30-40 5 10 9
TABLE 1-3. [cI-FUSED [1,2]DIAZEPINES mp ("C); Substituent
C ~ (OC/torr)l P
Solvent of Crystallization
Yield (%)
Spectra
Refs.
1.2-Benzodiazepines
I H-l,2-Benzodiazepines
None
6 3 4
i-Pr,O
61
4-Me
87-88
i-Pr,O
60
5-Me
63.5-64
i-Pr,O
79 38
Q\
m
ir, ms, pmr, uv ir, ms, pmr, uv ir, ms, pmr,
17a, b 17b 17a,b
uv
7-COOMe 7-C1 7-Me0 7-Me 8-Me0 8-Me
114-115 73-74 94.5-95.5 94.5-95.5 103-104.5 93.5-95
i-Pr,O/PhH i-Pr,O i-Pr,O i-Pr,O i-Pr,O i-Pr,O
3-COOEt 3-COOMe 3-CONH2 3-C1 3-CN 3-Et0
105
Et,O/i-Pr,O i-Pr,O/PhH i-Pr,O/PhH i-Pr,O i-Pr,O i-Pr,O
128-130 189-1 91 6849 7CL71 63.545
47 62 70
Pmr Pmr Pmr Pmr Pmr Pmr
17b 17b, 18 17b 17b 17b 17b
17 33 33 86 13 10
ir, pmr ir, ms, pmr ir, ms, pmr ir, prnr ir, ms, pmr ir, ms, prnr
18b 20b 20b 20a, b 20b 20b
50 5
TABLE 1-3. gcontd.) ~~
Substituent
Q\ Q\
3-Me0 3-CH(COOMe), 3,4-(COOEt), 3-COOEt-4-CN 3-COOEt-4-Me 3-COOEt-4-Ph 3-COOEt-5-Me 3-COOEt-5-Ph 3-COOMe-5-Me 3-CONH2-5-Me 3-CI-5-Me 3-CN-5-Me 3-Et0-5-Me 3-Me0-5-Me 3-CH(COOMe),-5-Me 3-Ac-5-Ph-7-CI 3-COPh-5-Ph-7-Cl 3-COOBu-t-5-Ph-7-CI 3-(4-N02C,H.+)-5-Ph-7-C1 3-SOzPh-5-Ph-7-Cl 1-Me 1,5-(Me), 3-COOH 4-COOEt 3-COOH-5-Ph-7-CI 3-COOH-5-Me 3-COOH-5-i-Pr 3-Me-7-CI 3-Et-7-CI
mp ("C); IbP (°C/torr)l 85-86
Solvent of Crystallization i-Pr,O
Oil
114 168 119 131 105 180 159-160 228.5-230 86-87 6748 91-93 94-95 Oil 140 168 195d 158 135 6142 Oil 115d 93-94 126d 120d 130d 184 140
Et,O/i-Pr,O Et,O/i-Pr,O i-Pr,O Et,O/i-Pr,O i-Pr,O Et,O/i-Pr,O i-Pr,O/PhH EtOH i-Pr,O i-Pr,O i-Pr,O i-Pr,O i-Pr,O i-Pr,O i-Pr,O i-Pr,O i-Pr,O
i-Pr,O i-Pr,O
Yield (YO)
Spectra
Refs.
66 59 68 65 66 54 47 75 26 34 89 12 9 55 47 62 81 79 55 54 8G90 8&90 89 52 90 86 87 36 45
ir, ms, pmr ir, ms, pmr ir, pmr ir, pmr ir, pmr ir, pmr ir, pmr ir, pmr ir, ms, pmr ir, ms, pmr ir, pmr ir, ms, pmr ir, ms, pmr ir, ms, pmr ir, ms, pmr ir, pmr ir, pmr ir, pmr ir, pmr ir, pmr
20a, b 20a, b 18a, b 18a, b 18b 18a, b 18b 18b 20b 20b 20a, b 20b 20b 20a b 20a, b 19 19 19 19 19 22 22 77 82 77 77 77 78 78
ir ir, uv, ms, pmr ir ir ir ir, pmr ir, pmr
3-n-Pr-7-Cl 3,4-COOMe 3-COOMe-4-Me 3-COOMe-4-Me-S-OAc, cis
143 154-155 87-88 199-200
3-COOMe-4-Me-5-OAc,rrans
150-151
None 3-Ac0 3-Meo 5-Me 3-Ac0-5-Me 3-Me0-5-Me 1-Oxide 1-Oxide-5-Me 2-Oxide 2-Oxide-5-Me
[125-1 28/ I]
3-C02Me-5-OAc
3-CN-5-OAc-l-[3,4-(MeO),C,H3]-3,4-Me,-S-Et-7,8-(MeO),3-ium Iodide Hydrate
84-85 53-54 [132-134/1] 6243 Oil 93-94 93-94 85-86 68-69
Oil Unstable
15C152d
i-Pr,O
38 35 88 100
i-Pr,O i-Pr,O i-Pr,O PhH/i-Pr,O PhH/i-Pr,O PhH/Pr,O PhH/i-Pr,O
95 88 14 93 83 44 22 20 55 63
ir, pmr ir, uv, ms, pmr ir, uv, ms, pmr ir, uv, ms pmr, 13C-nmr ir, uv, ms
ms, pmr, uv ir, ms, pmr ms, pmr ms, pmr, uv ir, ms, pmr ms, pmr ms, pmr, uv ms, pmr, uv ms, pmr, uv ms,pmr, uv
82 81 81 81
21, 23 20b, 21 21 21, 23 20b, 21 21 2Oa, b 20b 20a, b 20
84
60 60
84
uv, prnr
94
TABLE 1-3. ---(contd.)
Substituent
o\
O0
None 2-Ac 2-COOMe 5-Me 1924Ac)z 2-Ac-3-OMe 2-Ac-5-Me 2-COOEt-3-Et0 2-COOMe-5-Me 1,2-(Ac),-S-Me
mp ("C); [bP r C / t o r r ) l
Solvent of Crystallization
5658 108-109 109-1 10 75-76 78-80
i-Pr,O i-Pr,O i-Pr,O i-Pr,O PhH/i-Pr,O
89-90 86-87 100-101 104.5-1 05.5
164165 152-1 53 188-190
Yield (YO)
Spectra
Refs.
PhH/i-Pr,O Pe tr ether i-Pr,O PhH/i- Pr 0
96 89 61 94 91 6 93 59 79 94
ir, ms, pmr ir, ms, pmr ir, ms, pmr ir, ms, pmr ir, ms, pmr ir, pm+ ir, ms, pmr ir, ms, pmr, uv ir, ms, pmr ir, ms, pmr
17b 17b 17b 17b 17b 24 17b 25 17b 17b
i-Pr,O i-Pr,O MeOH
40 72 14
ir, pms, ms ir, pmr, "C-nmr I3C-nmr, ms ir, pmr
79 79 79
i-Pr,O/ n-Pentane
52
ir, pmr
79
,
4,5-Dihydro-lH-l,2-benzodiazepines
3,4-(COOEt),-4- Me-5-OH 3,4-(COOEt),-4-Me-5-OAc 3,4-(COOEt),-4-Ph-S-OAc 3,4-(COOEt),-4-Me-5 = 0
88-89
r-
m
w m m m
,s
i
. I
-9 ” \m /i ”
rn
s
w w w
“PI
WAZ Z S
m m N N
w
m
zz m
3
>
71
N m
a
N m
a
12
W N
i
W N
i
W N
Pyrimido[4,5-c] [I,Z]diuzepines
I,7-Dihydropyrimido[4,5-c] [I,2]diazepin-6(6H) -ones
250-253d 196d 244245d 205-220d 240.5-242.5d 187-196d 1-Me-3-COOEt-5-[2,4-(MeO),-C6H3]-8-NH, 162d 1-Me-3-COOEt-5-[3,4-(MeO),-C6H3]-8-NH, 1-Me-3-COOMe-5-(3-OH-C6H4)-8-NH, > 275 258-260d l-Me-3-COOMe-5-[3,4,5-(MeO),C,H,I-8-NH, 258-272d 1-Me-3-COOMe-5-(3-Pyridyl)-8-NH2
1,3,5-(Me),-8-NH2 1,3-(Me),-5-COOEt-8-NH, 1,5-(Me),-3-COOEt-8-NH, 1-Me-3,5-(Ph),-8-NH2 1-Me-3-COOEt-5-Ph-8-NH2
MeOH CC1, EtOAc CC1, PhH PhH EtOAc/hexane MeoH MeOH MeOH
41 11 30 29 9 28 7 49 45 56
ms, pmr, uv pK, ms, pmr, uv ms, pmr, uv ms, pmr, uv ms, pmr, uv pmr, uv pmr, uv pmr, uv ms, pmr, uv pmr, uv
33b 33b 33b 33b 33b 33b 33b 33b 33b 33b
I0 15 12 8 10
ms, ir, uv, ms, ir, uv, ms, ir, uv, ms, ir, uv,
32 87 87 87 87
Thieno[c] [l,2]diazepines
IH-Thieno[2,3-c] [1,2]diazepines
None 3,5-Me2 l-COOEt-3,5-Me2 1-Ac-3,5-Me2 l-COPh-3,5-Me2
81-83 96-91 134-135 102-104 Oil
pmr pmr pmr pmr
TABLE 1-3. g c o n t d . )
Substituent
mp ("C); P P (°C/torr)l
Solvent of Crystallization
Yield (YO)
Spectra
Refs
IH-Thieno[3,2-c] [I,Z]dazepine
None
32
65
94-95
-4
P
2.3-Benzodiazepines
I H-2.3- Benzodiazepines
None I-Et 1-Me I-Ph 4-Ph I-PhCH2-4-Ph 7,8-(MeO), 1-Me-4-Ph l-(4-MeC,H4)-4-Ph l-Ph-7,8-(MeO),
49-50 40-41 47 101-102 132-133 126-1 27 89-9 1 92-93 14&147 112-1 1 3
41
64 62 71 65 70 88 67 84
ms, pmr ms, pmr ms, pmr ms, pmr ms, pmr ms, pmr ms, pmr ms, pmr ms,pmr
35 35 34,35 35 35, 37 39 35 34, 35 34, 35 35
C
3-COOEt-8-COOMe I-Me-3-Ac 1,4-Me2-3-Ac
84-86 11cb111 Oil
i-Pr,O/Hexane
N --N
H
12 59 50
pmr, ir, uv, ms ir, pmr, ms, anal ir, pmr, ms, anal
90 91 91
ms, pmr
35 37 39 35 35 35 40,42
5H-2,3-Benzodiazepiner
-
1-Ph 4-Ph l-PhCH2-4-Ph 1-Me-4-Ph 1-(4-MeC,H4)-4-Ph l-Ph-7,8-(MeO), 1-[3,4-(MeO),C6H,]-4- Me-5-Et-7,8-(MeO), I-Me 4-Me 7-Me 9-Me 1,4-di-Me 8-Me0 1-Me-3-Ac 1,4-Me2-3-Ac Hydrochloride Hydrobromide Perchlorate Picrate
152-153 108-110 148-149
(EtOH) EtOH
69; 46 92 83
269-270 162-1 63 156157
PhH/EtOH EtOH i-PrOH
84 57; 82 71; 73
Oil
106-108 Oil Oil Oil Oil 11cb111 Oil 22cb221d 218-219d 2W202d 206-207d
phH/Hexane
i-Pr,O/Hexane MeOH i-PrOH/H,O i-PrOH/H,O EtOH
35 45 50 55 30 45 59 50
ms, pmr ms, pmr ms, pmr ir, ms, l3cnmr, pmr, uv Pmr Pmr Pmr Pmr Pmr Pmr ir, pmr, ms ir, pmr, ms ir, pmr, uv
uv
91 91 91 91 91 91 91 91 40 40 40 40
TABLE 1-3. 4 c o n t d . )
Substituent
mp ("C); P P ("C/torr)l
Solvent of Crystallization
Yield (%)
1-Et-4-[3,4-(MeO),C,H3]6,7-(Me0),-2-Naphthol adduct
168
EtOH
87.5
Pentane
20
Spectra
Refs.
40
4,5-Dihydro-l H-2.3-benzodiazepine
None
63
ir
GkH3
45
\
4 3 -Dihydro-3H-2,3-benzodiazepines
5
None Picrate 1-Ph 3-Ph 3-(4-C1C,H,) 3-(4-MeC6H,) 3-(2-N02C,jH4) 3-(4-NO2C,H,) 3-CONHPh 4-Ph 5-COOMe 1-Ph-3-CH2CH,OH l-(4-MeOC6H,)-3-CH,CH,OH 4-(4-HO-2,5-Me,C6H,]-8-N0,
72 18G190d 76-77 114-115 102-104 86-87 154-155 133-135 113-1 15 26G263 155-156 163-165 303d
Petr ether
42
Ligroin MeOH MeOH MeOH
40 57 50 47 20 54
MeOH Et,O
45 ir, ms, pmr, ir, ms, pmr, uv
55
ir DMF/H,O EtOH EtOH MeOH/EtOH
59.5 42 60 7C-80
48 46 46 46 47 46 45 37 49 48 48 54
I ,2-Dihyd~o-5H-2,3-benzodiazcpines
l-MeO-2-Ac-4-Ph l-EtO-2-Ac-4-Ph 1-PhO-2-Ac-4-Ph 1-EtS-2-Ac-4-Ph 1-PhS-ZAc-CPh
-1 -1
Oil [140/0.15 mmHg] Oil [150/0.2 mm Hg] 116-117 Oil [190/0.4 mm Hg] Oil [150/0.15 mm Hg]
EtOH
88
ir, pmr, I3C-nmr
98
81
ir, pmr, ' T - n m r
98
92 62
ir, pmr, I3C-nmr ir, pmr, 'V-nmr
98 98
74
ir, pmr, 13C-nmr
98
2,5-Dihydro-2,3-benzodiazepin-l ( I H)-ones
4-Ph 4-(4-HOC,H4) 4-(4-MeOC6H,) 4-(3-MeC,H4) 4-(4-MeC,H4) 4-(2-Me-4-HO-C6H,) 4-[2,3-(Me),-4-HO-C6H,] 4-[2,6-(Me),-4-HO-C,H2] 4-[3,5-(Me),-4-HO-C,H,] 4-[4,5-(Me),-2-HO-C6H2] 4-[4,6-(Me),-3-HO-C,H2] 2-Et-4-Ph 2-(2-Diethylaminoethyl)-4-Ph Maleate
202 243d 208 190-191 233 21 Id 250d 268d 256d 269d 211d 142 112
EtOH
8G85
EtOH EtOH EtOH MeOH/EtOH MeOH/EtOH MeOH/EtOH MeOH/EtOH MeOH/EtOH MeOH/EtOH Et OH/H 0 i-PrOH
80j88
,
50 87/92 7G80 70-80 70-80 70-80 7680 7&80 60
50, 55, 56 53 56 52 56 54 54 54 54 54 54 51 55
TABLE 1-3. -
Substituent
~
O0
2-(2-Hydroxyethyl)-4-Ph 2-Me-4-Ph 2-(2-Morpholinoethyl)-4-Ph Maleate 2-(2-Morpholinoethyl)-4-(4-MeOC6H,) Hydrochloride 2-(2-Morpholinoethy1)-4-(4-MeC6H4) Maleate 2-Morpholinomethyl-4-Ph 2-(3-Morpholinopropy1)-4-Ph Hydrochloride 2-NO-4-Ph 2-Ph-4-Me 2-(2-Pyrrolindinoethyl)-4-Ph Maleate 2-(3-Pyrrolidinopropyl)-4-Ph Maleate 4-Ph-8-MeO 4-[2,3-(Me),-4-HOC,H,]-8-HO 4-[2,5-(Me),-4-HOC6H,]-8-NH,
4-[2,5-(Me),-4-HOC,H2]-8-Me0 4-[3,5-(Me),-4-HOC,H,]-%Me0 4-[4,5-(Me),-2-HOC,H2]-8-H0 2-Me-4,5-Ph2 2-Me-4-Ph-5-Br
mp ("C); IbP (°C/torr)l
Solvent of Crystallization
141 131, 133 163
EtOH PhH i-PrOH
33
208 148 164 218 110 198-199 157 165 147 259d 277d 259d 288d 295d 145 164
EtOH PhH EtOH i-PrOH EtOH/H,O EtOH i-PrOH EtOH EtOH MeOH/EtOH MeOH/EtOH MeOH/EtOH MeOH/EtOH MeOH/EtOH EtOH
80 65 30 62
240
PhH/EtOH
Yield (YO)
60, 75 76
50 50 50 70-80 70-80 70-80 7G80
70-80 55
Spectra
Refs.
ir, pmr, uv
55 51, 55
55
ir, pmI
Pmr Pmr Pmr Pmr Pmr ir, pmr, uv ir, pmr
55 55 55 55 51 50 55 55 55 54 54 54 54 54 57 57
2,5-Dihydro-2,3-benzodiazepin- I ( I H ) -thione
4-(4-MeC6H,)
56
None
I-Me I-Ph I-PhCH2-3-Me 1-BrCH2-3-Me 1,3-Me, 1-Me-3-Ph 1-Ph-3-Me l-Ph-3-(2-Morpholinoethyl) Maleate
184.5-1 85.5 208; 212 139 148
Analysis only EtOH i-PrOH EtOH
60 60 15; 40
ir, pmr, uv ir, pmr
58 58 60, 61 63 63 63 58 60, 61c 61 61
158-158.5 131 72 159
DMF/H,O D M F/H ,O
169 167 229-230
EtOH i-PrOH CHCI,/EtOH
50 65
61 61 59
185
EtOH
35
61
189; 190 83-86
EtOH Hexane
40; 35 34
60,61 59
147 127; 137-138
i-PrOH EtOH
77; 53 60; 48; 62
215 210-212
EtOH EtOH
50 45
61 59
155-157
EtOH/Et,O
85
59
43 70; 62 50; 86.7 85
ir, pmr, uv
1-Ph-3-(3-Morpholinopropyl) Maleate 4 \o
I-Ph-3-(2-Pyrrolidinoethyl) Maleate 1-Ph-8-CI 1-(4-C1C,H,)-3-2-Morpholinoethyl
Maleate 1-(4-MeOC,H4-3-(2-Morpholinoethyl) Maleate l-Ph-3-(2-Dimethylaminoethyl)-8-C1 I-Ph-3-(2-Morpholinoethyl)-8-C1 Maleate I-Ph-3-Me-8-Cl 1-Ph-3-(2-Pyrrolidinoethyl)-8-CI Hydrochloride hydrate I-Me-7,8-(MeO), 1-Me-3-(2-Dimethylaminoethyl)7,8-(MeO),
40
ir, pmr, uv
60, 61 5941
TABLE 1-3. [c]-FUSED [l,Z]DIAZEPINES
Substituent ~~~
~
mp YC); IbP (°C/torr)l
Solvent of Crystallization
Yield (YO)
Spectra
Refs.
194 189 185 169
EtOH EtOH EtOH i-PrOH
82 72 64 20
ir, pmr ir, pmr
62 62
~
l-Me-3-Ph-7,8-(MeO),
1-Me-3-(4-BrC,H4)-7,8-(Me0), 1-Me-3-(4-C1C6H,)-7,8-(MeO),
l-Ph-3-(2-Morpholinoethyl)-5,5-Me2
ir, prnr
mH
62
61
\
2,3,4,5-Tetrahydro-1H-2,3-benzodiazepines
5
g
None Hydrochloride 2,3-Me2 Picrate
139-143
45
H,O, HCI
64
129-1 30
1,2,3,5-Tetrahydro-2,3-benzodiazepin-4(4H)-ones
1-COOMe-2-Me 1-COOMe-2-Ph
121-122 149-151
HZ0 EtOH
82 80
ir, pmr ir, pmr
65 65
2,3-Me2 2,3-Me2-5-Br
118-119 162-1 63
Hexane PhH/Hexane
84 76
ir, ms, pmr ir, pmr
64 66
W
m
N
m N
m N m
m m w w
> > I I
ii
.-i,g
W p' -v,
a w
81
D
ss
D D
PPPP
P
D
> 4 "
E i4
.-4-
TABLE 1-3. g c o n t d . )
Substituent
mp ("C); IbP (" C/torr)l
Solvent of Crystallization
Yield (%)
Spectra
Refs.
Pyrazolu[3,4-d][1,2]diazepines
6-COPh-8-Me
179-180
PhH
78
jr, pmr, uv
74
EtOH/H,O EtOH/H,O EtOH EtOH MeOH EtOH
16 56 60 39 57 49 52
ir, ms, pmr, uv ir, pmr, uv ir, pmr, uv ir, pmr, uv ir, pmr, uv
69a, b 74 74 74 74 74 74 69a 69a 69a 69a 69a 71
W h)
2,3,3a,6-Tetrahydropyrazolo[3,4-d] [1,2]diazepines
6-PhSO, 2-Ac-6-PhSO2 2-Ac-6-(4-MeC,H4SO,) 2-MeOCH,-6-(4-Me-C,H,SO,) 2-Ac-6-COPh-8-Me 2-Ac-6-PhS02-8-Me 2-(4-MeC,H,S02)-6-COPh-8-Me 3,3-Me,-6-COPh 3,3-Me,-6-COOEt 3,3-Me2-6-COOPr-i 3,3-Me,-6-PhS0, 3,3-(Me),-6-(4-Me-C,H,SO,) 2-Ac-3,3-Me2-6-COOEt
148-149 179-180 178 144-145 167-168 147 161 [SO/O.Ol mm] 135-137 136138 [40/0.01 mm] 148-149
PhH PhH
80 61 50 49
ir, pmr, uv ir, pmr, uv ir, ms, pmr, uv ir, ms, pmr, uv ir, ms, pmr, uv ir, ms, pmr, uv Pmr
33
t
iLI
rig
.-i,g
5 .-i,g
i;i 0 0
Y
83
P N
$: A
rn
4
vl
c
P 0
vt lv t -l
vl
I
3
v! 3
22
ez p: .-
84
3
2
8
m OI
>
m 00
00
E
W d 3
I W m 3
85
86
Bicyclic 1,2-Diazepines
F. REFERENCES 1. B. Ulbrich and H. Kisch, Angew. Chem., 90, 388 (1978). 2. (a) W. Sucrow, M. Slopianka, and V. Bardakos, Anyew. Chem., 87, 551 (1975). (b) W. Sucrow and M. Slopianka, Chem. Ber., 111, 780 (1978). 3. S. F. Nelsen and G. R. Weisman, Tetrahedron Lett., 2321 (1973). 4. S. F. Nelsen, V. Peacock, and G. R. Weisman, J . Am. Chem. Soc., 98, 5269 (1976). 5. S. F. Nelsen and J. M. Buschek, J . Am. Chem. Soc., 96, 6987 (1964). 6. S. F. Nelsen and G. R. Weisman, J . Am. Chem. Soc., 98, 7007 (1976). 7. G. Zinner and W. Deucker, Arch. Pharm., 296, 14 (1963). 8. (a) Ger. Offen. 2, 554,866, June 1976. (Mitsubishi Chemical Industries Ltd.): Tokyo or Jap. Kokai, 76 70820, June 1976; (b) Dutch Patent 7,507,233 (Mitsubishi Chemical Industries, Ltd.), Tokyo, December 1975 or Jap. Kokai 77 83687, July 1977; (c) Jap. Kokai 76 86489, July 1976. 9. S. S. Mathur and H. Suschitzky, J . Chem. Soc., Perkin Trans. I , 2474 (1975). 10. J. P. Luttringer and J. Streith, Tetrahedron Lett., 4163 (1973). 11. J. Streith and G. Wolff, Heterocycles, 5, 471 (1976). 12. R. Allmann and T. Debaerdemaeker, Cryst. Struct. Commun., 3, 365 (1974). 13. J. Streith, G. Wolff, and H. Fritz, Tetrahedron, 33, 1349 (1977). 14. W. Flitsch, U. Kramer, and H. Zimmermann, Chem. Ber., 102, 3268 (1969). 15. H. Koga, M. Hirobe, and T. Okamoto, Chem. Pharm. Bull., 22,482 (1974). 16. K. T. Potts and D. R. Choudhury, J. Org. Chem., 42, 1648 (1977). 17. (a) T. Tsuchiya, J. Kurita, H. Igeta, and V. Snieckus, J . Chem. Soc., Chem. Commun., 640, 1974; (b) T. Tsuchiya, J. Kurita, and V. Snieckus, J . Org. Chem., 42, 1856 (1977). 18. (a) L. Garanti, A. Scandroglio, and G. Zecchi, Tetrahedron Lett., 3349 (1975); (b) L. Garanti and G. Zecchi, J . Chem. Soc., Perkin Trans. I , 2092 (1977). 19. L. Chiodini, L. Garanti, and G. Zecchi, Synthesis, 603 (1978). 20. (a) T. Tsuchiya and J. Kurita, J . Chem. Soc., Chem. Commun., 419 (1976); (b) T. Tsuchiya and J. Kurita, Chem. Pharm. Bull., 26, 1896 (1978). 21. T. Tsuchiya and J. Kurita, Chem. Pharm. Bull., 26, 1890 (1978). 22. T. Tsuchiya, J. Kurita, and K. Takayama, Heterocycles, 9, 1549 (1978). 23. T. Tsuchiya and J. Kurita, J . Chem. Soc., Chem. Commun., 936 (1974). 24. T. Shiba, K. Yamane, and H. Kato, J . Chem. Soc., Chem. Commun., 1592 (1970). 25. Y . Tamura, S . Matsugashita, H. Ishibashi, and M. Ikeda, Tetrahedron, 29, 2359 (1973). 26. (a) A. Frankowski, J. Streith, and H. Normant, C. R . Acad. Sci., Paris (C), 276, 959 (1973); (b) A. Frankowski and J. Streith, Tetrahedron, 33, 427 (1977). 27. E. Fischer and H. Kuzel, Anal. Chem., 221, 261 (1883). 28. N. S. Gill, K. B. James, F. Lions, and K. T. Potts, J . Am. Chem. Soc., 74, 4923 (1952). 29. A. Sammour, A. Raouf, M. Elkasaby, and M. A. Ibrahim, Acta. Chim. Acad. Sci. Hung., 78,399 (1973). 30. A. Sammour and M. El-Hashash, Egypt. J . Chem., 16, 381 (1973). 31. T. Sasaki, K. Kanematsu, Y. Yukimoto, and E. Kato, Synth. Commun., 3, 249 (1973). 32. T. Tsuchiya, M. Enkaku, and H. Sawanishi, Heterocycles, 9, 621 (1978). 33. (a) R. W. Morrison, Jr., W. R. Mallory, and V. L. Styles, Presentation at the 174th National Meeting of the American Chemical Society, Chicago, Aug. 28-Sept. 2, 1977, O R G N 9; (b) European Patent Appl. 78,100,435.3 February 1979 (Wellcome Foundation, Ltd.). 34. J. T. Sharp and P. B. Thorogood, J . Chem. Soc., Chem. Commun., 1197 (1970). 35. A. A. Reid, J. T. Sharp, H. R. Sood, and P. B. Thorogood J . Chem. Soc., Perkin Trans. I , 2543 (1973). 36. R. 0. Gould and S. E. B. Gould, J . Chem. Soc., Perkin Trans. I I , 1075 (1974). 37. V. I. Bendall, J . Chem. Soc., Chem. Commun., 823 (1972). 38. A. A. Reid, J. T. Sharp, and S. J. Murray, J . Chem. Soc., Chem. Commun., 827 (1972). 39. A. A. Reid, H. R. Sood, and J. T. Sharp, J . Chem. Soc., Perkin Trans. I , 362 (1976).
F. References
87
40. (a) J. Korosi and T. Lang, Chem. Ber., 107,3883 (1974); (b) J. Korosi, T. Ling, E. Komlos, and L. Erdelyi, US. Patent 3,736,315, May 1973 (Egyesult Gyogyszeres Tapszergyar, Budapest, Hungary). 41. Hungarian Patent 155,572, Dez. 1966 (Gyogyszerkutato Intezet); Chem. Abstr., 70, 115026a (1969). 42. A. Neszmelyi, E. Gaez-Baitz, G . Horvath, T. Lang, and J. Korosi, Chem. Ber., 107, 3894 (1974). 43. G. Zolyomi, 0. Banfi, T. Lang, and J. Korosi, Chem. Ber., 107, 3904 (1974). 44. M. Lampert-Sreter, Acta Chim. Acad. Sci. Hung., 83, 115 (1974). 45. E. Schmitz and R. Ohme, Chem. Ber., 95, 2012 (1962). 46. Y. Tamura, J. Minamikawa, H. Matsushima, and M. Ikeda, Synthesis, 159 (1973). 47. J. Streith and C. Fizet, Tetrahedron Lett., 3297 (1977). 48. C. Van der Stelt, P. S. Hofman, and W. T. Nauta, Reel. Trau. Chim., 84, 633 (1965). 49. M. D. Nair and P. A. Malik, Indian J . Chem., 10, 341 (1972). 50. J. Gottlieb, Chem. Ber., 32, 958 (1899). 51. H. Wolbling, Chem. Ber., 38, 3845 (1905). 52. A. Lieck, Chem. Ber., 38, 3853 (1905). 53. M. Buu-Hoi, Compt. Rend., 209, 321 (1939). 54. A. Rose and N. P. Buu-Hoi, J . Chem. Soc., 2205 (1968). 55. M. Flammang and C. C. Wermuth, Eur. J . Med. Chem. (Chim. Ther.), 12, 121 (1977). 56. L. Legrand and N. Lozach, Bull. SOC.Chim. Fr., 2237 (1970). 57. M. Flammang, C . R. Acad. Sci., Paris ( C ) , 286, 671 (1978). 58. J. 0. Halford, R. W. Raiford, Jr., and B. Weissmann, J . Org. Chem., 26, 1898 (1961). 59. K. Nagarajan, J. David, and R. K. Shah, J . Med. Chem., 15, 1091 (1972). 60. C. C. Wermuth and M. Flammang, Tetrahedron Lett., 4293 (1971). 61. (a) M. Flammdng and C. C. Wermuth, Eur. J . Med. Chem. (Chim. Ther.), 11, 83 (1976); (b) Fr. Patent 2,104,998, April 1972 (Synthelabo S.A.); (c) Fr. Patent 2,085,645, December 1971 (Synthelabo S.A.). 62. A. Sotiriadis, P. Catsoulacos, and D. Theodoropoulos, J . Heterocycl. Chem., 11, 401 (1974). 63. M. Flammang, C. R. Acad. Sci, Paris (C), 283, 593 (1976). 64. G . Rosen and F. D. Popp, J . Heterocycl. Chem., 6, 9 (1969). 65. G . Cignarella, R. Cerri, F. Savelli, and A. Maselli, J . Heterocycl. Chem., 14, 465 (1977). 66. (a) G. M. Rosen, Dissertation “A study of 2,3-benzodiazepines.” b) Diss. Abstr., 32, 1463 (1971). 67. W. F. Whitmore and R. C. Cooney, J . Am. Chem. Soc., 66, 1237 (1944). 68. T. Sasaki, K. Kanematsu, and T. Kataoka, J . Org. Chem., 40, 1201 (1975). 69. (a) G . Kiehl, J. Streith, and G . Taurand, Tetrahedron, 30, 2851 (1974); (b) G . Taurand and J. Streith, Tetrahedron Lett., 3575 (1972). 70. (a) T. Tsuchiya, H. Arai, H. Hasegawa, and H. Igeta, Tetrahedron Lett., 4103 (1974); (b) T. Tsuchiya, H. Arai, H. Hasegawa, and H. Igeta, Chem. Pharm. Bull., 25, 2749 (1977). 71. Y. L. Chow, J. Streith, and G . Taurand, Org. Magn. Resonance, 5, 155 (1973). 72. M. Hieda, K. Omura, and S. Yurugi, J . Pharm. Soc. Japan, 92, 1327 (1972). 73. J. Streith, G. Kiehl, and H. Fritz, Tetrahedron Lett., 631 (1974). 74. J. R. Frost and J. Streith, J . Chem. Soc., Perkin Trans. I , 1297 (1978). 75. D. E. Ames and W. D. Doddis, J . Chem. Soc., Perkin Trans. I , 705 (1972). 76. M. R. Attwood, C. H. Hassall, R. W. Lambert, G . Lawton, and S. Redhaw, U.S. Patent 4,512,924, April 1985. 77. L. Garanti and G . Zecchi, J . Heterocycle. Chem., 16, 1061 (1979). 78. L. Garanti, G . Testoni, and G . Zecchi, Synthesis, 380 (1979). 79. L. Garanti and G . Zecchi, J . Chem. Soc., Perkin Trans. I , 1195 (1979). 80. A. Padwa and S. Nahm, J . Org. Chem., 44,4746 (1979). 81. A. Padwa and S. Nahm, J . Org. Chem., 46, 1402 (1981). 82. K. Saito, Chem. Lett. (Japan), 463 (1983). 83. T. Tsuchiya, K. Takayama, and J. Kurita, Chem. Pharm. Bull., 27: 10, 2476 (1979). 84. T. Tsuchiya and J. Kurita, J . Chem. Soc., Chem. Commun., 803 (1979).
88 85. 86. 87. 88. 89. 90. 91. 92. 93. 94. 95. 96. 97. 98. 99. 100.
101. 102. 103. 104.
Bicyclic 1,2-Diazepines T. Tsuchiya and J. Kuiita, Chem. Pharm. Bull., 86, 1890 (1978). T. Tsuchiya, M. Enkaku, and H. Sawanishi, Heterocycles, 12, 1 1 (1979). T. Tsuchiya, M. Enkaku, and S. Okajima, Chem. Pharm. Bull., 29, 3173 (1981). J. Kurita, M. Enkaku, and T. Tsuchiya, Chem. Pharm. Bull., 31, 3684 (1983). R. W. Morrison, Jr., W. R. Mallory, and V. L. Styles, U.S. Patent 4,235,905, November 1980. S. Lida and T. Mukai, Heterocycles, 11, 401 (1978). J. Kurita, M. Enkaku, and T. Tsuchiya, Chem. Pharm. Bull., 30, 3764 (1982). M. Enkaku, J. Kurita, and T. Tsuchiya, Heterocycles, 16, 11 (1981). J. Kovosi et al., US. Patent 4,423,044, December 1983. A. Neszmelyi, T. Ling, and J. Kovosi, Acta Chim. Hung., 114, 293 (1983). M. Flammang, C. R . Acad. Sci. Paris (C), 290, 349 (1980). M. Flammang and C.-G. Wermuch, C. R. Acad. Sci. Paris (C), 290, 361 (1980). D. P. Munro and J. T. Sharp, Tetrahedron Lett., 23, 345 (1982). D. P. Munro and J. T. Sharp, J . Chem. Soc., Perkin Trans. I, 1133 (1984). K. R. Motion, D. P. Munro, J. T. Sharp, and M. D. Walkinshaw, J . Chem. Soc., Perkin Trans. I , 2027 (1984). D. P. Munro and J. T. Sharp, J . Chem. Soc., Perkin Trans. I, 1718 (1980). T. Tsuchiya, H. Sawanish, M. Enkaku, and T. Hirai, Chem. Pharm. Bull., 29, 1539 (1981). T. Tsuchiya and J. Kurita, Chem. Pharm. Bull., 28, 1842 (1980). J. Kuritd, M. Enkaku, and T. Tsuchiya, J . Chem. Soc., Chem. Commun., 990 (1982). R. Allman, T. Debaerdemaeker, G. Kiehl, J. P. Luttringer, T. Tschamber, A. Wolff, and J. Streith, Justus Liehigs Ann. Chem., 1361 (1983).
CHAPTER II
Bicyclic 1.3.Diazepines R . Ian Fryer Department of Chemistry. Rutgers. State University of New Jersey. Newark. New Jersey
and
.
A Walser Chemical Research Department. Hoffmann-La Roche Inc., Nutley. New Jersey
A . [a]-Fused [1,3]diazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
92
1. 1,3-Diazeto[l, 2-a] [1.3]diazepines. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
92
2. Imidazoll. 2-a] [1.3]diazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
93 93
2.2. Reactions., . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
95
2.3. Imidazoll, 5-a] 11,3ldiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
95
3. Pyrido[l, 2-a] [1,3]diazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
96 96
3.2. Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
96
3.3. Dihydropyrido[ 1,2-a] [1,3ldiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Tetrahydropyrido[l, 2-a] [l, 3ldiazepines . . . . . . . . . . . . . . . . . . . . . . . . . .
97 98
4. Pyrimido[l, 2-a] 11,3ldiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
99
4.1. Pyrimido[l, 6-a] 11,3ldiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
99
5. Pyrrolo[l. 2-a] [I. 3ldiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
100
5.1. Tetrahydropyrrolo[l. 2-a] [1,3]diazepines . . . . . . . . . . . . . . . . . . . . . . . . . .
100
5.2. Hexahydropyrrolo[l,2-a] [1,3]diazepines . . . . . . . . . . . . . . . . . . . . . . . . . .
102
5.3. Octahydropyrrolo[l, 2-a] [l, 3ldiazepines . . . . . . . . . . . . . . . . . . . . . . . . . .
102
6. Thiazolol3. 2-a] 11,3ldiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
104
6.1. TetrahydrothiazoloC3,2-a] [l,3ldiazepines . . . . . . . . . . . . . . . . . . . . . . . . .
104
6.2. Hexahydrothiazolo[3, 2-a] [l, 3ldiazepines . . . . . . . . . . . . . . . . . . . . . . . . . 6.2.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2.2. Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
104 104 105
89
90
Bicyclic 1.3.Diazepines
6.3. Octahydrothiazolo[3, 2.01 [1.3]diazepines . . . . . . . . . . . . . . . . . . . . . . . . . .
106
6.4. Pyrazolo[l, 5-a] [1.3]diazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
106
7. 1.3.5-Triazino[l. 2-a] [l. 3ldiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
107
7.1. 1.2.4.Triazino[4. 3-a] [1.3]diazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
107
B . [cl-Fused [l.3ldiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
108
C. [dl-Fused [l. 3ldiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Benzo[d] [l.3ldiazepines (1. 3-benzodiazepines) . . . . . . . . . . . . . . . . . . . . . . . .
109 109
1.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
109
1.2. Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
111
1.3. Dihydro.l. 3.benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
112
1.3.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.3.2. Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
112 114
1.4. Dihydro.1.3.benzodiazepinones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
116
1.4.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.4.2. Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
116 118
1.5. Tetrahydro.1. 3.benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
118
1.6. Tetrahydro.1. 3.benzodiazepinones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
119
1.6.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.6.2. Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
119 121
1.7. Tetrahydro.1.3-benzodiazepindiones. . . . . . . . . . . . . . . . . . . . . . . . . . . . .
123
1.7.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.7.2. Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
123 126
1.8. Tetrahydro.1.3-benzodiazepin-2.thiones . . . . . . . . . . . . . . . . . . . . . . . . . . .
127
1.8.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.8.2. Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
127 128
1.9. Tetrahydro.2.cyanoimino-1.3-benzodiazepines . . . . . . . . . . . . . . . . . . . . . . .
128
2. IrnidazoC4.5-d] [1.3]diazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
129
2.1. Tetrahydroimidazo[4.5-d] [l.3ldiazepines . . . . . . . . . . . . . . . . . . . . . . . . . D . [el-Fused [l.3ldiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
130 131
1 . Benzo[e] [l.3ldiazepines (2.4-Benzodiazepines) . . . . . . . . . . . . . . . . . . . . . . . . .
132
1.1. 4.5.Dihydro.2. 4-benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
132
1.1.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1.2. Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
132 132
1.2. Dihydro-2.4.benzodiazepinones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
133
1.2.1. Synthesis . . . . . 1.2.2. Reactions . . . . .
......................... ......................... 1.3. Tetrahydro.2. 4.benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.4. Tetrahydro.2,4.benzodiazepinones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.4.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.4.2. Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.5. Tetrahydro-2,4.benzodiazepindiones. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.5.1. Synthesis . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . 1.5.2. Reactions . . . . . . . . . . . . . . . . . .. . . . . . . . . . . .
133 133 135 135 135 136 136 136 137
Introduction
91
1.6. Tetrahydro-2,4-benzodiazepin-1,3,5-triones .........................
137
1.7. 2,4-Benzodiazepinthiones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
137
1.7.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.7.2. Reactions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
137 139
1.8. 3-Cyanoimino-2,4-benzodiazepin. ..............................
140
1.8.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
140
2. Cyclopenta[e] [1,3]diazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
140
2.1. Synthesis.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
140
2.2. Reactions.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
141
3. Thieno[3,4-e] [1,3]diazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Synthesis.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
141
3.2. Reactions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
142
141
4. Furo[3,4-e] [1,3]diazepines and pyrrolo[3,4-e] [1,3]diazepines . . . . . . . . . . . . . . . . 142
E. Tables of Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . F. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
144
180
INTRODUCTION This chapter reviews the synthesis and chemistry of 1,3-diazepines of structure 1 with an additional ring of any size fused to side a, c, d , or e. The added rings can be carbocyclic or heterocyclic.
1
Sections A through D of the chapter deal with [a]-, [cl-, [dl-, and [el-fused 1,3-diazepines. Each section is subdivided according to the nature of the added ring and the subsections, in general, are listed in alphabetical order. An exception is made for the [dl- and [el-fused systems in which the benzodiazepines constitute the largest and most important class of compounds. These derivatives are given preference over the other ring systems and are discussed first in Sections C and D. When necessary, individual classes of compounds are further divided into groups according to the degree of saturation, with the fully unsaturated species being given precedence. In some instances, the paucity of published data does not warrant separate subsections for the reactions of the compounds under discussion. Bridged seven-membered rings are not covered. All compounds are named and numbered according to current Chemical Abstract rules.
92
Bicyclic 1,3-Diazepines
1,3-Diazepines have been reviewed by G. Hornyak, K. Lampert, and G. Simig [Kern. Kozlem., 33, 81 (1970)l; G. A. Archer and L. H. Sternbach [Chern. Rev., 68, 747 (1968)l; F. D. Popp and A. J. Noble (in Aduances in Heterocyclic Chemistry, Vol. 8, A. R. Katritzky and A. J. Boulton, Eds., Academic Press, New York and London, 1967, p. 21); J. A. Moore and E. Mitchell (in Heterocyclic Compounds,Vol. 9, R. C. Elderfield, Ed., Wiley, New York, 1967, p. 224); A. Nawojski [ Wiadomoici Chem., 23,673 (1964)l; and G. De Stevens [Rec. Chem. Progr., 23, 105 (1962)l.
A. [a]-FUSED [1,3]DIAZEPINES Only seven bicyclic ring systems with the general structure A have been reported in the literature. These are discussed in alphabetical order in the subsections that follow.
1. 1,3-DIAZETO[1,2-a] [1,3]DIAZEPINES
2
The only member of this ring system that is described in the literature is the disubstituted hexahydro derivative 5. This diazeto diazepine was prepared in good yield (Eq. 1) by reaction of 1,Cdiaminobutane with N-phenyldichloromethanimine (3). Compound 5 is believed to form by condensation of the diazepine intermediate 4 with a second molecule of dichloroimine. The structural assignment for 5 was based on spectroscopic data.
93
2. Imidazo[1,2-a] [1,3]Diazepines
5
2. IMIDAZO[~,~-UJ [1,3]DIAZEPINES 2.1. Synthesis
6a
6b
1H-Imidazo[l.2-a] [ 1.3ldiazepine
9H-lrnidazo[ l,2-u] [ 1.3ldiazepine
Partially reduced derivatives of both the 1H (6a) and 9 H (6b)imidazo[1,2,-u] [1,3]diazepines are known, but none of the five possible tautomers of the parent ring system has been reported in the literature. [1,3]diazepine 8 was prepared The 2,3,5,6,7,8-hexahydro-1H-imidazo[l,2,-u] in 63% yield (Eq. 2) by dehydrohalogenation of the 2-chloroethylamidine 7.' The structural assignment was based on both analytical data and on analogous cyclizations.
7
8
1-Substituted analogs 10 of the same ring system were shown to be accessible (Eq. 3) by intramolecular alkylation of the imidazolidine 9.3,93
Bicyclic 1,3-Diazepines
94
Compound 13, the 2,2-diphenyl-substituted analog of 6a, was prepared in low yield94 by treatment of 11 with Meerwein reagent in methylene chloride, followed by heating with ethanolic ammonia in a sealed tube.
Compounds 16, bearing a phenyl substituent at position 9, were obtained in low yields4 by a double alkylation of the 2-anilinoimidazolines 14 with the 1,4-dibromobutanes 15 (Eq. 5). The stereochemistry of the 6,7-disubstituted derivatives was not discussed.
c->NHo X
T ++ BrCH,CHCHCH,Br ? RY BrCH,CHCHCH,Br
-
15
14
The imidazo[1,2-a] [1,3]diazepine 18 was synthesized5 in low yield (Eq. 6) as a mixture of two diastereomers by cyclization of the anhydrodipeptide 17 in an aqueous medium at pH 5 and 100°C.
2. Imidazo[1,2-a] [1,3]Diazepines
95
2.2. Reactions Nitration of 2,3,5,6,7,8-hexahydro-lH-imidazo[ 1,2-a] [1,3]diazepine 8 with nitric acid in acetic anhydride (Eq. 7) afforded a quantitative yield of the nitrate salt of an N-nitro compound to which structure 19 was assigned.’”
20
Reaction of 8 with p-substituted benzenesulfonyl chlorides led to the N-sulfonyl derivatives 20.6 The possibility that the nitro group in 19 and the sulfonyl group in 20 are in fact attached to the nitrogen at the 9-position instead of the 1-position has not been excluded.
2.3. Irnidazo[1,5-a] [1,3]diazepines
21 lH-imidazo[1,5-a] [ 1,3]diazepine
96
Bicyclic 1,3-Diazepines
Although the parent compound represented by tautomer 21 is still unknown, the tetrahydro derivative 23 was prepared7 by cyclization of the 5-aminoimidazole- 1-butyric acid 22 with polyphosphoric acid (Eq. 8). Me
22
23
3. PYRID0[1,2-a] [1,3]DIAZEPINES 3.1. Synthesis
1
9c33 8)
?
5'4
24
A few substituted analogs of the parent ring system 24 have been described in the patent literature.' Compounds 27 were isolated as minor products from the cyclization of the enamines 25 with phosphorylchloride-polyphosphoric acid (Eq. 9). In general, the pyridopyrimidines 26 were the major products of the reaction, and only in the case of R, = Me and R, = H was the pyridodiazepine obtained in good yield. Dehalogenation of 27 (R,,R, = H) by catalytic hydrogenation over palladium on carbon led to compound 28 (R,,R, = H). Compound 28 (R, = Me, R, = H) has been claimed' to be formed by a mysterious reductive cyclization of the enamine 25 (R, = Me, R, = H) upon treatment with phosphorylbromide-polyphosphoric acid.
3.2. Reactions Nitration of 28 (R, = Me, R, = H) was assumed to occur at the 5-position to give 29 as the product. Alkaline hydrolysis of the ester 27 (R, = Me, R, = H) gave the corresponding acid 30.
97
3. Pyrido[ 1,2-a] [1,3]Diazepines
H g N H 2
+ CHOyCOOEt
COOEt
COOEt
COOEt
R2 Rl
28
(9)
21
30
3.3. Dihydropyrido[ 1,2421 [1,3]diazepines Thermal cyclization of the enamines 25 led to the isolation of both the substituted 4,5-dihydropyrido[ 1,2-a] [1,3]diazepin-5-ones 31 and the pyridopyrimidines 24 (Eq. 12). Other tautomeric forms of 31 have not been ruled out as alternative structures. It is quite likely that the 5-chloro derivatives 27 described in Section 3.1 arise by subsequent reaction of the initially formed lactams 31 with phosphorylchloride.
Bicyclic 1,3-Diazepines
98
2s
(12)
31
3.4. Tetrahydropyrido[ 1,2-a] [1,3]diazepines Fozard and Jones' reported the preparation of the quaternary salt 34 by means of a thermal ring closure of the 4-bromobutyramide 33 formed upon acylation of 32 (R = H) with 4-bromobutyryl bromide (Eq. 13). The structure of 34 was corroborated by ring opening to 36, which was characterized as a picrate salt. The same picrate was obtained from the product of alkylation of 2-pyridinamine with 4-bromobutanoic acid ethyl ester.
Br-
Br
33
34
i//
k
R
35
The corresponding imides 35 have been claimed" to be formed in moderate yields during the condensation of 4-bromobutyrimidate with the 2-pyridinamines 32. Although nmr spectroscopy was used to support the structures 35, the alternative 1-(2-pyridy1)-2-pyrrolidinimine structures 37 have not been rigorously excluded. Preference for the formation of a five-membered over a sevenmembered ring has been observed by Ott and Hess" in the reaction of 2-pyridinamines with tetraalkyl succinic acid anhydride at high temperature. They considered the pyrido[ 1,2-a] [I1,3]diazepine structures for the products of this condensation, but were able to show that these compounds were in fact N-(2-pyridyl) succinimides.
4.
Pyrimido[1,2-a] [1,3]Diazepines
99
According to a patent,12 the 9-phenyl derivative 39 was obtained by reaction of the N-(4-~hlorophenyl)pyridone38 with 1,Cbutanediamine in boiling 2-ethoxyethanol (Eq. 14).
0 39
38
4. PYRIMIDO[1,2-a] [1,3]DIAZEPINES
40
The parent ring system 40 has not been described, and the hexahydro derivative 42 appears to be the only representative of this class of compounds so far prepared. Compound 42 was isolated in low yield13 from the alkylation of the sodium salt of 2-amino-4-hydroxy-6-methylpyrimidine 41 with 1,4dibromobutane (Eq. 15).
0
41 42
4.1. Pyrirnido[1,6-a] [1,3]diazepines
Again, fully unsaturated compounds of the parent ring system 43 are unknown. The structures of the 1,lOa-dihydro derivatives 45 (X = 0,CH,) were
Bicyclic 1,3-Diazepines
100
43
assigned to the products obtained14 in very low yield by reaction of 4-aminopyrimidines 44 (X = 0, CH,) with dimethyl acetylenedicarboxylate (Eq. 16).
H2
QN&N
MeOOCC=CCOOMec
COOMe
N+N
COOMe COOMe
44
45
(16) Cyclization of compound 46 in boiling acetic anhydride (Eq. 17) has been reported to yield the trione 47.15a,b
5. PYRROLO[1,2-a] [1,3]DIAZEPINES No derivatives of the five possible tautomers, 48a48e of the parent ring system have been described in the literature.
5.1. Tetrahydropyrrolo[ 1,2-a] [1,3]diazepines The unsubstituted tetrahydropyrrolodiazepine 50 (R, = R, = R, = H) was reportedly obtained by Beckmann rearrangement of the oxime 49 (Eq. 18).16 The substituted analog 50 (R,, R, = Me, R, = CN), was prepared by ring closure of the pyrrole derivative 51, via intramolecular alkylation (Eq. 18)." The formation of a five-membered pyrolidine ring appears to be precluded in this
5. PyrroloC1,2-a] [1,3]Diazepines
101
48a lH-Pyrrolo[1,2-u] [ 1,3]diazepines
48b 3H-Pyrrolo[l,Z-u][1,3]diazepines
48c SH-Pyrrolo[l,2-u][1,3]diazepines
48d 7H-Pyrrolo[1,2-a][ 1,3]diazepines
48e
9H-Pyrrolo[ 1,241[ 1,3]diazepines
alkylation because anion formation occurs preferentially on the pyrrole nitrogen. The substituted dihydropyrrolodiazepine 54,96 was obtained by the catalytic hydrogenation of the cyclopropene ring of 53, which in turn was prepared by treatment of 52 with an excess of diazomethane at room temperature (Eq. 19).
J
52
54
53
102
Bicyclic 1,3-Diazepines 5.2. Hexahydropyrrolo[ 1,2-a] [1,3]diazepines
All the reported hexahydro derivatives of this ring system contain a saturated pyrrole ring. Thus, the hexahydro-2H-pyrrolo[ 1,2-a] [1,3]diazepine 56 was prepared’* in 80% yield by acid-catalyzed ring closure of 1-(4-aminobutyl)-2pyrrolidinone (55) at elevated temperature (Eq. 20).
56
55
Ducker and Gunter’ described the interesting formation of the related hexahydropyrrolodiazepine 61 by dimerization and hydration of 4-methyl-3pentenenitrile (57). Treatment of 57 with concentrated sulfuric acid at 0-20°C afforded 61 in 23% yield. These authors proposed that dimerization of the initially formed carbonium ion 58 would lead to the 1,6-diazacyclodecane 59, which would then undergo hydration and transannular ring closure to form the final product (Eq. 21). Hydrolysis of 61 catalyzed by silver oxide gave the 1,6-diazecin-2,7-dione 60.
=
Me 51
60
61
A similar transannular reaction was claimed2’ to be responsible for the interconversion (Eq. 22) of the 1,6-diazecin-2,7-dione 62 and the pyrrolidinone 64. Neither the intermediate pyrrolodiazepine 63 nor its dehydration product 65 were isolated, however. 5.3. Octahydropyrrolo[1,2-a] [1,3]diazepines Octahydropyrrolodiazepines bearing a carbonyl group at the 5- or 7-position have been prepared by two routes. The first method involves catalytic reduction
5. Pyrrolo[1,2-a] [1,3]Diazepines
103
62
64
65
of the corresponding tetrahydro derivative, as exemplified by the hydrogenation of amidine 61 over platinum’’ to give 66 in 65% yield (Eq. 23). In the second method, a 4-ketocarboxylic acid is condensed with 1,Cdiaminobutane. Wollweber” used this route to obtain 68 (R, = Me) from the reaction of ethyl levulinate 67 (R, = Et, R, = Me) with 1,Cdiaminobutane at 1OO0-15O0C (Eq. 24). The same principle was also used for the synthesis of compounds 68 (R, = aryl).” In this instance a mixture of the ketoacid 67 (R, = H, R, = aryl) and lP-diaminobutane was heated in refluxing chlorobenzene.
@ eJ
H,,PI
(23)
MeMe 0
MeMe 61
67
gye 66
68
Other substituted analogs of 68 are claimed in the patent l i t e r a t ~ r e , ,but ~ no physical data are given.
Bicyclic 1,3-Diazepines
104
6. THIAZOLO[3,2-a] [1,3JDIAZEPINES
69
Although the fully unsaturated parent compound 69 has not been described, a number of reduced derivatives have been prepared.
6.1. Tetrahydrothiazolo[3,2-u] [1,3]diazepines Chadha and coworkersz4 have applied the standard thiazole synthesis (i.e., the condensation of a 2-haloketone with a thioamide) in converting the 1,3diazepine 70 into a series of 5,6,7,8-tetrahydrothiazolo[3,2-a][ 1,3]diazepines 72. A later publicationz5 reported modification of this synthesis by forming the a-bromoketone in situ with N-bromosuccinimide in benzene. If the condensation of the bromoketone with the thiourea 70 was performed under milder conditions (in acetone at room temperature), the intermediate hydroxythiazolidines 71 could be isolatedz6 and subsequently dehydrated to 72 under more vigorous, acid-catalyzed conditions (Eq. 25).
H
CYS
.HX
.HX
::
C-cH7 1
x-
;[IN&; NYs -H",o
NH 70
* ( - yN L sR l
R2
71
R2
12
(25)
The same reaction scheme was used by Wei and Bel127a9bfor the preparation of the hydroxythiazolidine 71 (R, = CH2COOH, R, = 4-CIC6H,). The thiourea 70 was heated under reflux with the appropriate bromoketone in acetic acid. In this instance dehydration required prolonged boiling in acetic acid. The thiazolodiazepines 72 were generally isolated and characterized as salts.
6.2. Hexahydrothiazolo[3,2-a] [1,3]diazepines 6.2.1. Synthesis The 2,3,5,6,7,8-hexahydro derivative 73 was preparedz8 by reaction of the 1,3-diazepine-2-thione derivative 70 with 1,2-dibromoethane in boiling ethanol
6. Thiazolo[3,2-a] [1,3]Diazepines
70
105
13
R, -&H -COOEt
14
for R , = H
15
(Eq. 26). Compound 73 was characterized as the hydrobromide salt, and the structure assignment was based on analytical and infrared absorption data. Condensation of the cyclic thiourea 70 with a-haloesters was found to give the 3-ones 74 in good yield.24 Treatment of 74 (R, = H) with aromatic aldehydes in the presence of piperidine gave the 2-(arylmethylene)derivatives 75, which could also be prepared directly, by a one-pot procedure, from 70. The stereochemistry of the exocyclic double bond in 75 was not discussed. For steric reasons, the configuration depicted may be preferred. The synthesis of a series of substituted 2,3-diphenyl-3-ols has been reported in the patent l i t e r a t ~ r e . ~ ~
6.2.2. Reactions Treatment27a of the hydroxyacid 76 with acetic anhydride under reflux (Eq. 27) led to the lactone 77. The stereochemistry of the ring fusion was not studied.
The addition of bromine to 78 led to the dibromo derivative 80, the stereochemistry of which was not specified. Acid hydrolysis of the 2-benzylidene derivative 78 opened the seven-membered ring to give the thiazolidin-2,4-dione 79.24 This compound was also synthesized (Eq. 28) by condensation of the related hydrolysis product 81 (R, = H) with benzaldehyde.
106
Bicyclic 1,3-Diazepines
78
19
L
1Bb
PhCHO. AcOH
80
6.3. Octahydrothiazolo[3,2-u] [1,3]diazepines Structure 83 has been assignedz9 to the product obtained by fusion of the isothiuronium salt 82 with succinic anhydride. The structure of 83 is questionable, since it is based solely on poor microanalytical data.
HN
YS-(CH,)zNH, NHZ
.HCl
Go.
NH, . HCl N
(29)
0
82
83
6.4. Pyrazolo[1,5-a] [1,3]diazepines
3,7,8-Trisubstituted-6H-pyrazolo[ 1$a] [1,3]diazepin-6-ones (85) were prepared by heating a solution of the corresponding 3,6,7-trisubstitutedpyrazolo[ 1,5-a]pyrimidines (84) in acetic acid and water at 70°C.95
84
85
R, = CN, CONH,
7. 1,3,5-Triazino[1,2-a] [1,3]Diazepines
107
Structure assignments of compounds 85 were based on analytical and spectroscopic data.
7. 1,3,5-TRIAZINO[ 1,2-~][1,3]DIAZEPINES
86
A search of the chemical literature has not revealed the existence of any derivatives of the unsaturated ring system 86. Octahydro derivatives of structure 88 were obtained3' by reaction of the 2-benzylthio-1,3-diazepine 87 with aryl isothiocyanates (Eq. 31). The success of this synthesis appears to depend on the reactivity of the isothiocyanate. Thus, methyl isothiocyanate only added to the nitrogen of the diazepine to form the 1 : l adduct 89, whereas (4-dimethylaminophenyl)isothiocyanatefailed to react at all.
cgm
R
RRNCS =aryl
s
CYJLR N ,
N S
88
89
7.1. [1,2,4]-Triazino[4,3-a]
[1,3]diazepines
90
Once again, only reduced derivatives of the parent ring system 90 have been reported in the literature. Compounds 93 were synthesized31 by conversion of
Bicyclic 1,3-Diazepines
108
2-ethoxy-4,5,6,7-tetrahydro- 1H-1,3-diazepine (91)to the intermediate hydrazine 92 followed by condensation with a-ketoesters (Eq. 32). Infrared spectroscopic studies led to the conclusion that 93 is the predominant tautomeric form of the product in solution, whereas 94 is favored in the solid state.32 H NH NH
22_
Qoc2 N
/
91
YZ
H
CyB
R
8
0
93
94
B. [cI-FUSED [1,3]DIAZEPINES
95
A search of the literature revealed only one (patent) citation describing [clfused [1,3]diazepines of general structure 95.98The two compounds reported were synthesized from 3-(4-imidazolyl)propylamine(96)either by treatment with diphenylcyanoiminocarbonate (97: R = CN) or by treatment with diphenylbenzoyliminocarbonate (97: R = COPh). The initially formed intermediates 98 were cyclized in situ to give the corresponding 8-substituted [cl-fused [1,3]diazepines 99 (Eq. 33).98
N b N H NH
98
(33)
99
1. Benzo[d]-1,3-Diazepines (1,3-Benzodiazepines)
109
C. Id]-FUSED [1,3]DIAZEPINES
100
The most important class of compounds of general structure 100 consists of the 1,3-benzodiazepines. These derivatives are, therefore, given precedence over other fused systems in this section.
1. BENZO [d] -1,3-DIAZEPINES (1,3-BENZODIAZEPINES) 1.1. Synthesis
IOOb 3H-1,3-Benzodiazepines
1OOa
1 H-1.3-Benzodiazepines
I ooc 5 H - 1,3-Benzodiazepines
If the energetically less favored quinonoidal structures are disregarded, the parent 1,3-benzodiazepine, derived from the generic 100, may occur in any of the three tautomeric forms 100a-100c. Although none of the parent tautomers has been synthesized, derivatives of all these systems have been described. The substituted lH-1,3-benzodiazepine, 102 appears to be the first reported derivative of 100a. This compound was reportedly obtained33 by oximation of ketone 101 (Eq. 34). The structure was supported by spectral data, but solid proof is lacking. %OEt \
NHZOH
*
Q %OEt \
0 101
/
NHOH 102
(34)
Bicyclic 1,3-Diazepines
110
More recently, some substituted lH-1,3-benzodiazepine derivatives (104), were prepared by a photoinduced rearrangement of the isoquinoline N-imides 103 (Eq. 35).99.101If the R in the 5-position is an electron-donating group, the ring expansion is favored and benzodiazepines can be isolated in relatively good yields.
hv
Me COOEt
Me 103
B
fv
Me COOEt
In a similar manner, the 3H-1,3-benzodiazepine derivatives 106 were obtained by irradiation of the 2-methylquinoline N-imides 105 with an electrondonating group, such as OMe or NMe at either the 6- or the 8-position, (Eq. 36).99 The 3-substituted 3H-1,3-benzodiazepine 108 was isolated34 in 25% yield from the reaction mixture obtained by dehydration of 107 with molecular sieves in boiling benzene (Eq. 37). The indoline 109 was the major product of cyclization. The indoline was probably formed by transfer of the acetyl group to the primary aromatic amino group, followed by isomerization of the enamine to the imine, which would then cyclize to 109. Compound 107 was prepared by reduction of the corresponding nitro compound, which in turn was made by the addition of the anion of N-acetyl-o-toluidine to 2-nitrophenylacetylene.
R6wMe -F hv
RR
NCOOEt
R 6 c 4 N C O O E t R,
Me
(36)
The structures of SH-1,3-benzodiazepines 111 were assigned3’ to the minor products formed by addition of acetylene dicarboxylates (Eq. 38) to the quinazoline N3-oxide 110. The major components isolated from the reaction mixture were the ring-opened compounds 112. The structures of the benzodiazepines
1. Benzo[d]- 1,3-Diazepines (1,3-Benzodiazepines)
111
107 4 A molecular sieves
(37)
Bz, relluxlfH20
I
Me
COMe
10s
109
H
%
PiNCoM
+
COOR
.-’
111 112
110
t
I
ROHlBr ROOCC CCOOR
KT4
COOR
were elucidated with the help of spectral and analytical data and were supported by the formation of the alkaline hydrolysis products discussed in Section 1.2. Mechanistically, the formation of 111 was postulated to occur via the intermediates 113 and 114 and the 1H tautomer 115. 1.2. Reactions
Treatment of 116 with methanol or ethanol and acetic acid resulted in the formation of solvent adducts 117, which decomposed during isolation to give
112
Bicyclic 1,3-Diazepines ROH/H'
I Me COOEt
OR COOEt 117
116
I
HIO/H'
(39)
I
COOEt
COOEt
119
1 I8
the ring-opened product 118 and the 2-hydroxy-2,3-dihydroindolederivative 119 (Eq. 39).99 Hydrolytic ring cleavage of 108 to 107 was reported34 to occur upon contact with water. Alkaline hydrolysis of the ester 111 was accompanied by ring contraction (Eq. 40), with formation of the indole 120. The authors35 suggest that rearrangement and ring contraction could occur by a transannular attack at the 2-position by the carbanion that was initially formed at the 5-position. Decarboxylation may occur at any stage of this reaction sequence.
w
111 120
1.3. Dihydro-1,3-benzodiazepines 1.3.1. Synthesis A general synthetic method for the preparation of 4,5-dihydro-3H-1,3benzodiazepines 122 is the condensation of o-aminophenethylamines 121 with i m i d a t e ~or~ ~amidines (Eq. 41).37~38~'00~'03~'04 The first method was investigated exten~ively,~~ and the yield of benzodiazepines was found to be dependent on the nature of the R, substituent in the imidate. Good results were obtained with R, representing alkyl or haloalkyl groups, or phenyl groups with electron-withdrawing substituents. A modification of this bimolecular reaction
1. Benzo[d]-1,3-Diazepines (1,3-Benzodiazepines)
121
113
122
t
123
124
involving intramolecular amine exchange on the preformed amidine 124 often gave better results.36 Compound 124 was prepared by reaction of the o-nitrophenethylamine 123 with the imidate, followed by catalytic reduction of the nitro group. In the single instance reported,34 ring closure by dehydration gave a good yield of a dihydrobenzodiazepine. Thus heating the amide 125 under reflux in a mixture of methylene chloride and phosphorylchloride for 16 hours (Eq. 42) gave a 40% yield of the diazepine 126.
125
126
A variety of 2-amino-4,5-dihydro-3H-benzodiazepines have been described in the patent literature. Compounds 132 can be prepared by displacement of the thiomethyl group in 127 with amines in refluxing a ~ e t o n i t r i l e , ~ ~or. ~ by ' In reaction of the urea 128 (X = 0)with phosphorylchloride and an arnir~e.~' addition (Eq.43), compounds 132 may be synthesized by first converting the
114
Bicyclic 1,3-Diazepines
urea 128 to the 0-ethylisourea 129 and then treating this imino ether with In an example of still another reaction of o-aminophenethylamine~.~’ amine 130 with dichloroaryl isocyanides 131 led to compounds 132 bearing substituted anilino groups (R = aryl) at the 2-position. 2-Ethoxy-4,5-dihydro-1H-l,3-benzodiazepines 134 with substituents at the 5-position were prepared by Taylor and T ~ l l ywho , ~ ~added hydride, Grignard, and aryllithium reagents to the carbonyl group of 133. The resulting tertiary alcohols 134 were generally isolated and characterized as salts (Eq. 44).
(44)
X 0 133
134
An unusual pathway leading to the 3-substituted derivative 137 was published by Elslager and who obtained this compound in low yield by desulfurization of the thiazolo[2,3-b] [1,3]benzodazepine 136 with Raney nickel (Eq. 45). Compound 136 was obtained from the reaction of the 2-thione 135 with a-bromoacetophenone.
135
/ k m y
nickel
136
(45)
137
I .3.2. Reactions Alkylation of 138 (R = Ph, Me) with n-butyllithium and methyl p-toluenesulfonate yielded36 the 3-methyl derivatives 139. The site of alkylation was confirmed by unambiguous synthesis (Eq. 46). Reaction of 138 (R = Ph) with methyl iodide in boiling benzene led to the quaternary 1,3-dimethyl compound 140. Intramolecular aikylation of 138 (R = CH,CH,Cl) was reported to give the imidazobenzodiazepine 141.
1. Benzo[d]- 1,3-Diazepines (1,3-Benzodiazepines)
115
1. n-BuLi 2. M e O S 0 , O M c
Me0 139
(46)
Me0
Me0 140
141
Hydrolysis and methoxyaminolysis of the benzodiazepine 142 was studied in Methoxyaminolysis of 142 at pH 7.11 was shown to exhibit three distinct phases (Eq. 47). This was interpreted in terms of the initial formation of the kinetically favored product 143, followed by isomerization to the thermodynamically favored product 144, and finally, cleavage to a mixture of the diamine 145 and methoxyformamide.
H ~
MeONH,
c=N
.
H
AH,
142
143
+ H
MeONHCHO
AH3
$=CH-NHOMe 145
144
Treatment of 138 (R = CH,Cl) with amines R, R,NH led to chloride displacement and formation of 138 (R = CH2NR,R,).36 Taylor and T ~ l l y ~ ~ investigated the dehydration of the tertiary alcohol 146. When the hydrochloride salt of 146 was heated at 100°C for 20 minutes in dimethylformamide and the resulting mixture was poured into water (Eq. 48), the products 147,148, and 149 were isolated in 38, 23, and 22% yield. When the free base of 146 was heated under reflux in benzene solution for 48 hours, only the ring-opened carbamate 148 was isolated (52% yield).
Bicyclic 1,3-Diazepines
116
1. DMF. 1w C 2 H,O' _c
I46
147
%NHCOOEt \
N H 2 . HC1
148
149
1.4. Dihydro-1,3-benzodiazepinones 1.4.1. Synthesis An attempt to prepare the 1,3-dihydro-2H-1,3-benzodiazepin-2-one 147 from the carbinol 150 by standard methods of dehydration failed.33 As mentioned above however, this compound was formed as the major product by treatment of the hydrochloride 146 with dimethylformamide at 100°Cfollowed by aqueous workup (Eq. 49).
150
I47
146
(49)
An interesting synthesis by Woerner and coworkers45 involved reaction of the 2H-azirine 151 with the ketenimine 152 to give diazepinone 154 in 15% yield (Eq. 50). The intermediate aziridine 153 also was obtained in comparable amounts and could be converted almost quantitatively to 154 by heating in trichlorobenzene. The reaction probably proceeds via oxidative elimination of benzophenone, which is also isolated from the reaction mixture.
117
1. Benzo[d]-1,3-Diazepines (1,3-Benzodiazepines)
H
151
152
I54
A fairly general synthesis of the dihydrobenzodiazepin-4-ones156 has been disclosed in the patent l i t e r a t ~ r eCondensation .~~ of o-aminophenylacetic acids 155 with imidates in boiling a-butanol (Eq. 51) was claimed to give the benzodiazepines 156 in moderate yields. Similar approaches to these compounds reported in the literature have been less rewarding. For example, according to Rodriguez and reaction of the phenylacetamide 157 (R = H) with imidates failed to yield benzodiazepines. Attempts by Golik and 156 (R = Me) by cyclodehydration of the diamide 157 T a ~ to b prepare ~ ~ (R = Ac) were also unsuccessful,
NH-R
155
I56
157
(51) Dihydro- 1,3-benzodiazepin-5-oneswere found to be accessible via modification of the urea carbonyl in dione 158. Triethyloxonium tetrafluoroborate converted 158 to the isourea 159,33which could be converted to the 2-amino derivatives 160 by treatment with amines in boiling toluene (Eq. 52). 1,3-Benzodiazepin-5-one 161 was isolated unexpectedly in about 1% yield by F a r r a ~ -from , ~ ~ the reaction of p-anisidine with formaldehyde in hydrochloric acid (Eq. 53). The structure of 161 was derived from spectroscopic data. The presence of a ketone function was confirmed by the formation of a semicarbazone and a phenylhydrazone. The compound was found to undergo
Bicyclic 1,3-Diazepines
118
0 158
-
Me0 161
oxidation upon melting or upon treatment with permanganate in acetone to give a product which may be the corresponding 4,5-dione.
I .4.2. Reactions Reactions of the 2-ethoxy-1,3-benzodiazepin-5-one159,33such as reduction with sodium borohydride, addition of organometallic reagents, oxime formation, and displacement of the ethoxy group by amines have been discussed above. When 159 was subjected to prolonged heating under reflux with morpholine in toluene (Eq. 54), or if the reaction was carried out in the presence of one equivalent of p-toluenesulfonic acid, the initially formed guanidine 162 was transformed into the quinoline 165 in 30% yield.33 This ring contraction is thought to occur by formation of the intermediate enamine 163, followed by valence tautomerization to the aziridine 164 and finally the quinoline 165.
1.5. Tetrahydro-l,3-benzodiazepines
2,3,4,5-Tetrahydro-lH- 1,3-benzodiazepines are cyclic aminals and therefore would be expected to be sensitive compounds. These compounds can be obtained by reduction of the appropriate tetrahydrobenzodiazepinone with lithium aluminum hydride, as exemplified by the work of de Stevens and D ~ g h i . ~These ’ authors prepared the 3-methyl derivative 167 (R = H) by reduction of 166 (R = H), or in two steps via the intermediate 1-benzyl derivative 167 (R = CH,Ph) (Eq. 55). The product was characterized as the maleate salt.
1. Benzo[d]-1,3-Diazepines (1,3-Benzodiazepines)
/
0 159
119
0 162
(54) 164
J
163
g 165
a k
R
N-Me
LIAIH,
~
N-Me
\
(55)
167
166
1.6. Tetrahydro-1,3-benzodiazepinones
1.6.1.Synthesis Tetrahydro- 1,3-benzodiazepin-2-onesof structure 169 have been prepared by reaction of aminophenethylamines 168 with phosgene5' or N,N'carb~nyldiimidazole~~* 42* (Eq. 56). Derivatives with substituents at the 5-position were accessible33 via addition reactions to the carbonyl group of the 2,Sdiones 170. Thus, reduction with
Bicyclic 1,3-Diazepines
120
168
169
sodium borohydride led to the alcohol 171 (R, = H), whereas reaction with methylmagnesium iodide or aryllithium afforded the corresponding tertiary carbinols (Eq. 57).
170
171
The 5-hydroxy derivative 173 was synthesized5' in 90% yield by acidcatalyzed cyclization of the urea 172 (Eq. 58).
(Me0)2CH 172
I
OH 173
Condensation of o-aminophenylacetamides of general formula 174 with formaldehyde yielded the tetrahydro-1,3-benzodiazepin-4-ones175 (Eq. 59).469 5 0 * 5 3 With R, = H, formaldehyde reacted further to form 3-methyl01 derivatives 175 (R, = CHzOH).54 This ring closure with formaldehyde was also extended to the unsaturated amide 176, obtained by condensation of the appropriate phenylacetamide 174 (Rl,R, = H; R2 = Me) with a-methylphenylacetaldehyde (Eq. 59). In this manner, 177, a compound of unspecified stereochemistry, was prepared in 20% yield. A quite unusual synthesis of a tetrahydro-1,3-benzodiazepin-4-one has been reported by Tsuge and Watanabe,55 who heated a benzene solution of a mixture of the azaspiropentane 178 and the nitrone 179 under reflux and isolated the crystalline products 180, 182, and 184 (11.4,8.7, and 7.2% yield, respectively). The benzodiazepine 182 was found to undergo ring opening (Eq. 60) to 184 upon heating in methanol. Since 184 was also prepared in 60% yield by addition of the nitrone 179 to the ketenimine 181, it was concluded that the spirane 178 underwent thermal fragmentation to the ketenimine 181 and ethylene. Reaction 5 2 3
1. Benzo[d]-1,3-Diazepines (1,3-Benzodiazepines)
121
175
CH,O
0
0
176
177
of the ketenimine with the nitrone is believed to proceed via the intermediates 183 and 185.
1d.2. Reactions The conversion of the urea carbonyl in tetrahydro-1,3-benzodiazepin-2-ones to 2-eth0xy~~. 42 and 2-amino3" groups was presented above. Similarly, the reduction of the carbonyl group in tetrahydro- 1,3-benzodiazepin-4-oneswith has been lithium aluminum hydride to form tetrahydr0-1,3-benzodiazepines~~ discussed. In attempts to dehydrate the alcohols 186 (see above), Taylor and T ~ l l y , ~ observed that heating 186 (Rl, R,, R, = H) under reflux in acetic acid led to the formation of the acetate 187. On the other hand, when the tertiary alcohol 186 (Rl, R, = H, R, = Ph) was heated in formic acid for 24 hours, only the oxindole 188 was isolated (Eq. 60). The mechanism of this interesting ring contraction was not discussed. It is likely that the oxindole was formed by a transannular reaction after initial dehydration. The 1,3-dimethyl derivative 186 (Rl, R, = Me; R, = H) was found to rearrange5, to the oxazolidinone 189 under mild basic conditions, such as heating in the presence of bicarbonate or aluminum oxide (Eq. 61). More vigorous hydrolytic conditions, acidic or basic, gave the expected phenethylamine 190.
179
178
183
,/o
\
184
I
122
1. Benzo[d]-1,3-Diazepines (1,3-Benzodiazepines)
123
187
186
I
ncoon, A
QN-Me \
ti
188
189
1.7. Tetrahydro-1,3-benzodiazepinediones
1.7.1. Synthesis The synthesis of tetrahydro-1,3-benzodiazepin-2,4-diones was achieved56 by cyclization of the 2-ureidophenylacetic acids 192 using acetyi chloride for activation of the carboxyl group (Eq.62). Other attempts to cyclize 192 by
Kc:o-Na+ Me
R-N=C=O
191
* q \ N $ R
&3Rkl 193
COOH 192
(62)
Bicyclic 1,3-Diazepines
124
dehydration with acetic anhydride or dicyclohexylcarbodiimide failed and led to other products. The ureas 192 were prepared by reacting the sodium salt of methylaminophenylacetic acid 191 with isocyanates. Compound 193 (R = H) was also obtained in lower yield by reaction of 191 with cyanogen bromide. The reaction of sodium phenylacetylide with phenyl isocyanate was reported by Bird57 to lead to 194 in 4% yield (Eq. 63). The structure of this product was assigned on the basis of spectral data and its conversion to the dihydro derivative 198 by catalytic hydrogenation. The formation of 194 can be rationalised on the basis of an electrophilic attack by the alkyne substituent at the position ortho to the nitrogen of the aromatic ring in 196. The hydantoin 197, which is the major product of this reaction, could be formed by electrophilic attack of the alkyne on nitrogen as indicated in 195. Compound 194 was also obtained by Ohshiro and coworkers58 in 12% yield by heating a mixture of phenyl isocyanate, diphenylcarbodiimide, and phenylacetylene at 140--190"Cin the presence of iron pentacarbonyl.
r
0
_ _c .
195
w 197
196
0 198
1. Benzo[d]-1,3-Diazepines (1,3-Benzodiazepines)
125
Other compounds also related to 194, the 2-imino derivatives 199, were obtained by a three-component reaction involving an arylcarbodiimide, phenylbromoacetylene, and iron p e n t a ~ a r b o n y l . ~Coupling ~ of phenylbromoacetylene to give 1,4-diphenylbutadiyne was also observed, and in some instances it was the major reaction product. N,N-Bis(o-tolyl)carbodiimide, for example, gave a 17% yield of the benzodiazepine 199 (R = 2-MeC6H,, X = 9Me) and 36% of the butadiyne. This may be due to steric hindrance of the arylation step (i-e., cyclization of intermediate 202). The authors presented the following mechanistic explanation for the formation of 199. Successive insertion of 2 mol of the carbodiimide into the initially generated acetylide complex 200 would lead to intermediate 201. Fission of the iron-nitrogen bond and transfer
,R
1
[o'] 1
\
-CFe(CO),
200
20 3
w
t c
201
202
(64)
126
Bicyclic 1,3-Diazepines
to the triple bond would result in 202, which can cyclize and rearomatize by proton shift. Introduction of another phenylacetylene by coupling would lead to the 4-imino derivative 203. This compound was not isolated but underwent hydrolysis during workup to yield the observed product 199 (Eq. 64). The tetrahydro-1,3-benzodiazepin-2,5-dione206 was prepared (Eq. 65) by reaction of the diaminoacetophenone 204 with carb~nyldiimidazole.~~ The initially formed imidazolcarboxamide 205 could be isolated and subsequently cyclized to the benzodiazepine in 88% yield by heating in water at 90°C.
204
WH 0
206
1.7.2. Reactions Electrophilic substitution reactions were used33 successfully to prepare the 7-halo and 7-nitro derivatives 208. The 7-nitro compound was reduced to the corresponding amine 209 with stannous chloride (Eq. 66). Chloroacetylation of the amine yielded the chloroacetate 210 (R = CI), which was converted to basic derivatives by displacement of chloride with morpholine or piperidine.
0
6
207
208
(66)
X = NO,
0 209
0 210
1. Benzo[d]- 1,3-Diazepines (1,3-Benzodiazepines)
127
Reaction of 207 and 208 (X = NO,) with hydroxylamine (Eq. 67) gave the corresponding oximes 211 (X = H,NO,). When 207 was treated with pyrrolidine and a catalytic amount of p-toluenesulfonic acid in boiling toluene, the quinoline 212 was obtained. This would indicate that the anticipated enamine is formed, but is so reactive that it undergoes ring contraction in situ.
!yo 207 and 208 (X = NO,)
NH,OH
'x
W
H NOH 21 1
(67)
212
The expected reactivity shown by the 5-0XO group during the addition of hydride or metallorganic reagents has been discussed. The conversion of the urea carbonyl at the 2-position to 2-ethoxy and 2-amino groups also was mentioned above.
1.8. Tetrahydro-1,3-benzodiazepin-2-thiones 1.8.1. Synthesis The tetrahydro-1,3-benzodiazepin-2-thiones214 have been prepared (Eq. 68) by reaction of the phenethylamines 213 with thiophosgene in the presence of i m i d a ~ o l eor~ by ~ condensation with carbon d i ~ u l f i d e .40, ~ ~44 .
Rl
213
kl
214
Compound 216 was obtained in 78% yield56 by cyclodehydration of the thiourea 215, which was accessible by reaction of the o-methylaminophenylacetic acid sodium salt 191 with methyl isothiocyanate (Eq. 69). Ghosh60 assigned the structures of 1,3-benzodiazepin-2-thioxo-4,5-diones 219 to the compounds obtained by dehydration
Bicyclic 1,3-Diazepines
128
in boiling acetic anhydride (Eq. 70). The latter were formed by reaction of the sodium salt of the acid 217 with aryl isothiocyanates. The alternative isatin structure was excluded because the compound was found to be stable to hot hydrochloric acid.
219
1J.2. Reactions The conversion of the 2-thiones 214 to 2-thiomethyl derivatives by been discussed. Reaction of 220 with a variety of a l k y l a t i ~ n ~ ~40~ has . a-haloketones and a-haloesters led to the thiazolobenzodiazepines 221, 222, and 223 (Eq.71).44 399
1.9. Tetrahydro-2-cyanoimino-1,3-benzodiazepine
The 2-cyanoimino- 1,3-benzodiazepine 226 was prepared by cyclization of N-2-(2-aminophenyl)ethylbenzylamine (225) with dimethyl cyanoimidothiocarbonate. Compound 225 was prepared by hydrogenation of the corresponding nitro derivative 224, using a platinum catalyst. Reaction of 226 with ethyl bromoacetate gave the 1-ethoxycarbonylmethyl derivative 227 (Eq.72).'02
129
2. Imidazo[4,5-d] [1,3]Diazepines
1
Me
Me 223
222
224
225
J
(MeS),C=NCN
A
(72)
221
2. IMIDAZO[4,5-d] [1,3]DIAZEPINES
228
Of the large number of possible bicyclic systems consisting of a 1,3-diazepine with a [d]-fused heterocycle, representatives of the imidazo[4,5-d] [1,3]diazepine ring system appear to be the only known compounds of the type. The parent ring system, 228, is still unreported, but tetrahydro derivatives have been isolated from natural sources.
Bicyclic 1,3-Diazepines
130
2.1. Tetrahydroimidazo[4,5-d] [1,3]diazepines
229
230
According to a U.S. patent,6' the 1,6,7,8-tetrahydroimidazo [4,5-d] [1,3]diazepin-8-one 230 was prepared by reaction of the diamine 229 with thiethyl orthoformate in boiling ethanol (Eq. 73). This compound is the key intermediate used for the synthesis of the naturally occurring glycosides coformycin (231) and 2'-desoxycoformycin (covidarabine, 232). Both compounds were isolated from bacterial fermentations, coformycin6' from culture filtrates of Streptomyces kamikawaensis SF-557 ~ o v i d a r a b i n efrom ~ ~ Streptomyces antibioticus NRRL 3238. Both compounds are potent inhibitors of adenosine deaminase and therefore enhance the activity of nucleosides such as formycin and vidarabine. The structures of both c o f ~ r m y c i nand ~ ~ c~vidarabine~' have been elucidated by spectroscopic means and confirmed by X-ray crystallographic analyses.
OH 231
232
A synthesis of coformycin, which may mimic its biological formation, was achieved by ring expansion of a purine riboside.66 Photochemical addition of methanol to the acetylated 8-D-ribofuranosyl purine 233 (R = Ac) led stereospecifically to 234 (R = Ac) in 96% yield. The alcohol was converted to the mesylate, which was treated with potassium t-butoxide to form the intermediate aziridine 235. This intermediate was not isolated but subjected to hydrolysis to yield coformycin 231 in 35% overall yield from 234 (Eq. 74). A Belgian patent6' claims the synthesis of isocoformycin 236 in 21% yield by treatment of the mesylate of 234 with aqueous hydroxide. Baker and Putt61 have described a total synthesis of 232. The imidazodiazepinone 230 was alkylated with 3,5-di-O-(p-toluoyl)-cc-~-erythropentofuranosyl chloride 237 after protection with bis(trimethylsily1) acetamide.
2. Imidazo[4,5-d] [1,3]Diazepines
Rv
131
236
OH
OR OR 235
23 1
Deprotection with aqueous sodium bicarbonate then gave 238 (R = 4MeC,H,CO). Removal of the p-toluoyl groups by transesterification followed by reduction of the carbonyl group with sodium borohydride led to a mixture of 232 and its 8s isomer (Eq. 75). The sequence of reduction and transesterification could also be reversed.
+!)
HNLN N
*. I . McCON(SiMe,)> ' O D c , ( R =4-MeC6H,CO)b I
OR
230
237
3. HCO;
/// NaBH,
+>-
HNkp~
y
(75)
OR 238
232
and isomer
More recently, the synthesis of the related 8-desoxy analogs have been reported.lo5
D. [el-FUSED [1,3]DIAZEPINES This section reviews diazepines of general formula 239.The benzannelated system is given priority.
132
Bicyclic 1,3-Diazepines
N 239
I. BENZOCe] [1,3]DIAZEPINES (2,4-BENZODIAZEPINES) Neither of the two possible parent 2,4-benzodiazepine tautomers 240a or 240b has been described.
240b
240a
1 H-2,4-Benzodiazepines
3H-2.4-Benzodiazepines
1.1. 4,5-Dihydro-2,4-benzodiazepines 1.1.1. Synthesis Some of the methods used for the synthesis of 1,3-benzodiazepines were also found to be useful for the preparation of 2,4-benzodiazepines of the cyclic amidine type. Thus, condensation of the diamine 241 with i m i d a t e ~ ,6~8 ~ ~ . a m i d i n e ~ or , ~ ~nit rile^^^ led to 2,5-dihydro-1H-2,4-benzodiazepines 242, generally characterized as salts (Eq. 76).
241
242
3-Thioalkyl derivatives 244 were obtained37- 3 9 3 7 0 - 7 2 by alkylation of the thione 243 (Y= S). 3-Amino derivatives 245 were accessible (Eq.77) either by treatment of the urea 243 (Y= 0)with phosphoryl chloride and an amine36aor by displacement of the methylthio group of 244 (R = Me) with an a m i r ~ e . ~ ~
I .I .2. Reactions Several unsuccessful attempts were made to N-alkylate compounds 242.36a The displacement of the 3-methylthio group of 244 (R = Me) by amines was cited in Section 1.1.1.
1. Benzo[e] [1,3]Diazepines (2,4-Benzodiazepines)
133
245
1.2. Dihydro-2,4-benzodiazepinones 1.2.1. Synthesis Syntheses of 2,3-dihydro-5-phenyl- 1H-2,4-benzodiazepin- 1-ones 253 have been p ~ b l i s h e d ~and ~ , ~patented.76 ’ Treatment of the chloromethyl derivative 248 (R, = H,R, = OH) with aqueous ammonia in dioxane (Eq. 78) gave, after chromatography, a 12% yield of the benzodiazepine 253 (R, = H).This low yield conversion of the chloride 248 to the benzodiazepine 253 was improved considerably by preparing 250 (R, = OH)via the azide 249 and subjecting 250 (R, = OH)to acid-catalyzed dehydration. Boiling a solution of 250 (R, = C1, R, = OH) in benzene in the presence of a catalytic amount of para-toluenesulfonic acid afforded 253 (R, = Cl). The formation of 253 from 250 (R, = OH) may proceed via the benzophenone 251 (X = 0)or the diazetidine 252.Studies in our l a b ~ r a t o r i e sshowed ~~ that the reaction of 247 (R, = C1) with thionyl chloride also led to the dichloride 248 (R,, R, = C1) which could be converted to the diamine 250 (R, = C1, R, = NH,). This diamine was also transformed to the benzodiazepine upon heating in toluene solution containing acetic acid, possibly via the intermediate imine 251 (X = NH). Attempts47 to prepare the 2,5-dihydro-3-methyl-lH[2,4]benzodiazepin-lone 255 by cyclodehydration of the benzamide 254 were unsuccessful (Eq. 79).
I .2.2. Reactions Oxidation of the benzodiazepinones 253 with m-chloroperbenzoic acid ~ . ~ ~ of the 4-oxide 256 and the oxaziridine 257. (Eq. 80) a f f ~ r d e d a~ mixture Separation of these compounds was achieved by chromatography.
246
249
R%HcHzNHz
\ 25 1
RJ3$ \ 252
253
0
5,
H
255
254
134
3%
1. BenzoCe] [1,3]Diazepines (2,4-Benzodiazepines)
-N
R
m-CIC,H,CO,H+
R
-N
/
/
\
\
253
135
Y
R
-k
‘ 0
/ \
256
251
(80)
1.3. Tetrahydro-2,4-benzodiazepines The synthesis of 2,4-diaryl-2,3,4,5-tetrahydro-lH-2,4-benzodiazepines 259 was described in the early 1900s by Scholtz and coworkers,78979who obtained these compounds by reaction of the diamines 258 with aldehydes in boiling ethanol (Eq. 81). With R, = 2-Me, cyclization had to be effected in concentrated hydrochloric acid.79
259
258
1.4. Tetrahydro-2,4-benzodiazepinones 1.4.1. Synthesis Reaction of the diamines 260 with carbonyldiimidazole (Eq.82) gave the tetrahydro-2,4-benzodiazepin-3-ones 261 in high yield.36a,80
260
26 1
136
Bicyclic 1,3-Diazepines
1.4.2. Reactions Phosphoryl chloride converted 262 into the O-dichlorophosphate 263,36a an intermediate used in the preparation of 3-amino derivatives (Eq. 83).
NH
N
262
263
(83)
264
265
Oxidation of 262 with chromium trioxide was shown" to give the isoxindole 265 rather than the expected dione 264.It was postulated that 264 is in fact the primary oxidation product, but that it undergoes spontaneous rearrangement and ring contraction to give 265. 1.5. Tetrahydro-2,4-benzodiazepinediones
1.5.1. Synthesis Felix and Fryer" obtained the tetrahydro-2,4-benzodiazepin-1,3-dione 267 by oxidation of the 2,4-dibenzyl derivative 266 with chromium trioxide (Eq. 84). They reported that the minor product from the reaction of benzaldehyde azine with carbon monoxide, once believed to be 264,81actually has the ringcontracted structure 265. 0
CH,Ph (84) CH, Ph
266
261
A facile synthesis of the 1,5-dione 269 was in which condensation of phthaloyl chloride with the amidine 268 gave the benzodiazepine in 80% yield (Eq. 85).
1. BenzoCe] [1,3]Diazepines (2,4-Benzodiazepines)
137
Q I
N>Me HN
-
E1,N
c
269 268
1 S.2. Reactions Compound 269 was cleaved by hot polyphosphoric acid to give a mixture of N-phenylphthalimide and acetanilide in 76 and 48% yield. The phthalimide was also isolated from the reaction of 269 with chromic acid or bromine.
1.6. Tetrahydro-2,4-benzodiazepin-1,3,5-triones Syntheses of the trione 271 (Rl,R, = H)83384and (R, = H; R, = alkyl, a r ~ 1 ) ' have ~ been reported, but the assigned structures were shown to be wrong.86 More recently," the 2,4-dialkyl derivative 271 (R,, R, = CH,CH,Cl) was prepared in 95% yield by reaction of the oxazoline 270 with phthaloyl chloride (Eq. 86).
1.7. 2,4-Benzodiazepinthiones
1.7.1. Synthesis Treatment of 272 with phosphorus pentasulfide in pyridine gave the corresponding thione 273 (Eq. 87).88 Tetrahydro-2,4-benzodiazepin-3-thiones 275 were prepared by reaction of the diamine 274 with thiophosgene in the presence of imidazole,68 or by ring closure of the dithiocarbamic acid adduct 276 obtained from carbon disulfide and 274 (Eq. 88).70
138
Bicyclic 1,3-Diazepines
Fujita and sat^^^ synthesized a variety of tetrahydro-3-thioxo-2,4benzodiazepin- 1-ones 278 by base-catalyzed reaction of 2-chloromethylbenzoy1 chloride with the disubstituted thioureas 277 (Eq. 89). The isomeric 2,4benzothiazepines 279 were usually the predominant products, and the ratio of the two products 278 and 279 was found to be dependent on the substituents R,, R, of the thiourea and also on the choice of solvent and base. A high proportion
R2
1
211 base
4
R2
278
279
1. Benzo[e] [1,3]Diazepines (2,4-Benzodiazepines)
139
of the benzodiazepine 278 was obtained when R, and R, were methyl or benzyl groups. The structures of the products 278 obtained from unsymmetrically substituted thioureas were assigned on the basis of nmr spectroscopic comparison with the compounds prepared from symmetrically substituted thioureas. The 5-methylene protons in 278 appear as an AB system with J = 15 Hz, indicating slow ring inversion at room temperature.
1.7.2. Reactions Heating the thione 273 with acetylhydrazine in n-butanol gave the triazolophthalazine 280 in 60% yield (Eq.
qy -N
213
N-N MeCONHNH,, n- BuOH
280
Alkylations of the 3-thione 275 leading to 2,5-dihydro-3-alkylthio-lH-2,4b e n z o d i a ~ e p i n e s were ~ ~ * ~cited ~ earlier. A double alkylation of 275 with 42dibromoethane (Eq. 91) led to the tricyclic compound 281.70 Reaction with ahaloesters afforded 282,70 while a-haloketones yielded the thiazolo derivatives 283.70*72
282
283
140
Bicyclic 1,3-Diazepines
1.8. 3-Cyanoirnino-2,4-benzodiazepine 1J.1. Synthesis Ishikawa and Watanabe1O2 reported the synthesis of the 3-cyanoimino-2,4benzodiazepine (285) by reaction of o-xylene diamine (284) with dimethyl cyanoimidodithiocarbonate. Treatment of 285 with ethyl bromoacetate gave N-substituted compound 286, which upon heating in t-butanol and hydrochloric acid, gave the 2,3,5,1O-tetrahydro-lH-imidazo[2,1-b][2,4]benzodiazepin-2-one (287)(Eq.92).
qH2 (MeS),C=NCN
C\ F
NN C
N
H
NH2 285 I
284
I
BrCH,COOEi
CH2COOEt
/
~
HCI/t-BuOH
c k N c N N H
287
286
2. CYCLOPENTACe] [1,3]DIAZEPINES 2.1. Synthesis
288
Although the parent ring system 288 (also named 5,7-diazaazulene) is still unknown, the 3-dimethylamino derivative 290 was synthesized” in 50% yield by condensation of the cyclopentadiene 289 with dimethylguanidine in boiling ethanol (Eq. 93). The analogous reaction of 289 with acetamidine did not lead to the anticipated 3-methylcyclopenta[e] [1,3]diazepine, but instead gave a very low yield of
141
3. Thieno[3,4-e] [1,3]Diazepines
289
290
290. The structure of 290 was derived from spectral data and confirmed by X-ray crystallographic analysis.” 2.2. Reactions According to ultraviolet and nmr spectra, protonation of 290 occurs on the ring nitrogens. The action of acylating agents on 290 led to polymerization. Alkaline hydrolysis (Eq. 94) converted 290 to the sodium salt 291 in 70% yield.””
291
290
3. THIENO[3,4-e] [1,3]DIAZEPINES 3.1. Synthesis
292
Thieno [3,4-e] [1,3]diazepines represented by the 1H tautomer 292 have not been prepared, although tetrahydro derivatives are disclosed in the literaturey2 and are derived from the reaction of the thiophene 293 with hexamethylenetetramine (Eq. 95). Steam treatment of the quaternary hexamine salt of 293 gave the formyl derivative 294 in about 30% yield. The formation of 294 requires a redox reaction of a bis(hydroxymethy1) intermediate. The structure of 294 was supported both by alkaline hydrolysis to 295 and acid hydrolysis to the diamine 296. Reaction of 296 with formaldehyde and formic acid or condensation of 295 with methyl formate led to a recovery of 294.
Bicyclic 1,3-Diazepines
142
(95)
Me
Me 295
Me 296
3.2. Reactions Quaternization of 294 with methyl iodide led to 297, which was cleaved readily to the diamine 298 under hydrolytic conditions (Eq.96). Alkaline and acid hydrolysis of 294 was discussed in the preceding section.
Me
CHO
s x i
CHO
Me M
c
I
+
C
I
Me
N\ Me
294
i
krMe Me I -
Me 291
O H - or H,O;
sMx I
NMe,
Me 298
(96)
4. FURO[3,4-e] [1,3]DIAZEPINE AND PYRROLO[3,4-e] [I1,3]DIAZEPINE [1,3]Diazepin- 1,5-(2H)-dione 303 and [ 1,3]diazepin-l,5-(2H,7H)-dione 304 were prepared by treatment of the appropriate heterocyclic dicarboxylic acid
299
30 I
303
(97)
4. Furo[3,4-e] [1,3]Diazepines and Pyrrolo[3,4-e] [1,3]Diazepines
143
chloride 301 (Eq. 97) and 302 (Eq. 98) with N,N'-diphenylacetamidine in the presence of triethyIamine.'O6
300
0
304
Ph
105-1 06
02) 4S02) 02)
Ac MeOH Et20 EtOAc EtOAc EtOAc
216218 166.5-1 67.5 207-208.5 236238 110.5-111.5
MeOH
109-1 11 [118-122/0.26]
exahydro-IH-imidazo[l,2-a] [1,3]diazepines
no
-
Solvent of Crystallization
Diuze10[1,2-a][I ,3]diuzepines
mp ("C); [bp ("c/torr)l
xahydro-I ,J-dinzeto[I ,2-a][1,3]diazepine
a]-FUSED [1,3]DIAZEPINES
ES OF COMPOUNDS
100 63 72 86.5
63
66
Yield (%)
PK,
ir, pmr
Spectra
cmn m b
b b b W
>
.-i
$
z
2
vl
W
N N
2"
145
m
m m
LI
0
s L
.a
a"
146
m m m
T
9
. . .
GGSG 0 0 0 0
8888
N
-
147
.-L
3 .-i
w w
m r -v - , N N
&A
mv, "
148
>
-
m
m N m
,I=-
z i
."2
P
N
U 'c
n?
, ,
>
.-i
8 E
c
a"
0
1
149
!3&
.-i
z a .-i
Y
TZ-
m
150
r-a-
F?ZS
ul +
3-Ph Hydrobromide 3-(4-BrC6H,) Hydrobromide 3-(4-C1C6H4) Hydrobromide Hydrochloride 3-(4-HOCbH4) Hydrobromide ~-C~,~-(HO)ZC~H,I Hydrochloride 3-[2,3,4-(HO)jCcjHzI Hydrochloride 3-(4-MeC6H4) Hydrobromide 3-(4-NOzC6H4) Hydrobromide 3-(4-PhC6H4) Hydrobromide Hydrochloride 3-(3-CF3C,H4) Hydrochloride 2-Me-3-Ph Hydrobromide 2,3-(Ph),
94-96 216 125-1 26 212-2 14 219-220 206207
CHCI,
EtOH Acetone
210-211 264
64 55 55
ir
49
ir
35 EtOH
58
26 24 24 25 25 26 25
ir
24
295d
73
24
21 1-212 140d 210-21 Id 133 235 253-254d
39 70 84 72 77
25 24 24 24 24
198-199
26
238-239 102-105
25 24
54 65
2,3,5,6,7,8-Hexahydrothiazolo[3,2-a] [ I ,3]dazepines None Hydrobromide 3-HO-3-Ph Hydrobromide
223-224
EtOH/Et,O
59
18@182
Acetone
95
ir
28 26
TABLE 11-1. -(contd.) mp ("C); Substituent
VI
N
3-HO-3-(4-C1C6H4) Hydrobromide 3-HO-3-(4-MeOC6H,) Hydrobromide 3-HO-3-(4-PhC6H4) Hydrobromide 3-HO-3-(3-CF,C6H4) Hydrobromide 2-CH2COOH-3-HO-3-(4-C1C6H4) Hydrobromide
PP("C/torr)l
Solvent of Crystallization
Yield (%)
Spectra
Refs.
193-1 94
Acetone
92
26
164165
Acetone
28
26
237-238
Acetone
92
26
42
26
186188 163-165 165-1 67
MeCN MeCN
44 82
ir
27a 27b
235-236d
EtOAc/EtOH
75.5
ir
24
226228 107-108 153-1 54 217-218d 271-272d
EtOH PhH/Petr ether EtOAc/Petr ether
75 71, 62 73 65 60
ir ir
24 24 24 24 24
5,6,7,8- Tetruhydrothiuzo/o[3,2-u][1,3)diazepin-3(2H)-ones
None Hydrochloride 2-Me Hydrobromide 2-Benzylidene 2-[4-Dimethylaminobenzylidene] 2-Br-2-CHBrPh 2-Br-2-[CHBr(4-Me2NC6H4)]
+ vI
w
2-(o-Chlorophenyl)-3-(3,4-dimethoxyphenyl) Hydrochloride 2- Phenyl-3-(5-methyl-2-thienyl) 2-phenyl-3-phen yl Hydrochloride 2-( p-Chlorophenyl)-3-( p-Chlorophenyl) Hydrobromide 2-( p-Chlorophenyl)-3-phenyl Hydrobromide 2-Phenyl-3-(p-tolyl) Hydrobromide 2-Phenyl-3-(5-methyl-2-furyl) Hydrochloride 2-Phenyl-3-(3,4-xylyl) Hydrochloride 2-(p-Chloropheny1)3-[3,4-(methy1enedioxy)phenyll Hydrochloride 2-Phenyl-3-(3-methyl-2-thienyl) Hydrochloride 2-Phenyl-3-(2,4-dimethoxyphenyl) Hydrochloride 2-(o-Chlorophenyl)-3-(o-Chlorophenyl) Hydrochloride 2-(o-Chlorophenyl)3-[3,4-(methylenedioxy)-phenyl Hydrochloride
98-100 197-199 7&90 100-103 197-199
EtOH EtOH EtOH
91 97 97
EtOH/Ether
97
216-218
Acetone
97
19&192
Acetone
97
208-2 10
Acetone
91
193-195
Ether
97
184186
Acetone
91
184-186
EtOH
97
149-155
Acetone
97
202-203
EtOH
91
224-226
EtOH
91
18&182
Acetone
97
TABLE 11-1. -(contd.)
Substituent
mp ("C); IbP (.C/torr)l
Solvent of Crystallization
Yield (%)
Spectra
Refs.
2-(o-Fluorophenyl)-
3-[3,4-(methylenedioxy)-phenyl] Hydrochloride 2-(0-Fluorophenyl)-3-(2-thienyl) Hydrochloride
+ ul P
184-186
91
192-1 95
91
2,3,7,9a-Tetrahydrorhiazolo [3,2,-a] [I,3]diazepi~-5,8(6H,9H)dione
9a-NH2 Hydrochloride
209-2 10
EtOH/H,O
29
34.5
Pyrazolo[l,S-u][I,3]diazepines
3-CN
112-1 13
EtOH
74.4
3-CONH2
195-196
EtOH
83.3
pmr, ir, ms, 13C-nmr, anal pmr, ir, ms,anal
95 95
.L- .L-
Y
155
TABLE 11-2. [c]-FUSED [1,3]-DIAZEPINES
Substituent
mp ("C); [bp ("C/torr)]
Solvent of Crystallization
8-(NH-CO-Ph)
158-160
EtOH
8-(NH-CN)
21&215
Yield (%)
Spectra
Refs.
98 98
TABLE 11-3. [dl-FUSED [1,3]DIAZEPINES
Substituent
mp ("C); CbP (°C/torr)l
Solvent of Crystallization
Yield (%)
Spectra
Refs.
95
ir, pmr
33
40
99 99
20 15 20 10 20 I 30
ir, uv, ms pmr, anal ms, anal, ir, uv, pmr ir, uv, pmr, ms, anal ir, uv, pmr, ms, anal ir, uv, pmr, ms, anal ir, uv, pmr, rns, anal ir, uv, pmr, rns, anal ir, uv, prnr, ms, anal ir, uv, pmr, ms, anal
25
ir, ms, pmr
I .3-Benzodiazepines
2-EtO-5-NHOH
170
EtOH/H,O
l-COOEt-2-Me-6-OMe 1-COOEt-2-Me-6-NMe2 1-COOEt-2-Me 1-COOEt-2-Me-4-Me 1-COOEt-2-Me-5-Me 1-COOEt-2-COOEt l-COOCH2Ph-2-Me I-Ts-2-Me I-Ac-2-Me
105-107 Oil 7&7 1 Oil 53-55 9&98 71-78 22&22 1 98-99
35-40 Hexane/i-Pr,O Hexane/i-Pr,O Hexaneli-Pr,O Hexane/i-Pr,O Hexane/i-Pr,O Hexane/i-Pr,O Hexane/i-Pr,O
e I/r
4
101
101 101
101 101 101 101
3H-l,3-Benzodiazepine
2-Me-3-(2-MeC6H,)
[140/0.05]
34
TABLE 11-3.
~
(contd.)
Substituent 2-Me-3-COOEt-7-OMe 2-Me-3-COOE1-7-NMe2 2-Me-3-COOEt-7-Me 2-Me-3-COOEt-9-Me
mp ("C); IbP ("C/torr)l
Solvent of Crystallization
62-64 115-117 11cK111 Oil
Yield (YO)
Spectra
48 26 8
pmr, anal, ir, pmr, anal, ir, pmr, anal, ir, pmr, anal, ir,
Refs uv, ms uv, ms uv, ms uv, ms
99
99 99 99
5H-I ,.+Benzodiazepines
-
1/1
2-Me-4-Ph-5-COOMe 2-Me-4-Ph-5-COOEt
00
2-EtO-5-OH Hydrochloride 2-Et0-5-CH2Ph-5-OH Hydrochloride 2-Et0-5-Et-5-OH Hydrochloride 2-Et0-5-Me-5-OH Hydrochloride 2-EtO-5-Ph-5-OH Hydrochloride
168-1 70.5 112-113 [130/0.05]
Acetone/Et,O/Hexane Et,O/Hexane
ir, ms, pmr, uv ir, ms, pmr, uv
35 35
155d
EtOAc/MeOH
63
ir, pmr
33
158d
EtOAc/MeOH
52
ir, pmr
33
153d
EtOAc/MeOH
58
ir, pmr
33
155d
EtOAc/MeOH
55
ir, pmr
33
163, 215
EtOAc/MeOH
70
ir, pmr
33
w
a
2-Et0-5-(2-C1C,H4)-5-HO Sulfate 2-Et0-5-(3-C1C6H4)-5-H0 Hydrochloride 2-Et0-5-(4-C1C,H4)-5-H0 Hydrochloride 2-Et0-5-(4-EtC6H4)-5-H0 Hydrochloride 2-Et0-5-(3-FC6H,)-5-H0 Hydrochloride 2-Et0-5-(4-FC,H,)-5-HO Hydrochloride 2-Et0-5-(2-MeOC,H4)-5-H0 Hydrochloride 2-Et0-5-(3-MeOC6H,)-5-HO Hydrochloride 2-Et0-5-(4-MeOC,H4)-5-H0 Hydrochloride 2-Et0-5-(2-MeC,H4)-5-H0 Hydrochloride 2-Et0-5-(3-MeC6H,)-5-HO Hydrochloride 2-Et0-5-(4-MeC6H,)-5-HO Hydrochloride 2-EtO-5-(2-Thienyl)-5-HO Hydrochloride
2-Et0-5-(3-CF3C6H4)-5-H0 Hydrochloride 2-Et0-5-HO-7-N02
145d
EtOAc/MeOH
72
ir, pmr
33
153 -155
EtOAc/MeOH
58
ir, pmr
33
155
EtOAc/MeOH
66
ir, pmr
33
158-1 60
EtOAciMeOH
56
ir, pmr
33
162-1 64
EtOAciMeOH
63
ir, pmr
33
159
EtOAc/MeOH
63
ir, pmr
33
156, >200
EtOAc/MeOH
52
ir, pmr
33
145d
EtOAc/MeOH
52
ir, pmr
33
> 210d
EtOAc/MeOH
50
ir, prnr
33
173, > 200
EtOAc/MeOH
49
ir, pmr
33
1 5 6 1 58d
EtOAc/MeOH
54
ir, pmr
33
147d
EtOAciMeOH
46
ir, pmr
33
153, >200
EtOAc/MeOH
45
ir, pmr
33
156-157d 153
EtOAc/MeOH EtOH/H,O
47.5 66
ir, pmr ir, prnr
33 33
TABLE 11-3. -{contd.)
Substituent
rnp ("C); [bp ("Cjtorr)]
Solvent of Crystallization
Yield (%)
Spectra
114-116 112-1 14
CH,Cl, PhH
71
Pmr ir, prnr, uv
19&192
EtOH
39
178-180
i-PrOH
42
187-189.5
i-PrOH
39
203.5-205.5
i-PrOH
41
234236
i-PrOH
41
118-121
CH,CI,/Et,O
39, 41
204206
i-PrOH
40
199-200
i-PrOH/Et,O
42
24&242 21 1-213
i-PrOH i-PrOH
249-250
EtOH
Refs.
4,5-Dihydro-3H-l,3-benzodiazepines
+ o\
o
None Acetate 2-NHCH2Ph Hydrochloride 2-NH(CH2),C1 Hydrochloride 2-NH(CH2), [3,4-(Me0),-C,H3] Hydrochloride 2-NH(CH,),NMe2 Dihydrochloride 2-NH(CH,),NMe2 Dihydrochloride 2-Et0 Tetrafluoborate 2-[4-(2-Furoyl)- 1-piperazino] Hydroiodide 2-NH(CH,),OH Hydrochloride 2-Me Hydrochloride Tetrachlorornercurate 2-14-Me- 1-Piperazino] Hydroiodide
25
ir, ms,prnr, uv ir. uv
38 38
37 31 40
2-14-( 1,3-Benzodioxol-5-yl)methyl]-1-piperazino Hydroiodide 2-Morpholino Hydroiodide 2-NH(CH2),Ph Hydroiodide 2-[4-(2-Thienoyl)- 1-piperazino Hydroiodide 2-MeS Hydroiodide 2-Me-3-(2-MeC6H,) 3-(CHMePh)-5-Me Hydrochloride 2-NH2-7,8-(Me0), Hydrochloride +
2
2-CH2Ph-7,8-(MeO), Hydrochloride 2-(3-C00Et-C6H4)-7,8-(MeO), Hydrochloride 2-(4-COOEt-C6H4)-7,8-(MeO), Hydrochloride 2-(3-COOH-C6H,)-7,8-(MeO), Hydrochloride 2-CH2C1-7,8-(Me0), Hydrochloride 2-(3-C1C,H4)-7,8-(Me0), Hydrochloride, hydrate 2-(4-C1C,H4)-7,8-(Me0), Hydrochloride
213-275
MeOH
40
184186
MeCN/Et ,O
40
203.5-206
EtOH
39
232-234.5
MeOH
40
175 [160/0.1]
EtOH/MeOH/Et,O 70
269-272
Acetone
20Cb203 233
EtOH EtOH
34
EtOH
48
194- 196
n
ir, ms, pmr
39,41 34 44
10 ir, pmr, uv
36a 36b 36a
134137
EtOH
36b
251-253
EtOH
36b
258-288 126 282
EtOH PhH EtOH
36b
157-163
EtOH
273-276
EtOH
192-194
EtOH
36b
224-225
EtOH
36b
86
36a 36b
34
36a
~-[~,~-(M~O),C,H,]CH,-~,~-(MCO)~ Hydrochloride
2-[3,4-(MeO),C6H,]-7,8-(Me0), Hydrochloride, hydrate
TABLE 11-3. -(contd.)
Substituent 2-NH(CH,),NMe2-7,8-(MeO), Dihydrochloride 2-CH2NMe,-7,8-(Me0), Dihydrochloride, hydrate 2-NH(CH2),NMe2-7,8-(MeO), Dihydrochloride
mp (“C); [bp (“C/torr)]
Solvent of Crystallization
Yield (%)
Spectra
Refs.
41
227
MeOH
248-250
EtOH
264-265
i-PrOH/MeOH
41
250-252
EtOH
36b
225-227
EtOH
36b
257-2 59
EtOH
36b
281-286
EtOH
36b
235
MeOH
40
300-302
EtOH
36b
269-271
EtOH
204-205
EtOH
214-216
EtOH
14G144
EtOH
243
EtOH
63
36a
2-[4-(Me),NSO,C6H,]-7,8-(Me0),
m
N
Hydrochloride 2-(4-EtOC6H4)-7,8-(MeO), Hydrochloride 2-(3-FC,H,)-7,8-(MeO), Hydrochloride 2-(4-FC,H,)-7,8-(MeO), Hydrochloride 2-[4-(2-Furoyl)- l-piperazino]-7,8-(MeO), Hydroiodide, hydrate 2-(4-HOC6H,)-7,8-(MeO), Hydrochloride 24 1-Imidazolyl)CH2-7,8-(MeO), Dihydrochloride 2-(4-MeOC,H4)CH,-7,8-(MeO), Hydrochloride 2-CH2OMe-7,8-(Me0), Hydrochloride 2-(3-MeOC6H,)-7,8-(MeO), Hydrochloride 2-(4-MeOC6H,)-7,8-(MeO), Hydrochloride
65
36a 36b
64
36a 36b
38
36a, b
2-Me-7,8-(MeO), Hydrochloride 2-(4-Me-Piperazino)-7,8-( MeO), Hydroiodide 2-Morpholino-7,8-(MeO), Hydroiodide 2-(3-N0,C6H,)-7,8-(MeO), Hydrochloride 2-(4-N0,-C,H,)-7,8-(MeO)2 Hydrochloride 2-Ph-7,8-(MeO), Hydrochloride
36b 36a
110-112 300
EtOH
278-280
EtOH
40
257-259
CH,CN
40
262-264
EtOH
36
36a
200 107-109 276-278
EtOH EtOAc EtOH
41 88
36a 36a 36a
51
2-(4-Ph-I-Piperazino)-CH,-7,8-(MeO),
g
Dihydrochloride 2-(Piperidino)CHZ-7,8-(MeO), Dihydrochloride 2-Pyrrolidino-7,8-(MeO), Hydroiodide 2-MeS-7,8-(MeO), Hydroiodide
2-(3-CF,C6H,)-7,8-(Me0), Hydrochloride 2-(4-CF3C6H,)-7,8-(Me0), Hydrochloride
36b
228
36a
273-275
EtOH
62
268-270
EtOH
40
197-200 209-2 11
MeOH/Et,O EtOH
39,41 36b
237-239
EtOH
36a
281-282
EtOH
36a
165-167
EtOH
36b
267-269 150-152 267-268 187
EtOH EtOH EtOH PhH
52 59
258-259
MeCN
29
2-[3,4,5-(Me0),C6H,]-7,8-(MeO), Hydrochloride, hydrate 2,3-Me2-7,8-(Me0), Hydrochloride 2-Ph-3-Me-7,8-(MeO), Hydrochloride Methiodide 2-Ph-3-Me-4-Ph Hydrochloride
36a 36b 36a 36a
56
ir, pmr, anal
100
TABLE 11-3. 4 c o n t d . ) mp ("C); Substituent
3
o\
fi
2-Ph-4-Ph Hydrochloride 2-Ph-3-Me-4-[4-C1-C,H4] Hydrochloride 2-Ph-3-Me-4-[4-MeO-C,H,] Hydrochloride 2-Ph-3-Me-4-[4-Me-C6H4] Hydrochloride 2-Ph-3-Me-4-[4-F-C,H4] Hydrochloride ~-P~-~-MC-~-/~,~-(OMC)~-C,H,I Hydrochloride 2-SH-4-Ph 2-MeS-4-Ph Hydroiodide 2-C-N(CH2-CH,),N-Me-4-Ph 2-C-N(CH2CH,),0-4-Ph 2-SH-3-Me-4-Ph 2-MeS-3-Me-4-Ph 2,3-Me2 Hydrochloride 2,3-Me2-4-Ph 2,3-Me2-4-Ph Hydrochloride 4-Ph Hydrochloride 2-Me-4-Ph Hydrochloride
Solvent of Crystallization
Yield
244-247
MeCN
269-270
I ~ ( PV t o r d l
(YO)
Spectra
Refs
40
ir, pmr, anal
100
EtOH/Et,O
51
ir, pmr, anal
100
247-249
MeCN
79
ir, pmr, anal
100
268-270
EtOH/Et,O
57
ir, pmr, anal
100
27C272
EtOH/Et,O
66
ir, pmr, anal
100
175-1 80 21cL212
EtOH/Et,O i-BuOH
42 58
ir, pmr, aflal ir, pmr, anal
100 100
21 2-21 6 93-98 128-1 29 1 7 6 178 175-183
MeOH/Et,O Cyclohexane Toluene i-BuOH MeCN/Et,O
79 63 61 52 92
ir, pmr, anal ir, pmr, anal ir, pmr, anal ir, pmr, anal ir, pmr, anal
100 100 100 100 100
24cL24 1 145-1 46
i-PrOH i-PrOH/Hexane
83 62
24 1 - 242
i-PrOH
185-187
MeOH/Et,O
anal
104
194-197
EtOH/Et,O
anal
104
103
103 103
m
N IN . lN
P
3 m I N d
m N
.-
z
.-
z
N d
m
e4 p:e
165
iDiD N N -
% N
o lw m n N N
P 5,
166
m m m m m m m m
3-(4-MeOC6H,)-7-Me0 Phenylhydrazone, hydrate Semicarbazone
188,225 136138 21 8-2 19d
Ac
1
ir, pmr
48 48 48
uv
49 49
2,3,4,5-Tetrahydro-1H-1,3-benzodiazepines
-2
3-Me Maleate 1-CH2Ph-3-Me
99-101 Oil
EtOAc
1,343-Tetrahydro-I,3-benzodiazepin-2 (2H)-ones None 3-(CH,),NMe, Hydrochloride 3-Et 3-Me 3-(CH,),-Pyrrolidino Hydrochloride S-OAC 5-OH 3-(CH2),NMe,-6-CI
169-171 114-116 23 1-233 148-150 129-1 31
CHCI,/Hexane EtOAc EtOH MeOH MeOH
21 5-2 17 206d 181 173-175
MeOH/Et,O MeOH/Et,O
- 40
36b, 42 51 51 50 50
31 35
32 51
ir, pmr ir, pmr
51 33 33 51
TABLE 11-3.
- (contd.)
Solvent of Crystallization
Substituent ~
L
M
3-(CH,),NMe2-8-CI Hydrochloride 3-(CH2),NMe,-8-(i-Pr) Hydrochloride 5-HO-5-Me 5-HO-5-(2-Me-C6H,) 5-HO-5-Ph 5-HO-7-NHz 5-HO-7-N02 7,8-(MeO), 7,8-(OPr-i), 1,3-Me2-5-H0 3-Me-7,8-(MeO),
Yield
(YO)
Spectra
Refs.
~
51 51
148-150 256-2 58 215-217 210d 244d 224 195d 207 244-247 28G285 [160-1 62/0.7] 197-1 99
EtOAc EtOH EtOAc EtOH DMF/CHCI, H2O
29 70 38 69 76 79
ir, pmr ir, pmr ir, prnr ir, pmr ir, prnr
90
ir, rns, pmr
51 33 33 33 33 33 36a 36b 52 36b
1,2,3,5-Tetrahydro-I,3-benzodiazepin-4(4H)-ones
None 3-CH2Ph 3-Et 3-CH20H 3-Me 3-Ph 3-Pr 1-CH2Ph-3-Me 3-Et-7-CI
25 192 144145 150 197-199 128.5-130 118-120 140-142
HZO EtOH/H,O
6 78 71.5
EtOH/H,O H2O
87 71.5
ir, uv
if,
uv
54 49 49 54 49 50 49 49 50
3-Me-7-Br 3-Me-7-CI 3-Ph-7-Br 3-Ph-7-CI
172-174 154-1 56 217-218 217-219
2,3,5-(Ph), 2-PhenyEmino-3-Ph-5-[ 1,3-Ph,-2-propyn1-ylidene] 1-CHZPh-3-Me-7,8-(OMe),
156-1 57
I-(4-C1C6H,CH,)-3-Me-7,8-(Me0), 1-(4-MeOC6H,)-3-Me-7,8-(Me0),
-
24 p-Tolylirnino)-3-(4-Me-C6H,)-5-[1 ,3-Ph2-2-propyn1 -ylidene]-7-Me 2-(o-ToIylirnino)-3-(2-Me-C6H,)-5-[ 1,3-Ph2-2-propyn-1ylidenel-9-Me
H,O H,O EtOH/H,O EtOH/H,O
65 71 55 68 9
15&151 154-155 140-142 130-132
PhHiHexane
188-1 90 181-182
50 50 50 50 ir, ms, pmr, 'T-nmr
55
1441 73 57 72.5
ir, ms, pmr
59 53 53 53
PhH/Hexane
33
ir, ms, pmr
59
PhHiHexane
17
ir, ms, pmr
59
18
ir, uv
34 45
ir, uv ir, uv
ir ir, uv
56 56 56 57 57, 58
ir, pmr
33
EtOH
m
\o
3,5-Dihydro-1H-1,3-benzodiazepine-2,4-diones
1 -Me 1,3-(Me), I-Me-3-Ph 3-Ph-5-CHZPh 3-Ph-5-Benzylidene
203 136 186 122-124 202-203
EtOH MeOH/H,O
4; 12
3,4-Dihydro-1 H-I,3-benzodinzepine-2,5(5H)-diones
None
220d
DMF/CHCI,
88
TABLE 11-3. 4 c o n t d . )
Substituent
e
mp ('V; IbP ("C/torr)l
5-Oxime
255d
7-NH2 7-Br 7-CI 7-NHCOCH2C1 7-(Morpholinoacetyl)amino 7-NO2 5- 0xi m e 7-(Piperidinoacety1)amino
255d 254 240 250d 255 260d 250d 255
Solvent of Crystallization CHClJMeO CH,CH,OH EtOH DMF DMF/MeOH DMF/MeOH DMF/H ,O DMF/MeOH EtOH DMF/H,O
Yield (YO)
Spectra
Refs.
77.5 90 57.5 89, 89 60 70 84
ir ir, pmr ir, pmr ir, pmr ir, pmr ir, pmr ir, pmr :r ir, pmr
33 33 33 33 33 33 33 33 33
65
ir, pmr
39, 40 44 36b, 39, 40
78
ir, uv
56
0
1,3,4,5-Tetrahydro-l,3-henzodiazpine-2(2H)-thiones None 5-Me 7,8-(MeO),
195 1%-182 251-253
136
EtOH
I,3-Dihydro-2-thioxo-I ,3-benzodiazepine-4,5(4H, 5H)-diones
3-Ph 3-(2-MeC6H,)
155-1 57 205-206
Acetone EtOH
177-179 131-133
Me2C0 Et,O
182-184
H2O
60 60
1,3,4,5,-Tetrahydro-2-eyanoimino-l,3-benzodiazepines
3-CH2Ph 1-CH,COOEt-3-CH2-Ph
16 72
ir, pmr, anal ir, pmr, anal
102 102
3,6,7,8-Tetrahydroimidazo[4,5-d][I ,3]diazepines
3-(p-D-Ribofuranosyl)-8(R)-OH (coformycin) 3-(2-Deoxy-~-o-ribofuranosyl)-8(R)-OH(covidarabine) Tetraacetate
220-225 68-78
ms, uv, ORD, PK., X-ray
62, 64
ms, pmr, 3Cnmr, uv, X-ray, p K , ms, pmr
65 65
TABLE 11-3. 4contd.)
Substituent
mp ("C); Cbp ( V t o r r ) l
Solvent of Crystallization
Yield (%)
H,O/MeOH MeOH
48 40
MeOH
82
Spectra
Refs.
3,6,7,8- Tetrahydroimidazo[4,5-d][ I , 3ldiazepines
3-(2-Deoxy-/l-~-eryfhro-pentofuranosyl)-8-OH( R) 204-2 10 3-(2-Deoxy-/l-o-erythro-pentofuranosy~ )-8-OH(S)
13C-140
3-(2-Deoxy-a-D-eryt hrO-pentofurdnosyl)-8-OH(R,S)
uv, anal, ir, pmr uv, anal, ir, pmr uv, anal *
105 105 105
6,7-Dihydro-3H-imidazo[4,5-d] [1,3]diazepin-8(8H)-ones
None Hydrochloride 3-[3,5-Di-O-( p-toluoy1)-/l-~-erythro-pentafuranosyl] 3-[3,5-Di-O-( p-to1uoyl)-a-D-erythro-pentafurdnosyl]
250d 155
220d
EtOH EtOAc EtOAc
61 61 61
TABLE 11-4. [el-FUSED [1,3]DIAZEPINES
Substituent
mp ("C); IbP (°C/torr)l
Solvent of Crystallization
Yield (%)
Spectra
Refs.
2.4-Benzoidazepines
=;
3-NH2 Hydrochloride 3-PhCHz Hydrochloride 3-(4-COOEt-piperazino) Hydroiodide 3-CH2C1 Hydrochloride 3-(4-C1C6H4) Hydrochloride 3-OPOCI, Hydrochloride 3-NMe2 Hydrochloride 3-CH2NMe, Dihydrochloride 3-CH2OMe Hydrochloride 3-(4-MeOC,H4) Hydrochloride 3-Me H ydrochloride Trichloromercurate
219-281
EtOH
76
256259
EtOH
61
2w202
i-PrOH
263-264
EtOH
53
36a
266261
EtOH
46
36a
21 5
EtOH
12
36a
2 5 3-2 55
EtOH
69
36a
239-241
EtOH
78
36a
175-178
EtOH
28
36a
262-263 148-149 283-285 173-114
EtOH PhH EtOH i-PrOH
ir, uv
36a 36a 13a, b
ir, ms, pmr 59 58
ir, pmr
68 31 36a 37
TABLE 11-4. 4c ont d. )
Substituent
-
4
3-NHMe Hydrochloride 3-[4-(1,3-Benzodioxol-5-yl)piperazino] Hydroiodide, hydrate 3-[4-( 1,3-Benzodioxol-5-yl)met hylpiperazino] Hydroiodide 3-(3-NO,C,H,) Hydrochloride 3-(4-N02C6H4) Hydrochloride 3-Ph Hydrochloride Maleate 3-Piperidinomethyl Dihydrochloride 3-[4-(2-Thienyl)-1-piperazino] Hydroiodide 3-[4-(2-Thienylmethyl)-l-piperazino] Hydrochloride 3-PhCHZS Hydrochloride 3-MeS Hydroiodide 3-(2-CIC,H,CH,S) Hydrochloride 3-(2,5-Me,C6H,SCH,)C6H3] Hydrochloride 3-(2-Pyridylmethylthio) Hydrochloride
mp W ; CbP (°C/torr)l
Solvent of Crystallization
Yield (%)
Spectra
Refs.
216211
EtOH
68
179- 181.5
EtOH
73a, b
202-204
MeOH
73a, b
260
EtOH
55
36a
278-280
EtOH
36
36a
232-234 191-193
EtOH/Et,O EtOH
68 68
288-289
EtOH
68
192-193.5
EtOH
73a
194196
i-PrOH
73a, b
162-1 64
i-PrOH/Et,O
70
72
226d
MeOH/Et,O
100
70
209-2 11
i-PrOH
61
72
216218
i-PrOH
62
72
> 250
71
4
L d rw nm w
v, m
A
8; m -
,
r n r n
175
t-r-t-t-
m m m m
0
w 0
TABLE 11-4. d c o n t d . ) mp ("C); Substituent
[bP ("C/torr)l
Solvent of Crystallization
Yield
(YO)
Spectra
Refs.
anal
104
80
0
2,3,4,S-Tetruhydro-2,4-benzodiuzepine-l(IH)-ones
2,4-(Ph),-3-(Phenylimino)
189-190
82
4,S-Dihydro-2,4-benzodiuzepine-l,3 (2H)-dione
&Po
e
NH
4 Cn
2,4-(PhCH&
114.5-1 15.5
CClJHexane
26.5
ms
2,4-(Ph2),-3-Methylene 2,4-(4-Br-C6H,),-3-Methylene 2,4-(4-Et0-C6H,),-3-Methylene 2,4-(Ph),-3-(=CH-Ph) 2,4-(Ph),-3-Me 2,4-(Br-C,H4), 2,4-(Ph),-3-(-CH2-Ph) 2,4-(Ph),-3-(=N-Ph)
1 7 4 175 175-1 76 179-1 8 I 182-1 83 238-240 231-232 189-1 91 21 8-219
MeOH MeOH MeOH MeOH MeOH MeOH MeOH n-PrOH
80 81 95 71 89 60 94 84
ms, pmr anal anal anal anal anal anal anal
82 106 106 106 106 106 106 106
W t-
k
.-i
z
e e:.-
W
177
W rO w -
TABLE 11-4. d c o n t d . )
Substituent
4 00
2,4-(4-MeOC6H,CH,), 2,4-Me2 2-Me-4-P yrrolidinometh yl 2,4-(4-MeC6H,CH,), 2-Isobutyl-4-PhCH2 2-(3-Morpholinopropy1)-4-Me 2-(2-Pyrrolidinoethyl)-4-Ph
mp K ) ; CbP (°C/torr)l
117.5 170-171.5 136137 130-131 91-93.5 117-118 168-170
Solvent of Crystallization EtOH i-PrOH i-PrOH EtOH i-PrOH i-PrOH i-PrOH
Yield (%) 18.3 45.5 8.3 25.5 7.5 9 6
Refs.
Spectra ir, pmr, ir, pmr, ir, pmr, ir, pmr, ir, pmr, ir, pmr, ir, pmr
uv uv uv uv uv uv
89a 89a 89a 89a 89a 89a 89a
I ,2,4,S-Tetrahydro-3-cyanoirnino-2,4-benzodiazepines
NH None 2-CH2COOEt
249-25 1 1 89-1 9 1
EtOH CHCI,/Et,O
78 65
ir, anal ir, pmr, anal
103 170d
Petr ether
4G50
ir, pmr, uv X-ray
102 102
Cyelopenta[e] [I ,3]diuzepines
3-NMe, Picrate
90
"NPI
Y
o\o\QIo\
U
W
El
m
m
-
W
W
-2
179
180
Bicyclic 1,3-Diazepines
F. REFERENCES 1. J. Burkhardt and K. Hamann, Chem. Ber., 101, 3428 (1968). 2. (a) A. F. McKay and M.-E. Kreling, Can. J . Chem., 35, 1438 (1957). (b) A. F. McKay and M.-E. Kreling, Brit. Patent 826,837, January 1960. (c) A. F. McKay and M.-E. Kreling, Can. J . Chem., 40, 1160 (1962). 3. Jap. Patent J5-3079890, July 1978 (Daiichi Phar.). 4. (a) Ger. Offen. 2,118,261, April 1971 (C. H. Boehringer Sohn, Ingelheim). (b) Dutch Patent 71,743, October 1972 (C. H. Boehringer Sohn, Ingelheim), Chem. Abstr., 78, 29773. 5. C. R. Lee and R. J. Pollitt, Biochem. J., 126, 79 (1972). 6. (a) M.-E. Kreling and A. F. McKay, Can. J . Chem., 36, 775 (1958). (b) A. F. McKay and M.-E. Kreling, U.S. Patent 2,865,913, December 1958. 7. V. Sunjic, T. Fajdiga, and M. Japelj, J . Heterocycl. Chem., 7, 211 (1970). 8. Ger. Offen. 2,315,422, October 1973, (Chinoin Gyogyszeres Vegyeszeti Termekek Gyara RT). 9. A. Fozard and G. Jones, J . Chem. Soc., 2763 (1964). 10. Y. Okamoto, A. Takada, and T. Ueda, Chem. Pharm. Bull., 20, 725 (1972). 11. E. Ott and F. Hess, Arch. Pharm., 276, 181 (1938). 12. Ger. Offen. 2,731,982, January 1978 (Yamanouchi Pharm. Co. Ltd, Tokyo). 13. V. S. Reznik, I Sh. Salikhov, Yu. Shvetsov, A. N. Shirshov, V. S. Bakulin, and B. E. Ivanov, Izu. Akad. Nauk SSSR, Ser. Khim., 880 (1 977). 14. L. P. Prikazchikova, L. K. Kurilenko, and V. M. Cherkasov, Ukr. Khim. Zh., 42, 518 (1976). 15. (a) I. B. Toperman and 0. Yu. Magidson, Khim.-Farm. Zh., 2, 35 (1968). (b) 0.Yu. Magidson and I. B. Toperman, U.S.S.R 224,522, August 1968. 16. Japan Patent 74, 27,877, July 1974 (Fujisawa Pharm. Co. Ltd.); Chem. Abstr., 82, 156, 398g. 17. J. W. Sowell, and C. De Witt, Blanton, J . Pharm. Sci., 65, 908 (1976). 18. Fr. Patent 1,491,791, August 1967 (Farbenfarbriken Bayer). 19. J. W. Ducker and M. J. Gunter, Aust. J . Chem., 21, 2809 (1968). 20. G. I. Glover, R. B. Smith, and H. Rapoport, J . Am. Chem. SOC.,87, 2003 (1965). 21. (a) H. Wollweber, Anyew. Chem., Int. Edit., Engl., 8, 69 (1969). (b) Ger. Offen. 1,802,468, May 1970 (Farbenfabriken Bayer). 22. Belg. Patent 659,530, August 1965 (J. R. Geigy). 23. W. J. Houlihan, U S . Patent 3,334,099, August 1967 (Sandoz.) 24. V. K. Chadha, H. S. Chandhary, and H. K. Pujari, Aust. J . Chem., 22, 2697 (1969). 25. K. S. Dhaka, V. K. Chadha, and H. K. Pujari, Indian J . Chem., 11, 554 (1973). 26. R. E. Manning, US. Patent 3,763,142, October 1973 (Sandoz-Wander); Belg. Patent 777,241, June 1972 (Sandoz S.A.). 27. (a) S. C . Bell and P. H. L. Wei, J . Med. Chem., 19,524 (1976). (b) P. H. L. Wei and S. C. Bell, U.S. Patent 3,853,872, December 1974 (American Home Products Corp.). 28. V. K. Chadha, K. S. Sharma, and H. K. Pujari, Indian J . Chem., 9, 1216 (1971). 29. V. Wolf and W. Braun, Arzneimittel-Forsch., 10, 304 (1960). 30. F. DAngeli, C. Di Bello, and V. Giormani, Gazz. Chim. Ital., 95, 735 (1965). 31. M. Brugger and F. Korte, Justus Liebigs Ann. Chem., 764, 112 (1972). 32. D. J. Le Count and P. J. Taylor, Tetrahedron, 31,433 (1975). 33. J. B. Taylor and W. R. Tully, J . Chem. SOC.,Perkin Trans., 1331 (1976). 34. F. M. F. Chen and T. P. Forrest, Can. J . Chem., 51, 881 (1973). 35. U. Stauss, H. P. Harter, M. Neuenschwander, and 0. Schindler, Helv. Chim. Acta, 55, 771 (1972). 36. (a) H. R. Rodriguez, B. Zitko, and G. de Stevens, J . Org. Chem., 33, 670 (1968). (b) H. R. Rodriguez and G. de Stevens, U.S. Patent 3,681,340, August 1972. 37. J. M. Desmarchelier, N. A. Evans, R. F. Evans, and R. B. Johns, Aust. J . Chem., 21,257 (1968). 38. B. A. Burdick, P. A. Benkovic, and S. J. Benkovic, J . Am. Chem. SOC.,99, 5716 (1977). 39. J. T. Suh and R. A. Schnettler, US. Patent 3,780,023, December 1973. 40. J. T. Suh and R. A. Schnettler, US. Patent 3,838,122, September 1974.
F. References 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65.
181
J. T. Suh and R. A. Schnettler, U S . Patent 3,780,024, December 1973. T. Jen, P. Bender, H. Van Hoeven, B. Dienel, and B. Loer, J . Med. Chem., 16, 407 (1973). J. T. Suh and R. A. Schnettler, US. Patent 3,849,400, November 1974. E. F. Elslager, D. F. Worth, and S. C. Perricone, J . Heterocycl. Chem., 6, 491 (1969). F. P. Woerner, H. Reimlinger, and R. Merenyi, Chem. Ber., 104, 2768 (1971). Ger. Offen. 1,947,062, March 1970 (Yeda Research and Development Co. Ltd.). U. Golik and W. Taub, J . Heterocycl. Chem., 12, 1155 (1975). W. V. Farrar, Chem. Ind. (London) 1808 (1968). G. de Stevens and M. Dughi, J . Am. Chem. Soc., 83, 3087 (1961). 0. Hromatka, M. Knollmuller, and H. Deschler, Monatsh. Chem., 100, 469 (1969). W. B. Wright, Jr., U.S. Patent 3,474,090, October 1969 (American Cyanamid Co.). T. P. Forrest, G. A. Dauphinee, and F. M. F. Chen, Can. J . Chem., 52, 2725 (1974). G. de Stevens, U S . Patents 3,157,642, November 1964, and 3,310,582, March 1967. G. de Stevens, Rec. Chem. Prog., 23, 105 (1962). 0. Tsuge and H. Watanabe, Heterocycles, 7, 907 (1977). P. Gyulai and K. Lempert, Magyar Kem. Foly., 76, 96 (1970). C. W. Bird, J . Chem. Soc., 5762 (1965). Y.Ohshiro, K. Kinugasa, T. Manami, and T. Agawa, J . Org. Chem., 35, 2136 (1970). (a) A Baba, Y. Ohshiro, and T. Agawa, J . Organomet. Chem., 87, 247 (1975). (b) Japan. Kokai, 75,121,290, September 1975 (Mitsubishi Chemical Co. Ltd.). T. N. Ghosh, J . Indian Chem. SOC.,10, 583 (1933). D. C. Baker and S. R. Putt, U S . Patent 4,117,229, September 1978 (Warner-Lambert Co.). T. Tsurnoka, N. Ezaki, S. Amano, C. Uchida, and T. Niida, Meiji Seika Kenkyu Nempo 17 (1967); Chem. Abstr., 69, 8514r. A. Ryder, H. W. Dion, P. W. K. Woo, and J. D. Howells, U.S. Patent 3,923,785, 1975 (Parke, Davis & Co.). H. Nakamura, G. Koyama, Y. Iitaka, M. Ohno, N. Yagisawa, S. Kondo, K. Maeda, and H. Umezawa, J . Am. Chem. SOC.,96,4327 (1974). P. W. K. Woo, H. W. Dion, S. M. Lange, L. F. Dahl, and L. J. Durham, J . Heterocycl. Chem.,
11, 641 (1974). 66. (a) M. Ohno, N. Yagisawa, S. Shibahara, S. Kondo, K. Maeda, and H. Umezawa, J . Am. Chem. SOC.,96, 4326 (1974). (b) H. Umezawa, K. Maeda and S.Kondo, U S . Patent 3,959,257, May 1976. 67. Belg. Patent 864,711, November 1978 (Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai). 68. Brit. Patent 1,183,135, March 1970 (Ciba Ltd.). 69. Ger. Offen., 2,601,137, July 1976 (Merck & Co.). 70. E. F. Elslager, D. F. Worth, N. F. Haley, and S. C. Perricone, J . Heterocycl. Chem., 5, 609 (1968). 71. Ger. Offen. 2,504,252, August 1975 (Aktiebolaget Hassle, Molndal, Sweden). 72. E. F. Elslager, J. R. McLean, S. C. Perricone, D. Potoczak, H. Veloso, D. F. Worth, and R. H. Wheelock, J . Med. Chem., 14, 397 (1971). 73. (a) R. A. Schnettler and J. T. Suh, U S . Patent 3,867,388, February 1975. (b) US. Patent 3,905,980, September 1975 (Colgate-Palmolive Co.). 74. U. Golik, Tetrahedron Lett., 1327 (1975). 75. U. Golik, J . HeterocycL Chem., 12, 903 (1975). 76. W. Taub and U. Golik, U.S. Patent 3,939,152, February 1976 (Yeda Research & Development 77. 78. 79. 80. 81. 82. 83.
Co., Ltd.). E. Reeder, unpublished results. M. Scholtz and K. Jaross, Berichte, 34, 1504 (1901). M. Scholtz and R. Wolfrum, Berichte, 43, 2304 (1910). A. M. Felix and R. I. Fryer, J . Heterocycl. Chem., 5, 291 (1968). A. Rosenthal and S. Millward, Can. J . Chem., 42,956 (1964). H. W. Heine and C. Tintel, Tetrahedron Lett., 23 (1978). A. Piutti, Justus Liebigs Ann. Chem., 214, 17 (1882).
182
Bicyclic 1,3-Diazepines
T. W. Evans and W. M. Dehn, J . Am. Chem. Soc., 51, 3651 (1929). C. S. Smith and C. J. Cavallito, J . Am. Chem. Soc., 61, 2218 (1939). D. Grdenic and A. Bezjak, Arch. Kem., 25, 101 (1953). D. A. Tomalia, N. D. Ojha, and B. P. Thill, J . Org. Chem., 34, 1400 (1969). U. Golik, J . Heterocycl. Chem., 13, 613 (1976). (a) H. Fujita and Y. Sato, Chem. Pharm. Bull., 23, 1764 (1975). (b) Japan Kokai, 75,117,790, September 1975 (Sankyo Co., Ltd.); Chem. Abstr., 84, 105670. 90. (a) U. Miiller-Westerhoff and K. Hafner, Tetrahedron Lett., 4341 (1967). (b) K. Hafner, J . Heterocycl. Chem., 13, 33 (1976). (c) Brit. Patent 1,226,179, March 1971 (Studiengesellschaft Kohle m.b.H.). 91. H. J. Lindner, Chem. Ber., 103, 1828 (1970). 92. M. S. Kondakova and I. L. Goldfarb, Bull. Acad. Sci. USSR, 570 (1958). 93. A. Kosasayama, T, Konno, K. Higashi, and F. Ishikawa, Chem. Pharm. Bull., 2 7 4,841 (1979). 94. A. Kosasayama, T. Konno, K. Higashi, and F. Ishikawa, Chem. Pharm. Bull., 27: 4,848 (1979). 95. T. Kurihara, K. Nasu, F. Ishimori, and T. Tani, J . Heterocycl. Chem., 18, 163 (1981). 96. T. Kurihara, K. Nasu, and Y. Adachi, J . Heterocycl. Chem., 20, 81 (1983). 97. A. S. Tomcufcik, W. B. Wright, Jr., and J. W. Marsico, Jr., US. Patent 4,344,954, August 1982. 98. D. W. Hills and G. R. W. Harpenden, U.S. Patent 4,375,435, March 1983. 99. T. Tsuchiya, S. Okajima, M. Enkaku, and J. Kurita, Chem. Pharm. Bull., 30: 10, 3757 (1982). 100. L. L. Setescak, F. W. Dekow, J. M. Kitzen, and L. L. Martin, J . Med. Chem., 27, 401 (1984). 101. T. Tsuchiya, M. Enkaku, and S . Okajima, Chem. Pharm. Bull., 28: 9, 2602 (1980). 102. F. Ishikawa and Y. Watanabe, Chem. Pharm. Bull., 28: 4, 1307 (1980). 103. T. B. K. Lee and G. E. Lee, U.S. Patent, 4,374,067, February 1983. 104. L. L. Martin, M. Worm and C. A. Crichlow, US. Patent, 4,409,145, October 1983. 105. E. Chan, S. R. Putt, and H. D. H. Showalter, J . Org. Chem., 47, 3457 (1982). 106. H. W. Heine, D. W. Ludovici, J. A. Pardoen, R. C. Weber 11, E. Bonsall, and K. R. Osterhout, J . Org. Chem., 44: 22, 3843 (1979). 84. 85. 86. 87. 88. 89.
CHAPTER I11
1.4.Diazepines with [a]- or [d]-Fused Rings R . Ian Fryer Department of Chemistry. Rutgers. State Unioersity of New Jersey. Newark. New Jersey
and
.
A Walser Chemical Research Department. Hoffmann-La Roche Inc., Nutley. N e w Jersey
...................................
184
1. Azirinoll.2.~1[I. 4ldiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
A. [a]-Fused [I. 4ldiazepines
184
1.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
184
1.2. Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
185
2. Imidazo[l. 5-a] [1,4]diazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
186
3. PyridoCl.2-a] [1,4]diazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
186
3.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
186
3.2. Reactions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
188
4. Pyrrolo[l, 2-a] 11.4ldiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
189 189
4.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Reactions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. [d]-Fused[I ,4ldiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. ImidazoCl,2 4 1 [1.4]diazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2. Reactions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
191
2. Pyrido[l. 2-d] [lPldiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
193
3. Pyrrolo[l. 2-d] [I. 4ldiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
194
C . Tables of Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . D. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
196 207
183
191 191 192 192
184
1,4-Diazepines with [ a ] - or [dl-Fused Rings
INTRODUCTION The ring systems reviewed in this chapter contains an additional ring fused to sides a or d of the lP-diazepine 1.
I
The extensive work carried out in the area of [ b]-fused[ 1,4]diazepines (e.g., 1,5-benzodiazepines) is the subject of a separate chapter while the more voluminous work carried out in the area of [e]-fused[1,4]diazepines (e.g., 1,4benzodiazepines) is further subdivided into individual chapters depending on the position of the double bonds in the seven-membered ring. 1,4-Dazepines with either [ a ] - or [dl-fused rings have one nitrogen common to both rings and have been reviewed by F. D. Popp and A. C . Noble (in Advances in Heterocyclic Chemistry Vol. 8, A. R. Katritzky and A. J. Boulton, Eds., Academic Press, New York and London, 1967, p. 21).
A. [a]-FUSED [1,4]DIAZEPINES This section embraces all bicyclic systems of general structure 2. The ring systems are discussed in alphabetical order.
2
1. AZIRINO[192-a] [1,4]DIAZEPINES 1.1. Synthesis 1
'2 P2
2
6N\
5
3
lH-Azirino[l,Z-a][1,4]diazepine
6
4
1,5-Diazabicyclo[5.1.O]octane
185
1. Azirino[1,2-a] [1,4]Diazepines
The parent ring system represented by the 1H tautomer 3 is still unknown. A 3,7a-dihydro derivative, 6,was synthesized in about 25% yield by Padwa and (5) with cinnamGehrlein' by the reaction of trans-3-benzoyl-2-phenylaziridine aldehyde in the presence of ammonia and ammonium bromide in ethanol a t room temperature (Eq. 1). The indicated relative configuration was assigned on the basis of nuclear Overhauser effects, which suggested a proximal orientation of the hydrogens in the 1- and 3-positions.
5
6
1.2. Reactions
Sodium methoxide in methanol converted 6 in nearly quantitative yield to the dihydropyrimidine 7 (Eq. 2). A mechanism for this base-catalyzed rearrangement was proposed. Irradiation of a benzene solution of 6 gave the acyclic compound 8 in 80% yield. Thermal rearrangement of 8 was shown to give 10 and 11. Compounds 10 and 11 were also formed by thermolysis of 6 in boiling xylene. The major product of this reaction was the bicyclic compound 9. $'
P hN 8/ P h
Me0 MeOH
* Ph
6
I
1".
H Ph
AYPh
H Ph
10
/N
11
186
1,4-Diazepineswith [ a ] - or [d]-Fused Rings
An additional reaction of 6 with fumaronitrile is reported under pyrrolo[1,2-a] [1,4]diazepines. (Section 4.1).
2. IMIDAZO[~,S-U] [1,4]DIAZEPINES
12b
12a
lH-Imidazo[ 1,5-n] [1,4]diazepine
12c
3H-Imidazo[l,S-a] [ 1,4]diazepine
I2d 7H-Imidazo[ 1,5-0][1,4]diazepine
SH-lmidazo[ 1,5-a][1,4]diazepine
I2e
9H-Imidazo[ 1,5-a][t,4]diazepine
This parent ring system may exist in any of the five tautomeric forms 12a-12e. The tautomers with the aromatic five-membered ring should be thermodynamically favored. None of the fully unsaturated systems are known. The synthesis of substituted tetrahydro derivatives with an intact imidazole ring has been reported.2 Reaction of the 1-(3-aminopropyl)irnidazoles13 with formaldehyde in a buffered medium (Eq. 3) led to the imidazodiazepines 14 in 30-60% yields. Compounds 13 were accessible by cyanoethylation of the parent imidazole followed by reduction of the nitrile, either catalytically or by means of lithium aluminium hydride.
c$N R1
CH,O RCOOH RCOO Na'
R2
(3)
R2
14
13
3. PYRIDO[1,2-a] [1,4]DIAZEPINES 3.1. Synthesis
A tetrahydro derivative of the parent ring system 15 with the pyridine nitrogen quaternized was prepared by Fozar and Jones.3 Thermal ring closure
187
3. Pyrido[1,2-a] [1,4]Diazepines
15
and quaternization of the bromide 16 gave 17 (Eq. 4). Compound 16 was obtained by treatment of the corresponding alcohol with phosphorus tribromide.
8
0
Br-
Br
17
16
Perhydro derivatives of this ring system have received more synthetic attention. Paquette and Scott4 obtained the 3-one 19 as the minor product of the Schmidt reaction of the ketone 18. The major product from this rearrangement was the [dl-fused [1,4]diazepine 20 (Eq. 5).
19
20
Reaction of the piperidine derivative 21 with benzylamines 22 has been claimeds to yield the decahydropyridoC 1,241 [1,4]diazepines 23 (Eq. 6).
A variety of perhydro derivatives 25 bearing an aroyl group at the 4-position (Eq. 7) were prepared by condensation of the piperidine 24 with formaldehyde and an aryl methyl ketone in boiling acetic acid.6 The reported yields were 25-77%. It is likely that the initially formed a$-unsaturated ketone undergoes Michael addition by one amino group and that the ring is formed by condensation of a second molecule of formaldehyde with the remaining amino group and
188
1,4-Diazepineswith [ a ] - or [dl-Fused Rings
NHR, CH20
0
8
24
R2
25
cp Me
/
Me
C &
\
Me
27
26
the a-carbon of the ketone. This condensation was also carried out with benzyl phenyl ketone and 6-methoxy- l-tetralone to give 26 and 27, respectively.
3.2. Reactions Quaternization of 19 with methyl iodide afforded4 the salt 28, which upon treatment with hydroxide was reconverted to 19 by elimination of the methyl group (Eq. 8).
Compounds 29 (R, = Me) were reduced with lithium aluminum hydride or sodium borohydride to give a mixture of diastereomeric alcohols 306 (Eq. 9). Reaction of 29 with Grignard reagents led to the carbinols 31, of which generally only one isomer was isolated, often in high yield. Treatment of the tertiary carbinol 31 (R2, R,=Ph) with sulfuric acid led to the diphenylmethylene derivative 32. Replacement of the hydroxyl group in 30 (R,=Ph) with a morpholino moiety to give 33 was achieved via the chloride. Two 2-substituted perhydro pyrido[ 1,241 [1,4]diazepines 35, which were disclosed in the patent l i t e r a t ~ r e , ~were prepared by alkylation of the 2-hydroxyethyl derivative 34 with a diphenylmethylhalide (Eq. 10).
189
4. Pyrrolo[ 1,2-a] [1,4]Diazepines
SOCI, HNAO
u
33
c;4" 34
gR WJ /4
R
Dc"-xc
\
(10)
35
4. PYRROLO[1,2-a] [1,4]DIAZEPINES 4.1. Synthesis None of the tautomeric forms 36a-36e of the parent ring system are known. The tetrahydro derivative 38 with an intact pyrrole ring was described in the
1,4-Diazepines with
190
36a lH-Pyrrol0[1,2-a] [1.4ldiazepines
[a]-
or [dl-Fused Rings
36b 3H-Pyrrolo[ 1,2-a] [ 1,4]diazepines
36d 7H-PyrroloC1,2-a][1,4]diazepines
36c SH-Pyrrolo[ 1,2-a][ 1,4]diazepines
36e 9H-Pyrrolo[1,2-a][1,4]diazepines
patent literature.* This compound was reportedly obtained by Beckmann rearrangement from the oxime 37 (Eq. 11).
31
38
The polysubstituted 7,8,9,9u-tetrahydro-SH-pyrrolo[ 1,2-a] [1,4]diazepine 39 was formed in 76% yield by the 1,3-dipolar addition of fumaronitrile to the azirinodiazepine 6 in boiling xylene' (Eq. 12). The relative stereochemistry was derived from nmr data and was supported by the stereochemistry of the hydrolysis product 40 obtained in 70% yield.
& H
Ph
Ph
Ph
CN Ph N C e C N
N i H g J Ph
/ 6
Ph 39
CHO
40
The saturated pyrrolodiazepin-l-one, 43 was reportedly synthesised from L-proline ethyl ester as shown in Eq. 13." No experimental details were given.
191
1. Imidazo[1,2-d] [1,4]Diazepines
P O O E t
CH,=CHCN
~
W O O E t
H,!autoclave
N\CH2CH,CN
41 H '
43
42
(13)
4.2. Reactions
Reduction of 43 using lithium aluminum hydride was reported to give the fully saturated pyrrolo[ 1,2-a] [1,4]diazepine 44. Treatment of 44 with either substituted or unsubstituted benzhydryl bromides gave the N-substituted derivative 45 (Eq. 14).12
Ph LiAlH 2
43
R-Ph-CH-Br
44
45
(14)
B. [d ]-FUSED [1,4]DIAZEPINES
46
Ring systems of general structure 46, which are the subject of this section, are discussed in alphabetical order.
1. IMIDAZOC1,2-d] [1,4]DIAZEPINES
47a
1H-Imidazo[ 1,2-d] [1,4]diazepines
47b 3H-ImidazoC 1,2-d] [ 1,4]diazepines
192
1,4-Diazepineswith [a]- or [dl-Fused Rings
47c
47d
47e
SH-Imidazo[ 1,2-d][ 1,4]diazepines
'IH-Imidazo[ 1,2-d][ 1,4]diazepines
9H-Imidazo[ 1,2-d][1,4]diazepines
1.1. Synthesis None of the tautomeric forms 47a-47e of the parent ring system have been described in the literature. Hexahydro derivatives were disclosed in the patent literature.'. l o These compounds were synthesized by fusion of the imidazolone ring to the preformed diazepine (Eq. 15). The N-protected diazepinone 48 (R = benzyloxycarbonyl) was converted to the imino ether 49, which reacted with glycine to yield the amidine 50. Cyclodehydration of 50 by boiling in 2methoxyethanol led to the imidazo[ 1,241 [1,4]diazepine 52. The protecting group was removed by treatment with hydrogen bromide in glacial acetic acid. RN /
52
Condensation of 49 with 4-amino-N-methylpiperidine-4-carboxylic acid in boiling methanol gave the spiro compound 51 (R = benzyloxycarbonyl) directly in 45% yield. Removal of the protecting group followed by Eschweiler-Clarke methylation afforded 51 (R = Me). 1.2. Reactions
Although hydrogenation and quaternization reactions of 52 have been mentioned,'~'~experimental details are sparse and the products were not completely characterized.
2. Pyrido[1,2-d] [1,4]Diazepines
193
2. PYRIDO[l,Z-d] [1,4]DIAZEPINES
53
The parent ring system 53 has not yet been synthesized. Compounds with a quaternized pyridine ring were prepared by Blicke and Hughes'' by cyclization of 55 with sodium iodide in acetone to give 56. Compound 55 was obtained by chloroacetylation of the pyridine 54.
54
55
58 57
(16) The perhydro derivative 57 was accessible in good yield by hydrogenation of the quaternary salt 56 over platinum. Further reduction of 57 with lithium aluminum hydride (Eq. 16) gave 58. Compound 58 was also reported" to be formed upon reduction of 61 (R = H) with lithium aluminum hydride. The intermediate 61 was synthesized by quaternization of the chloroacetylpiperidine 59 to give 60, followed by thermal demethylation (Eq. 17). The phenyl analog 59
R
0
/
0
59
60
R
R
d 61
58: R = H
62: R = P h
1,4-Diazepineswith
194
[a]-
or [dl-Fused Rings
(R
= Ph) was obtained as a mixture of two diastereomers, which were separated by fractional crystallization. Both isomers were converted to their C I Irresponding perhydro derivatives 62. As previously mentioned [Section A.3.11, Schmidt reaction on the quinolizidine derivative 18 led to a mixture of the lactams 19 and 20. The major product 20 was obtained in 20% yield.4 Quaternization with methyl iodide (Eq. 18) gave the 6-methiodide 63, which underwent Hoffmann elimination to give the cis-olefin 64. The quaternary salt 63 could be regenerated in 29% yield by treatment of 64 with hydrogen iodide.
18
/
63
19
2o
64
Various 3-substituted perhydropyrido[ 1,2-d] [ 1,4]diazepines 66 were prepared by reaction of the dihalide 65 with amines (Eq. 19).5
65
66
Compound 66 [R = 2-(dipheny1methoxy)ethyll was disclosed in a patent7 and was prepared by alkylation of 66 (R = CH,CH,OH) with diphenylmethyl halide .
3. PYRROLO[l,Z-d] [1,4]DIAZEPINES This ring system may exist in any of the tautomeric forms 67a47e. The tautomers with an aromatic pyrrole ring 67a47c are considered to be thermodynamically favored. A representative of this bicyclic system was prepared containing a fully saturated diazepine ring. Thus, cleavage of the phthalimido protecting group of an appropriately substituted pyrrole 68 with aqueous hydrazine led to the tetrahydropyrrolo[ 1,2-d] [I1,4]diazepines 69 in yields of 27-37% (Eq. 2O).I3
195
3. Pyrrolo[1,2-d] [1,4]Diazepines
67c SH-PyrroloC 1,2-d][1,4]diazepine
67d 7H-Pyrroloc 1,2-d][1,4]diazepine
67e 9H-PyrroloC 1,2-d][1,4]diazepine
68
69
Previously, an octahydro analog had been prepared by Paquette and S ~ o t t , ~ who carried out a Schmidt reaction on the indolizine 70 (Eq. 21). This procedure gave 71 in 22% yield. As already described for the homologous pyrido[l,2-d] [l,rl]diazepine, 71 could be quaternized with methyl iodide to give 72. Hoffmann elimination gave the cis-@unsaturated compound 73 in 20% yield. Again, treatment of 73 with hydrogen iodide re-formed the quaternary 72 via transannular Michael addition.
72
73
z 0
z
-
W m
e
.m rI
I96
m
k k
w
c
N
m *
a
r
d
N
*-
m m
197
vi
v
w
Y
e. z
c
0,
vim
i
mvi
vim mvi
vim
198
w
o
z
r
a
-
2
W W
A
A
r-
0' vrI
5
63-65 225-226
Et,O MeOH
71
6
2-Me-4-(2-Furoyl) Monohydrate Dihydrochloride
49-50 228- 230
i-Pr,O MeOH
63
6 6
164-166 248-250 109-1 11 267-269
Acetone MeOH Acetone MeOH
46
146148 126-1 27
i-Pr,O i-Pr,O
47 46
145-146 254-255 121-1 24 243-244
i-Pr,O MeOH i-Pr,O MeOH
82 82
2-Me-4-[CH(OH)Ph] Isomer A Dihydrochloride Isomer B Dihydrochloride 2-Me-4-[CH(OH) (4-CIC,H4)] Isomer A Isomer B
c
$
6
2-Me-4-(4-FC,H,CO) Dihydrochloride
2-Me-4-[CH(OH) (4-MeOC,H4)] Isomer A Dihydrochloride Isomer B Dihydrochloride 2-Me-4-[CH(OH) (2-Naphthyl)] Isomers A and B 2-Me-4-[CH(OH) (2-Thienyl)] Isomer A Dihydrochloride
Isomer B Dihydrochloride 2-Me-4-[C(OH) (Ph),] Dihydrochloride
2-Me-4-[C(OH)(Ph)(4-FC,H4)] Dihydrochloride
2-Me-4-[C(OH)(Ph)(3-Indolyl)]
97.5
87-1 13 140-142 240-24 1 96-98 259-260
42
40 MeOH MeOH
41
124-126 272-273
IPE
90
134-1 35 281-283
MeOH MeOH
69
65-67
90
6 6
6
TABLE 111-1. 4 c o n t d . ) mp (" C); [bp (" Cjtorr)]
Solvent of Crystallization
Yield (%)
248-249
MeOH
65
6
291-298
D M SO/H 0
81
6
2-Me-4- [C( 0H) (4-F-C H ) Dihydrochloride
21&272
EtOH
I7
6
2-Me-4-[C(OH)(4-MeOC,H4),] Dihydrochloride
2 14-2 16
EtOH
90
6
224-225
MeOH
12
6
2-Me-4-[CH(Ph)(Morpholino)]
138-1 39
Petr ether
16
6
2-Me-4-(2-Naph thoyl) Dihydrochloride
92 198
Petr ether MeOH/Et,O
50
6 6
2-Me-4-(4-MeOC,H4CO) Dihydrochloride
2 14-21 6
EtOH
52
6
2-Me-4-(3-NO2C,H,CO) Dihydrochloride
22G22 1
MeOH
56
6
2-Me-4-(4-NO,C,H,CO) Dihydrochloride
185-186
MeOH
64
6
2-Me-4-(2-Thienoyl) Monohydrate Dihydrochloride
66-61 236-238
i-Pr,O MeOH
I1
Substituent 2-Me-4-[C(OH)(Ph)(4-MeOC,H4)] Dihydrochloride
2-Me-4-[C(OH)(Ph)(3-CF3C,H4)] Dihydrochloride
,
Spectra
Refs.
, ,,1
N
0
a
2-Me-4-[C(OH)(4-MeOC,H4)(2-Thienyl)] Dihydrochloride
6 6
W \ D
m
-
A A
W b d
L
.-
0.
20 I
r
r
r
>
-
W
9 /" m
W
2 .-i I )
2 2
2 22
203
i u
-?
-c
c pr
h
m
m m
m
m m
Y
m m
-a
, m Y
A
'0
A
m m
m 204
7 -
0
r
m m
0
9 mo
2,"
Y
m m
e
m m
a 2 -
0
-
m-f
M:: U
r+
m m
m
m m
r--
%!2 U
m
t-r-
m
m n
Y
d
d
205
3
a
,
N N O N N \ D
mddW 7""-
U
- N -
m - N m
m
$
-
1 P
m
n m
n
h
r-7
I
"1.
D. References
207
D. REFERENCES 1. A. Padwa and L. Gehrlein, J . Am. Chem. SOC.,94, 4933 (1972). 2. (a) M. Yamauchi and M. Masui, Chem. Pharm. Bull., 24, 1480 (1976). (b) M. Yamauchi and M. Masui, Chem. Ind., 31 (1976). 3. A. Fozard and G. Jones, J . Chem. SOC., 2763 (1974). 4. L. A. Paquette and M. K. Scott, J . Org. Chem., 33, 2379 (1968). 5. H. Kato and T. Mori, Ger. Offen., 2,141,464, March 1972 (Hokuriku Seiyaku Co., Ltd.). 6. H. Ulbrich, H. Biere, G. Paschelke, H. Wachtel, D. Palenschat, R. Horowski, and W. Kehr, Ger. Offen. 2,347,390, April 1975. 7. Japan Patent 74, 28,755, July 1974 (Hokuriku Pharm. Co. Ltd.); Chem. Abstr., 82, 156,396. 8. A. Morimoto and T. Watanabe, Japan Patent 74,27,877, July 1974 (Fujisawa Pharm. Co. Ltd.). 9. R. G. Groit, U.S. Patent 3,313,819, April 1967 (Sandoz, Hanover, NJ). 10. R. G. Groit, U.S. Patent 3,609,140, September 1971 (Sandoz, Hanover, NJ). 11. F. F. Blicke and J. L. Hughes, J . Org. Chem., 26, 3257 (1961). 12. H. Kato, T. Hishikana, and E. Koshinaka, U.S. Patent 4,093,630, June 1978 (Hokurika Pharm. Co. Ltd.). 13. H. Stetter and P. Lappe, Ann. Chem., 703 (1980).
This Page Intentionally Left Blank
CHAPTER IV
[l.41Diazepines with [b]=Fused Rings R . Ian Fryer Department of Chemistry. Rutgers. State University of New Jersey. Newark. New Jersey
and A. Walser Chemical Research Department. Hoffmann-La Roche Inc., Nutley. New Jersey
1. 1.5.Benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.1.1. From o-Phenylenediamines and 1,3-Dialdehydes . . . . . . . . . . . . . . . 1.1.2.From o-Phenylenediamines and 3-Ketoaldehydes (a-Hydroxymethylene-
214 214 214
ketones) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1.3. From o-Phenylenediamines and 8-Chlorovinylaldehydes or Ketones . . . 1.1.4. From o-Phenylenediamines and 1,3-Diketones . . . . . . . . . . . . . . . . 1.1.5. From o-Phenylenediamines and Acetylenic Ketones . . . . . . . . . . . . . 1.1.6. From o-Phenylenediamines and masked 1,3-Diketones . . . . . . . . . . . 1.1.7. Other Syntheses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1.8. Synthesis of 2(4)-Amino-1,5-benzodiazepines .................. 1.1.9. Synthesis of 2-Alkoxy-1,5-benzodiazepines . . . . . . . . . . . . . . . . . . . 1.1.10.Synthesis of 2.Alkylthio.l,5-benzodiazepines . . . . . . . . . . . . . . . . . .
216 216 217 220 220 220 222 224 224
1.2.Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2.1.Reactions with Electrophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2.1.1.Protonation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2.1.2.Halogenation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2.1.3.Nitration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2.1.4.Nitrosation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2.1.5.Reactions with Other Nitrogen Electrophiles . . . . . . . . . . . . . 1.2.1.6.Oxidation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2.1.7.Alkylation, Reactions with Aldehydes. . . . . . . . . . . . . . . . . . 1.2.1.8. Acylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2.2.Reactions with Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2.2.1.Hydrolysis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
225 225 225 226 227 228 228 228 230
209
230
233 233
[ 1.41Diazepines with [bl-Fused Rings
210
1.2.2.2. Reaction with Nitrogen Nucleophiles . 1.2.2.3. Reductions . . . . . . . . . . . . . . . . . 1.2.3. Miscellaneous Reactions . . . . . . . . . . . . . . 1.2.4. Metal Complexes . . . . . . . . . . . . . . . . . .
................. ................ ................ ................ 1.3. Spectral and Physical Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
236 238 238 238 239
2. Dihydro- 1 ,5-Benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
240
2.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
240
2.1.1. 2.1.2. 2.1.3. 2.1.4. 2.1.5. 2.1.6. 2.1.7.
From o-Phenylenediamines and @-Unsaturated Aldehydes . . . . . . . . . From o-Phenylenediamines and a,8-Unsaturated Ketones . . . . . . . . . . Condensation of o-Phenylenediamines with 8-Haloketones . . . . . . . . . From o-Phenylenediamines and 8-Aminoketones . . . . . . . . . . . . . . From o-Phenylenediamines and 8-Hydroxyketones . . . . . . . . . . . . . By Partial Reduction of 1,5-Benzodiazepines . . . . . . . . . . . . . . . . Other Syntheses. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2. Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.1. Reactions with Electrophiles . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.1.1. Nitrosation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.1.2. Oxidation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.1.3. Alkylation and Reactions with Aldehydes . . . . . . . . . . . . . . . 2.2.1.4. Acylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.2. Reactions with Nucleophiles. . . . . . . . . . . . . . . . . . . . . . . . . . . .
240 241 241 242 242 243 243 244 244 244 244 244 245 246
2.3. Spectral Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
246
3. Dihydro-1,5-Benzodiazepin-2-ones ...............................
247
3.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
247
3.1.1. 3.1.2. 3.1.3. 3.1.4. 3.1.5.
From o-Phenylenediamines and b-Ketoesters . . . . . . . . . . . . . . . . . . From o-Phenylenediamines and Diketene . . . . . . . . . . . . . . . . . . . . From o-Phenylenediamines and Cyclobutenediones . . . . . . . . . . . . . . Other Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Dihydrobenzodiazepin-2-ones with Heteroatom Substituents in Position 4
3.2. Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.1. Reactions with Electrophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.1.1. Halogenation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.1.2. Nitration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.1.3. Nitrosation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.1.4. Reactions with Other Nitrogen Electrophiles . . . . . . . . . . . . . 3.2.1.5. Oxidation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.1.6. Alkylation and Reaction with Aldehydes . . . . . . . . . . . . . . . . 3.2.1.7. Acylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.2. Reactions with Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.2.1. Hydrolysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.2.2. Reactions with Nitrogen Nucleophiles . . . . . . . . . . . . . . . . . 3.2.2.3. Reactions with Carbon Nucleophiles (Carbanions) . . . . . . . . . . 3.2.2.4. Reactions with Sulphur Nucleophiles . . . . . . . . . . . . . . . . . . 3.2.2.5. Other Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.2.6. Reduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.3. Pyrolysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
247 251 251 253 254 256 256 256 256 258 258 259 259 261 262 262 263 264 265 266 266 267
3.3. Spectral Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
268
4 . Tetrabydro-IH-1,SBenzodiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
269
4.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
269
[l.4lDiazepines with [bl-Fused Rings
21 1
4.1.1. By Alkylation of o-Phenylenediamine Derivatives . . . . . . . . . . . . . . . 4.1.2. By Aromatic Substitution or via Benzynes . . . . . . . . . . . . . . . . . . . 4.1.3. By Cyclodehydration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.4. By Reduction of 1,5-Benzodiazepines and 2,3-Dihydro.lH.l, 5-benzodiazepines 4.1.5. By Reduction of Benzodiazepinones . . . . . . . . . . . . . . . . . . . . . . . 4.1.6. By Addition of Hydrogen Cyanide to Imine Bonds . . . . . . . . . . . . . . 4.1.7. Other Syntheses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
269 270 271 27 1 272 272 273
4.2. Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
274
4.2.1. Reactions with Electrophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.1.1. Nitrosation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.1.2. Oxidation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.1.3. Alkylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.1.4. Acylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.2. Reactions with Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.3. Photoreactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
274 274 275 275 275 276 276
4.3. Spectral Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
277
............................... 5.1. 1.3.4,STetrahydro. 1.5.benzodiazepin.2(2H)-ones . . . . . . . . . . . . . . . . . . . . 5.1.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1.1.1. o-Phenylenediamine and a,8-Unsaturated Carboxylic Acids . . . . 5.1.1.2. o-Phenylenediamine and j-Halocarboxylic Acids . . . . . . . . . . . 5.1.1.3. By Ring Closure of o-Phenylenediamine Derivatives . . . . . . . . . 5.1.1.4. By Ring Expansion (Schmidt Reaction) . . . . . . . . . . . . . . . .
278
5 . Tetrahydro.1,5.Benzodiazepinones
5.1.1.5. By Reduction of 1,3.Dihydro.1,5-benzodiazepin-2(2H)-ones . . . . 5.1.1.6. Other Syntheses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1.2. Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1.2.1. Reactions with Electrophiles . . . . . . . . . . . . . . . . . . . . . . . A. Halogenation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Nitrosation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C. Oxidation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . D. Alkylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . E. Acylation, Reaction with Aldehydes . . . . . . . . . . . . . . . . . . . . 5.1.2.2. Reactions with Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . A . Hydrolysis, Alcoholysis . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Substitution Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . C. Reductions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
.
278 278 278 278 279 280 281 281 282 282 282 283 283 283 284 286 286 287 287
5.2. 1,2,4,5-Tetrahydro-l,5.benzodiazepin.3(3H)-ones . . . . . . . . . . . . . . . . . . . .
288
5.2.1. Synthesis . . . . . . . . . . . . . . . . . 5.2.2. Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
288 289
6. Tetrahydro-1, 5-Benzodiazepinediones and Triones . . .
289
6.1. 3,5-Dihydro-lH-l,5.bnzodiazepine-2,4(2H,4H )-diones . . . . . . . . . . . . . . . .
289
6.1.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1.1.1. o-Phenylenediamine and Malonic Acid or Esters . . . . . . . . . . . 6.1.1.2. o-Phenylenediamine and Malonyl Chlorides. . . . . . . . . . . . . . 6.1.1.3. By Cyclization of o-Aminoanilides . . . . . . . . . . . . . . . . . . . 6.1.1.4. By Oxidation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1.1.5. Other Syntheses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1.2. Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1.2.1. Reactions with Electrophiles . . . . . . . . . . . . . . . . . . . . . . . A . Halogenation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
289 289 290 291 291 292 293 293 293
212
[ 1. 41Diazepines with [bl-Fused Rings B. Nitration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C. Nitrosation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . D . Reactions with Other Nitrogen Electrophiles . . . . . . . . . . . . . . E . Oxidation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . F. Alkylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . G . Acylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1.2.2. Reactions with Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . A. Hydrolysis and Alcoholysis . . . . . . . . . . . . . . . . . . . . . . . . . B. Substitution Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . C. Reduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2. 1,5.Dihydro.1,5.benzodiazepine-2,3,4(2H.3..4. ).triones . . . . . . . . . . . . . . . 6.2.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2.2. Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3. Spectral Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7. 1,5.Benzodiazepinethiones . . . . . . . . . . . . . . . . . . . . . . . . . . 7.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.1.1. o-Phenylenediamine and Thioacid Derivatives . . . . . . . . . . . . . . . . . 7.1.2. By Thiation of Lactam Oxygen . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2. Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2.1. Reactions with Electrophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2.2. Reactions with Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . .
293 293 293 294 294 296 298 298 301 302 303 303 303 304 305 305 305 306 307 307 307
7.3. Spectral Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
308
8. Hexahydro-1, 5.Benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
308
....................
308
8.1.1. Synthesis and Spectral Data . . . . . . . . . . . . . . . . . . . . . . . . . . . .
308
8.2. 2,3,4,6,7,8.Hexahydro.lH.l, 5-benzodiazepines . . . . . . . . . . . . . . . . . . . . .
309
8.2.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.2.2. Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
309 309
8.1. 5a,6,7.8.9.9a.Hexahydro.lH-l. 5.benzodiazepines
9. Perhydro- 1H-1,5-Benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . .
310
10. Cyclobuta[b] [1.4ldiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
310
11 . Cyclopenta[b] [l. 4ldiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
311
12. Isoxazolo[4. 5-b] [1.4ldiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
312
12.1. Synthesis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12.2. Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
312 312
13. 1,2.5.0xadiazolo[3. 4.b] [l.4ldiazcpines . . . . . . . . . . . . . . . . . . . . . . . . . . . .
313
14. Pyrazolo[3. 4 4 1 [1,4ldiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
313
14.1. Synthesis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14.2. Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14.3. Spectral D a t a . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14.4. 4.8-DihydropyrazoloC3, 4.b] [ 1.4ldiazepin.5. 7( 1 H.6H ).diones . . . . . . . . . . . . . .
314 315 316 316
15. PyridoCb] [l,4ldiazepines
317
..............
15.1. Pyridol2. 3 4 1 [ I , 4ldiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15.1.1. Dihydropyrido[2, 3.b] [1.4]diazepines . . . . . . . . . . . . . . . . . . . . . 15.1.2. Dihydropyrido[Z. 3 4 1 [1,4ldiazepinones . . . . . . . . . . . . . . . . . . . 15.1.3. Tetrahydropyrido[2. 3.b] 11.4ldiazepines . . . . . . . . . . . . . . . . . . .
317 318 318 318
1. 1,5.Benzodiazepines 15.1.4. Tetrahydropyrido[2. 3-b] [1,4]diazepinones . . . . . . . . . . . . . . . . . . 1.5.1.5. Tetrahydropyrido[2, 3-b] [1,4]diazepinediones . . . . . . . . . . . . . . . . 15.2. PyridoC3,4-b] [l.4ldiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15.2.1. Dihydropyrido[3, 4-b] [1,4]diazepinones . . . . . . . . . . . . . . . . . . . . 15.2.2. Tetrahydropyrido[3, 4.b] [l,4ldiazepines and diones . . . . . . . . . . . . 15.3. Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15.3.1. Reaction with Electrophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . 15.3.2. Reaction with Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . 15.3.3. Thermal Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
213 320 321 322 322 323 323 323 324 324
16. PyrimidoC4,541 [1,4]Diazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16.1. Dihydropyrimido[4,5.b] [l, 4ldiazepinones . . . . . . . . . . . . . . . . . . . . . . 16.2. TetrahydropyrimidoL4,5.b] [1,4]diazepinones . . . . . . . . . . . . . . . . . . . . . 16.3. HexahydropyrimidoL4,541 [1,4]diazepinones . . . . . . . . . . . . . . . . . . . . . 16.4. Octahydropyrimido[4. 5.b] [l,4ldiazepinones . . . . . . . . . . . . . . . . . . . . . 16.5. HexahydropyrimidoL4,5-b] [1,4]diazepine-2.thiones . . . . . . . . . . . . . . . . . 16.6. Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16.6.1. Reactions with Electrophiles. . . . . . . . . . . . . . . . . . . . . . . . . . . 16.6.2. Reactions with Nucleophiles. . . . . . . . . . . . . . . . . . . . . . . . . . . 16.6.3. Pyrolysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
325 325 326 327 329 329 330 330 330 331
17. Pyrrolo[3.4.b] [ l . 4ldiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
331
18. TriazoloC4.5-b] [1,4]diazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
332
19. Tables of Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
334
20. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
420
INTRODUCTION This chapter reviews bicyclic systems of general structure 1. The extensive work carried out in the area of 1.5.benzodiazepines is given precedence over other ring systems. which are subsequently described in alphabetical order . The synthesis and reactions of these [bl-fused [1.4ldiazepines are divided into subsections based on the degree of saturation of the ring system .
Previous reviews of this general area have been carried out by D. Lloyd and H . P. Cleghorn (in Advances in Heterocyclic Chemistry. Vol. 17. A . R . Katritzky and A . J . Boulton. Eds., Academic Press. New York and London. 1974. p . 27); G. A . Archer and L . H . Sternbach [Chem. Rev., 68. 747 (1968)l; F. D. Popp and A . C . Noble (in Advances in Heterocyclic Chemistry. Vol . 8. A . R . Katritzky and
214
[ 1,4]Diazepines with [bl-Fused Rings
A. J. Boulton, Eds., Academic Press, New York and London, 1967, p. 21); J. A. Moore and E. Mitchell (in Heterocyclic Compounds, Vol. 8, R. C . Elderfield, Ed., Wiley, New York, 1967, p. 224); and E. Schulte [Dtsch. Apothek. Z., 115, 1253 ( 19791.
1. 1,5-BENZODIAZEPINES
2b
2a 1 H - 1.5-Benzodiazepines
3H-1,5-Benzodiazepines
1,5-Benzodiazepines may exist in either of the tautomeric forms 2a or 2b. While the 3H tautomer is, in general, thermodynamically preferred, monoprotonation renders the 1H tautomer energetically more favorable, and most of the salts of 1,5-benzodiazepines occur in this form. For this reason the tautomers are not disscussed separately.
1.1. Synthesis
The most common method of synthesis is the condensation of orthophenylenediamines with 1,3-dicarbonyl compounds.
1.I . I . From o-Phenylenediamines and 1,3-Dialdehydes The parent compound 2a was prepared’ and isolated in the form of various salts by the reaction of o-phenylenediamine 3 with l-ethoxy-1,3,3-trimethoxypropane in ethanol-acetic acid followed by treatment of the mixture with a strong acid to form the salt. Reaction of the diamine 3 with malondialdehyde 4 (R = H) (Eq. 1) under neutral conditions at room temperature led only to the monoimine 5 (R = H). Phenylmalondialdehyde gave, according to Rupe and Huber,’ a red benzodiazepine (7, R = Ph) incorrectly assigned the 1H-tautomeric structure. Ruske and Hiifner3 obtained the same compound 7 (R = Ph) and demonstrated with the help of infrared spectra that the red benzodiazepine was actually the 3H tautomer. The same tautomer was also isolated in the synthesis of the 3-bromo derivative 7 (R = Br), prepared in 33% yield3 from the diamine and bromomalondialdehyde 4 (R = Br). Both the 3-phenyl- and the 3-bromobenzodiazepine gave lighter colored hydrochloride salts and apparently undergo protonation
215
1. 1,5-Benzodiazepines
aNH2 +
NH,
H
3 4
6
without tautomerization. A blue-black hydrochloride salt of the 3-phenyl derivative, which is most probably the protonated 1H tautomer, was observed3 when a different synthesis was used. Reaction of the phenylenediamine with nitromalondialdehyde 4 (R = NO,) in hot, dilute hydrochloric acid gave the highly insoluble red benzodiazepine 7 (R = N0,).495The 7-chloro derivative was obtained6 in an analogous manner from 4-chloro-l,2-phenylenediamine. Another example involving a substituted malondialdehyde was published more recently. o-Phenylenediamine was condensed with the dialdehyde 4 (R = 6-chloro-2-benzoxazolyl) in propanol while maintaining the pH between 3 and 5 by addition of formic acid. The corresponding benzodiazepine 7 was isolated in 70% yield, again as a red c o m p o ~ n d . ~ Derivatives of malondialdehydes such as the enamine 6 have also been employed5 in the preparation of the 3-nitrobenzodiazepine 7 (R = NO,). Thus, condensation of 6 with the diamine 3 gave 7 and 4-aminobenzoic acid ethyl ester (Eq. 1). A stepwise approach to the synthesis of 1,5-benzodiazepines was demonstrated by Rupe and Huber,’ who obtained the 3-phenylbenzodiazepine 7 (R = Ph) by a reductive cyclization of the nitro compound 8 using either iron in acetic acid or tin in hydrochloric acid as the reducing agent (Eq. 2). The latter
+
CHO FPh CHO
8
7
216
[1,4] Diazepines with [bl-Fused Rings
method led to a blue-black hydrochloride salt, most likely the protonated 1H tautomer.
I .I .2. From o-Phenylenediarnines and 3-Ketoaldehydes (a-Hydroxyrnethyleneketones) Weissenfels and coworker^^^^ studied the condensation of o-phenylenediamine with various a-hydroxymethyleneketones. Initially, these authors prepared tricyclic 1,5-benzodiazepines from a-formylcycloalkanones,8 and later they a p ~ l i e d ~this . ~ ' reaction ~ to the aliphatic compounds 9. The primary products 10, were isolated and cyclized to 11 by means of perchloric acid in alcohol (Eq. 3).
NH
HO
10
9
HCIO,/EtOH
(3)
I .I .3. From o-Phenylenediarnines and 8-Chlorovinylaldehydes or Ketones It has been found that 1,5-benzodiazepines are also accessible, and can be synthesized in good yield, by the condensation of o-phenylenediamine with b-chloro-a,j-unsaturated aldehydes 12 (Eq. 4).This method was first applied to
R1
12
13 /
14
(4)
1. 1,5-Benzodiazepines
217
l-formyl-2-chlorocycloalkenes'oand later extended to the b-chlorocinnamaldehydes 12 (R, = Ph)." The same route was also used successfully to prepare l-methyl-l,5-benzodiazepines 14 (R, = Me)', from N-methyl-o-phenylenediamine. The imines 13 were shown' to be intermediates in this synthesis. Ruske and Grimm', have also demonstrated that 2-methyl-lH-1,5benzodiazepine hydrochloride (14, R, = R, = H, R, = Me) can be obtained by the condensation of o-phenylenediamine with b-chlorovinyl methyl ketone in ethanolic hydrogen chloride. Reaction of the dimethyldiamine 15 with the 8-chloroaldehyde 16 afforded the quaternary salt 17 (Eq. 9.'' Me
aNH I
Me TH
C1
+
Me I
Ph
Ph
OHCx16p h
15
a N > NpZ h
C10,
(5)
Me I 17
1.1.4. From o-Phenylenediamines and 1,3-Diketones The prototype of this reaction was the condensation of o-phenylenediamine 18 (R, = H) with pentane-2,4-dione 19 (R, = R, = Me), first described by Thiele
and Steimmig14 in 1907. This method has been widely used for the synthesis of variously substituted 1,5-benzodia~epines.~~~ The reaction was shown to be pHdependent,'^'^ and the best yields16.17 were obtained under slightly acidic conditions. The benzodiazepines were generally isolated as the deeply colored salts of the lH-tautomeric form 20. According to Schwarzenbach and Lutz,'* liberation of the base leads to the short-lived, yellow lH-benzodiazepine 21, which spontaneously tautomerizes to the more stable 3H isomer 22 (Eq. 6).
19
21
20
22
[ 1,4]Diazepines with [bl-Fused Rings
218
Substituted phenyl derivatives of 2,4-dimethyl-l,5-benzodiazepineshave been prepared by the same procedure. 9-25 A 2-methoxymethyl derivative' were obtained by the conand the 2,4-di(bromomethy1)-1,5-ben~odiazepine~~ densation of o-phenylenediamine with an appropriately functionalized pentane2,4-dione. The synthesis of 2-phenyl-4-methyl-l,5-benzodiazepinedescribed long ago by Thiele and SteimmigI4 was repeated.'6927.2' Matsumoto and coworkers2' claimed to have obtained the 1H tautomer as a hydrate by condensation of benzoylacetone with o-phenylenediamine in boiling xylene containing a catalytic amount of p-toluenesulfonic acid. It is more likely that this hydrate is identical to the uncyclized primary adduct 23 (R2 = Me, R, = Ph) (Eq. 7 ) described by Sulca and coworkers.29 Several analogs with substituents in the 2-phenyl group were prepared' 6,30,304 using Thiele's procedure or by heating under reflux a propanol solution of o-phenylenediamine with the appropriate 1,3-dione in the presence of molecular sieves.,' Thus, treatment of the diamine with the appropriate heteroaroylacetones has been shown to give 2-(2-selenophenyl)-4-methyl-1,5b e n ~ o d i a z e p i n e , ~2-(3-ethoxy-2-quinoxalyl)-4-methyl-1,5-ben~odia~epine,~~ ~ and 2-(4-hydroxy-3-coumarinyl)-4-methyl-1,5-ben~odia~epine.~~ '9'
18
19
23
1,5-Benzodiazepines bearing polyfluoroalkyl substituents in the 2- and/or 4-position were also prepared in good yield,, 5a,b provided the second substituent in the 2- or 4-position was either phenyl or perfluoroalkyl. The proportion of uncyclized primary product 23 recovered from the reaction was found to increase as the polyfluoroalkyl chain was extended in length. required more vigorous The formation of 2,4-diaryl-3H-1,5-benzodiazepines conditions than those chosen by Thiele and Steimmig.14 Thus, Finnar36 obtained 2,4-diphenyl-3H- 1,5-benzodiazepine in 50% yield by condensation of dibenzoylmethane with o-phenylenediamine in boiling ethanol containing acetic acid. A comparable yield was reported by Barltrop and coworkers,16 who performed this condensation in boiling xylene in the presence of p-toluenesulfonic acid with azeotropic removal of water. Eiden and Heja33v37 as well as Kulkarni and Thakar,38*39 synthesized substituted 2,4-diphenyl-3H-1,5benzodiazepines using acetic acid in combination with other solvents at elevated temperatures. The latter workers favored the lH-tautomeric structure on the basis of infrared spectra, but nmr indicate that the 3H-tautomer is preferred. The reactions of o-phenylenediamine with 1,3,4-triones 24 afforded the 1,5-benzodiazepines 25. The formation of quinoxalines 26 was not observed.
1. 1,5-Benzodiazepines
26
219
H 27
,
Thus, condensation of the diamine with hexane-2,3,5-trione 24 (R = R, =Me) was reported to yield 2-acetyl-4-methyl-3H-1,5-benzodiazepine (25; R, = Ac, R, = Me),40 while reaction with 1,6-diphenylhexane-l,3,4,6-tetraone yielded 83% of the corresponding benzodiazepine 25 (R, = Ph, R, = CH,COPh).36 A similar compound was obtained from the corresponding octane-2,4,5,7-tetraone. In this instance the remaining 1,3-dicarbonyl system reacted with phenylhydrazine to yield as the final product the pyrazolyl derivative 28.36 The structure of 4-methyl-l,5-benzodiazepine-2-carboxylic acid was tentatively assigned to the product obtained by condensation of o-phenylenediamine of 4-aryl-1,5-benzowith acetylpyruvic acid.41 More r e ~ e n t l y , ~ ,anilides ,~~ diazepine-2-carboxylic acids were prepared from the diamine and aroylpyruvic acid anilides. In this case, the formation of the quinoxalones 27 was also observed. Interestingly, the electronic character of the aroyl group was found to be the determining factor in the formation of either the quinoxalone 27 or the benzodiazepine 25. Thus, electron-donating groups in the para position of the benzoyl group promoted benzodiazepine formation, while electron withdrawing substituents favored the formation of a quinoxalone. Using the appropriate 1,3-diketone, condensation with o-phenylenediamine allowed the preparation of 3-substituted 1,5-benzodiazepines.Among the compounds obtained in this manner were the 2,3,4-trimethyl d e r i ~ a t e ,various ~~.~~ 3-arylsulfonyl derivative^,^^ the 3-benzoyl-2,4-diphenyl-1,5-benzodiazepine,z9 the 3-oximino-2,4-dimethyl-1,5-benzodiazepine,'4~47~48 and 3-diphenylmethylene-l,5-benzodia~epine.~~
220
[ 1,4]Diazepines with [bl-Fused Rings
1 . I .5. From o-Phenylenediamines and Acetylenic Ketones The synthesis of 1,5-benzodiazepines of type 22 by the reaction of ophenylenediamines 18 with acetylenic ketones 29 (Eq. 9) has been reported both by Ried and Koenig” and by Andreichikov and coworker^.^^*^^ In particular this method has been applied to the preparation of variously substituted 2,4diphenyl-3H-1,4-ben~odiazepines.~~-~~ The reaction has been carried out in boiling ethanol,52 methanol, or mixtures of ethanol and acetic a ~ i d . ’ The ~,~~ melting points reported for 2,4-diphenyl-7-methy1-3H-1,4-ben~odiazepine~~.~~ differ widely. The lower melting point reported by Amey and H e i ~ ~ dwould el~~ be more in line with those of closely related compounds.
22
1 . I .6. From o-Phenylenediamines and Masked 1,3-Diketones Van Allan and Chie Chang55 obtained 2-phenacyl-4-phenyl-1H-13benzodiazepines 33 by rearrangement of the pyrone derivatives 30 (Eq.10). The rearrangement was effected using 1,l-dimethylhydrazine in boiling acetonitrile. The starting imino-4H-pyranes 30 were synthesized by the addition of an appropriate o-phenylenediamine to the corresponding pyrylium salt, generated with phosphorus oxychloride. It was postulated5’ that the pyrone is opened by dimethylhydrazine via 31 to form intermediate 32, which, for steric reasons, would cyclize exclusively to the benzodiazepine rather than to the pyridine. The location of the substituent X in 33 has not been unequivocally established. On the basis of the nmr spectrum, the 1H-tautomeric form was assigned to 33 (X = H). The 3H tautomer 34 with an enolized carbonyl would fit the spectral data also. 2,4-Diphenyl-3H- 1,5-benzodiazepines 37 were accessible in 7&80% yields by hydrogenation of the isoxazolones 35 over palladium on carbon.56 Reductive cleavage of the N-0 bond would lead, as shown, to the intermediate 36, which would then cyclize with concomitant decarboxylation to yield the observed product 37 (Eq. 11).
1.1.7. Other Syntheses Bindra and Le G ~ f incorrectly f ~ ~ reported the unexpected formation of 2benzoyl-Cphenyl- 1H- 1,5-benzodiazepine 39 by reaction of o-phenylenediamine
221
1. 1,5-Benzodiazepines
MelNNH, I h reflux
MeCN
30
NMe,
/
33
X
ax
Ph
34
Ph
35
with 1,2-dibenzoylethylene in boiling acetic acid. Bass and coworkers58 reinvestigated this reaction and were able to show that the product was actually the quinoxaline 40, formed by dehydrogenation of the intermediate dihydro derivative 38 (Eq. 12).
[ 1,4]Diazepines with Cbl-Fused Rings
222
Ph
Ph 39
38
40
1.1.8. Synthesis of 2 (4)-Amino-l,5-benzodiazepines Okamoto and Ueda5’ obtained the 3H-1,5-benzodiazepines 42 in high yields by cyclization of the P-anilinoacrylonitriles 41 (R, = CN, COOEt). The starting materials were prepared by condensation of o-phenylenediamine with either ethoxymethylenemalononitrile or ethyl ethoxymethylenecyanoacetate. Reaction of 42 (R, = CN, R, = H) with aqueous guanidine or methylguanidine gave 44 (Eq. 13) instead of the expected the 2,4-diamino-3H-1,5-benzodiazepine pyrimidobenzodiazepine. The same compound was also formed by alkaline
41
42
(13)
1. 1,5-Benzodiazepines
223
hydrolysis of the nitrile 42 (R, = CN, R, = H). This conversion was mechanistically explained by an opening of the ring to form the intermediate hydroxymethylene derivative 43, which could then recyclize and decarbonylate to yield the diamine 44. In a later paper,60 Okamoto and Ueda described syntheses of some 8-chloro derivatives 42 (R, = Cl). A high yield s y n t h e s i ~ of ~ ~2-amino-4-(2-chlorophenyl)-3H-1,5-benzo,~~~ diazepine 46 involved the condensation of the acetylenic imidate 45 with o-phenylenediamine (Eq. 14).
c1-
45 46
Reaction of o-phenylenediamines with N-alkyl-N-phenylethoxycarbonylacetamides (47) and phosphorus oxychloride at elevated temperature gave the 2,4-disubstituted 3H-1,5-benzodiazepines 4962 in low yield, most likely via a 2-amino-4-chloro intermediate 48 (Eq. 15).
R 2 G N H 2 NH2
+
c1
oqcooEt POCI,
R 2 G ; l NPh
I
NPh
I
R1
RI 41
/
48
POCI,. 47
Ph
bf
R 2 a N fN' R ' N Ph
I
R1
49
The most widely used method3169319for the preparation of 2- and or 4-amino-1,5-benzodiazepines 51 is the displacement of the methylthio group in 50 with an amine (Eq. 16).
224
[ 1,4]Diazepines with [bl-Fused Rings
Using this displacement reaction, a variety of 2-cycloalkylamino-4-phenyl3H-1,5-ben~odiazepines~~~~~ and 2,4-diamino derivative^^^ were synthesized.
1.I .9.Synthesis of 2-Alkoxy-l,5-benzodiazepines This class of iminoethers has not been extensively investigated. S t a ~ h e l ~ ~ claimed to have obtained the 2-ethoxy-lH-l,5-benzodiazepine 53 in about 20% yield by the condensation of a-phenylenediamine with the ketene acetal 52 (X = S) in methanol solution and at room temperature (Eq. 17). While the different reactivity of the 0- and S-ketene acetals allowed the isolation of the monoadduct 53, the analogous reaction of the bisketene acetal52 (X = 0)led to the bis( 1,5-benzodiazepine) 54 in better yield. The structures assigned to 53 and 54 lack spectroscopic support.
H
0
XEt 53
52
OEt
0
SEt
12 54
1.1.10.Synthesis of 2-Alkylthio-l,5-benzodiazepines The title compounds 56 have been exclusively prepared by the standard method, alkylation of the corresponding thiones 55 (Eq. 18). Following their initial p ~ b l i c a t i o n Nardi , ~ ~ and coworkers prepared a series of thioethers 56 (R, = substituted phenyl, R, = basic side chain^).^*^^^.'^ In connection with a mass spectrometric analogs in which R, was -Ac or
225
1. 1,5-Benzodiazepines
55
56
-CD, were synthesized. Utilizing the procedure above, several 2-methylthio compounds were ~ r e p a r e d as ~ ~intermediates -~~ for the synthesis of the corresponding 2-amino derivatives. Nardi and coworkers72 also investigated the alkylation of the thiones 57 (R, = Me or CH,Ph), but isolated only the alkylation product 58 (R, = CH,CH,NEt,) in a crude state. Acylation of 57 (R, = Me or CH,Ph) with acetic anhydride, on the other hand, led to the crystalline acetylthio derivatives 58 (R, = Ac) (Eq. 19).
Peseke described7, and patented74 the preparation of the 2-hydroxy-4methylthio- 1H - 1,5-benzodiazepine-3-carboxylate60 by mild acid hydrolysis of the amidine 59 (Eq. 20).
59
60
(20)
In view of the insufficient spectral evidence presented, other tautomeric structures for 60 might also be considered. 1.2. Reactions
1.2.1. Reactions with Electrophiles 1.2.1.1. Protonation 1,5-Benzodiazepines (61) are weak bases and are protonated by strong acids to form deeply colored monocations. The color of the cations is attributed to the protonated lH-tautomeric form 62, in which the charge is delocalized (Eq. 21).
[1,4]Diazepines with [bl-Fused Rings
226
62
61
Strong acids in nonaqueous systems convert the colored cation to a colorless dication 63.The pK, for the first protonation of the 2,4-dimethyl derivative was determined to be 4.5 by potentiometric method^^^-'^ and 5.76 by spectroscopic means.77 The pK, for the monocation4cation equilibrium appears to be approximately - 1 . 0 . ' ~ ~ ~ 1.2.1.2. Halogenation Bromination of 2,4-dimethyl-3H-1,5-benzodiazepine(64, R = Me) with bromine in a mixture of acetic acid and nitromethane, was reported33 to yield the 3-bromo derivative 65 as the hydrobromide salt (Eq. 22). This method was also used79for the synthesis of the 2,4-diphenyl derivative 65 (R = Ph). Reaction of 64 (R = Me) with bromine in chloroform led to the hydrobromide of the
Br,/AcOH/McNO,
Br HBr
R=Me.Ph
R 65
64
R
a;p""
.HBr
Me 66
CHBr, 67
1. 1,s-Benzodiazepines
221
bromomethyl derivative 66.l 9 Treatment of the hydrogen sulfate salt of 64 (R = Me) with bromine in acetic acid afforded the tetrabromo derivative 67.19 Lloyd and coworkers’ had prepared the same tetrabromo compound previously but had assigned an incorrect structure. Further bromination of 67 in acetic acid at room temperature led to a nonabromide, which was assigned structure 70 (Eq. 23). This compound was also obtained by bromination of 68 via the hexabromide 69. Hydrogenation of 70 over platinum on carbon” led to the hexabromide 69. CHBr, Br,,AcOH ___)
Br
Br Me
CHBr, 69
68
(23) CBr,
CBr, 70
1.2.1.3. Nitration The direct introduction of a nitro substituent into the 1,5-benzodiazepine nucleus has not been reported. While an initial attempt to nitrate the benzodiazepine 71 led only to tars, Levshina and coworkers,80 using a nitration mixture of nitric and sulfuric acids (Eq. 24), were able to isolate compounds 72, 73, and 74 in 40, 26, and 8% yields, after fractional crystallization.
71
12
H
74
73
[ 1,4]Diazepines with
228
[bl-Fused Rings
The products may be rationalized as being formed by a combination of electrophilic attack at the 3-position, acid hydrolysis, and oxidative ring cleavage. The benzotriazole 74 probably arose from nitrosation of o-phen ylenediamine. 1.2.1.4. Nitrosation Barltrop and coworkers,’6 who studied the action of nitrous acid on the benzodiazepine 71, found that the major products of this reaction were the quinoxaline 73 and 2-methylbenzimidazole (75). A nitroso derivative assigned the 1,5-benzodiazepine structure 76 was also isolated in low yield (Eq. 25).
aExAc H
NaNO,. AcOH
+ a N &NM e
Me
13 ,”
Me I V l b
75
71
+ Me 76
This reaction is believed to proceed via initial formation of the N-nitroso compound 76, which then undergoes further transformations to give the major reaction products 73 and 75.
1.2.1.5. Reactions with Other Nitrogen Electrophiles Diazonium cations have also been reported to react at the 3-position of 1,5(77) benzodiazepines. Thus, coupling of 2,4-diphenyl-3H-1,5-benzodiazepine with 4-nitrobenzenediazonium cation led to a product which was assigned the phenylhydrazone structure 78 (Eq. 26).16
a;$h x
77
Ph
+ N 2 0 N o l
*
a l $ N - - N H a N o 2 I8
Ph (26)
1.2.1.6. Oxidation As with nitration and nitrosation, the reaction of 1,5-benzodiazepines 79 with peracids led to products of either ring cleavage or ring contraction (Eq. 27).
1. 1,5-Benzodiazepines
229
Thus, treatment of 79 with monopersulfuric acid, or preferably peracetic acid, gave the 2-acetylquinoxalines 80 (R, = Me, R, = Me, Ph).I6 On the other hand, oxidation of the 2,4-diphenyl derivative 79 (R, = R, = Ph) with aqueous peracetic acid gave the diamide 81 together with the minor products 82-84.'l It was speculated'' that 80 and 81 arose from different reaction paths, but it is more likely that the aqueous reaction medium is responsible for the predominance of ring cleavage over ring contraction in the case of the 2,4-diphenyl derivative.
a:$'
R, = Peracid Me, R, = Ph
R*
79
1.:
*
80
H,O,. AcOH = R, = P ;
II
H
NHCPh
(27)
+ N
NHC-CH-Ph XI
II
I
82
0 OH 0
mH-cph a 11
NO2
83
0
II
NHCPh
+
84
NHCPh 11 0
Photooxidation of the benzodiazepines 79 also led to the ring-contracted products 80 (Eq. 28). Interesting solvent effects were observed in this reaction." Thus irradiation of a benzene solution of 2-methyl-4-phenyl-3H-1,5benzodiazepine with a high pressure mercury arc under an oxygen atmosphere led to 2-benzoyl-3-methylquinoxaline(80; R, = Ph, R, = Me) in 25% yield, while in acetic acid solution, 2-acetyl-3-phenylquinoxaline was obtained, as in the peracid oxidation. Photooxidation of 2,4-dimethylbenzodiazepine in 0.1 N sulfuric acid gave 2-methylbenzimidazole as the major product and only 5% of the quinoxaline 80 (R, = R, = Me). The quinoxalin-2(1H)-one 85 that was isolated as a by-product was shown to be a photooxidation product of the 2-acyl-3-methylquinoxaline 80 (R, = Me). In the case of the 2,4-diphenylbenzodiazepine,photooxidation in benzene gave low yields of both the 3-one 86 (R, = R, = Ph) and the ring-open diamide The 3-ones 86 are believed to be precursors of the 2-acylquinoxalines in both
[ 1,4]Diazepines with [bl-Fused Rings
230
alil 79
R2
0z.hv
.
a:xo H
a ; e R R,O,.hv 1 = Me ~
Me 80
85
J
87
(28) peracid and photochemical oxidation reactions. Photochemical oxidation may proceed via the intermediate valence tautomer 87, while in the peracid oxidation it is probable that 86 undergoes solvolytic ring opening followed by reclosure with ring contraction. 1.2.1.7. Alkylation, Reactions with Aldehydes Treatment of 2,4-dimethyl-3H-1,5-benzodiazepine with a mixture of sodium amide and methyl iodide in tetrahydrofuran16 led to the 3-methyl derivative 88 (Eq. 29). Base-catalyzed condensation of 71 with benzaldehyde in the presence of aqueous potassium hydroxide led to a mixture of 89 and 91, while only the latter compound16 was obtained using ethoxide in ethanol as the base. Piperonaldehyde, on the other hand, gave only the 3-substituted derivative 90, together with a small amount of the diadduct 92, in either base system. The distyryl 91 could be partially hydrolyzed to 89 upon treatment with aqueous alkali. 1.2.1.8. Acylation Reaction pf the 7-amino-1,5-benzodiazepine93 (R = NH,) with an equimolar amount of acetic anhydride in benzene solution led to the corresponding acetate 93 (R = NHAc).” An excess of reagent caused ring cleavage with formation of the enamine 94 and the diamide 95 (Eq. 30). The unsubstituted benzodiazepine 93 (R = H) could be similarly ring opened. Benzodiazepines with 2-phenyl substituents have been shown to be less prone to ring cleavage. Boiling acetic anhydride converted 96 to the diacetates 97.31 Partial hydrolysis of the phenolic acetate afforded 99.Selective acylation of the phenol to yield 98 could be carried out by the low temperature reaction of 96 with an acyl halide in the presence of triethylamine (Eq. 31). The condensation of 2-methyl-3H-1,5-benzodiazepines 100 with diethyl oxalate was reported*’ to give the tricyclic compounds 101. A later paper revised
23 1
1. 1,5-Benzodiazepines
1 NaNH>,THF
2 Me1
Me
Me
'Me
Me
uo'
90
91
92
Me 93
94
95
these structures on the basis of spectral data and assignedE3the isomers 102 as the correct structures (Eq. 32). Acylation of 96 on carbon (3-position) could be carried out readily by using amide acetals such as dimethylformamide dimethylacetal to give the enamines 103, which subsequently underwent ring closure to the benzopyranobenzodiazepines 104 (Eq. 33).31,37 Paterson and ProctorE4reported the formation of the sulfonamide 105 by reaction of 2,4-dimethyl-3H-1,5-benzodiazepine with tosyl chloride in pyridine. The product was described as a deep red, amorphous material (mp > 360°C),
c-:”:(”-R1 -
Ac
Ac,O 4 h. reflux
N-
R2
96
R,
CICOR, NIEO,. acetone - 10°C
98
99
0
I03
96
Rl
232
/
1. 1,s-Benzodiazepines
233
I.\x"li' Ts
N'
he 105
unaffected by refluxing with acids and alkalies. These observations suggest that the assigned structure may be incorrect.
1.2.2. Reactions with Nucleophiles 1.2.2.1. Hydrolysis The imine bonds in the benzodiazepines 79 are hydrolyzed readily by aqueous acid to give the enamine 106 and, upon further hydrolysis, o-phenylenediamine and a 1,3-diketone. These components may recombine to form the enamine 106, which is in equilibrium with both the dihydrobenzimidazole 107 and the benzodiazepine 79. Aromatization of 107 by the indicated mechanism would lead irreversibly to a mixture of the corresponding benzimidazole 108 and a methyl ketone (Eq. 34).
19
106
/
H
108 107
+
MeCR, It 0 (34)
The formation of 2-methylbenzimidazole and acetone by the acid hydrolysis of 79 (R, = R, = Me) was reported by Thiele and Steimmig.14The unsymmetri79 (X = H, R, = Me, R, = Ph) cal 2-methyl-4-phenyl-3H-1,5-benzodiazepine yielded, as expected, 2-methylbenzimidazole and 2-phenylbenzimidazole together with acetone and a~etophenone.'~ The hydrolysis of the selenyl derivat-
234
[ 1,4]Diazepines with [bl-Fused Rings
ive 79 (R, = Me, R, = 2-selenyl) yielded only 2-methylben~imidazole.~~ This would suggest that the dihydrobenzimidazole 107 (R, = 2-selenyl, R, = Me) is both formed and fragmented preferentially. Hydrolytic cleavage of 1,5-benzodiazepines to o-phenylenediamines and 1,3diketones would also explain the formation of 2,3-dimethylquinoxaline from 79 (R, = R, = Me) in the presence of butane-2,3-dione and ferric chloride4' or aqueous acid.16 The imine functions of 1,5-benzodiazepines are also cleaved by alkaline hydrolysis. This cleavage is more facile if electron-withdrawing substituents are present in the aromatic ring. Thus, treatment of the 7-nitro derivative of 79 with aqueous hydroxide at room temperature led to the enamine 106 (X = NO,).'92' More vigorous conditions afforded the diamine.' The hydrolytic behavior of 3-arylidene derivatives is very similar to that of the 3-unsubstituted compounds. Treatment of 90 with hydrochloric acid in boiling ethanol gave the benzimidazole 109, 2-methylbenzimidazole, and the methylketone 110 (Eq. 35).16
Me 90
t
H
H
'
I09
AJ" n
N
0 110
U
(35) Reaction of the 3-benzoyl derivative 111 with concentrated hydrochloric acid resulted in cleavage to give the 2,4-diphenylbenzodiazepine77 and benzoic acid, along with 2-phenylbenzimidazole and dibenzoylmethane (Eq. 36).29
1. 1,5-Benzodiazepines
235
The same type of ketone cleavage would also explain the formation of 2,4dimethyl-3H-l,5-benzodiazepine(71) from o-phenylenediamine and triacetylmethane (Eq. 37).16
+
(Ac),CH
Me 71
Hydrolysis of the 3-oximino derivative 112 was shown to lead to the formation of q u i n ~ x a l i n e s . Thus, ' ~ ~ ~ ~acid hydrolysis of 112 with 10% sulfuric acid in the presence of ferric chloride led to a mixture of 2-acetyl-3methylquinoxaline (73) and the corresponding oxime 113 (Eq. 38). When 112 was treated with an acetic acid-ethanol mixture at room temperature for 30 hours, the oxime 113 and 2-methylbenzimidazole were isolated. The hydrolysis of 112 with hot water led to 2-methylben~imidazole.~~
he 112
73
113
114
Alkaline hydrolysis of 112 was even more complex and gave an array of products, of which the quinoxaline 114 (R = OH), 2-methylbenzimidazole, and o-phenylenediamine 115 (R = H) were isolated (Eq. 38).16 When the reaction was carried out with sodium carbonate in aqueous ethanol, the 2-aminoquinoxaline 114 (R = NH,) and the acetate 115 (R = Ac) were formed in addition to the three products mentioned above. Mild acid hydrolysis of the 2-alkylthiobenzodiazepines 116 yielded the lactam 117 as the major product (Eq. 39).67Further degradation was observed with the methylthio derivative 116 (R = Me), to yield o-phenylenediamine and benzimida~oles.~ Alkaline hydrolysis of the 2-aminobenzodiazepine 118 gave different products depending on the reaction conditions.60 The conversion of 118 to the 2,4-
[ 1,4]Diazepines with [bl-Fused Rings
236
H,O-
116
Ph
a'y "
117
+
RSH
(39)
Ph
diaminobenzodiazepine was mentioned in connection with the synthesis of the latter (see Section 1.1.8). Aqueous sodium hydroxide under controlled conditions transformed 118 to the 1,3,5-benzotriazepine 122 in 38% yield. This reaction may proceed via the intermediates 119 and 120 (Eq. 40).
H
HO I21
he 122
Treatment of 118 with a weak aqueous base such as 2-aminopyrimidine or ammonia gave the benzimidazole 121, apparently by hydrolytic cleavage of the 4,5-bond followed by a recyclization to the benzimidazole. 1.2.2.2. Reaction with Nitrogen Nucleophiles Cleavage of the benzodiazepine 123 (R, =R, = Me, R, = H) by phenylhydrazine to give o-phenylenediamine and 3,5-dimethyl-l-phenylpyrazole124 (R,=R, = Me, R, = H) was observed by Thiele and Steimmig (Eq. 41).14 F i n r ~ a r ,obtained ~ high yields of pyrazoles in the reaction of symmetrically
124
1. 1,5-Benzodiazepines
237
substituted 2,4-disubstituted 3H-1,5-benzodiazepines with phenylhydrazine in acetic acid. The unsymmetrical 2-methyl-4-phenyl-3H-1,5-benzodiazepine123 (R, = Me, R, = H, R, = Ph) gave 3-methyl-l,5-diphenylpyrazole in 68% yield, suggesting preferential attack at the less hindered 2-position. Compound 123 (R, = Ph, R, = H, R, = benzoylacetyl) yielded the dipyraBarltrop and zole 124 (R, = Ph, R, = H, R, = 1,3-diphenyIpyraz01-5-y1).~~ coworkers'6 applied the same reaction to the product obtained by methylation of 2,4-dimethyl-1,5-benzodiazepine and obtained the pyrazole 124 (R, =R,=R, = Me). This showed that methylation had occurred at the 3-position in 123 (R, = R, = R, = Me). Reaction of 123 (R, = R, = H, R, = 6-chlorobenzoxazol-2-yl) with boiling hydrazine or phenylhydrazine was reported to give the pyrazoles 125 (R = H, Ph) in low yield^.^ R I
I25
The action of several nitrogen nucleophiles on the 3-hydroxyiminobenzo' example, diazepine 112 has been studied by O'Callaghan and T ~ o m e y . ~For substituted hydrazines in methanol containing hydrogen chloride converted 112 to hydrazones of 2-acetyl-3-methylquinoxalines 126 (Eq. 42), not to the expected
I13
I21
I 28
[ 1,4]Diazepines with [bl-Fused Rings
238
benzodiazepine-3-hydrazones.The reaction of 112 with either semicarbazide or thiosemicarbazide hydrochloride was initially reported to lead to benzodiazepin-3-carbazone~,'~ but the assigned structures were later corrected4' to quinoxalines 126 (R = CONH,, CSNH,). The reaction of 112 with hydroxylamine hydrochloride afforded the oxime 113. Depending on the reaction temperature either the syn- or anti-oxime was obtained. Hydrazine cleaved 112 to o-phenylenediamine and the 4-nitrosopyrazole 127. In the presence of excess hydrazine, the 4-nitrosopyrazole was reduced to the 4-aminopyrazole 128. The reaction of 2-alkylthiobenzodiazepines with amines to produce the corresponding 2-amino-substituted derivatives was discussed above (see Section 1.1.8). 1.2.2.3. Reductions Reduction of the imine double bonds in 1,5-benzodiazepines is discussed in connection with the synthesis of dihydro- and tetrahydro- derivatives (see Sections 2.1.6. and 4.1.4). The nitro group in 2,4-dimethyl-7-nitro-3H-1,5benzodiazepine has been catalytically reduced with Raney nickel to an amino group without affecting the imine bonds.21
1.2.3. Miscellaneous Reactions The hydrochloride of the tert-butyl ester 129 was reported43 to rearrange to quinoxaline 130 upon dissolution in organic solvents or on storage (Eq. 43). Since water has to be involved in this transformation, the starting material may be in the form of a hydrate. The same type of reaction may apply to the pyrolysis of benzodiazepinium salts, which, in the case of 2,4-dimethyl- 1H-13benzodiazepine hydrochloride, was reported' to yield 2-methylbenzimidazole and acetone.
-a;5 0
Ph
(43)
129
I30
1.2.4. Metal Complexes Ouchi and coworker^^^*^' and Hunter and Webb88,89have prepared a variety of metal halide and metal sulfate complexes of structure 131 (R, = R, = Me) and 132 (R, = Me, R, = Ph) (Eq. 44). The latter compounds generally
239
1. 1,5-Benzodiazepines
131
I32
(44) contained water of crystallization. The complex with ferrosulfate had been discovered earlierg0 but was assigned the wrong stoichiometry. Both spectroscopic and magnetic properties of these complexes were reported. The structure of the tetraiodozincate 133was determined by X-ray crystallographic analy~is.~' The X-ray data confirmed the spectroscopic evidence that the benzodiazepinium cation does not coordinate with the metal in these complexes.
I33
1.3. Spectra and Physical Data The structures of the 1,5-benzodiazepines and the corresponding mono- and dications were, in large part, assigned on the basis of spectroscopic data. Nuclear magnetic resonance spectra were particularly i n f o r m a t i ~ e . ~ *For -~~ example, Mannschreck and coworkersg5 studied the temperature-dependent proton-nmr spectra of 2,4-disubstituted 3H-1,5-benzodiazepines. At normal operating temperatures the protons at C-3 generally appear as a singlet, but at low temperatures an AB system is observed. This result demonstrates the nonequivalence of the protons at C-3 and indicates that the 3H-1,5benzodiazepine ring is nonplanar. The conformation of the seven-membered ring can probably be represented best by the equilibrium between A and B (Eq. 45).
A
B
240
[1,4]Diazepines with [bl-Fused Rings
When the A % B interconversion is very rapid (as is the case at room temperature), the protons at C-3 become magnetically equivalent and appear as a singlet. The activation energy AGc at the coalescence temperature was determined to vary between 11 and 13 kcal/mol for 2,4-disubstituted 3H-1,5benzodiazepines. Phenyl-substituted derivatives usually gave higher values for AGP, possibly as a result of greater steric hindrance in the transition state for the A s B interconversion. The structures of 2,4-dimethyl-1,5-benzodiazepinium chloride dihydrate (and the isomorphous bromide) were analyzed by X-ray crystallography, which showed that the seven-membered ring was almost planar.96 A polarographic revealed two main study of several 2-phenyl-4-pyridyl-3H-1,5-benzodiazepines waves corresponding to a consecutive reduction of the 43- and the 1,2-imine double bonds.97
2. DIHYDRO-1,5-BENZODIAZEPINES 2.1. Synthesis 2,3-Dihydro-lH-l,5-benzodiazepines of structure 135 are generally accessible by the condensation of o-phenylenediamine with either an a,j-unsaturated or an appropriate precursor thereof, such as a carbonyl compound lM3109313 8-halo- or a 8-aminoketone (Eq. 46).
I35
I34
2.1 . I . From o-Phenylenediamines and a$-Unsaturated Aldehydes Ried and Stahlhofen9* reported the synthesis of 135 (R, =Me, R, = R, = H) by the condensation of o-phenylenediamine with crotonaldehyde. The same reaction has also been applied99 to the diphenylmethane derivative 136 to prepare 137 (Eq. 47). The structure of 137 was assumed to be symmetrical, with the more reactive amino group forming the imine.
L
L I36
137
2. Dihydro- 1,5-Benzodiazepines
24 1
2.1.2. From o-Phenylenediamines and a,P-Unsaturated Ketones The synthesis of 2,3-dihydro-2,2,4-trimethyl-1H-l,5-benzodiazepine 135 (R, = R, = R, = Me) from o-phenylenediamine and mesityl oxide was first described by Ried and Stahlhofen9* and Mushkalo.'OO Several later paPers'O '-,OS report the preparation of the same compound and the corresponding 7,8-dichloro derivativelo6 by generating mesityl oxide in situ from acetone in the presence of an acid catalyst. The condensation was facilitated by using either boron trifluoride etheratelo, or 2-naphthylsulfonic acid"' as a catalyst. Fukushima and coworkers'07 have shown that this method can also be used for the preparation of 2,3-dihydro-2,4-diphenyl- 1H-1,5-benzodiazepine. Reid and Stahlhofen" were not able to obtain 1,5-benzodiazepines from the reaction of o-phenylenediamine with cinnamaldehyde, benzylidene acetophenone, or benzylidene acetone. The latter investigators isolated the open-chain adducts 138 (Eq. 48) resulting from Michael addition of the amine to the double bond. By increasing the nucleophilic character of the carbonyl group, as in 1,3dipyridylpropenones, Samula and Jurkowska-Kowalczyk'" were able to obtain 2,4-diaryl derivatives 135 (R, =R, = Aryl, R, = H) in good yield. These authors also isolated the intermediate 139, indicating that addition to the reactive carbonyl group may be the first step in the reaction pathway.
$tR3 \
NH2
0
(48)
138 139
Herbert and Suschitzky' O 3 were able to obtain the benzodiazepine 135 (R, = Me, R,=R, = Ph) as a hydrate in 80% yield by the condensation of o-phenylenediamine with acetophenone in the presence of boron trifluoride etherate.
2.1.3. Condensation of o-Phenylenediamines with 8-Haloketones Both MushkalolOO and Ried and T o r i n u ~ ' ~ 'have demonstrated the equivalence of 2-bromo-2-methylpentan-4-one and mesityl oxide for the (135, synthesis of the 2,3-dihydro-2,2,4-trimethyl-1H-l,5-benzodiazepine R, = R, = R, = Me). This same bromoketone has also been used for the synthesis of the corresponding nitro- and carboxy-substituted analogs.' l o The position of the aromatic substituent in these products was not determined.
242
[ 1,4]Diazepines with [bl-Fused Rings
Mushkalo'" showed that this method may also be utilized in the preparation of N-substituted derivatives. Treatment of 2-bromo-2-methylpentan-4one with 2-aminodiphenylamine afforded 2,3-dihydro-2,2,4-trimethyl-l-phenyl1H - 1,5-benzodiazepine. This compound was not fully characterized but was used for further reactions. Hideg and Hideg-Hankovzky' prepared 2,3dihydro-4-phenyl-7,8-dimethyl1H- 1,5-benzodiazepine by reaction of the appropriate diamine with 8-chloropropiophenone.
2.I .4. From o-Phenylenediamines and P-Aminoketones The accessibility of Mannich bases of type 140 makes this synthesis attractive. Hideg and Hankovzky"' used this method for the preparation of numerous compounds of structure 141 (Eq. 49). The same reaction was utilized by Werner and coworkers' 1 3 * l4 and also by Curtze and Thomas.' l 5
141
140
2.1.5. From o-Phenylenediamines and P-Hydroxyketones
'
Hideg and Hideg-Hankovzky' ' have reported that 8-hydroxyketones can be successfully utilized for the synthesis of dihydro-1,5-benzodiazepines.Condensation of 4,Sdimethyl o-phenylenediamine with the hydroxyketone 142 in refluxing xylene with azeotropic removal of water gave the benzodiazepine 143 in 78% yield (Eq.50). OH
Me
-
NH2 142
H
143
(50)
243
2. Dihydro-1,5-Benzodiazepines
2.1.6. By Partial Reduction of 1,5-Benzodiazepines Reduction of 3H-1,5-benzodiazepines 64 with sodium borohydride to 2,3-dihydro-1H-1,5-benzodiazepines 144 has been reported for both the 2,4-dimethyl’ l6 and the 2,4-diphenyl derivatives (Eq. 51).’
64
144
2.1.7. Other Syntheses The 4-amino-2,3-dihydro-l H-1,5-benzodiazepine 146 was obtained118 by cyclization of the acrylonitrile adduct 145 using dry hydrogen chloride in tetrahydrofuran (Eq. 52).
.“aN] H
HClTHF
c1
”
145
NH,
146
The formation of the dihydrobenzodiazepine-2-thiocarboxamide148 by treatment of 147, the adduct of hydrogen cyanide with 2,4-dimethyl-1,5benzodiazepine, with ammonium hydrogen sulfide was reported by Bodforss (Eq. 53).lI9
I47
I48
[1,4]Diazepines with [bl-Fused Rings
244
2.2. Reactions
2.2.1. Reactions with Electrophiles 2.2.1.1. Nitrosation Ried and Stahlhofen9* obtained the dinitroso derivative assigned structure 150 by reaction of the dihydrobenzodiazepine 149 with sodium nitrite in acetic acid (Eq. 54).
I49
I50
2.2.1.2. Oxidation The oxidation of 8-chloro-4-amino-2,3-dihydro-l~-l,5-benzodiazepineto the corresponding 2-one"' is discussed in Section 3.1.5. 2.2.1.3. Alkylation and Reactions with Aldehydes Treatment of the dihydrobenzodiazepine 151 with methyl iodide in benzene led to quaternization of the imine nitrogen, yielding 152."' The salts of 151 as well as 152 were condensed with aldehydes to form cyanine dyes 153 (R3 = H, Me). Similar condensations were performed with 4-dimethylamino-
153
245
2. Dihydro-1,5-Benzodiazepines
'
benzaldehyde"', and with the benzopyran or benzothiopyran derivatives 154 (X = 0, S) in the presence of acetic anhydride (Eq. 55).12' Aldehyde equivalents such as the enamides 155"' and 156"' (Eq. 56) were also successfully condensed with 151 to give the corresponding dyes.
,Wn
Ac
lJ"l
Et 155
I56
Condensation of 151 (R, = %NO,) with the dianil of glutaconic aldehyde afforded the diadduct 157 (Eq. 57)."'
H 157
I58
Treatment of 151 with triethyl o-formate in pyridine"' or in acetic anhydride at 100°C afforded the dyes 158."' These dyes were most likely obtained via the intermediate 4-(2-ethoxyethylene)-1,5-benzodiazepine 153 (R, = OEt, R, = H). 2.2.1.4. Acylation According to the patent literat~re,''~reaction of 149 with furan-2-carboxylic acid chloride in the presence of triethylamine gave the 4-furoyl derivative 159 a
y
e
fJCOC1
a
H y Me e
7 NN Me 149
(58) &Me I59
[ 1,4]Diazepines with [bl-Fused Rings
246
(Eq. 58). The 1-substituted product was not reported and probably is not formed because of steric hindrance. Compounds lacking geminal methyl groups in the 2-position undergo acylation on the 1-nitrogen. Thus, treatment of 160 with methyl chloroformate or benzoyl chloride in pyridine (Eq. 59) afforded the anticipated products 161.' l 5 Similar acylations were performed on 2,3-dihydro-7,8-dimethyl-4-phenyl-lH1,5-benzodiazepines using chloroacetic acid anhydride and sodium acetate in acetic acid."' Treatment of 160 with acetic anhydride at 100°C yielded the tetracyclic compound 162 (R = Me). ?OR H
a:&' /
HO
160
a:b
RF')
/
/
HO
\
161
I
H,O+, R
=
Ph
(59)
162 163
The urethane 161 (R = MeO) required the more vigorous conditions of heating under reflux for conversion to the benzochroman 162 (R = MeO).
2.2.2. Reactions with Nucleophiles Hydrolysis of 161 (R = Ph) with 20% hydrochloric acid gave the benzimidazole 163 via an initial cleavage of the imine double bond followed by recyclization to the five-membered ring.' The addition of hydrogen and hydrogen cyanide to the imine double bond is discussed in Sections 4.1.5. and 4.1.6., which deal with the synthesis of tetrahydrobenzodiazepines.
'
2.3. Spectral Data Room temperature proton- and 13C-nmr spectra' 1 7 3 '" of the 2,3-dihydro2,2,4-trimethyl-lH-l,5-benzodiazepine 149 show a single resonance for the
3. Dihydro-1,5-Benzodiazepin-2-Ones
247
protons in the 3-position and for the geminal methyl groups. This would indicate a rapid conformational change at ambient temperature. By measuring the broadening of the methyl signal at lower temperatures, Hunter and Webb,lZ2have determined that the free energy of activation for the conformational change is about 9 kcal/mol. According to the proton-nmr analysis, the 2,3-dihydro-2,4-diphenyl-l H-1,5-benzodiazepine showed a fixed conformation and the ABX pattern assigned to the C-3 protons did not collapse to a singlet up to a temperature of 140". The mass spectral fragmentation of these compounds has also been studied.'"
3. DIHYDRO-1,5-BENZODIAZEPIN-2-ONES Dihydro-1,5-benzodiazepin-2-ones can exist either as the 3H tautomer 164 or the 5H tautomer 165. Since the latter has rarely been observed, the thermodynamically more stable tautomer is probably the 3H compound.
NH
I64
I65
3.1. Synthesis
3.1.I. From o-Phenylenediamines and b-Ketoesters The condensation of o-phenylenediamine with /?-ketoesters may be expected to lead to a 4-substituted 1,5-benzodiazepin-2-one, a 2-substituted benzimidazole, or a mixture of both products.306 Sexton'23 studied the reaction of o-phenylenediamine with ethyl acetoacetate and obtained two products, a benzodiazepine and a benzimidazole, to which he assigned structures 167 (R = Me) and 171 (R = Me). The structure assignment for 171 (R = Me) was later corrected by Dav011'~~ and by Rossi and coworker^,'^^ who recognized that the imidazole derivative was the 1-(2-propenyl)benzirnidazolone 169 (R = Me) arising from a thermal rearrangement of 167 (Eq. 60). It has been well established that the initial step in the reaction of o-phenylenediamine with a fl-ketoester is the formation of the enamine 166. Cyclization of 166 to the benzodiazepine 167 predominates under neutral or alkaline conditions at moderate temperatures, whereas acid catalysis favors the formation of the imidazoles 170. These compounds are most likely formed by cyclization of 166 to the intermediate 168, which may then aromatize with loss
248
[ 1,4]Diazepines with [b]-Fused Rings
167
IhX
I
171
of acetate. Acetate elimination should be facilitated by the indicated intramolecular proton shift (Eq. 60). The cyclization of the enamines 166 with alkoxide in alcohol has evolved as Conthe procedure of choice for the synthesis of benzodiazepin-2-0nes.'~~~'~~ densation of o-phenylenediamine with a variety of j-ketoesters in refluxing toluene or xylene has been successfully used for the selective preparation of the benzodiazepines 167 (e.g., with R = Me,'26 CH2Ph,'27CF3,lz8Ph,'29 cc13,'30 l-adamantyl,13' and 3 - p ~ r i d y l ' ~ ~ ) . When 8-ketoesters are condensed with unsymmetrically substituted o-phenylenediamines, both the expected regioisomers 172 and 174 are formed (Eq. 61). Such mixtures were obtained with X = Br,'33 C1,'34 Me,'329'34*13sMe0,'34 and (1,3-dihydro-4-methyl-l,5-benzodiazepin-2(2~)-one-7-(0r8)y~)methyl.~~~ The composition of this mixture was found to depend more on the nature of substituent X than on R.134In some instances a remarkable regioselectivity was reported. Thus, Kost and coworkers' 3 7 obtained the benzodiazepine 172 (X = R = Me) in 87% yield by carrying out the reaction of the diamine with ethyl acetoacetate in boiling xylene at high dilution. It is feasible that under these conditions, the initially formed enamine 173 rearranges to 176, freeing the more basic amino group for ring closure with the ester carbonyl. If the two enamines
3. Dihydro-1,5-Benzodiazepin-2-Ones
249
I
MeCOCH,COOEt X = Me
172
-
Me
2
I73
174
IT ~
I75
176
173 and 176 equilibrate via 175, the rate of amide bond formation will determine the product, and this amide bond would be expected to form more readily with the more basic amino group. The regioisomer 174 (X = R = Me), on the other hand, was obtained in 66% yield by cyclization of the enamine 173 with sodium ethoxide in ethanol.' 38 Compound 173 resulted from the preferential reaction of the keto group of ethyl acetoacetate with the more basic nitrogen of toluidine under mild conditions. The situation for 4-nitrophenylenediamine is reversed.'39 14' The amino group meta to the nitro substituent is the more nucleophilic one and would favor formation of the enamine 177. Cyclization of 177 with sodium ethoxide in ethanol led to the benzodiazepine 172 (X = NO,, R = Me). The regioisomer 174 (X = NO,, R = Me) was however accessible in 88% yield, by utilizing the high dilution technique in boiling xylene. In this case, a small amount of tautomer 178 was also 0 b ~ e r v e d . l ~ ~ ~
177
178
The same considerations were also shown to apply in the preparation of the dichloro derivatives 179 (X = C1) and 180 (X = Cl).14, Compound 179 (X = C1) was synthesized via the enamine in 89% yield, while the isomer 180 (X = C1) was
[1,4]Diazepines with [bl-Fused Rings
250
X
X NH2
NaOEf
x'
X
Me
8 3 " Me
180
obtained in 80% yield by refluxing in xylene. The dibromo analogs 179 (X = Br) and 180 (X = Br)'43 as well as the bromo derivatives 172 (X = Br, R = Me) and 174 (X = Br, R = Me)'44 were accessible in the same manner (Eq. 62). Pennini and coworkers'4s studied the condensation of the diamines 115 (R = Me, CH,Ph) with ethyl benzoylacetate in boiling xylene and obtained the corresponding benzodiazepinones 184, together with some benzimidazole derivatives. These authors isolated the benzoylacetate 181 (R = CH,Ph), which upon further heating in xylene formed the benzodiazepine 184 (R = CH,Ph). This conversion most likely proceeds by an acyl migration via 182 to give intermediate 183, which closes to the seven-membered ring (Eq. 63).
R
R o
COOEt
Ph
reflux /
25 1
3. Dihydro-1,5-Benzodiazepin-2-Ones
3.1.2. From o-Phenylenediamines and Diketene Ried and S t a h l h ~ f e n described '~~ the exothermic reaction of o-phenylenediamine with diketene leading to the benzodiazepine 185 (R = H) (Eq. 64). The same reaction was later extended to the preparation of 4-, 7-, and 8-substituted 315
185
3.1.3. From
0-Phenylenediamines
and Cyclobutenediones
The first synthesis of this type was reported by Ried and I ~ e n b r u c k ' ~who ' isolated the benzodiazepine 189 from the reaction of o-phenylenediamine with the cyclobutenedione 186 (Eq. 65). The initial product of this condensation is the pyrrolobenzimidazole 187, which must be formed by air oxidation of an intermediate imidazoline. Further addition of phenylenediamine to the reactive amide bond in 187 could then lead to intermediate 188 which would cyclize to the observed product 189. 0
N 186
188
189
3-Hydroxy-2,4-diphenylcyclobutenone190 was reported'48 to form a salt with o-phenylenediamine that, upon pyrolysis in boiling toluene, gave the benzodiazepine 193 (R = H) in 57% yield (Eq. 66). The 5H-tautomeric structure was assigned on the basis of spectral data. The same compound was also
[1,4]Diazepines with [bl-Fused Rings
252
Ph 192
isolated from the condensation of the diamine with ethyl 2,4-diphenyl-3oxobutyrate. Substituted diamines gave lower yields of 193, possibly because of the formation of regioisomers, only one of which was isolated. The relative position of the substituent (7 or 8) was unassigned. We believe that the structures assigned by these investigators are probably incorrect and that the products thought to be the benzodiazepines 193 are actually the benzimidazolones 192. Evidence for this is given by Zubovics and coworkers149 who studied the same reaction in boiling benzene and obtained the benzodiazepinones 191 with different melting points. These authors confirmed their structural assignment for compounds 191, including the location of the substitutent R, by an alternate synthesis. Zubovics and coworkers'49 condensed the substituted nitroanilines 194 with the cyclobutenone 190 and obtained the anilides 195, which were then reductively cyclized to the benzodiazepines 196 (R, = C1, R, = H; R, = MeO, R, = H; R , = Me, R, = H; and R, = H, R, = Me) (Eq. 67). Comparison of the derivatives prepared by reductive cyclization with the products obtained by direct condensation from substituted phenylenediamines indicated that the
+
190
-
I94
(67)
Ph 196
253
3. Dihydro-1,5-Benzodiazepin-2-Ones
more basic amino group of the diamine preferentially attacks the cyclobutenone to form the amide bond. Similar reductive cyclizations have been used for the preparation of both 7-chloro-1,3-dihydro-4-phenyl-1,5-benzodiazepin-2(2~)-0ne~~~ and 7-amino1,3-dihydro-4-phenyl-1,5-benzodiazepin-2(2H)-one.5 0
'
3.1.4. Other Methods The utility of an isoxazole-4-carboxylic acid as a 1,3-dicarbonyl equivalent was demonstrated by Ajello and coworker^'^^ in the synthesis of the 13benzodiazepinone 199. Thus, reduction of the anilide 197 over Raney nickel gave 198, which was cyclized to the benzodiazepine 199 in 50% yield by heating in toluene in the presence of a catalytic amount of p-toluenesulfonic acid. The acetyl group in 199 was easily removed by acid hydrolysis to give 200 (Eq. 68).
197
198
200
199
The benzodiazepinone 202 was formed in 50% yield from the coumann derivative 201 and 2 equivalents of o-phenylenediamine in refluxing xylene' 5 2 (Eq. 69). The benzimidazole 203 isolated as a second product resulted from the
w
201
HO 202
203
[ 1,4]Diazepines with [bl-Fused Rings
254
reaction of o-phenylenediamine with diphenylacetaldehyde formed from 201 by retroaldol cleavage.
3.1.5. Dihydrobenzodiazepin-2-ones with Heteroatom Substituents in Position 4
4-Amino-1,3-dihydro-l-phenyl-l,5-benzodiazepin-2(2H)-ones 206 were prepared”, from cyanoacetanilides 204 by reduction of the nitro group with zinc and hydrochloric acid followed by ring closure of 205 by hydrogen chloride (Eq. 70).
Zn,HCI
204
205
/
206
The reactive malonic acid derivatives 207 were utilized by Buyle and ViehelS4,l s 5 for the synthesis of the 4-aminobenzodiazepines 208 (Eq. 71). The location of the substituent R, (7- or 8-position) in 208 has not been determined.
a
R3
N
H
2
NHZ
+ c1
’R, N(Rz)z 207
-
H
O
R 3 a N > R 1
(71)
” N(R2)z 208
N-Phenyl-substituted o-phenylenediamine yielded a mixture of the two isomeric compounds 209 and 210 (Eq. 72). The predominant product was assigned structure 210 on the basis of nmr data. Roma and coworkers’56 also prepared 208 by the reaction of o-phenylenediamine with malonic ester amide in boiling phosphorus oxychloride. 1-Phenyl derivatives similar to 209 were accessible as well by this procedure.
3. Dihydro-1,5-Benzodiazepin-2-Ones
255
Conversion of a lactam to an amidine via an iminohalide has been used as a general method of preparation of many 4-aminobenzodiazepinones. Thus, the substituted 1-phenyl derivatives 212 (R, = aryl) were obtained by sequential reaction of the tetrahydrodiones 211 with a phosphorus pentahalide and an amine.118, 1 5 7 Another synthesis employed titanium tetrachloride and methyl amine to form the 4-methylamino analog."* The thiones 213 and the imino thio ethers 214 (X = S) were also used as precursors for the amidines 212.118*1s7 4-Hydrazine analogs 212 (R, = NH,, R, = H) were accessible by these rneth~ds,'~~ as*well ' ~ ~ as by reaction of the nitrosoamidine 212 (R, = NO, R, = Me) with hydrazine (Eq. 73).lS8
21 1
213
The imino ethers 214 (X = 0) were prepared by reaction of the dione 211 with Meerwein salt'61 or via the iminochloride. Treatment of the nitrosoamidines 212 (R, = Ph, R, = NO, R, = Me) with alcohol and base also led to the imino ethers."* Thio ethers 214 (X = S) were obtained161 by alkylation of the thiones 213 (Eq. 73). may also be obtained by oxidation of 215 with The 1,5-benzodiazepin-2-ones chromium trioxide in sulfuric acid118 to give the 4-amino compound 216 (Eq. 74).
[ 1,4]Diazepines with [bl-Fused Rings
256
215
216
The 3-quinoxalinyl-1,5-benzodiazepine218 was prepared via a ring transformation mechanism that occurs by reacting 3-(N,N-dimethylcarbamoyl)-furo[2,3-b]quinoxaline hydrochloride 217 with o-phenylenediamine (Eq.75).305
211 218
(75)
3.2. Reactions
3.2.1 Reactions with Electrophiles 3.2.1.1. Halogenation Bromination of 4-methyl-1,3-dihydro-1,5-benzodiazepin-2-(2~)-one has been reported16’ to take place primarily on the methyl group. Barchet and MerzI3’ obtained a monobromo compound by reaction of the 4-phenyl analog 200 with bromine and incorrectly assigned the tautomeric structure 221 (Eq.76). Solomko and coworkers’ 3 3 reinvestigated the bromination of 200 under various conditions and showed that N-bromosuccinimide in carbon tetrachloride and in the presence of benzoyl peroxide gave a 76% yield of the 3-bromo derivative 219, which was identical to the product obtained by the previous investigator^.'^' The same compound was also formed with bromine in acetic or sulfuric acid or mixtures of these acids. The spectroscopic data of this product clearly indicated structure 219 rather than 221. When bromination was carried out with bromine in sulfuric acid containing silver sulfate, a mixture of the 4-(4-bromophenyl) derivative 220 (R = H) and the 3-bromo-4-(4-bromophenyl) compound 220 (R = Br) was obtained (Eq. 76). 3.2.1.2. Nitration Nitration of the 4-methyl derivative 222 (R, = Me, R, = H) with potassium nitrate in sulfuric acid at - 10” to - 5°C gave the 7-nitro compound 223
3. Dihydro-1,5-Benzodiazepin-2-Ones
251
(R, = Me, R, = H)141 in good yield (Eq. 77). The 4-phenyl-1,5benzodiazepinone 222 (R, = Ph, R, = H)'" as well as the 8-methyl derivatives 222 (R, = Me, Ph, 4-MeOCsH4, R, = Me) were similarly converted to the corresponding 7-nitro derivatives 223 in high yields.' Compounds 222 (R, = Me, Ph, 4-MeOCsH4, R2 = C1, Br) were also successfully nitrated at the 7-position.' 64 Under similar conditions of nitration the 8-methoxy-4-methyl benzodiazepinone 222 (R, = Me, R, = MeO) gave the 7-nitro compound 223 (R, = Me, R, = MeO) and the 9-nitro analog 224 in approximately equal amounts. 163
222
223
(77)
224
In the case of the 7-methyl-substituted benzodiazepin-Zones 225 (R = Me, Ph, 4-MeOC6H,) the primary product of nitration was shown to be the 1-nitro compound 226, which subsequently rearranged to the 9-nitro derivative 228 (Eq. 78). To a lesser extent, the 8-nitro analog 227 was also formed by a slower reaction pathway.ls3
[ 1,4]Diazepines with [b]-Fused Rings
258
225
228
221
3.2.1.3. Nitrosation According to Dav011,'~~the reaction of 4-methyl-l,3-dihydro-1,5benzodiazepin-2(2H)-one with nitrous acid in 2 N hydrochloric acid led to an unstable nitroso compound, which was assigned structure 229 (Eq. 79).
ay N
Me
(79)
NO
NO
229
230
The nitrosoamidines 230 were obtained'58 by treatment of the corresponding amidines with sodium nitrite in glacial acetic acid. 3.2.1.4. Reaction with Other Nitrogen Electrophiles Benzenediazonium chloride reacted with 4-methyl-l,3-dihydro-1,5benzodiazepin-2(2H)-one in 2 N hydrochloric acid to give a red crystalline compound that was assigned the hydrazone structure 231.lZ4
231
3. Dihydro-1,5-Benzodiazepin-2-Ones
259
3.2.1.5. Oxidation The benzodiazepinone 191 was found to undergo air oxidation in boiling benzene to yield the benzoyl derivative 232 as the major product, in addition to a small amount of the dione 233 (Eq. 80).149Compound 232 was also isolated from the reaction of o-phenylenediamine with a,y-diphenylacetoacetate in boiling xylene.
O ' T P h N-
+ Ph
Ph
191
233
232
3.2.1.6. Alkylation and Reaction with Aldehydes The lactam nitrogen of the benzodiazepinones 234 could be alkylated by using an alkyl halide and base (e.g. methyl iodide and potassium carbonate,lZ6 2-dimethylaminoethyl bromide and sodium amide,I6' or 2-chloromethyl-3,4dihydroimidazole, and sodium amideL66)to give in each instance the appropriate l-substituted derivatives 235 (Eq. 81).
234
235
The alkylation of 4-amino-l-phenylbenzodiazepin-2-ones 236 (X = C1, NO,) was studied by Bauer and coworker^,'^^ who showed that the course of the reaction was affected by the choice of solvent and reagent. Treatment of 236 (X = NO,)with methyl iodide and sodium methoxide in dimethylacetamidegave a yield of the dimethylamino derivative 237 (X = NO,, R = Me) that exceeded 80%, while the same reagent in tetrahydrofuran gave mainly the monomethylated product 237 (X = NO,, R = H), together with the benzimidazolone 239 (X = NO,).The latter compound was the major product if the methylation was carried out in methanol. This ring contraction was shown to proceed via the 2,4-dione and will be discussed under reactions of the 2,4-diones. Methylation with fluorosulfonic acid methyl ester, on the other hand, gave high yields of the 5-methylated imino compounds 238 (X = NO,, C1) (Eq. 82).'67 Cyclization of the chloroethyl derivative 240 by an intramolecular alkylation using potassium carbonate in benzene4imethylacetamide was reported'67 to
260
[ 1,4]Diazepines with [bl-Fused Rings
'a? 'aNj I ' a $ . .:.i"r Ph
NaOMe Me1
N-
" NR
*
NH,
Me
236
231
C t ,SO,Me
(82)
Th I
Me NH
239 Me
238
give the triazepinobenzodiazepine 241 and the imidazolidinone 242, the latter being the major product (Eq. 83).
+ 'H 242
Condensation of 4-methyl-1,3-dihydro-1,5-benzodiazepin-2(2H)-one with benzaldehyde and piperidine in boiling benzene led to the styrene derivative 243 in 20% yield.49
243
3. Dihydro-1,5-Benzodiazepin-2-Ones
26 1
3.2.1.7. Acylation It is surprising that no N-acylations of the benzodiazepin-Zones 234 have been reported. According to the patent literature,’68 reaction of 234 (R, = Me) with substituted phenylisocyanates afforded the 3-carboxamides 244 in almost 90% yield (Eq. 84).
234
244
Ph 245
Acylation on the 3-position was also observed under Vilsmeier conditions. Thus, a mixture of N-methylpyrrolidinone and phosphorus oxychloride converted 234 (R, = Ph, R, = H) to the enamine 245.169The stereochemistry of 245 is unknown and the structure lacks rigorous proof. The 4-amino derivatives 246 (R, = H, Me) were converted to the monoacylated products 247 by reaction with acid chlorides, chloroformates, or Und er more vigorous conditions, the diacylated isocyanates (Eq. 85).167,170
R1
246
241 R 2 = CF,
(85)
R3
248
249
[ 1,4]Diazepines with [bl-Fused Rings
262
analogs 248 were obtained. Prolonged reflux of 246 (R, = H, R, = CF,) in acetic anhydride gave the triacetyl derivative 249.16" Acylation of the 4-hydrazinobenzodiazepin-2-one250 with chloroacetyl chloride gave the chloroacetate 251 in high yield. This compound was converted to the triazolobenzodiazepine 252 by heating to 140°C in acetic acid (Eq. 86).ls9
CICOCH,CI
/
250
251
Ph 252
3.2.2. Reactions with Nucleophiles 3.2.2.1. Hydrolysis Acid hydrolysis of the benzodiazepin-2-ones 234 (R, = Me, R, = H) with dilute sulfuric acid at reflux gave 2-methylbenzimidazole and acetone (Eq. 87).'24 The nitro analogs 234 (R, = Me, R, = 7- and 8-nitro) afforded the analogous reaction products,' 40 although complete hydrolytic cleavage of 234 (R, = Me, R, = 7-N02) to 4-nitrophenylenediamine was also 0 b ~ e r v e d . l ~ ~ Sexton,'23 on the other hand, reported the formation of 2-hydroxybenzimidazole and acetone by heating of 234 (R, = Me, R, = H) in 20% aqueous sulfuric acid. The 4-trifluoromethyl derivative 234 (R, = CF,, R, = H) was hydrolyzed in boiling 10% aqueous sulfuric acid to give a mixture of the benzimidazole 254 (R, = CF,) and o-phenylenediamine, while treatment with 10% aqueous Phenacylbromide sodium hydroxide at reflux led to 2-methylben~imidazole.'~~ was isolated from the acid hydrolysis of the 3-bromo derivative 255 (R, = Br, R, = Ph) (Eq. 87), while p-bromoacetophenone was recovered from the hydrolysis of 254 (R, = Br, R, = 4-BrC6H4),13, thus confirming the site of the attachment of the bromine. The cleavage of the acetyl group of 255 (R, = Ac, R, = Ph) by heating with hydrochloric acid in ethanol was mentioned above (Section 3.1.4). Both acidic and basic hydrolyses are best rationalized by an initial cleavage of the imine bond followed by recyclization to the benzimidazole intermediate 253. This intermediate may then either dehydrate to give 254 or fragment as indicated to form the 2-hydroxybenzimidazole. 2-Methylbenzimidazole would result from cleavage of the ketone 254 as shown in Eq. 87.
263
3. Dihydro-1,5-Benzodiazepin-2-Ones r
1
253
234
I H
R2f-J;40 -OH
254
3.2.2.2. Reactions with Nitrogen Nucleophiles Treatment of the 1,5-benzodiazepinone 234 (R, = CF,, R, = H) with hydroxylamine in ethanol at room temperature was reported',* to open the amide bond rather than the imine to yield the hydroxamic acid 256, although the alternate structure 257 has not been ruled out (Eq. 88). Both compounds could undergo the observed recyclization to the benzodiazepine 234 (R, = CF,, R, = H) upon treatment with acid. NH2
CONHOH
234
CF 3 256
251
[ 1,4]Diazepines with [bl-Fused Rings
264
The 4-amino group of the benzodiazepin-2-ones 258 has been described to undergo acid-catalyzed exchange with acetals of aminoacetaldehyde to yield the substituted amidines 259 (Eq. 89).153These compounds could be cyclized to the imidazobenzodiazepines 261 by heating in boiling formic acid. Compounds 261 were also accessible by the reaction of 258 with a - b r o m ~ k e t o n e s . 'Amine ~~ exchange with propargylamine was accompanied by in situ cyclization to the 1-methylimidazobenzodiazepine260.'53
258
260
259
26 I
(89)
Displacement of a 4-alkoxy or 4-alkylthio group by amines"8 was mentioned during the discussion of the synthesis of 4-amino compounds in Section 3.1.5. Also discussed was the utilization of an N-nitrosomethylamine function as a leaving group to prepare 4-hydrazino derivative^.'^^ Reaction of these nitrosoamidines 230 with acetylhydrazine and triethylamine in boiling butanol led to the formation of the triazolobenzodiazepines 262 (Eq. 90).15'
3.2.2.3. Reactions with Carbon Nucleophiles (Carbanions) The nitrosoamidine 230 reacted with the carbanions of nitromethane and dimethyl malonate to give the 4-methylene derivatives 263 (R, = NO,, R, = H, R,, R, = COOMe).'7' Condensation of 230 with the anion of ethyl isocyanoacetate gave the imidazobenzodiazepine 264 in one step. 17'
3. Dihydro-1,5-Benzodiazepin-2-Ones
Ph I
265
Me 0
’aN1NH,N H Ac
”
Et,N, BuOH
R’
NNO
-
Ph
Ph
263
R2
264
3.2.2.4. Reactions with Sulfur Nucleophiles 4-(Dialky1amino)-1-phenyl-l,3-dihydro-1,5-benzodiazepin-2-one (265), treated with phosphorus pentasulfide, afforded the corresponding benzodiazepin-2thiones 266 (Eq. 91). A reaction of 266 with sodium hydride and methyl iodide gave the corresponding 2-methylthio derivatives 267. Treatment of 267 with dialkylamines led to the formation of 2,4-bis-(dialkylamino)-1-phenyl-1H-1,5Ph
Ph
aNTl; ”
265
P A
N
\
QI”I’.: N’
N’
266
\
I
1. NaH 2. Me1
(91)
[ 1,4]Diazepines with [bl-Fused Rings
266
benzodiazepines 268. The bulkiness of R, had a great effect on the yields of these compounds (268). 3.2.2.5. Other Reactions The reaction of 4-(dialkylamino)-l,3-dihydro-2H-l,5-benzodiazepin-2-ones 269 with N,N-dimethylformamide in the presence of phosphorus pentachloride at room temperature produced 4-(dialkylamino)-3-[(dimethylamino)methy1ene]-l,3-dihydro-2H-l,5-benzodiazepin-2-one (270).309 Compounds 270 (Eq. 92) are useful starting materials for the synthesis of tricyclic 1,5-benzodiazepine derivatives. H
!I
0(XR
HCNMe A PCI,
R
270N-
\/
269
O
aN>$H
0
R
e2
(92)
R
Reaction with hydrazine of 270, which has the least steric hindrance of the 4-dialkylamino substituents (R = Me), afforded the pyrazolo[3,4-b] [1,5]benzodiazepine derivatives 271 (Eq. 93). However reaction of 270 with guanidine or amidines gave 5H-pyrimido-[4,5-b] [1,5]benzodiazepine derivatives 272. H
O
R
H,N-NHR
c--- 270
H,N-C=NH
(93)
R 271
272
D 1\
Treatment of 273 with a diazonium salt leads to 274, azo coupling ocurring at the exocyclic methyl group. Tosyl azide, on the other hand, reacts at the 3position to give compound 275. Further reaction of 275 with benzoylphenylketene gives the diazooxazinobenzodiazepine 276 without loss of the diazo nitrogen. However. interaction of 275 with phenyl isocyanate, yields the pyrazolo[4,3-b] [1,5]benzodiazepine 277 (Eq. 94).312 3.2.2.6. Reduction The reductions of the imine and the carbonyl functions of 1,3-dihydro-1,5benzodiazepin-2(2H)-ones are discussed in Section 4, dealing with the synthesis of tetrahydrobenzodiazepines. The nitro group in 1,3-dihydro-7-nitro-4-phenyl-1,5-benzodiazepin-2(2H)one has been catalytically reduced to an amino group with Raney nickel and hydrogen.’
3. Dihydro-1,5-Benzodiazepin-2-Ones
261
214
I
I
TosN,
Me 215
i
PhNCO
Ph
(94)
oAPh 276
I CONHPh
3.2.3. Pyrolysis Thermal ring contraction of 1,3-dihydro-1,5-benzodiazepin-2(3H)-ones 234 to the benzimidazoles 278 appears to be quite general and has been used as a diagnostic tool in establishing the location of the R, substituent.135- 137,140 - 144 As indicated below (Eq. 99, the rearrangement can be formulated as a transannular attack of the imine nitrogen on the amide carbonyl followed by cleavage of the 2,3-bond. Compounds 234, with substituents in the 3-position (e.g., 3-pheny1127.14’ and 3-acetyl’” derivatives) have been reported to undergo the same ring contrac-
268
[ 1,4]Diazepines with [bl-Fused Rings
* o
H A
(95) 234 218
tion. The imidazolones 278 were also formed by heating the benzodiazepines in boiling 2-ethoxyethanol in the presence of sodium 2-ethoxyethoxide. 24, 14' 3.3. Spectral Data
Nmr spectra of the benzodiazepinones 235 unsubstituted at position 1 (R, = H) exhibit a singlet for the two methylene protons at C-3. This is indicative of a rapid flipping of the seven-membered ring between two boat-type conformations. From a study of the signal broadening at low temperature, Mannschreck and coworkers9' estimated the activation energy for the ring inversion to be about 9.5 kcal/mol for the 4-methyl derivative 235 (R, = Me, R, = R, = H). Benassi and coworkers'73 reported a value of 10 kcal/mol for the 4-phenyl-substituted compound 235 (R, = Ph, R,=R, = H). Ring flipping is somewhat inhibited by the introduction of a substituent at the 1-position, which gives rise to an AB system for the methylene protons with a coupling constant at room temperature of 12 Hz. The free energy of activation at 298°K was determined to be 15.6 kcal/mol for 235 (R, = Ph, R, = H, R, = Me) and 16 kcal/mol for 235 (R, = Ph, R, = H, R, = CH,Ph).'73 Low energy barriers to ring flipping are also observed with 4-amino derivatives 235 (R, = NR4R,, R, = 8-CI, NO,, R, = Ph), in which the methylene protons at C-3 appear as a broad singlet or broad AB system.'67 The C-3 protons readily undergo exchange under acid catalysis (DCI in DMS0).'67
235
The mass spectra of compounds 235 (R, = Me; R, = 7- or 8-Br, C1, Me, NO,; R, = H) were r e ~ 0 r t e d . The l ~ ~principal path of fragmentation under ion impact was rupture of the 1,2-bond leading to ejection of ketene. The 7substituted isomers may be distinguished from the 8-substituted analogs on the basis of the relative intensities of the peaks corresponding to the molecular ions and its fragmentation species.'74
269
4. Tetrahydro-lH-1,5-Benzodiazepines
4. TETRAHYDRO-lH-l,5-BENZODIAZEPINES 4.1. Synthesis
4.1.I. By Alkylation of o-Phenylenediarnine Derivatives The synthesis of the parent compound 281, dates back to the nineteenth century. Hinsberg and Strupler' 75 prepared the 1,5-dibenzenesulfonate 280 (R = Ph) by alkylation of 279 (R = Ph) with 1,3-dibromopropane (Eq. 96). Subsequent cleavage of the sulfonamides with acid led to 281. The synthesis of 281 was eventually improved by Stetter,I7, who obtained the 1,5-ditosylamide 280 (R = 4-MeC,H4). Hydrolysis of this compound with 90% sulfuric acid for several days at room temperature led to the monotosylamide 282, while 281 was obtained in 70% yield under more vigorous conditions. More recently,' 77 this hydrolysis was reported to give 281 in 75% yield. This method was also applied and 1-(2to the synthesis of l-phenyltetrahydr0-lH-1,5-benzodiazepine'~~ methoxypheny1)tetrahydro-1H-1,5-ben~odiazepine.'~~ Alkylation of 279 (R = 4-MeC6H,) with 1,3-dibromobutane gave the corresponding 2-methyl analog of 280.12, The utility of this synthetic path was enhanced by the finding'" that the N-tosyl group can be conveniently removed photochemically in the presence of sodium borohydride.
S02R I
S02R
. I
Br (CH,), Br
a N H R = Ph, 4-MeC,H, rrJH I
I
SO2R R
= 4-MeC6H.
(96) R=4-McC6H,
Ts
H
I
H 28 1
H 282
Alkylation of the ditosylamide 279 (R = 4-MeC,H4) with 2,3-dibromopro284.'8' The same panol unexpectedly led to the 3-hydroxy-1,5-benzodiazepine product was also obtained with epibromohydrin, indicating that the epoxide 283 is probably an intermediate in this synthesis (Eq. 97). Hydrolysis of the
[ 1,4]Diazepines with [bl-Fused Rings
270
I
I
Ts
Br
I or BrCH,CH
NH SO,R
CH,
‘0’
I
Ts 283
Ts 284
ditosylamide 284 was carried out with sulfuric acid at room temperature to give 285. Another example of diazepine formation by double alkylation was the reaction of N,N’-dimethyl o-phenylenediamine with 3-chloro-2-chloromethylpropene. Heating of these reactants under reflux in methanol in the presence of triethanolamine gave the benzodiazepine 286 in moderate yield (Eq. 98).18’ Me ,NH
Me I
I
‘NH
(CICH2)2C=CH, rcflux I
I
Me
286
Me
4.1.2. By Aromatic Substitution or via Benzynes Reaction of 1,3-di(methylamino)propane with 1,3-dichIoro- and 1,2,3- or 1,2,4-trichlorobenzenes in the presence of sodium amide has been shown’83 to lead to 1,5-dimethyltetrahydro-1H-1,5-benzodiazepines289 (X = H, C1) (Eq. 99). Compound 289 (X = H) was formed in 40% yield from 1,3-dichlorobenzene. Both 1,2,3-trichlorobenzene and 1,2,4-trichlorobenzene gave mixtures of the 6-chloro and 7-chlorobenzodiazepines 289 (X = 6-C1,7-C1),with the latter being the major component. The dichloroanilines 287 were isolated as intermediates
4. Tetrahydro-lH-1,5-Benzodiazepines
HNMe
x&
-l-( YIH 2 ) 3
c1
27 1
x
NaNH
N(CH,),NHMe
HNMe
Me 287
N(CH2)3NHMe
1
I
28R
Me
1
Me 2x9
of the reaction of the trichlorobenzenes with the diamine. These intermediates are most likely formed by a nucleophilic substitution reaction. If the chloro substituent X in 287 were ortho to the aniline nitrogen, it would be converted to the benzodiazepine 289 (X = 6-C1 or 7-C1) by another substitution reaction. In the case of 287 (X = H or Cl), the aryne 288 (X = H or C1) is a likely intermediate (Eq. 99).
4.1.3. By Cyclodehydration This method has been used successfully for the synthesis of the 6-amino derivative 291,184obtained in high yield by heating the alcohol 290 in boiling aqueous hydrogen bromide (Eq. 100). The compound was characterized as a dihy drochloride.
&;m;H2)30H
HBr
*
&;I H
(loo)
290
29 1
4.1.4. By Reduction of 1 ,S-Benzodiazepines and 2,3-Dihydro-1H-1,5Benzodiazepines The most widely applied method for the synthesis of tetrahydrobenzodiazepines has been the reduction of the imine double bonds in 292 or 293 (Eq. 101).
212
[ 1,4]Diazepines with [bl-Fused Rings
292
NaBH,
\c
J
RYaBH'
z",
aNyi3 293
(101)
N
\
H
R4
294
Reduction was achieved either by catalytic h y d r o g e n a t i ~ n ~ ~or~ by '~~.~~~~ l 1z 1 6 9 1 7 9 18 5 , 1 8 6 While catalytic hydroreaction with sodium borohydride. genation led to mixtures of cis and trans isomers,107 reduction with sodium borohydride was more stereoselective, leading to the cis isomer in the case of the 2,4-dimethyl derivative 294 (R, = Me; R,, R, = H; R, = Me).117~185~186 ' 9
4.1.S.By Reduction of Benzodiazepinones Several syntheses of tetrahydrobenzodiazepines 297 by lithium aluminum hydride reduction of dihydrobenzodiazepinones295 or tetrahydrobenzodiazepinones 296 have been reported (Eq. 102).'07~"'~"7~'24~1x7
Q & ON'
ay
Rl
H R, R l
295
J
LIAIH,
\IHa
H
296
(102)
61:) H
R,
R2
291
4.1.6. By Addition of Hydrogen Cyanide to Imine Bonds Hydrogen cyanide adds to the imine double bonds of 1,5-benzodiazepines to form the 2,4-dicyano derivatives and 2,3-dihydro-lH-1,5-benzodiazepines
4. Tetrahydro-lH-l,5-Benzodiazepines
273
7 2
R,R,C=C-COR, KCN/AcOH
300
298119 and 2-cyano derivatives 2!W119 (Eq. 103). Compounds 299 were also formed by condensation of o-phenylenediamine with a,S-unsaturated carbonyl compounds in the presence of hydrogen ~ y a n i d e . ~When ~ . ' ~R, ~ = R, = R, = H and R, = Ph or 2-furyl, the intermediate adducts 300 can be isolated.'88,'89 The stereochemistry of the hydrogen cyanide adducts 298 and 299 has not been established. Corresponding acid derivatives 302 could be obtained from 301 in very low yields by alkaline hydrolysis (Eq. 104). Esters 303 were also prepared from 301 by a l c o h ~ l y s i s . ~ ~ ~
303
4.1.7. Other Syntheses Reductive desulfurization of the diazepinophenothiazine 304 with Raney nickel afforded the l-phenyltetrahydro-1,5-benzodiazepine306 (R = Ph) in 62% yield (Eq. 105).'78This method was later extendedlgOto the diazepinodi-
[1,4]Diazepines with [bl-Fused Rings
214
aNq U" \
305
304
H 306
benzthiazepine 305, which was desulfurized to the 1-benzyltetrahydro-13benzodiazepine 306 (R = CH,Ph). An unusual reductive cleavage of the phenoxazine 307 (R = Ts or H) upon ' form a 55% irradiation in presence of sodium borohydride was r e p ~ r t e d ' ~to yield of the l-(2-hydroxyphenyl)tetrahydro-1,5-benzodiazepine308 (Eq. 106).
308
4.2. Reactions
4.2.1. Reactions with Electrophiles 4.2.1.1. Nitrosation The formation of a 1,5-dinitroso derivative (309) upon treatment of the parent tetrahydro-lH-l,5-benzodiazepine281 with nitrous acid was first observed by Hinsberg and Str~pler.'~'The preparation of 1,5-dinitroso compounds was also described for the 3-hydroxy analog'" 285, and also for the 2,2,4-trirnethyl9' and 2,4-dicyano-2,4-dimethyl analogs."'
4. Tetrahydro-lH-1,5-Benzodiazepines
215
309
4.2.1.2. Oxidation Oxidation of the 3-hydroxytetrahydrobenzodiazepine284 with chromium trioxide and sulfuric acid was reported to give the corresponding ketone 310 (Eq. 107)."' Ts
T"
Ts
TS
310
284
4.2.1.3. Alkylation The monotosylamide 282 was benzylated using sodium hydride and benzyl bromide.lgO Phenylation of the same compound with iodobenzene and potassium carbonate in the presence of copper afforded l-phenyl-5-tosyl-2,3,4,5tetrahydro-1 H-l,5-benzodia~epine.'~'Reaction of 311 (R = Me) or the corresponding phenol (311, R = H) with methyl iodide in ethanolic potassium hydroxide led to the same 5-methyl derivative 312 (Eq. 108).
QOR
4.2.1.4. Acylation Reaction of 2,3,4,5-tetrahydro- 1H-1,5-benzodiazepine with p-toluenesulfonyl chloride has been reported to give either a monotosylamide'78 or a 1,5-
276
[1,4]Diazepines with [bl-Fused Rings
d i t ~ s y l a m i d e . ' ~ ~N-Tosylation of 2-methyl-2,3,4,5-tetrahydro-lH-l,5b e n ~ o d i a z e p i n e ' ~and ~ 1-benzyl-2,3,4,5-tetrahydro-lH-l,5-benzodia~epine'~~ has also been described. Other acylations have been carried out with 3-bromopropionyl chloride,"l benzoyl chloride,' 7 7 acetic anhydride,IE1 and (2-naphthy1oxy)thiocarbonyl chloride.' 92,308 Treatment of the 6-amino derivative 291 with boiling formic acid yielded the tricyclic compound 313 in 60% yield (Eq. 109).184
313
291
Reaction of the 3-hydroxy derivative 284 with either mesyl chloride or tosyl chloride gave the appropriate sulfonamides. 8 1
'
4.2.2. Reactions with Nucleophiles Hydrolytic cleavage of the sulfonamides 280 and 284 to give the tetrahydrobenzodiazepine 281 and the 3-hydroxy derivative 285 was mentioned above. The conversion of 2,4-dicyano-2,4-dimethyl-2,3,4,5-tetrahydro-lH-1,5benzodiazepine (147) to the thiocarboxamide 148'19 by reaction with ammonium hydrosulfide has also been described (Eq. 53). Selective removal of the benzoyl group in compound 314 was achieved with lithium aluminum hydride in ether (Eq. 110).177Sodium borohydride in pyridine effected the same transformation, but in poor yield.
4.2.3. Photoreactions Photolysis of I-tosyl-2,3,4,5-tetrahydrolH-l,5-benzodiazepine (282) in 70% ethanol containing sodium borohydride and sodium carbonate was reported to
4. Tetrahydro-1H-1,5-Benzodiazepines
277
give the parent tetrahydrobenzodiazepine 281 in quantitative yield."' Irradiation in benzene solution gave only a 12% yield of 281 and a small amount of a compound assigned structure 315.Using the conditions above 280 (R = 4-MeC,H,) and 316 were cleaved to 281 and 311 (R = Me).'79
QOMe
H
a:> H
Ts
Q l NN]
Ts
315
316
4.3. Spectral Data Proton-nmr spectra were employed to assign the cis configuration to tetrahydrobenzodiazepines (317)obtained by reduction of benzodiazepinium salts with sodium b ~ r o h y d r i d e . " ~ , ' ~A~detailed , ' ~ ~ analysis of the nmr spectrum of 317 (R, =R, = Me) indicated the preference of conformation 318.le5
Variable-temperature nmr studies indicate''2 that the unsubstituted tetrahydrobenzodiazepine and the 2,2-dimethyl derivative undergo rapid conformational changes at room temperature. The 2-methyl, 2,4-dimethyl, and 2,2,4trimethyl derivatives, on the other hand, exist in stable conformations that d o not undergo interconversion at temperatures up to 140°C. The mass spectra of several tetrahydrobenzodiazepines were recorded, and the nature of the fragmentation ions has been elucidated.'
'
278
[ 1,4]Diazepines with [bl-Fused Rings
5. TETRAHYDRO-l,5BENZODIAZEPINONES 5.1. 1,3,4,5-Tetrahydro-l,5-benzodiazepin-2(2H)-ones 5.1.I. Synthesis 5.1.1.1. o-Phenylenediamine and a$-Unsaturated Carboxylic Acids The first synthesis of this type, the condensation of o-phenylenediamine with acrylic acid, was reported by Bachman and Hekey.”, These authors obtained the parent compound 319 (R, =R, = R, = R, = H) in 67% yield by heating the diamine and 60% aqueous acrylic acid in concentrated hydrochloric acid on the steam bath for 3 hours (Eq. 111).Ried and U r l a ~ s ’ ’obtained ~ the 4-methyl analog 319 (R, = Me, R,=R,=R, = H) by fusion of the diamine with crotonic acid. The same compound was later using the conditions of Bachman and Heisey.lg3 4,CDimethyl derivatives 319 (R, = H, R, = R, = Me, R, = H, C1, Me) were similarly synthesized by condensation of the appropriate diamine with 3-methylcrotonic acid.Ig8 Condensation of 2aminodiphenylamine with acrylic acid afforded the 1-phenyl-benzodiazepinone 319 (R, = Ph, R, = R, = R, = H) in low yield.”’ Dandegaonker and DesaiZoo prepared a series of 4-phenyl derivatives 319 (R, = substituted Ph, R, = R, = R, = H) by fusion of the diamine with cinnamic acids.
319
Cinnamic acids with electron-releasing substituents in the phenyl ring gave excellent yields of the condensation products. Structural assignments for these compounds were based on analytical and ultraviolet data only. According to Solomko and coworkers,’” acrylic acid may be advantageously replaced by acrylamide. 5.1.1.2. o-Phenylenediamine and P-Halocarboxylic Acids
P-Halocarboxylic acids, which are well-known substitutes for a$unsaturated carboxylic acids, have also been used for the preparation of the benzodiazepinones 319.Thus, reaction of o-phenylenediamine with 3-bromobutyric acid led to the formation of 319 (R, = R, = R, = H, R, = Me) in reasonable yield.”’ While 2,2-dialkyl-3-halopropionic acids 320 cannot be converted to a$unsaturated acids, they could still be utilized for the preparation of the benzodiazepines 321,although the yields obtained were low (Eq. 112).2029203
5. Tetrahydro-1,s-Benzodiazepinones
279
5.1.1.3. By Ring Closure of o-Phenylenediamine Derivatives
3-(2-Aminoanilino)propionic acids 323 (R, = OH), prepared by reduction of the corresponding nitro derivatives 322, were cyclized in high yield to the benzodiazepinones 324 either by heating in boiling acetic acid in the presence of p-toluenesulfonic acid204 or by heating with polyphosphoric acid (Eq. 113).2053206 Reduction and ring closure could be carried out in one step by means of zinc and phosphoric acid in dioxane.,04 Dicyclohexylcarbodiimide has been used for a similar ring closure.203 The cyclization or reductive ring closure of esters and amides of the propionic acids 322 and 323 (R, = M e 0 or NH,) has been shown to give the benzoEven the hydrazide 323 (R, =R, = H, diazepinones 324 as R, = NHNH,) was found to undergo ring closure to 324 (R, =R, = H).’06
322
,
/
323
(113)
H 324
The 1-phenyl-substituted compounds 328 were obtained by cyclization of the propionic acids 325 using either thionyl chloride or acetic anhydride (for R, = Me) (Eq. 114).,07 Other ring closures have been effected by treatment of the 3-bromopropionanilides 326 with sodium bicarbonate and sodium iodide in boiling methan01.~” In addition, compounds 328 (R3 = H) were obtained in good yield by treatment of the 3-chloropropionanilides 327 (X = C1) with or with sodium amide in potassium carbonate in dimethylformamide’99~208~209 liquid ammonia.199*203~208*323 The conversion of 327 to 328 requires an acyl migration that can be rationalized by the formation of an intermediate b-lactam such as 329. Further intramolecular attack as illustrated would yield the benzodiazepinone 330 (Eq. 115).
[1,4]Diazepines with [bl-Fused Rings
280
321 328
-
R5
(115)
N R3 H R4 330
329
Compounds 330 with methyl substituents in the 3- and 4-positions were synthesized by this method.'" The possibility that p-lactams are intermediates in this reaction was supported by earlier work of Nicolaus and coworkers,203who were able to prepare p-lactams 331 (X = NH,) by reduction of the corresponding nitro compound 331 (X = NO,). Treatment of 331 (X = NH,) with acid effected rearrangement to the benzodiazepinones 332 (Eq. 116). Base treatment might possibly effect the same transformation.
33 1
H 332
5.1.1.4. By Ring Expansion (Schmidt Reaction) Misiti and coworkers'87 have carried out the Schmidt reaction on 1,2,3,4tetrahydroquinolin-4-ones (333) and obtained various ratios of 1,3,4,5-
28 1
5. Tetrahydro-1,s-Benzodiazepinones
R 1
RzQ
+ R2<> 0
0
R,
333
NH
335
334
tetrahydro- 1,5-benzodiazepin-2(2H)-ones (334) and 1,2,3,4-tetrahydro-1,4benzodiazepin-5(5H)-ones (335) (Eq. 117). These authors showed that earlier investigators2' were incorrect in their structural assignments. The best yields of 1,5-benzodiazepin-2-0nes 334 were obtained by using 1-acetyl derivatives (333, R, = Ac) while 1-methyl- or 1-phenyltetrahydroquinolin-4-onesled mainly to the 1,4-benzodiazepin-5-ones335. 5.1.1.5. By Reduction of 1,3-Dihydro-1,5-benzodiazepin-2(2H)-ones Reduction of the imine double bond in 1,3-dihydro-1,5-benzodiazepin2(2H)-ones (336) has been widely utilized for the preparation of the tetrahydro derivatives 337 (Eq. 118). Catalytic hydrogenation over Raney nickel was employed to prepare 337 (R, =R, = H, R, = Me;146 R, = H, R, = Me, R, = 8-C1;lo6 R, = H, R, = Me, R, = 8-Me;137,'38 R, = H, R, = Me, R, = 8-Br;'44 and R, = R, = H, R, = Ph or 2-furyl).'" The same reduction was ' ~ ~ ~ ' ~ ~ also achieved by using palladium as the ~ a t a l y s t . ' ~ ~ ~Under these conditions a nitro group in the 7-position was simultaneously reduced to the amino group to give 337 (R, = H, R, = Me, R, = 7-NH2).141 It was possible to reduce the imine double bond and retain the nitro function by using sodium borohydride, as shown by the preparation of 337 (R, = H, R, = Me, R, = 8-N0,).139 When compounds of type 336 are synthesized by the reductive cyclization of a nitro ketone, excessive reduction may lead directly to the tetrahydrobenzodiazepinone 337.' 34*149
336
331
5.1.1.6. Other Syntheses
4-(Alkoxycarbonyl)methylene-substituted 1,5-benzodiazepin-2-ones(339) were obtained by Merz and coworker^^^^^^^^ by condensation of o-phenylenediamine with dialkyl acetone dicarboxylates or their equivalents, the piperidin4-one derivatives 338, (R, = Me, Et; R2 = Ph, 2-pyridyl, 3-pyridyl, 2-quinolinyl; R, = H, Me, PhCH,) in boiling xylene (Eq. 119).
[ 1,4]Diazepines with [bl-Fused Rings
282
340
(1 19)
The direct condensation of o-phenylenediamine with dialkyl acetone dicarboxylates and the cyclization of the intermediate enamine 340 in boiling xylene gave superior yields. A different approach was used for the synthesis of the 1phenyl analog 342, which was prepared by hydrolysis and decarboxylation of the malonylidene derivative (Eq. 120).17' The formation of 341 was mentioned in Section 3.2.2.3.
on
~
f:
'
OOMe
342
341
5.1.2. Reactions 5.1.2.1. Reactions with Electrophiles A. Halogenation. Bromination of the 7,8-dichloro derivative 343 using either bromine in chloroform or a mixture of N-bromosuccinimide and benzoyl peroxide yielded the 6-bromo compound 344 (Eq. 121).'06
343
344
5. Tetrahydro-1,s-Benzodiazepinones
283
B. Nitrosation. Reaction of the benzodiazepines 345 with nitrous acid afforded the 5-nitroso compounds 346 (Eq. 122). Nitrosations were carried out for R,, R,, R, = H;'94 R,, R, = H, R, = Me;'46,'94 R,, R, = H, R, = Ph;lZ9and R, = Ph, R, = Et, R, = H.'03
345
346
Nitrosation of the methoxycarbonylmethylene derivative 342 occurred exclusively on carbon to give the oxime 347 in high yield (Eq. 123).I7l The indicated stereochemistry of the oxime appears to be favored because of hydrogen bonding to the imine nitrogen.
C . Oxidation. Nicolaus and coworkers203 oxidized the 3,3-disubstituted tetrahydrobenzodiazepinone 348 to the dihydro compound 349 by means of ferric chloride in boiling ethanol (Eq. 124).
The chromic acid oxidation of tetrahydrobenzodiazepinones to the corresponding 2,4-diones is discussed in Section 6.1.1, which describes the synthesis of these compounds.
D. Alkylation. Reaction of 348 with methyl iodide or ethyl iodide and sodium bicarbonate in boiling methanol led to the corresponding 5-alkyl derivatives203 However, arylation of the related 8-substituted compounds 350 took place on the lactam nitrogen to give the l-aryl analogs 351 (R, = H) (Eq. 125).'04*'15 These arylations were carried out by a modified Ullmann reaction
[1,4]Diazepines with [bl-Fused Rings
284
O(CH,),OMe 354
using an aryl halide, copper powder, cuprous chloride, and an acid receptor such as potassium acetate or pyridine in a polar nonprotic solvent (e.g., N , N dimethylacetamide). The reaction temperature ranged from 140 to 160°C and the yields were 45-95%.,04 In general, 2-substituted aryl halides, including 2-bromopyridine, gave lower yields of the N-aryl derivatives. Compounds 351 could be further alkylated at the 5-position by a variety of reagents such as alkyl halides,'999204* 2 0 7 - 2 1 0 alkenyl hal207, 2083 alkynyl halides,215and hydroxyalkyl halides207*215 to ~ ~give ~ 353. ~ ' ~Alkylation of the hydroxy give 352, or with ethylene o ~ i d e ' to group in 353 led to the ether 354. Basic side chains were attached to the 1position of 355 (R, = Me, Et) by alkylation with 2-(N,N-dimethylamino)ethyl bromide,', to give 356 (Rl, R, = Me) or by reaction with N-(2-bromoethyl)-Nmethyl- 1-adamantylamine and sodium amide in toluene2" to give 356 (R, = Me, R, = I-adamantyl) (Eq. 126). ,049
E. Acylation, Reaction with Aldehydes. Acylation agents preferentially attack the weakly basic nitrogen at the 5-position as shown by the acetylation of
5. Tetrahydro-1,5-Benzodiazepinones
’I
355
285
356
the 4-methyl-146’194 and 4-phenyl-1,3,4,5-tetrahydro-l,5-benzodiazepin-2-(2H)onesz1’, ’I6 by acetic anhydride. The same type of acylation was also achieved with acetyl chloride141*’03 and propionyl chloride.”’ A variety of 5-acyl were derivatives of l-phenyl-2,3,4,5-tetrahydro-l,5-benzodiazepin-2(1H)-ones prepared by acylations using either formic 2 1 7 various carboxylic acid chlorides,z04*’ I 7 sulfonyl chlorides,z04c h l o r ~ f o r m a t e sz,1~ ~or ~ ~isocyana t e ~5-Carboxamides . ~ ~ ~ were obtained by reaction of the tetrahydrobenzodiazepinone with sodium cyanate and acidzo3,’ I 7 or by reacting this compound with phosgene and subsequently with an amine.’ l 7 The 5-hydroxyalkyl derivatives 357 were acylated with either acetic or succinic anhydrides in pyridine to yield the corresponding esters 358 (R = Me, CH,CH,COOH) (Eq.127).’17 ’159
Condensation of the 4-(aminomethy1)benzodiazepinone 359, obtained by catalytic reduction of the 4-(nitromethylene) derivative in the presence of triethyl ortho-acetate, afforded the imidazoline 360 (Eq. 128).17’
McC(OEt),
359
~
360
[1,4]Diazepines with [bl-Fused Rings
286
The 5-aminotetrahydrobenzodiazepinone361 was acetylated with acetic anhydride to give a diacetate, formulated as either 362 or 363 (Eq. 129).’94
Ac,O
N Me NH, 361
\
N Me or HNAc 362
a’3 \
N
Me NAc,
363
364
Compound 361 formed the hydrazones 364 in good yields by reaction with benzaldehyde, 2-nitrobenzaldehyde, and benzophenone.’ 94 The imine 365 was obtained by condensation of the appropriate %amino derivative with 4-nitroben~aldehyde.”~ 5.1.2.2. Reactions with Nucleophiles A. Hydrolysis, Alcoholysis. Hydrolytic cleavage of the amide bond in 348 to give the acid 366 was effected in boiling concentrated hydrochloric acid (Eq. 130).203
348
366
While vigorous alkaline or acid hydrolysis cleaved the alkoxycarbonylmethylene derivative 339 to o-phenylenediamine and acetone, a more controlled alkaline hydrolysis gave a high yield of the decarboxylated product 367 with an endocyclic double bond (Eq. 131).’14 Treatment of 339 (R = Me, Et) with benzyl alcohol, 2-ethoxyethanol, or tetrahydrofuran-2-methanol and a catalytic amount of sodium gave good yields of the corresponding transesterified products.’ l 4
287
5. Tetrahydro-1,s-Benzodiazepinones
339
B. Substitution Reactions. The 5-(2-hydroxyethyl) derivative 368 was converted to the 2-chloroethyl analog 369 by treatment with thionyl chloride and pyridine (Eq. 132).'17
The Sandmeyer reaction was employed to transform the 8-amino compounds 370 to the 8-cyano and 8-hydroxy derivatives 372 (X = CN, OH; R = H). To avoid nitrosation of the 5-position during diazotization, the nitrogen was protected by trifluoroacetylation. The protecting group was easily removed, after reaction of the diazonium salt 371 (R = COCF,) with the nucleophile, by heating with aqueous ammonia.204 Reaction of the diazonium salts 371 (R = COCF,, NO) with 4-(N,N-diethylamino)anilineafforded the corresponding R = COCF,, NO) (Eq. 133).'04 azo compounds 372 (X = Et,NC,H,N=N--;
yJY'
Ph
"H2yJNT \
Th
rR 370
Th
...;-+NyJNP
N
R
371
x-
N
R
312
(133) C. Reductions. The reduction of the 2-carbonyl group by lithium aluminum hydride was discussed above (Section 4.1). 8-Nitro derivatives were catalytically reduced to the 8-amino analogs using palladium141 or Raney nicke1.'04 The latter catalyst was also effective in the reduction of the nitromethylene compound 373 to the amine 359 without dehalogenation (Eq. 134).17' The 5-nitroso derivatives 346 were reduced to the corresponding 5-amino analogs by zinc and acetic acid.1949'03
288
[ 1,4]Diazepines with [b]-Fused Rings
313
359
Reduction of the 1-(2-nitrophenyl) derivatives 374 with stannous chloride, zinc and phosphoric acid, or iron and hydrochloric acid led directly to the benzimidazo[1,2-a] [1,5]benzodiazepines 375 (Eq. 135).’18
R I
R l
314
315
5.2. 1,2,4,5-Tetrahydro-1,5-benzodiazepin-3(3H)-ones 5.2.1. Synthesis Only the di-N-tosyl derivative 310 of the parent ring system has been described. Paterson and ProctorE4prepared 310 by condensing the ditosylamide 376 with dibromoacetone in toluene in the presence of sodium carbonate (Eq. 136). Ts
I
I
Ts 316
Ts 310
The same compound was later’l9 isolated from the oxidation of the tetrahydroquinoxaline-2-methanol 377 with dicyclohexylcarbodiimide (DCC) and dimethyl sulfoxide in the presence of phosphoric acid. A third synthesis of 310 by Jones oxidation of the corresponding alcohol 284 was noted above (see Section 4.2.1.2).
6. Tetrahydro-1,s-Benzodiazepinediones and Triones
289
5.2.2. Reactions The ketone 310 formed typical derivatives including the oxime,'81 hydrazone,'81 tosylhydrazone,'" and 2,4-dinitrophenylhydra~one.'~~ 8 1 Sodium borohydride reduced the carbonyl group to the corresponding alcohol. " According to Paterson and elimination of sulfinic acid from 310 led to a red monotosylamide, which on the basis of spectral data was assigned structure 378 (Eq. 137). Depending on the base and solvent combination, the yield varied between 50 and 78%, with potassium t-butoxide in dimethyl sulfoxide giving the best results.
'
a'$
base
'
~
QJN>0H N Ts
N
Ts
310
(137)
378
6. TETRAHYDRO-1,5-BENZODIAZEPINEDIONES AND
TRIONES This section reviews the synthesis and chemistry of compounds related to structures 379,380,381 and of variously substituted analogs. 3,3-Dihydroxy-2,4ones are considered to be the hydrated form of the triones 381, and as such are discussed below (Section 6.2). No representatives of the 2,3-dione structure 380 have been described in the literature.
379
380
381
6.1. 3,5-Dihydro-1H-1,5-Benzodiazepine-2,4(2~,4~)-Diones 6.1.1. Synthesis 6.1.1.1. o-Phenylenediamine and Malonic Acid or Esters
The condensation of o-phenylenediamine with malonic acid constitutes the most fundamental synthesis of the parent compound 379 and dates back to
[ 1,4]Diazepines with [bl-Fused Rings
290
studies carried out by Meyer220-222early in this century and later by Phillips.Z23Phillips obtained both the dione 379 and the amide 382 (R = H) by heating a mixture of o-phenylenediamine and malonic acid in boiling 4 N hydrochloric acid. The amide 382 (R = H) was quantitatively cyclized to 383 (R = H) upon further heating in dilute hydrochloric acid (Eq. 138). Following Phillip's procedure, Shriner and B o e r m a n ~ ~obtained ~, the parent compound 379 in 62% yield. Several analogs with substituents at the 7-position were similarly prepared from the substituted o-phenylenediamine~.~~ 226
a
NHz
R
NHz
~
+
YOOH CHz COOH
4N HCI
~ ~ ~ c o c H 2 C 0 0 H
R
2
382
383
Meyer220-222also showed that malonic acid could be replaced by malonic esters. A modification of this method using base instead of acid catalysis was found to be preparatively useful for the synthesis of many 3-substituted derivati v e ~The . ~ 3-ally1 ~ ~ derivatives have been extensively studied by Brobanski and W a g ~ ~ e r , ' ~ *who - ~ ~ used ' sodium ethoxide and toluene to obtain improved yields of the benzodiazepinediones 384. This procedure was successfully extended to the preparation of 384 (R, = alkyl) from N-alkyl o-phenylenediamines (Eq. 139).229
384
6.1.1.2. o-Phenylenediamine and Malonyl Chlorides The reaction of malonyl chlorides with o-phenylenediamines has been used for the synthesis of benzodiazepin-2,4-diones. Particularly successful were the 3 , 3 - d i a l l -~2 3~0 ~and ~ 1-phenyl-5-acyl derivative^.^^' preparations of 7-1iitr0,~~' Compounds 385 (R, = aryl or heteroaryl, R, = H or alkyl) have also been claimed to be accessible by this process (Eq. 140).233
6. Tetrahydro-1,5-Benzodiazepinediones and Triones
29 1
385
6.1.1.3. By Cyclization of o-aminoanilides The most widely used syntheses of benzodiazepin-2,4-dionesinvolve formation of the two amide bonds in separate operations. Thus, 2-nitroanilines (386) are reacted with the chloride ester of malonic acid to yield the corresponding 2-nitroanilides 387. Reduction of the nitro group leads to the amines 388, which can cyclize with loss of alcohol (R3 = OH) to form the benzodiazepin-2,4-diones 389 (Eq. 141).
389
This approach was chosen by Rossi and and by Weber et al.236for the preparation of compounds 389 (R, = Me or Ph). They found that it was not necessary to isolate the intermediate amines 388. Cyclization of 388 was effected by acid catalysis and occurred spontaneously during the reduction step, particularly when zinc in hydrochloric acid was used as the ~ S the ~ cyclization ~ ~ - ~ of~ the ~ reducing agent.234Weber and C O W O ~ ~ de~ scribe amines 388 with various substituents under basic conditions using sodium ethoxide in ethanol at room temperature. Cyclization of the diacylated 2aminodiphenylamines 390 to compounds 391 by means of thionyl chloride was claimed in a Canadian patent (Eq. 142).240 6.1.1.4. By Oxidation According to the patent literature,241 1-phenyl-8-nitro-substitutedbenzodiazepin-2,4-diones (393) were prepared in high yield by oxidation of the
[ 1,4]Diazepines with [b]-Fused Rings
292
1 0
R2NyJNLoo \
CHCI, SOCI,
*
R2a:l
H
(142)
T
R&
Rl O 390
9
R
391
2
3 , , 02Nai
02NaNIp CrO,, CH,COCH, HISO.
(143)
N
Rl
RI
392
393
corresponding 2-ones 392 with Jones reagent (Eq. 143).Oxidation with manganese dioxide reportedly gave inferior yields. 6.1.1.5. Other Syntheses Van alp her^^^' described the formation of the parent benzodiazepinedione 379 by the reaction of o-phenylenediamine with carbon suboxide (Eq. 144).
319
The 3-substituted 1,5-benzodiazepin-2,4-diones395 were prepared by the reaction of o-phenylenediamine with diethyl a-(N-phenylbenzenesu1fonamido)malonate 394 (Eq. 145).317
394
395
6. Tetrahydro-1,5-Benzodiazepinediones and Triones
293
6.1.2. Reactions 6.1.2.1. Reactions with Electrophiles A. Halogenation. The malonic acid moeity in the tetrahydro-1,5benzodiazepin-2,4-diones 396 retains some of its expected reactivity towards electrophilic reagents. Thus, both bromine and chlorine, either in glacial acetic acid or in chloroform, halogenate 396 (R, = alkyl) at the 3-position to give 397 (Eq. 146).243Good yields of the 3-bromo derivatives were also obtained by bromination of the 3-carbanion generated with sodium hydride in tetrahydrofuran.
Me 398
R1 399
Chlorination of 396 (R, = H) with sodium hypochlorite led to the dichloro derivative 399. Compound 399 (R, = Me, R, = CF,) was accessible by treatment of the diazo compound 398 with chlorine in the presence of a copper catalyst.243 B. Nitration. According to the patent literature,226 nitration of the tetrahydrobenzodiazepin-2,4-dione383 (R = H) with fuming nitric acid at - 10°C gives the aromatic nitro derivative 400. At higher temperatures (OOC to room temperature), nitration also occurs at the 3-position to give 401 (R = H, C1, F, COOH) (Eq. 147).
C. Nitrosation. Although malonic acid derivatives are generally nitrosated with ease, Weber and B a ~ e r , ~were , unable to obtain any nitrosated product from the treatment of 396 with an alkylnitrite. Nitrous acid converted the 3-amino derivative 403 (R = Me, X = C1) to the diazo compound 404 (R = Me, X = C1) (Eq. 148).243
D. Reaction with Other Nitrogen Electrophiles. The 3-carbanions 402 reacted with electrophilic nitrogen compounds. Chloramine yielded the 3-amino derivatives 403,243while tosylazide formed the quite stable 3-diazo compounds 404 (Eq. 148).2439244
[ 1,4]Diazepines with [bl-Fused Rings
294
400
R 383
40 1
/ NH,CI
403 FNO.
Ph R 402
R 404
E. Oxidation. Bauer and Weber245-248investigated the oxidation of the 3-aminomethylene derivatives 405 with various reagents. Oxidation with potassium permanganate or chromic acid at room temperature gave the formyl derivatives 406 in about 50% yield (Eq. 149). If the oxidation was performed with permanganate in acetone at - 26 to - 30°C followed by warming to room temperature, the 3-hydroxy derivatives 407 were obtained as the major products. The formyl compounds 406, formed as by-products under these conditions, were separated by conversion to the hemiacetals 408. Under more vigorous reaction conditions, permanganate in acetone and sulfuric acid, the enamine 405 or the 3-hydroxy compounds 406 and 407 were oxidized to the 3,3dihydroxy derivatives 409. Manganese dioxide has also been claimed to effect the conversion of 407 to 409.247 F. Alkylation. Alkylations and arylations of the nitrogens at both the 1- and 5-positions have been extensively studied and a large variety of substituted derivatives have been prepared.
295
6. Tetrahydro-1,5-Benzodiazepinediones and Triones
-Ph..
Ph
NHR H
KMnO, CH,COCH,
a N ,
x
P N H
o
Ph H + x p N f I\ 'A CHO 'N% o H
"
406
405
I
/
/
/
OH
407
KMnO,/CH,COCH,/H,SO,
EIOH/H'
or MnO,
409
408
Shriner and B o e r m a n ~ ' demonstrated ~~ that methylation of 410 (R, = H) with sodium ethoxide and methyl iodide in ethanol led to the 1,Sdirnethyl derivative 411 (R, = H, R, = Me). Biichi and coworkers227 also obtained exclusive N-alkylation upon reaction of 410 (R, = Bu) with n-butyl bromide in ethanolic potassium hydroxide (Eq. 150). The acidity of the amide protons allows the use of relatively weak bases such as hydroxide in protic solvents. Under these conditions C-alkylation at the 3-position does not occur.
41 I
Rossi and ~ o w o r k e r sdescribe ~ ~ ~ , the ~ ~alkylation ~ of 1-methyl and 1-phenyl derivatives using a variety of halides and base-solvent combinations. Similar substitution reactions were carried out by Wagner228on 3,3-diallyl derivatives. Alkylations of 1-phenyl derivatives have been extensively described in the patent Methylation with methyl iodide and base has also been performed on a 3,3-dichloro compound243and a 3-dimethylaminomethylene derivative.247 Strong bases in aprotic solvents generate the 3-carbanion of 1,5-disubstituted compounds such as 412. These carbanions react with alkyl halides to form the 3-substituted derivatives 413 (Eq. 151).2393,3-Disubstituted compounds have not been prepared by this method.
296
[ l,.I]Diazepines with [bl-Fused Rings
A modified Ullmann reaction was found to be suitable for the introduction of aryl and heteroaryl substituents at the 1-position. Weber and C O W O ~ ~ prepared a variety of 1,5-disubstituted 1,5-benzodiazepin-2,4-diones 415 by this method. Reaction of 414 with an aryl or heteroaryl halide was performed in the presence of copper powder and potassium acetate at 10&160°C in dimethylformamide (Eq. 152).
414
~
~
S
~
415
Weber et al. also carried out kinetic studies comparing the rate of N-phenylation of the benzodiazepin-2,4-dione with that of acetanilide. A higher rate of arylation was observed for the cyclic amide, which was attributed to its fixed spatial orientation. The effect on the rate of arylation of substituents at the 7- and 8-positions indicated that electron-withdrawing substituents at the 8-position enhanced reactivity. The influence of the 5-alkyl substituent on the arylation rate appears to be mainly steric. The 5-isopropyl derivative exhibited a distinctly greater reactivity than the compounds bearing a straight-chain alkyl group. This phenomenon was attributed to the greater rigidity of the sevenmembered ring when substituted by an isopropyl group. This rigidity was evident by analysis of the nmr spectral data. An unusual intramolecular ~ ~ alkylation on oxygen was observed by Wagner and C O W O ~ ~ during a study of the hydration of 3-ally1 derivatives. Brief treatment of compounds 416 (R = i-Pr, Ph, cyclohexyl) with concentrated sulfuric acid or 85% phosphoric acid yielded the corresponding furobenzodiazepines 417 (Eq. 153). When R represented a less bulky substituent such as allyl, the hydrated form 418 was obtained.228The addition of hydroxide to the 2-position carbon was thus dependent on the steric bulk of the substituent R on the neighboring carbon atom.
G. Acylation. Acylation of the amide functions in 1,5-benzodiazepin-2,4diones 414 occurs on nitrogen to give 419 (Eq. 154). Generally, the amide is deprotonated by strong bases prior to reaction with an acyl halide or anhy-
S
~
~
6. Tetrahydro-1,5-Benzodiazepinedionesand Triones
417
416
297
(153)
418
R 1
R2qJ30
0
R 1
*
(1 54)
or (R,CO),O. R, -N=C=O
H
414
0
(R,NHCO) R 3 C 0 419
dride.234,251The reaction with m e t h y l i s ~ c y a n a t ewas ~ ~ ~ carried out with a catalytic amount of triethylamine, while acylation with acetic or propionic anhydride251 required heating neat or in the presence of pyridine. Thus, acetylation of the 3-hydroxy derivative 420 with acetic anhydride for 3 hours at 85°C gave the 3-acetoxy compound 421 (R = H) in 73% yield, while under the more vigorous conditions of reflux for 4-5 hours the 0,N-diacetyl derivative 421 (R = Ac) was obtained (Eq. 155).246
420
421
The 3-benzoyloxy analog of 421 (R = H) was prepared in moderate yield by Benzoylation of the treating 420 with sodium hydride and benzoyl 3-carbanion of 422 led in low yield to the 0-benzoylated enolate 423 of the 3-benzoyl derivative (Eq. 156).243 The enamines of 3-formyl derivatives were found to be readily accessible by reaction of compounds 424 with phosphorus pentachloride and dimethylrevealed that the first step may be f ~ r m a m i d e . " ~ Studies * ~ ~ ~of* this ~ ~ reaction ~ the formation of an 0-P bond involving the free amide function followed by reaction with immonium chloride to yield the intermediate 425 (Eq. 157). Mild
[1,4]Diazepines with [bl-Fused Rings
298
I . NaH, T H F 2. ClCOPh
*
c1.
a
N
p
Ph z
h
T o
,
Me
Me 422
423
PCI, DMF
*
i//
424
rh
Th
0
(157) RNH2
aN>N "OCHO Me2 426
f
427
428
hydrolytic workup with ice water gave the 4-formyloxy derivative 426 in 72% yield. Workup with dilute sodium hydroxide solution led to 428, presumably via 426. When a primary amine was used in the workup of the reaction mixture, compounds 427 were isolated in high yields (8&95%). Treatment of 428 with n-butylamine at room temperature resulted in the expected amine exchange to give 427 (R = n-Bu). 6.1.2.2. Reactions with Nucleophiles A. Hydrolysis and Alcoholysis. Shriner and BoermansZz4subjected the 1,5dimethyl derivative 429 to acid hydrolysis and isolated the benzimidazolidine 430 in 61% yield. This compound most likely was formed by cleavage of an amide bond and recylization to the imidazolium salt 431, which could then undergo decarboxylation and hydration to give thc observed product (Eq. 158).
6. Tetrahydro-1,SBenzodiazepinedionesand Triones
299
Weber and coworkers243 attempted to prepare the 3-benzoyl derivative 432 by mild alkaline hydrolysis of the benzoylated enolate 423 but observed only cleavage to the 3-unsubstituted compound 422 (Eq. 159).
422
Hydration of the double bond in 3-allyl- 1,5-benzodiazepin-2,4-diones(433) was extensively studied by Wagner and ~ o w o r k e r s . ~Using ~ ~ - 85% ~ ~ ~phosphoric acid at 100°C they obtained the benzimidazoles 437 as the major products. Under milder conditions, such as concentrated sulfuric acid at room temperature, compounds 435 and their ring-opened equivalents 436 could be isolated. Since 436 was converted to the benzimidazole 437 by heating in phosphoric acid, it is likely that 435 and 436 are the initial products of the reaction leading to 437 (Eq. 160). The initial step is believed to be protonation of the double bond with formation of a carbonium ion, which is intramolecularly trapped by the amide oxygen to form the cyclic carbonium ion 434. If R, is hydrogen, loss of this
[ 1,4]Diazepines with [b]-Fused Rings
300
435
417
1 436
proton leads to 417. Such imino ethers were stable enough to be isolated when R, was sufficiently bulky to impede attack of hydroxide at the 2 - p o ~ i t i o n . ' ~ ~ The quantitative conversion of compounds 385 to the benzimidazolones 440 by treatment with catalytic amounts of sodium ethoxide in ethanol was reported by Weber and coworkers.239Ethanolysis of one of the amide bonds followed by
439
30 1
6. Tetrahydro-1,5-Benzodiazepinediones and Triones
recyclization of intermediates 438 would give the intermediate hydroxybenzimidazolidines 439. Retroaldol-type cleavage would then lead to the benzimidazolones 440 and ethyl acetate (R2, R, = H) (Eq. 161). B. Substitution Reactions. The attempt to displace halogen in 397 (X = C1, Br) with nucleophiles was not The reaction of 397 (R, = Me) with methoxide gave only the benzimidazolone 441, while treatment with dimethylamine in the presence of copper effected dehalogenation to yield 396 (Eq. 162).
Me 44 I
397
Me 396
The 3-diazo derivatives 404, on the other hand, proved to be useful as substitutes for nucleophilic displacement reactions. Protonation to the diazonium salts 442 followed by loss of nitrogen generates the carbonium ions 443. Nucleophiles represented by Y - may then add to give the 3-substituted derivatives 444 (Eq. 163).
1
i
L 404
442
(1 63)
444
443
[ 1,4]Diazepines with [b]-Fused Rings
302
Reaction of 404 with water in the presence of copper or copper salts afforded the 3-hydroxy derivatives 444 (Y = OH) in high yields. Decomposition of the diazo compound in alcohols in the presence of catalytic amounts of boron trifluoride and copper powder led to the 3-alkoxy analogs 444 (Y = alkoxy). Boiling 404 in carboxylic acids under similar conditions produced 3-acyloxy compounds (444, Y = acyloxy). The 3-chloro compound 444 (Y = C1) was obtained by treatment of the diazo derivative with hydrogen chloride, potassium chloride, and copper powder in a ~ e t o n i t r i l e . ~ ~ ~
C. Reduction. Lithium aluminum hydride in tetrahydrofuran was capable of reducing both carbonyl groups in 410 (R, = H, Et) to give good yields of the tetrahydro-1,5-benzodiazepines445 (Eq. 164).231 H
R, H
o
410
LiAlH THF
a ; > R l
H 445
446
441
Under similar conditions, the 3,3-diethyl derivative 446 (R = Et) was reduced only to 447, while the 3,3-dipropyl analog did not undergo any reduction.231 Reduction of the nitro group in the 2-nitrophenyl derivatives 448 with stannous chloride, iron and hydrochloric acid, or zinc and phosphoric acid was accompanied by ring closure to give the benzimidazobenzodiazepines 449 (Eq. 165).”’
I
448
449
6. Tetrahydro-1,s-Benzodiazepinedionesand Triones
303
6.2. 1,5-Dihydro-l,5-benzodiazepin-2,3,4(2H,3H,4H)-triones 6.2.1. Synthesis The triones 450 were prepared by thermal dehydration of the corresponding 3,3-dihydroxy derivatives 409 (Eq.166).246,247
409
450
6.2.2. Reactions Heating the trione 450 (X = CF,) under reflux in wet xylene for one hour gave the quinoxaline 451 and carbon dioxide (Eq. 167).246 The 3-hydroxy compound 453 (X = CF,), which was detected in the reaction mixture, may have been formed by hydride abstraction from the solvent. The 3-hydroxy derivatives 453 are accessible in high yields by reduction of 450 with zinc and acetic Other reducing agents such as tin and hydrochloric acid or
454
304
[1,4]Diazepines with [bl-Fused Rings
sodium borohydride, or catalytic hydrogenation have also been claimed to effect the same t r a n ~ f o r m a t i o n . ~ ~ ~ Bauer and Weber246 describe the addition of nucleophiles to the reactive 3-keto group of the trione 450 (X = CF,). The high reactivity of this group was evident from the easy formation of the hydrate 409 (Eq. 166). Reaction of 450 (X = CF,) with n-butylamine in boiling benzene gave the quinoxaline derivative 452 (R = NHBu-n). The corresponding methylester 452 (R = OMe) was isolated from the reaction of 450 with sodium methoxide in acetone. Also isolated from this reaction was the quinoxalinedione 451 and the aldol product 454. The latter compound was also prepared in high yield by heating an acetone solution of 450 (X = CF,) under reflux in the presence of triethylamine. The formation of the quinoxalines 452 may best be explained by a benzilic acid type rearrangement as illustrated below. The reaction is initiated by the addition of a nucleophile X - to the 3-keto group to give the anion 455. Ring contraction as indicated would then lead to intermediate 456, which can either undergo dehydration to give 452 or be cleaved to 451 (Eq. 168).
455
6.3. Spectral Data
The flexibility of the seven-membered ring of the 2,4-dione 389 has been shown to be dependent on the bulk of the substituent R,. Thus, the methylene protons appear as a singlet in the room temperature nmr spectrum of 389 (R, = Et, R, = 8-C1) while the same protons in 389 (R, = i-Pr, R, = 8-C1) give rise to an AB system.239
389
I . 1,5-Benzodiazepinethiones
305
The large coupling constant of 14.5 Hz between the enamine proton and the NH in compounds 427 was attributed to the transoid orientation of these protons, which are fixed by hydrogen bonding.’”
427
Mass spectrometry was essential in studying the biotransformations of High pressure liquid triflubazam, 415 (R, = Me, R, = 8-CF3, Ar = Ph).253,2s4 chromatography was used to separate the metabolites of this c o r n p o ~ n d . ’ ~ ~
7. 1,5-BENZODIAZEPINETHIONES 7.1. Synthesis
7.1.1. o-Phenylenediamine and Thioacid Derivatives 1,3-Dihydro-2H-1,5-benzodiazepin-2-thiones 457 with a substituted phenyl group at the 4-position were preparedzs6 in good yield by condensation of o-phenylenediamine with an appropriate benzoyl dithioacetic acid (Eq. 169).
457
3-Carboxylic acid esters of structure 459 were found to be accessible from o-phenylenediamine and the dithiolane 458 (n = 1)257 or the trithiolane 458 (n = 2) (Eq. 170).258
[ 1,4]Diazepines with [bl-Fused Rings
306
7.1.2. By Thiation of Lactam Oxygen Thiation of the corresponding 1,5-benzodiazepin-2-onesor 2,4-diones has been the most widely used method of synthesizing thiones. Szarvasi and coworkers205extended the synthesis of the 1,3,4,5-tetrahydro1,5-benzodiazepin-2(2H)-thione 460 (R, = R, = H) described by Kiprianov and K h i l ~ a ’ to ~ ~several substituted derivatives and obtained compounds 461 (R, = H) in 6 6 8 4 % yield by allowing the lactams 460 (R, = H) to react with phosphorus pentasulfide in boiling pyridine (Eq. 171).
460
46 1
The same reagents were likewise used for the preparation of the 1-aryl analogs 461 (R, = aryl, R, = H) and for the thiation of 462 to give 463 (Eq. 172).145
462
463
Good regioselectivity was observed during the thiation of the 2,4-diones 464, affording mainly the 4-thione 465 (X = 0) and only small amounts of the 2,4-dithione 465 (X = S) (Eq. 173).159*161,260
464
465
307
7. 1,5-Benzodiazepinethiones
7.2. Reactions
7.2.1. Reactions with Electrophiles Alkylation and acylation of the thiones was discussed above in connection with the synthesis of dihydrobenzodiazepin-2-onescontaining alkylthio substituents at the 4-position. Reaction of the thione 461 (Rl, R,, R, = H) with bromoacetone in benzene has been reported’ 5 9 to yield the thiazolium salt 466. The thiazolobenzodiazepine 467 was obtained in low yield by reaction of the Structure thione 465 (R = CF,, X = 0) with l-brom0-2,2-diethoxyethane.~~~ 468 was assigned261to the product obtained by alkylation of 459 (R = Et) with methyl 2-bromopropionate in the presence of sodium ethoxide. Me.
Ph
A
466
461
468
7.2.2. Reactions with Nucleophiles Thiation has been used to activate the lactam carbonyl to prepare the 4-hydrazino derivatives 470 (Eq. 174).’59,160 The triazolobenzodiazepines 472
469
I
HC-CCH2NH, pTsOH
470
\
R1
47 1
412
[ 1,4]Diazepines with [bl-Fused Rings
308
(R, = Ph; X = 0, S, H2) were obtained in one step by condensing the appropriate thiones 469 either with acetylhydrazine in refluxing butanol' 5 9 * 2 6 0 or with various aroylhydrazines by heating neat or in refluxing trimethylbenzene 471 was accessible by reaction of or n - b ~ t a n o l The . ~ ~imidazobenzodiazepine ~ the appropriate thione with propargylamine in n-butanol containing p-toluenesulfonic acid.260
7.3. Spectral Data Benassi and coworker^"^ carried out an nmr study at various temperatures with the thiones 463. Compound 463 (R = H) showed a singlet for the C-3 protons at room temperature, as did the corresponding 2-one. At lower temperatures this singlet changed into an AB system. The 1-methyl- and l-benzylsubstituted analogs 463 (R = Me, CH,Ph) exhibited an AB system for the methylene protons even at room temperature. The coalescence temperature and free energy of activation for ring inversion were determined and are given below.
R
a'j "Ph
H Me CH,Ph
Tc (K)
AG' (kcal/mol)
248 407 397
11.2 19.7 19.0
463
The mass spectral fragmentation of thiones 463 (R the 4-phenyl ring has been described.262
= H) with
substituents on
8. HEXAHYDRO-l,5BENZODIAZEPINES 8.1. 5~,6,7,8,9,9u-Hexahydro-lH-l,5-benzodiazepines
8.1. l . Synthesis and Spectral Data The title compounds were accessible by condensation of 1,2-diaminocyclohexane 473 with 1,3-diketones (Eq. 175). The 2,4-dimethyl derivative 474 (R = Me) was first prepared and characterized by Lloyd and coworkers.'.263 The mass spectral data of this compound and of the 2,4-diphenyl analog were also reported.264Potter and coworkers26sprepared the cis and trans isomers of 474 (R = Me) and described the proton-nmr spectra of these compounds. l3C-Nmr spectra for of 474 (R = Me) were also obtained and compared with those of other 1 , 4 - d i a z e p i n e ~ . ~ ~ ~
8. Hexahydro-1,5-Benzodiazepines
309
414
8.2. 2,3,4,6,7,8-Hexahydro-lH-l,5-benzodiazepines
8.2.1. Synthesis McDougall and Malik267studied the reaction of 1,2-diketones with 1,3diamines and obtained the diazepine 475 by condensation of cyclohexan- 1,2dione with 1,3-diaminopropane (Eq. 176).The structure of 475 was supported by infrared and ultraviolet data.
4--11/ 4i"c0c10r PhN=C=O
(176)
RCO
416
411
8.2.2. Reactions Alkaline or acid hydrolysis of 475 resulted in cleavage to the starting diketone and diamine. Isomerization attempts with ethoxide and dehydrogenation experiments with chloranil were unsuccessful. Reaction of 475 with bromine in bromoform gave the hydrobromide of a dibromo derivative, to which structure 476 was assigned. Acylation with benzoyl chloride or phenylisocyanate led to unstable and ill-defined products assigned structures 477 (R = Ph, R = NHPh).
3 10
[ 1,4]Diazepines with [bl-Fused Rings
9. PERHYDRO-lH-1,5-BENZODIAZEPINES Settimj and coworkersz6*studied the reaction of diketones with diamines in the presence of cyanide (Strecker's synthesis). The 5~,9~-dicyanoperhydro1H 1,5-benzodiazepine 478 was prepared in 87% yield by condensation of cyclohexan- 1,2-dione with 1,3-diaminopropane in the presence of hydrogen cyanide (Eq. 177). The dimer 479 was isolated as a by-product.
478
(177)
+NH(CHZ)3NHw CN CN 479
The stereochemistry of 478 was not determined but could probably be assigned the thermodynamically more stable trans configuration.
10. CYCLOBUTA[b] [1,4]DIAZEPINES
480a 1 H-Cyclobuta[b][ I ,4]diazepines
480b 3H-Cyclobuta[ b][ I,.l]diazepines
41 N
480e 2H-Cyclobuta[b][ I ,4]diazepines
48od 6H-Cyclobuta[ b][ 1,4]diazepines
The only derivatives belonging to this ring system, represented by the four '~~ possible tautomers 480a430d, were synthesized by Seitz and M o r ~ k . These
11. CyclopentaCb] [1,4] Diazepines
311
authors reported the synthesis of the diazepines 483 by condensation of the diaminocyclobutenediones 481 with diethyl malonate at elevated temperature. Reaction of 481 (R = Me) led directly to the diazepine 483 (R = Me). The same condensation with 481 (R = H), on the other hand, gave the intermediate 482 (R = H) and required the use of sodium ethoxide to effect ring closure to the diazepine 483 (R = H) (Eq. 178).
BNHR CH,(COOEt),
NHR
0 48 I
0 O n N N/R H R0
0U O E t 482
-
x:j R
483
(178)
This difference of reactivity of methylated versus unmethylated 481 was attributed to a stabilization of the intermediate 482 (R = H) by intramolecular hydrogen bonding.
11. CYCLOPENTA[b] [1,4]DIAZEPINES
484
The aromatic diazaazulene 484 itself has not been reported in the literature. The hexahydro derivative 485 was accessible by condensation of 1,2-diaminocyclopentane with acetylacetone (Eq. 179).The effects of pH and temperwith acetylacetone were ature on the reaction of trans-1,2-diaminocyclopentane studied by Lloyd and Marshall.270 e
485
Yields of 80% were obtained at 59°C over a pH range of 4-10. At room temperature a minimum yield was observed at pH 8, while maximum yields were obtained at both pH 4 and pH 11. The trans as well as cis isomers of 485 were later prepared for proton-nmr investigation^.'^^
[ 1,4]Diazepines with [bl-Fused Rings
312
12. ISOXAZOLO[4,5-b] [1,4]DIAZEPINES
486a
486b
486c
6H-lsoxazolo[4,5-b][ 1,4]diazepines
4H-Isoxazolo[4,5-b][1,4]diazepines
8H-Isoxazolo[4,5-b][1,4]diazepincs
This ring parent may theoretically exist in any of eight tautomeric forms. Three of these, 486a486c, have an intact isoxazole ring and are considered to be thermodynamically favored. 12.1. Synthesis
Only the 3,5,7-trisubstituted derivatives 489 of the 6H tautomers 486b have been r e p ~ r t e d . The ~ ~se~compounds ,~~~ were synthesized by condensation of the 4,5-diaminoisoxazoles 487 with pentane-2,4-dione (Eq. 180). Treatment of 487 (R = Ph) with aqueous pentane-2,4-dione at room temperature resulted in the formation of the enamine that has been assigned structure 488. Ring closure of 488 to 489 (R = Ph) was achieved in refluxing ethanol in the presence of triethylamine.
0 MeCOCH,COMe RT
H,N
* M e Y 2 N G N Me
R
N H
Ph
489
12.2. Reactions
Protonation of 489 led to a deep violet-blue diazepinium cation believed to be derived from the 4H tautomer 486a or the 8H compound 486c. The
14. Pyrazolo[3,4-b] [lf Diazepines
313
formation of a dication was not observed. Acid hydrolysis resulted in cleavage of 489 to 487.
13. 1,2,5-OXADIAZOLO[3,4-b] [1,4]DIAZEPINES 8
1
H
3
6c;)$z
490b
490a
6H- 1,2,5-0xadiazolo[ 3,4-b] [ 1,4]diazepines
4H- 1,2,5-0xadiazolo[3,4-b] [1,4]diazepines
5,7-Disubstituted derivatives 492 of the parent ring system 490 were prepared by Gasco and coworkers273in the usual manner: that is, by condensation of the diamine 491 with 1,3-dicarbonyl compounds (Eq. 181).
R H,N
N
x Nb HZN
RCOCH,
E1OH.AcOH
49 1
492
Unlike the corresponding benzodiazepine derivatives, these compounds exist in the 4H tautomeric form 490a. Thus, the 5,7-dimethyl derivative showed two methyl signals in the nmr spectra at low temperature, with coalescence at - 29°C indicating localization of the exchangeable proton at the 4-position. At higher temperature the proton is rapidly exchanged between the 4- and 8positions, rendering the methyl groups attached to the 5- and 7-positions magnetically equivalent. The unsymmetrical 5-methyl-7-phenyl analog showed a preference for only one tautomer, the proton being attached to either the 4- or 8-nitrogen.
14. PYRAZOLO[3,4-b] [1,4]DIAZEPINES
4
493
[ 1,4]Diazepines with [b]-Fused Rings
314
14.1. Synthesis
The polysubstituted 1,6-dihydro derivative 495 of the parent ring system 493 was synthesized by Affane-Nguema and coworkers.274The diaminopyrazole 494 was condensed with acetylacetone to give an 85-90% yield of the diazepine 495 (Eq. 182). Under milder conditions the intermediate enamine 496 was formed in quantitative yield and could be cyclized (R = H) by refluxing in butanol.
J
494
R
=
495 ti
496
Cyclization could not be effected with the corresponding 3-methylaminopyrazole 496 (R = Me). The condensation of the diaminopyrazoles 494 (R, = H,Me) with ethyl acetoacetate and ethyl 2-acetopropionate was also Again the corresponding enamine intermediate 497 could be isolated in high yield and subsequently cyclized with sodium ethoxide in ethanol to the diazepinones 498 (R, = H; R, = H, Me) (Eq. 183).
?z
MeCOCHCOOEl R,=H
H2N 494
498
Me
H COOEt 491
499
Me
14. Pyrazolo[3,4-b] [1,4] Diazepines
315
Reaction of the diamines 494 (R, = H, Me) with the ketoester in boiling xylene gave the diazepinones 498 in much lower yield. Since the enamine 497 was not cyclized under thermal conditions, a different reaction path must account for the formation of 498 in refluxing xylene. In this instance, the amide bond may be established before the imine is formed.
14.2. Reactions
Alkylation of the pyrazolodiazepinones 498 (R, = H) with diazomethane led to the N - and 0-methylated products 498 (R, = Me) and 499, in 75 and 20% yield.274However, methylation with sodium methoxide and methyl iodide gave only 498 (R, = Me).275Reaction of 498 (R, = Me, R, = H) with methyl iodide in a sodium-liquid ammonia system yielded 50% of the 6,6-dimethyl compound 500 and a lesser amount of the monomethylated product 498 (R, = R, = Me). When the 8-position nitrogen carried a hydrogen substituent, reductive alkylation of the imine bond was observed as well. Thus, 498 (R, = H, R, = H) reacted with methyl iodide and sodium in liquid ammonia to give 501 (R, = H, R, = Me) and 501 (R, = R, = Me) in 40 and 30% yield. Diazomethane reacted with 501 (R, = R, = H) to form the 8-methyl derivative 501 (R, = Me, R, = H) as the major product. Small amounts of the dimethylated compound 501 (R, = R, = Me) were also obtained. The methylthio derivative 503 resulted from the alkylation of the thione 502 with diazomethane (Eq. 174). This thione was prepared by treatment of the corresponding lactam 498 (R, = R, = H) with phosphorus pentasulfide and pyridine.
500 50 1
502
503
Hydrogenation of the imine double bond in 498 (R, =R, = H) over palladium on carbon gave high yields of 501 (R, = R, = H). The same transformation was also achieved in lower yield by reduction with sodium in liquid ammonia.
316
[ 1,4]Diazepines with [bl-Fused Rings
Reduction of 498 (R, = R, = H) with lithium aluminum hydride in boiling ether for 6 hours afforded a mixture of 505 (R = H) and 501 (R, =R, = H) together with 504 (R = H) (Eq. 175). More vigorous conditions, 24 hours of reflux, led to the single product 505 (R = H) in 90% yield. Similar conditions converted 495 to 505 (R = Me), as well as 504 (R = H, Me) to 505 (R = H, Me). A highly selective reduction of the 7,8-imine leading to 504 (R = Me) was observed during the hydrogenation of 495 over palladium on carbon. Ph
~ e ~N / 495
he
Md
4e 504
\I;*'".
LIAIH,
505
14.3. Spectral Data
The mass spectral fragmentation of many of these pyrazolodiazepines has been reported.276
14.4. 4,8-Dihydropyrazolo[3,4-b] [1,4]diazepind,7(1H,CH)-diones
A pyrazolone compound was reacted at 0-5"C with benzenediazonium chloride in glacial acetic acid to form the phenylhydrazone 506, which upon treatment with boiling phosphorus oxychloride can be chlorinated at the 5-position to give the 4-phenylazo-5-chloropyrazole507. Subsequently, the chlorine was substituted with an appropriate amine (R,NH,) at 1W16O"C to form 508. Reaction of 508 with malonic acid derivative yielded 509 as a product. The azo group of 509 can be split by catalytic hydrogenation (with Pd, Pt, or Raney nickel) to form 510, cyclization of which gave 511 (Eq. 186).321* 322
15. PyridoCb] [lf Diazepines
317
506
N\
507
"\N/"H I R,
I?--N-CO-CH-COX R, R4
N
R.
' R5
508
509
510
51 1
(186)
15. PYRIDOCb] [1,4]DIAZEPINES 15.1. Pyrido[2,3-b] [1,4]Diazepines Examples of this parent ring system represented by the tautomers 512a-512c have not been described in the literature. Compounds with higher degree of saturation are discussed below.
512a
lH-Pyrido[2;3-b][1.41diazepines
512b 3H-Pyrido[2,3-b][1,4)diazepines
512c SH-Pyrido[2,3-b][1,4]diazepines
318
[1,4]Diazepines with [bl-Fused Rings
15.I . I . Dihydropyr id0 [2,3- b] [ I ,4] diazepines The 4,5-dihydro derivative 514 has been reported"' to be formed in the reaction of 2,3-diaminopyridine with the P-dimethylaminoketone 513 (Eq. 187). The structure of 514 has not been confirmed either spectroscopically or chemically.
15.I .2. Dihydropyrido[2,3-b] [1,4]diazepinones Israel and coworkers277 have investigated the condensation of 2,3-diaminopyridine with ethyl acetoacetate and reported the formation of the regioisomers 516 (R = Me) and 517 (R = Me) (Eq. 188). The enamine 515, arising from the reaction of the more basic amino group with the ketone, could be isolated and cyclized to 517 (R = Me) by treatment with sodium ethoxide in ethanol. The regioisomer 516 (R = Me) was formed thermally together with the imidazopyridines 520 and 521. According to spectroscopic data 516 (R = Me) and 517 also exist in the tautomeric forms 518 and 519. Structure 519 was assigned to the colorless crystalline form and structure 517 to the yellow tautomer in solution. On the basis of nmr data, 516 (R = Me) were present in solution together with the tautomer 518 in a ratio of about 1 :3. The reaction of 2,3-diaminopyridine with ethyl acetoacetate in refluxing xylene was also investigated by N a ~ o j s k i ' and ~ ~ later by Lavergne and coworkers279 who reported, respectively, yields of a 8.5 and 60% of the diazepinone 517 (R = Me). The analogous reaction with ethyl benzoylacetateZ8' gave 65% of the diazepine 517 (R = Ph). Condensation products with 4methoxybenzoyl acetate and 3,4,5,-trimethoxybenzoylacetatewere also described."' Two regioisomers corresponding to analogs of 516 (R = Me) and 517 (R = Me) were similarly obtained by the condensation of 5-bromo-2,3diamino-4-methylpyridine with ethyl acetoacetate in boiling toluene.28'
1S.1.3. Tetrahydropyrido[2,3-b] [ I ,4]diazepines The tetrahydro derivative 523 was prepared" by catalytic hydrogenation of the corresponding dihydro compound 522 (Eq. 189). Desulfurization of the
319
15. PyridoCb] [1,4]Diazepines
515
I
NaOEt
Q H o 516
517
ti
it
QEj N
H
R 519
518
thiones 524 (R = H, Br) gave good yields of the reduced product 525 (Eq. 190).282
522
524
523
525
320
[1,4]Diazepines with [bl-Fused Rings
The nitrile 526 was obtained by reaction of 2,3-diaminopyridine with cinnamaldehyde in the presence of hydrogen cyanide (Eq. 191).283The regiochemistry was assigned on the basis of nmr spectral data. The stereochemistry, which was not discussed, is probably trans.
1’ ‘NH2
AcOH
526
15.1.4. Tetrahydropyrido[2,3-b] [ I ,I]diazepinones According to the patent literaturezE4the 5-phenyl-7-chloro-substituted compounds 530 can be synthesized by thermal cyclization of the amino acids 529, which are obtained by reaction of the pyridine 527 with the anilinopropionic acid 528 followed by catalytic reduction of the nitro group (Eq. 192).
flr2
c1
r-C , OOH I Na,CO,/Z-PrOH
+
N
\
521 528 529
530
(192)
The tetrahydropyrido[2,3-b] [1,4]diazepin-2-ones 532 were isolated as minor products of the Schmidt reaction on the ketone 531.282The major products were the isomeric diazepines 533 (Eq. 193). Compounds 532 were converted in high yield to the corresponding thiones 534 by treatment with phosphorus pentasulfide in pyridine.282 The tetrahydropyrido[2,3-b] [1,4]diazepin-4-one 535 was prepared285by catalytic hydrogenation of 517 (R = Me) (Eq. 194).
321
15. PyridoCb] [lf Diazepines
iH I
531
532
II
533
534
517
535
15.1.5. Tetrahydropyrido[2,3-b] [ I ,I]diazepinediones The diones 536 (R, = H) were accessible2E6in 12-20% yield by condensation of substituted malonic acid esters with 2,3-diaminopyridine (Eq. 195). A better yield was reportedzE7for the preparation of the 3,3-diallyl derivative by using sodium ethoxide in boiling xylene.
536
Ring closure of the malonic ester amides 537 (Eq. 196) with sodium ethoxide in ethanol has been utilized for the synthesis of chloro-substituted pyridine derivatives including the 5-phenyl compounds 538 (R, = Ph).284 The starting materials 537 were prepared by acylation of the appropriate 2-amino-3nitropyridine followed by reduction of the nitro group.
[ 1,4]Diazepines with [bl-Fused Rings
322
531
538
15.2. Pyrido[3,4-b] [1,4]diazepines
539a 1 H-Pyrido[3,4-b]-
[1,4]diazepines
539b 3H-Pyrido[3,4-b][1,4]diazepines
539c SH-Pyrido[3,4-b] [1,4]diazepines
Maintaining the aromaticity of the pyridine ring would allow this ring system to exist as any of the three tautomers 539a-539c. Derivatives of the 3Htautomeric form, compounds 541, have been synthesized by the condensation of the diaminopyridines 540 with acetylacetone (Eq. 197).288
MeCOCH,COMe
Rl
540
N\ @ Rf le N- Me
( 197)
54 I
15.2.I . Dihydropyrido[3,4-b] [ I , 4 ]diazepinones The reaction of 3,4-diaminopyridine with ethyl acetoacetate in boiling xylene was first investigated by N a w o j ~ k i , who ~ ' ~ incorrectly assigned structure 544 to this product on the basis of spectral data (Eq. 198). Later work by Israel and Jonesz9' showed that this assignment was incorrect. The latter authors obtained 542 in 60% yield as a mixture of the 1H and 3H tautomers by condensation of the reactants in boiling toluene. The regioisomer 544, on the other hand, was synthesized via the enamine 543 by ring closure with sodium ethoxide in ethanol. Compound 544 existed only as the 3H tautomer in solution. Fragmentation of these compounds upon electron impact was discussed.279
15. PyridoCb] [1,4] Diazepines
glXe
g;;z
MeCOCH,COOEl PhMe
N\
323
N\
2
H
I
543
544
15.2.2. Tetrahydropyrido[3,4-b][1,4]diazepines and Diones Structure 545 (undefined stereochemistry) was assigned to the product obtained by the reaction of 3,4-diaminopyridine with cinnamaldehyde in the presence of hydrogen cyanide (Eq. 199).283
%:Iph CN
N\
g;I:
N\
545
(199)
H
546
Compound 546 (R = H) was prepared in 58% yield by reaction of 3,4diaminopyridine with malonyl chloride.231 The 3,3-diallyl derivative 546 (R = CH,CH=CH,) was accessible by condensation of the same diamine with diethyl diallylmalonate in boiling xylene in the presence of e t h ~ x i d e . , ~ ~ 15.3. Reactions
15.3.1. Reactions with Electrophiles Both tetrahydropyrido[2,3-b] [1,4]diazepin-2-ones 547 (X = H,, R, = Ph) and the corresponding 2,4-diones (X = 0)were alkylated at the 1-position by
[ 1,4]Diazepines with [bl-Fused Rings
324
reaction with sodium hydride followed by treatment with alkyl halides such as methyl iodide, allyl bromide, and 2-(dimethylamino)ethyl chloride to give the corresponding 1-substituted derivatives 548 (Eq. 200).284
NaH
R,
548
547
549
Arylation of 547 (X = 0, R, = H) with bromobenzene, potassium acetate, and copper in dimethylformamide gave a low yield of the 1,3-diphenyl derivative 549.284 Conversion of the 3,3-diallyl derivative 550 to the lactone 551 (Eq. 201) by treatment with phosphoric acid proceeded in analogy to the corresponding benzodiazepine.228s230 The initial step is thought to be an intramolecular alkylation on oxygen. Interestingly, the [3,4]-fused pyridodiazepine 546 (R = allyl) behaved quite differently and yielded hydrolysis products only.
550
55 1
15.3.2. Reactions with Nucleophiles Transformations of the lactam carbonyl to the thiolactam by treatment with phosphorus pentasulfide in pyridine were also successful in this series of 291 Fu rther conversion of the thione 552 to the amidine 553 by reaction with methylamine has been claimed (Eq. 202).291
15.3.3. Thermal Reactions Thermal ring contraction of the dihydropyridodiazepinones 554 to the imidazopyridines 555292appears to be general for compounds bearing the
325
16. Pyrimido[4,5-b] [1,4] Diazepines
554
555
nitrogen at any of the following positions: 6-,2777-,290 8-,290 or 9-2779280 (Eq. 203). Compounds 555 were isolated as the major products during the preparation of 554 in boiling ~ y l e n e .2~8 1~, 290 ~ . This general reaction is a useful diagnostic tool for the determination or confirmation of the structures of dihydropyridodiazepinones. Israel and coworkers292suggested a concerted mechanism for this reaction involving a [1,3]sigmatropic shift from carbon to nitrogen.
16. PYRIMIDO[4,5-6] [1,4]DIAZEPINES
556a SH-Pyrimido[4,S-b][1,4]diazepines
556b 7H-Pyrimmdo[4,S-b][ 1,4]diazepines
556c
9H-Pyrimido[4,5-b][ 1,4]diazepines
Compounds with this parent ring system represented by the tautomers 556a-556c have not been reported in the literature.
16.1. Dihydropyrimido[4,54] [1,4]diazepinones The first synthesis of a pyrimido[4,5-b] [1,4]diazepine was reported by Nyberg and who, on the basis of spectral data, assigned structure 557 (R = Me) to the product isolated in 38% yield from the condensation of ethyl acetoacetate with 4,5-diaminopyrimidine in boiling xylene (Eq. 204). The
[ 1,4]Diazepines with [bl-Fused Rings
326
I
558
551
559
Me
560
same reaction was later reinvestigated by Israel and coworkers,294who confirmed the structure of 557 and also prepared the regioisomer 559 (R = Me) by cyclization of the enamine 558 (R = Me) with sodium ethoxide in ethanol. Thermal ring closure of the acetoacetamide 560, thought to be the intermediate in the formation of 557, led to a mixture of 557 (R = Me) and 559 (R = Me), with the former being the predominant product. The formation of 559 (R = Me) from 560 may be due to an intramolecular transacylation. Some evidence of tautomerism was reported for 559 (R = Me).294A sublimed sample of this compound was colorless and exhibited an ultraviolet spectrum different from that of material recrystallized from ethanol. The structures 557 and 559 were confirmed by the base-catalyzed rearrangement to isopropenyl purinones (see Section 16.6, Reactions). A similar condensation of 4,5-diaminopyrimidine with ethyl (3,4,5trimethoxybenzoy1)acetate in refluxing xylene was reported"' to give an 82% yield of the 5H tautomer of 559 (R = 3,4,5-(Me0)&H2). 16.2. Tetrahydropyrimido[4,54] [1,4]diazepinones The synthesis of 562 by condensation of the diamine 561 with 1,3-diketones in polyphosphoric acid has been described by Fukushima and coworkers (Eq. 205).295 Structure 563 was assigned to the intermediate enamines obtained by heating the diamine and the diketone in boiling butanol. Ring closure of 563 was effected
16. Pyrimido[4,5-b] [1,4] Diazepines
321
Me
Me R,COCH2COR, PPA
0
0
563
by treatment with polyphosphoric acid. While the symmetrical diketones gave acceptable yields of product, the reaction of 561 with benzoylacetone gave the expected mixture of regioisomers 562 (R, = Me, R, = Ph) and 562 (R, = Ph, R, = Me) in low yield.
16.3. Hexahydropyrimido[4,54] [1,4]diazepinones The diamine 561 reacted smoothly with acetone or mesityl oxide (4-methylpent-3-en-2-one) to form a diazepine, which was assigned structure 564 on the basis of spectral data.296In particular, the infrared spectrum showed an absorption band indicating a free NH. The regioisomer would be expected to exhibit a chelated NH absorption band. According to the patent literature,297 condensation of 561 with 8-ketoesters led to the enamines 565 which could be cyclized in good yield to the diazepines 567 by treatment with sodium alkoxides or sodium hydroxide in methanol or ethanol (Eq. 206). The diazepines 567 were originally formulated as the 5H tautomers, but the later work of Fukushima and indicates clearly that the phenylsubstituted derivative 567 (R, = Ph, R, = H) has the structure shown in Eq. 206.These authors also synthesized the regioisomer 568 by thermal ring closure of the p-ketoamide 566, which was prepared by heating the diamine 561 with ethyl benzoylacetate in xylene. Again, the tautomeric form shown was preferred on the basis of nmr spectroscopy. An interesting condensation product was isolated299from the reaction of 561 with the unsaturated 1,4-diketone 569 in boiling acetic acid. On the basis of spectral data, the structure of the product was assigned as 570 (Eq. 207). A strong argument was the lack of the NH absorption bands in the infrared spectrum recorded in Nujol. However, it is not unlikely that 570 is in fact the 7 H tautomer in the solid state and a mixture of the 7 H and 5H tautomers in solution. In view of Bass's work on related benzodiazepines, structure 571 also has to be considered as a viable alternative.
MeCOMe or Me,C=CHCOMc
56 1
564
565
J
566
NaOR
23&240"C/2 mmHg
Ph
0 567
561
"Me
N 568
+ 569
Me 570
571
328
16. Pyrimido[4,5-b] [lf Diazepines
329
16.4. Octahydropyrimido[4,5-b] [1,4]diazepinones
The octahydrotriones 573 were prepared in good yield297by hydrogenation of the imine bond in 567 or by cyclization of the esters 572 with sodium ethoxide in ethanol. Compounds 572 were accessible by hydrogenation of the enamines 565 over platinum catalyst (Eq. 208).
H
R,
0
572
573
The stereochemistry of the product 573 (R, = Me, R, = Et), obtained by hydrogenation of the corresponding compound 567, was not established.
16.5. Hexahydropyrimido[4,5-b] [1,4]diazepine-2-thiones
While the condensation of the diaminopyrimidinedione 561 with ethyl acetoacetate in boiling xylene led only to an acetoacetamide of type 566, the corresponding 2-thione 574 gave a high yield of the diazepine 575 (Eq. 209).300 The reaction of 574 with diethyl ethoxymethylenemalonate was reported to lead to a diazepine of possible structure 576.301
NqrMe Me
Me
MeCOCH,COOEl A
H2N H
0 574
D
M
2
~
~
576
~
~
(
~
~
~
~
t ) 575
O ,
[ 1,4]Diazepines with [bl-Fused Rings
330
16.6. Reactions
16.6.1. Reactions with Electrophiles Nitrosation of 564 afforded a dinitroso compound that was assigned structure 577 (Eq. 210).296 Me H
Me HNOl
“Me
0
Me
(210)
0 511
564
16.6.2. Reactions with Nucleophiles Compound 557 (R = Me) was found to be very susceptible to hydrolysis. Cleavage of the enamine occurred during recrystallization from 95% ethanol to give the acetoacetamide 560 (Eq. 21 l).294
560
551
A similar ring opening took place during the reaction of 575 with 2,4dinitrophenylhydrazine in aqueous ethanolic-sulfuric acid, leading to the crystalline hydrazone 578 (Eq. 212).300
Me Me 2,4-(N02)2C,H3NHNH,
*
515
NO2 578
17. Pyrrolo[3,4-b] [ 1,4]Diazepines
331
Reaction of 559 (R = Me) with sodium 2-ethoxyethoxide in hot 2-ethoxyethanol resulted in ring contraction to 579 (Eq. 213).294This rearrangement helped in the structure determination of 559 (R = Me).
519
Hydrogenation of 564 with palladium on carbon was reported296 to give a perhydro derivative of structure 580 of unknown stereochemistry (Eq. 214).
580
564
Reduction of the imine functionality in 567 was mentioned above.
16.6.3. Pyrolysis Pyrolysis of either 557 (R = Me) or 559 (R = Me) at 250°C gave the purinone 581 (Eq. 215),294not the expected isopropylene-substituted analogs.
557, 559
2s0"c
*
o=@J
\ N
H 581
17. PYRROLO[3,4-b] [1,4]DIAZEPINES
582
[1,4]Diazepines with [bl-Fused Rings
332
The only representatives of the pyrrolo[3,4-b] [1,4]diazepine ring system 582 reported in the literature appear to be the hexahydrodiones 585.302These compounds were obtained by condensation of the diaminopyrrolinone 583 with ethyl acetoacetate and cyclization of the resulting enamine 584 using sodium ethoxide in ethanol (Eq. 216). Nmr spectra in dimethyl sulfoxide indicate the presence of a mixture of the tautomers 585 and 586 in a ratio of approximately 1 :2.
583
584 NaOEl
585
586
18. TRIAZOLO[4,5-b] [1,4]DIAZEPINES
587
Compounds derived from the parent ring system 587 were described by Lovelette and Long.303 These authors reacted the diaminotriazole 588 with ethyl acetoacetate and obtained in 90% yield the enamine that was assigned structure 589 (Eq. 217). This assignment was based on the assumption that the carbonyl group would react preferentially with the more reactive 4-amino
333
18. Triazolo[4,5-b] [1,4]Diazepines
function of 588. Compound 589 was then cyclized as usual to the diazepine 590 by heating in ethanolic sodium ethoxide under reflux. An nmr spectrum in deuterated pyridine solution indicated the presence of tautomer 590.
HzNI) MeCOCH,COOEt 60-C
H2N 588
HN NsOEt EtOH
Me&, COOEt
+
ty: N
Me 590
589
( 2 17)
19. TABLES OF COMPOUNDS TABLE IV-1. [b]-FLJSED[1,4]DIAZEPINES mp ("C);
Substituent
[bP ("C/torr)l
Solvent of Crystallization
Yield
(YO)
Spectra
Refs.
I .5-Benzodiazepines
IH-1 J-Benzodiazepines
W W
1-Me-2-(4-BrC,H4) Perchlorate 1-Me-2-(4-C1C,H4) Perchlorate 1-Me-2-(4-N0,C,H4) Perchlorate 2-PhCO-4-Ph 2-(PhCOCH2)-4-Ph
2-Et0-4-(3,3-Diethylthi0-2-propen-1-on-l-y1) 2-Et0-4-(2-Ethoxy-l H- 1,5-benzodiazepin-4-yl) 3-COOEt-4-NH2 Hydrochloride 3-CN-4-NH2 Hydrochloride 1-Me-2,3-(Ph), Perchlorate 5-Methoperchlorate
160-180d
69
uv
12
179-1 81d
77
uv
12
196d 169 185 162-165d 166-167.5
34 36 88 19 35
uv pmr, uv, ms Pmr
12 57
230d 203d 280d 210-21 Id 115-116d
PhMe MeCN MeCN/Dioxane EtOH EtOH
55
66 66
80 92
ir, pmr, ms
59,60 60 59,60
72 64
uv uv
12 12
l-Me-2-Ph-4-AcS 1-Me-2-Ph-4-SCH,CH,NEt, l-Me-2-Ph-CC(MeO)(Ph), 1,2-(Ph),-4-C(MeO)(Ph),
1-Ac-2-Me-4-(2-Ac0-5-C1-C6H3) 1-Ac-2-Ph-4-(2-AcOC6H4)
1-Ac-2-Ph-4-(2-Ac0-5-ClC6H3) 1-Ac-2-Ph-4-(2-HOC6H4) ~-Ac-~-P~-~-(~-HO-~-CIC,H,) l-PhCH2-2-Ph-4-AcS
l-PhCH,-2-Ph-4-SCH2CH2NEt,
w w
I-(4-MeC,H,SO,)-2,4-Me2 Perchlorate 1-NO-2,4-Me2 2-HO-3-COOEt-4-MeS 3-COOEt-4-NH2-8-C1 Hydrochloride 3-CN-4-NH2-8-Cl 1-Ph-2-SMe-4-NMe2 1-Ph-2-SMe-4-NEt2 1-Ph-2-SMe-4-N(CH2), I-Ph-2-NMe,-4-NMe2 I-Ph-2-NEt2-4-NMe, I-Ph-2-N(CH2),-4-NMe, 1-Ph-2-NMe,-4-NEt2 1-Ph-2-NEt,-4-N(CH2), I-Ph-2-N(CH,),-4-NMe2 I-Ph-2,4-(N(CH,),), I-Ph-2-N(CH,),-4-N(CH,), I-Ph-2-N(CH2),-4-Morpholino l-Ph-2-N(CH,),-4-(N(CHJ4N-Me) 2,4-Me,-7-CF, 2-Ph-4-(4-FC6H4)-7-CF3
166-169 Oil 178 180 153-1 54 121-123 135-137 163-164 171-1 72 179-182 Oil 360 185 80 202-204 223d 205d 11&117 84-85 182-183 148-149 152-153 151-152 95-96 113-1 14 190-1 9 I 202-203 213-214 179-1 80 185 214-215 228-230
EtOAc
82
CHCI,/MeOH PhH/MeOH EtOH EtOH Cyclohexane Cyclohexane Cyclohexane PhH/petr ether
42 57 56 43 70 28 30
ir, pmr ir, pmr ir, ms ir, ms ir, ms ir, ms ir, ms Pmr
H2O Petr ether EtOH
7.5 50
ir, pmr
H2O EtOH EtOH EtOH EtOH EtOH EtOH EtOH EtOH Petr ether EtOAc EtOAc Acetone n-BuOH n-BuOH EtOH/Et,O EtOH/Et,O
59 60 67.7 69.6 73.8 68.4 8.7 72.2 59.5 61.8 57 90.7 84.3 62.9 60.9 56 38
ms ir, ms ir, pmr ir, pmr ir, pmr ir, pmr ir, pmr ir, pmr ir, pmr ir, pmr ir, pmr ir, pmr ir, pmr ir, pmr ir, pmr ir, pmr ir, pmr
72 72 50 50 31 31 31 31 31 72 72 84 84 16 73,74 60 60 314 314 314 314 314 314 314 314 314 314 314 314 314 318 318
TABLE IV-I. g c o n t d . )
w w
m
Substituent
mp 0 3 ; CbP (°C/torr)l
Solvent of Crystallization
2-(4-FC6H,)-4-Me-7-CF, 2-(4-FC6H,)-4-Me-8-MeO 2-(4-FC6H,)-4-Me-7-NO, 2-Ph-4-(4-FC,H4)-7-N0, 2,4-(4-FC6HJ2-7-N02 2-(4-FC6H,)-4-Me-8-C1 2-Ph-4-(4-FC6H4)-8-C1 2,4-(4-FC,H,)2-8-C1
140 256 205 223-225 155 205 233 232
EtOH/Et,O EtOH/Et,O EtOH/Et,O EtOH/Et,O EtOH/Et,O EtOH/Et,O EtOH/Et,O EtOH/Et,O
Yield (YO)
Spectra
Refs.
35
ir, pmr ir, prnr ir, prnr ir, pmr ir, pmr ir, pmr ir, prnr ir, pmr
318 318 318 318 318 318 318 318
40 42 45 39 35 35 38
3H-l,5-Eenzodiazepinest
None Hydrochloride.H,O Hydrobrornide.ZH,O Perchlorate.H,O
80
196.5 187-189 192-196
MeOH/H,O
82
235-236 180-1 82
MeOH MeOH
74
uv
11 11
221-222 162-163
MeOH MeOH
78
uv
11
Monosubstituted
2-(4-BrC6H,) Perchlorate Hyd!ochloride 2-(4-C1C,H,) Perchlorate Hydrochloride
* 2-Amino-, 2,4-diarnino-, and 2-thio-substituted derivatives follow polysubstituted.
11
w
'4
-.I
2-(4-Me2NC,H,) Dihydrochloride 2-(4-MeOC6H,) Perchlorate Hydrochloride 2-Me Hydrochloride 2-Ph Hydrochloride Perchlorate 2-(4-N0,C,H4) Perchlorate Hydrochloride 2-(4-PhC,H,) Hydrochloride 3-Br 3-(6-CI-Benzoxazol-2-yl) 3-NOZ 3-Ph
179-1 8 1
MeOH
70
uv
11
180-1 81 225-226d
MeOH MeOH
78
uv
11 11
145d
EtOH
183d 212-21 3d
MeOH MeOH
82
uv
11 11
1 9 6 198 196-197
MeOH MeOH
75
uv
11 11
MeOH
65 33 70 57-81 23
uv ir
11 3 7 &6 2.3
142d 184d > 300 > 360 268d
13
ir, pmr
2.3 Disubstituted
2-PhCH2-3-Ph Perchlorate 2,3-Me, Perchlorate 2,3-Ph2 Hydrochloride Perchlorate
161-162
MeOH
78
uv
9
167-168
MeOH
39
uv
9
215-216d 259-260d
MeOH MeOH
14
uv
11
186-188d 110-113 146-147 131-134
EtOH Cyclohexane Cyclohexane Cyclohexane
58 30 85 38
ir
36 31 31 31
2.4 Disubstituted
2-(AcCH2CO)-4-Me 2-(2-AcOC6H4)-4-Ph 2-(2-Ac0-5-C1C6H3)-4-Ph 2-(2-Ac0-5-C1C6H,)-4-Me
ir, ms ir, ms ir, ms
TABLE IV-1. --(contd.)
Substituent
W
m
2-Ac-4-Me 2-(2-PhCOOC,H,)-4-Ph 2-(2-PhC00-5-CIC6H3)-4-Ph 2-(PhCOCH,CO)-4-Ph 2,4-(BrCH,), Picrate Picrolonate 2-BrCH2-4-Me Hydrobromide 2-(3-BrC6H,)-4-Ph 2-(4-BrC6H,)-4-Ph 2,4-(Br,CH), Hydrobromide 2-COOH-4-Me 2-COO-t-Bu-4-Ph Hydrochloride 2-COOEt-4-Ph 2-(COO-i-Pr)-4-Ph Hydrochloride 2-(COO-i-Pr)-4-(4-MeC6H,) 2-CONHPh-4-Ph 2-CONHPh-4-(4-MeOC6H4) 2-CONHPh-4-(4-MeC6H,) 2-CONH(4-BrC6H,)-4-Ph 2-CONH(4-BrC,H,)-4-(4-MeC6H4) 2-CONH(4-MeOC6H,)-4-Ph 2-CONH(4-MeOC,H,)-4-(4-MeC6H4) 2-CONH(4-MeOC,H4)-4-(4-BrC,H,)
mP ("C); CbP ("C/torr)l
Solvent of Crystallization
121-123 117-118 148-153 210 ca. llOd 138-14 1 149-1 5 1
MeOH Petr ether EtOH CHC1, Acetone/H,O PhH PhH
20 1 154 159-160
MeOH EtOH EtOH/H,O
30 81
360; 400 258
AcOH
71; 80
87-88 115-116 191-192 97-98 201-202 228-229 237-238 202-203 242-243 179-180 201-202 207-208
EtOH i-PrOH
50 26 35
EtOH MeCN MeCN MeCN MeCN MeCN MeCN MeCN MeCN
Yield (YO)
Spectra
40 60 83 65
ir, ms ir, ms ir
19 67; 84 76 87
64 99 42 96 44
Refs. 40 31 31 36 26 26 26
ir, pmr
19 38 52
ir, pmr
1, 19 41
ir ir ir ir ir ir ir ir
43 51 51 51 51 42,43 43 43 43 43 43 43 43
w W
2-CONH(4-MeC6H,)-4-Ph 2-(3-C1C,H4)-4-Ph 2-(4-ClC,H4)-4-Ph 2-(2-OCOOEt-5-C1C,H3)-4-Ph 2-(3-EtO-Quinoxalin-2-yl)-4-Me Perchlorate 2-CF3-4-Ph 2-C,F,-4-Ph 2-C,F1 ,-4-Ph 2-C7F1,-4-Ph 2,4-(C7F, 512 2-(2-HOC6H,)-4-Me 2-(2-HOC6H,)-4-Ph 2-(2-HOC6H,)-4-(3-Pyridyl) 2-(2-HOC,H4)-4-(4-Pyridyl) 2-(2-HOC,H4)-4-(2-Thienyl) 2-(2,4-(HO),C,H3)-4-(3-Pyridyl) 2-(2,4-(HO),C,H,)-4-(4-Pyridyl) 2-(2-HO-3-BrC,H,)-4-Ph 2-(2-HO-5-BrC,H,)-4-Ph
2-(2-HO-5-BrC,H,)-4-(3-Pyridyl) 2-(2-HO-5-BrC6H3)-4-(4-Pyridyl) 2-(2-HO-5-BrC,H,)-4-(2-Thienyl) 2-(2-HO-3-CIC6H3)-4-Ph 2-(2-HO-3-CIC6H,)-4-(3-Pyridyl) 2-(2-HO-3-CIC,H,)-4-(4-Pyridyl)
2-(2-HO-3-CIC6H,)-3-(2-Thienyl) 2-(2-HO-3,5-CI2C,H2)-4-Ph 2-(2-HO-3,5-CI2C,H,)-4- (3-Pyridyl)
2-(2-HO-3,5-CI2C,H,)-4-(4-Pyridyl) 2-(2-HO-3,5-C1,C6H,)-4-(2-Thienyl) 2-(2-H0-3-C1-5-EtC6H,)-4-Ph 2-(2-HO-4-C1C6H3)-4-Ph
201-202 171 149-150 116118 135-136 220d 81 98 86 102 66 125-128 184189 218-22 1 205-206 206 280-281 256257 170 197 202 165 193 155 169 169 185 199 193 186 195 203 183-184
MeCN EtOH EtOH/H,O EtOH Et,O EtOH
CCI,
Cyclohexane
EtOH
63 51 81 83 61 93 89 75 60,70 46 76 51 43-61 26 24 35
21 35 31 26 27 34 40 23 30 20 33 27 44 27 30
ir
ms pmr, uv
ir,
ms, pmr, uv
ir
43 38 52 31 33 35 35 35 35 35 31 37,38 39a, 97 39a, 97 39a 97 91 38 38 39a 39a 39a 38 39a 39a 39a 38 39a 39a 39a 38 38
TABLE IV-1. -{contd.)
Substituent
mp ("C); [bP ("C/torr)I
2-(2-HO-4-C1C6H,)-4-(3-Pyridyl) 2-(2-HO-4-ClC,H3)-4-(4-Pyridyl) 2-(2-HO-4-C1C6H,)-4-(2-Thienyl) 2-(2-HO-5-C1C,H3)-4-Me 2-(2-HO-5-ClC,H3)-4-Ph
235 208 146 156157 183-1 85
Solvent of Crystallization
Yield (%)
MeOH EtOH
25 20 30 60 36; 39
Spectra
ir
Refs.
39a 39a 39a 31 31,38
2-(2-HO-5-C1C6H,)-4-(3-Pyridyl) 190
31
39a
192
23
39a
I76 194
25 29
39a 38
2-(2-HO-5-C1C6H,)-4-(4-Pyridyl)
2-(2-HO-5-C1C6H,)-4-(2-Thienyl) 2-(2-HO-5-FC,H3)-4-Ph
2-(2-HO-4-MeOC6H,)-4-(3-Pyridyl) 209-210
97
2-(2-HO-4-MeOC,H3)-4-(4-Pyridyl) 2-(2-HO-3-MeC,H3)-4-Ph 2-(2-HO-3-MeC6H,)-4-(3-Pyridyl)
187-1 89 151
37
208 209
30
39a
145
30
39a
165 193
33 28
39a 38
22 1
40
39a
205
26
39a
-
ir
97 38
2-(2-HO-3-MeC6H,)-4-(4-Pyridyl) 2-(2-HO-3-MeC,H3)-4-(2-Thienyl)
2-(2-HO-3,4-Me,C,H2)-4-Ph
2-(2-HO-3,4-Me,C6H,)-4-(3-Pyridyl) 2-(2-HO-3,4-Me2C,H,)-4-(4-Pyridyl)
2-(2-HO-3,4-Me,C6H,)-4-(2-Thienyl) 2-(2-HO-3,5-Me2C,H,)-4-Ph
208 213; 168
30 35; 26
39a 38
161
25
39a
150
20
39a
190 147 225 150 2&207 215 203 169-1 70 173-175 139-141 268-270
EtOH EtOH/petr. Et,O EtOH/EtOAc EtOH/CHCI,
192-196
BziHexane
36 37 30 34 30 45 44 58 56 62 40 51 41
110-113 151-154 166 131-132 83-95 140 124 164 99-100 120-121 126
EtOH/H,O EtOH/Et,O Ligroin Ligroin EtOH Hexane Ligroin EtOAc EtOH/H,O Ligroin Hexane
49 68 56 45 68 32 61 53 70 56 38
2-(2-HO-3,5-Me,C6H2)-4-(3-Pyridyl) 2-(2-HO-3,5-Me,C6H,)-4-(4-Pyridyl) 2-(2-HO-3,5-Me,C6H2)-4-(2-Thienyl) 2-(2-HO-4-MeC6H,)-4-Ph 2-(2-HO-4-MeC6H,)-4-(3-Pyridyl) 2-(2-HO-4-MeC,H3)-4-(4-Pyridyl) 2-(2-HO-4-MeC6H,)-4-(2-Thienyl) 2-(2-HO-4-Me-5-C1C6H,)-4-Ph
2-(2-HO-4-Me-5-C1C,H2)-4-(3-Pyridyl) 2-(2-HO-C,H,)-4-(2-MeO-C6H4) 2-(2-HO-C,H4)-4-(3-MeO-C6H4) 2-(2-HO-C6H4)-4-(2-N02-C6H4) 2-(2-HO-C,H,)-4-(4-NO2-C6H4) 2-(2-C1C6H4)-4-NHZ 2-(2-C1C6H4)-4-NHZ 2-Ph-4-NHz 2-Ph-4-N(CH2), 2-Ph-4-N(CH2),NMe 2-NHMe-Ph 2-NHCHMe2-4-Ph 2-NHCHMePh-4-Ph 2-NHCHMeCH2Ph-4-Ph 2-NHCHzCHzPh-4-Ph 2-NHCHzCH,0H-4-Ph 2-NHCHzCH2NEtz-4-Ph 2-NH(CH2)3NEt,-4-Ph 2-NHC6Hl ,-4-Ph
ir
ir, pmr ir, pmr gc/ms gc/ms anal. ir, pmr ir, pmr, uv ir, pmr
39a 38 39a 39a 39a 38 39a 304 304 304 304 31 1 311 311 311 311
316 316 316 316 316 316 316 316 316
TABLE IV-I. -4contd.) mp ("C); [bP ("C/torr)l
Solvent of Crystallization
2-NMe2-4-Ph 2-N(CH2),-4-Ph 2-N(CH2),-4-Ph 2-N(CH2),0-4-Ph 2-N(CH2),NMe-4-Ph 2-(2-HO-4-Me-5-Clc,H2)-4-(4-Pyridyl) 2-(2-HO-4-Me-5-Clc,H2)-4-(2-Thienyl) 2-(2-HO-4,5-Me2C,H,-(3-Pyridyl) 2-(2-HO-4,5-Me2C,H,-(4-Pyridyl) 2-(2-HO-4,5-Me2C,H2-(2-Thienyl) 2-(2-HO-5-MeC,H3)-4-Ph
110-111 159 119-121 151 158 180 182-183 198 208 160-1 62
i-PrOH Ligroin Ligroin Ligroin Hexane
2-(2-HO-5-MeC,H3)-4-(3-Pyridyl)
184 135 165 211-218 91-99d 126-1 28 159-161 132-136
EtOH Acet one/H 0
185-188
EtOH/Et,O
Substituent ~~~~~~~
w P
~
~
Yield (%)
Spectra
Refs.
~
2-(2-HO-5-MeC,H3)-4-(4-Pyridyl) 2-(2-HO-5-MeC6H3)-4-2-Thienyl) 2-(4-HO-Coumarin-3-y1)-4-Me 2,4-UCH2), Hydrochloride Picrate Picrolonate 2-MeOCH2-4-Me H ydrochlotide 2-(3-MeOC,H4)-4-Me Hydrogen sulfate 2-(4-MeOC,H4)-4-Me Hydrogen sulfate 2-(Ph2CMeO)-4-Ph 2-(4-MeOC,H4)-4-Ph
163 191 151 105-106
CH,CI,/MeOH EtOH/H20
30 85 I1 81 71 48 32 30 22 26
316 316 316 316 316 39a 39a 39a 39a 39a 38 39a 39a 39a 34 26 26 26 26
42 141 34 35.5
1
30 41
uv
16
86 15 85
uv ir, ms, pmr
16 50
52
2,4-Me2 Hydrobromide.2 H,O Hydrochloride. 2 H,O Hydrogen sulfate Perchlorate 2-Me-4-Ph Hydrochloride Hydrogen sulfate.H,O 2-Me-4-(4-EtSeC,H4) 2-Me-4-(4-MeSeC,H4) 2-Me-4-(4-PrSeC,H4) 2-Me-4-(Selenen-2-yl) 2-Me-4-(1-Ph-3-Me-Pyrazol-5-yl) 2-Me-4-(PhCH=CH) 2-(3-MeC,H4)-4-Ph 2-(4-MeC,H,)-4-Ph 2-(4-N02C6H4)-4-Ph 2,4-Ph2 Hydrobromide. 0.5H20 Hydrochloride. H,O Hydrochloride. 3 H 2 0 Picrate 2,4-(PhCH=CH)2 3-NO2-7-C1
131-132 216 204-206 225-227 204205 87-88 190-1 92 173-1 75 102-103 107-108 92-93 98-99 166-167 128-129 166 160-1 6 1 204-205 140-1 4 1 221 242-244d 242-244d 216-217 164165 > 360
Et,O
75-80
ir, pmr, uv
H P
70; 87 74: 90
uv uv
75 40 40 40 38 57 23 30 79 52 45-86
uv
Acet one/pe t r ether Acetoneipetr ether Acetone/pe tr ether EtOH/H,O MeOH PhH/petr ether EtOH/H,O MeCN EtOH EtOH/H,O
--
uv
uv uv
MeOH 45 70
uv ir
14-17, 19 1 1, 14-16 16, 17 1 16, 27, 28 29 16, 29 30 30 30 32 36 16 38 52 54 16, 36, 50, 52, 56 16 16 16 16 16
7
2 J , k Trisubstituted
2,4-Me2-3-Br Hydrobromide 2,3,4-Me3 Hydrochloride 2,4-Me,-3-PhSO2 2,4-Me,-3-(4-MeC,H,SO,)
2,4-Me,-3-(3-COOH-4-HOC6H3S0,) 2,4-Me2-3-(3-COOMe-4-HOC,H3S02)
207; 225 85 214 206 213 216 194
MeNO,/Et,O Petr ether, sub1 EtOH EtOH EtOH EtOH
84 85
3, 79 16 16,45 46 46 46 46
TABLE IV-I. 4 c o n t d . )
w P P
Substituent
mP ("C); [bp ("C/torr)]
Solvent of Crystallization
2,4-Me2-3-(3-COOEt-4-HOC6H3SO2)
174
EtOH
46
233
EtOH
46
252
EtOH
46
214
EtOH
46
209
EtOH
46
EtOH EtOH EtOH EtOH EtOH EtOH
46 46 46 46 46 46
EtOH
46
EtOH
46
EtOH
46
2,4-Me2-3-(3-COOH-4-HONaphthyl-1-sulfonyl) 2,4-Me2-3-(3-COOMe-4HO-Naphthyl-1-sulfonyl) 2,4-Me2-3-(3-COOEt-4-HONaphthyl- 1-sulfonyl) 2,4-Me2-3-(3-COOPr-4-HONaphthyl- 1-sulfonyl) 2,4-Me,-3-(3-COOBu-4HO-Naphthyl-1-sulfonyl) 2-Me-3-PhS02-4-Ph 2-Me-3-(4-MeC6H,SO,)-4-Ph
206 184 182 2-Me-3-(3-COOH-4-HOC6H,S02)-4-Ph 217 2-Me-3-(3-COOMe-4-HOC6H,S02)-4-Ph24 1 2-Me-3-(3-COOEt-4-HOC6H,SO2)-4-Ph 226 2-Me-3-(3-COOMe-4HO-Naphthyl-l-sulfonyl)-4-Ph 230 2-Me-3-(3-COOEt-4HO-Naphthyl-1-sulfonyl)-4-Ph 228 2-Me-3-(3-COOPr-4-HONaphthyl- l-sulfonyl)-4-Ph 220 2-Me-3-(3-COOBu-4-HONaphthyl-l-sulfonyl)-4-Ph 207 2,4-Ph,-3-PhCO 169-1 70 2,4-Ph2-3-Br Hydrobromide.0.5H20 234
EtOH EtOH
Yield
30
(YO)
Spectra
Refs.
46 29 79
-
2,4,7(8) Trisubstituted
2-(PhCOCH2)-4-Ph-7-CI 2-(PhCOCH,)-4-Ph-7-NO2 2,4-(C,F, ,),-7-Me 2-C,F7-4-Ph-7(8)-Me 2-C5F, ,-4-Ph-7(8)-Me 2-C7F,,-4-Ph-7(8)-Me 2-(2-HOC6H,)-4-Ph-7-COOH 2-(2-HOC6H,)-4-Ph-7-C1 2-(2-HOC,H,)-4-(3-Pyridyl)-7-C1
m
193 230 63 97 80-8 1 85-86
130 189 180 2-(2-HOC,H,)-4-(2-Thienyl)-7-C1 109 2-(2-HO-3-MeC6H,)-4-Ph-7-CO0H 250 2-(2-H0-3-MeC6H,)-4-Ph-7-CI 178 2-(2-HO-3,5-(Me),C6H,)-4-Ph-7-COOH 280-282 2-(2-HO-3,5-(Me),C6H,)-4-Ph-7-C1 198 2-(2-HO-5-C1C6H3)-4-Ph-7-COOH 193 176 2-(2-HO-5-C1C6H,)-4-Ph-7-Cl
2-(2-HO-5-C1C6H,)-4-2-Thienyl)-7-C1 2-(2-HO-4,5-(Me),C,H2)-4-Ph-7-C1
PhMe Py/MeOH
150
204 2-(2-HO-5-MeC6H,)-4-Ph-7-CO0H 120 2-(2-HO-5-MeC6H,)-4-Ph-7-Cl 204-205 2-(2-HO-5-MeC6H,)-4-(2-Thienyl)-7-COOH 259 2-(2-HO-5-MeC6H,)-4-(2-Thienyl)-7-Cl 208-210 179-180 2,4-Me2-7-NH, Hydrochloride 210-2 13 203-206 Hydrochloride 0.5H,O 2,4-Me2-7-NHAc 139-142 Hydrate Hydrochloride. H,O 226 2,4-Me2-7-COOH Perchlorate 243-244 2,4-Mez-7-C1 Perchlorate 187-188 Chloroplatinate 180-1 85
EtOH EtOH EtOH EtOH EtOH EtOH EtOH EtOH EtOH EtOH EtOH EtOH EtOH EtOH EtOH EtOH PhH EtOH EtOH
91 84 60 50 58 38 22 42 25 29 30
44 31 31 33 38 29 29 2s 32 22 21
76
ir, uv uv
62
55 55 35 35 35 35 39b 39b 39b 39b 39b 39b 39b 39b 39b 39b 39b 39b 39b 39b 39b 39b 20 20, 21 21
20 20
PhHiEtOH
30
ir, uv
EtOH
55
uv
1
EtOH
41 54.5
uv
1
TABLE IV-1. 4 c o n t d . )
Substituent 2,4-Me,-7-CH,N(CH2CH,Cl), Dihydrochloride' 1.6H20 Dihydrochloride .0.87H2O Dihydrochloride .0.32H20 2,4,7-Me3 Perchlorate 2,4-Me2-7-Me0 Hydrogen sulfate
w
P
Q\
2,4-Me2-7-[(2,4-Dimethyl3H-1,5-benzodiazepin-7-yl) methyl] Dihydrochloride 2,4-Me2-7-[2-(2,4-Dimethyl3H-1,5-benzodiazepin-7-yloxy) ethoxy] Hydrogen sulfate 2,4-Me2-7-(CH,NHCH2COOH) Hydrochloride. H,O 2,4-Me,-7-(CH2NHCH2COOEt) Hydrochloride. H,O 2,4-Me,-7-[CH2NH(4-COOHC,H,)] Hydrochloride. H,O
mp CC); [bp ("C/torr)]
Solvent of Crystallization
118-122 62-66d 147-149d 154-155d 197-198
159-163
Yield (YO)
Spectra
Refs.
PhH/petr ether EtOH/Et,O EtOH/Et,O EtOH/Et,O
ir, uv
21 22 22 22
EtOH
uv
1
uv
1
ir, pmr, uv
EtOH/Et,O
uv
24
1
83-85
44
25
149-151
26
25
199-202
42
25
137-139
77.5
25
189-191
45
25
170-172
34
25
188-1 92
47
25
2,4-Me,-7-[CH,NH(4-C0OEt-C6H4)] Hydrochloride. H,O
2,4-Me2-7-[CH,NHCH(PhCH,)COOH] Hydrochloride. H,O 2,4-Me2-7-[CH,NHCH(PhCH,)COOEt] Hydrochloride. H,O
2,4-Me,-7-[CH2NHCH(Ph)CH2COOH] Hydrochloride. H,O
2,4-Me,-7-[CH,NHCH(Ph)CHzCOOEt] Hydrochloride.H,O 2,4-Me,-7-N02 Hydrochloride Nitrate 2,4-Me,-7-MeS Hydrochloride 2-Me-4-Ph-7-[(2-Me-CPh3H-1,5-Benzodiazepin-7-yl)methyl] Hydrogen sulfate 2-(4-N02C6H4)-4-Ph-7-COOH 2-(4-NOzC,H4)-4-Ph-7-C1 2-(4-N02C6H4)-4-Ph-7-Me 2,4-Ph,-7-COOH 2,4-Ph,-7-C1 w
P
2,4-Ph2-7-Me
I .
2,4-Ph,-7-N02 2-Ph-4-NHZ-7-Cl Hydrochloride 2-Ph-4-NH,-7-N02 2-Ph-4-SMe-7-NO2 2-(4-C1C6H4)-4-SMe-7-N02
2-(4-BrC,H4)-4-SMe-7-N0, 2-(4-C1C6H4)-4-SMe-7-CI 2-(2-Thienyl)-4-SMe-7-NO2 2-(4-C1C,H4)-4-NH,CHz-Ph-7-NOz
2-(4-CIC6H4)-4-Morpholino-’l-N0, 2-(4-C1C6H4)-4-N(CH,)4NMe-7-N0,
222-223
87
25
200-202 147
EtOH
83.5
uv
1
199-200
EtOH
51
uv
1
108-1 11 196199 292d 190-1 9 1 178-180 260 162-1 63 165-167 270-271 117-118 111 243-244 236
CHClJpetr ether EtOH/Et,O MeCN DMF/H20 MeCN MeCN EtOH MeCN EtOH EtOH EtOH EtOH
ir, pmr, uv 37 47 38 53 3; 46 37 40 25 70-80 50; 11 36
ir, pmr ir, pmr ir, pmr ir, pmr Pmr ir, pmr Pmr ir, pmr
295
34
ir, pmr, uv
157 177 I82 141 222 223 233 21 1
55 73 78 56 97 43 90 58
ir, pmr, uv ir, pmr, uv ir, pmr, uv ir, pmr, uv ir, pmr, uv
24 24 54 54 54 39b 54, 39b 53 54 53 56 53, 54 39b 311 31 1 319 319 319 319 319 319 319 319
TABLE IV-I. 4 c o n t d . ) mp ("C); Substituent
CbP ("C/tordl
Solvent of Crystallization
Yield (YO)
Spectra
Refs.
ir ir, pmr
19 19 35 35 35 35 23 19 19 54 54 54 54, 56
Polysubstituted
w
2,4-(Br2CH),-7,8-Br, Hydrobromide 2,4-(Br3C),-3,7,8-Br, 2,4-(C,F, J2-7,8-Me2 2-C3F,-4-Ph-7,8-Me, 2-C,F, -4-Ph-7,8-Me2 2-C,F, ,-4-Ph-7,8-Me2 2,4-Me2-7,8-(COOMe), Hydrogen sulfate 2,4-Me,-7,8-Br, Hydrogen sulfate 2-Me-4-Ph-7,8-Me2 2-(4-NO2C,H,)-4-Ph-7,8-Me, 2,4-Phz-6-N02-8-C1
285 195-196 89 120 115 107
AcOH THF
236-237d 130-132 220-221 115-117 208-209 230-234
EtOH
86
MeOH/Et,O MeCN MeCN MeCN
62 58 40 31
ir, pmr ir, pmr ir, pmr ir, pmr ir, pmr ir, pmr
2,4-Ph2-7,8-Me2
163-164
MeCN
21; 70-80
ir, pmr
167-1 69 285d 111-1 12.5 108-1 10.5 155-157 155.5-157.5
CH,C1, EtOH i-PrOH EtOH MeOH Cyclohexane
51 95 72 63 50 42
68 85 82 60 85
2-Amino-substituted I ,S-benzodiazepines
2-NH2-4-(2-C1C6H,) Hydrochloride 2-[HO(CH2),NMe]-4-Ph 2-NMe2-4-Ph 2-(4-Me-Piperazino)-4-Ph 2-(4-Me-Piperazino)-4-(4-C1C6H4)
uv UV
uv uv
61 61 63 63 63, 64 63, 64
2-(4-Me-Piperazino)-4-(4-FC6H4) 2-(4-Me-Piperazino)-4-(4-MeOC6H,) 2-(4-Me-Piperazin0)-4-(4-MeC6H4) 2-(4-Me-Piperazino)-4-Ph-8-C1 2-(4-Me-Piperazino)-4-Ph-7,8-Me2
2-(4-Me-Piperazino)-4-(4-FC6H,)-7,8-Me, 2-Morpholino-4-Ph 2-(4-Ph-Piperazino)-4-Ph 2-Piperidino-4-Ph 2-[4-(PhCH2)-Piperidino]-4-Ph 2-[4-(Ph2CH)-Piperidino]-4-Ph 2-(4-Ph-Piperidino)-4-Ph 2-(4-Ph-Piperidino)-4-(4-C1C6H,) 2-(4-Ph-Piperidino)-4-(4-FC6H,) 2-(4-Ph-Piperidino)-4-(4-MeOC6H4) 2-(4-Ph-Piperidino)-3-(4-MeC,H4) 2-(4-Ph-Piperidino)-4-Ph-8-CI 2-(4-Ph-Piperidino)-4-Ph-7,8-Me2
2-[4-(4-C1C6H,)-Piperidino]-4-Ph 2-[4-(3-CF3C,H,)-Piperidino]-4-Ph 2-[4-(4-CF,C6H,)-Piperidino]-4-Ph 2-[4-(4-MeOC6H,)-Piperidino]-4-Ph 2-[4-( 1-Piperidinyl) PiperidinolCPh 2-Pyrrolidino-4-Ph 2-(4-Ph-1,2,3,6-Tetrahydropyridinl-yl)-CPh
2-[4-(4-C1C,H4)-1,2,3,6-Tetrahydropyridin-l-yl]-4-Ph 2-[4-(4-CF,C,H4)-1,2,3,6-Tetrahydropyridin-l-yl]-4-Ph 2-[4-(4-MeC6H,)-1,2,3,6-Tetrahydropyridin1-yl]-4-Ph
157-1 58 148.5-1 50 129.5-132 125.5-126.5 131.5-134.5 169-170 15G152 172-172.5 115.5-118 97-99.5 170-172 205-207.5 170-171 173-175 158-1 60 158-160 134.5-136 174.5- 1 76.5 198.5-200 161.5-1 62.5 157-1 58.5 158.5-1 60 155-157 155-156 180.5-182 199-202 168-170 208-21 1
EtOAc/Hexane EtOAc/Hexane EtOAc/Hexane MeOH Hexane EtOAc/Hexane EtOH EtOAc/Hexane MeOH Hexane EtOAc/Hexane CHCI JHexane EtOAc/Hexane CHCIJHexane CHCIJHexane CHCIJHexane EtOAc/Hexane EtOAc/Hexane EtOAc EtOAc/Hexane EtOAc/Hexane EtOAc/Hexane MeOH EtOH EtOAc EtOAc CHCI,/Hexane CHCI,/Hexane
46 56 36 34 64 22 70 52 64 29 58
70 52 43 53 43 48 63 51 74 79 51 34 81 68 46 29 24
uv uv uv uv uv uv uv uv uv uv uv uv uv uv uv uv uv uv uv uv uv uv uv uv uv uv uv uv
63, 64 63, 64 63, 64 63, 64 63, 64 63, 64 63 63, 64 63 63 63 63 63 63 63 63 63 63 63 63 63 63 63 63 63 63 63 63
ms, pmr ms ir, pmr ir, pmr
59, 60 60 65 65
2,4-Dirunino-substituted
2,4-(NH2), Dih ydrochloride 2-NEt,-4-NMe2 2-NEt2-4-Morpholino
> 260 > 260 95-96 119-120
HZO EtOH i-PrOH i-PrOH
50.5
94.5 72
TABLE IV-I. -4contd.) Solvent of Crystallization
Yield (YO)
Spectra
Refs.
69-71 117-1 18 137-138 152-153 147-148 175-1 77 164-165 161-162 198-1 99 206-207 149-150 198-199
Petr ether EtOH EtOH Cyclohexane Petr ether i-PrOH Cyclohexane EtOH Cyclohexane i-PrOH i-PrOH Cyclohexane
44.5 11 18.5 11 65 84.5 10.5 14 23 67 79 61.5
ir, pmr ir, pmr ir, pmr ir, pmr ir, pmr ir, pmr ir, pmr ir, pmr ir, pmr ir, pmr ir, pmr ir, pmr
65
172 59 153 88
PhH Petr ether Petr ether Petr ether
85 71 76 52
ms, pmr ms, pmr ms,pmr Pmr
71 71 71 67
153 180
i-PrOH EtOH
64 85
67,68 68, 70
154 185
EtOAc EtOH
81 73
68, 69 68.69
149-150 175 192-193
EtOAc i-PrOH EtOH
70 61.5 67
69 68 68, 69
Substituent
3
2-NEt2-4-Pyrrolidino 2,4-(EtNPh), 2,4-(EtNPh),-7-C1 2,4-(EtNPh),-7,8-Me2 2,4-(NMe,), 2-NMe24-Pyrrolidino 2,4-(MeNPh), 2,4-(MeNPh),-7-C1 2,4-(MeNPh),-7,8-Me2 2-Morpholino-4-pyrrolidino 2-Piperidino-4-pyrrolidino 2,4-(Pyrrolidino),
62 62 62 65 65 62 62 62 65 65 65
2- Thio-substituted
2-(NH,COCH,S)-4-Ph 2-(EtOOCCH,S)-4-Ph 2-(NCCH2S)-4-Ph 2-(PhCH,S)-4-Ph 2-[Et,N(CH,),S]-4-Ph Hydrochloride Methiodide 2-[Et,N(CH,),S]-4-(4-BrC6H4) Hydrochloride Methiodide 2-[Et,N(CH,),S]-4-(2-C1C6H4) Hydrochloride Methiodide
2-[Et,N(CHJZS]-4-(3-C1C6H4) Hydrochloride Methiodide 2-[Et2N(CH2),S]-4-(4-C1C6H4) Hydrochloride Methiodide
175 149-150 177-178
i-PrOH EtOAc EtOH
62 61 68
69 68 68,69
159 179
EtOAc Acetone
67; 83 85
68, 70 68
188 176
EtOAc EtOH
90 70
68, 69 68, 69
169-170 186
EtOAc EtOH
80 60
68, 69 68. 69
119 139-140
EtOAc MeOH
55 62
69 69
167 184 81-82 167 62
60 88
68
68, 70 68, 70 68 68 68, 70
183
i-PrOH/Et,O EtOH Petr ether EtOH Petr ether EtOAc EtOH
85
68, 70
15G152 180
i-PrOH/Et20 EtOH
95 71
68, 70 68, 70
168-169 206
EtOAc MeOH
63; 77 83
68, 70 68, 70
192 136 124
EtOAc EtOAc EtOH
75
69 69 69
2-[EtzN(CH2),S]-4-(2,4-Cl2C6HJ Hydrochloride Methiodide
2-[EtzN(CH,)zS]-4-(3,4-C12C6H3) Hydrochloride Methiodide 2-[Et2N(CH,),S]-4-(2-Furyl) Citrate Methiodide
i;: F
2-[Et,N(CH,),S]-4-(4-MeOC6H4) Hydrochloride Methiodide
2-[Et,N(CH,)zS]-4-[2,4-(MeO)zC6H3] Methiodide
2-[Et,N(CH,),S]-4-(4-MeC,H4) Hydrochloride Methiodide 2-[Et,N(CH),S]-4-(4-PhOC6HJ Hydrochloride Methiodide
156
2-[Et,N(CH2),S]-4-(4-PhC6H4) Hydrochloride Methiodide 2-[Et2N(CH,),S]-4-(2-Thienyl) Hydrochloride Citrate Methiodide
72
TABLE IV-1. +conid.)
Substituent
mp YC); [bp ("C/torr)]
Solvent of Crystallization
Yield (%)
140
173
i-PrOH EtOH
90 80
68,69 68,69
172 188
EtOH EtOH
90 78
68,69 68,69
113 192
EtOAc EtOH
52
60
68,69 68,69
164 195
EtOAc MeOH
67 80
68,69 68,69
136 186
EtOAc EtOH
63 76
68,69 68,69
116 199-200
40
177
EtOAc EtOH Petr ether EtOH
71 68 73
68,69 68,69 68,69 68.69
100 172
EtOAc EtOH
70 60
68,69 68,69
184 196
i-PrOH EtOH
85 68
68,69 68,69
Spectra
Refs.
2-[Et,N(CH2)2S]-4-(4-PhCH,SC,H,)
IC)
VI
w
Hydrochloride Methiodide 2-[Et2N(CH2),S]-4[4-(Cyclohexylthio)]C,H, Hydrochloride Methiodide 2-[Et2N(CH2),S]-4-(4-EtSC6H4) Citrate Methiodide
2-[Et,N(CH,),S]-4-(4-MeSC6H4) Hydrochloride Methiodide 2-[Et,N(CH2),S]-4-(4-PrSC,H,) Hydrochloride Methiodide 2-[Et,N(CH2),S]-4-[4-i-PrSC,H,] Citrate Methiodide 2-[Et2N(CH2),S]-4-(4-B~SC6H4) Methiodide
42
2-[Et,N(CH,),S]-4-[4-(3-Me-Bu)C6H4] Citrate Methiodide 2-[Et2N(CH,),S]-4-(2-PhSC,H,) Hydrochloride Methiodide
2-[Et,N(CH,),S]-4-(3-PhSC6H4) Hydrochloride Methiodide.H,O
166 105
EtOH EtOH/H,O
93 60
68,69 68.69
150
EtOAc
162
i-PrOH
90 86
68.70 68.70
117 142
EtOH EtOH
65 63
68.69 68,69
87 158
EtOA/Et,O Acetone
so
68,70 68,70
I62
EtOAc EtOH
2-[Et,N(CH,),S]-4-(4-PhSC6H4) Hydrochloride Methiodide 2-[Et I N(CH,),S]-4-[4-Dodecylthio-C6H4] Citrate Methiodide 2-[Et,N(CHz)ZS]-4-Ph Hydrochloride. H,O Methiodide 2-[Et,N(CHZ)ZS]-4-(4-CIC6Ha) Hydrochloride Methiodide
163
13 56; 61
68,70 68,70
47
2-[Et,N(CH,),S]-4-(4-PhSC6H4) w VI w
Citrate Methiodide 2-[Et,N(CHZ),S]-4-(4-PhSC6H4) Tarwale. H,O 2 4 Et 2 N(CH2)ZSJ-4-(4-PhSC, HJ Citrate 2-MeS-4-NEt2 2-MeS-4-NMe2 2-MeS-4-Ph 2-CDIS-4-Ph 2-MeS-4-Pyrrolidino 2-[Me ,N(CHZ),S]-4-Ph Hydrochloride Methiodide
EtOAc EtOH
65 70
68,70 68,70
i-PrOH
64
68
EtOAc i-PrOH Petr ether Petr ether Hexane
89 88 70
123-1 24
i-PrOH
88.5
165-166 182
EtOAc MeOH
19
75
68,70 68.70
i-PrOH
53 80
68,70 68,I0
114-115 174 58-62
138 93-94
61-42 87-88 84-85
52.5 ir, pmr ir, pmr pmr
ms ir,
prnr
68 65 65
67 71 65
2-[Me,N(CH,)zS]-4-(4-PhSC6H,) Citrate Met hiodide
78 20 I
EtOH
TABLE IV-1. dc ont d. )
Substituent
mp W); Cbp ('C/torr)I
Solvent of Crystallization
Yield (YO)
2-[Me, N(CH,),S]-4- Ph Hydrochloride. 2-PrOH Methiodide
80 169
i-PrOH i-PrOH
43; 60 71
68,70 68, 70
111-1 12 20 1
i-PrOH EtOH
53 87
68, 70 68,70
172 170 121-122 86 175 177 185-188
i-PrOH/Et,O MeOH MeOH/Et,O Petr ether EtOH EtOH/H,O EtOH
80 78
65 92.5
68, 70 68, 70 68, 70 68, I 0 68, 70 68, 70 68, 70
228 226 167
i-PrOH MeOH MeOH
28; 41 72 65
68, 70 68, 70 68, 70
208 174 90 215 173
i-PrOH/Et,O MeOH i-PrOH i-PrOH EtOH
68 53 72 72.5 82
68, 70 68, 70 70 68, 70 68, 70
181 188
i-PrOH/Et,O i-PrOH
66 79
68, 70 68, 70
Spectra
Refs.
2-[Me2N(CH,),S]-4-(4-PhSC,H,) Hydrochloride Methiodide 2-[2-(4-Me-Piperazinoethyl)thio]-4-Ph Dihydrochloride Dimethiodide Methiodide vl
A
2-[2-(4-Me-Piperazinoethyl)thio]-4-(4-PhSC6H,) Citrate Dimethiodide Methiodide 2-[3-(4-Me-Piperazinopropyl)thio]-l-Ph Dih ydrochloride Dimethiodide Methiodide 2-[2-(MorpholinoethyI)thio]-4-Ph Hydrochloride Methiodide 2-[2-Morpholinoethy1)thio]-4-(4-PhSC6H,) Hydrochloride Methiodide
64
2-[2-(PiperidinoethyI)thio]-4-Ph Hydrochloride Methiodide
2-[2-(PiperidinoethyI)thio]-4-(4-PhSC6H,) Hydrochloride- H,O Methiodide
78 144-145 180
Ligroin i-PrOH EtOH
72
70 68, 70 68, 70
77
I ,S-Benzodiazepin-3-ones
W
2,4-Ph2 2,4-Me, Oxime 4-N02-Phenylhydrozone Semicarbazone Thiosemicarbazone N-Me-Thiosemicarbazone
2-(2-HOC,H,)-4-Me-10-NMe2 2-(2-HOC6H4)-4-Ph-lO-NMe2 2-(2-HO-5-C1C6H,)-4-Ph-lO-NMe2
1.4
120-1 2 1 215d 252-253 257-260 229-230 240-242
72-80 75-80 146-148 2-(2-HO-5-C1C6H,)-4-Me-lO-Me-lO-N(Me), 80-90 2-(2-HO-5-C1C6H,)-4-Ph-1O-Me-lO-NMe2 60-65 2-(2-HOC6H4)-4-Ph-10-Me-10-NMe2 207 2,4-Me2-10-[ 1,3-Benzodioxol-5-yl] 192-193 2,4-Me2-lO,IO-Ph, 156-157 2,4-Me,-7-C1-10,10-Ph, 156 2,4-Me,-7-N02-10,10-Ph, 205-206
82
MeOH EtOH/H,O Dioxane
80-100 19.5
16, 47, 48 16 85 85 85
EtOH/H,O MeOH/H,O EtOH EtOH/H,O MeOH/H,O Ligroin PhH/Petr ether MeOH MeOH MeOH
94
-
31 37 31 31 31 37 16 49 49 49
100
61 85 81 42 51
62.5 50 7
uv ir, pmr
TABLE IV-1.d c o n t d . )
Substituent 2,4,7-Me3-IO,lO-Ph, 2-Me-4-[2-( 1,3-Benzodioxol-5-yl) ethylene] lo-( 1,3-Benzodioxol-5-yl)
mp W); [bp (“Cjtorr)!
of Crystallization
Yield (YO)
141-142
MeOH
40
257-258
PhH
234 185, 204 4243 128-1 30 154-1 56 119-120 141-142 125-126 103-104 115.5-116
EtOH EtOH
192 192
EtOH EtOH
Solvent
1.5
Spectra
Refs. 49
uv
16
2,3-Dihy&o-I H-1,s-benzodiazepines w
VI
m
Monosubstituted
2-Me Picrate 4-Ph 4-(3-NH,C,H4) 4-(4-FC,H,) 4-(2-HOC,H4) 4-(2-HO-4-MeOC,H3) 4-[2,4-(MeO),C,H,] 4-[3,4,5-(MeO),C,H,] 4-(3-N0,C,H4)
21
EtOAc
60 94
EtOAc EtOH MeOH EtOH
90 74.5 92 92 82
98 98, 110 112 113, 114 111 112-1 14 113 113 113, 114 113, 114
Disubstituted
1-COPh-4-(2-HOC,H,) 1-COOMe-4-(2-HOC,H4)
41
32
115 115
g -.I
2,4-Me2 Picrate 2,4-Ph, 2-Me-4-[2-(4-Dimethylaminophenyl)ethenyl] Hydrobromide 2-(3-Pyridy1)-4-(2-HOC6H4) 2-(3-Pyridyl)-4-(2-HO-4-MeOC,,H3) 2-(4-Pyridy1)-4-(2-HOC6H,) 2-(4-Pyridyl)-4-(2-HO-4-MeOC6H,) 2-(4-Pyridyl)-4-(2-pyridyl) 2-Me-8-(2-Methyl-2,3-dihydro-lH-1,5-benzodiazepin-8-yl) methyl 2-(4-BrC6H,)-4-Ph 2-(4-MeOC6H,)-4-Ph 2-(4-NO2C,H,)-4-Ph 2-Ph-4-(4-MeC6H,) 2-Ph-4-(4-OMeC6H,) 2-Ph-4-(4-PhC6H4) 2-Ph-4-(4-BrC6H, 2-Ph-4-(4-C1C6H4) 2-Ph-4-(4-NOZC6H4) 2-CCI3-4-Ph 2-CC1,-(4-C1C6H4) 2-CC1,-(4-BrC6H,) 2-CCI,-(4-MeC6H,) 2-CCI3-(4-MeOC,H,) 2-CC13-(4-NO,C6H,) 3-Me-4-(4-MeC6H,) 4-Ph-7-COOH 4-Ph-7(8)-CI 4-(4-MeOC6H,)-7-Me 4-[2,4-(MeO),C,H3]-7-Me
64-65 182d 127-129 129-130 165 165- 166 163-164 162-164 [145-1471 190d 165-167 264 d 142 146147 189-190 127 139-140 179-180 142-143 129-130 104-105 125-129 112-115 118-121 119-122 93-96 15G-152 3639 360 4546 194-195 125-126
PhH Petr ether MeOH EtOH EtOH EtOH EtOH(Et,O) EtOH EtOH DMSO, H,O MeOH MeOH MeOH
MeOH MeOH EtOH/Heptane EtOH/Heptane EtOH/Heptane EtOH/Heptane EtOH/Heptane EtOH/Heptane
85
ir
25 85
Pmr ir, uv uv ir, pmr
60
54 58 64 64 9
97; 60 63 54 77 57 46 45 77 60 76 76
ir, pmr, uv ir, uv ir, uv ir, uv ir, uv ir. uv ir, uv ir, uv ir, uv ir, uv
116 116 107, 117, 122 310 100 108 108 108 108 108 99 310 310 310 310 310 310 310 310 310 313
70
313
78 72 70 52 76
313 313 313 313 112 111 112 111 111
48
TABLE IV-I. dcontd.)
Substituent 4-(2-Thienyl)-7-Me 4-NH2-8-C1
m p ("C); [bp ('Cjtorr)] 4344 143-144
Solvent of Crystallization
Yield
(YO)
Spectra
Refs. 111
CH,Cl,/i-Pr,O 118
65 Trisubstituted
2,2,4-Me3
127
Ligroin
77.85
13C-nmr n,
[125-127/2] w
v,
Methiodide Picrate 2,2-Me2-4-[2-(4-Dimethylaminophenyl)ethenyl] Hydrobromide 5-Methoperchlorate 2,2-Me2-4-[3-(4,4-Dimethyl-1,3,4,5-tetrahydro2H- 1,5-benzodiazepin-2-ylidene)propen1-yl] Hydrobromide 2,2-Me2-4-[3-( 1,4,4-Trimethyl-1,3,4,5-tetrahydro-2H-1,5benzodiazepin-2-y1idene)propen1-yl] 5-Methobromide 2,2-Me2-4-[3-(2H-Benzochrornan-2-ylidene)but1-en- 1-yl] Hydrochloride 2,2-Me2-4-[3-(6,7-Dimethyl-2H-benzothiochroman-2y1idene)but-1-en-I -yI] Hydrochloride 2,2-Me2-4-[3-(6,7-Diphenyl-2~-benzothiochroman-2y1idene)but-I-en-I-yl] Hydrochloride
ir, pmr, uv
98, 1 W 1 0 5 , 109, 122 104,121 110 110 106 100 100 110
212 161 d 122-132 222-223 175-176
Acetone EtOH
35
EtOH MeOH
66 79
204
EtOH
40
uv
100
142
MeOH
31
uv
110
206
Ac,O
51
uv
120
137
Ac,O/AcOH
60
uv
120
187
Ac,O/AcOH
5
uv
120
uv uv
2,2-Me2-4-[2-(4-Hydroxy-2,3-dihydro-2-thioxothiazo1-5y1)ethenyl] 2,2-Me2-4-[2-(3-Ethyl-4-Hydroxy-2,3-dihydro-2-thioxothiazol-5-y1)ethenyl 2,2-Me2-4-[3-(3-Methyl-2,3-dihydrobenzothiazol-2y1idene)propen-I-yl] Hydroiodide 2-Me-2,4-Ph2 2,4-Me2-2-CSNH, 2,3-Me2-4-[4-Dimethylaminophenyl)ethenyl] Hydrobromide 3-NHAc-4-(4-N02C6H4)-7-CI 4-(1-Naphthyl)-7,8-Me2 4-(2-Naphthyl)-7,8-Me2 4-Ph-7,8-Me 4-(4-EtOC6H,)-7,8-Me, 4-(2-HOC,H4)-7,8-Me2 4-(3-HOC6H,)-7,8-Me, 4-(3-MeOC6H,)-7,8-Me, 4-(4-MeOC6H,)-7,8-Me, 4-(4-NO,C6H,)-7,8-Me,
205-206
EtOH
45
uv
110
230-23 1
MeOH
75
uv
110
215 102 240 d
EtOH Petr ether CHCI,
58 80
uv ir, pmr
100
68
uv
110
198 24 1-242 115-117 176179 137-138 192-193 134-136 300 4748 173-174 279-282
103 119
111
EtOH/H,O
85
ir, pmr
87
Xylene
65 92 28
uv
111 111 111 111 112 111 112 112 112
Teirclsubsriruted
111
1-Ac-4-(4-MeOC,H4)-7,8-Me2 1-COCH,CI-4-(4-EtOC,H,)-7,8-Me2 1-Ph-2,2-Me2-4-[2-(4-Dimethylaminophenyl)ethenyl]
81-83 138-139
Hydrobromide 2,2,4-Me3-6-COOH Hydrobromide 2,2,4-Me3-6-NO, Hydrobromide 2,2,4-Me3-8-COOH Hydrobromide
208
EtOH
36
192-193
MeOH
60
110
104-106
MeOH
60
110
171-172
MeOH
60
110
111
78 uv
100
TABLE IV-1. -(contd.)
Substituent
mp W ) ; [bp (Tjtorr)]
Solvent of Crystallization
Yield (%)
2,2,4-Me,-8-N02 Hydrobromide
144.5 204205
MeOH/H,O MeOH
50
216-217 158-159
MeOH
84
168-1 69 203-205 144145 2 13-21 5
MeOH MeOH MeOH MeOH
22c221
Spectra
Refs. 110 110
2,2-Me2-4-[2-(4-Dimethylaminophenyl)ethenyl]-6-COOH Hydrobromide
2,2-Me,-4-[2-(4-Dimethylaminophenyl)ethenyl]-6-NO2
110 110 110 110
71
uv uv uv uv uv uv uv
MeOH
40
uv
110
23 5
MeOH
44
uv
110
153
EtOH
205-207 118-120 350
EtOH
79 78
uv ir
110 111 111 111
78
Hydrobromide
2,2-Me2-4-[2-(4-Dimethylaminophenyl)ethenyl-8-COOH Hydrobromide
2,2-Me,-4-[2-(4-Dimethylaminophenyl)ethenyl]-8-NO2
'
Hydrobromide
89
110 110 110
2,2-Me2-4-[3-(9-Nitro-4,4-dimethyl-1,3,4,5-tetrahydro2H-1,5-benzodiazepin-2-ylidene)propen-l-yl]-6-NO2 Hydrobromide 2,2-Me2-4-[3-(7-Nitro-4,4-dimethyl1,3,4,5-tetrahydro-yl]-8-N02 2H-1,5-benzodiazepin-2-ylidene)propen-l Hydrobromide 2,2-Me2-4-[7-(7-Nitro-4,4-dimethyl- 1,3,4,5-tetrahydro2H-1,5-benzodiazepin-2-ylidene)heptatrien1-yl]-8-N02 Hydrobromide 3-NHAc-4-(4-NO,C,H,)-7,8-Me2 3-Me-4-(4-MeOC,H,)-7,8-Me2 3-Ph-4-[2,4-(HO),C6H,]-7,8-Me, Pentasubstituted
1-COCH2C1-3-NHAc-4-(4-N02C6H4)-7,8-Me2 2,2,4-Me3-7,8-C1, 2,2,4-Me,-6,8-(N02), Hydrobromide
198-200 113
Hexane
169-171
MeOH
ir, ms, pmr, uv 72
111 106 110
2,2-Me2-4-[2-(4-Dimethylaminophenyl)ethenyl)-6,8-(7,9)-Me, Hydrochloride 2,2-Me,-4-[2-(4-Dimethylaminophenyl)ethenyl-6,8-(NO2), Hydrobromide
178
EtOH/Acetone
34
uv
100
21 3-215
MeOH
77
uv
110
2,5-Dihydro-lH-I,5-benzodiazepines
2,2,4-Me3-5-(2-Furoyl) 2,2-Me2-4-[2-(4-Dimethylaminophenyl)ethenyl]-5-Ph Hydrobromide 1,5-(NO),-2,2,4-Me3
105
73
120
uv
185 170
100 98
Dihydro- I .5-benzodiazepinones
I ,3-Dihydro-l,5-benzodiazepin-2 (ZH)-ones
Monosubstituted
4-( 1-Adamantyl) 4-CH2Ph 4-EtZN 4-EtNMe 4-EtNPh 4-Me2N 4-(2-Furyl) Picrate
251-252 147-149 151-152 135-136 181-182 201-202 250 195d
Acetone EtOH/Petr ether EtOH EtOH EtOH EtOH Dioxan EtOH
54 88 23 12 10 21.5
131 127 156 156 156 156 129 129
TABLE IV-1. --(contd.)
Substituent
w
m
N
4-Me Picrate 4-Ph Picrate 4-(4-BrC6H,) 4-(2-HOC,H,) 4-(3-Pyridyl) 4-Pyrrolidino 4-Styryl 4-CC1, 4-CF3 3-(3-0xo-1,2,3,4-tetrahydroquinoxalin-2-ylidene) hydrochloride 3-(3-0~0-3,4-dihydroquinoxalin-2-ylidene) 3-(3-Chloroquinoxalin-2-ylidene) 4-NHMe 4-NHEt 4-(CH2),COOEt
mp YC); [bp ('C/torr)] 147-1 5 1 177d 209-2 10 168 207-208 256-257 219-220 214215 2 18-21 9 193-194 183-185
Solvent
of Crystallization
Yield (%)
Spectra
Refs.
PhH/Petr ether EtOH EtOH EtOH EtOH/H,O EtOH
35-84
ir, uv
87
ir, uv
85.5 50
PhH EtOH PhH PhH
45 21 75 8G88
Pmr uv ir, uv Pmr
123-125 146 129, 132, 134 129 133 152 132 156 143 130 128 305
ir, pmr uv
305 305 306 306 315
23&23 1 222 143
EtOH EtOH BZ
91 26 59 61 66
128-129
Petr ether
19
145
10
165
54 43 13.5
166 145 153 156
ir, pmr ir, prnr ir, pmr
Disubstituted
1-CH2Ph-4-Ph 1-Me2N(CH,),-4-Ph Hydrochloride 1-[2-(4,5-Dihydroimidazolyl)methyl]-4-Ph Hydrochloride 1-Me-4-Ph 1-Ph4-NH2 l-Ph-4-Et2N
191-193 281d 69-13 251-252 164165
Petr ether PhH Acetone EtOH
ir, pmr Pmr
l-Ph-4-(EtO),CHCH2NH 1-Ph-4-Me2N 1-Ph-4-(MeO),CHCH2NH I-Ph-4-MeNH 1-Ph-4-MeNNO 1-Ph-4-Pyrrolidino 3-Ac-4-Ph 3-Br-4-Ph 3-Br-4-(4-BrC6H,) 3-Et-4-Et2N 3-Me-4-Et,N 3-Me-4-( 1-Piperidino) 3-Ph-4-( 2-Benzimidazolyl) 3-Ph-4-CH2Ph
w
OI
w
3-Ph-4-COPh 3-Ph-4-Et2N 3-(4-C1C6H,NHCO)-4-Me 3-(4-MeOC6H,NHCO)-4-Me 3-(4-CF3OC,H,NHCO)-4-Me 3-(=CHNMe2)-4-NHMe 3-(=CHNMe2)-4-NHEt 3-(=CHNMe,)-4-NMe, 3-( = CHNMe2)-4-NEt, 3-( = CHNMeJ-4-Pyrrolidine 3-N2-4-Me 3-N2-4-Ph 4-NH2-8-C1 4-Me-7-Br 4-Me-8-Br 4-Me-7-Cl
150-151 184-1 85 171-1 72 181-183 139-140 163-164 195-196 188 207-208 154-155 11571 15G151 156 275d 128-130 190 187-190 192 162-163 131-132 125.5-1 26.5 202-203 20 1-203 243-244 183-184 234-235 243-245 157 274-277 186
202 183 14G141
CH,Cl,/Hexane EtOH CH,Cl,/Hexane CH,Cl,/Hexane EtOAc/Hexane EtOH EtOH EtOH EtOH EtOH EtOH Petr ether DMFiEtOH i-PrOH MeCN i-PrOH EtOAc/Hexane i-Pr,O i-Pr,O i-Pr i-Pr Acetone Toluene Acetone
Acetone PhH/Hexane PhH
EtOH PhH
90 23 90
Pmr
16 50 55 98 6; 65 7 53 19 42; 43 51; 57 50 45 88 89
Pmr ir, ms, pmr, uv ir, pmr, uv Pmr ir, prnr Pmr ir, prnr ir, ms, prnr ir, pmr ir, pmr ir, ms, prnr ir, pmr
41 43 39 49 65 75 41 31.5 37 77 32, 89
ir, prnr ir, prnr ir, pmr
ir, pmr ir, pmr anal anal
ir, pmr
ir, pmr, uv
153 156 153 158 158 156 151 133 133 154, 156 156 154 147 149 148 149 154 168 168 168 306 306 309 309 309 312 312 118 144 143, 144 134 143
TABLE IV-1. -(contd.)
Substituent 4-Me-8-CI 4-Me-7-MeO 4-Me-8-Me0 4,7-Me2 4,8-Me2
mp ("C); [bp ("Cjtorr)]
Solvent of Crystallization
Yield
I 78 127 185 184 164165 174-175
EtOH EtOH MePh EtOH PhHjPetr ether PhH/Petr ether
133-1 36 165-168 241-243 227-228 204-205 197-1 97.5 217 24G241 21 5-216 230 217 225 213 254 213-21 7 202-203 238-240 239 250
Spectra
Refs.
93 56 82 38 87 66
ir, uv uv uv uv Pmr
106, 143 134 134 134 137 137, 138
PhH
70
ir, pmr, uv
136
PhMe DMF DMF Acetone Acetone EtOH
78 71 91 88 70
ir, pmr, uv pmr, uv
EtOH EtOH EtOH EtOH EtOH DMF
83 65 85 60 81 71
CCI, CCI,
56 25 44 44
136 139, 141 140 139 140 150 133 133 134 134 134 134 150 132 135 135 319 319
4-Me-7-[4-Methyl-1,3-dihydro-2-0~0-2HI,fi-benzodiazepin-7-yl)methyl]
(YO)
4-Me-8-[(4-Methyl-1,3-dihydro-2-0~0-2H1,5-benzoW
m P
diazepin-8-yl)Methyl] 4-Me-7-N02 4-Me-8-N02 4-Ph-7-NH2 4-Ph-7-Br 4-Ph-8-Br 4-Ph-7-CI 4-Ph-8-Cl 4-Ph-7-Me 4-Ph-8-Me 4-Ph-7-NO, 4-( 3- Pyridy1)- 7(8)-Me 4-CF3-7-Me 4-CF3-8-Me 4-Ph-8-N02 4-(4-C1C6H4)-8-N02
ir, pmr, uv
uv uv uv uv uv uv
ir, uv ir, pmr, uv ir, pmr, uv
Trisubstituted
1-NO2-4,7-Me, 1-Ph-3-Me-4-(I-Piperidino) 1-Ph-4-(Allylamino)-8-CI I-Ph-4-NH2-8-Br Methanesulfonate 1 -Ph-4-NH2-8-CI 1-Ph-4-NH2-8-F 1-Ph-4-NH2-8-N02 Methanesulfonate l-Ph-4-NH2-8-CF3 Hydrochloride Methanesulfonate I-Ph-4-AcNH-8-Br l-Ph-4-AcNH-8-Cl W
m vI
1-Ph-4-AcNH-8-NO2 I-Ph-4-AcNH-8-CF3 1-Ph-4-AcNMe-8-N02 I-Ph-4-PhCONH-8-N02 I-Ph-4-PhCH2OCONH-8-NO, 1-Ph-4-BuO-8-CF3 1-Ph-4-BuNH-8-C1 I-Phd-t-BuNH-8-Cl l-Ph-4-BuNEt-8-Cl I-Ph-4-BuNHCONMe-&NO2 l-Ph-4-ClCH2CONHNH-8-C1
1-Ph-4-CICH2CH,NHCONH-8-Br l-Ph-4-ClCH~CH~NHCONH-8-NO~ l-Ph-4-C1CH2CH2NHCONH-8-CF3 1-Ph-4-C1CH,CH2NHCO NMe-8-Br
122 250 173-176 248-249 276278 242-243 247-249 222-224 219-220 238-240 227-228 282-283 247-249 248-250 21621 1 C22622 71 231-237d 184186 174176 228-230 178-180 98-99 147-148 275-276 185-188 128-130 216215 2w201 196198 188-190 145-147
Et,O/Hexane MeOH THF/i-Pr,O CH,CI,/Et,O
26 7 48 49: 63
i-PrOH/MeOH CH,Cl,/i-Pr,O CH,Cl,/Et,O
39, 51 32 43
DMF CH,Cl,/i-Pr,O CH,Cl,/Et,O
68 54; 58
i-Pr,O
85
i-Pr,O
82; 90
EtOAc/i-Pr,O
50
MeOH
80; 88
EtOAcli-Pr,O
44 86
ir ir, pmr
163 154 157a 157 157a 157 153 157a 157b 157a 157a 157b 157b 167, 170 170 167, 170 170 167, 170 167, 170 167, 170 161 157 157 157b 170 159 167, 170 167, 170 167, 170 167, 170
TABLE IV-I. -(contd.)
Substituent I-Ph-4-(Cyclohexylcarbonylamino)-8-N02
1-Ph-4-(Cyc1ohexylcarbonylamino)-8-CF3 1-Ph-4-(Diallylamino)-8-C1 Hydrochloride l-Ph-4-(EtO),CHCH(Me) NH-8-CI 1-Ph-4-Me2N-8-CI l-Ph-4-Me,N-8-NO2 1-Ph-4-Me2N-8-CF,
1-Ph-4-Me,N(CH2),NH-8-C1 I-Ph-4-Me2N (CH,),NH-8-N02 1-Ph4-Me2N(CH,),NH-8-CF3 1-Ph-4-EtO-8-Br 1-Ph-4-Et0-8-C1 1-Ph-4-Et0-8-N02 1-Ph-4-EtO-8-CF3 I-Ph-4-EtOOCNH-8-Cl 1-Ph-4-Et00CNH-8-NOz 1-Ph-4-EtO (CHJ3NH-8-C1 l-Ph-4-EtNH-8-CI l-Ph-4-EtNH-8-NOz 1-Ph-4-EtNH-8-CF3 1-Ph-4-EtNHCONH-8-C1 1-Ph-4-NHNH2-8-CI Sesquihydrate I-Ph-4-HO(CH,)zNH-8-NOz 1-Ph-4-HO(CH,),NH-8-CF3 l-Ph-4-Me0-8-CI
mp ("C); [bp ('C/torr)]
Solvent of Crystallization
Yield (%)
Spectra
Refs.
188- 192 253-255
167, 170 167, 170
200d
157b
171-173 142-145 2 1 9-220 154155 278-280 148-153 171-173 142-143 97-100 182-184 145-147 187-189 212-2 13 169-170 183-184 243-245 181-183 226-228 102-103 191-193 188-189 136138
CH,Cl,/Hexane
73
CH,Cl,/i-Pr,O i-Pr,O
80; 87 63
MeOH
52
i-Pr,O EtOAcli-Pr,O EtOAc/i-Pr,O Et,O
50.5 68 62 76
EtOH i-Pr,O
91 43
MeOH
47 67
Et,O/Hexane
153 157b 157 157 157b 157b 157b 161 161 161 161 170 167, 170 157a 157b 157b 157a 170 158, 159 157 157 158a
I-Ph-4-MeO-8-CF3 1-Ph-4-[MeOOCC( = NOH)]-8-CI 1-Ph-4-MeNH-8-CI 1-Ph-4-MeNH-8-NO2 1-Ph-4-MeNH-g-CF, I-Ph-4-MeNNO-8-CI 1-Ph-4-(4-Methylpiperazino)-8-C1 1-Ph-4-14-(2-Methylphenyl)piperazino]-8-N02 1-Ph-4-(2-Methylpropanoylamino)-8-C1
w o\
4
1- Ph-4-MeS-8-CI 1-Ph-4-MeS-8-N02 1-Ph-4-MeS-8-CF3 I-Ph-4-(2-0xo- l-imidazolinyl)-8-Br I-Ph-4-(2-0xo- I-imidazolinyl)-8-NO, 1-Ph-4-(2-Oxo-l-imidazolinyl)-8-CF3 1-Ph-4-Piperidino-&NO2 l-Ph-4-Piperidino-8-CF3 1-Ph-4-i-PrNH-8-C1 1-Ph-4-i-PrNH-8-NO2 1-Ph-4-i-PrNH-8-CF3 1-Ph-4-i-Pro-8-CF3 1-(2-BrC6H,)-4-Et0-8-C1 1-(2-CICbH,)-4-AcNMe-8-CI 1-(2-C1C6H4)-4-NH,-8-C1 1-(2-C1CbH,)-4-Et0-8-CI I-(2-C1CbH4)-4-MeNH-8-CI 1-(2-FCbH4)-4-NH2-8-C1 1-(2-FCbH4)-4-BuNH-8-C1 1 -(2-FC6H4)-4-Et0-8-CI 1-(2-NO,C,H,)-4-AcNMe-8-CF3 1-(2-N02CbH4)-4-EtO-8-CI 1-(2-NO,C,H,)-4-MeNH-8-Cl
174175 271-273 2 17-220 217-219 201-203 123-126 217-21 9 223-225 173-175 123-1 26 113-115 160-161 177-1 79 267-270 268-270 253-255 175-176 144146 24C241 251-253 21 5-2 17 192-193 194196 176-178 26G262 191-192 224-225 258-259 2w202 128-130 178-180 161-1 62 26G262
THF CH,Cl,/i-Pr,O CH,Cl,/i-Pr,O CH,Cl,/i-Pr,O CH,CI,/Hexane
68 75 92; 95.5
CH,CI,/Hexane
i-Pr,O
48
i-Pr,O i-Pr,O
42 45
CH,CI,/Et,O
38
EtOAc
35
161 171, 158b 157a 157a 157a 158 157b 157 170 158 161 161 161 167, 170 167, 170 167 157b 157b 157b 157b 157a 161 161 167 157 161 157 153 I57 161 167, 170 161 157
TABLE IV-I. -(contd.)
Substituent 1 -(2-CF,C6H,)-4-BuNH-8-Cl
g
1-(2-CF,C6H,)-4-EtO-8-C1 3-Et-4-EtzN-7(8)-Cl 3-Ph-4-PhCH2-7-C1 3-Ph-4-PhCH2-8-C1 3-Ph-4-PhCH2-7-Me0 3-Ph-4-PhCH2-7(8)-Me0 3-Ph-4-PhCH2-7-Me 3-Ph-4-PhCH2-8-Me 3-Ph-4-PhCH,-7(8)NOz 4-Me-6,8-Br2 4-Me-7,9-Br2 4-Me-6,8-Cl2 4-Me-7,8-Cl2 4-Me-7,9-Cl2 4-Me-8-Me0-9-NO2 4,7,8-Me3 4,7-Me,-8-NO2 4,7-Me,-9-NO2 4,8-Me,-7-NO2 4-Me-7-N02-8-Br 4-Me-7-NO2-8-C1 4-Me-7-NO2-8-Me0 4-Ph-7-Me-8-NO2 4-Ph-7-Me-9-NO2 4-Ph-7-N02-8-Br 4-Ph-7-NOz-8-CI 4-Ph-7-NO2-8-Me
mp ("(3; [bp ("C/torr)] 184185 123-125 136 174-176 148-151 152-154 172-1 74 158-160 188-192 20G202 203 184 2 13-214 219d 189 195 186 218 136 235 248 248 258 246 223 267 265 268
Solvent of Crystallization
EtOAc i-PrOH i-PrOH MeCN MeCN MeCN PhH PhH PhH EtOH/H,O PhH EtOH PhH EtOH EtOH DMF DMF DMF DMF MePH EtOH DMF DMF DMF
Yield
(YO)
56 48 22 35; 30 34 48 35 30 80 90 80 80 89 34 88.5 5.5 33.5 87 62 92 40 24 30 70 82 93
Spectra
Refs. 157 161 154
ir, pmr ir, pmr ir, pmr
149
149 149 148
ir, pmr ir, pmr ir, pmr ir, pmr Pmr ir, uv Pmr ms, pmr, uv ir, pmr ms, pmr ms, pmr ms, pmr ms, pmr, uv ms, pmr, uv ms, pmr, uv ms, pmr ms, pmr ms, pmr, uv ms, pmr, uv ms, pmr
149 149 148 143 143 142 106 142 164 143 163 163 163 164 164 164 163 163 164
164 163
4-(4-MeOC,H,)-7-Me-&NO2 4-(4-MeOC,H,)-7-NO,-8-Br 4-(4-MeOC,H,)-7-N02-8-C1 4-(4-MeOC,H,)-7-NO,-8-Me
26 1 277 272 259
PhMe DMF DMF DMF
77 60 96 78
ms,pmr uv uv ms,pmr
163 164 164 163
255 260 247-249
THF Dioxan PhH
50
ir ir, pmr
168 126 126
210-212
PhH
77
Polysubstituted
3-PhNHCO-4-Me-7,8-Me2 4-Me-6,7,8,9-C14 1,4-Me2-6,7,8,9-C14 u
-
Me 169
'Ph
'\
4
H
3-(3-0~0-3,4-dihydroquinoxalin-2-ylidene) hydrochloride l-Ph-4-Ac2N-5-Ac-8-CF3
i-Pr,O
72 27
ir, pmr
305 167 167 167
l-Ph-4-PhCONH-5-PhCO-8-NOZ I-Ph-4-PhCONH-5-PhCO-8-CF3
204-206 270-213 252-254
1-Ph-4-(Cyclohexylcarbonylamino)-5-(cyclohexylcarbony1)-%NO2
240-242
167
242-244 211-213 147-149 l-Ph-4-(CF3CONH)-5-CF3CO-8-N02~Me,NAc
167 167 167
1-Ph-4-(Cyclohexylcarbonylamino)-5-(cyclohexylcarbonyl)-8-CF3
l-Ph-4-(Propenoylamin0)-5-propenoyl-8-C1
2
W m
4
0
m W
370
-6
P
m mW
E
n
E
'?
z
l-(4-MeC6H,SO,) I-Ph I-(2-HOC,H4) I-(2-MeOC6H,) 2-Me 2-Ph 2-(3-H,NC,H4) 2-[2,4-(MeO),C,H,] 3-Et 3-HO 6-NH, Dihydrochloride 7-Me0
16&167 [175/3.5 mm] 185-186 9 G 91 97-98 106-107 118-1 I9 12G122 82-83 139-141
EtOH EtOH EtOH MeOH EtOH EtOH EtOH
23 1-237 [11S120/0.005mm]
72; 68 62 55 63 33
ir, pmr ir, pmr pmr, uv
72 67 81
ir, pmr, uv
184
89 ir, pmr
176-1 78 178 179 179 124 107 113 113 23 1 181
187
Disubstituted cc)
3
I-Et-2-Me 1-PhCO-5-(4-MeC,H4SO,) 1-PhCH,-5-(4-MeC,H,SO,) 1,5-(BrCH,CH,CO), 1,5-Me2 I-Me-5-(2-MeOC6H,) l,5-(4-MeC,H4SO2),
1-(4-MeC,H,SO2)-5-(2-MeOC,H,) 1-(4-MeC,H4SO,)-5-Ph 1,5-(NO), 1,5-(PhSO,), 2-CN-4-(2-Furyl) 2-CN-4-Me 2-CN-4-Ph 2-CN-4-(2-Thienyl) 2,4-Me2, cis Picrate Perchlorate
51 183-184 124-125 127-129 193-194d 193 182-183 138 120 204-205 122-123.5 159-161 134135 155-156 5940 186; 175d 2ood
EtOH PhH EtOH AcOH EtOH
93 40, 55 80 41 31; 60 75 75 45; 28
ir ir, pmr
ir
68 86 99 63 Petr ether PhH EtOH/E t ,O
44;90
ir, ms, pmr
192 177 190 191 183 179 176 179 178 175 175 188 188 188 188 116, 117, 186 116, 117 116
TABLE IV-I. -(contd.) ~
Substituent
w
-4
N
2-Me-4-Ph, cis, trans mixture cis-Hydrochloride 2-Me-4-(4-BrC6H,), cis Hydrochloride 2-Me-4-(4-C1C6H,), cis Hydrochloride 2-Me-4-(4-EtOC6H4),cis Hydrochloride 2-Me-4-(4-MeOC6H,), cis Hydrochloride 2-Me-4-(4-MeC6H,), cis Hydrochloride 2-Me-4-(3-NO,C6H,) Hydrochloride 2,4- Ph 2 cis trans
2-Ph-7-CI
2-[3,4,5-(MeO),C6H,]-7-C1 2-CH,NH2-4-Ph 2-CHzNHCOCH=CH(4-PhC6H4) 2-CH2N=CHCH=CH(4-PhC6H4) 2-CH,NHCO(C6H,-4-Me) 2-CHzNHC0(4-PhC,H4) 2-COOH-4-Ph 2-COOH-4-Me 2-COOMe-4-Ph 2-COOEt-4-Ph Hydrochloride
~
~~~~~~
mp W ) ; [bp ("C/torr)]
Solvent of Crystallization
Yield (%)
Spectra
Refs.
64-65 220d
Petr ether EtOH/H,O
26 100
pmr, uv
107, 116 186
245-246
EtOH/H,O
100
116, 186
227-229; 275
EtOH/H,O
100
116, 186
205d
Et OH/H 0
,
100
116, 186
215d
EtOH/H,O
100
116, 186
230d
EtOH/H,O
100
116, 186
115-1 17d
EtOH/H,O
100
116, 186
136137 14G-141 183-184 58-59 183-184 151-153 123-127 147-149 22G221 207-210 17&171 158-1 62 146157 155-1 60
MeOH
Bz MeOH MeOH PhH/Hexane MeOH CHCI, CHCI, EtOH EtOH EtOH
7; 5.5 13
pmr, uv pmr, uv
25 62
ir, ir, ir, ir, ir, ir, ir, ir, ir.
64 57 64 8 5 57 35
pmr, uv uv uv uv uv uv uv uv uv
107 107 111 111 320 320 320 320 320 320 320 320 320 320
2-COOEt-4-Me Hydrochloride
154-162 147-151
EtOH EtOH
112 205-206 222-223 202-204 194-195 192-193 203-204 12&127
EtOH
32
ir, uv
320
Trisubstituted
l-Et-2-Me-5-(2-Naphthyloxy-thiocarbonyl ~,~-(Ac),-~-(~-HOC,H~) 1,5-(Ac)2-3-HO 1,5-(4-MeC6H,SO,),-2-Me l,5-(4-MeC,H4SO,),-3-HO
1,5-(4-MeC,H,SO,),-3-(4-MeC6H,SO3) 1,5-(4-MeC,H,SO,),-3-MeSO,
I*)
4
w
1,5-(NO),-3-HO 1,5-Me2-6-C1 1,5-Me2-7-C1 2,2,4-Me2 2-CN-2-Me-4-Ph 2-CN-4-Me-7-(2-Cyano-4-methyl-2,3,4,5-tetrahydro-lH-l,5-benzodiazepin-7-yl)methyl 2-CN-4-Ph-7-(2-Cyano-4-phenyl-2,3,4,5-tetrahydro-1 H-l,5-benzodiazepin-7-yI)methyl 2-(1-Naphthy1)-7,8-Me, Dihydrochloride 2-(2-Naphthy1)-7,s-Me, Dih ydrochloride 2-Ph-7,8-Me, Dih ydrochloride 2-(4-EtOC,H,)-7,8-Me2 2-(4-FC,H,)-7,8-MeZ Dih ydrochloride 2-(2-HOC,H,)-7,8-Me2 2-(4-MeOC,H4)-7,8-Me, 2-Me-2-COOEt-4-Ph
EtOH EtOH CHCl,/Petr ether CHCIJPetr ether PhH
93.5 54 41 97.5 74 93 8.5; 6 31: 37
ir, pmr, uv ir, pmr, uv ir, pmr, uv ir, pmr, uv ir, pmr, uv
Pmr Pmr
192 111 181 124 181 181 181 181 183 183 98
69 155-157
Petr ether
132-135
PhH
88
ir, pmr, uv
99
142-144 77-79 188-190 119-121 181-183 8&88 19&198 7G12 6&68 179-1 8 1 128-129 121-123 127-1 28 9c93
PhH
72
ir, pmr, uv
EtOH/H,O EtOH/Et,O
67; 75
99 111 111 111 111 111
188
90
EtOH/H,O EtOH
111
85 85 70 48
uv ir, uv
111 111 111 112 111 112 320
TABLE IV-I. -(contd.)
Substituent
mP (“C); [bp (“Citorr)]
Solvent of Crystallization
Yield (YO)
Spectra
Refs
148-152 14&145 147-149 203-205 204206
EtOH EtOH EtOH EtOH EtOH
37 36 41 39 30
ir, pmr ir, pmr ir, pmr ir, pmr ir, pmr
308 308 308 308 308
EtOH/H,O PhH PhH EtOH/H,O Acetone EtOH EtOH EtOH EtOH EtOH EtOH EtOH
90 60 55
Tetrasubstituted
1,5-Ac2-2-CN-4-Me 1,5-(COCH2CI),-2-CN-4-Me 1,5-(COEt),-2-CN-4-Me 1,5-(COPh),-2-CN-4-Me
2
1,5-(CO-4-C1C6H,),-2-CN-4-Me
P
Polysubstituted
1,5-Ac,-2-(2-HOC,H,)-7,8-Me2 1,5-Ac,-2-(4-MeOC,H4)-7,8-Me, 1,5-(BrCH2CH,CO),-2,4-Me, 1,5-(BrCH2CH,CO),-2-Me-4-Ph 1,5-(NO2)-2,2,4-Me, 1,5-(NO2)-2,4-(CN),-2,4-Me2 1,5-Ac2-2-Me-2-COOEt-4-Ph 1,S-(COCH2C1),-2-Me-2-COOEt-4-Ph
1,5-(COEt),-2-Me-2-COOEt-4-Ph
1,5-(COPh),-2-Me-2-COOEt-4-Ph 1 ,5(CO-4-C1C,H4),-2-Me-2-COOEt-4-Ph
2-CN-2,4,4-Me3 2,4-(CN),-2,4-Me2 2-CN-2,3,4-Me3
2-[3,4-(HO),C6H,]-3-Ph-7,8-Me,
251-252 187.5 134136 155-157 157 183d 173-175 131-132 15G152 173-175 202-2 14 141- 144 160d 165-168 208-209
57 40 57 68 8s 8 0 3s 74
ir, pmr ir, pmr ir, pmr ir, pmr ir, pmr
111 111 191 191 98 119 308 308 308 308 308 119, 188 119 188 111
2-(4-MeOC6H,)-3,7,8-Me, Dihydrochloride
35-36 238-240
111 111
Me I [98-100/1 mm]
34
182
1747
187, 193 201, 205, 206 20 1 20 1
76; 85
199, 323 199, 323 199. 323 199, 323 199, 323 199, 323 199, 323 199, 323 199, 323 199, 323 205 109, 146, 141, 194-197 194
Me
1,3,4,5-Tetrahydro-I,5-benzodiazepin-2 (2H)-ones
None
141-142
PhH/Hexane
191-192 186187
EtOH
17&171 149-1 50 183-184 197-1 98 211-212 233-234 127-1 28 188-189 198-1 99 147-148 201-202 185-186 203
EtOAc EtOAc i-PrOH EtOAc CHCI, DMF EtOAc EtOH i-PrOH i-Pr,O EtOH MeOH MeOH
W
4
Hydrochloride Picrate Monosubstituted
1-Ph 1-(2-CIC6H,) 1-(3-CIC,H,) 1-(2,5-C1zC,H,) 1-(2,6-C1,C,H3) 1-(4-CIC,H,) 1-(2-MeOC,H4) 1-(4-MeOC,H4) 1-(4-MeC6H,) 1-(3-CF,C,jH,) 3-Me 4-Me Picrate.MeOH
81 84
44- 100
TABLE IV-1. -(contd.)
Substituent 4-Ph 4-(4-Ac-3-MeOC6H3) 4-(2-HzNC6H4) Hydrochloride 4-(4-H,NC,H,) Hydrochloride 4-(2-HOC6H4) 4-(3-HOC,H,) 4-(4-HO-3-MeOC6H,) 4-(4-(MeOC,H, ) 4-(2-NO,C,H,) 4-(4-NOZC,H,) 5-Ac 5-Me 5-NO 5-Ph 7-Me0 8-Br 8-CI 8-Me0 &NOz 8-CF3 4-(2-Furyl)
mp CC); [bp ("Citorr)]
Solvent of Crystallization
163-167 195-1 96 155-156
EtOAC
23&231 255-257 148-149 169-170 141-142 129-1 30 8&81 184-185 159-1 6 1 138- 140 195-196 [221] I8 1.5-182.5 158-159 180-181 183-184 146.5-147 274.5-275 254-255 233d 169
Yield (YO)
Spectra
Refs.
46 49.5
129, 212 200 200
EtOH/Et,O
49.5
200
EtOH/Et,O
47 54
200 200 200 200 200 200 200 187 187 194 (211) 187 187 204 106, 187, 204 20 1 20 1 204 204 129
64
EtOAc/Hexane PhH/Hexane EtOH (PhH) EtOH EtOAc EtOAc/i-Pr,O EtOAc/Hexane PhH EtOH MeCN PhH
50.5 77 40 30.5 80 20.5 90 4.5
(91) 28.5 76 32; 65; 87 51 79 84 55
Disubstiruted
I-Ph-3-Me I-Ph-4-Me 1-Ph-5-Ally1 1-Ph-5-Et 1-Ph-5-Me I-Ph-7-CI I-Ph-7-Me0 1-Ph-7-Me 1-Ph-7-CF3 I-Ph-g-NH, 1-Ph-8-Br
W
4 4
I-Ph-8-Cl Hydrochloride I-Ph-8-CN l-Ph-8-(4-Diethylaminophenyl)azo 1-Ph-8-HO 1-Ph-8-N02 I-Ph-8-(4-NitrophenyI)-methanimino 1-Ph-8-CF3 I-Ph-9-CI 1-(2-BrC6H,)-8-C1 1-(4-BrC6H,)-8-C1 1-(2-CIC6H,)-5-Me 1-(2-C1C6H4)-7-CF3 1-(2-C1C6H4)-8-C1 1-(2-C1C,H4)-9-C1 1-(2-C1C6H4)-8-N02 1-(2-CIC,H,)-8-CF, 1-(2,3-C1,C,H3)-5-Me 1-(2,3-CI,C,H3)-8-C1 1-(2,5-Cl,C6H,)-5-Me
146147 13G131 7 1-72 92-93 103-104 203-204 216217 164165 168-1 69 284-285 192-1 93 183-185 179-180 158-161 182-185 260 192-193 24 1 188 164-165 213-214 186188 216217 128-1 29 176177 188-1 89 212-21 3 232-233 134 134135 144-145 133-134
EtOAc EtOAc Petr ether i-Pr,O i-Pr,O MeCOEt AcOH EtOAc EtOAc/Petr ether i-Pr,O EtOH
83
88 60 82
EtOH EtOAc/Et,O EtOH/H,O Et,O
48 83.5 38
PhMe i-PrOH EtOAc
58
MeCOEt i-PrOH i-PrOH i-PrOH EtOH
i-PrOH i-PrOH i-PrOH
210, 323 210, 323 199, 323 199, 323 199, 323 199, 323 199, 323 199, 323 199, 209, 323 204 209 204 199, 204, 323 207 204 204 204 204 204 209 199, 323 207 199, 323 199, 323 199, 209, 323 199, 323 199, 323 207 207 199, 323 208 199, 323
TABLE IV-1. -(contd.)
Substituent
w 4 00
1-(2,6-CI2C,H3)-8-C1 1-(3-C1C,H4)-5-Me 1-(4-C1C6H,)-4-Me 1-(4-CIC6H,)-5-Me 1-(4-C1C6H4)-8-C1 1-(2-FC6H4)8-C1 1-(2-MeOC,H4)-5-Me 1-(2-MeOC,H4)-8-C1 1-(3-MeOC6H,)-8-C1 1-(4-MeOC,H4)-5-AllyI 1-(4-MeOC,H4)-5-Me 1-(4-MeOC6H,)-8-C1 1-(2-MeC6H,)-8-CI 1-(3-MeC6H,)-8-C1 1-(4-MeC,H4)-8-CI 1-(2-N02C6H4)-8-C1 1-(2-N02C6H4)-8-N0, 1-(2-N0,C6H,)-8-CF, 1-(2-CF3C6H4)-8-C1 1-(3-CF3C,H,)-3-Me 1-(3-CF,C,H4)-5-Me 1-(3-CF3C6H4)-8-C1 1-(2-Pyridyl)-l-Br 1-(2-Pyridy1)-8-CF3 3,3-Et, 3-Et-3-Ph Hydrochloride
mp FC); [bp (“C/torr)] 25G251 87-88 159-160 89-90 203-204 168-169 129-130 147-148 178-179 [189-192/0.1] 78-79 198-199 150-151 172-173 208-209 171-172 233-235 156 132-133 147-148 168-169 104105 148-149 174176 150-152 2 11-2 1 3 143-145 218-219
Solvent
of Crystallization
Yield
(YO)
Spectra
AcOH i-Pr,O i-PrOH i-Pr,O EtOAc i-PrOH EtOAc EtOAc i-PrOH i-Pr,O EtOH i-PrOH EtOH MeCOEt CH,Cl,/i-Pr,O
208
73
61
EtOAc/Petr ether i-PrOH i-Pr,O i-Pr,O
EtOH Ligroin EtOH
Refs.
58 88
ir ir
199, 323 210, 323 199, 323 199, 323 199, 323 199, 208, 323 199 199, 323 199, 323 199, 323 199, 323 199, 323 199, 323 199, 323 207 207 207 207 208 199, 323 208, 323 208, 323 204 207 203 203
3,3-Me2 3-Me- 3- P h Hydrochloride 3-Me-7-CI 3-Me-8-CI 3-Me-8-MeO 3,3-Ph, 3,3-Pr2 4,4-Me2 4-Me-5-Ac
w
-4
a
4-Me-5-NH2 Oxalate 4-Me-5-(N-Diphenylmethanimino) 4-Me-5-[ N-(2-Nitrophenyl)-methanimino] 4-Me-5-NO 4-Me-5-(N-Phenylmethanimino) 4-Me-7-NH2 Hemithydrate Dih ydrochloride Picrate 4-Me-7-(Methyl-l,3,4,5-tetrahydro-2-0~01,5-benzodiazepin-7-yl)-methyI 4-Me-8-NH2 Picrate 4-Me-8-Br 4-Me-8-Cl 4,8-Me, 4-Me-8-N02 4-Ph-5-Ac 4-Ph-5-EtCO 4-Ph-5-NO 4-Ph-7-CI
191
PhH
22
ir, pmr
202
228-23 1 165-167 195-196 142-143 206207 171-173 248-250 177 190 176 173d 204 20 1 185 184
i-PrOH EtOH EtOH EtOH EtOH i-PrOH CHCIJHexane H2O Ligroin PhH EtOAc MeOH
74 94 86 34; 50 11 74 46.5 97
ir
203 205 205 205 203 203 198 194 146 194 194 194 194 146, 194 194
MeOH MeOH
156158 243-245d 154156 116-119
175-176.5 174176.5 21 3-21 4
PmI
ir ir, pmr
86 67 88 77 72
141 141 141
85
EtOH EtOAciPetr ether
198
PhH/Hexane MeOH/H,O
196197 247-250 2w202 224226 181d 161
MeOH MeCN MeCN MeOH PhH
70 84; 86.5 31 70; 87 72; 94
5
pmr, uv ir ir, uv
136 141 141 144 106 137, 138 139, 141 212, 216 212 129 134
TABLE IV-I. -(contd.) ~~~
~~
--
~
Substituent
mp ("C); [bp (Tjtorr)]
Solvent of Crystallization
5-Ac-7-Me0 5-Ac-8-C1 5-Me-7-Me0 5-Me-8-Cl 7,8-C1, 7,8-Me2
219-22 1 24G24 1 150-1 52 140-142 280 176-176.5
EtOAc/Hexane 81 EtOH 72 EtOAc/Hexane 32 EtOAc/Hexane 23 MeOCH,CH2OH/H204Q 70 PhH 56
170 132-134 238-240 122-125 226-228
CHCI,/Et,O Hexane i-PrOH PhH/Hexane i-PrOH
151-152 193-194 101-102 172-173 128-1 29 146147 97-98 108-109 17G172 167-168 209-2 10 188-190 178-1 79 118-119
i-PrOH EtOH i-Pr,O EtOAc i-PrOH i-Pr,O Et,O i-Pr,O EtOH i-PrOH MeOH
78 88
i-PrOH
92
Yield
(YO)
-
~
Spectra
Refs.
ir, ir, ir, ir,
187
pmr pmr pmr pmr
pmr, uv
187
187 187 106 20 1
Trisubstituted
w
00
0
I-Ac-4-Me-5-AcNH l-Me2N(CH2),-4-Ph-5-Ac Hydrochloride 1-Me,N(CH2),-4-Ph-5-COEt Hydrochloride 1-2(N-Methyl-l-adamantylamino)ethyl-4-Ph-5-A~ Hydrochloride 1-Ph-3,3-Me2 1-Ph-3,4-Me2 1-Ph-3,5-Me2 l-Ph-3-Me-7-CI l-Ph-3-Me-8-CI 1-Ph-4,4-Me2 1-Ph-4,5-Me2 l-Ph-4-Me-5-Allyl l-Ph-4-Me-7-CI 1-Ph-4-Me-8-C1 l-Ph-5-Ac-U-CI l-Ph-5-Ac-8-N02 1-Ph-5-(AcOCH2CH,)-8-C1
76
194 212 212 212 212 216 199, 210, 323 210, 323 199, 210, 323 199, 210, 323 199, 210, 323 199, 210, 323 199, 210, 323 210, 323 199, 210, 323 210, 323 217 204 204 217
l-Ph-S(Adamanty1) carbon yl-8-C1
w
2
l-Ph-5-Allyl-8-Br l-Ph-5-Allyl-8-Cl l-Ph-5-Allyl-8-NO2 1-Ph-5-Allyl-8-CF3 1-Ph-5-H2NCO-8-Cl 1-Ph-5-PhCO-8-N02 l-Ph-5-PhCH2-8-N02 l-Ph-5-(2-Butenoyl)-8-C1 1-Ph-5-(But-2-en-1-yl)-8-Br I-Ph-5-(But-2-en-l-y1)-8-N02 1-Ph-5-BuOCO-8-CI l-Ph-5-Bu-8-Br l-Ph-5-Bu-8-NO2 l-Ph-5-Bu-8-CF3 1-Ph-5-ClCH2CO-8-CF3 I-Ph-5-(4-Chloro-cis-but-2-en-l-yl)-8-N02 l-Ph-5-(2-Chloroethy1)-8-C1 l-Ph-5-(Cyclohexylmethyl)-8-N02 1-Ph-5-(Cyclopropyl) methyl-8-N02 l-Ph-5-Et2NCO-8-CF3 1-Ph-5-Ph,CHCO-8-Cl I-Ph-5-EtOCO-8-Cl l-Ph-5-EtOCO-8-NOz l-Ph-5-Et-8-CI l-Ph-5-Et-8-NOZ I-Ph-5-EtNHCO-8-Cl l-Ph-5-EtOOCC0-8-Cl l-Ph-5-EtOOCCO-8-N0, I-Ph-5-EtOOCCO-8-CF3 I-Ph-5-CHO-8-Br l-Ph-5-CHO-8-CI
16G168 158-160 135-136 126127 144145 197-198 235-237 Oil 108- 109 129-130 135-1 36 108-109 13G131 114115 88-89 185-1 8 7 167-168 180-181 Oil 127 12&128 233-234 172-173 127-1 29 135-136 160-162 214-216 186188 152-1 54 158-160 158-1 59 150-151
EtOH
86.5 83
EtOH
85
i-Pr20
63
MeCOEt
77
EtOAc
84 87
EtOH
i-Pr,O/Acetone i-PrOH
78 89
204 204, 207 199b, 207, 323 207 207 217 204 207 204 207 207 204 204 204 204 204 204 217 21 5 215, 217 204 204 217 204 199, 323 207 204 204 204 204 215 217
TABLE IV-1. -(contd.)
Substituent
m w
l-Ph-5-CHO-8-NO2 I-Ph-5-CHO-8-CF3 I-Ph-5-n-Hexyl-8-Br l-Ph-5-n-Hexyl-8-NO2 l-Ph-5-(HOCH,CH2)-8-Br l-Ph-5-(HOCH2CH,)-8-C1 l-Ph-5-(HOCH~CH,)-8-N0, 1-Ph-5-(HOCH2CHz)-8-CF3 l-Ph-5-[HO(CH2),]-8-Br l-Ph-5-(MeOCH,CH,)-8-C1 l-Ph-5-Me-8-Br l-Ph-5-Me-8-CI l-Ph-5-Me-8-NO2 1-Ph-5-Me-8-CF, l-Ph-5-Me-7-Cl l-Ph-5-Me-9-Cl 1-Ph-5-(2-MeC6H4CO)-%NO,
1-Ph-5-(4-MeC,H4SO,)-8-CI 1-Ph-5-(l-Naphthylsulfonyl)-8-C1 1-Ph-5-(4-NOzC6H40CO)-8-N0, I-Ph-5-(PhCH,CO)-8-C1 l-Ph-5-PhNHCO-8-CI 1-Ph-5-( trans-3-Phenylpropenoyl)-8-N02 l-Ph-5-(Propenoyl)-8-CI l-Ph-5-Pr-8-Br I-Ph-5-Pr-S-CI l-Ph-5-Pr-8-NO2 1-Ph-5-Pr-8-CF3
mP (“C); [bp (‘Cjtorr)] 19C191 141-142 14145 Oil 154-155 16C161 188-193 91-92 161-163 108-109 122-124 143-144 123-125 91-92 105-106 16G161 172-179 21 2-21 3 181-182 152-154 176178 250-253 168-170 176178 141-142 125-126 125-126 143-1 45
Solvent of Crystallization
Yield (Yo)
MeOH i-PrOH
51; 64 82
Et,O
27 16 67
EtOH EtOH
93 63
i-Pr,O i-PrOH
93
Spectra
Refs. 215 215 215 215 215 217 215 215 215 217 204 199b, 323 204 204 199, 323 199, 323 204 204 204 204 204 204 204 204 204, 207 207 207 207
l-Ph-5-i-Pr-8-Br 1-Ph-5-i-Pr-8-NO2 l-Ph-5-Stearyl-8-Cl l-Ph-5-[2-(Succinyloxy)-ethyl]-8-CI l-Ph-5-[3-(Succinyloxy)-propyl]-8-C1 1-Ph-5-CF,CO-8-NH2 1-Ph-5-CF3CO-8-(4-Diethylaminophenyl)azo 1-Ph-5-CF,CO-8-NO2 l-Ph-7,8-C12 1-(2-C1C6H4)-5-Ac-8-C1 l-(2-CIC6H4)-5-H,NCO-8-C1 1-(2-C1C6H,)-5-PhCO-8-CF, 1-(2-CIC6H4)-5-EtOCO-8-Cl 1-(2-C1C6H4)-5-Et,NCO-8-C1 1-(2-ClC,H4)-5-CHO-8-C1 1-(2-C1C6H4)-5-CHO-8-CF3 l-(2-C1C6H4)-5-HOCH~CH~-8-C1 W
1-(2-C1C6H4)-5-MeOCH2CH2-8-CI 1-(2-C1C,H4)-5-Me-7-CF, 1-(2-C1C6H4)-5-Me-8-C1 1-(2-C1C6H4)-5-Me-9-CI 1-(2-C1C6H4)-5-MeNHCO-8-Cl 1 -(2-C1C6H4)-5-(Prop-2-ynyl)-8-N02
1-(2-ClC6H4)-5-[2-(Succinyloxy)-ethyl]-8-C1 1-(4-C1C6H4)-4,5-Me2 1-(4-C1C6H4)-5-Me-8-C1 1-(2-FC6H4)-5-Ac-8-C1 1-(2-FC6H4)-5-CHO-8-Cl 1-(2-FC6H4)-5-Me-8-CI 1-(2-MeOC6H4)-5-Me-8-C1 1-(4-MeOC6H4)-5-Me-8-CI l-(2-MeC,H4)-5-Allyl-8-CI 1-(2-MeC,H4)-5-Me-8-C1
123-124 170-171 72-74 146-147 141-142 206-207 183-186 189 193-194 222-223 235-236 187-188 159-160 171-172 182-183 143-1 44 148-149 98-99 116-117 187-1 88 175-1 76 223-224 168-1 70 149-150 8&82 135-136 187-1 89 146147 116117 15G151 144-145 154-155 148-149
i-PrOH i-PrOH i-Pr,O EtOH/H,O
42
MeOH MeCOEt EtOH
92
i-PrOH i-PrOH i-PrOH
77 69 84
EtOAc i-PrOH i-PrOH i-PrOH i-PrOH EtOH
70
EtOAc Petr ether i-PrOH
81
EtOH/H,O EtOAc/Petr ether i-PrOH i-PrOH i-PrOH
88 86 85
85
58
82
75
79
207 207, 215 204 217 217 204 204 204 323 217 217 204 217 217 217 217 217 209 199, 323 199, 323 217 207 217 199, 323 199, 323 204 207 199, 323 199, 323 199, 323 208 199, 323
TABLE 1V-1.
w
00
~- (contd.)
Substituent
mp ("C); [bp ("C/torr)]
Solvent of Crystallization
1-(3-MeC,H,)-5-Me-8-CI 1-(2-NO,C,jH4)-5-CHO-S-C1 1-(2-NO 2C6H4)-5-Me-8-CI 1-(2-Pyridyl)-5-Ac-8-C1 1-(2-Pyridyl)-5-Allyl-8-Br 3,5-Et,-3-Ph 3-Et-3-Ph-5-Ac 3-Et-3-Ph-5-NH2 3-Et-3-Ph-5-HZNCO 3-Et-3-Ph-5-Me 3-Et-3-Ph-5-NO 3-Et-3-Ph-7-Br 3-Et-3-Ph-8-Br 3-Me-7,8-CI2 4,4,8-Me, 4-Me2-8-C1 4-Me-7,8-CI2 4-PH-7,9-C12 4-(2-H,NC6H4)-7,9-C12 4-(4-H2NC6H4)-7,9-Cl2 4-(2-HOC6H4)-7,9-CI2 4-(3-HOC6H4)-7,9-CI2 4-(4-HO-3-MeOC,H,)-7,9-C1, 4-(4-MeOC,H4)-7,9-CI2 4-(2-NO,C,H4)-7,9-C12 4-(4-NO,C,HJ-7,9-Cl2 6-Br-7,8-CI,
135-136 211-214 176-178 184 144146 131-133 175-1 76 139-141 226228 138- 140 177-179 167-170 162-164 179-1 8 1 23S232 239-240 238 115-116 148-149 188- 190 138-139 158-159 150-152 123-124 161-162 195-1 96 260
i-PrOH
Et,O EtOH Et,O PhH Et,O EtOH PhH/Petr ether AcOH EtOH CHCIJHexane CHCIJHexane DMSO/H,O
EtOH
Yield (YO)
69 68 37 63 94 28 36 71 47 20 60 49 33.5 33 25 32 27.5 26.5 26 23.5 75
Spectra
ir ir ir ir ir ir ir ir uv uv pmr, uv
pmr, uv
Refs. 199, 323 207 207 204 204 203 203 203 203 203 203 203 203 205 198 198 106 200 200 200 200 200 200 200 200 200 106
Polysubstituted
1-Ph-3,3-Me2-8-C1 1-Ph-3,4-Me2-8-C1 1-Ph-3,5-Mez-7-CI 1-Ph-3,5-Me2-8-C1 1-Ph-4,4-Me2-8-C1 1-Ph-4,5-Me2-7-C1 l-PH-4,5-Me2-8-CI 1 -Ph-5-Me-7,8-Cl2 1-Ph-3,4,5-Me3-8-CI 1 -Ph-3,3,5-Me2-8-C1
143-133 194-195 11&117 151-152 18C-181 122-123 113-114 109-1 10 116117 191-192
i-PrOH EtOH i-Pr,O i-PrOH i-Pr,O i-Pr,O EtOAc i-PrOH i-PrOH i-PrOH
199, 323 199, 323 199, 323 199, 323 199, 323 199 199, 323 199, 323 199, 323 199. 323
82
4-Methylene-l,3,4,5-tetrahydroI ,5-benzodiazepin-2 ( 2 H ) -ones
lO-PhCH,OCO 10-EtOCO 10-EtOCHzCH~OCO 10-MeOCO l0-(Tetrahydrofuran-2-yl)-rnethoxycarbonyl 1-Ph-10-NO, 1-Ph-8-CI-10-MeOCO I-Ph-8-CI-IO-NOz 1-Ph-8-C1-10,l O-(MeOCO),
I ,2,4,5- Tetrahydro-I ,5-benzodiazepin-3 (3H)-ones
197 228 160 255 173
2 3 3-23 5 199-201 26C-262 155-158
PhCH,OH EtOH EtOH EtOH EtOH CH,Cl,/EtOH CH,Cl,/MeOH CH,Cl,/MeOH MeOH
87 3&95 90 3C-95 55
ir, pmr
214 213, 214 214 213-214 214 171 171 160 171
TABLE IV-1. -(contd.)
Substituent
mp ( T I ; [bp ('Cjtorr)]
l,S-(4-MeC6H,SO,),
176178 179-1 80 198-1983 184185 187-188 2w201
Oxime Hydrazone Tosylhydrazone 2,4-Dinitrophenylhydrazone
Solvent
of Crystallization
Yield (%)
Spectra
Refs.
EtOAc CHCIJEtOH EtOH/H,O CHCI,/EtOH EtOH CHCI,/EtOH
25 89
ir, pmr ir, pmr
219 181 181 181 181 181
3,5-Dihydro-1H-l,5-benzodiazepin-2,4(2H, 4H)diones m
m
None
> 360
62
220, 221, 223-227
Monosubstituted
I-PhCH, 1-Bu 1-Cyclohexyl 1-Me 1-Ph I-(4-C1C,H4) 1-(2-MeOC,H4) 1-(3-MeOC,H,) 1-(4-MeOC,H,) 1-(2-Me-4-C1C6H,) 3-Ally1 3-n-Bu
214216 168-169 184185 24C242 27 1-272 248-250 295-297 213 286-290 245 282 312-31 5
EtOH/Dioxane EtOH EtOH/H,O HZ0 EtOH AcOH
H2O
54
PhNiEtOH PhNiEtOH
49 47
234 234 234 234, 235 234 234 236 236 236 234, 236 227 227
5.22
aaa
c s s
U-
A
5.
: A A
rm
3:
2
387
Y N m
m r-
z W
0;
r-
TABLE IV-I. - --(contd.)
w m
Substituent
mp ( T I ; CbP (cC/torr)l
Solvent of Crystallization
Yield (%)
I-Me-7-CF3 1-Me-8-CF3 1-Ph-5-n-Bu 1-Ph-5-Me 1-Ph-5-(Me,NCH,CH2) I-Ph-5-[Me,N(CH2),] 1-Ph-5-(4-MeOC,H4) 1-Ph-5-Me2POCH, l-Ph-7-CF3 1-Ph-8-Br 1-Ph-8-CI 1-Ph-8-CN 1-Ph-8-Me0 1-Ph-8-NO2 1-(2-BrC6H,)-8-C1 1-(2-C1C,H4)-8-CI 1-(2-C1C6h4)-8-N02 1 -(2,4-C1,C,H3)-8-C1 1 -(4-CIC,H4)-5-Me 1-(4-C1C,H4)-8-CI I-(2-FC,H4)-5-Me 1-(2-FC,H4)-8-CI 1 -(2-FC6H,)-8-NO, 1-(2-MeOC,H4)-5-Et 1-(2-MeOC,H4)-5-Me l-(3-MeOC,H4)-5-Me 1-(4-MeOC6H,)-5-PhCO 1-(4-MeOC,H4)-5-Me
192-194 193-194 122-1 24 144146 131-132 11 1-1 13 192-194 253-255 224-225 281-284 29Ck292 27&272 239-241 272-274 255-256 263 25G252 200-202 192-1 94 264-266 162-163 255-251 26Ck263 194-195 205-207 127 104-106 175
HZO
91
i-PrOH i-PrOH EtOH/H,O PhH/Et,O 16 87
MeOH/PhMe i-PrOH AcOH/H,O AcOH
42
EtOH/H,O MeCN
92
EtOH/H,O EtOH
EtOAc
65
Spectra
Refs. 237-239 239 234, 235 234 234 234 237 250 239 234 234 233 234 24 1 236 236, 231 24 1 237 234, 231 234, 237 236 236 241 236, 237 236, 231 236, 237 251 236, 237
w m W
1-(3-MeC,H4)-5-Me 1-(2,3-Me2C,H,)-5-Me 1-(2-NO,C,H4)-8-N0, 1-(2-CF,CsH4)-8-N02 Ethanolate 1,3-n-Pr2 1-n-Pr-7-CI 1-i-Pr-7-CI 1-(2-Pyridyl)-8-C1 3,3-Diallyl 3-Allyl-3-PhCH2 3-Allyl-3-Bu 3-Allyl-3-cyclohexyl 3-Allyl-3-(Et,NCH,CHz) 3-Allyl-3-[Me2N(CH2),1 3-Allyl-3-Et 3-Allyl-3-Me 3-Allyl-3-(3-methylbut-l-yl) 3-Allyl-3-Ph 3-Allyl-3-i-Pr 3,3-n-Bu2 3-n-Bu-7-NOz 3,3-Et2
3-Et-3-(3-Ethylb~t-l-yl) 3-Et-3-n-Pentyl 3-Et-3-i-Pr 3-Et-7-NO2 3,3-Me2 3J-(NOz), 3,3-n-Pr2 3-Pr-7-N02
163-164 222-224 285-286 118d 131-133 169-1 7 1 174-176 268-270 24G242 257 212-21 3 302 216 223 25&254 248-249 242 29 1 280 236 270 262-264 254-255 243.5 269 31G312 3 13-315 212-213 252.5 305-308
237 237 24 1 EtOH EtOH
CH,CH,/i-Pr,O EtOH EtOH EtOH EtOH EtOH EtOH EtOH EtOH EtOH EtOH EtOH EtOH PhH EtOH EtOH EtOH EtOH PhMe PY EtOH/H,O EtOH PhMe
35; 76 26 37 17 40 40 31; 34 42; 79.5 27 60 15; 23.5 36 78 43 41
44 35 65 54 43 70
24 1 227 239 239 233 227, 228, 307 230 228b, 230 230 230 230 228b, 230 228b, 230 230 230 228b, 230 227 23 1 227 227 227 227 23 1 227 226 227 23 1
TABLE IV-I. -(contd.)
Substituent
mp ("C); [bp ("C/torr)]
Solvent of Crystallization
178-179 155 145-148 96-91 144-146 114 246 Oil Oil 172 126 209-21 1 214216 267-269 264-266 278-280 26G264 243d 2 55-2 56 201-203 203-206 237-239 200-201 215-216 214-216 213-21 5 176178
AcOH/H,O PhH/Petr ether EtOH/Ligroin Ligroin Ligroin Acetone/H,O Acetone
Yield
(YO)
Spectra
Refs.
Trisubstituted
I-PhCO-5-Me-8-CI l-PhCHZ-3,3-Diallyl I-PhCH2-5-Me-8-CI 1,3,5-n-Bu3 1-n-Bu-3,3-Et2 1-(2-Carboxyethyl)-3,3-DiallyI I-(Carboxymethyl)-3,3-Diallyl
1-(Et,NCH,CH,)-3,3-Diallyl 1-[Me2N(CH,),]-3,3-Diallyl l-Et-3,3-Diallyl l-Me-3,3-Diallyl I-Naphtyl-5-Me-8-Cl 1-Ph-3-AcO-8-CF3 1-Ph-3-PhC00-8-CF3 l-Ph-3-HO-8-Br l-Ph-3-HO-8-CI 1-Ph-3-HO-8-CF3 1,5-Ph2-7-C1 1-Ph-5-Ac-8-C1 I-Ph-5-Allyl-8-CI l-Ph-5-Allyl-8-N02 1-Ph-5-PhCO-8-Br I-Ph-5-PhCO-8-CI l-Ph-5-PhCO-7-Me 1-Ph-5-PhCo-7-CF3 1-Ph-5-PhCO-8-CF3
EtOH EtOH EtOAc Et,O EtOH THF/Et,O THF CH,CI,/Petr ether PhH/Ligroin EtOH/H,O
Acetone
71
15 22 35 30 34 40 13 37.5 94
ir, pmr
ir, pmr 72 58
40 15 55; 51
234 237 234 221 227 237 237 231 237 230 230 231 246 246 245, 246 245,246 245 246 237, 239 234, 240, 251 234, 235, 231 24 1 240, 251 240, 251 251 251 240, 251
l-Ph-5-PhCH2-8-Cl 1-Ph-5-n-Bu-8-C1 1-Ph-5-ClCH,CO-8-Cl 1-Ph-5-(2-ClC,H4CO)-8-C1
1-Ph-5-(2,4-C1,C,H3C0)-8-CI 1-Ph-5-(2-C1C,H4)-7-C1 1-Ph-5-(trans-3-Chloroprop-2-en-1-yl)-8-C1 l-Ph-5-(3-Chloroprop-1-yl)-8-C1 1-Ph-5-Cyclohexyl-8-C1 1-Ph-5-(Cyclohexylcarbonyl)-8-C1 l-Ph-5-(Cyclopentyl)-8-C1 1-Ph-5-(Cyclopropyl)methyl-8-C1 1-Ph-5-(Et2NCH2CH2)-8-C1
I-Ph-5-(Me2NCH,CH,)-8-C1 Methiodide w
I-Ph-5-[Me2N(CH,),]-8-C1
2
1-Ph-5-Me,POCH2-8-CI l-Ph-5-n-Dodecanoyl-8-Cl l-Ph-5-EtOCO-8-Cl 1-Ph-5-EtOCH2CH,-8-C1 1-Ph-5-Et00CCH2-8-CI l-Ph-5-Et-8-Br l-Ph-5-Et-8-Cl I-Ph-5-Et-8-N02 l-Ph-5-Et-7-CF3 l-Ph-5-(2-FC,H,CO)-8-C1 I-Ph-5-CHO-8-Cl I-Ph-5-(2-Furoyl)-8-C1 l-Ph-5-n-Hexadecanoy1-8-Cl I-Ph-5-HOCH2CH2-8-CI l-Ph-5-HOCH2CH2-8-N0, I-Ph-5-HOCH,CH2-8-CF,
181-1 82 173-175 159-161 208-209 222-224 204-205 243-245 153-154 156-158 231-233 157-1 59 158-160 215-218 146-148 156-158 256-259 123-125 257-258 89-9 1 18&183 135-137 156-158 201-203 227-228 257-259 176-178 176-178 21G211 228-230 78-80 208-210 187-188 153-154
i-PrOH EtOH/H20
EtOH EtOH/Ligroin EtOH/Et,O EtOH/H20 EtOH/H20
58
71 EtOH PhH/Ligroin EtOH 90
EtOH
237 234, 235 234, 235 25 1 240, 251 251 237 237 237 237 240, 251 239 234, 235, 237 234, 237 234, 237 234 234 250 251 234, 251 237 234 237 234, 235, 237 24 1 237 25 1 240, 251 251 25 1 237 24 1 237
TABLE IV-1. -(contd.)
Substituent 1-Ph-5-HO(CH2),-8-CI 1-Ph-5-HO(CH,)3-8-CF3 1-Ph-5-(l-Hydroxy-2-propyl)-8-C1 l-Ph-5-MeOCH,CH,-8-C1 I-Ph-5-MeOCH,-8-C1
1-Ph-5-[3,4-(MeO),C,H3CO]-8-Cl I-Ph-5-Me-8-Ac I-Ph-5-Me-8-Br I-Ph-5-Me-7-Cl l-Ph-5-Me-X-Cl w W h)
l-Ph-5-Me-9-Cl l-Ph-5-Me-8-CN 1-Ph-5-Me-8-F I-Ph-5-Me-7-MeO I-Ph-5-Me-8-MeO 1-Ph-5,7-Me2 1-Ph-5,8-Me2 I-Ph-5-Me-8-MeOCO l-Ph-5-Me-8-N02 1-Ph-5-Me-7-CF3 1-Ph-5-Me-8-CF3 l-Ph-5-MeNHCO-8-CI
l-Ph-5-(3-Methyl-l-butyl)-8-C1 l-Ph-5(3-Methylbut-2-en-l-yl)-8-C1 1-Ph-5-(2-MeC,H4CO)-X-Cl 1-Ph-5-(4-MeC,H4CO)-8-C1 1-Ph-5(2,4-Me2C,H3)-7-C1
mP (“C); [bp (‘Cjtorr)] 211-213 157-159 192-194 175-178 164-1 65 134-137 134-137 201-203 161-162 166168 182-1 84 172-174 26G262 185-1 87 162-164 13&132 154-156 194-195 145-147 179-181 13&131 204-205 306308 136138 154-1 56 197-200 194-196 244-245
Solvent of Crystallization
Yield (%)
EtOH EtOH/H,O i-PrOH
EtOH/H,O
CH,Cl,/i-Pr,O CH,Cl,/i-Pr,O PhH/Ligroin
88; 40 89 75; 45
Spectra
Refs. 237 237 231 237 231 240, 251 237 234 237 234 237 237 237 237 237, 239, 249 234, 237 237 237, 249 231 24 1 237, 239 231, 239 25 1 234 237 240, 251 25 1 231
1-Ph-5-(2-Methylpropanoyl)-8-C1 1-Ph-5-(2-Methylpropenoyl)-8-C1
I-Ph-5-(2-Methylpropyl)-8-C1 1-Ph-5-(4-N0,C,H4CO)-8-C1 1-Ph-5-(Piperidino)propyl-8-C1
w W \o
I-Ph-5-PhCH2CO-8-CI 1-Ph-5-(trans-3-phenyl-propenoyl)-8-CI l-Ph-5-Propanoyl-8-Cl 1-Ph-5-n-Pr-R-C1 I-Ph-5-i-Pr-8-Cl 1-Ph-5-n-Pr-8-N02 l-Ph-5-i-Pr-8-N02 l-Ph-5-(2-Thienoyl)-8-C1 I-Ph-5-CF3CO-8-C1 1-(2-AcC,H4)-5-Me-8-C1 1-(2-BrC,H4)-5-PhCO-8-C1 1-(2-BrC,H4)-5-Me-8-Br 1 -(2-BrC,H4)-5-Me-8-C1 1-(2-BrC,H4)-5-Me-8-F 1-(2-BrC,H4)-5-Me-8-CF, l-(2-CIC,H4)-5-PhCO-8-C1 1-(2-C1C6H4)-5-Et-8-C1 1 -(2-CIC,H,)-5-HOCH,CH2-X-C1
1-(2-CIC,H4)-5-( l-Hydroxy-2-propyl)-8-C1 1-(2-C1C,H4)-5-Me-8-C1 1-(2-C1C,H4)-5-Me-8-F 1-(2-CIC,H4)-5-Me-8-CF, 1-(2-C1C,H4)-5-i-Pr-8-C1 1-(3-C1C6H,)-5-Me-8-C1 l-(4-CIC,H4)-5-PhCO-8-C1 1-(4-C1C6H,)-5-Me-8-C1 1-(2-CNC,H,)-5-Me-8-Cl 1-(2-EtC,H4)-5-Me-8-C1 1-(2-FC6H4)-5-PhCO-8-C1
11&118
149-151 198-200 21&218 142- 144 121-129 205-206 194-196 199-200 143-145 239-241 212-213 21&212 113-115 205-206 2 1&220 205-206 210-212 190-192 194-195 105-101 207-209 191-1 99 15&158 222-224 195-191 175-111 215-211 191-192 243-245 227-229 209-21 0 179-1 80 140-141
EtOH/H,O EtOH/H,O
PhH
8&90
PhHiLigroin 82
EtOH
240 234, 235 234 240, 251 231 240, 251 240, 251 234, 240, 251 234, 235, 239 234, 239 24 1 24 1 25 1 240, 251 231, 239 240 231 236, 231, 249 231 231 240 236, 231 236, 231 236, 231 236 236, 239 231 236, 231 231 251 234, 231 231 237 240
TABLE IV-1. -(contd.)
Substituent 1-(2-FC6H4)-5-Bu-8-N02
1-(2-FC,H,)-5-(Me,NCH,CH2)-8-C1
u
1-(2-FC,HA)-5-Me-8-CI - -. 1-(2-FC,H,)-5-Me-8-N02 Methanolate 1-(2-FC,H4)-5-Me-8-CF, 1-(4-HOC6H,)-5-Me-8-CF, I-(2-MeOC,H4)-5-Me-8-C1 1-(2-MeOC6H,)-5-Me-8-CF, 1-(2-MeC,H4)-5-Me-8-CI 1-(4-MeC,H,)-5-PhCO-8-CI 1-(4-MeC,H4)-5-Me-8-C1 1-(2,3-Me,C6H,)-5-Et-8-Cl 1-(2,3-Me2C,H,)-5-Me-8-C1 1-(2,4-Me,C6H,)-5-Me-8-CI 1-(2-Me-4-C1C6H,)-5-Me-8-C1 1-(2-N02C6H4)-5-AllyI-8-N02 I-(2-N02C6H4)-5-PHCO-8-C1
I-(2-N0,C6H4)-5-Cyclohexyl-8-C1 1-(2-N0,C6H4)-5-Et-8-N0, 1-(2-NO,C6H4)-5-HO(CH,),-8-C1 1-(2-NO2C,H,)-5-Me-8-C1 1-(2-NO2C,H,)-5-Me-8-CF, I-(2-N02C6H,)-5-i-Pr-8-N0, 1-(3-NO,C,H,)-5-Me-8-CF3 1-(4-NO2C,H,)-5-Me-8-CF, 1-(2-CF3C6H4)-3-OH-8-C1 I-(2-CF3C6H4)-5-PhCO-8-C1
mp ("C); [bp ("C/torr)] 164-166 134-136 153-154 195-196 113-115 184-186 268-270 221-222 199-201 201-203 165-168 203-204 201-203 200-202 19C-192 202-204 158-1 60 192 182-183 226-228 162-163 206-208 23C-232 2W242 185-186 1%-153 281-282 165
Solvent of Crystallization
Yield
MeOH
CH,CI,/Petr
EtOH
ether
80
89
(YO)
Spectra
Refs. 24 1 236, 237 237 236 24 1 236, 237, 239 239 237 239 237 251 237 237 237 237 236, 237 24 1 240 237, 238 24 1 237, 238 237, 238 231, 239 24 1 238 238 245, 246 240
1-(2-CF,C6H,)-5-Me-8-C1 1-(2-CF,C,H4)-5-Me-8-CF, 1-(3-CF3C,H,)-5-Me-8-CI
I-(2-Pyridy1)-5-AcOCH2CH2-8-Cl 1-(2-Pyridyl)-5-PhCHz-8-CI 1-(2-Pyridyl)-5-Bu-8-C1 1-(2-Pyridyl)-5-Cyclohexyl-8-C1 1-(2-Pyridyl)-j-Et-7-C1 1-(2-Pyridyl)-S-Et-8-C1 I-(2-Pyridyl)-5-Et-8-CF3 1-(2-Pyridyl)-5-HOCH,CH,-8-C1
I-(2-Pyridyl)-5-HOCH2CH,-8-CF3
w
W
1-(2-Pyridyl)-j-Me-8-Br 1-(2-Pyridyl)-5-Me-8-C1 l-(2-Pyridyl)-5-Me-8-NO2 1-(2-Pyridyl)-5-Me-8-CF3 1-(2-Pyridyl)-5-Ph-7-C1 1-(2-Pyridy1)-5-Pr-8-C1 1 -(2-Pyridyl)-5-i-Pr-8-C1 1-(4-C1-2-Pyridyl)-5-Me-8-C1 1-(5-Me-2-Pyridyl)-5-Me-8-C1 1 -(3-Pyridyl)-5-Et-8-C1 1-(3-Pyridyl)-5-Me-8-C1 1-(2-Pyrimidyl)-5-Me-8-C1 1-(2-Thienyl)-S-Me-8-C1 3,8-(N02),-7-COOH 3,8-(NO,)2-7-C1 3,8-(NOZ),-7-F 3-Et-3-Allyl-7-Cl 3,3-Diallyl-7-CI
204-205 164-165 192-1 93 196198 216218 148-149 190 194-196 194196 153-155 176178 149-1 5 1 242-243 231-233 176177 164-168 203-204 177-1 78 165-167 216217 225-227 196198 164-166 243-245 173-174
i-Pr,O
78
CH,Cl,/Petr ether
50-55
168-169 187-188d 242-244 229-230
EtOH EtOH
30 34
122-1 23 133-134
EtOH EtOH
ir, pmr ir, pmr
236, 237 237, 249 236, 237, 249 237 237 237 237 237 231 237 237 237 237 237, 239 24 1 237 237 237 237 237, 239 237, 239 237, 239 237 237, 239 237, 239 226 226 226 307 307
Tetrasubstituted
l,j-(PhCH,),-3,3-(B~), l,S-(PhCH2),-3,3-Et,
227 227
TABLE IV-1. -(contd.)
Substituent 1,5-n-B~,-3,3-Et,
1,5-(HOOCCH2),-3,3-Diallyl l,5-(Et2NCH,CH,),-3,3-DiaIlyl 1,5-(Me,NCH2CH,),-3,3-Diallyl 1,5-Me,-3,3-Et2 1,5-(COOMe)2-3-Et-3-AIlyl 1,5-(COOEt)2-3-Et-3-Allyl 1,5-(COOMe)-3,3-diallyl 1,5-(COOMe),-3-Et-3-(2-OH-Allyl)
1,5-(COOEt)~-3-Et-3-(2-OH-Allyl) 1,5-(COOMe),-3-Allyl-3-(2-OH-Allyl) l-Ph-3-AcO-S-Ac-8-CF3 1-Ph-3-AcO-5-Me-8-C1 l-Ph-3-AcCH2-3-HO-8-CF3 l-Ph-3-NH2-5-Me-8-C1 l-Ph-3-PhCOO-5-Me-8-CI l-Ph-3-Br-5-Me-8-CI 1-Ph-3-Br-5-Me-8-CF3 1-Ph-BuO-5-Me-8-CF3 1-Ph-3,3-CI2-8-CF3 1-Ph-2,8-Cl2-5-Me l-Ph-3-(EtO)zCH-3-HO-8-C1 l-Ph-3-EtO-5-Me-8-CF3 l-Ph-3-Et-3-Me-8-CI l-Ph-3-CHO-3-HO-8-CI 1-Ph-3-CHO-3-HO-8-N02 1-Ph-3-HC00-5-Me-8-CF3 I-Ph-3,3-(HO),-8-Br l-Ph-3,3-(HO)Z-8-C1
mp ("C); [bp ('C/torr)]
Solvent of Crystallization
90-92 193 Oil 28
Ligroin Acetone/H,O
112-114 76-78 106- 107 136-138 Oil 112-114 176-178 240-244 206 219-222 219-220 278-279 276-278 195-196 237-238 283-285 188-189 226-227 208-210 208-2 10 220-222 225d 190d
PhH/Petr ether EtOH PhH PhH PhH EtOH MeOH MeOH EtOAc MeCN CH,CI, CH,Cl,/i-Pr,O MeCN MeCN MeCN MeCN EtOH
Yield (YO)
Spectra
11 20 17 72 70 75 90 84 88 60.5 57 79 17 60 95 80 52 48 35 69 40
ir, pmr ir, pmr ir, pmr ir, pmr ir, pmr ir, pmr
45 51 30 88.5: 71
ir, pmr
ir, pmr ir, pmr
ir, pmr
ir, pmr
THF EtOAc/MeCN CH,CI,
Refs. 227 229 229 229 227 307 307 307 307 307 307 246 243 246 243 243 243 243 243 243 243 246 243 237 246 246 243 246, 247 247
190d 245d 178-1 80 256-257 235-236 21 7-2 19 269-271 262-264 255-258 252-254 245-248 20 1-203 258-260 254-256 21 8-220 155-157 116 157-158 1-(2-BrC,H4)-3-HO-5-Me-8-CI 253 ~-(~-CIC,H~)-~-HO-~-MC-~-CF~ 188-190 1-(4-C1C6H4)-3-HO-5-Me-8-CF3 239-241 1-(2-FC6H4)-3-HO-5-Me-8-CF3 195-197 1-(3-FC,H,)-3-HO-5-Me-8-CF3 188-189 1-(2-MeC,H4)-3,5-Me2-8-C1 195-1 97 l-(2-MeC,H4)-3-Me-5-Et-8-C1 173-174 1-(2--NO2C6H4)-3-HO-5-Me-8-CF3 189-190 1-(3-NO,C6H,)-3-H0-5-Me-8-CF, 23Cb233 1-(2-CF,C,H4)-3,3-(HO)2-8-C1 177d 1-(2-CF,C6H4)-3-HO-5-Me-8-CI 260-262 1-(3-CF3C,H4)-3-HO-5-Me-8-CF3 187- 188 1,5-n-Pr,-3,3-Et2 89-90 1-(2-Pyridy1)-3-HO-5-Me-8-Br 218-220 1-(2-Pyridyl)-3-HO-5-Me-8-C1 204-206 l-Ph-3,3-(HO),-8-N02 1-Ph-3,3-(HO),-8-CF3 l-Ph-3-HO-5-Allyl-8-CF3 l-Ph-3-HO-5-Et-8-Br 1-Ph-3-HO-5-Et-8-CF3 1-Ph-3-HO-5-HOCH2CH,-8-CF3 l-Ph-3-HO-5-Me-8-Br l-Ph-3-HO-5-Me-8-Cl 1-Ph-3-HO-5-Me-8-F 1-Ph-3-HO-5-Me-8-N02 1-Ph-3-HO-5-Me-8-CF3 l-Ph-3-HO-5-i-Pr-8-CF3 l-Ph-3-Me0-5-Me-8-Cl 1-Ph-3-MeO-5-Me-8-CF3 1-Ph-3,5-Me2-8-C1 l-Ph-3-Me-5-Pr-8-CI l-Ph-3-Me-5-i-Pr-8-CI l-Ph-3-i-PrO-5-Me-8-CF3
CH,CI, CH,C1,
63; 66 72 51 48
MeCN
82 40
Dioxan
80
ir, pmr
MeOH MeOH
61 88 64
ir, pmr
25
37
EtOH MeOH
75
246, 247 246 245 243, 245 243, 245 245 245 243, 245 245 243, 245 243, 245 245 243 243 237 237 237 243 245 245 245, 247 245 245 237 237 245 245 246 245 245 227 245 245
TABLE IV-1.
~
4contd.)
Substituent
mp ("C); [bp ("C/torr)]
Solvent of Crystallization
Yield
228-230 17&176 188-190
CH,Cl,/MeOH
50
THF
60
Acetone/H,O
77
(YO)
Spectra
Refs.
Pentosubstituted
1-Ph-3,3-CI2-5-Me-8-CF, 1-Ph-3,3-(HO),-5-Ally1-8-CF,
1-Ph-3,3-(HO),-5-Me-8-Br 1-Ph-3,3-(HO),-5-Me-8-CF3 Hydrate 1-Ph-3,3-(HO),-5-i-Pr-8-CF3
176d 177-1 78 1-(2-C1CbH4)-3,3-(HO)2-S-Me-8-CF, 163d 1-(4-C1C,H4)-3,3-(HO),-5-Me-8-CF, 193d 1-(2-FC,H4)-3,3-(HO),-5-Me-8-C1 169d 1-(4-HOC,H,)-3,3-(HO)2-S-Me-8-CF3193d 1-(2-N02C,H4)-3,3-(HO)2-5-Me-8-CF,177d 1-(3-NO,C,H4)-3,3-(H0),-5-Me-8-CF, 230d 1-(2-CF,C,H4)-3,3-(HO)2-S-Me-8-CF, 187-188 1-(3-CF,C,H4)-3,3-(HO),-5-Me-8-CF, 130d 1-(2-Pyridyl)-3.3-(HO),-5-Me-8-C1 165d
243 247 247 247 247 247 247 247 247 247 245 245 247 247
3-Diazo-1,5-dilrydro-3H-1,5-benzodia~epin-2,4(2H,4H)-diones
b
N H
O
Trisubstituted
1-Ph-5-Allyl-8-CF3 1-Ph-5-Et-8-Br 1-Ph-5-Et-8-CF3 1-Ph-5-HOCH2CH2-8-CF, l-Ph-5-Me-8-Br
138-140d 145-146d 147-148d 135-1 40d 160d
244 244 244 244 244
I-Ph-5-Me-8-CI I-Ph-5-Me-8-N02 1-Ph-5-Me-8-CF3 1-Ph-5-Me-8-F 1-Ph-5-i-Pr-8-CF3 1-(2-C1C,H4)-5-Me-8-CF, 1-(2-FC,H,)-5-Me-8-CF3 1-(3-FC,H4)-5-Me-8-CF, 1-(2-NO,C,H,)-5-Me-8-CF3 1-(2-CF3C,H4)-5-Me-8-C1 I-(2-Pyridyl)-5-Me-8-Br 1-(2-Pyridyl)-5-Me-8-CI
174-176d 156-1 58d 157d 163-165d 126-128d 134-1 35d 107-1 IOd 95-98d 156-1 57d 172d 158-160d 162-163d
EtOAc MeOH EtOH
70; 54 46 75; 44
235d 215-218 282-285 181-185 255-256 282-285 234-235 253-254 198-199 25G251 226-227 277-278 155-156 219-220
DMF/H,O
85.5
ir
243, 244 243, 244 243, 244 244 244 244 244 244 244 244 244 244
Trisubstituted
I-Ph-8-Br-10-BuNH 1-Ph-8-CI- 10-Allylamino 1-Ph-8-Cl-10-NH2 l-Ph-8-CI-10-BuNH I-Ph-8-C1-I0-Me3CNH
1-Ph-8-C1-10-Et2NCH2CH2NH I - P h - 8 4 - 10-Me,N 1-Ph-8-CI- 10-MeNH l-Ph-8-Cl- 10-(2-Methylpropyl)arnino l-Ph-8-N02-10-NH2 l-Ph-8-N02-IO-BuNH I-Ph-8-NO,-10-Me2N I-Ph-8-CF3-10-n-BuNH 1-Ph-8-CF,-10-Me2N
8&95
EtOAc
70.5
EtOAc
77 82-90 82-90
245, 248, 252 245, 248, 252 245, 248, 252 248,252 245, 248, 252 245, 248, 252 245, 248, 252 245, 248, 252 245, 248, 252 245, 248, 252 245, 248, 252 245, 248, 252 245, 248, 252 252
TABLE IV-1. 4 c o n t d . )
Substituent
rnp W ) ; [bp ('C/torr)]
1-(2-BrC6H,)-8-C1-10n-BuNH 1-(2-C1C,H4)-8-C1-10n-BuNH 1-(2-FC,H4)-8-C1-10-n-BuNH 1-(2-NO,C,H4)-8-C1-1O-n-BuNH 1-(2-CF,C,H,)-8-C1-10-n-BuNH
203 208-210 208 183 208-210
Solvent of Crystallization
Yield (YO)
Spectra
Refs.
245, 248, 252 245, 248, 252 248, 252 248, 252
Polysubstituted
l-Ph-5-Me-8-C1-lO-PhCOO-lO-Ph 1-Ph-5-Me-8-CF3-10-Me,N
222-223 164166
1-Ph-8-Br l-Ph-8-Cl 1-Ph-8-CF3
243d 239d 254d
MeOH Acetone/Et,O
69; 88.5 12 84 I .5-Benzodiazepin-thiones
1,3-Dihydro-1 ,S-benzodiazepin-2(2H)-thiones
20 16
ir, prnr
ir, pmr
243 245, 241
246, 247 246, 241 246, 241
Monosubstituted
0,
4-Ph 4-[4-(PhCH,S)C,H,] 4-(4-BrC6H,) 4-(4-n-BuSC,H,) 4-(2-C1C6H,) 4-(3-C1C6H4) 4-(4-C1C,H4) 4-(2,4-CIzC,H,) 4-(3,4-CIzC,H,) 4-(4-n-Dodecylthiophenyl) 4-(4-EtSC6H,) 4-(2-MeOC,H4) 4-(3-MeOC6H,) 4-(4-MeOC6H,) 4-[2,4(Meo), C,H,I 4-(2-MeC6H,) 4-(3-MeC6H,) 4-(4-MeC,H4) 4-11-Methylcyclohex-1-yl)methylthio]-phenyl 4-(4-MeSC6H,) 4-[4-(3-n-Pentylthio)phenyl] 4-(4-PhOC,H4) 4-(4-PhC,H4) 4-(2-PhSC,H,) 4-(4-PhSC,H4) 4-(4-PrSC6H,) 4-(4-i-PrSC6H,)
228-230 197 238 184 199 224-225 243-245 178 228-229 163 206 195 191 233d 179 186 204 243-245 189-190 214 171 225 229-230 214 229-230 196 20 1
EtOAc EtOAc EtOAc EtOAc EtOH EtOAc EtOAc EtOH EtOAc EtOAc EtOAc MeOH EtOAc EtOAC PhH/Petr ether PhH EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc i-PrOH EtOAc
127-1 28 109-110
EtOH EtOH
79
ms
ms
ms 13
ms
ms ms ms ms ms ms
50 73 50
256, 262 256 256 256 256, 262 256, 262 256, 262 256 256 256 256 256, 262 256, 262 256, 262 256 256, 262 256, 262 256, 262 256 256 256 256 256 256 256 256 256
Disubstituted
l-PhCHz-4-Ph 1-Me-4-Ph
70 82
145 145
v l f i
zzm
-ZJ
r
6
”\ /“
- 0 0
m m N N
z2
r-m
zi-
-iz
t5
” \m r/ ”
402
nom w w - N -
m m N N m N
m
r
W v,*
N 10
v,
N w
N
m *
w
mm*m"m
u
c
w w w w w N N N N N
d Q\
403
tN N
r-r-
3
w w
N
w
b b
v m,
i .-
>
N N
-
N
w w
I
m N
2 W
W
'p
m
m
404
W r-
zz
u u A A
N N
‘c)
w N
to‘c) -w N N
1 i
>
!zE
i
3
>
2a!
‘? v
a U
405
A N
r - tNN
r -c m r‘ 1 wI m r -e e
m m N N r-l.
>
TABLE IV-1. -4contd.)
Substituent 5-Me-7-Ph Hydrochloride 5,7-Ph2
mp ("C); [bp ('Cjtorr)] 154-1 55d 18 1-1 82d
221-222
Solvent of Crystallization PhH EtOH/Et,O PhH
Yield
(YO)
75 86
Spectra
Refs.
pmr, uv pmr, uv
273 273 273
ms, ms, ms, ms,
pmr pmr pmr pmr
274 274 275 274
ms, pmr ms, pmr
275 275
Pyrazolo[3,4-b][1 .I]diazepines P
$? 1,6-Dihydropyrazolo[3,4-b][1,4]diazepines
1-Ph3,5,7-Me3 1 -Ph-3,5-Me,-7-Me0 I-Ph-3,5-Me2-7-MeS 1-Ph-3,5,6-Me3-7-Me0
10&102
PhH
135-1 36
C6H6
85; 90 20 90 15
cNgN N
1,4,5,6- Tetrahydropyrazolo[3,4-b] [1,4]diazepines
H 1 -Ph-3,5-Me2-7-Me0
1-Ph-3,4,5-Me3-7-Me0
4W2
Pentane
10 5
m m
firN N -
f f N N N N N
3a a3 3a 5a
401
m m rN - r -N
0 m m 0
TABLE IV-1. j c o n t d . ) Substituent 1-Ph-3,S-Me2 1-Ph-3,4,S-Me3 1-Ph-3,5,6-Me3 1-Ph-3,S,8-Me3 1 -Ph-3,4,S,6-Me4 1 -Ph-3,4,S,8-Me4 1-Ph-3,5,8-Me4
mp ("C); [bp ("C/torr)]
120 121 114-1 15 169-170 108-109 165-1 66 88-90 144-1 45
Solvent of Crystallization PhH Et,O PhH PhH PhH PhH PhH
Yield (%)
Spectra
90; 20
ms, ms, ms, ms, ms, ms, ms,
40
90; 40 90 5 35 30 90; 5
pmr pmr pmr pmr pmr pmr pmr
Refs. 275 275 275 275 275 275 275
4,8-Dihydropyrazolo[3,4-b][ I ,41diarepin-5,7(I H,6H) -diones P
E 1-Et-3-Me-8-(2-MeC6H,) 1-Et-3-Me-8-(2-CIC6H,) 1,3-Me,-8-(4-MeC,H,) 1-Et-3-Me-8-(4-C1C,H4) 1-Et-3-Me-8-(4-MeC6H,) 1,3-Me2-8-(4-C1C,H,) 1,3-Me,-8-(2-MeC6H,) 1,3-Me,-8-(2-ClC,H4) 1-Ph-2-Me-8-(4-MeC,H4) 1,3,4-Me,-8-(4-MeC6H,) 1.3,4-Me,-8-(2-MeC,H4) 1,3,4-Me,-8-(4-C1C6H,) 1-Et-3,4-Me,-8-(2-C1C6H,) 1-Et-3,4-Me,-8-(4-MeC6H,) 1-Et-3,4,6-Me3-8-(4-MeC6H4)
221 206-207 251 186 183-1 84 261-262 235 228 245-246 165 163 165-166 181-1 82 157 152
32 1 321 321 321 321 321 321 321 321 321 321 321 321 321 321
1-Et-3,4-Me,-8-(4-C1C6H4)
185-186
1,3,4-Me,-8-(2-C1C6H,) I,3-Me2-4-(CH,CCH) 1-Et-3,4-Me,-8-(2-MeC6H4) 1,3,8-Me,-4-(2-C1C6H4) 1,3,8-Me,-4-(4-MeC,H4) 1,3,8-Me,-4-(4-FC,H4) 1,3,8-Me3-4-(4-C1C,H,) 1,3,8-Me,-4-(3-FC6H,) 1-Et-3,8-Me,-4-(2-C1C6H4) 1-Et-3,8-Me2-4-(4-FC,H,) 1-Et-3,8-Me,-4-(4-C1C6H4) l-Et-3,8-Me2-4-(4-MeC,H,) I-Et-3,8-Me,-4-(3-CIC6H4) 1-Et-3,8-Me,-4-(3-MeC6H4) 1-Et-3,8-Me,-4-(3-FC6H4) 1-i-Pr-3,8-Me,-4-(2-C1C6H4) 1-i-Pr-3,8-Me,-4-(2-MeC6H4)
188
1-i-Pr-3,8-Me,-4-(4-FC6H4) 1-i-Pr-3,8-Me2-4-(3-ClC6H4) 1-i-Pr-3,8-Me,-4-(4-CI-C6H4) 1-i-Pr-3,8-Me,-4-(2-FC6H4) 1+Pr-3-Me-8-(CH2CH20Me)
I-i-Pr-3,8-Me,-4-(3-FC6H4) 1,3,8-Me,-4-(2-FC6H,) 1-Et-3,8-Me,-4-(2-FC6H4) 1,8-Me2-3-Et 1,8-Me2-3-Cyclohexyl l-Et-3-Cyclohexyl-8-Me 3,8-Me2 l-Et-3-n-Pr-8-Me 1,8-Me2-3-n-Pr 1-CH2Ph-3,8-Me, 1,3-Me2-8-CH,Ph
161 161-162 181 220 219 246 207-208 163 155 153 156 194 194 167 229 154 198 160 196 182 136 155 181 117 181 223 163 262 129 142 158
134
321 321 321 321 322 322 322 322 322 322 322 322 322 322 322 322 322 322 322 322 322 322 322 322 322 322 322 322 322 322 322 322 322 322
h
4
? i
3
W c)
m
2 410
r--
N r - 0N 0
> s-
% G-g
.3
o m w w
.”
s W N
41 1
w m
N N d d d
N N N N N
r n r n M r n W
N Z Om r- nr w O
TABLE IV-I. gcontd.)
Substituent l-(Me,NCH,CH2)-S-Ph-7-C1 1 -Me-5-Ph-7-C1
1-Me-5-(2-FC6H,)-7-CI
mp (“C); [bp (Tjtorr)]
Solvent of Crystallization
128-130 189-191 16&162 144146
MeOH/H,O EtOH EtOH
Yield
(YO)
Spectra
so
Refs. 284, 291 284 29 1 284, 291
45
55 H
1,2,3,5-Tefrhyhopyrido[2,3-b][1,4]diazepin-4(4H)-ones
5
2-Me
172-173
MeOH/Et,O
ir, pmr, uv
285
ny H
7-Me 5-Ph-7-C1 7-Me-8-Br
248-249 22G222 225-221
EtOH PhH EtOH
282 29 1 282
i
.-i
O Q
N N N
m m m m m m
413
8 % N N
'? ir -o' tm
N
a
0
m N
>
3
rI 3
W
‘0
2 A
414
m N M
> i
E 2.-i
-r-
m oN N c
.-L
Pyrimidu[4,5-b][I ,I]diazepines
H
8-Me
25G252d
Xylem
38; 58
pmr, uv
293. 294
24G241 196197 206-207
EtOH
89
ir, uv
Xylene/EtOH
82
ir
294 111 111
48; 54 10; 29 1.3
ir, ms, pmr, uv ir, ms, pmr, uv ir, ms, pmr, uv ir, ms, pmr, uv
295 295 295 295
7,9-Dihydropyrimido[4,5-b] [I ,4]diazepin-8(8H)-ones
+
e v1
6-Me 6-(4-MeOC6H,) 6-[3,4,5-(MeO),C,Hz1
3,7-Dihydro-l H-pyrimido[4,5-b] [I,4]aSazepin-2,4(2H,4H)-aSones
cNyy "
H
0
1,3,6,8-Me4 1,3,6-Me3-8-Ph 1,3,8-Me3-6-Ph 1,3-Me,-6,8-Phz
185-186 228d 19Od 230-232d
EtOH
40
m m N
m 3
416
W N m
8
.-J
m \o N
00 N m
>
.-i
r-r-r-r-r.
m m m m m
Z 00,
G z
N N N N N
Z
(2 E
417
W
N m
.-i
TABLE IV-1. g c o n t d . )
Substituent
m p ("C); [bp (Tjtorr)]
Solvent of Crystallization H
1,3,6,8,8-Me5
216-218 227-229 238-242 187-1 88 232-237
(YO)
Spectra
Refs.
ir
296
H
207 O
1,3,6-Me3 1,3-Me2-6-Et 1,3-Me2-Ph 1,3-Me2-6-Pr 1,3,6-Me3-7-Et
Yield
H
H
Acetone EtOH Acetone EtOH MeOH
80 58; 66 79 57; 68 57.5
297 297 297 297 297
86
300
H
1,3,8-Me3
24G290d
EtOH
419
N N
XX
420
[ 1,4]Diazepines with [bl-Fused Rings
20. REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20.
D. Lloyd, R. H. McDougall, and D. R. Marshall, J . Chem. Soc., 3785 (1965). H. Rupe and A. Huber, Helu. Chim. Acta, 10, 846 (1927). W. Ruske and E. Hiifner, J . Prakt. Chem., 18, 156 (1962). F. E. King and P. C. Spensley, J . Chem. Soc., 2144 (1952). R. M. Acheson, J . Chem. Soc., 4731 (1956). D. P. Clifford, D. Jackson, R. V. Edwards, and P. Jeffrey, Pestic. Sci., 7, 453 (1976). S. M. Jain and R. A. Pawar, Indian J . Chem., 13, 304 (1975). M. Weissenfels, U. Thust, and M. Miihlstadt, J . Prakt. Chem., 13, 304 (1975). M. Weissenfels, R. Kache, and W. Krauter, J . Prakt. Chem., 35, 166 (1967). M. Weissenfels, Z . Chem., 4, 458 (1964). M. Weissenfels, H. Schurig, and Huhsam, Chem. Ber., 100, 584 (1967). M. Weissenfels and G. Dill, Z . Chem., 7, 456 (1967). W. Ruske and G. Grimm, J . Prakt. Chem., 18, 163 (1962). J. Thiele and G. Steimmig, Chem. Ber., 40, 955 (1907). C. A. C. Haley and P. Maitland, J . Chem. SOC., 3155 (1951). J. A. Barltrop, C. G. Richards, D. M. Russell, and G. Ryback, J . Chem. Soc., 1132 (1959). P. Neumann and F. Vogtle, Chem. Exp. Didakt., 2, 267 (1976). G. Schwarzenbach and G. Lutz, Helu. Chim. Acta, 23, 1147 (1940). R. L. Williams, W. Peaston, and J. Kern, J . Chem. Soc., Perkin Trans. I , 2353 (1976). K. V. Levshina, L. P. Glazyrina, and T. S. Safonova, Khim. Geterotsikl. Soedin., 6, 1135 (1970);
Chem. Heterocycl. Compd., 6, 1061 (1970). 21. K. V. Levshina, T. A. Andrianova, and T. S. Safonova, Zh. Org. Khim.,5, 162 (1969); J . Org. Chem. (USSR), 5, 158 (1969). 22. K. V. Levshina, E. I. Yumasheva, and T. S. Safonova, Khim. Geterotsikl Soedin., 7, 556 (1971); Chem. Heterocycl. Compd., 7, 519 (1971). 23. R. L. Williams and S. W. Shalaby, J . Heterocycl. Chem., 10, 891 (1973). 24. A. Nawojski and W. Nawrocka, Rocz. Chem., 48, 1073 (1974). 25. K. V. Levshina, E. I. Yumasheva, T. S. Safonova, A. I. Kravchenko, and V. A. Chernov, Khim.Farm. Zh., 5, 18 (1971). 26. A. Becker, Helu. Chim. Acta, 32, 1584 (1949). 27. S. Veibel and S . F. Hromadko, Chem. Ber., 93, 2752 (1960). 28. M. Matsumoto, Y. Matsumura, A. Lio, and T. Yonezawa, Bull. Chem. Soc. Japan, 43, 1496 ( 1970). 29. M. Sulca, A. Ya. Strakov, and I. Hirsbergs, Latu. PSR Zinat. Akad. Vestis, Kim. Ser., 186 (1971). 30. E. Hannig and H. Ziebandt, Pharmazie, 23, 688 (1968). 31. F. Eiden and G. Heja, Arch. Pharm., 310, 964 (1977). 32. Yu. K. Yur’ev, N. M. Magdesieva, and V. V. Titov, Zh. Org. Khim.,1, 163 (1965). 33. F. Eiden and G. Bachrnann, Arch. Pharm., 306,401 (1973). 34. M. Trkovnik, M. Kules, M. Lacan, and B. Babarevic, Z . Naturforsch, 29, 580 (1974). 35. (a) R. E. Pastor, C. A. Giovannoni, and A. R. Cambon, Chim. Ther. (Eur J . Med. Chem.) 9, 175 (1974). (b) A. Carnbon, C. Giovannoni, R. Paspor, and J. Riess, Ger. Offen. 2,424,652, December 1974; Chem. Ahstr., 84, 44179d (1976). 36. I. L. Finnar, J . Chem. Soc., 4094 (1958). 37. (a) F. Eiden and G. Heja, Synthesis, 148 (1973).(b) F. Eiden and G. Heja, Ger. Offen. 2,343,528; March 1975; Chem. Abstr., 83, 43395p (1975). 38. S. U. Kulkarni and K. Z. Thakar, J . Indian Chem. Soc., 52, 849 (1975). 39. (a) S. U. Kulkarni and K. Z. Thakar, J . Indian Chem. SOC.,53,279 (1976); (b) S. U. Kulkarni and K. Z. Thakar, J . Indian Chem. Soc., 53, 283 (1976). 40. H. Stetter and F. von Prann, Chem. Ber., 102, 1643 (1969). 41. J. Schmitt, Justus Liebigs Ann. Chem., 569, 17 (1950).
20. References
42 1
42. Yu. S. Andreichikov, S. P. Tendryakova, Yu. A. Nalimova, S. G. Pitirimova, and L. A. Voronova, J . Org. Chem. (USSR) 13, 483 (1977). 43. Yu. S. Andreichikov, S. G. Pitirimova, S. P. Tendryakova, R. F. Saraeva, and T. N. Tokmakova, Zh. Org. Khim., 14, 169 (1978); J . Org. Chem. (USSR), 14, 156 (1978). 44. S. B. Vaisman, Trans. Inst. Chem. Kharkou Uniu., 4, 157 (1938); Chem. Abstr., 34, 5847 (1940). 45. J. 0. Halford and R. M. Fitch, J . Am. Chem. Soc., 85, 3354 (1963). 46. R. K. Singhal, S. Kumar, U. C. Pant, and B. C. Joshi, Natl. Appl. Sci. Bull., 26, 1 (1974). 47. J. A. Barltrop and C. G. Richards, Chem. Ind. (London) 466 (1957). 48. C. N. OCallaghan and D. Twomey, J . Chem. Soc., 600 (1969). 49. S. Motoki, C. Urakawa, A. Kano, Y. Fushimi, T. Hirano, and K. Murata, Bull. Chem. Soc. Japan, 43, 809 (1970). 50. W. Ried and E. Koenig, Justus Liebigs Ann. Chem., 755, 24 (1972). 51. Yu. S. Andreichikov and R. F. Saraeva, Khim. Geterotsikl. Soedin., 8, 1702 (1972); Chem. Heterocyclic. Compd., 8, 1544 (1972). 52. S. P. Korshunov, V. M. Kazantseva, L. A. Vopilina, V. S. Pisareva, and N. V. Utekhina, Khim. Geterotsikl. Soedin., 9, 1421 (1973); Chem. Heterocycl. Compd., 9, 1287 (1973). 53. R. L. Amey and N. D. Heindel, Org. Prep. Proc. Int., 8, 306 (1976). 54. W. Ried and R. Teubner, Justus Liebigs Ann. Chem., 741 (1978). 55. J. A. Van Allan and S. Chie Chang, J . Heterocycl. Chem., 11, 1065 (1974). 56. W. Miiller, U. Kraatz, and F. Korte, Chem. Ber., 106, 332 (1973). 57. A. P. Bindra and E. Le Goff, Tetrahedron Lett., 1523 (1974). 58. R. G. Bass, D. D. Crichton, H. K. Meetz, and A. F. Johnson, Jr., Tetrahedron Lett., 2073 (1975). 59. Y. Okamoto and T. Ueda, J . Chem. Soc. Chem. Commun., 367 (1973). 60. Y. Okamoto and T. Ueda, Chem. Pharm. Bull., 23, 1391 (1975). 61. P. C. Unangst and P. L. Southwick, J . Heterocycl. Chem., 10, 399 (1973). 62. G. Roma, A. Balbi, and A. Ermili, Farmaco, Ed. Sci., 32, 393 (1977). 63. C. R. Ellefson, C. M. Woo, A. Miller, and J. R. Kehr, J . Med. Chem., 21, 952 (1978). 64. C. R. Ellefson and F. M. Hershenson, US. Patent 4,123,430, October 1978; Chem. Abstr., 90, 87528h (1979). 65. G. Roma, E. Vigevani, A. Balbi, and A. Ermili, Farmaco, Ed. Sci., 34, 62 (1979). 66. H. D. Stachel, Chem. Ber., 95, 2171 (1962). 67. D. Nardi, A. Tajana, and S. Rossi, J . Heterocycl. Chem., 10, 815 (1973). 68. D. Nardi, E. Massarani, and L. Degen, Swiss Patent 555,347, October 1974; Chem. Abstr., 82, 43480s (1974). 69. D. Nardi, E. Massarani, A. Tajana, R. Cappelletti, and M. Veronese, Farmaco, Ed. Sci., 30,727 (1975). 70. D. Nardi, E. Massarani, A. Tajana, R. Cappelletti, and M.Salvaterra, Farmaco, Ed. Sci., 30,248 (1975). 71. A. Trka, A. Frigerio, D. Nardi, A. Tajana, and U. Rapp, Farmaco, Ed. Sci., 33, 885 (1978). 72. D. Nardi, R. Pennini, and A. Tajana, J . Heterocycl. Chem., 12, 825 (1975). 73. K. Peseke, Tetrahedron, 32, 483 (1976). 74. East German Patent 117,219, January 1976; Chem. Abstr., 85, 21499q (1976). 75. G. Schwarzenbach and K. Lutz, Helu. Chim.Acta, 23, 1162 (1940). 76. D. Lloyd and D. R. Marshall, Chem. Ind. (London), 1760 (1964). 77. S. Veibel and J. I. Nielsen, Mat. Fys. Medd. Dan. Vid. Selsk., 35, 6 (1966). 78. D. Lloyd and H. P. Cleghorn, in Advances in Heterocyclic Chemistry, Vol. 17, A. R. Katritzky and A. J. Boulton, Eds., Academic Press, New York and London, 1974, p. 35. 79. P. W. W. Hunter and G. A. Webb, J. Inorg. Nucl. Chem., 35, 1457 (1973). 80. K. V. Levshina, L. P. Glazyrina, and T. S. Safonova, Khim. Geterotsikl. Soedin., 6, 1133 (1970); Chem. Heterocycl. Compd., 6, 1059 (1970). 81. M. Matsumoto, A. Iio, and T. Yonezawa, Bull. Chem. Soc. Japan, 43, 281 (1970). 82. T. Yonezawa, M. Matsumoto, and H. Kato, Bull. Chem. SOC.Japan, 41, 2543 (1968). 83. S. Veibel and J. I. Nielsen, Chem. Ber., 99, 2709 (1966).
422
[ 1,4]Diazepines with [b]-Fused Rings
84. W. Paterson and G. R. Proctor, J . Chem. Soc., 485 (1965). 85. V. C. Barry, M. L. Conalty, C. N. OCallaghan, and D. Twomey, Proc. Roy. Irish Acad., Sect. B, 65, 309 (1967). 86. A. Ouchi, T. Takeuchi, M. Nakatani, and Y.Takahashi, Bull. Chem. SOC.Japan, 44,434 (1971). 87. A. Furuhashi, S. Komatsu, and A. Ouchi, Bull. Chem. SOC.Japan, 45, 2942 (1972). 88. P. W. W. Hunter and G. A. Webb, J . Inorg. Nucl. Chem., 34, 1511 (1972). 89. P. W. W. Hunter and G. A. Webb, Inorg. Nucl. Chem. Lett., 9, 271 (1973). 90. B. Emmert and H. Gsottschneider, Chem. Ber., 66, 1871 (1933). 91. P. L. Orioli and H. C. Lip, Cryst. Struct. Commun., 3, 477 (1974). 92. H. A. Staab and F. Vogtle, Chem. Ber., 98, 2701 (1965). 93. W. J. Barry, I. L. Finar, and E. F. Mooney, Spectrochim. Acta, 21, 1095 (1965). 94. K. F. Turchin, Khim. Geterotsikl. Soedin., 10, 828 (1974). 95. A. Mannschreck, G. Rissmann, F. Vogtle, and D. Wild, Chem. Ber., 100, 335 (1967). 96. J. C. Speakman and F. B. Wilson, Acta Crystallogr., 32, 622 (1976). 97. K. Butkiewi, J . Electroanal. Chem., 90,271 (1978). 98. W. Ried and P. Stahlhofen, Chem. Ber., 90, 815 (1957). 99. A. Nawojski and W. Nawrocka, Rocz. Chem., 49, 1915 (1975). 100. L. K. Mushkalo, Nauk Zapiski Kiiu. Derzhau. Uniu., 16; 15, Zbirnik Khim. Fak. No. 8, 133 (1957); Chem. Abstr., 53, 18057 (1959). 101. A. N. Kost, S. F. Solomko, L. N. Polovina, and L. G. Gergel, Khim. Geterotsikl. Soedin., 7, 553 (1971); Chem. Heterocycl. Compd., 7, 516 (1971). 102. Q. Q. Dang, R. Caujolle, and T. D. Thi Bang, C.R. Acad. Sci. Paris (C), 272, 1518 (1971). 103. J. A. L. Herbert and H. Suschitzky, J . Chem. SOC.,Perkin Trans. I , 2657 (1974). 104. W. Jehn and R. Radeglia, J. Prakt. Chem., 317, 1035 (1975). 105. J. R. DeBaun, F. M. Pallos, and D. R. Baker, U.S. Patent 3,978,227; August 1976; Chem. Abstr., 86, 5498d (1977). 106. R. M. Acheson and W. R. Tully, J . Chem. SOC., 1117 (1970). 107. S. Fukushima, Y. Akahori, I. Sakamoto, K. Noro, and S. Kazama, Yakugaku Zasshi, 90,1076 (1970). 108. K. Samula and E. Jurkowska-Kowalczyk, Rocz. Chem., 48, 2287 (1974). 109. W. Ried and E. Torinus, Chem. Ber., 92, 2902 (1959). 110. L. K. Mushkalo and V. A. Chuiguk, Ukr. Khim. Zh., 35, 740 (1969). 111. K. Hideg and 0. Hideg-Hankovzky, Acta Chim. (Budapest), 75, 137 (1973). 112. K. Hideg and 0. H. Hankovzky, Acta. Chim. (Budapest), 57,213 (1968). 113. W. Werner, W. Jungstand, W. Gutsche, and K. Wohlrabe, East German Patent 122,247; September 1976; Chem. Abstr., 87, 39550a (1977). 114. W. Werner, W. Zschiesche, J. Guttner, and H. Heineke, Pharmazie, 31, 282 (1976). 115. J. Curtze and K. Thomas, Justus Liebigs Ann. Chem., 328 (1974). 116. N. M. Omar, Indian J . Chem., 12,498 (1974). 117. P. W. W. Hunter and G. A. Webb, Tetrahedron, 28, 5573 (1972). 118. A. Bauer, P. Danneberg, K. H. Weber, and K. Minck, J . Med. Chem., 16, 1011 (1973). 119. S . Bodforss, Justus Liebigs Ann. Chem., 745, 99 (1971). 120. L. K. Mushkalo, M. Chabuby, M. Weissenfels, M. Pulst, and H.-J. Hense, Z . Chem., 14, 187 (1974). 121. R. Radeglia and W. Jehn, J . Prakt. Chem., 318, 1049 (1976). 122. P. W. W. Hunter and G. A. Webb, Tetrahedron, 29, 147 (1973). 123. W. A. Sexton, J . Chem. SOC.,303 (1942). 124. J. Davoll, J . Chem. Soc., 308 (1960). 125. A. Rossi, A. Hunger, J. Kebrle, and K. Hoffmann, Helu. Chim. Acta, 43, 1298 (1960). 126. D. E. Burton, A. J. Lambie, D. W. J. Lane, G. T. Newbold, and A. Percival, J . Chem. Soc., 1268 (1968). 127. A. Rossi, A. Hunger, J. Kebrle, and K. Hoffmann, Helu. Chim. Acta, 43, 1046 (1960). 128. F. B. Wigton and M. M. Joullit, J . Am. Chem. Soc., 81, 5212 (1959). 129. W. Ried and P. Stahlhofen, Chem. Ber., 90, 828 (1957).
20. References
423
130. D. K. Wald and M. M. Joullit, J . Org. Chem., 31, 3369 (1966). 131. R. T. Blickenstaff and N. Wells, Org. Prep. Proc. Int., 6, 197 (1974). 132. R. Barchet and K. W. Merz, Tetrahedron Lett., 2239 (1964). 133. Z. F. Solomko, V. I. Avramenko, and L. V. Pribega, Khim. Geterotsikl. Soedin., 14, 411 (1978); Chem. Heterocycl. Compd., 14, 340 (1978). 134. T. S. Chrnilenko and Z. F. Solomko, Khim. Geterotsikl. Soedin., 13, 834 (1977); Chem. Heterocycl. Compd., 13, 681 (1977). 135. M. Israel, L. C. Jones, and M. M. Joullie, J . Heterocycl. Chem., 8, 1015 (1971). 136. A. Nawojski and W. Nawrocka, Rocz. Chem., 49, 203 (1975). 137. A. N. Kost, Z. F. Solornko, N. M. Prikhod’ko, and S . S. Teteryuk, Khim. Geterotsikl. Soedin., 7, 1556 (1971); Chem. Heterocycl. Compd., 7 , 1447 (1971). 138. A. M. Kost, Z. F. Solomko, V. G. Vinokurov, and V. S. Tkachenko, J . Org. Chem. (USSR), 8, 2080 (1972). 139. Z. F. Solomko, V. S. Tkachenko, A. N. Kost, V. A. Budylin, and V. L. Pikalov, Khim. Geterotsikb Soedin., 11, 533 (1975); Chem. Heterocycl. Compd., 11, 470 (1975). 140. A. N. Kost, Z. F. Solomko, V. A. Budylin, and T. S . Semenova,Khim. Geterotsikl. Soedin., 8,696 (1972); Chem. Heterocycl. Compd., 8, 632 (1972). 141. B. A. Puodzhyunaite and 2. A. Talaikite, Khim. Geterotsikl. Soedin., 10, 833 (1974); Chem. Heterocycl. Compd., 10, 724 (1974). 142. Z. F. Solomko, V. L. Pikalov, and L. V. Pribega, Ukr. Khim. Zh., 40,768 (1974). 143. A. A. Stolyarchuk, Yu. N. Furman, V. L. Pikalov, Z. F. Solomko, and V. S. Tkachenko, Chim.Farm. Zh., 9, 19 (1975). 144. Z. F. Solomko and V. L. Pikalov, Vopr. Khim. Khim. Tekhnol., 39, 93 (1975). 145. R. Pennini, A. Tajana, and D. Nardi, Farmaco, Ed. Sci., 31, 120 (1976). 146. W. Ried and P. Stahlhofen, Chem. Ber., 90, 825 (1957). 147. W. Ried and G. Isenbruck, Chem. Ber., 105, 337 (1972). 148. S. Linke, J. Kurz, and C. Wunsche, Justus Liebigs Ann. Chem., 936 (1973). 149. Z. Zubovics, G. Feher, and L. Toldy, Acta Chim. Acad. Sci. Hung., 92, 293 (1977). 150. T. S. Chmilenko, Z. F. Solomko, and A. N. Kost, Khim. Geterotsikl. Soedin., 13, 525 (1977); Chem. Heterocycl. Compd., 13, 423 (1977). 151. E. Ajello, 0. Migliara, L. Ceraulo, and S. Petruso, J . Heterocycl. Chem., 11, 339 (1974). 152. F. Eiden and E. Zimmermann, Arch. Pharm., 309,619 (1976). 153. T. Hara, H. Fujimori, Y. Kayama, T. Mori, K. Itoh, and Y. Hashimoto, Chem. Pharm. Bull., 25, 2584 (1977). 154. R. Buyle and H. G. Viehe, Tetrahedron, 25, 3453 (1969). 155. R. Buyle and H. G. Viehe, U.S. patent 3,644,374; February 1972; Chem. Abstr., 76, 140798k (1972). 156. G. Roma, A. Ermili, and A. Balbi, Farmaco, Ed. Sci., 32, 81 (1977). 157. (a) A. Bauer, K.-H. Weber, K. Minck, and P. Danneberg, US. patent 3,944,579; March 1976; Chem. Abstr., 85,21491f (1976). (b) A. Bauer, K.-H. Weber, K. Minck, and P. Danneberg, U.S. patent 3,862,136; January 1975 (Boehringer Ingelheim GmbH). 158. R. I. Fryer, L. H. Sternbach, and A. Walser, U.S. patent 4,111,934; September 1978; Chem. Abstr., 90, 152253f (1979). 159. R. B. Moffett, B. V. Kamdar, and P. F. Voigtlander, J . Med. Chem., 19, 192 (1976). 160. K. Peseke, East Ger. Patent 116,826; December 1975; Chem. Abstr., 83, 5703w (1975). 161. K.-H. Weber, A. Bauer, P. Danneberg, and K. Minck, U.S. patent 3,711,467; January 1973; Chem. Abstr., 78, 97729n (1973). 162. Z. F. Solomko, V. L. Pikalov, and V. I. Avramenko, All-Union Institute of Scientific and Technical Information Deposited Paper 1992-75; Ref. Zh. Khim., 24, 284 (1975). 163. Z. F. Solomko, T. S. Chmilenko, P. A. Sharbatyan, N. I. Shtemenko, and S. I. Khimyuk, Khim. Geterotsikl. Soedin., 14, 122 (1978); Chem. Heterocycl. Compd., 14, 100 (1978). 164. Z. F. Solomko, T. S. Chmilenko, P. A. Sharbatyan, L. V. Shevchenko, and N. Ya. Bozhanova, Khim. Geterotsikl. Soedin., 14, 551 (1978); Chem. Heterocycl. Compd., 14, 455 (1978). 165. J. Krapcho and C. F. Turk, J. Med. Chem., 9, 191 (1966).
424
[1,4]Diazepines with [bl-Fused Rings
L. H. Werner, S. Ricca, A. Rossi, and G. de Stevens, J . Med. Chem., 10, 575 (1967). A. Bauer, K.-H. Weber, K.-H. Pook, and H. Daniel, Justus Liebigs Ann. Chem., 969 (1973). J. M. McManus, US. patent 3,595,858; July 1971; Chem. Abstr., 75, 110345~(1971). M. R. Chandramohan and S . Seshadri, Zndian J . Chem., 12,940 (1974). A. Bauer, K.-H. Weber, and P. Danneberg, German patent 2,306,770; September 1974; Chem. Abstr., 82, 43312 (1975). 171. A. Walser and R. I. Fryer, U.S. patent 4,111,931; September 1978 (Hoffman-La Roche Inc.). 172. A. Walser, US.patent 4,118,386; October 1978; Chem. Abstr., 89, 59906n (1978). 173. R. Benassi, P. Lazzeretti, F. Taddei, D. Nardi, and A. Tajana, Org. Magn. Resonance, 8, 387 (1976). 174. A. N. Kost, P. A. Sharbatyan, P. B. Terent’ev, Z. F. Solomko, V. S. Tkachenko, and L. G. Gergel, Zh. Org. Khim., 8, 2113 (1972); J . Org. Chem. (USSR), 8, 2160 (1972). 175. 0. Hinsberg and A. Strupler, Justus Liebigs Ann. Chem., 287, 220 (1895). 176. H. Stetter, Chem. Ber., 86, 197 (1953). 177. H. Shirai, T. Hayazaki, and A. Maki, Nagoya Shiritsu Daigaku Yakugakubu Kenkyu Nempo, 19, 53 (1971). 178. T. Ichii, J. Pharm. SOC. Japan 82,992 (1962). 179. H. Shirai and T. Hayazaki, Yakugaku Zasshi, 91, 1109 (1971). 180. H. Shirai, T. Hayazaki, and M. Kawai, Nagoya Shiritsu Daigaku Yakugakubu Kenkyu Nempo, 20, 45 (1972). 181. G. H. Fisher and H. P. Schultz, J . Org. Chem., 39, 631 (1974). 182. H. Richter, K. Schulze, and M. Miihlstadt, Z . Chem., 8, 220 (1968). 183. L. Lallaz and P. CauMre, Synthesis, 10, 657 (1975). 184. W. Knobloch and G. Lietz, J . Prakt. Chem., 36, 113 (1967). 185. N. M. Omar, A. F. Youssef, M. A. El-Gency, and M. M. Kassab, Can. J . Pharm. Sci., 11, 89 (1976). 186. N. M. Omar, A. F. Youssef, and M. A. El-Gency, Arch. Pharm., Chem. Sci. Ed., 3,89 (1975). , F. Gatta, and R. Landi-Vittory, J . Heterocycl. Chem., 8, 231 (1971). 188. J. S. Walia, L. A. Heindl, A. S. Walia, and P. S . Walia, J . Chem. SOC., Chem. Commun., 962 (1972). 189. J. S. Walia, P. S. Walia, L. A. Heindl, and P. Zbylot, J . Chem. SOC.,Chem. Commun., 108 (1972). 190. H. Shirai, T. Hayazaki, and A. Maki, Yakugaku Zasshi, 91, 1228 (1971). 191. T. S. Safonova, K. W. Lewschina, W. A. Tschernow, T. A. Andrianowa, N. A. Grinewa, and S. M. Minakowa, Germ. Offen. 2,328,870; January 1975; Chem. Abstr., 82, 156397~(1975). 192. H. Boshagen and M. Plempel, US. patent 3,911,126; October 1975; Chem. Abstr., 84,155700m (1976). 193. G. B. Bachman and L. V. Heisey, J . Am. Chem. SOC.,71, 1985 (1949). 194. W. Ried and G . Urlass, Chem. Ber., 86, 1101 (1953). 195. H. Wahl and M. T. Le Bris, Znd. Chim. Belge, 32, 145 (1967). 196. M. T. Le Bris, Bull. SOC.Chim. Fr., 3411 (1967). 197. S. Raines and C. A. Kovacs, J . Heterocycl. Chem., 4, 305 (1967). 198. N. K. Khakimova, Ch. Sh. Kadyrov, and A. A. Shazhenov, Uzb. Khim. Zh., 19,53 (1975); Chem. Abstr., 83, 79210p (1975). 199. (a) 0. Bub., US. patent 4,108,852; August 1978; (b) 0.Bub, German Offen. 1,913,536; October 1970; Chem. Abstr., 73, 120691e (1970). 200. S. H. Dandegaonker and G. B. Desai, Zndian J . Chem., 1, 298 (1963). 201. Z. F. Solomko, A. N. Kost, L. N. Polovina, and M. A. Salimov, Khim. Geterotsikl. Soedin., 7, 987 (1971); Chem. Heterocycl. Compd., 7, 922 (1971). 202. G . Holan, J. J. Evans, and M. Linton, J . Chem. SOC.,Perkin Trans. I , 1200 (1977). 203. B. J. R. Nicolaus, E. Bellasio, G. Pagani, L. Mariani, and E. Testa, Helu. Chim. Acta, 48, 1867 (1965). 204. A. Bauer, K.-H. Weber, and M. Unruh, Arch. Pharm., 305, 557 (1972). 205. E. Szarvasi, M. Grand, J.-C. Depin, and A. Betbeder-Matibet, Eur. J . Med. Chem. (Chim. Ther.), 13, 113 (1978). 166. 167. 168. 169. 170.
20. References
425
206. Z. F. Solomko, V. T. Braichenko, and M. S. Malinovskii, Khim. Geterotsikl. Soedin.,8, 428 (1972); Chem. Heterocycl. Compd., 8, 395 (1972). 207. Belg. Patent 751,834; December 1970 (C.H. Boehringer Sohn, Ingelheim). 208. 0. Bub, Ger. Offen. 2,062,226; September 1971; Chem. Abstr., 76, 14602d (1972). 209. 0. Bub, Ger. Offen. 2,062,237; September 1971; Chem. Abstr., 76, 3913e (1972). 210. 0. Bub, Ger. Offen. 1,953,647; May 1971; Chem. Abstr., 75, 49153q (1971). 211. P. I. Ittyerah and F. G. Mann, J. Chem. SOC.,467 (1958) 212. J. Krapcho and C. Turk, US. patent 3,321,468; May 1967; Chem. Abstr., 68, 21970k (1968). 213. K. W. Merz, R. Haller, and E. Muller, Naturwissenschafen, 50, 663 (1963). 214. E. Muller, R. Haller, and K. W. Merz, Justus Liebigs Ann. Chem., 697, 193 (1966). 215. A. Bauer, K.-H. Weber, H. Merz, K. Zeile, R. Giesemann, and P. Danneberg, US. patent 3,816,409; June 1974; Chem. Abstr., 81, 105588~(1974). 216. J. Bernstein, US. patent 3,341,521; September 1967; Chem. Abstr., 68, 9587% (1968). 217. 0. Bub, H.-P. Hofmann, H. Kreiskott, and F. Zimmermann, US. patent 3,847,905; November 1974 (Knoll AG). 218. A. Bauer, K.-H., Weber, P. Danneberg, and F.-J. Kuhn, German Offen. 2,231,560; January 1974; Chem. Abstr., 80,96043s (1974). 219. M. P. Mertes and A. J. Lin, J. Med. Chem., 13, 77 (1970). 220. R. Meyer, Justus Liebigs Ann. Chem., 327, 1 (1903). 221. R. Meyer, Justus Liebigs Ann. Chem., 347, 17 (1906). 222. R. Meyer and H. Luders, Justus Liebigs Ann. Chem., 415, 29 (1918). 223. M. A. Phillips, J. Chem. SOC.,2393 (1928). 224. R. L. Shriner and P. G. Boermans, J. Am. Chem. SOC., 66, 1810 (1944). 225. G. Glotz, Bull. SOC. Chim. Fr., 3, 511 (1936). 226. D. R. Buckle, B. C. C. Cantello, and N. J. Morgan, Brit. patent 1,460,936; January 1977; Chem. Abstr., 87, 68438a (1977). 227. J. Biichi, H. Dietrich, and E. Eichberger, Helu. Chim. Acta, 39, 957 (1956). 228. (a) B. Brobanski, W. Roman, and E. Wagner, Farmaco, Ed. Sci., 26, 3 (1971); (b) B. Bobranski, E. Wagner, and W. Roman, Polish patent 71,544, October 1974; Chem. Abstr., 83, 792992 (1975). 229. E. Wagner, Disst. Pharm. Pharmacol., 2.4, 391 (1972). 230. E. Wagner, Rocz. Chem., 48, 1289 (1974). 231. M. M. El-Enany, K. M. Choneim, and M. Khalifa, Pharmazie, 32, 79 (1977). 232. Dutch patent 7,204,008; September 1972 (C.H. Boehringer Sohn, Ingelheim). 233. K.-H Weber, H. Merz, K. Zeile, R. Giesemann, and P. Danneberg, Ger. Offen. 1,918,073; October 1970; Chem. Abstr., 74, 3673k (1971). 234. S. Rossi, 0. Pirola, and R. Maggi, Chim. Ind. (Milan) 51, 479 (1969). 235. S. Rossi, US. patent 3,984,398; October 1976 (Roussel-UCLAF). 236. K.-H. Weber, K. Zeile, P. Danneberg, R. Giesemann, and K. H. Hauptmann, U.S. patent 3,836,653; September 1974; Chem. Abstr., 86, 29894f (1977). 237. K.-H. Weber, H. Merz, and K. Zeile, Ger. Offen. 1,934,607; January 1970; Chem. Abstr., 72, 100771g (1970). 238. K.-H. Weber, H. Merz, R. Giesemann, and P. Danneberg, Ger. Offen. 1,966,128; August 1971; Chem. Abstr., 75, 110348a (1971). 239. K.-H. Weber, A. Bauer, and K.-H. Hauptmann, Justus Liebigs Ann. Chem., 756, 128 (1972). 240. K.-H. Weber, and A. Bauer, Canadian patent 992,540, July 1976; Chem. Abstr., 86, 55499a (1977). 241. K.-H. Weber, A. Bauer, H. Merz, and K. Minck, US.patent 3,678,033; July 1972 (Boehringer Ingelheim GmbH). 242. J. Van Alphen, R e d . Trau. Chim., 43, 823 (1924). 243. K.-H. Weber and A. Bauer, Justus Liebigs Ann. Chem., 763, 66 (1972). 244. K.-H. Weber, A. Bauer, and K.-H. Pook, Ger. Offen. 2,103,746; August 1972; Chem. Abstr., 77, 140176b (1972).
426
[ 1,4]Diazepines with [bl-Fused Rings
245. K.-H. Weber, A. Bauer, P. Danneberg, K. Minck, K.-H. Pook, US. patent 3,707,538; December 1972 (Boehringer Ingelheim GmbH). 246. A. Bauer and K.-H. Weber, Justus Liebigs Ann. Chem., 762, 73 (1972). 247. A. Bauer, K.-H. Weber, P. Danneberg, and K. Minck, U S . patent 3,711,468; January 1973 (Boehringer Ingelheim GmbH). 248. A. Bauer, K.-H. Weber, and K.-H. Pook, U.S. patent 3,766,169; October 1973 (Boehringer Ingelheim GmbH). 249. K.-H. Hauptmann, K.-H. Weber, K. Zeile, P. Danneberg, and R. Giesemann, Brit. patent 1,217,217; December 1970; Chem. Abstr., 74, 141893h (1971). 250. H. Kuch and I. Hoffman, U.S. patent 3,718,645; February 1973 (Farbwerke Hoechst AG). 251. K.-H. Weber, K. Zeile, R. Giesemann, P. Danneberg, US. patent 3,624,076; November 1971 (Boehringer Ingelheim GmbH). 252. A. Bauer, K.-H. Pook, and K.-H. Weber, Justus Liebigs Ann. Chem., 757, 87 (1972). 253. K. B. Alton, J. E. Patrick, C. Shaw, and J. L. McGuire, Drug Metab. Dispos., 3, 445 (1975). 254. K. B. Alton, R. M. Grimes, C. Shaw, J. E. Patrick, and J. L. McGuire, Drug Metab. Dispos., 3, 352 (1975). 255. R. E. Huettemann and A. P. Shroff, J . Pharm. Sci., 64, 1339 (1975). 256. D. Nardi, E. Massarani, and L. Degen, Swiss patent 532,592; February, 1973; Chem. Abstr., 78, 136346k (1973). 257. K. Peseke, East Ger. patent 99,796; August 1973; Chem. Abstr., 80, 83081~(1974). 258. K. Peseke, East Ger. patent 106,041; August 1974; Chem. Abstr., 81, 169569a (1974). 259. A. I. Kiprianov and V. P. Khilya, Zh. Org. Khim., 3, 1091 (1976); J . Org. Chem. (USSR), 3, 1051 (1967). 260. A. W. Chow, F. J. Gyurik, and R. C. Parish, J . Heterocycl. Chem., 13, 163 (1976). 261. K. Peseke, East Ger. patent 105,235, April 1974; Chem. Abstr., 81, 1695682 (1974). 262. G . Belvedere, A. Frigerio, A. Malorni, and D. Nardi, Boll. Chim. Farm., 114, 151 (1975). 263. D. Lloyd, R. H. McDougall, and D. R. Marshall, J . Chem. Soc. C , 780, (1966). 264. D. Lloyd, H. McNab, and D. R. Marshall, Aust. J . Chem., 30,365 (1977). 265. G. W. H. Potter, M. W. Coleman, and A. M. Monro, J . Heterocycl. Chem., 12, 611 (1975). 266. D. Lloyd, R. K. Mackie, H. McNab, and K. S. Tucker, Tetrahedron, 32, 2339 (1976). 267. R. H. McDougall and S. H. Malik, J . Chem. Soc. C , 2044 (1969). 268. G. Settimj, F. Fraschetti, and S. Chiavarelli, Gazz. Chim. Ital., 96, 749 (1966). 269. G. Seitz and H. Morck, Arch. Pharm., 307, 113 (1974). 270. D. Lloyd and D. R. Marshall, J . Chem. Soc., 2597 (1956). 271. E. Abushanab, D. Y. Lee, and L. Goodman, J . Heterocycl. Chem., 10, 181 (1973). 272. G. Desimoni and G . Minoli, Tetrahedron, 26, 1393 (1970). 273. A. Gasco, G. Rua, E. Menziani, G . M. Nano, and G. Tappi, J . Heterocycl. Chem., 7, 131 (1970). 274. J.-P. Affane-Nguema, J.-P. Lavergne, and P. Viallefont, J . Heterocycl. Chem., 14, 391 (1977). 275. J.-P. Affane-Nguema, J.-P. Lavergne, and P. Viallefont, J . Heterocycl. Chem., 14, 1013 (1977). 276. J.-P. Affane-Nguema, J.-P. Lavergne, and P. Viallefont, Org. Mass Spectrom., 12, 136 (1977). 277. M. Israel, L. C. Jones, and E. J. Modest, J . Heterocycl. Chem., 4, 659 (1967). 278. A. Nawojski, Rocz. Chem., 42, 1641 (1968). 279. J.-P. Lavergne, P. Viallefont, and J. Daunis, Org. Mass. Spectrom., 11, 680 (1976). 280. M. Israel and L. C . Jones, J . Heterocycl. Chem., 6, 735 (1969). 281. M. Israel and L. C . Jones, J . Heterocycl. Chem., 10, 201 (1973). 282. S.Carboni, A. DaSettimo, D. Bertini, P. L. Ferrarini, 0. Livi, and I. Tonetti, Farmaco, Ed. Sci., 30, 237 (1975). 283. A. Nawojski and W. Nawrocka, Rocz. Chem., 48, 2275 (1974). ~ 284. W. Bebenburg, Ger. Offen. 2,360,852; June 1974; Chem. Abstr., 81, 1 0 5 5 9 1 (1974). 285. A. Nawojski, Rocz. Chem., 43, 573 (1969). 286. K. Winterfeld and M. Wildersohn, Pharm. Acta. Helu., 45, 323 (1970). 287. B. Brobanski and J. Stankiewicz, Diss. Pharm. Pharmacol., 24, 301 (1972). 288. N. S. Miroshnichenko and A. V. Stetsenko, Ukr. Khim. Zh., 41, 105 (1975). 289. A. Nawojski, Rocz. Chem., 43,979 (1969).
20. References
421
299. 300. 301. 302. 303. 304. 305. 306. 307. 308. 309. 310.
M. Israel and L. C. Jones, J. Heterocycl. Chem., 8, 797 (1971). Aust. Patent 325,054; October 1975; Chem. Abstr., 84, 44200d (1976). M. Israel, L. C. Jones, and E. J. Modest, Tetrahedron Lett., 4811 (1968). W. H. Nyberg, C. W. Noell, and C. C. Cheng, J. Heterocycl. Chem., 2, 110 (1965). M. Israel, S. K. Tinter, D. H. Trites, and E. J. Modest, J. Heterocycl. Chem., 7, 1029 (1970). S. Fukushima, A. Ueno, K. Noro, K. Iwagaya, T. Noro, K. Morinaga, Y. Akahori, H. Ishihara, and Y. Saiki, Yakugaku Zasshi, 97, 52 (1977). Q. Q. Dang, R. Caujolle, and T. B. T. Dang, C.R. Acad. Sci. Paris, Ser. C , 274, 885 (1972). French Patent 1,497,861; September 1967; Chem. Abstr., 69, 96792h (1968). S. Fukushima, A. Ueno, K. Noro, T. Noro, K. Morinaga, Y. Akahori, H. Ishihara, and Y.Saiki, Yakugaku Zasshi, 96, 1453 (1976). S. Wawzonek, J. Org. Chem., 41, 310 (1976). P. H. Stahl and K. W. Merz, Pharmazie 22, 630 (1967). P. H. Stahl, R. Barchet, and K. W. Merz, Arzneimittel-Forsch., 18, 1214 (1968). H. v. Dobeneck, A. Uhl, and L. Forster, Justus Liebigs Ann. Chem., 476 (1976). C. A. Lovelette and L. Long, Jr., J. Org. Chem., 37, 4124 (1972). A. L. Linand and J. M. Hoch, Arzneimittel-Forsch., 34, 640 (1984). Y. Kurasawa, J. Satoh, M. Ogura, Y. Okamato, and A. Takada, Heterocycles, 22, (1984). G. Roma, M. Di Braccio, M. Mazzei, and A. Ermili, Farmaco, Ed. Sci., 39, 477 (1984). E. Wagner, Pol. J . Chem., 56, 131 (1982). A. Nawojski, W. Nawrocka, and H. Liszkiewicz, Pol. J. Pharmacol. Pharm., 35, 531 (1983). G. Roma, A. Balbi, A. Ermili, and E. Vigevani, Farmaco, Ed. Sci., 38, 546 (1983). t.D. Orlov, N. N. Kolos, F. G. Yaremenko, and V. F. Lavrushin, Khim. Geterotsikl. Soedin.,
311. 312. 313. 314. 315. 316. 317. 318. 319. 320. 321. 322. 323.
P. C. Unangst, J . Heterocycl. Chem., 18, 1257 (1981). L. Capuano and K. Gartner, J. Heterocycl. Chem., 18, 1341 (1981). H. Voigt, 2. Chem., 21, 103 (1981). G. Roma, M. Di Braccio, M. Mazzei, and A. Ermili, Farmaco, Ed. Sci., 35, 997 (1980). T. Kato, N. Katagiri, and R. Sato, J. Chem. Soc., Perkin Trans. I , 525 (1979). A. Tajana, R. Pennini and D. Nardi, Farmaco, Ed, Sci., 35, 181 (1980). R. Grover and B. C. Joshi, J. Indian Chem. Soc., 56, 1220 (1979). K. C. Joshi, V. N. Pathak, P. Arya, and P. Chand, Pharmazie, 34, 718 (1979). A. Ushirogochi, Y. Tominaga, Y. Matsuda, and G. Kobayashi, Heterocycles, 14, 7 (1980). A. Nawojski, W. Nawrocka, and H. Liszkiewicz, Pol. J. Pharmacol. Pharm., 34, 423 (1982). G. Rackur and I. Hoffmann, U.S. Patent 4,305,952; December 1981. G. Rackur and I. Hoffman, U S . Patent 4,302,468; November 1981. 0. Bub, US. Patent 4,239,684; December 1980, (Knoll AG).
290. 291. 292. 293. 294. 295. 296. 297. 298.
16, 697 (1980).
Chapters V-IX [el-Fused[ 1,4]Diazepines Chapters V-IX are devoted to the synthesis and chemistry of [el-fused [1,4]diazepines, represented by the general structure 1.
1
Because of the large volume of published material describing members of this general ring system, a division into several chapters seemed appropriate. The 1,4-benzodiazepines constitute the largest class of compounds falling into this category. They will be discussed in Chapters V-VIII, separated according to the degree of saturation of the diazepine ring. will be treated after the benzo-fused The related hetero[e][1,4]diazepines system and will be presented in alphabetical order in Chapter IX. This review includes previously reviewed material. Earlier reviews were published by: G. A. Archer and L. H. Sternbach, Chem. Rev., 68, 747 (1968). S. J. Childress and M. I. Gluckman, J . Pharm. Sci., 53, 577 (1964). F. D. Popp and A. C. Noble, in Advances in Heterocyclic Chemistry, Vol. 8, A. R. Katritzky and A. J. Boulton, Academic Press, New York and London, 1967, p. 21. J. A. Moore and E. Mitchell, in Heterocyclic Compounds, Vol. 9, K. C. Elderfield, Ed., Wiley, New York, 1967, p. 227. L. H. Sternbach, L. 0. Randall, and S . Gustafson, in PsychopharmacologicaI Agents, Vol. 1, M. Gordon, Ed., Academic Press, New York, 1964, p. 137. L. H. Sternbach, L. 0. Randall, R. Banzinger and H. Lehr, in Medicinal Research Series, Vol. 25, A. Burger, Ed., Dekker, New York, 1968, p. 237. A. V. Bogatskii and S . A. Andronati, Russ. Chem. Rev., 39, 1064 (1970). R. I. Fryer, J . Heterocycl. Chem., 9, 747 (1972). L. H. Sternbach in The Benzodiazepines, S . Garattini, E. Mussini, and L. 0. Randall, Eds., Raven Press, New York, 1973, p. 1. 429
430
[el -Fused[ 1,4]Diazepines
L. 0. Randall, W. Schallek, L. H. Sternbach, and R. Y. Ning, in Psychopharmacological Agents, Vol. 3, M. Gordon, Ed., Academic Press, New York, 1974, p. 175. E. Schulte, Dtsch. Apoth. Z., 115, 1253 (1975). L. H. Sternbach, in Progress in Drug Research, Vol. 22, E. Tucker, Ed., Birkhauser Verlag, Base1 and Stuttgart, 1978, p. 229. L. H. Sternbach, Angew. Chem., Znt. Ed. Engl., 10, 34 (1971). H. Schutz, Benzodiazepines, A Handbook, Springer-Verlag, New York, 1982.
CHAPTER V
1.4.Benzodiazepines .
A Walser Chemical Research Department. Hofmann-La Roche Inc., Nutley. New Jersey
and
.
R Ian Fryer Department of Chemistry. Rutgers. State University of N e w Jersey. Newark. New Jersey
1. IH.l,4.Benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
433
1.1. Synthesis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
433
1.2. Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
435
1.2.1. Reactions with Electrophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2.2. Reactions with Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
435 437
2. 3H.1,4-Benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
438
2.1. 2-Hydrogen and 2-Carbon-substituted 3H.1, 4-Benzodiazepines . . . . . . . . . . . .
438
2.1.1. Synthesis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.2. Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.2.1. Reactions with Electrophiles . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.2.2. Reactions with Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . .
438 443 443
2.2. 2-Amino-substituted 3H.1, 4-Benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . .
447
2.2.1. Synthesis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.1.1. Synthesis by Ring Expansion . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.1.2. Synthesis from 2-Thio Compounds . . . . . . . . . . . . . . . . . . . . . 2.2.1.3. Other Syntheses. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.2. Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.2.1. Reactions with Electrophiles . . . . . . . . . . . . . . . . . . . . . . . . . A . Oxidation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Reactions with Nitrogen Electrophiles. . . . . . . . . . . . . . . . . . C. Reactions with Carbon Electrophiles . . . . . . . . . . . . . . . . . . C.1. Alkylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (2.2. Reactions with Aldehydes, Ketones, and Equivalents . . . . . . C.3. Acylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
43 1
444 447 447 449 450 453 453 453 454 455 455 458 461
432
1.4.Benzodiazepines 2.2.2.2. Reactions with Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . A. Reduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Reactions with Oxygen Nucleophiles . . . . . . . . . . . . . . . . . . C. Reactions with Nitrogen Nucleophiles . . . . . . . . . . . . . . . . . D. Reactions with Carbon Nucleophiles . . . . . . . . . . . . . . . . . . 2.2.2.3. Thermal and Photoreactions . . . . . . . . . . . . . . . . . . . . . . . . .
469 469 470 472 474 475
2.3. 2-Hydroxyamino-3H- 1,4-Benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . . .
416
2.3.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.2. Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
476 477
2.4. 2-Hydrazino-3H-1,4-Benzodiazepines ............................
478
478 2.4.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 480 2.4.2. Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 480 2.4.2.1. Reactions with Electrophiles . . . . . . . . . . . . . . . . . . . . . . . . . 480 A . Nitrosation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Reactions with Aldehydes and Ketones . . . . . . . . . . . . . . . . . 480 483 C. Acylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 486 2.4.2.2. Reactions with Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . 2.5. 2-0- and S-substituted 3H-I,4-Benzodiazepines . . . . . . . . . . . . . . . . . . . . . .
486
2.5.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5.2. Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5.2.1. Reactions with Electrophiles . . . . . . . . . . . . . . . . . . . . . . . . . 2.5.2.2. Reactions with Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . 2.5.2.3. Thermal Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
486 488 488 488 491
2.6. 2-Halo-3H- 1,4-Benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
491
2.6.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6.2. Reactions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
491 491
3. 5H- 1,4-Benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
492
3.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
492 494
4 . Tables of Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
496
5. References . . . . . . . . . . . . . .
539
INTRODUCTION This chapter reviews the synthesis and reactions of 1.Cbenzodiazepines represented by the three tautomers 2a-2c . Representatives of all three tautomers 2a-2c have been reported in the literature and are discussed separately in Sections 1-3 .
2a
1H-1.4.Benzodiazepine
2b 3H- 1.4-Benzodiazepine
2c 5H- 1 CBenzodiazepine
.
1. lH-l,4-Benzodiazepines
433
1. lH-1,4-BENZODIAZEPINES 1.1. Synthesis
The parent ring system, 2a, has not yet been reported. The 5-methoxy-8chloro analog 4 (R = MeO) and several 5-amino derivatives 4 (R = NHR,) were obtained'" in 15-50% yields by photolysis of the 4-azidoquinoline 3 in the presence of methoxide or an amine, respectively (Eq. 1).The enamine structure 4 (R = MeO) was assigned on the basis of proton- and l3C-nmr spectroscopy.'b The preliminary account of this workla contains no analytical or spectroscopic data for the product 4.
The trisubstituted derivatives 8 (X = H, F) were prepared by desulfurization of the 2-thioalkylbenzodiazepines6 (R, = Me; R, = H; R, = C1; R, = Me, Et; X = H, F) with Raney nickel in the presence of diethylamine'** or, in better yield, by dehydration of the 2-hydroxy compounds 7 (X = H, F) with mesyl chloride and pyridine (Eq. 2).2-4
base
5
6
I
Raney nickel
7
8
1,4-Benzodiazepines
434
The latter reaction gave as by-products orange dimers to which structure 9 was assigned on the basis of spectral and analytical data.5a The 2-thioalkyl . ~alkylation of the appropriate 2-thiones, 5, compounds 6 were ~ r e p a r e d , - ~by the preparation of which is discussed in Chapter VI, covering dihydro-1,4benzodiazepines. Oxidation of compounds 6 with m-chloroperbenzoic acid led to the corresponding s u l f ~ x i d e s ~and * ~ s*~~l f o n e s . ~ . ~ 11 was obtained in 66% yield by treatThe 2-cyano-lH-1,4-benzodiazepine ment of the corresponding 3H tautomer 10 with triethylamine in boiling tetrahydrofuran (Eq. 3).7 In this case, the enamine is stabilized by the cyano group, rendering the 1H tautomer the thermodynamically preferred form. A similar stabilization was encountered with the 3-carboxamide 13, which was synthesizeds by cyclization of the formamidine 12 in boiling toluene (Eq. 4). Compound 12 was accessible by cleavage of nitrazepam with methylamine followed by reaction with dimethylformamide dimethylacetal.
c1
THF Et,N
*
(3)
-N Ph 10
12
Ph 11
13
(4)
Acetylation of the 2-methylaminobenzodiazepine 14 with acetyl chloride or with a mixture of acetic anhydride and sodium acetate gave the diacetate 15 (Eq. 5).9 Reaction of the benzodiazepin-2-ones 16 (R, = H; R, = H, COOEt; X = C1, NO,) with sodium methoxide and ethyl chloroformate in dimethylformamide at - 30°C led to the N,O-dicarboxylates 17 (R, = COOEt; R, = H, COOEt).5b The 1-methyl compound 16 (R, = Me; R, = COOEt; X = C1)
1. lH-l,4-Benzodiazepines
435
under similar conditions yielded the O-acylated derivative 17 (R, R, = COOEt, X = C1) (Eq. 6).5b
Ac,O. AcCl NaOAc or
@""'
c1
-N Ph
* d
f
G
Me,
e
c1 Ph
14
15
d < O O E t
MCO~/CICOOEt
R,
DMF, -30°C
X
=
X Ph
" Ph 17
16
In the patent literature, structure 18 has been assigned to the product obtained from the reaction of chlordiazepoxide (Coxide of 14) with formaldehyde and hydrochloric acid.'O
18
1.2. Reactions
I .2.1. Reactions with Electrophiles The sulfones 19 were found to undergo rearrangement upon oxidation with rn-chloroperbenzoic acid to give the benzodiazepin-2-ones 21 (Eq. 7).' This transformation was assumed to proceed via an initial formation of epoxide 20, which then could rearrange with migration of the methylsulfonyl group as indicated.'
436
Oxidation of 13 with chromium trioxide in acetic acid led to the quinazoline2-carboxamide 23, most likely via the proposed intermediate 22 (Eq. 8).*
CHO
1
Ph 13
The 2-thioethyl compound 24 reacted with diethyl azodicarboxylate in boiling dioxane to form the adduct 25 (Eq. 9).' Dimethyl acetylene dicarboxylate under similar conditions added to 24 to yield the dibenzodiazepine 28.* Cyclobutadienes were proposed as possible intermediates,' however, it is equally plausible that the reagent adds first to the 3-position of 24 to form
1. lH-1,4-Benzodiazepines
437
26. Diels-Alder reaction with a second molecule of acetylene dicarboxylate would then lead to 27,which could aromatize to 28 by loss of ethanethiol.
c1
(NCOOEr)
___i
c1 I
OF
24
25
I
MeOOCC=CCOOMe
d
S
EtS COOMe O O COOMe M c
c1
26
-N
COOMe
21
I
COOMe
COOMe
28
(9)
1.2.2. Reactions with Nucleophiles Acid hydrolysis of the 3-carboxamide 13 gave the 2-substituted indole 30 (R = COCONHMe) as the major product plus a minor amount of 30 (R = H).’ This hydrolytic ring contraction was formulated to proceed via the benzophenone intermediate 29 (Eq. lo).’
1,4-Benzodiazepines
438
(r..NHMe-
13
H,O'
32N
Go Ph
30
29
Mild cleavage of 17 (R, = R, = COOEt, X anol gave the 1,3-dicarboxylate 31 (Eq. 1 l).5b
=
C1) with methoxide in meth-
COOEt
1 0
R1 OCOOEt
X <$R2
--N
A MeOH CI<>COOEt
Ph
-N
(11)
Ph
17
31
2. 3H-1,4-BENZODIAZEPINES While the parent compound is still unknown, the abundance of substituted derivatives of 3H- 1,4-benzodiazepines reported in the literature made it necessary to discuss this material in several subsections. The compounds are, therefore, classified according to the nature of the substituent attached to the 2-position.
2.1. 2-Hydrogen- and 2-Carbon-Substituted 3H-1,4-Benzodiazepines
2.1.1. Synthesis The 5-phenyl-7-chloro derivative 33 (R = H) and its 4-oxide appear to be the only 2-unsubstituted 3H-1,4-benzodiazepines described in the literat~re.~.'' These compounds were prepared by oxidation of the corresponding 2,3-dihydro derivatives 32 (R = H) with ordinary manganese dioxide in boiling benzene. Good yields of 33 (R = H) were found to be contingent on prior azeotropic removal of water from the manganese dioxide and by addition of a small amount of acetic acid. The dimer 34 was isolated as a by-product (Eq. 12).
2. 3H-1,4-Benzodiazepines
l& cc% 1= = :Q J
439
H
-N Ph 34
The 2-methyl analog 33 (R = and its corresponding 4-oxideI4 were also accessible by oxidation of the appropriate 2,3-dihydro derivatives with manganese dioxide. The same procedure was used for the preparation of the 2-cyanobenzodiazepine 33 (R = CN) and the 2-carboxamides 33 (R = CONH,)73'5and 33 (R = CONMe,).7b The 2-methyl 4-oxides 36 could be obtained in high yields by the ring expansion of 2-chloromethyl-2-methyl-1,2-dihydroquinazoline 3-oxides 35 using sodium hydroxide in boiling ethanol. This method was applied for the synthesis of 5-phenyl derivatives 36 (R, = Ph; R, = H, C1, NO,; R 3 -- H),12-14,16,17 5- (2-fluorophenyl)compounds," and a 5-methyl analog 36 (R, = Me, R, = R3 = MeO)." This ring expansion was postulated to proceed14 by initial abstraction of the proton in the 1-position followed by ring opening to the oxime anion 37.This intermediate would then undergo an intramolecular alkylation on nitrogen to form the seven-membered ring (Eq.13).
36
35
(13)
31
1,4-Benzodiazepines
440
2-Methyl benzodiazepines and their 4-oxides can also be obtained by alkaline hydrolysis and decarboxylation of the 2-acetic acid ester 42 (R, = COOMe) or by cleavage of the corresponding t-butyl ester 42 (R, = COOt-Bu) with trifluoroacetic acid (Eq. 15).5 The 2-cyanobenzodiazepine 39 was isolated from the reaction of the 2-nitromethylene derivative 38 (X = F) with phosphorus trichloride in pyridine (Eq. 14).19This transformation involves reduction of the nitro group to a nitroso derivative tautomeric with the oxime 41 (X = F). Dehydration of 41 would then lead to the nitrile 39.
(14)
40
36
The oximes 41 (X = F) and the 4-oxide of 41 (X = H) were formed by methylation of the appropriate nitromethylene derivative 38 with diazomethane and subsequent thermolysis in boiling benzene or toluene.” The 4-oxide of 41 (X = F) was also obtained by nitrosation of the 2-methyl benzodiazepine 36 (R, = 2-FC6H4, R2 = C1, R, = H).l8 The related oximes 43 (R, = COOR,,20-22 Ac,” CONR,R,,’ 2-pyridy1,’ were analogSO,Me,’ SO,NMe,’) and the nitroximes 43 (R, = N0,)23*24 ously prepared in high yields by nitrosation of the appropriate 2-methylene benzodiazepines 42 with sodium nitrite in glacial acetic acid
2. 3H-1,4-Benzodiazepines
441
(Eq. 15). The nitro group in the nitroximes 43 (R, = NO,) was susceptible to displacement with nucleophiles, and these compounds were converted to amidoximes 45 (R, = N R , R , , R, = H) by reaction with amines at room tempera t ~ r e . ~Methylthiolate , displaced the nitro group to give the thiomethyl oxime 45 (R, = MeS, R, = H).,, Methylation of the nitroxime 43 (R, = NO,) with diazomethane yielded 44 (R, = Me).23924 When this methylation was carried out in tetrahydrofuran, the 4-methoxybutyl derivatives 44 [R, = MeO(CH,),] were formed as by-product^,'^^ apparently by generation of a tetrahydrofuran oxonium ion. Compound 44 (R, = Me) reacted also with nucleophiles such as aminesZ4and alk~xides,~' to give the N-methoxyamidines 45 (R2 = NR,R,, R, = Me) and the N-methoxyimidates 45 (R, = MeO, R, = Me).
The 8-chloro-2-phenyl benzodiazepine 47 (R = MeO) resulted from the reaction of the 5-one 46 with Meerwein reagent.', The imino ether was converted to the 5-hydrazino compound 47 (R = N H N H , ) by treatment with hydrazine at room temperature (Eq. 16).',
R
0 46
41
1,CBenzodiazepines
442
The 4-oxide 49 was prepared by addition of phenylmagnesium bromide to the lactam 48 (Eq. 17).26
PhMgBr
(17)
c1
c1 Ph ‘0
49
48
Formation of a C-C bond at the 2-position has been achieved by reaction of the phosphoryl imidate 50 with the anion of acetaminomalonic ester yielding the 3H-benzodiazepines 51 (Eq. 18). This synthesis was described for R = 2-pyridyl, 2-halophenyl and X = C1, Br, CN.21
50
51
Structure 53 was assigned27 to the product isolated in 5% yield from the reaction of the 2-amino derivative 52 with acetylacetoiie (Eq. 19). HOwMe
C
I
l
Y
Ph
N
Ph
52
53
3H- 1,4-Benzodiazepinescan also be prepared by the isomerization of the 5Htautomers in the presence of methoxide,’* as demonstrated by the conversion of 54 to 55 (Eq. 20).
KfLe
c1
N
Ph 54
McO-
c1c
--N i e
f
Ph 55
(20)
2. 3H-1,4-Benzodiazepines
443
The 2-substituted 3H-1,Cbenzodiazepine 57 resulted from an intramolecular alkylation on carbon of the 3-chloropropionyl derivative 56, using triethylamine in boiling dimethylformamide (Eq. 21)." NHCO(CH,),CI
(21)
\ 56
51
2.1.2. Reactions 2.1.2.1. Reactions with Electrophiles Treatment of the 4-oxides 58 (X = H, F) with t-butyl hypochlorite led to the 2-chloromethyl derivatives 59 (Eq. 22)."
58
0
c1 Ph 60
61
Oxidation of 58 (X = H) with 3-chloroperbenzoic acid gave the 1,Cdioxide The nitrosation of 58 (X = F) to the 2-carboxaldoxime was mentioned above. Methylation of the nitroximes 43 (R, = NO,) to the 0-methyl oximes 44 (R, = Me) has also been discussed.
1,4-Benzodiazepines
444
The 3-acetoxy compound 61 (R = Ac) was prepared by rearrangement of the nitrone 58 (X = H) in acetic anhydride. The acetate was hydrolyzed to the alcohol 61 (R = H)using aqueous hydroxide in tetrahydrofuran.” The amidoxime 62 reacted with acetaldehyde in methylene chloride at room temperature to give the oxadiazole 63.24b Molecular sieves were used to bind the water eliminated in this reaction (Eq. 23).
62
63
2.1.2.2. Reactions with Nucleophiles Catalytic hydrogenation over Raney nickel converted 58 (X = H) to the 2,3-dihydro-lH-1,4-benzodiazepine 32 (R = Me) in which both the nitrone and the 1,2-imine were reduced (Eq. 24). Selective reduction of the nitrone function was reported for the 7-deschloro compound by employing the same reagent.’ 2,13,17
XNi/Hi =H
43
c1
-N
(24)
Ph
w
32
58
Hydrogenation of the oximes 43 (R, = COOR; Ac) over Raney nickel led to the enediamines 64 (Eq. 25).20921With the exception of 64 (R, = COOMe, X = Cl),” these enediamines were not characterized but were converted further to tricyclic systems such as imidazo[ 1,5-a][ 1,4]benzodiazepines. In the presence of methanolic ammonia, this catalytic hydrogenation proceeded with retention of the nitrone f ~ n c t i o n a l i t y . ~ ~
2. 3H - 1,4-Benzodiazepines
445
64
43
(25)
I
NaRH,
Ph 66 65
Selective reductions of the 1,2-iminewere carried out by using borohydride in ethanol both for the 2-methyl-3H-l,4-benzodiazepines58,'- 1 4 * 1 7 and for oximes of structure 43. Thus compounds 43 [(R, = H),I9 (R, = COOt-Bu, CONMe,, 2-~yridyl),'~(R, = NR4R5),z39z4(R, = MeS)24e] and the corresponding oxime 0-methyl ethers [(R, = m~rpholino)'~and (R, = Me0)z4e] were reduced to the corresponding 1,2-dihydro derivatives 65. Under the same conditions the nitroximes 43 (R, = NOz) and the corresponding 0-methyl ethers underwent initial displacement of the nitro group by hydride followed by a reduction of the 1,2-imine to yield 65 (R, = H) and the corresponding 0-methyl derivative, re~pectively.'~ Reduction of the 3-acetoxy compound 61 (R = Ac) with sodium borohydride 66 of undeterin methanol yielded the 3-methoxy-2,3-dihydrobenzodiazepine stereochemistry.'z~'3~'7 mined The benzodiazepine 67 reacted with a variety of nucleophiles to give the 2-substituted dihydro compounds 32 (Eq. 26). Thus, there exist reports of addition of water,z9 methanol,7*'' hydrogen ~yanide,~.' isopropylamine,' diethylamine,' aniline,' piperidine,6T' 2-mer~aptoethanol,~*~~*~ and benzylthiol.' ' Addition of hydrogen sulfide yielded the 2,Sbridged sulfide 68,7-30 and mercaptoacetic acid formed the cycloaddition products 697*30and 70.7 The cyano group in 10 was readily displaced by other n~cleophiles.~ Refluxing in methanol led to the 2-methoxy derivative 33 (R = MeO), while reaction Condensation with pyrrolidine at room temperature gave 33 (R = pyrr~lidino).~ with acetylhydrazine in boiling butanol led to the triazolobenzodiazepine 71 in 60% yield (Eq. 27).7,32
'
'
'9,
446
1,4-Benzodiazepines
H
R
CI
R-
CI
*
CI
Ph
Ph
10
33
I
NH,NHAc
c1 Ph 71
Treatment of the acetaminomalonyl derivatives 51 (R = 2-C1C6H,, 2-FC6H,; X = C1) with sodium ethoxide in ethanol yielded the decarboxylated compounds 72 (X = C1, F) (Eq. 28).” COOEt COOEt
(28)
X 51
72
2. 3H-1,4-Benzodiazepines
447
Refluxing ethanolic hydrogen chloride converted the 3H-benzodiazepine 67 to the 3-aminoquinoline 73.29A similar ring contraction was observed with the 2-substituted compound 53, which led to the pyrroloquinoline 75.27 The aziridine 74 was postulated as an intermediate in this ring contraction (Eq. 29).
HCI/EtOH
c1
c1 I
/”
Ph
[clq]
67
Ph
73
,NH
-
74
HO
/
Y
Me
\ 0
Ph 53
15
2.2. 2-Amino-substituted 3H-1,4-Benzodiazepines 2.2.1. Synthesis 2.2.1.1. Synthesis by Ring Expansion Following Sternbach’s pioneering discovery of chlordiazepoxide (79) by the (76) with reaction of 6-chloro-2-chloromethyl-5-phenylquinazoline-3-oxide r n e t h ~ l a m i n e ,this ~ ~ approach to the synthesis of 2-amino-1,4-benzodiazepines was applied for the preparation of a great variety of compounds. The initial step of the ring enlargement is now thought to involve the addition of the nucleophile (e.g., methylamine) at the electrophilic 2-position of the quinazoline 3-oxide to form the intermediate adduct 77. Cleavage of the 2,3-bond as indicated would then lead to the oxime anion 78, which is set up for an intramolecular alkylation on nitrogen to give nitrone 79 (Eq.30).
448
l,4-Benzodiazepines
Ph
Ph
78
' 0
79
It has been shown that the reaction of a quinazoline 3-oxide of general structure 80 with a nucleophile may lead to either the ring expansion product 81 or the displacement product 82 (Eq. 31). The course of the reaction, hence the structure of the product, depend on both the nucleophile and the substituents on the quinazoline 3-oxide. Thus, electron-withdrawing substituents attached at the 6-position of the quinazoline 3-oxide enhance the ring enlargement reaction by rendering the 2-position more electrophilic. An electron-releasing group such as methyl at the 6- or 8-positions made the displacement reaction more cornpetiti~e.~~~~~
81
HNR,R,
Rl
Successful ring expansions were carried out with ammonia and a large variety of primary aliphatic amines. The quinazoline 3-oxides used were most typically substituted by X = C1, Br, R, = H, Me, Et, and R, = Ph33-46 or substituted ~ycloalkyl,~~ benzo~ycloheptyl,~~ 2-thienyl;' ph,34,41,44,46-51 R = H," Me,53954 2 - p y r i d ~ 1pentade~terophenyl.~~ ,~~ The substituent R3 on the benzene moiety of
2. 3H-1,4-Benzodiazepines
449
80 was chosen from h a l ~ g e n , nitro,,* ~ ~ . ~ ~cyano, c a r b ~ m e t h o x y ,trifluoro~~ methy1,36,39,42 methylthi~,~' and others. Although the leaving group X employed has been mostly chloride or bromide, the methanesulfonyloxy moiety was reported to be equivalent in this ring expansion reaction.59 Mixtures of products resulting from both ring expansion and displacement of chloride were observed when 80 (X = C1) was treated with other primary amines such as all~lamine,,~ 2-metho~yethylamine,~~ 2-ethan0lamine,~' pr0pargylamine,4~2,2-dimethoxyethylamine,,, and with secondary amines such as dimethylamine6' and pyrrolidine.60-62 Treatment with piperazine was reported to give only the corresponding displacement p r ~ d u c t . ~ ' Guanidine converted 80 (R, = H, R, = Ph, R, = 6-C1, X = C1) to the corresponding benzodiazepine 81 [R, = H, R, = C(NH)NH,].,l A similar ring expansion with hydrazine was reported6, to lead to 2-hydrazinobenzodiazepines, but these structures were later found to be incorrect. Chlordiazepoxide 79 was also obtained by treatment of the 1,2-dihydro-2dichloromethylquinazoline 3-oxide 83 with methylamine.'7*64 It is likely that elimination of hydrogen chloride from 83 generated the 2-chloromethylquinazoline 3-oxide 76, which would then have undergone the usual ring expansion in situ (Eq. 32).
83
84
19
85
The 2-dichloromethylquinazolines 84 (X = C1, NO,, CF,) were reported to react with a variety of primary amines to give the 3-aminobenzodiazepines 85.65 The structures of compounds 85 were not verified. 2.2.1.2. Synthesis from 2-Thio Compounds Many 2-amino-3H-1,4-benzodiazepines 88 were prepared by reaction of the 2-thiones 86 or the 2-methylthio compounds 87 with amines. This procedure was extensively utilized for the general synthesis of amidines (Eq. 33).
450
1,4-Benzodiazepines
R2
86 1
RZ 88
R2
87
The following amines were successfully employed in this reaction: ammonia,66-70 a l k y l a m i n e ~ , ~dialkylamine~,~ ~-~~ pyrr~lidine~ , ~i ~p e r i d i n e , ~ ' . ~ ~ 2-diethylamin0ethylamine,~'?~~~ 2-morpholin~ethylarnine,~~~~~~ 2-methoxyethylamine, p r ~ p a r g y l a m i n e , ~3-metho~ypropylamine,~~ ~.~~ 2,2-dimethoxyl-amino-4e t h ~ l a r n i n e , ~g~l y- ~ ~i n e , ~ ~l-amin0-4-piperidino-2-butyne,~~ -*~ These hydro~y-2-butyne,'~" and 2-substituted 2-aminomethyl-1,3-dioxolanes.82 transformations were generally carried out with 86 or 87 (R, = H, Me; R, = Ph, substituted Ph, or 2 - p ~ r i d y 1 R, ; ~ ~= H, halogen, or nitro). 2.2.1.3. Other Syntheses 2-Amino-3H- 1,4-benzodiazepines 88 and their 4-oxides were prepared in good yields by amine exchange under acid catalysis in boiling ethanole3 or in dimethyl s u l f o ~ i d e . This ~~*~ displacement ~ of ammonia with other amines appears to be quite general and was carried out with a variety of primary 2,2-dimetho~yethylarnine,~~ and a m i n e ~ ' ~including ,~~ pr~pargylamine,~ ~ l-amin0-4-diethylamino-2-butyne.~~ The reaction of the lactams 89 with titanium tetrachloride and ammonia or a primary or secondary amine provided another general access to compounds 88 including their 4-0xides.'~ According to the more recent patent literature, this method was applied to prepare 2-(l-imidazolyl)-3H-1,4-benzodiazepines.'6 Conversion of the lactams 89 to phosphorylimidates 90 by reaction of the lactam anion with a phosphoryl halide followed by displacement of the phosphate by ammonia or an amine was an alternate approach to compounds 88 (Eq. 34). The crystalline dimorpholinochlorophosphate (R6= morpholino) received particular attention because it led to crystalline phosphorimidates 90 (R, = m o r p h ~ l i n o )q6-88 . ~ ~ The compounds 90 do not have to be isolated but can be further reacted in situ, as demonstrated by the conversion of the lactam 89 (R, = H, R, = Ph, R, = C1) to the 2-methylaminobenzodiazepine by means of diphenylchlorophosphate (Rs = PhO)e7 or diethylchlorophosphate (R, = EtO)?" More recently the cyclic chlorophosphate [(R,J2 = OCH,CH,O]
2. 3€€-1,4-Benzodiazepines
Rz 89
90
45 1
R2 /
f
88
91
was successfully applied for the preparation of various compounds 88." Compounds 90 (R, = AcO) were treated with secondary amines to yield 88 (R, = AcO), hydrolysis of which led to the corresponding 3-hydroxy derivatives." Benzodiazepines with other leaving groups in the 2-position were transformed to 2-aminobenzodiazepines. Thus the 2-chloro compound 91 (X = C1, R, = MeO, R, = 2-C1C6H4,R, = C1) reacted with ammonia to give the corresponding 2-amino d e r i ~ a t i v e .A~ ~2-(1-imidazolyl) derivative was synthesized by reaction of 91 (X, R, = C1; R, = H; R, = 2-ClC,H4) with imidazole in boiling tetrahydrofuran.86 Again, isolation of the 2-chloro compound, the synthesis of which is discussed in Section 2.6.1, is optional. Chlorides generated in situ were reacted with anilines to prepare 2-(phenylamino) derivatives." 2-Cyan0-~ and 2-alkoxyben~odiazepines~~ 91 (X = CN or MeO) underwent similar nucleophilic displacements with amines. The nitrosomethylamino group in 91 [X = N(NO)Me] was also described to be a suitable leaving group for the preparation of 2-arninoben~odiazepines.~~ Reaction of a 2-phosphonate 91 [X = PO(OEt),, R , = MeO, R, = 2-ClC6H,, R, = Cl] with ammonia at 50°C for 6 hours was reported to give a 75% yield of the corresponding 2-aminoben~odiazepine.~~ A direct conversion of the lactam 89 (R,= H, R, = Ph, R, = C1) to the 2-pyrrolidinobenzodiazepineby heating with pyrrolidine in boiling toluene in the presence of p-toluenesulfonic acid was described in a patent.85a While the successive treatment with phosphorus oxychloride and an amine was rarely applied7' to the benzodiazepin-2-ones, this procedure was used to prepare the 5-aminobenzodiazepines 95 from the 5-one 92." The 5-chloro compound 94 was isolated and characterized. Reaction of this chloroimine with phenylmagnesium bromide led to the 5-phenyl-3H-1,Cbenzodiazepine 96 (Eq. 35).93
452
c1 0 92 POCI,
I
1""H2 c1
I
N R< "R2
94
95
PhMBBr
i
c1
~
Ph 96
H-
c1q
q
H
2
RoPh 91
The 2,5-diamino derivative 95 (R, = H, R, = Me) was prepared by reaction Compound 93 resulted from the of the 5-phosphate 93 with methylamine.87a9b phosphorylation of 92 with sodium hydride and dimorpholinophosphinic chloride in t e t r a h y d r o f ~ r a n . ~ ~ ~ The benzodiazepine 96 was formed in 45-70% yields by short heating of the quinazoline derivatives 97 (R = H, Me, Et) with acetic acid.94 This rearrangement involves cleavage of the six-membered ring and recyclization to the sevenmembered ring. 2-Amino derivatives 100 were synthesized in good yields by cyclization of the cyanomethylimines 99 with hydroxide or with hydrogen chloride in methanol (Eq. 36).95*96The required nitriles 99 were accessible by acid-catalyzed amine exchange from the 2-hydroxyethylimines 98. A process for the preparation of chlordiazepoxide 79 made use of the addition of phenylmagnesium bromide to the nitrone 101 (Eq. 37).52 The resulting hydroxyamine 102 was then oxidized with ferricyanide to yield 74% of the desired product.97 Mercuric oxide also effected this t r a n ~ f o r m a t i o n . ~ ~ Chlordiazepoxide was formed also by thermal- or acid-catalyzed rearrangement of its photoproduct, the oxaziridine 103.98Dehydration of 102 by treat-
2. 3H-1,4-Benzodiazepines
453
ment with thionyl chloride in boiling chloroform led to the imine, 4-desoxychlordiazepoxide.
19
103
2.2.2. Reactions 2.2.2.1. Reactions with Electrophiles A. Oxidation. The 2-aminobenzodiazepines 104 were oxidized with mchloroperbenzoic acid to give the 1-oxides 10599or the 1,Cdioxide 106 (R, = H, R, = C1) (Eq. 38).loo Peracetic acid converted the acetylderivative 107 to the corresponding 4-oxide. l o l
454
104
105
0
4c
J3yOH2
c1<JNMe Ph 107
Oxidation of the 2-amidino compounds 108 with hypochlorite or with lead tetraacetate afforded the triazolobenzodiazepines 109 (Eq. 39).'O29'O3
(39)
x Ph 108
Ph 109
B. Reactions with Nitrogen Electrophiles. Nitrosation of the 2-methylaminoor with benzodiazepines 110 with sodium nitrite in glacial acetic nitrosylchloride in pyridine" gave the N-nitroso compounds 111 (Eq. 40). Treatment of chlordiazepoxide 110 (R, = Ph, R, = C1,4-oxide) with sodium nitrite in 3N-hydrochloric acid led in high yield to the quinazoline-2carboxaldoxime 113.94The same compound was obtained in 95% yield by action of 3N-hydrochloric acid on the nitrosoamidine 111 (R, = Ph; R, = C1, 4-oxide). The formation of 113 may be rationalized by a reversible hydrolytic cleavage of the nitrone followed by ring closure to the intermediate 112, which then undergoes irreversible oxidation to the oxime, possibly via an N-nitroso hydr~xyamine.~~
2. 3H- 1,4-Benzodiazepines
455
Me I
NHMe NaNOJ AcOH or NOCI/C,H,N
*
n
110
111
I
NaNOJ3N HCI R, = Ph, R2 = CI
(40)
3N HCI
H
1
N\yNHoH1 I NY=NoH
]
[cl&N\MeHo Ph
NaNO,
- c l q N \ Ho ~ Ph e 113
112
C. Reactions with Carbon Electrophiles C.l. Alkylation. Chlordiazepoxide 79 was alkylated at the nitrogen attached to the 2-position by sodium hydride in dimethylformamide and the following alkyl halides: methyl iodide,Io4 benzyl chloride,lo5 ally1 brornide,'O5 and methoxymethyl chlorideIo5 to give the appropriate product 114 (Eq. 41). Similar alkylations were more recently reported by Matsuo and coworker^'^ on the amidine 110 (R, = 2-C1C,H4, R, = Cl). Michael addition of acrylonitrile and ethyl acrylate to chlordiazepoxide yielded compounds 114 with R = CH,CH,CN and R = CH,CH2COOEt, respectively. R
Jy=+ NMe
NaH/DMF
c1
-N Ph 79
RX
0
c1
(41)
Ph ' 0 114
Attempted further methylation of 115 on carbon by the anion of dimethyl sulfoxide and dimethyl sulfate led to ring contraction with formation of five products 116, 117, and 118 in the amounts indicated (Eq. 42).'04 Mechanisms accounting for these rearranged products were proposed. lo4 The initial step was assumed to be abstraction of a proton from the 3-position followed by a transannular attack of the tautomeric 5-carbanion onto the 2-position to give the intermediate 119. Opening of the four-membered ring as indicated would lead to the oxime 120, which can suffer elimination of dimethylamine to give 121. The conversion of 121 to 122 involves a reduction, possibly by the anion of dimethyl sulfoxide used as a solvent. Methylation of 122 may then
456
116 R = CN (19%) R = CH=NOMe (25 %)
Ph ‘0 115
mhMe2 WNMe +
c1
117 R=CN(11%) R = CH=NOMe (8 %)
c1
(42)
Ph
118 (4 %)
give 116 (R = CH=NOMe) while the nitrile 116 (R = CN) may arise from loss of water from 122 or loss of methanol from the oxime methyl ether. The formation of compounds 117 from intermediate 120 was explained by the indicated migration of the aldoxime moiety from the 2-position to the 3-position of the indole. The quinoline 118 was thought to result from elimination of HNO from an intermediate dihydroquinoline 124, being formed by protonation of the postulated intermediate 123, which would arise from 120 by the indicated mechanism. It is possible that the anion of dimethyl sulfoxide may be involved in the formation of 118.
115
‘i”
/ 121
i H
117
122
i
116
2. 3H-1,4-Benzodiazepines
451
123
120
*
118
Ph 124
(44)
1 120
[c,QFq
c
118
Ph 126
For example, intermediate 120 (R = CN, CH=NOMe) may be attacked by the dimethyl sulfoxide anion to give the 3H-indole 125, which could undergo ring expansion as indicated to the dihydroquinoline 126. Elimination of HSOMe instead of H N O would then account for the formation of 118. Alkylations of 127 were carried out selectively on the phenolic group with 1-benzyloxycarbonylamino-3-bromopropaneand with 2-bromoacetic and acid methyl ester to give 128 with R = (CH,),NHCOOCH,Ph R = CH,COOMe, respectively (Eq. 45).49 Cleavage of the carbobenzoxy group NHMe
NHMe
CI
(45)
___t
NaH/DMF
OH 127
bR 128
458
l,4-Benzodiazepines
led to the corresponding amine 128 [R = (CH,),NH,]. The methyl ester was converted to the hydrazide 128 (R = CH,CONHNH,) by reaction with hydra~ine.~~ Treatment of the 2-chloroethyl ureas 129 with sodium hydride in tetrahydrofuran caused an intramolecular alkylation yielding the imidazolidinones 130 (R = H; X = H, C1) (Eq. 46).67 Compound 130 (R = H, X = H) was then methylated on nitrogen using methyl iodide and ethoxythallium in dimethylformamide to give 130 (R = Me, X = H).67
129
130
C.2. Reactions with Aldehydes, Ketones, and Equivalents. According to the patent literature,' O6 chlordiazepoxide hydrochloride 79 formed addition products with acetaldehyde, propionaldehyde, butyraldehyde, and furan-2carboxaldehyde to which structures 131 were assigned (Eq. 47). The aminoacetal 132 was obtained in about 10% yield by treatment of 131 (R = 2-furyl) with methanolic sodium hydroxide. lo6' The structures 133 assigned to the products formed by treatment of 131 (R = Et, Pr) with hydroxide'06a*bare most likely incorrect. Me
c1
c1
Ph 0 ' 79
131
(47)
IOH
4
J$--yp Me
I
Ph
b
132
c1
Ph 133
0
2. 3H-1,4-Benzodiazepines
459
Intramolecular condensations with aldehydes and ketones were applied for the synthesis of imidazo[1,2-a] [1,4]benzodiazepines. Thus, treatment of the or with concentrated sulfuric acetals or ketals 134 with Lewis acid 74-76,8 2 yielded the imidazobenzodiazepines 135 (R, = H). This ring system was also formed by reaction of the acetylenes 136 with concentrated sulfuric aCid74-76,8 2 or with p-toluenesulfonic acid in boiling butan01.~’
XC
?
N--N H 1 R3
134 / I
X
R3
GN IH
c1
136
137
Cyclodehydration of 137 (R, = phthalimidomethyl; X = H, C1) with concentrated sulfuric acid gave 135 (R, = phthalimidomethyl, R, = H, R, = phenyl or 2-C1C,H4, X = C1).82 The condensation of 52 with a-bromoketones provided still another access to compounds 135 (R, = Ph,
x = c1).107
The product resulting from the reaction of 52 with bromoacetone was 135 (R, = H, R, = Me, R, = Ph, X = C1) (Eq. 49). This means that the 2-amino group of 52 attacked the carbonyl carbon of the bromoketone to form an intermediate imine 138 (R, = Me, R, = H), which would convert to 135 by formal elimination of hydrogen bromide via an intramolecular alkylation on the 1-position nitrogen and subsequent tautomerization. Condensation of 52 with 3-bromo-2-butanone (R, = R, = Me) and with 3-bromo-2-pentanone (R, = Me, R, = Et) led to the expected 1,Zdisubstituted imidazo[1,2a] [1,4]benzodiazepines, although the 2-ethyl- and the 2-propyl-substituted compounds were interestingly formed as the major products in these condensations. The enamine 139 was proposed as an intermediate. The indicated Michael-type cyclization would violate Baldwin’s rule for ring closure. The
460
1,4-Benzodiazepines
cyclopropanone imine 140 may be an alternate possible intermediate (Eq. 49).
KTN
c1 Ph
/
52
-N Ph 138
R,=W
21
Ph
(49)
140
-
+ 135
c1 Ph 141
Reaction of the 2-aminobenzodiazepine 52 with ethoxymethylenemalonic acid diethyl ester afforded 142, which was cyclized thermally to the pyrimidobenzodiazepine 143 (Eq. 50).lo' COOEt EtOOCA
I
Ph I42
c1 fih 143
2. 3H-1,4-Benzodiazepines
461
An interesting transformation was observed during the reaction of the 1-oxides 105 with acetylene dicarboxylate in methanol at room temperature (Eq. 51). The products 146 were obtained in good yields and were converted to compounds 147 by heating in ethanol. A plausible mechanism for this transformation is a 3,3-sigmatropic rearrangement of the intermediate adduct 144 leading to 145. The latter would then aromatize and enolize to the product 146 by proton shift.
C.3. Acylation. The 2-aminobenzodiazepines 148 (R, = H, Me) were acetylated with acetic anhydride in pyridine or with acetyl chloride in pyridine at room With the temperature to the acetyl derivatives 149 (R, = Me).33’34,48*51,110
462
1,4-Benzodiazepines
4-oxides 148, the rearrangement of the nitrone to the 3-acetoxy derivative 151 (R, = Me) occurs to a minor extent under these conditions. This "Polonovski type" of rearrangement becomes prevalent under more vigorous conditions. 'O9 The same observations were made for the reaction of chlordiazepoxide with propionic anhydride or butyryl chloride in pyridine."' Short heating of chlordiazepoxide in acetic anhydride at 100°C' " or reaction with acyl halides in dimethylformamide' or tetrahydrofuran at reflux' caused "Polonovski" rearrangement of the nitrone without acylation of the methylamino group, thus giving 150 (Eq. 52). Treatment of the 4-oxide 148 (R, = H, X = H, Y = 7-C1) with acetic anhydride yielded in addition to the diacetate 151 (R, = H, R, = Me, X = H, Y = 7-C1) the oxazolobenzodiazepine 152 and, unexpectedly, the 3-one 153."' The same diacetate 151 was also obtained by acetylation of the 2-amino-3-hydroxy-3H-1,4-benzodiazepine with acetic anhydride.' " Compound 152 results from cyclization of the appropriate diacetate 151 with acetylation on the 1-position nitrogen.'"
''
IR,CO1201C,H,N or R,COCl/C,H,N
*
148
I
149
R,COCI, DMF I
NHMe
c1
NCORZ Y K 5 -N C O R 2
I
Ph 150
xb
/
151
Ac
J$-$xMe
c1
Ph 152
q?
c1
Ph 153
(52)
2. 3H-1,4-Benzodiazepines
463
The formation of the 3-one 153 involves an oxidation. Bell and coworkers suggested no mechanism.' l 1 It is possible that 153 is formed by an oxygen-tocarbon migration of the acetyl cation in the tautomer 154 to give intermediate 155, which would convert to 153 by elimination of acetaldehyde (Eq. 53). Compound 153 was obtained in 37% yield by heating the 1-oxide 105 (R, = H, R, = C1) with acetic anhydride at 100°C for 3.5 hours.99 While acetylation of 148 (R, = H, R, = 2-methylimidazolyl,X = H, Y = 7-C1) with acetic anhydride at 95°C for a few minutes led to the N-acetyl derivative 149, longer heating in acetic anhydride gave 38% yield of 153.99 H
H Ac
NHAc
c1
154
153
(53)
155
Acylation of the 2-aminobenzodiazepines 148 (R, = H) with diketene at room temperature gave high yields of the acetoacetates lS6.113-"s These compounds were cyclized with dehydration to the pyrimidobenzodiazepines 157
X
dP9 \
156
157
t
Ph 158
(54)
464
1,4-Benzodiazepines
by heating or in higher yields by treatment with methanolic hydrogen chloride at 0°C (Eq. 54).'13 The ring system 157 was also synthesized by condensation of the 2-aminobenzodiazepine 52 with acetylenic carboxylic acids or esters. Thus, reaction of 52 with acetylene carboxylic acid methyl ester or with acetylene dicarboxylic acid dimethyl ester in boiling methanol gave the pyrimidobenzoThe compound 157 diazepines 157 (R = H and R = COOMe, (R = Me, X = H, Y = 9-C1) was obtained by condensation of 52 with 2butynoic acid and carbonyldiimidazole in dimethylformamide."6 The formation of compounds 157 by this process implies that the intermediate acyl derivatives 158 are the primary products and undergo the indicated cyclization. Reaction of the 2-aminobenzodiazepines with isocyanates or isothiocyanates led to a variety of ureas 159 (X = 0)and thioureas (X = S) (Eq. 55). The reagents employed were methy1,66*117ethyl,"7 cyclopropyl,66 2 - ~ h l o r o e t h y l , (ethoxy~~,~~ carbonyl)methyl,66 ethoxycarbonyl,6691'8acety1,66 phenyl,'17 and 4-chlorophenyl"7 isocyanate, and methyl isothiocyanate."7
159
160
The urea 159 (R, = COOEt) was cyclized to the triazinobenzodiazepine 160 in 40% yield by heating in xylene.66g118If R, in the starting 2-aminobenzodiazepine was an amino group, the reaction with methyl isocyanate led to acylation of both amino groups.70 The reaction of chlordiazepoxide with methyl isocyanate was more complex because of the participation of the nitrone in the reaction. Thus, treatment of chlordiazepoxide with methyl isocyanate in tetrahydrofuran yielded 8.5% of 161 (R = H) and 60% of the urea 161 (R = CONHMe) (Eq. 56).'19 This major product was found to be unstable: it converted to the imidazobenzodiazepine 164 upon long storage at room temperature. Compound 164 was prepared in 27% yield by reacting chlordiazepoxide with methyl isocyanate in tetrahydrofuran in the presence of triethylamine. Under these conditions the urea 162 was formed in 11YOyield. The conversion of 161 (R = CONHMe) to 164 with loss of methylamine and carbon dioxide was formulated to proceed via the intermediate 163.
465
2. 3 H- 1,4-Benzodiazepines
I
c1 Ph ' 0 162
I64 163
Reaction of the 2-aminobenzodiazepines 165 with oxalyl chloride and pyndine in tetrahydrofuran at low temperature afforded the imidazoc 1,2-a][1,4]benzodiazepines 166 (Eq. 57).68s69A 61% yield was obtained when R, represented This reaction was also carried out with oxalyl chloride in boiling benzene'" for 165 (R, = Me, X = H). When chlordiazepoxide was
c1K 3 -NN H
@ I65
(57)
I66
0
I
Ph 167
Ph 168
1,CBenzodiazepines
466
subjected to these conditions, the nitrone underwent Polonovski-type rearrangement to give the chloro compound 166 (R, = Me, R, = C1) in nearly 80% yield. The bridged derivative 168 was formed as a by-product of this reaction. It was isolated in 8% yield and its structure was determined by X-ray analysis.’20 Compound 168 was formed in higher yield by treatment of the 3-acetoxy derivative 167 with oxalyl chloride in boiling benzene. Compound 166 (R, = Me, R, = OAc, X = H) was isolated as a minor by-product of this reaction.’ 2o The amino alcohols 169 (R, = H, Me; R, = OH) as well as chlordiazepoxide reacted with oxalic ester chloride in boiling benzene to give the oxazolobenzodiazepine 170 (Eq. 58).”O In the case of chlordiazepoxide and 169 (R, = Me, R, = OH), this conversion involves a demethylation. FOOEt COCI
c1 Ph
Ph
169
170
COCI,
(58)
Me
c1
c1 Ph
Ph
171
172
Phosgene reacted with 169 (R, = Me, R, = OH) to yield more than 70% of the oxazolone 171.lZ0The corresponding 3-acetoxy compound 169 (R, = Me, R, = OAc) formed the chlorocarbonyl derivative instead.”Ob The same reagent converted the ethanolamine 169 (R,= CH,CH,OH, R, = H) to 172.7b The reaction of chlordiazepoxide 79 with ethyl chloroformate in dimethylformamide in the presence of sodium hydride yielded 50% of the urethane 173.”’ The indolenine 174 was isolated as a by-product in 5% yield and its structure was determined by X-ray crystallographic analysis.”’ Its formation was rationalized by the mechanism indicated in Eq. 59, which follows the mechanisms proposed earlier for the rearrangements observed during alkylation of chlordiazepoxide with dimethyl sulfate in dimethyl sulfoxide and base.lo4 Boiling acetic anhydride converted 173 to the oxazolone 171 via the 3-acetoxy compound.
’
2. 3H- 1,4-Benzodiazepines
c1W Ph 0 '
467
d
C
N Ph
174
173
Me N-COOEt
(59)
Ph
/
177
176
178
Acq ..ition of the 2-amina,~nzodiazepines with dimethylmalonyl c,,.xide was studied by Moffett.'22 Compound 165 (R, = H, X = H, Y = C1) was thus transformed into the tricyclic compound 179 (Eq. 60). Under more vigorous conditions, 179 underwent further acylation with dimethylmalonyl chloride and led to the dimer 181b.Reaction of the 2-methylamino analog 165 (R, = Me, X = H, Y = C1) with this reagent cleanly gave 181a in 80% yield.'22 Intramolecular acylation of 165 (R, = CH,COOH) by means of dicyclohexylcarbodiimide led to the imidazobenzodiazepines 180.78-80 A 5-oxide of 180 (X = H, Y = C1) was obtained in 10% yield by heating the 4-oxide of 165 (R, = CH,COOEt; X = H, Y = C1) in refluxing acetic acid in the presence of sodium acetate." Triethyl orthoacetate or propionate at 150°C reacted with 2-aminobenzodiazepine hydrochloride^'^^ to give the imidates 182, which afforded the amidines 183 upon further treatment with ammonia in methanol (Eq. 61).102*103 The tricyclic compound 184 was formed in 25% yield by reacting the 2-aminobenzodiazepine 138 with formamide and phosphoryl chloride at 110oc.123
468
1,4-Benzodiazepines
X = H
c1 Ph 179 165
J Y 181 180
Ph
I83
(60)
469
2. 3H-1,4-Benzodiazepines
2.2.2.2. Reactions with Nucleophiles A. Reduction. The reduction of the 4-oxides to the corresponding imines was generally carried out with phosphorus trichloride in a chlorinated hydrocarbon solvent.33,34,40,41 ,5 1,60The same reagent was also used for the reduction of the 1-0xide.~ Raney ~ or palladium on carbon and hydrogen41 also converted 4-oxides to the 4-desoxy compounds. Hydrogenation of the nitrones 185 (R = H, Me) or the 4-desoxy compound (R = H) over platinum led to the 4,Sdihydro derivatives 186 (Eq. 62).33,60Using palladium as catalyst the hydrogenation of chlordiazepoxide 185 (R = H)gave in 70% yield the 7-deschloro derivative of 186 (R = H).33 Lithium aluminum hydride in tetrahydrofuran reduced chlordiazepoxide to the hydroxylamine 102.33
P
qTN'Me
PIlH,
c1
Ph
'.o
c1
Ph 186
102
187
The same reagent converted the nitrosoamidine 185 (R = NO)in 80% yield to the tetrahydro derivative 187.92The nitrosoamidine apparently suffered displacement by hydride to give the intermediate l,Zimine, which then reduced to 187. Reduction of the 3-one 153 with lithium aluminum hydride gave about 5 5 % of the deacetylated alcohol 188 (Eq. 63)."' NHAc LIAIH,
c1
c1 Ph 153
Ph 188
7-Nitro compounds were reduced to the 7-amino analogs by means of stannous chloride in hydrochloric acid.'O
410
1,4-Benzodiazepines
B. Reactions with Oxygen Nucleophiles. Acid salts of 2-aminobenzodiazepines 189 (R, = R, = R, = H; X = C1, NO,) were converted to the corresponding 2-ones 190 by boiling in methanol (Eq. 64).95If this hydrolysis was carried out with deuterium chloride in deuterium oxideAeuteromethano1, the lactam obtained contained 87% of deuterium in the 3-po~ition."~Exchange of the protons in the 3-position of 2-amino-7-chloro-5-phenyl-3H-1,4-benzodiazepine by deuterium was achieved by heating with sodium deuteromethoxide in deuterated methanol.' 24 Acid hydrolysis of the acetyl derivatives 189 (R, = Me, R, = Ac, R, = H) or their 4-oxides also gave the appropriate lactams lW.513125Methylacetamide was isolated in this case, indicating cleavage of the bond between C-2 and N after attack of hydroxide at the 2-po~ition."~This type of hydrolysis converted the diacetate 189 (R, = Me, R, = Ac, R, = OAc, X = C1) to the 3-acetoxy lactam 190 (R, = OAc, X = Cl). This transformation was carried out with either ethanolic hydrogen chloride' or with 1 N hydrochloric acid in dioxane."' Alkaline hydrolysis of the same diacetate with one equivalent of hydroxide at room temperature gave 34% yield of the monoacetate 189 (R, = Me, R, = H, R, = OAc, X = C1) by preferential cleavage of the N-acetyl group."' Further hydrolysis with 1 N sodium hydroxide led in high yield to the 2-methylamino-3h ydroxybenzodiazepine. O Cleavage of the N-acetyl group with formation of chlordiazepoxide from its N-acetyl derivative was observed during chromatography over basic alumina."' Treatment of the 3-acetoxy compound 189 (R, = H, R, = Me, R, = OAc, X = C1) with 1 N hydrochloric acid at 85°C or of the corresponding 3-hydroxy derivative at room temperature gave the quinazoline-2carboxyaldehyde 192.'l o This aldehyde and 2-amino-5-chlorobenzophenone
'
'
B 1
H,O+
X
Ph 189
I
Ph 190
H,O*. R,=ORorirnidazole x = CI
Ph 191
(64)
Ph 192
471
2. 3H-l,4-Benzodiazepines
were isolated also from the acid hydrolysis of the 3-imidazolyl compound 189 (R, = R, = H, R, = 2-methylimidazolyl, X = Cl).99The hemiacetal of 192 was obtained in 86% yield from the reaction of the 3-hydroxy compound with ethanolic hydrogen chloride at room temperature.' lo The formation of the quinazoline-2-carboxaldehydeby these reactions may be the result of hydrolytic cleavage of the 3,4-bond to give 191 and subsequent recyclization and elimination of the 2-amino function.
H
qq
c1
-N
____)
c1G
y
Ph
C
O
R
(65)
Ph
153
193
The 3-one 153 suffered similar ring contractions. Thus the ethyl ester = EtO) was formed during the reaction of 153 with ethanolic hydrogen chloride (Eq. 65)' Acetic acid converted 153 to the N-acetylcarboxamide 193 (R = NHAc), while reaction of 153 with hydroxide afforded the carboxylic acid 193 (R = OH).' These rearrangements are again initiated by fission of the 3,4-bond in 153,which is a reactive acylimine in this case. Treatment of the nitrosoamidine 194 with 1 N hydrochloric acid in tetrahydrofuran yielded 32% of the lactam 195,32% of chlordiazepoxide 79,and 14% of the quinazoline 113 (Eq. 66).94The latter was formed in 95% yield by reacting 194 with 3 N hydrochloric acid.94 Hydroxide converted 194 in high yield to the lactam 195 with liberation of d i a ~ o m e t h a n e . ~ ~ . ~ ~ Accordingly, alkoxides reacted smoothly with 194 to form the 2-alkoxybenzodiazepines l%.92
193 (R
'' ''
a>"' . Me
c1
H,O'
Ph
Ph '0 194
lo.
c1
\
113
c1 195
1%
+
79+195
1,4-Benzodiazepines
472
Acid hydrolysis of the 1-oxide 197 led to the benzisoxazole 198 (Eq. 67)." This compound was also formed in about 50% yield by reacting the 4-oxide of 197 with hydrogen sulfide."' Mild treatment of the 4-oxide of 197 with aqueous acetic acid gave 88% yield of the 1-hydroxy compound 199."' 2-Amino-3-acyloxybenzodiazepines150 underwent alcoholysis with ethanol or methanol to form the 3-alkoxy derivative^.^^^^
Q)=9f2- q 0
H,O+
c1
Ph
Cl
9
Ph 198
197
+ c1 Ph ' 0 199
C. Reactions with Nitrogen Nucleophiles. The acid-catalyzed exchange of the 2-amino group by other amines and the displacement of the 2-nitrosomethylamino function by amines was discussed above (Section 2.2.1.3). Various 2-aminobenzodiazepines 200 were claimed to react with acylhydrazines to form the triazolobenzodiazepines 201,126in particular by heating in hexamethyl phosphoric triamide'26c at 16&170"C (Eq. 68). The nitrosoamidine
NH2NHCOR,
HMPA 1M170"C
J
200
I
NH,NHCOMe
202
p, reflux
201
2. 3H-l,4-Benzodiazepines
473
200 (R, = Me; R, = NO; X = C1,4-oxide) reacted with acetylhydrazine t o give initially the hydrazide 202, which cyclized with loss of water to the triazole 201.92 3-Hydroxybenzodiazepines 203 were converted to 3-amino analogs 205 by treatment with thionyl chloride and subsequently reacting the crude chloride with an amine.' More recently, 2,3-diaminobenzodiazepines205 were prepared in good yields by reacting the 3-hydroxy compounds with 2-dialkylamino-4,5dihydro- 1,3-dioxa-2-phosphole 204 (Eq. 69).45
GIN;:
T 1
R1
SOCIz/NHR,R,+
c1
or Q-NR,R.
N-R,
c1
Ph 208
(69)
-N Ph
R,
205
204
Ammonia converted the carbonyl chloride 206 to the urea 207 (Eq. 70).lZob Me
Me
I
c1l:y$:J
NH,
I
.
N H 2cc :1 :$=Q f
Ph
(70) Ph
206
207
Ammonolysis of the imidazobenzodiazepine 208 was accompanied by ring opening and yielded the amide 209 (R = NH,).'Zoa Reaction with ethanol and triethylamine accordingly gave the 3-ethoxy derivative 209 (R = EtO) (Eq. 71).120b 0
Me 0 HR
(71)
c1 Ph 208
0
Ph 209
The reaction of the 1-oxide 105 with carbonyldiimidazole or a phosgeneimidazole combination interestingly yielded the 3-imidazolyl compounds 211.99 The oxadiazolone 210 was postulated as an i n t e m ~ e d i a t eThe . ~ ~ addition of the nucleophile to the 4-position of 210 with expulsion of carbon dioxide would lead to the observed products (Eq. 72).
414
0
R, 105
This reaction was used for the synthesis of a variety of compounds bearing 2-methylimidazole, 2-ethylimidazole, and benzimidazole substituents in the 3-po~ition.~~
D. Reactions with Carbon Nucleophiles. The reaction of the 2-aminobenzodiazepine 52 with 1,3-dicarbonyl compounds at 145-160°C afforded the pyrroloquinolines 212 (R = Me, EtO, t-BuO) (Eq. 73).” Boiling 52 with acetylacetone gave, besides the pyrroloquinoline 75 (Eq. 29), 5% yield of the benzodiazepine 53, which was proposed to be the initial product of the overall con~ersion.’~ For discussion of mechanism see Section 2.1.2.2.
52
212
The nitrosoamidines 111 reacted with stabilized carbanions such as the anions of nitroalkanes,” malonic esters,92 and rnalon~nitrile~’to give the
475
2. 3H-1,4-Benzodiazepines
2-methylene derivatives 213 (R, = NO,; R, = H, Me; R, = R, = COOR,, CN) (Eq. 74). The anion of ethyl isocyanoacetate underwent a similar displacement reaction with nitrosochlordiazepoxide to give the imidazobenzodiazepine 215, most likely via the intermediate isonitrile 214. l Z 7Protonation of 214 on the isonitrile carbon followed by cyclization as indicated would lead to the imidazole 215.
111
213
C=N7-
COOEt
1
I-
214
215
2.2.2.3. Thermal and Photoreactions Heating of the 5-phosphoryl derivative 93 in boiling 1,3,5-trimethylbenzene for 2 hours yielded the 5-one 216, resulting from migration of the phosphoryl group from oxygen to nitrogen (Eq. 75).87b
;X:i""'
c1
-
0,
P=O
93
The photochemistry of chlordiazepoxide was investigated in detail.98*'2 8 - 1 3 0 Irradiation at 350 nm converted the nitrone to the oxaziridine 103, which reverts to chlordiazepoxide thermally or by acid catalysis (Eq. 76).98,128Fu rther
476
1,4-Benzodiazepines
irradiation of the oxaziridine at 300nm led to the photoproducts 217 and 218, which can still suffer further photo rearrangement.lZ8
c1
--N Ph 0
H * or A
c1
79
(76)
+
c1
c1 218
217
2.3. 2-Hydroxyamino-3H-l,4-benzodiazepines
2.3.1. Synthesis The 2-hydroxyamino compounds 220 were prepared by reacting the 2-thiones 219 with hydroxy- or alkoxyamines112g1 3 1 - 1 3 5 or by displacing a suitable leaving group R, in 221 (Eq. 77). Such leaving groups were the
221
222
2. 3H-1,4-Benzodiazepines
477
methylthi~’~’ and the nitrosomethylamino moieties.’’ The products were formulated with either an endo- or exocyclic double bond. The tautomers 222 appear to be more compatible with the spectroscopic data9, than 220 (R, = H).
2.3.2. Reactions Alkylation of the 4-oxide of 223 (R = H) with ethyl bromoacetate and potassium t-butoxide as base led to the 0-alkylated product 224 (R, = CH,COOEt, 4-oxide), which was reduced to 224 (R, = CH,COOEt) by means of phosphorus tri~hloride.~” Addition of vinyl ether to the 4-oxide of 223 (R = H) yielded the acetal 224 [R, = CH(Me)OEt, 4-oxide] (Eq. 78).sa
R
I
I
Ph
Ph 223
\ R
J
R
o
224
= Me, CH,Ph
R I
R=R,=Me
c1 I
Ph
Ph
226
225
Me
Ph 221
Acylations of 2-hydroxyaminobenzodiazepines occurred on oxygen as shown by the conversion of 223 (R = H) to the 0-acetate 225 (R = H, R, = Me) by acetic anhydride in pyridine,I3’ by reaction of 223 (R = Me) with acetyl chloride or benzoyl chloride in the cold,’lZa and by treatment of 223 (R = Me) with isocyanates.’ While the reaction of 223 (R = H) with carbonyldiimidazole yielded 225 (R = H, R, = imidazolyl), the corresponding N-methyl compound 223 (R = Me) was converted to the 3-( 1-imidazolyl)benzodiazepine 227’
478
1,4-Benzodiazepines
under comparable conditions. This transformation involves formally a reduction of the nitrogen and oxidation of the carbon in the 3-position. This type of rearrangement was also observed when 223 (R = Me or CH,Ph) was heated at 100°C with acetic anhydride, leading to 226 (R = Me or CH,Ph, R, = Me, R, = H) in high yields."2" Compound 226 (R = R, = Me, R, = H) was also formed by heating the 0-acetate 225 (R = R, = Me) with acetic acid in dimethylformamide."2" The corresponding propionate 226 (R = Me, R, = Et, R, = H) was similarly obtained by heating 225 (R = R, = Me) with propionic acid. Reaction of 223 (R = Me) with a mixture of formic acid and acetic anhydride at room temperature led to the N-formyl derivative 226 (R = R, = Me, R, = CH0)."2a These experiments indicate that the rearrangement of 223 or 225 to 226 is not intramolecular. The authors' propose the following mechanism: a nitronium ion is generated by cleavage of the N-0 bond, which can then isomerize to a carbonium ion (3-position) and is trapped by the nucleophile. Phosgene in the presence of triethylamine converted 223 (R = H) to the Wh en the same reagents were applied to oxadiazolone 229 (Eq. 79).13,9 134, the N-methyl analog 223 (R = Me), the oxazolone 171 was formed in 20% yield with rearrangement."," Compound 171 was prepared in higher yield by thermal cyclization of the carbonate 226 (R = Me, R, = EtO, R, = H).'''" Treatment of 223 (R = Me) with ethyl chloroformate in tetrahydrofuran resulted in rearrangement with formation of the 3-ethoxy derivative 228.'
''"
223
CICOOEt/THF
R
=
Me
CI
I
Ph
COCI, E1,N
Me
(79)
\
CI 1
c1
I
Ph
Ph 229
171
2.4. 2-Hydrazino-3H-l,4-benzodiazepines 2.4.1. Synthesis The first reported synthesis63 of a 2-hydrazinobenzodiazepine by ring ex3-oxide with hydrapansion of 2-chloromethyl-6-chloro-4-phenylquinazoline
479
2. 3H-1,4-Benzodiazepines
zine was later shown to be in error.'36' Compounds 230 were first prepared ~~. or by exchanging the by reacting the 2-thiones 86 with h y d r a ~ i n e ' 136-141 amino group in 231 with hydrazine in the presence of an acid catalyst (Eq. 80).47913'-140 The latter method was also suitable to prepare the 4-oxides of 230,47,136-140
I
R2
91
23 1
The benzodiazepines 91 with a leaving group X in the 2-position were employed as well for the synthesis of 2-hydrazino compounds. Suitable groups displaced with hydrazine were b e n ~ y l t h i o , 'm ~ ~e t h y l t h i ~ , ' ~ ~ethoxy,14, -'~~ 14,9 144 and dimorpholinophosphoryloxy.87 nitro~omethylamino,~~~ Substituted hydrazines reacted in a similar fashion. Treatment of the thione 86 (R, = H, R, = Ph, R, = C1) with 1,2-dimethylhydrazinegave 232 (R, = Me, ' of the same thione with methR, = Me, R, = H) in 95% ~ i e 1 d . l ~Reaction ylhydrazine led to a mixture of hydrazinobenzodiazepines 232 (R, = Me, R, = R, = H) and (R, = R, = H, R, = Me).'46-'49 The former compound, resulting from the attack of the thione by the more nucleophilic methylated nitrogen, could be crystallized from the mixture. 14' The corresponding 4-oxide was obtained by treatment of N-nitrosochlordiazepoxide with methylhydra~ i n e . ~The , structure was confirmed by conversion to a formaldehyde hydrazone9' and by an X-ray analysis of the acetaldehyde hydrazone of 232 (R, = Me, Me
c1
C1
Ph 232
'
-N Ph
233
134-Benzodiazepines
480
R, = R, = H). Acid-catalyzed displacement of the methylamino group in chlordiazepoxide with methylhydrazine led to the 4-oxide of 232 (R, = R, = H, R, = Me). This compound was not characterized but was directly converted to triazolobenzodiazepines. Acylated hydrazines such as acetylhydrazine or ethoxycarbonylhydrazine 15' N-nitrosochlordiazepoxide,'43~144 underwent reactions with 2-thiones,' and the 2-(dimorpholinophosphoryloxy) derivativex7to give the hydrazides 232 (R, = R, = H, R, = Ac or COOEt) or the corresponding 4-oxides. Since these hydrazides may be cyclodehydrated in situ to triazolobenzodiazepines (see Section 2.4.2, Reactions), they were often not isolated. The acetylhydrazine derivative 232 (R, = H, R, = Me, R, = Ac) was formed by hydrolytic ring opening of the quaternized triazolobenzodiazepine 233 (Eq. 81).'48 509
2.4.2. Reactions 2.4.2.1. Reactions with Electrophiles A. Nitrosation. Nitrosation of the 2-hydrazinobenzodiazepine 232 (R, gave the tetrazolobenzodiazepine 234 in 80% yield.134,1 5 3
= R,
= R, = H)
B. Reactions with Aldehydes and Ketones. The hydrazones 235 resulted from condensation of the appropriate hydrazine with aldehydes or 145* lS4* 1 5 5 If R, and R, in the hydrazones 235 are both hydrogen, these compounds may be in equilibrium with the cyclic form 237. The latter may be removed from the equilibrium by oxidation to the triazole 239 (Eq. 82). Oxidizing agents used to convert 235 to 239 include air,'55 manganese dioxide,' 5 4 and diethyl azodicarboxylate.' 5 4 Reaction of the hydrazine 232 (R, = R, = H, R, = Me) or its 4-oxide with aliphatic aldehydes yielded the dihydrotriazolobenzodiazepines 236146-14x or their 5-0xides,~~ respectively. Compound 236 (R = Me) suffered oxidation and hydrolytic cleavage to the hydrazide 238 in the presence of air and water.'48 Since 238 was also obtained by hydrolysis of the quaternary triazolobenzodiazepine 233, the latter is most likely the intermediate in this conversion. Hydrazones of functionalized aldehydes and ketones were used for the synthesis of other heterofused benzodiazepines as well. Thus the a-chlorohydrazones 240 underwent an intramolecular alkylation to form the triazinobenzodiazepines 241.156,1 5 7 Examples for R, = H,'56 Me,'56 and CH,Cl"' were reported (Eq. 83). Treatment of the dimethylacetal of hydrazones 242 (R, = Me, R, = H) with concentrated sulfuric acid yielded more than 50% of the triazino derivatives 241 (R, = Me, R, = OH).'58 Hydrogen fluoride at - 80°C cyclized the hydrazone of butane-2,3-dione 242 (R, = R, = Me, X = H) to the methylene derivative 243 (R, = Me, X = H, Y = CH,) in 37% yield.lS9 Hydrazones of a-ketoacids were converted to the triazinobenzodiazepines 243 (Y = 0) by treatment with 14'9
CI I
Ph 234
235
14
I /R,
=
Me
c1 I
Ph 236
237
J
oxidation
q > N - N * c CI 1
Ph 238
R, = H
482
1,4-Benzodiazepines
carbonyldiimidazole in boiling tetrahydrofuran or in lower yield by heating in glacial acetic acid.'60 The same compounds were also formed by refluxing the esters 242 (R, = RO) in 1,2,4-trichlorobenzene.'60 Compounds 243 with R, = H, Me, (ethoxycarbonyl)methyl, 2-(ethoxycarbonyl)ethyl, and 3-(diethylamino)propyl were synthesized in this fashion.I6' The reaction of 2-hydrazinobenzodiazepineswith 1,3-dicarbonyl compounds was studied also.'61Pentane-2,Cdione condensed with the hydrazinobenzodiazepine 230 (R, = H, R, = Ph, R, = C1) or its 4-oxide to give the pyrazoline 244, which dehydrated to the pyrazole 245 upon treatment with trifluoroacetic acid.'61 Boiling the 4-oxide of 244 in xylene gave 40% yield of the triazolobenzodiazepine 239 (R, = Me, 5-oxide) beside 19% yield of the pyrazole 245 (4-oxide). Ye
Ph
Ph 245
244
i Me .€!@
a 3
c1
N '
(84)
c1
Ph 246
Ph 239
c
CN -l'
Ph 0 ' 241
248
2. 3H- 1,4-Benzodiazepines
483
The triazolobenzodiazepine 239 (R, = Me) was the exclusive product when 244 was heated to reflux in butanol in the presence of triethylamine overnight (Eq. 84).16' -163 The hydrazone of the cyclohexane-1,3-dione 247 was converted to the triazolobenzodiazepine 239 (R, = 4-oxobutyl, 5-oxide) under similar conditions, although in much lower yield. The spiro compound 248 may be an intermediate in this reaction.161 Methyl acetoacetate formed the hydrazone 249, which partially cyclized to the pyrazolone 250 upon boiling in butanoi-triethylamine. The major product formed was the 2-butoxybenzodiazepine 251 (Eq. 85).16'
H
Me
BuOH/Et,N
Ph '0 249
qXBu
c1
Ph
0
251
Since the pyrazolone 250 did not convert to 251 under the reaction conditions, the latter must have been formed by displacement of the 2-substituent from 249 or of some other intermediate species.
C. Acylation. 2-Hydrazinobenzodiazepines generally acylate at the terminal nitrogen to give 252. Such acylations have been carried out with acid anhydride^,^^^'^^.'^^^ '44*148 acid ~ h l o r i d e s , ~ ~ i- s' ~~ c~y,a' n~a~t e s , 1' ~6 s~ and ~ ' 6 5 Acylations with concomitant ring closure by dehydraisothio~yanates.'~~* tion led to the triazolobenzodiazepines 253.'40.141* 166-' 72 These compounds were also obtained in high yields by reaction of 2-hydrazinobenzodiazepines with orthoesters.47,136,137.139,143,144,172,173 Heating the 2-hydrazinobenzodiazepine with trifluoroacetic acid at 100°C for 2 hours yielded 19% of the 1trifluoromethyltriazolobenzodiazepine 253 (R, = Ph, R, = C1, R3 = CF3).172 Formic acid reacted in a similar fashion to give 253 (R,= Ph, R2 = C1, R, = H). The cyclization4ehydration of the hydrazides 252 (X = 0)to the triazoles 253 was carried out by heating,' 140*,'41 52 by refluxing in butanol,' 34, pyridine,139q140146 or acetic acid 166-17' and by heating with polyphosphoric acid (Eq. 86).140 349
484
1,4-Benzodiazepines
Compounds 252 (X = NH, R, = Ph, R, = C1, R, = Me), which were accessible by reacting the 2-hydrazinobenzodiazepine with acetimidate or acetamidine, were thermally cyclized to the triazolo compound^.'^^ The triazolobenzodiazepine 253 (R, = Ph, R, = C1, R, = H) was also formed by treatment of the 2-hydrazino derivative with formamide and sulfuric acid at l W C , or by heating with formamidine hydrochloride in the presence of 2-methylimidazole at 160°C.140 Heating the carbethoxyhydrazine derivatives 252 (R, = Ph or 2-C1C6H4, R, = C1, R, = EtO, X = 0) at about 200-230°C effected cyclization to the triazolone 254 (X = 0).'34*152,174 The same compounds were obtained by thermolysis or long refluxing in pyridine of the semicarbazones 252 (R, = NHR, X = O).'383165 The thiosemicarbazones 252 (R, = NHR, X = S) underwent ring closure under the same conditions to the triazolethione 254 (X = S).'38,'65 This compound was also formed by treating the 2-hydrazinobenzodiazepine with thiophosgene.' 7 2 , 1 7 5 , 1 7 6 Cyanogen bromide reacted with the 2-hydrazinobenzodiazepine to give the 1-aminotriazolo compound 253 (R, = Ph, R, = C1, R, = NH2).'72'175,176 Cyclization of the oxalyl derivative 252 (R, = Ph, R, = C1, R, = COOEt, X = 0)by boiling in pyridine for 2 hours yielded 80% of the triazinobenzodiazepine 255.'64 The 4-oxide of 256 (R, = H, R, = Me) reacted with phosgene to form the triazolone 257.5aThe thiatriazolobenzodiazepine 258 was synthesized by treating the hydrazide 256 (R, = H, R, = Ac) with thionyl chloride in pyridine (Eq. 87).'77 Reaction of the methylhydrazine 256 (R, = Me, R, = H) with orthoesters under acid catalysis yielded the quaternary triazolium salts 259 (R = H, Me).148,149
d$o 485
2. 3H- 1,4-Benzodiazepines
Me
O I :
Rl Clq > N \ N H R z
COCI,
c1
Ph
Ph
256
251
SOCI,
(87)
I__\
dJ-AC
0, ,N
c1
I
N '
c1
Ph
Ph
258
259
Compounds 259 (R = NH, and R = NHMe, NHPh) were obtained by condensation of the same hydrazine with cyanogen bromide and dichloroimines, respectively.i48*149 Phosgene and thiophosgene converted this hydrazine S-).'48*149 to zwitterionic compounds 259 (R = 0-, The 2-hydrazinobenzodiazepines 260, which are disubstituted on the terminal nitrogen, were cyclized to the triazinobenzodiazepines 261 (R = H, Me) by treatment with glacial acetic acid (Eq. 88).14' The structure 262 (R = Ac) was assigned to the product formed in 30% yield by treating compound 262 (R = H) with acetic anhydride in acetic acid.14' R R Y COOEt O 4 N Y M e NH-NMe
c1
C1
Ph 260
Ph 262
Ph 26 1
486
1,4-Benzodiazepines
2.4.2.2. Reactions with Nucleophiles Treatment of the 2-hydrazinobenzodiazepine 263 with Raney nickel in boiling ethanol converted it to the 2-aminobenzodiazepine 52.' 37 The dimer 264137or its 4-oxide5" were formed when 263 or its 4-oxide was heated in boiling methanol (Eq. 89). These dimers were also observed as by-products during the preparation of 2-hydrazinobenzodiazepines. Acid hydrolysis of the dimer 264 or the hydrazine 263 regenerated the lactam 265.13' The latter was also obtained in 40% yield by treatment of the hydrazine 263 with methanolic hydrogen chloride.136
NH
NH-NH, A
c1
c1 Ph
2
263
(89) A
1
I
Ph
Ph
52
265
2.5. 2-0- and 2 - 9 Substituted 3H-l,4Benzodiazepines
2.5.1. Synthesis
2-Alkoxy-3H-1,4-benzodiazepine 4-oxides 267 were obtained by ring expansion of the 2-chloromethylquinazoline 3-oxides 80 with alkoxides (Eq. 90).5a.91* 178 Displacement of the leaving group X in 3H-1,4-benzodiazepines 268 by alkoxides or phenoxidesgOwas used in the preparation of these imidates as well. Suitable leaving groups were ~ h l o r i d e , ' ~ y~a n i d e ,methylthio,180~181 ~ (2-dirnethylamino)ethylthi0,~~~ nitro some thy lam in^,^^ dimorpholinophosp h ~ r y l o x y and , ~ ~(N-hydroxyimin~)nitromethyl.~~~ The reaction of the lactams 269 with diazomethane'82-184 or diazopropane18' provided another access to 2-alkoxybenzodiazepines. The latter compounds were also obtained by alkylation of the 2-ones 269 using an alkyl halide and potassium carbonate in acetone. O
2. 3H-1,4-Benzodiazepines
487
H o
'3KTR1 -N
I
R2 268
269
Reductive ring closure of the azides 270 (X = N3) with Raney nickel in ethanol or zinc and ammonium chloride led to the 2-ethoxybenzodiazepines 271. Triphenylphosphine as reducing agent allowed the conversion of 270 (X = N,, R = NO,) to the corresponding ben~0diazepine.l~~ Compounds 271 were also prepared by treatment of the bromide 270 (X = Br) with liquid ammonia in the presence of sodium iodide (Eq. 91).'42
R Ph
Ph
270
27 1
qfR (91)
c1
c1
N
Ph 272
213
The dehydration of the hydroxylamines 272 (R = Me, Pr) by refluxing in 1,4dimethylpiperazine or in methanol containing methoxide gave the correspondThe 5-H-benzodiazepines 273 were also ing 3H- 1,4-benzodiazepines. converted to the 3H tautomers under these condition^."^ Phosphorylation of the lactams 269 on oxygen with chlorophosphates20,8 7 . 8 8 and base gave compounds 267 [R, = PO(OR,),], which were
'"
488
1,4-Benzodiazepines
generally not isolated but further reacted with nucleophiles in situ. Dimorpholinophosphorylchloride as phosphorylating agent led to crystalline isolable phosphorimidates 267 [R4 = P O ( r n ~ r p h o l i n o ) , ] . ~ ~ ~ ~ ~ 2-Thioalkyl-3H-1,Cbenzodiazepines were synthesized by reacting the 2-thiones 86 with alkylating agents. Alkylations were carried out with a variety of reagents such as dimethyl sulfate,71-7 2 , 7 3 methyl iodide,72,7 3 alkyl halides containing tertiary amino groups,'81s'86 and bromoacetic acid.18' Reaction of N-nitrosochlordiazepoxide with ethanethiol and base gave the 2-ethylthio derivative in moderate yield.92 Direct conversion of the lactam 269 to the 2-thioalkyl-3H-l,4-benzodiazepines 268 (X = SR) was achieved by means of a combination of thiol and titanium tetrachlorideE2", or tetrachlorosilane.'8E
2.5.2. Reactions 2.5.2.1. Reactions with Electrophiles The acetic acids 274 (R = H, Me) were cyclized to the thiazolobenzodiazepines 275 by treatment with acetic anhydride and triethylamine (Eq. 92).l E 7
2.5.2.2. Reactions with Nucleophiles The utility of 2-alkylthio, 2-alkoxy, and 2-phosphoryloxy benzodiazepines for the synthesis of 2-amino, 2-hydroxyamino, and 2-hydrazino derivatives was discussed earlier during the review of the synthesis of these compounds. Hydrolyses of 2-alkoxy and 2-thiomethyl benzodiazepines led to the lactams. Low temperature hydrolysis cleaved the 1,Zimine bond in 2-alkoxy benzodiazepines 276 to give the esters 277 in 45-50% yield (Eq. 93).18'
216
211
2. 3H-1,4-Benzodiazepines
489
The phosphoryl derivative 278 hydrolyzed to the lactam 265 in 52% yield ~~ upon standing in water-tetrahydrofuran for 7 days at room t e m p e r a t ~ r e . 'The 2-morpholino compound 279 was the major by-product of this hydrolysis (Eq. 94).87a
I
Ph 265 278
(94)
I.
q3ND
c1
qJ A
c1
279 Ph
A
*
NH2
280 Ph
2-Methylthio benzodiazepines 281 (R = SMe) were converted to triazolobenzodiazepines 282 in one step by heating with acylhydrazines in hexamethyl phosphoric triamide at 10&140"C (Eq. 95).125*189-191
283
284
490
1,4-Benzodiazepines
Reaction of 278 (X = H) with acetylhydrazine in boiling butanol also gave the triazolobenzodiazepine 282 (R, = H, R, = Ph, R, = C1, R, = Me) in one step and in 80% yield.87aThe same compound was claimed to be formed under similar conditions from the 2-methoxy benzodiazepine 281 (R, = MeO, R, = H, R, = Ph, R, = CN).", Reaction of 2-phosphoryloxy compounds with carbanions of n i t r ~ m e t h a n e , 'dialkyl ~~ malonates,20g87a ethyl acetoacetate,20 and acetylacetoneZo led to the 2-methylene benzodiazepines 283 (Eq. 95). In some cases, condensation of the phosphorimidates with the anion of acetaminomalonic ester mentioned in Section 2.1.1 gave the imidazobenzodiazepines 284 (R, = Me) directly as a by-product.21 The imidazobenzodiazepines 284 (R, = H) were prepared in good yields by reaction of the phosphorimidates with the anion of ethyl i~ocyanoacetate.'~~ The anion of the nitrone 285 condensed with the phosphorimidate 278 (X = F) to give the imidazobenzodiazepine 288 in a one-pot reaction. The postulated intermediates 286 and 287 indicate the proposed course of this overall conversion of 278 (X = F) to 288 (Eq. 96).19*
+
OH
286
c1 F \
287
288
The addition of phenylmagnesium bromide to the nitrone 289 afforded the hydroxyamine 272 (R = Pr) in 70% yield (Eq. 97).lE5
2. 3H-1,4-Benzodiazepines
491
212
289
2.5.2.3. Thermal Reactions Thermolysis of the phosphorimidate 278 (X = H) in boiling 1,2,4-trichlorobenzene gave the 2-morpholinobenzodiazepine 279 in 26% yield, in addition to 17% of the 3-aminoquinoline 280 (Eq. 94).87aThe latter was also formed in 35% yield by heating 279 in this solvent at reflux for 4 2.6. 2-Halo-3H-1,Cbenzodiazepines
2.6.1. Synthesis 2-Halobenzodiazepines 291 (X = F, C1, Br) were claimed to be accessible by reaction of the corresponding lactam 290 with carbonyl dihalides in a mixture of benzene and pyridine at room t e m p e r a t ~ r e . The ' ~ ~ yields appear to be generally low. An exception is the 3-methoxy derivative 291 (R, = MeO, R, = C1, R, = Cl), which was obtained in 50% yield by treatment of the corresponding lactam with phosphorus pentachloride in boiling methylene chloride (Eq..98).' 94
2.6.2. Reactions 2-Halobenzodiazepines were subjected to nucleophilic displacement reactions with ammonia,89 a m i n e ~ , imidazole,86 '~~ and e t h 0 ~ i d e . l 'Trialkylphos~ phite reacted with 291 (X = C1, R, = MeO, R, = R, = C1) to give the 2phosphonates 291 [X = PO(OR),] in 50-75%0 yield.'95 Ammonia at 50°C converted the latter to the 2-aminoben~odiazepine.~~
492
1,4-Benzodiazepines
Short boiling of the 2-chloro compound 291 (X = Cl, R, = MeO, R, = R, = C1) with the tetrazoles 292 (R = Me, 4-MeOC6H,) in pyridine gave the triazolobenzodiazepines 294. l g 6 The first step is most likely the displacement of the chloride to form 293 which, upon thermolysis, can lose nitrogen to give the triazole 294 (Eq. 99).
292
293
I
(99)
A
6" 294
3. SH-l94-BENZODIAZEPINES 3.1. Synthesis
5-Phenyl-SH-1,4-benzodiazepines 298 (R, = H, Me, ClCH,; R, = C1, NO,) were obtained by thermal rearrangement of the azirinoquinazolines 296, which were accessible by treating the appropriate 2-chIoromethyl-1,2dihydroquinazolines 295 with potassium t-butoxide in tetrahydrofuran (Eq, 1@)).11-14~1 6 , 1 7 Compound 298 (R, = Me, R, = C1) was also prepared in 40% yield by oxidation of the 2,5-dihydro-1H-1,4-benzodiazepine 297 with manganese of 298 (R, = ClCH,, R, = C1) with dimethylamine d i o ~ i d e . ' ~ - ' ~ , 'Reaction ' yielded the corresponding amine 298 (R, = Me,NCH,, R, = Cl)."
2. 5 H - 1 ,rl-Benzodiazepines
493
1-BuOK THF
Ph
Ph
295
296
H
c1<>Me
N\ Ph 0
1 %YR1
( 100)
A
+
N,
RZ
291
Ph
0
298
The structure 300 was assigned to the products obtained by treatment of the quinazolines 299 with methoxide (Eq. 101)."
The 5H tautomer 302 of chlordiazepoxide was formed in 70% yield by oxidation of the hydroxyamine 301 (R = NHMe) with potassium ferricyanide'97 or hypoch10rite.l~~ Dehydration of 301 (R = P r o ) by refluxing with phenyl isocyanate in a mixture of isobutyl acetate and 1,4-dimethylpiperazine for 15 minutes gave a 96% yield of the 5H-benzodiazepine 303 (Eq. 102).185
30 1
dfPr
c1
N
Ph
303
494
1,4-Benzodiazepines
5H- 1,4-Benzodiazepines 306 were synthesized by rearrangement and dehydration of the 1,2,3,4-tetrahydroquinazolines305 by boiling in benzene in the presence of a catalytic amount of p-toluenesulfonic acid with separation of the water formed." Compounds 305 are the adducts of the diamine 304 with 1,2diketones (R, = Me, Ph) (Eq.103).In the case of R, = Ph, the relative positions of the methyl group and the phenyl moiety in 306 were not established.18
3.2. Reactions Reductions of compounds 298 with lithium aluminum hydride or borohydride reagents led to the 4-hydroxy tetrahydrobenzodiazepines 307.''-14, 16, l 7 The reduction product 307 (R, = Me, R, = C1) was shown to be a mixture of diastereomers, which were separated by fractional crystallization. The stereochemistry was not assigned.'2p'4*'7 Reduction of 298 (R, = CH,Cl, R, = C1) with lithium aluminum hydride led to the 3-methyl compound 307 (R, = Me, R, = C1) (Eq.104).'2-14317 The tetrahydro derivatives 308, of unknown stereochemistry, resulted from the treatment of compounds 306 with sodium borohydride in methanol."
The 5H tautomer 302 was converted to chlordiazepoxide in 80% yield by treatment with alkoxide in ethanol.'97 Similar tautomerization of 2-alkoxy-5H1,4-benzodiazepines such as 303 to the 3H tautomers was mentioned earlier in Section 2.5.1.18' Treatment of 298 (R, = H, R, = C1) with methoxide in methanol effected tautomerization to the 3H-benzodiazepine which added methanol to the 1,2-imine bond to give 309 (Eq.105)."
2. SH-1,4-Benzodiazepines
298 ( R ,
=
H , R,
495 =
CI)
OMe
c1 Ph 310
309
I
Cl<>!-Ph
Ph 311
Dipolar addition of phenyl isocyanate to the same nitrone 298 led to the tricyclic compound 310." Treatment of 310 with triethylamine in benzene effected elimination of carbon dioxide to give a product assigned structure 311 (R = H) on the basis of spectral and analytical data. Acetylation of 311 (R = H) yielded an acetyl derivative formulated as 311 (R = Ac) (Eq. 105).18
4. TABLES OF COMPOUNDS
TABLE V-1, lH-1,4-BENZODIAZEPINES
Substituent
mp FC); [bp (“C/torr)]
Solvent of Crystallization
Yield (%)
Spectra
Refs.
P
\o o\
Disubstituted
5-PhCHZNH-8-CI 5-BuNH-843 5-t-BuNH-8-CI 5-C,jH1,NH-8-CI 5-EtzNCHzCH,NH-8-CI 5-MezNCH,CH,NH-8-CI 5-PrNH-8-Cl 5-i-PrNH-8-CI 5-Me0-8-CI
55 45 35 40 20 15 42 20, 50
ir, pmr, ‘jc-nmr
la la la la la la la la la, l b
15,45 66 51
pmr, uv ir, pmr ir, pmr, uv
3, 4 2, 3 7 8
35
115
Trisubstituted
l-Me-5-Ph-7-Cl 1-Me-5-(2-FC,H4)-7-CI 2-CN-5-Ph-7-CI 3-CONHMe-5-Ph-7-NO2
76-79 14G142 148-150 287-292
Hexane Et,O/Hexane Cyclohexane CHCIJEtOH
Tetrasubstituted
l-Ac-2-AcNMe-5-Ph-7-Cl l-EtOOC-2-EtOOCO-5-Ph-7-Cl
l-EtOOC-2-EtOOCO-5-Ph-7-NO~ l-[Et,NCH,CH,]-2-MeS-5-(2-FC6H4)-7-CI 1-HOCH,-2-MeNCH20H-5-Ph-7-C1 Hydrochloride
1-Me-2-EtS-5-(2-FC,H,)-7-CI l-Me-2-MeSO-5-Ph-7-CI
1-Me-2-MeSO-5-(2-FC6H,)-7-Cl l-Me-2-MeS02-5-Ph-7-CI
1-Me-2-MeS0,-5-(2-FC,H,)-7-C1 l-Me-2-MeS-5-Ph-7-Cl
1-Me-2-MeS-5-(2-ClC,H,)-7-N02 1-Me-2-MeS-5-(2-FC,H,)-7-C1 l-Me-3-[7-C1-2,3-Dihydro1-Me-5-Ph-1If-1,Cbenzodiazepin-2-yl1-5-Ph-7-Cl
2W203 104-107 1 6 110 Oil
ir, pmr ir, pmr Pmr
CH,Cl,/Petr ether EtOAc/Petr ether EtOAc/Petr ether
9 5b 5b 3 10 2, 6 3, 6 2 3 2 4, 6 3, 6 2
189-19Od 103-104 148-151 130-144 184188 145-1 51 77-81 135-140 72-76
CH,Cl,/MeOH CH,Cl,/Petr ether MeOH CH,CI,/MeOH CH,Cl,/MeOH Et,O/Petr ether CH,Cl,/Petr ether MeOH
175-178
Et,O
ir, ms, pmr, uv
5a
CH,Cl,/Et,O
ir, ms, pmr, uv
5a
Et,O/Hexane Et,O/Hexane Et,O/Hexane MeOH MeOH
ir, pmr ir, pmr ir, ms, pmr
5b 5b 2 2, 3 2, 3
1-Me-3-[7-C1-2,3-Dihydro-5-(2-FC6H4)-l-Me-1H-1,4225-230 benzodiazepin-2-yl]-5-(2-FC6H,)-7-C1
79 48
Pmr
55
Pmr
83
Pmr
Pentasubstituted
110-116 158-1 6 1 118-120 l-Me-2-EtS-3-N(COOEt)NHCOOEt-5-(2-FC6H,)-7-Cl 138-140 1,3-Me,-2-MeSO2-5-(2-FC,H,)-7-Cl 149-152 1,3-Me2-2-MeS-5-(2-FC,H,)-7-C1
1,3-(EtOOC)~-2-EtOOC0-5-Ph-7-C1 l-Me-2-EtOOCO-3-EtOOC-5-Ph-7-Cl
83 74
Pmr
TABLE V-2. 3H-1,4-BENZODIAZEPINES
Substituent
mp W ) ; [bp ("C/torr)]
Solvent of Crystallization
108-110 127-138 218-219 101-104 159-1 6 1 124-126
Cyclohexane EtOAc CH,Cl,/EtOH EtOAc EtOAc EtOAc
153-155
EtOH EtOH CH2Cl,/Et20 i-PrOH CHCl,/Et ,O CH,CI,/Petr ether CH,Cl,/Petr ether CH,Cl,/Petr ether EtOAc/Hexane Et,O Et,O/Hexane EtOH CH,CI,/Et,O CH,Cl,/MeOH/EtOAc EtOH
Yield (%)
Spectra
Refs.
Disubstituted
2-Me-5-Ph 2-Me-5-Ph, 4-Oxide 2-C(NOH)COO t-Bu-5-(2-C1C6H4) 5-Ph-7-Cl 5-Ph-7-C1, 4-Oxide 5-(2-FC6H4)-7-I
64
ir, pmr
12, 13, 17 12, 13, 17 20b I , 11 11 18
Trisubstituted
2-C(NHAc) (COOEt)2-5-(2-C1C,H,)-7-C1 2-C(NHAc) (COOEt),-5-(2-FC6H4)-7-C1 2-C(NHAc) (COOEt),-5-(2-FC6H4)-7-CN 2-C(NHAc) (COOEt),-5-(2-Pyridyl)-7-Br 2-CONH,-5-Ph-7-CI 2-CONH2-5-(2-FC,H,)-7-C1 2-CONMe2-5-Ph-7-C1 2-C1CH2-5-Ph-7-Cl,4-Oxide 2-C1CH,-5-(2-FC6H4)-7-C1,4-Oxide 2-CN-5-Ph-7-Cl 2-CN-5-(2-FC6H4)-7-C1 2-CHNOH-5-Ph-7-CI 2-CHNOH-5-Ph-7-C1,4-Oxide 2-CHNOH-5-(2-FC,H4)-7-CI 2-CHNOH-5-(2-FC6H,)-7-CI, 4-Oxide
185-195 138-1 40 178-180 219-22 1 178-1 80 124-127 122d 135d 151-154 1 0 6 110 217-221 22623 1 250-251d 203-21 5d
85
80 31 56 27
ir, ms, pmr
ir, pmr, uv ir, uv ir, ms, pmr pmr, uv ir, pmr, uv pmr, uv pmr, uv ir, pmr, uv
21 21 21 21 7, 15 15 7b 18 18 I , 15 19 19b 19 19 18
2-C(NOH)Ac-5-(2-ClC6H4)-7-C1
2-C(NOH)NH2-5-(2-FC6H4)-7-C1
P W W
2-C(NOH)NH,-5-(2-FC6H,)-7-C1, 4-Oxide 2-C(N0H)NHMe-5-(2-FC6H4)-7-C1 2-C(NOH)NMe,-5-(2-FC6H4)-7-C1 2-C(NOH)NMe,-5-(2-FC6H4)-7-C1, 4-Oxide 2-C(NOH)COOMe-5-Ph-7-CI 2-C(NOH)COOMe-5-Ph-7-C1,4-Oxide 2-C(NOH)COOMe-5-(2-CIC,H,)-7-CI 2-C(N0H)COOMe-5-(2-FC6H4)-7-CI 2-C(NOH)COOMe-5-(2-Pyridyl)-7-Br 2-C(NOH)COOEt-5-(2-ClC6H4)-7-CI 2-C(NOH)COOEt-5-(2-C1C6H4)-7-C1, 4-Oxide 2-C(NOH)COOEt-5-(2-FC,H,)-7-C1 2-C(NOH)COOEt-5-(2-FC6H,)-7-C1,4-Oxide 2-C(NOH)COO i-Pr-5-(2-FC6H,)-7-C1 2-C(NOH)COO i-Pr-5-(2-FC,H4)-7-CI, 4-Oxide 2-C(NOH)COO r-B~-5-(2-ClC,H,)-7-C1,4-Oxide 2-C(NOH)COO t-Bu-5-(2-FC6H4)-7-C1 2-C(NOH)COO t-Bu-5-(2-FC6H,)-7-C1, 4-Oxide 2-C(NOH)COO r-Bu-5-(2-F-4-MeOC6H,)-7-CI 2-C(N0H)CN-5-(2-FC6H4)-7-C1 2-C(NOH)CONMeZ-5-Ph-7-Cl 2-C(NOH)CONMe2-5-Ph-7-C1,4-Oxide
2-C(NOH)CONMe,-5-(2-FC,H4)-7-CI 2-C(NOH)CONEt,-5-(2-FC6H4)-7-C1 2-C(NOH)SO,NMe,-5-(2-ClC,H4)-7-Cl 2-C(NOH)SO,NMe,-5-(2-FC6H4)-7-C1 2-C(NOH)SMe-5-(2-FC6H,)-7-C1, 4-Oxide 2-C(NOH)NO,-5-(2-FC6H4)-7-CI 2-C(NOH)NO,-5-(2-FC6H,)-7-CI, 4-Oxide
2-C(N0H)Morpholino-5-(2-FC6H4)-7-CI 2-C(NOH)Morpholino-5-(2-FC6H4)-7-C1, 4-Oxide 2-C(NOH) (4-Me-Piperazino)-5-(2-FC6H,)-7-C1
189-192 248-249 258-260 223-225d 1-164 190-192d 235-237d 237-239d 2233225d 238-24 Id 203-204d 2 19-22 1 244-246 230-233 225-226 244-245d 231-233 233-234 2 12-2 14 191-192 215-216 248-250 26@262d 256255 245-255 251-253 168-1 70 149-150 220-222d 220-23Qd
d 191-193 21 1-21 3d 198-200
CH,CI,/Hexane THF/EtOH MeOH/EtOH/THF CH,CI,/EtO Ac/Hexane MeOH/EtOAc MeOH/EtOAc THF/MeOH DMF/MeOH MeOH/THF AcOH/H,O THF/PhH CH,CI,/EtOH THF/EtOH THF/EtOH THF/E t OH THF/i-PrOH CH,Cl,/EtOH i-PrOH CH,Cl,/Hexane CH,Cl,/EtOH Et,O THF/EtOH THF/EtOH THF/EtOH CH,Cl,/EtOH CH,CI,/EtOAc THF/EtOH MeOH/Et,O THF/EtOAc Et,O MeOH/EtOAc MeOH/EtOAc MeOH/THF/EtOAc EtOH
88.5
ir, pmr, uv
97
ir, pmr, uv ir, pmr, uv
Pmr
ir, uv
20a 23 23 23 23 23 21 21 20a, 21 21 20b 20b 20b 20b 20b 20b 20b 20b 20b 20b 20b 20b 20b 20b 20b 20b 20b 20b 24 22 22 23 23 23
TABLE V-2. gcontd.) Substituent 2-C(NOH) (4-Me-Piperazino)-5-(2-FC,H4)-7-Cl, 4-Oxide 2-C(NOH) (2-Pyridyl)-5-(2-FC,H4)-7-C1 2-C(NOH) (2-Pyridyl)-5-(2-FC,H6)-7-Cl, 4-0xide.0.66EtOH
2-C(NOH)Pyrro1idino-5-(2-FC,H4)-7-Cl 2-C(NOH)Pyrrolidino-5-(2-FC6H4)-7-C1, 4-Oxide 2-C(NOMe)NH,-5-(2-FC6H,)-7-C1 2-C(NOMe)NHMe-5-(2-FC,H4)-7-CI 2-C(NOMe)OMe-5-(2-FC,H4)-7-Cl 2-C(NOMe)OMe-5-(2-FC6H4)-7-CI, 4-Oxide.O.SEt,O
2-C(N0Me)Morpholino-5-(2-FC,H4)-7-Cl 2-C(NOMe)Morpholino-5-(2-FC,H4)-7-C1, 4-Oxide 2-C(NOMe)NO,-5-(2-FC6H,)-7-C1
2-C(NOMe)NO,-5-(2-FC,H4)-7-C1,4-0xide 2-C(NOMe) (2-Pyridyl)-5-(2-FC,H4)-7-C1
2-C[NO(CH,),0Me]-5-(2-FC6H4)-7-C1 2-C[NO(CH,),OMe]-5-(2-FC6H4)-7-Cl, 4-Oxide 2-Me-S-Ph-7-CI 2-Me-5-Ph-7-C1, 4-Oxide
mp CCk [bp (“C/torr)]
Solvent of Crystallization
184186d
220-222
EtOH MeOH
23 20b
191-193d 175-178 168-172 120-124 14&142 165-166 80-82 141-143 170-173 130-133 207-209 171-173 98-10 125-1 28 132-135 167- I69d
CH,Cl,/EtOH THF/EtOH MeOH/EtOAc Et,O/Hexane Et,O/Hexane EtOAc/Hexane Et,O CH,Cl,/Et,O/Hexane Et,O/Hexane Et,O/Hexane Et,O i-PrOH Et,O/Hexane Et,O Hexane EtOH
20b 23 23 23 23 24 24 24 23 23 22 20b 24 24 12, 13 12-14, 16, 17
Yield (%)
Spectra
Pmr Pmr ir, pmr, uv Pmr 78; 34
pmr, uv
Refs.
2-Me-5-Ph-7-CI, 1,4-Dioxide 2-Me-5-Ph-7-NO2, 4-Oxide 2-Me-5-(2-FC6H,)-7-C1, 4-Oxide 2,5-(Ph),-7-C1, 4-Oxide 2-Ph-5-Me0-8-CI 2-Ph-5-NHNH2-8-CI 2-(Phthalimido)CH2-S-Ph-7-C1, 4-Oxide
138-140 196200d 171-173 204-206 105-106 162-164 186188d 2-(5-COOMe-Pyrrolidin-2-one-5-yl)-5-(2-ClC,H,)-7-C1 2 1 G 212d
EtOAc/Hexane EtOAc EtOH MeOH Petr ether EtOAc/Hexane EtOAc/Et ,O EtOAciHexane
ir, pmr, uv
ir, pmr, uv ir, pmr, uv
18 12, 13, 17 18 26 25 25 18 28
ir, uv ir, pmr 38
35
2-(4,5-Dihydro-4,5-Me,-1,2,4-Oxadiazol-3-y1)-5(2-FC6H4)-7-Cl
133-135
Et,O/Hexane
ir, pmr, uv
24b
142-144 13C131.5 12 G 125d 146149d
Hexane EtOH EtOH/H,O EtOAc
Pmr
18 17 17 18
Tetrasubstituted
2,3-(Me),-5-Ph-7-CI 2-Me-3-Ac0-5-Ph-7-CI 2-Me-3-HO-5-Ph-7-CI 2,5-(Me),-7,8-(MeO),, 4-Oxide u
0,
ir, pmr, uv
TABLE V-3. 2-AMINO-3H-1,4-BENZODIAZEPINES
Substituent
mp YC); [bp ("C/torr)]
Solvent of Crystallization
Yield (%)
217-218 145-147 24&242
Me,CO MeOH, Me,CO CH,CI,/MeOH
7 0 76 74 92
95,96 99 66
258-261 238-238.5d 261-262 243-244 236237 264265d 245-246d 159-160 255-256; 278-283 245-246 22 1 21c211 184-185 158-161 222-223d 161-163 227-2284 214-216
MeOH
73 87 66.7
99 95 34 34, 46 34, 41, 66, 68, 96 41 95 99 33,46, 85a
Spectra
Refs.
Monosubstituted
5-Ph 1-Oxide, hemihydrate 5-(2-C1C6H4) Disubstituted VI
0 N
3-( l-Imidazolo)-5-Ph 5-Me-7-Cl 5-Ph-7-Br, 4-Oxide Hydrochloride S-Ph-7-Cl Hydrochloride Dihydrochloride 1-Oxide, hemihydrate 4-Oxide Hydrochloride 1,4-Dioxide 5-Ph-7-Me0 1-Oxide, hemihydrate 5-Ph-7-Me 1-0xide.0.33H2O 5-Ph-7-NOz
MeOH MeOH EtOH
61; 75
MeOH/EtOAc MeOH
75 60
MeOH/Et 0 EtOH MeOH/EtOAc CHCI, MeOH/Me,CO EtOH MeOH/Me,CO THF
47 53 8 0 85 70 63 75 93; 70
33,46 ir, ms, pmr, uv
100
99 95, 96 99 95, 96 99 95, 96
Dihydrochloride 4-0xide 5-Ph-7-CF3 Dihydrochloride 4-Oxide 5-(2-C1C6H4)-7-C1 5-(2-C1C6H4)-7-N02 5-(2-FC6H4)-7-NH2 5-(2-FC,H4)-7-NO, 5-(4-ClC6H4)-7-C1,4-Oxide 5-(4-MeOC6H4)-7-C1 1-Oxide.0.66H20 4-0xide 5-(4-HOC6H4)-7-C1,4-Oxide
95
234235d; 245-246 243d 19&193 215-223d 240-242 228-230 218-220 250-254 248-254 24&242 252-254 237-238 158-160 237-238 302-303d
EtOH Me,CO/Hexane
97 58
MeOH CH2C12/MeOH CHC1,/Hexane CH2C1,/EtOH CH2Cl, CH2C1,/EtOAc DMF/H,O MeOH MeOH/Me,CO Me2C0 DMF/H,O
81.5 87.5 6
285-286 27Cb273 302-303 253-254 250-252 176181d 265-266 216219 236240
MeOH/CHCI, MeOH/CH2C12 MeOH/CHCl, MeOH MeOH CH2C12/MeOH MeOH/CHCl, MeCN EtOH
70 92 82 59 55
270-271 25Cb252 228-23Od 208-209 26207d 2w202
MeOH MeOH MeOH MeOH Me,CO/Hexane MeOH
60;62 79 80 79 84 54
uv
72 86 67 54
38 95, 96 96 36, 39 66, 118 95 70 70 70 47 95 99 47 38b
Trisubstituted
3-(I-Benzimidazolo)-5-Ph-7-C1 3-(l-Benzimidazolo)-5-Ph-7-Me 3-(1-Benzimidazolo)-5-(4-MeOC6H4)-7-CI
3-(2-Et-l-Imidazolo)-5-Ph-7-Me 3-(2-Et-1-1midazolo)-5-(4-MeOC6H4)-7-C1 3-HO-5-Ph-7-CI 34 I-Imidazolo)-5-Ph-7-C1 3-Me0-5-(2-C1C6H4)-7-C1 3-Me-5-(2-C1C6H4)-7-NO,( + )
3-(2-Me-l-Imidazolo)-5-Ph-7-C1 3-(2-Me-l-Imidazolo)-5-Ph-7-MeO, hemihydrate 5-Ph-7-CI-9-CHzCOOEt 5-Ph-7-Cl-9-C(OH)COOEt, hemihydrate
5-(4-MeOC,H,)-7-CI-9-CH2COOEt 5-(4-MeOC6H,)-7-C1-9-C (COOEt)C(OH)COOEt
78; 39 m,75
+ 728.8 (DMSO 1%)
ol.[
ir, pmr ir, pmr ir, pmr
99 99 99 99 99 85b 99 70 70 99 99 109 109 109 109
TABLE V-4. 2-METHYLAMINO-3H-1,4-BENZODIAZEPINES
mp ("C); [bp("C/torr)]
Substituent
Solvent of Crystallization
Yield (%)
Spectra
Refs.
NHMe
Monosubstituted
4-Oxide, hydrochloride
191-192 219-221 227-229 216-218 190-191 225-226
5-(4-MeOC,H4), 4-Oxide Hydrochloride
251-252 218-219
5-[3,4-(MeO),C,H,], Hydrochloride
193- 194 223-224
5-Me, 4-Oxide 5-Ph 4-0xide
4-Oxide
743, 4-Oxide
245d
38b 41 51 34,41 46 34,46
Me,CO DMF Me,CO Me,CO/MeOH Et,O/Petr ether EtOH/Petr ether MeOH/Me,CO Petr ether EtOH/Petr ether MeOH/Me,CO Petr ether EtOH/Et,O
70
ir. uv
34, 46, 48 34.46 34 34
63
38b, 52
Disubstituted
5-(Benzocycloheptan-7-yl)-7-C1, 4-Oxide Hemiethanolate 5,7-C1, 5-Cyclohexyl-7-CI 4-Oxide
212-213 197-200 2 18-220 230-231 239-241
EtOH MeOH MeOH
87
ir, pmr, uv
56 18
41 55 41
5-MeNH-7-Cl 5-(4-Me-Piperazino)-7-C1 5-(Morpholino), PO2-7-C1 5-(l-Piperidino)-7-C1 5-Ph-7-Br, 4-Oxide Hydrochloride 5-Ph-7-CI Hydrochloride 4-Oxide
248-250 202-204d 210-21 2 226-228 242-243 239-24Od 242-245
EtOH i-PrOHIEtOAc EtOAc i-PrOH Me,CO MeOH/Et,O Me,CO
260-261 238.5-240.5
MeOH/Et,O EtOH
48
ir, ms, uv
47
ir, ms
18
68 95
82 X-ray I3C-nmr, pmr
Hydrochloride Hydrogen sulfate Dihydrogen phosphate 5-Ph-7-Me0, 4-Oxide 5-Ph-7-MeOOC, 4-Oxide 5-Ph-7-Me 4-Oxide Hydrochloride
215-216 214-2 15 206-207 231-233 259-260 218-220 214-215 224-225
5-Ph-7-(2-Me-1,3-Dioxolan-2-yl).0.35EtOH 5-Ph-7-MeS, 4-Oxide 5-Ph-7-NO2 4-Oxide 5-Ph-7-CF3, 4-Oxide
194-1 97 245-246 225-228 260-261d 264-265 267-268 222d 229-231 200-202 180-185and 288-290 247-248 243-246d
Hydrochloride 5-C6D,-7-C1, 4-Oxide 5-PhNH-7-CI 5-(4-H,NC6H,)-7-C1, 4-Oxide 5-(2-C1C6H,)-7-C1, 4-Oxide Hydrochloride
MeOH MeOH/Me,CO H,O/Me,CO PhH/Hexane MeOH CH,Cl, Me,CO MeOH/Me,CO Et,O EtOH MeCN MeOH EtOH/Et,O Et,O/Hexane MeOH MeOH/Et,O
uv 60
50
59 85
uv
87b 18 34,46 34,46 33, 41, 73, 85a, 93b 33 33, 46, 59, 74 198 199 33 33 33 38b 37 34,41 34,46 46 85c 40 85a 38 36, 39, 42 39 58
61
18
EtOH CH,CI,/MeOH PhH MeOH/Et,O
87a
50 80
ir, ms
49 34 34
TABLE V-4. 4contd.)
Substituent
5-( 2-CIC,H4)-7-N02 5-(4-C1C6H4)-7-C1 4-Oxide Hydrochloride 5-(2-FC6H4)-7-Ac 4-Oxide 5-(2-FC,H4)-7-C1 5-(2-FC,H4)-7-Et 4-Oxide 5-(2-FC,H4)-7<MeCHOH) 5-(2-FC,H,)-7-1, 4-Oxide 5-(2-FC,H4)-7-MeNHCONH 5-(2-FC,H,)-7-(MeNSMe) 4-Oxide 5-(2-FC,H4)-7-N02 5-(2,6-F,C6H,)-7-C1, 4-Oxide 5-(4-HOC,H,)-7-C1, 4-Oxide 5-(4- MeC, H4)-7-Br 4-Oxide 5-[4-(H,N(CH,), O)C,H4]-7-Cl, 4-Oxide, dihydrochloride 5-[4-PhCH,0CONH(CH,)30C6H4]-7-C1, 4-Oxide 5-[4-H,NNHCOCH,0C,H4]-7-C1, 4-Oxide 5-[4-MeOOCCH,0C6H4]-7-C1,4-Oxide 5-(2-pyridyl)-7-Br 4-0xide 5-(2-thienyl)-7-C1, 4-Oxide hydrochloride
mp ("C); [(bp 'C/torr)]
Solvent of Crystallization
219-221 241-242 254-255 245d 181-183 > 203d 204-206 172-174 201-203 216-218 2 18-219d 185-186 212-21 5 > 18od 214-2 16 230-234 278-279d 258-259 255-256
CH2C12/EtOF CHCI, EtOH EtOH
211-215d 103-106 254-256 106-110 208-214 231-233d 256-257
i-PrOH/MeOH CH,CI,/Et,O DMF/MeOH/H,O CH,CI, / Hexane CH,Cl,/Hexane Me,CO
MeCN THF/Et,O MeCN MeCN MeCN EtOH CH,CI, MeCN MeCN EtOAc MeOH/Et,O/Petr ether EtOAc CHCI, EtOH
Yield (%)
Spectra
Refs. 51
82 68
34 34,44, 51 34 85c 85c 178 51 85c 85c 18 70 85c 85c 70 9 49, 50
98
34
54 41.5 80 19 90 59
34,44, 51 ir ir, rns ir ir
49 49 49 49 143, 144 38b 41
Trisubstituted
3-Ac0-5-Ph-7-CI 3-Ac0-5-Ph-7-NOZ 3-Ac0-5-Ph-7-CF3 hydrochloride 3-Ac0-5-(4-MeOC6H,)-7-C1 3-HzN-5-Ph-7-Cl 3-C6H4C00-5-Ph-7-C1 3-BrCH2C00-5-Ph-7-C1 3-PrC00-5-Ph-7-CI
3-NCCH,CHz-5-(2-FC6H4)-7-C1
ln 0 -4
3-(EtO),CHCH,NH-5-Ph-7-C1 3-Et2N-5-Ph-7-C1 3-MezN-5-Ph-7-C1 3-Et0-5-Ph-7-Cl Hydrochloride 3-Et0-5-Ph-7-NOz 3-Et0,CO-5-Ph-7-CI hydrochloride 3-EtOzCCONH-5-Ph-7-Cl 3-HO-5-Ph-7-CI 3-HO-5-Ph-7-NOz 3-HO-5-Ph-7-CF3 3-(1 -Imidazolo)-5-Ph-7-C1 3-Me0-5-Ph-7-Cl 3-Me-S-Ph-7-C1-,4-Oxide Hydrochloride 3-Me-5-Ph-7-CF3, 4-Oxide 3-Me-5-(2-C1C6H4)-7-NO, (
+)
3-Me-5-(2-FC,H, )-7-C1 3-MeNH-5-Ph-7-Cl,4-Oxide 3-MeNH-5-Ph-7-NO2, 4-Oxide 3-MeNH-5-Ph-7-F3C, 4-Oxide
202-203 222-222.5 206-207 202-203 168-170 215-216 175-177 171-172 162-165 95-97 170-1 72 167-169 215-216 222-223 163-164 178-180 198-201 184-186 191-1 92d 161-163 177-178d 252-253 155-160 246-247 190-191 257-258d 207-209
Et,O/Petr ether Et ,O/ Petr ether EtOH EtOH THF/Et20 THF/Hexane Et,O THF/Et20 EtOAc/Hexane CH,CI,/Petr ether DMF/H20 MeCN PhH/Hexane PhH CH,Cl,/Petr ether Me,CO Me,CO/MeOH/Et,O MeCN CH,Cl, /Hexane
203-205 150-1 51 161-162 162-1 63
EtOH MeCN MeCN MeOH/H,O
ir
CH,CI,/Et20 THF/Hexane MeCN THF/Hexane CH,CI,/Hexane Me,CO CH,Cl,/Hexane
ir ir
62 68 63
ir ir, ms, pmr ir
87
60
ir, ms, pmr
[alo + 497.2 1% in CH,Cl,
110, 112a 38b 38b 110 9 110 9 110 70 9 45 45 112a 38b 112a 112a 9 110 110 38b 38b 112a
9 46 46 38b 70
70 65 65 65
TABLE V-4. 4c ont d. )
Substituent 3-MeNCH2Ph-5-Ph-7<1 3-(3-Me-Butanoyloxy)-5-Ph-7-C1 3-MeNPh-5-Ph-7-Cl 3-Morpholino-S-Ph-7-CI 3-(3-0xobut- 1-yl)-5-(2-C1C6H4)-7-NO, 3-(3-0xobut-l-yl)-5-(2-FC6H4)-7-N02 3-Piperidino-5-Ph-7-CI 3-EtC00-5-Ph-7-CI 3-Pr-5-Ph-7-C1, 4-Oxide Hydrochloride 3-Pyrrolidino-5-Ph-7-CI 5-Ph-7,8-CI2,4-Oxide Hydrochloride 5-Ph-7,9-CI2,4-Oxide Hydrochloride 5-Ph-7-C1-9-Me, 4-Oxide 5-Ph-7,8-Me2, 4-Oxide Hydrochloride 5-Ph-7,9-Me2, 4-Oxide Hydrochloride 5-(4-C1C6H,)-7,8-Me,, 4-Oxide Hydrochloride 5-(4-N0,C6H4)-7,8-Me2, 4-Oxide Hydrochloride
mp ("C); [(bp "C/torr)]
Solvent of Crystallization
Yield (YO)
EtOH
77
Spectra
Refs. 45 38b 45 45 70 70 45 110 33 33 45 34,46 34,46 34, 44 34 38b 34, 46 34, 46 38b 38b 34,46 34,46
169-1 71 180-1 81 156-158 212-2 14 198 181-183 157-1 59 197-198 221-222 187-189 163-165 233-234 231-232 251-252 204-207 219-220 259-261 230-231 215-216 225-226 258-259 247-248
EtOH EtOH EtOAc/Hexane Et,O EtOH Et,O Me,CO/Petr ether MeOH/Et,O EtOH MeOH MeOH/Et,O/Petr ether MeOH EtOH Me,CO Me,CO MeOH/Me,CO CH,Cl,/Petr ether MeOH/Et,O MeOH H,O/EtOH/Et,O
264-265
MeOH
38b
194-196
Et,O
70
Et,O
81 80
74 25
85
71
50
ir
Tetrasubstituted
3,3-[NCCH2CH2]-5-(2-FC,H,)-7-CI
TABLE V-5. N-MONOSUBSTITUTED-2-AMINO-3H-l,4-BENZODIAZEPINES
Substituent
mp W ) ; [bp ("C/torr)]
Solvent of Crystallization
13CL131 102-103 181-1 82 133-135
Et,O/i-Pr,O Hexane EtOAc EtOH
224-225 17CL171 219-220 181.5-187.5 163-165 223-225 206-209 167-169 202-203 171-173 21 5-220 154-155 136139 158-1 61 147-150
EtOAc CH,CI,/Et ,O/Petr ether MeOH/Et,O EtOAc/Hexane CH,CI,/Et,O
16.5 43
E t 0Ac/Hexane MeOH/H,O Me,CO i-PrOH/Me,CO/Et,O EtOH
12
Yield (Yo)
Spectra
Refs.
R: Other Substituents
Monosubstituted
Bu; 5-Ph (EtO),CHCH,; 5-Ph (MeO),CHCH,; 5-(2-CIC6H,) Et; 3-PhNMe
84 83 77a 45
85
Disubstitntcd
1-Adamantyl; 5-Ph-7-CI.O.SEtOAc H,NCH,CH,; 5-Ph-7-C1, 4-Oxide Dihydrochloride N,CH,COCH,; 5-Ph-7-Cl ( l-Aziridino)CH2CH,-5-Ph-7-CI, 4-Oxide PhCH,; 5-Ph-7-C1, 4-Oxide BrCH,COCH,; 5-Ph-7-CI Bu; 5-Ph-7-Cl 4-0xide Hydrochloride HOOCCH,; 5-Ph-7-CI HOOCCH,; 5-Ph-7-NOZ HOOCCH,; 5-(2-CIC,jH,)-7-C1 HOOCCH,; 5-(2-C1CfiH4)-7-N02 HOOCCH,; 5-(2-FCfiH4)-7-C1
MeOH/Et,O Et,O
pmr, uv
50 77 66 75; 87 83 88
ir, pmr
25 33 33 82b 92 41 82b 61 33,46 33,46 78-80 78-80 78-80 78-80 78,79
TABLE V-5.4contd.)
~l
r-.
0
Substituent
mp (“C); [bp (“C/tor~)]
HOOCCH,; 5-(2-FC6H4)-7-N0, 2-HOOCC6H4; 5-Ph-7-C1 (I-Cyclohexene)CH,CH,; 5-Ph-7-C1, 4-Oxide Cyclohexyl; 5-Pb-7-C1, 4-Oxide Cyclopropyk 5-Ph-7-C1, 4-Oxide (Cyclopropyl)CH,; 5-Ph-743, 4-Oxide (EtO),CHCH,; 5-Ph-7-C1 (EtO),CHCH,; 5-Ph-7-NOz (EtOOC),C=CH; 5-Ph-7-CI 4-Et2N-2-butyn-l-yl; 5-Ph-7-C1,4-Oxide Et2NCH2CH2;5-Ph-7-Cl Hydrochloride Dihydrochloride Dipicrate 4-Oxide Dihydrochloride~O.SH,O (MeO),CHCH,; 5-Ph-7-CI 4-Oxide (MeO),CHCH,; 5-(2-C1C,H4)-7-C1 (MeO),CHCH,; 5-(2-Pyridyl)-7-Br 3,4-(MeO),C,H3CH,CH,; 5-Ph-7-Cl (MeO),CHCHMe; 5-(2-C1C,H4)-7-C1 Me,NCH,CH,; 5-Ph-7-C1, dihydrochloride 4-Oxide, dihydrochloride Me,N(CH,),; 5-Ph-7-CI 4-Oxide, dihydrochloride Me,N(CH,),; 5-Ph-7-NO2 2-EtOOCC6H4; 5-Ph-7-Cl
144147 2 15-2 19 204-205 257-258 257-259d 234-236 131-132 114115 105-107 177 105-107 252-254 249-250 203-204 154-156 237-238 162 196-198 175.5-176.5 155-157 197-200 157 269-27Od 262-263 159-160 242-243d 13G-131 163-1 66
Solvent of Crystallization
Yield (YO) 45
CH,Cl,/Et,O MeOH CH,Cl,/Hexane Cyclohexane Et,O/Hexane Et,O
47
20 Pentane EtOH/Et,O i-PrOH THF/Et,O Cyclohexane EtOH PhH/C yclohexane EtOAc/Hexane EtOAc/Hexane CH,CI,/Hexane EtOAc/Hexane AcOH i-Pr,O MeOH
60 56; 75 76 85
Spectra
Refs. 78 81 38b 38b 38b 38b 25,83 83 108 81 61 61 61 83,84 45 41 43,74,75,77a 43, 74, 75 77a 77b 9 77a 25 41 83,84 41 83,84 81
e e
EtOOCCH,; 5-Ph-7-Cl 4-Oxide EtOOCCH,; 5-Ph-7-NO2 Et; 5-Ph-7-Br 4-Oxide Hydrochloride Et; 5-Ph-7-C1, 4-Oxide Hydrochloride (2-Furyl)CH2; 5-Ph-7-Cl 4-Oxide Hexyl; 5-Ph-7-C1 HOCHZCH,; 5-Ph-7-CI 4-Oxide Hydrochloride HO(CHJ3; 5-Ph-7-C1 MeOCH,CH,; 5-Ph-7-C1, 4-Oxide Hydrochloride MeqCH,),; 5-(2-C1C6H4)-7-CI MeO(CH,),; 5-(2-C1C6H,)-7-C1
97-98 208 194195 224 246248 232-233 231-233 208-209 15C151 225-227 149-150 172-173 216218 21C21 Id 203-205 225-226 207-209 185-189 175.5-179
i-Pr,O i-PrOH Me,CO/Hexane MeOH Me,CO MeOH/Et,O Me,CO EtOH/Et,O i-Pr,O PhH EtOH/H,O Et,O MeOH MeOH/Et,O EtOAc Me,CO MeOH/Et,O EtOH MeO(CH2)3NH2
22 78 86 69
86
45
78.6 89.1
83 75 83 34 34 34 33,46 33,46 83 45 61 83,84 33,46 33,46 83,84 33,46 33,46 73 73
(2-Me-4,5-Dihydro-l-imidazolo)CH,CH,; 5-Ph-7-C1, 4-Oxide Dihydrochloride.O.SH,O (4-Me-1-Piperazino) (CH,),; 5-Ph-7-C1, 4-Oxide (Morpholino)CH,CH,; 5-Ph-7-Cl 4-Oxide, dihydrochloride.H,O (Morpholino) (CH,),; 5-Ph-7-CI 4-Oxide, dihydrochloride Ph; 5-Ph-7-C1 PhCHzCH,; 5-Ph-7-Cl 4-0xide (Phthalimido)CH,COCH,; 5-Ph-7-Cl (Phthalimido)CH,COCH,; 5-(2-C1C6H4)-7-C1 44 l-Piperidino)-2-butyn-l-y1; 5-Ph-7-Cl 4-Oxide
245-246 216218 196198 277-278d 231-232d 205-208 137-138 203-205 142-145 2w202 168
41 41 61 41
CH,Cl,/Pentane
PhH/Petr ether EtOH/H,O EtOH Me,CO MeOH/EtOAc EtOAc
79
23 27
41 81 61 45 82b 82b 81 81
TABLE V-5. +contd.)
Substituent
h,
Propen-3-yl; 5-Ph-7-C1, 4-Oxide Hydrochloride Propen-3-yl; 5-(2-C1C6H,)-7-NO, i-Pr; 5-Ph-7-C1, 4-Oxide Propyn-3-yl; 5-Ph-7-CI 4-Oxide
mp rC); [bp ("C/torr)]
Solvent of Crystallization
202-204 221-227d 160 248-250 203.5-205 220 222
MeOH MeOH/Me,CO/Et,O Et,O EtOH MeOH i-PrOH BuOH
175-180 195-198 208-210 135-1 38 142-144
CH,Cl,/Et,O/Petr CH,CI,/Et,O Et,O MeCN MeCN
149-151
EtOAc
65
175-176d
EtOAc
65
155-156
PhH/Hexane
65
Yield (YO)
Spectra
35
Refs.
33,46 33,46 70 85a 76 43, 74, 75 43.74
78 70
Trisubstituted
AcNHCH,CH,; 3-Ac0-5-Ph-7-CI ACNHCH~CH, 3-OH-5-Ph-7-CI PhCH,; 3-Ac0-5-Ph-7-CI PhCH,; 3-PhCH2NH-5-Ph-7-CI, 4-Oxide Bu; 3-BuNH-5-Ph-7-C1, 4-Oxide Cyclohexyl; 3-(cyclohexyl)NH-5-Ph-7-C1 4-Oxide Cyclopentyl; 3-(cyclopentyl)NH-5-Ph-7-CI 4-Oxide (Cyclopropyl)CH,; 3-(cyclopropyl)CH,NH-5-Ph7-CI, 4-Oxide
9
ether
9
98
it, ms, pmr
112a 65 65
-
EtzNCHzCHz; 3-Ac0-5-Ph-7-CI EtzNCHzCHz; 3-HO-5-Ph-7-CI Et; 3-Ac0-5-Ph-7-CI Et; 3-PhCH,NMe-5-Ph-7-CI Et; 3-EtzN-5-Ph-7-CI Et; 3-Me2N-5-Ph-7-C1 Et; 3-EtNH-5-Ph-7-C1,4-Oxide Et; 3-HO-5-Ph-7-CI Et; 3-Morpholino-5-Ph-7-CI Et; 3-Piperidino-5-Ph-7-CI Et; 3-Pyrrolidino-5-Ph-7-CI (2-Furyl)CHz; 3-Ac0-5-Ph-7-CI (2-Furyl)CHz; 3-HO-5-Ph-7-CI (2-Furyl)CHz; 3-morpholin0-5-Ph-7-Cl PhCHzCHz; 3-Ac0-5-Ph-7-CI PhCHzCHz; 3-HO-5-Ph-7-CI i-Pr; 3-i-PrNH-S-Ph-7-C1,4-Oxide
169-17 1 201-203 158-160 121-123 16108 152-1 53 201-203 19G192 19G192 138-140 167-168 153-155 174-176 195-197 2w202 167-168.5
Cyclohexane Cyclohexane EtOH EtOH EtOH MeCN EtOH EtOH EtOH EtOH PhH PhH EtOH PhH PhH Hexane
62 91 78 72 58 77
45 45 45 45 45 45
65 45
92 71 57 71 68 87 80 75 89
45
45 45 45 45
45 45
45 65
W
Tetrasubstituted
Bu; 3,3-Mez-5-(2-FC,H,)-7-NHz
ir, ms, pmr
85d
TABLE V-6. N,N-DISUBSTITUTED-2-AMINO-3H-l,4-BENZODIAZEPINES
Substituent
mp W ) ; [bp (“C/torr)]
Solvent of Crystallization
Yield (%)
Spectra
Refs.
Substituents R,,R,; Other
Monosubstituted
PhCH,, Me; 5-(2-FC6H,) Bu,Me; 5-(2-FC6H,) Me,Me; 5-Ph Me,Me; 5-(2-C1C6H,) Me,Me; 5-(2-FC6H,)
Oil Oil 139 152 150
85d 85d 85d 85d 85d
CH,Cl,/Cyclohexane CH,CI,/Cyclohexane
Disubstituted
PhCH,,Me; 5-Ph-7-C1,4-Oxide PhCH,OCH,,Me; 5-(2-C1C6H4)-7-C1
204-204.5 83.S86.5
PhCH,OCH(Me),Me; 5-(2-C1C,H4)-7-C1 HOOC(CH,),,Me; 5-Ph-7-C1, 4-Oxide Sodium salt, hydrate NC(CH,),,Me; 5-Ph-7-C1,4-Oxide Hydrochloride Cyclohexyl, MeOCH,; 5-(2-C1C,H4)-7-C1 Cyclopropyl, MeOCH,; 5-(2-C1C6H,)-7-C1 EtOOC(CH,),, Me; 5-Ph-7-C1, 4-Oxide Hydrochloride Et,Et; 5-Ph-7-C1, 4-Oxide
115.5-1 17.5 206.5-207.5 204-205 155-1 56 172-173 144.5-146.5 68-82 149-150 186-187 133-135
BuOH EtOH/Hexane/ Cyclohexane EtOH/Hexane Et,O/Petr ether MeOH/Et,O/Petr ether Et,O MeOH/Et,O EtOH/Hexane Petr ether CH,C1,/Et2O/Petr ether MeOH/Et,O Hexane
65 42 24.6
4.6 21.3
76
ir, uv
105 13 73 44 44 44 44 73 73 44 44 45
~l
Et,MeOCH,; 5-(2-C1C,H4)-7-C1 (2-Furyl)CHOH,Me; 5-Ph-7-C1, 4-Oxide, hydrochloride (2-Furyl)CHOMe,Me; 5-Ph-7-C1, 4-Oxide (1-Hydroxybut-I-yl),Me; 5-Ph-7421, 4-Oxide, hydrochloride Butanal adduct (1-Hydroxyeth-1-yl),Me; 5-Ph-7-C1, 4-Oxide, hydrochloride (1-Hydroxprop- 1-yl),Me; 5-Ph-7-CI, 4-Oxide, hydrochloride Propanal adduct MeO(CH,),,Me; 5-(2-C1C,H4)-7-C1 MeOCH,,Me; 5-Ph-7-C1, 4-Oxide MeOCH,, Me; 5-(2-C1C,H4)-7-C1 MeOCH,, i-Pr; 5-(2-C1C,H4)-7-C1 MeqCH,),, Me; 5-(2-C1C,H4)-7-CI Me,Me; 5-Ph-7-Cl 4-Oxide Me,Me; 5-(2-FC,H4)-7-MeNHCONH Me,Me; 5-(2-FC,H4)-7-N0, Me,Propen-3-yl; 5-Ph-7-C1, 4-Oxide Me,i-PrO(CH,),; 5-(2-C1C,H4)-7-C1 Me, 3-(10,l l-Dihydro-5H-dibenzo[a,e]cyclohepten-5-y1idene)propyb 5-Ph-7-C1, hydrochloride
98.5-101
EtOH/Hexane
23.8
148-15Od 141-142
MeOH/Et,O/Petr ether MeOH/Et,O/Petr ether
10
194195d 193d
MeOH/Et,O MeOH/Et,O/Petr ether
106a,b,d 106a
17GI7Id
MeOH/Et,O
106d
192-194 194198d 112-1 15 139-140 111-1 12.5 159.5-161 Oil 178-180 205-209 2W203 235-236 275-276 126126.5 82.1-85
MeOH/Et,O MeOH/Et,O/Petr ether EtOH/Hexane EtOH EtOH/Hexane EtOH
- 110
Me,CO EtOH EtOH EtOAc/Et,O EtOAc i-PrOH Hexane/Petr ether Et,O
73 106c,d 106c
15 70.3 ir, uv 38.4 23.1 99.4
ir,uv
106 73 105 73 73 73 60,61 85a 60 70 70 105
73
67.8
ir, ms
85c
TABLE V-6. d c o n t d . ) mp ("C); [bp (T/torr)]
Solvent of Crystallization
Et,Et; 3-Ac0-5-Ph-7-CI Et,Et; 3-HO-5-Ph-7-Cl Et,Me; 3-Me-5-(2-C1C6H,)-7-NO, (+)
1-142 15C152 18C185
PhH PhH EtOH
75 85
Me,Me; 3-Ac0-5-Ph-7-Cl Me,Me; 3-PhCH2NMe-5-Ph-7-C1 Me,Me; 3-Et2N-5-Ph-7-C1 Me,Me; 3-Me2N-5-Ph-7-C1 Me,Me; 3-HO-5-Ph-7-CI Me,Me; 3-Morpholin0-5-Ph-7-Cl Me,Me; 3-Piperidino-5-Ph-7-Cl Me,Me; 3-Pyrrolidin0-5-Ph-7-Cl
132-134 144-146 12C122 161-163 142-144 la162 167-169 173-175
EtOH EtOH EtOH EtOH PhH EtOH EtOH EtOH
82 59 65 71
Substituent
Yield (%)
Spectra
Refs.
Trisubstituted
ul
m
[ale + 48.6" C: 1% CH,C1,
45 45 70 45 45
45 45 45 45 45 45
85
66 78 75
Tetrasubstituted
Me,Me; 3,3-Me,-5-(2-FC6H,)-7-NO,
ir, ms, pmr
85d
TABLE V-7. 3H-1,4-BENZODIAZEPINES WITH A NITROGEN HETEROCYCLE AmACHED AT POSITION 2
Substituent
mp ( T I ; [bp (.C/torr)]
Solvent of Crystallization
106 97 145
Et,O/Pentane Et,O/Pentane Et,O/Hexane
163-1 65 237-238 193-194 234-235 188-189 221-224 147-150 207-208 145- 146 16162 2 6 2 6 1d 154157 185-186
CH,CI,/Et,O
Yield (%)
Spectra
Refs.
Monosubstituted
,"
4-Me-Piperazino; 5-(2-FC6H,) Morpholino; 5-(2-FC6H,) Pyrrolidino; 5-(2-FC6H,)
85d 85d 85d
-4
Disubstituted
Aziridino; 5-Ph-7-C1, 4-Oxide Benzimidazolo; 5-Ph-7-Cl Benzimidazolo; 5-(2-C1C6H,)-7-CF, Benzimidazolo; 5-(2,6-F2C,H,)-7-CI 1-Benzotriazolo; 5-Ph-7-CI 3,5-Me2-Pyrazolo; 5-Ph-7-CI, 4-Oxide Imidazolo; 5-Ph-7-CI Imidazolo; 5-Ph-7-NO, Imidazolo; 5-(2-CIC6H,)-7-Br Imidazolo; 5-(2-C1C6H,)-7-CI 3-Me-5-HO-Pyrazolo; 5-Ph-7-C1, 4-Oxide 3-Me-5-HO-4,5-Dihydropyrazolo; 5-Ph-7-CI 4-Oxide
CH,CI,/Petr ether Et,O i-Pr,O CH,CI,/Petr ether CH,CI,/MeOH i-PrOH CH,CI,/Et,O
pmr, uv
68
ir, pmr, uv
12 50 91
ir, pmr, uv ir, pmr, uv ir, pmr, uv
92 86 86 86 86 161 86 86 86 86 161 161 161
TABLE V-7. gcontd.)
Substituent
VI 00
Morpholino; 5-Ph-7-CI Morpholino; 5-(2-FC6H,)-7-CN 2-Oxooxazolidino; 5-Ph-7-Cl 2-Oxopyrrolidino; 5-Ph-7-CI 2-Oxopyrrolidino; 5-(2-C1C,H4)-7-C1
2-0~0-3-(Me,NCH,CH,)-pyrrolidino; 5-Ph-7-CI 2-0x0-3-Me-pyrrolidino; 5-Ph-7-CI Piperidino; 5-Ph-7-CI 4-Oxide Pyrazolo; 5-Ph-7-CI Pyrazolo; 5-(2-FC6H,)-7-CI Pyrrolidino; 5-Ph-7-Cl 4-Oxide Pyrrolidino; 5-(2-C1C6H,)-7-NO, 1,2,4-Triazolo;5-Ph-7-CI
mp K ) ; [bp (“C/torr)]
Solvent of Crystallization
8G90 191-195 223-225 247-247.5 197-199 129-1 30.5 212-215 115-1 16 16&170 172-173 184-185 139-141 135-138 197-198 1977200 201-202
Hexane CH,CI,/Hexane PhH/Et,O i-PrOH EtOAc/Et,O Cyclohexane i-PrOH EtOH CH,CI,/Hexane
i-PrOH MeOH EtOH CH,Cl,/Et,O/Petr
ether
Yield (YO)
Spectra
74
ir, ms, uv
66 31 52 82 60; 89
ir, ms, pmr
Refs. 87a 9 7b 66, 67 66, 67 66 66, 67 61, 72a 85a 86 86 60, 85a 60, 61 70 86
TABLE V-8. N-METHYL-N-NITROSO-2-AMINO-3 H-1,4-BENZODIAZEPINES
Substituent
mp CC); [bp (“C/torr)]
Solvent of Crystallization
5-Ph 5-Ph-7-C1, 4-Oxide 5-(2-C1C,H4)-7-N0, 5-(2-FC6H4)-7-C1 5-(2-Pyridyl)-7-Br
192- 199d 158-16od 167-169 11c112 102-1 06
Et,O/Hexane CH,Cl,/EtOH Et,O i-PrOH
Yield (%)
60
Spectra
pmr, uv
Refs.
21 143, 144 21 19a 143, 144
TABLE V-9. N-ACYL 2-AMINO-3H-1,4-BENZODIAZEPINES
Substituent
mp ("C); Cbp ("C/torr)l
Solvent of Crystallization
188-190 148-148.5 15Od 255-257d 167-1 69d 218-219d 217-220 186188d 164167 155-158d 23&232d 208.5-211 179-1 80.5 176178 195-198 212-21 3d 20 1-203 248-249 243-244 193-194d 211-215 225-227d
MeCOEt CH,CI,/Hexane EtOAc
Yield (%)
Spectra
Refs.
R , , R,; Others H, AcNH 5-Ph-7-Cl H, AcCH,; 5-Ph-7-CI 4-Oxide H, AcCH,; 5-Ph-7-NO2, 4-Oxide H, AcCH,; 5-Ph-7-F3C, 4-Oxide H, HZN, 5-Ph-7-CI H, PhCH,NH; 5-Ph-7-CI H, CICH,CH,NH; 5-Ph-7-CI H, CICHZCHZNH; 5-(2-C1C6H4)-7-C1 H, 4-ClC6H4NH; 5-Ph-7-Cl H, (Cyclopropyl) NH; 5-Ph-7-Cl H, EtOOCNH; 5-Ph-7-CI H, EtOOCNH; 5-(2-C1C6H,)-7-C1 H, EtOOCCHZNH, 5-Ph-7-Cl H, EtNH; 5-Ph-7-CI H, MeO; 5-Ph-7-CI H, Me; 5-Ph-7-Br, 4-Oxide H, Me; 5-Ph-7-C1, 4-Oxide H, MeNH; 5-Ph H, MeNH; 5-Ph-7-CI 4-Oxide
CH,CI,/MeOH Me,CO EtOH EtOH DMF/H,O MeOCH,CH,OH EtOH EtOH EtOH DMF/H,O EtOAc Dioxane C,H,N/Ac,O PhH/Hexane EtOH DMF/H,O
12 92 65 78 83 81 56
ir, pmr
70 72 92 73 81 77 84
86
ir, uv
66 113, 115 114 113, 115 113, 115 113, 115 25 117 66, 67 66, 67 117 66 66, 118 66, 118 66 117 87a 34, 44 33 117 66, 117 117
H, MeNH; 5-Ph-7-MeO H, MeNH; 5-Ph-7-Me H, MeNH; 5-Ph-7-NO2 H, MeNH; 5-Ph-7-F3C H, MeNH; 5-(2-FC6H4)-7-MeNHCONH H, MeNH; 5-(4-MeOC6H,)-7-C1 H, PhNH; 5-Ph-7-CI H, PhNH; 5-Ph-7-NOz Bu, Me; 5-Ph-7-CI 4-Oxide Me, H,N; 3-Ac0-5-Ph-7-Cl
!2
Me, H,NCO 3-H2N-5-Ph-7-C1 Me, C1; 3-Ac0-5-Ph-7-Cl Me, CICH,CH,NH; 5-Ph-7-CI Me, EtOOC; 3-Et0-5-Ph-7-CI Me, Et; 5-Ph-7-C1, 4-Oxide Me, H; 3-Ac0-5-Ph-7-CI Me, Me; 3-Ac0-5-Ph-7-CI Me, Me; 5-Ph-7-CI 4-Oxide Me, Me; 5-Ph-7-Me, 4-Oxide Me, Me; 5-Ph-7,8-Me2, 4-Oxide Me, Me; 5-(4-C1C6H4)-7-C1,4-Oxide Me, Me; 5-(4-MeOC6H,), 4-Oxide Me, Me; 5-(4-MeOC6H,)-7-Cl, 4-Oxide Me, Me; 5-(4-MeC,H4)-7-Br, 4-Oxide Me, MeNH; 5-Ph-7-CI 4-Oxide
197-1 99 212-21 3d 214215d 207-210 255-257d 21G211 228-229d 230-23 Id 87-88 13G132 137-140 195-204 28G284 138-143 112-116 Oil 213-214 192-193 145-146 159-160 162 186187 205-206 193-194 191-192 181-182 2 18.5219.5 188-190 209-210 235-243 175-177
EtOH EtOH DMF/H,O MeOH EtOAc MeOH DMF/H,O DMF/H,O Hexane Me,CO/Hexane CH,CI,/Et,O
117 117 117 117 70 117 117 117 38b 38b 9
THF/EtOH CH,CI,/Hexane i-PrOH
9 9 66 9 44,110 112a
CH,CI,/Me,CO Et,O/Petr ether Et,O Et,O/Petr ether Et,O/Petr ether Me,CO Me,CO/Et,O Me,CO Me,CO CH,CI,/Hexane Me,CO/Petr ether i-PrOH CHCI,/EtOAc
72
32 34
ms, pmr ir ir, ms, pmr ir
82 54
ir
94 11
ir, ms, pmr, uv
110 51, 125 33,44, 51 34,44, 110 34,44, 51 34, 44 34, 44 48 110 34,44, 51 66 119
TABLE V-9. dc ont d. )
Substituent
mp CC); CbP ("C/torr)I
Solvent of Crystallization
Me, Pr; 5-Ph-7-C1, 4-Oxide
169-170
Et,O
Yield
(YO)
Spectra ir
Refs.
44, 110
H K N-CR
X,R; Others
2 h)
NH, NH,; 5-Ph-7-C1, 4-Oxide Hydrochloride NH, Et; 5-Ph-7-Cl NH, Me; 5-Ph-7-Cl 4-Oxide NH, Me; 5-Ph-7-NO2 NH, Me; 5-(4-MeOC6H,)-7-C1 S, MeNH; 5-Ph-7-Cl S, MeNH; 5-Ph-7-NO2
255-256d 146147 174-174.5 181-182 179-180 136138 21 1-212d 191-192d
41 102, 103 102, 103 102, 103 102, 103 102, 103 117 117
i-Pr,O EtOAc EtOAc EtOAc Me,CO DMF/H,O EtOH Me
5-(4-MeOC6H,)-7-C1
142-143
i-Pr,O
102, 103
TABLE V-10. N-HYDROXY 2-AMINO-3H-1,4-BENZODIAZEPINES Substituent
mp YC); [bp (Tjtorr)]
Solvent of Crystallization
126130 25Cb255d 155-160 212.5-213.5 12&127d 18&18 1.5 251.5-252.5 99- 100 113-114 121-123 181-183 214216d 105.5-106.5 185-186 232-234 158.5-159.5 124-128d 99d 117d 212-215 182-1 85d 224-226
EtOAc CH,Cl,/EtOH Et O/Hexane MeOH/EtOAc CH,C1, MeOH EtOAc EtOAc/Hexane Et,O/Hexane
Yield (YO)
Spectra
Refs.
58 73
uv ir, pmr, uv
56
ir, pmr, uv
54 14 91 31
uv
131, 132, 135 92 70 135 70 131, 135 131, 135 131, 135 131, 135 19b 19b 19b 135 131, 135 92 131, 135 112b 112b 112b 112b 112b 112b
R; Others
VI
N
w
H; 5-Ph-7-CI 4-Oxide H; 5-(2-C1C6H4)-7-NOz Ac; 5-Ph-7-Cl Ac; 5-(2-C1C6H4)-7-N02 PhCH,; 5-Ph-7-CI t-Bu; 5-Ph-7-CI EtzNCHzCHZ; 5-Ph-7-Cl.0.5NZO EtOOCCH,; 5-Ph-7-Cl 4-0xide EtO(Me)CH; 5-Ph-7-C1, 4-Oxide (14midazolo)CO; 5-Ph-7-C1 Me; 5-Ph-7-CI 4-Oxide Me; 5-(2-C1C6H4)-7-C1 PhNHCO; 3-PhCHzOCOO-5-Ph-7-C1 PhNHCO: 3-Me2NC00-5-Ph-7-C1 PhNHCO; 3-Me,NC00-5-(2-C1C6H4)-7-CI PhNHCO; 5-Ph-7-CI PhNHCO; 5-Ph-7-NO2 PhNHCO; 5-(2-ClC,H4)-7-C1
,
Et,O CH,CI,/Et,O EtOAc/Petr ether MeOH CH,CI,/EtOH EtOAc EtOH
DMF/H,O EtOH EtOH
uv uv uv ir, pmr, uv
52 62.5 79 70
ir, pmr, uv ir, pmr, uv uv ir, pmr, uv uv
TABLE V-10. g c o n t d . )
VI h)
Substituent
mp W ) ; [bp (Tjtorr)]
Solvent of Crystallization
PhNHCO; 5-(2-ClC,H4)-7-NOZ PhNHCO; 5-(2-FC6H4)-7-C1 PhNHCO; 5-(2-pyridyl)-7-Br (4-t-BuC6H4)NHCO;5-Ph-7-CI (3-CIC6H,)NHCO 3-Me2NC00-5-Ph-7-Cl (3-CIC6H,)NHCO, 3-Me2NC00-5-(2-C1C,H4)-7-C1 (3-CIC6H,)NHC0, 3-Me-5-(2-C1C,H,)-7-N02 (+) (3-CIC,H,)NHCO, 5-Ph-7-CI Hydrochloride (3-CIC6HJNHCO; 5-Ph-7-NOZ (3-CIC6H4)NHCO;5-(2-C1C6&)-7-C1 (3-ClC6HJNHCO; 5-(2-C1C6H,)-7-N02 (3-C1C,H,)NHCO; 5-(2-FC6H,)-7-C1 (3-CIC,H4)NHCO; 5-(2-FC6H4)-7-NO2 (3-CIC,H,)NHCO, 5-(2-Pyridyl)-7-Br (3-CI-4-MeC6H,)NHCO-5-Ph-7-C1 (4-CIC6HJNHCO 5-Ph-7-Cl (3,4-C12C6H3)NHCO;5-Ph-7-Cl (3,4-CIzC,H,)NHCO; 5-(2-CIC6H,)-7-N02 (4-EtOOCC6H4)NHCO; 5-Ph-7-Cl (2-FC6H4)NHCO; 5-Ph-7-CI (3-MeC,H4)NHCO; 5-Ph-7-Cl (4-MeC6H,)NHCO; 5-Ph-7-CI (2,5-Me,C,H,)NHCO; 5-Ph-7-CI
20 1-203 12&128 19G192 221-223 105d 121d 137-139 157-1 59 210 123-125 125-137 13G-135 194-196 126130 19G191 2 18-220 2W203 218-219 19G192d 212-2 14 193-195 156 22G221 181-183
EtOH i-PrOH EtOH EtOH
EtOH MeOH/DMF EtOH EtOH EtOH EtOH MeOH/EtOH MeOH MeOH EtOH EtOH EtOH EtOH EtOH EtOH EtOH
Yield (%)
Spectra
Refs. 112b 112b 112b 112b 112b 112b 112b 112b 112b 112b 112b 112b 112b 112b 112b 112b 112b 112b 112b 112b 112b 112b 112b 112b
(2,6-Me,C,H3)NHCO; 5-Ph-7-Cl (2-F3CC,H,)NHCO, 5-Ph-7-CI (3-F3CC,H,)NHCO, 5-Ph-7-Cl (4-F3CC,H,)NHCO; 5-Ph-7-CI Propen-3-yl; 5-Ph-7-CI Propen-3-yl; 5-Ph-7-N02 Propen-3-yl; 5-(2-CIC6H,)-7-C1 2-14c (1-Pyrrolidino)CH,CH,; 5-Ph-7-CI hydrate
198-200 190 95 215-218 134-1355 178-180 13C131 129-131 137.5-138.5
EtOH MeOH/DMF EtOH i-PrOH EtOAc EtOAc/Hexane EtOAc/Hexane
181-183 162-165 158-161 167-168 213-2 15d 126128 113-115 147-149 126128
Et,O Et,O/Petr ether Et,O/Petr ether EtOAc EtOH Et,O/Petr ether Et,O/Petr ether Et O/Pet r ether Et,O/Petr ether
EtOAc
36.5
uv
38 84 42; 44
uv uv
48 97 95 87
ir, ms, pmr ir, pmr ir, pmr ir, ms, pmr
98 75 94 98
ir, ms, pmr ir, ms, pmr ir, pmr ir, ms, pmr
112b 112b 112b 112b 131, 135 131 131, 135 133 131, 135
R , , R,; Others
2 vI
PhCH,, H; 5-Ph-7-Cl PhCH,, (Cyclohexyl)NHCO, 5-Ph-7-Cl PhCH,, PhNHCO; 5-Ph-7-CI Me, H; 5-Ph-7-CI 4-Oxide Me, Ac; 5-Ph-7-Cl Me, PhCO; 5-Ph-7-Cl Me, (Cyclohexy1)NHCO;5-Ph-7-CI Me, MeNHCO S-Ph-7-Cl
,
112a 112a 112a 112a 8% 112a 112a 112a 112a
TABLE V-1 1. 2-HYDRAZINO-3 H-l,4-BENZODIAZEPINES
Substit uen t
mp V J ; [bp/("C/torr)]
Solvent of Crystallization
168-169 116-118d 217.5-219 203-205d 262-263d 288-290 11G120 24&241 213-215 226d 266d 133-1 35d 285-28 7d 220-223d 230-233 > 300 126-129 214220 > 300 218-228d 224226
CHCI,/Hexane CH,CI,/PhH EtOAc CH,CI,/PhH CHCI,/Et,O CH,CI,/Et,O CHCI,/Et,O CHCI,/Et,O
Yield (%)
Spectra
Refs.
R; Others
H; 3-(2-Me-Prop-l-yl)-5-Ph-7-CI H; 5-Ph.0.33PhH H; 5-Ph-7-Cl WI h,
m
4-Oxide H; 5-Ph-7-MeO H; 5-Ph-7-Me
H, 5-Ph-7-NOz 4-Oxide H; 5-Ph-7-F,C 4-Oxide H; 5-(2-C1C6H4)-7-C1
H; 5-(4-C1C6H4)-7-C1,4-Oxide H; 5-(2-FC6HJ-7-Et H; 5-(4-MeOC6H4)-7-C1 4-0xide H; 5-(2-pyridyl)-7-Br
65 74 63-81 94 83 77 95
EtOH CHCI,/Hexane CHCI,/PhH CHCIJHexane THF/MeOH CHCI,/PhH MeOH PhH CHCI,/PhH MeOH CHClJMeOH
87 94 98 91 90 80 90
pmr, uv Pmr ms, pmr, uv
47, 140 47,140 134, 137, 175 47, 136, 146 47, 137, 143, 144 92 47, 140 47, 140 142 139a, 140 47 47, 140 47 47 143, 144 47 85c 140 47 141 173
Ac; 5-Ph-7-Cl 4-0xide Ac; 5-Ph-7-N02.0.5H,0 Ac; 5-(2,6-F,C,HJ-7-C1 PhCO, 5-Ph-7-Cl (7-C1-5-Ph-3H-1,4-Benzodiazepin-2-yl); 5-Ph-7-Cl (Cyclohexyl)CO, 5-Ph-7-Cl EtOOC; 5-Ph-7-C1 EtOOC; 5-(2-C1C,H4)
I .
EtOOC; 5-(3-MeOC6H,)-7-C1 EtOOCCO; 5-Ph-7-Cl HCO, 5-Ph-7-CI.0.5MeOH MeOOC; 5-Ph-7-Cl Me; 5-Ph-7-Cl.0.25EtOAc MeNHCO 5-Ph-7-Cl 4-Oxide MeNHCO, 5-Ph-7-N02 MeNHCO; 5-(4-MeOC6H,)-7-C1 (3-Oxocyclohexen-l-y1)-5-Ph-7-C1, 4-Oxide
(4-0~0-2-penten-2-yI)-5-Ph-7-C1 4-Oxide PhNHCO; 5-Ph-7-Cl PhNHCS; 5-Ph-7-Cl PhCHZCO: 5-Ph-7-Cl EtCO, 5-Ph-7-Cl
202-204d 209-210 25tL258 272-275d 184-185 274-277 207-208d 253-254 224-225 205-206d 198-199d 226228 214-215 177.5-178.5 173-1 75d 161-162 20 1-203d 209d 247d 251-252d 239-24Od 234235d 223-224d 1 5 4 157 185-186 22@221d 199-205d 224-225
186187d
CHClJMeOH MeOH DM F/H 0 DMF DMF/H,O EtOH CHClJMeOH CHCIJHexane DM F/H 0
,
,
CH,Cl,/EtOAc EtOH DMF EtOH/Et,O EtOH MeOH EtOAc EtOAc DMF/H,O DMF/H,O DMF/H,O DMF/H,O CH,CI,/MeOH/Et,O i-PrOH CH,Cl,/Et,O DM F/H ,O Me,CO DMF/H,O CHCIJMeOH
47, 150
81 71; 73 82 79; 89 26 93; 97
ms
77
uv
53 54
85
90 94
ir, pmr, uv
47, 140 143, 144 47 150 47, 140 136, 137 47. 140 134, 152 25 25 145, 164 47, 140 85c 146 146, 165 146, 165 146, 165 146, 165 161 162, 163 162, 163 146, 165 146, 165 47 47
TABLE V-11. -4contd.)
Substituent
mp K ) ; [bp/(”C/torr)]
Solvent of Crystallization
178.5-179.5 220-222 1-163 215-215.5d 142-1 46 175.5-176.5
EtOAc/Hexane CH,Cl,/i-PrOH MeOH/EtOAc EtOAc Et,O i-PrOH
Yield (%)
Spectra
Refs.
57
ir, pmr, uv pmr, uv
146, 148, 149 92 149 148 145 145
R , , R,; Others
VI
u
00
Me, H,5-Ph-7-CI 4-Oxide Me, H; 5-(2-C1C6H,)-7-C1 Me, Ac; 5-Ph-7-CI Me, EtOOCCO; 5-Ph-7-CI Me, Me; 5-Ph-7-CI
ir, ms, pmr, uv 35
95
Me
cr” H
/
--N
5-Ph-7-CI
R,, R,; Others
211.5-212.5 203-204d
EtOAc MeOH/EtOAc
ir, ms, pmr, uv
148 148
H, HOOC; 5-Ph-7-CI methanolate H, CICH,; 5-Ph-7-CI H, Et; 5-Ph-7-CI H, CH=CH,; 5-(2-CIC,H4)-7-C1 H, CH(OH)CH,OH; 5-Ph-7-C1, 4-Oxide H, MeOOC; 5-Ph-7-CI, 4-Oxide H, Me; 5-Ph-7-CI 4-Oxide H, Ph; 5-Ph-7-CI H,N, Me, 5-Ph-7-Cl HOOC, HOOCCH2CH2; 5-Ph-7-CI HOOC, EtZN(CHJ3; 5-Ph-7-CI HOOC, Me; 5-Ph-7-CI Methanolate HOOC, Me; 5-(2-C1C,H4)-7-C1, ethanolate CICH,, CICH,; 5-Ph-7-CI CICH,, Me; 5-Ph-7-CI CICH,, Me; 5-(2-C1C,H4)-7-C1 (MeO),CH, Me; 5-Ph-7-CI (MeO),CH, Me; 5-(2-C1C,H4)-7-C1 EtOOC, EtOOCCH,; 5-Ph-7-CI EtOOC, Me; 5-Ph-7-CI EtOOC, Me; 5-(2-Pyridyl)-7-Br MeOOC, MeOOC(CH,),; 5-Ph-7-CI MeOOC, Me; 5-Ph-7-CI MeOOC, Me; 5-(2-C1C,H4)-7-CI methanolate MeOOCCH,, Me; 5-Ph-7-C1, 4-Oxide Me, Me; 3-(Me2CHCH,)-5-Ph-7-C1 Me, Me; 5-Ph-7-CI 4-Oxide Me, Me; 5-Ph-7-Me
164166d 2 1G235d 149-150 157-159 20 1-203d 19G192d 151-1 52 162-164 198-2OOd 168-169 203-205d 212d
MeOH Et,O Me,CO CH,CI,/Petr ether CH,CI,/Et,O/MeOH CH,Cl,/i-PrOH Et,O
77 52
MeOH
95 60
183-1 85d 145-165d 147-15 Id 165-25Od 21G227d 202-2 17d 182-1 83 157-158
EtOAc MeOH EtOH CH,CI,/MeOH EtOAc i-PrOH EtOAc/Hexane EtOAc/Hexane
Me,CO MeOH
22 72 73 85
ir, pmr, uv
ir, uv pmr, uv ir, ms, pmr, uv pmr, uv
94.5 Pmr 76 97 94 64.5
79 97 60 81 Pmr Pmr
23G233d
CH,CI,/MeOH/Et,O
72
156157 171.5-1 76 109d 165-167 189-190 184.5-1 85.5 223-224 194-195
CHCI,/Et,O EtOAc MeOH CH,Cl,/Et,O/Petr
67 53 77.5 30
Pmr
Me,CO Me,CO
ether
ir, pmr, uv pmr, uv pmr, uv
145, 160 145, 156 155 154 154 154 154, 155 148 154 155 140 145, 160 160 145, 160 160 160 145, 157 145, 156 145, 156 145, 158 145, 158 160 160 145 160 145, 160 145 145, 160 161 47 47, 136, 137 47, 136, 137 47
TABLE V-11. g c o n t d . )
Substituent
mp ("C); [bp/("C/torr)]
Me, Me; 5-Ph-7-NO2 4-Oxide Me, Me; 5-Ph-7-F3C Me, Me; 5-(2-C1C6H,)-7-C1 Me, Me; 5-(4-C1C6H,)-7-C1, 4-Oxide
203-205 244-245 224225 167-168 211-213
Solvent of Crystallization
Me,CO/Hexane
Yield (%)
Spectra
Refs. 47 47 47 47, 145 47
97
R , , R,; Others 111 W
0 6
H, H; 5-Ph-7-CI H, Me; 5-Ph-7-CI
137-138 199-200
5
CH,CI,/Et,O EtOAc
ir, ms, pmr, uv X-ray
7b 148 148
R; O t k r s
CI; 5-Ph-7-Cl MeO; 5-Ph-7-CI
174177d
40 47
145 145
TABLE V-12. 2-OR-3H-1,4-BENZODIAZEPINES mp C' C); [bp (" C/torr)]
Substituent
Solvent of Crystallization
Yield (YO)
Spectra
Refs.
R; Others
VI W
Bu; 3,3-Me,-5-(2-C1C6H,)-7-NO, Bu; 3,3-Me,-5-(2-FC,H4)-7-NO,-9-CI Bu; 5-Ph-7-C1, 4-Oxide (EtO),PO,; 3-Me0-5-(2-C1C,H4)-7-CI Et,N(CH,),; 3,3-Me,-5-(2-FC,H,)-7-HzN-9-Cl Et,N(CH,),; 3,3-Me,-5-(2-FC,H4)-7-NO,-9-CI (MeO),PO,; 3-Me0-5-(2-C1C,H4)-7-CI Me,N(CH,),; 5-Ph-7-C1,4-Oxide (Morpholino),PO,; 3-(Et0),CH-5-(2-C1C6H,)-7-NO, (Morpholino),PO,; 3-Me-5-(2-C1C6H,)-7-NO, (+)
82 113 91-93 132-134 10&107 107-108 123-1 25 105-110 216 230-234
Petr ether Hexane/Petr ether CH,CI,/Petr ether PhMe/Hexane EtOH/Petr ether Et,O/Hexane PhMe Et,O Et,O PhH
30 50-75
50-75 42
ir, pmr, uv
pmr, uv
[alD
+ 375.5"
70 70 161 195 70 70 195 92 70 70
(1% in CH,Cl,)
(Morpholino),PO,; 3-Me-5-(2-C1C6H,)-7-NO, (-)
228-232
PhH
(Morpholino),PO,; (Morpholino),PO,; 4-Oxide (Morpholino),PO,; (Morpholino),PO,; (Morpholino),PO,; (Morpholino),PO,;
90-95 189-191 160-166 178-182 208-209 185-187 214-216
Et,O EtOAc PhH/Hexane CH,CI,/Et,O EtOAc CH,Cl,/Et,O CH,Cl,/Et,O
3-Me-5-(2-FC6H,)-7-C1 5-Ph-7-CI
5-Ph-7-(2-Me-1,3-dioxolan-2-yl 5-Ph-7-NO2 5-(2-C1C6H,)-7-C1 5-(2-C1C6H,)-7-NO,
[orlo - 375.5" (1y0 in CH,CI,) ir, ms, uv
ir, ms, uv ir, ms, uv
70 21 87b 200 9 21 87b 87b
TABLE V-12. 4 c o n t d . )
Substituent
W,
w h)
(Morpholino),PO,; 5-(2-FC6H,)-7-C1 (Morpholino),PO,; 5-(2-FC6H,)-7-CN (Morpholino),PO,; 5-(2-FC6H,)-7-I (Morpholino),PO,; 5-(2-FC,H,)-7-N02 (Morpholino),PO,; 5-(2-pyridyl)-7-Br Et; 3-Me0-5-(2-C1C6H,)-7-C1 Et; 3-Me-5-Ph-7-C1,4-Oxide Et; 3,3-Me,-5-(2-ClC,H4)-7-NO2 Et; 3,3-Me,-5-(2-FC,H4)-7-NO2-9-C1 Et; 5-Ph-7-CI Et; 5-Ph-7-NO2 Et; 5-(4-MeOC6H,)-7-C1 HO(CH,),; 3,3-Me,-5-(2-FC,H4)-7-NO,-9-C1 HqCH,),; 5-Ph-7-Cl HqCH,),; 5-(2-FC6H,)-7-C1 Me; 3-Me-5-Ph-7-CI 4-Oxide Me; 3,3-Me,-5-(2-FC,H4)-7-NO2-9-Br Me; 5-Ph-7-CI
4-Oxide Me; 5-Ph-7-CN Me; 5-(2-FC6H,)-7-C1 4-Oxide
mp (" C); [bp (" Cjtorr)] 140-142 194197 104-112 169-172 18&182 11&113 156157 151 Oil 143- 145 119-120 142-145 142-144 11&118 105-107.5 194-196 21&211 88-94 94-97 [141-148/0.1] 186188 142-142.5 79-8 1 192-195
Solvent of Crystallization PhH/Hexane CH2CI,/Et,0 CH,CI,/Et,O EtOAc CH,CI,/EtOAc Et,O Hexane Petr ether Et,O/Hexane Et ,O/Hexane i-Pr,O Et,O Et,O/Hexane Et,O/CH,CI,/Petr ether Hexane PhH CH,CI,/Petr ether Et,O/Petr ether Petr ether MeOH EtOAC/Hexane Et,O/Hexane Et,O
Yield (YO)
Spectra
55
22 ir, pmr ir, pmr
82
87 94
ir, pmr, uv
Refs 7b 9 21 21 21 179 178 70 70 142 142 142 70 87a 9 18 18 70 180 87a 185 92 184 9 24e
Me; 5-(2-FC6H,)-7-NO, Ph; 5-Ph-7-CI Ph; 5-Ph-7-N02 Ph; 5-(2-CIC6H,)-7-Br Ph; 5-(2-C1C6H,)-7-C1 Ph,5-(2-C1C6H,)-7-F 4-(AcNH)C,H,; 5-Ph-7-Cl 4-(AcNH)C6H4;5-(2-C1C6H4)-7-C1 2-(H2NCO)C6H4;5-Ph-7-CI 2-(PhCH,0)C6H4; 5-Ph-7-CI 4-BrC6H,; 5-Ph-7-CI 4-CIC6H4;5-Ph-7-CI 3-(Me,N)C,H,; 5-Ph-7-CI 4-(Me,N)C,H,; 5-Ph-7-CI 4-(Me,N)C,H,; 5-(2-C1C6H,)-7-C1 4-(Me,NCH,)C,H,; 5-Ph-7-CI 4-(Me,NCH,)C,H,; 5-(2-C1C,H4)-7-CI 4-(Me,NCH,)C,H,; 5-(2-FC6H,)-7-C1 3-MeC6H,; 5-Ph-7-CI 4-NO2C,H,; 5-Ph-7-CI 4-(PrOOC)C,H,; 5-Ph-7-Cl Propen-3-yl; 5-Ph-7-C1,4-Oxide Pr; 3,3-Me2-5-(2-FC,H,)-7-NO,-9-C1 Pr; 5-Ph-7-CI Pr; 7-C1, 4-Oxide i-Pr; 3,3-Me2-5-(2-C1C,H,)-7-NO, i-Pr; 3,3-Me,-5-(2-FC,H,)-7-H2N-9-C1 i-Pr; 3,3-Me,-5-(2-FC6H,)-7-NO,-9-C1
155-157 131-133 178-181 155-158 151-152 11G112 168-1 69 188-191 186-187 119-122 105-1 10 105-1 10 117-1 18 129-130 12&122 171-1 72 112-115 102-1 06 93-94 133-135 111 12&122 117-1 18 [1 6 4 170/0.25] 148-149 11c-112 92-93 102
20 1 90 90 90 90
Et,O/Petr ether
Et,O/Petr ether
90 90
Me,CO/Et,O
Me,CO/Hexane Et,O/Hexane/Petr ether
49
Me,CO Et,O/Petr ether Hexane Hexane/Petr ether
36
pmr, uv
Pmr
90 90 90 90 90 90 90 90 90 90 90 90 90 90 92 70 185
185 70 70 70
TABLE V-13. 2-SR-3H-1,4-BENZODIAZEPINES
Substituent
mp (" C); [bp (" Cjtorr)]
Solvent of Crystallization
73-75 Oil 123-125 182-184 107-1 11 191d
PhH
Yield (YO)
Spectra
Refs.
R; Others
VI
w
H2NCOCH2; 5-(2-C1C6H4)-7-C1 Bu; 5-(2-C1C6H4)-7-C1 PhCOOCH2CH2; 5-(2-CIC,H4)-7-C1 HOOCCH,; 3-Me-5-Ph-7-CI HOOCCH,; 5-Ph-7-CI HOOCCH,; 5-(2-CIC6H4)-7-C1 15-(2-C1C6H4)-7-Cl-3H-l,4-Benzodiazepin-2-y1]-S(CH2),; 5-(2-C1C,H4)-7-C1 Bu,N(CH,),; 5-(2-C1C6H4)-7-C1fumarate Et,N(CH,),; 5-(2-C1C6H4)-7-Clfumarate Hex,N, (CH,),; 5-(2-C1C6H4)-7-Clfumarate Me,N(CH,),,; 5-(2-C1C6H4)-7-C1fumarate Me,N(CH,),; 5-Ph-7-Cl fumarate Me,N(CH,),; 5-Ph-7-N02 maleate Me,N(CH,),; 5-(2-C1C6H4)7-C1fumarate
Maleate Me,N(CH,),; 5-(2-C1C,H4)-7-N02 maleate Me,N(CH,),; 5-(2-FC6H4)-7-Br
173-175 169-1 7 1 158-1 60 113-1 15 53-58 197-199 131-1 34 6&72 158-161 1W142 196198 105-108
PhH/Hexane CH,CI,/EtOH EtOH/H,O Et,O
85 80 84 uv 17.2
EtOH Me,CHCH,Ac Me,CHCH,Ac Et,O EtOAc/Et,O MeOH EtOH/Et,O
11.3 58 44 59 48
i-PrOH EtOAc i-PrOH/Me,CO MeOH Et,O/Hexane
72 48; 62; 75
ir, pmr
Pmr
55
48.5 ir, pmr
22.7 76.4
181 181 181 187 187 181 181 181, 186 181, 186 181, 186 181, 186 181, 186 181, 186 181 181 181, 187 186 181, 186 181, 186
Me,N(CH,),; Me,N(CH,),; Me,N(CH,),; Me,N(CH,),; Me,N(CH,),; Me,N(CH,),; Me,N(CH,),; Me,N(CH,),;
m m
5-(2-FC6H,)-7-C1 fumarate 5-(2-FC6H,)-7-NO, fumarate 5-(2-HOC6H,)-7-C1 5-(2-MeOC6Hd)-7-C1 maleate 5-(2-MeOC,Hd)-8-C1 fumarate 5-(2-C1C6H,)-7-C1 maleate 5-Ph-7-CI maleate 5-(2-C1C6H,)-7-C1 fumarate
Me,NCH,CHMe; 5-(2-C1C6H,)-7-CI fumarate i-Pr,N(CH,),; 5-(2-C1C6H,)-7-C1 fumarate EtO(CH,),; 5-(2-ClC,H4)-7-C1 Et; 5-Ph-7-C1, 4-Oxide Et; 5-(2-C1C6H4)-7-C1 EtS(CH,),; 5-(2-C1C6H,)-7-CI (Hexahydroazepino) (CH,),; 5-(2-C1C6H,)-7-C1 fumarate (Hexahydroazepino) (CH,),; 5-(2-C1C6H,)-7-C1 fumarate [4-(2-MeOC,H,)Piperazino]-(CH2),; 5-(2-C1C6H,)-7-C1-fumarate Me; 3-Me-5-(2-C1C,H,)-7-N02 Me; 3-Me-5-(2-FC6H,)-7-C1 Me; 3-(3-Hydroxyiminobut-1-yl)-5-(2-ClC6H4)-7-N02 Me; 3-(3-Methyliminobut-1-yl)-5-(2-C1C6H,)-7-NO, Me; 3-(3-Oxobut-l-yl)-5-(2-C1C6H4)-7-NO, Me; 3-(3-Oxobut-1-yl)-5-(2-FC6H4)-7-NO, Me; 5-Ph-7-CI Me; 5-(2-C1C6H,) Me; 5-(2-C1C6H,)-7-C1 Me; 5-(2-C1C,H4)-7-N0, Me; 5-(2-FC6H,)-7-C1
164166 153-157
i-PrOH EtOH
68 73.2
142-145 172-174 108-1 10 91; 13C133 154156
Me,CO/EtOAc
70
EtOAc Me,CO/Et,O EtOH/Me,CO i-PrOH i-PrOH/Et,O i-PrOH
65
ms
178-180 156158 Oil 142-144 114-118 7677 17G171 164167 18G181 160 145-147 165-167 165-167 135 163 132-134 109-1 11 118-120 123-125 164166 72-77
CH,Cl,/Et ,O/Hexane EtOH Hexane i-PrOH THF/Et,O i-PrOH EtOH/Et,O EtOH CH,CI,/Et,O/Petr ether Et,O/Petr ether EtOH/Petr ether EtOH/Et,O EtOH EtOAc/Petr ether EtO Ac/cyclohexane EtOH EtOH Et,O/Petr ether
41; 71 34.6; 52 56 37 28 73.5 63.5 66.4 39
76 45 84
pmr, uv
181. 186 181. 186 186 181, 186 186 181, 186 202 186 181 181, 186 181 181 92 181 181 181, 186 186 186 70 70 70 70 70 70 72, 73 126a,b 131, 135
181
70 9
TABLE V-13. d c o n t d . )
Substituent
mp("C); [bp (" Cjtorr)]
Solvent of Crystallization
Me; 5-(2-FC6H4)-7-MeNHCONH Me; 5-(2-FC,H,)-7-N02 (4-Me-Piperazino)(CH,),; 5-Ph-7-Cl difumarate (Morpholino) (CH,),; 5-(2-C1C6H,)-7-C1 fumarate (Morpholino)(CH,),; 5-(2-C1C6H,)-7-C1 fumarate Ph; 5-Ph-7-C1 (Phthalimido)(CH,),; 5-(2-C1C6H,)-7-C1 (Piperidino) (CH,),; 5-Ph-7-F3C fumarate (Piperidino) (CH,),; 5-(2-C1C6H,)-7-C1 fumarate (Piperidino) (CH,),; 5-(2-C1C6H,)-7-C1 fumarate Pr; 5-(2-C1C6H4)-7-C1 (Pyrrolidino) (CH,),; 5-(2-C1C6H,)-7-C1 fumarate (Pyrrolidino) (CH,),; 5-(2-C1C6H,)-7-C1 fumarate
211-212 161-163 193-1 94d 191-193 169-1 7 1 105-108 143- 146 132-134 198-199 11G112 71-72 184-188 148-1 5 1
EtOAc EtOH THF EtOH i-PrOH
42 53.5 59.5
Me,CHCH,A( :/Et,O Me,CO/Et,O MeOH THF/Et,O Hexane i-PrOH i-PrOH
77 38.5 67 76.8 75.5 55 54.8
Yield (%)
Spectra
Refs. 70 70 186 181, 186 181, 186 90 181 181, 186 181, 186 181, 186 181 181, 186 181, 186
TABLE V-14. 2-HALO-3H-1,4-BENZODIAZEPINES
Substituent
mp (" C); IbP (" C/torr)I
2-Br-5-Ph-7-CI 2,7-C1,-3-Me0-5-(2-CIC6H4) 2,7-C12-5-Ph 2,7-Cl2-5-(2-ClC,H,) 2,7-CI2-5-(2-FC,H,) 2,7-CI,-5-(2,6-F,C6H,) 2-C1-5-(2-C1C6H4)-7-Br 2-C1-5-(2-CIC,H4)-7-F,C 2-F-5-Ph-7-Cl
137-139 137-141 139-142 125-1 26 88-90 135-139 134-137 112-115 121-124
Solvent of Crystallization
MeCN/C yclohexane Ligroin Et,O/Petr ether Et,O/Petr ether
Yield ( % )
50
Spectra
Refs.
193 194 193 193 193 193 193 193 193
TABLE V-15. 5H-1,4-BENZODIAZEPINES
Substituent
2-Me0-3-Me-5-Ph-7-CI 4-Oxide 2-Me-3-Ph 2,3-Me2-5-Ph-7-C1 2-MeNH-SPh-7-C1,4-0xide 2-Pr0-5-Ph-7-Cl 3-C1CH2-5-Ph-7-C1, 4-Oxide 3-C1CH2-5-Ph-7-N0,, 4-Oxide 3-Me-5-Ph. 4-Oxide
3-Me-5-Ph-7-NO2,4-Oxide 3-Ph 3-Ph-7-Br 3-PhNH-5-Ph-7-Cl 3-PhNAc-5-Ph-7-Cl 5-Ph-7-C1,4-Oxide
mp (" C); [bp(" Cjtorr)]
Solvent of Crystallization
139-141 191-194 122-124 151-1 54 21e212 79-80 [154/0.1] 125-128d 139-141 182-184 196200 169-1 70d 165-175d 224-226d 117-120 127-129 107-109d 167-17Od 157-158.5
Hexane EtOAc Hexane MeOH EtOH Petr ether EtOAc EtOH Me,CO/Hexane Et,O CH,CI,/Hexane EtOAc PhH/Hexane EtOH EtOH Et,O/Hexane EtOAc/Petr ether EtOH
Yield (YO)
Spectra
Refs.
18 18 18 18 197 185
96 pmr, uv
pmr, uv
pmr, uv
12-14 18 12, 13 12, 13 14 12, 13 12, 13, 17 18 18 18 18 11, 14
5. References
539
5. REFERENCES 1. (a) F. Hollywood, E. F. V. Scriven, H. Suschitzky, D. R. Thomas, and R. Hull, J. Chem. Soc., Chem. Commun., 806 (1978). (b) F. Hollywood, Z. U. Khan, E. F. V. Scriven, R. K. Smalley, H. Suschitzky, and D. R. Thomas, J. Chem. Soc., Perkin Trans. I , 431 (1982). 2. R. I. Fryer, D. L. Coffen, J. V. Earley, and A. Walser, J . Heterocycl. Chem., 10, 473 (1973). 3. J. V. Earley, R. I. Fryer, and A. Walser, U S . Patent 3,836,521, September 1974. 4. J. V. Earley, R. I. Fryer, and A. Walser, US. Patent 3,838,116, September 1974. 5. (a) A. Walser and R. I. Fryer, Hoffmann-La Roche, Nutley, NJ, unpublished data. (b) A. Walser and J. Hellerbach, Hoffmann-La Roche, Nutley, NJ, unpublished data. 6. J. V. Earley, R. I. Fryer, and A. Walser, US. Patent 3,869,448, March 1975. 7. (a) D. L. Coffen, J. P. DeNoble, E. L. Evans, G. F. Field, R. I. Fryer, D. A. Katonak, B. J. Mandel, L. H. Sternbach, and W. J. Zally, J. Org. Chem., 39, 167 (1974). (b) D. L. Coffen et al., Hoffmann-La Roche, Nutley, NJ, unpublished data. 8. R. I. Fryer, J. V. Earley, and L. H. Sternbach, J. Org. Chem., 32, 3798 (1967). 9. R. I. Fryer et al., Hoffmann-La Roche, Nutley, NJ, unpublished data. 10. U. D. Shenoy, US. Patent 4,006,135, February 1977. 11. Neth. Patent 6,614,923, April 1967 (Hoffmann-La Roche & Co., Switzerland). 12. G. F. Field and L. H. Sternbach, U.S. Patent 3,594,365, July 1971. 13. G . F. Field and L. H. Sternbach, US. Patent 3,594,364, July 1971. 14. G. F. Field, W. J. Zally, and L. H. Sternbach, J. Am. Chem. Soc., 89, 332 (1967). 15. D. L. Coffen and R. I. Fryer, U.S. Patent 3,849,399, November 1974. 16. G. F. Field, W. J. Zally, and L. H. Sternbach, Tetrahedron Lett., 2609 (1966). 17. G. F. Field and L. H. Sternbach, US. Patent 3,625,959, December 1971. 18. G. F. Field et al., Hoffmann-La Roche, Nutley, NJ, unpublished data. 19. (a) A. Walser, L. E. Benjamin Sr., T. Flynn, C. Mason, R. Schwartz, and R. I. Fryer, J . Org. Chem., 43,936 (1978). (b) A. Walser et al., Hoffmann-La Roche, Nutley, NJ, unpublished data. 20. (a) A. Walser, T. Flynn, and R. I. Fryer, J . Heterocycl. Chem., 15,577 (1978). (b) A. Walser et al., Hoffmann-La Roche, Nutley, NJ, unpublished data. 21. (a) Belg. Patent 839,364, September 1976 (Hoffmann-La Roche & Co., Switzerland). (b) A. Walser and R. I. Fryer, US. Patent 4,280,957, July 1981. 22. G. F. Field and W. J. Zally, US. Patent 4,238,610, December 1980. 23. (a) A. Walser, US. Patent 4,226,771, October 1980. (b) A. Walser, US. Patent 4,240,962, December 1980. (c) A. Walser, US. Patent 4,247,463, January 1981. 24. (a) A. Walser, U.S. Patent 4,226,768, October 1980.(b) A. Walser, U.S. Patent 4,257,946, March 1981. (c) A. Walser, US. Patent 4,244,868, January 1981. (d) A. Walser, U.S. Patent 4,244,867, January 1981. (e) A. Walser, Hoffmann-La Roche, Nutley, NJ, unpublished data. 25. R. B. Moffett and B. V. Kamdar, J . Heterocycl. Chem., 16, 793 (1979). 26. A. Szente and J. Hellerbach, Hoffmann-La Roche and Co., Basel, Switzerland, unpublished data. 27. J. Smuszkovicz, L. Baczynskyi, C. C. Chidester, and D. Duchamp, J. Org. Chem., 41, 1743 (1976). 28. A. Walser, T. Flynn, and R. I. Fryer, J. Heterocycl. Chem., 20, 791 (1983). 29. K. Meguro and Y. Kuwada, Yakugaku Zasshi, 93, 1263 (1973). 30. D. L. Coffen and R. I. Fryer: (a) US. Patent 3,850,948, November 1974, (b) U.S. Patent 3,906,001, September 1975. 31. D. L. Coffen and R. I. Fryer, US. Patent 3,932,399, January 1976. 32. D. L. Coffen and R. I. Fryer, U.S. Patent 3,849,434, November 1974. 33. L. H. Sternbach and E. Reeder, J . Org. Chem., 26, 1111 (1961). 34. L. H. Sternbach, E. Reeder, 0. Keller, and W. Metlesics, J. Org. Chem., 26, 4488 (1961). 35. M. C. J. Kuchar, Ph.D. Thesis, Brigham Young University, University Microfilms Order 646643; Diss. Abstr., 25, 1572 (1964).
540
1,4-Benzodiazepines
36. G. Saucy and L. H. Sternbach, Helu. Chim. Acta, 45, 2226 (1962). 37. L. H. Sternbach, G. Saucy, F. A. Smith, M. Miiller, and J. Lee, Helu. Chim. Acta,46,1720(1963). 38. (a) L. H. Sternbach, R. I. Fryer, 0.Keller, W. Metlesics, G . Sach, and N. Steiger, J . Med. Chem. 6, 261 (1963). (b) L. H. Sternbach et al., Hoffmann-La Roche, Nutley, NJ, unpublished data. 39. L. H. Sternbach and G. Saucy, U.S. Patent 3,341,592, September 1967. 40. 0. Keller, N. Steiger, and L. H. Sternbach, U.S. Patent 3,121,103, February 1964. 41. S. C. Bell, C. Gochman, and S. J. Childress, J . Med. Pharm. Chem., 5, 63 (1962). 42. M. Gordon, I. J. Pachter, and J. W. Wilson, Arzneim-Forsch., 13, 802 (1963). 43. J.-P. Maffrand, G. Ferrand, and F. Eloy, Chim. Ther., 9, 539 (1974). 44. E. Reeder and L. H. Sternbach, U.S. Patent 3,051,701, August 1962. 45. F. Gatta, M. R. Del Giudice, L. Di Simone, and G. Settimj, J . Heterocycl. Chem., 17,865 (1980). 46. L. H. Sternbach, U.S. Patent 2,893,992, July 1959. 47. K. Meguro, H. Tawada, H. Miyano, Y. Sato, and Y. Kuwada, Chem. Pharm. Bull., 21, 2382 (1973). 48. G. N. Walker, J . Org. Chem., 27, 1929 (1962). 49. J. V. Earley, R. I. Fryer, and R. Y. Ning, J . Pharm. Sci., 68, 845 (1979). 50. R. V. Davis and R. I. Fryer, U.S. Patent 4,083,948, April 1978. 51. E. Reeder and L. H. Sternbach: (a) US. Patent 3,371,085, February 1968, (b) U.S. Patent 3,270,053, August 1966. 52. Neth. Patent 6,608,039, December 1966 (Grindstedvaerket, Denmark). 53. L. H. Sternbach et al., unpublished data. 54. H. S. Broadbent, R. C. Anderson, M. C. J. Kuchar, and P. D. Ziemer; First International Congress of Heterocyclic Chemistry, Albuquerque, NM, 1967; Abstracts. 55. L. Berger and L. H. Sternbach, U.S. Patent 3,179,656, April 1965. 56. Z. Vejdelek, M. Rajsner, E. Svatek, J. Holubek, and M. Protiva, Collect. Czech. Chem. Commun., 44,3604 (1979). 57. R. I. Fryer, R. A Schmidt, and L. H. Sternbach, J . Pharm. Sci., 53,624 (1964). 58. A. F. Fentiman, Jr. and R. L. Foltz, J . Labelled Compd. Radiopharm., 13, 579 (1977). 59. H. M. Wuest, U.S. Patent 3,189,602, June 1965. 60. J. L. Spencer, U.S. Patent 3,462,419, August 1969. 61. G. A. Archer and L. H. Sternbach, U.S. Patent 3,678,036, July 1972. 62. Neth. Patent 6,413,180, May 1965 (Hoffmann-La Roche & Co., Switzerland). 63. M. E. Derieg, R. I. Fryer, and L. H. Sternbach, J . Chem. Soc., C , 1103 (1968). 64. Neth. Patent 6,512,614, March 1966 (Hoffmann-La Roche & Co., Switzerland). 65. Neth. Patent 6,603,736, September 1966 (Hoffmann-La Roche & Co., Switzerland). 66. R. B. Moffett and A. D. Rudzik, J . Med. Chem., 16, 1256 (1973). 67. R. B. Moffett, US. Patent 3,847,935, November 1974. 68. Ger. Offen. 2,252,079, May 1973 (Upjohn Co., U.S.). 69. R. B. Moffett, US. Patent 3,846,443, November 1974. 70. A. Szente and A. Fischli, Hoffmann-La Roche & Co., Basel, Switzerland, unpublished data. 71. Belg. Patent 634,438, January 1964 (Hoffmann-La Roche & Co., Switzerland). 72. (a) G. A. Archer and L. H. Sternbach, J . Org. Chem., 29, 231 (1964). (b) G. A. Archer and L. H. Sternbach, US. Patent 3,422,091, January 1969. 73. M. Matsuo, K. Taniguchi, and I. Ueda, Chem. Pharm. Bull., 30, 1481 (1982). 74. J. P. Maffrand, G. Ferrand, and F. Eloy, Tetrahedron Lett., 3449 (1973). 75. Belg. Patent 798,677, August 1973 (Centre &Etudes pour I'Industrie Pharmaceutique, France). 76. J. B. Hester and A. R. Hanze: (a) U.S. Patent 3,933,794, January 1976, (b) U.S. Patent 3,927,016, December 1975, (c) U.S. Patent 3,917,627, November 1975. 77. M. Gall: (a) US. Patent 3,763,179, October 1973, (b) U.S. Patent 3,992,393, November 1976. 78. I. R. Ager, G. W. Danswan, D. R. Harrison, D. P. Kay, P. D. Kennewell, and J. B. Taylor, J . Med. Chem., 20, 1035 (1977). 79. J. B. Taylor and D. R. Harrison: (a) U.S. Patent 4,134,976, January 1979, (b) D. R. Harrison, U.S. Patent 4,044,142, August 1977. 80. J. B. Taylor and D. R. Harrison, U.S. Patent 4,185,102, January 1980.
5. References
54 1
81. French Patent 2,244,525, April 1975 (Centre $Etudes pour I’Industrie Pharmaceutique, France). 82. (a) M. Gall and B. V. Kamdar, J . Org. Chem., 46,1575 (1981).(b) M. Gall, US. Patent 3,910,946, October 1975. 83. K. Meguro, H. Tawada, and Y. Kuwada, US. Patent 3,795,673, March 1974. 84. K. Meguro, H. Natsugari, H. Tawada, and Y. Kuwada, Chem. Pharm. Bull., 21, 2366 (1973). 85. (a) J. V. Earley, R. I. Fryer, and L. H. Sternbach, US. Patent 3,644,335, February 1972. (b) J. V. Earley and R. I. Fryer, Hoffmann-La Roche, Nutley, NJ, unpublished data. (c) R. Y. Ning and L. H. Sternbach, Hoffmann-La Roche, Nutley, NJ, unpublished data. (d) Q. Branca and A. Fischli, Hoffmann-La Roche & Co., Basel, Switzerland, unpublished data. 86. Ger. Offen. 2,947,076, June 1981 (Asta-Werke AG). 87. (a) R. Y. Ning, R. I. Fryer, P. B. Madan, and B. C. Sluboski, J . Org. Chem., 41, 2724 (1976). (b) R. Y. Ning, R. I. Fryer, P. B. Madan, and B. C. Sluboski, J . Org. Chem., 41, 2720 (1976). 88. M. R. Del Giudice, F. Gatta, C. Pandolfi, and G. Settimj, Farmaco, Ed. Sci., 37, 343 (1982). 89. J. H. Sellstedt, U.S. Patent 3,897,416, July 1975. 90. Ger. Offen. 2,947,075, June 1981 (Asta-Werke AG). 91. Neth. Patent 6,412,484, May 1965 (Hoffmann-La Roche & Co., Switzerland). 92. A. Walser and R. I. Fryer, J . Org. Chem., 40,153 (1975). 93. (a) G. F. Field, L. H. Sternbach, and W. J. Zally, US. Patent 3,678,038, July 1972. (b) G. F. Field, L. H. Sternbach, and W. J. Zally, US. Patent 3,624,073, November 1971. 94. A. Walser, R. I. Fryer, L. H. Sternbach, and M. C . Archer, J . Heterocycl. Chem., 11,619 (1974). 95. K. Meguro, H. Tawada, and Y. Kuwada, Yakugaku Zasshi, 93, 1253 (1973). 96. K. Meguro, Y. Kuwada, and T. Masudd, U.S. Patent 3,687,941, August 1972. 97. P. Nedenskov and M. Mandrup, Acta Chem. Scand., B, 31, 701 (1977). 98. L. H. Sternbach, B. A. Koechlin, and E. Reeder, J . Org. Chem., 27, 4671 (1962). 99. H. Natsugari, K. Meguro, and Y. Kuwada, Chem. Pharm. Bull., 27, 2608 (1979). 100. R. Y. Ning, R. I. Fryer, and B. C. Sluboski, J . Org. Chem., 42, 3301 (1977). 101. Neth. Patent 6,514,541, May 1966 (Hoffmann-La Roche & Co., Switzerland). 102. H. Tawadd, K. Meguro, and Y. Kuwada, U.S. Patent 3,887,541, June 1975. 103. H. Tawada, K. Meguro, and Y. Kuwada, US. Patent 3,703,525, November 1972. 104. N. W. Gilman, J. F. Blount, and L. H. Sternbach, J . Org. Chem., 37, 3201 (1972). 105. S. Farber, H. M. Wuest, and R. I. Meltzer, J . Med. Chem., 7,235 (1964). 106. U. D. Shenoy: (a) U.S. Patent 4,145,417, March 1979,(b) US. Patent 4,061,745, December 1977, (c) US. Patent 4,065,474, December 1977, (d) U.S. Patent 4,060,608, November 1977. 107. T. Hara, K. Itoh, and N. Itoh, J . Heterocycl. Chem., 13, 1233 (1976). 108. J. Szmuszkovicz, U.S. Patent 3,842,080, October 1974. 109. H. Natsugari and Y. Kuwada, Chem. Pharm. Bull., 27, 2618 (1979). 110. L. H. Sternbach, E. Reeder, A. Stempel, and A. I. Rachlin, J . Org.Chem., 29, 332 (1964). 111. S. C. Bell, C. Gochman, and S. J. Childress, J . Org. Chem., 28, 3010 (1963). 112. (a) H.-G. Schecker and G. Zinner, Arch. Pharm., 313, 926 (1980). (b) M. Forsch and H. Gerhards, E P 0,041,242, December 1981. 113. H. Natsugari, K. Meguro, and Y. Kuwada, Chem. Pharm. Bull., 27, 2927 (1979). 114. A. I. Hanze, U S . Patent 3,734,912, May 1973. 115. Y. Kuwada, H. Natsugari, and K. Meguro, US. Patent 4,175,079, November 1979. 116. Ger. Offen. 2,400,425, July 1974 (Upjohn Co., U S ) . 117. K. Meguro, Y. Kuwada, Y. Nagawa, and T. Masuda, US.Patent 3,652,754, March 1972. 118. R. B. Moffett, US. Patent 3,773,765, November 1973. 119. R. B. Moffett, J . Org. Chem., 39, 568 (1974). 120. (a) R. I. Fryer, J. V. Earley, and J. F. Blount, J . Org. Chem., 42, 2212 (1977). (b) R. I. Fryer and J. V. Earley, Hoffmann-La Roche, Nutley, NJ, unpublished data. 121. T. Miyadera, T. Hata, C. Tamura, and R. Tachikawa, Chem. Pharm. Bull., 29, 2193 (1981). 122. R. B. Moffett, US. Patent 3,822,259, July 1974. 123. S. Kobayashi, Chem. Lett., 967 (1974). 124. H. Natsugari, K. Meguro, and Y. Kuwada, Chem. Pharm. Bull., 27, 2589 (1979).
542
1,4-Benzodiazepines
125. L. H. Sternbach and E. Reeder, J . Org. Chem., 26,4936 (1961). 126. (a) H. Allgeier and A. Gagneux, U.S. Patent 3,867,536, February 1975. (b) H. Allgeier and A. Gagneux, U.S. Patent, 3,946,032, March 1976. (c) Swiss Patent 561,722, May 1975 (CibaGeigy AG, Switzerland). 127. A. Walser, US. Patent 4,118,386, October 1978. 128. P. J. G. Cornelissen, G. M. J. Beijersbergen van Henegouwen, and K. W. Gerritsma, Int. J. Pharm., 3, 205 (1979). 129. G. F. Field and L. H. Sternbach, U.S. Patent 3,697,545, October 1972. 130. G. F. Field and L. H. Sternbach, J. Org. Chem., 33, 4438 (1968). 131. J. B. Hester, U.S. Patent 3,649,617, March 1972. 132. J. B. Hester, U.S. Patent 3,857,854, December 1974. 133. R. S. P. Hsi and T. D. Johnson, J. Labelled Compds. Radiopharm., 12, 613 (1976). 134. J. B. Hester, Jr., D. J. Duchamp, and C. G. Chidester, Tetrahedron Lett., 4039 (1970). 135. J. B. Hester, Jr. and A. D. Rudzik, J. Med. Chem., 17, 293 (1974). 136. K. Meguro and Y. Kuwada, Chem. Pharm. Bull., 21,2375 (1973). 137. K. Meguro and Y.Kuwada, Tetrahedron Lett., 4039 (1970). 138. K. Meguro and Y.Kuwada, U.S. Patent 3,864,356, February 1975. 139. (a) K. Meguro and Y. Kuwada, US. Patent 3,907,820, September 1975. (b) U.S. Patent 4,235,775, November 1980. 140. K. Meguro and Y.Kuwada, U.S. Patent 4,116,956, September 1978. 141. J. B. Hester, Jr., US. Patent 3,995,043, November 1976. 142. H. Tawada, H. Natsugari, K. Meguro, and Y.Kuwada, U.S. Patent 4,102,881, July 1978. 143. L. H. Sternbach and A. Walser, U.S. Patent 3,970,664, July 1976. 144. L. H. Sternbach and A. Walser: (a) U.S. Patent 3,879,406, April 1975, (b) U.S. Patent 4,044,016, August 1977. 145. R. B. Moffett, G. N. Evenson, and P. F. Von Voigtlander, J . Heterocycl. Chem., 14,1231(1977). 146. J. B. Hester and J. Smuszkovicz, U.S. Patent 3,862,956, January 1975. 147. Ger. Offen. 2,242,059, March 1973 (Upjohn Co., US.). 148. J. B. Hester, Jr., C. G. Chidester, and J. Smuszkovicz, J. Org. Chem., 44,2688 (1979). 149. J. B. Hester, Jr., U.S. Patent 4,082,761, April 1978. 150. J. B. Hester, Jr., U.S. Patent 3,741,957, June 1973. 151. J. B. Hester, Jr., US. Patent 3,701,782, October 1972. 152. J. B. Hester, Jr., U.S. Patent 3,646,055, February 1972. 153. J. B. Hester, Jr., U.S. Patent 3,717,653, February 1973. 154. A. Walser and G. Zenchoff, J. Med. Chem., 20, 1694 (1977). 155. Ger. Offen. 2,242,938, March 1973 (Upjohn Co., US.). 156. R. B. Moffett, U.S. Patent 4,016,165, April 1977. 157. R. B. Moffett, US. Patent 4,028,356, June 1977. 158. G. N. Evenson: (a) U.S. Patent 4,107,159, August 1978, (b) U.S. Patent 4,086,230, April 1978. 159. G. N. Evenson, U.S. Patent 4,073,785, February 1978. 160. R. B. Moffett, US. Patent 4,017,492, April 1977. 161. A. Walser and G. Zenchoff, J . Heterocycl. Chem., 15, 161 (1978). 162. R. I. Fryer and A. Walser, U.S. Patent 3,901,907, August 1975. 163. R. I. Fryer and A. Walser, U.S. Patent 3,864,328, February 1975. 164. R. B. Moffett, U.S. Patent 4,073,784, February 1978. 165. K. Meguro and Y.Kuwada, U.S. Patent 3,865,811, February 1975. 166. J. B. Hester, Jr., U.S. Patent 4,039,551, August 1977. 167. J. B. Hester, Jr., U.S. Patent 4,081,452, March 1978. 168. J. B. Hester, Jr., U.S. Patent 4,009,175, February 1977. 169. J. B. Hester, Jr., U.S. Patent 4,141,902, February 1979. 170. J. B. Hester, Jr., U.S. Patent 4,021,441, May 1977. 171. M. Gall, U.S. Patent 4,010,177, March 1977. 172. J. B. Hester, Jr. and P. Von Voigtlander, J. Med. Chem., 22, 1390 (1979). 173. J. B. Hester, Jr., U.S. Patent 3,996,230, December 1976.
5. References
543
174. J. B. Hester, Jr., US. Patent 3,708,592, January 1973. 175. J. B. Hester, Jr., US. Patent 3,751,426, August 1973. 176. Neth. Patent 7,205,629, October 1972 (Upjohn Co., US.). 177. J. B. Hester, Jr., US. Patent 3,737,434, June 1973. 178. S. C. Bell, T. S. Sulkowski, C. Gochman, and S. J. Childress, J . Org. Chem., 27, 562 (1962). 179. J. H. Sellstedt and D. M. Teller, U.S. Patent 4,056,525, November 1977. 180. J. V. Earley, R. I. Fryer, R. Y. Ning, and L. H. Sternbach, US. Patent 3,681,341, August 1972. 181. M. Matsuo, K. Taniguchi, and I. Ueda, Chem. Pharm. Bull., 30, 1141 (1982). 182. F. M. Vane and W. Benz, Org. Mass. Spectrom., 14, 233 (1979). 183. Neth. Patent 6,412,300, April 1965 (Hoffmann-La Roche & Co., Switzerland). 184. Ger. Offen. 2,302,525, August 1973 (Upjohn Co., US.). 185. Belg. Patent 777,138, January 1972 (Grindstedvaerket, Denmark). 186. 1. Ueda and M. Matsuo, U.S. Patent 4,094,870, June 1978. 187. J. B. Hester, Jr., U.S. Patent 3,897,446, July 1975. 188. T. Watanabe, M. Matsuo, K. Taniguchi, and I. Ueda, Chem. Pharm. Bu"., 30, 1473 (1982). 189. H. Allgeier and A. Gagneux, US. Patent 4,178,378, December 1979. 190. Swiss Patent 562,822, June 1975 (Ciba-Geigy AG, Switzerland). 191. Swiss Patent 551,723, May 1975 (Ciba-Geigy AG, Switzerland). 192. A. Walser, R. F. Lauer, and R. I. Fryer, J . Heterocycl. Chem., 15, 855 (1978). 193. Belg. Patent 823,613, April 1975 (Asta-Werke AG, West Germany). 194. J. H. Sellstedt, US. Patent 3,882,101, May 1975. 195. J. H. Sellstedt, US. Patent 3,880,835, April 1975. 196. J. H. Sellstedt and D. M. Teller, US. Patent 3,880,877, April 1975. 197. T. T. Moller, P. Nedenkov, and H. B. Rasmussen, U S . Patent 3,635,949, January 1972. 198. V. Bertolasi, M. Sacerdoti, and G. Gilli, Acta Crystallogr., 38, 1768 (1982). 199. R. Haran and J. P. Tuchagues, J . Heterocycl. Chem., 17, 1483 (1980). 200. C. W. Perry et al., Hoffmann-La Roche, Nutley, NJ, unpublished data. 201. W. Zwahlen et al., Hoffmann La Roche & Co., Basel, Switzerland, unpublished data. 202. E. Kyburz et al., Hoffmann-La Roche & Co., Basel, Switzerland, unpublished data.
CHAPTER VI
Dihydro.1. 4.Benzodiazepines A. Walser Chemical Research Department. Hoffmann-La Roche Inc., Nutley. New Jersey
and
R . Ian Fryer Department of Chemistry. Rutgers. State University of New Jersey. Newark. New Jersey
1. 2,3.Dihydro.lH.l. 4.benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
547
1.1. Synthesis of 2,3.Dihydro.lH.l, 4.benzodiazepines . . . . . . . . . . . . . . . . . . . .
547
1.1.1. From (2-Halopheny1)carbonyl Compounds . . . . . . . . . . . . . . . . . . . . 1.1.2. From 2-Aminobenzophenones . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1.3. By Oxidation of Indoles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1.4. By Bischler-Napieralski Type Reactions . . . . . . . . . . . . . . . . . . . . . . 1.1.5. By Reduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1.6. By Addition and Substitution . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1.7. By Oxidation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1.8. By Elimination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1.9. Other Syntheses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
547 548 552 554 557 559 561 561 562
1.2. Synthesis of 2.Imino.2,3.dihydr 0.1 H.1, 4.benzodiazepines . . . . . . . . . . . . . . .
563
1.3. Synthesis of 2.Methylene.l,3.dihydro.2H.l,
4.benzodiazepines . . . . . . . . . . . .
564
1.4. Synthesis of 3.Methylene.l,2.dihydro.3H.l,
4.benzodiazepine.s . . . . . . . . . . . .
567
1.5. Reactions of 2,3.Dihydr 0.1 H.l,4.benzodiazepines . . . . . . . . . . . . . . . . . . . . 1.5.1. Reactions with Electrophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.5.1.1. Protonation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.5.1.2. Halogenation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.5.1.3. Oxidation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.5.1.4. Reactions with Nitrogen Electrophiles . . . . . . . . . . . . . . . . . . A . Nitrosation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Nitration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C. Reactions with Other Nitrogen Electrophiles . . . . . . . . . . . . 1.5.1.5. Reactions with Carbon Electrophiles . . . . . . . . . . . . . . . . . . . A . Alkylation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
545
568 568 568 568 569 571 571 572 573 573 573
Dihydro.l. 4.Benzodiazepines
546
B. Reactions with Aldehydes. Ketones. and Epoxides . . . . . . . . . C. Acylation. Additions to Imine . . . . . . . . . . . . . . . . . . . . . 1.5.1.6. Sulfonation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.5.2. Reactions with Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.5.2.1. Reduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.5.2.2. Reactions with Oxygen and Sulfur Nucleophiles . . . . . . . . . . . . A . Hydrolysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Other Oxygen Nucleophiles . . . . . . . . . . . . . . . . . . . . . . C. Sulfur Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.5.2.3. Reactions with Nitrogen Nucleophiles . . . . . . . . . . . . . . . . . . 1.5.2.4. Reactions with Carbon Nucleophiles . . . . . . . . . . . . . . . . . . . 1.5.2.5. Miscellaneous Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . 1.5.3. Photo and Thermal Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . .
575 578 583 584 584 585 585 588 588 589 590 591 591
1.6. Spectral Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
592
2. 2,5-Dihydro-lH-l,4-benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
592
3. 4,5-Dihydro-lH-l,4-benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
593
4 . 4,5-Dihydro-3H-1.4-benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
594
4.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
594
4.2. Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
595
5. Tables of Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
596
6. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
626
INTRODUCTION This chapter covers the syntheses and reactions of dihydro.l, 4. benzodiazepines. Retaining the aromaticity of the benzene ring. the dihydro.1.4.benz o. diazepines 1-4 may be formulated. Representatives of all four tautomers. which have been described in the literature. are discussed in this chapter.
1
2
2.3.Dihydr o. lH.l. 4.benzodiazepine
2.5.Dihydr o. 1H - 1,4.benzodiazepine
H
NH 3
4.5.Dihydr o. 1 H - 1.4.benzodiazepine
K 3
NH
4
4.5.Dihydro.3 H. 1, 4.benzodiazepine
1. 2,3-Dihydro-1H-1,4-Benzodiazepines
547
1. 2,3-DIHYDRO-lH-l,4-BENZODIAZEPINES 1.1. Synthesis of 2,1Dihydro-lH-l,Qbenzodiazepines
I . I .I. From (2-Halopheny1)carbonyl Compounds The 2,3-dihydro-1H-1,4-benzodiazepines 7 were prepared by reacting the (2-halopheny1)carbonyl compounds 5 (X = halogen) with the diamine 6 (R, = H, Me) at elevated temperatures (Eq. 1).
This synthesis worked particularly well when R, was para to the halogen X and was a strongly electron-withdrawing substituent such as a nitro or a trifluoromethyl group. The following compounds 7 were successfully made by this procedure:
1, 2 2
3, 4
5, 6 7
Ph Ph 2-Pyridyl 3-Pyridyl 4-Pyridyl 2-Pyrimidyl 2-Thiazol yl 2-Me-3-pyrazolyl 1-Me-2-imidazolyl 1,2-thiazol-5-yl
NO29 F3C
H H H
NO2 NO2
H H, Me
NO2 F3C
Less activated halides could be employed if the reaction of the diamine 6 was carried out in boiling nitrobenzene in the presence of cupric acetate and potassium carbonate as shown by the preparation of compounds 7 [R, = Ph; R, = H, C1; R, = H, Me, (cyclopropyl)methyl] from the imines of the benzophenones 5 (R, = Ph; R, = H, C1; X = Cl).' According to a Belgian patent,g medazepam (12) was obtained by treating 8 under similar conditions with the diamine 6 (R3= Me) in the presence of hydrazine hydrate. Syntheses of 7
Dihydro-1,4-Benzodiazepines
548
(R, = alkenyl; R, = C1, F,C; R, = H) from ketone 5 (X = C1) and ethylenediamine were claimed in another patent," but the compounds were not properly characterized. Medazepam (12) was reported" to be synthesized by a stepwise modification shown in Eq. 2. The benzophenone 8 was reacted with the protected diamine 9 at 18CL20O"Cin the presence of cupric acetate and potassium carbonate to form 10, hydrazinolysis of which led to 12. Me HN
1
NH,NH,
8-t
Me
Me I HN
I
1, +? I
c1 Ph
Ph
11
12
Compound 12 was also claimed" to be accessible by reaction of 8 with the benzaldimine 11 in boiling nitrobenzene. An example of activation of the 2-chloro substituent by a p-sulfonamide functionality was provided by the conversion of 5 (R, = 2-amino-5chlorophenyl; R, = SO,NH,, X = C1) to the corresponding benzodiazepine by heating in ethylenediamine.', The susceptibility of fluorine on aromatic rings toward displacement by nucleophiles made the ketones 5 (X = F, R, = 2-pyridyl, R, = H), and (X = F, R, = indol-3-yl, R, = H)I4 suitable starting materials for the preparation of the corresponding benzodiazepines.
I . I .2. From 2-Aminobenzophenones Alkylation of the 2-aminobenzophenone 13 (R, = H, R, = C1) with N protected 2-aminoethyl bromides in hot dimethylformamide gave moderate yields of the products 14 (R, = phthalimido or benzamido). Removal of the protecting groups by acid hydrolysis led to the benzodiazepine 15 (Eq. 3).15
1. 2,3-Dihydro-lH-1,4-Benzodiazepines
549
I
Go
BrCH2CHIR,
R2
R,
= DMF H. R, =
CI
c1
Ph
13
Ph 15
The preparation of 10 by alkylation of the methylaminobenzophenone 13 (R, = Me, R, = C1) with N-(2-haloethyl)phthalimide and subsequent hydrazinolysis to 12 was claimed in a Belgian patent.I6 N-(2-Haloethyl)-aminobenzophenones 16 (R, = tosyl) were obtained by alkylation of the tosylated aminobenzophenone 13 (R, = tosyl) with 1,2-dibromoethane or 1-bromo-2-chloroethane. The tosyl group was removed by treatment with sulfuric acid to give 16 (R, = H), which was further alkylated with methyl iodide in dimethylformamide in the presence of barium oxide to give 16 (R, = Me)."
Ph
Ph 17
16
I
NH,OH
I
*
c1 Ph 18
\ 0
KKO, H,O/EtOH
Ph b H 19
The halides 16 (X = Br, C1) were converted to the benzodiazepines 17 (R, = H, Me; R, = C1) by treatment with methanolic ammonia at 12&130"C or in better yields by reaction with hexamethylenetetramine in refluxing
550
Dihydro- 1,4-Benzodiazepines
ethanol.”In the latter case, the initial formation of a quaternary adduct, which yielded the benzodiazepine upon reflux in ethanol, was observed.I8 The “hexamine” procedure was also applied to the preparation of 17 (R, = F3CCH,, R, = C1) (Eq. 4).” Reaction of the chloride 16 (R, = Me, R, = X = C1) with hydroxylamine in ethanol-water at reflux led to the nitrone 18.20-23Since the same compound was obtained by treating the oxime 19 (X = C1) with potassium carbonate,,, - 2 3 it is likely that 19 is an intermediate in the conversion of 16 to 18. The oxime 19 (X = C1) resulted from the reaction of 19 (X = OH) with thionyl chloride in pyridine.,’ - 2 3 Mihalic and c o ~ o r k e r s studied ~ ~ - ~ the ~ transformation of the halides 16 to benzodiazepines in detail and established the intermediacy of aziridinium ions 21 (Eq. 5). Thus, when the dideuterated chloride 20 (R, = Me, R, = X = C1, R, = R, = D, R, = H) was treated with ethanolic ammonia at 130°C a mixture of the benzodiazepines 22 (45%) and 24 (55%) was obtained. A similar ratio of the 2-methyl- and 3-methyl-benzodiazepines resulted when the bromide 20 (R, = R, = Me, R, = C1, R, = R, = H, X = Br) was subjected to ammonia. This demonstrates that the aziridinium ion 21 is formed and opened by the
+
Ph 24
1. 2,3-Dihydro-lH-l,4-Benzodiazepines
55 1
nucleophile, ammonia in this case, in both possible ways with little regioselectivity. The stereoselectivity of this reaction was in~estigated'~.'~ using the enantiomeric benzophenone 20 (R, = R, = R, = H,R, = NO,, R, = Et, X = Br) and aziridine 23 (R, = NO,, R, = Et, R, = R, = H) both with the S absolute configuration. Both the halide and the aziridine were converted to a mixture of 2-ethyl and 3-ethyl benzodiazepines. The benzodiazepines from the halide and from the aziridine were in the ratios of 92: 8 and 3: 1. The 2-ethyl benzodiazepine retained the absolute stereochemistry whether the halide or the aziridine was used as starting material. The 3-ethyl benzodiazepine was formed with retention of configuration from the halide but with a high degree of inversion from the aziridine. The authorsz4 gave mechanistic explanations for the results observed. Based on these studies, an efficient synthesis of medazepam (12) was developed.26The aziridine 23 (R, = C1, R, = R, = R, = H) was quaternized with methyl iodide to give the iodide 20 (R, = Me, R, = C1, R, = R4 = R, = H, X = I) via the unstable aziridinium salt 21. Treatment of this iodide with hexamethylenetetramine or ammonia led to medazepam in 92% overall yield from the aziridine. Compound 12 was also formed by a double alkylation of the benzophenone imine 25 with 1,Zdibromoethane (Eq. 6)." The 1-desmethyl analog 15 was obtained in low yield by reacting 2-amino-5-chlorobenzophenone with aziridine and aluminum chloride.'
A process leading to 12 in good yield involved catalytic hydrogenation of the nitrile 26 (R = Me) using Raney nickelZ8929 or cobalt" as a catalyst (Eq. 6). The nitrile 26 (R = Me) was prepared either by reacting 2-methylamino-5-chlorobenzophenone with formaldehyde and hydrogen cyanidez9 or by alkylation with chloroacetonitrile." According to the patent literat~re,~'. 3' 2,3-dihydro-lH-l,4-benzodiazepines 28 were obtained by cyclization and dehydration of the ethanolimines 27 in polyphosphoric acid alkyl esters at elevated temperature (Eq. 7). Thus, medazepam and its 1-desmethyl analog were claimed to be accessible in 90% yield by heating the appropriate aminobenzophenone hydroxyethylimine with phosphorus pentoxide and ethanol at 90°C for 3 hours.30 At higher temperatures (140"-160°C) alkylation of the 1-position nitrogen by the alkylphosphate was observed.
Dihydro-1,4-Benzodiazepines
552
Giacconi and coworkers32described the synthesis of the 2,3-diamino-substituted compounds 31 by reacting the benzophenone imines 29 (R = H, Me; Y = C1, NO,) with the 1,Zethanediiminium dibromides 30 (X = 0,NMe, CH2) (Eq. 8). In the case of R = H, the benzodiazepines 31 could be isolated only when Y was a nitro group. If Y was chlorine or hydrogen, elimination of the 2-aminofunction with formation of the 1,2-imine bond occurred readily, giving 3-substituted amino-3H-1,Cbenzodiazepines.
31
29 30
1.1.3. B y Oxidation of Indoles The oxidative cleavage of the 2,3-bond in 3-substituted indoles leading to derivatives of (2-aminopheny1)ketoneshas been widely used for the synthesis of benzodiazepines. Thus, l-acylated-2,3-dihydro- 1H-1,Cbenzodiazepines 33 were obtained from the oxidation of 3-phenyl-indoles 32 bearing a 2-aminoethyl moiety on the indole nitrogen (Eq. 9). R 1
/JH*
C=O
1. 2,3-Dihydro-lH-1,4-Benzodiazepines
553
The reaction of 32 (R, = R, = H, R, = C1) with chromium trioxide in glacial acetic acid-water was reported,, to give the 1-formyl derivative 33 (R, = R, = H, R, = Cl). In our hands this procedure did not lead to the expected product. Instead we obtained an unidentified compound with the reported melting point3, which, however, was quite different from that of an authentic sample of 7-chloro-l-formyl-2,3-dihydro-5-phenyl-l H-1,Cbenzodiazepine prepared by formylation of the parent benz~diazepine.~~ NHZ M e O g
mr
c1
34
eyM Ac
CrO, AcOH
* c1
Ph -N
35
38
H
OH- or
R1 OH'
39
40
Dihydro-1,CBenzodiazepines
554
If the indole 32 carried a substituent at the 2-position, the oxidation to the benzodiazepine 33 worked satisfactorily as shown for compounds with R, = Me,34935CH,0Me,34 CH,NMe,,36 and CONMe,.36 In addition to chromium trioxide, ozone and p e r i ~ d a t e ,were ~ successfully used to perform this oxidation. The indole 34 with a modified side chain at the 1-position allowed the preparation of the 2-methoxy analog 35 (Eq. Oxidation of the pyrazinoindoles 3634,37-39 and 3734 with chromium trioxide yielded the piperazin-2,3-diones 38, which were converted to the benzodiazepines 39 by alkaline37-39or acid hydrolysis (Eq. 1l).34Heating of 38 with concentrated hydrochloric acid was reported to give the imidazolidinone 40, which was subsequently converted to the benzodiazepine by alkaline hydroly~is.~'
I .I .4. By Bischler-Napieralski Type Reactions Kaegi and coworkers were the first to employ the Bischler-Napieralski reaction for the preparation of l-alkyl-2,3-dihydro-1H-1,4-benzodiazepines.41 Treating the benzamide 41 (R, = Me, R, = Ph, R, = Cl), radiolabeled on the carbonyl carbon, with a mixture of phosphorus oxychloride and phosphorus pentoxide at 110°C for 16 hours led to 14C5-labeledmedazepam (42: R, = Me, R, = Ph, R, = C1) in high yield (Eq. 12).
41
R2
42
This procedure was applied to the synthesis of the 14C,-labeled analog (R, = 2-FC6H4),42 the nitro-substituted compound 42 (R, = Me, R, = 2N0,C6H4; R, = Cl)?, the 1-trifluoroethyl-substituted derivative 42 (R, = F,CCH,, R, = 2-FC6H4,R, = and several other analogs.45aCompounds with aliphatic substituents at the 5-position (R, = Me; R, = ClCH,, CI,CH, trichloroethylene; R, = C1) were also obtained by this method.45b The cyclization of the benzamides 41 (R, = Me; R, = Ph; R, = H, Me) to the corresponding benzodiazepines was also effected by treatment with polyphosphoric acid at higher temperatures ( - 155°C).46 Liepmann and collaborator^^^ extended this reaction to the benzamides 43 and observed some interesting results. Refluxing 43 (R, = Ph, R, = C1) with phosphorus oxychloride gave a mixture of the diazocine 44 and the benzodiazepine 48. The authors showed that 44 and 48 did not interconvert under the reaction conditions employed for their formation and that 48 was formed via the
1. 2,3-Dihydro-lH-l,4-Benzodiazepines
555
aziridinium ion 45 and the chloride 47. Under more vigorous conditions, by heating in tetrachloroethane at 140"C,47the diazocines thermally rearranged to the 2-chloromethyl-1,4-benzodiazepines48, most likely via the aziridinium salt 46 (Eq. 13).
I
44
POCI,. 70 C
45
46
+I
Me
C1
reflux
Rl 48
The usefulness of this synthesis of 2-carbon-substituted benzodiazepines was enhanced by the finding that the diazocines 44 undergo a ring contraction when they are reacted with various nucleophiles. Thus, treatment of 44 with alkox~' phthalimide,47*50* 5 1 hydroxides,47 -49,54 cyanide,47.48 a ~ i d e , ~ ' .potassium ide,54 a~etate,"~phen~xide,~'or a m i n e ~ ~ 50 ~ , yielded ~ * , the corresponding benzodiazepines 49 (Eq. 14).
Dihydro- 1,4-Benzodiazepines
556
Reaction of the 3-hydroxydiazocine 50 with thionyl chloride in boiling benzene resulted in ring contraction and afforded the benzodiazepine 51 in 80% yield (Eq. 15).47 Me
Me
C1
F Y
clTcl SOCI, MeC6H,: reflux
50 \
51
A modification of the Bischler-Napieralski conditions in which the o-substituted benzamides 43 (R, = 2-CIC6H4,2-FC6H4; R, = C1) were reacted with phosphorus pentachloride and subsequently with aluminum chloride or stannic chloride gave improved yields.47,53 The methods described above were not limited to the synthesis of 5-phenylsubstituted benzodiazepines but were also applied to the preparation of com',~~ and 3 - f ~ r y l . ~ ' pounds 49 with R, = 2-thieny1,51g54Z - f ~ r y l , ~3-thieny1,'l Compounds 44 and 48 with R, = 2-pyridyl, 3-pyridyl, and 4-pyridyl were claimed to be obtained by reaction of the corresponding 3-hydroxybenzazocine with carbon tetrachloride and triphenylpho~phine.~' l-Alkyl-2,3-dihydro-M- 1,4-benzodiazepines were also accessible via nitrilium salts. Reaction of the anilines 52 (R, = H, C1; X = C1) with nitriles 53 (R2 = Ph, 2-CIC6H4, 1-cyclohexenyl, 2-chloro-1-cyclohexenyl)in the presence of aluminum chloride or stannic chloride at ll&130°C gave moderate yields of the corresponding benzodiazepines 54 (Eq. 16).34
Me
52
Me
Rz 54
The alcohol 52 (X = OH) could be used as the starting material as well, but the reaction with the nitrile required aluminum chloride and the higher temperature of 15&160°C.34The 5-thioethyl and 5-thiophenyl substituted compounds 54 (R, = C1; R, = EtS, PhS) were obtained in low yields by treating the chloride 52 with the respective thiocyanate and stannic ~hloride.~
1. 2,3-Dihydro-lH-1,4-Benzodiazepines
551
1.1.5. B y Reduction Benzodiazepines of higher oxidation level were reduced to 2,3-dihydro-1 H 1,Cbenzodiazepines by various methods. The parent compound 56 was isolated from the reduction of the 2,s-dione 55 with lithium aluminum hydride in refluxing tetrahydrofuran (Eq. 17).56
0
56
55
The same reagent in boiling ether57or tetrahydrofuran2-15and diborane in tetrahydrofuran at - 15 to - 10°C,58,59 effectively converted the 2-ones 57 to 59. Reduction of the 4-oxides 58 (R = H, Me) with lithium aluminum hydride in ether led to the hydroxyamines while in boiling tetrahydrofuran compounds 59 (R, = H, Me; R, = H; R, = Ph; X = 7-C1) were formed as major products, apparently by base-induced dehydration of 60 (Eq. 18).34
X
c1 Ph
R3
57 LIAIH, or B,H,
59
0
58
I 60
Lithium aluminum hydride at - 40 to - 50°C reduced the 5-phenyl-1,4benzodiazepine-2-ones 61 (Y = H, F) to the 2-hydroxy compounds 62 (Y = H, F) (Eq. 19).58960When diazepam (61: Y = H) was exposed to this reagent at room temperature, a dimer was isolated in 23% yield; it was assigned structure 63 (Eq. 19).
558
Dihydro-1,4-Benzodiazepines
Me
Me
I
LAIH,
c1
-4oc
c1
62
61
Me
(19)
Ph 63
A variety of 2,3-dihydro-lH-1,4-benzodiazepines 59 were obtained by other reduction procedures, such as desulfurization of the 2-thiones U6'or the 2-thioalkyl derivatives 65 (R, = EtS) with Raney nickel6'; reduction of the 3H-1,Cbenzodiazepines 66 with lithium aluminum hydride for R, = (Nnitros~)methylamino,~~ R, = dimorpholinophosphoryloxy;63and treatment of 65 (R, = H) with Raney nickel and hydrogen (Eq. 20).62Catalytic hydrogenation of the 4-oxide of 66 (R2 = Ph, R, = Me, X = 7-C1) over Raney nickel gave the corresponding 2,3-dihydro-1 H-1,4-benzodiazepine 67 (R, = Me).64The 1,2imine bond in several 2-substituted 3H-1,4-benzodiazepines 66 was reduced
X R2
64
R2
66
\
1. 2,3-Dihydro-lH-l,4-Benzodiazepines
559
selectively with sodium borohydride. Such reductions were reported for 66 with (hydroxyimino)nitromethy1,66(hydroxyR, = Me,64 hydr~xyiminomethyl,~~ imino)aminomethyl and related compounds,66 (hydroxyimino)methylthioand (methoxyimino)methoxymethyl.66The nitrone functionality in the corresponding 4-oxides was not touched by sodium borohydride under the conditions used. This reagent also converted the 3-amino derivatives 68 effectively to the 2,3-dihydro derivatives 69 (Eq. 2l).,’
1
I
Ph
Ph
68
69
I .1.6. B y Addition and Substitution 2-Substituted 2,3-dihydro-1H-1,4-benzodiazepines 71 were accessible by addition of nucleophiles to the 3H- 1,Cbenzodiazepines 70. Such additions were successfully carried out with a m i n e ~ , ~ a’ .l ~~~o h o l s ,hydrogen ~~,~~ ethanethiol,68 b e n ~ y l t h i o l and ,~~ Base-catalyzed addition of dimethyl malonate to 70 (R = Ph, X = 7-C1) led to 71 (Nu = CH(COOMe),, R = Ph, X = 7-C1) (Eq. 22).63
I
1
R
R 70
71
Displacement of the 2-hydroxy group in 1-substituted benzodiazepines 72 (R, = Me, CH,CH,) provided another method for the introduction of substituents at the 2-position. This approach was employed to prepare 2-cyano derivatives 73 (Nu = CN) by use of sodium cyanide in acetic acid or acetone cyanohydrin (Eq. 23).70g71 Reaction of 72 (R, = CF,CH,, R, = Ph, X = Cl), or its cyclic isomer 74, with ethanethiol yielded the 2-ethylthio compound 73 (R, = CF,CH,, R, = Ph, X = C1, Nu = EtS).72 The bridged sulfide 75 was similarly cleaved by 2-hydroxyethanethiol to afford 73 (R, = H, R, = Ph, X = C1, Nu = HOCH,CH,S).68c Introduction of a substituent at the 2-position was accomplished by taking advantage of the reactivity of carbons activated by a nitrosamino function. Compound 76 was reacted with benzaldehyde in the presence of potassium t-butoxide to give a mixture of the diastereomeric
Dihydro- 1,4-Benzodiazepines
560
d
- --N
H
Nu-
~
X I
R2
72
73
t
(CF3
H
I
c1
c1
NH I
Ph
Ph 74
75
alcohols 77 (R = NO).73 The nitroso group was removed by catalytic hydrogenation over Raney nickel, yielding 77 (R = H)(Eq. 24). NO
Xy-J
PhCHO
(24)
r-BuOK
c1
c1 Ph
Ph
77
76
The benzodiazepines bearing a heteroatom attached at the 5-position were prepared from the 5-ones 78 (X = 0) or Sthiones 78(X = S). Methylation of the latter with dimethyl sulfate led to the 5-methylthio compound 79 (R, = R4 = Me, R, = H, X = S ) (Eq. 25).55
Rl
R3qJH qR2
I:‘
R 3 = H
X
* Rz
XR4
1. 2,3-Dihydro-lH-1,4-Benzodiazepines
561
The corresponding iminoether 79 (R, = Me, R, = C1, R4X = EtO) was obtained by treatment of the appropriate 5-one with boron trifluoride etherate in the presence of 2-chloromethyloxirane.74~75 Reaction of 79 (R4X = MeS, EtO) with a m i n e ~ ,hydro~yamines,~~ ~~.~~ and h y d r a ~ i n e sled ~ ~ to 5-aminosubstituted benzodiazepines 80. Compounds 80 (R, = aryl; R, = H; R, = C1, CF,) were prepared by reacting the corresponding 5-one 78 (X = 0 ) with phosphorus pentachloride and an amine.77
I .I.7. B y Oxidation 2,3-Dihydro-lH-1,4-benzodiazepines 82 (R, = H, Ph, substituted Ph) were also prepared by oxidation of the corresponding tetrahydrobenzodiazepines81. The required amine-to-imine oxidation was effected by a variety of reagents such as manganese dioxide,78 diethyl azodi~arboxylate,~~ DDQ,78* 7 9 ruthenium dioxide,80 ~ h l o r a n i l ,h~y~p ~ i o d i t e ,and ~ ~ sulfur in boiling dimethylformamide." A low yield photochemical oxidation involving irradiation in dimethyl sulfoxide was also reported (Eq. 26).82
xd) NH
P I +
F x q >
(26)
R,
R2
82
81
The nitrones 84 resulted from the oxidation of the hydroxyamines 83 (R, = H, Ac; R, = H, Me) with mercuric oxide (Eq. 27).64*83,84
84
83
I .1.8. B y Elimination 2,3,4,5-Tetrahydro-1H-1,4-benzodiazepines 85, bearing a leaving group, R,, at the 4-position, were converted to 2,3-dihydro-1H-1,4-benzodiazepines 86, most likely by initial deprotonation at C-5 followed by loss of the leaving group (Eq. 28).
Dihydro-1,4-Benzodiazepines
562
86
B85
Thus the 4-sulfonates 85 (R, = Me, R, = MeSO,, 4-MeC6H4S0,; R, = H, Ph) were transformed into the corresponding compounds 86 by treatment with sodium hydride in dimethylf~rmamide.’~’~~ The 4-acyl derivatives 85 (R, = Me; R, = CHO, Ac; R, = Ph) similarly underwent eliminations of formaldehyde or acetaldehyde, respectively, to give the imines 86. Elimination of water from the 4-hydroxyderivatives 85 (R, = H, Me; R, = OH; R, = Ph) was achieved in high yield by heating in strong base such as sodium hydroxide in boiling ethanol.34Medazepam (86: R, = Me, R, = Ph), was also obtained when the 4-acetoxy compound 85 (R, = Me, R, = AcO, R, = Ph) was reacted with strong bases.34 Refluxing of the 4-hydroxy compound with dicyclohexylcarbodiimide in toluene effected elimination of water as well.34 In this case, the intermediate isourea 87, which could undergo the indicated elimination to medazepam (12), may be formed (Eq. 29).
Me
c1
I
Ph 12
87
1.1.9. Other Syntheses 2-Hydroxybenzodiazepines 72 (R, = H, Me; R, = Ph; X = C1, NO,) were synthesized by treatment of the acetals 88 with aqueous acid (Eq. 30).69
563
1. 2,3-Dihydro- 1 H - 1,4-Benzodiazepines
A synthesis reported in the patent literaturea6 involves oxidation of the benzhydrol89 with manganese dioxide or chromium trioxide in acetic acid to the corresponding benzophenone, which undergoes in situ cyclization to the diazepine 42 (Eq. 31).
1
R2 89
R2
42
Thermal rearrangement of the oxaziridines 90 (R, = CHO, Ac) afforded the corresponding nitrones 91 (Eq. 32).a3,84
90
91
1.2. Synthesis of 2-Imino-2,3dihydro-lH-l,4benzodiazepines The title compounds bearing a hydrogen at the 1-position exist as 2-amino3H-l,6benzodiazepines and were discussed in Chapter V. The 2-imino derivatives 93 (R, = Me, R, = Ph) were prepared in 80% yield by cyclization of the nitriles 92 with ethanolic hydrogen chloride.a7 A 1-benzyl-7nitro analog was similarly s y n t h e ~ i z e d . ~ The ~ " imines 92 were obtained by an amine exchange of the ethanolamine Schiff base with 2-aminoacetonitrile hydrogen sulfate in the presence of 2-methyl irnida~ole.'~ Compound 93 (R, = Me, R, = Me2N, R, = Ph, X = C1) resulted from the reaction of the 2-thione 94 (R, = Ph) with l,l-dimethylhydrazine.aaThe acetylhydrazine 93 (R, = Me, R, = AcNH, R, = 2-FC,H4, X = C1) was likewise formed from the appropriate 2-thione and acetylhydra~ine.~~ The 1-cyano-2-methylimine 93 (R, = CN,R, = Me, R, = Ph, X = C1) was isolated from the reaction of the quaternary triazolobenzodiazepine 95 with aqueous alkali (Eq. 33).90
564
Dihydro- 1,4-Benzodiazepines
q R1
X
/NfiCN
Ph
- dy-Rz ‘ HCI. EtOH
x’
-N
R3
93
92
(33) Me
45
c1
R3
94
c1
Ph 95
1.3. Synthesis of 2-Methylene-l,3dihydro-2H-l,4benzodiazepines
The benzodiazepines 97 with an exocyclic double bond at the 2-position were synthesized by reacting 3H-1,4-benzodiazepines (%) having a leaving group X at the 2-position with a stabilized carbanion, -CHR,R,. Suitable leaving groups X were N-nitrosomethylamino,gl~gz dimorpholinophosphorylOX^:^,'^ dietho~yphosphoryloxy,63’~~*~~ and diphenoxyphosph~ryloxy.~~ The carbanions employed were derived from dialkyl malonates,” malononitrile,” malonic acid ethyl ester dimeth~lamide,~, alkyl ~yanoacetate,~, alkyl a c e t ~ a c e t a t e , ~ ~a~etylacetone,’~ ,’~ diethyl acetonedi~arboxylate,~~ and nitroalkanes (Eq. 34).65,92The 4-oxides of 97 could be obtained in the same fashion.
-’,
Compounds 99 (R, = COOR) were accessible by alkaline hydrolysis of the corresponding malonyl derivatives 97 (R, = R, = COOR) followed by decarboxylation, which occurred usually under the conditions of hydrolysis (refluxing in alcohol-water in the presence of hydroxide). Under these conditions, compounds 97 with R, = COOMe, R4 = Ac or with R, = R, = Ac lost an acetyl group to form the ester 99 (R, = COOMe),93 and the methylketone 99
1. 2,3-Dihydro-lH-1,4-Benzodiazepines
565
(R, = Ac),'~respectively. The tertiary butyl ester 97 (R, = COOt-Bu, R, = Ac) was cleaved by trifluoroacetic acid and spontaneously decarboxylated to give 99 (R, = Ac, 4-des0xy).~~ The same reagent converted 97 (R, = COOt-Bu, R, = CN) to the corresponding acid, which was thermally decarboxylated to 99 (R, = CN, 4-de~oxy).~, A more direct synthesis of the nitrones 99 was provided by the ring expansion of the quinazolines 98 with carbanions. The carbanions successfully employed in this ring expansion include those generated from nitr~methane,~, ethyl acetate, i-propyl acetate, t-butyl acetate, N,N-dimethylacetamide, 1-acetyl-Cmethylpiperazine, acetonitrile, dimethyl sulfone, N,N-dimethylmethylsulfonamideand 2-methylpy1idine.~~The anions were formed with a strong, sterically hindered base, preferably lithium diisopropylamide. In the case of acetonitrile anion, the primary adduct 100 could be isolated and further converted to 99 (R, = CN) by treatment with a strong base like potassium t-butoxide (Eq. 35).95
98 -CHICN
/f
9f base
(35)
Fo 100
Analogously, reaction of the dihydroquinazolines 101 with alkoxide led to the benzodiazepines 99 (R3 = COOEt).96 As shown by the preparation of 103 (R = H, Me), the 2-dichloromethyl-l,2-dihydroquinazoline 102 (R = H, Me) may serve as the starting material in place of 98. However, the yield in this variation was considerably lower (Eq.36).94 The anion of nitromethane was conveniently formed with lithium amide in dimethyl s ~ l f o x i d e . ~ ~ The malonyl derivatives 107 were also found to be formed in good yields by reaction of the lactams 104 with the phosphorylated malonic ester of possible structure 105.97The phosphorylated malonic ester may react with the lactam,
%
Dihydro-1,CBenzodiazepines
566
E+k:;
c1
-CHzNoz*
clxlJ& "I2
(36)
F
/
\
\
103
102
generating the iminophosphate 106 with loss of ethanol; 106 could then rearrange in the indicated fashion to form 107 (Eq. 37).
a'& H
Y
O
COOEt -I- EtO'&P(oEt)2
6
---+
105
104
(37)
106
I
Y
COOEt
ox 107
Oxidation was another means for the introduction of an exocyclic methylene into compounds 108 (R, = H, Me; R, = CN, CONH2).63998 Manganese dioxide and chromium trioxide were the reagents of choice. When the tricyclic compound 110 was subjected to activated manganese dioxide, the formyl derivative 109 (R, = H, R, = CON(CHO)Me, X = F, Y = C1) was obtained as the major product (Eq. 38).63 The a-amino derivatives 112 (R, = ROOC, Ac; R, = H) resulted from the ' . ~the ~ presence of catalytic reduction of the oximes 111 over Raney n i ~ k e l . ~In ammonia, the nitrone function of the corresponding 4-oxides survived the catalytic h y d r o g e n a t i ~ n With . ~ ~ few exceptions, the unstable amines 112 were not characterized but used directly in further conversions (see Eq. 62, below).
1. 2,3-Dihydro-lH-1,4-Benzodiazepines
567
109
108
Me I
,"Yo
N-Acetyl derivatives 112 (R, = EtOOC, R, = Ac) were also prepared by decarboxylation of the malonates 113 (Eq. 39).92
1.4. Synthesis of 3-Methylene-1,2dihydro-3H-l,4-benzodiazepines These compounds were prepared exclusively by ring expansion of quinazolines. Compounds 116 (R, = H;R, = H, C1) and their 4-oxides were obtained by treatment of the corresponding quinazolines 114 with potassium t-butoxide in The isomers with an endocyclic double ether or tetrahydrofuran (Eq.
Dihydro-1,4-Benzodiazepines
568
bond were also formed in this reaction. The aziridines 115 are most likely intermediates in this conversion and may undergo the indicated rearrangement to 116.
Ph 115
114
H
J
ahRl
R2
Ph
116
Compound 116 (R, = EtOOC; R, = C1, 4-oxide) was isolated from the reaction of the quinazoline 3-oxide 114 (R, = EtOOC; R, = C1; X = Br, 3-oxide) with potassium t-butoxide in ethanol.96 1.5. Reactions of 2,SDihydro-1 H-l,4benzodiazepines
1 s.1. Reactions with Electrophiles 1.5.1.1. Protonation
As demonstrated for medazepam (12), the imine nitrogen is more basic than the aniline nitrogen. The pK values were determined spectroscopically to be 6.25 for the 4-position and - 1.45 for the l-position.'OO The 4-protonated species of 2,3-dihydro-1H-1,4-benzodiazepines are yellow to orange, while the diprotonated forms are virtually colorless. Me
I
Ph 12
1.5.1.2. Halogenation Introduction of a halogen atom at the 7-position was reported for a variety of 5-phenyl-substituted 2,3-dihydro-1H-1,4-benzodiazepines. Medazepam (12)
1. 2,3-Dihydro-1H-1,4-Benzodiazepines
569
was prepared by chlorination of 117 (R, = Me, R, = H, R, = Ph) with N-chlorosuccinimide, t-butyl hypochlorite, or chlorine (Eq. 41)."' N-Chloroand N-bromosuccinimide were used to halogenate compounds 117 (R, = Me; R, = MeOCH,, ClCH,; R, = Ph, 2-C1C,H4) at the 7-position.48*49*102 Reaction of 117 (R, = H, Me; R, = H; R, = Ph, 2-FC,H,) with iodine monochloride in acetic acid mixed with sulfuric acid gave high yields of the 7-iodo
derivative^.'^^' lo4
The chlorination of the 2-acetylidene analog 119 with t-butyl hypochlorite led to a mixture of two olefin isomers 120, which were separated by chromatography (Eq. 42).,,
ocl 120
119
1.5.1.3. Oxidation
2,3-Dihydro-lH-l,4-benzodiazepines121 (R, = H, Me; R, = H; R, = Ph) were oxidized to the corresponding 2-ones 122 by chromium trioxide in acetic acid46 or in sulfuric acid-acetone. l o 5 The same reagent oxidized the 2-hydroxy compounds to the 2-ones as well.69Ruthenium tetroxide allowed the introduction of a carbonyl group into the 2-position more effectively. Medazepam was thus converted to diazepam in 55% yield using this reagent in chloroform at o"C.80This procedure was applied also to 121 (R, = CF,CH,; R, = H; R, = 2ClC,H,, 2-FC6H,; X = Cl).lo6 N-Bromosuccinimide in tetrahydrofuran and aqueous sodium bicarbonate solution was reported to oxidize 121 (R, = Me, R, = H, R, = 2-FC6H,, X = C1) to the corresponding Lone.,' Milkowski and coworkers'07 studied the oxidation of 121 (R, = Me, R, = CICH,, R, = Ph, X = C1) under various conditions. Potassium permanganate in dilute hydrochloric acid yielded 57% of diazepam and 10% of the anthranil 123 as the major products. Diazepam was also the major product of
570
Dihydro-1,4-Benzodiazepines
c1G
O Ph 123
J$r
c1
Ph
124
the oxidation with chromium trioxide in dilute sulfuric acid. Treatment of the same compound with chromium trioxide in pyridine gave the quinazolinone 124 (30%), the 1-formyl derivative 121 (R, = HCO, R, = ClCH,, R, = Ph, X = Cl) (l8%), desmethyldiazepam (14%), and diazepam (4%). The 2-chloromethyl and the 2-hydroxymethyl compounds 121 (R, = Me; R, = ClCH,, HOCH,; R, = 2-C1C6H,; X = C1) were oxidized to the corresponding 2-ones in 20% yield using potassium permanganate in dilute hydrochloric acid (Eq. 43).,’ The oxidation of 2,3-dihydro-1H-1,4-benzodiazepines to 3H-1,Cbenzod i a ~ e p i n e s ~ ”by~ ’manganese dioxide was discussed in Chapter V, dealing with the synthesis of 3H-1,4-benzodiazepines. When the 5-unsubstituted benzodiazepine 125 was subjected to this reagent in refluxing benzene in the presence of a catalytic amount of acetic acid, the dimer 126 was isolated in 12% yield (Eq. 44).68”
126
Manganese dioxide and chromium trioxide were used also for the introduction of an exocyclic double bond into the 2-acetonitrilesg8and a 2 - a ~ e t a m i d e ~ ~ (see Section 1.3). l-Acylated-2,3-dihydro-l H-1,4-benzodiazepines 127 (R,= Ac, HCO; R, = Ph) were oxidized by peracetic or m-chloroperoxybenzoic acid to the oxaziridines 90, which were thermally rearranged to the corresponding n i t r ~ n e s . ~A~ * ’ ~ direct conversion of the imine 127 (R, = F3CCH,, R, = 2-FC6H,) to the N oxide 128 by m-chloroperoxyzoic acid was also reported (Eq. 45).,,
1. 2,3-Dihydro-lH-l,4-Benzodiazepines
571
RC0,H
c1 90
c,T, CH2CF,
\
(45)
0
128
1.5.1.4. Reactions with Nitrogen Electrophiles A. Nitrosation. The dihydrobenzodiazepine 129 (R, = H, R2 = Ph) was nitrosated by sodium nitrite in glacial acetic or by nitrosyl chloride in ~ y r i d i n eto~ the ~ 1-nitroso derivative 130 (R, = H, R, = Ph) (Eq. 46). Similar nitrosations were carried out on the nitrile 129 (R, = CN, R, = Ph)68dand the 2-acetic acid methyl ester 129 (R, = MeOOCCH,, R, = 2-FC6H4)62bto yield the corresponding 1-nitroso compounds.
Reaction of the 2-methylene derivatives 131 with sodium nitrite in glacial acetic acid led in high yields to the oximes 111 (Eq. 47). This conversion was described for a variety of substituents R, and also for the corresponding 4-oxides. Applicable substituents were R, = R00C,92,93,95+96A c , ~ ~ CN,95N02,66Me2NOC,95 Me2NS02,95and 2 - p ~ r i d y l . ~ ~
131
111
572
Dihydro-1,4-Benzodiazepines
Nitrosation of the a-amino derivatives 132 provided a high yield synthesis of the triazolobenzodiazepines 133 (Eq. 48).63Transformations of this type were carried out for R = MeO, EtO, t-BuO, and Me.63
132
I33
Several 7-amino-substituted 2,3-dihydro-1H-1,4-benzodiazepines’34 were subjected to the Sandmeyer reaction (e.g., diazotization to 135 and reaction of the diazonium salts with nucleophiles) (Eq. 49).2-5,7*112,113
134
I35
B. Nitration. Nitration of the benzodiazepine 136 led to the 7-nitro compound 137 (R = H) and the 79-dinitro derivative 137 (R = NO,). If the 7position was occupied by a chlorine, the nitro group entered the 9-position (Eq. 5O).lo6 YH2CF3
136
137
Nitration at the 7-position of 138 with concomitant demethylation (yielding 139) was observed during reaction with nitric acid in a mixture of sulfuric and acetic acids (Eq. 51).48
1. 2,3-Dihydro-1H-1,4-Benzodiazepines
Ph
573
Ph
138
139
C. Reactions with other Nitrogen Electrophiles. Diethyl azodicarboxylate added to the 2-methylene compounds 140 (R = MeO, Me; X = F, C1) to give the adducts 141 of undetermined stereochemistry (Eq. 52).63-l o *
cy
o-"
140
141
1.5.1.5. Reactions with Carbon Electrophiles
A. Alkylation. Methylations at the 1-position were carried out with dimethyl and with methyl iodide sulfate-sodium methoxide in dimethylf~rmamide~ using sodium h ~ d r i d e ' ~ . " O or p h e n y l l i t h i ~ m''I~ ~ ,as base. A high yield methylation by means of formaldehyde and sodium cyanoborohydride was also de~cribed.~' Similar alkylations were performed with cyclopropylmethyl brom2-phthalimido- 1-bromoethane, ide,' 2-diethylaminoethyl chloride,' and 2-bromo-N-methylacetamide. Quaternization of the 4-position nitrogen was achieved with dimethyl sulfate in refluxing benzene"4a or with ethyl iodide.114b Alkylations of various functional groups on 2,3-dihydro- 1H-1,Cbenzodiazepines were described. The alcohol 108 (R, = Me; R, = OH; X = Y = C1) was transformed into the propargyl ether 108 (R, = Me; R, = HCd-CH,; X
'
''
''
' ''' '
'
9
1
Ph
&I 108
17
Dihydro- 1,4-Benzodiazepines
514
= Y = C1) by reaction with 1-bromo-2-propyne and sodium hybride in benzene. The benzodiazepine-7-carboxylicacid 17 (R, = H; R, = COOH) was esterified by diazomethane to 17 (R, = H; R, = COOMe).’ The 2-chloroethylamides 142 underwent an intramolecular alkylation on oxygen to form the oxazolines 143 when treated with potassium carbonate in dimethylformamide in the presence of iodide (Eq. 53).’15
n
H yN-c1
O y N
142
143
Similarly, potassium carbonate in acetonitrile effected conversion of the chloroacylamides 144 (n = 1-3) to the cyclic compounds 145 (Eq. 54).’15
144
145
Intramolecular alkylations of the a-chloroacyl derivatives 146 (R = H, Me) by treatment with triethylamine in hot dimethylformamide yielded the pyrazinodiazepines 147 (R = H, Me) (Eq. 55).’16
COOMe El, N/DM F
(55)
c1
CI
0”’ 146
0”’ 147
575
1. 2,3-Dihydro-lH-l,4-Benzodiazepines
The 3-chloropropanoyl analog 148 gave under the same reaction conditions the pyrrolinone 149 (Eq. 56).'16 0
COOMe Et,N/DMF
(56)
I49
148
The 1-malonyl derivative 150 of unknown stereochemistry was subjected to intramolecular alkylation, which resulted in a mixture of two diastereomeric pyrrolidinones 151, separated by chromatography (Eq. 57).63
-
COOEt I
5COOEt
%OOMe I-BuOK
(57)
c1
c1
150
151
B. Reactions with Aldehydes, Ketones, and Epoxides. The oximes 152 (R = H; R, = H, Me,N, pyrrolidino, morpholino, MeO, MeS, 2-pyridyl) reacted with aldehydes in hot glacial acetic acid to give moderate yields of the imidazobenzodiazepines 153.66This reaction was also applied to a few 4-oxides. Under milder reaction conditions (e.g., refluxing in dichloroethane in the presence of pivalic acid), formaldehyde converted 152 (R = R, = H) to a mixture of the oxadiazine 154 (R, = R, = H) and the imidazoline N-oxide 155 (Eq. 58.)66 If R, in 152 was an electron-withdrawing moiety such as an ester (t-BuOOC) or amide (Me,NCO), the oxadiazines 154 (R, = t-BuOOC, Me,NCO; R, = H, Me) were formed e x c l ~ s i v e l y .Methylation ~~ of the oxime oxygen in 152 (R = Me) improved the yields of the imidazobenzodiazepines 153 by blocking the formation of the oxadiazines.66 Treatment of the morpholino derivative 156 with formaldehyde and pivalic acid in refluxing 1,2-dichloroethane gave the spiro compound 159 as the major product.66 Its formation was rationalized by hydroxymethylation of the oxime
576
153
152
OH
-
LNP0
NOH
CH,O
HO
-
\
-
577
1. 2,3-Dihydro-lH-1,4-Benzodiazepines
The structure of 159 was determined by single-crystal X-ray analysis. Ring formations with formaldehyde were carried out with other functionalized 2,3-dihydro-1,4-benzodiazepines.The 2-hydroxyethylthio derivative 160 was thus converted to the tricyclic compound 161 in 78% yield.68 The alcohol 162 and the methylamide 164 were similarly transformed into the 1,3-oxazine 163 and the pyrimidine 110 (Eq. 60).
e?,
q--oH - Qf-J H
c1
CH,O
CI
Ph
--N
Ph
160
161
bF 162
163
Me
Me
c1
c1
0 164
110
The amines 132 (R = MeO, EtO, t-BuO, Me) reacted with aliphatic and aromatic aldehydes to form unstable adducts, which oxidized in the presence of air or manganese dioxide to the imidazo[1,5-a] [l, 4lbenzodiazepines 165 (Eq. 61).92* 93
578
ox
o x
165
132
Acetylacetone added to 132 (R = MeO, X = 2-C1, Y = 7-CI) to form the enamine 166, which was thermally converted to the imidazobenzodiazepine with elimination of acetone. This transformation was postulated to proceed through the dihydroimidazole 167 as indicated in Eq. 62.93
o1 166
--c A
165
I’;>” 167
(62) Lewis acid catalyzed addition of ethylene oxide to the imine function in medazepam (12) yielded the oxazolidine 168 (Eq. 63).’” Me
Me
G s yqT N3 1
c1
Ph
12
Ph
(63)
0
168
C. Acylation. Additions to Imine. Acylations at the 1-position nitrogen were carried out for many 2,3-dihydro-1H-1,4-benzodiazepines using acid anhydrides, acid chlorides, and isocyanates. The reagents employed were formic acetic anhydride5’ in combination with pyriacid-acetic anhydride,’ dine’ 5 , 8 3 or potassium carbonate,68 acetyl chloride in dirnethylf~rmamide,~~ malonic acid chloride ethyl ester,63 and the following isocyanates: 2-chloroacetyi, 2-chloroethyl, 3-bromopropanoyl, 4-chlorobutanoyl, and 2-chloroacetylthio. 5983
’’
579
1. 2,3-Dihydro-lH-l,4-Benzodiazepines
The 2-aminomethyl derivatives 169 (R,
=
Me) were reacted with various acid
anhydride^,^^.^'"'^ acid ~ h l o r i d e s , ~l~8 ,isocyanates,' ~~,' l 8 and ethyl chloroformate118 to yield the derivatized amines 170 (Eq. 64).
0
R,
R2
171
Compound 169 (R, = H, R, = 2-FC6H,, R, = 7-C1) was monoacetylated on the primary amino group by acetic anhydride in methanol65 and diacetylated in pyridine-acetic anhydride to give 170 (R, = Ac, R2 = 2-FC6H4, R, = 7-C1, R, = Me).65 Phosgene and thiophosgene reacted with 169 (R, = H, R, = 2-FC6H,, R3 = 7-C1) to give the imidazolidinone 171 (X = 0) and the thione 171 (X = S) (Eq. 64).'19 Treatment of 169 (R, = H) with orthoesters afforded the imidazolines 172.65These imidazolines were also obtained by cyclization of the acylated derivatives 170 with polyphosphoric acid at elevated temperat~re.,~ Reaction of the amidine 171a with dimethylformamide dimethylacetal in refluxing toluene led to the imidazole 172a (Eq. 65).66a
DMF-DMA
171a
172a
Dihydro- 1,4-Benzodiazepines
580
The diastereomeric 2-(hydroxybenzyl) derivatives 173 reacted with phosgene to form the corresponding oxazolidinones 174 (Eq. 66).73The stereochemistry of the compounds was not determined.
c1
c1 Ph I73
I
Ph 174
MeCN/AICI,
Ph 175
One of the diastereomers 173 was converted to the imidazoline 175 by treatment with acetonitrile and aluminum chloride.73 The enamines of structure 132 were transformed into imidazo[1,5-a] [1,4]benzodiazepines 165 by acylation and subsequent ring closure or, better, by treatment with orthoesters or amide acetals (Eq. 67).92,93 Reaction of 132 (R = MeO, X = 2-C1, Y = 7-C1) with phosgene or thiophosgene led to the imidazole derivatives 176 (X = C1, Z = 0, S).’19 The 1-one 176 (X = C1, Z = 0) was also obtained by treatment of the appropriate 132 with carbonyldiimidazole.’08 Base-catalyzed cyclization of the urethane 177, resulting from the acylation of 132 with ethyl chloroformate, provided still another access to the 1-ones 176 (X = F, Z = 0)(Eq. 67).’19 An intramolecular acylation on carbon with dehydration (Dieckmann-type cyclization) allowed the conversion of the malonyl derivative 178 to the tricyclic compound 179 (Eq. 68).63 The 2-hydroxymethyl substituted 7-chloro-2,3-dihydro-l-methyl-5-phenyllH-l,4-benzodiazepine was reacted with ethyl isocyanate to give the corresponding ret thane.^' Methyl isocyanate acylated the 2-imino compound 180 to the urea 181 (Eq. 69).’” Acylations at the 4-position nitrogen with subsequent addition of a nucleophile to the 5-position were observed. Medazepam (12) reacted with ethyl chloroformate in the presence of aqueous sodium carbonate solution to give benzophenone 184 via the 5-hydroxy compound 182.”’ Intramolecular trapping by the nucleophile afforded tricyclic compounds. Thus, reaction of 12 with
1. 2,3-Dihydro-lH-l,4-Benzodiazepines
581
‘hT u
\. \
ox I
\
I32
z = CCI,
165
or
H
COOEt
1-BuOK
c1
cy 176
bF
178
Ph 180
d C1
T
‘
C
O
-N
O
M
bF I77
179
Ph 181
e
Dihydro-1,4-Benzodiazepines
582
malonic acids (R = H, Et) in the presence of acetic anhydride yielded the lactones 183 (Eq. 70).122 Me
Me
SOOH Ac,O
CH-R 1dOOH
i
qMe
c1
(70)
Me 1 N-”’’NHCOOEt
q0
c1
Ph
P h O Z
184
0 183
Related reactions are the addition of ketenes and nitrile oxides to the imine bond. Gunda and E n e b a ~ k reported ’~~ the addition of the N-protected glycine 185 to medazepam (12) to form the /?-lactam 186. Phosphorus oxychloride was used to activate the carboxyl group of 185 (Eq. 71).
<) Me
+
c1
Ph
Me
COOEt JNGcoo-Kf 185
c1
12
MeE C O O E t 186
Me
1. 2,3-Dihydro-lH-l,4-Benzodiazepines
583
Dipolar additions of the nitrile oxides 187 (R = Ph, COPh) to medazepam yielding 188 were studied by Jaunin and coworkers (Eq. 71).'24 The 4-oxides 189 (R = CHO, Ac) were converted to the 3-acetoxy derivatives 190 by treatment with refluxing acetic anhydride (Eq. 72).83 R
R Ac,O
*
c1q ) A c
(72)
c1 Ph
Ph 0 ' 189
190
The 5-hydroxylamino compound 191 was reacted with carbonyldiimidazole to form the tricyclic derivative 192 (Eq. 73).74" Me I
(73)
c1
c1 NHOH 191
192
Acylation of the aromatic amino group in 5-(2-aminophenyl)-substitutedand 7-amino-substituted compounds was carried out by standard r n e t h o d ~ . ~ . ~ ~ A 1-amino-substituted benzodiazepine was acylated by acetic anhydride. 1.5.1.6. Sulfonation Sulfonations at the 1-position were effected by tosyl and mesyl ch10ride.l~~ Selective tosylation of the 2-aminomethyl group was reported for 193 (R, = H, R, = H,NCH,, X = F).'26
193
194
The 2-hydroxy derivatives 193 (R, = Me; R, = HO; X = H, F) were treated with mesyl chloride and pyridine to form the lH-benzodiazepines 194 (Eq. 74).60.'27
584
Dihydro-1,4-Benzodiazepines
1.5.2. Reactions with Nucleophiles 1.5.2.1. Reduction The reduction of 2,3-dihydro-1H-l,4-benzodiazepines and their 4-oxides to 2,3,4,5-tetrahydro derivatives is discussed in the next chapter in the section describing the synthesis of such compounds. The 2-nitromethylene compounds 195 and their 4-oxides were reduced by hydrogen with Raney nickel as catalyst to the 2-aminomethyl derivatives 196.65,92Sodium borohydride in ethanol converted 195 (R, = H, R, = 2FC,H,, X = C1) to the bridged nitro compound 197.65
bf 197
198
This transformation involves reduction of the double bond followed by intramolecular attack of the a-nitro carbanion at the 5-position. Treatment of the same nitro compound 195 with phosphorus trichloride in the presence of pyridine led to the nitrile 198 in 30% yield via a reduction accompanied by a dehydration (Eq. 75).65 Reductions of aromatic nitro functions to the corresponding amines were generally carried out with Raney nickel and h y d r ~ g e n ~ -or~ with , ~ . stannous ~~ chloride. This catalyst was also used to hydrogenate a 3-methylene benzodiazepine to the corresponding 3-methyl derivativeg9 and a 2-azidomethyl derivative to the corresponding a m i ~ ~ e to , ~ remove O a 1-nitroso moiety,73and to reduce the N-hydroxyamidine 199 to the corresponding amidine 171a (Eq. 76).,,"
1. 2,3-Dihydro- 1H-1,4-Benzodiazepines
199
585
171a
(76) Phosphorus trichloride was most commonly used to reduce 4-oxides to the corresponding parent compounds.2' - 2 3 9 9 1 * 9 6 , 9 9 Hexachlorodisilane was used as The exocyclic double bond in the esters 200 (R = H, Me; X = F, C1) was reduced by triethylsilane in trifluoroacetic acid to the 2-acetic acid esters 201 (R = H, CH,; X = F, C1) (Eq. 77). COOMe
COOMe
CF,COOH* HSiE1,
200
@ ' . 6"
c1
-N
(77)
201
Lithium aluminum hydride converted the ester 201 (R = H, X = F) to the corresponding alcohol63 and reduced a 2-carboxamide to the aminomethyl derivative 1% (R, = H, R = 2-FC6H4, X = Cl).92 This reagent reduced the 1-nitroso compound to the 1-amino analog.83cA 7-acetyl group was reduced by sodium borohydride to the hydroxyethyl moiety.' O4 1.5.2.2. Reactions with Oxygen and Sulfur Nucleophiles A. Hydrolysis. The imine function in 2,3-dihydro-lH-1,4-benzodiazepines 202 was cleaved by aqueous hydrochloric acid to give the benzophenones 203 as hydrochloride salts (Eq. 78).',' The free base of 203 (R = H, Me; X = NO,) was stable enough to be isolated,2 while 203 (R = H, X = C1) cyclized back to the
benzodiazepine spontaneously upon liberation of the base.' The 7-trifluoromethyl analog 202 (R = H, X = F,C) yielded the carboxylic acid 203 (X = HOOC) together with the decarboxylated compound. These were recyclized to the corresponding benzodiazepines 202.' An analogous hydrolytic ring opening occurred when the 4-quaternary salt was subjected to aqueous base.'I4 The acetyl group at the 1-position was removed by aqueous sulfuric acid.34
Dihydro-1,4-Benzodiazepines
586
I
Ph
Ph 203
202
Acid hydrolysis converted 2-cyano derivatives to the c a r b o ~ a m i d e s . ~ ~ - ~ ~ Treatment of the 2-cyanomethylene compounds 204 with concentrated sulfuric acid yielded the corresponding amides 205 (Eq. 79).62s98
204
205
Mild acid hydrolysis (20% HCl at room temperature) converted the 3-amino derivatives 69 to the 3-hydroxy analogs 206 (Eq. 80).32
Ph 69
Ph 206
The 5-(3-indolyl)benzodiazepine 207 underwent rearrangement during acid hydrolysis to give the quinoline 210. The reaction, as outlined in Eq. 81, was proposed to proceed via intermediates 208 and 209.128 Alkaline hydrolysis of the 2-malonylidene compounds 211 (R, = COOR,, Ac) to the corresponding acetylidene derivatives 211 (R, = H) was mentioned in Section 1.1.3. Further hydrolysis and decarboxylation led to the 2-methyl-3H1,Cbenzodiazepine 212 (Eq. 82).63 The benzodiazepine 2-acetic acid methyl ester 201 (R = H, X = F), a similar ethyl ester,118 and an iminoetheF7 were hydrolyzed by hydroxide in methanol to the corresponding carboxylic acids. Mild treatment of the 3-acetoxy derivatives 213 (R = Ac, Me) with hydroxide in methanol or with aluminum oxide gave the corresponding alcohols,83 while more vigorous conditions (refluxing in methanolic sodium hydroxide for 3 hours) led to the indole 214."' The indole2-carboxaldehyde 216 was formed from the 3-hydroxy compound 215 under
1. 2,3-Dihydro-lH-l,r)-Benzodiazepines
COOR,
c1
base
c1d p 2
--N
R3
R3
211
212
7 1 bale
c1q
+
- Pho
A
c1
c
214
213
qoH &r0 Me I
C1
(83)
Me
obdSC rA
c1
Ph 215
216
comparable conditions (Eq. 83).'" The 4-oxide 189 (R = Ac) was deacetylated by refluxing in ethanolic sodium hydr~xide.'~ Displacement of the chloride in 2-chloromethyl benzodiazepines by hydroxide was r e p ~ r t e d . -~4'9 According
Dihydro- 1,4-Benzodiazepines
588
to the patent literature,lz9 the dihalides or ditosylates 217 gave the oxazinobenzodiazepines 218 (X = 0) upon treatment with sodium hydroxide in tetrahydrofuran (Eq. 84).
R2
rl qfy
base R,
--N
kl
Rl 217
218
B. Other Oxygen Nucleophiles. 2-Cyanobenzodiazepines 219 (R, = H, Me; X = H, F) were converted to the iminoesters 220 by treatment with methanolic hydrogen chloride67 or methanol in the presence of cyanide (Eq. 85).70,71b Further reaction with methanolic hydrogen chloride led to the 2-carboxylic acid methyl ester,67which was also prepared by the esterification of the corresponding 2-carboxylic
219
220
A benzodiazepine 2-acetonitrile was similarly transformed into the 2-acetic acid ethyl ester by hydrogen chloride in ethanol."s The chloride in several 2-chloromethyl derivatives was displaced by oxygen nucleophiles such as a l k o ~ i d e s , ~ phen~xide,~' ~ - ~ ~ ~ ~ and ~ ~acetate.47 ' ~ ~ C. Sulfur Nucleophiles. The 2-hydroxy benzodiazepine 221 reacted with hydrogen sulfide in acetic acid to yield the bridged sulfide 222 (Eq. 86).68 Me
Me I
(86)
c1
c1 Ph 221
NH Ph 222
1. 2,3-Dihydro-lH-l,4-Benzodiazepines
589
The thiazinobenzodiazepines 218 (X = S) were reported to be synthesized from the dihalides or ditosylates 217 by treatment with sodium hydrogen sulfide (Eq. 84).lz9 1.5.2.3. Reactions with Nitrogen Nucleophiles The halogen of 2-halomethyl derivatives was displaced by nitrogen nucleophiles such as sodium a ~ i d e , ~ ' . potassium '~ phthalimide,47.50 morphop i ~ e r i d i n e ,and ~ ~ other amine~.~'Reaction of the dihalide 217 with ammonia or methylamine led to the pyrazinobenzodiazepines 218 (X = NH, NMe).lz9 The 2-methoxy functionality was displaced by ~ i p e r i d i n e . ~ ~ The 5-ethoxy moiety in 223 (X = EtO, Y = C1) was replaced by various N-nucleophiles: h y d r ~ x y l a m i n e , ~m~e"t' h~ ~ x y a r n i n ehydroxylamine ,~~~ 0-acetic 4acid ethyl ester,74b e t h a n ~ l a m i n e , 2-(diethylamin0)ethylamine,~~"~~ ~~~ phenylpipera~ine,~~~ and hydrazine derivative^.^^"*'^^^^^^^' In the last case, and 225 were observed (Eq. 87).74"*7sSimilar reactions cyclizations to 22474a,130 were carried out with the 5-methylthio compound 223 (X = MeS, Y = H).55 Me
Y
&--
Me
c1
x
223
1
H
NH,NHCOR
224
Me
c1
N
225
Benzodiazepine-2-acetic acid esters or acids were converted to the corresponding amides either by direct a m i n ~ l y s i or s ~ via ~ activation of the carboxyl group."B Reaction of the 2-acetylidene derivatives 226 (X = H, F) with methanolic ammonia in the presence of ammonium chloride at 100°C yielded the spiro compounds 227 and the pyrroloquinolines 228 as the major products (Eq. 88).63 Cyclization of the nitrile 229 by refluxing in methanol and concentrated aqueous ammonia led to a mixture of 230 (R = H) and 230 (R = OH) in 11.5 and 33% yield.68"A better conversion of 229 to 230 (R = H) was achieved by
Dihydro- 1,4-Benzodiazepines
590
221
226
+
228
treating first with aqueous hydrochloric acid and subsequently with ammonia (Eq. 89). Me
Me I
NH+OH
(89)
c1 Ph 229
Ph 230
1.5.2.4. Reactions with Carbon Nucleophiles Displacement of the chloride in 2-chloromethyl-2,3-dihydro-lHi-1,4-benzodiazepines by cyanide led to the 2-a~etonitrile.s.~~ Acetone cyanohydrin or sodium cyanide in acetic acid reacted with 2-hydroxy benzodiazepines to give the 2-cyano analog^.^^^^^ The 7-cyano derivative 232 was obtained from the
23 1
232
1. 2,3-Dihydro- 1H- 1,4-Benzodiazepines
59 1
7-iodo compound 231 by means of cuprous cyanide in dimethylformamide (Eq. 90).'04 The nitrile was further reacted with methyllithium to yield the 7-acetyl c o r n p ~ u n d . ' ~ ~A~7-acetyl '~' derivative was prepared also by reacting the 7-diazonium salt with acetaldehyde semicarbazone.' 32 1.5.2.5. Miscellaneous Reactions Attempted cyclization of the acetyl derivative 233 by base led to the 2-cyanoindole 234 (Eq. 91).68a Ac
.._
bdSC
c1
c1
I
234
Ph 233
Treatment of the I-sulfonates 235 (R = Me, 4-MeC6H,) - with sodium hvdride in dimethylformamide resulted in ring opening to the vinylimines 236 (Eq. 92).125 -I
<> . eN4 R
SOzR
so2
NaHjDMF
c1
(92)
c1
Ph
235
Ph
236
1S.3. Photo and Thermal Reactions The photochemical rearrangement of the nitrones 91 (R, = Ac, CHO) to the oxaziridines 90 was described by Metlesics and coworkers (Eq. 32).83,84The reverse reaction was accomplished by heat.83s84 Irradiation of the 1-alkyl derivatives 237 led to the indoles 238 in a preparatively useful reaction (Eq. 93).'33 The I-alkyl group is required, since compounds 237 with R = H or Ac were photostable. A p-nitro group on the 5-phenyl substituent also made the benzodiazepine inert to this transformation.' 3 3 The photolysis proceeded well in methanol, glacial acetic acid, or acetic anhydride but poorly in benzene and not at all in dry acetonitrile.
592
Dihydro-1,4-Benzodiazepines
231
The 3-hydroxy compound 215 was rearranged thermally in nearly quantitative yield to the indole-2-carboxyaldehyde216 (Eq. 83). 1.6. Spectral Data
References to spectral data are given in the tables (Section 5). The ultraviolet, infrared and proton-nmr spectra of 2-chloromethyl and 2-hydroxymethyl benzodiazepines were thoroughly compared with those of the isomeric diazocines.' 34 Romeo and studied the conformation of medazepam and 1-desmethyl medazepam by proton-nmr spectroscopy using a ianthanide shift reagent. Computer-simulated lanthanide shifts were found to be consistent with complexation of the imine nitrogen. Two rapidly interconverting pseudoboat conformers a and b were observed in deuterochloroform at room temperature,
a
b
An X-ray analysis of m e d a ~ e p a m revealed '~~ that the seven-membered ring is in a twist-boat conformation similar to that of the 2-ones.
2. 2,5-DIHYDRO-lH-1,4-BENZODIAZEPINES The parent compound 239 is still unknown. The 4-desoxy analog of 242 (R = H, X = C1) was isolated from the electrochemical reduction of oxazepam in basic rnedi~rn.'~'The 3-methyl-substituted 4-oxides 242 were prepared by oxidation of the hydroxyamines 241 (X = H, C1) with mercuric oxide or by manganese dioxide (Eq. 94).64399
3. 4,5-Dihydro-lH-l,4-Benzodiazepines
593
XJ H
N
239
Ph 240
J
base CI
(94)
Ph '0 242
Two amidines (244: R = Ph, 4-MeC6H,SO,) were prepared by catalytic hydrogenation of the 5H-benzodiazepines 243 over platinum (Eq. 95).""
Ph
Ph 243
244
3. 4,5-DIHYDRO-lH-l,4-BENZODIAZEPINES Only one substituted representative of the parent compound 245 has been reported in the literature.
245
Deyrup and Gill'38 obtained 247 in 62% yield by reaction of 246 with a catalytic amount of potassium t-butoxide in refluxing diglyme for 10 hours. The structure was assigned on the basis of spectral data and chemical evidence, which consisted in the facile oxidation of 247 to 249 by methanolic hypochlorite. The chloride 248 was postulated as an intermediate (Eq. 96).
Dihydro-1,4-Benzodiazepines
594
\
CMe,
241
NO2
CN
__c
CMe, 249
248
4.
4,5-DIHYDRO-3H-l,CBENZODIAZEPINES 4.1. Synthesis
While the parent compound 250 has not been synthesized, several 2-amino derivatives 252 have been prepared by catalytic hydrogenation of the 4,5-double bond in 3H-1,4-benzodiazepines 251 using platinum and palladium as catal y s t ~ . In ' ~ the ~ latter case dechlorination at the 7-position was a concomitant reaction and gave 252 (X = H) (Eq. 97).'39
250
(97)
c1 Ph 251
Ph 252
The addition of phenylmagnesium bromide to the nitrones 253 (R = NHMe, alkoxy) opened a route to 4-hydroxy analogs 254 (Eq. 98).140-142 Compound 252 (X = C1) was also prepared by reaction of the 2-one with methylamine and titanium tetrachloride.' 43
595
4. 4,5-Dihydro-3H-1,4-Benzodiazepines
c1
PhMgBr
q=$
c1
(98)
Ph OH 253
254
4.2. Reactions
For a discussion of the oxidation of the hydroxyamine 254 (R = NHMe) to chlordiazepoxide and its 5H t a ~ t o m e r , ' ~ ' , and ' ~ ~ the dehydration of 254 (R = alkoxy) to the 5H-benzodia~epines,'~~~'~~ see Chapter V (Sections 2.2.1.3, 3.1, and 2.5.1). An attempt to catalytically hydrogenate the 1,Zirnine bond in 252 (X = C1) failed.'45 Electrochemical reduction gave the dihydroquinazoline 258 in 80% yield. 14' Its formation may be rationalized by the intermediates 255257, as indicated in E 1. 99.
252
A
-
c1
&%
c1
Ph
Ph 255
257
H+
/
256
258
5. TABLES OF COMPOUNDS TABLE VI-1. 2,3-DIHYDRO-lH-l,4-BENZODIAZEPINES Substituent
mp W); [bp ("C/torr)]
Solvent of Crystallization
Yield (%)
Spectra
Refs.
H
None
244-246
MeOH
ir. uv
56
Monosubstituted 5-(2-Benzofuryl)hydrochloride 5-(5-Br-3-Indolyl) 1-(2,3-Dihydro-1H-1,4-benzodiazepin-l-yl) 5-(3-Indolyl) Hydrochloride Methiodide 5-( 1-Me-3-Indolyl) 5-Ph 5-(2-H,N-5-C1C6H3)hydrochloride 5-(2-CIC,H.J 5-(2-FC,Hd) 5-(2-Pyridyl) 5-(2-Pyrimidyl) 5-(2-Thiazolyl)
225-226d 217-2 19 178-1 80 217-2 19 18&185d 259-262 144149 145-147 23&260 165-167 14&150 152-154 171-173 158-160
MeOH/Et,O EtOH/H,O Sublimed EtOH/H,O MeOH/Et,O CH,CI,/Petr ether EtOH Et ,O/MeOH PhH/Petr ether Et,O CH,CI,/Hexane PhH/Hexane Me,CO/Hexane
12
77
6, 11
ir, ms, pmr
128b 128b 68a 14 128b 128b 128b 2, 8, 35 14c 25 103 3a 3b lOlb
Disubstituted 1,5-Disubstituted
u W
4
l-Ac-5-Ph 1-Et-5-Ph I-Me-SNH, hydroiodide I-Me-5-(4-Benzylpiperazino) dimaleate 1-Me-5-CICH2 hydrochloride 1-Me-5-Cl2CH l-Me-5-(Et,NCH,CH,NH) dipicrate l-Me-5-(Et,N(CH2),NH) dipicrate I-Me-5-(4-EtOCO-Piperazino) l-Me-5-H2NNH I-Me-5-(4-HO(CH,),-Piperazino) dimaleate l-Me-5-(2-Indolyl) l-Me-5-(4-Me-Piperazino)dipicrate l-Me-5-(3-Me-Piperidino) picrate l-Me-5-(4-Me-Piperidino)picrate l-Me-5-[2-( l-Me-2,3-Dihydro-l H-1,4-benzodiazepin5-yl)hydrazino] 1-Me-5-MeS 1-Me-5-Morpholino 1-Me-5-Ph Picrate 1-Me-5-(2-C1C6H,) 1-Me-5-(4-C1C6H,) 1-Me-5-(2-FC6H,) 1-Me-5-(2-F3CC,H,) Hydrochloride I-Me-5-PhNHNH l-Me-5-(4-Ph-Piperazino) I-Me-5-Piperidino 1-Me-5-Pyrrolidino
149-150
PhH/C yclohexane
[14&150/0.5]
157 173-1 74 17G18Od 52-54 174 171 9697 148 166 158-1 60 238 131 197-198 221 66 88 111-1 13 [I50/0.5] [I571 97-99 151-153 114-1 17 83-85 25G252 147- 149 108-109 101 [12@122/0.2]
81 49 80 40
CHCIJPhMe MeOH i-PrOH/Me,CO Et,O/Hexane MeCN MeCN Heptane MeOH MeOH/Et 0 Et,O MeCN EtOH EtOH
46 78 83
Me,CO Petr ether Petr ether
69 85
,
Hexane MeOH Hexane MeOH EtOAc/Petr ether Hexane EtOH/Et,O EtOH EtOAc Petr ether
73 58 50 72 73
ir, pmr
ir, ms, pmr ir, pmr
35 35 55 55 45b 45b 55 55 55 76 55 128b 55 55 55 76 55 55 8, 46 46 99c 109
39
104
70 45 56 70
ir, pmr
109 86, 109 76 55 55 55
TABLE VI-1. 3contd.)
Substituent 1-Me-5-Trichloroethylene Hydrochloride 1-Ph-5-Me l-F9CCH,-5-(2-FC,HJ
mP (“C); [bp (‘C/torr)]
Solvent of Crystallization
Yield (YO)
Spectra
Refs. 45b 45b 128b 106
57-59 185-19Od 91-92 91-93
Hexane i-PrOH/Et,O Hexane Et ,O/Hexane
227-230
MeOH/Et,O
78
Oil Oil 147-150 109-1 10 249-252 148-1 5 1
MeOH/Et,O Et,O/Petr ether MeOH/Et ,O PhH
49 14C 14C 25 99c 99a, b
144-145
Cyclohexane
66
I ,7-Disubstituted 1-Me-7-C1 hydrochloride 23-Disubstituted
%
2-HZNCHz-5-Ph 2-H,NCH,-5-(2-FC,HJ Dimaleate hemihydrate 2-Me-5-Ph Hydrochloride 4-Oxide
85-90
3,3-Disubstituted
3-Me0-3-Ph
99c
33-Disubstituted
3-Me-5-Ph
165-167
10-15
25
3,7-Disubstituted
3-Et0-7-Br 3-(2-Propynyloxy)-7-Br
138-140 120-122d
Et,O CH,Cl,/Petr ether
225-228 243-245
CHCl,/Hexane CHCI,/CH,CI,
99c 99c
S,7-Disubstituted
5-(3-Indolyl)-7-Br 5-( 3-Indolyl)-7-C1
128b 128b
5-(3-1ndolyl)-7-F3C 5-(5-Isothiazolyl)-7-NO, 5-( l-Me-2-Irnidazolyl)-7-NO, 5 4 l-Me-5-Pyrazolyl)-7-N0, 5-Ph-7-H2N dihydrochloride 5-Ph-7-Br 5-Ph-7-HOOC hydrochloride Hydrate 5-Ph-7-Cl Hydrochloride 4-Oxide Ethiodide hydrate 5-Ph-7-MeO dihydrochloride.MeOH 5-Ph-7-MeOOC Hydrochloride 5-Ph-7-Me 5-Ph-7-NOz 5-Ph-7-F3C Hydrochloride 5-(2-H,N-5-CIC,H,)-7-H,NSO, 5-(2-CIC,H4)-7-C1 4-Oxide 5-(2-ClC6H4)-7-N0, 5-(2,6-F,C6H3)-7-C1 5-(2-FC,H4)-7-C1 Ethiodide 5-(2-FC6H4)-7-I 5-(2-FC,H4)-7-NO, 5-(2-Pyridyl)-7-H2N 5-(2-Pyridyl)-7-Br Hydrochloride 5-(2-Pyridyl)-7-C1
231-233 198-200 278-28Od 199-201 > 250 173-175 315-316d 174176 245-247 247-248 240-243 2m204 188d 191-193 251-252d 13CL-132 21CL211 116118 283-285 225-226 175-177 215-217 18CL183 180-186 163-164.5 244-247 157-159 220 148-150 197-198 147-150 187-188
EtOH/H,O CH,CI,/MeOH/Hexane MeOH CH,CI,/EtOAc
H,O CH,Cl,/Petr ether MeOH/Et,O EtOH MeOH MeOH/H,O MeOH/Et,O CH,CI,/Petr ether MeOH/Et ,O EtOH/H,O CHCIJMeOH Hexane MeOH/Et,O EtOH/H,O PhH/Petr ether EtOH CH,CI,/Hexane CH,CI,/Hexane CH,Cl,/i-PrOH/Et,O CHClJHexane Me,CO/Et,O CH,CI,/Hexane CH,CI,/Hexane MeOH/Et,O EtOH
128b 7 7 7 2 38 62 50, 71, 89
87
75-85 61
45
79 70
64
uv
2 15, 37, 57 15 57 83, 84 14c 89 2 2 3b 1 2 2 13 38, 59 61 89 14C 38,59 14c 103 89 3a 3a, 25, 31 3a 37,25
TABLE VI-1. 4 c o n t d . )
Substituent 5-(2-Pyridyl)-7-N02 Hydrochloride 5-(2-Pyridy1)-7-F3C 5-(3-Pyridyl)-7-N02 5-(4-Pyridyl)-7-NO2 5-(2-Pyrimidyl)-7-N02 5-(2-Thiazolyl)-7-N02 5-(2-Thienyl)-7-NO2
mp ( T I ; [bp (‘C/torr)] 261 209-21 1 >310 183-1 84 212-215 281-283 222-224 229-23Od 148-149
Solvent
of Crystallization
Yield
EtOH Me,CO MeOH/Et,O PhH/Hexane Me,CO EtOH EtOH/CH,Cl,/Hexane THF/Et,O EtOH
73 19 17 65 56 43
(YO)
Spectra
ir
Refs. 3, 4 31 3a 3a, 25 3a 3a 5, 6 7 45a
Trisubstituted
1,ZJ- Trisubstituted 1-Me-2-H2NCH,-5-Ph dihydrochloride 1-Me-2-N3CH,-5-Ph hydrochloride 1-Me-2-ClCH2-5-Phhydrochloride hemihydrate 1-Me-2-ClCH,-5-(2-C1C6H4)hydrochloride 1-Me-2-ClCH,-5-(2-FC,H4) 1-Me-2-HOCH,-5-(2-C1C6H4)
1-Me-2-MeOCH,-5-(2-ClC6H4) 1-Me-2-(4-Me-Piperazino)CH2-5-Ph 1-Me-2-PrNHCH2-5-Ph
l-Me-2-(2-Propynyl)NHCH2-5-Ph l-Me-2-(2-Thienoyl)NHCH2-5-Ph, dl-tartrate.0.4EtOH 1-Me-2-(2-Thienoyl)NHCH,-5-(2-FC6H4) hydrochloride l-Me-2-(2-Thienoyl)N(Me)CH,-5-Ph, dl-tartrate l-Me-2-(3-Thienoyl)NHCH2-5-Ph hydrochloride
209-2 13 181-183 195-198 198-200 Oil 133-134 Oil Oil Oil Oil 11C125
i-PrOH/Me,CO/Et ,O Me,CO/i-PrOH i-PrOH ir
EtOH/Et,O
104115d 234237.5
EtOAc/Me,CO/Et,O
176.5-177.5
CHCI,/Et,O
50 50 48a 48a 53 48a 102 48a 50 50 50 51a, b 50 50
1,S,bTrisubstituted
l-Me-5-Ph-6-MeO
14c
1,5,7- Trisubstituted
l-Ac-5-Ph-7-Cl 4-Oxide l-Ac-S-Ph-7-NOz l-Ac-5-(2-Pyridyl)-7-H,N l-Ac-5-(2-Pyridyl)-7-Br l-AcNH-5-Ph-7-CI l-H2N-5-Ph-7-CI hydrochloride l-BuNHCO-S-Ph-7-CI
1-CICH~CONHCO-5-(2-C1C~H4)-7-C1 l-CI(CH,),NHC0-5-Ph-7-CI 1-C1(CH,),NHCO-5-(2-CIC6H.J-7-CI l-CI(CH,),NHCO-5-(2-FC,H,)-7-CI
l-CI(CH,),NHCO-5-(2-FC6H,)-7-F
165- 166 222-224 160-160.5 166168 127-1 29 204-207 154156 152-156 16&161 15C153 138-140 160-162
l-CI(CH,),-5-Ph-7-NO, hydrochloride
l-(Cyclopropyl)CH,-5-Ph-7-C1 Hydrochloride
1-(Cyclopropyl)CH,-5-Ph-7-F3C hydrochloride l-(Cyclopropyl)CH,-5-(2-CIC6H4)-7-C1 1-EtZNCH,CO-5-Ph-7-CI 1-Et,NCH,CO-5-(2-FC6H,)-7-C1 dihydrochloride l-Et,N(CH,),-5-Ph-7-C1 dihydrochloride l-Et,N(CH,),-5-Ph-7-N0, dihydrochloride l-EtzNCOCO-5-Ph-7-Cl
1-(4,5-DihydrooxazoI-2-yl)-5-Ph-7-C1 1-(4,5-Dihydrooxazol-2-yl)-5-(2-CIC6H4)-7-Cl 1-(4,5-Dihydrooxazol-2-yl)-5-(2-FC6H4)-7-Cl 1-(4,5-Dihydro-4-oxooxazol-2-yl) 5-(2-C1C6H,)-7-C1 1-(4,5-Dihydrothiazol-2-yl)-5-(2-C1C6H,)-7-C1 l-(4,5-Dihydro 4-oxothiazol-2-yl)-5-(2-ClC6H,)-7-C1 l-(5,6-Dihydro-4-oxooxazin-2-yl)-5-(2-C1C6H4)-7-Cl l-Me,NCOCH,-5-Ph-7-H2N l-Me,NCOCH,-5-Ph-7-C1 hydrochloride
78-80 232-233d 244-246d 88-89 185-186 199-201d 234236 234236 171-173 125-126 11&111 18s-181 224228 123-124 217-218 124135 187-189 243-245
CH,Cl,/Et,O/Petr ether 92 EtOH 35, 76 i-PrOH 39 CH,CI,/Hexane CH,CI,/Hexane CH,CI,/Petr ether EtOH CH,CI,/Et,O Et,O CH,CI,/Hexane Et,O Et,O Et,O MeOH/Et,O i-Pr,O
i-PrOH i-PrOH/Et,O i-PrOH MeOH/Et,O PhH/Petr ether CH,CI,/Hexane Et,O/Hexane CH,CI,/Hexane Et,O CH,CI,/Hexane CH,CI,/Hexane Et,O/Hexane CH,CI,/Hexane MeOH/Et,O
uv
15, 83a 15, 83, 57 58
3b 3b 83c 83c 83c 115 115 115 115 115
3b 111 8, 86 59 59,111 36 36 112, 59, 111 111,112
36 115 115 115 115 115 115 115 3b 3b
TABLE VI-1. gcontd.)
Substituent 1-Me,NCOCH,-5-Ph-7-NOz hydrochloride 1-Me,N(CH2),-5-Ph-7-C1 dihydrochloride l-Me,N(CH,),-5-Ph-7-N0, dihydrochloride, hemihydrate 1-EtOCH2-5-Ph-7-C1citrate l-Et-5-Ph-7-CI l-HCO-5-Ph-7-Cl 4-Oxide I-MeOCHzCO-5-Ph-7-Cl 1-Me-5-(l-Adamantyl)-7-C1
l-Me-5-(2-Cl-Cyclohexen-1-yI)-7-C1 1-Me-5-(1-Cyclo hexen- 1-yl)-7-C1
l-Me-5-[Et,N(CH,),NH)]-7-C1 dihydrochloride l-Me-5-EtO-7-Cl Hydrochloride 1-Me-5-Et00CCH2ONH-7-C1 l-Me-5-EtS-7-CI l-Me-5-HONH-7-Cl I-Me-5-HO(CH,),NH-7-C1 1-Me-5-(Isothiazol-5-yl)-7-NOz l-Me-5-MeONH-7-CI 1-Me-5-(l-Me-Imidazol-2-yl)-7-H,N 1-Me-5-(l-Me-Imidazol-2-yl)-7-C1 1-Me-5-(l-Me-Imidazol-2-yl)-7-NO, 1-Me-5-(l-Me-Pyrazol-5-yl)-7-NO, 1-Me-5-Ph-7-Ac l-Me-5-Ph-7-AcNH 1-Me-5-Ph-7-H2N l-Me-5-Ph-7-N3
mp W); [bp (“C/torr)]
Solvent of Crystallization
242-245 255-257 26&262 136140 163-1 65 116119 15G153 140-141 74-77 8688 86 253-255 38.5-39 116.5 13G130.5 81-82 186.5-189 115-1 16.5 173-175 118-119 17G172 157-159 175-178 155-1 57 109-1 13 176177 158-1 59 8G82
MeOH/Et,O MeOH/Et,O MeOH/Et,O EtOH/Et,O CH,CI,/Petr ether CH,Cl,/Et,O Et,O/Hexane Petr ether Hexane Hexane MeOH/EtOAc Petr ether CH,CI,/EtOAc EtOAc/Hexane i-PrOH CH,Cl,/EtOAc EtOAc CHC1, / Hexane Hexane MeOH/Et,O EtOAc/Hexane MeOH/Et 0 EtOAc/Hexane CH,Cl,/Petr ether CH,CI,/Petr ether Et,O Petr ether
,
Yield
(YO)
Spectra
Refs. 3b
34 50
uv
71 62 28 15 77 60 22
ir, pmr
3b 3b 59 18, 31 83, 15 83, 84 34 117 34 34 74b, a 75, 74a, b 75 74b 55
74a, b 74b 7 74b 7 7 7 7 131, 132 2 2 lOlb
l-Me-5-Ph-7-Br Hydrochloride 1-Me-5-Ph-7-(2-HOOCC,H,CO) l-Me-5-Ph-7-CI Hydrochloride 4-Oxide I-Me-5-Ph-7-CN l-Me-5-Ph-7-Me2N Dih ydrochloride I-Me-5-Ph-7-1 l-Me-5-Ph-7-Me l-Me-5-Ph-7-NO2 1-Me-5-Ph-7-N,S03H 1-Me-5-Ph-7-F3C Hydrochloride
I-Me-5-(2-AcNHC,H4)-7-CI 1-Me-5-(2-H,NC,H41-Me-5-(2-C1C,H4)-7-CI lrMe-5-(2-C1C,H,)-7-I 1-Me-5-(4-C1C6H,)-7-C1 1-Me-5-(2,3-C1,C6H,)7-C1 1-Me-5-(2,6-C1,C6H,)-7-C1
1-Me-5-(2-FC6H,)-7-Ac 1-Me-5-(2-FC6H,)-7-H,N 1-Me-5-(2-FC6H,)-7-C1 Hydrochloride 1-Me-5-(2-FC6H,)-7-CN
1-Me-5-(2-FC6H4)-7-CH(OH)Me 1-Me-5-(2-FC6H,)-7-I
1-Me-5-(2-FC6H,)-7-MeNHCONH 1-Me-5-(2-MeSC,H4)-7-C1 l-Me-5-[2-MeS(O) C6H4]-7-Cl 1-Me-5-(2-NO,C6H,)-7-C1 hydrochloride
104-105 257-258d 27G290 102-103 248-250 165-167 139-142 149-150 115-1 17 252-254 153-155 138 186188 234-235d 150.5-152 261-262 200-201
Hexane MeOH/Et,O CH,CI,/MeOH Hexane MeOH/Et,O Et,O/Hexane CH,CI,/Petr ether Et,O EtOH/H,O EtOH/Et,O EtOH Hexane i-PrOH H,O PhH/Hexane MeOH/Et,O Me,CO/Petr ether
93-94.5 106109 106108 116117 143.5-144.5 112-1 14
Et,O/Petr ether Hexane CH,CI,/Et20 Petr ether Me,CO Et,O/Hexane Et,O EtOAc Me,CO/MeOH Et,O Et,O/Pentane Hexane CH,Cl,/Et,O
58, 75
uv
53 22
L
32 76 51
83
144
100-103 246247d 135-137 125-127 102-105 188 1w101 166167 197-208
Pmr
Et,O CH,CI,/Et,O Me,CO
37
2, 59 2 88 2, 37, 61a 21 21, 83b, 110 83a 109 109 103 46 2, 59, 109 132b 2, 59 2 45a 43 34 99c 126b 45a 45a 104 89 42 59 104 104 104 89 45a 45a 43
TABLE VI-I. gcontd.) ~~
Substituent
01
g
l-Me-5-(PhNH)-7-CI l-Me-5-(4-Ph-Piperazin0)-7-C1 l-Me-5-PhS-7-Cl l-Me-5-(2-Pyridyl)-7-H2N 1-Me-5-(2-Pyridyl)-7-C1 1-Me-5-(2-Pyridyl)-7-Me2N 1-Me-5-(2-Pyridyl)-7-NO2 Hydrochloride 1-Me-5-(2-Pyridy1)-7-F3C l-Me-5-(3-Pyridyl)-7-H2N l-Me-5-(3-Pyridyl)-7-C1 l-Me-5-(3-Pyridyl)-7-NO2 l-Me-5-(4-Pyridyl)-7-H2N l-Me-5-(4-Pyridyl)-7-CI dihydrochloride l-Me-5-(4-Pyridyl)-7-NO2 hydrochloride l-Me-5-(2-Pyrimidyl)-7-C1 l-Me-5-(2-Pyrimidyl)-7-NO2 l-Me-5-(2-Thiazolyl)-7-(1 -adamantoyl)NH
l-Me-5-(2-Thiazolyl)-7-H2N 1-Me-5-(2-Thiazolyl)-7-C1 l-Me-5-(2-Thiazolyl)-7-NO, l-Me-5-(2-Thienyl)-7-NO2 1-Me-5-(Trichloroethenyl)-7-C1 l-MeNHCO-5-Ph-7-Cl 1-MeNHCS-5-Ph-7-CI l-MeNHCOCH,-5-Ph-7-H2N l-MeNHCOCH2-5-Ph-7-CI Hydrochloride
mp W); [bp (“C/torr)]
Solvent of Crystallization
162-164 130-131 152-153 165-167 152-154 120.5-1 22 181-184 20&202d 127-129 170-173 88-90 266269d 174-176 223-225 25Ck251d 107-109 181-183d 262-263 164166 138-140 19Ck192 174-175 102-104 18Ck182 179-180 19Ck192 187-189 252-254
EtOH Et,O/Petr ether Hexane CH,CI,/Petr ether EtOH CH,CI,/Heptane PhH/EtOH MeOH/Et,O Hexane CH,CI,/Hexane MeOH EtOH MeOH/Et,O MeOH/Et,O CH,Cl,/Petr ether CH,CI,/Hexane EtOH PhH/Petr ether CHCI, / Hexane CHCl,/Petr ether Me,CO Et,O/Hexane CH,Cl,/Et,O CH,Cl,/Petr ether CH,Cl,/Hexane CH,Cl,/Hexane MeOH/Et,O
Yield (YO)
Spectra
Refs. 99c
23 7 64 31
ir, pmr
84 19 66 23 66 49 56 49 34 61
ir, ms
74b 55 3a, 4 3a, 4 lOlb 3a, 4 3a 3a, 4 3a 3a 3a 3a 3a 3a 6 6 7 7 7 7 45a 45b 83c 83c 113 113 113
I-MeNHCOCH,-5-Ph-7-NOz Hydrochloride
223-225 258-260 230-232 183-85 154156 158-159 170-173 119-121 175-176 170d
Me,CO Me,CO/MeOH Me,CO/Petr ether PhH/Hexane CHCI,/EtOH I-PrOH CHCI, / EtOH MeOH i-PrOH/Cyclohexane H,O
187-189.5 66-67.5 188-198 137-138 97-98 83-85 163-165 123-125
Et,O Petr ether EtOH/Et,O CH,CI,/Hexane Et,O/Hexane CH,CI,/Hexane CH,CI,/Hexane CH ,CI, /Hexane
40 42 66 82 75 83 14
l-Me-5-Ph-8-MeO
12G121
l-Ph-5-H2N-8-CI l-Ph-5-MeNH-g-CI
216-217 195-1 96
CH,CI,/Et,O/ Petr ether Et,O Et,O
53 52
235-243 138-143
MeOH/Et,O Et,O/Petr ether
169-1 71 210-213
i-PrOH/Et,O CH,C1, / Et ,O
1-MeNHCOCHz-5-(2-Pyridy1)-7-Br l-MeNHCOCH,-5-(2-Pyridyl)-7-N0, I-(4-MeC,H4)SO,-5-Ph-7-CI l-MeSCH2-5-Ph-7-CI maleate 1-MeSO2-5-Ph-7-CI l-NO-5-Ph-7-Cl
l-(Phthalimido)-(CH,),-5-Ph-7-C1 l-HSO3NHCO-5-Ph-7-CI 1-(4,5,6,7-Tetrahydro-4-oxo-1,3-oxazepin-2-yl)-5(2-C1C6H4)-7-C1 1-F3CCH2-5-Ph-7-C1 l-F3CCH2-5-(2-CIC,H,)-7-C1 4-Oxide
1-F,CCH,-5-(2-FC6H,)-7-Br m
8
1-F3CCH,-5-(2-FC6H4)-7-C1 4-Oxide 1-F3CCH,-5-(2-FC6H4)-7-N0,
113 113 113 113 125 59 125 83c, 73 111 124b
70 61 94
115 106 106 106 106 44b, 106 44b, 106 106
I>,& Trisubstituted
ir, pmr
14C 77 77
IJ,P Trisubstituted l-Me-5-Ph-9-Cl Hydrochloride 1-Me-5-(2-FC6H,)-9-CI
14c
14c
2,5,7- Trisubstituted
2-AcNHCH,-5-(2-FC6H,)-7-C1 maleate 2-HzNCO-5-Ph-7-Cl
60
ir, ms, pmr
63 68a, b
TABLE VI-I. +contd.)
Substituent
2-H2NCO-5-(2-FC6H4)-7-C1 2-H,NCOCH,-5-(2-FC,H,)-7-C1 2-H,N(HON)C-5-(2-FC6H4)-7-C1 2-H2NCH,-5-Ph-7-Cl, 4-Oxide 2-H,NCH,-5-(2-FC6H,)-7-C1 dimaleate
2-Aziridino(MeON)C-5-(2-FC6H4)-7-C1 2-t-BuOOC(H0N)C-5-(2-FC6H4)-7-C1
QI
2-HOOC-5-Ph-7-Cl hydrochloride 4-Oxide 2-HOOCCH2-5-(2-FC6H4)-7-C1 2-HOOCCH2S-5-Ph-7-C1 2-HOOCCH2NHC0-5-Ph-7-C1 2-C1CH,-5-Ph-7-N02 Hydrochloride
2-C1(Me00C)CH-5-(2-FC,H4)-7-CI 2-CN-5-Ph-7-Cl 2-CN-5-(2-FC6H4)-7-C1 2-CNCH2-5-(2-FC6H4)-7-C1
2-[(Cyclohexyl)NHCOCH,NHCO]-5-Ph-7-Cl 2-Et2N-5-Ph-7-C1,4-Oxide 2-Et2N(CH,),NHCO-5-Ph-7-C1 2-(4,5-Dihydroimidazol-l-yl)-5-Ph-7-C1, 4-oxide 2-Me2NCO-5-Ph-7-C1,hydrate 2-Me2NCO(HON)C-5-(2-FC,H,)-7-C1 2-Me,N(HON)C-5-(2-FC6H,)-7-CI 4-0xide.0.166Et20
2-Me,NSO,(HON)C-5-(2-FC6H4)-7-C1
mp ("C); [bp (Tjtorr)]
Solvent of Crystallization
192-193 228-230 216-218 165-167 196-198 161-164 203-204d 2 18-22 1 205-208d 126130 161-165 268-270 148-149 2 13-21 4 126127 181-183d 163-164 199-201 238 142-144d 157-158
CH,Cl,/Petr ether THF/EtOAc EtOAc/Hexane EtOAc/Hexane MeOH/i-PrOH/H,O EtOAc/Hexane EtOAc H,O/HCl MeOH MeOH/H,O CH,Cl,/MeOH DMF/Et,O
187-1 88 173-176 143-145 214-215 178-180 145-15Od 242-244
i-PrOH/Et,O Et,O/Hexane CH,Cl,/Hexane CH,Cl,/Cyclohexane EtOAc/Hexane CH,CI,/Et,O/EtOH EtOAc CH,Cl,/Et,O/ Petr ether MeOH CH,Cl,/Hexane Et,O CH,Cl,/EtOH MeOH/EtOAc EtOAc/Et ,O THF/EtOH
Yield
(YO)
Spectra
83
60
50
50
66
ir, ms, pmr
Refs. 68b 63 66b 99c 65 66b 95 68d 67 63 68d 68d 48a 48a 45b 68a, b 68b 45b 68d 67 68d 67 68d 95 66b 66b 95
2-Me,NSO,CH,-5-(2-FC6H4)-7-C1 2-Et0-5-Ph-7-C1, 4-Oxide 2-EtOOCCHzNHCO-5-Ph-7-CI 2-Et-SPh-7-NOZ 2-S Configuration 2-HO-5-Ph-7-CI hydrochloride Hydrate 2-HO-5-Ph-7-NO2 hydrochloride. 0.5Hz0
2-HOCH,CH,-5-(2-FC6H4)-7-C1
o\
5
2-HO(CH,),S-5-Ph-7-C1 2-(HON)CH-5-Ph-7-C1,4-Oxide 2-(HON)CH-5-(2-FC6H4)-7-C1 4-Oxide 2-HOCH(Ph)-5-Ph-7-CI 2-MeO-5-Ph-7-Cl Hydrochloride 4-Oxide 2-Me0-5-Ph-7-F3C, 4-Oxide 2-MeOOC-5-Ph-7-C1, 4-Oxide
2-MeOOCCH,-5-(2-FC6H4)-7-C1 2-MeO(HN)C-5-Ph-7-C1, 4-Oxide 2-Me-5-Ph-7-H2N 2-Me-S-Ph-7-Cl Hydrochloride 4-Oxide Hydrochloride 2-Me-5-Ph-7-NO2 Hydrochloride
2-MeNHCOCH,-5-(2-FC6H,)-7-C1 2-MeNHCOCH,-5-(5-Br-2-FC6H3)-7-C1 2-MeNH(HON)C-5(2-FC6H4)-7-C1 2-(4-MeC,H4)SOzNHCH,-5-(2-FC,H,)-7-C1 2-MeS02CH,-5-(2-F,H,)-7-C1 4-Oxide
181-183 132-133 142-144 146-148
EtOH EtOH CH,Cl,/Petr ether CCI,/Hexane
125d 125d 178d 139-141 135-14Od 195-198d 195-197 184-186 196-197 179-181d 185-193d 127-131 179-18 Id 154-156 122-124 168-1 7Id 190-194 146-147.5 260-265d 2W202.5 185-193d 152-153 276277 167-170 144-147 215-21 7d 145-147 143-145 186-188
Me,CO/H,O EtOH/H,O/HCI EtOH/H,O/HCI CH,CI,/Et,O Et,O EtOH CH,Cl,/EtOAc MeOH/E t 0Ac Et 0Ac/Hexane MeOH/Et,O MeOH/Et,O MeOH MeOH/Et,O i-PrOH/H,O CH,Cl,/Petr ether EtOAc EtOAc/Hexane EtOAc MeOH EtOH EtOH/Et,O EtzO MeOH CH,CI,/Hexane EtOAc/Hexane MeOH/EtOAc EtzO EtOAc/Hexane MeOH
65
79.5 80 78
ir
58
uv, pmr
93 85
92 50
uv
75
pmr, uv
68a, 67 67 67 67 14c 67 64 99a, b, 25 99a, b 99a, b 99a, b
64 64
2
61
45b 67 68d 25 24, 25 69b 69a 69a, b 63 68a 99c 65 66c 73
ir, ms, pmr
63 45b 66 126 45b 45b
TABLE VI-1. 4contd.)
Substituent 2-MeS(HON)C-5-(2-FC6H,)-7-CI,4-Oxide 2-[Morpholino(HON)C]-5-(2-FC6H4)-7-C1 4-Oxide
2-[Morpholino(HN)C]-5-(2-FC6H4)-7-C1 2-OzNCHz-5-(2-FC6H4)-7-C1 4-Oxide 2-PhNH-5-Ph-7-CI, 4-Oxide 2-PhCH2S-5-Ph-7-CI,4-Oxide 2-(Phthalimido)CH2-5-Ph-7-CI,4-Oxide 2-Piperidino-5-Ph-7-CI 4-Oxide 2-i-PrNH-5-Ph-7-C1, 4-Oxide 2-i-PrOCH,-5-Ph-7-NO2, hydrochloride
2-(2-Pyridyl)(HON)C-5-(2-FC6H,)-7-C1 2-Pyrrolidino(HON)C-5-(2-FC6H,)-7-C1 4-Oxide
2-F3CCONHCHz-5-(2-FC6H4)-7-C1
mp ("C); [bp (Tjtorr)]
Solvent of Crystallization
215-217d 133-137 192-193d 175-178
MeOH/EtOAc MeOH/EtOAc/Hexane MeOH/EtOAc THF/Hexane
66a 66 66 66a
142-143d 157-1 59 116123d 226-228 13&135d 177-181d 142-145d 233-235 211-213 2W202d 182-1 83d 11c112 14&143
EtOAc/Hexane EtOAc EtOAc EtOH EtOAc CH,CI,/Hexane EtOAc
99c 67 67 99c 67
Yield (YO)
94
Spectra
ir
Refs.
MeOH THF/EtOH EtOAc/MeOH
67 52 95 66 66
CH,Cl,/Hexane
14c
2,5,9- Trisubstituted
2-C1CH,-5-Ph-9-NO2
123-125
48a
3,3,7- Trisubstituted
3-CN-3-Me-7-Br 3-Me0-3-Me-7-Br
143-145 162-1 63
CH,Cl,/Hexane i-PrOH/THF/Petr ether
99c 99c
159-160 144-146
HZO CHCI,/Hexane
99c 99c
3,5,7- Trisubstituted
3-HOOC-5-Ph-7-CI 3-CN-5-Ph-7-Cl
3-Et0-5-Ph-7-CI 4-Oxide 3-EtOOC-5-Ph-7-CI hydrochloride 3-Et-5-Ph-7-NO2, 3s 3-Et-5-Ph-7-NOz, 3R 3-Et-5-Ph-7-NO2 3-Me-5-Ph-7-H2N dihydrochloride 3-Me-5-Ph-7-Cl 4-Oxide
144-148 196-199d 21C218d
EtOH/H,O EtOH EtOH/Et,O Calo
233-235 277-28Od 127-128 190-195d 2W203
[.lo EtOAc/Petr ether EtOHiEt,O Et,O/Petr ether EtOAc EtOAc
3-Me-5-Ph-7-N02
ir, pmr
8 70 10
uv, pmr
80
99c 99c 99c 24, 25 25 25 2 2, 99a, b, 59 99a, b, 2
5,7,8- Trisubstituted
5-Ph-7-HZNSO2-8-Cl
255-256
MeOH/H,O
117
5,7,PTrisubstitutcd
2
5-Ph-7-CI-9-Br hydrochloride
247-249d
MeOH/Et,O
83c
Tetrasubstituled
If J , 7 - Tetrasubstituted 1-Ac-2-AcNHCH2-5-(2-FC6H4)-7-CI l-Ac-2-CN-5-Ph-7-CI 1-Ac-2- MeO-5- Ph- 7-C1 l-ClCH,CH2-2-C1CH,-5-Ph-7-CI
213-215 208-210 195-1 97 114-1 16 1-EtOOCCHzCO-2-MeOOCCH,-5-(2-FC6H,)-7-CI 97-99
CH,CI,/Et,O EtOAc/Et,O MeOH
43 45
ir, pmr, uv ir, ms, pmr
Et,O/Hexane
65 68a 34 48a 63
1-Et00CCH,CO-2-Me00CCHC1-5-(2-CIC6H4)-7-Cl Isomer A Isomer B 1-Et-2-HOCH2-5-Ph-7-C1hydrochloride l-Et-2-Me-5-Ph-7-CI l-CHO-2-CICH2-5-Ph-7-Cl
141-143 143-145 196-202 205-210 151-152
CH,CI,/Hexane CH,Cl,/Et,O
i-PrOH
46 13
ir, ms, pmr,
45b 45b 48a 31 107
uv
1-Me00CCHzCO-2-(2-HO-1-Propyl)-5-(2-C1C,H4)7-Cl
158-160
CH,CI,/Hexane
45b
TABLE VI-1. +contd.)
Substituent
l-Me-2-AcNHCHZ-5-Ph-7-C1 hydrochloride 1-Me-2-AcNHCH,-5-(2-ClC6H4)-7-Cl l-Me-2-H2NCO-5-Ph-7-C1
1-Me-2-H,NCONHCH2-5-Ph-7-C1 hydrochloride 1-Me-2-H,NCONHCH,-5-(2-C1C6H4)-7-C1 hydrochloride
l-Me-2-H2NCOCH,-5-Ph-7-C1 hydrochloride 1-Me-2-H,NCH2-5-Ph-7-C1 dihydrochloride.0.5 i-PrOH 1-Me-2-PhCOOCH2-5-Ph-7-C1 hydrochloride 1-Me-2-BrCH,-5-(2-CIC6H4)-7-Cl hydrochloride l-Me-2-HOOC-5-Ph-7-Cl hydrochloride 1-Me-2-HOOCCH2-5-Ph-C1 hydrochloride 1-Me-2-HOOCCH,-5-(2-(CIC6H4)-7-CI hydrochloride 1-Me-2-C1CH2-5-(2-Furyl)-7-C1hydrochloride 1-Me-2-CICH2-5-Ph-7-Brhydrochloride 1-Me-2-CICHZ-5-Ph-7-Clhydroch1oride.i-PrOH 1-Me-2-CICH2-5-Ph-7-F hydrochloride 1-Me-2-ClCH2-5-Ph-7-MeO hydrochloride l-Me-2-ClCH2-5-Ph-7-Me hydroch1oride.i-PrOH l-Me-2-ClCH,-5-Ph-7-N0, hydrochloride
1-Me-2-C1CH,-5-(2-C1C6H4)-7-CI Hydrochloride
1-Me-2-C1CH,-5-(3,4-Cl,C6H3)-7-C1 hydrochloride 1-Me-2-CICH,-5-(2-FC6H4)-7-CI hydrochloride 1-Me-2-CICH,-5-(2-F,CC6H4)-7-CI 1-Me-2-CICH2-5-(2-Thienyl)-7-C1 hydrochloride
mp W ) ; [bp (T/torr)]
Solvent of Crystallization
184-186 113-121 204-206 231-232
i-PrOH/Et,O
Yield (YO)
Spectra
48a, 118 118 70, 71 48a, 118
MeOH i-PrOH/Et,O
2W205 224-226 206209 175 186-188 247-249 229d 221-222 198-199 95-98 110-112 178-180 180-184 191-193 130-133 2 13-214 116119 181-183 139-141 227-229 Oil 184-186
Refs.
118 48a. 118 48a 48a 53 71a 48a, 118 48a 54 48a 48a 50 48a, 53 48a 48a
i-PrOH/Et ,O H,O/HCI MeOH/Et,O Me,CO/EtOH i-PrOH
75
Et,O EtOH/Me,CO
7.5
ir, pmr, uv ir, uv
EtOAc/Me,CO
43
ir, pmr, uv ir
50
47 47,48a, 53 48a 47,48a, 53 53 54
l-Me-2-(7-Cl-l-Me-5-Ph-2,3,4,5-Tetrahydro-lH-1,4benzodiazepin-4-yl)-5-Ph-7-C1 281-285d 1-Me-2-(3-C1-2-MeC6H,)NHCOCH,-5-Ph-7-C1 hydrochloride 219-222 1-Me-2-(4-CIC6H,)OCH,-5-Ph-7-C1 hydrochloride 192-200 1- M ~ - ~ - ( C ~ ~ ~ ~ ~ O ~ I ) N H C H , - ~ - ( ~ - C ~ C , H , ) - ~ - C I hydrochloride 22e223 I-Me-2-CN-5-Ph-7-Cl 120-122 1-Me-2-CN-5-(2-FC,H4)-7-CI 124125 1-Me-2-(Cyclohexyl)NHCOCH,-S-(2-ClC6H4)-7-Cl hydrochloride 238-240 I-Me-2-CNCH2-5-Ph-7-C1 hydrochloride 213-215 1-Me-2-CNCH,-5-(2-CIC,H,)-7-CI 105-107 Hydrochloride 198-202 171-1 74 1-Me-2-Me2NCOCH,-5-Ph-7-CI hydrochloride 102- 105
THF
23
58 118 48a, 52
i-PrOH/Et,O
118
MeOH MeOH
i-PrOH/Et ,O Et,O Me,CO
70, 71 70, 71
87.5
ir, pmr, uv
118 48a, 118 47 47 48a 118
1-Me-2-Me,NCOCH,-5-(2-CIC6H4)-7-C1 F
hydrochloride hydrochloride 1-Me-2-Et00CNHCHZ-5-Ph-7-Cl 1-Me-2-Et00CNHCH,-5-(2-C1C,H4)-7-CI hydrochloride
1-Me-2-Et00CCH2-5-Ph-7-C1 hydrochloride 1-Me-2-EtOCH,-5-(2-BrC,H,)-7-Br hydrochloride
l-Me-2-EtOCH,-5-(2-ClC,H4)-7-Br hydrochloride 1-Me-2-EtOCH,-5-(2-ClC,H4)-7-CI hydrochloride 1-Me-2-EtOCH,-5-(2,6-C1,C6H,)-7-C1 hydrochloride I-Me-2-EtOCH,-5-(2-IC,H,)-7-Br hydrochloride 1-Me-2-EtOCH2-5-(2-F,CC,H,)-7-Br I-Me-2-EtNHCOOCH,-5-Ph-7-C1 I-Me-2-H2NNHCOCH,-5-Ph-7-CI hydrochloride l-Me-2-HO-5-Ph-7-Cl Hydrochloride.0.66H,O 1-Me-2-HO-5-(2-FC6H,)-7-C1
172-177 196197 205 2&208 154156 191-1 94 158-161 211-212 204-207 102-104 175-177 200 148-15 Id 108-1 1od 143-146
118 118
i-PrOH/Et,O i-PrOH/Et,O EtOH/Et,O EtOH EtOH i-PrOH/Et ,O
118 48a, 118 49 49 48a, 52 52 49 49 48a, 52 118
EtOH EtOH Me,CO Et,O EtOH/H,O/HCI THF/Et,O
97
58
90
69a, b 60
37
TABLE VI-1. d c o n t d . ) ~
Substituent
mP ("C); [bp ("C/torr)]
Solvent of Crystallization
Yield (%)
Spectra
Refs.
l-Me-2-HO(CH,),NHCOCH,-5-Ph-7-C1 hydrochloride l-Me-2-HOCH,-5-(2-Furyl)-7-C1hydrochloride 1-Me-2-HOCH2-5-Ph-7-Brhydrochloride 1-Me-2-HOCHz-5-Ph-7-CI hydrochloride l-Me-2-HOCH2-5-Ph-7-F hydrochloride. i-PrOH 1-Me-2-HOCH2-5-Ph-7-Me0 hydrochloride l-Me-2-HOCH2-5-Ph-7-Me hydrochloride 1-Me-2-HOCH2-5-Ph-7-MeS hydrochloride 1-Me-2-HOCH,-5-(2-BrC6H,)-7-C1 hydrochloride
h,
1-Me-2-HOCH,-5-(2-C1C6H,)-7-CI Hydrochloride Maleate
1-Me-2-HOCH,-5-(2,3-CI,C6H3)-7-CI hydrochloride 1-Me-2-HOCH,-5-(2,4-Cl,C6H3)-7-C1 hydrochloride 1-Me-2-HOCH,-5-(2,6-C1,C6H3)-7-C1 hydrochloride 1-Me-2-HOCH,-5-(3,4-ClzC6H3)-7-CI hydrochloride 1-Me-2-HOCH,-5-(2-FC6H4)-7-C1 Hydrochloride
208-2 10 22&227 241-242 227-235 99-101 18&189 192-195 196201 205-206 173-175 2 18-220 115-119 226-229 225 2 16-220 242-245 173-1 75 224227 1 8 6 189 196201 226228 214-218
1-Me-2-HOCH,-5-(2-MeC6H,)-7-C1 hydrochloride 1-Me-2-HOCH,-5-(2-F,CC6H4)-7-CI hydrochloride 1-Me-2-HOCH,-5-(3-F3CC6H4)-7-CI hydrochloride l-Me-2-HOCH,-5-(2-Thienyl)-7-C1 hydrochloride 1-Me-2-(l-HO-2-propyl)NHC0CH,-5-(2-ClC6H4)-7-C1 hydrochloride l-Me-2-MeOOC-5-Ph-7-Cl hydrochloride
208-210 212-214
Me,CO/EtOH i-PrOH/Et,O i-PrOH/Et,O i-PrOH/Et ,O i-PrOH/Et,O i-PrOH/Et,O i-PrOH/Et,O i-PrOH/Et,O i-PrOH EtOH EtOH i-PrOH/Et ,O i-PrOH/Et,O i-PrOH/Et,O Et,O EtOH/Me,CO i-PrOH/Et,O i-PrOH/Et,O i-PrOH/Et ,O
MeOH/Et,O
25
ir, pmr, uv
33
ir, pmr, uv
118 54 48a 48a 48a 48a 48a 48a 48a 47,48a 47 47 48a 48a 48a 48a 47,48a 48a 48a 48a 54 118 71a
1-Me-2-MeO(CH,),OCH,-5-(2-C1C6H,)-7-C1 hydrochloride
167-172
52
I-Me-2-MeO(HN)C-5-Ph-7-C1
142-144
Et,O
70, 71b
219-221
i-PrOH
54
198-2 10
i-PrOH/Et,O
48a, 52
185-187
EtOH
49
1 -Me-2-MeOCH2-5-(2-Furyl)-7-C1
hydrochloride l-Me-2-MeOCH2-5-Ph-7-C1 hydrochloride 1-Me-2-MeOCH,-5-(2-BrC6 H4)-7-Br hydrochloride I-Me-2-MeOCH,-5-(2-BrC6 H4)-7-C1 hydrochloride 1-Me-2-MeOCH,-5-(2-C1C6H4)-7Br hydrochloride 1-Me-2-MeOCH,-5-(2-C1C6H4)-7-C1 hydrochloride 1-Me-2-MeOCH,-5-(2,6-Cl, C,H3)-7-C1 hydrochloride 1-Me-2-MeOCH2-5-(2-FC, H4)-7-Br hydrochloride W
181-182
52
193-196
EtOH
192-195
i-PrOH/Me, CO
49 73
199-200 183-185
47, 52 52
EtOH
1-Me-2-Me0CH,-5-(2-FC6H,)-7-C1 hydrochloride 1-Me-2-MeOCH2-5-(2-IC6H4)-7-Br hydrochloride 1-Me-2-MeOCH,-5-(2-F3 CC, H4)-7-Br hydrochloride~0.5H2 0 1-Me-2-MeOCHz-5-(2-F,CC,H4)-7-C1
ir, pmr
Pmr ir, uv
49 47 47, 52
179-1 8 1
EtOH/Me,CO
223-225
EtOH
49
128-130 95-97
EtOH
49 52
226-229 9495.5
Me,CO/Et, 0
l-Me-2-MeOCH,-5-(2-Thienyl)-7-CI hydrochloride I-Me-2-Me-5-Ph-7-Cl
13.5
54 31, 24
I-Me-2-MeNHCOCH2-5-Ph-7-C1 hydrochloride
183-186
118
222-226
118
1-Me-2-MeNHCOCH,-5-(2-C1C6 H4)-7-C1 hydrochloride
1-Me-2-MeNHCONHCHZ-5-Pii-7-C1 dihydrochloride
1W150
i-PrOH/Et,O
48a
TABLE VI-I. dc ont d . )
Substituent
mp ("C); [bp ("C/torr)]
Solvent of Crystallization
Yield (YO)
Spectra
Refs.
1-Me-2-MeNHCONHCH,-5-(2-ClC6 H4)-7-C1 l-Me-2-MeNHCH2CONHCH,-5-Ph-7-CI 1-Me-2-MeNHCOOCHZ-5-Ph-7-CI
195 132-133 157-158
118 118 48a
l-Me-2-(3-Me-butanoyl)NHCH,-5-(2-C1C6H4)-7-C1 hydrochloride
23G23 1
118
hydrochloride
l-Me-2-(4-Me-Piperazino)-S-Ph-7-C1 trihydrochloride. EtOH
214216
EtOH
48a
185-187
i-PrOH/Et,O
48a
1-Me-2-(Morpholino)CH,-5-(2-ClC, H4)-7C1
237-245 136138
i-PrOH/Et, 0 EtOH
l-Me-2-PhOCH2-5-Ph-7-C1 hydrochloride
180
i-PrOH
48a, 52
198-207 14&145
i-PrOHIEt, 0
48a, 118 48a, 52
165-168 151-152 167-167.5 143-145 184185
i-PrOH/Et,O MeOH MeOH/Me,CO Et,O i-PrOH/Et,O
48a 48a, 118 47 48a 52
22G223
i-PrOH/Et,O
1-Me-2-(4-MeC,H,)SCH2-5-Ph-7-C1 hydrochloride
l-Me-2-(Morpholino)CH,-5-Ph-7-CI dihydrochloride
72
ir, pmr, uv
48a 47
l-Me-2-PhNHCONHCH2-5-Ph-7-C1 hydrochloride
1-Me-2-PhNHCOOCH2-5-Ph-7-C1 1-Me-2-PhCH2NHCH2-5-Ph-7-CI dihydrochloride
l-Me-2-(Phthalimido)CH2-5-Ph-7-CI 1-Me-2-(Phthalimido)CH,-5-(2-ClC, H4)-7-C1 l-Me-2-(Piperidino)CHZ-5-Ph-7-CI 1-Me-2-(2-Propenyloxy)CH,-5-(2-ClC, H4)-7-C1
60 65
ir, pmr, uv
1-Me-2-(i-PrNHCOCH, )-5-Ph-7-CI
hydrochloride
48a, 118
l-Me-2-(i-PrNHCOCHZ)-5-(2-C1C, H4)-7-C1 hydrochloride
24&24 1
48a
l-Me-2-(i-PrNHCONHCH2)-5-Ph-7-C1 dihydrochloride 1-Me-2-PrOCH,-5-(2-BrC6H4)-7-Br hydrochloride l-Me-2-(i-PrOCH,)-5-(2-C1C6 H4)-7-Br hydrochloride l-Me-2-PrOCH2-5-(2-C1C6H4)-7-Br hydrochloride
180-182
i-PrOH/Et,O
48a
143-146
EtOH
49
189-19 1.5
EtOH
49
152-154
EtOH
49
1-Me-2-PrOCH,-5-(2-CIC6H4)-7-Cl hydrochloride
52
144146
1-Me-2-(i-PrOCH2)-5-(2-C1C6 H4)-7-C1 193-196
i-PrOH/Et, 0
1-NO-2-Me00CCH,-5-(2-FC6H,)-7-C1
180 229-230 16149 8690
i-PrOH/Et, 0 CH,CI2/Et,O CH, CI,/Hexane Et,O/Petr ether
l-N0-2-Ph(OH)CH-5-Ph-7-C1 Isomer A Isomer B
17&172d 18&183d
CH,CI,/Et,O/Hexane EtOAc/Hexane
196202 11&111
EtOH/H,O
hydrochloride 1-Me-2-[3,4,5-(MeO),C6H2]CONHCH,-5-Ph-7-CI hydrochloride l-MeNHCO-2-CN-5-Ph-7-CI 1-NO-2-CN-5-Ph-7-C1 v,
48a, 52
71
ir, ms, pmr
30.5
ir, pmr, uv pmr, uv
48a 68a 68d 62b 73 73
l-PhCH,-2-HOCH,-5-Ph-7-C1 hydrochloride l-F,CCH,-2-EtS-5-Ph-7-C1
48a 72
1J3J.7-Tetrasubstituted l-Ac-3-AcO-5-Ph-7-Cl l-Ac-3-HO-5-Ph-7-CI l-HCO-3-AcO-5-Ph-7-CI l-Me-3-EtO-5-Ph-7-C1, 4-Oxide l-Me-3-Et-5-Ph-7-CI 1-Me-3-Et-5-(2-(FC6H4)-7-C1 l-Me-3-HO-5-Ph-7-CI l-Me-3-Me-5-Ph-7-CI
177-179 165-167d 165-167 106-109 114-115 120-121 155-156d 102-104 I-F~CCH~-~-ACO-~-(~-C~C~H,)-~-C~ 127-131
CH, ClJHexane CH,CI,/Et,O CH,Cl,/Et,O Et,O/Petr ether
59
uv
55 CH, CI, / Petr ether CH,CI,/Petr ether Et 0/ Hexane
,
24.5 34 63
uv
83, 110 83a 83 99c 31 31 83, 110 24,45b 106
TABLE VI-I. gc ont d . )
Substituent
mp K); [bp (“C/torr)]
Solvent of Crystallization
138-139 188-190
PhH/Hexane CH, CI,/Hexane
Yield (%)
Spectra
Refs.
Other Tetrasubstituted
% QI
1-F, CCH,-5-(2-FC6H4)-7-CI-9-N0, l-F,CCH,-5-(2-FC, H4)-7,9-(N02), 2-CICH,-5-Ph-7-C1-9-N0, hydrochloride 2-CICH2-5-Ph-7,9-(NO2), 2,2-Me2-5-Ph-7-CI 2-Me-3-Me0-5-Ph-7-CI 2-H, NCH,-3-Me-5-(2-FC6 H4)-7-C1 dimaleate 5-Ph-6,7,8-(MeO), hydrochloride 5-Ph-7,8,9-(MeO), hydrochloride
41
106
11
106
232-235 17@174 131-1 33 174-176
Hexane MeOH
48a 48a 99c 99a, b
188-189
i-PrOH
45b
22C227
EtOH/Et,O
28c
169d
EtOH/Et,O
28c
EtOH/Et,O EtOH
48a 28c 28,
Pentasubstituted
1-Me-2-CH,OH-5-[3,4-(Me0),C,H3]-7,8-(Me0), hydrochloride I-Me-5-Ph-6,7,8-(MeO), hydrochloride
l-Me-5-Ph-6,8-(Me0),-7-OH
111-1 15 207d 203-205
TABLE VI-2. 2-IMINO-2,3-DIHYDRO-lH-l,CBENZODIAZEPINES
Substituent
mp ("C); Cbp K/torr)l
Solvent of Crystallization
AcNH; 1-Me-5-(2-FC6H,)-7-C1
23&232
Me,N; l-Me-5-Ph-7-Cl H; l-Me-5-Ph-7-CI dihydrochloride Me; l-Me-5-Ph-7-CI MeNHCO, l-Me-5-Ph-7-CI
148-153 198-2OOd 186188d 167-169
CH ,CI,/Et 0 Petr ether Et,O/Petr ether EtOH EtOAc/Hexane MeOH/i-Pr,O
Yield (%)
Spectra
Refs.
89 14C
79 uv
87a, b 90 120
TABLE VI-3. 2-METHYLENE-2,3-DIHYDRO-lff-l,4-BENZODIAZEPINES
Substituent
mp W); [bp ("C/torr)]
Solvent of Crystallization
Yield (%)
Spectra
Refs.
62
ir, pmr, uv
93 63 98 98 98 98 98 98 98 98 63 99c 63 63 95 63 63 63 63
R; Other
Ac; 5-(2-CIC,H,)-7-C1
2
143-145; 118-120 Ac; 5-(2-FC6H4)-7-C1 157-159 H2NC01-Me-5-Ph-7-C1~0.4EtOH 179-1 81 H,NCO, 1-Me-5-(2-C1C6H,)-7-Br~0.75Me,C0 110-115 H,NCO, 1-Me-5-(2-C1C6H4)-7-C1 2 12-21 7 H,NCO 1-Me-5-(2-CIC6H,)-7-NO, 211-214 H,NCO, 1-Me-5-(2-FC,H4)-7-Br,.O.5Me,CO 154-155 H,NCO, 1-Me-5-(2-FC,H,)-7-C1~0.5H2O~0.33Me2CO 162-163 H,NCO; 1-Me-5-(2-F,CC,H,)-7-Br 115-120 H,NCO; 1-Me-5-(2-F3CC,H,)-7-C1 101-105 H 2 N C 0 5-(2-FC6H4)-7-C1 243-245 PhCONH; 5-Ph-7-C1, 4-Oxide 207-21Od t-BuOOC; 5-(2-ClC,H4) 17G-173 4-Oxide 219-220 t-BuOOC; 5-(2-C1C,H4)-7-CI, 4-Oxide 168-170 t-BuOOC; 5-(2-C1C6H,)-7-F, 4-Oxide 22G22 1 t-BuOOC; 5-(2-ClC,H4)-8-C1 158-160 4-Oxide 197-199 t-BuOOC; 5-(4-C1C6H,), 4-Oxide 16&162
Et,O/Hexane CH,CI,/Hexane EtOH Me,CO EtOH
75
Me,CO Me,CO
THF/Et 0Ac THF/H,O CH,CI,/EtOH CH,Cl,/EtOH Et,O Et,O CH,Cl,/EtOH Et,O Cyclohexane
87
t-BuOOC; 5-(4-C1C6H,)-7-C1, 4-Oxide t-BuOOC; 5-(2-FC6H4) 4-0xide t-BuOOC; 5-(2-FC6H4)-7-C1 4-Oxide t-BuOOC; 5-(2-F-4-MeOC,H3)-7-CI 4-Oxide CN; l-Me-5-Ph-7-Cl CN; 1-Me-5-(2-C1C6H,)-7-Br CN, 1-Me-5-(2-C1C,H4)-7-CI CN; 1-Me-5-(2-C1C6H,)-7-NO, CN; 1-Me-5-(2-FC6H,)-7-Br CN; 1-Me-5-(2-FC6H,)-7-C1 C N 1-Me-5-(2-F,CC6H4)-7-Br CN, 1-Me-5-(2-F,CC6H,)-7-C1 CN, 5-(2-FC6H4)-7-C1 4-Oxide Me,NCO; 3-Ac0-5-(2-FC6H,)-7-C1 Me,NCO, 5-Ph-7-Cl 4-Oxide Me,NCO; 5-(2-C1C6H,)-7-Cl 4-Oxide Me,NCO; 5-(2-FC6H,)-7-C1 4-Oxide Me,NSO,; 5-(2-C1C6H,)-7-C1 4-0xide Me,NSO,; 5-(2-FC6H,)-7-C1 4-0xide EtOOC; 5-(2-C1C6H,), 4-Oxide EtOOC; 5-Ph-7-C1,4-Oxide EtOOC; 5-(2-C1C6H4)-7-C1 4-Oxide EtOOC; 5-(2-FC6H4)-7-C1 4-0xide
195-196 155-157 186188d 158-160 182-183 178-180 128-131 225-227 178-179 162- 165 83-90 167-168 160-162 128-130 125-130 189-191 247-248 245-246 182-184 221-223 176-178 221-225 17Cb-172 159-1 60 161-163 182-1 84 15C-153 168-170 172-174 138-140 103-105 207-209 109-11 1 148-150
Hexane MeOH EtOH Hexane CH,CI,/Hexane Et,O/Hexane Et,O/Hexane EtOH
98
60
i-PrOH
EtOH THF/EtOH CH CI,/Et ,O CH,CI,/Et,O CH,CI,/EtOH EtOAc/Hexane EtOAc EtOH EtOH EtOH EtOAc/Hexane EtOAc/Hexane EtOAc/Et ,O CH2CI,/Et,0 EtOAc/Hexane CH,CI,/EtOH EtOH EtOH EtOAc/Hexane
ir ir
,
71 66
63 63 63 95 95 63 63 98 98 98 98 98 98 98 98 95 95 63 95 95 95 95 95
67 60 72.5 65 61
95 95 95 95 95 63 96 63 99c 95 95, 96
TABLE VI-3. -4contd.)
Substituent
mp W ) ; [bp (“C/torr)]
Solvent of Crystallization
CHO(Me)NCO; 5-(2-FC6H,)-7-Cl MeOOC; 5-Ph MeOOC, 5-(4-C1C6H,) MeOOC; 5-Ph-7-Cl 4-Oxide MeOOC; 5-(2-C1C6H,)-7-C1 MeOOC; 5-(2-C1C6H,)-7,9-C1, MeOOC; 5-(2-FC6H,)-7-C1 4-Oxide MeOOC; 5-(2-Pyridyl)-7-Br MeNHCO; 5-(2-FC6H,)-7-C1 (4-Me-Piperazino)CO, 5-(2-FC6H,)-7-C1, 4-Oxide MeSO,; 5-(2-FC,H,)-7-C1 4-0xide NO,; 3-Me-5-(2-C1C6H,)-7-NO, NO,; 3-Me-5-(2-FC6H,)-7-C1 4-Oxide NO,; 5-Ph NO,; 5-Ph-7-Cl 4-Oxide NO,; 5-Ph-7-(2-Me-1,3-Dioxolan-2-yl) NO,; 5-(2-C1C6H4)-7-C1 NO,; 5-(2-C1C6H4)-7-N02 NO,; 5-(2-FC6H,), 4-Oxide NO,; 5-(2-FC6H,)-7-C1 4-Oxide NO,; 5-(2-FC6H4)-7-Et NO,; 5-(2-FC6HA)-7-I NO,; 5-(2-FC6H,)-7-N0,, , 4-Oxide
18Gl83 13C132 129-1 31 171-173 215-216 158-159 177-179 161-162 192-1 93 178-180 203-205 202-204 131-134 185-1 87d 215-21 8 2 19-221 216218 141-142 184-186 253-254d 158-161 182-185 26243d 209-212d 174-176 26243 138-141 214-216 2 16220
Et20 Cyclohexane EtOAc/Hexane Et,O MeOH CH,Cl,/MeOH EtOH CH2C1,/Hexane MeOH/Et,O MeOH CH,Cl,/Hexane EtOH CH,Cl,/EtOH THF/EtOH Et,O/Petr ether CH,Cl,/MeOH CH,Cl,/ETOAc EtOH CH,Cl,/Et,O/Hexane CH2Cl, CH,Cl,/Hexane EtOH CH2C1,/EtOH THF/Hexane CH,CI,/EtOH DMF/H,O Et O/Hexane CH zCI,/Et 2 0 THF/Hexane
,
Yield (%)
Spectra
Refs. 63 63
90, 96
30
44 80
87
57
84 93
ir, pmr, uv
63 92,96 92,96 93 63 92, 96 96 63 63 95 95 95 89 92 94, 92 92 92 94 92 92 92 94 92 94 92 14C
36
94
NO,; 5-(2-Pyridyl)-7-Br i-PrOOC; 5-(2-FC6H,)-7-C1 4-Oxide 2-Pyridyl; 5-(2-FC6H,)-7-C1 4-Oxide
26245d 144-145 175-1 77 169-172 212-214d
THF/EtOH i-PrOH CH,Cl,/EtOH CH,Cl,/Hexane EtOAc
92 95 95 95 95
94 79 38.5
RI R , , R,; Other
~
Ac, Ac; 5-(2-C1C6H4)-7-C1 Ac, t-BuOOC; 5-(2-FC6H4)-7-C1 Ac, EtOOCNH(Et00C)N; 5-(2-C1C6H4)-7-C1 Ac, MeOOC; 5-(2-C1C6H,)-7-C1 AcNH, EtOOC; 5-(2-C1C6H,)-7-C1 maleate AcNH, EtOOC; 5-(2-FC6H,)-7-C1maleate AcNH, MeOOC; 5-(2-C1C6H,)-7-C1 HZN, t-BuOOC; S-(4-C1C6H4) HZN, EtOOC; 5-(2-CIC6H4)-7-Cl .EtOH H,N, MeOOC; 5-(2-Pyridyl)-7-Br H,NCO,CN; 5-Ph-7-C1,4-Oxide PhCONH, MeOOC; 5-(2-FC6H,)-7-C1 t-BuOOC, t-BuOOC; 5-Ph-7-C1, 4-Oxide t-BuOOC, CN; 5-(2-FC6H4)-7-C1 HOOC, CN; 5-(2-FC,H4)-7-C1 C1, MeOOC; 5-(2-C1C6H,)-7-Cl Isomer A Isomer B ClCH,CONH, MeOOC; 5-(2-C1C6H,)-7-C1 (2-Cl-Propanoyl)NH, MeOOC; 5-(2-C1C6H,)-7-C1 (3-Cl-Propanoyl)NH, MeOOC; 5-(2-CIC6H,)-7-C1 CN, CN; 5-Ph-7-Cl 4-0xide.0.5 dioxdne
205-207 160-1 62 184-186 142- 144 139-1 42d 149-151 177-1 79 190-195 145-15Od 119-121 193-196 246-248d 217-21 9 209-214d 174-177 182-184
CH,Cl,/i-PrOH Cyclohexane CH,Cl,/Hexane i-PrOH EtOAc EtOAc EtOAc/Hexane CH,Cl,/EtOH Et,O/Hexane THF/EtOH CH,Cl,/EtOH Et,O EtOAc/Hexane CH,Cl,/Et,O Et,O/Hexane THFiHexane
179-180 152-1 54 192-194d 128-130 176-179d 274-276 240-242d
EtOAc/Hexane Et,O/Hexane CH,Cl,/Et,O Et,O CH,CI,/Et,O THF/EtOAc Dioxane
27.5
ir, pmr, uv
25
72.5
ir, pmr, uv Pmr
98
Pmr
54
Pmr
58
79
uv. pmr
93 63 63 93 92 92 63 63 92,93 92, 93 63 63 92 63 63 63 63 63 116 63 116 91 91
TABLE VI-3. d c o n t d . )
Substituent
mp K); CbP (.C/torr)l
Solvent of Crystallization
207-208 236-2385 198-200 251-253 112-115 141-144 127.Sl30 191.5-1 94.5 176-179 197-200 182-184 190.5-193.5 151-1 54 188-19 1 211-214 195-200 156-158 135-138 135-138 165-166 138-140 194-195 205-207 172-175 128-130 17CL-172 171-173 153-155 218-22Od 203-206
CH,CI,/EtOH
63 97
CH,CI,/Et,O CH,CI,/Hexane Et,O
63
Yield (%)
Spectra
Refs.
~
CN, EtOOC; 5-Ph-7-C1, 4-Oxide CN, EtOOC; 5-(2-FC6H,)-7-C1 Me,NCO, EtOOC; 5-Ph-7-CI 4-Oxide EtOOC, EtOOC, 5-(2-C1C6H4) EtOOC, EtOOC; 5-Ph-7-Cl EtOOC, EtOOC; 5-Ph-7-NO2 EtOOC, EtOOC; 5-(2-C1C6H4)-7-C1 EtOOC, EtOOC; 5-(2-C1C6H4)-7-N02 EtOOC, EtOOC; 5-(2-FC6H4)-7-C1 EtOOC, EtOOC, 5-(2-FC6H4)-7-NO2 EtOOC, EtOOC; 5-(2-Pyridyl)-7-Br EtOOC, EtOOCCH,CO; 5-(2-C1C,H4)-7-C1 EtOOCNH, MeOOC; 5-(2-FC6H,)-7-C1 EtOOCNH(EtOOC)N, MeOOC; 5-(2-C1C6H,)-7-C1 EtOOCNH(EtOOC)N, MeOOC; 5-(2-FC6H,)-7-C1 MeOOC, MeOOC; 5-Ph MeOOC, MeOOC; 5-(2-C1C6H,) MeOOC, MeOOC; 5-(4-C1C6H,) MeOOC, MeOOC; 5-Ph-743 4-Oxide MeOOC, MeOOC; 5-(2-C1C,H4)-7-C1 MeOOC, MeOOC; 5-(2-C1C6H,)-7-NO, MeOOC, MeOOC; 5-(2-C1C,H,)-7,9-C12 MeOOC, MeOOC; 5-(2-FC6H,)-7-CI MeOOC, MeOOC; 5-(2-Pyridyl)-7-Br Me, NO,; 5-(2-FC6H,)-7-C1 (2-0xo-3-penten-4-yl)NH, MeOOC; 5-(2-C1C6H,)-7-C1 (Propenoyl)NH, MeOOC; 5-(2-C1C6H,)-7-C1
CH,CI,/Et,O
CH,C12/Et20 CH2C1,/EtOAc/Hexane EtOAc/Hexane EtOAc/Hexane i-PrOH Et,O EtOH i-PrOH CH2C1,/Hexane EtOAc CH,Cl,/Et,O/Hexane EtOH CH,Cl,/EtOH EtOAc CH,CI,/EtOH CH2C1,/EtOAc EtOAc/Et,O
95
ir, pmr, uv
83
ir, uv, pmr
69
ir, pmr, uv
62 90
ir, pmr, uv Pmr
63 63 97 97 97 97 63,97 97 97 63 1l9a, b 108 63 63 63 63 91,92 91,92 92 63 63 92 63 14C 93 116
TABLE VI-4. 3-METHYLENE-2,3-DIHYDRO-2H-l,4-BENZODIAZEPINES
Substituent
mP (“C); CbP (“C/torr)l
Solvent of Crystallization
136140 108-114d
EtOAc/Hexane MeOH/H,O EtOAc EtOH
Yield (%)
Spectra
Refs.
m W N
R; Others H; 5-Ph, 4-Oxide H; 5-Ph-7-Cl 4-Oxide EtOOC; 5-Ph-7-C1,4-Oxide
157-163d 186188
99
99 99 96
TABLE VI-5.2,5-DIHYDRO-lH-1,4-BENZODIAZEPINES
Substituent
mp ("C); CbP ("C/torr)l
Solvent of Crystallization
S-Ph-7-Cl 3-Me-5-Ph-7-C1, 4-Oxide 3-(4-MeC,H4SO,)NH-5-Ph-7-Cl 3-PhNH-5-Ph-7-CI
191-192 17G176d 228-23Od 202-208d
MeOH Me,CO EtOAc/Hexane
Yield (YO)
70
Spectra
Refs.
ir, ms, uv pmr, uv ir, uv ir, uv
137 64, 99a, b 99C
99c
TABLE VI-6. 4,5-DIHYDRO-1,4-BENZODIAZEPINES Substituent
mp W ) ; CbP YC/torr)I
Solvent of Crystallization
c>
Yield (%)
Spectra
Refs.
62
ir, pmr
138
H
4,SDihydro-1 H-1,Cbenzodiazepines
NH
2-(4-N0,C6H4)-3-CN-4-t-Bu-9-Me
c 7
4,5-Dihydro-3H-1,4-benzodiazepines
NH
m
% 2-MeNH-5-Ph Hydrochloride Dihydrochloride 2-MeNH-5-Ph-7-CI Dihydrochloride 2-MeNH-4-HO-SPh-7-Cl Isomer A Isomer B 2-MeNAc-4-AcO-5-Ph-7-Cl 2-Pr0-4-HO-5-Ph-7-Cl 2-Me0-4-HO-5-Ph-7-CI
153-155 240-242 240-242 179-180 226-238
Et,O/Petr ether EtOH/Et,O MeOH/Et,O/Petr ether Et,O/Petr ether MeOH/Et,O
181-183 196198 133-134 126127
Et,O CH,Cl,/Petr ether C yclohexane
70
63
139 139 139 139, 143 139
87 38 69
140, 141 141 45a 142 141, 142
626
Dihydro-1,4-Benzodiazepines
6. REFERENCES 1. J. A. Hill, A. W. Johnson, and T. J. King, J. Chem. SOC.,4430 (1961). 2. L. H. Sternbach, G. A. Archer, and E. Reeder, J . Org. Chem., 28, 3013 (1963). 3. (a) G. A. Archer, A. Stempel, S. S. Ho, and L. H. Sternbach, J. Chem. SOC.,C., 1031 (1966). (b) G. A. Archer, unpublished data, Hoffmann-La Roche, Nutley, NJ. 4. R. I. Fryer, R. A. Schmidt, and L. H. Sternbach, U.S. Patent 3,403,161, September 1968. 5. G. A. Archer, R. I. Kalish, R. Y. Ning, B. C. Sluboski, A. Stempel, T. V. Steppe, and L. H. Sternbach, J. Med. Chem., 20, 1312 (1977). 6. A. M. Felix, R. I. Fryer, and L. H. Sternbach, U.S. Patent 3,546,212, December 1970. 7. Ger. Offen. 2,223,648, November 1972 (Hoffmann-La Roche & Co., Switzerland). 8. H. Moriyama, H. Yamamoto, S. Inaba, and H. Nagata, U.S. Patent 3,817,984, June 1974. 9. Belg. Patent 770,749, August 1971 (Lab. Pharmedical S.A., Luxembourg). 10. S. T. Ross, U.S. Patent 3,555,010, January 1971. 1 1 . Belg. Patent 772,935, October 1971 (Lab. Pharmedical S.A., Luxembourg). 12. Belg. Patent 794,358, May 1973 (Lab. Pharmedical S.A., Luxembourg). 13. S. C. Bell and C. Gochman, U.S. Patent 3,538,082, November 1970. 14. (a) R. I. Fryer and L. H. Sternbach, U.S. Patent 3,391,158, July 1968. (b) R. I. Fryer and L. H. Sternbach, U.S. Patent 3,391,159, July 1968. (c) R. I. Fryer, unpublished data, Hoffmann-La Roche, Nutley, NJ. 15. L. H. Sternbach, E. Reeder, and G. A. Archer, J. Org. Chem., 28, 2456 (1963). 16. Belg. Patent 772,825, October 1971 (Lab. Pharmedical S.A., Luxembourg). 17. N. Blasevic and F. Kajfez, J . Heterocycl. Chem., 8, 845 (1971). 18. Neth. Patent 7,108,245, December 1971 (Compagnia di Ricerca Chimica S.A., Switzerland). 19. W. Schlesinger, U.S. Patent 4,155,904, May 1979. 20. G. A. Archer and L. H. Sternbach, US. Patent 3,583,978, June 1971. 21. G. A. Archer and L. H. Sternbach, U.S. Patent 3,803,233, April 1974. 22. G. A. Archer and L. H. Sternbach, U.S. Patent 3,887,604, June 1975. 23. G. A. Archer and L. H. Sternbach, U.S. Patent 3,646,011, February 1972. 24. M. Mihalic, V. Sunjic, and F. Kajfez, Tetrahedron Lett., 1011 (1975). 25. Swiss Patent 610,311, April 1979 (Compagnia di Ricerca Chimica S.A., Switzerland). 26. M. Mihalic, V. Sunjic, F. Kajfez, and M. Zinic, J. Heterocycl. Chem., 14, 941 (1977). 27. G. A. Archer and L. H. Sternbach, U.S. Patent 3,553,199, January 1971. 28. (a) J. Hellerbach and G. Zanetti, U.S. Patent 3,906,025, September 1975. (b) Neth. Patent 7,205,955, December 1972 (Hoffmann-La Roche & Co., Switzerland). (c) G. Zanetti, unpublished data, Hoffmann-La Roche & Co., Basel, Switzerland. 29. G. N. Walker, A. R. Engle, and R. J. Kempton, J. Org. Chem., 37, 3755 (1972). 30. Belg. Patent 775,710, May 1972 (VEB Arzneimittelwerk, Germany). 31. F. Kajfez, V. Sunjic, and V. Caplar, U.S. Patent 4,226,766, October 1980. 32. P. Giacconi, E. Rossi, R. Stradi, and R. Eccel, Synthesis, 789 (1982). 33. H. Yamamoto, S. Inaba, T. Okamoto, T. Hirohashi, K. Ishizumi, M. Yamamoto, I. Maruyama, K. Mori, and T. Kobayashi, U.S. Patent 4,002,611, January 1977. 34. A. Walser and J. Hellerbach, Hoffmann-La Roche & Co., Basel, Switzerland, unpublished data. 35. F. Gatta and S. Chiavarelli, Farmaco, Ed. Sci., 32, 33 (1977). 36. H. Yamamoto, S. Inaba, T. Okamoto, T. Hirohashi, K. Ishizumi, M. Yamamoto, I. Murayama, K. Mori, and T. Kobayashi, U.S. Patent 3,663,534, May 1972. 37. S. Inaba, K. Ishizumi, T. Okamoto, and H. Yamamoto, Chem. Pharm. Bull., 20, 1628 (1972). 38. H. Yamamoto, S. Inaba, T. Okamoto, T. Hirohashi, K. Ishizumi, M. Yamamoto, I. Maruyama, K. Mori, T. Kobayashi, and T. Izumi, U.S. Patent 3,702,321, November 1972. 39. Neth. Patent 7,112,297, March 1972 (Sumitomo Chemical Co., Japan). 40. H. Yamamoto, S. Inaba, T. Okamoto, T. Hirohashi, K. Ishizumi, M. Yamamoto, I. Maruyama, T. Kobayashi, and T. Izumi, U.S. Patent 3,875,142, April 1975.
6. References
627
41. H. H. Kaegi, J . Labelled Compd., 4, 363 (1968). 42. I. Nakatsuka, K. Kawahara, T. Kamada, F. Shono, and A. Yoshitake, J . Labelled Compd., 13, 453 (1977). 43. M. E. Derieg, R. I. Fryer, and L. H. Sternbach, U.S. Patent 3,651,046, March 1972. 44. M. Steinman, U.S. Patent 3,723,414, March 1973. 45. (a) L. H. Sternbach et al., unpublished data, Hoffmann-La Roche, Nutley, NJ. (b) A. Walser and R. I. Fryer, unpublished results, Hoffmann-La Roche, Nutley, NJ. 46. K.-H. Wiinsch, H. Dettmann, and S. Schonberg, Chem. Ber., 102, 3891 (1969). 47. H. Liepmann, W. Milkowski, and H. Zeugner, Eur. J . Med. Chem., 11, 501 (1976). 48. W. Milkowski, S. Funke, R. Hiischens, H.-G. Liepmann, W. Stiihmer, and H. Zeugner: (a) U.S. Patent 3,998,809, December 1976, (b) U.S. Patent 4,096,141, June 1978. 49. W. Milkowski, S. Funke, R. Hiischens, H.-G. Liepmann, W. Stiihmer, and H. Zeugner, U.S. Patent 4,098,786, July 1978. 50. Ger. Offen. 2,952,279, June 1981 (Kali-Chemie Pharma GmbH, W. Germany). 51. H. Zeugner, D. Roemer, H. Liepmann, and W. Milkowski: (a) E P 0,068,240, January 1983 (Kali-Chemie Pharma GmbH, W. Germany), (b) U.S. Patent 4,325,957, April 1982. 52. Ger. Offen. 2,353,160 November 1974 (Kali-Chemie AG, W. Germany). 53. Ger. Offen. 2,448,259, April 1976 (Kali-Chemie Pharma GmbH, W. Germany). 54. Ger. Offen. 2,314,993, October 1974 (Kali-Chemie Pharma GmbH, W. Germany). 55. C. Corral, R. Madronero, and S. Vega, J . Heterocycl. Chem., 14, 985 (1977). 56. (a) M. Uskokovic, J. Iacobelli, and W. Wenner, J . Org.Chem., 27,3606 (1962).(b) M. Uskokovic and W. Wenner, US. Patent 3,261,828, July 1966. 57. T. S. Sulkowski and S. J. Childress, J. Org.Chem., 28, 2150 (1963). 58. K. Ishizumi, S. Inaba, and H. Yamamoto, J. Org.Chem., 37,4111 (1972). 59. K. Ishizumi, K. Mori, T. Okamoto, T. Akase, T. Izumi, M. Akatsu, Y. Kume, S. Inaba, and H. Yamamoto, U.S. Patent 4,044,003, August 1977. 60. R. Ian Fryer, D. L. Coffen, J. V. Earley, and A. Walser, J . Heterocycl. Chem., 10, 473 (1973). 61. (a) G. A. Archer and L. H. Sternbach, J . Org.Chem., 29,231 (1964). (b) G. A. Archer and L. H. Sternbach, US. Patent 3,678,036, July 1972. (c) G. A. Archer and L. H. Sternbach, U S . Patent 3,422,091, January 1969. 62. (a) J. V. Earley, R. I. Fryer, and A. Walser, U.S. Patent 3,838,116, September 1974. (b) J. V. Earley, R. I. Fryer, and A. Walser, unpublished data. 63. A. Walser, T. Flynn, C. Mason, and R. I. Fryer, unpublished data, Hoffmann-La Roche, Nutley, N.J. 64. G. F. Field, W. J. Zally, and L. H. Sternbach, J . Am. Chem. Soc., 89, 332 (1967). 65. A. Walser, L. E. Benjamin, Sr., T. Flynn, C. Mason, R. Schwartz, and R. I. Fryer, J. Org.Chem., 43, 936 (1978). 66. (a) A. Walser and R. I. Fryer, J . Heterocycl Chem., 20, 551 (1983). (b) A. Walser, U.S. Patents 4,226,768, October 1980 4,240,962, December 1980; 4,244,868, January 1981. (c) A. Walser, US. Patents 4,226,771, October 1980; 4,247,463, January 1981. 67. Neth. Patent 6,614,923, April 1967 (Hoffmann-La Roche & Co., Switzerland). 68. (a) D. L. Coffen, J. P. DeNoble, E. L. Evans, G. F. Field, R. Ian Fryer, D. A. Katonak, B. J. Mandel, L. H. Sternbach, and W. J. Zally, J . Org.Chem., 39, 167 (1974). (b) D. L. Coffen and R. Ian Fryer, US. Patent 3,849,399, November 1974. (c) D. L. Coffen and R. Ian Fryer, U.S. Patents 3,932,399, January 1976; 3,906,001, September 1975; 3,850,948, November 1974. (d) D. L. Coffen et al., unpublished results, Hoffmann-La Roche, Nutley, NJ. 69. (a) K. Meguro and Y. Kuwada, Yakugaku Zasshi, 93, 1263 (1973). (b) K. Meguro, H. Tawada, Y. Kuwada, and T. Masuda, U.S. Patent 3,692,772, September 1972. 70. R. Y. Ning and M. A. Schwartz, U.S. Patent 3,925,358, December 1975. 71. (a) L. H. Sternbach and R. Y. Ning, US. Patent 3,873,525, March 1975. (b) Belg. Patent 818,132, January 1975 (Hoffmann-La Roche & Co., Switzerland). 72. M. Steinman, U.S. Patent 3,856,787, December 1974. 73. A. Walser, R. F. Lauer, and R. Ian Fryer, J . Heterocycl. Chemistry, 15, 855 (1978).
628
Dihydro-1,4-Benzodiazepines
74. (a) J. B. Hester, D. J. Duchamp, and C. G. Chidester, Tetrahedron Lett., 1609 (1971). (b) J. B. Hester, US. Patent 3,896,109, July 1975. 75. J. B. Hester, US. Patent 3,714,178. January 1973. 76. R. Madronero and S. Vega, J . Heterocycl. Chem., 15, 1127 (1978). 77. A. Bauer and K.-H. Weber, Z. Naturforsch., 29, 670 (1974). 78. G. A. Archer and L. H. Sternbach, US. Patent 3,671,517, June (1972). 79. E. Reeder and L. H. Sternbach, US. Patent 3,624,071, November 1971. 80. A. M. Felix, J. V. Earley, R. I. Fryer, and L. H. Sternbach, J. HeterocycL Chem., 5,731 (1968). 81. Neth. Patent 7,404,131, October 1974 (Dumex Ltd., Denmark). 82. K. Ishizumi, K. Mori, S. Inaba, and H. Yamamoto, Chem. Pharm. Bull., 23, 2169 (1975). 83. W. Metlesics and L. H. Sternbach (a) US. Patent 3,644,336, February 1972, (b) US. Patent 2,498,973, March 1970, (c) unpublished data, Hoffmann-La Roche, Nutley, NJ. 84. W. Metlesics, G. Silverman, and L. H. Sternbach, J. Org. Chem., 28, 2459 (1963). 85. R. I. Fryer and L. H. Sternbach: (a) US. Patent 3,625,957, December 1971, (b) U.S. Patent 3,706,734, December 1972. 86. Swiss Patent 544,762, January 1974 (Sumitomo Chemical Co., Japan). 87. (a) K. Meguro, H. Tawada, and Y. Kuwada, Yakugaku Zasshi, 93, 1253 (1973). (b) Ger. Offen. 1,966,616, May 1973 (Takeda Chemical Industries Ltd., Japan). 88. J. Earley and R. I. Fryer, unpublished data, Hoffmann-La Roche, Nutley, NJ. 89. A. Szente and J. Hellerbach, unpublished data, Hoffmann-La Roche & Co., Basel, Switzerland. 90. J. B. Hester, Jr., US. Patent 4,082,761, April 1978. 91. A. Walser and R. Ian Fryer, J. Org. Chem., 40,153 (1975). 92. A. Walser and R. 1. Fryer, U.S. Patent 4,280,957, July 1981. 93. A. Walser, T. Flynn, and R. I. Fryer, J . Heterocycl. Chem., 15, 577 (1978). 94. R. I. Fryer, J. V. Earley, N. W. Gilman, and W. Zally, J. Heterocycl. Chem., 13, 433 (1986). 95. A. Walser, T. Flynn, C. Mason, and R. I. Fryer, J. Heterocycl. Chem., 23, 1303 (1984). 96. G. F. Field and W. J. Zally, U.S. Patent 4,238,610, December 1980. 97. H. Niemczyk, US. Patent 4,335,042, June 1982. 98. H. Liepmann, R. Hiischens, W. Milkowski, H. Zeugner, R. Budden, and J. Bahlsen, US. Patent 4,170,649, October 1979. 99. (a) G. F. Field and L. H. Sternbach, US. Patent 3,594,364, July 1971. (b) G. F. Field and L. H. Sternbach, US. Patent 3,594,365, July 1971. (c) G. F. Field, unpublished data, Hoffmann-La Roche, Nutley, NJ. 100. R. Maupas and M. B. Fleury, Analysis, 10, 187 (1982). 101. R. Y. Ning and L. H. Sternbach, US. Patent 3,635,948, January 1972. 102. W. Milkowski, R. Budden, S. Funke, R. Hiischens, H.-G. Liepmann, W. Stiihmer, and H. Zeugner, U S . Patent 4,244,869, January 1981. 103. G. F. Field and L. H. Sternbach, US. Patent 3,651,047, March 1972. 104. R. Y. Ning and L. H. Sternbach, U.S. Patent 3,682,892, August 1972. 105. R. I. Fryer and L. H. Sternbach, US. Patent 3,322,753, May 1967. 106. M. Steinman, J. G. Topliss, R. Alekel, Y. Wong, and E. E. York, J. Med. Chem., 16, 1354(1973). 107. W. Milkowski, R. Hiischens, and H. Kuchenbecker, J. Heterocycl. Chem., 17, 373 (1980). 108. A. Walser and T. Flynn, J. Heterocycl. Chem., 17, 1697 (1980). 109. Swiss Patent 510,033, August 1971 (Hoffmann-La Roche & Co., Switzerland). 110. W. Metlesics, G. Silverman, and L. H. Sternbach, J . Org. Chem., 29, 1621 (1964). 111. T. Okarnoto, T. Akase, T. Izumi, M. Akatsu, Y. Kume, S. Inaba, and H. Yamamoto, U.S. Patent 3,882,244, August 1974. 112. G. A. Archer, R. I. Fryer, and L. H. Sternbach, US. Patent 3,299,053, January 1967. 113. G. A. Archer and L. H. Sternbach, U.S. Patent 3,236,838, February 1966. 114. S. Afr. Patent 66/5349 (Hoffmann-La Roche Inc., 1967). 115. P. K. Yonan, U.S. Patent 4,208,327, June 1980. 116. A. Walser, T. Flynn, and R. I. Fryer, J . Heterocycl. Chem., 20, 791 (1983). 117. M. E. Derieg and R. I. Fryer, unpublished results, Hoffmann-La Roche, Nutley, NJ.
6. References
629
118. Ger. Offen. 2,353,187, November 1974 (Kali-Chemie AG, W. Germany). 119. A. Walser, R. I. Fryer, and L. Benjamin: (a) U.S. Patent 4,125,726, November 1978, (b) U.S. Patent 4,147,875, April 1979. 120. K. Meguro, Y. Kuwada, Y. Nagawa, and T. Masuda, U.S. Patent 3,652,754, March 1972. 121. A. Szente, J. Hellerbach, and A. Walser, Hoffmann-La Roche & Co., Basel, Switzerland, unpublished data. 122. J. Hellerbach and A. Szente, US. Patent 3,696,095, October 1972. 123. T. E. Gunda and C. Eneback, Acta Chem. Scand., 37, 75 (1983). 124. (a) R. Jaunin, W. E. Oberhansli, and J. Hellerbach, Helu. Chim. Acta, 55, 2975 (1972). (b) R. Jaunin, unpublished data, Hoffmann-La Roche & Co., Basel, Switzerland. 125. R. I. Fryer, D. Winter, and L. H. Sternbach, J. Heterocycl. Chem., 4, 355 (1967). 126. (a) R. I. Fryer, J. Blount, E. Reeder, E. J. Trybulski, and A. Walser, J . Org. Chem., 43, 4480 (1978). (b) E. J. Trybulski, unpublished data, Hoffmann-La Roche, Nutley, NJ. 127. J. V. Earley, R. I. Fryer, and A. Walser, U.S. Patent 3,836,521, September 1974. 128. (a) E. E. Garcia, J. G. Riley, and R. I. Fryer, First International Congress of Heterocyclic Chemistry, Albuquerque, NM, 1967; Abstracts. (b) E. E. Garcia, unpublished data, HoffmannLa Roche, Nutley, NJ. 129. (a) H. Liepmann, R. Hiischens, W. Milkowski, H. Zeugner, I. Hell, and K.-U. Wolf, U.S. Patent 4,338,314, July 1982. (b). EP A,0,008,045. 130. J. B. Hester, U.S. Patent 3,717,654, February 1973. 131. R. Y. Ning and L. H. Sternbach, U.S. Patent 3,746,702, July 1973. 132. (a) P. A. Wehrli, R. I. Fryer, and L. H. Sternbach, US. Patent 3,553,206, January 1971. (b) P. A. Wehrli, unpublished data, Hoffmann-La Roche, Nutley, NJ. 133. M. Steinman and Y . 4 . Wong, Tetrahedron Lett., 2087 (1974). 134. E. Finner, F. Rosskopf, and W. Milkowski, Eur. J. Med. Chem.-Chim. Thep., 11, 508 (1976). 135. G. Romeo, M. C. Aversa, P. Giannetto, P. Ficarra, and M. G. Vigorita, Org. Magn. Resonance, 15, 33 (1981). 136. G. Gilli, V. Bortolasi, and M. Sacerdoti, Acta Crystallogr., 34, 3793 (1978). 137. M. M. Ellaithy, J. Volke, and J. Hlavaty, Collect. Czech. Chem. Commun., 41, 3014 (1976). 138. J. A. Deyrup and J. C. Gill, Tetrahedron Lett., 4845 (1973). 139. L. H. Sternbach and E. Reeder, J. Org. Chem., 26, 1 1 1 1 (1961). 140. Neth. Patent 6,608,039, December 1966 (Grindstedvaerket, Denmark). 141. P. Nedenskov and M. Mandrup, Acta Chim. Scand., 31, 701 (1977). 142. Belg. Patent 777,138, January 1972 (Grindstedvaerket, Denmark). 143. J. V. Earley, R. I. Fryer, and L. H. Sternbach, U.S. Patent 3,644,335, February 1972. 144. T. T. Moller, P. Nedenskov, and H. B. Rasmussen, US. Patent 3,635,949, January 1972. 145. H. Oelschlager and H. Hoffiann, Arch. Pharm., 300,817 (1967).
CHAPTER VII
Dihydro.1. 4.Benzodiazepinones and Thiones A. Walser Chemical Research Department. Hoffmann-La Roche h e . , Nutley. New Jersey
and
R . Ian Fryer Department of Chemistry. Rutgers. State University of New Jersey. Newark. New Jersey
1. 1,3.Dihydro.1.4.benzodiazepin.2(2H
).ones . . . . . . . . . . . . . . . . . . . . . . . . . .
1.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1.1. From (2-Aminophenyl)carbonyl Compounds . . . . . . . . . . . . . . . . . . 1.1.1.1. Via 2-Haloacetanilides . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1.1.2. By Reaction with N-protected a-Amino Acids . . . . . . . . . . . . . 1.1.1.3. By Reaction with a-Amino Acid Esters . . . . . . . . . . . . . . . . . 1.1.1.4. By Reaction with a-Amino Acids . . . . . . . . . . . . . . . . . . . . . 1.1.2. By Oxidation of Indoles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1.3. By Ring Expansion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1.4. By Ring Contraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1.5. By Oxidation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1.6. By Elimination and Rearrangement . . . . . . . . . . . . . . . . . . . . . . . . 1.1.7. By Hydrolysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1.8. Other Syntheses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
633 633 633 633 638 639
640 641 643 645 645 647 648 650
1.2. Reactions of 1,3-Dihydro-l,4-benzodiazepin.2(2H)-ones . . . . . . . . . . . . . . .
658
1.2.1. Reactions with Electrophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2.1.1. Halogenation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2.1.2. Oxidation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2.1.3. Reactions with Nitrogen Electrophiles . . . . . . . . . . . . . . . . . . A . Nitrosation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Nitration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C. Reaction with Other Nitrogen Electrophiles . . . . . . . . . . . . ............... 1.2.1.4. Reactions with Carbon Electrophiles A . Alkylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
658 658 660 663 663 663 665 665 665
63 1
632
Dihydro- 1.4.Benzodiazepinones and Thiones B. Reaction with Aldehydes. Ketones. and Epoxides . . . . . . . . . C. Acylations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . D . Sulfonation and Phosphorylation . . . . . . . . . . . . . . . . . . . 1.2.2.Reactions with Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2.2.1.Reduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2.2.2.Reactions with Halogen Nucleophiles . . . . . . . . . . . . . . . . . . 1.2.2.3.Reactions with Oxygen and Sulfur Nucleophiles . . . . . . . . . . . . A. Hydrolysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Reaction with Alkoxides and Acyloxides . . . . . . . . . . . . . . C . Reaction with Sulfur Nucleophiles . . . . . . . . . . . . . . . . . . 1.2.2.4.Reactions with Nitrogen Nucleophiles . . . . . . . . . . . . . . . . . . 1.2.2.5.Reactions with Carbon Nucleophiles . . . . . . . . . . . . . . . . . . 1.2.2.6.Photo and Thermal Reactions . . . . . . . . . . . . . . . . . . . . . . 1.2.2.7.Other Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.3. Spectral Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. 1,3-Dihydro-l,4-benzodiazepin-2(2H )-thiones . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.1.Reactions with Electrophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.2.Reactions with Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. 1,5-Dihydro-l,4-benzodiazepin-2(2H )-ones . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. 1,2-Dihydro-l,4-benzodiazepin-3(3H )-ones . . . . . . . . . . . . . . . . . . . . . . . . . . 5 . 4,5-Dihydro-l,4-benzodiazepin-3(3H )-ones . . . . . . . . . . . . . . . . . . . . . . . . . . 6. 1,2-Dihydro-1.4-benzodiazepin-5(5H )-ones . . . . . . . . . . . . . . . . . . . . . . . . . . 7. 1,4-Dihydro-l,.l-benzodiazepin-5(5H )-ones . . . . . . . . . . . . . . . . . . . . . . . . . . . 3,CDihydro-l,.l-benzodiazepin-5(5H )-ones . . . . . . . . . . . . . . . . . . . . . . . . . . 8 9. Dihydro- 1,4-benzodiazepinediones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10. Table of Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 1 . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
671 672 683 684 684 685 686 686 690 691 692 695 696 697 700 701 701 702 702 703 705 705 706 706 707 708 708 709 711 713 837
INTRODUCTION The subject of this chapter is the chemistry of dihydro.1. Cbenzodiazepinones and thiones. Leaving the aromaticity of the benzene ring undisturbed. the seven structures shown in Eq. 1 may be formulated . Representatives of the two tautomeric 2-ones 1 and 2. the 3-ones 3 and 4. and the 5-ones 5 and 6 (all with X = 0) have been reported in the literature. Of the corresponding thiones (X = S) the derivatives of the 2-thione 1 (X = S) have been described. The chemistry of these compounds is discussed in Sections 1-8. followed by the syntheses and reactions of the diones in Section 9. The 2-ones 1 were extensively explored and are by far the most numerous; several thousand derivatives have been reported in the literature and are listed in Tables VII.1.
1. 1,3-Dihydro-1,4-Benzodiazepin-2(2H)-Ones
633
c> H
3
5
H
6a
6b
1. 1,3-DIHYDRO- 1,CBENZODIAZEPIN-2( 2H)-ONES 1.1. Synthesis
1.1. I . From (2-Aminopheny1)carbonyl Compounds Most syntheses of 1,3-dihydro-1,4-benzodiazepin-2(2H)-ones (10) start from the (2-aminopheny1)carbonyl compounds 7 and incorporate the cl-amino acid moiety by first establishing the amide bond to give 8 and then closing the seven-membered ring by forming the 4,5-imine bond to give the benzodiazepine 10. Procedures using the reversed sequence i.e., first forming the imine to yield 9 and subsequently establishing the amide bond to form 10 were also widely used. The various methods involving these two pathways (Eq. 2) are discussed in the subsections that follow. 1.1.1.1. Via 2-Haloacetanilides
The 2-haloacylanilides 12 (Eq. 3) were generally prepared by acylation of the anilines 11 with the halides of a-halo alkanoic acids. The halogen X in 12 was then displaced directly by ammonia or by a nitrogen nucleophile, which could be converted to an amino group. For the direct displacement by ammonia, the bromides 12 (X = Br) were most often used. A large variety of benzodiazepin2-ones 14 were prepared by treating the 2-bromoacetyl derivatives 12 (X = Br, R4 = H) with liquid ammonia and a cosolvent such as methylene chloride or tetrahydr~furan.'-*~
Dihydro-1,4-Benzodiazepinonesand Thiones
634
I
H,NCH,CQ,R,
R2 9
7 1 I
I
I
1
R2
R2
12
11
I
R1
R
3
R4 .
R1
0 R, I1 I X-C-CHX
, "le
R4
qN d0 N H 2 A -HO R
3
q
N
R4
-0 R2 13
R2 14
Direct displacement of the chloride in 12 (X = C1) by ammonia required an elevated temperature. Diazepam 14 (R, = Me, R, = Ph, R, = 7-C1, R, = H) was obtained in 65% yield by heating the appropriate chloride 12 with ethanolic ammonia at 80°C in a sealed tube.30 A somewhat higher yield was achieved by substituting ammonia with ammonium carbonate.,' According to the patent literature, 14 (R, = Me, R, = Ph, R, = R, = H) was accessible in 63% yield by heating the corresponding chloride 12 in dimethyl sulfoxide at 100°C in the presence of ammonia.31The iodide 12 (X = I) reacts with ammonia under mild conditions, such as liquid ammonia in t e t r a h y d r o f ~ r a n .The ~ ~ . conversion, ~~ in situ, of the chloride to the iodide, by addition of catalytic amounts of potassium
1. 1,3-Dihydro-1,4-Benzodiazepin-2(2H)-Ones
635
iodide, has been proved to be a d v a n t a g e ~ u s . ~ ~Acetanilides -,~ 12 with X = 4Me-phenylsulfonyloxy were successfully converted to the benzodiazepinones by ammonolysis in a variety of solvent^.^' The amino compounds 13, resulting from the displacement of the leaving group X in 12 with ammonia, were isolated in many cases when R, represented hydrogen. When R, was alkyl, the amino derivatives 13 cyclized spontaneously to the benzodiazepinones 14 (Eq. 3). The rapid cyclization could be suppressed by protonation of the amino group. The salts of 13 (R, = alkyl) have been obtained in crystalline form. The higher stability of the amines 13 (R, = H) was attributed to hydrogen bonding of the aniline proton to the orthocarbonyl oxygen as shown for 15. The existence of such hydrogen bonding was evident from spectroscopic data, in particular from proton-nmr and infrared ~ p e c t r a . ~ ~The - ~ 'hydrogen bonding puts the molecule into a conformation which cannot undergo ring closure, and the hydrogen bond must be destroyed to allow the reactants to approach each other. This may be achieved by heating and is facilitated by employing polar protic and aprotic solvents. Heating 13 (R, = H) in ethanol or toluene in the presence of acetic acid is the preferred method for ring closure to 14.39According to a Dutch patent,,' ring closure was achieved by heating in dimethyl sulfoxide at 70-75°C. Due to steric crowding of the carbonyl group in the 2,6-dichlorobenzoyl derivative, 13 (R, = R, = H, R, = 2,6-C1,C6H,, R, = 4-C1) could not be cyclized to the benz~diazepinone.~' The corresponding 1-benzyl-substituted analog was induced to undergo ring closure by heating in toluene in the presence of pivalic acid, demonstrating again the more facile cyclization of 13 bearing a substituent on the aniline nitrogen.
R2 15
By employing weak acidic media for ring closure of the aminoacetanilides, which is routinely observed when comthe Smiles type of pounds 13 (R,#H, R, = electron-withdrawing group at the 4-position) are treated with ammonia, can be largely suppressed. Compounds 13, which have the propensity to undergo the Smiles-type rearrangement, are not accessible by direct amination of the halides and are, therefore, better prepared via the azide. The bromide or chloride in 12 (X = Br, C1) is displaced by azide in dimethylformamide at room temperature, and the resulting azidoacetanilide is reduced ~ a t a l y t i c a l l y " ~ to ~ ~the * ~amine, ~ * ~ ~which can cyclize in situ or in a separate step to the benzodiazepinone.
636
Dihydro-1,4-Benzodiazepinonesand Thiones
The reduction of the azidoacetanilides to the corresponding amines was also achieved with t r i p h e n y l p h o ~ p h i n e and ~ ~ ' ~triethyl ~ ph~sphite.,~ High yields of the benzodiazepinones were obtained when the azide was heated with triphenylphosphine in toluene. In a first reaction step, the azide is converted to an iminophosphorane, which cyclizes with elimination of triphenylphosphine oxide. Triphenylphosphine appears to function as a catalyst in this second step.46 Nitro-substituted benzodiazepinones were also accessible by this method. Hexamethylenetetramine has been used as an alternate source of ammonia in the preparation of ben~odiazepines.~*-~~ The haloacetanilides 12 (X = Br, C1; R, # H) were converted to the corresponding benzodiazepinones 14, via the intermediates 16, by heating to reflux in ethanol in the presence of hexamethylenetetramine. When R, represented hydrogen, the imidazolidinones 17 and 18 were formed almost exclusively (Eq. 4).49-51A notable exception was the hydrobromide of 12 (R, = R, = H, R2 = 2-pyridyl, R, = 4-Br), which could be converted to bromazepam 14 (R, = R, = H, R, = 2-pyridyl, R, = 7-Br), under conditions which transformed the corresponding phenyl analog to the imidazolinone 17.52The formation of the imidazolidinones 17 and 18 could be avoided either by reacting the halide with hexamine in the presence of ammoor by treating the halide with a mixture of ammonia and f~rmaldehyde.~, A slightly modified process using hexamethylenetetramine in combination with an aqueous solution of an ammonium salt such as ammonium bromide was also patented. 54
R2 16
The fate of hexamine in the conversion of 12 to 14 was studied in detail by Clarke and coworker^.^' The quaternary salt 16 (Eq. 4) is formed in the first step and undergoes cleavage by an internal redox reaction to give methyl formate and hexamine methochloride as the main decomposition products. According to
1. 1,3-Dihydro-l,4-Benzodiazepin-2(2H)-Ones
637
a Belgian patent,” hexamethylenetetramine can be replaced by dinitrosopentamet hylenetetramine to prepare 1-substituted benzodiazepinones and bromazepam, 7-bromo-1,3-dihydro-5-(2-pyndyl)-1,4-beodiazepin-2(2~)-one. Phthalimide was also used to displace halogen from the haloacetamido compounds (12) (see Section 1.1.1.2). Displacing the leaving group in 12 (X = I or sulfonyloxy) by hydroxylamine led to the hydroxyamine 19, which was cyclized preferably with acid catalysis to the nitrone 20 (Eq. 5).56-s8
OJHOH
R2
19
(5)
I
According to the patent literat~re,~’ the 3-acetamino derivative 22 was obtained by ammonolysis of the chloride 21. In the first step, the chloride is displaced by ammonia in boiling methanol and the intermediate obtained was cyclized by refluxing in methylene chloride-acetic acid (Eq. 6). NHAc I
‘
CId f N -N H A c 1
Ph 21
Ph 22
The formation of the 3-chloronitrone 24 by reaction of the dichloroacetanilide 23 with hydroxylamine in methanol was patented as well (Eq. 7).60 In this case, displacement of a chloride by hydroxylamine is unlikely, and 24 is probably formed by intermediacy of the benzophenone oxime.
638
Dihydro- 1,4-Benzodiazepinones and Thiones
(7)
c1
c1
Ph 23
‘0
24
1.1.1.2. By Reaction with N-protected a-Amino Acids (2-Aminopheny1)carbonyl compounds were coupled with N-protected tlamino acids to give the anilides 25 and 26 (Eq. 8). Because of the weakly basic character of the aniline nitrogen, the formation of the amide bond requires strong activation of the carboxyl function of the amino acid, preferentially the acid chloride. High yield acylations were carried out on various 2-aminobenzophenones with 2-phthalimidoacetyl chloride.61-73The phthalimido group in 25 was removed by standard hydrazinolysis and the amine obtained, if required, was cyclized to the benzodiazepinone as mentioned above. In many cases the substituent R, could be introduced into 25 (R, = H) by a l k y l a t i ~ n . ~Reacl-~~ tion of 25 (R, = R, = H, R, = Ph, R, = 4-C1) with methyl isocyanate gave the corresponding urea 25 (R, = MeNHCO), which upon hydrazinolysis yielded the benzodiazepinone with loss of the methylaminocarbonyl
R2
11
R, 25
R* 26
1. 1,3-Dihydro-1,4-Benzodiazepin-2(2H)-Ones
639
The benzyloxycarbonyl moiety represents another widely used N-protecting group. N-Benzyloxycarbonyl amino acids were coupled with the anilines 11 by activation of the carboxyl group via mixed anhydrides, dicyclohexylcarbodiimA conveniide, or acid chlorides to form 26 (R, = PhCH,0).3~"*20~33~3g~40~7s~76 ent method for activation of the carboxyl group occurs in situ by the generation of the acid chloride by reacting the N-protected amino acid with phosphorus pentachloride at low temperature in methylene chloride or tetrahydrof ~ r a n . ~7 -' 7,9~ Ph osphorus pentachloride was successfully replaced by thionyl chloride." The benzyloxycarbonyl group was removed by hydrogenolysis or hydrogen bromide in acetic acid. The t-butoxycarbonyl protecting group was applied with equal success, in particular for the preparation of 3-substituted optically active benz o d i a z e p i n ~ n e s . ~In ~ ,this ~ case, dicyclohexylcarbodiimide served as a carboxyl activating reagent and hydrogen bromide in acetic acid was used for deprotection. The amines corresponding to 26 were thus obtained as the hydrobromide salts and were cyclized as previously mentioned after conversion to the free bases. In a rare instance, the methoxycarbonyl group served as a protecting group8' and was cleaved by hydrogen bromide in boiling ethyl acetate. An application of the trifluoroacetyl group for the same purpose was described more recently.83 N-Trifluoroacetylglycine was activated by conversion to the acid chloride and reacted with the aminobenzophenone to yield 26 (R, = CF,). Treatment with alkali at room temperature cleaved the trifluoroacetyl group to give the corresponding amine, which was cyclized in the usual manner. Compounds 26 (R, = H) could be selectively alkylated on the aniline nitrogen as shown by conversion of the benzyloxycarbonyl derivatives 26 (R, = H) to the corresponding compounds with R, = CH,0Me7' and with R, = CH,NHCOOEt.84 The activation and the protection of glycine are present simultaneously in the reagent, 2-isocyanatoacetyl chloride. The application of this reagent for the preparation of benzodiazepinones has been described in the patent l i t e r a t ~ r e . ~ , The intermediate isocyanate was converted to the benzodiazepine by stirring in solution. A variant of this procedure takes advantage of the Leuch's anhydride, the 1,3-oxazolidin-2,5-dione,which can be looked at as an internally protected and activated amino acid. The reaction of 27 with the aniline 11 was generally carried out in methylene chloride or ether, catalyzed by hydrogen chloride (Eq. 8). A wide variety of benzodiazepinones were claimed to be accessible in high yields by this m e t h ~ d . ~ ~The - * ~3-carboxylic acid ethyl ester 14 (R, = COOEt) was similarly obtained by reaction of the appropriate aminobenzophenone with 27 (R, = COOEt) and hydrogen chloride in methylene chloride followed by ring closure in boiling acetic acid.82 1.1.1.3. By Reaction with a-Amino Acid Esters A general synthesis of benzodiazepin-2-ones involves the condensation of the (2-aminopheny1)carbonyl compounds 11 with esters of amino acids. It is likely that in this case the amino group of the amino acid ester reacts first with the
640
Dihydro-1,4-Benzodiazepinonesand Thiones
carbonyl function of 11 to form the imine 9 (Eq. 2), which then cyclizes with elimination of the alcohol R,OH. This method was first reported by Walkergo and by Sternbach and coworkers.2 It was subsequently applied for the preparation of many analog^.^'-'^^ In a standard procedure, the hydrochloride salt of the amino acid ester was heated with the aminobenzophenone in pyridine. The salt of the amino acid ester was present in large excess, because it undergoes conversion to diketopiperazine under the reaction conditions applied. The yields were better for compounds with R, = H. The application of glycine ester attached to a polymer in the synthesis of benzodiazepin-2-ones was reported with yields of 30-60%.'03 The synthesis employing amino acid esters was considerably improved by facilitating the first step, the formation of the imine. This was achieved by using the imine 28 instead of the corresponding ketone and exchanging the amine of 28 with the amino acid ester. The acid-catalyzed ring closure of the product 29 to the benzodiazepin-2-one 14 proceeds in high yield (Eq. 9).
- R,OH
14
This method was used with particular success for the preparation of benzodiazepin-2-one-3-carboxylic acid esters 14 (R, = COOR) starting from the imines 28 (R = H). The imines were accessible by the reaction of the appropriate nitrile with a Grignard reagent R2MgX.'04-'06 In addition to the imine, substituted imines 28 with R = Me,'08 R = CH,CH20H,'09 and R = CH2CH2NH,'10 were also applied for this purpose.
1.1.1.4.By Reaction with a-Amino Acids The condensation of a (2-aminopheny1)carbonyl compound with an a-amino acid by elimination of two molecules of water constitutes the most formally direct synthesis of 1,4-benzodiazepin-2-ones. Reeder and Sternbach''" reported the formation of the anticipated benzodiazepinone by reaction of 2-amino5-chlorobenzophenone with glycine in boiling pyridine in the presence of hydrogen chloride. The yield of this reaction was improved considerably by carrying out the reaction in a refluxing mixture of pivalic acid and toluene and azeotropi-
1. 1,3-Dihydro-1,4-Benzodiazepin-2(2H)-Ones
641
cally removing water. Diazepam, 31, was thus obtained in about 60% yield from the benzophenone 30 (Eq. 10).'O8 Me
Go I
c1
4f Me
c1
-N
Ph 30
(10)
Ph 31
Other procedures resorted to in situ activation of glycine by using phosphosphorus trichloride,' l 3 or thionyl chloride.114 phorus oxychloride,' Another equivalent method employs the acid chloride hydrochloride of the amino acid.' '9'
I .I .2. By Oxidation of Indoles The oxidative cleavage of the 2,3-double bond in substituted indoles to form the acylated (2-aminopheny1)carbonyl compounds was also studied for the While the synthesis of the required preparation of 1,4-benzodiazepin-2-ones. indoles may be cumbersome, this method can be useful to obtain certain substituted benzodiazepinones which are difficult to prepare by other routes. The most commonly used oxidizing agents were chromium trioxide in acetic acid-water, hydrogen peroxide with ammonium molybdate, and ozone. As pointed out in Chapter V, for the chromic acid oxidation to proceed smoothly to the desired product, the indole has to be substituted at both the 2- and the 3-positions. Treatment of the indole 32 (R, = Me, R, = R, = H, R, = 5-C1) with chromium trioxide yielded exclusively isatin. l 6 When ozone in acetic acid was used, a low yield (6.5%) of the expected benzodiazepin-2-one was obtained.lI6 A great number of variously substituted 1,4-benzodiazepin-2-ones were prepared by this method.' l 6 - I 3 , Based on our experience with this procedure,lo8 the oxidation of the indole 32 (R, = Ph) with chromium trioxide leads to the carbonyl compound 13, which can cyclize in situ to the benzodiazepin-Zone 14 (Eq. 11). By keeping the amino group in 13 protonated by a strong acid, the cyclization was slowed down enough to allow the isolation of the salt of 13. Oxidation of the l-(2-phthalimidoacetyl)indoles 33 (R = H, Me) with chromium trioxide led to the benzophenones 35 (R, = H) and the corresponding acyl derivatives 35 (R, = Ac, CHO), which were converted to the benzodiazepinone 36 by hydrazinolysis. Ozonization of 33 gave the ozonides 34, which were transformed directly to 36 by hydrazinolysis or to the benzophenones 35 by heating in ethanol (Eq.12).131*'32In the case of the oxidation of
642
Dihydro- 1,4-Benzodiazepinones and Thiones
I
R2
R2
32
13
I 14
a 1-acylated indole, the lack of a substituent at the 2-position of the indole does not seem to be detrimental to the course of the reaction. According to the patent l i t e r a t ~ r e , 'this ~ ~ method was applied to the preparation of alkyl- and alkoxy-substituted 5-phenyl-1,4-benzodiazepin-2-ones. We were, on the other hand, not successful in using the chromic acid oxidation for the synthesis of 7-methoxy-substituted compounds.134The 7-amino derivatives 38 were obtained by oxidation of the phthalimido compounds 37, followed by cleavage of the protecting groups with hydrazine (Eq. 13).'33
R1
& - )$y Rl
NPhth
PhthN
2 INH,NH, . 00,
-N
H2N
R2
31
Ph
38
(13)
1. 1,3-Dihydro-1,4-Benzodiazepin-2(2H)-Ones
643
1.1.3. By Ring Expansion The 4-oxides of 1,3-dihydro-1,4-benzodiazepin-2(2H)-ones, 40,were obtained in good yields by reaction of the 2-chloromethylquinazolines 39 with hydroxide.91,93,97,'35-'37 Following Sternbach's discovery of the ring expansion of 39 by primary amines to give 2-amino-3H-1,4-benzodiazepines(see Chapter V, Section 2.2.1.1), a variety of other nucleophiles were found to effect the same type of reaction. In the present case of ring expansion with hydroxide, the same mechanism probably applies. The hydroxide ion is thought to attack the 2-position of the quinazoline, generating the anion 41, which can undergo ring opening to form the oxime anion 42. Intramolecular alkylation on nitrogen would then convert 42 to the benzodiazepinone 40 (Eq. 14).
39
io" R2
R2
41
42
The 1,2-dihydro-2-dichloromethylquinazoline-3-oxides 43 were also found to undergo the same reaction. It is likely that an initial elimination of hydrogen chloride from 43 would lead to the chloromethylquinazoline 39 (R, = H) (Eq. 15).'38-'41 This process was applied to the preparation of 3-fluor0-'~' and 3-chloro-' 39,143 substituted benzodiazepinones. Thus the respective 2dihaloquinazolines 39 (R, = F, C1) were reacted with hydroxide at 0-5°C to give the 3-halo derivatives 40 (R,= F, C1; R, = Ph; R, = 7-C1, NO,, CF,) (Eq. 14). "J
R2
43
644
Dihydro- 1,4-Benzodiazepinones and Thiones
Treatment of the 1,2-dihydro-2-hydroxyquinazoline44 with sodium hydride in tetrahydrofuran at 0°C was reported to result in a low yield ring expansion to the 3-fluoro compound 45 (Eq. 16).144
The tetrahydroquinolones 46 (R, = COOR) were transformed to the corresponding benzodiazepin-2-ones by heating in refl uxing toluene or benzene in the presence of acetic a ~ i d . ~ ~ ,Th ' e~ 3-carboxylates ~ - ' ~ ~ 47 (R, = COOR) are most likely formed by a reversible ring opening of 46 to the benzophenone 48, which can dehydrate to the benzodiazepine 47 (Eq. 17).It is possible for the aziridine 49 to be an intermediate, since this compound could also be converted to the benzodiazepine 47.39 When the quinolone 46 (R, = Me, R, = COOMe, X = H, Y = C1) was heated to reflux in 80% acetic acid for 20 hours, it rearranged and decarboxylated to form diazepam (31) dire~tly.'~'
48
49
1. 1,3-Dihydro-1,4-Benzodiazepin-2(2H)-Ones
645
1.1.4. By Ring Contraction The 1,2-benzoxazocines 51, which were formed by treatment of the synoximes 50 with base, were found to rearrange to the 3-hydroxybenzodiazepines 53 upon reaction with hydroxide or methoxide in methanol at room temperature (Eq. 18).148
The mechanism of this ring contraction was proposed to involve abstraction of a proton from the methylene group followed by cleavage of the N-0 bond to lead to the imine anion 52. This intermediate would then undergo ring closure as indicated to form the 3-hydroxybenzodiazepinone 53. A related ring contraction was reported for the 1,4,5-benzotriazocinium salts 55, which were obtained by intramolecular quaternization of the chloroacetamido hydrazones 54 (Eq. 19).149Treatment of the triazocinium salts 55 with methoxide in methanol resulted in a rearrangement to the 3-aminobenzodiazepinones 57 in high yield. Fusion of the hydrazones 54 at 190°C was accompanied by evolution of an unidentified gas, and the benzodiazepinone 58 was isolated from the tarry residue. The formation of the benzodiazepinone was explained by intermediacy of the diazepinium salt 56, a compound isolated from a slightly less vigorous fusion of 55.
1.I .5. By Oxidation
1,3-Dihydro-1,4-benzodiazepin-2(2H)-ones were prepared by the oxidation of less saturated benzodiazepines by means of a variety of oxidizing agents. The oxidation of the 4,5-bond in the tetrahydro-2-ones 59 to form 60 was achieved by the following methods: bromine and sodium h y d r o ~ i d e , ~ ~ chromium ,'~'
646
Dihydro-1,4-Benzodiazepinonesand Thiones
NaI/Me,CO 24 h, RT
X
\
Ph
Ph
R2
55
54
I
r'
R,
R1
Ph 57
Ph 58
trioxide," 5 2 selenium dioxide,"' silver oxide,' 5 1 potassium permanga5 3 dichlorodicyanobenzoquinone,' 5 4 and dimethyl sulfoxide in combinate,' nation with ultraviolet light (Eq.20).'55*'56 Ruthenium tetroxide,' 57,158 manganese dioxide, diethyl azodicarb ~ x y l a t e , and ' ~ ~ iodine in combination with lead t e t r a a ~ e t a t e ' ~ ~ ' "were ~ ' also used to oxidize the amine 59 to the imine 60.A Dutch patent'59 claims the preparation of diazepam in 40% yield by oxidation of the 4-formyl derivative 61 (R,= Me, R, = Ph; R, = formyl, X = 7-C1) with chromium trioxide in acetic acid. Another publication' 5 6 reported a 26% yield for this transformation. The carbonyl group at the 2-position was also introduced by oxidation of 2,3dihydro-lH-l,4-benzodiazepines62 (R, = H) with various oxidizing reagents. Thus, compounds 62 (R3 = H) were converted to the 2-ones 60 by means of ruthenium t e t r ~ x i d e , ~ 7 , * * 6 o chromium trioxide,28v 6 2 N-bromosuc' 9 '
'*'
'
'
''
1. 1,3-Dihydro-1,4-Benzodiazepin-2(2H)-Ones
6'
\
R2
62
J
647
R2
59
R2
63
cinimide in tetrahydrofuran, containing aqueous sodium bicarbonate soluti01-1,'~~ or with manganese d i 0 ~ i d e . l ~ ' The 2-ones were also obtained in high yield by oxidation of the 2-hydroxy Various 2-substituted 2,3-dihydro-lH-l,Cbenderivatives 62 (R, = zodiazepines 62 (R, = CH2X) were oxidized down to the 2-ones 60 by potassium permanganate' '' or by chromic acid.'67 Such oxidations were described for 62 with R, = CH,C1,'66-'68 CH20H,'66v168CH,0Me,16' piperidinomethyl,'68 and COOH.169 These reagents also cleaved the double bond in the 2-methylene benzodiazepines 63.' 34
1.I .6.By Elimination and Rearrangement Elimination of the moiety R,H from the 4-substituted compounds 61, constitutes another synthesis of the benzodiazepin-Zones 60. Eliminations of this type were successfully carried out with the 4-sulfonyl derivatives 61 (R3= MeSO,, 4-MeC6H,SO,), using strong base in a variety of solvents (Eq. 21).72J54,'70-'73 Aprotic solvents favored the abstraction of a proton from the 3-position and gave predominantly the 5H tautomers 64. The 5H tautomer appears to be the kinetic product and can be equilibrated to the thermodynamically more favored 3H compound 60 by treatment with strong base in a protic solvent such as ethoxide in ethan01.'~ By carrying out the elimination in
648
Dihydro- 1,4-Benzodiazepinones and Thiones
a protic solvent, the 3H tautomers were obtained directly as the major
product^.'^'
60
I
R2
64
The 4-acetoxy derivatives 61 (R, = AcO) underwent a similar transformation. Heating the 4-acetoxy compound with ethanol and potassium t-butoxide to reflux led to the 3H tautomer 60, while the use of diethylamine or triethylamine in boiling ethanol afforded the 5H tautomer 7 4 * 1" Elimination of water from the 4-hydroxy compounds 61 (R, = OH) was achieved by means of phenyl isocyanate in combination with a weak base such as pyridine or 1,4-dimethylpipera~ine.'~~ This method gave the 3H tautomers in 75-90% yield. Elimination of water was also observed with dicyclohexylcarbodiimide in pyridine, thionylchloride in chloroform, concentrated sulfuric acid' 7 7 and phosphorus oxychloride in pyridine at reflux. 14' Dicyclohexylcarbodiimide in boiling toluene also dehydrated the 4-hydroxy compound effi~iently.~' According to the patent literature,'77b reaction of the 5H tautomer 64 (R, = H, R, = Ph, X = 7-C1) with N-bromosuccinimide and subsequently with aqueous dimethylformamide gave a low yield of the 3-hydroxy-3H-1,4-benzodiazepine, oxazepam.
1.1.7. By Hydrolysis The benzodiazepin-2-ones 66 were frequently obtained by hydrolyses of the 3 H-1,4-benzodiazepines 65 bearing a leaving group at the 2-position (Eq. 22). The leaving groups X, which were easily displaced by hydroxide, include the N-nitrosomethylamino moiety,'78 an alkylthio and the a-methoxyiminonitromethyl residue.O' Other groups, X, were replaced by
649
1. 1,3-Dihydro-1,4-Benzodiazepin-2(2H)-Ones
hydroxide under acid catalysis such as the 2-amin0,'~~.''~N-acetylmethylamino,' 5 * 1 839184 h y d r a ~ i n o , ' ~ ~ *methylthio, '~~" 186b and alkoxy moieties. 18791
H Y
q
Y -N R
l
Y
'~
O
-NY
R
I
(22)
R2
R2
66
65
The 1-hydroxy compound 68 resulted from the acid hydrolysis of the 1-oxide 67 (Eq. 23).lE9Related solvolytic reactions leading to 2-ones were described by Fryer and coworker^.'^^ Treatment of the imidazolindiones 69 and 70 with liquid ammonia led to the 2-ones 71 with R = EtO and R = MeNHCOCONH, respectively (Eq. 24).
68
67
'GNMe
c1G
c1 Ph 69
c1 Ph 71
T
-N z Ph 70
E
t
Dihydro-1,4-Benzodiazepinonesand Thiones
650
1.1.8. Other Syntheses The 5-phenyl derivatives 58 (X = H, C1, NO,) were reported to be formed in moderate yields by reaction of the benzisoxazoles 72 with glycine ethyl ester The converhydrochloride 73 in 2-methylimidazole at 120-130°C (Eq. 25).74*191 sion of the benzisoxazole to the benzodiazepin-2-one involves a reduction step, and it is not apparent which ingredient in the reaction mixture serves as the reducing agent.
H
X
0
Ph
,N
X
(25)
Ph
73
12
58
The 1-chloroacetylisatins 74 (X = H, Br) reacted with ammonia or primary and secondary aliphatic amines in ethanol to give the chloroacetanilides 75 (Eq. 26). 9 2 These compounds were then converted to the benzodiazepine5-carboxamides by conventional procedures. Although further reaction of 75 with ammonia led to the ben~odiazepine,~~ better results were achieved by first displacing the chloride with iodide. Amination of the iodide with liquid ammonia gave the corresponding aminoacetanilides, which were then cyclized under acid catalysis. Heating the isatins 74 (X = H, C1) with hexamethylenetetramine in alcohol, led directly to the benzodiazepin-5-carboxylicacid esters 76. The intermediate acetanilides 75 (R = OR') were not isolated in this instance.'93
OJ
OJ'
Xm o%x%o 0 R
14
H
X
O
q 7 --N
J
15
O
1. 1,3-Dihydro-1,4-Benzodiazepin-2(2H)-Ones
65 1
Both the 5-carboxamides and the corresponding esters were subjected to further derivatization. Hydrogenolysis of the ally1 ester afforded the corresponding carboxylic acid, which was decarboxylated by heating in tetrahydrofuran to yield the parent compound.' 93 Other functional group transformations are discussed in Sections 1.2. The 4-acyl derivatives of benzodiazepin-2,5-dioneswere found to react with phenylmagnesium chloride at the 5-carbonyl group.'94 The benzophenone 78 (R = Me) was thus prepared in 86% yield from the 4-acetyl-2,5-dione 77 (R = Me) (Eq. 27). The transformation of 78 into diazepam, 31, was achieved by methanolysis or by treatment with hydroxylamine followed by hydrolysis of the oxime 79 with sodium bisulfite in aqueous ethanol at reflux temperature. The 4-trifluoroacetyl derivative 77 (R = CF,) was converted to diazepam, 31, in 30% yield by reaction with phenylmagnesium chloride followed by acid Me I
Me
0
PhMgCl
c1 Ph 78 71
I
I
NHIOH
I PhMgCI
2 H,O'
Me I
NaHSO,/ FtOH/H,O
c1
OH
Ph Ph
19
31
1,3-Dihydro-1,4-benzodiazepin-2(2H)-ones, bearing a heteroatom attached at the 5-position, were synthesized from the 2,5-diones 80. The 5-alkoxy derivatives 81 (R, # H) were obtained by reaction of the 2,5-diones with triethyloxonium tetrafluoroborate in methylene chloride at room temperature or by displacement of the 5-chloride in 82 by alkoxides (Eq. 28).'95*'96 The iminochloride 82 resulted from the treatment of the 2,5-dione 80 with phosphorus pentachloride in carbon tetrachloride and chloroform at re flu^.'^^"^^ This chlorine atom (82) was also readily displaced by a variety of primary and secondary amines and phenyl thiol to give 83.'96 The reaction of 82 with hydrazine derivative^'^'^'^^ is discussed below (Section 1.2.2.3).
652
Dihydro- 1,4-Benzodiazepinonesand Thiones
I
1
c1 82
R3 83
Bell and obtained the 3-acetamino derivative 87 (R = Ac) by treatment of the N-acetoxyacetamide 84 with ammonia. The authors proposed the following mechanism: elimination of acetic acid from 84 would lead to the N-acetylimine 85, which could then add ammonia to give intermediate 86. Cyclization with dehydration would lead to the observed product 87 (Eq. 29). Methanolic hydrogen chloride at room temperature cleaved the acetyl group in 87 to give the 3-amino derivative. This method was later applied for the preparation of several 3-amino-l,3-dihydro- 1,4-benzodiazepin-2(2H)-ones.202 A related transformation was reported in the patent literat~re."~Reaction of the hydroxylamine 88 with ethyl chloroformate gave the N,O-diacylated compound 89, which was converted to the carbamate 87 (R = COOEt) by treatment with ammonia. Compound 89 was also formed from the nitrone 90 by treatment with ethyl chloroformate. The oxazolidine 91 was considered to be a likely intermediate in the conversion of 90 to 89. The hydroxylamine 88 could be prepared by reducing the nitroacetanilide 92 (Rl, R, = H) with zinc and acetic acid (Eq. 30).'04 Cyclization of the hydroxylamine 88 to the nitrone was carried out by acid catalysis such as treatment with ethanolic hydrogen chloride. When the nitroacetanilide 92 (R, = Me, R, = H) was subjected to zinc-acetic acid reduction, diazepam was i s ~ l a t e d . ~It~ is " likely that in this case the nitrone 93 was formed during the reduction and was further reduced to the imine 95 (R, = Me, R, = H) by excess reagent. Reduction of the nitro derivative 92 (R, = Me, R, = COOEt) or the oxime 94 with zinc and acetic acid followed by treatment with acetic acid in boiling benzene gave the 3-carboxylates 95 (R, = Me, R, = COOEt) in moderate
1. 1,3-Dihydro-1,4-Benzodiazepin-2(2H)-Ones AC
I
o,-oAc - HOAc
___)
c1 Ph 84
COOEt I
I
c1
-
I
0 II ClCOEt
c1
Ph 88
Ph 90
Ph byOEt
653
654
Dihydro- 1,4-Benzodiazepinonesand Thiones
I
92 Ph
Y
O
A
c
\
I.;
&,eoEt R1
Me
NOH
____) 2. 1 Zn/HOAc HOAc/A
0
c1
C1
Ph
Ph
95
94
yields.39 The nitrone 93 (Rl, R, = H) also resulted from the treatment of the diacylated hydroxylamine 84 with ethanolic hydrogen ~ h l o r i d e . ~ ~ ~ ~ ~ ~ A synthesis of the 3-hydroxy-4-oxide, 97, was reported in the patent litera96 was ring closed either by treatment t ~ r e .The ~ 2,2-diacetoxyacetanilide ~ ~ * ~ ~ ~ with trifluoroacetic acid (Eq. 31) or by reacting 96 with hydroxide to form the corresponding 2,2-dihydroxy derivative and subjecting this intermediate to trifluoroacetic acid or triethoxythallium. The nitrone 97 was converted to the 3-chloro derivative 98 by means of phosphorus trichloride. Reductive ring
O y E A ,
H
Ph
Ph
i//
/
96
qL H
-N
C1
Ph 98
O
97
O
.
1. 1,3-Dihydro-1,4-Benzodiazepin-2(2H)-Ones
655
closure of the oxime 96 using palladium on carbon in the presence of trifluoroacetic acid was claimed to give the 3-hydroxy benzodiazepine 97 (4-desoxy). A synthesis of nitrazepam (101) involves the reaction of the imino ether 99 (X = Br, I) with liquid ammonia, which leads to the glycine ester imine 100 (Eq. 32).208The latter was then cyclized to 101 by treatment with strong base such as methoxide or by heating with 2-methylimidazole at 140°C. In the case of the iodide 99 (X = I), the reaction with liquid ammonia also yielded nitrazepam directly.
Ph
Ph
99
100
(32)
Ph 101
Diazepam was prepared by reacting the imine 102 (R = Me, X = C1) with bromoacetyl bromide in a two-phase system of benzene and aqueous hydroxide (Eq. 33).209Reaction of the imine 102 with 2-bromo-2-fluoroacetyl chloride or 2-chloro-2-fluoroacetyl chloride and sodium hydride in tetrahydrofuran or
Ph
R2
I02
14
t
PhMgBr
b
cI*.l.:'j Ph
104
(33)
Dihydro- 1,4-Benzodiazepinones and Thiones
656
dimethylformarnide yielded similarly the 3-fluorodiazepam. Nitrazepam was obtained by reacting the urea 102 (R = MeNHCO, X = NO,) with bromoacetyl bromide and potassium carbonate in dimethylformamide at 60-65"C.74 Bergman and coworkers210~21 reported the syntheses of the benzodiazepines 14 (Rl, R, = H; R, = Ph; R, = H, Ph) by reacting the nitriles 103 (X = C1; R, = H, Ph) with phenylmagnesium bromide. The imine anion 104 is believed to be the intermediate leading to the benzodiazepines and the quinazoline by-products. Diazepam (31), was obtained in high yield by heating the hydrazone 105 in acetic acid (Eq. 34).,12 Compound 105 was prepared in several steps; first, the benzyloxycarbonylhydrazone of the corresponding benzophenone was formed. This was then reacted with 2-phthalimidoacetyl chloride. Sequential cleavage of the protecting groups by hydrogenolysis and hydrazinolysis afforded 105. Me
Me
1
.q T
1 0
HOAc
c1
c1
(34)
-N
Ph
Ph
105
31
The imidazolidines 106 were converted to the benzodiazepines 107 by heating to reflux in ethanolic hydrogen chloride (Eq. 35).,13 Compounds 106 resulted from the hexarnethylenetetramine process as discussed in Section 1.1.1.1.
a;NH Qj-$
c1
* c1
,N
E I 0H/ HC 1
R
R
106
107
(35)
A Hoffmann degradation was used for the preparation of the 1,3-dimethyl derivative 109. Thus, bromine and sodium hydroxide converted the amide 108 to the benzodiazepine 109 (Eq. 36).,14
Ph 108
Ph 109
657
1. 1,3-Dihydro-1,4-Benzodiazepin-2(2H)-Ones
The oxaziridines 110 were rearranged to the 3-hydroxy or 3-alkoxy derivatives 111 (R = OH, alkoxy) in the presence of ferrous sulfate in water or in alcohol, respectively (Eq. 37).’15 Reaction of 110 (R = Me) with ethylamine in tetrahydrofuran at room temperature yielded 12% of the 3-ethylamino derivative 111 (R, = EtNH).’lsb The rearrangement of the oxaziridine to the nitrone, thermally or by acid catalysis, was described earlier.216-2’8 A reductive transformation of the oxaziridines 110 (R = H, Me) to the corresponding imines was achieved with hydrogen iodide or with hydr~xylamine.’~~ Me
R
I
c1
R=Me
c1q
-NR
f
z
(37)
Ph 111
110
The tetracyclic compounds 112, which resulted from the treatment of the bromoacetanilide with ammonia in methanol, were reacted with methanolic hydrogen chloride to give the benzodiazepines 113 (Eq. 38).’23 Me
.‘_I\
112
Me
0 COMe 113
Migration of methyl from oxygen to nitrogen occurred when 2-methoxy3H-1,4-benzodiazepine 114 was heated to 24&260”C, leading to the formation of 31 (Eq. 39).’19 According to a Dutch patent,’” a synthesis of diazepam, 31, was achieved in moderate yields by condensation of the chloroacetanilide 115 with benzonitrile in titanium tetrachloride at 186188°C. While a similar process involving nitrilium ions worked for the synthesis of l-methyl-2,3-dihydro-lH-1,4-benzodiazepines (see Chapter VI), we were not able to prepare 2-ones such as diazepam by this method.’08 Dealkylation of the tetracyclic derivatives 116 (n = 2, 3) was reported’” to occur by the use of acetic anhydride in combination with sodium acetate or boron trifluoride, leading to diazepam, 31.
Dihydro-1,4-Benzodiazepinonesand Thiones
658
Me
OMe
c1
-N Ph
Ph
114 Ac,O/NaOAc or Ac,OlBF,
186-188°C
(39)
Me
I
Ph-CZN 115
1.2. Reactions of 1,3-Dihydro-1,4-benzodiazepin-2(2H)-ones
1.2.1. Reaction with Electrophiles 1.2.1.1. Halogenation Reaction of the 5-substituted benzodiazepin-2(2H)-ones 117 (R2# H) with hypochlorite led to the I-chloro compounds 118, which, in many instances, were By heating in a solvent in the stable enough to be characterized (Eq. 40).222-224
c1
1. 1,3-Dihydro-1,4-Benzodiazepin-2(2H)-Ones
659
presence of a radical initiator, the 1-chloro derivatives rearranged to the 3chloro analogs 119.When R,, in 119,represented an alkyl or cycloalkyl residue, the chlorine migrated further onto this group to form 120.222~224 Chlorination of 117 (R, = Ph, 2-pyridyl) with N-chlorosuccinimide in benzene in the presence of azodiisobutyronitrile afforded the 3-chloro derivatives 119 directly.225 Reaction of the 3-cyano analog 95 (R,= Me, R, = CN) with N-chlorosuccinimide was reported to lead to the 3-chlorinated product 121 (X = C1) (Eq. 41).”, This compound was not properly characterized but converted to the 3-methoxy analog 121 (X = MeO). The bromination of the 3-carboxylic acid ethyl ester 95 (R,= H, R, = COOEt), by treatment with bromine in methylene chloride at room temperature in the presence of benzoyl peroxide, similarly afforded the 3-bromo derivative, which was converted in situ to the 3-hydroxy and 3-methoxy analogs.’ 1 * 2 2 7 Fluorination at the 3-position was achieved by reacting the 3-carbanion, generated with lithium diisopropylamide or potassium t-butoxide, with perchloroyl fluoride or trifluoromethoxy fluoride.228
Ph 95
Ph 121
Chlorinations at the 7-position were described for 117 (R,= H, R, = Ph) by using a combination of chlorine, ferric chloride and nitrobenzene,’ and, under similar conditions, for 117 (R, = AcO, R, = Ph).”’ 7-Nitro compounds 122 (R,= R, = Me; R, = 2-C1C,H4, 2-FC6H,; Y = NO,) were chlorinated at the 9-position by treatment with chlorine in 1,2-dichloroethane in the presence of formic acid and hydrogen chloride to give 123 (X = C1) (Eq. 42).’,O These conditions also allowed the introduction of a chlorine into the 9-position of 122 (R,, R, = H; R, = 2-C1C,H4; Y = Cl).134 Bromination at the 9-position was similarly carried out with N-bromosuccinimide in a mixture of formic acid and hydrochloric acid.’”
R3 123
660
Dihydro- 1,4-Benzodiazepinonesand Thiones
Halogenations of the 7-amino derivatives 124 (R, = Me; R, = H, Me, Et; R, = H, Me; R, = 2-C1C,H4, 2-FC6H,; Y = H) were carried through by reactions with chlorine in hydrochloric acid or with bromine in acetic acid to give The 6,B-dichloro dethe corresponding 6-halogenated analogs (Eq. 43).230*231 rivatives 125 (X = C1) were a result of the chlorination of the 7-amino compounds 124 (Y = H) with N-chlorosuccinimide at room temperature,80s230 while the 6,g-dibromo analogs 125 (X = Br) were prepared similarly with N-bromosuccinimide in methylene chloride.230 Further treatment of the 7-amino-9-chloro compounds 124 (Y = C1) with N-chlorosuccinimide afforded the 6,8,9-trichloro compound 125 (X = Y = C1) along with the dichloro compounds 126 and 127.230
127
126
1.2.1.2. Oxidation Oxidations by peracids have been widely used to convert benzodiazepin~ ~ ~ ~ ~ ~ 2(2H)-ones to the corresponding 4 - o ~ i d e s . ~ ~ C~om,pounds with dialkylaminoalkyl residues attached at the 1-position were oxidized with m-chloroperbenzoic acid at the nitrogen in the side chain first and then at the 4 - p 0 s i t i o n . ~ ~Similarly, ~ * ~ ~ ~ l-methylthioalkyl derivatives were oxidized by peracetic or m-chloroperbenzoic acid to the sulfoxides, to the sulfones and then further to the 4-oxides of the ~ u l f o n e s .Hydrogen ~ ~ * ~ ~ peroxide ~ converted the 7-methylthio derivatives to the corresponding s u l f ~ x i d e s . ~ * ~ ~ Reaction of the benzodiazepines 128 (R, = H, Me; R, = H, OH; X = H, C1, F) with ruthenium tetroxide afforded the 3-ones 129 in approximately 50% yield (Eq. 44).'57*'58
1. 1,3-Dihydro-1,4-Benzodiazepin-2(2H)-Ones
66 1
I30
The major metabolic pathway of benzodiazepin-Zones has been shown to involve hydroxylation at the 3-position. The microsomal oxidation of the racemic 128 (Rl,R, = Me; X = H) was investigated and reportedz4’ to yield 5% of the 3-hydroxy derivative 130 (R, = R, = Me; X = H). Microbiological oxidation of a variety of 1-methyl- and 1-cyclopropylmethyl-substitutedbenzodiazepin-Zones led to optically active 3-hydroxy compounds with partial loss of the substituent at the l - p o ~ i t i o n . ’The ~ ~ 3-carboxylic acid esters 128 (R, = H, Me, MeOCH,; R, = COOR) were found to be readily oxidized by molecular oxygen in the presence of a strong base.242This reaction most likely proceeds via the 3-hydroperoxide, which may undergo reductive cleavage to the product. The 3-phosphonates 128 (R, = Me, R, = (EtO),OP or (MeO),OP, X = C1) underwent a similar type of oxidation when treated with sodium hydride and oxygen.243The corresponding 3-one 129 was thus obtained in 21% yield. The analog lacking the 1-methyl substituent could be prepared by avoiding an acid workup. The intermediate anion of 129 (R, = H) was reacted with trimethylsilyl chloride and the silylated amide was hydrolyzed under neutral conditions to give the 3-one 129 (R, = H, X = C1) in 43% yield. Ceric ammonium nitrate was described as a suitable reagent for the transformation of the 7-ethyl derivative 131 into the 7-acetyl analog 132 (Eq. 45).244 The olefinic side chain attached to the 1-position of 133 (R = H, AcOCH,) and also the 4-oxides thereof were converted to the corresponding diols 134 (R = H, HOCH,) by means of potassium permanganate (Eq. 46).237
Dihydro- 1,4-Benzodiazepinones and Thiones
662
132
131
133
134
Oxidation of the 7-hydroxyaminobenzodiazepinones 135 (R, = Me, MeOCH,) with manganese dioxide afforded the 7-nitroso derivatives 136 (Eq. 47).245,247If th’is oxidation is allowed to proceed slowly, the nitroso compound condenses with the hydroxyamine to yield the azoxy compound 137.245
MnO,
HON H
O=N
d--N
Ph
Ph 135
136
0,Me
I
Ph
,OMe
0 137
Ph
(47)
1. 1,3-Dihydro-1,4-Benzodiazepin-2(2H)-Ones
663
The aminophenol 138 was oxidized with Fremy's salt to yield the aminoquinone 139 (Eq. 48).245
XTe
cote
q+S Frcmy's
HZN
,N Ph
HO
salt
-N Ph
HZN
0
(48)
139
138
A U S . patent 248 outlines the preparation of a mixture of 5-(trifluoromethoxy)phenyl-substituted compounds 140 by treatment of 36 with trifluoromethoxy fluoride at - 78°C in hydrogen fluoride in the presence of light (Eq. 49).
&f
c1
,N
H
O
F,COF/HF hv
(49)
c1
Ph 36
&0CF3 140
1.2.1.3. Reactions with Nitrogen Electrophiles A. Nitrosation. 3-Aminobenzodiazepin-2-ones were nitrosated in aqueous medium to give the 3-hydroxy derivative^.'^^^^^^^^^^ If the nitrosation was carried out in acetic acid, the 3-acetoxy benzodiazepin-Zone was obtained.' 99 Reaction of the 3-hydrazino compound with nitrous acid and subsequent treatment with hydroxide also led to the 3-hydroxybenzodiazepin-2-one,most likely by intermediacy of the 3-azido analog.z49Nitrosation of the l-aminobenzodiazepin-Zone was reported to cause deamination, leading to the corresponding l a ~ t a m Several . ~ ~ ~ 7-amino-substituted compounds were converted to the diazonium salts, which were isolated in some instances as tetrafluoroborate salts.z51Reactions of diazonium salts in sit^'^^*^^^^^^^ are further discussed in Section 1.2.2.
B. Nitration. Reaction of 7-unsubstituted benzodiazepin-2-ones 141 (X= H) with potassium nitrate in concentrated sulfuric acid at &5"C led to the 7-nitro derivatives 142 (Eq. 50). Such nitrations were carried out with compounds 141 as follows:
664
Dihydro-1,4-Benzodiazepinonesand Thiones
Rl
R,
R3
Refs.
H H
H H
Ph 2-ClC6H4, 4-ClC6H4, 2-FC6H4, 2-OzNC6H4 2-F3CC6H4 Cyclohexyl Ph 2-Pyridyl, 4-Pyridyl 2-Thien yl Ph
136,254,255
H F,CCH, H
H H H
H H
H COOEt
136 6 94 69
3, 22 22 104, 107
In the 5-(2-thienyl) case,” the location of the nitro group introduced was not firmly established, and the possibility of primary nitration of the thienyl moiety is not ruled out. An 8-methyl-substituted compound was nitrated under these conditions at the 7 - p o ~ i t i o n . ’ ~ ~ Under slightly more vigorous nitration conditions (i.e., potassium nitrate in concentrated sulfuric acid at room temperature), 7-nitro- and 7-halo-substituted benzodiazepin-Zones were nitrated in the meta position of the 5-phenyl g r o ~ p . ~ ’ .When ~ ’ ~ the 5-phenyl ring was substituted by a halogen (C1 or F) in the ortho position, nitration was directed to the para position relative to this Further nitration halogen to give 2’-halo-5’-nitro derivatives 144.134~1s2~2s7-259 of 141 (X = C1, R, = R, = H,R3 = 3-OzNC6H4) occurred at the 9-position, leading to 143.15’ In the absence of a strong acid, the imine is not protonated and the nitronium ion attacks the 4-position nitrogen. Thus treatment of the 1-substituted benzodiazepin-2-ones 145 (R = Me, C1; X = C1, NO,) with fuming nitric acid in acetic anhydride yielded the addition products 146 (Eq. 51).260 While the 1-unsubstituted 7-nitro compound underwent the same addition reaction, the corresponding 7-chloro analog 145 (X = C1, R = H) did not. The reason for this divergent reactivity is not clear.
1. 1,3-Dihydro-1,4-Benzodiazepin-2(2H)-Ones
665
c1
143
144
(50)
&R,
HNO,/Ac,O
X
-N
Ph I45
____)
X AcO
Ph
I46
C. Reaction with Other Nitrogen Electrophiles. Aminations of benzoe~~~ diazepin-Zones in the 1-position were carried out by means of c h l ~ r a m i n or 0-(2,4-dinitrophenyl)hydro~ylamine.~~~ The benzodiazepinone was first deprotonated by a strong base to form the anion at the 1-position, which was then reacted with the electrophilic amine. The 4-hydroxy derivative 147 was coupled with the diazonium salt 148 to afford the azo compound 149 (Eq. 52).8
OH 147
1.2.1.4. Reactions with Carbon Electrophiles A. Alkylation. A great variety of 1-substituted 1,4-benzodiazepin-2-ones151 have been prepared by alkylation of the lactams 150. Generally, the proton at the 1-position is abstracted by a base to form the anion, which is reacted with the alkylating agent.
Dihydro-1,4-Benzodiazepinonesand Thiones
666
Methylations at the 1-position were carried out in several ways: with ~~~*~~~ dimethyl sulfate in aqueous sodium h y d r o ~ i d e , ~ ~ , ’in~ ~a stwophase system of methylene chloride and sodium hydroxide,’, with sodium methoxide as base in methan01,’~’ in benzene,” in toluene,2*’6and in dioxane.’ Using methyl iodide as the alkylating reagent, the following base-solvent combinations were applied: sodium methoxide in dimethylin methanol,” in a mixture of methanol and dimethylformamide,’ with potassium hydroxide in tetrahydr~furan,~~’ with potassium t-butoxide in dimethylf~rmamide,~~.’~~ and in tetrahydrofuran,,, ~ ~t~e~t ~r ~a *h ~y’d r o f ~ r a n , ~ ~ ~ , ~ ~ ’ with sodium hydride in d i r n e t h y l f ~ r m a r n i d e , ~in and in a mixture of dimethylformamide, l,Zdimethoxyethane, and 2m e t h ~ x y e t h a n o l with ; ~ ~ sodium amide in a mixture of dimethylformamide and tetrahydrofuran,’62 with solid potassium carbonate in acetone,62~80~230~231.251 The last combination was and barium oxide in dimethylf~rmamide.~~’~~*’~~ especially useful for methylation without racemization of 3-substituted optically active compounds. The use of phenyllithium as base has been described in the patent literature.268Radiolabeled methyl iodide was reacted with 150 (R, = H, R, = Ph, R, = 7-C1) and 150 (R, = H, R, = 2-FC6H,, R, = 7-0,N) in acetone and sodium hydroxide to give the corresponding 1-methyl analogs with a carbon-1 1 label.,,’ Other methylations occurred by treatment with trimethylsulfonium iodide or trimethylsulfoxonium iodide in dimethyl sulfoxide in the presence of sodium hydride or b~tyllithium.~’~ Diazomethane was reported to methylate both the 1-position nitrogen’’ and the 2-position oxygen yielding the 2-methoxy-3H- 1,Cbenzodiazepines 153 (Eq. 53).2713272
R4 R3
150
R3 151
I
base R , X
(53)
R3
R3
152
153
1. 1,3-Dihydro-1,4-Benzodiazepin-2(2H)-Ones
667
Higher, branched and unbranched alkyl groups were introduced into the Similarly, reaction of the anion 1-position in the same fashion.z~'8~91~'35~'36.251 of 150 with ally1 and propargyl halides afforded compounds with an unsaturC ompounds bearing an ated alkyl residue at the l-position.2~'8~91~'3s~z73~z7s alkyl group with an aromatic or aliphatic ring were also accessible by this procedure. Examples are l-benzylZT9l and 1-(cyclopropy1)methyl derivatives.268.276
The high reactivity of the 1-chloro-1-alkoxyalkyl derivatives (a-chloro ethers) allows the easy preparation of a number of 1-substituted benzodiazepin-2-ones by alkylation. The anions of 150 were again generated with methoxide in dimethylf~rmamide~~.~~~~~~~ or with sodium hydride in t e t r a h y d r ~ f u r a n ~ lor .~' in dimethylf~rmarnide.~~~ The use of such a-chlorothioethers as chloromethylmethylsulfide led in analogy to 1-methylthiomethyl derivatives 151 (R, = MeSCH,).72,'34 A large number of differently functionalized alkyl moieties were attached to the 1-position nitrogen of 150 in a similar manner. Such alkylations were carried out with the following reagents: 2-alkoxyethyl ~ h l o r i d e s , ~ ~ ~ 2-alkoxyethyl sulfates,28' 2-acetoxyethyl bromide,236 l-chloro-2,3-diacetoxypropane,236 l-brom0-2,3,4-triacetoxybutane,~~~ 2-brornoethan0l,~~~*~~~* 3-bromopropan01,~~~ l-chloro-2-hydroxy-3-methoxypropane,z8s 2-methylthioethyl ~ h l o r i d e ' ~and ~ , ~the ~ ~ corresponding sulfoxide,86c*286alkyl halides functionalized with amino group^.'^,^^,' 50,238,254,268,287,288 3-chlorol-(4-chlorobut-l-yl)-4-(4-fluorobenzoyl)piperidine,z9o l-ethylpiperidine,289 l-benzyloxycarbonylamino-2-bromoethane,233 and 1-chloromethyl pyrrolidin2 - 0 n e . I ~Other ~ alkylations at the 1-position were described for compounds having two halogens of different reactivity. Thus a 2,2,2-trifluoroethyl group was introduced by reaction of l,l,l-trifluoro-2-iodoethanewith the anion generated by sodium methoxide in dimethylf~rmamide.~~ Reaction of the anion with 1-bromo-3-chloropropane yielded the 1-(3-~hloropropyl)derivative 151 (R, = C1(CH,),).291 The higher reactivity of the chloride in the 1-position of 1,2-dichloro-l-methoxyethanefacilitated the synthesis of 151 (R, = 2-chloro1-methoxyeth-1-yl; R, = H, COOEt; R, = Ph; R, = 7-C1, NO,).72*278 Compounds with a (2-chloroethoxy)methyl group in the 1-position were also a c c e ~ s i b l eAlkylation .~~ reactions were also successful with a - h a l o k e t o n e ~ , ~ ~ * ~ ~ ~ a - h a l o e s t e r ~ and , ~ ~a-halocarboxamide~.~~~ ~~~~ Longer chain fatty acids were introduced by reaction of the anion of 150 with w-haloalkanoic acids or esters thereof.294Examples of alkylations with 2-bromobut-2-enoic acid methyl ester (trans isomer) were also reported.294A butyrophenone side chain was similarly attached to the 1-position of 150 (R, = H; R, = Ph, 2-FC6H,; R, = 7-C1) in the form of its 1,3-dioxolane derivative followed by hydrolytic liberation of the carbonyl group to yield the corresponding benzodiazepines 151 [R, = 3have not (4-fluorobenzoyl)prop-l - ~ l ] Benzodiazepin-2-one-1-acetaldehydes . ~ ~ ~ been described, but the dimethyl acetal 150 (R, = 2,2-dimethoxy-l-ethyl, R, = H, R, = Ph, R, = 7-C1) was obtained by alkylation of the appropriate anion 150 with l-brom0-2,2-dirnethoxyethane.~~~
668
Dihydro-1,4-Benzodiazepinonesand Thiones
Phosphorus-containing alkyl residues were attached to the amide nitrogen by means of chloroalkyl dialkylphosphine oxides to give 151 [R, = (R,),PO(CH,), where x = 1,2, 3 and R, = Me, Et, Pr].25 Another type of alkylation reaction at the 1-position is a Michael addition of the anion to acrylonitrile, leading to 151 (R, = NCCH,CH,; R, = H, OH; R, = Ph, 2When R, = OH, a selective reaction FC,H,, 2-CIC6H,; R, = 7-C1, at the 1-position occurred with benzyltriethyl ammonium hydroxide as a base.280 Other examples of addition reactions include the addition of ethylvinyl ether to 150 (R2 = H,R, = Ph, R, = 7-NOJ by heating in acetic acid” and addition of enamides generated in situ from N-tosyloxycarbamates and trieth~lamine.’~ If the benzodiazepine 150 is treated with 2 equivalents of a strong base in an aprotic solvent, a 1,3-dianion is generated. Reactions of the 1,3-dianion with alkylating agents have resulted in the formation of 1,3-disubstituted derivatives 152. I-Substituted compounds were similarly deprotonated at the 3-position and reacted with carbon electrophiles. Thus the 4-oxide of diazepam was alkylated at the 3-position with methyl iodide and benzyl chloride in dimethylformamide at low temperatures, using potassium t-butoxide for deprotonation, to yield the 3-methyl and the 3-benzyl derivatives, re~pectively.’~~ The same method was applied to introduce 3-ally1 s u b ~ t i t u e n t s ~onto ~ ’ this compound and the 5-methyl analog as well as to methylate the 1-methoxymethyl derivative 151 (R, = MeOCH,; R, = H, R, = Ph; R, = 7-C1, 4-oxide) at the 3-posit i ~ n . ’The ~ ~ 3-carbanion of diazepam was generated with lithium diisopropyl amide in tetrahydrofuran at - 60°C and subsequently reacted with alkyl iodides and benzyl chlorides.299 Double alkylations at the 3-position were observed with butyl iodide and propyl iodide, while the 3,3-dimethyl compound was not formed under the same conditions.299 Methylation of the 3-cyano compound 151 (R, = Me, R, = CN, R, = Ph, R, = 7-C1) was reported to yield the 3-methyl derivative.226This reaction was carried out with methyl iodide and potassium carbonate in dimethyl sulfoxide. Reaction of the 4-oxide of diazepam, 154,with 1,4-dibromobutane was found to give the spiro compound 155 (Eq. 54).13, Base-catalyzed addition of methyl acrylate to 154 yielded the 3-substituted derivative 156.298 The nitrogen in the 4-position of 1,3-dihydro-l,4-benzodiazepin-2(2H)-ones 151 is weakly basic ( ~ K ~ z 2 . 8and ) forms quaternary salts with reactive alkyl halides or sulfates. The quaternary salts described in the literature are listed as salts of the parent base in Tables VII.l. Quaternizations with methyl iodide34*35,”9and dimethyl were most common (Eq. 55). Benzodiazepin-2-ones with amino groups in side chains attached at the 1- or 3-position were also converted to quaternary ammonium salts. Thus, basic esters of structure 158 were reacted with methyl bromide in benzene at room temperature to give the ammonium salts 159 (Eq. 56).’47,301This reagent was also used to quaternize the 7-dimethylamino group of 151 (R, = Me, R, = H,
1. 1,3-Dihydro- 1,4-Benzodiazepin-2(2H)-Ones
669
155
I54
l o
base " , C q o M e
Me
c1 Ph
'0
156
R,
158
5" 159
R, = Ph, R, = 7-Me,N).95 A 3-diethylamino derivative was also converted to its quaternary salt by reaction with methyl bromide.302 Functional groups in various positions have been subjected to alkylation reactions. For example, 1-(2-hydroxyethyl) derivatives were reacted with ethyl bromoacetate,150c-150d 1-(2-methylaminoethyl) analogs were alkylated on nitrogen with this same reagent and with N-methyl bromoacetamide,150c~dand were reacted with acrylonitrile to yield the 3-hydroxy- 1,4-benzodiazepin-2-ones
Dihydro-1,4-Benzodiazepinonesand Thiones
670
corresponding 3-(2-cyanoethoxy) derivatives.280 Diazomethane was used to methylate the 1-hydroxy compound 68IE9and to convert the N-hydroxyamide 160 (R = F,CO) into the methoxy amide 161 (R = F,CO).245 The 7-hydroxyamino group in 160 (R = H) was also N,O-dimethylated by means of methyl iodide and potassium t-butoxide in dimethylf~rmamide.~~’ This combination was likewise applied to convert 160 (R = Ac) into 161 (R = Ac) (Eq. 57).245
rote
Qf+-J
R-N I OH
rote
CH2N, or
base/Mel
Ph
RN
q 7 --N
(57)
I
OMe
160
Ph 161
Chloromethylmethyl ether was reacted with the hydroxy group of 151 (R, = Et, R, = H, R, = 2-FC6H,, R, = 7-(l-hydroxyethyl)) using N,N-dimethyl aniline as an acid acceptor to give the corresponding 74 1methoxy-1-ethyl) deri~ative.’~’Reaction of a 7-aminobenzodiazepine with chloromethylmethylsulfide afforded the 7-methylthiomethylamino derivative.’,, Reductive methylations of the 7-nitro derivatives, by a reaction with formaldehyde, Raney nickel, and hydrogen, led to the 7-dimethylamino anal o g ~ .Introduction ~ ~ , ~ ~of ~aryl substituents into the l-position was possible by a modified Ullmann reaction. The lactams 162 (R = Me, Et; X = C1, F,C) were reacted with aryl bromides in dimethylacetamide at 140°C in the presence of copper powder and potassium acetate (Eq. 58).19 Ar ArBr,Cu
(58)
KOAc
R 162
R 163
2,CDinitrobenzene was reported to react with diazepam and tetramethylammonium hydroxide to form a blue adduct to which structure 164 was assigned on the basis of spectral data (Eq. 59).,03
31
164
1. 1,3-Dihydro-1,4-Benzodiazepin-2(2H)-Ones
67 1
1,4-Benzodiazepin-2-ones, which bear at the 1-position a side chain containing a leaving group, underwent intramolecular alkylation on oxygen, affording 166. The chlorides 165 (R, = H, MeO; R, = H, COOEt; X = C1, I) were treated with sodium hydride in dimethylformamide at 0-10°C (Eq. 60). The products, in particular 166 (R, = H), are sensitive to acid. The ethoxycarbonyl function of the keteneacetal-type structure 166 (R, = COOEt) exerts a stabilizing effect on the compound.z78
q$- k?R, R
X
q
Rz
R3
165
NaHfDMF
X
”
(60)
R3
166
B. Reaction with Aldehydes, Ketones, and Epoxides. The formation of 3-hydroxymethyl derivatives 168 (R, = R, = H) by condensation of 167 with formaldehyde and base was first described by Sternbach and coworker^.^'" However, it was initially thought that the product of the condensation was the I-hydroxymethyl derivative instead of the 3-hydroxymethyl derivative. This procedure was later applied to prepare other 3-hydroxymethyl analogs.264 BrogerI9, studied the reaction of diazepam with aromatic aldehydes in the presence of base and isolated the carbinols 168 (R, = H, R, = aryl), which underwent dehydration to the 3-arylidenes 170. A Soviet prepared several 3-methylene derivatives 170 by reaction of the lactams 167 (R, = H; R, = Ph; X = Br, C1, Me) with substituted benzaldehydes, heterocyclic aldehydes, and isatins. They carried out these condensations in acetic anhydride with sodium acetate at 140°C. Generation of the 3-carbanion with lithium diisopropyl amide and the addition of aldehydes and ketones was an effective way to prepare these compounds.z99 Some of the ketones that successfully added to the 3-position of diazepam were acetone, acetophenone, cyclohexanone, and benzophenone. The 7-amino-substituted compounds were condensed with several aromatic aldehydes to give the appropriate aldimines.202The aldimines were also formed from 3-amino derivatives.202The 7-hydrazino benzodiazepine was converted by reaction with ethyl pyruvate to the hydra20ne.I~~ Ethylene oxide was found to react in the presence of a Lewis acid, such as aluminum chloride, to give the If R, of the starting material 167 was oxazolino derivatives 169 (Eq. 61).3059306 hydrogen, alkylation of the nitrogen with formation of the 1-(2-hydroxyethyl) derivative 169 (R, = HOCH,CH,) was also observed. Reaction with propylene oxide in the presence of tin tetrachloride yielded a mixture of diastereoisomers in a ratio of 3:2. The major isomer had the R, methyl group in the trans configuration with respect to the R, phenyl moiety.306
672
Dihydro- 1,4-Benzodiazepinonesand Thiones
The oxazolines 169 were reported to rearrange to quaternary salts 171 by treatment with hydrogen chloride gas or by heating in ethanol with p-toluenesulfonic acid.307The salts 171 could rearrange back to the oxazolines 169 by reaction with sodium carbonate, pyridine, or just water.
R2
167
R2
168
1 R2
170
171
C. Acylations. A great variety of acylations were carried out with 1,3dihydro-1,4-benzodiazepin-2(2H)-onesand in particular with compounds bearing functional groups amenable to derivatization by acylation (Eq. 62). Acylations at the 1-position nitrogen of 172 to give the 1-acyl derivatives 173 were possible with acetic anhydride at r e f l ~ ~ , ~ ~ with * ~2- ~ ~ * ~ chloroacetic anhydride at 100"C,308with ethyl and methyl chloroformate and sodium hydride at low ternperat~re,"~or with ethyl chloroformate and pyridine.227
1. 1,3-Dihydro-1,4-Benzodiazepin-2(2H)-Ones
673
The 3-carboxylates 172 (R, = COOEt; R, = Ph; X = C1, NO,) were reacted with ethyl chloroformate and sodium hydride in dimethylformamide at low temperature to yield the N,O-diacylated compounds 174 (R, = COOEt, R, = Ph, R, = EtO, X = Cl).134The 1-methyl analog gave, under comparable conditions, the 0-acylated compound 175.134A related double acylation on the 1-nitrogen and the 2-oxygen of the lactams 176 (X = H, C1) was described in the patent literat~re.~”Dimethylmalonyl chloride reacted with the 5-phenyl-1,4benzodiazepin-2-ones 176 in the presence of triethylamine to form the tricyclic compounds 177 in approximately 75% yield (Eq. 63).
b” 176
I
177
“Acylation” at the 1-position nitrogen was also possible with isocyanates. Several 5-phenyl-substituted lactams 172 were reacted with a variety of alkyl and alkenyl isocyanates to give the urea derivatives 173 (R, = R,NH).27’,311*3123-Fluoro-substituted benzodiazepinones were reacted with methyl and ethyl isocyanate to give the 1-alkylaminocarbonyl derivative^.^^^,^^^
Dihydro- 1,4-Benzodiazepinonesand Thiones
614
Introduction of acyl groups into the 3-position of diazepam (31) was described by Reitter and coworkers.299They generated the anion of diazepam with lithium diisopropylamide (LDA) and added ethyl acetate and methyl benzoate to prepare the 3-acetyl and the 3-benzoyl derivatives 178 (R = Me, Ph) in 12 and 20% yield (Eq. 64). Me I
Me I 0
q T O *c1fqQ0 '
c1
-N
(64)
-N
0 I1
Ph
Ph
31
178
The 3-phosphonate 179 (R, = PO(OEt),, R, = 2-C1C,H4) was acetylated at the 3-position by reacting the anion generated with sodium hydride in dimethoxyethane with acetyl chloride to yield 180 [R, = PO(OEt),, R, = 2ClC,H,, R, = Me].',, The anion of the 3-cyano derivative 179 (R, = CN, R, = Ph), generated with sodium hydride in 1,2-dimethoxyethane, reacted with ethyl chloroformate to yield the 3-carboxylic acid ethyl ester 180 (R, = CN, R, = Ph, R, = OEt) (Eq. 65).226
R,
RZ
t 79
180
Trichloroacetyl isocyanate in tetrahydrofuran at room temperature was reported to acylate the 3-position of 36 to give the 3-trichloroacetylaminocarbony1 derivative 181 (Eq. 66).313
H
o
0
- qv II
CI,CCN=C=O
Qf-f
c1
Ph
36
c1
-N Ph
(66)
NHCCCI, 0 I1
181
As described in the patent literature,314the reaction of various lactams 167 with ethyl formate and sodium hydride afforded the enolized 3-formyl derivatives 182 [R, = H, Me, F,CCH2, Et,N(CH2),; R, = Ph, 2-C1C,H4; 2-FC6H,, X = C1, Br, I, NO,, F; Y = OH].314 The same compounds were also obtained by hydrolysis of the corresponding enamines 182 (Y = Me,N), which were
1. 1,3-Dihydro-1,4-Benzodiazepin-2(2H)-Ones
615
a product of the reaction of the lactams 167 with dimethylformamide diethyla~etal.~'
X R2
R2 I82
167
I
Ph 183
Ph 184
A similar acylation at the 3-position of 167 (R, = H, Me) using formamide in phosphorus oxychloride led to the pyrimidine 183 and its hydrolysis product 184.316 Acylations of the benzodiazepines 167 (R, = H, R, = Ph, X = C1) with chloroformate esters in the presence of potassium carbonate afforded the imine addition products 185 (R, = Ph; R, = Me, Et)."* Trapping of the intermediate acyliminium ion by a nucleophile delivered intramolecularly led to the cyclic derivatives 186 and 187 (Eq. 68). The 1,3oxazinone 186 resulted from the reaction of diazepam, 167 (R, = Me, R, = Ph, X = Cl), with diketene.317-319Reaction of 167 (R, = Me; R, = Ph, 2-FC6H,; X = C1, NO,) with malonic acids (R, = H, Et) and acetic anhydride afforded the oxazinediones 187.320 Coffen and coworkers32' reported the addition of mercaptoacetic acid to the imine bond of diazepam 167 (R, = Me, R, = Ph, X = Cl). The adduct 188 was obtained in 38% yield by heating diazepam and mercaptoacetic acid in benzene for 5 days at reflux. Intramolecular trapping of the acyliminium ion by the a-carbon of the acyl group led to the ,!?-lactams189. ,!?-Lactamformations were observed with chloroacetyl chloride and t r i e t h y l a r n i ~ ~and e ~ ~with l the enamine obtained from glycine and ethyl acetoacetate in the presence of phosphorus o x y c h l ~ r i d eJaunin . ~ ~ ~ and coworkers323studied the dipolar addition of nitrile oxides to the imine bond of 167 (R, = H, Me; R 2 = Ph) and obtained the expected adducts 190 (R, = H, Me; R, = Ph; R, = Ph, benzoyl, COOEt) (Eq. 69).
Dihydro-1,4-Benzodiazepinonesand Thiones
676
II
R,OCCI
X
R, = H
“COR, R2
167
0
ins
\
\ x
$3: 0
Me
Me
c1 R2
N
\
190
189
They also described the transformation of the 3-carboxamide 191 to the tricyclic derivatives 193.226Treatment of 191 with oxalyl chloride led to the intermediate acyliminium ion 192, which when reacted with such nucleophiles as ethanol, water, and mercaptoacetic acid ethyl ester, formed the adducts 193 (R = EtO, HO, EtOOCCH2S) (Eq. 70).
677
1. 1,3-Dihydro-1,4-Benzodiazepin-2(2H)-Ones
Me
Me 0
c1 Ph
0 0
c1
CNH2 II 0
191
192
J
c1’ v
> N Ph
NH 0
193
Reaction of the benzodiazepin-4-oxides 194 with acylating agents led to the 3-acyloxy compounds 195. This “Polonovski” rearrangement is initiated by acylation of the nitrone oxygen to give the acyloxyiminium ion 1%, which will then add an acyloxy anion at the 5-position. Elimination of the carboxylic acid R,COOH from this adduct should then lead to the intermediate 197. Migration of the acyloxy group from the 5-position to the 3-position may then occur by an
X &
II
1 R3
194
I 0 196
195
+
197
0
Dihydro-1,4-Benzodiazepinones and Thiones
678
intramolecular electrocyclic mechanism to yield the isolated products 195. An addition-elimination sequence may also be considered for the conversion of 197 to 195 (Eq. 71). This reaction has proved to be as useful way of functionalizing the 3-position of benzodiazepines. Since the discovery by Bell and ChildressZ6’ of a variation of the Polonovski rearrangement, many 3-acyloxy compounds have been prepared by this method. The most commonly used reagent was acetic anhydride at temperatures exceeding 80°C, preferably at reflux (see References 1,8,9, 44, 58, 69, 72, 97, 148, 184, 189, 227, 232-234, 254, 262, 263, 277, 282, 288, 309, 324 and 325). Other anhydrides used were 2-propylpentanoic anhydride,326 pivalic anhydride,329 and trifluoroacetic chloroacetic anhydride,263~265*327,328 anhydride.266.267Acid chlorides could also be successfully used in place of anhydride^.^^^,^^^ Reaction of the 4-oxide with ethyl chloroformate was reported to lead to the 3-chloro derivative,263 while methyl chloroformate at reflux temperature also gave the 3-methoxycarbonyloxy compound.265 The 3-chloro compound was also formed by treatment of the 4-oxide with oxalyl ch10ride.I~~ The 3-acetylthio derivative was a product of the reaction of the nitrone with a mixture of thioacetic acid and its a n h ~ d r i d e . ” ~ The tricyclic compound 199j30 was a product of an acylation of the nitrone 198 (R, = H, Me) by methyl isocyanate at the 4-position oxygen and an intramolecular trapping of the iminium ion. When R, = H, a simultaneous acylation at the 1-position occurs to give 199 (R, = MeNHCO) as a product (Eq. 72).
:“s
c1
\0
Ph
I98
- &To
R, (72)
MeN=C=O
c1
N,0 Me”\(
0
199
The 3-ally1 derivatives 200 (R, = Me, MeOCH,; R, = H, Me; R, = H, Me) were converted to the dienes 201 by heating in acetic anhydride. The 3-acetoxy compound which is initially formed undergoes elimination of acetic acid.”* The same reaction with the 3-benzyl derivative, afforded the benzylidene compound 203 (Eq. 73). Under the same conditions, the dienes 201 (R2 = H) were reacted to yield the pyrrolobenzodiazepines 202. Mechanisms for this cyclization have been proposed. Treatment of the corresponding 5-methyl analog 204 with acetic anhydride afforded the 5-acetoxymethyl derivative 205 by a normal Polonovski reaction (Eq. 74).”’
1. 1,3-Dihydro-1,4-Benzodiazepin-2(2H)-Ones
200
20 1
///i R,
=
679
H
(73) Me
Ph
Ph
I R3
203
202
Me
Me
Me
'0
iOCMe II
0 204
205
The 5-hydrazino derivatives 206 (R, = H) were obtained in situ by cleavage of the t-butoxycarbonyls 206 (R, = t-BuOOC). These derivatives were converted to the tricyclic systems 207 and 208 by acylation of the 4-position nitrogen. Reaction of the intermediate hydrazine with trifluoroacetic anhydride led to 207 (R2 = F,C) in 70% The analog 207 (R, = ClCH,) was similarly obtained by treating the hydrazine 206 (R, = t-BuOOC) with chloroacetic acid and subsequently with chloroacetic acid anhydride.' 98b Heating the same compound with a mixture of oxalic acid and diethyl oxalate led to both the triazole 207 (R2 = EtOOC) and the triazine 208 (Eq. 75). In addition to the acylations involving atoms of the benzodiazepine ring system, numerous acylations of functional groups attached to various positions were carried out. Thus 1-amino2'' and 1-hydroxyla9 benzodiazepin-2-ones were acetylated by reaction with acetic anhydride. Reaction of the 1-amino
680
Dihydro-1,4-Benzodiazepinonesand Thiones
4f Me
c1
R,COOH
NH I NHRl
Me I
qTO
c1
N
N, /&Rz N 207
206
i 0 II
COEl
I
COEl
II
Me
208
compounds 209 (X = H, C1) with carboxamides in hot polyphosphoric acid (PPA) gave the triazolobenzodiazepines 210 (Eq. 76).261
R
8” 209
210
A l-(2-aminoethyl) derivative was acylated with bromoacetyl bromide331 and was also converted to the thioisocyanate derivative.332Both compounds served as possible irreversible ligands for the benzodiazepine binding site. 1-(2-Hydroxyethyl) compounds were acylated with a variety of anhydrides, acid chlorides, and i s o c y a n a t e ~ . The ~ ~ *3-amino,’99~202*227 ~~~ and in particular, the 3-hydroxybenzodiazepin-2-ones, were converted to many different acyl derivatives. Reactions described included those with anhydrides,333 anhydrides and
1. 1,3-Dihydr0-1,4-Benzodiazepin-2(2H)-Ones
68 1
p y r i d i ~ ~ e , acid ~ ~ . ’chlorides ~~ and chloroformates or chlorocarbamates in the and represence of ~ y r i d i n e ~ ~ ,or- ~4-dimethylamin0pyridine,~~~*~~’.~~~*~~~ ~’ actions with carboxylic acids activated by carbonyldiimidazole or dicyclohexyl~arbodiimide.~ The sodium salt of the 3-hydroxymethylene derivative 182 (R, = Me, R, = 2-C1C,H4, X = Br, Y = OH), shown in Eq. 67, afforded the 3acetoxymethylene analog upon treatment with acetic anhydride in methanol.314 The 5-carboxylic acid hydrazide 211 (R, = H) was acetylated by acetic anhydride to the corresponding acetyl derivative 211 (R, = Ac). Compound 211 (R, = Ac) was then cyclized with dehydration by polyphosporic acid to give the oxadiazolyl analog 212 (Eq. 77).193 29333
93340
I
I
AN H N H R ,
0”
Me 21 1
)-N 212
Many acylations were carried out on 3-hydroxymethyl compounds giving The 7-amino derivatives were con3-acyloxymethyl benzodiazepin-2-0nes.’~~ verted to acety1,’34.25’.301trifluoroacetyl,80 and a variety of urea derivatives by reaction of the intermediate isocyanate with amines.80,230*231 7-Aminomethyl and 7-(I-amino- 1-ethyl) analogs were likewise converted to the corresponding ureas by the same method.251Reaction of 7-(1-hydroxy-1-ethyl) compounds with isocyanates led to the appropriate urethanes.251 The 7-hydroxyamino derivative 213 reacted with acetic anhydride in the presence of pyridine to yield the N,O-diacetyl analog, which was selectively hydrolized to the N-acetyl derivative 214 (R = Me). Trifluoroacetic anhydride in pyridine, at -50 to - 30°C, reacted in the same fashion, while the same reagents in boiling methylene chloride rearranged the hydroxyamine to the aminophenol 215 (Eq. 78).245 The amino group of 5-(2-aminophenyl)-7-chloro-1 -methyl-1,4-benzodiazepin-2(2H)-one was acetylated with acetic anhydride.16, The nitrogen in the side chain of flurazepam was attacked by cyanogen bromide, leading to dealkylation and formation of the N-cyano compound.233 Benzyl chloroformate’ 5 0 c and ethyl chloroformate were also used for similar dealkylation-acylation reactions. Fryer and S t e r n b a ~ h ~ described ~ l . ~ ~ ~ the reaction of diazepam, 216 (R = Me), and nordiazepam, 216 (R = H), with acetic anhydride. Depending on the reaction conditions the formation of different products was observed. Diazepam was heated to reflux for 2 hours in the presence of sodium acetate
Dihydro-1,4-Benzodiazepinones and Thiones
682
HN
I
Ph
OH
OH
Ph
213
214
,OMe
O H Ph 215
trihydrate to yield 23% of the quinolone 217. Its formation was proposed to be initiated by acetylation of the imine nitrogen, generating an acetyliminium ion, which could undergo ring contraction to an aziridinoquinoline. Rearrangement involving a proton shift would then lead to the isolated product. It is also possible that the acetyliminium ion is hydrolytically cleaved to the benzophenone 218, which would undergo cyclization and dehydration to form the quinolone 217 (Eq. 79). When nordiazepam was heated to reflux for 3 hours in acetic anhydride in the presence of catalytic amounts of concentrated sulfuric acid, the oxazoloquinoline 219 was obtained in 23% yield, along with a small amount (2%) of the benzophenone 218 (R = H).
4J0 -
Me I
Ac,O
NaOAc.3U2O
c1
R=Me
c1q : Ph m c
Ph
216
///’ R = Me
Ph 218
217
(79)
1. 1,3-Dihydro-1,4-Benzodiazepin-2( 2H)-Ones
683
Prolonged heating (19 hours) of nordiazepam, 58 (X = Cl), or the 7-deschloro analog 58 (X = H), in a mixture of acetic anhydride and pyridine, afforded The a 10% yield of the isoindoles 220 (X = C1 and H, respectively) (Eq. possible mechanisms involved in the formation of these isoindoles are discussed in Section 1.2.2.7.
Ph
Ph 58
220
D. Sulfonation and Phosphorylation. The methylsulfonyl group was introduced into the 3-position of 167 (R, = Me, R, = 2-FC6H,, X = C1) by means of sodium hydride and methanesulfonyl in dimethylformamide. Chlorosulfonic acid reacted with the 7-aminobenzodiazepine to yield the corresponding sulfamic acid.' 34 Szente301prepared the 1-methylsulfonyl derivatives of benzodiazepin-2-ones by a reaction of the lactams with methanesulfonyl chloride and base. Phosphorylation of benzodiazepin-2-ones on the oxygen of the lactam led to 2-phosphoryloxy derivatives, the syntheses and reaction of which were described in Chapter V. Phosphorylations were carried out with dimorand pholinophosphinic chloride,"4,344,34s diphenylchl~rophosphate,'~~~~~~ diethylchlorophosphate.'34~34s The hydroxy group of 1-(2-hydroxyethyl) derivatives was also p h ~ s p h o r y l a t e d The . ~ ~ 3-hydroxy ~ function of 221, when reacted with the cyclic chlorophosphate 222 and sodium hydride, gave the phosphate 223 (Eq. 81).348
The rearrangement of the nitrone 224 to the quinoxaline 225 by treatment with phosphorus oxychloride at reflux may be rationlized in the following manner. The initial phosphorylation of the nitrone oxygen gives the postulated cyclic intermediate 226. The indicated ring contraction would generate the carbonium ion 227, which could then react with chloride ion as shown, to form the isolated product 225 (Eq. 82).349
684
Dihydro- 1,4-Benzodiazepinonesand Thiones
45 1
c1
Ph
H POCI,
+
/Ql:y0
c1
\O
224
226
0APh 225
t
221
I .2.2. Reactions with Nucleophiles 1.2.2.1. Reduction The reduction of the 2-carbonyl function to a hydroxy function and further to a hydrocarbon was described in Chapter VI. The reduction of the 4,5-imine bond to the amine and the hydroxamine will be discussed in Chapter VIII, dealing with the tetrahydrobenzodiazepines. Electrochemical reduction of the 4,5-imine bond at the dropping mercury electrode has been used widely in analytical ~ o r k . ~ ~ ~ * ~ ~ ~ 3-Chlorobenzodiazepinones were dehalogenated to the parent compounds by hydrogen and palladium on carbon262or by Raney nickel in the presence of h y d r 0 ~ i d e . IIn ~ ~the latter case, the 4-oxide partially survived the dehalogenation. Sodium borohydride reduced the 3-hydroxymethylene derivative to the 3-hydroxymethyl analog.264Hydrogenation of the 3-methylene derivative over palladium on carbon afforded the 3-methyl compound.243 Reduction of the 4-oxides to the correponding imines was accomplished by a variety of reducing agents. Phosphorus trichloride was most commonly used. (See References 6, 7, 72, 91, 93, 97, 135, 138, 142, 143, 147, 150, 206, and 207). Other trivalent phosphorus compounds such as trimethylpho~phite'~~ and triethylph~sphite"~ were equally useful. Zinc-acetic acid was also used, although further reduction of the imine could Hydrogen in combina-
1. 1,3-Dihydro-1,4-Benzodiazepin-2(2H)-Ones
685
tion with a catalyst, such as Raney n i ~ k e l , ~ ~ ,platin~m,’~’ ’ ~ ~ , ’ ~ ~ or palladium was also used as a reducing agent. on Nitro groups attached at the 2-,16’ 3-,’34 and 4 - p o ~ i t i o n s of ’ ~ the ~ 5-phenyl moiety were reduced to the corresponding amino compounds by Raney nickel and hydrogen. 7-Nitro derivatives were similarly reduced to the amino com~ ~ ’ ~ ~ ~ ’ ~ ~ ~ pounds using hydrogen and Raney n i ~ k e 1 , ~ ~ ~ ~ ~ platin~m,’~’ and palladium on ~arbon.’~’Stannous chloride and hydrochloric acid were also successful reducing agent^.^^^^^^^^^^^^^^^^^^ Stannous chloride in the presence of sodium acetate reduced the 7-nitro compounds to the corresponding hydroxyamino derivatives.2453246 The reduction, in situ, of the 7-diazonium salt with stannous chloride afforded the 7-hydrazinobenzodiazepine.’34 The 7-hydroxyiminoalkyl and the 7-cyano derivatives were reduced to the corresponding amines by Raney nickel Desulfurization of the 7-methylthiomethylamino comand hydrogen.’ pound with Raney nickel led to the 7-methylamino ana10g.I~~ Reductive amination of the 7-acetyl compounds with sodium cyanoborohydride and aminoethanol or dimethylamine were described by Branca, Fischli, and S ~ e n t e . ’ ~The sodium borohydride reduction of 7-acetyl and 7-pentanoyl derivatives yielded the 7-hydroxylakyl b e n z ~ d i a z e p i n e s . ~ ~The . ’ ~ ~1-(acetyl) methyl and 1-(benzoy1)methyl analogs were similarly reduced to the corresponding alcohols by sodium b ~ r o h y d r i d e . ‘ ~ ~ The ally1 ester of the benzodiazepine 5-carboxylic acid was cleaved by hydrogenolysis using platinum as a c a t a 1 y ~ t . I ~ ~ 52c3,25
1.2.2.2. Reactions with Halogen Nucleophiles
with such reThe reaction of 1,3-dihydro-l,4-benzodiazepin-2(2H)-ones agents as p h ~ s g e n e , ~ ~phosphorus ’ - ~ ~ ~ penta~hloride,~’~ or a combination of carbon tetrachloride and t r i p h e n y l p h ~ s p h i n ehas ~ ~been ~ discussed in Chapter V, Section 25 dealing with 3H-1,4-benzodiazepines. The combination of carbon tetrachloride and triphenylphosphine was used to dehydrate a 3-carboxamide to the corresponding nitrile.266 The 3-hydroxy compounds were readily converted to the 3-chloro derivatives by treatment with ~ ~ ~ of~ 3-hydroxy-4~ ~ ’ ~ ’ ~ ~ ~ thionyl ~ h l o r i d e . ~ ’ ~ ~The~ reaction oxide with phosphorus trichloride gave the reduced 3-chloro compound, which could be further reacted in situ.’07 Partial exchange of fluorine by chlorine was observed when the 3-fluoro-4-oxide was reduced to the corresponding imine with phosphorus tri~hloride.’~’The 3-fluorobenzodiazepines were obtained by halogen exchange, using silver fluoride with the 3-bromo- or the 3-iodocompounds.’” The 3-fluoro compound was also prepared by reaction of the 4-oxide with antimony pentachloride in hydrogen fluoridezz8or by treatment of the 3-hydroxy compound with hydrogen fluoride and potassium fluoride in pyridine.228Other methods used to form the 3-flUOrO compounds were the reaction of the 3-chloro compound with antimony pentachloride in hydrogen fluoride, treatment of the 3-amino derivative with an alkylnitrite in hydrogen fluoride or diazotization of the 3-amino compound with sodium nitrite in
686
Dihydro- 1,4-Benzodiazepinonesand Thiones
hydrogen fluoride-pyridine, thallation at the 3-position and subsequent reaction with borontrifluoride, and finally electrolytic oxidation in hydrogen fluoride.228It was also f o ~ n d ' ~ that ~ , ~the ~ '3-fluoro analogs were a product of the reaction of 3-hydroxy compounds with diethylaminosulfur trifluoride. 7-Diazonium salts were reacted with iodide251,253 or chloride293to yield the corresponding 7-halo derivatives. A modified version of the Sandmeyer reaction was used to prepare a radioactive 7-bromo compound by incorporating bromi11e-75.~5 9 The diazonium bromide was converted to a triazene with piperidine and then heated in carbon tetrachloride with methanesulfonic acid. The 7-acetyl derivative by reaction compound was converted to the 7-(l,l-difluoro-l-ethyl) with molybdenum he~afluoride.~~' Compounds substituted by a 7-methylsulfinyl group were reacted with thionyl chloride to give the corresponding 7-chloromethylthio analog^.'^^^ The same reaction was used to prepare the 7-(l-chloro-l-ethylthio)compounds. Boron trifluoride in combination with acetonitrile was reacted with the 4-oxide 224 to give the 3-hydroxy compound 221 (Eq. 83).235Boron tribromide has been used to convert the 3-methoxy derivative to the 3-hydroxy analog."'
224
221
1.2.2.3. Reactions with Oxygen and Sulfur Nucleophiles A. Hydrolysis. The 4,5-imine bond in 167 is most sensitive to acid hydrolysis. Since the hydrolysis of the imine to the ring-opened form 228 is reversible, benzodiazepin-2-ones can tolerate low pH media at room temperature. The reversible ring opening was studied spectroscopically and the pH dependence of the equilibrium between protonated diazepam and its ring-opened form was determined.361 A similar study of the hydrolytic opening of flunitrazepam, flurazepam, and fludiazepam at body temperature was c o n d ~ c t e d . ~The ~' 4-quaternary salts 167 (R3 = alkyl) are readily hydrolyzed to the ring-opened benzophenones 229.363Under more vigorous conditions of acid hydrolysis, benzodiazepin-2-ones were cleaved to the corresponding benzophenones 230 (Eq. 84).6,69,94.256 The 3,4-bond of the 3-hydroxybenzodiazepin-2-onesappears to be most sensitive to acid hydrolysis. Treatment of oxazepam (221) for 10 minutes in boiling acetic acid led to the quinazoline-2-carboxaldehyde231 in about 60% yield.'83,349,364Hydrolysis of oxazepam in a mixture of hydrochloric acid and ethanol or methanol led also to the 2,2'-bis-quinazoline 232 and the indolylquinazoline 233 (Eq. 85)364 The 4-oxide of oxazepam could also exist in a ring-opened f ~ r r n . ~ ' ~ * ~ ' ~
1. 1,3-Dihydro-1,4-Benzodiazepin-2(2H)-Ones
687
R1
R2
228
167
+i
OH
R, X 4 < N -0 H R 3
X
q; R2
R2 229
230
Ph
Ph 221
231
c1
Ph
Ph
Ph 232
233
Acid hydrolysis of the 1-amino derivatives 234 or the 4-desoxy analogs led to the indazoles 235 (Eq. 86).250Acid or base-catalyzed hydrolysis of the 1-hydroxy compounds 236 or the corresponding 4-desoxy derivatives yielded the benzisoxazoles 237.'
Dihydro-1,4-Benzodiazepinonesand Thiones
688
234
235
Ph 236
231
While 1-unsubstituted benzodiazepin-2-ones 167 (R, = H) are quite stable to alkali, due to formation of the amide anion, hydroxide induces ring opening in 1-alkyl and 1-acyl derivatives to give the salt of the carboxylic acids 238 (Eq. 87).42*’34The sterically hindered imine 238 (R, = Me, R, = 2,6-Cl2C6H3) recyclized upon treatment with acid rather than hydrolyzing to the benzophen~ne.~’
430 X
-N R2
167
- GN+ R’ 0
0-
OH-
(87)
X
R2
238
Hydroxide converted the 1-acetyl-3-acetoxy derivative 239 (R, = Ac; R,, = H) to the 2-methyl quinazoline 240 (Eq. 88).309 Treatment of oxazepam with hydroxide led to the dihydroquinazoline-2-carboxylicacid 242, which was thermally decarboxylated.262Acid hydrolysis of the 3-acetoxy-3-methyl compound 239 (R, = H, R, = Me, R, = Ac) yielded 2-acetylquinazoline 241.227 The rearrangement of 3-hydroxy derivatives 243 to the corresponding 43dihydro-3-ones 244, by hydroxide, was a side reaction of the alkaline hydrolyses of 3-acyloxy compounds. Several cases of this protic rearrangement were re3-Amino derivatives 245 were analogously ported (Eq. 89).’48,233,262~26s~288,36s rearranged to the amidines 246.” sb To avoid this rearrangement, hydrolysis of the 3-acyloxy group must be carried out under mild conditions, such as hydroxtemperature.8.44.5 8 , 7 2.148.2 32 - 2 34,263,277,282,288.293 ide in methanol at The 3-trifluoroacetoxy function was easily
R,
1. 1,3-Dihydro-1,4-Benzodiazepin-2(2H)-Ones
689
Ph 242
R2
243
k2
R2
245
246
The 3-thiol was prepared by alkaline hydrolysis of the 3-acetylthio analog. 2 2 7 Acetoxyalkyl groups attached at the l - p o s i t i ~ nand ~ ~at the 5-positionZ9*were hydrolyzed to the alcohols. Benzodiazepin-2-one-3-carboxylicacid esters were converted by alkaline hydrolyses to the corresponding a ~ i d which are ~ stable , as alkali salts but decarboxylate readily when in the free acid form. Diazepam3-carboxylic acid, liberated from its alkali salt at low temperature, could be partially converted to the methyl ester by treatment with diazomethane, indicating that the decarboxylation at low temperature is not i n ~ t a n t a n e o u s . ' 1~~ Alkanoic acid ethyl ester was hydrolyzed to the corresponding acid by alkali.z94
~
690
Dihydro- 1,4-Benzodiazepinonesand Thiones
Hydroxide was reacted with the imide 181 (Eq. 66) to form the corresponding Hydrox3-carboxamide by selective hydrolysis of the trichloroacetyl ide was also used to cleave the trifluoroacetamide in the 4-position to give the 4-amino corn pound^.^,^ A 3-hydroxy compound was isolated from the reaction of the 3-azido derivative with hydroxide.249 Acid hydrolysis was used in the preparation of 3-amino derivatives from the corresponding a ~ e t a m i d e ' or ~ ~thioacetamide."' ,~~~ It was also used to cleave an acetone ketal to form the d i 0 1 , to ~ ~ring ~ open an aziridine to form an amino a t-butyl to convert a t-butyl ether to the corresponding ester to the corresponding acid,294 and finally to convert an epoxide to the corresponding di01.'~~ Concentrated sulfuric acid was able to hydrate nitriles to 5 0 ~ 2 2 6 , 2 3 3and to debenzylate I-benzyl H ydrolysis the of a cyanamide with sulfuric acid led to the corresponding A 3-(dimethy1amino)methylene derivative was converted to the 3-(hydroxymethylene) analog by treatment with aqueous oxalic acid in tetrahydr~furan.~ An' ~amino group, protected by a benzyloxycarbonyl group, was deprotected by reaction with hydrogen bromide in acetic a ~ i d . ~ HYq ~ ~ ~ , ~ drolysis of the 3-diazonium salt led to the 3-hydroxy c o m p ~ u n d . ' The ~~+~~~ reaction of nordiazepam in deuterium oxide and deuteromethanol, at reflux temperature, in the presence of deuterium chloride, resulted in a 50% exchange of the protons at the 3-position of nordiazepam.'82
B. Reaction with Alkoxides and Acyloxides. The 1,2-bond, in the 1(methoxycarbonyl) derivative 247 (X = C1, NO,), was selectively cleaved by methanol and triethylamine to give the ring-opened imines 248 (Eq. 90).'34 The stereochemistry of the imine was retained in this reaction.
Ph 241
Ph 248
Methanolyses have been carried out on several acetoxy derivatives using methanol and methoxide or triethylamine. Thus 1-acetoxyalkyl-substituted benzodiazepin-Zones were converted to the corresponding 1-hydroxyalkyl der i v a t i v e ~A. ~3-acetoxy ~~ and a 3-acetamino function2" were similarly converted to the 3-hydroxy and the 3-amino derivatives. The formation of 3-alkoxy compounds from 3-acyloxy derivatives was also ~ b s e r v e d . ~ ~ ~ , ~ ~ Optically active alkoxy derivatives were thus obtained by treating the enantiomeric 3-hemisuccinates with thionyl chloride and an When the 3-acetoxy-3-methyl compounds 249 (R, = Me, MeOCH,; R, = Ac) were treated with methanol and methoxide, a rearrangement to the bridged benzodiazepine 250 was observed (Eq. 91).277Mechanisms for this
1. 1,3-Dihydro- 1,4-Benzodiazepin-2(2H)-Ones
69 1
transformation were discussed. The 3-hydroxy-3-methyl compound 249 (R, = H) was obtained by treatment of the acetoxy derivative with concentrated sulfuric acid.277
Ph 249
Ph 250
Methanolysis served to cleave a trifluoroacetyl group from the 7-trifluoroacetyl-N-methoxyamino derivative245 and to convert an N-(2acetoxyethyl) urea to the corresponding hydroxyethyl~rea.~~' 3-Carboxylic acid aminoalkyl esters are the products of a basecatalyzed tran~esterification.'~~The reactive 3-chlorobenzodiazepin-2ones were treated with many alkoxides to form the 3-alkoxy derivatives.101,143,21 5 , 2 2 3 , 2 2 5 - 2 2 7 , 2 8 8 , 3 2 4 , 3 3 4 3 7 The latter were also obtained by etherification of the 3-hydroxy compounds (e.g., by treatment with methanol and sulfuric acid).22 The 3-acetoxy compounds were similarly obtained by displacing the chloride with Carboxylic acids were reacted with the 3-chloro compounds in the presence of triethylamine to form the 3-acyloxy derivatives.339The 3-diazonium salt could also be reacted to form the 3-acetoxy compound.'99 Exchange of chloride with acetate occurred at the side chains .~~~ of the 3-hydroxymethyattached at the 1-72 and 7 - p o ~ i t i o n s Acetalization lene derivative with trialkyl orthoformates in the appropriate alcohol led to the 3-(dia1koxy)methyl analogs, which were thermalized in the presence of sodium acetate to afford the enol ethers.314 5-Chlorobenzodiazepin-2-ones were reacted with alkoxides and phenoxides to yield the 5-alkoxy and 5-phenoxy derivative^.'^^ The aromatic fluorines in the 5-(2-fluorophenyl) and the 5-(2,6-difluorophenyl) derivatives were displaced by a l k o x i d e ~ . ' ~ ~ ~ The 5-chloroalkyl derivatives were dehalogenated to the corresponding alkenes by lithium carbonate in dimethylf~rmarnide.~~~~~'~ C. Reaction with Sulfur Nucleophiles. The conversion of 2-ones to 2-thiones will be discussed in Section 2, below. Reaction of 3-chlorobenzodiazepin-2-oneswith thiourea or thioacetamide gave the 3-thiol compound.367 The 3-thioalkyl derivatives were similarly obtained by treating the 3-chloro compound with thiols.227,367Treatment of the 3-acetoxy analog with thioacetic acid at 100°C for 50 minutes resulted in the formation of the 3-acetylthio compound.227 A 5-phenylthio compound was prepared by reacting the 5-chlorobenzodiazepine with phenylthi01.l~~ A 3-acetamino compound was converted to the corresponding 3-thioacetamide by treatment with phosphorus pentasulfide. O 2
Dihydro- 1,4-Benzodiazepinonesand Thiones
692
1.2.2.4. Reactions with Nitrogen Nucleophiles The transformation of 1,3-dihydro- 1,4-benzodiazepin-2(2H)-onesto 2amino-3H-1,4-benzodiazepines was discussed in Chapter V. Methylamine in dimethylformamide was reacted with nitrazepam (101) at room temperature to cleave the 1,Zbond and give the ring-opened amide 251 in 77% yield.368 Piperidine at reflux temperature effected the same type of transformation (Eq. 92).
101
251
Intramolecular attack of the amino group in 252 (X= NH,), at the These compounds 2-carbonyl group, led to the tricyclic amidines 253.233,291 were also obtained directly by displacement of the chloride in 252 (X = C1) with ammonia in hot ethanol containing sodium iodide (Eq. 93).291
x
I
R 252
R 253
3-Chlorobenzodiazepin-2-ones were reacted with a variety of amines to form the 3-amino derivatives. The amines included primary227*358 and secondary3" amines, and h y d r a ~ i n e Tertiary . ~ ~ ~ amines formed the quaternary salts when treated with the 3-chlorobenzodiazepin-2ones.227,334,356 The 3-amino compounds were also formed by substitution of a 3-phosphoryloxy group348 or by treating the 3-hydroxy derivatives with a p h ~ s p h o r y l a m i d eThe . ~ ~ 3-acetoxy ~ group of the 3-acetoxy-3-methyl derivative was directly displaced by diethylamine.227.325Amines have been demonstrated to be strong enough bases to deprotonate the 3-position and to rearrange the 3-amino compounds to the tautomeric amidines (see Eq. 89).215b,260 5-Chlorobenzodiazepin-2-ones were converted to the 5-amino compounds by treatment with various a m i n e ~ . 'The ~ ~ reaction of the chloride 254 with hydrazine and hydrazine derivatives was studied by Wade and coworkers.1979198 Hydrazine in ethanol at room temperature converted the 5-chloro compound to the 5-hydrazino analog 255 (R = H) in 32% yield,'98b
1. 1,3-Dihydro-1,4-Benzodiazepin-2(2H)-Ones
693
while the same reagent, neat or in boiling benzene, led to ring cleavage and gave the triazine 256. Heating the chloro compound 254 with formylhydrazine in refluxing 1,Zdimethoxyethane afforded the triazolobenzodiazepine 207 (R, = H) in 84% yield. Other triazoles 207 (R, = Ph, Me, CH,CN) were similarly obtained. The triazolone 257 was prepared in 94% yield by heating to reflux for 4 hours, the 5-chloro compound with ethoxycarbonylhydrazine in Refluxing the chloride 254 with oxamic hydrazide afforded the triazole carboxamide 207 (R, = CONH,). The morpholino derivative of oxamic hydrazide yielded 84% of the triazine 208 and only 7% of the triazole 207 (R, = morpholinocarbonyl) after heating in dimethylformamide at 100°C for 30 minutes (Eq. 94). Me Me
q?'
' 7 ' qIN 1
H,NNHR.
c1
c1
c1
254
\
I
-N NHNHR 255
CI'
256
251
207
208
A similar transformation to the triazole occurred when the 5-ethoxy derivative was heated to reflux with 2-chlorobenzoyl hydrazide in d i g l ~ m e . ~ ~ ~ Side chain chlorides at the 1-, 3-, and 5- positions were displaced by nitrogen nucleophiles. 1-Chloroalkyl derivatives were reacted with ammonia,291 with
694
Dihydro- 1,4-Benzodiazepinones and Thiones
potassium ~ h t h a l i m i d e and , ~ ~ with amines. Chloroacetyl functions attached at the 1- and 3-positions were similarly converted to the basic derivatives by treatment with a variety of amines.263,265*283,328 The 5-(haloalkyl) derivatives were reacted with amines to form the 5-(aminoalkyl) analogs.224 Reaction of the 5-(1-chloro-I-cyclohexyl) compound 258 with diethylamine led to elimination of hydrogen chloride with formation of the 5-cyclohexylidene derivative 259 (Eq. 95).224Other amines such as dimethylamine and N-methylpiperazine yielded the displacement products 260. The enamine 262 was obtained when the chloride 261 (R = Pr) was treated with p y r r ~ l i d i n e . ~Reaction ’~ of the dichloromethyl derivative 261 (R = C1) with dimethylamine led in low yield to the aminal 263.2z4 1s0c32549287
.;:”c’
H
O
HNEI,
-
258
259
261 260 Mc,NH
I
Me,NANMe, i
262
263
Exchanges of fluorine by nitrogen nucleophiles were observed with 5-(2fluoropheny1)- and 5-(2,6-difluorophenyl)-substitutedcompounds.134q1 s2c The 7-diazonium salts were converted to the 7-azido analogszs2and, in one instance, to a t r i a ~ e n e . ~Reaction ’~ of a 7-nitroso derivative with methylhydroxylamine led to the methylazoxy omp pound.^^^,^^^
1. 1,3-Dihydro-1,4-Benzodiazepin-2(2H)-Ones
695
Ester functions at the 3-, 5-, and 7- positions have been converted to amides and hydrazides by direct amination.5"5~'05~'07~'g3~zz6 Carboxylic acid and esters not directly attached to the ring system were also converted to amides and hydrazides.8 102,10Sd,357 3-Phenoxycarbonyloxy derivatives were reacted with ammonia and primary and secondary amines to yield urethanes.336Several 3-aminomethylene derivatives were accessible by an amine exchange of the 3-(dimethylaminomethylene) 9
The cyclization (aqueous potassium carbonate) of the thiourea 264 to the triazole 265 involves intramolecular attack of the carbonyl group by a urea nitrogen (Eq. 96).193
A NNHCNHMe
o/ O/ -
H H
264
II
MeNAN
)=I4
HS
265
The reaction of oxazepam (221) with methylamine in aqueous ethanol led to the methylimine of the quinazoline-2-carboxaldehyde266. Treatment with hydrazine hydrate in boiling ethanol afforded the corresponding hydrazone 266 (R = NH,) (Eq. 97).349
Ph
Ph 221
266
1.2.2.5. Reactions with Carbon Nucleophiles Methyllithium was reacted with the 7-cyano derivatives to yield the 7-acetyl compounds via the imines." These acetyl compounds were further converted, by this reagent, to the 2-hydroxy-2-propyl analogs.33 The 3-carboxylic acid ethyl ester reacted with excess methylmagnesium iodide to form the same type of carbinol,134the 3-(2-hydroxy-2-propyI) derivative. Phenylmagnesium bromide added to the nitrone 267 (R = H) to give the 4-hydroxy compounds 268 (R = H).' The 5-phenyl nitrone 267 (R = Ph, X = CI) underwent addition of phenylmagnesium bromide at the amide carbonyl, leading to the 2-phenyl3H-1,4-benzodiazepine ,269 (Eq. 98).jo1 Methylmagnesium iodide added in the 763177
Dihydro-1,4-Benzodiazepinones and Thiones
696
same fashion at the 5-position3” of the 5-phenyl derivative, giving 268 (R = Me, X = Cl). Phenyllithium reacted, at 30°C, with the carbonyl group of diazepam (31) to form the ring-opened phenylketone 270.301Ethylmagnesium bromide underwent the same type of reaction. According to Field,371treatment of the 5-chloro compound 254 with phenylmagnesium bromide resulted in the formation of the oxazole 271 by attack at the carbonyl group followed by ring opening and cyclization of the enolized ketone onto the chloride (Eq. 99).
X
- gf
ay0 R
MeMgl
R=Ph
N
X
‘OH
Ph
267
268
PhMgBr R = Ph, X
i
=
(98)
CI
Me I
Ph
45
c1q
c1
Ph ‘ 0
N
V 0R Ph
269
270
Me
Me 1 PhMgRr
(99)
CI
c1 2.54
Ph 271
Cuprous cyanide in dimethylformamide was used to displace a 7-iodo substituent with a cyano group.”l Displacement of the chloride in 5-(l-chloro1-cyclohexyl) derivative 258 (Eq. 95) by cyanide led to the corresponding nitrile.’ 24
1.2.2.6. Photo and Thermal Reactions Irradiation of the nitrones 272 with ultraviolet light led to the oxaziridines 273 (Eq. 100).Compound 273 (X = C1) was obtained in 78% yield by irradiating a tetrahydrofuran solution with a Hanovia medium pressure mercury lamp and a Pyrex filter.218,372 Wh’ile the oxaziridine 273 (X = C1) was relatively stable to further photolysis, the correspondi’ng methylthio analog 273 (X = MeS) was
1. 1,3-Dihydro-l,4-Benzodiazepin-2(2H)-Ones
697
further reacted to yield a mixture of the quinoxaline 275 and the diazoxecine 274. The photochemistry of nitrazepam was studied in detail by Roth and A d ~ m e i and t ~ ~by~Cornelissen and van H e n e g o ~ w e n . ~ ~ ~
213
212
274
275
Irradiation with ultraviolet or sunlight in protic solvents led to photoreduction of the nitro group to the amino moiety. The 7-nitroso and 7-hydroxylamino compounds, which were formed at the intermediate stage, underwent further reaction in situ to give the azoxy and azo compounds. If the irradiation was carried out in aqueous acidic medium, the compounds were hydrolyzed to the corresponding benzophenones. Flunitrazepam and clonazepam behave similarly.374aThe photochemical degradation of diazepam with ultraviolet light at 254 nm yielded benzophenones, 4-phenylquinazolinones, 4-phenylquinazolines, and g l y ~ i n e . ~ ~ ~ Among the few thermal reactions carried out with benzodiazepin-2-ones, the formation of the 1-vinyl derivatives 227 by pyrrolysis of the N-oxides of 1-(2-dialkylaminoethyl) compounds 276 (R = Me) was preparatively While the 2-(2-dimethylamino)ethylN-oxide 276 (R = Me) led exclusively to the alkene, the corresponding diethylamino derivative 276 (R = Et) yielded the hydroxyamine 278 in addition to the vinyl compound 277 (Eq. 101). Heating the 1,3-dicarboxylic acid ester 279 in boiling ethanol resulted in ring contraction to the isoindole 280 (Eq. 102).134 1.2.2.7. Other Reactions The ring contraction of benzodiazepin-2-ones to isoindoles, which has been shown to proceed thermally in Section, 1.2.2.6, is generally a base-catalyzed r e a c t i ~ nThe . ~ anion ~ ~ ~generated ~ ~ ~ at the 3-position is believed to attack the electrophilic carbon at the 9a-position intramolecularly, leading to cleavage of the 9 4 1-bond. Tautomerization of the lti-isoindole 281 (R, = H) would then produce the isoindole 283 (Eq. 103). This rearrangement was found to proceed
698
Dihydro-1,4-Benzodiazepinones and Thiones
3'"
276
277
R=Et
HONEt
278
I
Ph
Ph 219
280
more readily with the 3-carboxylic acid ethyl esters 141 (R, = COOR), which is consistent with the easier formation of the carbanion at the 3-position. 7-Nitro groups and electron-withdrawing substituents at the 1-position also facilitated this rearrangement.'34 The intermediates 281 (R, = COOR) preferentially lose the carboxamide function to form the isoindole-1-carboxylic acid esters 282. The quaternary salt of 141 (R, = Me, R, = H, R, = Ph, X = H) was shown to undergo the same ring contraction to the isoindole 283 (R, = Me, R, = Ph, X = H).,Oo Ethyl propiolate, in refluxing tetrahydrofuran, was added to the nitrone function of 154 to form the isoxazoline 284 in approximately 40% yield. The
1. 1,3-Dihydr0-1,4-Benzodiazepin-2(2H)-Ones
699
R3
R3
281
141
R3 282
quinoxaline 286 was isolated as the second product in about 33% yield. The structures were determined by X-ray crystallography (Eq. 104).377
Me
c1
C1 Ph 154
EtOC /I 0 284
Me
Me
285
286
Acrylonitrile also added to the nitrone functionality of 154 to give a mixture of two isomers to which the structure 285 was assigned on the basis of spectral data.' 34
700
Dihydro-1,4-Benzodiazepinones and Thiones
Benzodiazepin-2-ones can serve as ligands to metal ions. Complexes with cobalt with zinc and cadmium halides,379 with ~ t y p h n a t e s , ~and ~' with palladi~rn(I1)~~' were characterized. The complexes formed with bromazepam and chlorides, sulfates, and perchlorates of various divalent metal ions were investigated more recently.3 8 2 , 3
'
1.3. Spectral Data The pH dependence of the ultraviolet spectra of benzodiazepin-2-ones was studied to determine the pK, values of several c o m p o ~ n d s . ~ ~Ultravi~,~~',~~~ olet and circular dichroic spectra of optically active 3-substituted benzodiazepin-2-ones were analyzed.385 Proton-nmr spectroscopy allowed the investigation of the conformational mobility of the seven-membered ring. 1,3-Unsubstituted benzodiazepin-2-ones generally show the 3-protons as a broad singlet at room temperature. 1-Substituted derivatives are more rigid and the 3-protons appear as a distinct AB system at ambient temperature. The coalescence temperature and the activation energy for the interconversion of the two enantiomeric conformations 287 and 288 (Eq. 105) were determined for d i a ~ e p a m , ~ ' ~ . 'n' ~o r d i a ~ e p a m , ~ ni~~,~'~ t r a ~ e p a m , ~and ~ ' several other analog^.^^^-^^' Wh'ile the free energy of activation for the ring inversion is about 10-12 kcal/mol for the 1-unsubstituted compounds, the values for compounds carrying a substituent at the 1-position are considerably higher, between 16 and 19 kcal/mol. The energy barrier has been shown to be sufficiently large in the 1-t-butyl analogs to allow resolution of the two e n a n t i o m e r ~ . ~ ~ '
287
289
288
290
The conformation 290 with pseudoequatorial orientation of the 3-substituent is energetically favored with 3-monosubstituted compounds. Thus 3-methyl and 3-hydroxy derivatives were found to exist in only one conformation at room
2. 1,3-Dihydro-l,4-Benzodiazepin-2(2H)-Thiones
70 1
t e m p e r a t ~ r e . ~Thi ~ ' *s has ~ ~ ~been confirmed by X-ray crystallography for both R- and S-3-methyl-1,4-benzodiazepin-2-ones (290[R, =HI, is the S-alanine derived enantiomer). The methyl groups for both enantiomers were found to be in pseudoequatorial orientation in the crystal, R and S stereochemistry being maintained by inversion of the 7-membered ring."l In the 3,3-disubstituted compound 289 (R, = Me), two conformations were observed. The orientation of the 3-methyl group in the pseudoaxial arrangement was preferred, possibly due in part to hydrogen bonding of the 3-hydroxy group to the 2-carbonyl oxygen.393 Paramagnetic shift reagents were used for both and carbon-13 nmr s t ~ d i e s . ~ Ca ~ 'rbon-13 , ~ ~ ~ nmr s p e c t r ~ s c o p y ~ ~ ' con~~~"-~~~ firmed the conformational data derived from proton-nmr data. More nitrogen15 nmr data have been r e p ~ r t e d . ~ ~ ~Although .~'' mass spectra of many benzodiazepin-Zones were recorded (see Table VII.l), few studies about the fragmentation mechanism were carried The solid state structures of several benzodiazepin-2-ones were determined -414 by X-ray ~rystallography.~'~
2. 1,3-DIHYDRO-1,4-BENZODIAZEPIN-2(2H)-THIONES 2.1. Synthesis The 2-thiones 292 were, in most instances, prepared by treatment of the corresponding 2-ones 291 with phosphorus pentasulfide in pyridine 09, 7 9 * 2 5 , 4 1 - 4 2 (Eq. 106). Tetrahydrofuran in combination with 24979*1
9'
' '
293
102
Dihydro-1,4-Benzodiazepinonesand Thiones
t r i e t h ~ l a m i n edioxane?” ,~~ and ~ y l e n e ~was ’ ~also used as a reaction medium. The conversion of the 4-oxide of 291 (Rl, R, = H; R, = Ph; X = 7-C1) to the thione by means of phosphorus pentasulfide and pyridine was accompanied by a reduction to yield 292 (Rl, R, = H; R, = Ph; X = 7-C1).424The same thione was obtained in 78% yield by treatment of the iminophosphate 293 with hydrogen sulfide and trieth~lamine.,,~A European patent application describes the preparation of a 3-benzyloxycarbonyloxy-2-thione by thiation of the corresponding 2-one using dimeric 4-methoxyphenyl thionophosphine sulfide.425
2.2. Reactions
2.2.1. Reactions with Electrophiles Alkylation of 2-thiones 292 takes place on sulfur, leading to the 2-thioalkyl3H-1,4-benzodiazepines 294 (Eq. 107),or in case of 1-substituted compounds to 295. (See Chapter V for the synthesis the 2-thioalkyl-1H-l,4-benzodiazepines and reactions of these compounds.) Alkylations were carried out with methyl or ethyl iodide and sodium hydride in dimethyl or d i e t h y l f ~ r m a m i d e , ~ ~with ~.~’ dimethyl sulfate and sodium h y d r o ~ i d e , ~ and ’ ~ * with ~ ~ ~ amino-substituted alkylchlorides and various bases.’ 79,427 Bromoacetic acid in methanolic sodium hydroxide alkylated the thione in the same fashion.428
296
Alkylation of the 2-thione 292 (Rl, R, = H; R, = 2-C1C,H4; X = 7-C1) with 1,2-dibromoethane gave 11YOof the dimer and 4.3% of the tricyclic compound
2. 1,3-Dihydro-1,4-Benzodiazepin-2(2H)-Thiones
703
296.’7 9 Similar thiazolines (300) were formed by reacting the 2-thiones 297 (X = H, C1) with 1,2-dichloro-l-methoxyethaneand potassium t-butoxide in dimethylformamide and subsequently with sodium hydride.’ 34 Initial alkylation of the sulfur by the more reactive chloride formed the intermediate 298, which cyclizes, in the presence of sodium hydride, to the observed product 300 (Eq. 108). The only acylation of a 2-thione described was the reaction of 297 (X = H) with dimethylmalonyl dichloride, producing the thiazine derivative 299 in 28 YO yield.310
&$
c1
I-HuOK
____)
CICHCH,CI
cyx
I
OVe
i
298
291
Me
Me
o*o c1 Ph 299 300
2.2.2. Reactions with Nucleophiles Reduction, by desulfurization, of the 2-thiones with Raney nickel led to the 2,3-dihydro-1H-1,4-benzodiazepines.zss (See in Chapter VI, Section 1.1.5.). Lithium aluminum hydride in tetrahydrofuran at 0°C reduced the l-substituted 2-thiones 301 (R = Me, F,CCH,) to the corresponding thiols, which in turn cyclized to the bridged derivatives 302.429
104
Dihydro- 1,4-Benzodiazepinonesand Thiones
Ph
Ph
302
30 1
The 2-thiones 303 were reacted with a variety of nitrogen nucleophiles to form the 2-amino-3H-1,4-benzodiazepines304 (Eq. 110). The ~ ~ ~ ~ ~ * nitrogen nucleophiles included various a m i n e ~ , ~ ~hydroxy- 446 hydrazines’86,292*296-447 and acylated hydraamines,418,425,426,444 ZineS.24a,313.448 -4 54 If the reaction of the thione with the acylhydrazine was carried out at high temperatures, such as boiling in butanol for several hours, the intermediate 2-acylhydrazino derivatives 304 (R, = H, R, = NH-acyl) were cyclized in situ to the triazolobenzodiazepines 305 (Eq. 110). Other suitably functionalized amines 304 (R3= H, R, = 2-alkynyl, 2-acylmethyl) attached at the 2-position were further converted to imidazobenzodiazepines 306 by acid-442 catalyzed ring c10sure.430*431*437
R1
R1
304
303
/// XR, 305
k, 306
The thione 307 underwent the same rearrangement to the isoindole 308 as the corresponding 2-one (Eq. 111).Heating of 307 with sodium hydride in dimethylformamide yielded 80% of the thiocarboxamide 308.300
3. 1,5-Dihydro-1,4-Benzodiazepin-2(2H)-Ones
I
105
Ph
Ph 307
308
3. 1,5-DIHYDRO-1,4-BENZODIAZEPIN-2(2H)-ONES 3.1. Synthesis The 1,5-dihydro-1,4-benzodiazepin-2(2H)-ones 310 were obtained by elimination of leaving groups R, from the 4-position nitrogen of 309.Acetic acid was satisfactorily eliminated from 4-acetoxy compounds 309 (R, = AcO, R, = Ph, R, = H) by treatment with t r i e t h ~ l a m i n e or ~ ~ diethylamine ,~~~ in boiling ethan01.l~~ Dehydration of the 4-hydroxy derivative 309 (R, = OH, R, = Ph, R, = H), by heating in pyridine in the presence of phosphorus oxychloride, yielded the 1,s-dihydro tautomer in addition to the 1,3-dihydro c ~ m p o u n d . ' ~ ' Elimination of equivalents of sulfinic acid from the 4-tosyl derivative 309 (R, = 4-MeC6H,SO,) by means of sodium hydride in benzene gave the 1,5dihydro compound in 35% ~ i e l d . ' ~ ' - 5-Methoxy '~~ compounds 310 (R, = Ph, R, = MeO) were prepared by reaction of the 4-nitro derivatives 309 (R, = NO,, R, = Ph, R, = MeO) with sodium hydride in dimethylformamide at - 10°C (Eq. l12).456
309
310
An efficient synthesis of the 1,s-dihydro tautomers would be possible if the 141, generated by abstracanions of 1,3-dihydro-1,4-benzodiazepin-2(2H)-ones tion of a proton from the 3-position, could be exclusively reprotonated at the 5-position. Kinetic protonation does not seem to be selective, however. Under equilibrium conditions, the 1,3-dihydro compounds are energetically favored if the 3-position is unsubstituted. The 1,Sdihydro compounds become the more stable tautomers in the 3-hydroxy, 3-methoxy, and 3-amino derivatives. It is thus possible to rearrange the 3-hydroxy compounds quantitatively to the
706
Dihydro- 1,4-Benzodiazepinones and Thiones
2,3-diones, while the 3-methoxy and the 3-amino analogs rearrange to the imidates 311 (R, = OR) and amidines 311 (R, = NRR’), respectively (Eq. 113).’49,457A rearrangement occurred during alkylation of the 3-methoxy compound 141 (R, = H, R, = MeO, R, = 2-C1C,H4, X = C1) with l-chloro2-diethylaminoethane and potassium hydroxide in the presence of potassium iodide, giving the corresponding imidate 311 (Eq. 113).,”
I
R3
R3 141
311
3.2. Reactions The rearrangement, by based-catalyzed equilibration, of 1,5-dihydro-1,4benzodiazepin-2-(2H)-ones311 (R, = H) to the corresponding 1,3-dihydro compounds 141 was discussed in Section 1.1.6. The 5-methoxy analogs 310 (R, = H, R, = Ph, R, = MeO) were alkylated at the 1-position by methyl iodide and sodium hydride in dirnethylf~rmamide.~~~ From the reaction of 311 (Rl, R, = H, R 3 = Ph, X = Cl) with N-bromosuccinimide in benzene and subsequent treatment with water-dimethylformamide, oxazepam, 141 (R, = H, R, = OH, R3 = Ph, X = C1) was isolated in 3% yield.458
4. 1,2-DIHYDRO-1,4-BENZODIAZEPIN-3(3H)-ONES Although the parent compound is still unknown, the 2,2-dimethy1-5-phenyl derivative 313 was formed by reaction of the magnesium salt of the imine anion 312 with 2-bromo-2,2-dimethylacetyl bromide (Eq. 114).459The structure of this product was established by X-ray analysis.
Ph 312
I
Ph 313
5. 4,5-Dihydro-1,4-Benzodiazepin-3(3H)-Ones
707
5. 4,5-DIHYDRO-1,4-BENZODIAZEPIN-3(3H)-ONES The parent ring 317 was prepared in 43% yield by photolysis of the 3-azidoquinoline 314 in methanol containing potassium methoxide This ring expansion was formulated to proceed via the imidate (Eq. 115).460,461 315. The aminoquinoline 316 was formed as a by-product.
314
315
316
317
The 2-ethyl-5-phenyl derivative 320 was isolated from the reaction of the acylated anthranilonitrile 318 with phenylmagnesium bromide.462Compound 320 and the addition product 321, with phenylmagnesium bromide, were assumed to form via the aziridinone 319 as indicated in Eq. 116.
319
/
J
NH
NH 320
Ph
32 1
Ph
Compound 323 was the product formed when the emamine 322 was treated with sodium hypochlorite in methanol (Eq. 117).463
708
Dihydro- 1,4-Benzodiazepinonesand Thiones
(117)
N ‘CMe,
‘CMe,
322
323
6. l,ZDIHYDRO-1,4-BENZODIAZEPIN-5(5H)-ONES The only representative of this class of compounds was prepared by Field and coworkers.464 The tetrahydroquinazolinone 324 was reacted with potassium t-butoxide in tetrahydrofuran, at room temperature, to give 325 in approximately 50% yield (Eq. 118). Catalytic hydrogenation over platinum converted 325 to the tetrahydro derivative 326.
H r-BuOKTHF)
RT
N
0 324
0 325
H % - M e NH 0 326
7. 1,4-DIHYDR0-1,4-BENZODIAZEPIN-5(5H)-ONES The 8-chloro compound 328 was formed in 20% yield by photolysis of the 4-azidoquinoline 327 (Eq. 119).461
8. 3P-Dihydro- 1,4-Benzodiazepin-5(5H)-Ones
“W
_ MeO-/MeOH h i7
N3
321
709
“q> H
NH
(119)
0 328
8. 3,4-DIHYDRO-1,4-BENZODIAZEPIN-5(5H)-ONES While the parent compound 330 (Rl, R,, X = H) appears to be still unknown, the 2-phenyl derivatives 330 (R, = Ph, 2-C1C,H4) were synthesized by cyclization of the anthranil amides 329.465- 4 6 8 These anthranil amides were prepared either by reaction of isatoic anhydride with a-aminoacetophenones or by reduction of the nitro compounds with iron and hydrochloric acid (Eq. 120).468
329
330
2-Amino derivatives 332 (XR, = NRR’) were obtained by amination of the 2,5-diones 331 (X = 0)with an amine and titanium t e t r a c h l ~ r i d e -.4~7 1~ ~ . ~ ~ ~ Treatment of the 2-thiones 331 (X = S) with amines HNRR’ led also to the amidines 332 (XR, = NRR’).4712-Thiomethyl derivatives 332 (XR, = MeS) were obtained by alkylation of the 2-thiones (Eq. 121).The thiomethyl analogs reacted with amines to form the amidine~.~”
33 1
332
Nitrosation of the 2-methylamino compound 333 (R = H) led to the nitrosoamidine 333 (R = NO), which reacted with carbanions of nitromethane and dimethylmalonate to form other 2-substituted compounds 334 with liberation of diazomethane (Eq. 122).’34The malonyl derivative 334 (Rl, R, = COOMe) was hydrolyzed to the acetylidene compound 335. Nitrosation of the latter led to the oxime 336, which was transformed into the imidazobenzodiazepine 337 by reduction and subsequent condensation with triethyl orthoacetate (Eq. 122).134
Dihydro-1,4-Benzodiazepinones and Thiones
710
I CHR,R,.
NH
c1
c1
0
0 334
333
336
335 2. MeC(OEt),
0 337
A methyl group was introduced at the 4-position of 330 (R, = Ph, R, = H) by alkylation of 330 (R, = Ph, R, = H) with methyl iodide and sodium amide in toluene.468 Treatment of the 5-one 333 (R = H) with phosphorus oxychloride afforded the 5-chloro-3H-l,4-benzodiazepine, an intermediate, where further variation of the 5-position substituent is possible (see Chapter V).4699470 Phosphorylation of the same 5-one with dimorpholinophosphinic chloride gave the pho~phorylirnidate.~~~~~~~ Thermolysis of the imidate 338 afforded the 5-one 339 (Eq.123).344 333
H A
0 338
339
(123)
9. Dihydro-1,4-Benzodiazepinediones
711
For reductions of the 3,4-dihydro-1,4-benzodiazepin-5(5H)-ones to tetrahydro derivatives, see Chapter VIII, which deals with the synthesis and reactions of the tetrahydro-1,4-benzodiazepines.
9. DIHYDRO-1,4-BENZODIAZEPINEDIONES H
O NH
0 340
34 1
0 342
Of the three possible diones 340-342, representatives of only the 2,3-diones 340 have been synthesized. The 2,3-diones 343 were obtained by oxidation of the 2-ones 141 (R, = H, Me; R, = H, OH, R, = Ph) with ruthenium tetroxide or by treatment of the 3-hydroxy compounds 141 (R, = OH) with activated manganese dioxide (Eq. 124).157,'58Another method involves the oxidation of the 3-phosphoranes obtained by treatment of the 3-triphenylphosphonium salts 141 (R, = PPh,) with molecular oxygen.243
R 3
141
1
Ph 345
The 2,3-diones 343 are readily attacked by nucleophiles. Hydrolysis led to the quinazolinones 344,which were also formed as by-products during the preparation of the diones by 0xidati0n.l~' Reaction of 343 (R, = H, R, = Ph, X = C1) with aqueous potassium carbonate afforded 40% of the quinazoline-2-carboxylic acid 345 (R = OH). The amide 345 (R = NH,) was similarly formed and
Dihydro- 1,4-Benzodiazepinonesand Thiones
712
was isolated in 7% yield from the oxidation of oxazepam with ruthenium tetroxide.' An early report in the literature,472 describing the synthesis of the benwho zodiazepin-3,5-dione 347,was later corrected by Gilman and showed that the reported benzodiazepine 347 was actually the benzoxazinone 348.Compound 348 was obtained by heating the hydrazide 346 in acetic anhydride for several hours at reflux (Eq. 125). 0
z
3
-
E
P
h
0
*
q > No 0
346
h P h 1
Ac 34 7
I
(125)
A Ac,O
Gy
Ac
I NPh
0 348
10. TABLE OF COMPOUNDS TABLE VII-I. DIHYDRO-1,4-BENZODIAZEPINONES AND DIHYDRO-1,4-BENZODIAZEPINTHIONES
Substituent
mp ("C) or; [bp ("C/torr)]
Solvent of Crystallization
Yield (%)
Spectra
Refs.
83 86 70
ir, pmr, uv ir, pmr ir, ms, pmr
1 193
51 90 86
ir, pmr, uv
1 193 193 192 67b 474 193 86b 224 70 21 13 193 86b 67b
I .3-Dihydro-l.4-benzodiazepin-2(2H)-ones
Unsubstituted
None 4 +
W
4-Oxide Monosubstituted 3-Ac0 5-AcNHNHCO S-(Allyloxy)CO 5- H iN C0 S-(Z-Benzofuryl) 5-Bu 5-HOOC 5-Cycloheptyl 5-(Cyclohex-1-en-1-yl)-7-C1 5-Cyclohexyl 5-Et 5-Ferrocenyl 5-(NH,NHCO)
5-(3-H2NNHCO-Thien-2-yl) 5-(2-Indolyl)
225-227 215-217d 259-26Od
MeCN
197-198d 233-234 128-129 262-264 196-197d 75-76 139-140 158-160 207-208 199-201 123-124 224-227d 213-21 5d 235-237 223-225
THF
EtOH/H,O
MeOH/Ace.tone MeCOEt 80 EtOAc
80
EtOAc CH,CI,
80 91 81
MeOH EtOH
ir, pmr
1
TABLE VII-1. --(contd.)
Substituent 5-Me Hydrochloride 4-Oxide 5-( I-Me-3-Indolyl) 5-(5-Me-1,3,4-0xadiazol-2-yl)
mp ("C) or; [bp ('C/torr)]
Solvent of Crystallization
285-286 235-236 235-240 268-269 200
H2O Acetone/MeOH EtOH
Yield (%)
Spectra
32 38
5-(4-Me-3-HS-1,2,4-Triaz01-5-~1)
2
5-(3,5-Me,-Isoxazol-4yl 5-(3,6-Me2-Pyrazin-2-yl) 5-(2,2-Me2-Propyl) 5-(MeNHCSNHNHCO) 5-MeOOC 5-(3-MeOOC-Thien-2-y1) 5-(Naphth- 1-yl)-7-C1 5-Octyl-7-C1 5-Ph Hydrochloride 4-Oxide 5-(2-BrC,H4) 5-(2-C1C6H4) 4-Oxide 5-(2,4-C12C6H3) 5-(4-ClC,H4) 5-(2-HOOCC,jH4).H20 5-(2-FC,H4) 5-(2,6-F,C6H3) 5-(2-F-4-ClC,H,)
276-277d 269-27Od 138-139 2 14-2 15 173-175 193-1 94 192-194 98-99 178-179 251-253 250 220-222 2 12-2 13 230-232 218-220 262-263 215-230 243-244d 180-181 242-244 232-233
EtOH EtOH PhH/Hexane 68 51 MeOH PhH/Hexane PhH EtOH MeCN
85.5
CH,Cl,/EtOAc/Hexane CH2C12/Et,0 CH,Cl,/EtOH EtOAc/Et,O EtOH H,O/AcOH Acetone/Hexane MeOH EtOH
71
ir, pmr
Refs. 34 34 298 67b 193 193 13b 13b lb 193 193 86b 476 Ib 2, 35 34 34 134 91 134 134 91 15 2b 2 152c 152b
I .
L
5-(2-F-5-02NC6H3) 5-(4-FC,H,) 5-(2-F,CC,H,) 5-[2,5-(F,C),CeH,I 5-(3-F3CC6H4) 5-(4-F3CC6H4) 5-(2-02NC,jH4) 5-(3-02NC6H4) 5-(4-O,NC6H,) 5-(2-Ph-Ethyl) 5-(2-Pyridyl) 5-(4-Pyridyl) 5-(2-Thiazolyl) 4-Oxide 5-(2-Thienyl) 7-Br 7-C1 4-Oxide Disubstituted
219-222 188-190 187-188 280 204-205 219-220 206-208 224-227 279-281 152-153 232-234d 206-207 248-249 255-257 197-198 251-254 247-252d 255-257
PhH/Acetone Et,O/Hexane PhH MeOH MeOH PhH/Petr ether Acetone PhH CHCI,/Petr ether HOAC PhH/Hexane Acetone Acetone PhH
135-137 129-1 3 1 135-138 83-85 151-153
EtOH i-PrOH Et,O/Hexane Et,O/Hexane
38 Acetone/Hexane Et,O/Hexane
61
uv
37 70
uv
27 25 69 75
uv
152a 152c 4 17 4 4
41, 136 152a 152a 2b 3 3 21 33b 22 247 247 247
1.5-Disubstituted
1-(2-Ac0-Ethyl)-5-(2-FC6H4) l-[2-(N-H,NC0CH2-N-Me-Amino)ethyl]-5-Ph 1-Benzyl-5-(2-BrC,H4) l-t-Bu-5-Ph l-t-Bu-5-(2-CIC,H,) l-(Cyc1opropyl)CH2-5-Ph Hydrochloride 1-[2-(EtO-Acetoxy)ethyl]-5-(2-FC,H,) I-(2-Et2N-Ethyl)-5-Me l-(2-Et2N-Ethyl)-5-Ph
1-(2-Et2N-Ethyl)-5-(4-ClC6H4) 1-(2-Et,N-Ethyl)-5-(3-F3CC,H,)
204d 154-158 64-65 80-8 1 90-94 58-60
MeOH/Et,O Pentane Hexane Hexane Hexane
86b 302 134 391b 391b 86b 86b 255c 302 302 302
601-101
ZZ 1Z
E 12-ZIZ
3SSZ
SIZ
tE I E6Z
998 LlP 9E I PE I 2OE ESS2 325 I 10E 2
PP
ESS2
P I I-El I
881-S81 00-66 I
PZI-ZZI Pt7Zl-EZI 08 I-8LI z21-IZI LEI-SET 011-691 922-SZZ
PIT-Ell LEI-SEI
16
291-091 121-671
PE I
PE 1 WE
6lZ-9LZ 081-91 I
Em Z
9s I-PS I 012-602 WI-E91 601-101
9E I El 261 261 862 92 69
Soz-Eo2
I LZ-892 9Sl-SS1 6EI-8El
9d-S-aN- 1 ([K-p-[ozexos~-~a~-~'~)-~-a&q1 ~ b u a o i i a . ~ - ~ - aI ~ q N3-S-aJq- I O~N'H-S-~MI-I aP!xo-P 'aMI-S'I qd-S-'H33'd-I
l-(2-Me2N-Ethyl)-5-[2,5-(F,C)2C6H3] Dihydrochloride I-(3-Me2N-Propyl)-5-Ph
1-(3-Me,N-Propyl)-5-[2,5-(F,C),C6H3] Dihydrochloride 1-(3-Me2N-Propyl)-5-Me 1-MeOCH2-5-Ph 1-Me00CCH2-5-(2-C1C6H,)
1-(2-OxopyrroIidin-l-yl)CH,-5-Ph
- loo 145-146 - loo66-67 72-74 166-168 120
Et20 CH,CI,/Et,O/Petr ether
17 2b 17 25% 72c 292 478
Et ,O/Pentane Et20 MeOH
1,7-Disubstituted
1-(2-Et,N-Ethyl)-7-C1 4-Oxide 1-Me-7-Br I-Me-7-CI
88-90 117-120 105-107
Et,O Et,O EtOH/Cyclohexane
61 6.5
ir, ms, pmr
176a 152c 116
3,S-Disubstituted 4 +
4
3-AcNH-5-Ph 3-Ac0-5-Ph 3-Ac0-5-(2-C1C6H,) 3-H2N-5-Ph
3-(4-t-BuOOCNH-Butanoyloxy)-5-Ph~ 03-PrOH 3-(N-t-BuOOC-D-Phenylalanine ester)-5-Ph Isomer A Isomer B 3-(N-t-BuOOC-~-Phenylalanineester)-5-Ph Isomer A Isomer B 3-HOOC-5-Ph Dipotassium salt Potassium salt 3-Et-5-Ph 3-EtOOC-5-Ph 4-Oxide
222-224 229-23 1 290-291 178-179 124-126 116-1 19 204-205
42
202 263 134 202 478
CH,CI,/EtOAc 62 i-PrOH Cyclohexane
478 478
136 131
478 478 ir, uv
ir. uv 169 226 192-194
EtOAc EtOAc/EtOH
20 70
uv
104 104 100 104 108
TABLE VII-1. ~ q c o n t d . )
4
&
Substituent
mp ("C) or; [bp (Tjtorr)]
Solvent of Crystallization
3-EtOOC-5-(4-C1C6H4) 3-EtOOC-5-(2-F3CC6H4) 3-EtOOC-5-(4-MeC6H4) 3-EtOOC-5-(4-MeOC6H4) 3-HO-5-Ph 3-Me-5-Ph ( +)-Enantiomer 3-R-Me-5-(2-C1C,H4). OSEtOAc 3-S-Me-5-(2-C1C6H,). 0.5EtOAc 3-R-Me-5-(4-ClC,H4) 3-S-Me-5-(4-C1C6H,) 3-Me-5-(2-FC6H,) 3-Me2N-5-Ph 3-[2-(2-Oxopyrrolidin- 1-yl)acetoxy]-5-Ph 3-i-Pr-5-Ph
222-227d 183 189-1 91 187-192 194-195d 203-204 162-163 82-85d 82-85d 233-235 234-235 174 236-238 245 233
MeCN MeCN EtOH EtOH PhH EtOH EtOAc/Hexane EtOAc/Hexane CH,CI,/EtOH CH,CI,/EtOH Cyclohexane
Yield (%)
Spectra
Refs.
10
302 82 302 302 148 100 30 1 134 134 134 134 251b 149 478 100
18
2
44 28
84
5.6- Disubstituted
5-Ph-6-CI
244-245
PhH/Hexane
273-274
MeOH/Acetone
159-160 207-210 168 155-1 59 188 192- 193 169-179
EtOH/PhH CH,Cl,/PhH EtOAc CH,Cl,/i-Pr,O EtOAc PhH/Hexane PhH/Hexane
S,7-DisuLstituted
S-H2NCO-7-Br S-(Benzocyclohept-2-yl)-7-C1, complex with 2-(2-H2N-5-C1-benzoyl)benzocycloheptane 5-(1,3-Benzodioxolan-5-yl)-7-C1 5-Benzyl-7-Cl 5-Bu-7-CI 5-t-Bu-7-CI
192 28 33
79
49 92 18 124 18 lb lb
5-C6D5-7-C1 4-Oxide 5-(l-C1-Cyclohexan-l-yl)-7-C1 5-(1-C1-Cyclohexan-1-yl)-7-NOZ 5-(1-C1-Cyclopentan-l-yl)-7-C1 5-(1-Cl-eth-l-yl)-7-C1
5-(l,l-Cl,-eth-l-yl)-7-C1 5-Cl2CH-7-C1 5-c1,c-7-c1 541-Cl-but- 1-yl)-7-C1 54 1,1-CI,-but- 1-yl)-7-C1 5-(1-Cl- 1-Me-prop- 1-yl)-7-C1
5-(1-CN-Cyclohexan-l-yl)-7-C1 5-(Cyclohexen-l-yl)-7-C1 5-Cyclohexyl-7-CI
2
5-Cyclohexyl-7-F3C 5-Cyclohexyl-7-Me 5-Cyclohept yl-7-CI 5-Cyclohexyl-7-N0, 5-(Cylcopent-en-l-yl)-7-C1 5-Cyclopentyl-7-Cl 5-Cyclopropyl-7-CI 5-( 1,3-Dithian-2-yl)-7-C1 5-Et-7-C1 5-(3-EtO-Propyl)-7-C1 5-Ferrocenyl-7-1 5-(2-Furyl)-7-C1 5-(2-HO-Ethyl)NHCO-7-Br 5-(2-Indolyl)-7-C1 5-(Isothiazol-l-yl)-7-C1 5-Me-7-Br 5-Me-7-Cl
2 15-2 16 233-234d 196- 198 247 191d 197d 160,190d 21od 185d 128-129 208 141 236 207-208 212 200-202 179-183 165-166 159-1 61 232-233 204-205 182 170-1 7 1 198-200 157-159 134, 156 112-1 13 168-1 7Id 245-246 196-198 297-3OOd 247-249 223-224 226-228
EtOAc Xylene i-Pr,O EtOAC MeOH EtOH MeOH i-Pr,O EtOAc Et,O MeOH EtOAc EtOAc Hexane EtOAc MeOH/H,O Acetone EtOAc MeOH/H,O Acetone CH,Cl,/Hexane EtOAc PhH/Hexane CH,Cl,/Hexane Acetone CH,Cl,/MeOH Acetone EtOH MeOH EtOAc
41 78 77 87 70 61 73 56 40 81 78 50
ir, pmr, uv
50
80 90
66
38 62
51; 75 91
66
ir, pmr, uv
97 97 222 224 224 224 224 224 224 224 224 224 224 222 18 34 lb 18 70 70 224 18 70 lb 391b 18,21 lb 13 22 192 67b 13b 2b 18
TABLE VII-1. +contd.)
Substituent 5-Me-7-N02 5-(3-Me-Butyl)-7-C1 5-( 1-Me-Imidazol-2-yl)-7-C1 5-(3-Me-Isoxazol-5-y1)-7-C1 5-( 5-Me-Isoxazol-3-yl)-7-C1 5-( 3,5-Me,-Isoxazol-4-y1)-7-I 5-(4-Me-Piperazin-I-yl)-7-C1 5 4 (1 -(4-Me-Piperazin-1 -yl)cyclohex-l-yll-7-Cl 5 4 l-Me-prop-l-en-l-yl)-7-C1
. . I h)
5-(3,6-Me2-Pyrazin-2-yl)-7-Br 5-(2-Me-Pyrazol-3-yl)-7-C1
0
5-(4-Me-3-SH-1,2,4-Triazo1-5-yl)-7-C1 5-( l-Me,N-Cyclohex-l-yl)-7-C1
5-(3-Me2N-Propyl)-7-C1 5-(Me2N),CH-7-C1 5-MeOOC-7-CI 5-(4-MeOOCCH,O-C6H,)-7-C1 5-(6-MeS-2-Pyridyl)-7-Br 5-(6-MeOS-2-Pyridyl)-7-Br 5-(6-MeOZS-2-Pyridyl)-7-Br 5-Pentyl-7-Cl 5,7-Ph, 5-Ph-7-Ac 4-Oxide 5-Ph-7-AcNH 4-Oxide
mp ("C) or; [bp ("C/torr)]
Solvent of Crystallization
221-223 185-188 243-245d 243-245 241-242 253-254d 241-243d 240 168 221-222 264-266 196-197 216-218 > 300 222 209-2 11 188d 173-1 74 235-243 238 255 248 104 234-235 184-186 192-193 208-209
EtOH EtOH Acetone/Petr ether MeOH MeOH CH,Cl,/Hexane EtOAc EtOAc i-Pr,O
> 215
MeOH/EtOH
EtOH CHCIJHexane EtOAc/Petr ether EtOH EtOH/Et,O EtOAc MeOH EtOH EtOH EtOH Cyclohexane PhH/Petr ether PhH/Petr ether i-PrOH Acetone
Yield (%)
83 30 47
61 58 10 32
75 20
Spectra
Refs. 2b lb 27 479 479 13b 134 224 224 86b 28 27 27 193 224 Ib 224 193 152c 480 480 480 18 2 11
44 32, 44 251c
5-Ph-’l-(Adamant-l-yl)CONH
-1
5-Ph-7-H2N 4-0xide 5-Ph-7-H2NC0 5-Ph-7-(H,N-Hydroxyiminomethyl) 5-Ph-7-H2NS02 5-Ph-7-N, 4-Oxide 5-Ph-7-(Benzoyl)NH 5-Ph-7-Br 4-0xide 5-Ph-7-(4-BrC6H,CHN) 5-Ph-7-BU 5-Ph-7-t-Bu 5-Ph-7-BuS Hydrochloride 5-Ph-7-HOOCCH2S 5-Ph-7-(l-Carboxy-l-ethyl) 5-Ph-7-C1 4-Oxide Hydrochloride Methiodide Tosylate BF, . Et,O Adduct of 4-oxide 5-Ph-7-(4-C1C6H4) 5-Ph-7-(4-C1C,H,CHN) 5-Ph-7-(5-C1-2-HOC6H3)-N2 5-Ph-7-Diazonium Tetrafluoroborate 5-Ph-7-(1,3-Dioxolan-2-y1) 5-Ph-74 1-C1-Ethy1)S Hydrochloride 5-Ph-7-CICHZS Hydrochloride
327-329d 228-23 1 274-275d 268-27 1 273-275d 287-288d 174-175d 186-1 88d 261-262 220-221 230-231 196-198 145-147 244-245
MeCN EtOH DMF/EtOH
69 uv
DMFiEtOH CH,CI,/Hexane THF/Hexane MeOH Acetone CH,CI,/Petr ether
32 50 83 76 50
PhH/Petr ether EtOH
33b 136 252 5 33b 98 252 252 251c 2 91a 202 33b 479
247-249 230 252-255 216217 238-239 251-252 250-251 280-281 160-165d 27 1 192-193 288-290
EtOH/MeCN EtOH/H,O Et,O/Petr ether Acetone EtOH EtOH Acetone PhH
221d 153-154 195-196 236-238
HBF, EtOH EtOH
251b 32 7 7
258-26Od
MeOH
7
9 52
99
PhH PhH
72 54
ir, pmr
7 2b 20 20 30 30 30, 31 498 235 48 1 202 202
TABLE VII-I. 4 c o n t d . )
Substituent 5-Ph-7-CN 5-Ph-7-(Cyclohexyl)CONH 5-Ph-7-(1,3-Dihydro-2-0~0-5-Ph-2H1,4-benzodiazepin-7-yl)
4 h) h)
5-Ph-7-Et 5-Ph-7-Et0 5-Ph-7-(2-EtOOC-tmns-Ethen-l-y1) 5-Ph-7-EtS Hydrochloride 5-Ph-7-(Et)OS 5-Ph-7-(4-Et2NC6H4CHN) 5-Ph-7-OCH Hydrazone Oxime '0.5EtOH Thiosemicarbazone 5-Ph-7-F 5-Ph-7-FzCHO 5-Ph-7-F2CHS 5-Ph-7-F,CHSO2 5-Ph-7-F,C 4-Oxide
5-Ph-7-(2-F3C-1,3-Dithiolan-2-yl) 5-Ph-7-(Fornyl)NH 5-Ph-7-(2-Furyl)CHN 5-Ph-7-(Hexafluoro-2-HO-prop-2-y1) 5-Ph-7-HO 5-Ph-7-HONH 5-Ph-7-(1-HO-Butyl)
mp ("C) or; [bp ("C/torr)]
Solvent of Crystallization
256-257 188-1 90
MeNO, MeOH/Acetone/Hexane
5, 15 251c
348d 238d 194-195 174-1 76 190-192
THF
48 1 86b 33b 134 33b
273 195-196 255-257 155-158 219-221 240-242 266-268d 197-198 182-183 174-175 247-248 204-205 2 17-21 8 215-216 227-229 168-169 271-273 287-290 186-187 172-174
EtOH/MeCN Acetone
Yield
(YO)
Spectra
PhH/Petr ether CH,Cl,/EtOH EtOH
7 7 202 33b 33b 33b 33b
40 MeCN DMF/H,O EtOH/H,O DMF/H 0 Acetone/Petr ether PhMe PhMe EtOH PhH/Hexane PhH/Hexane CH,Cl, MeOH/Acetone/Hexane
,
76 70 84 46 25 84
39 EtOAc/Et ,O MeCN CH,Cl,/EtOH Et,O/Pentane
65
Refs.
n
L
ir, ms, pmr, uv ir, ms, pmr, uv ir, ms, pmr, uv
10 10 10 4 4 257 251c 202 482 L
246 33a
5-Ph-7-(l-HO-Ethyl) 4-0xide 5-Ph-7-(2-HO-Ethyl)S Hydrochloride 5-Ph-74 1-HO-Pentyl) 5-Ph-7-(4-HOC,H4CHN) 5-Ph-7-(3-HO-Propanoyl) 5-Ph-7-(1-Propyl) 5-Ph-7-(2-HO-Prop-2-yl) 5-Ph-7-(3-HO-Propyn-l-yl) 5-Ph-7-1 4-Oxide 5-Ph-7-Me 4-0xide
5-Ph-7-(2-Me-1,3-Dioxolan-2-y1) . . I
h,
W
4-Oxide 5-Ph-7-(2-Me-Propanoyl)NH 5-Ph-7-(2,2-Me2-Propanoyl)NH 5-Ph-7-MeNHS0, 5-Ph-7-Me0 4-Oxide 5-Ph-7-(4-MeO-Benzoyl)NH
5-Ph-7-MeOOC 5-Ph-7-MeONC 5-Ph-7-MeS 4 -0xide 5-Ph-7-(Me)OS 5-Ph-7-(Me)02S 4-0xide 5-Ph-7-Me2N N-Oxide 5-Ph-7-Me2NCH,
214-216 193-195
Et,O Acetone/Hexane
252-253d 171-1 74 276-277 165-185 179-1 81 227-229 205-207 226228 247-248 208-209 235-236 22C227 25Ck252 2W208 246 177-180 293-296 2 17-21 8 189-190 3W307 2 19-220 193-195 216218 191-193 193-194 254d 256258 256257d 245-247 196197d 175-1 79
EtOH/i-PrOH Et ,O/Pen t ane
33a 33b
70 CH,CI,/Hexane Et,O Et,O CHCI,/Hexane i-PrOH EtOH EtOH/Petr ether CH,CI,/Petr ether EtOH Acet one/Hexane EtOAc/Hexane EtOAc/Hexane EtOH/DMF PhH Acet one/Hexane MeOH MeOH MeCN Acetone EtOH/H,O Acetone EtOH/MeCN Acetone/ DMF/EtOH EtOAc EtOH/Et,O CH,Cl,/Petr ether
82
42
uv
uv
7 33b 202 33b 33a 33a 33b 371 371 2 34 91a 32 33b 251c 251c 2b 2 lb 251c 5 33b 7 7 218 7 7 33b 95 72c 38b
TABLE VII-I. ~ 3 c o n t d . j
Substituent 5-Ph-7-Me2NCHN Dihydrochloride 5-Ph-7-(4-Me,NC6H,CHN) 5-Ph-7-Me,NSO2 5-Ph-7-(Morpholino)CH2 5-Ph-7-NO2 4-Oxide
4
h)
5-Ph-7-(2-0,NC,H4CHN) 5-Ph-7-(3-0,NC,H4CHN) 5-Ph-7-(4-O,NC,H,CHN) 5-Ph-7-(4-O2N-BenzoyI)NH 5-Ph-7-(0xiran-2-yl) 5-Ph-7-(Pentanoyl 5-Ph-7-(PhCHN) 5-Ph-7-(Piperidin-l-yl) 5-Ph-7-Propanoyl 5-Ph-7-(Propanoyl)NH 5-Ph-7-Pr2(O)P 5-Ph-7-(Pyrrol-1-yl) 5-Ph-7-(3,4,5-Triaza tricyclo[5.2.1 .O]dec-4-en-3-y1) 5-Ph-7-Vinyl ~-(~-AcOC,H,)-~-CI 5-(4-H,NC,H,)-7-C1 4-Oxide 5-(4-H,NCOCH,0C6H4)-7-C1 5-(2-BrC6H,)-7-C1 S(2-BrC6HJ-7-F
mp ("C) or; [bp ("C/torr)]
Solvent of Crystallization
260-262d 2&243 226227 219-221 224-226 208-218d 218-22Od 154156 237-238 278-280 279-28 1 186d 6346 168-170 250-252 172-175 251-252 21421 5d 250-258 197-198d 213-21 5 225-228 262-266 256258 235-243 208-209 194196
EtOH i-PrOH Acetone EtOH EtOH EtOHiPetr ether
Yield (%)
Spectra
Refs.
61
ir
39 19
ir, ms ir
2b 202 98 38b 136 139 136 202 202 202 251c 33b 33b 202 95 33b 251c 483 67b 33b 33b 152c 302 8 8 2b 134
50 30
55
37 50
MeOH Et,O Et,O/Pentane EtOH EtOH/Petr ether Et,O MeOH/Acetone/Hexane i-PrOH/Et,O MeOH EtOAc THF CH,CI,/Hexane Acetone/H,O THF/MeOH CH,CI,/Et,O Petr ether THF/EtOH
4
t 4
5-(4-BrC,H,)-7-Br 4-Oxide 5-(4-BrC,H4)-7-C1 5-(2-HOOCC6H4)-7-C1 5-(2-CIC,H4)-7-AcNH 5-(2-C1C,H4)-7-HzN 5-(2-C1C6H4)-7-N3 5-(2-ClC,H4)-7-t-Bu 5-(2-C1C,H4)-7-C1 4-Oxide Methiodide 5-(2-CIC,H4)-7-CN 5-(2-C1C,H4)-7-Et0 5-(2-ClC,H4)-7-F 5-(2-ClC,H,)-7-HONH 5-(2-C1C,H4)-7-Me 5-(2-C1C,H4)-7-Me0 5-(2-CIC,H4)-7-MeS 5-(2-C1C,H4)-7-Me,N 5-(2-ClC,H4)-7-NOz 4-Oxide 5-(2-CIC,H4)-7-H03SNH Ammonium salt 5-(3-ClC,H,)-7-NO, 5-(2,3-CI,C6H3)-7-C1 5-(2,4-CI,C,H,)-7-C1 5-(2,5-C1,C6H3)-7-C1 5-(2,6-C1zC6H&7-C1 5-(2-CI-6-FC,H&7-C1 5-(2-C1-4-HOC6H3)-7-C1 5-(2-C1-5-HOC,H3)-7-C1 5-(2-C1-4-MeOC,H3)-7-C1 5-(2-C1-5-MeOC,H3)-7-C1
260-26 1 d 260-264 207-208d 292-300 23G232 186-1 87d 274-275 199-201 248-249 198-2Wd 232-233 228-230 197-199 182-183 223-224 224-228 221-223 245-248 237-239 254d 284-288d 182 225-227 231-233 27Cb271 231-233 234-235 222-225 280-290 292-294 229-230 221-223
CHCl,/EtOH THF/PhH THF/MeOH Petr ether EtOH CH,CI,/Hexane Et,O EtOH PhH/Petr ether MeCN EtOH CH,CI,/EtOAc EtOH CH,Cl,/MeOH/Et,O MeOH EtOAc/Et,O EtOH EtOAc CH,CI,/EtOH EtOH HZO EtOH/Hexane CH,CI,/Petr ether Acetone Acetone/Petr ether CHzCl,/Et20 EtOH
THF/Hexane MeOH/EtOAc CH,CI,/EtOH EtOAc/Hexane
70 75 93
ir, pmr
uv
358 152c 2b 152c 136 252 134 2 91a 179 5 , 15
134 134 134 uv
64
83 51
5, 91
134 7 95 12 8 134 301 2b 500 2b 42 2b 152c 134 134 134
TABLE VII-1. 4 c o n t d . )
Substituent
5-(2-Cl-5-0,NC6H3)-7-NOz 5-(3-ClC,H4)-7-CI 5-(3,4-C1,C6H,)-7-C1 5-(3,5-C1,C6H4)-7-C1 5-(4-ClC,H4)-7-Br 4-Oxide 5-(4-ClC,H4)-7-C1 5-(4-CIC,H4)-7-F 5-(4-C1C6H4)-7-Me0 5-(4-CIC,H4)-7-N0, 4-Oxide 5-( 3-C1-2-Pyridyl)-7-C1 5-(2-EtOC,H4)-7-EtO 5-(2-FC,H,)-7-Ac 4-Oxide ~-(~-FC,H~)-~-ACNH 4-Oxide 5-(2-FC,H4)-7-AcS 5-(2-FC6H4)-7-H2N 5-(2-FC6H4)-7-(H2N-Hydroxyiminomethyl) 5-(2-FC,H4)-7-H,NCHz Picrate 5-(2-FC,H4)-7-N3 5-(2-FC,H4)-7-Br 5-(2-FC6H4)-7-(Butanoy1)NH 5-(2-FC,H4)-7-C1 4-Oxide 5-(2-FC,HJ-7-CN 2-(2-FC,H4)-7-(Cyclopentyl)CONH
mp (“C) or; [bp (‘Cjtorr)]
Solvent of Crystallization
Yield (%)
Spectra
Refs.
33C331d 247-248 245-247 237-238
EtOH CH,CI,/MeOH Acetone
26&261d 247-248 23C232 219-22 1 253-254 25C252 221-222d 184187 21 1-213 215-216d
EtOH Acetone CH,CI,/EtOH CH,CI, MeOH CH,CI, EtOAc/Hexane Et,O/Petr ether Acetone
28C300 168-1 70 264-266 261-263d
CH,CI,/EtOH Et,O EtOH DMF
301 301 136 33b
194198 172-173 186187 2w204 205-206 22C223 239-240 165-1 70
THF/MeOH PhH Acetone/Petr ether EtOAc/Petr ether PhH/Hexane Acetone/MeOH Petr ether MeOH EtOAc/Et,O
152c 485 2 301 2 233 5 301
258
H2S04/H20
2
70
92 2b 34 91a 92
500
134 136, 86b 91a 484 134 11 2b
84 90 67 uv
5-(2-FC6H,)-7-(Cyclopropyl)CONH 5-(2-FC6H4)-7-Et 4-Oxide 5-(2-FC,H,)-7-EtNH 5-(2-FC,H4)-7-EtO 5-(2-FC6H,)-7-EtOCS2 S(2-FC6HJ-7-F
5-(2-FC,H,)-7-(l,l-F,-Ethyl) 5-(2-FC,H,)-7-[5-(2-FC6H4)-1,3-Dihydro-2-0~02H- 1,4-benzodiazepin-7-yl]thio 5-(2-FC,jH,)-7-OCHNH 5-(2-FC,H4)-7-HO 5-(2-FC,HJ-7-( 1-HO-Ethyl) 4-Oxide.0.6 H,O
5-(2-FC,H,)-7-(2-HO-Ethyl)NHCONH -1 h)
-.I
5-(2-FC6H,)-7-(1-HO-Iminoethyl) 5-(2-FC6H4)-7-(2-HO-prop-2-yl) 5-(2-FC6H,)-7-HS S(2-FC6HJ-7-1 5-(2-FC6H4)-7-MeNHCONH 5-(2-FC6H,)-7-[ 1-(4-MeC6H,SO,-Hydrazonoethyl] .2H,O 4-Oxide 5-(2-FC6H,)-7-Me0 5-(2-FC6H,)-7-MeS 4-Oxide 5-(2-FC6H,)-7-MeS(0) 5-(2-FC6H,)-7-MeSO, 4-Oxide 5-(2-FC,H4)-7-N0, 4-Oxide 5-(2-FC6H,)-7-(0ctadecanoyl)NH
278-280 199-201 173-175 17&178 187-190 182-1 84 197-200 210-212
EtOAc PhH/Petr ether CH,Cl,/Et,O Et,O EtOAc/Hexane Et,O Acetone EtOH
250-256d 250-254 31l3311d 222-224 125-140 Amorphous 232-233 230-232 194198d 222-224 183-19Od
EtOH EtOAc EtOAc/CH,Cl, Et,O Et,O EtOAc Et,O Et,O EtOH Et 0Ac/Et ,O
30 1 301 301 33a 33b 301 251b 33a 301 26 301
240-242 192-196 195-198 193-195 186188d 2W242d
EtOH EtOH CH ,C1 ,/E t 0Ac MeOH/Et,O CH,Cl,/Hexane CH,Cl,/Et,O
33b 141 134 192 192 301
24&245d 222-224 21c211 232-233 11tb118
EtOAc EtOH Acetone THF/Et,O Et,O
301 12 136 2b 301
93
301 33b 33b 301 134 301 500 360
POOEQ62
3251
PfZ-EEZ 9SZ-PSZ OOZ-661 LZZ9ZZ Z61Q6I S8I-E81 PL62-56Z 9LZ-f LZ IZZQZZ S81-81 PZZ-EZZ P6LI-8LI zzz-IZZ 861-L61 IOZQOZ 862-562 SLZ 602-SOZ EIZ-LOZ 1 12-807. 8OZ-PoZ 08I WZ-6EZ OZZQIZ fOE-86Z ZIZ EPZ-LEZ
3ZS I 6SZ 325 I
9 56 L
P 9 9 8 8 P8P 3ZS I Z ZSZ 9 9 Z 9SZ 'EZSI 652 32s I 3ZS I PE I 32s I 652 3251
I!
EP 99
EP SL L9
LP I8 !LS
EZ
f SZ-ISZ
5-(4-H,NNHCOCH,O)C6H,-7-C1~O.5 mol THF 5-(2-HOC6H4)-7-CI 5-(2-HO-4-FC6H&7-C1 5-(4-HOC6H4)-7-CI 4-Oxide 5-(4-MeOOCCH2OC,H,)-7-C1 5-(2-MeOC6H,)-7-C1 5-(2-MeOC6H,)-7-Me0 5-(3-MeOC6H,)-7-C1 5-(4-MeOC6H,)-7-C1 5-( 1-Me- 1-Pr)-7-C1 5-(2-MeC6H,)-7-C1 5-(2-MeC6H,)-7-F 5-(2,4-Me2C,H,)-7-C1 5-(3,4-Me2C,H,)-7-C1 5-(3-MeC6H,)-7-C1 5-(4-MeC6H,)-7-Br 4-Oxide 5-(2-Me2NC,H,)-7-C1 5-(2-MeSC6H,)-7-Cl 5-(Morpholino)CO-7-Br 5-(2-O2NC,H,)-7-Br 5-(2-O,NC,H,)-7-NO, 5-(3-O,NC,H,)-7-C1 5-(4-0,NC6H,)-7-C1 5-(3-O,NC,H,)-7-NOz 4-Oxide 5-(4-PhC,H,J-7-C1 5-(2-Ph-Ethenyl)-7-C1 5-PhSO2CH2-7-CI 5-(Piperidin-I-yl)CO-7-Br 5-(Piperidin-1-yl)CO-7-NO2
18&185
21&220 285-28 7 29&295 271-272 280-281d 212-275 205-207 189-192 219-220 212-2 14 136 180-181 175-176 185-186 210-212 24&242 198-199 239-240 237-23 8 239-240 184-185
237-238 22&222 226-228 234-238 248-250 25&254 243-244d 272-275 21&212 236238 183-186 225-228
THF/Hexane MeCN CHCIJEtOH Acetone Dioxane/H,O EtOH/CHCl, EtOH/H,O EtOAc/Hexane Acetone/Hexane PhH/Hexane i-Pr,O Et,O EtOAc/Hexane Et,O/Hexane CH,CI,/Hexane PhH/Petr ether Acetone CH,CI,/Petr ether CH,CI,/Hexane Acetone/Hexane EtOAc PhH/Hexane THF MeOH MeCN Acetone/Hexane DMF/EtOH EtOAc MeOH/H,O MeCN EtOAc Acetone
59 47
ir
67
ir
41 45
ir
54 52 71 88
48 66
54 72
8
2 152c 8 lb 8 2 134 2 2 18 2 134 92 92 2 2 91a 152c 7 192 162 136, 86b 256 302 256 33b 92 479 302 192 192
1-[2-(N-CNCH,-N-Me-Amino)ethyl]-5-(2-C1C6H4)7-CI 1-(2-CNCH,O-Ethyl)-5-(2-FC,H,)-7-C1
l-(Cy~10b~tyl)CH2-5-Ph-7-C1 1-(2-Cyclobutylmethoxy)ethyl-5-(2-ClC6H4)-7-Cl Hydrochloride l-(Cyclohexyl)NHCO-5-Ph-7-C1 1-[3-(Cyclohexyl)NH-propy1]-5-Ph-7-C1 Dihydrochloride
1-Cyclopentyl-5-(2-FC6H4)-7-N02 1-(2-Cyclopenty1methoxy)ethyl-5-(2-ClC6H4)-7-Cl Hydrochloride
1-[2-(Cyclopropyl)CO0-l-MeO-ethyl]-5-Ph-7-C1 l-(Cyclopropyl)NHCO-5-Ph-7-C1
115-117 101-102 165-167
EtOH Et,O/Hexane
177 134-136
MeOH/Et,O i-PrOH
265d 164-166
MeOH/Et,O EtOAc
302 251c
165-1 66 113-1 1 5 142-144d 2 13-21 5
MeOH/Et,O EtOH i-PrOH
28 1 72 311, 312 311, 312
195d 145-146 153-1 55 128-129 8688 195d 14145 98-100
MeOH/PhH EtOH
302 302 113
46
32
28 1 311, 312
l-(Cyclopropyl)CH,-5-benzyl-7-C1 4
Hydrochloride
l-(Cyclopropyl)CH,-5-Ph-7-C1
4-Oxide 1-(Cyclopropyl)CH,-542-ClC6H4)-7-C1 1-(Cyclopropyl)CH,-542-FC6H4)-7-CI Hydrochloride l-(Cyclopropyl)CH~-5~2-MeC6H4)-7-C1 l-[2-(Cyclopropyl)methoxyethyl]-5-Ph-7-Cl l-[2-(Cyclopropyl)methoxyethyl]-5-(2-FC6H4)-7-Cl 85 Hydrochloride 173 138-140 1-[(Cyclopropylmethoxycarbonyl)CH2]-5-Ph-7-Cl 1-[(Cyclopropylmethoxycarbonyl)CH,1-5-(2-FC6H4)-7-C1 1-[2-(Cyclopropyl methylthio)ethy1]-5-Ph-7-C1 82 1-[2-(Cyclopropyl methylthio)ethyl]-5-(2-FC6H4)-7-C1 95 l-Decyl-5-(2-FC6H,)-7-N0, Oil 1-(2-[3-(10,l l-Dihydr0-5H-dibenzo[a,d]cyclohepten-5~. ylidene)propyl]MeNCOO}-5-(2-FC6H4)-7-C1 85-95
65 76
EtOH/i-Pr,O Et,O/Petr ether
51
Acetone/Et,O Pentane
52.5 49 45 54
124 62 232 113 89 86b 276 66 66 66 66 66 251c
~
Et,O/Petr ether
33b
5,8-Disubstituted
5-Me-8-Cl 5-Ph-8-Cl 5-Ph-S-F,C 5-Ph-8-Me 5-Ph-8-MeO 5-Ph-&NOz
3 F
5-(2-C1C6H4)-8-F 5-(2-C1C6H4)-8-NOz 5-(2-FC6H4)-8-HzN 5-(2-FC6H4)-8-F 5-(2-FC6H,)-8-Me 5-(2,6-FzC6HJ-8-C1 ~-(~-F-~-OZNC,H~)-S-ACNH 5-(2-Thienyl)-8-MeO
19 2 4 86b 91 2 16 86b 136 134 258 257 134 257 152c 257 22
203-204 214-215 1 8 6 186 216218 255-256 186188 190-192 252d 262d 239-242 27Od 25@253 177-179 208-210 200-202 285-28 7 213-214
EtOAc/i-Pr,O Acetone PhH/Petr ether
175-1 76 184-185 146147 144145 198-200
Hexane/Acetone CHZC1,/Petr ether EtOH CH,Cl,/Et,O/Petr ether
2 91 86b 136 301
153-156
EtOAc/Hexane
134
193-195d
EtOAc/EtOH
134
190-194d 115-117
EtOAc/EtOH Et,O/Petr ether
134 391b
MeOH/MeCN Acetonemexam Acetone/Hexane
94 30
47 47
EtOH EtOAc/Hexane EtOAc HZO EtOAc/Hexane CH2C1,/EtOH MeOH THF/MeOH/Et 0 PhH/Hexane
5,9-Disubstifuted
5-Ph-9-CI 5-Ph-9-Me 5-Ph-9-NOz 5-(2-C1CsH4)-9-NOz
25
Trisubstituted 1.39-Trisubstituted
l-Ac-3-AcO-5-(2-ClC6H,) 1-Allyl-3-R-Me-5-(4-ClC,H4) Hydrochloride 1-Allyl-3-S-Me-5-(4-ClC,H4) Hydrochloride 1-t-Bu-3-Me-5-(2-C1C6H4)
TABLE VII-1. --(contd.)
Substituent I-Me-3-Allyl-5-Me 4-Oxide l-Me-3-Allyl-5-AcOCH, I-Me-3-Allyl-5-CHO 1-Me-3-Allyl-5-HOCH2 l-Me-3-S-Benzyl-S-Ph I-Me-3-EtOOC-S-Ph 4-Oxide
1-Me-3-S-Me-5-(4-C1C,H4) 1,3-Me,-5-(2,4-C1,C,H3)
mp ("C) or; [bp ("Cjtorr)]
Solvent of Crystallization
69-71 138-141 82-84 68-7 1 1&106 135-137
Et,O/Hexane EtOAc/Hexane Et O/Hexane Et,O/Hexane CH,CI,/Et,O/Hexane Acetone/H,O
188-190 115-1 17 151-152
EtOH Et,O/Hexane CH,Cl,/EtOH
108 134 134
142-143 246247
Et,O EtOAc/Et ,O
301 301
Et,O Et,O/Petr ether Et,O/Petr ether Et,O Cyclohexane Et,O THF Acetone CH,CI,/Hexane Et O/Hexane PhH EtOH
301 301 301 301 301 250 152c 293, 284 284 72 486 72 86b 88
Yield (%)
Spectra
Refs.
57 60
Pmr ir, pmr, uv ir, pmr, uv ir, pmr, uv
134 298 298 298 298
55
61
[a1
81
I>,& Trisubstituted
2:
1-Me-5-(2-FC,H4)-6-C1
h,
1-Me-5-(2-F-5-H,NS0,C6H3)-6-C1 IJ,?- Trisubstituted
150 95 142 184-186 l-(Ac4-~-~-glucopyranosyl)-5-Ph-7-Cl 9od 221-223 I-AcNH-~-(~-CIC,H~)-~-CI l-(2-AcNH-Ethyl)-5-(2-FC6H4)-7-CI 223-225 I-AcCH2-5-Ph-7-C1 169-1 71 I-AcCHZ-5-(2-Pyridyl)-7-Br 156-158 ~ - ( ~ - A c O - E ~ ~ O X ~ ) C H , - ~ - P ~ - ~ - C ~ 92-94 166167 1-(2-AcO-l-MeO-Ethyl)-5-Ph-7-AcNH 11(r-111 1-(2-AcO-l-MeO-Ethyl)-5-Ph-7-C1 1-(2-AcO-EthyI)-5-Ph-7-C1 102- 103 Hydrochloride 188-195d I-Ac-~-P~-~-NO, l-Ac-5-(2-ClC,H4)-7-C1 l-Ac-5-(2-ClC6H4)-7-NO, ~-Ac-~-(~-FC,H~)-~-AC~N
,
65
~-(~-AcO-E~~~I)-~-(~-CIC~H~)-~-CI 4-Oxide 1-(2-AcO-Ethyl)-5-(2-FC,H,)-7-C1 4-Oxide 1-[2,3-(AcO),-Propy1]-5-Ph-7-C1 1-(2-Ac0-3-MeO-Propyl)-5-Ph-7-C1
1-(4-AcO-2-Me-But-2-en-l-yl)-5-Ph-7-C1 1-(4-AcO-trans-But-2-en-l-yl)-5-(2-FC6H4)-7-C1 l-Allyl-5-Ph-7-Cl 4-Oxide l-Allyl-5-Ph-7-F,C l-Allyl-5-Ph-7-N02 l-Allyl-5-(2-CIC6H4)-7-C1 1-Allyl-5-(4-CIC6H4)-7-C1 1-Allyl-5-(2-FC6H4)-7-C1 4-Oxide
1-Allyl-5-(2-FC6H4)-7-(cyclopentyl)CONH W
w
l-Allyl-5-(2-FC6H4)-7-N02
1-Allyl-5-(4-MeOC6H4)-7-C1 1-Allyl-5-Cyclohexyl-7-C1 l-(AIlyl)NHCO-5-Ph-7-C1 l-(Allyl)NHCO-5-Ph-CN l-(Allyl)NHCOCH2-5-Ph-7-C1
1-(2-Allyl0~y)ethyl-5-Ph-7-C1 4-Oxide 1-(2-Allyl0~y)ethyl-5-(2-FC,H,)-7-C1 4-Oxide l-HzN-5-Ph-7-CI 4-Oxide I-HzN-5-Ph-7-NO2 4-Oxide 1-HzN-5-(2-C1C6H4)-7-C1
161-163 103-105 161-163 139-141 121-123 121-1 22
i-PrOH/i-Pr,O CH,Cl,/Hexane PrOH
105-106 150-151 127-128 124-125 128-1 30 145-146 126127 183 176178 150-151 125-1 26 111-112 102- 105
Hexane Acetone/Petr ether Et,O/Petr ether Et,O EtOH CH,CI,/Petr ether i-PrOH EtOH Et,O/Hexane EtOAc EtOAc/Hexane Hexane i-PrOH
137-139d 185-186 91-93 138-139 88-90 108-110 70-75 225 155-157d 200-203d 202-204
i-PrOH EtOH
62 58
MeOH ir, pmr
CH,CI,/PhH PhH PhH MeOH
57
.
40 85
L
.L.
75 67 89 75
64 44 20 78
365 283, 86b 282, 365 285 285 486 236 2 91a 2b 2b
ir ir ir ir
236 236 301 251c 134 18 312 311 311, 312 293 86d, 128 234 86d, 128 234 26 1 250 250 250 250, 261
TABLE VII-I. d c o n t d ) ~~~
Substituent
mp ("C) or; [bp ("C/torr)]
1-H2N-5-(2-C1C6H4)-7-N02 1-H2N-5-(2-Pyridyl)-7-Br
4
w
P
207-2 12 149-151 l-[2-(H2N-Acetoxy)-l-MeO-ethyl]-5-Ph-7-C1 115-116 ~-(~-H,NCO-BU~~~)-S-P~-~-CI 143-145 102-104 ~- ( ~- H, NCO- BU~~I)-~-(~-FC , H , )-~-C I 1-[2-(N-H,NCO-N-Et-Amino)ethyl]-5-(2-FC,H4)-7-Cl185-188 I-H,NCOCH,-5-Ph-7-CI 233-235 239-242 1-H,NCOCH,-5-Ph-7-CN 198-20 1 l-H,NCOCH2-5-(2-FC,H4)-7-C1 1-[2-(N-[1-H2NCO-I-Ethyl]-N-Me-amino)-ethyl]5-Ph-7-CI 143-145 1-[2-(N-2-H,NCO-Ethyl-N-Me-amino)ethyl]-5-Ph-7-C1 140-143 1-[2-(H2NCO-Methoxy)ethyl]-5-Ph-7-C1 97-100 1-[2-(H,NCO-Methoxy)ethyl]-5-(2-C1C6H4)-7-C1 198-200 1-[2-(H,NCO-Methoxy)ethyl]-5-(2-FC,H4)-7-C1 187-189 143-144 1-[2-(H2NC0-Methoxy)ethyl]-5-(2-pyridyl)-7-Br 1-[2-(N-H2NCOCH,-N-Et-Amino)ethyl]-5-Ph-7-C1 116118 1 -[2-(N-H2NCOCH,-N-Me-Amino)ethyl]-5-Ph-7H,N.EtOH 110-112 1-[2-(N-H,NCOCH2-N-Me-Arnino)ethyl]-5-Ph-7-Cl 146-148 4-Oxide 162-164d l-[2-(N-H2NCOCH,-N-Me-Amino)ethyl)-5-Ph-7-NO2 215-2 18d
Solvent of Crystallization CH,CI,/Petr ether MeOH Et,O/Cyclohexane CH,CI,/Et,O CH,CI,/Et,O CH,CI,/Et,O Acetone Acetone MeOH/Et,O/Petr ether
Yield (%)
90
Spectra
Refs. 152c 247 486 302 302 233 293, 86b 38b 152c
EtOH EtOH MeCN EtOH EtOH EtOH MeCN
15&, d 15Oc, d
EtOH Acetone MeCN MeCN
302 15Oc, d 15Oc 15Oc, d
CH,CI,/Et,O EtOH
lSOc, d 302 15Od
MeCN
15Oc, d
1%
15Od 15Od 15Od 1%
l-[2-(N-H,NCOCH2-N-Me-Amino)ethy1]-5(2-CIC,H4)-7-C1 4-Oxide
152-154 130-132 162-164d
I-[2-(N-H,NCOCH,-N-Me-Amino)ethyl]-5-(2-FC6H4)7-C1
130-132
1-[2-(N-H,NCOCH,-N-Me-Amino)ethyl]-5-(2-FC6H4)187-1 89 7-NO2 1-[2-(N-H,NCOCH,-N-Me-Amino)ethyl]-5-(2-pyridyl)7-Br 176178 I-[3-(N-H2NCOCH,-N-Me-Amino)propyl]-5-Ph-7-C1 136138 1-[3-(H2NCOCH,S)Propyl]-5-Ph-7-CI 135-137
EtOH
1.50~.d
EtOH CH,CI,/Et,O EtOH
15Oc, d 15Oc, d 15Od, 263
I-(~-H,N-E~~OX~)CH,-~-P~-~-C~ Hydrochloride
147-150
EtOAc/MeOH
2 18-22 1d
EtOH
2oa-201 9cb110 175-176 169-172 196200 174-175 105-106 174-175 151-152 115-118 206207 128-130 174-177 128-130 Oil
Acetone Et,O/CH,CI,/Petr ether CHZC12/Et,0 CH,Cl,/Et,O CH,Cl,/MeOH Ether EtOH Hexane CH,Cl,/Et,O/Peter ether CH,Cl,/Et,O/Peter ether Et O/Hexane CH,Cl,/Et,O Et,O/Hexane EtOAc/Hexane CH,Cl,/Et,O
72
l-(2-H,N-Ethyl)-5-(2-FC6H4)-7-C1 Dihydrochloride
233
I-(~-H,N-E~~YI)-~-(~-F-~-IC,HJ-~-C~ Hydrobromide 1-(2-H,NCO-EthyI)-5-Ph-7-C1
-1 W
1-(2-H,NCOCH,O-Ethyl)-5-Ph-7-C1 l-[2-H,NCO(Me)N-Ethyl]-5-Ph-7-F3C 1-[3-H,NCO(Me)N-Propyl]-5-Ph-7-N0, 1-[3-HzNCO(Me)N-Propyl]-5-(2-pyridyl)-7-Br I-(Benzoyl)CH2-5-Ph-7-CI I-Benzyl-5-Ph-7-CI 4-Oxide
I-Benzyl-5-(2-C1C,H4)-7-Me0 1-Benzyl-5-(2,6-C1,-C6H3)-7-Cl l-Benzyl-5-(2-FC6H4)-7-C1
l-Benzyl-5-(3-thieny1)-7-Br l-[2-(N-Benzyl-N-CNCHZ-amino)ethyl]-5-Ph-7-Cl 1-[2-(N-Benzylmethyl amino)ethyl]5-Ph-7-C1
,
259 293 302 152c 152c 152c 293,284 57
40 78
L
91a 91a, 109 134 42 152c 134 302 302
l-[2-(N-Benzyl-N-MeOOCCH2-amino)ethyl]-5Ph-7-CI
1-[2-(Benzyloxy-CONH)thyl]-5-(2-FC,H4)-7-CI I-[2-(Benzyloxy-CO-N-Me-amino)ethyl]-5-Ph-7-Cl Hydrochloride
l-(Benzyloxy)CH2-5-Ph-7-C1 l-(Benzyloxy)CH2-5-Ph-7-NO,
15Oc
MeOH
145-147 142-145
Et,O
176180 103-108 156158
Acetone EtOH EtOH
45
233
62
15Oc 71 56
TABLE VII-1. 4 c o n t d )
Substituent
Et,O/Petr ether EtOH EtOH/Hexane
140-143 114-116 134-136 1W103
CH,Cl,/Hexane Cyclohexane CH,CI,/Hexane Pentane
223-2253 Picrate 1-1-Bu-5-(2-C1C6H4)-7-(2-MeOOC-Benzoyl)(Me)N 198-199 185-187 1-t-Bu-5-(2-C1C,H4)-7-Phthalimido ~ - ~ - B U - ~ - ( ~ - C I C ~ H J - ~ CH2C12 -NO,.~.~ 21&212 208-21od
EtOH/H,O CH,Cl,/Hexane Acetonemexane EtOAc/Hexane CH,Cl,/Hexane
1-(1-Benzyloxy-1-ethyl)-5-(2-C1C6H4)-7-C1
1-(2-Benzyloxy)ethyl-5-Ph-7-C1 4-Oxide 1-(2-Benzy1oxy)ethyl-5-(2-ClC6H4)-7-C1
l-(2-Benzyloxy)ethyl-5-(2-FC6H4)-7-C1
cn
Solvent of Crystallization
104-106 128-1 30 120-122 133-135 155-156 104-106 114-116 123-124 169-171 223-225d 107-109 119-122 89-93 163-165 106-112 95-98 172-175
1-(Benzyloxy)CH,-5-(2-C1C6H4)-7-Cl 1-(Benzyloxy)CH,-5-(2-ClC6H4)-7-NO,
2
mp ("C) or; [bp ("C/torr)]
4-Oxide 1-[2-(2-Br-Acetamino)ethyl]-5-(2-FC6H4)-7-Cl Hydrochloride 1-(4-Br-Butyl)-5-Ph-7-C1 1-(4-Br-Butyl)-5-(2-pyridyl)-7-Br
1-(3-Br-Propy1)-5-Ph-7-C1 4-Oxide
l-(3-Br-Propyl)-5-(2-CIC6H4)-7-C1 143-Br-Propy1)-5-(2-FC6H4)-7-C1 4-Oxide 1-[2-(5-Br-3-Pyridincarbonyloxy)ethyl]-5-(2-FC6H4~ 7-C1
l-(trans-But-2-en-l-yl)NHCO-5-Ph-7-C1 l-Bu-5-(2-FC,H4)-7-N02 l-t-Bu-5-Ph-7-Cl
Yield
(YO)
Spectra
61
56
53
Et,O/Peter ether
EtOH MeCOEt/Hexane Et,O Et,O/Hexane CH,Cl,/MeOH CH,Cl,/Hexane Et,O CH,Cl,/Et,O/Peter
79
ether
23 67
Refs.
ir, ms, pmr ir, ms, pmr
71 71, 56 89 89 71 89 89 33 1 33 1 38b 67b 38b 134 192 38b 152c 283 311, 312 251c 14
~-~-Bu-~-(~-CIC~H~)-~-H,N 391b 391b 391b 391b 391b
l-{N-[6-(4-{3-t-BuNH-2-
HO-Propoxy}phenoxy)hexyl]NHCOCH2)-5Ph-7-Cl.0.5H20 1-[3-Bu (Me)N-Propyl]-5-Ph-7-C1 1-[2-(trans-But-2-enoyloxy)-l-MeO-ethyl]-5-Ph-7-C~
2 -.I
113-118 Oil 13G131 1-[2-(1-t-Bu00C-~-Prolylamino)ethyl]-5-(2-FC,H~)-7-CI88-92 1-(3-t-BuOOC-trans-Prop-2-en-l-y1)-5-Ph-7-C1 163-165 1-(1-t-BuOOC-trans-Prop-Len-l-yl)-5-Ph-7-C1 164-166 1-(2-B~O-Ethy1)-5-Ph-7-C1 4-Oxide 163-164 1-(2-BuO-Ethyl)-5-(2-FC,H,)-7-C1 4-Oxide 111-112 1-[2-(HCONH-Acetoxy)-I-MeO-ethyl]-5-Ph-7-C1 110-112 1-(4-HOOC-Butyl)-5-(2-FC,H3-7-C1 Hydrosulfate 205-209 1-(2-HOOC-Ethyl)-5-Ph-7-NO, 198-206 1-(2-HOOC-Ethyl)-5-(2-C1C,H,)-7-H2N 262-264 1-(2-HOOC-Ethyl)-5-(2-ClC6H4)-7-N0, 188-191 1-(2-HOOC-Ethy1)-5-(2-FC,H,)-7-C1 184-188 1-(2-HOOC-Ethyl)-5-(2-FCsH,)-7-NOz 188-192 1-(2-HOOC-Ethyl)-5-(2-pyndyl)-7-Br 102-109 l-HOOCCHZ-S-Ph-7-Cl 194-196 1-HOOCCH2-5-Ph-7-N0,.0.5 H2O 189-191d 1-HOOCCHz-5-(2-FC6H4)-7-C1 216-225d I-HOOCCH,-5-(2,6-F2C~H&7-C1.H20 172-176 l-HOOC(MeO)CH-5-Ph-7-C1 212-2 15d Ammonium salt
487 302 302 157b 302 294
Et,O EtOH Et,O/Petr ether MeCN MeCN
234 234 486
EtOAc/Petr ether Acetone/Et,O MeOH THF/Hexane MeOH CH,CIZ/Et,O MeOH MeOHpHF Acetone/Et,O MeOH/i-PrOH MeOH/Et,O/Petr ether CH,CI,/MeOH
65 30 10 44 19 8
294 294 152c 294 294 294 294 134 2b 152c 152c
MeOH/H,O
108
179-181d 174-180 Oil
Acetone/Et,O
15Oc 152c 152c
120-130
Amorphous
152c
1-[2-(HOOC-Methoxy)ethyl]-5-Ph-7-C1 Tosylate
1-[2-(HOOCCH,O)-Ethyl]-5-(2-FC~H4)-7-C1 1-(9-HOOC-Nonyl)-5-(2-FC6H4)-7-C1
1-{2-[N-(3-HOOC-Propanoyl)-N-Et-amino]ethyl}-5(2-FCeHJ-7-CI
TABLE VII-I. gcontd.)
Substituent
mp ("C) or; [bp ('C/torr)]
Solvent of Crystallization
Yield (%)
Spectra
Refs.
1-[2-(3-HOOC-Propanoyloxy)ethyl]-5-Ph-7-C1
2 O0
48
198d 152-156 167-169 191-192
MeOH MeOH/Et,O Acetone CH,CI,/Et,O
110-112
Acetone
302
153-157 143-147
CH,CI,/Hexane
283 283
MeOH/Et,O MeOH/Acetone MeOH/Et,O MeOH/Et ,O/Petr ether CHCIJHexane
I-(~-CI-BU~~I)-~-(~-FC~H~)-~-CI
268-27Od 220-222 166168 173-178 190-192 1 7 6 178 102 134 163-164 143-144d 135-137 124126 117-120 11C118 15&153 9e93
294 283 488 294 294 294 224 224 222 11, 224 283 302 302 302 302 254
1-{ 2-[2-(7-Cl-1,3-Dihydro-2-oxo-5-Ph-2H1,4benzodiazepin-1-yl)ethoxy]ethyl}-5-Ph-7-C1
164167
MeOH/Et,O
4-Oxide 1-[2-(3-HOOC-Propanoyloxy)ethyl]-5-(2-FC,H4)-7-CI 1-[2-(3-HOOC-Propanoyloxy)-1-MeO-ethyl]-S-Ph-7-CI 4-0xide 1-[2-(3-HOOC-Propanoyloxy)-l -MeO-ethyl]-5(2-FC,H4)-7-C1 1-[2-(3-HOOC-cis-Propenoyloxy)ethyl]-5(2-FC,H4)-7-C1 Sodium salt. MeOH 1-(3-HOOC-trans-Prop-2-en-I-yl)-5-Ph-7-C1 Tosylate Sodium salt 1-(3-HOOC-Propyl)-5-Ph-7-CI 1-(3-HOOC-Propyl)-5-(2-FC6H4)-7-CI
1-(3-HOOC-Propyl)-5-(2-FC6H4)-7-I 1-(3-HOOC-3,3-Me,-Propyl)-5-Ph-7-C1 1-Cl-5-(1-CI-Cyclohex-l-yl)-7-C1 1-CL5-(Cyclohex-1-en- 1-yl)-7-C1
l-C1-5-Cyclohexyl-7-C1 l-CI-5-Ph-7-Cl
1-[2-(C1-Acetoxy)ethyl-5-(2-FC,H4)]-7-C1 l-~2-(Cl-Acetoxy)-l-MeO-ethyl]-5-Ph-7-C1 1-[2-(CLAcetoxy)-l-MeO-ethyl]-5-Ph-7-NO2 1-[2-(Cl2-Acetoxy)-l-MeO-ethyl]-5-Ph-7-CI 1-[2-(4-C1-Benzoyloxy)-l-MeO-ethyl]-5-Ph-7-Cl
i-Pr,O i-Pr,O i-Pr,O EtOAc CH,CI,/Petr ether Et,O/Petr ether CH,C1,/Et20 Et,O/Petr ether EtOH Et,O/Hexane
87 55 62 56 91 64.91
365 283 302 302
487
1 -[3-(7-Cl- 1,3-Dihydro-2-oxo-5-Ph-2H1,4benzodiazepin-1 -yl)-propyl]-5-Ph-7-C1
23%241
CH,CI,/MeOH
487
MeOH/Et,O CH,CI,/EtOH CH,Cl,/EtOH CH,CI,/Hexane
152c 108 108 108
1-[2-(2-Cl-Eth0~y)ethyl]-5-(2-FC6H4)-7-C1 Hydrochloride
176-1 83d 147-148 163-166 190-191 I-(~-C~-E~~OX~)CH,-~-P~-~-H,N I-(~-C~-E~~OX~)CH,-~-P~-~-CI 9698 128-130 ~-(~-CI-E~~OX~)CH,-~-P~-~-NO, 97-99 I-(~-CI-E~~OX~)CH,-~-(~-CIC~H~)-~-CI 92-93 131-1 33 135-137 ~-(~-C~-E~~OX~)CH,-~-(~-FC,H,)-~-I 1-(2-CI-Ethyl)-5-Ph-7-C1 168-1 69 111-1 14 1-(2-Cl-Ethyl)-5-(2-FC,H,)-7-CI 11G112 1-(2-Cl-Ethyl)NHCO-5-Ph-7-C1 129-132 I-(2-Cl-l-EtO-Ethy1)-5-Ph-7-C1 210-22od 1-(2-CI-l-MeO-Ethyl)-5-Ph-7-H,N 152-172 1-(2-C1-1-MeO-Ethyl)-5-Ph-7-C1 214-215 4 0xide 162-164 142-Cl-1-MeO-Ethyl)-5-Ph-7-NO2 196-198 I-(2-C1-l-MeO-Ethyl)-5-(2-CIC6H4)-7-NO, 170-171 1-(2-C1-1-MeO-Ethyl)-5-(2-FC6H4)-7-C1 224-226d 1-(2-C1-1-MeO-Ethyl)-5-(2-FC,H4)-7-1 158-160 1-(2-CI-l-MeO-Ethyl)-5-(2-pyridyI)-7-Br 113-1 18 ~-(~,~,~-CI,-E~~OXY)CH,-~-P~-~-NO~ 8689 1-(3-CI-Propyl)-5-Ph-7-C1 87-90 118-123 1 -(3-C1-Propyl)-5-Ph-7-F3C 1-(3-CI-Propyl)-5-Ph-7-NO, Hydrochloride 8689 1-(3-CI-Propy1)-5-(2-FC6H4)-7-CI 103-106 1-(3-CI-Propyl)-5-(2-pyridyl)-7-Br
1-[2-Cl-1-(2-Cl-Eth0~y)ethyl]-5-Ph-7-C1 1-[2-Cl-l-(2-Cl-Eth0~~~thyl]-5-Ph-7-N0~
2:
-
1-[(4-Cl-BenzyIoxy)methyl]-5-Ph-7-C1
92-93
72 72
MeOH EtOH Et,O EtOH Acet one/Hexane Et,O i-PrOH EtOH EtOH CH,Cl,/MeOH EtOAc/EtOH CH,CI,/MeOH EtOH MeOH CH,CI,/EtOH CH,CI,/Et,O/Petr EtOH Et,O/Hexane Et,O/Hexane Et,O/Hexane
33
72 108 254 278 311,312 302 108 72 72
12
ether
86 50
302 302 278 302 72 125h 287,291 29 1 38b
Et,O/Hexane Et,O/Hexane Et,O/Petr ether
48 42
287,291 29 1 71
TABLE VII-I. 4contd.) Substituent 1-[(4-CI-Benzyloxy)methyl]-5-Ph-7-NO, 1-{4-[7-Br-1,3-Dihydro-2-oxo-5-(2-pyridyl)-2H-l,4-
4
8
m p ("C) or; [bp ("C/torr)] 146-147
257-260 benzodiazepin-l-yl]butyl}-5-(2-pyridyl)-7-Br 1-(7-C1-1,3-Dihydr0-2-0~0-5-Ph-2H-1,4-benzodia255-257 zepin-l-yl)CH2-5-Ph-7-CI 1-{4-[7-C1-1,3-Dihydro-2-0~0-5-Ph-2H-1,4-benzodia265-286 zepin-l-yl]butyl}-5-Ph-7-C1 1-{4-[7-C1-5-(2-FC,H4)-1,3-Dihydro-2-oxo-2H-l,4209-2 13 benzodiazepin-1-yl]butyl}-5-(2-FC6H4)-7-Cl I-(4-[5-(2-CIC,H4)-1,3-Dihydr0-7-NO,-2-0~0-2H272-275 1,4-benzodiazepin-l-yl] butyl}-5-(2-C1C,H4)-7-NO, 181-1 82 1-(6-C1-4-Ph-Quinazolin-2-yl)CH,-5-Ph-7-CI 273-274 4,3'-Dioxide 117-118 1-(2-CN-Ethyl)-5-Ph-7-C1 150 1-(2-CN-Ethyl)-5-(2-FC,H4)-7-C1 1-[2-(N-CN-N-Et-Amino)ethyl]-5-(2-FC6H4)-7-Cl 132-134 1-[2-(N-CN-Ethyl-N-Me-amino)ethyl]-5-Ph-7-Cl 82-83 > 2ood Dihydrochloride 5&54 l-[2-CN(Me)N-Ethyl]-5-Ph-7-F3C 154-156 I-[3-CN(Me)N-Propyl]-5-Ph-7-N02 1w104 1-[3-CN(Me)N-Propyl]-5-(2-pyridyl)-7-Br l-(2-NCCH20-Ethyl)-5-Ph-7-C1 > 22od Hydrochloride 1w101 l-[2-NCCH20-Ethyl]-5-(2-FC6H4)-7-C1 126-128 1-[2-NCCH,O-Ethy1]-5-(2-pyridyl)-7-Br l-NCCHZ-5-Ph-7-Cl 219-221d Hydrochloride 207-208 1-CNCH2-5-Ph-7-NO, 108-110 1-[2-(N-CNCH,-N-Me-Amino)ethy1]-5-Ph-7-C1
Solvent of Crystallization
Yield (%)
EtOH
16
Spectra
Refs. 71. 56 152c
CH,Cl,/MeOH DMF/MeCN
33b
CHCl,/EtOH
152c
CH,CI,/MeOH
152c
CHCI,/MeOH Et,O CHCI,/EtOH Et,O/Petrether Et,O CH,CI,/MeOH
152c 2b 2h 91 301 233
EtOH/Et,O Et,O/Petrether CH,Cl,/Et,O CH,Cl,/Et,O/Petr ether MeOH/Et,O Et,O/Heptane
EtOH
76
150c 150c
152c 152c 152c 150c 150c 150c
86b
EtOH Et,O
86b 150c
1-[2-(N-CNCH,-N-Me-Amino)ethyl]-5-(2-C1C6H4)7-CI 1-(2-CNCH,O-Ethyl)-5-(2-FC,H,)-7-C1
l-(Cy~10b~tyl)CH2-5-Ph-7-C1 1-(2-Cyclobutylmethoxy)ethyl-5-(2-ClC6H4)-7-Cl Hydrochloride l-(Cyclohexyl)NHCO-5-Ph-7-C1 1-[3-(Cyclohexyl)NH-propy1]-5-Ph-7-C1 Dihydrochloride
1-Cyclopentyl-5-(2-FC6H4)-7-N02 1-(2-Cyclopenty1methoxy)ethyl-5-(2-ClC6H4)-7-Cl Hydrochloride
1-[2-(Cyclopropyl)CO0-l-MeO-ethyl]-5-Ph-7-C1 l-(Cyclopropyl)NHCO-5-Ph-7-C1
115-117 101-102 165-167
EtOH Et,O/Hexane
177 134-136
MeOH/Et,O i-PrOH
265d 164-166
MeOH/Et,O EtOAc
302 251c
165-1 66 113-1 1 5 142-144d 2 13-21 5
MeOH/Et,O EtOH i-PrOH
28 1 72 311, 312 311, 312
195d 145-146 153-1 55 128-129 8688 195d 14145 98-100
MeOH/PhH EtOH
302 302 113
46
32
28 1 311, 312
l-(Cyclopropyl)CH,-5-benzyl-7-C1 -I
Hydrochloride
l-(Cyclopropyl)CH,-5-Ph-7-C1
4-Oxide 1-(Cyclopropyl)CH,-542-ClC6H4)-7-C1 1-(Cyclopropyl)CH,-542-FC6H4)-7-CI Hydrochloride l-(Cyclopropyl)CH~-5~2-MeC6H4)-7-C1 l-[2-(Cyclopropyl)methoxyethyl]-5-Ph-7-Cl l-[2-(Cyclopropyl)methoxyethyl]-5-(2-FC6H4)-7-Cl 85 Hydrochloride 173 138-140 1-[(Cyclopropylmethoxycarbonyl)CH2]-5-Ph-7-Cl 1-[(Cyclopropylmethoxycarbonyl)CH,1-5-(2-FC6H4)-7-C1 1-[2-(Cyclopropyl methylthio)ethy1]-5-Ph-7-C1 82 1-[2-(Cyclopropyl methylthio)ethyl]-5-(2-FC6H4)-7-C1 95 l-Decyl-5-(2-FC6H,)-7-N0, Oil 1-(2-[3-(10,l l-Dihydr0-5H-dibenzo[a,d]cyclohepten-5~. ylidene)propyl]MeNCOO}-5-(2-FC6H4)-7-C1 85-95
65 76
EtOH/i-Pr,O Et,O/Petr ether
51
Acetone/Et,O Pentane
52.5 49 45 54
124 62 232 113 89 86b 276 66 66 66 66 66 251c
~
Et,O/Petr ether
33b
TABLE VII-1. 4 c o n t d . )
Substituent
-1
P
h)
1-(243410,11-Dihydro-5H-dibenzo[n,d]cyclohepten-5ylidene)propyl]MeNCOON(Et)}-5-(2-FC6H4)-7-C1 I-( 1,4-Dioxan-2-yl)CH,-5-Ph-7-C1 1-(1,4-Dioxan-2-yl)CH,-5-(2-FC,H,)-7-C1 1-Et-5-(4-C1C,H4)-7-C1 1-Et-5-(2-FC6H4)-7-H2N l-Et-5-(2-FC,HJ-7-( I-HZN-Ethyl) l-Et-5-(2-FC,H,)-7-C1 l-Et-5-(2-FC,H,)-7-N02 l-Et-5-Cyclohexyl-7-C1 l-Et-5-EtO-7-Cl l-Et-5-Pentyl-7-CI l-Et-5-Ph-7-HzN l-Et-S-Ph-7-Cl 4-Oxide l-Et-5-Ph-7-NOz l-Et-5-(2-FC,H4)-7-A~ l-Et-5-(2-FC,HJ-7-( 1-AcO-Ethyl) l-Et-5-(2-FC,HJ-7-( l-HzN-Ethyl) 1-Et-5-(2-FC6H,)-7-[ 1-(Butylaminocarbonyloxy)ethyl] 1-Me-5-(2-FC6H,)-7-(1-EtOOCO-Ethyl) 1-Et-5-(2-FC6H,)-7-(1-Hydroxyiminoethyl) l-Et-5-(2-FC,H.+)-7-(1-HO-Ethyl) 1-Et-5-(2-FC6H,)-7-[1-(MeOCH,O)Ethyl] 1-Et-5-(2-FC,H4)-7-[ 1-(MeO-Methoxyimino)ethyl] 1-Et-5-(2-FC6H,)-7-[1-(Phenylaminocarbonyloxy)ethyl] l-Et-5-(2-Pyridyl)-7-Br
mp ("C) or; [bp (°C/torr)l
Solvent of Crystallization
95-1 10 142-144 129-131 128-130 207-208 53-55 103-105 105 11&115 91-93 [15c~160/0.05] 220 127-128 207-208 211-212 165-166 154-156 Oil 53-55 48-50 Oil 236238 55-57 Oil Oil 83-85 143-145
Et,O/Petr ether i-PrOH/i-Pr,O EtOH EtOH Acetone/Petr ethex EtOAc Hexane EtOH EtOH Acetone Acetone/Petr ether CH,Cl,/Et,O/Petr ether CH,Cl,/C yclohexane
C yclohexane CH,CI,/Hexane Cyclohexane
Cyclohexane CH,Cl,/Et,O/Hexane
Yield (%)
74
75 46 81
Spectra
Refs. 33b 28 5 285 2 72c 251b 152c 72c 18
195 18 72c 91a 91a
358 2b 251 25 1 25 1 251 251b 251 251 25 1 251b 251 134
1 -[2-(N-Et-N-MeqNH)C-amino)ethyl]-5-(2-FC,H4)-7-CI 91-100
I-( l-Et-Piperidin-3-yl)-5-Ph-7-C1 Dihydrochloride l-(l-Et-Piperidin-3-yl)-5-Ph-7-NO2 Dihydrochloride 1-( 1-Et-Piperidin-3-yl)-5-(2-FC6H4)-7-C1 Dihydrochloride 1-EtNHCOCH2-5-Ph-7-Cl 1-[2-(EtNHCO-Methoxy)ethyl]-5-(2-C1C6H,)-7-Cl
1-(2-EtNHCO0-1-MeO-Ethyl)-5-Ph-7-C1 1-(2-EtNH-Ethyl)-5-(2-FC,H,)-7-C1 Dih ydrochloride
1-[2-Et(HO)N-Ethyl]-5-(2-FC6H4)-7-C1 1-[2-(EtO-A~~toxy)ethyl]-5-(2-FC6H4)-7-C1
’
l-EtOOC-5-Ph-7-NOz 141-EtOOCNH- 1 -Ethyl)-5-Ph-7-C1 1-(2-EtOOCNH-Ethyl)-5-Ph-7-C1 1-(EtOOCNH)CH,-5-Ph-7-H2N
I-(EtOOCNH)CH,-5-Ph-7-C1 I-(EtOOCNH)CH,-5-Ph-7-N02 I-(EtOOCNH)CH,-5-(2-ClC~H&7-C1 l-(EtOOCNH)PhCH-5-Ph-7-C1 1-(4-Et00C-Butyl)-5-(2-FC6H4)-7-C1 Hydrochloride 1-(4-EtOOC-B~ty1)-5-(2-FC,H,)-7-1 Hydrochloride l-EtOOCCH2-5-Ph-7-CI
Et,O
152c
220-223d
EtOH/Et,O
289
213-215
EtOH
289
217-22Od 211-212 136138 117-119 215-21 7 132-133 154-158 167-169d 155-157 127-1 29 210 126129 157-160 147-149 177-180
EtOH Acetone CH,CI,/Et,O Et,O/Petr ether Et,O/Petr ether MeOH/Et ,O Et,O Acetone/Et,O EtOAc/Hexane EtOH Et,O/Petr ether MeOH/Et,O MeOH/H,O MeOH EtOH EtOH
289 293, 86b 15Oc 302 233 233 238 283
137-147
EtOH/Et,O
119-122 115-117 127-129 139-142 159-161 139-140 132-134 125-128
EtOH/Et,O
8&85
35 15
108
84 302 72c 84 84 84 84 45
294
79
294 86b 293 152c 152c 486 72c 311
Acetone/Hexane CH2C1,/MeOH CH,CI,/EtOH Cyclohexane Et20/Petr ether
i-PrOH
TABLE VII-I. -
Substituent
I-[2-(EtOOC-Methoxy)ethyl]-5-Ph-7-C1 1-[ 1,l -(EtOOC),-2-Phthalimidoethyl]-5-Ph-7-C1 1-(3-EtOOC-Propyl)-5-PH-7-N0, Hydrochloride 1 -(3-EtOOC-Propy1)-5-(2-C1C6H4)-7-NO, Hydrochloride 1-(3-Et00C-Propy1)-5-(2-FC6H4)-7-C1 Hydrochloride 1-(3-Et00C-Propy1)-5-(2-FC6H4)-7-1 Hydrochloride 4
2
1-[2-(2-EtO-Eth0~y)ethyl]-5-Ph-7-C1 1-[2-(EtO-Eth0~y)thyl]-5-(2-FC6H~)-7-C1 l-(l-EtO-l-Ethyl)-5-Ph-7-H,N 1-(1-EtO-l-Ethyl)-5-Ph-7-N0,
1-(2-EtO-Ethyl)-5-Ph-7-C1 Hydrochloride
1-(2-EtO-Ethyl)-5-(2-CIC6H4)-7-C1 l-(2-EtO-Ethyl)-5-(2-FC6H4)-7-C1 Hydrochloride
1-(2-Et0-Ethyl)-5-(2-MeC6H4)-7-C1 4-0xide
l-[2,2-(EtO),-Ethyl-5-(2-FC6H4)-7-C1 1-(l-EtO-2-HO-Ethyl)-5-Ph-7-C1 I-{ 3-[4-(2-EtO-Ethyl)piperazin-l-yl]propyl}5-(2-FC,H4)-7-C1 Trimaleate 1-[ l-EtO-2-(Pyridin-3-yI)COO-ethyl]-5-Ph-7-Cl 1-(2-EtOOC-Ethyl)-5-Ph-7-CI Hydrochloride
mp ("C) or; [bp ("C/torr)]
Solvent of Crystallization
Oil 194-195
EtOAc
150d 486
175-180
EtOH/Et,O
152c
170-174
EtOH/Et,O
152c
196198
EtOH/Et,O
64
294
187-189 78-79 76-77 152-1 53 184-187 156158 2 12-2 14d 142-143 98-100 20 1-203d 141-142 118-119 11&113 186189
EtOH/Et,O
50
294 89 89 72c 72 125h 279 125h 125h 125h 125h 234 152c 302
125-133 116-117
Acetone EtOH
24
287, 86b 302
225-227
MeOH/Et,O
Yield (%)
EtOAc/Petr ether EtOH PhH/Hexane MeOH/Acetone i-PrOH i-PrOH/Et,O
Et,O/Petr ether MeCN
Spectra
Refs.
293
CH,Cl,/Hexane CH,Cl,/Hexane EtOH EtOH
I-(2-EtSO2-Ethyl)-5-(2-FC6H4)-7-C1 1-[2-(EtZN-A~toxy)ethyl]-5-(2-FC6H4)-7-C1 1-(4-Et,N-B~tyl)-5-(2-FC6H4)-7-C1 Hydrochloride~O.5H,O I-Et,NCOCH,-5-Ph-7-C1
138-140 148-1 49 109-1 11
Acetone/Et,O Acetone/Hexane Et,O/Petr ether
137-138 9&96 79-8 1 121-122 85-86
Hexane Pentane Gt,O Et,O/Petr ether
2 18-22 1 15C155d 84-86
MeOH/Et,O CH,Cl,/Et,O Hexane
86b 302 302
232-233d 135-1 37 16&162 68-70 164-166 87 114-116d
MeOH/Et,O CH,Cl,/Et,O EtOAc Hexane EtOH EtOAc PhH
86b 391b 72c 287, 86b 288, 365 72c 258
1-(2-Et,NC00-1-MeO-Ethyl)-5-Ph-7-CI 1-(2-Et2N-Ethyl)-5-Ph-7-H,N
2
108 72 72 72 127 283
171-172 131-132 105-107 172-174 122-123 85-88
l-EtOCHZ-5-Ph-7-HZN I-EtOCHZ-5-Ph-7-Cl I-EtOCH,-5-Ph-7-NO, I-( l-EtO-l-Ethyl)-5-Ph-7-NO,
I-(2-Et2N-Ethyl)-5-Ph-7-Br l-(2-Et2N-Ethyl)-5-Ph-7-C1 4-Oxide 1-(2-Et,N-Ethyl)-5-Ph-7-F 1-(2-Et,N-Ethyl)-S-Ph-7-F,C Dihydrochloride
UI
1-(2-Et2N-Ethyl)-5-Ph-7-Me 1-(2-EtzN-Ethyl)-5-Ph-7-NOz Dihydrochloride
l-(2-Et,N-Ethyl)-5-(2-H~NC6H4)-7-Cl l-(2-EtZN-Ethyl)-5-(2-C1C6H4)-7-H,N 1-(2-Et,N-Ethyl)-5-(2-ClC4H&7-C1 4-Oxide
1-(2-EtZN-Ethyl)-5-(2-ClC6H4)-7-NO, N-oxide.2H2O
CH,ClZ/Et,O/Petr ether
254 293, 86b 302 72c 302 55, 287 287 2b
46 32
35 78
Pmr
1-(2-Et,N-Ethyl)-5-(3,4-ClZC6H&7-C1 205-207d 117-1 18 I-(~-E~,N-E~~Y~)-~-(~-FC~H~)-~-HZN164-165 Dihydrochloride
1-(2-Et,N-Ethyl)-5-(4-ClC6H4)-7-C1
302 302 2b
EtOH EtOH CH,Cl,/Petr Ether
1-(2-Et,N-Ethyl)-5-(2-FC6H4)-7-C1 Dihydrochloride
1w22od 211-212d
MeOH/Et,O i-PrOH
43; 25
287, 55 86b
TABLE VII-1. --(contd.)
Substituent 4-Oxide w-Oxide.H,O 4,w-Dioxide 1-(2-Et,N-Ethyl)-5-(2-FC6H4)-7-1 1-(2-EtzN-Ethy1)-5-(2-FC,H,)-7-N0, Dihydrochloride
1-(2-Et2N-Ethyl)-5-(3-FC6H4)-17-C1 l-(2-EtZN-Ethyl)-5-(4-FC6H4)-7-C1 1-(2-Et,N-Ethyl)-5-(4-MeOC6H4)-7-C1 1-(2-EtzN-Ethy1)-5-(2-pyridyl)-7-Br Hydrochloride
mp ("C) or; [bp ("C/torr)]
Solvent of Crystallization
122-124 9&95 141-142 92-95
Et,O/Petr ether EtOAc CH2C1,EtOAc/EtZ0 Et,O/Petr ether
196197 80-8 1 102-103 109-1 11
MeOH/Et,O i-prOH i-PrOH Hexane
176-18Od
MeOH/Et,O CH,Cl,/Et,O
1-{2-[N-(2-Et,N-Ethyl)-NHCOCH~O]ethyl)}-5-Ph-7-C1 93-95 1-{2-[N-(2-Et,N-Ethyl)-NHCOCHzO]ethyl}-5(2-FC6H4)-7-C1
Yield (%) 74 71 50
50
i-Pr,O Hexane EtOH/Et,O/Acetone
61 85
EtOH/E,O Xylene
86 45
l-F,CCH,-5-Ph-7-C1
182-192d 178-180 Oil Oil 149-159 164166
Hydrochloride 4-Oxide 1-F,CCH,-5-Ph-7-NO2 l-F,CCHZ-5-(2-ClC6H4)-7-C1 4-0xide
195-197d 192-194 161-162 105-107 208-201
Dihydrochloride
Refs.
Pmr Pmr
233 238 238 371 2b 489 489 302
84-86 89-91 208-2 10
l-(3-Et2N-Pr~pyl)-5-Ph-7-C1
Spectra
287 302 302 287 287
1(3-Et,N-Propyl)-5-(2-FC6H4)-7-C1 Dih ydrochloride l-[Et2P(O)CH,]-5-Ph-7Cl
1-[Et,P(O)CH,]-5-(4-i-PrC4H4)-7-C1 1-(4-F-Benzoyl)propy1-5-Ph-7-C1
l-(4-F-Benzoyl)propy1-5-(2-FC6H4)-7-C1
60 i-PrOH Acetone/Hexane
50
Acetone/Et,O Acetone/MeOH CH,Cl,/Hexane CH,Cl,/Hexane
70 20 57 19
287, 100 25 25 295 29 5 69, 125h, 86b 125h 69 69 69 69
1-F3CCH,-5-(2-FC6H4)-7-C1 4-Oxide
l-F,CCH,-5-(3-O,NC6HJ-7-C1 1-F3CF,CCH2-5-Ph-7-C1 1-{2-[(2-Furoyl)oxy]-l-MeO-Ethyl}-5-Ph-7-C1 l-(~-~-glucopyranosy1)-5-Ph-7-C1 1-[2-(~-Gluconamino)ethyl]-5-Ph-7-C1~0.9EtOH l-(Hexyloxy)CH,-5-Ph-7-NO,
124127 196199 230-231 196197 129-130 160-162 98-100 108-109
CH,Cl,/Hexane CH,CI,/Hexane Acetone CHCI,/Hexane EtOH EtOAc/EtOH EtOH Et,O
135d
i-PrOH
219-220
EtOAc
143-145
MeOH/THF
18C185d 129-131 158-1 59d 158-1 60 235d 115-1 16 235-236 239-24Od 178d 115-1 16 195-2ood 114116 194-196 128-135
MeOH/Et 0 Et,O PhH/Hexane EtOH EtOH
47
EtOH/CHC13 Acetone MeCN
50
206-208 199-203
MeOH/Et,O MeOH
121-123
Acetone
69 69 69 69 302 30 1 258 72
65 55 74 64
1-(3-H,NNHCO-Propyl)-5-Ph-7-CI
-A
5
Dihydrochloride l-HO-5-Ph-7-CI 4-Oxide 1-[2,3,4-(HO)3-B~tyl]-5-(2-FC,H3-7-C1 Hydrochloride 1-(2-HO-Eth0~y)ethyl-5-(2-FC,H,)-7-C1 Hydrochloride I-(~-HO-E~~OX~)CH,-~-P~-~-CI l-(2-HO-Ethyl)-5-Ph-7-N3 1-(2-HO-Ethyl)-5-Ph-7-C1 4-0xide I-(2-HO-Ethyl)-5-Ph-7-F3C 1-(2-HO-Ethyl)-5-Ph-7-N0, 4-Oxide 1-(2-HO-Ethyl)-5-(2-CIC,H,)-7-C1 Hydrochloride
1-(2-H0-Ethyl)-5-(2-FC6H4)-7-CI Hydrochloride
1-(2-HO-EthyI)-5-(2-FC6H4)-7-H,N~O.5MeOH 1-(2-HO-Ethyl)-5-(2-FC6H.J-7-1 Hydrochloride 1-( 2-HO-Ethyl)-5-(2-FCsH4)-7-NO, 1-{3-[4-(2-HO-Ethyl)-piperazin-l-yl]propyl}-5-Ph-7-C1 Dimaleate
488 88
189 236
,
MeOH/E t ,O EtOH/i-Pr,O MeOH/Et,O MeOH
ir, ms, pmr, uv
20
46
283 72 252 86a, 125h 365 86a 86a, 125h 279 365 86a 152c 88, 125h 86a, 233 152c 371 152c
79
287
TABLE VII-1. 4contd.)
Substituent
mp ("C) or; [bp (Tjtorr)]
Solvent of Crystallization
12G123 229-230 220-221 157-159 216217 201-203 188-1 90 172-174 201-203 110-111
Acetone EtOAc EtOAc EtOH EtOH MeCN EtOH MeCN EtOH EtOAc
216217
Acetone/MeOH
203-205 126128 116118 174-176 154-155 187-189
Acetone/MeOH/Et 0 Et,O/Petr ether i-Pr,O/CH,Cl, MeOH/EtOAc
284 284 285 486 285 285
188-190 135-1 37 12c-122 174-175 165-1 66
MeOH/Et,O EtOAc EtOH EtOH/EtOAc EtOAc
192 258 236 236 236
171
EtOH/EtOAc
236
Yield (%)
Spectra
Refs.
1-{3-[4-(2-HO-Ethyl)piprazin-l-yl]propyl}-5-
(2-FC6H,)-7-C1 Dimaleate
1-(2-HO-l-MeO-Ethyl)-5-Ph-7-AcNH 1-(2-HO-l-MeO-Ethyl)-5-Ph-7-H,N 1-(2-HO-I-MeO-Ethyl)-5-Ph-7-C1 4-Oxide
1-(2-HO-1-MeO-Ethyl)-5-Ph-7-N02 I-(2-HO-I-MeO-Ethyl)-5-(2-ClC6H4)-7-N0, 1-(2-HO-1-MeO-Ethyl-5-(2-FC6H,)-7-C1 1-(2-HO-1-MeO-Ethyl)-5-(2-Pyridyl)-7-Br 1-(4-HO-2-Me-But-2-en-I-yl)-5-Ph-7-C1 1-(2-HO-2-Ph-Ethyl)-5-Ph-7-C1 Hydrochloride 1 -(2-HO-Propyl)-5-Ph-7-C1 Hydrochloride 1-(2-HO-Propyl)-5-(2-pyridyl)-7-Br 1-(2-HO-3-MeO-Propyl)-5-Ph-7-C1
1-[2,3-(HO),-Propyl]-5-Ph-7-N02 l-[2,3-(HO),-Propyl]-5-Ph-7-C1 4-Oxide
51
287 486 486 72 302 302 302 302 302 486 284
,
I-[2,3-(HO),-Propyl]-5-(2-ClC6H4)-7-C1 Hydrochloride
1-[2,3-(HO),-Propyll-5-(2-ClC,H,)-7-NO, I-[2,3-(HO),-Propyl]-5-(2-FC6H,)-7-C1 Hydrochloride 4-Oxide
1-[2,3-(HO),-Propyll-5-(2-FC6H,)-7-1 Hydrochloride
1-(2-HO-3-i-PrNH-Propyl)-5-Ph-7-C1
4 P W
Hydrochloride 1-(3-HO-Propyl)-5-Ph-7-C1 1-{3-[4-(2-HO-3-i-PrNH-Propoxy)phenoxy]propyl}5-Ph-7-Cl (S)-Enantiomer 1-{3-[4-(2-{4-[2-HO-3-i-PrNHPropoxylphenoxy}ethyl)piperazin-1-yllpropyl} -5-Ph-7-C1 (S)-Enantiomer Trimaleate 1-(3-l-Propyl)-5-(2-C1C6H,)-7-C1 1,5-Me2-7-C1 1-Me-S-Allyloxy-7-C1 l-Me-5-H2NCO-7-Br l-Me-5-(Aziridin-l-yl)-7-C1 Hemifumarate 1-Me-5-(1,3-Benzodioxolan-5-yl)-7-C1 l-Me-5-Benzyl-7-Cl Hydrochloride
l-Me-5-(2-Br-Ethoxy)-7-C1 l-Me-5-Bu-7-Cl l-Me-5-t-Bu-7-Cl l-Me-5-C6D,-7-Cl 4-Oxide 1-Me-5,7-C12 Hydrochloride
l-Me-5-(2,2-CI,-Ethoxy)-7-C1 l-Me-5-(2-Cl-ethyl)NHCO-7-Br l-Me-S-CN-7-Br 1-Me-S-(Cyclohexen-l-yl)-7-CI l-Me-5-(Cyclohexen- 1-yl)-7-NO2 1-Me-5-Cyclohexyl-7-C1
257-258d 1 5 6 158
CH,Cl,/i-PrOH Acetone/Petr ether
285 279. 86a
110-111
CH,Cl,/Et,O
48 7
153-155 139-142 143 64 2W203
MeOH/EtOAc CH,CI,/Hexane Cyclohexane Et,O/Pentane CHClJPetr ether
48 7 192 18 195 192
224-225d 145- 147 110 214-216 110 55-56 [160/0.1] 80-8 1 131-132 184-186 133-135 70-8od 123 208-2 11 170-171 144 163 126127 149-150
EtOH CH,Cl,/Hexane i-Pr,O MeOH/C,H, Et,O/Pentane Hexane
43 28
46 60 40 80
ir, pmr
Hexane
PhH/CCl,
49 81 55
Et,O/Pentane Et,O/Hexane CH,CI,/Petr ether EtOAc
38
Hexane
82
52
ir, ms, pmr
ir, pmr, uv
196 92 18 116 195 18 124 lb 97 97 198b 196 195 192 192 222, 86b 86b 18 86b
TABLE VII-1. d c o n t d . ) mp ("C) or; [bp (Tjtorr)]
Solvent of Crystallization i-Pr,O EtOAc
50
Cyclohexane CClJPentane EtOAc CClJPentane Acetone/Hexane
70 75 46 57
l-Me-5-[2,2-(EtO),-ethyl]NH-7-CI
150 149-150 157-158 97 123 87-89 108-109 112-1 14
1-Me-5-(2,2,2-F3-Ethoxy)-7-C1 l-Me-5-(2,2,2-F3-1-Me-Ethoxy)-7-C1 1-Me-5-Ferrocenyl-7-1
128 95 154-156d
Et,O/Pentane Et,O/Pentane CH,CI,/Hexane
32 38 79
Substituent
l-Me-5-Et-7-CI l-Me-5-EtO-7-Cl l-Me-5-EtO-7-Me l-Me-5-EtO-7-NO2
-1
vl
Yield (%)
Spectra
Refs. 224 70 18 18 195 195 195 391b 195 195 13
0
l-Me-5-(2-HO-Ethyl)NHCO-7-Br l-Me-5-(Isothiazol-5-yl)-7-C1 1-Me-5-(l-Me-l-Pr)-7-C1
l-Me-5-(4-Me-l-Piperaziny1)-7-C1 l-Me-S-(MeNPh)-7-C1 Hydrochloride l-Me-5-(3-Me,N-Propylamino)-7-C1 Dihydrochloride l-Me-5-MeO-7-Cl l-Me-5-(3-Morpholin-l-yl-propylamino)-7-C1 Dihydrochloride 1-Me-5-Ph-7-Ac 4-Oxide l-Me-5-Ph-7-Ac(Allyl)N 1-Me-5-Ph-7-AcNH 4-Oxide
185-188 189-19 1 [15&160/0.05] 171
Acetone CH,CI,/Hexane CHC1,
192 13b 18 196
273-275
MeOH
196
268d 114-116
MeOH CClJPentane
275d 120-125 158-160 6547 196199 218-21 9
EtOH/Et,O CH,CI,/Et,O MeOH
81
MeOH EtOH/Et,O
60
196 195 196 160 2b 251c 251c 251c
l-Me-SPh-7-AqMe)N 1-Me-5-Ph-7-H2N
l-Me-5-Ph-7-(H,N-Hydroxyiminomethyl) l-Me-5-Ph-7-(H,N-Methoxyiminomethyl)
2
1-Me-5-Ph-7-H,NCH2 Dih ydrochloride l-Me-5-Ph-7-N3 l-Me-5-Ph-7-Br 1-Me-5-Ph-7-t-Bu 1-Me-5-Ph-7-CI 4-Oxide I-Me-5-Ph-7-ClCH2S 1-Me-5-Ph-7-(4-CIC,H4) l-Me-5-Ph-7-CN l-Me-S-Ph-7-( 1,3-Dioxolan-2-yl)
l-Me-5-Ph-7-[N-(l-EtOOC)-l-Iminoethyl]NH l-Me-5-Ph-7-OCH 1-Me-5-Ph-7-F I-Me-5-Ph-7-F2CHS 1-Me-5-Ph-7-F,CHSO2 1-Me-5-Ph-7-F3C 4-Oxide I-Me-5-Ph-7-(Formyl)NH 1-Me-5-Ph-7-H2NNH l-Me-5-Ph-7-HONH l-Me-5-Ph-7-(2-HO-Ethylamino)CONHCH, 1-Me-5-Ph-7-1 1-Me-5-Ph-7-Me 1-Me-5-Ph-7-(2-Me-1,3-dioxolan-2-yl)
l-Me-5-Ph-7-(2-Me-Propanoyl)NH 1-Me-5-Ph-7-MeNH
226229 229-23 1 238-240 253-255d 194-196 23Od 2 12-2 15d 123-125d 132-133 122-124 127-130 178-180 83-85 161-162 157-159 138-139 179-180 123-125 109-1 10 123-1 24 140 6345 [123/0.07] 184-186 145-147 178-180 211-213 20 1 136-138 131-133 122-124 162-1 65 134-135
EtOH
247
EtOH DMFiEtOH PhH/Hexane Et,O MeOH/Et ,O Acet one/Hexane Et,O MeOH/H,O Et,O PhMe Et,O EtOH PhH/Petr ether Et,O/Pentane CH,Cl,/Et,O/Hexane Et O/Pen tane Et,O/Petr ether Et,O/Petr ether Et,O/Petr ether
247 33b 33b 25 1 38b 252 2b 419
46
uv
,
PhH/Hexane MeOH/Acetone/Hexane i-PrOH CH,CI,/EtOH EtOH EtOH Et,O/Hexane Acetone/Hexane EtOAc/Hexane Et,O
60 69 70
ir, ms, pmr, uv ir, ms, pmr, uv
71
uv
49
30 2b 48 1 5 32 134 33b 2 10 10 490 4 251c 134 245 25 1 371 302 32 251c 134
TABLE VII-1. 4contd.) ~~~
Substituent
-I Ul
N
l-Me-5-Ph-7-Me2N 7-Methobromide l-Me-5-Ph-7-Me2NCONH l-Me-5-Ph-7-Me2NCHN 1-Me-5-Ph-7-Me0 l-Me-5-Ph-7-MeS 4-Oxide l-Me-5-Ph-7-Me(O)S Hydrochloride l-Me-5-Ph-7-MeSO2 l-Me-5-Ph-7-MeSCH2NH
l-Me-5-Ph-7-(l-Me-lH-Tetrazol-5-yl) I-Me-5-Ph-7-(2-Me-Tetrazol-5-yl) I-Me-5-Ph-7-NO2 4-Oxide l-Me-5-Ph-7-NO l-Me-5-Ph-7-(Propanoyl)NH
1-Me-S-Ph-7-[(Pyrrolidin-l-yI)CONHCH,] 1-Me-5-Ph-7-(1H-Tetrazol-5-yl) 1-Me-5-Ph-7-(3,4,5-Triazatricyclo[5.2.l.O]dec-4-en-3-y~)
l-Me-5-(2-benzyl-NHC,H4)-7-C1 l-Me-5-(2-AcNHC6H4)-7-C1 1-Me-5-[3-(4-AcNHC,H4-azo)-4-HOC,H,]-7-C1 1-Me-5-(2-H,NC6H,)-7-Br 1-Me-5-(2-H,NC,H3)-7-C1
1-Me-5-[3-(4-H,NC,H,-azo)-4-HOC,H3]-7-CI 1-Me-5-(2-C1C6H,)-7-AcNH 1-Me-5-(2-C1C6H,)-7-H,N
-
mp ("C) or; [bp ('C/torr)]
Solvent of Crystallization
141-143 19Od 130 161-163 109-110 3545 156158
EtOH/Et,O/Hexane MeOH/Et,O Amorphous CH,Cl,/Hexane Et,O Hexane MeOH
95 95 251b 247 72c 1 192
201-202 178-1 79 153-155 212-2 14 20 1-203 159-161 219-22 Id 126129 215-21 7 106 278-28Od 200-201d 173-176 250-251 276278 200-205 203-207 262-268 Foam 239-240
MeOH/Et,O CH,CI,/Et,O CH,CI,/Et ,O Hexane PhH/Hexane PhH/Hexane CH,CI,/MeOH Acetone/Hexane MeOH MeOH/EtOAc/Hexane Amorphous DMF/H,O EtOH CH,CI,/Et,O MeCN CH,Cl,/Petr ether CH,CI,/Hexane CH,Cl,/Hexane CH,Cl,/MeOH
2b 2b 134 252 252 36 lb 247 251c 251b 252 252 152c 162 152c 162 162 8 258 72c
EtOH
Yield (%)
Spectra
Refs.
8 46 71
82 87 100 87 57 45
ir
l-Me-5-(2-C1C6H,)-7-C1 4-Oxide
1-Me-5-(2-C1C6H4)-7-(2-HOethyl)NHCONH 1-Me-5-(2-ClC,H4)-7MeN HC0N H 1-Me-5-(2-C1C6H,)-7-Me,N I-Me-5-(2-C1C6H,)-7-MeS I-Me-5-(2-CIC6H,)-7-NO, 4-Oxide
1-Me-5-(2,3-C1,C,H3)-7-C1 1-Me-5-(2,4-C1,C,H3)-7-C1
1-Me-5-(2,6-C1,C6H,)-7-Cl 1-Me-5-(2-C1-5-H,NC,H3)-7-C1 1-Me-5-(2-C1-5-MeOC,H3)-7-C1 l-Me-5-(2-C1-5-0,NC6H,)-7-C1 1-Me-5-(3,4-C1,C,H3)7-C1 4
vl
w
1-Me-5-(4-C1C6H4)-7-C1 4-Oxide 1-Me-5-(4-C1C6H,)-7-F 1-Me-5-(4-CIC6H4)-7-NOz
l-Me-5-(4-C1-2-Me-Phenoxy)-7-C1 I-Me-5-[3-C1-2-Pyridyl]-7-C1 1-Me-5-(2-FC6H,)-7-Ac 4-0xidc.0.5 acetone 1-Me-5-(2-FC6H4)-7-AcNH 4-Oxide
1-Me-5-(2-FC6H,)-7-AcNHCH, 1-Me-5-(2-FC6H,)-7-Ac(Me)N 1-Me-5-(2-FC,H4)-7-(2-AcO-ethy1)NHCONH 1-Me-5-(2-FC,H4)-7(Allyl)NHCSNH 1-Me-5-(2-FC,H4)-7-(Allyloxy)CONH 1-Me-5-(2-FC6H,)-7-H,N
1-Me-5-(2-FC,H,)-7-(2-HzN-Acetyl)NH l-Me-5-(2-FC6H,)-7-NHCONH
135-136 218-220 150-165d
EtOH Acetone
2 358 30 1
2 1G220 110-115 115-1 18 194-195 201-204 164-165 178-1 81 16&161 210-212 130-132 237-239 154-157 1 5 6 156 238-240 160-163 131-135 179 125-126 117-120 85-86 172-175 212 199-200
Acetone/Petr ether Et,O/Hexane Et20/CH,C1, Et,O MeCN Acetone/Petr ether Acetone/Hexane Et,O/Petr ether EtOH Et,O CH,Cl,/EtOH MeOH/Petr ether Et,O THF/Hexane Acetone/Hexane Acetone/Hexane Et,O/Pentane CH,Cl,/Hexane CH,CI,/Petr ether Acetone EtOH/Hexane CH,CI,/Et,O CH,CI,/Hexane EtOAc EtOAc EtOAc Et,O THF/Hexane EtOAc/Et,O EtOH/Et,O
301 95 192 136 302 2b 500 42 134 134 134 92 2 152c 500 136 195 484 33b 2b 134 30 1 251b 30 1 23 1 301 301 252, 253 301 301
196198 168-170 140-144 26208d 134-137 216-217d
78
70
74 73 55
64
TABLE VII-1. gcontd.)
Substituent 1-Me-5-(2-FC6H,)-7-(2-H,N-Ethoxy)CONH
mp ("C) or; [bp (Tjtorr)]
127-13Od 248-249d Amorphous l-Me-5-(2-FC6H,)-7-H,NSO, 299-210 1-Me-542-FC,H,)-7-N, 97-99d 1-Me-5-(2-FC6H,)-7-(Aziridin-1-yl)CONH 18619Od 1-Me-5-(2-FC6H4)-7-(Benzoyl)NH 23&234 1-Me-5-(2-FC6H,)-7-(Benzyl)NHCONH 174-178 1-Me-5-(2-FC6H,)-7-(Benzyloxy)CONH 15Od 1-Me-5-(2-FC6H,)-7-(Benzyloxy)CO(Me)N 118-122 1-Me-5-(2-FC6H,)-7-(Benzyloxy)CSNH 192-193 ; i 1-Me-5-(2-FC6H,)-7-Br 132-1 33 1-Me-5-(2-FC6H,)-7-(Butanoyl)NH 140-150 1-Me-5-(2-FC,H4)-7-(Butanoyl)MeN 105-107 l-Me-5-(2-FC6H4)-7-BuNHCONH 213 1-Me-5-(2-FC,H4)-7-r-BuNHCONH 21Od 1-Me-5-(2-FC,H4)-7-(But-2-yl)0OCNH 13&14Od 1-Me-5-(2-FC6H4)-7-(But-2-yl)SCONH 174 1-Me-5-(2-FC6H,)-7-(But-2-yl)SCSNH 17618Od 1-Me-5-(2-FC,H4)-7-Bu0OCNH 154-158 1-Me-5-(2-FC6H4)-7-r-BuOOCNHCH, Amorphous 1-Me-5-(2-FC6H4)-7-(2-t-BuO-Ethyl)NHCONH 177 1-Me-5-(2-FC6H,)-7-(2-t-BuO-Ethyl)(benzyl)NCONH 82-86 160 l-Me-5-(2-FC,H,)-7-(HOOCCH,NH)CONH)CONH 170-175d 1-Me-5-(2-FC6H,)-7-C1 69-74 Hydrochloride 218-21 9 4-Oxide 177-178 1-Me-5-(2-FC,H,)-7-(2,2,2-CI,-Acety1)NHCONH 146148d
1-Me-5-(2-FC6H,)-7-H,NC(NH)NH 1-Me-5-(2-FC6H,)-7-HzNCHz
Solvent of Crystallization
Yield (%)
MeOH/Et,O EtOAcEtOH CH,Cl, EtOAc/Heptane EtOAc/Et,O EtOAc/CH,CI, EtOAc/Et,O EtOAc/Et,O/Hexane Et,O/Hexane Et,O EtzO EtOAc/Et,O Et,O/Petr ether CH,Cl,/EtOAc EtOH/Petr ether Et,O Et,O/Petr ether Et,O/Petr ether CH,Cl,/Et,O/Petr ether EtOAc CH,Cl,/Hexane CH,CI,/Hexane EtOH/H,O MeOH/H,O EtOH CH,/Cl,/Et,O/Petr EtOAc/Et,O
44
3
81
Spectra
Refs. 301 301 251 301 252 231 301 231 301 301 301 2 301 301 30 1 231 301 301 301 301 251b 23 1 231 301 301 2 86b
ether
152c 301
1-Me-5-(2-FC6H,)-7-(2-Cl-Ethyl)NHCONH 1-Me-5-(2-FC,H,)-744-ClC,H,)NHCONH 1-Me-5-(2-FC,H,)-7-bis-(4-ClC,H4NHCO)N 1-Me-5-(2-FC6H,)-7-CN
l-Me-5-(2-FC6H,)-7-(Cyclohexyl)NHCONH 1-Me-5-(2-FC6H,)-7-(Cyclohexyl)CONH 1-Me-5-(2-FC6H,)-7-(Cyclopenty1)CONH 1-Me-5-(2-FC,H4)-7-(Cyclopentyl)MeN 1-Me-.5-(2-FC6H,)-7-(CyclopropyI)NHCONH l-Me-5-(2-FC6H4)-7-(Cyclopropyl)CONH 1-Me-5-(2-FC6H4)-7-Diazonium Tetrafluoroborate
240d 223-225 188 177 233-234 245-250 202-203 122-1 24 230 180-185d
EtOAc CH,CI,/Et,O CH,CI,/EtOH EtOAc/Et,O EtOAc/CH,CI, EtOAc/Et ,O Et,O/Hexane EtOAc/EtOH/Et,O EtOAc
231 301 30 1 251 301 301 30 1 301 30 1 301 251
120-125
1-Me-5-(2-FC,H,)-7-[1,3-Dihydro-5-(2-FC,H4)-l-Me-
2 lcI
2-0x0-2H- 1,4-benzodiazepin-7-yl]NHCONH 230d 1-Me-5-(2-FC,H,)-7-[1,3-Dihydro-5-(2-FC,H,)-1 -Me2-0x0-2H- 1,4-benzodiazepin-7-yl]NHCONHNHCONH 230-245d
EtOH/Et,O/Petr ether
301
EtOAc
301
Acetone
301
EtOH/Et,O
30 1
CH,CI2/Et,O
251b
Et,O/Hexane Et,O/Petr ether THF/Et,O Acetone/Et,O EtOAc/Et,O MeOH/EtOAc EtOAc/Et,O EtOH/Et,O Et,O/Hexane
301 33b 301 23 1 231 301 301 301 301
1-Me-5-(2-FC,H,)-7-[1,3-Dihydro-5-(2-FC6H4)1-Me-2-oxo-2H-1,4-benzodiazepin-7-yl]220-232d NHCONHCH,CH,NHCONH 1-Me-5-(2-FC6H,)-7-{4-[1,3-Dihydro-5-(2-FC6H,)-I-Me2-0x0-2H- 1,4-benzodiazepin-7-yl]NHCO-piperazin-lyllNHC0-piperazin-1-yl}CONH 221d 1-Me-5-(2-FC6H,)-7-[ 1,3-Dihydro-5-(2-FC6H,)-l-Me2-oxo-2H-1,4-benzodiazepin-7-yl]oxyazo 240-242
1-Me-5-(2-FC,H,)-7-[1,3-Dihydro-5-(2-FC6H,)-2-oxo2H-1,4-benzodiazepin-7-yl]S 1-Me-5-(2-FC6H,)-7-Et
1-Me-5-(2-FC6H,)-7-EtNHCONH 1-Me-5-(2-FC6H,)-7-Et,NCONH 1-Me-5-(2-FC6H,)-7-Et(Me)NC0NH 1-Me-5-(2-FC,H,)-7-(EtOOCCH,NH)CONH 1-Me-5-(2-FC,H4)-7-(2-EtO-Ethy1)NHCONH 1-Me-5-(2-FC6H,)-7-EtOCSNH 1-Me-5-(2-FC6H,)-7-EtOCS,
120-14od 105-107 168-17Od 138-139 165-168 2 12-214 180-182 150-152 80-85d
TABLE VII-1. 4contd.)
Substituent
mp ("C) or; [bp ('C/torr)]
221-222d 150-154d 110-111 1-Me-5-(2-FC6H,)-7-F 173-175 1-Me-5-(2-FC,H,)-7-F3C0NH 189-1 91 1-Me-5-(2-FC,H,)-7-F3CO(Me)N 1-Me-5-(2-FC6H,)-7-(Formyl)NH 106107 176177 1-Me-5-(2-FC6H,)-7-(Formyl)MeN 17&180 1-Me-5-(2-FC6H,)-7-(2-Furoyl)NH 1-Me-5-(2-FC6H4)-7-(2-Furoyl)MeN 195-200 1-Me-5-(2-FC6H,)-7-HONH 228-23Od 1-Me-5-(2-FC6H,)-7-[2-(2-HO-Ethoxy)ethoxy]CONH 146-148 133-1 35 1-Me-5-(2-FC6H,)-7-(l-HO-Ethyl) 1-Me-5-(2-FC6H,)-7-(2-HO-Ethyl)NHCONH 15616Od 4-Oxide 256261 163-17Od
1-Me-5-(2-FC6H,)-7-EtSCONH 1-Me-5-(2-FC,H,)-7-EtSCSNH
21
Solvent of Crystallization EtOAc/Et,O CH,Cl,/Et,O Hexane Acetone/Hexane
Yield (YO)
82
EtOH MeOH/Et,O EtOAc EtOAc/CH,CI, EtOAc/Petr ether THF/EtOH EtOAc Et,O/Pentane Acetone Acetone EtOH/Et,O
52
Spectra
Refs. 301 301 500 134 134 301 301 301 301 245 301 33a 23 1 301 301
1-Me-5-(2-FC6H,)-7-(2-HO-Ethylaminocarbonylaminomethyl)
1-Me-5-(2-FC6H,)-7-(2-HO-Ethyl)(Me)NC0NH I . 1-Me-5-(2-FC,H4)-7-[4-(2-HO-Ethyl)piperain-l-yl]CONH
125 196-198 235
188-190 1-Me-5-(2-FC6H,)-7-(2-HO-Elhoxy)CONH 198-2ood 1-Me-5-(2-FC,H,)-7-HO(Me)NCONH 1-Me-5-(2-FC,H4)-7-(2-HO-Prop-l-y1)NHCONH 149-151d l-Me-5-(2-FC6H,)-7-(1-HO-Prop-2-y1)NHCONH
1-Me-5-(2-FC,H4)-7-(3-HO-Propy1)NHCONH 1-Me-5-(2-FC6H4)-7-(2-HO-Prop1-y1oxy)CONH l-Me-5-(2-FC6H4)-7-HS
l-Me-5-(2-FC,H4)-7-(2-HS-Ethy1)NHCONH 1-Me-5-(2-FC,H,)-7-HSO,
165-168d 118-1 19 116122d 125-126 18619Od 322d
Acetone
251 23 1
EtOH CH,CI, EtOAc/EtOH EtOAc Acetone Acetone Acetone/Et,O/Petr ether Et,O/Hexane CH2Cl,/Et,0 MeOH/H,O
301 301 30 1 23 1 231 23 1 301 30 1 301 301
1-Me-5-(2-FC6H,)-7-I Hydrochloride 4-0xide 1-Me-5-(2-FC,H,)-7-(2,2-Me2 -0xazolidin-3-y1)CONH
1-Me-5-(2-FC,H,)-7-(4-MeC~H4S0,)NHCONH 1-Me-5-(2-FC,H4)-7-(4-Me-Piperazin-l-yl)CONH 1-Me-5-(2-FC6H,)-7-(2-Me-Propanoyl)NH 1-Me-5-(2-FC,H4)-7-MeNH
1-Me-5-(2-FC,H4)-7-MeNHCONH 1-Me-5-(2-FC,H4)-7-MeNHCO(HO)N. EtOH 1-Me-5-(2-FC,H4)-7-MeNHCO(Me)N 1-Me-5-(2-FC,H4)-7-MeNHS0, 1-Me-5-(2-FC,H4)-7-MeNHCSNH 1-Me-5-(2-FC,H,)-7-Me2NCONH.0.5 EtOH 1-Me-5-(2-FC,H,)-7-(Me,NCONHCH2) 1-Me-5-(2-FC6H,)-7-Me,NSO,
2: I-Me-5-(2-FC,H,)-7-MeONHCONH 1-Me-5-(2-FC,H4)-7-MeOOCNH 1-Me-5-(2-FC,H4)-7-(2-MeO-Ethoxy)CONH l-Me-5-(2-FC6H,)-7-MeO(Me)NCONH 1-Me-5-(2-FC,H4)-7-(4-MeOC,H,)NHCONH 1-Me-5-(2-FC,H4)-7-MeS 1-Me-5-(2-FC6H,)-7-Me(O)S 1-Me-5-(2-FC,H4)-7-MeSO, 4-Oxide
1-Me-5-(2-FC,H,)-7-MeSOzNH 1-Me-5-(2-FC6H,)-7-(Morpholino)CONH 1-Me-5-(2-FC,H,)-7-NOz 4-Oxide
1-Me-5-(2-FC,H4)-7-(4-N0,-Benzyloxy)CONH 1-Me-5-(2-FC6H,)-7-NO
1-Me-5-(2-FC6H,)-7-(Octadecanoyl)NH~ EtOH 1-Me-5-(2-FC,H4)-7-(2-Oxoimidazolidin-l -yl)
107-110 226229 178-181 184188d 23CL234d 245-246 142-150 109-1 11 173 206-208d 75-80 200 21c212 97 105 198-200 144-146d 143-145d 16142 22c222 24od Amorphous 178d 173-174 198-200 166168 237-238d 165-167 17CL172 16&167 247-25Od Oil 75 129-1 32d
Et,O/Petr ether MeOH/Et,O EtOH EtOAc/Et,O Acetone EtOAC EtOAc/Et,O Et,O EtOAc EtOH EtOH/Petr ether EtOAc/Et,O CH,CI, EtOH/Petr ether
26 26 141 301 301 301 301 134 23 1 301 301 301 301 231 251 301 301 301 301 301 231 192 301 301 301 301 301
EtOAc/Et,O EtOAc Et,O CH $1 ,/Et ,O CH,CI,/EtOAc EtOAc CH,CI,/Et,O EtOAc/Et ,O EtOAc EtOAc Et,O/Petr ether CH,Cl,/Hexane CH,CI,/Et,O CH,C1, EtOH Et ,O/EtOH
3
55 136 2b 30 1 251b 30 1 301
TABLE VII-1. 4contd.) ~~
Solvent of Crystallization
Substituent
1-Me-5-(2-FC6H,)-7-(Pentanoyl)NH 1-Me-5-(2-FC6H,)-7-PhNHCONH 1-Me-5-(2-FC6H,)-7-(Piperazin-l-yl)CONH l-Me-5-(2-FC6H,)-7-(Piperidin-l-yl)CONH 1-Me-5-(2-FC6H,)-7-i-PrNHCONH 1-Me-5-(2-FC6H4)-7-i-PrNHSO,
l-Me-5-(2-FC,H4)-7-i-PrO0CNH l-Me-5-(2-FC,H4)-7-(Pyrrolidin-l-y1)CONH 1-Me-5-(2-FC,H,)-7-(Pyrrolidin-l-yl)CONHCH2 1-Me-5-(2-FC6H,)-7-SCN 1-Me-5-(2-FC6H4)-7-(Thiazolidin-3-yl)CONH
3 O0
1-Me-5-(2-FC6H4)-7-(2-Thienoyl)NH 1-Me-5-(2,6-F,C6H,)-7-C1 1-Me-5-(2,6-F,C,H,)-7-NO2
1-Me-5-(2-F-5-H,NS0,C6H,)-7-H,NS0, 1-Me-5-(2-F-5-MeNHSO2C,H,)-7-MeNHSO, 1-Me-5-{2-F-6-[(2-HOOC-Ethyl)MeN]C,H,}-7-CI l-Me-5-[2-F-6-(HOOCCH,)MeN]-7-C1 1-Me-5-[2-F-6-(3-HOOC-Propanoyl)NH]-7-C1 1-Me-5-[2-F-6-(Et00CCH,)MeN]C6H3-7-CI 1-Me-5-(2-F-6-HOC6H,)-7-Cl
1-Me-5-(2-F-6-HOOCCH,0C6H3)-7-CI l-Me-5-(2-F-6-MeNHC6H,)-7-CI 1-Me-5-(2-F-6-Me,NC6H,)-7-C1 l-Me-5-(2-F-6-MeOC6H,)-7-Cl
1-Me-5-(2-F-6-Me00CCH,0C6H3)-7-CI l-Me-5-(2-F-Phenoxy)-7-C1 1-Me-5-(3-FC6H,)-7-C1 1-Me-5-(4-FC6H,)-7-C1
14G144 209-210 181d 231-239 185-188d 173-174 164-166 159-160 145 150 185d 162-163d 158-162 182-184 280d 190 188-197 178-180 214-223d 174-178 18&188 235-23 8 172-1 77 123-127 177-185 173-177 128 Oil la162
~~
Yield (YO)
Spectra
Refs
X-ray
301 301 301 30 1 23 1 30 1 301 23 1 25 1 301 231 301 152c 152c 301 301 152c 152c 152c 152c 152c 152c 152c 152c 152c 152c 195 91a 403
EtOAc/Et,O EtOAc/Et,O EtOH/Et,O EtOAc EtOAc EtOAc/Et,O CH ,CI ,/E t ,O Acetone Et,O CH,CI,/EtOAc EtOAc CH,CI,/MeOH CH,CI,/Hexane Acetone/CH,Cl, EtOAc MeOH/H,O CH,CI,/Et,O/MeOH MeOH CH,CI,/EtOH CH,Cl,/Petr ether THF/Et,O/Petr ether CH,Cl,/Hexane Et,O/Petr ether PhH/Hexane CH,CI,/Petr ether Et,O/Pentane Et,O
50
I-Me-5-(3-F-2-Pyridyl)-7-C1
119-122 213-215 1-Me-5-(2-F,CC,H,)-7-NO, 198-199 1-Me-5-(2-F,CC6H4)-7-Me,N 11cb115 1-Me-5-[3-(4-F,CCONHC,H4)azo-4-HOC,H,]-7-C1 276-278 1-Me-5-H2NNH-7-CI 139-1 4 1 1-Me-5-(4-HOC6H,)-7-C1 255-259
1-Me-5-(2-F3CC,H,)-7-H,N
CH,CI,/Hexane MeOH Acetone Et,O/Hexane CH,CI,/Petr ether PhMe/Me-C-Hexane MeOH
70 32 6
ir ir, pmr
484 247 6 95 8 198b 8
1-Me-5-[4-(2-HO-3-i-PrNH-Propoxy)C6H4J-7-CI Maleate 1-Me-5-(2-MeC6H,)-7-C1
1-Me-5-(2,4-Me,C6H,)-7-C1 1-Me-5-(2-Me,NC,H4)-7-C1 I-Me-5-(l-Me-Imidazol-2-yl)-7-C1 1 -Me-5-(2-Me-Pyrazol-3-yl)-7-C1
l-Me-5-(2-MeOC,H4)-7-CI 1-Me-5-(4-MeOC,H4)-7-CI
2:
1-Me-5-[3,4,5-(Me0),C6H2]-7-C1
\o
I-Me-5-(2-0,NC,H4)-7-Br 1-Me-5-(2-O,NC6H,)-7-C1 1-Me-5-(2-0,NC,H4)-7-N0,
1-Me-5-(3-0,NC6H4)-7-N0, 1-Me-5-(4-O,NC6H,)-7-CI 1-Me-5-(4-PhC,H4)-7-C1 l-Me-5-PhO-7-CI I-Me-5-PhS-7-CI
1-Me-5-[2-(Piperidin-l-yl)C6H,]-7-I 1-[4-(4-Me-Piperazin-I-yl)butylJ-5-(2-pyridyI)-7-Br Dihydrochloride
1-[2-(4-Me-Piperazin-l-yl)ethyl]-5-Ph-7-C1 Diamaleate 1-[2-(4-Me-Piperazin-l-yl)ethyl]-5-(2-FC,H4)-7-C1 Trih ydrochloride 1-[3-(4-Me-Piperazin-l-yl)propylJ-S-Ph-7CI Diamaleate
487 2 92 152c 27 27 2 Ib 86b 162 162 136, 86h 152c 302 92 195 196 33b
167-1 70 137-139 174-176 157-1 58 169-1 7 1 144-147 161-162 112-1 15 14Ck142 189-190 174-175 209-2 12 2 18-2 19 162-163 187-189 111-1 13 147 182-1 84
Acetone/Et,O MeOH CH,CI,/Hexane Et,O CHCI,/Hexane CHCI,/Hexane PhH/Hexane Hexane
15cb163d 159-160 158-160
EtOH/Et,O Acetone/Hexane MeOHiHexane
66 59
67b 287, 86b 287
225-234
MeOH/Et ,O
37
287
18cb-182
MeOH
80
287
CH,CI,/Hexane CH,CI,/Hexane MeOH Acetone EtOH CH,Cl,/MeOH Et,O/Pentane MeOH Et 0Ac/Et ,O
90
8
68 40
55
TABLE VII-1. +ontd.)
Substituent 1-[3-(4-Me-Piperazin-l-yl)propyl]-5-Ph-7-C1 Dimaleate 1-[3-(4-Me-Piperazin-l-yl)propyl]-5-(2-FC,H4)-7-C1 Dimaleate l-Me-5-Pr-7-CI l-Me-5-i-Pr-7-CI l-Me-5-PrO-7-CI l-Me-S-(Propyn-3-yloxy)-7-C1 l-Me-5-(2-Pyridyl)-7-H2N l-Me-5-(2-Pyridyl)-7-Br 4,1'-Dioxide 1-Me-5-(2-Pyridyl)-7-Me2N l-Me-5-(2-Pyridyl)-7-MeS l-Me-5-(2-Pyridyl)-7-NO2 1-Me-5-(2-Pyrimidyl)-7-C1 1-Me-5-(2-Pyrirnidyl)-7-NO2
mp ("C) or; [bp (T/torr)]
Solvent of Crystallization
178-179
MeOH/Et,O
185-187 72; 87 108 70 120 228-230 136137 245-248 151-153 134-137 217-219d 157- 159 194- 197d l-Me-5-(2-Thiazolyl)-7-C1 204-206 l-Me-5-(2-Thiazolyl)-7-1 20&201 1-(3-Me-But-l-y1)-5-Ph-7-C1 84-85 1-(3-Me-But-l-yl)-5-Ph-7-N0, 121-122 1-(2,2-Me,-l,3-Dioxolan-Cyl)CH,-5-Ph-7-C1 115-1 18 142-Me-1,3-Dioxolan-2-yl)propyl-5-(2-FC6H4)-7-Cl 152-153 1-[2-(5-Me-Isoxazol-3-yl)COO-l-MeO-ethyl]5-Ph-7-C1 145-147 4-Oxide 21&211 1-[2-(4-Me-Oxazol-5-yl)COO-l-MeO-ethylI-5-Ph-7-Cl 151-154 1-(4-MeC,H,SO,NHCO)-5-Ph-7-NO2 242-243 1-[2-(2,2-Me,-Propanoyloxy)-l-MeO-ethyl]-5-Ph-7-C1 101-103 1-(2-Me-Prop-l-y1)-5-Ph-7-C1 9698 1-(2,2-Me,-Propyl)-5-Ph-7-C1 139-141
MeOH Hexane Hexane Et,O/Pentane Et,O/Pentane CH,CI,/PhH EtOAc CH,CI,/Hexane CH,Cl,/Heptane CH,CI,/Et,O/Hexane PhH CH,CI,/Et,O/Hexane CH,CI,/Hexane CH,CI,/MeOH CH,CI,/EtOH Et,O/Petr ether Et,O EtOH EtOH CH,CI,/Et ,O EtOH Acetone Et,O/Petr ether Et,O Hexane
Yield (Oh)
Spectra
Refs.
255c 78 70 75 15
40 70
6
ir
287 18 18 195 195 33b 3 152c 33b 192 33b 28 158 27 27 2b 136 285 302 302 302 302 49 1 302 2b lb
1-[2-Me-4-(Pyridin-3-yl)COO-but-2-enl-yll-5-Ph-7-Cl l-[2-Me3Si0-1-Me0-Ethyl]5-Ph-7-CI 1-MeNHCO-5-Ph-7-H2NEt,O l-MeNHCO-5-Ph-7-CI 1-MeNHCO-5-Ph-7-F3C 1-MeNHCO-5-Ph-7-1 1-MeNHCO-5-Ph-7-N02
1-MeNHCO-5-(2-CIC6H4)-7-N02 l-MeNHCO-5-(2-FC,H4)7-H2N~Et20 1-MeNHCO-5-(2-FC6H,)7-C1 1-MeNHCO-5-(2-FC6H4)7-I
1-MeNHCO-5-(2-FC4H,)-7-MeNHCONH 1-MeNHCO-5-(2-FC4H,)7-NO, 1-MeNHCO-5-(2-Pyridyl)-7-Br
I-(l-MeNHCO-Ethyl)5-Ph-7-C1 . I1-MeNHCOCH,-5-Ph-7-H2N
z
1-MeNHCOCH2-5-Ph-7-Br 1-MeNHCOCH2-5-Ph-7-C1 Methohydrosulfate 4-Oxide 1-MeNHCOCH2-5-Ph-7-CN 1-MeNHCOCH,-5-Ph-7-F3C 1-MeNHCOCH,-5-Ph-7-NO,
142-143 109-1 10 131-135 148-1 49 159-160 154-155 160 141-142 127-130 145-146 158-1 59 186d 144 158-160 26245 189-190 176178 257-259 252-254 173-175 269 224226 2&261
231-232
197-199 1-MeNHCOCH,-5-(2-ClC6H,)-7-C1 212-214 1-MeNHCOCH,-5-(2-FC6H4)-7-C1 207-208 l-MeNHCOCH,-5-L2-FC6H,)-7-N0, 23&232 l-MeNHCOCH2-5-(2-Pyridyl)-7-Br 16142 1-[2-(MeNHCO-Methoxy)thyl]-5-Ph-7-CI 131-133 1-[2-(MeNHCO-Methoxy)thyl]-5-(2-CIC6H4)-7-Cl I-[2-(N-MeNHCOCH2-N-Me-Amino)ethyl]-5-Ph-7-C1 111-1 13 1-[2-(N-MeNHCOCH,-N-Me-Amino)ethyl]-5-Ph-7-N02 158-160 1-(2-MeNHC00-Ethyl)-5-(2-FC6H4)-7-C1 Hydrochloride
175-180
MeOH MeCN Et,O Et,O CH,Cl,/Et,O/Petr ether CH,Cl,/Et,O/Petr ether PhH/Acetone CH,CI,/Et,O Et,O CH,CI,/Et,O CH,Cl,/Et,O/Petr ether EtOAc/Et,O/EtOH CH,CI,/Et,O
90
ir, pmr
486 302 2b 31 1 2b 2b 74 2b 301 2b 2b 301 301
Acetone Acetone/Petr ether CH,CI,/Et,O CH,Cl,/Et,O MeCN/Et 0 EtOH
2b 293 2b 25% 293, 86b 293 293 38b 293 293 293 86b 293 293 150d 302 15Oc, d 302
MeOH/Et,O
283
CH,CI,/Et,O/Petr ether Acetone CH,Cl,/Et,O EtOH Acetone MeOH/Et,O Acetone Acetone Acetone Acetone CH,Cl,/Hexane
,
TABLE VII-1. 4contd.)
Substituent
mp ("C) or; [bp ('Cjtorr)]
Solvent of Crystallization
1-(2-MeNHCOO-l-MeO-Ethyl)-5-Ph-7-C1
135-137
Et,O/Petr ether
208-210
EtOH
220-223d 23C232 168-1 70
MeOH/Et,O PhH/Et,O
47
193-196d 134139
MeOH/Et,O THF/Et ,O
86
195-197 161-163 168-170 165-167d 195-196 157-159
EtOAc CH,Cl,/Hexane EtOAc/Hexane EtOAc/Hexane MeOH MeOH
34
179-182d 137-138 139-141 193-194 147-150 195-196 157-159
MeOH/Et 0 MeOH MeOH CH,CI,/MeOH CH,C1,/Et20 CH,Cl,/MeOH MeOH
147-15Od 13C132 125-1 27
Acetone/Et ,O MeOH Et,O
Yield (%)
Spectra
Refs. 302
1-(2-MeHN-Ethoxy)CH,-5-Ph-7-C1 Oxalate
72
1-(2-MeNH-Ethy1)-5-5-Ph-7-C1 Dihydrochloride
1-[2-(2-Me-4-NO,-Imidazol-l-yl)ethyl]-5-Ph-7-C1 1-[2-(2-Me-5-NO,-Imidazol-l-yl)ethyl]-5-Ph-7-C1 1-(3-MeNH-Propy1)-5-(2-FC6H4)-7-C1 Dihydrochloride 4-Oxide l-MeO-5-Ph-7-Cl 4-Oxide 1-[2-[3,4,5-(MeO),Benzoyloxy]ethyl]-5-(2-FC6H4)-7-Cl l-MeOOC-5-Ph-7-CI 1-Me00C-5-Ph-7-NO2
l-MeOOC(MeO)CH-5-Ph-7-C1 l-MeOOC(MeO)CH-5-Ph-7-N0, 1-(2-MeOOC-Methoxy)ethyl-5-Ph-7-C1 Hydrochloride 1-Me00CCHz-5-Ph-7-CI
l-MeOOCCH,-5-Ph-7-N0,
1-MeOOCCH,-5-(2-CIC6H4)-7-C1 1-MeOOCCH,-5-(2-F-6-MeOOCCH,O-C6H,)-7-CI l-(MeOOC)MeOCH-5-Ph-7-C1 l-(MeOOC)MeOCH-5-Ph-7-N0, 1-[2-(N-MeOOCCH,-Amino)ethyI]-5-Ph-7-C1 Tosylate
1-(3-MeOOC-3,3-Me,-Propyl)-5-Ph-7-C1 1-( 1-MeOOC-Prop- 1-en-1-yl)-5-Ph-7-C1
,
42
150c 55 55 287, 86b 152c ir, ms,pmr
189 283 108 108 108 108 150c 293, 292 255c 292 152c 72 72 150c 294 294
1-(3-MeOOC-Prop-2-en-l-yl)-5-Ph-7-C1, trans
125-127 103-105 1-[2-(2-MeO-Ethoxy)ethyl]-5-Ph-7-C1 93-89 4-0xide 132-133 1-[2-(2-MeO-Ethoxy)ethyl]-5-(2-FC,H,)-7-Cl 7&72 1-(l-MeO-l-Ethyl)-5-Ph-7-C1 131-132 l-(l-Me0-l-Ethyl)-5-Ph-7-NO2 189- 190 1-(2-MeO-Ethoxy)CH,-5-Ph-7-NO2 12cb-121 1-(2-MeO-Ethyl)-S-Ph-7-C1 108- 109 4-Oxide 137-138 1-(2-MeO-Ethyl)-5-(2-FC6H4)-7-CI 93-95 1-(2-Me0-Ethyl)-5-(2-MeC6H4)-7-CI 115-1 17 1-[2,2-(MeO),-Ethyl]-5-Ph-7-C1 117-119 1-11-Me0-2-(1,5-Me2-Pyrazol-3-yl)C00]-5-Ph-7-C1 197-199 1-(l-Me0-2-PhNHCOO-ethyl)-5-Ph-7-C1 139-142d I-[ l-Me0-2-(3-Ph-trans-Propenoyloxy)ethyl]-5-Ph-7-CI 144-146 1-[1-Me0-2-(3-Phthalimidopropanoyloxy)ethy1]-5-Ph-7-C1 157-158 l-[l-MeO-2-(Pyridin-3-yl)COO-ethyl]-5-Ph-7-AcNH 203-205 1-[ 1-MeO-2-(Pyridin-3-y1)COO-ethyl]-5-Ph-7-N02 15&152 1-[ l-MeO-2-(Pyridin-3-y1)COO-ethyl]-5-(2-FC6H4)-7-Cl 155-156 I-[ l-MeO-2-(Pyridin-3-y1)COO-ethyl]-5-(2-pyridyl)-7-Br 147-15Od 1-MeOCH2-5-Ph-7-AcNH 15&151 l-MeOCH2-5-Ph-7-Ac(HO)N 205-208d 1-MeOCH,-5-Ph-7-AcjMeO)N 125-128 1-MeOCH,-5-Ph-7-H2N 146 4-Oxide 186188 1-MeOCH2-5-Ph-7-H2NCONH 223-224 l-Me0CH2-5-Ph-7-(Benzyloxy)CONH 169-171 I-MeOCH2-5-Ph-7-CI Oil 4-Oxide 164-166 1-MeOCH,-5-Ph-7-F3C 122-124 1-MeOCH,-5-Ph-7-F3CONH 172-174 4-0xide 23&232d I-MeOCH,-5-Ph-7-F,CCO(HO)N 175-178d l-[Z-(MeO-Acetoxy)- l-MeO-ethyll-5-Ph-7-CI
2 IC,
MeOH Et,O/Petr ether i-Pr,O/i-PrOH
CH,CI,/Hexane MeOH MeOH i-PrOH i-PrOH/i-Pr,O i-PrOH EtOH Et,O/Petr ether EtOH EtOH MeOH MeOH Et,O i-PrOH i-PrOH CH,Cl,/i-PrOH CH,CI,/Et,O/Hexane EtOAc/Petr ether i-PrOH/Et,O EtOH/Et,O CH,Cl,/Petr ether MeOH Hexane CH,Cl,/Et,O CH CI,/Et ,O CH,Cl,/MeOH/Et,O
73
45 46
pmr, uv
pmr, uv
68
53
,
75
ir, pmr, uv
302 302 89 89 89 108 72 72 45, 125h 234 125h 276 296 302 302 302 486 486 486 486 302 72c 245 245 72 108 72c 108 72 277,72 56 108 108 245
TABLE VII-1. gc ont d . )
Substituent
1-MeOCH,-5-Ph-7-F3CCO(MeO)N 1-MeOCH,-5-Ph-7-HONH 1-MeOCH,-5-Ph-7-MeNH l-MeOCH,-5-Ph-7-Me2N 1-MeOCH,-5-Ph-7-Me0 Hydrochloride 1-MeOCH,-5-Ph-7-MeOOCNH
I-MeOCH2-5-P~-7-MeOOC(Me)N l-MeOCH2-5-Ph-7-Me(MeO)N l-MeOCHZ-5-Ph-7-MeN(0)N l-MeOCHZ-5-Ph-7-MeONH l-MeOCH2-5-Ph-7-MeS(0) l-MeOCH,-5-Ph-7-MeSOzNH 1-MeOCH,-5-Ph-7-NO, 4-Oxide 1-MeOCH,-5-Ph-7-NO l-MeOCH2-5-Ph-7-N(O)N-[ 1,3-Dihydro-1-MeOCH, 2-oxo-5-Ph-2H- 1,4-benzodiazepin-7-yl] 4-Oxide
1-MeOCH,-5-(2-C1C6H4)-7-H,N 1-MeOCH,-5-(2-C1C6H,)-7-C1
1-MeOCH,-5-(2-C1C,H4)-7-HONH 1-MeOCH,-5-(2-C1C,H4)-7-NO, 1-MeOCH,-5-(2-FC6H,)-7-H,N 1-MeOCH2-5-(2-FC,H,)-7-C1 4-Oxide
l-MeOCH2-5-(2-FC,H,)-7-I 1-MeOCH,-5-(2-FC6H,)-7-Me,N 1-MeOCH,-5-(2-FC6H4)-7-NO,
mp ("C) or; [bp (T/torr)]
Solvent of Crystallization
11&112 168-170 116119 116117
Et,O/Hexane CH,CI,/Et,O CH,CI,/Petr ether EtOH
198-200 201-203 135-138
MeOH/Et,O THF/Petr ether CH,Cl,/Petr ether
11&115 147-149 Amorphous 163-165 139-141 213-2 15 Oil 24&242 212-2 15 2w202 139-140 205-208d 136137 169-1 70 113-114 15Cb-151 11 5-1 17 164-165 105-107
Et,O
Yield (%)
Spectra
Refs.
53 70
pmr, uv ir, pmr, uv
245 245 108 72c
12 37.5 84
Pmr pmr,
UV
55
EtOH PhH/EtOH CH,Cl,/EtOAc
CH,Cl,/Hexane CH,Cl,/EtOAc CH,Cl,/Hexane MeOH THF/i-PrOH MeOH EtOH/Et ,O MeOH Acetone/Heptane EtOH EtOH
55
Pmr
53
ms, pmr, uv
90
72c 108 108 245 245 245 56 72c 72 134 245 245 72 134 72 245 72 72c 72 234 134 72c 134
1-MeOCH,-5-(2-MeC6H4)-7-CI l-MeOCH,-5-(2-Pyridyl)-7-H,N
1-(2-MeO-BenzoyI)CH,-5-Ph-7-C1 1-[2-(3,4,5-Me0,-Benzoyloxy)ethyl]-5-(2-FC,H4)-7-Cl 1-[2-(3,4,5-Me0,-Benzoyloxy)-l-MeO-ethyll-5-Ph-7-CI 1-[2-(4-MeOC,H4)Acetoxy-l-MeO-ethyl]-5-Ph-7-C1 1-{3-[4-(2-MeOC6H4)-Piperazin-l-yl]propyl}-5-Ph-7-C1 Dihydrochloride 1-[2-(2-MeO-3-Pyridincarbonyloxy)ethyl]-5-(2-FC~H4)7-CI Dih ydrochloride
1-[2-(N-Me,NCO-N-Me-Amino)ethyl]-5-Ph-7-Cl
2
1-Me,NCOCH2-5-Ph-7-C1 Hydrochloride
1-[2-(Me,NCO-Methoxy)ethyl]-5-Ph-7-CI l-(2-Me2N-Ethoxy)CH,-5-Ph-7-CI Hydrochloride 1-(2-MezN-EthyI)-5-Ph-7-C1 Methochloride. H,O 4-Oxide Hydrochloride l-(2-Me2N-Ethyl)-5-Ph-7-F,C Dih ydrochloride 1-(2-Me,N-Ethyl)-5-Ph-7-N02 Dihydrochloride
1-(2-Me,N-Ethyl)-5-(2-C1C,H4)-7-C1 Dihydrochloride. i-PrOH 4-0xide o-Oxide.H,O
13C131 162-164
CH,CI,/Hexane
276 134
164-166
CH,CI,/Hexane
134
183-185 161-163 146-148 95-97
EtOH
245-250
CH,CI,/Acetone
488
154-158 128-131 179-1 8 1 243-245 12c-122
MeOH/Et ,O Et,O Acetone/Hexane MeOH/Et,O CH,Cl,/Et,O
283 302 293, 86b 293 15&, d
175-177 9&98 i85-in7 14&147 211-212 2 17-21 8
Acetone/Et,O Et,O/Hexane MeOH/Et,O Acetone/Petr ether
64
EtOH/Et,O
58
217-22 1 121-122 232-23 3d 178-180 168-1 70 152-154 131-133
MeOH/Et,O Et,O/Petr ether MeOH/Et ,O CH,CI,/Et,O/Hexane i-PrOH Et,O/Pentane CH CI,/Et ,O
52 44 40 76
67
CH,Cl,/Hexane Et,O/Hexane
,
23
in 63
ir, pmr, uv
65 86b 72 72
72 287 255c 287 358 287 287 287 287 238 134 2nn 238
TABLE VII-1. +ontd,)
Substituent
mp ("C) or; [bp (T/torr)]
Solvent of Crystallization
232-233d 156-159 134-135 165-i6ad
CH,Cl,/Hexane Hexane i-PrOH/Et,O
154-155 121-122 9&92
Yield (%)
Spectra
Refs.
l-(2-Me,N-Ethyl)-5-(2-FC,H4)-7-N0, Dih ydrochloride
1-(2-Me,N-Ethyl)-5-(2,6-F,C,H3)-7-C1 1-(2-Me2N-l-Me-Ethyl)-5-Ph-7-CI Dihydrochloride
50
126 152c 287 86b, 287
MeOH/Et,O Et,O Hexane
64
2b 2b 86b, 287
192- 193d
EtOH
60
287
202-207d 180-2OOd 149-151
MeOH/Et,O MeOH/Et,O CH,Cl,/Et,O/Hexane
61
86b 287 152c
130-146d 181-1 83d
MeOH/Et,O MeOH/Et,O
135-1 50d 97-99 170-172 17&175 154 174-175 193-195 240d 15&153 101-103
i-PrOH/Et ,O Et O/Cyclohexane Et,O Xylene/Ligroin PhHjC ycliohexane Xylene Xylene
55
1-(3-Me2N-Propyl)-5-Ph-7-Br Dinitrate 4-Oxide
l-(3-Me2N-Propyl)-5-Ph-7-C1 I-(2-Me2N-Propyl)-5-Ph-7-NO2 Hydrochloride I-(3-Me2N-Propyl)-5-(2-FC,H,)-7-C1 Dih ydrochloride 4-Oxide
1-(3-Me2N-Propyl)-5-(2-Pyridyl)-7-Br Dihydrobromide Dih ydrochloride 4-Oxide Hydrochloride
1-(3-Me2N-Propyl)-5-(4-Pyridyl)-7-Br 1-Me2CN-5-Ph-7-Cl 1-[Me2P(O)CH,CH,]-5-Ph-7-C1
1-[Me,P(0XCH2),]-5-Ph-7-C1 1-[Me,P(O)CH2]-5-Ph-7-C1 1-[Me,P(O)CH,]- 5-(2-C1C,H4)-7-C1 1-[Me, P(0)CH ,] - 5-(4-i-PrC,H4)-7-Cl
l-[2-(Me3-Acetoxy)-I-MeO-ethyl]-5-Ph-7-CI
48
,
42 47 52; 80 40 45
Et,O/Hexane
152c 86b, 287 67b 38b 247 25 25 25 25 25 25 72
1-(2-MeS-Ethyl)-5-Ph-7-C1 Hydrochloride 4-Oxide
1-(2-MeS-Ethyl)-5-(2-FC6H,)-7-C1 1-MeSCH,-5-Ph-7-H2N0.5 i-PrOH 1-MeSCH2-5-Ph-7-CI
l-MeSCH,-5-Ph-7-MeSCH2NH 1-MeSCH,-5-Ph-7-NO2
1-MeSCH,-5-(2-CIC,H4)-7-C1 1-[2-MeS(O)-Ethyl]-5-Ph-7-C1 1-MeSO,-5-Ph-7-NO2 1-MeS0,-5-(2-CIC,H4)-7-N0,
1-[2-MeSO,-Ethyl]-5-Ph-7-C1 4-Oxide
l-[2-MeS0,-Ethyl]-5-(2-FC6H4)-7-C1 1-MeS(O)CH,-5-Ph-7-H2N 1-MeS(O)CH2-5-Ph-7-C1 l-MeS(0)CH,-5-Ph-7-NOz l-MeS(O)CH,-5-(2-CIC,H,)7-C1 1-MeSO,CH,-5-Ph-7-H,N l-MeSO,CH,-5-Ph-7-CI l-MeSO,CH,-5-Ph-7-N0,
l-MeS0,CH,-5-(2-CIC,H4)-7-C1 .EtOH 4-Oxide
114-115 165-1 67d 174-175 77-79 123-125d 115-117 145-146 139-140 127-1 29 166-167 107-109 222d 215-21 7 160-161 214-215 155-156 189-191 158-159 190-192 150-152 160-161 162-164 190-192 110-115d 248-25W
128 86b 234 128 134 72 134 72 72 86c, 92 234 301 301 87 234 87 134 72 72 72 134 72 72 72 134
i-PrOH Et,O/Hexane CH,C12/Et,O EtOH EtOAc/Hexane EtOAc i-PrOH/i-Pr,O CH,CI, CH,CI, Acetone i-PrOH EtOAc/Hexane EtOAc EtOAc/Et,O CH2CI,/Et,O EtOAc/Et,O CH,Cl,/EtOH EtOH CH,CI,/EtOH
1-MeS0,CH,-5-(2-FC,H4)-7-C1 155-1 57 144-146 Maleate 156-157 l-[2-(Morpholino),PO,-ethyl]-5-(2-FC6H4)-7-C1 107-1 10 1-[3-(4-NO,-Phenoxy)CO-propyl]-5-Ph-7-C1 123-125 l-(Oxiran-2-yl)CH,-5-(2-ClC6H4)-7-C1 135-138 170-174 ~-(~-OXO~U~~I)-~-(~-CIC~H~)-~-NO, 1-(3-0~0b~tyl)-5-(2-FC,H,)-7-CI 121-123 4-Oxide
1-(2-Morpholinoethyl)-5-Ph-7-C1
Acetone/Hexane Acetone H,O/Et,PO, PhH/i-PrOH Et,O/Hexane EtOAc/Petr ether Et,O/Petr ether
83 79
234 287,86b 287 33b 488
192 301 301
TABLE W - 1 . --(contd.)
Substituent
mp ("C) Or; [bp ("c/torr)]
Solvent of Crystallization
173-175 I96 197-199 197-199 198-200 151-152
EtOAr: EtOH EtOAc CH$l dPctr ether CHzClzIPetr ether EtOH
202-2aQd 169-t71
MeOH/Acetone Et,O
199-2Md 136138d 220-222 Oil 165-166 238-240 131-132 187-1811
Yield (%)
Spectra
Refs. 108 478 478
247 391b 195
38
60 68
55 CHzCldPetr ether Acetone
11. MS,
pmr
I16 2 50
L 30 247 293 33b 45,89
CHCl,/ t-PrOH
89
89
234
254-257 222-224 138-139 167- 170 172-1786
Acetone
120-122
Acetone
235-255
MeOH /Et,O
69
65 301 72 38b
69
287 254
78
287
1-[2-(Piperidin-l -yl)ethyl]-5-Ph-7-C1 Maleate Maleate I-Pr-5-Ph-7-NO2 1-Pr-5-(2-FC6H4)-7-(Cyclopentyl)CONH 1-Pr-5-(2-FC6H,)-7-NO, 1-[2-(PrNH-Acetoxy)ethyl]-5-(2-FC6 H4)-7-C1 Hydrochloride
1-(2-PrO-Ethyl)-5-Ph-7-C1 4-Oxide
1-(2-Pr0-Ethyl)-5-(2-FC6 H4)-7-C1 4-0xide 1-PrOCH,-5-Ph-7-H2N l-PrOCH,-5-Ph-7-N0, 1-[Pr, P(O)CHZ]-5-Ph-7-Cl l-i-Pr-5-(2-ClC6H4)-7-C1 1-{2-[4-(2-{4-[3-i-PrNH-2-HO-Propoxy]phenoxy}ethy1)piperazin-I-yl]ethyl}-5-Ph-7-C1 (S)-Enantiomer Trimaleate I-(2-i-PrS0,-Ethyl)-5-(2-FC6H4)-7-C1 Hydrochloride 1-( l-Propyn-3-yl)-5-Ph-7-C1 Hydrochloride Hydrogen sulfate I-( l-Propyn-3-yl)-5-Ph-7-NO, Hydrochloride 1-(l-Propyn-3-yl)-5-(2-C1C6H4)-7-C1 Hydrochloride 1-(1-Propyn-3-yl)-5-(2-FC6H,)-7-H, N 1-( 1-Propyn-3-yl)-5-(2-FC6H4)-7-C1 Hydrochloride 1-(l-Propyn-3-yl)-5-(2-FC6 H4)-7-(cyclopentyl)CONH 1-(1-Propyn-3-yl)-5-(2-FC6H,)-7-N02
90-92 172-173 172-173 127-128 2w204 107-1 08
Hexane Acetone
219-222d 99-100 169-1 70 85-87 135-136 176177 73-76 157-160 148-150
MeOH/Et,O
CH, CI,/Hexane EtOH Xylene Et,O
137-141
MeOH/EtOAC
186187 1-146 229-231d 166168d 156158 216218 140-142 18C182 205-208 7G72 183-185 17&174 159-160
90 81
Et, 0 Et,O EtOAc / Hexane
65 17
287 287 86b 2b 301 251c 283 125h 234 125h 234 134 72 25 2
487 127
EtOH
PhH/Hexane EtOH Et,O MeOH Et, O/Hexane EtOAc
61
55
273 273 273 273 91 273 30 1 273 273 301 251c
TABLE VII-1. -4contd.)
Substituent
mp ("C) or; [bp ("C/torr)]
Solvent of Crystallization
1-[2-(2-Pyrazinyl)COO-l-MeO-ethyl]-5-Ph-7-CI
1 13-1 16d
MeOH
302
205-21Od 138-140 139-142 152-154 177-180
EtOH/Et,O MeOH CH,Cl,/Petr ether EtOH/Et, 0 EtOH
302 283, 86b 283,86b 302 302
244-246
MeOH/Et, 0
255c
163-166 106107 157-159 143-145 2 17-22Od 126127 102-104 145-146 13415 114-115 89-90 183-1 84 89-9 1 21621 8d 118-120 82-84
Acetone/Et, 0 Hexane Acetone EtOH MeOH/Et,O i-Pr,O/i-PrOH
115-122
Acetone
1-[2-( l-Pyridinium)-l-MeO-ethyl]-5-Ph-7-C1 Tosylate 1-[2-(3-Pyridinecarbonyloxy)ethyl]-5-(2-FC6H4)-7-C1 1-[2-(4-Pyridyl)C00-ethoxy]CH2-5-(2-FC6 H4)-7-C1
1-[2-(2-Pyridyl)COO-I-MeO-ethyl]-5-Ph-C1 1-[2-(4-Pyridyl)COO-I-MeO-ethyl]-5-Ph-7-C1 l-(2-Pyridyl)CHZ-5-Ph-7-C1 Dih ydrochloride I-[2-(Pyrrolidin- l-yl)ethoxy]CH,-5-Ph-7-C1 Hydrochloride ~
2
l-[2-(Pyrrolidin-l-yl)ethyl]-5-Ph-7-C1 Maleate 1-(2-SCN-Ethyl)-5-(2-FC6H,)-7-C1 Hydrochloride l-(2-Tetrahydropyran-2-yloxy)ethyl-5-Ph-7-C1 I-(2-Tetrahydropyran-2-yloxy)ethyl-5-(2-FC6 H4)-7-C1 4-0xide
1-[2-(2-Thienyl)COO-I-MeO-ethyl]-5-Ph-7-C1 1-Vinyl-5-(2-C1C6H4)-7-C1 1-Vinyl-5-(2-FC6H4)-7-C1 4-Oxide 1-(2-Vinyloxy)ethyl-5-Ph-7-C1 Hydrochloride H4)-7-C1 l-(2-Vinyloxy)ethyl-5-(2-C1C6 1-(2-Vinyloxy)ethyl-5-(2-FC6H4)-7-C1 1-{3-[4-(2-Vinyloxyethyl)-piperazinyl]propyl}-5(2-FC6H4)-7-C1 Dimaleate
EtOH Hexane Et,O/Hexane CH,CI,/Et, 0 i-PrOH/i-Pr, 0 CHCI, / i-PrOH
Yield (%)
88 79
92 57 50
15
Spectra
Refs.
72 287 287, 86b 331, 332 331, 332 89 89 89 486 238 238 238 128 86d, 128 86d 86d
287
13.8- Trisubstituted
l-(2-Et2N-Ethyl)-5-Ph-8-Cl l-Me-5-EtO-8-CI 1-Me-5-[2,2-(EtO),-Ethyl]NH-8-C1 1-Me-5-Ph-8-C1 1-Ph-5-Et-8-C1 1-Ph-5-Et-8-F3C l-Ph-5-Me-8-CI 1-(2-FC6H4)-5-Me-8-CI 1-(2-F, CC, H4)-5-Me-8-C1 l-(2-F,CC6H,)-5-Me-8-CI 1-(2-0, NC, H4)-5-Me-8-C1 1-(2-Pyridyl)-5-Me-8-C1 1-Ph-5-Me-8-F3C 4
I>,% Trisubstituied
=!
l-Me-5-Ph-9-CI 1-Me-5-(2-FC6H,)-9-C1
87-89 95-97 118-120 128-130 194-195 156-158 111-1 12 171-172 162-1 67 138-141 138-141 176-178 146148 133-1 35
Hexane EtOH EtOAc/Hexane EtOAc/Hexane Acetone/Hexane
139-143 148
CH,Cl,/Petr ether Et,O
212 265-276
Cyclohexane
EtOAcli-Pr, 0
302 195 391b 391b 152c 19 19 19 19 19 19 19 19 19
65
86
152c 301
3,3>- Trisubstituted
3,3-Me2-5-(2-FC6H,) 3,3-(spiro-Adamant-2-yl)-5-Ph
ir, uv
251b 115
3J,7- Trisubstituted
3-AcNH-5-Ph-7-Br 3-AcNH-5-Ph-7-CI 3-AcNH-5-Ph-7-Me 3-(AcNH-Acetoxy)-5-Ph-7-C1
3-(4-AcNH-Butanoyloxy)-5-Ph-7-C1 3-(4-AcNH-Butanoyloxy)-5-(2-C1C6H4)-7-C1~0.5 AcEt 3-Ac0-5-C, DS-7-Cl 3-AcO-5-Ph-7-AC
293-294 268-269 274-275 214216 210-211 199-201 120-121 236237d 238-239 227-229
41 MeCN EtOH AcEt MeCN AcEt
83 Acetone MeCN
96
202 59b 199 202 339 339 339 97 2b
44
TABLE VII-I. -4contd.) mp ("C) or; [bp ("C/torr)]
Solvent of Crystallization
3-AcO-5-Ph-7-MeS 3-Ac0-5-Ph-7-N02 3-Ac0-5-(2-C1C6H4)-7-AcNH 3-Ac0-5-(2-C1C6H4)-7-HZN ~-ACO-~-(~-CIC~H~)-~-C~ 3-Ac0-5-(2-C1C6H4)-7-N02 3-Ac0-5-(4-C1C,H4)-7-Br 3-Ac0-5-(2-FC6H4)-7-Ac 3-Ac0-S-(2-FC6H4)-7-AcNH 3-Ac0-5-(2-FC6H4)-7-CI 3-Ac0-5-(2-FC6H4)-7-(I-HO-Ethyl)
264266 239-241 233-237 242-243 23CL23 1 233-235 253-254d 267-268 231-233 233-237d 262-264 279-28 1 256-257 267-268 264268 239-247 2 13-21 5
EtOH/CH, Cl,/EtOAc EtOH/H,O EtOH/H,O Ac, 0 PhH/Hexane Acetone/Hexane CHCl,/Hexane THF/Hexane CHCI, CH,Cl,/THF/Petr ether
301 199, 225 223 263 lb 33b Ib lb 134 152c, 263
PhH
8 263 2b 301 233 33b
3-Ac0-5-(2-FC6H4)-7-1 3-Ac0-5-(2-FC6H4)-7-NO2 3-Ac0-5-(2,6-F2C6H3)-7-C1 3-AcO-5-(4-F3CONH)C6H4-7-C1 3-Ac0-5-(2-Pyridyl)-7-Br 3-AcO-5-(2-Thienyl)-7-C1 3-AcOCH2-5-Ph-7-CI
2 15-21 8 245-246 247-26Qd 257-262d 237-238d 269 172-173
CH, CI,/Hexane CH,Cl,/Et,O/Petr ether THF/Hexane CH, CI,/THF/Hexane THFiHexane Acetone/Hexane
371 2b 152c 8 148 263 Ib
3-AcOCH2-5-(2-C1C,H4)-7-AcNH 3-AcOCH2- 5-(2-C1C6H4)-7-NO, 3-AcOCH2-5-(2-FC,H,)-~-AcNH
234-236 170d 215-21 7d
EtOAc/Petr ether Et,O CH, CI,/EtOAc
30 1 301 301
Substituent 3-AcO-5-Ph-7-AcNH 3-Ac0-5-Ph-7-Cl
3-Ac0-5-Ph-7-F3C
3-A~0-5-Ph-7-(1-HO-Ethyl)
-1 4
t-~
Acetone EtOH/EtOAc MeOH Acetone/Hexane
Yield (%)
Spectra
76
87 50
ir, ms ir, pmr
Refs.
3-(AcO)Ph-Acetoxy-5-(2-C1C6 H4)-7-CI Mixture of diastereoisomers 3-AcS-5-Ph-7-CI
3-(Adamantyl)CONH-5-Ph-7-CI 3-(~-Alanyl)CO-5-Ph-7-C1 3-(~-Alanyl)CO-5-Ph-7-C1 3-(~-Alanyl)CO-5-Ph-7-N0,.0.5 EtOH 3-(Allyl)NH-5-(2-C1C6H4)-7-N0, 3-(Allyl),N-5-(2-C1C6H4)-7-N0, 3-H, N-5-Ph-7-Br 3-H2N-5-Ph-7-C1
Hydrochloride.O.5EtOH 3-H2N-5-Ph-7-Me . I3-H,N-5-(2-C1C6 H4)-7-N02 4 W Hydrochloride.acetone 3-H2NCO-5-Ph-7-C1 3-H,NCO-5-(2-C1C6H4)-7-N0, 3-H2NCOCH,-5-Ph-7-C1 3-H, NC00-5-Ph-7-CI 3-(3-H, NCO-l-Pyridinium)-5-Ph-7-CI Chloride 3-(3-H, NCO- 1-Pyridinium)-5-(2-C1C6H4)-7-C1 Chloride 3-(4-H, NCO- 1-Pyridinium)-5-(2-C1C6H4)-7-CI Chloride 3-N3CO-5-Ph-7-C1 3-(Aziridin-l-yl)-5-(2-CIC6H4)-7-NO, 3-Benzoyloxy-S-Ph-7-C1 3-Benzyl-5-Ph-7-CI R-(+ )-Enantiomer 3-Benzyl-5-(2-C1C6H4)-7-N0,
21&211 > 200 208-209 264 25&252d 278-28Od 280d 176d 192-194d 210-211 205-206 2 18-22Od 195-197d 225-226 2w202
72 EtOH EtOH EtOH CH, C1, /Hexane CH,CI,/EtOH EtOH CH,Cl,/Et,O MeCN MeCN EtOH
42 45 83
60
338 338 338 202 301 30 1 301 301 301 202 199, 202 260 225 143 199, 358 202
212-21 6d 255-256 290-295 26G264d 23&232
MeOH/ Acetone MeOH EtOH/Petr ether EtOH
244-246d
MeOH/Et, 0
261-263d
Acetone
80
356
222-224d 123d 230d 251-252
Acetone CH,CI,/MeOH CH,CI,/Et,O
90
356 488 30 1 263
107-110 202-204
Cyclohexane Et,O
74
302 105 30 302 336 334
112 301
TABLE VII-1. -(contdB.)
Substituent
mp ("C) or; [bp ('C/torr)]
Solvent of Crystallization
199-201 194 197-200 188-190 180-182d 174-175 184-187
MeCN MeOH
131 210-212
EtOH CH,CI,/EtOH
Yield (%)
Spectra
Refs.
~~
3-Benzyl(Me)N-5-(2-Clc6H,)-T-NO, 3-(2-Benzylidene-1-Me-hydrazin0)-5-(2-ClC6H4)-7-NO, 3-(4-BrC6H4)CHN-5-Ph-7-CI ~-Bu-~-(~-C~C~H,)-~-NO, 3-BuNH-5-(2-CIC, H,)-7-N02 ~ - ( B U ~ - ~ - ~ I ) N H - ~ - H,)-7-NO, (~-CIC, 3-t-BuNH-5(2-CIC, H,)-7-NO, 3-Bu0-5-Ph-7-CI ( +)-Enantiomer 3-Bu0-5-(2-CIC, H4)-7-NO,
302 301
202 301 301 301 302
40 CH,Cl,/Et,O/Petr EtOH/Et,O EtOH/Hexane EtOH
ether
Cal
366 301
3-(2-t-Bu00CNH-3-Ph-Propanoyloxy)-5-Ph-7-C1 Isomer A Isomer B 3-(4-t-BuOOCNH-Butanoyloxy)-5-Ph-7-C1
. I
2
3-(4-t-BuOOCNH-Butanoyloxy)-5-(2-ClC6 H4)-7-NO, 3-(5-t-BuOOCNH-Pentanoyloxy)-5-Ph-7-C1 3-HOOC-5-Ph-7-CI Dipotassium salt Potassium salt 3-HOOC-5-(2-CIC6H4)-7-CI Dipotassium salt.ZH,O 3-(2-HOOC-Ethoxy)-5-Ph-7-C1 3-HOOCCH2 NHCO-5-Ph-7-CI 3-HOOCCH20-5-Ph-7-Cl
3-(3-HOOC-Propanoyloxy)-5-Ph-7-H2 N 3-(3-HOOC-Propanoyloxy)-5-Ph-7-Br (+)-Enantiomer
-
205 175d 118-120 Amorphous 182-184 117
478 478 478 339 478 478
Et,O/Petr ether EtOAc
ir, uv ir, uv
240-241 242d 120 218-22Od > 19od 157
EtOH MeCN EtOH MeCN MeCN THF/CH,Cl,/Hexane EtOAc/Hexane
77
ir, pmr
65
ir, pmr
[a1
104 104 108 357 301 227 357 33b 499
3-(3-HOOC-Propanoyloxy)-5-Ph-7-C1 Hydrate Pyridinium salt ( +)-Enantiomer
152-153 11&112 139-141 178 158-159 159-1 60 187-1 90d 136 130 172-1 8Od 226-227 108-1 10 108-109 187-188 193-194 220 193-195d
EtOH/H, 0 EtOH/H,O EtOAc
161-162
CH, Cl,/Hexane
3-(Butanoyloxy)-5-Ph-7-C1
214215 182-186
EtOH
3-(Carboxy)CH, 5-Ph-7-Cl Hydrochloride Dipotassium salt
277-283 271-272d
H,O/HCl EtOH
(-)-Ephedrine salt 3-(3-HOOC-Propanoyloxy)-5-Ph-7-NO, ( + )-Enantiomer.ZH, 0 3-(3-HOOC-Propanoy1oxy)-5-(2-ClC6H4)-7-H, N 3-(3-HOOC-Propanoy1oxy)-5-(2-ClC6 H4)-7-NO, 3-(3-HOOC-Propoxy)-5-Ph-7-C1 3-R-Benzyl-5-Ph-7-Cl 3-S-Benzyl-5-Ph-7-CI
3-[(Benzyl-NHCO)methoxy]-5-Ph-7-C1
2
3-Benzyl(Me)N-5-Ph-7-C1 3-(Benzyloxy)CO-5-Ph-7-C1 4-Oxide
vI
3-[2-(Benzyloxy)CO(Me)N-ethoxy]CO-5-Ph-7-Cl 4-Oxide 3-BuNHC00-5-Ph-7Cl
74
337 227 227 499 499 499,499 33b 499 33b 33b 357 40 40 357 369, 348 301 108
80 EtOAc/Hexane CH, Cl,/Hexane EtOH/H,O THF/CH, Cl,/Hexane THF/CH,Cl,/Heptane MeCN
EtOH EtOH EtOH
70 82 82 44; 67
108 336 337
50
80
80
3-[(N-H0OCCH2-N-Me-Amino)acetoxy]-5(2-C1C6H4)-7-C1 Sodium salt.2 H,O 3-(3-Carboxy)propanoyloxy-5-Ph-7-N02 ( + )-Enaniomer (-)-Ephedrine salt
3-(3-Carboxy)propanoyloxy-5-Ph-7-NH2 3-(3-Carboxy)propanoyloxy-5-(2-C1C6 H4)-7-NO, 3-(3-Carboxy)propanoyloxy-5-(2-CIC, H4)-7-NH,
> 17Od 187-19Od
333 CH, CI,/Hexane
64
156
172-18Od
ir, pmr, uv
C 1. [.I CH, C1, /THF/Heptane
48 67 70
pmr, uv ir, uv ir
8 499 499 8 8 8
TABLE VII-1. g c o n t d . )
Substituent
Hydrochloride 4-Oxide 3-C1-5-Ph-7-F,C 4-Oxide 3-CI-5-(2-C1C6H4)-7-C1 3-C1-5-(2-ClCsH,)-7-N02 3-(CLAcetoxy)-5-Ph-7-C1 4 4 o\
3-(C1-Acetoxy)-5-(2-CIC,H4)-7-C1
3-(C1,-Acetoxy)-5-Ph-7-C1 ~-(CI~-ACX~OX~)-~-P~-~-C~ 3-CI-5-Ph-7-NOz 4-Oxide 3-(CI3CONHCO)-5-Ph-7-CI 3-(2-CLEthoxy)-5-Ph-7-C1 3-(2-Cl-Eth0~~)-5-Ph-7-N02 3-(2-CI-Etho~y)CO-5-Ph-7-C1 4-Oxide 3-(4-C1C, Hd)CHN-5-Ph-7-C1 3-(2,6-C1,C, H,)NH-5-Ph-7-C1 3-{ [2-(4-CI-Phenoxy)acetoxy ethyl]-(Me),ammonium}-5-(2-C1C6H4)-7-C1 Chloride 3-(2-C1-Propanoyloxy)-5-(2-C1C6 H4)-7-C1 3-(3-C1-Propoxy)-5-(2-C1C6 H4)-7-NO,
mp ("C) or; CbP ( V t o r r ) l 179d 120-122 139-14Od 151-153 210-21 Id
Solvent of Crystallization
Yield
(YO)
Spectra
Refs.
ir
263 356, 334 357 263 143
PhH PhH THFiHexane
222-223d 133-1 38 196199d 208-21Od 23G23 1 217-21 8 232-234 210-217 246248
(CH, OMe),/Hexane
2 15-21 6 231-233 189-19 1 197-198d 206207 188-19Od 180-182 227-229
THF/Hexane MeCN i-Pr,O/Et,O EtOAc/Et,O CH,CI,/Et,O CH,CI,/EtOAc
198-201 204-206 215d
Acetone EtOH CH,CI,/EtOH
87
98 97 THF/Hexane EtOH PhH CH,CI,/Et, 0 PhH C,H,/Petr ether
75 85 75 82 50
35 38
40 Acetone
85 53
Pmr
Pml
ir, ms, pmr ir, pmr
143 334 356 302 262, 263 337 265, 328 337 334 143 313 260 260 108 108 202 33b
356 337b 301
3-(3-C1-Propoxy)CO-5-Ph-7-CI 3-CN-5-Ph-7-CI 3-CN-S-Ph-7-NOZ 3-(2-CN-Ethyl)-5-(2-CIC,H4)-7-NO, 3-(2-CN-Ethyl)-5-(2-FC6H4)-7-C1 3-CN(HO)CH-5-(2-CIC6H4)-7-N02 3-(CyclohexyI)NHC00-5-Ph-7-C1 H,)-7-N02 3-(Cyc1opentyl)NH-5-(2-ClC6 3-(Cyclopentyl)MeN-5-(2-C1C6 H4)-7-NO, 3-(Cyclopropyl)NH-5-(2-C1C6 H,)-7-N02 3 4 3-[ 10,l l-Dihydro-5H-dibenzo[a,d]cycloheptatrien-5-ylidene]propyl]MeNH-5-Ph-7-CI 3-{3-( 10,l l-Dihydro-5H-Dibenzo[a,~cyclohept-Sy1idene)propyl-Me, -ammonium}-5-(2-C1C,H4)7-CI Chloride
3-(4,S-DihydrothiazoI-2-yl)thio-5-Ph-7-C1 -I 4 -I
3-Et-S-(2-CIC6H4)-7-NO, 3-Et-5-(2-FC,H4)-7-N0,
196-198 241-244d 261d 255-257d 167-168 216d 231-233 185-187 196-198d 148-1 50
CH,CI,
194-196
EtOAc/Hexane
168-170 213-215 242-243 260
EtOAc DMF CH2CI,/Et20 CH,CI,
70
356 227 23 1 231
268-272d
Acetone
67
356
256-26Od 199-200
Acetone MeCN
93
192-195d 171-1 72 131-134 214-216 225-227 171 22-225 194
MeOH/Acetone EtOH EtOH MeCN/H,O MeCN
CHCI, CH,CI,/Petr ether Et,O CH, C1, Dioxane/EtOH CH, CI,/EtOH CH,Cl,/EtOH EtOH
57 66
ir, pmr ir, pmr
301 260 260 301 301 30 1 336 301 30 1 301 33b
3-(3-Et-Imidazolium)-5-Ph-7-C1 Chloride 3-(3-Et-Imidazolium)-5-(2-CIC,H4)-7-C1 Chloride 3-EtNH-5-Ph-7-Cl 3-EtNH-5-(2-C1CsH4)-7-NO, Hydrochloride
3-(2-Et-Butanoyloxy)-S-Ph-7-C1 3-(2-Et-Kexanoyloxy)S-Ph-7-C1 3-Et0-5-Ph-7-CI 3-EtO-S-Ph-7-Br ( +)-Enantiomer 3-EtO-S-Ph-7-CI ( +)-Enantiomer 3-Et0-5-Ph-7-NO2 (+ )-Enantiatnet
242
ir, pmr, uv
356 215b
EtOH
Cal uv [a1
302 326 326 223 225 366 190 366
Dioxane/H,O
[a1
366
CH, CI,/Et, 0
68 83
44
TABLE VII-1. 4contd.)
Substituent
2
4-Oxide 3-Et00C-5-Ph-7-F 3-EtOOC-5-Ph-7-Me
m
3-EtOOC-5-Ph-7-NOz 4-Oxide 3-Et00C-5-(2-C1C6H4)-7-H2N 3-EtOOC-5-(2-ClC, H4)-7-C1 EtOH Solvate 4-Oxide 3-EtOOC-5-(2-ClC, H4)-7-NO,.EtOH 4-Oxide 3-EtOOC-5-(4-ClC6H,)-7-C1 3-EtOOC-5-(2-FC,H4)-7-C1 3-EtOOC-5-(2-FC,H,)-7-N02 3-EtOOC-5-(4-MeC6H4)-7-Me 3-EtOOC-5-(3-O,NC,H,)-7-N02 4-0xide
mp ("C) or; [bp ("Cjtorr)]
Solvent of Crystallization
253-255d 212d 183-197 225-226 208 187-189 305d 232-239 244 159-161d 225-23Od 260 229-231 237-238d 172-176d 27 1 235-238 138-140 128-13Od 2W201d 224 213 189-192 200 193- 194d 201d 2 15-22Od
EtOH
EtOH
301 301 152c 301 105 80 105 39 105 108 302 105 302 104 108 105 301 82 108 108 301 301 302 82 145 145 302
19C193d
PhH/Hexane
108
Yield
(YO)
Spectra
Et,O
CH,Cl,/Et,O Et20/Hexane EtOAc MeCN DMF/EtOH EtOH EtOAc PhH/CH,Cl, MeCN
40 Pmr 90 60 74
25 MeCN AcOH EtOH/Et20 EtOAc CH,Cl,/EtOH Et, 0 EtOH CH,Cl,/Hexane EtOH CH,Cl,/Et,O MeCN Et,O
66
55
Refs.
145 30 152c 243, 369
224-225 14G-145 235-245 172-174 175-177 18G182d 195-197 181-184d 256-258
EtOAc Et,O/Petr ether MeOH MeCN EtOH EtOH EtOH EtOH/Et,O EtOH
200-203d
Acetone
70
356
182-1 85d
Acetone
86
356
3-(2-Et2N-Ethyl)NHCO-5-Ph-7-C1
194-196d 185-186 180d 220 169-170
CH,CI,/EtOAc EtOH EtOAc EtOAc Acetone/Petr ether
3-(2-EtzN-Ethyl)S-5-Ph-7-CI Hydrochloride
260d
3-EtOOC-5-(2-Pyridyl)-7-Br 3-[ l,2-(EtOOC)2-Ethyl]-5-Ph-7-C1
3-EtOOCCH2NHCO-5-Ph-7-CI 3-(Et0),OP-5-(2-C1C6H4)-7-CI 3-Et2N-5-Ph-7-CI 3-EtzN-5-Ph-7-N02 3-Et,N-5-(2-ClC6H4)-7-N02 Methiodide 3-(Et,NCO)CH2-5-Ph-7-CI 3-(3-Et2NCO-l-Pyridinium)-5-Ph-7-C1 Chloride
74
ir, pmr
50
302 302 302 80
3-(3-Et,NCO-l-Pyridinium)-5-(2-C1C6H4)-7-C1 Chloride
3-(2-EtzN-Ethoxy)CO-5-Ph-7-CI Ethobromide 3-(2-Et2N-Ethyl)NH-5-Ph-7-C1
3-(2-Et,N-Ethyl)NH-5-(2-ClC6H4)-7-N02 \o
3-(2-Et2N-Ethyl)NHCO-5-Ph-7-C1
3-(2-Et2N-l-Me-Ethoxy)-C0-5-Ph-7-CI Hydrochloride
3-(3-Et2N-Propyloxy)CO-5-Ph-7-CI Hydrochloride Ethobromide Methobromide 4-Oxide, hydrochloride
41 90
147 348 301 105 336 367
,
225d 149-15Od 204-206d 155-1 60 17G174d 183d
CH CI z/Acetone Cyclohexane CH,CI,/Acetone PhH CH,CI,/EtOAc
147 147 147 147 147 147
165d
CH,CI,/Acetone
147
193-1 98d 216218 2 13-2 14d
CH,CI,/EtOAc CH,CI,/EtOAc CH,CI,
147 301 301
3-(3-Et2N-Propyloxy)CO-5-Ph-7-NO, Hydrochloride
3-(3-Et2N-Pr~pyl~~y)CO-5-(2-C1C6H4)-7-C1 Hydrochloride
3-(3-Et2N-Propyl)NHC0-5-Ph-7-C1 3-Et(Me)N-5-(2-C1C6H4)-7-N02
TABLE VII-1. +ontd.)
Substituent
-J W
O
3-F-5-Ph-7-Br 3-F-5-Ph-7-CI 4-Oxide 3-F-5-Ph-7-NOz 3-F-5-(2-C1C6H4)-7-C1 3-F-5-(2-FC6H,)-7-Br 3-F-5-(2-FC,H,)-7-C1 3-F,CCOO-5-Ph-7-Br 3-F3CC00-5-(2-FC,H4)-7-Br 3-(2-Furyl)CH2NH-5-Ph-7-CI 3-HzNNH-5-Ph-7-C1 3-HZNNH-5-(2-ClCsH4)-7-C1 3-H2NNHCO-5-Ph-7-C1 3-HO-5-C6D5-7-C1 3-HO-5-Ph-7-AC 3-HO-5-Ph-7-AcNH 3-HO-5-Ph-7-HzN 3-HO-5-Ph-7-N3 3-HO-5-Ph-7-Br 3-HO-5-Ph-7-CI Sodium salt 4-Oxide 3-HO-5-Ph-7-F3C 3-HO-5-Ph-7-(1-HO-Ethyl) 3-HO-5-Ph-7-1 3-HO-5-Ph-7-MeS 3-HO-5-Ph-7-NOZ
mp ("C) or; [bp ('Cjtorr)] 207-209d 190- 192d 207-208d 174-175 210-211d 195-197d 206-207d 181-183 175-177d 186-188 153-1 57 137- 142 215-220 194195 209-210 194-195 215-216 > 320 188-19Od 202-203 190-192 205-207 19621Od 174-175d 19CL191d 172-174 208-2 1Od 195-197d 211d
Solvent of Crystallization PhHjHexane HZO PhH/Heptane PhH/Hexane PhH/Heptane
EtOH MeCN
Yield (%) 88 82 93 83
67 99 80 10 74 71
Spectra ir, F-nmr, pmr F-nmr, pmr ir, pmr, F-nmr F-nmr, pmr F-nmr, pmr F-nmr, pmr F-nmr, pmr F-nmr, pmr F-nmr, pmr
EtOH/Et,O 78 Acetone EtOH MeCN MeCN THFjHexane EtOH EtOH EtOH MeCN EtOH Acetone/Hexane EtOH THFiHexane
90 17 65 70 85 81; 66 50
266, 267 266, 267 110 266, 267 266, 267 266, 267 266, 267 266, 267 266, 267 348 249 249 152c 97 2b 44 lb 252 252
Pmr ir
68
Refs.
202 266, 267 199, 260 148 206 lb 33b 371 lb 260
3-HO-5-(4-H2NC6H4)-7-C1 3-HO-5-(2-CIC6H4)-7-AcNH 3-HO-5-(2-C1C6H4)-7-H2N 3-HO-5-(2-C1C6H4)-7-C1 3-HO-5-(2-C1C6H4)-7-N02'0.5 Acetone 3-HO-5-(2-FC,H4)-7-Ac.0.5 THF 3-HO-5-(2-FC6H4)-7-AcNH' 0.5 H 2 0 3-HO-5-(2-FC6H4)-7-H2N 3-HO-5-(2-FC6H4)-7-Br 3-HO-5-(2-FC6H3)-7-C1
3-HO-5-(2-FC6H4)-7-(l-HO-Ethyl)
2 F
3-HO-5-(2-FC6H4)-7-N02 3-HO-5-(2,6-F2C6H4)-7-C1 3-H0-5-(4-HOC,H4)-7-C1 3-HO-5-(2-Pyridyl)-7-Br 3-HONH-5-Ph-7-Cl 3-(HO)PhCH-5-Ph-7-C1 3-(H0)PhCH-5-(2-ClC6H4)-7-C1 3-S-(4-HO-Benzyl)-5-Ph-7-C1 ~-(~-HO-BU~OX~)-~-P~-~-CI 3-(2-HO-Ethoxy)-S-Ph-7-C1 3-(2-H0-Ethoxy)-5-Ph-7-NO2 3-(2-HO-Ethoxy)-5-(2-C1C6H4)-7-CI 3-S-(I-HO-Ethyl)-5-Ph-7-C1
3-(2-HO-Ethyl)NH-5-(2-ClC6H4)-7-N02 3-(2-HO-Ethyl),N-5-(2-CIC6H4)-7-N0, ' CH2CI2 3-(2-HO-Ethyl)NHCO-5-Ph-7-C1 3-(2-HO-Ethyl)NHCOO-5-Ph-7-C1
3-(2-HO-Ethyl)MeNH-5-(2-C1C6H4)-7-NO, 3 4 1-(2-HO-Ethyl)-l-morpholiniurn]-5-Ph-7-C1 Chloride 3-[1-(2-HO-Ethyl)-l-morpholinium]-5-(2-ClC6H4) 7-Cl. Chloride
> 350 187-1 90d 340d 160-162 159-160 153-155 185-187 > 300 196198 197-200 125-140 193-195 197-200 178-179 197-198 178-18od 225 181-183 143-146 169-170 21G212 216-217 222-224d 225-226 118-121 208-21Od 118-12Od 265-268d 168-170 202-203d
THF/MeOH MeOH/H,O THF/MeOH
50
ir, ms, pmr
Acetone THF/Petr ether
30
ir
62 96
F-nmr, pmr
67 33 58 13
ir, pmr
60 75 97 34
ir, pmr
EtOH/Et,O EtOH THF/Hexane CH2C1, CH,C1,/Et20 THF/CHCl, Dioxane/H,O MeCN
ir, pmr ir
EtOAc MeCN EtOH Acetone MeOH
80 CH,CI,/EtOH CH,CI, CH,C1, EtOH CH,CI,/EtOH
ir, pmr ir, pmr
8 134 152c 263 8 2b 2b 152c 266 233 33b 152c 152c 148 148 260 304 192 72c 357 334 357,260 260 334 40 30 1 302 30 1 336 30 1
169-172d
Acetone
50
356
168-17Od
Acetone
70
356
TABLE VII-1. g c o n t d . ) mp ("C) or; CbP ("C/torr)l
Solvent of Crystallization
3-HOCHZ-5-Ph-7-Cl ~-HOCH,-~-(~-CIC,H.J-~-ACNH 3-HOCH2-5-(2-CIC6H4)-7-H2N 3-HOCH2-5-(2-C1C6H4)-7-NOz' EtOH
195-202d 126-128d 21 5-220 20 1-202 255-26Od 245-25Od 260-265
3-HOCH2-5-(2-FC6H4)-7-H2N 3-HOCHZ-5-(2-FC6H4)-7-NOz .EtOH 3-HO(Me0)CH-5-Ph-7-NO2 3-HO(MeO) CH-5-(2-C1C6H4)-7-NO, 3-[4-HOC6H4]CHz-5-Ph-7-C1 3-S-(4-HOC,HJCH2-5-Ph-7-CI
265-267 220-224 140d 225 151-153 139-141
Substituent
3-[2-(4-(2-HO-Ethyl)piperazin-l-yl) acetoxyll-5(2-C1C,H4)-7-C1 Dihydrochloride '2.5 H,O 3-(2-HO-Ethyl)S-5-(2-CIC6H4)-7-NO2 . MeOH
3-(Hydroxyimino)methyl-5-(2-ClC6H4)-7-NO,
4
3-(3-HO-Propoxy)-S-Ph-7-C1
3-[2,3-(0H),-Propoxy]-5-Ph-7-C1 3-(2-HO-Prop-2-yl)-5-Ph-7-C1 3-HS-5-Ph-7-CI .0.5 EtOH
3-(Imidazol-l-yl)-5-Ph-7-C1 3-S-(3-Indolyl)CH2-5-Ph-7-CI ' Ether. Acetone 3-(3-Indolyl)methyl-5-Ph-7-(l-carboxy-l-ethyl)
3-(Menthyloxy)acetoxy-5-(2-CIC6H4)-7-C1 3-Me-5-Cyclohexyl-7-CI 3-Me-5-Ph-7-Br
19&191 166-168 193-196d 179-180 140-141 249 149-1 5 1 150-152 244250 > l00d 140; 159 225
Yield (%)
Spectra
Refs.
EtOH/Et,O MeOH MeOH/H,O MeOH/Et,O EtOAc EtOAc/Et,O EtOH/CH,CI,/ Hexane/Petr ether EtOAc CH,CI,/EtOH MeOH MeOH/Petr ether PhH Et,O/Cyclohexane
46
Pmr
265, 328 302 30 1
42 76
[.I,
MeCN
60
ir, pmr
79
C1., pmr Pmr Pmr Pmr, [.I
Pmr
EtOH EtOH Et,O Acetone
82 Hexane
17 22
301 30 1 301 91a 30 1 301 301 301 2 40 357 334 134 367 227 478 40 40 20 338 18 100
3-Me-5-Ph-7-(I-Carboxy-1 -ethyl) 3-Me-5-Ph-7-Cl Hydrochloride 4-Oxide 3-R-Me-5-Ph-7-Cl 3-S-Me-5-Ph-7-Cl 3-S-Me-5-Ph-7-F3C 3-Me-5-Ph-7-NO2 ( + )-Enantiomer 3-S-Me-5-Ph-7-N02 3-Me-5-(2-C1C6H,)-7-AcNH 3-Me-5-(2-C1C6H,)-7-H,N 3-R-Me-5-(2-C1C6H,)-7-C1 Hydrochloride 3-S-Me-5-(2-C1C6H,)-7-C1 Hydrochloride 3-S-Me-5-(2-C1C6H,)-7-F. 0.5 Et,O Hydrochloride.0.25 H,O 3-Me-5-(2-C1C6H,)-7-NO, ( + )-Enantiomer (- )-Enantiomer 4-0xide 3-S-Me-5-(2-C1C6H,)-7-N02 3-Me-5-(3-C1C6H,)-7-NO, 3-Me-5-(2-FC6H,)-7-Ac 3-Me-5-(2-FC6H,)-7-H,N 3-Me-5-(2-FC6H,)-7-C1 (+)-Enantiomer ( -)-Enantiomer 3-Me-5-(2-FC6H,)-7-CN 3-Me-5-(2-FC6H,)-7-I 3-Me-5-(2-FC,H,)-7-NOz 3-S-Me-5-(2-FC6H,)-7-NO,
135-137 220-22 1 294295 268d 2W203 2W203 87-90 221-222 144-146 96-98 212-274 229-230 283-285 26C-265d 172-173 265-268d 73-75d 230-235d 193-196 193-196 228-229 300d 198-200 211-213 203 270 188-191 162-164 158-162 216 21 1 23G234 13&140
PhH/Petr ether EtOH
86 75
Pmr
la1 Acetone/H,O Acetone/H,O PhH/Hexane EtOH Acetone/H,O EtOH/Ligroin EtOH/Ligroin CH,Cl,/MeOH
90
Gal, Pmr
“I la1
EtOH Acet one/H,O EtOH Et,O EtOH Et,O/Petr ether CH,Cl,/Hexane Et,O/Hexane CH,CI,/EtOH Et,O MeOH CH,Cl,/Cyclohexane CH,Cl,/Et,O/Petr ether Et,O Et,O/Petr ether Cyclohexane Cyclohexane EtOAc/Petr ether Et,O/Petr ether
Cal
20 2 34 34 40 40 81 136 301 81 301 301 301 134 112 134 134 134 301 301 30 1 301 79 30 1 25 1 251 42 1 301 301 251 25 1 23 1 79, 231
TABLE VII-1. +ontd.)
Substituent
2
mp ("C) or; [bp ("Cjtorr)]
3-R-Me-5-(2-FC6H,)-7-NO, 130-140 3-Me-5-(2-Pyridyl)-7-Br 228-229 3-(Me2-Acetoxy)-5-Ph-7-CI 223-225 3-[2-Me-3-(2-Br-Ethyl)-4-NO2-l-imidazolium]-5-Ph-7-C1 Chloride 209-21 1 3-[2-Me-(2-Br-Ethyl)-4-NO,-l-imidazolium]-5(2-C1C6H4)-7-C1 Chloride 234-237 3-[(2,2-Me2-1,3-Dioxolan-4-yl)methoxy]-5-Ph-7-C1 194-196 210-211 3-(3-Me-l-ImidazoIium)-5-Ph-7-C1 Chloride 215-2 18 3-(3-Me-1-1midazolium)-5-(2-ClC,H,)-7-CI Chloride 26&263 3-(1-Me-Hydrazino)-5-(2-CIC6H.,)-7-NO, 184d 3-(4-MeC6H,SO,)CH,-5-Ph-7-CI 189-190 3-(4-Me-Piperazin-l-yl)-7-C1 223-225 3-MeNH-5-Ph-7-CI 227-230 197-200 182-183 3-MeNH-5-(2-CIC,H,)-7-NO2 196198d 3-MeNHCH2-5-(2-C1C,H,)-7-NO, 163 3-Me(2-MeO-Ethyl)N-5-(2-CIC,H4)-7-NO2 194-195 3-(4-Me-Piperazin-l-yl)-5-(2-C1C6H,)-7-NO, '0.5THF 198-2OOd 3-(4-Me-Piperazin-l-yl)-C00-5-Ph-7-C1 233-234 3-[2-(4-Me-Piperazin-1-yl)acetoxy]-5-(2-C1C6H4)-7-C1 Hydrochloride. H,O 233-234 Dihydrochloride .2H,O 202-204d Dihydrochloride H,O 2 18-220
Solvent of Crystallization
Yield (YO)
Et,O/Hexane Acetone i-PrOH
30 79
326
Acetone/MeOH
70
356
Acetone
70 80
356 334 334
Acetone
70
356
Acetone CH,CI, Dioxane/H,O
78
356 30 1 38b 149 358 260 348 30 1 30 1 30 1 302 336
Spectra
Refs 23 1 3
13 MeOH/Et,O EtOH CH,CI,/EtOH CH,Cl,/Et,O/Hexane EtOAc/Petr ether THF/Hexane DMF/EtOAc
99 15
MeOH/Et ,O MeOH/Et,O MeOH/Et,O
82 33 42
ir, pmr
265, 328 265, 328 265
Methanesulfonate Maleate.0.5 H,O
> 16od > 125d
MeOH/Et,O MeOH/Et,O
265, 328 265, 328
3-[2-(4-Me-Piperzin-1-yl)-ethoxy]CO-5-Ph-7-C1 Dihydrochloride 3-Me(Ph)N-5-Ph-7-C1 3-(2-Me-3-Ph-Propanoyloxy)-5-(2-ClC6H4)-7-Cl 3-(2-Me-Propanoyloxy)-5-Ph-7-C1 3-(2,2-Me,-Propanoy1oxy)-5-(2-C1C,H4)-7-Cl 3-(l,l-Me,-2-Propyn-l-y1)NH-5-(2-C1C,H,)-7-N0~ 3-MeNHCO-5-Ph-7-CI 3-MeNHCOCONH-5-Ph-7-Cl
3-(2-MeNH-Ethoxy)CO-5-Ph-7-C1 4-Oxide, hydrobromide 3-Me2N-5-Ph-7-C1
4
3-Me2N-5-Ph-7-Me 3-Me,N-5-(2-C1C6H4)-7-N0, Hydrochloride. 0.5 Acetone 3-Me2N-(2-Pyridyl)-7-Br 3-Me2NCO-5-Ph-7-C1 3-Me2NC00-5-Ph-7-C1 3-(2-Me2N-Ethoxy)CO-5-Ph-7-C1 Hydrochloride Methobromide 4-Oxide, hydrochloride 3-(2-Me2N-Ethyl)NH-5-Ph-7-CI 3-(2-Me2N-Ethyl)NHCO-5-Ph-7-C1 3-[2-(2-Me,N-Ethy1methylamino)acetoxy]-5~ (2-ClC6HJ-7-Cl Dihydrochloride .2H,O 3-(2-MezN-Ethyl)S-5-Ph-7-CI Hydrochloride 3-Me2NCH,-5-Ph-7-N0,
204-206d 232-233 2W206 197-198 198-200 204-206 294 307-3 1 3 230-23 1 195-2OOd 217-218d
CH,Cl,/MeOH/EtO Ac EtOH MeOH EtOH EtOH EtOAc/Petr ether EtOH CH,CI,/MeOH Acetone/EtOH CH,CI,
210-212 220-222
Hexane
248-250
MeOH/Acetone CH,CI,
> 21od 297 234-235 62 206208d 194-196 155d 182-183 24&242
CH,Cl,/Petr ether CH,CI,/Acetone CH,CI,/EtOAc Acetone/EtOAc EtOH EtOAc
221-223d
EtOH/Et,O
255-260 191-1 93d
EtOH MeOH/Et,O
79
147 369, 348 337b 326 329 301 105 190 336 147 149
41 88
369 149
33; 80 44 81 87 90 20
ms, pmr, uv
302 251b 105 336 147 147 301 147 227 301
20
265, 328 227 301
TABLE VII-I. -
Substituent
mp ("C) or; [bp ("C/torr)]
Solvent of Crystallization
3-Me,NCH,-5-(2-CIC,H4)-7-N0,
166d
EtOH/Et,O
301
CH,CI,/EtOAc MeOH CHCIJHexane Hexane MeCN MeOH/Et,O EtOH
147 80 2 109 101 260, 227 366 260 302 302 301 301 301 338 338 202 32 39 108 145 105 39 77 108 108 488 265
Yield (YO)
Spectra
Refs.
3-(2-Me,N-2,2-Me2-Ethoxy)CO-5-Ph-7-CI Hydrochloride 3-1(4-Me-Piperazin-l-yl)carbonyl]CH2-5-Ph-7-Cl 3-(2-Me-Prop-l-yl)-5-Ph-7-C1 S-Enantiomer 3-Me0-5-Ph-7-CI ( +)-Entantiomer
3-Me0-5-Ph-7-N02
2 Q\
3-Me0-5-(2-C1C6H,)-7-NO,
3-(2-MeO-Ethyl)NH-5-(2-CIC,H4)-7-NO, 3-(2-MeO-Ethoxy)-5-(2-ClC6H4)-7-NO, 3-(MeO),CH-5-(2-C1C,H4)-7-N0, 3-(Me0)Ph-Acetoxy-5-(2-CIC6H,)-7-CI Mixture of diastereoisomers
3-[3,4,5-(MeO),C,H,]CONH-5-Ph-7-Cl 3-MeOOC-5-Ph-7-Ac 3-MeOOC-5-Ph-7-CI 4-Oxide 3-Me00C-5-Ph-7-N02 3-Me00C-5-(2-C1C,H4)-7-CI 3-Me00C-5-(2-FC,H4)-7-I 3-Me00C-5-(2-FC,H4)-7-NO, 4-0xid e 3-MeOOCNH-5-Ph-7-CI 3-MeOOCO-5-(2-CIC,H,)-7-C1
176178 254-255 213-214 160-161 23&233 258-260 136 270d 255-259d 220-225 182d 217-2 19 205-206 163-1 64 >I16 267 195-196 2 17-219 182-184d 245d 226 216219 230-236d 22G222 185-186d 209d 223-225
15 39
[a1
87
la1 21
ir
63
ir
MeCN/MeOH THF/Hexane EtOH CH,CI,/EtOH Et,O Et,O EtOH PhH CH,CI,/MeOH MeOH EtOH MeOH MeOH/Et,O CH,CI,/Et,O EtOAc/MeOH EtOAc i-PrOH CH,CI,
76
47 70
3-(3-MeOOC-Propanoyloxy)-5-Ph-7-C1 3-(3-MeOOC-Pyridinium)-5-(2-ClC6H4)-7-C1 Chloride 3-MeOCH2-5-Ph-7-C1 3-(4-MeOC,H,)-5-Ph-7-CI 3-(Me0),0P-5-(2-C1C6H4)-7-C1 3-MeS-5-(2-C1C,H4)-7-N0, 3-(2-MeS-Ethyl)-5-Ph-7-CI
3-(2-MeS-Ethyl)-5-(2-C1C6H4)-7-NO, 3-Me(0)S-5-(2-C1C6H4)-7-N0, 3-Morpholino-5-Ph-7-CI
3-Morpholino-5-(2-C1C,H4)-7-NO, 3-(Morpholino)acetoxy-5-Ph-7-C1 Hydrochloride
3-(Morpholino)acetoxy-5-(2-CIC,H4)-7-C1 Hydrochloride. H,O 3-[4-(Morpholino)butoxylCO-5-Ph-7-CI Hydrochloride
3-(Morpholino)CO-5-(2-CIC6H4)-7-NO,
3-(Morpholino)CO-5-(2-FC6H4)-7-N0, 3-[2-(Morpholino)ethoxy]CO-5-Ph-7-CI0.Cyclohexane Hydrochloride
3-[2-(Morpholino)ethyl]NHCO-5-Ph-7-C1 3-[6-(Morpholino)hexoxy]CO-5-Ph-7-CI Hydrochloride
3-(Morpholino)CH,-5-(2-CIC6H4)-7-NO, 3-[3-(Morpholino)propoxy]CO-5-Ph-7-CI Hydrochloride
3-13-(Morpholino)propoxy]CO-5-(2-C1C6H4)-7-H,N
145-148
EtOH
69
326
216219 16&167 237-238 248d 244-246d 179-1 80 184 148-150 234236 226228 211-213 217-219d
Acetone Et,O
70 10
MeCN CH,CI,/Et,O EtOH EtOAc Et,O/Hexane CH,CI,/MeOH EtOH
73
EtOH
356 2 86b 243 301 2 105 301 301 149,369 358 302
EtOH EtOH
263 262
223-224 228-229 255-257d 128-1 30d 160-165
7 50
60;42
40 EtOAc CH,CI,/MeOH EtOAc
ir, pmr
Pmr
265 147
27G272 176 1W109d 174178d 254256 147-150 21Cb212d 194-195
Et,O Cyclohexane Acetone EtOAc Acetone/Petr ether CH,Cl,/MeOH/EtOAc CH,CI,/Petr ether
147 301 301 147 147 301 147 147 301
17G172d 215d
CH,CI,/Acetone Et,O
147 301
TABLE VII-I. 4 c o n t d . ) mp ("C) or; [bp ("C/torr)]
Solvent of Crystallization
203-204d 188-19Od 229-232d
PhH
147
Hydrochloride Methobromide
14&15Od
CH,CI, PhH/Acetone Et,O
147 147 147 202 30 1 478
Substituent
3-13-(Morpholino)propoxy]CO-5-(2-C1C6H4)-7-NO,
3-[3-(Morpholino)propoxy]CO-5-(2-FC6H4)-7-CI 3-(4-OzNC6H4)CHN-5-Ph-7-Cl 3-(3-0~0b~tyl)-5-(2-CIC,H,)-7-N0~ 3-(2-Oxopyrrolidin-l -yl)acetoxy-5-Ph-7-C1 3-(2-Oxopyrrolidin-I-yl)acetoxy-5-(2-C1C6H4)7-NO2 . T H F 3-( 1-Ph-Eth-1-yl)NHC00-5-(2-CIC6H4)-7-Cl 3-PhCHN-5-Ph-7-CI 3,5-PhZ-7-(I-Carboxy- I-ethyl) 3,5-Ph,-7-C1
3-Ph-5-(2-ClCsH4)-7-N0, 3-(2-Ph-Ethyl)NH-5-Ph-7-C1 3-(3-Ph-Propanoy1oxy)-5-(2-ClC6H4)-7-CI 3-PhOC00-5-Ph-7-CI 3-[2-(Piperazin-l-yl)ethoxy]CO-5-Ph-C1 Dih ydrochloride 3-[2-(Piperazin-l -yl)ethyl]NHCO-5-Ph-7-C1 Dihydrochloride OSMeOH. 0.5Hz0
3-(Piperidin-l-yl)-5-Ph-7-C1 3-(Piperidin- 1-yl)-5-Ph-7-NO2 3-(Piperidin- 1-yl)C00-5-Ph-7-C1 3-[2-( Piperidino)ethoxy]CO-5-Ph-7-C1 Dihydrochloride
170-172d 156-157 185 229-230 142 193-196 185-187
Yield (%)
Spectra
25 EtOAciPetr ether
THF Et,O EtOH
151-155
269-270 279d 220-225d 181-183 175-178 162-1 64
DMF PhMe THF/Hexane EtOH EtOH Dioxane/Ligroin
216-217d
Acetone/H,O
244-248 229-230 26&262 205-207d 224-226 152-153d 172-173d
CH,CI,/MeOH EtOH EtOH EtOAc CH,CI,/Acetone CH,CI, /Acetone
[XI 29 64 52
ir Pmr
20
44
Refs.
478 338 202 20 2 35 302 348 337b 336 147
72; 58 45 57
ir
30 1 149, 348 369 260 336 147 147
3-[2-Piperidino- 1 -Me-ethoxy]CO-S-Ph-7-C1 Hydrochloride
3-Propanoyloxy-5-Ph-7-CI 3-i-Pr-5-Ph-7-Br 3-i-Pr-5-Ph-(1-Carboxy- 1-ethyl) 3-i-Pr-5-Ph-7-CI 3-S-i-Pr-S-Ph-7-CI 3-Pr-5-(2-CIC,H4)-7-N0, 3-i-Pr-5-(2-FC,H4)-7-CI ( )-Enantiomer 3-i-Pr-5-(2-FC6H,)-7-NO, 3-Pr-5-(2-FC,H,)-7-NO2 3-PrNH-5-(2-CIC,H4)-7-N0, 3-i-PrNH-5-(2-CIC6H,)-7-NO, 3-Pr,N-5-(2-ClC,H4)-7-NO, 3-Pr0-5-(2-C1C6H4)-7-NO, 3-i-Pr0-5-(2-C1C6H,)-7-NO, 3-i-PrOOC-5-Ph-7-CI
+
3-(2-Pr-Pentanoyloxy)-5-(2-C1C6H,)-7-C1 3-(2-Pr-Pentanoyloxy)-5-(2-FC,H4)-7-CI 3-(2-Propyn-1-yl)NH-5-(2-CIC6H,)-7-NO, 3-(1-Pyridinium)-5-Ph-7-C1 Chloride Iodide
190d 228-230 234 13C-135 226-227 192-1 94 228-230
Acetone/EtOAc EtOH
Et,O/Petr ether CH,CI,/Petr ether CH,CI,/Petr ether
87 8 5s 9 87
147 326 100
Pmr
Gal, Pmr
20 2 40 301
190 208-210 245-246 178-1 80 183-185 204-205 24CL245 27C275d 235-238d 191-193 147-149 212-214d
Et20 Et,O/Petr ether CH,CI,/EtOH. EtOAc MeCN CH,CI,/EtOH CH,CI,/EtOH CH,CI,/EtOH
256251 234236d 24CL246d
MeCN H2O MeOH
80
227 356 67b
234237d 193-195
Acetone EtOH
90 20
356 348
238-240 241d 284 237-239d
MeOH/Acetone MeOH/CH,Cl,/i-Pr,O PhH CH,CI,
301 301 23 1 301 302 301 301 301 302 326 326 301
MeCN MeCN/H,O Et OAc/Hexane
3-( l-Pyridinium)-5-(2-CIC,H4)-7-CI Chloride
3-(Pyrrolidin-l-yl)-5-Ph-7-CI 3-(Pyrrolidin-1-yl)-5-(2-C1C6H,)-7-NO, Hydrochloride 34 1,2,3,4-Tetrahydroisoquinolin-2-yl)CO-5-Ph-7-C1
3-Thioacetamino-5-Ph-7-CI 3-(Thiazolidin-3-yl)-5-(2-C1C,H,)-7-N02
48
ir
302 488 202 301
TABLE VII-I. 4 c o n t d . ) mp ("C) or; [bp (Tjtorr)]
Solvent of Crystallization
21421 7d
MeCN
302
153-154
Cyclohexane
477
5-Ph-6-CI-7-HZN
300-303
MeCN
5-(2-FC6H,)-6-C1-7-H,N
310-320d
CH,CI,/EtOH
30 1
259-260 291-294 26&261 242-244 255-256 234235 218-2 19 192-193 259-260 216-217 238-239 262-264 27CL272 27C-215 237-239 15CL-155 217-218
DMF/Et,O Acetone/MeOH PhH/Hexane EtOAc MeOH CH,CI,/Petr ether PhH EtOH/Hexane CH,CI,/Petr ether CH,Cl,/Cyclohexane CH,Cl,/EtOH
2b 67b 2 475 2 91a 2b 134 2 257 257 257 257 257 257 257 257
Substituent
Yield (%)
Spectra
Refs
3,S,8- Trisubstituted
3-EtO2C-5-Ph-8-C1 339- Trisubstituted
3,5,9-Me3 5,6,7- Trisubstituted
33b
5,7,8- Trisubstituted -1 U Y
0
5-Me-7,8-(MeO), 4-Oxide 5-Ph-7-HzNSO2-8-Cl 5-Ph-7-Br-8-MeO 5-Ph-7,8-C1, 5-Ph-7,8-Me2 4-Oxide 5-Ph-7-NO2-8-Me 5-(2-CIC6H,)-7-F-8-Me 5-(2-C1C6H,)-7,8-Me, 5-(2-FC,H4)-7-Br-8-C1 5-(2-FC,H,)-7,8-C1 5-(2-FC6H4)-7-C1-8-H2N
5-(2-FC,H,)-7-C1-8-(H2N-Acetamino) 5-(2-FC,H4)-7-C1-8-(3-HO0C-Propionyl)NH 0.5 H,O 5-(2-FC6H4)-7-C1-8-Me 5-(2-FC6H4)-7-C1-8-N02 5-(2-FC6H,)-7-CN-8-C1
CH,CI,/THF DMSO/H,O CH,Cl,/EtOH CH,Cl, /Cyclohexane CH,Cl,/Cyclohexane
60 75
10
5-(2-FC6H,)-7-Me-8-C1 5-(2-F,H4)-7-NO,-8-C1 5-(4-0,NC6H,)-7,8-Me, 4-0xide 5-(2-Ph-Ethyl)-7,8-(MeO), 5-{2-[3,4-(MeO),C6H,]ethyl}-7,8-(MeO),
255-259 248-249
CH,Cl,/EtOH CH,Cl,/Cyclohexane
254-255 182-1 83 161-162
MeCN EtOH
195-197 207-208 274-276 236-238
EtOH Acetone PhH/EtOH PhH/MeOH
217-21 8 173-175 186189 189-1 9 1 209-210 21&211 202-204 216-217 20 1-202 199-200 260d 213-2 15 200 206207 260d 211-213 275 231-233 179 164167 239-241
MeOH EtOAc EtOH MeCN THF/Et,O Acetone Et,O EtOAc CH,CI,/Et,O
257 257 2b 2b 2b
5.79- Trisubstituted
5-Ph-7,9-Br2 5-Ph-7,9-CI2 5-Ph-7-CI-9-HO 4-Oxide
40 70
67b 2 67a 67a
5-Ph-7-C1-9-(2-HO-3-i-PrNH-Propoxy)
2
Oxalate 5-Ph-7-C1-9-1 5-Ph-7-CI-9-Me 5-Ph-7-Cl-9-MeS 5-Ph-7,9-IZ 5-Ph-7,9-Me2 5-Ph-7-NO2-9-Me 5-(2-C1C6H,)-7,9-Br, 5-(2-C1C6H4)-7,9-Cl2 5-(2-C1C6H4)-7-CI-9-Br 5-(2-CIC6H,)-7-C1-9-HOOC 5-(2-C1C6H,)-7-CI-9-MeOOC 5-(2-FC,H,)-7-H,N-9-C1 5-(2-FC6H4)-7,9-Br2 5-(2-FC,H,)-7-CI-9-HOOC 5-(2-FC,HJ-7-C1-9-I
5-(2-FC6H,)-7-(Cyclopentyl)CONH-9-C1 5-(2-FC,H4)-7,9-1, 5-(2-FC6H4)-7-NO2-9-CI 5-(3-0,NC6H4)-7-C1-9-N0, 5-(2-Pyridyl)-7,9-Br2
CHClJEtOAc EtOAc CH,Cl,/Et,O EtOAc MeOH/EtOAc EtOAc/CHCl, EtOAc/MeOH THF/Petr ether EtOAc MeOH/CH,CI, BuOH
20
492 493 371 7 371 91 2b 475 134 494 486 486 301 475 486 493 301 192 301 152a 67b
TABLE VII-1. 4 c o n t d . )
Substituent
mp ("C) or; [bp (Tjtorr)]
Solvent of Crystallization
154-156 165-168 171-173
EtOH CH,Cl,/Hexane EtOH
Yield
(Oh)
Spectra
Refs.
Tetrasubstituted I , 3,3,5-Tetrasubstituted
l-Me-3-Ac0-3-EtOOC-5-Ph1-Me-3-EtOOC-3-EtOOCNHC00-5-Ph-7-CI I-Me-3-EtOOC-3-HO-5-Ph
108 302 108
I,3,5,7- Tetrasubstituted
I-Ac-3-AcO-5-Ph-7-AC l-Ac-3-AcO-S-Ph-7-CI l-Ac-3-AcO-5-Ph-7-N02 1-Ac-3-AcO-5-(2-C1C6H4)-7-C1
15Ck-153 17&172 178-180 171-173 1-Ac-3-Ac0-5-(2-C1C6H4)-7-N02 206-208 l-Ac-3-Ac0-5-(2-FC6H4)-7-AcNH 2 18-224 ~-AC-~-ACO-~-(~,~-F,C,H,)-~-CI 158-162 196-198 1,3-(A~0),-5-Ph-7-C1 1,3-(Ac0),-5-(2-Pyridyl)-7-Br 19&191 1-(2-A~O-Ethyl)-3-A~0-5-Ph-7-C1 155-156 173-174 I-(~-ACO-E~~~I)-~-ACO-~-P~-~-NO, ~ - ( ~ - A C O - E ~ ~ ~ ~ ) - ~ - A C O - ~ - ( ~ - C ~ C , H , ) - ~ - C I 162-1 64 1-(2-A~O-Ethyl)-3-A~0-5-(2-F6H~)-7-C1 129-130 l-(3-AcO-Propyl)-3-AcO-5-Ph-C1 152-153 1-(2-A~O-Ethy1)-3-EtO-5-Ph-7-C1 112-1 14 155-156 l-Allyl-3-A~O-5-Ph-7-Cl 196 1-Ally1-3-EtOOC-5-(2-ClC6H~)-7-C1 138-140 l-Allyl-3-F-5-Ph-7-CI 149-1 5 1 1-Allyl-3-HO-5-Ph-7-C1 172-182d 1-Benzoyl-3-benzoyloxy-5-(2-C1C,H4)-7-NO, l-t-Bu-3-Me-5-Ph-7-Cl 144-146
EtOH Cyclohexane PhHiHexane
CH,Cl,/MeOH CH,Cl, CH,Cl,/Hexane THF/Petr ether PhH/Hexane i-PrOH MeOH i-PrOH i-PrOH MeOH Acetone/Petr ether CH,Cl,/Et,O/Petr ether Et,O Heptane Et,O THF/Hexane Et,O/Pentane
37 70
80 20 78 77 92 78 47 48
ir, ms, pmr, uv ir, pmr
F-nmr, pmr
44 309 33b 308 108 301 152c 189 148 365 365 365 365, 282 365 365 2b 275 266 2b 302 391b
1-t-Bu-3-Me-5-(2-CIC6H4)-7-H,N Picrate
1-t-Bu-3-Me-5-(2-C1C6H4)-7-N02 1-t-Bu-5-Me-5-(2-ClC6H4)-7-Phthalimide l-CI-3-Me-5-Ph-7-Cl
~-(CI-AR~~I)-~-ACO-~-P~-~-CI 1-(2-Cl-Ethyl)-3-EtO-5-Ph-7-C1 1-(2-C1-l-MeO-Ethy1)-3-Ac0-5-Ph-7-C1
202-204d 19&191 123-125d 185d 195- 197 209-210 193-195
1-(2-C1-l-MeO-Ethyl)-3-EtOOC-5-Ph-7-C1 1-(2-Cl-MeO-Ethyl)-3-HO-5-Ph-7-CI
157-159 191-193 205-206 1-(2-CN-Ethyl)-3-(2-CN-ethoxy)-5-Ph-7-C1 215-21 8 1-(2-CN-Ethyl)-3-(2-CN-ethoxy)-5-(2-ClC6H4)-7-CI 210-213 1-(2-CN-Ethy1)-3-(2-CN-ethoxy)-5-(2-FC6H4)-7-Cl 204-207 1-(2-CN-Ethy1)-3-HO-5-Ph-7-C1 192-194 1-(2-CN-Ethyl)-3-HO-5-Ph-7-N0, 185-188 1-(2-CN-Ethyl)-3-HO-5-(2-C1C,H4)-7-C1 198-202 l-(2-CN-Ethyl)-3-HO-5-(2-ClC6H4)-7-N0, 191-1 94 1-(2-CN-Ethyl)-3-HO-5-(2-FC6H4)-7-C1 190-193 1-(2-CN-Ethyl)-3-HO-5-(2-FC6H4)-7-NO2 183-186 1-[2-(N-CN-N-Et-amino)ethyl]-3-Ac0-5-(2-FC6H4)-7-C1 94-101 l-(Cyclopropyl)CH2-3-AcO-5-Ph-7-C1 195- 197 l-(Cyclopropyl)CH,-3-HO-5-Ph-7-C1 159-161 272-275 l-Et-3-F-5-Ph-7-Cl 156158
EtOH/H,O Acetone/Hexane Acetone/Hexane PhH EtOAc EtOH CH,CI,/Hexane EtOH EtOAc EtOH MeCN MeCN MeCN CHCl,
391b 391b 391b 224 308 365 72 143 278 72 199 280 280 280 280 280 280 280 280 280 152c 232 232 30 1 266
58 68 65
EtOAc EtOH MeOH/Et,O i-PrOH EtOH CH,CI,/Et,O Heptane
96 57
1-Et-3-Me-5-(2-ClC6H4)-7-H,N S( +)-Enantiomer 1-Et-3-Me-5-(2-CIC6H4)-7-N0, S ( + )-Enantiomer l-EtNHCO-3-F-5-Ph-7-CI 1,3-(EtOOC)2-5-Ph-7-C1
l-EtOOC-3-EtOOCNH-5-Ph-7-CI
209 141-142 ll(3-112 147-15Od 190-192
49 5
Cyclohexane CH,CI,/Et,O MeCN
F-nmr, pmr
495 266 108 227
TABLE VII-1. +ontd.)
Substit uen t
mp ("C) or; [bp ("C/torr)]
Solvent of Crystallization
Yield (%)
155-157
Et,O/Hexane EtOH/H,O CH,CI,/Hexane
71 70
214-218
Acetone/Et,O
84
Oil 101-102 115-117 138-140 128-129 118-121 196-203 Amorphous
Acetone/Et,O Hexane Et ,O/Pentane i-PrOH Et,O/Petr ether Acet one/Et 0
148 123-1 25 92-95
Et,O/Petr ether Cyclohexane/Et,O EtOH
Spectra
Refs.
Pmr
301 365 238, 365
1-Et00CCH,-3-Me-5-(2-ClC6H4)-7-N0, ( +)-Enantiomer
I-(~-E~ZN-E~~~I)-~-ACO-~-P~-~-CI 132-133 ~-(~-E~,N-E~~~I)-~-ACO-~-(~-CIC~H~)-~-CI 144-146 1-(2-Et,N-Ethyl)-3-Ac0-5-(2-FC6H4)-7-CI Hydrochloride
233
1-(2-Et,N-Ethyl)-3-(3-HOOC-propanoyloxy)5-(2-FC6H4)-7-C1 Succinate I \o
1-(2-Et,N-EthyI)-3-HO-5-Ph-7-C1 I-(2-Et~N-Ethyl)-3-H0-5-(2-ClC6H4)-7-C1
A
1-(2-Et,N-Ethyl)-3-HO-5-(2-FC6H4)-7-Cl Hydrochloride
l-(2-Et,N-Ethyl)-3-HOCH2-5-(2-C1C6H4)-7-Br l-(2-Et,N-Ethyl)-3-Me-5-(2-ClC6H4)-7-N0, (
+)-Enantiomer
I-(2-Et,N-Ethyl)-3-MeO-2-(2-ClC6H4)-7-C1 1-(2-Et,N-EthyI)-3-EtOOC-5-Ph-7-C1
,
152c 152c 365 288 365 233 233 264
88 12 60 73
68
1-(2-Et,N-Ethyl)-3-EtOOC-5-(2-FC,H,)-7-C1
ir, ms,pmr
30 1 288 147 145
ir, ms, pmr, uv
147 33b 69 69 69 264 189
Pmr
1-(2-Et,N-Ethyl)-3-(3-Et2N-propyloxy)CO-5-Ph-C1 Dihydrochloride 1-F3CO-3-F3C00-5-Ph-7-C1 I-F3CCH2-3-AcO-5-Ph-7-CI
I-F~CCH,-~-ACO-~-(~-FC~H.+)-~-CI 1-F3CCH,-3-HO-5-Ph-7-C1
1-F3CCH,-3-HOCH,-5-(2-ClC6H4)-7-Br 1,3-(HO),-S-Ph-7-C1
200-204 159-161 193-194 156-159 186-187 Amorphous 176-178d
(F3CC0)20
Acetone/Hexane CH,Cl,/Hexane EtOH/Hexane
75
EtOH/H,O
23
75
I-(~-HO-E~~~I)-~-ACO-~-P~-~-C~ 1-(2-HO-Ethyl)-3-Et0-5-Ph-7-C1
2
203-205 213-21 5 I-(2-HO-Ethyl)-3-EtOOC-5-Ph-7-C1 168-170 1-(2-HO-Ethyl)-3-(3-Et2N-propoxy)CO-5-Ph-7-Cl 118-120 1-(2-HO-Ethyl)-3-H0-5-Ph-7-C1 158-160 1-(2-HO-Ethyl)-3-HO-5-Ph-7-N02 178d I-(2-HO-Ethyl)-3-HO-5-(2-ClC~H4)-7-CI 171-173 1-(2-HO-Ethyl)-3-HO-5-(2-FC~H4)-7-CI 138-140 l-(2-HO-Ethyl)-3-Me,NC0-CH2-5-Ph-7-C1 163-165 1-(3-HO-PropyI)-3-HO-5-Ph-7-C1 151-153 I-Me-3-Ac-5-Ph-7-Cl 148 Methylhydrazone 174-176 1 -Me-3-(4-AcNH-Butanoyloxy)-5-Ph-7-C1 131-132 1 -Me-3-(4-AcNH-Butanoyloxy)-5-(2-ClC6H4)-7-C1 Amorphous 1-Me-3-Ac-(Et00C)CH-5-(Cyclohexen-l-yl)-7-C1 191 1-Me-3-AcCH2-5-(Cyclohexen-l-yl)-7-C1 163-165 I-Me-3-AcO-5-Ph-7-AcNH > 245 l-Me-3-AcO-5-Ph-7-CI 262-263 1-Me-3-Ac0-5-Ph-7-F3C 189-190 l-Me-3-AcO-5-Ph-7-MeS 209-212d I-Me-3-AcO-5-Ph-7-NO2 248-249 l-Me-3-AcO-5-(2-C1C6H,)-7-C1 219-22 1 1-Me-3-Ac0-5-(2-C1C,H4)-7-N0, 234-236 1-Me-3-Ac0-5-(4-CIC,H4)-7-C1 249-253 1-Me-3-AcO-5-(2-FC6H4)-7-Ac 145-147 I-Me-3-AcO-5-(2-FC,H4)-7-AcNH 280 1-Me-3-AcO-5-(2-FC,H4)-7-(2-AcO-Ethyl)NHCONH 183-186 1-Me-3-Ac0-5-(2-FC,H4)-7-H,N 259-260 I-Me-3-AcO-5-(2-FC6H,)-7-Cl 252-253 239-241d 1-Me-3-AcO-5-(2-FC,H4)-7-1 1-Me-3-AcO-5-(2-FC6H,)-7-N0, 219-220 l-Me-3-AcO-5-(2-Pyridyl)-7-Br 259-265d 1'-Oxide 235-245 > 350
MeOH
365 365 147 147 365 365 365 282, 365 302 365 299 301 339 339 72c 72c 251c 263 lb 192 lb 247 302 152c 2b 301 301 2b 152c 134 2b 152c
CH,Cl,/MeOH
152c
Acetone/H,O EtOH EtOH Et,O/Petr ether MeOAc/Hexane PrOH i-PrOH CH,CI, /Et,O CH,Cl,/Et,O EtOH/Et,O Pentane Et,O/Petr ether MeCN/i-Pr,O EtOH MeOH EtOH/Et,O Acetone/Hexane CH,Cl,/Et,O/Hexane THF/Hexane CH,Cl,/Et,O THF/Hexane Acetone Et,O Ac, O/Et ,O EtOAc CH,CI, /Et,O CH,Cl,/Et,O/Petr ether CH,Cl, /Hexane
I5 63
85 45 73 81 63 12
TABLE VII-I. 4contd.)
Substituent
mp ("C) or; [bp ("C/torr)]
Solvent of Crystallization
Yield (%)
Spectra
1-Me-3-AcOCH,-5-(2-CIC6H4)-7-Br 1-Me-3-AcOCH,-5-(2-CIC6H.,)-7-C1
121-123 Amorphous 1-Me-3-AcOCH,-5-(2-FC6H4)-7-H,N 205-207 1-Me-3-AcOCH,-5-(2-FC6H4)-7-CI 168- 170 1-Me-3-AcOCH,-5-(2-FC6H4)-7-(2-HO-Ethyl)NHCONH 175-177 l-Me-3-Allyl-5-Ph-7-CI 4-Oxide 183-185 1-Me-3-(Allyl)OOC-5-Ph-7-CI 171-172 l-Me-3-H2NCO-5-Ph-7-C1 242-247d I-Me-3-H,NCONHCO-5-Ph-7-C1 235-24Od I-Me-3-H,NC00-5-Ph-7-CI 216218
264 264 30 1 264 30 1
Et,O/Petr ether EtOAc/Et ,O MeOH PhH/Hexane MeOH MeOH Dioxane/Ligroin
Refs.
70
ir, pmr, uv
98
ir, pmr
298 490 226 302 336
1-Me-3-(3-H,NCO-l-Pyridinium)-5-Ph-7-C1 Chloride
205-207d
Acetone
273-276d 151-153 12od 199-200 120-123 151-152 180-182 135-137
Acetone EtOH MeOH CHCI,/Hexane
80
Hexane MeOH Petr ether
53
146147
CH,CI,/Petr ether
134
163-165 164165
CH,CI,/Et,O EtCOMe
134
I-Me-3-(3-Br-Propyloxy)-5-Ph-7-C1 l-Me-3-(trans-But-2-en-1-yl)-5-Ph-7-C1 4-Oxide
164-167
MeOH
334
1-Me-3-(4-H,NCO-l-Pyridinium)-5-Ph-7-C1 Chloride 1-Me-3-N3-5-Ph-7-C1 1-Me-3-N3CO-5-Ph-7-C1
l-Me-3-Eenzoyl-5-Ph-7-CI I-Me-3-(Benzoyloxy)CH~-5-(2-FC6H4)-7-C1 l-Me-3-Benzyl-5-Ph-7-Cl 4-Oxide
l-Me-3-S-Benzyl-5-Ph-7-CI l-Me-3-(4-Br-Butyl)-5-Ph-7-CI 4-Oxide
20
59
85-90
Pmr Gal, Pmr
356 33b 488 299 264 299 291 40
l-Me-3-(5-Br-Pentyl)-5-Ph-7-C1 4-Oxide
lb 30
298
l-Me-3-Bu-5-Ph-7-Cl
159-160
1-Me-3-(3-t-BuOOC-Propyl)-NHCOO-5-Ph-7-C1 157-159 l-Me-3-(3-Br-Propoxy)-5-Ph-7-CI 153-154 1-Me-3-(3-HOOC-Propanoy1oxy)-5-(2-FC6H4)-7-NOz 162- 165 1-Me-3-(3-HOOC-Propanoyloxy)CH,-5-(2-C1C6H4)7-Br 1-Me-3-(3-HOOC-trans-Propenoyloxy)CH,-5(2-C1C6H4)-7-Br (2-HO-Ethyl)Me,-ammonium salt l-Me-3-Cl-S-Ph-7-CI
1-Me-3-C1-5-(2-C1C6H4)-7-C1 1-Me-3-C1-5-(2-C1C6H4)-7-NO, 1-Me-3-C1-5-(2-FC6H4)-7-C1 1-Me-3-(CI-Acetoxy)-5<2-C1C6H4)-7-C1 1-Me-3-(C13-Acetoxy)-5-Ph-7-C1
2
l-Me-3-(4-C1-Benzoyloxy)-CH,-5-(2-FC,H,)-7-C1 l-Me-3-(4-Cl-Benzy1)-5-Ph-7-C1
1-Me-3-(4-C1C,H4)-5-Ph-7-Cl l-Me-3-CN-5-Ph-7-CI
1-Me-3-~3-(Cyclohexyl)-NH-propoxy]CO-5-Ph-7-C1 1-Me-3-13410,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-y1idene)propyllMeNC00-5-Ph-7-Cl
l-Me-3-(2-Et,N-Ethoxy)CO-5-Ph-7-C1 1-Me-3-F-5-Ph-7-Br l-Me-3-F-5-Ph-7-CI 4-0xide
299 478 324 152c
22
MeCOEt CH,CI,/Et,O
264
175-177d
133-135 98-100 108-110 217-219 240-245d 163-166 172-1 74 194-196 160-163 167-168 200-201 209-21 1
l-Me-3-(2-CN-Ethyl)-5-Ph-7-C1 4-0xide l-Me-3-(2-CN-Ethyl)-5-Ph-7-C1
Et,O/Pentane
Et,O Et,O MeCN CH,CI, CH,CI,/Hexane Et,O PhH/Petr ether
98
Hexane
60
EtOH
76
90
83 60
Pmr ir, uv Pmr
Pmr
ir, pmr
,
264 334, 356 215b 265 302 134 265, 328 334 264 299 86b 226
238-240 140-144 109-1 11
CH ,CI,/Et 0 Et,O/Petr ether Et,O
134 301 302
80-100 103-105
Et,O/Hexane EtOAc/Hexane
145-147 138-140 138-140 167-169 19&192d
EtOH Heptane Heptane MeCOEt CH,CI,/EtOH
33b 302 266 110 267 266
98
90 90
75 85
F-nmr, pmr pmr, F-nmr pmr, F-nmr F-nmr, pmr ir, pmr, F-nmr 'T-nmr
110
TABLE VII-1. dc ont d . ) ~
mp ("C) or; [bp ('Cjtorr)]
Solvent of Crystallization
1-Me-3-F-5-(2-FC,H4)-7-Br 1-Me-3-F-5-(2-FC6H,)-7-C1 1-Me-3-F3CC00-5-Ph-7-CI
204-205 127-130 91-95 209-2 11
PhH/Hexane Heptane
l-Me-3-Et-5-Ph-7-CI
180-181
l-Me-3-Et-5-(2-CIC6H,)-7-H,N 1-Me-3-Et-5-(2-C1C,H4)-7-N02 l-Me-3-Et-5-(2-FC6H,)-7-H,N 1-Me-3-Et-5-(2-CIC,H4)-7-(2-HO-Ethy1)NHCONH l-Me-3-Et-5-(2-FC6H,)-7-NO, l-Me-3-(3-Et-l-Imidazolium)-5-Ph-7-C1
198-199 161-162 185-186 177-1 8Od 175-176
Substituent
I .
2
~
~~
Yield (%)
Spectra
Refs.
60
F-nmr, pmr F-nmr, pmr F-nmr, pmr Pmr
CH,Cl,/Pentane
266 266 266 266 33b
CH2C1,/Petr ether EtOAc/Et,O EtOAc/Et,O EtOAc Acetone/Et,O EtOAc/Petr ether
23 1 23 1 23 1 301 23 1
1-Me-3-F-5-Ph-7-N02
1-Me-3-F-5-(2-C1C6H,)-7-C1
~~
50
23&233
Acetone ether
60 60
356 299
169-172 153-154
Acetone MeCOEt
70
356 324
Hydrochloride l-Me-3-(2,4-Dinitrocyclohexadien-l-yl)-5-Ph-7-CI Me,N-salt
204-206d
CH,Cl,/Acetone
1,3-Me2-5-Ph-7-C1 4-Oxide 1,3-R-Me2-5-Ph-7-C1 1,3-S-Me2-5-Ph-7-C1
110-112 185-188 48-50 47-50
Chloride
1-Me-3-(3-Et2NCO-1-Pyridinium)-5-Ph-7-C1 Chloride
1-Me-3-(3-Et2N-Propoxy)-5-Ph-7-C1 l-Me-3-(3-Et,N-Propyloxy)CO-5-Ph-7-C1
147 76
CHClJHexane EtOH Petr ether Petr ether
75 '13 85-90 85-90
ir, 'T-nmr, pmr, uv ir, pmr, uv
La1 Cal, Pmr
303 299 297 40 40
1,3-Me,-5-(2-CIC6H,)-7-H,N R( + )-Enantiomer S( -)-Enantiomer 1,3-Me,-5-(2-C1C6H,)-7-C1
1,3-Me,-5-(2-C1C,H4)-7-(2-HO-EthyI)NHCONH 1,3-Me,-5-(2-CIC,H,)-7-(4-MeC,H4SO2)NHCONH 1,3-Me,-5-(2-C1C,H4)-7-NO2 ( +)-Enantiomer ( -)-Enantiomer
1,3-Me,-5-(2,4-Cl,C,H3)-7-C1 1,3-Me,-5-(2-FC6H4)-7-Ac
1,3-Me,-5-(2-FC6H,)-7-H,N R( - )-Enantiomer .Et,O S( +)-Enantiomer. Et,O
180 218-220 219-222 130 233-237 196-200 17C174 149 152-154 158-159 65 178-180 95-11Od 10&11Od
EtOAc/Petr ether EtOH EtOH/Et,O Et,O/Ligroin Acetone/Et,O CH,CI,/EtOH Et,O/EtOH/Hexane Et,O Et,O Cyclohexene EtOAc Et,O Et,O
1,3-Me,-5-(2-FC,H4)-7-(1-H2N-Ethyl)
4
W W
48-50 122-127 69 1,3-Me2-5-(2-FC,H,>7-(2-HO-Ethyl)NHCONH 193-198 R( -)-Enantiomer > 130 S( +)-Enantiomer > 113d 1,3-Me,-5-(2-FC,H4)-7-(l-Hydroxyimino)ethy1 101-103 1,3-Me,-5-(2-FC6H,)-7-MeNHCONH 109-1 11 1,3-Me,-5-(2-FC,H,)-7-(4-MeC6H4SOz)NHCONH 229-23Od 1,3-Me,-5-(2-FC6H,)-7-MeS 137-139 1,3-Me,-5-(2,6-F,C,H,)-7-N02 186-195 137-139 1,3-Me,-5-Ph-7-(2-Me-l,3-Dioxolan-2-yl) 154-156 1,3-Me,-5-(2-FC6H,)-7-NO, 230-234 R( -)-Enantiomer 120 S( +)-Enantiomer 118-126d 1,3-Me,-5-(3-02NC6H,)-7-N0, 247-253 1,3-Me2-5-(2-Pyrimidyl)-7-C1 198-200 l-Me-3-EtNH-5-Ph-7-CI 214215 1,3-Me2-5-(2-FC,H,)-7-C1 1,3-Me2-5-(2-FC,C,)-7-( 1-HO-Ethyl)
“I Cal
MeOH
Acetone/CH,CI, EtOAc/Hexane EtOAc/Hexane Et,O/Hexane Acetone/Et 0 Et,O CH,CI,/Petr ether Hexane EtOAc/Petr ether EtOAc/Et,O Et,O/Hexane Et,O/Petr ether Acetone EtOAc MeCN
80b 301 301 301 301 301 80b 301 301 134 251 231 231 231 251 421 251b 301 301 301 251 231 301 192 152c
Cal Cal
33b 231 301 231 231 152c
lb ir, ms, pmr, uv
215b
TABLE VII-1. 4contd.)
Substituent
mp ("C) or; [bp ('C/torr)]
Solvent of Crystallization
122-123 218-22Od 222-224 148-150 122-1 24
CH,CI,/MeOH/Petr ether MeOH/Et,O/Acetone CH,CI,/Et,O EtOH Et,O
Yield (%)
Spectra
Refs.
l-Me-3-(2-EtzN-Ethyl)-5-Ph-7-CI 4-Oxide Hydrochloride l-Me-3-EtO-5-Ph-7-CI
l-Me-3-EtO(HO)CH-5-Ph-7-C1 1-Me-3-(EtO),CH-5-(2-ClC,H4)-7-Br l-Me-3-(EtO),CH-5-(2-FC6H,)-7-(2-HO-Ethyl)NHCONH l-Me-3-EtOOC-5-Ph-7-CI 4-Oxide
Amorphous 196-199 184-185 I-Me-3-(EtOOC),CH-5-(Cyclohexenl-yl)-7-C1 165-1 66 l-Me-3-(EtO),OP-S-Ph-7-C1 163-166 l-Me-3-(2-Furyl)(HO)CH-5-Ph-7-C1 213-21 5 1-Me-3-HzNNHCO-5-Ph-7-CI 208d l-Me-3-HO-5-Ph-7-AcNH > 240 l-Me-3-HO-5-Ph-7-CI 125-1 26 1-Me-3-HO-5-Ph-7-F3C 183-185 l-Me-3-HO-5-Ph-7-MeS 158-161 1-Me-3-HO-5-Ph-7-NO2 156-157 201-202 1-Me-3-HO-5-(2-C1C6H,)-7-C1 209-21 1 192-194 1-Me-3-HO-5-(2-ClC,H4)-7-NO, 225-23Od 1-Me-3-HO-5-(4-C1C6H,)-7-C1 195- 197 1-Me-3-HO-5-(2-FC6H,)-7-Ac 188-1 89 1-Me-3-HO-5-(2-FC,H4)-7-AcNH~0.5Et,0 158-160 1-Me-3-HO-5-(2-FC,H,)-7-H2N 21&212 1-Me-3-HO-5-(2-FC6H,)-7-Cl 159-161 1-Me-3-HO-5-(2-FC,H4)-7-(2-HO-EthyI)NHCONH 205-207
28
EtOH EtOH EtOH EtOAc/Hexane CH,CI,/Petr ether i-PrOH EtOH Et,O/Pentane
51,69
CH,CI,/Petr ether EtOAc/Et,O
56
THF/EtOH
81
MeOCH,CH,OH/Et,O THF/Hexane CH,CI,/Petr ether Acetone/Et,O CH,CI,/Petr ether Et,O EtOH
134 134 215 152c 314
73
55
ir, pmr
301 39 108 72c 243 192 488 251c 215 24 1 192 260 24 1 265 263 301 152c 2b 2b 152c 152c 301
I-Me-3-HO-5-(2-FC6H,)-7-I 1-Me-3-HO-5-(2-FC6H,)-7-NO, I-Me-3-HO-5-(2-Pyridyl)-7-Br 1’-Oxide
l-Me-3-HO-5-(2-Thiazolyl)-7-C1 l-Me-3-[3,4-(HO),-Benzyl]-5-Ph-7-C1 l-Me-3-(4-HO-Bemyl)-5-Ph-7-C1 1-Me-3-(2-HO-But-2-y1)-5-(2-FC6H4)-7-NO, 1-Me-3-(I-HO-Cyclohexan-l-yl)-5-Ph-7-C1 l-Me-3-(2-HO-Ethoxy)-5-Ph-7-C1 1-Me-3-HOCH2-5-Ph-7-Cl Hydrochloride 1-Me-3-HOCH2-5-(2-CIC,H,)-7-Br 1-Me-3-HOCH2-5-(2-CIC,H,)-7-Cl Hydrochloride
1-Me-3-HOCH,-5-(2-C1C6H4)-7-F 1-Me-3-HOCH,-5-(2-C1C6H4)-7-1 I-Me-3-HOCH2-5-(2-ClC6H,)-7-NO, 1-Me-3-HOCH,-5-(2-FC6H4)-7-Br 1-Me-3-HOCH,-5-(2-FC,H,)-7-C1 Hydrochloride
188-19Od 216-217 189-192 224-225d 209-21 Id 217-21 8 185-190 214-215 217-2 19 214-2 17d 198-201 182-184 176d 202-204 192-196d 229-23 1 152-155 141-143 202-2046
108 2b MeOH/Et,O THF/Hexane CHClJHeptane MeOH EtOH CHClJHexane CHCl,/Petr ether
75 85
152c 192 192 61 496 299 334 264 264 264 264 264 264 264 264 264 264
Et,O/Petr ether
PhMe
I-Me-3-HOCH,-5-(2-FC6H,)-7-(2-HO-Ethyl)NHCONH
I-Me-3-[(HO)Me,C]-5-Ph-7-C1 l-Me-3-[(HO)MePhC]-5-Ph-7-C1 I-Me-3-[(HO)PhCH]-5-Ph-7-C1 Isomer A Isomer B
I-Me-3-[(HO)Ph2C]-5-Ph-7-C1 1-Me-3-(3-HO-Propoxy)CO-5-Ph-7-C1 I-Me-3-[2,3-(HO),-Propoxy]-5-Ph-7-C1 l-Me-3-[(HO)(2-Pyndyl)CH]-5-Ph-7-C1 I-Me-3-(Imidazol-l-yl)C00-5-Ph-7-C1
2W204 165-168 216-219 17C171 172-175 218-220 20 1-204 14&148 199-202 1W192 195-197
Acetone/Et2O CHClJHexane Hexane/CH2C12 CHClJHexane CH,Cl,/Heptane CH,Cl,/Heptane CHClJHexane PhH/Hexane Et,O/Petr ether CH,Cl,/Et,O/Petr ether
16 22
44
60 98
301 299 299 299 192 192 299 302 334 192 478
TABLE VII-1. -(contd.)
Substituent
mp (“C) or; [bp (T/torr)]
Solvent of Crystallization
149-151
CH,CI,/Petr ether
199-202d
Acetone/MeOH
336-338
CH,CI,/MeOH/ether
209-2 12 153-157 227-229
Acetone EtOAc/i- Pr 0 Dioxane/Ligroin
Yield (%)
Spectra
Refs.
l-Me-3-(3-Me-But-2-en-l-yl)-5-Ph-7-C1 4-Oxide 1-Me-3-[2-Me-3-(2-Br-Ethyl)-4-NO,-l-imidazolium]5-Ph-7-CI Chloride 1-Me-3-[l-Me-l,3-Dihydro-5-(2-FC6H,)-7-C1-2-oxo2H-1,4-benzodiazepin-3-yl]-5-(2-FC6H4)-7-C1 l-Me-3-(3-Me-l-Irnidazolium)-5-Ph-7-C1 Chloride l-Me-3-MeNH-5-Ph-7-N02
I-Me-3-MeNHC00-5-Ph-7-Cl 1 -Me-3-(1 -Me- l-Aziridinium)-5-Ph-7-C1 Chloride
,
134
356
60
152c 80 56
ir, pmr
200-202
356 260 336 334
l-Me-3-(3-Me-But-2-en-I-yl)-5-Ph-7-C1 4-Oxide 1-Me-3-[(2,2-Me,-1,3-Dioxolan-4-yl)methoxy]-5-Ph7-CI 1-Me-3-(l-Me-l-Morpholinium)-5-Ph-7-C1 Chloride
149-1 51
MeOH
57
146148
Et O/Pet r ether
75
334
237-239d 223-225d
Acetone
67
356 334
Pmr
298
1 -Me-3-(1-Me-2-Et-5-[2-HO-Ethyl]- 1 -morpholinium)-
5-Ph-7-CI Chloride l-Me-3-( l-Me-3-Et-l-Morpholinium)-5-Ph-7-NO, Chloride 1-Me-3-[2-(4-Me-Pipr~n-l-yl)acetoxy]-5-(2-ClC6H~)7-CI Hydrochloride. H,O Dihydrochloride. 1.5H20
198-20 1
334
235-237d
334
27Cb27 1 >210d
MeOH/Et,O
265, 328 265, 328
Methanesulfonate 1-Me-3-(4-Me-Piperazin-l-yl)COO-5-Ph-7-C1 1-Me-3-(I-Me-l-Piperidinium)5-(2-ClC6H4)-7-Me0 Chloride l-Me-3-(1,2-Me2-Pyrimidinium)-5-Ph-7-C1 Chloride
m
8
1-Me-3-(2,2-Me,-Propanoyloxy)-5-Ph-7-C1 I-Me-3-Me2N-5-Ph-7-CI 1-Me-3-MezNCO0-5-Ph-7-C1 1-Me-3-(2-Me2N-Ethoxy)CO-5-Ph-7-C1 1-Me-3-Me,NCH,-5-(2-ClC6H4)-7-N0, l-Me-3-Me0-5-Ph-7-CI 1-Me-3-(MeO),CH-5-(2-CIC6H4)-7-Br 1 -Me-3-MeOOC-5-Ph-7-C1 1-Me-3-Me00C-5-(2-C1C6H4)-7-C1 1-Me-3-Me00C-5-(2-FC6H4)-7-1 I-Me-3-(2-MeOOC-Ethyl)-5-Ph-7-C1 4-Oxide 1-Me-3-Me00CO-5-(2-C1C6H4)-7-CI l-Me-3-(4-MeO-Benzyl)-5-Ph-7-CI
1-Me-3-(4-MeOC6H4)-5-Ph-7-C1 1 -Me-3-[3,4,5-(MeO),-Benzoyloxy]-5-Ph-7-C1 l-Me-3-[3,4-(MeO),-Bnzy1]-5-Ph-7-C1
1-Me-3-[3,4-(MeO),-ar-HO-Benzyl]-5-Ph-7-C1 l-Me-3-(MeO)(HO)OP-5-Ph-7-Cl
l-Me-3-(MeO),OP-5-Ph-7-C1 l-Me-3-MeO2S-5-Ph-7-CI
I-Me-3-Me0,S-5-(2-FC6H4)-7-C1 l-Me-3-(3-MeS03-Propoxy)CO-5-Ph-7-C1 1-Me-3-(Morpholino)acetoxy-5-(2-ClC6H4)-7-Cl Hydrochloride. H,O
l-Me-3-(Morpholino)COO-5-Ph-7-C1 l-Me-3-[2-(Morpholino)ethoxy]C0-5-Ph-7-CI
238-241 185-187
MeOH/Et,O
85
328 336
218-22od 23@-232 199-201 144-145 174-176 131-132 143-144 146-147 125-127 224-226 2 w 2 01 135-139 179-182 193-195 121-122 177-178 266-230 155-157 227-23od 171d 185-187 25G-255 224-228 138-139 237-238 2w202 167- 169
334
EtOH CH,CI,/Hexane EtOAc EtOAc/Pentane Et,O/Petr ether Et,O
88 78
CH,Cl,/MeOH MeOH CH,CI,/Hexane
91
CH,C1,/Et20 EtOAc Et ,O/Pentane
34 64
Acetone CH,Cl,/Petr ether CH,Cl,/Petr ether MeCN EtOAc/Hexane CHClJEtOH CH,Cl,/Et,O PhHiPentane
36 61
61 EtOAcIPentane
ir, pmr
ir, pmr ir, pmr
334 329 149 335 302 301 2b 314 39 108 60 298 265 299 86b 2b 192 192 243 243 152c 343 302 265 336 302
TABLE VII-1. 4contd.)
Substituent
mp ("C) or; [bp ("Cjtorr)]
Solvent of Crystallization
16S-162 172-175d 232-234
CH,Cl,/EtOAc EtzO Ace1one/Hexane
147 147 33b
16G162
CHZC1,/EtOAc
301
MeOH
134 336 490 336 23 1 23 1 231 30 1 301 30 1
Yield (%)
Spectra
Refs.
1-Me-3-[2-(Morpholino)ethoxy]CO-5-(2-C1C6H,)7-NOz Hydrochloride 1-Me-3-(Morpholin0)~PO~-5-Ph-7-C1
1-Me-3-[3-(Morpholino)propoxy]CO-5-(2-C1C,H4)7-NOz l-Me-3-(3-Oxo-but-l-yl)-5-Ph-7-C1 4-Oxide I-Me-3-(Piperidin-l-yl)COO-5-Ph-7-C1 l-Me-3-PhOOC-5-Ph-7-Cl I-Me-3-PhOC00-5-Ph-7-Cl
179-182 201-203 21 1-212d 176178 112-116 1-Me-3-Pr-542-FC,H,)-7-HzN 1-Me-3-Pr-5-(2-FC,H4)-7-(2-HO-Ethy1)NHCONH 105-110 128-130 1-Me-3-Pr-5-(2-FC,H4)-7-NO2 213-21 5 1-Me-3-i-Pr-5-(2-FC,H,)-7-HzN I-Me-3-i-Pr-5-(2-FC,H4)-7-(2-HO-Ethy1)NHCONH 125-13Od 136138 1-Me-3-i-Pr-542-FC,H,)-7-NO, 1-Me-3-(I-Pyridinium)-5-Ph-7-C1 229-23 1 Chloride 210-212 l-Me-3-(Pyrrolidin-l-yl)COO-5-Ph-7-C1 210-212 l-Me-3-i-PrO-5-Ph-7-CI 223-224 1-Me-3,5-Phz-7-C1 184-186 l-Me-3-Ph2PO,-5-Ph-7-C1 134-136 l-Me-3-(2-Pr-Pentanoyloxy)-5-Ph-7-C1 170-171 l-MeNHC0-3-AcO-5-Ph-7-Cl 155d 1-MeNHCO-3-Et00C-5-(2-C1C6H,)-7-C1 169 1-MeNHCO-3-Et00C-5-(2-FC6H,)-7-C1 224-225 I-MeNHCO-3-F-5-Ph-7-CI 174-175 l-MeNHC0-3-MeNHC00-5-Ph-7-Cl
CHzC1,/Petr ether Dioxane/EtOH Et,O EtOAc/Hexane Et,O/Pe tr ether EtzO Acetone/Et,O
Acetone
80
Et,O/Pentane PhH/MeOH EtOAc/Et,O i-PrOH EtCOMe Cyclohexane Et,O EtOH i-PrOH
65
ir, pmr, uv
82
F-nmr, pmr 70
356, 334 336 215 61 33b 326 311 275 275 266, 267 311
1-MeNHCOCH2-3-AcO-5-Ph-7-CI 1-MeNHCOCH2-3-HO-5-Ph-7-C1 1-(2-Me2N-EthyI)-3-Ac0-5-Ph-7-C1 l-(2-Me,N-Ethyl)-3-C1-5-(2-CIC,H4)-7-C1 l-(2-Me2N-Ethyl)-3-EtOOCO-5-(2-C1C,H,)-7-C1 1-(2-Me2N-Ethyl)-3-HO-5-Ph-7-C1 l-(2-Me2N-Ethyl)-3-Me0-5-(2-C1C,H,)-7-C1 l-(3-Me2N-Propyl)-3-MeO-5-(2-C1C,H,)-7-C1 Hydrochloride. H,O 1-(2-MeO-Ethyl)-3-HO-5-Ph-7-C1
l-MeOCH2-3-AcO-5-Ph-7-C1 l-MeOCH2-3-AcO-5-Ph-7-NO, 1-MeOCH2-3-allyl-5-Ph-7-Cl 4-Oxide
m
8
189-1 91 140-145 187-1 88 158-160 119-121 144146 136137
Acetone/Et,O CH ,C1 ,/Hexane CH,CI,/Petr ether Et,O/Pentane Et,O/Pentane EtOH Et,O/Pentane
115-13Od 16161 131-133 163-165
Et,O EtOAc Et,O Et 0Ac/Hexane
16
137-139
EtOH
50
1-MeOCH2-3-[(7-C1-1,3-Dihydro-l-MeOCH2-2-oxo2H-1,4-benzodiazepin-3-yl)Methyl]-5-Ph-7-CI 255-260 1-MeOCH,-3-EtO0C-5-Ph-7-H2N 218-220 1-MeOCH2-3-Et00C-5-Ph-7-C1 161-164 1-MeOCH2-3-EtOOC-5-Ph-7-N0, 156-159 l-MeOCH,-3-(3-Et2N-Propyloxy)CO-5-Ph-7-C1
2.4 15
Pmr Pmr
24
Pmr
293 293 254 288 288 2b 288 288 280 72 72
Pmr
298
CH,CI,/MeOH EtOH CH,C1,/Et20 CH,CI,/Hexane
108 108 72 108
1-MeOCH2-3-HO-5-Ph-7-NO, l-MeOCH,-3-Me-5-Ph-7-(benzyloxy)CO(Me)N
103-105d 165-167 138-139 16G162 95-98
CH,CI,/Acetone EtOH/Petr ether EtOH CH,CI,/Et,O CH,CI,/Et,O/Petr
147 72c 72 72 108
1-MeOCH2-3-Me-5-Ph-7-C1 4lOxide 1 -MeOCH2-3-Me-5-Ph-7-Me(MeO)N
133-136 148-150
EtOH MeOH/H,O
112-115
Et,O/Hexane
301
19Od 168d
Acetone/Et ,O PhH/Et,O
147 147
Hydrochloride
1-MeOCH2-3-HO-5-Ph-7-H2N 1-MeOCH2-3-HO-5-Ph-7-CI
ether 55 15
Pmr pmr, uv
277 245
1-MeOCH,-3-Me-5-(2-ClC6H4)-7-NO2
+
( )-Enantiomer
l-MeOCH2-3-(3-Morpholinopropyloxy)CO-5-Ph-7-CI Hydrochloride Methobromide
TABLE VII-I. 4 c o n t d . ) mp ("C) or; [bp ("C/torr)]
Solvent of Crystallization Et,O/EtOAc Et,O/CH,CI, i-Pr20 EtOAc Hexane
l-Ph-3-Me-5-(2-C1C6H,)-7-N0, 1- ( ~ - P ~ O - E ~ ~ ~ I ) - ~ - A C O - ~ - ( ~ - F C , H , ) - ~ - C I 1- ( ~ - P ~ O - E ~ ~ Y I ) - ~ - H O - ~ - ( ~ - F C , H , ) - ~ - C I
128-130 153d 128-130 95-97 103-105 9&92 233-235 Oil 180-181
1-(Propyn-3-yl)-3-EtOOC-5-(2-CIC6H4)-7-C1
164
l-(Propyn-3-yl)-3-EtOOC-5-(2-FC6H4)-7-C1 1-[2-(Pyrrolidin- l-yl)ethyl]-3-EtOOC-5-Ph-7-C1 1-(2-Tetrahydropyran-2-yloxy)ethyl-3-AcO-5-(2-FC6H4)-
173 126-128
Et,O EtOH EtOH
Substituent
Yield (%)
Spectra
Refs.
l-MeOCH,-3-(3-Morpholinopropyloxy)CO-5-(2-ClC6H4)7-NO2 Hydrochloride
1-[2-MeS(O)-Ethyl]-3-Ac0-5-Ph-7-C1 1-[2-MeS(O)-Ethyl]-3-HO-5-Ph-7-C1 1-[2-MeS0,-Ethyl]-3-AcO-5-Ph-7-C1 1-[2-MeSO,-EthyI]-3-HO-5-Ph-7-C1
7-CI
CH2C12/MeOH ir
147 147 234 234 234 234 391b 234 234 275 275 302
Oil
ir
234
Oil
ir
234
1-(2-Tetrahydropyran-2-yloxy)ethyl-3-HO-5-(2-FC6H,)7-CI 1,5,6,7- Tetrasubstituted
1-Me-5-(2-C1C,H,)-6-Cl-7-H2N 1-Me-5-(2-C1C,H4)-6-C1-7-(2-HO-Ethyl)NHCONH
1-Me-5-(2-C1C6H,)-6-CI-7-MeNHCONH 1-Me-542-FC,H,)-6-Br-7-H2N 1-Me-5-(2-FC6H,)-6-Br-7-(2-HO-Ethyl)NHCONH 1-Me-5-(2-FC,H4)-6-C1-7-AcNH 1-Me-5-(2-FC6H,)-6-C1-7-(Ally1)00CNH 1-Me-5-(2-FC6H,)-6-CI-7-H,N 1-Me-5-(2-FC,H6)-6-CI-7-HzNCONH
215-2 16
156-160 224-228d 252-254 155-16Od 175-176 159-162 138-140 240 234
EtOAc/CH2C12 Acetone/Et,O EtOAc/Petr ether EtOAc/CH,CI, Acetone/Et,O EtOH/Et,O Et,O/Petr ether Et,O/Petr ether EtOAc/Et ,O/Hexane CH,Cl,/Et,O
301 301 301 301 301 301 301 301 231 301
1-Me-5-(2-FC,H,)-6-C1-7-HzN(NH) CNH 1-Me-5-(2-FC,H,)-6-C1-7-(Benzyl)NHCONH 1-Me-5-(2-FC6H,)-6-CI-7-(Benzyloxy)CONH~ Et,O 1-Me-5-(2-FC6H,)-6-C1-7-(Benzoloxy)O(Me)N 1-Me-5-(2-FC6H,)-6-CI-7-(Benzyloxy)SNH 1-Me-5-(2-FC6H,)-6-Cl-7-BuNHCONH 1-Me-5-(2-FC,H4)-6-CI-7-t-BuNHCONH 1-Me-5-(2-FC,H4)-6-C1-7-BuOOCNH 1-Me-5-(2-FC,H4)-6-CI-7-(But-2-yloxy)ONH
153-155 185-187 7&80d 145-150 17&174 196-198 206-208d 160-162 174-176d 160-162 162-164 194-198d 168-172 134-138
EtOAc EtOAc/Et,O Et,O/Petr ether Et,O/Hexane Et,O/Hexane Acetone/Et,O Et,O/Hexane Et O/Hexane Et,O/Petr ether Et,O/Petr ether Et,O/Petr ether CH,Cl,/Et,O/Petr ether Et,O/Petr ether Et,O
301 301 301 301 301 231 231 301 301 301 301 301 301 301
NHCONH 276-277 I-Me-5-(2-FC6H,)-6-C1-7-(5-C1-2-Me0C6H3)NHCONH 270-274 1-Me-5-(2-FC,H,)-6-C1-7-(2-C1C6H,)NHCONH 220-222 l-Me-5-(2-FC,H,)-6-C1-7-(4-C1-C6H4)NHCONH 285 l-Me-5-(2-FC,H,)-6-C1-7-(4-C1C6H4)OOCNH 206-2 10 1-Me-5-(2-FC,H4)-6-CI-7-(CyclopentyI)CONH 224-228 l-Me-5-(2-FC6H,)-6-C1-7-[(Cyclopentyl)CO],N 170-174 1-Me-5-(2-FC6H4)-6-CI-7-EtNHCONH 155-16Od 1-Me-5-(2-FC,H,)-6-C1-7-Et2NCONH 190-191 1-Me-5-(2-FC6H,)-6-CI-7-Et(Me)NCONH 184-186 147 1-Me-5-(2-FC6H,)-.6-C1-7-EtOCSNH 1-Me-5-(2-FC6H,)-6-CI-7-EtSCSNH 178-182d
301 301 301 231 301 301 301 231 231 231 301
175-176 150-153 218-220
EtOAc EtOAc EtOAc/Et,O CH,CI,/EtOH Et,O/Petr ether CH,CI,/Et,O Et,O/Petr ether EtOAc/Et,O EtOAc/Et,O EtOAc/Et,O Et,O/CH,CI,/Petr ether Et,O/Petr ether EtOAc EtOH/Et,O Acetone
301 301 231 231
173
EtOAc/Et ,O
301
(+)-Enantiomer ( -)-Enantiomer 1 -Me-5-(2-FC6H4)-6-C1-7-(But-2-yl)SOCNH
1-Me-5-(2-FC,H4)-6-CI-7-(2-But-2-yl)SCSNH 1-Me-5-(2-FC6H,)-6-C1-7-(4-C1-Benzyl)OOCNH l-Me-5-(2-FC6H,)-6-C1-7-[6-C1-1,3-Dihydro-5(2-FC6H,)-2-oxo-2H1,4-benzodiazepin-7-yl]00
3
1-Me-5-(2-FC6H,)-6-C1-7-(Hexyl)NHCONH 1-Me-5-(2-FC6H,)-6-C1-7-(2-HO-Ethyl)NHCONH 1-Me-5-(2-FC6H,)-6-C1-7-(2-HO-Ethyl) (Me)NCONH 1 -Me-5-(2-FC6H,)-6-CI-7-[4-(2-HO-Ethyl)piprazinI-yllCONH
,
TABLE VII-I. 4contd.)
Substituent
1-Me-5-(2-FC6H,)-6-C1-7-(2-HS-Ethyl)NHCONH 1-Me-5-(2-FC6H4)-6-C1-7-( 1-Iminoeth-1-yl)NH
l-Me-5-(2-FC,H4)-6-CI-7-MeNH 1-Me-5-(2-FC6H,)-6-CI-7-MeNHCONH 1-Me-5-(2-FC6H,)-6-CI-7-MeNHCSNH 1-Me-5-(2-FC,H,)-6-CI-7-MeZNCONH 1-Me-5-(2-FC6H,)-6-C1-7-(3-Me-Butyl)NHCONH l-Me-5-(2-FC,H4)-6-C1-7-(4-MeC,H,SO,)NHCONH 1-Me-5-(2-FC6H,)-6-C1-7-(4-Me-Piperazin1-y1)CONH 1-Me-5-(2-FC,H,)-6-Cl-7-(2-MeO-Ethoxy)CONH 1-Me-5-(2-FC6H,)-6-C1-7-[2-(2-MeO-Ethoxy)thoxy]O0
%
CONH
mp ("C) or; [bp (T/torr)]
Solvent of Crystallization
168-170 198-2ood 204-206 145-16Od 194-195 17k-175 230 186 154 148-150
EtOAc/Et,O EtOAc/Et,O Et,O EtOAc/Et,O EtOAc/Et,O Et,O EtOAc/Et,O CH,CI,/Et,O EtOAc/Et,O/Hexane Et,O/Petr ether
301 301 301 23 1 30 1 301 301 301 23 1 30 1
EtOAc/Et,O/Petr ether EtOAc/Et,O CH,CI,/Et,O CH,Cl,/Hexane EtOAc/Et,O Et,O/Petr ether
301 23 1 301 301 301 301 301 301 23 1 301 301 301 30 1 301 301 301 245
106-1 10 126 17G174 148 208 18419Od Amorphous 195 13G140 162-1 66d 165 195-197d 222d 1-Me-5-(2-FC6H,)-6-MeNHCOO-7-H,N l-Me-5-(2-FC,H4)-6-MeNHCO0-7-MeNHCONH 166-170 1-Me-5-(2-FC,H,)-6-Me0-7-H2N 234 1-Me-5-(2-FC,H4)-6-MeO-7-(2-HO-Ethy1)NHCONH 166168d 204-206 l-MeOCH,-5-Ph-6-HO-7-H,N
1-Me-5-(2-FC6H,)-6-C1-7-(Morpholin-1-yl)CONH 1-Me-5-(2-FC,H4)-6-C1-7-(4-NO,-Benzyl)0OCNH 1-Me-5-(2-FC,H4)-6-CI-7-(2-0xoimidailidin1-yl) 1-Me-5-(2-FC6H,)-6-C1-7-(Pentyl)NHCONH l-Me-5-(2-FC,H4)-6-CI-7-Ph00CNH 1-Me-5-(2-FC,H4)-6-CI-7-(Piperazin1-y1)CONH 1-Me-5-(2-FC6H4)-6-C1-7-(Piperidin1-yl)CONH l-Me-5-(2-FC6H4)-6-CI-7-i-PrNHCONH l-Me-5-(2-FC,H4)-6-CI-7-i-Pr00CNH 1-Me-5-(2-FC,H4)-6-C1-7-SCN 1-Me-5-(2-FC6H4)-6-HO-7-H,N
EtOAc/Et ,O EtOAc/Hexane Et,O/Petr ether Et,O CH,CI,/EtOH EtOAc CH,CI,/EtOAc CH,CI,/EtOAc CH,CI,/Et,O CH,CI,/MeOH/Et,O
Yield (%)
Spectra
pmr, uv
Refs.
1.5.6.8- Tetrasubstituted
I-Me-5-(2-FC6H4)-6,8-C1,
193
Et,O
301
la163 185-186 215-2 18
CH,CI,/Hexane MeOH CH,CI, /Cyclohexane
152c 475 257
208-211d 1@&102 143-145 108-109 142-143 210 156-157 173-175 184 183-185
MeOH/Et,O CHCIJPentane EtOH Et,O/Petr ether EtOAc EtOAc/CH,CI, EtOAc EtOH EtOAc EtOH
1,5,?,8- Tetrasubstituted
1,5-Me2-7,8-(Me0), 1-Me-5-Ph-7,8-CI2
1-Me-5-(2-FC6H4)-7-C1-8-H,N 1,s. 7,PTetranbstitnted
1-(2-Et,N-Ethyl)-S-Ph-7,9-C1, Dihydrochloride 1-Me-5-Et0-7-C1-9-N02 1-Me-5-Ph-7,9-C12 1-Me-5-Ph-7,9-Me2 1-Me-5-(2-CIC6H4)-7,9-Br,
1-Me-5-(2-FC6H4)-7-H2N-9-C1 1-Me-5-(2-FC6H4)-7,9-Br, 1-Me-5-(2-FC6H4)-7,9-I,
1-Me-5-(2-FC6H,)-7-N02-9-C1 l-Me-5-(2-Pyridyl)-7,9-Br2
53
302 195 496 2b 475 301 475 192 301 67b
3,3,5,7- Tetrasnbrtitnted
~ - A c O - ~ - ( ~ - C I - E ~ ~ O X ~ ) C O - ~ - P ~ - ~ - C ~ 192-195 18&188 ~-AC-~-(E~O),OP-~-(~-CIC~H~)-~-CI 3-Ac0-3-Me-5-Ph-7-Cl
3-Ac0-3-Me-5-(2-C1C6H4)-7-N02 3-CN-3-Me-5-Ph-7-CI 3,3-(2-CN-Ethy1)2-5-(2-FCsH,)-7-C1 3-Et-3,5-Ph,-7-C1 3-Et2N-3-Me-5-Ph-7-C1 3-Et0-3-Et00C-5-Ph-7-Cl’O.5 EtOH 3-EtO-3-Me-5-Ph-7-Cl 3-EtOOC-3-HO-5-Ph-7-CI
179-180 2 w 2 10 23&234d 188-189 219-221 178-179 164-166 167-168 18&182 19&193
MeOH EtOAc/Hexane EtOH CH,Cl,/Petr ether EtOH Et,O Acetone/Hexane EtOH/H,O Hexane MeCN CH,CI,/EtOH
108
325 301 302 301 lb 325 101 lb 101 242
TABLE VII-1. gcontd.)
Substituent 3-EtOOC-3-MeO-5-Ph-7-Cl Hydrobromide
3,3-Me2-5-(2-CIC,H,)-7-H,N 3,3-Me,-5-(2-CIC6H,)-7-(2-HO-Ethyl)NHCONH 3,3-Me,-5-(2-C1C6H,)-7-NO, 3,3-Me2-5-(2-FC,H,)-7-Ac
3,3-Me2-5-(2-FC,H,)-7-H,N 3,3-Me2-5-(2-FC,H,)-7-CN 3,3-Me,-5-(2-FC6H4)-7-Diazonium Tetrafluoroborate 3,3-Me2-5-(2-FC,H,)-7-( 1-HO-Ethyl) 3,3-Me2-5-(2-FC,H,)-7-I 3,3-Me,-5-(2-FC6H4)-7-NO, 3-Me-3-Me0-5-Ph-7-CI
3-Me-3-Me0-5-(2-C1C6H,)-7-NO, 3,3-Tetramethylene-5-Ph-7-C1 3,3-(spiro-Adamant-2-yl)-5-Ph-7-Br 3,3-(spiro-Adamant-2-yl)-5-Ph-7-C1 3,3-(spiro-Adamant-2-yl)-5-Ph-7-Me
mp ("C) or; [bp (T/torr)]
Solvent of Crystallization
168-170 18G181 214 255 242 206 229-23 1 212
EtOH/H,O EtOAc Et O/Hexane EtOAc CH,Cl,/Hexane
203 205 202 24 1 177-178 233-234 238-240 305-307 3W302 278-280
Yield (%)
Spectra
Refs 101 101
,
EtOAc Cyclohexane
30 1 301 114 251 251 251
Cyclohexane Et,O Hexane EtOH EtOH
251 251b 251 114 Ib 30 1 35
EtOH
55
115 115 115
3,5,6,7-Tetrasubstituted
3-Me-5-(2-C1C6H,)-6-Br-7-H,N S( - )-Enantiomer
231-232
495
1w101
495
160
495
12od
49 5
3-Me-5-(2-C1C6H,)-6-Br-7-(2-HO-Ethyl)NHCONH S( +)-Enantiomer 3-Me-5-(2-ClC6H,)-6-Br-7-(3-HO-Propyl)NHCONH S( + )-Enantiomer
3-Me-5-(2-ClC6H,)-6-Br-7-(Morpholino)CONH
+
S( )-Enantiomer
3-Me-5-(2-C1C6H4)-6-CI-7-H,N.MeOH 3-Me-5-(2-C1C6H4)-6-CI-7-N02
248-250 253-254
CH,CI,/MeOH CH,CI,/MeOH
301 301
236240 215-2 18d 182-184d 213-2 14
MeOH PhH MeCN EtOH/CH,CI, Et,O
152c 225 302
188-189 199-200 239-240
Et,O EtOAc EtOAc
486 486 486
192-194 223-225 222-224 214-215 196-197 203-204 229-231
Acetone Acetone MeOH Acetone EtOAc/Et,O CH,CI,/EtOAc CH,Cl,/EtOH
35,7,9- Tetrasubstituted
3-Ac0-5-Ph-7,9-Br2 3-Ac0-5-(2-Pyridyl)-7,9-Br2 3-Et00C-5-Ph-7,9-Cl2
3-Me-5-(2-C1C,H4)-7-N0,-9-CI
30 1
5,6,7,8- Tetrasubstituted
5-Ph-6,7,8-(MeO), 4-Oxide 5-Ph-6,8-(Me0),-7-HO 5,7,8,PTetrasubstituted
Q,
r
,-
5-Cyclopropyl-7,8-Me2-9-CN 5,7,8-Me3-9-CN 5-Me-7,8,9-(MeO), 5-Ph-7,8-Me2-9-CN 5-Ph-7,8,9-(MeO), 4-Oxide 5-(2-FC6H4)-7,8-Me,-9-CN
69 91 82
75
ir, pmr
29 29 486 29 486 486 29
Pentasubstituted
1.3.3,5.7-Pentasubstituted
1-Bu-3,3-Me,-5-(2-C1C6H4)-7-H2N 155-156 1-Bu-3,3-Me,-5-(2-C1C6H4)-7-(2-HO-Ethyl)NHCONH 163-164 1-Bu-3,3-Me,-5-(2-C1C6H4)-7-NO, 129 1-Et-3,3-Me,-5-(2-C1C6H4)-7-H2N 178 1-Et-3,3-Me,-5-(2-C1C6H4)-7-(2-HO-Ethyl)NHCONH la162 1-Et-3,3-Me,-5-(2-C1C6H4)-7-N02 174 1-(2-Et,N-Ethyl)-3,3-Me,-5-(2-C1C6H4)-7-H2N 70
Et,O/Hexane Acet one/Et ,O Et,O/Hexane Et,O Acetone/Et,O Et,O EtOH/H,O
301 301 230 230 301 230 230
TABLE VII-1. --(contd.) mp ("C) or; [bp ("C/torr)]
Solvent of Crystallization
155-175d
EtOH/H,O
30 1
165-170 109 192-194
Acetone/Et,O Et,O/Hexane EtOAc/Et,O
301 230 230
1,3-Mez-3-Ac0-5-Ph-7-CI
175-176 124-125 150-152
EtOH/EtOAc Et,O/Hexane CH,CI,/Hexane
66
pmr, uv
230 230 277
1,3-Mez-3-CN-5-Ph-7-CI 1,3-MeZ-3-HO-5-Ph-7-C1
205-207 156158d
EtOH CH,CI,/Hexane
79
ir, pmr, uv
302 277
1,3,3-Me3-5-Ph-7-C1
125-128 177-178 125-127 85-110
Et,O/Petr ether Et,O/Hexane CH,CI,/EtOAc
152c 230 230 230
Acetone EtOAc/Et,O Cyclohexane
301 230 251 251 230 25 1 230 251b 251 301
Substituent
Yield (%)
Spectra
Refs.
1-(2-Et,N-Ethyl)-3,3-Me,-5-(2-ClC6H4)-7-[5-(2-ClC~H4)~ 1-(2-Et,N-Ethyl)-l,3-dihydro-3,3-Me,-2-0~0-2H-1,4benzodiazepin-7-yll NHCONH
1-(2-Et,N-Ethyl)-3,3-Me,-5-(2-CIC6H4)-7-(2-HOethy1)NHCONH
1-(2-Et,N-Ethyl)-3,3-Me2-5-(2-ClC6H4)-7-NO2 1-(2-HO-Ethyl)-3,3-Me,-5-(2-C1C6H4)-7-H,N 1-(2-HO-Ethyl)-3.3-Me,-5-(2-C1C6H4)-7(2-HO-eth yl)NHCONH
1-(2-HO-Ethyl)-3,3-Me,-5-(2-ClC6H4)-7-NO~
h,
1,3,3-Me,-5-(2-C1C,H4)-7-H,N 1,3,3-Me,-5-(2-C1C6H4)-7-NO, 1,3,3-Me,-5-(2-C1C,H4)-7-(2-H0-Ethyl)NHCONH 1,3,3-Me3-5-(2-C1C6H,)-7-(4-MeC6H,SO,)NHCONH Hydrochloride
180-185 248-250 59 1,3,3-Me3-5-(2-FC,H,)-7-( 1-AcO-Ethyl) Oil 1,3,3-Me3-5-(2-FC,H,)-7-H,N 190-191 1,3,3-Me3-5-(2-FC,H,)-7-(I-H,N-Ethyl) 50-51 1,3,3-Me3-5-(2-FC,H,)-7-(2-H~N-2-Me-propanoyl)NH 250 1,3,3-Me,-5-(2-FC6H,)-7-( 1-BuNHC00-Ethyl) 54-56 1,3,3-Me3-5-(2-FC,H,)-7-(l-HO-Ethyl) 68 1,3,3-Me,-5-(2-FC6H4)-7-(2-HO-Ethyl)NHCONH 148-150
1,3,3-Me,-5-(2-C1C,H4)-7-(Pyrrolidin-l-yI)CONH 1,3,3-Me,-5-(2-FC6H,)-7-Ac
Et,O
EtOAc/Et,O
EtOAc/Hexane
1,3,3-Me,-5-(2-FC6H,)-7-[ 1-(2-HOEthylaminocarbonylamino)ethyl] 1,3,3-Me,-5-(2-FC6H,)-7-(1-Hydroxyiminoethyl
83 199
Et,O
25 1 251
286-287
EtOAc/Et,O
230
208-214 128-129 226229 159-161 186188 213-2 15 147-149 169-172 2G204d 236238 235-238 232-234 198-1 99 137-138
Acetone/Et 0 Ph H/Hexane/Petr ether CH,CI,/Petr ether CH,CI,/EtOH
301 230 343 108
EtOH CH,CI,/Et,O/ MeOH/Et,O/Hexane
302
1,3,3-Me,-5-(2-FC6H,)-7-(4,4-Me,-2,5Dioxoimidazolidin- 1-yl)
1,3,3-Me3-5-(2-FC,H,)-7-(4-MeC6H4S02)NHCONH Hydrochloride. Et,O
1,3,3-Me3-5-(2-FC6H,)-7-N0, 1,3-Me,-3-Me0,S-5-(2-FC6H4)-7-CI l-Me-3-AcO-3-EtOOC-5-Ph-7-CI ~-M~-~-Ac-~-(E~O),OP-~-P~-~-CI l-Me-3-AcNH-3-EtOOC-5-Ph-7-CI 1-Me-3-H2N-3-EtOOC-5-Ph-7-CI
oo c
w
1-Me-3-HZN-3-MeO0C-5-Ph-7-C1 1-Me-3-H2NCO-3-EtO0C-5-Ph-7-C1 l-Me-3-H2NCO-3-Me-5-Ph-7-CI I-Me-3-H2NCO-3-MeO-5-Ph-7-CI l-Me-3-H,NC0-3-MeOOC-5-Ph-7-C1 l-Me-3-H,NCONHCO-3-EtOOC-5-Ph-7-C1 1-Me-3,3-Bu2-5-Ph-7-C1
,
i-PrOH EtOH MeCN EtOH CH,CI,/Hexane
93 72 96
ir, pmr ir, pmr ir, pmr
10
302 226 226 226 302 302 299
l-Me-3-HOOC-3-HO-5-Ph-7-CI Sodium salt l-Me-3-CN-3-CNCH2-5-Ph-7-C1
l-Me-3-CN-3-EtO-5-Ph-7-CI l-Me-3-CN-3-EtOOC-5-Ph-7-CI 1-Me-3-CN-3-Et00CCH2-5-Ph-7-CI l-Me-3-CN-3-Me-SPh-7-Cl 1-Me-3-CN-3-MeO-5-Ph-7-C1 1-Me-3,3-(2-CN-Ethyl),-5-Ph-7-C1 1-Me-3,3-Et2-5-Ph-7-C1
l-Me-3-Et0-3-EtOOC-5-Ph-7-CI 1-Me-3-EtOOC-3-HO-5-Ph-7-C1
l-Me-3-HO-3-MeOOC-5-Ph-7-CI l-MeOCH,-3-EtOOC-3-HO-S-Ph-7-C1
22&225d 181-183 165-167 146148 172-174 204-206 172-1 76d 194-196 133-136 142-1 43 174-176 208-211d 187-189
Acetone/H,O EtOH EtOH EtOH EtOH Et,O Et,O/Petr ether Et,O/Hexane EtOH/Et,O CH,CI,/MeOH EtOH
68
ir, pmr
77 78
ir, pmr ir, pmr
242 302 302 226 302 226 226 301 152c 302 242 108 72
TABLE VII-I. g c o n t d . )
Substituent
mp ("C)or; [bp ("Cjtorr)]
Solvent of Crystallization
Yield (%)
Spectra
Refs.
l-MeOCH2-3-AcO-3-Me-5-Ph-7-CI
154-157
CH,CI,/Et,O/Hexane
57
ir, pmr
277
195-196d
CH,CI,/EtOAc Et,O/Hexane CH,C1,/C1CH,CH2CI Et,O/Hexane
1 -Me-3-(3-Et2N-Propyloxy)CO-3-HO-5-Ph-7-C1
Hydrochloride
169-170 1-i-Pr-3,3-Me,-5-(2-CIC6H4)-7-H2N 243-244 1-i-Pr-3,3-Me,-5-(2-ClC6H4)-7-(2-HO-EthyI)NHCONH 197-198 1-i-Pr-3,3-Me2-5-(2-CIC6H4)-7-NO2
147 230 230 230
I , 3,5,6,7-Pent1uubstituted
I-Et-3-Me-5-(2-CIC,H,)-6-Br-7-H2N S( -)-Enantiomex
495
2W207
l-Et-3-Me-5-(2-C1C,H4)-6-Br-7-(2-H0-Ethyl)m
NHCONH S(+)-Enantiomer
495
75
1-Et-3-Me-5-(2-CIC,H,)-6-Br-7-(3-HO-Propyl)NHCONH S( + )-Enantiomer
495
118-120
l-Et-3-Me-5-(2-C1C4H,)-6-Br-7-(Morpholino)CONH S( + )-Enantiomer
1-Me-3-Et-5-(2-CIC,H4)-6-Br-7-H,N 1-Me-3-Et-5-(2-CIC,H.)-6-Br-7-(2-HO-Ethyl)NHCONH
115d 251d
CH2C12/Et20/Petrether
495 23 1
23&237
Acetone
23 1
234-235 248
Acetone/CH,CI, Et,O
301 23 1
218-222 250
Acetone/Et 2O EtOH
23 1 23 1
243-244
Acetone/Et,O
23 1
I-Me-3-Et-5-(2-C1C,H4)-6-C1-7-(2-HO-Ethyl)NHCONH
1-Me-3-Et-5-(2-FC,H4)-6-Br-7-H2N l-Me-3-Et-5-(2-FC,H4)-6-Br-7-(2-H0-Ethyl)NHCONH
1-Me-3-Et-5-(2-FC,H,)-6-C1-7-H2N 1-Me-3-Et-5-(2-FC,H4)-6-CI-7-(2-HO-Ethyl)NHCONH
1,3-Me,-5-(2-C1C6H4)-6-Br-7-H,N R( + )-Enantiomer S( -)-Enantiomex
254-256d 241-242d 241-243d
EtOAc/Et,O MeCN EtOH
231 301 301
204-206d
Acetone/Et,O Acetone/Et,O Acetone/Et,O
23 1
1,3-Me,-5-(2-C1C6H4)-6-Br-7-(2-HO-Ethyl)NHCONH R( -)-Enantiomer S( + )-Enantiomer
224-226 224-226
301 301
1,3-Me,-5-(2-CIC6H4)-6-Br-7-(3-HO-Propyl)NHCONH S( +)-Enantiomer
301
155
1,3-Me,-5-(2-C1C6H4)-6-Br-7-(2-HS-Ethyl)NHCONH.H,O.0.5 i-PrOH
200
i-PrOH
301
16&175d
Acetone/Et,O
301
210
EtOAc
301
215
EtOAc
301
144d
EtOAc
301
1,3-Me,-5-(2-C1C6H4)-6-Br-7-(4-MeC6H4SO~)NHCONH
-
1,3-Me,-5-(2-C1C6H4)-6-Br-7-(2-MeS-Ethyl)NHCONH
1,3-Me,-5-(2-C1C6H4)-Br-7-(2-M~O)S-Ethyl)NHCONH
1,3-Me,-5-(2-C1C6H4)-6-Br-7-(2-MeS0,-Ethyl)NHCONH
1,3-Me,-5-(2-C1C6H4)-6-Br-7-(Morpholino)ONH S( +)-Enantiomer 1,3-Me,-5-(2-C1C6H4)-6-Br-7-(2-Ph,CS-Ethyl)NHCONH
240
EtOH EtOAc Acetone
301 231 231
168-174 255d
Acetone/Et,O EtOAc/Et,O
301 23 1
21(3212
Acetone/Et,O
231
155-16od
Acetone/Et,O
301
240-242d 1,3-Me,-5-(2-C1C6H4)-6-CI-7-H,N 233-236d 1,3-Me,-5-(2-C1C6H4)-6-Cl-7-(2-HO-Ethyl)NHCONH 1,3-Me,-5-(2-C1C6H4)-6-Cl-7-(4-MeC6H4S0,)NHCONH
1,3-Me,-5-(2-FC6H4)-6-Br-7-H,N 1,3-Me,-5-(2-FC6H4)-6-Br-7-(2-HO-Ethyl)NHCONH
301
189-190
1,3-Me,5-(2-FC6H,)-6-Br-7-(4MeC6H4SO~)NHCONH .Acetone
TABLE VII-I. d c o n t d . )
Substituent
mp ("C) or; [bp (Tjtorr)]
Solvent of Crystallization
1,3-Me2-5-(2-FC,H,)-6-C1-7-H,N R( -)-Enantiomer S( +)-Enantiomer
224-226 222-226
Et,O EtOAc/Et 2O
1a1
147d 178-184d
EtOAc/Hexane EtOAc/Hexane CH,CI,/EtOAc
Cal Cal
163-17Od
Acetone/Et,O
301
105 195-197 124-125 164 17&175 168-169
Et,O/Hexane EtOAc/Hexane Hexane/Petr ether Et,O/Hexane Et,O/Petr ether
230 301 301 230 230 301
273
EtOAc/MeOH
301
2 13-21 4 192-193
EtOAc EtOAc
486 486
262-265
AcOH
497
1,3-Me,-5-(2-FC6H4)-6-C1-7-(2-HO-Ethyl)-
Yield (%)
C1.
Spectra
Refs. 23 1 23 1
NHCONH R( - FEnantiomer S( +)-Enantiomer
1,3-Me2-5-(2-FC,H,)-6-CI-7-MeNHCONH 1,3-Me,-5-(2-FC,H,)-6-C1-7-(4-MeC6H4S0,)00
NHCONH
1 lood
23 1 23 1 301
L
3,3,5,7,PPentasnbstituted
3,3-Me,-5-(2-C1C,H4)-7-NO,-9-C1 3,3-Me,-5-(2-FC,H,)-7-HzN-9-C1 3,3-Me2-5-(2-FC,H4)-7,9-C1 3,3-Me,-5-(2-FC,H4)-7-NO2-9-Br 3,3-Me2-5-(2-FC,H,)-7-NO,-9-C1
I,5,6.7,8-Pent~rnbstitnted
1-Me-5-Ph-6,8-C1,-7-H2N l-Me-5-Ph-6,7,8-(MeO),
l-Me-5-Ph-6,8-(MeO),-7-HO 1-Me-5-(2-C1C,H,)-6,8-Clz-7-H,N 1-Me-5-(2-FC6H,)-6,8-Br,-7-H,N 1-Me-5-(2-FC,H4)-6,8-CI,-7-AcNH 1-Me-5-(2-FC6H,)-6,8-CI,-7-H,N
228 205 129-130 198-199 186-187 213-216 198-200 234
CH,Cl,/EtOAc CH,CI,/EtOAC Cyclohexane MeOH CH,Ct,/Hexane CH,CI,/EtOAc Et,O CH,CI,/EtOAc
80b 251c 486 486 80b 301 251b 80b
Et,O Et,O Acetone Et,O Et,O Et,O
251b 80b 251b 301 80b 80b 251b
1-Me-5-(2-FC6H4)-6,8-C1,-7-[4-(2-C1-Ethyl)piperazinl-yl]CONH
c1 J
13&133
238-240 I-Me-5-(2-FC,H,)-6.8-CI,-7-F3CCONH 213 1-Me-5-(2-FC6H,)-6.8-C1,-7-(Formyl)NH 1-Me-5-(2-FC6H,)-6,8-Clz-7-(2-HO-Ethy1)NHCONH242-246d 1-Me-5-(2-FC6H4)-6,8-Cl2-7-MeNHCONH 213-214 145-147 1-Me-5-(2-FC,H,)-6,8-ClZ-7-Me~NCONH 1-Me-5-(2-FC6H,)-6,8-C1,-7-(4-Me-Piperazin-1-yl)CONH193-195 1-Me-5-(2-FC6H,)-6,8-C1,-7-[4~2-HO-Ethyl)piperazin-lyl]CONH 1-Me-5-(2-FC6H4)-6,8-C1,-7-[2-MorpholinoethylaminolCONH 1-Me-5-(2-FC6H4)-6,8-C1,-7-(PyrrolidinI-y1)CONH
80b
232-233
CH,CI,/Hexane
174176 166-167
Et,O Et,O
80b 251b
208-209
CH,CI,/Et,O
301
19Cb192
CH,CI,/Et,O
301
138-139 109-1 10
EtOAc Et,O/Cyclohexane
486 486
1,5,6,7,PPent~rubstituted
1-Me-5-(2-FC,H4)-6,9-Clz-7-H,N 1,5,6,8,PPent~substituted
1-Me-5-(2-FC6H4)-6,8,9-C13 1,5,7,8,PPentasnbstitnted
1,5-Me2-7,8,9-(Me0), I-Me-5-Ph-7,8,9-(Me0),
TABLE VII-I. g c o n t d . )
Substituent
mp ("C) or; [bp (Tjtorr)]
Solvent of Crystallization
188-189
EtOAc/Et,O
230
214218 195-196
230
254
Acetone/Et,O EtOAc/Et,O Hexane Et,O/Hexane
222d
Acetone/Et,O
301
158-16Od 217-220
Acetone/Et,O EtOAc/Et,O
301 230
202 192-1 93
EtOH/EtOAc,'Hexane Et,O/Petr sther
230 230
146147 235
Acetone/Et,O Et,O
230 301
Et,O/Hexane CH,CI,/Et,O/Hexane EtOAc/Petr ether Et,O/Hexane
301 301 301 301
EtOAc
301
Yield (%)
Spectra
Refs.
Hexasubstituted
1,3,3,5,6,7-Hexasubstituted
1,3,3-Me,-5-(2-C1C6H4)-6-Br-7-H,N 1,3,3-Me,-5-(2-C1C6H,)-6-Br-7-(2-HO-Ethyl)NHCONH
1,3,3-Me,-5-(2-C1C,H4)-6-C1-7-H,N
1,3,3-Me,-5~2-C1C,H,)-7-HzN-9-C1 1,3,3-Me,-5-(2-C1C6H4)-6-C1-7-(2-HO-Ethyl)", 00
NHCONH
230 230
1,3,3-Me,-5-(2-C1C6H4)-6-C1-7-(4-MeC6H4SOz)NHCONH
1,3,3-Me,-5-(2-FC,H,)-6-Br-7-H2N 1,3,3-Me,-5-(2-FC6H,)-6-Br-7-(2-HO-EthyI)NHCONH 1 ,3,3-Me,-5-(2-FC6H,)-6-C1-7-H,N
1,3,3-Me,-5-(2-FC6H,)-6-C1-7-(2-HO-Ethyl)NHCONH
1,3,3-Me,-5-(2-FC,H4)-6-CI-7-MeNHCONH I ~~,5,7,8-Hexasubstituted
1,3,3-Me,-5-(2-FC,H,)-7-HzN-8-C1 206-209 1,3,3-Me,-5-(2-FC,H,)-7-HzN-8-Me 214215 1,3,3-Me,-5-(2-FC,H,)-7-H~N-8-(Morpholino)S02CH~276 1,3,3-Me,-5-(2-FC6H4)-7-HO-8-Me 219-220 1,3,3-Me,-5-(2-FC,H4)-7-(2-H0-Ethyl)NHCONH8-Me
1,3,3-Me,-542-FC6H,)-7-(2-HO-Ethyl)NHCONH-
1,3,3-Me,-5-(2-FC6H,)-7-i-PrNH-8-Cl 1,3,3-Me,-542-FC6H,)-7-N02-8-Me 1,3,3-Me,-5-(2-FC,H,)-7-NO2-8-Me,NSO,CH, 1,3,3-Me3-5-(2-FC,H,)-7-N0,-8-(Morpholino)-
199-200 21G212 209-210
EtOAc/Et,O Acetone Et,O/Hexane Et,O Et,O
SO,CH, 1,3,3-~e3-~-(2-FC,H,)-7-NO,-8-(Morpholino)S0,CHCl
213-214
EtOAc
301
178-179
Et,O/Hexane/ Petr ether
301
151 125-127 156 117-120 180-183 11 1-112 188-189 145-146 121 228 227 212 125-127 100-101 113-115 15G151 168-169 167 180 237-238 146147 227
Et,O/Hexane Hexane/ether Et,O/Hexane Et,O/Hexane EtOAc/Et,O Hexane Et,O Et,O/Hexane Et,O/Hexane CH,C12/Petr ether Et,O/Petr ether Et,O Hexane Hexane Hexane Et,O/Petr ether Et,O/Hexane Hexane Et,O/Petr ether i-PrOH CH,Cl,/i-PrOH Et,O/Petr ether
230 230 230 230 301 301 301 301 230 230 301
8-morpholino)SO2CH,
23&23 1
301 301 301 301
1~~~.7,PHexlrsubstituted
oo e
\O
1-Bu-3,3-Me2-5-(2-FC6H4)-7-H2N-9-C1 1-Bu-3,3-Me,-5-(2-FC6H4).7-N0,-9-C1 1-Et-3,3-Me2-5-(2-FC4H4)-7-H2N-9-C1 1-Et-3,3-Me,-5-(2-FC6H4)7-N0,-9-C1 1-(2-Et,N-Ethyl)-3,3-Me,-5-(2-FC6H4)-7-H~N-9-Cl 1-(2-Et,N-Ethyl)-3,3-Me,-5-(2-FC6H4)-7-NO2-9-Cl 1-(2-HO-Ethyl)-3,3-Me,-5-(2-FC6H,)-7-H2N-9-C1 I-(2-HO-Ethyl)-3,3-Me,-5-(2-FC,H4)-7-NO2-9-C1 1,3,3-Me,-5-(2-CIC,H,)-7-NO2-Y -C1 1 ,3,3-Me,-5-(2-FC,H,)-7-H2N-9-Br 1 ,3,3-Me,-5-(2-FC,H4)-7-HzN-9-C1
1,3,3-Me,-5-(2-FC,H4)-7-(Benzyloxy)0NH-9-Cl
1,3,3-Me3-5-(2-FC,H,)-7-(Benzyloxy)CON(Et)-9-Cl 1,3,3-Me,5-(2-FC6H,)-7,9-C1,
1,3,3-Me3-5-(2-FC,H,)-7-BuNH-9-Cl 1,3,3-Me,-5-(2-FC6H,)-7-EtNH-9-CI 1,3,3-Me,-5-(2-FC6H,)-7-MeNH-9-Cl 1,3,3-Me,-5-(2-FC,H4)-7-Me,N-9-C1 1,3,3-Me,-5-(2-FC,H4)-7-NO2-9-Br 1,3,3-Me,-5-(2-FC,H,)-7-H2N-9-C1 1,3,3-Me3-5-(2-FC,H,)-7-NO,-9-C1 1,3,3-Me,-5-(2-FC,H4)-7-Me,N-Y-Cl
230
230 301 230 230 301 301 230 230 230 230
TABLE VII-1. 4 c o n t d . )
Substituent
mp ("C) or; [bp ('Cjtorr)]
Solvent of Crystallization
1 -Pr-3,3-Me,-5-(2-FC,H,)-7-H2N-9-C1
178-179
1-Pr-3,3-Me,-5-(2-FC6H4)-7-N02-9-CI
142-143 248-249 168
EtOAc/Et,O EtOAc/Et,O/Hexane Et,O/Hexane Et,O Et,O/Petr ether
197-198
EtOH/Et,O
213-215
Acetone/Et,O Cyclohexane/CH,CI,
1,3,3-Me,-5-(2-FC,H4)-7-(Pyrrolidin-l-yl)CONH-9-CI 218-2 19 1-i-Pr-3,3-Me,-5-(2-FC,H,)-7-H2N-9-CI
1 -i-Pr-3,3-Me,-5-(2-FC6H4)-7-NO2-9-CI
Yield (YO)
Spectra
Refs. 301
230 230 301 301
I ;1,5,6,7,8-Hexasubstiiuted
1-Me-3-Et-5-(2-FC,H,)-6,8-C1,-7-H2N 1-Me-3-Et-5-(2-FC,H,)-6,8-C12-7-(2-HO-Ethyl). NHCONH
301
212 114-115d 18O-2OOd 1 ,3-Me,-5-(2-C1C6H,)-6,8-Br2-7-(2-C1-Ethyl)NHCONH
1,3-Me,-5-(2-C1C6H,)-6,8-Br,-7-H2N S( -)-Enantiomer, EtOH
EtOH Et 0Ac/Et ,O
1,3-Me,-5-(2-CIC,H4)-6,8-Br,-7-(2-HO-Ethyl)NHCONH
222-225
195-2OOd 1,3-Me,-5-(2-C1C6H,)-6,8-Br,-7-(2-HS-Ethyl)NHCONH 1,3-Me,-5-(2-C1C,H,)-6,8-Br2-7-(2-MeS-Ethy1)NHCONH l,3-Me,-5-(2-C1C,H,)-6,8-Br2-7-(2-Me(0)S-Ethyl)NHCONH 1,3-Me,-5-(2-C1C6H,)-6,8-Br,-7-(2-MeSO2-Ethy1)NHCONH 1,3-Me,-5-(2-C1C6H,)-6,8-C12-7-H,N 1.3-Me,-5-(2-FC,H,)-6,8-C1,-7-H2N R( -)-Enantiomer S( + )-Enantiomer
EtOAc EtOAc/CH,Cl,/Et,O
234
EtOAc/Et,O
226
Acetone
259 186-1 87
Et,O/Cyclohexane CH,Cl,
165 165-166
Et,O Et,O
301 301 301 301 301 301 301 301 301 301 301 301
I~J5,7,8,PHexasubstituted
l-Ac-3-Ac0-5-Ph-7,8,9-(MeO),
156157
EtOAc
486
150
Et,O
301
I ~,6,7,8,PHexasubstituted
1-Me-5-(2-FC,H,)-6,8,9-C13-7-H,N 3;1,5,6,7,8-Hexrrsubstituted
3,3-Me,-5-(2-FC,H4)-6,8-Br,-7-H,N
255d
251b
Heptasubstituted
1,3,3-Me,-5-(2-C1C,H4)-6,8-Br,-7-H,N 1,3,3-Me,-5-(2-ClC,H,)-6,8-C1,-7-H2N 1,3,3-Me,-5-(2-FC,H4)-6,8-Br,-7-H,N 1,3,3-Me,-5-(2-FC,H,)-6,8-C1,-7-H2N 1,3,3-Me,-5-(2-FC,H,)-6,9-Cl2-7-H2N 1,3,3-Me,-5-(2-FC,H,)-7-H2N-8,9-Cl, 1,3-Me,-5-(2-ClC,H,)-6,8,9-C1,-7-H2N oo
E
S( -)-Enantiorner
110
CH,Cl,/Hexane Cyclohexane/CH,Cl,
208 190-192 169-1 72 271 227
Cyclohexane/CH,Cl, Et,O/Hexane Et,O Et,O Et,O
230 230 230 230 230 230 251b 251b
165-166
Et,O/Hexane
230
105 202
Octasubstituted
1,3,3-Me,-5-(2-FC,H4)-6,8,9-C1,-7-H2N R,,R , ; other
3-Methylene-I .3-dihydro-l.4-benzodiazepin-2 ( 2 H )-ones
H, H; 5-Ph-7-Cl H, H; 5-(2-CIC,jH,)-7-CI H, H; 1-Me-5-(2-C1C,H4)-7-C1 AcO, H; 1-Me-5-(2-C1C6H,)-7-Br HZN, H; 5-Ph-7-Cl H,N, H; 5-(2-C1C6H,)-7-Br
200-202d 163-165 155-157 244247 216218d
MeCN MeCN MeOH
63 52
Pmr ir, pmr
243 243 314 314 315
TABLE VII-1. +ontd.)
Substituent
00
N
u
H2N, H; 5-(2-CIC,H4)-7-CI H2N, H; 5-(2-C1C6H4)-7-F H2N, H; 5-(2-CIC,H4)-7-1 H2N, H; 5-(2-FC6H4)-7-CI H,N, H; l-Me-5-Ph-7-CI H,N, H; 1-Me-5-(2-C1C6H4)-7-Br H,N, H; 1-Me-5-(2-C1C6H4)-7-C1 H,N, H; 1-Me-5-(2-C1C,H4)-7-F H,N, H; 1-Me-5-(2-C1C,H4)-7-I H,N, H; 1-Me-5-(2-C1C6H4)-7-NO, (Allyl),N, H; 5-Ph-7-CI (All~l)~N H;, 5-Ph-7-NO2 (Allyl),N, H; 5-(2-C1C6H4)-7-C1 (Allyl),N, H; 5-(2-ClC,H4)-7-N02 (Allyl),N, H; 5-(2-FC,H4)-7-N02 (Allyl),N, H; 1-Me-5-(2-CIC6H,)-7-C1 (Allyl),N, H; 1-Me-5-(2-C1C6H4)-7-N02 BuNH, H; 5-(2-C1C6H4)-7-C1 BuNH, H; 5-(2-C1C6H4)-7-N0, t-BuNH, H,5-(2-C1C6H4)-7-C1 BuNH, H; I-Me-5-Ph-7-CI BuNH, H; 1-Me-5-(2-C1C6H4)-7-Br BuNH, H; 1-Me-5-(2-C1C6H4)-7-C1 BuNH, H, 1-Me-5-(2-C1C6H4)-7-N0, t-BuNH, H; 1-Me-5-(2-C1C6H4)-7-C1 BuZN, H; 5 - P h - 7 4 Bu2N, H; 5-(2-C1C6H4)-7-C1 Bu,N, H; l-Me-5-Ph-7-Cl Bu,N, H; 1-Me-5-(2-C1C6H4)-7-C1
mp ("C) or; [bp (Tjtorr)] 22G222 173-174 167-172d 275-280 Amorphous 186-189 201-204 105-1
LO
130d 14&143d 173-1 75 194-195 165-167 179-181 201-202 Amorphous 55-60
173 222-224 230 Amorphous 142-145 11G-113 90d 175-177 138-140 211-213 95-97 Amorphous
Solvent of Crystallization
Yield (%)
Spectra
Refs. 315 315
315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315
315
30 h)
w
Cyclohexyl(Me)N, H; 5-Ph-7-CI Cyclohexyl(Me)N, H; 5-(2-C1C6H,)-7-C1 Cyclohexyl(Me)N,H; 5-(2-ClC,H,)-7-NO, Cyclohexyl(Me)N, H; l-Me-5-Ph-7-Cl Cyclohexyl(Me)N, H; 1-Me-5-(2-C1C6H,)-7-CI Cyclohexyl(Me)N, H; 1-Me-5-(2-ClC,H,)-7-NO, (Cyclopropyl)NH, H; 1-Me-5-(2-CIC6H,)-7-Br EtNH, H; 5-(2-C1C6H,)-7-Br EtNH, H; 5-(2-C1C,H4)-7-Cl EtNH, H, 5-(2-C1C6H4)-7-F EtNH, H; 5-(2-C1C,H4)-7-I EtNH, H; 5-(2-C1C6H,)-7-N02 EtNH, H; 5-(2-FC6H4)-7-N02 EtNH, H,I-Me-5-(2-C1C6H,)-7-Br EtNH, H; 1-Me-5-(2-C1C6H4)-7-C1 EtNH, H; 1-Me-5-(2-C1C,H4)-7-I EtNH, H; ~ - M c - ~ - ( ~ - C ~ C , H ~ ) - ~ - N O Z EtNH, H; l-Me-5-(2-FC,H4)-7-C1 EtNH, H; 1-Me-5-(2-FC,H4)-7-NOZ EtzN, H, 5-Ph-7-Cl EtzN, H; 5-(2-C1C,H4)-7-C1 Et2N, H; 5-(2-C1C6H4)-7-N0Z EtzN, H; 1-Et-5-(2-C1C6H4)-7-C1 EtzN, H; 1-(2-M~zN-Ethyl)-5-(2-ClC~H4)-7-NOZ Et,N, H; l-Me-5-Ph-7-Cr Et,N, H; 1-Me-5-(2-C1C6H,)-7-Br Et2N, H; ~ - M c - ~ - ( ~ - C I C ~ H ~ ) - ~ - C I EtZN, H; ~ - M c - ~ - ( ~ - C I C , H , ) - ~ - N O ~ (2-Et2N-Ethyl)NH, H; 5-(2-C1C6H4)-7-C1 (2-EtZN-Ethyl)NH, H; 5-(2-ClC,H,)-7-NOZ (2-Et,N-Ethyl)NH, H; l-Me-5-Ph-7-Cl (2-Et,N-Ethyl)NH, H, l-Me-5-(2-CIC,H,)-7-C1 EtMeN, H; l-Me-5-Ph-7-CI EtMeN, H; l-Me-5-(2-ClC,H4)-7-C1
247-250 197-200 209-21 1 167-169 17G172 107-109 136-138d 227-229 21 3-21 5 138-141 2 12-2 14 260-261 240-24 1 173-1 75 122 202-206 159-1 61 151-154 175-176 23&238 204-206 208-209 Amorphous 103 192-194 131-133 135-137 148-150 Amorphous 164-165 Amorphous Amorphous 98-101 88-91
EtOH
ir
315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315
TABLE VII-1. d c o n t d . )
Substituent
oo
EtO, H; 1-Me-5-(2-ClC,H4)-7-Br (EtOOCCH,)NH, H; 1-Me-5-(2-C1C6H,)-7-Br 2-Furyl, H; 5-Ph-7-Cl 2-Fury1, H; l-Me-5-Ph-7-CI (2-Furyl)NH, H; 1-Me-5-(2-C1C6H,)-7-Br Hexahydroazepino, H; 5-Ph-7-C1 Hexahydroazepino, H; 5-(2-C1C6H,)-7-C1 Hexahydroazepino, H; 5-(2-C1C,H,)-7-N02 Hexahydroazepino, H; l-Me-5-Ph-7-Cl Hexahydroazepino, H; 1-Me-5-(2-C1C6H,)-7-Br Hexahydroazepino, H; 1-Me-5-(2-CIC6H,)-7-C1 Hexahydroazepino, H; 1-Me-5-(2-C1C6H,)-7-NO, HO, H; 5-Ph-7-Cl HO, H; 5-(2-C1C6H,)-7-Br Hydrochloride HO, H; 5-(2-C1C6H4)-7-C1 HO, H; 5-(2-C1C,H4)-7-F Hydrochloride HO, H; 5-(2-C1C6H4)-7-N02 HO, H; l-(2-Et,N-Ethyl)5-(2-ClC,H4)-7-Br Sodium salt HO, H; 1-(2,2,2-F,-Ethy1)5-(2-ClC,H4)-7-Br Hydrochloride HO, H; 1-Me-5-(2-CIC6H,)-7-Br Hydrochloride Sodium salt HO, H; 1-Me-5-(2-C1C,H4)-7-C1 Sodium salt
mp ("C) or; [bp ('C/torr)]
Solvent of Crystallization
175-176 175-177 275-277 169-1 7 I 81-83 248-250 238-239 2 17-21 8 196-198 14G-142 Amorphous 98-105 155-157
Et,O
Yield (%)
52 Et,O/Petr ether
Spectra
ir
Refs. 314 315 304 192 315 315 315 315 315 315 315 314
205d 117-123d
314 314
> 120d 21 3-21 9d
314 314
155-165d
314
175-177d 137-139d 185-1 87d > 260d 117-123d 183-1 84d
314 314 314 314 314 314
THF/Et,O
m
N
111
HO, H; l-Me-5-(2-C1C6H4)-7-I Sodium salt.H,O HO, H; 1-Me-5-(2-C1C6H4)-7-N02 Sodium salt HO, H; 1-Me-5-(2-FC6H,)-7-Br Sodium salt HO, H; 1-Me-5-(2-FC6H4)-7-CI Sodium salt (2-HO-Ethyl)NH, H; 5-Ph-7-Cl (2-HO-Ethyl)NH, H; 5-(2-C1C6H,)-7-C1 (2-HO-Ethyl)NH, H; 1-Me-(2-C1C6H4)-7-CI (2-HO-Ethyl)NH, H; l-Me-5-Ph-7-CI MeO, H; 1-Me-5-(2-C1C6H,)-7-Br MeNH, H; 5-Ph-7-Cl MeNH, H; 5-Ph-7-NO, MeNH, H; 5-(2-ClC,H4)-7-Br MeNH, H; 5-(2-C1C6H,)-7-C1 MeNH, H; l-Me-5-Ph-7-Cl MeNH, H; 1-Me-5-(2-C1C6H4)-7-C1 Me,N, H; 5-Ph-7-CI Me2N, H;5-Ph-7-NOZ Me,N, H; 5-(2-C1C6H,)-7-Br Me,N, H; 5-(2-C1C6H4)-7-C1 Me2N, H; 5-(2-C1C6H4)-7-F Me,N, H; 2-(2-C1C,H4)-7-I M c ~ NH; , 5-(2-C1C6H,)-7-N02 MeZN, H; 5-(2-FC,H4)-7-N0, Me,N, H; 1-(Cyclopropy1)methyl-5-(2-ClC6H4)-7-C1 Me,N, H; 1-(2,2,2-F,-Ethyl)-5-(2-CIC6H4)-7-Br Me2N, H; I-Me-5-Ph-7-Cl Me2N, H;l-Me-5-Ph-7-N02 Me2N, H; 1-Me-5-(2-C1C6H,)-7-Br Me2N, H; 1-Me-5-(2-CIC,H4)-7-C1 Me2N, H; 1-Me-5-(2-C1C6H4)-7-F
115-125d 287-294d 149-151d 21 5-21 7d
314 314 314 314
18G19Od
314
> 220d 228-230 231-233 155-1 57 Amorphous 203-205 210 247-249 157-158 225 201-202 155-158 237-240 2-264d 22G223 239-241 21G211 227-230 241d 243-244d 188-1 90 216217 204-205 228-230 198-199 202-203 177-1 79
314 315 315 315 315 314 315 152c 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315
DMF/MeOH
MeOH
i-PrOH
TABLE VII-I. gc ont d . ) mp ("C) or; [bp ('C/torr)]
Substituent ~
00 h) o\
~~~
Solvent of Crystallization
Yield (YO)
Spectra
Refs.
~~
Me,N, H, 1-Me-5-(2-C1C6H,)-7-I Me,N, H; 1-Me-5-(2-C1C6H,)-7-NO, Me,N, H; 1-Me-5-(2-FC6H,)-7-Br Me,N, H; 1-Me-5-(2-FC6H,)-7-C1 Me,N, H; 1-Me-5-(2-FC,H,)-7-NOz Me,N, H; 1-(2-Me,N-Ethyl)-5-(2-C1C6H,)-7-C1 Me(2-Me2N-ethyl)N, H,5-Ph-7-NO2 Me(2-Me,N-Ethyl)N, H, 5-(2-C1C6H,)-7-C1 Me(2-Me2N-Ethyl)N, H;1-Me-5-(2-C1C,H4)-7-C1 Me(MorpholinocarbonyI)methylamino, H; 1-Me-5(2-C1C,H4)-7-Br Me(Ph)N, H; 1-Me-5-(2-C1C,H4)-7-C1 Me(Ph)N, H; 1-Me-5-(2-C1C6H,)-7-NO, 4-Me-Piperazino, H; 5-(2-C1C,H4)-7-C1 4-Me-Piperazino, H; l-Me-5-Ph-7-Cl 4-Me-Piperazino, H; 1-Me-5-(2-C1C6H,)-7-C1 (2-Me-Prop-l-en-l-y1), H; l-Me-5-Ph-7-Cl Morpholino, H, 5-Ph-7-Cl Morpholino, H; 5-Ph-7-NO2 Morpholino, H; 5-(2-C1C6H,)-7-Br Morpholino, H; 5-(2-C1C,H4)-7-C1 Morpholino, H; 5-(2-C1C6H,)-7-F Morpholino, H; 5-(2-C1C,H4)-7-I Morpholino, H, 5-(2-C1C6H4)-7-NO, Morpholino, H; 5-(2-FC6H,)-7-NO, Morpholino, H; 1-(cyclopropyl)CH,-5-(2-ClC6H4)-7-C1 Morpholino, H; l-Me-5-Ph-7-CI Morpholino, H; 1-Me-5-Ph-7-N02 Morpholino, H; 1-Me-5-(2-C1C6H,)-7-Br
182-1 84 182-183 172-173 157-159 193-195 Amorphous 2w202 202-205 13Ck132 2w202 197-199 183-184 194-196 141-143 Amorphous 163-166 251-252 243-245d 156185d 209-21 1 243-246d 218-221 246-248 246-249d Amorphous 169-1 71 211-212 148-153
315 315 315 315 315 315 315 315 315 THF
CH,Cl,/Petr ether
45
ir, pmr,
UY
315 315 315 315 315 315 298 315 315 315 315 315 315 315 315 315 315 315 315
00
3
Morpholino, H; 1-Me-5-(2-C1C,H4)-7-C1 Morpholino, H; 1-Me-5-(2-C1C,H4)-7-F Morpholino, H; 1-Me-5-(2-61C6H,)-7-l Morpholino, H; 1-Me-5-(2-C1C,H,)-7-N02 Morpholino, H; 1-Me-5-(2-FC6H,)-7-C1 Morpholino, H; 1-Me-5-(2-FC,H,)-7-NOz Ph, H; 5-Ph-7-CI Ph, H; 5-Ph-7-Me Ph, H; l-Me-5-Ph-7-Cl Ph, H, 5-(2-C1C6H4)-7-C1 4-AcO-3-MeOC6H,, H; 5-Ph-7-Cl 4-ClC6H4, H; 5-Ph-7-Cl 4-Me2NC,H,, H; 5-Ph-7-Cl 3,4-(MeO),C,H,, H; l-Me-5-Ph-7-CI 2-N02C6H4,H; 5-Ph-7-CI 4-NOzCsH4, H; 5-Ph-7-CI 4-iPrC,H,, H; 5-Ph-7-CI Piperidino, H; 5-Ph-7-Cl Piperidino, H; 5-(2-C1C,H4)-7-C1 Piperidino, H, 5-(2-CIC6H,)-7-NO, Piperidino, H; 1-(2-Me,N-ethyl)-5-(2-ClC,H,)-7-N02 Piperidino, H; 1-Me-5-Ph-7-Cl Piperidino, H; 1-Me-5-(2-C1C6H,)-7-C1 Piperidino, H; 1-Me-5-(2-C1C6H,)-7-NO, Piperidino, H; I -Me-5-(2-CIC6H,)-7-Br PrNH, H; 5-(2-C1C6H,)-7-C1 PrNH, H; 1-Me-5-(2-C1C,H4)-7-C1 Pr,N, H; 5-Ph-7-Cl Pr,N, H; 5-(2-C1C,H4)-7-C1 Pr,N, H; 5-(2-C1C6H,)-7-NO, Pr,N, H; l-Me-5-Ph-7-Cl Pr,N, H; 1-Me-5-(2-C1C,H4)-7-C1 Pr,N, H; 1-Me-5-(2-C1C6H,)-7-NO, i-PrNH, H; 5-(2-C1C,H4)-7-C1
158-160 110-115 193-195 102- 105 172-174 187-188 235 210 189-191 230-232 198-200 220-222 248-249 125-128 260-261 284 222-223 242-243 245-248 d 235-236 103-106 158d Amorphous
139-141 176178 186 146147 2 W 2 01 226-227 241-242 134-135 13G-132 71-75 188-19 1
MeOH CH,CI,/Hexane
40 55 67
ir, ms, uv ir
43 36 48
ir ir
53 42 40
ir ir
EtOH
315 315 315 315 315 315 304 304 298,299 192 304 304 304 192 304 304 304 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315 315
TABLE VII-1. g c o n t d . ) Substituent
mp ("C) or; [bp ('C/torr)]
i-Pr,N, H; iPr,NH; 5-Ph-7-CI 248-250 i-Pr,N, H; 5-(2-CIC6H4)-7-C1 222-224 i-Pr,N, H; 5-(2-C1C6H4)-7-N02 211-213 i-Pr,N, H; l-Me-5-Ph-7-CI Amorphous i-Pr,N, H; 1-Me-5-(2-C1C6H4)-7-C1 147-149 i-Pr,N, H; 1-Me-5-(2-C1C6H4)-7-N02 156-158 3-Pyridyl, H; l-Me-5-Ph-7-CI 149-1 5 1 Pyrrolidino, H; 5-Ph-7-Cl 252-254 Pyrrolidino, H; 5-(2-C1C6H4)-7-C1 247-249 Pyrrolidino, H; 5-(2-C1C6H4)-7-N02 251-252 Pyrrolidino, H; l-(2-Me,N-ethyl)-5-(2-C1C6H,)-7-N0, 209-21 0 Pyrrolidino, H; l-Me-5-Ph-7-Cl 184186 181-183 Pyrrolidino, H; 1-Me-5-(2-C1C,H4)-7-C1 Pyrrolidino, H; 1-Me-5-(2-C1C6H4)-7-N0, 184-185 139-141 Pyrrolidino, H; l-(2-MezN-ethyl)-5-Ph-7-CI Pyrrol-2-yl, H; 5-Ph-743 25G252 223-226d Pyrrol-2-yl, H; l-Me-5-Ph-7-CI 252-254 Thien-2-yl, H; 5-Ph-7-Cl Thiomorpholine, H 1-Me-5-(2-C1C,H4)-7-C1 Amorphous S-Oxide 185-1 9 Id
Solvent of Crystallization
Yield (YO)
Spectra
Et,O/Petr etheI
47 CHCl,/Petr ether
I .3-Dihydro- I ,I-benzodiazepin-2( 2 H )-1hiones
40
ir ir
Refs. 315 315 315 315 315 315 192 315 315 315 315 315 315 315 315 304 192 304 315 315
Monosubstituted
5-Ph 5-(2-C1C6H4)
100, 255 416 419
256-257 234-235 228-229
EtOH CH,CI,/EtOH EtOH
18 1-1 82 133-136 166167
MeOH EtOH MeOH
255 255 301
221-223
CHCIJHexane
478
205-206 255-256 244246 238-239 215-217 223d 228-229 234236 260-261 250-253 222-224 2 10-2 12d 209-2 14 211-212d 251-253 242-244 219-221d 245-241 229-232 2 1Ck215d
EtOAc EtOH EtOH
40
34 78
Disubstituted
I-Me-5-(4-CIC6H,) I-Me-5-(2-F,CC,H4)
1-(Me00CCH2)-5-(2-C1C6H4) 5,6- Disubstituted
5-Ph-6-CI 5,7-Disubstituted
m -~
5-Me-7-Cl 5-Ph-7-Br 5-Ph-7-CI
h \D )
5-Ph-7-Et
5-Ph-7-1 5-Ph-7-Me 5-Ph-7-Me2N 5-Ph-7-Mes 5-Ph-7-NO2
5-(2-CIC,H,)-7-N0, 5-(2-C1C,H4)-7-Me 5-(2-FC6H4)-7-C1 5-(2-FC,H,)-7-Et
MeCN CH,CI, /EtOH CH,CI,/EtOH THF/Hexane EtOH EtOH EtOH i-PrOH EtOH CH,Cl,/EtOH EtOH EtOH CH,CI, /EtOH EtOH EtOH
417
57 53 12
64
25 57 78 66 73
100,255 100, 255 418 33b 24 416 33b 255 255 255 416 255 416 255 418 416 255 255,416 33b
TABLE VII-I. 4 c o n t d . ) mp ("C) or; Substituent
[bp ("C/torr)]
Solvent of Crystallization
5-(2-FC6H,)-7-I 5-(2,6-F2C6H3)-7-C1 5-(2-MeOC6H,)-7-C1 5-(3-MeOC6H,)-7-C1 5-(2-Pyridyl)-7-Br
226-229 222-224 222-224 225-236d 245-246d
MeCN EtOH/H,O EtOH MeOH EtOH
l-(2-EtzN-Ethyl)-5-(2-FC,H,)-7-C1 Hydrochloride I-F3CCH2-5-Ph-7-C1
98-100 223-225 169-170
MeOH MeOH/Et,O CH,C1,/
415 415 422a
1-F3CCH2-5-(2-FC6H4)-7-C1 I-Me-5-Ph-7-Cl 1-Me-5-Ph-7-Me2N 1-Me-5-(2-C1C6H,)-7-C1 1-Me-5-(2-C1C,H4)-7-NO, 1 -Me-5-(2-FC6H,)-7-H,N 1-Me-5-(2-FC6H,)-7-C1
137-1 39 162- 164 185-187 16G-163 204-206 255-257d 144146 153-16Od 22&226d 144-146
CH,CI,/Hexane EtOH EtOH PhH/Hexane MeOH CH,CI, EtOH EtOAc/Et,O CH,CI,/Et,O Et,O/Petr ether EtOH Et,O MeOH
422a 255 255 255 415 301 255c 301 30 1
Yield (%)
Spectra
74 80 uv
Refs. 33b 24,416 255 313 417
Trisubstituted 1,5,7- Trisubstituted
1-Me-5-(2-FC6H,)-7-MeNHCONH I-Me-5-(2-FC,H,)-7-NO,
I-(2-CN-Ethyl)-5-(2-FC,H,)-7-C1 1-(2-Me,N-EthyI)-5-(2-C1C,H4)-7-CI 1-(Me00CCH2)-5-Ph-7-CI
1-(Me00CCH2)-5-(2-C1-C,H,)-7-C1
128-130 188-189 193-1 94
67
ir, pmr
301 179 30 1 301
3,5,7-Trisuhstituted
3-(Benzyloxy-C00)-5-Ph-7-C1 3-Me-5-(2-CIC,H,)-7-NOz ( + )-Enantiomer ( - )-Enantiomer 3-Me-5-(2-FC,H4)-7-NOz ( +)-Enantiomer
3-(2-Me-l-PropyI)-5-Ph-7-CI
113d 260 258-260 250
CH,CI,/EtOH CH,CI,/Petr ether CH,CI,/EtOH/Hexane
250d 17G171
EtOH
43
104-109 in6188
Et,O/Petr ether Et,O/Petr ether
58
250d 165-170d
EtOAc/Et,O EtOAc/Et,O
Cal 1a1 1a1
425 301 19 301 79 109
Tetrasuhstituted 1,3,5,7- Tetrusubstituted
1,3-Me2-5-(2-FC,H,)-7-C1 1-Me-3-(2-CN-Ethyl)-5-Ph-7-C1
343 301
I ,5,6,7-Tetrusuhstituted
1-Me-5-(2-FC,H4)-6-CI-7-H,N oo
z
1-Me-5-(2-FC,H4)-6-C1-7-MeNHCONH
301 301
I .5-Dihydro- I ,I-benzodiazepin-2 ( 2 H )-ones
Disuhstituted 5,P-Disubstituted
5-Ph-7-AC 5-Ph-7-CI
2 w 2 01 202-210 215-217 248-250
CH,CI,/Petr ether CH,Cl,/Hexane
35 ir, pmr, uv
32 170 455 455
TABLE VII-1. 4 c o n t d . )
Substituent
mp ("C) or; [bp ("C/torr)]
Solvent of Crystallization
191-195
CH,Cl,/Hexane
197-199 249-251d 282-284
EtOAc/i-Pr,O MeOH EtOH
188 205d
Yield (%)
Spectra
Refs.
Trisubstituted 15.7- Trisubstituted
1-Me-5-(2-FC6H,)-7-I
141. 175
35.7- Trisubstituted 00 W h)
3-MeNH-5-Ph-7-Cl 3-Me0-5-Ph-7-Cl 3-Me0-5-(2-C1C6H,)-7-C1
31 75
ir, pmr ir, pmr Pmr
260 260 457
i-Pr,O CH,Cl,/Et,O
68 92
ir, pmr ir
260 260
148-150 211-213 193-194 179-180
Cyclohexane EtOAc CH,Cl,/Hexane Cyclohexane
46 84 88
Pmr ir, pmr ir, pmr ir, pmr
45 7 260 149 45 7
146-147 163-164
Et,O CH,Cl,/i-Pr,O
61 14
ir ir, pmr
260, 456 260,456
5.5.7- Trisubstituted
5-Me0-5-Ph-7-Cl 5-Me0-5-Ph-7-NO2 Tetrasubstituted 1,3,5,7-Tetrasubstituted
1-(2-Et,N-Ethyl)-3-MeO-5-(2-ClC6H4)-7-C1 1-Me-3-MeNH-5-Ph-7-N02 l-Me-3-MeZN-5-Ph-7-C1
1-Me-3-Me0-5-(2-C1C6H,)-7-C1 155.7-Tetrasubstituted
l-Me-5-MeO-5-Ph-7-Cl l-Me-5-MeO-5-Ph-7-N02
5-Methylene-l,S-dihydro-l .I-benzodiazepin-2-(2H)-ones
Acetone
218
None
51
224
I ,2-Dihydro-I .I-benzodiazepin-jl(3H)-ones 9
H
p J - - ( I -N
00 W W
5
2,2-Me2-5-Ph Conformer A Conformer B
195-197 193-195
ir ir
459 459
43
ir, pmr
70
ir, pmr
460,461 462 463
4.5-Dihydro-I .I-benzodiazepin-3(3H)-ones
NH
None 2-Et-5-Ph 2-(4-NO2C,H,)-4-t-Bu-9-Me
m W
8 34
w
car-mm W W W W
d d d d
w w
2-Ph-4-Me 2-Ph-4-i-Pr 2-(2-Ph-Ethyl)NH-4-Me 2-MeNH-7-C1 2-Me(NO)N-7-C1 2-MeOOCC(NOH)-7-C1 2-Ph-7-C1 2-(4-C1C6H,)-4-Me 2-(4-MeC6H,)-4-Me 2-H2N-3-Ph-4-Me 2-(2-Me2N-Ethy1)NH-3-Ph-4-Me Dihydrochloride~0.5H,O 2-MeS-3-Ph-4-Me 2-(2-Ph-Ethyl)NH-3-Ph-4-Me 2-BenzyIamino-4-Me-7-Cl 2-(2,6-C1,C6H,)NH-4-Me-7-Cl 2-[2-(3,4-[Benzyloxy],-C6H,)ethyl]amino-4-Me-7-C1 Hydrochloride
133-135 138-139 15C151 246249d 193-195 189-191 16C-162 186187 172-1 74 282-286
MeOH MeOH EtOAc MeOH Et,O THF/Hexane Xylene MeOH MeOH EtOH/Et,O
90
ir
468 468 47 1 469 134 134 465 468 468 47 1
246-25Od 13&132 173-175 158-160 247-250
EtOAc/Et,O EtOAc i-PrOH/MeOH
471 471 47 1 47 1 47 1
158-162
EtOH/Et,O
47 1
2-MeNH-4-(Morpholino)2-PO-7-C1
179-18Od 22C-222 177-179 236-238
EtOH/Et,O MeCOEt/Et,O EtOH/Et,O MeCN
471 47 1 47 1 344
2-(3-Me2N-Propyl)NH-4-Me-7-C1 Dih ydrochloride 2-MeS-4-Me-7-Ci 2-Ph-3,4-Me2 2-Ph-4-Me-7-Br 2-Ph4Me-7-Cl 2-Ph-4,7-Me2 2-Ph-4-Me-8-Br 2-Ph-4-Me-8-Cl
261-264d 124127 106-108 144-146 156-157 165-166 145- 146 133-134
MeOH MeOH/H,O MeOH MeOH MeOH
2-[2-(3,4-[H0],C,H3)-Ethyl]amino-4-Me-7-CI Hydrochloride.O.5MeOH 2-[2-(Indol-3-yl)ethyl]amino-4-Me-7-C1 2-[2-(3,4-[Me0],C,H3)Ethyl]arnino-4-Me-7-C1
MeOH MeOH MeOH
80
ir, ms, pmr, uv
47 1 471 468 468 468 468 468 468
TABLE VII-1. +ontd.)
Substituent 2-(2-Ph-Ethyl)NH-4-Me-7-C1 2-H2N-3-Ph2-Ph-4-Me-7,8-(MeO),
mp ("C) or; [bp ('Cjtorr)]
Solvent of Crystallization
196-198
EtOH/Et,O
47 1
157-159
MeOH
468
Yield (YO)
Spectra
Refs.
1H- 1,4-Benzodiazepin-2,3(2H,3H)-diones
5-Ph-7-CI 5-(2-C1C6H4)-7-C1 l-Me-5-Ph-7-Cl 1-Me-5-(2-C1C6H4)-7-C1
248-25ld 258d 169-1 74 204-206
CH,Cl,/Petr ether MeCN CH2C12/Hexane EtOAc
57 43 45 21
ir, pmr
157, 158 243 157, 158 243
17
pmr, uv
245a
ir, pmr
1,4-Benzodiazepinetriones ,OMe
2 19-22Od
CH2C1,/MeOH/Et20
11. References
837
11. REFERENCES 1. (a) A. Stempel, I. Douvan, and L. H. Sternbach, J . Org. Chem., 33,2963 (1968). (b) A. Stempel, unpublished data, Hoffmann-La Roche, Nutley, NJ. 2. (a) L. H. Sternbach, R. Ian Fryer, W. Metlesics, E. Reeder, G. Sach, G. Saucy, and A. Stempel, J. Org. Chem., 27, 3788 (1962). (b) L. H. Sternbach, unpublished data, Hoffmann-La Roche, Nutley, NJ. 3. R. Ian Fryer, R. A. Schmidt, and L. H. Sternbach, J . Pharm. Sci., 53, 264 (1964). 4. G. Saucy and L. H. Sternbach, Helu. Chim. Acta, 45, 2226 (1962). 5. L. H. Sternbach, G. Saucy, F. A. Smith, M. Mueller, and J. Lee, Helu. Chim. Acta, 46, 1720 (1963). 6. L. H. Sternbach and G. Saucy, U S . Patent 3,341,592, September 1967. 7. 0. Keller, N. Steiger, and L. H. Sternbach, U S . Patent 3,121,103, February 1964. 8. J. V. Earley, R. Ian Fryer, and R. Y. Ning, J . Pharm. Sci., 68, 845 (1979). 9. R. V. Davis and R. Ian Fryer, US.Patent 4,083,948, April 1978. 10. S. A. Andronati, A. V. Bogat-skii, G. N. Gordiichuk, Z. I. Zhilina, and L. M. Yagupol'skii, Chem. Heterocycl. Comp., 11, 230 (1975). 11. R. Y. Ning and L. H. Sternbach: (a) U.S. Patent 3,686,308, August 1972, (b) US. Patent 3,823,166, July 1974. 12. A. Focella and A. I. Racblin, U S . Patent 3,335,181, August 1967. 13. (a) R. Kalish, T. V. Steppe, and A. Walser, J. Med. Chem., 18, 222 (1975), (b) R. Kalish, unpublished data, Hoffmann-La Roche, Nutley, NJ. 14. N. W. Gilman and L. H. Sternbach, J . Heterocycl. Chem., 8, 297 (1971). 15. G. Saucy, F. A. Smith, and L. H. Sternbach, U.S. Patent 3,329,701, July 1967. 16. L. H. Sternbach and A. Stempel, US. Patent 3,336,295, August 1967. 17. W. J. Houlihan, US. Patent 3,609,146, September 1971. 18. French Patent 1,391,752, February 1965 (Etablissements Clin-Byla, France). 19. A. Bauer, K.-H. Weber, P. Danneberg, and K. Minck, U.S. Patent 3,786,051, January 1974. 20. M. Zinic, D. Kolbah, N. Blasevic, F. Kajfez, and V. Sunjic, J . Heterocycl. Chem., 14, 1225 (1977). 21. Yu. S. Shabarov, T. P. Surikova, and S. S. Mochalov, Chem. Heterocycl. Compd., 10,498 (1974). [Khim. Geterotsikl. Soedin., 572 (1974)l. 22. Belg. Patent 619,101, December 1962 (Hoffmann-La Roche & Co. AG, Switzerland). 23. T. L. Lemke, J. B. Hester, and A. D. Rudzik, J. Pharm. Sci., 61, 275 (1972). 24. (a) J. B. Hester, Jr., U.S. Patent 3,701,782, October 1972. (b) J. B. Hester and A. R. Hanze, U S . Patents 3,933,794, January 1976; 3,917,627, November 1975; 3,927,016, December 1975. 25. E. Wolf, H. Kohl, and G. Haertfelder, US. Patent 3,849,559, November 1974. 26. G. F. Field and L. H. Sternbach: (a) Swiss Patent 561,706, May 1975, (b) Swiss Patent 562,222, April 1975. 27. Ger. Offen. 2,223,648, November 1972 (Hoffmann-La Roche & Co. AG, Switzerland). 28. G. A. Archer, R. I. Kalish, R. Y. Ning, B. C. Sluboski, A. Stempel, T. V. Steppe, and L. H. Sternbach, J. Med. Chem., 20, 1312 (1977). 29. A. A. Fatmi, N. A. Vaidya, W. B. Iturrian, and C. DeWitt Blanton, Jr., J. Med. Chem., 27, 772 (1984). 30. G. M. Clarke, J. B. Lee, F. J. Swinbourne, and B. Williamson, J. Chem. Res. (S), 398 (1980). 31. A. Ziggiotti, G. Riva, and F. Mauri, U.S. Patent 3,852,270, December 1974. 32. Belg. Patent 777,098, June 1972 (Hoffmann-La Roche & Co. AG, Switzerland). 33. (a) R. Y. Ning and L. H. Sternbach, U.S. Patent 3,682,892, August 1972. (b) R. Y. Ning, unpublished data, Hoffmann-La Roche, Nutley, NJ. 34. S. C. Bell and S. J. Childress, US. Patent 3,714,145, January 1973. 35. S. C. Bell, T. S. Sulkowski, C, Gochman, and S. J. Childress, J . Org. Chem., 27, 562 (1962). 36. T. Sugasawa, M. Adachi, T. Toyoda, and K. Sasakura, J. Heterocycl. Chem., 16, 445 (1979).
838
D i h ydro- 1,4-Benzodiazepinones and Thiones
37. H. Moriyama, H. Yamamoto, S. Inaba, H. Nagata, T. Tamaki, and T. Hirohashi, US. Patent 3,524,848, August 1970. 38. (a) M. E. Derieg, R. M. Schweininger, and R. Ian Fryer, J. Org. Chem., 34, 179 (1969).(b) M. E. Derieg, unpublished data, Hoffmann-La Roche, Nutley, NJ. 39. A. Walser, A. Szente, and J. Hellerbach, J . Org. Chem., 38, 449 (1973). 40. V. Sunjic, F. Kajfez, I. Stromar, N. Blasevic, and D. Kolbah, J . Heterocycl. Chem., 10, 591 (1973). 41. Neth. Patent 7,207,637, December 1972 (Sumitomo Chemical Co., Ltd., Japan). 42. R. Ian Fryer, W. Leimgruber, and E. J. Trybulski, J . Med. Chem., 25, 1050 (1982). 43. N. W. Gilman, P. Levitan, and L. H. Sternbach, J . Org. Chem., 38, 373 (1973). 44. Belg. Patent 778,191, May 1972 (Grindstedvaerket, Denmark). 45. Neth. Patent 7,117,351, June 1972 (Sumitomo Chemical Co., Ltd., Japan). 46. J. Ackrell, E. Galeazzi, J. M. Muchowski, and L. Tokes, Can. J . Chem., 57, 2696 (1979). 47. Ger. Offen. 2,504,937, August 1975 (Specta International B.V., Netherlands). 48. N. Blasevic and F. Kajfez, J . Heterocycl. Chem., 7, 1173 (1970). 49. Z. Vejdelek, M. Rajsner, E. Svatek, J. Holubek, and M. Protiva, Collect. Czech. Chem. Commun., 44, 3604 (1979). SO. G. 0. Chase, unpublished data, Hoffmann-La Roche, Nutley, NJ. 51. G. M. Clarke, J. B. Lee, F. J. Swinbourne, and B. Williamson, J . Chem. Res. (S), 399 (1980);400 (1980). 52. G. 0. Chase, U S . Patent 3,886,141, May 1975. 53. G. 0. Chase, US. Patent 3,996,209, December 1976. 54. W. Schlesinger, U S . Patent 4,155,904, May 1979. 55. Belg. Patent 871,280, February 1979 (KRKA, Yugoslavia). 56. S. C. Bell, R. J. McCaully, and S. J. Childress, J . Heterocycl. Chem., 4, 647 (1967). 57. S. C. Bell, U.S. Patent 3,401,200, September 1968. 58. S. C. Bell, US. Patent 3,458,501, July 1969. 59. R. J. McCaully: (a) U.S. Patent 3,763,171, October 1973, (b) US. Patent 3,896,170, July 1975. 60. S. C. Bell, U.S. Patent 3,445,458, May 1969. 61. Neth. Patent 6,500,446, July 1965 (Delmar Chemicals Ltd., Canada). 62. F. H. McMillan and I. Pattison, U S . Patent 3,304,313, February 1967. 63. S. P. Hsi, J . Labelled Compds., 10, 389 (1974). 64.C. Podesva and K. Vagi, U S . Patent 3,842,094, October 1974. 65. Z . Vejdelek, M. Rajsner, A. Dlabac, M. Ryska, J. Holubek, E. Svatek, and M. Protiva, Collect. Czech. Chem. Commun., 45, 3593 (1980). 66. French Patent 2,253,501, July 1975 (Synthelabo S.A. France). 67. (a) E. E. Garcia, L. E. Benjamin, R. Ian Fryer, and L. H. Sternbach, J . Med. Chem., 15, 986 (1972). (b) E. E. Garcia, unpublished data, Hoffmann-La Roche, Nutley, NJ. 68. R. I. Fryer and L. H. Sternbach, U S . Patent 3,691,157, September 1972. 69. M. Steinman, J. G. Topliss, R. Alekel, Y.-S. Wong, and E. E. York, J . Med. Chem., 16, 1354 (1973). 70. Belg. Patent 772,825, September 1971 (Lab. Pharmedical S.A., Luxembourg). 71. Belg. Patent 794,536, July 1973 (Fujisawa Pharmaceutical Co., Japan). 72. (a) J. Hellerbach and A. Walser, US.Patent 3,784,542, January 1974. (b) J. Hellerbach and A. Walser, U.S. Patent 3,886,214, May 1975. (c) J. Hellerbach, unpublished data, Hoffmann-La Roche & Co. AG, Bask, Switzerland. 73. T. Kishimoto, M. Matsuo, and I. Ueda, Chem. Pharm. Bull., 30, 1477 (1982). 74. I. Mikami, Y. Hara, and Y. Usui, J . Takeda Res. Lab., 31, 11 (1972). 75. A. Stempel and F. W. Landgraf, J . Org. Chem., 27, 4675 (1962). 76. A. Stempel, U.S. Patent 3,202,699, August 1965. 77. G. F. Field and L. H. Sternbach, Swiss Patent 561,705, May 1975. 78. Z s . Tagyey, G. Maksay, and L. Otvos, J . Labelled Compd., 16, 377 (1978). 79. A. Szente, US. Patent 4,031,078, June 1977.
11. References
839
80. Q. Branca, A. E. Fischli, and A. Szente: (a) U.S. Patent 4,361,511, November 1982, (b) European Patent A1 0,033,973, August 1981. 81. F. Kajfez, N. Blasevic, and V. Sunjic, U.S. Patent 3,998,811, December 1976. 82. H. Demarne and A. Hallot, European Patent A1 0,022,710, January 1981. 83. H. H. Kaegi and W. Burger, J. Labelled Compd., 19, 975 (1982). 84. J. Hellerbach, A. Walser, H. Bretschneider, and W. Rudolph, U.S. Patent 3,772,271, November 1973. 85. K. Ishizumi, K. Mori, S. Inaba, and H. Yamamoto, U.S. Patent 3,991,048. 86. H. Yamamoto, S. Inaba, T. Hirohashi, M. Yamamoto, K. Ishizumi, M. Akatsu, I. Maruyama, Y. Kume, K. Mori, and T. Izumi: (a) US. Patent 3,812,101, May 1974, (b) U.S. Patent 3,778,433, December 1973, (c) U.S. Patent 3,867,372, February 1975, (d) U.S. Patent 4,010,154, March 1977, (e) U.S. Patent 3,989,829, November 1976. 87. Ger. Offen. 2,166,472, February 1974 (Sumitomo Chemical Co., Ltd., Japan). 88. Belg. Patent 764,034, March 1971 (Sumitomo Chemical Co., Ltd., Japan). 89. M. Akatsu, Y. Kume, T. Hirohashi, K. Ishizumi, M. Yamamoto, I. Maruyama, K. Mori, T. Izumi, S . Inaba, and H. Yamamoto, U.S. Patent 3,910,889, October 1975. 90. G. N. Walker, J. Org. Chem., 27, 1929 (1962). 91. (a) E. Reeder and L. H. Sternbach, US. Patent 3,371,085, February 1968, (b) E. Reeder and L. H. Sternbach, U.S. Patent 3,402,171, September 1968, (c) E. Reeder and L. H.Sternbach, unpublished data, Hoffmann-La Roche, Nutley, NJ. 92. R. Littell and D. S. Allen, Jr., J. Med. Chem., 8, 892 (1965). 93. 0. Keller, N. Steiger, and L. H. Sternbach, U.S. Patent 3,121,075, February 1964. 94. (a) L. Berger and L. H. Sternbach, US. Patent 3,179,656, April 1965, (b) L. Berger and L. H. Sternbach, US. Patent 3,268,586, August 1966, (c) L. Berger, unpublished data, Hoffmann-La Roche, Nutley, NJ. 95. Belg. Patent 629,352, October 1963 (Hoffmann-La Roche & Co AG, Switzerland). 96. R. I. Fryer, L. H. Sternbach, and J. V. Earley, U.S. Patent 3,520,877, July 1970. 97. A. F. Fentiman, Jr. and R. L. Foltz, J. Labelled Compd., 13, 579 (1977). 98. R. B. Moffett, U.S. Patent 3,609,145, September 1971. 99. G. F. Field and L. H. Sternbach, Swiss Patent 561,703, May 1975. 100. A. V. Bogatskii, S. A. Andronati, V. P. Gul'tyai, Yu. I. Vikhylaev, A. F. Galatin, Z. I. Zhilina, and T. A. Klygul', J . Gen. Chem., USSR, 41, 1364 (1971). 101. R. J. McCaully, U.S. Patent 3,678,043, July 1972. 102. E. Manghisi and A. Salimbeni, Bull. Chim. Farm., 113, 642 (1974). 103. F. Camps, J. Cartells, and J. Pi, Ann. Quim., 70, 848 (1974). 104. J. Schmitt, P. Comoy, M. Suquet, G. Callet, J. Le Meur, T. Clim, M. Brunaud, J. Mercier, J. Salle, and G. Siou, Chim. Ther., 239 (1969). 105. J. Schmitt, U.S. Patent 3,966,793, June 1976. 106. Neth. Patent 7,500,364, April 1975 (CM Industries S.A., France). 107. Neth. Patent 6,507,637, December 1965 (Etablissement Clin-Byla S.A., France). 108. A. Walser and J. Hellerbach, unpublished data, Hoffmann-La Roche & Co. AG, Basel, Switzerland. 109. K. Meguro, H. Tawada, H. Miyano, Y. Sato, and Y. Kuwada, Chem. Pharm. Bull., 21, 2382 (1973). 110. F. Krausz, U.S. Patent 4,051,127, September 1977. 111. H. Boemches and H. Meyer, Ger. Offen. 2,252,378, May 1973. 112. F. Kajfez and V. Sunjic, U.S. Patent 4,010,153, May 1977. 113. Neth. Patent 7,117,350, June 1972 (Sumitomo Chemical Co., Ltd., Japan). 114. Q. Branca, A. E. Fischli, and A. Szente, European Patent A1 0,033,974, August 1981. 115. A. V. Bogat-skii, S. A. Andronati, Z. I. Zhilina, S. D. Isaev, and A. G. Yurchenko, Chem. Heterocycl. Compd., 13, 694 (1977). 116. S. Inaba, M. Akatsu, T. Hirohashi, and H. Yamamoto, Chem. Pharm. Bull., 24, 1076 (1976). 117. H. Yamamoto, S. Inaba, T. Hirohashi, and K. Ishizumi, Chem. Ber., 101, 4245 (1968).
840
Dihydro- 1,4-Benzodiazepinonesand Thiones
S. Inaba, K. Ishizumi, T. Okamoto, and H. Yamamoto, Chem. Pharm. Bull., 23, 3279 (1975). K. Ishizumi, S. Inaba, and H. Yamamoto, Chem. Pharm. Bull., 20, 592 (1972). S. Inaba, K. Ishizumi, K. Mori, and H. Yamamoto, Chem. Pharm. Bull., 19, 722 (1971). S. Inaba, K. Ishizumi, and H. Yamamoto, Chem. Pharm. Bull., 19, 263 (1971). S. Inaba, T. Hirohashi, and H. Yamamoto, Chem. Pharm. Bull., 17, 1263 (1969). G. N. Walker, A. R. Engle, and R. J. Kempton, J. Org. Chem., 37, 3755 (1972). H. Yamamoto, S. Inaba, T. Hirohashi, M. Akatsu, I. Maruyama, and T. Izumi, U.S. Patent 3,781,299, December 1973. 125. H. Yamamoto, S. Inaba, T. Okamoto, T. Hirohashi, K. Ishizumi, M. Yamamoto, I. Maruyama, K. Mori, and T. Kobayashi: (a) U.S. Patent 3,632,574, January 1972, (b) U.S. Patent 3,362,573, January 1972, (c) U.S. Patent 3,770,767, November 1973, (d) U.S. Patent 3,723,464, March 1973, (e) U.S. Patent 3,652,551, March 1972, (f) U.S. Patent 3,925,364, December 1975, (9) U.S. Patent 3,828,027, August 1974, (h) U.S. Patent 3,922,264, November 1975, (i) US. Patent 3,631,029, December 1971. 126. H. Yamamoto, S. Inaba, T. Hirohashi, K. Ishizumi, I. Maruyama, and K. Mori, U.S. Patent 3,632,805, January 1972. 127. Ger. Offen. 2,166,473, February 1974 (Sumitomo Chemical Co., Ltd., Japan). 128. East Ger. Patent 91,045 July 1972 (Sumitomo Chemical Co., Ltd., Japan). 129. H. Yamamoto, S. Inaba, T. Hirohashi, M. Akatsu, I. Maruyama, and T. Izumi, U.S. Patent 3,634,402, January 1972. 130. H. Yamamoto, S. Inaba, T. Hirohashi, M. Akatsu, I. Maruyama, and T. Izumi, Ger. Offen. 1,966,206, January 1972. 131. K. Ishizumi, K. Mori, S. Inaba, and H. Yamamoto, Chem. Pharm. Bull., 21, 1027 (1973). 132. H. Yamamoto, S. Inaba, T. Okamoto, T. Hirohashi, K. Ishizumi, M.Yamamoto, I. Maruyama, K. Mori, T. Kobayashi, and T. Izumi, U.S. Patent 3,702,323, November 1972. 133. K. Ishizumi, K. Mori, S. Inaba, and H. Yamamoto, US. Patent 3,812,102, May 1974. 134. A. Walser, unpublished data, Hoffmann-La Roche, Nutley, NJ. 135. L. H. Sternbach and E. Reeder, J. Org. Chem., 26, 4936 (1961). 136. L. H. Sternbach, R. Ian Fryer, 0.Keller, W. Metlesics, G. Sach, and N. Steiger, J. Med. Chem., 6, 261 (1963). 137. Neth. Patent 7,204,248, October 1972 (Hoffmann-La Roche & Co. AG, Switzerland). 138. G. F. Field and L. H. Sternbach, U.S. Patent 3,594,365, July 1971. 139. G. F. Field and L. H. Sternbach, U.S. Patent 3,625,959, December 1971. 140. Neth. Patent 6,512,614, March 1966 (Hoffmann-La Roche & Co. AG, Switzerland). 141. G. F. Fidd and L. H. Sternbach, Swiss Patent 561,189, April 1975. 142. W. J. Middleton, U.S. Patent 4,182,760, January 1980. 143. A. Stempel, E. Reeder, and L. H. Sternbach, J. Org. Chem., 30, 4267 (1965). 144. W. J. Middleton, U.S. Patent 4,141,895, February 1979. 145. J. Hellerbach, A. Szente, and A. Walser, U.S. Patent 3,657,223, April 1972. 146. G. F. Field and L. H. Sternbach, Swiss Patent 562,221, May 1975. 147. J. Hellerbach, A. Szente, and A. Walser, U.S. Patent 3,671,518, June 1972. 148. A. Stempel, I. Douvan, E. Reeder, and L. H. Sternbach, J . Org. Chem., 32, 2417 (1967). 149. H. Natsugari, K. Meguro, and Y. Kuwada, Chem. Pharm. Bull., 27, 2084 (1979). 150. (a) Neth. Patent 7,110,495, February 1972 (Richter Gedeon Vegyeszeti Gyar RT, Hungary). (b) G. F. Field and L. H. Sternbach, Swiss Patent 561,704, March 1975. (c) R. Jaunin and J. Hellerbach, Ger. Offen. 2,150,075, April 1972. (d) R. Jaunin and J. Hellerbach, Swiss Patent 566,324, July 1975. 151. R. I. Fryer, G. A. Archer, B. Brust, W. Zally, and L. H. Sternbach, J. Org. Chem., 30,1308 (1965). 152. (a) R. I. Fryer, J. V. Earley, and L. H. Sternbach, J. Org. Chem., 30,521 (1965).(b) R. 1. Fryer and L. H. Sternbach, US. Patent 3,322,753, May 1967. (c) R. I. Fryer and J. V. Earley, unpublished data, Hoffmann-La Roche, Nutley, NJ. 153. S. J. Childress, S. C. Bell, and T. S. Sulkowski, U.S. Patent 3,321,522, May 1967. 154. R. I. Fryer and L. H. Sternbach, U.S. Patent 3,567,710, March 1971.
118. 119. 120. 121. 122. 123. 124.
11. References
84 1
155. S. Inaba, T. Okamoto, T. Hirohashi, K. Ishizumi, M. Yamamoto, I. Murayama, K. Mori, T. Kobayashi, and H. Yamamoto, U.S. Patent 3,666,643, May 1972. 156. K. Ishizumi, K. Mori, S. Inaba, and, H. Yamamoto, Chem. Pharm. Bull., 23, 2169 (1975). 157. (a) A. M. Felix, J. V. Earley, R. I. Fryer, and L. H. Sternbach, J. Heterocycl. Chem., 5,731 (1968). (b) A. M. Felix, unpublished data, Hoffmann-La Roche, Nutley, NJ. 158. A. M. Felix, R. I. Fryer, and L. H. Sternbach, U.S. Patent 3,546,212, December 1970. 159. Neth. Patent 7,508,659, February 1976 (Sumitomo Chemical Co., Ltd., Japan). 160. P. A. Wehrli, R. I. Fryer, and L. H. Sternbach, US. Patent 3,553,206, January 1971. 161. K.-H. Wuensch, H. Dettmann, and S. Schoenberg, Chem. Ber., 102, 3891 (1969). 162. M. E. Derieg, R. I. Fryer, and L. H. Sternbach, US. Patent 3,651,046, March 1972. 163. I. Nakatsuka, K. Kawahara, T. Kamada, F. Shono, and A. Yoshitake, J. Labelled Compd., 13, 453 (1977). 164. K. Meguro and Y. Kuwada, Yakugaku Zasshi, 93, 1263 (1973). 165. K. Meguro, H. Tawada, Y. Kuwada, and T. Masuda, U.S. Patent 3,692,772, September 1972. 166. H. Liepmann, W. Milkowski, and H. Zeugner, Eur. J. Med. Chem. Chim. Ther., 11, 501 (1976). 167. W. Milkowski, R. Hueschens, and H. Kuchenbecker, J. Heterocycl, Chem., 17, 373 (1980). 168. W. Milkowski, S. Funke, R. Hueschens, H. G. Liepmann, W. Stuehmer, and H. Zeugner, Ger. Offen. 2,221,536, November 1973. 169. L. H. Sternbach and R. Y. Ning, U.S. Patent 3,873,525, March 1975. 170. R. I. Fryer, and D. Winter, and L. H. Sternbach, J. Heterocycl. Chem., 4, 355 (1967). 171. R. I. Fryer and L. H. Sternbach, US. Patent 3,706,734, December 1972. 172. R. I. Fryer and L. H. Sternbach, US. Patent 3,625,957, December 1971. 173. G. F. Field and L. H. Sternbach, Swiss Patent 562,224, May 1975. 174. G. F. Field and L. H. Sternbach, Swiss Patent 561,190, April 1975. 175. G. F. Field and L. H. Sternbach, Swiss Patent 562,223, May 1975. 176. (a) P. Nedenskov and Mandrup, Acta Chem. Scand., 31,701 (1977). (b) Neth. Patent 6,608,039, December 1966 (Grindstedvaerket, Denmark). 177. S. A. Christensen, Br. Patent 1,247,554, September 1971. 178. A. Walser, R. I. Fryer, L. H. Sternbach, and M. A. Archer, J. Heterocycl. Chem., 11,619 (1974). 179. M. Matsuo, K. Taniguchi, and I. Ueda, Chem. Pharm. Bull., 30,1141 (1982). 180. A. Walser and R. I. Fryer, J . Heterocycl. Chem., 20, 551 (1983). 181. K. Meguro, H. Tawada, and Y. Kuwada, Yakugaku Zasshi, 93, 1253 (1973). 182. H. Natsugari, K. Meguro, and Y. Kuwada, Chem. Pharm. Bull., 27, 2589 (1979). 183. L. H. Sternbach, E. Reeder, A. Stempel, and A. I. Rachlin, J . Org. Chem., 29, 332 (1964). 184. S. C. Bell, C. Gochman, and S. J. Childress, J. Org. Chem., 28, 3010 (1963). 185. K. Meguro and Y. Kuwada, Chem. Pharm. Bull., 21, 2375 (1973). 186. (a) K. Meguro and Y. Kuwada, Tetrahedron Lett., 4039 (1970). (b) G. A. Archer and L. H. Sternbach, J. Org. Chem., 29, 231 (1964). 187. H. Tawada, H. Natsugari, K. Meguro, and Y. Kuwada, US. Patent 4,102,881, July 1978. 188. Neth. Patent 6,412,484, May 1965 (Hoffmann-La Roche & Co. AG, Switzerland). 189. R. Y. Ning, R. I. Fryer, and B. C. Sluboski, J. Org. Chem., 42, 3301 (1977). 190. R. I. Fryer, J. V. Earley, and J. F. Blount, J. Org. Chem., 42, 2212 (1977). 191. T. Masuda, Y. Usui, Y. Hara, and T. Komatsu, U.S. Patent 3,644,339, February 1972. 192. E. Broger, unpublished data, Hoffmann-La Roche, Nutley, NJ. 193. M. Ogata and H. Matsumoto, Chem. Ind., (London), 1067 (1976). 194. M. Gates, J. Org. Chem., 45, 1675 (1980). 195. J. H. Gogerty, R. G. Griot, D. Habeck, L. C. Iorio, and W. J. Houlihan, J . Med. Chem., 20,952 (1977). 196. R. G. Griot, U.S. Patent 3,414,563, December 1968. 197. P. C. Wade, B. R. Vogt, and M. S. Puar, Tetrahedron Lett., 1699 (1977). 198. (a) B. R. Vogt, P. C. Wade, and M. S. Puar, Tetrahedron Lett., 1931 (1976). (b) P. C. Wade, B. R. Vogt, B. Toeplitz, and M. S. Puar, J. Org. Chem., 44, 88 (1979).(c) P. C. Wade and B. R. Vogt, U.S. Patent 4,022,765, May 1977. (d) B. R. Vogt and P. C. Wade, U.S. Patent 3,895,005, July
842
Dihydro- 1,4-Benzodiazepinonesand Thiones
1975. (e) B. R. Vogt and P. C. Wade, US. Patent 3,894,011, July 1975. (f) P. C. Wade and B. R. Vogt, US.Patent 3,898,212, August 1975. (g) B. R. Vogt and P. C. Wade, U.S. Patent 3,898,211, August 1975. 199. S. C. Bell, R. J. McCaully, and S. J. Childress, J. Org. Chem., 33, 216 (1968). 200. S. C. Bell, R. J. McCaully, and S. J. Childress, Tetrahedron Lett., 2889 (1965). 201. S. C. Bell, S. J. Childress, U.S. Patent 3,344,136, September 1967. 202. Z. I. Zhilina, A. V. Bogat-Skii, S. A. Andronati, and N. I. Danilina, Chem. Heterocycl. Cornpd., 15, 447 (1979). 203. S. C. Bell, US. Patent 3,652,634, March 1972. 204. Neth. Patent 7,502,283, September 1975 (Hoffmann-La Roche & Co AG, Switzerland). 205. S. C. Bell, US. Patent 3,257,382, June 1966. 206. R. J. McCaully, US. Patent 3,875,213, April 1975; 3,873,604, March 1975. 207. R. J. McCaully, US. Patent 3,926,952, December 1975. 208. H. Tawada, H. Natsugari, K. Meguro, and Y. Kuwada, US. Patent 3,746,701, July 1973. 209. R. I. Fryer and L. H. Sternbach, U.S. Patent 3,376,290, April 1968. 210. J. Bergman, A. Brynolf, and B. Elman, Heterocycles, 20, 2141 (1983). 211. J. Bergman, A. Brynolf, and B. Elman, Heterocycles, 21, 511 (1984). 212. Y. Ban and M. Nagai, Swiss Patent 513,886, October 1971. 213. F. Kajfez and N. Blasevic, Swiss Patent 547,293, February 1974. 214. Neth. Patent 7,402,020, August 1974 (Sumitomo Chemical Co., Ltd., Japan). 215. (a) R. Y.Ning, W. Y. Chen, and L. H. Sternbach, J. Org. Chem., 38,4206 (1973). (b) R.Y. Ning, W. Y. Chen, and L. H. Sternbach, J. Org. Chem., 36, 1064 (1971). 216. L. H. Sternbach, B. A. Koechlin, and E. Reeder, J. Org. Chem., 27,4671 (1962). 217. G. F. Field and L. H. Sternbach, J . Org. Chem., 33, 4438 (1968). 218. R. Y. Ning, G. F. Field, and L. H. Sternbach, J. Heterocycl. Chem., 7, 475 (1970). 219. J. V. Earley, R. I. Fryer, R. Y. Ning, and L. H. Sternbach, US. Patent 3,681,341, August 1972. 220. Neth. Patent 7,111,035, February 1972 (Chugai Seiyaku, Japan). 221. Neth. Patent 7,117,532, June 1972 (Sankyo Co., Ltd., Japan). 222. J. Schmitt, P. Comoy, M. Suquet, J. Boitard, J. Le Meur, J.-J. Basselier, M. Brunaud, and J. Salk, Chim. Ther., 2, 254 (1967). 223. R. I. Fryer, E. E. Garcia, and L. H. Sternbach, U S . Patent 3,371,083, February 1968. 224. Neth. Patent 6,600,095, July 1966 (S.A. Etablissement Clin-Byla, France). 225. R. I. Fryer, E. E. Garcia, and L. H. Sternbach, U S . Patent 3,371,084, February 1968. 226. R. Jaunin and W. Arnold, Helu. Chim. Acta, 56, 2569 (1973). 227. S. C. Bell, R. J. McCaully, C. Gochman, S. J. Childress, and M. I. Gluckman, J. Med. Chem., 11, 457 (1968). 228. E. Poetsch, J. Uhl, D. Marx, W. Strehlow, H. Mueller-Calgan, and G. Dolce, US. Patent 4,232,016, November 1980. 229. A. Ziggiotti, F. Mauri, and G. Riva, US. Patent 3,852,271, December 1974. 230. Q. Branca, A. E. Fischli, and A. Szente, US. Patent 4,377,522, March 1983. 231. A. E. Fischli and A. Szente: (a) U S . Patent 4,294,758, October 1981, (b) US. Patent 4,299,767, November 1981. 232. R. M. Novack, U.S. Patent 3,549,623, December 1970. 233. J. V. Earley, R. I. Fryer, D. Winter, and L. H. Sternbach, J . Med. Chem., 11, 774 (1968). 234. Belg. Patent 786,951, November 1972 (Sumitomo Chemical Co., Ltd., Japan). 235. L. H. Schlager, Tetrahedron Lett., 4519 (1970). 236. J. Hellerbach, H. Hoffmann, and G. Zanetti, U S . Patent 3,963,777, June 1976. 237. Belg. Patent 805,054, March 1974 (Hoffmann-La Roche & Co. AG, Switzerland). 238. A. Walser and R. I. Fryer, J. Med. Chem., 17, 1228 (1974). 239. P. Nedenskov, US. Patent 3,970,645, July 1976. 240. W. Sadee, K.-H. Beyer, and J. Schwandt, Third International Congress of Heterocyclic Chemistry, Japan, 1971; Abstracts.
11. References
843
241. H. Yamamoto, S. Inaba, H. Wada, S. Ogino, and F. Kishimoto, U.S. Patent 3,806,418, April 1974. 242. J. Hellerbach and A. Walser, U.S. Patent 3,763,144, October 1972. 243. (a) J. H. Sellstedt, J . Org. Chem., 40, 1508 (1975), (b) J. H. Sellstedt, US. Patent 3,915,961, October 1975. 244. R. Y. Ning and L. H. Sternbach, U.S. Patent 3,781,353, December 1973. 245. A. Walser, G . Zenchoff, and R. I. Fryer, J . Med. Chem., 19, 1378 (1976). 246. R. I. Fryer and A. Walser: (a) U.S. Patent 3,989,681, November 1976, (b) U.S. Patent 3,865,815, February 1975. 247. W. Metlesics, unpublished data, Hoffmann-La Roche, Nutley, NJ. 248. J. Kollonitsch and G. A. Doldouras, US. Patent 3,859,276, January 1975. 249. Belg. Patent 880,419, April 1980 (KRKA, Farmacevtika Kemija, Yugoslavia). 250. W. Metlesics, R. F. Tavares, and L. H. Sternbach, J . Org. Chem., 30, 1311 (1965). 251. (a) Q. Branca, A. E. Fischli, and A. Szente, U.S. Patent 4,327,026, April 1982, (b) Q. Branca, unpublished data, Hoffmann-La Roche & Co. AG, Basel, Switzerland, (c) A. E. Fischli, unpublished data, Hoffmann-La Roche & Co. AG, Basel, Switzerland. 252. (a) R. Y. Ning, L. H. Sternbach, W. Pool, and L. 0. Randall, J . Med. Chem., 16, 879 (1973). (b) R. Y. Ning and L. H. Sternbach, U.S. Patent 3,644,334, February 1972. 253. G. F. Field and L. H. Sternbach, Swiss Patent 561,191, March 1975. 254. G. A. Archer, R. I. Fryer, and L. H. Sternbach, US. Patent 3,299,053, January 1967. 255. (a) G. A. Archer and L. H. Sternbach, U.S. Patent 3,678,036, July 1972. (b) G. A. Archer and L. H. Sternbach, US. Patent 3,422,091, January 1969. (c) G. A. Archer, unpublished data, Hoffmann-La Roche, Nutley, NJ. 256. R. I. Fryer, B. Brust, and L. H. Sternbach, J . Chem. SOC.,4977 (1963). 257. D. L. Coffen, unpublished data, Hoffmann-La Roche, Nutley, NJ. 258. H. Hoffmann, unpublished data, Hoffmann-La Roche & Co. AG, Basel, Switzerland. 259. M. Gerecke, unpublished data, Hoffmann-La Roche & Co. AG, Basel, Switzerland. 260. M. Ogata, H. Matsumoto, and K. Hirose, J . Med. Chem., 20, 776 (1977). 261. A. Gagneux, R. Heckendron, and R. Meier, U S . Patent 3,852,300, December 1974. 262. S. C. Bell and S. J. Childress, J . Org. Chem., 27, 1691 (1962). 263. S. C. Bell, US. Patent 3,296,249, January 1967. 264. H. Pieper, G . Krueger, J. Keck, and K.-R. Noll, Ger. Offen. 2,311,714, September 1974. 265. G. Nudelman, R. J. McCaully, and S. C. Bell, J . Pharm. Sci., 63, 1880 (1974). 266. E. M. Bingham and W. J. Middleton, U.S. Patent 4,246,270, January 1981. 267. E. M. Bingham and W. J. Middleton, US. Patent 4,120,856, October 1978. 268. T. Okamoto, T. Akase, T. Izumi, M. Akatsu, Y. Kume, S. Inaba, and H. Yamamoto, U.S. Patent 3,832,344, April 1974. 269. M. Maziere, J.-M. Godot, G. Berger, Ch. Prenant, and D. Comar, J. Radioanal. Chem., 56,229 (1980). 270. M. E. Derieg, R. I. Fryer, and L. H. Sternbach, US. Patent 3,534,021, October 1970. 271. J. Hester, Jr., Ger. Offen. 2,302,525, August 1973. 272. Neth. Patent 6,412,300, April 1965 (Hoffmann-La Roche & Co. AG, Switzerland). 273. Belg. Patent 803,315, December 1973 (L. Zambeletti S.A., Italy). 274. E. Reeder and L. H. Sternbach, French Patent 1,343,085, October 1963. 275. H. Demarne and A. Hallot, U.S. Patent 4,235,897, November 1980. 276. Belg. Patent 766,098, June 1971 (Sumitomo Chemical Co., Ltd., Japan). 277. A. Walser, G. Silverman, J. Blount, R. I. Fryer, and L. H. Sternbach, J . Org. Chem., 36, 1465 (1971). 278. R. I. Fryer and A. Walser, US. Patent 3,796,722, March 1974. 279. Neth. Patent 6,510,539, February 1966 (Hoffmann-La Roche & Co. AG, Switzerland). 280. L. H. Schlager, Ger. Offen, 2,950,235, June 1980 (Gerot-Pharmazeutica GmbH, Austria). 281. H. Najer and P. M. J. Manoury, Ger. Offen. 3,008,852, September 1980.
844 282. 283. 284. 285. 286. 287. 288. 289. 290. 291. 292. 293. 294. 295. 296. 297. 298. 299. 300. 301. 302. 303. 304. 305.
306. 307. 308. 309. 310. 311. 312. 313. 314. 315. 316. 317. 318. 319. 320. 321.
Dihydro- 1,4-Benzodiazepinones and Thiones G . F. Tomagnone, M. V. Torrielli, and F. de Marchi, J . Pharm. Pharmacol, 26, 567 (1974). R. I. Fryer and L. H. Sternbach, US. Patent 3,819,602, June 1974. G . A. Archer and L. H. Sternbach, U.S. Patent 3,391,138, July 1968. M. Akatsu, Y. Kume, T. Hirohashi, S. Inaba, H. Yamamoto, and H. Sato, U.S. Patent 3,906,003, September 1975. H. Yamamoto, S. Inaba, T. Hirohashi, M. Yamamoto, K. Ishizumi, M. Akatsu, I. Maruyama, K. Mori, Y. Kume, and T. Izumi, US. Patent 4,079,053, March 1978. L. H. Sternbach, G . A. Archer, J. V. Earley, R. I. Fryer, E. Reeder, N. Wasyliw, L. 0. Randall, and R. Banziger, J . Med. Chem., 8, 815 (1965). Br. Patent 1,346,176, February 1974 (American Home Products Corp., New York). H. Yamamoto, S. Kitagawa, S. Inaba, S. Sakai, T. Hirohashi, I. Maruyama, M. Akatsu, and T. Izumi, U.S. Patent 3,641,002, February 1972. W. J. Welstead, Jr., R. F. Boswell, Jr., U.S. Patent 4,151,285, April 1979. M. E. Derieg, R. I. Fryer, R. M. Schweininger, and L. H. Sternbach, J . Med. Chem., 11, 912 (1968). J. Szmuskovicz, U.S. Patents 3,901,881, August 1975; 3,882,112, May 1975; 3,818,003, June 1974; 3,933,816; January 1976. G . A. Archer and L. H. Sternbach, U.S. Patent 3,236,838, February 1966. J. V. Earley, R. I. Fryer, and L. H. Sternbach, U.S. Patent 3,703,510, November 1972. Belg. Patent 775,256, November 1971 (A.H. Robins Co. Inc., Richmond, VA). R. B. Moffet, U.S. Patent 4,016,165, April 1977. A. Walser, G . Silverman, R. I. Fryer, L. H. Sternbach, and J. Hellerbach, J . Org. Chem., 36,1248 (1971). A. Walser, G . Silverman, and R. I. Fryer, J . Org. Chem., 38, 3502 (1973). B. E. Reitter, Y. P. Sachdeva, and J. F. Wolfe, J . Org. Chem., 46, 3945 (1981). R. I. Fryer, J. V. Earley, and L. H. Sternbach, J . Org. Chem., 34, 649 (1969). A. Szente, unpublished data, Hoffmann-La Roche & Co. AG, Basel, Switzerland. R. Jaunin, unpublished data, Hoffmann-La Roche & Co. AG, Basel, Switzerland. K.-A. Kovar and B. Biegert, Arch. Pharm., 309,522 (1976). A. V. Bogat-skii, S. A. Andronati, Z. I. Zhilina, 0. V. Kobzareva, P. A. Sharbatyan, R. Yu. Ivanova, and T. K. Chumachenko, J . Gen. Chem., USSR, 45, 384 (1975). M. E. Derieg, J. V. Earley, R. I. Fryer, and L. H. Sternbach, U.S. Patent 3,965,151, June 1976; 3,905,956, September 1975; 3,997,591, December 1976; 4,049,666, September 1977; 4,049,667, September 1977; 4,017,531, April 1977; 4,017,532, April 1977. M. E. Derieg, J. V. Earley, R. I. Fryer, R. J. Lopresti, R. M. Schweiniger, L. H. Sternbach, and H. Wharton, Tetrahedron 27, 2591 (1971). R. Tachikawa, H. Takagi, T. Kamioka, M. Fukunaga, Y. Kawano, and T. Miyadera, U.S. Patent 3,696,094, October 1972. S. C. Bell, U S . Patent 3,514,445, May 1970. S. C. Bell and P. H. L. Wei, J . Org. Chem., 30,3576 (1965). R. B. Moffett, U.S. Patent 3,822,259, July 1974. R. B. Moffett, and A. D. Rudzik, J . Med. Chem., 15, 1079 (1972). R. B. Moffett, U.S. Patent 3,718,646, February 1973. R. B. Moffett and B. V. Kamdar, J . Heterocycl. Chem., 16, 793 (1979). H. Pieper, G . Krueger, J. Keck, and K. Noll, Ger. Offen. 2,304,095, August 1974. (a) H. Pieper, G . Krueger, J. Keck, K.-R. Noll, and J. Kahling, US. Patent 3,872,090, March 1975. (b) E. Ger. Patent 106,172, June 1974 (Dr. K. Thomae, GmbH). S . Kobayashi, Tetrahedron Lett., 967 (1974). S . Kobayashi, Bull Chem. Soc. Japan, 48, 302 (1975). J. Szmuszkovicz, C. G . Chidester, D. J. Duchamp, F. A. MacKellar, and G . Slomp, Tetrahedron Lett., 3665 (1971). V. Hach, Ger. Offen. 2,512,092, September 1975. J. Hellerbach and A. Szente, US. Patent 3,696,095, October 1972. D. L. Coffen, J. P. DeNoble, E. L. Evans, G . F. Field, R. I. Fryer, D. A. Katonak, B. J. Mandel, L. H. Sternbach, and W. J. Zally, J . Org. Chem., 39, 167 (1974).
11. References
845
T. E. Gunda and C. Enebaeck, Acta Chem. Scand., 37, 75 (1983). R. Jaunin, W. E. Oberhaensli, and J. Hellerbach, Helu. Chim. Acta, 55, 2975 (1972). L. H. Sternbach and A. Stempel, U.S. Patent 3,450,695, June 1969. S. C. Bell: (a) U.S. Patent 3,401,159,September 1968, (b) US. Patent 3,418,315, December 1968. L. H. Schlager U.S. Patent 4,261,987, April 1981. A. Nudelman and R. J. McCaully, U S . Patent 3,825,533, July 1974. (a) R. J. McCaully and A. Nudelman, US. Patent 3,886,276, May 1975. (b) Neth. Patent 7,204,228, October 1972 (American Home Products Corp. New York). 329. Germ. Patent 2,519,329, April 1975 (Laboratories Ferrer S.L., Spain). 330. R. B. Moffett, J . Org. Chem., 39, 568 (1974). 331. E. F. Williams, K. C. Rice, S. M. Paul, and P. Skolnick, J . Neurochem., 35, 591 (1980). 332. K. C. Rice, E. Williams, and P. Skolnick, 178th Meeting of the American Chemical Society, September 1979; Abstracts. 333. A. Nudelman and R. J. McCaully, U.S. Patent 3,903,276, September 1975. 134. F. Kajfez, T. Kovac, and V. Sunjic, U.S. Patent 3,852,274, December 1974. 335. Belg. Patent 828,222, August 1975 (Siphar S.A., Switzerland). 336. G. Ferrari and C. Casagrande, U.S. Patent 3,799,920, March 1974. 337. (a) G. Maksay, Z. Tegyey, and L. Oetvoes, Z . Physiol. Chem., 359, 879 (1978). (b) E. Simon-Trompler, G. Maksay, I. Lukovits, J. Volford, and L. Oetvoes, Arzneim.-Forsch, 32, 102 (1982). 338. A. Nudelman and R. J. McCaully, U S . Patent 3,801,568, April 1974. 339. A. Baglioni, European Patent application A l , 0,122,889, October 1984. 340. A. Nudelman and R. J. McCaully, U.S. Patent 3,860,581, January 1975. 341. R. I. Fryer and L. H. Sternbach, J . Org. Chem., 30,524 (1965). 342. R. I. Fryer, B. Brust, J. V. Earley, and L. H. Sternbach, J . Chem. Soc., C, 366 (1967). 343. R. I. Fryer, D. L. Coffen, J. V. Earley, and A. Walser, J . Heterocycl. Chem., 10, 473 (1973). 344. R. Y. Ning, R. I. Fryer, P. B. Madan, and B. C. Sluboski, J . Org. Chem., 41, 2720 (1976). 345. A. Walser, U.S. Patent 4,118,386, October 1978. 346. R. Y. Ning, R. I. Fryer, P. B. Madan, and B. Sluboski, J . Org. Chem., 41, 2724 (1976). 347. A. Nussbaum, unpublished data, Hoffmann-La Roche, Nutley NJ. 348. M. R. Del Giudice, F. Gatta, C. Pandolfi, and G. Settimj, Farmaco, Ed. Sci., 37, 343 (1982). 349. S. C. Bell and S. J. Childress, J . Org. Chem., 29, 506 (1964). 350. J. Volke, M. M. Ellaithy, and 0. Manousek, Talanta, 25, 209 (1978). 351. B. Maupas and M. B. Fleury, Analysis, 10, 187 (1982). 352. Belg. Patent 823,615, April 1975 (Asta-Werke AG, Germany). 353. G. Scheffler, F. Bourseaux, N. Brock, and J. Pohl, Ger. Offen. 2,947,076 June 1981. 354. G. Scheffler, F. Bourseaux, N. Brock, and J. Pohl, Ger. Offen. 2,947,075 June 1981. 355. J. H. Sellstedt, US. Patent 3,882,101, May 1975. 356. T. Kovac, F. Kajfez, V. Sunjic, and M. Oklobdzija, J . Med. Chem., 17, 766 (1974). 357. W. A. Khan and P. Singh, Org. Prep. Proc. Znt., 10, 105 (1978). 358. S. C. Bell, U.S. Patent 3,198,789, August 1965. 359. H. Scholl, P. Laufer, G. Kloster, and G. Stoecklin, J . Labelled Compd., 19, 1294 (1982). 360. R. Y.Ning and L. H. Sternbach, U S . Patent 3,801,569, April 1974. 361. M. Nakano, N. Inotsume, N. Kohri, and T. Arita, Int. J . Pharm., 3, 195 (1979). 362. N. Inotsume and M. Nakano, Int. J . Pharm., 6, 147 (1980). 363. J. B. Hester, Jr., D. J. Duchamp, and C. G. Chidester, Tetrahedron Lett., 1609 (1971). 364. J. Gasparic, J. Zimak, P. Sedmera, Z. Breberova, and J. Volke, Collect. Czech. Chem. Commun., 44,2243 (1979). 365. G. F. Tamagnone, R. De Maria, and F. De Marchi, Arzneim-Forschung., 25, 720 (1975). 366. G. Jommi, F. Mauri, and G. Riva, U S . Patent 3,689,478, September 1972. 367. Br. Patent 1,035,918, July 1966 (J. Wyeth & Brother Ltd., England). 368. R. 1. Fryer, J. V. Earley, and L. H. Sternbach, J . Org. Chem., 32, 3798 (1967). 369. F. Gatta, M. R. Del Giudice, and G. Settimj, Synthesis, 718 (1979). 370. F. G. Kathawala, U.S. Patent 3,869,450, March 1975. 371. G. F. Field, unpublished data, Hoffmann-La Roche, Nutley, NJ.
322. 323. 324. 325. 326. 327. 328.
846
Dihydro- 1,4-Benzodiazepinonesand Thiones
372. G. F. Field, R. Y. Ning, and L. H. Sternbach, US.Patent 3,591,581, July 1971. 373. H. J. Roth and M. Adomeit, Arch. Pharmaz., 306,889 (1973). 374. (a) P. J. G. Cornelissen and G. M. J. Beijersbergen van Henegouwen, Pharm. Wkbl., 3, 800 (1981). (b) P. J. G. Cornelissen and G. M. J. Beijersbergen van Henegouwen, Photochem. PhotobioL, 30,337 (1979). 375. P. J. G. Cornelissen and G. M. J. Beijersbergen van Henegouwen, and K. W. Gerritsma, Int. J . Pharm., 1, 173 (1978). 376. R. I. Fryer, J. V. Earley, and L. H. Sternbach, J . Am. Chem. Soc., 88, 3173 (1966). 377. J. P. Freeman, D. J. Duchamp, C. G. Chidester, G. Slomp, J. Szmuszkovicz, and M. Raban, J . Am. Chem. SOC., 104, 1380 (1982). 378. A. V. Bogat-skii, S. A. Andronati, L. V. Komogortseva, and Z. I. Zhilina, J . Gen. Chem., USSR, 46,1828 (1976). 379. C. Preti and G. Tosi, Transition Met. Chem., 3, 246 (1978). 380. M. Gajewska, E. Lugowska, M. Ciszewska-Jedrasik, and M. Rzedowski, Chem. Anal., 26, 517 (1981). 381. J. H. Mendez, C. G. Perez, and M. I. G. Martin, An. Quim., B, 80, 390 (1984). 382. J. A. Real and J. Borras, Synth. React. lnorg. Met.-Org. Chem., 14, 843 (1984). 383. J. A. Real and J. Borras, Synth. React. Inorg. Met.-Org. Chem., 14, 857 (1984). 384. J. A. Groves and W. F. Smith, Spectrochim. Acta, 35, 603 (1979). 385. G. Snatzke, A. Konowal, A. Sabljic, N. Blasevic, and V. Sunjic, Croat. Chem. Acta, 55,435 (1982). 386. P. Linscheid and J. M. Lehn, Bull. SOC. Chim. Fr., 992 (1967). 387. W. Bley, P. Nuhn, and G. Benndorf, Arch. Pharm., 301, 444 (1968). 388. M. Sarrazin, M. Bourdeaux-Pontier, C. Briand, and E. J. Vincent, Org. Magn. Resonance, 7,89 (1975). 389. M. Raban, E. H. Carlson, J. Szmuszkovicz, G, Slomp, C. G. Chidester, and D. J. Duchamp, Tetrahedron Lett., 139 (1975). 390. L. Cazaux, C. Vidal, and M. Pasdeloup, Org. Magn. Resonance, 21, 190 (1983). 391. N. W. Gilman, P. Rosen, J. V. Earley. C. Cook and L. Todaro, J . Am. Chem. SOC.,112, 3969 (1990). 391b. N. W. Gilman, Unpublished data, Hoffman-La Roche Inc., Nutley, NJ. 392. W. Sadee, H.-J. Schwandt, and K.-H. Beyer, Arch. Pharm., 306,751 (1973). 393. V. Sunjic, A. Lisini, A. Sega, T. Kovac, and F. Kajfez, J . Heterocycl. Chem., 16, 757 (1979). 394. H.-H. Paul, H. Sapper, W. Lohmann, and H.-0. Kalinowski, Org. Magn. Resonance, 19, 49 (1982). 395. R. Haran and J. P. Tuchagues, J . Heterocycl. Chem., 17, 1483 (1980). 396. A. Patra, A. K. Mukhopadhyay, A. K. Mitra, and A. K. Acharyya, Org. Magn. Resonance, 15, 99 (1981). 397. K.-A. Kovar, D. Linden, and E. Breitmaier, Arch. Pharm., 314, 186 (1981). 398. H.-H. Paul, H. Sapper, W. Lohmann, and H. 0. Kalinowski, Org. Magn. Resonance, 21, 319 (1983). 399. B. Unterhalt, Arch. Pharm., 314, 733 (1981). 400. T. A. Scahill and S . L. Smith, Org. Magn. Resonance, 21, 621 (1983). 401. F. M. Vane and W. Benz, Org. Mass Spectrom., 14, 233 (1979). 402. A. Camerman and N. Camerman, J . Am. Chem. SOC., 94, 268 (1972). 403. L. H. Sternbach, F. D. Sancilio, and J. F. Blount, J . Med. Chem., 17, 374 (1974). 404. G. Gilli, V. Bertolasi, M. Sacerdoti, and P. A. Borea, Acta Crystallogr., B33, 2664 (1977). 405. G. Gilli, V. Bertolasi, M. Sacerdoti, and P. A. Borea, Acta Crystal!ogr., B34, 2826 (1978). 406. M. Sikirica and I. Vickovic, Cryst. Struct. Commun., 11, 1293 (1982). 407. A. A. Karapetyan, V. G. Andrianov, Y. T. Struchkov, A. V. Bogatskii, S. A. Andronati, and T. I. Korotenko, Bioorg Khim., 5, 1684 (1979). 408. G. Bandoli and D. A. Clemente, J . Chem. SOC.,Perkin Trans. 11, 413 (1976). 409. Z . Galdecki and M. L. Glowka, Acta Crystallogr., B36, 3044 (1980). 410. P. Chananont, T. A. Hamor, and I. L. Martin, Cryst. Struct. Commun., 8, 393 (1979). 411. P. Chananont, T. A. Hamor, and I. L. Martin, Acta Crystallogr., B37, 1371 (1981).
11. References 412. 413. 414. 415. 416. 417. 418. 419. 420. 421. 422.
841
R. F. Dunphy and H. Lynton, Can. J . Chem., 49, 3401 (1971). G. Brachtel and M. Jansen, Cryst. Struct. Commun., 10, 669 (1981). P. Chananont, T. A. Hamor, and I. L. Martin, Acta Crystallogr., B36, 2115 (1980). J. V. Earley, R. I. Fryer, and A. Walser, U.S. Patent 3,869,448, March 1975. J. B. Hester, Jr., A. D. Rudzik, and B. V. Kamdar, J . Med. Chem., 14, 1078 (1971). R. B. Moffet, U.S. Patent 3,846,443, November 1974. R. S. P. Hsi and T. D. Johnson, J . Labelled Compd. Radiopharm., 12, 613 (1976). J. B. Hester, Jr., US. Patent 4,018,788, April 1977. J. B. Hester, Jr., U.S. Patent 3,741,957, June 1973. J. V. Earley, R. I. Fryer, and A. Walser, U.S. Patent 3,836,521, September 1974. M. Steinman: (a) U.S. Patent 3,920,818, November 1975, (b) U.S. Patent 3,845,039, October 1974. 423. (a) R. B. Moffett, Ger. Offen 2,252,079, May 1973, (b) J. B. Hester, Jr., Ger. Offen. 2,220,623, November 1972. 424. J. B. Hester, Jr., U.S. Patent 3,674,777, July 1972. 425. M. Foersch and H. Gerhards, European Patent Al 0,041,242 December 1981. 426. J. B. Hester, Jr., US. Patent 3,649,617, March 1972. 427. I. Ueda and M. Matsuo, U.S. Patent 4,094,870, June 1978. 428. J. B. Hester, Jr., U.S. Patent 3,897,446, July 1975. 429. M. Steinman, US. Patent 3,856,787, December 1974. 430. Belg. Patent 798,677, August 1973 (Centre #Etudes pour I'Industrie Pharmaceutique, France). 431. J.-P. Maffrand, G. Ferrand, and F. Eloy, Eur. J . Med. Chem., 9, 539 (1974). 432. French Patent 2,244,525, April 1975 (Centre d'Etudes pour I'Industrie Pharmaceutique, France). 433. R. B. Moffett, and A. D. Rudzik, J . Med. Chem., 16, 1256 (1973). 434. R. B. Moffett, U S . Patent 3,847,935, November 1974. 435. M. Gall, U.S. Patent 3,910,946, October 1975. 436. M. Gall and B. V. Kamdar J . Org. Chem., 46, 1575 (1981). 437. J. B. Taylor and D. R. Harrison, U.S. Patent 4,185,102, January 1980. 438. J. B. Taylor and D. R. Harrison, U S . Patent 4,134,976, January 1979. 439. I. R. Ager, G. W. Danswan, D. R. Harrison, D. P. Kay, P. D. Kennewell, and J. B. Taylor, J . Med. Chem., 20, 1035 (1977). 440. M. Gall, U.S. Patent 3,992,393, November 1976. 441. M. Gall, US. Patent 3,763,179, October 1973. 442. J. P. Maffrand, G. Ferrand, and E. F. Eloy, Tetrahedron Lett., 3449 (1973). 443. Belg. Patent 634,438, January 1964 (Hoffmann-La Roche & Co. AG, Switzerland). 444. J. B. Hester, Jr., and A. D. Rudzik, J . Med. Chem., 17, 293 (1974). 445. J. B. Hester, Jr., U.S. Patent 3,857,854, December 1974. 446. H.-G. Schecker and G. Zinner, Arch. Pharm., 313, 926 (1980). 447. J. B. Hester, Jr., U.S. Patent 4,082,761, April 1978. 448. J. B. Hester, Jr., U.S. Patent 3,734,922, May 1973. 449. R. B. Moffett, U.S. Patent 3,743,652, July 1973. 450. J. B. Hester, Jr., U.S. Patent 3,995,043, November 1976. 451. J. Szmuskovicz, U.S. Patent 3,856,802, December 1974. 452. Neth. Patent 7,206,300, November 1972 (Upjohn Co., Kalamazoo, MI). 453. Neth. Patent 7,205,705, October 1972 (Upjohn Co., Kalamazoo, MI). 454. J. B. Hester, Jr., U.S. Patent 3,886,174, May 1975. 455. S. C. Bell, R. J. McCaully, and S. J. Childress, J . Med. Chem., 11, 172 (1968). 456. M. Ogata and H. Matsumoto, U S . Patent 4,041,026, August 1977. 457. R. J. McCaully and A. Nudelman, U.S. Patent 3,803,129, April 1974. 458. R. J. McCaully, U.S. Patent 3,446,800, May 1969. 459. J. Bergman and A. Brynolf, Heterocycles, 20, 2145 (1983). 460. F. Hollywood, E. F. V. Scriven, H. Suschitzky, and D. R. Thomas, J . Chem. Soc., Chem. Commun., 806 (1978).
848
Dihydro- 1,4-Benzodiazepinones and Thiones
461. F. Hollywood, Z, U. Khan, E. F. V. Scriven, R. K. Smalley, H. Suschitzky, and D. R. Thomas, J . Chem. Soc., Perkin Trans. I , 431 (1982). 462. J. Bergman, A. Brynolf, and B. Elman, Heterocycles, 20, 2141 (1983). 463. J. A. Deyrup and J. C. Gill, Tetrahedron Lett., 4845 (1973). 464. G. F. Field, W. J. Zally, and L. H. Sternbach, J . Org. Chem., 36, 777 (1971). 465. A. A. Santilli and T. S . Osdene, J . Org. Chem., 29, 1998 (1964). 466. A. A. Santilli and T. S . Osdene, J . Org. Chem., 30, 2100 (1965). 467. A. A. Santilli and T. S. Osdene, U S . Patent 3,336,300, August 1967. 468. K. H. Weber, Arch. Pharm., 302,584 (1969). 469. J. V. Earley, R. I. Fryer, and L. H. Sternbach, U.S. Patent 3,644,335, February 1972. 470. G. F. Field, L. H. Sternbach, and W. J. Zally: (a) U S . Patent 3,624,073, November, 1971, (b) U S . Patent 3,678,038, July 1972. 471. R. J. Mohrbacher and P. P. Grous: (a) U.S. Patent 4,022,767, May 1977, (b) US. Patent 4,031,079, June 1977, (c) U.S. Patent 4,020,055, April 1977, (d) U.S. Patent 4,002,610, January 1977. 472. S. Gaertner, Justus Liebigs Ann. Chem., 332,226 (1904). 473. N. W. Gilman, J. F. Blount, and R. I. Fryer, J . Org. Chem., 41, 737 (1976). 474. C.-M. Liu, unpublished data, Hoffmann-La Roche, Nutley, NJ. 475. C. W. Perry, unpublished data, Hoffmann-La Roche, Nutley, NJ. 476. H. Lehr, unpublished data, Hoffmann-La Roche, Nutley, NJ. 477. J. M. Osbond, unpublished data, Roche Products Ltd., Welwyn, England. 478. W. Hunkeler, unpublished data, Hoffmann-La Roche, Basel, Switzerland. 479. E. Wenis, unpublished data, Hoffmann-La Roche, Nutley, NJ. 480. H. Shimizu, unpublished data, Nippon Roche K.K., Tokyo. 481. W. Voegtli, unpublished data, Hoffmann-La Roche & Co., AG, Basel, Switzerland. 482. K. E. Fahrenholtz, unpublished data, Hoffmann-La Roche, Nutley, NJ. 483. R. W. Lambert, unpublished data, Roche Products Ltd., Welwyn, England. 484. R. F. Lauer, unpublished data, Hoffmann-La Roche, Nutley, NJ. 485. E. Kyburz, unpublished data, Hoffmann-La Roche & Co., AG, Basel, Switzerland. 486. G. Zanetti, unpublished data, Hoffmann-La Roche & Co., AG, Basel, Switzerland. 487. R. A. LeMahieu, unpublished data, Hoffmann-La Roche, Nutley, NJ. 488. H. Ramuz, unpublished data, Hoffmann-La Roche & Co., AG, Basel, Switzerland. 489. U. Koelliker, unpublished data, Hoffmann-La Roche & Co., AG, Basel, Switzerland. 490. W. Aschwanden, unpublished data, Hoffmann-La Roche & Co., AG, Basel, Switzerland. 491. H. Pauling, unpublished data, Hoffmann-La Roche & Co., AG, Basel, Switzerland. 492. P. J. Machin, unpublished data, Roche Products Ltd., Welwyn, England. 493. A. A. Liebman, unpublished data, Hoffmann-La Roche, Nutley, NJ. 494. R. Schwob, unpublished data, Hoffmann-La Roche & Co., AG, Basel, Switzerland. 495. J. M. Cassal, unpublished data, Hoffmann-La Roche & Co., AG, Basel, Switzerland. 496. W. Zwahlen, unpublished data, Hoffmann-La Roche & Co., AG, Basel, Switzerland. 497. B. Pecherer, unpublished data, Hoffmann-La Roche, Nutley, NJ. 498. A. V. Bogat-skii, Yu. I. Vikhlyaev, S. A. Andronati, T. A. Klygul, and Z. I. Zhilina, Chem. Heterocycl. Compd., 9, 1413 (1973). 499. (a) G. Jommi, G. Riva, F. Mauri, and L. Mauri, US. Patent 3,654,267, April 1972. (b)G. Jommi, G. Riva, and F. Mauri, U.S. Patent 3,798,212, March 1974. 500. R. I. Fryer, B. Brust, J. Earley, and L. H. Sternbach, J . Med. Chem., 7,386 (1964). 501. J. F. Blount, R. I. Fryer, N. W. Gilman, and L. J. Todaro, Molec. Pharm., 24,425 (1983).
CHAPTER VIII
Tetrahydro- and Polyhydro.1. 4. Benzodiazepines A. Walser Chemical Research Department. Hoffmann-La Roche Inc., Nutley. New Jersey
and
R. Ian Fryer Department of Chemistry. Rutgers. State University of New Jersey. Newark. New Jersey
1. 2.3.4.5.Tetrahydro.lH.l. 4.benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1.1. By Reduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1.2. Other Syntheses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2. Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2.1. Reactions with Electrophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2.1.1.Oxidation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2.1.2. Reactions with Nitrogen Electrophiles . . . . . . . . . . . . . . . . . . 1.2.1.3.Reactions with Carbon Electrophiles . . . . . . . . . . . . . . . . . . A. Alkylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Reaction with Aldehydes and Ketones . . . . . . . . . . . . . . . C. Acylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2.1.4.Sulfonation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2.2.Reactions with Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2.2.1.Reduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2.2.2.Hydrolytic Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2.2.3.Other Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. 1,3,4,5-Tetrahydro-1,4-benzodiazepin-2(2H )-ones . . . . . . . . . . . . . . . . . . . . . . 2.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.1.By Reduction and Oxidation . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.2.By Additions to the 4, 5-Double Bond . . . . . . . . . . . . . . . . . . . . . . . 2.1.3.By Ring Expansion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.4. Other Syntheses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 849
851
851 851 854 858
858 858 858 859 859
859 860 861 861 861 861 862
864 864 864 866 867 868
850
Tetrahydro- and Polyhydro.1. 4.Benzodiazepines
2.2. Reactions of 1.3,4,5.Tetrahydro.l,4.benzodiazepin.2(2H).ones
. . . . . . . . . . . . . 869
2.2.1. Reactions with Electrophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.1.1. Halogenation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.1.2. Oxidation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.1.3. Reactions with Nitrogen Electrophiles . . . . . . . . . . . . . . . . . 2.2.1.4. Reactions with Carbon Electrophiles . . . . . . . . . . . . . . . . . . A. Alkylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Reactions with Aldehydes and Ketones . . . . . . . . . . . . . . C. Acylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.1.5. Sulfonation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.2. Reactions with Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.2.1. Reduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.2.2. Reactions with Oxygen Nucleophiles . . . . . . . . . . . . . . . . . . 2.2.2.3. Reactions with Nitrogen Nucleophiles . . . . . . . . . . . . . . . . . 2.2.2.4. Other Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. 1,2,4,5-Tetrahydro-1,4-benzodiazepin-3(3H )-ones
869 869 869 869 870 870 871 872 873 874 874 874 875 876
...................... ........................................... 3.2. Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. 1,2,3,4-Tetrahydro.1,4.benzodiazepin.5(5H )-ones . . . . . . . . . . . . . . . . . . . . . . 4.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
876 876
From Anthranilic Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . By Ring Expansion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . By Reduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Other Syntheses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
878 879 881 882
...........................................
883
3.1. Synthesis
4.1.1. 4.1.2. 4.1.3. 4.1.4.
4.2. Reactions
878 878 878
4.2.1. Reactions with Electrophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.2. Reactions with Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.2.1. Reduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.2.2. Reactions with Oxygen Nucleophiles . . . . . . . . . . . . . . . . . . 4.2.2.3. Reactions with Nitrogen Nucleophiles . . . . . . . . . . . . . . . . . 4.2.2.4. Other Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
883 884 884 885 886 887
5. 4,S-Dihydro-lH.1,4.benzodiazepin-2,3(2H,3H)-diones . . . . . . . . . . . . . . . . . . . 5.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6. 3,4-Dihydro-lH.l,4-benzodiazepin.2,5(2H,5H)-diones . . . . . . . . . . . . . . . . . . . 6.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1.1. From Anthranilic Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1.2. By Ring Expansion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1.3. Other Syntheses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2. Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2.1. Reactions with Electrophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2.2. Reactions with Nucleophiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7. 2,4-Dihydro-lH.l,4-benzodiazepin.3,5(3H,5H)-diones . . . . . . . . . . . . . . . . . . . 8. Tetrahydro-1,4.benzodiazepinthiones . . . . . . . . . . . . . . . . . . . . . . . 8.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.2. Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9. Octahydro- and Decahydro-1,4-benzodiazepines . . . . . . . . . . . . . . . . . . . . . .
887 887 888 889 889 889 891 893 894 894 895 897 898 898 899 900
1. 2,3,4,5-Tetrahydro- 1 H - 1,4-Benzodiazepines
851
.......................................
901
11. References.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
943
10. Table of Compounds
INTRODUCTION This chapter describes the chemistry of tetra-, octa-, and decahydrol,Cbenzodiazepines, as well as the carbonyl and thiocarybonyl derivatives, such as 2-ones, 3-ones, 5-ones, 2,3-diones, 2,5-diones, and 3,5-diones. The octa- and decahydro compounds discussed in Section 9 could also be considered as cyclohexa [el [ 1,4]diazepines. The related carbocyclic system cyclopenta [el [1,4]diazepine ring system is reviewed in Chapter IX, Section 1.
1. 2,3,4,5-TETRAHYDRO-lH-1,4-BENZODIAZEPINES 1.1. Synthesis
I . I . I . By Reduction Most tetrahydro-1,4-benzodiazepineswere prepared by reduction of comR,, R,, pounds with higher oxidation levels. Thus, the parent compound 2 (Rl, R4,X = H)was obtained by reduction of the corresponding 2,5-dione 1 with The same compound was also prepared by lithium aluminum hydride (Eq. cleavage of the 1-benzyl derivative 2 (R, = PhCH,; R,, R,, R,, X = H),which was accessible by reduction of the appropriate 2,5-dione with lithium aluminum hydride., Several 1-, 3-, and 4-substituted tetrahydro-1,4-benzodiazepineswere analogously obtained from the substituted 2,5-dione~.’*~-’ 1).’s2
//I
1
LiAIH,
4$-TR3 0 3
2
t
LiAIH,
R4 4
852
Tetrahydro- and Polyhydro-1,4-Benzodiazepines
Similar reductions were also carried out on the 5-ones 38*9and the 5-ones 4.10."
5-Substituted tetrahydro derivatives 8 were synthesized by reduction of 5 and The transformation of 6 to 8 worked well with lithium aluminum hydride in the presence of aluminum chloride', or with diborane in boiling tetrahydrofuran (Eq. 2).14,15 Treatment of 6 with a combination of sodium borohydride and boron trifluoride in refluxing tetrahydrofuran also gave good yields of the totally reduced products 8.'' The 5-phenyl derivatives 8 (R,, R, = H; R, = Ph; X = H, 7-C1) were obtained by reduction of the 3-ones 7 (X = H, C1) with lithium aluminum hydride.16 6.12- I5
The pentasubstituted derivative 10 was prepared by treatment of the 2,3dione 9 with lithium aluminum hydride in refluxing tetrahydrofuran (Eq. 3)."
9
10
The reduction of the nitrones 11 and 12, where (R, = H, Me; R, = H, Me; R, = Ph; R, = H; X = 7-C1)20*21 and 1318*22 with lithium aluminum hydride afforded the 4-hydroxy compounds 14 (Eq. 4). Reduction of 11 (R, = Me, R, = H, R, = Ph, X = 7-Cl)" and 11 [R, = N(NO)Me, R, = H, R, = Ph, X = 7-C1] gave 14 (Rl, R,, R3, R, = H; R, = Ph; X = 7-C1) as a product." Treatment of the spiro compound 12 [R, = Me; R,, R, = +CH,),-; R, = Ph; X = 7-C1] with lithium aluminum hydride yielded the 2,4-dihydroxy R, = Ph; X = 7derivative 14 [R, = Me; R, = OH; R,, R, = -(CHJ,-;
1. 2,3,4,5-Tetrahydro-1 H-1,4-Benzodiazepines
853
Cl].” The sterically hindered carbonyl function at the 2-position was reduced only to the carbinolamine.
The nitrone 15 could be reduced by lithium aluminum hydride to the 4-hydroxy compound 16 with retention of the acetyl group. Under more vigorous conditions the acetyl group could be reduced to give 16 (R = H) (Eq. 5).’, A commonly applied method for the preparation of the tetrahydro1H-1,Cbenzodiazepines 18 involved the reduction of the imine bond in 17. Zinc and acetic acid,24 iron and hydrochloric acid,’ and catalytic hydrogenation using platinumz6 have been successfully used for this transformation. Hydrogenation of the 3-hydroxy derivative 17 (Rl, R, = H; R, = OH; R, = Ph; X = C1) over platinum as a catalyst led to the tetrahydro compound 18 (Rl, R,, R, = H; R, = Ph; X = Cl).”
15
16
ZniHOAc HZiR or
Xd
y R4 ---N R
* 4 X
17
f
R
3 R4 NH 18
,
Tetrahydro- and Polyhydro-1,4-Benzodiazepines
854
The 4-hydroxy compounds 20 (R = H, Me) were products of the reduction of the aziridinoquinazolines 19 (R = H, Me, CH,Cl) with sodium borohydride in diglyme at 5-10°C (Eq. 6).l8sZ2 H NaBH,
c1 Ph
+
Jqb
c1
N\
Ph OH
19
20
The quaternary salts 21 (R, = alkyl) could be reduced by hydride reagents to the 4-alkyl-substituted tetrahydrobenzodiazepines22 (Eq. 7).28
1.I.2. Other Syntheses The 4-acyliminium intermediate 21 (R, = R4CO), generated by addition of acyl chlorides to the imine, were reacted with such nucleophiles as hydroxide and alkoxides to form the 4-acyl derivatives 24.'7*29 Compounds 24 (R4 = MeO, benzyloxy, EtO, Me; R, = H, Me, Et) were thus obtained by treatment of the imines 23 with alkoxycarbonyl chloride or acetyl chloride in the presence of aqueous or alcoholic potassium carbonate.
Compound 26 (R, = H, R, = Ph) was accessible by addition of phenylmagnesium bromide to the 5-unsubstituted imine 25 (R,= H),30 while the 5 3 disubstituted compounds 26 were synthesized by addition of Grignard or lithium reagents to the imine of 25 (R, = Ph) (Eq. Q Z 9 The reagents that could
1. 2,3,4,5-Tetrahydro-lH-1,4-Benzodiazepines
855
successfully react with the imine 25 (R, = Ph) included phenyllithium, butyllithium, and 3-Me2N-propylmagnesium chloride. Me
Me
25
26
The 4-formyl derivatives 28 (R = H, Ph) were synthesized by reaction of the N-(2-aminoethyl)aniline 27 with formaldehyde and benzaldehyde, respectively, in formic acid (Eq. 9).,'s3' The tropanyl analogs 29 were similarly transformed into the benzodiazepines 30 by heating with formaldehyde in formic acid.32 Ye
Ye
O N M N H ,
c1 R
21
o
28
(9) 7 1
r
XD & N -
Me 30
29
The 1,Cditosylate 32 [R, = R, = (4-MeC6H,)SO,, R, = X = H] was prepared by a double alkylation of the aniline 31 [R, = R, = (4-MeC6H,)SO,, R, = X = H] with 12-dibromoethane and sodium butoxide (Eq. lo).,, Removal of the tosyl groups by hydrolysis with sulfuric acid led in high yield to the parent compound. A related alkylation of the diamine 31 (R, = Me, R, = H, R, = Ph, X = C1) with 1,Zdibromoethane at reflux temperature led to the benzodiazepine 32 (R, = Me, R, = H, R, = Ph, X = Cl).,, kl
-QQ P1
B , W B ' basc
XG
W R3R 31
,
X
R3 N\ Rz
32
(10)
856
Tetrahydro- and Polyhydro-l,4-Benzodiazepines
Intramolecular trapping of the carbonium ion by an amide nitrogen was found to be a successful way of obtaining tetrahydrobenzodiazepine34.The ring closure of the benzhydrol 33 to 34 was conveniently carried out with concentrated sulfuric acid at approximately 0°C (Eq. ll).” Me
Me
I
(11)
c1
c1
OMe Ph
Ph
33
0
34
Reductive cleavage of the carbon-oxygen bond in the tricyclic compound 35 by sodium borohydride gave the alcohol 36 (Eq. 12).35
Q-j - q> Me I
Me
NaBH
c1
C1
(12)
N*OH
Ph 36
35
The l-phenyl compound 38 was prepared by desulfurization of the tetracyclic diazepine 37 (Eq. 13).33
31
38
Reaction of the 2-chloromethylquinazoline 3-oxide 39 with the anion of N,Ndimethylacetamide, generated with lithium diisopropylamide in tetrahydrofuran at low temperature, gave the 2-acetylidene derivative 40 in addition to the expected nitrone. Compound 40 was apparently formed by addition of a second mole of the acetamide anion to the initial product.” Addition of nitromethane anion to the 4,5-imine bond leading to 42 was observed during the reaction of the nitrosoamidine 41 with nitromethane and potassium t-butoxide (Eq. 14).36
1. 2,3,4,5-Tetrahydro1H-1,4-Benzodiazepines
857
0 I1 Mc,NCCH;
c1
CI Ph 39
No
b’
42
41
The 2-methylene derivative 44 resulted from the reduction of the oxime 43 (R = CN) with zinc and acetic acid followed by a reaction with dimethylformamide dimethylacetal. Compound 45 was similarly prepared by the reduction of its corresponding 4,5-azomethine precursor with zinc and acetic acid. l 7 The tetrahydro derivative 46 resulted from the treatment of the oxime 43 (R = COOEt) with sodium borohydride (Eq. 15)”
c1
onR=CN
44
43
c1
c1 45
46
(15)
858
Tetrahydro- and Polyhydro-1,4-Benzodiazepines
The 5-dichloromethylene-l,4-benzodiazepine 48 was formed by the reaction of the dichloroacetyl derivative 47 with phosphorus oxychloride and phosphorus pentachloride (Eq. 16).17
Me
41
48
1.2. Reactions
1.2.1. Reactions with Electrophiles 1.2.1.1. Oxidation 18 to the The oxidation of the 2,3,4,5-tetrahydro-lH-l,4-benzodiazepines 2,3-dihydro-lH-l,4-benzodiazepines 17 and of the 4-hydroxy analogs to the corresponding nitrones was discussed in Chapter VI, Section 1.1.7. Introduction of a carbonyl group at the 2-position of tetrahydro derivatives will be discussed in this chapter, in Section 2.1. Oxidation of the l-methyl-5,5-diphenyl compound 49 with chromium trioxide led to the 1-formyl analog 50 (Eq. 17).29
Me
OYH
49
50
1.2.1.2. Reactions with Nitrsgen Electrophiles The 4-acetyl compounds 51 (X = H, C1) were nitrosated at the 1-position to give compounds 52 (Eq. 18).37
N\ .-a2
NO
H
I
HNO
X
N ‘Ac 51
(18)
X ‘AC
52
859
1. 2,3,4,5-Tetrahydro-1 H-1,4-Benzodiazepines
1.2.1.3. Reaction with Carbon Electrophiles A. Alkylation. A basic side chain was attached by alkylation at the 4-position of 53 (X = C1, NO,) to yield the 4-dialkylaminoalkyl derivatives 54 (Eq. 19).38 Me
Jy-J I
Me I
/Rz
CKCHAN,
X
Rl
(19)
R1
NH 53
R* 54
Arylation of the 4-tosyl derivative 55 with iodobenzene in the presence of copper and potassium carbonate yielded the 1-Ph-4-tosyl compound 56 (R = 4MeC,H,SO,). Subsequent hydrolysis yielded the 4-hydrogen analog (Eq. 20).33 Ph
H
K) I
S3c-J
PhVCuKKO,
\
~
N\
So2cs H,Me
55
(20)
R
56
Quaternizations of the 4-position nitrogen were carried out on several 4-alkyl derivatives., The 4-tropanyl compounds 30 (R, = Me, Et; X = H), when heated with methyl iodide, formed the diquaternary salts 57 (Eq. 21).32The monomethiodide was also isolated with the tropanyl nitrogen quaternized. Me
Kj
X
@\
N@
Me
30
(21)
NLMe I Me
57
B. Reaction with Aldehydes and Ketones. Reaction of the parent compound 58 (R, = H) with formaldehyde or benzaldehyde yielded the 1,Cbridged compounds 59 (R, = H; R, = H, Ph).39 Treatment of the 5-phenyl analog 58 (R, = Ph) with formaldehyde in refluxing benzene gave similarly 92% of 59 (R, = Ph, R, = H) (Eq. 22).26
860
Tetrahydro- and Polyhydro- 1,4-Benzodiazepines
H
, R1
, R,
58
59
The 1-amino compound 60 was converted to the tetrahydrocarbazole 61 by reaction with cyclohexanone under conditions of the Fischer indc ' e synthesis (Eq. 23).37
n
g-2 Ac
60
6-2) N\ Ac
HOAc
(23)
61
C. Acylation. Double acylations at the 1- and 4-positions were carried out on the parent 2,3,4,5-tetrahydro-lH-l,4-benzodiazepine with acetic anhydride at 100°C.6 Selective acetylation of the more basic nitrogen in the 4-position was possible with acetic anhydride in refluxing ether in the presence of t r i e t h ~ l a m i n eCompounds .~~ substituted at the 1-position were acylated at the 4-position using standard procedures.' ' g 4 0 Compounds bearing a substitutent a t the 4-position were likewise acylated at the l-positi~n.~.' Introduction of the guanidino functionality at the 4-position, to yield 64, was achieved by transfer of the guanidino moiety from the pyrazole 63 to the parent compound 62 (R,= X = H), as well as to the 1-methyl and 7-chloro analogs of 62 by heating at 190-200°C (Eq. 24)' R'
R I
Me
63
64
The guanidine 66 was prepared by reaction of the 4-phenyl derivative 65 with cyanamide (Eq. 25).4
K>
HNYNH2
H
H NCY A
Qf-J
N\
Ph 65
(25)
66
Ph
1. 2,3,4,5-Tetrahydro-lH-1,4-Benzodiazepines
86 1
1.2.1.4. Sulfonation The parent tetrahydrobenzodiazepine 67 (R, = R, = H) was selectively tosylated at the 4-position nitrogen to yield 68 (R, = R, = H, R, = 4MeC,H,SO,) (Eq. 26).,, Other tosylations were carried out on 67 (R, = Me, R, = Ph, X = Cl)31 and on 67 (R, = Me, R, = H, X = Cl).30 Reaction of the latter compound with methanesulfonyl chloride led similarly to the mesylate 68 (R, = R, = Me, R, = H, X = Cl) (Eq. 26).30
67
68
1.2.2. Reactions with Nucleophiles 1.2.2.1. Reduction Lithium aluminum hydride was used to reduce the 1,Cdiacetyl derivative 69 to the 1,Cdiethyl analog 70 (Eq. 27)., The 1-nitroso compound 52 (X = H) was reduced to the 1-amino derivative 60 by zinc and acetic
<> Ac I
N
‘Ac
Et I
LIAIH,
-
K-
69
(27)
Et
70
1.2.2.2. Hydrolytic Reactions Tosyl groups attached at the 1 and 4-positions were cleaved by treatment with 90% sulfuric acid at 110°C.33Selective hydrolysis of the 4-acetoxy moiety of 71 afforded the hydroxyamine 72 (Eq. 28).20
71
72
862
Tetrahydro- and Polyhydro-l,4-Benzodiazepines
Hydrolytic ring opening of compounds 24 (R, = Me; R, = Ph; R, = Me, MeO, EtO, benzyloxy; X = 7-C1) afforded the corresponding benzophenones 73 (Eq. 29).29
13
24
Treatment of the bismethiodide 57 with the hydroxide form of the ionexchange resin IRA400 was reported to yield the vinylamine 74, characterized as a dipicrate (Eq. 30).,’
14
hie 51
1.2.2.3. Other Reactions Abstraction of a proton from the 5-position of 75, in which R, represents a leaving group, leads to the formation of the 2,3-dihydro-lH-1,4-benzodiazepines 76.This synthesis of 76 is discussed in detail in Chapter VI, Section 1.1.8. When the 4-hydroxy compounds 75 (R, = HO) were treated with thionyl chloride, the tetrahydroquinoxalines 80 were formed.” When phosphorus oxychloride was used in place of thionyl chloride, the formation of the quinoxaline became the main reaction. An electron-rich nitrogen at the l-position of the benzodiazepine 75 is essential for this ring contraction to proceed, since treatment of the l-acetyl derivative 75 (R, = Ac, R, = H, R, = HO, X = 7-C1) with phosphorus oxychloride gave only the dehydration product 76. The mechanism of this ring contraction was formulated as shown in Eq. 31. The intermediacy of the ions 78 or 79 was supported by isolation of the 4-benzyltetrahydroquinoxaline from a reductive workup. Phenyl isocyanate could also effect the ring contraction as well as the dehydration steps. When 75 (R, = Me, R, = H, R, = HO, X = 7-C1) was heated in toluene to reflux in the presence of excess phenyl isocyanate, the urea 81 was the major isolated product.” The oxidation of 7-chloro-l-methyl-5-phenyl-2,3,4,5-tetrahydro-lH-1,4benzodiazepine to the corresponding imine was reported to proceed in di-
1. 2,3,4,5-Tetrahydro-lH-1,4-Benzodiazepines
863
Ph 16
.2
1
Hzo
.
c1
H un
19
Me
75
+
aN1
c1
N
O ~ IN H Ph 81
methyl sulfoxide in the presence of ultraviolet light to yield about 4% of the irni~~e.~’ The amidine 44 was thermally cyclized to the imidazobenzodiazepine 82 by heating in acetic acid (Eq. 32).17
l
o-” 44
5’ 82
864
Tetrahydro- and Polyhydro-1,4-Benzodiazepines
2. 1,3,4,5-TETRAHYDRO-1,4-BENZODIAZEPIN-2(2H)-ONES 2.1. Synthesis
2.1.1. By Reduction and Oxidation Most tetrahydrobenzodiazepin-2-ones were prepared by reduction of the imine bond in the dihydrocompounds 6 (Eq. 33). Reagents of choice were zinc and acetic and hydrogen over platinum ~ a t a l y s t . ~ , -Catalytic ’~ hydrogenation over palladium on carbon was also reported to effect reduction of the imine 6 (R, = R, = X = H, R, = Ph) to the corresponding amine 5.57,58The parent compound 5 (R, = R, = R, = X = H) was obtained in 60% yield by hydrogenation of the corresponding imine 6 or its 4-oxide over Raney nickel.59 This catalyst generally left the imine untouched. The reduction of the imine in 5-substituted compounds 6 was rarely observed.60
R3 6
Xd \ f
R”\ 2 R3 83
R4 84
The 4-oxides of 6 were reduced to the amines 5 in quantitative yield by zinc and acetic a ~ i d . ~ ’ ,Reduction ~ ~ , ~ ’ of 83 (R4= 0),with hydrogen in acetic acid solution, using platinum as catalyst, led to the 4-hydroxy compounds 84 (R, = OH).41,47*49,51 The parent 4-hydroxy 84 (R, = R, = R, = X = H, R, = OH) was formed in 15% yield during the hydrogenation of the corresponding 4-oxide with palladium on carbon as catalyst5’ High yield imine reductions were observed with sodium borohydride in acetic or with sodium cyanoborohydride in methanol containing hydrochloric acid.60 Aluminum amalgam was reported to reduce 6 (R, = H, R, = COOEt, R, = Ph, X = 7-C1) to the corresponding amine of undefined stereo~hemistry.~~ The 4-hydroxy compound 84 (R, = Me, R, = H, R, = 2-FC6H,, R, = OH,
1. 2,3,4,5-Tetrahydro-lH-1,4-Benzodiazepines
865
X = 7-1) was prepared by treatment of the appropriate nitrone with sodium borohydride in ethanol-tetrahydrofuran at 50-60"C.6s This reagent allowed also the conversion of the quaternary salts 83 to the 4-alkyl derivatives 84 (R, = a1ky1).54*58,66 Catalytic hydrogenation of the oxazolobenzodiazepines 85 and 86 (R = Me) over platinum catalyst led to the 4-(2-hydroxyethyl) derivative 87 (R = Me) (Eq. 34).67The reduction of the carbon-oxygen bond of the oxazole 86 (R = H) to yield 87 (R = H) was also possible with sodium b ~ r o h y d r i d e . ~ ~
81
As demonstrated in Eq. 35, the 1,5-dihydro tautomer 88 could also be reduced to the amine 89 by hydrogen over platinum catalyst.68
88
89
A reductive alkylation of the imines 90 (X = H, C1, NHCH,SMe) was observed, when these compounds were treated with Raney nickel in refluxing ethanol. The 7-chloro compound was thus converted to the 4-ethyl derivative 91 (X = H) by concomitant dehalogenation. The methylthio function of Me
X
&f ' -N Ph
90
Me Raney nickel ElOH
(36)
* X
Ph 91
Et
866
Tetrahydro- and Polyhydro-1,4-Benzodiazepines
90 (X = MeSCH,NH) was cleaved under these conditions and led to 91
(X = MeNH) (Eq. 36).37 The patent literature describes the direct conversion of the carbobenzoxy compounds 92 to the tetrahydro-2-ones 93 by catalyic hydrogenation over palladium on carbon in the presence of acetic or hydrochloric acid. The 7-amino derivative 93 (R, = H, X = NH,) was also formed, in 84% yield, by this process (Eq. 37).69
Ph
Ph 93
92
A few syntheses of tetrahydrobenzodiazepin-2-onesby oxidation were also reported. The 4-acetyl derivative 94 (R = Ac) was oxidized to the corresponding 2-one 95 by potassium permanganate in approximately 95% yield (Eq. 38).70 Introduction of a 2-carbonyl function into the tetrahydro compound 94 (R = H) was achieved in 15% yield by using chromium trioxide in sulfuric a ~ i d . ~ ' , ~ ,
94
95
2.1.2. By Additions to the 4J-Double Bond 5,5-Disubstituted compounds 97 were obtained by addition of a variety of nucleophiles to the quaternary salts 96 (R, = alkyl). Nucleophiles added to % include ammonia, a m i n e ~ , ~alk~xides,~, , and Grignard reagent^^,,^^ (Eq. 39). The intermediate acyliminium ions 96 (R, = acyl), generated by addition of acyl chlorides son the appropriate imine, also added nucleophiles such as alkox97 (R, = H, Me; R, = COOMe, COOEt; R3 = Ph, i d e ~ . ' ~Compounds ,~~ 2-pyridyl; R, = OEt, OMe) were formed when the corresponding imines were stirred in methylene chloride with alkyl chloroformate and solid potassium carbonate.
2. 1,3,4,5-Tetrahydro-l,4-Benzodiazepin-2(2H)-Ones
8
R3
867
.
R2
97
96
The formation of the 4-nitro compound 97 (R, = C1,R, = NO,, R, = Ph, R, = AcO, X = 7-C1) by the reaction of the corresponding imine with nitric acid in acetic anhydride may be rationalized by addition of acetate anion to the The reaction of diaintermediate 4-nitroiminium species 96 (R, = zepam (98) with acetylene dicarboxylate in methanol led to 99 (Eq. 40).75 This transformation represents another example of the successive addition of electrophile and nucleophile to the imine bond. Me
@y '
c1
---N Ph
Me00C-CzC-COOMe MeOH
* c1
(40) COOMe
98 99
The 4-hydroxybenzodiazepin-2-ones101 resulted from the addition of Grignard reagents to the nitrone 100 (Eq. 41). The Grignard reagents used were phenylmagnesium b r ~ m i d eand ~ ~ methylmagnesium ,~~ bromide.29
2.1.3. By Ring Expansion A Beckmann rearrangement of the oximes of tetrahydroquinolin-4-ones 102 provided another method for the preparation of benzodiazepin-2-ones 103.56,77,78 The Schmidt reaction on the quinolone 102 gave higher yields of the Compound 103 (R = H, X = C1) was obtained in 48% yield product 103.56,78 by treating the quinolone 102 (R = H, X = C1) with excess sodium azide in concentrated sulfuric acid (Eq. 42).78
Tetrahydro- and Polyhydro- 1,4-Benzodiazepines
868
x
4N,R - .-c'-I
(42)
X
Ph
Ph
R
103
102
2.1.4. Other Syntheses According to a Russian patent,79 the benzhydrols 104 may be converted in high yields to the tetrahydrobenzodiazepin-2-onesby first treating the benzhydrole with trifluoroacetic anhydride and triethylamine at low temperature and subsequently treating with glycine methyl ester hydrochloride and triethylamine in refluxing chloroform (Eq. 43).
104
105
The method mentioned above may be considered a variation of the synthesis, previously reported, which involved preparation of the glycine derivative 106 followed by ring closure and by dehydration to form 89. The ring closure could be effected by heating in xylene and azeotropically removing ~ a t e r , ~or~ by ,'~ using phosphorus pentachloride (Eq. 44).'l H
c1<>COOH
NH
-",Ow
O
Qf--SH
c1
(44)
Ph 106
89
Generating the carbonium ion of the benzhydrol 107 led to ring closure through an intramolecular trapping by the nitrogen atom of the glycine moiety. Thus 107 (R, = Et,NCH,CH,, R, = H, R, = 2-FC6H,) was converted to the benzodiazepine 108 by treatment with hydrogen bromide in acetic acid (Eq. 45).*, The 4-acyl derivatives 108 (R, = Ac, COOEt) were obtained in high yield when the corresponding benzhydrols were stirred in cold concentrated sulfuric acid.
2. 1,3,4,5-Tetrahydro-l,4-Benzodiazepin-2(2H)-One~
R 1
q
r
N
H
c1
R
2
H,SO,
OH
.
c1
869
(45)
R3
R3
I07
R2
108
2.2. Reactions of 1,3,4,5-Tetrahydro-l,4-benzodiazepin-2(2H)-ones
2.2.1. Reactions with Electrophiles 2.2.1.1. Halogenation The 4-bromo derivatives 110 (X = Br) are most likely intermediates in the oxidation of 109 to the corresponding i m i n e ~ . ' ~ *The * ~ 4-bromo compound 110 [R, = Me, R 2 = 3,4-(MeO),-benzyl, X = Br] was isolated and characterized by B r ~ g e r . ~ ~
df
c1
NH R2
x2
.
c14
f
R N\2 h
Ph
(46)
X
110
109
2.2.1.2. Oxidation to the corThe oxidation of 1,3,4,5-tetrahydro-l,4-benzodiazepin-2(2H)-ones responding 1,3-dihydro and 1,5-dihydro derivatives was discussed in Chapter VII, Section 1.1.5.
2.2.1.3. Reactions with Nitrogen Electrophiles The 4-nitroso compounds 111 were prepared by reaction of the tetrahydrobenzodiazepin-2-ones 93 with nitrous acid (Eq. 47).86
93
111
870
Tetrahydro- and Polyhydro- 1,4-Benzodiazepines
Nitration of compound 112 (R = X = H) with potassium nitrate in concentrated sulfuric acid gave a mixture of the 4'- and 3'-nitro derivatives, 113 and 115 (X = H) (Eq. 48).52*87 The 2'-fluoro analog 112 (R = H, X = F) afforded, under similar conditions, 81% of the 5'-nitro compound 115 (X = F).87The 4-hydroxybenzodiazepine 112 (R = OH, X = H) was reported to nitrate at the 7-position when treated with nitric acid in acetic acid-methylene chloride at O"C.76Nitration of the same compound with nitric acid in sulfuric acid at 0°C was found to lead directly to nitrazepam, by elimination of water and nitration at the 7-po~ition.'~The 7-chloro derivative of 112 (R = OH, X = F) was nitrated in the para position to the fluorine, yielding 114."
112
114
1 I5
2.2.1.4. Reactions with Carbon Electrophiles A. Alkylation. Compounds 116 were selectively alkylated at the 1-position by generating the anion with a strong base such as sodium methoxide or sodium hydride and reacting this anion with the alkylating agent at temperatures ranging from - 10 to 25°C. Alkylations at the 1-position were thus carried out with methyl iodide43 and with 4-bromobutanoic acid ethyl ester (Eq. 49)." 4-Alkyl and 4-acyl derivatives 116 (R = alkyl, acyl) were readily alkylated at the 1-position under similar ~ o n d i t i o n s . ~ ~ , ~ ~ , ~ ~ The anions of 116 (R, = H) were reacted with excess alkylating agents at slightly elevated temperature to form the 1P-dialkyl derivatives 118. Such double alkylations were carried out with methyl iodide,43,45,46,49 ally1 broCompounds 116 (R, = H) could mide,43g49and N-methylbrornoa~etamide.~~ also be selectively alkylated at the 4-position nitrogen. Successful monoalkyla-
2. 1,3,4,5-Tetrahydro-l,4-Benzodiazepin-2(2H)-Ones
1 I6
118
\
87 1
117
1 I9
tions at the 4-position were reported with methyl benzyl chloride,56 and ethyl brom~acetate~'to give the 4-alkyl derivatives 119. Compounds bearing a substituent at the 1-position were similarly reacted with methyl iodide,29,43*54*55 dimethyl sulfate,29 ethyl i ~ d i d e , "ally1 ~ proand l-chloro-2-(diethylamino)pargyl bromide,29N-methylbrom~acetamide,~~ to give the corresponding 4-alkyl derivatives. Ethyl acrylate, added to the 4-position nitrogen in a Michael fashion and ~~ yielded the corresponding 4-(2-ethoxycarbonyl)ethyl d e r i ~ a t i v e .Quaternizations of the 4-methyl compounds49 with methyl iodide was reported to give the 4,4-dimethyldiazepinium salts. However, for 117 (R, = 2-Et2N-ethyl, R, = Me, R, = 2-FC6H,, X = 7-C1), quaternization yielded the quaternary salt on the nitrogen in the side chain.55
B. Reactions with Aldehydes and Ketones. The 4-amino compound 120 was reacted with a variety of substituted benzaldehydes to form the imines 121 (Eq. 50).*,
120
121
Condensation of the diamine 122 (X = Br, C1) with benzaldehyde and acetone led to the tetracyclic quinazolinobenzodiazepines123 (Eq. 51).53
872
Tetrahydro- and Polyhydro-l,.l-Benzodiazepines
C . Acylation. Acylations of the 4-position nitrogen were carried out with a variety of reagents under standard conditions. They included acid anhyd r i d e ~ , ~acid ~ , chlorides,29390 ~ ~ ~ * ~ ~ phosgene,” chloroform ate^,^^^^^^^^ and i s o c y a n a t e ~The . ~ ~4-formyl ~ ~ ~ ~ derivatives were obtained by reaction of 124 with ethyl formate.” Addition of phosgene to 124 resulted in the formation of the 4-chlorocarbonyl compounds 125 (R, = C1) (Eq. 52).90The urea 126 was obtained in 66% yield from the reaction of 124 (R, = Me, R, = Ph, X = 7-C1) with phosgene.” The 4-aminocarbonyl derivatives 125 (R3 = NH,) were prepared by means of potassium cyanate and acetic Amino acids were attached the 4-position of 124 by the mixed anhydride method, followed by deprotection of the amino f ~ n c t i o n . ~ ~ . ~ ~
R2 124
Me
c1 Ph
8
Ph
126
The 4-hydroxy derivatives were converted to the corresponding 4-acetoxy compounds by reaction with acetic anhydride.4’,47.9’s92Treatment of the 4-hydroxy compound with phenylisocyanate and 1,4-dimethylpiperazine or pyridine in refluxing 2-acetoxybutane led to elimination of water with formation of the 4,5-double bond.75 The same transformation was noticed when the 4-hydroxy compounds were reacted with dicyclohexylcarbodiimide in ~ y r i d i n eor~ in ~ refluxing toluene:’ Acylations of the 4-amino group in 120 were also reported.86
2. 1,3,4,5-Tetrahydro-1,4-Benzodiazepin-2(2H)-Ones
873
An intramolecular acylation was observed with the ester 127, which upon heating in quinoline, cyclized in 54% yield to the pyrrolobenzodiazepine 128 of undefined stereochemistry (Eq. 53).62 Me
c1d
NH 0
W
.
t
-
#h 127 128
Reaction of the diamines 122 (X = Br, C1) with carbonyldiimidazole afforded 129.53Compound 130 (R = H) resulted from the reaction of 122 (X = C1) with triethyl orthoformate, while the methyl analog 130 (R = Me) was formed by cyclization of the 2’-acetylamino derivative (Eq. 54).53
122 X=CI
129
I
130
2.2.1.5. Sulfonation Reaction of the 4-position nitrogen with p-toluenesulfonyl chloride41,47,68*78*82q93 and with methanesulfonyl ~ h l o r i d e led ~ ~ to , ~ the ~ 4-sulfonylated benzodiazepines. Treatment of the 4-hydroxy compound with thionyl chloride in chloroform yielded 34% of the dehydration This dehydration was also effected by phosphorus oxychloride in ~ y r i d i n e . ~ ~
874
Tetrahydro- and Polyhydro- 1,4-Benzodiazepines
2.2.2. Reactions with Nucleophiles 2.2.2.1. Reduction The reduction of the 2-carbonyl group to the hydrocarbon level was discussed in Section 1.1.1 above. The 4-nitroso derivatives 111 were reduced to the corresponding 4-amino derivatives by zinc and acetic acid.86The 7-nitro-4-nitroso analog was similarly converted to the 4,7-diamino compound.86 The l-chloro compound 131 was reduced by methylamine in methylene chloride at room temperature to the lactam 132 (Eq. 55).74 The chloronium ion was apparently transferred from 131 to the methylamine.
131
132
Hydrogenolysis of the 4-benzyl derivative was carried out over palladiuin catalyst in the presence of acetic and hydrochloric 2.2.2.2. Reactions with Oxygen Nucleophiles The hydrolysis of 89 to the ring-opened acid 106 was effected by barium hydroxide in boiling methanol-water (Eq. 56).51980
Ph 89
Ph 106
The 4-nitro derivatives 133 were hydrolyzed by water to the benzophenones 134.74The 4-acyl compounds 135 underwent the same type of hydrolytic ring opening to yield the benzophenones 136 (Eq. 57).'7329
133
134
2. 1,3,4,5-Tetrahydro-1,4-Benzodiazepin-2(2H)-Ones
875
0
Ph 135
136
(57)
Other reported hydrolytic transformations include removal of a 4-acetyl group7' or conversion of side chain ester functions attached at the 1- and 4-positions of the corresponding acid8' or a l c ~ h o l . ~ ' 2.2.2.3. Reactions with Nitrogen Nucleophiles Compound 89 was converted to the amidine 137 by reaction with methylamine and titanium tetrachloride (Eq. 58).95
Ph
Ph 137
89
The 4-nitro compounds 133 reacted with ammonia and other amines in a mixture of methanol and methylene chloride at room temperature to form the 3-amino benzodiazepines 138 (Eq. 59).74 Reaction of the same compounds with triethylamine resulted in deprotonation at the 3-position followed by elimination of the 4-nitro group to give compounds 139, which were converted to the 3-amino derivatives 138 by reaction with a m i n e ~ . ~ ~
138
133
(59)
R,R,NH
/'
X
4,R20
139
Ph N
Me
@TY
c1
Ph
140
0R
876
Tetrahydro- and Polyhydro-1,4-Benzodiazepines
The 4-chlorocarbonyl compound 140 (R = C1) was reacted with a variety of amines, including ammonia and hydrazine, to yield the corresponding ureas 140 (R = NRlR2).90 The 7-amino compound 141 was subjected to a nitro Sandmeyer reaction to give the corresponding 7-nitro analog 142 (Eq. 60).83
2.2.2.4. Other Reactions Elimination of the elements HY from the 4-substituted compounds 143 led to a mixture of the tautomers 144 and 145. Such eliminations were carried out with using a variety of strong bases, with 4-acet4-sulfonyl derivatives41~68~82*93~94 oxy corn pound^,^^^^^^^^ 4-nitro derivative^,^^'^^ and 4-hydroxy compounds (Eq. 61).” The 4-hydroxy compounds were, for this purpose, converted in situ to acyl derivatives with phenyl isocyanate” or dicyclohexylcarbodiimide.41
X
143
qf N
2
1
145
3. 1,2,4,5-TETRAHYDRO-1,4-BENZODIAZEPIN-3(3H)-ONES 3.1. Synthesis
The 3-one 147 was prepared by heating to reflux the ethyl ester 146 (R = Et) in pyridine and hydrochloric acid.I6 The corresponding acid 146 (R = H) was
2. 1,3,4,5-Tetrahydro-1,4-Benzodiazepin-2(2H)-Ones
877
also converted to 147, in this case by boiling in xylene and azeotropically removing water (Eq. 62).16
Ph
Ph
146
147
Compound 148 was isolated from the mixture resulting from the oxidation of the tetrahydrobenzodiazepine 49 with chromic acid (Eq. 63)."
Ye
49
148
Bergman and coworkersg7 reported the formation of the 3-one 150 by the reaction of the a-chloro amide 149 with phenylmagnesium bromide (Eq. 64). The authors rationalized the formation of 150 by invoking the intermediates 151 and 152. Intramolecular attack of the imine anion on the carbonyl group of the aziridinone 151 would generate 152, which could then undergo a hydride transfer to form a 1,2-imine bond, which could be susceptible to another addition of phenylmagnesium bromide to give 150 as a product. Enolization of the 3-one may protect it from further reaction with the Grignard reagent.
149
1
Ph 150
PhMgBr
4
t
PhMgBr
1
B' I
Ph 151
I
Ph 152
_1
878
Tetrahydro- and Polyhydro-1,4-Benzodiazepines
The structure 153 was assigned to one of the products obtained from the treatment of diazepam (98),with phenyllithium (Eq. 65)" It is possible that the carbonyl group was created by air oxidation of an intermediate enamine. Me I
qY
c1
PhLi
Me
. c1
Ph -N
I53
98
3.2. Reactions The reduction of the carbonyl group of 147 to the hydrocarbon by lithium aluminum hydride was mentioned in Section 1.1. Removal of the chlorine at 7-position from 147 was achieved by catalytic hydrogenation over palladium on carbon in the presence of potassium acetate.I6 Alkylation of 147 with dimethyl sulfate afforded the lP-dimethyl derivati~e.~'
4. 1,2,3,4-TETRAHYDRO-1,4-BENZODIAZEPIN-S(SH)-ONES 4.1. Synthesis
4.1 . I . From Anthranilic Acids The tetrahydrobenzodiazepin-5-ones155 (R = Me, benzyl; X = H, 7-C1) were synthesized by an intramolecular alkylation of the anthranilamides 154 (R = Me, benzyl) using sodium hydride in refluxing benzene (Eq. 66).3,8*98,99
R NaH
y
0 154
AICI,
R
."-Xc"
/
X
6 155
t
OMe
0 I56
157
4. 1,2,3,4-Tetrahydro-1,4-Benzodiazepin-S(SH)-Ones
879
Several 1-substituted compounds 155 were prepared in 50-70% yield by reaction of the anthranilate 156 with ethylenimine and aluminum chloride in benzene."' Reduction of the nitrile 157 (R, = Me) followed by ring closure provided another route to compounds 155, in particular to 1-aryl-substituted analogs."' Reduction of the carboxylic acid 157 (R, = Ph, R, = H, X = 4-NOJ with Raney nickel and hydrazine led to the amino acid, which was cyclized by methoxide in boiling methanol to yield the 1-phenyl-8-aminobenzodiazepine.l o 2 4.1.2. By Ring Expansion The ring expansion of variously substituted tetrahydroquinazolin-4-ones was extensively studied by Field and coworker^.'^^ Treatment of 158 (R = H) with potassium t-butoxide in methanol at room temperature gave an almost quantitative yield of the 3-methoxybenzodiazepin-5-one159 (Eq. 67). The 3-methyl analog 158 (R = Me) rearranged to the 3-methylene derivative 160 when it was reacted with potassium t-butoxide in tetrahydrofuran. The exocyclic double bond was hydrogenated over platinum to afford the 3-methyl compound 161. H Me
..
160
161
The 1-methylquinazolinone 162 reacted with potassium t-butoxide in tetrahydrofuran at room temperature to give 48% of the 2-methylenebenzodiazepin-5-one 163, which was similarly hydrogenated to the 2-methyl compound (Eq. 68).'03 Me Me I Me 1-BuOK
THF
* 0
162
163
880
Tetrahydro- and Polyhydro-l,4-Benzodiazepines
Refluxing the dichloromethylquinazolinone 164 in methanol-methoxide led, in high yield, to the 2,3-dimethoxybenzodiazepine165, while the quinazolinone 166 was rearranged by potassium t-butoxide in tetrahydrofuran to the 3-chloromethylene derivative 167 (Eq. 69). Further transformations of these compounds are described in Section 4.2.
164
165
(69)
q H
I-BuOKpHF
NH
0 166
167
These ring expansions were explained by the formation of intermediate aziridines. The aziridine 169 (R = Ph) was actually isolated, and its reaction with various nucleophiles was studied (Eq. 70).’04 The nucleophiles used to open the aziridine ring were hydride, ethanol or methanol, acetate, and ethanethiol or phenylthi01.l~~
170
The quinazolinium salt 171 was reported to react with diazomethane in ethanol to give the 3-ethoxybenzodiazepine 172 (R = H) in 67% yield (Eq. 71).’05 Phenyldiazomethane underwent the same reaction but gave a lower yield of the 2-phenyl analog 172 (R = Ph).
4. 1,2,3,4-Tetrahydro-l,4-Benzodiazepin-5(5H)-Ones
171
88 1
I72
The Schmidt reaction on tetrahydroquinolin-4-ones represents another ring expansion path to benzodiazepin-5-ones. This reaction was first studied by Itterah and Mann,lo6 on 173 (R, = Me, Ph). These authors assigned the structure of a 1,5-benzodiazepine175 to the products. These products were later shown by Wuensch and coworkers'07 to be 1,4-benzodiazepin-5-ones174. Misiti and coworkers' investigated this reaction in detail and reported that it leads to a mixture of 1,2,3,4-tetrahydro-l,4-benzodiazepin-5(5H)-ones (174) and 1,2,3,5-tetrahydro-1,5-benzodiazepin-4(4H)-ones (175). The ratio of these two products was dependent on the substituent on the quinoline nitrogen. Thus, a phenyl substituent at the 1-position of the quinoline favored alkyl migration to predominantly form the lP-diazepines 174.
173
174
Rl
175
The ring expansion reaction of Eq. 72 was used to prepare a variety of 1-phenyl derivatives with substituents in the para position."'
4.1.3. By Reduction The 1,Zimine bond in 176 was reduced catalytically with platinum and hydr~gen'~~ or' ~ by ~ lithium aluminum hydride in tetrahydrofuran (Eq. 73).11~1'0Compound 178 was similarly reduced by catalytic hydrogenation over platinum to the 3-methyl derivative 179.'03
Tetrahydro- and Polyhydro- 1,4-Benzodiazepines
882
177
176
(73)
H
H N 0
0 178
179
4.1.4. Other Syntheses Reaction of the isocyanates 180 (X = H, C1) with aluminum chloride in dichlorobenzene at 150"C afforded the 1-acylbenzodiazepin-5-ones181 (X = H, C1) in 30% yield (Eq. 74).''' oy"--N
Me
nN*v
I
I
Me
AICI,
X
C/I 0
180
*
ax (74)
X 0 181
Benzodiazepin-5-ones 183 with exocyclic methylene groups in the 2-position were obtained by reaction of 182 bearing a leaving group at the 2-position with carbanions (Eq. 75). Useful leaving groups were the N-nitrosomethylamino f~nctionality,'~ as well as the chloride and the phosphoryloxy groups."' The carbanions that reacted with 182 include those of nitromethane and dimethyl malonate.
4. 1,2,3,4-Tetrahydro-l,4-Benzodiazepin-5(5H)-Ones
883
4.2. Reactions
4.2.1. Reactions with Electrophiles Nitrosation of the acetylidene derivatives 184 with sodium nitrite in acetic acid led to the oximes 185 (Eq. 76).'7"'' The oximes were intermediates for the synthesis of imidazo [1,5-a] [l,4] benzodiazepines. COOR,
x<$ 0
N\ R2
184
xqf HON
COOR,
HNol
b
(76)
N\
0
R2
185
The 8-amino derivative 186 was diazotized and the resulting diazonium salt was reacted in situ with various nucleophiles.'0'*'02 During the Sandmeyer reactions with bromide and nitrite, bromination and nitration were observed to occur concomitantly at the para position of the 1-phenyl substituent."' Compound 186 was thus converted to the substituted analogs 187 (X = Br, NO,) (Eq. 77).
x
(77) 0 186
0 187
Methylation of the 1-position was carried out reductively with formaldehyde and hydrogen over palladium in carbon. lo5 The 1-phenyl-8-chlorobenodiazepin-5-one was methylated at the 4-position by treatment with methyl iodide and sodium methoxide in tetrahydrofuran.' O 'JO 2 The conversion of the 5-one to 5-ethoxy-2,3-dihydro-lH-l,4-benzodiazepines by reaction with Meerwein salt is discussed in Chapter VI. 1,2,3,4-Tetrahydro-1,4-benzodiazepin-5(5H)-ones were acylated at the 1-position,"' at the 4 - p 0 s i t i o n , ~ ~ ~ and ' ~ ' simultaneously at both nitrogens." The reagents used include acetic anhydride, propionic anhydride, and benzoyl chloride.
Tetrahydro- and Polyhydro- 1,4-Benzodiazepines
884
4.2.2. Reactions with Nucleophiles 4.2.2.1. Reduction The reduction of the 5-carbonyl function to the hydrocarbon level was discussed in Section 1.1, which dealt with the synthesis of 2,3,4,5-tetrahydro1H-1,Cbenzodiazepines. The 2,3-dimethoxy compound 165 was reduced by lithium aluminum hydride to the 3-methyl analog 179 with retention of the carbonyl group (Eq. 78).'03 H
q
OMe
NH
e Me
H
---%>Me LIAIH,
(78)
NH 0
165
179
Reduction of the 3-chloromethylene derivative 167 with sodium borohydride yielded 179.'03 When tetramethylammonium borohydride in methanol was used as the reducing agent, the chloromethyl functionality survived and yielded 188 (Eq. 79).
qy H
NH
0 167
H
Me,N'BH; MeOH
Qy-y NH
(79)
0 188
Stannous chloride in acetic acid selectively reduced the 7-nitro group of 189 and gave 59% of the 7-amino analog 190 (Eq. 80).'08
The 2-nitromethylene derivative 191 was reduced catalytically with Raney nickel to the intermediate 2-aminomethyl compound 192, which was further reacted with triethyl orthoacetate to yield the imidazoline 193 (Eq. 81)."
4. 1,2,3,4-Tetrahydro-1,4-Benzodiazepin-5(5H)-Ones
c1
885
c1 0
0
191
192 MeC(OE1),
c1 0 193
4.2.2.2. Reactions with Oxygen Nucleophiles The amide bond in the parent compound 194 was cleaved by hydroxide to give the ring-opened amino acid 195 (Eq. 82).'07
194
I95
Acid hydrolysis of the 3-methoxy compound 159 led to the methyl ketone 1% (R = X = H).'03 Compound 1% (R = Me, X = C1) was the hydrolysis product of the 3-methylene-4-methyl derivative 160, while 197 resulted from the hydrolytic cleavage of the 1-methyl-2-methylene analog 163 (Eq. 83).'03
159
197
160
886
Tetrahydro- and Polyhydro-1,4-Benzodiazepines
The malonylidene derivatives 198 were transformed into the corresponding acetylidene compounds 184 by treatment with hydroxide in refluxing methanol (Eq. 84).179"'
198
184
Ethanolysis in the presence of hydrochloric acid removed the acetyl group from a 1-(4-acetylaminophenyl)-substitutedcompound to give the corresponding amine."' The 2-methoxy group in 165 was displaced by the acetoxy moiety by treatment with sodium acetate in acetic acid (Eq. 85).'03 Compound 199 was thus obtained in 40% yield. The stereochemistry remains unknown. H
OMe
H
OAc
NaOAcIHOAc
OMe NH
0 165
%ye
(85)
199
4.2.2.3. Reactions with Nitrogen Nucleophiles Reaction of the 3-chloromethyl derivative 188 with amines resulted in substitution of the chloride by such groups as piperidine, morpholine, and butylamine (Eq. 86).'03 Compounds 200 were formed in yields ranging from 70 to 80%.
The conversion of the 5-ones 201 to the amidines 202 was carried out by reaction with phosphorus pentachloride followed by treatment with an amine (Eq. 87)."' This transformation was also described in Chapter VI.
5. 4,s-Dihydro-1H - 1,4-Benzodiazepin-2,3(2H,3H)-Diones
201
887
202
4.2.2.4. Other Reactions The conversion of the 5-ones to the 5-thiones by means of phosphorus pentasulfide will be discussed in Section 8.1.
5. 4,5-DIHYDRO-lH-1,4-BENZODIAZEPIN-2,3(2H,3H)-
DIONES 5.1. Synthesis
Most of the 5-phenyl derivatives 204 (R, = Ph, substituted phenyl) were prepared by protic rearrangement of the 3-hydroxy compounds 203. This transformation was achieved in high yields by treatment of the 3-hydroxybenzodiazepines with a strong base such as hydroxide or alkoxide (Eq. 88).113-118 Compound 204 (R, = H, R, = Ph, X = 7-C1) was formed in low yield by nitrosation of the 3-amino derivative 2O5.li9Chromic acid oxidation of the pyrrolotienzodiazepine 206 also gave this 2,3-di0ne.~’
205
206
888
Tetrahydro- and Polyhydro-1,4-Benzodiazepines
Compound 9 was prepared by reaction of the diamine 207 with oxalyl chloride (Eq. 89).17 Me
Me
c1
c1 Me 207
9
Treatment of the 3-cyano derivatives 208 (R = H, Me) with oxygen in the presence of sodium ethoxide led to the 5-cyano-2,3-diones 209, apparently via a 3-hydroperoxide (Eq. 9O).l2O
R CN
base
0,
*
c1
C1 Ph 208
209
The 5-methyl derivative 211 was isolated from the reaction of the 4-oxide 210 with methylmagnesium iodide (Eq. 91).29Its formation may involve an oxidation, possibly by air.
210
21 1
5.2. Reactions
Oxidation of the 2,3-dione 212 (R = Me) with ruthenium tetroxide yielded 25% of the quinazolinone 213 (Eq. 92)."' Methylation of 212 (R = H) with dimethyl sulfate in aqueous ethanol, in the presence of hydroxide, afforded the 1-methyl analog 212 (R = Me).'13 The 1,Cdimethyl derivative 214 was obtained under the same conditions with an excess of dimethyl sulfate."3 Compound 209 (R = Me) (Eq. 90) was methylated at the 4-position by methyl iodide and a base.'" The same compound was also benzoylated by means of benzoyl chloride. l Z o
6. 3P-Dihydro- 1H-1,4-Benzodiazepin-2,5(2H,SH)-Diones
889
Treatment of the 2,3-dione 212 (R = H)with sodium hydroxide in boiling ethanol led to the dihydroquinazoline 215.,13
6.
3,4-DIHYDRO-lH-1,4-BENZODIAZEPIN-2,5(2H,5H)DIONES 6.1. Synthesis
6.1.I. From Anthranilic Acids Most syntheses of benzodiazepin-2,5-diones217 start from derivatives of anthranilic acids and are built up by sequential formation of the two amide bonds. The precursors 216 are converted to 217 by elimination of R,OH. Compounds 216 were prepared by a variety of procedures. The most convenient way was by reduction of the appropriate 2-nitrobenzoyl compound, which led to 216 (R, = H).2*s3122-127 When 216 (R, = H;R, = H, Me, Et) was prepared by reduction of the appropriate nitro compound, cyclization to the benzodiazepin-2,Sdione occurred during the hydrogenation This observation was also made during the reduction of 2-nitrohippuric acid with Raney nickel, which constituted the first synthesis of a 1,4-benzodia~epine.'~~ Reduction of the nitro group with iron in a mixture of ethanol, acetic acid, and water also led in high yield to the benzodiazepines.' The esters 216 (R, = Et) could be cyclized in several ways: thermally,'27 by treatment with methoxide in methano1,'26 or by heating to reflux in methanol in the presence of piperidine.12, The acids 216 (R, = H)were cyclized neat or by heating in solvents such as water, xylene, or ethylene
890
Tetrahydro- and Polyhydro- 1,4-Benzodiazepines
Compounds 216 are intermediates in the reaction of the isatoic anhydrides 218 with amino acids or their esters, which directly leads to the benzodiazepinThe condensation of sarcosine with various 2,5-di0nes.'*~*~*~~' isatoic anhydrides was carried out in dimethyl sulfoxide at approximately lWC,"'" '' while the reaction with glycine ethyl ester hydrochloride was performed in refluxing pyridine.'~'z9~'30 In a two-step modification, the reaction of 218 (R, = Me, X = 6-C1) with glycine in aqueous triethylamine followed by heating to reflux in acetic acid, was reported to give a 92% yield of the benzodiazepin-2,5-dione. '' Heating the piperidine 219 to reflux in acetic acid also afforded the parent benzodiazepin-2,5-dione 217 (Eq. 93).' 32g133 117112,129-131
0
R,
216
211
R,NH I C O O H /
4
.qY 0
\
0 218
219
Another widely used method for the preparation of benzodiazepine-2,5diones is the reaction of the haloacylated anthranilic acid esters 220 with amines (Eq. 94).79129*'32-'35 It is likely that the amine is first displacing the halide Y in 220 to give the intermediate 221, which in situ forms the benzodiazepine. Syntheses, in which the 3,4-bond was formed by an alkylation reaction in the last step, were also reported. The haloacylated anthranilamides 222 were treated with a strong base, such as methoxide, to give 217 (Eq. 94).79'369137This method was used to prepare the 4-rneth0xy'~~ derivatives and the 4-phosphorylated compound.' 3 7 Rl
Rz
R1 R,NHz
x<+
0 OR4 220
R,
x<$NHR'
0 OR4 221
89 1
6. 3,4-Dihydro-1H-1,4-Benzodiazepin-2,5(2H,5H)-Diones
217
222
(94) Intramolecular alkylation by an epoxide was used for the synthesis of 224. The epoxide 223, obtained from the corresponding olefin, was reacted with potassium t-butoxide in t-butanol to give the benzodiazepine 224 (Eq. 95).125*138 The stereochemistry of this compound is based on the trans opening of the epoxide, but the orientation of the 3-position substituent has not been determined.
-KvH H
O
(95)
r-BuOK/t-BuOH
HNMe
0
223
224
N\
Ph Me
6.1.2. By Ring Expansion
Quinazolines of structure 225 (X = C1, Br; R = aryl) were found to rearrange to the benzodiazepin-2,5-diones226 in the presence of hydroxide. This ring expansion may proceed in a fashion similar to that for the rearrangement of the 2-chloromethylquinazoline-3-oxides; i.e., hydroxide adding to the 2-position. This would result in the opening of the 2,3-bond to give the anion of the haloacetylated anthranilamide which, as shown in Eq. 94, may be converted to the benzodiazepin-2,5-dionesby an intramolecular alkylation. When 225 (X = C1, R = 2-MeC,H4) was reacted with sodium carbonate in water-dioxane at 70°C for 2 hours, 63% of the corresponding product 226 was formed.' 39 The closely related 4-phenyl compound 226 (R = Ph) was reported to be a result of the reaction of the bromide 225 (X = Br, R = Ph) with dimethyl sulfoxide and base (Eq. 96).140
225
226
Tetrahydro- and Polyhydro-1,4-Benzodiazepines
892
Podesva and coworker^'^' described the rearrangement of the quinoline 227 to the benzodiazepin-2,5-dione 228 by treatment with a catalytic amount of Triton B in refluxing methanol. Similarly, the same compound was formed by reacting the 3-phenyl-3-aminoquinoline 229,which was proposed to be a possible intermediate in the conversion of 227 to 228 (Eq. 97). Interestingly, the benzodiazepine 228 forms in much better yield from 227 than from the postulated intermediate 229. Me
Me
NH
&$Ph
6
H
228
/
221
J
(97)
Me
ti 229
6.1.3. Other Syntheses Palladium-catalyzed carbonylation of the aryl bromides 230 represents another useful method for the preparation of the 2,5-diones 231 (Eq. 98). These reactions were carried out with 230 (R, = Me, CH,OMe; R, = Ac, Me, benzyl; X = H, C1) and palladium acetate, triphenyl phosphine, tributyl amine, and 4 atm of carbon monoxide in HMPA at 110-120°C for 40-48 The yields of the benzodiazepines obtained varied from between 40 to 50%.
qy T1
P1 0
0 (98)
n N r N CO/Pd(OAcl, PPh,jNBu, H R 2
X
‘ Br
X
N\ R2
230
231
Benzodiazepin-2,5-diones233 (R = Ph, Me) were also isolated in low yields from the ozonization of the corresponding indoles 232 (R,= Ph, R, = Me; R, = Me, R, = H), in acetic acid (Eq. 99).144
6. 3,4-Dihydro-lH-l,4-Benzodiazepin-2,5(2H,5H)-Diones
232
893
233
6.2. Reactions
6.2.1. Reactions with Electrophiles Reaction of the 1-acetyl derivative 234 with sodium hypochlorite in aqueous dioxane led to the 1-chloro derivative 235 (Eq. 100).'23*'43 Ac NaOCl
$+ N\
\
(100)
Me
0 235
234
The 7-amino group was converted to the 7-diazo functionality by reaction with nitrous acid.'45 Nitration of the 1-methyl compound 236 (X = H)with sodium nitrate in sulfuric acid yielded the 7-nitro derivative 236 (X = NO,).The 7-chloro compound 236 (X = CI), under the same conditions, nitrated at the 9-position to give 237 (Eq. 101).'29
X
df) NH
0 236
HN03/H2S0, x = c1
xf
c1
NH
(101)
0
231
Oxidation of the double bond in 238 was effected by rn-chloroperoxybenzoic acid in methylene chloride for 1 4 2 7 days to give 10-37% of the epoxides 239 (R = H,OAC)(Eq. 102).'389'43
238
239
894
Tetrahydro- and Polyhydro- 1,4-Benzodiazepines
Diazomethane methylated the 1-position of the 4-methyl derivative to give the 1P-dimethyl ana10g.I~~ Compounds 239 (R = H, OH) were likewise alkylated by this reagent at the l-position with simultaneous methylation of the phenolic h y d r o ~ i d e . " ~ *Do ' ~uble ~ alkylation at the 1- and 4-positions was also carried out with methyl iodide and sodium m e t h 0 ~ i d e . IReaction ~~ of 1-alkyl derivatives with Meerwein salts led to the imino ethers 241 (X = OMe, OEt) (Eq. 103).'35 Compound 241 (X = C1) was formed by the reaction of the lactam 240 with phosphorus pentachloride in refluxing chloroform. The displacement of the chloride in 241 (X = C1) and of the alkoxide in the imino ethers 241 (X = OMe, OEt) was discussed in Chapter VII.
240
241
Condensation of the 4-methyl derivative 242 with benzaldehyde by means of sodium acetate and acetic anhydride at 150°C for 3 hours led to a mixture of stereoisomers with the geometry of 238 predominating (Eq. 104). Under these conditions, the 1-position was also partially a ~ e t y l a t e d . ' ~ ~ * ' ~ * ~ ' ~ ~
242
238
High yield acylations were reported for the 1-methyl compound 240 (R = Me) to yield the 4-acyl derivatives. The reagents used include acetic anhydride, trifluoroacetic anhydride, and higher homologous anhydrides.' ' The 1-phenyl analog 243 was similarly acetylated at the 4-position. Compound 243 reacted with propionyl chloride in the presence of pyridine to give the 4-propionyl derivative, while the 4-formyl compound 244 resulted from the treatment of 243 with dimethylformamide and phosphorus pentachloride (Eq. 105).14'
cldy
DMF/PCI,
0 NH
243
244
6. 3,4-Dihydro-lH-l,4-Benzodiazepin-2,5(2H,5~)-Diones
895
The hydroxy function of 224 (Eq. 95) was acetylated under standard
condition^.'^^ The anions of the 4-substituted 2,5-diones 245 were phosphorylated by diethyl chlorophosphate or diphenyl chlorophosphate to give the imino phosphates 246.Compounds 246 were reacted in situ with nucleophiles, in particular carbanions such as malonate anion or the anion of isocyanoacetates, to form 247 and 248, respectively (Eq. 106).1"~1'2
/
245
241
246
248
6.2.2. React ions with Nucleoph iles The reductions of the carbonyl groups of the 2,5-diones were discussed in Section 1.1 of this ~ h a p t e r . " ~ . ~ - ' . ' ~The ~ , 'l-chloro ~~ derivative 235 (Eq.100) was reduced by potassium iodide to the corresponding l-H c ~ m p o u n d . ' ~ ~ * ' * ~ Catalytic hydrogenation of the double bond in 238 (R = H) was achieved over a platinum ~ a t a l y s t . A ' ~l-benzyl ~ group was submitted to hydrogenolysis with palladium catalyst in acetic acid.'32 Reduction of a 7-nitro group to the 7-amino function was achieved by hydrogenation over the same ~atalyst.'~' Hydrolysis of the parent 2,5-dione with 70% sulfuric acid at 140°C for 15 minutes led to anthranilic acid.'32 Treatment of the 4-methyl analog with 2N hydrochloric acid at reflux for 3 hours effected the partial cleavage of either amide bond. The reaction led to sarcosine and anthranilic acid as well.'23 The epoxides 239 (R = H,OH), on the other hand, underwent rearrangement under mild hydrolytic conditions. Thus 239 (R = H) yielded the quinolone 249 (R = H),methylamine, and carbon dioxide when treated with 2N hydrochloric acid at 87 "Cfor 3 h o u r ~ . ' ~The ~ ' 'oxidative ~~ degradation of 239 (R = H)with hydrogen peroxide in acetic acid gave the quinazolinone 250 in 30% yield (Eq. 107).'46
896
Tetrahydro- and Polyhydro- 1,4-Benzodiazepines
250
Acid hydrolysis allowed the removal of the 1-methoxymethyl moiety from the 1-methoxymethyl-4-methylcompound to give the 4-methyl 2,5-dione 242.143 The conversion of the 2,5-diones 245 (R, = H, alkyl) to the amidines 251 by reaction with an amine and titanium tetrachloride was discussed in Chapter VII, Section 8. (Eq. 108).95*'37,'48*'49
245
25 I
Reaction of the diazonium salt 252 with piperidine led to the triazene 253 (Eq. 109).14'
Qf-1JL 4f N\
+ N2
0 252
Me
(109)
Me
ON=" 253
The 4-acyl derivatives 254 (R = Me, F3C) reacted with phenylmagnesium halides to form the benzophenones 255. Hydrolysis of 255 gave diazepam as a product (Eq. l10).13'
7. 2,4-Dihydrool~-1,4-Benzodiazepin-3,5(3H,5H)-Diones
Me
Me
Q(----R -c1
8,
I PhMgBr 2. n,o
c1
0
897
(110)
Ph 255
254
Thermal elimination of acetic acid converted the acetate 256 to the olefin 257, yielding only one stereoisomer (Eq. 111). l 2 5 * 13 8
256
257
7. 2,4-DIHYDRO-lH-l,4-BENZODIAZEPIN-3,5(3H,5H)-
DIONES The 4-substituted 3,5-diones 259 were synthesized by dehydration of the carboxylic acids 258 using dicyclohexylcarbodiimide.l The esters corresponding to the acids 258 were obtained by alkylation of the anthranilamide with bromoacetates (Eq. 112).
258
259
The 2-acetylidene derivatives 261 were prepared in moderate yields by treatment of the diesters 260 (X = H, C1) with sodium methoxide in boiling methan01.'~' The compounds 260 were obtained in high yield by addition of anthranilamide to acetylene dicarboxylate (Eq. 113). COOMe X @ E M/ O#
NaOMe/MeOHc
Xq
$
ONH
NH2 260
261
(113)
898
Tetrahydro- and Polyhydro-1,4-Benzodiazepines
8. TETRAHYDRO-1,4-BENZODIAZEPINTHIONES 8.1. Synthesis
Several benzodiazepin-2-thiones 262 were prepared by thiation of the 2-ones 84 with phosphorus pentasulfide in pyridine.28q66When the 4-acetyl derivative 84 (R, = Me, R2 = H, R, = 2-FC6H4, R, = Ac, X = 7-C1) was reacted with these reagents, the acetyl group was simultaneously converted to the thioacetyl moiety.” The 3-one 263 was similarly converted to the 3-thione 264 (X = H,).Z* The 2,3-dithione 264 (X = S) was also formed in this reaction.28 The 5-thiones 266 (R = Me, benzyl) were synthesized by this method from the corresponding 5-ones 265 (Eq. 114).338,’52
84
262
263
264
265
266
The 3-thione 267 resulted from the reaction of the 2,3-dione 214 with phosphorus pentasulfide (Eq. 115).28 This reagent converted the 2,5-diones 268 to the corresponding 2-thiones 270.112*1492,4-Bis(Crnethoxyphenyl)1,3,2,4-dithiadiphosphetane-2,4-disulfide, 269, was successfully used for this thiation. l 1
8. Tetrahydro-1,4-Benzodiazepinthiones
214
899
267
268
270
The 2,5-dithione 272 was obtained in 75% yield by reaction of the iminophosphate 271 with hydrogen sulfide and triethylamine in tetrahydrofuran (Eq. 116).ls3 NHMe
c1
df "a N,f'o )
O\,/
o/'
HIS/Et3N THF
c1
NH
(116)
S
272
271
8.2. Reactions
The 2-thione 262 (R, = Me, R, = R, = X = H, R, = Ph) was methylated and acetylated at the 4-po~ition.~' Compound 262 (R, = R, = H, R, = Me, R, = 2-C1C,H4, X = 7-C1) and the 2-thiones 270 were alkylated at sulfur to 14' give the iminothioethers 273 and 274, respectively.663
q=
c,J3gN 0
\
273
274
R2
900
Tetrahydro- and Polyhydro- 1,4-Benzodiazepines
The reaction of the 2-thiones 270 with amines to give 2-amino derivatives was discussed in Chapter VII.'49
9. OCTAHYDRO- AND DECAHYDRO-l,4BENZODIAZEPINES The 2,4,5,5a,6,7,8,9-octahydro-1,4-benzodiazepin-3(3H)-one 276 was synthesized by reacting the cyclohexanone derivative 275 with bromoacetyl bromide and subsequently with liquid ammonia (Eq. 117).'54
Two isomeric decahydro-1,4-benzodiazepin-2-ones278 were prepared through ring closure of cyclohexylamines 277 by boiling in acetic acid (Eq. 118).154
qxN, 2
Ph
277
"OAc
*
<-
(1 18)
Ph
278
The decahydro-2,5-dione 280 resulted from a similar ring closure of the cyclohexanecarboxylic acid 279 (Eq. 119).155
10. TABLE OF COMPOUNDS TABLE VIII.1. TETRAHYDRO- AND POLYHYDRO-1,4-BENZODIAZEPINES
Substituent
mp ("C) or; [bp ("C)/(torr)]
Solvent of Crystallization
Yield (YO)
Spectra
Refs.
2,3,4.5-Tetrahydro- 1 H-I .I-benzodiazepines
n
None Dih ydrochloride
93-96 24&248
Et,O MeOH
1, 2,33 5
90 97
Monosnbstitnted
1-Ac
[115-1 20/0.05]
1-Benzyl dihydrochloride.H,O 1-Me Dihydrochloride 1-Ph Maleate 4-AC 4-Allyl Dihydrochloride CH,N(iminomethyl) nitrate
134-136 [60-70/0.005] 188-190 [155/2mm] 132 84-86 [84-85/0.13] 190-199d 235-231
C(Cyclopropyl)CH, dihydrochloride 4-Me dihydrochloride Methbdide 4-(4-MeC6H,)SO,
210-215 210-215 201-203
ir, pmr EtOH/Acetone
Et,O MeOH H,O
82
EtOH MeOH EtOH
99 92
110
115-117
ir, pmr ir uv uv
MeOH/Acetone
CH C1,/E t 0
9 3, 8 9 3, 8 33
33 31 5 2, 5 2, 5 5 6 33 28
TABLE VIII.l. +ontd.)
Substituent 4-Ph 4-(2-Ph-Ethyl) 5-Ph 5-(2-Thiazolyl)maleate 7-C1
mp("C) or; [bp ("C)/(torr)] 103-105 80-83 82-83 163-165 95-98
Solvent of Crystallization EtOH Hexane Hexane i-PrOH/Et,O
Yield (%)
Spectra
62 71 58
Et,O
Pmr
Refs. 4 2, 5 26 119b 2
Disubstituted I,4-Disubstituted W
E3
1,4-Acz 1-Ac-4-Ally1hydrochloride l-Ac-4-(2-Ph-Ethyl) hydrochloride 1-H,N(Iminomethyl)-4-Ph hydrochloride 1-Benzoyl-4-Ally1hydrochloride 1-Butanoyl-4-ally1hydrochloride 1,4-Etz methiodide l-Et-4-(3-Tropanyl) Methiodide Bismethiodide 1,4-Me, methiodide 1-Me-4-HzN(Iminomethy1)nitrate 1-Me-4-Ph 1-Me-4-(2-MeOC,H4) 1-Me-4-(4-MeOC6H,)
1-Me-4-[3,4,5-(Me0),C6Hz] l-Me-4-(3-Tropanyl) Bismethiodide 1,4-[(4-MeC,H,)SOz]z
119-120 230-231 240-241 249-251 2 19-22 1d 185-188 174-176 [171-175/0.2] 227-229 266267d 155-156 21G213d [16&162/0.3] 78-79 64-65 113-1 14 [18&182/0.7] 253-254 155
EtOH/Et,O EtOH/Et,O i-PrOH EtOH/Et,O EtOH/Et,O EtOH
84 75 31 64 61
EtOH HZO EtOH HZO Petr ether Petr ether Petr ether HZO
57 64 75 62
6 2, 5 2, 5 4 2, 5 2, 5 6 32 32 32 6 2 7 7 7 7 32 32 33
1-Propanoyl-4-ally1 hydrochloride 1-Propanoyl-4-(cyclopropyl)CH, hydrochloride 1-Propanoyl-4-Me hydrochloride l-Propanoy1-4-(2-Ph-ethyl) hydrochloride
237-239 22&227 229-232 214-216
EtOH MeOH MeOH i-PrOH
63 72 74 77
128-1 29
Cyclohexane
63 48
I J-Disubstitured
1-Ac-5-Ph 1-Et-5-Ph 1-Me-5-Ph hydrochloride
[155-1 63/0.3]
26 26 119b
238-244d
MeOH/i-PrOH
26&261 106-107
MeOH Acetone/Peti ether
238d
EtOH/Et,O
50
10
MeOH
25
11
1,7-Disubstituted
1-Me-7-CI hydrochloride 1-Me-7-NO2
30 38
2,4-Disubstifuted
2-Ph-4-Me dihydrochloride v,
8
2,7-Dis~bstituted
2-Ph-7-C1
60-68
3,4-Disubstituted
3-Me-4-Ally1
5
[9&93/0.2]
3,b-Disubsritufed
3-(3-Indolyl)CH,-8-C1, (S)-enantiomer Dihydrochloride
205d
EtOH/Et,O
156
157-160
MeOH
119b
4J-Disubstituted
4-Me-5-(3-Indolyl) maleate 4,7-Disubstituted
4-Ac-7-CI 4-Allyl-7-benzyloxy 4-Allyl-7-HO 4-Benzyl-7-Me0
95-96 77-79 97-1 11 4349
Et,O 65 EtOAc Et,O/Petr ether
37 2, 5 5 28
TABLE VIII.1. gc ont d . )
Substituent
m p ( T ) or; [bp (“C)/(torr)]
Solvent of Crystallization
Yield (%)
Spectra
Refs.
4,8-Disubstituted
4-Allyl-8-Me0 dihydrochloride 4-H,N(Iminomethyl)-7-C1 nitrate Dih ydrochloride 4-HO-5-Ph
182-186 27G272 183-186 142-144
MeOH H,O EtOH CH,CI,/Petr ether
95 52
5 2 5 17
259-261 101-103 216217 275-28Od 138-140 283-285
MeOH/Acetone Hexane EtOH MeOH/Et,O CH,CI,/Hexane MeOH/Et ,O
72
12, 14, 16 89 14 23d 29 28
2w201
EtOH/Et,O
52
235-236d 57-58 239-240 235-236 9G9 1 154-156 273-274 87-88 138-139 119-120
EtOH Et,O MeOH/Et,O MeOH/Et,O Hexane Acetone MeOH Petr ether PhH CH,CI,/Hexane
57
5,7-Disubstituted
E
5-Ph-7-CI hydrochloride 5-Ph-7-MeS 5-Ph-7-NO, 5-(2-C1C6H4)-7-C1hydrochloride 5-(2-CIC,H4)-7-NO, 5-(3-FC,H4)-7-C1hydrochloride Trisubstituted IJ,CTrisubstitutcd
l-Propanoyl-3-Me-4-allyl hydrochloride I,4,7-Trisubstituted
l-Ac-4-Allyl-7-CI hydrochloride 1,4-Me,-7-NO, l-Me-4-(2-EtzN-Ethyl)-7-CI dihydrochloride I-Me-4-(2-Et,N-Ethyl)-7-NO, dihydrochloride I-Me-4-Formyl-7-CI l-Me-4-Formyl-7-NO2 l-Me-4-(3-Me,N-PropyI)-ll-C1 dihydrochloride 1-Me-4-(4-MeOC6H4)-7-C1
1-Me-4-(4-MeC,H4)S0,-7-C1 1-Me-4-MeS02-7-C1
58
2, 5 38 38 38 30 38 38 7 30 30
l-Me-4-(2-Morpholinoethyl)-7-C1 dihydrochloride 1-Me-4-(2-Piperidinoethyl)-7-C1dihydrochloride l-Me-4-(3-Tropanyl)-7-Me l-Propanoyl-4-allyl-7-HO hydrochloride
38 38 32 2,5
288-289 2733275d [180-183/0.1] 245-246
EtOH/H,O EtOH/H,O/Acetone MeOH
43
210-212
MeOH
41
115
MeOH
29
122-125 242-25Od 6668 257-259d 202-204 96-99 295-297d 147- 148 133-135 90-9 1 172-173 103-105 177-1 78 82-83
Cyclohexane/Hexane
35 28 12, 14 12, 13 12 14 14 35 23d 17 89 25 25 35
127-1 28 204-205d 155-1 58
Et,O Et,O Et,O
1,4,8- Trisubstituted
l-Propanoyl-4-allyl-8-MeOhydrochloride 1.5,s- Trisubstituted
1-Me-5,5-Ph2 1,5,7- Trisubstituted
l-(3-H2N-Propyl)-5-Ph-7-C1 l-Me-5-Ph-7-(2-HOOC-Benzoyl) l-Me-5-Ph-7-Cl Hydrochloride Picrate 1-Me-5-Ph-7-NO2 Hydrochloride 1-Me-5-(2-H2NC,H,)-7-CI 1-Me-5-(2-C1C6H,)-7-C1 1-Me-5-(2-FC,H4)-7-C1 Hydrochloride 1-Me-5-(Thiazol-2-yl)-7-NO, Maleate
1-Propyl-5-(2-FC,H4)-7-C1
Pentane Et,O EtOH i-PrOH EtOH Et,O/Hexane PhH/Hexane Et,O/Hexane MeOH/Et,O CH,Cl,/Et,O MeOH/Et,O Petr ether
2,5,7- Trisubstituted
2-H,NCH,-5-(2-FC6H4)-7-C1
~-[~-BuOOC(HON)C]-~-(~-FC~H,)-~-C~ 2-MeOOCCH,-5-(2-FC,H4)-7-CI
27
24 17 28
TABLE VIII.l. d c o n t d . ) Solvent of Crystallization
Yield (%)
Spectra
Refs.
196-198 180-182
MeOH MeOH
60 40
ir, ms, pmr ir, pmr
24 24
103-106 4349 165-1 67 170-172 153-154 155-175
Et,O/Hexane Et,O/Petr ether PhH/Hexane i-PrOH Et,O/Hexane Acet one/Et 0
1,3-Me2-5-Ph-7-C1hydrochloride
261-263d
MeOH/Et,O
17
I,4,53Tetrasubstituted l-Me-4-(Benzyloxy)CO-5-MeO-5-Ph
110-113
Et,O/Petr ether
29
134136 160-162 246-248 189-196 79-80 68-70 99-103 10&108 228-229
Et,O/Hexane EtOAc/Hexane Hexane Acetone/Et,O EtOH MeOH Pentane Et,O/Petr ether PhH
Substituent
mp (“C) or; [bp (“C)/(torr)]
2-(4-MeC,H,SO,)NHCH,-5-(2-FC6H4)-7-C1 Isomer A Isomer B 4,5,7- Trisubstituted
4-Benzyl-5-Ph-7-CI 4-Benzyl-5-Ph-7-MeO 4-HO-5-Ph-7-CI 4-HO-5-(2-C1C6H4)-7-C1 4-Me-5-Ph-7-CI hydrochloride
28 56 18,22 19,21 17 28
35 65 80
,
Tetrasubstituted 1,3,5,7- Tetrasubstituted
I ,4,5,7- Tetrasubstituted
l-Ac-4-AcO-5-Ph-7-CI l-Ac-4-HO-5-Ph-7-Cl 1-(3-AcNH-Propyl)-4-Ac-5-Ph-7-C1
1,4-Et2-5-(2-FC,H,)-7-C1 hydrochloride 1,4-Me2-5-Ph-7-CI 1,4-Me2-5-(2-FC,H,)-7-CI l-Me-4-Ac-5-Ph-7-Cl 1-Me-4-Ac-5-(2-Pyrimidyl)-7-AcNH
68 77
11
ir, uv
20 20 35 28 28 28 15 31 89
l-Me-4-Benzoy1-5-Ph-7-Cl
l-Me-4-[7-C1-2,3-Dihydro-5-Ph-2H1,4-benzodiazepin2-yll-5-Ph-7-CI 1-Me-4-Et-5-(2-FC6H,)-7-C1 hydrochloride l-Me-4-(Et2N-Acety1)-5-Ph-7-C1 dihydrochloride 1-Me-4-(2-Et2N-Ethyl)-5-Ph-7-C1 1-Me-4-Formyl-5-Ph-7-C1 l-Me-4-Formyl-5-(2-FC,H,)-7-C1
1-Me-4-Formyl-5-[2-(diformyl)NC,H,]-7-C1 l-Me-4-HO-5-Ph-7-Cl 1-Me-4-HO-5-(2-C1C6H,)-7-C1 l-Me-4-(2-HO-Ethyl)-5-Ph-7-C1hydrochloride.H,O I-Me-4-(MeNH-Acetyl)-S-Ph-7-C1 dihydrochloride l-Me-4-(2-MeNH-Ethyl)-5-Ph-7-C1 hydrochloride l-Me-4-MeOOC-S-Ph-7-CI
s W
1-Me-4-(4-MeC,H4)SO2-5-Ph-7-CI
156157 281-285 182-185d 240-242 [172/0.05] 12C123 121-122 100-101 201-204 2&143 158-159 134-136 165-18Od 222-224 111-1 14 127-130
157
MePh/Cyclohexane THF MeOH/Et,O MeOH/Et,O
23
i-PrOH Hexane PhH/Hexane EtOH MeOH Et O/Hexane EtOH/Et,O EtOH/Et,O EtOH/Et,O Et,O/Hexane CH,CI,/Hexane
87
,
52
15 28 17 17 40 31 89 35 20 17 35 17 17 17 31
1,493- Tetrasubstituted
1,4,5-Me3-5-Ph
88-89
73
Et,O/Hexane
15.5.7- Tetrasubstituted
l-Formyl-5,5-Ph2-7-C1 l-Me-5-Bu-5-Ph-7-CI
1-Me-5-(3-Me2N-Propyl)-5-Ph-7-C1 dihydrochloride 1-Me-5,5-Ph2-7-C1hydrochloride.0.3 MeOH
154-155 89-92 205-2 1Od 26C261d
Et,O/Petr ether MeOH Acetone/EtOH MeOH/Et,O
129-1 3 1
MeOH
18d
168-173 202-203d
EtOH EtOAc/Hexane
18ax 18d
29 29
29 29
2,3,5,7- Tetrasubstituted
2,3-Me2-5-Ph-7-C1 2,4,5,7- Tetrasubstituted
2-Me-4-HO-5-Ph-7-CI
2-0,NCH2-4-HO-5-(2-FCsH,)-7-C1
TABLE VIII.1. d c o n t d . ) m p ( T ) or; [bp (“C)/(torr)]
Solvent of Crystallization
20421od 185-2OOd 222-228d
EtOH EtOAc THF/H,O
1,3-Me2-4-HO-5-Ph-7-CI l-Me-3-Benzyl-4-HO-
135-136
Et,O/Petr ether
l-Me-4-Ac-5-Et0-5-Ph-7-CI
168-174 140-143 198-202 170d 115-116 175-180 128-1 29 153-155 160-162 127-130 116117 163-165 176178 165-167
MeOH CH,CI,/Hexane CH,CI,/EtOH CH,CI,/EtOH Et,O/Heptane MeOH EtOH MeOH MeOH EtOH/H,O Et,O/Heptane MeOH Petr ether EtOH
Substituent
Yield (YO)
SptXtrd
Refs.
3,4,5,7- Tetrasubstituted
3-Me-4-HO-5-Ph-7-CI Isomer A Isomer B 3-Me-4-HO-5-Ph-7-NO2
18a, c 18d 18a-c
rg
Pentasubstituted
5-Ph-7-CI 1-Me-4-(Benzyloxy)CO-5-EtO-5-Ph-7-C1
1-Me-4-(Benzy1oxy)CO-5-EtO-5-(2-FC4H4)-7-Cl l-Me-4-(Benzyloxy)CO-5-HO-5-Ph-7-C1 l-Me-4-(Benzyloxy)CO-5-MeO-5-Ph-7-C1 l-Me-4-(EtOOC-Acetyl)-5,5-Ph,-7-C1 1,4-Mez-5,5-Ph2-7-C1
I-Me-4-EtSOC-5-Et0-5-Ph-7-Cl I-Me-4-MeOOC-5-Et0-5-Ph-7-CI l-Me-4-MeOOC-5-HO-5-Ph-7-CI l-Me-4-MeOOC-5-Me0-5-Ph-7-Cl 1-Me-4-Propenoyl-5,5-Ph,-7-C1 2,2-Me2-4-HO-5-Ph-7-CI
75
pmr, uv
81
Pmr
20 29 20 29 29 29 29 29 17 17 29 29 17 29 18d
2-Methylene-l.3,4.5-tetrahydro-2H-l .I-benzodiazepines R,
R , , R,; Other H, Me,NCO; 4-HO-5-Ph-5-(Me,NCOCH,)-7-C1 H, NO,; 5-(2-FC,H,)-5-(NO,CH,)-7-Et MeOOC, MeOOC; 5-Ph-7-C1 CN, Me,NCH=N; 5-(2-FC,H4)-7-C1
182-183 183-185 133-135 215-21 8
CH,Cl,/EtOH CH,Cl,/Hexane MeOH CH,CI,/EtOAc
17 36 17 17
5-Methylene-I,2.3,4-tetrahydro-SH-I .4-benzodiazepines
R+R,
R,, R,; Other C1, C1; 1-Me-4-C12P0
92-93
Et,O/Hexane
17
CH,CI,/Petr ether
17
Spiro Compounds
137-139d
TABLE VIII.l. 4contd.)
Substituent
mp(”C) or; [bp (“C)/(totr)]
Solvent of Crystallization
Yield (%)
Spectra
Refs.
None
151-154
MeCN
67
ir, pmr
59
207-208 169-1 7 1 139-140 145- 146 14&147 147-148 241 187-189 192- 195 162-163 178-179 188-189 158-160 285-300 235-237 144145 188-190
MeCN CH,CI,/Et20 PhH/Hexane Cyclohexane 2-PrOH Acetone/Petr ether MeCN EtOAc CH,CI,/Hexane CH,CI, Acetone/Hexane Acetone/Petr ether Acetone/Hexane
15
ir, ms, pmr
Monosubstituted
4-HO 5-Benzyl 5-Me 5-Ph
Hydrochloride 5-(2-C1C,H4) 5-(4-C1C6H4) 5-(2-FC,H,) 5-(2-F-4-CIC,H3) 5-(2-F-S-NOzC,H,) 5-(3-NOZC,H,) Hydrochloride 5-(4-NOzC,HJ 5-(2-Thiazolyl) 7-c1
MeOH Acetone/Hexane MeOH
50 80 84
98 92 81 23 48
59 13 38 58 69 43 57 49 43, 52 43,49 52 87 87 52 87 119b 28
Disubstituted I ,5-Disubstituted
141-143 177-180 123-124
Et,O Et,O Acetone/Petr ether
4-H2NCO-5-Ph 4-Benzyl-5-Ph
227-228 156159
4-BuNHCO-5-Ph 4-HO-5-Ph 4,5-Me2 4-Me-5-Ph methiodide Methochloride 4-Me-5-(2-FC6H,) 4-MeNHCO-5-Ph CMeOOC-5-Ph 4-PhNHCO-5-Ph
202-204 2w202 123-124 19G191 199-201 123-125 1&144 2 15-21 8 227-228
EtOH CH,CI,/Et,O/ Petr ether MeCN
1-Me-5-Ph 1-Me-5-(2-C1C,H4) 1-Me-5-(2-FC,H4)
38 49 28
4,5-Disubstituted
c.
CH,Cl,/Hexane EtOH MeOH/Et,O CH,Cl, MeCN CH,CI,/Et,O/Hexane MeCN
74
88
50 96 82
90 28 90 76 73 49 49 43 90 73 90
4,7-Disubstituted
4-Benzyl-7-Me0
145- 148
CH,CI,/Petr ether
28
184186 148-154 182-1 84 155-158 191-192 184-186 152-153 159-161 15G153 174176
MeCN EtOAc PhH DM F/H ,O DMF/H,O DM F/H 0 MeOH Et,O/Pentane Acetone/Hexane EtOH
47 29 69 35 43,49 51 43 48 56 43,49
5,7-Disubstituted
5-Ph-7-AC 5-Ph-7-AcNH 5-Ph-7-H2N 5-Ph-7-H2NS0, 5-Ph-7-Br 5-Ph-74 5-Ph-7-F,C 5-Ph-74 1-HO-1-Ethyl) 5-Ph-7-Me0 5-Ph-7-Me
,
85 79 87 72 87 50
TABLE VIII.1. 4contd.)
Substituent 5-Ph-7-Me2N 5-Ph-7-(2-Me-1,3-Dioxolan-2-yl) 5-Ph-7-MeS 5-Ph-7-NOz 5-(4BrC,H4)-7-CI 5-(2-C1C6H4)-7-CI 5-(2,4-CIC,H&7-C1 5-(4-C1C6H4)-7-F ~-(~-FC~H,)-~-ACNH 5-(2-FC6H,)-7-Br 5-(2-FC,H4)-7-C1
2 N
5-(2-FC6H,)-7-(Cyclopentyl)CONH S(2-FC6HJ-7-F 5-(2,6-FzC6H3)-7-C1 5-(2-Me2NC,H,)-7-C1 5-(2-MeC6H4)-7-CI 5-(2-Pyridyl)-7-Br
mp('C) or; [bp ("C)/(torr)]
Solvent of Crystallization
174-176 181-182 151-153 232-234 180-184 235-237 208-210 177-178 150-155d 224-225 214-215 230-232 174-177 243-245 160-168d 248-249 192-194
EtOH MeCN EtOH CH,CI, CHzC1,/Hexane AcOH/H,O Acetone PhH CH,CI,/EtOAc MeOH Acetone CH,CI,/Hexane/EtOH Acetone/Hexane CHCIJEtOH Et,O DMF/H,O EtOH
115-116 240-241 132-133 119-122 146-147 143-144 178-1 79 115-120 136-138
CH,CI, Acet one/Et 0 Et,O/Petr ether Hexane Et,O CH,CI,/Et ,O/Hexane EtOH/Et,O Et,O/Hexane Et,O
Yield (%)
40 75 49 87 90 96
91
Spectra
Refs. 50 47 46 83 28 43,49 43 43 29 43,49 43,49 29 43 28 28 43,49 158
Trisubstituted I ,4,E Trisubstituted
1,4-Me2-5-Ph 1,4-Me,-5-(2-C1C,H4) hydrochloride 1,4-Me,-S-(4-C1C,H4) 1,4-Me,-5-(2-FC6H,) 1-Me-4-(2S-H2N-3-Ph-Propanoyl)-5-Ph
1-Me-4-(2R-H2N-3-Ph-Propanoyl)-5-Ph l-Me-4-[2-(Benzyloxy)CONH-3-Ph-propanoyl]-5-Ph l-Me-4-Et-5-Ph l-Me-4-MeOOC-5-Ph
,
32 76 59
43 49 43 43 73 73 73 17 73
13.7- Trisubstituted
l-(2-H,NCOCH,0-Ethyl)-5-(2-FC6H4)-7-C1 1- ( ~ - H O O C - B U ~ Y ~ ) - ~ - ( ~ - F C , H , ) - ~ - C I 1-(3-Cl-Propy1)-5-Ph-7-C1 hydrochloride 1-Et-5-(2-FC6H,)-7-CI 1-Et-5-(2-FC6H,)-7-[ 1-(2-HO-Ethyl)amino-l -ethyl] 1-Et-5-(2-FC6H,)-7-( 1-HO-Imino-1-ethyl) 1-Et-5-(2-FC6H,)-7-( 1-MeNH-Ethyl) 1-Et-5-(2-FC6H,)-7-( 1-Me,N-1-Ethyl) dihydrochloride 1-Et-5-(2-FC,H4)-7-( 1-Pyrrolidin- 1-yl)ethyl 1-(4-Et00C-Butyl)-5-(2-FC6H,)-7-C1 hydrochloride I-(2-EtNH-Ethyl)-5-(2-FC,H,)-7-C1 dihydrochloride l-(4-Et,N-Butyl)-5-(2-FC6H4)-7-C1 dihydrochloride
1-(2-Et2N-Ethyl)-5-(2-FC6H4)-7-C1 Dihydrochloride
2 W
1-(2-Et2N-Ethyl)-5-(2-pyridyl)-7-Brdihydrobromide
168-170 149- 15 5 215-220 165-167 49-50 237-239 140- 142 160 Oil 162- 164 235-240 230-238d 98-99 215-225 175-190 214-22Od
EtOH MeOH MeOH MeOH
87
Et,O
EtOH/Et,O MeOH/Et,O MeOH/Et,O Et,O/Petr ether EtOH/Et,O MeOH/Et,O MeOH/Et,O
84 88 35 43 60 60 60b 60 60b 88 28
72
55 44,55
72
44
82 55
1-(3-Et,N-Propy1)-5-(2-FC,H,)-7-C1
dih ydrochloride l-Me-5-Ph-7-AcNH l-Me-5-Ph-7-Cl Hydrochloride 2-14c (-)-Enantiomer 2-14c ( +)-Enantiomer Camphor sulfonate l-Me-5-Ph-7-CN l-Me-5-Ph-7-Me2N 1-Me-5-(2-AcNHC6H4)-7-C1 1-Me-5-(2-H,NC6H,)-7-Br
237-242d 131-133 144-145 110-112 266-269d
116 293 134-135 152-154 203-205 205-208
MeOH/Et,O EtOH/Et,O Et,O
70 76
EtOH/H,O
70
Et,O EtOH EtOH CH,Cl,/Hexane
88
44,55
60c 43, 52 70 70 42 42 42, 166 166 38 50 53 53
TABLE VIII.1. g c o n t d . )
Substituent 1-Me-5-(2-H2NC,H,)-7-C1 1-Me-5-(2-C1C,H4)-7-CI 1-Me-5-(2,4-C1,C6H,)-7-C1 1-Me-5-(4-C1C6H,)-7-C1 1-Me-5-(4-C1C6H,)-7-Fhydrochloride 1-Me-5-(2-FC6H,)-7-AcNH.0.5 EtOAc
1-Me-5-(2-FC6H,)-7-AcN(Me) 1-Me-5-(2-FC6H,)-7-H,N 1-Me-5-(2-FC6H,)-7-C1 1-Me-5-(2-FC6H,)-7-F hydrochloride 1-Me-5-(2-FC6H,)-7-I
5
1-Me-5-(2-FC,H4)-7-BuNHCONHCH2 1-Me-5-(2-FC6H,)-7-MeNHCONH 1-Me-5-(2,6-F2C,H,)-7-C1 l-MeNHCOCH2-5-Ph-7-CI Hydrochloride
mp(’C) or; [bp (“C)/(torr)]
Solvent of Crystallization
203-205 169-172 169-172 134-135 20 1-205 130-133 14G141 218 135-136 219-239 171-173 172 12Cb-140 150-155 179-1 8 1 299-302
CH,CI,/Hexane CH,CI,/Et,O Acetone/Hexane Et,O MeOH/Et,O EtOAc EtOAc CH,CI, Acetone/Petr ether MeOH CH,CI,/Hexane EtOAc EtOAc/Et,O CH,CI,/MeOH EtOH/H,O MeOH/Acetone
193-196d 273-278d 186-2OOd 243-248d 136-138
MeOH/Et,O EtOH/H,O MeOH/Et,O MeOH/Et,O EtOH
15Cb155 172-174 180-182 104-106 135-136
EtOH
29
MeCN Et,O/Petr ether CH,CI,/Hexane
64 29 35
Yield
51 69 63 92
(YO)
Spectra
Refs. 28 43 43 43 43 29 29 60b 55
35
43 61 60 29 28 54 54
l-(3-MeNH-Propyl)-5-(2-FC6H,)-7-C1 dihydrochloride.H,O 1-(3-Me2N-Propyl)-5-Ph-7-C1 dihydrochloride 1-(3-Me,N-Propy1)-5-(2-FC,H,)-7-CI dihydrochloride 1-(3-Me2N-Propyl)-5-(2-Pyridyl)-7-Br dihydrochloride 1-MeOCH2-5-Ph-7-CI
73
85
44,5 5 35 44,5 5 158 41
3,5,7-Trisubstituted
3-(Benzyloxy)CO-5-Ph-7-C1 3-EtOOC-5-Ph-7-Cl
3-(3-Et2N-Propyloxy)CO-5-Ph-7-CI 3-HOCH2-5-Ph-7-CI
453,-Trisubstituted
4,5,5-Me3
185-186
CH,CI,/Hexane
73
MeOH/Et,O Acetone MeCN CH,CI,/MeOH EtOAc Acetone/Hexane Ac,O Ac,O Ac,O CH2CI2/Et2O MeCN EtOH EtOH CH,CI,/Et,O/Petr ether CH,Cl,/Petr ether EtOH i-PrOH
60c 38 90 28 29 28 47 92 92 29 86 90 90 78, 56 78, 56 83 83 84 28 90 90 90 35 35 90 90 90 90 28 90
43,7-Trisubstituted
4-Ac-5-Ph-7-AcNH 4-Ac-S-Ph-7-CI 4-Ac-5-Ph-7-N02 4-Ac-5-(4-BrC6H,)-7-C1
~-Ac-~-(~-FC~H,)-~-ACNH.O.~ EtOAc 4-Ac-5-(2-FC6H4)-7-C1 4-AcO-5-Ph-7-AC 4-Ac0-5-Ph-7-CI 4-Ac0-5-(2-C1C6H,)-7-C1
4-Allyl-5-(2-FC6H,)-7-(cyclopentyl)CONH
z
VI
4-H2N-5-Ph-7-H,N 4-H2NCO-5-Ph-7-C1 4-H2NCO-5-Ph-7-N02 4-Benzyl-5-Ph-7-CI 4-Benzyl-5-Ph-7-MeO 4-Benzyloxy(CO)-5-Ph-7-H2N 4-Benzyloxy(CO)-5-Ph-7-N02 4-Benzyloxy(CO)-5-(2-FC6H4)-7-CI
4-(Br-Acety1)-5-(2-FC6H4)-7-CI 4-t-Bu0OC-5-Ph-7-NO2 4-BuNHC0-5-Ph-7-CI 4-BuNHCO-5-Ph-7-N02 4-(2-HOOC-Ethyl)-5-Ph-7-C1 4-HOOCCH2-5-Ph-7-CI 4-(4-C1-Benzy1oxy)CO-5-Ph-7-NO, 4-ClC0-5-Ph-7-Cl
4-Cyclohexanoyl-5-Ph-7-CI 4-Cyclopentanoyl-5-Ph-7-N02 4-Et-5-(2-FC6H4)-7-C1 4-Et00C-5-Ph-7-NO2
> 230 232-233 258-260 231-236 27&274 202-203 187-188 193-195 193-195 274276 218-221 242-245 239-241 197-204 145- 148 165-1 68 179-1 8 1 169-1 70 232-234 138-139 226229 204-208 218-219 21 7-220 203-205 181-184 181-183 248-251d 154156 130-132
Acetone EtOH EtOH MeCN EtOH/H,O DMF/H,O EtOH PhH EtOH EtOH MeOH/H,O EtOH
98
40
56 98 73 55
81 90
65
91 88
67
64 70 80 75
TABLE VIII.1. g c o n t d . )
Substituent
mp ("C) or; [bp ("C)/(torr)]
Solvent of Crystallization
4-(2-EtOOC-Ethy1)-5-Ph-7-C1 4-Et00CCH2-5-Ph-7-CI 4-EtNHCO-5-Ph-7-N02 ~-FOITIIYI-~-P~-~-H,N 4-Formyl-5-Ph-7-N02 4-HO-5-Ph-7-AC 4-HO-5-Ph-7-CI 4-HO-5-Ph-7-N02 4-HO-5-(2-C1C,H4)-7-C1 4-HO-5-(2-FC6H4)-7-CI 4-HO-5-(2-F-5-0,NC6H3)-7-C1 4-(Menthyloxy)CO-5-Ph-7-C1 4-Me-5-Ph-7-AcNH 4-Me-5-Ph-7-CI Methiodide 4-Me-5-Ph-7-MeO 4-Me-5-Ph-7-N02 4-Me-5-(2-C1C,H4)-7-C1 4-Me-5-(2-FC,H4)-7-NHAc 4-Me-5-(2-FC,H4)-7-C1 4-Me-5-(2-Pyridyl)-7-Br 4-MeNHCO-5-Ph-7-CI 4-MeNHCO-5-Ph-7-N02 4-MeOOC-SPh-7-Cl 4-(4-MeC6H,)SO,-5-Ph-7-Ac 4-(4-MeC,H4)SO,-5-Ph-7-Br 4-(4-MeC,H,)SO,-5-Ph-7-CI 4-(4-MeC,H,)SO,-5-Ph-7-N02
146-148 185-186 185-189 239-241 258-261 201-203 215-216 219-22Od 203-205 235-253 24&265 220 16G164 20&208 231-240 214-215 182-185 232-235 16G170 185-186 211-213 235-238 179-1 80 173-175 265-266 177-179 246-252 245-247
CH,CI,/Hexane EtOH EtOH EtOH Acetone CH,C1, AcOH Acetone MeCN MeOH MeOH
Yield
(YO)
Spectra
35 35 90 90
72 90
90 47
60 77
51
57 EtOAc EtOH MeOH/Et,O CH,CI, MeOH EtOH/Acetone EtOAc CH,CI,/Petr ether EtOH EtOH EtOH MeOH/Et,O MeCN CH,CI,/EtOH CHCIJEtOH CH,CI,/Et,O
Refs.
38 20
60
88 97
80
ir, pmr
75 92 28 28 90 29 43, 58 49 56, 77 28 66 29 49 158 90 90 17 47 17 68. 92 17
4-(4-MeC,H4)S02-5-(2-FC,H4)-7-CI 4-MeS0,-5-Ph-7-C1 4-( 1-Naphthy1)NHCO-5-Ph-7-NO, 4-NO-5-Ph-7-NO2 4-PhNHC0-5-Ph-7-Cl 4-PhNHCO-5-Ph-7-NO2 4-(1-Ph-1 -Ethoxy)C0-5-Ph-7-C1 4-Propenoyl-5-Ph-7-NO2 4-(2-Propyn-l-yl)-5-(2-FC,H,)-7-(cyclopentyl)CONH
242-243 203-206 19&196 211-212 232-237 222-224 17G-172 225-227 23G234
CH,Cl,/Petr ether CHCIJEtOH EtOAc EtOH MeCN THF/Hexane EtOAc/Et,O EtOH CH2C12/Et20
237-240
THF/Et20
199-203
EtOH
102-103 102-104
EtOH EtOH
15G152 153-154
Et ,O/Hexane Et,O/Hexane
17 17
173-1 75
CHClJPetr ether
85
219-221d 150-155 177-180
MeOH/Et,O CHzCIz/Petr ether CHzCIz/Et20
85 85 62
12G-121
Et,O/Hexane
31 68 90 86 90 90 90 90 29
86 95 80 82 63 78 72
5,7,8-Trisubstituted
5-Ph-7-HzNS02-8-C1
28
5,7,9-Trisubstituted
5-(2-Pyridyl)-7,9-Br2
158
Tetrasubstituted
5 4
1;1,5,7-Tetrerubstituted
1,3-Me2-5-Ph-7-C1 3S,5S-Enantiomer 3 R,SR-Enantiomer 1-Me-3-EtOOC-5-Ph-7-C1 Isomer A Isomer B
l-Me-3-[3,4-(MeO),-Benzy1]-5-Ph-7-C1 Isomer A 1-Me-3-[3,4-(MeO),C,H3](HO)CH-5-Ph-7-CI hydrochloride Isomer B
l-Me-3-(2-MeOOC-l-Ethyl)-5-Ph-7-C1
95 86
66
“I 1a1
ir, pmr, uv
63 63
I ,4,5,5- Tetrasubstituted 1,4,5-Me,-5-Ph
73
TABLE VIII.l. 4 c o n t d . )
Substituent
mp ("C) or; [bp ("C)/(torr)]
Solvent of Crystallization
Yield
(YO)
Spectra
Refs.
1,4,5,7- Tetrasubstituted
1,4-Ac2-5-Ph-7-C1 1,4-(Allyl),-5-Ph-7-C1hydrochloride
\o
+ 00
185-186 CH,CI, 19e191 CH,CI,/Et,O ~ - ( ~ - H O ~ C - B U ~ ~ I ) - ~ - M C - ~ - ( ~ - F C ~ H 167-174 ~)-~-CI MeOH 1,4-Et,-5-(2-FC6H,)-7-CI 92-93 Hexane l-Et-4-Ac-5-(2-FC6H,)-7-CI 18G181 MeOH 1-Et-4-Me-5-(2-FC,H4)-7-CI 132-133 Acetone/Hexane ~-(~-E~OOC-BU~~~)-~-MC-~-(~-FC,H,)-~-CI hydrochloride 158-167 EtOH/Et,O 1-(2-Et,N-Ethyl)-CMe-5-(2-FC,H4)-7-C1 83-85 Petr ether Methiodide 185-190 Acetone/ether ~-(~-E~,N-E~~~I)-C(~-MCC~H~)SO,-~-(~-FC,H~)-~-CI 179-182 MeOH 1,4-Me2-5-Ph-7-AcNH 21 8-21 9 EtOH/Et,O 1,4-Me2-5-Ph-7-Br 166172 MeOH/Et,O 1,4-Me2-5-Ph-7-C1 9&9 1 Hexane 1,4-Me,-5-Ph-7-F3C 77-79 Hexane 1,4-Me2-5-Ph-7-Me 71-73 Hexane Methiodide 16&161d MeOH/Et,O 1,4-Me2-5-Ph-7-MeS 9698 Et,O/Hexane 1,4-Me2-5-Ph-7-MeS(O) 16G161 Acetone/Hexane 134135 1,4-Me,-5-(2-C1C6H,)-7-Br Et,O 1,4-Me,-5-(2-C1C,H4)-7-C1hydrochloride 24&24 1 Acetone/Et,O 1,4-Me,-5-(2,4-C1,C6H,)-7-C1 Hexane 15G153
57
38 43,49 88 43 28 43
78
88 44, 55
43 47
55
20 31 48 15
50 30 X-ray
1,4-Me,-5-(4-C1C6H,)-7-F
1,4-MeZ-5-(2-FC,H,)-7-AcNH 1,4-Me,-5-(2-FC,H4)-7-Br 1,4-Me,-5-(2-FC,H4)-7-CI
109-112 242-244 134135 124125
Hexane EtOAc Et,O Et,O
60 41
82 60c 43,49 43,49 43,45 43,49 49 46 46 49 43 43 159 43 29 43 49
1,4-Me2-5-(2-FC,H,)-7-F
1,4-Me2-5-(2-FC,H,)-7-(Me)AcN 1,4-Me,-5-(2-FC6H,)-7-MeNHCONH 1,4-Me2-5-(2,6-F,C,H,)-7-C1
1,4-Me,-5-(2-Me2NC,H,)-7-C1 dihydrochloride 1,4-Me,-5-(2-MeC6H4)-7-C1hydrochloride 1 -Me-4-Ac-5-Ph-7-NHAc l-Me-4-Ac-5-Ph-7-CI
1-Me-4-Ac-5-(2-FC6H,)-7-AcNH.0.25 EtOAc I -Me-4-Ac-5-(2-FC6H,)-7-C1 1-Me-4-Ac-5-(2-FC6H4)-7-(Me)AcN 1-Me-4-AcO-5-(2-FC6H,)-7-I l-Me-4-(2-AcO-Ethyl)-5-Ph-7-C1 W
L
W
1-Me-4-H2N-5-Ph-7-Cl I-Me-4-AcNH-5-Ph-7-Cl
1-Me-4-(H2N-Acety1)-5-Ph-7-C1 1-Me-4-(H2N-Acetyl)NH-5-Ph-7-C1 1-Me-4-(2S-H2N-3-Ph-Propanoyl)-5-Ph-7-CI 1-Me-4-(2R-H2N-3-Ph-Propanoy1)-5-Ph-7-C1 l-Me-4-Allyl-5-Ph-7-Cl 1-Me-4-H2NCO-5-Ph-7-C1 (+)-Enantiomer (-)-Enantiomer I-Me-4-Benzyl-5-Ph-7-Cl 1-Me-4-(Benzyloxycarbonylarnino)acetyl-5-Ph-7-C1
118-120 13Cb135 17G176d 183-187 152-163 197-215 > 240 188-192 177-182 201-203 256 20k207 2w201 172-1 74 128-1 30 147- 148 198-206 158-160 173-1 75 179-182 172- 174 108- 109 2 17-21 9 215-2 17
Hexane Et,O/Petr ether EtOAc/Et,O Et,O/Petr ether CH,Cl,/Hexane MeOH/Et,O EtOH/Et,O Et,O Et,O EtOH EtOAc Acetone/Hexane EtOAc MeOH CH,Cl,/Hexane i-PrOH MeCN PhH EtOAc CH,Cl,/Et,o
84
66
76 95 74
ir
59 74 79 76
Hexane
57
EtOH
95
EtOH
87
214-271 151-154 158-160
EtOH MeOH EtOH
87
184-190 177-178 172 28Cb282 197-200
EtOH EtOH EtOAc EtOH Acetone
72 90
90
43 29 29 28 28 43,49 60c 40 70 90 29 28 29 91 35 86 86 90 86 73 73 43,49 90
[a3 X-ray
Cal
90 160
90 78 90
1-Me-4-[(Benzyloxycarbonylamino)acetyl]NH-5-Ph7-C1 1-Me-4-t-BuOOC-5-Ph-7-CI
1-Me-4-BuNHCO-5-(2-FC6H4)-7-BuNHCONH 1-Me-4-(2-HOOC-Benzoyl)-S-Ph-7-C1
l-Me-4-(Cl-Acetyl)-5-Ph-7-C1
81
86 90 60b 89 90
TABLE VI1I.I. g c o n t d . )
Substituent
I-Me-4-(Cl-Acetyl)NH-5-Ph-7-C1 1 -Me-4-(2-CI-Benzoyl)-5-Ph-7-C1 I-Me-4-(4-Cl-Benzoyl)-5-Ph-7-CI 1-Me-4-(2-C1C,H4-MethyIene)amino-5-Ph-7-Cl 1-Me-4-(4-CI-Benzyloxy)CO-5-Ph-7-C1 l-Me-4-CICO-5-Ph-7-Cl ( -)-Enantiomer 1-Me-4-Cyclohexanoyl-5-Ph-7-C1 l-Me-4-CyclopentanoyI-5-Ph-7-Cl l-Me-4-Et-5-H2NCO-7-Br I-Me-4-Et-5-Ph-7-Cl l-Me-4-Et-5-Ph-7-MeNH 1-Me-4-Et-5-(2-FC6H,)-7-C1 l-Me-4-EtOOC-5-Ph-7-CI
1-Me-4-(Et2N-Acetyl)-5-Ph-7-C1 I-Me-4-(2-Et,N-Ethyl)-5-(2-FC,H,)-7-C1 hydrochloride I-Me-4-Formyl-5-Ph-7-Cl
1-Me-4-H2NNHCO-5-Ph-7-C1 l-Me-4-HO-5-Ph-7-CI Isomer A Isomer B 1-Me-4-HO-5-(2-FC6H;)-7-I l-Me-4-(2-HO-Ethyl)-5-Ph-7-C1
l-Me-4-(4-HOC6H,-Methylene)amino-5-Ph-7-Cl 1-Me-4-(2-Me-Propanoyl)-5-(2-FC6H,)-7-C1 I -Me-4-MeOOC-5-Ph-7-C1
mp (“C) or; [bp (“C)/(torr)]
Solvent of Crystallization
227-229 25G253 238-240 185-187 153-1 54 186-187 20 1-203 189-191 229-232d 19G192 111-1 14 168-170 115-116 173-174 129-130
MeCN MeCN MeCN EtOH EtOH PhH Acetone EtOH EtOH CH,Cl,/Et,O Et,O CH,CI,/Et,O/Hexane Hexane EtOH EtOH
74 88 96 91 82 91 67 74 80
186193 162-164 167-169 187-189
Acetone/Et,O i-PrOH EtOH PhH/CHCl,
30 47 68 87
190 209 212-218 2 1&220 135-136 135-1 37 203-204 155-157
PhH PhH/Petr ether MeOH CH,CI,/Hexane Et,O PhH EtOAc MeOH
20 33
Yield
(YO)
Spectra
[.I
92
89
ir
Refs. 86 90 90 86 90 90 90 90 90 85 28 17 28 90 17 44,55 40 90 90 75 75 17 65 35 86 60c 17
I-Me-4-Me00C-5-(2-FC6H4)-7-MeNHCONH l-Me-4-(Menthyloxy)CO-5-Ph-7-C1 1-Me-4-(Menthyloxy)CO-5-Ph-7-N02
l-Me-4-(4-MeC6H,)SO,-5-Ph-7-CI 1-Me-4-(4-MeC,H,)SO,-5-(2-FC,H,)-7-1 1-Me-4-(4-Me-Piperidino)CO-5-Ph-7-C1 l-Me-4-(Morpholino)CO-5-Ph-7-C1 1-Me-4-(l-Naphthyl)NHCO-5-Ph-7-C1 1-Me-4-(2-O,NC6H,-Methylene)amino-5-Ph-7-Cl 1-Me-4-(3-O,NC6H,-Methylene)amino-5-Ph-7-Cl 1-Me-4-(4-0,NC,H4-Methylene)amino-5-Ph-7-Cl
l-Me-4-NO-5-Ph-7-CI 1-Me-4-(Ph-Acetyl)-5-Ph-7-CI
1-Me-4-PhNHCO-5(2-FC6H,)-7-PhNHCONH 1-Me-4-(l-Ph-Ethoxy)-CO-5-Ph-7-C1
\o
h)
l-Me-4-(N-Ph-Methylene)amino-5-Ph-7-C1 l-Me-4-(3-Ph-Propanoyl)-5-Ph-7-C1 l-Me-4-(Piperidino)CO-5-Ph-7-C1 I-Me-4-Propenoyl-5-Ph-7-CI I,4-(MeNHCOCH2),-5-Ph-7-C1 Hydrochloride
1,4-(MeNHCOCH2),-5-Ph-7-CI 1-MeNHCOCH2-4-Me-5-Ph-7-CI Hydrochloride
l-MeOCH2-4-AcO-5-Ph-7-C1 1-MeOCH2-4-HO-5-Ph-7-C1 1-MeOCH,-4-(4-MeC,H4)S0,-5-Ph-7-C1
29 90 90 31 93 90 90 90 86 86 86 86 90 60b 90 86 161 90 90 54 54 89 54 54 41 41 17
2w244d 144-145 206-207 2-262 255-258 240-242 184-185 27 1-273 187-188 224-226 202-204 18G182 228-23 1 Amorphous 163-165 157-158 169-171 136137 169-1 7 1 177-179 208-2 10 177-179 155-157 23 1-233 103-106 173-175 216218
EtOAc/Et,O EtO Ac/Hexane EtOH CH,CI,/Et,O CH,CI,/Et,O MeCN EtOH DMF EtOH EtOH EtOH EtOH EtOH
230-234 19C-192
CH,CI CH,CI,/Et,O/Hexane
29 29
210-212 230-232
Et,O/Petr ether CH,CI,/EtOH
29 17
EtOH EtOH CH,CI,/Et,O EtOH EtOH Acetone MeOH/Et,O Acetone CH,CI,/Hexane MeOH/Et,O MeOH EtOH EtOAc
39
95 89 72 90 93 88 88 94 75 80 87 85
1,5,6,7- Tetrasubstituted
1-Me-5-(2-FC6H,)-6-C1-7-H,N 1-Me-5-(2-FC6H,)-6-CI-7-(Cyclopentyl)CONH 4,5,5,7- Tetrasubstituted
4-(Benzyloxy)CO-5-EtO-5-Ph-7-C1 4-EtOOC-5-EtO-5-Ph-7-Cl
TABLE VIII.1. g c o n t d . )
Substituent
\O h)
N
4-EtOOC-5-Et0-5-(2-Pyridyl)-7-Br 4-HO-5-Me-5-Ph-7-Cl 4,5-MeZ-5-Ph-7-C1 4-Me-5-{ -[3-Azabicyclo(3,2,2)non-3-yl]propyn1-yl}-5-Ph-7-C1 4-Me-5-CN-SPh-7-Cl 4-Me-5-Me0-5-Ph-7-Cl 4-Me-5-MeNH-5-Ph-7-Cl 4-Me-5-Ph-5-(3-Tetrahydropyranyloxy-propynl-yl)-7-C1 4-MeOOC-5-Me0-5-Ph-7-CI 4-NO2-5-Ac0-5-Ph-7-Cl 4-N0,-5-Ac0-5-Ph-7-N02 4-NO2-5-Me0-5-Ph-7-C1 4-NO,-5-Me0-5-Ph-7-NO,
m p ( T ) or; [bp (“C)/(torr)]
Solvent of Crystallization
236 211-213d 178-1 8 1
Et,O MeOH MeOH
202-203 196-198d 201-203 193-195
i-PrOH MeOH
161-162 227-230 138-142d 174-175d 208-21Od 208d
MeOH EtOAc Et OAc/E t ,O CH,CI,/EtOAc MeOH CH,CI,/MeOH
191-192
Et,O
162
13G132 114-115
EtOAc EtOAc
162 162
241-242 208 207-208 186189
EtOH EtOH EtOH
Yield (YO)
85
94 75 81 88
Spectra
Refs.
ir
29 29 72
ir, pmr ir, pmr ir, pmr ir
72 72 72 72
ir, pmr
72 17 74 74 74 74
ir, pmr ir, pmr
ir, pmr ir
5,6,7,8- Tetrasubstituted
S-Ph-6,7,8-(MeO), 5,7,8,9- Tetrasubstituted
5-Me-7,8,9-(MeO), Acetate 5-Ph-7,8,9-(MeO), Pentasubstituted
1,3-Me2-4-H,NCO-5-Ph-7-C1 3S,SS-Enantiomer 3R,5R-Enantiomer
1,3-Me2-4-(2-HO-Ethyl)-5-Ph-7-C1
81 15
63 63 63 67
1-Me-3-[3,4-(MeO),C,H4]-(HO)CH-4-Br-5-Ph-7-Cl 176178 1-C1-4-NOz-5-A~0-5-Ph-7-CI 132d 1,4,5-Me3-5-Ph-7-CI 1,4-Me2-5-H,N-5-Ph-7-C1
1,4-Me,-5-H,N-5-Ph-7-NO, 1,4-Me,-5-H,N-5-(2-FC,H4)7-C1 1,4-Mez-5-(Benzyl)NH-5-Ph-7-CI 1,4-Me2-5-Bu-5-Ph-7-C1
1,4-Me2-5-BuNH-5-Ph-7-C1 1,4-Mez-5-CN-5-Ph-7-CIethanolate 1.4-Me2-5-CN-5-Ph-7-N0, 1,4-Me,-5-CN-5-(2-F-C6H4)-7-C1 1,4-Me2-5-Et-5-Ph-7-C1 1,4-Mez-5-Et0-5-Ph-7-CI
1,4-Me2-5-EtNH-5-Ph-7-CI 1,4-Mez-5-EtNH-5-(2-FC,H,)-7-Cl
1,4-Me,-5-(2-Et2N-Ethyl)NH-5-Ph-7-CI 1,4-Me2-5-H,NNH-5-Ph-7-C1 1,4-Me2-5-(2-HO-EthyI)NH-5-Ph-7-CI 1,4-Me2-5-Me0-5-Ph-7-C1 1,4-Me2-5-Me0-5-(2-FC6H,)-7-CI
1,4-Me2-5-MeNH-5-Ph-7-CI 1,4-Me2-S-MeNH-5-Ph-7-N0,
1,4-Me2-5-MeNH-5-(2-FC6H4)-7-C1 I-Me-4-EtOOC-5-Et0-5-Ph-7-CI
l-Me-4-EtOOC-5-Et0-5-(2-Pyridy1)-7-Br 1-Me-4-[1,2-(MeOOC),-Ethenyl]-5-Me0-5-Ph-7-C1 1-Me-4-NO2-5-Ac0-5-Ph-7-CI 1-Me-4-NOz-5-AcO-5-Ph-7-NO, 1-Me-4-NO2-5-Me0-5-Ph-7-CI 1-Me-4-NO2-5-Me0-5-Ph-7-NO2 1,4-Me,-5-(2-FC6H4)-6-C1-7-(CyclopentyI)CONH 1,4-Me,-5-(2-FC6H4)-6-CI-7-(CyclopentyI)CON( Me) l-Me-S-Ph-6,7,8-(MeO), hydrochloride
149-150 185-186 214-216 186188 17C-172 137-140 116118 134-135 164166 165-166 139-141 1w102 144-145 173- 175 162-164 Oil Oil 107- 108 91-93 196198 238-240 202-203 207-208 220 162-1 63d 158-1 59d 146147d 198-199d 202-204d 218-220 195-200 238d
Et,O/Petr ether Ac,O/Et,O MeOH
76
MeOH EtOH 2-PrOH EtOH MeOH MeOH
95 92 79
ir ir, pmr ir, ms ir ir ir ir, pmr ir ir, pmr ir, pmr ir, pmr ir, pmr ir, pmr
ir ir ir ir, pmr ir, pmr ir, ms
MeOH EtOH
ir
ir PhH/EtOH EtOAc MeCN CH,CI,/EtOAc CH, CI,/EtOAc EtOAc/i-Pr, 0 EtOAc/i-Pr, 0 EtOAc EtOAc/Petr ether MeOH /EtOAc
84 77 67 59
ir ir ir, pmr ir, pmr
85 74 72 72 72 72 72 72 72 72 72 72 72 72 72 72 72 72 72 72 72 72 72 72 17 29 119b 74 74 74 74 29 29 162
TABLE VIII.l. 4 c o n t d . )
Substituent
mp(T) or; [bp ("C)/(torr)]
Solvent of Crystallization
Yield
(YO)
Spectra
Refs.
I .2,4.5-Te1ruhydro-l,4-benzodiuzepin-3(3H)-ones
rg
5-Ph 5-Ph-7-CI 2-Et-2,5-Ph2 1,4-Me2-5-Ph-7-CI 1-Me-5,5-Ph2-7-C1 l-Me-2-HO-4-Me-5-Ph-7-CI 1-Me-2,5,5-Ph3-7-C1
187-188 185-187
Acetone/Et,O Xylene
1 1 4 1 16 25G254 16G164 17G-173
Et,O/Petr ether Acetone CH, CI,/Hexane Et,O
16 16 97 89 29 28 29
I .2,3,4Tetruhydro-l,4-benzodiuzepin-5 ( 5 H ) -ones
None
155-156
EtOAc/Hexane
174176 260-262 268-270 141-142
EtOAc i-PrOH EtOH PhH/Petr ether
ir, pmr
9
ir, pmr Pmr Pmr
9 108 108 100
Monosubstituted
1-Ac 1-(4-AcNHC,H,) 1-(4-H, NC6H,) 1-Benzyl
74 58 50
1-Cyclohexyl 1-Me
1-[2-(N-Me-N-Ph-Ethylamino)]NHCO 1-Ph 3-BuNHCHZ 3-CICH2 3-Me 3-(Morpholino)CH, 3-(Piperidino)CH, 4-Me 4-Ph 7-CI 8-Me0
110 176 169-170 135-136 227 145-147 179-181 214-216 151-1 52 175-1 77 185-188 227-230 223-224 150-151 192-194
Et,O/Petr ether EtOH EtOH EtOAc
170-172
PhH/Hexane
104-106 84-85 190-192 124-126 256-258 107-108 224-226 125-127 258-259 118-120 19C192
EtOH Hexane Acetone Hexane Acetone Hexane Acetone Petr ether Acetone Petr ether Acetone
PhH/Petr ether PhH PhH MeOH EtOH EtOAc EtOH EtOH EtOAc EtOH
35 68
50
pmr, uv ir, pmr ir, pmr ir, pmr
100 100 9 100 100 103 103 103 103 103 112 23d 104 9 9 9
45
ir, pmr, uv
103
30 50 70 85 62 70 80
ir, pmr ir, pmr ir ir, uv ir, uv ir ir
\o
Disubstituted I ,2-Disubstituted
1,2-Me2 I ,CDisubstituted
1-Me-4-Ac I-Ph-4-(2-Et2N-Ethyl) Methiodide 1-Ph-4-(2-Me2N-Ethyl) Methiodide l-Ph4-(l-Me2N-Prop-2-yl) Methiodide 1-Ph-4-(3-Me2N-Propyl) Methiodide l-Ph-4-(2-Piperidinoethyl) Methiodide
75
18d 108 108 108 108 108 108 108 108 108 108
TABLE VIII.1. 4 c o n t d . )
Substituent 1 - Ph-4-(2-Pyrrolidinoethyl)
Methiodide 1-Propanoyl-4-Me
mp("C) or; [bp ("C)/(torr)]
Solvent of Crystallization
138-140 176-178 173-175
Petr ether Acetone EtOAc
204-206 179-180 167-168 188-190 243-245 184186
EtOAc MeOH MeOH EtOH/THF
Yield
(YO)
Spectra
Refs. 108 108 112
I ,7-Disubstituted
$
I-Ac-7-C1 1-12-(N-4-C1C6H, -N-Me-Amino)ethyl]NHCO-7-C1 I-Cyclohexyl-7-C1 1-Me-7-CI 1-(4-0, NC6 H,)-7-NH, 1-(4-02NC6H4)-7-N02
MeOH/i-PrOH
31 41 42 59 69
a\
ir, pmr ir, pmr ir, pmr Pmr Pmr ir, pmr
9 100 100 100 108 108 9
I ,8-Disubstituted
1-Ac-8-Me0 1-Me-8-Me0 1-Cyclohexyl-8-C1 1-Ph-8-H2N 1-Ph-8-Br I-Ph-8-CI 1-Ph-8-F 1-Ph-8-F3C 1-Ph-8-HO 1-Ph-8-N02 1-(4-BrC, H4)-8-Br 1-(2-C1C6H4)-8-C1 1-(4-02NC6H,)-8-N02
205-206 161-162 184185 2 17-218 218-220 182 179-181 173-175 23 1 163-1 64d 211-216 262-264 21&217 229-23 1
EtOAc EtOAc PhH MeOH MeOH PhH MeOH MeOH MeOH MeOH EtOAc MeOH
41 87 34 20 78 43 90 50 29 42 10
ir, ir, ir, ir,
pmr pmr pmr pmr
ir, ms, pmr
ms Pmr
9 9 100 101 101 100 101 101 101 101 102 101 101 101
2,4-Disubstituted
2-Ph-4-Me
202-203
MeOH
63
17Gl73
EtOAc
33
ir
165-1 68d
MeOH
90
ir, uv
162-1 64d 163-1 65 192-193 227-23 Id 19G192 183-185
PhH EtOH EtOH MeOH EtOH EtOH
74 85 19 67 61 60
pmr, uv
212-214
i-PrOH
18d
240-244
DMF/H,O
23d
14@142
EtOH
10
89-90
i-Pr,O
142-145
EtOH
107-108 97-99
EtOAc/Et,O i-Pr,O
10
2,7-Disuhstituted
2-Ph-7-Cl
11. 109
3,3-Disuhstituted
3-Me0-3-Me 3,4-Disuhstituted
3-Ac0-4-Ph 3-Et0-4-Ph 3-EtS-4-Ph 3-Me0-4-Ph 3,4-Me2 3-PhS-4-Ph \o h)
4
pmr, uv pmr, uv ir, pmr pmr, uv
104
104 104 104 103 104
3,7-Disubtituted
3-Me-7-Cl 4,7-Disubstituted
4-Ph-7-Cl Trisubstituted I,2,4- Trisuhstituted
1 -Ac-2-Ph-4-Me I ,3,4- Trisuhstituted
I-Me-3-EtO-4-Ph
67
pmr, uv
105
I ,4,7- Trisuhstituted
2-Me-4-Ac-7-CI
18d
I ,4,8- Trisuhstituted
l-Ph-4-Ac-8-CI 1-Ph-4-Ac-8-F3C
78 93
ir, pmr
101 101
TABLE VIII.1. g c o n t d . )
Substituent
mp(T) or; [bp ("C)/(torr)]
Solvent of Crystallization
l-Ph-4-Benzoyl-8-F3C l-Ph-4-Me-8-CI
1w102 126127
i-Pr,O
Yield
(YO)
Spectra
Refs.
87 90
ir, pmr
101
EtOH/H,O
37
ir, pmr
100
18C183 153-1 56d
EtOAc MeOH
40 80
ir, pmr, uv ir, pmr, uv
103 103
17C173d 217-2 19 176177 234-236 132-133 174-176 125-128 176179 19C192 227-229
CH,Cl,/Petr ether CH, CI,/PhH EtOH THF i-PrOH EtOH c-PrOH EtOH EtOAc/Hexane CH,Cl,/MeOH
76 19 28 88 67 76
184-186d
EtOH
30
189-192
THF
101
1,7,9- Trisubstituted
1-Me-7,9-CI2
97-99
2,3,3- Trisubstituted
2-Ac0-3-Me-3-MeO 2,3-(Me0),-3-Me 3,4,7- Trisubstituted
3-Ac0-4-Ph-7-CI 3-Benzylthio-4-Ph-7-CI 3-Et0-4-Ph-7-Cl 3-Et0-4-Ph-7-N02 3-Et0-4-(2-C1C6H4)-7-C1 3-Et0-4-(2-MeC6H4)-7-C1 3-Et0-4-(4-MeC6H4)-7-Me0 3-Et0-4-(2,4-Me2C, H3)-7-C1 3,4-Me2-7-C1 3-Me0-4-Ph-7-CI
23d 23d 104 104
104 104 104 104 18d 23d
Tetrasubstituted 1,2,3,4- Tetrasubstituted
1-Me-2,4-Ph2-3-Et0
pmr, uv
105
2,3,3,7- Tetrasubstituted
2,3-(Me0),-3-Me-7-C1
18d
Pentmubstituted
2-Me0-3-Benzyl-4,8-Me,-9-HO
\o
R , , R,; Other H, H; 1-Me H, EtOOC; 4-Me H, MeOOC; 7-C1 H, NO2; 7-C1 EtOOC, EtOOC; 4-Benzyl EtOOC, EtOOC; 4-Me EtOOC, EtOOC; 4-[3,4-(MeO),-Benzyl] MeOOC, MeOOC; 7-CI
122-123 MeOH/Et,O bMeihylene-1.2.3.4-tetrahydro-1.4-benzodiazepin-S(S~) -ones
163
48 127-129 PhH/Hexane 149-150 284-287 THF 241-244d DMF 141-142 MeOH 139 Hexane 133-134 EtOH DMF 3W303 3-Methylene-I.2.3,4-~etrahydro-l.4-benzodiazepin-5(5H)-ones
ir, pmr, uv
103 112 17 17 112 112 112 17
ir, prnr, uv ir, pmr
103 103
R , , R,; Other H, H; 4-Me-7-CI H, C1
162-165 107-108d
i-PrOH EtOAc
70 60
TABLE VIII.1. g c o n t d . ) mp ("C)or; [bp ("C/torr)]
Substituent
Solvent of Crystallization
Yield (%)
Spectra
Refs.
Pmr ir, pmr
113 114 118
4,s-Dihydro-1 H-lj4-benzodiazepin-2,3 (2H,3H)-diones
5.7-Disubstituted \o W
0
5-Ph-7-Cl 5-(2-C1C6H4)-7-C1 5-(2-Pyridyl)-7-Br
297-298 33G331 269-272d
EtOH
157-159 169-1 7 1 203-205 184187 224225 239-241 264-267d 233-235 23G232 194195
CH,CI,/Pentane Acetone/Petr ether EtOH CH2C1,/Et,0/EtOH
THF/Hexane CH2CI,/Et,0 Acetone CH,Cl,/Petr ether
113 114 28 17 7.89 38
192-195d 210-213d
MeCN MeOH
120 29
DMF/H,O
I ,5,7- Trisubstituted
l-(2-Et2N-Ethyl)-5-(2-CIC,H,)-7-C1 0.5 H2O 1 -(2-Et2N-Ethyl)-5-(2-FC6H4)-7-C1 1-(2-HO-Ethyl)-5-Ph-7-C1 1-(2-HO-Ethyl)-5-(2-FC6H4)-7-C1 l-Me-5-Ph-7-Cl 1 -Me-5-(2-C1C6H,)-7-C1 1-Me-5-(4-C1C6H4)-7-CI 1-Me-5-(2-FC6H4)-7-CI 1-Me-NHCOCH2-5-Ph-7-C1 1 -(2-Me2N-Ethyl)-5-Ph-7-C1 '
62 65 15
Pmr
Pmr
1I5 117 116
5.5.7- Trisubstituted
5-CN-5-Ph-7-CI 5-Me-S-Ph-7-Cl
Tetrasubstituted
1,4-Me2-5-Ph-7-C1 l-Me-5-CN-5-Ph-7-CI
268-270 195-200d
CH,Cl,/Hexane MeCN
28 120
234-236 276-278 224226
EtOH PhH/CH,CI, MeCN
120 17 120
Pentasubstituted
1,4-Me2-5-CN-3-Ph-7-CI 1,4-Me2-5,5-Ph,-7-C1 l-Me-4-Benzoyl-5-CN-5-Ph-7-Cl
3,4-Dihydro- I H- I .4-benzodiazepin-Z.S(2H,SH)-diones
\o + W
None
327-328
AcOH/H,O
189-190 194-197 262-264 221-224 270-272 275-278 320-321 331-333 252 266 172-175 248-252 151-152
CH,Cl,/Et,O Acetone MeOH CH,CI,/Et,O Acetone DMF/H,O MeOH
ir, uv
132
ir, uv
132 130, 133 133 134 124 128 133 130 128 128 112 133, 143 111
Monosubstituted
I-Benzyl 1-Me 1-(4-N02-Benzyl) 1-Ph 3-Benzyl 3-Me 3-(2-Me-Propyl) 3-i-Pr 4-Benzyl 4-Me 4-[2,4-(MeO),-Benzyl]
DMF/H,O DMF/H,O MeOH EtOAc
52 40 38
ir, uv
ir, ms, pmr
44 46 55
64 84
ir, ms, pmr
TABLE VIII.l. 4 c o n t d . )
Substituent 4-Ph 4-(2-Benzoyl-4-C1C6H,) 4-(4-C1C6H4) 4-(4-HOC,H4) 4-(2-MeC6H,) 4-i-Pr 4-(2-Pyridyl) 7-C1
mp("C) or; [bp ("C)/(torr)] 203-204 199-200 246-247 192-1 94 304306 249-250 196-200 242-243 325-328d
Solvent of Crystallization
MeCN 1,3-Propandiol MeCN DMF/H,O EtOH
Yield (YO)
Spectra
Refs.
52 88
ir, pmr ir
63
ms
140 127 164 164 164 139 112 164 131
MeCN 72
Disubstituted w W
1,3-Disubstituted
h)
I-Benzyl-3-Me l-(Cyclohexyl)CH,-3-Me 1,3-Me2
209-233 184-186 253-255
Acetone/Et,O Acetone/Et,O MeOH
133 133 133
113-1 16 150-151 147 132-134 197-199 199-200 148-1 5 1 Oil
Et,O/Hexane Acetone/Et,O PhMe PhMe PhMe MeOH Acetone
133 133 136 136 136 133 133 143
202-203 146147
Acetone/Et 2O EtOAc/EtOH
I ,I-Disubstituted
1-Benzyl-4-Bu
1-Benzyl-4-Me 1-Benzyl-CMeO 1-(4-Cl-Benzy1)-4-MeO l-(4-C1C,H4)-4-Me0 l-(4-NO2-Benzyl)-4-Me 1,4-Me, l-MeOCH2-4-Me
58 54 56
ir, ms, pmr
41
ir, ms, pmr
I , 7-Disubstituted
1-Benzyl-7-C1 I-Et-7-CI
55
133 135, 129
1,7-Me2 1-Me-7-CI
1-Me-7-NO2 1-Ph-7-C1
170 171-173 178-179 177-1 79 271-272 199-20 1 203-205
Acetone/EtOH CH,CI,/Et20 MeOH Et,O DMF i-PrOH/i-Pr,O EtOAc
92 71 28 35
129 133 135 131 129 144 129
21cb211
Acetone/Et ,O
40
129, 133
100-103 95-98 233-235 195-197
Acetone/Hexane
14cb144 136137 236 242-244
EtOH PhMe PhMe DMF/H,O
255-257
EtOH
156
23cb232 214-217d 245-247 237-238 200-202 196-198 287-289
MeOH/Et,O
165 111 165 111 111 112 145
50
1,8-Disubsfitufed
I-Me-8-CI 3,4-Disubsfituted
W
3-Benzyl-4-Me (S)-Enantiomer 3-(AcOCHPh)-4-Me 3-(HOCHPh)-4-Me 3-Me-4-[3,4-(MeO),-Benzyl] (S)-Enantiomer (R)-Enantiomer 3-Ph-4-MeO
ir, ms, pmr 45
80
52
Cal
143 125 138 138, 125 112 112 136 137
3,8-Disubsfifufed
3-(Indol-3-yl)CH2-8-C1 S-Enantiomer 4,6-Disubsfituted
4-Me-6-Br 4-Me-6-F 4-Me-6-Cl 4,6-Me2 4-Me-6-Me0 4-Me-6-N02
DMSO/H,O EtOH EtOH
TABLE VIII.1. 4 c o n t d . )
Substituent
mp('C) or; [bp ("C)/(torr)]
Solvent of Crystallization
Yield
(YO)
Spectra
Refs.
4,7-Disubstituted
4-Benzyl-7-Cl 4-Me-7-H2N 4-Me-7-Br 4-Me-7-Cl 4-Me-7-Diazonium hexaflurophosphate
rg
&
4-Me-7-F 4-Me-7-F3C 4-Me-7-Me0 4-Me-74 Piperidino)azo 4-[2,4-(MeO),-benzyl]-7-F 4-(Morpholino),OP-7-C1 4-Ph-7-C1
183-184 266d 26G261 253-255 215d 259-262 262-263 203-206 208-209 194-194d 19G192 216-218 197-199
MeOH Acetone/Et,O 47 DMSO/H,O EtOH EtOAc EtOAc/Petr ether DMSO/H,O EtOH MeOH/Et,O
65
ir, pmr, uv
112 145 111 133 145 130 111 111 112 145 111 137 23d
4% Disubstituted
4-Et-8-C1 4-Me-8-Cl 4-Me-8-Me0
75
126 112 112
212-214 282-285 216-218
EtOH
183-185 147-1 48
EtOAc EtOAc/Hexane
112 112
292-294d
MeOH
163
137-139 183
Et,O PhMe
4,PDisubstituted
4-Me-9-Cl 4-Me-9-MeO 8,9-Disubstituted
8-Me-9-HO Trisubstituted I ,3,4- Trisubstituted
l-Benzyl-3,4-Me2 l-Benzyl-3-Ph-4-MeO
60
133 136
1,3,4-Me,
137-139
Acetone
21&211 234-235
EtOAc/EtOH MeOH
1,4-Me,-7-H2N 1,4-Me2-7-C1 1,4-Me2-7-NO, l-Me-4-Ac-7-CI
197-198 182-1 83 2 17-21 8 207-209
MeOH Acetone/Et,O
l-Me-4-Benzyl-7-CI l-Me-4-Butanoyl-7-Cl I-Me-4-F3CCO-7-C1 1-Me-4-Me0-7-N02 l-Me-4-(2-Me-Propanoyl)-7-C1 1-Me-Propanoyl-7-C1
135-137 136137 176178 183-1 85 111-112 158-159
132b
1,3,7-Trisubstituted
1,3-Me2-7-C1 l-Me-3-Ph-7-CI
131 141
44 51
1,4,7- Trisubstitvted
% v,
Acetone Ac,O Acetone/Hexane EtOAc/Cyclohexane
48 95 42 95
(F3CC0)20
MeOH EtOAc/Cyclohexane MeOH
51 90 96
Cyclohexane Acet one/E t ,O EtOAc/i-Pr,O
57
ir, ms, pmr ir, ms, pmr ir, ms, pmr Pmr ir, ms, prnr Pmr Pmr
145 133 145 143 131 143 131 131 136 131 131
1.4.8- Trisubstituted
1-(4-C1-Benzyl)-4-Me0-8-C1 1,4-Me2-8-CI I-Ph-4-Ac-8-Cl 1-Ph-4-Ac-8-N02
I-Ph-4-(4-HzN-Benzoyl)-8-C1 l-Ph-4-Benzoyl-8-Cl l-Ph-4-Benzoyl-8-NOz l-Ph-4-(Benzyloxy)CO-8-CI l-Ph-4-Butanoyl-8-NOz I-P~-~-(BU~OX~)CO-~-C~ I-P~-~-(CI-ACZ~~I)-~-CI l-Ph-4-(CI-A~~tyl)-8-N0~
l-Ph-4-Cyclohexanoyl-8-C1
95-98 198-200 137-138 204-205
21G212 21c211 205-206 138-140 183-1 84 9699 189-191 236238 185-186
84
136 133 147 147 147 147 147 147 147 147 147 147 147
TABLE VII1.I. 4 c o n t d . ) ~
Suhstituent 1-Ph-4-Cyclohexanoyl-8-N02 1-Ph-4-EtNHCO-8-CI l-Ph-4-EtOOC-8-CI l-Ph-4-Formyl-8-CI 1-Ph-4-Formyl-8-NO2 l-Ph-4-(I-Acetyl)-8-C1 l-Ph-4-(I-A~tyl)-8-NO~ I-Ph-4-Me0-8-Cl I-Ph-4-(Me2-Acetyl)-8-NO2
l-Ph-4-(3-Me-Butanoy1)-8-C1 1-Ph-4-(4-MeC,H,SO2)-8-C1 l-Ph-4-(2-Me-Propanoy1)-8-C1 1-Ph-4-(2-Me-Propanoyl)-8-N02 l-Ph-4-PhOOC-8-Cl I-Ph-4-PhNHCO-8-C1 1-Ph-4-(3-Ph-Propenoy1)-8-N02 l-Ph-4-Propanoyl-8-CI 1-Ph-4-Propanoyl-8-N02 1-(2-C1C,Ha)-4-Ac-8-C1
1-(2-C1C,H4)-4-Benzoyl-8-CI 1-(2-FC6H,)-4-Ac-8-C1
m p ( T ) or; [hp f'C)/(torr)] 193-194 196-198d 189-191 196-198 183-185 141-142 189-190 165-1 70 167-168 149-1 50 186187 158-160 215-216 197-198 206-208 237-238 185-186 191-192 207-208 191-192 162-163
Solvent of Crystallization
Yield (YO)
64
Ligroin
53
CH,Cl,/Et,O
74
237-238
DMF
56
24G241 305-306 256258
CH,CI,/MeOH M e 0 H/Et ,O MeOH
Spectra
Refs 147 147 147 147 147 147 147 136 147 147 147 147 147 147 147 147 147 147 147 147 147
1,7,9- Trisubstituted
1-Me-7-C1-9-N02
129
3.89- Trisubstituted
3-(S)-Benzyl-8-Me-9-benzyloxy 3-(S)-Benzyl-8-Me-9-HO
3-(3-HO-Benzyl)-8-Me-9-benzyloxy
163 163 163
3-(3-HO-Benzyl)-g-Me-9-H0 3-(S)-(4-HO-Benzyl)-8-Me-9-benzyloxy 3-(S)-(4-HO-Benzyl)-8-Me-9-H0 3-(S)-[3,4-(HO),-Benzyl]8-Me-9-benzyloxy
3-(S)-[3,4-(HO),-Benzyl]8-Me-9-H0
272-275 273-239 325-335 244-246 155-157
Acetone CH,C12/Et20 Acetone Acetone/Et,O MeOH/Et,O
163 163 163 163 163
238-239 239-241
CH,Cl,/Et,O Acetone
163 163
194196
EtOAc
162
165-166
CH,Cl,/MeOH
131
196-197
CH,Cl,/Et,O
163
141-143
Et,O
162
4,8,P Trisubstituted
4,8-Me2-9-Benzyloxy 4,8-Me2-9-H0 7.8.9- Trisubsfituted
7,8,9-(MeO), Tetrasubstituted I ,3.4,7- Tetrasubstituted
1,3-Me,-4-Ac-7-C1 \o
!$
3,4,8,9- Tetrasubstituted
3-Benzyl-4,8-Me2-9-H0 Pentasubstituted
l,4-Me2-7,8,9-(MeO),
3-Merhylene-3.4-dihydro-IH-~.4-benzodiazepin-2.512H,5H) -diones
R, R,; Other H, Ph; I-Ac-4-Me H, Ph; I-c1-4-M~ H, Ph; 4-Me
0
177-179 129-130 208-209 207-208
MeOH CHClJPetr ether
pmr, uv uv
CHCIJPetr ether
ir,
pmr
pmr, uv
123 123 138 123
TABLE VIII.l. g c o n t d . )
Substituent
mp (“C)or; [bp (“C)/(torr)]
Solvent of Crystallization
Yield (%)
Spectra
Refs.
H, 3-AcOC,H,; 4-Me H, 3-AcOC,H,; 1-Ac-4-Me Ph, H; 4-Me
Amorphous 180-182 185
EtOAc/Hexane
10 24
ir, ms, pmr ir, ms, pmr ir, pmr, uv
143 143 123
“1
133 146 123, 138 146 143 123 143 123, 146
Spiro Compounds
\o
w W
R; Other Ph; 4-Me Racemic Ph; 1,4-Me2 3-AcOC6H,; 4-Me 3-HOC6H,; 4-Me Racemic 3-MeOC6H,; 1,4-Me2
179-180 183-184 193-195 206 193-195 21G211 209-2 1 1 167-169
CH,C1,/EtZO Et,O/Hexane 24
EtOAc/PhH Acetone/Hexane
2,4-Dihydro-IH-l.4-benzodiazepin-3,S (3H,SH)-diones
ir, pmr ir, pmr, uv ir, pmr ir, ms, pmr Cal, pmr, uv ir, ms, pmr ir, ms
14G142 193-194 198-199
4-Benzyl 4-(4-MeC,H4) 4-Ph
i-PrOH i-PrOH i-PrOH
60
ir
70
ir ir, pmr
150 150 150
2-Methylene-2.4-dihydro-I H-l,4-benzodiazepin-3,5( 3 H S H )-diones
R , , R,; Other
H, MeOOC, H, MeOOC; 7-CI
234-236 291-292
151 151
MeOH
Tetrahydro- I ,4-benzodiazepinthiones
W W
W
1,3,4,5- Tetrahydro-I ,4-benzodiazepin-2(2H)-thiones
I-Me-5-Ph 1,4-Me2-5-Ph 1-Me-4-Ac-5- Ph 1-Me-5-(2-FC,H4)-7-C1 4-Me-5-(2-C1C,H4)-7-C1 1,4-Me,-S-(2-FC,H4)-7-CI
1-Me-4-Thioacetyl-5-(2-FC,H4)-7-C1
117-125 141-145 225-227 128-132 157-160 138-140 183-187
Hexane MeOH MeOH MeOH PhH CH,Cl,/MeOH CH,Cl,/Petr ether
50
ir, pmr
28 28 28 28 66 28 28
N
m
2
m
N
m m
d
m
vl
N r-
0 N m
940
m m 3
Vl
m- m- N
94 1
2 N r-
s
3
zz 3
m
r
11. References
943
11. REFERENCES 1. 2. 3. 4.
D. H. Kim, U S . Patent 3,925,361, December 1975. P. M. Carabateas and L. S. Harris, J. Med. Chem., 9,6 (1966). A. A. Santilli and T. S. Osdene, J. Org. Chem., 31,4268 (1966). J. Krapcho, U.S. Patent 3,869,447, March 1975. 5. P. M. Carabateas, US. Patent 3,384,635, May 1968. 6. D. H. Kim, US. Patent 3,904,603, September 1975. 7. C.-M. Lee, J. Hetercycl. Chem., 1, 235 (1964). 8. A. A. Santilli and T. S. Osdene, U.S. Patent 3,457,258, July 1969. 9. D. Misiti, F. Gatta, and R. Landi-Vittory, J . Heterocycl. Chem., 8, 231 (1971). 10. K. H. Weber, Arch. Pharmaz., 302,584 (1969). 11. A. A. Santilli and T. S. Osdene, J. Org. Chem., 29, 1998 (1964). 12. L. H. Sternbach, E. Reeder, and G. A. Archer, J . Org. Chem., 28, 2456 (1963). 13. Neth. Patent 7,207,500, December 1972 (Sumitomo Chemical Co. Ltd., Japan). 14. K. Ishizumi, K. Mori, T. Okamoto, T. Akase, T. Izumi, M. Akatsu, Y. Kume, S. Inaba, and H. Yamamoto, U.S. Patent 4,044,003, August 1977. 15. K. Ishizumi, S. Inaba, and H. Yamamoto, J. Org. Chem., 37, 4111 (1972). 16. G. A. Archer and L. H. Sternbach (a) U.S. Patent 3,531,467, September 1970, (b) U.S. Patent 3,317,518, March 1967. 17. A. Walser, unpublished data, Hoffmann-La Roche, Nutley, NJ. 18. (a) G. F. Field and L. H. Sternbach, U.S. Patent 3,625,959, December 1971. (b) G. F. Field and L. H. Sternbach, U.S. Patent 3,594,365, July 1971. (c) G. F. Field and L. H. Sternbach, US. Patent 3,594,364, July 1971. (d) G. F. Field, unpublished data, Hoffmann-La Roche, Nutley, NJ. 19. A. Walser and R. I. Fryer, J. Org. Chem., 40,153 (1975). 20. A. Walser, G. Silverman, R. I. Fryer, L.H. Sternbach, and J. Hellerbach, J. Org. Chem., 36, 1248 (1971). 21. T. S. Sulkowski and S. J. Childress, J. Org. Chem., 28, 2150 (1963). 22. G. F. Field, W. J. Zally, and L. H. Sternbach, J. Am. Chem. SOC.,89, 332 (1967). 23. (a) W. Metlesics, G. Silverman, and L. H. Sternbach, J. Org. Chem., 28, 2459 (1963). (b)W. Metlesin and L. H. Sternbach, U.S. Patent 3,644,336, February 1972. (c) W. Metlesics and L. H. Sternbach, US. Patent 3,498,973, March 1970. (d) W. Metlesics, unpublished data, Hoffmann-La Roche, Nutley, NJ. 24. R.I. Fryer, J. Blount, E. Reeder, E. J. Trybulski, and A. Walser, J. Org. Chem., 43,4480 (1978). 25. E. Broger, G. F. Field, and L. H. Sternbach, Ger. Offen. 2,223,648, November 1972. 26. F. Gatta and S. Chiavarelli, Farmaco, Ed. Sci., 32,33 (1977). 27. W. Metlesics, G. Silverman, and L. H. Sternbach, J. Org. Chem., 29, 1621 (1964). 28. R. I. Fryer and J. V. Earley, unpublished data, Hoffmann-La Roche, Nutley, NJ. 29. A. Szente, unpublished data, Hoffmann-La Roche & Co., AG, Basel, Switzerland. 30. G. A. Archer and L. H. Sternbach: (a) US. Patent 3,671,517, June 1972, (b) Swiss Patent 511,866, August 1971. 31. R. I. Fryer and L. H. Sternbach, U.S. Patent 3,706,734, December 1972. 32. S. Archer, T. R. Lewis, M. J. Unser, J. 0. Hoppe, and H. Lape, J. Am. Chem. SOC.,79, 5783 (1957). 33. T. Ichii, J. Pharm. SOC.Japan, 82,999 (1962). 34. G. A. Archer and L. H. Sternbach, U.S. Patent 3,553,199, January 1971. 35. M.E. Derieg, unpublished data, Hoffmann-La Roche, Nutley, NJ. 36. R. Kalish, unpublished data, Hoffmann-La Roche, Nutley, NJ. 37. D. H. Kim, U.S. Patent 3,914,250, October 1975. 38. L. H. Sternbach and E. Reeder, unpublished data, Hoffmann-La Roche, Nutley, NJ. 39. S. Shiotani and K. Mitsuhashi, Yakugaku Zasshi, 84,656 (1964). 40. K. Ishizumi, K. Mori, S. Inaba, and H. Yamamoto, Chem. Pharm. Bull., 23, 2169 (1975).
944
Tetrahydro- and Polyhydro-1,4-Benzodiazepines
41. J. Hellerbach and A. Walser, U.S. Patent 3,784,542, January 1974. 42. Zs. Tegyey, G. Maksay, and L. Otvos, J. Labelled Compd., 16, 377 (1978). 43. R. I. Fryer, B. Brust, J. Earley, and L. H. Sternbach, J. Med. Chem., 7, 386 (1964). 44. L. H. Sternbach, G. A. Archer, J. V. Earley, R. I. Fryer, E. Reeder, N. Wasyliw, L. 0. Randall, and R. Benziger, J. Med. Chem., 8, 815 (1965). 45. L. H. Sternbach and G. Saucy, U.S. Patent 3,341,592, September 1967. 46. 0. Keller, N. Steiger, and L. H. Sternbach, US. Patent 3,121,103, February 1964. 47. Belg. Patent 777,096, June 1972 (Hoffmann-La Roche & Co. AG, Switzerland). 48. R. Y. Ning and L. H. Sternbach, U.S. Patent 3,682,892, August 1972. 49. E. Reeder and L. H. Sternbach, US. Patent 3,371,085, February 1968. 50. Belg. Patent 629,352, October 1963 (Hoffmann-La Roche & Co. AG, Switzerland). 51. L. H. Sternbach and E. Reeder, J. Org. Chem., 26, 4936 (1961). 52. R. I. Fryer and L. H. Sternbach, U.S. Patent 3,322,753, May 1967. 53. M. E. Derieg, R. I. Fryer, and L. H. Sternbach, US. Patent 3,651,046, March 1972. 54. G. A. Archer and L. H. Sternbach, US. Patent 3,236,838, February 1966. 55. G. A. Archer, R. I. Fryer, E. Reeder, and L. H. Sternbach, U.S. Patent 3,299,053,January 1967. 56. R. I. Fryer, J. V. Earley, E. Evans, J. Schneider, and L. H. Sternbach, J. Org. Chem., 35,2455 (1970). 57. S. C. Bell and S. J. Childress, US. Patent 3,714,145, January 1973. 58. S. C. Bell and T. S. Sulkowski, C. Gochman, and S. J. Childress, J. Org. Chem., 27, 562 (1962). 59. A. Stempel, I. Douvan, and L. H. Sternbach, J . Org. Chem., 33, 2963 (1968). 60.(a) Q. Branca, A. E. Fischli, and A. Szente, U.S. Patent 4,327,026, April 1982. (b) Q. Branca, unpublished data, Hoffmann-La Roche & Co. AG, Basel, Switzerland. (c) A. E. Fischli, unpublished data, Hoffmann-La Roche & Co. AG, Basel, Switzerland. 61. G. F. Field and L. H. Sternbach, Swiss Patent 561,704, March 1975. 62. A. Walser, G. Silverman, and R. I. Fryer, J. Org. Chem., 38, 3502 (1973). 63. J. Roechricht, L. Kisfaludy, M. Kajtar, E. Palosi, and L. Szporny, U.S. Patent 4,329,341, May 1982. 64. R. J. McCaully, US. Patent 3,410,844, November 1968. 65. G. F. Field and L. H. Sternbach, Swiss Patent 561,189, March 1975. 66. M. Matsuo, K. Taniguchi, and I. Ueda, Chem. Pharm. Bull., 30,1141 (1982). 67. A. Terada, Y. Yabe, T. Miyadera, and R. Tachikawa, presentation at the Third International Congress of Heterocyclic Chemistry, August 1971, Sendai, Japan. 68. R. I. Fryer, D. Winter, and L. H. Sternbach, J . Heterocycl. Chem., 4, 355 (1967). 69. Neth. Patent 7,110,356, February 1972 (Richter Gedeon Vegyeszeti Gyar, Hungary). 70. Neth. Patent 7,311,309, February 1974 (Sumitomo Chemical Co, Japan). 71. R. I. Fryer, G. A. Archer, B. Brust, W. Zally, and L. H. Sternbach, J. Org. Chem., 30,1308 (1965). 72. J. Katsube, Y. Takashima, T. Hirohashi, K. Ishizumi, M. Akatsu, K. Mori, I. Katsuki, Y. Kume, H. Sato, S. Inaba, and H. Yamamoto, U.S. Patent 3,864,330, February 1975. 73. P. M. Mueller and A. Fischli, unpublished data, Hoffmann-La Roche & Co. AG, Basel, Switzerland. 74. M. Ogata, H. Matsumoto, and K. Hirose, J . Med. Chem., 20, 776 (1977). 75. P. Nedenskov and M. Mandrup, Acta Chem. Scand., 31, 701 (1977). 76. S. A. Christensen, Br. Patent 1,247,554, September 1971. 77. R. I. Fryer and L. H. Sternbach, US.Patent 3,501,474, March 1970. 78. J. V. Earley, R. I. Fryer, and L. H. Sternbach, U.S. Patent 3,551,415, December 1970. 79. 0. P. Rudenko, T. L. Karaseva and A. I. Lisitsyna, Russ. Patent 1,051,081-A, October 1983, Derwent No. 84-170270/27. 80. G. A. Archer and L. H. Sternbach, US. Patent 3,370,091, February 1968. 81. S. J. Childress, S. C. Bell, and T. S. Sulkowski, U.S. Patent 3,321,522, May 1967. 82. R. I. Fryer and L. H. Sternbach, U.S. Patent 3,567,710, March 1971. 83. Neth. Patent 7,110,495, February 1972 (Richter Gedeon Vegyeszeti Gyar, Hungary). 84. R. Jaunin and J. Hellerbach, Ger. Offen. 2,150,075, April 1972.
1 1. References
945
85. E. Broger, unpublished data, Hoffmann-La Roche, Nutley, NJ. 86. L. Kisfaludy, J. Roehricht, L. Uroegdi, S. Szeberenyi, E. Palosi, and L. Szporny, U.S. Patent 4,021,421, May 1977. 87. R. I. Fryer, J. V. Earley, and L. H. Sternbach, J . Org. Chem., 30, 521 (1965). 88. J. V. Earley, R. I. Fryer, and L. H. Sternbach, U.S. Patent 3,703,510, November 1972. 89. G. A. Archer, unpublished data, Hoffmann-La Roche, Nutley, NJ. 90.J. Roehricht, L. Kisfaludy, L. Urogdi, E. Palosi, S. Szeberenyi, and L. Szporny, U.S. Patents 4,045,433, August 1977, and 4,342,755, August 1982. 91. G. F. Field and L. H. Sternbach, Swiss Patent 561,190, March 1975. 92. S. C. Bell, R. J. McCaully, and S. J. Childress, J . Med. Chem., 11, 172 (1968). 93. G. F. Field and L. H. Sternbach, Swiss Patent 562,224, April 1975. 94. R. I. Fryer and L. H. Sternbach, U.S. Patent 3,625,957, December 1971. 95. J. V. Earley, R. I. Fryer, and L. H. Sternbach, U.S. Patent 3,644,335, February 1972. 96. M. Ogata and H. Matsumoto, U.S. Patent 4,041,026, August 1977. 97. J. Bergman, A. Brynolf, and Bjoern Elman, Heterocycles, 20, 2141 (1983). 98. J. B. Hester, U.S. Patent 3,896,109, January 1975. 99. J. B. Hester, U.S. Patent 3,714,178, January 1973. 100. C. Corral, R. Madronero, and S. Vega, J. Heterocycf. Chem., 14,99 (1977). 101. A. Bauer and K.-H. Weber, Z. Naturforsch., 29b,670 (1974). 102. A. Bauer and K.-H. Weber, Ger. Offen. 2,165,310, July 1973. 103. G. F. Field, W. J. Zally, and L. H. Sternbach, J . Org. Chem., 36, 777 (1971). 104. Y. Yamada, T. Oine, and I. Inoue, Chem. Pharm. Bull., 22,601 (1974). 105. Y. Yamada, T. Oine, and I. Inoue, Bull. Chem. SOC. Japan, 47,339 (1974). 106. P. I. Itterah and F. G. Mann, J . Chem. Soc., 471 (1958). 107. K.-H. Wuensch, K.-H. Stahnke, and P. Gomoll, Z. Chem., 10, 219 (1970). 108. C. Bagolini, P. de Witt, L. Pacifici, and M. T. Ramacci, J. Med. Chem., 21, 476 (1978). 109. A. A. Santilli and T. S. Osdene, J. Org. Chem., 30,2100 (1965). 110. A. A. Santilli and T. S. Osdene, U.S. Patent 3,336,300, August 1967. 111. (a) M. Gerecke, W. Haefely, W. Hunkeler, E. Kyburz, H. Moehler, L. Pieri, and P. Polc, U.S. Patent 4,363,762, December 1982. (b) W. Hunkeler and E. Kyburz, U.S. Patent 4,352,818, October 1982. 112. W. Hunkeler, unpublished data, Hoffmann-La Roche & Co. AG, Basel, Switzerland. 113. S. C. Bell and S. J. Childress, J. Org. Chem., 27,1691 (1962). 114. A. Nudelman, R. J. McCaully, and S. C. Bell, J. Pharm. Sci., 63,1880 (1974). 115. Brit. Patent 1,346,176, February 1974 (American Home Products Corp., New York). 116. G. F. Tamagnone, R. De Maria, and F. De Marchi, Arznernit. Forsch., 25, 720 (1975). 117. J. V. Earley, R. I. Fryer, D. Winter, and L. H. Sternbach, J . Med. Chem., 11, 774 (1968). 118. A. Stempel, I. Douvan, E. Reeder, and L. H. Sternbach, J. Org. Chem., 32,2417 (1967). 119. (a) R. Y. Ning, W. Y.Chen, and L. H. Sternbach, J. Org. Chem., 36, 1064 (1971). (b) R. Y. Ning, unpublished data, Hoffmann-La Roche, Nutley, NJ. 120. R. Jaunin, unpublished data, Hoffmann-La Roche & Co. AG, Basel, Switzerland. 121. A. M. Felix, J. V. Earley, R. I. Fryer, and L. H. Sternbach, J. Heterocycf. Chem., 5, 731 (1968). 122. K. Miyatake and S. Kaga, J . Pharm. SOC.Japan, 72,1160 (1952). 123. P. K. Martin, H. Rapoport, H. W. Smith, and J. L. Wong, J. Org. Chem., 34, 1359 (1969). 124. R. P. Rhee and J. D. White, J. Org. Chem., 42,3650 (1977). 125. J. Framm, L. Nover, A. El Azzouny, H. Richter, K. Winter, S. Werner, and M. Luckner, Eur. J . Biochern., 37,78 (1973). 126. K.-H. Weber, A. Bauer, and K.-H. Hauptmann, Justus Liebigs Ann. Chem., 756, 128 (1972). 127. J. Krapcho and C. F. Turk, J. Med. Chem., 9, 191 (1966). 128. E. Hoffmann and B. Jagnicinski, J. Heterocycl. Chem., 3, 348 (1966). 129. J. H. Gogerty, R. G. Griot, D. Habeck, L. C. Iorio, and W. J. Houlihan, J . Med. Chem.,20,952 (1977). 130. D. H. Kim, J. Heterocycl. Chem., 12, 1323 (1975).
Tetrahydro- and Polyhydro-1,4-Benzodiazepines
946
131. M. Gates, J. Org. Chem., 45, 1675 (1980). 132. (a) M. Uskokovic, J. Iacobelli, and W. Wenner, J. Org. Chem., 27, 3606 (1962). (b) 133. 134. 135. 136. 137. 138. 139. 140. 141. 142. 143. 144. 145. 146. 147. 148. 149.
1977. 150. 151. 152. 153. 154. 155. 156. 157. 158. 159. 160. 161. 162. 163. 164. 165. 166.
M.
Uskokovic, unpublished data, Hoffmann-La Roche, Nutley, NJ. M. R. Uskokovic and W. Wenner, US. Patent 3,261,828, July 1966. J. Iacobelli, M.Uskokovic, and W. Wenner, J . Heterocycl. Chem., 2, 323 (1965). R. G. Griot, U.S. Patent 3,414,563, December 1968. E. Wolf and H. Kohl, Justus Liebigs Ann. Chem., 1245 (1975). R. Y.Ning, R. I. Fryer, P. B. Madan, and B. C. Sluboski, J . Org. Chem., 41, 2720 (1976). H. Smith, P. Wegfahrt, and H. Rapoport, J. Am. Chem. SOC.,90, 1668 (1968). C. Bogentoft, 0. Ericsson, and B. Danielsson, Acta Pharm. Suec., 11, 59 (1974). M. Z. Kirmani and K. Sethi, Tetrahedron Lett., 2917 (1979). C. Podesva, K. Vagi, and C. Solomon, Can. J. Chem., 46, 2263 (1968). M. Mori, M. Ishikura, T. Ikeda, and Y. Ban, Heterocycles, 16, 1491 (1981). M. Ishikura, M. Mori, T. Ikeda, M. Terashima, and Y. Ban, J. Org. Chem., 47, 2456 (1982). S. Inaba, M. Akatsu, T. Hirohashi, and H. Yamamoto, Chem. Pharm. Bull., 24, 1076 (1976). E. Kyburz, unpublished data, Hoffmann-La Roche & Co. AG, Basel, Switzerland. Y. S. Mohammed and M. Luckner, Tetrahedron Lett., 1953 (1963). A. Bauer, K.-H. Weber, P. Danneberg, and F. J. Kuhn, Ger. Offen. 2,257,171, May 1974. G. F. Field, L. H. Sternbach, and W. J. Zally: (a) US. Patent 3,624,073, November 1971. (b)U.S. Patent 3,678,038, July 1972. R. J. Mohrbacher and P. P. Grous, (a) U.S. Patent 4,022,767, May 1977, (b) U.S. Patent 4,031,079, June 1977, (c) US. Patent 4,020,055, April 1977, (d) US. Patent 4,002,610, January G. Stavropoulos and D. Theodoropoulos, J. Heterocycl. Chem., 14, 1139 (1977). N. D. Heindel and T. F. Lemke, J. Heterocycl. Chem., 3, 389 (1966). C. Corral, R. Madronero, and S. Vega, J . Heterocycl. Chem., 14, 985 (1977). R. Y. Ning, R. I. Fryer, P. B. Madan, and B. C. Sluboski, J . Org. Chem., 41, 2724 (1976). J. T. Plati and H. A. Albrecht, unpublished data, Hoffmann-La Roche, Nutley, NJ. 0. Schnider, unpublished data, Hoffmann-La Roche & Co. AG, Basel, Switzerland. A. Focella, unpublished data, Hoffmann-La Roche, Nutley, NJ. J. Maricq, unpublished data, Hoffmann-La Roche, Nutley, NJ. E. Garcia, unpublished data, Hoffmann-La Roche, Nutley, NJ. J. Karle and I. L. Karle, J. Am. Chem. SOC.,89, 804 (1967). M. Czugler and A. Kalman, Tetrahedron Lett., 917 (1977). E. M. Wilka, unpublished data, Hoffmann-La Roche & Co. AG, Basel, Switzerland. G. Zanetti, unpublished data, Hoffmann-La Roche & Co. AG, Basel, Switzerland. W. Leimgruber, unpublished data, Hoffmann-La Roche, Nutley, NJ. A. I. Rachlin, unpublished data, Hoffmann-La Roche, Nutley, NJ. R. Joos, unpublished data, Hoffmann-La Roche & Co. AG, Basel, Switzerland. Neth. Patent 7,110,498, February 1972 (Richter Gedeon Vegyeszeti Gyar, Hungary).
CHAPTER IX
Hetero Ring[e] [l.41Diazepines .
A Walser Chemical Research Department. Hoffmann-La Roche Inc., Nutfey. New Jersey
and
.
R Ian Fryer Department of Chemistry. Rutgers. State University of New Jersey. Newark. New Jersey
1. Cyclopenta[e][ 1.4ldiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
949
2. Furo[e][l. 4ldiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
950
3. Imidazo[4.5.e][1. 4ldiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
951
4. Isoxazolo[e][l. 4ldiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
952
4.1. Isoxazolo[4.3.e][l. 4ldiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
953
4.2. Isoxazolo[5.4.e][1. 4ldiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
953
5. Isothiazolo[3.4.e][1. 4ldiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
954
6. Oxazolo[e][l. 4ldiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
954
7. Pyrano[2.3.e][l. 4ldiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
955
8 . PyrazinoCZ. 3-e][ 1.4ldiazepines
956
................................. 9. Pyrazolo[e][I. 4ldiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.1. Pyrazolo[3.4.e][1. 4ldiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.1. 1. 1.6.Dihydropyrazolo[3.4.e][1. 4ldiazepines . . . . . . . . . . . . . . . . . . . 9.1.1.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.1.1.2. Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.1.2. 1.6.7.8-Tetrahydropyrazolo[3.4.e][1. 4ldiazepines . . . . . . . . . . . . . . . . 9.1.2.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.1.2.2. Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.1.3. 1.6.7.8.Tetrahydropyrazolo[3.4-e][l.4]diazepin. 7.ones . . . . . . . . . . . . . 9.1.3.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.1.3.2. Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.1.4. 1.4.5.6.7.8.Hexahydropyrazolo[3.4.e][l. 4ldiazepines . . . . . . . . . . . . . .
941
956 957 957 957 958 959 959 960 961 961 963 964
948
Hetero RingCe] [1.41Diazepines
9.2. Pyrazolo[4.3.e][1. 41diazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
964
9.2.1. 1,6-Dihydropyrazolo[4,3-e][1. 4ldiazepines . . . . . . . . . . . . . . . . . . . 9.2.2. 1,4.5.6-Tetrahydropyrazolo[4,3-e][1,4]diazepin- 5-ones . . . . . . . . . . . . . 9.2.2.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.2.2.2. Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9.2.3. 2,4,5,6-Tetrahydropyrazol0[4,3-e][1,4]diazepin- 5-ones . . . . . . . . . . . . . 9.2.4. 1,6,7,8-Tetrahydropyrazolo[4,3-e][1,4]diazepin-8-ones . . . . . . . . . . . . . 9.2.5. 1,4,5,6,7.8-HexahydropyrazoIo[4, 3-el [1,4]diazepin-5-ones . . . . . . . . . . .
965 965 965 966 967 968 969
10. Pyridole] [I, 4ldiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.1. Pyrido[2,3-e][1. 4ldiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.1.1. 1,3-Dihydropyrido[2,3-e][l,4]diazepin-2(2H )-ones . . . . . . . . . . . . . . 10.1.2. 2,3,4,5-Tetrahydro-lH-pyrid0[2,3-e][1, 41diazepines . . . . . . . . . . . . . 10.1.3. 1,2,4,5-Tetrahydropyrido[2,3-e][1,4]diazepin-3(3H )-ones . . . . . . . . . . 10.1.4. 1,2,3.4-Tetrahydropyrido[2,3-e][l,4]diazepin-5(5H )-ones . . . . . . . . . . 10.1.5. 3,4-Dihydro-lH-pyrido[2,3-e][l,4]diazepin-2,5(2H,5H)-diones . . . . . . . 10.1.6. 1.2,3.4,5a,6,7,8-0ctahydropyrido[2,3-e][1,4]diazepin-5(5H )-ones . . . . . . 10.1.7. 1.2,3,4,6,7.8.9-0ctahydropyrido[2, 3-el [1,4]diazepin-5(5H)-ones . . . . . . 10.2. Pyrido[3,2-e][1. 4ldiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.2.1. 3H-Pyrido[3,2-e][1. 4ldiazepines . . . . . . . . . . . . . . . . . . . . . . . . 10.2.2. 2,3-Dihydro-lH-pyrid0[3,2-e][1,4ldiazepines . . . . . . . . . . . . . . . . . 10.2.3. 1.3-Dihydropyrido[3,2-e][l,4]diazepin-2(2H )-ones . . . . . . . . . . . . . . 10.2.3.1. Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.2.3.2. Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.2.4. 3,4.Dihydro-lH-pyrido[3,2-e][l,4]diazepin-2,5(2H,5H)-diones . . . . . . . 10.3. Pyrido[3,4-e][1, 4ldiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.4. Pyrido[4.3-e][l, 4ldiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11. Pyrimido[e][l. 4ldiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.1. Pyrimido[4,5-e][1, 4ldiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.2. Pyrimido[5.4-e][l. 41diazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12. Pyrrolo[e][l, 4ldiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12.1. Pyrrolo[2,3-e][l, 4ldiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12.2. Pyrrolo[3, 2-el [1.4ldiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12.3. PyrroloC3,4-el[ 1.4ldiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13. [1.2,5]Thiadiazolo[3.4-e][ 1,4ldiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14. Thiazolo[e][l, 4ldiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14.1. Thiazolo[4,5-e][1. 41diazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14.2. Thiazolo[5,4-e][1,4ldiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15. Thieno[e][ 1,4ldiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15.1. ThienoC2,3-el [1,4ldiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15.1.1. 3H-Thieno[2,3-e][1. 4ldiazepines . . . . . . . . . . . . . . . . . . . . . . . . 15.1.2. 2.3-Dihydro- 1H-thieno[2,3-el [1 ,4ldiazepines . . . . . . . . . . . . . . . . . 15.1.3. 1,3-Dihydrothieno[2.3-e][l.4]diazepin-2(2H )-ones . . . . . . . . . . . . . . 15.1.4. 3.4.Dihydrothieno[2,3-e][l,4]diazepin-5(5H )-ones . . . . . . . . . . . . . . 15.2. Thieno[3.2-e][1, 4ldiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15.2.1. 3H-Thieno[3.2-e][1, 4ldiazepines . . . . . . . . . . . . . . . . . . . . . . . . 15.2.2. 1,3-Dihydrothieno[3,2-e][l,4]diazepin-2(2H )-ones . . . . . . . . . . . . . . 15.2.3. 3.4-Dihydro-lH-thieno[3.2-e][l.4]diazepin-2,5(2H,5H)-diones . . . . . . .
969 970 970 970 971 971 972 973 973 973 913 915 975 975 976 977 978 978 979 979 981 981 982 982 982 985 985 985 987 987 988 988 990 992 994 995 995 995 997
1. Cyclopenta[e] [1,4]Diazepines
949
15.3. Thieno[3,4-e][1,4]diazepines.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
15.3.1.1,3-Dihydrothieno[3,4-e][l,4]diazepin-2(2H)-ones. . . . . . . . . . . . . . 15.3.2. 3,4-Dihydro-1H-thieno[3,4-e][l,4]diazepin-2,5(2H,5H)-diones. . . . . . . 16. [1,2,4]Triazino[5,6-e][ 1,4]diazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
17. Table of Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
997 997 999 999 loo0 1050
INTRODUCTION This chapter deals with the chemistry of 1,Cdiazepines having a heterocycle fused to the e-bond, represented by the general structure 1. Also included in this chapter is a discussion of the carbocyclic cyclopentaCe] [1,4]diazepine ring system. The related cyclohexa[e] [1,4]diazepines have been reviewed as perhydro derivatives of the benzodiazepine ring system (Chapter VIII, Section 9). The various ring systems reported in the literature will be discussed in alphabetical order. Unpublished data generated in the laboratories of Hoffmann-La Roche in Nutley, New Jersey, in Basel, Switzerland, and in Welwyn Garden City, United Kingdom are included in the review.
2
1
1. CYCLOPENTACe] [1,4]DIAZEPINES While the parent ring system 2 appears to be still unknown, derivatives with a higher degree of saturation were prepared by Broger' in our laboratories. The
Ph 3
Ph
/
4
Ph
Ph
5
6
Hetero Ring[e] [1,4]Diazepines
950
bromoacetylated enamine 3 (X = Br), derived from 2-benzoylcyclopenantone was converted to the corresponding azide 3 (X = N3),hydrogenation of which led to the diazepine 4 (Eq. 1). Further hydrogenation of 4 afforded the saturated derivative 5 of undetermined stereochemistry. Acetylation of 5 with acetic anhydride gave 6, again of unknown stereochemistry.
2. FURO[e][1,4]DIAZEPINES Of the three possible furo[e][ 1,4]diazepines 7-9, derivatives of the furo[2,3-e][1,4]diazepine 7 with a higher degree of saturation have been reported in the literature.
8
7
9
Reaction of the nitrile 10 with ethylenediamine in water at room temperature gave 30% yield of the diazepine 11 (R, = R, = Me, R, = H) (Eq. 2)., This compound and a few analogs were later obtained by treatment of the amino esters 12 with ethylenediamine in refluxing ethan01.~ Acetylation of 11 (R, = R, = R, = H) in boiling acetic anhydride afforded the 1P-diacetyl derivative 13.
qN Ac
0 12
13
Perhydrofuro[2,3-e][1,4]diazepines 16 (R, = H, Me; R, = Me, Bu) were more recently4" prepared by condensation of the dihydrofurans 14 (R, = H, Me) with the 1,3-dialkylimidazolidines 15 (R2 = Me, Bu) by means of trifluoroacetic
951
3. Imidazo[4,5-e] [1,4]Diazepines
acid (Eq. 3). Compound 16 (R, = H; R, = Me) was obtained as the cis-fused isomer, while a mixture of cis and trans isomers was generally formed.
3. IMIDAZO[4,5-e] [1,4]DIAZEPINES Derivatives of the parent ring 17, in particular compounds with an intact aromatic imidazole ring, were synthesized by applying the methods developed for the preparation of 1,4-benzodiazepines. Thus the aminoimidazole 18 (X = 0)was reacted with bromoacetyl bromide to form the amide 19. Treatment of this compound with ammonia in 1,Zdichloroethane gave the diazepine 20 (R = Me) in 57% yield (Eq. 4).5 Xy-,LR
HZN
,,/
-
2I N HH ' , MeOH
/ I
' i 2 N CXH=2 C NO HO E t
r??&R O
N
H 20 Mel/NaOMe/DMF
Ph
r>;+c1 N 0 21
1
Me 22
Me
I
(4)
Hetero Ringre] [1,4]Diazepines
952
Compound 20 (R = H) was obtained by reaction of the imine 18 (R = H, X = NH) with glycine ethyl ester hydrochloride.6 Chlorination of 20 with sulfuryl chloride led to the 2-chloro analog (20: R = Cl), while nitration at the 3-position of the phenyl moiety yielded 21. The methylation of 20 (R = C1) with methyl iodide and sodium methoxide in dimethylformamide led to 22.6 The 5,8-dione 24 (R = H) was synthesized by treatment of the glycine ester 23 with sodium ethoxide in ethanol7 The 7-phenyl analog was accessible by an intramolecular alkylation, by reaction of the chloroacetyl derivative 25 with sodium methoxide (Eq. 5).7
N 23
4. ISOXAZOLO[e] [1,4]DIAZEPINES Derivatives of the parent rings 27 and 29 have appeared in the literature, while the isomers 26 and 28 appear to be unknown.
26
[3,4-e]
27
[4,3-e]
H
H 28
[4,5-e]
29 [5,4-e]
4. Isoxazolo[e][ 1,4]Diazepines
953
4.1. Isoxazolo[4,3-e][l,4]diazepines The 8-phenyl-substituted compounds 34 were recently patented and synthesized as shown in Eq. 6.8 The chlorooximes 30 (X = F,C1) were reacted with nitroacetone in the presence of triethylamine to form the isoxazoles 32. The nitro group was reduced to the amino function by stannous chloride, and the amine was bromoacetylated to give 33. The standard reaction with ammonia followed by a thermally effected ring closure in methanol and acetic acid, led to the diazepine 34 (R = H). Alkylations of 34 were carried out with methyl iodide, 2-diethylaminoethyl chloride, and propargyl bromide.
8
+
"yMe Et3N
NO2 30
Po
O
O 0 2N X
31
2. I . NU, H'IMeOH
T Me 0
32
rx
0 0'
Br
o Me
I R
Me
34
33
4.2. Isoxazol0[5,4-e][1,4]diazepines The synthesis of the 3-methyl-4-phenyl derivative 38 was reported by J a ~ n i n The . ~ protected amino nitrile 35 was reacted with phenylmagnesium bromide to yield, after acid hydrolysis, the amino ketone 36.This intermediate was converted to the diazepine 38 (R = H) via the bromoacetyl compound 37. Hexamethylenetetramine was used for the conversion of 37 to 38 (Eq. 7). When 38 (R = H) was subjected to diazomethane, methylation occurred predominantly on the nitrogen to yield 38 (R = Me). The 7-methoxy compound 39 was isolated in 8% yield as a by-product of this reaction.
954
Hetero Ringre] [1,4]Diazepines
36
35
/
BrCH,COBr
Br
0 H
x I Ph
R
N Me
I
Ph
31
Me
38
Me0
5. ISOTHIAZOLO[3,4-e] [1,4]DIAZEPINES A representative of this ring system, which is one of four possible isothiazolo[e][ lfdiazepines, was prepared by Fryer and coworkers. l o The protected nitrile 40 was reacted with 2-thiazolyl lithium to form an intermediate imine, which after hydrolysis led to the amino ketone 41. The conversion to the diazepine was carried out in a standard fashion by bromoacetylation of 41 to form 42 which upon treatment with ammonia, yielded the diazepine 43 (Eq. 8).
6. OXAZOLO[e][ 1,4]DIAZEPINES This ring system has received little attention. Of the two possible parent rings
44 and 45, only one derivative with the oxazolo[5,4-e][1,4]diazepine structure was described in the literature. The 4-thione 47 resulted from the reaction of the dithio ester 46 with ethylenediamine (Eq. 9).'
'
955
7. Pyrano[2,3-e] [1,4]Diazepines
*
NC
Me
41
40
42
43
c;k)
H
N
H 44
[4,5-e]
45
[5,4-r]
7. PYRANO[2,3-e][1,4]DIAZEPINES The perhydro derivatives 49 of the parent ring 50 were synthesized by condensation of dihydropyran with 1,3-dialkylimidazolidinesin the presence of trifluoroacetic acid.4 The products 49 were obtained as a mixture of &/trans isomers, with the trans ring fusion predominating. Treatment of 49 with lithium aluminum hydride led to the diazepines 51. Representatives of the other three possible pyrano[e] [1,4]diazepines appear to be unknown.
Hetero Ring[ el [1,4] Diazepines
956
R
R
0 "1 I
+
CF,COOH_
(-:;aR
I
49
R
I
15
48
I N
O
LiAIH,
(10)
R I
50
8. PYRAZINO[2,3-e][1,4]DIAZEPINES The synthesis of the 2-ones 55 (X = H, C1; R = H, Me) has been described in the patent literature.I2 The amino ketone 54 was accessible by reaction of the nitrile 52 or the pyrrolidine derivative 53 with phenylmagnesium bromide (Eq. 11). The transformation of 54 to the diazepines 55 (R = H) was carried out by standard methods. Compound 55 (X = C1, R = H) was methylated at the 1-position by means of dimethyl sulfate and potassium ethoxide.
0
52
Ph 54
Ph 55
9. PYRAZOLO[e][1,4]DIAZEPINES The parent rings 56 and 57 remain unknown, but many derivatives with a higher degree of saturation have been described for both ring systems. In all these compounds the aromaticity of the pyrazole ring has been retained.
951
9. Pyrazolo[e] [1,4]Diazepines
57
56 [3,4-e]
[4,3-e]
9.1. Pyrazolo[3,4-e][1,4]diazepines 9.1.1. I,bDihydropyrazolo[3,4-e][1,4]diazepines 9.1.1.1. Synthesis The 1,3,4-trisubstituted compound 59 was obtained by oxidation of the corresponding tetrahydro derivative 58 (R, = R, = Me, R, = 2-C1C6H4, X = H,) with manganese dioxide (Eq. l2).I3 Compounds 60 bearing a methylthio group at the 7-position were accessible by methylation of the 7-thiones 58 (X = S) with methyl iodide.14 The 7-amino derivatives 61 were synthesized by reaction of the 7-thiones 58 (X = S) or the 7-methylthio compounds 60 with a primary amineI5 or by amination of the 7-ones 58 (X = 0)with a primary amine and titanium tetrachloride (Eq. 12).'O
7ge I
N/ 58
\ 59
Me1 (X = SI
I
R3 60
' R2
'
R3
R2
61
The oxime 63 was prepared from the malonylidene derivative 62 via a hydrolysis, decarboxylation, and nitrosation of the intermediate acetylidene compound (Eq. 13).16
Hetero Ring[e] [1,4]Diazepines
958
go C
MeO,
NOH
Me
Me
I
1.
on-
2. HNO,
Ph
Ph
62
63
(13)
9.1.1.2. Reactions Nitrosation of the amidine 64 with nitrosyl chloride in the presence of pyridine led to the nitrosoamidine 65 in high yield.16 This compound reacted with the anion of dimethyl malonate to give the malonylidene derivative 62 (Eq. 14).
H MeN ?%N
NO
I
Me
I
MeN
TXTNOCl
Me
?7+I
N'
NPh
Et
Ph
62
Et
65
64
(14) Reaction of the 7-methylthio compound 66 with acetylhydrazine afforded the triazolodiazepine 67 (Eq. 15).14 The imidazopyrazolodiazepines69 (R = H, Me; X = H, F, C1) were obtained by treatment of the acetylenes 68 with sulfuric acid in the presence of mercuric oxide.' The amidines 68 were accessible by reaction of the 7-methylthio compounds 66 or the 7-thiones with the acetylenic amines in refluxing ethanol.
Me
I
MeS
H,NNHAc
66
67
959
9. Pyrazolo[e] [1,4]Diazepines
68
The imidazo[1,5-a]pyrazolo[4,3-f][ 1,4]diazepine 71 was synthesized via the oxime 63. Reduction of this oxime with zinc dust and acetic acid in methylene chloride gave presumably the intermediate enamine 70, which was reacted in situ with triethyl orthoacetate to yield 71 (Eq. 16).16
I1
N
f Ph
l Et
1I
I
Ph
Et
70
Addition of hydrogen cyanide to the 7,8-imine bond of 59 led to the 7-cyano derivative 72 (Eq. 17).13 Me Me
59
12
9.1.2. 1,6,7,8-Tetrahydropyrazolo[3,4-e][l ,4)diazepines 9.1.2.1. Synthesis A variety of 1,6,7,8-tetrahydro compounds 75 were synthesized by reaction of the 5-chloropyrazoles 73 with the diamine 74 (Eq. 18).13.17The best results were
Hetero Ring[e] [1,4]Diazepines
960
obtained by refluxing the chloropyrazole with the diamine and by partial distillation of the diamine. Yields of diazepines varied from 25 to 78%.
73
74
75
As exemplified by the preparation of 77 (Eq. 19), 1,6,7,8-tetrahydro derivatives may also be synthesized by reduction of the 7-ones, such as 76, with aluminum hydride.’j
O
H
Me I
H AIH,
Me
(1 9) Me
N/
c1
c1
\
77
76
9.1.2.2. Reactions The 4-phenyl compound 78 (X = R = H) was brominated in the meta position of the phenyl moiety with bromine and silver sulfate in concentrated sulfuric acid.” Oxidation of the 8-trifluoroacetyl derivative 78 (X = C1, R = CF3CO) with m-chloroperoxybenzoic acid afforded the 5-oxide 79 (R = CF,CO). The trifluoroacetyl group was readily removed by alkaline hydrolysis to yield 79 (R = H) (Eq. 2O).I3 Nitration of 78 (X = R = H) with potassium nitrate in concentrated sulfuric acid occurred at the 3-position of the 4-phenyl group, giving 80. The nitro group was reduced to the amino function by hydrogenation over Raney nickel, and this amine was diazotized. The diazonium salt was reacted with azide and cyanide to yield 81 (X = N3) and 81 (X = CN). Nitrosation of 78 (X = C1, R = H) led to the 8-nitroso analog 78 (X = C1, R = NO). Acylations at the 8-position were carried out with acetic and trifluoroacetic anhydrides. Alkylations at this nitrogen were performed with 3-dimethylaminopropyl chloride and l-(2-chloroethyl)pyrrolidine in dimethylformamide using sodium hydride as base. Reduction of 8-acyl derivatives by aluminum hydride, as shown by the conversion of the 8-acetyl compound 78 (X = C1, R = Ac) to the corresponding 8-ethyl derivative, provided another method for the preparation of 8-alkyl compounds.
9. Pyrazolo[e] [1,4]Diazepines
R 1
961
Me
Me
1
m-CIC, H, CO1H
c1
X 78
' 79
R,X=H
H 1. HJRancy nickel 2. HNOl
3.
Me I
m
x-
X 81
80
Demethylation at the 1-position of 82 was achieved by refluxing in pyridine hydrochloride for 6 hours. Compound 83 was thus obtained in 40% yield (Eq. 2 l ) . I 3 Me H H H I
C,H,N HCI
c1
y;
c1
\
83
82
9.1.3. 1,6,7,8-Tetrahydropyrazolo[3,4-e][1,4]diazepin-7-ones 9.1.3.1. Synthesis
The 4-aroyl-5-amino-pyrazoles84 were converted to the haloacetamides 85. The halogen Y was then displaced by ammonia, azide, or phthalimide anion. The azide was reduced to the amine catalytically or by treatment with triphenylphosphine, while the phthalimido group was cleaved by standard hydrazinolysis. The aminoacetamides 85 (X = NH,) were not characterized but were
Hetero Ring[e] [1,4]Diazepines
962
cyclized in situ to the diazepinones 86 (Eq. 22).'8919 The azide method was also applied to convert the bromide 85 (R, = R, = R, = Me, R, = 3-C1, R4 = H) to the corresponding diazepinone 86.13
///
85
m-CIC, H,CO,H
86
81
89
88 1. HNO,
2. N,-
I
Me Me
I
90
I
9. Pyrazolo[e] [If
Diazepines
963
The 5-oxides 87 (X = H, F) were prepared by oxidation of the appropriate compounds 86 with rn-chloroperoxybenzoic acid in acetic acid.' 9.1.3.2. Reactions Oxidation of the 2'-amino group of 88 with trifluoroperoxyacetic acid led to the nitro derivative 89 (Eq. 23)" The azide 90 resulted from diazotization of the amine 88 followed by displacement of the diazonium group by azide.' Alkylations of 86 (R4 = H) to the corresponding 8-alkyl analogs 86 (R4 = alkyl) were carried out with methyl iodide, ethyl iodide, and ally1 bromide in dimethylformamide using sodium hydride for deprotonation.'09'8-zo The N-oxides 87 were reacted with acetic anhydride to give the 6-acetoxy compounds 91, which, upon hydrolysis with aqueous sodium hydroxide in methanol, gave the corresponding 6-hydroxy derivatives 92 (Eq. 24).18 O
87 AC20_
Me
I
H
5 H O ?N-g M e
N-
x
Me
\
\
91
o$
I
92
H
H
. CI H 5 N . H C I R
=
Me
F / 94
\
93
i Me
Me Me C,H,N.HCI
R = Me
HN
95
Me I
H
96
(24)
Hetero Ring[e] [1,4]Diazepines
964
Reduction of the imine bond in 93 (R = Me, Et) was achieved by catalytic hydrogenation over palladium catalyst, giving 95 in high yields (Eq. 25).1892 While an attempt to remove the 1-methyl group from 93 (R = Me) led to the pyrazoloquinolone 94, the demethylation of the reduced imine 95 (R = Me) in refluxing pyridine hydrochloride was successful and gave directly the desired product 96, apparently by simultaneous oxidation of the amine to the imine.” The hydrolytic opening of the imine bond of 97 to the amino ketone 98 was studied in detail (Eq. 26).” At pH 3.7, for example, the equilibrium mixture was determined to contain 18% of the open-chain 98.
x”. Me Me
0
Me
I
N\
F N-
Me
I
nlo
I
+
H 3 N + ? z M e
\
(26)
\
98
91
9.1.4.1,4,5,6,7,8-Hexahydropyrazolo[3,4-e][I,4]diazepines The hexahydro derivative 100 (R = Et) was obtained by reduction of the 8-acetyl compound 99 (X = H, R = Ac) with aluminum hydride (Eq. 27).13 Reoxidation to the imine 99 (X = H,, R = Et) was achieved in low yield by treatment with manganese dioxide. The carbonyl compound 99 (X = 0,R = H) was reduced by aluminum hydride to the hexahydro analog 100 (R = H),17 which was reoxidized to the tetrahydro compound 99 (X = H,, R = H) by means of diethyl azodicarboxylate.
R
Me
reduction
___)
oxidation
Hy;e R ‘
I
(27)
c1 99
Me
‘ 100
9.2. Pyrazolo[4,3-e] [1,4]diazepines The fully unsaturated parent ring system 57 remains unknown. However, derivatives with a higher level of saturation and, in particular, compounds that retain the aromaticity of the pyrazole ring, have been described.
9. Pyrazolo[e] [1,4]Diazepines
965
9.2.1. 1,6-Dihydropyrazolo[4,3e][l,4]diazepines The 5-methylthio derivatives 102 and the amidine 103, apparently the only representatives of this class described in the literature, were prepared by alkylation of the thione 101 with dimethyl sulfate and sodium hydroxide in metha n 0 1 , ~followed ~ by displacement of the methylthio group by methylamine (Eq. 28).23a
MeS 101
//
Me I02
MeNH,
Ph
";'"
H 103
9.2.2. 1,4,5,6-Tetrahydropyrazolo[4,3-e][I ,4]diazepin-5-ones 9.2.2.1. Synthesis The 1,3-dialkyl derivatives 106 were synthesized by the standard methods from the aminopyrazoles 104b. These aminopyrazoles were obtained by reduction of the corresponding nitropyrazoles, which were derived from the nit~ ~or- by reaction ropyrazole carboxylic acid 104a by Friedel-Crafts a r y l a t i ~ n 26 of the corresponding nitrile with aryllithium reagents (Eq. 29).24,27The amines 104b could be converted in one step to the diazepinones 106 by reaction with glycine ethyl ester hydrochloride in refluxing ~ y r i d i n e ,or ~ ~via the bromoacetate 105 (X = Br). The bromide in 105 (X = Br) was displaced by azide, and the azido compound 105 (X = N3)was reduced catalytically over palladium on carbon. The resulting amine was heated in toluene in the presence of acetic acid to complete the cyclization to the d i a ~ e p i n o n e .Compound ~~ 105 (X = benzyloxycarbonylamino) was formed by reaction of 104b with benzyloxycarbonyl glycine and dicyclohexylcarbodiimide and was cleaved by hydrogen bromide in acetic acid to give the dihydrobromide of the amine 105 (X = NH2).24
966
Hetero Ring[e] [ 1,4]Diazepines
104b
104n
KS
108
107
The 7-oxides 107 were accessible by reaction of the bromides 105 (X = Br) with hydroxylamine or by oxidation of the imines 106 with m-chloroperoxybenzoic a ~ i d . ' ~ 6-Acetoxy ,'~ compounds 108 (X = Ac) were prepared by heating the 7-oxides 107 with acetic anhyd~ide.'~Alkaline hydrolysis of these acetoxy derivatives led to the corresponding 6-hydroxy analogs 108 (X = H). The thiation of the lactam 106 (R, = R, = Me, R, = Ph, R, = Rs = H) to the thione 101 was performed with phosphorous pentasulfide in pyridine.',
9.2.2.2. Reactions Bromination of the 8-phenyl compound 109 with bromine and silver sulfate in concentrated sulfuric acid afforded the 3-bromophenyl derivative 110 (X = Br) (Eq. 30).', The 3-nitrophenyl analog was similarly prepared by nitration in the same medium.24 Alkylations of 106 (R, = H) or the N-oxides 107 (R, = H) were carried out in the standard fashion using sodium hydride and the alkyl halide in dimethylformamide.24*26~28 The reagents employed include methyl iodide, ethyl iodide,
967
9. Pyrazolo[e] [ 1,4]Diazepines
3-dimethylaminopropyl chloride, 2-diethylaminoethyl chloride, and 2,2,2-trifluoroethyl bromide and propargyl bromide. Reaction of 111 (R = Me) with fluoromethyl sulfate followed by hydrolytic workup led to the open-chain methylated amine 112, characterized as a hydrochloride (Eq. 3 1).30Quaternization with methyl iodide in acetonitrile at 100°C afforded the methiodide salt 114. The equilibria of the diazepinones 111 (R = H, Me) with the corresponding ring-opened hydrolysis products 113 were in~estigated.~'At a given pH, the 4-Me analog 111 (R = Me) was ring opened to a larger degree than the 4-H compound. Ph
Ph Ph
Et
'I
I
\Methylent
112
111
OH-
n,o+
I
\e
9.2.3.2,4,5,6-Tetrahydropyrazolo[4,3-e][1,4]diazepin-5-ones Compounds 116 (R, = H) were prepared by reaction of the aminopyrazoles 115 with glycine ethyl ester in boiling pyridine (Eq. 32).', The aminopyrazoles 115 were accessible via the nitropyrazoles mentioned in Section 9.2.2.1. The
Hetero RingCe] [1,4]Diazepines
968
substituent at the 4-position was introduced by alkylating 116 (R, = H), using the method described for the preparation of 116 (R4= Me, Et).24
'
" R,
R,
116
115
9.2.4. I ,6,7,8-Tetrahydropyrazolo[4,3-e][1,4]diazepin-8-ones Baraldi and coworkers3' recently synthesized the 5-phenyl derivatives 118 (X = H, Me, C1, Br, Ph) by reductive cyclization of the nitro compounds 117, using iron powder in a refluxing mixture of water and 2-methoxyethanol (Eq. 33).
X' 118
117
The nitro amides 117 were obtained by treating the diketopiperazine 120 with the appropriate a-amino ketone. The diketopiperazine resulted from the treatment of the pyrazole carboxylic acid 119 with thionyl chloride (Eq. 34). The protected amino acid 121 was alternatively reacted with the amino ketone by means of dicyclohexylcarbodiimide to yield 122, which cyciized to 118 (X = NO,) upon cleavage of the protecting group.
1I9
120
9 69
10. PyridoCe] [1,4]Diazepines
118
121
9.2.5. 1,4,5,6,7,8-Hexahydropyrazolo[4,3-e][ 1,4]diazepin-5-ones The hexahydro derivatives 124 were prepared by catalytic hydrogenation of the imine bond in 123, employing palladium on carbon as the catalyst of choice (Eq. 35).32Reaction of the amines 124 with formaldehyde and formic acid led to the 7-methyl analogs 125.
123
124
(35) J
125
10. PYRIDO[e] [1,4]DIAZEPINES Representatives of all four possible pyrido[e][ 1,4]diazepines, the 1H tautomers of which are shown, (126129), have been reported in the literature. The [3,2-e] isomers have received most attention, because of their interesting pharmacological properties.
Hetero RingCe] [1,4]Diazepines
970
126 [2,3-el
128
[3,4-e]
127
[3,2-e]
129 [4,3-e]
10.1. Pyrido[2,3-e][1,4]diazepines 10.I . I . I ,3-Dihydr opy r id0 [2,3-e][ I ,4]diazepin-2 ( 2 H )-ones The 5-phenyl compound 131 was prepared by Littell and Allen33in 1965, and it is the only representative with this oxidation state. The aminopyridine 130 was reacted with benzyloxcarbonylglycine in the presence of dicyclohexylcarbodiimide, and subsequent cleavage of the protecting group by hydrogen bromide in acetic acid led to the diazepinone 131 (Eq. 36).
Ph 130
Ph 131
10.1.2. 2,3,4,S-Tetrahydro-lH-Pyrido[2,3-e] [ I ,4]diazepines The 8-methyl compounds 133 were prepared by desulfurization of the 5thiones 132 (X = H,Br) by Raney nickel in ethanol (Eq. 37).34The 1-phenyl derivative 135 (R = H)was obtained by reduction of the 3-one 134 with lithium aluminum h ~ d r i d eCompound .~~ 135 (R = H)was methylated at the 4-position to give 135 (R = Me) and acylated with acetic anhydride or 4-chlorobenzoyl chloride to yield the 4-acyl derivatives 135 (R = Ac, 4-C1C,H4CO), re~pectively.~~
10. Pyrido[e] [1,4]Diazepines
97 1
R 1 R a n q nickel EtOH
X
NH
NH
S I32
I33
Ph
Ph
I
I
NH
NR I35
134
10.1.3.1,2,4,5-Tetrahydropyrido[2,3-e][l,4]diazepin-3(3H)-ones Compound 134, the only representative of this class, was synthesized by alkylation of 136 with ethyl bromoacetate to give 137 (Eq. 38), which was, in turn, subjected to catalytic hydrogenation and ring closure to the diazepinone 134. The ring closure and hydrogenation processes occurred ~ i m u l t a n e o u s l y . ~ ~ Ph I
BrCH,COOEt
CN 136
Mew-coE I
11
A
134
CN
137
10.1.4.1,2,3,4-Tetrahydropyrido[2,3-e][1,4]diazepin-S(5H)-ones Several substituted 8-methyl derivatives 139 were accessible in high yields by performing the Schmidt reaction on the tetrahydronaphthyridines 138 (Eq. 39).34,36Compound 139 (R, = R, = X = H) was also prepared by ring closure of the amino ester 140.35 The conversion of the lactams 139 to the corresponding 5-thiones 132 was carried out with phosphorus pentasulfide in refluxing pyridine. 4,3 Acetylation of 139 (R, = R, = X = H) with acetyl chloride led to the 1-acetyl d e r i ~ a t i v e The . ~ ~ 7-nitro compound 139 (R, = R, = H, X = NO,) was prepared by nitration of the 7-H analog.34
972
Hetero Ringce] [If Diazepines
I39
138
//I Meq+-$2 (39)
R,
H
I
M
e
q
z
N
H
2
X
0
S 132
140
10.1.5. 3,4,-Dihydro-lH-pyrido[2,3-e][ I ,4]diazepin-2,5( 2 H S H )diones The 4-methyl compound 142 was prepared by reaction of the oxazinone 141 with sarcosine ethyl ester in dimethylformamide and triethylamine at 80°C (Eq. 40).37 This lactam was further transformed into the imidazodiazepine 143 by reaction with diethyl chlorophosphate and subsequent condensation of the intermediate iminophosphate with the anion of ethyl isocyanoacetate. H
qxo 0
143
MeNHCH,COOEl Et,N/DMF 80°C. 2 h
*
@To
0 N,
Me
10. PyridoCe] [1,4]Diazepines
973
10.1.6.1,2,3,4,Sa,6,7,8-Octahydropyrido[2,3-e][1 ,4]diazepinS (SH) -ones The octahydro derivatives 145 (R = H, Et) were obtained when the tetrahydropyridines 144 (R = H, Et) were heated with ethylenediamine in boiling ethanol (Eq. 41).38*39 H q : E t
H, NlCH,), NH,
XIH
(41)
RO 144
145
10.1.7.1,2,3,4,6,7,8,9-0ctahydropyrido~2,3-e~~1,4~diazepin5 (5H) -ones The 9-alkyl derivatives 147 (R = Me, Et) were synthesized by reaction of the tetrahydropyridines 146 (R = Me, Et) with ethylenediamine (Eq. 42).39,40
b
R
KiEt q> I
H, N I C H A N H ,
NH
0
146
(42)
0
147
10.2. Pyrido[3,2-e][ 1,4]diazepines Many of the reactions carried out with the 1,4-benzodiazepines were applied to this ring system, but, in particular to the 7-chloro-substituted genus.
10.2.1.3H-Pyrido[3,2-e][1,4]diazepines In analogy to the benzodiazepines, reaction of the pyridopyrimidine 148 with methylamine resulted in ring expansion to the diazepine 149.41The 4-desoxy analog of 149 was also prepared by amination of the lactam 150 with methylamine and titanium tetrachloride (Eq. 43).41 The 2-hydrazino compounds 152 were accessible by reaction of the nitrosoamidines 151 with hydrazine. The nitrosoamidines were formed by nitrosation of the corresponding amidines. The hydrazines 152 were converted to the tetrazolodiazepines 153 by nitrous acid and to several triazolodiazepines 154 (R = H, OEt) and 155 by reaction with orthoesters and carbonyldiimidazole.
974
Hetero Ring[e] [1,4]Diazepines
Gr c1
H NMe 2 McNH_
‘ 0
148
149
/
/
\ 150
152
154
151
153
155
10. PyridoCe] [1,4]Diazepines
975
10.2.2. 2,3-Dihydro-1 H-Pyrido[3,2-e] [I,4]diazepines The 2-hydroxy compound 157 (R = OH) was prepared by reduction of the 2-one 156 with sodium diethoxyaluminum hydride at 0°C in tetrahydrofuran (Eq. 44).42 Treatment of the 2-hydroxy derivative with ethanolic hydrogen chloride led to the 2-ethoxy analog 157 (R = OEt). Lithium aluminum hydride in tetrahydrofuran reduced the carbonyl group to a hydrocarbon, yielding 157 (R = H).43 Me
Me (44) Ph 157
156
10.2.3. 1,3-Dihydropyrido[3,2-e][1,4]diazepin-2(2H)-ones 10.2.3.1. Synthesis The 5-phenyl compound 159 was synthesized by Littell and Allen33 by coupling 3-amino-2-benzoylpyridine 158 with benzyloxycarbonyl glycine. Subsequent cleavage of the protecting group, followed by cyclization, yielded 159 (Eq. 45).
Ph 158
Ph 159
Synthesis of 7-substituted analogs of 159 was achieved by using the 2,6-dichloro-3-nitropyridine 160 as the starting material. Compound 160 was reacted with phenylacetonitriles and base to give 161. These intermediates were then oxidized by alkaline hydrogen peroxide to the ketones 162 (Eq. 46). Since chloride was partially displaced by hydroxide during this oxidation, the 6hydroxypyridine had to be reconverted to the 6-chloro compound by treatment with a mixture of phosphorus pentachloride, phosphorus oxychloride, and phosphorus trichloride. The nitro group was reduced by catalytic hydrogenation over Raney nickel to the amines 163.43,44Displacement of the chloride in 162 (X = C1) by various secondary amines led to the 6-amino pyridines 162 (X = NR1R2).44
Hetero RingCe] [1,4]Diazepines
976
R,CH,CN
R3
160
161
R3 162
R3
163
The aminopyridines 163 were then transformed into the diazepinones 164 by standard methods, such as by bromoacetylation followed by treatment with ammonia or by the addition of a benzyloxycarbonyl-protected amino The 7-amino derivative 164 (R, = Ph, R, = H, X = NH,) was prepared by condensation of the diaminopyridine 163 (R, = Ph, X = NH,) with glycine ethyl ester hydrochloride in an imidazole melt at 110-1 15°C.44The preparation of the 7-chloro analog by this method was patented as well.45The 4-oxides 150 (X = 0)were also obtained by ring expansion of the pyridopyrimidines 148 with hydroxide (Eq. 43).43*46 10.2.3.2. Reactions Oxidation of 164 (R, = H, R, = Ph, X = C1) with rn-chloroperoxybenzoic acid led to the corresponding 4-0xide.~~ A variety of substituents were introduced at the 1-position of 164 (R, = Ph, substituted Ph) by the standard alkylation using sodium hydride and the appropriate alkyl halide (R,Y)in dimethylformamide. Moieties (R,) attached in this fashion include methyl, propyl, butyl, allyl, cyclopropylmethyl, 2-dimethylaminoethyl, 2-hydroxyethyl, 2-morpholinoethyl, and 2-piperidinoSimilar alkylations were carried out with chloroacetone, chloroacetonitrile, ethyl bromoacetate, a-chloroacetophenones, 3-bromopropionic acid, and 4-chlorobutyronitrile.47.48 A 3-hydroxy derivative, 165 (R, = Me,
10. PyridoCe] [1,4]Diazepines
911
R, = OH,R,
= 2-C1C,H4), was converted to the 3-methoxy analog by reaction with methyl iodide and sodium hydride in dimethylf~rmarnide.~~ The dimethylamino group at the 7-position of 164 (R, = H, R3 = Ph, X = Me,N) was quaternized by reaction with methyl iodide.44 Acylations at the 1-position of 164 were performed with acetic anhydride The 4-oxides were rearranged under re flu^,^ and with a variety of i~ocyanates.~’ in the usual fashion to the 3-acetoxy derivatives by treatment with acetic a r ~ h y d r i d e . ~The ~ , 3-hydroxy ~ ~ , ~ ~ compound 164 (R, = OH,R, = 2-C1C,H4, X = Cl) was acylated by succinic anhydride to the 3-hemis~ccinate.~~ The chloride at the 7-position of 164 (R, = H, R, = Ph, 2-halophenyl; X = C1) was displaced by a variety of amines, such as dimethylamine, ethanolamine, morpholine, pyrrolidine, and N-methylpipera~ine.~~ Compounds 166 (X = H, C1) were converted to the thioamides 167 by treatment with hydrogen sulfide in methanolic ammonia (Eq. 47).48
(47)
c1
c1
167
166
A few of the 2-ones were transformed into the corresponding thiones by the standard reaction with phosphorus pentasulfide in ~ y r i d i n e . , ~Reaction of the 2-thione 150 (X = S, Y = H) with acetylhydrazine in dioxane afforded the 2-hydrazino derivative 152 (R = Ac, Y = H) (Eq. 43).
10.2.4. 3,4-Dihydr o-I H-pyr ido[ 3,2-e][ I ,4]diazepin-2,5 ( 2H,5H ) diones The 4-methyl compound 169 was synthesized by Hunkeler and Kyburz3’ by reaction of the oxazinone 168 with sarcosine ethyl ester (Eq. 48). This dione (169) was converted to the corresponding imidazodiazepine3-carboxylic acid ethyl ester as shown for compound 143 depicted in Eq. 40.
168
169
978
Hetero Ring[e] [1,4]Diazepines
10.3. Pyrido[3,4-e][1,4]diazepines
The only representative of this ring system described in the literature was prepared by Littell and Allen.33They converted the 3-amino-4Lbenzoylpyridine to the diazepinone 172 by the benzyloxycarbonyl glycine method. The benzoylpyridine 171 resulted from addition of phenylmagnesium bromide to the oxazinone 170 (Eq. 49).
0
Ph
170
H
O
J
/
171
(49)
Ph 172
10.4. Pyrid0[4,3+][1,4]diazepines
The 5-phenyl derivative 176 was synthesized, according to the procedures discussed above for the positional isomers, from the oxazinone 173 (R = Me), via the aminobenzoylpyridine 174 (Eq. 50).33The related oxazinedione 173 (R = OH) was used for the preparation of the 2,Sdione 175, which was further 1. PhMgBr
R
=
Me
0 173
HN-CH,
Me I
Ph 174
I
-COOEi R = OH
175
I 176
(50)
11. PyrimidoCe] [1,rllDiazepines
979
reacted to form the imidazodiazepine in the same fashion as the two positional isomers previously discussed.37 The 1,3,4,5-tetrahydro-2-one 178 was one of four products formed in 15% yield from the reaction of bromopyridine 177 with potassium amide in liquid ammonia (Eq. 51).50A possible mechanism for the formation of 178 is given by an addition of ammonia to the intermediate aryne, followed by a ring closure.
177
178
11. PYRIMIDO[e] [1,4]DIAZEPINES 11.1. Pyrirnido[4,5-e][1,4]diazepines
None of the many possible tautomers of the parent ring system has been reported in the literature, although compounds with a higher degree of saturation and with an aromatic pyrimidine ring are known. The structure 6,9-dihydro-SH-pyrirnido[4,5-e][1,4]diazepine (182: R = OH) was assigned to the product resulting from the treatment of thiamine 179 with hydroxide (Eq. 52).5’*52The cyclization is believed to proceed via the ring-open intermediate 180 by loss of hydrogen sulphide. The reaction of thiamine anhydride 181 with 4-substituted phenylthiols was reported to lead to the diazepines 182 (R = SC,H,X with X = H, Me, Br).’j The diazepine was hydrolyzed at pH 8-9 and at 100°C to give the open aminoketone 183. Reaction of 182 with 2 equivalents of 5-hydroxy-3-mercaptopentan-2-one formed 184 with stereochemistry unassigned.’ Kim and Santilli5, prepared the 6,7,8,9-tetrahydro-5-one 186 by reaction of the chloropyrimidine 185 with N,N’-dimethylethylenediamine(Eq. 53). 5,6,8,9-tetrahydro-7-one 188 by catalytic hydrogenation K o ~ synthesised h ~ ~ of the nitrile 187 with concomitant ring closure (Eq. 54). Jauningbprepared several 4,8-diones 191 by ring closure of the imines 190, which resulted from the reaction of the ketones 189 with glycine ethyl ester. Compounds with R, = H, Me, benzyl, 2-dimethylaminoethyl and R, = Ph, Me were thus obtained. The 5-phenyl compounds were further alkylated at the 9-position by methyl iodide and 2-dimethylaminoethyl chloride using standard procedures (Eq. 55).9b
’
980
Hetero Ringre] [1,4]Diazepines
0
Me
HO
180
179
I I
t
H H S G X
Me
DMF, RT
0
(52)
Me 0 OH 183
C1
I N+fPh
184
Me I MeNH(CH,),NHMe
(53)
Ef O&N
N
Me’
0 185
187
0 I86
188
98 1
12. Pyrrolo[e] [1,4]Diazepines
189
190
(55)
191
192
11.2. Pyrimido[5,4-e][1,4]diazepines The only representatives of this heterocyclic system were described by Santilli and S ~ o t e s e .These ~ ~ investigators reacted the oxadiazinones 193 with ethylenediamine in boiling methanol (Eq. 56). Compounds 193 resulted from the addition of dimethyl acetylenedicarboxylate to the appropriate amidoxime and subsequent cyclization. Diazepines 194 (R = 4-C1C6H,, morpholinocarbonylmethyl, piperidinocarbonylmethyl) were reported.
&xR
H,N(CHi)zNHi
*
H [ - - i
H
Me0 193
(56)
o
194
12. PYRROLO[e][1,4]DIAZEPINES Partially saturated representatives of all three positional isomers have been synthesized.
982
Hetero Ring[e] [1,4]Diazepines
12.1. Pyrrolo[2,3-e][1,4]diazepines The octahydro-5-one 196 was obtained by refluxing the ester 195 with ethylenediamine in ethanol for 16 hours (Eq. 57).38The question of stereochemistry was not addressed, but the trans configuration may be assumed to be thermodynamically preferred.
H
(fln:;
H,N(CH,hNHi
0
Ph
*
K
2
(57)
0
Ph
195
H
196
12.2. Pyrrolo[3,2-e][1,4]diazepines Garcia56 synthesized the 5-phenyl-2-ones 198 (R = CN, COOEt, CONH,) from the corresponding aminopyrroles 197 by the now standard method of bromoacetylation and subsequent cyclization reaction with ammonia (Eq. 58).
Ph I 97
n
Ph 198
12.3. Pyrrolo[3,4-e][1,4]diazepines This class of compounds has received much attention because of the interesting pharmacological properties of such 5-phenyl-2-ones as premazepam 202 (R, = Ph, R, = R, = Me). Fontanella and c o - ~ o r k e r s ~prepared ~ * ~ * several substituted 2-ones 202 starting with the enamines 199,which were cyclized to the unstable aminopyrroles 200 by treatment with sodium ethoxide (Eq. 59). The aminopyrroles were acylated with bromoacetyl chloride, bromide or phthalimidoacetyl chloride to give the amides 201 (X = C1, Br, phthalimido). Hydrazinolysis of the phthalimido group led to the corresponding amine, which was thermally cyclized to the diazepine. We5’ prepared the same amines from the bromide via the azide 201 (X = N3) by hydrogenation of the latter. Ring closure took place upon heating in toluene or xylene in the presence of acetic acid. The substituent R, was introduced by alkylation of the pyrrole 201 (X = phthalimido or azido) using methyl iodide and potassium carbonate in boiling methyl ethyl ketone.
983
12. PyrroloCe] [1,4]Diazepines
R3
R 3
IrTTT
I
R2
R,
The 4-oxides of 202 were similarly prepared by reacting the iodoacetates 201 = I) with hydroxylamine.60 Halogenation or nitration of premazepam (203) afforded the 8-chloro, bromo, or nitro derivatives 204 (E = C1, Br, NO,) (Eq. 60).61
(X
205
206
Treatment of the same compound with in-chloroperoxybenzoic acid in trifluoroacetic acid led to the methylenepyrrolinone 205.59 The hydroxymethyl derivative 206 was reported to be a metabolite of premazepam,62 but was only characterized ~pectroscopically.~~ Substituents such as methyl and ethyl groups were introduced at the 1-position of 202 by alkylation with an alkyl iodide in liquid ammonia containing sodium amide.57*58
984
Hetero Ring[e] [1,4]Diazepines
The 3-hydroxy compounds 207 (R, = H) (Eq. 61) were obtained by hydrolysis of the 3-acetoxy analogs 207 (R, = COCH,), which resulted in turn from the Polonovski rearrangement of the 4-oxides with acetic anhydride.60 The 3-hydroxy group was acylated by a variety of acid chlorides.60 The 3-alkoxy compounds 207 (R2 = Me, Et) and the 3-amino derivative 208 [X = NH(CH,),COOEt] were synthesized by converting the 3-hydroxy comp o u n d ~ ~(R,~ '= H) to the chloride 208 (X = C1) by means of thionyl chloride and then displacing the chloride either by alkoxide or by an amineO6'
R4-
207
208
The lactams 209 (X = H, C1) were transformed into the imidazodiazepines 210 by conversion to the iminophosphate and condensation with the anion of ethyl isocyanoacetate (Eq. 62).s9
0
The 6,8-diones 212 (R = H, Ph) were prepared in 77% yield by reacting the maleimides 21 1 with ethylenediamine (Eq. 63).64 o
211
H
212
14. Thiazolo[e] [1,4]Diazepines
985
13. [1,2,5]-THIADIAZOLO[3,4-e][1,4]DIAZEPINES Compound 214, the only representative of this heterocycle, was prepared by Ning65 by the bromoacetylation of 3-amino-4-benzoylthiadiazole (213) and subsequent reaction with ammonia (Eq. 64). Ph
213
Ph
214
14. THIAZOLO[e][1,4]DIAZEPINES Compounds belonging to either of the two possible thiazolo[e][ 1,4]diazepines illustrated were reported in the literature.
14.1. Thiazolo[4,5-e] [1,4]diazepines The oxathiolium salts 215 (X = H, C1; R, = Me,N, piperidino, morpholino, 4-C1C6H,) reacted with cyanamide in the presence of base to form the aminothiazoles 216 (R, = H) (Eq. 65).66 Methylation of these compounds afforded the methylamino derivatives 216 (R, = Me). Among the several methods investigated, the condensation of the benzyloxycarbonyl-protected amino acid with 216 by means of thionyl chloride, followed by deprotection with hydrogen bromide in acetic acid and acid-catalyzed cyclization, proved to be best suited for the synthesis of the diazepinones 217. Compound 217 (R, = morpholino, R, = R, = X = H) was converted to the thione 218 by phosphorus pentasulfide and pyridine in dichloromethane. Reaction of the thione with acetylhydrazine led to 219, which was converted to the triazolo compound 220 by heating in acetic acid.66
986
Hetero Ring[e] [1,4]Diazepines
218
The thiazoline-2-thiones 221 (R = Me, Et) were obtained by reacting benzoylacetonitrile with methyl or ethyl isothiocyanate and sulfur in dimethylformamide in the presence of t r i e t h ~ l a m i n e .The ~ ~ amino ketones 221 were transformed into the diazepinones 222 (R = Me, Et) by chloroacetylation and reaction with liquid ammonia (Eq. 66).67
987
15. ThienoCe] [1,4]Diazepines
221
222
14.2. Thiazolo[5,4-e][1,4]diazepines The 8-phenyl derivative 224 (R, = Ph, R, = H) was synthesized by Szente,6 who reacted the imine 223 (R, = Ph) with bromoacetyl bromide in the presence of sodium bicarbonate (Eq. 67). The imine 223 resulted from the addition of phenyllithium to the corresponding nitrile. Fryer and Earley prepared the 2-thiazolyl analog 224 (R, = 2-thiazolyl) by the same method." Methylation of 224 (R, = Ph, R, = H) with dimethyl sulfate and potassium carbonate afforded the 4-methyl derivative 224 (R, = Me), which was nitrated by nitric acid in concentrated sulfuric acid to yield 225.6
Hzps> - r>j R,
HNL
N
0
R1
1
R2
223 I Me,SO,IK,CO, 2
nNo,jnIso, R , = Ph. R, = H
(67)
Me 225
15. THIENO[e][ 1,4]DIAZEPINES Representatives of all three positional isomers have been reported in the literature.
988
Hetero Ring[e] [1,4]Diazepines
15.1. Thieno[2,3-e][1,4]diazepines
15.1.1. 3H- Thieno[2,3e][ I ,4]diazepines The 2-amino-3H-thieno[2,3-e] [1,4]diazepines 227 were prepared either by reacting the 2-ones 226 (X= 0)with titanium tetrachloride and an amine,68-71 or by treatment of the 2-thiones 226 (X = S)with an amine.” The 2-thiomethyl derivative 228 resulted from methylation of the appropriate 2-thione. Compound 227 [R, = 2-C1C,H4, R, = R, = H, R, = Et, R, = CH,CH(OEt),)J was converted to the imidazothienodiazepine 229 (Eq. 68).72373
I
I
Me1 X = S
SMe
6-” 228
229
The nitrosoamidines 230 (X = H,Cl) accessible by nitrosation of the corresponding amidines, were reacted with the anions of nitromethane and dimethyl malonate to give the 2-methylene derivatives 231 (R,= NO,, R, = H)and 231 (R, = R, = COOMe), respectively (Eq. 69).16The latter was hydrolyzed, decarboxylated, and nitrosated in acetic acid to yield the oxime 232.Compound 232
15. ThienoCe] [1,4]Diazepines
989
was further converted to the imidazo compound 233 (R = H, Me) by hydrogenation over Raney nickel and subsequent condensation with triethyl orthoformate or acetate.I6
NO -
<:'
A
230
H cl
y1
-N
ox 231
The 2-hydrazino compounds 234 (R, = H) were predominantly synthesized by treatment of the 2-thiones 226 (X = S) with h y d r a ~ i n e . ~ ' . ~Displace~.~~-~~ ment of a 2-amino group by a 2-hydrazino functionality was reported to succeed by a catalyzed reaction with N-rnethylimidaz~le.~~ 2-Hydrazino compounds have been demonstrated to form 1,Zdisubstituted hydrazines upon boiling in ethanol-acetic acid.68 Compounds 234 (R, = acyl) were similarly obtained from the reaction of 2-thiones with acylhydrazines or by acylation of the 2-hydrazino derivative^.^'^^^^^^.^^^^' Many of these 2-hydrazino compounds 234 were converted to the triazolothienodiazepines 235,by one of two routes: (a) the or (b) reaction with orthoesters, imidates, or amidines when R, = H68,69,74976 The ethylcarbacyclization with dehydration (R, = COR,) (Eq. 70).68,69*74,77-79 mate 234 (R, = 2-ClC6H,, R, = H, R, = Br, R, = COOEt) was cyclized to the triazolo analog 235 (R, = EtO) by heating in xylene in the presence of silica gel.78 Phosgene in the presence of triethylamine converted the hydrazine 234 (R, = 2-C1C6H,, R, = R, = H, R, = Et) to the triazolone 237,75while the tetrazolo derivative 236 was formed by nitrosation of the same hydrazine.
990
Hetero Ring[e] [1,4]Diazepines
236
237
The oxadiazolones 239 resulted from the treatment of the 2-hydroxyamines 238 (R = Me, Et) with phosgene and triethylamine (Eq. 71).73 Although the preparation of the hydroxyamines 238 was not described, these products may be obtained by reaction of the 2-thiones with hydroxylamine.
238
239
15.1.2. 2,3-Dihydro-IH-thien0[2,3-e][1,4]diazepines The 5-phenyl derivatives 241 were obtained in high yields by reduction of the 2-ones 240 with the sodium aluminium hydride reagent at room temperature (Eq. 72).80,81These compounds were reacted with a variety of isocyanates, aminocarbonyl chlorides, and thioisocyanates to form the 1-aminocarbonyl derivatives 242 (Y = 0)or the thio analogs 242 (Y = S).
15. ThienoCe] [1,4]Diazepines
99 1
240
242
Lithium aluminum hydride reduced the 2-nitromethylene compound 243 to the 2-aminomethyl derivative 244. Compound 244 was converted in low yield to the imidazothienodiazepine 245 by reaction with triethyl orthoacetate and subsequent oxidation of the intermediate imidazoline to the imidazole by activated manganese dioxide (Eq. 73).16
Ph 245
Hetero RingCe] [1,4]Diazepines
992
15.1.3. I ,3-Dihydrothieno[2,3-e][1,4]diazepin-2(2H)-ones Three teams of researcher^'^^^^^^^ synthesized the title compounds almost simultaneously. The 2-aminothiophenes 246, prepared by several methods, were converted to the diazepinones by the standard procedures worked out for the synthesis of 1,4-benzodiazepines. The methods described include haloacetyl~ ation to 247 (X = Br, I) and subsequent reaction with a m m ~ n i a ' ~ - 'hydrogenation of the azide 247 (X = N,),*, and coupling of the amine 246 with N-protected amino acids, such as benzyloxycarbonyl glycine or phthalimidoacetyl chloride to form the amides 247 (X = benzyloxycarbonylamino; phthalimido), which were then deprotected by standard methods.82.86The resulting amines 247 (X = NH,) could be cyclized to compounds 248 by several methods. The methods included heating in ethanol or with acetic acid and pyridine in benzene with azeotropic removal of water,86 and refluxing in ethanol in the presence of formic acid or heating in acetic, isobutyric, or pivalic acid (Eq. 74).87The application of a polymeric acrylic acid resin in a mixture of dioxane and ethylene glycol was also described."
NH
R,
R2 246
241
/ 248
(74)
249
The thienodiazepinones 248 (R4 = H) were also accessible by reaction * ~with ' the Leuch's anof the aminothiophenes 246 with glycine ethyl e ~ t e r ' ~ or hydride of glycine." The 4-oxides of 248 were generally obtained by oxidation with m-chloroperoxybenzoic a ~ i d , ~ or~ with * ~ ~hydrogen , ~ ~ peroxide in acetic acid-acetic anhydride.94 Reaction of the iodides 246 (X = I) with hydroxylamine and ring closure under acid catalysis was another viable method for the preparation of the 4-oxides of 248.82 In turn, the 4-oxides of 248
15. ThienoCe] [1,4]Diazepines
993
underwent the usual rearrangement to the 3-acetoxy derivatives 248 (R, = OAc) upon heating in acetic Hydrolysis of the acetoxy group afforded the corresponding 3-hydroxy analog^.^'.^^ A variety of substituents were introduced at the 1-position by alkylation. The R, residues of 249 thus attached include the methyl, ethyl, isopropyl, butyl, benzyl, propargyl, allyl, cyclopropylmethyl, methoxymethyl, 2-hydroxyethyl, and 2-diethylaminoethyl groUps.82,85-87,89,92,94-99 A methylaminocarbonyl group was attached at the 1-position of 248 (R, = 2-C1C,H4, R, = R, = H, R, = Et) by reaction with methyl isocyanate to give the corresponding derivative 249 with R, = CONHMe.'" Electrophilic reagents attacked 250 (R, = H) at the 7-position. Thus, halogenation of these thienodiazepines with sulfuryl chloride in acetic acid or with bromine in chloroform led to the 7-halo derivatives 251 (X = C1, Br).83-85,88*92,97 The 7-nitro analogs were similarly obtained by nitration in concentrated sulfuric a ~ i d . ~ Iodine ~ , ~in~the * presence ~ ~ * ~of ~mercuric oxide allowed the iodination of 250 (R, = H) to give the 7-iOdO analogs 251 (X = I).97 If the 7-position in 250 was occupied, nitration would occur at the 6-position, leading to 252 (X = N02).88*95 Reaction of 250 (R, = R, = H, R, = 2-C1C,H4, R, = Et) with chloramine or 2,4-dinitrophenoxyamine and sodium hydride in dimethylformamide gave in high yield the 1-amino derivative 253 (Eq. 79.'''
R3
R3
250
25 1
R,+H x'
I
u2 = n, R, =
(75) ph\
x
I
Ph 252 253
The hydrolytic ring opening of etizolam (254) to the amino ketone 255 was investigated and compared with that of triazolobenzo- and triazolothienodiazepines."' Etizolam was found to be little affected by treatment at 37°C for
Hetero RingCe] [1,4]Diazepines
994
100 minutes in 0.1N hydrochloric acid. The pK, of this compound was given as 4.11."' +NH3 Me O\d
254
255
Nmr spectroscopy of thienodiazepinones 250 (R, = H, Me; R, = H; R, = Et, Ph, 2-halophenyl; R, = H, C1, NO,) and their 4-oxides revealed that the chemical shift of the proton in the 6-position depended on the bulkiness of the ortho substituent on the 5-phenyl ring. The degree of shielding was determined not only by the out-of-plane orientation of the phenyl ring but also by the ring system.93 With 5-(2-fluorophenyl)-substitutedcompounds, a long-range coupling of the fluorine with the proton at the 6-position was observed. The value of this coupling constant depended on the spatial relation of the two nuclei."'
15.I .4. 3,4-Dihydrothieno[2,3-e][ I ,4]diazepin-5(5H)-ones The 2-amino derivative 259 was prepared by treatment of the nitrile 258 with sodium methoxide (Eq. 77). The 2-aminothiophene 258 resulted from the reaction of dimeric mercaptoacetaldehyde 256 with the cyanoacetamide 257 in refluxing ethanol containing triethylamine (Eq. 77).'03
(77)
0
0
259
260
15. Thieno[e] [1,4]Diazepines
995
The diazepine 259 was converted to the triazolo derivative 260 by heating with acetylhydrazine in hexamethylphosphoric triamide for 2 hours at 140°C.l o 3
15.2. Thieno[3,2-e][1,4]diazepines
15.2.1. 3H- Thieno[3,2-e][1 ,4]diazepines The 2-methylamino compound 262 (R = H)was obtained by amination of the lactam 261 with methylamine and titanium tetrachloride. It was nitrosated to form the nitrosoamidine 262 (R = NO),which was reacted with the anion of nitromethane to yield the 2-nitromethylene derivative 263 (Eq. 78). The 2-aminomethyl derivative 264 was obtained from the catalytic hydrogenation of the nitro compound 263 over Raney nickel and was characterized as a maleate salt. Compound 264 was further converted to an imidazothienodiazepine by condensation with triethyl orthoacetate and subsequent oxidation with activated manganese dioxide.
R
I
Ph
Ph 262
261 R=NO
Ph
Ph
263
264
15.2.2. 1,3-Dihydrothieno[3,2-e][1,4]diazepin-2(2H)-ones The 2-ones 271 were synthesized by haloacetylation of the 3-aminothiophenes 269 to give 270 (X = C1, Br, I). Displacement of the halide by ammonia, ' ~ ~required -'~~ followed by ring closure, afforded 271 as a p r o d ~ c t . ~ ~ ,The aminothiophenes were synthesized by the three methods shown in Eq. 79. Compounds 269 (R, = Ph; R, = H, CF,; R, = H) were obtained by treatment
Hetero Ringre] [1,4]Diazepines
996
of the oxazinone 265 with aryl Grignard reagents and subsequent hydrol y s i ~ . ' ~ ~Friedel-Crafts *'~~ acylation of the thiophenes 266 (R, = H, C1) provided another access to the aminothiophenes.lo6.lo' The 3-amino-4cyanothiophenes 269 (R, = Ph; R, = morpholino, piperidino; R, = CN) were derived from the 1,3-oxathiolium ions 267. Reaction of these ions with malononitrile in the presence of triethylamine may proceed via the intermediate 268.66
0
,
265
E1,N
CN 1
'CN
261
X
R, 270
R3
271
The substituent R, at the l-position of 271 was again introduced by alkylaThe possibility of alkylattion of the parent compound (R, = ing the amino group of the aminothiophene 269 before establishing the diazepine ring also existed. Because of the propensity of N-methylated acetamides to undergo a Smiles-type rearrangement during ammonolysis or hydrazinolysis, the diazepine ring was best formed by the benzyloxycarbonyl glycine method.66 The 4-oxides of 271 can be obtained by the standard oxidation with rn-chloroperoxybenzoic acid, as demonstrated for 261.'04 Nitration of 261 with nitric acid in concentrated sulfuric acid at G5"C led to the 8-nitro derivative 272 (Eq. 80). The location of the nitro group was established by hydrolysis of 272 to the ketone 274 and removal of the amino group from 274 by diazotization and treatment with hypophosphoric acid. The resulting 2-benzoyl4-nitrothiophene was compared with an authentic ample.'^' Nitration under H).'04,10631079109
15. ThienoCe] [1,4]Diazepines
997
more vigorous conditions led to the dinitro compound 273. The position of the nitro group in the phenyl ring was proved by oxidative degradation to 3nitrobenzoic acid by permanganate.
Kf
NO2 H
I
Ph 261
273
i
KMnO,
COOH
15.2.3. 3,4- !hydro-lH-thieno[3,2-e][1,4]diazepin-2,5(2H,5t
ones
The 4-methyl compound 276 was prepared by heating the oxazinone 275 with sarcosine ethyl ester in dimethyl sulfoxide for 1.5 hours at 110°C (Eq. Sl).' l o This compound was further transformed into the imidazothienodiazepine as shown in Eq. 84 for the [3,4-e]-fused isomer.
0 215
216
15.3. Thieno[3,4-e][1,4]diazepines
15.3.1. 1,3-Dihydrothien0[3,4-e][1,4]diazepin-2(2H)-ones The key to the synthesis of the diazepines 281 was again the preparation of the aminothiophenes 280. Hromatka and coworkers obtained 280 (R, = Ph, 2-F3CC,H,, R2 = R, = H) by reaction of the oxazinone 277 with the aryl
998
Hetero Ring[e] [1,4]Diazepines
Grignard reagent (Eq. 82).111-113 The 3-amino-4-benzoylthiophene 280 (R, = Ph, R, = R, = H) was also accessible by Friedel-Crafts acylation, by reacting the acid chloride 278 with aluminum chloride in benzene."' This method was later applied to prepare several 2,5-dimethyl analogs of 280 from the thiophene 279.lI4 The conversion of the amino ketones 280 to the diazepinones was carried out in the standard fashion by haloacetylation and subsequent ammonolysis of the halide, preferentially the iodide. Ring closures of intermediate aminoacetamides occurred upon heating in pyridine114 or refluxing in ethanol in the presence of pivalic a ~ i d . " ~ ~ " ~
S 0
ePh 0
211
218 R ,MgBr
Me
H
S Y A C
c1
I
i__j___\
1
PhHIAICI,
,
R COCl/AlCl,
Me' 219
280
28 I
Chlorination and nitration of the thienodiazepinones 282 (R = Ph, 2F3CC,H4) were shown to occur at the 8-position, leading to 283 (X = C1, NO,) (Eq. 83)."2911s
R
R
282
283
16. [1,2,4]Triazino[5,6-e] [1,4]Diazepines
999
15.3.2. 3,4-Dihydro-1H-thieno[3,4-e][1,4]diazepine-2,5( 2 H J H ) -d'zones Compound 285, the only representative of this class of compounds reported in the patent literature,"' was prepared by thermal cyclization of the methylamino derivative 284 (X = NHMe) (Eq. 84). This amine was obtained by treatment of the iodide (X = I) with methylamine. The dione 285 was transformed into the imidazo derivative 287 via the intermediate iminophosphate 286 by means of ethyl isocyanoacetate. l 1O
I MeNH,
N 0
'Me
0
n
284
285
(84)
286
287
16. [1,2,4]TRIAZINO[5,6-e][1,4]DIAZEPINES The 9-one 290 (Eq. 85) appears to be only derivative of the parent ring 288 that is described in the literature.'I6 This triazinodiazepine was obtained by reaction of the triazine 289 with symmetrical N,N'-dimethylethylenediamine.
288
(85)
0
Etoy;Aph
I
Me 289
290
17. TABLE OF COMPOUNDS TABLE IX-1.[e]-FUSED[1,4]DIAZEPINES
Substituent
mp (“C) or; [bp (“C)/(torr)]
Solvent of Crystallization
Yield (%)
Spectra
Refs.
3 3
Furo[2,3-e][ I ,I]diazepines U
H
q 1
I ~;1,4,6,7-Hex~y&ofuro[2,3-e][l,4]diazepin-5(5H)-ones
NH
0 None 7-Me 1,4-A~, 6,7-Me2
7,7-Me2
1,4-Bu2,cisltrans 1,4-Me2,cis 1,4, la-Me, cisltrans
155-158 146149 120-125 166-170 168-170 206210
[82-84/0.003] [1 10-111/28] [11 5-120/15]
EtOH EtOH EtOH/Petr ether EtOH EtOH EtOH
45 69
pmr, uv pmr, uv
60 31 63
pmr, uv pmr, uv pmr, uv
35 41 20
ms, pmr ms, pmr Pmr
4 4 4
1002
w w m w
m r-
0, L;j
t-r-
4,6-Dihydroisoxazolo[4,3-e] [ 1,~aYazepin-S(SH)-ones
3-Me-8-(2-C1C,H4) 3-Me-8-(2-FC,H4) 3-Me-8-(2,6-F2C,H3) 3-Me-8-(2-F,CC,H,) 3,4-Me2-8-(2-C1C,H,) 3,4-Me2-8-(4-C1C,H,) 3,4-Me2-8-(2-FC,H,) 3,4-Me,-8-(2,6-F2C,H,) 3,4-Me,-8-(2-F,CC,H,) 3-Me-4-(2-Et2N-Ethyl)-8-(2-FC,H,)
3-Me-4-(2-Et,N-Ethyl)-8-(2-F3CC,H4) 3-Me-4-(2-Propyn-1-yl)-8-(2-F,CC6H4)
258-260 212-2 14 258-260 218-2 18 136138 133-145 174-175 19C191 11 5-1 17 Oil Oil Oil
EtOH PrOH PrOH EtOH EtOAc/CH,Cl, EtOAc/CH,Cl, EtOH EtOH EtOAc/CH,Cl,
8 8
29 66 12 27 77 66 50 39 70 54 66 40
8 8 8 8 8 8 8 8
8 8
BH-lsoxazolo[S,I-e][ I ,I]diazepines
113-116
,
Et O/Hexane
8
ir, pmr
9
1004
c
> i
% .-i
2
N
1005
222
TABLE IX-1. -4contd.)
Substituent
mp (“C) or; [bp (Tjtorr)]
Solvent of Crystallization
Yield (%)
Spectra
Refs.
Pyrazolo[jl,l-e][ I ,l]diuzepines
L
8
o\
1,3-Me2-4-(3-C1C,H,) l-Me-CPh-7-EtNH 1,3-Me2-4-Ph-7-(l-Butyn-3-yl)NH 1,3-Me2-4-Ph-7-MeS 1,3-Me2-4-Ph-7-(2-Propyn-1-y1)NH 1,3-Me24-(2-C1C,H,)-7-MeS 1,3-Me,-4-(2-C1C6H4)-7-(2-Propyn1-yl)NH 1,3-Me,-4-(2-FC6H,)-7-MeS 1,3-Me,-4-(2-FC6H4)-7-(2-Propyn1-y1)NH l-Me-3-Et-4-Ph-7-MeNH 1-Me-3-Et-4-Ph-7-Me(NO)N
l-Me-3-Et-4-Ph-7-MeOOC(HON)C
63
105-107 187-189 193-195d 117-118 193-195 Oil 176178d 11&112 202-204d 218-220 12G-122 225-227
Et,O Et,O CH,Cl,/Et,O CH,Cl,/Et,O/Hexane CH,Cl,/Et,O
81 82 35
16 16 16
2W203
MeCN
40
13
Et,O EtOAc EtOH Et,O
13 117 15 14 15 14 15 14 15
1,6,7,8Tetrahydropyrazolo[3,4-e][1,4]diazepines Disubstituted
3-Me-4-(3-C1C6H,)
Trisubstituted
8
1-Et-3-Me-4-(3-F3CC,H,) 1,3-Me2-4-Ph Hydrochloride 1,3-Me,-4-(3-BrC6H,) 1,3-Me,-4-(2-C1C6H,) 1,3-Me2-4-(3-C1C,H,) Hydrochloride 5-Oxide 1,3-Me2-4-(4-C1C,H,) 1,3-Me2-4-(3,4-C1,C,H,) hydrochloride.0.5 H,O 1,3-Me2-4-(3-CNC,H,) 1,3-Me2-4-(3-FC,H,) hydrate Hemihydrate 1,3-Me,-4-(3-H2NC,H,) dihydrochloride 1,3-Me2-4-(3-HOC,H,) dihydrochloride. iPrOH 1,3-Me,-4-(2-Me-3-C1C6H3) 1,3-Me2-4-(3-MeC,H,) hydrochloride 1,3-Me2-4-(4-MeC,H,) 1,3-Me2-4-(2,5-Me,C,H,) hydrochloride 1,3-Me,-4-(3,5-Me2C,H,) 1,3-Me,-4-(4-MeOC6H,) 1,3-Me2-4-[3,5-(MeO),C,H,] 1,3-Me2-4-(3-N,C,H,) 1,3-Me,-4-(3-NOZC,H,) hydrochloride 1-Me-3-Et-4-(3-BrC6H,) hydrochloride 1-Me-3-Et-4-(3-FC6H4) 1-Me-3-Et-4-(3-MeC6H,) oxalate
184-185 14G141 300 153-155 209-212 186188 279-281 225-228 184-186 150 183-1 85 114-116 95-98 296 115-1 18 204-206 244-246 227-229 197-200 221-223 198-200 145-147 129-131 242-245 289-29 1 143- 145 177-1 80
MeCN CHCl,/Isooctane i-PrOH Acetone PhMe MeCN i-PrOH/THF i-PrOH EtOAc/Petr ether i-PrOH Acetone Acetone Et,O/Petr ether i-PrOH i-PrOH Acetone i-PrOH EtOAc/Petr ether i-PrOH EtOAc/Petr ether EtOAc/Petr ether EtOAc/Petr ether Acetone i-PrOH i-PrOH EtOAc/Petr ether MeCN
65 53 52 25 37 22 89 26 52 78 51 17 35 57 11 38 41 50 52 41
13 17 13 13 13 13 13 13 13 13 13 13 13, 17 13 13 13 13 13 13 13 13 13 13 13 13 13 13
274-215 96-98 260
i-PrOH EtOAc/Petr ether i-PrOH
30 37 42
13 13 13
40 40 62
40 5C70
Tetrasubstituted
1-Et-3-Me-4-(2-C1C,H4)-8-Mehydrochloride 1,3,6-Me3-4-(3-C1C,H,) 1,3,8-Me3-4-Ph hydrochloride
TABLE IX-I. 4 c o n t d . )
Substituent
1,3,8-Me3-4-(2-C1C,H,) dihydrochloride 1,3,8-Me,-4-(3-C1C6H,) dihydrochloride 1,3,8-Me,-4-(4-HOC,H4) dihydrochloride.H,O 1,3-Me,-4-Ph-8-(3-Me2N-Propyl) 1,3-Me,-4-(2-CIC,H,)-8-(3-Me,”Propyl) 1,3-Me2-4-(2-C1C,H,)-7-CN.H20 1,3-Me2-4-(3-C1C,H,)-8-Ac hydrochloride 1,3-Me,-4-(3-C1C6H,)-8-Et dihydrochloride 1,3-Me,-4-(3-C1C6H,)-8-F3CC0
1,3-Me,-4-(3-ClC,H,)-8-(3-Me,N-Propyl) 1,3-Me2-4-(3-C1C,H4)-8-NO 1,3-Me,-4-(3-C1C6H4)-8-(2-Pyrrolidinoethyl)dihydrochloride
1,3-Me,-4-(3-FC,H,)-8-(3-Me2N-Propyl) 1,3-Me,-4-(3-MeC,H,)-8-(3-Me2N-Propyl) 1,3-Me,-4-(4-MeC,H,)-8-(3-Me,”Propyl) 1-Me-3-Et-4-(3-FC,H,)-8-(3-Me,”Propyl) .0.5H,O
mp (“C) or; [bp (“C/torr)]
Solvent of Crystallization
255 17G172 195-197 79-81 5G53 140-142 267-268 175 183-185 75-71 118-120
i-PrOH i-PrOH i-PrOH EtOAc/Petr ether Petr ether i-PrOH i-PrOH Petr ether Petr ether EtOAc/Petr ether
265 80-82 12G124 99-101 73-75
Yield
35
(YO)
Spectra
Refs.
20 28
13 13 13 13 13 13 13 13 13 13 13
i-PrOH Petr ether Petr ether Petr ether
69 30 65 35
13 13 13 13
Petr ether
55
13
EtOAc/Petr ether EtOAc/Petr ether Acetone
57 20
13 13 13
MeCN
30
36 35 44 72 85 12
Pentasubstituted
1 ,3,6,6-Me,-4-(3-ClC6H,) 1,3,6,6-Me,-4-(3-MeC,H4).0.5 H,O 1,3,6,7-Me,-4-Ph.0.5H20
155-157 128-130 101-102
35
R I , R,, Other
COOMe, COOMe; l-Me-3-Et-4-PH
MeOH
145-148 O
I ,6,7,8Tetrahydropyrazolo-[3,4-e] [ I ,4]diazepin-7-ones
24
16
20
117 18 10
H
T N-- -
S
N
Disubstituted
1-Me-4-Ph Hydrochloride. H,O 1-Ph-4-(2-Thiazolyl)
2 18-220 285 237-240
EtOH/THF i-PrOH/Et,O CH,CI,/Hexane
203-205 183-185 137-139 246-248 25C252 265-267 245-248 255-257 235-237 295d 228-230 163-165 191-193 253-255 268-270 258-260 253-255 263-265 247-250 179-180
MeOH Et,O Et,O PhMe PhMe PhMe PhMe Acetone PhMe Acetone/AcOH PhMe THF/Petr ether Et,O MeCN MeOH PhMe Acetone Acetone Acetone Acetone
Trisubstituted
1-Cyclohexyl-3-Me-4-(2-ClC~H4) 1-Bu-3-Me-4-(2-C1C6H,) 1-Bu-3-Me-4-(3-C1C6H,) 1-Et-3-Me-4-(2-C1C,H4) 1-Et-3-Me-4-(2-FC,H4) 1,3-Me2-4-Ph 1,3-Me2-4-(2-C1C,H,) 1,3-Me,-4-(3-C1C6H,) 1,3-Mez-4-(2-FC,H,) Hydrobromide 1,3-Me2-4-(2-Thienyl) 1,8-Me2-4-Ph 1-Me-3-Bu-4-(2-C1C6H4) l-Me-3-CI-4-Ph l-Me-3-Et-4-Ph 1-Me-3-Et-4-(2-C1C,H4) 1-Me-3-Et-4-(2-FC6H,) 1-Me-3-Et-4-(3-FC,H4) 1-Me-3-Et-4-(4-FC6H,) 1-Me-3-Pr-4-(2-C1C6H4)
30 17 65 84 95
18 18 18 18 18 18 18 18
40
18
65
40 65
4 41
44 35 18 81 19 33 48
19 18 117 18 18 18 18 18 18 18 18
TABLE IX-1. 4 c o n t d . ) ___
Substituent
mp ("C) or; [bp ("C/torr)]
Solvent of Crystallization
1-Me-3-i-Pr-4-(2-C1C6H4) 1,4-Ph2-3-Me 1-Ph-3-Me-4-(2-C1C6H4) l-Ph-4-(2-Thiazolyl)-8-Me 1-Pr-3-Me-4-(2-C1C6H4) 1-i-Pr-3-Me-4-(2-C1C6H4)
223-224 255-257 229-231 213-223 171-173 253-255
PhMe Acetone PhMe CH,CI,/Hexane Et,O EtOAc
Amorphous Amorphous 105-108 74-77 Amorphous 183-185 180d 232-235 169-17 1 265d 183-185 248d 182-184 247-250
Et,O Et,O Et,O Hexane Et,O PhMe i-PrOH/HCI Acetone Et,O i-PrOH MeOH/Et,O i-PrOH i-PrOH/Et,O i-PrOH/THF Et,O EtOAc/Petr ether MeCN Et,O Et,O Et,O Et,O
Yield (%)
Spectra
Refs.
29
18
30
18
12
18 10 18 18
40 20
Tetrasubstituted
L
s o
1-Bu-3,8-Me,-4-(2-C1C6H4) l-Cyclohexyl-3,8-Me,-4-(2-C1C6H4) 1-Et-3,8-Me,-4-(2-C1C6H4) 1-Et-3,8-Me,-4-(2-FC6H4)
1-Et-3-Me-4-(2-C1C6H4)-8-Allyl 1,3,8-Me3-4-Ph Hydrochloride 5-Oxide 1,3,8-Me,-4-(2-BrC6H4) 1,3,8-Me,-4-(2-C1C6H4)hydrochloride 1,3,8-Me,-4-(2-FC6H4) Hydrochloride 5-Oxide 1,3,8-Me,-4-(2,6-F,C6H3) 1,3,8-Me,-4-(2-H2NC6H,) 1,3,8-Me,-4-(2-N,C6H4) 1,3,8-Me,-4-(2-N0,C6H4) 1,3-Me,-4-(2-FC6H4)-8-Et 1,8-Me,-3-Bu-4-(2-C1C6H4) 1,8-Me2-3-Et-4-Ph 1,8-Me,-3-Et4-(2-C1C6H4)
160
137-139 184186 133-135 9&98 193-195 115-117
95
60 20 70 50 34 90 73 80 90 86
18 18 18 18 18 18 18 18 18
18 18 18
85 81 90 40 11 27 42 79 70
18 18 18 18 18 18 18 18 18
1,8-Me2-3-Et-4-(2-FC6H4) 1,8-Me,-3-Et-4-(3-FC6H4) 1,8-Me,-3-Et-4-(4-FC6H4)
1,8-Me,-3-Me0-4-(2-FC6H4) 1,8-Me,-3-Pr-4-(2-C1C6H4)
1,8-Me,-3-i-Pr-4-(2-C1C6H4) l-Ph-4-(2-Thiazolyl)-6,8-Me2 1-Pr-3,8-Me,-4-(2-C1C6H4)
165-1 68 163-165 2 16-21 8 212-214 120- 122 168-1 70 168- 170 Amorphous
Et,O Et,O PhMe CHCl,/Et,O Et,O/Petr ether Et,O CH,CI,/Hexane Et,O
210 218-220 243-245 203-205 250-252
Acetone EtOAc MeOH/H,O PhH/Petr ether MeOH/H,O
50 50 40 80 20 56
60
18 18 18 18 18 18 10 18
Pentasubstituted
1,3,6,6-Me4-4-(3-C1C6H4) 1,3,8-Me3-4-Ph-6-Ac0 1,3,8-Me3-4-Ph-6-H0
1,3,8-Me,-4-(2-FC6H4)-6-Ac0 1,3,8-Me,-4-(2-FC6H4)-6-HO c-.
S
0
CL
c-.
I ,6,7,8- Tetrahydropyrazolo[3,4-e][ I ,4]diazepin-7-thiones 1,3-Me2-4-Ph 1,3-Me,-4-(2-C1C6H4) 1,3-Me,-4-(2-FC6H4)
83 56 81 90
13 18 18 18 18
"
7 - N N--
268-269 243-245 243-245
1,4,5,6,7,8-Herahy&opyrazolo[3,4-e] [ I ,4]diazepines
(-MN
14 14 14
N H
1,3-Me,-4-(3-C1C6H4)dihydrochloride 1,3-Me,-4-(3-C1C6H4)-8-Et dihydrochloride
255d 19Od
i-PrOH/Et,O i-PrOHIEtOAc
17 17
TABLE IX-1. 4 c o n t d . ) ~~~~~
Substituent
~
mp ("C)or; [bp (Tjtorr)]
~
-~
Solvent of Crystallization
Yield ( ' Y o )
i-PrOH i-PrOH
93 70
Spectra
Refs.
1,4,5,6,7,8-Herahydropyratolo[3,4-e] [I ,4]diarepin-7-ones N
H 1,3,8-Me3-4-(2-FC,H,) 1,8-Me2-3-Et-4-Ph
218-220 202-204
18 18
Pyrazolo [4,3-e][I ,4]diazepines
4
1,3-Me2-5-MeNH-8-Ph 1,3-Me2-5-MeS-8-Ph
218-221 106- 109
Acetone Hexane
212-215 221-223 265-268d 265
PhMe PhMe MeOH/EtOAc PhMe/Et,O
23 23
1,4,5,6-Tetrahydropyrazolo[4,3-e][1,4]diazepin-5-ones
Trisubstituted 1,3-Et2-8-Ph l-Et-3-Me-8-Ph Sulfate Methanesulfonate
52 70
24 24 25 25
Sodium salt.H,O 7-Oxide 1-Et-3-Me-8-(3-BrC,H4) 1-Et-3-Me-8-(3-C1C,H4) 1-Et-3-Me-8-(4-C1C,H4)
I-Et-3-Me-8-(5-C1-2-Thienyl)
c.
w
1-Et-3-Me-8-(4-FC6H,) 1-Et-3-Me-8-(2-F,CC,H4) 1-Et-3-Me-8-(4-MeC6H,) 1-Et-3-Me-8-(4-MeOC,H,) 1-Et-3-Me-8-(3-N0,C,H4) 1-Et-3-Me-8-(2-ThienyI) 7-Oxide 1,3-Me2-8-Ph Hydrochloride 7-Oxide 1,3-Me,-8-(4-FC,H4) 1,3-Me2-8-(2-Thienyl) l-Me-3-Et-8-Ph I-Pr-3-Me-8-Ph I-i-Pr-3-Me-8-Ph Hydrobromide
>.300d 198-200 27-228 224-225 240-242 189-192 198-200 195-197 199-201 198-200 155-157 205-206 226-228 267-270 295 242-243 218-222 246-247 236-239 168- 172 207-210 305d
DMF/Et,O EtOH EtOAc Xylene PhMe EtOH MeCN PhMe PhMe PhMe MeOH EtOH EtOH PhMe CHCI,/MeOH/Et,O MeCN PhMe EtOH PhMe i-PrOH PhMe AcOH/HBr
99- 102 145-147 230d 189-192 223-226 79-81 188-193 178-180 201-203 217-219
Cyclohexane EtOAc MeCN/Et,O i-PrOH PhMe Et,O i-PrOH/Et,O i-PrOH/Et,O EtOAc MeCN/Et,O
25 28 24 24 24 24 24 24 24 24 24 24 27 24 25 28 24 24 24 24 24 25
71 30 51 15 69 49 37 36 88 10 70
24 19 50 71 34
Tetrasubstituted
1-Et-3,4-Me2-8-Ph 7-Oxide 7-Methiodide 1-Et-3,4-Me2-8-(2-Thienyl)-7-oxide 1-Et-3,6-Me2-8-Ph 1,3-Et2-4-Me-8-Ph 1-Et-3-Me-4-(2-Et2N-Ethyl)-8-Ph hydrobromide 1-Et-3-Me-4-(3-Me2N-Propyl)-8-Ph hydrobromide l-l?t-3-Me-6-Ac0-8-Ph I-Et-3-Me-6-HO-8-Ph
72 19 43 54 48 10
uv
24 28 30 27 24 24 24 24 29 29
TABLE IX-I. +contd.)
Substituent
mp ("C) or; [bp ("C/torr)]
Solvent of Crystallization
1,4-Et2-3-Me-8-Ph 1,3,4-Me3-X-Phhydrochloride.H,O 7-Oxide I,3-MeZ-4-F,CCH,-8-Ph 1,3-Me2-4-(Propyn-3-y1)-8-Ph 1,3-MeZ-6-Ac0-8-Ph 1,3-Me2-6-HO-8-Ph 1,4-Me2-3-Et-8-Ph 1 -Pr-3,4-Me2-8-Ph 1-i-Pr-3,4-Me2-8-Ph
91-93 213-215 150-152 186- 187 128-130 235-241 246-248 91-93 82-84 145-147
Cyclohexane i-PrOH i-PrOH/Pentane PhMe Et,O/Petr ether
173-175 188-190 180-182 211-213
EtOH/Et,O MeCN PhMe/Pentane MeCN/Et,O
DMF Et,O PhH/Petr ether PhMe
Yield (YO)
68 37 50
32 82 20
Spectra
Refs. 24 24
28 24 26 29 29 24 24 24
Pentasuhstituted
I-Et-3,4-Me2-6-Ac0-8-Ph 1-Et-3,4-MeZ-6-HO-8-Ph I ,3,4-Me3-6-Ac0-8-Ph 1,3,4-Me3-6-HO-8-Ph
29 29 29 29
1,6,7,8Tetrahydropyrazolo[4,3-e][l,l]diazepin-8-ones
3-Me-5-Ph 3-Me-5-(4-BrC6H,) 3-Me-5-(4-CIC6H4) 3-Me-5-(4-MeOC,H4) 3-Me-5-(4-NO2C,H,) 3-Me-5-(4-PhC6H,)
249-251 266-268 258-260 234-236 > 310 281-283
DMF/H,O DMF/H,O DMF/H,O DMF/H,O DMF/H,O
DMFIH~O
53 53 48 61 56 49
31 31 31 31 31 31
2,4,5,6- Tetrahydropyrazolo [4,3-e] [I ,4]diazepin-5-ones
O
LNUH H
Trisubstituted
2-Et-3-Me-8-Ph 2,3-Me2-8-Ph 2,3-Me2-8-(5-C1-1,3-Me2-Pyrazol-4-yl) 2-i-Pr-3-Me-8-Ph
213-215 265-267 253-255 210-21 2
EtOH EtOh PhMe MeOH
45 55 53 30
24 24 24 24
130-1 32 170-173 154-156
PhH/Petr ether CHCI,/Petr ether EtOAc/Petr ether
44
24 24 24
185-187 186- 188 176- 178
EtOH EtOH EtOHiPentane
32 32 32
176-179 248-250 179-181 222-225 166- 168
EtOH EtOH/Et,O EtOH EtOH/Et,O MeCN
32 32 32 32 32
Tetrasubstituted
2-Et-3,4-Me2-8-Ph 2,3,4-Me3-8-Ph 2,3-Me2-4-Et-8-Ph
50
71
+
z
111
I ,4,5,6,7,8-Hexahydropyrazo10-[4,3-e] [ I ,4]diazepin-5-ones
Trisubstituted
l-Et-3-Me-8-Ph 1,3-Me2-8-Ph l-Pr-3-Me-8-Ph Tetrasubstituted
1-Et-3,7-Me2-8-Ph 1,3,4-Me3-8-Ph hydrochloride 1,3,7-Me3-8-Ph 1-Pr-3,4-Me2-8-Ph hydrochloride 1-Pr-3,7-Me2-8-Ph
TABLE IX-I.g c o n t d . )
Substituent
mp ("C) or; [bp ("Cjtorr)]
Solvent of Crystallization
229-232 97-99
EtOH/Et,O PhH/Pentane
Yield (%)
Spectra
Refs.
Penrasubstituted
1,3,4,7-Me4-8-Ph hydrochloride 1-Pr-3,4,7-Me3-8-Ph
32 32
Pyrido [2,3-e] [I ,4]diazepines
I ,3-Dihydropyrido[2,3-e] [1,4]diazepin-2(2H)-ones c
z
QI
5-Ph
203-205
CHClJHexane
c-
45
33
83 85 85
34 36 36 35 35 35 35 36
H
2,3,4,5-Tetrahydro-IH-pyrido[2,3-e] [1,4]diazepines
8-Me 1-Et-8-Me picrate 1,8-Me, picrate 1-Ph-&Me oxalate l-Ph-4-Ac-8-Me 1-Ph-4-(4-CI-Benzoyl)-8-Me 1-Ph-4,8-Me2 hydrochloride 3-Benzyl-8-Me
H
103-105 182-184 211-212 175-179d 129-1 3 1 145-146 260d 72-74
PhH/Ligroin AcOH AcOH MeOH/Et,O CH,Cl,/Et,O CH,CI,/Et,O MeOH/Et,O Ligroin
76
H 1,2,4,5-Tetrahydropyrido[2,3-e][ I ,4]dazepin-3(3H)-ones
1-Ph-8-Me 1-Ph-4-(2-Me2N-Ethyl)-8-Mehydrochloride 1 -Ph-4-(3-Me2N-Propyl)-8-Mehydrochloride
c H 0
157-1 58 225-226d 213-21 5d
35 35 35
CH,Cl,/Et,O MeOH/Et,O MeOH/Et,O
H
I ,2,3,4-Tetrahydropyrido[2,3-e][1,4]dazepin-5(SH)-ones H 0
z
4
8-Me Hydrochloride 1-Ac-8-Me I-Et-8-Me 1,8-Me, 3-Benzyl-8-Me 4-Allyl-8-Me 4-Benzyl-8-Me 4-Et-8-Me 4,8-Me2 7-Br-8-Me 7-NO2-8-Me 4-Benzyl-7-Br-8-Me 4-Et-7-Br-8-Me 4-Me-7-Br-8-Me
27C212 212-274 32&321d 19C191 15C152 166-169 227-230 85-86 105-107 109-112 186188 302-305d > 320 154-156 135-137 221-223
MeOH H2O MeOH PhH PhH PhH EtOH PhH/Ligroin Ph H / Ligroin PhH/Petr ether PhH DMF DMF EtOAc PhH/Ligroin MeOH
79
57 79 78 64 69 80 69 92 73 72 33 45 66
34 35 35 34 36 36 36 36 36 36 36 34 34 36 36 36
d w w w b m m m m m
5
0
z
( m I
c1 d
m
N d
r-
=Yo
1018
m m-
m
m m
rw- mw
0
9-Et 9-Me
149-150 151-152
EtOAc EtOAc
61
40 40
Pyrido[3,2-e][ I ,I]diuzepines
3H-Pyrido[3,2-e] [l,l]diozepines
+
E \o
2-AcNHNH-5-Ph-7-Cl 2-MeNH-5-Ph-7-CI 2-MeNH-5-(2-CIC,H4)-7-C1 4-Oxide 2-Me(N0)N-5-(2-CIC,H,)-743, 4-oxide
176 214 228-230 242-244 196198
EtOH PhH EtOH
43 43 41 41 41
H
2,3-Dihydro-l H-pyrido[3,2-e][ I ,I]diazepines
5-Ph-7-CI Maleate l-Me-2-EtO-5-Ph-7-CI 1 -Me-2-HO-5-Ph-7-C1
161 186187d 16142 128-130
PhH EtOH EtOH/NH,OH Et,O/Petr ether
43 43 42 42
TABLE IX-1. 4 c o n t d . )
Substituent
mp ("C) or; [bp ("Cjtorr)]
Solvent of Crystallization
Yield
207-209
MeOH/PhMe
58
33
CHClJHexane MeOH i-PrOH Acetone/i-PrOH EtOH EtOH EtOH MeOH PrOH
69
33 43 43 45 43 43 46
(YO)
Spectra
Refs.
Monosubstituted
5-Ph Disubstituted
1-Me-5-Ph 5-Ph-7-Br 5-Ph-7-CI Hydrochloride 4-Oxide Hydrate 5-Ph-7-F 5-Ph-7-H2N 5-Ph-7-(2-HO-Ethyl)NH 5-Ph-7-Me2N Methiodide 5-Ph-7-(4-Me-Piperazino) 5-Ph-7-Morpholino 5-(2-CIC6H,)-7-(Benzy1)NH 5-(2-C1C6H4)-7-C1 4-Oxide 5-(2-C1C,H,)-7-Me2N Hydrochloride 5-(2-CIC6H,)-7-Pyrrolidino
182-184 202-204 198 > 300 215 15&158 218-220 242-244 21G215 24 1-245d 23 1-233d 226-228 265-210 195-197 20 1 241-243 242-243 > 300 158-1 60
PrOH EtOH PhH Dioxane/Petr ether EtOH Acetone/i-PrOH EtOH
44 44 44 44 44 44 44 43 43
44 44 44
5-(2,5-CI,C,H,)-7-C1 5-(2-FC6H4)-7-C1 4-Oxide 5-(2-FC6H,)-7-Morpholino
240 195-196 239 227-240
PrOH Acetone/MeOH EtOH/Petr ether
43 43 46 44
Trisubstituted
l-Ac-5-Ph-7-Cl l-AcCH2-5-Ph-7-CI 1-AcCH,-5-(2-CIC6H,)-7-C1, 4-oxide l-Allyl-5-Ph-7-Cl 1-Allyl-5-(2-CIC6H,)-7-C1 hydrochloride 4-Oxide 1-Allyl-5-(2-CIC6H4)-7-Me,N 1-(Allyl)NHCO-5-Ph-7-Cl +
1-(Allyl)NHCO-5-(2-FC6H4)-7-C1 1-(Benzoyl)CH,-5-(2-C1C6H4)-7-CI 4-Oxide 1-Bu-5-Ph-7-C1
1-(4-C1-Benzoyl)CH,-5-Ph-7-C1 l-(Cyano)CHz-5-Ph-7-CI 1-(Cyano)CH,-5-(2-C1C6H4)-7-C1 4-Oxide 1-(3-Cyanopropyl)-5-Ph-7-CI l-(Cyclohexyl)NHCO-5-Ph-7-C1 l-(Cyclopropyl)CH,-5-Ph-7-C1hydrochloride l-EtNHCO-5-Ph-7-CI 1-EtNHCO-5-(2-C1C6H,)-7-CI,4-oxide l-EtNHCO-5-(2-FC,H,)-7-C1 l-EtOOCCHZ-5-Ph-7-Cl l-H,NCSCH,-5-Ph-7-CI
l-H,NCSCH,-5-(2-ClC,H4)-7-C1 1-(2-HO-Ethyl)-5-(2-FC6H4)-7-C1 1-(2-HOOC-Ethyl)-5-Ph-7-C1 l-Me-5-Ph-7-Br
256260 176 112-1 14 94 2W202d 220 113-1 15 137-139 138- 140 161-163 240 108-1 10 216-218 222-224 176 220 17C-174 252 180-188 127 129 119-121 184-186 216d 204 1 5 6 156 198-202 148-150
DMSO EtOH EtOH Aceton+-PrOH DMF/EtOH EtOH EtOH DMFiEtOH DMF/MeOH Acetone DMFiEtOH DMFiEtOH CHCI,/Petr ether DMF/MeOH i-PrOH/Et,O i-PrOH Petr ether THF EtOAc DMF/EtOH DMFiEtOH EtOH CHCIJPetr ether EtOH
43 47 48 43 43 43 44 49 49 47 41 43 47 47 48 48 47 49 43 49 49 49 47 48 48 43 47 43
TABLE IX-1. 4 c o n t d . )
Substituent l-Me-5-Ph-7-CI 1-Me-5-(2-C1C6H,)-7-C1 4-Oxide 1 -Me-5-(2-ClC,H4)-7-Me,N l-Me-5-(2-FC6H,)-7-C1 1-(2-Me2N-Ethyl)-5-Ph-7-CI
l-(2-Me,N-Ethyl)-5-(2-ClC6H,)-7-Me,N
N
1-(2-Morpholinoethyl)-5-Ph-7-C1 1-(2-Piperidinoethyl)-5-Ph-7-C1 l-Pr-5-Ph-7-Cl 3-Ac0-5-(2-C1C6H,)-7-C1 3-Benzyl-5-Ph-7-CI
3-(3-HOOC-Propanoyloxy)-5-(2-ClC,H4)-7-Cl 3-HO-5-Ph-7-CI 3-HO-5-(2-C1C6H4)-7-Cl 3-HO-5-(2-FC6H,)-7-C1 3-Me-5-Ph-7-Cl S-Enantiomer 3-i-Pr-5-Ph-7-CI
mp ("C) or; [bp ("Cjtorr)]
Solvent of Crystallization
154 204206d 23 1 158-162 139 154 119-120 162-164 136-137 139-142 243 234 170-171 177 2w202 177-1 79 182 113-116 225-226
PhH/Petr ether EtOH EtOH/Petr ether MeOH EtOH PhH/Petr ether CH,CI,/Hexane EtOH EtOH MeOH Ac,O/AcOH EtOH/H,O EtOH EtOH PrOH PhH/Petr ether PhH/Petr ether PhH/Petr ether
43 43 43 43 43 43 43 43 43 43 43 43
203-207 235-237
MeOH EtOH
43 48
248 178-180 159-163d 178-179
Ac,O/AcOH CHCI,/Et,O
48 48 49 43
Yield
(YO)
Spectra
Refs. 43 43 43
44 43 43
44
Tetrasubstituted
~-AC-~-ACO-~-(~-C~C~H,)-~-C~
~-ACCH~-~-HO-~-(~-C~C,H,)-~-CI 1 -Allyl-3-Ac0-5-2-C1
l-(Cyano)CH,-3-AcO-5-(2-ClC,H4)-7-C1 1-(Cyano)CH,-3-HO-5-(2-ClC6H4)-7-CI 1-EtNHCO-3-HO-5-(2-ClC,H,)-7-C1
1-Me-3-Ac0-5-(2-C1C6H,)-7-C1
Ac,O/AcOH
m m m m W W W W
I c l m m om00 r4--
1023
m r-
m
m m m m m m
1024
p'
m
W
p'
N W N W
IH- Pyrimido[4,5-e] [1,4]diazepines
(-BN
HN
0 2,7-Me2-8-(2-HO-Ethy1) 2,7-Mez-6-Fonnyl-8-(2-HO-ethyl) c-
2,7-Me2-6-Formyl-8-(2-PhS-ethyl) 2,7-Mez-6-Formyl-8-[2-(4-BrC6H4)S-ethyl] 27-Mez-6-Formyl-8-[2-(4-MeC6H.)S-ethyl]
148-15Od 146148 104-107
(-BN
34 13 27
PK PK
51 51, 52 53 53 53
Pmr
54 54
pmr, uv, PK
HN
0
2-Ph-6,9-Et 2 2-Ph-6,9-Mez
116-1 18 155-158
Cyclohexane Cyclohexane
2-Me
214-275
MeOH/Et,O
35
TABLE IX-I. - (contd.) ~~
Substituent
~~~~
mp (“C)or; [bp (Tjtorr)]
~
Solvent of Crystallization
Yield ( Y O )
Spectra
Refs.
0
3,4,7,9-Tetrahydropyrimido[4,5-e][1,4]diazepin-4,8(8H)-diones 0
5-Ph 3,5-Me2 3-Benzyl-5-Ph 3-Me-5-Ph 3-(2-Me,N-Ethyl)-S-Ph 3-Benzyl-S-Ph-9-Me 3,9-Me2-5-Ph 3,9-(2-Me,N-Ethy1)2-5-Ph
21Od 245-25Od 246-248 259-261 226228 132-134 154-156 160-162
9b 9b 9b 9b 9b 9b 9b 9b
EtOH EtOH EtOH MeCN MeCN EtOH MeCN/Et,O/Hexane EtOAc
3,4,5,6,7,8-Hexal?ydropyrimido[5,4-e] [1,4]diazepin-4,9 (9H)dones 0 2-(4-CIC,H.J 2-(Morpholino)COCH2 2-(Piperidino)COCH2
264-266 234-236 234-236
EtOH EtOH EtOH
ir
55 55 55
Pyrrolo[Z,3-e][Z ,I]diuzepines
1,2,3,4,5,5a,6,7-Octuhydropyrrolo[2,3-e] [ I ,qldiazepinJ-ones 0 6-Ph
175-176
38
Acetone
Pyrrolo[3,Z-e][1,I]diuzepines
1,2,3,6-Tetruhydropyrrolo[3,2-e][Z,4]&uzepin-2-ones L
0
5
5-Ph-8-CN 5-Ph-8-EtOOC 5-Ph-8-H,NCO
3 15-3 18d 21 1-212 2OCL203d
56 56 56
DMF/i-PrOH CH2C1,/MeOH DMF/Et,O
Pyrrolo[3,4-e][l,l]diuzepines
1,2,3,7- Tetruhydropyrrolo[3,4-e][1,4]diazepin-2-ones
5-Ph-6-Me 5-(2-C1C,H4)-6-Me 5-(2-FC,H4)-6-Me 5-(4-MeOC,H4)-6-Me
1300 315d > 340 > 300
MeOH EtOH EtOH MeOH
64
37 45 35
57 57 57 57
TABLE IX-1. 4contd.)
Substituent
mp (“C) or; [bp (“C/torr)]
Solvent of Crystallization
Yield (%)
Spectra
Refs
ir, pmr
57 60 57 57 57 57 57 57
Trisubstituted
e
5-Ph-6,7-Me2 4-0xid e 5-Ph-6-Me-8-Et 5-Ph-6-Me-7-Bu 5-Ph-6-Me-7-Et 5-Ph-6-Me-7-(2-Me-Prop-l-y1) 5-Ph-6-Me-7-Pr 5,8-Ph2-6-Me
27Od 255-258 29Od 152-1 53 229-231 191-193 163-1 65 31C312
MeOH HZO i-PrOH EtOAc EtOAc EtOAc EtOAc EtOH
136-138 237-239 198-200 255-256 198-200 235-237 209-210 187-188
CHClJEtOH i-PrOH i-PrOH Ac,O i-PrOH i-PrOH i-PrOH EtOH
125-1 27 211-213 243d 153-155 210-212 200-202 195d
Acetone/Et,O EtOH EtOH EtOH EtOH MeOH EtOH
67 52 36 42 41 33 43
Tetrusubstituted
1-Et-5-Ph-6,7-Me2 1,6,7-Me3-5-Ph 1,6,7-Me3-5-(2-C1C,H,), 4-oxide 3-Ac0-5-Ph-6,7-M~, 3-Butanoyloxy-5-Ph-6,7-Me2
3-(4-t-Bu-Benzoyloxy)-5-Ph-6,7-Me, 3-(Cyclohexyl)C00-5-Ph-6,7-Me2 3-(Decanoyloxy)-5-Ph-6,7-Me2 3{3-[N-(3-EtOOC-Propyl)aminocarbonyl] propanoy10xy}-5-Ph-6,7-Me2 hydrochloride 3-(4-F-Benzoyloxy)-5-Ph-6,7-Me2 3-HO-5-Ph-6,7-Me2
3-(3-HOOC-Propanoyloxy)-5-Ph-6,7-Me, 3-(4-Phtha1imidobutanoy10xy)-5-Ph-6,7-Me2 5-Ph-6,7-Me2-8-Br 5-Ph-6,7-Me2-8-C1
47 62
ir, pmr
57 57 60 60 60 60 60 60 60 60 60 60 60 61 61
5-Ph-6,7-Me2-8-Et 5-Ph-6,7-Me2-8-NO,
254-256 232-234
MeOH MeOH
202-204 228-229 11&111 105-107 182-183 173-1 75 171-173 173-175 221-222 101-103 138-140 173-175 232-234
EtOH EtOH Et,O i-PrOH/Et,O EtOAc i-PrOH EtOH EtOH EtOH Et,O EtOH CHCI,/MeOH MeOH
57 61
32
Penfasubstituted
1,6,7-Me,-3-Ac0-5-(2-CIC6H4)
CL
i3 \o
1,6,7-Me,-3-Benzoyloxy-5-(2-CIC6H4) 1,6,7-Me,-3-Et0-5-(2-CIC6H4) hydrochloride 1,6,7-Me,-3-(3-EtOOC-Propy1)NH-5-(2-C1)C6H, 1,6,7-Me,-3-HO-5-(2-CIC6H4) 1,6,7-Me,-3-(3-HOOC-Propanoyloxy)-5-(2-CIC,H, 1,6,7-Me,-3-(2-Me-Benzoyloxy)-5-(2-ClC6H4) 1,6,7-Me,-3-(2-Me-Propanoy1oxy)-5-(2-C1C6H,) 1,6,7-Me,-3-(2.2-Me,-Propanoy1oxy)-5-(2-ClC6H4) 1,6,7-Me,-3-Me0-5-(2-ClC6H4) hydrochloride.H,O 1,6,7-Me,-3-(4-Me0-Benzoy1oxy)-5-(2-C1C6H,) 1,6,7-Me,-3-(4-Ph-Benzoyloxy)-5-(2-ClC6H4) 1,6,7-Me,-5,8-Ph2
O
60 60
60 60 60 60 60 60 60 60 60 60 57
45
H
1,2.3,7- Tetrahydropyrrolo[3,4-e] [1,4]diazepin-6,8(6H,8H)-diones
0
5-Me 5-Me-7-Ph
262-264 22&221
MeOH EtOH
77 77
ir, pmr ir, pmr
64 64
6-Methylene-l,3,6,7-tetrahydropyrrolo[3,4-e] [ I ,Ildiclzepin-2,8(2H,8H)-diones
5-Ph-7-Me
215-217
EtOAciHexane
59
TABLE IX-1.
~
{contd.) mp (“C)or; [bp (“Cjtorr)]
Substituent
Solvent of Crystallization
Yield (Yo)
Spectra
Refs.
I H - Thiudiuzolo[3,4-e] [I,l]diuzepines
4,6-Dihydrothi&zolo[3,4-e]
[ I ,4]&azepinJ (SH)-thiones
8-Ph
65
178-1 80
Acetone/Hexane
226-228
Acetone
44
66
EtOAc EtOAc
17 17
66 66
6H- Thiazolo[4,5-e] [l,l]diazepines
2-Morpholino-5-AcNHNH-8-Ph
4,6-Dihydrothiazolo[4,5-e][ I ,4]diazepin-5(5H)-ones O
2-(4-CIC,H,) 2-Me2N-8-Ph
194-195 226227
H
2-Morpholino-8-Ph 2-Piperidino-8-Ph 2-Me2N-4-Me-8-Ph 2-Me2N-6-Benzyl-8-Ph 2-Me2N-6-Me-8-Ph
2-Morpholino4-Me-8-(4-ClC,H4) 2-Piperidino-4-Me-8-Ph
EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc
2w201 191-193 138-139 181-182 204-207 222-223 145-1 47
30 29 22 66 19 31 31
13C -nmr Pmr
66 66 66 66 66 66 66
4,6-Dihy&othiazolo[4,.5-e][ I ,4]dazepin-S(SH)-thiones
2-Morpholino-8-Ph
66
4H-Thiazolo[5,4-e] [1,4]diazepines
H
4,6-Dihydrothiazolo[S,4-e][ I .4]dazepin-S (SH)-ones
8-Ph 8-(2-Thiazolyl) 4-Me-8-Ph 3-Me-8-(3-O,NC6H,)
258-260 183-185d
120 186
CH,CI,/EtOH CH,CI,/MeOH Et,O/Petr ether CH,CI,/EtOH
6 10
6 6
TABLE IX-1. 4 c o n t d . )
Substituent
mp ("C) or; [bp ("C/torr)]
Solvent of Crystallization
Yield (%)
Spectra
Refs.
3.4,5,6-Tetrahydro-S-oxo thiazolo [4,5-e][1,4]aYazepin-2(IH)-thiones O 3-Et-8-Ph 3-Me-8-Ph
B
H
H
129-13 1 177-179
EtOH EtOH
17 49
194-196 190-195 188-189 103 155d 124
EtOAc EtOAc/EtOH EtOH/CHCI, Et,O/Pentane
67 74
231-235 211-213 196-198 220 207-209 257-260
EtOH/DMF EtOAc EtOH/CHCI, EtOAc MeOH MeOH
67 67
3H- Thieno[ZJ-e][ I ,4]aYazepines
t 4
2,5-Disubstituted
2-AcNHNH-5-Ph 2-H,NNH-5-(2-CIC6H4) 2-Me2N-5-(2-C1C,H4) 24 l-Me-Piperidin-3-yl)CONHNH-5-(2-C1C6H4) 2-Pyrroljdino-5-(2-CIC6H4)
Et,O/Hexane
77 68 68 71 78 71
2,5,7-Tridstituted
2-AcNHNH-5-Ph-7-Et ~-AcNHNH-~-(~-CIC~H~)-~-C~ ~-AcNHNH-~-(~-C~C~H~)-~-E~ 2-AcNHNH-5-(2-ClC6H4)-7-Me ~-AcNHNH-~-(~-FC~H~)-~-C~ 2-AcNHNH-5-(2,6-F2C,H3)-7-C1
72 78 74
68 77 68 68 77 77
2-AcNHNH-5-(2-Pyridy1)-7-C1
2-(Benzoy1)NHNH-5-(2-ClC6H4)-7-Et 2-BuNH-5-(2-C1C,H4)-7-Et
2-(Cyc1ohexyl)CONHNH-5-(2-BrC6H4)-7-Br 2-(Cyclohexyl)CONHNH-5-(2-C1C,H,)-7-Br
2-Cyc1ohexyl)CONHNH-5-(2-ClC6H4)-7-C1 2-(Cyc1ohexyl)CONHNH-5-(2-C1C6H,)-7-Et 2-(Cyclopentyl)CONHNH-5-(2-C1C,H,)-7-Br
2-(Cyclopropyl)CONHNH-5-(2-ClC6H4)-7-Br 2-EtNH-5-(2-ClC6H4)-7-Et Oxalate 2-EtOOC(Me)NNH-542-ClC6H4)-7-Et 2-EtOOCNHNH-542-C1C6H4)-7-Br
2-[2,2-(EtO),-Ethyl]NH-5-(2-ClC6H4)-7-Et
E;
2-HzN-5-(2-C1C6H4)-7-Et 2-HzNNH-5-Ph-7-Cl 2-H2NNH-5-Ph-7-Et 2-HZNNH-5-(2-BrC,H4)-7-Et 2-H,NNH-5-(2-C1C6H,)-7-Br 2-HzNNH-5-(2-CIC6H4)-7-Et 2-HzNNH-5-(2-CIC6H4)-7-I 2-H,NNH-5-(2-C1C,H4)-7-Me 2-H2NNH-5-(2-FC,H,)-7-Et
2-HzNNH-5-(4-FC6H,)-7-Et 2-H,NNH-5-(2-MeC6H4)-7-Et 2-H,NNH-5-(2-MeOC,H,)-7-Et 2-H,NNH-5-(4-MeOC6H,)-7-Et 2-H2NNH-5-(2-Pyridyl)-7-Et 2-H,NNH-5-(3-Pyridyl)-7-Et 2-MeNH-5-Ph-7-Cl 2-MeNH-S-Ph-7-Et 2-MeNH-S-(2-C1C,H4)-7-C1 2-MeNH-542-C1C,H4)-7-Et Hydrochloride
193-1 95 228-230 165-168 220d 140d 177d 203 110d 236d 188-190 186187 172-174 236 143-146 247-248 204-207 195- 196 189-1 90 3ood 216216 145d 216218 203-204 218-219 205-207 207-208 1 8 6 186 164165 182-183 247-250 243-245 259-262 216217 232-234
MeOH EtOH
Ligroin BuOH EtOH CHClJEtOH MeOH EtOH/CHCl, EtOHiDMF THF/Et,O EtOHiDMF Et,O EtOH/DMF EtOH MeOH/CHCl, EtOH/DMF EtOH/CHCI, EtOH/CHCl, MeOH EtOH CH,Cl, THF/Hexane CHCI,/EtOH
64
75 90 80 92 73 58 53 84 62 76 62 75 68 81
77 68 70 78 78 78 78 78 78 70 70 75 78 72 70 77 68 68 74 68 76 68 68 68 68 68 68 68 68 16 70 16 70 70
TABLE IX-1. d c o n t d . )
Substituent
2-MeNH-5-(2-C1C6H4)-7-Me
2-MeNHCONHNH-5-(2-CIC6H4)-7-Et 2-Me2N-5-Ph-7-Et 2-Me,N-5-(2-CIC6H,)-7-Et Hydrochloride 2-Me(NO)N-5-Ph-7-CI 2-Me(N0)N-5-(2-CIC,H4)-7-C1
2-(MeO-Acetyl)NHNH-5-(2-NO~C6H4)-7-C1
+
2: A
2-MeOOC(HON)C-5-(2-C1C6H,)-7-C1 2-(4-Me-Piperazino)-5-(2-C1C6H,)-7-Et dimaleate 2-(1-Me-Piperidin-3-yl)CONHNH-5-(2-C1C,H4)-7-Br 2-(l-Me-Piperidin-3-yl)CONHNH-5-(2-ClC,H4)-7-Et 2-Morpholino-5-(2-C1C6H4)-7-Etdihydrochloride 2-Piperidino-5-(2-C1C,H4)-7-Et dihydrochloride 2-(Piperidin-4-yl)CONHNH-5-(2-ClC,H4)-7-Br 2-(Propanoyl)NHNH-5-(2-ClC,H4)-7-Et 2-PrNH-5-(2-CIC6H,)-7-Et
2-(Pyridin-2-yl)CONHNH-5-(2-ClC,H4)-7-Br 2-Pyrrolidino-5-(2-CIC6H4)-7-Et
2-(Pyrrolidin-2-yl)CONHNH-5-(2-CIC6H4)-7-Br 2-(Tetrahydrofuran-2-yl)CONHNH-5-(2-BrC,H,)-7-Br 2-(Tetrahydrofuran-2-y1)CONHNH-5-(2-ClC,H,)-7-Br 2-(Tetrahydrofuran-3-yl)CONHNH-5-(2-ClC6H4)-7-Br 2-(Tetrahydropyran-2-y1)CONHNH-5-(2-ClC,H,)-7-Br 2-(Tetrahydropyran-3-yl)CONHNH-5-(2-ClC6H4)-7-Br 2-(Tetrahydropyran-3-yl)CONHNH-5-(2-ClC6H4)-7-Et 2-(Tetrahydrothien-2-y1)CONHNH-5-(2-ClC6H4)-7-Br 2-(Tetrahydrothiopyran-2-yl)CONHNH-5-(2-ClC,H4)7-Br
mp(T) or; [bp (T)/(torr)] 241-243 213-21 5 141-143 249-25Od 111-113 104-107 198-200 242-245d 156158 2 17-218d 165-1 68d 167-17 190-192 196d 187 174176 217d 1W142 21 5-22Od 172d 199-200 212d 185 200d 197d 1977198d 213d
Solvent
of Crystallization
Yield
80 92 23
EtOH/EtOAc EtOH/Ligroin
68
EtOH
60
EtOH
Spectra
Refs. 70 75 70
CHCIJLigroin
EtOH/EtOAc Et,O/Hexane Et,O/Petr ether MeOH THF/MeOH
(YO)
70 16 16 77 16 70 78 78 70 70 78 68 70 78 70 78 78 78 78 78 78 78 78 78
2-(Tetrahydrothiopyran-4-y1)CONHNH-5-(2-CIC,H,)7-Br 2-(Thien-2-y1)CONHNH-5-(2-ClC6H4)-7-Br
78 78
204206 215-218d
Tetrasubstituted
2-H,NNH-5-Ph-6,7-Me2 2-H,NNH-5-(2-C1C,H4)-6,7-Me, 2-MeNH-5-Ph-6,7-Me2
225-227 220-222 275-278
EtOH/CHCI, EtOH/CHCI,
84 83
68 68 70
H Z,.?-DihydreIH-thieno[Z,.?+] [ l , 4 ]diazepines
Disubstituted
5-Ph-7-Et 5-(2-CIC,H,)-7-Et 5-(2-C1C,H4)-7-Me 5-(2-MeC6H,)-7-Et 5-(2-MeOC6H4)-7-Et
19@191 178-1 79 205-206 185-186 177-1 78
CH,Cl,/Petr ether
90
80 80 80 80
SO
Trisubstituted
1-BuNHCO-5-(2-C1C,H4)-7-Et hydrochloride
142-CIC6H4)NHCO-5-(2-ClC6H4)-7-Et 1-Et,NCO-5-(2-C1C,H4)-7-Ethydrochloride l-(2-Et2N-EthyI)NHCO-5-(2-C1C,H,)-7-Et dihydrochloride.H,O 1-Me-5-(2-C1C6H,)-7-Ethydrochloride.H,O 1-MeNHCO-5-(2-CIC6H,)-7-Et 1-MeNHCO-5-(2-MeC,H,)-7-Et hydrochloride 1-MeNHCO-5-(2-MeOC,H4)-7-Et hydrochloride 1-MeNHCS-5-(2-ClC,H4)-7-Et hydrochloride 1-Me,NCO-5-Ph-7-Et hydrochloride 1-Me,NCO-5-(2-BrC6H,)-7-Et hydrochloride
20 1 128-130 224-226d 15G151d 247-248 137-138 207-208 213-214 155-156 237-238d 242-243d
80 80 81
MeOH/EtOAc MeOH/EtOAc CHCl,/Petr ether
83
MeOH EtOH EtOH
67
81 80 80 80 80 80 81 81
TABLE IX-1. g c o n t d . )
Substituent
mp("C) or; [bp ("C)/(torr)]
of Crystallization
e
1-Me,NCO-5-(2-CIC,H4)-7-CI l-Me2NCO-5-(2-CIC,H,)-7-Et hydrochloride 1-Me2NCO-5-(2-CIC,H,)-7-Me hydrochloride l-Me2NCO-5-(4-CIC,H,)-7-Et hydrochloride 1-Me,NCO-5-(3,4-CI2C,H,)-7-Et hydrochloride 1-Me2NCO-5-(4-FC,H,)-7-Et hydrochloride 1-Me,NCO-5-(2-MeC,H4)-7-Et hydrochloride 1-Me,NCO-5-(4-MeC,H4)-7-Et hydrochloride I-Me2NCO-5-(2-MeOC,H,)-7-Et hydrochloride 1-Me2NCO-5-(4-MeOC,H,)-7-Et hydrochloride l-Me2NCO-5-(2-PyridyI)-7-Et dihydrochloride
132-133 24Cb241d 238-239d 208-21Od 219-221d 216-218d 225-226d 2 1 6 218d 219--22Od 204-206d 183-192d
EtOH/Ligroin EtOAc/MeOH Acetone/H,O EtOH EtOH EtOH MeOH/EtOAc EtOH MeOH/EtOAc EtOH EtOH
81 81 81 81 81 81 81 81 81 81 81
8
1-(2-Me,N-Ethyl)NHCO-5-(2-ClC6H4)-7-Et 16CL162d 248-25Od
MeOH/EtOAc Acetone/H,O
81 81
223-224d 234-235d
MeOH/EtOAc MeOHiEtOAc
81 81
225-238d 237-238d
MeOH/EtOAc
81 81
dihydrochloride,H,O
l-(4-Me-Piperazino)C0-5-(2-ClCtiH4)-7-Et .0.5H20 1-(3-Me,N-Propyl)NHCO-5-(2-CIC6H4)-7-Et dihydrochloride
I-(Morpholino)CO-5-(2-CIC6H4)-7-Et hydrochloride l-(3-Morpholinopropy1)NHCO-5-(2-CIC6H4)7-Et dihydrochloride l-(Piperidino)CO-5-(2-C1CtiH4)-7-Ethydrochloride 1-(2-Piperidinoethyl)NHCO-5-(2-CIC6H4)-7-Et dihydrochloride~0.5H20 l-(Pyrrolidino)CO-5-(2-CICbH4)-7-Et hydrochloride 2-H2NCH,-5-Ph-7-CI dimaleate 5-Ph-6,7-Me2
2 15-21 6d 236-237d 176178 203-205
Solvent
EtOH MeOH/Acetone EtOAc/EtOH
Yield
28
(YO)
Spectra
Refs.
81 81 16 80
Tetrasubstituted
1-MeNHCO-5-Ph-6,7-Me2
1-Me,NCO-5-(2-CIC6H,)-6,7-Me, hydrochloride
225-227 246d
MeOH/EtOAc
80 81
2-Methylene-I,3-dhydr0-2H-thieno[2,3-e][1 ,I]dazepines
R,, R,; Other
H, NO,; 5-Ph-7-Cl MeOOC, MeOOC; 5-(2-C1C6HJ-7-C1
164-165 158-1 60
EtOAc/Hexane EtOH
68 70
137-140 200d 203 26263d 222-225 201-203 196199 201-202 235-237 205-207 21 3-21 5 2 17-220 270-27 1 258-260 255-257 223-225 263-266d 272-274d
Et,O Acetone EtOAc EtOH EtOH PhH Dioxane EtOH Dioxane EtOH PhH MeOH Dioxane EtOH CH,CI, EtOH EtOH EtOH
17
16 16
I ,3-Dihydrothieno[2,3-e][1,4]diazepin-2(2H)-ones Monosubstituted
II
5-Et 5-Me 5-Ph 4-Oxide 5-(2-C1C,H,) 5-(2,3-Cl,C,H,) 5(2-FC6H,)
5-(2,6-FzC,H,) 5-(2-F,CC,H,) 5-(2-MeC6H,) 5-(2-Me-3-N0,C6H,) 5-(2-MeOC6H,) 5-(2-MeSO,C,H,) 5-(2-NO,CbH,) 5-(3-NO,C,H,) 5-(2-Pyridyl) 5-(3-Me-2-Pyridyl)
ir, pmr, uv
75
63 89 75 42 52 80 45 56 45 53
ir, pmr, uv
93 6 85 85 97 87 87 93 87 87 87 87 87 87 88 95 84 84
TABLE IX-1. -4contd.)
Substituent
mp ("C) or; [bp ("C)/(torr)]
Solvent of Crystallization
116120 82-83 169-171 136-138 1 3 4 135 158-1 59 109-113 162-164 109-1 11 163-164 139-141 148-1 50 113-116 115-117 81-85 99-100 97-100 104-107 11C113 1 3 6 138 161d 123-124 125-127 149-1 5 1 13C132 129-130 149-1 51
Et,O Et,O EtOH/Et,O EtOH EtOH EtOH/CCI, EtOH EtOH/CCI, Et,O EtOH/CCI, EtOH EtOH Cyclohexane EtOH EtOH Et,O Et,O EtOH MeOH EtOH EtOH/CCI, EtOH EtOH EtOH EtOH Cyclohexane MeOH
Yield (%)
Refs.
Spectra
I ,S-Disubstituted
1,5-Me2 1-Me-5-Et 4-Oxide 1-Me-5-Ph 4-Oxide 1-Me-5-(2-BrC,H4) 4-0xid e 1-Me-5-(2-CIC,H4) 4-Oxide 1-Me-5-(4-CIC,H4) 1-Me-5-(2,3-C1,C6H,) 1-Me-5-(2-FC,H4) 4-0xide.EtOH 1-Me-5-(2,6-F2C,H,) 4-Oxide 1-Me-5-(2-F3CC,H,) 1-Me-5-(2-IC,H4) 4-Oxide 1-Me-5-(2-MeC6H,) 4-oxide 1-Me-5-(2-Me-3-NO2C,H,) 1-Me-5-(2-MeOC6H,) l-Me-5-(2-NO2C,H,)
18 47 86 67 32 61 56 73 76 87 71 84 83 77 55 55 89
48 18 63 74 55
72 53 83
ir, pmr, uv
ir, ir, ir, ir, ir, ir,
pmr, pmr, pmr, pmr, pmr, pmr
uv uv uv uv uv
ir, pmr, uv ir, pmr, uv ir, pmr, uv ir, pmr, uv ir, pmr, uv ir, pmr, uv
ir, pmr, uv ir, pmr, uv
6 93 93 85 93 93 93 93 93 93 93 87 87 93 93 87 102 102 87 93 93 87 93 93 87 87 88
1-Me-5-(3-NO,C6H,) l-Me-5-(2-Pyridyl) 1-Me-5-(3-Me-2-Pyridyl)
196198 142-144 137-1 40
EtOH MeOH Cyclohexane
122 189-190
Et,O/Petr ether Et,O
251-253
MeCN
95 84 84
3,SDisubstituted
3-EtOOC-5-Ph 3-Me-5-Ph
6 6
5,6-Disubstituted
5,6-Ph2 5-Ph-6-Cyclopropyl Hydrochloride 5-Ph-6-Me
!E; g
5-Ph-6-i-Pr 5-(2-NOzC6H4)-6-Et 5-(2-NO,C6H,)-6-Me 5-(2-Thienyl)-6-Me 5-(2-Thienyl)-7-N02
23
160
264 248-250 253-254d 23C232 22C222 245-248 211-213 260d
Acetone/Et,O MeOH CH,CI,/EtOH EtOH/Hexane EtOH EtOH MeOH Acetone
230-232 163-164 25G252d 194-195 213-215 207-210 246248 266268d 208-209 248d 237d 204-206 225d
MeCN i-PrOH EtOH PhMe EtOHjPhH
60
52 62 30
82 98 98 82 83 86 88 88 82 77b
S,7-Disnbstituted
5,7-Ph2 5-Ph-7-Bu 5-Ph-7-CI 5-Ph-7-Et 5-Ph-7-Me 5-Ph-7-MeOOC 5-Ph-7-NO2 5-(2-BrC,H4)-7-Et (5-(2-C1C6H,)-7-Br 5-(2-C1C6H4)-7-C1 5-(2-C1C6H4)-7-Et 4-Oxide
EtOH EtOH EtOH/Hexane EtOH EtOH PhMe
40
70
79
81
82 86 85 86 92, 83 86 96 85 86 97 97 86 94
TABLE IX-1.gcontd.)
Substituent 5-(2-ClC,H4)-7-I 5-(2-C1C6H,)-7-Me 5-(2-ClC,H,)-7-N02 5-(2-C1C6H4)-7-i-Pr 5-(2,3-CI2C,H,)-7-C1 5-(?,3-Cl,C,H,)-7-N02 5-(2-FC6H4)-7-CI 5-(2-FC,H,)-7-Et 5-(2-FC6H,)-7-I 5-(2-FC,H,)-7-NO, 5-(2,3-F2C,H,)-7-C1 5-(2,6-F,C,H,)-7-C1 5-(2,6-F2C6H3)-7-N02 5-(2-F,CC,H,)-7-CI 5-(2-MeC,H,)-7-C1 5-(2-MeC6H,)-7-Et 5-(2-Me-3-NO2C,H,)-7-C1 5-(2-Me-3-NO,C6H3)-7-N0, 5-(2-MeOC6H,)-7-C1 5-(2-MeOC6H,)-7-Et 5-(2-MeSO2C,H,)-7-C1 5-(2-MeSO2C,H,)-7-NO, 5-(2-NO,C,H4)-7-Ac 5-(2-N0,C,H4)-7-C1 5-(2-NO,C,H.+)-7-Et 5-(2-NO2C,H,)-7-Me
mp ("C) or; [bp ("Cjtorr)]
Solvent of Crystallization
214216 222-224 212-213 269d 243-246d 253-255 253-255 256259 178-180 212-2 14 258-259 245-247 245-247 268-269 278-281 237-241 182-183 275-280 238-240 25G252 168-169 27G272 268-270 26&262 243-246 253-254 19G-192 225-227
Dioxane EtOH EtOH/Hexane Dioxane EtOH EtOH PhH EtOH EtOH/Hexane EtOH EtOH EtOH EtOH Dioxane EtOH EtOH PhMe EtOH Dioxane EtOH PhMe EtOH EtOH PhH CH,CI, CH,Cl, EtOH EtOH
Yield (YO)
87 74 84 50 92 77 82 60 89 52
75 62 76 45 57 41
64 74 80 21 28 46 34
Spectra
Refs. 97 76 86 97 86 87 87 87 86 87 87 87 97 97 87 87 86 87 87 87 86 87 87 88 88 97 88 88
5-(2-N02C6H4)-7-N02 5-(3-N0,C6H4)-7-C1 5-(4-N0,C6H4)-7-C1 5-(2-Pyridyl)-7-C1 5-(2-Pyridyl)-7-Et 5-(3-Me-2-Pyridyl)-7-C1
267-269 232-234 267 25&252d 228-234d 237-239d
Dioxane EtOH CH,CI, EtOH EtOH Dioxane
116118 158-160 238 202-203 205-206 167-169 204-206
Cyclohexane MeOH Acetone/Et,O MeOH EtOH EtOH EtOH
93-95 95-97 91-93 167-1 68 110-112 153-154 157-1 59 143-145 17Od 7678 171-172 120-122 117-1 19 194-195 103-104 97-100 234-235d
Cyclohexane Cyclohexane MeOH MeOH MeOH EtOH EtOH Et,O CH,CI,/Et,O Et,O Et,O EtOH EtOH EtOH/CCl, EtOH CH,Cl, EtOH/EtOAc
80
88 95 77b 77 89 84
48
I>,& Trisubstituted
l-Allyl-5-Ph-6-Me l-Et-5-Ph-6-Me 1-Me-5-Ph-6-Cyclopropyl hydrochloride l-Me-5-Ph-6-Me 1-Me-5-(2-N02C,H,)-6-Et 1-Me-5-(2-NO,C,H,)-6-Me
74 80
82 82 98 82 83 88 88
83 80 77 67
I J,7- Trisubstituted
I-Allyl-5-(2-N02C,H4)-7-C1 I-(Cyclopropyl)CH2-5-Ph-7-CI l-(Cyclopropyl)CH,-5-(2-N02C6H,)-7-C1 1-Et-5-(2-N0,C,H4)-7-C1 I-(2-Et2N-Ethyl)-5-(2-N0,C6H4)-7-C1 1-H,N-5-(2-C1C,H4)-7-Et 1 -H,N-5-(2-N0,C6H4)-7-C1 l-(2-HO-Ethyl)-5-(2-NOZC,H4)-7-C1 1,5-Me,-7-NO, l-Me-5-Et-7-Cl 4-Oxide l-Me-SPh-7-CI 4-Oxide I-Me-5-Ph-7-Et l-Me-5-Ph-7-Me Hydrochloride
90
16 25
ir, pmr ir, pmr
80
40 64 85 70
ir, pmr, uv
97 85 97 97 97 100 77b 97 6 93 93 85 93 93 86 83 86
TABLE IX-1. 4contd.) Solvent of Crystallization
Substituent l-Me-5-Ph-7-MeOOC 1-Me-5-Ph-7-NO, 1-Me-5-(2-BrC6H,)-7-C1 1-Me-5-(2-BrC6H,)-7-Et 1-Me-5-(2-C1C6H,)-7-C1
147-149 195-197 8689 100-102 83-85
MeOH EtOH Et,O Et OH/Hexane Cyclohexane
4-Oxide 1-Me-5-(2-C1C6H,)-7-Et 4-Oxide 1-Me-5-(2-C1C6H,)-7-I I-Me-5-(2-CIC6H,)-7-Me hydrochloride 1-Me-5-(2-C1C6H,)-7-NO, 1-Me-5-(4-C1C6H,)-7-C1
95-97 105-106 117-1 18 117-1 18 232-234d 162-165 2 12-2 14 100-105 97-98 101-103 153-1 54 203-204d 174-177 1w102 224-225 217-22 1 81-82 128-1 30 171-173 145-147 12&127 1&108 143-145
CCI, Hexane PhH/Hexane Et,O EtOH/EtOAc EtOH/PhH EtOH/CHCI, Et,O Cyclohexane i-PrOAc Et,O/Hexane Acetone/EtOH PhH Cyclohexane Dioxane EtOH EtOH EtOH Dioxane MeOH EtOH Et,O MeOH
1-Me-5-(2,3-C1,C6H,)-7-C1
1-Me-5-(2-FC6H,)-7-C1 4-Oxide 1-Me-5-(2-FC6H,)-7-Et hydrochloride I-Me-5-(2-FC,H,)-7-NO, 1-Me-5-(2-F,CC6H,)-7-C1 1-Me-5-(2-F,CC,H,)-7-NO, 1 -Me-5-(2-IC6H,)-7-C1 hydrochloride 1-Me-5-(2-MeC6H,)-7-CI
1-Me-5-(2-Me-3-N02C,H,)-7-C1 1-Me-5-(2-Me-3-NO3C,H,)-7-NO, 1-Me-5-(2-NO,C6H,)-7-C1 1-Me-5-(2-NO,C6H,)-7-Et 1-Me-5-(2-NO,C,H,)-7-Me 1-Me-5-(2-NO,C,H,)-7-NO,
Yield (YO)
Spectra
49 80
ir, pmr, uv
28 54 88 95
ir, pmr, uv ir, pmr, uv
68 83 70 65 73 83 68 83 65
ir, pmr, uv ir, pmr, uv
32
ir, pmr
65
44 52 69 80 81 78
ir, pmr, uv
Refs. 96 85 93 86 97 93 93 86 94 97 86 97 93 87 87 93 93 86 87 87 97 93 87 87 87 88 88 88 88
m
-p'
8
m m
8
m m
I
m
1043
TABLE IX-I. --(contd.)
Substituent 5-(2-NO,C6H,)-6-Me-7-C1 5-(2-N0,C6H,)-6-Me-7-N0,
5-(2-NO,C,H,)-6-NOz-7-Et 5-(2-NO,C,H,)-6-NO,-7-Me
mp (“C) or; [bp (T/torr)]
Solvent of Crystallization
2 15-21 7 273 2 19-22 1 26 1
EtOH EtOH PhH EtOH
Yield (YO) 28 56 85
Spectra
Refs. 88 88 77b 88
1,3,5,7- Tetrasuhstituted
l-Me-3-Ac0-5-(2-C1C,H4)-7-Et 1-Me-3-Ac0-5-(2-ClC,H4)-7-Me l-Me-3-HO-5-(2-ClC,H4)-7-Et
1-Me-3-HO-5-(2-C1C6H,)-7-Me
E;
1,5,6,7- Tetrasuhstituted
2
1-Me-5-Ph-6, 7-CI, 1-Me-5-Ph-6, 7-Me, l-Me-5-Ph-6-Me-7-Br l-Me-5-Ph-6-Me-7-CI l-Me-5-Ph-6-Me-7-NO2 l-Me-5-Ph-6-NO2-7-CI 1-Me-5-(2-ClC,H,)-6,7-Me, hydrochloride 4-Oxide
1-Me-5-(4-C1C,H4)-6,7-Me, 1-Me-5-(2-NO,C,H,)-6-Et-7-CI 1-Me-5-(2-NO,C,H,)-6-Et-7-NO2
1-Me-5-(2-N02C,H,)-6,7-Me, I-Me-5-(2-NO2C,H,)-6-Me-7-C1 1-Me-5-(2-NO2C,H,)-6-Me-7-NO~ 1-Me-5-(2-N0,C6H,)-6-N0,-7-Et 1-Me-5-(2-N0,C6H,)-6-N0,-7-Me
94 94 94 94
Oil 20 1-202 142- 143 168-1 69
147-1 49 121 137-140 193-194 139-142 199-201 179-181 235-236 180-181 182-184 207-210 217-2 I9 149-151 189-190 169-1 7 1 164-166 193-1 95
MeOH EtOH/Hexane Cyclohexane EtOH EtOH CCI, PhH EtOH EtOH/Hexane EtOH Dioxane EtOH EtOH EtOH PhH EtOH
70 90
83 76 82 71 82 58 81 85 89
99 86 83 83 83 83 95 86 94 86 88 88 88 88 88 88 88
Pentasubstituted
1-Me-3-AcO-5-(2-CIC,H,)-6,7-Me,
1-Me-3-HO-5-(2-C1C6H,)-6,7-Me2
I J-Dihy&othien0[2,3-e] [1,4]diazepin-2(2H)-thiones
111-112 183-1 84d
94 94
d-s --N
Monosubstituted
5-Ph 5-(2-C1C,H,) 5-(2-NO,C,H,)
210 206-208 221-223 207-209
MeOH/CHCI, MeOH/CHCI, CH,CI, MeOH
223-225d 202-203 194195 214d 223-225d 202 198-199 218-219 230 188-189 225-227 223-225 189-190 202-203 213-215 199-200 223-225
MeOH EtOH MeOH/CHCI, CH,CI, MeOH Et20 EtOH/CHCl, EtOH/CHCl, EtOH/CHCI, EtOH Et OH/CHCI EtOH EtOH/CHCI, MeOH MeOH CHCI, EtOH
52 85
68 68 77 71
Disubstituted 111
5-Ph-7-Cl 5-Ph-7-Et 5-(2-BrC6H,)-7-Et 5-(2-C1C6H,)-7-Br 5-(2-CIC,H,)-7-C1 5-(2-C1C6H,)-7-I 5-(2-CIC,H,)-7-Et 5-(2-C1C6H4)-7-Me 5-(4-CIC,H,)-7-Et 5-(2-FC6H4)-7-Et 5-(4-FC,H,)-7-Et 5-(2-MeC6H,)-7-Et 5-(2-MeOC6H,)-7-Et 5-(4-MeOC6H,)-7-Et 5-(2-NO2C,H,)-7-C1 5-(2-Pyridyl)-7-Et 5-(3-Pyridyl)-7-Et
,
92
71 68 68 74 77 76
84
68
64
68 68 68 68 68 68 68 77 68 68
58 71 50
76 43 63 48 68 81
44 75
2
22
m
m w w m
m m
ri-.
I-. m
v)
z$o
c=
w w Nv,
3
zz
m m rN N 4
2' NA "
Y
1046
m d
2-Methylene-l,3-dihydro-2H-thieno[3,2-e] [ I ,I]diazepines
R , . R,; Other
H, NO,; 5-Ph
163-164
MeOH
170 205-206 266-27Od
EtOH EtOH
16
45
1,3-Dihydrothien0[3,2-e] [1,4]diazepin-2( 2H)-ones Monosubstituted
$
5-Me 5-Ph 4-Oxide
ir, pmr
108 104 104
Disubstituted
1 -(Cyclopropyl)CH2-5-Ph I-Me-5-Ph 5-Ph-7-CI 5-Ph-8-C1 5-Ph-8-Me 5-Ph-8-NOI 5-(2-C1C6H,)-7-CI 5-(2-ClC,H,)-7-FSC 5-(3-N0,C,H4)-8-N02
142-145 159-161 220-221 200-203 233-238 215d 220 227-228 230d
EtOH EtOH PhH
104
EtOH
107
EtOH EtOH EtOH PhH EtOH
60 60
77b 109 106 105 109
147-149 152-1 54 183-186 127-1 28
EtOH Cyclohexane EtOH Cyclohexane
50 62
107 77b 109 106
104 106
58
Trisubstituted
l-Me-5-Ph-8-Cl l-Me-5-Ph-8-Me 1-Me-5-Ph-8-NO2 1-Me-5-(2-C1C,H4)-7-C1
P-w s w
>
c
E
.-c
P-ww o w *
k$
3
m
22 "
1048
2 3
- N c 3 c
N- r r O '
3 3
N
1049
n
d
F=;\ z
2..
1050
Hetero Ring[e] [1,4]Diazepines
18. REFERENCES 1. 2. 3. 4.
E. Broger, unpublished data, Hoffmann-La Roche, Nutley, NJ. P. L. Pacini and R. G. Ghirardelli, J . Org. Chem., 31, 4133 (1966). H. Wamhoff, C. Materne, and F. Knoll, Chem. Ber., 105, 753 (1972). (a) H. Griengl, G. Prischl, and A. Bleikolm, Justus Liebigs Ann. Chem., 400 (1979).(b) H. Griengl and A. Bleikolm, Ger. Offen. 2,609,601, September 1976. 5. A. Edenhofer, Helu. Chim. Acta, 58, 2192 (1975). 6. A. Szente, unpublished data, Hoffmann-La Roche & Co. AG, Basel, Switzerland. 7. B. P. Tong, unpublished data, Roche Products Ltd., Welwyn, England. 8. J. J. Tegeler and J. Diamond, U.S. Patent 4,514,410, April 1985. 9. (a) R. Jaunin, H e b . Chim. Acta, 57, 1934 (1974). (b) R. Jaunin, unpublished data, Hoffmann-La Roche & Co. AG, Basel, Switzerland. 10. R. I. Fryer and J. V. Earley, unpublished data, Hoffmann-La Roche, Nutley, NJ. 11. R. F. C. Brown, I. D. Rae, J. S. Shannon, S. Sternhell, and J. M. Swan, Aust. J . Chem., 19, 503 (1966). 12. G. F. Field, L. H. Sternbach, and A. Walser, US. Patent 3,880,840, April 1975. 13. H. A. DeWald, S. Lobbestael, and B. P. H. Poschel, J . Med. Chem., 24, 982 (1981). 14. D. E. Butler, US. Patent 3,770,762, November 1973. 15. D. E. Butler, U.S. Patent 4,075,408, February 1978. 16. R. I. Fryer, J. V. Earley, and A. Walser, J . HeterocycL Chem., 15, 619 (1978). 17. H. A. DeWald and S. J. Lobbestael, US. Patent 3,823,157, July 1974. 18. H. A. DeWald, S. Lobbestael, and D. E. Butler, J . Med. Chem., 20, 1562 (1977). 19. H. A. DeWald and D. E. Butler, U.S. Patent 3,558,605, January 1971. 20. H. A. DeWald and D. E. Butler, Ger. Offen. 2,023,453, October 1975. 21. H. A. DeWald, J . Heterocycl. Chem., 11, 1061 (1974). 22. W.-H. Hong and D. H. Szulczewski, J . Pharm. Sci., 70, 691 (1981). 23. L. R. Swett: (a) U.S. Patent 3,657,271, April 1972, (b) Br. Patent 1,357,978, June 1974. 24. H. A. DeWald, I. C. Nordin, I. J. L'Italien, and R. F. Parcell, J . Med. Chem., 16, 1346 (1973). 25. H. A. DeWald, U.S. Patent 3,557,095, January 1971. 26. L. R. Swett, US. Patent 3,764,688, October 1973. 27. Y.J. L'Italien and I. C. Nordin, US. Patent 3,553,209, January 1971. 28. I. C. Nordin, US. Patent 3,553,210, January 1971. 29. I. C. Nordin, US. Patent 3,553,207, January 1971. 30. W. H. Hong, C. Johnston, and D. Szulczewski, J . Pharm. Sci., 66, 1703 (1977). 31. P. G. Baraldi, S. Manfredini, V. Periotto, D. Simoni, M. Guarneri, and P. A. Borea, J . Med. Chem., 28, 683 (1985). 32. I. C. Nordin, US.Patent 3,700,657, October 1972. 33. R. Littell and D. S. Allen, J . Med. Chem., 8, 722 (1965). 34. S. Carboni, A. Da Settimo, D. Bertini, P. L. Ferrarini, 0. Livi, and I. Tonetti, Farmaco, Ed. Sci., 30,237 (1975). 35. W. Koch, unpublished data, Hoffmann-La Roche & Co. AG, Basel, Switzerland. 36. S. Carboni, A. Da Settimo, D. Bertini, P. L. Ferrarini, 0. Livi, and I. Tonetti, Farmaco, Ed. Sci., 31, 322 (1976). 37. W. Hunkeler and E. Kyburz, US. Patent 4,362,732, December 1982. 38. M. K. Eberle and W. J. Houlihan, US. Patent 3,682,897, August 1972. 39. B. M. Pyatin and R. G. Glushkov, Khim. Farm. Zh., 3, 26 (1969). 40. B. M. Pyatin and R. G. Glushkov, Khim. Farm. Zh., 3, 13 (1969). 41. W. von Bebenburg, N. Schulmeyer, and V. Jakovlev, U.S. Patents 4,110,455, August 1978, 4,207,322, June 1980. 42. W. von Bebenburg and H. Offermanns, US. Patent 3,917,629, November 1975. 43. W. von Bebenburg and H. Offermanns, U.S. Patent 4,008,223, February 1977. 44. W. von Bebenburg and H. Offermanns, U.S. Patent 4,009,271, February 1977.
18. References 45. 46. 47. 48. 49. 50. 51. 52.
105 1
W. von Bebenburg and N. Schulmeyer, Ger. Offen. 2,428,469, August 1976. Belg. Patent 821,016, March 1975 (Degussa, Germany). W. von Bebenburg and H. Offermanns, US. Patent 3,900,466, August 1975. W. von Bebenburg and H. Offermanns, US. Patent 3,972,873, August 1976. W. von Bebenburg and H. Offermanns, US. Patent 3,920,633, November 1975. I. Ahmed, G. W. H. Cheeseman, and P. Jaques, Tetrahedron, 35, 1145 (1979). C. Kawasaki and H. Yokoyama, Vitamins (Japan), 41, 190 (1970). C. Kawasaki, H. Yokoyama, G. Kurata, T. Sakai, and T. Miyahara, Vitamins (Japan), 37, 165 (1968). 53. A. Takamizawa, K. Hirai, and T. Ishaba, Tetrahedron Lett., 437 (1970). 54. (a) D. H. Kim and A. A. Santilli, J. Med. Chem., 12,1121 (1969).(b) D. H. Kim and A. A. Santilli, US. Patent 3,535,310, October 1970. 55. A. A. Santilli and A. C. Scotese, J. Heterocycl. Chem., 16, 213 (1979). 56. E. Garcia, unpublished data, Hoffmann-La Roche, Nutley, NJ. 57. L. Fontanella, L. Mariani, G. Tarzia, and N. Corsico, Chim. Ther., 11, 217 (1976). 58. L. Fontanella, L. Mariani, G. Tarzia, US. Patent 4,022,766, May 1977. 59. A. Walser, unpublished data, Hoffmann-La Roche, Nutley, NJ. 60. L. Mariani and G. Tarzia, European Patent 0,102,602 Al, March 1984. 61. L. Mariani and G. Tarzia, Ger. Offen. 3,221,400 Al, December 1982. 62. B. Vitiello, G. Buniva, A. Bernareggi, A. Assandri, A. Perazzi, L. M. Fuccella, and R. Palumbo, Int. J . Clin.Pharm., 22, 273 (1984). 63. A. Assandri, D. Baroni, P. Ferrari, A. Perazzi, A. Ripamonte, G. Tuan, L. F. Zerilli, Drug M e t . Disp., 12, 257 (1984). 64. Y. Sakamoto and T. Kurihara, Yakugaku Zasshi, 99, 818 (1979). 65. R. Y. Ning, unpublished data, Hoffmann-La Roche, Nutley, NJ. 66. K. Hirai, H. Sugimoto, and T. Ishiba, J. Org. Chem., 45, 253 (1980). 67. K. A. Maier and 0. Hromatka, Monatsh. Chem., 102, 1010 (1971). 68. T. Tahara, K. Araki, M. Shiroki, H. Matsuo, and T. Munakata, Arzneim.-Forsch., 28, 1153 (1978). 69. M. Nakanishi, T. Tahara, K. Araki, and M. Shiroki, U.S. Patent 3,904,641, September 1975. 70. M. Nakanishi, T. Tahara, K. Araki, and M. Shiroki, US. Patent 3,828,039, August 1974. 71. Q. Branca, unpublished data, Hoffmann-La Roche & Co. AG, Basel, Switzerland. 72. T. Tahara, H. Matsuki, K. Araki, and M. Shiroki, US. Patent 3,952,006, April 1976. 73. M. Nakanishi, T. Tahara, K. Araki, and M. Shiroki, US. Patent 3,920,679, November 1975. 74. K. -H. Weber, A. Bauer, P. Danneberg, and J. Kuhn, US. Patent 4,094,984, June 1978. 75. M. Nakanishi, K. Araki, T. Tahara, and M. Shiroki, US. Patent 3,965,111, June 1976. 76. K. -H. Weber, A. Langbein, E. Lehr, K. Boeke, and F. J. Kuhn, Ger. Offen. 2,701,752, July 1978. 77. (a) J. Hellerbach, P. Zeller, D. Binder, and 0. Hromatka, US. Patent 4,155,913, May 1979. (b) 0. Hromatka and J. Hellerbach, unpublished data, Hoffmann-La Roche & Co. AG, Basel, Switzerland. 78. K.-H. Weber, A. Bauer, P. Danneberg, and F. J. Kuhn, US. Patent 4,199,588, April 1980. 79. J. Hellerbach, P. Zeller, D. Binder, and 0. Hromatka, Ger. Offen. 2,405,682, August 1974. 80. M. Nakanishi, K. Araki, T. Tahara, and M. Shiroki, U.S. Patent 3,840,558, October 1974. 81. M. Nakanishi, K. Araki, T. Tahara, and M. Shiroki, US. Patent 4,010,184, March 1977. 82. F. J. Tinney, J. Sanchez, and J. A. Nogas, J. Med. Chem., 17, 624 (1974). 83. 0.Hromatka, D. Binder, C. R. Noe, P. Stanetty, and W. Veit, Monatsh. Chem., 104,715 (1973). 84. 0. Hromatka, D. Binder, P. Stanetty, and G. Marischler, Monatsh. Chem., 107, 233 (1976). 85. 0. Hromatka, and D. Binder, Monatsh. Chem., 104, 704 (1973). 86. (a) M. Nakanishi, T. Tahara, K. Araki, M. Shiroki, T. Tsumagari, and Y.Takigawa, J. Med. Chem., 16, 214 (1973). (b) M. Nakanishi, K. Araki, T. Tahara, and M. Shiroki, US. Patent 3,849,405, November 1974. 87. D. Binder, 0.Hromatka, C. R. Noe, F. Hillebrand, and W. Veit, Arch. Pharm., 313,587 (1980). 88. D. Binder, 0. Hromatka, C. R. Noe, Y.A. Bara, M. Feifel, G. Habison, and F. Leierer, Arch. Pharm., 313, 636 (1980).
1052 89. 90. 91. 92. 93. 94. 95. 96. 97. 98. 99. 100. 101. 102. 103. 104. 105. 106. 107. 108.
109. 110. 111. 112. 113. 114. 115. 116. 117.
Hetero Ring[e] [1,4]Diazepines
M. Nakanishi, M. Shiroki, T. Tahara, and K. Araki, U.S. Patent 3,806,512, April 1974. Belg. Patent 771,951, September 1971 (Yoshitomi Pharm. Ind., Ltd., Japan). Belg. Patent 811,726, June 1974 (Lab. Made S.A., Spain). 0. Hromatka and D. Binder, U.S. Patent 3,669,959, June 1972. T. Hirohashi, S. Inaba, and H. Yamamoto, Bull. Chem. SOC.Japan, 48, 147 (1975). M. Nakanishi, M. Shiroki, T. Tahara, and K. Araki, US. Patent 3,859,275, January 1975. 0. Hromatka, D. Binder, and P. Stanetty, Monatsh. Chem., 104, 709 (1973). 0. Hromatka, D. Binder, and W. Veit, Monatsh. Chem., 104, 973 (1973). 0. Hromatka and D. Binder, US.Patent 3,872,089, March 1975. J.-C. Cognacq, US.Patent 4,156,009, May 1979. 0. Hromatka, D. Binder, and P. Stanetty, Monatsh. Chem., 104, 920 (1973). M. Nakanishi, M. Shiroki, T. Tahara, and K. Araki, US. Patent 3,887,543, June 1975. M. Inotsume and M. Nakano, G e m . Pharm. Bull., 28,2536 (1980). T. Hirohashi, S. Inaba, and H. Yamamoto, Bull. Chem. SOC.Japan, 48, 974 (1975). K.-H. Weber, and H. Daniel, Justus Liebigs Ann. Chem., 328 (1979). 0. Hromatka, and D. Binder, Monatsh. Chem., 104, 1343 (1973). 0. Hromatka, D. Binder, and K. Eichinger, Monatsh. Chem., 105, 138 (1974). 0. Hromatka, D. Binder, and G. Pixner, Monatsh. Chem., 106, 1103 (1975). 0. Hromatka, D. Binder, and G. Pixner, Monatsh. Chem., 104, 1348 (1973). G. Ah-Kow, C. Paulmier, and P. Pastour, Bull. SOC. Chim., 151 (1976). 0. Hromatka, and D. Binder, Monatsh. Chem., 104, 1105 (1973). M. Gerecke, W. Haefeli, W. Hunkeler, E. Kyburz, H. Moehler, L. Pieri, and P. Polc, U.S. Patent 4,316,839, February 1982. 0. Hromatka, D. Binder, and K. Eichinger, Monatsh. Chem., 104, 1513 (1973). 0. Hromatka, D. Binder, and K. Eichinger, Monatsh. Chem., 105, 123 (1974). 0. Hromatka, D. Binder, and K. Eichinger, Monatsh. Chem., 105, 135 (1974). (a) K. Grohe and H. Heitzer, Justus Liebigs Ann. Chem., 1947 (1977). (b) K. Grohe, F. Hoffmeister, and W. Wuttke, Ger. Offen. 2,047,013, March 1972. 0. Hromatka, D. Binder, and K. Eichinger, Monatsh. Chem., 104, 1599 (1973). M. Brugger, H. Wamhoff, and F. Korte, Justus Liebigs Ann. Chem., 758, 173 (1972). G. F. Field, unpublished data, Hoffmann-La Roche, Nutley, NJ.
Author Index
Page citations followed by numbers in parentheses indicate that an author’s work is discussed on that page without his name being given in the text. The parenthetical numbers are used to designate the appropriate literature references cited on any given page. Page numbers giving full literature references at the end of each chapter are italicized and are to be used with the citations that immediately preceed them. Page numbers that appear in italics at the beginning of each chapter indicate full literature references for previous review articles. In a general way the italicized numbers may also be used to indicate chapter separations. Unpublished data from the files of the Hoffmann-La Roche company reported in Chapter VII, were in general, not included in this index. Abushanab, E., 312(271), 405(271), 426 Acharyya, k K., 701(396), 846 Acheson, R. M., 215(5), 241(106), 248(106), 281-282(106), 337(5), 358(106), 360(106), 364(106), 368(106), 376(106), 379-380(106), 334(106), 420, 422 Ackrell, J., 636(46), 838 Adachi, Y., 101(96), 150(96), 182, 635(36), 685(36), 752(36), 837 Adomeit, M., 697,846 Affane-Nguema, J.-P., 314,315(274,275), 316(276), 406-407(274,275), 408(275), 426 Agawa, T., 124(58), 125(59), 169(58,59), 181 Ager, I. R., 450(78), 467(78), 509-510(78), 540, 704(439), 847 Ah-Kow, G., 995-996(108), 1047(108),1052 Ahmed, I., 979(50), 1024(50), 1051 Ajello, E., 233,267(151), 363(151), 423 Akahori, Y., 241,272(107), 284(107), 326(295), 327(298), 357(107), 371-371(107), 415(295), 417(298), 422, 427 Akase, T., 557(59), S72( 11l), 599(59), 601( 11l), 601-603(59), 605(59,111), 609(59), 627, 666(268), 667(268), 843, 852(14), 904(14), 905(14), 943 Akatsu, M.. 557(59), 573(11l), 599(59), 601(111), 601-603(59), 605(59,111), 609(59), 627, 628, 639(86,89), 641(116, 124,129,130), 666(268), 667(86,89,268,285, 286,289), 713-716(86), 717(116), 718(124), 720(86), 722(86), 726(86), 729(86), 73 1-734(86), 733(285), 736(89), 740(86), 741(86,89,124), 742(285), 743(86,289), 744(86,89), 745-747(86), 748-749(285), 749(86,124), 754(86), 759(86), 760(285), 761-762(86), 763(89), 765-767(86), 768(89, 116,130), 769(86), 770(86,89), 787(86),
797(86), 803(86), 839, 840, 843, 844, 852(14), 866(72), 892(144),904(14), 905(14), 922-923(72), 933(144), 943, 944, 946 Albrecht, H. A, 899-900(154), 941-942(154), 946 Alekel, R., 569(106), 572(106), 598(106), 615-616(106), 628, 638(69), 660(69), 664(69), 678(69), 686(69), 716(69), 747(69), 794(69), 838 Allen, D. S., 640(92), 718(92), 721(92), 726(92), 729(92), 749(92), 753(92), 759(92), 767(92), 839, 970,975,978, 1016(33), 1020(33), 1023(33), 1024(33), 1050 Allgeier, H., 472(126), 489(189), 525(126), 542, 543 Allmann, R., 10(12,104), 62(104), 63(104),86, 88 Alton, K. B., 305(253,254), 426 Amano, S., 130(62), 171(62), 181 Ames. D. E., 56(75), 83(75), 87 Amey, R. L., 220(53), 347(53),421 Anderson, R. C., 448(54), 540 Andreichikov, Yu. S., 219(42,43),220(43,51), 238(43), 338(42), 338-339(43,51), 421 Andrianov, k A,, 701(407),846 Andrianova, T. A, 218(21), 238(21), 276(191), 345(21), 346(21), 371(191), 374(191), 420, 424 Andronati, S. A, 429, 633(10), 640(100), 641(115), 652(202), 663(202), 666(10), 67 1(202,304),680(202), 685(202), 690-691(202), 700(378), 701(100,407), 7 17(100,202), 718( loo), 721(498), 72 1-724(202), 722(lo), 746( loo), 75 1(lo), 765(498), 771(115,202), 773-774(202), 776(202), 780(202), 781(304), 782(100),
1053
1054
Author Index
Andronati, S. A (Continued) 786(202), 788-789(202,789(100), 810(115), 824(304), 827-828(304), 829(100), 837, 839, 842, 844, 846, 848 Arai, H., 52(70), 81(70), 87 Araki, K., 988(68,69,70,72,73), 989(68,69,75), 990(73,80,81), 992-993(86,89,94), 993( loo), 1032(68), 1033(72,75), 1033-1035(68,70), 1035(75,80,81),1036(80,81), 1039(94), 1039-1044(86), 1041(89,100), 1042-1044(94), 1043(89,100), 1045-1046(68), 1051, 1052 Archer, G. A, 3, 92,213, 429, 449(61), 450(72), 488(72), 509-51 1(61), 515(61), 518(61,72), 535(72),540, 547(2,3,5), 548( 15), 550(20-23), 551(15,27), 557(2,15), 558(61), 561-562(78), 572(2), 572-573(3,5, 112,113), 574(2), 584(3,5), 585(2,15,20-23) 596(2,3), 598(78), 599(2,15.61), 599-602(3), 600(5). 601(112), 601-602(15), 602-603(2), 603(61), 604(3,5,21,113), 605(113), 609(2), 626, 628, 633(28), 646(28,151), 649(186), 663(254), 664(255), 667(284,287,293), 668(293), 670(255), 678(254), 685(254,284, 287,293), 686(293), 688(293), 694(254,287), 701-703(255), 704(186), 716(255,293), 720(28), 730(28), 732(284,293), 733(293), 735(284,293), 738-739(254), 739(287), 743-745(293), 744-748(287), 745(254), 748(284). 759-760(287), 760(28), 761-762(293), 762(287), 765(293), 765-770(287), 768(254,293), 805(254,293), 829(255), 830(255), 840, 841, 843, 844, 852(12.16), 854-855(30), 855(34), 861(30), 864(44,54,55), 865(54), 866(71), 868(71,80), 870(55,89), 871(54,55), 874(80,89), 878( 16), 903(30), 904(16,30,89), 905(12,89), 906-907(89), 913(44,55), 914(54,55), 9 18(44,55), 9 19(89), 920(44,55), 92 1(54,89), 924(16,89), 930(89), 943, 944, 945 Archer, M. C., 452(94), 454(94), 472(94), 541, 648(178). 841 Archer, S., 855(32), 859(32), 902(32), 905(32), 943 Arita, T., 686(361), 845 Arnold, W., 659(226), 674(226), 676(226), 690(226), 695(226), 796-797(226), 813(226), 842 Arya, P., 216(38), 335-336(318), 427 Assandri, A, 983(62,63), 1051 Attwood, M. R., 60(76), 87 Aversa, M. C., 592(135), 629 Avramenko, V. I., 248(133), 256(133,162), 262(133), 362-364(133), 423
Baba, A, 125(59), 169(59), 181 Babarevic, B., 218(34), 253(34), 342(34), 420 Bachman, G. B., 278(193), 375(193), 424 Bachmann, G., 218(33), 226(33), 339(33), 420 Baczynskyi, L., 442(27), 447(27), 474(27), 539 Baglioni, A.. 681(339), 771(339), 774(339), 795(339), 845 Bagolini, C . , 881(108), 884(108), 886(108), 924-926(108), 945 Bahlsen, J., 566(98), 570(98), 586(98), 618-619(98), 628 Baker, D. C., 130, 172(61), 181 Baker, D. R., 241(105), 245(105), 358(105), 361(105), 422 Bakulin, V. S., 99(13), 147(13), 180 Balbi, A, 223(62), 234(65), 254(156), 266(309), 334(65), 350(62), 361-363(156), 363(309), 368(156), 421, 423, 427 Ban, Y., 656(212), 842, 892(142,143), 893-896( 143), 93 1-933( 143), 935-938( 143), 946 Bandoli, G., 701(408), 846 Banfi, O., 36(43), 87 Banziger, R., 429, 667(287), 685(287), 894(287), 739(287), 744-748(287), 759-760(287), 762(287), 765-770(287), 844, 864(44), 913(44), 918(44), 920(44), 944 Bara, Y A., 992-993(88), 1037-1044(88), 1051 Baraldi, P. G., 968, 1014(31), 1050 Barchet, R., 248(132), 256,332(301), 362(132), 364(132), 419(301), 423, 427 Bardakos, V., 5(2), 59(2), 86 Barltrop, J. A, 217-218(16), 219(47), 228(16), 230(16), 234-235(16,47), 237, 335(16), 342-343(16), 355(16,47),420, 421 Baroni, D., 983(63), 1051 Barry, V. C., 238(85), 355(85), 422 Barry, W. J., 239(93), 422 Bass, R. G., 221-222(58), 327,421 Basselier, J.-J., 658(222), 659(222), 666(222), 691(222), 719(222), 738(222), 749(222), 842 Bauer, A., 243-244(118), 255(118,157,161), 259(167), 261(170), 262(167), 264(118), 268(167), 279(204), 283-285(215), 283-286(204), 288(218), 293(243,244), 294(245,246,248), 295(239,243), 297( 118,239,243,246,248,252), 299(243), 300(237), 301(243), 302(218,243), 303(246), 304(239,245,246), 305(252), 306(161), 363(118), 365-367(157,161,170), 365(167), 367(167), 368(161). 369(167), 376-378(204), 380-384(204), 38 1-383(2 15), 387-395(239,241), 390(245,246), 390-394(240), 394(245,246), 396(246),
Author Index 396-400(243), 397(245,246), 398(244), 399(244,245,248,252),400(245,247,248,252), 403(161), 422-426, 561(77), 605(77), 628, 633(19), 670(19), 731(19), 771(19), 837, 879(101,102), 883(101,102), 886(IOl), 889(126), 894(147), 926(102), 926-928(101), 934(126), 935-936(147), 945, 946, 989(74,78), 1032-1035(78), 1033(74), 1045(74), 1051 Bebenburg, W. von, 320-321(284), 324(284), 41 1-413(284), 426, 973(41), 975(42-44), 976(43-48), 977(43,44,46,48,49), 1019(41-43), 1020(43-46). 102l(43.44, 46-49), 1022(43,48,49), 1023(43), 1050, 1051 Becker, A, 218(26), 338(26), 342(26), 420 Beijersbergen van Henegouwen, G. M. J., 475-476(128), 542, 697(374-375), 846 Bell, S. C., 104, 105(27a), 152(27), 180, 448-449(41), 462(111), 463,469(41,111), 471(111), 486(178), 502(41), 504-506(41), 506(178), 507(111), 509-510(41), 522(41), 532(178), 540, 541, 543, 548(13), 599(13), 626, 635(34,35), 637(56,57,58,60), 646(153), 649(184), 652( 199-201,203), 654(56,205), 659(227), 660(34), 663(199,200), 666(34, 262,263,265), 668(34,35), 672(227,308,309), 678(,58,227,262,263,265,309,325),680( 199, 227), 68 1(60,265), 683(349), 684(262), 685(262,263,265,358),685(34,35), 686(349), 688(58,227,262,263,265,309), 689(227), 690(263), 689(227), 690(199,201), 691(199), 692(199,227,325,358), 694(263,265), 695(349), 705(455), 714(34,35), 7 17(263), 719(34), 723(34), 725(358), 726(34), 730(34), 735(56,263), 736(56), 740(56), 742(358), 753(358), 764(56), 765(358), 771-773(199), 772(263), 773(263,358), 774(227), 775(227), 776(262,263,265), 777(227), 780(199), 78 1(263), 782(227,265), 783(34), 784(358), 784-787(265), 785-787(227), 787(262,263,358), 788(35). 792(308,309), 793( 199,227,308),795(263), 797(265), 800(263,265), 802-803(265), 803(60), 809(325), 810(35), 831(455), 837, 838,840-845, 847, 864(57,58), 865(58), 868(81), 872(92), 876(92), 887(114), 887-889(113), 910(57,58), 915(92), 916(58,92), 930(113,114), 944, 945 Bellasio, E., 278-280(203), 283(203), 285-287(203), 379(203), 384(203), 424 Belvedere, G., 308(262), 401(262), 426 Benassi, R., 268,(173), 308, 424 Bendall, V. I., 34,42(37), 74-76(37), 86
1055
Bender, P., 114(42), 119(42), 121(42), 160(42), 167(42), 181 Benjamin, Sr., L. E., 440(19), 445(19), 474(19), 498(19), 519(19), 523(19), 539, 559(65), 564(65), 579(65,119), 580(119), 584(65), 606-607(65), 609(65), 622(119), 627, 629, 638(67), 660(67), 791(67), 838 Benkovic, P. A, 112(38), 115(38), 132(38, 160(38), 180 Benkovic, S. J., 112(38), 115(38), 132(38, 160(38), 180 Benndorf, G., 700(387), 846 Benz, W., 486(182), 488-489(182), 543, 701(401), 846 Berger, G., 666(269), 843 Berger, L., 448(55), 504(55), 540, 640(94), 664(94), 666(94), 686(94), 730(94), 839 Bergman, J., 656(210,21 l), 707(460,462), 833(460,462), 842, 847, 848, 877,924(97), 945 Bernareggi, A, 983(62), I051 Bernstein, J., 285(216), 379-380(216), 425 Bertimi, D., 970(34), 971(34,36), 1016-1018(34,36), I050 Bertini, D., 319-320(282), 324(282), 411-412(282), 426 Bertolasi, R., 505(198), 543 Bertolasi, V., 701(404,405), 846 Betbeder-Matibet, A,, 279(205), 306(205), 308(205), 375(205), 379(205), 384(205), 402(205), 424 Beyer, K-H., 661(240), 701(392), 842, 846 Bezjak, A, 137(86), 182. Biegert, B., 670(303), 844 Biere, H., 187(6), 198-201(6), 207 Binder, D., 989(77,79), 992-993(83-85,87,88,92), 993(95-97,99), 995-996(104-107), 996(109), 998(111-113,115), 1032-1033(77), 1035(77,84,87,88), 1037(95,97), 1038(85, 87,88), 1039(77,83-85,88,92,95-97), 1040-1042(87,88,97), 1041(77,83-85,95), 1042(85,96), 1043(84,97), 1043-1044(83,88, 95,99), 1043-1045(77), 1047(77,104-107, 109) 1048(107,111,112),1049(112,113,115), 1051,1052 Bindra, A P., 220(57), 334(57), 421 Bingham, E., 666(266,267), 673(266,267), 678(266,267), 685(266), 686(266,267), 780(266,267), 781(266), 787(267). 792-793(266), 797-798(266), 8041266,267). 843 Bird, C . W., 124, 169(57), I81 Blanton, Jr., C . D e Witt, 100(17), 148(17), 180, 633(29), 811(29), 837
1056
Author Index
Blasevic, N., 549-550(17), 626, 633(20), 635(40), 636(48), 639(20,40,81), 656(213), 666(40,81), 700(385), 721(200,732(8l), 775(40), 781-783(40), 782(20), 783(20,81), 788(20), 789(20,40), 796(40), 798(40). 837-839, 842, 846 Bleikolm, A, 950(4), 955(4), 1001(4), 1005(4), 1050
Bley, W., 700(387),846 Blicke, F. F., 193,203(1I), 205-20q1 I), 207 Blickenstaff, R. T., 248(131), 361(131), 423 Blount, J, F., 455(104), 465(120), 466-467(104), 473(120), 541, 583(126), 603(126), 605(126), 607(126), 629, 649(190), 667(277), 668(277), 678(277), 688(277), 690-691(277), 701(403,501), 7l2(473), 7 16(403), 768(403), 777(190), 785(190), 801(190), 805(277), 812(277), 814(277), 841. 843, 846, 848, 853(24), 905-906(24), 943 Bodforss, S., 243,273-274(119), 276(119). 359(119), 374(119), 422 Boeke, K., 989(76), 1033(76), 1040(76), 1045(76), 1051 Boemches, H., 641(111), 839 Boermans, P. G., 295,298,386-387(224), 425 Bogat-Skii, A. V., 429, 633(10), 640(100), 641(115), 652(202), 663(202), 666(10), 671(202,304), 680(202), 685(202), 690-691(202), 700(378), 701(100,407), 717(100,202),718(100), 721(498), 721-724(202), 722(lo), 746( loo), 751(lo), 765(498), 771(115,202), 773-774(202), 776(202), 780(202), 781(304), 782(100), 786(202), 788-789(202), 789(100), 810(115), 824(304), 827-828(304), 829(100), 837, 839, 842, 844, 846, 848 Bogentoft, C., 891(139), 932(139), 946 Boitard, J., 658(222),659(222), 666(222), 691(222), 719(222), 738(222), 749(222), 842 Bonsall, E., 136(106), 143(106), 176(106), 179(106), 182 Borea, P. A,, 701(404,405),846, 968(31), 1014(31), 1050 Borras, J., 700(382,383), 846 Bortolasi, V., 592(136), 629 Boshagen, H., 276(192), 371(192), 373(192), 424 Boswell, Jr., R. F., 667(290), 844 Boulton, k J., 429 Bourdeabx-Pontier, M., 700(388), 846 Bourseaux, F., 685(353,354), 845 Bozhanova, N. Ya., 257(164), 368-369(164), 423 Brachtel, G., 701(413), 847 Braichenko, V. T., 279(206), 375(206), 425
Branca, Q., 450-451(85), 492-493(85), 495-496(85), 512-5 15(85), 5 18(85), 525-527(85), 541, 639(80), 641(114), 659(230), 660(80,230), 666(80,230), 670(251), 681(80,230), 685, 685(80), 686(230,251), 696(251), 742(251), 751(251), 754-758(251), 775(80), 778-779(80), 783(114,251), 786(80), 799(80,251), 810(114,251), 811(230), 812-813(251), 813-814(230), 816(230), 817(80), 818-821(230), 839, 842, 843, 864(60), 872(60), 913-915(60), 918-921(60), 944, 988(71), 1032(71), 1051 Braun, W., 106(29), 154(29), 180 Breitmaier, E:, 701(397), 846 Bretschneider, H., 639(84), 668(84), 743(84), 839 Briand, C., 700(388), 846 Broadbent, H. S., 448(54), 540 Brobanski, B., 295-296(228), 299(228), 321(287), 323(287), 324(228), 389(228), 413-414(287), 425, 426 Brock, N., 685(353,354), 845 Broger, E., 650(192), 671,841,853(25),869, 905(25), 917(85), 920(85), 923(85), 943, 945, 949, lOOO(l), 1050 Brown, R. F. C.,954(11), 1005(11), 1050 Brugger, M., 107(31), 155(31), 180, 999(116), 1049(116), 1052 Brunaud, M., 640(104), 658(222), 659(222), 664(104), 666(222), 685(104), 691(222), 717(104), 719(222), 738(222), 749(222), 774(104), 778(104), 839, 842 Brust, B., 646(151), 664(256), 681(342), 683(342), 686(256), 725-727(500). 728-729(256), 753(500), 756(500), 802(256), 840, 843, 845, 848, 864(43), 866(71), 868(71), 870-871(43), 910-914(43), 916(43), 918-919(43), 944 Brynolf, A., 656(210,21l), 707(460,462), 833(460,462), 842, 847, 848, 877(97), 924(97), 945 Bub, O., 278(210), 278-279(199), 279(208,209, 323). 280(210), 284(199,208-210), 285(217), 287(217), 375( 199,323), 377(209,210), 377-378( 199,208,323),380(210), 380-383(217,323), 383(208,209), 384-385(323), 389-385(199), 424, 425, 427 Buchi, J., 295,386-387(227), 389-390(227), 395-397,425 Buckle, D. R., 293(226), 386-387(226), 389(226), 395(226), 425 Budden, R., 566(98), 569(102), 570(98), 586(98), 588(102), 600(102), 618-619(98), 628
Author Index Budylin, V. A, 249(139,140), 262(140), 267( 140), 28 I( 139), 364( 139,140), 379( 139), 423 Buniva, G., 983(62), 1051 Burdick, B. A, 112(38), 115(38), 132(38, 160(38), 180 Burger, W., 639(83), 839 Burkhardt, J., 92(1), 180 Burton, S. A, 248(126), 259(126), 369(126), 422 Buschek, J. M., 6,86 Butkiewi, K., 240(97), 339-340(97), 422 Butler, D. E., 957(13), 959(13), 960(13), 961(13), 962( 13,18,19), 963( 18-20), 964(l3,18), lOO6-1008( 13), 1011(13), 1050 Buu-Hoi, M., 45,77(53), 87 Buu-Hoi, N. P., 44(54), 76-78(54), 87 Buyle, R., 254(154,155), 363(154), 365(154), 368( 154), 370( 154), 423 Callet, G., 640(104), 664(104), 685(104), 717(104), 774(104), 778(104),839 Cambon, A. R., 218(35), 339(35), 345(35), 420 Camerman, A,, 701(402),846 Camerman, N., 701(402), 846 Camps, F., 640(103), 839 Cantello, B. C. C..293(226), 386-387(226), 389(226), 395(226), 425 Cappelletti, R., 224(70), 350(69,70), 351-356(70), 351-353(69), 421 Capuano, L., 266(312), 363(312). 427 Carabateas, P. M., 851(2,5), 860(2,5), 889(2,5), 890(2,5), 895(2,5), 901-905(2,5), 943 Carboni, S., 3 19-320(282), 324(282), 411-412(282). 426, 970(34), 971(34,36). 1016- 1018(34,36), 1050 Carlson, E. H., 700(389). 846 Cartells, J., 640(103), 839 Casagrande, C., 681(336), 695(336), 773(336), 775(336), 777(336), 779(336), 781(336), 784-785(336), 788(336), 796(336), 802-804(336), 845 Catsoulacos, P., 46(62), 80(62), 87 Caubere, P., 270(183), 371(183), 373(183), 424 Caujolle. R., 241(102), 327(296), 330-33 1(296), 358(102), 416(296), 418(296), 422, 427 Cavallito, C. J., 137(85), 182 Cazaux, L., 700-701(390), 846 Ceraulo, L., 233,267(151), 363(151), 423 Cerri, R., 50(65), 80(65),87 Chabuby, M., 245(120), 358(120), 422 Chadha. V. K., 104(2425,28), 105(24), 150- 152(24), 15 1(25,28), I80 Chan, E., 172(105),182 Chand. P., 216(38), 335-336(318), 427 Chandhary, H. S., 104-105(24), 150-152(24),
1057
180 Chandramohan, M. R., 261(169), 369(169), 424 Chang, S. Chie, 220(55), 334-335(55), 421 Channanont, P., 701(410,411,414), 846, 847 Chase, G. O.,636(50,52,5.3), 763(52), 838 Cheeseman, G. W. H., 979(50), 1024(50), I051 Chen, F. M. F., 110(34), 112-113(34), 120-121(52), 157(34), 161(34), 168(52), 180,
181 Chen, W. Y., 657(215), 685(215), 688(215), 692(2 15), 777(2 15), 797(215), 799(21 5), 800(215), 804(215), 842, 887(119), 902-903(119), 910(119), 923(119), 945 Cheng, C. C., 325(293), 415(293), 427 Cherkasov, V. M., 100(14), 148(14), 180 Chemov, V. A, 218(25), 345(25), 346(25), 347(25), 420 Chiaverelli, S., 210(268), 404(268), 426, 554(35), 596-597(35), 626, 853(26), 859(26), 872(26), 902-903(26), 943 Chidester, C. G., 442(27), 447(27), 474(27), 479-480(148), 483-485(148), 528-530(148), 539, 542, 561(74), 589(74), 602(74). 604(74), 628, 675(318), 686(363), 699(377), 700(389), 844-846 Chiguk,V.A..241(110),245(110), 356(110), 358-361(110), 422 Childress, S. J.. 429, 448-449(41), 462-463(11 l), 469(41,111), 471(111), 486(178), 502(41), 504-506(41), 506(178), 507(111), 509-510(41), 522(41), 532(178), 540, 541, 543, 557(57), 599(57), 601(57), 627, 635(34,35), 637(56), 646(153), 649(184), 652(201), 654(56), 659(227), 660(34), 666(34,262), 668(34,35), 672(227). 678,678(227), 680(227), 683(349), 684-685(262), 685(34,35), 686(349), 688(227,262), 689(227), 690(201), 69 l(227). 692(227), 695(349), 705(455), 7 14(34,35), 719(34), 723(34), 726(34), 730(34), 735-736(56), 740(56), 764(56), 774(227), 775(227). 776(262), 777(227), 782(227), 783(34), 785-786(227), 787(262). 788(35), 789(227), 793(227), 810(35), 831(455). 837, 838, 840-843, 845, 847, 852(21), 864(57,58), 865(58), 868(81), 872(92), 876(92), 887-889(113), 906(21), 910(57,58), 915(92), 916(58,92), 943-945 Chiodini, L., 16(19), 66(19), 86 Chmilenko, T. S., 248(134), 253(150), 257(150). 259(165,166), 266(150), 269(134). 28 1(134), 362( 165,166). 362-364( 134). 364(150), 366(165), 379(134), 423 Choeim. K. M., 302(231), 323(231), 371(231),
Author Index
1058
Choeim, K. M. (Continued) 389(231), 414(231), 425 Choudhury. D. R., 12,86 Chow, A. W., 306-308(260), 426 Chow, Y. L., 54(71), 82(71), 87 Christensen, S. A, 648(177), 695(177), 713(177), 841, 867(76), 870(76), 872-873(76), 91 1(76), 944 Chumachenko, T. K., 671(304), 781(304), 824(304), 827-828(304), 844 Cignarella, G., 50, 80(65), 87 Ciszewska-Jesrasik M., 700(380), 846 Clarke, G. M., 634(30), 636,721(30), 751(30), 773(30), 779(30), 837, 838 Cleghorn, H. P., 213,226(78), 421 Clemente, D. A, 701(408), 846 Clifford, D. P., 215(6), 337(6), 420 Clim, T., 640(104), 664(104), 685(104), 717(104), 774(104), 778(104), 839 Coffen, D. L., 433-436(2), 434(7), 438-439(7), 439(15), 445(7,15,30-32), 466(7), 486(7), 496(7), 496-497(2), 498(7,15), 518(7), 530(7), 532(7), 539, 557(60), 559(68), 570-571(68), 577(68), 583(60), 586(68), 588-589(68), 591(68), 596(68), 605-606(68), 608-609(68), 611(60), 615(68), 627, 675, 683(343), 702(343), 803(343), 813(343), 831(343), 844, 845 Cognacq, J.-C., 993(98), 1039(98), 1041(98), 1052 Coleman, M. W., 308,311(265), 403(265), 405(265). 426 Comar, D., 666(269), 843 Comoy, P., 640(104), 658(222), 659(222), 664(104), 666(222), 685(104), 691(222), 717(104), 719(222), 738(222), 749(222). 774(104), 778(104), 839, 842 Conalty, M. L., 238(85), 355(85), 422 Cook, Ch.. 700(391), 864 Cooney, R. C., 51(67), 87 Coplar, V., 551(31), 603(31), 609(31), 613(31), 615(31), 626 Cornelissen, P. J. G., 475-476(128), 542, 697(374-375), 846 Corral, C., 556(55), 560-561(55), 589(55), 597(55), 602(55), 604(55), 627, 879(100), 882(100), 898(152), 924-926(100), 928(100), 941(152), 945, 946 Corsico, N., 982(57), 983(57). 1027-1029(57), 1051 Crichlow, C. A, 112(104), 164-165(104), 176(104), 182 Crichton, D. D., 221-222(58), 421 Curtze, J., 245, 246(115), 356(115), 422 Czueler. M... 919(160). 946 Y
\
DAngelli, F., 107(30), 155(30), 180 Da Settimo, A, 970(34), 971(34,36), 1016- 1018(34,36),1050 Dahl, L. F., 130(65), 171(65), 181 Dandegaonker, S . H., 278(200), 376(200), 384(200), 424 Dang, Q. Q., 241(102), 327(296), 330-33 1(296), 358(102), 416(296), 418(296), 422, 427 Dang, T. B. T., 327(296), 330-331(296), 416(296), 418(296), 427 Daniel, H., 259(167), 262(167), 268(167), 365(167), 367(167), 369(157), 424, 994-995(103), 1046(103), 2052 Danielsson, B., 891(139), 932(139), 946 Danilina, N. I., 652(202), 663(202), 671(202), 680(202), 685(202), 690-691(202), 717(202), 721-724(202), 77 1(202), 773-774(202), 776(202), 780(202), 786(202), 788-789(202), 842 Danneberg, P., 243-244(118), 255(118,157, 161), 261(170), 264(118), 283-285(215), 288(218), 294(245,247), 295(236,247,249), 297(118,251), 302(218), 303(247), 304(245), 306(161), 363(118), 365-367(157,161,170), 368(161), 381-383(215), 386(236), 388(236,251), 388-389(233), 390(245), 390-394(25 I), 392(249), 393-395(236), 394(245), 395(249), 396-398(247), 397(245), 399(245), 400(245,247), 403(161), 422-426, 633(19), 670(19), 731(19), 771(19), 837, 894(147), 935-936(147), 946, 989(74,78), 1032-1035(78), 1033(74), 1045(74), 1051 Danswan, G. W., 450(78), 467(78), 509-510(78), 540, 704(439), 847 DaSettimo, A, 319-320(282), 324(282), 411-412(282), 426 Daunis, J., 3 18(279), 41 1(279), 426 Dauphinee, G. A, 120-121(52), 168(52), 181 David, J., 46(59), 48(59), 79(59), 87 Davis, R. V., 448(50), 506(50), 540, 633(9), 660(9), 666(9), 678(9), 690(9), 837 Davoll, J., 247,248(124), 258,262(124), 268(124), 272(124), 276(124), 362(124), 370-37 1(124), 373(124), 422 De Marchi, F., 678(282), 688(282,365), 733(282,365), 738(365), 745(365), 747(282,365), 792(282), 792-795(365), 795(282), 844, 845, 887(116), 930(116), 945 De Maria, R., 688(365), 733(365), 738(365), 745(365), 747(365), 792-795(365), 845, 887(116), 930(116), 945 de Stevens, G., 92, 112-115(36), 118, 119(36), 120(53,54), 121(36,49),127(36),-128(36b), 132(36a), 135-136(36a), 161-163(36), 166(49), 167(36b), 168(36,49,54), 170(36b),
Author Index 173-175(36a), 180, 181, 259(166), 362(166), 424 De Win, P., 881(108), 884(108), 886(108), 924-926(108), 945 Debaerdemaeker, T., 10(12,104), 62(104), 63(104), 86, 88 DeBaun, J. R., 241(105), 245(105), 358(105), 361(105), 422 Degen, L., 224(68), 305(256), 350-356(68), 401(256), 421, 426 Dehn, W. M., 137(84), 182 Dekow, F. W., 112(100), 163-164(100), 182 Del Giudice, M. R., 448(45), 450,451(88), 473(45), 487(88), 507-51 1(45), 513-514(45), 540, 541, 683(348), 692(348,369), 775(348, 369), 779(348,369), 780(348), 784(348), 785(348,369), 787(369), 788(348,369), 789(348), 845 Demame, H., 639(82), 667(275), 673(275), 718(82), 778(82), 792(275), 804(275), 806(275), 839, 843 DeNoble, J. P., 434(7), 438-439(7), 445(7), 46q7), 486(7), 496(7), 498(7), 518(7), 530(7), 532(7), 539, 559(68), 570-571(68), 577(68), 586(68), 588-589(68), 591(68), 596(68), 605-606(68), 608-609(68), 615(68), 627, 675(321), 844 Depin, J.-C., 279(205), 306(205), 308(205), 375(205), 379(205), 384(205), 402(205), 424 Derieg, M. E., 449(63), 478(63), 540, 554(43), 578(117), 583(43), 602(117), 603(43), 627, 628, 635(38), 646(162), 666(162,270), 667(29l), 67 1(305,306), 68 1(162), 685( 162), 692-693(291), 729(162), 752(162), 759(162), 739(291), 838, 841, 843, 844, 856(35), 864(53), 865(35), 871(35,53), 873(53), 875(35), 905-907(35), 91 l(3.5). 913(53), 913-916(35), 919-92-(35). 943, 944 Desai, G. B., 278(200), 376(200), 384(200), 424 Deschler, H., 119-120(50), 167-169(50), 181 Desimoni, G., 312(272), 405(272), 426 Desmarchelier, J. M., 112(37). 132(37), 160(37), 173(37), 180 Dettmann, H., 554(46), 469(46), 597(46), 603(46), 627, 646( 161), 841 Deucker, W., 7,20(7), 61(7), 86 DeWald. H. A., 957(13), 959(13,17), 960(13,17), 961( 13), 962(13,18.19), 963( 18-20), 964(13,17,18,21). 965(24,25), 966-968(24), 1006-1008(13), 1011(13), 1012-1013(25), 1012-1015(24), I050 Deyrup, J. A, 593(138), 625(138), 629, 707(463), 833(463), 848 Dhaka, K S., 104(25), 151(25), 180 Di Bello, C., 107(30), 155(30), 180
1059
Di Braccio, M., 247(306), 335(314), 362-363(306), 427 Di Simone, L., 448(45), 473(45), 507-5 11(45), 513-514(45), 540, 541 Diamond, J., 953(8), 1003(8), 1050 Dienel, B., 114(42), 119(42), 121(42), 160(42), 167(42), 181 Dietrich, H., 295(227), 386-387(227), 389-390(227), 395-397,425 Dill, G., 217(12), 334(12), 420 Dion, H. W., 130(63,65), 171(65), 181 Dlabac, A., 638(65), 667(65), 765(65), 768(65), 838 Doddis, W. D., 56(75), 83(75), 87 Dolce, G., 659(228), 685(228), 686(228), 842 Doldouras, G. A., 663(248), 843 Douvan, I., 633(1), 645(148), 672(148), 678( 1,148), 688(148), 713( I), 718( 148). 772(148), 780-781(148), 792(148), 837, 840, 864(59), 887(118), 910(59), 930(118), 944, 945 Duchamp, D. J., 442(27), 447(27), 474(27), 476(134), 478-480(134), 483-484(134), 526-527(134), 539, 542, 561(74), 589(74), 602(74), 604(74), 628, 675(318), 686(363), 699(377), 700(389), 844-846 Ducker, J. W., 102, 103(19), 149(19), I80 Dughi, M., 118, 121(49), 166(49), 168(49), 181 Dunphy, R. F., 701(412), 847 Durham, L. J., 130(65), 171(65), 181 Earley, J. V., 433-434(2-4), 434(6,8), 435-436(2), 436-437(8), 445(6), 448(49), 450-451(85). 457-458(49), 465( 120), 473(120), 486(180), 492-493(85), 495-496(85), 496(8), 496-497(2,3), 497(4,6), 505-506(49), 5 12-5 15(85), 5 18(85), 525-527(85), 532(180), 539-541, 543, 557(60), 558(62), 561(80), 563(88), 565(94), 569(80), 571(62), 583(60,127), 586(62), 594(143), 603(88), 611(60), 615(62), 620(94), 625(143), 627, 628, 629, 633(8), 640(96), 646(152,157), 649(190), 657(219), 660(8,157,233), 664(152), 665(8), 667(233,287,294), 668(233,300), 67 l(233, 305,306), 678(8), 68 1(342), 683(342,343), 685(8,152,287), 688(8,233), 689(294), 690(8,233), 691(152), 692(233,368), 694(152, 287), 695(8), 697(300,376), 698(300), 700(39 l), 701(415,421), 702(343,415), 704(300), 709-710(469), 711(157), 712(157), 714-7 15(l52), 716(300),724(8), 725(8), 725-727(500), 726(233), 728(8,152), 729(8), 734-735(233), 737-738(294), 739(287), 740(233), 743(233), 743-744(294),
1060
Author Index
Earley, J. V. (Continued) 744-748(287), 746-747(233), 752(8), 753(500), 756(500), 759(8), 759-760(287), 762(287,294), 765-770(287), 772(8,233), 775(8), 777(190), 781(8,233), 783(421), 785(190), 791(152), 794(233), 799(421), 801(190), 803(343), 813(343), 830(415), 831(343), 835(469), 836(157),837, 839-842, 844-848, 854(28), 864(43,44,56), 867(56,78), 870(28,43,87,88), 871(43,56), 873(78), 874(56,78), 875(88,95), 887(117), 888(121), 896(95), 898-899(28), 901(28), 903-907(28), 906(56), 910(87), 910-914(43), 910-920(28), 91 1(56), 913(44,88), 915(56,78), 916(43,56), 918(44,88), 918-919(43), 919(78), 920(44), 924(28), 930(117), 930-931(28), 939-940(28), 943-945, 954(10), 957(10,16), 958(16), 959(16), 963(10), 987(10), 988(16), 989(16), 991(16), 995(16), 1004(10), 1006(16), 1009(10,16). 101O( lo), 1011(lo), 1031(10), 1033(16), 1034(16), 1036(16), 1037(16), 1046(16), 1047(16), I050 Eberle, M. K., 973(38), 982(38), 1018(38), 1027(38), I050 Eccel, R., 552(32), 573(32), 586(32), 626 Edenhofer, A, 951(5), 1002(5), I050 Edwards, R. V., 215(6), 337(6), 420 Eichberger, E., 295(227), 386-387(227), 389-390(227), 395-397,425 Eichinger, K., 995-996(105), 998(111-113,115), 1047(105), 1048(111,112), 1O49(112, 113,115), I052 Eiden, F., 218(31,33,37), 226(33), 230-231(31), 231(37), 253(152), 335(31), 337-340(31), 339(33,37),355(31,37), 362(152), 420, 423 El Azzouny, A, 889(125), 891(125),897(125), 933(125), 945 El-Enany, M. M., 302(231), 323(231), 371(231), 389(231), 414(231), 425 El-Gency, M. A, 272(185,186), 277(185,286), 371-372(186), 424 El-Hashash, M., 27(30), 28(30), 70(30), 71(30), 86 Elkasaby, M., 27(29), 70(29), 86 Ellaithy, M. M., 592(137), 623(137), 629, 684(350), 700(350), 845 Ellefson, C. R., 224-224(63,64), 348-349(63, 64),421 Elman, B., 656(210,21l), 707(462), 833(462), 842, 848, 877(97), 924(97), 945 Eloy, F., 448-449(43), 450(74), 459(74), 505(74), 510(43,74), 512(43,74), 540, 704(431,442), 847 Elslager, E. F., 114, 127-128(44), 132(70,72), 137(70), 139(70,72), 161(44), 170(44), 174(70,72), 181
Emmert, B., 239(90), 422 Eneback, C., 582(123), 629, 675(322),845 Engle, A R., 551(29), 626, 641(123), 657(123), 840 Enkaku, M., 21(88,103), 29(32,86), 30(87), 35(91,92),39(91), 57(101), 58(101), 71-74(32), 73(87), 75(91), 84(101), 85(101), 86, 88, 110(99,101), 112(99), 157(101), 157-158(99), 182 Erdelyi, L., 36(40), 75(40), 76(40), 87 Ericsson, O., 891(139), 932(139), 946 Ermili, A, 223(62), 234(65), 247(306), 254(156), 266(309), 334(65), 335(314), 350(62), 361-363( 156), 362-363(306), 363(309), 368(156), 421, 423, 427 Evans, E. L., 434(7), 438-439(7), 445(7), 466(7), 486(7), 496(7), 498(7), 518(7), 530(7), 532(7), 539, 559(68), 570-571(68), 577(68), 586(68), 588-589(68), 591(68), 596(68), 605-606(68), 608-609(68), 615(68), 627, 675(321), 844 Evans, J. J., 278(202), 379(202), 424 Evans, N. A, 112(37), 132(37), 160(37), 173(37), 180 Evans, R. F., 112(37), 132(37), 160(37), 173(37), 180 Evans, T. W., 137(84), 182 Evenson G. N., 479-480(145), 480(158,159), 483(145), 485(145), 527-530( 149, 529(158), 542 Ezaki, N., 130(62), 171(62), I81 Fajdiga, T., 96(7), 180 Farber, S., 455(105), 541 Farrar, W. V., 117, 166(48), I81 Fatmi, A A, 633(29), 81 1(29), 837 Feher, G., 252,259(149), 267(149), 281(149), 363(149), 368(149), 423 Feifel, M., 992-993(88), 1037-1044(88), I051 Felix, A M., 135(80), 136, 175(80), 181, 547(6), 561(80), 569(80), 573(6), 600(6), 604(6), 626, 628, 646(157,158), 660(157,158), 71 1(157,158), 712( 157), 760( 158), 836( 157, 158), 841, 888(121), 945 Fentiman, A F., 448(56), 504(56), 540, 640(97), 643(97), 678(97), 684(97), 7 19(97), 749(97), 771(97), 780(97), 839 Ferrand, G., 448-449(43), 450(74), 459(74), 505(74), 510(43,74), 512(43,74),540, 704(431,442), 847 Ferrari, G., 681(336), 695(336), 773(336), 775(336), 777(336), 779(336), 781(336), 784-785(336), 788(336), 796(336), 802-804(336), 845 Ferrari, P., 983(63), 1051 Ferrarini, P.L., 319-320(282), 324(282),
This Page Intentionally Left Blank
This Page Intentionally Left Blank
A u t h o r Index 989(16), 991(16), 995(16), 1004(10), 1006(16), 1009(10,16), 1010(10), 1011(10), 1031(10), 1033(16), 1034(16), 1036(16), 1037(16), 1046(16), 1047(16),I050 Fuccella, L. M., 983(62), 1051 Fujimori, H., 254(153), 264(153), 362-363(153), 365-367(153), 423 Fujita, H., 138, 177-178(89a), I82 Fukunaga, M., 672(307), 844 Fukushima, S., 241,272(107), 284(107), 326, 327,357(107), 371-371(107), 415(295), 417(298), 422, 427 Funke, S., 555(48,49), 569(48,49,102), 572(48), 587(48), 588(48,49,102), 589(48), 598(49), 600(102), 601(48), 606(48), 608-616(48), 611(49), 613(49), 616(49), 627, 628, 647(168), 841 Furman, Yu. N., 250(143), 267(143), 362-364(143), 368(143), 423 Furuhashi, A, 238(87), 422 Fushimi, Y., 219(49), 251(49), 260(49), 355(49), 421 Gaertner, S., 712(472), 848 Gagneux, A., 472(126), 489(189), 525(126),542, 543, 665(251), 680(261), 733(261), 804(261), 843 Gajewska, M., 700(380), 846 Galatin, A F., 640(100), 701(100), 717-718(100), 746(100), 782(100), 789(100), 829(100), 839 Galdecki, Z., 701(409), 846 Galeazzi, E., 636(46), 838 Gall, M., 450(77,82), 459(77,82), 483(171), 488(82), 509(82), 509-510(77), 511(82), 540-542, 704(435,436,440,441),847 Garanti, L., 13, 15(77), 16(79), 65(18), 66(18,19,77,78), 68(79), 86, 87 Garcia, E. E., 586(128), 596-599(128), 629, 638(67), 658(223), 659(225), 660(67), 692(225), 772(223,225), 773(225), 777(223,225), 791(67), 81 1(225), 838, 842, 912( 158), 914( 158), 916-917( 158), 946, 982, 1027(56), I051 Gartner, K., 266(312), 363(312),427 Gasco, A., 213,405-406(273), 426 Gasparic, J., 686(364), 845 Gates, M., 651(194), 841, 890(131), 894(131), 896(131), 932-933(131), 935(131). 937(131), 946 Gatta, F., 272(187), 280(187), 375-376(187), 380(187), 424. 448(45), 450-451(88), 473(45), 487(88), 507-51 l(45). 513-514(45), 540, 541, 554(35), 596-597(35), 626, 683(348), 692(348,369), 775(348,369),
1063
779(348,369), 780(348), 784(348), 785(348,369), 787(369), 788(348,369), 789(348), 845, 852(9), 853(26), 858(26), 872(26), 881(9), 901(9), 902-903(26), 924-926(9), 943 Geaz-Baitz, E., 40(42), 75(42), 87 Gehrlein, L., 185, 190(1), 196(1),201(1), 207 Gerecke, M., 882-883( 11I), 886( 11I), 890(11I), 895(111), 931(111), 933-934(111), 945, 997(110), 999(1 lo), 1048-1049(1 lo), 1052 Gergel, L. G., 241(101), 268(174), 358(101), 422, 424 Gerhards, H., 452(112), 476-478(112), 512(112), 521(112), 523-525(112), 541, 702(425), 704(425), 83 1(425),847 Gerritsma, K W., 475-476(128), 542 Ghirardelli, R. G., 950(2), 1001(2), 1050 Ghosh, T. N., 127, 171(60), 181 Giacconi, P., 552(32), 573(32), 586(32), 626 Giannetto, P., 592(135), 629 Giesemann, R., 283-285(215), 295(236,249), 297(238,25I), 300(238), 381-383(2 15), 386(236), 388(238,251), 388-389(233), 390-394(25 I), 392(249), 394(238), 394-395(236), 395(249), 425, 426 Gill, J. C . , 593(138), 625(138), 629, 707(463), 833(463), 848 Gill, N. S., 27(28), 28(28), 70(28), 86 Gilli, G., 505(198), 543, 592(136), 629, 701(404,405), 846 Gilman, N. W., 455(104), 466-467(104), 541, 565(94), 620(94), 628, 633(14), 635(14,43), 700(391), 701(501), 712(473), 736(14), 837, 838, 846, 848 Giormani, V., 107(30), 155(30), I80 Giovannoni, C. A., 218(35), 339(35), 345(35), 420 Glazyrina, L. P., 218(20), 227(80), 230(20), 345(20), 420, 421 Glotz, G., 386(225), 425 Glover, G. I., 102(20), I80 Glowka, M. L., 701(409), 846 Gluckman, M. I., 429, 659(227), 672(227), 678(227), 680(227), 688(227), 691-692(227), 774-775(227), 777(227), 782(227), 785-786(227), 789(227), 793(227), 842 Glushov, R. G., 973(39,40), 1018(39), 1019(40), I050 Gochman, C., 448-449(41), 462-463(11 I), 469(41,111), 471(111), 486(178), 502(41), 504-506(41), 506(178), 507(111), 509-510(41), 522(41), 532(178),540, 541, 543, 548(13), 599(13), 626, 635(35), 649(184), 659(227), 668(35), 672(227), 678(227), 680(227), 685(35), 688(227),
1064
Author Index
Gochman, C. (Continued) 691-692(227), 714(35), 774-775(227), 777(227), 782(227), 785-786(227), 788(35), 789(227), 793(227), 810(35),837, 841,842, 864(58), 865(58), 910(58), 916(58), 944 Godot, J. -M., 666(269), 843 Gogerty, J. H., 651(195), 691(195), 742(195), 749-750( 195), 753(195), 758-760(195), 768(195), 771(195), 841, 890(129), 893(129), 932(129), 933(129), 936(129), 945 Goldfarb, I. L., 141(92), 179(92), 182 Golik, U., 117, 133(74,75,76), 137(88), 139(88), 171(88), 175(74,76), 181. I82 Gomoll, P., 881(107), 885(107), 945 Goodman, L., 312(271), 405(271), 426 Gordiichuk, G. N.. 633(10), 666(10), 722(10), 751(10), 837 Gordon, M., 448-449(42), 504-505(42), 510(42), 540 Gottlieb, J., 44,77(50), 78(50), 87 Gottschneider, H., 238(90), 422 Gould, R. O., 34(36), 86 Gould, S. E. B., 34(36), 86 Grand, M., 279(205), 306(205), 308(205), 375(205), 379(205), 384(205), 402(205), 424 Grdenic, D., 137(86), 182 Griengl, H., 950(4), 955(4), 1001(4), 1005(4), 1050
Grimes, R. M., 305(254), 426 Grimm, G., 217(13), 337(13), 420 Grinewa, N. A, 276(191), 371(191), 374(191), 424 Griot, R. G., 651(195,196), 691(195,196), 692(196), 742(195), 749-750(195,196), 753(195), 758-760(195), 759(196), 768(195), 771(195), 841. 890(129, 135), 893(129), 894(135), 932(129,135), 933(129, 135), 936(129), 945, 946 Grohe. K. 998(114), 1049(114), 1052 Groit, R., 192(9,10), 203(10), 207 Grous, P. P., 709(471), 835-836(471), 848, 896(149), 898-900(148), 940(148), 946 Grover, R., 292(317), 387(317), 427 Groves, J. A, 700(384), 846 Guameri, M., 968(31), 1014(31), 1050 Gul’tyai, V. P., 640(100), 701(100), 7 17-71 8(loo), 746(100), 782(loo), 789(IOO), 829(100), 839 Gunda, T. E., 582(123), 629, 675(322), 845 Gunter, M. J., 102,103(19), 149(19), 180 Gustafson, S., 429 Guttner, J., 242,272(113), 356(113), 373(113), 422 Gyulai, P., 123(56), 127(56), 169-170(56), 181 Gprik, F. J., 306-308(260), 426
Habeck D., 651(195), 691(195), 742(195), 749-750(195), 753(195), 758-760(195). 768(195), 771(195), 841, 890(129), 893(129), 932(129), 933(129), 936(129), 945 Habison, G., 992-993(88), 1037-1044(88), 1051
Hach, V., 675(319), 844 Haefely, W., 882-883( 11l), 886(11l), 890( 11l), 895(111), 931(111), 933-934(111), 945, 997(110), 999(110), 1048-1049(1 lo), 1052 Haertfelder, G., 633(25), 668(25), 746(25), 766(25), 769(25), 837 Hafner, K., 140-141(90), 178(90), 182 Haley, N. F., 132(70), 137(70), 139(70), 174(70), 181 Halford, J. O., 45,46-47(58), 49(58), 79(58), 87, 219(45), 343(45), 421 Haller, R., 281(213,214), 286-287(214), 385(2 13,214), 425 Hallot, A, 639(82), 667(275), 673(275), 718(82), 778(82), 792(275), 804(275), 806(275), 839, 843 Hamann, K, 92(1), 180 Hamor, T., 701(410,411,414),846, 847 Hannig, E., 218(30), 343(30), 420 Hanze, A R., 450(76), 459(76), 463(114), 512(76), 520(114), 540, 541, 633(24), 701(24), 704(24), 829(24), 837 Hara, T., 254(153), 264(153), 362-363(153), 365-367(153), 423, 459(107), 515(107), 541 Hara, Y., 638(74), 650(74,191), 656(74), 761(74), 838, 841 Haran, R., 505(199), 543, 701(395), 846 Harpenden, G. R. W., 108(98), 156(98), 182 Harris, L. S., 851(2), 860(2), 889(2), 890(2), 895(2), 901-905(2), 943 Harrison, D. R., 450(78,79,80), 467(78,79,80), 509(79,80), 509-510(78), 540, 704(437439), 847 Harter, H. P., 110(35), 112(35), 158(35), 180 Hasegawa, H., 52(70), 81(70), 87 Hashimoto, Y., 254(153), 264(153), 362-363(153), 365-367(153), 423 Hassall, C . H., 60(76), 87 Hata, T., 456(121), 541 Hauptmann, K-H., 295(236239), 297(239251), 300(239), 304(239), 386(236), 387-395(239), 388(236,251), 390-394(251), 393-395(236), 425, 426, 889(126), 934(126), 945 Hayazaki, T., 269(177,179,180), 273(190), 274( 179), 275( 190), 276(177), 277( 179,180), 371(177,179,190),424 Hayley, C. A. C., 217(15), 343(15), 420 Heckendron, R.. 665(251), 680(261), 733(261), 804(261), 843
Author Index Heindel, N. D., 897(151), 939(151), 946 Heindl, L. A., 273(188,189), 371(188), 373-374(188), 424 Heine, H. W., 136(82,106), 143(106), 176(106), 179(106), 181, 182 Heineke, H., 242, 272(113), 356(113), 373(113), 422 Heisey, L. V., 278(193), 375(193), 424 Heitzer, H., 998(114), 1049(114), 1052 Heja, G., 218(31,37),230-231(31), 231(37), 335(31), 337-340(31), 339(37), 355(31,37), 420 Hell, I., 588(129), 589(129), 629 Hellerbach, J., 434-435(5), 438(5), 440(5), 442(26), 444-445(5), 477(5), 480(5), 497(5), 501(26), 539-542, 551(28), 553-554(34, 556-557(34), 562(34), 563(89), 580(121), 582(122), 583(124), 585(34), 599(89), 602-603(34), 603(89), 609(34), 617(89), 620(89), 626, 628. 629. 635(39), 638(72). 639(39,84), 644(39,145,147), 645(72,150), 654(39), 660(236), 661(242), 667(150,236), 668(72,84,147,297), 669(150), 675(108,320, 323), 68 1(150), 684(147,150), 689(72,145, 242), 690(72,147,150,236), 691(72), 694(72, 150), 732(72), 733(236), 734-735(150), 735(72), 737(150), 739(72), 740(150), 741(72), 743(84), 743-744(150), 744-745(72), 747-748(72,236), 761-762( 150), 763-770(72), 765(150), 778(39,145), 779(145,147), 785-789( 147), 786(39,145), 794(145), 794-795(147), 796(297), 798(147, 297), 800(39, 803(39), 804-806( 147), 805(72), 809(242), 813(72,242), 814( 147), 838-840, 842-845, 852(20), 861-862(20), 864(41), 868(84), 870(84), 872(84), 872-873(41), 876(41), 906-908(20), 913(84), 914(41), 915(84), 921(41), 943, 944, 989(77,79), 1032-1033(77), 1035(77), 1039(77), 1041(77), 1043-1045(77), 1047(77), 1051 Hense, H.-J., 245(120), 358(120), 422 Herbert, J. A. L., 241,358-359(103), 422 Hershenson, F. M., 224-224(64), 348-349(64), 421 Hess, F., 98,180 Hester, Jr., J. B., 450(76), 459(76), 476(131,132, 134,135), 477(135), 478(132,134,135), 479( 141), 479-480( 134,146,148,149), 480( 150-153), 483( 141,146,148,166-170, 172,173), 483-484(134,152), 484( 172, 174-177), 484485(148,149), 488-489(187), 5 12(76), S23(131,132,135), 5 2 3 131,135), 526( 134,135,173,175), 527( 134,15O,IS2), 527-528(146), 528(149), 528-530(148),
1065
534(187), 535(131,135),540, 542, 543, 561(74,75), 563(90), 583(75), 589(74,75, 130), 602(74,75), 604(74), 617(90), 628, 629, 633(23,24), 667(271), 686(363), 701(24,416, 419,420), 702(423,424,426,428),704(24,426, 444,445,447,448,450,454), 728(23), 829(24, 416,419), 830(24,416), 836(445), 837, 843, 845, 847, 878(98,99), 945 Heubdek N. D., 220(53), 347(53), 421 Hideg, K., 242,246( 11l), 272( 111,112), 318(111), 326(111), 356-360(111), 356-357(112), 359(112), 372-373(11 I), 373(112), 375(111), 410411(111), 415(111). 422 Hideg-Hankovzky, O., 242,246(111), 272(111, 112), 318(111), 326(111), 356-36q1 Il), 356-357(112), 359(112), 372-373(1 I l ) , 373(112), 3 7 3 11I), 410-41 l(11 I), 4lS(11 I), 422 Hieda, M., 54(72), 83(72), 87 Higashi, K, 93-94(93,94), 145(93,94), 182 Hill, J. A., 547(1), 599(1), 626 Hillebrand, F., 992-993(87), 1037-1038(87). 1040-1042(87), 1051 Hills, D. W., 108(98), 156(98), 182 Hinsberg, O., 269,274,371(175). 424 Hirai, K, 979(53), 985(66), 995-996(66), 1025(53), 1030-1031(66), 1048(66), 1051 Hirai, T., 57(101), 58(101), 84-85(101), 88 Hirano, T., 219(49), 251(49), 260(49), 355(49), 421 Hirobe, M., 12(15), 86 Hirohashi, T., 553(33), 554(36,38,40), 599(38), 601(36), 626, 635(37), 639(86,89), 641(116-117,122,124-126,129,130,132), 642(125), 646( I S ) , 667(86,89,285,286,289), 713-716(86), 717( 116). 718( 124). 720(86), 722(86), 726(86), 729(86), 73 1-734(86), 733(285), 736(89), 739(125), 740(86), 741(86,89,124), 742(285), 743(86,289), 744(86,89,125), 745(86), 746-747(86, 125), 748-749(285), 749(86,124), 754(86), 759(86), 760(285), 761-762(86), 763(89,125), 765-767(86), 766(126), 768(89,116,130), 769(86,125), 770(86,89), 787(86), 797(86), 803(86), 838-841, 844, 866(72), 892(144), 922-923(72), 933( 144), 944, 946, 992(93), 994(93,102), 1037- 1038(93), 1038(102). 1041- 1042(93), 1052 Hirose, K., 664(260), 692(260), 773(260), 776-777(260), 780(260), 784(260), 786(260), 788(260), 800(260), 802(260), 832(260), 843, 867(74), 874-876(74), 922-923(74), 944 Hirsbergs, I., 218-219(29). 234(29), 343-344(29), 420
1066
Author Index
Hishikana, T., 190-191(12), 202(12), 207 Hlavaty, J., 592(137), 623(137), 629 Ho, S. S., 547(3), 572-573(3), 584(3), 596(3), 599-602(3), 604(3), 626 Hoch, J. M., 217(304), 218(304), 341(304), 247 Hoffmann, E., 889(128), 931(128), 945 Hoffmann, H., 595(145), 629 Hoffmann, I., 295(250), 3 16(321), 388(250), 391(250), 408-409(321), 409-410(322), 426, 42 7 Hoffmann, K, 247,248(127), 267(127), 281(125,127), 361(127), 362(125), 422 Hoffmeister, F., 998(114), 1049(114), 1052 Hofman, P. S., 42(48), 76(48), 87 Hofmann, H. P., 285(217), 287(217), 380-383(217), 425 Holan, G., 278(202), 379(202), 424 Hollywood, F., 433(1), 496(1), 539, 707(460), 707-708(461), 833(460), 833-834(461), 847, 848 Holubek, J., 448(56), 504(56), 540, 636(49), 638(65), 667(65), 718(49), 765(65), 768(65), 838 Hong, W.-H., 964(22), 967(30), 1013(30), 1050 Hoppe, J. O., 855(32), 859(32), 902(32), 905(32), 943 Hornyak, G., 92 Horowski, R., 187(6), 198-201(6), 207 Horvath, G., 40(42), 75(42), 87 Houlihan, W. J., 103(22), 149-150(22), 180, 633( 17), 651( 195), 667(17), 691( 199, 715(17), 717(17), 742(195), 749-750(195), 753(195), 758-760(195), 768(195), 771(195), 837, 841, 890(129), 893(129), 932(129), 933(129), 936(129), 945, 973(38), 982(38), 1018(38), 1027(38),1050 Howells, J. D., 130(63), 181 Hromadko, S. F., 218(27), 230(27), 234(27), 343(27), 420 Hromatka, O., 119-120(50), 167-169(50), 181, 986(67), 989(77,79), 992-993(83-85,87, 88,92), 993(95-97,99), 995-996(104-107). 996(109). 997,998(111-113,115), 1028(67), 1032(67), 1032-1033(77), 1035(77,84,87, 88,95,97), 1038(85,87,88),1039(77,83-85, 88,92,95-97), 1040-1042(87,88,97), 1041(77,83-85,95), 1042(85,96), 1043(84, 95, 97,99), 1043-1044(83,88), 1043-1045(77), 1044(95,99), 1047(77, 104-107,109), 1048(107,111,112),1049(112, 113,115),1051, 1052 Hsi, R. S. P., 476(133), 525(133), 542, 638(63), 701(418), 704(418), 829(418), 838, 847 Huber, A, 214(2), 215(2), 337(2), 420 Hueschens, R., 647(167,168),841
Huetteman, R. E., 305(255), 426 Hufner, E., 214(3), 215(3), 337(3), 343(3), 420 Hughes, J. L., 193,203(11), 205-206(1 l), 207 Huhsam, 217(11), 336(11), 337(11), 420 Hull, R., 433(1), 496(1), 539 Hunger, A, 247,248(127), 267(127), 281(125, 127), 361(127), 362(125), 422 Hunkeler, W., 882-883( 11l), 883(112), 886(11l), 890(111,112), 895(111,112), 898(112), 925-926(112), 929(112), 931(111, 112), 932(112), 933-934(111,112), 940(112), 945, 972(37), 977,979(37), 997(110), 999(1 lo), 1018(37), 1023(37), 1024(37), 1048-1049(110), 1050, 1052 Hunter, P. W. W., 226(79), 238(88,89), 243(117), 246(117), 247(122), 272(117), 277(117,122), 343-344(79), 357(117,122), 358(122), 371(117), 421, 422 Huschens, R., 555(48,49), 566(98), 569(48,49, 102,107), 570(98), 572(48), 586(98), 587(48), 588(48,49,102,129),589(48,129), 598(49), 600(102), 601(48), 606(48), 608-616(48), 61 1(49), 613(49), 616(49), 618-619(98), 627, 628, 629 Iacobelli, J., 557(56), 627, 890(132,134), 895(132), 931(132, 134), 935(132), 946 Ibrahim, M. A, 27(29), 70(29), 86 Ichii, T., 269(178), 273(178), 275(178), 371(178), 424, 855-856(33), 859(33), 861(33), 901-902(33), 943 Igeta, H., 13(17), 22(17a), 23(17a), 25(17a), 29(17), 52(70), 65(17), 68(17), 69(17), 81(70), 86, 87 Iitaka, Y., 130(64), 171(64), 181 Ikeda, M., 25(25), 26(25), 41(46), 67(25), 76(46), 86, 87 Ikeda, T., 892(142,143), 893-896(143), 931-933(143), 935-938(143), 946 Inaba, S., 547(8), 553(33), 554(36-38,40), 557(58,59), 561(82), 573(37,11l), 596-597(8), 599(37,38,59), 600(37), 601(8, 36,58,59,11I), 602(59), 603(37,59), 605(59, 11l), 609(59), 61 1(58),626-628, 635(37), 639(85,86,89), 641(1 16- 122,124- 126, 129-133), 642(125,133), 646(155, 1-56), 661(241), 666(268), 667(86,89,268,285,286, 289), 713-716(86), 717(116),718(124), 720(86), 722(86), 726(86), 729(86), 731-734(86), 733(285), 736(89), 739(125), 740(86), 741(86,89,124), 742(285), 743(86, 289), 744(86,89,125), 745(86), 746-747(86, 125), 748-749(86,285), 749( 124), 754(86), 759(86), 760(285), 761-762(86), 763(89, 125), 765-767(86), 766(126), 768(89,116.
Author I n d e x 130), 769(86,125), 770(86,89), 787(86), 797(86), 800(241), 803,838-841, 843, 844, 852(14,15), 860(15,40), 863(40), 866(72), 892(144), 904(14), 905(14), 906(15), 907(15.40), 919-920(40), 922-923(72), 933(144), 943, 944, 946, 992(93), 994(93, 102), 1037-1038(93), 1038(102), 1041- 1042(93), 1052 Inotsume, M., 993-994(101), 1052 Inotsume, N., 686(361,362), 845 Inoue, I., 880(104,105), 883(105), 925(104), 927-928(104,105), 945 Iorio, L. C., 651(195). 691(195), 742(195), 749-750(195), 753(195), 758-760(195), 768(195), 771(195), 841, 890(129), 893(129), 932(129), 933(129), 936(129), 945 Isaev, S. D., 641(115), 771(115), 810(115), 839 Isenbruck G., 251(147), 363(147), 423 Ishaba, T., 979(53), 1025(53), 1051 Ishiba, T., 985(66), 995-996(66), 103C-1031(66), 1048(66), 1051 Ishibashi, H., 25(25), 26(25), 67(25), 86 Ishihara, H., 326(295), 327(298), 415(295), 417(298), 427 Ishikawa, F., 93-94(93,94), 128(102), 140, 145(93,94), 171(102), 178(102),182 Ishikura, M., 892(142,143), 893-896(143), 931-933(143), 935-938(143), 946 Ishimori, F., 106(95), 154(95), 182 Ishizumi, K., 553(33), 554(36-38,40), 557(58, 59). 561(82), 573(37), 599(37.38,59), 600(37), 601(36,58), 601-603(59), 603(37), 605(59). 609(59), 626, 627, 628, 639(85,86, 89), 641(117-121,125,126,131-132), 642(125), 646(155,156), 667(86,89,286), 713-716(86), 720(86), 722(86), 726(86), 729(86), 731-734(86), 736(89), 739(125), 740(86). 741(86,89), 743(86), 744(86,89, 125), 745(86), 746-747(86,125), 749(86), 754(86), 759(86), 761-762(86), 763(89,125), 765-767(86), 766(126), 768(89), 769(86, 125), 770(86,89),787(86), 797(86), 803(86), 839-841, 844, 852(14,15), 860(15,40), 863(40), 866(72), 904(14), 905(14), 906( 15), 907(40), 907(15), 919-920(40), 922-923(72), 943, 944 Israel, M., 248(135), 267(135), 318,318(280, 281). 322, 324(292), 325(277,280,281,290, 292), 326,330-331(294), 364(135), 410-41 1(277,281). 41 1(280), 413-414(290), 415(294), 423, 426, 427 Itoh, K., 254(153), 264(153), 362-363(153), 365-367(153), 423, 459(107), 515(107), 541 Itoh, N., 459(107), 515(107),541 Itterah, P. I., 881, 945
1067
Ittyerah, P. I., 281(211), 376(211), 425 Iturrian, W. B., 633(29), 81 1(29), 837 Ivanov, B. E., 99(13), 147(13), 180 Ivanova, R. Yu., 671(304), 781(304), 824(304), 827-828(304), 844 Iwagaya, K., 326(295), 415(295), 427 Izumi, T., 554(38,40), 557(59), 573(11 l), 599(38,59), 601(111), 601-603(59), 605(59, l l l ) , 609(59), 626, 627, 628, 639(86,89), 641( 124,129,130,132), 666(268), 667(86,89, 268,286,289). 7 13-7 16(86), 7 14( 124). 720(86), 722(86), 726(86), 729(86), 731-734(86), 736(89), 740(86), 741(86,89, 124), 743(86,289), 744(86,89), 745-747(86), 749(86,124), 754(86). 759(86), 761-762(86), 763(89), 765-767(86), 768(89,130), 769(86), 770(86,89), 787(86), 797(86), 803(86), 839, 840, 843, 844, 852(14), 904(14), 905(14), 943 Jackson, D., 215(6), 337(6), 420 Jagnicinski, B., 889(128), 931(128), 945 Jain, S. M., 215(7), 237(7), 337(7), 343(7), 420 Jakovlev, V., 973(41), 1019(41), 1050 James, K. B., 27(28), 28(28), 70(28), 86 Jansen, M., 701(413), 847 Japelj, M., 96(7), 180 Jaques, P., 979(50), 1024(50), 1051 Jaross, K., 135(78), 179(78), 181 Jaunin, R., 583(124), 629, 645(150), 659(226). 667(150), 669(150,302), 674(226), 675, 676(226), 681(150), 684(150), 690( 150,226), 694(150), 695(226), 734-735(150), 737(150), 740(150), 743-744(150), 761 -762(150), 765(150), 796-797(226), 813(226), 840, 842, 844, 845, 868(84), 870(84), 872(84), 888(120), 913(84), 915(84), 930-931(120), 944, 945, 953,979, 1003(9), 1004(9), 1026(9), 1050 Jeffrey, P., 215(6), 337(6), 420 Jehn, W., 241(104), 246(121), 358(104,121), 422 Jen, T., 114(42), 119(42), 121(42), 160(42), 167(42),181 Johns, R. B., 112(37), 132(37), 160(37), 173(37),180 Johnson, A. W., 547(1), 599(1), 626 Johnson, Jr., A. F., 221-222(58), 421 Johnson, T. D., 476(133), 525(133), 542, 701(418), 704(418), 829(418), 847 Johnston, C., 967(30), 1013(30), 1050 Jones, G., 98,147(9), 180, 186, 197(3), 207 Jones, L. C., 248(135), 267(135), 318(277,280, 281), 322,324(292), 325(277,280,281,290, 292). 364(135), 410-41 1(277,281),41 1(280), 413-414(290), 423, 426, 427
1068
Author Index
Joos, R., 933(165), 946 Joshi, B. C., 219(46), 292(317), 343-344(46), 387(317), 421,427 Joshi, K. C., 216(38), 335-336(318). 427 Joullie, M. M., 247(128), 248(130,135). 267( 128,135), 281( 128), 361( 128), 362( 130), 364(135), 422, 423 Jurkowska-Kowalczyk, E., 241,357(108), 422 Kache, R., 216(9), 337(9), 420 Kadyrov, Ch. Sh., 278(198), 379(198), 384(198), 424 Kaegi, H., 554(41), 627, 639(83), 839 Kaga, S., 889(122),945 Kahling, J., 675(315), 695(315), 821-828(315), 844 Kajfez, F., 549-550(17), 550(24,26), 551(24,26, 31), 603(31), 607(24), 609(24,31), 613(24,31), 615(24,31), 626, 633(20), 635(40), 636(48), 639(20,40,81), 641(112), 656(213), 666(40, 81). 681(334), 685(356), 690(334), 692(334, 356), 701(393),732(81), 773(112,334,356), 775(40), 776(334), 776-777(356), 779(356), 781(40,334,356), 782(20,40,112,334), 783(20,40,81), 784(334,356), 787(356), 788(20), 789(20,40,356), 796(40,334), 796-798(356), 797(334), 798(40), 801-804(334), 802(356), 804(356), 837-839, 842, 845, 846 Kajtar, M., 864(63), 872(63), 917(63),922(63), 944 Kalinowski, H. O., 701(394,398),846 Kalish, R. I., 547(5), 572-573(5), 584(5), 5), 626, 633(13,28), 646(28), 666(13), 713(13), 716(13), 719(13), 720(28), 730(28), 750(13), 760(28), 837, 856(36), 909(36), 943 Kalman, A, 919(160), 946 Kamada, T., 554(42), 569(42), 582(42), 603(42), 627, 647(163), 841 Kamdar, B. V., 255(159), 262(159), 306-308(159), 365-366(159), 403(159), 423, 441(25), 444(25), 450(77,82), 459(77,82), 488(82), 501(25), 509(82), 509-510(25,77), 51 1(82), 520(25), 527(25), 539-542, 674(313), 690(313), 701(416), 704(313), 776(313), 829-830(416), 830(313), 844, 847 Kamioka, T., 672(307), 844 Kanematsu, K., 29(31), 51(68), 71(31), 81(68), 86.87 Kano, A, 219(49), 251(49), 260(49), 355(49), 421 Karapetyan, A. A, 701(407), 846 Karaseva, T. L., 868(79), 944 Karle, 1. L., 918(159), 946
Karle, J., 918(159), 946 Kassab, M M., 272(185), 277(185), 424 Katagiri, N., 241(315), 362(315), 427 Kataoka, T., 51(68), 81(68), 87 Kathawala, F. G., 693(370), 845 Kato, E., 29(31), 71(31), 86 Kato, H., 13(24), 25(24), 67(24), 86, 187(5), 190-191(12), 194(5), 197-198(5), 202(12), 204(5), 207 Kato, T., 241(315), 362(315), 427 Katonak, D. A, 434(7), 438-439(7), 445(7), 466(7), 486(7), 496(7), 498(7), 518(7), 530(7), 532(7), 539, 559(68), 570-571(68), 577(68), 586(68), 588-589(68), 591(68), 596(68), 605-606(68), 608-609(68), 615(68), 627, 675(321), 844 Katritzky, A. R., 429 Katsube, J , 866(72), 922-923(72), 944 Katsuki, I., 866(72), 922-923(72), 944 Kawahara, K, 554(42), 569(42), 582(42), 603(42), 627, 647(163), 841 Kawai, M., 269(180), 277(180), 424 Kawano, Y., 672(307), 844 Kawasaki, C ,979(51,52), 1025(51,52),1051 Kay, D. P., 450(78), 467(78), 509-510(78), 540, 704(439), 847 Kayama, Y., 254(153), 264(153), 362-363(153), 365-367(153), 423 Kazama, S., 241,272(107), 284(107), 357(107), 371-371( 107), 422 Kazantseva, V. M., 220(52), 338-339(52), 342-343(52), 421 Kebrle, J.. 247,248(127), 267(127), 281(125, 127), 361(127), 362(125). 422 Keck, J., 666(264), 671(264), 674(314), 675(315). 681(264,314). 684-685(264), 688(264), 690-691(314), 695(315), 776(264), 787(264), 800(314), 802(314), 821(314), 821-828(315), 824-825(314), 843, 844 Kehr, J. R., 224-224(63), 348-349(63), 421 Kehr, W., 187(6), 198-201(6), 207 Keller, O., 448-449(34,38,40), 461(34), 469(34. 40), 502(34), 503-508(38), 504-506(34), 505(40), 508(34), 510(38), 51 1(34), 520-521(34), 521(38), 539, 540, 633(7), 640(93), 643(93), 660(7,93), 666(7,93), 684(7,93), 686(7,93), 72 1-723(7), 725(7). 728-729(7), 752(7), 791(7), 837, 839, 864(46), 870(46), 912(46), 918(46), 944 Kempton, R. J., 551(29), 626, 641(123), 657(123), 840 Kennewell, P. D., 450(78), 467(78), 509-510(78), 540, 704(439), 847 Kern, J., 218(19), 343(19), 348(19), 420 Kevshina, K. V., 218(20,21,22,25), 230(20),
Author Index 238(2 l), 345(20,21,25), 346(2 1,25), 347(25), 420 Khakimova, N. K., 278(198), 379(198), 384(198), 424 Khalifa, M., 302(231), 323(231), 371(231), 389(23 I), 414(23 I), 425 Khan, W. A, 685(357), 695(357), 774-776(357), 781-782(357), 845 Khan, Z. U., 433(1), 496(1), 539, 707-708(461), 833-834(461), 848 Khilya, V. P., 306,307(259), 402(259), 426 Khimyuk S. I., 257(163), 365(163), 368-369(163), 423 Kiehl, G., 10(104), 52(69), 54(69,73), 62(104), 63(104), 81-83(69), 87, 88 Kim, D. H., 851(1,6), 858(37), 859(6), 860(1,6,37), 861(6,37), 876-877(6), 890(l,6,130), 895(1,6), 901(1,6,37), 902(6), 903(37), 931(130), 934(130), 943, 945, 979, 1025(54), 1051 King, F. E., 215(4), 337(4), 420 King, T. J., 547(1), 599(1), 626 Kinugasa, R,124(58), 169(58), I81 Kiprianov, A I., 306.307(259), 402(259), 426 Kirmani, M. Z., 891(140), 932(140), 946 Kisch, H., 4, 59 (l), 86 Kisfaludy, L., 864(63), 869(86), 871(86), 872(63,86,90), 874(86), 876(90), 91 1(90), 9 15(86,9O),9 16(90), 9 17(63,86,90), 919-921(86,90). 922(63), 944, 945 Kishimoto, F., 616(241), 800(241), 843 Kishimoyo, T., 638(73), 838 Kitagawa, S., 667(289), 743(289), 844 Kitzen, J. M., 112(100), 163-164(100), 182 Kloster, G., 686(359), 694(359), 845 Klyg~l,T. A, 640(100), 701(100), 717-718(100), 721(498), 746(100), 765(498), 782(100), 789(100), 829(100), 839, 848 Knobloch, W., 271(184), 276(184), 371(184), 424 Knoll, F., 950(3), 1001(3), 1050 Knollmuller, M., 119-120(50), 167-169(50), 181 Kobayashi, G., 223(319), 347(319), 364(319), 42 7 Kobayashi, S., 467(123), 541, 675(316,317), 844 Kobayashi, T., 553(33), 554(36,38,40), 599(38), 601(36), 626, 641(125,132), 642(125), 646(155), 739(125), 744(125), 746-747(125), 763(125). 769(125), 840, 841 Kobzareva, 0.V., 671(304), 781(304), 824(304), 827-828(304), 844 Koch, W., 970-971(35), 979, 1016-1017(35), 1025(35). 1050 Koechlin: B: A. 452(98), 475(98), 541,
1069
657(216), 842 Koenig, E., 220(50), 335(50), 342-343(50), 421 Koga, H., 12(15), 86 Kohl, H., 633(25), 668(25), 746(25), 766(25), 769(25), 837, 890(136), 932-936( 136), 946 Kohri, N., 686(361), 845 Kolbah, D., 633(20), 635(40), 636(40), 639(20), 666(40), 721(20), 775(40), 781-783(40), 782-783(20), 788(20), 789(20,40), 796(40), 798(40), 837, 838 Kollonitsch, J., 663(248), 843 Kolos, N. N., 240(310), 357(310), 427 Komatsu, S., 238(87), 422 Komatsu, T., 650(191), 841 Komlos, E., 36(40), 75(40), 76(40), 87 Kornogortseva, L. V., 700(378), 846 Kondakova, M. S., 141(92), 179(92), 182 Kondo, S., 130(64,66), 171(64), 181 Konno, T., 93-94(93,94), 145(93,94),182 Konowal, A, 700(385), 846 Korosi, J., 36(40,43), 39,40(42,94), 67(94), 75(40,42), 76(40), 87, 88 Korotenko, T. I., 701(407), 846 Korshunov, S. P., 220(52), 338-339(52), 342-343(52), 421 Korte, F., 107(31), 155(31), 180, 220(56), 343(56), 348(56), 421, 999(116), 1049(116), 1052 Kosasayama, A. 93(93). 94(94), 145(93,94), I82 Koshinaka, E., 190-191(12), 202(12), 207 KOSCA. N., 241(101), 248(137), 249(138-140), 253(150), 257(150), 262(140), 266(150), 267(137,140), 268(174), 278-279(201), 281(137-139), 358(101), 364(137-139, 140,150), 375-376(201), 379(137-139). 380(201), 422-424 Kovac, T., 681(334), 685(356), 690(334), 692(334,356), 701(393), 773(334,356), 776(334), 776-777(356), 779(356), 781(334, 356), 782(334), 784(334,356), 787(356), 789(356), 796(334), 796-798(356), 797(334), 801-804(334), 802(356), 804(356), 845, 846 Kovacs, C. A., 278(197), 375(197), 424 Kovar, K.-A, 670(303), 701(397), 844, 846 Koyama, G., 130(64), 171(64), 181 Kraatz, U., 220(56), 343(56), 348(56), 421 Kramer, U., 11(14),64(14), 86 Krapcho, J., 259(165), 281(212), 284-285(212), 362(165), 366(165), 376(212), 379-380(212), 423, 425, 851(4), 860(4), 889(127), 902(4), 932(127), 943, 945 Krausz, F., 640( 1lo), 780( 1lo), 783( 1 lo), 839 Krauter, W., 216(9), 337(9), 420
1070
Author Index
Kravchenko, A. I., 218(25), 345(25), 346(25), 347(25), 420 Kreiskott, H., 285(217), 287(217), 380-383(217), 425 Kreling, M.-E., 93(2), 95(2a,6), 144(2a,c,6), 145(6), 180 Krueger, G., 666(264), 671(264), 674(314), 675(315). 681(264,314), 684-685(264), 688(264), 690-691(314), 695(315), 776(264), 787(264), 8OO(314), 802(314), 821(314), 821-828(315), 824-825(314), 843, 844 Kuch, H., 295(250),388(250), 391(250), 426 Kuchar, M. C . J., 448(35,54), 539, 540 Kuchenbecker, H., 569(107), 628, 647(167), 841 Kuhn, F. J., 288(218), 302(218), 425, 894(147), 935-936( 147). 946, 989(74,76,78), 1032-1035(78), 1033(74,76), 1040(76), 1045(74,76), I051 Kules, M., 218(34), 253(34), 342(34), 420 Kulkarni, S. U., 218(38,39), 338(38), 340-342(38,39), 343(38), 345(39), 347(39), 420 Kumar. S . , 219(46), 343-344(46), 421 Kume, Y., 557(59), 573( 11l), 599(59), 601(111), 601-603(59), 605(59,111), 609(59), 627, 628, 639(86,89), 666(268), 667(86,89,268,285,286),7 13-7 16(86), 720(86), 722(86), 726(86), 729(86), 731-734(86), 733(285), 736(89), 740(86), 741(86,89), 742(285), 743(86), 744(86,89), 745-747(86), 748-749(285), 749(86), 754(86), 759(86), 760(285), 761-762(86), 763(89), 765-767(86), 768(89), 769(86), 770(86,89), 787(86), 797(86), 803(86), 839, 843, 844, 852(14), 866(72), 904(14), 905(14), 922-923(72), 943, 944 Kurasawa, Y., 256(305), 362(305), 369(305), 42 7 Kurata, G., 979(52), 1025(52), 1051 Kurihara, T., 101(96), 106(95), 150(96), 154(95), 182, 984(64), 1029(64), 1051 Kurilenko, L. K, 100(14), 148(14), 180 Kurita, J., 13(17), 18(21,22), 20(83,102), 21(88,103), 22(20,21), 23(84,85), 24(85), 25(17a,b,23),26(17b), 29(17), 35(92), 39(91), 65(17), 66(22), 67(21,23,84), 68(17), 69(17,22), 75(91), 86, 87, 88, 110(99), 112(99), 157-158(99), 182 KurzJ., 251(148), 363(148), 423 Kuwada, Y., 445(29), 447(29), 448(47), 450(83,84), 452(95,96), 453(99), 454(102,103), 462(109), 463(115), 463-464(113), 467(102,103), 463(99), 464(117), 469(99), 470(95,124),
47 I-474(99), 479(47,136-140,142). 480( 136), 483(47,136- 140,165), 484( 138, 140,165),487( 142), 502-503(95,96,99), 503(47,109), 509-511(83,84), 520(113,115), 520-522(117), 522(102,103), 526(139,142), 526-527(47,136,137,140), 527( 165), 529(136,137,140),529-530(47), 532(142), 539-542, 559(69), 562(69), 563(87), 569(69), 580(120), 607(69), 61 1(69), 617(87,120), 627-629, 640(109), 645(149), 647( 164,165), 649( 181,182,185,186,187), 655(208), 690(182), 701(109), 704(186), 706(149), 718(149), 735(109), 783(149), 785(149), 786(109), 787-788(149), 803(149), 831(109), 832(149), 839-842 Kuzel, H., 27,69(27), 86 Kyburz, E., 537(202), 543, 882-883( 11l), 88q11 l), 890(11 l), 893(145), 895(111,145), 896(145), 931(11I), 933-934(111,145), 935(145), 945, 946, 972(37), 977.979(37), 997(110), 999(110), 1018(37), 1023(37), 1024(37), 1048-1049(110), 1050, 1052 L'Italien, Y.J., 965(27), 1013(27), 1050 Lacan, M., 218(34), 253(34), 342(34), 420 Lallaz, L., 270(183), 371(183), 373(183), 424 Lambert, R. W., 60(76), 87 Lambie, A J., 248(126), 259(126), 369(126), 422 Lampert, K., 92 Lampert-Sreter, M., 36(44), 87 Landgraf, F., 639(75), 762(75), 838 Landi-Vittory, R., 852(9), 881(9), 901(9), 924-926(9), 943 Landi-Vottory, R., 272(187), 280(187), 375-376(187), 380(187), 424 Lane, D. W. J., 248(126), 259(126), 369(126), 422 Lang, T., 36(40,43), 40(42,94), 67(94), 75(40,42), 76(40), 87, 88 Langbein, A, 989(76), 1033(76), 1040(76), 1045(76), 1051 Lange, S. M., 130(65), 171(65), I81 Lape, H., 855(32), 859(32), 902(32), 905(32), 943 Lappe, P., 194(13), 206(13), 207 Lauer, R. F., 490(192), 543, 560(73), 571(73), 580(73), 584(73), 607(73), 615(73), 627 Laufer, P., 686(359), 694(359), 845 Lavergne, J.-P., 314(274), 315(274,275), 316(276), 318, 406-407(274,275), 408(275), 41 1(279), 426 Lavrushin, V. F., 240(310), 357(310), 427 Lawton, G., 60(76), 87 Lazzeretti, P., 268,(173), 424
Author Index Le Bris, M. T., 278(195,196), 375(195.196), 424 Le Count, D. J., 108(32), 180 Le Goff, E., 220(57), 334(57), 421 Le Mew, J., 640(104), 658(222), 659(222), 664(104), 666(222), 685(104), 691(222), 717(104), 719(222), 738(222), 749(222), 774(104), 778(104), 839, 842 Lee, C.-M., 851(7), 890(7), 895(7), 902(7), 904(7), 943 Lee, C. R.. 94(5), 145(5), 180 Lee, D. Y., 312(271), 405(271), 426 Lee, G. E., 112(103), 164(103), I82 Lee, J., 448-449(37), 505(37), 540, 633(5), 666(5), 695(5), 721-723(5), 725-726(5), 751(5), 837 Lee, J. B., 634(30), 636(51), 721(30), 751(30), 773(30), 779(30), 837, 838 Lee,T. B. K., 112(103), 164(103), 182 Lehn, J. M., 700(386), 846 Lehr, E., 989(76), 1033(76), 1040(76), 1045(76), 1051 Lehr, H., 429 Leierer, F., 992-993(88), 1037-1044(88), 1051 Leimgruber, W., 635(42), 688(42), 690(42), 725(42), 735(42), 753(42), 838, 929(163), 934(163), 936-937(163), 946 Lemke, T. F., 633(23), 728(23), 830(23), 837, 897(151), 939(151), 946 Lempert, K., 123(56), 127(56), 169-170(56), I81 Levitan, P., 635(43), 838 Levshina, K V., 227(80), 421 Lewis, T. R., 855(32), 859(32), 902(32), 905(32), 943 Lewschina, K. W., 276(191), 371(191). 374(191), 424 Lida, S., 35, 75(90), 88 Lieck, A, 45,77(52), 87 Liepmann, H., 554-556(47), 555(48,49,51), 556(51), 566(98), 569(48,49,102), 570(47,98), 572(48), 587(48), 579(51), 586(98), 587-590(47), 588(48,49.102.129), 589(48,5 I, 129), 598(49), 600(48,51,102), 606(48), 608-616(48), 610-614(47), 611(49), 6 13(49), 6 l4(48), 6 15(49), 6 18-61 9(98), 627, 628, 629, 647(166,168), 841 Lietz, G., 271(184), 276(184), 371(184), 424 Lin, A. J., 288(219), 386(219), 425 Linand, A. L., 217(304), 218(304), 341(304), 42 7 Linden, D., 701(397), 846 Lindner, H. J., 141(91), I82 Linke, S., 251(148), 423 Linscheid, P., 700(386). 846 Linton, M., 278(202), 379(202), 424
107 1
Lio, A, 218(28), 229(81), 343(28). 420, 421 Lions, F., 27(28), 28(28), 70(28), 86 Lip, H. C., 239(91), 422 Lisini, A, 701(393), 846 Lisitsyna, A. I., 868(79), 944 Liszkiewicz, H., 273(320), 276(308), 316(320), 372-373(320), 374(208), 427 Littell, R., 640(92), 718(92), 721(92), 726(92), 729(92), 749(92), 753(92), 759(92), 767(92), 839, 970,975,978, 1016(33), 1020(33), 1023(33), 1024(33), I050 Livi, 0..319-320(282), 324(282), 41 1-412(282), 426, 970(34), 97 1(34,36), 1016-101 8(34,36), I050 Lloyd, D., 213, 214(1), 217(1), 218(1), 226(1, 76,78), 227(1), 234(1), 238(1), 308, 308(264,266), 31 1(270), 336(1), 342( l), 343(1), 345-347(1), 403(263,264,266), 405(270), 420, 421, 426 Lobbestael, S., 957(13), 959(13,17), 960(13,17), 961( l3), Y62( l3,18), 963( 18). 964( 13,17,18), 1006-1008(13), 1011(13), 1050 Loer, B., 114(42), 119(42), 121(42), 160(42), 167(42), 181 Lohmann, W., 701(394,398). 846 Long, Jr., L., 332,419(303), 427 Lopresti, R. J., 671(306), 844 Lovelette, C. A,, 332,419(303), 427 Luckner, M., 889(125), 891(125), 894-895(146), 897(125), 933(125), 938(146), 945, 946 Luders, H.. 387(222), 425 Ludovici, D. W., 136(106), 143(106), 176(106), 179(106),182 Lugowska, E., 700(380), 846 Lukovits, I., 681(337), 775-776(337), 785(337), 788(337), 845 Luttringer, J. P., 9(10), 10(104), 62(10,104), 63(104), 86, 88 Lutz, K., 217(18), 227(18), 226(75), 420, 421 Lynton, H., 701(412), 847
MacKellar, F. A, 675(318), 844 Mackie, R. K, 308(266), 403(266), 426 Madan, P. B., 450(87), 452(87), 475(87), 479-480(87), 486-491(87), 505(87), 518(87), 520(87), 531-532(87), 541, 683(344,346), 702(346), 709-710(344), 835(344), 845, 89q 137). 896( 137). 899( 153). 933-934( 137), 941(153), 946 Madronero, R., 556(55), 560-561(55). 561(76), 589(55,76), 597(55,76), 602(55), 604(55), 627, 628, 879(100), 882(100), 898(152), 924-926(100), 928(100), 941(152), 945, 946 Maeda, K, 130(64,66), 171(64), 181
1072
Author Index
Maffrand, J.-P., 448-449(43), 450(74), 459(74), Maruyama, I., 553(33), 554(36,38,40), 599(38), 505(74), 510(43,74), 512(43,74), 540, 601(36), 626, 639(86,89), 641(124- 126,129, 704(431,442),847 130,132), 642( 129, 667(86,89,286,289). Magdesieva, N. M., 218(32), 234(32), 343(32), 713-716(86), 718(124), 720(86), 722(86), 420 726(86), 729(86), 73 1-734(86), 736(89), Maggi, R., 295(234), 297(234), 386-388(234), 739(125), 740(86), 741(86,89,124), 390-393(234), 425 743(86,289), 744(86,89,125), 745(86), Magidson, 0.Yu., 100(15), 148(15), 180 746-747(86,125), 749(86,124), 754(86), Maier, K. A, 986(67), 1028(67), 1032(67), 1051 759(86), 761-762(86), 763(89,125), Maitland, P., 217(15), 343(15), 420 765-767(86), 766( 126), 768(89,130), Maki, A, 269(177), 273(190), 275(190), 769(86,125), 770(86,89), 787(86), 797(86), 276(177), 37 1(177,190),424 803(86), 839-840, 844 Maksay, G., 639(78), 681(337),775-776(337), Marx, D., 659(228), 685(228), 686(228), 842 Maselli, A., 50(65), 80(65), 87 785(337), 788(337), 838, 845, 864(42), Mason, C.,440(19), 445(19), 474(19), 498(19), 913(42), 944 Malik P. A., 44(49), 47(49), 76(49), 87 519(19), 523(19), 539, 558-559(63), 559(65), Malik, S . H., 309(267), 403-404(267), 426 564(65), 564-566(63), 565-566(95), Malinovskii, M. S., 279(206), 375(206), 425 569-570(63), 571(95), 572-575(63), 579(65), Mallory, W. R., 32(33,89), 73(33), 86, 88 580(63), 584(65), 585(63), 589(63), 605-607(63), 606-607(65), 608(95), Malorni, A. 308(262). 401(262), 426 609(63,65), 618-622(63), 619-621(95), 627, Manami, T., 124(58), 169(58), 181 Mandel, B. J., 434(7), 438-439(7), 445(7), 628 Massarani, E., 224(68,70), 305(256), 466(7), 486(7), 496(7), 498(7), 518(7), 530(7), 532(7), 539, 5.59(68), 570-571(68), 350(68-70). 351-356(68,70), 351-353(69), 401(256), 421, 426 577(68). 586(68), 588-589(68), 591(68), 596(68), 605-606(68), 608-609(68), 615(68), Masuda, T., 452(96), 464(117), 502-503(96), 627, 674(321),844 520-522(117), 541, 559(69), 562(69), Mandrup, M., 452(97), 541, 594-595(141), 569(69), 580(120), 607(69), 611(69), 625(141), 629, 648(176), 695(176), 717(176), 617(120), 62% 629, 647(165), 650(191), 841 Masui, M., 186(2), 196(2a), 207 841, 867(75), 872(75), 876(75), 916(75), Materne, C., 950(3), 1001(3), lo50 920(75), 944 Manfredini, S., 968(31), 1014(31), 1050 Mathur, S . S., 8(9), 86 Manghisi, E., 640(102), 689(102), 695(102), 839 Matsuda, Y.,223(319), 347(319), 364(319), 427 Mann. F. G., 281(211), 376(211),425, 881,945 Matsugashita, S., 25(25), 26(25), 67(25), 86 Matsuki, H., 988(72), 1033(72), I M I Manning, R. F., 104(26), 151-152(26), I80 Mannschreck A., 239(95), 268(95), 422 Matsumoto, H., 650(193), 651(193), 664(260), 681(193), 685(193), 692(260), 695(193), Mariani, L., 278-280(203), 283(203), 706(457), 713-714(193), 720(193), 773(260), 285-287(203), 379(203), 384(203), 424, 982(57,58), 983(57,58,60,61), 984(60,61), 776-777(260), 780(260), 784(260), 786(260), 1027- 1029(57), 1028(60), 1029(60,61), 1051 788(260), 800(260), 802(260), 832(260,457), Maricq, J., 907(157), 946 841. 843, 847, 867(74), 874-876(74), Marischler, G., 992-993(84), 1037(84), 876(96), 922-923(74), 944, 945 Matsumoto, M., 218(28), 229(81), 343(28), 420, 1039(84), 1041(84), 1043(84), lo51 Marshall, D. R., 214(1), 217(1), 218(1), 421 Matsumura, Y., 218(28), 343(28), 420 226(1,76), 227(1), 234(1), 238(1), 308, Matsuo, H., 988(68), 989(68), 1032-1035(68), 308(263,264), 311(270), 336(1), 342(1), 1045- 1046(68), 1M I 343(1), 345- 347(1), 403(263,264), 405(270), 420, 421, 426 Matsuo M., 450(73), 455, 486(181), 488(73,181, Marsico, Jr., J. W. 153-154(97), 182 186,188), 489( 181,186,188), 505(73), Martin. I. L., 701(410,411,414),846, 847 511(73),514-515(73), 534-536(181,186), Martin, L. L., 112(100,104), 163-164(100), 535(73), 540, 543, 638(73), 648(179), 164-165(104), 176(104), 182 668(179), 701(179), 702(179,427), 703(179), Martin, M. I. G., 700(381), 846 725(179), 830(179), 838, 841, 84% 865(66), Martin, P. K., 889(123), 893-895(123), 898-899(66), 916(66), 939(66), 944 Matsushima, H., 41(46), 76(46), 87 937-938(123), 945
Author Index Maupas, B., 684(351), 700(351), 845 Maupas, R., 568(100), 628 Mauri, F., 634(31), 659(3 1,229), 690(366), 721(31), 774(366), 777(366), 786(366), 837, 842, 845 Maziere, M., 666(269), 843 Mazzei, M., 247(306), 335(314), 362-363(306), 42 7 McCaully, R. J., 637(56,59), 640(101), 652(199,200), 654(56,206,207), 657( 101), 659(227), 663(199,200), 666(265), 672(227), 678(227,265,327,328), 680( 199,227,333), 68 1(265,327,328,338,340), 684(206,207), 685(207,265), 686( 101,206,207), 688(227, 265), 689(101,227), 690(199), 691-692(199, 227), 694(265,328), 705(455), 706(457,458), 735-736(56), 740(56), 746(59), 764(56), 771(59), 771-773(199), 773(338), 774(227), 775(227,333),776(265,328), 777(227), 780(199,206), 782(227,265,328,338), 784-785(265,328), 785(227), 786( 101,227, 265,338), 787(265), 788(338), 789(227), 793(199,227), 797(265,328), 800(265), 802-803(265,328), 809-810( 101), 831(455), 832(457), 838, 842, 843, 845, 847, 8&1(64). 872(92), 876(92), 887(114), 914(64), 915-916(92), 930(114), 944,945 McDougall, R. H., 214(1), 217(1), 218(1), 226(1), 227(1), 234(1), 238(1), 308, 308(263), 309(267), 336(1), 342(1), 343( I), 345-347( l), 403(263,267), 404(267), 420, 426 McGuire, J. L., 305(253,254), 426 McKay, A. F., 93(2), 95(2a,6), 144(2a,c,6), 145(6), 180 McLean, J. R., 132(72), 139(72), 174(72), I81 McManus, J. M., 261(168), 363(168), 369(168), 424 McMillan, F. H., 638(62), 666(62), 741(62), 838 McNab, 308(264,266), 403(264,266), 464 Meetz, H. K, 221-222(58), 421 Meguro, K, 445(29), 447(29), 448(47), 450(83,84), 452(95,96), 453(99), 454(102, 103), 463(99,115), 463-464(113), 464(117), 467( 102,103), 469(99), 470(95,124), 47 1-474(99), 479(47,136- 140,t42), 480( 136), 483(47,136- 140,16S), 484( 138, 140,165), 487(142). 502-503(95,96,99), 503(47), 509-511(83,84), 520(113,115), 520-522(117), 522(102,103), 526(139.142), 526-527(47,136,137,140), 527(165), 529(136,137,140), 529-530(47), 532(142), 539-542, 559(69), 562(69), 56387,569(69), 580(120), 607(69), 611(69), 617(87,120),
1073
627-629, 640(109), 645(149), 647(164.165), 649(181,182,185,186,187),655(208), 690(182), 701(109), 704(186), 706(149), 718(149), 783(149), 735(109). 785(149), 786(109), 787-788(149), 803(149). 831(109), 832(149), 839-842 Meier, R., 665(251), 680(261), 733(261), 804(261), 843 Meltzer, R. I., 455(105), 541 Mendez, J. H., 700(381), 846 Menziani, E., 213(273), 405-406(273), 426 Mercier, J., 640(104), 664(104). 685(104), 717(104), 774(104), 778(104), 839 Merenyi, R., 116(45), 165(45), 181 Mertes, M. P., 288(219), 386(219), 425 Merz, H., 283-285(215), 296(237), 297(238), 300(238), 381-383(215), 387-395(237,241), 388(238), 388-389(233), 394(238), 396-397(237), 425 M e n , K. W., 248(132), 256,281(213,214), 286-287(214), 329(300,301), 330(300), 362(132), 364(132), 385(213,214), 41 8(300), 419(301), 423, 425, 427 Metlesics, W., 448-449(34.38), 461(34), 469(34), 502(34), 503-508(38), 504-506(34), 508(34), 510(38), 51 l(34). 520-.521(34). 521(38), 539, 540, 561(83,84). 563(83,84), 570(83,84), 571(83), 573(1 10). 583(83), 585(83), 586(83,1to), 587(84,110), 591(83,84), 599(83,84). 601-605(83), 602(84), 603(1 lo), 605(1 lo), 609(83), 615(83,110), 628, 633(2), 640(2), 662(247), 663(250), 665(250), 666-667(2), 679(250), 687(250), 714(2), 716(2), 718(2), 720-723(2), 726(2), 728-729(2), 731(2), 732(250), 733(2,250),735(2),742(2), 75 1(2), 753-754(2), 759(2), 768(250), 782-783(2), 786-790(2), 837, 843, 853(23,27), 904-905(23), 925(23), 927-928(23), 934(23), 943 Meyer, H., 64(111), 839 Meyer, R., 386-387(220,221). 387(222). 425 Middleton, W. J., 643(142), 644(144), 656(144), 666( 142,266,267), 673(266,267), 678(266, 267),684(142), 685( 142,266), 68q266,267), 780(266,267), 78 1(266), 787(267), 792-793(266), 797-798(266), 804(266,267), 832(142), 840, 843 Migliara, O., 233,267(151), 363(151), 423 Mihalic, M., 550(24,26), 551(24,26), 607(24), 609(24), 613(24), 615(24), 626 Mikami, I., 638(74), 650(74), 656(74), 761(74), 838 Milkowski, W., 554-556(47), 555(48,49,5I), 556(5l), 566(98), 569(48,49,102,107),
1074
Author Index
Milkowslu, W. (Continued) 570(47,98). 572(48,134), 587(48), 579(51), 586(98), 587-590(47), 588(48,49,102,129), 589(48,51,129),592( 134), 598(49), 600(48, 51,102) 606(48), 608-616(48), 610-614(47), 61 1(49), 613(49), 614(48), 615(49), 618-619(98), 627, 628, 629, 647(166-168), 841 Miller, A,, 224-224(63), 348-349(63), 421 Millward, S., 136(81), 181 Minakowa, S. M., 276(191), 371(191), 374(191), 424 Minamikawa, J., 41(46), 76(46), 87 Minck, K., 243-244(118), 255(118,157,161), 264(118), 294(245,247), 295(247), 297(118,252), 303(247), 304(245), 305(252), 306(161), 363( 118), 36S-367( 1S7,161), 368( 161), 387-395(241), 390(245), 394(245), 396-398(247), 399(245,252), 400(245,247. 252) 403(161), 422, 423, 425. 426, 633(19), 670(19), 731(19), 771(19), 837 Minoli, G., 312(272), 405(272), 426 Miroshnichenko, N. S. 322(288), 413(288), 426 Misiti, D., 272(187). 280, 375-376(187), 380(187), 424, 852(9), 881,901(9), 924-926(9), 943 Mitchell, E., 3, 92, 213, 429 Mitra, A. K., 701(396),846 Mitsuhashi, IC,859(39), 943 Miyadera, T., 456(121), 541, 672(307), 844, 865(67), 922(67), 944 Miyahara, T., 979(52), 1025(52), 1051 Miyano, H., 448(47), 479(47), 483(47), 503(47), 526-327(47), 529-530(47), 540, 640(109), 701(109), 735(109), 786(109), 831(109), 839 Miyatake. IC,889(122), 945 Mochalov, S. S., 633(21), 713(21), 719(21), 837 Modest, E. J., 318,(277), 324(292), 325(277, 292). 326(294), 330-331(294), 410-411(277), 415(294), 426, 427 Moehler, H., 882-883( 11I), 886(1 1l), 890( 11l), 895(111), 931(111), 933-934(111), 945, 997(1 lo), 999(110), 1048-1049(110), I052 Moffett, R. B., 255(159), 262(159), 306-308(159), 365-366(159), 403(159), 423, 441(25), 444(25), 450(66,67,69), 458(67), 464(66,67,118,119), 465(65), 467, 479-480( 145), 480(156,157),482(160), 483(145,164), 484(164), 485(145), 501(25), 502-503(66), 503(118), 509-510(25), 518(66,67), 520(25,67), 520-521(66), 527(25,164), 527-530(145), 529(156,157, 160), 539-542, 640(98), 667(296), 673(310-312), 674(313), 678(330), 690(313), 701(417), 702(423), 703(310), 704(296,313,
417,433,434,449), 706(449), 72 1(98), 724(98), 733(311,312), 736(311,312), 739(311,312), 741(311,312), 743(31 I), 761(311), 763(296), 776(313), 804(311), 829-830(417), 830(313), 839, 844, 845, 847 Mohammed, Y. S., 894-895(146), 938(146), 946 Mohrbacher, R. J., 709(471), 835-836(471), 848, 896(149), 898-900(148), 940(148), 946 Moller, T. T., 493-494(197), 538(197), 543, 595(144), 629 Monoury, P. M. J., 667(281), 741(281), 843 Monro, A. M., 308,311(265), 403(265), 405(265), 426 Mooney, E. F., 239(93), 422 Moore, J. A,, 3, 92, 213,429 Morck, H., 301,404(269), 426 Morgan, N. J., 293(226), 386-387(226), 389(226), 395(226), 425 Mori, K., 553(33), 554(36,38), 557(59), 561(82), 599(38,59), 601(36,59), 602-603(59), 605(59), 609(59), 626-628, 639(85,86,89), 641(120, 125,126,131-133), 642(125,133), 646(155,156),667(86,89), 7 13-716(86), 720(86). 722(86), 726(86), 729(86), 731-734(86), 736(89), 739(125), 740(86), 741(86,89), 743(86), 744(86,89,125), 745(86), 746-747(86,125), 749(86), 754(86), 759(86), 761-762(86), 763(89,125), 765-767(86), 766(126), 768(89), 769(86,125), 770(86,89), 787(86). 797(86), 803(86), 839-841, 8.52(14), 860(40), 863(40), 866(72), 904(14), 905(14), 907(40), 919-920(40), 922-923(72), 943, 944 Mori, M., 892(142,143), 893-896(143), 93 1-933(143), 935-938(143). 946 Mori, T., 187(5), 194(5), 197-198(5), 204(5), 207, 254(153), 264(153), 362-363(153), 365-367(153), 423 Morimoto, A, 190(8), 202(8), 207 Morinaga, K., 326(295), 327(298), 415(295), 417(298), 427 Moriyama, H., 547(8), 596-597(8), 601(8), 626, 635(37), 838 Morrison, Jr., R. W., 32(89), 73(33), 86, 88 Motion, K. R., 38(99), 88 Motoki, S. M., 219(49), 251(49), 260(49), 355(49), 421 Muchowski, J. M.. 636(46), 838 Mueller, P. M., 633(5), 666(5), 695(5), 72 1-723(S), 725-726(5), 75 1( S ) , 837, 866(73), 872(73), 907(73), 910-912(73), 915(73), 917(73), 919(73), 944 Mueller-Calgan, H., 659(228), 685(228), 686(228), 842
Author Index Muhlstadt, M., 21q8). 270(182), 375(182), 420, 424 Mukai, T., 35, 75(90), 88 Mukhopadhyay, A. K., 701(396), 846 Muller, E., 281(213,214), 286-287(214), 385(213,214), 425 Muller, M., 448-449(37), 505(37), 540 Muller, W., 220(56), 343(56), 348(56), 421 Muller-Westerhoff, U., 140(90), 141(90a), 178(90), 182 Munakata, T., 988(68), 989(68), 1032-1035(68), 1045-1046(68), I051 Munro, D. P., 36(97,98), 38(99), 56, 77(98), 84-85(100), 88 Murata, K., 219(49), 251(49), 260(49), 355(49), 421 Murayama, I., 646(155), 841 Murray, S. J., 34(38), 86 Mushkalo, L. K, 241,241(110), 242,245(100, 110,120).356(110), 357-359(100), 358-361(110), 358(120), 361(100), 422 Nagai, M., 656(212), 842 Nagarajan, K., 46(59), 48(59), 79(59), 87 Nagata, H., 547(8), 596-597(8), 601(8), 626, 635(37), 838 Nagawa, Y., 464( 117), 520-522( 117), 541, 580(120), 617(120), 629 Nahm, S., 16, 17(81), 67(81), 69(81), 87 Nair, M. D., 44(49), 47(49), 76(49), 87 Najer, H., 667(281), 741(281),843 Nakamura, H., 130(64), 171(64), 181 Nakanishi, M., 988(69,70,73), 989(69,75), 990(73,80,8l), 992-993(86,89,94), 993( loo), 1033(75), 1033-1035(70), 1035(75,80,81), 1036(80,81), 1039(94), 1039-1044(86), 1041(89,100), 1042-1044(94), 1043(89,100), 1051, 1052 Nakano, M., 686(361,362), 845, 993-994(101), 1052 Nakatani, M., 238(86), 422 Nakatsuka, I., 554(42), 569(42), 582(42), 603(42), 627, 647(163), 841 Nalimova. Yu. A, 219(42), 338(42), 421 Nano, G. M., 213(273), 405-406(273), 426 Nardi, D.. 223(316), 224(67,68,70,71), 225(72), 235(67), 268,(173), 335(72),250(145), 305(256), 3Oq145), 308(262), 341-342(316), 350(67-71), 351-356(68,70), 351-353(69), 353(67,71), 362(145), 401(145,256262), 421, 423, 424, 426, 427 Nastasi, M., 3 Nasu, K, 101(96), I06(95), 150(96), 154(95), 182 Natsugari, H., 450(84), 453(99), 462(109),
1075
463(99,115), 463-464(113), 469(99), 470(124), 471-474(99), 479(142), 487(142), 502-503(99). 503(109), 509-51 1(84), 520(113,115), 526(142), 532(142), 541, 542, 645(149), 649(182,187), 655(208), 690(182), 706(149), 718(149), 783(149), 785(149), 787-788(149), 803(149), 832(149), 840-842 Nauta, W. T., 42(48), 76(48), 87 Nawojski, A, 3, 92, 218(24), 240(99), 248(136). 267(136), 273(99,320), 276(308), 281(136), 316(320), 318, 320(283,285). 322,323(283), 325(278), 346-347(24), 357(99), 364(136), 372-373(320), 373(99), 374(308), 379(136), 41 1(278,283), 412(285), 413(289), 414(283), 420, 422, 423, 426, 427 Nawocka, W., 218(24), 240(99), 248(136), 267(136), 273(99,320), 276(308), 281(136), 320(283), 323(283), 346-347(24), 357(99), 364(136), 372-273(320), 373(99), 374(308), 379(136), 41 1(283), 414(283), 420, 422, 423, 426, 427 Nedenkov, P., 452(97), 493-494(197), 538(197), 541, 543, 594-595(141), 595(144), 625(141), 629 Nedenskov, P., 648(176), 660(239), 695(176), 717(176), 841, 842, 867(75), 872(75), 876(75), 916(75), 920(75), 944 Nelsen, S. F., 6, 6(3,4,5,6), 60(3,4), 86 Neszmelyi, A, 40(42,94), 67(94), 75(42), 87, 88 Neuenschwander, M., 110(35), 112(35), 158(35), 180 Neumann, P., 217(17), 343(17), 420 Newbold, G. T., 248(126), 259(126), 369(126), 422 Nicolaus, B. J. R., 278-280(203), 283(203), 28.5-287(203), 379(203), 384(203), 424 Nielsen, J. I., 226(77), 231(83), 421 Niemczyk, H., 565(97), 622(97), 628 Niida, T., 130(62), 171(62), 181 Ning, R. Y.,430, 448(49), 450(87), 450-451(85), 452(87), 453(100), 457-458(49), 472(100), 475(87), 479-480(87), 486-491(87), 492-493(85), 495-496(85), SOS(87), 505-506(49), 5 12-51 5(85), 5 18(85,87), 520(87). 525-527(85), 531-532(87), 540, 541. 543, 547(5), 559(70,71), 569(101,104), 572-573(5), 584(5), 585(104), 586(70), 588(70,71), 590(70,71), 591(104,131), 596(101), 597(104), 600(5), 602(101.131), 603(104), 604(101), 610-61 1(70,7l), 612(71), 613(70,71), 626-629, 633(8,11,28), 634(33), 635(1 I), 639(11,33), 646(28), 647(169), 649(189), 657(215,218,219), 660(8), 661(244), 663(252), 665(8). 667(169),
1076
Author Index
Ning, R. Y. (Continued) 670(189), 678(8). 678-679(189), 683(344, 346). 684(189), 685(8,33,215,252), 686(360), 688(8,215), 690(8), 692(215), 694(252), 695(8,11,33), 696(218,372), 702(346), 709-710(344), 720(11,28), 721(252), 722(33). 723(33,218), 724(8), 725(8,252), 726(1 l), 727(33,360), 728(8,252), 729(8), 730(28), 738(1l), 747(189,252), 751-754(252), 752(8), 759(8), 760(28), 762(189), 772(8), 775(8), 777(215), 780(33, 252), 781(8,33), 792(189), 794(189), 797(215), 799-800(215), 804(215), 830(33), 835(344), 837, 841-843, 845, 846, 864(48), 887(119), 890(137), 896(137), 899(153), 902-903(119), 910(119), 911(48), 923(119), 933-934(137), 941(153), 944-946, 985, 1030(65), I051 Noble, A. C., 3, 92, 184, 213, 429 Noe, C. R., 992-993(83,87,88), 1037(87,88), 1038(87,88), 1039(83,88), 1040-1042(87,88), 1041(83), 1043(83,88), 1044(83,88), 1051 Noell, C. W., 325(293), 415(293), 427 Nogas, J. A, 992-993(82), 1039(82), 1041(82), 1043(82), I051 Noll, K-R., 666(264), 671(264), 674(314), 675(3 15), 681(264,314), 684-685(264), 688(264), 690-691(314). 695(315), 776(264), 787(264), 800(314), 802(314), 821(314), 821-828(315), 824-825(314), 843, 844 Nordin, I. C., 965(27), 966(28,29), 969(32), 1013(272829), 1014(28,29), 1015-1016(32), 1050 Normant, H., 26(26a), 70(26), 86 Noro, K., 241,272(107), 284(107), 326(295), 327(298), 357(107), 371-371(107), 415(295), 417(298), 422, 427 Noro, T., 326(295), 327(298), 415(295), 417(298), 42 7 Novack, R. M., 660(232), 678(232), 688(232). 741(232), 793(232), 842 Nover, L., 889(125), 891(125), 897(125), 933(125), 945 Nudelman, A, 666(265), 678(265,327,328), 680(333). 681(265,327,328,338.340), 685(265), 688(265), 694(265,328), 706(457), 773(338), 775(333), 776(265,328), 782(265,328,338), 784-785(328), 784-787(265), 786(338), 788(338), 797(265, 328), 800(265), 802-803(265,328), 832(457), 843, 845, 847, 887(114), 930(114),945 Nuhn, P., 700(387), 846 Nussbaum, A, 683(347), 845 Nyberg, W. H., 325(293), 415(293). 427
Oberhansli, W. E., 583(124), 629, 675(323), 845 OCallaghan, C. N., 219(48), 235(48), 237, 238(48,85), 355(48.85), 421, 422 Oelschlager, H., 595(145), 629 Oetvoes, L., 68 l(337). 775-776(337), 785(337), 788(337), 845 Ogata, M., 650(193), 651(193), 664(260), 681(193), 685(193), 692(260),695(193), 705-706(456), 713-714(193), 720(193), 773(260), 776-777(2@), 780(260), 784(260), 786(260), 788(260), 800(260), 802(260), 832(260), 841, 843, 847, 867(74), 874-876(74), 876(96), 922-923(74), 944, 945 Ogino, S., 661(241), 800(241), 843 Ogura, M., 256(305), 362(305), 369(305), 427 Ohme, R., 41,43(45), 44(45), 49(45), 76(45), 80(45), 87 Ohno, M., 130(64,66),171(64), 181 Ohshiro, Y., 124,125(59), 169(58,59), 181 Oine, T., 880(104,105), 883(105), 925(104), 927-928(104,105), 945 Ojha, N. D., 137(87), 177(87), 182 Okajima, S., 30(87), 73(87), 88, 110(99,101), 112(99), 157(101), 157-158(99), I82 Okamoto, T., 12(15), 86, 553(33), 554(36-38, 40),557(59), 573(37,111), 599(37.38,59), 600(37), 601(36,59,11l), 602(59), 603(37, 59), 605(59,11I), 609(59), 626, 627, 641(1 18,125,132),642( 125). 646(155). 666(268), 667(268), 739(125), 744( 125), 746-747(125), 763(125), 769(125), 840, 841, 843, 852(14), 904(14), 905(14), 943 Okamoto, Y., 98(10), 147(10), 180, 223(60), 235(60), 256(305), 334(59,60), 335(60), 350(59,60), 362(305), 369(305), 421, 427 Oklobdzija, M., 685(356),692(356),773(356), 776-777(356), 779(356), 78 1(356), 784(356), 787(356), 789(356), 796-798(356), 802(356), 804(356), 845 Omar, N. M., 243( 116), 272(116,185,186). 277(185,286), 357(116), 371-372(186),422, 424 Omura, K.. 54(72). 83(72), 87 Orioli, P.L., 239(91), 422 Orlov, V. D., 240(310), 357(310),427 Osdend, T. S., 709(465-467) 834(467), 835(465), 848, 851(3), 852(8,1I), 878(3.8), 88l(lI,l09,110), 898(3,8), 901(3,8), 903(1 I), 927(11,109). 941(3,8),943, 945 Osterhout, K. R., 136(106), 143(106), 176(106), 179(106), 182 Ott, E., 98,180
Author Index Otvos, L., 639(78), 838, 864(42), 913(42), 944 Ouchi, A., 238(86,87), 422 Pachter, I. J.,448-449(42), 504-505(42), 510(42), 540 Pacifici, L., 881(108), 884(108), 886(108), 924-926(108), 945 Pacini, P. L., 950(2), 1001(2), 1050 Padwa, A, 16, 17(81), 67(81), 69(81), 87, 185, 190(1), 196(1), 201(1), 207 Pagani, G., 278-280(203), 283(203), 285-287(203), 379(203), 384(203), 424 Palenschat, D., 187(6), 198-201(6), 207 Pallos, F. M., 241(105). 245(105), 358(105), 361(105), 422 Palosi, E., 864(63), 869(86), 871(86), 872(63,86,90), 874(86), 876(90), 91 1(90), 9 15(86,9O), 9 16(90), 9 17(63,86,W), 919-921(86,90), 922(63), 944, 945 Pandolfi, C., 450-451(88), 487(88), 541, 683(348), 692(348), 775(348), 779(348), 780(348), 784(348), 785(348), 788(348), 789(348), 845 Pant, U. C., 219(46), 343-344(46), 421 Paquette, L. A,, 187, 188(4), 194-195(4), 201(4), 205-206(4), 207 Pardoen, J. A, 136(106), 143(106), 176(106), 179(106), I82 Paschelke, G., 187(6), 198-201(6), 207 Pasdeloup, M., 700-701(390), 846 Pastor, R. E., 218(35), 339(35), 345(35), 420 Pastour, P., 995-996(108), 1047(108), 1052 Paterson, W., 231(84), 288,289, 335(84), 422 Pathak, V. N., 216(38), 335-336(318), 427 Patrick, J. E., 305(253,254),426 Pattison, I., 638(62), 666(62), 741(62), 838 Paul, H.-H., 701(394,398), 846 Paul, S. M., 680(331), 736(331), 770(331), 845 Paulrnier, C., 995-996(108), 1047(108), 1052 Peacock, V., 6(3), 60(3), 86 Peaston, W., 218(19), 343(19), 348(19), 420 Pennini, R., 223(316), 225(72), 250,306(145), 335(72), 341-342(316), 362(145), 401(145). 421, 423, 427 Perazzi, A,, 983(62,63),I05I Percival, A, 248(126), 259(126), 369(126), 422 Perez, C. G., 700(381), 846 Periotto, V., 968(31), 1014(31), 1050 Perricone, S. C., 114(44), 127-128(44), 132(70,72), 137(70), 139(70,72), 161(44), 170(44), 174(70,72), 181 Perry, C. W., 531(200), 543 Peseke, K., 225(73,160), 305(257,258), 307(160,261), 335(73), 370(160), 385(160),
1077
402(257,258), 421, 423, 426 Petra, A, 701(396), 846 Petruso, S., 233,267(151), 363(151), 423 Pewar, R. A, 215(7), 237(7), 337(7), 343(7), 420 Phillips, M. A, 386(223), 425 Pi, J., 640(103), 839 Pieper, H., 666(264), 671(264), 674(314), 675(315), 681(264,314), 684-685(264), 688(264), 690-691(314), 695(315), 776(264), 787(264), 800(314), 802(314), 821(314), 821-828(315), 824-825(314), 843, 844 Pieri, L., 882-883(11 I), 88q11 I), 890( 11l), 895(111), 931(111), 933-934(111), 945, 997(110), 999(110), 1048-1049(110), I052 Pikalov, V. L., 249(139,142), 250(143,144), 256(162), 267( 142-144), 28 1(139,144), 362(143), 363(143,144), 364(139), 368(142, 143), 379(139,144), 423 Pirola, O., 295(234), 297(234), 386-388(234), 390-393(234), 425 Pisareva, V. S., 220(52), 338-339(52). 342-343(52), 421 Pitirimova, S. G., 219(42,43), 220(43), 238(43). 338(42,43), 339(43), 421 Piutti, A, 137(83), 181 Pixner, G.,995-996(106,107), 1047(106,107), 1048(107),1052 Plati, J. T., 899-900(154), 941-942(154), 946 Plernpel, M., 276(192), 371(192), 373(192), 424 Plumbo, R., 983(62), I051 Podesva, C., 638(64), 838, 892,935(141), 946 Poetsch, E., 659(228), 685(228), 686(228), 842 Pohl, J., 685(353,354), 845 Polc, P., 882-883(11 I), 886( 11I), 890( 11l), 895(111), 931(111), 933-934(111), 945, 997(110), 999(110), 1048-1049(110), I052 Pollitt, R. J., 94(5), 145(5), I80 Polovina, L. N., 241(101), 278-279(201), 358(101), 375-376(201), 380(201), 422, 424 Pook, K.-H., 259(167), 262(167), 268(167), 293(244), 294(245,248), 297(248,252), 300(245), 305(252), 365(167), 367(167), 369(157), 390(245), 394(245). 397(245), 398-399(244), 399(245), 399-400(247,252), 400(245), 424, 425, 426 Pool, W., 663(252), 685(252), 694(252), 721(252), 725(252), 728(252), 747(252), 751-754(252), 780(252), 843 Popp, F. D., 3, 49(64), 51(64), 80(64), 87, 92, 184, 213, 429 Poschel, B. P., 957(13), 959-962(13), 964(13), 1006- 1008(13). 1011(13), I050 Potoczak, D., 132(72), 139(72), 174(72), I81
1078
Author Index
Potter, G. W. H., 308,311(265),403(265), 405(265), 426 Potts, K. T., 12,27(28), 28(28), 70(28), 86 Prenant, Ch., 666(269), 843 Preti, C., 700(379), 846 Pribega, L. V., 248(133), 249(142), 256(133), 262(133), 267(142), 362-364(133), 368(142), 423 Prikazchikova, L. P., 100(14), 148(14), 180 Prikhod'ko, N. M., 248(137), 267(137), 281(137), 364(137), 379(137), 423 Prischl, G., 950(4), 955(4), 1001(4), 1005(4), 1050 Proctor, G. R., 231(84), 288,289,335(84), 422 Protiva, M., 448(56), 504(56), 540, 636(49), 638(65), 667(65), 718(49), 765(65), 768(65), 838 Puar, M. S., 651(197,198), 679(198), 692( 197,198), 693(198), 749(198), 759(198), 841 Pujari, H. K., 104-105(24), 104(25,28), 150-152(24), 151(25,28), 180 Pulst, M., 145(120), 358(120), 422 Puodzhyunaite, B. A, 249(141), 262(141), 267-268(141), 281(141), 285(141), 287(141), 364(141), 375(141), 379(141), 423 Putt, S. R., 130, 172(61,105),181, 182 Pyatin, B. M., 973(39,40), 1018(39), 1019(40), 1050 Raban, M., 699(377), 700(389), 846 Rachlin, k I., 461-462(1 lo), 470-471(1 lo), 507-508(110), 521-522(110), 541, 633(12), 649(183), 686(183), 725(12), 727(12), 837, 841, 932(164), 946 Rackur, G., 316(321), 408-409(321), 409-410(322), 427 Radeglia, R., 241(104), 246(121), 358(104,121), 422 Rae, I. D., 954(11), 1005(11), 1050 Raiford Jr., R. W., 45-47(58), 49(58), 79(58), 87 Raines, S., 278(197), 375(197), 424 Rajsner, M., 448(56), 504(56), 540, 636(49), 638(65), 667(65), 718(49), 765(65), 768(65), 838 Ramacci, M. T., 881(108), 884(108), 886(108), 924-926(108), 945 Randall, L. O., 429, 430, 663(252), 667(287), 685(252,287), 694(252,287), 72 1(252), 725(252), 728(252), 739(287), 744-748(287), 747(252), 75 1-754(252), 759-760(287), 762(287), 765-770(287), 780(252), 843, 844, 864(44), 913(44), 918(44), 920(44), 944 Raouf, A., 27(29), 70(29), 86 Rapoport, H., 102(20), 180, 889(123), 891(138),
893-895(123,138), 897(138), 933(138), 937-938(123,138), 945, 946 Rapp, U., 224(71), 350(71), 353(71), 421 Rasmussen, H. B., 493-494(197), 538(197), 543, 595(144), 629 Real, J. A, 700(382,383), 846 Redshaw, S., 60(76), 87 Reeder, E., 133(77), 181, 447-449(33), 448(44,51), 448-449(34), 452(98), 453(33), 461(33,34,51), 461-462(1 lo), 469(33,34), 469-470(51), 470(125), 470-471(110), 475(98), 489(125), 502(33,34), 504(51), 504-506(34), 505(33), 506(44,51), 507-508( 1lo), 508(34,44), 508-509(33), 511(34), 511-512(33), 514(44), 520-521(33, 34,44), 521(51,110,125), 522(44,1lo), 539-542, 547(2), 548(15), 551(15), 557(2,15), 561(79), 572(2), 574(2), 583(126), 585(2,15), 594(139), 596(2), 599(2,15), 601-602( 15). 602-603(2), 603(126), 605(126), 607(126), 609(2), 625(139), 626, 628, 629,633(2), 640, 643(91,135,143), 645( 148), 649( 135,183), 657(2 l6), 666(2,9I, 135), 667(2,9I, 135,274, 287), 668(91), 671(91), 672(148), 678(148), 684(91,135,143), 685(91,135,287), 686(183), 688(148), 694(287), 714(2,91), 716(2,91), 7 18(2,148). 720-723(2), 723(9 1), 725(9 I), 726(2,91), 728(2), 729(2,91), 731(2,91), 733(2,91), 735(2,91), 739(287), 740(91), 741(91), 742(2), 744-748(287), 751(2), 753-754(2), 758(91), 759(2), 759-760(287), 762(287), 765-770(287), 769(91), 772(148), 773(143), 776(143), 780-781(148), 782(2,91), 783(2), 786-790(2), 790-791(91), 792(148), 793(143), 837, 839-844, 852(12), 853(24), 859(38), 864(44,49,55), 870(49,55), 871(55), 887(118), 903-904(38), 905(12,38), 905-906(24), 910-91 1(38,49), 912(49), 913(38,44,55), 914(55), 915(38), 916(49), 918(38,44,49,55), 919(49), 920(44,55), 930(38,118), 943, 944, 945 Reid, A. A., 33(35), 34(35,38,39), 36(35,39), 39(35), 40(35), 74(35,39), 75(35,39), 86 Reimlinger, H., 116(45), 165(45), 181 Reitter, B. E., 668(299), 671(299), 674, 795-798(299), 801(299), 803(299), 813(299), 826-827(299), 844 Reznik V. S., 99(13), 147(13), 180 Rhee, R. P., 889(124), 931(124), 945 Ricca, S., 259(166), 362(166), 424 Rice, K. C., 680(331,332), 736(331), 770(331, 3321,845 Richards, C . G., 217-218(16), 219(47), 228(16), 230(16), 234-235(16,47), 237,335(16),
Author Index 342-343(16), 355(16,47), 420, 421 Richter, H., 270(182), 375(182), 424, 889(125), 891(125), 897(125), 933(125), 945 Ried, W., 220(50,54), 240(98), 241,242, 248(129), 251(146,147), 272(98), 275(98), 278(109,194), 281(129,146), 283(129,146, 194), 285(146), 285-287(194), 335(50), 342-343(50), 343(54), 347-348(54), 356(98), 358(98,109), 361(98), 361-362(129), 362(146), 363(147), 368(146), 373(98), 375(109,146,194),376(129,194), 379(129), 379-380(194), 421, 422, 424 Riley, J. G., 586(128), 596-599(128), 629 Rissmann, G., 239(95), 268(95), 422 Riva, G., 634(31), 659(31,229), 690(366), 721(31), 774(366), 777(366), 786(366), 837, 842, 845 Rodriguez, H. R., 92, 112-115(36), 119(36), 121(36),127(36), 128(36b), 132(36a), 135-136(36a), 161-163(36), 167(36b), 168(36), 170(36b), 173-175(36a), 180, 181 Roechrichf J., 864(63),872(63), 917(63), 922(63), 944 Roehricht, J., 869(86), 871(86), 872(86,90), 874(86),876(90), 91 1(90), 915(86,90), 9 16(9O), 9 17(86,90),9 19-92 1(86,90), 945 Roemer, D., 555-556(51), 579(51), 589(51), 600(51),627 Roma, G., 223(62), 234(65), 247(306), 254, 266(309), 334(65), 335(314), 350(62), 361-363(156), 362-363(306), 363(309), 368(156), 421, 423, 427 Roman, W., 295-296(228), 299(228), 324(228), 389(228), 425 Romeo, G., 592(135), 629 Rose, A,, 44(54), 76-78(54), 87 Rosen, G., 49(64), 50,51(64), 80(64), 87 Rosen, P., 700(391), 846 Rosenthal, A, 136(81), 181 Ross, S. T., 548(10), 626 Rossi, A, 247,248(127), 259(166), 267(127), 281(125,127), 361(127), 362(125,166), 422, 424 Rossi, E., 552(32), 573(32), 586(32), 626 Rossi, S., 224(67), 235(67), 295,297(234), 350(67), 353(67), 386-388(234,235), 390-391(234,235), 392(234), 393(234,235), 421. 425 Rosskopf, F., 572(134), 592(134), 629 Roth, H. J., 697,846 Rua, G., 213(273), 405-406(273), 426 Rudenko, 0. P., 868(79), 944 Rudolph, W., 639(84), 668(84), 743(84), 839 Rudzik, A D., 450(66), 464(66),476-478(135), 502-503(66), 518(66), 520-521(66),
1079
523(135), 525-526(135), 535(135), 540, 542, 633(23), 673(31l), 701(416), 704(433), 728(23), 733(3 1l), 736(31 l), 739(3 11). 741(311), 743(31 l), 761(311), 804(31 l), 829-830(416), 830(23), 837, 844, 847 Rupe, H., 214(2), 215(2), 337(2), 420 Ruske, W., 214(3), 215(3), 217(13), 337(3,13), 343(3), 420 Russell, D. M., 217-218(16), 228(16), 230(16), 234-235( 16), 237( 16), 335(16), 342-343( 16), 355(16), 420 Ryback,G., 217-218(16), 228(16), 230(16), 234-235(16), 237(16), 335(16), 342-343(16), 355(16), 420 Ryder, A., 130(63), 181 Ryska, M., 638(65), 667(65), 765(65), 768(65), 838 Rzedowski, M., 700(380),846 Sabljic, A, 700(385), 846 Sacerdoti, M., 505(198), 543, 701(404,405),846 Sach, G., 448-449(38), 503-508(38), 510(38), 521(38), 540, 633(2), 640(2), 666-667(2), 714(2), 716(2), 718(2), 720-723(2), 726(2), 728-729(2), 731(2), 733(2), 735(2), 742(2), 751(2), 753-754(2), 759(2), 782-783(2), 786-790(2), 837 Sachdeva, Y. P., 668(299), 671(299), 674, 795-798(299), 801(299), 803(299), 813(299), 826-827(299), 844 Sadee, W., 661(240), 701(392), 842, 846 Safonova, T. S., 218(20,21,22,25), 227(80), 230(20), 238(21), 276(191), 345(20,21,25), 346(21,25), 347(25), 371(191), 374(191), 420, 421, 424 Saiki, Y., 326(295), 327(298), 415(295), 417(298), 427 Saito, K., 18,(82), 66-67(82), 87 Sakai, S., 667(289), 743(289), 844 Sakai, T., 979(52), 1025(52), 1051 Sakamoto, I., 241,272(107), 284(107), 357( 107), 371-371( 107), 422 Sakamoto, Y., 984(64), 1029(64), 1051 Salikhov, I. Sh., 99(13), 147(13), 180 Salimbeni, A, 640(102), 689(102), 695(102), 839 Salimov, M. A, 278-279(201), 375-376(201), 380(201), 424 Salle, J., 640(104), 658(222), 659(222), 664(104), 666(222), 685(104), 691(222), 717(104), 719(222), 738(222). 749(222), 774(104), 778(104), 839, 842 Salvaterra, M., 224(70), 350-356(70), 421 Sammour, A., 27(30), 27(29), 28(30), 70(29,30), 71(30), 86
1080
Author Index
Samula, K, 241, 357(108), 422 Sanchez, J., 992-993(82), 1039(82), 1041(82), 1043(82),I051 Sancilio, F. D., 701(403), 716(403), 768(403), 846 Santilli, A. A., 709(465-467), 834(467), 835(465), 848, 851(3), 852(8,1l), 878(3,8), 881(11,1G9,110), 898(3,8), 901(3,8), 903(1l), 927(11,109,110), 941(3,8), 943, 945, 979, 981, 1025(54), 1026(55), 1051 Sapper, H., 701(394,398), 846 Saraeva, R. F., 219(43), 220(43,51), 238(43), 338-339(43,51), 421 Sarcedoti, M., 592(136), 629 Sarrazin, M.. 700(388), 846 Sasaki, T., 29, 51(68), 71(31), 81(68), 86, 87 Sasakura, R,635(36), 685(36), 752(36), 837 Sato, H., 667(285),733(285), 742(285), 748-749(285), 760(285), 844, 866(72), 922-923(72), 944 Sato. R.. 241(315). 362(315), 427 Sato, Y., 138, 177-178(89a), 182, 448(47), 479(47), 483(47), 503(47), 526-527(47), 529-530(47), 540, 640(109), 701(109), 735(109), 786(109), 831(109), 839 Satoh, J., 256(305), 362(305), 369(305), 427 Saucy, G., 448-449(36,37,39), 503(36,37,39), 505(36,37,39), 521(39), 540, 633(2,4-6,15), 640(2),664(6), 666(2,5,15), 667(2), 684(6), 685-686(6), 695(5,15), 714(2,15), 7 15(4), 716(2), 718(2), 720-723(2), 721(5), 722(4,5,15), 723(5), 725(5, 6,15), 726(2), 728(2,4,6), 729(2), 731(2,4), 733(2), 735(2), 742(2), 751(2,4,5), 753-754(2), 759(2,6), 782-783(2), 786-790(2), 837, 864(45), 870(45), 918(45), 944 Savelli, F., 50(65), 80(65). 87 Sawanishi, H., 29(32,86), 57(101), 58(101), 71-74(32), 84(101), 85(101), 86, 88 Scahill, T. A, 701(400), 846 Scandroglio, A, 13(18a), 65(18a), 66(18a), 86 Schallek, W., 430 Schecker, H.-G., 704(446), 847 Scheffler, G., 685(353,354), 845 Scheker, H.-G., 452(112),476-478(112), 512(112), 521(112), 523-525(112), 541 Schindler, O., 110(35), 112(35), 158(35), 180 Schlager, L. H., 660(235), 667(280), 668(280), 670(280), 678(326), 687(235), 72 1(236), 777(326), 784-785(326), 787(326), 789(326), 793(280), 804(326), 805(280), 842, 843, 845 Schlesinger, W., 550(19), 626, 636(54), 666(54), 838 Schmidt, R. A., 448(57), 540, 547(4), 572-573(4), 584(4), 600(4), 604(4), 626,
633(3), 639(3), 664(3), 715(3), 730(3), 760(3), 784(3), 837 Schmitt, J., 219(41), 338(41), 420, 640(104,105), 658(222), 659(222), 664(104), 666(222), 685(104,105), 691(222), 695(105), 717(104), 719(222), 738(222), 749(222), 773(105), 774(104), 778(104,105), 779(105), 785-787(105), 839, 842 Schmitz, E., 41,43(45),44(45), 49(45), 76(45), 80(45), 87 Schneider, J., 864(56), 867(56), 871(56), 874(56), 906(56), 91 1(56), 915-916(56), 944 Schnettler, R. A, 113(39,40,41), 114(43), 127-128(39,40), 132(39,73), 160-161(39), 160-163(40,41), 170(39,40), 173-174(73), 180, 181 Scholtz. M., 135(78,79), 175(78,79), 177(78), 181 Schonberg, S., 554(46), 469(46), 597(46), 603(46), 627, 646(161), 841 Schulmeyer, N., 973(41), 976(45), 1019(41), 1020(45), 1050, 1051 Schulte, E., 213, 430 Schultz, H. P., 269(181), 274-276(181), 289(181), 371(181), 373(181), 386(181), 424 Schulze, K, 270(182), 375(182), 424 Schurig, H., 217(11), 336(11), 337(11), 420 Schutz, H., 430 Schwandt, J., 661(240), 701(392), 842, 846 Schwartz, R., 440(19), 445(19), 474(19), 498(19), 519(19), 523(19), 539, 559(65,70), 564(65), 579(65), 584(65), 586(70), 588(70), 590(70), 606-607(65), 609(65), 610-61 1(70), 613(70), 627 Schwarzenbach, G., 217(18), 227(18), 226(75), 420, 421 Schweiniger, R. M., 635(38), 667(291), 671(306),692-693(291), 739(291), 838, 844 Scotese, A. C., 981, 1026(55), I051 Scott, M. K., 187, 188(4), 194-195(4), 201(4), 205-206(4), 207 Scriven, E. F. V., 433(1), 496(1), 539, 707(460), 707-708(461), 833(460), 833-834(461), 847, 848 Sedmera, P., 686(364), 845 Sega, A, 701(393), 846 Seitz, G ,301,404(269), 426 Sellstedt, J H ,451(89), 486(179),491(89,179, 194-196), 531(195), 532(179), 537(194), 541, 543, 661(243),674(243), 684(243), 685(355), 71 1(243), 779(243), 787(243), 800(243), 803(243), 821(243). 843, 845 Semenova. T. S., 249(140), 262(140), 267(140), 364(140), 423 Seshadri, S., 261(169), 369(169), 424
Author Index Setescak L. L., 112(100), 163-164(100), 182 Sethi, K., 891(140), 932(140), 946 Settimj, G., 210,404(268), 426, 448(45), 450-451(88), 473(45), 487(88), 507-51 1(45), 513-514(45), 540, 541, 683(348), 692(348, 369), 775(348,369), 779(348,369), 780(348), 784(348), 785(348,369), 787(369), 788(348, 369), 789(348), 845 Sexton, W. A, 247,262,362(123), 422 Shabarov, Yu.S., 633(21), 713(21), 719(21),837 Shah, R. IC, 46(59), 48(59), 79(59), 87 Shalaby, S. W., 218(23), 346-347(23), 420 Shannon, J. S., 954(11), 1005(11), 1050 Sharbatyan, P. A, 257(163,164), 268(174), 365(163), 368-369(163,164), 423, 424, 671(304), 781(304), 824(304), 827-828(304), 844 Sharma, K. S., 104(28), 151(28), 180 Sharp, J. T., 33, 34, 36(35,39,97,98), 38(99), 39(35), 40(35), 56. 74(34,35,39), 75(35,39), 77(98), 84-85(100), 86, 88 Shaw, C., 305(253,254), 426 Shazhenov, A. A, 278(198), 379(198), 384(198), 424 Shenoy, U. D., 435(10), 457(106), 497(10), 515(106), 539, 541 Shevchenko, L. V., 257(164),368-369(164), 423 Shiba, T., 13(24), 25(24), 67(24), 86 Shibahara, S., 130(66), 181 Shiotani, S., 859(39), 943 Shirai, H., 269(177,179,180), 273(190), 275(190), 274(179), 276(177), 277(179,180), 371(177,179,190),424 Shiroki, M., 988(68,69,70,72,73),989(68,69.75), 990(73,80,81), 992-993(86,89,94), 993(loo), 1032(68), 1033(72,75), 1033-1035(68,70), 1035(75,80,81), 1036(80,81), 1039(94), 1039-1044(86), 1041(89,100), 1042- 1O44(94), 1043(89,loo), 1045-1046(68), 1051, 1052 Shirshov, A N., 99(13), 147(13), 180 Shnider, O., 900(155), 942(155), 946 Shono, F., 554(42), 569(42), 582(42), 603(42), 627, 647(163), 841 Showalter, H. D. H., 172(105), 182 Shriner, R. L., 295,298,386-387(224), 425 Shroff, A. P., 305(255), 426 Shtemenko, N. I., 257(163), 365(153), 368-369(163), 423 Shvetsov, Yu., 99(13), 147(13), 180 Sikirica, M., 701(406), 846 Silverman, G., see Zenchoff, G. Simig, G., 92 Simon-Trompler, E., 681(337), 775-776(337),
1081
785(337), 788(337), 845 Simoni, D., 968(31), 1014(31), 1050 Singh, P.,685(357), 695(357), 774-776(357), 781-782(357), 845 Singhal, R. K., 219(46), 343-344(46), 421 Siou, G., 640(104), 664(104), 685(104), 717(104), 774(104), 778(104), 839 Skolnick, P., 680(331,332), 736(331), 770(331, 332), 845 Slomp, G., 675(318), 699(377), 700(389), 844, 846 Slopianka, M., 5(2), 59(2), 86 Sluboslu, B. C.,450(87), 452(87), 453(100), 472(100), 475(87), 479-480(87), 486-491(87), 505(87), 518(87), 520(87), 531-532(87), 541, 547(5), 572-573(5), 584(5), 600(5), 626, 633(28), 646(28), 649(189), 670(189), 678-679(189), 683(344, 346), 684(189), 702(346), 709-710(344), 720(28), 730(28), 747(189), 760(28), 762(189), 794(189), 835(344), 837, 841, 845, 890(137), 896(137), 899(153), 933-934(137), 941(153), 946 Smalley, R. K., 433(1), 496(1), 539, 707-708(461), 833-834(461), 848 Smith, C. S., 137(85), I82 Smith, F. A., 448-449(37), 505(37), 540, 633(5,15), 666(5,15), 695(5,15), 714(15), 721-723(5), 722(15), 725(5,15), 726(5), 751(5), 837 Smith, H. W., 889(123), 891(138), 893-895(123, 138), 897(138), 933(138), 937-938(123,138), 945, 946 Smith, R. B., 102(20), 180 Smith, S. L., 701(400), 846 Smith, W. F., 700(384), 846 Snatzke, G., 700(385), 846 Snieckus, V., 3, 13(17),22(17), 23(17). 25(17), 26(17), 29(17), 65(17), 68(17), 69(17), 86 Solomko, Z. F., 241(101), 248(133,134,137), 249( 139- 140,142). 250( 143,144). 253( 150), 256,256(162), 257(150), 259(165,166), 262(133,140), 266(150), 267(137,140, 142-144), 268(174), 269(134), 278-279(201), 279(206), 28 1(134,138,139,144), 358( 10l), 362(143,165,166), 362-364( 133,134), 363(143,144), 3% 137- 140,150), 366( 165) 368(142,143), 375(206), 375-376(201), 379(137-139,144), 380(201), 422-425 Solomon, C., 892(141), 935(141), 946 Sood, H. R., 33(35), 34(35), 36(35), 39(35), 40(35), 74(35), 75(35), 86 Sotiriadis, A, 46(62), 80(62), 87 Southwick P. L., 223(61), 348(61), 421 Sowell, J. W., 100(17), 148(17), 180
1082
Author I n d e x
Speakman, J. C., 240(96), 422 Spenser, J. L., 449(60), 469(60), 515(60), 518(60), 540 Spensley, P. C . ,215(4), 337(4), 420 Staab, H. A,, 239(92), 422 Stachel, H. D., 224(66), 334(66), 421 Stahl, P. H., 329(301), 329-330(300), 418(300), 419(301), 427 Stahlhofen, P., 240(98), 241,242,248(129), 251,272(98), 275(98), 281(129,146), 283(129,146), 285(146), 356(98), 358(98), 361(98), 361-362(129), 362(146), 368(146), 373(98), 375(146), 376(129), 379(129), 422, 423 Stahnke, K.-H., 881(107), 885(107), 945 Stanetty,P., 992-993(83,84), 993(95,99), 1037(84,95), 1039(83,84,95), 1041(83,84,95), 1043(83,84,95,99), 1044(83,95,99), 1051, 1052 Stankiewicz, J., 321(287), 323(287), 413-414(287), 426 Stauss, U., 110(35), 112(35), 158(35), 180 Stavropoulos, G., 897(150), 939(150), 946 Steiger, N., 448-449(38,40), 469(40), 503-508(38), 505(40), 510(38), 521(38), 540, 633(7), 640(93), 643(93), 660(7,93), 666(7,93), 684(7,93), 686(7,93), 721-723(7), 725(7), 728-729(7), 752(7), 791(7), 837, 839, 864(46), 870(46), 912(46), 918(46), 944 Steimmig, G., 217-219(14), 233(14), 236, 343(14), 420 Steinman, M., 554(44), 559(72), 569(106), 570(44), 572(106), 591(133), 598(106), 605(44), 6 15(72,106), 616( 106), 627-629, 638(69), 660(69), 664(69), 678(69), 686(69), 702(422), 703(429), 716(69), 747(69), 794(69), 830(422), 838, 847 Stempel, A, 461-462(110), 470-471(110), S07-508(110), 521-522(1 lo), 541, 547(3,5), 572-573(3,5), 584(3), 584(5), 596(3), 599-602(3), 600(5),604(3), 626, 633(1,2,16,28), 639(75,76), 642(2), 643(143), 645(148), 646(28), 649(183), 650(76), 666(2,16), 667(2), 672(148), 678(1,148,324), 684(143), 685(324), 686(183), 688(148), 7 13(10). 7 14(2), 7 16(2), 7 18(2,148), 720(2,28),721-723(2), 726(2), 728-729(2), 730(28), 731(2,16), 733(2), 735(2), 742(2), 751(2), 753-754(2), 759(2), 760(28), 762(75), 772(148), 773(143), 776(143), 780-781( 148) 780-783(2), 786-790(2), 792(148), 793(143), 797-798(324), 837, 838, 840, 841, 845, 864(59), 887( 118), 910(59), 930(118), 944, 945 Steppe, T. V., 547(5), 572-573(5), 584(5),
600(5), 626, 633(13,28), 646(28), 6W13), 713(13), 716(13), 719(13), 720(28), 730(28), 750(13), 760(28), 837 Stembach, L. H., 3, 92, 213, 255(158), 258(158), 264(158), 363(158), 366-367(158), 374(158), 423, 429, 430, 434(7,8), 436-437(8). 438(1 I), 438-439(7), 439( 12-14,16,17), 444-445( 12,13,17), 445(7,1 l,14), 447,448(44,46,51,53,55,57), 448-449(33,34,36-40), 449(17,61,63), 450(72), 450-451(85), 451(93), 452(94,98), 453(33), 454(94), 455(104), 461(33,34,51), 461-462(1 lo), 466(7), 466-467(104), 469(33,34,40), 469-470(51), 470( 125), 470-471(1 lo), 472(53,94), 475(98,129,130), 478(63), 479-480(143,144), 483(143,144), 486(7.180), 488(72), 489(125), 492(11-14, 16,17), 492-493(85), 494(11- 14,16,17), 495-496(85), 496(7,8), 498(7,11-13,17), 500( 14), 500-501( 12.13.16,17), 502(33,34). 502-505(46), 503(36,38,39), 504(38,5 1,55), 504-506(34), 505(33,36-40,93), 506(44,5I, 143,144), 506-508(38), 507(1 lo), 507-509(46), 508(34,44,1 lo), 508-509(33), 509-51 1(61), 510(38), 51 1(34), 511-5 12(33, 46). 512-515(85), 514(44), 515(61). 518(7, 6 1,72,85), 5 19(143,144), 520-52 1(33,34,44), 521(38,39,51,110,125), 522(44,1lo), 525-527(85), 526-527( 143,144), 530(7), 532(180), 535(72), 532(7), 538(11-14,17), 539-542, 547(2-6), 548(14,15), 550(20-23), 551(15,27), 554(43,45), 557(2,15), 558(61, 64).559(64,68,71), 561(64,78-80,83,84), 562(78,85), 563(83,84), 567(99), 569(80,101, 103-105), 570(84), 570-571(68,83), 572(2, 4,5), 572-573(3,112,113), 573(4,5,6,15,110), 574(2), 577(68), 583(43,83,125), 584(3,4,5, 99). SSS(2,15,20-23,83,99,104), 586(68,83, 1lo), 587(84,110), 588(71), 588-589(68), 590(7 l), 591(68,83,84,104,125,131,132). 592(64,99). 593(99), 594( 139,143), 596(2,3, 68,101,103),597(104), 598(78), 599(2,15, 61,83,84,103), 599-602(3), 600(4,5,6), 601( 112), 601-602( 1533). 602(84,101,13 1, 132), 602-603(2), 603(43,6 1,83,103,104, 110,132), 604(3,4,6,21,83,101,113), 605(83, 110,113,125), 605-606(68), 607(64), 608(68), 609(2,68,83), 610-613(71), 615(68, 83,l 10). 624(64), 625(139,143),626-629, 633(1-7,11,14-16,26,28), 634(33), 635(11, 14,43),638(67,68),639(3,11.33,77),640, 640(93,94,96,99), 643(91,93,135,136,138, 139,141,143), 644(146), 645(148,150), 646(28,151,152,154,157,158.160,162), 647( 138,154,169- 173), 648( 141,170,174,
Author Index 175,178), 649(135,183,186), 655(209), 657(215-219), 658(223), 659(225), 660(7, 67,93,157,158,233), 661(244), 663(250,252, 253,254), 664(3,694,136,152,255,256), 665(250), 666(2,5,7,15,16,26,77,91,93,94, 135,141,162,270), 667(2,91,135,136,150, 169,233,274,277,283,284,287,291,293,294), 668(91,233,277,293,297,300),670(255), 671(233,305-306), 672( 148), 675(321), 678(148,254,277,324), 671,678(1), 679(250), 680(283), 681, 681(163), 683(342), 684(6,7, 91,93,135,138,143,150), 685(6,33,91,135, 136,152,162,215,252-254,284,287,293,324), 686(6,7,93,94,183,253,256,293,360), 687(250), 688(148,215,233,277,293), 689(77,294), 690(233,277), 691(277), 692(215.225,291,368), 693(233,29 I), 694(252,254,283,287), 695(5,11,15,33), 696(2 18,372), 697(300,376), 698(300). 701(403), 701-703(255), 704(186,300). 705(141,170-172,175), 708(464), 709-710(469,470), 71 1(157,158), 7 12(157), 713(1), 714(2,15,91), 714-715(152), 715(3,4,136), 7 l6(2,91,255,293,3OO,403), 7 18(2,148),720(2,1128), 72 1(2,5,7,136252), 722(2,4,5,7,15,33), 723(2,5,7,33,91,218), 724( 136,139), 725(5,7,15,91,252), 725-727( 136,5OO), 726(2,5,11,91,233), 727(26,33,141,360), 728(2,4,6,7,152,252, 256), 729(2,7,91,136,162,256), 730(3,28,94), 73 1(2,4,16,9 1,136). 732(250,284,293), 733(2,91,233,250,283,293),734(233,283), 735(2,91,284,293), 736(14), 737(294), 738(11,254,283,294), 739(254,287,29 l), 740(233), 740-741(91), 742(2), 743(233, 283,293,294). 744(287,293,294), 745(254, 283,293), 745-748(287), 746(233), 747(233, 252), 748(284), 750(160), 751(2,4,5), 751-754(252), 752(7,162), 753(2,136,253, 500). 754(2), 756(33,500), 757(26,136,141), 758(91), 759(2,6,136,162,287), 760(3,28, 136,158,287), 761-762(283,293), 762(287, 294), 765(283,293), 765-770(297), 768(250, 254,293,403), 769(91), 769-770(283), 772(148,223,225,233), 773(143,225), 776( 143), 777(215,223,225), 780(33,148), 781(33,148,233), 782(2,91), 783(2,136), 784(3), 786(2,77), 787-790(2), 790-791(91), 79 1(7,67,152), 792(148), 793( 143), 794(233), 796(297), 797(215), 797-798(324), 798(297), 799(215), 800(215), 802(256), 804(215), 805(254,277,293). 81 1(225), 812(277), 814(277), 829-830(255), 830(33), 831(170), 832(175), 834(464), 835(469), 836(157,158),837-846, 848, 852(12,16,
1083
18,20,22), 853(23,25,27), 854(18,22,30), 855(30,34),859(38), 861(20,30), 862(20), 864(44-46,48,49,5 1-56,59,61), 865(54,65, 68), 866(52,71), 867(56,77,78), 868(71,80, 82), 870(45,46,49,52,55,87,88). 87 l(53-56), 872(91), 873(53,65,68,78,82,93,94),874(51, 56,78,80,88,95), 876(68,82,91,93,94), 878(16). 879(103), 881(103), 884-886( 103), 887(117-119), 888(121), 896(95,148), 902(119), 903(30,38,119),904(16,30,38), 905( 12,25,38), 906(22,56), 906-908( 18,20), 910(49,52,59,87,119), 910-91 1(38), 911(48, 49,51,56), 912(46,49), 913(44,52,53,55,82, 88), 914(54,55,61), 915(38,56,78), 916(49, 5 1,56,68,77), 917(68), 918(38,44-46,49,55, 82,88), 919(49,78,91), 920(44,55,65), 921(54,93), 923(119), 924(16), 925(18,103), 927-928(18,103), 929(103), 930(38,117,118), 943-946, 956(12), 1005(12), I050 Sternhell, S., 954(11), 1005(11), I050 Stetsenko, A V., 322(288), 413(288), 426 Stetter, H., 194(13), 206(13), 207,219(40), 269, 338(40), 371(176), 420, 424 Stoecklin, G., 686(359), 694(359), 845 Stolyarchuk A A,, 250(143), 267(143), 362-364(143), 368(143), 423 Stradi, R., 552(32), 573(32), 586(32), 626 Strakov, A Ya., 218-219(29), 234(29), 343-344(29), 420 Strehlow, W., 659(228), 685(228), 686(228), 842 Streith, J., 3, 9, 10(13,104), 26, 41, 52, 54(71, 73,74), 62(10,11,104), 63(104), 64(13), 70(26), 76(47), 81-83(69,71,73,74), 86-88 Stromar, I., 635(40), 636(40), 666(40), 775(40), 781-783(40), 789(40), 796(40), 798(40), 838 Struchkov, Y. T., 701(407), 846 Strupler, A, 269,274,371(175), 424 Stuehmer, W., 647(168), 841 Stuhmer, W., 555(48,49), 569(48,49,102), 572(48), 587(48), 588(48,49,102), 589(48), 598(49), 600(102), 601(48), 606(48), 608-616(48), 61 1(49), 613(49), 616(49), 627 Styles, V. L., 32(33,89), 73(33), 86, 88 Sucrow, W., 5(2), 59(2), 86 Sugasawa, T., 635(36), 685(36), 752(36), 837 Sugimoto, H., 985(66), 995-996(66), 1030-1031(66), 1048(66), 1051 Suh, J. T., 113(39,40,41), 114(43), 127-128(39, 40), 132(39,73), 160-161(39), 160-163(40, 41), 170(39,40), 173-174(73), 180, I81 Sulca, M., 218-219(29), 234(29), 343-344(29), 420 Sulkowski, T. S., 486(178), 506(178), 532(178), 543, 557(57), 599(57), 601(57), 627,
1084
Author Index
Salkowski, T. S. (Continued) 635(35), 646(153), 668(35), 685(35), 714(35), 788(35), 810(35), 837. 840, 852(21), 864(57,58), 865(58), 868(81), 906(21), 910(57,58), 916(58), 943, 944 Sunjic, V., 96(7), 180, 550(24,26), 551(24,26, 31), 603(31), 607(24), 609(24,31), 613(24,3 l), 615(24,31), 626, 633(20), 635(40), 639(20, 40,81), 641(112), 666(40,81), 681(334), 685(356), 690(334), 692(334,356), 701(393), 721(20), 732(81), 773(112,334,356), 775(40), 776(334), 776-777(356), 779(356), 78 l(40, 334,356), 782(20,40,334), 783(20,40,81), 784(112,334,356), 787(356), 788(20), 789(20,40,356), 796(40,334), 796-798(356), 797(334), 798(40), 801-804(334), 802(356), 804(356), 837-839, 845, 846 Suquef M., 640(104), 658(222), 659(222), 664(104), 666(222), 685(104), 691(222), 717(104), 719(222), 738(222), 749(222), 774(104), 778(104), 839, 842 Surikova, T. P., 633(21), 713(21), 719(21), 837 Suschitzky, H., 8(9), 86, 241,358-359(103), 422, 433(1), 496(1), 539, 707(460), 707-708(461), 833(460), 833-834(461), 847, 848
Svatek, E., 448(56), 504(56), 540, 636(49), 638(65), 667(65), 718(49), 765(65), 768(65), 838 Swan, J. S., 954(1 l), 1005(11), 1050 Swett, L. R., 965-966(23,26), 1012(23), 1041(26), 1050 Swinbourne, F. J., 634(30), 636(51), 721(30), 751(30), 773(30), 779(30), 837. 838 Szarvasi, E., 279(205), 306,308(205), 375(205), 379(205), 384(205), 402(205), 424 Szeberenyi, S., 869(86), 871(86), 872(86,90), 874(86), 876(90), 91 1(90), 915(86,90), 916(90), 917(86,90), 919-921(86,90), 945 Szente, A, 442(26), 450-451(70), 464(70), 469(70), 486(70), 501(26), 503(70), 506-508(70), 512(70), 515(70), 521(70), 523(70), 531-533(70), 535-536(70), 539, 540, 563(89), 580(121), 582(122), 599(89), 603(89), 617(89), 620(89), 628, 629, 635(39), 638(79,80), 639(39), 641(114), 644(39,145,147), 654(39), 659(230), 660(80,230,23 I), 666(80,230,23l), 668(147), 670(251), 675(301,320), 68 1(80,230,231, 301), 683,684(147), 685,685(80), 686(230, 251), 689(145), 690(147), 690-691(231), 695-696(301), 696(251), 701-702(79), 742(251), 751(251), 753(231), 754-758(231, 251), 775(80), 777(231), 778(39,80), 778-779(145), 779(80,147), 783(79,114)31,
251), 784(231), 785-789(147), 786(39,80, 145), 789(231), 794(145), 794-795(147), 798(147,231), 799(80,231,251), 800(39), 803(39), 804(231), 804-806(147), 806-808(231), 810(114,251), 81 1(230), 812(251), 813(230,251), 814(147,230,23l), 8 16(230)3 l), 817(80), 8 18-82 1(230), 831(79), 838-840, 842-844, 854(29), 858(29), 862(29), 864(60), 866-867(29), 871(29), 872(60), 874(29), 877-878(29), 888(29), 904-908(29), 91 1-912(29), 913-915(60), 914-919(29), 918-92 1(60), 921-924(29), 930(29), 943, 944, 952(6), 987, 1002(6), 1031(6), 1037-1039(6), 1041(6), 1043(6), 1050 Szmuszkovicz, J., 442(27), 447(27), 460(108), 474(27), 479-480( 146,148), 483( 146), 483-485(148), 510(108), 527-528(146), 528-530( 148), 539, 541, 542, 667(292), 675(3 18), 699(377), 700(389), 704(292,45l), 717(292), 762(292), 844, 846, 847 Szporny, L., 864(63), 869(86), 871(86), 872(63,86,90), 874(86), 876(90), 91 1(90), 9 15(86.90), 9 16(9O), 9 17(63,86,90), 919-921(86,90), 922(63), 944, 945 Szulczewski, D. H., 964(22), 967(30), 1013(30), 1050
Tachikawa, R., 456(121), 541, 672(307), 844, 865(67),922(67), 944 Taddei, F., 268,(173), 424 Tagyey, Zs., 639(78), 838 Tahara, T., 988(68,69,70,72,73),989(68,69,75), 990(73,80,8l), 992-993(86,89,94), 993( l o ) , 1032(68), 1033(72,75), 1033-1035(68,70), 1035(75,80,81), 1036(80,81), 1039(94), 1039-1044(86), 1041(89,100), 1042- 1044(94), 1043(89,100), 1045-1046(68), 1051, 1052 Tajana, A, 223(316), 224(67,70,71), 225(72), 235(67), 250(145) 268(173). 306(145), 335(72), 341-342(316), 350(67,69-71), 351-356(70), 351-353(69), 353(67,71), 362(145), 401(145), 421, 423, 424, 426 Takada, A., 98(10), 147(10), 180, 256(305), 362(305), 369(305), 427 Takagi, H., 672(307), 844 Takahashi, Y., 238(86), 422 Takamizawa, A, 979(53), 1025(53), 1051 Takashima, Y., 866(72), 922-923(72), 944 Takayama, K, 18(22), 20(83), 66(22), 69(22), 86, 87 Takeuchi, T., 238(86), 422 Takigawa, Y. 992-993(86), 1039-1044(86), I051
Author Index Talailute, Z. A., 249(141), 262(141), 267-268(141), 281(141), 285(141), 287(141), 364(141), 375(141), 379(141). 423 Tamagnone, G. F., 688(365), 733(365), 738(365), 745(365), 747(365). 792-795(365), 845, 887(116), 930(116), 945 Tamaki, T., 635(37), 838 Tamura, C., 456(121), 541 Tamura, Y., 25(25), 26(25), 41,67(25), 76(46), 86, 87 Tani, T., 106(95), 154(95), 182 Taniguchi, K., 450(73), 455(73), 486(181), 488(73,181,188),489( 181,188), 505(73), 51 1(73), 514-515(73), 534-536(181), 535(73), 540, 543, 648(179), 668(179), 701(179), 702(179), 703(179). 725(179), 830(179), 841, 865(66), 898-899(66), 916(66), 939(66), 944 Tappi, G., 213(273), 405-406(273), 426 Tarzia, G., 982(57,58), 983(57,58,60,61), 984(60,61), 1027- 1029(57), 1028(60), I029(6O,61). 1051 Taub, W., 117, 133(76), 181 Taurand, G., 52(69), 54(69,71), 81-83(69), 82(71), 87 Tavares, R. F., 663(250), 665(250), 679(250), 687(250), 732(250), 733(250), 768(250), 843 Tawada, H., 448(47), 450(83,84), 452(95), 454(102,102),467(102,103),470(95), 479(47,142),483(47), 487( 142), 502-503(95), 503(47), 509-51 1(83,84), 522(102,103), 526(142), 526-527(47), 529-530(47), 532(142), 540-542, 559(69), 562(69), 563(87), 569(69), 607(69), 611(69), 617(87), 627, 628, 640(109), 647(165), 649(181,187), 655(208), 701(109), 735(109), 786(109), 831(109), 839, 841, 842 Taylor, J. B., 109(33), 114, 115, 116-1 19(33), 121(33), 126(33), 157-159(33), 165-170(33), 180, 450(78,79,80), 467(78,79,80), 509(79,80), 509-510(78), 540, 704(437-439), 847 Taylor, P. J., 108(32), 180 Tegeler, J. J., 953(8), 1003(8), 1050 Tegyev, Zs., 681(337), 775-776(337), 785(337), 788(337), 845, 864(42), 913(42), 944 Teller, D. M., 486(179), 491(179), 492(196), 532(179), 543 Tendryakova, S. P. 219(42,43), 220(43), 238(43), 338(42,43), 339(43), 421 Terada, A, 865(67), 922(67), 944 Terashima, M., 892(142,143), 893-896(143), 931-933(143), 935-938(143), 946 Terent’ev, P. B., 268(174), 424 Testa, E., 278-280(203), 283(203), 285-287(203).
1085
379(203), 384(203), 424 Testoni, G., 16(78),66(78), 87 Teteryuk, S. S., 248(137), 267(137), 281(137), 364(137), 379(137), 423 Teubner, R., 220(54), 345(54), 347-348(54), 421 Thakar, Z. K., 218(38,39), 338(38), 340-342(38, 39), 343(38), 345(39), 347(39), 420 Theodoropoulos, D., 46(62), 80(62), 87, 897(1SO), 939( 1SO), 946 Thi Bang, T. D., 241(102), 358(102),422 Thiele, J., 217-219(14), 233(14), 236,343(14), 420 Thill, B. P., 137(87), 177(87), 182 Thomas, D. R., 433(1), 496(1), 539, 707(460), 833(460), 847 Thomas, K, 245,246(115), 356(115), 422 Thorogood, P. B., 33,34(35), 36(35), 39(35), 40(35), 74(34,35), 75(35), 86 Thust, U., 216(8), 420 Tinney, F. J., 992-993(82), 1039(82), 1041(82), 1043(82), 1051 Tintel, C., 136(82), 181 Tinter, S. K., 32q294), 330-331(294), 415(294), 42 7 Titov, V. V., 218(32), 234(32), 343(32), 420 Tkachenko, V. S., 268(174), 424 Todaro, L. J., 700(391), 701(501),846, 848 Toeplitz, B., 651(198), 679(198), 692(198), 693(198), 749(198), 759(198), 841 Tokes, L., 636(46), 838 Tokmakova, T. N., 219(43), 220(43), 238(43), 338(43), 421 Toldy, L., 252,259(149), 267(149), 281(149), 363(149), 368(149), 423 Tomagnone, G. F., 678(282), 688(282), 733(282), 747(282), 792(282), 795(282), 844 Tomalia, D. A, 137(87), 177(87), 182 Tomcufcik, k S., 153-154(97), 182 Tominaga, Y., 223(319), 347(319), 364(319), 42 7 Tonetti, I., 319-320(282), 324(282), 41 1-412(282), 426,970(34), 971(34,36), 1016- 1018(34,36), I050 Tong, B. P., 952(7), 1002(7), 1050 Toperman, I. B., 100(15), 148(15), I80 Topliss, J. G., 569(106). 572(106), 598(106), 615-61@106), 628, 638(69), 660(69), 664(69), 678(69), 686(69), 716(69), 747(69), 794(69), 838 Torinus, E., 241,278(109), 358(109), 375(109), 422 Torrielli, M. V., 678(282), 688(282), 733(282), 747(282), 792(282), 795(282), 844 Torsi, G., 700(379), 846 Toyoda, T., 635(36), 685(36), 752(36), 837
1086
A u t h o r Index
Trites, D. H., 326(294), 330-331(294), 415(294), 42 7
Trka, A, 224(71), 350(71), 353(71), 421 Trkovnik, M., 218(34), 253(34), 342(34), 420 Txybulski, E. J., 583(126), 603(126), 605(126), 607(126), 629, 635(42), 688(42), 690(42), 725(42), 735(42), 753(42), 838, 853(24), 905-906(24), 943 Tschamber, T., 10(104),62(104), 63(104), 88 Tschernow, W. A, 276(191), 371(191), 374(191), 424 Tsuchiya, T., 3, 13, 18(20,21,22),20(20,83,102), 21(88,103), 22(20,21), 23(84,85), 24(85), 25(17,23), 26(17b), 29(32,86), 30(87), 35(91,92), 39(91), 52, 55(17,20), 57, 58(101), 65-67(20), 66(22), 67(21,23,84), 68(17), 69(17,22), 71-74(32), 73(87), 75(91), 81(70),84(101), 85(101), 86-88, 110(99,101), 112(99), 157(101), 157-158(99), 182
Tsuge, 0.. 120, 169(55), 181 Tsumagari, T., 992-993(86), 1039-1044(86),
I051 Tsurnoka, T., 130(62), 171(62), 181 Tuan, G., 983(63), 1051 Tuchagues, J. P., 505(199), 543, 701(395), 846 Tucker, K S., 308(266), 403(266), 426 Tully, W. R., 109(33), 114, 115, 116-119(33), 121(33), 126(33), 157-159(33), 165-170(33), 180, 241(106), 248(106), 281-282(106), 358(106), 360(106), 364(106), 368(106), 376(106), 379-380(106), 384(106), 420, 422 Turchin, K, 239(94), 422 Turk, C. F., 259(165), 281(212), 284-285(212), 362(165), 366(165), 376(212), 379-380(212), 423, 425, 851(4), 860(4), 889(127), 902(4), 932(127), 943, 945 Twomey, D., 219(48), 235(48), 237,238(48,85), 355(48,85), 421,422 Uchida, C., 130(62), 171(62), 181 Ueda, I., 450(73), 455(73), 486(181), 488(73, 181,186,188), 489( 181,186,188),505(73), 5 11(73), 514-5 15(73), 534-536( 181,186), 535(73), 540, 543, 638(73), 648(179), 668(179), 701(179), 702(179,427), 703(179), 725(179), 830(179), 838, 841, 847, 865(66), 898-899(66), 916(66), 939(66), 944 Ueda, T., 98(10), 147(10),180, 223(60), 235(60), 334(59,60), 335(60), 350(59,60), 421
Ueno, A, 326(295), 327(298), 415(295), 417(298), 427 Uhl, A., 332(302), 419(302), 427 Uhl, J., 659(228), 685(228), 686(228), 842
Ulbrich, B., 4, 59 (l), 86 Ulbrich, H., 187(6), 198-201(6), 207 Umezawa, H., 130(64,66), 171(64), 181 Unangst, P. C., 223(61,31l), 341(31l), 347(311), 348(61), 421, 427 Unruh, M., 279(204), 283-286(204), 376-378(204), 380-384(204), 424 Unser, M. J., 855(32), 859(32), 902(32), 905(32), 943 Unterhalt, B., 701(399), 846 Urakawa, C., 219(49), 251(49), 260(49), 355(49), 421 Urlass, G., 278(194), 283(194), 284-287(194), 375-376(194), 379-380(194), 424 Uroegdi, L., 869(86), 87 1(86), 872(8690), 874(86), 876(90), 911(90), 915(86,90), 9 16(90), 9 17(86,90),9 19-92 1(86,90), 945 Ushirogochi, A, 223(319), 347(319), 364(319), 42 7 Uskokovic, M., 557(56), 627, 890(132-134), 894(133), 895(132,133), 93 l(132-134). 932-935(133), 935(132), 938(133), 946 Usui, Y., 638(74), 650(74,191), 656(74), 761(74), 838, 841 Utekhina, N. V., 220(52), 338-339(52), 342-343(52), 421 v. Dobeneck, H., 332(302), 419(302), 427 Vagi, K., 638(64), 838, 892(141), 935(141), 946 Vaidya, N. A., 633(29), 811(29), 837 Vaisman, S. B., 218(44), 421 Van Allan, J. A 220(55), 334-335(55), 421 Van Alphen, J., 292,425 Van der Stelt, C.,42(48), 76(48), 87 Van Hoeven, H., 114(42), 119(42), 121(42), 160(42), 167(42), 181 Vane, F. M., 486(182), 488-489(182), 543, 701(401), 846 Vega, S., 556(55), 560-561(55), 561(76), 589(55,76), 597(55,76), 602(55), 604(55), 627, 879(100), 882(100), 898(152), 924-926(100), 928(100), 941(152), 945, 946 Veibel, S., 218(27), 230(27), 231(83), 234(27), 343(27), 226(77), 420, 421 Veit, W., 992-993(83,87), 993(96), 1037-1038(87), 1039(83,96), 1040-1042(87), 1041(83), 1042(96), 1043-1044(83), 1051, 1052
Vejdelek, Z., 448(56), 504(56), 540, 636(49), 638(65), 667(65), 718(49), 765(65), 768(65), 838
Veloso, H., 132(72), 139(72), 174(72), 181 Veronese, M., 350(69), 351-353(69), 421 Vickovic, I., 701(406), 846 Vidal, C., 700-701(390), 846
Author Index Viehe, H. G., 254(154,155), 363(154), 365(154), 368(154), 370(154), 423 Vigevani, E., 234(65), 266(309), 334(65), 363(309), 421, 427 Vigorita, M. G., 592(135), 629 Vikhlyarv, Yu.I., 640(100), 701(100), 717-718(100), 721(498), 746(100), 765(498), 782(100), 789(100), 829(100), 839, 848 Villefont, P., 3 14(274), 315(274,275), 316(276), 3 18(279), 406-407(274,275), 408(275), 411(279), 426 Vincent, E. J., 700(388), 846 Vinokurov, V. G., 249(138), 281(138), 364(138), 379(138), 423 Vitiello, B., 983(62), 1051 Vogt, B. R., 651(197,198), 679(198), 692(197, 198), 693(198), 749(198), 759(198), 841 Vogtle, F., 217(17), 239(92), 343(17), 420, 422 Voigt, H., 240(313), 357(313), 427 Volford, J., 681(337), 775-776(337), 785(337), 788(337), 845 Volke, J., 592(137), 623(137), 629, 684(350), 686(364), 700(350), 845 von Prann, F., 219(40), 338(40), 420 Von Voightlander, P. F., 255(159), 262(159), 306-308(159), 365-366(159), 403(159), 423, 479-480( 145),483(145), 485( 145). 527-530(145), 542 Vopilina, L. A., 220(52), 338-339(52), 342-343(52), 421 Voronova, L. A., 219(42), 338(42), 421 Waber, K-H., 561(77), 605(77), 628 Wachtel, H.. 187(6), 198-201(6), 207 Wada, H., 661(241), 800(241), 843 Wade, P. C . , 651(197,198), 679(198), 692(197, 198), 693(198), 749(198), 759(198), 841 Wagner, E., 295,296,296(228), 299,324(228, 230), 389(228,230,307), 390(230), 395-396(307), 396(229), 425 Wahl, H., 278(195), 375(195), 424 Wald, D. K, 248(130), 362(130), 423 Walia, A S., 273(188), 371(188), 373-374(188), 424 Walia, J. S., 273(188,189), 371(188), 373-374(188), 424 Walia, P. S., 273(188,189), 371(188), 373-374(188), 424 Walker, G N., 448(48), 461(48), 503-504(48), 540, 551(29), 626, 640,641(123), 657(123), 839, 840 Walkinshaw, M. D., 38(99), 88 Walser, A, 255(158), 258(158), 264(158,171, 172), 282-283(171), 285(171), 287(171), 363(158), 366-367(158), 367(171),
1087
374(158,171), 385(171), 423, 424, 433-434(2-4), 434(6), 434-435(5), 435-436(2), 438(5), 440(5,19,20,2 1,23,24), 440-445(5), 441(23,24), 442(21), 443(28), 444(2021), W6,192324), 446(20), 450(5), 45 1(92), 452(94), 454(21,92,94), 469(92), 472(92,94), 473-474(92), 474(19), 475(127), 477(5,92), 479(92,143,144), 480(5,143,144, 154). 482-483(161-163), 483(143,144), 484(5), 486(5,24,92), 487-488(20), 488(92), 490(20,21,127,192), 496-497(2,3), 497(4, 5,6), 498(19,21), 498-500(20), 499(21,23), 499-501(24), 500(23), 501(28), 509(92), 506(143,144), 519(19,21,143,144), 523(19, 92), 526(92), 526-527(143,144), 527( 161- 163), 528(92), 529( 154,161). 53 1(161), 531-532(21,92), 532(24), 535(92), 539, 541, 542, 553-554(34), 554(45), 556-557(34), 557(60), 558(62,63), 559(63,65,66), 560(73), 562(34), 564(65, 91-93), 564-566(63), 565(93,95), 566(92, 93,95), 567(92), 569-570(63), 571(62,66, 73,92,93,95), 572-573(63), 573( 108), 574(116), 575(63,66,116), 577(92,93), 578(93), 579(65,66,119), 580(63,73,92,93, 108,119,121), 583(60,126,127), 584(65,66, 73,92), 585(34,63,66,91,92), 586(62), 589(63), 597-598(45), 600(45), 602-603(34), 603(126), 603-604(45), 605(126), 605-607(63), 606-607(45,65,66), 607(73, 126), 608(66,95), 609(34,45,63,65), 61 1(60), 615(62), 615(73), 6 15-6 16(45), 6 18(93), 618-622(63), 619(95), 620(92,93,95), 62 l(9 1-93,95,116), 622(91-93,108,116,119), 625(45), 626-629, 633(13), 635(39), 638(72), 639(39,84), 642(134), 644(39,145, 47), 645(72), 646-647(134), 648(178,180), 654(39), 657(108), 659(134), 660(238), 661(242), 662(245,246), 663(245), 666(13), 666-668( 134), 667(238,277,278). 668(72,84, 147,277297,298),670( 134,249, 67 1(278), 673(134), 678(134277,298), 681(245), 683(343,345), 684( 147), 685(245246), 688(134,277), 689(72,134,145,242,298), 690(72,147,277), 691(72,245,277), 694(72, 245,246), 695(134), 697(238), 697-699(134), 701(415,421), 702(343,415), 703(134), 709(134), 713( 13), 7 14(298), 716( 13,298), 719(13), 722(246), 732(72,298), 735(72), 739(72,278), 741(72), 743(84,238), 744-745(72), 746(238), 747-748(72), 750(13), 751(245), 756(245), 763-764(245), 763-770(72), 765(238), 770(238), 778(39, 45), 779(145,147), 783(421), 785-789(147), 786(39,145), 793(278), 794(145),
1088
Author Index
Walser, k (Continued) 794-795( 147), 796(297,298), 798(147,297), 799(42 l), 800(39), 802(298), 803(39,298, 343), 804-806(147), 805(72,245,277,298), 808(245), 809(242), 812(277), 813(72.242, 343), 814(147,277), 826(298), 830(415), 831(343), 838-841, 843-845, 847, 852(17, 19,20), 853(24), 854(17), 856-858(17), 861-862(20), 863(17), 864(41,62), 866(17), 868(17), 872(41), 873(41,62), 874(17), 876(41), 882-884(17), 886(17), 887(62), 888(17), 904-909(17), 905-906(24), 906(19, 20), 907(20), 908(20), 908-909(17), 912(17), 9 14(41), 916-917( 17), 917(62), 92O-923( 17), 921(41), 929-931(17), 943, 944, 956(12), 957(16), 958(16), 959(16), 982-984(59), 988(16), 989(16), 991(16), 995(16), 1005(12), 1006(16), 1009(16), 1029(59), 1033(16), 1034(16), 1036(16), 1037(16), 1046(16), 1047(16), 1050 Wamhoff, H., 950(3), 1001(3), 999(116), 1049(116), 1050, 1052 Wasyliw, N., 667(287), 685(287), 894(287), 739(287), 744-748(287), 759-760(287), 762(287), 765-770(287), 844, 864(44), 913(44), 918(44), 920(44), 944 Watanabe, H., 120, 169(55), 181 Watanabe, T., 190(8), 202(8), 207, 488-489(188), 543 Watanabe, Y., 128(102), 140, 171(102), 178(102), 182 Wawzonek, S., 327(299), 427 Webb, G. A, 226(79), 238(88,89), 243(117), 246(117), 247(122), 272(117), 277(117,122), 343-344(79), 357(117,122), 358(122), 371(117), 421, 422 Weber 11, R. C., 136(106), 143(106), 176(106), 179(106), 182 Weber, K-H., 243-244(118), 255(118,157,161), 259(167), 261(170), 262(167), 264(118), 268(167), 279(204), 283-285(204,215), 286(204), 288(218), 293(243244), 294,295, 295(236,239,243,247,249,250), 297,297(118,243,246248,251,252),299, 300,300(238), 301-302(243), 302(218), 303(246,247), 304(239,245246), 305(252), 306(161), 363(118), 365-367(157,161,170), 365(167), 368(161), 369(167), 376-378(204), 380-384(204), 381-383(215), 386(236), 387(237) 387-395(239,241), 388(236,238, 25025 l), 388-389(233), 389-397(236), 390(245,246), 390-394(240,251), 391(250), 392(249), 393-395(236), 394(238,245,246), 395(249), 396(246), 396-398(243,247), 397(245246), 398-399(244), 399-400(243,
247,248), 400(246,247,252), 403( 161), 422-426, 633(19), 670(19), 709-710(468), 731(19), 771(19), 834-836(468), 837, 848,
852(10), 879(101,102), 881(10), 883(10, 101,102), 886(101), 889(126), 894(147), 903(10), 926(102), 926-928(101), 927(10), 934(126), 935-936(147), 943, 945, 946, 989(74,76,78),994-995(103), 1032-1035(78), 1033(74,76), 1040(76), 1045(74,76), 1046(103), 1051, 1052 Wegfahrt, P., 891(138), 893-895(138), 897(138), 933(138), 937-938(138), 946 Wehrli, P. A, 591(132), 602-603(132), 629, 646(160), 750(160), 841 Wei, P. H. L., 104, 105(27a), 152(27), 180, 672(309), 678(309), 688(309), 792(309), 844 Weisman, G. R., 6(3,4,6), 60(3,4), 86 Weissenfels, M., 245(120), 358(120), 422 Weissmann, B., 45-47(58), 49(58), 79(58), 87 Wells, N., 248(131), 361(131), 423 Welstead, Jr., W. J., 667(290), 844 Wenner, W., 557(56), 627, 890(132-134) 894(133), 895( 132,133), 93 1(132-134), 932-935(133), 935(132), 938(133), 946 Wermuth, C.-G., 45(55), 46-47,48(61), 47(55), 48(96), 77-78(55), 79-80(60,61), 87, 88 Werner, L. H., 259(166), 362(166), 424 Werner, S., 889(125), 891(125), 897(125), 933(125), 945 Werner, W., 242,272(113), 356(113), 373(113), 422
Wharton, H., 671(306), 844 Wheelock, R. H., 132(72), 139(72), 174(72), 181
White, J. D.. 889(124), 931(124), 945 Whitmore. W. F., 51(67), 87 Wigton, F. B., 247(128), 267(128), 281(128), 361(128), 422 Wild, D., 239(95), 268(95), 422 Wildersohn, M., 321(286), 413(286), 426 Wilka, E. M., 921(161), 946 Williams, E. F., 680(331,332), 736(33l), 770(331,332), 845 Williams, R. L., 218(19,23), 343(19), 346-347(23), 348(19), 420 Williamson, B., 634(30), 636(51), 721(30), 751(30), 773(30), 779(30), 837, 838 Wilson, F. B., 240(96), 422 Wilson, J. W., 448-449(42), 504-505(42), 510(42), 540 Winter, D., 583(125), 591(125), 605(125), 629, 647(170), 648(170), 660(233), 667(233), 668(233), 671(233), 688(233), 690(233), 692(233), 705(170), 726(233), 734-745(233), 740(233), 743(233), 746-747(233), 772(233),
Author Index
1089
781(233), 794(233), 831(170), 841, 842, 602(59), 603(37,59), 605(59,11l), 609(59), 865(68), 873(68), 876(68), 887(117), 611(58), 626-628, 635(37), 639(85,86,89), 916-917(68), 930(117), 944, 945 641(116-122,124,126,129-132), 642(125, Winter, K, 889(125), 891(125), 897(125), 133), 643( 129-133), 646(155,156), 933(125), 945 661(241), 666(268), 667(86,89,268,285,286, Winterfeld, K, 321(286), 413(286), 426 289), 7 13-716(86), 7 17(116), 7 18(124), Wissenfels, M., 216(8,9), 217(10-12), 334(12), 720(86), 722(86), 726(86), 729(86), 336(11), 337(9,11), 420 731-734(86), 733(285), 736(89), 739(125), Woerner, F. P., 116, 165(45), 181 740(86), 741(86,89,124), 742(285), 743(86, Wolbling, H., 41,45,47(51), 48,77(51), 78(51), 289), 744(86,89,125),745(86), 746-747(86, 87 125), 748-749(285), 749(86,124), 754(86), Wolf, E., 633(25), 668(25), 746(25), 766(25), 759(86), 760(285), 761-762(86), 763(89, 769(25), 837, 890(136), 932-936(136), 946 125), 765-767(86), 766(126), 768(89,116, Wolf, K.-U., 588(129), 589(129), 629 130), 769(86,125), 770(86,89), 787(86), Wolf, V., 106(29), 154(29), 180 797(86), 800(241), 803(86), 838-841, 843, Wolfe, J. F., 668(299), 671(299), 674, 844, 852(14,15), 860(15,40), 863(40), 795-798(299), 801(299), 803(299), 813(299), 866(72), 892(144), 904(14), 905(14), 826-827(299), 844 906(15), 907( 15,49), 919-920(40), Wolff, G.,9(11), 10(13,104), 62(11,104), 922-923(72), 933( 144), 943, 944, 946, 63(104), 64(13), 86, 88 992(93), 994(93,102), 1037- 1038(93), Wolfrum, R., 135(79), 178(79), 181 1038(102), 1041-1042(93), 1052 Wollweber, H., 103, 149(21), 180 Yamamoto, M., 553(33), 554(36,38,40), 599(38), Wong, J. L., 889(123), 893-895(123), 60 1(36), 626, 639(86,89), 641(125,132), 937-938(123), 945 642(125), 646(155), 667(86,89,286), Wong, Y.-S., 569(106), 572(106), 591(133), 713-716(86), 720(86), 722(86), 726(86), 598(106), 615-616(106), 628, 629, 638(69), 729(86), 731-734(86), 736(89), 739(125), 660(69), 664(69), 678(69), 686(69), 740(86), 741(86,89), 743-747(86), 744(89, 716(69), 747(69), 794(69), 838 125), 746-747(125), 749(86), 754(86), WOO,C. M., 224-224(63), 348-349(63), 421 759(86), 761-762(86), 763(89,125), 768(89), Woo, P. W. K, 130(63,65), 171(65), 181 765-767(86), 769(86,125), 770(86,89), Worm, M., 112(104), 164-165(104), 176(104), 787(86), 797(86), 803(86), 839-841, 844 182 Yamane, K, 13(24), 25(24), 67(24), 86 Worth, D. F., 114(44), 127-128(44), 132(70,72), Yamauchi, M., 186(2), 196(2a),207 137(70), 139(70,72), 161(44), 170(44), Yaremenko, F. G., 240(310), 357(310), 427 174(70,72),181 Yokoyama, H., 979(51,52), 1025(51,52), 1051 Wright, Jr., W. B., 119(51), 153-154(97), Yonan, P. K., 574(115), 601(115), 605(115), 628 167-168(51), 181, 182 Yonezawa, T., 218(28), 229(81), 343(28), 420, Wuensch, K-H., 646(161), 841, 881, 421 885(107), 945 York, E. E., 569(106), 572(106), 598(106), Wuest, H. M., 449(59), 455(105), 505(59), 540, 615-616(106), 628, 638(69), 660(69), 541 664(69), 678(69), 686(69), 716(69), 747(69), Wunsch, K-H., 554(46), 569(46), 597(46), 794(69), 838 603(46), 627 Yoshitake, A, 554(42), 569(42), 582(42), Wunsche, C., 251(148), 363(148), 423 603(42), 627, 647(163), 841 Wuttke, W., 998(114), 1049(114),1052 Youssef, A. F., 272(185,186), 277(185,286), 371-372(186), 424 Yabe, Y., 865(67), 922(67), 944 Yuguri, S., 54(72), 83(72), 87 Yagisawa, N., 130(64,66), 171(64), 181 Yukimoto, Y., 29(31), 71(31), 86 Yagupol'skii, L. M., 633(10), 666(10), 722(10), Yumasheva, E. I., 218(22,25), 345(25), 346(25), 751(10), 837 347(25), 420 Yur'ev, Yu. K, 218(32), 234(32), 343(32), 420 Yamada, Y., 880(104,105), 883(105), 925(104), 927-928(104,105), 945 Yurchenk0.A G., 641(115), 771(115), 810(115), Yamamoto, H., 547(8), 553(33), 554(36-38,40), 839 557(58,59), 561(82), 573(11l), 596-597(8), 599(37,38,59), 600(37), 601(8,36,58,59,11l), Zally, W. J., 434(7), 438-439(7), 439(14,16),
1090
Author Index
Zally, W. J. (Continued) 440(22), 445(7,14), 451(93), 466(7), 486(7), 492(14,16), 494(14,16), 496(7), 498(7), 499(22), 500(14,22), 500-501(16), 505(93), 518(7), 530(7), 532(7), 538(14), 539, 558-559(64), 559(68), 561(64), 565(94), 565(96), 568(96), 570-571(68), 571(96), 577(68), 585(96), 586(68), 588-589(68), 591(68), 592(64), 596(68), 605-606(68), 607(64), 608-609(68), 615(68), 619(96), 620(94,96), 623(96), 624(64), 627, 628, 646(151), 675(321), 708(464), 709-710(470), 834(464), 840, 844, 848, 852(22), 854(22), 866(71), 868(71), 879(103), 881(103), 884-886(103), 896(148), 906(22), 925(103), 927-929( 103), 943-946 Zanetti, G., 551(28), 626, 922-923(162), 937(162), 946 Zbylot, P., 273(189),424 Zecchi, G., 13(18), 15(77), 16(19,78,79),65(18), 66(18,19,87,88), 68(79), 86, 87 Zeile, K, 283-285(215), 295(236,237,249), 297(251), 381-383(215), 387-397(237), 386(236), 388(236251), 388-389(233), 390-394(251), 392(249), 393-395(236), 395(249), 425, 426 Zeller, P., 989(77,79), 1032-1033(77), 1035(77), 1039(77), 1041(77), 1043-1045(77), 1047(77), 1051 Zenchoff, G. (nee Silverman), 480(154), 482-483( 161), 527(161), 529( 154,161), 531(161), 542, 561(84), 563(84), 570(84), 573(110), 586(110), 587(84,110), 591(84), 599(84), 602(84), 603(110), 605(1 lo), 615(1lo), 628, 662-663(245), 668(277,297, 298), 668(277), 670(245), 678(277,298), 681(245), 685(245), 688(277), 689(298), 690(277), 69 1(245,277), 694(245), 714(298), 716(298), 732(298), 751(245), 756(245), 763-764(245), 796(297,298), 798(297), 802(298), 803(298), 805(245,277,298), 808(245), 812(277), 814(277), 826(298), 843, 844, 852(20), 853(23,27), 861-862(20), 864(62), 873(62), 887(62), 906-908(20), 917(62), 943, 944
Zerilli, L. F., 983(63), 1051 Zeugner, H., 554-556(47), 555(48,49,51), 556(51), 566(98), 569(48,49,102), 570(47, 98), 572(48), 579(51), 586(98), 587(48), 587-590(47), 588(48,49,102,129),589(48, 51,129), 598(49), 600(48,51,102), 606(48), 608-616(48), 610-614(47), 61 1(49), 613(49), 614(48), 615(49), 618-619(98), 627-629, 647(166,168), 841 Zhilina, Z. I., 633(10), 640(100), 641(115), 652(202), 663(202), 666(10), 671(202,304), 680(202), 685(202), 690-691(202), 700(378), 701(1OO,4O7), 7 17(100,202), 718( loo), 721(498), 721-724(202), 722(10), 746(100), 75 1(lo), 765(498), 77 1(115,202), 773-774(202), 776(202), 780(202), 781(304), 782(100), 786(202), 788-789(202), 789(100), 810(115), 824(304), 827-828(304), 829(100), 837, 839, 842, 844, 846, 848 Ziebandt, H., 218(30), 343(30), 420 Ziemer, P. D., 448(54), 540 Ziggotti, A, 634(31), 659(31,229), 721(31), 837, 842 Zimak, J., 686(364), 845 Zimmermann, E., 254(152), 362(152), 423 Zimrnermann, F., 285(217), 287(217), 380-383(217), 425 Zimmermann, H., 11(14), 64(14), 86 Zinic, M., 550(26), 551(26), 626, 633(20), 639(20), 72 1(20), 782-783(20), 788-789(20), 837 Zinner, G., 7,20(7), 61(7), 86, 452(112), 476-478( 112), 5 12(112), 521(112). 523-525(112), 541, 704(446), 847 Zitko, B., 92, 112-115(36a), 119(36a), 121(36a), 127(36a), 132(36a), 135-136(36a), 161-163(36a), 168(36a), 173-175(36a), 180, 181 Zolyorni, G., 36(43), 87 Zschiesche, W., 242,272(113), 356(113), 373(113), 422 Zubovics, Z., 252,259(149), 267(149), 281(149), 363(149), 368(149), 423 Zwahlen, W., 533(201), 543
Subject Index
Page numbers followed by the letter “t”, indicate the beginning page for the appropriate table of compounds. References to “Name” reactions and rearrangements within the text are exemplary only and were not used consistently. Each entry under “Generic Names” is followed by chemical nomenclature, in order to avoid possible confusion. References to spectral data listed in the tables are not indexed. Due to the volume of tabular material for dihydro-1,4benzodiazepin-2-ones (Chapter VII), indexing of this material has been subdivided according to the number of ring substituents for ease of reference. This index should be used in conjunction with the individual chapter indices and does not duplicate information provided therein. [a]-fused-[IZIdiazepines, 4ff pyrazolo[l2-a] [1,2]diazepines, 4 dihydropyrazolo[l,2-a][ 1,2]diazepinones, 59t hexahydropyrazolo [ 1,2-a][ 1,2]diazepine, 59t octahydropyridazino[ 1,2-a][ 1,2]diazepines, 60t pyridazino[ 1,2-a][1,2]diazepines, 6 tctrahydropyrazolo[l,2-a] [1,2]diazepinones, 59t triazolo[l,2-a][12]diazepines, 7 tetrahydrotriazol0[1,2~a][1,2]diazepindiones, 61t diazepindithiones, 61t diazepinone-thiones, 61t [a]-fused-[1,3]diazepines, 89ff 1,3 diazeto[l,2-a][1,3]diazepines. 92 imidazo[ 1,2-a][ 1,3]diazepines, 93 imidazo[l,5-a][ 1,3]diazepines, 95 pyrazolo[ 1,5-a][1,3]diazepines, 106 1,2,4-triazino[4,3-a][ 1,3]diazepines, 107 1,3,5-triazino[1.2-a][ 1,3]diazepines, 107 pyrido[1,2-a][1,3]diazepines, 96 dihydropyrido, 97 tetrahydropyrido, 98 pyrimido[l,2-n] [ 1,3]diazepines, 99 pyrimido[ 1,6-a][ 1,3]diazepines, 99 pyrrolo[l,2-a] [1,3]diazepines, 100 hexahydropyrrolo, 102 octahydropyrrolo, 102 tetrahydropyrrolo, 100 thiazolo[3,2-a] [ 1,3]diazepines, 104 hexahydro, 104 octahydro, 106 tetrahydro, 104 [a]-fused-[1,4]diazepines, 184ff
azirino[l2-a][1,4]diazepines, 184 imidazo[l,5-a]1,4]diazepines, 186 pyrido(l2-aI [1,4]diazepines. 186 pyrrolo[1,2-~][1,4]diazepines, 189 Acetanilides: 2-amino-, 633-641 2-azido-. 635 2-halo-, 633 hydrogen bonding, 635 Acetylamides: 2-amino, 951,953,954,961,998 2-azido, 950,961,965 2-bromo. 950,951,953,954,962,965, 985-987,998 2-phthalimido, 961 h i d e s , N-alkylation, methods, 666 N-alkylation of chiral benzodiazepines with retention of optical activity, see Racemization of 1,4-benzodiazepines during N-alkylation Amidines, 447-453 a-Amino acids: esters, use of, 639-640,965 N-protected. use of, 638-639 Azetidinobenzodiazepines, 616 Azeto[l,2-b][1,2]diazepines, 9 Aziridinoquinolines, 644 Azirino[l,2-a][1,4]diazepines, 184, 196t [b]-fused-[12]diazepines, 9ff azeto[l,2-b][l,2]diazepines, 9 5-carbethoxy-7-dimethylamrnonium-8,Xdimethyl, 63t dihydro, 62t oxazolo[4,5-b][ 1,2]diazepines, 10 dihydro, 63t pyrrolo[l,2-b][ 1,2]diazepines, 11
1091
1092
Subject Index
[b]-fused-[ 1,2]diazepines (Continued) 3H-derivatives, 64t thiazolo[3,2-b] [1,2]diazepines, 12 [b]-fused-[1,4]diazepines, 209ff 1.5-benzodiazepindiones,370t, 398t 1,s-benzodiazepines, 214, 334t -3-methylene 355t 1,s-benzodiazepinones,2 4 8 dihydro-1,s-benzodiazepindiones,386t -3-methylene, 399t dihydro-1,s-benzodiazepindithiones, 403t dihydro- 1,5-benzodiazepines, 240,356t dihydro-1,s-benzodiazepinones,361t dihydro-1,s-benzodiazepinthiones, 400t -4-OXO,402t dihydro-1,s-benzodiazepintriones, 400t hexahydro-1.5-benzodiazepines,403t octahydro-1,s-benzodiazepines, 404t perhydro-1,s-benzodiazepines, 404t tetrahydro-1 ,5-benzodiazepines, 370t tetrahydro-l,S-benzodiazepinones,375t, 389 -4-methylene, 3 8 3 tetrahydro-1,s-benzodiazepinthiones,402t Beckmann rearrangement, 190,867 Benzimidazole, 233 Benzisoxazoles, 687 by ring contraction, 472 BenzoIb] [1,4]diazepines, see also [b]-fused[ 1.41diazepines 1,2-Benzodiazepines, see also [c]-fused[ 1,2]diazepines, Id]-fused-[1,2]diazepines, benzo[c] [ 1,2]diazepines, 13 1,3-Benzodiazepines, 108, 156t. See also [c]fused-[1,3]diazepines [d]-fused- [ 1,3]diazepines, benzo[d][1,3]diazepines, 109, 157t 1,4-Benzodiazepines, 429ff. See also [elfused-[1,4]diazepines, benzo[e] [1,4]diazepines dihydro-1,4-Benzodiazepines,545ff 1.5-Benzodiazepines, 209,334t. See also [b]fused- 1,4]diazepines, benzo[b] [ 1,4]diazepines 2,3-Benzodiazepines, 32. See also [d]-fused[12]diazepines, Benzo[d] [ 1,2]diazepines 2,4-Benzodiazepines, 173t. See also [elfused-[ 1,3]diazepines benzo[e][2,4]diazepines Benzodiazocines, 555,556 Benzodiazoxecines, 697 Benzotriazepines (-inium salts), 645 Benzotriazole, 227 Benzoxazines, 712
1,2-Benzoxazocines, 645 Beta-lactams, see Azetidinobenzodiazepines Bischler-Napieralski ring closure, 554-556 [c] -fused-[ 1,2]diazepines, 12ff
benzo[c] [ 1,2]diazepines: 1,2-benzodiazepines, 13,21 -N-oxides, 18 dihydro- 1,2-benzodiazepines, 24,68t dihydro-1,2-benzodiazepinones,69t hexahydro-1,2-benzodiazepines,27,70t tetrahydro- 1,2-benzodiazepines, 26,69t, 70t cyclopenta[c] [ 1,2]diazepines, 29 hexahydrocyclopenta [ c ][ 1,2]diazepines, 70t, 71t cyclopropa [b][ 1,4]diazepines: hexahydrocyclopropa [b][1.4)diazepines, 405t cyclopropa[c] [ 1,2]diazepines, 29 dihydrocyclopropa [c] [ 1.21diazepinones, 71t hetero[c] [ 1,2]diazepines, 29 furo[2,3-c][12]diazepines, 71t furo[3,2-c][ 1,2]diazepines, 71t pyrido[2,3-c][ 1,2]diazepines, 72t pyrido[3,2-c][ 1,2]diazepines, 72t pyrimido[4,5-c][12ldiazepinones dihydro, 73t thieno[2,3-c] [12]diazepines,73t thieno[3,2-c] [ 1,2]diazepines, 74t [c]-fused[1,3]diazepines, 108, 156t dihydro-imidazo[3,4-c][ 1,3]diazepines, 156t I3C magnetic resonance, see under Spectra Chapman rearrangement, see under Rearrangements Compounds, see Tables of compounds Conformational analysis, 39.40, 139,239, 247,268,277,304,308,592,700,701. See also Ring Inversion Cyclohexadiazepines, see under corresponding Hexahydro-, Octahydro-, and Perhydrodiazepines Cyclopenta[c] [ 1,2]diazepines,see under [c]fused[ 12]diazepines, 29 Cyclopenta[d][l,2]diazepines,51, 81t Cyclopenta[e] [1,3]diazepines, 140, 178t Cyclopenta[e] [1,4]diazepines,949, l0OOt Cyclopropa[c] [ 12]diazepines,see under [c]fused[ 1,2]diazepines, 29 Cyclopropa[d][1,2]diazepines, 52 [d]-fused-[12]diazepines, 32ff benzo[d][ 1,2]diazepines, 32
Subject Index 2,3-benzodiazepines, 32-34, 35,74t, 75t dihydro, 41,76t, 71t dihydro-2,3-benzodiazepindiones, 80t dihydro-2,3-benzodiazepinones,44,45, 71t, 78t tetrahydro-2,3-benzodiazepines, 49, 80t tetrahydro-2,3-benzodiazepinones, 50, 80t cyclopenta[d] [1,2]diazepines, 51, 81t cyclopenta[e][ 1,4]diazepines, 949, lOOOt cyclopropa[d][ 12]diazepines, 52 tetrahydro, 81t hetero[d] [12]diazepines,see under appropriate Heterocycle oxireno[d] [1,2]diazepines, 52 hexahydrooxireno[d] [ 1,2]diazepinones, 81t tetrahydrooxireno [d][ 1,2]diazepinones, 81t pyrazolo[3,4-d] [ 12]diazepines, 54 dihydropyrazolo[3,4-d][ 1,2]diazepines, 82t dihydropyrido [3,2-d][ 1,2]diazepinones, 83t pyrido[3,2-d][1,2]diazepines, 56 tetrahydropyrazolo [3,4-d][ 1.21diazepindiones, 83t tetrahydropyrazolo [3,4-d][ 1.21diazepines, 82t, 83t thieno[d][ 1,2]diazepines, 56 thieno[2,3-d] [ 12]diazepines, 84t, 85t dihydro, 85t thieno[3,2-d] [ 1,2]diazepines, 84t [d]-fused [ 1,3]diazepines, 109ff benzo[d][l,3]diazepines,109, 157t
dihydro-1,3-benzodiazepindiones (sometimes as tetrahydro-), 123, 169t
dihydro-1,3-benzodiazepines,112, 158t dihydro-1,3-benzodiazepinones, 116, 163 tetrahydro-I ,3-benzodiazepindiones. 123, 169t. See also Dihydro, -diones tetrahydro-1,3-benzodiazepines,118, 167t tetrahydro-1,3-benzodiazepinones, 119, 167-168t tetrahydro-1,3-benzodiazepinthiones, 127, 170t
tetrahydro-2-cyanoimino-1,3-benzodiazepines, 128. 171t imidazo[4,5-d][ 1,3]diazepines, 129 dihydroimidazo[5,4-b] [ 1,3]diazepinones, 130. 172t tetrahydroimidazo[4,5-d] [ 1,3]diazepines,
1093
130, 171t [d]-fused [1,4]diazepines, 191 imidazo[l,2-d] [1,4]diazepines, 191, 203t pyrido[I,2-d][1,4]diazepines, 193,203t pyrrolo[l,2-d] [1,4]diazepines, 194,206t Decahydro-, see also Perhydro-: 1,4+enzodiazepines, 924t pyrano[2,3-e][ 1A)diazepines. 1005t pyrido[l,2-a][1,4]diazepines, 186, 197t pyrido[l.2-d] [1,4]diazepines, 193,203t Diazabicyclo-: decanes, 4 nonanes, 9 octanes, 24, 52, 184 undecanes, 6 Diaza-oxabicyclo octanes, 53 Diazeto[ 1,2-a][ 1,3]diazepines, 92, 144t Diazo-dihydro-l,5-benzodiazepin-diones, 398t Diekmann type ring closures, 580 Diels-Alder adducts, 10,29,437 Dihydro-: azeto[l2-b] [1,2]diazepines, 62t azirino[l2-a] [ 1,4]diazepines, 184, 196t 1,2-benzodiazepines, 24,68t diazepinones. 69t 1,3-benzodiazepines, 112 diazepinones, 116 1,4benzodiazepines, 545,596t 1.2-3H-3-methylene-, 567, 623t 1,2-3H-3-ones, 706, 833t 1,2-5H-5-ones, 708, 834t 1,3-2H-, 564,623t 1,3-2H-2-methylene-, 564,618t 1.3-2H-3-methylene-2-ones, 82 1t 1,3-2H-2-ones,633, 713t ff disubstituted, 715t-731 t heptasubstituted, 821t hexasubstituted, 818t-82 1t monosubstituted, 7 13t-7 15t octasubstituted, 821t pentasubstituted, 81lt-818t tetrasubstituted, 795t-81 It trisubstituted, 73 It-793 unsubstituted, 713t 1,3-2H-2-thiones, 701,828t 1,4-5H-5-ones,708, 834t 1,5-2H-5-methylene-2-ones, 833t 1,5-2H-2-ones,705,83 It 2,3-1H-, 547, 568, 596t 2-imino-, 563,617t 2,5-1H-, 592, 624t 3,4-5H-5-ones, 709, 834t 4,5-1H-, 593, 625t
1094
Subject Index
Dihydro- (Continued) 4,5-3H-, 594, 625t 4,5-3H-3-ones, 707,833t 1,4-benzodiazepinediones, 71 1 1H-2,3(2H.3H)-diones, 836t 2,4-dihydro-: lH-3,5(3H,5H)-diones, 897,938t 2-methyIene-lH-3,5(3H. 5H)-diones, 939t 3,4-dihydro-: lH-2.5(W 5H)-diones, 889,931t 1H-2.5(2H,5H)-dithones, 941t lH-5(5H)-one-2(2H)-thiones, 940t 3-methylene- lH-2,5(2H.5H)-diones, 937t 4,5-dihydro-: lH-2(2H)-one-3(3H)-thiones,940t 1H-2,3(2H,3H)-diones, 887,930t 1,4-benzodiazepinetriones, 836t 1,5-benzodiazepindiones,386t 3-diazo, 398t 3-methylene, 399t 1,5-benzodiazepindithiones,403t 1,5-benzodiazepines, 240,356t 1,5-benzodiazepinones, 361t 1,5-benzodiazepinthiones, 400t 4-0X0,402t 1,5-benzodiazepintriones, 400t 2,3-benzodiazepindiones, 80t 2,3-benzodiazepines, 41,76t, 77t 2,3-benzodiazepinones, 44,45,77t, 78t 2,4-benzodiazepines, 132 2,4benzodiazepinones, 133 cyclopropa[c] [ 1,2]diazepinones, 71t imidazo[3,4-c] [ 1,3]diazepines, 156t imidazo[4,5-e] [ 1,4]diazepinones, 1002t isothiazolo[3,4-e][l,4]diazepinones, 1004t isoxazolo[4,3-e] [ 1,4]diazepinones, 1003t isoxazolo[5,4-e] [ 1,4]diazepinones, 1004t oxazolo[4,5-b] [ 1,2]diazepines, 63t pyrazino[2,3-e] [ 1,4]diazepinones, 1003 pyrazolo[l,2-a] [1,2]diazepinones, 59t pyrazolo[3,4-b] [ 1,4]diazepindiones, 40% pyrazolo[3,4-b] [ 1,4]diazepines,406t pyrazolo [3,441[ 1,4]diazepinones, 407t pyrazolo [3,4-d][ 1,2]diazepindiones, 82t pyrazolo[3,4-e] [ 1,4]diazepines, 1006t pyrazolo[4,3-e][ 1,4]diazepines, 1012t pyrido[l,2-a] [1,3]diazepines, 97 pyrido[2,3-b] [1,4]diazepines, 414t pyrido[2,3-b][1,4]diazepinones, 41 I t pyrido[2,3-e] [ 1,4]diazepindiones, 1018t pyrido[2,3-e] [1,4]diazepines, 1019t pyrido[2,3-e][ 1,4]diazepinones, 1016t
pyrido[3,2-d] [1,2]diazepinones. 83t pyrido[3,2-e][ 1,4]diazepindiones, 1023t pyrido[3,2-e][ 1,4]diazepinones, 1023t pyrido [3,2-e][1,4]diazepinthiones, 1023t pyrido[3,4-b][lAldiazepindiones, 413t pyrido[3,4-b] [1,4]diazepinones, 413t pyrido [3,4-el[1,4]diazepinones, 1023t pyrido [4,3-e][ 1.41diazepindiones, 1024t pyrido[4,3-e][ 1,4]diazepinones, 1024t pyrimido[4,5-b][ 1,4]diazepindiones, 418t pyrimido[4,5-b][ 1,4]diazepinones, 414t pyrimido[4,5-c][ 1,2]diazepinones, 73t pyrimido[4,5-e] [ 1,2]diazepines, 1023 thiadiazolo[3,4-e][ 1,4]diazepinthiones, 1030t thiazolo[4,5-e] [ 1,4]diazepinones, 1030t thiazolo[4,5-e] [1,4]diazepinthiones, 1031t thiazolo[5,4-e][ 1,4]diazepinones, 103It thieno[2,3-d] [12]diazepines,85t thieno[2,3-e] [ l,4]diazepines, 1035t 2-methylene, 1037t thieno[2,3-e] [ 1,4]diazepinones, 1037t. 1046t thieno[2,3-e] [ 1,4]diazepinthiones, 1043 thieno [3,2-e] [ 1.41diazepindiones, 1048t thieno[3,2-e] [ 1,4]diazepines, 1046t 2-methylene, 1047t thieno[3,2-e] [1,4]diazepinones. 1047t thieno[3,4-e] [ 1,4]diazepindiones, 1049t thieno[3,4-e] [ 1,4]diazepinones. 1048 triazolo[4,5-b] [1,4]diazepinones, 419t Diketopiperazines, 640 -dipyrazolo (tricyclic), 968 [el-fused[ 1,3]diazepines, 131ff benzo[e][ 1,3]diazepines (2,4benzodiazepines), 132 dihydro-2,4-benzodiazepines. 132 dihydro-2,4-benzodiazepinones, 133 benzodiazepinthiones. 137 tetrahydro-2,4-benzodiazepindiones, 136 tetrahydro-2,4-benzodiazepines, 135 -3-cyanoimino, 140 tetrahydro-2,4-benzodiazepinones, 135 diazepinthiones, 137 tetrahydro-2,4-benzodiazepintriones. 137 cyclopenta[e] [ 1,3]diazepines, 140 thieno[3,4-e][ 1,3]diazepines, 141 furo[3,4-e][ 1.31diazepines. 142 pyrrolo[3,4-e][1,3]diazepines, 142 [el-fused [ 1,4]diazepines, 429ff lH-1,4-benzodiazepines, 433,496t 3H-1,4-benzodiazepines, 438,498t
Subject Index
2-amino-3H-l,4-benzodiazepines, 447, 502t 2-methylamino-, 504t N-acyl-2-amino-, 520t N-Methyl-N-nitroso-2-amino-, 5 19t N,N-disubstituted 2-amino-, 514t other N-substituted 2-amino-, 509t 2-carbon substituted, 438,496t 2-halogen substituted, 491,537t 2-hydrazino-3H-l.4-benzodiazepines. 478, 526t N-substituted 2-hydrazino-, 52% 2-hydroxyamino-3H- 1.4benzodiazepines. 476,523t 2-oxygen substituted, 486,531t N-alkoxy-2-amino-, 525t 2-thio substituted, 486,534t 5H-1,4-benzodiazepines. 492,538t decahydro-, 900 dihydro-, see also Dihydro-, 1,4benzodiazepines 1.4-benzodiazepindiones,71 1 2.4-1H-1,4-benzodiazepin-3,5-diones, 897 3,4-1H-1,4-benzodiazepin-2,5-diones, 889 4 5 1H-l.4-benzodiazepin-2,3-diones, 887 1,Cbenzodiazepines, 545ff 1,4-benzodiazepinones and -thiones, 631ff 1,3-2H-1,4-benzodiazepin-2-ones, 633 1,3-2H-1,4-benzodiazepin-2-thiones, 701 1,5-2H-1,4-benzodiazepin-2-ones, 705 706 1,2-3H-1,4-benzodiazepin-3-ones, 4.5-38- 1,4-benzodiazepin-3-ones, 707 1,2-5H-1,4-benzodiazepin-5-ones, 708 1,4-5H-1,4-benzodiazepin-5-opes, 708 3.4-2H-1,4-benzodiazepin-5-ones. 709 octahydro-, 900 tetrahydro-, see also Dihydro-, diones, 849ff 1.4-benzodiazepines, 85 1 134-benzodiazepin-: 2-ones, 964 3-ones, 867 5-ones, 878 thiones, 898 Electrophiles, reactions with, see individual chapter Table of Contents Eliminations, synthesis by, see individual chapter Table of Contents Energy, see Ring, inversion, energy required for Eschweiler-Clarke degradation, 192
1095
Fermentation, metabolites: from streptomyces antibioticus NRRL 3238, 130 from streptomyces kamikawaensis, 130 Fischer indole synthesis, 860 Free energy, see Ring inversion, energy required for Friedel-Crafts acylation, 965,996,998 Furan, dihydro, 950 Furo[2,3-c][12]diazepines, 71t Furo[2,3-e][1,4]diazepines, 950, 1003t Furo[3,2-c][1,2]diazepines, 71t Furo[3,4-e][1,3]diazepines, 142, 179t Generic names, see also Natural products bromazepam [7-bromo-1,3-dihydro-5(2pyridy1)-1,4-benzodiazapin-2-(2H)-one], 636,637,700 chlordiazepoxide [7-chloro-2-methylamino5-phenyl-(3H)- 1,4-benzodiazapine 4oxide], 447,448,452-454,458,462,464, 466,480,595 N-nitrosochlordiazepoxide 17-Chloro-2(N-nitroso)methylamino-5-phenyl-(3H)l,4-benzodiazapine 4-0xide],479,480 clonazepam [5(2-chlorophenyl)-l,3dihydro-1-methyl-7-nitro- 1,4benzodiazapin-2-(2H)-one], 697 diazepam, [7-chloro-1,3-dihydro-l-rnethyl-
5-phenyl-l,4-benzodiazapin-2-(2H)one], 569,634, 641, 644,646, 651, 655, 656, 651,668, 671. 674, 675, 681, 697, 700,878,896 desmethyldiazepam (nordiazepam), [ 7-
chloro-1,3-dihydro-5-phenyl-1,4benzodiazapin-2-(2H)-one],570,681, 682,683,700 etizolam, [5(2-chlorophenyl)-7-ethyl- 1methyl- 1,3-dihydrothienyo[2,3993 el [ 1,4]diazepin-2(2H)-one], fludiazepam, [7-chloro-1,3-dihydro-5-(2fluoropheny1)-1-methyl- 1,4benzodiazapin-2-(2H)-one].686 flunitrazepam, 686,697 [5(2-fluorophenyl)-l-methyl-7-nitro1.3dihydro-1,4-benzodiazapin-2-(2H)-one] flurazepam, [7-chloro-l-diethylaminoethyl1,3-dihydro-5-(2-fluorophenyl)-1,4benzodiazapin-2-(2H)-one],687 medazepam, [7-chloro-l-methyl-5-phenyl1,2,3,4-tetrahydro-l,4-benzodiazapineI1 547-549,551,562,568, 578,580,582, 583 desmethylmedazepam, [7-chloro-5-
1096
Subject Index
Imidazo[ 1,2-a][ 1,3]diazepines, 93, 144t Imidazo[l,2-d][1,4]diazepines. 191 Imidazo[ 1,5-a][ 1,3]diazepines, 95. 145t Imidazo[l,S-a][ 1,4]diazepines, 186 Imidazo[4,5-d][1,3]diazepines, 129, 171t Imidazo[4,5-e] [1,4]diazepines,951. 1002t Imidazolidines, 950,956 Imidazopyrazolodiazepines. 958,959 Imidazopyridodiazepines, 972 Imidazopyrrolodiazepines, 984 1,3-dihydro-l,4-benzodiazapin-2-(2H)- Imidazothienodiazepines, 988,989,991. one 4-oxide1, 686 999 Indazoles, 19.20,23,24,687 premazepam, [6,7-dimethyl-5-phenylIndene. 22 1,2,3,7-tetrahydropyrrol0[3.4Indoles. 24, 112,437,455-457.466. 52, 586, el [1,4]diazepin-2-one],938 591,592,642,892. See also Isatins triflubazam, [5-methyl-l-phenyl-8trifluoromethyl-3,5-dihydro-lH1,5oxidation of, see individual chapter Table benzodiazepin-2,4(W,4H)dione],305 of Contents Grignard reaction, 866,867, 877,953,956, Infra-red, see Spectra, infra-red 996.998 Ironpentacarbonyl, 125 Isatins, 650 Haloacetanilides. synthetic utility of, see Isocoumarin, 44,45 Acetanilides; individual chapter Table of Isoindoles, 34,683,698, 704 Contents diazeto-, 34 Hexahydro-: Isoindolobenzodiazepines, 657 1,2-benzodiazepines, 27,70t Isoquinolones, 45,47,48 1,4-benzodiazepines, 900 Isothiazolo[3,4-e] [ 1,4]diazepines, 954, 1004t 1,5-benzodiazepines, 403t Isoxazolobenzodiazepines,699 cyclopenta[c][ 1,2]diazepines, 70t, 71t Isoxazolo [4,3-el[1,4]diazepines, 953, 1003t cyclopropa[b][ 1,4]diazepines, 403 furo[2,3-e][ 1,4]diazepinones. l00lt Isoxazolo [4,5-b][ 1.41diazepines, 4 0 3 Isoxazolo[5,4-e][ 1,4]diazepines, 953, 1003t imidazo[l,2-d] [1,4]diazepines, 191,203t oxireno[d][1,2]diazepinones. 81t Kinetic Studies, 296. See also Conformational pyrazolo(l,2-a][l,2]diazepine,59t pyrazolo[3,4-b] [1,4]diazepines, 406t Analysis, Ring inversion pyrazolo[3,4-e] [1,4]diazepines, 101It pyrazolo [3,4-e][ 1,4]diazepinones, 1012t List of compounds, see Tables of compounds pyrazolo [4,3-el[1,4]diazepinones, 1015t Magnetic resonance, see Spectra pyrimido[4,5-b] [ 1,4]diazepindiones, 418t pyrimido[4,5-b] [ lA]diazepintriones, 4 1 8 Mass spectra, see Spectra, general, other pyrimido [5,4-e] [ 1,4]diazepindiones, 1026t Metabolites, see also Fermentation; Natural pyrrolo[l,2-a][ 1,3]diazepines, 102 Products of triflubazam, 305 thiazolo[3,2-a] [ 1,3]diazepines, 104 of premazepam, 983 Hexamethylenetetramine, 636, 637 Metal complex, 239, 700 Hoffmann elimination (degradation), 194, 2-Methylene-dihydrothieno[2,3-e] [ 1.41di195,656 azepines, 1047t Homodiazepines, see Cyclopropa[d] [ 1,2]di3-Methylene-1,5-benzodiazepines, 353 azepines 4-Methylene-tetrahydro-1,5-benzodiazepin-2Homophthalic anhydride, 51 ones, 3 8 3 Hydrolysis, syntheses by, see individual 6-Methylene-tetrahydropyrrolo[3,4chapter Table of Contents el [1,4]diazepines, 1029t 7-Methylene-tetrahydropyrazolo[3,4Imidazobenzodiazepines, 578-58 1,590,649, e][l,4]diazepines, 1008t 676,692,704,710,885,895 Generic names (Continued) phenyl- 1,2,3,4-tetrahydro-1,4benzodiazepine], 551.592 nitrazepam. [7-nitro-5-phenyl-l,3-dihydro1,4-benzodiazapin-2-(2H)-one], 655. 656,692,697,700,871 oxazepam, [7-chloro-3-hydroxy-5-phenyl)1,3-dihydro-1,4-benzodiazapin-Z-(2H)one], 686,688, 695, 712 4-oxide, [7-chloro-3-hydroxy-5-phenyl)-
Subject Index
1097
Michael type addition, 187, 195,241,455, 459,871
Oxindole, 121 Oxireno[d][1,2]diazepines, 52, 81t
Naphthiridines, 976 Natural products, see also Fermentation metabolites coformycin, 130, 139 covidarabine, 139 2'-desoxycoformycin, 130 Nitrosamines, the activation of adjacent carbon atom by, 559,560 N-imides, rearrangement, 110 N-oxides. nitrones, 447-449 activation of adjacent methylene groups, 18,22. See also Oxaziridines; Polonovski rearrangement Nuclear magnetic resonance, see Spectra Nucleophiles, reactions with, see individual chapter Table of Contents
pK,, for protonation, 215,225-226, 568,668, 700,994 Perhydro-, 187. 193,331,955, See also Decahydro; Dihydro; Hexahydro; Octahydro; Tetrahydro 1,4benzodiazepines, 941t, 942t 1,5-benzodiazepines, 404t furodiazepine, 950 Piperidinobenzodiazepines, 580 Polonovski rearrangement, 462,677,678, 984,993 Polyhydro, see PerhydroProton magnetic resonance, see Spectra, pmr (nmr) Pyrano[2,3-e][l,4]diazepines, 955, 1009 Pyrans, dihydro, 955 Pyrazines, 956 Pyrazinobenzodiazepines,574 Pyrazino[2,3-e][1,4]diazepines, 956, 1003 Pyrazoles, 960,962,964,966-969 Pyrazolo[l,2-a] [12]diazepines,4 Pyrazolo[l,5-a] [1,3]diazepines. 106, 154t Pyrazolo[3,4-b][ 1,4]diazepindiones. 408t Pyrazolo[3,4-b][ 1,4]diazepines, 406t Pyrazolo[3,4-b][ 1,4]diazepinones, 407t Pyrazolo[3,4-d] [ 1,2]diazepines, 54, 82t, 83t Pyrazolo[3,Ce][1,4]diazepines, 956,964, 1006t, lOllt Pyrazolo[3,4-e][ 1,4]diazepinones, thiones, 961, 1009t Pyrazolo[4,3-e][1,4]diazepines, 964, 1012t Pyrazolo [4,3-e][1,4]diazepinones, 965, 1012t Pyrazolopyrimidine, 106 Pyrazoloquinolinones, 964 Pyridazino[ 1,2-a][ 1,2]-diazepines, 6 Pyridines, 970,973,975,976,978 Pyrido[l,Z-a][1,3]diazepines, 96, 146t Pyrido[l,2-a] [1,4]diazepines, 186 Pyrido[l,2-d][1,4]diazepines, 193 Pyrido[2,3-b][ 1,4]diazepindiones, 412t Pyrido[2,3-b][1,4]diazepines. 410t Pyrido[2,3-b][ 1,4]diazepinones, 41 It Pyrido[2,3-b][ 1,4]diazepinthiones, 412t Pyrido[2,3-c][1,2]diazepines. 72t Pyrido[2,3-e][1,4]diazepindiones,972, 1018t Pyrido[2.3-e][lAldiazepines, 969, 1016t Pyrido[2,3-e][ 1,4]diazepinones, thiones, 97 1, 973, 1016t, 1019t Pyrido[3,2-d][ 1,2]diazepines, 56,83t Pyrido[3,2-e][ 1,4]diazepindiones, thiones, 977, 1023t
Octahydro-: 1,4-benzodiazepines, 900,941t, 942t 1,5-benzodiazepines. 404t cyclopenta[e] [ lAIdiazepinones, lOoot furo[2,3-e][1,4]diazepines. l00lt pyridazino[ 1,2-a][ lZjdiazepines, 60t pyrido[ 1,2-a][ 1,4]diazepine-ones,201t pyrido[ 1,2-d][ 1,4]diazepine-ones, 193,205t pyrido[2,3-e][1,4]diazepinones. 1018, 1019t pyrrolo[l,2-a][ 1,4jdiazepines, 203t pyrrolo[ 1,2-d][ 1,4]diazepinones, 194,206t pyrrolo[l,2-a] [ 1,3]diazepines, 100 pyrrolo[2,3-e][ 1,4]diazepinones, 1027t thiazolo[3,2-a][ 1,3]diazepines, 106 Optical activity, see Racemization of 1,4benzodiazepines during N-alkylation Oxadiazolobenzodiazepines, 675, 678 Oxadiazolo[3,4-b][ 1,4]diazepines,405t Oxadiazolothienodiazepines, 990 Oxathiazocinobenzodiazepine, 577 Oxathiolium salts, 985 Oxazinobenzodiazepines, 577,588,657,673, 675 Oxaziridines, rearrangement to nitrones, 453,856,865 Oxaziridinobenzodiazepines, 657,697 Oxazoles, 954,955 Oxazolidinobenzodiazepines, 578,580 Oxazolobenzodiazepines, 657,671,672 Oxazolo[4,5-b][ 1,2]diazepines, 10 Oxazolo[5,4-e][ 1,4]diazepines,954, 1004t Oxazoloquinolines, 682 Oxidations, synthesis by, see individual chapter Table of Contents
1098
Subject Index
Pyrido[3,2-e][1,4]diazepines,973, 1019t Pyrido[3,2-e][ lA]diazepinones, 975, 1020t Pyrido[3,4-b][ 1,4]diazepindiones, 414t Pyrido[3,4-b][ 1,4]diazepines,413t Pyrido[3,4-b][1,4]diazepinones, 413t Pyrido[3,4-e][ 1,4]diazepinones, 978, 1023t Pyrido[4,3-e][ 1,4]diazepinones, 978, 1024t Pyridopyrimidine, 97 Pyridoxazinones, 972,978 Pyrimidines, 980,981 Pyrimidobenzodiazepines, 567,577,675,693 Pyrimido[ 1,2-a][ 1,3]diazepines,99, 147t Pyrimido[l.6-a] [ 1,3]diazepines,99, 148t Pyrimido[4,5-b] [ 1,4]diazepindiones, 415t Pyrimido[4,5-b][ 1,4]diazepines,415t Pyrimido[4,5-b] [ 1,4]diazepinones, 415t Pyrimido [4,5-b][ 1,4]diazepintriones, 4 18t Pyrimido[4,5-c][1,2]diazepines, 73t Pyrimido[4,5-e][ 1,4]diazepines,979, 1025t Pyrimido[5,4-e][1,4]diazepines,981, 1026t Pyrrolidinobenzodiazepines, 515 Pyrroles, 982,983 Pyrrolobenzodiazepines, 678 Pyrrolo[1,2-a][1,3]diazepines, 100, 148t Pyrrolo[l,2-a] [1,4]diazepines, 189 Pyrrolo[ 1,2-d][1,4]diazepines, 194 Pyrrolo[l,6-a] [1,3]diazepines, 100, 148t Pyrrolo[l,2-b] [12]diazepines, 11 Pyrrolo[2,3-e][ 1,4]diazepines,982, 1027t Pyrrolo[3,2-e][ 1,4]diazepines,982, 1027t Pyrrolo[3,4-c][ 1,4]diazepindiones, 419t Pyrrolo[3,4-e][1,3]diazepines, 142, 179t Pyrrolo[3,4-e][ 1,4]diazepines, 982, 1027- 1029t Pyrroloquinolines, 590 Quinazolines, via ring contraction, 470, 595 N-oxides, ring enlargement, 447-449 Quinazolones, 879,880,881,889,891 Quinolines, 456,586 -ones, 897 -ones, rearrangement of, 892 Quinoxalines, 221,227-229,683,697,699,863 Racemization of 1,4benzodiazepines during N-alkylation, method for avoiding, 666 Reactions of, see also individual chapter Table of Contents named: Diels-Alder, 10, 29,437 Eschweiler-Clarke, 192 Fischer indole synthesis, 860 Friedel-Crafts, 965,996,998
Grignard reaction, 866, 867, 877,953, 956,996,998 Hoffmann degradation, 194, 195,656 Sandmeyer, 287,876,883 Ullmann, 296,670 with electrophiles, nucleophiles, other, see individual chapter Table of Contents Rearrangements, named: Beckmann, 190,867 Chapman, 657,842 Polonovski, 677,678,984,993 Schmidt, 187, 194, 195,280-281,320,867, 881,971 Smiles, 635. 996 Rearrangements, synthetic utility of, see individual chapter Table of Contents Reductions, see individual chapier, Table of Contents Ring: closure, name reactions: Bischler-Napieralski, 554-556 Diekmann type, 580 contraction, syntheses by, see individual chapter Table of Contents expansion, syntheses by, see individual chapter Table of Contents inversion, energy required for, 23, 39,40, 240,247,268,308,700. See also Conformational analysis Sandmeyer reaction, 287,876,883 Schmidt reaction, 187, 194, 195,280-281, 320,867,881,971 Smiles rearrangement, 635,996 Spectra (excludes tabular references): I3C nmr, 36,40,246,433,701 general, other (ms, uv etc.), 10, 51.92, 107, 109, 111, 124, 130, 141,218,224, 225, 231,239,247,251,268, 277,278, 305, 308,309, 316, 318, 322, 325,326, 327,477, 495, 592, 593, 635, 670, 699, 700 infra-red, 29,42,44, 108,214,218,309, 327,592,635 pmr (nmr), 6, 11, 13, 18,23, 39,40, 54, 56, 98, 139, 141, 185, 190, 218, 220, 239,246,268,277,296,304,308.3 11, 313, 318, 320, 332, 333,433, 592. 635,700,701,994 x-ray, 33, 54, 130, 141,239,240,466(2), 479.577,592,699,701,706 Syntheses, methods of, see individual chapter Table of Contents
Subject Index Tables of compounds, 59t, 143, 196t, 334t, 496t, 596f 713t, 901t, lOO0t Tetracyclic-diazepines and other compounds, 657.856.860 Tetrahydro-: 1,2-benzodiazepines, -ones, 26, 69t, 70t 1,3-benzodiazepines, 118, 119, 128 1,3-benzodiazepinones, 119 1,3-benzodiazepindiones,123 1,3-benzodiazepinthiones, 127 1,4-benzodiazepines, 849. See also Dihydro-, diones etc.; Octahydro-, Decahydro-1,4- benzodiazepines 1,2,3,4-: 2-methylene-S(5H)-ones, 929t 3-methylene-5(5H)-ones, 929t -5(5H)-ones, 878,924t -thiones, 941t -5H-5-methylene, 909t 1,2,4,5-3H3-ones, 876,924t 3-thiones, 940t 1,3,4,5-W-: -2-methylene, 909t -2-ones, 864,910t -2-thiones, 898,939t 2,3,4,5-1H-, 851,901t l,S-benzodiazepines, 370t -4-methylene-2-ones. 385t -2-ones, 3751 -2-thiones, 402t -3-ones, 3 8 3 2,3-benzodiazepines, -ones, 49, 50, 80t 2,4-benzodiazepindiones, 136 2.4-benzodiazepines. 135, 140 2,4-benzodiazepinones, 135 2,4-benzodiazepinthiones, 137 2,4-benzodiazepintriones. 137 cyclopenta[e] [ 1,4]diazepinones, l000t cyclopropa[d][ 1,2]diazepines, 81t imidazo[4,5-d][1,3]diazepines, 130 imidazo[4,5-e][ 1,4]diazepindiones, 1002t 4-methylene-1,5-benzodiazepin-2-ones, 38% oxireno[d] [1,2]diazepinones, 81t oxazolo[5,4-e][1,4]diazepinthiones, 1003 pyrazolo[l,2-a][1,2]diazepinones, 59t pyrazolo[3,4-b] [ 1,4]diazepines, 406t pyrazolo [3,441[ 1,4]diazepinones, 407t pyrazolo [3,4-d][ 1.21diazepines, -dione, 82t, 83t
1099
pyrazolo[3,4-e][ 1,4]diazepines, 1006t 7-methylene-, 1008t pyrazolo[3,4-e][ 1,4]diazepinones, 1009t pyrazolo[3,4-e][1,4]diazepinthiones. 101It pyrazolo[4,3-e] [1,4]diazepinones. 1012t. 1014t pyrido[l,2-a [1,3]diazepines, 98 pyrido[l,2-a][1,4]diazepiniums, 186, 197t pyrido[l2-d] [1,4]diazepiniums, 193, 203t pyrido(2.3-bI(1,4]diazepines, 41 It pyrido[2,3-b][1,4]diazepinones, 41 It pyrido[2,3-b][1,4]diazepinthiones, 412t pyrido[2,3-e][ 1,4]diazepines, 1016t pyrido[2,3-e][1,4]diazepinones, 1017t pyrido[2,3-e][1,4]diazepinthiones, 1018t pyrido[3,4-b][1,4]diazepines. 414t pyrido[4,3-e][ 1,4]diazepinones. 1024t pyrimido[4,5-b] [ 1,4]diazepindiones, 4 16t -2-thioxo, 418t pyrimido[4,5-b] [ 1,4]diazepintriones, 416t pyrimido[4,5-e][ 1,4]diazepindiones, 1026t pyrimido[rl,S-e][1,4]diazepinones, 1025t pyrrolo[l2-a] [ 1,3]diazepines, 100, 148t pyrrolo[ 1,2-a][ 1,4]diazepines, -ones, 201t, 202t pyrrolo[l,2-d] [ 1,4]diazepinones, 194,206t pyrrolo [3,2-e][ 1,4]diazepinones, 1027t pyrrolo[3,4-c][ 1,4]diazepindiones, 419t pyrrolo[3,4-e][ 1,4]diazepindiones, 1029t -6-methylene, 1029t pyrrolo[3,4-e][ 1,4]diazepinones 1027t thiazolo[3,2-~] [1,3]diazepines, 104, 150t thiazolo[4,5-e] [1,4]diazepin-ones-thiones, 1032t triazino[5,6-e][ 1,4]diazepinones, 1049t triazolo[ 1,2-a][ 1,2]diazepin-diones, -dithiones. -thiones, 61t Tetrazolothienodiazepine,989 Thiadiazoles, 985 Thiadiazolo[3,4-e][ 1,4]diazepines, 985, 1030t Thiazinobenzodiazepines, 703 Thiazole, 955 Thiazolobenzodiazepines, 675.702.703 Thiazolo[3,2-a][1,3]diazepines, 104, 150t Thiazolo[3,2-b] [ 1,2]diazepines, 12 Thiazolo[4,5-e] [1,4]diazepines, 985, 1030t Thiazolo[5,4-e] [1,4]diazepines, 987, 1031t Thien0[2,3-~][1.2]diazepines, 73t Thieno[2,3-d] [ 1,2]diazepines. 56, 84t, 85t Thieno[2,3-e][1,4]diazepines, 987, 1032t Thieno[2,3-e][ 1,4]diazepinones, thiones, 992, 1037t Thieno[3,2-c][ 1,2]diazepines, 74t
1loo
Subject Index
Thieno[3,2-d] [1,2]diazepines, 56, 84t Thieno[3,2-e] [ 1,4]diazepindiones, 997, 1049t Thieno[3,2-e] [1,4]diazepines, 995, 1046t Thieno[3,2-e] [ 1,4]diazepinones, 995, 1047t Thieno[3,4-e] [1,3]diazepines, 141, 179t Thieno[3,4-e] [ lP]diazepines (-ones and -diones). 997, 1048t Thienoxazinones, 996,997 Thiophenes, 992,994,996-998 Triazines, 999 Triazinobenzodiazepines, 679,693 1,2,4-Triazino[4,3-a][1,3]diazepines. 107, 155t 1,2,4-Triazino[5,6-e][ 1,4]diazepines (-ones and -diones), 999, 1049t 1,3,5-Triazino[1,2-a][1,3]diazepines, 107, 155t Triazolobenzodiazepines, 679,680,693,704 Triazolopyrazolodiazepine,958 Triazolopyridodiazepine, 974 Triazolothiazolodiazepine, 985 Triazolothienodiazepine, 989,994 Tricyclic diazepines and other heterocycles, Chapter 5. See also Azetidinobenzodiazepines, Imidazo, -benzodiazepines, -pyrazolodiazepines,
-pyridodiazepines, -pyrrolodiazepines. -thienodiazepines; Isoxazolobenzodiazepines; Oxadiazolo, -benzodiazepines; -thienodiazepines; Oxathiazocino; Oxazino; Oxaziridino; Oxazolo; Piperidino; Pyrazino; Pyrimido; Pyrrolo, -benzodiazepines; Pyrimidinobenzodiazepines;Pyrrolo, -benzodiazepines, -quinolines; Tetrazolothienodiazepines;Thiazinobenzodiazepines; Thiazolobenzodiazepines; Triazinobenzodiazepines; Triazolo, -benzodiazepines, -pyrazolodiazepines, -pyridodiazepines, -thiazolodiazepines, -thienodiazepines Triazolobenzodiazepines, 564,572,589 Triazolo[l,2-a] [ 12]diazepines,7 Triazolo[4.5-b][1,4]diazepinones, 419t Triazolophthalazine, 139 Ultra-violet spectra, see Spectra, general X-ray, see Spectra
Printed in the US/BNB
